Immunomodulatory o-het / aryl nitrogen lactones

Abstract

Immunomodulatory compounds of Formula (1), stereoisomers thereof, and pharmaceutically acceptable salts thereof are defined herein; and compositions comprising the compounds are provided, wherein R 0 , R 1 , R 2 , R 10 , W, ring C, and n are as defined herein, stereoisomers thereof, and pharmaceutically acceptable salts thereof. The present application also includes methods for treating an inflammatory and / or immune disease or disorder in an animal by administering a therapeutically effective amount of a compound of Formula (1), stereoisomers thereof, and pharmaceutically acceptable salts thereof; or use of the compounds of Formula (1) for the manufacture of a medicament for treating an inflammatory and / or immune disease or disorder in an animal.

Description

Technical Field

[0001] This document defines anti-inflammatory and immunomodulatory compounds; as well as non-antibacterial, anti-inflammatory, and immunomodulatory compounds; their stereoisomers; and their pharmaceutically acceptable salts. This invention comprises a corresponding 13-membered macrolide ring compound in equilibrium with a 15-membered macrolide ring compound. This invention also comprises pharmaceutical compositions including the compounds of this invention and methods for treating inflammatory and / or immune diseases or conditions in animals. The compounds of this invention are nitrogen-ring lactones. Background Technology

[0002] Macrolides are antimicrobial compounds composed of macrolide rings containing 12 to 16 atoms, which are linked to at least one or two deoxyglucoses via glycosidic bonds. Nitrogen-ring lactones are a class of macrolides in which the lactone ring contains a nitrogen atom. It is a semi-synthetic macrolide (nitrogen-cyclic lactone) antibiotic, sold as a ready-to-use sterile parenteral preparation containing tulathromycin. The preparation consists of an equilibrium mixture of two isomers of tulathromycin in a 9:1 (Tula-A:Tula-B) ratio. Tula-A has a 15-membered lactone ring structure, while Tula-B has a 13-membered lactone ring structure. Equilibrium is pH- and time-dependent. Tulathromycin is marketed under the trade name... Commercially available for use in bovine respiratory disease (BRD) and swine respiratory disease (SRD).

[0003] Macrolides are known to inhibit protein synthesis in (Gram-positive and Gram-negative) bacteria 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. The activity of macrolides against Gram-negative pathogens of BRD and their ability to concentrate in lung tissue contribute to their excellent therapeutic efficacy. Macrolides are first-line 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 tylosin. In addition, some macrolides have been shown to possess anti-inflammatory and immunomodulatory properties. For example, azithromycin, as a broad-spectrum antibiotic, inhibits interleukin-12p40 expression in lipopolysaccharide (LPS) and interferon-γ-stimulated macrophages and attenuates LPS-induced introduction of CXCL8 (IL-8) and GM-CSF from primary bronchial epithelial cells; it also interacts with phospholipids and Erk1 / 2 in epithelial cells, subsequently downregulating the release of transcription factors AP-1, NFκB, inflammatory cytokines, and mucins upon LPS stimulation. US2016-0031925 describes certain azithromycin analogues that possess immunomodulatory properties but have been modified to reduce or eliminate antibiotic activity. Clarithromycin has immunomodulatory effects on ERK-mediated inflammation induced by Pseudomonas aeruginosa flagellin. Erythromycin inhibits interleukin-6 and interleukin-8 expression and promotes in vitro apoptosis of activated human neutrophils. Tilmicosin regulates COX-2 and iNOS gene expression and LPS-stimulated cytokine production in macrophages and monocytes. Roxithromycin downregulates Th2 chemokine production through keratinocyte and chemokine receptor expression on Th2 cells. Tylosin promotes apoptosis and downregulates pro-inflammatory mediators such as leukotrienes B4 and CXCL8; and induces the production of anti-inflammatory and prolipolytic lipoxygenin A4. These findings confirm that these antibacterial macrolides regulate certain excessive immune responses, which in turn cascade into certain anti-inflammatory benefits.

[0005] Inflammation and pro-inflammatory mediators negatively impact production in livestock by reducing growth, feed and water intake, reproduction, milk production, and metabolic health. Increased clinical use of macrolide antibiotics is associated with increased resistance to macrolides in pneumococcus and to BRD pathogens. Recent concerns from global government agencies and the public have arisen regarding the use of antibiotics in feed-producing animals (e.g., cattle and pigs) as they are believed to lead to cross-resistance to human pathogens. Bovine respiratory disease (BRD) remains a major problem in contemporary cattle production, and sensible management is crucial for both animal welfare and human food security. Indeed, *Mannheimia haemolytica* is the primary bacterium isolated from respiratory diseases in domestic cattle and a major component of endemic pneumonia in newborn calves. One hallmark of BRD is an elevated inflammatory response in the host that promotes the progression of the entire BRD complex. Inhibiting or reversing host inflammation has the ability to prevent or control the development of BRD in cattle and other inflammatory diseases or conditions in animals. Therefore, the need to develop novel anti-inflammatory and immunomodulatory agents lacking the known antibacterial effects of macrolides has not been met. Anti-inflammatory and immunomodulatory compounds have been shown to be non-antibacterial in a variety of bacterial species and, at lower doses, exhibit 5-20 times greater immunomodulatory activity than existing macrolides (e.g., azithromycin, erythromycin, and tylosin). Thus, these compounds can be used to control or prevent the onset of bacterial or viral infections, which can be achieved through inflammatory and / or immune responses induced by stress events or other environmental factors, thereby preventing or mitigating the progression of the pathobiological cascade to a full-disease complex. The compounds of the present invention presented herein are non-antibiotic, anti-inflammatory, and immunomodulatory macrolides for reducing inflammatory states in animals where antibiotic use in animals can be reduced. Summary of the Invention

[0006] In one aspect of the invention, there is a nitrogen-cyclic lactone compound of formula (1),

[0007]

[0008] Where W is H or a compound of formula (A).

[0009]

[0010] Where X is -R a -R c NR 5 R 6 -R c OR 7 -R c SR 7 -R c N3, -Rc CN or -R c X';

[0011] X' is F, Cl, I, or Br;

[0012] Ring C is phenyl, naphthyl, a 5-6 membered monocyclic heteroaryl ring, or a 9-11 membered fused heteroaryl ring; wherein each of the heteroaryl rings contains at least one heteroatom selected from the group consisting of N, O, and S; and wherein ring C is optionally separated by at least one R 10 Substituent substitution;

[0013] R a R b R 0 and R 1 Each is independently an H or C1-C6 alkyl group;

[0014] Or R 1 It is optionally subject to at least one R 9 Substituent-substituted benzyl group;

[0015] Or R 1 It is -CH2Het, wherein Het is a 5- to 6-membered heteroaryl ring containing at least one heteroatom selected from N, O, and S; and wherein the heteroaryl ring is optionally separated by at least one R 9 Substituent substitution;

[0016] R c It is a C1-C4 alkyl group;

[0017] R 2 It is H, C1-C6 alkyl, C0-C3 alkyl, C3-C6 cycloalkyl, -C(O)NR 3 R 4 C1-C3 alkylaryl, C1-C3 alkyl heterocyclic, C1-C3 alkyl heteroaryl, wherein the heterocycle is a 5- or 6-membered saturated or partially saturated heterocycle; wherein the heteroaryl is a 5- or 6-membered heteroaryl ring; wherein the heterocycle and the heteroaryl ring each contain at least one heteroatom selected from N, O, and S; and wherein the cycloalkyl, the aryl, the heterocycle, and the heteroaryl ring are each optionally separated by at least one R 9 Substituent substitution;

[0018] R 3 and R 4 Each of the following is independently H, C1-C6 alkyl, C0-C3 alkyl, C3-C6 cycloalkyl, -R c NR a R bThe cycloalkyl group, C0-C3 alkyl heterocycle, wherein the heterocycle is a 5- or 6-membered saturated or partially saturated heterocycle; the C0-C3 alkyl heteroaryl group, wherein the heteroaryl group is a 5- or 6-membered monocyclic heteroaryl ring or a 9- or 11-membered fused heteroaryl ring; wherein the heterocycle and the heteroaryl ring each contain at least one heteroatom selected from N, O, and S; and wherein the cycloalkyl group, the aryl group, the heterocycle, and the heteroaryl ring are each optionally separated by at least one R 9 Substituent substitution;

[0019] Or R 3 and R 4 Together with the nitrogen atom to which it is attached, it forms ring A, i.e., a 4- to 8-membered heterocycle or a 5-membered heteroaryl ring, each ring optionally containing at least one additional heteroatom selected from N, O, and S, and each ring optionally being separated by at least one R 10 Substituents are used for substitution; and each ring is optionally fused with Y;

[0020] R 5 and R 6 Each is independently selected from H; each is optionally substituted with at least one hydroxyl group of C1-C6 alkyl or 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)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 a -S(O) p R 8 -S(O) p R 8 NR a Rb -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 alkyl heterocyclic, and C0-C4 alkyl heteroaryl; wherein the heterocycle and the heteroaryl ring are 5-6 membered monocyclic or 9-10 membered fused rings, each ring containing at least one heteroatom selected from the group consisting of N, O, and S; and wherein the aryl, the cycloalkyl, the heterocycle, and the heteroaryl ring are each optionally separated by at least one R 10 Substituent substitution;

[0021] Or R 5 and R 6 Together with the nitrogen atom to which it is attached, it forms a ring B, namely a 4- to 8-membered heterocycle or a 5-membered heteroaryl ring, each ring optionally containing at least one additional heteroatom selected from N, O, and S, and each ring optionally being separated by at least one R 9 Substituents are used for substitution; and each ring is optionally fused with Y;

[0022] R 7 It is H, C1-C6 alkyl, -R c NR a R b -R c OR a -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 b ;

[0023] R 8 It is C1-C6 alkyl, C1-C6 haloalkyl, C0-C4 alkyl, C3-C6 cycloalkyl, -NR a R bThe ring may contain a phenyl, a 5- or 6-membered heterocyclic ring or a heteroaryl ring, each containing at least one heteroatom selected from N, O and S; and wherein the cycloalkyl, the phenyl, the heterocyclic and the heteroaryl moiety are each optionally substituted by at least one substituent selected from: C1-C4 alkyl, halogen, C1-C4 alkoxy, C1-C4 haloalkyl and C1-C4 haloalkoxy.

[0024] R 9 Independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, C0-C4 alkyl, C3-C6 cycloalkyl, halogen, oxygen, hydroxyl, cyano, -NR a R b C1-C6 haloalkyl, C1-C6 haloalkoxy, -S(O) p R 8 phenyl and 5- or 6-membered heterocyclic or heteroaryl rings, each ring containing at least one heteroatom selected from the group consisting of N, O and S;

[0025] R 10 Independently selected from the group consisting of: C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C0-C4 alkyl, C3-C6 cycloalkyl, halogen, -NR a R b -S(O) p R 8 nitro, oxygen, cyano, -C(O)H, -C(O)R 8 -C(O)OR a -OC(O)OR a -NHR c C(O)R a -C(O)NR a R b The mixture comprises hydroxyl groups, 5-6 membered heterocycles, 5-6 membered heteroaryl rings, 9-10 membered fused heteroaryl rings, and phenyl groups, wherein each heterocycle and heteroaryl ring contains at least one heteroatom selected from the group consisting of N, O, and S; and wherein each of the phenyl groups, the heterocycles, and the heteroaryl rings is optionally separated by at least one R group. 9 Substituent substitution;

[0026] Y is phenyl, pyridinyl, pyrimidinyl, pyrazolyl, thiophenyl, thiazolyl, triazolyl, isothiazolyl, pyrroleyl, oxazolyl, oxadiazolyl, imidazolyl, furanyl, indolyl, benzothiophenyl, or naphthyl;

[0027] n is an integer 0, 1, 2, or 3;

[0028] p is an integer 0, 1, or 2; its stereoisomers and its pharmaceutically acceptable salts.

[0029] In another aspect, it is a compound of formula (1), which is a non-antimicrobial compound of formula (1), its stereoisomer, and its pharmaceutically acceptable salt. In another aspect, it is a composition comprising a compound of formula (1) or a non-antimicrobial compound of formula (1); its stereoisomer, and its pharmaceutically acceptable salt. In another aspect, the composition further comprises a pharmaceutically acceptable carrier.

[0030] In another aspect, it is a method for treating or preventing an inflammatory response in an animal by administering a therapeutically effective amount of a compound of formula (1) or a non-antimicrobial compound of formula (1), its stereoisomers, and its pharmaceutically acceptable salts to the animal in need. In another aspect, it is a method for treating or preventing an inflammatory response in an animal, wherein the inflammatory response is caused by bacterial, viral, or fungal infection, stress, and / or environmental factors. In another aspect of the method, treating or preventing the inflammatory response in the animal prevents or mitigates the progression of a respiratory disease or condition in the animal. In another aspect of the method, the animal is a domestic animal; and wherein the respiratory disease or condition is a bovine respiratory disease or a swine respiratory disease. In another aspect of the method, the method for treating or preventing an inflammatory response in an animal downregulates TNF-α and IL-6 in the animal.

[0031] In another aspect, there is the use of a compound of formula (1), its stereoisomers, and its pharmaceutically acceptable salts for the preparation of a medicament for the treatment or prevention of an inflammatory response in animals, wherein the inflammatory response is caused by bacterial, viral, or fungal infection, stress, and / or environmental factors. In another aspect of the use, the medicament for the treatment or prevention of an inflammatory response in the animal prevents or alleviates the progression of a respiratory disease or condition. In another aspect of the use, the animal is a domestic animal; and the respiratory disease or condition is bovine respiratory disease or swine respiratory disease. In another aspect of the use, TNF-α and IL-6 are downregulated in the animal.

[0032] In another aspect of the invention, R a and R b Each can be independently H, methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl, or tert-butyl. On the other hand, R... a and R b Each can be independently H, methyl, ethyl, propyl, or isopropyl. On the other hand, R a and R b Each can be independently H, methyl, ethyl, or propyl. On the other hand, R a and R b Each is independently either H or methyl.

[0033] On the other hand, X' is F, Cl, or Br. On the other hand, X' is F or Cl. On the other hand, X' is F. On the other hand, X' is Cl.

[0034] In another aspect of the invention, R 0 and R 1 Each of the following is independently H, methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl, or tert-butyl; or R 1 It is benzyl, -CH2pyridine, -CH2pyrimidine, -CH2pyridazine, -CH2pyrazine, -CH2pyrrole, -CH2furan, -CH2thiophene, -CH2pyrazole, -CH2imidazol, -CH2triazole, -CH2tetrazole, -CH2oxazole, -CH2isooxazole, -CH2thiazole, -CH2isothiazole, or -CH2oxadiazole, each optionally being selected from at least one of the following R 9 Substituents: methyl, ethyl, propyl, methoxy, ethoxy, F, Cl, oxy, hydroxy, cyano, -NR a R b -CF3 and -OCF3. On the other hand, R 0 and R 1 Each is independently H, methyl, ethyl, propyl, or isopropyl; or R 1 It is benzyl, -CH2pyridine, -CH2pyrimidine, -CH2pyrazole, -CH2imidazol, -CH2triazole, -CH2tetrazole, -CH2oxazole, -CH2isooxazole, -CH2thiazole, -CH2isothiazole, or -CH2oxadiazole, each optionally being selected from at least one of the following R 9 Substituents: methyl, ethyl, propyl, methoxy, ethoxy, F, Cl, hydroxy, cyano, -NH2, -CF3, and -OCF3. On the other hand, R... 0 It is H, methyl, ethyl, or propyl; and R 1 It is methyl, ethyl, propyl, isopropyl; or R 1 It is benzyl, -CH2pyridine, -CH2pyrimidine, -CH2pyrazole or -CH2imidazole, each optionally being composed of at least one R selected from the following 9 Substituents: methyl, ethyl, methoxy, ethoxy, F, Cl, hydroxy, -CF3, and -OCF3. On the other hand, R... 0 It is H, methyl, ethyl, or propyl; and R 1 It is methyl, ethyl, propyl, or isopropyl. On the other hand, R 0 It is H or methyl; and R 1 It is methyl, ethyl, propyl, or isopropyl. On the other hand, R 0 It is H or methyl and R 1 It is a methyl group.

[0035] In another aspect of the invention, R c It is methyl, ethyl, propyl, isopropyl, n-butyl, or tert-butyl. In another aspect of the invention, R... c It is methyl, ethyl, propyl, isopropyl, or tert-butyl. In another aspect of the invention, R... c It is methyl, ethyl, propyl, or isopropyl. In another aspect of the invention, R... c It is methyl, ethyl, or propyl. On the other hand, R c It is a methyl group. On the other hand, R c It is ethyl. On the other hand, R c It is propyl.

[0036] In another aspect of the invention, R 2 It is H, C1-C6 alkyl, C0-C3 alkyl, C3-C6 cycloalkyl, -C(O)NR 3 R 4 C1-C3 alkylphenyl, C1-C3 alkyl heterocyclic, C1-C3 alkyl heteroaryl, wherein the heterocyclic is a 5- or 6-membered saturated or partially saturated heterocyclic ring; wherein the heteroaryl is a 5- or 6-membered heteroaryl ring; wherein the heterocyclic ring and the heteroaryl ring each contain at least one heteroatom selected from N, O, and S; and wherein the cycloalkyl group, the phenyl group, the heterocyclic ring, and the heteroaryl ring are each optionally separated by at least one R 9 Substituent substitution. On the other hand, R 2 It is H, methyl, ethyl, propyl, isopropyl, cyclopropyl, C1-cyclopropyl, cyclobutyl, C1-cyclobutyl, cyclopentyl, cyclohexyl, or -C(O)NR 3 R 4 ; or -C1 phenyl, -C1 azacyclobutane, -C1 tetrahydrofuran, -C1 tetrahydrophenylthio, -C1 pyrrolyl, -C1 tetrahydropyranyl, -C1 piperidinyl, -C1 piperazine, -C1 morpholinyl, -C1 pyrroleyl, -C1 furanyl, -C1 phenylthio, -C1 pyrazolyl, -C1 imidazolyl, -C1 isoxazolyl, -C1 oxazolyl, -C1 isothiazolyl, -C1 thiazolyl, -C1 triazolyl, -C1 pyridinyl, -C1 pyridazinyl, -C1 pyrimidinyl, or -C1 pyrazine, each optionally being influenced by at least one R 9 Substituent substitution. On the other hand, R 2 It is H, methyl, ethyl, propyl, isopropyl, cyclopropyl, C1-cyclopropyl, cyclobutyl, C1-cyclobutyl, cyclopentyl, cyclohexyl, or -C(O)NR 3 R 4; or -C1 phenyl, -C1 pyrrolidinyl, -C1 piperidinyl, -C1 piperazine, -C1 morpholinyl, -C1 pyrrolidinyl, -C1 pyrazolyl, -C1 imidazolyl, -C1 isoxazolyl, -C1 oxazolyl, -C1 isothiazolyl, -C1 thiazolyl, -C1 pyridinyl, or -C1 pyrimidinyl, each optionally being composed of at least one R selected from the group consisting of the following 9 Substituents: methyl, ethyl, propyl, isopropyl, tert-butyl, hydroxy, methoxy, ethoxy, F, Cl, Br, cyano, cyclopropyl, N(CH3)2, -CHF2, -CF3, -OCHF2, and -OCF3. On the other hand, R... 2 It is H, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, or -C(O)NR 3 R 4 ; or -C1 phenyl, -C1 pyrrolidinyl, -C1 piperidinyl, -C1 piperazine, -C1 morpholinyl, -C1 pyrrolidinyl, -C1 pyrazolyl, -C1 pyridinyl or -C1 pyrimidinyl, each optionally being composed of at least one R selected from the group consisting of ; 9 Substituents: methyl, ethyl, hydroxy, methoxy, ethoxy, F, Cl, cyano, -N(CH3)2, and -CF3. On the other hand, R... 2 It is H, methyl, ethyl, cyclopropyl, cyclobutyl, or -C(O)NR 3 R 4 ; or -C1 phenyl, -C1 pyrrolidinyl, -C1 piperidinyl, -C1 piperazine, -C1 morpholinyl, -C1 pyrrolidinyl, -C1 pyrazolyl, -C1 pyridinyl or -C1 pyrimidinyl, each optionally being composed of at least one R selected from the group consisting of ; 9 Substituents: methyl, ethyl, hydroxy, methoxy, ethoxy, F, Cl, cyano, -N(CH3)2, and -CF3. On the other hand, R... 2 It is H, methyl or -C(O)NR 3 R 4 On the other hand, R 2 It is H or methyl. On the other hand, R 2 It is a methyl group.

[0037] On the other hand, R 3 and R 4Each is independently H or C1-C6 alkyl; or C0-C3 alkyl-C3-C6 cycloalkyl, C0-C3 alkylphenyl, C0-C3 alkyl heterocyclic, or C0-C3 alkyl heteroaryl; wherein the heterocyclic moiety is pyrrolidinyl, piperidinyl, piperazinyl, tetrahydro-2H-pyran, morpholinyl, or thiomorpholinyl; and wherein the heteroaryl moiety is pyrrolidinyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or triazinyl; and wherein the cycloalkyl, the phenyl, the heterocycle, and the heteroaryl ring are each optionally and independently formed by at least one R selected from the group consisting of the following. 9 Substituents: C1-C3 alkyl, hydroxyl, C1-C3 alkoxy, halogen, cyclopropyl, cyano, -N(CH3)2, C1-C3 haloalkyl, and C1-C3 haloalkoxy. In another aspect of the invention, R 3 and R 4 Each is independently H or C1-C6 alkyl; or C0-C2 cyclopropyl, C0-C2 cyclobutyl, C0-C2 cyclopentyl, C0-C2 cyclohexyl, C0-C2 phenyl, C0-C2 piperidinyl, piperazine, morpholinyl, tetrahydro-2H-pyran, pyrroloyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl, each optionally being R selected from the group consisting of at least one of the following. 9 Substituents: methyl, ethyl, propyl, isopropyl, tert-butyl, hydroxy, methoxy, ethoxy, F, Cl, Br, cyano, -N(CH3)2, -CHF2, -CF3, -OCHF2, and -OCF3. In another aspect of the invention, R... 3 and R 4 Each is independently H or C1-C6 alkyl; or cyclopropyl, -C1 cyclopropyl, cyclobutyl, -C1 cyclobutyl, cyclopentyl, -C1 cyclopentyl, cyclohexyl, -C1 cyclohexyl, phenyl, -C1 phenyl, piperidinyl, -C1 piperidinyl, -C2 piperidinyl, piperazine, morpholinyl, tetrahydro-2H-pyran, pyrroloyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl, each optionally being R selected from the group consisting of at least one of the following. 9 Substituents: methyl, ethyl, propyl, isopropyl, tert-butyl, hydroxy, methoxy, ethoxy, F, Cl, Br, cyano, -N(CH3)2, -CHF2, -CF3, -OCHF2, and -OCF3. On the other hand, R... 3 and R 4Each is independently H or C1-C6 alkyl; or cyclopropyl, -C1 cyclopropyl, cyclobutyl, -C1 cyclobutyl, cyclopentyl, -C1 cyclopentyl, cyclohexyl, -C1 cyclohexyl, phenyl, -C1 phenyl, piperidinyl, -C1 piperidinyl, -C2 piperidinyl, piperazine, morpholinyl, tetrahydro-2H-pyran, pyrroloyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl, each optionally being R selected from the group consisting of at least one of the following. 9 Substituents: methyl, ethyl, propyl, isopropyl, tert-butyl, hydroxy, methoxy, ethoxy, F, Cl, Br, cyano, cyclopropyl, -N(CH3)2, -CHF2, -CF3, -OCHF2, and -OCF3. On the other hand, R... 3 and R 4 Each is independently H or C1-C6 alkyl; or cyclopropyl, -C1 cyclopropyl, cyclobutyl, -C1 cyclobutyl, cyclopentyl, -C1 cyclopentyl, cyclohexyl, -C1 cyclohexyl, phenyl, -C1 phenyl, piperidinyl, -C1 piperidinyl, -C2 piperidinyl, piperazine, morpholinyl, tetrahydro-2H-pyran, pyrroloyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl, each optionally being R selected from the group consisting of at least one of the following. 9 Substituents: methyl, ethyl, propyl, isopropyl, tert-butyl, hydroxy, methoxy, ethoxy, F, Cl, Br, cyano, cyclopropyl, -N(CH3)2, -CHF2, -CF3, -OCHF2, and -OCF3. On the other hand, R... 3 It is H, methyl, ethyl, isopropyl, cyclopropyl, -CF3, -CHF2, -CH2F, -CH2CF3, or phenyl. On the other hand, R 3 It is H, methyl, ethyl, cyclopropyl, or phenyl. On the other hand, R 3 It is H, methyl, or ethyl. On the other hand, R 3 It is H or methyl. On the other hand, R 4 It is H, methyl, ethyl, propyl, or isopropyl; or cyclopropyl, cyclobutyl, cyclohexyl, phenyl, -C1 phenyl, piperidinyl, -C1 piperidinyl, -C2 piperidinyl, piperazinyl, morpholinyl, tetrahydro-2H-pyran, pyrazolyl, pyrimidinyl, or pyridinyl, each optionally being R selected from the group consisting of at least one of the following. 9 Substituents: methyl, ethyl, hydroxy, methoxy, ethoxy, F, Cl, cyano, -N(CH3)2 and -CF3.

[0038] In another aspect of the invention, R 3 and R 4Together with the nitrogen atom to which it is attached, it forms a ring A, namely a 4- to 8-membered heterocycle or a 5-membered heteroaryl ring, each ring optionally containing at least one additional heteroatom selected from N, O, and S; and wherein each ring is optionally separated by at least one R 10 Substituent substitution; and wherein each ring is further optionally fused with Y as a phenyl, pyridinyl, pyrimidinyl, pyrazolyl, thiophene, thiazolyl, or triazolyl group. On the other hand, R 3 and R 4 Together with the nitrogen atom to which it is attached, it forms a ring A, namely a 4- to 8-membered heterocycle or a 5-membered heteroaryl ring, each ring optionally containing at least one additional heteroatom selected from N, O, and S; and wherein each ring is optionally separated by at least one R 10 Substituents are used, and each ring is further optionally fused with Y, which is phenyl, pyridine, or pyrimidine. On the other hand, R... 3 and R 4 Together with the nitrogen atom to which it is attached, it forms ring A, which is an azacyclic butyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyrrolylyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl group, each optionally separated by at least one R group selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F, Cl, Br, CN, -N(CH3)2, hydroxyl, -CHF2, -CF3, -OCHF2, -OCF3, and oxy group. 10 Substituent substitution; and wherein each ring is further optionally fused with Y as a phenyl or pyridyl group. On the other hand, R 3 and R 4 Together with the nitrogen atom to which it is attached, it forms a ring A, said ring being pyrroleyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally being surrounded by at least one R selected from the group consisting of... 10 Substituents: methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F, Cl, Br, CN, -N(CH3)2, hydroxyl, -CHF2, -CF3, -OCHF2, -OCF3, and oxy; and wherein each ring is further optionally fused with Y as a phenyl group. On the other hand, R 3 and R 4 Together with the nitrogen atom to which it is attached, it forms a ring A, which is pyrroloyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally being bonded by at least one R selected from the group consisting of... 10 Substituents: methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F, Cl, Br, CN, -N(CH3)2, hydroxyl, -CHF2, -CF3, -OCHF2, -OCF3, and oxy; and wherein each ring is further optionally fused with Y as a phenyl group. On the other hand, R 3and R 4 Together with the nitrogen atom to which it is attached, it forms a ring A, said ring being pyrroloyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally selected from at least one of the following R groups. 10 Substituents: methyl, ethyl, F, Cl, oxy, and -CF3; or ring A is optionally substituted with at least one oxy group as a dihydroindolyl, isodihydroindolyl, tetrahydroquinolinyl, dihydrobenzoxazinyl, or dihydrobenzothiazinyl. On the other hand, R... 3 and R 4 Together with the nitrogen atom to which it is attached, it forms a ring A, which is pyrroloyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally being bonded by at least one R selected from the group consisting of... 10 Substituents: methyl, ethyl, F, Cl, oxy, and -CF3.

[0039] In another aspect of the invention, R 5 and R 6 Each is independently H; each is optionally substituted with at least one hydroxyl group of C1-C6 alkyl or 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)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 a -S(O) p R 8 -S(O) p R 8 NR a R b -Rc S(O) p NR a R b or -R c NR a S(O) p R 8 ; or C0-C4 alkylphenyl, C0-C4 alkylC3-C6 cycloalkyl, C0-C4 alkyl heterocyclic, or C0-C4 alkyl heteroaryl, wherein the heterocycle and the heteroaryl ring are each a 5- or 6-membered monocyclic ring, and wherein each heterocycle and the heteroaryl ring contains at least one heteroatom selected from the group consisting of N, O, and S; and wherein the phenyl, the cycloalkyl, the heterocycle, and the heteroaryl ring are each optionally separated by at least one R 10 Substituent substitution. On the other hand, R 5 and R 6 Each is independently H; each is optionally substituted with at least one hydroxyl group of C1-C6 alkyl or 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)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 a -S(O) p R 8 -S(O) p R 8 NR a R b -R c S(O) p NR a R b or -Rc NR a S(O) p R 8 ; or phenyl, C1 alkylphenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 1- C2 alkylcyclopropyl, C 1- C2 alkylcyclobutyl, C 1- C2 alkylcyclopentyl, C 1- C2 alkylcyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, oxazolyl, pyrrolidinyl, piperidinyl, piperazineyl, morpholinyl, C 1- C2 alkyltetrahydrofuranyl, C1-C2 alkyloxazolyl, C 1- C2 alkyltetrahydropyranyl, C 1- C2 alkylpyrrolidinyl, C 1- C2 alkylpiperidinyl, C 1- C2-alkylpiperazinyl, C1-C2-morpholinyl; pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, C 1- C2 alkylpyrazolyl, C 1- C2 alkylimidazolium, C 1- C2 alkyltriazole group, C 1- C2 alkyltetrazole, C 1- C2 alkyloxazolyl, C 1- C2 alkylpyridinyl, C 1- C2 alkylpyridazinyl, C 1- C2 alkylpyrimidinyl or C 1- C2 alkylpyrazine group; each optionally surrounded by at least one R 10 Substituent substitution. On the other hand, R 5 and R 6 Each is independently H; each is optionally substituted with at least one hydroxyl group of C1-C6 alkyl or 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 -R c OR a -S(O) p R 8 -S(O) p R 8 NR a R b or -R c S(O) p NR a R b ; or phenyl, C1 alkylphenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 1- C2 alkylcyclopropyl, C 1- C2-alkylcyclobutyl, oxazolyl, pyrrolyl, piperidinyl, piperazine, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, C1-C2 alkyloxazolyl, C 1- C2 alkylpyrrolidinyl, C 1- C2 alkylpiperidinyl, C 1- C2alkylpiperazinyl, C1-C2morpholinyl, C1-C2 tetrahydrofuran, C1-C2 tetrahydropyran, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, C 1- C2 alkylpyrazolyl, C 1- C2 alkylimidazolium, C 1- C2 alkylpyridinyl, C 1- C2 alkylpyrimidinyl or C 1- C2 alkylpyrazinyl groups, each optionally composed of at least one R group selected independently from the following 10 Substituents: methyl, ethyl, propyl, methoxy, ethoxy, -CHF2, -CF3, -OCF3, F, Cl, -NHCH3, -N(CH3)2, -S(O)2CH3, nitro, cyano, -C(O)CH3, -NHCH2C(O)CH3, -NHCH2CH2C(O)CH3, -C(O)NHCH3, hydroxyl, and phenyl. On the other hand, R... 5 and R 6 Each is independently H; each is optionally substituted with at least one hydroxyl group of C1-C6 alkyl or 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) pR 8 -R c NR a R b -R c OR a or -S(O) p R 8 ; or phenyl, C1 alkylphenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 1- C2 alkylcyclopropyl and C 1- C2-alkylcyclobutyl, oxazolyl, pyrrolyl, piperidinyl, piperazine, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, C1-C2-alkyloxazolyl, C 1- C2 alkylpyrrolidinyl, C 1- C2 alkylpiperidinyl, C 1- C2alkylpiperazinyl, C1-C2morpholinyl, C1-C2morpholinyl, C1-C2piperidinyl, C1-C2tetrahydropyranyl, C1-C2tetrahydrofuranyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, C 1- C2 alkylpyrazolyl, C 1- C2 alkylimidazolium, C 1- C2 alkylpyridinyl, C 1- C2 alkylpyrimidinyl or C 1- C2 alkylpyrazine group; each optionally consisting of at least one R group selected independently from the following 10 Substituents: methyl, ethyl, methoxy, ethoxy, -CHF2, -CF3, -OCF3, F, Cl, -NHCH3, -N(CH3)2, -S(O)2CH3, cyano, and hydroxyl. On the other hand, R... 5 and R 6 Each is independently H; each is optionally substituted with at least one hydroxyl group of C1-C6 alkyl or 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 a or -S(O) p R 8 ; or phenyl, C1 alkylphenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 1- C2 alkylcyclopropyl and C 1- C2-alkylcyclobutyl, oxazolyl, pyrrolyl, piperidinyl, piperazine, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, C1-C2-alkyloxazolyl, C1- C2 alkylpyrrolidinyl, C 1- C2 alkylpiperidinyl, C 1- C2alkylpiperazinyl, C1-C2morpholinyl, C1-C2tetrahydropyranyl, C1-C2tetrahydrofuranyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, C 1- C2 alkylpyrazolyl, C 1- C2 alkylimidazolium, C 1- C2 alkylpyridinyl, C 1- C2 alkylpyrimidinyl or C 1- C2 alkylpyrazine group; each optionally consisting of at least one R group selected independently from the following 10 Substituents: methyl, ethyl, methoxy, ethoxy, -CHF2, -CF3, -OCF3, F, Cl, -NHCH3, -N(CH3)2, -S(O)2CH3, cyano, and hydroxyl. On the other hand, R... 5 It is H, C1-C6 alkyl, morpholino, piperidinyl, -CH2morpholino, -CH2piperidinyl, -(CH2)2morpholino, or -(CH2)2piperidinyl. On the other hand, R 5 It is H, methyl, ethyl, propyl, isopropyl, -CH2morpholinyl, -CH2piperidinyl, -(CH2)2morpholinyl, or -(CH2)2piperidinyl, and R 6 It is H, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -CF3, -OCF3, -C(O)NR a R 8 -R c S(O) p R 8 -R c NR a R b -R c OR a or -S(O) p R 8 ; or phenyl, C1 alkylphenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 1- C2 alkylcyclopropyl and C 1- C2-alkylcyclobutyl, oxazolyl, pyrrolyl, piperidinyl, piperazine, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, C1-C2-alkyloxazolyl, C 1- C2 alkylpyrrolidinyl, C 1- C2 alkylpiperidinyl, C 1- C2alkylpiperazinyl, C1-C2morpholinyl, C1-C2tetrahydropyranyl, C1-C2tetrahydrofuranyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, C 1- C2 alkylpyrazolyl, C1- C2 alkylimidazolium, C 1- C2 alkylpyridinyl, C 1- C2 alkylpyrimidinyl or C 1- C2 alkylpyrazine group; each optionally consisting of at least one R group selected independently from the following 10 Substituents: methyl, ethyl, methoxy, ethoxy, -CHF2, -CF3, -OCF3, F, Cl, -NHCH3, -N(CH3)2, -S(O)2CH3, cyano, and hydroxyl. On the other hand, R... 5 It is H, methyl, ethyl, propyl, or isopropyl; and R 6 It is H, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -CF3, -OCF3, -C(O)NR a R 8 -R c S(O) p R 8 -R c NR a R b -R c OR a or -S(O) p R 8 ; or phenyl, C1 alkylphenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 1- C2 alkylcyclopropyl and C 1- C2-alkylcyclobutyl, oxazolyl, pyrrolyl, piperidinyl, piperazine, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, C1-C2-alkyloxazolyl, C 1- C2 alkylpyrrolidinyl, C 1- C2 alkylpiperidinyl, C 1- C2alkylpiperazinyl, C1-C2morpholinyl, C1-C2tetrahydropyranyl, C1-C2tetrahydrofuranyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, C 1- C2 alkylpyrazolyl, C 1- C2 alkylimidazolium, C 1- C2 alkylpyridinyl, C 1- C2 alkylpyrimidinyl or C 1- C2 alkylpyrazinyl groups, each optionally composed of at least one R group selected independently from the following 10 Substituents: methyl, ethyl, methoxy, ethoxy, -CHF2, -CF3, -OCF3, F, Cl, -NHCH3, -N(CH3)2, -S(O)2CH3, cyano, and hydroxyl; and wherein R a and R b Each is independently H, methyl, or ethyl; R cIt is methyl, ethyl, or propyl; and R 8 It is methyl, ethyl, cyclopropyl, or phenyl; and wherein the cyclopropyl and the phenyl are each optionally substituted by at least one substituent selected from the following: C1-C4 alkyl, halogen, C1-C4 alkoxy, -CF3, and -OCF3.

[0040] In another aspect of the invention, R 5 and R 6 Together with the nitrogen atom to which it is attached, it forms a ring B, namely a 4- to 8-membered heterocycle or a 5-membered heteroaryl ring, each optionally containing at least one additional heteroatom selected from N, O, and S; and wherein each ring is optionally separated by at least one R 9 Substituent substitution; and wherein each ring is further optionally fused with Y, which is phenyl, pyridinyl, pyrimidinyl, pyrazolyl, thiophene, thiazolyl, or triazolyl. On the other hand, R 5 and R 6 Together with the nitrogen atom to which it is attached, it forms ring B, i.e., a 4- to 8-membered heterocycle or a 5-membered heteroaryl ring, each optionally containing at least one additional heteroatom selected from N, O, and S; and wherein each ring is optionally separated by at least one R 9 Substituents are used for substitution; and each ring is further optionally fused with Y as a phenyl, pyridyl, or pyrimidinyl group. On the other hand, R... 5 and R 6 Together with the nitrogen atom to which it is attached, it forms a ring B, said ring being an azacyclic butyl, pyrrolidinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally being atomized by at least one R selected from the group consisting of... 9 Substituents: methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F, Cl, Br, CN, -N(CH3)2, hydroxyl, -CHF2, -CF3, -OCHF2, -OCF3, and oxy; and wherein each ring is further optionally fused with Y as a phenyl or pyridyl group. On the other hand, R 5 and R 6 Together with the nitrogen atom to which it is attached, it forms a ring B, said ring being pyrroleyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally being atomized by at least one R selected from the group consisting of... 9 Substituents: methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F, Cl, Br, CN, -N(CH3)2, hydroxyl, -CHF2, -CF3, -OCHF2, -OCF3, and oxy; and wherein each ring is further optionally fused with Y as a phenyl group. On the other hand, R 5 and R 6Together with the nitrogen atom to which it is attached, it forms a ring B, said ring being pyrroloyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally being bonded by at least one R selected from the following 9 Substituents: methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F, Cl, Br, CN, -N(CH3)2, hydroxyl, -CHF2, -CF3, -OCHF2, -OCF3, and oxy; or ring B is optionally substituted with at least one oxy group as a dihydroindolyl, isodihydroindolyl, tetrahydroquinolinyl, dihydrobenzoxazinyl, or dihydrobenzothiazinyl. On the other hand, R... 5 and R 6 Together with the nitrogen atom to which it is attached, it forms a ring B, said ring being pyrroloyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally being bonded by at least one R selected from the following 9 Substituents: methyl, ethyl, F, Cl, cyano, hydroxy, oxygen and -CF3.

[0041] In another aspect of the invention, R 7 It is H, C1-C6 alkyl, -(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 and -(CH2) m NHC(O)CH3; where m is an integer 1, 2, or 3. On the other hand, R 7 It is H, C1-C6 alkyl, -(CH2) m NH2、-(CH2) m NHCH3、-(CH2) m N(CH3)2、-(CH2) m C(O)CH3、-(CH2) m S(O) p CH3 and (CH2) m NHC(O)CH3; where m is an integer 1 or 2. In another aspect of the invention, R 7It is H, C1-C6 alkyl, -(CH2)NH2, -(CH2)NHCH3, -(CH2)N(CH3)2, -(CH2)C(O)CH3, -(CH2)S(O) p CH3 and -(CH2)NHC(O)CH3. On the other hand, R 7 It is H, methyl, ethyl, propyl, isopropyl, tert-butyl, -(CH2) m NH2, -(CH2)NHCH3, -(CH2)N(CH3)2, -(CH2)C(O)CH3, -(CH2)S(O) p CH3 or -(CH2)NHC(O)CH3. On the other hand, R 7 It is H, methyl, ethyl, propyl, isopropyl, tert-butyl, -CH2NH2, -CH2NHCH3, or -CH2N(CH3)2. On the other hand, R 7 It is H, methyl, ethyl, propyl, isopropyl, or -CH2N(CH3)2. On the other hand, R 7 It is H, methyl, ethyl, or propyl.

[0042] In another aspect of the invention, R 8 It is a C1-C6 alkyl, C1-C6 haloalkyl, -NR a R b ; or C0-C4 alkyl, C3-C6 cycloalkyl, phenyl, pyrroloyl, pyrazolyl, pyridyl, or pyrimidinyl, each optionally substituted by at least one substituent selected from: C1-C6 alkyl, C1-C6 haloalkyl, -NH2, -NHCH3, -N(CH3)2, halogen, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy. On the other hand, R 8 It is methyl, ethyl, propyl; or cyclopropyl, C1 alkylcyclopropyl, phenyl, or pyridyl, each optionally substituted by at least one substituent selected from: C1-C4 alkyl, halogen, C1-C4 alkoxy, -CF3, and -OCF3. On the other hand, R 8 It is methyl, ethyl; or cyclopropyl or phenyl, each optionally substituted by at least one substituent selected from the following: C1-C4 alkyl, halogen, C1-C4 alkoxy, -CF3 and -OCF3.

[0043] In another aspect of the invention, each R 9 Independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, halogen, oxygen, hydroxyl, cyano, -NR a R b C1-C6 haloalkyl, C1-C6 haloalkoxy, -S(O) p R 8, phenyl, tetrahydrofuranyl, tetrahydrophenylthio, pyrrolyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, piperazine, pyrrolyl, furanylphenylthio, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrimidinyl, and pyrazinyl. On another aspect, each R 9 Independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, halogen, oxygen, hydroxyl, cyano, -NR a R b C1-C6 haloalkyl, C1-C6 haloalkoxy, -S(O) p R 8 , phenyl, tetrahydrofuranyl, pyrrolylyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazine, pyrrolyl, furanyl, phenylthiopyrazolyl, imidazolyl, isoxazolyl, pyridinyl, pyrimidinyl, and pyrazine. On the other hand, each R 9 Independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, halogen, oxygen, hydroxyl, cyano, -NR a R b C1-C6 haloalkyl, C1-C6 haloalkoxy, -S(O) p R 8 phenyl, piperidinyl, morpholinyl, piperazinyl, and pyridinyl. On the other hand, each R... 9 Independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, halogen, oxygen, hydroxyl, cyano, -NHCH3, -N(CH3)2, -N(CH2CH3)2, -CHF2, -CF3, -OCHF2, -OCF3, -S(O)2CH3, phenyl, piperidinyl, morpholinyl, piperazine, and pyridinyl. On another aspect, each R... 9 Independently selected from the group consisting of: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, F, Cl, Br, oxy, hydroxy, cyano, -NHCH3, -N(CH3)2, -N(CH2CH3)2, -CHF2, -CF3, -OCHF2, -OCF3, -S(O)2CH3, phenyl, piperidinyl, morpholinyl, piperazine, and pyridinyl. On the other hand, each R... 9 Independently selected from the group consisting of: methyl, ethyl, methoxy, ethoxy, isopropoxy, F, Cl, Br, oxy, hydroxy, cyano, -NHCH3, -N(CH3)2, -N(CH2CH3)2, -CHF2, -CF3, -OCHF2, -OCF3, -S(O)2CH3, phenyl, piperidinyl, morpholinyl, piperazine, and pyridinyl. On another aspect, each R... 9Independently selected from the group consisting of: methyl, ethyl, propyl, methoxy, ethoxy, F, Cl, oxy, hydroxy, cyano, -NH2, -NHCH3, -N(CH3)2, -CF3, and -OCF3. On the other hand, at least one R 9 Substituents are integers (n) that are 1, 2, or 3.

[0044] In another aspect of the invention, each R 10 Independently selected from C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, halogen, -NR a R b -S(O) p R 8 nitro, oxygen, cyano, -C(O)R a -C(O)OR a -OC(O)OR a -NR c C(O)R a -C(O)NR a R b , hydroxyl, 5-6 membered heterocycle, 5-6 membered heteroaryl ring and phenyl; wherein each heterocycle and heteroaryl ring each contains at least one heteroatom selected from the group consisting of N, O and S; and wherein each of the phenyl, the heterocycle and the heteroaryl ring is optionally surrounded by at least one R selected from the group consisting of 9 Substituents: C1-C6 alkyl, C1-C6 alkoxy, halogen, oxy, hydroxy, cyano, -NHCH3, -N(CH3)2, -N(CH2CH3)2, -CHF2, -CF3, -OCHF2, -OCF3, -S(O)2CH3, phenyl, piperidinyl, morpholinyl, piperazine, and pyridinyl. On the other hand, each R... 10 Independently selected from C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, halogen, -NHCH3, -N(CH3)2, -S(O)2CH3, nitro, oxy, cyano, -C(O)CH3, -C(O)OCH3, -NHCH2C(O)CH3, -NHCH2CH2C(O)CH3, -C(O)NHCH3 and hydroxy; phenyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazineyl, pyrrolidinyl, furanyl, pyrazolyl, imidazolyl, pyridinyl and pyrazinyl, each optionally and independently being selected from at least one R group from the group consisting of the following. 9Substituents: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, halogen, oxygen, hydroxyl, cyano, -NHCH3, -N(CH3)2, -N(CH2CH3)2, -CHF2, -CF3, -OCHF2, -OCF3, and -S(O)2CH3. On the other hand, each R... 10 Independently selected from methyl, ethyl, propyl, methoxy, ethoxy, -CHF2, -CF3, -OCF3, F, Cl, -NHCH3, -N(CH3)2, -S(O)2CH3, nitro, cyano, -C(O)CH3, -NHC(O)CH3, -NHCH2CH2C(O)CH3, -C(O)NHCH3 and hydroxy; phenyl, pyrrolyl, piperidinyl, morpholinyl, piperazine and pyridinyl, each optionally and independently being selected from at least one R group from the group consisting of methyl, ethyl, propyl, methoxy, ethoxy, -CHF2, -CF3, -OCF3, F, Cl, -NHCH3, -N(CH3)2, -S(O)2CH3, nitro, cyano, -C(O)CH3, -NHC(O)CH3, -NHCH2CH2C(O)CH3, -C(O)NHCH3 and hydroxyl ... being selected from at least one R group from the group consisting of methyl, ethyl, propyl, methoxy, ethoxy, -CHF2, -CF3, -OCF3, F, Cl, -NHCH3, -N(CH3)2, - 9 Substituents: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, halogen, oxygen, hydroxyl, cyano, -NHCH3, -N(CH3)2, -N(CH2CH3)2, -CHF2, -CF3, -OCHF2, -OCF3, and -S(O)2CH3. On the other hand, each R... 10 Independently selected from methyl, ethyl, propyl, methoxy, ethoxy, -CHF2, -CF3, -OCF3, F, Cl, -NHCH3, -N(CH3)2, -S(O)2CH3, nitro, cyano, -C(O)CH3, -NHCH2C(O)CH3, -NHCH2CH2C(O)CH3, -C(O)NHCH3, and hydroxyl. On the other hand, at least one R 10 Substituents are integers (n) that are 1, 2, or 3.

[0045] In another aspect, Y is phenyl, pyridinyl, pyrimidinyl, pyrazolyl, thiophenyl, thiazolyl, triazolyl, isothiazolyl, or pyrroloyl. In another aspect, Y is phenyl, pyridinyl, pyrimidinyl, or pyrazolyl. In another aspect, Y is phenyl, pyridinyl, or pyrimidinyl. In another aspect, Y is phenyl or pyridinyl. In another aspect, Y is phenyl. In another aspect, Y is pyridinyl. In another aspect, when optionally substituted ring A or ring B is fused with Y, ring A or ring B is optionally substituted with at least one oxygen group and is a dihydroindolyl, isodihydroindolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, dihydropyrrolopyridinyl, dihydropyrrolopyrimidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxaline, dihydrobenzoxazine, or dihydrobenzothiazine.

[0046] In another aspect of the invention, ring C is phenyl, naphthyl, a 6-membered monocyclic heteroaryl ring, or a 9- to 11-membered fused heteroaryl ring; wherein each of the heteroaryl rings contains at least one heteroatom selected from the group consisting of N, O, and S; and wherein ring C is optionally separated by at least one R10 Substituent substitution. In another aspect, ring C is phenyl, naphthyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrazinyl, pyridin-2(1H)-one; or a 9- to 11-membered fused heteroaryl ring; wherein each of the heteroaryl rings contains at least one heteroatom selected from the group consisting of N, O, and S; and wherein ring C is optionally substituted with at least one R 10 Substituents. On the other hand, the ring C is phenyl, naphthyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridinyl-2(1H)-one, quinolinyl, isoquinolinyl, cenolinyl, quinazolinyl, benzofuranyl, benzobenzylthio, indolyl, benzimidazolyl, indazole, or pyrrolopyridinyl, each optionally substituted with at least one R 10 Substituent substitution. On the other hand, the ring C is phenyl, naphthyl, pyridinyl, pyridinyl, pyrazinyl, pyridin-2(1H)-one, quinolinyl, isoquinolinyl, cenolinyl, quinazolinyl, benzofuranyl, benzobenzenthio, indolyl, benzimidazolyl, indazole, or pyrrolopyridinyl, each optionally being substituted with at least one R selected from the group consisting of... 10 Substituents: methyl, ethyl, propyl, methoxy, ethoxy, -CHF2, -CF3, -OCF3, F, Cl, -NHCH3, -N(CH3)2, -S(O)2CH3, nitro, cyano, -C(O)CH3, -NHC(O)CH3, -NHCH2CH2C(O)CH3, -C(O)NHCH3, and hydroxyl. On the other hand, the ring carbon is phenyl, naphthyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrazinyl, pyridin-2(1H)-one, quinolinyl, isoquinolinyl, benzofuranyl, benzobenzylthio, indoleyl, benzimidazolyl, or indazoleyl, each optionally being replaced by at least one R selected from the group consisting of... 10 Substituents: methyl, ethyl, propyl, methoxy, ethoxy, -CHF2, -CF3, -OCF3, F, Cl, -NHCH3, -N(CH3)2, -S(O)2CH3, nitro, cyano, -C(O)CH3, -NHC(O)CH3, -NHCH2CH2C(O)CH3, -C(O)NHCH3, and hydroxyl. On the other hand, the ring C is phenyl, naphthyl, pyridinyl, pyrazinyl, pyrazinyl, pyridin-2(1H)-one, quinolinyl, isoquinolinyl, benzofuranyl, benzobenzylthio, indoleyl, benzimidazolyl, or indazoleyl, each optionally substituted with at least one R 10 Methyl, ethyl, propyl, methoxy, ethoxy, -CHF2, -CF3, -OCF3, F, Cl, -NHCH3, -N(CH3)2, -S(O)2CH3, nitro, cyano, -C(O)CH3, -NHCH2C(O)CH3, -NHCH2CH2C(O)CH3, -C(O)NHCH3 and hydroxyl substitution.

[0047] In another aspect of the invention, 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'; where m is an integer 1 or 2. On the other hand, X is R. a On the other hand, X is -CH2NR 5 R 6 On the other hand, X is -CH2OR 7 On the other hand, X is -CH2SR 7 On the other hand, X is -CH2N3. On the other hand, X is -CH2CN. On the other hand, X is -CH2X'.

[0048] In another aspect of the invention, p is an integer 0. In another aspect, p is an integer 1. In another aspect, p is an integer 2. In another aspect of the invention, n is an integer 0, 1, or 2. In yet another aspect, n is an integer 0 or 1. In yet another aspect, n is an integer 0. In yet another aspect, n is an integer 1. In yet another aspect, n is an integer 2. In yet another aspect, n is an integer 3.

[0049] In another aspect of the invention, there is a compound of formula (1), wherein W is of formula (A), and the compound of formula (1) is a compound of formula (1A), wherein R 0 R 1 R 2 R 10 X, ring C and n

[0050]

[0051] As defined herein; its stereoisomers and its pharmaceutically acceptable salts.

[0052] In another aspect of the invention, formula (A) is formula (A0), formula (A1), formula (A2), formula (A3), formula (A4), formula (A5), or formula (A6). In another...

[0053]

[0054] In one aspect, the compound of formula (A) is a compound of formula (A0). In another aspect, the compound of formula (A) is a compound of formula (A1). In another aspect, the compound of formula (A) is a compound of formula (A2). In another aspect, the compound of formula (A) is a compound of formula (A3). In another aspect, the compound of formula (A) is a compound of formula (A4). In another aspect, the compound of formula (A) is a compound of formula (A5). In another aspect, the compound of formula (A) is a compound of formula (A6). In another aspect, it is preferred that formula (A) is formula (A1).

[0055] In another aspect of the invention, there is a compound of formula (1), wherein W is of formula (A) and formula (A) is of formula (A0), and the compound of formula (1) is a compound of formula (1-A0).

[0056]

[0057] Where R a R 0 R 1 R 2 R 10 The ring C and n are as defined herein; its stereoisomers and its pharmaceutically acceptable salts. On the other hand, it is a compound of formula (1-A0), wherein R... a and R 0 Each is independently either H or methyl; and R 1 R 2 R 10 The ring C and n are as defined herein; its stereoisomers and its pharmaceutically acceptable salts. On the other hand, it is a compound of formula (1-A0), wherein R... a R 0 and R 1 Each is independently either H or methyl; and R 2 R 10 The ring C and n are as defined herein; its stereoisomers and its pharmaceutically acceptable salts. On the other hand, it is a compound of formula (1-A0), wherein R... a R 0 and R 1 Each is independently either H or methyl; R 2 It is H, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, or -C(O)NR 3 R 4 ; or -C1 phenyl, -C1 pyrrolidinyl, -C1 piperidinyl, -C1 piperazine, -C1 morpholinyl, -C1 pyrrolidinyl, -C1 pyrazolyl, -C1 pyridinyl or -C1 pyrimidinyl, each optionally being composed of at least one R selected from the group consisting of ; 9Substituents: methyl, ethyl, hydroxy, methoxy, ethoxy, F, Cl, cyano, -N(CH3)2 and -CF3; R 3 and R 4 Each is independently H, C1-C6 alkyl, or -CH2CH2N(CH3)2; or cyclopropyl, C1 cyclopropyl, cyclobutyl, C1 cyclobutyl, cyclopentyl, C1 cyclopentyl, cyclohexyl, C1 cyclohexyl, phenyl, C1 phenyl, piperidinyl, C1-piperidinyl, C2-piperidinyl, piperazine, morpholinyl, tetrahydro-2H-pyran, pyrroloyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl, each optionally being R selected from the group consisting of at least one of the following groups. 9 Substituents: methyl, ethyl, propyl, isopropyl, tert-butyl, hydroxy, methoxy, ethoxy, F, Cl, Br, cyano, cyclopropyl, -N(CH3)2, -CHF2, -CF3, OCHF2 and -OCF3; or R 3 and R 4 Together with the nitrogen atom to which it is attached, it forms a ring A, said ring being pyrroleyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally being surrounded by at least one R selected from the group consisting of... 10 Substituents: methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F, Cl, Br, CN, -N(CH3)2, hydroxyl, -CHF2, -CF3, -OCHF2, -OCF3, and oxy; or ring A is a dihydroindolyl, isodihydroindolyl, tetrahydroquinolinyl, dihydrobenzoxazinyl, or dihydrobenzothiazinyl, optionally substituted with at least one oxy group; and ring C is phenyl, naphthyl, pyridinyl, pyridinyl, pyrazinyl, pyridinyl-2(1H)-one, quinolinyl, isoquinolinyl, cenolinyl, quinazolinyl, benzofuranyl, benzobenzylthio, indolyl, benzimidazolyl, indazole, or pyrrolopyridinyl, each optionally substituted with at least one R group selected from the group consisting of: 10 Substituents: methyl, ethyl, propyl, methoxy, ethoxy, -CHF2, -CF3, -OCF3, F, Cl, -NHCH3, -N(CH3)2, -S(O)2CH3, nitro, cyano, -C(O)CH3, -NHC(O)CH3, -NHCH2CH2C(O)CH3, -C(O)NHCH3, and hydroxyl; their stereoisomers and their pharmaceutically acceptable salts. On the other hand, it is a compound of formula (1-A0), wherein R... a R 0 and R 1 Each is independently either H or methyl, R 2 It is H, methyl, ethyl, cyclopropyl, cyclobutyl, or -C(O)NR 3 R 4; or -C1 phenyl, -C1 pyrrolidinyl, -C1 piperidinyl, -C1 piperazine, -C1 morpholinyl, -C1 pyrrolidinyl, -C1 pyrazolyl, -C1 pyridinyl or -C1 pyrimidinyl, each optionally being composed of at least one R selected from the group consisting of ; 9 Substituents: methyl, ethyl, hydroxy, methoxy, ethoxy, F, Cl, cyano, -N(CH3)2 and -CF3; R 3 It is H, methyl, ethyl, cyclopropyl, or phenyl; R 4 It is H, methyl, ethyl, propyl, or -CH2CH2N(CH3)2; or cyclopropyl, cyclobutyl, phenyl, C1 phenyl, piperidinyl, C1-piperidinyl, C2-piperidinyl, piperazinyl, morpholinyl, tetrahydro-2H-pyran, pyrazolyl, or pyridinyl, each optionally being R selected from the group consisting of at least one of the following. 9 Substituents: methyl, ethyl, hydroxy, methoxy, ethoxy, F, Cl, cyano, -N(CH3)2, and -CF3; and the ring C is phenyl, naphthyl, pyridinyl, pyridinyl, pyrazinyl, pyridin-2(1H)-one, quinolinyl, isoquinolinyl, benzofuranyl, benzobenzylthio, indoleyl, benzimidazolyl, or indazoleyl, each optionally being substituted with at least one R 10 Methyl, ethyl, propyl, methoxy, ethoxy, -CHF2, -CF3, -OCF3, F, Cl, -NHCH3, -N(CH3)2, -S(O)2CH3, nitro, cyano, -C(O)CH3, -NHCH2C(O)CH3, -NHCH2CH2C(O)CH3, -C(O)NHCH3, and hydroxyl substitutions. On the other hand, it is a compound of formula (1-A0), wherein R... a It is H, R 0 and R 1 Each is independently either H or methyl, R 2 The ring carbon is H or methyl, and the ring carbon is phenyl, naphthyl, pyridinyl, pyrazinyl, pyridinyl, pyridin-2(1H)-one, quinolinyl, isoquinolinyl, benzofuranyl, benzobenzylthio, indolyl, benzimidazolyl, or indazoleyl, each optionally separated by at least one R. 10 Methyl, ethyl, propyl, methoxy, ethoxy, -CHF2, -CF3, -OCF3, F, Cl, -NHCH3, -N(CH3)2, -S(O)2CH3, nitro, cyano, -C(O)CH3, -NHCH2C(O)CH3, -NHCH2CH2C(O)CH3, -C(O)NHCH3, and hydroxyl-substituted compounds; their stereoisomers and pharmaceutically acceptable salts thereof. On the other hand, it is a compound of formula (1-A0) Table A, its stereoisomers, and its pharmaceutically acceptable salts. On the other hand, it is a non-antibacterial compound of formula (1-A0) Table A, its stereoisomers, and its pharmaceutically acceptable salts.

[0058] In another aspect, there is a composition comprising a compound of formula (1-A0), its stereoisomer, and a pharmaceutically acceptable salt thereof. In another aspect, there is a composition comprising a compound of formula (1-A) Table A, its stereoisomer, and a pharmaceutically acceptable salt thereof. In another aspect, there is a composition comprising a non-antimicrobial compound of formula (1-A0) Table A, its stereoisomer, and a pharmaceutically acceptable salt thereof. In another aspect, the composition further comprises a pharmaceutically acceptable carrier.

[0059] In another aspect, a method is provided for treating or preventing an inflammatory response in an animal by administering a therapeutically effective amount of a compound of formula (1-A0), its stereoisomers, and its pharmaceutically acceptable salts to the animal in need. In another aspect, a method is provided for treating or preventing an inflammatory response in an animal by administering a therapeutically effective amount of a compound of formula (1-A0) Table A, its stereoisomers, and its pharmaceutically acceptable salts to the animal in need. In another aspect, a method is provided for treating or preventing an inflammatory response in an animal by administering a therapeutically effective amount of a non-antimicrobial compound of formula (1-A0) Table A, its stereoisomers, and its pharmaceutically acceptable salts to the animal in need. In another aspect, a method is provided for treating or preventing an inflammatory response in an animal, wherein the inflammatory response is caused by bacterial, viral, or fungal infection, stress, and / or environmental factors. In another aspect of the method, treating or preventing the inflammatory response in the animal prevents or alleviates the progression of a respiratory disease or condition in the animal. In another aspect of the method, the animal is a domestic animal; and wherein the respiratory disease or condition is a bovine respiratory disease or a swine respiratory disease. In another aspect of the method, TNF-α and IL-6 are downregulated in the animals.

[0060] In another aspect, there is the use of a compound of formula (1-A0), its stereoisomers, and pharmaceutically acceptable salts thereof for the preparation of a medicament for the treatment or prevention of inflammatory responses in animals. In another aspect, there is the use of a compound of formula (1-A0) Table A, its stereoisomers, and pharmaceutically acceptable salts thereof for the preparation of a medicament for the treatment or prevention of inflammatory responses in animals. In another aspect, there is the use of a non-antibacterial compound of formula (1-A0) Table A, its stereoisomers, and pharmaceutically acceptable salts thereof for the preparation of a medicament for the treatment or prevention of inflammatory responses in animals. In another aspect of the use, the inflammatory response is caused by bacterial, viral, or fungal infection, stress, and / or environmental factors. In another aspect of the use, the use of the medicament for the treatment or prevention of inflammatory responses in the animal prevents or alleviates the progression of a respiratory disease or condition. In another aspect of the use, the animal is a domestic animal. In another aspect of the use, the respiratory disease or condition is bovine respiratory disease or swine respiratory disease. In another aspect of the stated use, the administration of the drug to the animal to treat or prevent an inflammatory response in the animal results in a downregulation of TNF-α and IL-6 in the animal.

[0061] On the other hand, there is a compound of formula (1-A0), wherein R 2 It is -C(O)NR 3 R 4 ,

[0062]

[0063] The compound is a compound of formula (1-A0a), wherein R a R 0 R 1 R 3 R 4 R 10 The ring C and n are as defined herein; its stereoisomers and its pharmaceutically acceptable salts. On the other hand, it is a compound of formula (1-A0a), wherein R... a R 0 and R 1 Each is independently either H or methyl; and R 3 R 4 R 10 The ring C and n are as defined herein; its stereoisomers and its pharmaceutically acceptable salts. On the other hand, it is a compound of formula (1-A0a), wherein R... a and R 0 Each is independently either H or methyl, R 1 It is methyl; R 3 It is H, methyl, ethyl, cyclopropyl, or phenyl; R 4It is H, methyl, ethyl, propyl, or isopropyl; or cyclopropyl, cyclobutyl, cyclohexyl, phenyl, -C1 phenyl, piperidinyl, -C1 piperidinyl, -C2 piperidinyl, piperazinyl, morpholinyl, tetrahydro-2H-pyran, pyrazolyl, pyrimidinyl, or pyridinyl, each optionally being R selected from the group consisting of at least one of the following. 9 Substituents: methyl, ethyl, hydroxy, methoxy, ethoxy, F, Cl, cyano, -N(CH3)2 and -CF3; or R 3 and R 4 Together with the nitrogen atom to which it is attached, it forms a ring A, which is pyrroloyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally being bonded by at least one R selected from the group consisting of... 10 Substituents: methyl, ethyl, F, Cl, oxy, and -CF3; or ring A is a dihydroindolyl, isodihydroindolyl, tetrahydroquinolinyl, dihydrobenzoxazinyl, or dihydrobenzothiazinyl, optionally substituted with at least one oxy group; and ring C is phenyl, naphthyl, pyridinyl, pyridinyl, pyrazinyl, pyridinyl-2(1H)-one, quinolinyl, isoquinolinyl, benzofuranyl, benzobenzylthio, indolyl, benzimidazolyl, or indazoleyl, each optionally substituted with at least one R group. 10 Methyl, ethyl, propyl, methoxy, ethoxy, -CHF2, -CF3, -OCF3, F, Cl, -NHCH3, -N(CH3)2, -S(O)2CH3, nitro, cyano, -C(O)CH3, -NHCH2C(O)CH3, -NHCH2CH2C(O)CH3, -C(O)NHCH3, and hydroxyl-substituted compounds; their stereoisomers and their pharmaceutically acceptable salts. On the other hand, there are compounds of formula (1-A0a), wherein R... a and R 0 Each is independently either H or methyl, R 1 It is methyl; R 3 It is H, methyl, ethyl, cyclopropyl, or phenyl; R 4 It is H, methyl, ethyl, propyl, or isopropyl; or cyclopropyl, cyclobutyl, cyclohexyl, phenyl, -C1 phenyl, piperidinyl, -C1 piperidinyl, C2 piperidinyl, piperazine, morpholinyl, tetrahydro-2H-pyran, pyrazolyl, pyrimidinyl, or pyridinyl, each optionally being R selected from the group consisting of at least one of the following. 9 Substituents: methyl, ethyl, hydroxy, methoxy, ethoxy, F, Cl, cyano, -N(CH3)2 and -CF3; and the ring C is phenyl, naphthyl, pyridinyl, pyridinyl, pyrazinyl, pyridin-2(1H)-one, quinolinyl, isoquinolinyl, benzofuranyl, benzobenzylthio, indoleyl, benzimidazolyl or indazoleyl, each optionally being replaced by at least one R 10Methyl, ethyl, propyl, methoxy, ethoxy, -CHF2, -CF3, -OCF3, F, Cl, -NHCH3, -N(CH3)2, -S(O)2CH3, nitro, cyano, C(O)CH3, -NHCH2C(O)CH3, -NHCH2CH2C(O)CH3, -C(O)NHCH3, and hydroxyl-substituted compounds; their stereoisomers and their pharmaceutically acceptable salts. On the other hand, there are compounds of formula (1-A0a), wherein R... a and R 0 Each is independently either H or methyl, R 1 It is methyl; R 3 and R 4 Together with the nitrogen atom to which it is attached, it forms a ring A, which is pyrroloyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally being bonded by at least one R selected from the group consisting of... 10 Substituents: methyl, ethyl, F, Cl, oxy, and -CF3; or ring A is a dihydroindolyl, isodihydroindolyl, tetrahydroquinolinyl, dihydrobenzoxazinyl, or dihydrobenzothiazinyl, optionally substituted with at least one oxy group; and ring C is phenyl, naphthyl, pyridinyl, pyridinyl, pyrazinyl, pyridinyl-2(1H)-one, quinolinyl, isoquinolinyl, benzofuranyl, benzobenzylthio, indolyl, benzimidazolyl, or indazoleyl, each optionally substituted with at least one R group. 10 Methyl, ethyl, propyl, methoxy, ethoxy, -CHF2, -CF3, -OCF3, F, Cl, -NHCH3, -N(CH3)2, -S(O)2CH3, nitro, cyano, -C(O)CH3, -NHCH2C(O)CH3, -NHCH2CH2C(O)CH3, -C(O)NHCH3 and hydroxyl-substituted; their stereoisomers and their pharmaceutically acceptable salts.

[0064] In another aspect of the invention, there is a compound of formula (1), wherein W is H; said compound is a descladinose compound as a compound of formula (1.1).

[0065]

[0066] Where R 0 R 1 R 2 R 10 The ring C and n are as defined herein; its stereoisomers and its pharmaceutically acceptable salts. On the other hand, there is a compound of formula (1.1), wherein R... 0 and R 1 Each is independently either H or methyl; and R 2 R 10The ring C and n are as defined herein; its stereoisomers and its pharmaceutically acceptable salts. On the other hand, there is a compound of formula (1.1), wherein R... 0 and R 1 Each is independently either H or methyl; and R 2 It is H, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, or -C(O)NR 3 R 4 ; or -C1 phenyl, -C1 pyrrolidinyl, -C1 piperidinyl, -C1 piperazine, -C1 morpholinyl, -C1 pyrrolidinyl, -C1 pyrazolyl, -C1 pyridinyl or -C1 pyrimidinyl, each optionally being composed of at least one R selected from the group consisting of ; 9 Substituents: methyl, ethyl, hydroxy, methoxy, ethoxy, F, Cl, cyano, -N(CH3)2 and -CF3; R 3 and R 4 Each is independently H, C1-C6 alkyl, or -CH2CH2N(CH3)2; or cyclopropyl, C1 cyclopropyl, cyclobutyl, C1 cyclobutyl, cyclopentyl, C1 cyclopentyl, cyclohexyl, C1 cyclohexyl, phenyl, C1 phenyl, piperidinyl, C1-piperidinyl, C2-piperidinyl, piperazine, morpholinyl, tetrahydro-2H-pyran, pyrroloyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl, each optionally being R selected from the group consisting of at least one of the following groups. 9 Substituents: methyl, ethyl, propyl, isopropyl, tert-butyl, hydroxy, methoxy, ethoxy, F, Cl, Br, cyano, cyclopropyl, -N(CH3)2, -CHF2, -CF3, -OCHF2, and -OCF3; and the ring C is phenyl, naphthyl, pyridinyl, pyrazinyl, pyridinyl, pyridin-2(1H)-one, quinolinyl, isoquinolinyl, cyclophosphinyl, quinazolinyl, benzofuranyl, benzobenzylthio, indolyl, benzimidazolyl, indazole, or pyrrolopyridinyl, each optionally being replaced by at least one R selected from the following 10 Substituents: methyl, ethyl, propyl, methoxy, ethoxy, -CHF2, -CF3, -OCF3, F, Cl, -NHCH3, -N(CH3)2, -S(O)2CH3, nitro, cyano, -C(O)CH3, -NHC(O)CH3, -NHCH2CH2C(O)CH3, -C(O)NHCH3, and hydroxyl; their stereoisomers and their pharmaceutically acceptable salts. On the other hand, there is a compound of formula (1.1), wherein R... 0 It is H or methyl; R 1 It is H; and R 2It is H, methyl, ethyl, cyclopropyl, or cyclobutyl; or -C1 phenyl, -C1 pyrrolyl, -C1 piperidinyl, -C1 piperazine, -C1 morpholinyl, -C1 pyrroleyl, -C1 pyrazolyl, -C1 pyridinyl, or -C1 pyrimidinyl, each optionally being R selected from the group consisting of at least one of the following. 9 Substituents: methyl, ethyl, hydroxy, methoxy, ethoxy, F, Cl, cyano, -N(CH3)2, and -CF3; and the ring C is phenyl, naphthyl, pyridinyl, pyridinyl, pyrazinyl, pyridin-2(1H)-one, quinolinyl, isoquinolinyl, cenolinyl, quinazolinyl, benzofuranyl, benzobenzylthio, indolyl, benzimidazolyl, indazole, or pyrrolopyridinyl, each optionally being replaced by at least one R selected from the group consisting of: 10 Substituents: methyl, ethyl, propyl, methoxy, ethoxy, -CHF2, -CF3, -OCF3, F, Cl, -NHCH3, -N(CH3)2, -S(O)2CH3, nitro, cyano, -C(O)CH3, -NHC(O)CH3, -NHCH2CH2C(O)CH3, -C(O)NHCH3, and hydroxyl; their stereoisomers and their pharmaceutically acceptable salts. On the other hand, it is the compound of formula (1.1) Table B, its stereoisomers, and its pharmaceutically acceptable salts. On the other hand, it is the non-antimicrobial compound of formula (1.1) Table B, its stereoisomers, and its pharmaceutically acceptable salts.

[0067] In another aspect of the invention, there is a decladinose compound of formula (1.1), wherein R 2 It is -C(O)NR 3 R 4 The compound is a compound of formula (1.1a).

[0068]

[0069] Where R 0 R 1 R 3 R 4 R 10 The ring C and n are as defined herein; its stereoisomers and its pharmaceutically acceptable salts. On the other hand, there is a compound of formula (1.1a), wherein R... 0 R 1 and R 3 Each is independently either H or methyl; R 4 , ring C, R 10 And n as defined herein; its stereoisomers and its pharmaceutically acceptable salts. On the other hand, is a compound of formula (1.1a), wherein R... 0 It is H or methyl; R 1 and R 3Each is a methyl group; and R 4 , ring C, R 10 And n as defined herein; its stereoisomers and its pharmaceutically acceptable salts. On the other hand, is a compound of formula (1.1a), wherein R... 0 It is H or methyl; R 1 and R 3 Each is a methyl group; and R 4 It is H, methyl, ethyl, propyl, or -CH2CH2N(CH3)2; or cyclopropyl, cyclobutyl, phenyl, C1 phenyl, piperidinyl, C1-piperidinyl, C2-piperidinyl, piperazinyl, morpholinyl, tetrahydro-2H-pyran, pyrazolyl, or pyridinyl, each optionally being R selected from the group consisting of at least one of the following. 9 Substituents: methyl, ethyl, hydroxy, methoxy, ethoxy, F, Cl, cyano, -N(CH3)2 and -CF3 or R 3 and R 4 Together with the nitrogen atom to which it is attached, it forms a ring A, which is pyrroloyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally being bonded by at least one R selected from the group consisting of... 10 Substituents: methyl, ethyl, F, Cl, oxy, and -CF3; or ring A is a dihydroindolyl, isodihydroindolyl, tetrahydroquinolinyl, dihydrobenzoxazinyl, or dihydrobenzothiazinyl, optionally substituted with at least one oxy group; and ring C is phenyl, naphthyl, pyridinyl, pyridinyl, pyrazinyl, pyridinyl-2(1H)-one, quinolinyl, isoquinolinyl, benzofuranyl, benzobenzylthio, indolyl, benzimidazolyl, or indazoleyl, each optionally substituted with at least one R group selected from the group consisting of... 10 Substituents: methyl, ethyl, propyl, methoxy, ethoxy, -CHF2, -CF3, -OCF3, F, Cl, -NHCH3, -N(CH3)2, -S(O)2CH3, nitro, cyano, -C(O)CH3, -NHCH2C(O)CH3, -NHCH2CH2C(O)CH3, -C(O)NHCH3, and hydroxyl; their stereoisomers and their pharmaceutically acceptable salts. On the other hand, there is a compound of formula (1.1a), wherein R... 0 It is H or methyl, R 1 and R 3 Each is a methyl group; and R 4 It is H, methyl, ethyl, propyl, or -CH2CH2N(CH3)2; or cyclopropyl, cyclobutyl, phenyl, C1 phenyl, piperidinyl, C1-piperidinyl, C2-piperidinyl, piperazinyl, morpholinyl, tetrahydro-2H-pyran, pyrazolyl, or pyridinyl, each optionally being R selected from the group consisting of at least one of the following. 9Substituents: methyl, ethyl, hydroxy, methoxy, ethoxy, F, Cl, cyano, -N(CH3)2, and -CF3, and the ring C is phenyl, naphthyl, pyridinyl, pyridinyl, pyrazinyl, pyridin-2(1H)-one, quinolinyl, isoquinolinyl, benzofuranyl, benzobenzylthio, indolyl, benzimidazolyl, or indazoleyl, each optionally being replaced by at least one R selected from the group consisting of... 10 Substituents: methyl, ethyl, propyl, methoxy, ethoxy, -CHF2, -CF3, -OCF3, F, Cl, -NHCH3, -N(CH3)2, -S(O)2CH3, nitro, cyano, -C(O)CH3, -NHCH2C(O)CH3, -NHCH2CH2C(O)CH3, -C(O)NHCH3, and hydroxyl; their stereoisomers and their pharmaceutically acceptable salts. On the other hand, it is the compound of formula (1.1a) Table C, its stereoisomers, and its pharmaceutically acceptable salts. On the other hand, it is the non-antimicrobial compound of formula (1.1a) Table C, its stereoisomers, and its pharmaceutically acceptable salts.

[0070] In another aspect of the invention, there is a decladinose compound of formula (1.1), wherein R 2 It is -C(O)NR 3 R 4 And R 3 and R 4 It connects with the nitrogen atom it shares to form ring A, which is a compound of formula (1.1b).

[0071]

[0072] Where R 0 R 1 R 10 Ring A, ring C, and n are as defined herein; their stereoisomers and their pharmaceutically acceptable salts. On the other hand, there is a compound of formula (1.1b), wherein R... 0 and R 1 Each is independently either H or methyl; and R 10 Ring A, ring C, and n are as defined herein. On the other hand, there is a compound of formula (1.1b), where R... 0 It is H or methyl; R 1 It is methyl; and R 10 Ring A, ring C, and n are as defined herein. On the other hand, there is a compound of formula (1.1b), where R... 0 It is H or methyl; R 1 It is methyl; ring A is pyrrole, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally being composed of at least one R selected from the group consisting of...10 Substituents: methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F, Cl, Br, CN, -N(CH3)2, hydroxyl, -CHF2, -CF3, -OCHF2, -OCF3, and oxy; or ring A is a dihydroindolyl, isodihydroindolyl, tetrahydroquinolinyl, dihydrobenzoxazinyl, or dihydrobenzothiazinyl, optionally substituted with at least one oxy group; and ring C is phenyl, naphthyl, pyridinyl, pyridinyl, pyrazinyl, pyridinyl-2(1H)-one, quinolinyl, isoquinolinyl, cenolinyl, quinazolinyl, benzofuranyl, benzobenzylthio, indolyl, benzimidazolyl, indazole, or pyrrolopyridinyl, each optionally substituted with at least one R group selected from the group consisting of: 10 Substituents: methyl, ethyl, propyl, methoxy, ethoxy, -CHF2, -CF3, -OCF3, F, Cl, -NHCH3, -N(CH3)2, -S(O)2CH3, nitro, cyano, -C(O)CH3, -NHC(O)CH3, -NHCH2CH2C(O)CH3, -C(O)NHCH3, and hydroxyl; their stereoisomers and their pharmaceutically acceptable salts. On the other hand, there is a compound of formula (1.1b), wherein R... 0 It is H or methyl; R 1 It is methyl; ring A is pyrrole, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally being composed of at least one R selected from the group consisting of... 10 Substituents: methyl, ethyl, F, Cl, oxy, and -CF3; or ring A is a dihydroindolyl, isodihydroindolyl, tetrahydroquinolinyl, dihydrobenzoxazinyl, or dihydrobenzothiazinyl, optionally substituted with at least one oxy group; and ring C is phenyl, naphthyl, pyridinyl, pyridinyl, pyrazinyl, pyridinyl-2(1H)-one, quinolinyl, isoquinolinyl, benzofuranyl, benzobenzylthio, indolyl, benzimidazolyl, or indazoleyl, each optionally substituted with at least one R group selected from the group consisting of... 10 Substituents: methyl, ethyl, propyl, methoxy, ethoxy, -CHF2, -CF3, -OCF3, F, Cl, -NHCH3, -N(CH3)2, -S(O)2CH3, nitro, cyano, -C(O)CH3, -NHCH2C(O)CH3, -NHCH2CH2C(O)CH3, -C(O)NHCH3, and hydroxyl; their stereoisomers and their pharmaceutically acceptable salts. On the other hand, it is the compound of formula (1.1b) Table D, its stereoisomers, and its pharmaceutically acceptable salts. On the other hand, it is the non-antimicrobial compound of formula (1.1b) Table D, its stereoisomers, and its pharmaceutically acceptable salts.

[0073] In another aspect, there is a composition comprising a compound of formula (1-A0a), its stereoisomer, and a pharmaceutically acceptable salt thereof. In another aspect, there is a composition comprising a compound of formula (1.1), its stereoisomer, and a pharmaceutically acceptable salt thereof. In another aspect, there is a composition comprising a compound of formula (1.1) Table B, its stereoisomer, and a pharmaceutically acceptable salt thereof. In another aspect, there is a composition comprising a compound of formula (1.1a), its stereoisomer, and a pharmaceutically acceptable salt thereof. In another aspect, there is a composition comprising a compound of formula (1.1a) Table C, its stereoisomer, and a pharmaceutically acceptable salt thereof. In another aspect, there is a composition comprising a non-antimicrobial compound of formula (1.1a) Table C, its stereoisomer, and a pharmaceutically acceptable salt thereof. In another aspect, there is a composition comprising a compound of formula (1.1b), its stereoisomer, and a pharmaceutically acceptable salt thereof. In another aspect, there is a composition comprising a compound of formula (1.1b) Table D, a stereoisomer thereof, and a pharmaceutically acceptable salt thereof. In yet another aspect, the composition further comprises a pharmaceutically acceptable carrier.

[0074] In another aspect, it is a method for treating or preventing an inflammatory response in an animal by administering a therapeutically effective amount of a compound of formula (1-A0a), its stereoisomers, and its pharmaceutically acceptable salts to the animal in need. In another aspect, it is a method for treating or preventing an inflammatory response in an animal by administering a therapeutically effective amount of a compound of formula (1.1), its stereoisomers, and its pharmaceutically acceptable salts to the animal in need. In another aspect, it is a method for treating or preventing an inflammatory response in an animal by administering a therapeutically effective amount of a compound of formula (1.1a), its stereoisomers, and its pharmaceutically acceptable salts to the animal in need. In another aspect, it is a method for treating or preventing an inflammatory response in an animal by administering a therapeutically effective amount of a compound of formula (1.1a), its stereoisomers, and its pharmaceutically acceptable salts to the animal in need. In another aspect, it is a method for treating or preventing an inflammatory response in an animal by administering a therapeutically effective amount of a non-antimicrobial compound of formula (1.1a) table C, its stereoisomers, and its pharmaceutically acceptable salts to the animal in need. In another aspect, a method is provided for treating or preventing an inflammatory response in an animal by administering a therapeutically effective amount of a non-antimicrobial compound of formula (1.1a) Table C, its stereoisomers, and its pharmaceutically acceptable salts to an animal in need. In another aspect, a method is provided for treating or preventing an inflammatory response in an animal by administering a therapeutically effective amount of a compound of formula (1.1b), its stereoisomers, and its pharmaceutically acceptable salts to an animal in need. In another aspect, a method is provided for treating or preventing an inflammatory response in an animal, wherein the inflammatory response is caused by bacterial, viral, or fungal infection, stress, and / or environmental factors. In another aspect of the method, treating or preventing the inflammatory response in the animal prevents or mitigates the progression of a respiratory disease or symptom in the animal. In another aspect of the method, the animal is a domestic animal; and wherein the respiratory disease or symptom is bovine respiratory disease or swine respiratory disease. In another aspect of the method, TNF-α and IL-6 are downregulated in the animals.

[0075] In another aspect, there is the use of a compound of formula (1-A0a), its stereoisomers, and pharmaceutically acceptable salts thereof for the preparation of a medicament for the treatment or prevention of inflammatory responses in animals. In another aspect, there is the use of a compound of formula (1.1), its stereoisomers, and pharmaceutically acceptable salts thereof for the preparation of a medicament for the treatment or prevention of inflammatory responses in animals. In another aspect, there is the use of a compound of formula (1.1) Table B, its stereoisomers, and pharmaceutically acceptable salts thereof for the preparation of a medicament for the treatment or prevention of inflammatory responses in animals. In another aspect, there is the use of a compound of formula (1.1a), its stereoisomers, and pharmaceutically acceptable salts thereof for the preparation of a medicament for the treatment or prevention of inflammatory responses in animals. In another aspect, there is the use of a non-antibacterial compound of formula (1.1a) Table C, its stereoisomers, and pharmaceutically acceptable salts thereof for the preparation of a medicament for the treatment or prevention of inflammatory responses in animals. In another aspect, there is the use of a compound of formula (1.1b), its stereoisomers, and pharmaceutically acceptable salts thereof for the preparation of a medicament for the treatment or prevention of an inflammatory response in animals. In another aspect, there is the use of a compound of formula (1.1b), its stereoisomers, and pharmaceutically acceptable salts thereof for the preparation of a medicament for the treatment or prevention of an inflammatory response in animals. In another aspect of the use, the inflammatory response is caused by bacterial, viral, or fungal infection, stress, and / or environmental factors. In another aspect of the use, the use of the medicament for the treatment or prevention of an inflammatory response in the animal prevents or alleviates the progression of a respiratory disease or condition. In another aspect of the use, the animal is a domestic animal. In another aspect of the use, the respiratory disease or condition is bovine respiratory disease or swine respiratory disease. In another aspect of the use, the use of the medicament administered to the animal to treat or prevent an inflammatory response in the animal results in the downregulation of TNF-α and IL-6 in the animal.

[0076] In another aspect of the invention, there is a compound of formula (1), wherein W is of formula (A) and formula (A) is of formula (A1), and the compound of formula (1) is a compound of formula (1-A1).

[0077]

[0078] Where R 0 R 1 R 2 R 5 R 6 R 10 The ring C and n are as defined herein; its stereoisomers and its pharmaceutically acceptable salts. On another front, there are compounds of formula (1-A1), wherein R... 0 It is H, methyl, ethyl, or propyl; and R1 R 2 R 5 R 6 R 10 The ring C and n are as defined herein; its stereoisomers and its pharmaceutically acceptable salts. On another front, there are compounds of formula (1-A1), wherein R... 0 It is H or methyl; and R 1 R 2 R 5 R 6 R 10 The ring C and n are as defined herein; its stereoisomers and its pharmaceutically acceptable salts. On another front, there are compounds of formula (1-A1), wherein R... 0 It is H or methyl; R 1 It is H, methyl, or ethyl; or R 1 It is benzyl, -CH2pyridine, -CH2pyrimidine, -CH2pyrazole or -CH2imidazole, each optionally being composed of at least one R selected from the following 9 Substituents: methyl, ethyl, methoxy, ethoxy, F, Cl, hydroxy, -CF3 and -OCF3; R 2 It is H, methyl, ethyl, cyclopropyl, cyclobutyl, or -C(O)NR 3 R 4 ; or -C1 phenyl, -C1 pyrrolidinyl, -C1 piperidinyl, -C1 piperazine, -C1 morpholinyl, -C1 pyrrolidinyl, -C1 pyrazolyl, -C1 pyridinyl or -C1 pyrimidinyl, each optionally being composed of at least one R selected from the group consisting of ; 9 Substituents: methyl, ethyl, hydroxy, methoxy, ethoxy, F, Cl, cyano, -N(CH3)2 and -CF3; R 3 and R 4 Each is independently H or C1-C6 alkyl; or C0-C2 cyclopropyl, C0-C2 cyclobutyl, C0-C2 cyclopentyl, C0-C2 cyclohexyl, C0-C2 phenyl, C0-C2 piperidinyl, piperazine, morpholinyl, tetrahydro-2H-pyran, pyrroloyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl, each optionally being R selected from the group consisting of at least one of the following. 9 Substituents: methyl, ethyl, propyl, isopropyl, tert-butyl, hydroxy, methoxy, ethoxy, F, Cl, cyano, -N(CH3)2, -CHF2, -CF3, -OCHF2 and -OCF3; or R 3 and R 4 Together with the nitrogen atom to which it is attached, it forms a ring A, which is pyrroloyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally being bonded by at least one R selected from the group consisting of... 10Substituents: methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F, Cl, Br, CN, -N(CH3)2, hydroxyl, -CHF2, -CF3, -OCHF2, -OCF3, and oxy; or ring A is optionally substituted with at least one oxy group as a dihydroindolyl, isodihydroindolyl, tetrahydroquinolinyl, dihydrobenzoxazinyl, or dihydrobenzothiazinyl; R 5 and R 6 Each is independently H; each is optionally substituted with at least one hydroxyl group of C1-C6 alkyl or 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 a or -S(O) p R 8 ; or phenyl, C1 alkylphenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 1- C2 alkylcyclopropyl and C 1- C2-alkylcyclobutyl, oxazolyl, pyrrolyl, piperidinyl, piperazine, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, C1-C2-alkyloxazolyl, C 1- C2 alkylpyrrolidinyl, C 1- C2 alkylpiperidinyl, C 1- C2alkylpiperazinyl, C1-C2morpholinyl, C1-C2morpholinyl, C1-C2piperidinyl, C1-C2tetrahydropyranyl, C1-C2tetrahydrofuranyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, C 1- C2 alkylpyrazolyl, C 1- C2 alkylimidazolium, C 1- C2 alkylpyridinyl, C 1- C2 alkylpyrimidinyl or C 1- C2 alkylpyrazine groups, each optionally composed of at least one R group selected from the following 10 Substituents: methyl, ethyl, methoxy, ethoxy, -CHF2, -CF3, -OCF3, F, Cl, -NHCH3, -N(CH3)2, -S(O)2CH3, cyano and hydroxyl; or R 5 and R 6Together with the nitrogen atom to which it is attached, it forms a ring B, said ring being pyrroloyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally being bonded by at least one R selected from the following 9 Substituents: methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F, Cl, Br, CN, -N(CH3)2, hydroxyl, -CHF2, -CF3, -OCHF2, -OCF3, and oxy; or ring B is a dihydroindolyl, isodihydroindolyl, tetrahydroquinolinyl, dihydrobenzoxazinyl, or dihydrobenzothiazinyl, optionally substituted with at least one oxy group; and ring C is phenyl, naphthyl, pyridinyl, pyridinyl, pyrazinyl, pyridinyl-2(1H)-one, quinolinyl, isoquinolinyl, benzofuranyl, benzobenzylthio, indolyl, benzimidazolyl, or indazoleyl, each optionally substituted with at least one R group selected from the group consisting of... 10 Substituents: methyl, ethyl, propyl, methoxy, ethoxy, -CHF2, -CF3, -OCF3, F, Cl, -NHCH3, -N(CH3)2, -S(O)2CH3, nitro, cyano, -C(O)CH3, -NHC(O)CH3, -NHCH2CH2C(O)CH3, -C(O)NHCH3, and hydroxyl; their stereoisomers and their pharmaceutically acceptable salts. On the other hand, it is a compound of formula (1-A1), wherein R... 0 and R 1 Each is independently either H or methyl; R 2 It is methyl or -C(O)NR 3 R 4 ;R 3 and R 4 Each is independently H or C1-C6 alkyl; or cyclopropyl, -C1 cyclopropyl, cyclobutyl, -C1 cyclobutyl, cyclopentyl, -C1 cyclopentyl, cyclohexyl, -C1 cyclohexyl, phenyl, -C1 phenyl, piperidinyl, -C1 piperidinyl, -C2 piperidinyl, piperazine, morpholinyl, tetrahydro-2H-pyran, pyrroloyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl, each optionally being R selected from the group consisting of at least one of the following. 9 Substituents: methyl, ethyl, propyl, isopropyl, tert-butyl, hydroxy, methoxy, ethoxy, F, Cl, Br, cyano, cyclopropyl, -N(CH3)2, -CHF2, -CF3, -OCHF2 and -OCF3; or R 3 and R 4 Together with the nitrogen atom to which it is attached, it forms a ring A, which is pyrroloyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally bonded by at least one R selected from methyl, ethyl, F, Cl, oxy, and -CF3. 10Substituent substitution; or ring A is optionally substituted with at least one oxygen group: dihydroindolyl, isodihydroindolyl, tetrahydroquinolinyl, dihydrobenzoxazinyl, or dihydrobenzothiazinyl; R 5 and R 6 Each is independently H; each is optionally substituted with at least one hydroxyl group of C1-C6 alkyl or 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 a or -S(O) p R 8 ; or phenyl, C1 alkylphenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 1- C2 alkylcyclopropyl and C 1- C2-alkylcyclobutyl, oxazolyl, pyrrolyl, piperidinyl, piperazine, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, C1-C2-alkyloxazolyl, C 1- C2 alkylpyrrolidinyl, C 1- C2 alkylpiperidinyl, C 1- C2alkylpiperazinyl, C1-C2morpholinyl, C1-C2tetrahydropyranyl, C1-C2tetrahydrofuranyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, C 1- C2 alkylpyrazolyl, C 1- C2 alkylimidazolium, C 1- C2 alkylpyridinyl, C 1- C2 alkylpyrimidinyl or C 1- C2 alkylpyrazinyl groups, each optionally composed of at least one R group selected independently from the following 10 Substituents: methyl, ethyl, methoxy, ethoxy, -CHF2, -CF3, -OCF3, F, Cl, -NHCH3, -N(CH3)2, -S(O)2CH3, cyano and hydroxyl; or R 5 and R 6 Together with the nitrogen atom to which it is attached, it forms a ring B, said ring being pyrroloyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally being bonded by at least one R selected from the following 9 Substituents: methyl, ethyl, F, Cl, cyano, hydroxy, oxygen, and -CF3; their stereoisomers and their pharmaceutically acceptable salts. On the other hand, there are compounds of formula (1-A1), wherein R... 0 and R 1Each is independently either H or methyl; R 2 It is methyl; R 5 It is H, methyl, ethyl, propyl, or isopropyl; and R 6 It is H, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -CF3, -OCF3, -C(O)NR a R 8 -R c S(O) p R 8 -R c NR a R b -R c OR a or -S(O) p R 8 ; or phenyl, C1 alkylphenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 1- C2 alkylcyclopropyl and C 1- C2-alkylcyclobutyl, oxazolyl, pyrrolyl, piperidinyl, piperazine, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, C1-C2-alkyloxazolyl, C 1- C2 alkylpyrrolidinyl, C 1- C2 alkylpiperidinyl, C 1- C2alkylpiperazinyl, C1-C2morpholinyl, C1-C2tetrahydropyranyl, C1-C2tetrahydrofuranyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, C 1- C2 alkylpyrazolyl, C 1- C2 alkylimidazolium, C 1- C2 alkylpyridinyl, C 1- C2 alkylpyrimidinyl or C 1- C2 alkylpyrazine groups, each optionally selected independently from at least one of the following R groups. 10 Substituents: methyl, ethyl, methoxy, ethoxy, -CHF2, -CF3, -OCF3, F, Cl, -NHCH3, -N(CH3)2, -S(O)2CH3, cyano, and hydroxyl; and wherein R a and R b Each is independently H, methyl, or ethyl; R c It is methyl, ethyl, or propyl; and R 8 It is methyl, ethyl, cyclopropyl, or phenyl; and wherein said cyclopropyl and said phenyl are each optionally substituted by at least one substituent selected from: C1-C4 alkyl, halogen, C1-C4 alkoxy, -CF3, and -OCF3; or R 5 and R 6Together with the nitrogen atom to which it is attached, it forms a ring B, said ring being pyrroloyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally being bonded by at least one R selected from the following 9 Substituents: methyl, ethyl, F, Cl, cyano, hydroxy, oxy, and -CF3; and the ring C is phenyl, naphthyl, pyridinyl, pyridinyl, pyrazinyl, pyridin-2(1H)-one, quinolinyl, isoquinolinyl, benzofuranyl, benzobenzylthio, indolyl, benzimidazolyl, or indazoleyl, each optionally being replaced by at least one R selected from the group consisting of: 10 Substituents: methyl, ethyl, propyl, methoxy, ethoxy, -CHF2, -CF3, -OCF3, F, Cl, -NHCH3, -N(CH3)2, -S(O)2CH3, nitro, cyano, -C(O)CH3, -NHCH2C(O)CH3, -NHCH2CH2C(O)CH3, -C(O)NHCH3, and hydroxyl; their stereoisomers and their pharmaceutically acceptable salts. On the other hand, it is a compound of formula (1-A1), wherein R... 0 and R 1 Each is independently either H or methyl; R 2 It is methyl; R 5 It is H, methyl, ethyl, propyl, or isopropyl; and R 6 It is H, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -CF3, -OCF3, -C(O)NR a R 8 -R c S(O) p R 8 -R c NR a R b -R c OR a or -S(O) p R 8 ; or phenyl, C1 alkylphenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 1- C2 alkylcyclopropyl and C 1- C2-alkylcyclobutyl, oxazolyl, pyrrolyl, piperidinyl, piperazine, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, C1-C2-alkyloxazolyl, C 1- C2 alkylpyrrolidinyl, C 1- C2 alkylpiperidinyl, C 1- C2alkylpiperazinyl, C1-C2morpholinyl, C1-C2tetrahydropyranyl, C1-C2tetrahydrofuranyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, C 1- C2 alkylpyrazolyl, C 1-C2 alkylimidazolium, C 1- C2 alkylpyridinyl, C 1- C2 alkylpyrimidinyl or C 1- C2 alkylpyrazinyl groups, each optionally composed of at least one R group selected independently from the following 10 Substituents: methyl, ethyl, methoxy, ethoxy, -CHF2, -CF3, -OCF3, F, Cl, -NHCH3, -N(CH3)2, -S(O)2CH3, cyano, and hydroxyl; and wherein R a and R b Each is independently H, methyl, or ethyl; R c It is methyl, ethyl, or propyl; and R 8 It is methyl, ethyl, cyclopropyl, or phenyl; and wherein the cyclopropyl and the phenyl are each optionally substituted by at least one substituent selected from: C1-C4 alkyl, halogen, C1-C4 alkoxy, -CF3, and -OCF3; and the ring C is phenyl, naphthyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrazinyl, pyridin-2(1H)-one, quinolinyl, isoquinolinyl, benzofuranyl, benzobenzylthio, indolyl, benzimidazolyl, or indazoleyl, each optionally substituted by at least one R 10 Methyl, ethyl, propyl, methoxy, ethoxy, -CHF2, -CF3, -OCF3, F, Cl, -NHCH3, -N(CH3)2, -S(O)2CH3, nitro, cyano, -C(O)CH3, -NHCH2C(O)CH3, -NHCH2CH2C(O)CH3, -C(O)NHCH3, and hydroxyl-substituted compounds; their stereoisomers and pharmaceutically acceptable salts thereof. On the other hand, it is a compound of formula (1-A1) listed as E, its stereoisomers, and its pharmaceutically acceptable salts. On the other hand, it is a non-antibacterial compound of formula (1-A1) listed as E, its stereoisomers, and its pharmaceutically acceptable salts.

[0079] In another aspect, there is a composition comprising a compound of formula (1-A1), its stereoisomer, and a pharmaceutically acceptable salt thereof. In another aspect, there is a composition comprising a compound of formula (1-A1)E, its stereoisomer, and a pharmaceutically acceptable salt thereof. In another aspect, there is a composition comprising a non-antimicrobial compound of formula (1-A1)E, its stereoisomer, and a pharmaceutically acceptable salt thereof. In another aspect, the composition further comprises a pharmaceutically acceptable carrier.

[0080] In another aspect, a method is provided for treating or preventing an inflammatory response in an animal by administering a therapeutically effective amount of a compound of formula (1-A1), its stereoisomers, and its pharmaceutically acceptable salts to the animal in need. In another aspect, a method is provided for treating or preventing an inflammatory response in an animal by administering a therapeutically effective amount of a compound of formula (1-A1) Table E, its stereoisomers, and its pharmaceutically acceptable salts to the animal in need. In another aspect, a method is provided for treating or preventing an inflammatory response in an animal by administering a therapeutically effective amount of a non-antimicrobial compound of formula (1-A1) Table E, its stereoisomers, and its pharmaceutically acceptable salts to the animal in need. In another aspect, a method is provided for treating or preventing an inflammatory response in an animal, wherein the inflammatory response is caused by bacterial, viral, or fungal infection, stress, and / or environmental factors. In another aspect of the method, treating or preventing the inflammatory response in the animal prevents or alleviates the progression of a respiratory disease or condition in the animal. In another aspect of the method, the animal is a domestic animal; and wherein the respiratory disease or condition is a bovine respiratory disease or a swine respiratory disease. In another aspect of the method, TNF-α and IL-6 are downregulated in the animals.

[0081] In another aspect, there is the use of a compound of formula (1-A1), its stereoisomers, and pharmaceutically acceptable salts thereof for the preparation of a medicament for the treatment or prevention of inflammatory responses in animals. In another aspect, there is the use of a compound of formula (1-A1)E, its stereoisomers, and pharmaceutically acceptable salts thereof for the preparation of a medicament for the treatment or prevention of inflammatory responses in animals. In another aspect, there is the use of a non-antibacterial compound of formula (1-A1)E, its stereoisomers, and pharmaceutically acceptable salts thereof for the preparation of a medicament for the treatment or prevention of inflammatory responses in animals. In another aspect of the use, the inflammatory response is caused by bacterial, viral, or fungal infection, stress, and / or environmental factors. In another aspect of the use, the use of the medicament for the treatment or prevention of inflammatory responses in the animal prevents or alleviates the progression of a respiratory disease or condition. In another aspect of the use, the animal is a domestic animal. In another aspect of the use, the respiratory disease or condition is bovine respiratory disease or swine respiratory disease. In another aspect of the stated use, the administration of the drug to the animal to treat or prevent an inflammatory response in the animal results in a downregulation of TNF-α and IL-6 in the animal.

[0082] In another aspect of the invention, there is a compound of formula (1-A1), wherein R 2 It is C(O)NR 3 R 4 The compound of formula (1-A1) is a compound of formula (1-A1a).

[0083]

[0084] Where R 0 R 1 R 3 R 4 R 5 R 6 R 10 The ring C and n are as defined herein; its stereoisomers and its pharmaceutically acceptable salts. On the other hand, it is a compound of formula (1-A1a), wherein R... 0 It is H or methyl; and R 1 R 3 R 4 R 5 R 6 R 10 The ring C and n are as defined herein; its stereoisomers and its pharmaceutically acceptable salts. On the other hand, it is a compound of formula (1-A1a), wherein R... 0 It is H or methyl; R 1 It is methyl; and R 3 R 4 R 5 R 6 R 10 The ring C and n are as defined herein; its stereoisomers and its pharmaceutically acceptable salts. On the other hand, it is a compound of formula (1-A1a), wherein R... 0 It is H or methyl; R 1 It is methyl; R 3 It is H, methyl, ethyl, cyclopropyl, or phenyl; R 4 It is H, methyl, ethyl, propyl, or isopropyl; or cyclopropyl, cyclobutyl, cyclohexyl, phenyl, -C1 phenyl, piperidinyl, -C1 piperidinyl, -C2 piperidinyl, piperazinyl, morpholinyl, tetrahydro-2H-pyran, pyrazolyl, pyrimidinyl, or pyridinyl, each optionally being R selected from the group consisting of at least one of the following. 9 Substituents: methyl, ethyl, hydroxy, methoxy, ethoxy, F, Cl, cyano, -N(CH3)2 and -CF3; R 5 It is H, methyl, ethyl, propyl, or isopropyl; and R 6 It is H, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -CF3, -OCF3, -C(O)NR a R 8 -R c S(O) p R 8 -R c NR a R b -Rc OR a or -S(O) p R 8 ; or phenyl, C1 alkylphenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 1- C2 alkylcyclopropyl and C 1- C2-alkylcyclobutyl, oxazolyl, pyrrolyl, piperidinyl, piperazine, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, C1-C2-alkyloxazolyl, C 1- C2 alkylpyrrolidinyl, C 1- C2 alkylpiperidinyl, C 1- C2alkylpiperazinyl, C1-C2morpholinyl, C1-C2tetrahydropyranyl, C1-C2tetrahydrofuranyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, C 1- C2 alkylpyrazolyl, C 1- C2 alkylimidazolium, C 1- C2 alkylpyridinyl, C 1- C2 alkylpyrimidinyl or C 1- C2 alkylpyrazinyl groups, each optionally composed of at least one R group selected independently from the following 10 Substituents: methyl, ethyl, methoxy, ethoxy, -CHF2, -CF3, -OCF3, F, Cl, -NHCH3, -N(CH3)2, -S(O)2CH3, cyano, and hydroxyl; and wherein R a and R b Each is independently H, methyl, or ethyl; R c It is methyl, ethyl, or propyl; and R 8 It is methyl, ethyl, cyclopropyl, or phenyl; and wherein the cyclopropyl and the phenyl are each optionally substituted by at least one substituent selected from the group consisting of: C1-C4 alkyl, halogen, C1-C4 alkoxy, -CF3, and -OCF3; and the ring C is phenyl, naphthyl, pyridinyl, pyridinyl, pyrazinyl, pyridin-2(1H)-one, quinolinyl, isoquinolinyl, benzofuranyl, benzobenzylthio, indolyl, benzimidazolyl, or indazoleyl, each optionally substituted by at least one R group selected from the group consisting of: 10 Substituents: methyl, ethyl, propyl, methoxy, ethoxy, -CHF2, -CF3, -OCF3, F, Cl, -NHCH3, -N(CH3)2, -S(O)2CH3, nitro, cyano, -C(O)CH3, -NHCH2C(O)CH3, -NHCH2CH2C(O)CH3, -C(O)NHCH3, and hydroxyl; their stereoisomers and their pharmaceutically acceptable salts. On the other hand, there are compounds of formula (1-A1a), wherein R... 0 It is H or methyl, R 1 and R 3Each is a methyl group; R 5 It is H; R 6 It is propyl; R 4 It is H, methyl, ethyl, propyl, or isopropyl; or cyclopropyl, cyclobutyl, cyclohexyl, phenyl, -C1 phenyl, piperidinyl, -C1 piperidinyl, -C2 piperidinyl, piperazinyl, morpholinyl, tetrahydro-2H-pyran, pyrazolyl, pyrimidinyl, or pyridinyl, each optionally being R selected from the group consisting of at least one of the following. 9 Substituents: methyl, ethyl, hydroxy, methoxy, ethoxy, F, Cl, cyano, -N(CH3)2, and -CF3; and the ring C is phenyl, naphthyl, pyridinyl, pyridinyl, pyrazinyl, pyridin-2(1H)-one, quinolinyl, isoquinolinyl, benzofuranyl, benzobenzylthio, indolyl, benzimidazolyl, or indazoleyl, each optionally being replaced by at least one R selected from the group consisting of: 10 Substituents: methyl, ethyl, propyl, methoxy, ethoxy, -CHF2, -CF3, -OCF3, F, Cl, -NHCH3, -N(CH3)2, -S(O)2CH3, nitro, cyano, C(O)CH3, -NHCH2C(O)CH3, -NHCH2CH2C(O)CH3, -C(O)NHCH3, and hydroxyl; their stereoisomers and their pharmaceutically acceptable salts. On the other hand, it is the compound of formula (1-A1a) F, its stereoisomers, and its pharmaceutically acceptable salts. On the other hand, it is the non-antibacterial compound of formula (1-A1a) F, its stereoisomers, and its pharmaceutically acceptable salts.

[0085] In another aspect, there is a composition comprising a compound of formula (1-A1a), its stereoisomer, and a pharmaceutically acceptable salt thereof. In another aspect, there is a composition comprising a compound of formula (1-A1a), its stereoisomer, and a pharmaceutically acceptable salt thereof. In another aspect, there is a composition comprising a non-antimicrobial compound of formula (1-A1a), its stereoisomer, and a pharmaceutically acceptable salt thereof. In another aspect, the composition further comprises a pharmaceutically acceptable carrier.

[0086] In another aspect, there is a method for treating or preventing an inflammatory response in an animal by administering a therapeutically effective amount of a compound of formula (1-A1a), its stereoisomers, and its pharmaceutically acceptable salts to the animal in need. In another aspect, there is a method for treating or preventing an inflammatory response in an animal by administering a therapeutically effective amount of a compound of formula (1-A1a) Table F, its stereoisomers, and its pharmaceutically acceptable salts to the animal in need. In another aspect, there is a method for treating or preventing an inflammatory response in an animal by administering a therapeutically effective amount of a non-antimicrobial compound of formula (1-A1a) Table F, its stereoisomers, and its pharmaceutically acceptable salts to the animal in need. In yet another aspect, there is a method for treating or preventing an inflammatory response in an animal, wherein the inflammatory response is caused by bacterial, viral, or fungal infection, stress, and / or environmental factors. In another aspect of the method, treating or preventing the inflammatory response in the animal prevents or alleviates the progression of respiratory disease or symptom in the animal. In another aspect of the method, the animal is a domestic animal; and the respiratory disease or symptom is a bovine respiratory disease or a swine respiratory disease. In another aspect of the method, TNF-α and IL-6 are downregulated in the animal.

[0087] In another aspect, there is the use of a compound of formula (1-A1a), its stereoisomers, and pharmaceutically acceptable salts thereof for the preparation of a medicament for the treatment or prevention of inflammatory responses in animals. In another aspect, there is the use of a compound of formula (1-A1a), its stereoisomers, and pharmaceutically acceptable salts thereof for the preparation of a medicament for the treatment or prevention of inflammatory responses in animals. In another aspect, there is the use of a non-antibacterial compound of formula (1-A1a), its stereoisomers, and pharmaceutically acceptable salts thereof for the preparation of a medicament for the treatment or prevention of inflammatory responses in animals. In another aspect of the use, the inflammatory response is caused by bacterial, viral, or fungal infection, stress, and / or environmental factors. In another aspect of the use, the use of the medicament for the treatment or prevention of inflammatory responses in the animal prevents or alleviates the progression of a respiratory disease or condition. In another aspect of the use, the animal is a domestic animal. In another aspect of the use, the respiratory disease or condition is bovine respiratory disease or swine respiratory disease. In another aspect of the stated use, the administration of the drug to the animal to treat or prevent an inflammatory response in the animal results in a downregulation of TNF-α and IL-6 in the animal.

[0088] In another aspect of the invention, there is a compound of formula (1-A1a), wherein R 3 and R 4 It connects with the nitrogen atom it shares to form ring A, which is a compound of formula (1-A1b), wherein R 0 R1 R 5 R 6 R 10 Ring A, Ring C and n

[0089]

[0090] As defined herein; its stereoisomers and its pharmaceutically acceptable salts. On another front, it is a compound of formula (1-A1b), wherein R... 0 It is H or methyl; and R 1 R 5 R 6 R 10 Ring A, ring C, and n are as defined herein; their stereoisomers and their pharmaceutically acceptable salts. On another front, there is a compound of formula (1-A1b), wherein R... 0 It is H or methyl; R 1 It is methyl; and R 5 R 6 R 10 Ring A, ring C, and ring n are as defined herein; their stereoisomers and their pharmaceutically acceptable salts. On the other hand, there are compounds of formula (1-A1b), wherein R... 0 It is H or methyl; R 1 It is methyl; R 5 It is H, methyl, ethyl, propyl, or isopropyl; R 6 It is H, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -CF3, -OCF3, -C(O)NR a R 8 -R c S(O) p R 8 -R c NR a R b -R c OR a or -S(O) p R 8 ; or phenyl, C1 alkylphenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 1- C2 alkylcyclopropyl and C 1- C2-alkylcyclobutyl, oxazolyl, pyrrolyl, piperidinyl, piperazine, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, C1-C2-alkyloxazolyl, C 1- C2 alkylpyrrolidinyl, C 1- C2 alkylpiperidinyl, C 1-C2alkylpiperazinyl, C1-C2morpholinyl, C1-C2tetrahydropyranyl, C1-C2tetrahydrofuranyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, C 1- C2 alkylpyrazolyl, C 1- C2 alkylimidazolium, C 1- C2 alkylpyridinyl, C 1- C2 alkylpyrimidinyl or C 1- C2 alkylpyrazinyl groups, each optionally composed of at least one R group selected independently from the following 10 Substituents: methyl, ethyl, methoxy, ethoxy, -CHF2, -CF3, -OCF3, F, Cl, -NHCH3, -N(CH3)2, -S(O)2CH3, cyano, and hydroxyl; and wherein R a and R b Each is independently H, methyl, or ethyl; R c It is methyl, ethyl, or propyl; and R 8 It is methyl, ethyl, cyclopropyl, or phenyl; and wherein said cyclopropyl and said phenyl are each optionally substituted by at least one substituent selected from the following: C1-C4 alkyl, halogen, C1-C4 alkoxy, -CF3, and -OCF; ring A is pyrroloyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally substituted by at least one R selected from the following 10 Substituents: methyl, ethyl, F, Cl, oxy, and -CF3; or ring A is tetrahydroquinolinyl, dihydrobenzoxazinyl, or dihydrobenzothiazinyl, optionally substituted with at least one oxy group; and ring C is phenyl, naphthyl, pyridinyl, pyridinyl, pyrazinyl, pyridinyl-2(1H)-one, quinolinyl, isoquinolinyl, benzofuranyl, benzobenzylthio, indolyl, benzimidazolyl, or indazoleyl, each optionally substituted with at least one R group selected from the group consisting of... 10 Substituents: methyl, ethyl, propyl, methoxy, ethoxy, -CHF2, -CF3, -OCF3, F, Cl, -NHCH3, -N(CH3)2, -S(O)2CH3, nitro, cyano, -C(O)CH3, -NHCH2C(O)CH3, -NHCH2CH2C(O)CH3, -C(O)NHCH3, and hydroxyl; their stereoisomers and their pharmaceutically acceptable salts. On the other hand, there is a compound of formula (1-A1b), wherein R... 0 It is H or methyl; R 1 It is methyl; R 5 It is H; R 6 It is propyl; ring A is piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally surrounded by at least one R selected from the following 10Substituents: methyl, ethyl, F, Cl, oxy, and -CF3; and the ring C is phenyl, naphthyl, pyridinyl, pyrazinyl, pyridinyl, pyridin-2(1H)-one, quinolinyl, isoquinolinyl, benzofuranyl, benzobenzylthio, indolyl, benzimidazolyl, or indazoleyl, each optionally being replaced by at least one R selected from the group consisting of: 10 Substituents: methyl, ethyl, propyl, methoxy, ethoxy, -CHF2, -CF3, -OCF3, F, Cl, -NHCH3, -N(CH3)2, -S(O)2CH3, nitro, cyano, -C(O)CH3, -NHCH2C(O)CH3, -NHCH2CH2C(O)CH3, -C(O)NHCH3, and hydroxyl; their stereoisomers and their pharmaceutically acceptable salts. On the other hand, it is a compound of formula (1-A1b) G, its stereoisomers, and its pharmaceutically acceptable salts. On the other hand, it is a non-antibacterial compound of formula (1-A1b) G, its stereoisomers, and its pharmaceutically acceptable salts.

[0091] In another aspect, there is a composition comprising a compound of formula (1-A1b), its stereoisomer, and a pharmaceutically acceptable salt thereof. In another aspect, there is a composition comprising a compound of formula (1-A1b) EpiG, its stereoisomer, and a pharmaceutically acceptable salt thereof. In another aspect, there is a composition comprising a non-antimicrobial compound of formula (1-A1b) EpiG, its stereoisomer, and a pharmaceutically acceptable salt thereof. In another aspect, the composition further comprises a pharmaceutically acceptable carrier.

[0092] In another aspect, there is a method for treating or preventing an inflammatory response in an animal by administering a therapeutically effective amount of a compound of formula (1-A1b), its stereoisomers, and its pharmaceutically acceptable salts to the animal in need. In another aspect, there is a method for treating or preventing an inflammatory response in an animal by administering a therapeutically effective amount of a compound of formula (1-A1b) Table G, its stereoisomers, and its pharmaceutically acceptable salts to the animal in need. In another aspect, there is a method for treating or preventing an inflammatory response in an animal by administering a therapeutically effective amount of a non-antimicrobial compound of formula (1-A1b) Table G, its stereoisomers, and its pharmaceutically acceptable salts to the animal in need. In yet another aspect, there is a method for treating or preventing an inflammatory response in an animal, wherein the inflammatory response is caused by bacterial, viral, or fungal infection, stress, and / or environmental factors. In another aspect of the method, treating or preventing the inflammatory response in the animal prevents or alleviates the progression of respiratory disease or symptom in the animal. In another aspect of the method, the animal is a domestic animal; and the respiratory disease or symptom is a bovine respiratory disease or a swine respiratory disease. In another aspect of the method, TNF-α and IL-6 are downregulated in the animal.

[0093] In another aspect, there is the use of a compound of formula (1-A1b), its stereoisomers, and pharmaceutically acceptable salts thereof for the preparation of a medicament for the treatment or prevention of inflammatory responses in animals. In another aspect, there is the use of a compound of formula (1-A1b) Table G, its stereoisomers, and pharmaceutically acceptable salts thereof for the preparation of a medicament for the treatment or prevention of inflammatory responses in animals. In another aspect, there is the use of a non-antibacterial compound of formula (1-A1b) Table G, its stereoisomers, and pharmaceutically acceptable salts thereof for the preparation of a medicament for the treatment or prevention of inflammatory responses in animals. In another aspect of the use, the inflammatory response is caused by bacterial, viral, or fungal infection, stress, and / or environmental factors. In another aspect of the use, the use of the medicament for the treatment or prevention of inflammatory responses in the animal prevents or alleviates the progression of a respiratory disease or condition. In another aspect of the use, the animal is a domestic animal. In another aspect of the use, the respiratory disease or condition is bovine respiratory disease or swine respiratory disease. In another aspect of the stated use, the administration of the drug to the animal to treat or prevent an inflammatory response in the animal results in a downregulation of TNF-α and IL-6 in the animal.

[0094] In another aspect of the invention, there is a compound of formula (1-A1), wherein R 5 and R 6 It connects with the nitrogen atom it shares to form ring B, which is a compound of formula (1-A1c), wherein R 0 R1 R 2 R 9 R 10 Ring B, Ring C and n

[0095]

[0096] As defined herein; its stereoisomers and its pharmaceutically acceptable salts. On another front, it is a compound of formula (1-A1c), wherein R... 0 It is H or methyl; and R 1 R 2 R 9 R 10 Rings B, C, and n are as defined herein; their stereoisomers and their pharmaceutically acceptable salts. On another front, there are compounds of formula (1-A1c), wherein R... 0 and R 2 Each is independently either H or methyl; R 1 It is methyl; and ring B is pyrrole, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally being composed of at least one R selected from the group consisting of... 9 Substituents: methyl, ethyl, F, Cl, cyano, hydroxy, oxy, and -CF3; or ring B is tetrahydroquinolinyl, dihydrobenzoxazinyl, or dihydrobenzothiazinyl, optionally substituted with at least one oxy group; and ring C is phenyl, naphthyl, pyridinyl, pyridinyl, pyrazinyl, pyridinyl-2(1H)-one, quinolinyl, isoquinolinyl, benzofuranyl, benzobenzylthio, indolyl, benzimidazolyl, or indazoleyl, each optionally substituted with at least one R group selected from the group consisting of: 10 Substituents: methyl, ethyl, propyl, methoxy, ethoxy, -CHF2, -CF3, -OCF3, F, Cl, -NHCH3, -N(CH3)2, -S(O)2CH3, nitro, cyano, -C(O)CH3, -NHCH2C(O)CH3, -NHCH2CH2C(O)CH3, -C(O)NHCH3, and hydroxyl; their stereoisomers and their pharmaceutically acceptable salts. In another aspect, there are compounds of formula (1-A1c), wherein R... 0 R2 and R2 are each independently H or methyl; R 1 It is methyl; ring B is piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally separated by at least one R selected from the following 9 Substituents: methyl, ethyl, F, Cl, cyano, hydroxy, oxy, and -CF3; and the ring C is optionally replaced by at least one R selected from the following 10Substituent-substituted phenyl groups: methyl, ethyl, propyl, methoxy, ethoxy, -CHF2, -CF3, -OCF3, F, Cl, -NHCH3, -N(CH3)2, -S(O)2CH3, nitro, cyano, -C(O)CH3, -NHCH2C(O)CH3, -NHCH2CH2C(O)CH3, -C(O)NHCH3, and hydroxyl; their stereoisomers and their pharmaceutically acceptable salts. On the other hand, it includes compounds of formula (1-A1c) represented by H, their stereoisomers, and their pharmaceutically acceptable salts.

[0097] In another aspect, there is a composition comprising a compound of formula (1-A1c), its stereoisomers, and a pharmaceutically acceptable salt thereof. In yet another aspect, there is a composition comprising a compound of formula (1-A1c), its stereoisomers, and a pharmaceutically acceptable salt thereof. In yet another aspect, the composition further comprises a pharmaceutically acceptable carrier.

[0098] In another aspect, it is a method for treating or preventing an inflammatory response in an animal by administering a therapeutically effective amount of a compound of formula (1-A1c), its stereoisomers, and its pharmaceutically acceptable salts to the animal in need. In another aspect, it is a method for treating or preventing an inflammatory response in an animal by administering a therapeutically effective amount of a compound of formula (1-A1c), its stereoisomers, and its pharmaceutically acceptable salts to the animal in need. In another aspect, it is a method for treating or preventing an inflammatory response in an animal, wherein the inflammatory response is caused by bacterial, viral, or fungal infection, stress, and / or environmental factors. In another aspect of the method, treating or preventing the inflammatory response in the animal prevents or alleviates the progression of a respiratory disease or condition in the animal. In another aspect of the method, the animal is a domestic animal; and wherein the respiratory disease or condition is a bovine respiratory disease or a swine respiratory disease. In another aspect of the method, TNF-α and IL-6 are downregulated in the animal.

[0099] In another aspect, there is the use of a compound of formula (1-A1c), its stereoisomers, and pharmaceutically acceptable salts thereof for the preparation of a medicament for the treatment or prevention of inflammatory responses in animals. In another aspect, there is the use of a compound of formula (1-A1c), its stereoisomers, and pharmaceutically acceptable salts thereof for the preparation of a medicament for the treatment or prevention of inflammatory responses in animals. In another aspect of the use, the inflammatory response is caused by bacterial, viral, or fungal infection, stress, and / or environmental factors. In another aspect of the use, the use of the medicament for the treatment or prevention of inflammatory responses in the animals prevents or alleviates the progression of respiratory diseases or conditions. In another aspect of the use, the animal is a domestic animal. In another aspect of the use, the respiratory disease or condition is bovine respiratory disease or swine respiratory disease. In another aspect of the use, the use of the medicament administered to the animal to treat or prevent an inflammatory response in the animal results in the downregulation of TNF-α and IL-6 in the animal.

[0100] In another aspect of the invention, there is a compound of formula (1), wherein W is of formula (A) and formula (A) is of formula (A2), and the compound of formula (1) is a compound of formula (1-A2).

[0101]

[0102] Where R 0 R 1 R 2 R 7 R 10 The ring C and n are as defined herein; its stereoisomers and its pharmaceutically acceptable salts. On another front, there is a compound of formula (1-A2), wherein R... 0 It is H, methyl, ethyl, or propyl; and R 1 R 2 R 7 R 10 The ring C and n are as defined herein; its stereoisomers and its pharmaceutically acceptable salts. On another front, there is a compound of formula (1-A2), wherein R... 0 It is H or methyl; and R 1 R 2 R 7 R 10 , ring C and n as defined herein; its stereoisomers and its pharmaceutically acceptable salts.

[0103] In another aspect of the invention, there is a compound of formula (1), wherein W is of formula (A) and formula (A) is of formula (A3), and the compound of formula (1) is a compound of formula (1-A3).

[0104]

[0105] Where R 0 R 1 R 2 R 7 R 10 The ring C and n are as defined herein; its stereoisomers and its pharmaceutically acceptable salts. On another front, there are compounds of formula (1-A3), wherein R... 0 It is H, methyl, ethyl, or propyl; and R 1 R 2 R 7 R 10 The ring C and n are as defined herein; its stereoisomers and its pharmaceutically acceptable salts. On another front, there are compounds of formula (1-A3), wherein R... 0 It is H or methyl; and R 1 R 2 R 7 R 10 , ring C and n as defined herein; its stereoisomers and its pharmaceutically acceptable salts.

[0106] In another aspect of the invention, there is a compound of formula (1), wherein W is of formula (A) and formula (A) is of formula (A4), and the compound of formula (1) is a compound of formula (1-A4).

[0107]

[0108] Where R 0 R 1 R 2 R 10 X', ring C, and n are as defined herein; their stereoisomers and their pharmaceutically acceptable salts. On another front, there is a compound of formula (1-A4), wherein R... 0 It is H, methyl, ethyl, or propyl; and R 1 R 2 R 10 X', ring C, and n are as defined herein; their stereoisomers and their pharmaceutically acceptable salts. On another front, there is a compound of formula (1-A4), wherein R... 0 It is H or methyl; and R 1 R 2 R 10 X', ring C and n are as defined herein; their stereoisomers and their pharmaceutically acceptable salts.

[0109] In another aspect of the invention, there is a compound of formula (1), wherein W is of formula (A) and formula (A) is of formula (A5), and the compound of formula (1) is a compound of formula (1-A5).

[0110]

[0111] Where R 0 R 1 R 2 R 10 The ring C and n are as defined herein; its stereoisomers and its pharmaceutically acceptable salts. On another front, there are compounds of formula (1-A5), wherein R... 0 It is H, methyl, ethyl, or propyl; and R 1 R 2 R 10 The ring C and n are as defined herein; its stereoisomers and its pharmaceutically acceptable salts. On another front, there are compounds of formula (1-A5), wherein R... 0 It is H or methyl; and R 1 R 2 R 10 , ring C and n as defined herein; its stereoisomers and its pharmaceutically acceptable salts.

[0112] In another aspect of the invention, there is a compound of formula (1), wherein W is of formula (A) and formula (A) is of formula (A6), and the compound of formula (1) is a compound of formula (1-A6).

[0113]

[0114] Where R 0 R 1 R 2 R 10 The ring C and n are as defined herein; its stereoisomers and its pharmaceutically acceptable salts. On another front, there are compounds of formula (1-A6), wherein R... 0 It is H, methyl, ethyl, or propyl; and R 1 R 2 R 10 The ring C and n are as defined herein; its stereoisomers and its pharmaceutically acceptable salts. On another front, there are compounds of formula (1-A6), wherein R... 0 It is H or methyl; and R 1 R 2 R 10 The ring C and n are as defined herein; its stereoisomers and its pharmaceutically acceptable salts. On the other hand, it is a compound of formula (1-A2), formula (1-A3), formula (1-A4), formula (1-A5), or formula (1-A6), wherein R... 0 It is H or methyl; R 1 It is methyl; R 2And the ring C is as defined in this paper; and for equations (1-A2) and (1-A3), R 7 As defined herein; and for formula (1-A4), X' is as defined herein; its stereoisomers and its pharmaceutically acceptable salts. On the other hand, it is a compound of formula (1-A2), formula (1-A3), formula (1-A4), formula (1-A5), or formula (1-A6), wherein R... 0 It is H or methyl; R 1 It is methyl; R 2 It is H, methyl or -C(O)NR 3 R 4 ; and ring C is as defined in this paper; and for equations (1-A2) and (1-A3), R 7 As defined herein; and for formula (1-A4), X' is as defined herein; its stereoisomers and its pharmaceutically acceptable salts. On the other hand, it is a compound of formula (1-A2), formula (1-A3), formula (1-A4), formula (1-A5), or formula (1-A6), wherein R... 0 It is H or methyl; R 1 It is methyl; R 2 It is H, methyl or -C(O)NR 3 R 4 ;where R 3 It is H, methyl, ethyl, cyclopropyl, or phenyl; R 4 It is H, methyl, ethyl, propyl, or isopropyl; or cyclopropyl, cyclobutyl, cyclohexyl, phenyl, -C1 phenyl, piperidinyl, -C1 piperidinyl, -C2 piperidinyl, piperazinyl, morpholinyl, tetrahydro-2H-pyran, pyrazolyl, pyrimidinyl, or pyridinyl, each optionally being R selected from the group consisting of at least one of the following. 9 Substituents: methyl, ethyl, hydroxy, methoxy, ethoxy, F, Cl, cyano, -N(CH3)2, and -CF3; ring C is phenyl, naphthyl, pyridinyl, pyridinyl, pyrazinyl, pyridin-2(1H)-one, quinolinyl, isoquinolinyl, benzofuranyl, benzobenzylthio, indoleyl, benzimidazolyl, or indazoleyl, each optionally being replaced by at least one R selected from the group consisting of: 10 Substituents: methyl, ethyl, propyl, methoxy, ethoxy, -CHF2, -CF3, -OCF3, F, Cl, -NHCH3, -N(CH3)2, -S(O)2CH3, nitro, cyano, -C(O)CH3, -NHCH2C(O)CH3, -NHCH2CH2C(O)CH3, -C(O)NHCH3 and hydroxyl; and for formulas (1-A2) and (1-A3), R 7It is H, methyl, ethyl, propyl, isopropyl, or CH2N(CH3)2; and for formula (1-A4), X' is F or Cl; its stereoisomers and its pharmaceutically acceptable salts. On the other hand, it is a compound of formula (1-A2), formula (1-A3), formula (1-A4), formula (1-A5), or formula (1-A6), wherein R... 0 It is H or methyl; R 1 It is methyl; R 2 It is H or methyl; the ring C is phenyl, naphthyl, pyridinyl, pyridinyl, pyrazinyl, pyridin-2(1H)-one, quinolinyl, isoquinolinyl, benzofuranyl, benzobenzylthio, indolyl, benzimidazolyl or indazole, each optionally being composed of at least one R selected from the following 10 Substituents: methyl, ethyl, propyl, methoxy, ethoxy, -CHF2, -CF3, -OCF3, F, Cl, -NHCH3, -N(CH3)2, -S(O)2CH3, nitro, cyano, -C(O)CH3, -NHCH2C(O)CH3, -NHCH2CH2C(O)CH3, -C(O)NHCH3 and hydroxyl; and for formulas (1-A2) and (1-A3), R 7 It is H, methyl, ethyl, propyl, isopropyl, or -CH2N(CH3)2; and for formula (1-A4), X' is F or Cl; its stereoisomers and its pharmaceutically acceptable salts.

[0115] In another aspect, there is a composition comprising a compound of formula (1-A2), its stereoisomer, and a pharmaceutically acceptable salt thereof. In another aspect, there is a composition comprising a compound of formula (1-A3), its stereoisomer, and a pharmaceutically acceptable salt thereof. In another aspect, there is a composition comprising a compound of formula (1-A4), its stereoisomer, and a pharmaceutically acceptable salt thereof. In another aspect, there is a composition comprising a compound of formula (1-A5), its stereoisomer, and a pharmaceutically acceptable salt thereof. In another aspect, there is a composition comprising a compound of formula (1-A6), its stereoisomer, and a pharmaceutically acceptable salt thereof. In yet another aspect, the composition further comprises a pharmaceutically acceptable carrier.

[0116] In another aspect, there is a method for treating or preventing an inflammatory response in an animal by administering a therapeutic amount of a compound of formula (1-A2), its stereoisomers, and a pharmaceutically acceptable salt thereof. In another aspect, there is a method for treating or preventing an inflammatory response in an animal by administering a therapeutic amount of a compound of formula (1-A3), its stereoisomers, and a pharmaceutically acceptable salt thereof. In another aspect, there is a method for treating or preventing an inflammatory response in an animal by administering a therapeutic amount of a compound of formula (1-A4), its stereoisomers, and a pharmaceutically acceptable salt thereof. In another aspect, there is a method for treating or preventing an inflammatory response in an animal by administering a therapeutic amount of a compound of formula (1-A5), its stereoisomers, and a pharmaceutically acceptable salt thereof. In another aspect, there is a method for treating or preventing an inflammatory response in an animal by administering a therapeutic amount of a compound of formula (1-A6), its stereoisomers, and a pharmaceutically acceptable salt thereof. In another aspect, there is a method for treating or preventing an inflammatory response in an animal, wherein the inflammatory response is caused by bacterial, viral, or fungal infection, stress, and / or environmental factors. In another aspect of the method, treating or preventing the inflammatory response in the animal prevents or mitigates the progression of a respiratory disease or condition in the animal. In another aspect of the method, the animal is a domestic animal; and wherein the respiratory disease or condition is bovine respiratory disease or swine respiratory disease. In another aspect of the method, TNF-α and IL-6 are downregulated in the animal.

[0117] In another aspect, there is the use of a compound of formula (1-A2), its stereoisomers, and its pharmaceutically acceptable salts for the preparation of a medicament for the treatment or prevention of inflammatory responses in animals. In another aspect, there is the use of a compound of formula (1-A3), its stereoisomers, and its pharmaceutically acceptable salts for the preparation of a medicament for the treatment or prevention of inflammatory responses in animals. In another aspect, there is the use of a compound of formula (1-A4), its stereoisomers, and its pharmaceutically acceptable salts for the preparation of a medicament for the treatment or prevention of inflammatory responses in animals. In another aspect, there is the use of a compound of formula (1-A5), its stereoisomers, and its pharmaceutically acceptable salts for the preparation of a medicament for the treatment or prevention of inflammatory responses in animals. In another aspect, there is the use of a compound of formula (1-A6), its stereoisomers, and its pharmaceutically acceptable salts for the preparation of a medicament for the treatment or prevention of inflammatory responses in animals. In another aspect of the said uses, the inflammatory response is caused by bacterial, viral, or fungal infection, stress, and / or environmental factors. In another aspect of the stated use, the use of the drug for treating or preventing an inflammatory response in the animal prevents or alleviates the progression of a respiratory disease or condition. In another aspect of the stated use, the animal is a domestic animal. In another aspect of the stated use, the respiratory disease or condition is a bovine respiratory disease or a swine respiratory disease. In another aspect of the stated use, the administration of the drug to the animal to treat or prevent an inflammatory response in the animal results in a downregulation of TNF-α and IL-6 in the animal.

[0118] On the other hand, it is a compound of formula (1) that is a non-antimicrobial compound of Table A of formula (1-A0), the compound being selected from the group consisting of: examples A-6, A-9, A-11, A-12, A-18, A-19, A-21, A-23 to A-33, A-35, A36, A-37, A-39, A-40, A-41, A-45 and A-47; or a non-antimicrobial compound of Table B of formula (1.1), the compound being selected from the group consisting of examples B-1 to B-13; or a non-antimicrobial compound of Table C of formula (1.1a), the compound being selected from examples C-1 to C-11, C-12, C-14. The group consisting of C34 and C-36 to C-54; or compounds of non-antimicrobial formula (1.1b) D, selected from the group consisting of D-1 to D-4; or compounds of non-antimicrobial formula (1-A1) E, selected from the group consisting of: Examples E-3, E-4, E6, E8, E-10, E-11, E-12, E-13, E-15, E-19, E24 to E-28; E-30, E-31, E-34, E-37 to E-43; E-45 to E-52; E-57, E-60, E-62, E-63, E-64, E-68, E-69, E-71, E -72, E-75, E-76, E-78, E-79, E-81, E-84, E-86, E-87, E-89, E-91 to E-94; E-98 to E-100; E-102, E-108, E-109, E-111 to E-117; E-120, E-121, E-124 to E-132; E-135, E-136, E-138, E-139 and E-141 to E-144; E-156 and E157; or non-antimicrobial compounds of formula (1-A1a) listed in Table F, said compounds being selected from F-1 to F-9, F-12 to F-19, F-2 2. The group consisting of F-23 and F-25 to F-32; or a non-antimicrobial compound of formula (1-A1b) G, wherein the compound is example B-3; or a non-antimicrobial compound of formula (1-A1c) H, wherein the compound is selected from the group consisting of examples H-1 to H-4 and H-6; its stereoisomers and pharmaceutically acceptable salts thereof; a composition comprising one of these non-antimicrobial compounds; a method of using one of these non-antimicrobial compounds to treat or prevent an inflammatory response in an animal; or use of one of these non-antimicrobial compounds in the preparation of a medicament for treating or preventing an inflammatory response in an animal.

[0119] discuss Attached Figure Description

[0120] Figure 1 Mechanisms of immunomodulators in the context of BRD progression

[0121] Figure 2 Summary of clinical and genomic time data

[0122] Figure 3 Plasma cytokine (IL-6, IL-8, IL-10, and IFN-γ) levels in calves at risk of BRD arriving at the farm

[0123] Figure 4 : Biomarker assessment for M9 intratracheal lung provocation; Results of IL-6 (4A) and CD163 biomarkers (4B)

[0124] It should be understood that the present invention is not limited to the specific methods, schemes, and reagents defined herein, and therefore can be varied. The terminology used herein is for the purpose of describing embodiments only and is not intended to limit the scope of the invention, which is defined only by the claims.

[0125] Unless otherwise defined, the scientific and technical terms used with respect to the compounds of the invention as defined herein shall have the meanings commonly understood by one of ordinary skill in the art. Furthermore, unless the context otherwise requires, singular terms shall include plural terms and plural terms shall include singular terms. Generally, the nomenclature and techniques used in conjunction with the chemical synthesis, macrolides, and immunomodulation as defined herein are well known and commonly used in the art.

[0126] definition

[0127] For the purposes of this invention, as described and claimed herein, the following terms and phrases are defined as follows:

[0128] As used herein, unless otherwise stated, "another agent" means, as defined herein, another pharmaceutical compound or product that provides a therapeutically effective amount of the agent for treating bacterial infections and / or modulating immune responses in animals.

[0129] As used herein, unless otherwise stated, "alkoxy" refers to the oxygen moiety having an additional alkyl substituent. The alkyl moiety of the alkoxy group (i.e., the alkyl portion) is defined in the same way as defined below. Non-limiting examples include: -OCH3, -OCH2CH3, -OCH(CH3)2, etc.

[0130] As used herein, unless otherwise stated, "alkyl" refers to the general formula C n H 2n+1A saturated monovalent hydrocarbon alkane radical. Alkane radicals can be straight-chain or branched, and can be unsubstituted or substituted. For example, the term "(C1-C6)alkyl" refers to a monovalent, straight-chain or branched aliphatic group containing 1 to 6 carbon atoms; similarly, C1-C3 alkyl refers to a monovalent, straight-chain or branched aliphatic group containing 1 to 3 carbon atoms, and so on. Non-exclusive examples of (C1-C6)alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, sec-butyl, tert-butyl, n-propyl, n-butyl, isobutyl, sec-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, 3,3-dimethylpropyl, 2-methylpentyl, hexyl, and so on. The alkyl moiety can be attached to the chemical moiety by any carbon atom of the aliphatic chain. Alkyl groups are optionally substituted as defined herein. Furthermore, when used in compound words such as alkylphenyl, the alkyl moiety has the same meaning as defined herein and can be linked to the chemical moiety via any carbon atom of the aliphatic chain. Non-limiting examples of compound words C0-C4 alkylphenyl include: C0 phenyl (phenyl), C1 alkylphenyl (-CH2 phenyl, benzyl), C2 alkylphenyl (-CH2CH2 phenyl), etc.

[0131] As used herein, unless otherwise stated, "animal" means a single animal as a mammal. Specifically, mammals refer to human and non-human vertebrates that are taxonomically members of the 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 (domestic cattle and bison). Cattle are preferred livestock.

[0132] As used herein, unless otherwise stated, "antimicrobial" means a compound with a minimum inhibitory concentration (MIC) ≤ 64 μg / mL against BRD pathogens, namely *M. haemolytica* and *P. multocida*. As used herein, unless otherwise stated, "non-antimicrobial" means a compound with an MIC > 64 μg / mL against BRD pathogens, namely *M. haemolytica* and *P. multocida*.

[0133] As used herein, unless otherwise stated, “aryl” refers to a 6-carbon unsaturated aromatic monocyclic ring or a 10- to 14-carbon unsaturated aromatic polycyclic ring. Examples of such aryl rings include, but are not limited to, phenyl, naphthalenyl, or anthracene. Further, when used in compound terms such as alkylaryl (e.g., alkylphenyl), the alkyl and aryl moieties have the same meaning as defined herein and can be attached to the chemical moieties by any carbon atom of an aliphatic chain or a ring carbon. Examples of C0-C3 alkylphenyls include, for example: C0 alkylphenyl is phenyl; C1-alkylphenyl is -CH2phenyl (benzyl); and C2-alkylphenyl is -CH2CH2phenyl. The phenyl ring may optionally be substituted as defined herein.

[0134] As used herein, unless otherwise stated, "nitrogen-containing lactones" refers to a class of macrolides containing a nitrogen atom in their ring, which imparts different pharmacokinetic properties and is associated with greater molecular stability.

[0135] As used herein, unless otherwise stated, “chirality” refers to the structural property of a molecule that prevents it from being superimposed on its mirror image (e.g., “R” and “S” enantiomers).

[0136] As used herein, unless otherwise stated, "composition" means a compound of the present invention formulated with at least one pharmaceutically acceptable carrier for administration.

[0137] As used herein, unless otherwise stated, “Compounds of the present invention” includes compounds of formulas (1), (1A), (1.1), (1.1a), (1.1b), (1-A0), (1-A0a), (1-A1), (1-A1a), (1-A1b), (1-A1c), (1-A2), (1-A3), (1-A4), (1-A5), and (1-A6), their stereoisomers, and their pharmaceutically acceptable salts. The term also includes corresponding 13-membered macrolides in equilibrium with 15-membered macrolides. The term “O-Het / aryl” refers to both the O-Het (i.e., O-heteryl) and O-aryl moiety of formula (1); it is further defined as -ORf in the scheme (spatial context) and -O-cyclic C in the claims and specification, wherein the cyclic C can be (R 10 ) n replace.

[0138] As used herein, unless otherwise stated, "cycloalkyl" includes a fully or partially saturated carbocycloalkyl moiety, i.e., a 3- to 6-membered ring containing only carbon atoms, and can be part of a monocyclic or fused ring or a bridged ring moiety. Examples of saturated carbocyclocycles (cycloalkyl) include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Non-limiting examples of partially saturated cycloalkyl include cyclopropylene, cyclobutene, etc. Preferably, cycloalkyl is a 3- to 6-membered saturated monocyclic ring comprising cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The cycloalkyl group can be attached to the chemical moiety by any carbon atom within the carbocyclocycle. The cycloalkyl group is optionally substituted with at least one substituent. Further, when used in compound terms such as alkylcycloalkyl, the alkyl and cycloalkyl moiety have the same meaning as defined herein and can be attached to the chemical moiety by any carbon atom of the aliphatic chain. Examples of C0-C4 alkyl-C3-C6 cycloalkyl groups include, for example: C0 alkyl-C3-C6 cycloalkyl groups are C3-C6 cycloalkyl groups (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl); C1-alkyl-C3-C6 cycloalkyl groups are -CH2C3-C6 cycloalkyl groups (e.g., -CH2-cyclopropyl, -CH2-cyclohexyl, etc.); C2-alkyl-C3-C6 cycloalkyl groups are -CH2CH2C3-C6 cycloalkyl groups (e.g., -CH2CH2-cyclopropyl, -CH2CH2-cyclopentyl, etc.). The cycloalkyl moiety is optionally substituted as defined herein.

[0139] As used herein, unless otherwise stated, “cytokine” refers to a general category of biomolecules that act on / affect all types of cells and influence immune responses and non-immune biological processes. This definition is intended to include, but is not limited to, biomolecules that act locally or systemically, and biomolecules used to regulate or modulate immune responses in animals when used in the compositions or methods of the present invention. Exemplary cytokines used in practicing the present invention include, but are not limited to, interleukins (e.g., IL-1 to IL-29, specifically IL-1, IL-1β, IL-6, IL-9, IL-10, and IL-12), chemokines (e.g., CCL2-5, CCL10, CCL11, CXCL8 (IL-8), and CXCL10), tumor necrosis factors (e.g., TNF-α and TNF-β), and specifically, NFK-B, which mediates the induction of pro-inflammatory cytokines such as TNF-α, IL-1, and IL-6 in monocytes and macrophages.

[0140] As used herein, unless otherwise stated, “halogen” or “halogen group” means fluorine, chlorine, bromine, and iodine. Further, when used in compound terms such as “haloalkyl,” “haloalkoxy,” or “haloalkenyl,” the alkyl, alkoxy, and alkenyl groups may be partially or wholly substituted with the same or different halogen atoms, and the alkyl, alkoxy, and alkenyl groups have the same meaning as described above and can be linked to the chemical moiety via any carbon atom of the aliphatic chain. Examples of “haloalkyl” include F3C-, ClCH2-, CF3CH2-, and CF3CCI2-, etc. The term “haloalkoxy” is defined similarly to the term “haloalkyl.” Examples of “haloalkoxy” include CF3O-, CCl3CH2O-, HCF2CH2CH2O-, and CF3CH2O-, etc. The term “haloalkenyl” is defined similarly to the term “haloalkyl,” except that the aliphatic chain contains at least one carbon-carbon double bond. Examples of “haloalkenyl” include CF3C=C-, CCl3C=C-, HCF2C=C-, and CF3C=CC-, etc.

[0141] As used herein, unless otherwise stated, “heteroaryl” or “Het” refers to a 5- or 6-membered aromatic monocyclic ring or an 8- or 10-membered fused aromatic ring, wherein the monocyclic portion and the fused ring portion each contain one or more heteroatoms, preferably one to four heteroatoms, each independently selected from N, O, and S. Non-exclusive examples of monocyclic heteroaryl groups include pyrroleyl, furanyl, phenylthio, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, thiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridinyl, pyrazinyl, etc. Non-exclusive examples of fused heteroaryl groups include benzofuranyl, benzophenylthio, indolyl, benzimidazolyl, inazolyl, benzotriazolyl, thieno[2,3-c]pyridine, thieno[3,2-b]pyridine, benzo[1,2,5]thiadiazole, etc. A heteroaryl group can be attached to the chemical moiety by any one of the carbon or nitrogen heteroatoms within a monocyclic or fused ring. Further, when used in compound terms such as alkyl heteroaryl (e.g., C0-C4 alkyl heteroaryl), the alkyl moiety and the heteroaryl moiety have the same meaning as defined herein and can be attached to the chemical moiety by any one of the carbon atoms of the aliphatic chain. For example, a C0 alkyl heterocycle is a heterocycle (e.g., pyrazolyl, imidazolyl, pyridinyl, piperazine, etc.), a C1 alkyl heteroaryl is a -CH2 heteroaryl (e.g., -CH2imidazolyl, -CH2pyridinyl, etc.), a C2 alkyl heteroaryl is a -CH2CH2 heteroaryl (e.g., -CH2CH2pyrazolyl, -CH2CH2oxazolyl, -CH2CH2pyrimidinyl, etc.), and so on. The heteroaryl group may optionally be substituted as defined herein.

[0142] As used herein, unless otherwise stated, "heterocycle" refers to a partially saturated or saturated 3- to 10-membered monocyclic, fused, or bridging ring structure containing one or more heteroatoms, preferably one to four heteroatoms, each independently selected from N, O, and S. Non-exclusive examples of heterocycles include ethylene oxide, thiaranyl, aziridinyl, oxadienoyl, aziridinyl, thiatanyl, tetrahydrofuranyl, pyranyl, pyrazolyl, oxazolyl, tetrahydrophenylthio, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxathianyl, tetrahydropyridinyl, 2H-azirinyl, 2,3-dihydro-azetyl, 3,4-dihydro-2H-pyrrolidinyl, and so on. Heterocyclic groups can be attached to the chemical moiety via any one of the carbon or nitrogen atoms within the ring. Further, when used in compound terms such as alkyl heterocycles (e.g., C0-C4 alkyl heterocycles), the alkyl moiety and the heterocyclic moiety have the same meaning as defined herein and can be attached to the chemical moiety via any one of the carbon atoms of the aliphatic chain. For example, a C0 heterocycle is a heterocycle (e.g., piperidinyl, morpholinyl, aza-butyl, etc.), a C1 alkyl heterocycle is a -CH2 heterocycle (e.g., -CH2morpholinyl, etc.), a C2 alkyl heterocycle is a -CH2CH2 heterocycle (e.g., CH2CH2pyrrolidinyl, -CH2CH2thiomorpholinyl, etc.), and so on. Heterocycles may optionally be substituted as defined herein.

[0143] As used herein, unless otherwise stated, "macrolides" refers to compounds characterized by containing a macrolide ring of 12 to 16 carbon atoms linked by a glycosidic bond, i.e., one or more deoxy sugars; and includes nitrogen-ringed lactones.

[0144] The phrase “optionally substituted” is used interchangeably with the phrase “substituted” or “unsubstituted” herein. Unless otherwise stated, an optionally substituted group may have a substituent at each substituted position of the group, and each substitution is independent of the others. An optionally substituted group may also be unsubstituted. Therefore, the phrase “optionally substituted by at least one substituent” means that the number of substituents can vary from zero to multiple substituted positions. In R 9 and R 10 In the case of at least one optional substitution, the number of substitutions can vary from zero to three (n), which also depends on the number of positions available for substitution.

[0145] As used herein, unless otherwise stated, a "pharmaceutically acceptable" indicator substance or composition must be chemically and / or toxicologically compatible with the formulation, other components of the composition, and / or the animal to be treated. The terms "pharmaceutical" or "pharmaceutical" have the same meaning as listed as "veterinary" or "veterinary".

[0146] As used herein, unless otherwise stated, "saturated" or "partially saturated" means a cycloalkyl ring having 3-6 carbon atoms and a heterocycle having 2-5 carbon atoms and at least one heteroatom selected from N, O, and S; and each saturated ring contains a single bond between adjacent carbon atoms or carbon heteroatoms; for example: cyclobutane, cyclopentane, cyclohexane, ethylene oxide, oxacyclobutane, tetrahydrofuran, piperidine, etc. A partially saturated ring contains at least one double bond between adjacent carbon atoms or carbon heteroatoms; for example: cyclobutene, cyclopentene, cyclohexyl-1,3-diene, 2,3-dihydroazacyclobutadiene, 2,5-dihydrofuran, 2H-thiopyran, etc.

[0147] As used herein, unless otherwise stated, "stereoisomer" refers to a compound of the present invention having more than one asymmetric carbon atom. In the general formulas depicted herein, solid wedge-shaped indicators are above the plane of the paper, and broken wedge-shaped indicators are below the plane of the paper. The compounds of the present invention may occur as single enantiomers or diastereomers, or mixtures thereof, including racemic mixtures. All such isomers are included within the scope of this invention.

[0148] As used herein, unless otherwise stated, “stress” or “stressed” refers to specific or nonspecific responses of varying degrees. A stressor is a specific event, experience, or environmental stimulus that affects an animal’s health and can be acute, chronic, disruptive, or considered uncontrollable. Non-exclusive examples of stressors in animal health include: natural disasters (e.g., floods, fires, and earthquakes), major life events (e.g., relocation / transportation, weaning, maternal separation and herd separation, synergy between animals from different sources, tail docking, tooth extraction with needles, pain, food and water scarcity, and acute or chronic illness), and acute / chronic disruptions (e.g., changes in temperature and humidity, confinement, transport, inadequate nutrition and hydration, storms, loud noise (e.g., thunder, barking, fireworks, etc.), environmental changes, and pollutants, etc.).

[0149] As used herein, unless otherwise stated, "therapeutic effective amount" means the amount of a compound of the present invention that (i) treats or prevents a particular disease or condition, (ii) alleviates, improves or eliminates one or more symptoms of a particular disease or condition, or (iii) prevents or delays the onset of one or more symptoms of a particular disease or condition.

[0150] As used herein, unless otherwise stated, "treatment," "curing," etc., means controlling, preventing, reversing, alleviating, weakening, or suppressing inflammation driven by environmental, bacterial, viral, fungal, or parasitic infections and / or internal diseases by reducing the immune response. As used herein, these terms also encompass, depending on the animal's condition, prevention of the onset of a symptom or illness, or symptoms associated with a symptom or illness, including reducing the severity of a symptom or illness or related symptoms. Treatment can also refer to the administration of the compounds of the invention to animals that are not infected at the time of administration, have an immune response, or have a symptom or complex of disease. It is understood that it is not always possible to distinguish between "prevention" and "suppression" of a disease or illness, as the eventual inducing event may be unknown or potential.

[0151] Except in operational examples or elsewhere indicated, in all instances, all quantities used herein to indicate the amount of an ingredient or reaction condition shall be understood to be modified by the term “about”.

[0152] The compounds of this invention have several asymmetric centers. Compounds having asymmetric centers produce enantiomers (optical isomers), diastereomers (configurational isomers), or both, and it is intended that all possible enantiomers and diastereomers in mixtures, as well as pure or partially purified compounds, be included within the scope of this invention. This invention is intended to cover all stereoforms of the compounds of this invention. This invention includes all stereoisomers of the compounds of this invention.

[0153] The independent synthesis or chromatographic separation of stereoisomerized enriched compounds can be accomplished with appropriate modifications to the methods disclosed herein, as is known in the art. If necessary, their complete stereochemistry can be determined by X-ray crystallography of the crystalline product or the derived crystalline intermediate using a reagent containing an asymmetric center of known absolute configuration. If desired, racemic mixtures of compounds can be separated, allowing for the separation of individual enantiomers or diastereomers. 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. Coupling reactions typically involve the formation of salts using enantiomerizing pure acids or bases.

[0154] The derivative can then be converted into a purified stereoisomer by cleaving the added chiral residues. Racemic mixtures of the compounds can also be directly separated by chromatography using a chiral stationary phase, methods known in the art. Alternatively, any stereoisomer of the compound can be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configurations, methods known in the art.

[0155] During any method used to prepare the compounds of the present invention, protecting any sensitive or reactive groups on any relevant molecules may be necessary and / or desirable. This can be achieved by conventional protecting groups, such as those described in *Protective Groups in Organic Chemistry*, edited by J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene and P.G. W. Muts, *Protective Groups in Organic Synthesis*, John Wiley & Sons, 1991. Protective groups can be removed at convenient subsequent stages using methods known in the art.

[0156] Macrolides

[0157] Macrolides are known to have a strong binding affinity for the P site of the 50S subunit of bacterial ribosomes and are used to inhibit protein synthesis. Modification of the erythromycin deoxyglycosamine group of macrolides blocks this interaction by modifying the dimethylamino group to block the salt bridge and / or by modifying adjacent hydroxyl groups that affect hydrogen bond formation, thereby removing the antibacterial activity of the compounds of this invention. Although erythromycin modification has a relatively small effect on bacterial ribosome binding, it may affect the physicochemical properties, pharmacokinetics, and cell permeability of the compounds. By modifying the macrolide structure, thus isolating molecules from bacteria or enhancing bacterial efflux, even if the compound has the ability to bind bacterial ribosomes, this reduces or eliminates antibacterial activity.

[0158] Lipophilic

[0159] The lipophilicity of organic compounds can be described by the partition coefficient logP, which can be defined as the ratio of the concentration of the unionized compound in equilibrium between the organic and aqueous phases. Generally, more lipophilic compounds are less soluble in aqueous media. A negative logP 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; a positive logP indicates a higher concentration in the lipid phase (lipophilicity). Lipophilicity is a major determinant of compound absorption, distribution in vivo, permeation across important membranes and biological barriers, metabolism, and excretion. The compounds of the present invention are lipophilic (logP of about 2.234 to 6.449), which facilitates the transport and absorption of the compounds into respiratory tissues, such as the lungs.

[0160] Composition / Formulation

[0161] The pharmaceutical compositions of the present invention can be manufactured using processes known in the art, such as conventional mixing, dissolving, granulation, sugar-coated pelleting, grinding, emulsification, encapsulation, embedding, lyophilization, or spray drying. The pharmaceutical compositions used according to the present invention can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers, which facilitates the formulation of the active compound for administration to animals in need. The formulations of the present invention can be designed to be short-acting, rapid-release, long-acting, and sustained-release. Therefore, the pharmaceutical formulations can also be formulated for controlled-release or sustained-release purposes, depending on the chosen route of administration.

[0162] Pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are therefore included in this invention. Such excipients and carriers (containing water) are described in, for example, Remington's Pharmaceutical Sciences, Mack Pub. Co., New Jersey (1991).

[0163] For BRD and SRD, pharmaceutical compositions are typically formulated, for example, in a liquid carrier for parenteral administration, or adapted to be reconstituted into a liquid solution or suspension for parenteral administration. Typically, such compositions include a pharmaceutically acceptable carrier. Pharmaceutical carriers according to the invention can be sterile liquids, such as, but not limited to, water, saline solutions, glucose solutions, glycerol solutions; and / or oils, comprising petroleum, animal, plant, or synthetic sources, such as soybean oil, mineral oil, sesame oil, etc. Suitable pharmaceutical carriers are described in EWMartin's "Remington Pharmaceutical Sciences," 18th edition. Pharmaceutical compositions comprising compounds of the invention can be administered orally, topically, or parenterally (i.e., intramuscular, subcutaneous, intravenous, and intradermal injections). Pharmaceutical compositions comprising compounds of the invention can also be administered via intramammary and intrauterine injections.

[0164] Pharmaceutical compositions and formulations as defined herein can be prepared by mixing a compound 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 mordant applied together with a compound of the present invention. Pharmaceutically acceptable carriers are generally non-toxic to recipients at the doses and concentrations used and include, but are not limited to: 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, thioglycerol, propyl gallate, etc.); preservatives (e.g., octadecyl dimethyl benzyl ammonium chloride, hexachlorobenzyl quaternary ammonium chloride, benzalkonium chloride, benzyl chloride, phenol, butyl or benzyl alcohol, chlorobutanol, thimerosal, alkyl parabens such as methyl paraben or propyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol, m-cresol, etc.); and hydrophilic polymers (e.g., polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), poly...). The composition may contain: polyvinyl alcohol (PVA), polyacrylic acid, polyacrylamide, xanthan gum, etc.; amino acids (e.g., glycine, glutamine, asparagine, histidine, arginine, lysine, etc.); chelating agents such as EDTA; monosaccharides, disaccharides, and other carbohydrates containing sugars such as sucrose, mannitol, trehalose or sorbitol, glucose, mannose, or dextrin; and salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes). The carrier may be a solvent, reconstitution medium, or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, etc.) and suitable mixtures thereof. For intravenous administration, suitable carriers include physiological saline, antibacterial water, or phosphate-buffered saline (PBS). Prolonged absorption of injectable compositions can be achieved by including agents that delay absorption (e.g., aluminum monostearate and gelatin) in the composition.

[0165] Solutions or suspensions intended for parenteral administration typically contain one or more of the following components: a sterile carrier, such as water for injection, saline solution, fixative oil, polyethylene glycol, glycerol, propylene glycol, or other synthetic solvents; an antimicrobial agent, such as benzyl alcohol or methylparaben; an antioxidant, such as ascorbic acid, BHA, BHT, thioglycerol, or sodium bisulfite; a chelating agent, such as ethylenediaminetetraacetic acid; a buffer, such as acetate, citrate, or phosphate; and an agent for adjusting osmotic pressure, such as sodium chloride or dextran. The pH can be adjusted with an acid or base such as hydrochloric acid, citric acid, or sodium hydroxide. Such formulations can be encapsulated in ampoules, disposable syringes, or multi-dose vials made of glass or plastic. Preparations intended for in vivo administration are typically sterile. Sterility can be readily achieved, for example, by filtration through a sterile filter membrane and radiation. Injectable compositions may contain an active ingredient (drug) in an amount ranging from about 1 to 250 mg / mL, and more preferably, in a concentration ranging from about 1 to 100 mg / mL. Without limiting the range of constituent components, injectable compositions comprising compounds of formula (1), or pharmaceutically acceptable salts thereof (e.g., acetates), can be prepared by dissolving the compounds (e.g., 1 to 25 mg / mL) in a composition comprising citric acid, propylene glycol, water, and optionally an antioxidant (e.g., thioglycerol). As described herein, the composition may contain about 90% (± about 6%) of lactone A and 10% (± about 6%) of lactone B of formula (1). The pH of the composition may be adjusted as needed with NaOH and / or HCl. Methods for preparing such formulations will be readily apparent to those skilled in the art and can be carried out according to the procedure described in U.S. Patent US6514945.

[0166] For oral use, the pharmaceutical compositions of the present invention can be administered, for example, in the form of tablets or capsules, powders, dispersible granules or tablets, or in the form of aqueous solutions or suspensions. Oral compositions typically contain an inert or edible carrier. The oral compositions may be encapsulated in gelatin capsules or compressed into tablets. For oral administration, the therapeutic agent may be combined with a carrier and used in the form of tablets, lozenges, or capsules. Pharmaceutically compatible binders and / or adjuvant materials may be included as part of the composition. Tablets, pills, capsules, lozenges, etc., may contain any of the following components or compounds with similar properties: binders, such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients, such as starch or lactose; disintegrants, such as alginate, primogel, sodium glycolate starch, or corn starch; lubricants, such as magnesium stearate or stearic acid; glidants, such as colloidal silica; sweeteners, such as sucrose or saccharin; or flavoring agents.

[0167] dose

[0168] Pharmaceutical compositions suitable for use in this invention comprise compositions containing an amount of active ingredient sufficient to achieve their intended purpose. More specifically, a therapeutically effective amount means an amount in which the compound of this invention effectively prevents, alleviates, or improves the symptoms / signs of a disease or prolongs the survival of a treated animal. The amount of the active component of the compound of this invention in the pharmaceutical composition and its unit dosage form can vary widely or be adjusted depending on the manner of administration, the potency of the particular compound, and the desired concentration. The determination of a therapeutically effective amount is entirely within the capabilities of those skilled in the art. Typically, the amount of the active component will be in the range of 0.01% to 99% of the weight of the composition.

[0169] Typically, the therapeutically effective dose of the active ingredient will be in the range of about 0.01 mg / kg to about 10 mg / kg of body weight, preferably about 0.02 mg / kg to about 1 mg / kg of body weight, more preferably about 0.04 mg / kg to about 0.8 mg / kg of body weight, and even more preferably about 0.06 mg / kg to about 0.6 mg / kg of body weight. A preferred dosage regimen is parenteral administration via subcutaneous injection at a dose of about 0.05 mg / kg to about 0.8 mg / kg of body weight. It should be understood that the dosage can vary depending on the needs of each animal and the severity of the condition or disease to be treated. During the course of treatment, it is desirable that the dosage be conveniently provided as a single dose or in divided doses administered at appropriate intervals. The preferred route of administration is parenteral. Parenteral administration includes intravenous, intramuscular, and subcutaneous injection. The preferred route of administration is subcutaneous injection. The compounds of the present invention can be administered to animals at the onset of the first signs of stress or bacterial infection, before transport from the farm or ranch or upon arrival at the farm.

[0170] The compounds of the present invention can be administered alone in a pharmaceutically acceptable form, or in combination with one or more other agents that modulate the mammalian immune system, or with anti-inflammatory agents, or with one or more antibacterial agents. Additionally, the compounds of the present invention can be co-administered with vitamins and / or minerals. Non-limiting examples of anti-inflammatory agents include: ketoprofen, cyclosporine A, rapamycin, FK-506 (tacrolimus), leflunomide, deoxyguanidine, mycophenolate mofetil, azathioprine, daclizumab, aspirin, acetaminophen, ibuprofen, naproxen, piroxicam, and anti-inflammatory steroids (e.g., prednisolone or dexamethasone). Non-limiting examples of antimicrobial agents include: novobiocin, aminoglycosides (e.g., gentamicin, neomycin, dihydrostreptomycin, spectinomycin, etc.), florfenicol, ceftiofur, cefphapirin, ormetoprim, danofloxacin, enrofloxacin, bambermycins, ionotropic agents (e.g., laidlomycin, lasalocid, monensin, narasin, thalinomycin). Salinomycin, lincomycin, pirlimycin, macrolides (e.g., erythromycin, gamithromycin, tildipirosin, tilmicosin, tulathroycin, tulathroycin M9 metabolite, tylosin, tylvalosin, etc.), avilamycin, penicillins (e.g., amoxicillin, ampicillin, cloxacillin, penicillin, etc.), tiamulin, polymyxin B B), bacitracin, carbadox, virginiamycin, sulfadiazine, sulfamethazine, chlorotetracycline, oxytetracycline, and tetracycline.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, with B vitamins including: thiamine (B1), riboflavin (B2), niacin (B3), pantothenic acid (B5), pyridoxine (B6), biotin (B7), folic acid (B9), and B12. These additional combination agents may be administered as part of the same or separate dosage forms, via the same or different routes of administration, and according to the same or different administration regimens as known to those skilled in the art.

[0171] Medical and veterinary uses

[0172] The methods defined herein are typically performed on animals in need. Animals in need can be those that have, are diagnosed with, are suspected of having, or are at risk of having a disease, condition, or symptom associated with a bacterial infection, viral infection, parasitic infection, inflammation, or immune response. Diseases or conditions can include respiratory diseases, reproductive diseases such as mastitis or metritis, inflammatory bowel disease, bovine viral diarrhea virus (BVDV), bovine infectious rhinotracheitis (IBR), bovine respiratory syncytial virus (BRSV), parainfluenza virus, bovine coronavirus, psoriasis, multiple sclerosis, rheumatoid arthritis, allergic autoinflammatory diseases, or autoimmune diseases. Generally, a safe and effective amount of the compounds of the present invention is, for example, an amount that induces the desired therapeutic effect in the animal while minimizing undesirable side effects. In various embodiments, an effective amount of the compounds of the present invention can substantially attenuate an inflammatory or immune response, slow the progression of a disease, condition, or symptom associated with an inflammatory or immune response, or limit the development of a disease, condition, or symptom associated with an inflammatory or immune response.

[0173] The compounds of this invention are macrolide (aza-cyclic lactone) analogs lacking antibacterial activity against BRD pathogens, and have been shown to possess immunomodulatory properties for preventing and / or controlling symptoms of BRD in artificially infected domestic cattle. Therefore, these macrolides are therapeutic agents useful for treating and / or controlling respiratory diseases that may be induced by environmental stimuli, stress, and bacterial infections. Some non-limiting macrolides for treating BRD include: (Tylamycin) (Tai Di Luo Xin) and (Gamimycin), etc.

[0174] This product is indicated as an injectable solution for the treatment of bovine respiratory disease (BRD) associated with *Mannella hemolyticus*, *Pasteurella multocida*, *Histophilus somni*, and *Mycoplasma bovis*; and for the control of respiratory disease in domestic cattle at high risk of developing BRD associated with these pathogens. Domestic cattle are given a subcutaneous dose of 2.5 mg / kg. In pigs, It is indicated for the treatment of porcine 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 already diagnosed with SRD. Pigs receive 2.5 mg / kg intramuscularly.

[0175] The compounds of this invention can treat, reduce, or prevent diseases, conditions, or symptoms associated with inflammation or immune responses. Inflammation is a critical response to potential danger signals and damage in bodily organs. Often referred to as an inflammatory cascade, it can be acute or chronic. Acute inflammation, as part of an immune response, is the body's immediate response to damage or attack caused by bodily trauma, infection, stress, or a combination of all three. Acute inflammation helps prevent further damage and promotes healing and recovery processes. However, when inflammation becomes self-sustaining, it can lead to chronic or long-term inflammation.

[0176] Trauma, inflammation, or infection triggers the activation of an inflammatory cascade. Initially, pro-inflammatory activation occurs, but this is almost immediately followed by a reactive, inhibitory anti-inflammatory response. This systemic inflammatory response (SIR) typically manifests as an increase in the systemic expression of both pro-inflammatory and anti-inflammatory species. The SIR begins with inflammation as a response to exogenous (microbial, physical, or chemical) agents or endogenous (immunological or neurological) factors. The response is triggered when inflammatory cells, such as macrophages located at sites of inflammation, are activated and rapidly produce TNF-α and IL-1. These cytokines then activate the cytokine cascade, leading to 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 pro-inflammatory cytokines, while naturally occurring pro-inflammatory cytokine inhibitors neutralize pro-inflammatory cytokine activity by binding to pro-inflammatory cytokine receptors, decoy receptor antagonists, and cytokine-binding proteins. The interactions between these pro-inflammatory cytokines, anti-inflammatory cytokines, and naturally occurring cytokine inhibitors determine the inflammatory response and its effectiveness in inhibiting the inflammatory response and reversing the initiating process. The main known mediators involved in the evolution of SIRS are cytokines, nitric oxide, platelet-activating factor (PAF), and eicosanoic acid-like substances. The systemic response to infection is mediated by macrophage-derived cytokines targeting receptors in damaged or infected peripheral organs. However, anti-inflammatory proteins and lipid molecules are also produced to attenuate and halt the inflammatory response. These mediators begin to directly affect overlapping processes in endothelial, cardiovascular, hemodynamic, and coagulation mechanisms. If a balance between pro-inflammatory and anti-inflammatory substances is not established and homeostasis is not restored, a large-scale pro-inflammatory response (i.e., SIRS) and multiple organ dysfunction syndrome (MODS) may subsequently occur. Therefore, after the initial release of pro-inflammatory mediators, the body mounts a compensatory anti-inflammatory response to the initial inflammatory response. The anti-inflammatory response may be as strong as, and sometimes even stronger than, the pro-inflammatory response. In addition to pro-inflammatory cytokines, other mediators such as NO, PAF, prostaglandins, and leukotrienes are produced. These molecules are also responsible for activating complement, coagulation, and kinin cascades.

[0177] Diseases associated with inflammation or immune response may include, but are not limited to: bacterial infections; viral infections; fungal infections; parasitic infections; asthma; allergies; age-related macular degeneration; dermatitis; pain; mastitis; endometritis; autoinflammatory diseases; autoimmune diseases; inflammatory bowel disease; dermatitis; multiple sclerosis; osteoarthritis; osteoporosis; psoriasis; rheumatoid arthritis and osteoarthritis; synovitis; acne; impetigo; bone hyperplasia; airway and respiratory diseases (e.g., equine airway disease). Diseases and canine infectious respiratory diseases); respiratory disease complexes (cattle and pigs), ischemia-reperfusion, feline chronic kidney disease, feline and canine degenerative mitral valve disease (inflammatory complexes; for example, heart failure with upregulation of pro-inflammatory cytokines in valves and myocardium through cytokines, chemokines, and adhesion molecules), psoriasis, multiple sclerosis, rheumatoid arthritis, autoinflammatory diseases, peptic ulcers, tuberculosis, periodontitis, otitis media, ulcerative colitis, Crohn's disease. Diseases including lupus, sinusitis, hepatitis, celiac disease, pelvic inflammatory disease, glomerulonephritis, transplant rejection, chronic obstructive pulmonary disease, gout, ankylosing spondylitis, myositis, laminitis, gingivitis, scleroderma, vasculitis, malaria, Lyme disease, babesiosis, ehrlichiosis, anaplasmosis, tularemia, amebiasis, giardiasis, fascioliasis, fasciolopsiasis, elephantiasis, cryptosporidiosis, leishmaniasis, microsporidiosis, trypanosomiasis, toxoplasmosis, etc.; as well as other inflammatory and immune diseases and conditions. The compounds of the present invention can treat inflammation-related diseases, conditions or symptoms by modulating cytokines, chemokines and inflammatory markers such as IL6, IL-1β, NFKB, CSP136, LCN, CXCL8 (IL-8), and TNFα, and induce TLR4 signaling.

[0178] Macrolides for Immunomodulation

[0179] The chemical action of macrolides provides a basis for understanding their immunomodulatory effects. Macrolides are defined as cationic amphiphilic drugs; cell penetration is primarily determined by their lipophilic and cationic properties at physiological pH. Macrolide cell membrane penetration leads to phospholipid depolarization, causing both the drug and phospholipids to tend to enter the cytosol and lysosomes, ultimately resulting in the cellular state of phospholipidosis. Intracellular polarity-related inhibition of phospholipids, primarily phosphatidylcholine, suppresses their natural degradation via phospholipases, leading to a reduction in primary cellular signaling components such as arachidonic acid. It is hypothesized that the reduction in arachidonic acid prevents the normal production of eicosanoic acid metabolites, including prostaglandins, thromboxanes, leukotrienes, and lipoproteins. Furthermore, indirect inhibition of the production of inflammatory mediators such as the COX family, NF-κB, and AP-1, as well as their derived pro-inflammatory cytokines, has been observed. The reduced ability of cells to signal both intracellularly and extracellularly depends on the host environment. In healthy animals, macrolide treatment has been shown to stimulate neutrophil and macrophage responses to disease stimuli. However, in the presence of acute or chronic inflammatory states, suppression or reversal of inflammation has been observed.

[0180] The regulation 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, and with leukocytes (macrophages, polymorphonuclear leukocytes or neutrophils, monocytes or mononuclear leukocytes, T cells, and dendritic cells). The cellular accumulation of macrolides is a passive transport mechanism into cells, which requires no cellular energy, carrier proteins, and is unsaturated. This mechanism differs from and is therefore unrelated to ribosome binding associated with antibiotic activity. As an example, azithromycin ligands exhibiting no antibiotic activity demonstrate high levels of induced phospholipidosis (J. Parnham et al., Pharmacology & Therapeutics 143(2014) 225-245). Azithromycin penetrates the cell membrane bilayer and stabilizes the membrane, thereby reducing fluidity and neutralizing the phospholipid charge on the inner lobular membrane. This leads to reduced release of fatty acids and the release of electrostatically charged enzymes onto the membrane, resulting in the regulation of signal transduction pathways and the inhibition of activation of transcription factors containing AP-1 and NFκB. The most affected signal transduction pathways may depend on the specific cell, its activation state, and the stimulus that activates it. Molecules dependent on negatively charged phospholipids are also affected. Azithromycin accumulates in lysosomes, thereby regulating enzymes and MPR transport of lipids via lipid remodeling in the lysosomal membrane. One of its well-documented aspects is its ability to reduce inflammatory responses, as demonstrated by downregulating the production of exacerbated cytokines (IL-1β, TNF-α, IL-6) through the NFκB pathway and its effects on granulocytes; as well as gene expression.

[0181] Immune activity can also be assessed by analyzing CD163. CD163 is a scavenger receptor that binds to hemoglobin / haptoglobin and is expressed on macrophages, which are thought to be involved in innate immune sensing. This helps to clear activated macrophages and thus prevent oxidative damage to tissues.

[0182] CD163 also acts as an innate immune sensor for both Gram-positive and Gram-negative bacteria. Therefore, high CD163 expression in macrophages is a characteristic of tissue response to inflammation and is considered a highly relevant biomarker of inflammation. The clearance of oxidative and pro-inflammatory hemoglobins leading to the stimulation of heme oxygenase-1 and the production of anti-inflammatory heme metabolites suggests that CD163 indirectly contributes to the anti-inflammatory response (Antioxidant Redox Signaling, Etzerodt et al., 2013, 18(17), pp. 2352-2363). CD163 may be involved in the processes leading to lung lesions in BRD. CD163 expression may also be associated with elevated IL-6 levels, as observed in BRD, where CD163 surface expression experimentally induced 253+ / -4.9% in monocytes and macrophages upon incubation with IL-6 (Journal of Leukocyte Biology; Buechler et al., Vol. 67, January 2020; pp. 97-103). Alternatively, cross-linking of CD163 with monoclonal antibodies on alveolar macrophages induces protein tyrosine kinase-dependent signaling, leading to slow-type calcium mobilization, inositol triphosphate production, and the 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 and immunomodulatory drug tacrolimus showed a slight increase in CD163 expression (PLOS ONE; Kannegleter et al., January 2017; pp. 1–19); however, a subsequent study (HHS Public Access; Motta et al., Oral Dis. 2018, 24(4) pp. 580–590) reported that the therapy did not result in altered CD163 expression. Similarly, azithromycin (British Journal of Pharmacology, Vrancic et al.; 2012, 165; pp. 1348–1360) reported enhanced CD163 expression. CD163 expression was upregulated by glucocorticoids, IL-6, IL-10, and hemoglobin; and downregulated by IL-4, IFN-γ, TNF-α, CXCL4, and GM-CSF. In contrast, CD163 was suppressed in domestic cattle treated with M9 and 2-21, which is related to the proposed mechanism of reduced inflammatory state.

[0183] Cytokines are considered a broad and loosely structured class of small proteins (5-20 kDa) that play important roles in cell signaling. Their release influences the behavior of surrounding cells. Cytokines can be considered immunomodulators involved in autocrine, paracrine, and endocrine signaling. Cytokines are generally known to include chemokines, interferons, interleukins, lymphokines, and tumor necrosis factor (TNF), but typically do not include hormones or growth factors. Cytokines can be produced by a variety 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; a given cytokine can be produced by more than one cell type. Cytokines act through receptors and are particularly important in the immune system. Cytokines can regulate the balance between humoral and cellular immune responses, and can modulate the maturation, growth, or responsiveness of specific cell populations. Some cytokines can enhance or inhibit the effects of other cytokines in complex ways. Cytokines may be important in health and disease, specifically in the host's response to infection, immune response, inflammation, stress, trauma, sepsis, cancer, and reproduction.

[0184] Interleukin-6 (IL-6) is a pleiotropic cytokine that acts as both a pro-inflammatory and anti-inflammatory myocytokine. IL-6 is produced and secreted by a variety of cells, including B cells, T cells, endothelial cells, and macrophages, to stimulate immune responses via the classical signaling pathway when it binds to the transmembrane IL-6 receptor (IL-6R), or via the trans signaling pathway when it binds to the soluble form of IL-6R (sIL-6R); leading to inflammation during infection and after tissue trauma. Trans signaling is responsible for the pro-inflammatory effects of IL-6 and most of its pathological functions. Dysregulation of the IL-6 pathway has been reported to be associated with the development of several disease states encompassing various inflammatory conditions. IL-6 has been reported to induce the production of vascular endothelial growth factor, which enhances angiogenesis and increases vascular permeability, characteristic of several inflammatory conditions. IL-6 is also associated with increased neutrophil activity, monocyte / macrophage recruitment, and blockade of anti-inflammatory regulatory T cells. In chronic inflammation, IL-6 plays a detrimental role, leading to the accumulation of monocytes at sites of injury. This can result in elevated serum levels of IL-6 and sIL-6R, thus providing a basis for the expansionary steps of the chronic inflammatory response. IL-6 is associated with the development of lung neutrophils by increasing both neutrophil recruitment and neutrophil survival in the blood and bone marrow. The role of IL-6 as an anti-inflammatory cytokine is mediated through its inhibition of TNF-α and IL-1, and its activation of IL-1ra and IL-10.

[0185] Like other inflammatory cytokines, IL-6 has been shown to be elevated in various lung diseases in humans and mice. IL-6 is elevated in bovine BRD (Mannophila hemolytica) challenge and is associated with elevated rectal temperature, lung lesions, and mortality. The compounds M9 and tylosin of the present invention significantly reduce IL-6 levels, which is also associated with overall animal survival. Therefore, the immunomodulatory compounds of the present invention alleviate the pathological increase in IL-6, consistent with dosage and clinical outcomes.

[0186] IL-36 is a member of the IL-1 superfamily of cytokines and comprises three agonists (IL-36α, IL-36β, and IL-36γ) and one antagonist (IL-36RA). IL-36 agonists bind to the heterodimeric IL-36 receptor (IL-36R) complex to produce a pro-inflammatory response. The antagonist binds to IL-36R, thereby inhibiting IL-36 signaling. IL-36 signaling occurs through the formation of the heterotrimeric complex of IL-36, IL-36R, and IL-1AcP (an IL-1 accessory protein), activating the adaptor protein myelodifferentiation protein 88 (MyD88), mitogen-activated protein kinase (MAPK), and nuclear factor-κB (NF-κB) signaling pathways and inducing an inflammatory response. IL-36RA blocks the interaction between IL-1AcP and its receptor ligand complex. IL-36 protein is widely expressed in T cells, keratinocytes, and skin cells, lung cells, and intestinal cells. IL-36 agonists bind to and are then activated by their receptors [IL-36R and IL-1 receptor accessory protein (IL-1RAcP)]. Ultimately, these pathways initiate the regulation of target genes. 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 the production of pro-inflammatory factors. IL-36 has attracted considerable attention due to its dysregulation in inflammatory diseases. For example, serum and tissue expression of IL-36 is increased in inflammatory and immune diseases and conditions such as psoriasis, rheumatoid arthritis, and inflammatory bowel disease.

[0187] Chemokines

[0188] 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 responsive cells (i.e., chemokines); this stimulates the recruitment of leukocytes. The primary function of chemokines is to manage the migration (homing) of leukocytes to their respective anatomical locations during inflammatory processes and homeostasis. These chemokines are secondary pro-inflammatory mediators, induced by primary pro-inflammatory mediators such as IL-1 or TNF. Based on the position of cysteine ​​residues, there are two main subfamilies of chemokines: CXC and CC. All members of the CXC chemokine subfamily have an intermediate amino acid between the first two cysteine ​​residues; members of the CC chemokine subfamily have two adjacent cysteine ​​residues. As a general rule, members of the CXC chemokine subfamily are chemotactic towards neutrophils, and CC chemokines are chemotactic towards a small subset of monocytes and lymphocytes. Some chemokines are considered pro-inflammatory and can induce the recruitment of immune system cells to sites of infection or tissue damage during an immune response, while others are considered homeostatic and involved in controlling cell migration in normal processes of tissue maintenance or development (e.g., angiogenesis).

[0189] Inflammatory chemokines are formed under pathological conditions (in response to pro-inflammatory stimuli such as IL-1, TNF-α, LPS, or viruses) and actively participate in the inflammatory response, thereby attracting immune cells to sites of inflammation. These inflammatory chemokines include CXCL8 (IL-8), CCL2, CCL3, CCL4, CCL5, CCL11, and CXCL10. These inflammatory chemokines are produced in high concentrations during infection or injury and identify inflammatory leukocytes migrating to the damaged area. A typical example is CXCL8, which acts as a chemical attractant for neutrophils. In contrast to homeostatic chemokine receptors, there is significant confounding (redundancy) associated with both binding receptors and inflammatory chemokines.

[0190] Interleukin-8 (IL-8) is a pro-inflammatory chemokine that attracts and activates immune and inflammatory cells. IL-8 mediates a range of biological effects, including several involving neutrophils: inflammatory cell activation and chemotaxis, production of reactive oxygen species, increased expression of integrin CD11b-CD18, enhanced cell adhesion to endothelial cells, promotion of angiogenesis, and regulation of histamine release. IL-8 is produced by a variety of cells, including neutrophils, monocytes, macrophages, mast cells, vascular endothelial cells, stromal cells, and epithelial cells, in response to innate extrinsic / endogenous stimuli. In target cells, IL-8 induces a series of physiological responses required for migration and phagocytosis, such as intracellular calcium release. 2+ Increased exocytosis (e.g., histamine release).

[0191] Recruiting inflammatory cells, such as neutrophils in response to tissue damage like infection, is a normal physiological response to eliminate infectious agents, remove damaged or dead cells, and initiate the healing process. However, excessive recruitment, prolonged residence time, and cell death of these cells lead to tissue damage. Therefore, an influx of excessive inflammatory cells 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 bacterial pneumonia) in humans. This has also been observed in bovine respiratory disease (BRD) and bacterial pneumonia. Controlling the recruitment and activation of these cells in the lungs would be an attractive strategy for therapeutic intervention. Under all these conditions, IL-8 appears to be important for the recruitment and activation of neutrophils and T cells entering the respiratory tract.

[0192] In experimental bovine challenge studies containing *Mannella vulgaris*, one of the main pathogens of BRD, serum and tissue IL-8 levels were upregulated. In this challenge model, the compounds of this invention showed downregulation of IL-8 production, which was associated with a weakened anti-inflammatory response and disease.

[0193] Biology of BRD

[0194] The pathobiology of BRD has long been considered to originate from stress-induced immunosuppression, making calves vulnerable to the myriad microorganisms they encounter during their transfer from heifer farms to feedlots. This doctrine suggests that stimulating the innate immune system would have a positive impact on clinical outcomes. However, to date, interventions consistent with this doctrine, including the use of DNA immunostimulants, have achieved little success. To better understand the progression of BRD, early research suggested that it is an early, unresolved, enhanced inflammatory state, rather than immunosuppression, that leads to its progression.

[0195] Based on current research into the etiology of BRD, a new understanding of the immunological state has shown that while an enhanced pro-inflammatory state is prevalent in at-risk domestic cattle, the persistence or absence of resolution / reduction of this state is consistent with disease outcomes. Upon arrival at the farm, the pro-inflammatory state is characterized, in particular, by damage to the nasal mucosal epithelial cell barrier and the release of pre-formed mediators, such as members of the IL-1 cytokine family. Activation of the danger-associated molecular pattern (DAMP), including pattern recognition receptor (PRR) TLR-4 and inflammasome signaling, indicates a response of epithelial cells and resident bone marrow cells to co-localized microorganisms in the upper airway. TLR4 signaling is induced by bacterial components such as lipopolysaccharide (LPS; lipoprotein and endotoxin), and transcription factors such as NF-κB induce the expression of key cytokines involved in maintaining inflammatory processes, such as IL-1β, IL-6, and TNF-α. Furthermore, bone marrow-derived granulocytes, including macrophages and neutrophils, are recruited and activated. These cascades create an environment where bacteria normally confined to the upper airways can cross over into the lungs and cause disease. Biomarkers of the inflammatory process, such as elevated levels of secreted cytokines like IL-6 and acute-phase proteins, are clinically relevant to the disease. Also clinically relevant are markers of neutrophil activation, such as the expression of the scavenger receptor CD163 on macrophages and related mediators like LCN and CXCL8. The compounds of this invention effectively alleviate the enhanced pro-inflammatory state in at-risk domestic cattle by balancing the immune response and reducing the pathological inflammatory cascade. This mechanism of immunomodulatory agents is described in the context of BRD progression. Figure 1 .

[0196] The compounds of this 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 alleviate pathological congenital inflammation that occurs during transport, enabling animals to recover homeostasis within a timeframe consistent with clinical disease protection.

[0197] Plans and trials

[0198] In the following formulations and preparations, the following acronyms are included: tetrahydrofuran (THF); methanol (MeOH), ethanol (EtOH), dichloromethane (DCM), ethyl acetate (EtOAc); trifluoroacetic acid (TFA), hydrogen peroxide (H2O2), potassium cyanide (KCN), TEA.3HF (triethylamine trihydrofluoride), tert-butanol (t-BuOH or TBA); triethylamine (TEA), isopropanol (IPA), dimethylformamide (DMF), bromine (Br2), dichloroethane (DCE), palladium / carbon (Pd / C); disodium ethylenediaminetetraacetate (EDTA), acetic acid (AcOH), dimethyl sulfoxide (DMSO), ammonium hydroxide (NH4OH), acetonitrile (MeCN or Acn), sodium triacetoxyborohydride (STAB), and so on. Sodium alkoxide (NaONMe), cerium(III) chloride (CeCl3), sodium azide (NaN3), sodium bicarbonate (NaHCO3), ammonium chloride (NH4Cl), magnesium sulfate (MgSO4), sodium sulfate (Na2SO4), ammonium sulfate ((NH4)2SO4), copper sulfate (CuSO4), copper acetate (II) (Cu(OAc)2), sodium cyanoborohydride (NaBH3CN), 1-butanol (N-BuOH), hexafluoroacetone ((CF3)2CO-H2O), N-methyl-2-pyrrolidine (NMP); methyl tert-butyl ether (MTBE); N,N-diisopropylethylamine (DIPEA); phenyl (Ph); and copper acetate II (Cu(OAc)2), hours (hr, hrs), overnight (ON) and room temperature (RT).

[0199] Tyromycin A is a 15-membered (lactone A) closed-ring antibacterial macrolide (nitrogen ring lactone). The nitrogen ring lactone is converted to a 13-membered (lactone B) closed-ring tyromycin B. This conversion occurs at an equilibrium ratio of approximately 9:1 (A:B), and is described below.

[0200]

[0201] Tylamycin N-cyclic lactone can also be represented by the following structure:

[0202]

[0203] Tylopycin 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; and tylopycin The precursor tulamycin 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]oct-6-yl)oxy)-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one.

[0204] One of the metabolites of tylosin A is demethylazolidinyl lactone (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), which is described in the figure below:

[0205]

[0206] Tylosin B is also metabolized to β-demethylazine lactone.

[0207] M9 analogues can be used as starting materials for the preparation of compounds of the present invention. The process for producing desmethylteratin (M9) is a two-step process starting with teratin A, and the intermediates are generally not separated, but can be separated. The first step is to oxidize the tertiary amine to N-oxide using any number of known oxidants for oxidizing tertiary amines. The second step is Polonovski-type demethylation, which can utilize any known metal to enable this type of transformation. Iron is typically used, but copper salts (Cu(II)) can also be used.

[0208] Add 1.22 g (5.1 mmol) of commercially available 32% peracetic acid solution to a cold (<0°C) solution of tyromycin A (4.0 g, 5.0 mmol) in n-butanol (20 mL). After 30 minutes, extract the product into a 0.25 M EDTA aqueous solution (15 mL). Alkalize the aqueous solution to pH 9.5 with concentrated ammonia and extract with tert-butyl methyl ether (20 mL). The N-oxide product was concentrated into a heavy oil, but not separated, [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 hours. The solution was cooled to 25 °C and water (8 mL) containing hydroxylamine hydrochloride (0.75 g, 10 mmol) was added. After 2 hours, the product was partitioned between water (28 mL, adjusted to pH 9.5 with ammonia) and dichloromethane (20 mL). The organic matter was concentrated into an oil, and the product was crystallized from hot acetonitrile (40 mL). The resulting white crystalline powder was dried to provide 3.2 g of M9. LCMS[M+H] + =792.5. HPLC purity >98%. 1 1H NMR (600MHz, d6-DMSO): N-Me (3H, 2.42ppm, S) compared to tylosin NMe2 (6H, 2.26ppm).

[0209] Alternatively, M9 can be prepared as follows: A solution of tylosin A (4.0 g, 5.0 mmol) in n-butanol (10 mL) at 20 °C is mixed, and then hexafluoroacetone trihydrate (0.27 g, 1.2 mmol) is added, followed by a 30% aqueous hydrogen peroxide solution (0.62 g, 5.5 mmol). After 4 hours, acetic acid (0.31 g, 5.5 mmol) is added, followed by methyl tert-butyl ether (6 mL) and water (25 mL). The upper organic layer is discarded. Methyl tert-butyl ether (8 mL) is added, and the pH of the aqueous layer is adjusted to 9.8 with ammonia. The lower aqueous layer is discarded. The N-oxide product is concentrated into a heavy oil, but not separated. [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 hour. The solution was cooled to 25 °C and water (8 mL) containing hydroxylamine hydrochloride (0.75 g, 10 mmol) was added. After 2 hours, the product was partitioned between water (28 mL, adjusted to pH 9.5 with ammonia) and dichloromethane (20 mL). The organic matter was concentrated into an oil, and the product was crystallized from hot acetonitrile (40 mL). The resulting white crystalline powder was dried to provide 3.2 g of product; LCMS[M+H] + =792.5. HPLC purity >98%. 1H NMR (600MHz, d6-DMSO): N-Me (3H, 2.42ppm, S) compared to tylosin NMe2 (6H, 2.26ppm).

[0210] Alternatively, M9 can be prepared by: epoxide precursor of tylosin A (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, A solution of 5-dioxaspiro[2.5]oct-6-yl)oxy)-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one (tula-epx) (20.0 g, 27 mmol) in methanol (40 mL) was mixed, and then acetic acid (1.6 mL, 30 mmol), hexafluoroacetone trihydrate (0.38 mL, 3 mmol) and then 30% hydrogen peroxide aqueous solution (0.62 g, 30 mmol) were added.

[0211]

[0212] After continuing the reaction at 35°C for 4 hours, the reaction was cooled to 20°C, and anhydrous copper(II) sulfate (4.5 g, 29 mmol) was added. The reaction was then heated to 60°C for 1 hour. After cooling to 20°C, 60 mL of dichloromethane and 80 mL of water were added. The mixture was alkalized to approximately pH 9.8 with concentrated ammonia. The organic compound was concentrated to a solid under vacuum, and 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 solvent was removed by concentration under vacuum. Acetonitrile (120 mL) was added and the mixture was heated to 78°C. The mixture was cooled to 10°C, and the product was separated by filtration. The resulting white crystalline powder was dried to provide 12 g of product; LCMS [M+H] + =792.5. HPLC purity >98%. 1H NMR (600MHz, d6-DMSO): N-Me (3H, 2.42ppm, S) compared to tylosin NMe2 (6H, 2.26ppm).

[0213] Azithromycin (as described below) is a nitrogen-ring lactone similar to tylosin, except that the N core ring is replaced by a methyl group (1') and the erythromycin is not further replaced by ethylpropylamine (2'); as described below.

[0214]

[0215] Azithromycin can be derivatized to prepare demethylated analogs similar to M9. Further derivatizations can be performed according to the protocols and experiments defined herein to prepare immunomodulatory azithromycin derivatives that are inactive (i.e., non-antibacterial) against BRD bacterial pathogens. Besides azithromycin, other macrolides, such as erythromycin, tilmicosin, clarithromycin, gamimycin, fedamycin, roxithromycin, telithromycin, dirithromycin, josamycin, midecamycin, oleandomycin, etc., can be modified in a similar manner to M9 to prepare immunomodulatory analogs lacking antibacterial properties against BRD and other bacterial pathogens in animals including humans.

[0216] For illustrative purposes, the reaction schemes described below demonstrate potential routes for the synthesis of key intermediates and compounds of the present invention. For a more detailed description of each reaction step, please refer to the Examples section below. Those skilled in the art will understand 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. Furthermore, many compounds prepared by the methods described below can be prepared using conventional chemistry and / or modified.

[0217] The compounds of the present invention can be used in their natural form or as salts. When it is desirable to form a stable, non-toxic acid salt, administration of the compound as a pharmaceutically acceptable salt may be suitable. For the purposes of this invention, the term "pharmaceutically acceptable salt" refers to those salts suitable for contact with animal tissues and organs without exhibiting toxicity, irritation, allergic responses, etc., within a reasonable medical assessment range, and which are commensurate with a reasonable benefit / risk ratio. Further, the compounds of the present invention have a secondary or tertiary amine group, which is characterized by basicity, and thus can form acid addition salts, which can be pharmaceutically acceptable acids. Therefore, pharmaceutically acceptable salts according to the present invention comprise those pharmaceutically acceptable acid addition salts formed with organic and inorganic acids and those pharmaceutically acceptable salts formed with optically active acids. Representative acid addition salts include, but are not limited to, acetates, adipic acid salts, alginates, ascorbic acid salts, citrates, aspartate salts, benzoates, benzenesulfonates, besylates, bicarbonates / carbonates, bisulfates / sulfates, borates, butyrates, camphorates, camphorsulfonates, camsylates, citrates, diglucuronates, ethanedisulfonates, ketoglutarate, ethanesulfonates, formates, fumarates, glucohepanoates, glucuronates, glucuronates, glutamates, and glycosides. Oleate phosphates, hemisulfates, heptanates, hexafluorophosphates, hexanoates, fumarates, hydrochlorides, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates, hydroxyethylsulfonates, lactates, malates, maleates, malonates, methanesulfonates, methyl sulfates, naphthalates, 2-naphthalenesulfonates, nicotinates, nitrates, orotates, oxalates, palmitates, dihydroxynaphthalates, pectates, persulfates, phosphates / hydrogen phosphates / dihydrogen phosphates, picrates, neopentanoates, propionates, saccharides, stearates, succinates, tartrates, thiocyanates, toluenesulfonates, and trifluoroacetates.

[0218] In the following schemes, demethylation or a polonowski reaction occurs when an amine oxide reacts with an acylating agent. The accepted mechanism involves proton removal to yield a nitrogen ylide, which loses an acetate (using acetic anhydride) attacking a carbon atom adjacent to the nitrogen atom, thus yielding α-acetoxyamine.

[0219] The central characteristic of the Polonowski reaction is the conversion of the N-oxide into an imine ion intermediate. Depending on the substrate and the structure of the anhydride or other activating agent used, the formation of the imine ion can occur through the loss of an α-hydrogen or through the fragmentation of the Cα-carbon bond. Similarly, depending on the conditions, the reaction will stop at this stage and the imine ion will become the Polonowski product, or the reaction may continue to yield an enamine or tertiary amine and / or a secondary amine and an aldehyde.

[0220] In principle, any reagent capable of activating N-oxide towards imine ion formation can be used to trigger the Polonowski reaction. However, three main types of activators can be used: acid anhydrides and chlorides (including chloroformates), iron or copper salts and complexes, and sulfur dioxide.

[0221] In the following scheme, variable R f The ring C is a phenyl, naphthyl, 5-6 membered monocyclic heteroaryl ring, or 9-11 membered fused heteroaryl ring; wherein each heteroaryl ring contains at least one heteroatom selected from the group consisting of N, O, and S; and wherein the ring C is optionally separated by at least one R 10 Substituent substitution; all of these are defined in this paper; and are described as R only in the context of the spatial background. f Compounds of formula (1) can be prepared according to the following scheme and procedure:

[0222] Scheme 1a: Preparation of compounds (1-A1) to (1-A6) of formula (1):

[0223]

[0224] Analogs of formulas (1-A1) to (1-A6) can be prepared using the three-step procedure outlined in scheme 1a. First, commercially available tylosin epoxide intermediates can be demethylated using, but not limited to, the Polonowski reaction. The N-oxide can be formed using various oxidizing agents, such as, but not limited to, peracetic acid or hydrogen peroxide. The demethylation of the N-oxide can be triggered by such reagents, but not limited to, iron or copper salts. The second step is a Chan-Lam type coupling selectively to the erythromycin deoxyglycosamine hydroxyl group. When aryl or heteroarylboronic acids or boronic esters are stirred with a copper salt, such as, but not limited to, copper acetate (II), in the presence of a weak base such as pyridine, a drying agent such as a molecular sieve, and oxygen, they can be selectively coupled to the erythromycin deoxyglycosamine hydroxyl group. In the final step, various nucleophiles, such as primary and secondary amines, alcohols, thiols, cyanides, azides, or halide anions, can be used at higher temperatures in alcoholic solvents, such as, but not limited to, 1-propanol, 1-butanol, or 2-propanol, to ring-open the epoxide functional group and obtain the final O-Het / aryl analogue. Weak bases such as NaHCO3 or salts such as NH4Cl or (NH4)2SO4 can sometimes accelerate the epoxide ring-opening reaction. This third step is detailed in Scheme 1b. For any scheme presented herein, the “nucleophile” of the substituted erythromycete ring may include, but is not limited to, the following: HNR 5 R 6 HOR 7 HS(O) p R 7 NaN3, CeCl3, TEA.3HF and KCN, of which R 5 R 6 R 7 p is as defined in this paper.

[0225] Option 1b: Details of step 3 in Option 1a

[0226]

[0227] For (s1b-A1) analogs, alcohol solvents, such as, but not limited to, various primary or secondary amines from methanol, ethanol, 1-propanol, etc., can be used to open the ring-opening reaction of the epoxide functional groups to obtain the final analog. For (s1b-A2) analogs, different alcohols used as solvents, such as, but not limited to, methanol, ethanol, 1-propanol, etc., can be used to open the ring-opening reaction of the epoxide functional groups to obtain the final O-Het / aryl analog. Weak bases such as NaHCO3 or salts such as NH4Cl or (NH4)2SO4 can sometimes accelerate the ring-opening reaction of the epoxide. For (s1b-A3) analogs, alcohol solvents, such as, but not limited to, various thiols from ethanol or 1-propanol, such as, but not limited to, ethanethiol, propanethiol, isopropylthiol, etc., can be used to open the ring-opening reaction of the epoxide functional groups to obtain the final O-Het / aryl analog. Weak bases such as, but not limited to, NaHCO3, are used to accelerate the ring-opening reaction of the epoxide. For (s1b-A4) analogs, alcoholic solvents, such as but not limited to ethanol or various halides of the reagent from 1-propanol, such as but not limited to CeCl3 or Br2, can be used to ring-open the epoxide functional groups to obtain the final O-Het / aryl analogs. Weak bases such as NaHCO3 or salts such as NH4Cl or (NH4)2SO4 can sometimes accelerate the epoxide ring-opening reaction. For (s1b-A5) analogs, alcoholic solvents, such as but not limited to ethanol or various sources of azide anions from 1-propanol, such as but not limited to NaN3, can be used to ring-open the epoxide functional groups to obtain the final O-Het / aryl analogs. Weak bases such as NaHCO3 or salts such as NH4Cl or (NH4)2SO4 can sometimes accelerate the epoxide ring-opening reaction. For (s1b-A6) analogs, alcoholic solvents, such as but not limited to IPA or different sources of cyanide anions in 1-propanol, such as but not limited to KCN, can be used to open the epoxide functional groups to obtain the final O-Het / aryl analogs. Weak bases such as NaHCO3 or salts such as NH4Cl or (NH4)2SO4 can sometimes accelerate the epoxide ring-opening reaction.

[0228] Scheme 2a: Preparation of compounds (1-A1) to (1-A6) of formula (1)

[0229]

[0230] Alternatively, the analogue can be prepared according to the reaction outlined in Scheme 2a. In the first step, a commercially available tylosin epoxide intermediate is treated with various nucleophiles, such as, but not limited to, primary and secondary amines, ethanol, thiols, cyanides, azides, or halide anions, at a higher temperature in an alcoholic solvent, such as, but not limited to, 1-propanol, 1-butanol, or 2-propanol. Weak bases such as NaHCO3 or salts such as NH4Cl or (NH4)2SO4 can sometimes accelerate the ring-opening reaction of the epoxide. This step is detailed in Scheme 2b below. In the second step, the tertiary dimethylamine on the erythromycin deoxyglycosamine can be demethylated using the Polonowski-type conditions described above. Details of step 2 are shown in Scheme 2c. The final analogue can be prepared by reacting the Polonowski reaction product with aryl or heteroarylboronic acids or boronic esters and copper salts such as, but not limited to, copper(II) acetate, in the presence of a weak base such as pyridine, a drying agent such as a molecular sieve, and oxygen. Details of this third and final step are shown in scheme 2d.

[0231] Option 2b: Details of step 1 in Option 2a (nucleophilic epoxide ring opening)

[0232]

[0233] For (s2b-A1) compounds, alcohol solvents, such as, but not limited to, various primary or secondary amines from methanol, ethanol, 1-propanol, etc., can be used to open the ring-opening reaction of the epoxide functional groups. For (s2b-A2) compounds, various alcohols used as solvents, such as, but not limited to, methanol, ethanol, 1-propanol, etc., can be used to open the ring-opening reaction of the epoxide functional groups. Weak bases such as NaHCO3 or salts such as NH4Cl or (NH4)2SO4 can sometimes accelerate the ring-opening reaction of the epoxide. For (s2b-A3) compounds, alcohol solvents, such as, but not limited to, various thiols from ethanol or 1-propanol, such as, but not limited to, ethanethiol, propanethiol, isopropylthiol, etc., can be used to open the ring-opening reaction of the epoxide functional groups. Weak bases such as, but not limited to, NaHCO3 are used to accelerate the ring-opening reaction of the epoxide. For (s2b-A4) compounds, alcohol solvents, such as, but not limited to, various halides from the reagent from ethanol or 1-propanol, such as, but not limited to, CeCl3 or Br2, can be used to open the ring-opening reaction of the epoxide functional groups. Weak bases such as NaHCO3 or salts such as NH4Cl or (NH4)2SO4 can sometimes accelerate the ring-opening reaction of epoxides. For (s2b-A5) compounds, the ring-opening reaction of epoxide functional groups can be achieved using alcoholic solvents, such as, but not limited to, ethanol or 1-propanol, with different sources of azide anions, such as, but not limited to, NaN3. Weak bases such as NaHCO3 or salts such as NH4Cl or (NH4)2SO4 can sometimes accelerate the ring-opening reaction of epoxides. For (s2b-A6) compounds, the ring-opening reaction of epoxide functional groups can be achieved using alcoholic solvents, such as, but not limited to, IPA or 1-propanol, with different sources of cyanide anions, such as, but not limited to, KCN. Weak bases such as NaHCO3 or salts such as NH4Cl or (NH4)2SO4 can sometimes accelerate the ring-opening reaction of epoxides.

[0234] Solution 2c: Details of step 2 in Solution 2a (demethylation):

[0235]

[0236] All compounds (s2b-A1) to (s2b-A6) can undergo Polonowski-type demethylation as described above to yield the corresponding compounds (s2c-A1) to (s2c-A6). N-oxides can be formed using various oxidizing agents, such as, but not limited to, peracetic acid or hydrogen peroxide. Demethylation of N-oxides can be triggered by such reagents, but not limited to, iron or copper salts.

[0237] Scheme 2d: Details of step 3 in Scheme 2a: (O-Het / arylation)

[0238]

[0239] In the final step of the sequence, the final analogue can be prepared by reacting the Polonowski reaction product with aryl or heteroarylboronic acids and copper salts such as, but not limited to, copper(II) acetate in the presence of a weak base such as pyridine, a drying agent such as a molecular sieve, and oxygen.

[0240] Scheme 3a: Preparation of compounds (1-A1) to (1-A6) of formula (1):

[0241]

[0242] Alternatively, the analogue can be prepared as described in Scheme 3a. In the first step, the commercially available tylosin epoxide intermediate can be demethylated in, but not limited to, the Polonowski reaction described above. The resulting M9-epoxide can then be reacted with various nucleophiles, such as, but not limited to, primary and secondary amines, ethanol, thiols, cyanides, azides, or halide anions, at higher temperatures in alcoholic solvents, such as, but not limited to, 1-propanol, 1-butanol, or 2-propanol, to partially open the epoxide ring. Weak bases such as NaHCO3 or salts such as NH4Cl or (NH4)2SO4 can sometimes accelerate the ring-opening reaction of the epoxide. Details of this second step are shown in Scheme 3b below. In the final step, the final O-Het / aryl analogue can be prepared by reacting the product from the second step with aryl or heteroaryl borates or borate esters and copper salts such as, but not limited to, copper(II) acetate, in the presence of a weak base such as pyridine and a drying agent such as a molecular sieve and oxygen. The details of this final transformation are shown in scheme 3c below.

[0243] Option 3b: Details of step 2 in Option 3a (nucleophilic epoxide ring opening)

[0244]

[0245] The M9-epoxide formed by the demethylation of commercially available tylosin epoxide (scheme 3a) can be reacted to give the following compounds having the following formula:

[0246] (s3b-A1) - Has an alcohol solvent, such as, but not limited to, various primary or secondary amines in methanol, ethanol, or 1-propanol; (s3b-A2) - Has various alcohols used as solvents, such as, but not limited to, methanol, ethanol, or 1-propanol. Weak bases such as NaHCO3 or salts such as NH4Cl or (NH4)2SO4 can sometimes accelerate the ring-opening reaction of epoxides; (s3b-A3) - Has an alcohol solvent, such as, but not limited to, various thiols in ethanol or 1-propanol, such as, but not limited to, ethanethiol, propanethiol, isopropylthiol, etc. Weak bases such as, but not limited to, NaHCO3 are used to accelerate the ring-opening reaction of epoxides; (s3b-A4) - Has an alcohol solvent, such as, but not limited to, halides from reagents in ethanol or 1-propanol, such as, but not limited to, CeCl3 or Br2. Weak bases such as NaHCO3 or salts such as NH4Cl or (NH4)2SO4 can sometimes accelerate the ring-opening reaction of epoxides; (s3b-A5)- have alcohol solvents, such as, but not limited to, azide anions from ethanol or 1-propanol, such as, but not limited to, NaN3. Weak bases such as NaHCO3 or salts such as NH4Cl or (NH4)2SO4 can sometimes accelerate the ring-opening reaction of epoxides; and (s3b-A6) have alcohol solvents, such as, but not limited to, IPA or cyanide anions from 1-propanol, such as, but not limited to, KCN. Weak bases such as NaHCO3 or salts such as NH4Cl or (NH4)2SO4 can sometimes accelerate the ring-opening reaction of epoxides.

[0247] Solution 3c: Details of step 3 in Solution 3a: (O-Het / Arylation)

[0248]

[0249] In the final step, the final analogues of formulas (s3c-A1), (s3c-A2), (s3c-A3), (s3c-A4), (s3c-A5), and (s3c-A6) can be prepared by reacting the corresponding (s3b-A#) analogue with aryl or heteroaryl borate or borate esters and copper salts such as, but not limited to, copper(II) acetate in the presence of a weak base such as pyridine and a drying agent such as a molecular sieve.

[0250] Scheme 4a: Preparation of compounds (1-A1) to (1-A6) of formula (1):

[0251]

[0252] Alternatively, the analogue can be prepared as described in Scheme 4a. In the first step, commercially available tylosin epoxide can be reacted with various nucleophiles, such as, but not limited to, primary and secondary amines, ethanol, thiols, cyanides, azides, or halide anions, at higher temperatures in an alcoholic solvent, such as, but not limited to, 1-propanol, 1-butanol, or 2-propanol, to partially open the epoxide ring. Weak bases such as NaHCO3 or salts such as NH4Cl or (NH4)2SO4 can sometimes accelerate the ring-opening reaction of the epoxide. Details of this first step are shown in Scheme 4b below. In the second and final steps, the final O-Het / aryl analogue can be prepared by reacting the product from the first step with aryl or heteroaryl borates or borate esters and copper salts such as, but not limited to, copper(II) acetate, in the presence of a weak base such as pyridine and a drying agent such as a molecular sieve and oxygen. Details of this final transformation are shown in Scheme 4b below.

[0253] Option 4b: Details of step 1 in Option 4a (nucleophilic epoxide ring opening)

[0254]

[0255] Tula epoxides can be reacted to give the following compounds having the following formula:

[0256] (s4b-A1) - Has an alcohol solvent, such as, but not limited to, various primary or secondary amines in methanol, ethanol, or 1-propanol; (s4b-A2) - Has various alcohols used as solvents, such as, but not limited to, methanol, ethanol, or 1-propanol. Weak bases such as NaHCO3 or salts such as NH4Cl or (NH4)2SO4 can sometimes accelerate the ring-opening reaction of epoxides; (s4b-A3) - Has an alcohol solvent, such as, but not limited to, various thiols in ethanol or 1-propanol, such as, but not limited to, ethanethiol, propanethiol, isopropylthiol, etc. Weak bases such as, but not limited to, NaHCO3 are used to accelerate the ring-opening reaction of epoxides; (s4b-A4) - Has an alcohol solvent, such as, but not limited to, halides from reagents in ethanol or 1-propanol, such as, but not limited to, CeCl3 or Br2. Weak bases such as NaHCO3 or salts such as NH4Cl or (NH4)2SO4 can sometimes accelerate the ring-opening reaction of epoxides; (s4b-A5)- have alcohol solvents, such as, but not limited to, azide anions from ethanol or 1-propanol, such as, but not limited to, NaN3. Weak bases such as NaHCO3 or salts such as NH4Cl or (NH4)2SO4 can sometimes accelerate the ring-opening reaction of epoxides; and (s4b-A6) have alcohol solvents, such as, but not limited to, IPA or cyanide anions from 1-propanol, such as, but not limited to, KCN. Weak bases such as NaHCO3 or salts such as NH4Cl or (NH4)2SO4 can sometimes accelerate the ring-opening reaction of epoxides.

[0257] Solution 4c: Details of step 2 in Solution 4a: (O-Het / Arylation)

[0258]

[0259] In the final step, the final analogues of formulas (s4c-A1), (s4c-A2), (s4c-A3), (s4c-A4), (s4c-A5), and (s4c-A6) can be prepared by reacting the corresponding (s4b-A#) product with aryl or heteroaryl borate or borate ester and copper salts such as, but not limited to, copper(II) acetate in the presence of a weak base such as pyridine and a drying agent such as a molecular sieve.

[0260] Scheme 5: Preparation of alkylated nucleocyanate (1) compounds by reductive amination

[0261]

[0262] Alkyl-tula-epx intermediates can be readily synthesized from tula epoxides (tula-epx) by various methods, such as, but not limited to, reductive amination with the corresponding aldehyde and hydrides such as, but not limited to, STAB or NaBH3CN, in solvents such as alcohols or DMF, and at temperatures between 0°C and 60°C. This can be achieved by, for example, using R… 2 Alkylated tylosin epoxide intermediate (alkyl-tula-epx) replaces the starting material Tula-epoxide (where R) in all schemes 1-4 2 It is propyl), used to prepare the compounds of the present invention (wherein the macrocyclic lactone nucleus is made of various R... 2 The subsequent chemical reactions (alkylation of the group) can be carried out using schemes 1-4 (e.g., Polonowski-type demethylation, epoxide ring opening, and Chan-Lam coupling).

[0263] Option 6: Subjected to various R 1 and R 2 Preparation of compounds of formula (1) with substituent groups: Preparation of the common intermediate M8 epoxide (M8-epx)

[0264]

[0265] The (M8-epx) intermediate can be readily synthesized from the M9 epoxide by various methods, such as secondary demethylation with I2 and NaOMe or a triple sequence, wherein the M9 epoxide is first protected with a 4-methoxybenzyl group and then demethylated using Polonowski demethylation. The M8 epoxide is revealed by removing the protecting group under hydrogenolysis conditions using an alcohol solvent, such as, but not limited to, methanol, ethanol, or trifluoroethanol, with Pd / C and H2 gas. The M8 epoxide can be used in various ways to prepare the compounds of the present invention, as shown in Scheme 7 below.

[0266] Option 7: Various R... (The sentence is incomplete and requires more context to translate accurately.) 1 and R 2 Preparation of compounds of formula (1) with substituent groups

[0267]

[0268] M8 epoxides can be reacted under Chan-Lam coupling conditions to yield the compounds of this invention. Selective reactions for the deoxyglycosamine oxygenation of erythromyces can be carried out using copper(II) acetate, aryl or heteroaryl boric acids or boronic esters, weak bases such as pyridine, drying agents such as molecular sieves, and oxygen to yield the desired compounds as shown in Scheme 7.

[0269] M8 epoxide can also be used with the corresponding R 1 Aldehydes and hydrides such as, but not limited to, STAB or NaBH3CN, undergo reductive amination in solvents such as alcohols, DMF, DCM, or DCE, and at temperatures between 0°C and 60°C. This is achieved through the substitution of R... 1 (M8-R 1 ) replace the starting material M9-epoxide in all schemes 1-3 for the preparation of the compound of the present invention (wherein R 1 It is not CH3, because in tyromycin-derived analogues, the subsequent chemical reactions can be accomplished using schemes 1-3 (e.g., ring-opening of the epoxide and Chan-Lam coupling). Similarly, M8 epoxide can also be used with the corresponding R... 1 Aldehydes and R 2 Aldehydes and hydrides such as, but not limited to, STAB or NaBH3CN undergo two consecutive reductive aminations in solvents such as alcohols, DMF, DCM, or DCE at temperatures between 0°C and 60°C. This is achieved by using substituted R... 1 and R 2 (M8-R 1 R 2 ) replace the starting material M9-epoxide in all schemes 1-3 for the preparation of the compound of the present invention (wherein R 1 and R 2Not CH3, because in tylosin-derived analogues, the subsequent chemical reactions can be accomplished using schemes 1-3 (e.g., epoxide ring-opening and Chan-Lam coupling).

[0270] Scheme 8: Preparation of compound of formula (1-A0) of formula (1) by reductive amination with azithromycin

[0271]

[0272] Azithromycin can be used as a starting material for the synthesis of compounds of formula (1) of the present invention, as shown in Scheme 7. Azithromycin can be reacted with boric acid or borate esters to prepare analogs under Chan-Lam coupling conditions. Azithromycin can also undergo demethylation reactions similar to those of tylosin under similar conditions, such as, but not limited to, the Polonowski reaction as defined herein. Demethylated azithromycin can be reacted with boric acid or borate esters to prepare analogs under Chan-Lam coupling conditions using copper salts such as copper acetate and weak bases such as pyridine in aprotic solvents such as DMF.

[0273] Furthermore, demethylazithromycin can undergo secondary demethylation with I2 and NaOMe as described above, followed by R... 1 The aldehyde is subjected to reductive amination. R 2 Substituted demethylated azithromycin can also be reacted under the Chan-Lam conditions shown herein to prepare the compounds of the present invention. Bis-demethylated azithromycin materials can also be reacted under Chan-Lam conditions to obtain the compounds of the present invention.

[0274] Scheme 9: Preparation of urea compounds of formula (1)

[0275]

[0276] Alternatively, compounds of formula (1) substituted with a urea group on erythromycin deoxyglycosamine (i.e., formula (1-A1a)) can be synthesized according to the sequence shown in Scheme 9. The first three steps of the sequence are detailed in Schemes 2a, 2b, 2c, and 2d, and consist of ring-opening of the epoxide portion of the tylosin epoxide, followed by Polonowski demethylation and Chan-Lam coupling (see Schemes 2a-d above for details). The final step of the sequence is a urea-forming reaction using a reagent such as, but not limited to, carbamoyl chloride, isocyanate, or phosgene, and a corresponding amine in an aprotic solvent and a weak base such as, but not limited to, TEA or DIPEA, to obtain the desired analog.

[0277] Scheme 10: Preparation of the erythromycin-free compound of formula (1.1)

[0278]

[0279] The deerythromycin compound of formula (1.1) can be readily synthesized from any compound of formula (1A) by stirring the compound in an aqueous acetic acid or hydrochloric acid solution at a temperature between 0°C and 60°C in a solvent such as, but not limited to, THF, MeCN or H2O for 1 hour to 72 hours, as shown in Scheme 10.

[0280] Scheme 11: Preparation of the compound deerythromycin urea of ​​formula (1.1)

[0281]

[0282] The deerythromycin glycosuria compound of formula (1.1) can be synthesized according to the sequence shown in Scheme 11. Azithromycin can be demethylated according to the Polonowski demethylation conditions described herein. The erythromycin glycosuria of demethylated azithromycin can be cleaved in acidic aqueous solution with acids such as acetic acid or hydrochloric acid and other solvents such as THF or acetonitrile. In the presence of a weak base such as pyridine and a drying agent such as molecular sieve and oxygen in an aprotic solvent such as DMF, copper acetate and aryl or heteroarylboronic acids or borate esters are used, and the O-Het / aryl (cyclic C) function can be selectively mounted on the erythromycin deoxyglycosamine sugar oxygen. In the final step, the secondary amine on the erythromycin deoxyglycosamine sugar can be reacted with carbamoyl chloride or isocyanate or various amines activated with phosgene to form the urea functional group of the desired deerythromycin glycosuria compound.

[0283] Example

[0284] Preparation of Example A-9 of Formula (1-A0):

[0285]

[0286] Step 1: In a 500 mL round-bottom flask under N2 atmosphere, add 40 mL of MeOH containing azithromycin (20 g, 26.77 mmol, 1 equivalent), 3.4 mL of glacial acetic acid (53.54 mmol, 2.2 equivalents), 1.9 mL of hexafluoroacetone (13.38 mmol, 0.5 equivalents), and 5 mL of H2O2 (30% w / w in H2O). Stir the reaction mixture at room temperature (25 °C) for 16 hours, then add anhydrous CuSO4 (6.4 g, 40.15 mmol, 1.5 equivalents). The round-bottom flask is equipped with a reflux condenser, and the reaction mixture is stirred at 80 °C under N2 atmosphere for 6 hours. The reaction mixture is then cooled to room temperature, concentrated to remove MeOH, and diluted with DCM (300 mL). The solution is filtered through diatomaceous earth, and the filtrate is alkalized to pH 10 with ammonia solution. The organic phase was separated, washed with water and brine, dried over anhydrous Na2SO4, and concentrated to obtain a crude material. The crude material was ground with a pentane-diethyl ether (2:1) solution to obtain the desired demethylated azithromycin (13 g, 66.2%) as a grayish-white solid.

[0287] Step 2: The following substances from Step 1 were added: desmethylazithromycin (250 mg, 0.34 mmol, 1.0 equivalent), (4-fluorophenyl)boric acid (74 mg, 0.51 mmol, 1.5 equivalent), copper(II) acetate (154 mg, 0.85 mmol, 2.5 equivalent), and molecular sieve (…). A mixture of activator (0.5 g) and pyridine (55 μL, 2 equivalents, 0.68 mmol) in DMF (5.0 mL) was stirred for 3 days at room temperature under dry air. Once the reaction was complete as determined by LCMS analysis, the mixture was poured into MTBE (20 mL) and 1 mL of 10% NH3, and then filtered through diatomaceous earth. The mixture was then separated and washed with water (10 mL), 2M NaOH (1 mL), and brine (10 mL) before evaporation to give a pale purple solid as a crude material. The crude material was purified by reversed-phase rapid chromatography on a C18 column using 0.5% AcOH as a modifier. The fraction containing the desired product was lyophilized to give the desired product as acetate (143 mg, 47%).

[0288] Preparation of Example A-19 of Formula (1-A0):

[0289]

[0290] Azithromycin (250 mg, 0.33 mmol, 1.0 equivalent), phenylboronic acid (72 mg, 0.50 mmol, 1.5 equivalent), copper(II) acetate (152 mg, 0.83 mmol, 2.5 equivalent), and molecular sieve ( A mixture of activator (0.5 g) and pyridine (54 μL, 2 equivalents, 0.67 mmol) in DMF (5.0 mL) was stirred for 3 days at room temperature under dry air. Once the reaction was complete as determined by LCMS analysis, the mixture was poured into MTBE (20 mL) and 1 mL of 10% NH3, and then filtered through diatomaceous earth. The mixture was then separated and washed with water (10 mL), 2M NaOH (1 mL), and brine (10 mL) before evaporation to obtain a pale purple solid as a crude material. The crude material was purified by reversed-phase rapid chromatography on a C18 column using 0.5% AcOH as a modifier. The fraction containing the desired product was lyophilized to obtain the desired product as acetate (121 mg, 44%).

[0291] Compounds of formula (1-A0) from Table A can be prepared under similar conditions, starting with azithromycin and changing the boric acid reagent in the Chan Lam coupling step, in a manner similar to that shown above for examples A-9 and A-19. Coupling can be effectively used for both azithromycin and desmethylazithromycin, as shown in the examples above.

[0292] Preparation of erythromycin-free saccharides from Formula (1.1) of Example E-1 in Example B-4

[0293]

[0294] Add 10.0 mL of 2N HCl to Example (E-1) (500.0 mg) and heat the resulting mixture at 45 °C for 2 hours, then cool to room temperature. Pour the crude reaction mixture into ice-cold NH4OH solution (pH > 7), stir for 5 minutes, then concentrate and lyophilize. Purify the crude material by preparative HPLC using ammonium acetate as a buffer, and pass the purified material through an SCX column to obtain the desired free base product. Compounds of formula (1.1) from Table B can be prepared under similar conditions but for starting materials of formulas (1-A0) and (1-A1) in a manner similar to that shown above for Example B-4.

[0295] Preparation of deerythromycin from Example F-7 of Formula (1.1a) (Example C-7)

[0296]

[0297] 1N HCl (10.0 mL) was added to Example F-7 (200.0 mg), and the resulting mixture was heated at room temperature for 12 hours, then cooled to room temperature. The crude reaction mixture was poured into ice-cold NH4OH solution (pH > 7), 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 obtain the desired free base product.

[0298] Compounds of formula (1.1a) derived from tylosin from Table C can be prepared under similar conditions but for starting materials of formula (1-A1) in a manner similar to that shown above for example C-7.

[0299] Preparation of Example C-12 of Formula (1.1a) without Erythromycin

[0300]

[0301] Step 1: In a 500 mL round-bottom flask under N2 atmosphere, add 40 mL of MeOH containing azithromycin (20 g, 26.77 mmol, 1 equivalent), 3.4 mL of glacial acetic acid (53.54 mmol, 2.2 equivalents), 1.9 mL of hexafluoroacetone (13.38 mmol, 0.5 equivalents), and 5 mL of H2O2 (30% w / w in H2O). Stir the reaction mixture at room temperature (25 °C) for 16 hours, then add anhydrous CuSO4 (6.4 g, 40.15 mmol, 1.5 equivalents). The round-bottom flask is equipped with a reflux condenser, and the reaction mixture is stirred at 80 °C under N2 atmosphere for 6 hours. The reaction mixture is then cooled to room temperature, concentrated to remove MeOH, and diluted with DCM (300 mL). The solution is filtered through diatomaceous earth, and the filtrate is alkalized to pH 10 with ammonia solution. The organic phase was separated, washed with water and brine, dried over anhydrous Na2SO4, and concentrated to obtain a crude material. The crude material was ground with a pentane-diethyl ether (2:1) solution to obtain the desired demethylated azithromycin (13 g, 66.2%) as a grayish-white solid.

[0302] Step 2: Add 1N HCl (10.0 mL) to the desmethylazithromycin (500.0 mg) from Step 1, and heat the resulting mixture at room temperature for 12 hours, then cool to room temperature. Pour the crude reaction mixture into an ice-cold NH4OH solution (pH > 7), stir for 5 minutes, then concentrate and lyophilize. Purify the crude material by preparative HPLC using 0.1% TFA as a modifier. Combine the desired fractions, adjust the pH to approximately 9.8 with NH4OH, and extract three times with DCM. Combine the organic layers, dry over anhydrous magnesium sulfate, and remove volatiles under reduced pressure to obtain the desired material as a grayish-white amorphous solid.

[0303] Step 3: Combine the following from Step 2: Erythromycin (250 mg, 0.42 mmol, 1.0 equivalent), phenylboronic acid (80 mg, 0.63 mmol, 1.5 equivalent), copper(II) acetate (192 mg, 1.1 mmol, 2.5 equivalent), and molecular sieve (…). A mixture of activator (0.5 g) and pyridine (59 μL, 2 equivalents, 0.84 mmol) in DMF (5.0 mL) was stirred for 3 days at room temperature under dry air. Once the reaction was complete as determined by LCMS analysis, the mixture was poured into MTBE (20 mL) and 1 mL of 10% NH3, and then filtered through diatomaceous earth. The mixture was then separated and washed with water (10 mL), 2 M NaOH (1 mL), and brine (10 mL) before evaporation to obtain a pale purple solid as a crude material. The crude material was purified by preparative HPLC using 0.1% TFA as a modifier. The desired fractions were combined, the pH was 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 were removed under reduced pressure to obtain the desired material as a grayish-white amorphous solid.

[0304] Step 4: In a dry round-bottom flask, dissolve the material from Step 3 (200 mg, 0.31 mmol, 1.0 equivalence) in dry DCM (5 mL), and add DIPEA (0.134 mL, 2.5 equivalence), followed by N-methyl-N-phenyl-carbamoyl chloride (62 mg, 1.2 equivalence, 0.37 mmol). Stir the mixture overnight, after which LCMS analysis indicates that all starting material has been consumed. Remove volatiles under N2 flow, and purify the crude material by reversed-phase chromatography on preparative HPLC using 0.1% TFA as a modifier. Combine the fractions containing the desired product, adjust the pH to approximately 12 with NH4OH, and extract three times with 50 mL DCM to obtain the desired free base product (93 mg, 39% yield).

[0305] The azithromycin-derived compounds of formula (1.1a) from Table C can be prepared under similar conditions as shown above for example C-12 by changing the boric acid in the Chan Lam coupling step and the urea-forming agent in the final step.

[0306] Compounds of formula (1.1b) derived from tylosin from Table D can be prepared under similar conditions, but with respect to the starting material of formula (1-A1a), in a manner similar to that shown above with respect to Example C-7. Compounds of formula (1.1b) derived from azithromycin from Table D can be prepared under similar conditions, in a manner similar to that shown above with respect to Example C-12, by changing the boric acid in the Chan Lam coupling step and the urea-forming agent in the final step.

[0307] Preparation of Example E-1 of Formula (1-A1):

[0308]

[0309] 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-1,5-dioxaspiro[2.5]oct-6-yl) A solution of 20.0 g (27 mmol) of hexamethyl-1-oxa-6-azacyclopentadecan-15-one (tula-epx) in methanol (40 mL) was mixed with acetic acid (1.6 mL (30 mmol), hexafluoroacetone trihydrate (0.38 mL (3 mmol)), and then with a 30% aqueous solution of hydrogen peroxide (0.62 g (30 mmol) and stirred at 35 °C for 4 hours. After the starting material was consumed as determined by LCMS, the reaction mixture was cooled to 20 °C, and anhydrous copper(II) sulfate (4.5 g (29 mmol) was added. The reaction mixture was then heated to 60 °C for 1 hour. After the reaction was complete as determined by LCMS, the reaction mixture was cooled to 20 °C, and 60 mL of DCM and 80 mL of H₂O were added. The mixture was alkalized to approximately pH 9.8 with concentrated ammonia. The mixture was concentrated to a solid under vacuum and recrystallized from acetone / water to give 60 g of white crystalline product (M9-epx) with a purity of LCMS 95%, which was used in the next step.

[0310] Step 2: The solution of 10 g (13.14 mmol) M9-epx from Step 1 and 10.9 mL n-propylamine (10.0 equivalent, 131.4 mmol) in 100 mL 1-propanol was heated to 80 °C for 16 hours. After the reaction was completed as determined by LCMS analysis, the volatiles were removed under reduced pressure, dissolved in 100 mL DCM and H2O, 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, and the crude material purified on C18 silica was obtained by reversed-phase rapid chromatography using 1.0% AcOH as a modifier (H2O containing 0 to 100% MeCN). The desired fractions were combined, the pH was adjusted to approximately 9.8 with NH4OH, and the crude material was extracted three times with DCM. The organic layers were combined, dried with anhydrous magnesium sulfate, and the volatiles were removed under reduced pressure to obtain the desired material, which is a grayish-white amorphous solid.

[0311] Step 3: The product of Step 2 (3.6 g, 4.5 mmol), (4-fluorophenyl)boric acid (2.5 g, 18.0 mmol, 4 equivalents), copper(II) acetate (1.24 g, 1.5 equivalents, 6.8 mmol), and molecular sieve ( A mixture of activator (4.0 g) and pyridine (1.5 mL, 4 equivalents, 18.0 mmol) in DMF (35.0 mL, 100% by mass) was stirred for 3 days at room temperature under dry air. Once the reaction was complete as determined by LCMS analysis, the mixture was poured into MTBE (70 mL) and 20 mL of 10% NH3, and then filtered through diatomaceous earth. The mixture was then separated and washed with water (50 mL), 2M NaOH (10 mL), and brine (10 mL) before evaporation to give a pale purple solid (5.0 g) as crude material. The crude material was purified by reversed-phase rapid chromatography on a C18 column using 0.5% AcOH as a modifier. The fraction containing the desired product was lyophilized to give the desired compound as an acetate.

[0312] Compounds of formula (1-A1) derived from desmethylteratin from Table E (R) 1 It is methyl and R 2 H) can be prepared under similar conditions as shown above for example E-1 by changing the boric acid in the Chan Lam coupling step and the amine in the epoxide ring-opening step.

[0313] Preparation of Example E-3 of Formula (1-A1):

[0314]

[0315] Compound (1-A1) was prepared according to Scheme 3. Tylamycin A (3.6 g, 4.5 mmol), phenylboronic acid (2.2 g, 18.0 mmol, 4 equivalents), copper(II) acetate (1.24 g, 1.5 equivalents, 6.8 mmol), molecular sieve ( A mixture of activator (4.0 g) and pyridine (1.5 mL, 4 equivalents, 18.0 mmol) in DMF (35.0 mL, 100% by mass) was stirred for 3 days at room temperature under dry air. Once the reaction was complete as determined by LCMS analysis, the mixture was poured into MTBE (70 mL) and 20 mL of 10% NH3, and then filtered through diatomaceous earth. The mixture was then separated and washed with water (50 mL), 2M NaOH (10 mL), and brine (10 mL) before evaporation to give a pale purple solid (5.0 g) as crude material. The crude material was purified by reversed-phase rapid chromatography on a C18 column using 0.5% AcOH as a modifier. The fraction containing the desired product was lyophilized to give the desired compound as an acetate.

[0316] Compounds of formula (1-A1) derived from tylosin from Table E (R) 1 and R 2 (The methyl group) can be prepared under similar conditions by changing the boric acid in the Chan Lam coupling step in a manner similar to that shown above for example E-3.

[0317] Example E-157 of formula (1-A1) is prepared using a modification of scheme 5, wherein the aldehyde used in the first step is propionaldehyde, and the nucleophile used to open the ring of the epoxide in the final step is 1-propylamine:

[0318]

[0319] Step 1: Add STAB to a solution of (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]oct-6-yl)oxy)-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one (tula-epx) (1.0 g, 1.34 mmol) in dry DMF (10 mL) and stir the resulting solution at 35 °C for 4 hours. After the starting material was determined to be consumed by LCMS, the reaction was cooled to 0°C, and 2 mL of saturated NH4Cl solution was added, followed by stirring for 5 minutes. The reaction mixture was then diluted with DCM (30 mL and H2O) and transferred to a separatory funnel. The pH was adjusted to approximately 12 with NH4OH, and the mixture was extracted three times with 20 mL of DCM. The organic matter was combined, dried over MgSO4, and removed under reduced pressure to obtain a crude material, which was purified by reversed-phase chromatography on a C18 column using a gradient of 1% AcOH / MeCN and H2O. The fractions containing the desired product were combined, the pH was adjusted to approximately 12 with NH4OH, and the mixture was extracted three times with 50 mL of DCM to obtain the desired product as a free base (600 mg, 57% yield).

[0320] Step 2: 600 mg of the product from Step 1 (0.76 mmol, 1.00 equivalent) was dissolved in 10 mL of dry EtOH and peracetic acid (32% dilution in acetic acid; 1.2 equivalent, 192 μL) was added. The resulting solution was stirred at room temperature for 45 min, after which LCMS showed complete conversion to the corresponding N-oxide. The reaction mixture was then diluted with DCM (30 mL and H2O) and transferred to a separatory funnel. The pH was adjusted to approximately 12 with NH4OH and extracted three times with 20 mL of DCM. The organic matter was combined and dried over MgSO4 under reduced pressure to obtain crude N-oxide. The crude N-oxide (0.76 mmol, 1.0 equivalent) was dissolved in 10 mL of dry ethanol and copper(II) sulfate pentahydrate (5.0 equivalent; 950 mg) was added, and the solution was stirred at 65 °C for 16 h, after which LCMS showed complete reaction. The reaction mixture was diluted with 20 mL of DCM and H2O, and the pH was adjusted to approximately 12 with NH4OH. The crude material was extracted three times with DCM, and the organic matter was combined, dried over MgSO4, and the volatiles were removed under reduced pressure to obtain the crude desired product with an LCMS purity >90%, which was used in the following steps.

[0321] Step 3: Add (propyl-M9-epx) (250 mg, 0.32 mmol, 1.0 equivalent), phenylboronic acid (61 mg, 0.48 mmol, 1.5 equivalent), copper(II) acetate (0.15 g, 2.5 equivalent, 0.81 mmol), and molecular sieve from Step 2. A mixture of activator (0.2 g) and pyridine (52 μL, 2 equivalents, 0.64 mmol) in DCM (5 mL) was stirred in dry air at room temperature for 3 days. Once the reaction was complete as determined by LCMS, the reaction mixture was filtered through diatomaceous earth, and volatiles were removed under reduced pressure. The crude material was purified by reversed-phase rapid chromatography on a C18 column using 0.5% AcOH as a modifier. Fractions containing the desired product were combined, the pH was adjusted to approximately 12 with NH4OH, and the mixture was extracted three times with 50 mL of DCM to obtain the free base (56 mg, 20% yield).

[0322] Step 4: Add the product from Step 3 (56 mg, 0.066 mmol, 1 equivalent) and N-propanol (2 mL) to a pressure vial, followed by N-propylamine (65 μL, 0.79 mmol, 12 equivalents). Stir the reaction mixture at 70 °C for 16 hours. The reaction mixture was then concentrated under vacuum, and the crude product was purified by reversed-phase chromatography using a C18 column with a 1% AcOH / MeCN gradient and H₂O. The fraction containing the desired product was lyophilized to give the desired product as acetate (16 mg, 27% yield).

[0323] Compounds of formula (1-A1) derived from alkylated tylosin from Table E (R) 0 Unlike H), it can be prepared under similar conditions in a manner similar to that shown above for Example E-157. By replacing propionaldehyde with any other alkyl aldehyde, such as, but not limited to, formaldehyde or acetaldehyde, in the first step of the sequence, the alkyl group R on the nucleus nitrogen... 0 These can be varied. Similar to other examples shown in this paper, the boric acid in the Chan-Lam coupling step and the amine in the epoxide ring-opening step can be varied.

[0324] Example E-155 of formula (1-A1) is prepared using a modification of scheme 7, wherein the nucleophile used to open the ring of the epoxide in the final step is N-propylamine, and R... 1 It is H and R 2 It is the isopropyl group derived from the reductive amination reaction using isobutyraldehyde.

[0325]

[0326] Step 1: In a 50 mL round-bottom flask, dissolve 1.0 g (1.36 mmol, 1.00 equivalent) of M9 epoxide in 10 mL of dry DMF, and add 2.0 equivalent of p-methoxybenzaldehyde (0.332 mL, 2.73 mmol), followed by 1.17 g of sodium triacetoxyborohydride (STAB, 4.0 equivalent, 5.5 mmol). Heat the resulting solution at 40 °C for 2 hours. Add another 0.6 g (2.7 mmol, 2.0 equivalent) of STAB and heat the resulting solution at 40 °C overnight. LCMS analysis showed that the starting material was consumed. Cool the reaction mixture to 0 °C and add 5 mL of saturated NH4Cl solution, stirring for 5 minutes. Dilute the reaction mixture with DCM (30 mL and H2O) and transfer to a separatory funnel. Adjust the pH to approximately 12 with NH4OH and extract three times with 20 mL of DCM. The organic matter was combined and dried over MgSO4, then removed under reduced pressure to obtain a crude material. This crude material was purified by reversed-phase chromatography on a C18 column eluted with a 1% AcOH / MeCN gradient and H2O. Fractions containing the desired product were combined, the pH was adjusted to approximately 12 with NH4OH, and the fractions were extracted three times with 50 mL of DCM to obtain the desired product (1008 mg, 87%) as a free base.

[0327] Step 2: 1008 mg of product from Step 1 (1.18 mmol, 1.00 equivalent) was dissolved in 10 mL of dry EtOH and peracetic acid (32% solution diluted in acetic acid; 304 μL, 1.5 equivalent) was added. The resulting solution was stirred at room temperature for 45 min, after which LCMS showed complete conversion to the corresponding N-oxide. Anhydrous copper(II) sulfate (3.0 equivalent; 566 mg) was then added, and the solution was stirred at 65 °C for 4 h, 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 H2O, and the pH was adjusted to approximately 12 with NH4OH. The crude material was extracted three times with DCM, and the organic matter was 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 using a gradient of 1% AcOH / MeCN and H2O. The fractions containing the desired product were combined, the pH was adjusted to approximately 12 with NH4OH, and the fractions were extracted three times with 50 mL of DCM to obtain the free base (250 mg, yield 25%).

[0328] Step 3: The product from Step 2 (250 mg, 0.30 mmol, 1.0 equivalence) was dissolved in 10 mL of CF3CH2OH. 5% Pd / C (25 mg) was added, and the resulting slurry was hydrogenated overnight at 40 °C under balloon pressure H2, after which LCMS showed complete reaction. Pd / C was filtered through diatomaceous earth, and volatiles were removed under reduced pressure to give M8 epoxide (M8-epx) (195 mg, 91%) as a white powder.

[0329] Step 4: In a 25 mL round-bottom flask, dissolve the product from Step 3 (M8-epx, 250 mg, 1.0 equivalent, 0.35 mmol) in 5 mL of dry MeOH and cool the solution to 0 °C. Add propionaldehyde (1.2 equivalent, 30 μL), followed by fractional addition of sodium triacetoxyborohydride (5 equivalent, 369 mg). Stir the solution at 0 °C to room temperature for 2 hours, after which LCMS shows complete conversion to the desired product. Then cool the reaction mixture to 0 °C and add 1 mL of saturated NH4Cl solution, stirring the solution for 5 minutes. Dilute the reaction mixture with DCM (30 mL and H2O) and transfer to a separatory funnel. Adjust the pH to approximately 12 with NH4OH and extract three times with 20 mL of DCM. Combine the organic matter and dry it with MgSO4 and remove it under reduced pressure to give the desired product (250 mg) as a white solid material with approximately 80% LCMS purity, which will be used for subsequent epoxide ring-opening.

[0330] Step 5: Combine the product from Step 4 (65 mg, 0.084 mmol, 1.0 equivalent), phenylboronic acid (21 mg, 0.17 mmol, 2.0 equivalent), copper(II) acetate (38 mg, 2.5 equivalent, 0.21 mmol), and molecular sieve ( A mixture of activator (0.1 g) and pyridine (14 μL, 2 equivalents, 0.17 mmol) in MeCN (2 mL) was stirred at 40 °C under dry air for 12 hours. Once the reaction was complete as determined by LCMS, the reaction mixture was filtered through diatomaceous earth, and volatiles were removed under reduced pressure. The crude material was purified by preparative HPLC using 0.1% TFA as a modifier. The desired fractions were combined, 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 volatiles were removed under reduced pressure to give the desired material as a grayish-white amorphous solid (25 mg, 40% yield).

[0331] Step 6: Add the product from Step 2 (25 mg, 0.03 mmol, 1 equivalent) and EtOH (2 mL) to a pressure vial, followed by N-propylamine (48 μL, 0.6 mmol, 20 equivalents). Stir the reaction mixture at 60 °C for 16 hours. The reaction mixture was then concentrated under vacuum, and the crude product was purified by preparative HPLC using 0.1% TFA as a modifier. The desired fractions were combined, the pH was adjusted to approximately 9.8 with NH4OH, and the mixture was extracted three times with DCM. The organic layers were combined, dried over anhydrous magnesium sulfate, and the volatiles were removed under reduced pressure to give the desired product (10 mg, 42% yield) as a grayish-white amorphous solid.

[0332] Following this example, by replacing propionaldehyde with any other alkyl aldehyde or ketone, such as but not limited to acetaldehyde or cyclohexanone or formaldehyde such as benzaldehyde or 2-pyridylformaldehyde, in the fourth step of the sequence, the alkyl group R on the nitrogen of the erythromycin deoxyglycoamine is... 2 It can be varied. Similar to other examples shown in this article, epoxides can be ring-opened with various amines.

[0333] Preparation of Example F-7 of Formula (1-A1a):

[0334]

[0335] 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-1,5-dioxaspiro[2.5]oct-6-yl) A solution of 20.0 g (27 mmol) of hexamethyl-1-oxa-6-azacyclopentadecan-15-one (tula-epx) in methanol (40 mL) was mixed with acetic acid (1.6 mL (30 mmol), hexafluoroacetone trihydrate (0.38 mL (3 mmol)), and then with a 30% aqueous solution of hydrogen peroxide (0.62 g (30 mmol) and stirred at 35 °C for 4 hours. After the starting material was consumed as determined by LCMS, the reaction mixture was cooled to 20 °C, and anhydrous copper(II) sulfate (4.5 g (29 mmol) was added. The reaction mixture was then heated to 60 °C for 1 hour. After the reaction was complete as determined by LCMS, the reaction mixture was cooled to 20 °C, and 60 mL of DCM and 80 mL of H₂O were added. The mixture was alkalized to approximately pH 9.8 with concentrated ammonia. The mixture was concentrated to a solid under vacuum and recrystallized from acetone / water to give 60 g of white crystalline product (M9-epx) with a purity of LCMS 95%, which was used in the next step.

[0336] Step 2: The solution of 10 g (13.14 mmol) M9-epx from Step 1 and 10.9 mL n-propylamine (10.0 equivalent, 131.4 mmol) in 100 mL 1-propanol was heated to 80 °C for 16 hours. After the reaction was completed as determined by LCMS analysis, the volatiles were removed under reduced pressure, dissolved in 100 mL DCM and H2O, 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, and the crude material purified on C18 silica was obtained by reversed-phase rapid chromatography using 1.0% AcOH as a modifier (H2O containing 0 to 100% MeCN). The desired fractions were combined, the pH was adjusted to approximately 9.8 with NH4OH, and the crude material was extracted three times with DCM. The organic layers were combined, dried with anhydrous magnesium sulfate, and the volatiles were removed under reduced pressure to obtain the desired material, which is a grayish-white amorphous solid.

[0337] Step 3: The product from Step 2 (250 mg, 0.32 mmol, 1.0 equivalent), (3,4-dimethoxyphenyl)boric acid (88 mg, 0.47 mmol, 1.5 equivalent), copper(II) acetate (143 mg, 2.5 equivalent, 0.79 mmol), and molecular sieve ( A mixture of activator (0.2 g) and pyridine (51 μL, 2 equivalents, 0.63 mmol) in DMF (5.0 mL) was stirred for 3 days at room temperature under dry air. Once the reaction was deemed complete by LCMS analysis, the mixture was filtered through diatomaceous earth, and volatiles were removed under reduced pressure. The crude material was purified on C18 silica using reversed-phase rapid chromatography with 1.0% AcOH as a modifier (H₂O containing 0 to 100% MeCN). The desired fractions were combined, the pH was adjusted to approximately 9.8 with NH₄OH, and extracted three times with DCM. The organic layers were combined, dried over anhydrous magnesium sulfate, and volatiles were removed under reduced pressure to obtain the desired material as a grayish-white amorphous solid.

[0338] Step 4: In a dry round-bottom flask, dissolve the material from Step 3 (150 mg, 0.16 mmol, 1.0 equivalence) in dry DCM (3 ml), and add DIPEA (69 μL, 2.5 equivalence), followed by N-methyl-N-phenyl-carbamoyl chloride (32 mg, 1.2 equivalence, 0.19 mmol). Stir the mixture overnight, after which LCMS analysis indicates that all starting material has been consumed. Remove volatiles under N2 flow, and purify the crude material by reversed-phase chromatography using a C18 column with a 1% AcOH / MeCN gradient and H2O. Lyophilize the fraction containing the desired product to give the desired product as acetate (99 mg, 55% yield).

[0339] Compounds of formula (1-A1a) derived from desmethylteratin from Table F (R) 1 It is methyl and R 2 H) can be prepared under similar conditions as shown above for example F-7 by changing the boric acid in the Chan Lam coupling, the amine in the epoxide ring-opening step, and the urea forming agent.

[0340] Compound (R) of formula (1-A1b) derived from desmethylterbinycin from Table G 1 It is methyl and R 2 H) can be prepared under similar conditions as shown above for example F-7 by changing the boric acid in the Chan Lam coupling, the amine in the epoxide ring-opening step, and the urea-forming agent derived from the secondary amine.

[0341] Derivatives from desmethylteratin epoxide (R) from Table H 1 It is methyl and R 2 It is H) or tylosin epoxide (R) 1 and R 2 Compounds of formula (1-A1c) with methyl group can be prepared under similar conditions as shown above for example E-1 by changing the boric acid in the Chan Lam coupling step and the cyclic secondary amine in the epoxide ring-opening step.

[0342] Table J (note: there is no Table I) provides the NMR of the instances presented in Table AH.

[0343] Compounds of formula (1-A0) below were prepared using the methods and formulations defined herein; shown in Table A, wherein R a It's H.

[0344]

[0345] The names of the corresponding compounds are provided below Table A.

[0346] Table A: Compounds of Formula (1-A0)

[0347]

[0348]

[0349]

[0350]

[0351] For at least one BRD strain, * MIC≤64μg / mL

[0352] Table A instance name:

[0353] A-1. 4-(((2S,3R,4S,6R)-4-(dimethylamino)-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-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl)oxy)benzamide;

[0354] A-2.(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-(4-ethoxyphenoxy)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one;

[0355] A-3. 2-(((2S,3R,4S,6R)-4-(dimethylamino)-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-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl)oxy)benzylnitrile;

[0356] A-4.(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-(3-isopropoxy-4-methoxyphenoxy)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one;

[0357] A-5.(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-3-((6-chloropyridin-3-yl)oxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one;

[0358] A-6. 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-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-3-yl)oxy)benzylnitrile;

[0359] A-7.(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-((2-methoxypyrimidin-5-yl)oxy)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one;

[0360] A-8.(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-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-11-(((2S,3R,4S,6R)-6-methyl-4-(methylamino)-3-(quinolin-6-yloxy)tetrahydro-2H-pyran-2-yl)oxy)-1-oxa-6-azacyclopentadecan-15-one;

[0361] A-9.(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-11-(((2S,3R,4S,6R)-3-(4-fluorophenoxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one;

[0362] A-10.(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-3-(2-chlorophenoxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one;

[0363] A-11. 4-(((2S,3R,4S,6R)-4-(dimethylamino)-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-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl)oxy)benzylnitrile;

[0364] A-12.(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-(3-fluoro-4-methoxyphenoxy)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one;

[0365] A-13.(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-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-11-(((2S,3R,4S,6R)-6-methyl-4-(methylamino)-3-((5-(trifluoromethyl)pyridin-3-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)-1-oxa-6-azacyclopentadecan-15-one;

[0366] A-14.(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-11-(((2S,3R,4S,6R)-3-(5-fluoro-2-methoxyphenoxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one;

[0367] A-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-dimethyltetrahydro-2H-pyran-2-yl)oxy)-11-(((2S,3R,4S,6R)-3-((2-methoxypyrimidin-5-yl)oxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one;

[0368] A-16.(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-3-(2,4-dimethoxyphenoxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one;

[0369] A-17.(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-3-(4-ethoxyphenoxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one;

[0370] A-18.(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-6-methyl-3-((5-(trifluoromethyl)pyridin-3-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one;

[0371] A-19.(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-6-methyl-3-phenoxytetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one;

[0372] A-20.(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-(3-methoxyphenoxy)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one;

[0373] A-21.(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-3-(2,4-dimethoxyphenoxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one;

[0374] A-22.(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-11-(((2S,3R,4S,6R)-3-(4-fluoro-3-(methylsulfonyl)phenoxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one;

[0375] A-23.(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-(4-fluorophenoxy)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one;

[0376] A-24.(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-(isoquinoline-7-yloxy)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one;

[0377] A-25.5-(((2S,3R,4S,6R)-4-(dimethylamino)-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-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl)oxy)-2-fluorobenzonitrile;

[0378] A-26.(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-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-11-(((2S,3R,4S,6R)-6-methyl-4-(methylamino)-3-phenoxytetrahydro-2H-pyran-2-yl)oxy)-1-oxa-6-azacyclopentadecan-15-one;

[0379] A-27.(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-(3-(ethylsulfonyl)phenoxy)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one;

[0380] A-28.(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-6-methyl-3-(quinolin-3-yloxy)tetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one;

[0381] A-29.(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-3-((6-chloro-4-methylpyridin-3-yl)oxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one;

[0382] A-30.(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-dimethyltetrahydro-2H-pyran-2-yl)oxy)-11-(((2S,3R,4S,6R)-3-(2-methoxyphenoxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one;

[0383] A-31.(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-3-((2-ethoxypyridin-3-yl)oxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one;

[0384] A-32.(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-((2-ethoxypyridin-3-yl)oxy)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one;

[0385] A-33.(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-dimethyltetrahydro-2H-pyran-2-yl)oxy)-11-(((2S,3R,4S,6R)-3-((2-methoxypyridin-3-yl)oxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one;

[0386] A-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-dimethyltetrahydro-2H-pyran-2-yl)oxy)-11-(((2S,3R,4S,6R)-3-(3-isopropoxy-4-methoxyphenoxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one;

[0387] A-35.(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-3-(2,5-dimethoxyphenoxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one;

[0388] A-36. 2-(((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-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-3-yl)oxy)benzylnitrile;

[0389] A-37.(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-dimethyltetrahydro-2H-pyran-2-yl)oxy)-11-(((2S,3R,4S,6R)-3-((6-methoxy-2-methylpyridin-3-yl)oxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one;

[0390] A-38.(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-((6-methoxy-2-methylpyridin-3-yl)oxy)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one;

[0391] A-39. 5-(((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-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-3-yl)oxy)-2-fluorobenzonitrile;

[0392] A-40.(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-3-(3,4-dimethoxyphenoxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one;

[0393] A-41.(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-11-(((2S,3R,4S,6R)-3-(3-(ethylsulfonyl)phenoxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one;

[0394] A-42.(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-3-((2,6-dimethoxypyridin-3-yl)oxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one;

[0395] A-43.(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-3-((2,6-dimethoxypyridin-3-yl)oxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one;

[0396] A-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-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-11-(((2S,3R,4S,6R)-6-methyl-4-(methylamino)-3-(quinolin-3-yloxy)tetrahydro-2H-pyran-2-yl)oxy)-1-oxa-6-azacyclopentadecan-15-one;

[0397] A-45.(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-3-((6-chloro-4-methylpyridin-3-yl)oxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one;

[0398] A-46.(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-(2-methoxyphenoxy)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one;

[0399] A-47.(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-6-methyl-3-(quinolin-6-yloxy)tetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one;

[0400] A-48.(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-3-(3,5-dimethoxyphenoxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one.

[0401] The following formula (1.1) is used to remove erythromycin compounds.

[0402]

[0403] Prepared according to the schemes and formulations defined herein; these are shown in Table B. The corresponding compound names are provided below the table.

[0404] Table B: Formula (1.1) De-erythromycin compounds

[0405]

[0406]

[0407] Table B instance name:

[0408] B-1.(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-(((2S,3R,4S,6R)-6-methyl-4-(methylamino)-3-phenoxytetrahydro-2H-pyran-2-yl)oxy)-1-oxa-6-azacyclopentadecan-15-one;

[0409] B-2,2-(((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-4-(methylamino)tetrahydro-2H-pyran-3-yl)oxy)ethyl benzoate;

[0410] B-3.(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-11-(((2S,3R,4S,6R)-3-(3-fluorophenoxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one;

[0411] B-4.(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-11-(((2S,3R,4S,6R)-3-(4-fluorophenoxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one;

[0412] B-5.(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-3-((2,3-dihydrobenzofuran-5-yl)oxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one;

[0413] B-6.(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-11-(((2S,3R,4S,6R)-3-(4-methoxyphenoxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one;

[0414] B-7.(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-3-(3-chlorophenoxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one;

[0415] B-8.4-(((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-4-(methylamino)tetrahydro-2H-pyran-3-yl)oxy)methyl benzoate;

[0416] B-9.(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-3-((3,6-dimethoxypyridazine-4-yl)oxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one;

[0417] B-10.(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-11-(((2S,3R,4S,6R)-6-methyl-4-(methylamino)-3-phenoxytetrahydro-2H-pyran-2-yl)oxy)-1-oxa-6-azacyclopentadecan-15-one;

[0418] B-11.(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-3-(benzo[d]thiazolyl-6-yloxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one;

[0419] B-12.(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-3-(5-chloro-2-(trifluoromethyl)phenoxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one; and

[0420] B-13.(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-((2-(3,5-dimethyl-1H-pyrazol-4-yl)propyl-2-yl)(methyl)amino)-6-methyl-3-phenoxytetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one.

[0421] The compounds of formula (1.1a) below were prepared according to the schemes and procedures defined herein and are presented in Table C, wherein R 1 and R 3 Each is a methyl group. The corresponding compound names are shown in the table below.

[0422]

[0423] Table C: Compounds of Formula (1.1a)

[0424]

[0425]

[0426]

[0427]

[0428] For at least one BRD strain, * MIC≤64μg / mL

[0429] Table C instance name:

[0430] C-1. 1-((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)-1,3-dimethyl-3-phenylurea;

[0431] C-2. 1-((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)-1,3-dimethyl-3-phenylurea;

[0432] C-3. 1-((2S,3R,4S,6R)-3-(4-cyanophenoxy)-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)-1,3-dimethyl-3-phenylurea;

[0433] C-4. 1-((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)-1,3-dimethyl-3-phenylurea;

[0434] C-5. 1-((2S,3R,4S,6R)-3-(4-chlorophenoxy)-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)-1,3-dimethyl-3-phenylurea;

[0435] C-6. 1-((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)-1,3-dimethyl-3-phenylurea;

[0436] C-7. 1-((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)-1,3-dimethyl-3-phenylurea;

[0437] C-8. 1-((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)-1,3-dimethyl-3-phenylurea;

[0438] C-9. 1-((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)-1,3-dimethyl-3-phenylurea;

[0439] C-10. 1-((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)-1,3-dimethyl-3-phenylurea;

[0440] C-11. 1-((2S,3R,4S,6R)-3-(benzo[d]thiazolyl-6-yloxy)-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-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;

[0441] C-12. 1-((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)-1,3-dimethyl-3-phenylurea;

[0442] C-13. 1-((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-methoxyphenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;

[0443] C-14. 1-((2S,3R,4S,6R)-3-(5-chloro-2-(trifluoromethyl)phenoxy)-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-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;

[0444] C-15. 1-((2S,3R,4S,6R)-3-((3,6-dimethoxypyridazine-4-yl)oxy)-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-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;

[0445] C-16. 1-((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)-1,3-dimethyl-3-(4-(trifluoromethyl)phenyl)urea;

[0446] C-17. 1-((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)-1,3-dimethyl-3-(pyrimidin-2-yl)urea;

[0447] C-18. 1-(4-chlorophenyl)-3-((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)-1,3-dimethylurea;

[0448] C-19. 1-Cyclohexyl-3-((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)-1,3-dimethylurea;

[0449] C-20. 1-Cyclopropyl-3-((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)-1,3-dimethylurea;

[0450] C-21. 1-Cyclobutyl-3-((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)-1,3-dimethylurea;

[0451] C-22. 1-((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)-1,3-dimethyl-3-(pyrimidin-2-yl)urea;

[0452] C-23. 1-((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)-1,3-dimethyl-3-propylurea;

[0453] C-24. 1-((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)-1,3-dimethyl-3-(4-(trifluoromethyl)phenyl)urea;

[0454] C-25. 1-((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-2-methylphenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-1,3,3-trimethylurea;

[0455] C-26. 1-(1,5-dimethyl-1H-pyrazol-3-yl)-3-((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)-1,3-dimethylurea;

[0456] C-27. 1-Cyclopropyl-3-((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)-1,3-dimethylurea;

[0457] C-28. 1-Cyclobutyl-3-((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)-1,3-dimethylurea;

[0458] C-29. 1-((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-2-methylphenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(pyrimidin-2-yl)urea;

[0459] C-30. 1-(1,5-dimethyl-1H-pyrazol-3-yl)-3-((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)-1,3-dimethylurea;

[0460] C-31. 1-((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)-1,3-dimethyl-3-propylurea;

[0461] C-32. 1-((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-2-methylphenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;

[0462] C-33. 1-((2S,3R,4S,6R)-3-((6-chloropyridin-3-yl)oxy)-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)-1,3-dimethyl-3-phenylurea;

[0463] C-34. 1-((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-(3-isopropoxy-4-methoxyphenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;

[0464] C-35. 1-((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-(quinolin-6-yloxy)tetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;

[0465] C-36. 1-(4-(dimethylamino)phenyl)-3-((2S,3R,4S,6R)-3-(3-ethoxyphenoxy)-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)-1,3-dimethylurea;

[0466] C-37. 1-((2S,3R,4S,6R)-3-(3-ethoxyphenoxy)-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)-1,3-dimethyl-3-phenylurea;

[0467] C-38. 1-((2S,3R,4S,6R)-3-(2-chlorophenoxy)-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)-1,3-dimethyl-3-phenylurea;

[0468] C-39. 1-((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)-3-isopropyl-1,3-dimethylurea;

[0469] C-40. 1-((2S,3R,4S,6R)-3-(3-chlorophenoxy)-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)-3-cyclobutyl-1,3-dimethylurea;

[0470] C-41. 1-((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-((2-methoxypyrimidin-5-yl)oxy)-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl–3-phenylurea;

[0471] C-42. 1-((2S,3R,4S,6R)-3-(3,5-difluoro-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)-1,3-dimethyl-3-phenylurea;

[0472] C-43. 1-((2S,3R,4S,6R)-3-(2-chlorophenoxy)-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)-3-(4-cyanophenyl)-1,3-dimethylurea;

[0473] C-44. 1-Cyclopropyl-3-((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-(quinoline-6-yloxy)tetrahydro-2H-pyran-4-yl)-1,3-dimethylurea;

[0474] C-45. 1-((2S,3R,4S,6R)-3-((6-chloropyridin-3-yl)oxy)-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-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;

[0475] C-46. 1-((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-(3-isopropoxy-4-methoxyphenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;

[0476] C-47. 1-((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-(quinolin-6-yloxy)tetrahydro-2H-pyran-4-yl)-3-isopropyl-1,3-dimethylurea;

[0477] C-48. 1-((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)-3-isopropyl-1,3-dimethylurea;

[0478] C-49. 1-((2S,3R,4S,6R)-3-(3,5-difluoro-4-methoxyphenoxy)-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-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;

[0479] C-50. 1-((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-(quinolin-6-yloxy)tetrahydro-2H-pyran-4-yl)-3-isopropyl-1,3-dimethylurea;

[0480] C-51. 1-((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-2-methylphenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(pyrimidin-2-yl)urea;

[0481] C-52. 1-((2S,3R,4S,6R)-3-(3-ethoxy-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)-1,3-dimethyl-3-phenylurea;

[0482] C-53. 1-Cyclopropyl-3-((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-((2-methoxypyrimidin-5-yl)oxy)-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethylurea; and

[0483] C-54. 1-((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-(quinoline-6-yloxy)tetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea.

[0484] Compounds of formula (1.1b) below are prepared using the methods and formulations defined herein; and furthermore, R... 1 It is methyl; the compound is shown in Table D. The corresponding compound name is provided below the table.

[0485]

[0486] Table D: Compounds of Formula (1.1b)

[0487]

[0488]

[0489] Table D instance name:

[0490] D-1.N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyl-3-phenoxytetrahydro-2H-pyran-4-yl)-N-methyl-3,4-dihydroquinoline-1(2H)-formamide;

[0491] D-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)-6-methyl-3-phenoxytetrahydro-2H-pyran-4-yl)-N-methyl-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxamide;

[0492] D-3.N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyl-3-phenoxytetrahydro-2H-pyran-4-yl)-N-methyl-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxamide; and

[0493] D-4.4-Ethyl-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-(3-isopropoxy-4-methoxyphenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-N-methylpiperazin-1-carboxamide.

[0494] The following compound (1-A1) is prepared using the methods and formulations defined herein; and further wherein R 0 R 1 R 2 R 5 R 6 and ring C(±R) 10 As defined in Table E. 1 It is methyl; and R 0 It is the upper part of the table, H and R. 0 The methyl group is the one in the lower part of the table; the compound is shown in Table E. The corresponding compound name is provided below the table.

[0495]

[0496] Table E: Compounds of Formula (1-A1)

[0497]

[0498]

[0499]

[0500]

[0501]

[0502]

[0503]

[0504]

[0505] For at least one BRD strain, * MIC≤64μg / mL

[0506] Table E instance name:

[0507] E-1.(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-11-(((2S,3R,4S,6R)-3-(4-fluorophenoxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-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;

[0508] E-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)-11-(((2S,3R,4S,6R)-3-(4-methoxyphenoxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one;

[0509] E-3.(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-6-methyl-3-phenoxytetrahydro-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;

[0510] E-4.(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-11-(((2S,3R,4S,6R)-6-methyl-4-(methylamino)-3-(quinolin-6-yloxy)tetrahydro-2H-pyran-2-yl)oxy)-1-oxa-6-azacyclopentadecan-15-one;

[0511] E-5.(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-11-(((2S,3R,4S,6R)-6-methyl-4-(methylamino)-3-(2-(trifluoromethoxy)phenoxy)tetrahydro-2H-pyran-2-yl)oxy)-1-oxa-6-azacyclopentadecan-15-one;

[0512] E-6.(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-((pro...

Claims

1. A compound of formula (1), Where W is H or equation (A) Where X is -R a or -R c NR 5 R 6 ; The ring C is phenyl, pyridinyl, pyridinyl, pyrazinyl, quinolinyl, or isoquinolinyl, each optionally surrounded by at least one R. 10 Substituent substitution; R a R b R 0 and R 1 Each is independently an H or C1-C6 alkyl group; R c It is a C1-C4 alkyl group; R 2 It is H, C1-C6 alkyl, cyclopropyl, cyclobutyl, C1-C3 alkyl, C3-C6 cycloalkyl, -C(O)NR 3 R 4 C1 alkylphenyl or a heteroaryl ring selected from C1 alkylpyrrolidinyl, -C1 alkylpiperidinyl, -C1 alkylpiperazinyl, -C1 alkylmorpholinyl, -C1 alkylpyrrolidinyl, C1 alkylpyrazolyl, -C1 alkylpyridinyl or C1 alkylpyrimidinyl; each optionally bound by at least one R 9 Substituent substitution; R 3 It is H, methyl, or ethyl; R 4 It is H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, phenyl, -C1 alkylphenyl, piperidinyl, -C1 alkylpiperidinyl, C2 alkylpiperidinyl, piperazine, morpholinyl, tetrahydro-2H-pyran, pyrazolyl, pyrimidinyl, or pyridinyl, each optionally marked with at least one R 9 Substituent substitution; Or R 3 and R 4 Together with the nitrogen atom to which it is attached, it forms a ring A, which is pyrroloyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally bonded by at least one R selected from methyl, ethyl, F, Cl, oxo, and CF3. 10 Substituent substitution; R 5 It is H, methyl, ethyl, propyl, or isopropyl; R 6 It is a C1-C6 alkyl group, -R c NR a R b -R c OR a Tetrahydropyran, cyclopropyl, -C1 alkylcyclopropyl, cyclobutyl, phenyl, pyridyl, pyrimidinyl, imidazolyl, thiazolyl, each of which may be optionally substituted with cyano or Cl; Or R 5 and R 6 Together with the nitrogen atom to which it is attached, it forms a ring B, which is piperidinyl, morpholinyl, or thiomorpholinyl; each of these rings is optionally bonded by at least one R group selected from methyl, ethyl, F, Cl, cyano, hydroxyl, oxo, and -CF3. 9 Substituent substitution; R 9 Independently selected from the group consisting of the following: methyl, ethyl, propyl, methoxy, ethoxy, F, Cl, oxo, hydroxy, cyano, NH2, NHCH3, -N(CH3)2, -CF3 and -OCF3; R 10 The following groups are selected independently: methyl, ethyl, methoxy, ethoxy, isopropoxy, cyano, amino, hydroxy, -OCF3, -CF3, F, Cl, -C(O)NH2, -S(O)2CH3 and -S(O)2CH2CH3; n is an integer 0, 1, 2, or 3; and its pharmaceutically acceptable salt.

2. The compound of formula (1) according to claim 1, wherein W is a compound of formula (A), which is a compound of formula (A0) or formula (A1), And its pharmaceutically acceptable salts.

3. The compound according to claim 2, wherein W is of formula (A1), and the compound is a compound of formula (1-A1). Where R 0 and R 1 Each is independently either H or methyl; And its pharmaceutically acceptable salts.

4. The compound of formula (1-A1) according to claim 3, wherein the compound is a compound of formula (1-A1a). And its pharmaceutically acceptable salts.

5. The compound of formula (1-A1) according to claim 3, wherein it is a compound selected from the group consisting of the following: E-3. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-6-methyl-3-phenoxytetrahydro-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; E-4. (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-11-(((2S,3R,4S,6R)-6-methyl-4-(methylamino)-3-(quinolin-6-yloxy)tetrahydro-2H-pyran-2-yl)oxy)-1-oxa-6-azacyclopentadecan-15-one; E-6. (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-11-(((2S,3R,4S,6R)-6-methyl-4-(methylamino)-3-(quinolin-5-yloxy)tetrahydro-2H-pyran-2-yl)oxy)-1-oxa-6-azacyclopentadecan-15-one; E-8. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-3-((6-chloropyridin-3-yl)oxy)-6-methyl-4-(methylamino)tetrahydro-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; E-10. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-11-(((2S,3R,4S,6R)-3-(3-fluoro-4-methoxyphenoxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-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; E-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-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-11-(((2S,3R,4S,6R)-6-methyl-4-(methylamino)-3-(3,4,5-trimethoxyphenoxy)tetrahydro-2H-pyran-2-yl)oxy)-1-oxa-6-azacyclopentadecan-15-one; E-12. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-3-(4-ethoxyphenoxy)-6-methyl-4-(methylamino)tetrahydro-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; E-13. (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-(3-ethoxyphenoxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one; E-15. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-3-(2,4-dimethoxyphenoxy)-6-methyl-4-(methylamino)tetrahydro-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; E-19. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-3-(3-ethoxy-4-methoxyphenoxy)-6-methyl-4-(methylamino)tetrahydro-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; E-24. 4-(((2S,3R,4S,6R)-4-(dimethylamino)-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-3-yl)oxy)benzylnitrile; E-25. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-3-((2-chloropyridin-3-yl)oxy)-6-methyl-4-(methylamino)tetrahydro-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; E-26. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-11-(((2S,3R,4S,6R)-3-(2-fluorophenoxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-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; E-27. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-((2-methoxypyrimidin-5-yl)oxy)-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; E-30. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-3-((5-chloropyridin-2-yl)oxy)-6-methyl-4-(methylamino)tetrahydro-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; E-31. 2-(((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)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-3-yl)oxy)pyrimidine-5-nitrile; E-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-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-11-(((2S,3R,4S,6R)-3-(2-hydroxyphenoxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one; E-37. (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)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-(4-fluorophenoxy)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one; E-38. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-3-((2-chloropyrimidin-5-yl)oxy)-6-methyl-4-(methylamino)tetrahydro-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; E-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-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-11-(((2S,3R,4S,6R)-6-methyl-4-(methylamino)-3-(quinolin-3-yloxy)tetrahydro-2H-pyran-2-yl)oxy)-1-oxa-6-azacyclopentadecan-15-one; E-40. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(((1H-imidazol-1-yl)amino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-6-methyl-3-phenoxytetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one; E-41. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-11-(((2S,3R,4S,6R)-3-(3-(ethylsulfonyl)phenoxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-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; E-42. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-(3-fluoro-4-methoxyphenoxy)-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; E-43. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-(4-methoxyphenoxy)-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; E-45. 3-(((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)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-3-yl)oxy)benzylnitrile; E-47. (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-11-(((2S,3R,4S,6R)-6-methyl-4-(methylamino)-3-(2-nitrophenoxy)tetrahydro-2H-pyran-2-yl)oxy)-1-oxa-6-azacyclopentadecan-15-one; E-48. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-(4-fluorophenoxy)-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; E-49. 2-(((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)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-3-yl)oxy)benzylnitrile; E-50. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-3-(2-aminophenoxy)-6-methyl-4-(methylamino)tetrahydro-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; E-52. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-(5-fluoro-2-methoxyphenoxy)-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; E-57. 3-(((2S,3R,4S,6R)-4-(dimethylamino)-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-3-yl)oxy)benzylnitrile; E-60. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-11-(((2S,3R,4S,6R)-3-(4-fluoro-3-(methylsulfonyl)phenoxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-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; E-62. (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-11-(((2S,3R,4S,6R)-6-methyl-4-(methylamino)-3-(m-tolyloxy)tetrahydro-2H-pyran-2-yl)oxy)-1-oxa-6-azacyclopentadecan-15-one; E-63. (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-((2-methoxypyridin-3-yl)oxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one; E-64. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-3-((6-chloropyridin-3-yl)oxy)-4-(dimethylamino)-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; E-68. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-(2-methoxyphenoxy)-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; E-69. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-6-methyl-3-(quinolin-6-yloxy)tetrahydro-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; E-71. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-6-methyl-3-(3,4,5-trimethoxyphenoxy)tetrahydro-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; E-72. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-(4-ethoxyphenoxy)-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; E-75. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-3-(2,5-dimethoxyphenoxy)-6-methyl-4-(methylamino)tetrahydro-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; E-76. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-(3-ethoxyphenoxy)-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; E-78. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-3-(2-ethoxyphenoxy)-6-methyl-4-(methylamino)tetrahydro-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; E-79. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-6-methyl-3-(quinolin-3-yloxy)tetrahydro-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; E-80. (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-11-(((2S,3R,4S,6R)-6-methyl-4-(methylamino)-3-(4-(methylsulfonyl)phenoxy)tetrahydro-2H-pyran-2-yl)oxy)-1-oxa-6-azacyclopentadecan-15-one; E-81. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-(4-fluoro-3-(methylsulfonyl)phenoxy)-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; E-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-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-11-(((2S,3R,4S,6R)-6-methyl-4-(methylamino)-3-((5-(trifluoromethyl)pyridin-3-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)-1-oxa-6-azacyclopentadecan-15-one; E-87. (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)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-6-methyl-3-phenoxytetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one; E-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-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-11-(((2S,3R,4S,6R)-3-(2-methoxyphenoxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one; E-91. (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-((6-methoxypyridin-3-yl)oxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one; E-92. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-3-(3,5-dimethoxyphenoxy)-6-methyl-4-(methylamino)tetrahydro-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; E-93. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-3-((6-chloro-4-methylpyridin-3-yl)oxy)-6-methyl-4-(methylamino)tetrahydro-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; E-94. (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-(3-methoxyphenoxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one; E-98. (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-11-(((2S,3R,4S,6R)-6-methyl-4-(methylamino)-3-(3-(methylsulfonyl)phenoxy)tetrahydro-2H-pyran-2-yl)oxy)-1-oxa-6-azacyclopentadecan-15-one; E-99. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-6-methyl-3-(3-(methylsulfonyl)phenoxy)tetrahydro-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; E-100. (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-((6-methoxy-2-methylpyridin-3-yl)oxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one; E-102. (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-((2-methoxypyridin-3-yl)oxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one; E-108. (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-((2-methoxypyrimidin-5-yl)oxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one; E-109. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-6-methyl-3-((2-methylpyridin-3-yl)oxy)tetrahydro-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; E-110. 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-((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-methyl-4-(methylamino)tetrahydro-2H-pyran-3-yl)oxy)benzamide; E-111. 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-((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-methyl-4-(methylamino)tetrahydro-2H-pyran-3-yl)oxy)benzylnitrile; E-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-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-11-(((2S,3R,4S,6R)-6-methyl-4-(methylamino)-3-phenoxytetrahydro-2H-pyran-2-yl)oxy)-1-oxa-6-azacyclopentadecan-15-one; E-113. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-(4-fluorophenoxy)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-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-1-oxa-6-azacyclopentadecan-15-one; E-114. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-(4-fluorophenoxy)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-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-1-oxa-6-azacyclopentadecan-15-one; E-115. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-3-(2,5-dimethoxyphenoxy)-4-(dimethylamino)-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; E-116. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-(4-fluorophenoxy)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-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-1-oxa-6-azacyclopentadecan-15-one; E-117. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-(4-fluorophenoxy)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-5-((isopropylamino)methyl)-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one; E-120. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-6-methyl-3-phenoxytetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(((tetrahydro-2H-pyran-4-yl)amino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one; E-124. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-((2-ethoxypyridin-3-yl)oxy)-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; E-125. (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-11-(((2S,3R,4S,6R)-6-methyl-4-(methylamino)-3-phenoxytetrahydro-2H-pyran-2-yl)oxy)-1-oxa-6-azacyclopentadecan-15-one; E-126. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-((cyclobutylamino)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-11-(((2S,3R,4S,6R)-6-methyl-4-(methylamino)-3-phenoxytetrahydro-2H-pyran-2-yl)oxy)-1-oxa-6-azacyclopentadecan-15-one; E-127. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-5-((isopropylamino)methyl)-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-11-(((2S,3R,4S,6R)-6-methyl-4-(methylamino)-3-phenoxytetrahydro-2H-pyran-2-yl)oxy)-1-oxa-6-azacyclopentadecan-15-one; E-128. (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-11-(((2S,3R,4S,6R)-6-methyl-4-(methylamino)-3-phenoxytetrahydro-2H-pyran-2-yl)oxy)-1-oxa-6-azacyclopentadecan-15-one; E-129. (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-11-(((2S,3R,4S,6R)-6-methyl-4-(methylamino)-3-phenoxytetrahydro-2H-pyran-2-yl)oxy)-1-oxa-6-azacyclopentadecan-15-one; E-130. (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-11-(((2S,3R,4S,6R)-6-methyl-4-(methylamino)-3-phenoxytetrahydro-2H-pyran-2-yl)oxy)-1-oxa-6-azacyclopentadecan-15-one; E-131. (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-(((3-methoxypropyl)amino)methyl)-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-11-(((2S,3R,4S,6R)-6-methyl-4-(methylamino)-3-phenoxytetrahydro-2H-pyran-2-yl)oxy)-1-oxa-6-azacyclopentadecan-15-one; E-132. (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-11-(((2S,3R,4S,6R)-6-methyl-4-(methylamino)-3-phenoxytetrahydro-2H-pyran-2-yl)oxy)-1-oxa-6-azacyclopentadecan-15-one; E-134. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-3-(3,4-dimethoxyphenoxy)-4-(dimethylamino)-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; E-135. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-3-((6-chloro-4-methylpyridin-3-yl)oxy)-4-(dimethylamino)-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; E-136. (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-11-(((2S,3R,4S,6R)-6-methyl-4-(methylamino)-3-phenoxytetrahydro-2H-pyran-2-yl)oxy)-1-oxa-6-azacyclopentadecan-15-one; E-138. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(((1H-imidazol-1-yl)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-11-(((2S,3R,4S,6R)-6-methyl-4-(methylamino)-3-phenoxytetrahydro-2H-pyran-2-yl)oxy)-1-oxa-6-azacyclopentadecan-15-one; E-139. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(((1H-pyrazol-1-yl)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-11-(((2S,3R,4S,6R)-6-methyl-4-(methylamino)-3-phenoxytetrahydro-2H-pyran-2-yl)oxy)-1-oxa-6-azacyclopentadecan-15-one; E-141. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-((cyclobutylamino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-6-methyl-3-phenoxytetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one; E-142. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-6-methyl-3-phenoxytetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-5-((isopropylamino)methyl)-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one; E-143. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-6-methyl-3-phenoxytetrahydro-2H-pyran-2-yl)oxy)-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-1-oxa-6-azacyclopentadecan-15-one; E-144. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-6-methyl-3-phenoxytetrahydro-2H-pyran-2-yl)oxy)-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-1-oxa-6-azacyclopentadecan-15-one; E-145. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-6-methyl-3-phenoxytetrahydro-2H-pyran-2-yl)oxy)-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-1-oxa-6-azacyclopentadecan-15-one; E-146. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-6-methyl-3-phenoxytetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-5-(((3-methoxypropyl)amino)methyl)-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one; E-147. (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)-4-((4-methoxybenzyl)(methyl)amino)-6-methyl-3-phenoxytetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one; E-148. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(benzyl(methyl)amino)-6-methyl-3-phenoxytetrahydro-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; E-149. (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-11-(((2S,3R,4S,6R)-6-methyl-4-(methyl(pyridin-3-ylmethyl)amino)-3-phenoxytetrahydro-2H-pyran-2-yl)oxy)-1-oxa-6-azacyclopentadecan-15-one; E-151. (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-(4-methoxyphenoxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one; E-152. (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-11-(((2S,3R,4S,6R)-6-methyl-4-(methylamino)-3-phenoxytetrahydro-2H-pyran-2-yl)oxy)-1-oxa-6-azacyclopentadecan-15-one; and E-153. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-11-(((2S,3R,4S,6R)-3-(4-fluorophenoxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-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-1-oxa-6-azacyclopentadecan-15-one; Or the compound of formula (1-A1a) according to claim 4, wherein R 3 For methyl, R 5 For H and R 6 It is propyl, and it is a compound selected from the group consisting of the following: F-1. 1-((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-fluorophenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea; F-2. 1-((2S,3R,4S,6R)-3-(4-cyanophenoxy)-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)-1,3-dimethyl-3-phenylurea; F-3. 1-((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)-6-methyl-3-phenoxytetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea; F-4. 1-((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)-1,3-dimethyl-3-phenylurea; F-5. 1-((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)-1,3-dimethyl-3-phenylurea; F-6. 1-((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)-1,3-dimethyl-3-phenylurea; F-7. 1-((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)-1,3-dimethyl-3-phenylurea; F-8. 1-((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)-6-methyl-3-phenoxytetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(pyrimidin-2-yl)urea; F-9. 1-((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)-6-methyl-3-phenoxytetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(4-(trifluoromethyl)phenyl)urea; F-12. 1-((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-2-methylphenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(pyrimidin-2-yl)urea; F-13. 1-Cyclohexyl-3-((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)-6-methyl-3-phenoxytetrahydro-2H-pyran-4-yl)-1,3-dimethylurea; F-14. 1-(4-chlorophenyl)-3-((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)-6-methyl-3-phenoxytetrahydro-2H-pyran-4-yl)-1,3-dimethylurea; F-15. 1-((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-2-methylphenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea; F-16. 1-((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-2-methylphenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-1,3,3-trimethylurea; F-17. 1-Cyclobutyl-3-((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)-6-methyl-3-phenoxytetrahydro-2H-pyran-4-yl)-1,3-dimethylurea; F-18. 1-Cyclopropyl-3-((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)-6-methyl-3-phenoxytetrahydro-2H-pyran-4-yl)-1,3-dimethylurea; F-22. 1-((2S,3R,4S,6R)-3-((6-chloropyridin-3-yl)oxy)-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)-1,3-dimethyl-3-phenylurea; F-25. 1-((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)-6-methyl-3-(quinoline-6-yloxy)tetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea; F-26. 1-((2S,3R,4S,6R)-3-(3-chlorophenoxy)-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)-3-cyclobutyl-1,3-dimethylurea; F-27. 1-((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)-6-methyl-3-phenoxytetrahydro-2H-pyran-4-yl)-3-isopropyl-1,3-dimethylurea; F-28. 1-((2S,3R,4S,6R)-3-(3,5-difluoro-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)-1,3-dimethyl-3-phenylurea; F-29. 1-((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-(quinolin-6-yloxy)tetrahydro-2H-pyran-4-yl)-3-isopropyl-1,3-dimethylurea; F-30. 1-((2S,3R,4S,6R)-3-(2-chlorophenoxy)-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)-3-(4-cyanophenyl)-1,3-dimethylurea; F-31. 1-((2S,3R,4S,6R)-3-(3-ethoxy-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)-1,3-dimethyl-3-phenylurea; and F-32. 1-Cyclopropyl-3-((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)-6-methyl-3-(quinoline-6-yloxy)tetrahydro-2H-pyran-4-yl)-1,3-dimethylurea; And its pharmaceutically acceptable salts.

6. The compound of formula (1) according to claim 2, wherein W is of formula (A0), and the compound of formula (1) is a compound of formula (1-A0). Where R a It is H, and R 0 and R 1 Each is independently H or methyl; or is a compound of formula (1-A0), selected from the group consisting of the following: A-6. 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-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-3-yl)oxy)benzylnitrile; A-9. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-11-(((2S,3R,4S,6R)-3-(4-fluorophenoxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one; A-11. 4-(((2S,3R,4S,6R)-4-(dimethylamino)-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-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl)oxy)benzylnitrile; A-12. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-(3-fluoro-4-methoxyphenoxy)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one; A-18. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-6-methyl-3-((5-(trifluoromethyl)pyridin-3-yl)oxy)tetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one; A-19. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-6-methyl-3-phenoxytetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one; A-21. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-3-(2,4-dimethoxyphenoxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one; A-23. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-(4-fluorophenoxy)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one; A-24. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-(isoquinoline-7-yloxy)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one; A-25. 5-(((2S,3R,4S,6R)-4-(dimethylamino)-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-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl)oxy)-2-fluorobenzonitrile; A-26. (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-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-11-(((2S,3R,4S,6R)-6-methyl-4-(methylamino)-3-phenoxytetrahydro-2H-pyran-2-yl)oxy)-1-oxa-6-azacyclopentadecan-15-one; A-27. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-(3-(ethylsulfonyl)phenoxy)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one; A-28. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-6-methyl-3-(quinolin-3-yloxy)tetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one; A-29. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-3-((6-chloro-4-methylpyridin-3-yl)oxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one; A-30. (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-dimethyltetrahydro-2H-pyran-2-yl)oxy)-11-(((2S,3R,4S,6R)-3-(2-methoxyphenoxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one; A-31. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-3-((2-ethoxypyridin-3-yl)oxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one; A-32. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-((2-ethoxypyridin-3-yl)oxy)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one; A-33. (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-dimethyltetrahydro-2H-pyran-2-yl)oxy)-11-(((2S,3R,4S,6R)-3-((2-methoxypyridin-3-yl)oxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one; A-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-dimethyltetrahydro-2H-pyran-2-yl)oxy)-11-(((2S,3R,4S,6R)-3-(3-isopropoxy-4-methoxyphenoxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one; A-35. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-3-(2,5-dimethoxyphenoxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one; A-36. 2-(((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-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-3-yl)oxy)benzylnitrile; A-37. (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-dimethyltetrahydro-2H-pyran-2-yl)oxy)-11-(((2S,3R,4S,6R)-3-((6-methoxy-2-methylpyridin-3-yl)oxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one; A-39. 5-(((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-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-3-yl)oxy)-2-fluorobenzonitrile; A-40. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-3-(3,4-dimethoxyphenoxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one; A-41. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-11-(((2S,3R,4S,6R)-3-(3-(ethylsulfonyl)phenoxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one; A-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-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-11-(((2S,3R,4S,6R)-6-methyl-4-(methylamino)-3-(quinolin-3-yloxy)tetrahydro-2H-pyran-2-yl)oxy)-1-oxa-6-azacyclopentadecan-15-one; A-45. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-3-((6-chloro-4-methylpyridin-3-yl)oxy)-4-(dimethylamino)-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one; and A-47. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-6-methyl-3-(quinolin-6-yloxy)tetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one; And its pharmaceutically acceptable salts.

7. The compound of formula (1) according to claim 1, wherein W is H, is a compound of formula (1.1). Where R 0 and R 1 Each is independently either H or methyl; R 2 It is H, methyl, ethyl, cyclopropyl, cyclobutyl, -C(O)NR 3 R 4 -C1 alkylphenyl, -C1 alkylpyrrolidinyl, -C1 alkylpiperidinyl, -C1 alkylpiperazinyl, -C1 alkylmorpholinyl, -C1 alkylpyrrolidinyl, -C1 alkylpyrazolyl, -C1 alkylpyridinyl or -C1 alkylpyrimidinyl, each optionally being an R selected from the group consisting of at least one of the following. 9 Substituents: methyl, ethyl, hydroxy, methoxy, ethoxy, F, Cl, cyano, -N(CH3)2 and -CF3; R 3 It is H, methyl, or ethyl; R 4 It is H, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, phenyl, C1 alkylphenyl, piperazine, morpholino, tetrahydro-2H-pyran, pyrazolyl, or pyridinyl, each optionally being selected from at least one R group consisting of the following: 9 Substituents: methyl, ethyl, hydroxy, methoxy, ethoxy, F, Cl, cyano, -N(CH3)2 and -CF3; Or R 3 and R 4 Together with the nitrogen atom to which it is attached, it forms ring A, which is piperidinyl or piperazine, each optionally substituted with methyl or ethyl; or ring A is dihydrobenzoxazine or tetrahydroquinolinyl. And its pharmaceutically acceptable salts.

8. The compound of formula (1.1) according to claim 7, wherein it is a compound selected from the group consisting of: B-1. (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-(((2S,3R,4S,6R)-6-methyl-4-(methylamino)-3-phenoxytetrahydro-2H-pyran-2-yl)oxy)-1-oxa-6-azacyclopentadecan-15-one; B-3. ​​(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-11-(((2S,3R,4S,6R)-3-(3-fluorophenoxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one; B-4. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-11-(((2S,3R,4S,6R)-3-(4-fluorophenoxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one; B-6. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-11-(((2S,3R,4S,6R)-3-(4-methoxyphenoxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one; B-7. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-3-(3-chlorophenoxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one; B-9. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-3-((3,6-dimethoxypyridazine-4-yl)oxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one; B-10. (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-11-(((2S,3R,4S,6R)-6-methyl-4-(methylamino)-3-phenoxytetrahydro-2H-pyran-2-yl)oxy)-1-oxa-6-azacyclopentadecan-15-one; and B-12. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-3-(5-chloro-2-(trifluoromethyl)phenoxy)-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one; Or it may be a compound of formula (1.1), wherein R 2 It is -C(O)R 3 R 4 The compound is selected from the group consisting of the following: C-1. 1-((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)-1,3-dimethyl-3-phenylurea; C-2. 1-((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)-1,3-dimethyl-3-phenylurea; C-3. 1-((2S,3R,4S,6R)-3-(4-cyanophenoxy)-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)-1,3-dimethyl-3-phenylurea; C-4. 1-((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)-1,3-dimethyl-3-phenylurea; C-5. 1-((2S,3R,4S,6R)-3-(4-chlorophenoxy)-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)-1,3-dimethyl-3-phenylurea; C-6. 1-((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)-1,3-dimethyl-3-phenylurea; C-7. 1-((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)-1,3-dimethyl-3-phenylurea; C-8. 1-((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)-1,3-dimethyl-3-phenylurea; C-9. 1-((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)-1,3-dimethyl-3-phenylurea; C-10. 1-((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)-1,3-dimethyl-3-phenylurea; C-12. 1-((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)-1,3-dimethyl-3-phenylurea; C-14. 1-((2S,3R,4S,6R)-3-(5-chloro-2-(trifluoromethyl)phenoxy)-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-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea; C-15. 1-((2S,3R,4S,6R)-3-((3,6-dimethoxypyridazine-4-yl)oxy)-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-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea; C-16. 1-((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)-1,3-dimethyl-3-(4-(trifluoromethyl)phenyl)urea; C-17. 1-((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)-1,3-dimethyl-3-(pyrimidin-2-yl)urea; C-18. 1-(4-chlorophenyl)-3-((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)-1,3-dimethylurea; C-19. 1-Cyclohexyl-3-((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)-1,3-dimethylurea; C-20. 1-Cyclopropyl-3-((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)-1,3-dimethylurea; C-21. 1-Cyclobutyl-3-((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)-1,3-dimethylurea; C-22. 1-((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)-1,3-dimethyl-3-(pyrimidin-2-yl)urea; C-23. 1-((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)-1,3-dimethyl-3-propylurea; C-24. 1-((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)-1,3-dimethyl-3-(4-(trifluoromethyl)phenyl)urea; C-25. 1-((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-2-methylphenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-1,3,3-trimethylurea; C-26. 1-(1,5-dimethyl-1H-pyrazol-3-yl)-3-((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)-1,3-dimethylurea; C-27. 1-Cyclopropyl-3-((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)-1,3-dimethylurea; C-28. 1-Cyclobutyl-3-((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)-1,3-dimethylurea; C-29. 1-((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-2-methylphenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(pyrimidin-2-yl)urea; C-30. 1-(1,5-dimethyl-1H-pyrazol-3-yl)-3-((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)-1,3-dimethylurea; C-31. 1-((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)-1,3-dimethyl-3-propylurea; C-32. 1-((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-2-methylphenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea; C-33. 1-((2S,3R,4S,6R)-3-((6-chloropyridin-3-yl)oxy)-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)-1,3-dimethyl-3-phenylurea; C-36. 1-(4-(dimethylamino)phenyl)-3-((2S,3R,4S,6R)-3-(3-ethoxyphenoxy)-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)-1,3-dimethylurea; C-37. 1-((2S,3R,4S,6R)-3-(3-ethoxyphenoxy)-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)-1,3-dimethyl-3-phenylurea; C-38. 1-((2S,3R,4S,6R)-3-(2-chlorophenoxy)-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)-1,3-dimethyl-3-phenylurea; C-39. 1-((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)-3-isopropyl-1,3-dimethylurea; C-40. 1-((2S,3R,4S,6R)-3-(3-chlorophenoxy)-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)-3-cyclobutyl-1,3-dimethylurea; C-41. 1-((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-((2-methoxypyrimidin-5-yl)oxy)-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl–3-phenylurea; C-42. 1-((2S,3R,4S,6R)-3-(3,5-difluoro-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)-1,3-dimethyl-3-phenylurea; C-43. 1-((2S,3R,4S,6R)-3-(2-chlorophenoxy)-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)-3-(4-cyanophenyl)-1,3-dimethylurea; C-44. 1-Cyclopropyl-3-((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-(quinoline-6-yloxy)tetrahydro-2H-pyran-4-yl)-1,3-dimethylurea; C-45. 1-((2S,3R,4S,6R)-3-((6-chloropyridin-3-yl)oxy)-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-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea; C-46. 1-((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-(3-isopropoxy-4-methoxyphenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea; C-47. 1-((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-(quinolin-6-yloxy)tetrahydro-2H-pyran-4-yl)-3-isopropyl-1,3-dimethylurea; C-48. 1-((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)-3-isopropyl-1,3-dimethylurea; C-49. 1-((2S,3R,4S,6R)-3-(3,5-difluoro-4-methoxyphenoxy)-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-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea; C-50. 1-((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-(quinolin-6-yloxy)tetrahydro-2H-pyran-4-yl)-3-isopropyl-1,3-dimethylurea; C-51. 1-((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-2-methylphenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(pyrimidin-2-yl)urea; C-52. 1-((2S,3R,4S,6R)-3-(3-ethoxy-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)-1,3-dimethyl-3-phenylurea; C-53. 1-Cyclopropyl-3-((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-((2-methoxypyrimidin-5-yl)oxy)-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethylurea; and C-54. 1-((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-(quinolin-6-yloxy)tetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea; Or it may be a compound of formula (1.1a), wherein R 3 and R 4 Together with the nitrogen atoms they are attached to, they form ring A. This compound is selected from the group consisting of the following: D-1. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyl-3-phenoxytetrahydro-2H-pyran-4-yl)-N-methyl-3,4-dihydroquinoline-1(2H)-formamide; D-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)-6-methyl-3-phenoxytetrahydro-2H-pyran-4-yl)-N-methyl-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxamide; D-3. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyl-3-phenoxytetrahydro-2H-pyran-4-yl)-N-methyl-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxamide; and D-4. 4-Ethyl-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-(3-isopropoxy-4-methoxyphenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-N-methylpiperazin-1-carboxamide; And its pharmaceutically acceptable salts.

9. The compound of formula (1-A1) according to claim 3, wherein R 5 and R 6 Together with the nitrogen atom it is attached to, it forms ring B, and the compound has the formula (1-A1c). Compounds in which ring B is piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally substituted with methyl or ethyl; or compounds of formula (1-A1c), selected from the group consisting of: H-1. (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-11-(((2S,3R,4S,6R)-6-methyl-4-(methylamino)-3-phenoxytetrahydro-2H-pyran-2-yl)oxy)-1-oxa-6-azacyclopentadecan-15-one; H-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-11-(((2S,3R,4S,6R)-6-methyl-4-(methylamino)-3-phenoxytetrahydro-2H-pyran-2-yl)oxy)-1-oxa-6-azacyclopentadecan-15-one; H-3. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-6-methyl-3-phenoxytetrahydro-2H-pyran-2-yl)oxy)-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-1-oxa-6-azacyclopentadecan-15-one; H-4. (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-11-(((2S,3R,4S,6R)-6-methyl-4-(methylamino)-3-phenoxytetrahydro-2H-pyran-2-yl)oxy)-1-oxa-6-azacyclopentadecan-15-one; and H-5. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-(4-fluorophenoxy)-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-(morpholinomethyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one; and H-6. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-(4-fluorophenoxy)-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-((4-methylpiperazin-1-yl)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one; And its pharmaceutically acceptable salts.

10. A composition comprising a compound according to any one of claims 1-9, and a pharmaceutically acceptable salt thereof; and wherein said composition further comprises a pharmaceutically acceptable carrier.

11. Use of the compound according to any one of claims 1-9, and its pharmaceutically acceptable salt, in the preparation of a medicament for treating or preventing an inflammatory response in said animals.

12. The use according to claim 11, wherein the inflammatory response is caused by bacterial, viral or fungal infection, stress and / or environmental factors.

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