Immunomodulatory urea azalactones

Abstract

This article defines an immunomodulatory compound of formula (1), wherein R, R 0 R 1 R 2 R 3 And W as defined herein; its stereoisomers and pharmaceutically acceptable salts thereof; and compositions comprising said compounds. The invention also includes methods for treating inflammatory and / or immune diseases or conditions in animals by administering therapeutically effective amounts of a compound of formula (1), its stereoisomers and pharmaceutically acceptable salts thereof; or the use of said compound of formula (1) in the preparation of a medicament for treating inflammatory and / or immune diseases or conditions in animals.

Description

Technical Field

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

[0002] Macrolides are antimicrobial compounds composed of a macrocyclic lactone ring containing 12 to 16 atoms, which are attached to at least one or two deoxyglucoses via glycosidic bonds. Azalides are a class of macrolides in which the lactone ring contains nitrogen atoms. It is a semi-synthetic macrolide (azalide) antibiotic, sold as a ready-to-use sterile parenteral preparation containing tulathromycin. This 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, and Tula-B has a 13-membered lactone ring structure. Equilibrium is dependent on pH and time. Tulathromycin is marketed under the trade name... We sell products for the treatment of bovine respiratory disease (BRD) and swine respiratory disease (SRD).

[0003] Macrolides are known to inhibit protein synthesis in bacteria (Gram-positive and Gram-negative) by reversibly binding to the P site of the 50S ribosomal unit. They tend to be bacteriostatic and may have bactericidal effects against certain pathogens. Their activity against BRD Gram-negative pathogens and their ability to concentrate in lung tissue make them excellent therapeutic agents. They are first-line treatments 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. Furthermore, some macrolides have been shown to possess anti-inflammatory and immunomodulatory properties. For instance, azithromycin (a broad-spectrum antibiotic) inhibits interleukin-12p40 expression in lipopolysaccharide (LPS) and interferon-γ-stimulated macrophages and attenuates LPS-induced CXCL8 (IL-8) and GM-CSF induction from primary bronchial epithelial cells; in epithelial cells, LPS stimulation downregulates the release of transcription factors AP-1, NFκB, inflammatory cytokines, and mucins, subsequently interacting with phospholipids and Erk1 / 2. US2016-0031925 describes certain azithromycin analogues with immunomodulatory effects, but which have been modified to reduce or eliminate antibiotic efficacy. Clarithromycin has immunomodulatory effects on ERJ-mediated inflammation induced by Pseudomonas aeruginosa flagellin. Erythromycin inhibits the expression of interleukin-6 and interleukin-8 in vitro and promotes apoptosis of activated human neutrophils. Tilmicosin regulates the expression of COX-2 and iNOS genes and the production of cytokines in LPS-stimulated macrophages and monocytes. Roxithromycin downregulates the production of Th2 chemokines by keratinocytes and the expression of chemokine receptors by Th2 cells. Tylamycin promotes apoptosis and downregulates pro-inflammatory mediators such as leukotrienes B4 and CXCL8; and induces the production of anti-inflammatory and remission-promoting lipoxygenin A4. These results suggest that these antibacterial macrolides regulate certain excessive immune responses, which in turn cascade into certain anti-inflammatory benefits.

[0005] Inflammation and pro-inflammatory mediators adversely affect production in the food animal industry by reducing growth, feed and water intake, reproduction, milk production, and metabolic health. The increased clinical use of macrolide antibiotics is associated with increased macrolide resistance in pneumococcus and BRD pathogens. Recent concerns from global government agencies and the public regarding the use of antibiotics in food production animals (e.g., cattle and pigs) are believed to lead to cross-resistance to human pathogens. Bovine respiratory disease (BRD) remains a major problem in modern cattle production, and sensible management is crucial for animal welfare and human food safety. Indeed, *Mannheimia haemolytica* is a major bacterium isolated from respiratory diseases in farmed cattle and is a significant component of endemic pneumonia in newborn calves. One characteristic of BRD is an exacerbated inflammatory response in the host, which promotes progression to complete BRD syndrome. Suppressing or reversing host inflammation can prevent or control the development of BRD in cattle and other inflammatory diseases or conditions in animals. Therefore, the desire to develop novel anti-inflammatory and immunomodulatory agents lacking known macrolide antibacterial activity remains unfulfilled. The compounds of this invention have shown non-antibacterial activity in a variety of bacterial species and, at lower doses, exhibit 5 to 20 times higher immunomodulatory activity than current macrolides (e.g., azithromycin, erythromycin, and tylosin). Therefore, these compounds can be used to control or prevent the onset of bacterial or viral infections resulting from inflammatory and / or immune responses induced by stress events or other environmental factors, thereby preventing or mitigating the development of a pathobiological cascade into a complete disease syndrome. The compounds of this invention provided herein are non-antibiotic, anti-inflammatory, and immunomodulatory macrolides with the potential to reduce inflammatory states in animals and thus reduce antibiotic use in animals. Summary of the Invention

[0006] In one aspect of the invention, there are anti-inflammatory and immunomodulatory azalide compounds of formula (1); or non-antibacterial, anti-inflammatory and immunomodulatory azalide compounds of formula (1); their stereoisomers and their pharmaceutically acceptable salts.

[0007]

[0008] Where W is H or equation (A)

[0009]

[0010] Where X is -R a -R c NR 5 R 6 -R c OR 7 -R c SR 7 -R cN3, -R c CN or -R c X';

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

[0012] R is H, C1-C3 alkyl, or -C(O)NR. a R d or -C(O)OR 8 ;

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

[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, S, and O; 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 d It is a phenyl group substituted with H, C1-C6 alkyl, C3-C6 cycloalkyl or optionally C1-C3 alkyl, C1-C3 alkoxy, halogen, cyano, hydroxyl, amino, -NHCH3, -N(CH3)2, C1-C3 haloalkyl or C1-C3 haloalkoxy;

[0018] R 2 and R 3 Each is independently H, C1-C6 alkyl, R c NR a R b C0-C3 alkyl-C3-C6 cycloalkyl, C0-C3 alkyl aryl, C0-C3 alkyl heterocycle, wherein the heterocycle is a 5- to 6-membered saturated or partially saturated heterocycle; or C0-C3 alkyl heteroaryl, wherein the heteroaryl is a 5- to 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, aryl, heterocycle, and heteroaryl ring are each optionally separated by at least one R 9 Substituent substitution;

[0019] or R 2 and R 3Together with the nitrogen atoms to which they are attached, they form ring A, 4 to 8-membered heterocycles, or 5-membered heteroaryl rings, each optionally containing at least one additional heteroatom selected from N, O, and S; each ring is optionally 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 a C1-C6 alkyl or C1-C6 alkoxy group substituted with at least one hydroxyl group; or 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 -R c NR a S(O) p R 8; or C0-C4 alkylaryl, C0-C4 alkylC3-C6 cycloalkyl, C0-C4 alkyl heterocyclic, or C0-C4 alkyl heteroaryl, wherein the heterocycle and heteroaryl ring are each a 5- to 6-membered monocyclic ring or a 9- to 10-membered fused ring, each containing at least one heteroatom selected from the group consisting of N, O, and S; and wherein the aryl, cycloalkyl, heterocyclic, and heteroaryl ring are optionally separated by at least one R 10 Substituent substitution;

[0021] or R 5 and R 6 Together with the nitrogen atoms to which they are attached, they form ring B, 4 to 8-membered heterocycles, or 5-membered heteroaryl rings, each optionally containing at least one additional heteroatom selected from N, O, and S; each ring is optionally 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 b The cycloalkyl, phenyl, heterocyclic and heteroaryl groups are each optionally substituted by at least one of the following groups: phenyl, 5- or 6-membered heterocycles containing at least one heteroatom selected from N, O and S; and wherein the cycloalkyl, phenyl, heterocycle and heteroaryl groups are each optionally substituted by at least one of the following groups: 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,

[0025] C0-C4 alkyl, C3-C6 cycloalkyl, halogen, oxo, hydroxyl, cyano, -NR a R b C1-C6 haloalkyl, C1-C6 haloalkoxy, -S(O) p R 8 phenyl and 5- to 6-membered monocyclic heterocyclic or heteroaryl rings, each containing at least one heteroatom selected from the group consisting of N, O and S;

[0026] 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 , hydroxyl group, 5- to 6-membered heterocycle, 5- to 6-membered heteroaryl ring, 9- to 10-membered fused heteroaryl ring, wherein each heterocycle and heteroaryl ring each contains at least one heteroatom selected from the group consisting of N, O and S; and phenyl; and wherein the phenyl, heterocycle and heteroaryl ring are each optionally separated by at least one R 9 Substituent substitution;

[0027] Y is phenyl, pyridinyl, pyrimidinyl, pyrazolyl, thiophenyl, thiazolyl, triazolyl, isothiazolyl, pyrroleyl, oxazolyl, oxadiazolyl, imidazolyl, furanyl, indolyl, benzothiophenyl, or naphthyl;

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

[0029] On the other hand, it is a composition comprising a compound of formula (1), its stereoisomers, and its pharmaceutically acceptable salts. On the other hand, the composition further comprises a pharmaceutically acceptable carrier.

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

[0031] In another aspect, is the use of a compound of formula (1), its stereoisomers, and its pharmaceutically acceptable salts; to prepare a medicament for the treatment or prevention of inflammatory responses in animals, wherein the inflammatory response is caused by bacterial, viral, or fungal infection, stress, and / or environmental factors. In another aspect of this use, the medicament is used for the treatment or prevention of inflammatory responses in animals, and for the prevention or reduction of the progression of respiratory diseases or conditions. In another aspect of this use, the animal is a domestic animal. In another aspect of this use, the respiratory disease or condition is bovine respiratory disease or swine respiratory disease. In another aspect of this use, the medicament is administered to an animal to treat or prevent inflammatory responses in animals, and for the downregulation of TNFα and IL-6 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 can be either H or methyl.

[0033] 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 cIt is ethyl. On the other hand, R c It is propyl.

[0034] In another aspect of the invention, R d It is a phenyl group substituted with C1-C6 alkyl, C3-C6 cycloalkyl, or optionally with C1-C3 alkyl, C1-C3 alkoxy, halogen, cyano, hydroxyl, amino, -NHCH3, -N(CH3)2, C1-C3 haloalkyl, or C1-C3 haloalkoxy. On the other hand, R d It is a C1-C6 alkyl, C3-C6 cycloalkyl, or optionally substituted with a C1-C3 alkyl, C1-C3 alkoxy, halogen, cyano, hydroxyl, amino, -NHCH3, -N(CH3)2, -CF3, or -OCF3 phenyl. On the other hand, R d It is a phenyl group substituted with methyl, ethyl, cyclopropyl, cyclobutyl, or optionally substituted with methyl, ethyl, methoxy, ethoxy, F, Cl, cyano, hydroxy, amino, -NHCH3, -N(CH3)2, -CHF2, -CF3, or -OCF3. On the other hand, R d It is a methyl, ethyl, or phenyl group optionally substituted with methyl, ethyl, methoxy, ethoxy, F, Cl, cyano, hydroxy, amino, -NHCH3, -N(CH3)2, -CHF2, -CF3, or -OCF3.

[0035] 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 methyl, ethyl, propyl, methoxy, ethoxy, F, Cl, oxo, hydroxy, cyano, -NR a R b R of -CF3 and -OCF3 9 Substituent substitution. On the other hand, R 0 and R 1 Each is independently H, methyl, ethyl, propyl, or isopropyl; or R 1It is benzyl, -CH2pyridine, CH2pyrimidine, -CH2pyrazole, -CH2imidazolium, -CH2-triazole, -CH2-tetrazole, CH2oxazole, -CH2isooxazole, -CH2thiazole, -CH2isothiazole, or -CH2oxadiazole, each optionally separated by at least one R selected from methyl, ethyl, propyl, methoxy, ethoxy, F, Cl, hydroxy, cyano, -NH2, -CF3, and -OCF3. 9 Substituent substitution. On the other hand, R 0 It is H, methyl, ethyl, or propyl; R 1 It is methyl, ethyl, propyl, isopropyl; or R 1 It is benzyl, CH2pyridine, -CH2pyrimidine, -CH2pyrazole or -CH2imidazole, each optionally separated by at least one R selected from methyl, ethyl, methoxy, ethoxy, F, Cl, hydroxy, -CF3 and -OCF3. 9 Substituent substitution. 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.

[0036] In another aspect of the invention, R 2 and R 3 Each is independently H, C1-C6 alkyl, R c NR a R b C1-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, tetrahydropyranyl, morpholinyl, or thiomorpholinyl; and wherein the heteroaryl moiety is pyrrolidinyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazolyl, tetrazolyl, or 6,7-dihydro-5H-cyclopentadien[d]pyrimidine; and wherein the cycloalkyl, phenyl, heterocyclic, and heteroaryl rings are each optionally composed of at least one R selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, hydroxyl, halogen, cyclopropyl, cyclobutyl, cyano, amino, -NHCH3, -N(CH3)2, C1-C3 haloalkyl, and C1-C3 haloalkoxy. 9 Substituent substitution. In another aspect of the invention, R 2 and R 3Each of the following is independently H, C1-C6 alkyl, -CH2N(CH3)2, -CH2CH2N(CH3)2; or C0-C2 cyclopropyl, C0-C2 cyclobutyl, C0-C2 cyclopentyl, C0-C2 cyclohexyl, C0-C2 phenyl, C0-C2 piperidinyl, piperazine, morpholinyl, tetrahydropyran, pyrroloyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl, each optionally being R selected from the group consisting of methyl, ethyl, propyl, isopropyl, tert-butyl, hydroxy, methoxy, ethoxy, F, Cl, Br, cyano, amino, -N(CH3)2, -CHF2, -CF3, -OCHF2, and -OCF3. 9 Substituent substitution. In another aspect of the invention, R 2 and R 3 Each of the following is independently H, C1-C6 alkyl; -CH2N(CH3)2, -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, tetrahydropyran, pyrroloyl, pyrazolyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazine, each optionally being R selected from the group consisting of methyl, ethyl, propyl, isopropyl, tert-butyl, hydroxy, methoxy, ethoxy, F, Cl, Br, cyano, amino, -N(CH3)2, -CHF2, -CF3, -OCHF2, and -OCF3. 9 Substituent substitution. On the other hand, R 2 and R 3 Each of the following is independently H, C1-C6 alkyl; -CH2N(CH3)2, -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, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazine, each optionally being R selected from the group consisting of methyl, ethyl, propyl, isopropyl, tert-butyl, hydroxy, methoxy, ethoxy, F, Cl, Br, cyano, cyclopropyl, amino, -N(CH3)2, -CHF2, -CF3, -OCHF2, and -OCF3. 9 Substituent substitution. On the other hand, R 2 and R 3Each of the following is independently H, C1-C6 alkyl; -CH2N(CH3)2, -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 at least one of the group consisting of methyl, ethyl, propyl, isopropyl, tert-butyl, hydroxy, methoxy, ethoxy, F, Cl, Br, cyano, cyclopropyl, amino, -N(CH3)2, -CHF2, -CF3, -OCHF2, and -OCF3. 9 Substituent substitution. On the other hand, R 2 It is H, methyl, ethyl, isopropyl, cyclopropyl, CF3, CHF2, -CH2F, -CH2CF3, or phenyl. On the other hand, R 2 It is H, methyl, ethyl, cyclopropyl, or phenyl. On the other hand, R 2 It is H, methyl, or ethyl. On the other hand, R 2 It is H or methyl. On the other hand, R 2 It is H. On the other hand, R 2 It is a methyl group. On the other hand, R 3 It is H, methyl, ethyl, propyl, isopropyl, tert-butyl; -CH2N(CH3)2, -CH2CH2N(CH3)2; or cyclopropyl, cyclobutyl, phenyl, C1 phenyl, piperidinyl, C1-piperidinyl, C2-piperidinyl, piperazine, morpholinyl, tetrahydro-2H-pyran, pyrazolyl, or pyridinyl, and wherein each ring is optionally composed of at least one R selected from the group consisting of methyl, ethyl, hydroxy, methoxy, ethoxy, F, Cl, cyano, amino, -N(CH3)2, and -CF3. 9 Substituent substitution.

[0037] In another aspect of the invention, R 2 and R 3 Together with the nitrogen atoms to which they are attached, they form ring A, 4 to 8-membered heterocycles, or 5-membered heteroaryl rings, 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 10 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... 2 and R 3 Together with the nitrogen atoms to which they are attached, they form ring A, 4 to 8-membered heterocycles, or 5-membered heteroaryl rings, 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 10Substituents are used, and each ring is further optionally fused with Y, which is phenyl, pyridyl, or pyrimidinyl. On the other hand, R... 2 and R 3 Together with the nitrogen atoms to which they are attached, they form a ring A, which is an azacyclic butyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyrrolyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl group, each optionally being surrounded 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 oxo. 10 Substituent substitution; and wherein each ring is further optionally fused with Y, which is phenyl, pyridyl, or pyrimidinyl. On the other hand, R... 2 and R 3 Together with the nitrogen atoms to which they are attached, they form a ring A, which is pyrroloyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally surrounded by at least one R selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F, Cl, Br, CN, -N(CH3)2, hydroxyl, -CHF2, -CF3, -OCHF2, -OCF3, and oxo. 10 Substituent substitution; and wherein each ring is further optionally fused with Y, which is phenyl, pyridyl, or pyrimidinyl. On the other hand, R... 2 and R 3 Together with the nitrogen atom to which they are attached, they form a ring A, which is pyrroloyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally surrounded by at least one R selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F, Cl, Br, CN, N(CH3)2, hydroxyl, -CHF2, -CF3, -OCHF2, -OCF3, and oxo. 10 Substituent substitution; and wherein each ring is further optionally fused with Y, which is phenyl or pyridyl. On the other hand, R... 2 and R 3 Together with the nitrogen atoms to which they are attached, they form a ring A, which is pyrroloyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally surrounded by at least one R selected from methyl, ethyl, F, Cl, oxo, and -CF3. 10 Substituents are used for substitution; and each ring is further optionally fused with Y, where Y is phenyl. On the other hand, R... 2 and R 3 Together with the nitrogen atoms to which they are attached, they form a ring A, which is pyrroloyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally surrounded by at least one R selected from methyl, ethyl, F, Cl, oxo, and -CF3.10 Substituent substitution; or ring A is optionally substituted with at least one oxo group of indololinyl, isoindololinyl, tetrahydroquinolinyl, dihydropyrrolopyrazinyl, tetrahydroisoquinolinyl, dihydrobenzoxazinyl, or dihydrobenzothiazinyl. On the other hand, R 2 and R 3 Together with the nitrogen atoms to which they are attached, they form a ring A, which is pyrroloyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally surrounded by at least one R selected from methyl, ethyl, F, Cl, oxo, and -CF3. 10 Substituent substitution; or ring A is optionally substituted with at least one oxo group of indololinyl, isoindololinyl, tetrahydroquinolinyl, dihydrobenzoxazinyl, or dihydrobenzothiazinyl. On the other hand, R... 2 and R 3 Together with the nitrogen atoms to which they are attached, they form a ring A, which is pyrroloyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally surrounded by at least one R selected from methyl, ethyl, F, Cl, oxo, and -CF3. 10 Substituent substitution.

[0038] In another aspect of the invention, R 5 and R 6 Each is independently H; each is a C1-C6 alkyl or C1-C6 alkoxy group optionally substituted with at least one hydroxyl group; 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 -R c NR a S(O) p R 8 ; C0-C4 alkylphenyl, C0-C4 alkylC3-C6 cycloalkyl, C0-C4 alkyl heterocyclic, C0-C4 alkyl heteroaryl, wherein the heterocycle and heteroaryl ring are each a 5- to 6-membered monocyclic ring, and wherein each heterocycle and heteroaryl ring contains at least one heteroatom selected from the group consisting of N, O, and S; and wherein the phenyl, cycloalkyl, heterocyclic, and heteroaryl rings 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 a C1-C6 alkyl or C1-C6 alkoxy group optionally substituted with at least one hydroxyl group; 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 -R c NR a S(O) p R 8 ; 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; wherein the phenyl, cycloalkyl ring, heterocyclic ring, and heteroaryl ring are 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 a C1-C6 alkyl or C1-C6 alkoxy group optionally substituted with at least one hydroxyl group; 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 -Rc C(O)NR a R b -R c NR a C(O)H, -R c S(O) p R 8 -R c NR a R b S(O) p R 8 -S(O) p R 8 NR a R b -R c S(O) p NR a R b ; Phenyl, C1 alkylphenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 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 alkylpyrazine group; wherein the phenyl, cycloalkyl ring, heterocyclic ring, and heteroaryl ring are each optionally surrounded by at least one R 10 Substituents are selected independently from methyl, ethyl, propyl, methoxy, ethoxy, -CHF2, -CF3, -OCF3, F, Cl, amino, -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 as a C1-C6 alkyl or C1-C6 alkoxy group; C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(O)R 8 -C(O)NR a R8 -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 -S(O) p R 8 ; Phenyl, C1 alkylphenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 1- C2 alkylcyclopropyl, 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; wherein the phenyl, cycloalkyl ring, heterocyclic ring, and heteroaryl ring are each optionally surrounded by at least one R 10 Substituents are selected independently from 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 as a C1-C6 alkyl or C1-C6 alkoxy group; 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 -S(O) p R 8; Phenyl, C1 alkylphenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 1- C2 alkylcyclopropyl, 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 group; wherein the phenyl, cycloalkyl ring, heterocyclic ring, and heteroaryl ring are each optionally surrounded by at least one R 10 Substituents are selected independently from methyl, ethyl, methoxy, ethoxy, -CHF2, -CF3, -OCF3, F, Cl, amino, -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, CH2morpholino, -CH2piperidinyl, (CH2)2morpholino, or (CH2)2piperidinyl. On the other hand, R 5 It is H, methyl, ethyl, propyl, or isopropyl. On the other hand, R 6 H; C1-C6 alkyl or C1-C6 alkoxy groups, each optionally substituted with at least one hydroxyl group; 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 -S(O) p R 8 ; Phenyl, C1 alkylphenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 1- C2 alkylcyclopropyl, 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 group; wherein the phenyl, cycloalkyl ring, heterocyclic ring, and heteroaryl ring are each optionally surrounded by at least one R 10 Substituents are selected independently from methyl, ethyl, methoxy, ethoxy, -CHF2, -CF3, -OCF3, F, Cl, -NHCH3, -N(CH3)2, -S(O)2CH3, cyano, and hydroxyl. On the other hand, R... 6 It is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, -CH2CF3, -CF3, -OCF3; C(O)NR a R 8 , where R a It is H or methyl and R 8 It is a phenyl group that is H, methyl, cyclopropyl, optionally substituted with F, Cl, or -CF3; -(CH2)S(O)2R 8 , where R 8 It is methyl or phenyl; -CH2NR a R b or -(CH2)2NR a R b , where R a and R b Each can be independently H or methyl; -(CH2)2OCH3, -(CH2)3OCH3; phenyl, C1 alkylphenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 1- C2 alkylcyclopropyl, C 1- C2 alkylcyclobutyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, C 1- C2 alkylpyrrolidinyl, C 1- C2 alkylpiperidinyl, C 1- C2alkylpiperazinyl, C1-C2morpholinyl, C1-C2tetrahydropyranyl, pyrazolyl, imidazoleyl, pyridyl, pyrimidinyl, pyrazinyl, C 1- C2 alkylpyrazolyl, C1- C2 alkylimidazolium, C 1- C2 alkylpyridinyl, C 1- C2 alkylpyrimidinyl or C 1- C2 alkylpyrazine group; wherein the phenyl, cycloalkyl ring, heterocyclic ring, and heteroaryl ring are each optionally surrounded by at least one R 10 Substituents are selected independently from methyl, ethyl, methoxy, ethoxy, -CHF2, -CF3, -OCF3, F, Cl, amino, -NHCH3, -N(CH3)2, -S(O)2CH3, cyano, and hydroxyl.

[0039] In another aspect of the invention, R 5 and R 6 Together with the nitrogen atoms to which they are attached, they form ring B, 4 to 8-membered heterocycles, or 5-membered heteroaryl rings, 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 atoms to which they are attached, they form ring B, 4 to 8-membered heterocycles, or 5-membered heteroaryl rings, 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, pyridyl, or pyrimidinyl. On the other hand, R... 5 and R 6 Together with the nitrogen atoms to which they are attached, they form a ring B, which is an azacyclic butyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyrrolyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl group, each optionally surrounded 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 oxo. 9 Substituent substitution; and wherein each ring is further optionally fused with Y, which is phenyl or pyridyl. On the other hand, R... 5 and R 6 Together with the nitrogen atoms to which they are attached, they form a ring B, which is pyrroloyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally surrounded by at least one R selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F, Cl, Br, CN, -N(CH3)2, hydroxyl, -CHF2, -CF3, -OCHF2, -OCF3, and oxo.9 Substituents are used for substitution; and each ring is further optionally fused with Y, where Y is phenyl. On the other hand, R... 5 and R 6 Together with the nitrogen atom to which they are attached, they form a ring B, which is pyrroloyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally surrounded by at least one R selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F, Cl, Br, CN, -N(CH3)2, hydroxyl, -CHF2, -CF3, -OCHF2, -OCF3, and oxo. 9 Substituents are used for substitution; and each ring is further optionally fused with Y, where Y is phenyl. On the other hand, R... 5 and R 6 Together with the nitrogen atoms to which they are attached, they form a ring B, which is pyrroloyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally surrounded by at least one R selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F, Cl, Br, CN, -N(CH3)2, hydroxyl, CHF2, CF3, -OCHF2, -OCF3, and oxo. 9 Substituent substitution; or ring B is optionally substituted with at least one oxo group of indololinyl, isoindololinyl, tetrahydroquinolinyl, dihydropyrrolopyrazinyl or tetrahydroisoquinolinyl, dihydrobenzoxazinyl or dihydrobenzothiazinyl. On the other hand, R 5 and R 6 Together with the nitrogen atoms to which they are attached, they form a ring B, which is pyrroloyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally surrounded by at least one R selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F, Cl, Br, CN, -N(CH3)2, hydroxyl, CHF2, CF3, -OCHF2, -OCF3, and oxo. 9 Substituent substitution.

[0040] 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) mNHC(O)N(CH3)2 or -(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 or -(CH2) m NHC(O)CH3; where m is an integer 1 or 2. In another aspect of the invention, R 7 It can be H, C1-C6 alkyl, -(CH2)NH2, -(CH2)NHCH3, (CH2)N(CH3)2, (CH2)C(O)CH3, or -(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, -(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.

[0041] 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, pyrrolyl, pyrazolyl, pyridyl, or pyrimidinyl, each optionally substituted with 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 8It is methyl, ethyl, propyl; or cyclopropyl, C1 alkylcyclopropyl, phenyl, or pyridyl, each optionally substituted with 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 C1-C4 alkyl, halogen, C1-C4 alkoxy, -CF3 and -OCF3.

[0042] In another aspect of the invention, each R 9 Independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, halogen, oxo, hydroxyl, nitro, cyano, -NR a R b C1-C6 haloalkyl, C1-C6 haloalkoxy, -S(O) p R 8 , phenyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolylyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, piperazine, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrimidinyl, and pyrazine. In another aspect, each R 9 Independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, halogen, oxo, hydroxyl, nitro, cyano, -NR a R b C1-C6 haloalkyl, C1-C6 haloalkoxy, -S(O) p R 8 phenyl, tetrahydrofuranyl, pyrrolylyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazineyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, pyridinyl, pyrimidinyl, and pyrazinyl. In another aspect, each R... 9 Independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, halogen, oxo, hydroxyl, nitro, cyano, -NR a R b C1-C6 haloalkyl, C1-C6 haloalkoxy, -S(O) p R 8 phenyl, piperidinyl, morpholinyl, piperazinyl, and pyridinyl. On another front, R 9 Independently selected from the group consisting of: C1-C6 alkyl, C1-C6 alkoxy, halogen, oxo, hydroxyl, cyano, -NHCH3, -N(CH3)2, -N(CH2CH3)2, CHF2, CF3, -OCHF2, -OCF3, -S(O)2CH3, phenyl, piperidinyl, morpholinyl, piperazine, and pyridinyl. In another aspect, R9 Independently selected from the group consisting of: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, F, Cl, Br, oxo, hydroxy, cyano, -NHCH3, -N(CH3)2, -N(CH2CH3)2, -CHF2, -CF3, -OCHF2, -OCF3, -S(O)2CH3, phenyl, piperidinyl, morpholinyl, piperazine, and pyridinyl. In another aspect, R 9 Independently selected from the group consisting of: methyl, ethyl, methoxy, ethoxy, isopropoxy, F, Cl, Br, oxo, hydroxy, nitro, cyano, -NHCH3, -N(CH3)2, -N(CH2CH3)2, -CHF2, -CF3, -OCHF2, -OCF3, -S(O)2CH3, phenyl, piperidinyl, morpholinyl, piperazine, and pyridinyl. In another aspect, each R... 9 Independently selected from the group consisting of: methyl, ethyl, propyl, methoxy, ethoxy, F, Cl, oxo, hydroxy, nitro, cyano, -NR a R b -CF3 and -OCF3. On another front, each R... 9 Independently selected from the group consisting of: methyl, ethyl, propyl, methoxy, ethoxy, F, Cl, oxo, hydroxy, nitro, cyano, -NH2, -NHCH3, -N(CH3)2, CF3, and -OCF3. On the other hand, at least one R 9 The substituent is an integer (n), which is 1, 2 or 3.

[0043] 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, oxo, 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 group, 5- to 6-membered heterocycle, 5- to 6-membered heteroaryl ring, wherein each heterocycle and heteroaryl ring each contains at least one heteroatom selected from the group consisting of N, O and S; and phenyl; and wherein the phenyl, heterocycle and heteroaryl ring are each optionally separated by at least one R 9Substituents are selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halogen, oxo, hydroxyl, 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, oxo, cyano, C(O)CH3, -C(O)OCH3, -NHCH2C(O)CH3, -NHCH2CH2C(O)CH3, -C(O)NHCH3 and hydroxyl; phenyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazine, pyrrolidinyl, furanyl, pyrazolyl, imidazolyl, pyridinyl and pyrazinyl, each optionally and independently influenced by at least one R 9 Substituents are selected from the group consisting of methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, halogen, oxo, 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 hydroxyl; phenyl, pyrrolyl, piperidinyl, morpholinyl, piperazineyl and pyridinyl, each optionally and independently constituting an R 9 Substituents are selected from the group consisting of methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, halogen, oxo, 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 The substituent is an integer (n), which is 1, 2 or 3.

[0044] On the other hand, R is H, -C(O)NR a R d or -C(O)OR 8 In another aspect, R is H, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -C(O)NHCH2CH3, -C(O)NHCH(CH3)2, -C(O)NHC(CH3)3, or -C(O)NHphenyl, wherein the phenyl group is optionally substituted with at least one substituent independently selected from F, Cl, -CF3, cyano, methoxy, ethoxy, and -OCF3. In another aspect, R is H, -C(O)NHCH3, -C(O)N(CH3)2, or -C(O)NHphenyl, wherein the phenyl group is optionally substituted with at least one substituent independently selected from F, Cl, -CF3, cyano, methoxy, ethoxy, and -OCF3. In another aspect, R is H or -C(O)NHphenyl, wherein the phenyl group is optionally substituted with at least one substituent independently selected from F, Cl, -CF3, cyano, methoxy, ethoxy, and -OCF3. On the other hand, R is H or -C(O)NHphenyl. On the other hand, R is H.

[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 or pyridinyl. In another aspect, Y is phenyl. In another aspect, Y is pyridinyl. In yet another aspect, when optionally substituted ring A or ring B is fused with Y, ring A or ring B is optionally substituted indolinyl, isoindolinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, dihydropyrrolopyridinyl, dihydropyrrolopyrimidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxaline, dihydrobenzoxazine, or dihydrobenzothiazine.

[0046] 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.

[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 a 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 are compounds of formula (1), their stereoisomers, and their pharmaceutically acceptable salts, wherein R is H and W is of formula (A), which is a compound of formula (1A), wherein R 0 R 1 R 2 R 3 And X

[0050]

[0051] Defined as in this article.

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

[0053]

[0054] Its stereoisomers and its pharmaceutically acceptable salts. In another aspect, compound (A) is of formula (A0). In another aspect, formula (A) is of formula (A1). In another aspect, formula (A) is of formula (A2). In another aspect, formula (A) is of formula (A3). In another aspect, formula (A) is of formula (A4). In another aspect, formula (A) is of formula (A5). In another aspect, formula (A) is of formula (A6). In another aspect, the preferred formula (A) is formula (A1).

[0055] In another aspect of the invention, there is a compound of formula (1), wherein R and W are both H; which is a decradinose compound of formula (1.1);

[0056]

[0057] And R 0 R 1 R 2 and R 3 As defined herein; its stereoisomers and its pharmaceutically acceptable salts. On the other hand, it is a compound of formula (1.1), its stereoisomers, and its pharmaceutically acceptable salts, wherein R 0 It is H, methyl, ethyl, or propyl; and R 1 R 2 and R 3 As defined herein. On the other hand, it refers to compounds of formula (1.1), their stereoisomers, and their pharmaceutically acceptable salts, wherein R... 0 It is H or methyl; and R 1 R 2 and R 3 As defined herein. On the other hand, it refers to compounds of formula (1.1), their stereoisomers, and their pharmaceutically acceptable salts, wherein R... 0 It is H or methyl; R 1 It is methyl; and R 2 and R 3 As defined herein. On the other hand, it is a compound of formula (1.1), where R... 0 It is H or methyl; R 1 It is methyl; and R 2 and R 3 Each of these elements is independently H, C1-C6 alkyl, -CH2N(CH3)2, -CH2CH2N(CH3)2; or C0-C2 cyclopropyl, C0-C2 cyclobutyl, C0-C2 cyclopentyl, C0-C2 cyclohexyl, C0-C2 phenyl, C0-C2 piperidinyl, piperazine, morpholinyl, tetrahydropyran, pyrroloyl, pyrazolyl, triazolyl, tetraazolyl, 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, amino, -N(CH3)2, -CHF2, -CF3, -OCHF2 and -OCF3; or R 2 and R 3 Together with the nitrogen atoms to which they are attached, they form a ring A, which is an azacyclic butyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyrrolyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl group, each optionally being surrounded 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 oxo. 10Substituents are used to replace the rings; and each ring is further optionally substituted with Y, which is phenyl, pyridyl, or pyrimidinyl; its stereoisomers and its pharmaceutically acceptable salts. In another aspect, it is a compound of formula (1.1), wherein R... 0 It is H or methyl; R 1 It is methyl; and R 2 and R 3 Each is independently H, C1-C6 alkyl; -CH2N(CH3)2, -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, pyrroleyl, pyrazolyl, triazolyl, 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, amino, -N(CH3)2, -CHF2, -CF3, -OCHF2 and -OCF3; or R 2 and R 3 Together with the nitrogen atoms to which they are attached, they form a ring A, which is pyrroloyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally surrounded by at least one R selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F, Cl, Br, CN, -N(CH3)2, hydroxyl, -CHF2, -CF3, -OCHF2, -OCF3, and oxo. 10 Substituents; or ring A is indololinyl, isoindololinyl, pyrrolopyridyl, pyrrolopyrimidinyl, dihydropyrrolopyridyl, dihydropyrrolopyrimidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxaline, dihydrobenzoxazine, or dihydrobenzothiazine, optionally substituted with at least one oxo group; its stereoisomers and its pharmaceutically acceptable salts. In another aspect, it is a compound of formula (1.1), wherein R... 0 It is H or methyl; R 1 It is methyl; R 2 It is H, methyl, ethyl, isopropyl, cyclopropyl, -CF3, -CHF2, -CH2F, -CH2CF3 or phenyl; and R 3 It is H, methyl, ethyl, propyl, isopropyl, tert-butyl; -CH2N(CH3)2, -CH2CH2N(CH3)2; or cyclopropyl, cyclobutyl, phenyl, C1 phenyl, piperidinyl, C1-piperidinyl, C2-piperidinyl, piperazine, 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, amino, -N(CH3)2 and -CF3; or R 2 and R 3 Together with the nitrogen atoms to which they are attached, they form a ring A, which is pyrroloyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally surrounded by at least one R selected from methyl, ethyl, F, Cl, oxo, and -CF3. 10 Substituents; stereoisomers thereof and pharmaceutically acceptable salts thereof. On the other hand, it is compound A of formula (1.1), its stereoisomers and its pharmaceutically acceptable salts.

[0058] In another aspect, it is a composition comprising a compound of formula (1.1), its stereoisomer, and a pharmaceutically acceptable salt thereof. In another aspect, it is a composition comprising a compound of formula (1.1) Table A, its stereoisomer, and a pharmaceutically acceptable salt thereof. In yet another aspect, the composition further comprises a pharmaceutically acceptable carrier.

[0059] In another aspect, there is a method for treating or preventing an inflammatory response in animals by administering to the animal in need a therapeutically effective amount of a compound of formula (1.1), its stereoisomers, and its pharmaceutically acceptable salts. In another aspect, there is a method for treating or preventing an inflammatory response in animals by administering to the animal in need a therapeutically effective amount of a compound of formula (1.1) Table A, its stereoisomers, and its pharmaceutically acceptable salts. In another aspect of this method, the inflammatory response is caused by bacterial, viral, or fungal infection, stress, and / or environmental factors. In another aspect of this method, the method for treating or preventing an inflammatory response in animals prevents or mitigates the progression of a respiratory disease or condition. In another aspect of this method, the animal is a domestic animal. In another aspect of this method, the respiratory disease or condition is bovine respiratory disease or swine respiratory disease. In another aspect of this method, the method for treating or preventing an inflammatory response in animals downregulates TNF-α and IL-6 in the animal.

[0060] In another aspect, the use of the compound of formula (1.1), its stereoisomers, and pharmaceutically acceptable salts thereof; is to prepare a medicament for the treatment or prevention of inflammatory responses in animals. In another aspect, the use of the compound of formula (1.1) Table A, its stereoisomers, and pharmaceutically acceptable salts thereof; is to prepare a medicament for the treatment or prevention of inflammatory responses in animals. In another aspect of this use, the inflammatory response is caused by bacterial, viral, or fungal infection, stress, and / or environmental factors. In another aspect of this use, the use of the medicament for the treatment or prevention of inflammatory responses in animals is to prevent or reduce the progression of respiratory diseases or conditions. In another aspect of this use, the animal is a domestic animal. In another aspect of this use, the respiratory disease or condition is bovine respiratory disease or swine respiratory disease. In another aspect of this use, the use of administering the medicament to animals to treat or prevent inflammatory responses in animals is to downregulate TNF-α and IL-6 in animals.

[0061] In another aspect of the invention, there is a compound of formula (1), wherein R is H and W is formula (A), and formula (A) is formula (A0); which is formula (1-A0).

[0062]

[0063] Compound, and wherein R a R 0 R 1 R 2 and R 3 As defined herein; its stereoisomers and its pharmaceutically acceptable salts. On the other hand, it is a compound of formula (1-A0), its stereoisomers, and its pharmaceutically acceptable salts, wherein R... 0 It is H, methyl, ethyl, or propyl; and R a R 1 R 2 and R 3 As defined herein. On the other hand, it refers to compounds of formula (1-A0), their stereoisomers, and their pharmaceutically acceptable salts, wherein R... 0 It is H, methyl, ethyl, or propyl; R a It is H or methyl; and R 1 R 2 and R 3 As defined herein. On the other hand, it refers to compounds of formula (1-A0), their stereoisomers, and their pharmaceutically acceptable salts, wherein R... 0 It is H or methyl; R a It is H or methyl; and R 1 It is H or methyl; and R 2 and R 3As defined herein. On the other hand, it refers to compounds of formula (1-A0), their stereoisomers, and their pharmaceutically acceptable salts, wherein R... 0 It is H or methyl; R 1 It is methyl; and R 2 and R 3 As defined herein. On the other hand, it is a compound of formula (1-A0), wherein R... 0 It is H or methyl; R 1 It is methyl; and R 2 and R 3 Each of these elements is independently H, C1-C6 alkyl, -CH2N(CH3)2, -CH2CH2N(CH3)2; or C0-C2 cyclopropyl, C0-C2 cyclobutyl, C0-C2 cyclopentyl, C0-C2 cyclohexyl, C0-C2 phenyl, C0-C2 piperidinyl, piperazine, morpholinyl, tetrahydropyran, pyrroloyl, pyrazolyl, triazolyl, tetraazolyl, 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, amino, -N(CH3)2, -CHF2, -CF3, -OCHF2 and -OCF3; or R 2 and R 3 Together with the nitrogen atoms to which they are attached, they form ring A, 4 to 8-membered heterocycles, or 5-membered heteroaryl rings, 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 10 Substituents are used to replace the rings, and each ring is further optionally fused with Y, which is phenyl, pyridyl, or pyrimidinyl; its stereoisomers and its pharmaceutically acceptable salts. On the other hand, it is a compound of formula (1-A0), wherein R... 0 It is H or methyl; R 1 It is methyl; and R 2 and R 3 Each of the following is independently H, C1-C6 alkyl; -CH2N(CH3)2, -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, pyrroleyl, pyrazolyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl, each optionally being R selected from the group consisting of at least one of the following groups. 9Substituents: methyl, ethyl, propyl, isopropyl, tert-butyl, hydroxy, methoxy, ethoxy, F, Cl, Br, cyano, cyclopropyl, amino, -N(CH3)2, -CHF2, -CF3, -OCHF2 and -OCF3; or R 2 and R 3 Together with the nitrogen atoms to which they are attached, they form a ring A, which is pyrroloyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally surrounded by at least one R selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F, Cl, Br, CN, -N(CH3)2, hydroxyl, -CHF2, -CF3, -OCHF2, -OCF3, and oxo. 10 Substituents; or ring A is indololinyl, isoindololinyl, pyrrolopyridyl, pyrrolopyrimidinyl, dihydropyrrolopyridyl, dihydropyrrolopyrimidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxaline, dihydrobenzoxazine, or dihydrobenzothiazine, optionally substituted with at least one oxo group; its stereoisomers and its pharmaceutically acceptable salts. In another aspect, it is a compound of formula (1-A0), wherein R... 0 It is H or methyl; R 1 It is methyl; R 2 It is H or methyl; and R 3 It is H, methyl, ethyl or propyl; -CH2N(CH3)2, -CH2CH2N(CH3)2; or cyclopropyl, cyclobutyl, phenyl, C1 phenyl, piperidinyl, C1-piperidinyl, C2-piperidinyl, piperazine, 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 2 and R 3 Together with the nitrogen atoms to which they are attached, they form a ring A, which is pyrroloyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally surrounded by at least one R selected from methyl, ethyl, F, Cl, oxo, and -CF3. 10 Substituent substitution; its stereoisomers and its pharmaceutically acceptable salts. On the other hand, it is a compound of formula (1-A0) Table B, its stereoisomers and its pharmaceutically acceptable salts. On the other hand, it is a non-antibacterial compound of formula (1-A0) Table B, its stereoisomers and its pharmaceutically acceptable salts.

[0064] In another aspect, it is a composition comprising a compound of formula (1-A0), its stereoisomer, and a pharmaceutically acceptable salt thereof. In another aspect, it is a composition comprising a compound of formula (1-A0) Table B, its stereoisomer, and a pharmaceutically acceptable salt thereof. In another aspect, it is a composition comprising a non-antibacterial compound of formula (1-A0) Table B, its stereoisomer, and a pharmaceutically acceptable salt thereof.

[0065] In another aspect, it is a composition comprising a compound of formula (1-A0), its stereoisomer, and a pharmaceutically acceptable salt thereof. In another aspect, it is a composition comprising a compound of formula (1-A0) Table B, its stereoisomer, and a pharmaceutically acceptable salt thereof. In another aspect, it is a composition comprising a non-antibacterial compound of formula (1-A0) Table B, its stereoisomer, and a pharmaceutically acceptable salt thereof. In another aspect, the composition further comprises a pharmaceutically acceptable carrier.

[0066] In another aspect, there is a method for treating or preventing an inflammatory response in animals by administering to the animal in need a therapeutically effective amount of a compound of formula (1-A0), its stereoisomers, and its pharmaceutically acceptable salts. In another aspect, there is a method for treating or preventing an inflammatory response in animals by administering to the animal in need a therapeutically effective amount of a compound of formula (1-A0) Table B, its stereoisomers, and its pharmaceutically acceptable salts. In another aspect, there is a method for treating or preventing an inflammatory response in animals by administering to the animal in need a therapeutically effective amount of a non-antimicrobial compound of formula (1-A0) Table B, its stereoisomers, and its pharmaceutically acceptable salts. In another aspect of this method, the inflammatory response is caused by bacterial, viral, or fungal infection, stress, and / or environmental factors. In another aspect of this method, the method for treating or preventing an inflammatory response in animals prevents or mitigates the progression of respiratory diseases or symptoms. In another aspect of this method, the animal is a domestic animal. In another aspect of this method, the respiratory disease or symptoms are bovine respiratory diseases or swine respiratory diseases. In another aspect of this method, methods for treating or preventing inflammatory responses in animals downregulate TNF-α and IL-6 in the animals.

[0067] In another aspect, the use is of a compound of formula (1-A0), its stereoisomers, and pharmaceutically acceptable salts thereof; to prepare a medicament for the treatment or prevention of inflammatory responses in animals. In another aspect, the use is of a compound of formula (1-A0) Table B, its stereoisomers, and pharmaceutically acceptable salts thereof; to prepare a medicament for the treatment or prevention of inflammatory responses in animals. In another aspect, the use is of a non-antimicrobial compound of formula (1-A0) Table B, its stereoisomers, and pharmaceutically acceptable salts thereof; to prepare a medicament for the treatment or prevention of inflammatory responses in animals. In another aspect of this use, the inflammatory response is caused by bacterial, viral, or fungal infection, stress, and / or environmental factors. In another aspect of this use, the medicament is used to treat or prevent inflammatory responses in animals, and to prevent or reduce the progression of respiratory diseases or symptoms. In another aspect of this use, the animal is a domestic animal. In another aspect of this use, the respiratory disease or symptom is bovine respiratory disease or swine respiratory disease. In another aspect of this use, administering the drug to animals to treat or prevent inflammatory responses in animals downregulates TNF-α and IL-6 in the animals.

[0068] In another aspect of the invention, there is a compound of formula (1), wherein R is H and W is formula (A), and formula (A) is formula (A2); which is formula (1-A2).

[0069]

[0070] Compound; wherein R 0 R 1 R 2 R 3 and R 7 As defined herein; its stereoisomers and its pharmaceutically acceptable salts. On the other hand, it is formula (1-A2).

[0071] Compound; wherein R 0 It is H, methyl, ethyl, or propyl; R 1 It is H or methyl; and R 2 R 3 and R 7 As defined herein; its stereoisomers and its pharmaceutically acceptable salts. On the other hand, it is a compound of formula (1-A2); wherein R 0 It is H or methyl; R 1 It is H or methyl; and R 2 and R 3Each of the following is independently H, C1-C6 alkyl; -CH2N(CH3)2, -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, amino, -N(CH3)2, -CHF2, -CF3, -OCHF2 and -OCF3; or R 2 and R 3 Together with the nitrogen atoms to which they are attached, they form a ring A, which is pyrroloyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally surrounded by at least one R selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F, Cl, Br, CN, -N(CH3)2, hydroxyl, -CHF2, -CF3, -OCHF2, -OCF3, and oxo. 10 Substituent substitution; or ring A is indololinyl, isoindololinyl, pyrrolopyridyl, pyrrolopyrimidinyl, dihydropyrrolopyridyl, dihydropyrrolopyrimidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxaline, dihydrobenzoxazine, or dihydrobenzothiazine, optionally substituted with at least one oxo group; and 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 or (CH2) m NHC(O)CH3; where m is an integer 1 or 2; its stereoisomers and its pharmaceutically acceptable salts. On the other hand, it is formula (1-A2), its stereoisomers and its pharmaceutically acceptable salts, where R... 0 It is H or methyl; R 1 It is methyl; R 2 It is H, methyl, ethyl, cyclopropyl, or phenyl; R 3It is H, methyl, ethyl, propyl, isopropyl, isobutyl, -CH2N(CH3)2, -CH2CH2N(CH3)2; or cyclopropyl, cyclobutyl, phenyl, C1 phenyl, piperidinyl, C1-piperidinyl, C2-piperidinyl, piperazine, 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, nitro, cyano, -N(CH3)2 and -CF3; or R 2 and R 3 Together with the nitrogen atoms to which they are attached, they form a ring A, which is pyrroloyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally surrounded by at least one R selected from methyl, ethyl, F, Cl, oxo, and -CF3. 10 Substituent substitution; and R 7 It is H, methyl, ethyl, propyl, isopropyl, tert-butyl, -CH2NH2, -CH2NHCH3, or -CH2N(CH3)2. On the other hand, it is the compound represented by formula (1-A2), its stereoisomers, and its pharmaceutically acceptable salts.

[0072] In another aspect of the invention, there is a compound of formula (1), wherein R is H and W is formula (A), and formula (A) is formula (A3); it is a compound of formula (1-A3).

[0073]

[0074] Where R 0 R 1 R 2 R 3 and R 7 As defined herein; its stereoisomers and its pharmaceutically acceptable salts. On the other hand, it is a compound of formula (1-A3); wherein R 0 It is H, methyl, ethyl, or propyl; and R 1 R 2 R 3 and R 7 As defined herein; its stereoisomers and its pharmaceutically acceptable salts. On the other hand, it is a compound of formula (1-A3); wherein R 0 It is H, methyl, ethyl, or propyl; R 1 It is H or methyl; and R 2 R 3 and R 7 As defined herein; its stereoisomers and its pharmaceutically acceptable salts. On the other hand, it is a compound of formula (1-A3); wherein R 0 It is H or methyl; R 1It is H or methyl; and R 2 and R 3 Each of the following is independently H, C1-C6 alkyl; -CH2N(CH3)2, -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, amino, -N(CH3)2, -CHF2, -CF3, -OCHF2 and -OCF3; or R 2 and R 3 Together with the nitrogen atoms to which they are attached, they form a ring A, which is pyrroloyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally surrounded by at least one R selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F, Cl, Br, CN, -N(CH3)2, hydroxyl, -CHF2, -CF3, -OCHF2, -OCF3, and oxo. 10 Substituent substitution; or ring A is indololinyl, isoindololinyl, pyrrolopyridyl, pyrrolopyrimidinyl, dihydropyrrolopyridyl, dihydropyrrolopyrimidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxaline, dihydrobenzoxazine, or dihydrobenzothiazine, optionally substituted with at least one oxo group; and 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 or -(CH2) m NHC(O)CH3; where m is an integer 1 or 2; its stereoisomers and its pharmaceutically acceptable salts. On the other hand, it is formula (1-A3), its stereoisomers and its pharmaceutically acceptable salts, where R... 0 It is H or methyl; R 1 It is methyl; R 2 It is H, methyl, ethyl, cyclopropyl, or phenyl; R 3It is H, methyl, ethyl, propyl, isopropyl, tert-butyl, -CH2N(CH3)2, -CH2CH2N(CH3)2; or cyclopropyl, cyclobutyl, phenyl, C1 phenyl, piperidinyl, C1-piperidinyl, C2-piperidinyl, piperazine, 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, nitro, cyano, -N(CH3)2 and -CF3; or R 2 and R 3 Together with the nitrogen atoms to which they are attached, they form a ring A, which is pyrroloyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally surrounded by at least one R selected from methyl, ethyl, F, Cl, oxo, and -CF3. 10 Substituent substitution; and R 7 It is H, methyl, ethyl, propyl, isopropyl, tert-butyl, -CH2NH2, -CH2NHCH3, or -CH2N(CH3)2. On the other hand, it is a compound of formula (1-A3) D, its stereoisomers, and its pharmaceutically acceptable salts. On the other hand, it is a non-antibacterial compound of formula (1-A3) D, its stereoisomers, and its pharmaceutically acceptable salts.

[0075] In another aspect of the invention, there is a compound of formula (1), wherein R is H and W is formula (A), and formula (A) is formula (A4); it is a compound of formula (1-A4).

[0076]

[0077] Where R 0 R 1 R 2 R 3 And X' as defined herein; its stereoisomers and its pharmaceutically acceptable salts. On the other hand, it is a compound of formula (1-A4); wherein R... 0 It is H, methyl, ethyl, or propyl; and R 1 R 2 R 3 And X' as defined herein; its stereoisomers and its pharmaceutically acceptable salts. On the other hand, it is a compound of formula (1-A4); wherein R... 0 It is H, methyl, ethyl, or propyl; R 1 It is H or methyl; and R 2 R 3 And X' as defined herein; its stereoisomers and its pharmaceutically acceptable salts. On the other hand, it is a compound of formula (1-A4); wherein R... 0 It is H or methyl; R 1It is H or methyl; and R 2 and R 3 Each of the following is independently H, C1-C6 alkyl; -CH2N(CH3)2, -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, amino, -N(CH3)2, CHF2, -CF3, -OCHF2 and -OCF3; or R 2 and R 3 Together with the nitrogen atoms to which they are attached, they form a ring A, which is pyrroloyl, pyrazolyl, 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 oxo; or ring A is indololinyl, isoindololinyl, pyrrolopyridyl, pyrrolopyrimidinyl, dihydropyrrolopyridyl, dihydropyrrolopyrimidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxaline, dihydrobenzoxazine, or dihydrobenzothiazine, optionally substituted with at least one oxo group; and X' is F, Cl, or Br; its stereoisomers and its pharmaceutically acceptable salts. In another aspect, it is formula (1-A4), wherein R... 0 It is H or methyl; R 1 It is methyl; R 2 It is H, methyl, ethyl, cyclopropyl, or phenyl; R 3 It is H, methyl, ethyl, propyl, isopropyl, tert-butyl, -CH2N(CH3)2, -CH2CH2N(CH3)2; or cyclopropyl, cyclobutyl, phenyl, C1 phenyl, piperidinyl, C1-piperidinyl, C2-piperidinyl, piperazine, 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, nitro, cyano, -N(CH3)2 and -CF3; or R 2 and R 3Together with the nitrogen atoms to which they are attached, they form a ring A, which is pyrroloyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally surrounded by at least one R selected from methyl, ethyl, F, Cl, oxo, and -CF3. 10 Substituents; and X' is F or Cl; its stereoisomers and its pharmaceutically acceptable salts. On the other hand, it is compound E represented by formula (1-A4), its stereoisomers and its pharmaceutically acceptable salts.

[0078] In another aspect of the invention, there is a compound of formula (1), wherein R is H and W is formula (A), and formula (A) is formula (A5); which is formula (1-A5).

[0079]

[0080] Compound; wherein R 0 R 1 R 2 and R 3 As defined herein; its stereoisomers and its pharmaceutically acceptable salts. On the other hand, it is a compound of formula (1-A5); wherein R 0 It is H, methyl, ethyl, or propyl; and R 1 R 2 and R 3 As defined herein; its stereoisomers and its pharmaceutically acceptable salts. On the other hand, it is a compound of formula (1-A5); wherein R 0 It is H, methyl, ethyl, or propyl; R 1 It is H or methyl; and R 2 and R 3 As defined herein; its stereoisomers and its pharmaceutically acceptable salts. On the other hand, it is a compound of formula (1-A5); wherein R 0 It is H or methyl; R 1 It is H or methyl; and R 2 and R 3 Each of the following is independently H, C1-C6 alkyl; -CH2N(CH3)2, -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. 9Substituents: methyl, ethyl, propyl, isopropyl, tert-butyl, hydroxy, methoxy, ethoxy, F, Cl, Br, cyano, cyclopropyl, amino, -N(CH3)2, -CHF2, -CF3, -OCHF2 and -OCF3; or R 2 and R 3 Together with the nitrogen atoms to which they are attached, they form a ring A, which is pyrroloyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally surrounded by at least one R selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F, Cl, Br, CN, -N(CH3)2, hydroxyl, -CHF2, -CF3, -OCHF2, -OCF3, and oxo. 10 Substituents; or ring A is indololinyl, isoindololinyl, pyrrolopyridyl, pyrrolopyrimidinyl, dihydropyrrolopyridyl, dihydropyrrolopyrimidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxaline, dihydrobenzoxazine, or dihydrobenzothiazine, optionally substituted with at least one oxo group; its stereoisomers and its pharmaceutically acceptable salts. In another aspect, it is formula (1-A5), wherein R... 0 It is H or methyl; R 1 It is methyl; R 2 It is H, methyl, ethyl, cyclopropyl, or phenyl; R 3 It is H, methyl, ethyl, propyl, isopropyl, tert-butyl, -CH2N(CH3)2, -CH2CH2N(CH3)2; or cyclopropyl, cyclobutyl, phenyl, C1 phenyl, piperidinyl, C1-piperidinyl, C2-piperidinyl, piperazine, 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, nitro, cyano, -N(CH3)2 and -CF3; or R 2 and R 3 Together with the nitrogen atoms to which they are attached, they form a ring A, which is pyrroloyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally surrounded by at least one R selected from methyl, ethyl, F, Cl, oxo, and -CF3. 10 Substituent substitution; its stereoisomers and its pharmaceutically acceptable salts. On the other hand, it is the compound of formula (1-A5) F, its stereoisomers and its pharmaceutically acceptable salts. On the other hand, it is the non-antibacterial compound of formula (1-A5) F, its stereoisomers and its pharmaceutically acceptable salts.

[0081] On the other hand, it is a compound of formula (1), wherein R is H, W is formula (A), and formula (A) is formula (A6), which is a compound of formula (1-A6), wherein R 0 R1 ,

[0082]

[0083] R 2 and R 3 As defined herein; its stereoisomers and its pharmaceutically acceptable salts. On the other hand, it is a compound of formula (1-A6), wherein R... 0 It is H, methyl, ethyl, or propyl; and R 1 R 2 and R 3 As defined herein; its stereoisomers and its pharmaceutically acceptable salts. On the other hand, it is a compound of formula (1-A6); wherein R 0 It is H, methyl, ethyl, or propyl; R 1 It is H or methyl; and R 2 and R 3 As defined herein; its stereoisomers and its pharmaceutically acceptable salts. On the other hand, it is a compound of formula (1-A6); wherein R 0 It is H or methyl; R 1 It is H or methyl; and R 2 and R 3 Each of the following is independently H, C1-C6 alkyl; -CH2N(CH3)2, -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, amino, -N(CH3)2, -CHF2, -CF3, -OCHF2 and -OCF3; or R 2 and R 3 Together with the nitrogen atoms to which they are attached, they form a ring A, which is pyrroloyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally surrounded by at least one R selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F, Cl, Br, CN, -N(CH3)2, hydroxyl, -CHF2, -CF3, -OCHF2, -OCF3, and oxo. 10Substituents; or ring A is indololinyl, isoindololinyl, pyrrolopyridyl, pyrrolopyrimidinyl, dihydropyrrolopyridyl, dihydropyrrolopyrimidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxaline, dihydrobenzoxazine, or dihydrobenzothiazine, optionally substituted with at least one oxo group; its stereoisomers and its pharmaceutically acceptable salts. In another aspect, it is formula (1-A6), wherein R... 0 It is H or methyl; R 1 It is methyl; R 2 It is H, methyl, ethyl, cyclopropyl, or phenyl; R 3 It is H, methyl, ethyl, propyl, isopropyl, tert-butyl, -CH2N(CH3)2, -CH2CH2N(CH3)2; or cyclopropyl, cyclobutyl, phenyl, C1 phenyl, piperidinyl, C1-piperidinyl, C2-piperidinyl, piperazine, 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, nitro, cyano, -N(CH3)2 and -CF3; or R 2 and R 3 Together with the nitrogen atoms to which they are attached, they form a ring A, which is pyrroloyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally surrounded by at least one R selected from methyl, ethyl, F, Cl, oxo, and -CF3. 10 Substituents; stereoisomers thereof and pharmaceutically acceptable salts thereof. On the other hand, it is compound G represented by formula (1-A6), its stereoisomers, and its pharmaceutically acceptable salts.

[0084] In another aspect, it is a composition comprising a compound of formula (1-A2), its stereoisomer, and a pharmaceutically acceptable salt thereof. In another aspect, it is a composition comprising a compound of formula (1-A2) Table C, its stereoisomer, and a pharmaceutically acceptable salt thereof. In another aspect, it is a composition comprising a compound of formula (1-A3), its stereoisomer, and a pharmaceutically acceptable salt thereof. In another aspect, it is a composition comprising a compound of formula (1-A3) Table D, its stereoisomer, and a pharmaceutically acceptable salt thereof. In another aspect, it is a composition comprising a non-antibacterial compound of formula (1-A3), its stereoisomer, and a pharmaceutically acceptable salt thereof. In another aspect, it is a composition comprising a compound of formula (1-A4), its stereoisomer, and a pharmaceutically acceptable salt thereof. In another aspect, it is a composition comprising a compound of formula (1-A4) Table E, its stereoisomer, and a pharmaceutically acceptable salt thereof. In another aspect, it is a composition comprising a compound of formula (1-A5), its stereoisomer, and a pharmaceutically acceptable salt thereof. In another aspect, it is a composition comprising a non-antimicrobial compound of formula (1-A5), its stereoisomer, and a pharmaceutically acceptable salt thereof. In another aspect, it 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.

[0085] In another aspect, there is a method for treating or preventing an inflammatory response in animals by administering to the animal in need a therapeutically effective amount of a compound of formula (1-A2), its stereoisomer, and its pharmaceutically acceptable salt. In another aspect, there is a method for treating or preventing an inflammatory response in animals by administering to the animal in need a therapeutically effective amount of a compound of formula (1-A2) Table C, its stereoisomer, and its pharmaceutically acceptable salt. In another aspect, there is a method for treating or preventing an inflammatory response in animals by administering to the animal in need a therapeutically effective amount of a compound of formula (1-A3), its stereoisomer, and its pharmaceutically acceptable salt. In another aspect, there is a method for treating or preventing an inflammatory response in animals by administering to the animal in need a therapeutically effective amount of a compound of formula (1-A3) Table D, its stereoisomer, and its pharmaceutically acceptable salt. In another aspect, there is a method for treating or preventing an inflammatory response in animals by administering to the animal in need a therapeutically effective amount of a non-antimicrobial compound of formula (1-A3) Table D, its stereoisomer, and its pharmaceutically acceptable salt. In another aspect, there is a method for treating or preventing an inflammatory response in animals by administering to the animal in need a therapeutically effective amount of a compound of formula (1-A4), its stereoisomer, and its pharmaceutically acceptable salt. In another aspect, there is a method for treating or preventing an inflammatory response in animals by administering to the animal in need a therapeutically effective amount of a compound of formula (1-A4) Table E, its stereoisomer, and its pharmaceutically acceptable salt. In another aspect, there is a method for treating or preventing an inflammatory response in animals by administering to the animal in need a therapeutically effective amount of a compound of formula (1-A5), its stereoisomer, and its pharmaceutically acceptable salt. In another aspect, there is a method for treating or preventing an inflammatory response in animals by administering to the animal in need a therapeutically effective amount of a compound of formula (1-A5) Table F, its stereoisomer, and its pharmaceutically acceptable salt. In another aspect, there is a method for treating or preventing an inflammatory response in animals by administering to the animal in need a therapeutically effective amount of a non-antimicrobial compound of formula (1-A5) Table F, its stereoisomer, and its pharmaceutically acceptable salt. In another aspect, there is a method for treating or preventing an inflammatory response in animals by administering to the animal in need a therapeutically effective amount of a compound of formula (1-A6), its stereoisomer, and its pharmaceutically acceptable salt. In another aspect, there is a method for treating or preventing an inflammatory response in animals by administering to the animal in need a therapeutically effective amount of a compound of formula (1-A6) Table G, its stereoisomer, and its pharmaceutically acceptable salt. In another aspect of this method, the inflammatory response is caused by bacterial, viral, or fungal infection, stress, and / or environmental factors.In another aspect of the method, the method of treating or preventing inflammatory responses in animals prevents or mitigates the progression of respiratory diseases or conditions. In another aspect of the method, the animal is livestock. In another aspect of the method, the respiratory disease or condition is bovine respiratory disease or swine respiratory disease. In another aspect of the method, the method of treating or preventing inflammatory responses in animals downregulates TNF-α and IL-6 in the animal.

[0086] In another aspect, the use of compounds of formula (1-A2), their stereoisomers, and pharmaceutically acceptable salts thereof; the preparation of medicaments for the treatment or prevention of inflammatory responses in animals. In another aspect, the use of compounds of formula (1-A2) Table C, their stereoisomers, and pharmaceutically acceptable salts thereof; the preparation of medicaments for the treatment or prevention of inflammatory responses in animals. In another aspect, the use of compounds of formula (1-A3), their stereoisomers, and pharmaceutically acceptable salts thereof; the preparation of medicaments for the treatment or prevention of inflammatory responses in animals. In another aspect, the use of non-antibacterial compounds of formula (1-A3) Table D, their stereoisomers, and pharmaceutically acceptable salts thereof; the preparation of medicaments for the treatment or prevention of inflammatory responses in animals. In another aspect, the use of compounds of formula (1-A4), their stereoisomers, and pharmaceutically acceptable salts thereof; the preparation of medicaments for the treatment or prevention of inflammatory responses in animals. In another aspect, the use is of compounds of formula (1-A4) Table E, their stereoisomers, and pharmaceutically acceptable salts thereof; to prepare medicaments for the treatment or prevention of inflammatory responses in animals. In another aspect, the use is of compounds of formula (1-A5), their stereoisomers, and pharmaceutically acceptable salts thereof; to prepare medicaments for the treatment or prevention of inflammatory responses in animals. In another aspect, the use is of non-antimicrobial compounds of formula (1-A5), their stereoisomers, and pharmaceutically acceptable salts thereof; to prepare medicaments for the treatment or prevention of inflammatory responses in animals. In another aspect, the use is of compounds of formula (1-A6), their stereoisomers, and pharmaceutically acceptable salts thereof; to prepare medicaments for the treatment or prevention of inflammatory responses in animals. In another aspect, the use is of compounds of formula (1-A6) Table G, their stereoisomers, and pharmaceutically acceptable salts thereof; to prepare medicaments for the treatment or prevention of inflammatory responses in animals. In another aspect of this use, the inflammatory response is caused by bacterial, viral, or fungal infection, stress, and / or environmental factors. In another aspect of this use, the drug is used to treat or prevent inflammatory responses in animals, and to prevent or reduce the progression of respiratory diseases or conditions. In another aspect of this use, the animals are livestock. In another aspect of this use, the respiratory disease or condition is bovine respiratory disease or swine respiratory disease. In another aspect of this use, the drug is administered to animals to treat or prevent inflammatory responses in animals, and to downregulate TNF-α and IL-6 in animals.

[0087] In another aspect of the invention, there is a compound of formula (1), wherein R is H and W is formula (A), and formula (A) is formula (A1); it is a compound of formula (1-A1);

[0088]

[0089] And R 0 R 1 R 2 R 3 R 5 and R 6 As defined herein; its stereoisomers and its pharmaceutically acceptable salts. On the other hand, it is a compound of formula (1-A1), its stereoisomers, and its pharmaceutically acceptable salts, wherein R 0 It is H, methyl, ethyl, or propyl; and R 1 R 2 R 3 R 5 and R 6 As defined herein. On the other hand, it refers to compounds of formula (1-A1), their stereoisomers, and their pharmaceutically acceptable salts, wherein R... 0 It is H, methyl; ethyl or propyl; R 1 It is H or methyl; and R 2 R 3 R 5 and R 6 As defined herein. On the other hand, it refers to compounds of formula (1-A1), their stereoisomers, and their pharmaceutically acceptable salts, wherein R... 0 and R 1 Each is independently H or methyl; R 2 R 3 R 5 and R 6 As defined herein. On the other hand, it refers to compounds of formula (1-A1), their stereoisomers, and their pharmaceutically acceptable salts, wherein R... 0 It is H or methyl; R 1 It is methyl; and R 2 R 3 R 5 and R 6 As defined herein. On the other hand, it is a compound of formula (1-A1), wherein R... 0 It is H or methyl; R 1 It is methyl; R 2 and R 3Each of the following is independently H, C1-C6 alkyl; -CH2N(CH3)2, -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, tetrahydropyran, pyrroleyl, pyrazolyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazineyl, 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, amino, -N(CH3)2, -CHF2, -CF3, -OCHF2 and -OCF3; or R 2 and R 3 Together with the nitrogen atoms to which they are attached, they form a ring A, which is pyrroloyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally surrounded by at least one R selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F, Cl, Br, CN, -N(CH3)2, hydroxyl, -CHF2, -CF3, -OCHF2, -OCF3, and oxo. 10 Substituent substitution; and wherein each ring is further optionally fused with Y, which is phenyl, pyridyl, or pyrimidinyl; R 5 and R 6 Each is independently H; each is optionally substituted with at least one hydroxyl group as a C1-C6 alkyl or C1-C6 alkoxy group; 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 -S(O) p R 8 ; or phenyl, C1 alkylphenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 1- C2 alkylcyclopropyl, 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, which is optionally surrounded by at least one R 10 Substituents are selected independently from 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 atoms to which they are attached, they form a ring B, which is pyrroloyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally surrounded by at least one R selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F, Cl, Br, CN, -N(CH3)2, hydroxyl, -CHF2, -CF3, -OCHF2, -OCF3, and oxo. 9 Substituents are used for substitution; and each ring is further optionally fused with Y, which is phenyl, pyridyl, or pyrimidinyl; its stereoisomers and its pharmaceutically acceptable salts. In another aspect, it is a compound of formula (1-A1), wherein R... 0 It is H or methyl; R 1 It is methyl; R 2 and R 3 Each of the following is independently H, C1-C6 alkyl; -CH2N(CH3)2, -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, amino, -N(CH3)2, -CHF2, -CF3, -OCHF2 and -OCF3; or R 2 and R 3Together with the nitrogen atoms to which they are attached, they form a ring A, which is pyrroloyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally surrounded by at least one R selected from methyl, ethyl, F, Cl, oxo, and -CF3. 10 Substituents; and each ring is further optionally fused with Y, which is phenyl; R 5 and R 6 Each is independently H; each is optionally substituted with at least one hydroxyl group as a C1-C6 alkyl or C1-C6 alkoxy group; 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 -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 surrounded by at least one R 10 Substituents are selected independently from methyl, ethyl, methoxy, ethoxy, CHF2, CF3, -OCF3, F, Cl, amino, -NHCH3, -N(CH3)2, -S(O)2CH3, cyano, and hydroxyl; or R 5 and R 6 Together with the nitrogen atoms to which they are attached, they form a ring B, which is pyrroloyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally surrounded by at least one R selected from methyl, ethyl, F, Cl, cyano, hydroxyl, oxo, and -CF3. 9Substituent substitution; and wherein each ring is optionally further fused with Y, which is phenyl; its stereoisomers and its pharmaceutically acceptable salts. In another aspect, it is a compound of formula (1-A1), wherein R... 0 It is H or methyl; R 1 It is methyl; R 2 It is H, methyl, ethyl, isopropyl, cyclopropyl, -CF3, -CHF2, -CH2F, -CH2CF3, or phenyl; R 3 It is H, methyl, ethyl, propyl, isopropyl, tert-butyl, -CH2N(CH3)2, -CH2CH2N(CH3)2; or cyclopropyl, cyclobutyl, phenyl, C1 phenyl, piperidinyl, C1-piperidinyl, C2-piperidinyl, piperazine, 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, amino, -N(CH3)2 and -CF3; or R 2 and R 3 Together with the nitrogen atoms to which they are attached, they form a ring A, which is pyrroloyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally surrounded by at least one R selected from methyl, ethyl, F, Cl, oxo, and -CF3. 10 Substituent substitution; or ring B is indololinyl, isoindololinyl, pyrrolopyridyl, pyrrolopyrimidinyl, dihydropyrrolopyridyl, dihydropyrrolopyrimidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxaline, dihydrobenzoxazine, or dihydrobenzothiazine, optionally substituted with at least one oxo group; R 5 It is H, C1-C6 alkyl, morpholino, piperidinyl, -CH2morpholino, -CH2piperidinyl, -(CH2)2morpholino, or (CH2)2piperidinyl; R 6 It is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, -CH2CF3, -CF3 or -OCF3; -C(O)NR a R 8 , where R a It is H or methyl and R 8 It is a phenyl group that is H, methyl, cyclopropyl, or optionally substituted with F, Cl, or CF3; -(CH2)S(O)2R 8 , where R 8 It is methyl or phenyl; -CH2NR a R b or -(CH2)2NR a R b , where R a and R bEach can be independently H or methyl; -(CH2)2OCH3, -(CH2)3OCH3; or phenyl, C1 alkylphenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 1- C2 alkylcyclopropyl, C 1- C2 alkylcyclobutyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, C 1- C2 alkylpyrrolidinyl, C 1- C2 alkylpiperidinyl, C 1- C2alkylpiperazinyl, C1-C2morpholinyl, C1-C2tetrahydropyranyl, pyrazolyl, imidazoleyl, pyridyl, pyrimidinyl, pyrazinyl, C 1- C2 alkylpyrazolyl, C 1- C2 alkylimidazolium, C 1- C2 alkylpyridinyl, C 1- C2 alkylpyrimidinyl and C 1- C2 alkylpyrazine group; each optionally surrounded by at least one R 10 Substituents are selected independently from methyl, ethyl, methoxy, ethoxy, -CHF2, -CF3, -OCF3, F, Cl, amino, -NHCH3, -N(CH3)2, -S(O)2CH3, cyano, and hydroxyl; or R 5 and R 6 Together with the nitrogen atoms to which they are attached, they form a ring B, which is pyrroloyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally surrounded by at least one R selected from methyl, ethyl, F, Cl, cyano, hydroxyl, oxo, and -CF3. 9 Substituents; or ring B is optionally substituted with at least one oxo group of indololinyl, isoyindololinyl, tetrahydroquinolinyl, dihydrobenzoxazinyl, or dihydrobenzothiazinyl; its stereoisomers and its pharmaceutically acceptable salts. In another aspect, it is a compound of formula (1-A1), wherein R... 0 It is H or methyl; R 1 It is methyl; R 2 It is H or methyl; R 3 It is methyl, ethyl or propyl, isopropyl, tert-butyl, -CH2N(CH3)2, -CH2CH2N(CH3)2; or cyclopropyl, cyclobutyl, phenyl, C1 phenyl, piperidinyl, C1-piperidinyl, piperazinyl, morpholinyl or pyridinyl, each optionally being R selected from at least one of the following groups. 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; R 6It is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, -CH2CF3, -CF3, -OCF3; -C(O)NR a R 8 , where R a It is H or methyl and R 8 It is a phenyl group that is H, methyl, cyclopropyl, optionally substituted with F, Cl, or -CF3; -(CH2)S(O)2R 8 , where R 8 It is methyl or phenyl; -CH2NR a R b or -(CH2)2NR a R b , where R a and R b Each can be independently H or methyl; -(CH2)2OCH3, -(CH2)3OCH3; or phenyl, C1 alkylphenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 1- C2 alkylcyclopropyl, C 1- C2 alkylcyclobutyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, C 1- C2 alkylpyrrolidinyl, C 1- C2 alkylpiperidinyl, C 1- C2alkylpiperazinyl, C1-C2morpholinyl, C1-C2tetrahydropyranyl, pyrazolyl, imidazoleyl, 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 surrounded by at least one R 10Substituents are selected independently from methyl, ethyl, methoxy, ethoxy, -CHF2, -CF3, -OCF3, F, Cl, amino, -NHCH3, -N(CH3)2, -S(O)2CH3, cyano, and hydroxyl; their stereoisomers and pharmaceutically acceptable salts thereof. On the other hand, it is a compound of formula (1-A1)H, its stereoisomers, and its pharmaceutically acceptable salts. On the other hand, it is a non-antibacterial compound of formula (1-A1)H, its stereoisomers, and its pharmaceutically acceptable salts. On the other hand, it is formula (1-A1), which is 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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea, its stereoisomers, and its pharmaceutically acceptable salts.

[0090] In another aspect, it is a composition comprising a compound of formula (1-A1), its stereoisomers, and a pharmaceutically acceptable salt thereof. In another aspect, it is a composition comprising a compound of formula (1-A1)H, its stereoisomers, and a pharmaceutically acceptable salt thereof. In another aspect, it is a composition comprising a non-antibacterial compound of formula (1-A1)H, its stereoisomers, and a pharmaceutically acceptable salt thereof. In another aspect, it is a composition comprising a compound of formula (1-A1), H-11; 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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea; its stereoisomers and its pharmaceutically acceptable salts. In another aspect, the composition further comprises a pharmaceutically acceptable carrier.

[0091] In another aspect, there is a method for treating or preventing an inflammatory response in animals by administering to the animal in need a therapeutically effective amount of a compound of formula (1-A1), its stereoisomers, and its pharmaceutically acceptable salts. In another aspect, there is a method for treating or preventing an inflammatory response in animals by administering to the animal in need a therapeutically effective amount of a compound of formula (1-A1), its stereoisomers, and its pharmaceutically acceptable salts. In another aspect, there is a method for treating or preventing an inflammatory response in animals by administering to the animal in need a therapeutically effective amount of a non-antimicrobial compound of formula (1-A1), its stereoisomers, and its pharmaceutically acceptable salts. In another aspect, there is a method for treating or preventing an inflammatory response in animals by administering to the animal in need a therapeutically effective amount of Example H-11.

[0092] 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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea, its stereoisomers, and pharmaceutically acceptable salts thereof. In another aspect of this method, the inflammatory response is caused by bacterial, viral, or fungal infection, stress, and / or environmental factors. In another aspect of this method, the method of treating or preventing an inflammatory response in animals prevents or mitigates the progression of respiratory diseases or conditions. In another aspect of this method, the animal is livestock. In another aspect of this method, the respiratory disease or condition is bovine respiratory disease or swine respiratory disease. In another aspect of this method, the method of treating or preventing an inflammatory response in animals downregulates TNF-α and IL-6 in the animal.

[0093] In another aspect, the use of compounds of formula (1-A1), their stereoisomers, and pharmaceutically acceptable salts thereof; the preparation of medicaments for the treatment or prevention of inflammatory responses in animals. In another aspect, the use of compounds of formula (1-A1)H, their stereoisomers, and pharmaceutically acceptable salts thereof; the preparation of medicaments for the treatment or prevention of inflammatory responses in animals. In another aspect, the use of non-antibacterial compounds of formula (1-A1)H, their stereoisomers, and pharmaceutically acceptable salts thereof; the preparation of medicaments for the treatment or prevention of inflammatory responses in animals. On the other hand, it is H-11;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-2 Uses of H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea; its stereoisomers and pharmaceutically acceptable salts thereof; preparation of medicaments for the treatment or prevention of inflammatory responses in animals. In another aspect of this use, the inflammatory response is caused by bacterial, viral or fungal infection, stress and / or environmental factors. In another aspect of this use, the medicament is used to treat or prevent inflammatory responses in animals, and to prevent or reduce the progression of respiratory diseases or conditions. In another aspect of this use, the animals are livestock. In another aspect of this use, the respiratory disease or condition is bovine respiratory disease or swine respiratory disease. In another aspect of this use, the medicament is administered to animals to treat or prevent inflammatory responses in animals, and to downregulate TNF-α and IL-6 in animals.

[0094] In another aspect of the invention are compounds of formula (1-A1), their stereoisomers, and their pharmaceutically acceptable salts, wherein R 1 It is methyl and R 2 and R 3 Together with the nitrogen atoms to which they are attached, they form a group optionally bound by at least one R 10 The substituent ring A is a compound of formula (1-A1b), wherein R is a substituent ring A. 0 R 5 R 6 Ring A, R 10 and n

[0095]

[0096] As defined herein. On the other hand, it refers to compounds of formula (1-A1a), their stereoisomers, and their pharmaceutically acceptable salts, wherein R... 0 It is H or methyl; and R 5 R 6 R 10 Ring A and n are as defined herein. On the other hand, it is a compound of formula (1-A1a), where R... 0 It is H or methyl; R 5 It is H, methyl, ethyl, propyl, isopropyl, -CH2morpholinyl, -CH2piperidinyl, -(CH2)2morpholinyl, or (CH2)2piperidinyl; R 6 H; C1-C6 alkyl or C1-C6 alkoxy groups, each optionally substituted with at least one hydroxyl group; 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, 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 surrounded by at least one R 10The substituents are each independently selected from methyl, ethyl, methoxy, ethoxy, -CHF2, -CF3, -OCF3, F, Cl, -NHCH3, -N(CH3)2, -S(O)2CH3, cyano, and hydroxy; and ring A is pyrrolo, pyrazolol, pyrrolidinyl, piperidinyl, piperazinyl, morpholino, or thiomorpholino, each optionally being replaced by at least one R selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F, Cl, Br, CN, -N(CH3)2, hydroxyl, -CHF2, -CF3, -OCHF2, -OCF3, and oxo. 10 Substituents; or ring A is indololinyl, isoindololinyl, pyrrolopyridyl, pyrrolopyrimidinyl, dihydropyrrolopyridyl, dihydropyrrolopyrimidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxaline, dihydrobenzoxazine, or dihydrobenzothiazine, optionally substituted with at least one oxo group; its stereoisomers and its pharmaceutically acceptable salts. In another aspect, it is a compound of formula (1-A1a), wherein R... 0 It is H or methyl; R 5 It is H, methyl, ethyl, propyl, or isopropyl; R 6 It is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, -CH2CF3, -CF3, OCF3; -C(O)NR a R 8 , where R a It is H or methyl and R 8 It is a phenyl group that is H, methyl, cyclopropyl, optionally substituted with F, Cl, or -CF3; -(CH2)S(O)2R 8 , where R 8 It is methyl or phenyl; -CH2NR a R b or -(CH2)2NR a R b , where R a and R b Each can be independently H or methyl; -(CH2)2OCH3, (CH2)3OCH3; or phenyl, C1 alkylphenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 1- C2 alkylcyclopropyl, C 1- C2 alkylcyclobutyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, C 1- C2 alkylpyrrolidinyl, C 1- C2 alkylpiperidinyl, C 1- C2alkylpiperazinyl, C1-C2morpholinyl, C1-C2tetrahydropyranyl, pyrazolyl, imidazoleyl, 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 surrounded by at least one R 10 The substituents are each independently selected from methyl, ethyl, methoxy, ethoxy, -CHF2, -CF3, -OCF3, F, Cl, amino, -NHCH3, -N(CH3)2, -S(O)2CH3, cyano, and hydroxy; and ring A is pyrrolo, pyrazolol, pyrrolidinyl, piperidinyl, piperazinyl, morpholino, or thiomorpholino, each optionally being replaced by at least one R selected from methyl, ethyl, F, Cl, oxo, and -CF3. 10 Substituents; or ring A is optionally substituted with at least one oxo-substituted indololinyl, isoyindololinyl, tetrahydroquinolinyl, dihydrobenzoxazinyl, or dihydrobenzothiazinyl; or ring A is pyrroleyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally substituted with at least one R selected from methyl, ethyl, F, Cl, oxo, and -CF3. 10 Substituent substitution; its stereoisomers and its pharmaceutically acceptable salts. On the other hand, it is a compound of formula (1-A1a) Table I, its stereoisomers and its pharmaceutically acceptable salts. On the other hand, it is a non-antibacterial compound of formula (1-A1a) Table I, its stereoisomers and its pharmaceutically acceptable salts.

[0097] In another aspect, it is a composition comprising a compound of formula (1-A1a), its stereoisomers, and a pharmaceutically acceptable salt thereof. In yet another aspect, it is a composition comprising a compound of formula (1-A1a) listed in Table I, its stereoisomers, and a pharmaceutically acceptable salt thereof.

[0098] In another aspect, the composition comprises a non-antimicrobial compound of formula (1-A1a) Table I, its stereoisomer, and a pharmaceutically acceptable salt thereof. In yet another aspect, the composition further comprises a pharmaceutically acceptable carrier.

[0099] In another aspect, there is a method for treating or preventing an inflammatory response in animals by administering to the animal in need a therapeutically effective amount of a compound of formula (1-A1a), its stereoisomers, and its pharmaceutically acceptable salts. In another aspect, there is a method for treating or preventing an inflammatory response in animals by administering to the animal in need a therapeutically effective amount of a compound of formula (1-A1a) Table I, its stereoisomers, and its pharmaceutically acceptable salts. In another aspect, there is a method for treating or preventing an inflammatory response in animals by administering to the animal in need a therapeutically effective amount of a non-antimicrobial compound of formula (1-A1a) Table I, its stereoisomers, and its pharmaceutically acceptable salts. In another aspect of this method, the inflammatory response is caused by bacterial, viral, or fungal infection, stress, and / or environmental factors. In another aspect of this method, the method for treating or preventing an inflammatory response in animals prevents or mitigates the progression of respiratory diseases or symptoms. In another aspect of this method, the animal is a domestic animal. In another aspect of this method, the respiratory disease or symptoms are bovine respiratory diseases or swine respiratory diseases. In another aspect of this method, methods for treating or preventing inflammatory responses in animals downregulate TNF-α and IL-6 in the animals.

[0100] In another aspect, the use is of a compound of formula (1-A1a), its stereoisomers, and pharmaceutically acceptable salts thereof; to prepare a medicament for the treatment or prevention of inflammatory responses in animals. In another aspect, the use is of a compound of formula (1-A1a) Table I, its stereoisomers, and pharmaceutically acceptable salts thereof; to prepare a medicament for the treatment or prevention of inflammatory responses in animals. In another aspect, the use is of a non-antibacterial compound of formula (1-A1a) Table I, its stereoisomers, and pharmaceutically acceptable salts thereof; to prepare a medicament for the treatment or prevention of inflammatory responses in animals. In another aspect of this use, the inflammatory response is caused by bacterial, viral, or fungal infection, stress, and / or environmental factors. In another aspect of this use, the medicament is used to treat or prevent inflammatory responses in animals, and to prevent or reduce the progression of respiratory diseases or symptoms. In another aspect of this use, the animal is a domestic animal. In another aspect of this use, the respiratory disease or symptoms are bovine respiratory diseases or swine respiratory diseases. In another aspect of this use, administering the drug to animals to treat or prevent inflammatory responses in animals downregulates TNF-α and IL-6 in the animals.

[0101] In another aspect of the invention, there is a compound of formula (1-A1), wherein R 1 It is methyl, and R 5 and R 6 Together with the nitrogen atoms to which they are attached, they form a group optionally bound by at least one R 9 The substituent ring B; it is a compound of formula (1-A1b); wherein R 0 R2 R 3 Ring B, R 9 and n are as defined in this paper;

[0102]

[0103] Its stereoisomers and its pharmaceutically acceptable salts. On the other hand, there are compounds of formula (1-A1b), wherein R... 0 It is H or methyl; and R 2 R 3 Ring B, R 9 And n is as defined herein. On the other hand, it is a compound of formula (1-A1b), where R... 0 It is H or methyl; R 2 It is H, methyl, ethyl, isopropyl, cyclopropyl, -CF3, -CHF2, -CH2F, -CH2CF3, or phenyl; R 3 It is H, methyl, ethyl, propyl, isopropyl, tert-butyl, -CH2N(CH3)2, -CH2CH2N(CH3)2; or cyclopropyl, cyclobutyl, phenyl, C1 phenyl, piperidinyl, C1-piperidinyl, C2-piperidinyl, piperazine, 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, amino, -N(CH3)2 and -CF3; or R 2 and R 3 Together with the nitrogen atoms to which they are attached, they form a ring A, which is pyrroloyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally surrounded by at least one R selected from methyl, ethyl, F, Cl, oxo, and -CF3. 10 Substituents; and each ring is further optionally fused with Y, which is phenyl; and R 5 and R 6 Together with the nitrogen atoms to which they are attached, they form a ring B, which is pyrroloyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally surrounded by at least one R selected from methyl, ethyl, hydroxyl, F, Cl, cyano, oxo, and -CF3. 9 Substituent substitution; and wherein each ring is optionally further fused with Y, which is phenyl; its stereoisomers and its pharmaceutically acceptable salts. In another aspect, it is a compound of formula (1-A1b), wherein R... 0 It is H or methyl; R 2 It is H or methyl; and R 3It is methyl, ethyl, propyl, isopropyl, tert-butyl, -CH2N(CH3)2, -CH2CH2N(CH3)2; or cyclopropyl, cyclobutyl, phenyl, C1 phenyl, piperidinyl, C1-piperidinyl, piperazinyl, morpholinyl, or pyridinyl, each optionally being R selected from at least one of the following groups. 9 Substituents: methyl, ethyl, hydroxy, methoxy, ethoxy, F, Cl, cyano, -N(CH3)2, and -CF3; and ring B is pyrrolo, pyrazolol, pyrrolidinyl, piperidinyl, piperazinyl, morpholino, or thiomorpholino, each optionally being replaced by at least one R selected from methyl, ethyl, F, Cl, hydroxy, cyano, oxo, and -CF3. 9 Substituents; or ring A is indololinyl, isoindololinyl, pyrrolopyridyl, pyrrolopyrimidinyl, dihydropyrrolopyridyl, dihydropyrrolopyrimidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxaline, dihydrobenzoxazine, or dihydrobenzothiazine, optionally substituted with at least one oxo group; or ring B is pyrroleyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally substituted with at least one R group selected from methyl, ethyl, F, Cl, hydroxyl, cyano, oxo, and -CF3. 9 Substituent substitution; its stereoisomers and its pharmaceutically acceptable salts. On the other hand, it is the compound represented by formula (1-A1b), its stereoisomers and its pharmaceutically acceptable salts. On the other hand, it is the non-antibacterial compound represented by formula (1-A1b), its stereoisomers and its pharmaceutically acceptable salts.

[0104] In another aspect, it is a composition comprising a compound of formula (1-A1b), its stereoisomer, and a pharmaceutically acceptable salt thereof. In another aspect, it is a composition comprising a compound of formula (1-A1b), its stereoisomer, and a pharmaceutically acceptable salt thereof. In another aspect, it is a composition comprising a non-antibacterial compound of formula (1-A1b), its stereoisomer, and a pharmaceutically acceptable salt thereof. In yet another aspect, the composition further comprises a pharmaceutically acceptable carrier.

[0105] In another aspect, there is a method for treating or preventing an inflammatory response in animals by administering to the animal in need a therapeutically effective amount of a compound of formula (1-A1b), its stereoisomers, and its pharmaceutically acceptable salts. In another aspect, there is a method for treating or preventing an inflammatory response in animals by administering to the animal in need a therapeutically effective amount of a compound of formula (1-A1b), its stereoisomers, and its pharmaceutically acceptable salts. In another aspect, there is a method for treating or preventing an inflammatory response in animals by administering to the animal in need a therapeutically effective amount of a non-antimicrobial compound of formula (1-A1b), its stereoisomers, and its pharmaceutically acceptable salts. In another aspect of this method, the inflammatory response is caused by bacterial, viral, or fungal infection, stress, and / or environmental factors. In another aspect of this method, the method for treating or preventing an inflammatory response in animals prevents or mitigates the progression of respiratory diseases or symptoms. In another aspect of this method, the animal is a domestic animal. In another aspect of this method, the respiratory disease or symptoms are bovine respiratory diseases or swine respiratory diseases. In another aspect of this method, methods for treating or preventing inflammatory responses in animals downregulate TNF-α and IL-6 in the animals.

[0106] In another aspect, the use is of a compound of formula (1-A1b), its stereoisomers, and pharmaceutically acceptable salts thereof; to prepare a medicament for the treatment or prevention of inflammatory responses in animals. In another aspect, the use is of a non-antimicrobial compound of formula (1-A1b), its stereoisomers, and pharmaceutically acceptable salts thereof; to prepare a medicament for the treatment or prevention of inflammatory responses in animals. In another aspect, the use is of a non-antimicrobial compound of formula (1-A1b), its stereoisomers, and pharmaceutically acceptable salts thereof; to prepare a medicament for the treatment or prevention of inflammatory responses in animals. In another aspect of this use, the inflammatory response is caused by bacterial, viral, or fungal infection, stress, and / or environmental factors. In another aspect of this use, the medicament is used to treat or prevent inflammatory responses in animals, and to prevent or reduce the progression of respiratory diseases or symptoms. In another aspect of this use, the animal is a domestic animal. In another aspect of this use, the respiratory disease or symptom is bovine respiratory disease or swine respiratory disease. In another aspect of this use, administering the drug to animals to treat or prevent inflammatory responses in animals downregulates TNF-α and IL-6 in the animals.

[0107] 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 R is -C(O)NHR. d ;R 0 and R 2 Both are H, R 1 It is methyl, R 5 and R 6They are linked together with the shared N atom to form a ring B, which is a 4-methylpiperazine, selected from the following compounds:

[0108] (2S,3R,4S,6R)-4-(3-(tert-butyl)-1-methylurea)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((4-methylpiperazin-1-yl)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-ylethylcarbamate;

[0109] (2S,3R,4S,6R)-4-(3-(tert-butyl)-1-methylurea)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((4-methylpiperazin-1-yl)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yltert-butylcarbamate;

[0110] (2S,3R,4S,6R)-4-(3-(4-(dimethylamino)phenyl)-1-methylurea)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((4-methylpiperazin-1-yl)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl(4-(dimethylamino)phenyl)carbamate; and

[0111] (2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((4-methylpiperazin-1-yl)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyl-4-(1-methyl-3-phenylureo)tetrahydro-2H-pyran-3-ylphenylcarbamate. In another aspect of the invention, there is a compound of formula (1), its stereoisomers, and its pharmaceutically acceptable salts, wherein W is formula (A), and formula (A) is formula (A2), R 0 and R 2 Both are H, R 1 It is methyl, R 3 It is phenyl, R 7 It is an ethyl group, and R is -C(O)NH phenyl: it is (2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(ethoxymethyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyl-4-(1-methyl-3-phenylureo)tetrahydro-2H-pyran-3-ylphenylcarbamate.

[0112] In another aspect of the invention, there are compounds of formula (1), their stereoisomers, and their pharmaceutically acceptable salts, wherein W is formula (A), and formula (A) is formula (A3), R 0 and R 2 Both are H, R 1 It is methyl, R 3 It is phenyl, R 7It is propyl, and R is -C(O)NHphenyl: it is (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-((propylthio)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-(1-methyl-3-phenylureo)tetrahydro-2H-pyran-3-ylphenylcarbamate. In another aspect of the invention, there are compounds of formula (1), their stereoisomers, and their pharmaceutically acceptable salts, wherein W is of formula (A), formula (A) is of formula (A4), and R 0 and R 2 Both are H, R 1 It is methyl, R 3 X' is phenyl, and R is -C(O)NHphenyl: It is 2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(chloromethyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyl-4-(1-methyl-3-phenylureo)tetrahydro-2H-pyran-3-ylphenylcarbamate.

[0113] In another aspect of the invention, there are compounds of formula (1), their stereoisomers, and their pharmaceutically acceptable salts, wherein W is of formula (A), formula (A) is of formula (A6), and R 0 and R 2 Both are H, R 1 It is methyl, R 3It is a phenyl group and R is -C(O)NH phenyl: it is (2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(cyanomethyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyl-4-(1-methyl-3-phenylurea)tetrahydro-2H-pyran-3-ylphenylcarbamate. In another aspect, it is a composition comprising any one of the compounds of formula (1) phenylcarbamate, wherein the composition further comprises a pharmaceutically acceptable carrier. In another aspect, it is a method of treating or preventing an inflammatory response in an animal using any one of the compounds of formula (1) phenylcarbamate, by administering to the animal in need a therapeutically effective amount of the compound of formula (1), its stereoisomer, and its pharmaceutically acceptable salt. In another aspect, it is the use of any one of the compounds of formula (1) in the preparation of a medicament for treating or preventing an inflammatory response in an animal.

[0114] In another aspect of the invention, there is a combination of a compound of formula (1), its stereoisomers, and a pharmaceutically acceptable salt thereof; and at least one other agent, which may be an antibacterial agent, an anti-inflammatory agent, a vitamin, a mineral, or a mixture thereof. The compounds of the invention may be administered simultaneously, separately, or sequentially with one or more other agents for the treatment of bacterial infections in animals and / or the prevention of inflammatory and / or immune responses from a cascade to complete BRD disease syndrome.

[0115] In another aspect of the invention, there is a composition comprising M9, its stereoisomers, and pharmaceutically acceptable salts thereof. In yet another aspect, the composition comprising M9 further comprises a pharmaceutically acceptable carrier. In yet another aspect of the invention, there is a method for treating or preventing an inflammatory response in an animal by administering a therapeutically effective amount of M9, its stereoisomers, and pharmaceutically acceptable salts thereof to an 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 yet another aspect, there is a method for treating or preventing an inflammatory response in an animal, wherein M9 alleviates the progression of a respiratory disease or symptom. In yet another aspect, the animal is a domestic animal. In yet another aspect, the respiratory disease or symptom is bovine respiratory disease or swine respiratory disease.

[0116] On the other hand, it is a compound of formula (1), which is a non-antimicrobial compound of formula (1.1) Table A, selected from the group consisting of examples A-1, A-2, A-3, A-4, A-6, A-7, A-9 to A-12, A-14 to A-21 and A-22 to A-26; or a non-antimicrobial compound of formula (1-A0) Table B, selected from the group consisting of examples B-1a to B-6 and B-8 to B-15; or a non-antimicrobial compound of formula (1-A2) Table C, selected from the group consisting of examples C-1 and C-3; or selected from example C-1 or C-2 is a non-antimicrobial compound of formula (1-A3) listed as D; or a non-antimicrobial compound of formula (1-A4) listed as E, selected from the group consisting of examples E-1 to E-3; or a non-antimicrobial compound of formula (1-A5) listed as F, which is example F-1 or F-2; or a non-antimicrobial compound of formula (1-A6) listed as G, selected from the group consisting of examples G-1 to G-3; or a non-antimicrobial compound of formula (1-A1) listed as H, selected from examples H-1, H-2, H-4, H-6, H-8 to H-14, H16, H-17, H-21, H... The group consisting of H-24, H-25, H-27, H-28, H-29, H-31 to H-35, H-37, H-39 to H-43, H-47, H-48, H49, H-51 to H-57, H-59, H-60, H-62 to H-65, H-77, H-79, H-80, H-82 to H-86, H-88, H-91 to H-97 and H-99 to H-103; or non-antimicrobial compounds of formula (1-A1a) Table I, selected from Examples I-1 and I-3 to I-7. The group consisting of; or non-antimicrobial compounds of formula (1-A1b) listed in Table J, selected from the group consisting of examples J-4, J-10, J-12, J-13, J-15, J-16, J-19 to J-24 and J-27 to J-31; their stereoisomers and their pharmaceutically acceptable salts; compositions comprising one of these non-antimicrobial compounds; a method of treating or preventing an inflammatory response in animals using one of these non-antimicrobial compounds; or use of one of these non-antimicrobial compounds in the preparation of a medicament for treating or preventing an inflammatory response in animals.

[0117] discuss Attached Figure Description

[0118] Figure 1 Mechanisms of immunomodulators in the context of BRD progression

[0119] Figure 2 Summary of clinical and genomic time data

[0120] Figure 3 Plasma cytokine (IL-6, IL-8, IL-10, and IFN-γ) levels in calves at risk of BRD upon arrival at the farm.

[0121] Figure 4 Example H-11 dose-dependent cytokine assay – whole blood assay: IL-6 (A), TNF-α (B), and IL-1β (C)

[0122] Figure 5 Changes in IL-36RA (%) during the naturally infected cattle study

[0123] Figure 6 Biomarker assessment of M9 and Draxxin intratracheal lung attack; IL-6 (A) and CD163 biomarker (B) results.

[0124] Figure 7 Biomarker assessment of intratracheal lung attack in case H-91: Results of IL-6 (A) and CD163 biomarkers (B)

[0125] Figure 8 Biomarker assessment of intratracheal lung attack in case H-11: neutrophils (A), IL-6 (B), and CD163 (C) results

[0126] Figure 9 Intracellular flow cytometry characterization of CD4+ T helper cell subtypes

[0127] Figure 10 IL-17 levels in the airways of animals challenged with *M. haemolytica* (Example H-11)

[0128] 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.

[0129] Unless otherwise defined, scientific and technical terms used in conjunction with 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 requires otherwise, 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 those well-known and commonly used in the art.

[0130] definition

[0131] For the purposes of this invention, as described and claimed herein, the following terms and phrases are defined as follows:

[0132] Unless otherwise stated, “another or more agents” as used herein means other pharmaceutical compounds or products that provide a therapeutically effective amount of the agent and can be used to treat bacterial infections and / or modulate immune responses in animals, as defined herein.

[0133] Unless otherwise stated, as used herein, "alkoxy" refers to the oxygen moiety having an additional alkyl substituent. The alkyl moiety of an alkoxy group (i.e., the alkyl portion) has the same definition as below. Non-limiting examples include: -OCH3, OCH2CH3, OCH(CH3)2, -OC(CH3)3, etc.

[0134] Unless otherwise stated, as used herein, "alkyl" refers to the general formula C n H 2n+1 The alkyl group is a saturated monovalent hydrocarbon. The alkyl group 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, etc. Non-exclusive examples of (C1-C6)alkyl 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, etc. The alkyl moiety can be attached to the chemical moiety via any carbon atom of the aliphatic chain. The alkyl group is optionally substituted as defined herein. Furthermore, when used in compound terms (such as alkylphenyl), the alkyl moiety has the same meaning as defined herein and can be attached to the chemical moiety by any one of the carbon atoms in the aliphatic chain. Non-limiting examples of compound terms C0-C4 alkylphenyl include: C0 phenyl (phenyl), C1 alkylphenyl (-CH2 phenyl), C2 alkylphenyl (-CH2CH2 phenyl), etc.

[0135] Unless otherwise stated, "animal" as used herein refers to an individual animal that is a mammal. Specifically, mammals are human and non-human vertebrates that are 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, cattle (both calves and mules).

[0136] Unless otherwise stated, as used herein, "antimicrobial agent" means a compound having a minimum inhibitory concentration (MIC) ≤ 64 μg / mL against BRD pathogens *Mannella hemolyticus* and *Pasteurella multocida*. Unless otherwise stated, as used herein, the term "non-antimicrobial" means a compound having an MIC > 64 μg / mL against BRD pathogens *Mannella hemolyticus* and *Pasteurella multocida*.

[0137] Unless otherwise stated, as used herein, “aryl” refers to an unsaturated aromatic monocyclic ring with 6 carbon members or an unsaturated aromatic polycyclic ring with 10 to 14 carbon members. Examples of such aromatic rings include, but are not limited to, phenyl, naphthyl, or anthracene. Furthermore, 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 one of the carbon atoms 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 benzene ring may optionally be substituted as defined herein.

[0138] Unless otherwise stated, "azalactones" as used herein refers to a class of macrolides containing a nitrogen atom in the macrolide ring, which imparts different pharmacokinetic properties and is associated with greater molecular stability.

[0139] Unless otherwise stated, “chirality” as used herein refers to a molecule’s structural features that make it impossible to superimpose them on their mirror image (e.g., “R” and “S” enantiomers).

[0140] Unless otherwise stated, as used herein, “composition” means a compound of the present invention formulated with at least one pharmaceutically acceptable excipient for dosage administration.

[0141] Unless otherwise stated, as used herein, "Compounds of the present invention" or "compounds of the invention" includes compounds of formulas (1), (1A), (1.1), (1-A0), (1-A1), (1-A1a), (1-A1b), (1-A2), (1-A3), (1-A4), (1-A5), and (1-A6), their stereoisomers, and their pharmaceutically acceptable salts. The term also includes the corresponding 13-membered macrolide in equilibrium with the 15-membered macrolide ring of the stated formula; and includes azalactones.

[0142] Unless otherwise stated, as used herein, "cycloalkyl" includes a fully saturated or partially saturated carbocycloalkyl moiety, i.e., a 3- to 6-membered ring containing only carbon atoms, and can be part of a monocyclic, fused, or bridged ring moiety. Examples of saturated carbocyclic (cycloalkyl) rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Non-limiting examples of partially saturated cycloalkyl include cyclopropylene, cyclobutene, etc. Preferred cycloalkyl are 3- to 6-membered saturated monocyclic rings, including cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. A cycloalkyl moiety can be attached to a chemical moiety by any one carbon atom within the carbocyclic ring. A cycloalkyl moiety may optionally be substituted with at least one substituent. Furthermore, 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 a chemical moiety by any one of the carbon atoms of an 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.

[0143] Unless otherwise stated, as used herein, “cytokine” refers to a general class of biomolecules that affect / influence all types of cells and affect immune responses and non-immunobiological processes. This definition is intended to include, but is not limited to, those biomolecules that act locally or systemically and, when used in the compositions or methods of the present invention, are used to regulate or modulate the immune response in animals. Exemplary cytokines used in carrying out the present invention include, but are not limited to, interleukins (e.g., IL-1 to IL-29, particularly 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), particularly NF-κB, which mediates the induction of pro-inflammatory cytokines (such as TNF-α, IL-1, and IL-6) in monocytes and macrophages.

[0144] Unless otherwise stated, "halogen" or "halogenated" as used herein refers to fluorine, chlorine, bromine, and iodine. Furthermore, when used in compound terms such as "halogenated alkyl" or "halogenated alkoxy," the alkyl and alkoxy groups may be partially or completely substituted with the same or different halogen atoms, and the alkyl and alkoxy groups have the same meaning as above and can be attached to the chemical part by any of the carbon atoms in the aliphatic chain. Examples of "halogenated alkyl" include F3C-, ClCH2-, CF3CH2-, and CF3CCI2-, etc. The term "halogenated alkoxy" is defined similarly to the term "halogenated alkyl." Examples of "halogenated alkoxy" include CF3O-, CCl3CH2O-, HCF2CH2CH2O-, and CF3CH2O-, etc.

[0145] Unless otherwise stated, as used herein, “heteroaryl” or “Het” refers to a 5- to 6-membered aromatic monocyclic ring or an 8- to 10-membered fused aromatic ring, wherein the monocyclic and fused ring portions contain one or more heteroatoms, each independently selected from N, O, and S, preferably one to four heteroatoms. Non-exclusive examples of monocyclic heteroaryl groups include pyrroleyl, furanyl, thiopheneyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, thiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, etc. Non-exclusive examples of fused heteroaryl groups include benzofuranyl, benzothiopheneyl, 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. Furthermore, when used in compound terms (such as alkyl heteroaryl (e.g., C0-C4 alkyl heteroaryl)), the alkyl and heteroaryl moieties have the same meaning as defined herein and can be attached to the chemical moiety by any one of the carbon atoms of an 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.), etc. The heteroaryl group may optionally be substituted as defined herein.

[0146] Unless otherwise stated, as used herein, "heterocycle" refers to a partially saturated or saturated 4- to 10-membered monocyclic, fused, or bridged ring structure containing one or more heteroatoms, each independently selected from N, O, and S, preferably one to four heteroatoms. Non-exclusive examples of heterocycles include oxobutyryl, azahelyl, thiobutyryl, tetrahydrofuranyl, pyranyl, pyrazolyl, oxazolyl, tetrahydrothiophene, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxothiohexyl, tetrahydropyridinyl, 2H-acridinyl, 2,3-dihydro-azayl, 3,4-dihydro-2H-pyrroleyl, etc. Heterocyclic groups can be attached to the chemical moiety by either a carbon atom or a nitrogen heteroatom within the ring. Furthermore, when used in compound terms (such as alkyl heterocycles (e.g., C0-C4 alkyl heterocycles)), the alkyl and heterocyclic moieties have the same meaning as defined herein and can be attached to the chemical moieties by 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.), etc. The heterocycle may optionally be substituted as defined herein.

[0147] Unless otherwise stated, as used herein, “macrolide” refers to a compound characterized by a macrolide ring containing 12 to 16 carbon atoms, the macrolide ring being attached to one or more deoxyglucoses via glycosidic bonds; and includes azalides.

[0148] The term “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 unsubstituent. Therefore, the phrase “optionally substituted by at least one substituent” means that the number of substituents can vary from zero to the number of 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 (i.e., n is an integer 0, 1, 2 or 3), which also depends on the number of positions available for substitution.

[0149] Unless otherwise stated, "pharmaceutical acceptable" as used herein means that the substance or composition must be chemically and / or toxicologically compatible with other components comprising the formulation, composition, and / or the animal treated therewith. The terms "pharmaceutical" or "medicinal" have the same meaning as "veterinary" or as described in veterinary medicine.

[0150] Unless otherwise stated, as used herein, “protecting group” or “Pg” refers to a substituent commonly used to block or protect alcohols on a compound, thereby protecting its functional groups while allowing other functional groups on the compound to react. Examples of non-exclusive alcohol protecting groups include: 2,2,2-trichloroethyl carbonate (Troc), 2-methoxyethoxymethyl ether (MEM), 2-naphthylmethyl ether (Nap), 4-methoxybenzyl ether (PMB), acetate (Ac), benzoate (Bz), benzyl ether (Bn), benzyloxymethyl acetal (BOM), ethoxyethyl acetal (EE), methoxymethyl acetal (MOM), methoxypropyl acetal (MOP), methyl ether, tetrahydropyranyl acetal (THP), triethylsilyl ether (TES), benzyloxycarbonyl (Cbz), triisopropylsilyl ether (TIPS), trimethylsilyl ether (TMS), tert-butyldimethylsilyl ether (TBS, TBDMS), and tert-butyldiphenylsilyl ether (TBDPS).

[0151] Unless otherwise specified, "saturated" or "partially saturated" as used herein refers to cycloalkyl rings having 3 to 6 carbon atoms and heterocycles containing 2 to 5 carbon atoms and at least one heteroatom selected from N, O, and S; and wherein 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. Partially saturated rings contain 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-thiaran, etc.

[0152] Unless otherwise stated, "stereoisomer" as used herein refers to a compound of the present invention having more than one asymmetric carbon atom. In the general formulas described herein, a solid wedge bond indicates that the bond is above the plane of the paper, while a broken wedge bond indicates that the bond is below the plane of the paper. The compounds of the present invention may exist as individual enantiomers or diastereomers or mixtures thereof (including racemic mixtures). All such isomers are included within the scope of this invention.

[0153] Unless otherwise stated, “stress” or “stressed” as used herein 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 perceived as 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, separation of mothers and herds, mixing of animals from different sources, tail butting, pin tooth removal, pain, food and water deprivation, and acute or chronic illness), and acute / chronic disruptions (e.g., changes in temperature and humidity, confinement, shipping, inadequate nutrition and hydration, storms, loud noise (e.g., thunder, barking dogs, fireworks, etc.), environmental changes, and pollutants, etc.).

[0154] Unless otherwise stated, "therapeutic effective amount" as used herein means (i) the amount of the compound of the present invention used to treat or prevent a particular disease or condition, (ii) reduce, improve or eliminate one or more symptoms of a particular disease or condition, or (iii) prevent or delay the onset of one or more symptoms of a particular disease or condition.

[0155] Unless otherwise stated, as used herein, "treatment," "treating," etc., refers to controlling, preventing, reversing, reducing, mitigating, or suppressing inflammation caused by environmental, bacterial, viral, fungal, or parasitic infections and / or internal diseases by modulating the immune response. As used herein, these terms also cover the prevention of the onset of a symptom or condition or symptoms associated with a symptom or condition, including reducing the severity of the symptom or condition or symptoms associated with it. Treatment can also refer to the administration of the compounds of the present invention to animals that are not suffering from an infection, immune response, or disease symptom or syndrome at the time of administration. It should be understood that because the eventual induction may be unknown or potential, it is not always possible to distinguish between "prevention" and "suppression" of a disease or condition.

[0156] Except in operational examples or where otherwise stated, all figures used herein to indicate the amount of an ingredient or reaction conditions shall be understood to be modified by the term “about” in all cases.

[0157] The compounds of this invention have several asymmetric centers. Compounds with asymmetric centers produce enantiomers (optical isomers), diastereomers (configurational isomers), or both, and it is intended that all possible enantiomers and diastereomers, in mixtures and 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.

[0158] The independent synthesis of stereoisomer-enriched compounds or their chromatographic separation can be achieved by suitable modifications of the methods disclosed herein, as known in the art. Their absolute stereochemistry can be determined by X-ray crystallography of the crystalline product or crystalline intermediate, which, if desired, is derivatized with a reagent containing an asymmetric center of known absolute configuration. If desired, racemic mixtures of compounds can be separated, thereby isolating individual enantiomers or diastereomers. Separation can be carried out by methods well known in the art, such as coupling of racemic mixtures of compounds, followed by separation of individual stereoisomers by standard methods such as fractional crystallization or chromatography. Coupling reactions typically involve the formation of salts using enantiomerically pure acids or bases.

[0159] The derivative can then be converted into a pure stereoisomer by cleaving the added chiral residues. Racemic mixtures of the compounds can also be directly separated using chromatographic methods with chiral stationary phases, methods well known in the art. Alternatively, any stereoisomer of the compound can be obtained stereoselectively using optically pure starting materials or reagents of known configurations, methods well known in the art.

[0160] In any method of preparing the compounds of this invention, it may be necessary and / or desirable to protect any sensitive or reactive groups on the relevant molecules. This can be achieved with 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. M. Uts, *Protective Groups in Organic Synthesis*, John Wiley & Sons, 1991. Protecting groups can be removed at a convenient subsequent stage using methods known in the art.

[0161] Macrolide Chemistry

[0162] Macrolides are known to have a strong binding affinity for the P-site on the 50S subunit of bacterial ribosomes and to inhibit protein synthesis. Modification of the deoxyglycosamine group of macrolides, by modifying the dimethylamino group to block the salt bridge and / or modifying adjacent hydroxyl groups that affect the hydrogen bonds formed, blocks this interaction, thereby removing the antibacterial activity of the compounds of the present invention. Although cladinose modifications have a relatively small effect on bacterial ribosome binding, they have the potential to affect the physicochemical properties, pharmacokinetics, and cell permeability of the compounds. By modifying the macrolide structure, thereby isolating molecules from bacteria or enhancing their efflux from bacteria, antibacterial activity is reduced or eliminated, even if the ability to bind bacterial ribosomes is present.

[0163] lipophilic

[0164] The lipophilicity of organic compounds can be described by the partition coefficient logP, which can be defined as the ratio of the concentrations of unionized compounds at equilibrium between the organic and aqueous phases. Generally, compounds with higher lipophilicity have lower solubility in aqueous media. A negative logP value indicates that the compound has a higher affinity for the aqueous phase (hydrophilicity); when logP = 0, the compound is uniformly partitioned between the lipid and aqueous phases; a positive logP value indicates a higher concentration in the lipid phase (lipophilic). Lipophilicity is a major determinant of compound absorption, distribution in vivo, osmosis across important membranes and biological barriers, metabolism, and excretion. The compounds of this invention are lipophilic (logP about 0.503 to 5.96), which facilitates their transport and absorption into respiratory tissues, such as the lungs.

[0165] Composition / Formulation

[0166] The pharmaceutical compositions of the present invention can be prepared by methods known in the art, such as conventional methods of mixing, dissolving, granulation, forming sugar-coated pellets, grinding, emulsifying, encapsulating, embedding, lyophilizing, 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 facilitate the processing of the active compound into a formulation for administration to animals in need. The formulations of the present invention can be designed for short-acting, rapid-release, long-acting, and sustained-release purposes. Therefore, pharmaceutical formulations can also be formulated for controlled release or for slow release, depending on the chosen route of administration.

[0167] 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 (including water) are described, for example, in Remington's Pharmaceutical Sciences, MACK Publishers, New Jersey (1991).

[0168] For BRD and SRD, pharmaceutical compositions are typically formulated for parenteral administration, for example, in a liquid carrier or suitable for reconstitution into a liquid solution or suspension for parenteral administration. Generally, such compositions typically contain a pharmaceutically acceptable carrier. Pharmaceutical carriers according to the invention can be sterile liquids, such as, but not limited to, water, saline solutions, aqueous glucose solutions, aqueous glycerol solutions; and / or oils, including petroleum, animal, plant, or synthetic sources, such as soybean oil, mineral oil, sesame oil, etc. Suitable pharmaceutical carriers are described in EW Martin's *Remington's Pharmaceutical Sciences*, 18th edition. Pharmaceutical compositions containing compounds of the invention can be administered orally, topically, or parenterally (i.e., intramuscular, subcutaneous, intravenous, and intradermal injections). Pharmaceutical compositions containing compounds of the invention can also be administered via intramammary and intrauterine injections.

[0169] The pharmaceutical compositions and formulations defined herein can be prepared by mixing compounds of the present invention having the desired purity with one or more pharmaceutically acceptable carriers in the form of lyophilized formulations or aqueous solutions. The term "carrier" refers to a diluent, excipient, or medium applied together with the compounds 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, monothioglycerol, propyl gallate, etc.); preservatives (e.g., octadecyl dimethyl benzyl ammonium chloride, hexamethylammonium chloride, benzalkonium chloride, benzyl chloride, phenol, n-butyl, tert-butyl or benzyl alcohol, chlorobutanol, thimerosal, alkyl parabens (e.g., methyl paraben or propyl paraben), catechol, resorcinol, cyclohexanol, 3-pentanol, m-cresol, etc.); and hydrophilic polymers (e.g., polyvinylpyrrolidone (PVP), polyethylene glycol (PEG)). The carrier can be a solvent, reconstitution medium, or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycine, glutamine, asparagine, histidine, arginine, lysine, etc.); amino acids (e.g., glycine, glutamine, asparagine, histidine, arginine, lysine, etc.); chelating agents such as EDTA; monosaccharides, disaccharides, and other carbohydrates, including 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 can 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, water, or phosphate-buffered saline (PBS). Prolonged absorption of the injectable composition can be achieved by including a delay-absorption agent (e.g., aluminum monostearate and gelatin) in the composition.

[0170] Solutions or suspensions intended for parenteral administration typically comprise one or more of the following components: a sterile carrier, such as water for injection, saline solution, non-volatile 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 a tonic agent, such as sodium chloride or glucose. pH can be adjusted with an acid or base, such as hydrochloric acid, citric acid, or sodium hydroxide. Such formulations may be packaged in ampoules, disposable syringes, or multi-dose vials made of glass or plastic. Formulations intended for in vivo administration are typically sterile. Sterility can be readily achieved, for example, through filtration via sterile membranes and irradiation. Injectable compositions may contain an active ingredient (drug) in an amount ranging from about 1 to 250 mg / mL, more preferably in a concentration range of about 1 to 100 mg / mL. Without limiting the range of compositional components, injectable compositions comprising a compound of formula (1) (e.g., a free base) and a pharmaceutically acceptable salt thereof (e.g., an acetate) can be prepared by dissolving the compound (e.g., 1 mg / mL to 25 mg / mL) in a composition comprising citric acid, propylene glycol, water, and optionally an antioxidant (e.g., monothioglycerol). As described herein, the composition may contain about 90% (± about 6%) of lactone A and 10% (± about 6%) of lactone B of a compound of formula (1) (preferably a non-antimicrobial surface H compound). The composition can be administered by injection (e.g., subcutaneously). The pH of the composition may be adjusted as needed with NaOH and / or HCl. Methods for preparing such formulations are readily apparent to those skilled in the art and can be prepared according to the procedure described in U.S. Patent US6514945.

[0171] For oral use, the pharmaceutical compositions of the present invention may be administered, for example, in the form of tablets or capsules, powders, dispersible granules or tablets, or as aqueous solutions or suspensions. Oral compositions typically include an inert or edible carrier. They 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 excipients may be included as part of the composition. Tablets, pills, capsules, lozenges, etc., may contain any of the following ingredients or compounds of similar nature: binders, such as microcrystalline cellulose, tragacanth gum or gelatin; excipients, such as starch or lactose; disintegrants, such as alginate, progelatin, sodium hydroxyacetate of starch or corn starch; lubricants, such as magnesium stearate or stearate; glidants, such as colloidal silica; sweeteners, such as sucrose or saccharin; or flavoring agents.

[0172] dose

[0173] Pharmaceutical compositions applicable to the present invention include compositions in which the content of the active ingredient is sufficient to achieve the intended purpose. More specifically, a therapeutically effective amount refers to the amount of the compound of the present invention that effectively prevents, alleviates, or improves the symptoms / signs of a disease or prolongs the survival of the treated animal. The amount of the active component, which is a compound of the present invention, in the pharmaceutical composition and its unit dosage form can vary widely or be adjusted depending on the method of administration, the potency of the particular compound, and the desired concentration. The determination of the therapeutically effective amount is entirely within the competence of those skilled in the art. Typically, the amount of the active component ranges from 0.01% to 99% by weight of the composition.

[0174] Typically, the therapeutically effective dose of the active ingredient is in the range of about 0.01 mg / kg to about 10 mg / kg body weight, preferably about 0.02 mg / kg to about 1 mg / kg body weight, more preferably about 0.04 mg / kg to about 0.8 mg / kg body weight, and even more preferably about 0.06 mg / kg to about 0.6 mg / kg body weight. A preferred dosing regimen is parenteral administration via subcutaneous injection of about 0.05 mg / kg to about 0.8 mg / kg 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 being treated. The required dose can be conveniently administered as a single dose or in divided doses at appropriate intervals during treatment. The preferred route of administration is parenteral administration. 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 first signs of stress or bacterial infection, before shipment from the farm or ranch, or upon arrival at the farm.

[0175] 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 administered co-administered with vitamins and / or minerals. Non-limiting examples of anti-inflammatory agents include: ketoprofen, cyclosporin A, rapamycin, FJ-506 (tacrolimus), leflunomide, deoxyspergualin, mycophenolate, azathioprine, daclizumab, aspirin, acetaminophen, ibuprofen, naproxen, piroxicam, and anti-inflammatory steroids (e.g., prednisolone or dexamethasone).Non-limiting examples of antimicrobial agents include: novobiocin, aminoglycosides (e.g., gentamicin, neomycin, dihydrostreptomycin, spectinomycin, etc.), florfenicol, ceftiofur, cefepirine, ormetoprim, danofloxacin, enrofloxacin, bambermycins, and iontophores. (e.g., laidlomycin, lasalocid, monensin, narasin, salinomycin, lincomycin, pirlimycin, macrolides (e.g., M9 metabolites of erythromycin, gamithromycin, tildipirosin, tilmicosin, tulathroymycin, tylosin, tivalmycin, etc.), a Abilamicin, penicillins (e.g., amoxicillin, ampicillin, cloxacillin, penicillin, etc.), tiamulin, polymyxin B, bacitracin, carbadox, virginiamycin, sulfadimethoxine, sulfamethazine, chlortetracycline Examples of non-limiting minerals include calcium, magnesium, phosphorus, potassium, sodium, sulfur, cobalt, copper, iodine, iron, manganese, selenium, chromium, and zinc. Examples of non-limiting vitamins include vitamins A, D, E, K, and B, including thiamine (B1), riboflavin (B2), niacin (B3), pantothenic acid (B5), pyridoxine (B6), biotin (B7), folate (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 at the same or different schedules of administration according to standard medical or veterinary practice known to those skilled in the art.

[0176] Medical and veterinary uses

[0177] 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, a disease, condition, or symptom associated with a bacterial infection, viral infection, parasitic infection, inflammation, or immune response, or are at risk of developing such a disease, condition, or symptom. Diseases or symptom can include respiratory diseases, reproductive diseases such as mastitis or metritis, inflammatory bowel disease, bovine viral diarrhea virus (BVDV), infectious bovine bronchitis (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 this invention is, for example, an amount that induces the desired therapeutic effect in animals while minimizing undesirable side effects. In various embodiments, effective amounts of the compounds of the present invention can significantly reduce inflammation or immune response, slow the progression of disease, condition or symptom associated with inflammation or immune response, or limit the development of disease, condition or symptom associated with inflammation or immune response.

[0178] The compounds of this invention are macrolide (azalide) analogs that lack antibacterial activity against BRD pathogens but have been shown to possess immunomodulatory properties for the prevention and / or control of BRD symptoms in artificially infected cattle. Therefore, these macrolides are useful therapeutic agents for the treatment and / or control of respiratory diseases that may be caused by environmental stimuli, stress, and bacterial infections. Some non-limiting macrolides for the treatment of BRD include: (Tylamycin) (Tai Di Luo Xin) and (Gamimycin), etc.

[0179] This is an injectable solution indicated for the treatment of bovine respiratory disease (BRD) associated with *Mannella hemolyticus*, *Pasteurella multocida*, *Histophilus somnioides*, and *Mycoplasma bovis*; and for the control of respiratory disease in cattle at high risk of developing BRD associated with these pathogens. Cattle receive a subcutaneous dose of 2.5 mg / kg. In pigs, This medicine 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 pigs already diagnosed with SRD. Pigs are administered 2.5 mg / kg intramuscularly.

[0180] The compounds of this invention can treat, alleviate, or prevent diseases, conditions, or symptoms associated with inflammation or immune responses. Inflammation is a critical response to potential danger signals and damage in the body's organs. Often referred to as the inflammatory cascade, it can be acute or chronic. Acute inflammation is part of the immune response and is the body's immediate response to damage or attack caused by physical 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-pervasive, it can lead to chronic or long-term inflammation.

[0181] Trauma, inflammation, or infection triggers the activation of an inflammatory cascade. Initially, pro-inflammatory activation occurs, but almost immediately thereafter, a reactive inhibitory anti-inflammatory response follows. This systemic inflammatory response (SIR) is typically characterized by an increased systemic expression of both pro-inflammatory and anti-inflammatory substances. The SIR begins with an inflammatory response to exogenous (microbial, physical, or chemical) agents or endogenous (immune or neurological) factors. This response begins when inflammatory cells (such as macrophages) at the site 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 among these pro-inflammatory cytokines, anti-inflammatory cytokines, and naturally occurring cytokine inhibitors determine the inflammatory response and its effectiveness in suppressing it.

[0182] This leads to the decline of the initiation process. The main known mediators involved in the evolution of SIRS are cytokines, nitric oxide, platelet-activating factor (PAF), and arachidic acid. The systemic response to infection is mediated by macrophage-derived cytokines, which respond to receptors targeting peripheral organs in response to damage or infection. However, the production of anti-inflammatory proteins and lipid molecules also attenuates and halts the inflammatory response. These mediators trigger overlapping processes that directly affect endothelial, cardiovascular, hemodynamic, and coagulation mechanisms. If a balance between pro-inflammatory and anti-inflammatory substances is not established and homeostasis is not restored, massive pro-inflammatory responses (i.e., SIRS) and multiple organ dysfunction syndromes (MODS) may follow. Therefore, after the release of the first pro-inflammatory mediator, the body produces 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.

[0183] Diseases associated with inflammation or immune responses can include, for example but not limited to: bacterial infections; viral infections; fungal infections; parasitic infections; asthma; allergies; age-related macular degeneration; dermatitis; pain; mastitis; metritis; autoinflammatory diseases; autoimmune diseases; inflammatory bowel disease; dermatitis; multiple sclerosis; osteoarthritis; osteoporosis; psoriasis; rheumatoid and osteoarthritis-related arthritis; synovitis; acne; impetigo; bone hyperplasia; airway and respiratory diseases (e.g., equine airway disease and canine infectious respiratory disease); respiratory disease syndromes (cattle and pigs); ischemia-reperfusion; feline chronic kidney disease; feline and canine degenerative mitral valve disease (inflammatory syndromes; for example, via cytokines, chemokines) (Upregulation of pro-inflammatory cytokines in heart failure and adhesion molecules in valves and myocardium), psoriasis, multiple sclerosis, rheumatoid arthritis, autoinflammatory diseases, peptic ulcers, tuberculosis, periodontitis, otitis, ulcerative colitis, Crohn's disease, lupus, sinusitis, hepatitis, celiac disease, pelvic inflammatory disease, glomerulonephritis, transplant rejection, chronic obstructive pulmonary disease, gout, ankylosing spondylitis, myositis, spondylitis, gingivitis, scleroderma, vasculitis, malaria, Lyme disease, babesiosis, erythrozoonosis, anaplasmosis, tularemia, amoebiasis, giardiasis, liver fluke infection, fascioliasis, 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 (e.g., IL6, IL-1β, NFKB, CSP136, LCN, CXCL8 (IL-8), TNFα) and induce TLR4 signaling.

[0184] Macrolide Immunomodulation

[0185] The chemistry of macrolides provides the basis for understanding their immunomodulatory effects. Macrolides are defined as cationic amphiphilic drugs; cell permeability is primarily determined by their lipophilic and cationic properties at physiological pH. Cell membrane permeation via macrolides leads to phospholipid depolarization, resulting in drug and phospholipid deposition in cytosols and lysosomes, ultimately leading to the cellular state of phospholipidosis. Intracellular polar association with phospholipids (primarily phosphatidylcholine) inhibits the spontaneous degradation of phospholipases, resulting in a reduction of primary cellular signaling components such as arachidonic acid. It is hypothesized that the reduction of arachidonic acid prevents the normal production of arachidonic acid metabolites, including prostaglandins, thromboxanes, leukotrienes, and lipoxygenases. In addition, indirect inhibition of the production of inflammatory mediators such as the COX family, NF-κB, and AP-1, and their pro-inflammatory cytokines, has been observed. The reduced ability of cells to signal both intracellularly and extracellularly is dependent on the host environment. In healthy animals, macrolide treatment has been shown to stimulate neutrophil and macrophage responses in response to disease stimuli. However, suppression or reversal of inflammation has been observed in the presence of acute or chronic inflammatory states.

[0186] 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, requiring no cellular energy, carrier proteins, and is unsaturated. This mechanism differs from ribosome binding, which is associated with antibiotic activity, and is therefore unrelated. As an example, azithromycin glycosides without antibiotic activity demonstrate high levels of phospholipid induction (J. Parnham et al. / Pharmacology & Therapeutics 143(2014) 225–245). Azithromycin penetrates the cell membrane bilayer and stabilizes the membrane, reducing fluidity and neutralizing phospholipid charges on the inner lobular membrane. This leads to reduced fatty acid release and the release of enzymes bound to the membrane via electrostatic charge, resulting in the regulation of signaling pathways and the inhibition of activation of transcription factors, including AP-1 and NFκB. The most affected signaling 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, regulating MPR transport of enzymes and lipids and lipid remodeling in the lysosomal membrane. One well-documented aspect is their ability to regulate inflammatory responses, as demonstrated by downregulation of exacerbated cytokine production (IL-1β, TNF-α, IL-6) via the NFκB pathway and their effects on granulocytes; as well as gene expression.

[0187] 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, thereby preventing oxidative damage to tissues.

[0188] CD163 also serves as an innate immune sensor for both Gram-positive and Gram-negative bacteria. Therefore, high expression of CD163 in macrophages is characteristic of inflammatory tissues and is considered a highly relevant biomarker of inflammation. The oxidative and pro-inflammatory hemoglobin clearance leading to heme oxygenase-1 stimulation 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 can also be associated with elevated IL-6 levels, as observed in BRD. CD163 surface expression has been induced by incubation with IL-6 in monocytes and macrophages at a 253+ / -4.9% experimental rate (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, production of inositol triphosphate, and secretion of IL-6 and GM-CSF (Journal of Leukocyte Biology; Van de Heuvel et al., Vol. 66, November 1999; pp. 858-866). The anti-inflammatory and immunomodulatory drug tacrolimus showed a slight increase in CD163 expression (PLOS ONE; Kannegleter et al., January 2017; pp. 1–19); however, a later study (HHS Public Access; Motta et al., Oral Dis. 2018, 24(4), pp. 580–590) reported no change in CD163 expression after treatment. Similarly, azithromycin (British Journal of Pharmacology, Vrancic et al.; 2012, 165; pp. 1348–1360) reported enhanced CD163 expression. CD163 expression upregulated glucocorticoids, IL-6, IL-10, and hemoglobin, and downregulated IL-4, IFN-γ, TNF-α, CXCL4, and GM-CSF. Conversely, CD163 was suppressed in cattle treated with M9 and H-91, which is related to the proposed mechanism of reduced inflammatory state.

[0189] Cytokines are considered a broad and loosely structured class of small proteins (5-20 kDa) that are important in cell signaling. Their release influences the behavior of surrounding cells. Cytokines can be considered immunomodulators involved in autocrine, paracrine, and endocrine signaling. Commonly known cytokines include chemokines, interferons, interleukins, lymphokines, and tumor necrosis factor (TNF), but typically exclude 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 regulate the balance between humoral and cellular immune responses, and they 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 can be important in health and disease, particularly in host responses to infection, immune responses, inflammation, stress, trauma, sepsis, cancer, and reproduction.

[0190] Interleukin-6 (IL-6) is a pleiotropic cytokine that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine. IL-6 is produced and secreted by various 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); it contributes to inflammation during infection and after tissue trauma. Trans signaling is responsible for the pro-inflammatory effects of IL-6 and most pathological functions. Dysregulation of the IL-6 pathway has been reported to be associated with the development of several disease states, including a variety of 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 involved in the enhancement of neutrophil and monocyte / macrophage recruitment and the blockade of anti-inflammatory regulatory T cells. In chronic inflammation, IL-6 has a detrimental effect and leads to the accumulation of monocytes at sites of injury. This may lead to increased serum levels of IL-6 and sIL-6R, providing a basis for the expansionary steps of the chronic inflammatory response. IL-6 is involved in the development of pulmonary neutrophilia by enhancing neutrophil recruitment and 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.

[0191] 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 (Hemolytic Mansonia) challenge and is associated with higher rectal temperature, lung lesions, and mortality. The compounds of the present invention, M9, and tylosin 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 dose and clinical outcomes.

[0192] 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 myeloid differentiation 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 cells in the skin, lung, and intestinal tract. IL-36 agonists bind to their receptors [IL-36R and IL-1 receptor accessory protein (IL-1RAcP)] and are subsequently activated. These pathways then 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 interest due to its dysregulation in inflammatory diseases. For example, serum and tissue IL-36 expression is increased in inflammatory and immune diseases and conditions such as psoriasis, rheumatoid arthritis, and inflammatory bowel disease.

[0193] Chemokines

[0194] Chemokines are a family of small cytokines or signaling proteins secreted by cells. They are named for their ability to induce directed chemotaxis in nearby responding cells (i.e., chemokines); they stimulate the recruitment of leukocytes. The primary function of chemokines is to control the migration (homing) of leukocytes to appropriate anatomical locations during inflammatory and homeostatic processes. They 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 insert amino acid between the first two cysteine ​​residues; members of the CC chemokine subfamily have two adjacent cysteine ​​residues. Generally, members of the CXC chemokine subfamily are chemotactic towards neutrophils, while CC chemokines are chemotactic towards monocytes and small lymphocyte subsets. Some chemokines are considered pro-inflammatory and can be induced during an immune response to recruit cells of the immune system to sites of infection or tissue damage, while others are considered homeostatic and involved in controlling cell migration during normal processes of tissue maintenance or development (e.g., angiogenesis).

[0195] Inflammatory chemokines are formed under pathological conditions (on pro-inflammatory stimuli such as IL-1, TNF-α, LPS, or viruses) and actively participate in the inflammatory response that attracts immune cells to the site of inflammation. These include CXCL8 (IL-8), CCL2, CCL3, CCL4, CCL5, CCL11, and CXCL10. These inflammatory chemokines are produced in high concentrations during infection or injury and determine the migration of inflammatory leukocytes to the damaged area. A typical example is CXCL8, which acts as a chemical attractant for neutrophils. In contrast to homeostatic chemokine receptors, there is significant confounding (redundancy) associated with both binding receptors and inflammatory chemokines.

[0196] 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. Many cells, including neutrophils, monocytes, macrophages, mast cells, vascular endothelial cells, stromal cells, and epithelial cells, produce IL-8 in response to innate exogenous / endogenous stimuli. In target cells, IL-8 induces a series of physiological responses required for migration and phagocytosis, such as intracellular calcium... 2+ Increased exocytosis (e.g., histamine release).

[0197] The recruitment of inflammatory cells (such as neutrophils) in response to tissue damage (e.g., 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 human inflammatory conditions like chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), asthma, pulmonary fibrosis, and bacterial pneumonia. This has also been observed in bovine respiratory disease (BRD) and bacterial pneumonia. Controlling the recruitment and activation of these cells in the lungs would be an attractive strategy for therapeutic intervention. In all these conditions, IL-8 appears to be important for the recruitment and activation of neutrophils and T cells in the respiratory tract.

[0198] In experimental challenge studies of cattle with *Mannella vulgaris* (one of the main pathogens of BRD), serum and tissue levels of IL-8 were upregulated. The compounds of this invention showed downregulation of IL-8 production in this challenge model, and this was associated with reduced anti-inflammatory responses and disease.

[0199] Biology of BRD

[0200] For a long time, it has been believed that the pathobiology of BRD originates from stress-induced immunosuppression, making calves vulnerable to a variety of microorganisms they encounter during the transition from calf handling to farm work. This dogma suggests that stimulating the innate immune system will have a positive impact on clinical outcomes. However, to date, interventions conforming to this dogma have had little success, including the use of DNA immunostimulants (...). To better understand the progression of BRD, early research suggested that it is the exacerbation of an early, unresolved inflammatory state, rather than immunosuppression, that leads to its progression.

[0201] Based on current research advancing the etiology of BRD, a new understanding of immune status has shown that while an exacerbated pro-inflammatory state is prevalent in at-risk cattle, its persistence or absence, or lack of resolution / remission, 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) demonstrates the response of epithelial and resident myeloid cells to microbes co-localized in the upper airway. Bacterial components such as lipopolysaccharide (LPS; lipopolysaccharide and endotoxin) induce TLR4 signaling, 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), and myeloid granulocytes, including macrophages and neutrophils, are recruited and activated. These cascades create an environment where bacteria normally confined to the upper airway can invade the lungs and cause disease. Biomarkers of inflammatory processes, such as elevated levels of secreted cytokines (e.g., IL-6) and acute-phase proteins, are associated with clinical disease. Also associated with clinical disease are markers of cell activation, such as expression of the scavenger receptor CD163 on macrophages and neutrophil-associated mediators, such as LCN and CXCL8. The compounds of this invention effectively alleviate the highly pro-inflammatory state in at-risk cattle by balancing the immune response and reducing the pathological inflammatory cascade. Figure 1 This mechanism of immunomodulators in the context of BRD progression is described.

[0202] The compounds of this invention represent a novel approach to treating 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 shipment, enabling animals to recover homeostasis within a timeframe consistent with clinical disease protection.

[0203] Plan and Experiment

[0204] In the protocols and experimental procedures provided herein, the following acronyms are defined: benzyloxycarbonyl (Cbz); ON (overnight, 16 to 24 hours); protecting group (Pg); leaving group (Lg); triethylamine (TEA); dichloromethane (DCM); cyano (CN); tetrahydrofuran (THF); palladium supported on carbon (Pd / C); trifluoroacetic acid (TFA); acetic acid (AcOH); tert-butanol (t-BuOH or TBA); room temperature (RT); ethyl acetate (EtOAc); dimethylformamide (DMF); N-methyl-2-pyrrolidine (NMP); methyl tert-butyl ether (MTBE); N,N-diisopropylethylamine (DIPEA); phenyl (Ph); and copper acetate II (Cu(OAc)2).

[0205] Tylopycin A is a 15-membered (lactone A) closed-ring antibacterial macrolide (azalide). Azalide is converted into a 13-membered (lactone B) closed-ring, namely tylopycin B. This conversion occurs at an equilibrium ratio of approximately 9:1 (A:B), as described below.

[0206]

[0207] Tylamycin azalactones can also be represented by the following structures:

[0208]

[0209] 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's The precursor, 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.

[0210] In addition to the tulamycin azalactones (tulaA and tulaB) just described above, the compounds of example H-11, lactones A and B, are shown below:

[0211]

[0212] H-11 lactones were separated by HPLC at 50 °C over 16 min using an Agilent 1100 quaternary pump and a diode array detector (250 nm) with an X-select CSH C18 column (150 x 4.6 mm, 2.5 μm) and a gradient mobile phase (mp) containing 0.03% H₂SO₄ (mpA) and acetonitrile (mpB) in water. Lactone A eluted at 5.8 min (area % 92.4) and lactone B eluted at 5.2 min (area % 7.6).

[0213] In aqueous solution, example H-11 exists as an equilibrium mixture of two lactone isomers as shown above. The ratio of lactone A:B is approximately 9:1. The equilibrium rate depends on pH and temperature, with neutral pH yielding a faster equilibrium, pH around 5 to 6 yielding a much slower equilibrium, and higher temperatures leading to a faster equilibrium. Equilibrium occurs within 1 hour at pH > 6 and temperatures > 60°C. H-11 isomerization is a 6-membered exocyclic cyclization reaction, which is a favorable reaction according to Baldwin's rule. The major isomer endone-A is a 15-membered macrocyclic lactone, while the minor isomer endone-B is a 13-membered macrocyclic lactone. H-11 exhibits pH-dependent water solubility, where it is very readily soluble at acidic pH conditions, but has lower solubility when the pH is close to neutral. Due to the pH-dependent solubility of H-11 and other compounds of the present invention, it may be necessary to dissolve organic acids (e.g., citric acid) in water before adding surfactants (e.g., H-11) to ensure complete dissolution, especially for higher concentration solutions, thereby providing a solution with sufficient solubility buffering capacity.

[0214] One of the metabolites of tylosin A is demethylazalide, (2R,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), as shown in the figure below:

[0215]

[0216] Tylamycin B is also metabolized into β-demethylazalolone.

[0217] M9 analogues can be used as raw materials for the preparation of the compounds of the present invention. The method for preparing demethylteratin (M9) from teratin A is a two-step process, 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. The second step is a Polonowski-type demethylation, which can be achieved using any known metal. It is typically iron, but copper salts (Cu(II)) can also be used.

[0218] 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 disodium salt aqueous solution (15 mL). Alkalize the aqueous solution to pH 9.5 with concentrated ammonia and extract with tert-butyl methyl ether (20 mL). Concentrate the N-oxide product to a viscous oil, but do not separate it, [M+H] + =822. The oily substance 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 to 2 hours. The solution was cooled to 25 °C, and an 8 mL solution of hydroxylamine hydrochloride (0.75 g, 10 mmol) in water 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 oily substance, and the product was crystallized from hot acetonitrile (40 mL). The resulting white crystalline powder was dried to give 3.2 g of M9. LCMS[M+H] + =792.5. HPLC purity >98%. 1 ¹H NMR (600MHz, d6-DMSO): N-Me (3H, 2.42ppm, S) compared with tylosin NMe2 (6H, 2.26ppm).

[0219] Alternatively, M9 can be prepared as follows: A solution of tylosin A (4.0 g, 5.0 mmol) at 20 °C in n-butanol (10 mL) is mixed, followed by the addition of hexafluoroacetone trihydrate (0.27 g, 1.2 mmol), and then 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 thick oil, but not separated. [M+H] +=822. The oily substance 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 hydroxylamine hydrochloride (0.75 g, 10 mmol) was added in water (8 mL). 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 oily substance, and the product was crystallized from hot acetonitrile (40 mL). The resulting white crystalline powder was dried to give 3.2 g of the product; LCMS[M+H] + =792.5. HPLC purity >98%. 1H NMR (600MHz, d6-DMSO): compared with tylosin NMe2 (6H, 2.26ppm), N-Me (3H, 2.42ppm, S).

[0220] Alternatively, M9 can be prepared as follows: The 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-1,5 A solution of 20.0 g (27 mmol) of dioxaspiro[2.5]oct-6-yl)oxy)-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one (tula-epx) 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% aqueous hydrogen peroxide solution (0.62 g, 30 mmol) were added.

[0221]

[0222] After 4 hours at 35°C, 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 matter 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 give 12 g of the product; LCMS [M+H] +=792.5. HPLC purity >98%. 1H NMR (600MHz, d6-DMSO): compared with tylosin NMe2 (6H, 2.26ppm), N-Me (3H, 2.42ppm, S).

[0223] Azithromycin (as shown below) is a terbinazone similar to tylosin, except that the N core ring is substituted with a methyl group (1') and the cladinose is not further substituted with methylpropylamine (2'); as shown below.

[0224]

[0225] Azithromycin can be derivatized to prepare M9-like demethylated analogs. Further derivatization can be performed according to the protocols and experiments defined herein to prepare immunomodulatory azithromycin derivatives inactive against BRD bacterial pathogens (i.e., non-antibacterial). Besides azithromycin, other macrolides, such as erythromycin, tilmicosin, clarithromycin, gamimycin, fedamycin, roxithromycin, telithromycin, terlithromycin, josamycin, midecamycin, pyruvicin, and roxithromycin, can be modified in a manner similar to M9 to prepare immunomodulatory analogs lacking antibacterial properties against BRD and other bacterial pathogens in animals (including humans).

[0226] For illustrative purposes, the reaction schemes described below demonstrate potential pathways for the synthesis of key intermediates and compounds of the present invention. For a more detailed description of each reaction step, see 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, as well as their various derivatives. Furthermore, many compounds prepared by the methods described below can be prepared and / or modified using conventional chemical methods.

[0227] The compounds of the present invention can be used in their natural form or as salts. In cases where the formation of a stable, non-toxic acid salt is required, administration of the compound in the form of 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 within a reasonable medical evaluation range without exhibiting toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. Furthermore, the compounds of the present invention have secondary or tertiary amine groups, which are basic in nature and therefore can form acid addition salts, which can be pharmaceutically acceptable acids. Thus, pharmaceutically acceptable salts according to the present invention include 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, adipates, alginates, ascorbic acid salts, citrates, aspartate salts, benzoates, benzenesulfonates, benzenesulfonates, bicarbonates / carbonates, bisulfates / sulfates, borates, butates, camphorates, camphorsulfonates, camphorsulfonates, citrates, diglucuronates, ethanedisulfonates, ethaneglutarate, ethanesulfonates, formates, fumarates, glucohepanoates, glucuronates, glucuronates, glutamates, glycerophosphates, hemisulfates, heptanates, hexafluorophosphates, and caproates. Benzoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, hydroxyethylsulfonate, lactate, malate, maleate, malonate, methanesulfonate, methyl sulfate, naphthate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, phosphate / hydrogen phosphate / dihydrogen phosphate, picrate, neopentanoate, propionate, saccharide, stearate, succinate, tartrate, thiocyanate, toluenesulfonate, and trifluoroacetate.

[0228] In the following scheme, demethylation or a Polonovski reaction occurs when the 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), the acetate attacking a carbon atom adjacent to the nitrogen atom to yield an α-acetoxyamine.

[0229] The central characteristic of the Polonovski reaction is the conversion of the N-oxide to the 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 breaking of the Cα-carbon bond. Similarly, depending on the conditions, the reaction may stop at this stage and the imine ion becomes the Polonovski product, or it may continue to yield an enamine or tertiary amide and / or secondary amine and aldehyde.

[0230] In principle, any reagent capable of activating N-oxide oxygen to form imine ions, thereby triggering the Polonovski reaction, can be used. However, three main types of activators can be used: acid anhydrides and chlorides (including chloroformates), iron or copper salts and complexes, and sulfur dioxide.

[0231] In the following schemes and preparations, the following abbreviations are used: methanol (MeOH), ethanol (EtOH), dichloromethane (DCM), trifluoroacetic acid (TFA), hydrogen peroxide (H2O2), potassium cyanide (KCN), triethylamine (TEA), triethylamine trifluoride (TEA.3HF), dimethylformamide (DMF), potassium cyanide (KCN), N,N-diisopropylethylamine (DIPEA), dichloroethane (DCE), isopropanol (IPA), ethylenediaminetetraacetic acid (EDTA), acetic acid (AcOH), ammonium hydroxide (NH4OH), acetonitrile (MeCN or Acn), sodium triacetoxyborohydride (STAB), sodium methoxide (MeONa), cerium(III) chloride (CeCl3), sodium azide (NaN3), sodium bicarbonate (NaHCO3), ammonium chloride (NH4Cl), magnesium sulfate (MgSO4), bromine (Br 2 Sodium sulfate (Na2SO4), ammonium sulfate ((NH4)2SO4), copper sulfate (CuSO4), sodium cyanoborohydride (NaBH3CN), 1-butanol (N-BuOH), hexafluoroacetone ((CF3)2CO-H2O), methoxy (OMe), ethoxy (OEt), room temperature (RT), overnight (ON), and water (H2O).

[0232] Scheme 1a. Preparation of urea compounds (1-A1) to (1-A6) of formula (1)

[0233]

[0234] Urea analogs can be prepared according to the three-step procedure outlined in Scheme 1a above. First, commercially available tula-epx epoxide can be demethylated via, but not limited to, the Polonovski reaction, to give M9 epoxide (M9-epx). Various oxidants (such as iodine, N-iodosuccinimide, peracetic acid, or hydrogen peroxide) can be used to form the N-oxide. Demethylation of the N-oxide can be initiated by iron or copper salts. Urea-forming reagents (such as isocyanates); active carbamoyl chlorides, imidazoles, N-methylimidazoles; p-NO2-phenol esters, etc., can be used to convert the resulting secondary amines into various ureas. Sometimes a weak base (such as TEA or DIPEA) can be used to promote the urea formation reaction. Non-limiting examples of leaving groups (LG) include chlorine, imidazole, methylimidazole, p-NO2-phenol, etc. 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 (e.g., but not limited to 1-propanol, 1-butanol, or 2-propanol) to ring-open the epoxide functional group to obtain the final urea analog. This reaction can be completed overnight. Weak bases such as NaHCO3 or salts such as NH4Cl or (NH4)2SO4 may sometimes accelerate the ring-opening reaction of the epoxide. For any of the schemes presented herein, the “nucleophile” for the ring-opening step of the epoxide on the cladinose ring can be one of, but not limited to, 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.

[0235] Option 1b: Details of step 3 (nucleophilic epoxide ring opening) in Option 1a

[0236]

[0237] For (s1b-A1) analogs, different primary or secondary amines can be used in alcohol solvents (e.g., but not limited to methanol, ethanol, 1-propanol, etc.) to ring-open the epoxide functional groups to obtain the final urea analog. For (s1b-A2) analogs, different alcohols (e.g., but not limited to methanol, ethanol, 1-propanol, etc.) can be used as solvents to ring-open the epoxide functional groups to obtain the final urea analog. Weak bases such as NaHCO3 or salts such as NH4Cl or (NH4)2SO4 may sometimes accelerate the ring-opening reaction of the epoxide. For (s1b-A3) analogs, different thiols (e.g., but not limited to ethanethiol, propanethiol, isopropanethiol, etc.) can be used in alcohol solvents (e.g., but not limited to ethanol or 1-propanol) to ring-open the epoxide functional groups to obtain the final urea analog. Weak bases (e.g., but not limited to NaHCO3) are used to accelerate the ring-opening reaction of the epoxide. For (s1b-A4) analogs, the epoxide functional groups can be ring-opened in an alcohol solvent (e.g., but not limited to ethanol or 1-propanol) using a halide different from the reagent (e.g., but not limited to CeCl3 or Br2) to obtain the final urea analog. Weak bases such as NaHCO3 or salts such as NH4Cl or (NH4)2SO4 may sometimes accelerate the ring-opening reaction of the epoxide. For (s1b-A5) analogs, the epoxide functional groups can be ring-opened in an alcohol solvent (e.g., but not limited to ethanol or 1-propanol) using azide anions from different sources (e.g., but not limited to NaN3) to obtain the final urea analog. Weak bases such as NaHCO3 or salts such as NH4Cl or (NH4)2SO4 may sometimes accelerate the ring-opening reaction of the epoxide. For (s1b-A6) analogs, the epoxide functional groups can be ring-opened in an alcohol solvent (e.g., but not limited to IPA or 1-propanol) using cyanide anions from different sources (e.g., but not limited to KCN) to obtain the final urea analog. Weak bases such as NaHCO3 or salts such as NH4Cl or (NH4)2SO4 may sometimes accelerate the ring-opening reaction of epoxides.

[0238] Scheme 2a. Preparation of urea compounds (1-A1) to (1-A6) of formula (1)

[0239]

[0240] Alternatively, urea analogs can be prepared according to scheme 2a. In the first step, a commercially available tylosin epoxide intermediate is treated at a higher temperature in an alcohol solvent (e.g., but not limited to 1-propanol, 1-butanol, or 2-propanol) with various nucleophiles (e.g., but not limited to primary and secondary amines, alcohols, thiols, cyanides, azides, or halide anions). This reaction can occur overnight. Weak bases such as NaHCO3 or salts such as NH4Cl or (NH4)2SO4 may sometimes accelerate the ring-opening reaction of the epoxide. In the second step, the tert-dimethylamine on the deoxyglycosamine sugar can be demethylated using the Polonovski-type conditions described above. The final urea analog can be prepared by reacting the secondary methylamine moiety with a urea-forming agent (e.g., but not limited to isocyanates); active carbamoyl chlorides, imidazoles, N-methylimidazolium; p-NO2 phenol esters, etc.

[0241] Option 2b: Details of step 1 (ring-opening of nucleophilic epoxide) in Option 2a:

[0242]

[0243] For (s2b-A1) compounds, different primary or secondary amines can be used in alcohol solvents (e.g., but not limited to methanol, ethanol, 1-propanol, etc.) to open the ring-opening reaction of the epoxide functional groups. For (s2b-A2) compounds, different alcohols (e.g., but not limited to methanol, ethanol, 1-propanol, etc.) can be used as solvents to open the ring-opening reaction of the epoxide functional groups. Weak bases such as NaHCO3 or salts such as NH4Cl or (NH4)2SO4 may sometimes accelerate the ring-opening reaction of the epoxide. For (s2b-A3) compounds, different thiols (e.g., but not limited to ethanethiol, propanethiol, isopropanethiol, etc.) can be used in alcohol solvents (e.g., but not limited to ethanol or 1-propanol) to open the ring-opening reaction of the epoxide functional groups. Weak bases (e.g., but not limited to NaHCO3) are used to accelerate the ring-opening reaction of the epoxide. For (s2b-A4) compounds, the ring-opening of the epoxide functional groups can be achieved using halides different from the reagents (e.g., but not limited to CeCl3 or Br2) in an alcohol solvent (e.g., but not limited to ethanol or 1-propanol). Weak bases such as NaHCO3 or salts such as NH4Cl or (NH4)2SO4 may sometimes accelerate the ring-opening reaction of the epoxide. For (s2b-A5) compounds, the ring-opening of the epoxide functional groups can be achieved using azide anions (e.g., but not limited to NaN3) from different sources in an alcohol solvent (e.g., but not limited to ethanol or 1-propanol). Weak bases such as NaHCO3 or salts such as NH4Cl or (NH4)2SO4 may sometimes accelerate the ring-opening reaction of the epoxide. For (s2b-A6) compounds, the ring-opening of the epoxide functional groups can be achieved using cyanide anions (e.g., but not limited to KCN) from different sources in an alcohol solvent (e.g., but not limited to IPA or 1-propanol). Weak bases such as NaHCO3 or salts such as NH4Cl or (NH4)2SO4 may sometimes accelerate the ring-opening reaction of epoxides.

[0244] Option 2c: Details of step 2 (demethylation) in Option 2a:

[0245]

[0246] All compounds (s2b-A1) to (s2b-A6) can undergo Polonovski-type demethylation as described above to yield the corresponding compounds (s2c-A1) to (s2c-A6). Various oxidizing agents (such as iodine, NIS, peracetic acid, or hydrogen peroxide) can be used to form N-oxides. The demethylation of N-oxides can be initiated by reagents such as iron or copper salts.

[0247] Solution 2d: Details of Step 3 (Urea Formation) of Solution 2a

[0248]

[0249] In the final step of this sequence, the final analogue can be prepared by reacting the Polonovski reaction product (s2c-A#) with a urea-forming agent (e.g., but not limited to isocyanates); an active carbamoyl chloride, -imidazolium, -N-methylimidazolium; p-NO2 phenol ester, etc. Details of this final transformation are shown in scheme 2d above.

[0250] Scheme 3a. Preparation of compounds (1-A1) to (1-A6) of formula (1):

[0251]

[0252] Alternatively, analogs can be prepared as described in Scheme 3a. In the first step, commercially available tylosin epoxides can be demethylated under a Polonovski reaction as described above. The resulting M9-epoxide can be reacted with various nucleophiles (e.g., but not limited to primary and secondary amines, alcohols, thiols, cyanides, azides, or halide anions, etc.) at higher temperatures in an alcohol solvent (e.g., 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 may 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 urea analog can be prepared by reacting a secondary methylamine portion with a urea-forming agent (e.g., but not limited to isocyanates); an active carbamoyl chloride, -imidazole, -N-methylimidazole; p-NO2 phenol ester, etc. Details of this final transformation are shown in Scheme 3c below.

[0253] Option 3b: Details of step 2 (ring-opening of nucleophilic epoxide) in Option 3a

[0254]

[0255] 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:

[0256] (s3b-A1) – Reaction with various primary or secondary amines in alcoholic solvents (e.g., but not limited to methanol, ethanol, or 1-propanol); (s3b-A2) – Reaction with various alcohols (e.g., but not limited to methanol, ethanol, or 1-propanol) used as solvents. Weak bases such as NaHCO3 or salts such as NH4Cl or (NH4)2SO4 may sometimes accelerate the ring-opening reaction of epoxides; (s3b-A3) – Reaction with various thiols (e.g., but not limited to ethanethiol, propanethiol, isopropanethiol, etc.) in alcoholic solvents (e.g., but not limited to ethanol or 1-propanol). The use of weak bases (e.g., but not limited to NaHCO3) to accelerate the ring-opening reaction of epoxides; (s3b-A4) – Reaction with halides different from the reagent (e.g., but not limited to CeCl3 or Br2) in alcoholic solvents (e.g., but not limited to ethanol or 1-propanol). Weak bases such as NaHCO3 or salts such as NH4Cl or (NH4)2SO4 may sometimes accelerate the ring-opening reaction of epoxides; (s3b-A5) reacts with azide anions from various sources (e.g., but not limited to NaN3) in alcoholic solvents (e.g., but not limited to ethanol or 1-propanol). Weak bases such as NaHCO3 or salts such as NH4Cl or (NH4)2SO4 may sometimes accelerate the ring-opening reaction of epoxides; and (s3b-A6) reacts with cyanide anions from various sources (e.g., but not limited to KCN) in alcoholic solvents (e.g., but not limited to IPA or 1-propanol). Weak bases such as NaHCO3 or salts such as NH4Cl or (NH4)2SO4 may sometimes accelerate the ring-opening reaction of epoxides.

[0257] Option 3c: Details of step 3 (urea formation) in Option 3a

[0258]

[0259] In the final step of this sequence, the final analogues of formulas (s3c-A1) to (s3c-A6) can be prepared by reacting the corresponding (s3b-A#) analogue with a urea-forming agent (e.g., but not limited to isocyanates); active carbamoyl chloride, -imidazolium, -N-methylimidazolium; p-NO2 phenol ester, etc., in an aprotic solvent such as DCM and a weak base (e.g., but not limited to TEA or DIPEA).

[0260] Scheme 4a. Preparation of urea compounds (1-A1) to (1-A6)

[0261]

[0262] Alternatively, urea can be prepared according to Scheme 4a. This four-step synthesis begins with a commercially available benzyloxycarbonyl (Cbz)-protected tyromycin epoxide. In the first step, the dimethylamine moiety on the deoxyglycosamine sugar is partially demethylated using Polonovski-type conditions as defined herein. In the second step, the secondary methylamine is activated with phosgene in the presence of a weak base such as dimethylpyridine and quenched in situ with the desired amine to form the urea functional group. In subsequent steps, the epoxide is partially ring-opened in an alcoholic solvent (e.g., but not limited to 1-propanol, 1-butanol, or 2-propanol) at higher temperatures using various nucleophiles (e.g., but not limited to primary and secondary amines, alcohols, thiols, cyanides, azides, or halide anions, etc.). This reaction can be completed overnight. Weak bases such as NaHCO3 or salts such as NH4Cl or (NH4)2SO4 may sometimes accelerate the ring-opening reaction of the epoxide. Details of this third step are given in Scheme 4b below. The final analogue was revealed by removing the Cbz protecting group with H2 gas in an alcohol solvent (such as ethanol, methanol, or trifluoroethanol) under catalytic Pd / C-mediated hydrogenolysis. Details of this final step are shown in scheme 4c below.

[0263] Option 4b: Details of step 3 (nucleophilic epoxide ring opening) in Option 4a

[0264]

[0265] OCbz urea epoxide can react to give the following compounds:

[0266] (s4b-A1) – Reaction with various primary or secondary amines in alcoholic solvents (e.g., but not limited to methanol, ethanol, or 1-propanol); (s4b-A2) – Reaction with various alcohols (e.g., but not limited to methanol, ethanol, or 1-propanol) used as solvents. Weak bases such as NaHCO3 or salts such as NH4Cl or (NH4)2SO4 may sometimes accelerate the ring-opening reaction of epoxides; (s4b-A3) – Reaction with various thiols (e.g., but not limited to ethanethiol, propanethiol, isopropanethiol, etc.) in alcoholic solvents (e.g., but not limited to ethanol or 1-propanol). The use of weak bases (e.g., but not limited to NaHCO3) to accelerate the ring-opening reaction of epoxides; (s4b-A4) – Reaction with halides different from the reagent (e.g., but not limited to CeCl3 or Br2) in alcoholic solvents (e.g., but not limited to ethanol or 1-propanol). Weak bases such as NaHCO3 or salts such as NH4Cl or (NH4)2SO4 may sometimes accelerate the ring-opening reaction of epoxides; (s4b-A5) reacts with azide anions from various sources (e.g., but not limited to NaN3) in alcoholic solvents (e.g., but not limited to ethanol or 1-propanol). Weak bases such as NaHCO3 or salts such as NH4Cl or (NH4)2SO4 may sometimes accelerate the ring-opening reaction of epoxides; and (s4b-A6) reacts with cyanide anions from various sources (e.g., but not limited to KCN) in alcoholic solvents (e.g., but not limited to IPA or 1-propanol). Weak bases such as NaHCO3 or salts such as NH4Cl or (NH4)2SO4 may sometimes accelerate the ring-opening reaction of epoxides.

[0267] Solution 4c: Details of step 4 (removing protection) in Solution 3a

[0268]

[0269] In the final step of this sequence, the final analogues of formulas (s4c-A1) to (s4c-A6) can be prepared by deprotecting the Cbz protecting group on the corresponding (s4b-A#) analogue with a catalytic amount of Pd / C in an alcohol solvent under hydrogenation conditions.

[0270] Scheme 5. Preparation of compounds of formula (1) with alkylated core nitrogen by reductive amination.

[0271]

[0272] Alkyl-tula-epx intermediates can be readily synthesized from tula epoxides (tula-epx) using various methods, including, but not limited to, reductive amination with the corresponding aldehyde and hydride source (e.g., but not limited to STAB or NaBH3CN) in solvents such as alcohols or DMF at temperatures ranging from 0°C to 60°C. Preparation of the macrolide core nitrogen is achieved by various R... 0The subsequent chemistry of the alkylated compounds of the present invention can be achieved through schemes 1 to 3, such as Polonovski-type demethylation, epoxide ring-opening, and urea formation, which are achieved by using R 0 The alkylated tylosin epoxide intermediate (alkyl-tula-epx) replaces the starting material Tula-epoxide in all schemes 1 to 3; for example, where R 0 It's propyl. Scheme 6. Use various R... 1 and R 2 Preparation of compounds of formula (1) with substituent groups: Preparation of the general intermediate M8 epoxide (M8-epx)

[0273]

[0274] The (M8-epx) intermediate can be readily synthesized from the M9 epoxide by various methods, such as a second demethylation with I2 and NaOMe or a triple sequence, wherein the M9 epoxide is first protected with a 4-OMe benzyl group and then demethylated using Polonovski demethylation. The M8 epoxide is shown by removing the protecting group under hydrogenolysis conditions in an alcoholic solvent (e.g., but not limited to methanol, ethanol, or trifluoroethanol) using 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.

[0275] Option 7. Preparation of various R from M8 epoxide (M8-epx) 1 Compounds of formula (1) with substituent groups

[0276]

[0277] M8 epoxide can react with urea to form reagents (e.g., but not limited to isocyanates); active carbamoyl chlorides, imidazoles, N-methylimidazolium; p-NO2 phenol esters, etc., in aprotic solvents such as DCM and weak bases (e.g., but not limited to TEA or DIPEA), as shown in Scheme 7, to obtain the compounds of the present invention (s7'-A1) to (s7'-A6) after ring opening of the epoxide. This chemistry is an adaptation of the chemistry described in Schemes 1 to 3.

[0278] M8 epoxide can also be used with the corresponding R 1 Aldehydes and hydride sources (e.g., but not limited to STAB or NaBH3CN) are reductively amination in solvents (e.g., alcohols, DMF, DCM, or DCE) at temperatures ranging from 0°C to 60°C. Preparation of compounds of the present invention (wherein R...) 1The subsequent chemical process (not CH3 in analogues derived from tylamycin) can be accomplished by modifying the chemical process of schemes 1 to 3 shown herein to form a urea on the deoxyglucosamine nitrogen and to open the ring of the cladinose epoxide with various nucleophiles. The urea functional group can be assembled in aprotic solvents such as DCM and weak bases such as TEA or DIPEA using different urea-forming agents (e.g., but not limited to isocyanates); active carbamoyl-chlorides, -imidazoles, -N-methylimidazoles; p-NO2 phenol esters, etc., in weak bases such as DCM, wherein the epoxide can be ring-opened at higher temperatures in alcoholic solvents (e.g., but not limited to 1-propanol, 1-butanol, or 2-propanol) using different nucleophiles (e.g., primary and secondary amines, alcohols, thiols, cyanides, azides, or halide anions, etc.), as shown in scheme 7, to obtain the compounds of the present invention (s7^-A1) to (s7^-A6).

[0279] Scheme 8. Preparation of compound (1-A0) of formula (1) from azithromycin via reductive amination.

[0280]

[0281] As shown in Scheme 8, azithromycin can be used as a starting material for synthesizing the compound of formula (1) of the present invention. Azithromycin can undergo a demethylation reaction similar to tylosin under similar conditions (e.g., but not limited to the Polonovski reaction as defined herein). Demethylated azithromycin can be reacted with urea-forming agents (e.g., but not limited to isocyanates); active carbamoyl-chloride, -imidazole, -N-methylimidazole; p-NO2 phenol esters, etc., in an aprotic solvent such as DCM and a weak base (e.g., but not limited to TEA or DIPEA), as shown in Scheme 8, to obtain the compound of the present invention (s8'-A0). In addition, demethylated azithromycin can be second demethylated using I2 and NaOMe as described above, followed by R 1 The aldehyde is reduced and amination is performed. The compound of the present invention (s8^-A0) can be synthesized by reacting bis(demethyl)azithromycin with a urea to form a reagent (e.g., but not limited to isocyanate); an active carbamoyl chloride, -imidazolium, -N-methylimidazolium; p-NO2 phenol ester, etc., in an aprotic solvent such as DCM and a weak base (e.g., but not limited to TEA or DIPEA), as shown in Scheme 8.

[0282] Scheme 9. Preparation of decladinose compounds of formula (1.1)

[0283]

[0284] The decladinose compound of formula (1.1) can be readily synthesized from the compound of formula (1A), as shown in Scheme 9, by stirring the compound in a solvent (e.g., but not limited to THF, MeCN, or H2O) in aqueous acetic acid or hydrochloric acid at a temperature of 0°C to 60°C for 1 to 72 hours.

[0285] Scheme 10. Preparation of decladinose compounds of formula (1.1)

[0286]

[0287] The decladinyl urea compound of formula (1.1) can also be synthesized according to the sequence shown in Scheme 10. The tula epoxide or N-nucleosubstituted tula epoxide (such as the alkyl tula epoxide synthesized in Scheme 5) can be demethylated according to the Polonovski demethylation conditions described herein. The cladinyl sugar of the demethylated product can be cleaved under aqueous acidic conditions in a solvent such as THF or acetonitrile with an acid such as acetic acid or hydrochloric acid. The urea functional group can be installed using urea-forming agents (e.g., but not limited to isocyanates); active carbamoyl-chlorides, -imidazolium, -N-methylimidazolium; p-NO2 phenol esters, etc., in aprotic solvents such as DCM and weak bases (e.g., but not limited to TEA or DIPEA), as shown in Scheme 10, to obtain the desired decladinyl urea compound of the present invention (s10-1.1).

[0288] Example

[0289] Preparation of decladinose example A-13 of formula (1.1).

[0290]

[0291] 2N HCl (10.0 mL) was added to crude sample H-11 (600.0 mg), and the resulting mixture was heated at 45 °C for 2 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 substance was purified by preparative HPLC using ammonium acetate as a buffer, and the purified substance was passed through an SCX column to give the product in the form of a free base.

[0292] Apart from the starting materials of formula (1-A1), the compounds of formula (1.1) can be prepared under similar conditions as shown in Example A-13 above.

[0293] Example B-6 of the preparation formula (1-A0); this is an application of scheme 8.

[0294]

[0295] Step 1: At 0°C and under a N2 atmosphere, azithromycin (20 g, 26.77 mmol, 1 equivalent), hexafluoroacetone (1.9 mL, 13.38 mmol, 0.5 equivalent), and H2O2 (30% w / w in H2O, 5 mL) dissolved in MeOH (40 mL) and glacial acetic acid (3.4 mL, 53.54 mmol, 2.2 equivalents) were added sequentially to a 500 mL round-bottom flask. The reaction mixture was stirred at room temperature (25°C) for 16 hours, and then anhydrous CuSO4 (6.4 g, 40.15 mmol, 1.5 equivalents) was added. The round-bottom flask was fitted with a reflux condenser, and the reaction mixture was stirred at 80°C for 6 hours under a N2 atmosphere. The reaction mixture was then cooled to room temperature, concentrated to remove MeOH, and diluted with DCM (300 mL). The solution was filtered through diatomaceous earth and the filtrate was alkalized to pH 10 using an ammonia solution. The organic phase was separated, washed with water and brine, dried over anhydrous Na2SO4, and concentrated to obtain a crude substance. The crude substance was ground with a pentane-diethyl ether (2:1) solution to obtain the desired desmethylazithromycin as a grayish-white solid (13 g, 66.2%).

[0296] Step 2: At room temperature, N-methyl-N-[4-(trifluoromethyl)phenyl]carbamoyl chloride (107 mg, 0.449 mmol, 1 equivalent) and Et3N (0.083 mL, 0.82 mmol, 2 equivalent) were added to a stirred solution of desmethylazithromycin (300 mg, 0.408 mmol, 1 equivalent) in anhydrous DCM (5 mL). The reaction mixture was stirred at room temperature for 12 hours, after which LCMS analysis showed complete conversion of the starting material. The mixture was concentrated under reduced pressure, and the crude product was purified by reversed-phase rapid chromatography on C18 silica using 1.0% AcOH as a modifier (0 to 100% MeCN in H2O). The desired fractions were lyophilized to give the desired urea product as a white solid acetate (260 mg, 64%).

[0297] Compound (1-A0) can be prepared similarly to (B-6) above under similar conditions by changing the urea-forming reagent or raw materials and using tylosin epoxide instead of azithromycin.

[0298] Preparation of Example C-1 of Formula (1-A2):

[0299]

[0300] Step 1: A solution of tula-epx (20.0 g, 27 mmol) in methanol (40 mL) and acetic acid (1.6 mL, 30 mmol), hexafluoroacetone trihydrate (0.38 mL, 3 mmol), and then a 30% aqueous hydrogen peroxide solution (0.62 g, 30 mmol) were mixed together and stirred at 35 °C for 4 hours. After determining the consumption of starting materials 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 determining the completion of the reaction 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 95% determined by LCMS, which was used as is in the next step.

[0301] Step 2: Dissolve M9 epoxide (M9-epx; 1.00 g, 1.36 mmol, 1.0 equivalent) in 10 mL of anhydrous EtOH in a pressure MW vial. Heat the resulting solution to 120 °C for 12 hours in a microwave reactor. Then remove volatiles under reduced pressure and purify the crude product using reversed-phase rapid chromatography on C18 silica with 1.0% AcOH as a modifier (0 to 100% MeCN in H2O). Combine 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 product in free base form (220 mg, 20%).

[0302] Step 3: The product from Step 2 (0.14 mmol, 110 mg, 1.00 equivalent) was dissolved in DCM (5 ml) and cooled to -78°C. Then, phenyl isocyanate (1.0 equivalent, 16 μL, 0.14 mmol) was added, and the reaction mixture was warmed to room temperature with stirring for 60 minutes. After the reaction was confirmed by LCMS analysis, volatiles were removed under N2 flow, and the crude product was purified by C18 reversed-phase rapid chromatography using 0.5% AcOH as a modifier (0 to 100% MeCN in H2O). The fraction containing the desired product was lyophilized to obtain the desired product in acetate form (15 mg, 11%).

[0303] Preparation of Example D-2 of Formula (1-A3)

[0304]

[0305] Step 1: A solution of tula-epx (20.0 g, 27 mmol) in methanol (40 mL) and acetic acid (1.6 mL, 30 mmol), hexafluoroacetone trihydrate (0.38 mL, 3 mmol), and then a 30% aqueous hydrogen peroxide solution (0.62 g, 30 mmol) were mixed together and stirred at 35 °C for 4 hours. After determining the consumption of starting materials 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 determining the completion of the reaction 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 95% determined by LCMS, which was used as is in the next step.

[0306] Step 2: In a 25 mL round-bottom flask, M9 epoxide (M9-epx 1.00 g, 1.36 mmol, 1.0 equivalent) was dissolved in 10 mL of anhydrous 1-propanol. Potassium bicarbonate (3.0 equivalent, 4.1 mmol, 410 mg) was added, followed by 1-propanethiol (5.0 equivalent, 6.8 mmol, 640 μL). The resulting solution was heated to 50 °C overnight, and LCMS analysis showed that the starting material was consumed. The reaction mixture was diluted with 20 mL of DCM and H₂O, and the pH was adjusted to approximately 12 with NH₄OH. The mixture was extracted three times with 30 mL of DCM to obtain the desired product (1053 mg, 95%) in the free base form, which was used unchanged in the next step.

[0307] Step 3: The product from Step 2 (0.25 mmol, 200 mg, 1.0 equivalence) was dissolved in DCM (5 ml) and TEA (2.0 equivalence, 70 μL, 0.49 mmol), and then N-methyl-N-phenyl-carbamoyl chloride (1.0 equivalence, 42 mg, 0.25 mmol) was added. The resulting solution was stirred overnight at room temperature. After the reaction was determined by LCMS analysis, volatiles were removed under N2 flow, and the crude product was purified by C18 reversed-phase rapid chromatography using 0.5% AcOH as a modifier (0 to 100% MeCN in H2O). The fraction containing the desired product was lyophilized to obtain the desired product in acetate form (135 mg, 55%).

[0308] Preparation of Example E-3 of Formula (1-A4):

[0309]

[0310] Step 1: A solution of tula-epx (20.0 g, 27 mmol) in methanol (40 mL) and acetic acid (1.6 mL, 30 mmol), hexafluoroacetone trihydrate (0.38 mL, 3 mmol), and then a 30% aqueous hydrogen peroxide solution (0.62 g, 30 mmol) were mixed together and stirred at 35 °C for 4 hours. After determining the consumption of starting materials 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 determining the completion of the reaction 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 95% determined by LCMS, which was used as is in the next step.

[0311] Step 2: In a 250 mL round-bottom flask, M9 epoxide (M9-epx 5.00 g, 6.82 mmol, 1.0 equivalent) was dissolved in 100 mL of anhydrous 1-propanol. Ammonium chloride (3.0 equivalent, 20.5 mmol, 1.1 g) was added, followed by cerium chloride (3.0 equivalent, 20.5 mmol, 5.1 g). The resulting solution was heated to 70 °C overnight, and LCMS analysis thereafter showed consumption of the starting material. The reaction mixture was diluted with 100 mL of DCM and H2O, and the pH was adjusted to approximately 12 with NH4OH. The mixture was extracted three times with 100 mL of DCM to obtain the desired product (5091 mg, 97%) in the free base form, which was used unchanged in the next step.

[0312] Step 3: The product from Step 2 (0.26 mmol, 200 mg, 1.0 equivalence) was dissolved in DCM (5 ml) and TEA (2.0 equivalence, 73 μL, 0.52 mmol), and then N-methyl-N-[4-(trifluoromethyl)phenyl]carbamoyl chloride (1.0 equivalence, 62 mg, 0.26 mmol) was added. The resulting solution was stirred overnight at room temperature. After the reaction was determined by LCMS analysis, volatiles were removed under N2 flow, and the crude product was purified by C18 reversed-phase rapid chromatography using 0.5% AcOH as a modifier (0 to 100% MeCN in H2O). The fraction containing the desired product was lyophilized to obtain the desired product in acetate form (119 mg, 44%).

[0313] Preparation of Example F-2 of Formula (1-A5):

[0314]

[0315] Step 1: A solution of tula-epx (20.0 g, 27 mmol) in methanol (40 mL) and acetic acid (1.6 mL, 30 mmol), hexafluoroacetone trihydrate (0.38 mL, 3 mmol), and then a 30% aqueous hydrogen peroxide solution (0.62 g, 30 mmol) were mixed together and stirred at 35 °C for 4 hours. After determining the consumption of starting materials 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 determining the completion of the reaction 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 95% determined by LCMS, which was used as is in the next step.

[0316] Step 2: In a 250 mL round-bottom flask, M9 epoxide (M9-epx 6.00 g, 8.19 mmol, 1.0 equivalent) was dissolved in 100 mL of anhydrous 1-propanol. Ammonium chloride (3.0 equivalent, 24.6 mmol, 1.31 g) was added, followed by sodium azide (3.0 equivalent, 24.6 mmol, 1.6 g). The resulting solution was heated to 80 °C overnight, and LCMS analysis showed that the starting material was consumed. The reaction mixture was diluted with 100 mL of DCM and H2O, and the pH was adjusted to approximately 12 with NH4OH. The mixture was extracted three times with 100 mL of DCM to obtain the desired product (5981 mg, 94%) in the free base form, which was used unchanged in the next step.

[0317] Step 3: The product from Step 2 (0.36 mmol, 282 mg, 1.0 equivalence) was dissolved in DCM (5 ml) and TEA (2.0 equivalence, 102 μL, 0.73 mmol), and then N-methyl-N-phenyl-carbamoyl chloride (1.0 equivalence, 62 mg, 0.36 mmol) was added. The resulting solution was stirred overnight at room temperature. After the reaction was determined by LCMS analysis, volatiles were removed under N2 flow, and the crude product was purified by C18 reversed-phase rapid chromatography using 0.5% AcOH as a modifier (0 to 100% MeCN in H2O). The fraction containing the desired product was lyophilized to obtain the desired product in acetate form (180 mg, 51%).

[0318] Preparation of Example G-3 of Formula (1-A6):

[0319]

[0320] Step 1: A solution of tula-epx (20.0 g, 27 mmol) in methanol (40 mL) and acetic acid (1.6 mL, 30 mmol), hexafluoroacetone trihydrate (0.38 mL, 3 mmol), and then a 30% aqueous hydrogen peroxide solution (0.62 g, 30 mmol) were mixed together and stirred at 35 °C for 4 hours. After determining the consumption of starting materials 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 determining the completion of the reaction 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 95% determined by LCMS, which was used as is in the next step.

[0321] Step 2: In a 100 mL round-bottom flask, M9 epoxide (M9-epx 3.00 g, 4.09 mmol, 1.0 equivalent) was dissolved in 50 mL of anhydrous 2-propanol. Ammonium sulfate (3.0 equivalent, 12.3 mmol, 1.6 g) was added, followed by potassium cyanide (6.0 equivalent, 24.6 mmol, 1.6 g). The resulting solution was heated to 80 °C for 48 hours, after which LCMS analysis showed the consumption of the starting material. The reaction mixture was diluted with 100 mL of DCM and H2O, and the pH was adjusted to approximately 12 with NH4OH. The mixture was extracted three times with 30 mL of DCM to obtain the desired product (2922 mg, 94%) in the free base form, which was used unchanged in the next step.

[0322] Step 3: The product from Step 2 (0.13 mmol, 100 mg, 1.0 equivalence) was dissolved in DCM (5 ml) and TEA (2.0 equivalence, 37 μL, 0.26 mmol), and then N-methyl-N-phenyl-carbamoyl chloride (1.0 equivalence, 22 mg, 0.13 mmol) was added. The resulting solution was stirred overnight at room temperature. After the reaction was determined by LCMS analysis, volatiles were removed under N2 flow, and the crude product was purified by C18 reversed-phase rapid chromatography using 0.5% AcOH as a modifier (0 to 100% MeCN in H2O). The fraction containing the desired product was lyophilized to obtain the desired product in acetate form (58 mg, 46%).

[0323] Compounds of formula (1-A2 to 1-A6) can be prepared under similar conditions as shown above (examples C-1, D-2, E-3, F-2 and G-3) by changing the urea-forming reagent or starting material and using (alkyl-tula-epx) as the starting material instead of the tylosin epoxide shown in Scheme 5.

[0324] Preparation of example H-11 of formula (1-A1):

[0325]

[0326] Step 1: To a solution of tula (20.0 g, 24.8 mmol) in methanol (40 mL) and acetic acid (1.6 mL, 28 mmol), hexafluoroacetone trihydrate (0.62 g, 2.8 mmol) was added, followed by 30% aqueous hydrogen peroxide solution (2.88 mL, 28 mmol), and the mixture was stirred at 35 °C for 4 hours. After determining the consumption of starting materials by LCMS, the reaction mixture was cooled to 20 °C, and anhydrous copper(II) sulfate (4.35 g, 28 mmol) was added. The reaction mixture was then heated to 60 °C for 2 hours. After determining the completion of the reaction 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 14.2 g of white crystalline product (M9-epx) with a purity >95% by LCMS, which was used as is in the next step.

[0327] Step 2: Dissolve M9 (0.25 mmol, 200 mg, 1.0 equivalence) from Step 1 in DCM (5 ml) and TEA (2.0 equivalence, 70 μL, 0.49 mmol), then add (N-methyl-N-phenyl-carbamoyl chloride (1.0 equivalence, 42 mg, 0.25 mmol), and stir the resulting solution overnight at room temperature. After the reaction is complete as determined by LCMS analysis, remove volatiles under N2 flow and purify the crude product by C18 reversed-phase rapid chromatography using 0.5% AcOH as a modifier (0 to 100% MeCN in H2O). Lyophilize the fraction containing the desired product to obtain the desired product in acetate form (175 mg, 71%).

[0328] Equation (1-A1; Table H) and Equation (1-A1a; where R 5 It is H and R 6The propyl compounds (Table I) can be prepared under similar conditions as shown above with respect to Example (H-11) by changing the urea-forming reagent or starting material and using (alkyl-tula-epx) as the starting material instead of the tylosin epoxide shown in Scheme 5. The following (1-A1) compounds are prepared according to the method of Example (H-11), showing only the final urea-forming step.

[0329] Preparation of Example H-8. Isocyano(trimethyl)silane (1.5 equivalents, 0.3788 mmol) was added to a solution of M9 (200 mg, 0.2525 mmol) in DCM (3 mL, 46.80 mmol), and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated, and MeOH (10 mL) was added, followed by evaporation. The residue was purified by preparative HPLC to give a white solid, TFA salt (79 mg).

[0330] Preparation of Example H-72: M9 (400 mg, 0.505 mmol) and 3-aminopyridine (47.53 mg, 0.505 mmol) were added to DCM (5 mL) in a dry round-bottom flask. The reaction mixture was cooled to -78 °C, and triphosgene (44.962 mg, 0.152 mmol) was added. After 10 minutes, triethylamine (0.141 mL, 1.01 mmol) was added. The mixture was stirred at -78 °C for 1 hour. The mixture was then concentrated and purified by preparative HPLC using ammonium acetate as a buffer. Similar fractions were combined, concentrated, and lyophilized. The lyophilized material was passed through an SCX / PL-HCO3 resin column to prepare the free base. The free base was then dissolved in 1 N AcOH solution, stirred at room temperature for 30 minutes, concentrated, dissolved in t-BuOH, and lyophilized to give the product in acetate form.

[0331] Preparation of Example H-91: Phenyl isocyanate (3.76 gm, 31.6 mmol) was slowly added to a solution of M9 (21.0 gm, 27 mmol) in dichloromethane (200 mL) at 0 °C. After 15 minutes, an aqueous solution of acetic acid (3.19 gm, 53.0 mmol) in 200 mL was added, and the product was extracted into the aqueous layer. The organic matter was discarded. Methyl tert-butyl ether (175 mL) was added to the aqueous solution, and the aqueous layer was alkalized to pH 7.9 with 2N sodium hydroxide aqueous solution. The organic layer containing the product was concentrated into a solid. The solid was dissolved in methyl tert-butyl ether (80 mL) at 55 °C, and acetic acid (1.7 gm, 28 mmol) was added. The resulting slurry was cooled to 5 °C, and the acetate product was separated by filtration. The solid was dried under vacuum to give 11.0 g of a white solid.

[0332] Preparation of Example I-4. Indoline-1-carbonyl chloride (126 mg, 0.69 mmol) and 4-dimethylaminopyridine (4 mg, 0.05 mmol) were added to a solution of M9 (500 mg, 0.63 mmol) and TEA (114 μL, 1.3 equivalents, 0.82 mmol) in DCM (5 mL). The mixture was stirred at room temperature for 3 hours. The mixture was quenched with NaHCO3 (saturated aqueous solution), separated, and the solvent was evaporated. The crude mixture was purified by passing it through a preparative SFC (2PIC column) with 25% MeOH and NH3 to give a white solid.

[0333] Preparation of Example I-6: 3,4-dihydro-2H-1 A solution of 6,4-benzothiazine 1,1-dioxide (183 mg, 0.99874 mmol) and pyridine (2 equivalents, 1.9975 mmol) in DCM (5 mL, 78.00 mmol) was added dropwise at -20 °C under N2 to a solution of triphosgene (0.4 equivalents, 0.39950 mmol) in DCM (5 mL, 78.00 mmol). The reaction mixture was heated to room temperature over 30 minutes and then stirred at room temperature for 2 hours. The reaction was quenched with 2 M aqueous hydrogen chloride solution, separated, and added to a solution of M9 (700 mg, 0.8838 mmol), TEA (1.3 equivalents, 1.149 mmol), and 4-dimethylaminopyridine (0.05 equivalents, 0.04419 mmol) in DCM (5 mL, 78.00 mmol). The mixture was stirred overnight at room temperature. The mixture was quenched and separated with NaHCO3 (saturated aqueous solution), and the solvent was evaporated. The crude mixture was purified by preparative SFC (BiP column, eluted with 26% MeOH and NH3 (aqueous solution)) to give a white solid.

[0334] Preparation of Example H-27 of Formula (1-A1)

[0335]

[0336] 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]octyl-6- A solution of 3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one (tula-epx) (20.0 g, 27 mmol) in methanol (40 mL) and acetic acid (1.6 mL, 30 mmol), hexafluoroacetone trihydrate (0.38 mL, 3 mmol), and then a 30% aqueous hydrogen peroxide solution (0.62 g, 30 mmol) were mixed together and stirred at 35 °C for 4 hours. After determining the consumption of starting materials by LCMS, the reaction mixture was cooled to 20 °C and anhydrous copper(II) sulfate (4.5 g, 29 mmol) was added, and the reaction mixture was heated to 60 °C for 1 hour. After determining the completion of the reaction 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 into a solid under vacuum and recrystallized from acetone / water to obtain 60 g of white crystalline product (M9-epx), which was determined to be 95% pure by LCMS and was used as is in the next step.

[0337] Step 2: The solution of 10 g (13.14 mmol) M9-epx from Step 1 and 9.12 mL of cyclopropylamine (10.0 equivalent, 131.4 mmol) in 100 mL of 1-propanol was heated to 80 °C for 16 hours. After the reaction was determined by LCMS, volatiles were removed under reduced pressure, and the solution was then dissolved in 100 mL of 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. Volatiles were removed under reduced pressure to obtain the crude substance, which was purified by reversed-phase rapid chromatography on C18 silica gel using 1.0% AcOH as a modifier (0 to 100% MeCN in H2O). The desired fractions were combined, the pH was adjusted to approximately 9.8 with NH4OH, and the solution 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 substance, which was a grayish-white amorphous solid (8.2 g).

[0338] Step 3: The product from Step 2 (0.39 mmol, 300 mg, 1.00 equivalent) was dissolved in DCM (5 ml), and then N-methyl-N-phenyl-carbamoyl chloride (1.0 equivalent, 63 mg, 0.39 mmol) was added. The resulting solution was stirred overnight at room temperature. After the reaction was determined by LCMS analysis, volatiles were removed under N2 flow, and the crude product was purified by C18 reversed-phase rapid chromatography using 0.5% AcOH as a modifier (0 to 100% MeCN in H2O). The fraction containing the desired product was lyophilized to give the desired compound in acetate form (212 mg).

[0339] The compounds of formula (1-A1) and formula (1-A1a) shown in Tables H and I can be prepared under similar conditions as shown in Example (H-27) above by changing the amine or urea forming agent or starting material used in the second step to open the epoxide functional group and using (alkyl-tula-epx) as the starting material instead of the tylosin epoxide shown in Scheme 5.

[0340] Preparation of Example J-7 of Formula (1-A1b):

[0341]

[0342] Step 1: A solution of tula-epx (20.0 g, 27 mmol) in methanol (40 mL) and acetic acid (1.6 mL, 30 mmol), hexafluoroacetone trihydrate (0.38 mL, 3 mmol), and then a 30% aqueous hydrogen peroxide solution (0.62 g, 30 mmol) were mixed together and stirred at 35 °C for 4 hours. After determining the consumption of starting materials 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 determining the completion of the reaction 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 95% determined by LCMS, which was used as is in the next step.

[0343] Step 2: The solution of 10 g (13.14 mmol) M9-epx from Step 1 and 14.7 mL of 1-methylpiperazine (10.0 equivalent, 131.4 mmol) in 100 mL of 1-propanol was heated to 80 °C for 16 hours. After the reaction was determined by LCMS, volatiles were removed under reduced pressure, and the solution was then dissolved in 100 mL of 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. Volatiles were removed under reduced pressure to obtain the crude substance, which was purified by reversed-phase rapid chromatography on C18 silica gel using 1.0% AcOH as a modifier (0 to 100% MeCN in H2O). The desired fractions were combined, the pH was adjusted to approximately 9.8 with NH4OH, and the solution was 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 substance as a grayish-white amorphous solid.

[0344] Step 3: The product from Step 2 (0.390 mmol, 300 mg, 1.00 equivalent) was dissolved in DCM (5 ml) and cooled to -78°C. Then, phenyl isocyanate (1.0 equivalent, 44 μL mg) was added, and the reaction was stirred for 60 minutes while the temperature was slowly raised to room temperature. After the reaction was confirmed by LCMS analysis, volatiles were removed under N2 flow, and the crude product was purified by C18 reversed-phase rapid chromatography using 0.5% AcOH as a modifier (0 to 100% MeCN in H2O). The fraction containing the desired product was lyophilized to obtain the desired compound in acetate form (184 mg).

[0345] The compound of formula (1-A1b) shown in Table J can be prepared under similar conditions as shown in Example (J-7) above by changing the amine or urea forming agent or starting material used to open the epoxide functional group in the second step and using (alkyl-tula-epx) as the starting material instead of the tylosin epoxide shown in Scheme 5.

[0346] Example H-69 of formula (1-A1) was prepared using an improved scheme 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 derived from the propyl group obtained through a reductive amination reaction with propionaldehyde.

[0347]

[0348]

[0349] 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 anhydrous DMF, and add 2.0 equivalent of p-anisaldehyde (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 complete consumption of the starting material. Then cool the reaction mixture to 0 °C, add 5 mL of saturated NH4Cl solution, and stir 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. The organic compounds were combined, dried over MgSO4 and removed under reduced pressure to obtain crude material, which was purified by reversed-phase chromatography on a C18 column using a gradient elution of 1% AcOH in MeCN and H2O. Fractions containing the desired product were combined, the pH was adjusted to approximately 12 with NH4OH, and extracted three times with 50 mL of DCM to obtain the desired product in free base form (1008 mg, 87%).

[0350] Step 2: 1008 mg of the product from Step 1 (1.18 mmol, 1.00 equivalent) was dissolved in 10 mL of anhydrous EtOH and peracetic acid (32% dilute acetic acid solution; 1.5 equivalent, 304 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. 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 product was extracted three times with DCM, the organic matter was combined, dried over MgSO4, and volatiles were removed under reduced pressure. The crude product was purified by reversed-phase chromatography on a C18 column using a gradient of 1% AcOH in MeCN and H2O. The fractions containing the desired product were combined, the pH was adjusted to approximately 12 with NH4OH, and the product was extracted three times with 50 mL of DCM to obtain the desired product in free base form (250 mg, 25% yield).

[0351] 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). LC-MS showed complete reaction thereafter. Pd / C was filtered off onto diatomaceous earth, and volatiles were removed under reduced pressure to give the desired product (M8 epoxide; M8-epx) as a white powder (195 mg, 91%).

[0352] 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 anhydrous 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, add 1 mL of saturated NH4Cl solution, and stir the solution for 5 minutes. Dilute the reaction mixture with DCM (30 mL and H2O) and transfer it 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, dry with MgSO4, and remove under reduced pressure to obtain the desired product (250 mg) as a white solid with an LCMS purity of approximately 80%, which was used unchanged for subsequent epoxide ring-opening.

[0353] Step 5: In a dry round-bottom flask, dissolve the substance from Step 4 (200 mg, 0.32 mmol, 1.0 equivalence) in anhydrous DCM (5 mL) and add DIPEA (0.141 mL, 2.5 equivalence), followed by N-methyl-N-phenyl-carbamoyl chloride (66 mg, 1.2 equivalence, 0.39 mmol). Stir the mixture overnight, and LCMS analysis thereafter indicates that all the starting material has been consumed. Remove volatiles under N2 flow and purify the crude substance by reversed-phase chromatography on a C18 column using a gradient of 1% AcOH in MeCN and H2O. Combine the fractions containing the desired product, adjust the pH to approximately 12 with NH4OH, and extract three times with 50 mL of DCM to obtain the desired product in free base form (93 mg, 32% yield).

[0354] Step 6: Add the product from Step 2 (93 mg, 0.10 mmol, 1 equivalent) and EtOH (2 mL) to a pressure vessel, followed by N-propylamine (103 μL, 1.25 mmol, 12 equivalents). Stir the reaction mixture at 80 °C for 16 hours. Then concentrate the reaction mixture under vacuum and purify the crude product by reversed-phase chromatography on a C18 column using a gradient of 1% AcOH in MeCN and H₂O. Lyophilize the fraction containing the desired product to obtain the desired product in acetate form as a white solid (35 mg, 33% yield).

[0355] According to this example, the alkyl R on the deoxyglycoamine nitrogen can be changed by replacing propionaldehyde in the fourth step of the sequence with any other alkyl aldehyde (e.g., but not limited to acetaldehyde, isobutyraldehyde, or formaldehyde, such as benzaldehyde or 2-pyridylformaldehyde, etc.). 1 Similar to other examples shown in this paper, in the final step, the epoxide can be ring-opened in an alcohol solvent (e.g., but not limited to, 1-propanol, 1-butanol, or 2-propanol) at a higher temperature using a variety of nucleophiles (e.g., but not limited to primary and secondary amines, alcohols, thiols, cyanides, azides, or halide anions).

[0356] Example H-102 of formula (1-A1) was prepared using an improved scheme 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 last step is 1-propylamine:

[0357]

[0358] Step 1: STAB was added to a solution of tula-epx (1.0 g, 1.34 mmol) in anhydrous DMF (10 mL), and the resulting solution was stirred at 35 °C for 4 hours. After determining the consumption of the starting material by LCMS, the reaction was cooled to 0 °C, 2 mL of saturated NH4Cl solution was added, and the solution was stirred 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 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 substance, which was purified by reversed-phase chromatography on a C18 column using a gradient of 1% AcOH in MeCN and H2O. The fractions containing the desired product were combined, the pH was adjusted to approximately 12 with NH4OH, and extracted three times with 50 mL of DCM to obtain the desired product in the free base form (600 mg, 57% yield).

[0359] Step 2: 600 mg of the product from Step 1 (0.76 mmol, 1.00 equivalent) was dissolved in 10 mL of anhydrous EtOH and peracetic acid (32% dilute acetic acid solution; 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, dried over MgSO4, and removed under reduced pressure to obtain crude N-oxide. The crude N-oxide (0.76 mmol, 1.0 equivalent) was dissolved in 10 mL of anhydrous ethanol and copper(II) sulfate pentahydrate (5.0 equivalent; 950 mg) was added. 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, the organic matter was combined, dried with MgSO4 and volatiles were removed under reduced pressure to obtain the desired crude product with LCMS purity >90%, which was then used as is in the next step.

[0360] Step 3: In a dry round-bottom flask, dissolve the substance from Step 2 (250 mg, 0.32 mmol, 1.0 equivalence) in anhydrous DCM (5 mL) and add DIPEA (0.141 mL, 2.5 equivalence), followed by N-methyl-N-phenyl-carbamoyl chloride (66, 1.2 equivalence, 0.39 mmol). Stir the reaction mixture at room temperature for 16 hours, after which LCMS analysis showed that all starting materials were consumed. Remove volatiles under N2 flow and purify the crude substance by reversed-phase chromatography on a C18 column using a gradient of 1% AcOH in MeCN and H2O. Combine the fractions containing the desired product, adjust the pH to approximately 12 with NH4OH, and extract three times with 50 mL of DCM to obtain the desired product in free base form (150 mg, 51% yield).

[0361] Step 4: Add the product from Step 3 (150 mg, 0.17 mmol, 1 equivalent) and N-propanol (5 mL) to a pressure vessel, followed by N-propylamine (117 μL, 2.0 mmol, 12 equivalents). Stir the reaction mixture at 70 °C for 16 hours. Then concentrate the reaction mixture under vacuum and purify the crude product by reversed-phase chromatography using a C18 column with a gradient of 1% AcOH in MeCN and H2O. Lyophilize the fraction containing the desired product to obtain the desired product in acetate form (90 mg, 53% yield).

[0362] Based on this example, the alkyl R on the core nitrogen can be changed by replacing propionaldehyde in the first step of the sequence with any other alkyl aldehyde (e.g., but not limited to formaldehyde or acetaldehyde). 2 Similar to other examples shown in this paper, in the final step, the epoxide can be ring-opened in an alcohol solvent (e.g., but not limited to, 1-propanol, 1-butanol, or 2-propanol) at a higher temperature using a variety of nucleophiles (e.g., but not limited to primary and secondary amines, alcohols, thiols, cyanides, azides, or halide anions).

[0363] The NMR data for each instance is provided under the corresponding instance table / name.

[0364] Example

[0365] Compound (1) is prepared according to the schemes and procedures defined herein and those known in the art.

[0366] Prepare compounds of formula (1.1) as defined herein; where R 0 It is H and R 1 It is methyl; as shown in Table A. The names of the compounds are provided in the table below.

[0367]

[0368] Table A. Compounds of Formula (1.1)

[0369]

[0370]

[0371] Table A instance name:

[0372] A-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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-(pyrimidin-2-yl)urea;

[0373] A-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)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-(pyrazin-2-yl)urea;

[0374] A-3. 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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-(pyridin-2-yl)urea;

[0375] A-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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-(pyridin-3-yl)urea;

[0376] A-5. 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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-(pyridin-4-yl)urea;

[0377] A-6. 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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-(1-methyl-1H-pyrazol-4-yl)urea;

[0378] A-7. 3-(1,5-dimethyl-1H-pyrazol-3-yl)-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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea;

[0379] A-8. 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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-3-(2-methoxyphenyl)-1-methylurea;

[0380] A-9. 3-(4-cyanophenyl)-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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea;

[0381] A-10. 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-(3-(trifluoromethyl)phenyl)urea;

[0382] A-11. 3-(3-cyanophenyl)-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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea;

[0383] A-12. 3-(2-chlorophenyl)-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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea;

[0384] A-13. 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-phenylurea;

[0385] A-14. 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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-(o-tolyl)urea;

[0386] A-15. 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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-(4-(trifluoromethyl)phenyl)urea;

[0387] A-16. 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-(2-(trifluoromethyl)phenyl)urea;

[0388] A-17. 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-3-(2-fluorophenyl)-1-methylurea;

[0389] A-18. 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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-3-(4-fluorophenyl)-1-methylurea;

[0390] A-19. 3-(4-chlorophenyl)-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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea;

[0391] A-20. 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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-3-(3-fluorophenyl)-1-methylurea;

[0392] A-21. 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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-3-(3-methoxyphenyl)-1-methylurea;

[0393] A-22. 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-3-(4-methoxyphenyl)-1-methylurea;

[0394] A-23. 3-(3-chlorophenyl)-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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea;

[0395] A-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)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-(p-tolyl)urea;

[0396] A-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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-(m-tolyl)urea; and

[0397] A-26. 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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea.

[0398] Table A Example NMR

[0399]

[0400]

[0401]

[0402] Compounds of formula (1-A0) below were prepared according to the scheme and procedure defined herein, wherein R 1It is a methyl group; as shown in Table B. The names of the compounds are provided in the table below. Examples B-1a, B-2a, B-3a, and B-13a are stereoisomers of B-1, B-2, B-3, and B-13, respectively (i.e., in R...). a The diastereomer of the hydroxyl group at the α-carbon (5R instead of 5S)

[0403]

[0404] Table B. Compounds of Formula (1-A0)

[0405]

[0406] *MIC ≤ 64 μg / mL for at least one BRD strain

[0407] Table B instance name:

[0408] B-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-4,5,6-trimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;

[0409] B-1a.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,5R,6S)-5-hydroxy-4-methoxy-4,5,6-trimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;

[0410] B-2. 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-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(4-(trifluoromethyl)phenyl)urea;

[0411] B-2a.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,5R,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(4-(trifluoromethyl)phenyl)urea;

[0412] B-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-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;

[0413] B-3a.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,5R,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;

[0414] B-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-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-phenylurea;

[0415] B-5. 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-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;

[0416] B-6. 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-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(4-(trifluoromethyl)phenyl)urea;

[0417] B-7. 3-(4-(dimethylamino)phenyl)-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-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea;

[0418] B-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-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-(4-(trifluoromethyl)phenyl)urea;

[0419] B-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-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-3-(4-fluorophenyl)-1-methylurea;

[0420] B-10. 3-Cyclohexyl-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-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea;

[0421] B-11. 3-(tert-butyl)-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-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea;

[0422] B-12. 3-(4-cyanophenyl)-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-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea;

[0423] B-13. 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-4,5,6-trimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(4-(trifluoromethyl)phenyl)urea;

[0424] B-13a.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,5R,6S)-5-hydroxy-4-methoxy-4,5,6-trimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(4-(trifluoromethyl)phenyl)urea;

[0425] B-14. 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-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-6-propyl-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(4-(trifluoromethyl)phenyl)urea (964); and

[0426] B-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-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-6-propyl-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea (896).

[0427] Table B Example NMR

[0428]

[0429]

[0430]

[0431] ^acetate

[0432] Compounds of formula (1-A2) below were prepared according to the schemes and procedures defined herein; and wherein R 0 It is H, R 1 It is methyl and R 7 It is ethyl; provided in Table C. The names of the compounds are provided in the table below.

[0433]

[0434] Table C. Compounds of Formula (1-A2)

[0435]

[0436] Table C instance name:

[0437] C-1. 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(ethoxymethyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-phenylurea;

[0438] C-2. 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(ethoxymethyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea; and

[0439] C-3. 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(ethoxymethyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(4-(trifluoromethyl)phenyl)urea.

[0440] Table C Example NMR

[0441]

[0442] ^acetate

[0443] Compounds of formula (1-A3) below were prepared according to the schemes and procedures defined herein; wherein R 0 It is H, R 1 It is methyl and R 7 It is propyl; as shown in Table D. The names of the compounds are provided in the table below.

[0444]

[0445] Table D. Compounds of Formula (1-A3)

[0446]

[0447] *MIC ≤ 64 μg / mL for at least one BRD strain

[0448] Table D instance name:

[0449] D-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-((propylthio)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-phenylurea;

[0450] D-2. 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-((propylthio)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea; and

[0451] D-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-((propylthio)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(4-(trifluoromethyl)phenyl)urea.

[0452] Table D Example NMR

[0453]

[0454]

[0455] ^acetate

[0456] Compounds of formula (1–A4) below were prepared according to the schemes and procedures defined herein; wherein R 0 It is H, R 1 X' is methyl and X' is chlorine; as shown in Table E. The names of the compounds are provided in the table below.

[0457]

[0458] Table E. Compounds of Formula (1-A4)

[0459]

[0460] Table E instance name:

[0461] E-1. 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(chloromethyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-phenylurea;

[0462] E-2. 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(chloromethyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea; and

[0463] E-3.1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(chloromethyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-(4-(trifluoromethyl)phenyl)urea.

[0464] Table E Example NMR

[0465]

[0466] ^acetate

[0467] The following compounds (1–A5) were prepared according to the schemes and procedures defined herein; wherein R 0 It is H and R 1 It is methyl; as shown in Table F. The names of the compounds are provided in the table below.

[0468]

[0469] Table F. Compounds of Formula (1-A5)

[0470]

[0471] *MIC ≤ 64 μg / mL for at least one BRD strain

[0472] Table F instance name:

[0473] F-1. 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(azidomethyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-phenylurea;

[0474] F-2. 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(azidomethyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea; and

[0475] F-3. 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(azidomethyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(4-(trifluoromethyl)phenyl)urea.

[0476] Table F Example NMR

[0477]

[0478]

[0479] Compounds of formula (1–A6) below were prepared according to the schemes and procedures defined herein; wherein R 0 It is H and R 1 It is methyl; as shown in Table G. The names of the compounds are provided in the table below.

[0480]

[0481] Table G. Compounds of Formula (1-A6)

[0482]

[0483] Table G instance name:

[0484] G-1. 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(cyanomethyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-phenylurea;

[0485] G-2. 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(cyanomethyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea; and

[0486] G-3. 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(cyanomethyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(4-(trifluoromethyl)phenyl)urea.

[0487] Table G Example NMR

[0488]

[0489] ^acetate

[0490] Compounds of formula (1-A1) below were prepared using the schemes and procedures defined herein; R 0 It is H, methyl, or propyl, as defined in Table H. Compound Names (mass [M+H]) + The following table provides the information.

[0491]

[0492] Table H. Compounds of formula (1-A1-1)

[0493]

[0494]

[0495]

[0496]

[0497]

[0498] *MIC ≤ 64 μg / mL for at least one BRD strain

[0499] Table H instance name:

[0500] H-1.3-Cyclopropyl

[0501] -1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-((3-cyclopropyl-1-(2-morpholinoethyl)ureoyl)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea(1029);

[0502] H-2. 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-((dimethylamino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-phenylurea (897);

[0503] H-3.

[0504] 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(((2-(dimethylamino)ethyl)amino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-phenylurea (940);

[0505] H-4. 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-((diethylamino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-phenylurea (925);

[0506] H-5. 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(((2-(dimethylamino)ethyl)amino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-propylurea (906);

[0507] H-6.3-(2-(dimethylamino)ethyl)-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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea (906);

[0508] H-7. 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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-(2-(piperidin-1-yl)ethyl)urea (946);

[0509] H-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)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-3-methyl-1-propyl-3-(4-(trifluoromethyl)phenyl)urea (1021);

[0510] H-9. 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(((2-(dimethylamino)ethyl)(propyl)amino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea (878);

[0511] H-10. 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-13-(((2R,4R,5S,6S)-5-((3-(4-fluorophenyl)-1-propylurea)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-3-(4-fluorophenyl)-1-methylurea (1066);

[0512] H-11. 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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea (925);

[0513] H-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-((1-propyl-3-(4-(trifluoromethyl)phenyl)ureoyl)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-(4-(trifluoromethyl)phenyl)urea (1166);

[0514] H-13. 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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(4-(trifluoromethyl)phenyl)urea (993);

[0515] H-14. 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)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-3-methyl-1-phenylurea (951);

[0516] H-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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-(pyridin-2-yl)urea (913);

[0517] H-16. 1-Ethyl-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)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-3-methyl-1-phenylurea (939);

[0518] H-17. 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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-3-isopropyl-1-methyl-3-phenylurea (953);

[0519] H-18. 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-5-(((2-methoxyethyl)amino)methyl)-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea (941);

[0520] H-19. 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-5-(((3-methoxypropyl)amino)methyl)-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea (955);

[0521] H-20. 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(((2-(dimethylamino)ethyl)amino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea (968);

[0522] H-21. 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12...

Claims

1. Compounds of formula (1-A1), R 0 It is H or methyl; R 1 It is methyl; R 2 It can be H, methyl, ethyl, isopropyl, cyclopropyl, -CF3, -CHF2, -CH2F, -CH2CF3 or phenyl; R 3 The R is H, methyl, ethyl, propyl, isopropyl, tert-butyl, -CH2N(CH3)2, CH2CH2N(CH3)2; or cyclopropyl, cyclobutyl, phenyl, C1 alkylphenyl, piperidinyl, C1 alkylpiperidinyl, C2 alkylpiperidinyl, piperazine, morpholinyl, tetrahydro-2H-pyran, pyrazolyl, or pyridinyl, each optionally selected from at least one R of methyl, ethyl, hydroxy, methoxy, ethoxy, F, Cl, cyano, amino, N(CH3)2, and -CF3. 9 Substituent substitution; Or R 2 and R 3 Together with the nitrogen atoms to which they are attached, they form a ring A, which is pyrroloyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally selected from at least one R group selected from methyl, ethyl, F, Cl, oxo, and CF3. 10 Substituent substitution; R 5 It can be H, C1-C6 alkyl, morpholino, piperidinyl, -CH2morpholino, -CH2piperidinyl, -(CH2)2morpholino, or -(CH2)2piperidinyl; R 6 The following are possible values: H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, -CH2CF3, -CF3, or -OCF3; or R 6 -C(O)NR a R 8 , where R a H or methyl, R 8 It is H, methyl, cyclopropyl, or a phenyl group optionally substituted with F, Cl, or -CF3; or R 6 -(CH2)S(O)2R 8 , where R 8 It is methyl or phenyl; or R 6 -CH2NR a R b or -(CH2)2NR a R b , where R a and R b Each can be independently H or methyl; or R 6 For -(CH2)2OCH3, -(CH2)3OCH3; or R 6 The derivatives are phenyl, C1 alkylphenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C1-C2 alkylcyclopropyl, C1-C2 alkylcyclobutyl, pyrrolyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, C1-C2 alkylpyrrolyl, C1-C2 alkylpiperidinyl, C1-C2 alkylpiperazinyl, C1-C2 alkylmorpholinyl, C1-C2 alkyltetrahydropyranyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, C1-C2 alkylpyrazolyl, C1-C2 alkylimidazolyl, C1-C2 alkylpyridinyl, C1-C2 alkylpyrimidinyl, and C1-C2 alkylpyrazinyl; each optionally containing at least one R 10 Substituent substitution, R 10 The substituents are each independently selected from methyl, ethyl, methoxy, ethoxy, -CHF2, -CF3, -OCF3, F, Cl, amino, -NHCH3, -N(CH3)2, -S(O)2CH3, cyano, and hydroxyl; Or R 5 and R 6 Together with the nitrogen atoms to which they are attached, they form a ring B, which is pyrroloyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each optionally selected from at least one R group selected from methyl, ethyl, F, Cl, cyano, hydroxyl, oxo, and -CF3. 9 Substituent substitution; or ring B is indolanyl, isoindolanyl, tetrahydroquinolinyl, dihydrobenzoxazinyl or dihydrobenzothiazinyl, which are optionally substituted with at least one oxo group; And its pharmaceutically acceptable salts.

2. The compound according to claim 1, wherein... R 2 It is H, methyl, ethyl, or isopropyl; R 5 It is H, methyl, ethyl, propyl, or isopropyl; And its pharmaceutically acceptable salts.

3. The compound according to claim 1, wherein the compound is selected from the group consisting of: 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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea; 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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(4-(trifluoromethyl)phenyl)urea; 1-Ethyl-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)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-3-methyl-1-phenylurea; 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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-3-isopropyl-1-methyl-3-phenylurea; 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-((methylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea; 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-((butylamino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea; 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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(pyridin-2-yl)urea; 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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(pyrazin-2-yl)urea; 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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(pyridazin-3-yl)urea; 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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(pyrimidin-2-yl)urea; 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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(pyrimidin-5-yl)urea; 1-(5-chloropyrimidin-2-yl)-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)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethylurea; 1-(5-Cyclopropylpyrimidin-2-yl)-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)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethylurea; 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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(pyridin-3-yl)urea; 1-(2,6-Dimethylpyrimidin-4-yl)-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)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethylurea; 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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(pyridin-4-yl)urea; 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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(3-methylpyridin-4-yl)urea; 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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-3-methyl-3-phenyl-1-propylurea; 3-(4-cyanophenyl)-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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea; 3-(3-cyanophenyl)-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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea; 3-(2-Chlorophenyl)-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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea; 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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-(o-tolyl)urea; 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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-3-(2-fluorophenyl)-1-methylurea; 3-(4-Chlorophenyl)-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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea; 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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-3-(3-fluorophenyl)-1-methylurea; 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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-3-(3-methoxyphenyl)-1-methylurea; 3-(3-Chlorophenyl)-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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea; 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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-phenylurea; 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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethylurea; 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-((cyclopropylamino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-propylurea; 1-((2S,3R,4S,6R)-2-(((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-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-propylurea; 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-(((4-(trifluoromethyl)phenyl)amino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-propylurea; 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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea; 3-(2-(dimethylamino)ethyl)-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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea; 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)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(4-(trifluoromethyl)phenyl)urea; and 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)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea; And its pharmaceutically acceptable salts.

4. The compound according to claim 3, wherein the compound is 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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea; or 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-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-phenylurea (H-91); And its pharmaceutically acceptable salts.

5. Compounds of formula (1-A2), formula (1-A3), formula (1-A4), formula (1-A5), or formula (1-A6), in: X' is Cl; R 0 It is H; R 1 It is methyl; R 2 It is H or methyl; R 3 It is a phenyl group, optionally substituted with at least one substituent selected from the group consisting of F, Cl, and -CF3; and R 7 It is methyl, ethyl, or propyl; And its pharmaceutically acceptable salts.

6. The compound according to claim 5, wherein the compound is: Compounds of formula (1-A2) are selected from 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(ethoxymethyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15 -oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-phenylurea; 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(ethoxymethyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-4-yl) 1-((2S,3R,4S,6R)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea; or 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13 -(((2R,4R,5S,6S)-5-(ethoxymethyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(4-(trifluoromethyl)phenyl)urea; The compound of formula (1-A3) is 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-((propylthio)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl- 3-Phenylurea; or 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-((propylthio)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenyllurea; Compound of formula (1-A4) is 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(chloromethyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl- 15-Oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-phenylurea; 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(chloromethyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H -pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea; or 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R) -13-(((2R,4R,5S,6S)-5-(chloromethyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-(4-(trifluoromethyl)phenyl)urea; Compound of formula (1-A5) is 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(azidomethyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl- 15-Oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-phenylurea; 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(azidomethyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H- pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea; or 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13 -(((2R,4R,5S,6S)-5-(azidomethyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(4-(trifluoromethyl)phenyl)urea; or Compound of formula (1-A6) is 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(cyanomethyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl- 15-Oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-3-phenylurea; 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(cyanomethyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H- pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea; or 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-1 3-(((2R,4R,5S,6S)-5-(cyanomethyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-(4-(trifluoromethyl)phenyl)urea; And its pharmaceutically acceptable salts.

7. The compound of formula (1-A1) according to claim 1, wherein it is a compound of formula (1-A1a). in R 5 It is H, methyl, ethyl, propyl, or isopropyl; And its pharmaceutically acceptable salts.

8. The compound of formula (1-A1) according to claim 1, wherein it is a compound of formula (1-A1b). in R 2 It is H or methyl; R 3 It is methyl, ethyl, or propyl; or cyclopropyl, cyclobutyl, phenyl, C1 alkylphenyl, piperidinyl, C1 alkylpiperidinyl, piperazine, morpholinyl, or pyridinyl, and wherein each ring is optionally composed of at least one R selected from the group consisting of methyl, ethyl, methoxy, ethoxy, F, Cl, cyano, -N(CH3)2, and -CF3. 9 Substituent substitution; And its pharmaceutically acceptable salts.

9. A composition comprising the compound according to any one of claims 1-8, wherein the composition further comprises a pharmaceutically acceptable carrier.

10. Use of the compound according to any one of claims 1-8 in the preparation of a medicament for treating or preventing inflammatory responses in animals.

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