RU2811591C1 - Immunomodulatory azalides based on urea - Google Patents

Abstract

FIELD: chemistry and pharmaceuticals.

SUBSTANCE: immunomodulatory compounds of formula (1), its stereoisomers and its pharmaceutically acceptable salts and a method for treating or preventing an inflammatory response using them. In the general formula (1), W represents H or formula (A), where X represents -R^a, -R^cNR⁵R⁶, -R^cOR⁷, -R^cSR⁷, -R^cN₃, -R^cCN or -R^cX'; X' is F, Cl, I or Br; R represents H; each of R^a, R^b, R⁰ and R¹ independently represents H or C₁-C₆ alkyl; or R¹ represents benzyl, optionally substituted with methoxy; or R¹ represents -CH₂Het, where Het represents a 5-6 membered heteroaryl ring containing at least one heteroatom selected from N, S and O; and wherein the heteroaryl ring is optionally substituted with at least one R⁹ substituent; each of R² and R³ independently represents H, C₁-C₆ alkyl, R^cNR^aR^b, C₀-C₃ alkyl, С₃-C₆ cycloalkyl, C₀-C₃ alkylaryl, C₀-C₃ alkyl heterocycle, where the heterocycle is a 5-6 membered saturated heterocyclic ring; or C₀-C₃ alkylheteroaryl, where heteroaryl represents a 5-6 membered heteroaryl ring; wherein each of the heterocyclic ring and the heteroaryl ring contains at least one heteroatom selected from N and O; and wherein each of the cycloalkyl, aryl, heterocyclic and heteroaryl rings is optionally substituted with at least one R⁹ substituent; or R² and R³ together with the nitrogen atom to which they are attached form ring A, a 4-8 membered heterocyclic ring optionally containing at least one additional heteroatom selected from N, O and S; each ring is optionally substituted with at least one R¹⁰ substituent; and wherein each ring is optionally fused with Y. The remaining meanings of the radicals are indicated in the claims.

EFFECT: immunomodulary compounds are proposed.

14 cl, 10 dwg, 11 tbl

Description

TECHNICAL FIELD OF THE INVENTION

Anti-inflammatory and immunomodulatory compounds are identified herein; non-antibacterial anti-inflammatory and immunomodulatory compounds; their stereoisomers and pharmaceutically acceptable salts. The present invention includes corresponding compounds with a 13-membered macrolide ring that are in equilibrium with compounds with a 15-membered macrolide ring. The invention also includes pharmaceutical compositions containing a compound of the invention and methods for treating an inflammatory and/or immunological disease or disorder in an animal. The compounds of the invention are azalides.

BACKGROUND OF THE INVENTION

Macrolides are antibacterial compounds that consist of a large macrocyclic lactone ring containing 12-16 atoms that are attached via glycosidic bonds to at least one or two deoxysugars. Azalides are a class of macrolides in which the lactone ring contains a nitrogen atom. Draxin® is a semi-synthetic macrolide (azalide) antibiotic, which is sold as a ready-to-use sterile preparation containing tulathromycin. This drug consists of a balanced mixture of two isomeric forms of tulathromycin in a 9:1 ratio (Tula-A:Tula-B). Tula-A is a 15-membered lactone ring structure, whereas Tula-B is a 13-membered lactone ring structure. Equilibrium depends on pH and time. Tulathromycin is marketed for use in bovine respiratory disease (BRD) and porcine respiratory disease (PRD) under the trade name Draxin®.

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. In most cases they are bacteriostatic and may be bactericidal against some pathogens. Their activity against Gram-negative RBD pathogens and ability to concentrate in lung tissue make them excellent therapeutic agents. They are the first-line treatment for RCD and are also used to treat respiratory infections in humans.

Known macrolide antibiotics include, for example, erythromycin, tilmicosin, azithromycin, clarithromycin, gamithromycin, fidaxomicin, roxithromycin, tulathromycin and others. In addition, some macrolides have been shown to have anti-inflammatory and immunomodulatory properties. For example, azithromycin, a broad-spectrum antibiotic, suppresses interleukin 12p40 expression in macrophages stimulated with lipopolysaccharide (LPS) and interferon-gamma and attenuates LPS-induced induction of CXCL8 (IL-8) and GM-CSF from primary bronchial epithelial cells; and in epithelial cells, interactions with phospholipids and Erk1/2 are accompanied by down-regulation of transcription factors AP-1, NFκB, inflammatory cytokines and mucin released after LPS stimulation. US2016-0031925 describes certain azithromycin analogues that are immunomodulatory but have been modified to reduce or eliminate the antibiotic effect. Clarithromycin has an immunomodulatory effect on ERJ-mediated inflammation induced by Pseudomonas aeruginosa flagellin. Erythromycin inhibits the expression of interleukin-6 and interleukin-8 and stimulates apoptosis of activated human neutrophils in vitro. Tilmicosin modulates COX-2 and iNOS gene expression and cytokine production in LPS-stimulated macrophages and monocytes. Roxithromycin reduces Th2 chemokine production by keratinocytes and chemokine receptor expression on Th2 cells. Tulathromycin stimulates apoptosis and down-regulates pro-inflammatory mediators such as leukotriene B4 and CXCL8; and also induces the production of the anti-inflammatory and pro-resolving lipid lipoxin A4. Research data demonstrate that these antibacterial macrolides modulate certain excess immune responses, which in turn translate into certain anti-inflammatory beneficial effects.

Inflammatory and proinflammatory mediators negatively impact productivity in the meat and dairy industry by impairing growth, food and water intake, reproduction, milk yield, and metabolic health. The increase in the clinical use of macrolide antibiotics is associated with an increase in resistance to macrolides among pneumococci and resistance of RKRS pathogens. Recently, concerns have been raised by government agencies around the world and the public about the use of antibiotics in food-producing animals (e.g., cattle and pigs), with concerns that this may lead to cross-resistance with human pathogens. Bovine respiratory disease (BRD) remains a major problem in modern livestock production, making sound management vital to both animal welfare and human food safety. It is known that Mannheimia haemolytica is the main bacterium isolated during respiratory disease of grazing livestock, and is an essential component of enzootic pneumonia in newborn calves. One of the hallmarks of RBD is the increased inflammatory response of the host, which promotes progression to full RBD complex. Inhibiting or reversing inflammation in the host has the potential to prevent or control the development of RBD in cattle, as well as other inflammatory diseases and disorders in animals. Therefore, there is an unmet need to develop a new anti-inflammatory and immunomodulatory agent that lacks the antibacterial effects of known macrolides. The compounds of the invention have been shown to be non-antibacterial against many bacterial species and to have 5-20 times greater immunomodulatory activity at lower dosages than existing macrolides (eg, azithromycin, erythromycin and tulathromycin). Therefore, these compounds can be used to control or prevent the onset of bacterial infection or viral infection through the inflammatory and/or immune response due to a stressful event or other environmental factor(s), thereby preventing or attenuating the development of the pathobiological cascade in full complex of the disease. The compounds of the invention provided herein are non-antibiotic, anti-inflammatory immunomodulatory macrolides for reducing inflammatory conditions in animals with the potential to reduce the use of antibiotics in animals.

SUMMARY OF THE INVENTION

In one aspect of the invention there is provided an anti-inflammatory and immunomodulatory azalide compound of formula (1); or a non-antibiotic, anti-inflammatory and immunomodulatory azalide compound of formula (1); its stereoisomers and its pharmaceutically acceptable salts,

where W represents H or formula (A)

where X is -R ^a , -R ^c NR ⁵ R ⁶ , -R ^c OR ⁷ , -R ^c SR ⁷ , -R ^c N ³ , -R ^c CN or -R ^c X';

X' represents F, Cl, I or Br;

R represents H, C ₁ -C ₃ alkyl, -C(O)NR ^a R ^d or -C(O)OR ⁸ ;

each of R ^a , R ^b , R ⁰ and R ¹ independently represents H or C ₁ -C ₆ alkyl;

or R ¹ is benzyl, regardless of R ⁹ ;

or R ¹ represents -CH ₂ Het, where Het represents a 5-6 membered heteroaryl ring containing at least one heteroatom selected from N, S and O; and wherein the heteroaryl ring is optionally substituted with at least one R ⁹ substituent;

R ^c represents C ₁ -C ₄ alkyl;

R ^d represents H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or phenyl, optionally substituted with C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, halogen, cyano, hydroxy, amino, -NHCH ₃ , -N(CH ₃ ) ₂ , C ₁ -C ₃ haloalkyl or C ₁ -C ₃ haloalkoxy;

each of R ² and R ³ independently represents H, C ₁ -C ₆ alkyl, R ^c NR ^a R ^b , C ₀ -C ₃ alkyl, _{C 3} -C ₆ cycloalkyl, C ₀ -C ₃ alkylaryl, C ₀ -C ₃ an alkyl heterocycle, where the heterocycle is a 5-6 membered saturated or partially saturated heterocyclic ring; or C ₀ -C ₃ alkylheteroaryl, where heteroaryl represents a 5-6 membered heteroaryl ring; wherein each of the heterocyclic ring and the heteroaryl ring contains at least one heteroatom selected from N, O and S; and wherein each of the cycloalkyl, aryl, heterocyclic and heteroaryl rings is optionally substituted with at least one R ⁹ substituent;

or R ² and R ³ together with the nitrogen atom to which they are attached form a ring A, a 4-8 membered heterocyclic ring or a 5-membered heteroaryl ring, each of which optionally contains at least one additional heteroatom selected from N, O and S; each ring is optionally substituted with at least one R ¹⁰ substituent; and wherein each ring is optionally fused to Y;

each of R ⁵ and R ⁶ is independently selected from H; C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy, each of which is optionally substituted with at least one hydroxy; or cyano, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, -C(O)R ⁸ , -C(O)NR ^a R ⁸ , -C(O)R ^c NR ^a R ^b , -C( O)OR ^c R ⁸ , -C(O)ONR ^a R ^b , -R ^c NR ^a C(O)R ⁸ , -R ^c C(O)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 C ₀ -C ₄ alkylaryl, C ₀ -C ₄ alkylC ₃ -C ₆ cycloalkyl, C ₀ -C ₄ alkylheterocycle or C ₀ -C ₄ alkylheteroaryl, wherein each of the heterocyclic and heteroaryl rings is a 5-6-membered monocyclic a ring or a 9-10 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 rings are optionally substituted with at least one R ¹⁰ substituent;

or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a ring B, a 4-8 membered heterocyclic ring or a 5-membered heteroaryl ring, each of which optionally contains at least one additional heteroatom selected from N, O and S; each ring is optionally substituted with at least one R ⁹ substituent; and wherein each ring is optionally fused to Y; R ⁷ represents H, C ₁ -C ₆ alkyl, -R ^c NR ^a R ^b , -R ^c OR ^a , -R ^c S(O)PR ^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 ;

R ⁸ represents C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₀ -C ₄ alkyl, _{C 3} -C ₆ cycloalkyl, -NR ^a R ^b , phenyl, a 5-6 membered heterocyclic ring containing at least one heteroatom selected from N, O and S, or a 5-6 membered heteroaryl ring containing at least one heteroatom selected from N, O and S; and wherein each of cycloalkyl, phenyl, heterocycle and heteroaryl is optionally substituted with at least one substituent selected from C ₁ -C ₄ alkyl, halogen, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkyl and C ₁ -C ₄ haloalkoxy;

R ⁹ is independently selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₀ -C ₄ alkyl, _{C 3} -C ₆ cycloalkyl, halogen, oxo, hydroxy, cyano, -NR ^a R ^b , C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, -S(O) _p R ⁸ , phenyl and a 5-6 membered monocyclic heterocyclic or heteroaryl ring, each of which contains at least one heteroatom selected from the group consisting from N, O and S;

R ¹⁰ is independently selected from the group consisting of C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkyl, C 1 -C ₃ haloalkoxy, _{C 0 -C 4} alkyl, C _{3 -C 6} cycloalkyl, halogen , -NR ^a R ^b , -S(O) _p R ⁸ , nitro, oxo, 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 , hydroxy, 5-6 membered heterocyclic ring, 5-6 membered heteroaryl ring, 9-10 membered fused heteroaryl ring, wherein each of the heterocyclic and heteroaryl rings contains at least one heteroatom selected from the group consisting of N, O and S; and phenyl; and wherein each of the phenyl, heterocyclic and heteroaryl rings is optionally substituted with at least one R ⁹ substituent;

Y is phenyl, pyridinyl, pyrimidyl, pyrazonyl, thienyl, thiazolyl, triazolyl, isothiazolyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl, furanyl, indolyl, benzothienyl or naphthyl;

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

In another aspect, there is provided a composition containing a compound of formula (1), stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect, the composition further comprises a pharmaceutically acceptable carrier.

In another aspect, a method is provided for treating or preventing an inflammatory response in an animal by administering to said animal in need thereof a therapeutically effective amount of a compound of formula (1), stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect of the method, the inflammatory response occurs due to a bacterial, viral or fungal infection, stress and/or environmental factor. In another aspect of the method, a method of treating or preventing an inflammatory response in an animal prevents or reduces the progression of a respiratory disease or disorder. In another aspect of the method, the animal is a farm animal. In another aspect of the method, the respiratory disease or disorder is bovine respiratory disease or porcine respiratory disease. In another aspect of the method, a method of treating or preventing an inflammatory response in an animal provides down-regulation of TNFα and IL-6 in the animal.

Another aspect provides the use of a compound of formula (1), stereoisomers thereof, and pharmaceutically acceptable salts thereof for the manufacture of a medicament for treating or preventing an inflammatory response in an animal, wherein the inflammatory response is due to a bacterial, viral or fungal infection, stress, and/or environmental factor. environment. In another aspect of use, the use of a medicament to treat and/or prevent an inflammatory response in an animal prevents or reduces the progression of a respiratory disease or disorder. In another aspect of application, the animal is a farm animal. In another aspect of use, the respiratory disease or disorder is bovine respiratory disease or porcine respiratory disease. In another aspect of use, administering a drug to an animal to treat or prevent an inflammatory response in the animal provides down-regulation of TNFα and IL-6 in the animal.

In another aspect of the invention, R ^a and R ^b are each independently H, methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl or tert-butyl. In another aspect, R ^a and R ^b are each independently H, methyl, ethyl, propyl or isopropyl. In another aspect, R ^a and R ^b are each independently H, methyl, ethyl or propyl. In another aspect, R ^a and R ^b are each independently H or methyl.

In another aspect of the invention, R ^c is methyl, ethyl, propyl, isopropyl, n-butyl or tert-butyl. In another aspect of the invention, R ^c is methyl, ethyl, propyl, isopropyl or tert-butyl. In another aspect of the invention, R ^c is methyl, ethyl, propyl or isopropyl. In another aspect of the invention, R ^c is methyl, ethyl or propyl. In another aspect, R ^c is methyl. In another aspect, R ^c is ethyl. In another aspect, R ^c is a cut.

In another aspect of the invention, R ^d is C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or phenyl, optionally substituted with C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, halogen, cyano, hydroxy, amino, -NHCH ₃ , -N(CH ₃ ) ₂ , C ₁ -C ₃ haloalkyl or C ₁ -C ₃ haloalkoxy. In another aspect, R ^d is C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or phenyl, optionally substituted with C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, halogen, cyano, hydroxy, amino, -NHCH ₃ , -N(CH ₃ ) ₂ , -CF ₃ or -OCF ₃ . In another aspect, R ^d is methyl, ethyl, cyclopropyl, cyclobutyl or phenyl, optionally substituted with methyl, ethyl, methoxy, ethoxy, F, Cl, cyano, hydroxy, amino, -NHCH ₃ , -N(CH ₃ ) ₂ , - CHF ₂ , -CF ₃ or -OCF ₃ . In another aspect, R ^d is methyl, ethyl or phenyl, optionally substituted with methyl, ethyl, methoxy, ethoxy, F, Cl, cyano, hydroxy, amino, -NHCH ₃ , -N(CH ₃ ) ₂ , -CHF ₂ , - CF ₃ or -OCF ₃ .

In another aspect of the invention, R ⁰ and R ¹ are each independently H, methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl or t-butyl; or R ¹ is benzyl, -CH ₂ pyridine, -CH ₂ pyrimidine, -CH ₂ pyridazine, -CH ₂ pyrazine, -CH ₂ pyrrole, -CH ₂ furan, -CH ₂ thiophene, -CH ₂ pyrazole, -CH ₂ imidazole, -CH ₂ -triazole, -CH ₂ tetrazole, -CH ₂ oxazole, -CH ₂ isoxazole, -CH ₂ thiazole, -CH ₂ isothiazole or -CH ₂ oxadiazole, each of which is optionally substituted with at least one R ⁹ substituent selected from methyl, ethyl, propyl, methoxy, ethoxy, F, O, oxo, hydroxy, cyano, -NR ^a R ^b , -CF ₃ and -OCF ₃ . In another aspect, R ⁰ and R ¹ are each independently H, methyl, ethyl, propyl or isopropyl; or R ¹ is benzyl, -CH ₂ pyridine, -CH ₂ pyrimidine _, -CH ₂ pyrazole, -CH ₂ imidazole, -CH 2 -triazole, -CH ₂ tetrazole, -CH ₂ oxazole, -CH ₂ isoxazole, -CH ₂ thiazole, -CH ₂ isothiazole or -CH ₂ oxadiazole, each of which is optionally substituted with at least one R ⁹ substituent selected from methyl, ethyl, propyl, methoxy, ethoxy, F, O, hydroxy, cyano, -NH ₂ , -CF ₃ and -OCF ₃ . In another aspect, R ⁰ represents H, methyl, ethyl or propyl; R ¹ represents methyl, ethyl, propyl, isopropyl; or R ¹ is benzyl, -CH ₂ pyridine, -CH ₂ pyrimidine, -CH ₂ pyrazole or -CH ₂ imidazole, each of which is optionally substituted with at least one R ⁹ substituent selected from methyl, ethyl, label, ethoxy, F, Cl, hydroxy, -CF ₃ and -OCF ₃ . In another aspect, R ⁰ represents H, methyl, ethyl or propyl; a R ¹ is methyl, ethyl, propyl or isopropyl. In another aspect, R ⁰ represents H or methyl; a R ¹ is methyl, ethyl, propyl or isopropyl. In another aspect, R ⁰ is H or methyl and R ¹ is methyl.

In another aspect of the invention, R ² and R ³ are each independently H, C ₁ -C ₆ alkyl, R ^c NR ^a R ^b , C ₀ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, C ₀ -C ₃ alkylphenyl, C ₀ -C ₃ alkylheterocycle or C ₀ -C ₃ alkylheteroaryl; wherein the heterocyclic moiety is pyrrolidinyl, piperadinyl, piperazinyl, tetrahydropyran, morpholinyl or thiomorpholinyl; and wherein the heteroaryl moiety is pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazolyl, tetrazolyl or 6,7-dihydro-5H-cyclopenta[d]pyrimidine; and wherein each of the cycloalkyl, phenyl, heterocyclic and heteroaryl rings is optionally substituted with at least one R ⁹ substituent selected from the group consisting of C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, hydroxy, halogen, cyclopropyl, cyclobutyl , cyano, amino, -NHCH ₃ , -N(CH ₃ ) ₂ , C ₁ -C ₃ haloalkyl and C ₁ -C ₃ haloalkoxy. In another aspect of the invention, R ² and R ³ are each independently H, C ₁ -C ₆ alkyl, -CH ₂ N(CH ₃ ) ₂ , -CH ₂ CH ₂ N(CH ₃ ) ₂ ; or C ₀ -C ₂ cyclopropyl, C ₀ -C ₂ cyclobutyl, C ₀ -C ₂ cyclopentyl, C 0 -C ₂ cyclohexyl, C ₀ -C ₂ phenyl, C _{0 -C 2} piperadinyl, piperazinyl, morpholinyl, tetrahydropyran, pyrrolyl , pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl, each of which is optionally substituted with at least one R ⁹ substituent selected from the group consisting of methyl, ethyl, propyl, isopropyl, tert-butyl, hydroxy, methoxy, ethoxy, F, Cl, Br, cyano, amino, -N(CH ₃ ) ₂ , -CHF ₂ , -CF ₃ , -OCHF ₂ and -OCF ₃ . In another aspect of the invention, R ² and R ³ are each independently H, C ₁ -C ₆ alkyl; -CH ₂ N(CH ₃ ) ₂ , -CH ₂ CH ₂ N(CH ₃ ) ₂ ; or cyclopropyl, C ₁ cyclopropyl, cyclobutyl, C 1 cyclobutyl, cyclopentyl, C ₁ cyclopentyl, cyclohexyl, C ₁ cyclohexyl, phenyl, _{C 1 phenyl} , piperadinyl, C ₁ -piperadinyl, C ₂ piperadinyl, piperazinyl, morpholinyl, tetrahydropyran, pyrrolyl, pyrazolyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl, each of which is optionally substituted with at least one R ⁹ substituent selected from the group consisting of methyl, ethyl, propyl, isopropyl, tert-butyl, hydroxy, methoxy, ethoxy, F , Cl, Br, cyano, amino, -N(CH ₃ ) ₂ , -CHF ₂ , -CF ₃ , -OCHF ₂ and -OCF ₃ . In another aspect, R ² and R ³ are each independently H, C ₁ -C ₆ alkyl; -CH ₂ N(CH ₃ ) ₂ , -CH ₂ CH ₂ N(CH ₃ ) ₂ ; or cyclopropyl, C ₁ cyclopropyl, cyclobutyl, C ₁ cyclobutyl, cyclopentyl, C 1 cyclopentyl, cyclohexyl, C ₁ cyclohexyl, phenyl, _{C 1 phenyl} , piperadinyl, C ₁ -piperadinyl, C ₂ piperadinyl, piperazinyl, morpholinyl, tetrahydro-2H- pyran, pyrrolyl, pyrazolyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl, each of which is optionally substituted with at least one R ⁹ substituent selected from the group consisting of methyl, ethyl, propyl, isopropyl, tert-butyl, hydroxy, methoxy , ethoxy, F, Cl, Br, cyano, cyclopropyl, amino, -N(CH ₃ ) ₂ , -CHF ₂ , -CF ₃ , -OCHF ₂ and -OCF ₃ . In another aspect, R ² and R ³ are each independently H, C ₁ -C ₆ alkyl; -CH ₂ N(CH ₃ ) ₂ , -CH ₂ CH ₂ N(CH ₃ ) ₂ ; or cyclopropyl, C ₁ cyclopropyl, cyclobutyl, C ₁ cyclobutyl, cyclopentyl, C 1 cyclopentyl, cyclohexyl, C ₁ cyclohexyl, phenyl, _{C 1 phenyl} , piperadinyl, C ₁ -piperadinyl, C ₂ piperadinyl, piperazinyl, morpholinyl, tetrahydro-2H- pyran, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl, each of which is optionally substituted with at least one R ⁹ substituent selected from the group consisting of methyl, ethyl, propyl, isopropyl, tert-butyl, hydroxy, methoxy, ethoxy , F, Cl, Br, cyano, cyclopropyl, amino, -N(CH ₃ ) ₂ , -CHF ₂ , -CF ₃ , -OCHF ₂ and -OCF ₃ . In another aspect, R ² is H, methyl, ethyl, isopropyl, cyclopropyl, -CF ₃ , -CHF ₂ , -CH ₂ F, -CH ₂ CF ₃ or phenyl. In another aspect, R ² is H, methyl, ethyl, cyclopropyl or phenyl. In another aspect, R ² represents H, methyl or ethyl. In another aspect, R ² represents H or methyl. In another aspect, R ² is H. In another aspect, R ² is methyl. In another aspect, R ³ is H, methyl, ethyl, propyl, isopropyl, tert-butyl; -CH ₂ N(CH ₃ ) ₂ , -CH ₂ CH ₂ N(CH ₃ ) ₂ ; or cyclopropyl, cyclobutyl, phenyl, C ₁ phenyl, piperadinyl, C ₁ -piperadinyl, C ₂ piperadinyl, piperazinyl, morpholinyl, tetrahydro-2H-pyran, pyrazolyl or pyridinyl, and wherein each ring is independently substituted with at least one R ⁹ substituent selected from the group consisting of methyl, ethyl, hydroxy, methoxy, ethoxy, F, O, cyano, amino, -N(CH ₃ ) ₂ and -CF ₃ .

In another aspect of the invention, R ² and R ³ together with the nitrogen atom to which they are attached form ring A, an 8-membered heterocyclic ring, or a 5-membered heteroaryl ring, each of which optionally contains at least one additional heteroatom selected from N, O and S; and wherein each ring is optionally substituted with at least one R ¹⁰ substituent; and wherein each ring is further optionally fused to Y which is phenyl, pyridinyl, pyrimidyl, pyrazolyl, thienyl, thiazolyl or triazolyl. In another aspect, R ² and R ³ together with the nitrogen atom to which they are attached form a ring A, 4 8-membered heterocyclic or 5-membered heteroaryl ring, each of which optionally contains at least one additional heteroatom selected from N, O and S; and wherein each ring is optionally substituted with at least one R ¹⁰ substituent, and wherein each ring is additionally optionally fused to Y which is phenyl, pyridinyl or pyrimidyl. In another aspect, R ² and R ³ together with the nitrogen atom to which they are attached form a ring A which is azetidinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, each of which optionally substituted with at least one ^R10 substituent selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F, Cl, Br, CN, -N( _CH3 ) ₂ , hydroxyl, _-CHF2 , _-CF3 , -OCHF ₂ , -OCF ₃ and oxo; and wherein each ring is further optionally fused to Y which is phenyl, pyridinyl or pyrimidyl. In another aspect, R ² and R ³ together with the nitrogen atom to which they are attached form a ring A which is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, each of which is optionally substituted at least one ^R10 substituent selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F, Cl, Br, CN, -N( _CH3 ) ₂ , hydroxyl, _-CHF2 , _-CF3 , -OCHF ₂ , -OCF ₃ and oxo; and wherein each ring is further optionally fused to Y which is phenyl, pyridinyl or pyrimidinyl. In another aspect, R ² and R ³ together with the nitrogen atom to which they are attached form a ring A that is pyrrolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, each of which is optionally substituted with at least one substituent R ¹⁰ selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F, Cl, Br, CN, -N(CH ₃ ) ₂ , hydroxyl, -CHF ₂ , -CF ₃ , -OCHF ₂ , -OCF ₃ and oxo; and wherein each ring is further optionally fused to Y, which is phenyl or pyridinyl. In another aspect, R ² and R ³ together with the nitrogen atom to which they are attached form a ring A that is pyrrolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, each of which is optionally substituted with at least one substituent R ¹⁰ selected from methyl, ethyl, F, Cl, oxo and -CF ₃ ; and wherein each ring is further optionally fused to Y, which is phenyl. In another aspect, R ² and R ³ together with the nitrogen atom to which they are attached form a ring A that is pyrrolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, each of which is optionally substituted with at least one substituent R ¹⁰ selected from methyl, ethyl, F, Cl, oxo and -CF ₃ ; or ring A which is indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydropyrrolopyrazinyl, tetrahydroisoquinolinyl, dihydrobenzooxazinyl or dihydrobenzothiazinyl, optionally substituted with at least one oxo. In another aspect, R ² and R ³ together with the nitrogen atom to which they are attached form a ring A that is pyrrolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, each of which is optionally substituted with at least one substituent R ¹⁰ selected from methyl, ethyl, F, Cl, oxo and -CF ₃ ; or ring A which is indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydrobenzooxazinyl or dihydrobenzothiazinyl, optionally substituted with at least one oxo. In another aspect, R ² and R ³ together with the nitrogen atom to which they are attached form a ring A that is pyrrolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, each of which is optionally substituted with at least one substituent R ¹⁰ selected from methyl, ethyl, F, Cl, oxo and -CF ₃ .

In another aspect of the invention, R ⁵ and R ⁶ are each independently H; C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy, each of which is optionally substituted with at least one hydroxy; cyano, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, -C(O)R ⁸ , -C(O)NR ^a R ⁸ , -C(O)R ^c NR ^a R ^b , -C(O )OR ^c R ⁸ , -C(O)ONR ^a R ^b , -R ^c NR ^a C(O)R ⁸ , -R ^c C(O)OH, -R ^c C(O)NR ^a R ^b , - R ^c NR ^a C(O)H, -R ^c S(O)PR ⁸ , -R ^c NR ^a R ^b , -R ^c OR ^a , -S(O)PR ⁸ , -S(O)PR ⁸ NR ^a R ^b , -R ^c S(O) _p NR ^a R ^b , -R ^c NR ^a S(O) _p R ⁸ ; C ₀ -C ₄ alkylphenyl, C ₀ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₀ -C ₄ alkylheterocycle, C ₀ -C ₄ alkylheteroaryl, wherein each of the heterocyclic and heteroaryl rings is a 5-6-membered monocyclic ring and wherein each of the heterocyclic and heteroaryl rings contains at least one heteroatom selected from the group consisting of N, O and S; and wherein each of the phenyl, cycloalkyl ring, heterocyclic ring and heteroaryl ring is optionally substituted with at least one R ¹⁰ substituent. In another aspect, R ⁵ and R ⁶ are each independently H; C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy, each of which is optionally substituted with at least one hydroxy; cyano, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, -C(O)R ⁸ , -C(O)NR ^a R ⁸ , -C(O)R ^c NR ^a R ^b , -C(O )OR ^c R ⁸ , -C(O)ONR ^a R ^b , -R ^c NR ^a C(O)R ⁸ , -R ^c C(O)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 ; phenyl, C ₁ alkylphenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C ₁ -C ₂ alkylcyclopropyl, C ₁ -C ₂ alkylcyclobutyl, C ₁ -C ₂ alkylcyclopentyl, C ₁ -C ₂ alkylcyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, oxazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, C ₁ -C ₂ alkyltetrahydrofuranyl, C ₁ -C ₂ alkyloxazolidinyl, C ₁ -C ₂ alkyltetrahydropyranyl, C ₁ -C ₂ alkylpyrrolidinyl, C ₁ -C ₂ alkylpiperidinyl, C ₁ -C ₂ alkylpiperazinyl, C ₁ -With ₂ morpholinyl; pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, pyridinyl, _pyridazinyl , pyrimidinyl, pyrazinyl, C ₁ -C 2 alkylpyrazolyl, C _{1 -C 2} alkylimidazolyl, C 1 -C ₂ alkyltriazolyl, C ₁ -C ₂ alkyltetrazolyl, C ₁ -C ₂ alkyloxazolyl, C ₁ -C ₂ alkylpyridinyl, C ₁ -C ₂ alkylpyridazinyl, C ₁ -C ₂ alkylpyrimidinyl or C ₁ -C ₂ alkylpyrazinyl; and wherein each of the phenyl, cycloalkyl ring, heterocyclic ring and heteroaryl ring is optionally substituted with at least one R ¹⁰ substituent. In another aspect, R ⁵ and R ⁶ are each independently H; C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy, each of which is optionally substituted with at least one hydroxy; cyano, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, -C(O)R ⁸ , -C(O)NR ^a R ⁸ , -C(O)R ^c NR ^a R ^b , -C(O )ONR ^a R ^b , -R ^c NR ^a C(O)R ⁸ , -R ^c C(O)NR ^a R ^b , -R ^c NR ^a C(O)H, -R ^c S(O)PR ⁸ , -R ^c NR ^a R ^b , S(O)PR ⁸ , -S(O) _p R ⁸ NR ^a R ^b , -R ^c S(O) _p NR ^a R ^b ; phenyl, C ₁ alkylphenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C ₁ -C ₂ alkylcyclopropyl, C ₁ -C ₂ alkylcyclobutyl, oxazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, C ₁ -C ₂ alkyloxazolidinyl, C ₁ -C ₂ alkylpyrrolidinyl, C _{1 -C 2} alkylpiperidinyl, C 1 -C 2 alkylpiperazinyl, C ₁ -C ₂ morpholinyl, C ₁ -C ₂ tetrahydrofuran, C _{1 -C 2} tetrahydropyran, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl , C ₁ -C ₂ alkylpyrazolyl, C ₁ -C ₂ alkyl imidazolyl, C ₁ -C ₂ alkylpyridinyl, C ₁ -C ₂ alkylpyrimidinyl or C ₁ -C ₂ alkylpyrazinyl; and wherein each of the phenyl, nicloalkyl ring, heterocyclic ring and heteroaryl ring is optionally substituted with at least one R ¹⁰ substituent independently selected from methyl, ethyl, propyl, methoxy, ethoxy, -CHF ₂ , -CF ₃ , -OCF ₃ , F, Cl, amino, -NHCH ₃ , -N(CH ₃ ) ₂ , -S(O) ₂ CH ₃ , nitro, cyano, -C(O)CH ₃ , -NHCH ₂ C(O)CH ₃ , -NHCH ₂ CH ₂ C(O)CH ₃ , -C(O)NHCH ₃ , hydroxy and phenyl. In another aspect, R ⁵ and R ⁶ are each independently H; C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy, each of which is optionally substituted with at least one hydroxy; C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, -C(O)R ⁸ , -C(O)NR ^a R ⁸ , -C(O)R ^c NR ^a R ^b , -R ^c S(O ) _p R ⁸ , -R ^c NR ^a R ^b , -R ^c OR ^a , -S(O) _p R ⁸ ; phenyl, C ₁ alkylphenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C ₁ -C ₂ alkylcyclopropyl, C ₁ -C ₂ alkylcyclobutyl, oxazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, C ₁ -C ₂ alkyloxazolidinyl, C ₁ -C ₂ alkylpyrrolidinyl, C ₁ -C ₂ alkylpiperidinyl, C ₁ -C ₂ alkylpiperazinyl, C ₁ -C ₂ morpholinyl, C ₁ -C ₂ morpholinyl, C ₁ -C ₂ piperadinyl, C ₁ -C ₂ tetrahydropyranyl, C ₁ -C ₂ tetrahydrofuranyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, C ₁ -C ₂ alkylpyrazolyl, C ₁ -C ₂ alkyl imidazolyl, C ₁ -C ₂ alkyl pyridinyl, C ₁ -C ₂ alkylpyrimidinyl or C ₁ -C ₂ alkylpyrazinyl; and wherein each of the phenyl, cycloalkyl ring, heterocyclic ring and heteroaryl ring is optionally substituted with at least one R ¹⁰ substituent independently selected from methyl, ethyl, methoxy, ethoxy, -CHF ₂ , -CF ₃ , -OCF ₃ , F, Cl, -NHCH ₃ , -N(CH ₃ ) ₂ , -S(O) ₂ CH ₃ , cyano and hydroxy. In another aspect, R ⁵ and R ⁶ are each independently H; C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy, each of which is optionally substituted with at least one hydroxy; C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, -OCF ₃ , -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)PR ⁸ ; phenyl, C ₁ alkylphenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C ₁ -C ₂ alkylcyclopropyl, C ₁ -C ₂ alkylcyclobutyl, oxazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, C ₁ -C ₂ alkyloxazolidinyl, C ₁ -C ₂ alkylpyrrolidinyl, C _{1 -C 2} alkylpiperidinyl, C 1 -C 2 alkylpiperazinyl, C ₁ -C ₂ morpholinyl, C ₁ -C ₂ tetrahydropyranyl, C _{1 -C 2} tetrahydrofuranyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl , C ₁ -C ₂ alkylpyrazolyl, C ₁ -C ₂ alkyl imidazolyl, C ₁ -C ₂ alkyl pyridinyl, C ₁ -C ₂ alkylpyrimidinyl or C ₁ -C ₂ alkylpyrazinyl; and wherein each of the phenyl, cycloalkyl ring, heterocyclic ring and heteroaryl ring is optionally substituted with at least one R ¹⁰ substituent independently selected from methyl, ethyl, methoxy, ethoxy, -CHF ₂ , -CF ₃ , -OCF ₃ , F, Cl, amino, -NHCH ₃ , -N(CH ₃ ) ₂ , -S(O) ₂ CH ₃ , cyano and hydroxy. In another aspect, R ⁵ is H, C ₁ -C ₆ alkyl, morpholinyl, piperadinyl, -CH ₂ morpholinyl, -CH ₂ piperadinyl, -(CH ₂ ) ₂ morpholinyl or (CH ₂ ) ₂ piperadinyl. In another aspect, R ⁵ is H, methyl, ethyl, propyl, isopropyl, -CH ₂ morpholinyl, -CH ₂ piperadinyl, -(CH ₂ ) ₂ morpholinyl or (CH ₂ ) ₂ piperadinyl. In another aspect, R ⁵ is H, methyl, ethyl, propyl or isopropyl. In another aspect, R ⁶ represents H; C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy, each of which is optionally substituted with at least one hydroxy; C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, -OCF ₃ , -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, C ₁ alkylphenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C ₁ -C ₂ alkylcyclopropyl, C ₁ -C ₂ alkylcyclobutyl, oxazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, C ₁ -C ₂ alkyloxazolidinyl, C ₁ -C ₂ alkylpyrrolidinyl, C _{1 -C 2} alkylpiperidinyl, C 1 -C 2 alkylpiperazinyl, C ₁ -C ₂ morpholinyl, C ₁ -C ₂ tetrahydropyranyl, C _{1 -C 2} tetrahydrofuranyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl , C ₁ -C ₂ alkylpyrazolyl, C ₁ -C ₂ alkyl imidazolyl, C ₁ -C ₂ alkylpyridinyl, C ₁ -C ₂ alkylpyrimidinyl or C ₁ -C ₂ alkylpyrazinyl; and wherein each of the phenyl, cycloalkyl ring, heterocyclic ring and heteroaryl ring is optionally substituted with at least one R ¹⁰ substituent independently selected from methyl, ethyl, methoxy, ethoxy, -CHF ₂ , -CF ₃ , -OCF ₃ , F, Cl, -NHCH ₃ , -N(CF ₃ ) ₂ , -S(O) ₂ CH ₃ , cyano and hydroxy. In another aspect, R ⁶ is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, -CH ₂ CF ₃ , -CF ₃ , -OCF ₃ ; -C(O)NR ^a R ⁸ where R ^a is H or methyl and R ⁸ is H, methyl, cyclopropyl, phenyl, optionally substituted with F, Cl or -CF ₃ ; -(CH ₂ )S(O) ₂ R ⁸ where R ⁸ represents methyl or phenyl; -CH ₂ NR ^a R ^b or -(CH ₂ ) ₂ NR ^a R ^b , wherein R ^a and R ^b are each independently H or methyl; -(CH ₂ ) ₂ OCH ₃ , -(CH ₂ ) ₃ OCH ₃ ; phenyl, C ₁ alkylphenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C ₁ -C ₂ alkylcyclopropyl, C ₁ -C ₂ alkylcyclobutyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, C ₁ -C ₂ alkylpyrrolidinyl, C ₁ - C ₂ alkylpiperidinyl, C ₁ -C ₂ alkylpiperazinyl, C ₁ -C ₂ morpholinyl, C ₁ -C ₂ tetrahydropyranyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, C ₁ -C ₂ alkylpyrazolyl, C ₁ -C ₂ alkyl imidazolyl, C ₁ -C ₂ alkyl pyridinyl, C ₁ -C ₂ alkylpyrimidinyl or C ₁ -C ₂ alkylpyrazinyl; and wherein each of the phenyl, cycloalkyl ring, heterocyclic ring and heteroaryl ring is optionally substituted with at least one R ¹⁰ substituent independently selected from methyl, ethyl, methoxy, ethoxy, -CHF ₂ , -CF ₃ , -OCF ₃ , F, Cl, amino, -NHCH ₃ , -N(CH ₃ ) ₂ , -S(O) ₂ CH ₃ , cyano and hydroxy.

In another aspect of the invention, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a ring B, a 4-8 membered heterocyclic or 5 membered heteroaryl ring, each of which optionally contains at least one additional heteroatom selected from N, O and S; and wherein each ring is optionally substituted with at least one R ⁹ substituent; and wherein each ring is further optionally fused to Y which is phenyl, pyridinyl, pyrimidyl, pyrazolyl, thienyl, thiazolyl or triazolyl. In another aspect, R ⁵ and R ⁶ , together with the nitrogen atom to which they are attached, form a ring B, a 4-8 membered heterocyclic ring, or a 5-membered heteroaryl ring, each of which optionally contains at least one additional heteroatom selected from N, O and S; and wherein each ring is optionally substituted with at least one R ⁹ substituent, and wherein each ring is additionally optionally fused to Y which is phenyl, pyridinyl or pyrimidyl. In another aspect, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a ring B which is azetidinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, each of which optionally substituted with at least one ^R9 substituent selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F, Cl, Br, CN, -N( _CH3 ) ₂ , hydroxy, _-CHF2 , _-CF3 , -OCHF ₂ , -OCF ₃ and oxo; and wherein each ring is further optionally fused to Y, which is phenyl or pyridinyl. In another aspect, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a ring B which is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, each of which is optionally substituted at least one ^R9 substituent selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F, Cl, Br, CN, -N( _CH3 ) ₂ , hydroxy, _-CHF2 , _-CF3 , -OCHF ₂ , -OCF ₃ and oxo; and wherein each ring is further optionally fused to Y, which is phenyl. In another aspect, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a ring B which is pyrrolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, each of which is optionally substituted with at least one substituent R ⁹ selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F, Cl, Br, CN, -N( _CH3 ) ₂ , hydroxy, _-CHF2 , _-CF3 , _-OCHF2 , _-OCF3 and oxo; and wherein each ring is further optionally fused to Y, which is phenyl. In another aspect, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a ring B which is pyrrolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, each of which is optionally substituted with at least one substituent R ⁹ selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F, Cl, Br, CN, -N( _CH3 ) ₂ , hydroxy, _-CHF2 , _-CF3 , _-OCHF2 , _-OCF3 and oxo; or ring B, which is indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydropyrrolopyrazinyl, tetrahydroisoquinolinyl, dihydrobenzooxazinyl or dihydrobenzothiazinyl, optionally substituted with at least one oxo. In another aspect, R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a ring B which is pyrrolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, each of which is optionally substituted with at least one substituent R ⁹ selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F, Cl, Br, CN, -N( _CH3 ) ₂ , hydroxy, _-CHF2 , _-CF3 , _-OCHF2 , _-OCF3 and oxo.

In another aspect of the invention, R ⁷ represents H, C ₁ -C ₆ alkyl, -(CH ₂ ) _m NH ₂ , -(CH ₂ ) _m NHCH ₃ , -(CH ₂ ) _m N(CH ₃ ) ₂ , -( CH ₂ ) _m C(O)H, -(CH ₂ ) _m C(O)CH ₃ , -(CH ₂ ) _m S(O) _p CH ₃ , -(CH ₂ ) _m NHC(O)C _m , -(CH ₂ ) _m NHC(O)NHCH ₃ , -(CH ₂ ) _m NHC(O)N(CH ₃ ) ₂ or -(CH ₂ ) _m NHC(O)CH ₃ ; where m is an integer 1, 2 or 3. In another aspect, R ⁷ represents H, C ₁ -C ₆ alkyl, -(CH ₂ ) _m NH ₂ , -(CH ₂ ) _m NHCH ₃ , -(CH ₂ ) _m N(CH ₃ ) ₂ , -(CH ₂ ) _m C(O)CH ₃ , -(CH ₂ ) _m S(O) _p CH ₃ or -(CH ₂ ) _m NHC(O)CH ₃ ; where m represents the integer 1 or 2. In another aspect of the invention, R ⁷ represents H, C ₁ -C ₆ alkyl, -(CH ₂ )NH ₂ , -(CH ₂ )NHCH ₃ , -(CH ₂ )N( CH ₃ ) ₂ , -(CH ₂ )C(O)CH ₃ , -(CH ₂ )S(O) _p CH ₃ or -(CH ₂ )NHC(O)CH ₃ . In another aspect, R ⁷ is H, methyl, ethyl, propyl, isopropyl, tert-butyl, -(CH ₂ ) _m NH ₂ , -(CH ₂ )NHCH ₃ , -(CH ₂ )N(CH ₃ ) ₂ , -(CH ₂ )C(O)CH ₃ , -(CH ₂ )S(O) _p CH ₃ or -(CH ₂ )NHC(O)CH ₃ . In another aspect, R ⁷ is H, methyl, ethyl, propyl, isopropyl, t-butyl, -CH ₂ NH ₂ , -CH ₂ NHCH ₃ or -CH ₂ N(CH ₃ ) ₂ . In another aspect, R ⁷ is H, methyl, ethyl, propyl, isopropyl or -CH ₂ N(CH ₃ ) ₂ . In another aspect, R ⁷ is H, methyl, ethyl or propyl.

In another aspect of the invention, R ⁸ represents C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, -NR ^a R ^b ; or C ₀ -C ₄ alkylC ₃ -C ₆ cycloalkyl, phenyl, pyrrolyl, pyrazolyl, pyridinyl or pyrimidinyl, each of which is optionally substituted with at least one substituent selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , halogen, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkyl and C ₁ -C ₄ haloalkoxy. In another aspect, R ⁸ is methyl, ethyl, propyl; or cyclopropyl, C ₁ alkylcyclopropyl, phenyl or pyridinyl, each of which is optionally substituted with at least one substituent selected from C ₁ -C ₄ alkyl, halogen, C ₁ -C ₄ alkoxy, -CF ₃ and -OCF ₃ . In another aspect, R ⁸ is methyl, ethyl; or cyclopropyl or phenyl, each of which is optionally substituted with at least one substituent selected from C ₁ -C ₄ alkyl, halogen, C ₁ -C ₄ alkoxy, -CF ₃ and -OCF ₃ .

In another aspect of the invention, each R ⁹ is independently selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, oxo, hydroxy, nitro, cyano, -NR ^a R ^b , C ₁ -C ₆ haloalkyl _{. silt ,} ^isothiazolyl , thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl. In another aspect, each R ⁹ is independently selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, oxo, hydroxy, nitro, cyano, -NR ^a R ^b , C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, -S(O) _p R ⁸ , phenyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, pyridinyl, pyrimidinyl and pyrazinyl. In another aspect, each R ⁹ is independently selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, oxo, hydroxy, nitro, cyano, -NR ^a R ^b , C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, -S(O) _p R ⁸ , phenyl, piperidinyl, morpholinyl, piperazinyl and pyridinyl. In another aspect, R ⁹ is independently selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, oxo, hydroxy, cyano, -NHCH ₃ , -N(CH ₃ ) ₂ , -N(CH ₂ CH ₃ ) ₂ , -CHF ₂ , -CF ₃ , -OCHF ₂ , -OCF ₃ , -S(O) ₂ CH ₃ , phenyl, piperidinyl, morpholinyl, piperazinyl and pyridinyl. In another aspect, R ⁹ is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, F, Cl, Br, oxo, hydroxy, cyano, -NHCH ₃ , -N(CH ₃ ) ₂ , -N(CH ₂ CH ₃ ) ₂ , -CHF ₂ , -CF ₃ , -OCHF ₂ , -OCF ₃ , -S(O) ₂ CH ₃ , phenyl, piperidinyl, morpholinyl, piperazinyl and pyridinyl. In another aspect, R ⁹ is independently selected from the group consisting of methyl, ethyl, methoxy, ethoxy, isopropoxy, F, Cl, Br, oxo, hydroxy, nitro, cyano, -NHCH ₃ , -N(CH ₃ ) ₂ , -N (CH ₂ CH ₃ ) ₂ , -CHF ₂ , -CF ₃ , -OCHF ₂ , -OCF ₃ , -S(O) ₂ CH ₃ , phenyl, piperidinyl, morpholinyl, piperazinyl and pyridinyl. In another aspect, each R ⁹ is independently selected from the group consisting of methyl, ethyl, propyl, methoxy, ethoxy, F,Cl, oxo, hydroxy, nitro, cyano, -NR ^a R ^b , -CF 3 and -OCF ₃ . In another aspect, each R ⁹ is independently selected from the group consisting of methyl, ethyl, propyl, methoxy, ethoxy, F, Cl, oxo, hydroxy, nitro, cyano, -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -CF ₃ and -OCF ₃ . In another aspect, at least one substituent R9 is an integer (n) that is 1, 2 or 3.

In another aspect of the invention, each R ¹⁰ is independently selected from C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ 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 , hydroxy, a 5-6 membered heterocyclic ring, 5-6 membered heteroaryl ring, wherein each of the heterocyclic and heteroaryl rings contains at least one heteroatom selected from the group consisting of N, O and S ; and phenyl; and wherein each of the phenyl, heterocyclic and heteroaryl rings is optionally substituted with at least one R ⁹ substituent selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, oxo, hydroxy, cyano, - NHCH ₃ , -N(CH ₃ ) ₂ , -N(CH ₂ CH ₃ ) ₂ , -CHF ₂ , -CF ₃ , -OCHF ₂ , -OCF ₃ , -S(O) ₂ CH ³ , phenyl, piperidinyl, morpholinyl, piperazinyl and pyridinyl. In another aspect, each R ¹⁰ is independently selected from C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ haloalkoxy, halogen, -NHCH ₃ , -N(CH ₃ ) ₂ , -S(O) ₂ CH ₃ , nitro, oxo, cyano, -C(O)CH ₃ , -C(O)OCH ₃ , -NHCH ₂ C(O)CH ₃ , -NHCH ₂ CH ₂ C(O )CH ₃ , -C(O)NHCH ₃ and hydroxy; phenyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, pyrrolyl, furanyl, pyrazolyl, imidazolyl, pyridinyl and pyrazinyl, each of which is optionally and independently substituted with at least one R ⁹ substituent selected from the group consisting of methyl, ethyl , propyl, isopropyl, methoxy, ethoxy, halogen, oxo, hydroxy, cyano, -NHCH ₃ , -N(CH ₃ ) ₂ , -N(CH ₂ CH ₃ ) ₂ , -CHF ₂ , -CF ₃ , -OCHF ₂ , -OCF ₃ and -S(O) ₂ CH ₃ . In another aspect, each R ¹⁰ is independently selected from methyl, ethyl, propyl, methoxy, ethoxy, -CHF ₂ , -CF ₃ , -OCF ₃ , F, Cl, -NHCH ₃ , -N(CH ₃ ) ₂ , -S( O) ₂ CH ₃ , nitro, cyano, -C(O)CH ₃ , -NHC(O)CH ₃ , -NHCH ₂ CH ₂ C(O)CH ₃ , -C(O)NHCH ₃ and hydroxy; phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl and pyridinyl, each of which is optionally and independently substituted with at least one R ⁹ substituent selected from the group consisting of methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, halogen, oxo, hydroxy , cyano, -NHCH ₃ , -N(CH ₃ ) ₂ , -N(CH ₂ CH ₃ ) ₂ , -CHF ₂ , -CF ₃ , -OCHF ₂ , -OCF ₃ and -S(O) ₂ CH ₃ . In another aspect, each R ¹⁰ is independently selected from methyl, ethyl, propyl, methoxy, ethoxy, -CHF ₂ , -CF ₃ , -OCF ₃ , F, Cl, -NHCH ₃ , -N(CH ₃ ) ₂ , -S( O) ₂ CH ₃ , nitro, cyano, -C(O)CH ₃ , -NHCH ₂ C(O)CH ₃ , -NHCH ₂ CH ₂ C(O)CH ₃ , -C(O)NHCH ₃ and hydroxy. In another aspect, at least one substituent R ¹⁰ refers to an integer (n) that is 1, 2 or 3.

In another aspect, R is H, -C(O)NR ^a R ^d or -C(O)OR ⁸ . In another aspect, R is H, -C(O)NH ₂ , -C(O)NHCH ₃ , -C(O)N(CH ₃ ) ₂ , -C(O)NHCH ₂ CH ₃ , -C(O )NHCH(CH ₃ ) ₂ , -C(O)NHC(CH ₃ ) ₃ or -C(O)NH-phenyl, wherein the phenyl is optionally substituted by at least one substituent independently selected from F, Cl, -CF ₃ , cyano, methoxy, ethoxy and -OCF ₃ . In another aspect, R is H, -C(O)NHCH ₃ , -C(O)N(CH ₃ ) ₂ or -C(O)NH-phenyl, wherein the phenyl is optionally substituted with at least one substituent independently selected from F, Cl, -CF ₃ , cyano, methoxy, ethoxy and -OCF ₃ . In another aspect, R is H or -C(O)NH-phenyl, wherein the phenyl is optionally substituted with at least one substituent independently selected from F, Cl, -CF ₃ , cyano, methoxy, ethoxy and -OCF ₃ . In another aspect, R is H or -C(O)NH-phenyl. In another aspect, R is H.

In another aspect, Y is phenyl, pyridinyl, pyrimidyl, pyrazolyl, thienyl, thiazolyl, triazolyl, isothiazolyl, or pyrrolyl. In another aspect, Y is phenyl, pyridinyl, pyrimidyl or pyrazolyl. In another aspect, Y is phenyl, pyridinyl or pyrimidyl. In another aspect, Y is phenyl or pyridinyl. In another aspect, Y is phenyl. In another aspect, Y is pyridinyl. In another aspect, when an optionally substituted ring A or ring B is fused to Y, ring A or ring B is optionally substituted with indolinyl, isoindolinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, dihydropyrrolopyridinyl, dihydropyrrolopyrimidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxaline, dihydrobenzooxazine, or di hydrobenzothiazine.

In another aspect, X' is F, Cl or Br. In another aspect, X' is F or Cl. In another aspect, X' is F. In another aspect, X' is Cl.

In another aspect of the invention, X is R ^a , -(CH ₂ ) _m NR ⁵ R ⁶ , -(CH ₂ ) _m OR ⁷ , -(CH ₂ ) _m SR ⁷ , -(CH ₂ ) _m N ₃ , -( CH ₂ ) _m CN or -(CH ₂ ) mX'; where m represents the integer 1 or 2. In another aspect, X represents R ^a . In another aspect, X is -CH ₂ NR ⁵ R ⁶ . In another aspect, X is -CH ₂ OR ⁷ . In another aspect, X is -CH ₂ SR ⁷ . In another aspect, X is -CH ₂ N ₃ . In another aspect, X is -CH ₂ CN. In another aspect, X is -CH ₂ X'.

In another aspect of the invention, p is the integer 0. In another aspect, p is the integer 1. In another aspect, p is the integer 2. In another aspect of the invention, n is the integer 0, 1, or 2. In another aspect, n is the integer 0 or 1. In another aspect, n is the integer 0. In another aspect, n is the integer 1. In another aspect, n is the integer 2. In another aspect, n is the integer 3.

In another aspect of the invention there is provided a compound of formula (1) wherein R is H and W is formula (A), that is, a compound of formula (1A) wherein ^R0 , ^R1 , ^R2 , ^R3 and X are

as defined herein, its stereoisomers and its pharmaceutically acceptable salts.

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),

their stereoisomers and their pharmaceutically acceptable salts. In another aspect, the compound of formula (A) is formula (A0). In another aspect, formula (A) is formula (A1). In another aspect, formula (A) is formula (A2). In another aspect, formula (A) is a compound of formula (A3). In another aspect, formula (A) is formula (A4). In another aspect, formula (A) is formula (A5). In another aspect, formula (A) is formula (A6). In another aspect, preferred formula (A) is formula (A1).

In another aspect of the invention there is provided a compound of formula (1), wherein R and W are both H; that is, the des-cladinose compound of formula (1.1);

and wherein R ⁰ , R ¹ , R ² and R ³ are as defined herein; its stereoisomers and its pharmaceutically acceptable salts. In another aspect, there is a compound of formula (1.1) wherein R ⁰ is H, methyl, ethyl or propyl; a R ¹ , R ² and R ³ are as defined herein, stereoisomers thereof and pharmaceutically acceptable salts thereof. In another aspect, there is provided a compound of formula (1.1), wherein R ⁰ represents H or methyl; a R ¹ , R ² and R ³ are as defined herein, stereoisomers thereof and pharmaceutically acceptable salts thereof. In another aspect, there is provided a compound of formula (1.1), wherein R ⁰ represents H or methyl; R ¹ represents methyl, and R ² and R ³ are as defined herein, stereoisomers thereof and pharmaceutically acceptable salts thereof. In another aspect, there is provided a compound of formula (1.1), wherein R ⁰ represents H or methyl; R ¹ represents methyl; and each of R ² and R ³ independently represents H, C ₁ -C ₆ alkyl, -CH ₂ N(CH ₃ ) ₂ , -CH ₂ CH ₂ N(CH ₃ ) ₂ ; or C ₀ -C ₂ cyclopropyl, C ₀ -C ₂ cyclobutyl, C ₀ -C ₂ cyclopentyl, C 0 -C ₂ cyclohexyl, C ₀ -C ₂ phenyl, C _{0 -C 2} piperadinyl, piperazinyl, morpholinyl, tetrahydropyran, pyrrolyl , pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl, each of which is optionally substituted with at least one R ⁹ substituent selected from the group consisting of methyl, ethyl, propyl, isopropyl, tert-butyl, hydroxy, methoxy, ethoxy, F, Cl, Br, cyano, amino, -N(CH ₃ ) ₂ , -CHF ₂ , -CF ₃ , -OCHF ₂ and -OCF ₃ ; or R ² and R ³ together with the nitrogen atom to which they are attached form a ring A which is azetidinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, each of which is optionally substituted at least one ^R10 substituent selected from the group consisting of methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F, Cl, Br, CN, -N( _CH3 ) ₂ , hydroxyl, _-CHF2 , -CF ₃ , -OCHF ₂ , -OCF ₃ and oxo; and wherein each ring is further optionally substituted with Y, which is phenyl, pyridinyl or pyrimidinyl; its stereoisomers and its pharmaceutically acceptable salts. In another aspect, there is provided a compound of formula (1.1), wherein R ⁰ represents H or methyl; R ¹ represents methyl; and each of R ² and R ³ independently represents H, C ₁ -C ₆ alkyl, -CH ₂ N(CH ₃ ) ₂ , -CH ₂ CH ₂ N(CH ₃ ) ₂ ; or cyclopropyl, C ₁ cyclopropyl, cyclobutyl, C ₁ cyclobutyl, cyclopentyl, C 1 cyclopentyl, cyclohexyl, C ₁ cyclohexyl, phenyl, _{C 1 phenyl} , piperadinyl, C ₁ -piperadinyl, C ₂ piperadinyl, piperazinyl, morpholinyl, tetrahydro-2H- pyran, pyrrolyl, pyrazolyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl, each of which is optionally substituted with at least one R ⁹ substituent selected from the group consisting of methyl, ethyl, propyl, isopropyl, tert-butyl, hydroxy, methoxy , ethoxy, F, Cl, Br, cyano, cyclopropyl, amino, -N(CH ₃ ) ₂ , -CHF ₂ , -CF ₃ , -OCHF ₂ and -OCF ₃ ; or R ² and R ³ together with the nitrogen atom to which they are attached form a ring A which is pyrrolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, each of which is optionally substituted with at least one R ¹⁰ substituent, selected from the group consisting of methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F, Cl Br, CN, -N(CH ₃ ) ₂ , hydroxyl, -CHF ₂ , -CF ₃ , -OCHF ₂ , -OCF ₃ and oxo; or ring A is indolinyl, isoindolinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, dihydropyrrolopyridinyl, dihydropyrrolopyrimidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxaline, dihydrobenzooxazinyl or dihydrobenzothiazinyl, optionally substituted with at least one oxo; its stereoisomers and its pharmaceutically acceptable salts. In another aspect, there is provided a compound of formula (1.1), wherein R ⁰ represents H or methyl; R ¹ represents methyl; R ² is H, methyl, ethyl, isopropyl, cyclopropyl, -CF ₃ , -CHF ₂ , -CH ₂ F, -CH ₂ CF ₃ or phenyl; a R ³ represents H, methyl, ethyl, propyl, isopropyl, tert-butyl; -CH ₂ N(CH ₃ ) ₂ , -CH ₂ CH ₂ N(CH ₃ ) ₂ ; or cyclopropyl, cyclobutyl, phenyl, C ₁ phenyl, piperadinyl, C ₁ -piperadinyl, C ₂ piperadinyl, piperazinyl, morpholinyl, tetrahydro-2H-pyran, pyrazolyl or pyridinyl, each of which is optionally substituted with at least one R ⁹ substituent selected from the group consisting of methyl, ethyl, hydroxy, methoxy, ethoxy, F, Cl, cyano, amino, -N(CH ₃ ) ₂ and -CF ₃ ; or R ² and R ³ together with the nitrogen atom to which they are attached form a ring A which is pyrrolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, each of which is optionally substituted with at least one R ¹⁰ substituent, selected from methyl, ethyl, F, Cl, oxo and -CF ₃ ; its stereoisomers and its pharmaceutically acceptable salts. In another aspect, a compound of formula (1.1) from Table A, stereoisomers thereof, and pharmaceutically acceptable salts thereof are provided.

In another aspect, a composition is provided containing a compound of formula (1.1), stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect, a composition is provided containing a compound of formula (1.1) from Table A, stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect, the composition further comprises a pharmaceutically acceptable carrier.

In another aspect, a method is provided for treating or preventing an inflammatory response in an animal by administering to said animal in need thereof a therapeutically effective amount of a compound of formula (1.1), stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect, a method of treating or preventing an inflammatory response in an animal is provided by administering to said animal in need thereof a therapeutically effective amount of a compound of formula (1.1) of Table A, its stereoisomers, and pharmaceutically acceptable salts thereof. In another aspect of the method, the inflammatory response occurs due to a bacterial, viral or fungal infection, stress and/or environmental factor. In another aspect of the method, a method of treating or preventing an inflammatory response in an animal prevents or reduces the progression of a respiratory disease or disorder. In another aspect of the method, the animal is a farm animal. In another aspect of the method, the respiratory disease or disorder is bovine respiratory disease or porcine respiratory disease. In another aspect of the method, a method of treating or preventing an inflammatory response in an animal provides down-regulation of TNF-α and IL-6 in the animal.

In another aspect, the use of a compound of formula (1.1), its stereoisomers and its pharmaceutically acceptable salts for the manufacture of a medicament for treating or preventing an inflammatory response in an animal is provided. In another aspect, the use of a compound of formula (1.1) from Table A, its stereoisomers and pharmaceutically acceptable salts thereof for the manufacture of a medicament for treating or preventing an inflammatory response in an animal is provided. In another aspect of application, the inflammatory response occurs due to a bacterial, viral or fungal infection, stress and/or environmental factor. In another aspect of use, the use of a medicament to treat or prevent an inflammatory response in an animal prevents or reduces the progression of a respiratory disease or disorder. In another aspect of application, the animal is a farm animal. In another aspect of use, the respiratory disease or disorder is bovine respiratory disease or porcine respiratory disease. In another aspect of use, administering a drug to an animal to treat or prevent an inflammatory response in the animal provides down-regulation of TNF-α and IL-6 in the animal.

In another aspect of the invention there is provided a compound of formula (1), wherein R is H and W is formula (A) and formula (A) is formula (A0); that is, it is a compound of formula (1-A0),

and wherein R ^a , R ⁰ , R ¹ , R ² and R ³ are as defined herein; its stereoisomers and its pharmaceutically acceptable salts. In another aspect, there is a compound of formula (1-A0), wherein ^R0 is H, methyl, ethyl or propyl; a R ^a , R ¹ , R ² and R ³ are as defined herein, their stereoisomers and their pharmaceutically acceptable salts. In another aspect, there is a compound of formula (1-A0), wherein ^R0 is H, methyl, ethyl or propyl; R ^a represents H or methyl; a R ¹ , R ² and R ³ are as defined herein, stereoisomers thereof and pharmaceutically acceptable salts thereof. In another aspect, there is a compound of formula (1-A0), wherein ^R0 is H or methyl; R ^a represents H or methyl; R ¹ represents H or methyl; a R ² and R ³ are as defined herein, stereoisomers thereof and pharmaceutically acceptable salts thereof. In another aspect, there is a compound of formula (1-A0), wherein ^R0 is H or methyl; R ¹ represents methyl, and R ² and R ³ are as defined herein, stereoisomers thereof and pharmaceutically acceptable salts thereof. In another aspect, there is a compound of formula (1-A0), wherein ^R0 is H or methyl; R ¹ represents methyl; and each of R ² and R ³ independently represents H, C ₁ -C ₆ alkyl, -CH ₂ N(CH ₃ ) ₂ , -CH ₂ CH ₂ N(CH ₃ ) ₂ ; or C ₀ -C ₂ cyclopropyl, C ₀ -C ₂ cyclobutyl, C ₀ -C ₂ cyclopentyl, C 0 -C ₂ cyclohexyl, C ₀ -C ₂ phenyl, C _{0 -C 2} piperadinyl, piperazinyl, morpholinyl, tetrahydropyran, pyrrolyl , pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl, each of which is optionally substituted with at least one R ⁹ substituent selected from the group consisting of methyl, ethyl, propyl, isopropyl, tert-butyl, hydroxy, methoxy, ethoxy, F, Cl, Br, cyano, amino, -N(CH ₃ ) ₂ , -CHF ₂ , -CF ₃ , -OCHF ₂ and -OCF ₃ ; or R ² and R ³ together with the nitrogen atom to which they are attached form a ring A, 4 8-membered heterocyclic or 5-membered heteroaryl ring, each of which optionally contains at least one additional heteroatom selected from N, O and S; and wherein each ring is optionally substituted with at least one R ¹⁰ substituent and wherein each ring is additionally optionally fused with Y, which is phenyl, pyridinyl or pyrimidyl; its stereoisomers and its pharmaceutically acceptable salts. In another aspect, there is a compound of formula (1-A0), wherein R ⁰ represents H or methyl; R ¹ represents methyl; and each of R ² and R ³ independently represents H, C ₁ -C ₆ alkyl, -CH ₂ N(CH ₃ ) ₂ , -CH ₂ CH ₂ N(CH ₃ ) ₂ ; or cyclopropyl, C ₁ cyclopropyl, cyclobutyl, C 1 cyclobutyl, cyclopentyl, C ₁ cyclopentyl, cyclohexyl, C ₁ cyclohexyl, phenyl, C ₁ phenyl, piperadinyl, C ₁ -piperadinyl, Crpiperadinyl, piperazinyl, morpholinyl, tetrahydro-2H-pyran _, pyrrolyl, pyrazolyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl, each of which is optionally substituted with at least one R ⁹ substituent selected from the group consisting of methyl, ethyl, propyl, isopropyl, tert-butyl, hydroxy, methoxy, ethoxy , F, Cl, Br, cyano, cyclopropyl, amino, -N(CH ₃ ) ₂ , -CHF ₂ , -CF ₃ , -OCHF ₂ and -OCF ₃ ; or R ² and R ³ together with the nitrogen atom to which they are attached form a ring A which is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, each of which is optionally substituted with at least at least one substituent R ¹⁰ selected from the group consisting of methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F, Cl, Br, CN, -N(CH ₃ ) ₂ , hydroxyl, -CHF ₂ , -CF ₃ , -OCHF ₂ , -OCF ₃ and oxo; or ring A is indolinyl, isoindolinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, dihydropyrrolopyridinyl, dihydropyrrolopyrimidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxaline, dihydrobenzooxazinyl or dihydrobenzothiazinyl, optionally substituted with at least one oxo; its stereoisomers and its pharmaceutically acceptable salts. In another aspect, there is a compound of formula (1-A0), wherein R ⁰ represents H or methyl; R ¹ represents methyl; R ² represents H or methyl; a R ³ represents H, methyl, ethyl or propyl; -CH ₂ N(CH ₃ ) ₂ , -CH ₂ CH ₂ N(CH ₃ ) ₂ ; or cyclopropyl, cyclobutyl, phenyl, C ₁ phenyl, piperadinyl, C ₁ -piperadinyl, C ₂ piperadinyl, piperazinyl, morpholinyl, tetrahydro-2H-pyran, pyrazolyl or pyridinyl, each of which is optionally substituted with at least one R ⁹ substituent selected from the group consisting of methyl, ethyl, hydroxy, methoxy, ethoxy, F, Cl, cyano, -N(CH ₃ ) ₂ and -CF ₃ ; or R ² and R ³ together with the nitrogen atom to which they are attached form a ring A which is pyrrolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, each of which is optionally substituted with at least one R ¹⁰ substituent, selected from methyl, ethyl, F, Cl, oxo and -CF ₃ ; its stereoisomers and its pharmaceutically acceptable salts. In another aspect, a compound of formula (1-A0) from Table B, stereoisomers thereof, and pharmaceutically acceptable salts thereof are provided. In another aspect, a non-antibacterial compound of formula (1-A0) from Table B, stereoisomers thereof, and pharmaceutically acceptable salts thereof are provided.

In another aspect, there is provided a composition containing a compound of formula (1-A0), stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect, a composition is provided containing a compound of formula (1-A0) from Table B, stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect, a composition is provided comprising a non-antibacterial compound of formula (1-A0) from Table B, stereoisomers thereof, and pharmaceutically acceptable salts thereof.

In another aspect, there is provided a composition containing a compound of formula (1-A0), stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect, a composition is provided containing a compound of formula (1-A0) from Table B, stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect, a composition is provided comprising a non-antibacterial compound of formula (1-A0) from Table B, stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect, the composition further comprises a pharmaceutically acceptable carrier.

In another aspect, a method is provided for treating or preventing an inflammatory response in an animal by administering to said animal in need thereof a therapeutically effective amount of a compound of formula (1-A0), stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect, a method is provided for treating or preventing an inflammatory response in an animal by administering to said animal in need thereof a therapeutically effective amount of a compound of formula (1-A0) of Table B, stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect, a method is provided for treating or preventing an inflammatory response in an animal by administering to said animal in need thereof a therapeutically effective amount of a non-antibacterial compound of formula (1-A0) of Table B, stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect of the method, the inflammatory response occurs due to a bacterial, viral or fungal infection, stress and/or environmental factor. In another aspect of the method, a method of treating or preventing an inflammatory response in an animal prevents or reduces the progression of a respiratory disease or disorder. In another aspect of the method, the animal is a farm animal. In another aspect of the method, the respiratory disease or disorder is bovine respiratory disease or porcine respiratory disease. In another aspect of the method, a method of treating or preventing an inflammatory response in an animal provides down-regulation of TNF-α and IL-6 in the animal.

In another aspect, the use of a compound of formula (1-A0), its stereoisomers and its pharmaceutically acceptable salts for the manufacture of a medicament for treating or preventing an inflammatory response in an animal is provided. In another aspect, the use of a compound of formula (1-A0) from Table B, its stereoisomers and pharmaceutically acceptable salts thereof for the manufacture of a medicament for treating or preventing an inflammatory response in an animal is provided. In another aspect, the use of a non-antibacterial compound of formula (1-A0) from Table B, its stereoisomers and pharmaceutically acceptable salts thereof for the manufacture of a medicament for treating or preventing an inflammatory response in an animal is provided. In another aspect of application, the inflammatory response occurs due to a bacterial, viral or fungal infection, stress and/or environmental factor. In another aspect of use, the use of a medicament to treat or prevent an inflammatory response in an animal prevents or reduces the progression of a respiratory disease or disorder. In another aspect of application, the animal is a farm animal. In another aspect of use, the respiratory disease or disorder is bovine respiratory disease or porcine respiratory disease. In another aspect of use, administering a drug to an animal to treat or prevent an inflammatory response in the animal provides down-regulation of TNF-α and IL-6 in the animal.

In another aspect of the invention there is provided a compound of formula (1), wherein R is H and W is formula (A) and formula (A) is formula (A2); that is, it is a compound of formula (1-A2),

where R ⁰ , R ¹ , R ² , R ³ and R ⁷ are as defined herein; its stereoisomers and its pharmaceutically acceptable salts. In another aspect, there is provided a compound of formula (1-A2);

where R ⁰ represents H, methyl, ethyl or propyl; R ¹ represents H or methyl; a R ² , R ³ and R ⁷ are as defined herein, their stereoisomers and their pharmaceutically acceptable salts. In another aspect of the invention there is provided a compound of formula (1-A2); where R ⁰ represents H or methyl; R ¹ represents H or methyl; and each of R ² and R ³ independently represents H, C ₁ -C ₆ alkyl; -CH ₂ N(CH ₃ ) ₂ , -CH ₂ CH ₂ N(CH ₃ ) ₂ ; or cyclopropyl, C ₁ cyclopropyl, cyclobutyl, C ₁ cyclobutyl, cyclopentyl, C 1 cyclopentyl, cyclohexyl, C ₁ cyclohexyl, phenyl, _{C 1 phenyl} , piperadinyl, C ₁ -piperadinyl, C ₂ piperadinyl, piperazinyl, morpholinyl, tetrahydro-2H- pyran, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl, each of which is optionally substituted with at least one R ⁹ substituent selected from the group consisting of methyl, ethyl, propyl, isopropyl, tert-butyl, hydroxy, methoxy, ethoxy , F, Cl, Br, cyano, cyclopropyl, amino, -N(CH ₃ ) ₂ , -CHF ₂ , -CF ₃ , -OCHF ₂ and -OCF ₃ ; or R ² and R ³ together with the nitrogen atom to which they are attached form a ring A which is pyrrolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, each of which is optionally substituted with at least one R ¹⁰ substituent, selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F, Cl, Br, CN, -N(CH ₃ ) ₂ , hydroxyl, -CHF ₂ , -CF ₃ , -OCHF ₂ , -OCF ₃ and oxo; or ring A is indolinyl, isoindolinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, dihydropyrrolopyridinyl, dihydropyrrolopyrimidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxaline, dihydrobenzooxazinyl or dihydrobenzothiazinyl, optionally substituted with at least one oxo; a R ⁷ represents H, C ₁ -C ₆ alkyl, -(CH ₂ ) _m NH ₂ , -(CH ₂ ) _m NHCH ₃ , -(CH ₂ ) _m N(CH ₃ ) ₂ , -(CH ₂ ) _m C(O)CH ₃ , -(CH ₂ ) _m S(O) _p CH ₃ or -(CH ₂ ) _m NHC(O)CH ₃ ; where m is an integer 1 or 2; its stereoisomers and its pharmaceutically acceptable salts. In another aspect, there is a compound of formula (1-A2), wherein R ⁰ represents H or methyl; R ¹ represents methyl; R ² represents H, methyl, ethyl, cyclopropyl or phenyl; R ³ represents H, methyl, ethyl, propyl, isopropyl, isobutyl, -CH ₂ N(CH ₃ ) ₂ , -CH ₂ CH ₂ N(CH ₃ ) ₂ ; or cyclopropyl, cyclobutyl, phenyl, C ₁ phenyl, piperadinyl, C ₁ -piperadinyl, C ₂ piperadinyl, piperazinyl, morpholinyl, tetrahydro-2H-pyran, pyrazolyl or pyridinyl, each of which is optionally substituted with at least one R ⁹ substituent selected from the group consisting of methyl, ethyl, hydroxy, methoxy, ethoxy, F, Cl, nitro, cyano, -N(CH ₃ ) ₂ and -CF ₃ ; or R ² and R ³ together with the nitrogen atom to which they are attached form a ring A which is pyrrolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, each of which is optionally substituted with at least one R ¹⁰ substituent, selected from methyl, ethyl, F, Cl, oxo and -CF ₃ ; a R ⁷ represents H, methyl, ethyl, propyl, isopropyl, tert-butyl, -CH ₂ NH ₂ , -CH ₂ NHCH ₃ or -CH ₂ N(CH ₃ ) ₂ , stereoisomers thereof and pharmaceutically acceptable salts thereof. In another aspect, a compound of formula (1-A2) from Table C, stereoisomers thereof, and pharmaceutically acceptable salts thereof are provided.

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

where R ⁰ , R ¹ , R ² , R ³ and R ⁷ are as defined herein; its stereoisomers and its pharmaceutically acceptable salts. In another aspect, there is provided a compound of formula (1-A3);

where R ⁰ represents H, methyl, ethyl or propyl; a R ¹ , R ² , R ³ and R ⁷ are as defined herein, their stereoisomers and their pharmaceutically acceptable salts. In another aspect, there is a compound of formula (1-A3) wherein R ⁰ is H, methyl, ethyl or propyl; R ¹ represents H or methyl; a R ² , R ³ and R ⁷ are as defined herein; its stereoisomers and its pharmaceutically acceptable salts. In another aspect of the invention there is provided a compound of formula (1-A3); where R ⁰ represents H or methyl; R ¹ represents H or methyl; and each of R ² and R ³ independently represents H, C ₁ -C ₆ alkyl; -CH ₂ N(CH ₃ ) ₂ , -CH ₂ CH ₂ N(CH ₃ ) ₂ ; or cyclopropyl, C ₁ cyclopropyl, cyclobutyl, C ₁ cyclobutyl, cyclopentyl, C 1 cyclopentyl, cyclohexyl, C ₁ cyclohexyl, phenyl, _{C 1 phenyl} , piperadinyl, C ₁ -piperadinyl, C ₂ piperadinyl, piperazinyl, morpholinyl, tetrahydro-2H- pyran, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl, each of which is optionally substituted with at least one R ⁹ substituent selected from the group consisting of methyl, ethyl, propyl, isopropyl, tert-butyl, hydroxy, methoxy, ethoxy , F, Cl, Br, cyano, cyclopropyl, amino, -N(CH ₃ ) ₂ , -CHF ₂ , -CF ₃ , -OCHF ₂ and -OCF ₃ ; or R ² and R ³ together with the nitrogen atom to which they are attached form a ring A which is pyrrolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, each of which is optionally substituted with at least one R ¹⁰ substituent, selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F, Cl, Br, CN, -N(CH ₃ ) ₂ , hydroxyl, -CHF ₂ , -CF ₃ , -OCHF ₂ , -OCF ₃ and oxo; or ring A is indolinyl, isoindolinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, dihydropyrrolopyridinyl, dihydropyrrolopyrimidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxaline, dihydrobenzooxazinyl or dihydrobenzothiazinyl, optionally substituted with at least one oxo; a R ⁷ represents H, C ₁ -C ₆ alkyl, -(CH ₂ ) _m NH ₂ , -(CH ₂ ) _m NHCH ₃ , -(CH ₂ ) _m N(CH ₃ ) ₂ , -(CH ₂ ) _m C(O)CH ₃ , -(CH ₂ ) _m S(O) _p CH ₃ or -(CH ₂ ) _m NHC(O)CH ₃ ; where m is an integer 1 or 2; its stereoisomers and its pharmaceutically acceptable salts. In another aspect there is provided a compound of formula (1-A3), wherein R ⁰ represents H or methyl; R ¹ represents methyl; R ² represents H, methyl, ethyl, cyclopropyl or phenyl; R ³ represents H, methyl, ethyl, propyl, isopropyl, tert-butyl, -CH ₂ N(CH ₃ ) ₂ , -CH ₂ CH ₂ N(CH ₃ ) ₂ ; or cyclopropyl, cyclobutyl, phenyl, C ₁ phenyl, piperadinyl, C ₁ -piperadinyl, C ₂ piperadinyl, piperazinyl, morpholinyl, tetrahydro-2H-pyran, pyrazolyl or pyridinyl, each of which is optionally substituted with at least one R ⁹ substituent selected from the group consisting of methyl, ethyl, hydroxy, methoxy, ethoxy, F, Cl, nitro, cyano, -N(CH ₃ ) ₂ and -CF ₃ ; or R ² and R ³ together with the nitrogen atom to which they are attached form a ring A which is pyrrolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, each of which is optionally substituted with at least one R ¹⁰ substituent, selected from methyl, ethyl, F, Cl, oxo and -CF ₃ ; a R ⁷ represents H, methyl, ethyl, propyl, isopropyl, tert-butyl, -CH ₂ NH ₂ , -CH ₂ NHCH ₃ or -CH ₂ N(CH ₃ ) ₂ , stereoisomers thereof and pharmaceutically acceptable salts thereof. In another aspect, a compound of formula (1-A3) of Table D, stereoisomers thereof, and pharmaceutically acceptable salts thereof are provided. In another aspect, the non-antibacterial compound of formula (1-A3) of Table D, stereoisomers thereof, and pharmaceutically acceptable salts thereof are provided.

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

where R ⁰ , R ¹ , R ² , R ³ and X' are as defined herein; its stereoisomers and its pharmaceutically acceptable salts. In another aspect, there is provided a compound of formula (1-A4);

where R ⁰ represents H, methyl, ethyl or propyl; a R ¹ , R ² , R ³ and X' are as defined herein, stereoisomers thereof and pharmaceutically acceptable salts thereof. In another aspect, there is a compound of formula (1-A4) wherein R ⁰ is H, methyl, ethyl or propyl; R ¹ represents H or methyl; and R ² , R ³ and X' are as defined herein; its stereoisomers and its pharmaceutically acceptable salts. In another aspect, there is a compound of formula (1-A4) wherein ^R0 is H or methyl; R ¹ represents methyl; and each of R ² and R ³ independently represents H, C ₁ -C ₆ alkyl, -CH ₂ N(CH ₃ ) ₂ , -CH ₂ CH ₂ N(CH ₃ ) ₂ ; or cyclopropyl, C ₁ cyclopropyl, cyclobutyl, C ₁ cyclobutyl, cyclopentyl, C 1 cyclopentyl, cyclohexyl, C ₁ cyclohexyl, phenyl, _{C 1 phenyl} , piperadinyl, C ₁ -piperadinyl, C ₂ piperadinyl, piperazinyl, morpholinyl, tetrahydro-2H- pyran, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl, each of which is optionally substituted with at least one R ⁹ substituent selected from the group consisting of methyl, ethyl, propyl, isopropyl, tert-butyl, hydroxy, methoxy, ethoxy , F, Cl, Br, cyano, cyclopropyl, amino, -N(CH ₃ ) ₂ , -CHF ₂ , -CF ₃ , -OCHF ₂ and -OCF ₃ ; or R ² and R ³ together with the nitrogen atom to which they are attached form a ring A which is pyrrolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, each of which is optionally substituted with at least one R ¹⁰ substituent, selected from the group consisting of methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F, Cl, Br, CN, -N( _CH3 ) ₂ , hydroxyl, _-CHF2 , _-CF3 , _-OCHF2 , -OCF ₃ and oxo; or ring A is indolinyl, isoindolinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, dihydropyrrolopyridinyl, dihydropyrrolopyrimidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxaline, dihydrobenzooxazinyl or dihydrobenzothiazinyl, optionally substituted with at least one oxo; and X' represents F, Cl or Br; its stereoisomers and its pharmaceutically acceptable salts. In another aspect, formula (1-A4) is provided, wherein R ⁰ represents H or methyl; R ¹ represents methyl; R ² represents H, methyl, ethyl, propyl, isopropyl, tert-butyl, -CH ₂ N(CH ₃ ) ₂ , -CH ₂ CH ₂ N(CH ₃ ) ₂ ; or cyclopropyl, cyclobutyl, phenyl, C ₁ phenyl, piperadinyl, C ₁ -piperadinyl, C ₂ piperadinyl, piperazinyl, morpholinyl, tetrahydro-2H-pyran, pyrazolyl or pyridinyl, each of which is optionally substituted with at least one R ⁹ substituent selected from the group consisting of methyl, ethyl, hydroxy, methoxy, ethoxy, F, Cl, nitro, cyano, -N(CH ₃ ) ₂ and -CF ₃ ; or R ² and R ³ together with the nitrogen atom to which they are attached form a ring A which is pyrrolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, each of which is optionally substituted with at least one R ¹⁰ substituent, selected from methyl, ethyl, F, Cl, oxo and -CF ₃ ; and X' represents F or Cl; its stereoisomers and its pharmaceutically acceptable salts. In another aspect, a compound of formula (1-A4) from Table E, stereoisomers thereof, and pharmaceutically acceptable salts thereof are provided.

In another aspect of the invention there is provided a compound of formula (1), wherein R is H, and W is formula (A), and formula (A) is formula (A5); that is, it is a compound of formula (1-A5),

where R ⁰ , R ¹ , R ² and R ³ are as defined herein; its stereoisomers and its pharmaceutically acceptable salts. In another aspect, there is provided a compound of formula (1-A5); where R ⁰ represents H, methyl, ethyl or propyl; a R ¹ , R ² and R ³ are as defined herein, stereoisomers thereof and pharmaceutically acceptable salts thereof. In another aspect, there is a compound of formula (1-A5) wherein ^R0 is H, methyl, ethyl or propyl; R ¹ represents H or methyl; a R ² and R ³ are as defined herein; its stereoisomers and its pharmaceutically acceptable salts. In another aspect, there is a compound of formula (1-A5) wherein ^R0 is H or methyl; R ¹ represents methyl; and each of R ² and R ³ independently represents H, C ₁ -C ₆ alkyl, -CH ₂ N(CH ₃ ) ₂ , -CH ₂ CH ₂ N(CH ₃ ) ₂ ; or cyclopropyl, C ₁ cyclopropyl, cyclobutyl, C ₁ cyclobutyl, cyclopentyl, C 1 cyclopentyl, cyclohexyl, C ₁ cyclohexyl, phenyl, _{C 1 phenyl} , piperadinyl, C ₁ -piperadinyl, C ₂ piperadinyl, piperazinyl, morpholinyl, tetrahydro-2H- pyran, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl, each of which is optionally substituted with at least one R ⁹ substituent selected from the group consisting of methyl, ethyl, propyl, isopropyl, tert-butyl, hydroxy, methoxy, ethoxy , F, Cl, Br, cyano, cyclopropyl, amino, -N(CH ₃ ) ₂ , -CHF ₂ , -CF ₃ , -OCHF ₂ and -OCF ₃ ; or R ² and R ³ together with the nitrogen atom to which they are attached form a ring A which is pyrrolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, each of which is optionally substituted with at least one R ¹⁰ substituent, selected from the group consisting of methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F, Cl, Br, CN, -N(CH ₃ ) ₂ , hydroxyl, -CHF ₂ , -CF ₃ , -OCHF ₂ , -OCF ₃ and oxo; or ring A is indolinyl, isoindolinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, dihydropyrrolopyridinyl, dihydropyrrolopyrimidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxaline, dihydrobenzooxazinyl or dihydrobenzothiazinyl, optionally substituted with at least one oxo; its stereoisomers and its pharmaceutically acceptable salts. In another aspect, formula (1-A5) is provided, wherein R ⁰ represents H or methyl; R ¹ represents methyl; R ² represents H, methyl, ethyl, propyl, isopropyl, tert-butyl, -CH ₂ N(CH ₃ ) ₂ , -CH ₂ CH ₂ N(CH ₃ ) ₂ ; or cyclopropyl, cyclobutyl, phenyl, C ₁ phenyl, piperadinyl, C ₁ -piperadinyl, C ₂ piperadinyl, piperazinyl, morpholinyl, tetrahydro-2H-pyran, pyrazolyl or pyridinyl, each of which is optionally substituted with at least one R ⁹ substituent selected from the group consisting of methyl, ethyl, hydroxy, methoxy, ethoxy, F, Cl, nitro, cyano, -N(CH ₃ ) ₂ and -CF ₃ ; or R ² and R ³ together with the nitrogen atom to which they are attached form a ring A which is pyrrolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, each of which is optionally substituted with at least one R ¹⁰ substituent, selected from methyl, ethyl, F, Cl, oxo and -CF ₃ ; its stereoisomers and its pharmaceutically acceptable salts. In another aspect, there is provided a compound of formula (1-A5) from Table F, stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect, a non-antibacterial compound of formula (1-A5) from Table F, stereoisomers thereof, and pharmaceutically acceptable salts thereof are provided.

In another aspect, there is a compound of formula (1), wherein R is H, W is formula (A), and formula (A) is formula (A6), that is, a compound of formula (1-A6), wherein R ⁰ , R ¹ ,

R ² and R ³ are as defined herein; its stereoisomers and its pharmaceutically acceptable salts. In another aspect, there is a compound of formula (1-A6) wherein R ⁰ is H, methyl, ethyl or propyl; a R ¹ , R ² and R ³ are as defined herein, stereoisomers thereof and pharmaceutically acceptable salts thereof. In another aspect, there is a compound of formula (1-A6) wherein R ⁰ is H, methyl, ethyl or propyl; R ¹ represents H or methyl; a R ² and R ³ are as defined herein; its stereoisomers and its pharmaceutically acceptable salts. In another aspect, there is a compound of formula (1-A6), wherein R ⁰ represents H or methyl; R ¹ represents methyl; and each of R ² and R ³ independently represents H, C ₁ -C ₆ alkyl; -CH ₂ N(CH ₃ ) ₂ , -CH ₂ CH ₂ N(CH ₃ ) ₂ ; or cyclopropyl, C ₁ cyclopropyl, cyclobutyl, C ₁ cyclobutyl, cyclopentyl, C 1 cyclopentyl, cyclohexyl, C ₁ cyclohexyl, phenyl, _{C 1 phenyl} , piperadinyl, C ₁ -piperadinyl, C ₂ piperadinyl, piperazinyl, morpholinyl, tetrahydro-2H- pyran, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl, each of which is optionally substituted with at least one R ⁹ substituent selected from the group consisting of methyl, ethyl, propyl, isopropyl, tert-butyl, hydroxy, methoxy, ethoxy , F, Cl, Br, cyano, cyclopropyl, amino, -N(CH ₃ ) ₂ , -CHF ₂ , -CF ₃ , -OCHF ₂ and -OCF ₃ ; or R ² and R ³ together with the nitrogen atom to which they are attached form a ring A which is pyrrolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, each of which is optionally substituted with at least one R ¹⁰ substituent, selected from the group consisting of methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F, Cl, Br, CN, -N( _CH3 ) ₂ , hydroxyl, _-CHF2 , _-CF3 , _-OCHF2 , -OCF ₃ and oxo; or ring A is indolinyl, isoindolinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, dihydropyrrolopyridinyl, dihydropyrrolopyrimidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxaline, dihydrobenzooxazinyl or dihydrobenzothiazinyl, optionally substituted with at least one oxo; its stereoisomers and its pharmaceutically acceptable salts. In another aspect, formula (1-A6) is provided, wherein R ⁰ represents H or methyl; R ¹ represents methyl; R ² represents H, methyl, ethyl, propyl, isopropyl, tert-butyl, -CH ₂ N(CH ₃ ) ₂ , -CH ₂ CH ₂ N(CH ₃ ) ₂ ; or cyclopropyl, cyclobutyl, phenyl, C ₁ phenyl, piperadinyl, C ₁ -piperadinyl, C ₂ piperadinyl, piperazinyl, morpholinyl, tetrahydro-2H-pyran, pyrazolyl or pyridinyl, each of which is optionally substituted with at least one R ⁹ substituent selected from the group consisting of methyl, ethyl, hydroxy, methoxy, ethoxy, F, Cl, nitro, cyano, -N(CH ₃ ) ₂ and -CF ₃ ; or R ² and R ³ together with the nitrogen atom to which they are attached form a ring A which is pyrrolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, each of which is optionally substituted with at least one R ¹⁰ substituent, selected from methyl, ethyl, F, Cl, oxo and -CF ₃ ; its stereoisomers and its pharmaceutically acceptable salts. In another aspect, a compound of formula (1-A6) from Table G, stereoisomers thereof, and pharmaceutically acceptable salts thereof are provided.

In another aspect, there is provided a composition containing a compound of formula (1-A2), stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect, a composition is provided containing a compound of formula (1-A2) from Table C, stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect, there is provided a composition containing a compound of formula (1-A3), stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect, a composition is provided containing a compound of formula (1-A3) from Table D, stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect, a composition is provided containing a non-antibacterial compound of formula (1-A3), stereoisomers thereof and pharmaceutically acceptable salts thereof. In another aspect, there is provided a composition containing a compound of formula (1-A4), stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect, a composition is provided containing a compound of formula (1-A4) from Table E, stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect, there is provided a composition containing a compound of formula (1-A5), stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect, a composition is provided comprising a non-antibacterial compound of formula (1-A5) from Table F, stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect, there is provided a composition containing a compound of formula (1-A6), stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect, the composition further comprises a pharmaceutically acceptable carrier.

In another aspect, a method is provided for treating or preventing an inflammatory response in an animal by administering to said animal in need thereof a therapeutically effective amount of a compound of formula (1-A2), stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect, a method is provided for treating or preventing an inflammatory response in an animal by administering to said animal in need thereof a therapeutically effective amount of a compound of formula (1-A2) of Table C, its stereoisomers, and pharmaceutically acceptable salts thereof. In another aspect, a method is provided for treating or preventing an inflammatory response in an animal by administering to said animal in need thereof a therapeutically effective amount of a compound of formula (1-A3), stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect, a method is provided for treating or preventing an inflammatory response in an animal by administering to said animal in need thereof a therapeutically effective amount of a compound of formula (1-A3) of Table D, stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect, a method is provided for treating or preventing an inflammatory response in an animal by administering to said animal in need thereof a therapeutically effective amount of a non-antibacterial compound of formula (1-A3) of Table D, stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect, a method is provided for treating or preventing an inflammatory response in an animal by administering to said animal in need thereof a therapeutically effective amount of a compound of formula (1-A4), stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect, a method is provided for treating or preventing an inflammatory response in an animal by administering to said animal in need thereof a therapeutically effective amount of a compound of formula (1-A4) of Table E, its stereoisomers, and pharmaceutically acceptable salts thereof. In another aspect, a method is provided for treating or preventing an inflammatory response in an animal by administering to said animal in need thereof a therapeutically effective amount of a compound of formula (1-A5), stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect, a method of treating or preventing an inflammatory response in an animal is provided by administering to said animal in need thereof a therapeutically effective amount of a compound of formula (1-A5) of Table F, stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect, a method is provided for treating or preventing an inflammatory response in an animal by administering to said animal in need thereof a therapeutically effective amount of a non-antibacterial compound of formula (1-A5) of Table F, stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect, a method is provided for treating or preventing an inflammatory response in an animal by administering to said animal in need thereof a therapeutically effective amount of a compound of formula (1-A6), stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect, a method of treating or preventing an inflammatory response in an animal is provided by administering to said animal in need thereof a therapeutically effective amount of a compound of formula (1-A6) of Table G, stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect of the method, the inflammatory response occurs due to a bacterial, viral or fungal infection, stress and/or environmental factor. In another aspect of the method, a method of treating or preventing an inflammatory response in an animal prevents or reduces the progression of a respiratory disease or disorder. In another aspect of the method, the animal is a farm animal. In another aspect of the method, the respiratory disease or disorder is bovine respiratory disease or porcine respiratory disease. In another aspect of the method, a method of treating or preventing an inflammatory response in an animal provides down-regulation of TNF-α and IL-6 in the animal.

In another aspect, the use of a compound of formula (1-A2), its stereoisomers and its pharmaceutically acceptable salts for the manufacture of a medicament for treating or preventing an inflammatory response in an animal is provided. In another aspect, the use of a compound of formula (1-A2) from Table C, its stereoisomers and pharmaceutically acceptable salts thereof for the manufacture of a medicament for treating or preventing an inflammatory response in an animal is provided. In another aspect, the use of a compound of formula (1-A3), its stereoisomers and its pharmaceutically acceptable salts for the manufacture of a medicament for treating or preventing an inflammatory response in an animal is provided. In another aspect, the use of a non-antibacterial compound of formula (1-A3) from Table D, its stereoisomers and pharmaceutically acceptable salts thereof for the manufacture of a medicament for treating or preventing an inflammatory response in an animal is provided. Another aspect provides the use of a compound of formula (1-A4), stereoisomers thereof, and pharmaceutically acceptable salts thereof for the manufacture of a medicament for treating or preventing an inflammatory response in an animal. In another aspect, the use of a compound of formula (1-A4) from Table E, its stereoisomers and pharmaceutically acceptable salts thereof for the manufacture of a medicament for treating or preventing an inflammatory response in an animal is provided. In another aspect, the use of a compound of formula (1-A5), its stereoisomers and pharmaceutically acceptable salts thereof is provided for the manufacture of a medicament for treating or preventing an inflammatory response in an animal. Another aspect provides the use of a non-antibacterial compound of formula (1-A5), stereoisomers thereof, and pharmaceutically acceptable salts thereof for the manufacture of a medicament for treating or preventing an inflammatory response in an animal. In another aspect, the use of a compound of formula (1-A6), its stereoisomers and its pharmaceutically acceptable salts for the manufacture of a medicament for treating or preventing an inflammatory response in an animal is provided. In another aspect, the use of a compound of formula (1-A6) from Table G, its stereoisomers and pharmaceutically acceptable salts thereof for the manufacture of a medicament for treating or preventing an inflammatory response in an animal is provided. In another aspect of application, the inflammatory response occurs due to a bacterial, viral or fungal infection, stress and/or environmental factor. In another aspect of use, the use of a medicament to treat or prevent an inflammatory response in an animal prevents or reduces the progression of a respiratory disease or disorder. In another aspect of application, the animal is a farm animal. In another aspect of use, the respiratory disease or disorder is bovine respiratory disease or porcine respiratory disease. In another aspect of use, administering a drug to an animal to treat or prevent an inflammatory response in the animal provides down-regulation of TNF-α and IL-6 in the animal.

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

and wherein R ⁰ , R ¹ , R ² , R ³ , R ⁵ and R ⁶ are as defined herein; its stereoisomers and its pharmaceutically acceptable salts. In another aspect, there is a compound of formula (1-A1), wherein R ⁰ represents H, methyl, ethyl or propyl; and R ¹ , R ² , R ³ , R ⁵ and R ⁶ are as defined herein, stereoisomers thereof and pharmaceutically acceptable salts thereof. In another aspect, there is a compound of formula (1-A1), wherein R ⁰ represents H, methyl, ethyl or propyl; R ¹ represents H or methyl; and R ² , R ³ , R ⁵ and R ⁶ are as defined herein, stereoisomers thereof and pharmaceutically acceptable salts thereof. In another aspect, there is provided a compound of formula (1-A1), wherein each of R ⁰ and R ¹ independently represents H or methyl; R ² , R ³ , R ⁵ and R ⁶ are as defined herein, their stereoisomers and pharmaceutically acceptable salts thereof. In another aspect, there is provided a compound of formula (1-A1), wherein R ⁰ represents H or methyl; and R ² , R ³ , R ⁵ and R ⁶ are as defined herein, stereoisomers thereof and pharmaceutically acceptable salts thereof. In another aspect, there is provided a compound of formula (1-A1), wherein R ⁰ represents H or methyl; R ¹ represents methyl; each of R ² and R ³ independently represents H, C ₁ -C ₆ alkyl; -CH ₂ N(CH ₃ ) ₂ , -CH ₂ CH ₂ N(CH ₃ ) ₂ ; or cyclopropyl, C ₁ cyclopropyl, cyclobutyl, C 1 cyclobutyl, cyclopentyl, C ₁ cyclopentyl, cyclohexyl, C ₁ cyclohexyl, phenyl, _{C 1 phenyl} , piperadinyl, C ₁ -piperadinyl, C ₂ piperadinyl, piperazinyl, morpholinyl, tetrahydropyran, pyrrolyl, pyrazolyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl, each of which is optionally substituted with at least one R ⁹ substituent selected from the group consisting of methyl, ethyl, propyl, isopropyl, tert-butyl, hydroxy, methoxy, ethoxy, F , Cl, Br, cyano, amino, -N(CH ₃ ) ₂ , -CHF ₂ , -CF ₃ , -OCHF ₂ and -OCF ₃ ; or R ² and R ³ together with the nitrogen atom to which they are attached form a ring A which is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, each of which is optionally substituted with at least at least one substituent R ¹⁰ selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F, Cl, Br, CN, -N(CH ₃ ) ₂ , hydroxyl, -CHF ₂ , -CF ₃ , -OCHF ₂ , -OCF ₃ and oxo; and wherein each ring is further optionally fused to Y which is phenyl, pyridinyl or pyrimidinyl; R ⁵ and R ⁶ are each independently H; C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy, each of which is optionally substituted with at least one hydroxy; C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, -C(O)R ⁸ , -C(O)NR ^a R ⁸ , -C(O)R ^c NR ^a R ^b , -R ^c S(O ) _p R ⁸ , -R ^c NR ^a R ^b , -R ^c OR ^a , -S(O) _p R ⁸ ; or phenyl, C ₁ alkylphenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C ₁ -C ₂ alkylcyclopropyl, C ₁ -C ₂ alkylcyclobutyl, oxazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, C ₁ -C ₂ alkyloxazolidinyl, C ₁ -C ₂ alkylpyrrolidinyl, C ₁ -C ₂ alkylpiperidinyl, C ₁ -C ₂ alkylpiperazinyl, C ₁ -C ₂ morpholinyl, C ₁ -C ₂ morpholinyl, C ₁ -C ₂ piperadinyl, C ₁ -C ₂ tetrahydropyranyl, C ₁ -C ₂ tetrahydrofuranyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, C ₁ -C ₂ alkylpyrazolyl, C ₁ -C ₂ alkyl imidazolyl, C ₁ -C ₂ alkyl pyridinyl, C ₁ -C ₂ alkylpyrimidinyl or C ₁ -C ₂ alkylpyrazinyl, each of which is optionally substituted with at least one R ¹⁰ substituent independently selected from methyl, ethyl, methoxy, ethoxy, -CHF ₂ , -CF ₃ , -OCF ₃ , F, Cl, -NHCH ₃ , -N(CH ₃ ) ₂ , -S(O) ₂ CH ₃ , cyano and hydroxy; or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a ring B which is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, each of which is optionally substituted with at least at least one substituent ^R9 selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F, Cl, Br, CN, -N( _CH3 ) ₂ , hydroxy, _-CHF2 , _-CF3 , _-OCHF2 , -OCF ₃ and oxo; and wherein each ring is further optionally fused to Y which is phenyl, pyridinyl or pyrimidinyl; its stereo isomers and its pharmaceutically acceptable salts. In another aspect, there is provided a compound of formula (1-A1), wherein R ⁰ represents H or methyl; R ¹ represents methyl; each of R ² and R ³ independently represents H, C ₁ -C ₆ alkyl; -CH ₂ N(CH ₃ ) ₂ , -CH ₂ CH ₂ N(CH ₃ ) ₂ ; or cyclopropyl, C ₁ cyclopropyl, cyclobutyl, C ₁ cyclobutyl, cyclopentyl, C 1 cyclopentyl, cyclohexyl, C ₁ cyclohexyl, phenyl, _{C 1 phenyl} , piperadinyl, C ₁ -piperadinyl, C ₂ piperadinyl, piperazinyl, morpholinyl, tetrahydro-2H- pyran, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl, each of which is optionally substituted with at least one R ⁹ substituent selected from the group consisting of methyl, ethyl, propyl, isopropyl, tert-butyl, hydroxy, methoxy, ethoxy , F, Cl, Br, cyano, cyclopropyl, amino, -N(CH ₃ ) ₂ , -CHF ₂ , -CF ₃ , -OCHF ₂ and -OCF ₃ ; or R ² and R ³ together with the nitrogen atom to which they are attached form a ring A which is pyrrolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, each of which is optionally substituted with at least one R ¹⁰ substituent, selected from methyl, ethyl, F, Cl, oxo and -CF ₃ ; and wherein each ring is further optionally fused to Y, which is phenyl; R ⁵ and R ⁶ are each independently H; C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy, each of which is optionally substituted with at least one hydroxy; C ₁ -C ₆ haloalkyl, -OCF ₃ , -C(O)NR ^a R ⁸ , -R ^c S(O) _p R ⁸ , -R ^c NR ^a R ^b , -R ^c OR ^a , -S(O ) _p R ⁸ ; or phenyl, C ₁ alkylphenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C ₁ -C ₂ alkylcyclopropyl and C ₁ -C ₂ alkylcyclobutyl, oxazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, C ₁ -C ₂ alkyloxazolidinyl, C ₁ -C ₂ alkylpyrrolidinyl, C ₁ -C ₂ alkylpiperidinyl, C 1 -C ₂ alkylpiperazinyl, C ₁ -C ₂ morpholinyl, C ₁ -C ₂ tetrahydropyranyl, C _{1 -C 2} tetrahydrofuranyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, C ₁ -C ₂ alkylpyrazolyl, C ₁ -C ₂ alkyl imidazolyl, CC ₁ -C ₂ alkylpyridinyl, C ₁ -C ₂ alkylpyrimidinyl or C ₁ -C ₂ alkylpyrazinyl, each of which is optionally substituted with at least one R ¹⁰ substituent, independently selected from methyl, ethyl, methoxy, ethoxy, -CHF ₂ , -CF ₃ , -OCF ₃ , F, Cl, amino, -NHCH ₃ , -N(CH ₃ ) ₂ , -S(O) ₂ CH ₃ , cyano and hydroxy; or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a ring B which is pyrrolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, each of which is optionally substituted with at least one R ⁹ substituent, selected from methyl, ethyl, F, O, cyano, hydroxy, oxo and -CF ₃ ; and wherein each ring is further optionally fused to Y, which is phenyl; its stereoisomers and its pharmaceutically acceptable salts. In another aspect, there is provided a compound of formula (1-A1), wherein R ⁰ represents H or methyl; R ¹ represents methyl; R ² is H, methyl, ethyl, isopropyl, cyclopropyl, -CF ₃ , -CHF ₂ , -CH ₂ F, -CH ₂ CF ₃ or r-phenyl; R ³ represents H, methyl, ethyl, propyl, isopropyl, tert-butyl, -CH ₂ N(CH ₃ ) ₂ , -CH ₂ CH ₂ N(CH ₃ ) ₂ ; or cyclopropyl, cyclobutyl, phenyl, C ₁ phenyl, piperadinyl, C ₁ -piperadinyl, C ₂ piperadinyl, piperazinyl, morpholinyl, tetrahydro-2H-pyran, pyrazolyl or pyridinyl, each of which is optionally substituted with at least one R ⁹ substituent selected from the group consisting of methyl, ethyl, hydroxy, methoxy, ethoxy, F, Cl, cyano, amino, -N(CH ₃ ) ₂ and -CF ₃ ; or R ² and R ³ together with the nitrogen atom to which they are attached form a ring A which is pyrrolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, each of which is optionally substituted with at least one R ¹⁰ substituent, selected from methyl, ethyl, F, Cl, oxo and -CF ₃ ; or ring B is indolinyl, isoindolinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, dihydropyrrolopyridinyl, dihydropyrrolopyrimidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxaline, dihydrobenzooxazine or dihydrobenzothiazine, optionally substituted with at least one oxo; R ⁵ is H, C ₁ -C ₆ alkyl, morpholinyl, piperadinyl, -CH ₂ morpholinyl, -CH ₂ piperadinyl, -(CH ₂ ) ₂ morpholinyl or (CH ₂ ) ₂ piperadinyl; R ⁶ is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, -CH ₂ CF ₃ , -CF ₃ or -OCF ₃ ; -C(O)NR ^a R ⁸ where R ^a is H or methyl and R ⁸ is H, methyl, cyclopropyl, phenyl, optionally substituted with F, Cl or -CF ₃ ; -(CH ₂ )S(O) ₂ R ⁸ where R ⁸ represents methyl or phenyl; -CH ₂ NR ^a R ^b or -(CH ₂ ) ₂ NR ^a R ^b , wherein R ^a and R ^b are each independently H or methyl; -(CH ₂ ) ₂ OCH ₃ , -(CH ₂ ) ₃ OCH ₃ ; or phenyl, C ₁ alkylphenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C ₁ -C ₂ alkylcyclopropyl, C ₁ -C ₂ alkylcyclobutyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, C ₁ -C ₂ alkylpyrrolidinyl, C ₁ -C ₂ alkylpiperidinyl, C ₁ -C ₂ alkylpiperazinyl, C ₁ -C ₂ morpholinyl, C ₁ -C ₂ tetrahydropyranyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, C ₁ -C ₂ alkylpyrazolyl, C ₁ -C ₂ alkyl imidazolyl, C ₁ -C ₂ alkylpyridinyl, C ₁ -C ₂ alkylpyrimidinyl and C ₁ -C ₂ alkylpyrazinyl; each of which is optionally substituted with at least one R ¹⁰ substituent independently selected from methyl, ethyl, methoxy, ethoxy, -CHF ₂ , -CF ₃ , -OCF ₃ , F, Cl, amino, -NHCH ₃ , -N(CH ₃ ) ₂ , -S(O) ₂ CH ₃ , cyano and hydroxy; or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a ring B which is pyrrolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, each of which is optionally substituted with at least one R ⁹ substituent, selected from methyl, ethyl, F, Cl, cyano, hydroxy, oxo and -CF ₃ ; or ring B is indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydrobenzooxazinyl or dihydrobenzothiazinyl, optionally substituted with at least one oxo; its stereoisomers and its pharmaceutically acceptable salts. In another aspect, there is provided a compound of formula (1-A1), wherein R ⁰ represents H or methyl; R ¹ represents methyl; R ² represents H or methyl; R ³ is methyl, ethyl or propyl, isopropyl, tert-butyl, -CH ₂ N(CH ₃ ) ₂ , -CH ₂ CH ₂ N(CH ₃ ) ₂ ; or cyclopropyl, cyclobutyl, phenyl, C ₁ phenyl, piperadinyl, C ₁ -piperadinyl, piperazinyl, morpholinyl or pyridinyl, each of which is optionally substituted with at least one R ⁹ substituent selected from the group consisting of methyl, ethyl, hydroxy, methoxy , ethoxy, F, Cl, cyano, -N(CH ₃ ) ₂ and -CF ₃ ; R ⁵ is H, methyl, ethyl, propyl or isopropyl; R ⁶ represents H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, -CH ₂ CF ₃ , -CF ₃ , -OCF ₃ ; -C(O)NR ^a R ⁸ where R ^a is H or methyl and R ⁸ is H, methyl, cyclopropyl, phenyl, optionally substituted with F, Cl or -CF ₃ ; -(CH ₂ )S(O) ₂ R ⁸ where R ⁸ represents methyl or phenyl; -CH ₂ NR ^a R ^b or -(CH ₂ ) ₂ NR ^a R ^b , wherein R ^a and R ^b are each independently H or methyl; -(CH ₂ ) ₂ OCH ₃ , -(CH ₂ ) ₃ OCH ₃ ; or phenyl, C ₁ alkylphenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C ₁ -C ₂ alkylcyclopropyl, C ₁ -C ₂ alkylcyclobutyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, C ₁ -C ₂ alkylpyrrolidinyl, C ₁ -C ₂ alkylpiperidinyl, C ₁ -C ₂ alkylpiperazinyl, C ₁ -C ₂ morpholinyl, C ₁ -C ₂ tetrahydropyranyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, C ₁ -C ₂ alkylpyrazolyl, C ₁ -C ₂ alkyl imidazolyl, C ₁ -C ₂ alkylpyridinyl, C ₁ -C ₂ alkylpyrimidinyl or C ₁ -C ₂ alkylpyrazinyl; each of which is optionally substituted with at least one R ¹ 0 substituent independently selected from methyl, ethyl, methoxy, ethoxy, -CHF ₂ , -CF ₃ , -OCF ₃ , F, Cl, amino, -NHCH ₃ , -N( CH ₃ ) ₂ , -S(O) ₂ CH ₃ , cyano and hydroxy; its stereoisomers and its pharmaceutically acceptable salts. In another aspect, a compound of formula (1-A1) from Table H, stereoisomers thereof, and pharmaceutically acceptable salts thereof are provided. In another aspect, a non-antibacterial compound of formula (1-A1) from Table H, stereoisomers thereof, and pharmaceutically acceptable salts thereof are provided. In another aspect, formula (1-A1) is presented, that 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.

In another aspect, there is provided a composition containing a compound of formula (1-A1), stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect, a composition is provided containing a compound of formula (1-A1) from Table H, stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect, a composition is provided comprising a non-antibacterial compound of formula (1-A1) from Table H, stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect, there is provided a composition containing a compound of formula (1-A1), that 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-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.

In another aspect, a method is provided for treating or preventing an inflammatory response in an animal by administering to said animal in need thereof a therapeutically effective amount of a compound of formula (1-A1), stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect, a method is provided for treating or preventing an inflammatory response in an animal by administering to said animal in need thereof a therapeutically effective amount of a compound of formula (1-A1) of Table H, its stereoisomers, and pharmaceutically acceptable salts thereof. In another aspect, there is provided a method of treating or preventing an inflammatory response in an animal by administering to said animal in need thereof a therapeutically effective amount of a non-antibacterial compound of formula (1-A1) of Table H, stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect, a method is provided for treating or preventing an inflammatory response in an animal by administering to said animal in need thereof a therapeutically effective amount of Example H-11; 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12R,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 of the method, the inflammatory response occurs due to a bacterial, viral or fungal infection, stress and/or environmental factor. In another aspect of the method, a method of treating or preventing an inflammatory response in an animal prevents or reduces the progression of a respiratory disease or disorder. In another aspect of the method, the animal is a farm animal. In another aspect of the method, the respiratory disease or disorder is bovine respiratory disease or porcine respiratory disease. In another aspect of the method, a method of treating or preventing an inflammatory response in an animal provides down-regulation of TNF-α and IL-6 in the animal.

In another aspect, the use of a compound of formula (1-A1), its stereoisomers and its pharmaceutically acceptable salts for the manufacture of a medicament for treating or preventing an inflammatory response in an animal is provided. In another aspect, the use of a compound of formula (1-A1) from Table H, its stereoisomers and its pharmaceutically acceptable salts for the manufacture of a medicament for treating or preventing an inflammatory response in an animal is provided. In another aspect, the use of a non-antibacterial compound of formula (1-A1) from Table H, its stereoisomers and pharmaceutically acceptable salts thereof for the manufacture of a medicament for treating or preventing an inflammatory response in an animal is provided. In another aspect, the use of N-11 is presented; 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, for the manufacture of a medicament for treating or preventing an inflammatory response in an animal. In another aspect of application, the inflammatory response occurs due to a bacterial, viral or fungal infection, stress and/or environmental factor. In another aspect of use, the use of a medicament to treat or prevent an inflammatory response in an animal prevents or reduces the progression of a respiratory disease or disorder. In another aspect of application, the animal is a farm animal. In another aspect of use, the respiratory disease or disorder is bovine respiratory disease or porcine respiratory disease. In another aspect of use, administering a drug to an animal to treat or prevent an inflammatory response in the animal provides down-regulation of TNF-α and IL-6 in the animal.

In another aspect of the invention there is provided a compound of formula (1-A1) wherein R ¹ is methyl and R ² and R ³ together with the nitrogen atom to which they are attached form a ring A which is optionally substituted with at least one R ¹⁰ substituent , which is a compound of formula (1-A1b), where R ⁰ , R ⁵ , R ⁶ , ring A, R ¹⁰ and n are as defined

herein, its stereoisomers and its pharmaceutically acceptable salts. In another aspect, there is a compound of formula (1-A1a), wherein R ⁰ represents H or methyl; and R ¹ , R ⁶ , R ¹⁰ , ring A, and n are as defined herein, stereoisomers thereof and pharmaceutically acceptable salts thereof. In another aspect, there is a compound of formula (1-A1a), wherein R ⁰ represents H or methyl; R ⁵ is H, methyl, ethyl, propyl, isopropyl, -CH ₂ morpholinyl, -CH ₂ piperadinyl, -(CH ₂ ) ₂ morpholinyl or (CH ₂ ) ₂ piperadinyl; R ⁶ represents H; C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy, each of which is optionally substituted with at least one hydroxy; C ₁ -C ₆ haloalkyl, -OCF ₃ , -C(O)NR ^a R ⁸ , -R ^c S(O) _p R ⁸ , -R ^c NR ^a R ^b , -R ^c OR ^a or -S(O ) _p R ⁸ ; or phenyl, C ₁ alkylphenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C ₁ -C ₂ alkylcyclopropyl, C ₁ -C ₂ alkylcyclobutyl, oxazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, C ₁ -C ₂ alkyloxazolidinyl, C ₁ -C ₂ alkylpyrrolidinyl, C ₁ -C ₂ alkylpiperidinyl, C 1 -C ₂ alkylpiperazinyl, C ₁ -C ₂ morpholinyl, C ₁ -C ₂ tetrahydropyranyl, C _{1 -C 2} tetrahydrofuranyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, C ₁ -C ₂ alkylpyrazolyl, C ₁ -C ₂ alkyl imidazolyl, C ₁ -C ₂ alkylpyridinyl, C ₁ -C ₂ alkylpyrimidinyl or C ₁ -C ₂ alkylpyrazinyl, each of which is optionally substituted with at least one R ¹⁰ substituent, independently selected from methyl, ethyl, methoxy, ethoxy, -CHF ₂ , -CF ₃ , -OCF ₃ , F, Cl, -NHCH ₃ , -N(CH ₃ ) ₂ , -S(O) ₂ CH ₃ , cyano and hydroxy; and ring A is pyrrolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, each of which is optionally substituted with at least one R ¹⁰ substituent selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, F, Cl, Br, CN, -N(CH ₃ ) ₂ , hydroxyl, -CHF ₂ , -CF ₃ , -OCHF ₂ , -OCF ₃ and oxo; or ring A is indolinyl, isoindolinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, dihydropyrrolopyridinyl, dihydropyrrolopyrimidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxaline, dihydrobenzooxazine or dihydrobenzothiazine, optionally substituted with at least one oxo; its stereoisomers and its pharmaceutically acceptable salts. In another aspect, there is a compound of formula (1-A1a), wherein R ⁰ represents H or methyl; R ⁵ is H, methyl, ethyl, propyl or isopropyl; R ⁶ represents H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, -CH ₂ CF ₃ , -CF ₃ , -OCF ₃ ; -C(O)NR ^a R ⁸ where R ^a is H or methyl and R ⁸ is H, methyl, cyclopropyl, phenyl, optionally substituted with F, Cl or -CF ₃ ; -(CH ₂ )S(O) ₂ R ⁸ where R ⁸ represents methyl or phenyl; -CH ₂ NR ^a R ^b or -(CH ₂ ) ₂ NR ^a R ^b , where each of R ^a and R ^b is independently H or methyl; -(CH ₂ ) ₂ OCH ₃ , (CH ₂ ) ₃ OCH ₃ ; or phenyl, C ₁ alkylphenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C ₁ -C ₂ alkylcyclopropyl, C ₁ -C ₂ alkylcyclobutyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, C ₁ -C ₂ alkylpyrrolidinyl, C ₁ -C ₂ alkylpiperidinyl, C ₁ -C ₂ alkylpiperazinyl, C ₁ -C ₂ morpholinyl, C ₁ -C ₂ tetrahydropyranyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, C ₁ -C ₂ alkylpyrazolyl, C ₁ -C ₂ alkylimidazolyl, C ₁ -C ₂ alkylpyridinyl, C ₁ -C ₂ alkylpyrimidinyl or C ₁ -C ₂ alkylpyrazinyl; each of which is optionally substituted with at least one R ¹⁰ substituent independently selected from methyl, ethyl, methoxy, ethoxy, -CHF ₂ , -CF ₃ , -OCF ₃ , F, Cl, amino, -NHCH ₃ , -N(CH ₃ ) ₂ , -S(O) ₂ CH ₃ , cyano and hydroxy; and ring A is pyrrolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, each of which is optionally substituted with at least one R ¹⁰ substituent selected from methyl, ethyl, F, Cl, oxo and -CF ₃ ; or ring A is indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydrobenzooxazinyl or dihydrobenzothiazinyl, optionally substituted with at least one oxo; or ring A is pyrrolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, each of which is optionally substituted with at least one R ¹⁰ substituent selected from methyl, ethyl, F, Cl, oxo and -CF ₃ ; its stereoisomers and its pharmaceutically acceptable salts. In another aspect, a compound of formula (1-A1a) from Table I, stereoisomers thereof, and pharmaceutically acceptable salts thereof are provided. In another aspect, a non-antibacterial compound of formula (1-A1a) from Table I, stereoisomers thereof, and pharmaceutically acceptable salts thereof are provided.

In another aspect, there is provided a composition containing a compound of formula (1-A1a), stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect, a composition is provided containing a compound of formula (1-A1a) from Table I, stereoisomers thereof, and pharmaceutically acceptable salts thereof.

In another aspect, a composition is provided containing a non-antibacterial compound of formula (1-A1a) from Table I, stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect, the composition further comprises a pharmaceutically acceptable carrier.

In another aspect, a method is provided for treating or preventing an inflammatory response in an animal by administering to said animal in need thereof a therapeutically effective amount of a compound of formula (1-A1a), stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect, a method is provided for treating or preventing an inflammatory response in an animal by administering to said animal in need thereof a therapeutically effective amount of a compound of formula (1-A1a) of Table I, stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect, a method is provided for treating or preventing an inflammatory response in an animal by administering to said animal in need thereof a therapeutically effective amount of a non-antibacterial compound of formula (1-A1a) of Table I, stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect of the method, the inflammatory response occurs due to a bacterial, viral or fungal infection, stress and/or environmental factor. In another aspect of the method, a method of treating or preventing an inflammatory response in an animal prevents or reduces the progression of a respiratory disease or disorder. In another aspect of the method, the animal is a farm animal. In another aspect of the method, the respiratory disease or disorder is bovine respiratory disease or porcine respiratory disease. In another aspect of the method, a method of treating or preventing an inflammatory response in an animal provides down-regulation of TNF-α and IL-6 in the animal.

Another aspect provides the use of a compound of formula (1-A1a), stereoisomers thereof, and pharmaceutically acceptable salts thereof for the manufacture of a medicament for treating or preventing an inflammatory response in an animal. In another aspect, the use of a compound of formula (1-A1a) from Table I, its stereoisomers and its pharmaceutically acceptable salts for the manufacture of a medicament for treating or preventing an inflammatory response in an animal is provided. In another aspect, the use of a non-antibacterial compound of formula (1-A1a) from Table I, its stereoisomers and pharmaceutically acceptable salts thereof for the manufacture of a medicament for treating or preventing an inflammatory response in an animal is provided. In another aspect of application, the inflammatory response occurs due to a bacterial, viral or fungal infection, stress and/or environmental factor. In another aspect of use, the use of a medicament to treat or prevent an inflammatory response in an animal prevents or reduces the progression of a respiratory disease or disorder. In another aspect of application, the animal is a farm animal. In another aspect of use, the respiratory disease or disorder is bovine respiratory disease or porcine respiratory disease. In another aspect of use, administering a drug to an animal to treat or prevent an inflammatory response in the animal provides down-regulation of TNF-α and IL-6 in the animal.

In another aspect of the invention there is provided a compound of formula (1-A1) wherein R ¹ is methyl and R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a ring B which is optionally substituted with at least one R ⁹ substituent which is a compound of formula (1-A1b) wherein R ⁰ , R ² , R ³ , ring B, R ⁹ and n are as defined herein,

its stereoisomers and its pharmaceutically acceptable salts. In another aspect, there is a compound of formula (1-A1b), wherein R ⁰ represents H or methyl; a R ² , R ³ , ring B, R ⁹ n are as defined herein. In another aspect, there is a compound of formula (1-A1b), wherein R ⁰ represents H or methyl; R ² is H, methyl, ethyl, isopropyl, cyclopropyl, -CF ₃ , -CHF ₂ , -CH ₂ F, -CH ₂ CF ₃ or phenyl; R ³ represents H, methyl, ethyl, propyl, isopropyl, tert-butyl, -CH ₂ N(CH ₃ ) ₂ , -CH ₂ CH ₂ N(CH ₃ ) ₂ ; or cyclopropyl, cyclobutyl, phenyl, C ₁ phenyl, piperadinyl, C ₁ -piperadinyl, C ₂ piperadinyl, piperazinyl, morpholinyl, tetrahydro-2H-pyran, pyrazolyl or pyridinyl, each of which is optionally substituted with at least one R ⁹ substituent selected from the group consisting of methyl, ethyl, hydroxy, methoxy, ethoxy, F, Cl, cyano, amino, -N(CH ₃ ) ₂ and -CF ₃ ; or R ² and R ³ together with the nitrogen atom to which they are attached form a ring A which is pyrrolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, each of which is optionally substituted with at least one R ¹⁰ substituent, selected from methyl, ethyl, F, Cl, oxo and -CF ₃ ; and wherein each ring is further optionally fused to Y, which is phenyl; a R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a ring B, which is pyrrolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, each of which is optionally substituted with at least one R ⁹ substituent. selected from methyl, ethyl, hydroxy, F, Cl, cyano, oxo and -CF ₃ ; and wherein each ring is further optionally fused to Y, which is phenyl; its stereoisomers and its pharmaceutically acceptable salts. In another aspect, there is a compound of formula (1-A1b), wherein R ⁰ represents H or methyl; R ² represents H or methyl; and R ³ is methyl, ethyl, propyl, isopropyl, tert-butyl, -CH ₂ (CH ₃ ) ₂ , -CH ₂ CH ₂ N(CH ₃ ) ₂ ; or cyclopropyl, cyclobutyl, phenyl, C ₁ phenyl, piperadinyl, C ₁ -piperadinyl, piperazinyl, morpholinyl or pyridinyl, each of which is optionally substituted with at least one R ⁹ substituent selected from the group consisting of methyl, ethyl, hydroxy, methoxy , ethoxy, F, Cl, cyano, -N(CH ₃ ) ₂ and -CF ₃ ; and ring B is pyrrolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, each of which is optionally substituted with at least one R ⁹ substituent selected from methyl, ethyl, F, Cl, hydroxy, cyano, oxo and -CF ₃ ; or ring A is indolinyl, isoindolinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, dihydropyrrolopyridinyl, dihydropyrrolopyrimidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxaline, dihydrobenzooxazine or dihydrobenzothiazine, optionally substituted with at least one oxo; or ring B is pyrrolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, each of which is optionally substituted with at least one R ⁹ substituent selected from methyl, ethyl, F, Cl, hydroxy, cyano, oxo and -CF ₃ ; its stereoisomers and its pharmaceutically acceptable salts. In another aspect, there is provided a compound of formula (1-A1b) from Table J, stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect, a non-antibacterial compound of formula (1-A1b) from Table J, stereoisomers thereof, and pharmaceutically acceptable salts thereof are provided.

In another aspect, there is provided a composition containing a compound of formula (1-A1b), stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect, a composition is provided containing a compound of formula (1-A1b) from Table J, stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect, there is provided a composition comprising a non-antibacterial compound of formula (1-A1b) from Table J, stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect, the composition further comprises a pharmaceutically acceptable carrier.

In another aspect, a method is provided for treating or preventing an inflammatory response in an animal by administering to said animal in need thereof a therapeutically effective amount of a compound of formula (1-A1b), stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect, a method is provided for treating or preventing an inflammatory response in an animal by administering to said animal in need thereof a therapeutically effective amount of a compound of formula (1-A1b) of Table J, stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect, a method is provided for treating or preventing an inflammatory response in an animal by administering to said animal in need thereof a therapeutically effective amount of a non-antibacterial compound of formula (1-A1b) of Table J, stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect of the method, the inflammatory response occurs due to a bacterial, viral or fungal infection, stress and/or environmental factor. In another aspect of the method, a method of treating or preventing an inflammatory response in an animal prevents or reduces the progression of a respiratory disease or disorder. In another aspect of the method, the animal is a farm animal. In another aspect of the method, the respiratory disease or disorder is bovine respiratory disease or porcine respiratory disease. In another aspect of the method, a method of treating or preventing an inflammatory response in an animal provides down-regulation of TNF-α and IL-6 in the animal.

Another aspect provides the use of a compound of formula (1-A1b), stereoisomers thereof, and pharmaceutically acceptable salts thereof for the manufacture of a medicament for treating or preventing an inflammatory response in an animal. In another aspect, the use of a compound of formula (1-A1b) of Table J, its stereoisomers and pharmaceutically acceptable salts thereof for the manufacture of a medicament for treating or preventing an inflammatory response in an animal is provided. In another aspect, the use of a non-antibacterial compound of formula (1-A1b) from Table J, its stereoisomers and pharmaceutically acceptable salts thereof for the manufacture of a medicament for treating or preventing an inflammatory response in an animal is provided. In another aspect of application, the inflammatory response occurs due to a bacterial, viral or fungal infection, stress and/or environmental factor. In another aspect of use, the use of a medicament to treat or prevent an inflammatory response in an animal prevents or reduces the progression of a respiratory disease or disorder. In another aspect of application, the animal is a farm animal. In another aspect of use, the respiratory disease or disorder is bovine respiratory disease or porcine respiratory disease. In another aspect of use, administering a drug to an animal to treat or prevent an inflammatory response in the animal provides down-regulation of TNF-α and IL-6 in the animal.

In another aspect of the invention there is provided a compound of formula (1), wherein W is formula (A) and formula (A) is formula (A1), R is -C(O)NHR ^d ; both R ⁰ and R ² are H, R ¹ is methyl, R ⁵ and R ⁶ are joined together with a common N atom to form ring B, which is 4-methylpiperazine, that is, a compound selected from:

(2S,3R,4S,6R)-4-(3-(tert-butyl)-1-methylureido)-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-methylpiperazine- 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 ethylcarbamate; (2S,3R,4S,6R)-4-(3-(tert-butyl)-1-methylureido)-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-methylpiperazine- 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 tert-butylcarbamate;

(2S,3R,4S,6R)-4-(3-(4-(dimethylamino)phenyl)-1-methylureido)-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-azacyclopentadecane-11- yl)oxy)-6-methyltetrahydro-2H-pyran-3-yl(4-(dimethylamino)phenyl)carbamate; And

(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-phenylureido )tetrahydro-2H-pyran-3-yl phenylcarbamate. In another aspect of the invention there is provided a compound of formula (1), wherein W is formula (A) and formula (A) is formula (A2), R ⁰ and R ² are both H, R ¹ is methyl, R ³ is phenyl, R ⁷ is ethyl, and R is -C(O)NH-phenyl: that 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-phenylureido)tetrahydro-2H-pyran-3-yl phenylcarbamate, its stereoisomers and its pharmaceutically acceptable salts.

In another aspect of the invention there is provided a compound of formula (1), wherein W is formula (A) and formula (A) is formula (A3), R ⁰ and R ² are both H, R ¹ is methyl, R ³ is phenyl, R ⁷ is propyl, and R is -C(O)NH-phenyl: that 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-phenylureido)tetrahydro-2H-pyran -3-yl phenylcarbamate, its stereoisomers and its pharmaceutically acceptable salts. In another aspect of the invention there is provided a compound of formula (1) wherein W is formula (A), formula (A) is formula (A4), R ⁰ and R ² are both H, R ¹ is methyl, R ³ is phenyl, X' is chlorine, and R is -C(O)NH-phenyl: i.e. 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-phenylureido)tetrahydro-2H-pyran-3-yl phenylcarbamate, its stereoisomers and pharmaceutically acceptable salts thereof.

In another aspect of the invention there is provided a compound of formula (1), wherein W is formula (A), formula (A) is formula (A6), R ⁰ and R ² are both H, R ¹ is methyl, R ³ is is phenyl and R is -C(O)NH-phenyl: that 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-phenylureido)tetrahydro-2H-pyran-3-yl phenylcarbamate, its stereoisomers and its pharmaceutically acceptable salts. In another aspect, there is provided a composition containing any of the phenylcarbamate compounds of formula (1), and wherein the composition further comprises a pharmaceutically acceptable carrier. In another aspect, a method is provided for using any of the phenylcarbamate compounds of formula (1) to treat or prevent an inflammatory response in an animal by administering to said animal in need thereof a therapeutically effective amount of the phenylcarbamate compound of formula (1), stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect, the use of any of the phenylcarbamates of formula (1) is provided for the manufacture of a medicament for treating or preventing an inflammatory response in an animal.

In another aspect of the invention there is provided a combination of a compound of formula (1), stereoisomers thereof and pharmaceutically acceptable salts thereof; with at least one additional pharmaceutical 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 co-administered with additional pharmaceutical agent(s) simultaneously, separately or sequentially to treat a bacterial infection and/or prevent the animal from developing an inflammatory and/or immune response into the full spectrum of RBD disease.

In another aspect of the invention there is provided a composition containing M9, its stereoisomers and its pharmaceutically acceptable salts. In another aspect, the composition containing M9 further comprises a pharmaceutically acceptable carrier. In another aspect of the invention, there is provided a method of treating or preventing an inflammatory response in an animal by administering to said animal in need thereof a therapeutically effective amount of M9, stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect, a method is provided for treating or preventing an inflammatory response in an animal, wherein the inflammatory response occurs due to a bacterial, viral or fungal infection, stress and/or environmental factor. In another aspect, a method of treating or preventing an inflammatory response in an animal is provided, wherein M9 reduces the progression of a respiratory disease or disorder. In another aspect, the animal is a farm animal. In another aspect, the respiratory disease or disorder is bovine respiratory disease or porcine respiratory disease.

In another aspect, a compound of formula (1) is provided, which is a non-antibacterial compound of formula (1.1) from 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-antibacterial compound of formula (1-A0) from Table B selected from the group consisting of Examples B-1a to B-6 and B-8 to B-15; or a non-antibacterial compound of formula (1-A2) from Table C selected from the group consisting of Examples C-1 and C-3; or a non-antibacterial compound of formula (1-A3) from Table D selected from Examples C-1 or C-2; or a non-antibacterial compound of formula (1-A4) from Table E selected from the group consisting of Examples E-1 to E-3; or a non-antibacterial compound of formula (1-A5) from Table F, which is an example of F-1 or F-2; or a non-antibacterial compound of formula (1-A6) from Table G selected from the group consisting of Examples G-1 to G-3; or a non-antibacterial compound of formula (1-A1) from Table H, selected from the group consisting of examples H-1, H-2, H-4, H-6, H-8 to H-14, H16, H-17 , N-21, N-24, N-25, N-27, N-28, N-29, from N-31 to N-35, N-37, from N-39 to N-43, N-47 , N-48, N49, from N-51 to N-57, N-59, N-60, from N-62 to N-65, N-77, N-79, N-80, from N-82 to N-86, N-88, from N-91 to N-97 and from N-99 to N-103; or a non-antibacterial compound of formula (1-A1a) from Table I, selected from the group consisting of Examples I-1 and I-3 to I-7; or a non-antibacterial compound of formula (1-A1b) from 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; its stereoisomers and its pharmaceutically acceptable salts; a composition containing any of these non-antibacterial compounds; a method of using any of these non-antibacterial compounds to treat or prevent an inflammatory response in an animal; or the use of any of these non-antibacterial compounds for the manufacture of a medicament for treating or preventing an inflammatory response in an animal.

DISCUSSION

Description of graphic materials

Fig. 1. The mechanism of the immunomodulator in the context of progression of RCC

Fig. 2. Generalized clinical and genomic temporal data

Fig. 3. Plasma levels of cytokines (IL-6, IL-8, IL-10, and IFN-γ) after arrival at the feedlot for calves at risk of RBD.

Fig. 4. Example H-11, analysis of dose-dependent levels of cytokines in whole blood:

IL-6 (A), TNF-α (B), and IL-1β (C) FIG. 5. Change in IL-36RA (%) in natural infection studies in cattle

Fig. 6. Assessment of biomarkers during endotracheal stimulation of the lungs with M9 and Draxin; results for biomarkers IL-6 (A) and CD163 (B)

Fig. 7. Evaluation of biomarkers for endotracheal pulmonary stimulation in example H-91: results for biomarkers IL-6 (A) and CD163 (B)

Fig. 8. Biomarker assessment for endotracheal lung stimulation in example H-11: results for neutrophils (A), IL-6 (B) and CD163 (C)

Fig. 9. Intracellular characteristics of CD4+T helper cell subtypes according to flow cytometry

Fig. 10. Levels of IL-17 from the respiratory tract of animals stimulated by administration of M. haemolytica in example H-11

It should be understood that the invention is not limited to the specific methodology, protocols, reagents, etc. defined herein and, therefore, may vary. The terminology used herein is for descriptive purposes only and is not intended to limit the scope of the present invention as defined solely by the claims.

Unless otherwise stated, scientific and technical terms used in connection with the compounds of the invention as defined herein are intended to have meanings that are commonly known to those skilled in the art. In addition, unless the context otherwise requires, terms in the singular include the plural and terms in the plural include the singular. In general, the nomenclature used in connection with chemical synthesis, macrolides and immunomodulation, and related technologies defined herein is well known and commonly used in the art.

Definitions

For purposes of the present invention described and claimed herein, the following terms and expressions are defined as follows:

As used herein, “additional pharmaceutical agents,” unless otherwise specified, refer to other pharmaceutical compositions or products that provide a therapeutically effective amount of the specified agents that are useful for treating a bacterial infection in an animal and/or modulating an immune response as defined herein .

As used herein, “alkoxy,” unless otherwise noted, refers to an oxygen moiety having an additional alkyl substituent. The alkyl moiety (i.e. alkyl moiety) of an alkoxy group has the same definition as below. Non-limiting examples include: -OSH ₃ , -OSH ₂ CH ₃ , -OSH(CH ₃ ) ₂ , -OS(CH ₃ ) ₃ and the like.

As used herein, "alkyl", unless otherwise indicated, refers to saturated monovalent hydrocarbon alkane radicals of the general formula _{CnH2n +1} . The alkane radical may be linear or branched and may be unsubstituted or substituted. For example, the term "(C ₁ -C ₆ )alkyl" refers to a monovalent, straight or branched aliphatic group containing 1-6 carbon atoms; similarly, C ₁ -C ₃ alkyl refers to a monovalent, linear or branched aliphatic group containing 1-3 carbon atoms, etc.

Non-exclusive examples of (C ₁ -C ₆ ) alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, sec-butyl, tert-butyl, n-propyl, n-butyl, isobutyl, c-butyl, n- pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, 3,3-dimethylpropyl, 2-methylpentyl, hexyl, etc. An alkyl moiety may be attached to a chemical moiety at any of the carbon atoms of the aliphatic chain. Alkyl groups are optionally substituted as defined herein. Additionally, when used in names of compounds such as alkylphenyl, the alkyl moiety has the same meaning as defined herein and may be attached to a chemical moiety at any of the carbon atoms of the aliphatic chain. Non-limiting examples of _C0 - _C4 alkylphenyl compound names include: _C0 phenyl (phenyl), C ₁ alkylphenyl (-CH ₂ phenyl), C ₂ alkylphenyl (-CH ₂ CH ₂ phenyl), and the like.

As used herein, “animal,” unless otherwise specified, refers to an individual animal that is a mammal. Specifically, mammal refers to a vertebrate animal that is a human or different from a human, which is a member of the taxonomic class Mammals. Non-exclusive examples of non-human mammals include companion animals and farm animals. Non-exclusive examples of companion animals include dogs, cats and horses. Non-exclusive examples of farm animals include pigs, camels, rabbits, goats, sheep, deer, elk, bovine (cattle).

As used herein, the term “antibacterial,” unless otherwise noted, refers to a compound with a minimum inhibitory concentration (MIC) of ≤64 μg/mL against the CDB pathogens M. haemolytica and P. multocida. As used herein, the term “non-antibacterial”, unless otherwise noted, refers to a compound with an MIC of >64 μg/mL against the CDB pathogens M. haemolytica and P. multocida.

As used herein, "aryl", unless otherwise indicated, refers to an unsaturated aromatic monocyclic ring of 6 carbon members or an unsaturated aromatic polycyclic ring of 10-14 carbon members. Examples of such aryl rings include, but are not limited to, phenyl, naphthalenyl, or anthracenyl. Additionally, when used in names of compounds such as alkylaryl (e.g., alkylphenyl), said alkyl and aryl moieties have the same meanings as defined herein and may be attached to a chemical moiety at any of the aliphatic chain carbon atoms or atoms carbon rings. Examples of C ₀ -C ₃ alkylphenyls, for example:

Soalkylphenyl is phenyl; C ₁ -alkylphenyl is -CH ₂ phenyl (benzyl); and is C ₂ -alkylphenyl is -CH ₂ CH ₂ phenyl. The phenyl ring is optionally substituted as defined herein.

As used herein, “azalide,” unless otherwise noted, refers to a class of macrolides that contain a nitrogen atom on the macrolide ring, which provides different pharmacokinetic properties and is associated with greater stability of the molecule.

As used herein, the term “chiral,” unless otherwise noted, refers to a structural characteristic of a molecule that allows compatibility with its mirror image (eg, “R” and “S” enantiomers).

As used herein, “composition,” unless otherwise indicated, refers to a compound of the invention that is formulated with at least one pharmaceutically acceptable excipient for dosage administration.

As used herein, "compounds of the present invention", "compounds of the invention", unless otherwise indicated, include a compound of formula (1), (1A), (1.1), (1-A0), (1-A1), ( 1-A1a), (1-A1b), (1-A2), (1-A3), (1-A4), (1-A5) and (1-A6), its stereoisomers and its pharmaceutically acceptable salts. The term also includes the corresponding 13-membered macrolides that are in equilibrium with the 15-membered macrolide ring of the formula indicated; and includes the azalide class.

As used herein, “cycloalkyl”, unless otherwise specified, includes fully saturated carbocyclic alkyl moieties, i.e. 3-6 membered rings containing only carbon atoms, and may be monocyclic or part of a fused ring or bridged ring moiety. Examples of saturated carbocyclic (cycloalkyl) rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Non-limiting examples of partially saturated cycloalkyls include: cyclopropene, cyclobutene, and the like. Preferred cycloalkyls are 3-6 membered saturated monocyclic rings, including cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The cycloalkyl group can be attached to a chemical moiety at any of the carbon atoms on the carbocyclic ring. The cycloalkyl groups are optionally substituted with at least one substituent. Additionally, when used in names of compounds such as alkyl cycloalkyl, the alkyl and cycloalkyl moieties have the same meaning as defined herein and may be attached to a chemical moiety at any of the carbon atoms of the aliphatic chain. Examples of _C0 - _C4 alkylC3- _C6 cycloalkyl include, for example: _{C0 alkylC3} - _C6 cycloalkyl is _{C3 -C6 cycloalkyl} (ie, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl); C ₁ -alkylC ₃ -C ₆ cycloalkyl is -CH ₂ C ₃ -C ₆ cycloalkyl (for example, -CH ₂ -cyclopropyl, -CH ₂ -cyclohexyl, etc.); C ₂ -alkylC ₃ -C ₆ cycloalkyl is -CH ₂ CH ₂ C ₃ -C ₆ cycloalkyl (for example, -CH ₂ CH ₂ -cyclopropyl, -CH ₂ CH ₂ -cyclopentyl), etc. Cycloalkyl moieties are optionally substituted as defined herein.

As used herein, the term “cytokine,” unless otherwise noted, refers to a general class of biological molecules that have an effect/influence on all cell types and influence immunological responses and non-immunological biological processes. This definition is intended to include, but is not limited to, biological molecules that act locally or systemically and that, when used in the compositions or methods of the present invention, serve to regulate or modulate the immune response of an animal. Exemplary cytokines for use in the practice of the 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 (eg, CCL2-5, CCL10, CCL11, CXCL8 (IL-8) and CXCL10), tumor necrosis factors (eg, TNF-α and TNF-β) and, in particular, NFJ-B, which mediates the induction of proinflammatory cytokines such as TNF-α, IL-1 and IL-6 in monocytes and macrophages.

As used herein, “halogen,” unless otherwise noted, refers to fluorine, chlorine, bromine and iodine. Additionally, when used in compound names such as "haloalkyl" or "haloalkoxy", said alkyl and alkoxy may be partially or fully substituted by halogen atoms, which may be the same or different, and said alkyl and alkoxy moieties have the same values as above and can be attached to a chemical moiety at any of the carbon atoms of the aliphatic chain. Examples of "haloalkyls" include F ₃ C-, ClCH ₂ -, CF ₃ CH ₂ - and CF ₃ CCI ₂ - and the like. The term "haloalkoxy" is defined similarly to the term "haloalkyl". Examples of "haloalkoxy" include CF ₃ O-, CCl ₃ CH ₂ O-, HCF ₂ CH ₂ CH ₂ O- and CF ₃ CH ₂ O- and the like.

As used herein, "heteroaryl" or "Het", unless otherwise specified, refers to a 5-6 membered aromatic monocyclic ring or 8-10 membered fused aromatic ring, wherein said monocyclic or fused ring moiety contains one or more heteroatoms, each of which is independently selected from N, O and S, preferably from one to four heteroatoms. Non-exclusive examples of monocyclic heteroaryls include pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and the like. Non-exclusive examples of fused heteroaryls include benzofuranyl, benzothiophenyl, indolyl, benzimidazolyl, indazolyl, benzotriazolyl, thieno[2,3-c]pyridine, thieno[3,2-b]pyridine, benzo[1,2,5]thiadiazole and the like . The heteroaryl group may be attached to a chemical moiety at any of the carbon atoms or heteronitrogen atoms in a monocyclic or fused ring. Additionally, when used in names of compounds such as alkylheteroaryl (e.g., C ₀ -C ₄ alkylheteroaryl), said alkyl and heteroaryl moieties have the same meanings as defined herein and may be attached to a chemical moiety at either atom carbon of the aliphatic chain. For example, C ₀ lkylheterocycle is a heterocycle (for example, pyrazolyl, imidazolyl, pyridinyl, piperazinyl, etc.), slalkylheteroaryl is -CH ₂ heteroaryl (for example, -CH ₂ imidazolyl, -CH ₂ pyridinyl, etc.) , C ₂ alkylheteroaryl is -CH ₂ CH ₂ heteroaryl (for example, -CH ₂ CH ₂ pyrazolyl, -CH ₂ CH ₂ oxazolyl, -CH ₂ CH ₂ pyrimidinyl, etc.), etc. Heteroaryls are optionally substituted as defined herein.

As used herein, "heterocycle", unless otherwise specified, refers to a partially saturated or saturated 4-10 membered monocyclic ring, fused ring or bridged ring structure containing one or more heteroatoms, each independently selected from N, O and S, preferably from one to four heteroatoms. Non-exclusive examples of heterocycles include oxetanyl, azetidinyl, thiatanyl, tetrahydrofuryl, pyranyl, pyrazolidinyl, oxazolidinyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxathianyl, tetrahydropyridinyl, 2H-azirinyl, 2,3-dihydroazetyl, 3,4- dihydro-2H-pyrrolyl and the like. A heterocyclic group may be attached to a chemical moiety at any of the carbon atoms or nitrogen heteroatoms in the ring. Additionally, when used in names of compounds such as an alkyl heterocycle (e.g., a _C0 - _C4 alkylheterocycle), said alkyl and heterocyclic moieties have the same meanings as defined herein and may be attached to a chemical moiety in any of carbon atoms of the aliphatic chain. For example, Coheterocycle is a heterocycle (for example, (piperidinyl, morpholinyl, azetidinyl, etc.); C ₀ alkyl heterocycle is -CH ₂ heterocycle (for example, -CH ₂ morpholinyl, etc.), C ₂ alkyl heterocycle is CH ₂ CH ₂ heterocycle (eg, -CH ₂ CH ₂ pyrrolidinyl, -CH ₂ CH ₂ Thiomorpholinyl, etc.), etc. Heterocycles are optionally substituted as defined herein.

As used herein, "macrolides", unless otherwise specified, refer to compounds characterized by the presence of a large lactone ring containing 12-16 carbon atoms to which one or more deoxysugars are attached via glycosidic bonds; and include the azalide class.

The expression "optionally substituted" is used herein interchangeably with the expression substituted or unsubstituted. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and each substitution is independent of the others. An optionally substituted group may also have no substituents. Therefore, the expression "optionally substituted by at least one substituent" means that the number of substituents can vary from zero to the number of positions available for substitution. In the case of R ⁹ and R ¹⁰ , at least one optional substitution means that 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 replacement.

As used herein, the expression “pharmaceutically acceptable,” unless otherwise stated, indicates that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients in the formulation, composition, and/or the animal to be treated therewith. The term "pharmaceutical" or "pharmaceutical" has the same meaning as given to the term "veterinary" or "veterinary".

As used herein, a “protecting group” or “Pg,” unless otherwise specified, refers to a substituent that is typically used to block or protect the alcohol in a compound, thereby protecting its functionality while allowing other functional groups to react in connection. Non-exclusive examples of alcohol protecting groups include: 2,2,2-trichloroethyl carbonate (Troc), 2-methoxyethoxymethyl ether (MEM), 2-naphthyl methyl ether (Nap), 4-methoxybenzyl ether (PMB), acetate (Ac), benzoate (Bz ), benzyl ether (Bn), benzyloxymethyl acetal (BOM), ethoxyethylacetal (EE), methoxymethyl acetal (MOM), methoxypropylacetal (MOP), methyl ether, tetrahydropyranyl acetal (THP), triethylsilyl ether (TES), benzyloxycarbonyl (Cbz), triisopropylsilyl ether ( TIPS), trimethylsilyl ether (TMS), tert-butyl dimethylsilyl ether (TBS, TBDMS) and tert-butyl diphenylsilyl ether (TBDPS).

As used herein, the expressions "saturated" or "partially saturated", unless otherwise indicated, refer to cycloalkyl rings having 3-6 carbon atoms and heterocyclic rings containing 2-5 carbon atoms and at least one heteroatom selected from N, O and S; and wherein each saturated ring contains single bonds between adjacent carbon atoms or carbon heteroatoms, for example: cyclobutane, cyclopentane, cyclohexane, oxirane, oxetane, tetrahydrofuran, piperadine and the like. Partially saturated rings contain at least one double bond between adjacent carbon atoms or heteroatoms, for example: cyclobutene, cyclopentene, cyclohexa-1,3-diene, 2,3-dihydroazet, 2,5-dihydrofuran, 2H-thiopyran, etc. P.

As used herein, “stereoisomers,” unless otherwise specified, refer to compounds of the invention that have more than one asymmetric carbon atom. In the general formulas given herein, a solid wedge bond indicates that the bond is above the plane of the paper, and a non-solid wedge bond indicates that the bond is below the plane of the paper. The compounds of the invention may exist as individual enantiomers or diastereomers, or mixtures thereof, including racemic mixtures. All such isomeric forms are included in the present invention.

In the context of this document, “stress” or “stressful”, unless otherwise specified, represents a specific or nonspecific response, the degree of which varies. Stressors are specific events, incidents or environmental stimuli that have a negative impact on the health of the animal and which may be acute, chronic, destructive or considered uncontrollable. Non-exclusive examples of animal health stressors include: natural disasters (e.g., floods, fires, and earthquakes), major life events (e.g., moving/transporting, weaning, separation from mother and herd, mixing of animals from different locations, tail clipping, needle extraction, pain, food and water deprivation, and acute or chronic illness) and acute/chronic disorders (eg, changes in temperature and humidity, confinement, transportation, inadequate nutrition and water supply, storms, loud noises (eg , thunder, barking, fireworks, etc.), environmental changes and pollution, etc.).

As used herein, the expression "therapeutically effective amount", unless otherwise specified, refers to an amount of a compound of the invention that provides (i) treatment or prevention of a particular disease or disorder, (ii) attenuation, mitigation or elimination of one or more symptoms of a particular disease or disorder, or (iii) preventing or delaying the onset of one or more symptoms of a particular disease or disorder.

As used herein, the terms “treat,” “treat,” and the like, unless otherwise noted, refer to the control, preventative measures, reversal, mitigation, reduction, or suppression of environmental, bacterial, viral, fungal, or parasitic inflammation. infection, and/or internal disease through regulation of the immune response. As used herein, these terms also include, depending on the condition of the animal, preventing the occurrence of a disorder or condition or symptoms associated with the disorder or condition, including reducing the severity of the disorder or condition or symptoms associated therewith. Treatment may also refer to the administration of a compound of the invention to an animal that, at the time of administration, does not have an infection, immunological episode or disease, disorder or complex. It should be understood that it is not always possible to distinguish “prevention” from “suppression” of a disease or disorder because the underlying event or events may be unknown or latent.

Except in the worked examples or where otherwise indicated, all numbers expressing amounts of ingredients or reaction conditions used herein are to be understood as being modified in all cases by the term “about.”

The compounds of the present invention have multiple asymmetric centers. Compounds with asymmetric centers provide 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 are included within the scope of the invention. It is also intended that the present invention include all steric forms of the compounds of the invention. The present invention includes all stereoisomers of the compounds of the invention.

Independent synthesis of stereomerically enriched compounds or their chromatographic separation can be carried out, as is known in the art, by appropriate modification of the methodology described herein. Their absolute stereochemistry can be determined by X-ray crystallography of the crystalline products or crystalline intermediates, which are derivatized, if necessary, with a reagent containing an asymmetric center with a known absolute configuration. If necessary, racemic mixtures of compounds can be separated to isolate individual enantiomers or diastereomers. The separation can be carried out by methods well known in the art, such as conjugation of a racemic mixture of compounds followed by separation of the individual stereoisomers by standard methods such as fractional crystallization or chromatography. A conjugation reaction often involves the formation of salts using an enantiomerically pure acid or base.

The derivatives can then be converted to pure stereomers by cleavage of the added chiral moiety. Racemic mixtures of compounds can also be separated directly by chromatographic methods using chiral stationary phases, which are well known in the art. Alternatively, any stereomers of a compound can be prepared by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.

During any of these processes to prepare the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules in question. This can be achieved through traditional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. Protecting groups can be removed at a suitable subsequent step using methods known in the art.

Macrolide chemistry

It is known that macrolides have high binding affinity to the P site on the 50S subunit of the bacterial ribosome and inhibit protein synthesis. Modification of the desosamine group of the macrolide blocks this interaction by modifying the dimethylamino group to block the salt bridge and/or modifying the adjacent hydroxy group to interfere with the hydrogen bond formed, thereby eliminating the antibacterial activity of the compounds of the invention. Although modifications of cladinose have a comparatively lesser effect on bacterial ribosome binding, they can potentially affect the physicochemical properties, pharmacokinetics, and cell penetration of the compound. Therefore, by modifying the structure of macrolides, keeping molecules from entering bacteria or increasing efflux from bacteria reduces or eliminates antibacterial activity even with the ability to bind bacterial ribosomes.

Lipophilicity

The lipophilicity of an organic compound can be described using the partition coefficient logP, which can be defined as the ratio of the concentration of the non-ionized compound at equilibrium between the organic and aqueous phases. In general, more lipophilic compounds are less soluble in aqueous media. A negative logP value means that the compound has higher affinity for the aqueous phase (hydrophilic); when logP=0, the compound is equally distributed between the lipid and aqueous phases; a positive logP value means a higher concentration in the lipid phase (lipophilic). Lipophilicity is a major determining factor for a compound's absorption, distribution in the body, penetration through vital membranes and biological barriers, metabolism and excretion. The compounds of the invention are lipophilic (logP ~ 0.503-5.96), which facilitates their transport and absorption in the tissues of the respiratory organs, for example, the lungs.

Composition/composition

The pharmaceutical compositions of the present invention can be prepared by methods well known in the art, for example, through conventional processes of mixing, dissolution, granulation, panning, trituration, emulsification, encapsulation, confinement, lyophilization or spray drying. Pharmaceutical compositions for use in accordance with the present invention can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers which facilitate processing of the active compound into preparations for administration to an animal in need thereof. The compositions of the invention can be formulated as short-acting, immediate-release, long-acting and sustained-release formulations. Thus, pharmaceutical formulations can also be formulated for controlled release or slow release, depending on the chosen route of administration.

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

In the case of RKRS and RZS, the pharmaceutical compositions are typically formulated for parenteral administration, for example in a liquid carrier, or are suitable for reconstitution in a liquid diluent or suspension for parenteral administration. In general, such compositions will typically contain a pharmaceutically acceptable carrier. Pharmaceutical carriers in accordance with the invention may be sterile liquids such as, but not limited to, water, saline solutions, aqueous dextrose solutions, aqueous glycerol solutions; and/or oils, including oils of petroleum, animal, vegetable or synthetic origin, such as soybean oil, mineral oil, sesame oil and the like. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E. W. Martin, 18th Edition. Pharmaceutical compositions containing a compound of the invention can be administered orally, topically, parenterally (ie, by intramuscular, subcutaneous, intravenous and intradermal injection). Pharmaceutical compositions containing a compound of the invention can also be administered by injection into the mammary gland and into the uterus.

The pharmaceutical compositions and formulations defined herein can be prepared by admixing a compound of the invention having the required purity with one or more pharmaceutically acceptable carriers in the form of lyophilized formulations or liquid solutions. The term "carrier" refers to the diluent, excipient or carrier medium with which the compound of the invention is administered. Pharmaceutically acceptable carriers are generally nontoxic to recipients at the dosages and concentrations used and include, but are not limited to: buffers (e.g., NaOH, KOH, HCl, phosphate, citrate, and other organic acids (e.g., citric acid, acetic acid, benzoic acid, malic acid, etc.); antioxidants (for example, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), sodium metabisulfite, monothioglycerol, propyl gallate, etc.); preservatives (for example, octadecyldimethylbenzylammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, n-butyl, tert-butyl or benzyl alcohol, chlorobutanol, thimerosal, alkylparabens such as methyl or propylparaben, catechol, resorcinol, cyclohexanol, 3-pentanol, m-cresol and the like. ); hydrophilic polymers (e.g. polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyvinyl alcohol (PVA), polyacrylic acid, polyacrylamides, xanthan gum, 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 dextrins; and salt-forming counterions such as sodium; metal complexes (eg Zn-protein complexes). The carrier may be a solvent or reconstitution medium or dispersion containing, for example, water, ethanol, polyol (eg, glycerol, propylene glycol and liquid polyethylene glycol, etc.), and suitable mixtures thereof. For intravenous administration, suitable vehicles include saline, bacteriostatic water, water, or phosphate-buffered saline (PBS). Prolonged absorption of injectable compositions can be achieved by including in the composition a substance that retards absorption, for example, aluminum monostearate and gelatin.

Solutions or suspensions used for parenteral use typically contain one or more of the following: a sterile carrier such as water for injection, saline, fatty oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparabens; antioxidants such as ascorbic acid, BHA, BHT, monothioglycerol or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates; and agents to regulate tonicity, such as sodium chloride or dextrose. The pH can be adjusted with acids or bases such as hydrochloric acid, citric acid or sodium hydroxide. Such drugs may be contained in ampoules, disposable syringes, or multi-dose vials made of glass or plastic. Formulations intended for in vivo administration are generally sterile. Sterility can be easily achieved, for example, by filtration through sterile filter membranes and irradiation. Injectable compositions may contain active ingredients (drug) in amounts ranging from about 1 to 250 mg/ml and, more preferably, in concentrations ranging from about 1 to 100 mg/ml. Without limiting the scope of the composition components, an injectable composition containing a compound of Formula (1) (e.g., free base), a pharmaceutically acceptable salt thereof (e.g., acetate), can be prepared by dissolving the compound (e.g., 1-25 mg/ml) in the composition, containing citric acid, propylene glycol, water and optionally an antioxidant (eg monothioglycerol). As described herein, the composition may contain about 90% (±~6%) lactone A and 10% lactone B (±~6%) of a compound of formula (1) and preferably a non-antibacterial compound from Table H. The composition can be administered by injection (eg, subcutaneous). The pH of the composition can be adjusted, if necessary, with NaOH and/or HCl. Methods for preparing such compositions are known to those skilled in the art, and they can be prepared in accordance with the procedures described in US Pat. No. 6,514,945.

In the case of oral administration, the pharmaceutical compositions of the present invention can be administered, for example, in the form of tablets or capsules, powders, dispersible granules or starch capsules, or in the form of aqueous solutions or suspensions. Compositions for oral administration generally contain an inert carrier or an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets. When administered orally, the therapeutic agents can be combined with carriers and used in the form of tablets, lozenges or capsules. Pharmaceutically compatible binding agents and/or adjuvant materials may also be included as part of the composition. Tablets, pills, capsules, lozenges, etc. may contain any of the following ingredients or compounds of a similar nature; a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrant such as alginic acid, Primogel, sodium starch glycolate or corn starch; a lubricant such as magnesium stearate or stearates; a glidant such as colloidal silica; a sweetener such as sucrose or saccharin; or flavoring.

Dosage

Pharmaceutical compositions suitable for use in the present invention include compositions in which the active ingredients are contained in an amount sufficient to achieve the intended purpose. More specifically, a therapeutically effective amount means an amount of a compound of the invention that is effective to prevent, alleviate, or ameliorate the symptoms/signs of a disease or to prolong the survival of the animal being treated. The amount of the active component, which is a compound of the invention, in the pharmaceutical composition and its unit dosage form can be varied or adjusted over a wide range depending on the route of administration, the activity of the particular compound and the required concentration. Determination of a therapeutically effective amount is within the skill of the art. In general, the amount of active ingredient will range from 0.01% to 99% by weight of the composition.

In general, a therapeutically effective dose amount of the active ingredient will range from about 0.01 mg/kg to about 10 mg/kg body weight, preferably from about 0.02 mg/kg to about 1 mg/kg body weight, more preferably from about 0.04 mg/kg to about 0.8 mg/kg body weight, even more preferably from about 0.06 mg/kg to about 0.6 mg/kg body weight. The preferred dosage schedule is parenteral administration of about 0.05 mg/kg to about 0.8 mg/kg body weight by subcutaneous injection. It should be understood that dosages may vary depending on the requirements of each animal and the severity of the disorder or disease being treated. The required dose may conveniently be expressed as a single dose or as divided doses administered at appropriate intervals throughout the course of treatment. The preferred route of administration is parenteral. Parenteral administration includes intravenous, intramuscular and subcutaneous injection. The preferred route of administration is subcutaneous injection. The compounds of the invention may be administered to an animal at the first sign of stress or bacterial infection, prior to transport from a farm or ranch, or upon arrival at a feedlot.

A compound of the invention may be administered in a pharmaceutically acceptable form alone or in combination with one or more additional agents that modulate the immune system of a mammal, or with anti-inflammatory agents, or with one or more antibacterial agents. In addition, the compounds of the invention can also be administered together with vitamins and/or minerals. Non-limiting examples of anti-inflammatory agents include: ketoprofen, cyclosporine A, rapamycin, FJ-506 (tacrolimus), leflunomide, deoxyspergualine, mycophenolate, azathioprine, daclizumab, aspirin, acetaminophen, ibuprofen, naproxen, piroxicam, and anti-inflammatory steroids (eg, prednisolone or dexamethasone). Non-limiting examples of antibacterial agents include: novobiocin, aminoglycosides (e.g., gentamicin, neomycin, dihydrostreptomycin, spectinomycin, etc.), florfenicol, ceftiofur, cephapirin, ormethoprim, danofloxacin, enrofloxacin, bambermycins, ionophores (e.g., laidlomycin, lasaloci d, monensin, narasin, salinomycin, lincomycin, pirlimycin), macrolides (for example, erythromycin, gamithromycin, tildipirosin, tilmicosin, tulathromycin, M9 metabolite of tulathromycin, tylosin, tylvalosin, etc.), avilamycin, penicillins (for example, amoxicillin, ampicillin, cloxacillin, penicillin, etc.), tiamulin, polymyxin B, bacitracin, carbadox, virginiamycin, sulfadimethoxine, sulfamethazine, chlortetracycline, oxytetracycline and tetracycline. Non-limiting examples of minerals include: calcium, magnesium, phosphorus, potassium, sodium, sulfur, cobalt, sulfur, copper, iodine, iron, manganese, selenium, chromium and zinc. Non-limiting examples of vitamins include: vitamins A, D, E, K and B, including: thiamine (B1), riboflavin (B2), niacin (B3), pantothenic acid (B5), pyridoxine (B6), biotin (B7), folate (B9) and B12. These additional combination agents may be administered as part of the same or as a separate dosage form, by the same or different route of administration, and according to the same or different schedule of administration, in accordance with standard medical or veterinary practice, as known to those skilled in the art.

Medical and veterinary applications

The methods defined herein are generally applied to an animal in need. An animal in need may be an animal that has, is diagnosed with, or is suspected of having or is at risk of developing a disease, disorder, or condition associated with a bacterial infection, viral infection, parasitic infection, inflammation, or immune response. The disease or disorder may include a respiratory disease, reproductive system disease such as mastitis or metritis, inflammatory bowel disease, bovine diarrhea virus (BVDV), infectious bovine rhinotracheitis (IBR), bovine respiratory syncytial virus (BRSV) , parainfluenza virus, bovine coronavirus, psoriasis, multiple sclerosis, rheumatoid arthritis, allergic autoinflammatory disease or autoimmune disease. In general, a safe and effective amount of a compound of the invention is, for example, that amount that will produce the desired therapeutic effect in an animal while having minimal unwanted side effects. In various embodiments, an effective amount of a compound of the invention can significantly reduce inflammation or an immune response, slow the progression of a disease, disorder, or condition associated with inflammation or an immune response, or limit the development of a disease, disorder, or condition associated with inflammation or an immune response. answer.

The compounds of the invention are macrolide analogues (azalides) that lack antibacterial activity against RBD pathogens and have been shown to have immunomodulatory properties that allow the prevention and/or control of RBD symptoms in artificially infected cattle. Accordingly, these macrolides are useful as therapeutic agents for the treatment and/or control of respiratory diseases that may be caused by environmental stimuli, stress and bacterial infection. Some non-limiting macrolides used for the treatment of RBD include: Draxin® (tulathromycin), Zuprevo® (yldipirosin) and Zaktran® (gamithromycin), etc.

Draxin®, solution for injection, is indicated for the treatment of bovine respiratory disease (BRD) associated with Mannheimia haemolytica, Pasteurella multocida, Histophilus somni and Mycoplasma bovis; and for the control of respiratory disease in cattle at high risk of developing RBD associated with Mannheimia haemolytica, Pasteurella multocida, Histophilus somni and Mycoplasma bovis. Cattle receive a 2.5 mg/kg subcutaneous dose of Draxin®. In pigs, Draxin® is indicated for the treatment of respiratory disease (RD) associated with Actinobacillus pleuropneumoniae, Pasteurella multocida, Bordetella bronchiseptica, Haemophilus parasuis and Mycoplasma hyopneumoniae; and to control RRD associated with Actinobacillus pleuropneumoniae, Pasteurella multocida and Mycoplasma hyopneumoniae in groups of pigs diagnosed with RRD. Pigs receive a 2.5 mg/kg intramuscular injection of Draxin®.

A compound of the invention may treat, ameliorate, or prevent a disease, disorder, or pathological condition associated with inflammation or an immune response. Inflammation is a critical response to potential danger signals and damage in the body's organs. Commonly referred to as the inflammatory cascade, it can be acute or chronic. Acute inflammation, part of the immune response, is the body's immediate response to injury or damage due to physical trauma, infection, stress, or a combination of all three. Acute inflammation helps prevent further damage and facilitates the healing and recovery process. However, when inflammation becomes self-sustaining, it can lead to chronic or long-term inflammation.

Trauma, inflammation, or infection lead to activation of the inflammatory cascade. Pro-inflammatory activation occurs initially, but almost immediately thereafter a reactive suppressive anti-inflammatory response occurs. This systemic inflammatory response (SIR) typically manifests itself as increased systemic expression of both pro-inflammatory and anti-inflammatory molecules. The systemic inflammatory response begins with inflammation in response to exogenous (microbial, physical or chemical) agents or endogenous (immunological or neurological) factors. Initiation of the response occurs when inflammatory cells at the site of inflammation, such as macrophages, become activated and begin to rapidly produce TNF-α and IL-1. These cytokines in turn activate the cytokine cascade, leading to the generation of proinflammatory cytokines, IL-6 and IL-8, as well as other chemokines. Inflammatory stimuli also initiate 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, whereas natural pro-inflammatory cytokine inhibitors neutralize the activity of pro-inflammatory cytokines by binding to pro-inflammatory cytokine receptors, decoy receptor antagonist and cytokine binding proteins. . The interaction between these pro-inflammatory cytokines, anti-inflammatory cytokines and natural cytokine inhibitors determines the inflammatory response and its effectiveness in maintaining the inflammatory response and allowing resolution of the initiating process. The main known mediators involved in the development of SIRS are cytokines, nitric oxide, platelet activating factor (PAF) and eicosanoids. The systemic response to infection is mediated by macrophage cytokines targeting end organ receptors in response to injury or infection. At the same time, the production of pro-inflammatory protein and lipid molecules will also occur in order to weaken and stop the inflammatory response. These mediators initiate overlapping processes that directly influence endothelial, cardiovascular, hemodynamic and coagulation mechanisms. If the balance between pro- and anti-inflammatory substances is not established and homeostasis is not restored, a widespread pro-inflammatory response (ie, SIRS) and multiple organ failure (MOF) may occur. Thus, after the release of the first pro-inflammatory mediators, the body initiates a compensatory anti-inflammatory response to the initial inflammatory response. The anti-inflammatory response can be strong and sometimes even stronger than the pro-inflammatory response. In addition to proinflammatory cytokines, other mediators such as NO, PAF, prostaglandins and leukotrienes are also produced. These molecules are responsible for complement activation, coagulation and also kinin cascades.

Diseases associated with inflammation or the immune response may include, for example, but are not limited to: bacterial infection; viral infection; fungal infection; parasitic infection; asthma; allergies; age-related macular degeneration; dermatitis; pain; mastitis; metritis; autoinflammatory disease; autoimmune disease; inflammatory bowel disease; dermatitis, multiple sclerosis; osteoarthritis; osteoporosis; psoriasis; rheumatoid arthritis and osteoarthritis; synovitis, acne, pustulosis, hyperostosis, respiratory and respiratory diseases (for example, equine respiratory disease and canine infectious respiratory disease); respiratory disease complex (cattle and porcine), ischemia-reperfusion, feline chronic kidney disease, feline and canine degenerative mitral valve anomaly (inflammatory complex; e.g., proinflammatory cytokines in heart failure through upregulation of valvular and myocardial expression of cytokines, chemokines and adhesion molecules), psoriasis, multiple sclerosis, rheumatoid arthritis, autoinflammatory disease, gastric 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, laminitis, gingivitis, scleroderma, vasculitis, malaria, Lyme disease, babesiosis, ehrlichiosis, anaplasmosis, tularemia, amoebiasis, giardiasis, fascioliasis, fasciolopsiasis, elephantitis, cryptosporidiosis, leishmaniasis, microsporidiosis, trypanosomiasis, toxoplasmosis, etc.; and other inflammatory and immune diseases and disorders. A compound of the invention may provide treatment for a disease, disorder or condition associated with inflammation by modulating cytokines, chemokines and inflammatory markers, for example, IL6, IL-1β, NFKB, CSP136, LCN, CXCL8 (IL-8), TNFα, and induction of TLR4 signaling.

Immunomodulation of macrolides

Macrolide chemistry provides the basis for understanding the effects of immunomodulation. Macrolides are by definition cationic amphiphilic drugs; the ability to penetrate cells is determined mainly by their lipophilicity and cationic nature at physiological pH. The permeation of macrolides across cellular membranes results in depolarization of phospholipids, resulting in the movement of both drug and phospholipid into the cytosol and lysosomes, ultimately leading to the cellular state of phospholipidosis. Polar association with phospholipids, mainly phosphatidylcholine, in cells inhibits natural degradation by phospholipase enzymes, resulting in a decrease in primary cell signaling components such as, but not limited to, arachidonic acid. Decreased arachidonic acid presumably prevents the normal production of eicosanoid metabolites, including prostaglandins, thromboxanes, leukotrienes, and lipoxins. In addition, there is indirect inhibition of the COX family of inflammatory mediators NFkB and AP-1 and their resulting production of proinflammatory cytokines. The reduced capacity of cells for signaling, both intra- and extracellular, is host context-dependent. In healthy animals, macrolide treatment has been demonstrated to stimulate neutrophil and macrophage responses following a noxious stimulus. However, in the presence of a state of acute or chronic inflammation, inhibition or reversal of inflammation is observed.

Modulation of host defense by azithromycin and other macrolide antibiotics occurs through interaction with structural cells, such as epithelial and endothelial cells, smooth muscle cells or fibroblasts, as well as with leukocytes (macrophages, polymorphonuclear leukocytes or neutrophils, mononuclear leukocytes or monocytes, T cells and dendritic cells ). Cellular accumulation of macrolides is a mechanism of passive transport into cells that does not require cellular energy, carrier proteins, and is nonsaturable. This mechanism is distinct from, and therefore unrelated to, ribosome binding associated with antibiotic activity. As an example, azithromycin aglycone, which does not exhibit antibiotic activity, exhibits high levels of induced phospholipidosis (J. Parnham et al. / Pharmacology & Therapeutics 143 (2014) 225-245). Azithromycin penetrates the double layer of the cell membrane and stabilizes the membrane by reducing fluidity and neutralizing the phospholipid charge on the inner layer of the membrane. This results in decreased fatty acid release and release of membrane-bound enzymes due to electrostatic charge, leading to modulation of signaling pathways and inhibition of activation of transcription factors including AP-1 and NFκB. The signaling pathway most affected likely depends 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, modulating the MPR transport of enzymes and lipids, and through lipid remodeling in lysosome membranes. One well-studied aspect is their ability to attenuate inflammatory responses, as demonstrated by down-regulation of increased cytokine production (IL-1β, TNF-α, IL-6) through the NFκB pathway and effects on granulocytes; and gene expression.

Immunological activity can also be assessed by analyzing CD163. CD163 is a phagocytic receptor that binds hemoglobin/haptoglobin and is expressed on macrophages and is thought to be involved in innate immune sensing that helps clear activated macrophages, thereby preventing oxidative tissue damage.

CD163 also functions as an innate immune sensor for Gram-positive and Gram-negative bacteria. Accordingly, high expression of CD163 in macrophages is characteristic of tissues responding to inflammation and is considered a highly correlated biomarker of inflammation. The uptake of oxidative and proinflammatory hemoglobin, leading to stimulation of heme oxygenase-1 and the production of anti-inflammatory heme metabolites, indicates that CD163 is thus indirectly involved in the anti-inflammatory response (Antioxid Redox Signal., Etzerodt et.al., 2013, 18( 17), p.2352-2363). CD163 may be involved in the process leading to lung lesions in RCC. CD163 expression may also correlate with the increased levels of IL-6 observed in RCC, CD163 surface expression was experimentally induced by 253+/-4.9% in monocytes and macrophages after incubation with IL-6 (Journal of Leukocyte Biology; Buechler et al vol.67 January 2020; p.97-103). Alternatively, cross-linking of CD163 on alveolar macrophages with a monoclonal antibody induced a protein tyrosine kinase-dependent signal that resulted in slow-type calcium mobilization, inositol triphosphate production, and secretion of IL-6 and GM-CSF (Journal of Leukocyte Biology; Van de Heuvel et al. vol. 66 November 1999; p.858-866). The anti-inflammatory immunomodulatory drug tacrolimus has been shown to slightly increase CD163 expression (PLOS ONE; Kannegleter, et.al., January, 2017; p.1-19); whereas a more recent study (HHS Public Access; Motta, et.al., Oral Dis. 2018, 24(4) p.580-590) showed that therapy did not change CD163 expression. Similarly, azithromycin (British Journal of Pharmacology, Vrancic, et.al; 2012, 165; p.1348-1360) has been reported to increase CD163 expression. CD163 expression is up-regulated on glucocorticoids, IL-6, IL-10 and hemoglobin; and down-regulation on IL-4, IFN-γ, TNF-γ, CXCL4 and GM-CSF. In contrast, suppression of CD163 was observed in cattle treated with M9 and H-91, which correlates with the proposed mechanism for reducing the inflammatory state.

Cytokines are considered a broad and vague category of small proteins (5–20 kDa) that are important in cell signaling. Their release affects the behavior of the cells around them. Cytokines can be said to be involved in autocrine signaling, paracrine signaling and endocrine signaling as immunomodulatory agents. It is generally known that cytokines include chemokines, interferons, interleukins, lymphokines and tumor necrosis factors (TNF), but generally not hormones or growth factors. Cytokines can be produced by a wide range of cells, including immune cells such as macrophages, neutrophils, B lymphocytes, T lymphocytes and mast cells, as well as epithelial cells, endothelial cells, fibroblasts and various stromal cells; a given cytokine can be produced by more than one cell type. Cytokines can act through receptors and are particularly important in the immune system. Cytokines can modulate the balance between humoral and cellular immune responses and can regulate the maturation, growth, or responsiveness of specific cell populations. Some cytokines can enhance or inhibit the actions of other cytokines in complex pathways. Cytokines may be important in health and disease, particularly in host responses to infection, immune responses, responses to inflammation, stress, trauma, sepsis, cancer, and reproduction.

Interleukin 6 (IL-6) is a pleiotropic cytokine that acts as a pro-inflammatory cytokine and an anti-inflammatory myokine. IL-6 is produced and secreted by a number of cells, including B cells, T cells, endothelial cells and macrophages, stimulating an immune response through the classical signaling pathway when it binds to the transmembrane IL-6 receptor (IL-6R), or through trans- signaling pathway after binding to the soluble form of IL-6R (sIL-6R), during infection and after tissue injury, leading to inflammation. Trans signaling is responsible for the proinflammatory actions and most of the pathological effects of IL-6. Dysregulation of the IL-6 pathway has been reported to be associated with the development of several disease conditions, including a number of inflammatory disorders. IL-6 has been reported to induce the production of vascular endothelial growth factor, which enhances angiogenesis and increases vascular permeability, a feature of several inflammatory disorders. IL-6 is also associated with increased recruitment of neutrophils, monocytes/macrophages and blockade of anti-inflammatory T-regulatory cells. In chronic inflammation, IL-6 plays a detrimental role and leads to the accumulation of mononuclear cells at the site of injury. This may lead to increased serum levels of IL-6 and sIL-6R, providing the basis for a step in enhancing chronic inflammatory responses. IL-6 has been associated with the development of pulmonary neutrophilia by increasing neutrophil recruitment from blood and bone marrow and neutrophil survival. The role of IL-6 as an anti-inflammatory cytokine is due to its inhibitory effects on TNF-alpha and IL-1 and the activation of IL-1ra and IL-10.

IL-6, as well as other inflammatory cytokines, has been shown to be elevated in various lung diseases in humans and mice. IL-6 was increased upon stimulation of bovine RBC (M. hemolyticd) and correlated with higher rectal temperature, lung lesions, and mortality. The compounds of the invention, M9 and tulathromycin significantly reduced IL-6 levels, which also correlated with the overall survival of the animals. Therefore, the immunomodulatory compounds of the invention reduce the pathological increase in IL-6 levels in a dose and clinical manner.

IL-36 is a member of the IL-1 cytokine superfamily and includes three agonists (IL-36α, IL-36β, and IL-36γ) and an antagonist (IL-36RA). IL-36 agonists bind to heterodimeric IL-36 receptor (IL-36R) complexes, leading to a proinflammatory response. Antagonists bind to IL-36R, thereby interfering with IL-36 signaling. IL-36 signaling occurs through the formation of a heterodimeric complex of IL-36, IL-36R and IL-1AcP (IL-1 accessory protein) and activates the myeloid differentiation adapter protein 88 (MyD88), mitogen-activated protein kinase (MAPK) and nuclear factor signaling pathways kappa B (NF-κB), and induces inflammatory responses. IL-36RA interferes with the interaction between IL-1AcP and the receptor-ligand complex. IL-36 proteins are widely expressed in T cells, keratinocytes, and skin, lung, and intestinal cells. IL-36 agonists bind to receptors [IL-36R and IL-1 receptor accessory protein (IL-1RAcP)] and then activate them. Finally, these pathways initiate the regulation of target genes. Recent evidence suggests that IL-36 regulates the function of both nonimmune cells and immune cells and is involved in immune cell activation, antigen presentation, and the production of proinflammatory factors. IL-36 has attracted much interest due to its dysregulation in inflammatory diseases. For example, serum and tissue expression of IL-36 has been increased in inflammatory and immune diseases and disorders such as psoriasis, rheumatoid arthritis, and inflammatory bowel disease.

Chemokines

Chemokines are a family of small cytokines or signaling proteins secreted by cells. Their name refers to their ability to induce targeted chemotaxis in nearby susceptible cells (i.e., chemotactic cytokines), which stimulates leukocyte recruitment. The main function of chemokines is to control the migration of leukocytes (homing) in the corresponding anatomical locations in inflammatory and homeostatic processes. They are secondary proinflammatory mediators induced by primary proinflammatory mediators such as IL-1 or TNF. There are two main chemokine subfamilies based on the location of cysteine residues, i.e. CXC and SS. All members of the CXC chemokine subfamily have an intermediate amino acid between the first two cysteine residues; members of the CC chemokine subfamily have two adjacent cysteine residues. In general, in general, members of the CXC chemokines are chemotactic toward neutrophils, and CXC chemokines are chemotactic toward monocytes and small subsets of lymphocytes. Some chemokines are considered proinflammatory and can be induced during an immune response to recruit immune cells to the site of infection or tissue damage, whereas others are considered homeostatic and are involved in the control of cell migration during normal processes of tissue maintenance or development (eg, angiogenesis).

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

Interleukin-8 (IL-8) is one of the proinflammatory chemokines that attracts and activates immune and inflammatory cells. IL-8 mediates a number of biological effects, including several involving neutrophils: activation and chemotaxis of inflammatory cells, production of reactive oxygen species, increased expression of CD1 integrin 1b-CD18, increased cell adhesion to endothelial cells, stimulation of angiogenesis, and modulation of histamine release. IL-8 is produced by many cells, including neutrophils, monocytes, macrophages, mast cells, vascular endothelial cells, stromal cells and epithelial cells, in response to innate exogenous/endogenous stimuli. In target cells, IL-8 induces a number of physiological responses necessary for migration and phagocytosis, such as increased intracellular Ca ²⁺ and exocytosis (eg, histamine release).

Recruitment of inflammatory cells such as neutrophils in response to tissue injury such as infection is a normal physiological response to clear the infectious agent, remove damaged or dead cells, and initiate the healing process. However, excessive recruitment of these cells, prolonged retention time, and cell death lead to tissue damage. The influx of excess inflammatory cells is therefore considered instrumental in the pathophysiology of pulmonary diseases such as human inflammatory pathological conditions such as 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 lung would be an attractive strategy for therapeutic intervention. In all of these pathological conditions, IL-8 is important for the recruitment and activation of neutrophils and T cells in the airways.

In an experimental study challenging cattle with M. hemolytica, levels of one of the major causative factors of RBC, IL-8, were increased in serum and tissues. The compounds of the invention have been shown to reduce IL-8 production in this stimulation model, which correlates with attenuation of the anti-inflammatory response and disease.

Biology of RZKRS

The pathobiology of RBD has long been thought to be related to stress-induced immune suppression, rendering calves susceptible to the myriad of microorganisms they encounter during transport from suckler calves to feedlots. This belief suggests that stimulation of the innate immune system would have a beneficial effect on clinical outcome. However, to date there have been few successful results consistent with this belief, including the use of the DNA immunostimulant (Zelnate®). To better understand the progression of RBD, earlier studies suggest that it is an early unresolved state of increased inflammation, rather than immunosuppression, that drives the progression of RBD.

With current research into the etiology of RBD, new understanding of immunological status has shown that although a state of increased inflammation is ubiquitous among at-risk cattle, the persistence or lack of resolution/improvement of this state coincides with disease outcome. Following transport and upon arrival at the feedlot, the proinflammatory state is particularly characterized by innate immune components such as damage to the nasal-mucosal barrier of epithelial cells and the release of preformed mediators such as members of the IL-1 family of cytokines. Activation of danger-associated molecular patterns (DAMPs), including the pattern recognition receptor (PRR) TLR-4, and inflammasome signaling demonstrate the response of epithelial and resting myeloid cells to colocalized microorganisms in the upper respiratory tract. When bacterial components such as lipopolysaccharides (LPS; lipoglycans and endotoxins) induce TLR4 signaling, transcription factors such as NF-κB induce the expression of key cytokines involved in the maintenance of the inflammatory process, such as IL-1β, IL-6 and TNF-α, and myeloid granulocytes, including macrophages and neutrophils, are recruited and activated. These cascades create conditions where bacteria normally confined to the upper respiratory tract can travel to the lungs and cause disease. Inflammatory biomarkers such as elevated levels of secreted cytokines such as IL-6 and acute phase proteins are associated with clinical disease. Also associated with clinical disease are markers of cellular activation, such as expression of the phagocytic receptor CD163 on macrophages and neutrophil-associated mediators such as LCN and CXCL8. The compounds of the invention effectively attenuate the state of increased inflammation in at-risk cattle by balancing the immune response and reducing the intensity of the pathological inflammatory cascade. This immunomodulatory mechanism in the context of RCC progression is depicted in FIG. 1.

The compounds of the invention represent a new approach to a highly complex disease and have the potential to significantly reduce the incidence of RBD and the need for antibiotic treatment. They effectively reduce the pathological characteristic inflammation that occurs during transport, allowing the animal to regain homeostasis within a time frame consistent with clinical protection from disease.

Designs and experimental conditions

The following abbreviations are used in the designs and experimental procedures presented herein: benzyloxycarbonyl (Cbz); TN (overnight, 16-24 hours); protecting group (Pg); leaving group (Lg); triethylamine (TEA); dichloromethane (DCM); cyano (CN); tetrahydrofuran (THF); palllium on carbon (Pd/C); trifluoroacetic acid (TFA); acetic acid (AcOH); tert-butyl alcohol (t-BuOH or TBS); 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 ).

Tulathromycin A is an antibacterial macrolide (azalide) based on a 15-membered (lactone A) closed ring. The azalide is converted to a 13-membered (lactone B) closed ring, tulathromycin B. This conversion occurs at an equilibrium ratio of about 9:1 (A:B) and is depicted below.

Tulathromycin azalides can also be represented by the following structures:

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

In addition to the tulathromycin azalides (tulaA and tulaB) shown above, the lactone A and B compound from Example H-11 is illustrated below:

H-11 lactones were separated by HPLC using an Agilent 1100 quaternary pump and diode array detector (250 nm) with an X-select CSH C18 column (150 x 4.6 mm, 2.5 μm) at 50°C using mobile phase gradient (MP) containing 0.03% H ₂ SO ₄ in water (mpA) and acetonitrile (mpB) for 16 minutes. Lactone A eluted at 5.8 minutes (area % 92.4) and lactone B eluted at 5.2 minutes (area % 7.6).

In aqueous solution, the compound of Example H-11 exists as a balanced mixture of two lactone isomers, as shown above. The ratio is approximately 9:1 lactone A:B. The rate of equilibration depends on pH and temperature, with neutral pH providing faster equilibration, pH~5-6 providing much slower equilibration, and high temperatures resulting in faster equilibration. Equilibration occurs within 1 hour at pH>6 and temperatures>60°C. The H-11 isomerization is a 6 exo-Trig cyclization and is the predominant Baldwin's rule reaction. The dominant isomer, lactone-A, is a 15-membered macrocyclic lactone, and the minor isomer, lactone-B, is a 13-membered macrocyclic lactone. H-11 exhibits pH-dependent solubility in water when it is highly soluble at acidic pH under acidic conditions and has less solubility as the pH approaches neutral conditions. Due to the pH-dependent solubility of H-11 and other compounds of the invention, it may be necessary to dissolve the organic acid (eg citric acid) in water before adding the active agent (eg H-11) to ensure complete dissolution, particularly in the case of solutions with higher concentrations, thereby providing a solution with sufficient buffer capacity for dissolution.

One of the metabolites of tulathromycin A is des-methylazalide, (2S,3S,4R,5S,8R,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), illustrated in the following diagrams below:

Tulathromycin B is also metabolized to B-des-methylazalide.

The M9 analogue can be used as a starting material for the preparation of the compounds of the invention. The process for producing des-methyl tulathromycin (M9) is a two-step process from tulathromycin A in which the intermediate is not usually isolated but may exist. The first step is the oxidation of the tertiary amine to an N-oxide using a series of oxidizing agents known as oxidizing tertiary amines. The second stage is demethylation according to the Polonovsky reaction, in which any metal that affects this type of transformation can be used. This is usually iron, but a copper salt (Cu(II)) can also be used.

To a cold (<0°C) solution of tulathromycin A (4.0 g, 5.0 mmol) in n-butanol (20 ml) was added 1.22 g (5.1 mmol) of a commercial 32% peroxyacetic acid solution. After 30 minutes, the product was extracted into a 0.25 M aqueous solution of disodium ethylenediaminetetraacetic acid (EDTA, 15 ml). The aqueous solution was made alkaline to pH 9.5 with concentrated aqueous ammonia and extracted with tert-butyl methyl ether (20 ml). The N-oxide product was concentrated to a thick oil, but not isolated, [M+H] ⁺ =822. The oil was dissolved in methanol (16 ml). Copper (II) sulfate pentahydrate (1.5 g, 6.1 mmol) and acetic acid (0.28 ml) were added and the reaction was heated to 60°C for 12 hours. The solution was cooled to 25°C and hydroxylamine hydrochloride (0.75 mg, 10 mmol) in water (8 ml) was added. After 2 hours, the product was partitioned between water (28 ml, adjusted to pH 9.5 with aqueous ammonia) and methylene chloride (20 ml). The organics were concentrated to an oil and the product crystallized from hot acetonitrile (40 ml). The resulting white crystalline powder was dried to obtain 3.2 g of M9. LCMS [M+H] ⁺ =792.5. Purity by HPLC>98%. ¹ H NMR (600 MHz, d ₆ -DMSO): N-Me (3H, 2.42 ppm, s) versus tulathromycin NMe ₂ (6H, 2.26 ppm).

Alternatively, M9 can be prepared by mixing a 20°C solution of tulathromycin A (4.0 g, 5.0 mmol) in n-butanol (10 ml) and then adding hexafluoroacetone trihydrate (0.27 g, 1.2 mmol) followed by by adding 30% hydrogen peroxide (0.62 g, 5.5 mmol). After 4 hours, acetic acid (0.31 g, 5.5 mmol) was added, followed by methyl tert-butyl ether (6 ml) and water (25 ml). The top organic layer was discarded. Methyl tert-butyl ether (8 ml) was added and the aqueous layer was adjusted to pH 9.8 with aqueous ammonia. The lower aqueous layer was drained. The N-oxide product was concentrated to a thick oil but not isolated. [M+N] ⁺ =822. The oil was dissolved in methanol (12 ml). Anhydrous copper(II) sulfate (0.97 g, 6.1 mmol) and acetic acid (0.28 ml) were added and the reaction was heated to 60°C for 1 hour. The solution was cooled to 25°C and hydroxylamine hydrochloride (0.75 mg, 10 mmol) in water (8 ml) was added. After 2 hours, the product was partitioned between water (28 ml, adjusted to pH 9.5 with aqueous ammonia) and methylene chloride (20 ml). The organics were concentrated to an oil and the product crystallized from hot acetonitrile (40 ml). The resulting white crystalline powder was dried to obtain 3.2 g of product; LCMS [M+H] ⁺ =792.5. Purity by HPLC>98%. 1H NMR (600 MHz, (16-DMSO): N-Me (3H, 2.42 ppm, s) versus tulathromycin NMe ₂ (6H, 2.26 ppm).

Alternatively, M9 can be prepared by mixing a solution of tulathromycin A epoxide precursor, (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)- 4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((3S,4S,6R,8R) -8-methoxy-4,8-dimethyl-1,5-dioxaspiro[2.5]octan-6-yl)oxy)-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecane- 15-one (tula-epx), (20.0 g, 27 mmol) in methanol (40 ml) and then adding acetic acid (1.6 ml, 30 mmol), hexafluoroacetone trihydrate (0.38 ml, 3 mmol), and then - a 30% aqueous solution of hydrogen peroxide (0.62 g, 30 mmol).

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

Azithromycin (pictured below), an azalide similar to tulathromycin except for the core N ring, is substituted with a methyl group (1'), and the cladinose sugar is additionally unsubstituted with methylpropanamine (2'); as pictured below.

Azithromycin can be derivatized to produce a des-methyl analogue similar to M9. Additional derivatization can be carried out in accordance with the schemes and experimental conditions defined herein to obtain immunomodulatory azithromycin derivatives that are not active (ie, are non-antibacterial) against bacterial pathogens of RBD. In addition to azithromycin, other macrolides, such as erythromycin, tilmicosin, clarithromycin, gamithromycin, fidaxomicin, roxithromycin, telithromycin, dirithromycin, josamycin, midecamycin, oleandomycin, roxithromycin and others, can be modified similarly to M9 to produce immunomodulatory analogues that lack antibacterial properties against RBD. and other bacterial pathogens in animals, including humans.

For illustrative purposes, the following reaction schemes demonstrate potential routes for the synthesis of key intermediates and compounds of the invention. For a more detailed description of the individual reaction steps, see the examples section below. Those skilled in the art will appreciate that other suitable starting materials, reagents and synthetic routes can be used to synthesize the intermediates and compounds of the invention and a number of derivatives thereof. In addition, many of the compounds produced by the methods described below can be prepared and/or modified using conventional chemistry.

The compounds of the invention can be used in their native form or as a salt. In cases where the formation of a stable, non-toxic acid salt is desired, it may be advisable to administer the compound in the form of a pharmaceutically acceptable salt. For the purposes of the present invention, the term "pharmaceutically acceptable salt" refers to salts that are medically suitable for use in contact with animal tissues and organs without causing toxicity, irritation, allergic reaction, etc., and correspond to a reasonable benefit/risk ratio . In addition, the compounds of the invention have a secondary or tertiary amino group, which is basic in nature and therefore can form acid addition salts, which can be pharmaceutically acceptable acids. Therefore, pharmaceutically acceptable salts according to the present invention include pharmaceutically acceptable acid addition salts formed with organic and inorganic acids and pharmaceutically acceptable salts formed with optically active acids. Representative acid addition salts include, but are not limited to, acetate, adipate, alginate, ascorbate, citrate, aspartate, benzoate, benzenesulfonate, besylate, bicarbonate/carbonate, bisulfate/sulfate, borate, butyrate, camphorate, camphorsulfonate, camsylate, citrate, digluconate, edisylate, ethoglutarate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glycerophosphate, hemisulfate, heptanoate, hexafluorophosphate, hexanoate, gibensate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, isethionate, lactate, malate, maleate, malonate, mesylate, methyl sulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmiate, pamoate, pectinate, persulfate, phosphate/hydrogen phosphate/dihydrogen phosphate, picrate, pivalate, propionate, saccharate, stearate, succinate, tartrate, thiacyanate, tosylate and trifluoroacetate.

In the following diagrams, the demethylation reaction or Polonovsky reaction occurs when the amine oxide reacts with an acylating agent. The commonly known mechanism involves the removal of a proton to produce a nitrogen ylide, which loses acetate (via acetic anhydride), which attacks the carbon adjacent to the nitrogen atom to produce α-acetoxyamine. The main feature of the Polonovsky reaction is the conversion of an N-oxide to an intermediate iminium ion. Depending on the structure of the substrate and the acid anhydride or other activating reagent used, formation of the iminium ion may occur through the loss of α-hydrogen or through fragmentation of the Cα-carbon bond. Again, depending on the conditions, the reaction at this stage will either stop and the iminium ions become Polonovsky products, or it will continue to form enamines or tertiary amides and/or secondary amines and aldehydes.

In principle, any reagent can be used that can activate the oxygen of the N-oxide towards the formation of an iminium ion, thereby initiating the Polonovsky reaction. Three main types of activating agents can be used, acid anhydrides and chlorides (including chloroformate esters), iron or copper salts and complexes, and sulfur dioxide.

In the following schemes and preparation methods, the following abbreviations include: methanol (MeOH), ethanol (EtOH), dichloromethane (DCM), trifluoroacetic acid ( _{TFA), hydrogen peroxide (H2O2 )} , potassium cyanide (KCN), triethylamine (TEA) , triethylamine trihydrofluoride (TEA.3HF), dimethylformamide (DMF), potassium cyanide (KCN), N,N-diisopropylethylamine (DIPEA), dichloroethane (DCE), isopropyl alcohol (IPA), ethylenediaminetetraacetic acid (EDTA), acetic acid (AcOH ), ammonium hydroxide ( _NH4OH ), acetonitrile (MeCN or Acn), sodium triacetoxyborohydride (TABN), sodium methoxide (MeONa), cerium chloride (lll) ( _{CeCl3), sodium azide (NaN3 )} , sodium bicarbonate (NaHCO ₃ ), ammonium chloride (NH ₄ Cl), magnesium sulfate (MgSO ₄ ), bromine (Br ² ), sodium sulfate (Na ₂ SO ₄ ), ammonium sulfate ((NH ₄ ) ₂ SO ₄ ), copper sulfate (CuSO ₄ ), sodium cyanoborohydride (NaBH ₃ CN), 1-butanol (N-BuOH), hexafluoroacetone ((CF ₃ ) ₂ CO-H ₂ O), methoxy (OMe), ethoxy (OEt), room temperature (RT), in overnight (ON) and water (H ₂ O).

Scheme 1a. Preparation of urea compounds of formula (1) from (1-A1) to (1-A6)

Urea analogues can be prepared by following the 3-step procedure shown in Scheme 1a above. First, commercially available tulathromycin epoxide (tula-epx) can be demethylated in, but not limited to, a Polonovsky reaction to produce M9 epoxide (M9-epx). N-oxide can be prepared using various oxidizing agents such as iodine, N-iodosuccinimide, peroxyacetic acid or hydrogen peroxide. Demethylation of N-oxide can be initiated by iron or copper salts. The secondary amine thus obtained can be transformed into various ureas using urea-forming reagents such as isocyanates; activated carbamoyl chlorides, -imidazoles, -N-methylimidazoles; p-NO ₂ phenolic ethers and others. Sometimes weak bases such as TEA or DIPEA can be used to facilitate the formation of urea. Non-limiting examples of leaving groups (LG) include chlorine, imidazole, methylimidazole, p-NO ₂ -phenol, and the like. As a final step, the epoxy functionality can be opened to give the final urea analogues using different nucleophiles such as primary and secondary amines, alcohols, thiols, cyanide, azide or halogen anions and others at high temperature in alcoholic solvents such as but not limited to 1-propanol, 1-butanol or 2-propanol. This reaction can be carried out completely overnight. Sometimes weak bases such as NaHCO ₃ or salts such as NH ₄ Cl or (NH ₄ ) ₂ SO ₄ can be used to speed up the opening reaction of the epoxide. For any of the schemes presented herein, the "nucleophile" from the epoxide opening step on the cladinose ring can be one of, but is not limited to: HNR ⁵ R ⁶ , HOR ⁷ , HS(O) _p R ⁷ , NaN ₃ , CeCl ₃ , TEA.3GF and KCN, where R ⁵ , R ⁶ , R ⁷ and p correspond to the definition in this document.

Scheme 1b: Details of Scheme 1a, step 3 (nucleophilic epoxide opening)

In the case of analogues (s1b-A1), the epoxy functionality can be opened to obtain the final urea analogues using various primary or secondary amines in alcohol solvents such as, but not limited to, methanol, ethanol, 1-propanol and others. In the case of analogues (s1b-A2), the epoxy functionality can be opened to obtain the final urea analogues using various alcohols used as solvents such as, but not limited to, methanol, ethanol, 1-propanol and others. Sometimes weak bases such as NaHCO ₃ or salts such as NH ₄ Cl or (NH ₄ ) ₂ SO ₄ can be used to speed up the opening reaction of the epoxide. In the case of analogues (s1b-A3), the epoxy functionality can be opened to give the final urea analogues using various thiols such as, but not limited to, ethanethiol, propanethiol, isopropyl mercaptan, and other alcohol solvents such as, but not limited to, ethanol or 1-propanol. To speed up the epoxide opening reaction, weak bases are used, such as, but not limited to, NaHCO ₃ . In the case of analogues (slb-A4), the epoxy functionality can be opened to give the final urea analogues using different halides from reagents such as, but not limited to, CeCl ₃ or Br ₂ , in alcohol solvents such as, but not limited to , ethanol or 1-propanol. Sometimes weak bases such as NaHCO ₃ or salts such as NH ₄ Cl or (NH ₄ ) ₂ SO ₄ can be used to speed up the opening reaction of the epoxide. In the case of analogues (slb-A5), the epoxy functionality can be opened to give the final urea analogues using various sources of azide anions, such as, but not limited to, NaN ₃ , in alcohol solvents, such as, but not limited to, ethanol or 1-propanol Sometimes weak bases such as NaHCO ₃ or salts such as NH ₄ Cl or (NH ₄ ) ₂ SO ₄ can be used to speed up the opening reaction of the epoxide. In the case of the (s1b-A6) analogues, the epoxy functionality can be opened to give the final urea analogues using various sources of cyanide anions such as, but not limited to, KCN, in alcohol solvents such as, but not limited to, IPA or 1 -propanol Sometimes weak bases such as NaHCO ₃ or salts such as NH ₄ Cl or (NH ₄ ) ₂ SO ₄ can be used to speed up the opening reaction of the epoxide.

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

Alternatively, urea analogues can be prepared according to Scheme 2a. In the first step, a commercially available tulathromycin epoxide intermediate is treated with various nucleophiles, such as, but not limited to, primary and secondary amines, alcohols, thiols, cyanide, azide or halogen anions, and others, at high temperature in alcohol solvents such as but not limited to 1-propanol, 1-butanol or 2-propanol. This reaction can occur overnight. Sometimes weak bases such as NaHCO ₃ or salts such as NH ₄ Cl or (NH ₄ ) ₂ SO ₄ can be used to speed up the opening reaction of the epoxide. In a second step, the tertiary dimethylamine on the desosamine sugar can be demethylated using Polonovsky type conditions as described above. The final urea analogues can be prepared by reacting the secondary methylamine moiety with urea-forming reagents such as, but not limited to, isocyanates; activated carbamoyl chlorides, -imidazoles, -N-methylimidazoles; P-NO ₂ phenolic ethers, etc.

Scheme 2b: Details of Scheme 2a, Step 1 (Nucleophilic Epoxide Opening):

In the case of compounds (s2b-A1), the epoxy functionality can be opened using various primary or secondary amines in alcohol solvents such as, but not limited to, methanol, ethanol, 1-propanol and others. In the case of compounds (s2b-A2), the epoxy functionality can be opened using various alcohols used as solvents such as, but not limited to, methanol, ethanol, 1-propanol and others. Sometimes weak bases such as NaHCO ₃ or salts such as NH ₄ Cl or (NH ₄ ) ₂ SO ₄ can be used to speed up the opening reaction of the epoxide. In the case of compounds (s2b-A3), the epoxy functionality can be opened using various thiols such as, but not limited to, ethanethiol, propanethiol, isopropyl mercaptan, and other alcohol solvents such as, but not limited to, ethanol or 1-propanol . To speed up the epoxide opening reaction, weak bases are used, such as, but not limited to, NaHCO ₃ . In the case of compounds (s2b-A4), the epoxy functionality can be opened using various halides from reagents such as, but not limited to, CeCl ₃ or Br ₂ in alcohol solvents such as, but not limited to, ethanol or 1- propanol Sometimes weak bases such as NaHCO ₃ or salts such as NH ₄ Cl or (NH ₄ ) ₂ SO ₄ can be used to speed up the opening reaction of the epoxide. In the case of compounds (s2b-A5), the epoxy functionality can be opened with an azide anion using different sources of azide anions such as, but not limited to, NaN ₃ , in alcohol solvents such as, but not limited to, ethanol or 1 -propanol Sometimes weak bases such as NaHCO ₃ or salts such as NH ₄ Cl or (NH ₄ ) ₂ SO ₄ can be used to speed up the opening reaction of the epoxide. In the case of (s2b-A6) compounds, the epoxy functionality can be opened with a cyanide anion using different sources of cyanide anions such as, but not limited to, KCN, in alcohol solvents such as, but not limited to, IPA or 1- propanol Sometimes weak bases such as NaHCO ₃ or salts such as NH ₄ Cl or (NH ₄ ) ₂ SO ₄ can be used to speed up the opening reaction of the epoxide.

Scheme 2c: Details of Scheme 2a, step 2 (demethylation):

All compounds (s2b-A1) to (s2b-A6) can be subjected to Polonovsky demethylation as described above to give the corresponding compounds (s2c-A1) to (s2c-A6). N-oxide can be prepared using various oxidizing agents such as iodine, NIS, peroxyacetic acid or hydrogen peroxide. Demethylation of the N-oxide can be initiated by reagents such as iron or copper salts.

Scheme 2d: Details of Scheme 2a, step 3 (urea formation)

In the last step of the sequence, the final analogs can be prepared by reacting the Polonovsky reaction product (s2c-A#) with urea-forming reagents such as, but not limited to, isocyanates; activated carbamoyl chlorides, -imidazoles, -N-methylimidazoles; p-NO ₂ phenolic esters, etc. Details of this last transformation are shown in diagram 2d above.

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

Alternatively, analogues can be prepared as illustrated in Scheme 3a. In a first step, commercially available tulathromycin epoxide can be demethylated, without limitation, in the Polonovsky reaction described above. The M9-epoxide thus obtained can be reacted with various nucleophiles, such as, but not limited to, primary and secondary amines, alcohols, thiols, cyanide, azide or halogen anions and others, at high temperature in alcoholic solvents such as, but not limited to, 1-propanol, 1-butanol or 2-propanol, to open the epoxy moiety. Sometimes weak bases such as NaHCO ₃ or salts such as NH ₄ Cl or (NH ₄ ) ₂ SO ₄ can be used to speed up the opening reaction of the epoxide. Details of this second stage are shown below in Figure 3b. as a final step, the final urea analogues can be prepared by reacting the secondary methylamine moiety with urea-forming reagents such as, but not limited to, isocyanates; activated carbamoyl chlorides, -imidazoles, -N-methylimidazoles; p-NO ₂ phenolic ethers, etc. Details of this last transformation are given in Figure 3c below.

Scheme 3b: Details of Scheme 3a, step 2 (nucleophilic epoxide opening)

M9-epoxide, obtained by demethylation of the commercially available tulathromycin epoxide (Scheme 3a), can be reacted to give the following compounds of the formula:

(s3b-A1) - with various primary or secondary amines in alcohol solvents such as, but not limited to, methanol, ethanol or 1-propanol; (s3b-A2) - with various alcohols used as solvents such as, but not limited to, methanol, ethanol or 1-propanol. Sometimes weak bases such as NaHCO ₃ or salts such as NH ₄ Cl or (NH ₄ ) ₂ SO ₄ can be used to speed up the opening reaction of the epoxide; (s3b-A3) - with various thiols such as, but not limited to, ethanethiol, propanethiol, isopropyl mercaptan and others, in alcohol solvents such as, but not limited to, ethanol or 1-propanol. To speed up the epoxide opening reaction, weak bases such as NaHCO ₃ are used; (s3b-A4) - with halides from reactants such as, but not limited to, CeCl ₃ or Br ₂ , in alcoholic solvents such as, but not limited to, ethanol or 1-propanol. Sometimes weak bases such as NaHCO ₃ or salts such as NH ₄ Cl or (NH ₄ ) ₂ SO ₄ can be used to speed up the opening reaction of the epoxide; (s3b-A5) - with an azide anion from sources such as, but not limited to, NaN ₃ , in alcohol solvents such as, but not limited to, ethanol or 1-propanol. Sometimes weak bases such as NaHCO ₃ or salts such as NH ₄ Cl or (NH ₄ ) ₂ SO ₄ can be used to speed up the opening reaction of the epoxide; (s3b-A6) - with cyanide anion from sources such as, but not limited to, KCN, in alcohol solvents such as, but not limited to, IPA or 1-propanol. Sometimes weak bases such as NaHCO ₃ or salts such as NH ₄ Cl or (NH ₄ ) ₂ SO ₄ can be used to speed up the opening reaction of the epoxide.

Scheme 3c: Details for Scheme 3a, step 3 (urea formation)

As a final step in the sequence, the final analogues of formula (s3c-A1) to (s3c-A6) can be prepared by reacting the corresponding analogues (s3b-A#) with urea-forming reagents such as, but not limited to, isocyanates; activated carbamoyl chlorides, -imidazoles, -N-methylimidazoles; p-NO ₂ phenolic esters and the like, in aprotic solvents such as DCM, and weak bases such as, but not limited to, TEA or DIPEA.

Scheme 4a. Preparation of urea compounds from (1-A1) to (1-A6)

Alternatively, ureas can be prepared according to Scheme 4a. This 4-step synthesis begins with the commercially available benzyloxycarbonyl (Cbz) protected tulathromycin epoxide. In the first step, the tertiary dimethylamine moiety on the desosamine sugar is demethylated using Polonovsky type conditions defined herein. In the second step, the secondary methylamine is activated with phosgene in the presence of a weak base such as lutidine and quenched with the necessary amines to form the urea functional group. In a subsequent step, the epoxy moiety is opened with various nucleophiles such as, but not limited to, primary and secondary amines, alcohols, thiols, cyanide, azide or halogen anions and others, at high temperature in alcohol solvents such as, but not limited to, 1-propanol, 1-butanol or 2-propanol. This reaction can be carried out completely overnight. Sometimes weak bases such as NaHCO ₃ or salts such as NH ₄ Cl or (NH ₄ ) ₂ SO ₄ can be used to speed up the opening reaction of the epoxide. Details of this third stage are shown in Figure 4b below. The final analogues are identified by removal of the Cbz protecting group under Pd/C catalytically mediated hydrogenolysis with H ₂ gas in an alcohol solvent such as ethanol, methanol or trifluoroethanol. Details of this last step are given in Diagram 4c below.

Scheme 4b: Details of Scheme 4a, step 3 (nucleophilic epoxide opening)

OCbz-urea epoxide can be reacted to give the following compounds of the formula:

(s4b-A1) - with various primary or secondary amines in alcohol solvents such as, but not limited to, methanol, ethanol or 1-propanol; (s4b-A2) - with various alcohols used as solvents such as, but not limited to, methanol, ethanol or 1-propanol. Sometimes weak bases such as NaHCO ₃ or salts such as NH ₄ Cl or (NH ₄ ) ₂ SO ₄ can be used to speed up the opening reaction of the epoxide; (s4b-A3) - with various thiols such as, but not limited to, ethanethiol, propanethiol, isopropyl mercaptan and others, in alcohol solvents such as, but not limited to, ethanol or 1-propanol. To speed up the epoxide opening reaction, weak bases such as NaHCO ₃ are used; (s4b-A4) - with halides from reactants such as, but not limited to, CeO ₃ or Br ₂ , in alcoholic solvents such as, but not limited to, ethanol or 1-propanol. Sometimes weak bases such as NaHCO ₃ or salts such as NH ₄ Cl or (NH ₄ ) ₂ SO ₄ can be used to speed up the opening reaction of the epoxide; (s4b-A5) - with an azide anion from sources such as, but not limited to, NaN ₃ , in alcohol solvents such as, but not limited to, ethanol or 1-propanol. Sometimes weak bases such as NaHCO ₃ or salts such as NH ₄ Cl or (NH ₄ ) ₂ SO ₄ can be used to speed up the opening reaction of the epoxide; (s4b-A6) - with cyanide anion from sources such as, but not limited to, KCN, in alcohol solvents such as, but not limited to, IPA or 1-propanol. Sometimes weak bases such as NaHCO ₃ or salts such as NH ₄ Cl or (NH ₄ ) ₂ SO ₄ can be used to speed up the opening reaction of the epoxide.

Scheme 4c: Details of Scheme 3a, stage 4 (unprotection)

In the last step of the sequence, the final analogs of formula (s4c-A1) to (s4c-A6) can be prepared by deprotecting the Cbz groups on the corresponding analogs (s4b-A#) under hydrogenation conditions with catalytic amounts of Pd/C in alcohol solvents.

Scheme 5. Preparation of compounds of formula (1) with alkylated crustal nitrogen through reductive amination

The alkyl-tula-epx intermediate can be readily synthesized from tulathromycin epoxide (tula-epx) by a number of methods, such as, but not limited to, reductive amination with an appropriate aldehyde and a hydride source such as, but not limited to, TABN or NaBH ₃ bCN , in solvents such as alcohols or DMF, and at temperatures from 0°C to 60°C. Subsequent chemical reactions to obtain compounds of the invention, in which the core macrolide nitrogen is alkylated with various R ⁰ groups, can be carried out according to schemes 1-3, for example, demethylation according to the Polonovsky reaction, opening of the epoxide and formation of urea, by replacing the starting material Tula-epoxide in all schemes 1-3 R ⁰ -alkylated tulathromycin epoxide intermediate (alkyl-tula-epx); for example, where R ⁰ represents a cut.

Scheme 6. Preparation of compounds of formula (1) substituted with various groups R ¹ and R ² : Preparation of the general intermediate epoxide M8 (M8-erx)

This intermediate (M8-epx) can be easily synthesized from the M9 epoxide by a number of methods, such as a second demethylation of I ₂ and NaOMe or a ternary sequence in which the M9 epoxide is first protected with a 4-OMe-benzyl group and then demethylated using Polonovsky demethylation. Epoxide M8 is revealed by deprotection under hydrogenolysis conditions using Pd/C and H ₂ gas in alcohol solvents such as, but not limited to, methanol, ethanol or trifluoroethanol. Epoxide M8 can be used in various methods to prepare the compounds of the invention, as shown in Scheme 7 below.

Scheme 7. Preparation of compounds of formula (1) substituted with various R1 groups of their epoxide M8 (M8-erx)

Epoxide M8 can be reacted with reagents to form ureas such as, but not limited to, isocyanates; activated carbamoyl chlorides, -imidazoles, -N-methylimidazoles; p-NO ₂ phenolic ethers, etc., in aprotic solvents such as DCM and weak bases such as, but not limited to, TEA or DIPEA, as shown in Scheme 7, to obtain the compounds of the invention from (s7 '-A1) to (s7'-A6) after opening the epoxide. This chemical reaction is an adaptation of the chemical reactions described in Schemes 1-3.

Epoxide M8 can also be reductively aminated with an appropriate aldehyde R ¹ and a hydride source such as, but not limited to, TABN or NaBH ₃ CN, in solvents such as alcohols, DMF, DCM or DCE, and at temperatures from 0°C to 60°C. The subsequent chemical reaction to produce compounds of the invention wherein R ¹ is not CH ₃ as in the tulathromycin-derived analogues can be accomplished by adapting the chemical reactions from Schemes 1-3 herein to form urea on the desosamine nitrogen and open cladinose epoxide by various nucleophiles. The urea functional group can be established using various urea-forming reagents such as, but not limited to, isocyanates; activated carbamoyl chlorides, -imidazoles, -N-methylimidazoles; P-NO ₂ phenolic esters, etc., in aprotic solvents such as DCM and weak bases such as, but not limited to, TEA or DIPEA, while epoxide can be opened using various nucleophiles such as primary and secondary amines, alcohols, thiols, cyanide, azide or halogen anions and others, at high temperature in alcohol solvents such as, but not limited to, 1-propanol, 1-butanol or 2-propanol, as shown in Scheme 7, c obtaining compounds of the invention from (s7^-A1) to (s7^-A6).

Scheme 8. Preparation of compounds of formula (1-A0) of formula (1) by reductive amination from azithromipine

Azithromycin can be used as a starting material for the synthesis of compounds of formula (1) of the invention, as shown in Scheme 8. Azithromycin can be subjected to a demethylation reaction similar to tulathromipine under similar conditions, such as, but not limited to, the Polonovsky reaction as defined herein. Demethylated azithromycin can be reacted with reagents to form ureas such as, but not limited to, isopianates; activated carbamoyl chlorides, -imidazoles, -N-methylimidazoles; p-NO ₂ phenolic esters, etc., in aprotic solvents such as DCM and weak bases such as, but not limited to, TEA or DIPEA, as shown in Scheme 8, to obtain the compounds of the invention from (s8 '-A0). In addition, des-methyl azithromycin can be subjected to a second demethylation as described above using I ₂ and NaOMe, followed by reductive amination with the appropriate aldehydes R1. The compounds of the invention (s8A-A0) can be synthesized by reacting doubly demethylated azithromycin with urea-forming reagents such as, but not limited to, isocyanates; activated carbamoyl chlorides, -imidazoles, -N-methylimidazoles; P-NO ₂ phenolic esters, etc., in aprotic solvents such as DCM, and weak bases such as, but not limited to, TEA or DIPEA, as shown in Scheme 8.

Scheme 9. Preparation of des-cladinose compounds of formula (1.1)

Des-cladinose compounds of formula (1.1) can be easily synthesized from compounds of formula (1A) by stirring said compound in an aqueous solution of acetic acid or hydrochloric acid at a temperature of from 0°C to 60°C in solvents such as, but not limited to, THF, MeCN or H ₂ O for 1 to 72 hours, as shown in Scheme 9.

Scheme 10. Preparation of des-cladinose compounds of formula (1.1)

Des-cladinose urea compounds of formula (1.1) can also be synthesized according to the sequence shown in Scheme 10. Tulathromycin epoxide (tula epx) or N-cor-substituted tulathromycin epoxide (alkylated tulathromycin epoxide, synthesized as shown in Scheme 5) can be demethylate according to the Polonovsky demethylation conditions described herein. The cladinose sugar of the des-methyl product can be cleaved under aqueous acidic conditions with acids such as acetic or hydrochloric and others, in solvents such as THF or acetonitrile. The urea functional group can be established using urea-forming reagents such as, but not limited to, isocyanates; activated carbamoyl chlorides, -imidazoles, -N-methylimidazoles; p-NO ₂ phenolic esters, etc., in aprotic solvents such as DCM and weak bases such as, but not limited to, TEA or DIPEA, as shown in Scheme 10, to obtain the desired des-cladinose urea compounds according to the invention (s10-1.1).

Examples

Preparation of des-cladinose compound of example A-13 of formula (1.1).

To the crude compound of Example H-11 (600.0 mg) was added 2N. HCl (10.0 ml) and the resulting mixture was heated at 45°C for 2 hours before cooling to room temperature. The crude reaction mixture was poured into ice-cold NH ₄ OH solution (pH>7), stirred for 5 minutes, then concentrated and lyophilized. The crude material was purified by preparative HPLC using ammonium acetate as a buffer and the purified material was passed through an SCX column to obtain the product as the free base.

Compounds of formula (1.1) can be prepared in a similar manner as shown above for Example A-13, under similar conditions, but using starting materials of formula (1-A1).

Preparation of the compound of example B-6 of formula (1-A0), which is the application of scheme 8.

Step 1: In a 500 mL round bottom flask, azithromycin (20 g, 26.77 mmol, 1 eq.) in MeOH (40 mL) and glacial acetic acid (3.4 mL, 53.54 mmol, 2.2 eq.) were sequentially added. ), hexafluoroacetone (1.9 ml, 13.38 mmol, 0.5 eq.) and H ₂ O ₂ (30% w/w in H ₂ O, 5 ml) at 0°C under N ₂ atmosphere. The reaction mixture was stirred at RT (25°C) for 16 hours before adding anhydrous CuSO ₄ (6.4 g, 40.15 mmol, 1.5 eq.). A round bottom flask was equipped with a reflux condenser and the reaction mixture was stirred at 80°C for 6 hours under an N ₂ 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 celite and the filtrate was made alkaline to pH 10 using aqueous ammonia. The organic phase was separated, washed with water and brine, dried over anhydrous Na ₂ SO ₄ and concentrated to obtain the crude material. The crude material was triturated with a solution of pentane and diethyl ether (2:1) to obtain the desired demethylated azithromycin as an off-white solid (13 g, 66.2%).

Step 2: To a stirred solution of des-methyl azithromycin (300 mg, 0.408 mmol, 1 eq.) in dry DCM (5 ml) add N-methyl-N-[4-(trifluoromethyl)phenyl]carbamoyl chloride (107 mg, 0.449 mmol , 1.1 eq.) and Et ₃ N (0.083 ml, 0.82 mmol, 2 eq.) at RT. The reaction mixture was stirred at RT for 12 hours, after which LCMS analysis showed complete conversion of the starting material. The mixture was concentrated under reduced pressure and the crude material was purified on a C18 silica gel column using reverse flash chromatography with 1.0% AcOH as modifier (0-100% MeCN in H ₂ O). The required fractions were lyophilized to obtain the desired urea product as a white solid acetate salt (260 mg, 64%).

Compounds of formula (1-A0) can be prepared in a manner similar to that shown above (B-6), under similar conditions, varying the urea reagent or starting material and using tulathromycin epoxide instead of azithromycin.

Preparation of the compound of example C-1 of formula (1-A2):

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), then 30 % aqueous hydrogen peroxide (0.62 g, 30 mmol) was mixed together and stirred for 4 hours at 35°C. After consumption of the starting material by LCMS, the reaction was cooled to 20°C, anhydrous copper(II) sulfate (4.5 g, 29 mmol) was added and the reaction was heated to 60°C for 1 hour. After completion of the reaction according to LCMS, the reaction mixture was cooled to 20°C and 60 ml of DCM and 80 ml of H ₂ O were added. The mixture was acidified to approximately pH 9.8 with concentrated aqueous ammonia. The mixture was concentrated in vacuo to a solid and recrystallized from acetone/water to give 60 g of a white crystalline product (M9-epx), which was 95% pure by LCMS and which was used as such in the next step.

Step 2: Epoxide M9 (M9-erx; 1.00 g, 1.36 mmol, 1.0 eq.) was dissolved in 10 ml dry EtOH in a high pressure microwave vial. The resulting solution was heated to 120°C in a microwave reactor for 12 hours. Volatiles were then removed under reduced pressure and the crude material was purified on a C18 silica gel column using reverse flash chromatography with 1.0% AcOH as modifier (0-100% MeCN in H ₂ O). Fractions containing the desired product were combined, adjusted to pH~12 with NH ₄ OH and extracted 3 times with 50 mL DCM to obtain the desired product as the free base (220 mg, 20%).

Step 3: The product from Step 2 (0.14 mmol, 110 mg, 1.00 eq) was dissolved in DCM (5 ml) and cooled to -78°C followed by the addition of phenyl cyanate (1.0 eq, 16 µL, 0.14 mmol) and allowed the reaction to warm to RT with stirring for 60 minutes. Once the reaction was complete by LCMS analysis, volatiles were removed under a stream of N ₂ and the crude material was purified by C18 reverse flash chromatography with 1.5% AcOH as modifier (0-100% MeCN in H ₂ O). Fractions containing the desired product were lyophilized to obtain the desired product as the acetate salt (15 mg, 11%).

Preparation of Example D-2 of Formula (1-A3)

Step 1: 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), then 30% aqueous Hydrogen peroxide (0.62 g, 30 mmol) was mixed together and stirred for 4 hours at 35°C. After consumption of the starting material by LCMS, the reaction was cooled to 20°C, anhydrous copper(II) sulfate (4.5 g, 29 mmol) was added and the reaction was heated to 60°C for 1 hour. After completion of the reaction according to LCMS, the reaction mixture was cooled to 20°C and 60 ml of DCM and 80 ml of H ₂ O were added. The mixture was acidified to approximately pH 9.8 with concentrated aqueous ammonia. The mixture was concentrated in vacuo to a solid and recrystallized from acetone/water to give 60 g of a white crystalline product (M9-epx), which was 95% pure by LCMS and which was used as such in the next step.

Step 2: Epoxide M9 (M9-erx, 1.00 g, 1.36 mmol, 1.0 eq.) was dissolved in 10 ml of dry 1-propanol in a 25 ml round bottom flask. Potassium bicarbonate (3.0 eq, 4.1 mmol, 410 mg) was added followed by 1-propanethiol (5.0 eq, 6.8 mmol, 640 µl) and the resulting solution was heated to 50°C overnight , after which LCMS analysis showed consumption of the starting material. The reaction mixture was diluted with 20 ml DCM and H ₂ O, adjusted to pH ~ 12 with NH ₄ OH and extracted 3 times with 30 ml DCM to obtain the desired product as the free base (1053 mg, 95%) and used as such for next stage.

Step 3: The product from Step 2 (0.25 mmol, 200 mg, 1.0 eq.) was dissolved in DCM (5 ml) and TEA (2.0 eq., 70 µl, 0.49 mmol) was added, and then N-methyl-N-phenylcarbamoyl chloride (1.0 eq., 42 mg, 0.25 mmol) and the resulting solution was stirred at RT overnight. Once the reaction was complete by LCMS analysis, volatiles were removed under a stream of N ₂ and the crude material was purified by C18 reverse flash chromatography with 0.5% AcOH as modifier (0-100% MeCN in H ₂ O). Fractions containing the desired product were lyophilized to obtain the desired product as the acetate salt (135 mg, 55%).

Preparation of the compound of example E-3 of formula (1-A4):

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 30 % aqueous hydrogen peroxide (0.62 g, 30 mmol) was mixed together and stirred for 4 hours at 35°C. After consumption of the starting material by LCMS, the reaction was cooled to 20°C, anhydrous copper(II) sulfate (4.5 g, 29 mmol) was added and the reaction was heated to 60°C for 1 hour. After completion of the reaction according to LCMS, the reaction mixture was cooled to 20°C and 60 ml of DCM and 80 ml of H ₂ O were added. The mixture was acidified to approximately pH 9.8 with concentrated aqueous ammonia. The mixture was concentrated in vacuo to a solid and recrystallized from acetone/water to give 60 g of a white crystalline product (M9-epx), which was 95% pure by LCMS and which was used as such in the next step.

Step 2: Epoxide M9 (M9-erx, 5.00 g, 6.82 mmol, 1.0 eq.) was dissolved in 100 ml of dry 1-propanol in a 250 ml round bottom flask. Ammonium chloride (3.0 eq, 20.5 mmol, 1.1 g) was added, followed by cerium chloride (3.0 eq, 20.5 mmol, 5.1 g), and the resulting solution was heated to 70°C overnight, after which LCMS analysis showed consumption of the starting material. The reaction mixture was diluted with 100 ml DCM and H ₂ O, and the pH was adjusted to pH~12 with NH ₄ OH and extracted 3 times with 100 ml DCM to obtain the desired product as the free base (5091 mg, 97%) and used as such at the next stage.

Step 3: The product from Step 2 (0.26 mmol, 200 mg, 1.0 eq.) was dissolved in DCM (5 ml) and TEA (2.0 eq., 73 µl, 0.52 mmol) was added, and then N-methyl-N-[4-(trifluoromethyl)phenyl]carbamoyl chloride (1.0 eq., 62 mg, 0.26 mmol) and the resulting solution was stirred at RT overnight. Once the reaction was complete by LCMS analysis, volatiles were removed under a stream of N ₂ and the crude material was purified by C18 reverse flash chromatography with 1.5% AcOH as modifier (0-100% MeCN in H ₂ O). Fractions containing the desired product were lyophilized to obtain the desired product as the acetate salt (119 mg, 44%).

Preparation of the compound of example F-2 of formula (1-A5):

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 30 % aqueous hydrogen peroxide (0.62 g, 30 mmol) was mixed together and stirred for 4 hours at 35°C. After consumption of the starting material by LCMS, the reaction was cooled to 20°C, anhydrous copper(II) sulfate (4.5 g, 29 mmol) was added and the reaction was heated to 60°C for 1 hour. After completion of the reaction according to LCMS, the reaction mixture was cooled to 20°C and 60 ml of DCM and 80 ml of H ₂ O were added. The mixture was acidified to approximately pH 9.8 with concentrated aqueous ammonia. The mixture was concentrated in vacuo to a solid and recrystallized from acetone/water to give 60 g of a white crystalline product (M9-epx), which was 95% pure by LCMS and which was used as such in the next step.

Step 2: Epoxide M9 (M9-erx, 6.00 g, 8.19 mmol, 1.0 eq.) was dissolved in 100 ml of dry 1-propanol in a 250 ml round flask. Ammonium chloride (3.0 eq, 24.6 mmol, 1.31 g) was added followed by sodium azide (3.0 eq, 24.6 mmol, 1.6 g) and the resulting solution was heated to 80°C overnight, after which LCMS analysis showed consumption of the starting material. The reaction mixture was diluted with 100 ml DCM and H ₂ O, and the pH was adjusted to pH~12 with NH ₄ OH and extracted 3 times with 100 ml DCM to obtain the desired product as the free base (5981 mg, 94%) and used as such at the next stage.

Step 3: The product from Step 2 (0.36 mmol, 282 mg, 1.0 eq.) was dissolved in DCM (5 ml) and TEA (2.0 eq., 102 µl, 0.73 mmol) was added, and then N-methyl-N-phenylcarbamoyl chloride (1.0 eq., 62 mg, 0.36 mmol) and the resulting solution was stirred at RT overnight. Once the reaction was complete by LCMS analysis, volatiles were removed under a stream of N ₂ and the crude material was purified by C18 reverse flash chromatography with 1.5% AcOH as modifier (0-100% MeCN in H ₂ O). Fractions containing the desired product were lyophilized to obtain the desired product as the acetate salt (180 mg, 51%).

Preparation of the compound of example G-3 of formula (1-A6):

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 30 % aqueous hydrogen peroxide (0.62 g, 30 mmol) was mixed together and stirred for 4 hours at 35°C. After consumption of the starting material by LCMS, the reaction was cooled to 20°C, anhydrous copper(II) sulfate (4.5 g, 29 mmol) was added and the reaction was heated to 60°C for 1 hour. After completion of the reaction according to LCMS, the reaction mixture was cooled to 20°C and 60 ml of DCM and 80 ml of H ₂ O were added. The mixture was acidified to approximately pH 9.8 with concentrated aqueous ammonia. The mixture was concentrated in vacuo to a solid and recrystallized from acetone/water to give 60 g of a white crystalline product (M9-epx), which was 95% pure by LCMS and which was used as such in the next step.

Step 2: Epoxide M9 (M9-erx, 3.00 g, 4.09 mmol, 1.0 eq.) was dissolved in 50 ml of dry 2-propanol in a 100 ml round bottom flask. Ammonium sulfate (3.0 eq., 12.3 mmol, 1.6 g) was added, followed by potassium cyanide (6.0 eq., 24.6 mmol, 1.6 g), and the resulting solution was heated to 80°C within 48 hours, after which LCMS analysis showed consumption of the starting material. The reaction mixture was diluted with 100 ml DCM and H ₂ O, and the pH was adjusted to pH ~ 12 with NH ₄ OH and extracted 3 times with 30 ml DCM to obtain the desired product as the free base (2922 mg, 94%) and used as such at the next stage.

Step 3: The product from Step 2 (0.13 mmol, 100 mg, 1.0 eq.) was dissolved in DCM (5 ml) and TEA (2.0 eq., 37 µl, 0.26 mmol) was added, and then N-methyl-N-phenylcarbamoyl chloride (1.0 eq., 22 mg, 0.13 mmol) and the resulting solution was stirred at RT overnight. Once the reaction was complete by LCMS analysis, volatiles were removed in an n ₂ stream and the crude material was purified by C18 reverse flash chromatography with 0.5% AcOH as modifier (0-100% MeCN in H ₂ O). Fractions containing the desired product were lyophilized to obtain the desired product as the acetate salt (58 mg, 46%).

Compounds of formula (1-A2 to 1-A6) can be prepared in the same way as shown above (examples C-1, D-2, E-3, F-2 and G-3), under similar conditions, varying the reagent for urea formation or starting material and using (alkyl-tula-epx) as starting material instead of tulathromycin epoxide as shown in Scheme 5.

Preparation of the compound of example H-11 of formula (1-A1):

Step 1: To a solution of tulathromycin (tula) (20.0 g, 24.8 mmol) in methanol (40 ml) add together acetic acid (1.6 ml, 28 mmol), hexafluoroacetone trihydrate (0.62 ml, 2. 8 mmol) and then 30% aqueous hydrogen peroxide (2.88 g, 28 mmol) and stirred for 4 hours at 35°C. After consumption of the starting material by LCMS, the reaction was cooled to 20°C, anhydrous copper(II) sulfate (4.35 g, 28 mmol) was added and the reaction was heated to 60°C for 2 hours. After completion of the reaction according to LCMS, the reaction mixture was cooled to 20°C and 60 ml of DCM and 80 ml of H ₂ O were added. The mixture was acidified to approximately pH 9.8 with concentrated aqueous ammonia. The mixture was concentrated in vacuo to a solid and recrystallized from acetone/water to give 14.2 g of a white crystalline product (M9-epx) which was >95% pure by LCMS and which was used as such in the next step.

Step 2: M9 from Step 1 (0.25 mmol, 200 mg, 1.0 eq.) was dissolved in DCM (5 ml) and TEA (2.0 eq., 70 µl, 0.49 mmol) was added, and then N-methyl-N-phenylcarbamoyl chloride (1.0 eq., 42 mg, 0.25 mmol) and the resulting solution was stirred at RT overnight. Once the reaction was complete by LCMS analysis, volatiles were removed under a stream of N ₂ and the crude material was purified by C18 reverse flash chromatography with 1.5% AcOH as modifier (0-100% MeCN in H ₂ O). Fractions containing the desired product were lyophilized to obtain the desired product as the acetate salt (175 mg, 71%).

Compounds of formula (1-A1; table H) and formula (1-A1a; table I), where R ⁵ represents H and R ⁶ represents propyl, can be prepared in a similar manner as shown above for example (H-11) by varying the urea reagent or starting material and using (alkyl-tula-epx) as the starting material instead of tulathromycin epoxide as shown in Scheme 5. The following compounds (1-A1) were prepared following the procedure of Example (H-11) , and only the last stage of urea formation is shown.

Preparation of compound example H-8. To a solution of M9 (200 mg, 0.2525 mmol) in DCM (3 mL, 46.80 mmol) was added isocyanato(trimethyl)silane (1.5 eq., 0.3788 mmol) and the reaction was stirred at room temperature for 16 hours. The reagents were evaporated, MeOH (10 ml) was added and then evaporated. The residue was purified by preparative HPLC to give a white solid as the TFA salt (79 mg).

Preparation of Example H-72: In a dry round bottom flask, M9 (400 mg, 0.505 mmol) and 3-aminopyridine (47.53 mg, 0.505 mmol) were added to DCM (5 mL). The reaction mixture was cooled to -78°C and triphosgene (44.962 mg, 0.152 mmol) was added, followed 10 minutes later by triethylamine (0.141 ml, 1.01 mmol). 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. Such fractions were pooled, concentrated and lyophilized. The lyophilized material was passed through a SCX/PL-HCO ₃ resin column to obtain the free base. The free base was then dissolved in 1N. AcOH solution, stirred for 30 minutes at room temperature, concentrated, dissolved in t-BuOH and lyophilized to give the acetate salt product.

Preparation of Example H-91: Phenyl isocyanate (3.76 mg, 31.6 mmol) was slowly added to a solution of M9 (21.0 mg, 27 mmol) in methylene chloride (200 ml) at 0°C. After 15 minutes, a solution of acetic acid (3.19 mg, 53.0 mmol) in water (200 ml) was added and the product was extracted into the aqueous layer. Organic matter was drained. Methyl tert-butyl ether (175 ml) was added to the aqueous solution and the aqueous layer was made alkaline to pH 7.9 with 2N. aqueous sodium hydroxide. The product-containing organic layer was concentrated to a solid. The solids were dissolved in methyl tert-butyl ether (80 ml) at 55°C and acetic acid (1.7 mg, 28 mmol) was added.

The resulting suspension was cooled to 5°C, and the product in the form of an acetate salt was isolated by filtration. The solids were dried in vacuo to obtain 11.0 g of a white solid.

Preparation of the compound of example 1-4. Indoline-1-carbonyl chloride (126 mg, 0.69 mmol) was added to a solution of M9 (500 mg, 0.63 mmol) and TEA (114 μl, 1.3 eq., 0.82 mmol) in DCM (5 ml). and 4-dimethylaminopyridine (4 mg, 0.05 eq., 0.032 mmol). The mixture was stirred at room temperature for 3 hours. The mixture was quenched with NaHCO ₃ (saturated aq. solution), separated and the solvent was evaporated. The crude mixture was purified by preparative SLC (2PIC column), 25% MeOH with NH ₃ to give a white solid.

Preparation of the compound of Example 1-6: A solution of 3,4-dihydro-2H-1λ6,4-benzothiazine 1,1-dioxide (183 mg, 0.99874 mmol) and pyridine (2 eq. 1.9975 mmol) in DCM (5 ml, 78.00 mmol) was added dropwise to a solution of triphosgene (0.4 eq., 0.39950 mmol) in DCM (5 ml, 78.00 mmol) at -20°C under N ₂ atmosphere. The reaction mixture was allowed to warm to room temperature for 30 minutes and then stirred for 2 hours at room temperature. The reaction was quenched with a 2 M aqueous solution of hydrogen chloride, separated and added to a solution of M9 (700 mg, 0.8838 mmol) and TEA (1.3 eq., 1.149 mmol) and 4-dimethylaminopyridine (0.05 eq., 0.04419 mmol) in DCM (5 ml, 78.00 mmol). The mixture was stirred at room temperature overnight. The mixture was quenched with NaHCO ₃ (saturated aq. solution), separated and the solvent was evaporated. The crude mixture was purified by preparative SLC (BiP column, eluting with 26% MeOH with NH ₃ (aq) to give a white solid.

Preparation of the compound of example H-27 of formula (1-A1)

Step 1: Solution of (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy- 6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((3S,4S,6R,8R)-8-methoxy-4,8-dimethyl -1,5-dioxaspiro[2.5]octan-6-yl)oxy)-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one (tula-epx) (20 .0 g, 27 mmol) in methanol (40 ml) and acetic acid (1.6 ml, 30 mmol), hexafluoroacetone trihydrate (0.38 ml, 3 mmol), and then 30% aqueous hydrogen peroxide (0.62 g , 30 mmol) were mixed together and stirred for 4 hours at 35°C. After consumption of the starting material by LCMS, the reaction was cooled to 20°C, anhydrous copper(II) sulfate (4.5 g, 29 mmol) was added and the reaction was heated to 60°C for 1 hour. After completion of the reaction according to LCMS, the reaction mixture was cooled to 20°C and 60 ml of DCM and 80 ml of H ₂ O were added. The mixture was acidified to approximately pH 9.8 with concentrated aqueous ammonia. The mixture was concentrated in vacuo to a solid and recrystallized from acetone/water to give 60 g of a white crystalline product (M9-epx), which was 95% pure by LCMS and which was used as such in the next step.

Step 2: A solution of 10 g (13.14 mmol) M9-epx from step 1 and 9.12 ml cyclopropylamine (10.0 eq, 131.4 mmol) in 100 ml 1-propanol was heated to 80°C for 16 hours. Once the reaction was complete by LCMS analysis, volatiles were removed under reduced pressure, then dissolved in 100 mL DCM and H ₂ O and adjusted to pH ~ 9.8 with NH ₄ OH. The aqueous layer was extracted with DCM 3 times, and the organic layers were combined and dried over anhydrous magnesium sulfate. Volatiles were removed under reduced pressure to obtain the crude material, which was purified on a C18 silica gel column using reverse flash chromatography with 1.0% AcOH as modifier (0-100% MeCN in H ₂ O). The required fractions were combined, the pH was adjusted to ~9.8 with NH ₄ OH and extracted 3 times with DCM. The organic layers were combined, dried over anhydrous magnesium sulfate, and the volatiles were removed under reduced pressure to give the desired material as an off-white amorphous solid (8.2 g).

Step 3: The product from Step 2 (0.39 mmol, 300 mg, 1.00 eq) was dissolved in DCM (5 ml) followed by N-methyl-N-phenylcarbamoyl chloride (1.0 eq, 63 mg, 0 .39 mmol), and the resulting solution was stirred at RT overnight. Once the reaction was complete by LCMS analysis, volatiles were removed under a stream of N ₂ and the crude material was purified by C18 reverse flash chromatography with 1.5% AcOH as modifier (0-100% MeCN in H ₂ O). Fractions containing the desired product were lyophilized to obtain the desired compound as the acetate salt (212 mg).

The compounds of formula (1-A1) and formula (1-A1a) shown in Tables H and I can be prepared in a manner similar to that shown above for Example (H-27) by varying the amine used in the second step to open the epoxide functionality , or urea reagent or starting material and using (alkyl-tula-epx) as starting material instead of tulathromycin epoxide as shown in Scheme 5.

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

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 30 % aqueous hydrogen peroxide (0.62 g, 30 mmol) was mixed together and stirred for 4 hours at 35°C. After consumption of the starting material by LCMS, the reaction was cooled to 20°C, anhydrous copper(II) sulfate (4.5 g, 29 mmol) was added and the reaction was heated to 60°C for 1 hour. After completion of the reaction according to LCMS, the reaction mixture was cooled to 20°C and 60 ml of DCM and 80 ml of H ₂ O were added. The mixture was acidified to approximately pH 9.8 with concentrated aqueous ammonia. The mixture was concentrated in vacuo to a solid and recrystallized from acetone/water to give 60 g of a white crystalline product (M9-epx), which was 95% pure by LCMS and which was used as such in the next step.

Step 2: A solution of 10 g (13.14 mmol) M9-epx from step 1 and 14.7 ml 1-methylpiperazine (10.0 eq, 131.4 mmol) in 100 ml 1-propanol was heated to 80°C in within 16 hours. Once the reaction was complete by LCMS analysis, volatiles were removed under reduced pressure, then dissolved in 100 ml DCM and H ₂ O and adjusted to pH ~ 9.8 with NH ₄ OH. The aqueous layer was extracted with DCM 3 times, and the organic layers were combined and dried over anhydrous magnesium sulfate. Volatiles were removed under reduced pressure to obtain the crude material, which was purified on a C18 silica gel column using reverse flash chromatography with 1.0% AcOH as modifier (0-100% MeCN in H ₂ O). The required fractions were combined, the pH was adjusted to ~9.8 with NH ₄ OH and extracted 3 times with DCM. The organic layers were combined, dried over anhydrous magnesium sulfate, and the volatiles were removed under reduced pressure to give the desired material as an off-white amorphous solid.

Step 3: The product from Step 2 (0.390 mmol, 300 mg, 1.00 eq.) was dissolved in DCM (5 ml) and cooled to -78°C, followed by the addition of phenyl isocyanate (1.0 eq., 44 µl), and the reaction was stirred for 60 minutes, slowly raising the temperature to room temperature. Once the reaction was complete by LCMS analysis, volatiles were removed under a stream of N ₂ and the crude material was purified by C18 reverse flash chromatography with 1.5% AcOH as modifier (0-100% MeCN in H ₂ O). Fractions containing the desired product were lyophilized to obtain the desired compound as the acetate salt (184 mg).

The compounds of formula (1-A1b) shown in Table J can be prepared in a similar manner as shown above for Example (J-7) by varying the amine used in the second step to open the epoxide functionality, or the urea-forming reagent, or the starting material material and using (alkyl-tula-epx) as a starting material instead of tulathromycin epoxide, as shown in Scheme 5.

Example H-69 compound of formula (1-A1) was prepared using a modification of Scheme 7 in which the nucleophile used in the last step to open the epoxide is N-propylamine, and such that R ¹ is propyl from the reductive amination reaction with propionaldehyde .

Step 1: 1.0 g (1.36 mmol, 1.00 eq) M9 epoxide was dissolved in 10 ml dry DMF in a 50 ml round bottom flask and 2.0 eq was added. p-anisaldehyde (0.332 ml, 2.73 mmol), and then - 1.17 g sodium triacetoxyboron hydride (TABN, 4.0 eq., 5.5 mmol). The resulting solution was heated to 40°C for 2 hours. An additional 0.6 g (2.7 mmol, 2.0 eq) of TABN was added and the resulting solution was heated to 40° C. overnight, after which LCMS analysis indicated complete consumption of the starting material. Then the reaction mixture was cooled to 0°C, 5 ml of a saturated NH ₄ Cl solution was added and the solution was stirred for 5 minutes. The reaction mixture was then diluted with DCM (30 ml and H ₂ O) and transferred to a separatory funnel. The pH was adjusted to pH ~ 12 with NH ₄ OH and extracted 3 times with 20 ml DCM. The organic layers were combined, dried over MgSO ₄ and removed under reduced pressure to obtain the crude material, which was purified by reverse phase chromatography on a C18 column eluting with a gradient of 1% AcOH in MeCN and H ₂ O. Fractions containing the desired product; combined, adjusted to pH ~ 12 with NH ₄ OH and extracted 3 times with 50 ml DCM to obtain the desired product as the free base (1008 mg, 87%).

Step 2: 1008 mg of the product from Step 1 (1.18 mmol, 1.00 eq) was dissolved in 10 ml dry EtOH and peroxyacetic acid (32% dil. in acetic acid; 1.5 eq, 304 µl) was added. The resulting solution was stirred at RT for 45 minutes, after which LCMS showed complete conversion of the corresponding N-oxide. Anhydrous copper(II) sulfate (3.0 eq; 566 mg) was then added and the solution was stirred at 65°C for 4 hours, after which LCMS indicated completion of the reaction with 41% debenzylated product and 44% demethylated product. The reaction mixture was diluted with 20 ml DCM and H ₂ O, and the pH was adjusted to ~ 12 with NH ₄ OH. The crude material was extracted 3 times with DCM, the organics were combined, dried over MgSO ₄ and the volatiles were removed under reduced pressure. The crude material was purified by reverse phase chromatography on a C18 column with a gradient of 1% AcOH in MeCN and H ₂ O. Fractions containing the desired product were combined, adjusted to pH ~ 12 with NH ₄ OH and extracted 3 times with 50 ml DCM with obtaining the desired product in the form of a free base (250 mg, 25% yield).

Step 3: The product from Step 2 (250 mg, 0.30 mmol, 1.0 eq.) was dissolved in 10 ml CF ₃ CH ₂ OH. 5% Pd/C (25 mg) was added and the resulting suspension was hydrogenated under H ₂ balloon pressure at 40° C. overnight, after which LCMS indicated completion of the reaction. Pd/C was filtered on celite and volatiles were removed under reduced pressure to obtain the desired product (epoxide M8; M8-erx) as a white powder (195 mg, 91%).

Step 4: The product from Step 3 (M8-epx, 250 mg, 1.0 eq, 0.35 mmol) was dissolved in 5 ml dry MeOH in a 25 ml round bottom flask and cooled the solution to 0°C. Propionaldehyde (1.2 eq., 30 µl) was added followed by sodium triacetoxyborohydride (5 eq., 369 mg) added in portions. The solution was stirred at 0°C to RT for 2 hours, after which LCMS showed complete conversion to the desired product. Then the reaction mixture was cooled to 0°C, 1 ml of a saturated NH ₄ Cl solution was added and the solution was stirred for 5 minutes. The reaction mixture was then diluted with DCM (30 ml and H ₂ O) and transferred to a separatory funnel. The pH was adjusted to pH ~ 12 with NH ₄ OH and extracted 3 times with 20 ml DCM. The organics were combined, dried over MgSO ₄ and removed under reduced pressure to give the desired product (250 mg) as a white solid of ~80% LCMS purity, which was used as such in subsequent epoxide discovery.

Step 5: The material from Step 4 (200 mg, 0.32 mmol, 1.0 eq.) was dissolved in dry DCM (5 mL) in a dry round bottom flask and DIPEA (0.141 mL, 2.5 eq.) was added, and then - N-methyl-N-phenylcarbamoyl chloride (66 mg, 1.2 eq., 0.39 mmol). The mixture was stirred overnight, after which LCMS analysis indicated that all starting material had been consumed. Volatiles were removed under a stream of N ₂ and the crude material was purified by reverse phase chromatography on a C18 column with a gradient of 1% AcOH in MeCN and H ₂ O. Fractions containing the desired product were pooled and the pH was adjusted to pH ~ 12 with NH ₄ OH and extracted 3 times with 50 ml DCM to obtain the desired product as the free base (93 mg, 32% yield).

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

According to this example, the alkyl group R ¹ on the desosamine nitrogen can be varied by replacing propionaldehyde in the fourth step of the sequence with any other alkyl aldehyde, such as, but not limited to, acetaldehyde, or isobutylaldehyde, or carbaldehydes, such as benzaldehyde or 2-pyridylcarbaldehyde and others. Similar to other examples provided herein, the epoxide can be opened with a variety of nucleophiles, such as, but not limited to, primary and secondary amines, alcohols, thiols, cyanide, azide or halogen anions and others, at high temperature in alcohol solvents such as , but not limited to, 1-propanol, 1-butanol or 2-propanol, in the last step.

Preparation of Example H-102 of Formula (1-A1) using a modification of Scheme 5 in which the aldehyde used in the first step is propionaldehyde and the nucleophile used in the last step to open the epoxide is 1-propylamine:

Step 1: To a solution of tula-epx (1.0 g, 1.34 mmol) in dry DMF (10 ml) was added TABN and the resulting solution was stirred for 4 hours at 35°C. After consumption of the starting material according to LCMS data, the reaction was cooled to 0°C, 2 ml of a saturated NH ₄ Cl solution was added and the solution was stirred for 5 minutes. The reaction mixture was then diluted with DCM (30 ml and H ₂ O) and transferred to a separatory funnel. The pH was adjusted to pH ~ 12 with NH ₄ OH and extracted 3 times with 20 ml DCM. The organic layers were combined, dried over MgSO ₄ and removed under reduced pressure to obtain the crude material, which was purified by reverse phase chromatography on a C18 column with a gradient of 1% AcOH in MeCN and H ₂ O. Fractions containing the desired product were combined and the pH was adjusted to pH ~ 12 with NH ₄ OH and extracted 3 times with 50 ml DCM to obtain the desired product as the free base (600 mg, 57% yield).

Step 2: 600 mg of the product from Step 1 (0.76 mmol, 1.00 eq) was dissolved in 10 ml dry EtOH and peroxyacetic acid (32% dil. in acetic acid; 1.2 eq, 192 µl) was added. The resulting solution was stirred at RT for 45 minutes, after which LCMS showed complete conversion of the corresponding N-oxide. The reaction mixture was then diluted with DCM (30 ml and H ₂ O) and transferred to a separatory funnel. The pH was adjusted to pH ~ 12 with NH ₄ OH and extracted 3 times with 20 ml DCM. The organics were combined, dried over MgSO ₄ and removed under reduced pressure to obtain the crude N-oxide. Crude N-oxide (0.76 mmol, 1.0 eq.) was dissolved in 10 ml of dry ethanol, copper (II) sulfate pentahydrate (5.0 eq., 950 mg) was added and the solution was stirred at 65°C for 16 hours, after which LCMS showed the completion of the reaction. The reaction mixture was diluted with 20 ml DCM and H ₂ O, and the pH was adjusted to ~ 12 with NH ₄ OH. The crude material was extracted 3 times with DCM, the organics were combined, dried over MgSO ₄ and the volatiles were removed under reduced pressure to obtain the crude desired product of >90% LCMS purity, which was used as such in the next step.

Step 3: The material from Step 2 (250 mg, 0.32 mmol, 1.0 eq.) was dissolved in dry DCM (5 mL) in a dry round bottom flask and DIPEA (0.141 mL, 2.5 eq.) was added, and then - N-methyl-N-phenylcarbamoyl chloride (66, 1.2 eq., 0.39 mmol). The reaction was stirred for 16 h at RT, after which LCMS analysis showed that all starting material had been consumed. Volatiles were removed under a stream of N ₂ and the crude material was purified by reverse phase chromatography on a C18 column with a gradient of 1% AcOH in MeCN and H ₂ O. Fractions containing the desired product were pooled and the pH was adjusted to pH ~ 12 with NH ₄ OH and extracted 3 times with 50 ml DCM to obtain the desired product as the free base (150 mg, 51% yield).

Step 4: The product from Step 3 (150 mg, 0.17 mmol, 1 eq) and N-propanol (5 ml) were added to the pressure vial, followed by N-propylamine (117 µl, 2.0 mmol, 12 eq.). The reaction mixture was stirred at 70°C for 16 hours. The reaction mixture was then concentrated in vacuo and the crude product was purified by reverse phase chromatography using a C18 column with a gradient of 1% AcOH in MeCN and H ₂ O. Fractions containing the desired product were lyophilized to give the desired product as the acetate salt (90 mg , yield 53%).

According to this example, the alkyl group R ² on the core nitrogen can be varied by replacing propionaldehyde in the first step of the sequence with any other alkyl aldehyde such as, but not limited to, formaldehyde or acetaldehyde and others. Similar to other examples provided herein, the epoxide can be opened with a variety of nucleophiles, such as, but not limited to, primary and secondary amines, alcohols, thiols, cyanide, azide or halogen anions and others, at high temperature in alcohol solvents such as , but not limited to, 1-propanol, 1-butanol or 2-propanol.

NMR data for the listed examples are given below each table/each corresponding example title.

EXAMPLES

Compounds of formula (1) were prepared in accordance with the schemes and procedures defined herein and known in the art.

The following compounds of formula (1.1) were prepared as described herein; where R ⁰ represents H and R ¹ represents methyl; and they are given in Table A. The corresponding names of the compounds are given below the table.

Table A. Names of examples:

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;

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;

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;

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;

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;

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;

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;

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;

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;

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;

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;

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;

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;

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;

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;

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;

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;

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;

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;

A-20. 1-((2S,3R,4S,6R)-2-(((2R3S,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;

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;

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;

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;

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;

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-(t-tolyl)urea; And

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.

The following compounds of formula (1-A0) were prepared in accordance with the schemes and procedures defined herein, where R ¹ represents methyl; and they are given in Table B. The corresponding names of the compounds are given below the table. Examples B-1a, B-2a, B-3a and B-13a are stereoisomers B-1, B-2, B-3 and B-13, respectively (i.e. hydroxyl diastereomers at the alpha carbon R ^a ( 5R instead of 5S))

Table B. Names of examples:

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;

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;

AT 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;

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;

AT 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;

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;

AT 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;

AT 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;

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;

AT 7. 3-(4-(dimethylamino)phenyl)-1-((2S,3R,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;

AT 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;

AT 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;

AT 10 O'CLOCK. 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;

AT 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;

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;

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;

V-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;

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

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).

The following compounds of formula (1-A2) were prepared in accordance with the schemes and procedures defined herein, where R ⁰ represents H, R ¹ represents methyl, and R ⁷ represents ethyl; and they are given in Table C. The corresponding names of the compounds are given below the table.

Table C. Example names:

S-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;

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

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.

The following compounds of formula (1-A3) were prepared in accordance with the schemes and procedures defined herein, where R ⁰ represents H, R ¹ represents methyl, and R ⁷ represents propyl; and they are given in Table D. The corresponding names of the compounds are given below the table.

Table D. Example names:

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;

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

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.

The following compounds of formula (1-A4) were prepared in accordance with the schemes and procedures defined herein, where R ⁰ represents H, R ¹ represents methyl, and X' represents chlorine; and they are given in Table E. The corresponding names of the compounds are given below the table.

Table E. Names of examples:

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;

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

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.

The following compounds of formula (1-A5) were prepared in accordance with the schemes and procedures defined herein, where R ⁰ represents H and R ¹ represents methyl; and they are given in Table F. The corresponding names of the compounds are given below the table.

Table F. Example names:

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;

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

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.

The following compounds of formula (1-A6) were prepared in accordance with the schemes and procedures defined herein, where R ⁰ represents H and R ¹ represents methyl; and they are given in Table G. The corresponding names of the compounds are given below the table.

Table G. Example names:

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;

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

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.

The following compounds of formula (1-A1) were prepared in accordance with the schemes and procedures defined herein; R ⁰ represents H, methyl or propyl, as described in Table H. The corresponding names of the compounds (mass [M+H] ⁺ ) are given below the table.

Table H. Names of examples:

N-1. 3-cyclopropyl-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)ureido)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);

N-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);

N-3. 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);

N-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);

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);

N-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);

N-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);

N-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);

N-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);

N-10. 1-((2S,3R,4S,6R)-2-(((2R3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-13-(((2R,4R, 5S,6S)-5-((3-(4-fluorophenyl)-1-propylureido)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);

N-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);

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)ureido)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);

N-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);

N-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);

N-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);

N-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);

N-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);

N-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);

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);

N-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);

N-21. 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-(((2-(methylsulfonyl)ethyl)amino)methyl)tetrahydro-2H-pyran -2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H -pyran-4-yl)-1,3-dimethyl-3-phenylurea (989);

N-22. 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-propylureido)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 (878);

N-23. 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-13-(((2R, 4R,5S,6S)-5-((ethylamino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,4,10-trihydroxy-3 ,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1 ,3-dimethyl-3-phenylurea (911);

N-24. 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-5-((isobutylamino)methyl)-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3 ,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1 ,3-dimethyl-3-phenylurea (939);

N-25. 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S, 6S)-5-(((3-(1H-imidazol-1-yl)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)-1,3-dimethyl-3-phenylurea (991);

H-26. 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 (897);

N-27. 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 ,3-dimethyl-3-phenylurea (923);

N-28. 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 (939);

N-29. 1-((2R,3R,4S,6R)-2-(((2R,3R,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy -13-(((2R,4R,5S,6S)-5-hydroxy-5-((isopentylamino)methyl)-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3 ,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1 ,3-dimethyl-3-phenylurea (953);

N-30. 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-methylpiperidin-4-yl)methyl)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)-1,3-dimethyl-3-phenylurea (994);

N-31. 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S, 6S)-5-((((1-acetylpiperidin-4-yl)methyl)amino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2 -ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6- methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea (1022);

N-32. 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-((phenylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)- 3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)- 1,3-dimethyl-3-phenylurea (959);

H-33. 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-(((2-(tetrahydro-2H-pyran-4-yl)ethyl)amino )methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3 -hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea (995);

N-34. 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S, 6S)-5-(((2-cyclopropylethyl)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 (951);

N-35. 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-(((3-(2-oxopyrrolidin-1-yl)propyl)amino)methyl )tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy -6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea (1008);

N-36. 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S, 6S)-5-((([1,1'-biphenyl]-4-ylmethyl)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 (1049);

N-37. 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S, 6S)-5-((cyclobutyl(methyl)amino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10 -trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4- yl)-1,3-dimethyl-3-phenylurea (951);

N-38. 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-(((3-(piperidin-1-yl)propyl)amino)methyl)tetrahydro -2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6 -methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea (1008);

N-39. 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-3,3-diphenylurea (987);

H-40. 1-benzyl-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 (939);

N-41. 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S, 6S)-5-(((cyclopropylmethyl)amino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4D0-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 (937);

N-42. 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-(((2-morpholinoethyl)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)-1,3-dimethyl-3-phenylurea (996);

N-43. 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-(((2-(phenylsulfonyl)ethyl)amino)methyl)tetrahydro-2H-pyran -2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H -pyran-4-yl)-1,3-dimethyl-3-phenylurea (1051);

N-44. 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)phenethyl)amino)methyl)tetrahydro-2H-pyran -2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H -pyran-4-yl)-1,3-dimethyl-3-phenylurea (1055);

N-45. 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 (926);

N-46. 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 (927);

H-47. 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-(((3-(2-oxopyridin-1(2H)-yl)propyl) amino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)- 3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea (1018);

N-48. 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 (927);

N-49. 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 (927);

N-50. 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 (927);

N-51. 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 (962);

N-52. 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 (967);

N-53. 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 (926);

H-54. 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-phenyl-3-(2,2,2-trifluoroethyl)urea (993);

N-55. 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-phenyl-3-(tetrahydro-2H-pyran-4-yl)urea (995);

N-56. 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-(1,2,4-triazin-3-yl)urea (928);

N-57. 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 (955);

N-58. 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-(1-methyl-1H-pyrazol-4-yl)urea (929);

N-59. 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 (926);

N-60. 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-(4-methoxybenzyl)-3-methyl-3-phenylurea (1031);

N-61. 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-(thiazol-2-yl)urea (932);

N-62. 1-((2S,3R,4S,6R)-2-(((2R,3R,4R,5R,8R,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 (940);

N-63. 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-((3-methyl-3-phenyl-1-propylureido)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 (1058);

N-64. 1-((2S,3R,4R,16R)-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-(thiazol-2-ylmethyl)urea (1008);

N-65. 1-benzyl-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-phenylurea (1001);

N-66. 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S, 6S)-5-(aminomethyl)-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 (883);

N-67. 1-(6,7-dihydro-5H-cyclopenta[d]pyrimidin-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-azacyclopentadecane-11- yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethylurea (967);

H-68. 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-4-yl)urea (927);

N-69. 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 (953);

N-70. 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-isobutyl-3-methyl-3-phenylurea (967)

N-71. 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-(pyridin-3-ylmethyl)urea (1002);

N-72. 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-3-yl)urea (913);

N-73. 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-4-yl)urea (913);

N-74. 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-(1-methyl-1 H-pyrazol-4-yl)urea (916);

N-75. 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-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 (930);

N-76. 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-methoxyphenyl)-1-methylurea (942);

N-77. 3-(4-cyanophenyl)-1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl -3,4D0-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 (937);

N-78. 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-(3-(trifluoromethyl)phenyl)urea (980);

N-79. 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 (937);

N-80. 3-(2-chlorophenyl)-1-((2S,3S,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12R,13R,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 (946);

N-81. 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 (926);

H-82. 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 (930);

N-83. 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-(4-fluorophenyl)-1-methylurea (930);

N-84. 3-(4-chlorophenyl)-1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl -3,4D0-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 (946);

N-85. 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 (930);

N-86. 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 (942);

N-87. 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-(4-methoxyphenyl)-1-methylurea (942);

N-88. 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 (946);

H-89. 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-(p-tolyl)urea (925);

N-90. 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-(t-tolyl)urea (926);

N-91. 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 (911);

H-92. 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,1R,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 (849);

N-93. 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 (875);

N-94. 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 (889);

N-95. 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 (979);

H-96. 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 (835);

N-97. 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);

N-98. 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);

N-99. 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-(4-hydroxyphenyl)-1,3-dimethylurea (941);

N-100. 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 (1007);

N-101. 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 (939);

N-102. 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-6-propyl-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4 -yl)-1,3-dimethyl-3-phenylurea (967); And

H-103. 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-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 (1035).

The following compounds of formula (1-Ala) were prepared using the schemes and procedures defined herein; where R0 represents H and R ⁵ represents H; and they are given in Table I. The corresponding names of the compounds are given below the table.

Table I. Example names:

I-1. 4-ethyl-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4 ,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((methylamino)methyl)tetrahydro-2H-pyran-2-yl )oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4 -yl)-N-methylpiperazine-1-carboxamide;

1-2. 4-ethyl-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4 ,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl )oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4 -yl)-N-methylpiperazine-1-carboxamide;

I-3. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy -13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)- 3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)- N-methylindoline-1-carboxamide;

I-4. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3A10-trihydroxy-13-( ((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5, 8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methyl- 3,4-dihydroquinoline-1(2H)-carboxamide;

1-5. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy -13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)- 3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-

N-methyl-2,3-dihydro-4H-benzo[b][1,4]thiazine-4-carboxamide 1,1-dioxide;

I-6. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy -13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)- 3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)- N-methyl-2,3-Dihydro-4H-benzo[b][1,4]oxazine-4-carboxamide;

I-7. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy -13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)- 3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)- N-methylisoindoline-2-carboxamide

The following compounds of formula (1-Alb) were prepared using the schemes and procedures defined herein; where R ⁰ represents H; and they are given in Table J. The corresponding names of the compounds are given below the table.

Table J. Example names:

J-1. 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-dimethyl-5-((4-methylpiperazin-1-yl)methyl)tetrahydro-2H -pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro -2H-pyran-4-yl)-1-methylurea;

J-2. 3-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-((4-methylpiperazin-1-yl)methyl)tetrahydro-2H -pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro -2H-pyran-4-yl)-1-methylurea;

J-3. 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-dimethyl-5-((4-methylpiperazin-1-yl)methyl )tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy -6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea;

J-4. 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy -13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((3-morpholinoazetidin-1-yl)methyl)tetrahydro-2H-pyran-2 -yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran -4-yl)-1,3-dimethyl-3-phenylurea;

J-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-dimethyl-5-((4-methylpiperazin-1-yl)methyl)tetrahydro-2H-pyran-2 -yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran -4-yl)-1-methylurea;

J-6. 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-dimethyl-5-((4-methylpiperazine-1- yl)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)- 3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methylurea;

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

J-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-((4-methylpiperazin-1-yl)methyl)tetrahydro-2H-pyran-2 -yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran -4-yl)-1-methyl-3-(pyridin-3-yl)urea;

J-9. 3-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-((4-methylpiperazin-1-yl)methyl)tetrahydro-2H -pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro -2H-pyran-4-yl)-1-methylurea;

J-10. 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-(morpholinomethyl)tetrahydro-2H-pyran-2-yl)oxy)-3.5 ,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3 -dimethyl-3-phenylurea;

J-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-(thiomorpholinomethyl)tetrahydro-2H-pyran-2-yl)oxy)-3.5 ,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3 -dimethyl-3-phenylurea;

J-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-(pyrrolidin-1-ylmethyl)tetrahydro-2H-pyran-2-yl)oxy) -3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl) -1,3-dimethyl-3-phenylurea;

J-13. 1-((2S,3R,4S,6R)-2-(((2R,3S,14R,5R,8R,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-(pyrimidin-2-yl)piperazin-1-yl)methyl) tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy- 6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;

J-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-dimethyl-5-((4-(trifluoromethyl)piperazin-1-yl)methyl)tetrahydro-2H- pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro- 2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;

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

J-16. 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S, 6S)-5-((5,7-dihydro-6H-pyrrolo[3,4-b]pyrazin-6-yl)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran- 2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy )-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;

J-17. 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S, 6S)-5-((4,4-difluoropiperidin-1-yl)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3 ,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H- pyran-4-yl)-1,3-dimethyl-3-phenylurea;

J-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-4,6-dimethyl-5-(piperidin-1-ylmethyl)tetrahydro-2H-pyran-2-yl)oxy) -3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl) -1,3-dimethyl-3-phenylurea;

J-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-4,6-dimethyl-5-((3-(piperidin-1-yl)azetidin-1-yl)methyl) tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy- 6-methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;

J-20. 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-phenylpiperidin-1-yl)methyl)tetrahydro-2H-pyran-2 -yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran -4-yl)-1,3-dimethyl-3-phenylurea;

J-21. 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-(methylsulfonyl)piperidin-1-yl)methyl)tetrahydro-2H- pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro- 2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;

J-22. 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S, 6S)-5-(azetidin-1-ylmethyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy- 3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)- 1,3-dimethyl-3-phenylurea;

J-23. 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S, 6S)-5-((1H-pyrazol-1-yl)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4 ,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran- 4-yl)-1,3-dimethyl-3-phenylurea;

J-24. 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S, 6S)-5-((1H-imidazol-1-yl)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4 ,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran- 4-yl)-1,3-d imethyl-3-phenylurea;

J-25. 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S, 6S)-5-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2- ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro -2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;

J-26. 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S, 6S)-5-((3-(dimethylamino)azetidin-1-yl)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl- 3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H -pyran-4-yl)-1,3-dimethyl-3-phenylurea;

J-27. 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S, 6S)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2 -ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6- methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;

J-28. 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S, 6S)-5-((1H-1,2,3-triazol-1-yl)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2 -ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6- methyltetrahydro-2H-pyran-4-yl)-1,3-dimethyl-3-phenylurea;

J-29. 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S, 6S)-5-((1H-tetrazol-1-yl)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4 ,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran- 4-yl)-1,3-dimethyl-3-phenylurea; And

J-30. 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S, 6S)-5-((2H-tetrazol-2-yl)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4 ,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran- 4-yl)-1,3-dimethyl-3-phenylurea.

BIOLOGICAL EXAMPLES

Pathogens of RBD include, for example, Pasteurella multocida; Mannheimia haemolytica; Histophilus somni; and Mycoplasma bovis. There is debate as to whether M. bovis is a primary pathogen, a secondary pathogen, or a predisposing factor for other RBD agents. The polymicrobial nature of RBD makes it difficult to attribute specific pathogen(s) to a single case of RBD, as affected animals typically exhibit nonspecific clinical signs. The epidemiology of RBD is well known, with cases appearing within 6–10 days of entry into a feedlot (Figure 1). Therefore, antimicrobial metaphylaxis is a routine procedure for incoming cattle considered to be at high risk of developing RBD. Parenteral metaphylaxis can also be used in low-risk cattle. Macrolides are typically the first antimicrobials administered to high-risk livestock.

Primary screening of the compounds of the invention included assessment of the antibacterial activity of the analogues by determining the microbial inhibitory concentration (MIC) according to CLSI guidelines. This screening panel included relevant RBD pathogens: 1) M haemolytica (eg, 12726, 46571 and 49023, all AHDRCC; and 33396 (ATCC)); and 2) P. multocida (e.g., 34135 and 46572 (both AHDRCC) and 43137 (ATCC)). In some cases, the pathogen H. somni (A700025K) was also included in the screening panel. AHDRCC strains were obtained from the Zoetis RBD/RHD research program and belong to the Agency for Veterinary Development and Research culture collection. Additionally, the screen assessed S. aureus (29213 ATCC) as a representative gram-positive isolate, E. faecalis (19433 ATCC) as a commensal gram-positive gastrointestinal bacterium, and E. coli (100, 3110, and 25922 (ATCC)) to assess efflux potential . A screening panel of RBC pathogens was evaluated to determine the antibacterial activity of compounds of formula (1).

All relevant RBD pathogens were first tested at a maximum concentration of 64 μg/ml of the compound of formula (1) in twelve-point serial dilutions. The analogues were then characterized based on their minimum inhibitory concentration (MIC) values against RBD pathogens, with a target of >64 μg/mL for progression and to be considered non-antibiotic compounds. Compounds of formula (1) were considered non-antibacterial if the pathogen MIC was >64 μg/ml for M. haemolytica and P. multocida strains. In addition, the compounds of formula (1) were also tested against the H. somni strain, in order to be considered non-antibacterial, the MIC was also >64 μg/ml. In general, if analogues had an MIC of >64 μg/ml against RBD pathogens, then the MIC against S. aureus, E. faecalis and E. coli was also >64 μg/ml. In most cases, compounds of the invention with a MIC result in the initial screening of RBD pathogens >64 μg/ml were not tested at concentrations above this maximum concentration, since this MIC value was determinative of the lack of antibacterial activity. Additionally, it should be noted that some examples described in the tables that are labeled as antibacterial (i.e. MIC≤64 μg/ml) may in fact be non-antibacterial except for potential residual (minor impurities) of the antibacterial starting material (i.e. e. tulathromycin epoxide, M9 epoxide, M8 epoxide or azithromycin), which was used in their preparation. If the example compound was further purified, the MIC shifted by almost two dilutions among all strains tested in the screening panel.

In-vitro MIC model

Compounds were assayed for antibacterial activity against a panel of specific veterinary Gram-positive and Gram-negative clinical strains by diluting the compounds in DMSO to the appropriate starting concentration to determine the minimum inhibitory concentration (MIC) by a semi-automated broth microdilution method (CLSI reference method) with QC strains and antimicrobial agents. Specifically, bacteria were grown overnight on TSA/5% sheep blood agar plates and diluted in saline to a McFarland standard of 0.5, then further diluted in cation- and ion-adjusted Mueller-Hinton broth to a final concentration of approximately 5 × 10 ⁵ CFU/ml. 100 μl of inoculated medium was added to 96-well plates with 3 μl of serially diluted compound in each row. Depending on the strain (see CLSI reference method), the bacteria were incubated for 18-22 hours at 35-37°C in ambient air with 5% CO ₂ or anaerobically (up to 48 hours).

In-vitro immunoassays

Whole Blood Analysis—Fresh bovine whole blood samples were collected in heparinized vacuum tubes. Analytical plates were prepared with 25 μl of the drug diluted in PBS at different concentrations in 96 round-bottomed wells, then 225 μl of blood was added and the plates were incubated at 37°C for 4 hours. Cells were stimulated with LPS (or PBS for control) by adding 25 μl to the plates at a final concentration of 1 μg/ml and incubated at 37°C for 18 hours. To collect plasma, plates were centrifuged at 2000xg for 10 minutes and 100 μl of supernatant was transferred to a 96-well polypropylene plate, which was sealed and stored at -80°C. Samples were analyzed for cytokines using the Meso Scale Discovery (MSD) platform (described below), from plasma obtained directly from drug-treated animals, as well as from plasma collected in a whole blood assay.

Cytokine Detection - The MSD U-Plex Cytokine Assay was developed based on the MSD U-Plex manual protocol and included the use of biotinylated capture antibodies against: bovine interleukin (IL)-1β (Biorad), bovine IL-6 (R&D Systems), and bovine factor tumor necrosis (TNF)-α (R&D Systems). Anti-IL-1β antibody was biotinylated using EZ-Link Sulfo-NHS-Biotin (Thermo Scientific) at a stimulation level of 1:20 according to the manufacturer's instructions. Analytical calibrators (Kingfisher) were diluted to a concentration of 40,000 pg/ml in control lithium heparin plasma, followed by 4-fold serial dilutions in plasma. Detection antibodies were sulfo-tagged following the MSD rapid conjugation protocol guidelines using a stimulating ratio of 1:20. Antibodies were used at the following concentrations: anti-IL-1β at 1 μg/ml, anti-IL-6 at 1 μg/ml, and anti-TNF-α at 0.5 μg/ml. Cytokine quantification was performed according to the manufacturer's instructions using chemiluminescent data. Briefly, 0.5 ml of all biotinylated antibodies were diluted to 10 μg/ml in diluent 100 and coupled with their respective linkers by adding 750 μl of the supplied linker solution, and incubated for 30 minutes followed by the addition of stop solution for an additional 30 minutes. Bound antibodies were then diluted 10-fold in stop solution. The plates were coated by adding 50 μl of antibody solutions per well and incubated, covered and shaking, for 1 hour at room temperature. The plates were washed three times with PBS/Tween20 before adding samples or standards at 30 μl per well and incubated as described above. The plates were washed three times before adding detection antibodies along with 2% goat and rabbit serum for blocking and incubated as described above. The plates were washed three more times before adding 150 μl of 2X reading buffer and immediately read on an SI6000 instrument (MSD). For soluble protein levels, the BCA protein kit (Thermofisher) was used. Cytokine concentrations (pg/mL) were normalized to total protein levels for each sample.

CD 163 expression by flow cytometry - fresh bovine whole blood samples were placed on ice and processed within two hours of collection. Blood was placed into 96-well round-bottom plates at 30 μl per well, 5 μl of goat serum was added as a blocking reagent, and the plate was shaken at 4°C for approximately 15 minutes. To label cells, 10 μl of a panel antibody master mix containing anti-CD14 (BioLegend, #301854), anti-CD172a (BioRad, #MCA2041C), anti-CD163 (Kingfisher, #WSC0832B-100) and anti-CD163 (Kingfisher, #WSC0832B-100) were added to the samples. CD16 (BioRad, #MCA5665F), and left at 4°C (protected from light) for 30 minutes. Single-strain controls were included for use in compensatory matrices. Red blood cells were removed by adding 200 μl of lysis buffer and incubating for 10 minutes at room temperature with shaking. The plate was then centrifuged at 270xg for three minutes and the supernatant was removed. This step was repeated until the supernatant became clear. 200 μl of FACS buffer was added to each well to wash the cells, centrifuged as described above, resuspended in 80 μl of FACS buffer, and immediately read on a FACS Canto II HTS digital flow pitometer (BD Bioscience). Data were analyzed using FlowJo software (BD Bioscience). Macrophage subpopulations were determined using markers CD172, CD14, CD16, and assessed for CD163 expression.

In vivo model (mouse) of stimulation of lung infection in mice

The stimulant organism was P. multocida 46572. The target stimulant concentration was 5x10 ² CFU/mouse. Isolated colonies, after growth overnight (37°C with 5% CO ₂ ) on blood and trypticase soy agar (TSA II) plates, were transferred to brain heart extract broth (BHIB) at room temperature. The culture in the broth was incubated for 3.5-4 hours until approximately mid-logarithmic growth, determined by forward light scattering at 600 nm (OD600, 0.200). The culture was centrifuged to collect the bacterial pellet. The pellet was resuspended in BHIB and adjusted to provide an approximate concentration of 2.7 log ¹⁰ colony forming units (CFU) per 0.04 ml at the highest concentration. The stimulating inoculum concentration was confirmed by serial dilutions of the inoculum to establish CFU. On day -5, female CD-I mice were obtained. The mice were given a standard rodent diet and water ad libitum. On day 0, each mouse (n=36) received an intranasal inoculum (0.04 ml). The compounds of the invention were administered at a dose of 20 mg/kg (0.1 ml) in a buffered (~ pH 5.4) solution of propylene glycol, monothioglycerol and water by subcutaneous injection. The animals were observed for days 1-10. The study ended on day 10. In addition, some treatment groups took samples 6, 24, and 48 hours after bacterial challenge for RNA-seq analysis of lung tissue.

In vivo model of stimulation of lung infection in cattle

The stimulus organism was M. haemolytica (OSU-012103-BHI). The challenge organism was grown in 100 ml of brain heart extract (BHI) medium in a 250 ml baffled flask and inoculated with 0.1 ml of thawed stock bacterial culture. The culture was incubated overnight (~15-18 hours) at 150 rpm in a shaker incubator at 37°C. A 2 ml aliquot of the overnight culture was used to inoculate every 100 ml of medium in a baffled flask containing fresh BHI medium at a ratio of broth to total flask volume of ~1/3. The culture was incubated for about 2-6 hours at 150 rpm at 37°C. When the optical density (OD) at 650 nm reached 0.800 (approximately 1 X 10 ⁹ CFU/ml), the culture was cooled in an ice bath. The culture was centrifuged to collect the bacterial pellet. The pellet was resuspended in phosphate-buffered saline (PBS) to the original absorbance value. The resulting suspension was further diluted to the appropriate stimulating concentration. For each stimulating dose, the appropriate amount of the original culture was added to a pre-measured volume of PBS medium to obtain a dose of 120 ml. The dilution was prepared immediately before stimulation was applied. 30 ml of BHI medium or PBS was infused into the lungs immediately after administration of the stimulating material. Male (or castrated) Holstein cattle were obtained on day -10. Animals received a dose of advocin ^® before transportation and a) had antibody titers to M. haemolytica leukotoxin with an S/P ratio of less than 0.85 before distribution, as determined by the serological ELISA method for M. haemolytica leukotoxin; b) have tested negative for persistent BVDV infection as determined by ear plucking before arrival; c) did not have a systemic disease or signs of immunocompromise; and d) were in good health. Animals were fed an antibiotic-free diet and water was provided ad libitum. A group of pre-stimulation animals (N=4/group) received a stimulation dose (~ ^3.3x108 CFU/dose or ~ ^1x109 CFU/dose) and treatment (10 mg/kg) on day -8 to determine optimal stimulating dose. The stimulating material was injected into the lungs through a plastic cannula after local anesthesia with lidocaine. The treatment dose was administered by subcutaneous injection, and the treatment drug was solubilized in a buffered (~pH 5-6) composition containing propylene glycol and water. On day 0, the remaining animals (N=24/group) were stimulated and then treated with 0.2, 0.5, 2.5 or 10 mg/kg of test compound (100 mg/ml). Animals were assessed throughout the study, which ended on day 6, for clinical signs of disease. Lung smears were obtained to determine bacterial presence, and lung lesions were scored based on the percentage of lung involvement and the severity of respiratory disease was determined.

In vivo time course study

The clinical and genomic time course study was conducted to simulate the typical cattle management that leads to the development of RBD. The design included extensive genomic sampling throughout the study, including the respiratory tract, as well as comprehensive clinical assessment to link disease mechanism to clinical phenotype. The study resulted in a 20% incidence of classic RCD, as assessed by standard clinical criteria. To enable data analysis, animals were assigned to phenotypic groups based on clinical signs, lung lesions, and treatment qualifications according to feedlot standards. This study provided a basis for interpreting the biological processes that resulted in the presence of healthy, subclinical, and diseased animals at the typical intervention point of arrival at the feedlot. For example, comparison of whole transcriptome RNA sequencing data from nasopharyngeal swabs collected at a time point similar to arrival at a feedlot can be correlated with a known clinical outcome from a study.

This study demonstrates that, contrary to belief, there is an increase in innate inflammatory pathways prior to transportation and upon arrival at the feedlot after transportation. A state of increased inflammation is observed in almost all animals, regardless of the final clinical result. Additional analysis of the comprehensive data revealed that animals that progressed to developing RAD continued to have elevated innate airway inflammatory signatures, whereas healthy and subclinical animals (the healthy cohort) showed self-suppression of inflammatory signaling within a couple of days (Figure 2). ).

What is important is the presence of an unresolved state of increased inflammation on days 4 to 6, which leads to differential participation of H.somni and M.haemolytica bacteria and transition to the full complex of RBC disease. Using RNA-seq analysis, it was confirmed that the healthy and diseased cohorts had the same viral and bacterial exposure during the period from day -1 to day 4. The healthy cohort (without disease and subclinical) was capable of early resolution of the inflammatory state on day 0 or day 1. In the RKRS cohort (presence of disease), there was no resolution of the inflammatory state and observed progression to the full RKRS complex. A significant increase in the number of typical RKRS-associated microorganisms (M- bovis, H. somni and M. haemolytica) was not detected until the innate inflammatory pathways were unresolved on days 4-6. It is believed that it is the unresolved process of inflammation that allows progression to the full RCD complex.

From this interim study, pathways for intervention were identified. These include TLR-4 pattern recognition receptor (PRR) activation, inflammasome signaling, NF-κB transcription and STATs, which have become targets for reducing the pathological innate inflammatory cascade before disease onset. Some key inflammatory cytokines included IL-1β, IL-6, IL-36 and TNF-α, which were further confirmed using in vitro cell-based assays and ex vivo models of bovine infection. This study also served to identify biomarkers correlated with disease severity (CD 163, IL-6, IL-36, and haptoglobin).

Plasma samples collected from at-risk calves upon arrival at the feedlot were assessed for cytokine levels. These data were correlated with the final disease state (CDC) as assessed by clinical assessment within seven days. In the group, 14 animals were healthy, and 24 were diagnosed with RBD. As predicted for the etiology and pathogenesis of RBD, NF-κB-mediated cytokines, including IL-6, were highest in animals that developed clinical RBD. Interestingly, there was a correlation between the higher levels of IFN-γ in animals upon arrival found in animals that did not progress to clinical RCD (Figure 3). These data further support that calves with elevated levels of certain proinflammatory cytokines (IL-6 and IL-8) upon arrival at the feedlot are associated with poor clinical outcome, whereas calves that have elevated levels of IFN-γ, a cytokine associated with excretion pathogens are correlated with staying healthy and not progressing to RCD.

In-vitro studies

The compounds of the invention had MIC values against several pathogenic bacterial strains of the RKRS M. haemolytica and P. multocida and other pathogenic bacterial strains, including E. coli, S. Aureus and E. faecalis, which were considered non-antibacterial (i.e. MIC>64 µg/ml). Bacterial strains included the following: E. coli (A25922K/T, W3110WT, AG100T, AG100AT); E. faecalis (A19433K/T); M. haemolytica (12726K, 46571K/T, A33396K/T, 49023T and others); P. multocida (46572K, 43137K, 34135T and others); S. aureus (A29213K/T); and N. somni (A7000025K);. K and T represent a specific strain at two study sites. For example, the compound of Example H-91 had MIC values that were ≥256 μg/ml in 25 different strains each of M. haemolytica and P. multocida; and MIC>64 for H. somni (31 strains). Example H-11 had MIC values >64 for the same strains of M. haemolytica, P. multocida and H. somni. As defined herein, non-antibacterial compounds had MIC values of >64 μg/ml in the bacterial strains tested. Some of the compounds identified herein were considered to have some antibacterial properties as a result of at least one MIC value of ≤64 μg/ml for any of the bacterial strains tested. With the exception of a few compounds of the invention, the majority had MIC values >64 μg/ml for RBD bacterial strains as well as other non-RBD strains. K and T represent a specific strain at two different study sites.

In comparison, gamithromycin had MIC values in the range of about 0.5-1 μg/ml and 1-2 μg/ml for the same strains of M. haemolytica and P. multocida, respectively; and about 0.25-8 μg/ml for H. somni strains. For the same H. somni strains, florfenicol and enrofloxacin had MICs in the range of 0.12–2 μg/ml and <0.06–1 μg/ml, respectively; which clearly shows their antibacterial potential against these bacterial strains. In addition, the MIC values (µg/ml) for tulathromycin and M9 for the following bacterial isolates are given in Table 1.

In the Ames mutagenicity test, Example H-91 (1-5000 μg/plate; using the plate method and a standard panel of bacterial (E. coli and Salmonella) isolates) was negative (non-mutagenic).

Overall, Examples H-11 and H-91 demonstrate a lack of in vitro activity against clinically relevant pathogenic strains of RBD (M. haemolytica and P. multocida), and no clinically relevant MIC values have been found against all zoonotic bacteria tested to date. . In addition, the compounds were nonmutagenic in the Ames test.

The compounds of the invention exhibit the most commonly reported immune effects of the parent macrolide class, including modulation of proinflammatory cytokine production and granulocyte migration/behavior. A decrease in the levels of IL-1β, IL-6, IL-36 and TNFα by the compounds of the invention was observed, which was consistently associated with a positive clinical outcome. The compounds of the invention also consistently reduced increases in the biomarkers IL-6, IL-36, CD163 and haptoglobin, which were also associated with clinical disease outcome. Therefore, the underlying mechanism of the compounds of the invention is likely to be related to broad modulation of the innate inflammatory response.

The in vitro systems were functional, demonstrating inhibition of the cytokines TNF-α, IL-6, and IL-1β in RBC-relevant primary cell types, including bovine alveolar macrophages and nasopharyngeal epithelial cells. The effect of multiple cytokines was not easy to quantify using a single cell type. Consequently, a fresh bovine whole blood assay was developed with LPS as a stimulant (TLR-4 agonist) and with IL-1β and TNF-α as recording parameters. The compounds of the invention were evaluated in comparison to a positive control for their ability to inhibit LPS-induced IL-1β and TNF-α as an overall assessment of relative potency and modulation of target pathways (Table 6).

In a second in vitro immunomodulation assay, the antiphospholipidosis potential of the compounds of the invention in bovine alveolar macrophages was assessed. This assay is used to determine the cellular uptake of compounds of the invention in relevant bovine and murine cell types. This assay uses the commercially available LipidTox HCS detection kit from Invitrogen with an Incucyte real-time fluorescence reader to observe variations in EC ₅₀ and phospholipidosis profiles based on compound concentrations. Murine intraperitoneal macrophages were also used in this assay to assess species variability for potential correlation with murine efficacy results. The combination of a bovine whole blood assay and a phospholipidosis assay enabled a ranking order to move toward in vivo testing in a murine challenge model.

Transcriptional changes do not always correlate with protein levels and the observed phenotype. Whole blood analysis was used to correlate RNA sequencing data with changes in cytokine levels. Compound Example H-11 reduced LPS-induced production of pathology-associated cytokines including IL-1β, TNF-α and IL-6. The results (Table 2) demonstrate reductions in the levels of three cytokines that were identified as relevant to the disease state of RBC. The increase (a.v.) shown in Table 2 is observed for IL-1β cytokine levels when the compound is inhibitory at lower concentrations but fails to reach the IC ₅₀ value. The resulting increase represents a general stimulation of cytokine levels due to cellular stress or potential toxicity as concentrations of the compound increase, with a typical bell-shaped response curve for immunomodulatory activity. In addition, analysis of LPS-stimulated bovine whole blood (4 independent studies with multiple blood donors) with Example H-11 compound showed a dose-dependent reduction in the expression of key cytokines (IL-6, TNF-α, and IL-1β) associated with RBC (Fig. 4), which additionally indicates inhibition of cytokines.

Additional evidence supporting this hypothesis includes studies in mice with P. multocida infection in mice. For example, M9 and example compound H-91 were clinically effective when airway tissues were collected throughout the study and assessed in transcriptomic analysis. Based on these results, specific transcriptional expression demonstrated the presence of regulators consistent with several key RCD pathways (PRR, cytokines, STAT) and cellular cross-activity.

Mouse study

Compounds of the invention were selected to be effective in mice or greater based on significantly increased MICs (target >64 μg/mL) for all bacterial strains in the screening panel. This assessment was combined with in vitro immunomodulatory efficacy equal to or better than M9, IC50 of TNF-α and IL-1β ~250 μM for both cytokines and EC ₅₀ for phospholipidosis of 3.74 mM.

The mouse model of efficacy (P. multocida stimulation) was optimized and the treatment group size was such that a statistically significant improvement in survival to the expected ranges for immunomodulatory compounds could be observed. The experimental design was a randomized complete block design. Mice were individually identified and treatment groups were mixed within a cage, with each treatment group being evenly represented among the cages. The primary variable was mortality. Mortality data were analyzed using a generalized mixed model with a fixed treatment effect and a random blocking effect. Survival time was also analyzed using the SAS PHREG (survival analysis) procedure to determine whether there was a significant difference between the treatment and control groups. In this model, multiple compounds of the invention and M9 (positive control) were tested at a dose of 20 mg/kg. Typical survival rates for untreated controls are in the range of 0-20%, allowing for inter-assay variation in stimulus inoculum and infection level. The analogues studied had an MIC against the stimulating strain of ≥ 64 μg/ml compared to M9 (8 μg/ml). The mouse survival rate for M9 was around 90-100%, further confirming its antibacterial properties against the bacterial strain (Table 3). Survival values presented are consistent with comparative host survival rates.

In one murine study with intranasal P. multocida challenge, mice were given tulathromycin (16 mg/kg; T02), M9 (32 mg/kg; T03), or ceftiofur (9 mg/kg; T04) by subcutaneous injection 18 hours after bacterial challenge. (5×10 ³ CFU/mouse) for RNA sequence analysis from lung tissue. Survival at day 7 was approximately 80%, 50% and 90% for T02, T03 and T04, respectively, compared to placebo (0%). Differential gene expression from global RNA-seq analysis of lung tissues revealed that at least 226 unique genes were up- or down-regulated (with significance) in case T03. The results of complex pathway analysis of these unique genes allowed us to predict the major upstream regulators of the involved pathways. Data were analyzed based on the number of genes modulated in one direction that were associated with a given upstream regulator, an activation z-score of 2 or more was considered significant, and a change in direction was indicated as + (activation) or − (inhibition). The first 5 pathways included: IL-9 signaling, glucocorticoid receptor signaling, prolactin signaling, JAK STAT signaling, and IL-17 signaling. The top 6 upstream regulators (activation z-score) included: lipopolysaccharide (-6.725), TNF (-4.669), IFNG (-5.759), IL-16 (-5.947), STAT1 (-2.787), and poly rl:rC- PHK (-5.289). Even though this study was conducted in a murine model, the first upstream modulators identified as being modulated by M9 involve almost widespread overlap with pathways identified in natural disease studies as key mediators of RBD, and therefore modulate highly relevant pathways in the pathobiology of RBD.

Single cell RNA sequencing was used using the whole blood assay described above, demonstrating drug-induced changes in cytokine protein expression to further confirm cell type and pathway modulation by compounds of the invention. Whole blood contains various types of immune cells, including both myeloid (eg, neutrophils and macrophages) and lymphoid (eg, T and B cells) cells, as well as additional cell type-specific differentiated subsets. Cells with transcriptional similarity were pooled together and identities were projected based on reference lists of markers that were cross-validated with the first differentially expressed genes against our established panel of markers based on bovine antibodies. In the absence of any stimulation, H-91 affected genes that correlated, in particular, with clusters of cells identified as neutrophils/macrophages, monocytes, and T and B lymphocytes. Samples were sequenced at 30 min, 4 h, and 20 h post-stimulation (LPS as described above), with relatively the greatest changes observed at 20 h. Genes with the highest differential expression values included, but were not limited to, cytokines such as IL-16, chemokines such as CXCL2 and CXCL8, and members of the interferon-stimulated gene (ISG) family (data not shown).

Focusing on clusters of cells identified in drug effect correlations, lists of significantly modulated genes (adjusted p < 0.05 and absolute 1og (fold change) > 0.25) were used to identify predicted upstream regulators of associated pathways. These regulators include (but are not limited to) components important for putative pathological pathways in BCRS, such as TNFα, LPS (TLR4 agonist), NFκB, IL-1β, and IL-6. As previously described, reductions in the intensity of these inflammatory pathways, which are elevated in RCD, correlate with positive clinical outcome. In this experimental system, LPS was administered to activate inflammatory pathways observed in calves at risk for RBD and whole transcriptome sequencing was used to determine the effect of the drug on these key pathways. In populations of myeloid cells, cluster

neutrophils/activated macrophages and a cluster of monocytes, the drug reduced the activation of most of the inflammatory pathways described above. In B-lymphocyte populations, the drug reduced LPS-induced activation of almost all of the first identified pathway regulators. This result makes sense because the PRR-associated pathways described herein are stably expressed in myeloid cell populations and B cells (both of which can serve as professional antigen-presenting cells). T cells express the PRR family to a much lesser extent, suggesting that the pathway targeted by the drug is less amenable to interference in this cell type. Interestingly, the group of pathway regulators that were upregulated by the drug in the context of stimulation (in myeloid and T cell clusters) were pathways often associated with immunity against viral-type pathogens, interferons and STAT (which is a signaling molecule for the interferon family). This finding extends to the mechanism of action described above, where the drug attenuates/aggravates innate pro-inflammatory pathways associated with bacterial pathobiology and may also enhance immune defense against viral pathogens known to be a major component in RCD.

Given the overlap between the immunomodulatory properties of macrolides and the described target pathways, the des-methyl metabolite of tulathromycin M9 with reduced antimicrobial activity was used in a natural bovine respiratory disease study. The primary clinical endpoint for efficacy was treatment failure/success during the 14-day follow-up period. Clinically normal calves (150-200 kg) with moderate risk of RBD were dosed upon arrival at the feedlot. Animals (N = 114/group) received saline (T01), 5 mg/kg M9 (T02), 10 mg/kg M9 (T03), or zaktran (T04). Treatment failure rates were 43%, 19.3%, 8.8%, and 29.8% for groups T01, T02, T03, and T04, respectively. Bacterial isolates were collected at necropsy and MICs were assessed (Table 4). In a separate PK study, the maximum plasma concentration after a dose of 10 mg/kg was 5 mcg/ml. Based on the observed MIC (Table 4) and maximum plasma concentration, it was suggested that the residual MIC activity of M9 was not responsible for the significant overall result, and the effectiveness was mainly due to the immunomodulatory effects of M9. M9 demonstrated efficacy in a study of natural RBC infection with statistical superiority demonstrated over untreated controls in reducing lung lesion volume and treatment failure (condition, rectal temperature and respiratory rate/respiratory effort, and nasal/ocular discharge). However, as can be seen for some bacterial isolates, M9 has antibacterial properties (i.e. MIC < 64 μg/ml).

A separate field study using a compound of the invention (Example H-91) used crossbred cattle (bulls, steers, heifers) ranging in age from 5 months or older and weighing 300-500 pounds. Animals were kept in pens and given antibiotic-free diets and water ad libitum. Animals (N = 114/group) received a single dose of saline placebo (T01) or a treatment dose of Example H-91 at 0.5 mg/kg (T02) or 2.5 mg/kg H-91 (T03) at day 0 by subcutaneous injection. The compound (20 mg/ml) was solubilized in a buffered (~pH 5-6) solution containing propylene glycol and water. The study also included an active control group (N = 57), in which each animal received a labeled dose of Zuprevo (tildipirosin, 4 mg/kg, T04). Animals in a separate group (N = 3) received a dose of 0.5 mg/kg or 2.5 mg/kg of compound Example H-91 on day 2. Animals were observed and clinically monitored (eg, plasma, rectal temperature, condition , respiratory parameters (respiratory rate/respiratory effort and nasal/eye discharge) until the end of the study on day 7 to assess RBC.Bacterial swabs were also taken from cattle (treatment failure and lung lesions) and cultured and isolated for M. haemolytica, P multocida, N. somni and M. bovis Successful treatment rates were 43.0% (T01), 57.9% (T02), 43.9% (T03) and 86.0% (T04). it can be said that lower doses of the compound of the invention may be necessary to reduce the innate immune and inflammatory response in the target animal.This correlates well with in vitro data indicating that at high concentrations the immune response in cells is often increased, as this observed for IL-1β.

Another field study used crossbred cattle (bulls, castrate steers, heifers) ranging in age from 5 months or older and weighing 300,500 pounds. Animals were kept in pens and given antibiotic-free diet and water ad libitum. Animals (N = 84/group) received a single treatment with the compound of example H-11 at 0.03 mg/kg (T02), 0.1 mg/kg (T03), 0.3 mg/kg (T04), 1 mg/kg kg (T05) or 0.05 ml/kg saline solution (T01). A subgroup of 42 animals received a single dose of 4 mg/kg Zuprevo (T06; 180 mg/ml). Animals in groups T01-T06 were dosed on day 0. The route of administration in all treatment groups was subcutaneous injection. The active substances were solubilized in a buffered (~pH 5-6) solution containing propylene glycol and water to prepare 1.2 mg/ml (T02), 4 mg/ml (T03), 12 mg/ml (T04) and 40 mg /ml (T05). Animals were observed and clinically monitored (e.g., plasma, rectal temperature, condition, respiratory parameters (respiratory rate/respiratory effort, and nasal/eye discharge) until the end of the study on day 7 to assess RBD. Bacterial swabs were also taken from cattle ( unsuccessful treatment and lung lesions) and carried out their cultivation and isolation of M. haemolytica, P. multocida, N. somni and M. bovis.Successful treatment was 32.1% (T01), 58.3% (T02), 60.7% (T03), 51.2% (T04), 40.5% (T05) and 85.7% (T06) Compared to T01, T02 (0.0008), T03 (0.0003), T04 (0 .0133) and T06 (<.0001) were statistically significant at the .20 level.

Intensive sampling was conducted over a 96-hour period in a subset of cattle that were treated with Example compound H-91 (0.5 mg/kg) or H-11 (0.1 mg/kg) in natural bovine infection studies. These compounds exhibited a rapid and transient increase in IL-36RA levels of up to about 275% for Example H-91 and about 50% for Example H-11 over baseline within 1 hour (FIG. 5). IL-36RA remained elevated for approximately 8 hours, and then the concentration dropped to -55% of the initial concentration. A dose-dependent reduction was observed between 48 and 96 hours. The compounds of the invention demonstrated upregulation of IL-36RA, which then binds to IL-36R, limiting the proinflammatory IL-36 response. In addition, IL-8 levels in one natural infection study with Example H-91 increased by 270% over the course of the control animal study. In contrast, IL-8 levels in animals administered Example H-91 were reduced by about 15%.

To evaluate immunomodulation effects and potential biomarkers, a model study was performed with endotracheal lung challenge with bovine M. haemolytica (strain: OSU-012103-BHI) using M9 treatment in the presence and absence of bacterial challenge and the comparator Draxin®. It is important to note that the MIC for M9 against the challenge strain is >64 μg/ml, indicating that the observed effects were primarily due to immunomodulation rather than reduction in bacterial challenge. Animals were injected with 0.05 ml/kg saline solution (T01), 10 mg/kg M9 (T02); 2.5 mg/kg Draxin (T03) and 10 mg/kg M9 (T04) by subcutaneous injection on day -1. The dose was based on body weight. Animals were stimulated on day 0 with the exception of T04. Blood was drawn throughout the study to evaluate a panel of biomarkers (eg, IL-6 and CD163), including two baseline pre-treatment samples. The results of the study are presented in Table 5 and Fig. 6. In FIG. 6A illustrates the percentage of lung lesion score versus the area under the concentration curve for IL-6 protein for individual animals, and FIG. Figure 6B illustrates the relationship between the percentage of lung lesions and the fold change in the area under the CD163 curve for individual animals. Data are presented as the percentage of lung damage based on the area under the curve (AUC) for IL-6 protein (immunoassay results expressed in pg/ml) and CD163 (fold change in mean fluorescence intensity (AUC) from baseline according to flow cytometry). In both analyses, a 2-fold change was generally considered relevant.

IL-6 was elevated and correlated with higher rectal temperature (data not shown) and mortality. M9 and Draxin® significantly reduced IL-6 levels, which also correlated with overall animal survival or disease progression. CD163 mRNA expression was observed after the initial innate inflammatory signaling cascade in animals that exhibited clinical signs of RCD within a few days. Increased expression of CD163 on macrophages correlates with clinical disease progression based on data collected from whole blood samples collected throughout the study. M9 reduces the pathological increase in CD163 expression.

Overall, M9 demonstrates statistically significant efficacy in both natural RBC infection compared with saline (T01) and in the M. haemolytica stimulation model. In a separate study, 10 mg/kg M9 demonstrated statistical superiority over saline control in reducing lung injury (20% vs 31%, p=0.023) and mortality (13% vs 38.9%, p=0.025). In addition, a decrease in biomarker levels was observed, consistent with the proposed mechanism. However, the residual antibacterial activity of M9 (MIC ≤ 64 μg/ml) against target pathogens was not consistent with the nonantibiotic immunomodulatory profile (>64 μg/ml).

In a separate study with endotracheal lung challenge with bovine M. haemolytica, the compound of Example H-91 was administered 24 hours before the bacterial challenge according to the on-arrival/preventive control product profile. The study design also included assessment of biomarkers of immunomodulation. Animals (n = 24/group) received a subcutaneous dose of saline (0.05 ml/kg; T01); 0.5 mg/kg (T02) or 2.5 mg/kg (T03; n = 23) of the compound of example H-91; or 10 mg/kg (T04) M9.

The dose amount was based on body weight. On day 0, animals were stimulated with M. haemolytica. Animals T01-T04 were evaluated for clinical scores, lung injury, and mortality to assess statistical success. Outcomes included: respiratory sign severity score 0 = normal, 1 = mild clinical signs, 2 = acute clinical disease of RBD, 3 = severe clinical disease of RBD; condition rating 0 = normal, 1 = mildly depressed, 2 = moderately or significantly depressed, 3 = dying. Treatment failure was defined as: a) a clinical score of 3 or b) a combination of scores of 2+2 with a rectal temperature >104°F. Daily clinical scores were scored on a 0–3 scale, including condition and respiratory signs with rectal temperature measurement. Lung involvement was assessed at autopsy. On day 6, the study was completed and all remaining animals were sacrificed. The animal is described as surviving (euthanized due to end of study; no) or dead/euthanized (euthanized or dying before scheduled necropsy due to stimulation; yes) based on data collected on the final decision form and summarized by treatment. In tables 6 and 7 and Fig. Table 7 summarizes the results of this endotracheal study. In FIG. 7A illustrates the percentage of lung lesion score as a function of the area under the concentration curve for IL-6 protein for individual animals, and FIG. 7B illustrates the percentage lung lesion score as a function of fold change in CD163 area under the curve for individual animals as analyzed by flow cytometry with mean fluorescence intensity data expressed as fold change from baseline (>2 is considered biologically relevant).

As can be seen from Table 6, statistical significance (p<0.2) was found for compound Example H-91 for T02 and T03, as well as for the positive control group, T04, compared to T01.

As can be seen from Table 7, statistical significance (p<0.2) was demonstrated for mortality compared to the untreated saline group for Example H-91 for T02 and T03, as well as for the positive control group, T04, for compared to T01.

The data presented in Fig. 7 are presented as a percentage assessment of lung damage depending on the area under the curve (AUC) for IL-6 protein (immunoassay results expressed in pg/ml) and CD163 (fold change in mean fluorescence intensity (AUC) relative to baseline according to flow cytometry). In both analyses, a 2-fold change was generally considered relevant.

Overall, the endotracheal challenge study with M. haemolytica demonstrated efficacy for Example H-91 at doses of 0.5 mg/kg and 2.5 mg/kg administered subcutaneously. The compound exhibited an MIC of >256 μg/ml against the stimulating strain M haemolytica. In addition, an MIC of >256 μg/mL was also found for all M. haemolytica target pathogens tested. After a 2.5 mg/kg dose of N-91, the maximum plasma concentration (Cmax) was 152 ng/ml. The efficacy provided by Example H-91 at both doses of 0.5 mg/kg and 2.5 mg/kg is due to its activity as an immunomodulator, but not as an antibiotic. Biomarker analysis demonstrated reductions in IL-6 and CD163 levels consistent with dose and clinical outcome. Biomarker evaluation supports the proposed mechanism of immunomodulation.

In a separate endotracheal lung stimulation study with bovine M. haemolytica, with a design similar to that described above, the compound of Example H-11 was evaluated. The compound of Example H-11 was administered at a dose of 0.5 mg/kg (T03) and 2.5 mg/kg (T04); saline placebo (negative control, T01) and M9 (positive control, 10 mg/kg, T05) were also evaluated. Doses were administered to animals by subcutaneous injection 24 hours before bacterial challenge. Lung injury and mortality data are shown in Tables 8 and 9, respectively. Data on neutrophil counts, IL-6 and CD163 are shown in Fig. 8. There was a 43% (median) decrease in IL-6 levels 32 hours post-stimulation, while the geometric mean showed a 51% decrease in IL-6 levels. Treatment with the drug 24 hours before stimulation reduced the number of neutrophils in the blood, plasma levels of IL-6 and the expression of the phagocytic receptor CD163 on blood macrophages, all of which were consistent with the clinical outcome.

As can be seen from Table 8, statistical significance (p<0.2) was found for the compound of example H-11 (T04), as well as for the positive control group, T05, compared to T01.

As can be seen from Table 9, statistical significance (p<0.2) was demonstrated for mortality compared to the untreated saline group for Example H-11 (T03), as well as for the positive control group, T05, compared from T01.

As previously demonstrated, M9 and Example compounds H-11 and H-91 reduced elevated plasma levels of IL-6 and CD163 (two independent studies). As described, CD163 is an acute phase protein receptor expressed on activated monocytes in peripheral blood and macrophages in tissues that binds haptoglobin and hemoglobin to limit oxidative inflammation in the tissue. During chronic inflammatory diseases, CD163 expression is increased, and we observed the same expression profile in the M. haemolytica stimulation model and in natural RCC disease. These data indicate drug-mediated reduction in levels of biomarkers of inflammatory pathways. This reduction in biomarker levels was associated with positive clinical outcome in natural RCD.

The lymphocyte population was also assessed in a separate in vivo stimulation genomics model conducted to further elucidate the drug's mechanism of action. Animals (n = 8/group; Holstein, 4-5 months old) were administered placebo (saline, T01), a dose of 0.1 mg/kg H-11 (T02), or a dose of 2.5 mg/kg H-11 solution. 11 (T03) by subcutaneous injection 24 hours before endotracheal stimulation of M. haemolytica. Because this was a genomics study, animals were not allowed to progress to endpoint disease, so necropsies were performed on animals (n = 4/group) at 24 and 48 hours postchallenge. As part of the study, samples were collected throughout the study for biomarker and genomics assessments. T cell surface markers included cytotoxic (CD8+) T cells, γδ T cells, and NK cells, with the most dramatic effects observed in helper T cells. Cytokine production in T helper subtypes was assessed using intracellular staining, allowing identification of the specific cell type that produces the cytokine. Treatment with the drug resulted in a shift in the balance between T helper type 1 (Th1) and type 17 (Th17) cells, as assessed by the production of IFN-γ and IL-17 (specifically IL-17A), respectively. In FIG. Figure 9 illustrates the intracellular characteristics of CD4+ T helper cell subtypes as determined by flow cytometry in the blood of animals 24 and 48 hours after treatment with H-11 at 0.1 mg/kg (T02). Helper T cells were identified by dual expression of CD3 and CD4, whereas CD8-negative Th17 cells were characterized by IL-17 expression and Th1 were characterized by IFN-γ expression. The increase in the Th1:Th17 ratio after treatment suggests a functional shift consistent with the stimulation of a more productive pathogen-fighting immune system (Th1) versus a response associated with pathological inflammatory responses (Th17) in RCD, consistent with a role IL-17-producing T helper cells in recruiting neutrophils to sites of diseased tissue and activating them. The shift described in FIG. 9 by intracellular staining was small in magnitude but consistent with the treatment-related decrease in IL-17 levels (specifically IL-17A) observed in bronchoalveolar lavage fluid (BAL) and lesional consolidated lung tissue at autopsy (Figure 10) . In FIG. 10 demonstrates a decrease in IL-17 levels measured in the respiratory tract of animals challenged with M. haemolytica as a result of H-11 treatment. The observed absence of IL-17 in healthy lung tissue supports the relevance of small protein changes. Additionally, these results are consistent with transient analysis of the airways of exposed calves in a previously described natural disease study in which IL-17 expression levels correlated with poor clinical outcome. Given what is known regarding the pathobiology of RBD and the role of T helper lymphocyte populations in having a significant influence on the type and/or direction of the inflammatory response, the shift away from Th17 suggests not only a pathway by which pathological inflammation in RBD is controlled, but potentially allows suggest a mechanism by which treatment may enhance a more productive Th1 response that may promote pathogen clearance.

The data presented herein support the immunomodulatory (non-antibiotic) effect of the compounds of the invention in that a) all animals in the study exhibited a state of increased inflammation upon arrival at the feedlot, as indicated by increased genomic signatures for the PRR, TLR4, IL- 1βp, TNF-α and JAK/STAT; b) it was confirmed through genomic analysis that all animals were exposed to the same pathogens during the study; c) it is the natural ability of the host to reduce this inflammatory condition that predicts the animal's ability to progress to full RCD; d) the reduction of this inflammatory state determines the point of intervention for the use of an immunomodulator (a compound of the invention); f) the immunomodulatory effects observed for macrolides are consistent with interventions needed to combat excessive innate immune inflammatory responses in target animals and progression to RCD; and (1) the use of M9 (antibiotic activity) demonstrated reduced MIC activity against target pathogens. Additional data on immunological markers obtained in in vitro immunological models are shown in Table 10. If a compound results in a value of “>” for an immunological marker, this is presumably due to some characteristic effect of the model that is causing the results for IC ₅₀ and/or or OS cannot be determined accurately.

The results presented in Table 10 demonstrate a significant increase in the inhibition of TNFα, IL-1β and/or IL-6 for the studied compounds of formula (1) compared to M9 at the same drug concentrations (250 μM). In M9, the highest dose of 500 μM was not high enough to detect IL-1β overstimulation, which was recorded as “no data” (n/a). Additional evidence supporting this hypothesis includes studies in mice with P. multocida infection in mice. For example, M9 was clinically effective when airway tissues were collected throughout the study and assessed in transcriptomic analysis. Example compounds H-11 and H-91 were also found to be clinically effective. Based on these results, specific transcriptional expression demonstrated the presence of regulators consistent with several key RCD pathways (PRR, cytokines, STATs), and cellular cross-activity was assessed.

TNFα is a cell signaling protein, a cytokine, that plays a key role in systemic inflammation when it is produced in excess. In an in vitro screening assay in bovine whole blood, TNFα inhibition induced by lipopolysaccharide (LPS) stimulation and measured as half-maximal inhibitory concentration (IC ₅₀ ) is considered the primary biomarker of immunomodulatory efficacy following pretreatment with the compounds of the invention. IL-1β is a mediator of the inflammatory response and is involved in a number of cellular activities, including proliferation, differentiation and apoptosis. IL-1β is also released after cellular stress or cytotoxicity or after TLR stimulation. In the bovine whole blood assay, stimulation of IL-1β release following increasing concentrations of the test compound is considered a potential cellular toxicity signal induced by the test compound. To estimate the therapeutic index from the in vitro assay, the difference between the IC ₅₀ of TNFα (immune modulation efficacy) and the concentration of perceived cellular toxicity (IL-1β release or overstimulation) was used. We therefore hypothesized that for a compound to be effective in vivo, its therapeutic index should be >2 (IL-1β/IC ₅₀ TNFα overstimulation), with higher indices being predictive of greater potential for an effective dose in vivo. A lower IC ₅₀ of TNFα indicates a lower total dose in mg/kg in vivo, provided that a sufficient therapeutic index is > 2. Since the index in the in vitro assay approaches 1, it has been suggested that the balance between immunomodulation and cytotoxicity is too narrow to achieve an effective dose in vivo.

Drug Binding Partners as Potential Biological Targets The data provided herein regarding the immunological mechanistic activity of the compounds of the invention are consistent with the pathways presented herein that have been identified as important in the pathobiology of RBD. Key pathways associated with natural disease onset include NFκ, TLR4 (often represented by its agonist such as LPS), JAJ-STAT, TNFα, and IL-1β. Subsequent signaling of these pathways leads to the induction of proinflammatory cytokines such as TNFα, IL-1β and IL-6 and chemokines such as CXCL8. The same pathways and their components are modulated both in vitro and in vivo by these compounds. Additionally, cell types known to be involved in these pathways, including macrophages, neutrophils and lymphocytes, were used in a whole blood LPS stimulation format (both in vitro and ex vivo) to demonstrate drug-induced changes in gene expression. expression of cytokines and activation of cell surface receptors. In addition to classical immune cells, tissue epithelial and endothelial cells can express innate immune receptors and activate the canonical pathway.

To further examine the direct activity characteristics of the compounds of the invention, experiments were performed to identify direct drug binding partners in the host in order to identify potential biological targets. Bovine primary cells (peripheral blood mononuclear cells [PBMCs] and polymorphonuclear cells [PMN/neutrophils]) and tissue (trachea, lung) protein homogenates were mixed with M9 and the macrolide, gamithromycin, as a comparator. Tissue interactions were allowed to form using a heterogeneous assembly method (Nematic Protein Organizing Technology, NPOT; Inoviem Scientific) and conventional Western blotting to identify natively structured proteins associated with the compound. Mass spectrometric analysis identified eight proteins involved in the interaction with M9 compared to gamithromycin. The antibacterial macrolide gamithromycin was used as a comparator to isolate specific binding to M9. These proteins were considered to be direct drug binding partners or directly involved in drug:target interactions (Figure 11).

To further clarify the identification of binding partners, surface plasmon resonance (SPR) technology was used. LCN2 and SLAMF9 were identified as direct binding targets at pH levels corresponding to intracellular compartments of myeloid cells and disease-affected tissue sites in RCC. These targets were unique to this class of drugs compared to gamithromycin, a macrolide antibiotic used in the treatment of RBD. Both targets are consistent with the paradigm that the immunological mechanism of action is associated with pathways that are of key importance as being down-regulated in RCD and modulated by M9. LCN2 is expressed by neutrophils following activation of toll-like receptors (TLRs) and is a component of the innate inflammatory response. The binding of the drug to LCN suggests a direct interaction with and effect on neutrophils. There is very little information available on SLAMF9 at this time. It is a member of the signaling adapter protein family and is thought to lack signal transduction capacity. More recent studies have demonstrated that SLAMF9 can modulate the LPS-induced TNF response of macrophages and influence cellular functions. This finding is highly consistent with the immunological effects that have been demonstrated by the compounds of the invention, further demonstrating interactions with key innate inflammatory pathways.

KD is the equilibrium dissociation constant that was used to represent drug/target affinity. Surface plasmon resonance (SPR) measurements of identified drug-bound targets were performed to determine the KD. As can be seen from the table, good drug/target binding was observed for LCN2 and SLAMF9 at biologically relevant pH; whereas binding for NLRX1, LPO and TLR4 was indirect.

Claims (178)

1. Compound Formula (1) where W represents H or formula (A) where X is -R ^a , -R ^c NR ⁵ R ⁶ , -R ^c OR ⁷ , -R ^c SR ⁷ , -R ^c N ₃ , -R ^c CN or -R ^c X'; X' represents F, Cl, I or Br; R represents H; each of R ^a , R ^b , R ⁰ and R ¹ independently represents H or C ₁ -C ₆ alkyl; or R ¹ is benzyl, optionally substituted with methoxy; or R ¹ represents -CH ₂ Het, where Het represents a 5-6 membered heteroaryl ring containing at least one heteroatom selected from N, S and O; and wherein the heteroaryl ring is optionally substituted with at least one R ⁹ substituent; R ^c represents C ₁ -C ₄ alkyl; each of R ² and R ³ independently represents H, C ₁ -C ₆ alkyl, R ^c NR ^a R ^b , C ₀ -C ₃ alkyl, _{C 3} -C ₆ cycloalkyl, C ₀ -C ₃ alkylaryl, C ₀ -C ₃ an alkyl heterocycle, where the heterocycle is a 5-6 membered saturated heterocyclic ring; or C ₀ -C ₃ alkylheteroaryl, where heteroaryl represents a 5-6 membered heteroaryl ring; wherein each of the heterocyclic ring and the heteroaryl ring contains at least one heteroatom selected from N and O; and wherein each of the cycloalkyl, aryl, heterocyclic and heteroaryl rings is optionally substituted with at least one R ⁹ substituent; or R ² and R ³ together with the nitrogen atom to which they are attached form ring A, a 4-8 membered heterocyclic ring optionally containing at least one additional heteroatom selected from N, O and S; each ring is optionally substituted with at least one R ¹⁰ substituent; and wherein each ring is optionally fused to Y; each of R ⁵ and R ⁶ is independently selected from H; C ₁ -C ₆ alkyl, optionally substituted with at least one hydroxy; or cyano, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, -C(O)R ⁸ , -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 C ₀ -C ₄ alkylaryl, C ₀ -C ₄ alkylC ₃ -C ₆ cycloalkyl, C ₀ -C ₄ alkylheterocycle or C ₀ -C ₄ alkylheteroaryl, wherein each of the heterocyclic and heteroaryl rings is a 5-6 membered monocyclic ring containing at least one heteroatom selected from the group consisting of N, O and S; and wherein the aryl, cycloalkyl, heterocyclic and heteroaryl rings are optionally substituted with at least one R ¹⁰ substituent; or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a ring B, a 4-6 membered heterocyclic ring or a 5 membered heteroaryl ring, each of which optionally contains at least one additional heteroatom selected from N, O and S; each ring is optionally substituted with at least one R ⁹ substituent; and each ring is optionally fused with Y; R ⁷ represents H, C ₁ -C ₆ alkyl or -R ^c S(O) _p R ^a ; R ⁸ represents C ₁ -C ₆ alkyl, C ₀ -C ₄ alkyl, _{C 3} -C ₆ cycloalkyl, -NR ^a R ^b , phenyl, and each of cycloalkyl and phenyl is optionally substituted with at least one halogen; R ⁹ is independently selected from the group consisting of C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, cyclopropyl, halogen, cyano, -NR ^a R ^b , C ₁ -C ₆ haloalkyl, -S(O) _p R ⁸ , phenyl and a 6-membered monocyclic heterocyclic or heteroaryl ring, each of which contains at least one heteroatom selected from the group consisting of N and O; R ¹⁰ is independently selected from the group consisting of C ₁ -C ₃ alkyl, oxo and -C(O)R ⁸ ; Y represents phenyl or pyrimidyl; p represents the integer 0 or 2; its stereoisomers and its pharmaceutically acceptable salts. 2. The compound of formula (1) according to claim 1, characterized in that W is a compound of formula (A) selected from the group consisting of formula (A0), formula (A1), formula (A2), formula (A3) , formula (A4), formula (A5) or formula (A6): its stereoisomers and its pharmaceutically acceptable salts. 3. The compound of formula (1) according to claim 1 or 2, which is a compound of formula (1-A1) its stereoisomers and its pharmaceutically acceptable salts. 4. The connection according to claim 3, characterized in that R ⁰ represents H, methyl, ethyl or propyl; R ¹ represents H, methyl, ethyl, propyl or benzyl; R ² and R ³ are each independently H, C ₁ -C ₆ alkyl, -CH ₂ N(CH ₃ ) ₂ , -CH ₂ CH ₂ N(CH ₃ ) ₂ ; or C ₀ -C ₂ cyclopropyl, C ₀ -C ₂ cyclobutyl, C ₀ -C ₂ cyclopentyl, C 0 -C ₂ cyclohexyl, C ₀ -C ₂ phenyl, C _{0 -C 2} piperadinyl, piperazinyl, morpholinyl, tetrahydro-2H -pyran, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl, each of which is optionally substituted with at least one R ⁹ substituent selected from the group consisting of methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, methoxy, ethoxy, F, Cl, Br, cyano, -N(CH ₃ ) ₂ , -CHF ₂ and -CF ₃ ; R ⁵ and R ⁶ are each independently H; C ₁ -C ₆ alkyl; cyano, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, -C(O)R ⁸ , -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, C ₁ alkylphenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C ₁ -C ₂ alkylcyclopropyl, C 1 -C ₂ alkylcyclobutyl, C ₁ -C ₂ alkylcyclopentyl, C _{1 -C 2} alkylcyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, oxazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, C ₁ -C ₂ alkyltetrahydrofuranyl, C ₁ -C ₂ alkyloxazolidinyl, C ₁ -C ₂ alkyltetrahydropyranyl, C ₁ -C ₂ alkylpyrrolidinyl, C ₁ -C ₂ alkylpiperidinyl, C ₁ -C ₂ alkylpiperazinyl, C ₁ -C ₂ morpholinyl; pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, pyridinyl, _pyridazinyl , pyrimidinyl, pyrazinyl, C ₁ -C 2 alkylpyrazolyl, C ₁ -C ₂ alkylimidazolyl, C ₁ -C ₂ alkyltriazolyl, C ₁ -C ₂ alkyltetrazolyl, C ₁ -C ₂ alkyloxazolyl, C ₁ -C ₂ alkylpyridinyl, C ₁ -C ₂ alkylpyridazinyl, C ₁ -C ₂ alkylpyrimidinyl and C ₁ -C ₂ alkylpyrazinyl; and wherein each of the phenyl, cycloalkyl ring, heterocyclic ring and heteroaryl ring is optionally substituted with at least one R ¹⁰ substituent; or R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a ring B, a 4-6 membered heterocyclic ring or a 5 membered heteroaryl ring, each of which optionally contains at least one additional heteroatom selected from N, O and S; and wherein each ring is optionally substituted with at least one R ⁹ substituent; and wherein each ring is further optionally fused to Y, stereoisomers thereof, and pharmaceutically acceptable salts thereof. 5. The compound according to claim 4, characterized in that R ² represents H, methyl, ethyl or isopropyl; R ³ represents H, C ₁ -C ₆ alkyl; -CH ₂ N(CH ₃ ) ₂ , -CH ₂ CH ₂ N(CH ₃ ) ₂ ; or cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl, each of which is optionally substituted with at least one R ⁹ substituent selected from the group consisting of methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, F, Br, cyano, cyclopropyl, -N(CH ₃ ) ₂ , -CHF ₂ and -CF ₃ ; R ⁵ is H, methyl, ethyl, propyl or isopropyl; and R ⁶ is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, -CH ₂ CF ₃ , -CF ₃ , -OCF3; -CH ₂ S(O) ₂ CH ₃ , -CH ₂ S(O) ₂ phenyl, -(CH ₂ ) ₂ OCH ₃ , -(CH ₂ ) ₃ OCH ₃ ; -CH ₂ NR ^a R ^b or -(CH ₂ ) ₂ NR ^a R ^b , wherein R ^a and R ^b are each independently H or methyl; -C(O)NR ^a R ⁸ where R ^a is H or methyl and R ⁸ is methyl, cyclopropyl, phenyl, optionally substituted with F, Cl or -CF ₃ ; phenyl, C ₁ alkylphenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C ₁ -C ₂ alkylcyclopropyl and C ₁ -C ₂ alkylcyclobutyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, C ₁ -C ₂ alkylpyrrolidinyl, C ₁ - C ₂ alkylpiperidinyl, C ₁ -C ₂ alkylpiperazinyl, C ₁ -C ₂ morpholinyl, C ₁ -C ₂ tetrahydropyranyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, C ₁ -C ₂ alkylpyrazolyl, C ₁ -C ₂ alkyl imidazolyl, C ₁ -C ₂ alkylpyridinyl, C ₁ -C ₂ alkylpyrimidinyl and C ₁ -C ₂ alkylpyrazinyl, each optionally substituted with at least one R ¹⁰ substituent, stereoisomers thereof and pharmaceutically acceptable salts thereof. 6. The compound according to claim 5, which 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-((butylaminomethyl)-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-(((2R,3S,4R,5R,8R,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-(((2R,3S,4R,5R,8R,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)-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)-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; its stereoisomers and its pharmaceutically acceptable salts. 7. The compound according to claim 6, 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 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, its stereoisomers and its pharmaceutically acceptable salts. 8. A compound according to claim 1, characterized in that W represents H, which is a compound of formula (1.1) where R ⁰ represents H; R ¹ represents methyl; And R ² represents H or methyl; And R ³ is pyrazole, optionally substituted with at least one methyl; pyridine, pyrimidine or pyrazine; or phenyl, optionally substituted with at least one R ⁹ substituent selected from methoxy, cyano, trifluoromethyl, fluorine, chlorine or methyl; its stereoisomers and its pharmaceutically acceptable salts. 9. A compound according to claim 1, which is a compound of formula (1-A0), formula (1-A2), formula (1-A3), formula (1-A4), formula (1-A5) or formula (1 -A6): or where X' represents F, Cl or Br; R ⁰ represents H, methyl, ethyl or propyl; R ^a is H, methyl or ethyl; R ¹ represents H or methyl; R ² represents H, methyl, ethyl, cyclopropyl or phenyl; R ³ represents H, methyl, ethyl, propyl, isopropyl, tert-butyl, -CH ₂ N(CH ₃ ) ₂ , -CH ₂ CH ₂ N(CH ₃ ) ₂ ; or cyclopropyl, cyclobutyl, phenyl, C ₁ phenyl, piperadinyl, C ₁ -piperadinyl, piperazinyl, morpholinyl or pyridinyl, and wherein each ring is independently substituted with at least one R ⁹ substituent selected from the group consisting of methyl, ethyl, methoxy , ethoxy, F, Cl, cyano, -N(CH ₃ ) ₂ H and -CF ₃ ; And R ⁷ is H, methyl, ethyl, propyl, isopropyl or tert-butyl; its stereoisomers and its pharmaceutically acceptable salts. 10. The compound according to claim 9, which is a non-antibacterial compound of formula (1-A0) selected from: 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; 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; 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; 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; 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; 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; 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; 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; 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; 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; 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; 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; 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; 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; 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; 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; 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-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; or a compound of formula (1-A2) 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-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 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; or a non-antibacterial compound of formula (1-A3) selected from 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-phenylurea; or a compound of formula (1-A4) selected from: 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; And 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; or a non-antibacterial compound of formula (1-A5) selected from 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 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-phenylurea; or a compound of formula (1-A6) selected from: 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; And 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; their stereoisomers and their pharmaceutically acceptable salts. 11. The compound of formula (1-A1) according to claim 3, which is a compound of formula (1-A1a) where R ⁰ represents H, methyl, ethyl or propyl; R ⁵ is H, methyl, ethyl, propyl or isopropyl; R ⁶ represents H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, ethoxy, -CH ₂ CF ₃ , -CF ₃ , -OCF ₃ ; -C(O)NR ^a R ⁸ where R ^a is H or methyl and R ⁸ is methyl, cyclopropyl, phenyl, optionally substituted with F, Cl or -CF ₃ ; -(CH ₂ )S(O) ₂ R ⁸ where R ⁸ represents methyl or phenyl; -CH ₂ NR ^a R ^b or -(CH ₂ ) ₂ NR ^a R ^b , wherein R ^a and R ^b are each independently H or methyl; -(CH ₂ ) ₂ OCH ₃ , -(CH ₂ ) ₃ OCH ₃ ; phenyl, C ₁ alkylphenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C ₁ -C ₂ alkylcyclopropyl, C ₁ -C ₂ alkylcyclobutyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, C ₁ -C ₂ alkylpyrrolidinyl, C ₁ - C ₂ alkylpiperidinyl, C ₁ -C ₂ alkylpiperazinyl, C ₁ -C ₂ morpholinyl, C ₁ -C ₂ tetrahydropyranyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, C ₁ -C ₂ alkylpyrazolyl, C ₁ -C ₂ alkyl imidazolyl, C ₁ -C ₂ alkylpyridinyl, C ₁ -C ₂ alkylpyrimidinyl or C ₁ -C ₂ alkylpyrazinyl; and wherein each of the phenyl, cycloalkyl ring, heterocyclic ring and heteroaryl ring is optionally substituted with at least one R ¹⁰ substituent independently selected from methyl and ethyl; Ring A is pyrrolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, each of which is optionally substituted with at least one R ¹⁰ substituent selected from methyl, ethyl and oxo; or Ring A is indolinyl, isoindolinyl, tetrahydroquinoline, tetrahydroisoquinoline, dihydrobenzothiazine or dihydrobenzooxazine, each of which is optionally substituted with at least one R ¹⁰ substituent selected from methyl, ethyl and oxo; its stereoisomers and its pharmaceutically acceptable salts. 12. The compound of formula (1-A1) according to claim 3, which is a compound of formula (1-A1b) where R ⁰ represents H, methyl, ethyl or propyl; R ² represents H or methyl; R ³ is methyl, ethyl or propyl; or cyclopropyl, cyclobutyl, phenyl, C ₁ phenyl, piperadinyl, C ₁ -piperadinyl, piperazinyl, morpholinyl or pyridinyl, and wherein each ring is independently substituted with at least one R ⁹ substituent selected from the group consisting of methyl, ethyl, methoxy , ethoxy, F, Cl, cyano, -N(CH ₃ ) ₂ and -CF ₃ ; ring B is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, each of which is optionally substituted with at least one R ⁹ substituent selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy , F, Cl, Br, CN, -N(CH ₃ ) ₂ , -CHF ₂ , -CF ₃ and oxo; or Ring B is indolinyl, isoindolinyl, tetrahydroquinoline, tetrahydroisoquinoline, dihydrobenzothiazine or dihydrobenzooxazine, each of which is optionally substituted with at least one R ¹⁰ substituent selected from methyl, ethyl and oxo, stereoisomers thereof and pharmaceutically acceptable salts thereof. 13. The compound of formula (1-A1a) according to claim 11, which is a non-antibacterial compound selected from: 4-ethyl-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4 ,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((methylamino)methyl)tetrahydro-2H-pyran-2-yl )oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4 -yl)-N-methylpiperazine-1-carboxamide; N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy -13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)- 3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)- N-methylindoline-1-carboxamide; N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy -13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)- 3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)- N-methyl-3,4-dihydroquinoline-1(2H)-carboxamide; N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy -13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)- 3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)- N-methyl-2,3-dihydro-4H-benzo[b][1,4]thiazine-4-carboxamide-1,1-dioxide; N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy -13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)- 3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)- N-methyl-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxamide; And N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy -13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)- 3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)- N-methylisoindoline-2-carboxamide; or a compound of formula (1-a1b) according to claim 12, which is a non-antibacterial compound selected from: 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-dimethyl-5-((4-methylpiperazin-1-yl)methyl)tetrahydro-2H -pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro -2H-pyran-4-yl)-1-methylurea; 3-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-((4-methylpiperazin-1-yl)methyl)tetrahydro-2H -pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro -2H-pyran-4-yl)-1-methylurea; 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-dimethyl-5-((4-methylpiperazin-1-yl)methyl )tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy -6-methyltetrahydro-2H-pyran-4-yl)-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-((3-morpholinoazetidin-1-yl)methyl)tetrahydro-2H-pyran-2 -yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran -4-yl)-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-((4-methylpiperazin-1-yl)methyl)tetrahydro-2H-pyran-2 -yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran -4-yl)-1-methylurea; 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-dimethyl-5-((4-methylpiperazine-1- yl)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)- 3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-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-((4-methylpiperazin-1-yl)methyl)tetrahydro-2H-pyran-2 -yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran -4-yl)-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-((4-methylpiperazin-1-yl)methyl)tetrahydro-2H-pyran-2 -yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran -4-yl)-1-methyl-3-(pyridin-3-yl)urea; 3-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-((4-methylpiperazin-1-yl)methyl)tetrahydro-2H -pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro -2H-pyran-4-yl)-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-(morpholinomethyl)tetrahydro-2H-pyran-2-yl)oxy)-3.5 ,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-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-(pyrrolidin-1-ylmethyl)tetrahydro-2H-pyran-2-yl)oxy) -3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl) -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-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl) tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy- 6-methyltetrahydro-2H-pyran-4-yl)-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-((3,3-difluoroazetidin-1-yl)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3 ,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H- pyran-4-yl)-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-((5,7-dihydro-6H-pyrrolo[3,4-b]pyrazin-6-yl)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran- 2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy )-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-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-((3-(piperidin-1-yl)azetidin-1-yl)methyl) tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy- 6-methyltetrahydro-2H-pyran-4-yl)-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-((4-phenylpiperidin-1-yl)methyl)tetrahydro-2H-pyran-2 -yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran -4-yl)-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-((4-(methylsulfonyl)piperidin-1-yl)methyl)tetrahydro-2H- pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11 -yl)oxy)-3-hydroxy-6-methyltetrahydro- 2H-pyran-4-yl)-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-(azetidin-1-ylmethyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy- 3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)- 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-((1H-pyrazol-1-yl)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4 ,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran- 4-yl)-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-((1H-imidazol-1-yl)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4 ,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran- 4-yl)-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-((3-(dimethylamino)azetidin-1-yl)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl- 3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H -pyran-4-yl)-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 -((1H-1,2,4-triazol-1-yl)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2 -ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6- methyltetrahydro-2H-pyran-4-yl)-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-((1H-1,2,3-triazol-1-yl)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2 -ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6- methyltetrahydro-2H-pyran-4-yl)-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 -((1H-tetrazol-1-yl)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4 ,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran- 4-yl)-1,3-dimethyl-3-phenylurea; And 1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S, 6S)-5-((2H-tetrazol-2-yl)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4 ,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran- 4-yl)-1,3-dimethyl-3-phenylurea; their stereoisomers and their pharmaceutically acceptable salts. 14. A method of treating or preventing an inflammatory response in an animal by administering to said animal in need thereof a therapeutically effective amount of a compound of claim 7, stereoisomers thereof, and pharmaceutically acceptable salts thereof.