RU2842666C2 - Immunomodulatory azalides - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (1)

where W is a compound of formula (A)

where X is -(CH₂)_mNR⁵R⁶; R is H, phenyl or 5- or 6-member monocyclic heteroaryl ring, wherein the heteroaryl ring contains one N or S heteroatom; and wherein each phenyl and heteroaryl rings are substituted (R⁹)_n; each R^a, R⁰ and R¹ is independently H or C₁-C₆alkyl; or R¹ is benzyl, optionally substituted (R⁹)_n; or R¹ is -CH₂Het, where Het is 6-membered heteroaryl ring containing one N heteroatom; and wherein the heteroaryl ring is optionally substituted (R⁹)_n; or R¹ is C₃-C₆cycloalkyl, optionally substituted (R⁹)_n; R^b is H, C₁-C₄alkyl, C₁-C₄haloalkyl, C₀-C₃alkylphenyl, C₃-C₆cycloalkyl, C₀-C₃alkylheterocycle, C₀-C₃alkylheteroaryl; wherein heterocycle is 6-membered saturated or partially saturated monocyclic ring; heteroaryl is 5- or 6-membered monocyclic ring; and where each of the heterocyclic and heteroaryl rings contains one or two N heteroatoms; and wherein the phenyl, heterocyclic and heteroaryl rings are each substituted (R⁹)_n; R^c is C₁-C₄alkyl; R² is C₁-C₆alkyl, -R^cOR^b, C₁-C₆haloalkyl, C₀-C₃alkylC₃-C₆cycloalkyl, -R^cNR^aR^b, -R^cS(O)_pR⁸, -NR^aR^b, -NR^bR^b, C₀-C₃alkylphenyl, C₀-C₃alkylheterocycle, which is 5- or 6-membered saturated or partially saturated heterocyclic ring; C₀-C₃alkylheteroaryl, wherein heteroaryl is 5- or 6-member heteroaryl ring; and where each of the heterocyclic and heteroaryl rings contains one or two heteroatoms selected from N, O and S; and wherein each phenyl, heterocyclic and heteroaryl rings are substituted with (R⁹)_n, and wherein each ring is optionally condensed with Y; or R and R² are bonded to form a condensed dioxo-oxathiazole ring, which is

each R⁵ and R⁶ is independently selected from H; C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, C₁-C₆haloalkoxy, -R^cNR^aC(O)R⁸, -R^cC(O)NR^aR^b, -R^cS(O)_pR⁸, -R^cNR^aR^b, -R^cOR^b, -S(O)_pR⁸ or -R^cS(O)_pNR^aR^b; or C₀-C₄alkylphenyl, C₀-C₄alkylC₃-C₆cycloalkyl, C₀-C₄alkylheterocycle and C₀-C₄alkylheteroaryl; wherein the heterocyclic and heteroaryl rings are 5- or 6-member monocyclic ring each of which contains one or two heteroatoms selected from the group consisting of N, O and S; and wherein each phenyl, heterocyclic and heteroaryl rings are substituted (R⁹)_n; or R⁵ and R⁶, taken together with a nitrogen atom to which they are bonded, form ring B, which is 4–6 membered heterocyclic ring or 5-membered heteroaryl ring, each of which optionally contains one, two or three additional heteroatoms selected from N, O and S; and wherein each ring is optionally substituted (R⁹)_n, and wherein each ring is optionally condensed with Y; R⁸ is C₁-C₆alkyl, -NR^aR^b or phenyl; R⁹ is independently selected from the group consisting of C₁-C₆alkyl optionally substituted with hydroxy; C₁-C₆alkoxy, halogen, oxo, nitro, cyano, -NR^aR^b, C₁-C₆haloalkyl, -S(O)_pR⁸, -SF₅, phenyl; 5- or 6-membered heterocyclic or heteroaryl ring, each of which contains one or two heteroatoms selected from the group consisting of N and O; and wherein the heteroaryl ring is additionally optionally substituted with -CF₃; Y is phenyl, pyridinyl or thiophenyl; m is equal to integer 1; n is equal to integer 0, 1 or 2; and p is equal to integer 1 or 2; or pharmaceutically acceptable salts thereof, as well as to a pharmaceutical composition having the activity of modulators of the production of pro-inflammatory cytokines selected from TNFα, IL-1β and IL-6, which contains a therapeutically effective amount of a compound selected from a group, as well as to a method of treating or preventing an inflammatory response, which involves pro-inflammatory cytokines selected from TNFα, IL-1β and IL-6, in the animal by administering to said animal in need thereof a therapeutically effective amount of a compound selected from the group, and to the use of the compound selected from the group.

EFFECT: obtaining novel non-antibacterial, anti-inflammatory and immunomodulatory compounds which can be used in treating an inflammatory and/or immunological disease or disorder in an animal.

13 cl, 4 dwg, 5 tbl, 264 ex

Description

This document defines anti-inflammatory and immunomodulatory compounds; non-antibacterial, anti-inflammatory and immunomodulatory compounds; stereoisomers thereof and pharmaceutically acceptable salts thereof. This invention includes corresponding 13-membered macrolide ring compounds that are in equilibrium with 15-membered macrolide ring compounds. This invention also includes pharmaceutical compositions containing a compound of this invention and methods for treating an inflammatory and/or immunological disease or disorder in an animal. The compounds of this invention are azalides.

LEVEL OF TECHNOLOGY

Macrolides are antibacterial compounds consisting of a large macrocyclic lactone ring containing 12 to 16 atoms that are attached via glycosidic bonds to at least one or two deoxy sugars. Azalides are a class of macrolides in which the lactone ring contains a nitrogen atom. Draxxin® is a semisynthetic macrolide (azalide) antibiotic that is marketed as a ready-to-use sterile parenteral preparation containing tulathromycin. The preparation is an equilibrium mixture of the two isomeric forms of tulathromycin in a 9:1 ratio (Tula-A:Tula-B). Tula-A is a 15-membered lactone ring structure, where Tula-B is a 13-membered lactone ring structure. Equilibrium is pH and time dependent. Tulathromycin is marketed for the treatment of bovine respiratory disease (BRD) and swine respiratory disease (SRD) under the trade name, Draxxin®.

Macrolides are known to inhibit protein synthesis in bacteria (Gram-positive and Gram-negative) by reversibly binding to the P-site of the 50S ribosome unit. Macrolides are bacteriostatic and may have bactericidal activity against some pathogens. Their activity against Gram-negative BRD pathogens and their ability to concentrate in lung tissue make them an excellent therapeutic agent. They are first-line drugs against BRD and are also used to treat respiratory infections in humans.

Well-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 the expression of interleukin 12p40 in lipopolysaccharide (LPS)- and interferon-gamma-stimulated macrophages and attenuates LPS-induced induction of CXCL8 (IL-8) and GM-CSF from primary bronchial epithelial cells; and in epithelial cells, interaction with phospholipids and Erk1/2 is accompanied by downregulation of transcription factors AP-1, NFκB, inflammatory cytokines and mucin release after LPS stimulation. US 2016-0031925 describes certain azithromycin analogs that have immunomodulatory activity but have been modified to reduce or eliminate the effect of the antibiotic. 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 promotes 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 suppresses Th2 chemokine production by keratinocytes and the expression of chemokine receptors on Th2 cells. Tulathromycin promotes apoptosis and suppresses the activity of proinflammatory mediators such as leukotriene B4 and CXCL8; and induces the production of the anti-inflammatory and lipid-reducing lipoxin A4. Research findings indicate that these antibacterial macrolides modulate certain excessive immune responses, which in turn lead to certain anti-inflammatory effects.

Inflammatory and proinflammatory mediators negatively impact livestock production by reducing growth, feed and water intake, reproduction, milk production and metabolism. Increased clinical use of macrolide antibiotics is associated with increasing macrolide resistance in pneumococci and resistance in BRD pathogens. Recent concerns by global government agencies and the general public about antibiotic use in food animals (e.g., cattle and pigs) are thought to result in cross-resistance to human pathogens. Bovine respiratory disease (BRD) remains a major problem in modern livestock production and its prudent management is vital for both animal welfare and human food safety. In fact, Mannheimia haemolytica is the main bacterium isolated in bovine respiratory disease in feedlot cattle and is an important component of enzootic pneumonia in neonatal calves. One of the hallmarks of BRD is an increased inflammatory response in the host, which contributes to the progression of the complete BRD complex. Inhibition or reversal of host inflammation allows the prevention or control of BRD in cattle and other inflammatory diseases or disorders in animals. Therefore, there is an unmet need for the development of a new anti-inflammatory and immunomodulatory agent devoid of the antibacterial effects of known macrolides. The compounds of the present invention have been shown to have no antibacterial activity against many bacterial species and to have 5-20 times greater immunomodulatory activity at lower doses than current macrolides (e.g., azithromycin, erythromycin, and tulathromycin). Therefore, the compounds can be used to control or prevent the occurrence of a bacterial infection or a viral infection that is activated by an inflammatory and/or immune response due to a stress event or other environmental factor(s), thereby preventing or mitigating the pathobiological cascade from progression to a full disease complex. A number of other non-antibiotic immunomodulatory azalide analogues have been developed and recently published WO 2021/183758, WO 2021/183754, WO 2021/183759 and WO 2021/183762. The compounds of the invention provided herein are non-antibiotic, anti-inflammatory and immunomodulatory macrolides for reducing the inflammatory state in animals with the potential to reduce the use of antibiotics in animals.

ESSENCE OF THE INVENTION

In one aspect of the invention there is provided an anti-inflammatory and immunomodulatory compound of formula (1); or a non-antibacterial, anti-inflammatory and immunomodulatory compound of formula (1);

where W is H or a compound of formula (A)

where X is ^Ra , -(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 ) _m X';

X' represents F, Cl, I, or Br;

R is H, phenyl, naphthyl, a 5- or 6-membered monocyclic heteroaryl ring, or a 9- or 11-membered fused heteroaryl ring, and wherein each of the heteroaryl rings contains at least one heteroatom selected from N, O, and S; and wherein phenyl

(R ⁹ ) _n ; and wherein each of the heteroaryl rings contains at least one heteroatom selected from N, O and S; and wherein each phenyl, naphthyne and heteroaryl ring is substituted with (R ⁹ ) _n ;

each R ^a , R ⁰ and R ¹ independently represents H or C ₁ -C ₆ alkyl; or R ¹ represents benzyl substituted with (R ⁹ ) _n ;

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

or R ¹ is C ₃ -C ₆ cycloalkyl substituted with (R ⁹ ) _n ;

R ^b is H, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₀ -C ₃ alkylphenyl, C ₀ -C ₃ alkylC ₃ -C ₆ cycloalkyl, C ₀ -C ₃ alkylheterocycle, C ₀ -C ₃ alkylheteroaryl; wherein the heterocycle is a 5- or 6-membered saturated or partially saturated monocyclic ring; the heteroaryl is a 5- or 6-membered monocyclic ring; and wherein each of the heterocyclic and heteroaryl rings contains at least one heteroatom selected from N, O and S; and wherein the cycloalkyl, phenyl, heterocyclic and heteroaryl rings are each substituted with (R ⁹ ) _n ;

R ^c is C ₁ -C ₄ alkyl;

R ² is H, C ₁ -C ₆ alkyl, -R ^c OR ^b , C ₁ -C ₆ haloalkyl, C ₀ -C ₃ alkylC ₃ -C ₆ cycloalkyl, -R ^c NR ^a R ^b ,

-NR ^a R ^c S(O) _p R ⁸ , -NR ^a R ^c C(O)NR ^a R ^c , R ^c CN, -R ^c S(O) _p R ⁸ , -NR ^a R ^b , -NR ^b R ^b , C ₀ -C ₃ alkylaryl, C ₀ -C ₃ alkylheterocycle which is a 5- or 6-membered saturated or partially saturated heterocyclic ring; C ₀ -C ₃ alkylheteroaryl, wherein heteroaryl is a 5- or 6-membered heteroaryl ring; and wherein each of the heterocyclic and heteroaryl rings contains at least one heteroatom selected from N, O and S; and wherein each cycloalkyl, aryl, heterocyclic and heteroaryl ring is substituted with (R ⁹ ) _n and wherein each ring is optionally fused with Y;

or R and R ² join to form a bond to form a fused dioxo-oxathiazole ring, which is

each R ⁵ and R ⁶ is independently selected from H; C ₁ -C ₆ alkyl optionally substituted with hydroxy; C ₁ -C ₆ alkoxy, cyano, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, -C(O)R ⁸ , -C(O)NR ^a R ⁸ , -C(O)R ^c NR ^a R ^b , -C(O)OR ^c R ⁸ , -C(O)ONR ^a R ^b , -R ^c NR ^a C(O)R ⁸ , -R ^c C(O)R ^b , -R ^c C(O)OH, -R ^c C(O)NR ^a R ^b , -R ^c NR ^a C(O)H, -R ^c S(O) _p R ⁸ , -R ^c NR ^a R ^b , -R ^c OR ^b , -S(O) _p R ⁸ , -S(C-)pR ⁸ NR ^a R ^b , -R ^c S(O) _p NR ^a R ^b or -R ^c NR ^a S(O) _p R ⁸ ; or C ₀ -C ₄ alkylaryl, C ₀ -C ₄ alkylC ₃ -C ₆ cycloalkyl, C ₀ -C ₄ alkylheterocycle and C ₀ -C ₄ alkylheteroaryl; wherein the heterocyclic and heteroaryl rings are a 5- or 6-membered monocyclic ring or a 9- or 10-membered fused ring, each containing at least one heteroatom selected from the group consisting of N, O and S; and wherein each aryl, cycloalkyl, heterocyclic and heteroaryl ring is substituted with (R ⁹ ) _n ; or R ⁵ and R ⁶ taken together with the nitrogen atom to which they are attached form a B ring, a 4- to 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 substituted with (R ⁹ ) _n ; and wherein each ring is optionally fused with Y;

R ⁷ is H, C ₁ -C ₆ alkyl, phenyl, -R ^c NR ^a R ^b , -R ^c OR ^b , -R ^c S(O) _p R ^a , -R ^c NR ^a C(O)R ^b , -R ^c C(O)NR ^a R ^b , -R ^c NR ^a C(O)NR ^a R ^b or -R ^c NR ^a C(O)OR ^b ;

R ⁸ is C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₀ -C ₄ alkylC ₃ -C ₆ cycloalkyl, -NR ^a R ^b , phenyl, a 5- or 6-membered heterocyclic ring or a heteroaryl ring, each of which contains at least one heteroatom selected from N, O and S; and wherein each cycloalkyl, phenyl, heterocyclic and heteroaryl rings is substituted with (R ⁹ ) _n , independently selected from the group consisting of methyl, ethyl, isopropyl, methoxy, F, Cl, Br, I, oxo, cyano, -NH ₂ , -N(CH ₃ ) ₂ , -CF ₃ , -CHF ₂ and -OCHF ₂ ;

R ⁹ is independently selected from the group consisting of C ₁ -C ₆ alkyl optionally substituted with hydroxy; C ₁ -C ₆ alkoxy, C ₀ -C ₄ alkyl, _{C 3} -C ₆ cycloalkyl, halogen, oxo, nitro, hydroxy, -R ^c OR ^b , cyano, -NR ^a R ^b , C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, -S(O) _p R ⁸ , -SF ₅ , phenyl; a 5- or 6-membered heterocyclic or heteroaryl ring, each containing at least one heteroatom selected from the group consisting of N, O and S; and wherein the phenyl, heterocyclic and heteroaryl rings are further optionally substituted with F, Cl, cyano or -CF ₃ ;

Y is cyclopentyl, cyclohexyl, phenyl, pyridinyl, pyrimidyl, pyrazolyl, thiophenyl, thiazolyl, triazolyl, isothiazolyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl, furanyl or tetrahydrothiophenyl, each of which is optionally substituted with methyl, F, O, cyano, oxo or _-CF3 ;

m is equal to an integer 1, 2 or 3;

n is an integer 0, 1, 2, or 3; and when n is 2 or 3, then each substituent R ⁹ may be the same or different;

p is an integer 0, 1, or 2;

its stereoisomers or its pharmaceutically acceptable salts.

In another aspect, a composition is provided comprising a compound of formula (1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another aspect, the composition further comprises a pharmaceutically acceptable carrier.

In another aspect, a method for treating or preventing an inflammatory response in an animal is provided by administering to said animal in need thereof a therapeutically effective amount of formula (1), its stereoisomer or a pharmaceutically acceptable salt thereof. In another aspect of the method, the inflammatory response is caused by a bacterial, viral or fungal infection, stress and/or an environmental factor. In another aspect of the method, the method for treating or preventing an inflammatory response in an animal prevents or mitigates the progression of a respiratory disease or disorder. In another aspect of the method, the animal is livestock. 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, the method for treating or preventing an inflammatory response in an animal reduces the regulation of TNFα and IL-6 in the animal.

In another aspect, there is provided the use of a compound of formula (1); a stereoisomer thereof or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating or preventing an inflammatory response in an animal, wherein the inflammatory response is caused by a bacterial, viral or fungal infection, stress and/or an environmental factor. In another aspect of the use, the use of a medicament for treating or preventing an inflammatory response in an animal prevents or mitigates the progression of a respiratory disease or disorder. In another aspect of the use, the animal is livestock. In another aspect of the use, the respiratory disease or disorder is bovine respiratory disease or porcine respiratory disease. In another aspect of the use, administering a medicament to an animal for treating or preventing an inflammatory response in an animal reduces the regulation of TNFα and IL-6 in the animal.

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

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

In another aspect, X' is F, O, 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, each R ⁰ and R ¹ is independently H, methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl or t-butyl; or R ¹ is benzyl, cyclopentyl, cyclohexyl, -CH ₂ pyridinyl, -CH ₂ pyrimidinyl, -CH ₂ pyridazinyl, -CH ₂ pyrazinyl, CH ₂ pyrrolyl, -CH ₂ furanyl, -CH ₂ thiophenyl, -CH ₂ pyrazolyl, -CH ₂ imidazolyl, -CH ₂ -triazolyl, -CH 2 tetrazolyl, -CH ₂ oxazolyl, -CH ₂ isoxazolyl, -CH ₂ thiazolyl, CH ₂ isothiazolyl or -CH ₂ oxadiazolyl, each of which is substituted with (R ⁹ ) _n , independently selected from methyl, ethyl, isopropyl, methoxy, F, Cl, Br, I, oxo, cyano, -NH ₂ , -N(CH ₃ ) _{2 ,} -CF ₃ , _-CHF2 , _-OCHF2 , -S(O) _{2NH2 , -SCH3} , -S(O) _CH3 and -S(O) _2CH3 . In another aspect, each ^R0 and ^R1 is independently H, methyl, ethyl, propyl, isopropyl or _isobutyl ; or R ¹ is benzyl, cyclopentyl, cyclohexyl, -CH ₂ pyridinyl, -CH ₂ pyrimidinyl, -CH ₂ pyrazolyl, -CH ₂ imidazolyl, -CH ₂ -triazolyl, -CH ₂ tetrazolyl, -CH ₂ oxazolyl, -CH ₂ isoxazolyl, -CH ₂ thiazolyl, -CH ₂ isothiazolyl or -CH ₂ oxadiazolyl, each of which is substituted with (R ⁹ ) _n , independently selected from methyl, ethyl, isopropyl, methoxy, F, Cl, Br, I, oxo, cyano, -NH ₂ , -N(CH ₃ ) ₂ , -CF ₃ , -CHF ₂ , -OCHF ₂ , -S(O) ₂ NH ₂ , -SCH ₃ , -S(O)CH ₃ and -S(O) ₂ CH ₃ . In another aspect, R ⁰ is H, methyl, ethyl or propyl; and R ¹ is methyl, ethyl, propyl or isobutyl; or R ¹ is benzyl, cyclopentyl, cyclohexyl, -CH ₂ pyridinyl, -CH 2 pyrimidinyl, -CH ₂ pyrazolyl, -CH ₂ thiazolyl or -CH ₂ imidazolyl, each of which is substituted with (R ⁹ ) _n , independently selected from methyl, ethyl, isopropyl, methoxy, F, Cl, Br, I, oxo, cyano, -NH ₂ , -N(CH ₃ ) ₂ , -CF ₃ , -CHF ₂ , -OCHF ₂ , -S(O) ₂ NH ₂ , -SCH ₃ , -S(O)CH ₃ and -S(O) ₂ CH ₃ . In another aspect, R ⁰ is H, methyl, ethyl or propyl; and R ¹ is methyl, ethyl, propyl or isobutyl; or R ¹ is cyclohexyl, benzyl, -CH ₂ pyridinyl or -CH ₂ thiazolyl; each of which is substituted with (R ⁹ ) _n , independently selected from methyl, ethyl, isopropyl, methoxy, F, Cl, Br, I, oxo, cyano, -NH ₂ , -N(CH ₃ ) ₂ , -CF ₃ , -CHF ₂ , -OCHF ₂ , -S(O) ₂ NH ₂ , -SCH ₃ , -S(O)CH ₃ and -8(O) ₂ CH ₃ . In another aspect, R ⁰ is H or methyl; and R ¹ is methyl, propyl or isobutyl. In another aspect, R ⁰ is H or methyl and R ¹ is methyl.

In another aspect of the invention, R is H; or phenyl, naphthyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl, indolyl, benzimidazolyl or indazolyl, each of which is substituted with (R ⁹ ) _n . In another aspect, R is H; or phenyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, indolyl, benzimidazolyl or indazolyl, each of which is substituted with (R ⁹ ) _n . In another aspect, R is H; or phenyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, triazolyl, thiophenyl, pyridinyl, pyrimidinyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl or indazolyl, each of which is substituted with (R ⁹ ) _n . In another aspect, R is H; or phenyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, triazolyl, thiophenyl, pyridinyl, pyrimidinyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl or indazolyl, each of which is substituted with (R ⁹ ) _n independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, -NH ₂ , -N(CH ₃ ) ₂ , -CF ₃ , -CHF ₂ , -OCHF ₂ , -S(O) ₂ NH ₂ , -SCH ₃ , -S(O)CH ₃ and -S(O) ₂ CH ₃ . In another aspect, R is H; or phenyl, pyrazolyl, imidazolyl, thiazolyl, thiophenyl, pyridinyl or pyrimidinyl, each of which is substituted with (R ⁹ ) _n , independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, -NH ₂ , -N(CH ₃ ) ₂ , -CF ₃ , -CHF ₂ , -OCHF ₂ , -S(O) ₂ NH ₂ , -SCH ₃ , -S(O)CH ₃ and -8(O) ₂ CH ₃ . In another aspect, R is H; or phenyl substituted with (R ⁹ ) _n , independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, -NH ₂ , -N(CH ₃ ) ₂ , -CF ₃ , -CHF ₂ , -OCHF ₂ , -S(O) ₂ NH ₂ , -SCH ₃ , -S(O)CH ₃ and -S(O) ₂ CH ₃ . In another aspect, R is H; or phenyl substituted with (R ⁹ ) _n , independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, -NH ₂ , -N(CH ₃ ) ₂ , -CF ₃ , -CHF ₂ , -OCHF ₂ , -S(O) ₂ NH ₂ , -SCH ₃ , -S(O)CH ₃ and -S(O) ₂ CH ₃ .

In another aspect of the invention, R ² is H, C ₁ -C ₆ alkyl, -CH ₂ CN, -R ^c OR ^b , -R ^c S(O) _p ^Ra , C ₁ -C ₆ haloalkyl, C ₀ -C ₃ alkylC ₃ -C ₆ cycloalkyl, -R ^c NR ^a R ^b , -NR ^a R ^b , pyrrolyl, -CH ₂ pyrrolyl, -CH ₂ CH ₂ pyrrolyl, tetrahydrofuranyl, -CH ₂ tetrahydrofuranyl, -CH ₂ CH ₂ tetrahydrofuranyl, tetrahydrothiophenyl, -CH ₂ tetrahydrothiophenyl, -CH ₂ CH ₂ tetrahydrothiophenyl, tetrahydropyranyl, -CH ₂ tetrahydropyranyl, -CH ₂ CH ₂ tetrahydropyranyl, tetrahydrothiopyranyl, -CH ₂ tetrahydrothiopyranyl, -CH ₂ CH ₂ tetrahydrothiopyranyl, pyrrolidinyl, -CH ₂ pyrrolidinyl, -CH ₂ CH ₂ pyrrolidinyl, piperidinyl, CH ₂ piperidinyl, -CH ₂ CH ₂ piperidinyl, piperazinyl, CH ₂ piperazinyl, -CH ₂ CH ₂ piperazinyl, morpholinyl, -CH ₂ morpholinyl, CH ₂ CH ₂ morpholinyl, furanyl, -CH ₂ furanyl, -CH ₂ CH ₂ furanyl, thiophenyl, -CH ₂ thiophenyl, -CH ₂ CH ₂ thiophenyl, pyrazolyl, -CH ₂ pyrazolyl, -CH ₂ CH ₂ pyrazolyl, imidazolyl, -CH ₂ imidazolyl, -CH ₂ CH ₂ imidazolyl, isoxazolyl, -CH ₂ isoxazolyl, CH ₂ CH ₂ isoxazolyl, oxazolyl, -CH ₂ oxazolyl, -CH ₂ CH ₂ oxazolyl, isothiazolyl, -CH ₂ isothiazolyl, -CH ₂ CH ₂ isothiazolyl, thiazolyl, -CH ₂ thiazolyl, -CH ₂ CH ₂ thiazolyl, triazolyl, -CH ₂ triazolyl, -CH ₂ CH ₂ triazolyl, oxadiazolyl, -CH ₂ oxadiazolyl, -CH ₂ CH ₂ oxadiazolyl, thiadiazolyl, -CH ₂ thiadiazolyl, -CH ₃ CH ₂ thiadiazolyl, tetrazolyl, -CH ₂ tetrazolyl, -CH ₂ CH ₂ tetrazolyl, phenyl, -CH ₂ phenyl (benzyl), -CH ₂ CH ₂ phenyl, pyridinyl, -CH ₂ pyridinyl, -CH ₂ CH ₂ pyridinyl, pyrimidinyl, -CH ₂ pyrimidinyl, -CH ₂ CH ₂ pyrimidinyl, pyridazinyl, -CH ₂ pyridazinyl, -CH ₂ CH ₂ pyridazinyl, pyrazinyl, -CH ₂ pyrazinyl or -CH ₂ CH ₃ pyrazinyl; and wherein each cycloalkyl, phenyl, heterocyclic and heteroaryl ring is substituted with (R ⁹ ) _n , and wherein each ring is optionally fused with Y. In another aspect, R ² is H, C ₁ -C ₆ alkyl, -CH ₂ OCH ₃ , -(CH ₂ ) ₂ OCH ₃ , -CH ₂ CN, -CH ₂ F, -CHF ₂ , -CH ₂ CF ₃ , -CF ₃ , -CH ₂ S(O) ₂ CH ₃ , cyclopropyl, -CH ₂ cyclopropyl, cyclobutyl, -CH ₂ cyclobutyl, cyclopentyl, CH ₂ cyclopentyl, cyclohexyl, -CH ₂ cyclohexyl, -R ^c NR ^a R ^b , -NR ^a R ^b , pyrrolyl, -CH ₂ pyrrolyl, tetrahydrofuranyl, -CH ₂ tetrahydrofuranyl, tetrahydrothiophenyl, CH ₂ tetrahydrothiophenyl, tetrahydropyranyl, -CH ₂ tetrahydropyranyl, tetrahydrothiopyranyl, -CH ₂ tetrahydrothiopyranyl, pyrrolidinyl, -CH ₂ pyrrolidinyl, piperidinyl, -CH ₂ piperidinyl, piperazinyl, -CH ₂ piperazinyl, morpholinyl, -CH ₂ morpholinyl, furanyl, -CH ₂ furanyl, thiophenyl, -CH ₂ thiophenyl, pyrazolyl, -CH ₂ pyrazolyl, imidazolyl, -CH ₂ imidazolyl, isoxazolyl, -CH ₂ isoxazolyl, oxazolyl, -CH ₂ oxazolyl, isothiazolyl, -CH ₂ isothiazolyl, thiazolyl, -CH ₂ thiazolyl, triazolyl, -CH ₂ triazolyl, oxadiazolyl, _{-CH2oxadiazolyl} , thiadiazolyl, _{CH2thiadiazolyl} , tetrazolyl, _{-CH2tetrazolyl} , phenyl, _-CH2phenyl (benzyl), pyridinyl, _{-CH2pyridinyl} , pyrimidinyl, _{-CH2pyrimidinyl} , pyridazinyl, _{CH2pyridazinyl} , pyrazinyl or _{-CH2pyrazinyl} ; and wherein each cycloalkyl, phenyl, heterocyclic and heteroaryl ring is substituted with ( ^R9 ) _n and wherein each ring is optionally fused with Y which is cyclopentyl, cyclohexyl, thiophenyl or phenyl. In another aspect, R ² is H, C ₁ -C ₆ alkyl, -CH ₂ OCH ₃ , -(CH ₂ ) ₂ OCH ₃ , -CH ₂ CN, -CH ₂ F, -CHF ₂ , -CH ₂ CF ₃ , -CF ₃ , -CH ₂ S(O) ₂ CH ₃ , cyclopropyl, -CH ₂ cyclopropyl, cyclobutyl, -CH ₂ cyclobutyl, cyclopentyl, -CH ₂ cyclopentyl, cyclohexyl, -CH 2 cyclohexyl, -CH ₂ cyclohexyl, -R ^c NR ^a R ^b , -NR ^a R ^b , pyrrolyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, phenyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl; and wherein each cycloalkyl, phenyl, heterocyclic and heteroaryl ring is substituted with (R ⁹ ) _n and wherein each ring is optionally fused with Y which is cyclopentyl, cyclohexyl, thiophenyl or phenyl. In another aspect, R ² is H, C ₁ -C ₆ alkyl, -CH ₂ OCH ₃ , -(CH ₂ ) ₂ OCH ₃ , -CH ₂ F, -CH ₂ CF ₃ , -CF ₃ , -CH ₂ S(O) ₂ CH ₃ , -CH ₂ CN, -NHR ^b , -NCH ₂ R ^b , cyclopropyl, -CH ₂ cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl; and wherein each cycloalkyl, phenyl, heterocyclic and heteroaryl ring is substituted with (R ⁹ ) _n , and wherein each ring is optionally fused with Y, which is cyclopentyl, cyclohexyl, thiophenyl or phenyl. In another aspect, R ² is H, C ₁ -C ₆ alkyl, -CH ₂ OCH ₃ , -(CH ₂ ) ₂ OCH ₃ , -CH ₂ CN, -CH ₂ CF ₃ , -CF ₃ , -CH ₂ S(O) ₂ CH ₃ , -NHR ^b or -NCH ₂ R ^b , wherein R ^b is methyl, cyclohexyl, phenyl or pyridinyl, and wherein the phenyl and pyridinyl rings are optionally substituted with F, O, cyano or -CF ₃ ; or R ² is cyclopropyl, -CH ₂ cyclopropyl, cyclohexyl, furanyl, piperidinyl, piperazinyl, pyrrolodinyl, morpholinyl, phenyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl; and when condensed with Y is benzofuranyl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazolyl, benzo[b]thiophenyl, dihydroimidazo[1,2a]pyridinyl, tetrahydroisoquinolinyl or isoindolinyl; and wherein each cycloalkyl, phenyl, heterocyclic and heteroaryl ring is substituted with (R ⁹ ) _n , independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, -NFh, -N(CH ₃ ) ₂ , -CF ₃ , -CHF ₂ , -OCHF ₂ , -S(O) ₂ NH ₂ , -SCH ₃ , -S(O)CH ₃ and -S(O) ₂ CH ₃ ; or R ² is phenyl or pyridinyl, each of which is substituted with morpholine. In another aspect, R ² is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, n-butyl, -CH ₂ OCH ₃ , -(CH ₂ ) ₂ OCH ₃ , -CH ₂ CF ₃ , -CF ₃ , -CH ₂ S(O) ₂ CH ₃ , -NHR ^b or -NCH ₂ R ^b , wherein R ^b is methyl, cyclohexyl, phenyl or pyridinyl, and wherein the phenyl and pyridinyl rings are optionally substituted with F, Cl, cyano or -CF ₃ ; or R ² is cyclopropyl, -CH ₂ cyclopropyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, phenyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, pyridinyl or pyrimidinyl; and wherein each cycloalkyl, phenyl, heterocyclic and heteroaryl rings is substituted with (R ⁹ ) _n , independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, -NH ₂ , -N(CH ₃ ) ₂ , -CF ₃ , -CHF ₂ , -OCHF ₂ , -S(O) ₂ NH ₂ , -SCH ₃ , -S(O)CH ₃ and -S(O) ₂ CH ₃ ; or R ² is phenyl or pyridinyl, each of which is substituted with morpholine. In another aspect, R ² is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, n-butyl, -CH ₂ OCH ₃ , -(CH ₂ ) ₂ OCH ₃ , -CH ₂ CF ₃ , -CF ₃ , -CH ₂ S(O) ₂ CH ₃ , -NHR ^b or -NCH ₂ R ^b , wherein R ^b is methyl, cyclohexyl, phenyl or pyridinyl and wherein the phenyl and pyridinyl rings are optionally substituted with F, Cl, cyano or -CF ₃ ; or R ² is cyclopropyl, -CH ₂ cyclopropyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, phenyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, pyridinyl or pyrimidinyl; and wherein each cycloalkyl, phenyl, heterocyclic and heteroaryl ring is substituted with (R ⁹ ) _n , independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, -NH ₂ , -N(CH ₃ ) ₂ , -CF ₃ , -CHF ₂ , -OCHF ₂ , -S(O) ₂ NH ₂ , -SCH ₃ , -S(O)CH ₃ and -S(O) ₂ CH ₃ ; or R ² is phenyl or pyridinyl, each of which is substituted with morpholine.

In another aspect of the present invention, R and R ² join to form a bond to form a dioxo-oxathiazolyl ring,

wherein R ¹ is as defined herein. In another aspect, R and R ² join to form a bond to form a dioxo-oxathiazolyl ring, wherein R ¹ is H, methyl, phenyl, or benzyl, wherein the phenyl moiety is substituted with (R ⁹ ) _n . In another aspect, R and R ² join to form a bond to form a dioxo-oxathiazolyl ring, wherein R ¹ is H, methyl, phenyl or benzyl, wherein the phenyl moiety is substituted with (R ⁹ ) _n , independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, -NH ₂ , -N(CH ₃ ) ₂ , -CF ₃ , -CHF ₂ , -OCHF ₂ , -S(O) ₂ NH ₂ , -SCH ₃ , -S(O)CH ₃ and -S(O) ₂ CH ₃ . In another aspect, R and R ² join to form a bond to form a dioxo-oxathiazolyl ring, wherein R ¹ is H, methyl, phenyl or benzyl, wherein the phenyl moiety is substituted with (R ⁹ ) _n , independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, -NH ₂ , -N(CH ₃ ) ₂ , -CF ₃ , -CHF ₂ , -OCHF ₂ , -S(O) ₂ NH ₂ , -SCH ₃ , -S(O)CH ₃ and -S(O) ₂ CH ₃ . In another aspect, R and R ² join to form a bond to form a dioxo-oxathiazolyl ring, wherein R ¹ is H, methyl, phenyl or benzyl, wherein the phenyl moiety is substituted with (R ⁹ ) _n , independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, -NH ₂ , -N(CH ₃ ) ₂ , -CF ₃ , -CHF ₂ , -OCHF ₂ , -S(O) ₂ NH ₂ , -SCH ₃ , -S(O)CH ₃ and -S(O) ₂ CH ₃ .

In another aspect of the invention, each R ⁵ and R ⁶ independently represents H; C ₁ -C ₆ alkyl optionally substituted with hydroxy; C ₁ -C ₆ alkoxy, cyano, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, -C(O)R ⁸ , -C(O)NR ^a R ⁸ , -C(O)R ^c NR ^a R ^b , -C(O)OR ^c R ⁸ , -C(O)ONR ^a R ^b , -R ^c NR ^a C(O)R ⁸ , -R ^c C(O)OH, -R ^c C(O)NR ^a R ^b , -R ^c NR ^a C(O)H, -R ^c S(O) _p R ⁸ , -R ^c NR ^a R ^b , -R ^c OR ^b , -S(O) _p R ⁸ , -S(O) _p R ⁸ NR ^a R ^b , -R ^c S(Q)PNR ^a R ^b , -R ^c NR ^a S(O) _p R ⁸ ; C ₀ -C ₄ alkylphenyl, C ₀ -C ₄ alkylC ₃ -C ₆ cycloalkyl, C ₀ -C ₄ alkylheterocycle, C ₀ -C ₄ alkylheteroaryl, wherein each heterocyclic and heteroaryl ring is a 5-6 membered monocyclic ring, and wherein each heterocyclic and heteroaryl ring comprises at least one heteroatom selected from the group consisting of N, O and S; and wherein each phenyl, cycloalkyl ring, heterocyclic ring and heteroaryl ring is substituted with (R ⁹ ) _n - In another aspect, each R ⁵ and R ⁶ is independently H; C ₁ -C ₆ alkyl optionally substituted with hydroxy; C ₁ -C ₆ alkoxy, cyano, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, -C(O)R ⁸ , -C(O)NR ^a R ⁸ , -C(O)R ^c NR ^a R ^b , -C(O)OR ^c R ⁸ , -C(O)ONR ^a R ^b , -R ^c NR ^a C(O)R ⁸ , -R ^c C(O)OH, -R ^c C(O)NR ^a R ^b , -R ^c NR ^a C(O)H, -R ^c S(O) _p R ⁸ , -R ^c NR ^a R ^b , -R ^c OR ^b , -S(O) _p R ⁸ , -S(O) _p R ⁸ NR ^a R ^b , -R ^c S(O) _p NR ^a R ^b , -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 -C ₂ morpholinyl; pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, _C1 - _C2 alkylpyrazolyl, _C1 - _C2 alkylimidazolyl, _C1 - _C2 alkyltriazolyl, _C1 - _C2 alkyltetrazolyl, C1- _C2 alkyloxazolyl, _C1 - _C2 alkylpyridinyl, _{C1 - C2} alkylpyridazinyl, _C1 - _C2 alkylpyrimidinyl or _C1 - _C2 alkylpyrazinyl; and wherein each phenyl, cycloalkyl ring, heterocyclic ring and heteroaryl ring is substituted with ( ^R9 ) _n . In another aspect, each ^R5 and ^R6 is independently H; _C1 - _C6 alkyl optionally substituted with hydroxy; C ₁ -C ₆ alkoxy, cyano, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, -C(O)R ⁸ , -C(O)NR ^a R ⁸ , -C(O)R ^c NR ^a R ^b , -C(O)ONR ^a R ^b , -R ^c NR ^a C(O)R ⁸ , -R ^c C(O)NR ^a R ^b , -R ^c NR ^a C(O)H, -R ^c S(O) _p R ⁸ , -R ^c NR ^a R ^b , S(O) _p R ⁸ , -S(O) _p R ⁸ NR ^a R ^b , -R ^c S(O) _p NR ^a R ^b ; phenyl, 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 alkylimidazolyl, _C1 - _C2 alkylpyridinyl, _C1 - _C2 alkylpyrimidinyl or _C1 - _C2 alkylpyrazinyl; and wherein each phenyl, cycloalkyl ring, heterocyclic ring and heteroaryl ring is substituted with ( ^R9 ) _n independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, _-NH2 , -N( _CH3 ) ₂ , _-CF3 , _-CHF2 , _-OCHF2 , -S(O) _2NH2 , _-SCH3 , -S(O) _CH3 and _{-S(O)2CH3 .} In another aspect _, each ^R5 and ^R6 is independently H; C ₁ -C ₆ alkyl optionally substituted with 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 ^b , -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 piperidinyl, 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 alkyl pyrazinyl; and wherein each phenyl, cycloalkyl ring, heterocyclic ring and heteroaryl ring is substituted with (R ⁹ ) _n , independently selected from the group of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, -NH ₂ , -N(CH ₃ ) ₂ , -CF ₃ , -CHF ₂ , -OCHF ₂ , -S(O) ₂ NH ₂ , -SCH ₃ , -S(O)CH ₃ and -S(O) ₂ CH ₃ . In another aspect, each R ⁵ and R ⁶ is independently H; C ₁ -C ₆ alkyl optionally substituted with hydroxy; C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, -OCF ₃ , -C(O)NR ^a R ⁸ , -R ^c S(O) _p R ⁸ , -R ^c NR ^a R ^b , -R ^c OR ^b , -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 alkylimidazolyl, _C1 - _C2 alkylpyridinyl, _C1 - _C2 alkylpyrimidinyl or _C1 - _C2 alkylpyrazinyl; and wherein each phenyl, cycloalkyl ring, heterocyclic ring and heteroaryl ring is substituted with ( ^R9 ) _n independently selected from methyl, ethyl, isopropyl, methoxy, ethoxy, F, Cl, Br, I, oxo, hydroxy, cyano, nitro, _-NH2 , _-NHCH3 , -N( _CH3 ) ₂ , _-CF3 , -CHF2, _-CH2F , _-OCF3 , _-OCHF2 , _{-S(O)2NH2 , -SCH3 ,} -S(O) _CH3 and -S(O) _{2CH3 .} In another aspect, R ⁵ is H, C ₁ -C ₆ alkyl, morpholinyl, piperidinyl, -CH ₂ morpholinyl, -CH ₂ piperidinyl, -(CH ₂ ) ₂ morpholinyl, or (CH ₂ ) ₂ piperidinyl. In another aspect, R ⁵ is H, methyl, ethyl, propyl, isopropyl, -CH ₂ morpholinyl, -CH ₂ piperidinyl, -(CH ₂ ) ₂ morpholinyl, or (CH ₂ ) ₂ piperidinyl. In another aspect, R ⁵ is H, methyl, ethyl, propyl, or isopropyl. In another aspect, R ⁶ is H; C ₁ -C ₆ alkyl optionally substituted with hydroxy; C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, -OCF ₃ , -C(O)NR ^a R ⁸ , -R ^c S(O) _p R ⁸ , -R ^c NR ^a R ^b , -R ^c OR ^b , -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 alkylimidazolyl, _C1 - _C2 alkylpyridinyl, _C1 - _C2 alkylpyrimidinyl or _C1 - _C2 alkylpyrazinyl; and wherein each phenyl, cycloalkyl ring, heterocyclic ring and heteroaryl ring is substituted with ( ^R9 ) _n independently selected from methyl, ethyl _, isopropyl, methoxy, F, Cl, Br, I, oxo, cyano, _-NH2 , -N( _{CH3 ) 2} , -CF3, _-CHF2 , _-OCHF2 , -S(O) _2NH2 , _-SCH3 , -S( _O ) _CH3 and -S(O) _2CH3 . In another aspect, R ⁶ is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, methoxy, ethoxy, -CH ₂ CF ₃ , -CF ₃ , -OCF ₃ ; -C(O)NR ^a R ⁸ , wherein ^Ra 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 , wherein R ⁸ is methyl or phenyl; -CH ₂ NR ^a R ^b or -(CH ₂ ) ₂ NR ^a R ^b , wherein each ^Ra and R ^b is 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 phenyl, cycloalkyl ring, heterocyclic ring and heteroaryl ring is substituted with (R ⁹ ) _n , independently selected from methyl, ethyl, isopropyl, methoxy, F, Cl, Br, I, oxo, cyano, -NH ₂ , -N(CH ₃ ) ₂ , -CF ₃ , -CHF ₂ , -OCHF ₂ , -S(O) ₂ NH ₂ , -SCH ₃ , -S(O)CH ₃ and -S(O) ₂ CH ₃ .

In another aspect of the invention, R ⁵ and R ⁶ , taken together with the nitrogen atom to which they are attached, form a ring B, a 4- to 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 substituted with (R ⁹ ) _n ; and wherein each ring is further optionally fused with Y which is phenyl, pyridinyl, pyrimidyl, pyrazolyl, thiophenyl, thiazolyl or triazolyl. In another aspect, R ⁵ and R ⁶ , taken together with the nitrogen atom to which they are attached, form a ring B, a 4- to 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 substituted with (R ⁹ ) _n ; and wherein each ring is further optionally fused with Y which is phenyl, pyridinyl or pyrimidyl. In another aspect, R ⁵ and R ⁶ , taken together with the nitrogen atom to which they are attached, form a ring B which is azetidinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, each of which is substituted with (R ⁹ ) _n , independently selected from methyl, ethyl, isopropyl, methoxy, F, Cl, Br, I, oxo, cyano, -NH ₂ , -N(CH ₃ ) ₂ , -CF ₃ , -CHF ₂ , -OCHF ₂ , -S(O) ₂ NH ₂ , -SCH ₃ , -S(O)CH ₃ and -S(O) ₂ CH ₃ ; and wherein each ring is further optionally fused with Y, which is phenyl or pyridinyl. In another aspect, R ⁵ and R ⁶ , taken 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 substituted with (R ⁹ ) _n , independently selected from methyl, ethyl, isopropyl, methoxy, F, Cl, Br, I, oxo, cyano, -NH ₂ , -N(CH ₃ ) ₂ , -CF ₃ , -CHF ₂ , -OCHF ₂ , -S(O) ₂ NH ₂ , -SCH ₃ , -S(O)CH ₃ and -S(O) ₂ CH ₃ ; and wherein each ring is further optionally fused with Y, which is phenyl. In another aspect, R ⁵ and R ⁶ , taken 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 substituted with (R ⁹ ) _n , independently selected from methyl, ethyl, isopropyl, methoxy, F, Cl, Br, I, oxo, cyano, -NH ₂ , -N(CH ₃ ) ₂ , -CF ₃ , -CHF ₂ , -OCHF ₂ , -S(O) ₂ NH ₂ , -SCH ₃ , -S(O)CH ₃ and -S(O) ₂ CH ₃ ; and wherein each ring is further optionally fused with Y, which is phenyl. In another aspect, R ⁵ and R ⁶ , taken 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 substituted with (R ⁹ ) _n , independently selected from methyl, ethyl, isopropyl, methoxy, F, Cl, Br, I, oxo, cyano, -NH ₂ , -N(CH ₃ ) ₂ , -CF ₃ , -CHF ₂ , -OCHF ₂ , -S(O) ₂ NH ₂ , -SCH ₃ , -S(O)CH ₃ and -S(O) ₂ CH ₃ ; or when condensed with Y, which is phenyl, ring B is indolinyl, isoindolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, or dihydrobenzooxazinyl. In another aspect, R ⁵ and R ⁶ , taken 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 substituted with (R ⁹ ) _n , independently selected from methyl, ethyl, isopropyl, methoxy, F, Cl, Br, I, oxo, cyano, -NH ₂ , -N(CH ₃ ) ₂ , -CF ₃ , -CHF ₂ , -OCHF ₂ , -S(O) ₂ NH ₂ , -SCH ₃ , -S(O)CH ₃ and -S(O) ₂ CH ₃ .

In another aspect of the invention, R ⁷ is H, C ₁ -C ₆ alkyl, phenyl, -(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)CH ₃ , -(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 of 1, 2, or 3. In another aspect, R ⁷ is H, C ₁ -C ₆ alkyl, phenyl, -(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 of 1 or 2. In another aspect of the invention, R ⁷ is H, C ₁ -C ₆ alkyl, phenyl, -(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, t-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 is C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, -NR ^a R ^b ; or C ₀ -C ₄ alkyl _{C 3} -C ₆ cycloalkyl, phenyl, pyrrolyl, pyrazolyl, pyridinyl or pyrimidinyl, each of which is substituted with (R ⁹ ) _n , independently selected from the group consisting of methyl, ethyl, isopropyl, methoxy, F, Cl, Br, I, oxo, cyano, -NH ₂ , -N(CH ₃ ) ₂ , -CF ₃ , -CHF ₂ and -OCHF ₂ . In another aspect, R ⁸ is methyl, ethyl, propyl; or cyclopropyl, Clalkylcyclopropyl, phenyl or pyridinyl, each of which is substituted with (R ⁹ ) _n , independently selected from the group consisting of methyl, ethyl, isopropyl, methoxy, F, Cl, Br, I, oxo, cyano, -NH ₂ , -N(CH ₃ ) ₂ , -CF ₃ , -CHF ₂ and -OCHF ₂ . In another aspect, R ⁸ is methyl, ethyl; or cyclopropyl, or phenyl, each of which is optionally substituted with one or two substituents independently selected from the group consisting of methyl, methoxy, F, O, Br, oxo, cyano and -CF 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, -CH ₂ OH, nitro, cyano, -NR ^a R ^b , C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, -S(O) _p R ⁸ ; or phenyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, piperazinyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl, each of which is further optionally substituted with fluoro, chloro, cyano or _-CF3 . 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, -CH ₂ OH, nitro, cyano, -NR ^a R ^b , C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, -S(O) _p R ⁸ ; or phenyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, pyridinyl, pyrimidinyl and pyrazinyl, each of which is optionally substituted with fluoro, chloro, cyano or -CF ₃ . 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, -CH ₂ OH, nitro, cyano, -NR ^a R ^b , C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, -S(O) _p R ⁸ ; or phenyl, piperidinyl, morpholinyl, piperazinyl and pyridinyl, each of which is optionally substituted with fluoro, chloro, cyano or -CF ₃ . 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, -CH ₂ OH, cyano, nitro, -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -N(CH ₂ CH ₃ ) ₂ , -CHF ₂ , -CF ₃ , -CH ₂ F, -OCHF ₂ , -OCF ₃ , -S(O) ₂ NH ₂ , -SCH ₃ , -S(O)CH ₃ , -S(O) ₂ CH ₃ ; or phenyl, piperidinyl, morpholinyl, piperazinyl and pyridinyl, each of which is optionally substituted with fluoro, chloro, cyano or -CF ₃ . In another aspect, R ⁹ is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, -NH ₂ , -N(CH ₃ ) ₂ , -CF ₃ , -CHF ₂ , -OCHF ₂ , -S(O) ₂ NH ₂ , -SCH ₃ , -S(O)CH ₃ and -S(O) ₂ CH ₃ ; or phenyl, piperidinyl, morpholinyl, piperazinyl and pyridinyl, each of which is optionally substituted with fluoro, chloro, cyano or -CF ₃ . In another aspect, R ⁹ is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, -NH ₂ , -N(CH ₃ ) ₂ , -CF ₃ , -CHF ₂ , -OCHF ₂ , -S(O) ₂ NH ₂ , -SCH ₃ , -S(O)CH ₃ and -8(O) ₂ CH ₃ . In another aspect, each R ⁹ is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, -NH ₂ , -N(CH ₃ ) ₂ , -CF ₃ , -CHF ₂ , -OCHF ₂ , -S(O) ₂ NH ₂ , -SCH ₃ , -S(O)CH ₃ and -S(O) ₂ CH ₃ . In yet another aspect, each R ⁹ is independently selected from the group consisting of methyl, methoxy, F, Cl, Br, I, oxo, cyano, -NHCH ₃ , -N(CH ₃ ) ₂ and -CF ₃ .

In another aspect of the invention, X is ^Ra , ( _CH2 ) _mNR5R6 , -(CH2 ₎ ^mOR7 , -( _CH2 ) ^mSR7 , -( _CH2 ) ^mN3 , -( _{CH2 ) mCN} , or - ⁽ _CH2 ) _{mX ' ;} wherein m is an integer of 1 or 2. In another aspect _, X is ^Ra . In another aspect ^, X is _CH2NR5R6 . In another aspect, X is ^-CH2OR7 . In another aspect, X is _-CH2SR7 . In another aspect, X _{is -CH2N3 .} In another aspect ^, _{X is -CH2CN .} In another aspect ^, X is _CH2X '.

In another aspect of the invention, Y is cyclopentyl, cyclohexyl, phenyl, pyridinyl, pyrimidyl, pyrazolyl, thiophenyl, thiazolyl, triazolyl, isothiazolyl, pyrrolyl, imidazolyl or tetrahydrothiophenyl, each of which is optionally substituted with methyl, F, O, cyano, oxo or _-CF3 . In another aspect, Y is cyclopentyl, cyclohexyl, phenyl, pyridinyl, thiophenyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl or tetrahydrothiophenyl, each of which is optionally substituted with methyl, F, O, cyano, oxo or _-CF3 . In another aspect, Y is cyclopentyl, cyclohexyl, phenyl, pyridinyl, thiophenyl, thiazolyl or tetrahydrothiophene, each of which is optionally substituted with methyl, F, O, cyano, oxo or _-CF3 . In another aspect, Y is cyclopentyl, phenyl or thiophenyl, each of which is optionally substituted with methyl, F, O, cyano, oxo or _-CF3 . In another aspect, Y is cyclopentyl, phenyl or thiophenyl. In another aspect, when Y is fused to a 5- or 6-membered heterocyclic or heteroaryl ring, the fused moiety is selected from benzofuranyl, 6,7-dihydro-5H-pyrrolo[1,2-a]imidazolyl, thieno[3,2b]pyridinyl, 3,4-dihydroisoquinolinyl, isoindolinyl and imidazo[1,2-a]pyridinyl.

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 yet another aspect, n is the integer 0 or 1. In yet another aspect, n is the integer 0. In yet another aspect, n is the integer 1. In yet another aspect, n is the integer 2.

In another aspect, there is provided a compound of formula (1), wherein W is formula (A), which is

formula (1A), wherein R, R ⁰ , R ¹ , R ² and X are as defined herein, the stereoisomers thereof and the pharmaceutically acceptable salts thereof. In another aspect, a compound of formula (1A), wherein R ⁰ is H, methyl, ethyl or propyl; and R is H, phenyl, or a 5- or 6-membered heteroaryl ring containing at least one heteroatom selected from N, O and S; and wherein the phenyl and heteroaryl ring are substituted with (R ⁹ ) _n ; R ¹ is C ₁ -C ₆ alkyl or cyclohexyl; or R ¹ is benzyl, -CH ₂ pyridinyl or -CH ₂ thiazolyl, each of which is substituted with (R ⁹ ) _n , independently selected from methyl, fluoro, chloro, methoxy, cyano and -CF ₃ ; R ² , n and X are as defined herein; or R and R ² join to form bonds to form a dioxo-oxathiazolyl ring, stereoisomers thereof and pharmaceutically acceptable salts thereof. In another aspect, there is provided a compound of formula (1A), wherein R ⁰ is H, methyl, ethyl or propyl; and R is H or phenyl, pyridinyl or thiophenyl, each of which is substituted with (R ⁹ ) _n ; R ¹ is C ₁ -C ₆ alkyl or cyclohexyl; or R ¹ is benzyl, -CH ₂ pyridinyl or -CH ₂ thiazolyl, each of which is substituted with (R ⁹ ) _n , independently selected from methyl, ethyl, isopropyl, methoxy, F, Cl, Br, I, oxo, cyano, -NH ₂ , -N(CH ₃ ) ₂ , -CF ₃ , -CHF ₂ , -OCHF ₂ , -S(O) ₂ NH ₂ , -SCH ₃ , -S(O)CH ₃ and -S(O) ₂ CH ₃ ; R ² , n and X are defined herein; the stereoisomers thereof and the pharmaceutically acceptable salts thereof.

In another aspect, a composition is provided comprising a compound of formula (1A), a stereoisomer thereof, and a pharmaceutically acceptable salt thereof. In another aspect, the composition further comprises a pharmaceutically acceptable carrier.

In another aspect, a method for treating or preventing an inflammatory response in an animal is provided by administering to said animal in need thereof a therapeutically effective amount of formula (1A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another aspect of the method, the inflammatory response is caused by a bacterial, viral, or fungal infection, stress, and/or an environmental factor. In another aspect of the method, the method for treating or preventing an inflammatory response in an animal prevents or mitigates the progression of a respiratory disease or disorder. In another aspect of the method, the animal is livestock. 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, the method for treating or preventing an inflammatory response in an animal reduces the regulation of TNFα and IL-6 in the animal.

In another aspect, there is provided the use of a compound of formula (1A); a stereoisomer thereof or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating or preventing an inflammatory response in an animal, wherein the inflammatory response is caused by a bacterial, viral or fungal infection, stress and/or an environmental factor. In another aspect of the use, the use of a medicament for treating or preventing an inflammatory response in an animal prevents or mitigates the progression of a respiratory disease or disorder. In another aspect of the use, the animal is livestock. In another aspect of the use, the respiratory disease or disorder is bovine respiratory disease or porcine respiratory disease. In another aspect of the use, administering a medicament to an animal for treating or preventing an inflammatory response in an animal downregulates TNFα and IL-6 in the animal.

In another aspect of the present invention, formula (A) is selected from the group consisting of: formula (AO), formula (A1), formula (A2), formula (A3), formula (A4), formula (A5) or formula (A6)

stereoisomers thereof and pharmaceutically acceptable salts thereof. In another aspect, the compound of formula (A) is formula (AO). 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, a preferred formula (A) is formula (A1).

In another aspect of the present invention, there is provided a compound of formula (1), wherein W is H, which is a compound of formula (1.1), wherein B.0, B, R ¹ and R ² 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 is H, methyl, ethyl or propyl; and R, R ¹ and R ² 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 is H or phenyl substituted with (R ⁹ ) _n ; R ⁰ is H, methyl, ethyl or propyl; R ¹ is methyl, ethyl, propyl, isopropyl, isobutyl or cyclohexyl; or R ¹ is benzyl, -CH ₂ pyridinyl or -CH ₂ thiazolyl, each of which is substituted with (R ⁹ ) _n ; and wherein each R ⁹ is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, -NH ₂ , -N(CH ₃ ) ₂ , -CF ₃ , -CHF ₂ , -OCHF ₂ , -S(O) ₂ NH ₂ , -SCH ₃ , -S(O)CH ₃ and -S(O) ₂ CH ₃ ; R ² and n are defined herein, the stereoisomers thereof and the pharmaceutically acceptable salts thereof. In another aspect, a compound of formula (1,1) is provided, wherein R is H or phenyl substituted with (R ⁹ ) _n ; R ⁰ is H, methyl, ethyl or propyl; R ¹ is methyl, ethyl, propyl or cyclohexyl; or R ¹ is benzyl, -CH ₂ pyridinyl or -CH ₂ thiazolyl, each of which is substituted with (R ⁹ ) _n ; R ² is cyclopropyl, cyclopentyl, cyclohexyl, 6,7-dihydro-5H-pyrrolo[1,2- a ]imidazolyl; or R ² is phenyl, thiophenyl, benzofuranyl, thiazolyl, imidazolyl, pyridinyl or -NHphenyl, each of which is substituted with (R ⁹ ) _n ; or R ² is phenyl or pyridinyl, each of which is substituted with morpholine; and wherein each R ⁹ is independently selected from methyl, ethyl, isopropyl, methoxy, F, Cl, Br, I, oxo, cyano, -NH ₂ , -N(CH ₃ ) ₂ , -CF ₃ , -CHF ₂ , -OCHF ₂ , -S(O) ₂ NH ₂ , -SCH ₃ , -S(O)CH ₃ , -S(O) ₂ CH ₃ and morpholine; and wherein n is as defined herein, the stereoisomers thereof and the pharmaceutically acceptable salts thereof. In another aspect, a compound of formula (1.1) is provided wherein R is H or phenyl substituted with (R ⁹ ) _n ; R ⁰ is H or methyl; R ¹ is methyl; R ² is cyclopropyl, cyclohexyl, 6,7-dihydro-5H-pyrrolo[1,2 -a ]imidazolyl; or R ² is phenyl, thiophenyl, benzofuranyl, thiazolyl, imidazolyl, pyridinyl or -NHphenyl, each of which is substituted with (R ⁹ ) _n ; or R ² is phenyl or pyridinyl, each of which is substituted with morpholine; and wherein each R ⁹ is independently selected from methyl, ethyl, isopropyl, methoxy, F, Cl, Br, I, oxo, cyano, -NH ₂ , -N(CH ₃ ) ₂ , -CF ₃ , -CHF ₂ , -OCHF ₂ , -S(O) ₂ NH ₂ , -SCH ₃ , -S(O)CH ₃ and -S(O) ₂ CH ₃ ; a wherein n is defined herein, the stereoisomers thereof and the pharmaceutically acceptable salts thereof. In another aspect, there is provided a compound of formula (1.1) wherein R is H or phenyl substituted with (R ⁹ ) _n ; R ⁰ is H or methyl; R ¹ is methyl; R ² is cyclopropyl, cyclohexyl or 6,7-dihydro-5H-pyrrolo[1,2 -a ]imidazolyl; or R ² is phenyl, thiophenyl, benzofuranyl, thiazolyl, imidazolyl, pyridinyl or -NHphenyl, each of which is substituted with (R ⁹ ) _n ; and wherein each R ⁹ is independently selected from methyl, ethyl, isopropyl, methoxy, F, Cl, Br, I, oxo, -NO ₂ , cyano, -NH ₂ , -N(CH ₃ ) ₂ , -CF ₃ , -CHF ₂ , -OCHF ₂ , -S(O) ₂ NH ₂ , -SCH ₃ , -S(O)CH ₃ , and -S(O) ₂ CH ₃ ; or R ² is phenyl or pyridinyl, each of which is substituted with morpholine; and wherein n is an integer of 0, 1, or 2, the stereoisomers thereof, and the pharmaceutically acceptable salts thereof. In another aspect, a compound of formula (1.1) is provided, wherein R is H or phenyl substituted with (R ⁹ ) _n ; R ⁰ is H or methyl; R ¹ is methyl; R ² is phenyl substituted with (R ⁹ ) _n ; and wherein each R ⁹ is independently selected from methyl, methoxy, F, O, Br, cyano and -CF ₃ ; and wherein n is an integer of 0, 1 or 2, its stereoisomers and pharmaceutically acceptable salts thereof. In another aspect, there is provided a compound of formula (1.1), which is a compound of Table A, its stereoisomers and pharmaceutically acceptable salts thereof. In another aspect, there is provided a non-antibacterial compound of formula (1.1) of Table A, its stereoisomers and pharmaceutically acceptable salts thereof. In another aspect, there is provided a compound of formula (1), which is a compound of formula (1.1), which is example A-9, its stereoisomers and pharmaceutically acceptable salts thereof.

In another aspect, there is provided a composition comprising a compound of formula (1.1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another aspect, there is provided a composition comprising a non-antibacterial compound of formula (1.1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another aspect, there is provided a composition comprising a compound of formula (1.1) of Table A, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another aspect, there is provided a composition comprising a non-antibacterial compound of formula (1.1) of Table A, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another aspect, there is provided a composition comprising a non-antibacterial compound of formula (1.1) of Table A, which is example A-9, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another aspect, the composition further comprises a pharmaceutically acceptable carrier.

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 formula (1.1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another aspect, there is provided a method of treating or preventing an inflammatory response in an animal by administering to said animal in need thereof a therapeutically effective amount of a non-antibacterial compound of formula (1.1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another aspect, there is provided a method of treating or preventing an inflammatory response in an animal by administering to said animal in need thereof a therapeutically effective amount of a non-antibacterial compound of formula (1.1) of Table A, which is example A-9, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another aspect of the method, the inflammatory response in the animal is caused by a bacterial, viral or fungal infection, stress and/or an environmental factor. In another aspect of the method, treating or preventing the inflammatory response in the animal prevents or mitigates the progression of a respiratory disease or disorder in the animal. In another aspect of the method, the animal is livestock; and wherein the respiratory disease or disorder is bovine respiratory disease or porcine respiratory disease. In another aspect of the method, IL-6 and TNF-α are downregulated in animals.

In another aspect, there is provided the use of a compound of formula (1.1); a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating or preventing an inflammatory response in an animal. In another aspect, there is provided the use of a non-antibacterial compound of formula (1.1); a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating or preventing an inflammatory response in an animal. In another aspect, there is provided the use of a non-antibacterial compound of formula (1.1) of Table A; a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating or preventing an inflammatory response in an animal. In another aspect, there is provided the use of a non-antibacterial compound of formula (1.1) of Table A, which is example A-9; a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating or preventing an inflammatory response in an animal. In another aspect of the use, the inflammatory response is caused by a bacterial, viral, or fungal infection, stress, and/or an environmental factor. In another aspect of the use, the use of a medicament for treating or preventing an inflammatory response in an animal prevents or mitigates the progression of a respiratory disease or disorder. In another aspect of the use, the animal is livestock. In another aspect of the use, the respiratory disease or disorder is bovine respiratory disease or porcine respiratory disease. In another aspect of the use, administering a medicament to an animal for treating or preventing an inflammatory response in the animal reduces the regulation of TNF-α and IL-6 in the animal.

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

wherein R, R ^a , R ⁰ , R ¹ and R ² are as defined herein, the stereoisomers thereof and pharmaceutically acceptable salts thereof. In another aspect, there is provided a compound of formula (1-A0), wherein R ^a is H, methyl or ethyl; R ⁰ is H, methyl, ethyl or propyl; and R, R ¹ and R ² are as defined herein, the stereoisomers thereof and pharmaceutically acceptable salts thereof. In another aspect, there is provided a compound of formula (1-A0), wherein R ^a is H or methyl; R ⁰ is H, methyl, ethyl or propyl; and R, R ¹ and R ² are as defined herein, the stereoisomers thereof and pharmaceutically acceptable salts thereof. In another aspect, there is provided a compound of formula (1-A0), wherein R ^a is H; R ⁰ is H, methyl, ethyl or propyl; and R, R ¹ and R ² are as defined herein, the stereoisomers thereof and pharmaceutically acceptable salts thereof. In another aspect, there is provided a compound of formula (1-A0), wherein R ^a is H; R ⁰ is H, methyl, ethyl, or propyl; R ¹ is C ₁ -C ₆ alkyl or cyclohexyl; or R ¹ is benzyl, -CH ₂ pyridinyl, or -CH ₂ thiazolyl, each of which is substituted with (R ⁹ ) _n ; R is H, or R is phenyl, thiophenyl, or pyridinyl, each of which is substituted with (R ⁹ ) _n ; and wherein R ² , R ⁹ and n are as defined herein; or R and R ² join to form a bond to form a dioxo-oxathiazolyl ring; stereoisomers thereof and pharmaceutically acceptable salts thereof. In another aspect, there is provided a compound of formula (1-A0), wherein R ^a is H; R ⁰ is H, methyl, ethyl, or propyl; R ¹ is C ₁ -C ₆ alkyl or cyclohexyl; or R ¹ is benzyl, -CH ₂ pyridinyl or -CH ₂ thiazolyl, each of which is substituted with (R ⁹ ) _n ; R is H, or R is phenyl, thiophenyl or pyridinyl, each of which is substituted with (R ⁹ ) _n ; and wherein R ² is defined herein; and wherein each R ⁹ is independently selected from halogen, methyl, ethyl, isopropyl, methoxy, -CF ₃ , cyano, nitro, oxo, amino, -N(CH ₃ ) ₂ , -S(O)CH ₃ , -S(O) ₂ CH _{3 , -SCH 3 and} -S(O) ₂ NH ₂ ; and n is an integer of 0, 1 or 2; or R and R ² join to form a bond to form a dioxo-oxathiazolyl ring; stereoisomers thereof and pharmaceutically acceptable salts thereof. In another aspect, there is provided a compound of formula (1-A0) wherein R ^a is H; R ⁰ is H, methyl, ethyl or propyl; R ¹ is C ₁ -C ₆ alkyl or cyclohexyl; or R ¹ is benzyl, -CH ₂ pyridinyl or -CH ₂ thiazolyl, each of which is substituted with (R ⁹ ) _n ; R is H, or R is phenyl, thiophenyl or pyridinyl, each of which is substituted with (R ⁹ ) _n ; R ² is phenyl, thiophenyl, benzofuranyl, thiazolyl, imidazolyl, pyridinyl or -NHphenyl, each of which is substituted with (R ⁹ ) _n ; or R ² is phenyl or pyridinyl, each substituted with morpholine; and wherein each R ⁹ is independently selected from methyl, ethyl, isopropyl, methoxy, F, Cl, Br, I, oxo, cyano, -NH ₂ , -N(CH ₃ ) ₂ , -CF ₃ , -CHF 2 , -OCHF ₂ , -S(O) ₂ NH ₂ , -SCH ₃ , -S(O)CH ₃ and -S(O) ₂ CH ₃ ; an is an integer of 0, 1 or 2 _, the stereoisomers thereof and the pharmaceutically acceptable salts thereof. In another aspect, a compound of formula (1-A0) is provided, wherein both ^Ra and R ⁰ are H; R ¹ is methyl; R is H, or R is phenyl, thiophenyl or pyridinyl, each of which is substituted with (R ⁹ ) _n ; R ² is phenyl, thiophenyl, benzofuranyl, thiazolyl, imidazolyl, pyridinyl or -NHphenyl, each of which is substituted with (R ⁹ ) _n ; or R ² is phenyl or pyridinyl, each of which is substituted with morpholine; and wherein each R ⁹ is independently selected from halogen, methyl, ethyl, isopropyl, methoxy, -CF ₃ , cyano, nitro, oxo, amino, -N(CH ₃ ) ₂ , -S(O)CH ₃ , -S(O) ₂ CH ₃ , -SCH ₃ and -S(O) ₂ NH ₂ ; an is an integer of 0, 1 or 2; stereoisomers thereof and pharmaceutically acceptable salts thereof.

In another aspect, a composition is provided comprising a compound of formula (1-A0), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another aspect, a composition is provided comprising a non-antibacterial compound of formula (1-A0), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another aspect, the composition further comprises a pharmaceutically acceptable carrier.

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 formula (1-A0), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another aspect, there is provided a method of treating or preventing an inflammatory response in an animal by administering to said animal in need thereof a therapeutically effective amount of a non-antibacterial compound of formula (1-A0), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another aspect of the method, the inflammatory response in the animal is caused by a bacterial, viral, or fungal infection, stress, and/or an environmental factor. In another aspect of the method, treating or preventing an inflammatory response in an animal prevents or mitigates the progression of a respiratory disease or disorder in the animal. In another aspect of the method, the animal is livestock; and wherein the respiratory disease or disorder is bovine respiratory disease or porcine respiratory disease. In another aspect of the method, IL-6 and TNF-α are downregulated in animals.

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

In another aspect of the present invention, there is provided a compound of formula (1), wherein W is formula (A) and formula (A) is formula (A1), which is represented by a compound of formula (1-A1),

wherein R, R ⁰ , R ¹ , R ² , R ⁵ and R ⁶ are as defined herein, the stereoisomers thereof and the pharmaceutically acceptable salts thereof. In another aspect, there is provided a compound of formula (1-A1) wherein R ⁰ is H, methyl, ethyl or propyl; and R, R ¹ , R ² , R ⁵ and R ⁶ are as defined herein, the stereoisomers thereof and the pharmaceutically acceptable salts thereof. In another aspect, there is provided a compound of formula (1-A1) wherein R ⁰ is H, methyl, ethyl or propyl; R is H or phenyl, pyridinyl or thiophenyl, each substituted with (R ⁹ ) _n ; R ¹ is C ₁ -C ₆ alkyl, cyclohexyl; or R ¹ is or benzyl, -CH ₂ pyridinyl or -CH ₂ thiazolyl, each substituted with (R ⁹ ) _n ; R ² is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, n-butyl, -CH ₂ OCH ₃ , -(CH ₂ ) ₂ OCH ₃ , -CH ₂ CF ₃ , -CF ₃ , -NHR ^b , -NCH ₂ R ^b , wherein R ^b is methyl, cyclohexyl, phenyl or pyridinyl, and wherein the phenyl and pyridinyl rings are optionally substituted with F, Cl, cyano or -CF ₃ ; or R ² is cyclopropyl, -CH ₂ cyclopropyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, phenyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, pyridinyl or pyrimidinyl, each of which is substituted with (R ⁹ ) _n ; or R ² is phenyl or pyridinyl, each of which is substituted with morpholine; each R ⁵ and R ⁶ independently is H; C ₁ -C ₆ alkyl optionally substituted with hydroxy; C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, -OCF ₃ , -C(O)NR ^a R ⁸ , -R ^c S(O) _P R ⁸ , -R ^c NR ^a R ^b , -R ^c OR ^b or -S(O)PR ⁸ ; or _C0 - _C3 alkylphenyl, C0 _{- C3} alkylC3 _{-C6 cycloalkyl} , C0- _{C3 alkyloxazolidinyl, C0-C3 alkylpyrrolidinyl , C0-} C3 alkylpiperidinyl, _C0 - _C3 alkylpiperazinyl, C0 _{- C3} alkylmorpholinyl, _C0 - _C3 alkyltetrahydropyranyl, _C0 - _C3 alkyltetrahydrofuranyl, _C0 - _C3 alkylpyrazolyl, C0- _C3 alkylimidazolyl, _{C0 - C3} alkylpyridinyl, _C0 - _C3 alkylpyrimidinyl, _{C0 - C3} alkylpyridazinyl, _C0 - _C3 alkylthiazolyl, or _C0 - _C3 alkylpyrazinyl, _each of which substituted with (R ⁹ ) _n , or R ⁵ and R ⁶ taken together with the nitrogen atom to which they are attached form a ring B which is azetidinyl, pyrrolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, imidazolyl, azathianyl, tetrazolyl, triazolyl, 3,4-dihydroisoquinolinyl or thiomorpholinyl, each of which is substituted with (R ⁹ ) _n , or ring B is indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydrobenzooxazinyl or dihydrobenzothiazinyl optionally substituted with at least one oxo; and wherein each R ⁹ is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, -NH ₂ , -N(CH ₃ ) ₂ , -CF ₃ , -CHF ₂ , -OCHF ₂ , -S(O) ₂ NH ₂ , -SCH ₃ , -S(O)CH ₃ and -S(O) ₂ CH ₃ ; and n is defined herein; stereoisomers thereof and pharmaceutically acceptable salts thereof. In another aspect, a compound of formula (1-A1) is provided wherein R ⁰ is H, methyl, ethyl or propyl; R is H or phenyl, pyridinyl or thiophenyl, each of which is substituted with (R ⁹ ) _n ; R ¹ is methyl; or R ¹ is benzyl, -CH ₂ pyridinyl or -CH ₂ thiazolyl, each of which is substituted with (R ⁹ ) _n ; R ² is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, n-butyl, -CH ₂ OCH ₃ , -(CH ₂ ) ₂ OCH ₃ , -CH ₂ CF ₃ , -CF ₃ , -NHR ^b , -NCH ₂ R ^b , wherein R ^b is methyl, cyclohexyl, phenyl or pyridinyl and wherein the phenyl and pyridinyl rings are optionally substituted with F, Cl, cyano or -CF ₃ ; or R ² is cyclopropyl, -CH ₂ cyclopropyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, phenyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, pyridinyl or pyrimidinyl, each of which is substituted with (R ⁹ ) _n ; or R ² is phenyl or pyridinyl, each of which is substituted with morpholine; R ⁵ is H or C ₁ -C ₆ alkyl; and R ⁶ is H; C ₁ -C ₆ alkyl optionally substituted with hydroxy; C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, -OCF ₃ , -C(O)NR ^a R ⁸ , -R ^c S(O) _p R ⁸ , -R ^c NR ^a R ^b , -R ^c OR ^b or -S(O) _p R ⁸ ; or _C0 - _C3 alkylphenyl, C0 _{- C3} alkylC3 _{-C6 cycloalkyl} , _C0 - _C3 alkylpyrrolidinyl, C0- _C3 alkylpiperidinyl, _{C0 -} C3 alkylpiperazinyl _, C0- _C3 alkylmorpholinyl, _C0 - _C3 alkyltetrahydropyranyl, pyrazolyl, imidazolyl, pyridazinyl, _{C0 - C3} alkylpyridinyl or _C0 - _C3 alkylthiazolyl, each of which is substituted with ( ^R9 ) _n ; or R ⁵ and R ⁶ taken together with the nitrogen atom to which they are attached form a B ring which is azetidinyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morphoinyl, imidazolyl, azathianyl or tetrazolyl, each of which is substituted with (R ⁹ ) _n ; and wherein each R ⁹ is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, -NH ₂ , -N(CH ₃ ) ₂ , -CF ₃ , -CHF ₂ , -OCHF ₂ , -S(O) ₂ NH ₂ , -SCH ₃ , -S(O)CH ₃ and -S(O) ₂ CH ₃ ; an is an integer of 0, 1 or 2; stereoisomers thereof and pharmaceutically acceptable salts thereof. In another aspect, there is provided a compound of formula (1-A1) wherein R ⁰ is H; R is H, phenyl, pyridinyl or thiophenyl, each of which is substituted with (R ⁹ ) _n ; R ¹ is methyl; R ² is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, n-butyl, -CH ₂ OCH ₃ , -(CH ₂ ) ₂ OCH ₃ , -CH ₂ CF ₃ , -CF ₃ , -NHR ^b , -NCH ₂ R ^b , wherein R ^b is methyl, cyclohexyl, phenyl or pyridinyl and wherein the phenyl and pyridinyl rings are optionally substituted with F, Cl, cyano or -CF ₃ ; or R ² is cyclopropyl, -CH ₂ cyclopropyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, phenyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, pyridinyl or pyrimidinyl, each of which is substituted with (R ⁹ ) _n ; or R ² is phenyl or pyridinyl, each of which is substituted with morpholine; R ⁵ is H or C ₁ -C ₆ alkyl; and R ⁶ is H; C ₁ -C ₆ alkyl, methoxy, ethoxy, C ₁ -C ₆ haloalkyl, -OCF ₃ , -CH ₂ OCF ₃ , -(CH ₂ ) ₂ OCF ₃ , -CH ₂ CN, -R ^c S(O) _p CH ₃ ; -R ^c S(O) _p NR ^a R ^b ; R ^c S(O) _p is phenyl, -R ^c NR ^a R ^b , R ^c OR ^b , -R ^c NHC(O)CH ₃ ; where each R ^a and R ^b is independently H, methyl and ethyl; or R ⁶ is either C ₀ -C ₃ alkylphenyl, C ₀ -C ₃ alkylC ₃ -C ₆ cycloalkyl, C ₀ -C ₃ alkylpyrrolidinyl, C ₀ -C ₃ alkylpiperidinyl, piperazinyl, morpholinyl, C ₀ -C ₃ alkyltetrahydropyranyl, pyrazolyl, imidazolyl, pyridazinyl, C ₀ -C ₃ alkylpyridinyl or C ₀ -C ₃ alkylthiazolyl, each of which is substituted with (R ⁹ ) _n ; and wherein each R ⁹ is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, -NH ₂ , -N(CH ₃ ) ₂ , -CF ₃ , -CHF ₂ , -OCHF ₂ , -S(O) ₂ NH ₂ , -SCH ₃ , -S(O)CH ₃ and -S(O) ₂ CH ₃ ; an is an integer of 0, 1 or 2; stereoisomers thereof and pharmaceutically acceptable salts thereof. In another aspect, a compound of formula (1-A1) is provided, wherein R ⁰ is H; R is H, phenyl substituted with (R%); R ¹ is methyl; R ² is imidazole optionally substituted with methyl; phenyl, ^-NHRb , _-NCH2Rb , wherein ^Rb is cyclohexyl or phenyl, each optionally substituted with F, O, cyano or _-CF3 ; or R ² is phenyl substituted with ( ^R9 ) _n or ^{R 2} is imidazolyl optionally substituted with methyl; R ⁵ is H; and R ⁶ is propyl; and wherein each R ⁹ is independently selected from the group consisting of methyl, methoxy, F, O, cyano and _-CF3 ; and n is an integer of 0, 1 or 2; stereoisomers thereof and pharmaceutically acceptable salts thereof. In another aspect, there is provided a compound of formula (1-A1) of Table B, stereoisomers thereof and pharmaceutically acceptable salts thereof. In another In one aspect, the compound is a non-antibacterial compound of formula (1-A1) of Table B, its stereoisomers and pharmaceutically acceptable salts thereof. In another aspect, the compound is a compound of formula (1-A1) of Table B, selected from the group consisting of example B-26, B-41, B-48, B-49, B-50, B-58, B-60, B-107, B-113 or B-148, its stereoisomers and pharmaceutically acceptable salts thereof.

In another aspect, there is provided a composition comprising a compound of formula (1-A1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another aspect, there is provided a composition comprising a non-antibacterial compound of formula (1-A1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another aspect, there is provided a composition comprising a compound of formula (1-A1) of Table B, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another aspect, there is provided a composition comprising a non-antibacterial compound of formula (1-A1) of Table B, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another aspect, there is provided a composition comprising a non-antibacterial compound of formula (1-A1) of Table B selected from the group consisting of B-26, B-41, B-48, B-49, B-50, B-58, B-60, B-107, B-113, or B-148, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another aspect, the composition further comprises a pharmaceutically acceptable carrier.

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

In another aspect, there is provided the use of a compound of formula (1-A1); a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating or preventing an inflammatory response in an animal. In another aspect, there is provided the use of a non-antibacterial compound of formula (1-A1); a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating or preventing an inflammatory response in an animal. In another aspect, there is provided the use of a non-antibacterial compound of formula (1-A1) of Table B; a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating or preventing an inflammatory response in an animal. In another aspect, there is provided the use of a non-antibacterial compound of formula (1-A1) of Table B selected from the group consisting of B-26, B-41, B-48, B-49, B-50, B-58, B-60, B-107, B-113 or B-148, a stereoisomer thereof or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating or preventing an inflammatory response in an animal. In another aspect of the use, the inflammatory response is caused by a bacterial, viral or fungal infection, stress and/or an environmental factor. In another aspect of the use, the use of the medicament for treating or preventing an inflammatory response in an animal prevents or mitigates the progression of a respiratory disease or disorder. In another aspect of the use, the animal is livestock. In another aspect of the use, the respiratory disease or disorder is bovine respiratory disease or porcine respiratory disease. In another aspect of the use, administration of a drug to an animal for treating or preventing an inflammatory response in the animal downregulates TNF-α and IL-6 in the animal.

In another aspect of the present invention there is provided a compound of formula (1-A1), wherein R ⁵ and R ⁶ with a common nitrogen atom forming ring B, substituted with (R ⁹ ) _n , which is represented by a compound of formula (1-A1a),

wherein R, R ⁰ , R ¹ , R ² , R ⁹ , Ring B and n are as defined herein, the stereoisomers thereof and pharmaceutically acceptable salts thereof. In another aspect, there is provided a compound of formula (1-A1a) wherein R ⁰ is H, methyl, ethyl or propyl; and R, R ¹ , R ² , Ring B, R ⁹ and n are as defined herein, the stereoisomers thereof and pharmaceutically acceptable salts thereof.

In another aspect, there is provided a compound of formula (1-A1a) wherein R ⁰ is H, methyl, ethyl or propyl; R is H or phenyl, pyridinyl or thiophenyl, each of which is substituted with (R ⁹ ) _n ; R ¹ is C ₁ -C ₆ alkyl or cyclohexyl; or R ¹ is benzyl, -CH ₂ pyridinyl or -CH ₂ thiazolyl, each of which is substituted with (R ⁹ ) _n ; R ² is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, n-butyl, -CH ₂ OCH ₃ , -(CH ₂ ) ₂ OCH ₃ , -CH ₂ CF ₃ , -CF ₃ , -NHR ^b , -NCH ₂ R ^b , wherein R ^b is methyl, cyclohexyl, phenyl or pyridinyl, and wherein the phenyl and pyridinyl rings are optionally substituted with F, O, cyano or -CF ₃ ; or R ² is cyclopropyl, -CH ₂ cyclopropyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, phenyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, pyridinyl or pyrimidinyl, each of which is substituted with (R ⁹ ) _n ; or R ² is phenyl or pyridinyl, each of which is substituted with morpholine; ring B is azetidinyl, pyrrolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, imidazolyl, azathianyl, tetrazolyl, triazolyl, 3,4-dihydroisoquinolinyl or thiomorpholinyl, each of which is substituted with (R ⁹ ) _n ; or ring B when condensed with Y is indolinyl, isoindolinyl, tetrahydroquinolinyl, dihydrobenzooxazinyl or dihydrobenzothiazinyl; and wherein each R ⁹ is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, -NH ₂ , -N(CH ₃ ) ₂ , -CF ₃ , -CHF ₂ , -OCHF ₂ , -S(O) ₂ NH ₂ , -SCH ₃ , -S(O)CH ₃ and -S(O) ₂ CH ₃ ; and n is defined herein; stereoisomers thereof and pharmaceutically acceptable salts thereof. In another aspect, a compound of formula (1-A1a) is provided wherein R ⁰ is H, methyl, ethyl or propyl; R is H or phenyl, pyridinyl or thiophenyl, each of which is substituted with (R ⁹ ) _n ; R ¹ is methyl; or R ¹ is benzyl, -CH ₂ pyridinyl or -CH ₂ thiazolyl, each of which is substituted with (R ⁹ ) _n ; R ² is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, n-butyl, -CH ₂ OCH ₃ , -(CH ₂ ) ₂ OCH ₃ , -CH ₂ CF ₃ , -CF ₃ , -NHR ^b , -NCH ₂ R ^b , wherein R ^b is methyl, cyclohexyl, phenyl or pyridinyl, and wherein the phenyl and pyridinyl rings are optionally substituted with F, Cl, cyano or -CF ₃ ; or R ² is cyclopropyl, -CH ₂ cyclopropyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, phenyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, pyridinyl or pyrimidinyl, each of which is substituted with (R ⁹ ) _n ; or R ² is phenyl or pyridinyl, each of which is substituted with morpholine; ring B is azetidinyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, imidazolyl, azathianyl or tetrazolyl, each of which is substituted with (R ⁹ ) _n ; and wherein each R ⁹ is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, -NH ₂ , -N(CH ₃ ) ₂ , -CF ₃ , -CHF ₂ , -OCHF ₂ , -S(O) ₂ NH ₂ , -SCH ₃ , -S(O)CH ₃ and -S(O) ₂ CH ₃ ; an is an integer of 0, 1 or 2; stereoisomers thereof and pharmaceutically acceptable salts thereof. In another aspect, a compound of formula (1-A1a) is provided, wherein R ⁰ is H; R is H or phenyl, pyridinyl or thiophenyl, each of which is substituted with (R ⁹ ) _n ; R ¹ is methyl; R ² is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, n-butyl, -CH ₂ OCH ₃ , -(CH ₂ ) ₂ OCH ₃ , -CH ₂ CF ₃ , -CF ₃ , -NHR ^b , -NCH ₂ R ^b , wherein R ^b is methyl, cyclohexyl, phenyl or pyridinyl and wherein the phenyl and pyridinyl rings are optionally substituted with F, Cl, cyano or -CF ₃ ; or R ² is cyclopropyl, -CH ₂ cyclopropyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, phenyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, pyridinyl or pyrimidinyl, each of which is substituted with (R ⁹ ) _n ; or R ² is phenyl or pyridinyl, each of which is substituted with morpholine; ring B is azetidinyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, imidazolyl, azathianyl or tetrazolyl, each of which is substituted with (R ⁹ ) _n ; and wherein each R ⁹ is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, -NFh, -N(CH ₃ ) ₂ , -CF ₃ , -CHF ₂ , -OCHF ₂ , -S(O) ₂ NH ₂ , -SCH ₃ , -S(O)CH ₃ and -S(O) ₂ CH ₃ ; an is an integer of 0, 1, or 2; stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect, there is provided a compound of formula (1-A1a), wherein R ⁰ is H; R is H, phenyl, or piperidinyl, each substituted with (R ⁹ ) _n ; R ¹ is methyl; R ² is -NHphenyl or phenyl, each substituted with (R ⁹ ) _n ; ring B is piperidine; and wherein each R ⁹ is independently selected from the group consisting of methyl, methoxy, F, Cl, Br, cyano, -NH ₂ , -N(CH ₃ ) ₂ and -CF ₃ ; and n is an integer of 0, 1, or 2; stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect, there is provided a compound of formula (1-A1a) of Table C, stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect, it is a non-antibacterial compound of formula (1-A1a) of table C, its stereoisomers and pharmaceutically acceptable salts thereof. In another aspect, it is a non-antibacterial compound of formula (1-A1a) of table C, which is an example of C-4 or C-11, its stereoisomers and pharmaceutically acceptable salts thereof.

In another aspect, there is provided a composition comprising a compound of formula (1-A1a), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another aspect, there is provided a composition comprising a non-antibacterial compound of formula (1-A1a), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another aspect, there is provided a composition comprising a compound of formula (1-A1a) of Table C, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another aspect, there is provided a composition comprising a non-antibacterial compound of formula (1-A1a) of Table C, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another aspect, there is provided a composition comprising a non-antibacterial compound of formula (1-A1a) of Table C, which is an example of C-4 or C-11, a stereoisomer thereof, and a pharmaceutically acceptable salt thereof. In another aspect, the composition further comprises a pharmaceutically acceptable carrier.

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 formula (1-A1a), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another aspect, there is provided a method of treating or preventing an inflammatory response in an animal by administering to said animal in need thereof a therapeutically effective amount of a non-antibacterial compound of formula (1-A1a), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another aspect, there is provided a method of treating or preventing an inflammatory response in an animal by administering to said animal in need thereof a therapeutically effective amount of a non-antibacterial compound of formula (1-A1a) of Table C, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another aspect, there is provided a method of treating or preventing an inflammatory response in an animal by administering to said animal in need thereof a therapeutically effective amount of a non-antibacterial compound of formula (1-A1a) of Table C, which is an example of C-4 or C-11, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another aspect of the method, the inflammatory response in the animal is caused by a bacterial, viral or fungal infection, stress and/or an environmental factor. In another aspect of the method, treating or preventing an inflammatory response in an animal prevents or mitigates the progression of a respiratory disease or disorder in the animal. In another aspect of the method, the animal is livestock; and wherein the respiratory disease or disorder is bovine respiratory disease or porcine respiratory disease. In another aspect of the method, IL-6 and TNF-α are downregulated in animals.

In another aspect, there is provided the use of a compound of formula (1-A1a); a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating or preventing an inflammatory response in an animal. In another aspect, there is provided the use of a non-antibacterial compound of formula (1-A1a); a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating or preventing an inflammatory response in an animal. In another aspect, there is provided the use of a non-antibacterial compound of formula (1-A1a) of Table C; a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating or preventing an inflammatory response in an animal. In another aspect, there is provided the use of a non-antibacterial compound of formula (1-A1a) of Table C, which is an example of C-4 or C-11; a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating or preventing an inflammatory response in an animal. In another aspect of the use, the inflammatory response is caused by a bacterial, viral, or fungal infection, stress, and/or an environmental factor. In another aspect of the use, the use of a medicament for treating or preventing an inflammatory response in an animal prevents or mitigates the progression of a respiratory disease or disorder. In another aspect of the use, the animal is livestock. In another aspect of the use, the respiratory disease or disorder is bovine respiratory disease or porcine respiratory disease. In another aspect of the use, administering a medicament to an animal for treating or preventing an inflammatory response in the animal reduces the regulation of TNF-α and IL-6 in the animal.

In another aspect of the present invention there is provided a compound selected from the group consisting of the following:

N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-ok co-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-(4-methoxyphenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide (A-9);

N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N,4-dimethylbenzenesulfonamide (B-26);

(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-[[(4-chlorophenyl)methyl-methylsulfamoyl]methylamino]-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one (B-41);

(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl(phenylsulfamoyl)amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane(B-48);

(2S,3R,4S,6R)-11-[(2S,3R,4S,6R)-4-[[cyclohexyl(methyl)sulfamoyl]methylamino]-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one (B-49);

(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane (B-50);

4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(((3-(piperidin-1-yl)propyl)amino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide (B-58);

4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide (B-60);

N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)ox an-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(4-fluorophenoxy)-6-methyloxan-4-yl]-N,1-dimethylimidazol-2-sulfonamide (B-107);

(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-(2S,4R,5S,6R)-3-hydroxy-6-methyl-4-[methyl-[methyl-[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one (B-113);

N-(-(2S,4R,5S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-(4-methoxybenzyl)benzenesulfonamide (B-148);

4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,44R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide (C-4); and

(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane (C-11), their stereoisomers and pharmaceutically acceptable salts.

In another aspect, a compound is provided selected from the group consisting of the following:

(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane (B-50);

N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)ox an-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(4-fluorophenoxy)-6-methyloxan-4-yl]-N,1-dimethylimidazol-2-sulfonamide (B-107);

(2R,3S,4R,5R,8R,10R,44R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-(2R,4R,5S,6S)-3-hydroxy-6-methyl-4-[methyl-[methyl-[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one (B-113); and

4-chloro-N-((2R,4R,5S,6S)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide (C-4), their stereoisomers and pharmaceutically acceptable salts.

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

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

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

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

In another aspect, there is provided a composition comprising an illustrative example of a compound selected from the group consisting of A-9, B-26, B-41, B-48, B-49, B-50, B-58, B-60, B-107, B-113, B-148, C-4 and C-11, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another aspect, there is provided a composition comprising an exemplified compound selected from the group consisting of B-50, B-107, B-113 and C-4, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another aspect, there is provided a composition comprising an example of B-50, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another aspect, there is provided a composition comprising an example of B-107, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another aspect, a composition is provided comprising example B-113, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another aspect, a composition is provided comprising example C-4, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another aspect, the composition further comprises a pharmaceutically acceptable carrier.

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 an illustrative example compound selected from the group consisting of A-9, B-26, B-41, B-48, B-49, B-50, B-58, B-60, B-107, B-113, B-148, C-4 and C-11, a stereoisomer thereof or a pharmaceutically acceptable salt thereof. In another aspect, 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 an illustrative example compound selected from the group consisting of B-50, B-107, B-113 and C-4, a stereoisomer thereof or a pharmaceutically acceptable salt thereof. In another aspect, 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 example B-50, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another aspect, there is provided a method of treating or preventing an inflammatory response in an animal by administering to said animal in need thereof a therapeutically effective amount of example B-107, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another aspect, there is provided a method of treating or preventing an inflammatory response in an animal by administering to said animal in need thereof a therapeutically effective amount of example B-113, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another aspect, there is provided a method of treating or preventing an inflammatory response in an animal by administering to said animal in need thereof a therapeutically effective amount of example C-4, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In another aspect of the method, the treatment or prevention of an inflammatory response in an animal prevents or mitigates the progression of a respiratory disease or disorder in the animal. In another aspect of the method, the animal is livestock; and wherein the respiratory disease or disorder is bovine respiratory disease or porcine respiratory disease. In another aspect of the method, IL-6 and TNF-α are down-regulated in animals.

Another aspect provides the use of an illustrative example of a compound selected from the group consisting of A-9, B-26, B-41, B-48, B-49, B-50, B-58, B-60, B-107, B-113, B-148, C-4 and C-11, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the prevention or treatment of an inflammatory response in an animal. Another aspect provides the use of an illustrative example of a compound selected from the group consisting of B-50, B-107, B-113 and C-4, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the prevention or treatment of an inflammatory response in an animal. Another aspect provides the use of example B-50, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the prevention or treatment of an inflammatory response in an animal. In another aspect, there is provided the use of example B-107, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the prevention or treatment of an inflammatory response in an animal. In another aspect, there is provided the use of example B-113, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the prevention or treatment of an inflammatory response in an animal. In another aspect, there is provided the use of example C-4, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the prevention or treatment of an inflammatory response in an animal. In another aspect, the use of a medicament for the treatment or prevention of an inflammatory response in an animal prevents or mitigates the progression of a respiratory disease or disorder in the animal. In another aspect of the use, the animal is livestock; and wherein the respiratory disease or disorder is bovine respiratory disease or porcine respiratory disease. In another aspect of the example, the animals are down-regulated in IL-6 and TNF-α.

In another aspect of the present invention, there is provided a compound of formula (1), wherein W is formula (A) and formula (A) is formula (A2), which is represented by a compound of formula (1-A2),

wherein R, R ⁰ , R ¹ , R ² and R ⁷ are as defined herein, the stereoisomers thereof and the pharmaceutically acceptable salts thereof. In another aspect, there is provided a compound of formula (1-A2) wherein R ⁰ is H, methyl, ethyl or propyl; and R, R ¹ , R ² and R ⁷ are as defined herein, the stereoisomers thereof and the pharmaceutically acceptable salts thereof. In another aspect, there is provided a compound of formula (1-A2) wherein R ⁰ is H or methyl; R ¹ is methyl; R is H or phenyl optionally substituted with (R ⁹ ) _n ; R ² is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, n-butyl, -CH ₂ OCH ₃ , -(CH ₂ ) ₂ OCH ₃ , -CH ₂ CF ₃ , -CF ₃ , -NHR ^b or -NCH ₂ R ^b , wherein R ^b is methyl, cyclohexyl, phenyl or pyridinyl, and wherein the phenyl and pyridinyl rings are optionally substituted with F, Cl, cyano or -CF ₃ ; or R ² is cyclopropyl, -CH ₂ cyclopropyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, phenyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, pyridinyl or pyrimidinyl, each of which is substituted with (R ⁹ ) _n ; or R ² is phenyl or pyridinyl, each of which is substituted with morpholine; and wherein each R ⁹ is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, NH ₂ , -N(CH ₃ ) ₂ , -CF ₃ , -CHF ₂ , -OCHF ₂ , -S(O) ₂ NH ₂ , -SCH ₃ , -S(O)CH ₃ and -S(O) ₂ CH ₃ ; an is an integer of 0, 1 or 2, its stereoisomers and its pharmaceutically acceptable salts.

In another aspect of the present invention, there is provided a compound of formula (1), wherein W is formula (A) and formula (A) is formula (A3), which is represented by a compound of formula (1-A3),

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

In another aspect of the present invention, there is provided a compound of formula (1), wherein W is formula (A) and formula (A) is formula (A4), which is represented by a compound of formula (1-A4),

wherein R, R ⁰ , R ¹ , R ² and X' are as defined herein, the stereoisomers thereof and the pharmaceutically acceptable salts thereof. In another aspect, there is provided a compound of formula (1-A4) wherein R ⁰ is H, methyl, ethyl or propyl; and R, R ¹ , R ² and X' are as defined herein, the stereoisomers thereof and the pharmaceutically acceptable salts thereof. In another aspect, there is provided a compound of formula (1-A4) wherein R ⁰ is H or methyl; R ¹ is methyl; R is H or phenyl optionally substituted with (R ⁹ ) _n ; X' is F or Cl; and R ² is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, n-butyl, -CH ₂ OCH ₃ , -(CH ₂ ) ₂ OCH ₃ , -CH ₂ CF ₃ , -CF ₃ ,

-NHR ^b or -NCH ₂ R ^b , wherein R ^b is methyl, cyclohexyl, phenyl or pyridinyl and wherein the phenyl and pyridinyl rings are optionally substituted with F, Cl, cyano or -CF ₃ ; or R ² is cyclopropyl, -CH ₂ cyclopropyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, phenyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, pyridinyl or pyrimidinyl, each of which is substituted with (R ⁹ ) _n ; or R ² is phenyl or pyridinyl, each of which is substituted with morpholine; and wherein each R ⁹ is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, NH ₂ , -N(CH ₃ ) ₂ , -CF ₃ , -CHF ₂ , -OCHF ₂ , -S(O) ₂ NH ₂ , -SCH ₃ , -S(O)CH ₃ and -S(O) ₂ CH ₃ ; an is an integer of 0, 1 or 2, its stereoisomers and its pharmaceutically acceptable salts. In another aspect, it is a non-antibacterial compound of formula (1-A4), which is 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(chloromethyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide (example No.A4-1; [M+H] ⁺ =944; i.e., R ⁰ is H, R ¹ is methyl, R ² is 4-chlorophenyl and X' is chlorine)), its stereoisomers and its pharmaceutically acceptable salts.

In another aspect of the present invention, there is provided a compound of formula (1), wherein W is formula (A) and formula (A) is formula (A5), which is represented by a compound of formula (1-A5),

wherein R, R ⁰ , R ¹ and R ² are as defined herein, the stereoisomers thereof and the pharmaceutically acceptable salts thereof. In another aspect, there is provided a compound of formula (1-A5), wherein R ⁰ is H, methyl, ethyl or propyl; and R, R ¹ and R ² are as defined herein, the stereoisomers thereof and the pharmaceutically acceptable salts thereof. In another aspect, there is provided a compound of formula (1-A5), wherein R ⁰ is H or methyl; R ¹ is methyl; R is H or phenyl optionally substituted with (R ⁹ ) _n , and R ² is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, n-butyl, -CH ₂ OCH ₃ , -(CH ₂ ) ₂ OCH ₃ , -CH ₂ CF ₃ , -CF ₃ , -NHR ^b or -NCH ₂ R ^b , wherein R ^b is methyl, cyclohexyl, phenyl or pyridinyl, and wherein the phenyl and pyridinyl rings are optionally substituted with F, Cl, cyano or -CF ₃ ; or R ² is cyclopropyl, -CH ₂ cyclopropyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, phenyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, pyridinyl or pyrimidinyl, each of which is substituted with (R ⁹ ) _n ; or R ² is phenyl or pyridinyl, each of which is substituted with morpholine; and wherein each R ⁹ is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, NH ₂ , -N(CH ₃ ) ₂ , -CF ₃ , -CHF ₂ , -OCHF ₂ , -S(O) ₂ NH ₂ , -SCH ₃ , -S(O)CH ₃ and -S(O) ₂ CH ₃ ; an is an integer of 0, 1 or 2, its stereoisomers and its pharmaceutically acceptable salts.

In another aspect of the present invention, there is provided a compound of formula (1), wherein W is formula (A) and formula (A) is formula (A6), which is represented by a compound of formula (1-A6),

wherein R, R ⁰ , R ¹ and R ² are as defined herein, the stereoisomers thereof and the pharmaceutically acceptable salts thereof. In another aspect, there is provided a compound of formula (1-A6) wherein R ⁰ is H, methyl, ethyl or propyl; and R, R ¹ and R ² are as defined herein; or R and R ² join to form a bond to form a dioxo-oxathiazolyl ring; the stereoisomers thereof and the pharmaceutically acceptable salts thereof. In another aspect, there is provided a compound of formula (1-A6) wherein R ⁰ is H or methyl; R ¹ is methyl; R is H or phenyl optionally substituted with (R ⁹ ) _n , and R ² is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, n-butyl, -CH ₂ OCH ₃ , -(CH ₂ ) ₂ OCH ₃ , -CH ₂ CF ₃ , -CF ₃ , -NHR ^b or -NCH ₂ R ^b , wherein R ^b is methyl, cyclohexyl, phenyl or pyridinyl and wherein the phenyl and pyridinyl rings are optionally substituted with F, Cl, cyano or -CF ₃ ; or R ² is cyclopropyl, -CH ₂ cyclopropyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, phenyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, pyridinyl or pyrimidinyl, each of which is substituted with (R ⁹ ) _n ; or R ² is phenyl or pyridinyl, each of which is substituted with morpholine; and wherein each R ⁹ is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, NH ₂ , -N(CH ₃ ) ₂ , -CF ₃ , -CHF ₂ , -OCHF ₂ , -S(O) ₂ NH ₂ , -SCH ₃ , -S(O)CH ₃ and -S(O) ₂ CH ₃ ; an is an integer of 0, 1 or 2, its stereoisomers and its pharmaceutically acceptable salts. In another aspect, it is a non-antibacterial compound of formula (1-A6), which is 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(cyanomethyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide (example No.A6-1; [M+H] ⁺ 935; i.e., R ⁰ is H, R ¹ is methyl, and R ² is 4-chlorophenyl); its stereoisomers and its pharmaceutically acceptable salts.

In another aspect, there is provided a composition comprising a compound of formula (1-A0), (1-A2), (1-A3), (1-A4), (1-A5) or (1-A6), a stereoisomer thereof or a pharmaceutically acceptable salt thereof. In another aspect, there is provided a composition comprising a non-antibacterial compound of formula (1-A0), (1-A2), (1-A3), (1-A4), (1-A5) or (1-A6), a stereoisomer thereof or a pharmaceutically acceptable salt thereof. In another aspect, there is provided a composition comprising a non-antibacterial compound of formula (1-A3) which is example A3-1; a non-antibacterial compound of formula (1-A4) which is example (A4-1) or a non-antibacterial compound of formula (1-A6) which is example (A6-1), a stereoisomer thereof or a pharmaceutically acceptable salt thereof. In another aspect, the composition further comprises a pharmaceutically acceptable carrier.

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

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

In another aspect of the present invention, there is provided a compound of formula (1), wherein R and R ² join to form a bond to form a 2-dioxo-oxathiazolyl ring, which is a compound of formula (2), wherein W, R ⁰ and R ¹ are as defined herein, stereoisomers thereof or

pharmaceutically acceptable salts thereof. In another aspect, there is provided a compound of formula (2), wherein R ⁰ is H, methyl, ethyl or propyl; and W and R ¹ are as defined herein, its stereoisomers, and pharmaceutically acceptable salts thereof. In another aspect, there is provided a compound of formula (2), wherein R ⁰ is H; and W and R ¹ are as defined herein, its stereoisomers, and pharmaceutically acceptable salts thereof.

In another aspect of the present invention, there is provided a compound of formula (2), wherein W is H, which is a compound of formula (2.1), wherein R ⁰ and R ¹ are as described herein,

stereoisomers thereof and pharmaceutically acceptable salts thereof. In another aspect, there is provided a compound of formula (2.1), wherein R ⁰ is H, methyl, ethyl or propyl; and R ¹ is described herein, its stereoisomers and pharmaceutically acceptable salts thereof. In another aspect, there is provided a compound of formula (2.1), wherein R ⁰ is H; and R ¹ is described herein, its stereoisomers and pharmaceutically acceptable salts thereof.

In another aspect, a compound of formula (2.1) is provided, wherein R ⁰ is H or methyl; R ¹ is C ₁ -C ₆ alkyl; or R ¹ is benzyl, -CH ₂ pyridinyl, or -CH ₂ thiazolyl, each of which is substituted with (R ⁹ ) _n ; and wherein each R ⁹ is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, NH ₂ , -N(CH ₃ ) ₂ , -CF ₃ , -CHF ₂ , -OCHF ₂ , -S(O) ₂ NH ₂ , -SCH ₃ , -S(O)CH ₃ and -S(O) ₂ CH ₃ ; and n is an integer of 0, 1, or 2; its stereoisomers and its pharmaceutically acceptable salts.

In another aspect of the present invention, there is provided a compound of formula (2), wherein W is formula (A), wherein X is R ^a and R ^a is H, which is a compound of formula (2-A0), wherein R ⁰ and R ¹ are described herein, its stereoisomers and its pharmaceutically acceptable

,1

salts. In another aspect, there is provided a compound of formula (2-A0), wherein ^Ra is H; R ⁰ is H, methyl, ethyl, or propyl; and R ¹ is described herein, its stereoisomers, and pharmaceutically acceptable salts thereof. In another aspect, there is provided a compound of formula (2-A0), wherein Ra is H; R ⁰ is H or methyl; R ¹ is C ₁ -C ₆ alkyl; or R ¹ is benzyl, -CH ₂ pyridinyl, or -CH ₂ thiazolyl, each of which is substituted with (R ⁹ ) _n ; and wherein each R ⁹ is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, NH ₂ , -N(CH ₃ ) ₂ , -CF ₃ , -CHF ₂ , -OCHF ₂ , -S(O) ₂ NH ₂ , -SCH ₃ , -S(O)CH ₃ and -S(O) ₂ CH ₃ ; and n is an integer of 0, 1 or 2; stereoisomers thereof and pharmaceutically acceptable salts thereof.

In another aspect of the present invention, there is provided a compound of formula (2), wherein W is formula (A), wherein X is -(CH ₂ ) _m NR ⁵ R ⁶ , am is an integer of 1, which is a compound of formula (2-A1),

wherein R ⁰ , R ¹ , R ⁵ and R ⁶ are as described herein, the stereoisomers thereof and the pharmaceutically acceptable salts thereof. In another aspect, there is provided a compound of formula (2-A1) wherein R ⁰ is H, methyl, ethyl or propyl; and R ¹ , R ⁵ and R ⁶ are as described herein, the stereoisomers thereof and the pharmaceutically acceptable salts thereof. In another aspect, there is provided a compound of formula (2-A1) wherein R ⁰ is H or propyl; R ⁵ is H and R ⁶ is propyl; and R ¹ is C ₁ -C ₆ alkyl or cyclohexyl; or R ¹ is benzyl, -CH ₂ pyridinyl or -CH ₂ thiazolyl, each of which is substituted with (R ⁹ ) _n ; or R ⁵ and R ⁶ , taken together with the nitrogen atom to which they are attached, form a ring B which is piperidinyl or piperazinyl, each of which is substituted with (R ⁹ ) _n ; and wherein each R ⁹ is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, NH ₂ , -N(CH ₃ ) ₂ , -CF ₃ , -CHF _{2 , -OCHF 2 ,} -S(O) ₂ NH ₂ , -SCH ₃ , -S(O)CH ₃ and -S(O) ₂ CH ₃ ; an is an integer of 0, 1 or 2; the stereoisomers thereof and the pharmaceutically acceptable salts thereof. In another aspect, there is provided a compound of formula (2-A1), wherein R ⁰ is H or propyl; R ⁵ is H and R ⁶ is propyl; and R ¹ is methyl or benzyl optionally substituted with (R ⁹ ) _n ; or R ⁵ and R ⁶ taken together with the nitrogen atom to which they are attached form piperidine; and wherein each R ⁹ is independently selected from the group consisting of methyl, methoxy, F, Cl, cyano and -CF ₃ ; and n is an integer of 0, 1 or 2; stereoisomers thereof and pharmaceutically acceptable salts thereof. In another aspect, there is provided a compound of formula (2-A1) of Table D, stereoisomers thereof and pharmaceutically acceptable salts thereof.

In another aspect, a composition is provided comprising a compound of formula (2-A1) or formula (2-A1) of Table D, a stereoisomer thereof, or a pharmaceutically acceptable salt 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 (2-A1) or formula (2-A1) of Table D, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

In another aspect of the method, the inflammatory response in the animal is caused by a bacterial, viral or fungal infection, stress and/or an environmental factor. In another aspect of the method, treating or preventing the inflammatory response in the animal prevents or mitigates the progression of a respiratory disease or disorder in the animal. In another aspect of the method, the animal is livestock; and wherein the respiratory disease or disorder is bovine respiratory disease or porcine respiratory disease. In another aspect of the method, IL-6 and TNF-α are downregulated in animals.

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

In another aspect of the invention, there is provided a compound of formula (2), wherein W is formula (A), wherein X is -(CH ₂ ) _m OR ⁷ or X is -(CH ₂ ) _m SR ⁷ ; am is an integer of 1, which is a compound of formula (2-A2) or formula (2-A3), wherein R ⁰ , R ¹ and R ⁷

described herein, the stereoisomers thereof, or the pharmaceutically acceptable salts thereof, respectively. In another aspect, there is provided a compound of formula (2-A2) or formula (2-A3), wherein R ⁰ is H, methyl, ethyl, or propyl; and R ¹ and R ⁷ are described herein, the stereoisomers thereof, and the pharmaceutically acceptable salts thereof. In another aspect, there is provided a compound of formula (2-A2) or formula (2-A3), wherein R ⁰ is H, methyl, ethyl, or propyl; R ¹ is C ₁ -C ₆ alkyl or cyclohexyl; or R ¹ is benzyl, -CH ₂ pyridinyl, or -CH ₂ thiazolyl, each of which is substituted with (R ⁹ ) _n ; 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 ; and wherein each R ⁹ is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, NH ₂ , -N(CH ₃ ) ₂ , -CF ₃ , -CHF ₂ , -OCHF ₂ , -S(O) ₂ NH ₂ , -SCH ₃ , -S(O)CH ₃ and -S(O) ₂ CH ₃ ; an is an integer of 0, 1 or 2, its stereoisomers and its pharmaceutically acceptable salts. In another aspect, there is provided a compound of formula (2-A2) or formula (2-A3), wherein R ⁰ is H; R ¹ is methyl; and R ⁷ is H, methyl, ethyl or propyl, its stereoisomers and pharmaceutically acceptable salts thereof.

In another aspect of the invention, there is provided a compound of formula (2), wherein W is formula (A), wherein X is -(CH ₂ ) _m X' or X is -(CH ₂ ) _m N3, or X is -(CH ₂ ) _m CN; am is an integer of 1, which is a compound of formula (2-A4), formula (2-A5), or formula (2-A6), wherein R ⁰ , R ¹

and X' are described herein, the stereoisomers thereof, or the pharmaceutically acceptable salts thereof, respectively. In another aspect, there is provided a compound of formula (2-A4), formula (2-A5), or formula (2-A6), wherein R ⁰ is H, methyl, ethyl, or propyl; X' is fluoro or chloro; and R ¹ is described herein, the stereoisomers thereof, and the pharmaceutically acceptable salts thereof. In another aspect, there is provided a compound of formula (2-A4), formula (2-A5), or formula (2-A6), wherein R ⁰ is H, methyl, ethyl, or propyl; X' is fluoro or chloro; and R ¹ is C ₁ -C ₆ alkyl or cyclohexyl; or R ¹ is benzyl, -CH ₂ pyridinyl, or -CH ₂ thiazolyl, each of which is substituted with (R ⁹ ) _n ; and wherein each R ⁹ is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, NH ₂ , -N(CH ₃ ) ₂ , -CF ₃ , -CHF ₂ , -OCHF ₂ , -S(O) ₂ NH ₂ , -SCH ₃ , -S(O)CH ₃ and -S(O) ₂ CH ₃ ; an is an integer of 0, 1 or 2, stereoisomers thereof, and pharmaceutically acceptable salts thereof. In another aspect, there is provided a compound of formula (2-A4), formula (2-A5) or formula (2-A6), wherein R ⁰ is H, methyl, ethyl or propyl; R ¹ is methyl; stereoisomers thereof, and pharmaceutically acceptable salts thereof.

In another aspect, there is provided a composition comprising a compound of formula (2.1), formula (2-A0), formula (2-A2), formula (2-A3), formula (2-A4), formula (2-A5) or formula (2-A6), a stereoisomer thereof or a pharmaceutically acceptable salt thereof. In another aspect, the composition further comprises a pharmaceutically acceptable carrier.

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 an effective amount of compound (2.1), formula (2-A0), formula (2-A2), formula (2-A3), formula (2-A4), formula (2-A5) or formula (2-A6), a stereoisomer thereof or a pharmaceutically acceptable salt thereof. In another aspect of the method, the inflammatory response in the animal is caused by a bacterial, viral or fungal infection, stress and/or an environmental factor. In another aspect of the method, treating or preventing an inflammatory response in an animal prevents or mitigates the progression of a respiratory disease or disorder in the animal. In another aspect of the method, the animal is livestock; and wherein the respiratory disease or disorder is bovine respiratory disease or porcine respiratory disease. In another aspect of the method, IL-6 and TNF-α are downregulated in animals.

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

DISCUSSION

Brief description of graphic materials

Fig. 1 Mechanism of action of immunomodulator in the context of BRD progression

Fig. 2 Summary of clinical and genomic time course data

Fig. 3 Plasma cytokine levels (IL-6, IL-8, IL-10 and IFN-γ) on arrival at feedlot for calves at risk for developing BRD

Fig. 4 Evaluation of biomarkers for intratracheal exposure to M9 in the lungs; IL-6 (A) and CD 163 (B) biomarker results

It should be understood that the present invention is not limited to the particular methodology, protocols and reagents, etc., defined herein and may vary in substance. As used herein, the terminology is intended to describe embodiments only and is not intended to limit the scope of the present invention, which is defined solely by the claims.

Unless otherwise indicated, scientific and technical terms used in connection with the compounds of the invention defined herein shall have the meanings commonly understood by those skilled in the art. Furthermore, unless the context otherwise requires, singular terms shall include the plural, and plural terms shall include the singular. In general, the nomenclatures used in connection with chemical synthesis, macrolides, and immunomodulation defined herein and their procedures are well known and widely used in the art.

Definitions

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

"Additional pharmaceutical agent(s)" as used herein, unless otherwise specified, refers to other pharmaceutical compounds or products that provide a therapeutically effective amount of the specified agents useful for treating a bacterial or parasitic infection in an animal and/or modulating the immune response, as defined herein.

"Alkoxy" as used herein, unless otherwise specified, refers to an oxygen moiety having an additional alkyl substituent. The alkyl portion (i.e., alkyl group) of an alkoxy group has the same definition as below.

Non _- limiting examples include: _-OCH3 , _-OCH2CH3 , -OCH( _CH3 ) ₂ , -OC( _CH3 ) ₃ , and the like.

The term "alkyl", as used herein, unless otherwise specified, refers to saturated monovalent hydrocarbon alkane radicals of the general formula C _n H _2n+1 The alkane radical may be straight chain or branched and may be unsubstituted or substituted. For example, the term "(C ₁ -C ₆ )alkyl" refers to a monovalent, straight or branched chain aliphatic group containing from 1 to 6 carbon atoms; similarly, C ₁ -C ₃ alkyl refers to a monovalent, straight or branched chain aliphatic group containing from 1 to 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, t-butyl, n-propyl, n-butyl, isobutyl, sec-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, 3,3-dimethylpropyl, 2-methylpentyl, hexyl, and the like. The alkyl moiety may be attached to the chemical moiety through any of the carbon atoms of the aliphatic chain. Alkyl groups are optionally substituted as defined herein. Additionally, when used in compound words such as alkylphenyl, said alkyl moiety has the same meaning as defined herein and may be attached to the chemical group through any of the carbon atoms of the aliphatic chain. Non-limiting examples of the compound word C ₀ -C ₄ alkylphenyl include: C ₀ phenyl (phenyl), C ₁ alkylphenyl (-CH ₂ phenyl; benzyl), C ₂ alkylphenyl (-CH ₂ CH ₂ phenyl), and the like.

"Animal(s)" as used herein, unless otherwise specified, refers to an individual animal that is a mammal. In particular, "mammal" refers to human and non-human vertebrates that are members of the taxonomic class Mammalia. Non-exclusive examples of non-human mammals include domestic animals and livestock. Non-exclusive examples of domestic animals include dogs, cats, and horses. Non-exclusive examples of livestock include pigs, camels, rabbits, goats, sheep, deer, elk, and bovine animals (cattle and bison). Preferred livestock are cattle.

The term “antibacterial” in this document, unless otherwise specified, refers to a compound with a minimum inhibitory concentration (MIC) ≤ 64 μg/mL for any BRD strain, M. haemolytica and P. multocida. The term “non-antibacterial” in this document, unless otherwise specified, refers to a compound with a MIC > 64 μg/mL for BRD (all strains tested), M. haemolytica and P. multocida.

"Aryl" as used herein, unless otherwise specified, refers to an unsaturated aromatic monocyclic ring of 6 carbon atoms or an unsaturated aromatic polycyclic ring of 10 to 14 carbon members. Examples of such aryl rings include, but are not limited to, phenyl, naphthalenyl, or anthracenyl. Additionally, when used in compound words such as alkylaryl (e.g., alkylphenyl), said alkyl and aryl moiety have the same meaning as defined herein and may be attached to the chemical moiety through any of the carbon atoms of the aliphatic chain or ring carbon. Examples of C ₀ -C ₃ alkylphenyl are, for example: C ₀ alkylphenyl is phenyl; C ₁ -alkylphenyl is -CH ₂ phenyl (benzyl); and C ₂ -alkylphenyl is -CH ₂ CH ₂ phenyl. The phenyl ring is optionally substituted as defined herein.

The term "azalide", as used herein, unless otherwise specified, refers to a class of macrolides that contain a nitrogen atom in the macrolide ring, which confers different pharmacokinetic properties and is associated with greater stability of the molecule.

The term "chiral" in the context of this document, unless otherwise specified, refers to a structural characteristic of a molecule that makes it impossible to superpose it with its mirror image (e.g., "R" and "S" enantiomers).

"Composition" as used herein, unless otherwise indicated, refers to a compound of the invention that is formulated with at least one pharmaceutically acceptable excipient for dosage administration.

"Compounds of the present invention" and "compounds", as used herein, unless otherwise specified, include an azalide compound of formula (1), (1A), (1,1), (1-A0), (1-A1), (1-A1a), (1-A2), (1-A3), (1-A4), (1-A5), (1-A6), (2), (2A), (2,1), (2-A0), (2-A1), (2-A2), (2-A3), (2-A4), (2-A5) and (2-A6), its stereoisomers and pharmaceutically acceptable salts thereof. The term(s) also includes the corresponding 13-membered macrolides that are in equilibrium with the 15-membered macrolide ring. Furthermore, whenever an example No. is provided in the description, for example, as a compound, a composition containing said compound, a method of using said compound, and a use of said compound as a medicine, then said example No. is equivalent to the name of the chemical compound as further described herein. For example, B-113 is equivalent to (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5R,6R)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[methyl-[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one, as defined in Table B.

"Cycloalkyl," as used herein, unless otherwise specified, includes fully saturated or partially saturated carbocyclic alkyl moieties, i.e., a 3- to 6-membered ring 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- to 6-membered saturated monocyclic rings, including cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The cycloalkyl group may be attached to the chemical moiety through any of the carbon atoms within the carbocyclic ring. Cycloalkyl groups are optionally substituted with at least one substituent. Furthermore, when used in compound words such as alkylcycloalkyl, said alkyl and cycloalkyl moieties have the same meaning as defined herein and may be attached to the chemical group via any of the carbon atoms of the aliphatic chain. Examples of C ₀ -C ₄ alkylC ₃ -C ₆ cycloalkyl include, for example: C ₀ alkylC ₃ -C ₆ cycloalkyl is C ₃ -C ₆ cycloalkyl (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl); C ₁ -alkylC ₃ -C ₆ cycloalkyl is -CH ₂ C ₃ -C ₆ cycloalkyl (e.g., -CH ₂ -cyclopropyl, -CH ₂ -cyclohexyl, etc.); _{C2- alkylC3} - _C6cycloalkyl is _{-CH2CH2C3 - C6cycloalkyl} ( _e.g. , _{-CH2CH2 -} cyclopropyl, _{-CH2CH2 -} cyclopentyl), etc. Cycloalkyl moieties are optionally substituted as defined herein.

"Cytokine", as used herein, unless otherwise indicated, refers to a general class of biological molecules that act/influence all cell types and influence immunological responses and non-immunological biological processes. The definition is intended to include, but is not limited to, those biological molecules that act locally or systemically and that, when used in the compositions or methods of the invention, serve to regulate or modulate the immune response of an animal. Typical cytokines for use in the practice of the present invention include, but are not limited to, interleukins (e.g., IL-1 to IL-29, in particular IL-1, IL-1β, IL-6, IL-9, IL-10 and IL-12), chemokines (e.g., CCL2-5, CCL10, CCL11, CXCL8 (IL-8) and CXCL10), tumor necrosis factors (e.g., TNF-α and TNF-β) and in particular NFK-B, which mediates the induction of proinflammatory cytokines such as TNF-α, IL-1 and IL-6 in monocytes and macrophages.

"Halogen" as used herein, unless otherwise specified, refers to fluorine, chlorine, bromine and iodine. Additionally, when used in compound words such as "haloalkyl" or "haloalkoxy", said alkyl and alkoxy may be partially or completely substituted by halogen atoms which may be the same or different, and said alkyl and alkoxy group has the same meaning as above and may _be attached to the chemical moiety at any of the carbon atoms _{of the} aliphatic chain. Examples of "haloalkyl" include _F3C- , _ClCH2- , _CF3CH2- and _CF3CH2CH2- and the like. The term "haloalkoxy" is defined similarly to the term "haloalkyl". Examples of "haloalkoxy" include _{CF3O- , CCl3CH2O- , HCF2CH2CH2O- ,} and _CF3CH2O- and _the like.

"Heteroaryl" or "Het" as used herein, unless otherwise specified, refers to a 5-6 membered aromatic monocyclic ring or an 8-10 membered fused aromatic ring, wherein said monocyclic and fused ring moiety contains one or more heteroatoms each 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]thiadiazolyl and the like. A heteroaryl group may be attached to the chemical moiety through any of the carbon atoms or nitrogen heteroatoms in a monocyclic or fused ring. Additionally, when used in compound words such as alkylheteroaryl (e.g., _C0 - _C4 alkylheteroaryl), said alkyl and heteroaryl moieties have the same meaning as defined herein and may be attached to the chemical moiety through any of the carbon atoms of the aliphatic chain. For example, a C ₀ alkyl heterocycle is a heterocycle (e.g., pyrazolyl, imidazolyl, pyridinyl, piperazinyl, and the like), a C ₁ alkyl heteroaryl is a CH ₂ heteroaryl (e.g., -CH ₂ imidazolyl, -CH ₂ pyridinyl, and the like), a C ₂ alkyl heteroaryl is -CH ₂ CH ₂ heteroaryl (e.g., -CH ₂ CH ₂ pyrazolyl, -CH ₂ CH ₂ oxazolyl, -CH ₂ CH ₂ pyrimidinyl, and the like), and the like. Heteroaryls are optionally substituted as defined herein.

"Heterocycle" as used herein, unless otherwise specified, refers to a partially saturated or saturated 3- to 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 heterocycle include oxiranyl, thiaranyl, aziridinyl, oxetanyl, azetidinyl, thiatanyl, tetrahydrofuranyl, 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. The heterocyclic group may be attached to the chemical moiety through any of the carbon atoms or nitrogen heteroatoms within the ring. Furthermore, when used in compound words such as alkyl heterocycle (e.g., C ₀ -C ₄ alkyl heterocycle), said alkyl and heterocyclic moiety have the same meaning as defined herein and may be attached to the chemical moiety through any of the carbon atoms of the aliphatic chain. For example, a C ₀ heterocycle is a heterocycle (e.g., (piperidinyl, morpholinyl, azetidinyl, etc.); a C ₁ alkyl heterocycle is a CH ₂ heterocycle (e.g., -CH ₂ morpholinyl, etc.), a C ₁ alkyl heterocycle is -CH ₂ CH ₂ heterocycle (e.g., CH ₂ CH ₂ pyrrolidinyl, -CH ₂ CH ₂ thiomorpholinyl, etc.), and the like. Heterocycles are optionally substituted as defined herein.

"Macrolide(s)" as used herein, unless otherwise indicated, refers to compounds characterized by a large lactone ring containing from 12 to 16 carbon atoms to which one or more deoxy sugars are attached via glycosidic linkages; and includes the class of azalides.

"Optionally substituted" is used interchangeably with the phrase "substituted" or "unsubstituted" as used herein. Unless otherwise specified, an optionally substituted group may have a substituent at each substitutable position of the group, and each substitution is independent of the other. An optionally substituted group may also have no substituents. Therefore, the phrase "optionally substituted (R ⁹ ) _n " means that the number of substituents may vary from zero, one, two, or three possible substitutions, since n is defined herein as an integer of 0, 1, 2, or 3.

The term "pharmaceutically acceptable" as used herein, unless otherwise specified, means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation, composition, and/or the animal being treated therewith.

"Protecting group" or "Pg", as used herein unless otherwise noted, refers to a substituent that is typically used to block or protect an alcohol in a compound, thereby protecting its functionality while allowing other functional groups of the compound to react. Non-exclusive examples of alcohol protecting group 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), ethoxyethyl acetal (EE), methoxymethyl acetal (MOM), methoxypropyl acetal (MOP), methyl ether, tetrahydropyranyl acetal (THP), triethylsilyl ether (TES), benzyloxycarbonyl (Cbz), triisopropylsilyl ether (TIPS), trimethylsilyl ether (TMS), tert-butyldimethylsilyl ether (TBS, TBDMS) and tert-butyldiphenylsilyl ether (TBDPS).

"Saturated" or "partially saturated" as used herein, unless otherwise specified, refers 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 mutually 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 mutually adjacent carbon atoms or carbon heteroatoms; for example: cyclobutene, cyclopentene, cyclohexa-1,3-diene, 2,3-dihydroazete, 2,5-dihydrofuran, 2H-thiopyran and the like.

The term "stereoisomers", as used herein, unless otherwise indicated, refers to compounds of the invention that have more than one asymmetric carbon atom. In the general formulae depicted herein, a solid wedge bond indicates that the bond is above the plane of the paper, and a broken wedge bond indicates that the bond is below the plane of the paper. The compounds of the invention may occur as individual enantiomers or diastereomers, or mixtures thereof, including racemic mixtures. All such isomeric forms are included in the invention.

"Stress" or "stressful", as used in this document, unless otherwise specified, is a specific or non-specific response that varies in degree. Stressors are specific events, experiences, or environmental stimuli that affect the health of an animal and may be acute, chronic, disruptive, or perceived as uncontrollable. Non-exclusive examples of animal health stressors include: natural disasters (e.g., floods, fires, and earthquakes), major life events (e.g., relocation/transportation, weaning, maternal separation from the herd, mixing of animals from different sources, tail docking), needle extraction, pain, food and water deprivation, and acute or chronic illnesses) and acute/chronic disturbances (e.g., temperature and humidity fluctuations, confinement, transportation, poor nutrition, hydration, and storms), loud sounds (e.g., thunder, barking, fireworks, etc.), environmental changes, pollutants, etc.

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

"Treatment," "treating," and the like, as used herein, unless otherwise indicated, refer to the control, prophylaxis, reversal, alleviation, mitigation, or inhibition of inflammation caused by environmental factors, bacterial, viral, fungal, or parasitic infection, and/or internal disease by attenuating the immunological response. As used herein, these terms also encompass, depending on the condition of the animal, the prevention of 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 with it. Treatment may also refer to the administration of a compound of the invention to an animal that is not suffering from an infection, immunological episode, or disease disorder or complex at the time of administration. It is understood that it may not always be possible to distinguish between "prevention" and "suppression" of a disease or disorder, since the ultimate inductive event or events may be unknown or latent.

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

The compounds of this invention have several asymmetric centers. Compounds with asymmetric centers give rise to 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 this invention. It is intended that this invention encompass all steric forms of the compounds of this invention. This invention includes all stereoisomers of the compounds of this invention.

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

The derivatives can then be converted into pure stereomers by cleavage of the added chiral residue. The racemic mixture of compounds can also be separated directly by chromatographic methods using chiral stationary phases, and these methods are well known in the art. Alternatively, any stereomers of the 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 the processes for preparing the compounds of this 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 by using conventional protecting groups such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting groups can be removed at a convenient subsequent stage using methods known in the art.

Macrolide chemistry

Macrolides are known to have a strong binding affinity to the P-site of the 50S subunit of the bacterial ribosome and inhibit protein synthesis. Modification of the desosamine group of a macrolide blocks this interaction either by modifying the dimethylamino group to block the salt bridge or by modifying the adjacent hydroxyl group to affect the resulting hydrogen bond, thereby eliminating the antibacterial activity of the compounds of this invention. Although modifications of cladinose have a relatively lesser effect on the binding of bacterial ribosomes, they can potentially affect the physicochemical properties, pharmacokinetics and cellular permeability of the compound. Modifying the structure of a macrolide in this way isolates the molecule from entering the bacteria or enhances the efflux from the bacteria, which reduces or eliminates the antibacterial activity even with the ability to bind the bacterial ribosome.

Lipophilicity

The lipophilicity of an organic compound can be described by the partition coefficient logP, which can be defined as the ratio of the concentration of the unionized compound at equilibrium between the organic and aqueous phases. Generally speaking, more lipophilic compounds are less soluble in aqueous media. A negative logP value means that the compound has a higher affinity for the aqueous phase (hydrophilic); at 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 determinant of compound absorption, distribution in the body, penetration through vital membranes and biological barriers, metabolism and excretion. The compounds of the present invention are lipophilic (logP from ~1 to 5758), which facilitates their transport and absorption into respiratory tissues, such as the lungs.

Composition / Structure

The pharmaceutical compositions of the present invention can be prepared by methods well known in the art, for example, by conventional processes of mixing, dissolving, granulating, dragee making, levitating, emulsifying, encapsulating, encapsulating, lyophilizing or spray drying. The pharmaceutical compositions for use according to the present invention can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers that facilitate processing of the active compound into preparations for administration to an animal in need thereof. The formulations of the present invention can be designed to be short-acting, fast-release, long-acting and sustained release. Thus, the pharmaceutical compositions can also be formulated for controlled release or for slow release; and depend on the chosen route of administration.

Pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are thus 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).

For BRD and SRD, the pharmaceutical compositions are typically formulated for parenteral administration, such as in a liquid carrier or are suitable for reconstitution into a liquid solution or suspension for parenteral administration. In general, such compositions typically contain a pharmaceutically acceptable carrier. The pharmaceutical carriers of the present invention can be sterile liquids such as, but not limited to, water, saline solutions, aqueous dextrose solutions, aqueous glycerol solutions; and/or oils, including paraffin, animal, vegetable or synthetic oils 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 this invention can be administered orally, topically, parenterally (i.e., intramuscular, subcutaneous, intravenous, and intradermal injection). Pharmaceutical compositions containing a compound of this invention can also be administered by intramammary and intrauterine injection.

The pharmaceutical compositions and formulations defined herein can be prepared by using a compound of the invention having the desired degree of purity with one or more pharmaceutically acceptable carrier(s) in the form of lyophilized formulations or aqueous solutions. The term "carrier" refers to a diluent, excipient or vehicle with which the compound of the invention is administered. Pharmaceutically acceptable carriers are generally nontoxic to recipients at the dosages and concentrations employed 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 (e.g., butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), sodium metabisulfite, monothioglycerol, propyl gallate, etc.); preservatives (e.g., octadecyldimethylbenzylammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl or benzyl alcohol, chlorobutanol, thimerosal, alkyl parabens such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol, m-cresol, etc.); hydrophilic polymers (e.g. polyvinylpyrrolidone (PVP), polyethyleneglycol (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 (e.g. Zn-protein complexes). The carrier can be a solvent or a reconstitution medium or a dispersion medium containing, for example, water, ethanol, a polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol, etc.) and suitable mixtures thereof. For intravenous administration, suitable carriers include saline, bacteriostatic water or phosphate buffered saline (PBS). Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

Solutions or suspensions used for parenteral administration usually include one or more of the following: a sterile vehicle such as water for injection, saline, fixed oils, polyethyleneglycols, glycerol, 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 for the adjustment of tonicity such as sodium chloride or dextrose. The pH may be adjusted with acids or bases such as hydrochloric acid, citric acid, or sodium hydroxide. Such preparations may be enclosed in ampoules, disposable syringes, or multiple-dose vials made of glass or plastic. Formulations used for in vivo administration are typically sterile. Sterility can be readily achieved, for example, by filtration through sterile filter membranes and irradiation. Injectable compositions may contain the active ingredient (drug) in amounts of about 1 to 250 mg/mL, and more preferably in concentrations of about 1 to 100 mg/mL. Without limiting the scope of the composition components, an injectable composition containing a compound of formula (1), a pharmaceutically acceptable salt (e.g., acetate) thereof, can be prepared by dissolving the compound (e.g., 1 to 25 mg/mL) in a composition containing citric acid, propylene glycol, water, and optionally an antioxidant (e.g., monothioglycerol). As described herein, the composition may contain about 90% (±~6%) lactone A and 10% lactone B (±~6%) of the compound of formula (1). If necessary, the pH of the composition can be adjusted with NaOH and/or HCl. Methods for preparing such compositions will be apparent to those skilled in the art and may be prepared in accordance with the procedures described in U.S. Patent No. 6,514,945.

For oral administration, the pharmaceutical compositions of the invention can be administered, for example, in the form of tablets or capsules, powders, dispersible granules or wafers, or as aqueous solutions or suspensions. Compositions for oral administration typically include an inert carrier or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For oral administration, the therapeutic agents can be combined with carriers and used in the form of tablets, troches or capsules. Pharmaceutically compatible binders and/or excipients can be included as part of the composition. Tablets, pills, capsules, troches and the like can contain any of the following ingredients or compounds of a similar nature; a binder such as microcrystalline cellulose, tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, sodium starch glycolate or corn starch; a lubricant such as magnesium stearate or stearates; a lubricant such as colloidal silicon dioxide; a sweetener such as sucrose or saccharin; or a flavoring agent.

Dosage

Pharmaceutical compositions suitable for use in the present invention include those 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 present invention that is effective in preventing, alleviating or improving the symptoms/signs of a disease or prolonging the survival of an animal undergoing treatment. The amount of the active component, which is a compound of the present invention, in the pharmaceutical composition and its unit dosage form can be varied or adjusted within wide limits depending on the route of administration, the potency of the particular compound and the desired concentration. Determination of a therapeutically effective amount is within the competence of those skilled in the art. Typically, the amount of the active component will be in the range of from 0.01% to 99% by weight of the composition.

Generally, a therapeutically effective amount of the active ingredient will be in the range of 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, still more preferably from about 0.06 mg/kg to about 0.6 mg/kg body weight. A preferred dosage regimen is parenteral administration of from about 0.05 mg/kg to about 0.8 mg/kg body weight by subcutaneous injection. It will be understood that dosages may vary depending on the requirements of each animal and the severity of the disorder or disease being treated. The desired dosage may conveniently be presented as a single dose or as divided doses administered at appropriate intervals during the course of treatment. The preferred route of administration is parenteral. Parenteral administration includes intravenous, intramuscular and subcutaneous administration. 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 departure from a farm or ranch, or upon arrival at a feedlot.

The compound of the present invention can be administered in a pharmaceutically acceptable form either alone or in combination with one or more additional agents that modulate the mammalian immune system, or with anti-inflammatory agents, or with one or more antibacterial agents. In addition, the compounds of the present invention can also be co-administered with vitamins and/or minerals. Non-limiting examples of anti-inflammatory agents include: ketoprofen, cyclosporine A, rapamycin, FK-506 (tacrolimus), leflunomide, deoxyspergualin, mycophenolate, azathioprine, daclizumab, aspirin, acetaminophen, ibuprofen, naproxen, piroxicam, and anti-inflammatory steroids (e.g. prednisolone or dexamethasone). Non-limiting examples of antibacterial agents include: novobiocin, aminoglycosides (e.g. gentamicin, neomycin, dihydrostreptomycin, spectinomycin, etc.), florfenicol, ceftiofur, cephapirin, ormetoprim, danofloxacin, enrofloxacin, bambermycins, ionophores (e.g. laylomycin, lasalocid, monensin, narasin, salinomycin, lincomycin, pirlimycin, macrolides (e.g. erythromycin, gamithromycin, tildipirosin, tilmicosin, tulathromycin, M9-metabolite of tulathromycin, tylosin, tilvalosin, etc.), avilamycin, penicillins (e.g. amoxicillin, ampicillin, cloxacillin, penicillin and 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, 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 separate dosage forms, by the same or different routes of administration, and on the same or different schedules of administration in in accordance with standard medical or veterinary practice known to one skilled in the art.

Medical and veterinary use

The methods defined herein are typically administered to animals in need thereof. An animal in need thereof may be an animal that has, has been diagnosed with, is suspected of having, or is at risk of developing a disease, disorder, or condition associated with a bacterial infection, a viral infection, a parasitic infection, inflammation, or an immune response. The disease or disorder may include a respiratory disease, reproductive diseases such as mastitis or metritis, inflammatory bowel disease, bovine viral diarrhea virus (BVDV), infectious bovine rhinotracheitis (IBR), bovine respiratory syncytial virus (BRSV), parainfluenza virus, bovine coronavirus, psoriasis, multiple sclerosis, rheumatoid arthritis, allergic autoinflammatory diseases, or autoimmune diseases. Typically, a safe and effective amount of a compound of this invention is, for example, an amount that can cause a desired therapeutic effect in an animal while minimizing unwanted side effects. In various embodiments, an effective amount of a compound of this invention can significantly alleviate 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.

The compounds of the present invention are macrolide (azalide) analogs that lack antibacterial activity against BRD pathogens and have been shown to have immunomodulatory properties that can prevent and/or control the symptoms of BRD in cattle. Accordingly, these macrolides are useful therapeutic agents for the treatment and/or control of respiratory diseases that can be triggered by environmental irritants, stress, and bacterial infection. Some non-limiting macrolides used to treat BRD include: Draxxin® (tulathromycin), Zuprevo® (tildipirosine), and Zactran® (gamitromycin), and the like.

Draxxin®, injectable solution, is indicated for the treatment of bovine respiratory disease (BRD) associated with Mannheimia haemolytica, Pasteurella multocida, Histophilus somni, and Mycoplasma bovis; and for the control of respiratory disease in cattle at high risk of developing BRD associated with Mannheimia haemolytica, Pasteurella multocida, Histophilus somni, and Mycoplasma bovis. Cattle receive a subcutaneous dose of 2.5 mg/kg Draxxin®. In swine, Draxxin® is indicated for the treatment of porcine respiratory disease (SRD) associated with Actinobacillus pleuropneumoniae, Pasteurella multocida, Bordetella bronchiseptica, Haemophilus parasuis, and Mycoplasma hyopneumoniae; and for the control of SRD associated with Actinobacillus pleuropneumoniae, Pasteurella multocida and Mycoplasma hyopneumoniae in groups of pigs diagnosed with SRD. Pigs are administered 2.5 mg/kg Draxxin® intramuscularly.

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

Trauma, inflammation, or infection result in activation of the inflammatory cascade. Initially, proinflammatory activation occurs, but almost immediately thereafter, a reactive, suppressive anti-inflammatory response occurs. This systemic inflammatory response (SIR) typically manifests as increased systemic expression of both proinflammatory and anti-inflammatory substances. The SIR begins with inflammation as a response to exogenous (microbial, physical, or chemical) agents or endogenous (immunologic or neurologic) factors. The response begins when inflammatory cells at the site of inflammation, such as macrophages, become activated and rapidly produce TNF-α and IL-1. These cytokines, in turn, activate the cytokine cascade, resulting in the production of the proinflammatory cytokines IL-6 and IL-8, as well as other chemokines. Inflammatory stimuli also trigger the synthesis of anti-inflammatory cytokines and specific cytokine inhibitors, which control the extent of the inflammatory response. Anti-inflammatory cytokines such as IL-4, IL-10, IL-11, and IL-13 inhibit the synthesis of proinflammatory cytokines, while natural inhibitors of proinflammatory cytokines neutralize the activity of proinflammatory cytokines by binding to proinflammatory cytokine receptors, decoy receptor antagonists, and cytokine binding proteins. The interplay of these proinflammatory cytokines, anti-inflammatory cytokines, and naturally occurring cytokine inhibitors determines the inflammatory response and its effectiveness in curbing the inflammatory response and resolving the initiating process. The major 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-derived cytokines, which target target organ receptors in response to injury or infection. However, in order to attenuate and stop the inflammatory response, anti-inflammatory protein and lipid molecules will also be produced. These mediators initiate overlapping processes that directly affect the endothelium, cardiovascular, hemodynamic and coagulation mechanisms. If the balance between pro- and anti-inflammatory substances is not established and homeostasis is not restored, a massive pro-inflammatory reaction (i.e. SIRS) and multiple organ dysfunction (MODS) can occur. Thus, after the release of the first pro-inflammatory mediators, the body initiates a compensatory anti-inflammatory response to the initial inflammatory reaction. The anti-inflammatory response can be as strong as, and sometimes even stronger than, the pro-inflammatory reaction. In addition to pro-inflammatory cytokines, other mediators such as NO, PAF, prostaglandins and leukotrienes are also produced. These molecules are also responsible for the activation of the complement, coagulation and 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 allergy age-related macular degeneration dermatitis pain mastitis metritis autoinflammatory disease autoimmune disease inflammatory bowel disease dermatitis multiple sclerosis osteoarthritis osteoporosis psoriasis rheumatoid and osteoarthritic arthritis synovitis acne pustulosis hyperostosis airway and respiratory diseases (e.g. equine respiratory disease and canine infectious respiratory disease) respiratory disease complex (bovine and porcine), ischemia-reperfusion injury, feline chronic kidney disease, feline and canine degenerative mitral valve disease (inflammatory complex; e.g., proinflammatory cytokines in heart failure via increased expression of cytokines in valves and myocardium, chemokines, and adhesion molecules), psoriasis, multiple sclerosis, autoinflammatory diseases rheumatoid arthritis, peptic ulcer disease, tuberculosis, periodontitis, otitis media, 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, amebiasis, giardiasis, fascioliasis, fasciolopsiasis, elephantitis, cryptosporidiosis, leishmaniasis, microsporidiosis, trypanosomiasis, toxoplasmosis and the like; and other inflammatory and immune diseases and disorders. The compound of the present invention can treat a disease, disorder or condition associated with inflammation by modulating cytokines, chemokines and inflammatory markers, such as IL6, IL-1β, NFKB, CSP136, LCN, CXCL8 (IL-8), TNFα, and induce TLR4 signaling.

Immunomodulation with macrolides

The chemical composition of macrolides provides the basis for understanding their immunomodulatory actions. Macrolides are defined as cationic amphiphilic drugs; cellular penetration is determined primarily by their lipophilicity and cationic nature at physiological pH. Penetration of macrolides into the cell membrane results in depolarization of phospholipids, resulting in translocation of both drug and phospholipid into the cytosol and lysosomes, ultimately leading to a cellular state of phospholipidosis. Polar association with phospholipids, primarily phosphatidylcholine, within cells inhibits natural degradation by phospholipase enzymes; resulting in a decrease in primary cellular signaling components such as arachidonic acid and others. Decreased arachidonic acid is thought to prevent 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, as a result, their production of proinflammatory cytokines. The reduced ability of cells to transmit signals both intracellularly and extracellularly depends on the host context. In healthy animals, macrolide treatment has been shown to stimulate the response of neutrophils and macrophages to a painful stimulus. However, in the presence of acute or chronic inflammation, inhibition or reversal of inflammation is observed.

Modulation of host defense by azithromycin and other macrolide antibiotics occurs through interactions with structural cells such as epithelial or endothelial cells, smooth muscle cells or fibroblasts, and leukocytes (macrophages, polymorphonuclear leukocytes or neutrophils, mononuclear leukocytes or monocytes, T cells, and dendritic cells). Cellular accumulation of macrolides represents a mechanism of passive transport into cells that does not require cellular energy or carrier proteins and is nonsaturable. This mechanism is distinct from ribosome binding, which is associated with antibiotic activity and is therefore unrelated to it. For example, the aglycone of azithromycin, which has no antibiotic activity, exhibits high levels of induced phospholipidosis (J. Parnham et al. / Pharmacology & Therapeutics 143 (2014) 225-245). Azithromycin penetrates the cell membrane bilayer and stabilizes the membrane by reducing fluidity and neutralizing the charge of phospholipids on the inner leaflet membrane. This results in decreased release of fatty acids and release of enzymes electrostatically bound to the membrane, 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 by which it is activated. Molecules dependent on negatively charged phospholipids are also affected. Azithromycin accumulates in lysosomes, modulating MPR transport of enzymes and lipids, as well as through lipid remodeling in lysosomal membranes. One well-documented aspect is their ability to mitigate inflammatory responses, as evidenced by the suppression of increased cytokine production (IL-1β, TNF-α, IL-6) via the NFκB pathway and effects on granulocytes and/or gene expression.

Immunological activity can also be assessed by analyzing CD163. CD163 is a scavenger receptor that binds hemoglobin/haptoglobin and is expressed on macrophages, which are thought to be involved in innate immune sensing, which promotes the clearance of activated macrophages, thereby preventing oxidative tissue damage.

CD163 also acts as an innate immune sensor for Gram-positive and Gram-negative bacteria. Accordingly, high expression of CD 163 in macrophages is a characteristic of tissues responding to inflammation and is considered a highly correlated biomarker of inflammation. Clearance of oxidative and proinflammatory hemoglobin, leading to stimulation of heme oxygenase-1 and production of anti-inflammatory heme metabolites, suggests that CD 163 thereby indirectly contributes to 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 injury in BRD. CD163 expression may also correlate with elevated IL-6 levels, which is observed in BRD. CD163 surface expression was experimentally induced by 253 +/- 4.9% in monocytes and macrophages upon incubation with IL-6 (Journal of Leukocyte Biology; Buechler et al. vol. 67 January 2020; pp. 97-103). Alternatively, cross-linking of CD163 on alveolar macrophages with monoclonal antibodies induced a protein tyrosine kinase-dependent signal that resulted in slow-type calcium mobilization, inositol triphosphate production, and IL-6 and GM-CSF secretion (Journal of Leukocyte Biology; Van de Heuvel et al. vol. 66 November 1999; pp. 858-866). The anti-inflammatory immunomodulatory drug tacrolimus has been shown to modestly increase CD163 expression (PLOS ONE; Kannegleter, et. al., January, 2017; pp, 1-19); however, a more recent study (HHS Public Access; Motta, et. al., Oral Dis. 2018, 24(4) pp, 580-590) reported that therapy did not result in changes in CD163 expression. Similarly, azithromycin (British Journal of Pharmacology, Vrancic, et. al; 2012, 165; pp, 1348-1360) has been reported to increase CD163 expression. CD163 expression increases glucocorticoids, IL-6, IL-10, and hemoglobin levels; and suppresses IL-4, IFN-γ, TNF-α, CXCL4 and GM-CSF. In contrast, CD 163 was suppressed in M9-treated cattle, which correlates with the proposed mechanism of reduced inflammatory state.

Cytokines are considered to be a broad and loose category of small proteins (5-20 kDa) that play important roles in cell signaling. Their release influences 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. Cytokines as known include chemokines, interferons, interleukins, lymphokines, and tumor necrosis factors (TNF), but usually not hormones or growth factors. Cytokines can be produced by a wide variety of cells, including immune cells such as macrophages, neutrophils, B lymphocytes, T lymphocytes, and mast cells, as well as epithelial cells, endothelial cells, fibroblasts, and various stromal cells; a given cytokine may 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 regulate the maturation, growth, or sensitivity of specific cell populations. Some cytokines can enhance or inhibit the action of other cytokines in complex ways. Cytokines may play important roles in health and disease, particularly in the body’s responses to infection, immune responses, inflammation, stress, injury, sepsis, cancer, and reproduction.

Interleukin 6 (IL-6) is a pleotropic cytokine that acts both as a proinflammatory cytokine and an anti-inflammatory myokine. IL-6 is produced and secreted by a variety of cells, including B cells, T cells, endothelial cells, and macrophages, to stimulate the immune response via the classical signaling pathway when it binds to the IL-6 transmembrane receptor (IL-6R) or via the trans-signaling pathway when it binds 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 action 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 states, including various inflammatory diseases. IL-6 has been reported to induce the production of vascular endothelial growth factor, which enhances angiogenesis and increases vascular permeability, a hallmark of some inflammatory diseases. IL-6 has also been implicated in enhancing the 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 IL-6 and sIL-6R levels, setting the stage for the amplification stage of chronic inflammatory responses. IL-6 has been implicated in the development of pulmonary neutrophilia by enhancing both the recruitment of neutrophils from blood and bone marrow and neutrophil survival. The role of IL-6 as an anti-inflammatory cytokine is mediated through its inhibitory effects on TNF-α and IL-1, as well as the activation of IL-1ra and IL-10.

IL-6, like other inflammatory cytokines, has been shown to be elevated in various lung diseases in humans and mice. IL-6 was elevated in bovine BRD (M. hemolytica) infection and correlated with higher rectal temperature, lung injury, and mortality. The compounds of the invention, M9, and tulathromycin significantly reduced IL-6 levels, which also correlated with overall animal survival. Thus, the immunomodulatory compounds of the invention attenuate pathological IL-6 elevation in a dose- and clinical outcome-dependent manner.

IL-36 is a member of the IL-1 superfamily of cytokines and includes three agonists (IL-36α, IL-36β, and IL-36γ) and an antagonist (IL-36RA). IL-36 agonists bind to heterodimeric IL-36 receptor (IL-36R) complexes, inducing a proinflammatory response. The antagonist binds to IL-36R, thereby inhibiting IL-36 signaling. IL-36 signaling occurs through the formation of a heterotrimeric complex of IL-36, IL-36R, and IL-1AcP (IL-1 accessory protein) and the activation of the adaptor protein, myeloid differentiation protein 88 (MyD88), mitogen-activated protein kinase (MAPK), and nuclear factor kappa B (NF-κB) signaling pathways and induces inflammatory responses. IL-36RA prevents the interaction between IL-1AcP and the receptor-ligand complex. IL-36 proteins are widely expressed in T cells, keratinocytes, skin, lung and intestinal cells. IL-36 agonists bind to the receptors [IL-36R and IL-1 receptor accessory protein (IL-1RAcP)] and are then activated. Finally, these pathways initiate the regulation of target genes. Recent evidence suggests that IL-36 regulates the function of both non-immune and immune cells; and is involved in immune cell activation, antigen presentation and the production of proinflammatory factors. IL-36 has attracted much interest due to its dysregulation in inflammatory diseases. For example, IL-36 expression in serum and tissues was 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 derives from their ability to induce directed chemotaxis in nearby susceptible cells (i.e., chemotactic cytokines); this stimulates leukocyte recruitment. The primary function of chemokines is to direct leukocyte migration (homing) to appropriate anatomical sites during inflammatory and homeostatic processes. They are secondary inflammatory mediators that are induced by primary inflammatory mediators such as IL-1 or TNF. Depending on the position of the cysteine residues, two main subfamilies of chemokines are distinguished: CXC and CC. All members of the CXC chemokine subfamily have an intervening amino acid between the first two cysteines; members of the CC chemokine subfamily have two adjacent cysteines. In general, members of the CXC chemokines are chemotactic for neutrophils, and CC chemokines are chemotactic for monocytes and a small subset of lymphocytes. Some chemokines are considered proinflammatory and may be induced during an immune response to recruit immune system cells to the site of infection or tissue injury, while others are considered homeostatic and are involved in the control of cell migration during normal tissue maintenance or developmental processes (e.g., angiogenesis).

Inflammatory chemokines are produced under pathological conditions (in response to proinflammatory stimuli such as IL-1, TNF-α, LPS or viruses) and actively participate in the inflammatory response by attracting 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 damaged area. A typical example is CXCL8, which acts as a chemoattractant for neutrophils. Unlike homeostatic chemokine receptors, there is considerable promiscuity (redundancy) associated with receptor binding and inflammatory chemokines.

Interleukin-8 (IL-8) is a proinflammatory chemokine that recruits and activates immune and inflammatory cells. IL-8 mediates a number of biological effects, including several involving neutrophils: inflammatory cell activation and chemotaxis, reactive oxygen species production, increased CD11b-CD18 integrin expression, 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 an innate exogenous/endogenous stimulus. In target cells, IL-8 induces a number of physiological responses required 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 aimed at eliminating the infectious agent, removing damaged or dead cells and initiating the healing process. However, excessive recruitment of these cells, prolonged residence time and cell death lead to tissue injury. Thus, the influx of excess inflammatory cells is thought to play an important role in the pathophysiology of pulmonary diseases such as human inflammatory conditions such as chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), asthma, pulmonary fibrosis and bacterial pneumonia. It has also been observed in bovine respiratory disease (BRD) and bacterial pneumonia. Controlling the recruitment and activation of these cells in the lung could be an attractive strategy for therapeutic intervention. In all these conditions, IL-8 appears to be important for the recruitment and activation of neutrophils and T cells into the airways.

In an experimental study of cattle infection with M. hemolytica, one of the main causative agents of BRD, IL-8 levels were increased in serum and tissues. The compounds of the present invention were shown to suppress IL-8 production in this infection model, and this correlated with attenuation of the anti-inflammatory response and disease progression.

Biology of BRD

The pathobiology of BRD has long been thought to be due to stress-induced immune suppression, which leaves calves vulnerable to the myriad of microorganisms they encounter during the transition from the cow shed to the feedlot. The dogma suggests that stimulation of the innate immune system will have a positive impact on clinical outcome. However, to date, interventions consistent with this dogma, including the use of DNA immunostimulants (Zelnate®), have had limited success. In an effort to better understand the progression of BRD, earlier studies have shown that it is the early, unresolved exacerbation of the inflammatory process, rather than immunosuppression, that drives the progression of BRD.

Based on ongoing research into the etiology of BRD, new insights into the immunological status have revealed that although an elevated proinflammatory state is ubiquitous in at-risk cattle, the persistence or lack of resolution/mitigation of this state coincides with disease outcome. Following delivery, upon arrival at the feedlot, the proinflammatory state is particularly characterized by innate immune components such as disruption of the nasal mucosal epithelial cell barrier and release of preformed mediators such as members of the IL-1 cytokine family. Activation of danger-associated molecules (DAMPs), including the pattern recognition receptor (PRR) TLR-4 and inflammatory signaling, demonstrates the response of epithelial and resident myeloid cells to co-localized microbes in the upper respiratory tract. As 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 inflammation such as IL-1β, IL-6 and TNF-α and myeloid-derived granulocytes including macrophages and neutrophils are recruited and activated. These cascades create an environment in which bacteria normally restricted to the upper respiratory tract can invade the lungs and cause disease. Biomarkers of inflammation such as elevated levels of secreted cytokines such as IL-6 and acute phase proteins are associated with clinical disease. Markers of cellular activation such as expression of the scavenger receptor CD 163 on macrophages and neutrophil-associated mediators such as LCN and CXCL8 are also associated with clinical disease. The compounds of the present invention effectively alleviate the elevated proinflammatory state in at-risk cattle by balancing the immune response and reducing the pathological inflammatory cascade. This mechanism of action of the immunomodulator in the context of BRD progression is depicted in Fig. 1.

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

Schemes and experiments

Tulathromycin A is a 15-membered (lactone A) closed-ring antibacterial macrolide (azalide). The azalide is converted to a 13-membered (lactone B) closed-ring, tulathromycin B. This conversion occurs at equilibrium at about 9:1 (A:B) and is shown 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 precursor of tulathromycin, tulathromycin epoxide (tula-epx), is (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((3S,4S,6R,8R)-8-methoxy-4,8-dimethyl-1,5-dioxaspiro[2.5]octan-6-yl)oxy)-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one.

One of the metabolites of tulathromycin A is desmethylazalide, (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)-tetrahydro-2H-pyran-2-yl)oxy)-11-(((2S,3R,4S,6R)-3-hydroxy-6-methyl-4-(methylamino)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one (M9), shown in the following diagrams below:

Tulathromycin B is also metabolized to B-desmethylazalide.

An analogue of M9 can be used as a starting material for the preparation of compounds of the present invention. The process for preparing desmethyltulathromycin (M9) is a two-step process from tulathromycin A, and the intermediate is not usually isolated, but can be isolated. The first step is the oxidation of the tertiary amine to the N-oxide using any number of oxidizing agents known to oxidize tertiary amines. The second step is a Polonovski-type demethylation, which can use any metal known to effect this type of transformation. Typically this is 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 commercial 32% peracetic acid. After 30 min, the product was extracted with 0.25 M aqueous disodium ethylenediaminetetraacetic acid (EDTA, 15 mL). The aqueous solution was basified to pH 9.5 with concentrated aqueous ammonia and extracted with tert-butyl methyl ether (20 mL). The N-oxide product was concentrated to a thick oil but 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 mixture was heated to 60 °C for 1-2 h. The solution was cooled to 25 °C and hydroxyamine hydrochloride (0.75 g, 10 mmol) in water (8 mL) was added. After 2 h, the product was partitioned between water (28 mL, pH adjusted to 9.5 with aqueous ammonia) and methylene chloride (20 mL). The organic phases were concentrated to an oil and the product was crystallized from hot acetonitrile (40 mL). The resulting white crystalline powder was dried to give 3.2 g of M9. LCMS [M+H] ⁺ = 792.5. HPLC purity >98%. ^1H 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 30% aqueous hydrogen peroxide solution (0.62 g, 5.5 mmol). After 4 h, acetic acid (0.31 g, 5.5 mmol) was added, followed by methyl tert-butyl ether (6 mL) and water (25 mL). The upper organic layer was discarded. Methyl tert-butyl ether (8 mL) was added and the pH of the aqueous layer was adjusted to 9.8 with aqueous ammonia. The lower aqueous layer was discarded. The N-oxide product was concentrated to a thick oil but not isolated. [M+H] ⁺ = 822. The oil was dissolved in methanol (12 mL). Anhydrous copper(II) sulfate (0.97 g, 6.1 mmol) and acetic acid (0.28 mL) were added and the reaction mixture was heated to 60 °C for 1 h. The solution was cooled to 25 °C and hydroxyamine hydrochloride (0.75 g, 10 mmol) in water (8 mL) was added. After 2 h, the product was partitioned between water (28 mL, pH adjusted to 9.5 with aqueous ammonia) and methylene chloride (20 mL). The organic phases were concentrated to an oil and the product was crystallized from hot acetonitrile (40 mL). The resulting white crystalline powder was dried to give 3.2 g of product; LCMS [M+H] ⁺ = 792.5. HPLC purity >98%. 1H NMR (600 MHz, d6-DMSO): N-Me (3H, 2.42 ppm, s) versus tulathromycin NMe2 (6H, 2.26 ppm).

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

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

Azithromycin (pictured below), an azalide similar to tulathromycin except that the N core is substituted with a methyl group (1') and the cladinose sugar is not further substituted with N-methylpropan-1-amine (2'); pictured below.

Azithromycin can be derivatized to produce a desmethyl analog similar to M9. Further derivatizations can be carried out in accordance with the schemes and experiments defined herein to produce immunomodulatory derivatives of azithromycin that are inactive (i.e., non-antibacterial) against BRD bacterial pathogens. In addition to azithromycin, other macrolides such as erythromycin, tilmicosin, clarithromycin, gamithromycin, fidaxomicin, roxithromycin, telithromycin, dirithromycin, josamycin, midecamycin, oleandomycin, roxithromycin and other modulatory analogs that lack antibacterial properties against BRD and other bacterial pathogens in animals, including humans, can be modified similarly to M9 to prepare immune preparations.

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

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

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

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

The following schemes and experimental preparations use the following abbreviations: methanol (MeOH), ethanol (EtOH), dichloromethane (DCM), dichloroethane (DCE); hexafluoroisopropyl sulfamate (HFIPS); trifluoroacetic acid (TFA), hydrogen peroxide ( _H2O2 ), _potassium cyanide (KCN), triethylamine (TEA), ethylenediaminetetraacetic acid (EDTA), acetic acid (AcOH), ammonium hydroxide ( _NH4OH ), acetonitrile (MeCN or Acn), ethyl acetate (EtOAc), tert-butyl alcohol (t-BuOH) or to be announced); sodium methoxide (MeONa); N-methyl-2-pyrrolidine (NMP); Cerium (III) chloride (CeCl ₃ ), sodium azide (NaN ₃ ), sodium hydrogen carbonate (NaHCO ₃ ), ammonium chloride (NH ₄ Cl), N-iodosuccinimide (NIS), magnesium sulfate (MgSO ₄ ); sodium sulfate (Na ₂ SO ₄ ), ammonium sulfate ((NH ₄ ) ₂ SO ₄ ), copper sulfate (CuSO ₄ ), sodium triacetoxyborohydride (STAB); N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC.HCl); sodium cyanoborohydride (NaBH ₃ CN); N,N-diisoethylpropylamine (DIPEA); dimethylformamide (DMF); 1-butanol (N-BuOH); hexafluoroacetone ((CF ₃ ) ₂ CO-H ₂ O), hydrochloric acid (HCl); water ( _H2O ), methoxy (OMe); fluorine (F); chlorine (O); methyl (Me); trifluoromethyl ( _CF3 ); room temperature (RT); and overnight (OV).

In the following schemes, for example, in scheme 1a, the formulas are depicted as s1a-A1 through s1a-A6; refers to scheme 1a (s1a), and -A1 refers to formula A1, as described herein; and then s1a-A2, s1a-A3, s1a-A4, s1a-A5 and s1a-A6 refer to the corresponding formulas A2, A3, A4, A5 and A6, as described herein.

Scheme 1a. Obtaining formula (1) Sulfonamide compounds from 1-A1 to 1-A6

Sulfonamide analogs can be prepared by following the three-step procedure outlined in Scheme 1a above. First, the commercially available tulathromycin epoxide (tula-epx) can be demethylated via, but not limited to, the Polonovski reaction to yield the M9 epoxide (M9-epx). The N-oxide can be formed using various oxidizing agents such as iodine, N-iodosuccinimide, peracetic acid, or hydrogen peroxide. Demethylation of the N-oxide can be catalyzed by iron or copper salts. The secondary amine thus formed can be converted to various sulfonamides using sulfonylating reagents such as sulfonyl chlorides, fluorides, and others. Mild bases such as TEA or DIPEA can sometimes be used to facilitate the sulfonamide formation reaction. In the final step, the epoxide functionality can be opened to give the final sulfonamide analogs using various nucleophiles such as primary and secondary amines, alcohols, thiols, cyanide, azide or halogen anions and others, at higher temperature in alcoholic solvents such as, but not limited to, 1-propanol, 1-butanol or 2-propanol. This reaction can be completed overnight. Mild bases such as _NaHCO3 or salts such as _NH4Cl or ( _NH4 ) _{2SO4 can} sometimes accelerate the epoxide opening reaction. For any of the schemes presented herein, the "nucleophile" of the epoxide opening step in the cladinose ring may be, but is not limited to, the following: HNR ⁵ R ⁶ , HOR ⁷ , HS(O) _p R ⁷ , NaN ₃ , CeCl ₃ , TEA.3HF and KCN, where R ⁵ , R ⁶ , R ⁷ and p are defined herein.

For analogs (s1b-A1), the epoxide functionality can be opened to give the final sulfonamide analogs using various primary or secondary amines in alcoholic solvents such as, but not limited to, methanol, ethanol, 1-propanol, and others. For analogs (s1b-A2), the epoxide functionality can be opened to give the final sulfonamide analogs using various alcohols used as solvents such as, but not limited to, methanol, ethanol, 1-propanol, and others. Mild bases such as _NaHCO3 or salts such _{as NH4Cl or (NH4)2SO4 can sometimes accelerate} the epoxide opening reaction. For analogs (s1b-A3), the epoxide functionality can be opened to give the final sulfonamide analogs using various thiols such as but not limited to ethanethiol, propanethiol, isopropyl mercaptan, and others in alcoholic solvents such as but not limited to ethanol or 1-propanol. Mild bases such as but not limited to NaHCO ₃ are used to accelerate the epoxide opening reaction. For analogs (s1b-A4), the epoxide functionality can be opened to give the final sulfonamide analogs using various halides from reagents such as but not limited to CeCl ₃ or Br ₂ in alcoholic solvents such as but not limited to ethanol or 1-propanol. Mild bases such as _NaHCO3 or salts such as _NH4Cl or ( _HN4 ) _2SO4 can sometimes accelerate the epoxide opening reaction. For analogs (s1b-A5), the epoxide functionality can be opened _to give the final sulfonamide analogs using various azide anion sources such as, but not limited to, _NaN3 in alcoholic solvents such as, but not limited to, ethanol or 1-propanol. Mild bases such as _NaHCO3 or salts such _{as NH4Cl or (NH4)2SO4 can sometimes accelerate} the epoxide opening reaction. For analogs (s1b-A6), the epoxide functionality can be opened to give the final sulfonamide analogs using various cyanide anion sources such as, but not limited to, KCN in alcoholic solvents such as, but not limited to _{, IPA or 1-propanol. Mild bases such as NaHCO3 or salts such as NH4Cl or (NH4)2SO4 can sometimes accelerate the} epoxide opening reaction.

Alternatively, sulfonamide analogs 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 higher temperature in alcoholic solvents such as, but not limited to, 1-propanol, ₁ -butanol or 2- _{propanol. This reaction can occur overnight. Mild bases such as NaHCO3 or salts such as NH4Cl or (NH4)2SO4 can sometimes accelerate} the epoxide opening reaction. In the second step, the tertiary dimethylamine in the desosamine sugar can be demethylated using Polonovski-type conditions as described above. The final sulfonamide analogues can be prepared by reacting the secondary methylamine moiety with sulfonylating reagents such as sulfonyl chlorides or fluorides, etc.

For compounds (s2b-A1), the epoxide functional group can be opened using various primary or secondary amines in alcohol solvents such as, but not limited to, methanol, ethanol, 1-propanol, and others. For compounds (s2b-A2), the epoxide functional group can be opened using various alcohols used as solvents such as, but not limited to, methanol, ethanol, 1-propanol, and others. Mild bases such as _NaHCO3 or salts such as _NH4Cl or ( _NH4 ) _{2SO4 can} sometimes accelerate the epoxide opening reaction. For compounds (s2b-A3), the epoxide functionality can be opened using 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. Mild bases such as, but not limited to, NaHCO ₃ are used to accelerate the epoxide opening reaction. For compounds (s2b-A4), the epoxide 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. Mild bases such as _NaHCO3 or salts such as _NH4Cl or ( _NH4 ) _2SO4 can sometimes accelerate the epoxide opening reaction. For compounds ₍ s2b-A5), the epoxide functionality can be opened with azide ion using various azide anion sources such as, but not limited to, _NaN3 in alcoholic solvents such as, but not limited to, ethanol or 1-propanol. Mild bases such as _NaHCO3 or salts such _{as NH4Cl or (NH4)2SO4 can sometimes accelerate} the epoxide opening reaction. For compounds (s2b-A6), the epoxide functionality can be opened with cyanide ion using various cyanide anion sources such as, but not limited to, KCN in alcoholic solvents such as, but not limited to, IPA or 1- _{propanol. Mild bases such as NaHCO3 or salts such as NH4Cl or (NH4)2SO4 can sometimes accelerate the} epoxide opening reaction.

All compounds (s2b-A1)-(s2b-A6) can undergo Polonovski-type demethylation as described above to form the corresponding compounds (s2c-A1)-(s2c-A6). The N-oxide can be formed using various oxidizing agents such as iodine, NIS, peracetic acid or hydrogen peroxide. Demethylation of the N-oxide can be initiated by reagents such as iron or copper salts.

In the last step of the sequence, the final analogs can be prepared by reacting the Polonovsky reaction product (s2c-A1/A6) with sulfonylating reagents such as, but not limited to, sulfonyl chlorides and fluorides, etc. The details of this last transformation are illustrated in Scheme 2d above.

Alternatively, analogs can be prepared as depicted in Scheme 3a. In the first step, commercially available tulathromycin epoxide can be demethylated via, but not limited to, the Polonovsky reaction as described above. The thus obtained M9 epoxide 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 higher temperature in alcoholic solvents such as, but not limited to, 1-propanol, 1-butanol or 2-propanol to open the epoxide moiety. Mild bases such as _NaHCO3 or salts such as _NH4Cl or ( _NH4 ) _{2SO4 can} sometimes accelerate the epoxide opening reaction. The details of this second step are illustrated in Scheme 3b below. In the final step, the final sulfonamide analogs can be prepared by reacting the secondary methylamine moiety with sulfonylating reagents such as, but not limited to, sulfonyl chlorides or fluorides, etc. The details of this last transformation are illustrated in Scheme 3c below.

The M9 epoxide formed by demethylation of commercially available tulathromycin epoxide (Scheme 3a) can be reacted to form the following compounds of the formula: (s3b-A1) with various primary or secondary amines in alcoholic solvents such as, but not limited to, methanol, ethanol, or 1-propanol; (s3b-A2) with various alcohols used as solvent such as, but not limited to, methanol, ethanol, or 1-propanol. Mild bases such as NaHCO ₃ or salts such as NH ₄ Cl or (NH ₄ ) ₂ SO ₄ can sometimes accelerate the epoxide opening reaction; (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. Mild bases such as but not limited to NaHCO ₃ are used to accelerate the epoxide opening reaction; (s3b-A4) - with halides from reactants such as but not limited to CeCl ₃ or Br ₂ , in alcohol solvents such as but not limited to ethanol or 1-propanol. Mild bases such as NaHCO ₃ or salts such as NH ₄ Cl or (HN ₄ ) ₂ SO ₄ can sometimes accelerate the epoxide opening reaction; (s3b-A5) - with 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. Mild bases such as NaHCO ₃ , or salts such as NH ₄ Cl or (NH ₄ ) ₂ SO ₄ , can sometimes accelerate the epoxide opening reaction; and (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. Mild bases such as NaHCO ₃ , or salts such as NH ₄ Cl or (NH ₄ ) ₂ SO ₄ , can sometimes accelerate the epoxide opening reaction.

In the last step of the sequence, the final analogs of formula (s3c-A1), (s3c-A2), (s3c-A3), (s3c-A4), (s3c-A5) and (s3c-A6) can be prepared by reacting the corresponding analogs (s3b-A1/A6) with sulfonylating reagents such as, but not limited to, sulfonyl chlorides or fluorides, etc., in aprotic solvents such as DCM and mild bases such as, but not limited to, TEA or DIPEA.

Sulfonamide analogs can be prepared by the three-step procedure outlined in Scheme 4a above. First, commercially available tulathromycin epoxide (tula-epx) can be demethylated via, but not limited to, the Polonovsky reaction to afford the M9 epoxide (M9-epx). The N-oxide can be formed using various oxidizing agents such as iodine, N-iodosuccinimide, peracetic acid, or hydrogen peroxide. Demethylation of the N-oxide can be initiated with iron or copper salts. The secondary amine thus formed can be converted to various sulfonamides using sulfamoyl fluorides or chlorides, among others. Mild bases such as TEA or DIPEA can sometimes be used to facilitate the sulfonamide formation reaction. Many sulfamoyl fluorides or chlorides are commercially available or can be readily prepared from the corresponding amines using procedures such as described in Ansgew Chem. Int. Ed. 2018, 57, 2605-2610. In the final step, the epoxide functionality can be opened to afford the final sulfonamide analogues using various nucleophiles such as primary and secondary amines, alcohols, thiols, cyanide, azide or halogen anions and others, at higher temperature in alcoholic solvents such as but not limited to 1-propanol, ₁ -butanol or 2- _{propanol. This reaction can be completed overnight. Mild bases such as NaHCO3 or salts such as NH4Cl or (HN4)2SO4 can sometimes accelerate} the epoxide opening reaction. For any of the schemes presented herein, the "nucleophile" of the epoxide opening step in the cladinose ring may be, but is not limited to, the following: HNR ⁵ R ⁶ , HOR ⁷ , HS(O) _p R ⁷ , NaN ₃ , CeCl ₃ , TEA.3HF and KCN, where R ⁵ , R ⁶ , R ⁷ and p are defined herein.

For the (s4b-A1) analogs, the epoxide functionality can be opened to give the final sulfonamide analogs using various primary or secondary amines in alcoholic solvents such as, but not limited to, methanol, ethanol, 1-propanol, and others. For the (s4b-A2) analogs, the epoxide functionality can be opened to give the final sulfonamide analogs using various alcohols used as solvents such as, but not limited to, methanol, ethanol, 1-propanol, and others. Mild bases such _{as NaHCO3 or salts such as NH4Cl or (NH4)2SO4 can sometimes accelerate the} epoxide opening reaction. For the (s4b-A3) analogs, the epoxide functionality can be opened to give the final sulfonamide analogs using various thiols such as, but not limited to, ethanethiol, propanethiol, isopropyl mercaptan, and others in alcoholic solvents such as, but not limited to, ethanol or 1-propanol. Mild bases such as, but not limited to, NaHCO ₃ are used to accelerate the epoxide opening reaction. For the (s4b-A4) analogs, the epoxide functionality can be opened to give the final sulfonamide analogs using various halides from reagents such as, but not limited to, CeCl ₃ or Br ₂ in alcoholic solvents such as, but not limited to, ethanol or 1-propanol. Mild bases such as _NaHCO3 or salts such as _NH4Cl or ( _NH4 ) _2SO4 can sometimes accelerate the epoxide opening reaction. For analogs ₍ s4b-A5), the epoxide functionality can be opened to give the final sulfamide analogs using various azide anion sources such as, but not limited to, _NaN3 in alcoholic solvents such as, but not limited to, ethanol or 1-propanol. Mild bases such as _NaHCO3 or salts such _{as NH4Cl or (NH4)2SO4 can sometimes accelerate} the epoxide opening reaction. For analogs (s4b-A6), the epoxide functionality can be opened to give the final sulfonamide analogs using various cyanide anion sources such as, but not limited to, KCN in alcoholic solvents such as, but not limited to _{, IPA or 1-propanol. Mild bases such as NaHCO3 or salts such as NH4Cl or (NH4)2SO4 can sometimes accelerate the} epoxide opening reaction.

Alternatively, sulfonamide analogs can be prepared according to Scheme 5a. 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 higher temperature in alcoholic solvents such as, but not limited to, 1-propanol, ₁ -butanol or 2- _{propanol. This reaction can occur overnight. Mild bases such as NaHCO3 or salts such as NH4Cl or (NH4)2SO4 can sometimes accelerate} the epoxide opening reaction. In the second step, the tertiary dimethylamine in the desosamine sugar can be demethylated using Polonovski-type conditions as described above. The final sulfonamide analogs can be prepared by reacting the secondary methyl amine moiety with sulfamoyl fluorides or chlorides, etc. Mild bases such as TEA or DDPEA can sometimes be used to facilitate the formation of sulfonamides. Many sulfamoyl fluorides or chlorides are commercially available or can be readily prepared from the corresponding amines using procedures such as those described in Angew Chem. Int. Ed. 2018, 57, 2605–2610.

For compounds (s5b-A1), the epoxide functional group can be opened using various primary or secondary amines in alcohol solvents such as, but not limited to, methanol, ethanol, 1-propanol, and others. For compounds (s5b-A2), the epoxide functional group can be opened using various alcohols used as solvents such as, but not limited to, methanol, ethanol, 1-propanol, and others. Mild bases such as _NaHCO3 or salts such as _NH4Cl or ( _NH4 ) _{2SO4 can} sometimes accelerate the epoxide opening reaction. For compounds (s5b-A3), the epoxide functionality can be opened using various thiols such as, but not limited to, ethanethiol, propanethiol, isopropyl mercaptan, and others in alcoholic solvents such as, but not limited to, ethanol or 1-propanol. Mild bases such as, but not limited to, NaHCO ₃ are used to accelerate the epoxide opening reaction. For compounds (s5b-A4), the epoxide functionality can be opened using various halides from reagents such as, but not limited to, CeCl3 or Br2 in alcoholic solvents such as, but not limited to, ethanol or 1-propanol. Mild bases such as _NaHCO3 or salts such as _NH4Cl or ( _NH4 ) _2SO4 can sometimes accelerate the epoxide opening reaction. For compounds ₍ s5b-A5), the epoxide functionality can be opened with azide ion using various azide anion sources such as, but not limited to, _NaN3 in alcoholic solvents such as, but not limited to, ethanol or 1-propanol. Mild bases such as _NaHCO3 or salts such _{as NH4Cl or (HN4)2SO4 can sometimes accelerate} the epoxide opening reaction. For compounds (s5b-A6), the epoxide functionality can be opened with cyanide ion using various cyanide anion sources such as, but not limited to, KCN in alcoholic solvents such as, but not limited to, IPA or 1- _{propanol. Mild bases such as NaHCO3 or salts such as HN4Cl or (HN4)2SO4 can sometimes accelerate the} epoxide opening reaction.

All compounds (s5b-A1)-(s5b-A6) can undergo Polonovski-type demethylation as described above to form the corresponding compounds (s5c-A1)-(s5c-A6). The N-oxide can be formed using various oxidizing agents such as iodine, NIS, peracetic acid or hydrogen peroxide. Demethylation of the N-oxide can be initiated by reagents such as iron or copper salts.

In the last step of the sequence, the final analogs can be prepared by reacting the Polonovski reaction product (s5c-A1/A6) with sulfamoyl fluorides or chlorides, etc. Sometimes, mild bases such as TEA or DIPEA can be used to facilitate the formation of sulfonamides. Many sulfamoyl fluorides or chlorides are commercially available or can be readily prepared from the corresponding amines using procedures such as those described in Angew Chem. Int. Ed. 2018, 57, 2605–2610. The details of this last transformation are illustrated in Scheme 5d above.

Cyclic sulfamate analogs can be prepared according to Scheme 6a. First, commercially available tulathromycin epoxide (tula-epx) can be demethylated via, but not limited to, the Polonovsky reaction to yield epoxide M9 (ME-epx). The N-oxide can be formed using various oxidizing agents such as iodine, N-iodosuccinimide, peracetic acid, or hydrogen peroxide. Demethylation of the N-oxide can be initiated with iron or copper salts. The resulting secondary amine can be converted to the fluorosulfonamide by reacting the M9 epoxide with commercially available 1-(fluorosulfonyl)-2,3-dimethyl-1H-imidazol-3-ium trifluoromethanesulfonate. In the final step, two transformations occur upon heating in alcoholic solvents such as 1-propanol. First, the epoxide functionality can be opened using a variety of nucleophiles such as primary and secondary amines, alcohols, thiols, cyanide, azide or halogen anions and others at higher temperature in alcoholic solvents such as but not limited to 1-propanol, 1-butanol or 2-propanol. This reaction can be completed overnight. Second, the fluorosulfonamide functionality undergoes intramolecular cyclization to form a cyclic sulfamate moiety under the same conditions. Mild bases such as _NaHCO3 , TEA or DIPEA or salts such _{as NH4Cl or (NH4)2SO4 can sometimes accelerate} the epoxide opening and sulfamate cyclization reaction. For any of the schemes presented herein, the "nucleophile" of the epoxide opening step in the cladinose ring may be, but is not limited to, the following: HNR ⁵ R ⁶ , HOR ⁷ , HS(O)PR ⁷ , NaN ₃ , CeCl ₃ , TEA.3HF and KCN, where R ⁵ , R ⁶ , R ⁷ and p are defined herein.

For compounds (s6b-A1), the epoxide functionality can be opened using various primary or secondary amines in alcoholic solvents such as, but not limited to, methanol, ethanol, 1-propanol, and others while cyclization toward the cyclic sulfamate occurs simultaneously. For compounds (s6b-A2), the epoxide functionality can be opened using various alcohols used as solvents such as, but not limited to, methanol, ethanol, 1-propanol, and others while cyclization toward the cyclic sulfamate occurs simultaneously. Mild bases such as _NaHCO3 or salts such as _NH4Cl or ( _NH4 ) _{2SO4 can} sometimes accelerate the epoxide opening reaction. For compounds (s6b-A3), the epoxide functionality can be opened using various thiols such as but not limited to ethanethiol, propanethiol, isopropyl mercaptan and others in alcoholic solvents such as but not limited to ethanol or 1-propanol while cyclization toward the cyclic sulfamate occurs simultaneously. Mild bases such as but not limited to NaHCO ₃ are used to accelerate the epoxide opening reaction. For compounds (s6b-A4), the epoxide functionality can be opened using various halides from reagents such as but not limited to CeCl ₃ or Br ₂ in alcoholic solvents such as but not limited to ethanol or 1-propanol while cyclization toward the cyclic sulfamate occurs simultaneously. Mild bases such as NaHCO ₃ or salts such as NH ₄ Cl or (NH ₄ ) ₂ SO ₄ can sometimes accelerate the epoxide opening reaction. For compounds (s6b-A5), the epoxide functionality can be opened with azide ion using various azide anion sources such as but not limited to NaN ₃ in alcoholic solvents such as but not limited to ethanol or 1-propanol while cyclization toward the cyclic sulfamate occurs simultaneously. Mild bases such as NaHCO ₃ or salts such as NH ₄ Cl or (NH ₄ ) ₂ SO ₄ can sometimes accelerate the epoxide opening reaction. For compounds (s6b-A6), the epoxide functionality can be opened with cyanide ion using various cyanide anion sources such as, but not limited to, KCN in alcoholic solvents such as, but not limited to, IPA or 1-propanol while cyclization toward the cyclic sulfamate occurs simultaneously. Mild bases such as _NaHCO3 or salts such as _NH4Cl or ( _NH4 ) _{2SO4 can} sometimes accelerate the epoxide opening reaction.

The alkyl-tula-epx intermediate can be readily synthesized from the tula epoxide (tula-epx) by a variety of methods such as, but not limited to, reductive amination with the appropriate aldehyde and a hydride source such as, but not limited to, STAB or NaBHsCNB in solvents such as alcohols or DMFA and at a temperature between 0°C and 60°C. Subsequent chemistry to prepare compounds of the invention in which the macrolide nucleus nitrogen is alkylated with various R0 groups can be accomplished via Schemes 1-3, for example, by Polonovski-type demethylation, epoxide opening, and sulfonamide formation by replacing the Tula epoxide starting material in Schemes 1-3 with an ^R0 -alkylated tulathromycin epoxide intermediate (alkyl-tula-epx); for example, where ^R0 is propyl.

The alkyl-tula-epx intermediate can be readily synthesized from the tula epoxide (tula-epx) by a variety of methods such as, but not limited to, reductive amination with the appropriate aldehyde and a hydride source such as, but not limited to, STAB or _NaBH3CNB in solvents such as alcohols or DMF and at a temperature between 0°C and 60°C. Subsequent chemistry to prepare compounds of this invention in which the macrolide nucleus nitrogen is alkylated with various ^R0 groups can be accomplished via Schemes 4-5, for example, by Polonovski-type demethylation, epoxide opening and sulfamide formation by replacing the Tula epoxide starting material in Schemes 4-5 with the ^R0 -alkylated foot of the tulathromycin epoxide intermediate (alkyl-tula-epx); for example, where ^R0 is propyl.

The alkyl-tula-epx intermediate can be readily synthesized from the tula epoxide (tula-epx) by a variety of methods such as, but not limited to, reductive amination with the appropriate aldehyde and a hydride source such as, but not limited to, STAB or _NaBH3CN in solvents such as alcohols or DMFA and at temperatures between 0°C and 60°C. Subsequent chemistry to prepare compounds of the invention in which the macrolide nucleus nitrogen is alkylated with various R0 groups can be accomplished via Scheme 6, for example, via Polonovski-type demethylation, formation of the fluorosulfonamide, followed by epoxide opening and simultaneous cyclization by replacing the Tula-epoxide starting material in Scheme 6(a/b) with an R0 ^- alkylated tulathromycin epoxide intermediate (alkyl-tula-epx); for example, where R ⁰ represents propyl.

Scheme 10. Preparation of compounds of formula (1) substituted with various R ¹ groups: Preparation of a common intermediate epoxide M8 (M8-erx)

The intermediate (M8-epx) can be readily synthesized from epoxide M9 by a variety of methods, such as a second demethylation with _I2 and NaOMe or a ternary sequence where epoxide M9 is first protected with a benzyl group of 4-OMe and then demethylated using Polonovsky demethylation. Epoxide M8 is opened by removing the protecting group under hydrogenolysis conditions using Pd/C and _H2 gas in alcoholic solvents such as, but not limited to, methanol, ethanol or trifluoroethanol. Epoxide M8 can be used in a variety of ways to prepare compounds of the present invention, as illustrated in Schemes 11, 12 and 14 below.

Scheme 11. Preparation of sulfonamide compounds of formula (1), substituted with various R ¹ groups, from epoxide M8 (M8-erx)

Epoxide M8 can be reacted with sulfonamide forming reagents such as sulfonyl chlorides, fluorides, in aprotic solvents such as DCM, and mild bases such as but not limited to TEA or DIPEA, as illustrated in Scheme 11, to provide the sulfonamide compounds of this invention s11a-A1 through s11a-A6. Epoxide M8 can also undergo reductive amination with an appropriate R ¹ aldehyde and a hydride source such as but not limited to STAB or NaBH ₃ CN in solvents such as alcohols, DMF, MeOH, DCM or DCE, and at a temperature from 0°C to 60°C. Subsequent chemistry for preparing the sulfonamide compounds of this invention wherein R ¹ is not CH ₃ , as analogs derived from tulathromycin, can be prepared using sulfonyl chlorides or fluorides in aprotic solvents such as DCM and mild bases such as, but not limited to, TEA or DIPEA, as illustrated in Scheme 11, to provide compounds of this invention s11b-A1 through s11b-A6.

Scheme 12. Preparation of sulfamide compounds of formula (1) substituted with various R ¹ groups from epoxide M8 (M8-erx)

Epoxide M8 can be reacted with sulfamide forming reagents such as sulfamoyl chlorides or fluorides in aprotic solvents such as DCM and mild bases such as, but not limited to, TEA or DIPEA, as illustrated in Scheme 12, to produce the sulfamide compounds of this invention s12a-A1 through s12a-A6. Epoxide M8 can also undergo reductive amination with an appropriate R ¹ aldehyde and a hydride source such as, but not limited to, STAB or NaBH ₃ CN in solvents such as alcohols, DMF, MeOH, DCM or DCE and at temperatures from 0°C to 60°C. Subsequent chemistry for preparing the sulfonamide compounds of this invention wherein R ¹ is not CH ₃ , as analogs derived from tulathromycin, can be prepared using sulfamoyl chlorides or fluorides in aprotic solvents such as DCM and mild bases such as, but not limited to, TEA or DIPEA, as illustrated in Scheme 12, to provide compounds of this invention s12b-A1 through s12b-A6.

Scheme 13. Preparation of primary sulfonamide compounds of formula (1) substituted with various R ⁰ groups from tulathromycin epoxide (tula-epx)

Tulathromycin epoxide can be demethylated via, but not limited to, the Polonovsky reaction to form the M9 epoxide (M9-ex). The N-oxide can be formed using various oxidizing agents such as iodine, N-iodosuccinimide, peracetic acid, or hydrogen peroxide. Demethylation of the N-oxide can be initiated by iron or copper salts. The secondary amine thus formed can be converted to a primary sulfonamide using various sulfonylating reagents such as HFIPS described in OL, 2021, pp. 3373-3378. In the final step, the epoxide functionality can be opened to give the final sulfonamide analogs using various nucleophiles such as primary and secondary amines, alcohols, thiols, cyanide, azide or halogen anions and others at higher temperature in alcoholic solvents such as, but not limited to, 1-propanol, 1-butanol or 2-propanol to give the final compounds of this invention s13a-A1 through s13a-A6. This reaction can be completed overnight. Mild bases such as _NaHCO3 or salts such as _NH4Cl or ( _NH4 ) _{2SO4 can} sometimes accelerate the epoxide opening reaction. For any of the schemes presented herein, the "nucleophile" of the epoxide opening step in the cladinose ring may be, but is not limited to, the following: HNR ⁵ R ⁶ , HOR ⁷ , HS(O) _p R ⁷ , NaN ₃ , CeCl ₃ , TEA.3HF and KCN, where R ⁵ , R ⁶ , R ⁷ and p are defined herein.

Similarly, the epoxide of tulathromycin can be alkylated at the ring nitrogen to form an alkyl-tula-epx intermediate by a variety of methods such as, but not limited to, reductive amination with an appropriate aldehyde and a hydride source such as, but not limited to, STAB or _NaBH3CN in solvents such as alcohols or DMF and at temperatures from 0°C to 60°C. The subsequent chemical process for preparing the compounds of this invention s13b-A1 through s13b-A6, in which the ring nitrogen of the macrolide is alkylated with different ^R0 groups, can be accomplished according to the same steps explained above, namely, by forming a primary sulfonamide followed by opening of the epoxide moiety.

Scheme 14. Preparation of cyclic sulfamate compounds of formula (1), substituted with various R ¹ groups, from epoxide M8 (M8-erx)

Epoxide M8 can be reacted with 1-(fluorosulfonyl)-2,3-dimethyl-1H-imidazol-3-ium trifluoromethanesulfonate to produce a fluorosulfonamide, which can be cyclized to form a cyclic sulfamate via an epoxide opening reaction as described in detail previously. Scheme 14 (left) illustrates the preparation of the cyclic sulfamate compound s14a-A1 through s14a-A6, where R ¹ = H. Epoxide M8 can also undergo reductive amination with an appropriate R ¹ aldehyde and a hydride source such as, but not limited to, STAB or NaBH ₃ CN in solvents such as alcohols, DMF, MeOH, DCM, or DCE and at temperatures from 0 °C to 60 °C. Subsequent chemical transformations to prepare the cyclic sulfamate compounds of this invention, wherein R ¹ is not CH ₃ as in the analogs derived from tulathromycin, can be accomplished in the same manner as detailed in Scheme 6. Scheme 14 (right side) illustrates the preparation of the cyclic sulfamate compound s14b-A1 through s14b-A6, wherein R ¹ is other than H or methyl.

Scheme 15. Preparation of sulfonamide (1-A0) compounds of formula (1) by reductive amination from azithromycin

Azithromycin can be used as a starting material for the synthesis of sulfonamide compounds of formula (1) of the present invention, as illustrated in Scheme 15. Azithromycin can undergo a demethylation reaction similar to tulathromycin under analogous conditions, such as, but not limited to, the Polonovsky reaction defined herein. The demethylated azithromycin can be reacted with sulfonamide forming reagents such as, but not limited to, sulfonyl chlorides, fluorides in aprotic solvents such as DCM, and mild bases such as, but not limited to, TEA or DIPEA, as illustrated in Scheme 15, to yield compounds of the present invention s15a-A0.

Moreover, desmethylazithromycin can undergo a second demethylation as described above using _I2 and NaOMe followed by reductive amination with the appropriate ^R1 aldehydes. Compounds s15b-A0 of this invention can be synthesized by reacting ^R1 -substituted azithromycin with sulfonamide forming reagents such as, but not limited to, sulfonyl chlorides, fluorides in aprotic solvents such as DCM, and mild bases such as, but not limited to, TEA or DIPEA, as illustrated in Scheme 15.

Scheme 16. Preparation of sulfamide (1-A0) compounds of formula (1) by reductive amination from azithromycin

Azithromycin can be used as a starting material for the synthesis of sulfonamide compounds of formula (1) of the present invention, as illustrated in Scheme 16. Azithromycin can undergo a demethylation reaction similar to tulathromycin under analogous conditions, such as, but not limited to, the Polonovsky reaction defined herein. The demethylated azithromycin can be reacted with sulfonamide-forming reagents such as, but not limited to, sulfamoyl chlorides, fluorides in aprotic solvents such as DCM, and mild bases such as, but not limited to, TEA or DIPEA, to produce the compounds of the present invention s16a-A0.

Moreover, desmethylazithromycin can undergo a second demethylation as described above using _I2 and NaOMe followed by reductive amination with the corresponding ^R1 aldehydes. The s16b-A0 compounds of this invention can be synthesized by reacting ^R1 -substituted azithromycin with sulfamide forming reagents such as, but not limited to, sulfamoyl chlorides, fluorides in aprotic solvents such as DCM, and mild bases such as, but not limited to, TEA or DIPEA.

Scheme 17. Preparation of sulfonamide O-aryl/heteroaryl compounds of formula (1)

Compounds of formula (1) further substituted with an aryl/heteroaryl group R on the hydroxyl group of the desosamine sugar can be synthesized according to the sequence illustrated in Scheme 17. The first three steps of the sequence are illustrated in detail in Schemes 2a, 2b and 2c and consist of opening of the epoxide moiety of the Tula epoxide followed by Polonovsky demethylation. The third step is a Chan-Lam type coupling with selectivity for the hydroxyl of the desosamine sugar. Aryl or heteroaryl boronic acids or boronate esters can be selectively coupled to the hydroxyl of desosamine by stirring with copper salts such as, but not limited to, copper(II) acetate, in the presence of weak bases such as pyridine, a desiccant such as molecular sieves and oxygen. The final step of the sequence is a sulfonamide forming reaction using reagents such as, but not limited to, sulfonyl chlorides, fluorides, and others in aprotic solvents and mild bases such as, but not limited to, TEA or DIPEA to provide the desired O-aryl/heteroaryl sulfonamide compounds s17-A1 through s17-A6.

Scheme 18. Preparation of sulfamide O-aryl/heteroaryl compounds of formula (1)

Compounds of formula (1) further substituted with an aryl/heteroaryl group R on the hydroxyl group of the desosamine sugar can be synthesized according to the sequence illustrated in Scheme 18. The first three steps of the sequence are illustrated in detail in Schemes 5a, 5b and 5c and consist of opening of the epoxide moiety of the Tula epoxide followed by Polonovsky demethylation. The third step is a Chan-Lam type coupling with selectivity for the hydroxyl of the desosamine sugar. Aryl or heteroaryl boronic acids or boronate esters can be selectively coupled to the hydroxyl of desosamine by stirring with copper salts such as, but not limited to, copper(II) acetate, in the presence of weak bases such as pyridine, a desiccant such as molecular sieves and oxygen. The final step of the sequence is a sulfonamide forming reaction using reagents such as, but not limited to, sulfamoyl chlorides, fluorides, and others in aprotic solvents and mild bases such as, but not limited to, TEA or DIPEA to produce the desired O-aryl/heteroaryl sulfonamide compounds S18-A1 through s18-A6.

Scheme 19. Preparation of sulfonamide compounds of descladiose of formula (1.1)

The descladine sulfonamide compounds of formula (1.1) can be readily synthesized from compounds of formula (1A) by stirring said compound in aqueous 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 _H2O for from 1 to 72 hours as illustrated.

Scheme 20. Obtaining sulfonamide compounds of descladiose of formula (1.1)

The descladiose sulfamide compounds of formula (1.1) can be readily synthesized from compounds of formula (1A) by stirring said compound in aqueous 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 _H2O for from 1 to 72 hours as illustrated.

Examples

Preparation of example (A-20) of the sulfonamide compound descladinose of formula (1.1).

To the crude compound of example B-18 (300.0 mg) was added 2N HCl (5.0 mL) and the resulting mixture was heated at 45 °C for 2 h before cooling to room temperature. The crude reaction mixture was poured into ice-cold NH ₄ OH solution (pH>7), stirred for 5 min, 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 afford the title compound as a free base.

Compounds of formula (1.1) can be prepared in a manner similar to that illustrated above, for example A-20, under similar conditions, but starting materials for compound of formula (1-A1) are used instead of those used for example B-18.

Preparation of example (A-37) of the sulfonamide compound descladinose of formula (1.1).

To the crude compound of Example C-66 (100.0 mg) was added 2N HCl (2.0 mL) and the resulting mixture was heated at 45 °C for 2 hours before cooling to room temperature. The crude reaction mixture was poured into ice-cold _NH4OH solution (pH>7), stirred for 5 minutes, then concentrated and lyophilized. The crude material was purified by preparative HPLC using ammonium acetate as a buffer and the purified material was passed through an SCX column to give the title compound as the free base. Compounds of formula (1.1) can be prepared analogously to those illustrated above, for example A-37, under analogous conditions, but starting materials for compound of formula (1-A1a) are used instead of those used for Example C-66.

Preparation of example (B-8) of sulfonamide compound of formula (1-A1):

Step 1: To a solution of (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,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 (tula) (20.0 g, 24.8 mmol) in methanol (40 mL) and Hexafluoroacetone trihydrate (0.62 g, 2.8 mmol) was added to acetic acid (1.6 mL, 28 mmol) followed by the addition of 30% aqueous hydrogen peroxide solution (2.88 mL, 28 mmol) and stirring for 4 h at 35 °C. After the starting material was consumed as assessed by LCMS, the reaction mixture was cooled to 20 °C and anhydrous copper(II) sulfate (4.35 g, 28 mmol) was added and the reaction mixture was heated to 60 °C for 2 h. After the reaction was complete as assessed by LCMS, the reaction mixture was cooled to 20 °C and 60 mL DCM and 80 mL _H2O were added. The mixture was basified to about 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), which was 95% pure by LCMS and was used as such in the next step.

Step 2: M9 from step 1 (0.38 mmol, 300 mg, 1.0 equiv) was added and dissolved in DCM (5 mL) and DIPEA (1.5 equiv, 100 µL, 0.57 mmol), followed by the addition of propane-1-sulfonyl chloride (1.1 equiv, 59 mg, 0.42 mmol) at 0 °C. The reaction mixture was stirred initially at 0 °C and then warmed to room temperature over 2 h. After reaction completion as assessed by LCMS, the reaction mixture was diluted with DCM, washed with water and brine. The organic portion was dried _over anhydrous _Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by reverse phase C18 flash chromatography with 0.5% AcOH as a modifier (0 to 100% MeCN in _H2O ). Fractions containing the desired product were lyophilized to give the desired compound as the acetate salt (16 mg).

Compounds of formula (1-A1) illustrated in Table B, wherein R ⁵ is H, R ⁶ is propyl, can be prepared analogously to that shown above for Example B-8, under analogous conditions, either by changing the sulfonamide-forming reagent or the starting material and using (alkyl-tula-ex) as the starting material instead of tulathromycin epoxide, as illustrated in the schemes herein.

Preparation of example (B-50) of sulfamide compound of formula (1-A1):

Step 1: To a solution of (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(cimethylamino)-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 (tula) (20.0 g, 24.8 mmol) in methanol (40 mL) and Hexafluoroacetone trihydrate (0.62 g, 2.8 mmol) was added to acetic acid (1.6 mL, 28 mmol) followed by the addition of 30% aqueous hydrogen peroxide solution (2.88 mL, 28 mmol) and stirring for 4 h at 35 °C. After the starting material was consumed as assessed by LCMS, the reaction mixture was cooled to 20 °C and anhydrous copper(II) sulfate (4.35 g, 28 mmol) was added and the reaction mixture was heated to 60 °C for 2 h. After the reaction was complete as assessed by LCMS, the reaction mixture was cooled to 20 °C and 60 mL DCM and 80 mL H ₂ O were added. The mixture was basified to about 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), which was 95% pure by LCMS and was used as such in the next step.

Step 2: M9 from step 1 (0.51 mmol, 400 mg, 1.0 equiv) was added and dissolved in DCM (10 mL) and TEA (3.0 equiv, 210 µL, 0.56 mmol), followed by the addition of N-[4-(trifluoromethyl)phenyl]sulfamoyl fluoride (1.1 equiv, 135 mg, 0.42 mmol) at 0 °C. The reaction mixture was stirred initially at 0 °C for 2 h and then warmed to room temperature over 4 h. After reaction completion as assessed by LCMS, the reaction mixture was diluted with DCM, washed with water and brine. The organic portion was dried _over anhydrous _Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by reverse phase C18 flash chromatography with 0.5% AcOH as a modifier (0 to 100% MeCN in _H2O ). Fractions containing the desired product were lyophilized to give the desired compound (B-50) as the acetate salt (194 mg).

Compounds of formula (1-A1) illustrated in Table B, wherein R ⁵ is H, R ⁶ is propyl, can be prepared analogously to that shown above for Example B-50, under analogous conditions, or by changing the sulfamide-forming reagent or the starting material and using (alkyl-tula-ex) as the starting material in place of tulathromycin epoxide, as illustrated in the schemes herein.

Preparation of a sulfonamide compound which is an example of B-93 of formula (1-A1):

Step 1: A solution of (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((3S,4S,6R,8R)-8-methoxy-4,8-dimethyl-1,5-dioxaspiro[2.5]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 solution (0.62 g, 30 mmol) were mixed together and stirred for 4 h at 35 °C. After consumption of the starting material as assessed by LCMS, the reaction mixture was cooled to 20 °C and anhydrous copper(II) sulfate (4.5 g, 29 mmol) was added and the reaction mixture was heated to 60 °C for 1 h. After the reaction was complete as assessed by LCMS, the reaction mixture was cooled to 20 °C and 60 ml DCM and 80 ml _H2O were added. The mixture was basified to about pH 9.8 with concentrated aqueous ammonia solution. The mixture was concentrated in vacuo to a solid and recrystallized from acetone/water to give 60 g of a white crystalline product (M9-exx), which was 95% pure by LCMS and was used as such in the next step.

Step 2: A solution of 10 g (13.14 mmol) of M9-ex from step 1 and 10.9 mL of N-ethylamine (10.0 equiv, 131.4 mmol) in 100 mL of 1-propanol was heated to 80 °C for 16 h. After the reaction was complete, as judged by LCMS analysis, the volatiles were removed under reduced pressure, then dissolved in 100 mL of N-DCM and H ₂ O, and the pH was adjusted to ~9.8 with NH ₄ OH. The aqueous layer was extracted 3 times with N-DCM, and the organic layers were combined and dried over anhydrous magnesium sulfate. The volatiles were removed under reduced pressure to give a crude material which was purified on C18 silica gel using reverse phase flash chromatography with 1.0% AcOH as feed (0 to 100% MeCN in _H2O ). The desired fractions were combined, pH adjusted to ~9.8 with _NH4OH 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 a white amorphous solid with a metallic tint.

Step 3: A mixture of the product of step 2 (250 mg, 0.32 mmol, 1.0 equiv), (3,4-dimethoxyphenyl)boronic acid (88 mg, 0.47 mmol, 1.5 equiv), copper(II) acetate (143 mg, 2.5 equiv, 0.79 mmol), molecular sieves (4 Å, activated, 0.2 g), and pyridine (51 µL, 2 equiv, 0.63 mmol) in DMF (5.0 mL) was stirred at room temperature in dry air for 3 days. When the reaction was complete, as judged by LCMS, the mixture was filtered through celite and the volatiles were removed under reduced pressure. The crude material was purified on C18 silica gel using reverse phase flash chromatography with 1.0% AcOH as feed (0 to 100% MeCN in _H2O ). The desired fractions were combined, pH adjusted to ~9.8 with _NH4OH 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 afford the desired material as a white amorphous solid with a metallic tint.

Step 4: The material from step 3 (150 mg, 0.16 mmol, 1.0 equiv) was dissolved in dry DCM (3 mL) in a dry round bottom flask and DIPEA (69 µL, 2.5 equiv) was added followed by benzenesulfonyl chloride (32 mg, 1.2 equiv, 0.19 mmol). The mixture was stirred overnight after which LCMS analysis showed that all starting material was consumed. The volatiles were removed under _N2 flow and the crude material was purified by reverse phase chromatography using a C18 column with a gradient of 1% AcOH in MeCN and _H2O . Fractions containing the desired product were lyophilized to afford the desired product as the acetate salt (99 mg, 55% yield).

Preparation of the sulfonamide compound of example (B-107) of formula (1-A1):

Step 1: A solution of (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((3S,4S,6R,8R)-8-methoxy-4,8-dimethyl-1,5-dioxaspiro[2.5]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) was mixed with hexafluoroacetone trihydrate (0.38 mL, 3 mmol) followed by the addition of 30% aqueous hydrogen peroxide (0.62 g, 30 mmol) and stirring for 4 h at 35 °C. After the starting material was consumed as assessed by LCMS, the reaction mixture was cooled to 20 °C and anhydrous copper(II) sulfate (4.5 g, 29 mmol) was added and the reaction mixture was heated to 60 °C for 1 h. After the reaction was complete as assessed by LCMS, the reaction mixture was cooled to 20 °C and 60 mL DCM and 80 mL _H2O were added. The mixture was basified to about pH 9.8 with concentrated aqueous ammonia. The mixture was concentrated in vacuo to a solid and recrystallized from acetone/water to give 16 g of a white crystalline product (M9-exx), which was 95% pure by LCMS and was used as such in the next step.

Step 2: A solution of 10 g (13.14 mmol) of M9-ex from step 1 and 10.9 mL of N-propylamine (10.0 equiv, 131.4 mmol) in 100 mL of 1-propanol was heated to 80 °C for 16 h. After the reaction was complete, as judged by LCMS analysis, the volatiles were removed under reduced pressure, the remaining crude solid was then dissolved in 100 mL of DCM and H ₂ O, and the pH was adjusted to ~9.8 with NH ₄ OH. The aqueous layer was extracted 3 times with DCM, and the organic layers were combined and dried over anhydrous magnesium sulfate. The volatiles were removed under reduced pressure to give a crude material which was purified on C18 silica gel using reverse phase flash chromatography with 1.0% AcOH as feed (0 to 100% MeCN in _H2O ). The desired fractions were combined, pH adjusted to ~9.8 with _NH4OH 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 a white amorphous solid with a metallic tint.

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

Step 4: The material from Step 3 (642 g, 0.72 mmol, 1.0 equiv) was dissolved in dry DCM (20 mL) in a dry round bottom flask and TEA (203 µL, 2.0 equiv) was added followed by 1-methyl-1H-imidazole-2-sulfonyl chloride (165 mg, 1.2 equiv, 0.87 mmol) at 0 °C. The mixture was stirred overnight while the reaction temperature slowly approached room temperature, after which LCMS analysis showed that all starting material was consumed. The volatiles were removed under a stream _{of N2} and the crude material was purified by reverse phase chromatography using a C18 column with a gradient of 1% AcOH in MeCN and _H2O . Fractions containing the desired product were lyophilized to give the desired product (B-107) as the acetate salt (150 mg, 19% yield).

Preparation of the sulfamide compound of example (B-113) of formula (1-A1):

Step 1: A solution of (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((3S,4S,6R,8R)-8-methoxy-4,8-dimethyl-1,5-dioxaspiro[2.5]octan-6-yl)oxy)-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopenadecan-15-one (tula-epx) (20.0 g, 27 mmol) in methanol (40 mL) and acetic acid (1.6 ml, 30 mmol) was mixed with hexafluoroacetone trihydrate (0.38 ml, 3 mmol) followed by 30% aqueous hydrogen peroxide solution (0.62 g, 30 mmol) and stirred for 4 h at 35 °C. After consumption of the starting material as assessed by LCMS, the reaction mixture was cooled to 20 °C and anhydrous copper(II) sulfate (4.5 g, 29 mmol) was added and the reaction mixture was heated to 60 °C for 1 h. After the reaction was complete as assessed by LCMS, the reaction mixture was cooled to 20 °C and 60 ml DCM and 80 ml H ₂ O were added. The mixture was basified to about pH 9.8 with concentrated aqueous ammonia solution. The mixture was concentrated in vacuo to a solid and recrystallized from acetone/water to give 16 g of a white crystalline product (M9-exx), which was 95% pure by LCMS and was used as such in the next step.

Step 2: To a solution of 5.0 g (6.83 mmol) of M9-ex from step 1 and 1.8 mL of TEA (1.5 equiv, 10.2 mmol) in 50 mL of dry DCM at 0 °C was added a solution of N-methyl-4-(trifluoromethyl)phenylsulfamoyl chloride (1.2 equiv) in DCM (5 mL) over 5 min. The reaction mixture was stirred initially at 0 °C and then slowly warmed to room temperature over 24 h. After the reaction was complete as assessed by LCMS analysis, the reaction mixture was diluted with DCM and washed with water followed by brine. The organic layer was dried over _{anhydrous Na2SO4} , concentrated under reduced pressure and the resulting material was triturated with 30% _Et2O in pentane to give a solid free base material (~5.2 g), which was used as such in the next step.

Step 3: The product from step 2 (0.22 mmol, 200 mg, 1.00 equiv) was dissolved in n-PrOH (2.5 mL) and n-propylamine (5.0 equiv, 0.11 mL, 1.10 mmol) was added. The resulting solution was stirred at 70 °C overnight. After the reaction was complete, volatiles were removed under N ₂ flow as judged by LCMS analysis and the crude product was purified by C18 reverse phase flash chromatography with 0.5% AcOH as modifier (0 to 100% MeCN in H ₂ O). Fractions containing the desired product were lyophilized to afford the desired compound (B-113) as the acetate salt (48 mg, 25%).

The preparation of the sulfonamide compound of formula (1-A1), which is example B-142, using a modification of Scheme 7, wherein the nucleophile used in the last step to open the epoxide is N-propylamine and such that R ¹ is propyl, by a reductive amination reaction with propionaldehyde, which is illustrated below:

Step 1: 1.0 g (1.36 mmol, 1.00 equiv) of epoxide M9 was dissolved in 10 mL of dry DMF in a 50 mL round-bottomed flask and 2.0 equiv of p-anisaldehyde (0.332 mL, 2.73 mmol) was added followed by 1.17 g of sodium triacetoxyborohydride (STAB, 4.0 equiv, 5.5 mmol). The resulting solution was heated at 40 °C for 2 h. An additional 0.6 g (2.7 mmol, 2.0 equiv) of STAB was added and the resulting solution was heated at 40 °C overnight, after which LCMS analysis showed complete consumption of the starting material. The reaction mixture was then cooled to 0 °C and 5 mL of saturated NH ₄ Cl solution was added and the solution was stirred for 5 min. 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 of DCM. The organic phases were combined and dried over MgSO ₄ and removed under reduced pressure to give a crude material that was purified by reverse phase C18 column chromatography eluting with a gradient of 1% AcOH in MeCN and H ₂ O. Fractions containing the desired product were combined, the pH was adjusted to pH ~12 with NH4OH and extracted 3 times with 50 mL of DCM to give 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 equiv) were dissolved in 10 mL of dry EtOH and peracetic acid (32% dilute solution in acetic acid; 1.5 equiv, 304 µL) was added. The resulting solution was stirred at room temperature for 45 min, at which point LCMS analysis showed complete conversion to the corresponding N-oxide. Anhydrous copper(II) sulfate (3.0 equiv; 566 mg) was then added and the solution was stirred at 65 °C for 4 h, at which point LCMS analysis showed complete reaction with 41% debenzylated product and 44% demethylated product. The reaction mixture was diluted with 20 mL of 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 and the organic phases were combined, dried over MgSO ₄ and the volatiles were removed under reduced pressure. The crude material was purified by reverse phase C18 column chromatography with a gradient of 1% AcOH in MeCN and H ₂ O. Fractions containing the desired product were pooled, the pH was adjusted to pH ~12 with NH ₄ OH and extracted 3 times with 50 mL of DCM to give the desired product as the free base (250 mg, 25% yield).

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

Step 4: The product from step 3 (M8-ex, 250 mg, 1.0 equiv, 0.35 mmol) was dissolved in 5 mL of dry MeOH in a 25 mL round bottom flask and the solution was cooled to 0 °C. Propionaldehyde (1.2 equiv, 30 µL) was added followed by sodium triacetoxyborohydride (5 equiv, 369 mg) in portions. The solution was stirred at 0 °C to room temperature for 2 h, at which time LCMS analysis indicated complete conversion to the desired product. The reaction mixture was then cooled to 0 °C and 1 mL of saturated NH ₄ Cl solution was added and the solution was stirred for 5 min. 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 _NH4OH and extracted 3 times with 20 mL DCM. The organic phases were combined and dried over _MgSO4 and removed under reduced pressure to give the desired product (250 mg) as a white solid with ~80% purity by LC-MS, which was used as is in the subsequent epoxide opening.

Step 5: The material from Step 4 (200 mL, 0.32 mmol, 1.0 equiv) was dissolved in dry DCM (5 mL) in a dry round bottom flask and DIPEA (0.141 mL, 2.5 equiv) was added followed by 4-chlorobenzenesulfonyl chloride (1.2 equiv) in DCM (5 mL). The mixture was stirred overnight after which LCMS analysis showed that all starting material had been consumed. The volatiles were removed under N ₂ flow 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, the pH was adjusted to pH ~12 with NH ₄ OH and extracted 3 times with 50 mL DCM to give the desired product as the free base (93 mg, 32% yield).

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

Following this example, the alkyl group R ¹ on the desosamine nitrogen can be changed by replacing the propionaldehyde in the fourth step of the sequence with any other alkyl aldehyde such as, but not limited to, acetaldehyde or isobutyl aldehyde, or carbaldehydes such as benzaldehyde or 2-pyridyl carbaldehyde, and others. Similar to the other examples illustrated herein, the epoxide can be opened with various nucleophiles such as, but not limited to, primary and secondary amines, alcohols, mines, cyanide, azide, or halogen anions, and others, at higher temperature in alcoholic solvents such as, but not limited to, 1-propanol, 1-butanol, or 2-propanol in the final step.

Preparation of an example C-4 sulfonamide compound of formula (A1a):

Step 1: A solution of (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((3S,4S,6R,8R)-8-methoxy-4,8-dimethyl-1,5-dioxaspiro[2.5]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) was mixed with hexafluoroacetone trihydrate (0.38 ml, 3 mmol) and then mixed with 30% aqueous hydrogen peroxide solution (0.62 g, 30 mmol) and stirred for 4 h at 35 °C. After consumption of the starting material as assessed by LCMS, the reaction mixture was cooled to 20 °C and anhydrous copper(II) sulfate (4.5 g, 29 mmol) was added and the reaction mixture was heated to 60 °C for 1 h. After the reaction was complete as assessed by LCMS, the reaction mixture was cooled to 20 °C and 60 ml DCM and 80 ml H ₂ O were added. The mixture was basified to about pH 9.8 with concentrated aqueous ammonia solution. The mixture was concentrated in vacuo to a solid and recrystallized from acetone/water to give 60 g of a white crystalline product (M9-exx), which was 95% pure by LCMS and was used as such in the next step.

Step 2: To a solution of 5.0 g (6.83 mmol) of M9-ex from step 1 and 1.8 mL of DIPEA (1.5 equiv, 10.2 mmol) in 50 mL of DCM at 0 °C was slowly added a solution of 4-chlorobenzenesulfonyl chloride (1.2 equiv) in DCM (5 mL). The reaction mixture was stirred initially at 0 °C and then slowly warmed to room temperature over 24 h. After the reaction was complete as assessed by LCMS analysis, the reaction mixture was diluted with DCM and washed with water followed by brine. The organic layer was dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure, and the resulting material was triturated with 30% Et ₂₀ in pentane to give a solid free base material (~5.2 g), which was used as such in the next step.

Step 3: The product from step 2 (0.22 mmol, 200 mg, 1.00 equiv) in n-BuOH (1.5 mL) was added to piperidine (5.0 equiv, 0.11 mL, 1.10 mmol) and the resulting solution was dissolved at 90 °C overnight. After the reaction was complete, as judged by LCMS analysis, the volatiles were removed under N ₂ flow and the crude product was purified by C18 reverse phase flash chromatography with 0.5% AcOH as modifier (0 to 100% MeCN in H ₂ O). Fractions containing the desired product were lyophilized to afford the desired compound as the acetate salt (48 mg).

Compounds of formula (1-A1a) illustrated in Table C can be prepared analogously to the compounds illustrated above for Example C-4, under analogous conditions, by changing either the amine used in the third step to open the epoxide functionality, or the sulfonamide forming reagent, or the starting material and using (alkyl-tula-ex) as the starting material in place of tulathromycin epoxide, as illustrated in the schemes herein.

Preparation of example C-54 sulfonamide compound of formula (1-A1a):

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

Step 2: 590 mg of the product from step 1 (0.76 mmol, 1.00 equiv) was dissolved in 10 mL of dry EtOH and peracetic acid (32% dilute solution in acetic acid; 1.2 equiv, 192 µL) was added. The resulting solution was stirred at room temperature for 45 min after which LCMS analysis showed complete conversion to the corresponding N-oxide. The reaction mixture was then diluted with DCM (30 mL and _H2O ) and transferred to a separatory funnel. The pH was adjusted to pH~12 with _NH4OH and extracted 3 times with 20 mL of DCM. The organic phases were combined and dried over _MgSO4 and removed under reduced pressure to give the crude N-oxide. The crude N-oxide (0.76 mmol, 1.0 equiv) was dissolved in 10 mL of dry ethanol and copper(II) sulfate pentahydrate (5.0 equiv; 950 mg) was added and the solution was stirred at 65 °C for 16 h, at which time LCMS analysis indicated the reaction was complete. The reaction mixture was diluted with 20 mL of 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 and the organic phases were combined, dried over MgSO ₄ and the volatiles were removed under reduced pressure to give the crude desired product with LCMS purity >90%, which was used as such in the next step.

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

Step 4: The product from step 3 (150 mg, 0.17 mmol, 1 equiv) and N-propanol (5 mL) were added to a pressure vessel, followed by piperidine (117 µL, 2.0 mmol, 12 equiv). The reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was then concentrated in vacuo and the crude product was purified by reverse phase chromatography using a C18 column with a gradient of 1% AcOH in MeCN and H ₂ O. Fractions containing the desired product were lyophilized to afford the desired product (C-54) as the acetate salt (90 mg, 53% yield).

Following this example, the alkyl group R ⁰ on the nitrogen of the core can be changed by replacing the acetaldehyde in the first step of the sequence with any other alkyl aldehyde, such as, but not limited to, formaldehyde or propionaldehyde, etc. Similar to other examples illustrated herein, the epoxide can be opened with various nucleophiles, such as, but not limited to, primary and secondary amines, alcohols, thiols, cyanide, azide or halogen anions, etc., at higher temperature in alcoholic solvents, such as, but not limited to, 1-propanol, 1-butanol or 2-propanol in the last step.

Compounds of formula (1-A1a) illustrated in Table C can be prepared analogously to the compounds illustrated above for Example C-54, under analogous conditions, by changing either the amine used in the fourth step to open the epoxide functionality, or the sulfonamide or sulfamide forming reagent, or the starting material and using (alkyl-tula-epx) as the starting material in place of tulathromycin epoxide, as illustrated in the schemes herein.

Preparation of example (C-17) of a cyclic sulfamate compound of formula (1-A1a):

Step 1: To a solution of (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((3S,4S,6R,8R)-8-methoxy-4,8-dimethyl-1,5-dioxaspiro[2.5]octan-6-yl)oxy)-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one (tula-epx) (1.0 g, 1.34 mmol) and propionaldehyde (2.0 equiv., 2.68 mmol) in dry DMF (10 mL) was added STAB (4.0 equiv, 5.36 mmol) and the resulting solution was heated for 4 h at 45 °C. After consumption of the starting material as determined by LCMS, the reaction mixture was cooled to 0 °C and 2 mL of saturated NH ₄ Cl solution was added, and the solution was stirred for 5 min. 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 of DCM. The organic phases were combined and dried over MgSO ₄ and removed under reduced pressure to give a crude material which was purified by reverse phase C18 column chromatography with a gradient of 1% AcOH in MeCN and H ₂ O. Fractions containing the desired product were pooled, the pH was adjusted to pH ~12 with NH ₄ OH and extracted 3 times with 50 mL DCM to give the desired product as the free base (600 mg, 57% yield).

Step 2: 590 mg of the product from step 1 (0.76 mmol, 1.00 equiv) was dissolved in 10 mL of dry EtOH and peracetic acid (32% dilute solution in acetic acid; 1.2 equiv, 192 µL) was added. The resulting solution was stirred at room temperature for 45 min after which LCMS analysis showed complete conversion to the corresponding N-oxide. The reaction mixture was then diluted with DCM (30 mL and _H2O ) and transferred to a separatory funnel. The pH was adjusted to pH~12 with _NH4OH and extracted 3 times with 20 mL of DCM. The organic phases were combined and dried over _MgSO4 and removed under reduced pressure to give the crude N-oxide. The crude N-oxide (0.76 mmol, 1.0 equiv) was dissolved in 10 mL of dry ethanol and copper(II) sulfate pentahydrate (5.0 equiv; 950 mg) was added and the solution was stirred at 65 °C for 16 h, at which time LCMS analysis indicated the reaction was complete. The reaction mixture was diluted with 20 mL of 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 and the organic phases were combined, dried over MgSO ₄ and the volatiles were removed under reduced pressure to give the crude desired product with LCMS purity >85%, which was used as such in the next step.

Step 3: The material from Step 2 (150 mL, 0.19 mmol, 1.0 equiv) was dissolved in dry DCM (1.4 mL) in a dry round bottom flask and pyridine (0.6 mL, 40.0 equiv) was added followed by [2,2,2-trifluoro-1-(trifluoromethyl)ethyl]sulfamate (Organic Letters, Vol. 23, 2021, pp. 3373-3378) (1.2 equiv, 0.57 mg, 0.23 mmol) after which the solution was stirred at 40 °C for 24 h after which time LCMS analysis showed that all starting material was consumed. The volatiles were removed under N ₂ flow and the crude material was purified by reverse phase C18 column chromatography with a gradient of 1% AcOH in MeCN and H ₂ O. Fractions containing the desired product were pooled, pH adjusted to pH ~12 with NH ₄ OH and extracted 3 times with 50 mL DCM to give the desired product as the free base (105 mg, 64% yield).

Step 4: The product from step 3 (250 mg, 0.29 mmol, 1 equiv) and N-propanol (4 mL) were added to a pressure vessel followed by piperidine (434 µL, 4.4 mmol, 15 equiv). The reaction mixture was stirred at 75 °C for 16 h. The reaction mixture was then concentrated in vacuo and the crude product was purified by reverse phase chromatography using a C18 column with a gradient of 1% AcOH in MeCN and _H2O . Fractions containing the desired product were lyophilized to afford the desired product (C-17) as the acetate salt (58 mg, 20% yield).

Following this example, the alkyl group R ⁰ on the core nitrogen can be changed by replacing the acetaldehyde in the first step of the sequence with any other alkyl aldehyde such as, but not limited to, formaldehyde or propionaldehyde, etc. The sequence can also start with the epoxide of tulathromycin and skip the reductive amination step so that R ⁰ = H. Similar to the other examples illustrated herein, the epoxide can be opened with various nucleophiles such as, but not limited to, primary and secondary amines, alcohols, thiols, cyanide, azide or halogen anions, etc., at higher temperature in alcoholic solvents such as, but not limited to, 1-propanol, 1-butanol or 2-propanol in the last step.

Preparation of example D-2 of the cyclic sulfamate compound of formula (2-A1):

Step 1: To a solution of (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-(((2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-13-(((3S,4S,6R,8R)-8-methoxy-4,8-dimethyl-1,5-dioxaspiro[2.5]octan-6-yl)oxy)-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one (tula-epx) (1.0 g, 1.34 mmol) and propionaldehyde (2.0 equiv., STAB (4.0 equiv. f 5.36 mmol) was added to a solution of dry DMF (10 mL) and the resulting solution was heated at 45 °C for 4 h. After the starting material was consumed according to LCMS, the reaction mixture was cooled to 0 °C and 2 mL of saturated NH ₄ Cl solution was added and the solution was stirred for 5 min. 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 of DCM. The organic phases were combined and dried over MgSO ₄ and removed under reduced pressure to give a crude material which was purified by reverse phase C18 column chromatography with a gradient of 1% AcOH in MeCN and H ₂ O. Fractions containing the desired product were pooled, the pH was adjusted to pH ~12 with NH ₄ OH and extracted 3 times with 50 mL DCM to give the desired product as the free base (600 mg, 57% yield).

Step 2: 590 mg of the product from step 1 (0.76 mmol, 1.00 equiv) was dissolved in 10 mL of dry EtOH and peracetic acid (32% dilute solution in acetic acid; 1.2 equiv, 192 µL) was added. The resulting solution was stirred at room temperature for 45 min after which LCMS analysis showed complete conversion to 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 of DCM. The organic phases were combined and dried over MgSO ₄ and removed under reduced pressure to give the crude N-oxide. The crude N-oxide (0.76 mmol, 1.0 equiv) was dissolved in 10 mL of dry ethanol and copper(II) sulfate pentahydrate (5.0 equiv; 950 mg) was added and the solution was stirred at 65 °C for 16 h, at which time LCMS analysis indicated the reaction was complete. The reaction mixture was diluted with 20 mL of 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 and the organic phases were combined, dried over MgSO ₄ and the volatiles were removed under reduced pressure to give the crude desired product with LCMS purity >85%, which was used as such in the next step.

Step 3: The material from Step 2 (150 mg, 0.19 mmol, 1.0 equiv) was dissolved in dry MeCN (1.5 mL) in a dry round bottom flask and DIPEA (0.338 mL, 10.0 equiv) was added followed by 1-(fluorosulfonyl)-2,3-dimethyl-1H-imidazol-3-ium trifluoromethanesulfonate (1.3 equiv, 0.84 mg, 0.25 mmol), after which the solution immediately turned orange. The reaction mixture was stirred for 15 min at room temperature, after which time LCMS analysis showed that all starting material was consumed. The volatiles were removed under N ₂ flow and the crude material was purified by reverse phase C18 column chromatography with a gradient of 1% AcOH in MeCN and H ₂ O. Fractions containing the desired product were pooled, pH adjusted to pH ~12 with NH ₄ OH and extracted 3 times with 50 mL DCM to give the desired product as the free base (39 mg, 24% yield).

Step 4: The product from step 3 (39 mg, 0.046 mmol, 1 equiv) and ethanol (3 mL) were added to a pressure vessel followed by 1-propylamine (187 µL, 2.27 mmol, 50 equiv). The reaction mixture was stirred at 75 °C for 6 h, at which time LCMS analysis indicated the reaction was complete. 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 afford the desired product (D-2) as the acetate salt (20 mg, 49% yield).

Following this example, the alkyl group R ⁰ on the core nitrogen can be changed by replacing the acetaldehyde in the first step of the sequence with any other alkyl aldehyde, such as, but not limited to, formaldehyde or propionaldehyde. The sequence can also start with the epoxide of tulathromycin and skip the reductive amination step so that R ⁰ = H. Similar to the other examples illustrated 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 higher temperature in alcoholic solvents, such as, but not limited to, 1-propanol, 1-butanol or 2-propanol in the last step.

Compounds of formula (1-A1a) illustrated in Table C can be prepared analogously to the compounds illustrated above for Example C-54, under analogous conditions, by changing either the amine used in the fourth step to open the epoxide functionality, or the sulfonamide or sulfamide forming reagent, or the starting material and using (alkyl-tula-epx) as the starting material in place of tulathromycin epoxide, as illustrated in the schemes herein.

The following compounds of formula (1.1) were prepared according to the schemes and procedures described in this document and are listed in Table A. The names of the corresponding compounds of formula (1.1)

are shown in the table below.

Names of examples of compounds of formula (1.1) of Table A:

A-1. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptameth yl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(4-methoxyphenoxy)-6-methyloxan-4-yl]-N-methylbenzenesulfonamide;

A-2. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-ok ca-6-azacyclopentadecan-11-yl)oxy)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide;

A-3. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,6,8,10,12,14-heptamethyl -15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyl-3-phenoxytetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide;

A-4. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hec samethyl-11-[(2R,3S,4R,6S)-6-methyl-4-[methyl(phenylsulfamoyl)-amino]-3-phenoxyoxan-2-yl] hydroxy-15-oxo-1-oxa-6-azacyclopentadecane;

A-5. 3-chloro-N-((2S,3R,4S,6R)-3-(3-chloro-4-(trifluoromethyl)phenoxy)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5, 8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-4-yl)-4-fluoro-N-methylbenzenesulfonamide;

A-6. 3-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-ox a-6-azacyclopentadecan-11-yl)oxy)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-4-fluoro-N-methylbenzenesulfonamide;

A-7. N-((2S,3R,4S,6R)-3-(3-chloro-4-(trifluoromethyl)phenoxy)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5, 8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide;

A-8. N-((2S,3R,4S,6R)-3-(3,4-dimethoxyphenoxy)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10, 12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide;

A-9. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-ox o-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-(4-methoxyphenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide;

A-10. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-ox a-6-azacyclopentadecan-11-yl)oxy)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide;

A-11. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-ox o-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-3-methoxy-N-methylbenzenesulfonamide;

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

A-13. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-ox o-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-3,4-difluoro-N-methylbenzenesulfonamide;

A-14. 3-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-1 5-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-4-fluoro-N-methylbenzenesulfonamide;

A-15. 3-cyano-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl- 15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-4-fluoro-N-methylbenzenesulfonamide;

A-16. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-1 5-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide;

A-17. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-o xo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-4-fluoro-N-methylbenzenesulfonamide;

A-18. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-ok co-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methyl-2-nitrobenzenesulfonamide;

A-19. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-ok co-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methyl-4-nitrobenzenesulfonamide;

A-20. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-ox o-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-4-methoxy-N-methylbenzenesulfonamide;

A-21. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-ok ca-6-azacyclopentadecan-11-yl)oxy)-3-(4-fluorophenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-N-methyl-6-morpholinopyridine-3-sulfonamide;

A-22. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-ox o-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-(4-fluorophenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-N-methylthiophene-2-sulfonamide;

A-23. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-o xo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-(4-fluorophenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide;

A-24. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-1 5-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(4-fluorophenoxy)-6-methyloxan-4-yl]-N-methyl-1-benzofuran-2-sulfonamide;

A-25. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo -1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-(4-fluorophenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-4-fluoro-N-methylbenzenesulfonamide

A-26. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo -1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-(4-fluorophenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-N-methylthiazolyl-5-sulfonamide;

A-27. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-o xa-6-azacyclopentadecan-11-yl)oxy)-3-(4-fluorophenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-H,1-dimethyl-1H-imidazole-2-sulfonamide;

A-28. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacy clopentadecan-11-yl)oxy)-3-(4-fluorophenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-N-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-sulfonamide;

A-29. 6-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-(4-fluorophenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-N-methylpyridine-2-sulfonamide

A-30. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-1 5-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-(4-fluorophenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide;

A-31. N-((2S,3R,4S,6R)-3-(3-chloro-4-(trifluoromethyl)phenoxy)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,1 2,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-4-yl)-N,1-dimethyl-1H-imidazol-2-sulfonamide;

A-32. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15- oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyl-3-phenoxytetrahydro-2H-pyran-4-yl)-N-methylcyclopropanesulfonamide;

A-33. 5-bromo-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15- oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-(4-fluorophenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-N-methylpyridin-2-sulfonamide;

A-34. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-az acyclopentadecan-11-yl)oxy)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-N,1-dimethyl-1H-imidazole-2-sulfonamide;

A-35. N-((2S,3R,4S,6R)-3-(3-chloro-4-methoxyphenoxy)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14 -hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-4-yl)-N,1-dimethyl-1H-imidazol-2-sulfonamide;

A-36. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-11-[(2R,3S,4R,6S)-3-(4-methoxyphenoxy)-6-methyl-4-[methyl(phenylsulfamoyl)amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane; and

A-37. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-11-[(2R,3S,4R,6S)-3-(4-fluorophenoxy)-6-methyl-4-[methyl(phenylsulfamo yl)amino]oxan-2-yl]oxy-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane.

The following compounds of formula (1-A1), prepared according to the schemes and procedures described herein, are illustrated in Table B. The corresponding names of the compounds are given below the table.

For clarity, the substitution of -NH-4-CF ₃ phenyl in the following tables is

Names of examples of compounds of formula (1-A1) of Table B:

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

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

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

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

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

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

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

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

B-9. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylthieno[3,2-b]pyridine-6-sulfonamide;

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

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

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

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

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

B-15. N1-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N1-methylbenzene-1,4-disulfonamide;

B-16. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N,1-dimethyl-1H-imidazole-4-sulfonamide;

B-17. 6-cyano-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylpyridine-3-sulfonamide;

B-18. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-4-methoxy-N-methylbenzenesulfonamide;

B-19. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methyl-4-(1H-pyrazol-1-yl)benzenesulfonamide;

B-20. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-((benzylamino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-4-chloro-N-methylbenzenesulfonamide;

B-21. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,3S,4R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-5-((isopentylamino)methyl)-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide;

B-22. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-((cyclopentylamino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide;

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

B-24. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(((cyclopropylmethyl)amino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide;

B-25. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(((4-(trifluoromethyl)benzyl)amino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide;

B-26. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,3S,4R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N,4-dimethylbenzenesulfonamide;

B-27. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-5-(((4-methoxybenzyl)amino)methyl)-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide;

B-28. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(((2-(dimethylamino)ethyl)(methyl)amino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide;

B-29. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(((2-(pyridin-4-yl)ethyl)amino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide;

B-30. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-(((4-chlorophenyl)amino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide;

B-31. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(((4-(trifluoromethyl)phenethyl)amino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide;

B-32. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((phenylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide;

B-33. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-13-(((2R,4R,5S,6S)-5-((ethylamino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide;

B-34. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(((2-(tetrahydro-2H-pyran-4-yl)ethyl)amino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide;

B-35. 4-chloro-N-((2SJ3R54S,6R)-2-(((2R53S,4R,5RJ8R510R511R512S,13SJ14R)-13-(((2R,4R,5S,6S)-5-(((2-(dimethylamino)ethyl)amino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide;

B-36. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-5-(((2-methoxyethyl)amino)methyl)-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide;

B-37. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(((thiazol-4-ylmethyl)amino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide;

B-38. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((methylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide;

B-39. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((pyridazin-4-ylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide;

B-40. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl(2-phenylethylsulfamoyl)amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

B-41. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-[[(4-chlorophenyl)methyl-methylsulfamoyl]methylamino]-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one;

B-42. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-H-methyl-3,4-dihydroisoquinoline-2(1H)-sulfonamide;

B-43. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl(2,2,2-trifluoroethylsulfamoyl)amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

B-44. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-[[benzyl(methyl)sulfamoyl]methylamino]-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one;

B-45. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylisoindolin-2-sulfonamide;

B-46. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((pyridin-4-ylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide;

B-47. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylpiperidine-1-sulfonamide;

B-48. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl(phenylsulfamoyl)amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

B-49. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-[[cyclohexyl(methyl)sulfamoyl]methylamino]-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one;

B-50. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6S)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

B-51. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-[dimethylsulfamoyl(methyl)amino]-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one;

B-52. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-[benzylsulfamoyl(methyl)amino]-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

B-53. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-11-[(2S,3R,4S,6R)-4-[(4-fluorophenyl)sulfamoyl-methylamino]-3-hydroxy-6-methyloxan-2-yl]oxy-3,4,10-trihydroc si-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

B-54. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl(pyridin-4-ylsulfamoyl)amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

B-55. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl(methylsulfamoyl)amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

B-56. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-[cyclohexylsulfamoyl(methyl)amino]-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

B-57. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[methyl(phenyl)sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one;

B-58. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(((3-(piperidin-1-yl)propyl)amino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide;

B-59. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methyltetanesulfonamide;

B-60. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide;

B-61. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-11-[(2S,3R,4S,6R)-4-[[(4-fluorophenyl)methylsulfamoyl]methylamino]-3-hydroxy-6-methyloxan-2-yl]oxy-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one;

B-62. 4-[[[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-hydroxy-6-methyloxan-4-yl]methylsulfamoyl]methylamino]benzonitrile;

B-63. 2-(cyclopropylamino)-N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-hydroxy-6-methyloxan-4-yl]-N-methylbenzenesulfonamide;

B-64. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2R,4R,5S,6S)-5-(anilinomethyl)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

B-65. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-[(3,3,3-trifluoropropylamino)methyl]oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

B-66. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-[[2-(oxan-4-yl)ethylamino]methyl] oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

B-67. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2R,4R,5S,6S)-5-[(2-cyclopropylethylamino)methyl]-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

B-68. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-[(2-pyrrolidin-1-ylethylamino)methyl]oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

B-69. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2R,4R,5S,6S)-5-[(cyclohexylamino)methyl]-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

B-70. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2R,4R,5S,6S)-5-[(cyclopropylamino)methyl]-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

B-71. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2R,4R,5S,6S)-5-[(3,3-dimethylbutylamino)methyl]-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

B-72. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2R,4R,5S,6S)-5-(butylaminomethyl)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

B-73. (2R,3S,4R, 5R,8R,10R,11R,12S,13S, 14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-[(3-methylbutylamino)methyl]oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

B-74. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2R,4R,5S,6S)-5-[[3-(dimethylamino)propylamino]methyl]-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

B-75. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-[(3-piperidin-1-ylpropylamino)methyl]oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

B-76. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(methylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

B-77. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-13-[(2R,4R,5S,6S)-5-(ethylaminomethyl)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-3,4,10-trihydroxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

B-78. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-13-[(2R,4R,5S,6S)-5-(ethylaminomethyl)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-3,4,10-trihydroxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

B-79. (2R,3S,4R,5R,8R,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-[4-(trifluoromethyl)phenyl]ethylamino]methyl]oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6 methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]ocean-2-yl] oke-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane

B-80. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2R,4R,5S,6S)-5-[(cyclobutylamino)methyl]-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

B-81. N-(2-((((2S,3S,4R,6R)-6-(((2R,3S^R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-11-(((2S,3R,4S,6R)-3-hydroxy-6-methyl-4-(methyl(N-(4-trifluoromethyl)phenyl)sulfamoyl)amino)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-13-yl)oxy)-3-hydroxy-4-methoxy-2,4-dimethyltetrahydro-2H-pyran-3-yl)methyl)amino)ethyl)acetamide;

B-82. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2R,4R,5S,6S)-5-[[2-(dimethylamino)ethylamino]methyl]-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

B-83. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2R,4R,5S,6S)-5-[(2-ethoxyethylamino)methyl]-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

B-84. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-5-[(2-methoxyethylamino)methyl]-4,6-dimethyloxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

B-85. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-[(2-methylpropylamino)methyl]oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

B-86. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-[[(4-phenylphenyl)methylamino]methyl]oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

B-87. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-[[3-(2-oxopyrrolidin-1-yl)propylamino]methyl]oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

B-88. N-[3-[[(2S,3S,4R,6R)-6-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-13-yl]oxy]-3-hydroxy-4-methoxy-2,4-dimethyloxan-3-yl]methyl amino] propyl] acetamide;

B-89. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-[(pyridin-4-ylmethylamino)methyl]oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

B-90. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2R,4R,5S,6S)-5-[(benzylamino)methyl]-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

B-91. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-13-[(2R,4R,5S,6S)-5-[(3-fluoropropylamino)methyl]-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-3,4,10-trihydroxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

B-92. 2-[[(2S,3S,4R,6R)-6-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-13-yl]oxy]-3-hydroxy-4-methoxy-2,4-dimethyloxan-3-yl]methylamino]-N,N-dimethylethanesulfonamide;

B-93. N-((2S,3R,4S,6R)-3-(3,4-dimethoxyphenoxy)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-13-(((2R,4R,5S,6S)-5-((ethylamino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide;

B-94. N-((2S,3R,4S,6R)-3-(3,4-dimethoxyphenoxy)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-3R,-13-(((2R,4R,5S,6S)-5-((N-ethylphenylsulfonamido)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide;

B-95. N-((2S,3R,4S,6R)-3-(3-chloro-4-(trifluoromethyl)phenoxy)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide;

B-96. 3-chloro-N-((2S,3R,4S,6R)-3-(3-chloro-4-(trifluoromethyl)phenoxy)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-tridoxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-4-yl)-4-fluoro-N-methylbenzenesulfonamide;

B-97. N-((2S,3R,4S,6R)-3-(3-chloro-4-methoxyphenoxy)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-3R,-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide;

B-98. 3-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-4-fluoro-N-methylbenzenesulfonamide;

B-99. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide;

B-100. N-(((2S,3S,4R,6R)-6-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-11-(((2S,3R,4S,6R)-3-(4-fluoro-3-(trifluoromethyl)phenoxy)-6-methyl-4-(N-methylphenylsulfonamido)tetrahydro-2H-pyran-2-yl)oxy)-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-13-yl)oxy)-3-hydroxy-4-methoxy-2,4-dimethyltetrahydro-2H-pyran-3-yl)methyl)-N-propylbenzenesulfonamide;

B-101. 3-chloro-N-((2S,3R,4S,6R)-3-(3-chloro-4-methoxyphenoxy)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-3R,-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-4-yl)-4-fluoro-N-methylbenzenesulfonamide;

B-102. 3-chloro-N-((2S,3R,4S,6R)-3-(3,4-dimethoxyphenoxy)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-3R,-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-6-methyltetrahydro-2H-pyran-4-yl)-4-fluoro-N-methylbenzenesulfonamide;

B-103. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(4-methoxyphenoxy)-6-methyloxan-4-yl]-N,5-dimethyl-1-phenylpyrazole-4-sulfonamide;

B-104. 4-bromo-N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-zacyclopentadec-11-yl]oxy]-3-(4-methoxyphenoxy)-6-methyloxan-4-yl]-N-methylbenzenesulfonamide;

B-105. 4,5-dibromo-N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(4-methoxyphenoxy)-6-methyloxan-4-yl]-N-methylthiophene-2-sulfonamide;

B-106. 4-chloro-N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(4-fluorophenoxy)-6-methyloxan-4-yl]-N-methylbenzenesulfonamide;

B-107. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)ox an-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(4-fluorophenoxy)-6-methyloxan-4-yl]-N,1-dimethylimidazol-2-sulfonamide;

B-108. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(4-fluorophenoxy)-6-methyloxan-4-yl]-4-fluoro-N-methylbenzenesulfonamide;

B-109. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(4-fluorophenoxy)-6-methyloxan-4-yl]-N-methylbenzenesulfonamide;

B-110. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,3S,4R)-2-ethyl-3,4,10-trihydroxy-13-[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxane-2- yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(2-fluoro-6-methylphenoxy)-6-methyloxan-4-yl]-N,1-dimethylimidazole-2-sulfonamide;

B-111. 5-chloro-N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(4-methoxyphenoxy)-6-methyloxan-4-yl]-N,1-dimethylimidazole-4-sulfonamide;

B-112. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[methyl(2,2,2-trifluoroethyl)sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one;

B-113. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-|methyl-[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one;

B-114. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxane -2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(4-fluorophenoxy)-6-methyloxan-4-yl]-N,4-dimethyl-1,3-thiazol-5-sulfonamide;

B-115. 6-chloro-N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(4-fluorophenoxy)-6-methyloxan-4-yl]-N-methylpyridine-2-sulfonamide;

B-116. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(4-methoxyphenoxy)-6-methyloxan-4-yl]-N,3,5-trimethyl-1,2-oxazole-4-sulfonamide;

B-117. 5-bromo-6-chloro-N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(4-methoxyphenoxy)-6-methyloxan-4-yl]-N-methylpyridine-3-sulfonamide;

B-118. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(4-methoxyphenoxy)-6-methyloxan-4-yl]-N-methylimidazo[1,2-a]pyridine-3-sulfonamide;

B-119. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(4-methoxyphenoxy)-6-methyloxan-4-yl]-N,1-dimethylimidazole-2-sulfonamide;

B-120. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(4-methoxyphenoxy)-6-methyloxan-4-yl]-N-methyl-5-(1,3-oxazol-5-yl)thiophene-2-sulfonamide;

B-121. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(4-fluoro-2-methylphenoxy)-6-methyloxan-4-yl]-N,1-dimethylimidazole-2-sulfonamide;

B-122. N-[(2S,3R,4S,6R)-3-(3-cyano-4-fluorophenoxy)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S ,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl -5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-6-methyloxan-4-yl]-N,1-dimethylimidazol-2-ulfonamide;

B-123. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(4-methoxyphenoxy)-6-methyloxan-4-yl]-N-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]pyrazole-4-sulfonamide;

B-124. 2-chloro-N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(4-methoxyphenoxy)-6-methyloxan-4-yl]-N-methylpyridine-3-sulfonamide;

B-125. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-5-[(4-methoxyanilino)methyl]-4,6-dimethyloxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl(sulfamoyl)amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

B-126. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(((2-methylsulfonyl)ethyl)amino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methyl-4-(trifluoromethyl)benzenesulfonamide;

B-127. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(((2-(2-oxopiperidin-1-yl)ethyl)amino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methyl-4-(trifluoromethyl)benzenesulfonamide;

B-128. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2R,4R,5S,6S)-5-[[2-(benzenesulfonyl)ethylamino]methyl]-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

B-129. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-[[2-(trifluoromethoxy)ethylamino]methyl]oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

B-130. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4S,5R,6R)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)-oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-6-methyl-3-pyridin-2-yloxyoxan-4-yl]-N-methylbenzenesulfonamide;

B-131. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4S,5R,6R)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)-ox an-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-6-methyl-3-pyridin-2-yloxyoxan-4-yl]-N,1-dimethylimidazol-2-sulfonamide;

B-132. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4S,5R,6R)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)ox an-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-6-methyl-3-thiophen-3-yloxyoxan-4-yl]-K,1-dimethylimidazol-2-sulfonamide;

B-133. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4S,5R,6R)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-[3-(hydroxymethyl)phenoxy]-6-methyloxan-4-yl]-N-methylbenzenesulfonamide;

B-134. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4S,5R,6R)-5-hydroxy-4-methoxy-4,6-dimethyl-5-propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-[3-(hydroxymethyl)phenoxy]-6-methyloxan-4-yl]-N,1-dimethylimidazole-2-sulfonamide;

B-135. N-[(2S,3R,4S,6R)-3-(5-chloropyridin-2-yl)oxy-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-3R,-3,4,10-trihydroxy-13-[(4S,5R,6R)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-6-methyloxan-4-yl]-N-methylbenzenesulfonamide;

B-136. N-[(2S,3R,4S,6R)-3-(4-chlorophenoxy)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2 -ethyl-3,4,10-trihydroxy-13-[(4S,5R,6R)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(pr opylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-6-methyloxan-4-yl]-N,1-dimethylimidazole-2-sulfonamide;

B-137. N-[(2S,3R,4S,6R)-3-(5-chloropyridin-2-yl)oxy-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-3R,-3,4,10-trihydroxy-13-[(4S,5R,6R)-5-g idroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11 -yl]oxy]-6-methyloxan-4-yl]-N,1-dimethylimidazole-2-sulfonamide;

B-138. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4S,5R,6R)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-6-methyl-3-(3-methylsulfinylphenoxy)oxan-4-yl]-N-methylbenzenesulfonamide;

B-139. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydr hydroxy-13-[(4S,5R,6R)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxane-2 -yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-6-methyl-3-(3-methylsulfinylphenoxy)oxan-4-yl]N,1dimethylimidazol-2-sulfonamide;

B-140. (2R,3S,4R, 5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-

[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl(sulfamoyl)amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

B-141. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((4S,5R,6R)-5-((benzylamino)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-(4-fluorophenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-N, 1-dimethyl-III-imidazole-2-sulfonamide;

B-142. 4-chloro-N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-hydroxy-6-methyloxan-4-yl]-N-propylbenzenesulfonamide;

B-143. N-benzyl-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,68)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-1-methyl-1H-imidazole-2-sulfonamide;

B-144. N-benzyl-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,4R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-4-methoxybenzenesulfonamide;

B-145. N-benzyl-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,4R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)benzenesulfonamide;

B-146. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-(4-methoxybenzyl)-1-methyl-1H-imidazole-2-sulfonamide;

B-147. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-4-methoxy-N-(4-methoxybenzyl)benzenesulfonamide;

B-148. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-H-(4-methoxybenzyl)benzenesulfonamide;

B-149. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-isobutyl-4-methoxybenzenesulfonamide;

B-150. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-isobutylbenzene sulfonamide;

B-151. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-6-propyl-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide;

B-152. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3 S,4R,5R, 8R,10R,11R,12S,13S,14R)-2,6-diethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide;

B-153. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide;

B-154. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-6-propyl-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N,4-dimethylbenzenesulfonamide;

B-155. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2,6-diethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N,4-dimethylbenzenesulfonamide;

B-156. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N,4-dimethylbenzenesulfonamide;

B-157. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-5-[(4-methoxyanilino)methyl]-4,6-dimethyloxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl(sulfamoyl)amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-6-propyl-1-oxa-6-azacyclopentadecane;

B-158. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl(sulfamoyl)amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-6-propyl-1-oxa-6-azacyclopentadecane;

B-159. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

B-160. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-6-propyl-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-(4-fluorophenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide;

B-161. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2,6-diethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-(4-fluorophenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide; and

B-162. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-(4-fluorophenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-N,1-dimethyl-1H-imidazole-2-sulfonamide.

The following compounds of formula (1-A1a), prepared according to the schemes and procedures described herein, are presented in Table C.

The corresponding names of the compounds are given below the table.

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

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

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

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

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

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

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

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

C-9. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-(((2R,4R,5S,6S)-5-((1H-tetrazol-1-yl)methyl)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-4-chloro-N-methylbenzenesulfonamide;

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

S-11. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-11-[(2 S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

C-12. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-13-[(2R,4R,5S,6S)-5-[(4-ethylpiperazin-1-yl)methyl]-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-3,4,10-trihydroxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

C-13. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2R,4R,5S,6S)-5-[(1,1-ahokco-1,4-thiazinan-4-yl)methyl]-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

C-14. (2R,3S,4R, 5R,8R, 10R, 11R, 12S, 13S, 14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-[(4-propan-2-ylpiperazin-1-yl)methyl]oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

C-15. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-[(4-methylsulfonylpiperazin-1-yl)methyl]oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

S-16. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl ]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl(sulfamoyl)amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

C-17. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl(sulfamoyl)amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-6-propyl-1-oxa-6-azacyclopentadecane;

C-18. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-hydroxy-6-methyloxan-4-yl]-N-methyl-4-(trifluoromethyl)benzenesulfonamide;

C-19. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-hydroxy-6-methyloxan-4-yl]-4-fluoro-N-methylbenzenesulfonamide;

S-20. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2,6-diethyl-3,4,10-trihydroxy-13-[(2R,4R,58,68)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl] hydroxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl(phenylsulfamoyl)amino]-oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

C-21. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl(phenylsulfamoyl]amino]-2-yl]oxy-3,5,8,10,14-hexamethyl-15-oxo-6-propyl-1-oxa-6-azacyclopentadecane;

C-22. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2R,3S,4R,6S)-4-[(4-tert-butylphenyl)sulfamoylmethylamino]-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-3,5,8,1 OD 2,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

S-23. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2R,3S,4R,6S)-4-[(3-chlorophenyl)sulfamoyl-methylamino]-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy -13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)-oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

S-24. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-11-[(2R,3S,4R,6S)-4-[(3-fluorophenyl)sulfamoyl-methylamino]-3-hydroxy-6-methyloxan-2-yl]oxy-3,4,10-trihydroxy -13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)-oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

C-25. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2R,3S,4R,6S)-4-[[3-(dimethylamino)phenyl]sulfamoylmethylamino]-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

C-26. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-11-[(2R,3S,4R,6S)-3-hydroxy-6-methyl-4-[methyl-[(3-methylphenyl)sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

C-27. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-11-[(2R,3S,4R,6S)-3-hydroxy-4-[(4-methoxyphenyl)sulfamoylmethylamino]-6-methyloxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

S-28. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2R,3S,4R,6S)-4-[(3,4-dichlorophenyl)sulfamoyl-methylamino]-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydro si-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)-oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

C-29. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2R,3S,4R,6S)-4-[(4-bromophenyl)sulfamoylmethylamino]-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)-oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

S-30. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-11-[(2R,3S,4R,6S)-3-hydroxy-4-[(4-iodophenyl)sulfamoyl-methylamino]-6-methyloxan-2-yl]oxy- 13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)-oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

C-31. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2R,3S,4R,6S)-4-[[4-chloro-3-(trifluoromethyl)phenyl]sulfamoylmethylamino]-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

C-32. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-11-[(2R,3S,4R,6S)-3-hydroxy-6-methyl-4-[methyl-[(4-methylphenyl)sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

C-33. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2R,3S,4R,6S)-4-[(3,4-dimethylphenyl)sulfamoylmethylamino]-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

C-34. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-11-[(2R,3S,4R,6S)-3-hydroxy-6-methyl-4-[methyl-[(1-methylimidazol-2-yl)sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

S-35. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-[diethylsulfamoyl(methyl)amino]-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-1 3-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one;

S-36. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2,6-diethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-11-[ (2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]-sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

C-37. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-hydroxy-6-methyloxan-4-yl]-N-methyl-1-methylsulfonylmethanesulfonamide;

C-38. 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((6R)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide;

S-39. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5 -hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-11-[(2S,3R,4 S,6R)-3-hydroxy-6-methyl-4-[pyridin-3-ylmethyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

C-40. 4-chloro-N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-hydroxy-6-methyloxan-4-yl]-N-propylbenzenesulfonamide;

C-41. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-hydroxy-6-methyloxan-4-yl]-4-methoxy-N-propylbenzenesulfonamide;

C-42. 4-chloro-N-cyclohexyl-N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R58R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-hydroxy-6-methyloxan-4-yl]benzenesulfonamide;

C-43. N-cyclohexyl-N-[(2S3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,3S,4R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-hydroxy-6-methyloxan-4-yl]-4-methoxybenzenesulfonamide;

S-44. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)- 5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-11-[(2S,3R ,4S,6R)-3-hydroxy-6-methyl-4-[2-methylpropyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

S-45. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-[cyclohexyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-tr ihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

S-46. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5- Hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-11-[(2S,3R,4S ,6R)-3-hydroxy-6-methyl-4-[[1,3-thiazol-2-ylmethyl-[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, acetic acid;

C-47. N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((6R)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methyl-4-(pentafluoro-16-sulfaneyl)benzenesulfonamide;

S-48. N-[(2S,3R,4S,6R)-3-(5-chloropyridin-2-yl)oxy-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(6R)-5-hydroxy-4-methoxy-4,6-dimethyl-5 -(piperidin-1-ylmethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-6-methyloxan-4-yl]-N-methylbenzenesulfonamide;

S-49. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydro xy-13-[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan- 2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(2-fluoropyridin-4-yl)oxy-6-methyloxan-4-yl]-N,1-dimethylimidazol-2-sulfonamide;

S-50. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-1 1-[(2R,3S,4R,6S)-3-(4-methoxyphenoxy)-6-methyl-4-[methyl(phenylsulfamoyl)amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

S-51. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-11-[(2R,3S,4R,6S)-3-(4-fluorophenoxy)-6-methyl-4-[methyl(phenylsulfamoyl)amino]oxan-2-yl]oxy-3,4,10-trihydroxy -13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane;

C-52. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-11-[(2R,3S,6S)-6-methyl-4-[methyl(phenylsulfamoyl)amino]-3-phenoxyoxan-2-yl]oxy-15-oxo-1-oxa-6-azacyclopentadecane;

S-53. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(6R)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylme til)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-6-methyl-3-phenoxyoxan-4-yl]-N-methylbenzenesulfonamide;

S-54. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(6R)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl) oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(4-fluorophenoxy)-6-methyloxan-4-yl]-N-methylbenzenesulfonamide;

S-55. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(6R)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxane -2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(2-fluoropyridin-4-yl)oxy-6-methyloxan-4-yl]-N-methylbenzenesulfonamide;

S-56. N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,12S,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(6R)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxane -2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(4-fluorophenoxy)-6-methyloxan-4-yl]-N,1-dimethylimidazol-2-sulfonamide;

S-57. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-11-[(2S ,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacyclopentadecane, acetic acid; And

S-58. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)- 5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-11-[(2S,3R ,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-6-propyl-1-oxa-6-azacyclopentadecane, acetic acid.

The following compounds of formula (2-A1) were prepared according to

schemes and procedures described herein, wherein R ⁰ , R ¹ , R ⁵ and R ⁶ have the meanings defined below in Table D; or R ⁵ and R ⁶ are joined together to form a B ring, which is also defined below in Table D. The corresponding names of the compounds are provided below the table.

Names of examples of compounds of formula (2-A1) of Table D:

D-1. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[[(3aR,4S,6R,7aS)-1,6-dimethyl-2,2-dioxo-4,6,7,7a-tetrahydro-3aH-pyrano[4,3-d]oxathiazol-4-yl]oxy]-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one; acetic acid;

D2. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[[(3aR,4S,6R,7aS)-1,6-dimethyl-2,2-dioxo-4,6,7,7a-tetrahydro-3aH-pyrano[4,3-d]oxathiazol-4-yl]oxy]-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-6-propyl-1-oxa-6-azacyclopentadecan-15-one;acetic acid;

D3. (2R,3S,4R,5R,8R,10R,11R,125,13S,14R)-11-[[{3aR,4S,6R,7aS)-1-[(4-methoxyphenyl)methyl]-6-methyl-2,2-dioxo-4,6,7,7a-tetrahydro-3aH-pyrano[4,3-d]oxathiazol-4-yl]oxy]-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-6-propyl-1-oxa-6-azacyclopentadecan-15-one; acetic acid;

D4. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[[(3aR,4S,6R,7aS)-1-[(4-methoxyphenyl)methyl]-6-methyl-2,2-dioxo-4,6,7,7a-tetrahydro-3aH-pyrano[4,3-d]oxathiazol-4-yl]oxy]-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one;acetic acid;

D5. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[[(3aR,4S,6R,7aS)-1,6-dimethyl-2,2-dioxo-4,6,7,7a-tetrahydro-3aH-pyrano[4,3-d]oxathiazol-4-yl]oxy]-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one;acetic acid;

D6. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[[(3aR,4S,6R,7aS)-1,6-dimethyl-2,2-dioxo-4,6,7,7a-tetrahydro-3aH-pyrano[4,3-d]oxathiazol-4-yl]oxy]-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-6-propyl-1-oxa-6-azacyclopentadecan-15-one; and

D7. (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[[(3aR,4S,6R,7aS)-1-[(4-methoxyphenyl)methyl]-6-methyl-2,2-dioxo-4,6,7,7a-tetrahydro-3aH-pyrano[4,3-d]oxathiazol-4-yl]oxy]-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one;acetic acid.

Examples of NMR spectra

A-1. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.36 - 1.25 (m, 23Н) 1.27 - 2.13 (m, 17Н) 2.16 - 2.67 (m, 7Н) 3.36 - 3.62 (m, 4Н) 3.69 - 3.84 (m, 1Н) 4.03 - 4.32 (m, 2Н) 4.49 - 4.71 (m, 1H) 4.78 - 5.00 (m, 1H) 6.42 - 6.74 (m, 3H) 6.48 - 6.72 (m, 2H) 7.25 - 7.52 (m, 2H) 7.58 - 7.80 (m, 2H);

A-2. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.31 - 1.54 (m, 25N) 1.59 - 2.14 (m, 10N) 2.25 - 2.73 (m, 2H) 3.43 - 3.68 (m, 3H) 3.80 - 3.92 (m, 1H) 4.14 - 4.33 (m, 1H) 4.53 - 4.71 (m, 1H) 4.84 - 5.00 (m, 1H) 6.76 - 7.07 (m, 3H) 6.78 - 6.97 (m, 2H) 7.25 - 8.08 (m, 5H) 7.30 - 7.58 (m, 3H) 7.35 - 7.56 (m, 3H) 7.58 - 7.85 (m, 2H);

A-3. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.29 - 1.67 (m, 32H) 1.70-2.14 (m, 5H) 2.39 - 2.98 (m, 6H) 3.52 - 3.76 (m, 3H) 3.82 - 4.27 (m, 3H) 4.62 - 5.07 (m, 4H) 4.98 - 5.13 (m, 1H) 6.54 - 6.83 (m, 3H) 6.88 - 7.10 (m, 2H) 7.24 - 7.51 (m, 3H) 7.71 (lat d, J=7.82 Hz, 2H);

A-4. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.8-1.5 (m, 32H), 1.6-2.0 (m, 11H) (including 2 protons of acetate salt), 2.1-2.5 (m, 4H), 2.6-2.9 (m, 3H), 3.2-3.5 (m, 5H), 4.00-4.02 (m, 3H), 4.9-5.2 (m, 3H), 6.83-7.02 (m, 4H), 7.12-7.24 (m, 6H);

A-5. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.17 - 1.43 (m, 20Н) 1.47 - 2.26 (m, 5Н) 2.47 - 3.16 (m, 6Н) 3.26 - 3.52 (m, 3Н) 3.54 - 3.85 (m, 5Н) 3.85 - 4.03 (m, 1Н) 4.20 - 4.34 (m, 1H) 4.65 - 5.10 (m, 3H) 5.14 - 5.41 (m, 1H) 5.43 - 5.71 (m, 1H) 6.52 - 6.87 (m, 2H) 6.60 - 6.87 (m, 2H) 7.02 - 7.18 (m, 1H) 7.48 (s, 1H) 7.55 - 7.97 (m, 4H) 8.26 - 8.64 (m, 1H) 9.18 - 9.56 (m, 1H);

A-6. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.40 - 1.67 (m, 32H) 1.85 - 2.35 (m, 4H) 2.49 - 3.20 (m, 6H) 3.29 - 3.90 (m, 6H) 4.18 - 4.34 (m, 1H) 4.71 - 4.99 (m, 2H) 5.58 - 5.69 (m, 1H) 6.76 - 7.00 (m, 2H) 7.07 - 7.26 (m, 2H) 7.55 - 7.67 (m, 1H) 7.69 - 7.87 (m, 1H);

A-7. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm -0.23 - 2.25 (m, 41H) 2.49 - 2.93 (m, 2H) 3.04 - 4.01 (m, 6H) 4.15 - 4.44 (m, 1H) 4.77 - 5.08 (m, 2H) 6.59 - 6.76 (m, 1H) 6.90 - 7.09 (m, 1H) 7.29 - 7.55 (m, 1H) 7.29 - 7.58 (m, 2H) 7.62 - 7.83 (m, 1H) 8.27 - 8.59 (m, 1H) 9.33 - 9.56 (m, 1H);

A-8. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.44 - 1.60 (m, 32Н) 1.68 - 2.69 (m, 12Н) 2.92 - 3.45 (m, 4Н) 3.50 - 3.90 (m, 9Н) 4.08 - 4.26 (m, 1Н) 4.70 - 4.83 (m, 1Н) 4.85 - 4.97 (m, 1H) 6.26 - 6.41 (m, 2H) 6.46 - 6.62 (m, 1H) 6.51 - 6.69 (m, 1H) 7.33 - 7.61 (m, 3H) 7.64 - 7.87 (m, 2H);

A-9. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.50 - 1.53 (m, 30H) 1.67 - 2.34 (m, 9H) 2.49 - 3.04 (m, 6H) 3.12 - 3.27 (m, 1H) 3.45 (d, J=2.20 Hz, 1H) 3.62 - 3.85 (m, 6H) 3.86 - 4.08 (m, 2H) 4.17 - 4.41 (m, 2H) 4.73 - 4.88 (m, 1H) 4.96 (d, J=7.58 Hz, 1H) 6.58 - 6.78 (m, 3H) 6.60 - 6.63 (m, 1H) 7.39 - 7.64 (m, 3H) 7.71 - 7.80 (m, 1H) 7.77 - 7.84 (m, 1H) 7.79 - 7.87 (m, 1H) 7.84 - 7.87 (m, 1H);

A-10. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.43 - 1.68 (m, 31H) 1.70 - 2.18 (m, 7H) 2.30 - 2.98 (m, 5H) 3.10 - 3.90 (m, 5H) 4.01 - 4.30 (m, 1H) 4.80 - 5.07 (m, 2H) 6.46 - 6.75 (m, 4H) 7.26 - 7.52 (m, 3H) 7.62 - 7.81 (m, 2H);

A-11. ¹ H NMR (400 MHz, METHANOL) δ ppm 0.69 - 1.87 (m, 38H), 2.00 - 2.18 (m, 6H), 2.39 - 2.73 (m, 5H), 2.86 - 3.61 (m, 3H), 3.62 - 4.01 (m, 4H) 6.98 - 7.11 (m, 1H) 7.18 - 7.46 (m, 3H);

A-12. ¹ H NMR (400 MHz, METHANOL) δ ppm 0.73 - 1.57 (m, 30N), 1.58 - 1.72 (m, 8N). 2.44 - 2.71 (m, 8H), 3.03 - 3.20 (m, 1H) 3.22 - 3.28 (m, 2H) 3.43 (s, 1H) 3.50 (d, J=10.27 Hz, 2H) 3.61 (s, 1H) 3.74 (lat d, J=3.67 Hz, 1H) 4.60 (br.d, J=7.34 Hz, 2H) 7.10-7.14 (m, 1H) 7.71-7.75 (m, 1H) 7.90-7.97 (m, 1H);

A-13. ¹ H NMR (400 MHz, METHANOL-d4) δ ppm 0.76 - 1.20 (m, 35N). 1.33 - 2.17 (m, 9H), 2.39 - 2.98 (m, 6H), 3.08 - 3.19 (m, 1H) 3.37 (s, 1H), 3.84 (td, J=11.07, 4.77 Hz, 1H) 7.30-7.33 (m, 1H) 7.62 (m, 1H) 7.68 - 7.81 (m, 1H);

A-14. ¹ H NMR (400 MHz, METHANOL-d4) δ ppm 0.76 - 1.57 (m, 38H), 1.68-2.15 (m, 6H), 2.50 -3.00 (m, 6H), 3.09 - 3.19 (m, 1H) 3.37 (s, 1H), 3.85 (lat d, J=3.91 Hz, 1H) 7.29 (t, J=8.68 Hz, 1H) 7.72-7.77 (m, 1H), 7.91 (dd, J=6.60, 1.22 Hz, 1H);

A-15. ¹ H NMR (400 MHz, METHANOL) δ ppm 0.77 1.55 (m, 36H), 1.58-2.19 (m, 6H), 2.42 - 2.73 (m, 5H), 3.01 (br d, J = 9.05 Hz, 1H) 3.08 - 3.21 (m, 1H) 3.39 (s, 1H), 3.72 - 3.95 (m, 1H) 4.59 (br d, J = 7.34 Hz, 2H) 7.43 (t, J = 8.80 Hz, 1H) 8.01 - 8.17 (m, 1H) 8.22 (m, 1H);

A-16. ¹ H NMR (400 MHz, METHANOL) δ ppm 0.81 - 1.47 (M, 32H), 1.57 - 2.24 (M, 9H), 2.56 - 3.02 (m, 5H), 3.07 - 3.19 (m, 2H) 3.41 (s, 1H) 3.50 (br d, J=10.27 Hz, 2H) 3.58 (s, 1H) 3.88 (br d, J=6.36 Hz, 1H) 7.41 - 7.54 (m, 3H) 7.78 (d, J=7.82 Hz, 2H);

A-17. ¹ H NMR (400 MHz, METHANOL) δ ppm 0.76 - 1.51 (m, 35H), 1.59 - 2.62 (m, 11H), 2.66 - 3.19 (m, 5H), 3.37 (s, 1H) 3.86 (td, J=10.94, 5.01 Hz, 1H) 7.16 (t, J=8.68 Hz, 2H) 7.83 (dd, J=8.44, 5.26 Hz, 2H);

A-18. ¹ H NMR (400 MHz, METHANOL) δ ppm 0.76 - 1.51 (m, 36H), 1.57 -2.18 (m, 9H), 2.55 - 2.99 (m, 6H), 3.37 (s, 1H), 3.88 (br d, J=3.42 Hz, 1H) 7.59 - 7.70 (m, 3H) 8.08 (d, J=7.58 Hz, 1H);

A-19. ¹ H NMR (400 MHz, METHANOL) δ ppm 0.75 - 1.50 (m, 32H) 1.53 - 2.18 (m, 11H) 2.43 - 2.97 (br d, J=9.05 Hz, 6H) 3.12 (dd, J=10.03, 7.58 Hz, 1H) 3.21 (br d, J=0.98 Hz, 1H) 3.35 (s, 1H) 3.85 (td, J=11.19, 4.52 Hz, 1H) 7.99 (m, J=8.56 Hz, 2H) 8.25 (m, J=8.56 Hz, 2H);

A-20. ¹ H NMR (400 MHz, METHANOL-d4) δ ppm 0.76 - 1.52 (m, 32H), 1.67 - 2.17 (m, 9H), 2.53 -3.19 (m, 7H), 3.38 (s, 1H) 3.50 (d, J=14.18 Hz, 3H) 3.77 (s, 3H) 3.85 (td, J=10.82, 5.50 Hz, 1H) 6.94 (d, J=8.56 Hz, 2H) 7.70 (d, J=8.80 Hz, 2H);

A-21. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.35 - 1.53 (m, 29Н) 1.62 - 2.26 (m, 9Н) 2.44 - 2.98 (m, 7Н) 3.34 - 3.80 (m, 2Н) 3.80 - 3.94 (m, 2Н) 4.14 - 4.27 (m, 2Н) 4.90 - 5.01 (m, 2H) 5.01-5.11 (m, 1H) 5.37 - 5.48 (m, 1H) 6.37 - 6.47 (m, 1H) 6.57 - 6.76 (m, 5H) 7.55 - 7.74 (m, 2H) 8.37 - 8.50 (m, 2H) 8.50 - 8.68 (m, 1H) 9.27 - 9.47 (m, 1H);

A-22. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.41 - 1.40 (m, 25N) 1.51 - 2.25 (m, 12N) 2.34 - 3.00 (m, 6N) 3.22 - 3.93 (m, 3H) 4.15 - 4.25 (m, 1H) 4.84 - 5.08 (m, 2H) 5.34 - 5.55 (m, 1H) 6.57 - 7.02 (m, 5H) 7.32 - 7.56 (m, 2H) 8.29 - 8.65 (m, 1H) 9.25 - 9.57 (m, 1H);

A-23. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.41 - 1.52 (m, 23Н) 1.56 - 2.69 (m, 17Н) 2.82 - 3.03 (m, 2Н) 3.34 - 3.51 (m, 3Н) 3.59 - 3.95 (m, 4Н) 4.14 - 4.29 (m, 1Н) 4.79 - 5.06 (m, 2H) 6.53 - 6.79 (m, 3H) 7.31 - 7.56 (m, 2H) 7.70 - 7.86 (m, 2H) 8.38 - 8.56 (m, 1H) 9.24 - 9.53 (m, 1H);

A-24. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.35 - 1.56 (m, 30H) 1.69 - 2.29 (m, 4H) 2.35 - 3.08 (m, 7H) 3.28 - 4.02 (m, 3H) 4.09 - 4.37 (m, 2H) 4.77 - 5.10 (m, 3H) 5.35 (lat. s, 1H) 6.30 - 6.73 (m, 4H) 7.23 (s, 4H) 7.52 - 7.65 (m, 1H) 8.44 - 8.63 (m, 1H) 9.21 - 9.51 (m, 1H);

A-25. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.51 - 1.47 (m, 24H) 1.56 - 2.11 (m, 11H) 2.11 - 2.56 (m, 6H) 2.87 - 4.06 (m, 1H) 4.08 - 4.45 (m, 3H) 4.56 - 4.92 (m, 3H) 4.98 - 5.22 (m, 1H) 5.33 - 5.53 (m, 1H) 6.39 - 6.99 (m, 4H) 7.32 - 7.54 (m, 2H) 7.62 - 7.78 (m, 2H) 8.63 - 8.96 (m, 1H) 9.38 - 9.65 (m, 1H);

A-26. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.41 - 1.52 (m, 25H) 1.69 - 2.29 (m, 8H) 2.45 - 2.94 (m, 8H) 3.08 - 3.73 (m, 7H) 3.82 - 4.05 (m, 2H) 4.09 - 4.33 (m, 2H) 4.58 - 5.05 (m, 3H) 6.42 - 7.02 (m, 4H) 8.72 - 8.93 (m, 1H);

A-27. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.49 - 1.68 (m, 30N) 1.78 - 2.16 (m, 5N) 2.43 - 2.84 (m, 6 N) 3.11 - 3.48 (m, 4 N) 3.47 - 3.75 (m, 3N) 3.75 - 3.91 (m, 4N) 4.15 - 4.30 (m, 1H) 4.71 - 4.82 (m, 1H) 4.88 - 5.01 (m, 1H) 6.73 - 7.06 (m, 6H);

A-28. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.45 - 1.33 (m, 29H) 1.36 - 2.05 (m, 9H) 2.42 - 2.80 (m, 6H) 3.22 (br s, 2H) 3.40 (br s, 1H) 3.48 - 3.83 (m, 2H) 3.76 - 3.98 (m, 4H) 4.15 -4.37 (m, 2H) 4.68 - 4.98 (m, 3H) 6.72 - 6.92 (m, 4H) 7.27 - 7.32 (m, 1H);

A-29. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.48 - 1.75 (m, 29N) 1.96 - 2.05 (m, 1N) 2.00 - 2.91 (m, 6 N) 3.27 - 3.52 (m, 5 N) 3.54 - 3.74 (m, 3 N) 3.75 - 4.12 (m, 4N) 4.23 - 4.35 (m, 1H) 4.69 - 4.91 (m, 2H) 5.03 - 5.13 (m, 1H) 6.60 - 6.68 (m, 2H) 6.71 - 6.86 (m, 4H) 7.68 - 7.84 (m, 1H);

A-30. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.38 - 1.53 (m, 22N) 1.56 - 2.25 (m, 15 N) 2.50 - 2.59 (m, 3 N) 2.86 - 3.01 (m, 2 N) 3.23 - 3.81 (m, 2N) 3.82 - 3.92 (m, 1H) 4.07 - 4.27 (m, 2H) 4.76 - 5.01 (m, 3H) 6.43 - 6.59 (m, 2H) 6.65 - 6.81 (m, 2H) 7.28 - 7.45 (m, 2H) 7.49 - 7.73 (m, 2H) 8.16 - 8.36 (m, 1H) 8.57 - 8.72 (m, 1N);

A-31. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.41 - 1.56 (m, 30H) 1.80 - 2.61 (m, 15H) 2.63 - 3.01 (m, 1H) 3.16 - 3.22 (m, 1H) 3.35 - 3.53 (m, 1H) 3.48 - 3.64 (m, 1H) 3.69 - 3.78 (m, 3H) 3.84 - 4.09 (m, 1H) 4.34 - 4.50 (m, 1H) 4.94 - 5.15 (m, 1H) 6.71 - 6.84 (m, 1H) 6.86 - 6.97 (m, 1H) 6.97 - 7.10 (m, 1H) 7.11 - 7.20 (m, 2H);

A-32. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.50 - 1.40 (m, 32H) 1.40 - 2.26 (m, 11H) 2.30 - 3.36 (m, 6H) 3.31 - 3.93 (m, 5H) 3.94 - 4.14 (m, 1H) 4.67 - 4.86 (m, 2H) 6.76 - 7.00 (m, 3H) 7.04 - 7.17 (m, 2H);

A-33. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.04 - 1.34 (m, 29N) 1.39 - 2.20 (m, 16N) 2.52 - 3.02 (m, 4H) 3.39 - 4.01 (m, 2H) 4.19 - 4.37 (m, 1H) 4.70 - 5.03 (m, 3H) 6.45 - 6.62 (m, 2H) 6.66 - 6.85 (m, 2H) 7.65 - 7.80 (m, 1H) 7.85 - 7.95 (m, 1H) 8.28 - 8.46 (m, 1H);

A-34. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.39 - 1.60 (m, 22H) 1.69 - 2.41 (m, 1H) 1.69 - 3.08 (m, 5H) 1.76 - 2.26 (m, 10H) 2.51 - 3.15 (m, 1H) 2.54-3.11 (m, 1H) 2.67-3.01 (m, 4H) 2.85 - 3.04 (m, 1H) 3.34 - 3.52 (m, 3H) 3.55 - 4.00 (m, 2H) 4.01 - 4.44 (m, 3H) 4.91 - 5.13 (m, 2H) 6.77-7.17 (m, 5H);

A-35. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.32 - 1.47 (m, 30Н) 1.46 - 2.73 (m, 7Н) 2.75 - 3.50 (m, 4Н) 3.58 - 3.84 (m, 2Н) 3.87 - 4.06 (m, 1) 4.13 - 4.28 (m, 1Н) 4.84 - 5.10 (m, 1H) 5.10 - 5.22 (m, 1H) 6.96 - 7.17 (m, 3H) 7.24 - 7.44 (m, 1H) 7.45 - 7.60 (m, 1H);

A-36. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.8-1.5 (m, 32H), 1.6-2.0 (m, 9H) (including 1 proton of acetate salt), 2.1-2.5 (m, 4H), 2.6-2.9 (m, 3H), 3.2-3.5 (m, 4H), 3.6-3.8 (m, 5H), 4.0-4.3 (m, 2H), 4.9-5.2 (m, 3H), 6.86 (d, 2H, J=8.92 Hz), 7.00-7.04 (m, 1H), 7.13 (d, 2H, J=7.6 Hz), 7.24-7.28 (m, 2H);

A-37. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.5-1.5 (m, 33H), 1.6-2.1 (m, 7H) (including 1 proton of acetate salt), 2.4-2.9 (m, 5H), 3.1-3.5 (m, 5H), 3.9-4.2 (m, 3H), 4.9-5.2 (m, 3H), 6.92-7.03 (m, 5H), 7.12 (d, 2H, J=7.92 Hz), 7.23-7.27 (m, 2H), 9.82 (br s, 1H);

B-1. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.8-1.5 (m, 48H), 1.6-2.3 (m, 10H) (including 1 acetate salt proton), 2.4-2.8 (m, 10H), 3.1-3.7 (m, 13H), 4.09 (s, 1H), 4.3-4.4 (m, 2H), 4.7-4.9 (m, 2H), 5.1-5.2 (m, 1H);

B-2. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.8-1.5 (m, 48H), 1.6-2.3 (m, 12H) (including 2 acetate salt protons), 2.4-2.8 (m, 9H), 3.0-3.5 (m, 5H), 3.7-3.8 (m, 4H), 4.07 (s, 1H), 4.37-4.39 (m, 2H), 4.81-4.84 (m, 3H), 8.01 (d, 2H, J=8.64 Hz), 8.33 (d, 2H, J=8.64 Hz);

B-3. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.8-1.5 (m, 54H), 1.6-2.3 (m, 14H) (including 2 acetate salt protons), 2.4-2.9 (m, 13H), 3.0-3.7 (m, 8H), 4.06 (br s, 1H), 4.40-4.41 (m, 2H), 4.82-4.86 (m, 2H), 5.1-5.2 (m, 1H);

B-4. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.8-1.5 (m, 47H), 1.6-2.3 (m, 10H) (including 1 proton of acetate salt), 2.4-2.8 (m, 14H), 3.1-3.5 (m, 6H), 3.6-3.8 (m, 2H), 4.08 (s, 1H), 4.1-4.2 (br. s, 1H), 4.36-4.40 (m, 2H), 4.81-4.85 (m, 2H), 4.99-5.01 (m, 1H);

B-5. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.8-1.5 (m, 48H), 1.6-2.3 (m, 16H) (including 2 protons of the acetate salt), 2.4-2.8 (m, 10H), 3.1-3.3 (m, 4H), 3.4-3.5 (m, 4H), 3.6-3.9 (m, 2H), 4.12 (s, 1H), 4.40-4.43 (m, 2H), 4.82-4.87 (m, 2H), 5.18 (br s, 1H), 7.66 (s, 1H);

B-6. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.8-1.5 (m, 47H), 1.6-2.3 (m, 12H) (including 2 protons of the acetate salt), 2.4-2.9 (m, 10H), 3.0-3.5 (m, 5H), 3.7-3.9 (m, 4H), 4.07 (s, 1H), 4.4-4.5 (m, 2H), 4.82-4.86 (m, 3H), 8.06 (d, 1H, J=8.28 Hz), 8.37 (d, 1H, J=8.32 Hz), 9.04 (s, 1H);

B-7. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.8-1.5 (m, 48H), 1.6-2.3 (m, 12H) (including 2 protons of the acetate salt), 2.6-2.8 (m, 10H), 3.0-3.5 (m, 6H), 3.6-3.9 (m, 2H), 4.07 (s, 1H), 4.39-4.41 (m, 2H), 4.82-4.87 (m, 3H), 7.30-7.31 (m, 1H), 7.51-7.60 (m, 2H), 7.79 (d, 2H, J=7.48 Hz);

B-8. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.8-1.5 (m, 46H), 1.6-2.2 (m, 16H) (including 2 acetate salt protons), 2.3-2.8 (m, 12H), 3.0-3.2 (m, 3H), 3.3-3.4 (m, 5H), 3.6-3.8 (m, 3H), 4.08 (s, 1H), 4.39-4.41 (m, 2H), 4.82-4.86 (m, 2H), 5.15-5.16 (m, 1H);

B-9. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.8-1.5 (m, 44H), 1.6-2.3 (m, 12H) (including 2 protons of the acetate salt), 2.4-2.8 (m, 10H), 3.0-3.5 (m, 5H), 3.7-3.9 (m, 4H), 4.07 (s, 1H), 4.38-4.39 (m, 2H), 4.81-4.85 (m, 4H), 7.66 (d, 2H, J=5.32 Hz), 8.41 (d, 2H, J=5.4 Hz), 8.93 (s, 2H);

B-10. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.2-0.3 (m, 2H), 0.5-0.6 (m, 2H), 0.8-1.5 (m, 50H), 1.6-2.2 (m, 12H) (including 2 protons of the acetate salt), 2.4-2.8 (m, 10H), 3.0-3.5 (m, 7H), 3.6-3.7 (m, 2H), 4.09 (s, 1H), 4.39-4.41 (m, 2H), 4.81-4.85 (m, 2H), 5.10 (m, 1H);

B-11. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.8-1.5 (m, 48H), 1.6-2.3 (m, 9H) (including 1 proton of acetate salt), 2.4-2.8 (m, 10H), 3.1-3.3 (m, 5H), 3.4-3.9 (m, 4H), 4.06 (s, 1H), 4.20 (br. s, 1H), 4.38-4.41 (m, 2H), 4.83-4.87 (m, 3H), 8.01 (d, 2H, J=8.48 Hz), 8.06 (d, 2H, J=8.48 Hz);

B-12. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.8-1.5 (m, 46H), 1.6-2.3 (m, 10H) (including 1 proton of acetate salt), 2.4-2.8 (m, 9H), 3.1-3.5 (m, 5H), 3.6-3.9 (m, 3H), 4.08 (s, 1H), 4.20 (br s, 1H), 4.3-4.4 (m, 2H), 4.82-4.86 (m, 3H), 7.55-7.58 (m, 1H), 8.13 (d, 1H, J=8.04 Hz), 8.76 (d, 1H, J=3.84 Hz), 8.91 (s, 1H);

B-13. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.8-1.5 (m, 44H), 1.6-2.3 (m, 14H) (including 2 protons of acetate salt), 2.4-2.8 (m, 13H), 3.0-3.5 (m, 5H), 3.6-3.9 (m, 2H), 4.08 (s, 1H), 4.37-4.40 (m, 2H), 4.82-4.86 (m, 3H), 7.92 (d, 2H, J=8.32 Hz), 8.01 (d, 2H, J=8.32 Hz);

B-14. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.8-1.5 (m, 46H), 1.6-2.3 (m, 9H) (including 1 acetate salt proton), 2.4-2.9 (m, 9H), 3.0-3.5 (m, 6H), 3.7-3.9 (m, 4H), 4.09 (s, 1H), 4.4-4.5 (m, 2H), 4.81-4.85 (m, 3H), 7.90 (d, 2H, J=7.88 Hz), 7.98 (d, 2H, J=8.04 Hz);

B-15. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.8-1.5 (m, 46H), 1.6-2.3 (m, 9H) (including 1 proton of acetate salt), 2.4-2.9 (m, 9H), 3.0-3.5 (m, 6H), 3.6-3.9 (m, 5H), 4.4-4.5 (m, 3H), 4.8-4.9 (m, 3H), 7.5-7.7 (br. s, 1H), 7.93-7.98 (m, 4H);

B-16. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.8-1.5 (m, 48H), 1.6-2.3 (m, 10H) (including 1 proton of acetate salt), 2.6-2.9 (m, 9H), 3.1-3.7 (m, 8H), 3.8-4.0 (m, 1H), 4.09 (s, 1H), 4.20 (br. s, 1H), 4.4-4.5 (m, 2H), 4.84-4.87 (m, 2H), 5.11 (s, 1H), 7.56 (s, 1H), 7.79 (s, 1H);

B-17. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.8-1.5 (m, 43H), 1.6-2.3 (m, 11H) (including 1 proton of acetate salt), 2.4-2.9 (m, 12H), 3.0-3.5 (m, 6H), 3.7-3.9 (m, 2H), 4.04 (s, 1H), 4.34-4.40 (m, 2H), 4.83-4.85 (m, 3H), 8.21 (d, 1H, J=8.16 Hz), 8.32 (dd, 1H, J=8.16 Hz, 2 Hz), 8.98 (d, 1H, J=1.6 Hz);

B-18. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.8-1.5 (m, 46H), 1.6-2.3 (m, 10H) (including 1 acetate salt proton), 2.4-2.9 (m, 12H), 3.0-3.5 (m, 5H), 3.6-3.9 (m, 6H), 4.09 (br. s, 1H), 4.39-4.41 (m, 2H), 4.8-4.9 (m, 3H), 7.05 (d, 1H, J=8.76 Hz), 7.72 (d, 1H, J=8.76 Hz);

B-19. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.8-1.5 (m, 43H), 1.6-2.3 (m, 10H) (including 1 proton of acetate salt), 2.4-2.8 (m, 10H), 3.1-3.5 (m, 5H), 3.6-3.9 (m, 2H), 4.09 (s, 1H), 4.40-4.42 (m, 2H), 4.82-4.87 (m, 3H), 6.61 (s, 1H), 7.82 (s, 1H), 7.89 (d, 2H, J=8.68 Hz), 8.01 (d, 2H, J=8.72 Hz), 8.64 (s, 1H);

B-20. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm. 0.77-1.5 (m, 39H), 1.7-2.3 (m, 18H) (including 2 protons of acetate salt), 2.4-2.8 (m, 6H), 3.13 (br s, 2H), 3.31-3.39 (m, 3H), 3.66-3.80 (m, 4H), 3.98 (br s, 1H), 4.16 (br s, 1H), 4.35-4.38 (m, 3H), 4.82-4.88 (m, 3H), 7.25-7.34 (m, 5H), 7.60 (d, 2H, J=8 Hz), 7.78 (d, 2H, J=8 Hz);

B-21. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.77-1.5 (m, 42H), 1.7-2.3 (m, 12H) (including 1 acetate salt proton), 2.4-2.8 (m, 16H), 3.13 (br s, 1H), 3.69 (br s, 2H), 3.72-3.79 (m, 4H), 3.85 (s, 1H), 4.11 (br s, 1H), 4.38 (d, 2H, J=8 Hz), 4.81-4.84 (m, 2H), 7.60 (d, 2H, J=8 Hz), 7.78 (d, 2H, J=8 Hz);

B-22. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.77-1.5 (m, 39H), 1.7-2.3 (m, 18H) (including 3 acetate salt protons), 2.4-2.8 (m, 13H), 3.13 (br. s, 1H), 3.25-3.70 (m, 6H), 3.75-3.82 (br. s, 4H), 4.07 (br s, 1H), 4.42-4.46 (m, 2H), 4.81-4.84 (m, 3H), 7.60 (d, 2H, J=8 Hz), 7.77 (d, 2H, J=8 Hz);

B-23. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm. 0.19-0.25 (m, 2H), 0.37 (br s, 2H), 0.77-1.5 (m, 35H), 1.7-2.3 (m, 12H) (including 1 proton of acetate salt), 2.4-2.8 (m, 8H), 3.13 (br s, 1H), 3.25-3.50 (m, 5H), 3.79 (br s, 1H), 3.80 (br s, 1H), 4.10-4.23 (m, 4H), 4.39 (br s, 1H), 4.49 (d, 2H, J=8 Hz), 4.82-4.84 (m, 3H), 7.60 (d, 2H, J=8 Hz), 7.78 (d, 2N, J=8 Hz);

B-24. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm. 0.08-0.10 (m, 2H), 0.39-0.42 (m, 2H), 0.77-1.5 (m, 37H), 1.7-2.3 (m, 15H) (including 1 proton of acetate salt), 2.4-2.8 (m, 8H), 3.13 (br. s, 2H), 3.31-3.45 (m, 6H), 3.80 (lat s, 1H), 3.98 (lat s, 1H), 4.09 (lat s, 1H), 4.38-4.40 (m, 2H), 4.81-4.87 (m, 2H), 7.60 (d, 2H, J=8 Hz), 7.78 (d, 2H, J=8 Hz);

B-25. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm. 0.77-1.5 (m, 40H), 1.7-2.3 (m, 15H) (including 2 acetate salt protons), 2.4-2.8 (m, 9H), 3.08 (br s, 1H), 3.64 (br s, 2H), 3.72-3.86 (m, 4H), 4.09 (br s, 1H), 4.36-4.39 (m, 2H), 4.61-4.65 (m, 1H), 4.80-4.88 (m, 3H), 7.56-7.60 (m, 4H), 7.68 (d, 2H, J=8 Hz), 7.79 (d, 2H, J=8 Hz);

B-26. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.76 - 1.19 (m, 32H) 1.27 - 1.48 (m, 7H) 1.62 - 1.81 (m, 2H) 1.86 - 1.95 (m, 6H) 2.00 - 2.07 (m, 1H) 2.12 - 2.19 (m, 1H) 2.35 - 2.39 (m, 3H) 2.56 - 2.70 (m, 9H) 2.79 - 2.84 (m, 1H) 3.06 - 3.13 (m, 1H) 3.30 - 3.32 (m, 3H) 3.41 - 3.51 (m, 2H) 3.61 - 3.73 (m, 1H) 3.78 - 3.89 (m, 1H) 4.07 - 4.14 (m, 1H) 4.36 - 4.45 (m, 2H) 4.77 - 4.90 (m, 3H) 7.28 - 7.41 (m, 2H) 7.59 - 7.76 (m, 2H);

B-27. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm. 0.77-1.5 (m, 38H), 1.7-2.3 (m, 18H) (including 3 protons of acetate salt), 2.4-2.8 (m, 6H), 3.13 (br s, 1H), 3.25-3.50 (m, 3H), 3.66 (s, 3H), 3.79 (br s, 1H), 3.85 (br s, 1H), 4.13 (br s, 1H), 4.37-4.47 (m, 3H), 4.83-4.86 (m, 2H), 4.97 (br s, 1H), 6.59 (d, 2H, J=8 Hz), 6.71 (d, 2H, J=8 Hz), 7.60 (d, 2H, J=8 Hz), 7.79 (d, 2H, J=8 Hz);

B-28. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.77-1.5 (m, 45H), 1.7-2.3 (m, 9H), 2.4-2.8 (m, 13H), 3.13 (br s, 1H), 3.20-3.47 (br s, 4H), 3.78-3.81 (br s, 3H), 4.06 (br s, 1H), 4.43-4.47 (m, 2H), 4.80-4.83 (m, 3H), 7.59 (d, 2H, J=8 Hz), 7.77 (d, 2H, J=8 Hz);

B-29. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm. 0.77-1.5 (m, 40H), 1.7-2.3 (m, 15H) (including 2 protons of acetate salt), 2.4-2.8 (m, 8H), 3.08 (br s, 1H), 3.28-3.31 (br s, 4H), 3.43 (br s, 2H), 3.64 (br s, 2H), 3.78 (br s, 1H), 4.08 (br s, 1H), 4.34-4.37 (m, 2H), 4.85 (br s, 3H), 7.24 (d, 2H, J=8 Hz), 7.60 (d, 2H, J=8 Hz), 7.78 (d, 2H, J=8 Hz), 8.43 (d, 2H, J=8 Hz);

B-30. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm. 0.77-1.5 (m, 38H), 1.7-2.3 (m, 12H) (including 1 proton of acetate salt), 2.4-2.8 (m, 6H), 3.13 (br s, 1H), 3.25-3.50 (m, 5H), 3.79 (br s, 1H), 3.85 (br s, 1H), 4.13 (br s, 1H), 4.33-4.49 (m, 2H), 4.61-4.65 (m, 1H), 4.79-4.86 (m, 2H), 4.97 (br s, 1H), 6.68 (d, 2H, J=8 Hz), 7.07 (d, 2H, J=8 Hz), 7.60 (d, 2H, J=8 Hz), 7.79 (d, 2H, J=8 Hz);

B-31. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm. 0.77-1.5 (m, 40H), 1.7-2.3 (m, 12H) (including 1 acetate salt proton), 2.4-2.8 (m, 11H), 3.08 (br s, 1H), 3.64 (br s, 2H), 3.72-3.86 (m, 4H), 4.09 (br s, 1H), 4.36-4.39 (m, 2H), 4.61-4.65 (m, 1H), 4.83-4.85 (m, 3H), 7.44 (d, 2H, J=8 Hz), 7.58-7.63 (m, 4H), 7.79 (d, 2H, J=8 Hz);

B-32. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm. 0.77-1.5 (m, 38H), 1.7-2.3 (m, 18H) (including 2 protons of acetate salt), 2.4-2.8 (m, 6H), 3.13 (br s, 2H), 3.25-3.50 (m, 5H), 3.79 (br s, 1H), 3.85 (br s, 2H), 4.16 (br s, 1H), 4.37-4.49 (m, 2H), 4.83-4.85 (m, 3H), 4.97 (br s, 1H), 6.54 (t, 1H, J=8 Hz), 6.68 (d, 2H, J=8 Hz), 7.07 (d, 2H, J=8 Hz), 7.60 (d, 2H, J=8 Hz), 7.79 (d, 2H, J=8 Hz);

B-33. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm. 0.77-1.5 (m, 38H), 1.7-2.3 (m, 15H) (including 2 protons of acetate salt), 2.4-2.8 (m, 9H), 3.13 (br s, 1H), 3.25-3.50 (m, 5H), 3.79 (br s, 1H), 3.85 (br s, 1H), 4.10-4.23 (m, 4H), 4.39 (br s, 1H), 4.49 (d, 2H, J=8 Hz), 4.81-4.86 (m, 3H), 7.60 (d, 2H, J=8 Hz), 7.78 (d, 2H, J=8 Hz);

B-34. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.77-1.5 (m, 40H), 1.7-2.3 (m, 12H) (including 1 proton of acetate salt), 2.4-2.8 (m, 15H), 3.13 (br. s, 1H), 3.25-3.70 (m, 7H), 3.75-3.82 (br. s, 4H), 4.09 (br s, 1H), 4.38-4.40 (m, 2H), 4.81-4.86 (m, 3H), 7.60 (d, 2H, J=8 Hz), 7.77 (d, 2H, J=8 Hz);

B-35. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.77-1.5 (m, 42H), 1.7-2.3 (m, 18H) (including 3 acetate salt protons), 2.4-2.8 (m, 15H), 3.13 (br s, 1H), 3.69 (br s, 2H), 3.72-3.79 (m, 4H), 3.85 (s, 1H), 4.11 (br s, 1H), 4.38 (d, 2H, J=8 Hz), 4.81-4.85 (m, 2H), 7.60 (d, 2H, J=8 Hz), 7.78 (d, 2H, J=8 Hz);

B-36. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm. 0.77-1.5 (m, 39H), 1.7-2.3 (m, 18H) (including 3 protons of acetate salt), 2.4-2.8 (m, 9H), 3.10 (br s, 1H), 3.25 (s, 3H), 3.69 (br s, 2H), 3.72-3.79 (m, 4H), 3.83 (s, 1H), 4.09 (br s, 1H), 4.38 (d, 2H, J=8 Hz), 4.81-4.85 (m, 2H), 7.60 (d, 2H, J=8 Hz), 7.78 (d, 2H, J=8 Hz);

B-37. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.77-1.5 (m, 35H), 1.7-2.3 (m, 15H) (including 2 acetate salt protons), 2.4-2.8 (m, 12H), 3.13 (br s, 1H), 3.43 (br s, 2H), 3.64 (br. s, 2H), 3.76-3.83 (m, 4H), 4.10 (br. s, 1H), 4.35-4.37 (m, 3H), 4.81-4.86 (m, 2H), 7.49 (s, 1H), 7.60 (d, 2H, J=8 Hz), 7.78 (d, 2H, J=8 Hz), 9.05 (s, 1H);

B-38. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm. 0.77-1.5 (m, 38H), 1.7-2.3 (m, 15H) (including 2 protons of acetate salt), 2.4-2.8 (m, 8H), 3.13 (br s, 1H), 3.25-3.50 (m, 7H), 3.79 (br s, 1H), 3.85 (br s, 1H), 4.10 (br s, 1H), 4.39 (br s, 1H), 4.49 (d, 2H, J=8 Hz), 4.81-4.85 (m, 3H), 7.60 (d, 2H, J=8 Hz), 7.78 (d, 2H, J=8 Hz);

B-39. ¹ H NMR (400 MHz, DMSO-d) 5 ppm. 0.77-1.5 (m, 37H), 1.7-2.3 (m, 15H) (including 3 protons of acetate salt), 2.4-2.8 (m, 5H), 3.13 (br s, 2H), 3.25-3.50 (m, 4H), 3.85 (br s, 2H), 4.16 (br s, 1H), 4.37-4.61 (m, 5H), 4.83-4.85 (m, 3H), 4.97 (br s, 1H), 7.02 (br s, 1H), 7.60 (d, 2H, J=8 Hz), 7.79 (d, 2H, J=8 Hz), 8.45 (d, 2H, J=8 Hz);

B-40. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.5-1.5 (m, 39H), 1.7-2.3 (m, 18H) (including 3 protons of the acetate salt), 2.4-2.8 (m, 10H), 3.1-3.4 (m, 9H), 3.5-3.7 (m, 5H), 4.1 (s, 1H), 4.39-4.41 (m, 2H), 4.81-4.86 (m, 3H), 6.94 (br. s, 1H), 7.15-7.26 (m, 5H);

B-41. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.5-1.5 (m, 39H), 1.7-2.3 (m, 12H) (including 1 proton of acetate salt), 2.4-2.8 (m, 10H), 3.1-3.4 (m, 8H), 3.5-3.7 (m, 5H), 4.1 (s, 1H), 4.24-4.25 (m, 2H), 4.40-4.44 (m, 2H), 4.81-4.87 (m, 2H), 7.34 (d, 2H, J=8 Hz), 7.41 (d, 2H, J=8 Hz);

B-42. ^1H NMR (400 MHz, DMSO-d6) 5 ppm 0.5-1.5 (m, 40H), 1.7-2.3 (m, 10H), 2.4-2.8 (m, 10H), 3.1-3.4 (m, 9H), 3.5-3.7 (m, 5H), 4.1 (s, 1H), 4.32-4.41 (m, 4H), 4.79-4.84 (m, 2H), 5.13 (d, 1H, J=5 Hz), 7.10-7.14 (m, 4H);

B-43. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.5-1.5 (m, 40H), 1.7-2.3 (m, 16H) (including 2 protons of the acetate salt), 2.4-2.8 (m, 11H), 3.14-3.16 (m, 1H), 3.28-3.49 (m, 7H), 3.6-3.7 (m, 5H), 4.1 (s, 1H), 4.3-4.4 (m, 2H), 4.81-4.87 (m, 2H);

B-44. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.5-1.5 (m, 40N), 1.7-2.3 (m, 9H), 2.4-2.8 (m, 10N), 3.1-3.4 (m, 9N), 3.5-3.7 (m, 5H), 4.1 (s, 1H), 4.25-4.30 (m, 2H), 4.40-4.44 (m, 2H), 4.84-4.86 (m, 2H), 5.10 (d, 1H, J=5 Hz), 7.28-7.37 (m, 5H);

B-45. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.5-1.5 (m, 39H), 1.7-2.3 (m, 15H) (including 2 protons of the acetate salt), 2.4-2.8 (m, 10H), 3.1-3.4 (m, 8H), 3.5-3.7 (m, 4H), 4.1 (s, 1H), 4.39-4.42 (m, 2H), 4.56 (s, 4H), 4.81-4.83 (m, 2H), 5.10 (br s, 1H), 7.27 (s, 4H);

B-46. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm. 0.77-1.5 (m, 34H), 1.7-2.3 (m, 18H) (including 3 protons of acetate salt), 2.4-2.8 (m, 6H), 3.08 (br s, 1H), 3.29-3.40 (m, 5H), 3.79 (br s, 1H), 3.82-3.86 (m, 2H), 4.14 (br s, 1H), 4.28-4.32 (br s, 2H), 4.49-4.55 (m, 2H), 4.82-4.85 (m, 3H), 5.04 (br s, 1H), 6.83 (d, 2H, J=8 Hz), 7.59 (d, 2H, J=8 Hz), 7.77 (d, 2H, J=8 Hz), 8.18 (d, 2H, J=8 Hz);

B-47. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.5-1.5 (m, 44H), 1.7-2.3 (m, 9H), 2.4-2.8 (m, 12H), 3.1-3.4 (m, 9H), 3.5-3.7 (m, 5H), 4.1 (s, 1H), 4.2-4.4 (m, 3H), 4.81-4.97 (m, 3H);

B-48. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.5-1.5 (m, 40H), 1.7-2.3 (m, 16H) (including 2 protons of the acetate salt), 2.4-2.8 (m, 11H), 3.10-3.15 (m, 2H), 3.3-3.4 (m, 6H), 3.6-3.7 (m, 3H), 4.1 (s, 1H), 4.3-4.4 (m, 2H), 4.82-4.87 (m, 2H), 6.99 (t, 1H, J=7 Hz), 7.14-7.27 (m, 4H);

B-49. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.5-1.5 (m, 49H), 1.7-2.3 (m, 13H) (including 1 proton of acetate salt), 2.4-2.8 (m, 11H), 3.1-3.4 (m, 9H), 3.5-3.7 (m, 5H), 4.1 (s, 1H), 4.39-4.41 (m, 2H), 4.81-4.89 (m, 3H);

B-50. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.5-1.5 (m, 39H), 1.7-2.3 (m, 12H) (including 1 proton of acetate salt), 2.4-2.8 (m, 9H), 3.1-3.4 (m, 10H), 3.5-3.7 (m, 5H), 4.1 (s, 1H), 4.39-4.41 (m, 2H), 4.81-4.86 (m, 2H), 7.20 (d, 2H, J=8 Hz), 7.52 (d, 2H, J=8 Hz);

B-51. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.5-1.5 (m, 39H), 1.7-2.3 (m, 15H) (including 2 protons of the acetate salt), 2.4-2.8 (m, 14H), 3.1-3.4 (m, 9H), 3.5-3.7 (m, 5H), 4.1 (s, 1H), 4.39-4.41 (m, 2H), 4.81-4.84 (m, 2H), 5.07 (br s, 1H);

B-52. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.5-1.5 (m, 39H), 1.7-2.3 (m, 12H) (including 1 proton of acetate salt), 2.4-2.9 (m, 10H), 3.1-3.4 (m, 9H), 3.5-3.7 (m, 4H), 4.04-4.05 (m, 2H), 4.12 (s, 1H), 4.40-4.43 (m, 2H), 4.86-4.91 (m, 3H), 7.24-7.34 (m, 5H);

B-53. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.5-1.5 (m, 39H), 1.7-2.3 (m, 15H) (including 2 protons of the acetate salt), 2.4-2.8 (m, 10H), 3.1-3.4 (m, 9H), 3.5-3.7 (m, 5H), 4.1 (s, 1H), 4.39-4.42 (m, 2H), 4.81-4.85 (m, 2H), 7.03-7.07 (m, 4H);

B-54. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.5-1.5 (m, 39H), 1.7-2.3 (m, 15H) (including 2 protons of the acetate salt), 2.4-2.8 (m, 9H), 3.1-3.4 (m, 10H), 3.5-3.7 (m, 5H), 4.1 (s, 1H), 4.39-4.41 (m, 2H), 4.84-4.86 (m, 2H), 6.77 (d, 2H, J=4 Hz), 8.02 (br s, 2H);

B-55. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.5-1.5 (m, 39H), 1.7-2.3 (m, 18H) (including 3 protons of acetate salt), 2.4-2.8 (m, 11H), 3.1-3.4 (m, 9H), 3.5-3.7 (m, 5H), 4.1 (s, 1H), 4.39-4.41 (m, 2H), 4.81-4.85 (m, 3H), 6.7 (br s, 1H);

B-56. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.5-1.5 (m, 49H), 1.7-2.3 (m, 13H) (including 1 proton of acetate salt), 2.4-2.8 (m, 8H), 3.1-3.4 (m, 9H), 3.5-3.7 (m, 5H), 4.1 (s, 1H), 4.38-4.40 (m, 2H), 4.81-4.89 (m, 3H), 6.74 (d, 1H, J=6 Hz);

B-57. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.5-1.5 (m, 39H), 1.7-2.3 (m, 18H) (including 3 protons of the acetate salt), 2.4-2.8 (m, 10H), 3.0-3.4 (m, 10H), 3.5-3.7 (m, 5H), 4.1 (s, 1H), 4.39-4.42 (m, 2H), 4.84-4.87 (m, 2H), 5.15 (br. s, 1H), 7.23-7.25 (m, 1H), 7.31-7.39 (m, 4H);

B-58. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm. 0.77-1.5 (m, 47H), 1.7-2.3 (m, 18H) (including 3 protons of the acetate salt), 2.4-2.8 (m, 17H), 3.13 (br s, 1H), 3.44 (br s, 1H), 3.70 (br s, 1H), 3.78 (br s, 1H), 3.85 (br s, 2H), 4.08 (br s, 1H), 4.41-4.44 (m, 2H), 4.81-4.84 (m, 3H), 7.60 (d, 2H, J=8 Hz), 7.78 (d, 2H, J=8 Hz);

B-59. ^1H NMR (400 MHz, CHLOROFORM-d) δ 0.78-0.87 (m, 6H), 0.87-0.96 (m, 6H), 0.98-1.03 (m, 3H), 1.03-1.33 (m, 22H), 1.33-1.51 (m, 5H), 1.52-1.61 (m, 1H), 1.62-1.73 (m, 1H), 1.74-2.03 (m, 5H), 2.06-2.14 (m, 1H), 2.40-2.65 (m, 5H), 2.65-2.73 (m, 2H), 2.74-2.79 (m, 3H), 2.83-2.90 (m, 3H), 3.02-3.12 (m, 1H), 3.18-3.32 (m, 4H), 3.37-3.42 (m, 1H), 3.61-3.73 (m, 3H), 3.91-4.05 (m, 3H), 4.25-4.36 (m, 1H), 4.64 (s, 1H), 4.72-4.79 (m, 1H), 4.79-4.86 (m, 1H);

B-60. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.8-1.5 (m, 48H), 1.6-2.3 (m, 6H), 2.6-2.8 (m, 8H), 3.0-3.4 (m, 5H), 3.44-3.46 (m, 1H), 3.6-3.9 (m, 2H), 4.08 (s, 1H), 4.39-4.41 (m, 2H), 4.82-4.86 (m, 3H), 7.60 (d, 2H, J=8.04 Hz), 7.78 (d, 2H, J=8 Hz);

B-61. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.5-1.5 (m, 39H), 1.7-2.3 (m, 15H) (including 2 protons of the acetate salt), 2.4-2.8 (m, 10H), 3.1-3.4 (m, 10H), 3.5-3.7 (m, 5H), 4.1 (s, 1H), 4.39-4.42 (m, 2H), 4.85-4.86 (m, 2H), 5.18 (d, 1H, 5 Hz), 7.15 (t, 2H, J=8.8 Hz), 7.41-7.45 (m, 2H);

B-62. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.5-1.5 (m, 39H), 1.7-2.3 (m, 18H) (including 3 protons of acetate salt), 2.4-2.8 (m, 10H), 3.1-3.4 (m, 10H), 3.5-3.7 (m, 5H), 4.1 (s, 1H), 4.39-4.41 (m, 2H), 4.81-4.85 (m, 2H), 5.2 (br s, 1H), 7.54 (d, 2H, J=8 Hz), 7.77 (d, 2H, J=8 Hz);

B-63. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm. 0.3-1.5 (m, 42H), 1.6-1.9 (m, 10H) (including 1 proton of acetate salt), 2.0-2.7 (m, 16H), 2.8-2.9 (m, 1H), 3.12 (br. s, 2H), 3.4-3.5 (m, 5H), 3.6-3.9 (m, 3H), 4.09 (s, 1H), 4.3-4.4 (m, 2H), 4.8-4.9 (m, 2H), 5.07-5.08 (m, 1H), 6.43 (s, 1H), 6.6-6.7 (m, 1H), 7.11 (d, 1H, J=8.04 Hz), 7.4-7.5 (m, 1H), 7.58 (d, 1H, J=8 Hz);

B-64. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm. 0.77-1.5 (m, 35H), 1.6-2.5 (m, 16H) (including 2 protons of acetate salt), 2.6-2.8 (m, 9H), 3.1-3.28 (m, 4H), 3.47 (br s, 2H), 3.63 (br s, 2H), 3.79 (br s, 2H), 4.20 (br s, 1H), 4.36 (br s, 1H), 4.48 (br s, 1H), 4.82 (br s, 2H), 4.97 (br s, 1H) 6.54 (t, 1H, J=8 Hz), 6.62 (d, 2H, J=8 Hz), 6.81 (d, 2H, J=8 Hz), 7.06 (t, 2H, J=8 Hz), 7.24 (d, 2H, J=8 Hz);

B-65. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.77-1.5 (m, 35H), 1.6-2.1 (m, 12H) (including 1 proton of acetate salt), 2.4-2.9 (m, 13H), 3.1-3.25 (m, 6H), 3.43 (br. s, 1H), 3.65 (br. s, 2H), 3.75 (br. s, 2H), 3.99 (br s, 1H), 4.37-4.42 (m, 3H), 4.83-4.88 (m, 2H), 7.30 (br s, 2H), 7.60 (br s, 2H);

B-66. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.77-1.5 (m, 45H), 1.6-2.4 (m, 13H) (including 1 proton of acetate salt), 2.6-2.8 (m, 17H), 3.05-3.19 (m, 2H), 3.42 (br s, 2H), 3.65 (br s, 1H), 3.80-3.84 (m, 2H), 4.02 (br s, 2H), 4.41 (br s, 2H), 4.88 (br s, 2H), 7.28 (br s, 2H), 7.60 (br s, 2H);

B-67. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm. 0.011 (br s, 2H), 0.36 (br s, 2H), 0.77-1.5 (m, 37H), 1.6-2.4 (m, 18H) (including 2 protons of acetate salt), 2.6-2.8 (m, 11H), 3.13 (br s, 2H), 3.2-3.35 (m, 2H), 3.45 (br s, 2H), 3.65 (br s, 2H), 3.75 (br s, 2H), 4.11 (br s, 1H), 4.38 (d, 2H, J=8 Hz), 4.84 (br s, 2H), 6.95 (br s, 2H), 7.33 (br s, 2H);

B-68. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm. 0.77-1.5 (m, 39H), 1.6-2.4 (m, 12H) (including 1 proton of acetate salt), 2.6-2.8 (m, 17H), 3.12 (br s, 1H), 3.13-3.47(m, 5H), 3.32 (br s, 2H), 3.65 (br s, 1H), 3.79 (br s, 2H), 4.09 (br s, 1H), 4.39-4.41 (m, 3H), 4.81-4.84 (m, 2H), 7.16 (br s, 2H), 7.52 (br s, 2H);

B-69. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.77-1.5 (m, 40H), 1.6-2.4 (m, 16H) (including 1 proton of acetate salt), 2.6-2.8 (m, 11H), 3.1-3.25 (m, 6H), 3.45 (br s, 1H), 3.65 (br s, 1H), 3.75 (br s, 2H), 4.09 (br s, 3H), 4.40 (d, 2H, J=8 Hz), 4.81-4.86 (m, 2H), 7.19 (br s, 2H), 7.50 (br s, 2H);

B-70. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm. 0.19 (br s, 2H), 0.37 (br s, 2H), 0.77-1.5 (m, 35H), 1.6-2.4 (m, 12H) (including 1 proton of acetate salt), 2.6-2.8 (m, 9H), 3.13 (br s, 2H), 3.2-3.35 (m, 2H), 3.45 (br s, 2H), 3.63 (br s, 2H), 3.88 (br s, 3H), 4.08 (br s, 1H), 4.36-4.38 (m, 3H), 4.84 (br s, 3H), 7.21 (br s, 2H), 7.53 (br s, 2H);

B-71. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.77-1.5 (m, 44H), 1.6-2.4 (m, 18H) (including 2 protons of acetate salt), 2.6-2.8 (m, 11H), 3.1-3.25 (m, 6H), 3.45 (br s, 2H), 3.65 (br s, 1H), 3.75 (br s, 2H), 4.09 (br s, 1H), 4.40 (d, 2H, J=8 Hz), 4.84 (br s, 2H), 7.16 (br s, 2H), 7.50 (br s, 2H);

B-72. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.77-1.5 (m, 41H), 1.6-2.4 (m, 15H) (including 1 proton of acetate salt), 2.6-2.8 (m, 11H), 3.13 (br s, 1H), 3.2-3.35 (m, 5H), 3.45 (br s, 1H), 3.65 (br s, 1H), 3.75 (br s, 2H), 4.08 (br s, 1H), 4.40 (d, 2H, J=8 Hz), 4.86 (br s, 2H), 7.17 (br s, 2H), 7.51 (br s, 2H);

B-73. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.77-1.5 (m, 43H), 1.6-2.4 (m, 15H) (including 1 proton of acetate salt), 2.6-2.8 (m, 11H), 3.13 (bt, 1H), 3.25-3.35 (m, 5H), 3.45 (br s, 1H), 3.65 (br s, 1H), 3.75 (br s, 2H), 4.08 (br s, 1H), 4.40 (d, 2H, J=8 Hz), 4.85 (br s, 2H), 7.19 (br s, 2H), 7.52 (br s, 2H);

B-74. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.77-1.5 (m, 44H), 1.6-2.4 (m, 12H), 2.6-2.8 (m, 11H), 3.13 (br C, 1H), 3.2-3.35 (m, 5H), 3.45 (br C, 1H), 3.65 (br C, 1H), 3.78 (br C, 2H), 4.09 (br C, 1H), 4.38-4.40 (m, 2H), 4.81-4.86 (m, 2H), 7.20 (br C, 2H), 7.53 (br C, 2H);

B-75. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.77-1.5 (m, 45H), 1.6-2.4 (m, 19H) (including 3 protons of acetate salt), 2.6-2.8 (m, 17H), 3.05-3.19 (m, 2H), 3.32 (br C, 2H), 3.52 (br C, 2H), 3.79 (br C, 2H), 4.25 (br C, 2H), 4.53 (br C, 2H), 4.81-4.90 (m, 2H), 6.87 (br C, 2H), 7.28 (br C, 2H);

B-76. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm. 0.77-1.5 (m, 41H), 1.6-2.4 (m, 11H) (including 2 protons of acetate salt), 2.6-2.8 (m, 11H), 3.13 (br C, 1H), 3.2-3.35 (m, 5H), 3.45 (br C, 1H), 3.65 (br C, 1H), 3.75 (br C, 1H), 4.10 (br C, 1H), 4.40 (br C, 2H), 4.82-4.88 (m, 2H), 7.23 (d, 2H, J=8 Hz), 7.56 (d, 2H, J=8 Hz);

B-77. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm. 0.77-1.5 (m, 41H), 1.6-2.4 (m, 15H) (including 2 protons of the acetate salt), 2.6-2.8 (m, 11H), 3.13 (br C, 1H), 3.2-3.35 (m, 5H), 3.45 (br C, 1H), 3.65 (br C, 1H), 3.75 (br C, 1H), 4.10 (br C, 1H), 4.40 (br C, 2H), 4.82-4.86 (m, 2H), 7.17 (d, 2H, J=8 Hz), 7.51 (d, 2H, J=8 Hz);

B-78. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.77-1.5 (m, 41H), 1.6-2.4 (m, 15H) (including 1 proton of acetate salt), 2.6-2.8 (m, 11H), 3.13 (br C, 1H), 3.2-3.35 (m, 5H), 3.45 (br C, 1H), 3.65 (br C, 1H), 3.75 (br C, 2H), 4.08 (br C, 1H), 4.40 (d, 2H, J=8 Hz), 4.86 (br C, 2H), 7.21 (br s, 2H), 7.54 (br s, 2H);

B-79. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm. 0.77-1.5 (m, 35H), 1.6-2.1 (m, 12H) (including 1 proton of acetate salt), 2.4-2.8 (m, 15H), 3.1-3.25 (m, 6H), 3.45 (s, 1H), 3.65 (br s, 1H), 3.75 (br s, 2H), 4.09 (s, 1H), 4.33-4.38 (m, 2H), 4.83-4.85 (m, 2H), 7.19 (br s, 2H), 7.44 (d, 2H, J=S Hz), 7.51 (br s, 2H), 7.62 (d, 2H, J=8 Hz);

B-80. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.77-1.5 (m, 36H), 1.6-2.4 (m, 16H) (including 1 proton of acetate salt), 2.6-2.8 (m, 13H), 3.1-3.25 (m, 6H), 3.45 (br s, 1H), 3.65 (br s, 1H), 3.75 (br s, 2H), 4.09 (br s, 1H), 4.40 (br s, 2H), 4.83 (br s, 2H), 7.19 (br s, 2H), 7.50 (br s, 2H);

B-81. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.77-1.5 (m, 40H), 1.6-2.4 (m, 19H) (including 2 protons of acetate salt), 2.6-2.8 (m, 17H), 3.13 (br s, 2H), 3.32 (br s, 2H), 3.52 (br s, 2H), 3.65 (br s, 1H), 3.79 (br s, 2H), 4.07 (br s, 1H), 4.40 (br s, 2H), 4.86-4.88 (br s, 2H), 7.20 (br s, 2H), 7.54 (br s, 2H);

B-82. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.77-1.5 (m, 42H), 1.6-2.4 (m, 18H) (including 2 protons of acetate salt), 2.6-2.8 (m, 11H), 3.13 (br s, 1H), 3.2-3.35 (m, 5H), 3.45 (br s, 1H), 3.65 (br s, 1H), 3.78 (br s, 2H), 4.09 (br s, 1H), 4.39 (br s, 2H), 4.81-4.84 (m, 2H), 7.20 (br s, 2H), 7.53 (br s, 2H);

B-83. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.77-1.5 (m, 41H), 1.6-2.4 (m, 15H) (including 1 proton of acetate salt), 2.6-2.8 (m, 11H), 3.13 (br s, 1H), 3.2-3.45 (m, 5H), 3.65 (br s, 1H), 3.75 (br s, 2H), 4.09 (br s, 1H), 4.37-4.41 (m, 2H), 4.81-4.86 (m, 2H), 7.20 (d, 2H, J=8 Hz), 7.53 (d, 2H, J=8 Hz);

B-84. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm. 0.77-1.5 (m, 41H), 1.6-2.4 (m, 13H) (including 1 proton of acetate salt), 2.6-2.8 (m, 11H), 3.13 (br s, 1H), 3.2-3.35 (m, 5H), 3.45 (br s, 1H), 3.65 (br s, 1H), 3.75 (br s, 2H), 4.08 (br s, 1H), 4.37-4.40 (m, 2H), 4.84-4.86 (m, 2H), 7.21 (d, 2H, J=8 Hz), 7.54 (d, 2H, J=8 Hz);

B-85. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.77-1.5 (m, 43H), 1.6-2.4 (m, 16H) (including 2 protons of acetate salt), 2.6-2.8 (m, 11H), 3.13 (br s, 1H), 3.25-3.35 (m, 5H), 3.45 (br s, 1H), 3.65 (br s, 1H), 3.75 (br s, 2H), 4.10 (br s, 1H), 4.40 (d, 2H, J=8 Hz), 4.85 (br s, 2H), 7.19 (br s, 2H), 7.50 (br s, 2H);

B-86. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm. 0.77-1.5 (m, 35H), 1.7-2.3 (m, 15H) (including 2 protons of the acetate salt), 2.4-2.8 (m, 10H), 3.0-3.5 (m, 6H), 3.69 (br s, 1H), 3.72-3.79 (m, 4H), 3.85 (s, 1H), 4.11 (s, 1H), 4.38 (d, 2H, J=8 Hz), 4.88-4.95 (m, 2H), 7.16 (br s, 3H), 7.34 (t, 1H, J=8 Hz), 7.41-7.47 (m, 5H), 7.61-7.67 (m, 4H);

B-87. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.77-1.5 (m, 39H), 1.6-2.4 (m, 12H) (including 1 proton of acetate salt), 2.6-2.8 (m, 17H), 3.12 (br s, 1H), 3.13-3.47(m, 5H), 3.32 (br s, 2H), 3.65 (br s, 1H), 3.77 (br s, 2H), 4.09 (br s, 1H), 4.39 (br s, 3H), 4.81-4.85 (m, 2H), 7.22 (br s, 2H), 7.53 (br s, 2H);

B-88. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm. 0.77-1.5 (m, 44H), 1.6-2.4 (m, 19H) (including 2 protons of acetate salt), 2.6-2.8 (m, 17H), 3.13 (br s, 2H), 3.32 (br s, 2H), 3.52 (br s, 2H), 3.65 (br s, 1H), 3.79 (br s, 2H), 4.07 (br s, 1H), 4.40-4.41 (br s, 2H), 4.86-4.88 (br s, 2H), 7.25 (d, 2H, J=8 Hz), 7.57 (d, 2H, J=8 Hz);

B-89. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm. 0.77-1.5 (m, 35H), 1.6-2.5 (m, 11H) (including 1 proton of acetate salt), 2.6-2.8 (m, 11H), 3.1-3.28 (m, 4H), 3.47 (br s, 2H), 3.63 (br s, 2H), 3.70-3.77 (m, 4H), 4.07 (br s, 1H), 4.37-4.39 (m, 2H), 4.81-4.89 (m, 2H), 7.24 (d, 2H, J=8 Hz), 7.34 (br s, 2H), 7.55 (d, 2H, J=8 Hz), 8.24 (s, 1H), 8.49 (br s, 1H);

B-90. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm. 0.77-1.5 (m, 35H), 1.6-2.5 (m, 19H) (including 3 protons of acetate salt), 2.6-2.8 (m, 9H), 3.1-3.28 (m, 4H), 3.47 (br s, 2H), 3.63 (br s, 2H), 3.79 (br s, 2H), 4.20 (br s, 1H), 4.36 (br s, 1H), 4.48 (br s, 1H), 4.82 (br s, 2H), 4.97 (br s, 1H), 6.54 (t, 1H, J=8 Hz), 6.62 (d, 2H, J=8 Hz), 6.81 (d, 2H, J=8 Hz), 7.06 (t, 2H, J=8 Hz), 7.24 (d, 2H, J=8 Hz);

B-91. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm. 0.77-1.5 (m, 36H), 1.6-2.4 (m, 18H) (including 2 protons of acetate salt), 2.6-2.8 (m, 11H), 3.13 (br s, 1H), 3.2-3.35 (m, 5H), 3.45 (br s, 1H), 3.65 (br s, 1H), 3.75 (br s, 2H), 4.08 (br s, 1H), 4.39-4.45 (m, 3H), 4.55 (br s, 1H), 4.86 (br s, 2H), 7.23 (d, 2H, J=8 Hz), 7.55 (d, 2H, J=8 Hz);

B-92. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.77-1.5 (m, 39H), 1.6-2.4 (m, 19H) (including 1 proton of acetate salt), 2.6-2.8 (m, 15H), 3.13 (br s, 2H), 3.32 (br s, 2H), 3.52 (br s, 2H), 3.65 (br s, 1H), 3.79 (br s, 2H), 4.10 (br s, 1H), 4.40 (br s, 2H), 4.81-4.87 (br s, 2H), 7.17 (br s, 2H), 7.50 (br s, 2H);

B-93. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.57 - 1.83 (m, 43N) 1.90 - 2.42 (m, 14N) 2.44 - 2.93 (m, 6N) 2.98 - 4.00 (m, 12N) 4.04 - 4.43 (m, 3H) 4.62 - 4.84 (m, 2H) 4.91 - 5.09 (m, 1H) 6.33 - 6.70 (m, 3H) 7.34 - 7.54 (m, 3H) 7.65 - 7.83 (m, 2H);

B-94. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.55 - 1.73 (m, 42N) 1.75 - 2.83 (m, 10N), 2.86 - 3.61 (m, 12N) 3.65 - 3.97 (m, 9N) 4.01 - 4.10 (m, 1H) 4.13 - 4.24 (m, 1H) 4.28 - 4.43 (m, 1H) 4.58 - 4.70 (m, 1H) 4.81 - 4.99 (m, 2H) 5.10 - 5.19 (m, 1H), 6.22 - 7.81 (m, 13H);

B-95. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm. 0.33 - 1.87 (m, 43Н) 1.92 - 2.38 (m, 6Н) 2.43 - 3.20 (m, 9Н) 3.23 - 3.64 (m, 7Н) 3.80 - 4.19 (m, 4Н) 4.26 - 4.45 (m, 2Н) 4.48 - 4.67 (m, 1H) 4.71 - 4.92 (m, 2H) 5.03 - 5.14 (m, 1H) 6.98 - 7.19 (m, 3H) 7.37 - 7.59 (m, 3H) 7.66 - 7.87 (m, 2H);

B-96. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm. 0.32 - 1.65 (m, 37N) 1.68 - 2.22 (m, 12N) 2.27 - 2.91 (m, 10N) 2.97 - 3.62 (m, 9N) 3.72 - 3.96 (m, 2H) 4.05 - 4.40 (m, 4H) 4.49 - 4.63 (m, 1H) 6.74 - 6.90 (m, 1H) 7.02 - 7.14 (m, 2H) 7.22 (lat d, J=8.56 Hz, 1H) 7.54 - 7.72 (m, 1H) 7.75 - 7.84 (m, 1H);

B-97. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.38 - 1.82 (m, 33Н) 1.87 - 2.35 (m, 8Н) 2.36 - 3.27 (m, 11Н), 3.31 - 3.60 (m, 6Н) 3.66 - 3.96 (m, 14Н) 4.01 - 4.30 (m, 2Н) 4.32 - 4.47 (m, 1H) 4.52 - 5.15 (m, 3H) 6.68 - 6.96 (m, 4H) 7.46 - 7.86 (m, 4H);

B-98. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm. 0.29 - 1.56 (m, 39Н) 1.57 - 2.20 (m, 8Н) 2.89 - 3.24 (m, 12Н), 3.29 - 3.49 (m, 5Н) 3.50 - 3.62 (m, 1Н) 3.76 - 3.93 (m, 2Н) 4.05 - 4.19 (m, 1H) 4.20 - 4.44 (m, 2H) 4.53 - 4.65 (m, 1H) 4.65 - 4.82 (m, 2H) 4.87 - 4.98 (m, 1H) 5.00 - 5.12 (m, 1H) 6.88 - 7.11 (m, 2H) 7.11 - 7.18 (m, 1H) 7.18 - 7.29 (m, 1H) 7.54 - 7.73 (m, 1H) 7.77 -7.91 (m, 1H);

B-99. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.31 - 1.82 (m, 43Н) 1.85 - 2.30 (m, 4Н) 2.33 - 2.90 (m, 7Н) 2.95 - 3.95 (m, 13Н) 3.99 - 4.17 (m, 1Н) 4.18 - 4.44 (m, 2Н) 4.63 - 4.87 (m, 2H) 4.92 - 5.17 (m, 1H) 6.78 - 7.15 (m, 3H) 7.36 - 7.53 (m, 3H) 7.56 - 7.81 (m, 2H);

B-100. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm. 0.28 - 1.50 (m, 41H) 1.52 - 2.26 (m, 18H) 2.32 - 3.35 (m, 1H) 2.34 - 3.45 (m, 1H) 3.25 - 3.44 (m, 2H) 3.47 - 3.57 (m, 1H) 3.61 - 3.89 (m, 4H) 4.12 (lat d, J=4.89 Hz, 1H) 4.17 - 4.31 (m, 1H) 4.32 - 4.43 (m, 1H) 4.65 - 4.82 (m, 2H) 4.94 - 5.04 (m, 1H) 6.67 - 6.92 (m, 3H) 7.35 - 7.58 (m, 6H) 7.61 - 7.85 (m, 4H);

B-101. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.39 - 1.60 (m, 45H) 1.63 - 2.12 (m, 15H) 2.17 - 2.79 (m, 7H), 2.84 - 3.64 (m, 5H) 3.68 - 3.92 (m, 4H) 4.01 - 4.34 (m, 1H) 4.48 - 5.09 (m, 1H), 6.65 - 6.89 (m, 2H) 7.16 - 7.35 (m, 2H) 7.59 - 7.74 (m, 1H) 7.80 - 7.98 (m, 1H);

B-102. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.50 - 1.60 (m, 45N) 1.65 - 2.35 (m, 8N) 2.37 - 3.00 (m, 9N) 3.03 - 3.99 (m, 14N) 4.03 - 4.34 (m, 3H) 4.56 - 5.00 (m, 4N) 5.01 - 5.25 (m, 2H) 6.21 - 6.34 (m, 1H) 6.40 - 6.67 (m, 3H) 7.55 - 7.71 (m, 1H) 7.74 - 7.85 (m, 1H);

B-103. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm. 0.40 - 1.56 (m, 34Н) 1.59 - 2.77 (m, 9Н) 2.77 - 3.06 (m, 12Н) 3.33 - 3.42 (m, 8Н) 3.46 - 3.76 (m, 6Н) 3.69 - 4.27 (m, 4Н) 4.28 - 4.52 (m, 3H) 4.60 - 4.83 (m, 3H) 4.89 - 4.99 (m, 2H) 6.46 - 6.75 (m, 6H) 7.29 - 7.53 (m, 3H) 7.76 - 7.84 (m, 1H);

B-104. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.69 - 1.53 (m, 30Н) 1.69 - 2.22 (m, 9Н) 2.60 -3.41 (m, 10Н) 3.51 - 3.63 (m, 3Н) 3.64 - 3.82 (m, 4Н) 3.86 - 4.12 (m, 7Н) 4.25 - 4.53 (m, 7H) 4.71 - 4.95 (m, 5H) 4.96 - 5.13 (m, 3H) 7.13 - 7.39 (m, 4H) 7.52 - 7.69 (m, 4H);

B-105. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm. 0.45 - 1.56 (m, 34N) 1.64 - 2.57 (m, 19N) 2.68 - 3.00 (m, 2N) 3.09 - 3.79 (m, 21N) 3.87 - 4.13 (m, 1H) 4.16 - 4.55 (m, 3H) 4.56 - 4.76 (m, 1H) 4.80 - 5.12 (m, 3H) 5.12 - 5.30 (m, 1H) 6.59 - 6.79 (m, 2H) 6.75 - 7.00 (m, 2H) 7.27 - 7.60 (m, 2H) 8.51 - 8.78 (m, 1H) 9.23 - 9.51 (m, 1N);

B-106. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm. 0.44 - 1.55 (m, 42Н) 1.59 - 1.89 (m, 5Н) 2.06 - 2.54 (m, 8Н) 2.87 - 3.25 (m, 6Н) 3.31 - 3.88 (m, 7Н) 3.94 - 4.11 (m, 1Н) 4.16 - 4.47 (m, 2H) 4.58 - 4.87 (m, 3H) 4.95 - 5.07 (m, 1H) 6.59 - 6.89 (m, 4H) 6.99 - 7.15 (m, 2H) 7.65 - 7.83 (m, 2H);

B-107. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.5-1.5 (m, 45H), 1.6-2.3 (m, 10H), 2.4-2.7 (m, 10H), 3.2-3.5 (m, 5H), 3.9-4.1 (m, 3H), 4.35-4.37 (m, 1H), 4.6-4.8 (m, 3H), 6.9-7.0 (m, 5H), 7.4 (s, 1H), 8.1 (br s, 1H);

B-108. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm. 0.39 - 1.47 (m, 28N) 1.58 - 1.96 (m, 12N) 2.10 - 3.22 (m, 12N) 3.30 - 3.64 (m, 7N) 3.72 - 3.90 (m, 2H) 3.96 - 4.37 (m, 4H) 4.46 - 4.97 (m, 4H) 4.98 - 5.19 (m, 2H) 5.31 - 5.52 (m, 1H) 6.45 - 6.84 (m, 4H) 7.30 - 7.55 (m, 2H) 7.56 - 7.79 (m, 2H) 8.67 - 8.92 (m, 1H) 9.32 - 9.56 (m, 1N);

B-109. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.52 - 1.26 (m, 29N) 1.30 - 2.53 (m, 18N) 2.83 - 3.93 (m, 13N) 4.03 - 4.46 (m, 6N) 4.67 - 4.88 (m, 3H) 4.99 - 5.15 (m, 2H) 5.42 - 5.58 (m, 2H) 6.61 - 6.91 (m, 5H) 7.37 - 7.77 (m, 4H) 8.76 - 9.04 (m, 1H) 9.32 - 9.56 (m, 1H);

B-110. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.28 - 1.84 (m, 48N) 1.95 - 2.43 (m, 10N) 2.46 - 2.97 (m, 8N) 3.23 - 3.98 (m, 8N) 4.38 - 4.76 (m, 3H) 5.02 - 5.37 (m, 2H) 6.57 - 7.10 (m, 5H);

B-111. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm. 0.50 - 1.83 (m, 40N) 1.96 - 2.64 (m, 9N) 2.79 - 3.56 (m, 12N) 3.61 - 3.97 (m, 5N) 4.02 - 4.43 (m, 3H) 4.56 - 4.72 (m, 2H) 4.75 - 4.92 (m, 1H) 4.94 - 5.29 (m, 3H) 5.35 - 5.57 (m, 1H) 6.45 - 6.96 (m, 5H) 7.26 - 7.45 (m, 1H) 8.18 - 8.41 (m, 1H) 8.42 - 8.58 (m, 1H) 8.83 - 8.96 (m, 1H) 9.27 - 9.49 (m, 1H);

B-112. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.5-1.5 (m, 39H), 1.7-2.3 (m, 12H) (including 1 proton of acetate salt), 2.4-2.8 (m, 12H), 3.1-3.4 (m, 10H), 3.5-3.7 (m, 5H), 4.1 (s, 1H), 4.39-4.41 (m, 2H), 4.81-4.85 (m, 2H), 5.15 (br s, 1H);

B-113. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.5-1.5 (m, 39H), 1.7-2.3 (m, 12H) (including 1 proton of acetate salt), 2.4-2.8 (m, 10H), 3.0-3.4 (m, 10H), 3.5-3.7 (m, 5H), 4.1 (s, 1H), 4.35-4.47 (m, 2H), 4.82-4.86 (m, 2H), 5.23 (br s, 1H), 7.59 (d, 2H, J=8 Hz), 7.67 (d, 2H, J=8 Hz);

B-114. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.53 (br. d, 3H), 0.75 - 1.21 (m, 33H), 1.29 - 1.49 (m, 6H), 1.54 - 1.82 (m, 8H), 1.90 (s, 2H, AcOH), 2.01 (br. d, 1H), 2.15 (br. d, 1H), 2.39 - 2.48 (m, 2H), 2.56 (s, 3H), 2.62 (s, 3H), 2.69 (lat d, 2H), 2.80 (br d, 1H), 3.24 (br s, 1H), 3.38 (s, 3H), 3.48 (lat d, 1H), 3.62 - 3.67 (m, 1H), 3.87 - 3.93 (m, 1H), 4.03 - 4.16 (m, 4H), 4.40 (width, 1H), 4.65 (width, 1H), 4.79 (width, 1H), 4.84 (width, 1H), 6.65 (width, 2H), 6.92 (width, t, 2H), 9.24 (s, 1H);

B-115. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.50 (br. d, 3H), 0.77 - 1.19 (m, 32 N), 1.27 - 1.50 (m, 6H), 1.56 - 1.84 (m, 8H), 1.90 (s, 2H, AcOH), 2.01 (br. d, 1H), 2.14 (br. d, 1H), 2.40 - 2.47 (m, 2H), 2.60 (lat d, 2H), 2.66 (s, 3H), 2.67 - 2.72 (m, 2H), 2.80 (br d, 1H), 3.24 (br d, 1H), 3.37 (s, 3H), 3.48 (br d, 1H), 3.62 - 3.71 (m, 1H), 3.87 (lat. d, 1H), 4.03 (lat. d, 1H), 4.08 - 4.20 (m, 2H), 4.37 - 4.44 (m, 1H), 4.64 (lat. d, 1H), 4.78 (lat. d, 1H), 4.84 ( lat. d, 1H), 6.61 (br dd, 2H), 6.90 (br t, 2H), 7.78 (d, 1H), 7.87 (d, 1H), 8.13 (t, 1H);

B-116. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm. 0.38 - 2.24 (m, 51Н) 2.40 - 3.10 (m, 11Н) 3.15 - 3.60 (m, 8Н) 3.63 - 4.00 (m, 6Н) 4.01 - 4.23 (m, 2Н) 4.25 - 4.38 (m, 1Н) 4.57 - 4.67 (m, 1H) 4.74 - 4.84 (m, 1H) 4.93 - 5.04 (m, 1H) 6.32 - 6.51 (m, 2H) 6.51 - 6.66 (m, 2H) 8.08 - 8.18 (m, 1H) 8.55 - 8.68 (m, 1H);

B-117. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.49 - 1.98 (m, 45N) 2.02 - 2.76 (m, 13N) 3.06 - 3.91 (m, 14N) 3.99 - 4.29 (m, 3H) 4.58 - 4.80 (m, 2H) 4.90 - 5.10 (m, 2H) 6.45 - 6.91 (m, 4H) 7.32 - 7.72 (m, 2H) 8.20 - 8.40 (m, 1H) 8.42 - 8.59 (m, 1H);

B-118. ¹ H NMR (400 MHz, DMSO-de) δ ppm 0.43 (br.d, 3H), 0.68 - 1.52 (m, 42H), 1.60 - 1.84 (m, 6H), 1.90 (s, 3H, AcOH), 1.98 - 2.05 (m, 1H), 2.14 - 2.19 (m, 1H), 2.43 - 2.49 (m, 1H), 2.52 - 2.57 (m, 1H), 2.63 (s, 3H), 2.69 - 2.75 (m, 1H), 2.80 (lat d, 1H), 3.23 (br d, 1H), 3.39 (s, 3H), 3.44 (br d, 1H), 3.61 (s, 3H), 3.65 - 3.67 (m, 1H), 3.68 (s, 1H), 3.70 (d, 1H), 3.86 - 3.94 (m, 1H), 4.00 - 4.12 (m, 2H), 4.40 (k, 1H), 4.60 (br d, 1H), 4.78 (br dd, 1H), 4.84 (br d, 1H), 6.26 (br d, 1H), 6.48 - 6.51 (m, 1H), 6.70 - 6.75 (m, 1H), 6.76 - 6.81 (m, 1H), 7.09 - 7.15 (m, 1H), 7.55 - 7.61 (m, 1H), 7.86 (d, 1H), 8.08 (s, 1H), 8.50 (br. dd, 1H);

B-119. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm. 0.45 - 1.56 (m, 45N) 1.61 - 2.29 (m, 10N) 2.32 - 2.96 (m, 8N) 3.03 - 3.64 (m, 2H) 3.67 - 3.89 (m, 2H) 3.74 - 4.96 (m, 2H) 3.93 - 4.09 (m, 1H) 4.14 - 4.28 (m, 1H) 4.35 - 4.41 (m, 1H) 4.42 - 4.92 (m, 3H) 4.94 - 5.13 (m, 1H) 4.99 - 5.11 (m, 1H) 6.31 - 6.92 (m, 4H) 7.07 - 7.23 (m, 2H) 7.22 - 7.31 (m, 1H) 7.24 - 7.30 (m, 1H) 7.36 - 7.51 (m, 1H) 7.71 - 7.95 (m, 1H);

B-120. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.35 - 1.89 (m, 42Н) 2.03 - 2.66 (m, 18Н) 2.81 - 3.14 (m, 4Н) 3.17 - 3.81 (m, 3Н) 3.74 - 4.91 (m, 3Н) 4.96 - 5.17 (m, 1Н) 6.28 - 6.69 (m, 3H) 6.83 - 7.13 (m, 2H) 7.25 - 7.43 (m, 1H) 7.54 - 7.76 (m, 1H) 7.88 - 8.07 (m, 1H) 8.35 - 8.49 (m, 1H);

B-121. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm. 0.43 - 1.82 (m, 53Н) 1.86 - 2.32 (m, 9Н) 2.40 - 3.00 (m, 5Н) 3.09 - 3.52 (m, 5Н) 3.56 - 4.09 (m, 2Н) 4.19 - 4.49 (m, 2Н) 4.54 - 4.73 (m, 1H) 4.75 - 4.90 (m, 1H) 4.94 - 5.06 (m, 1H) 5.36 - 5.51 (m, 1H) 6.55 - 7.13 (m, 5H) 8.64 - 8.85 (m, 1H) 9.01 - 9.24 (m, 1H);

B-122. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.27 - 1.62 (m, 40N) 1.65 - 2.42 (m, 10N) 2.46 - 3.03 (m, 13N) 3.04 - 4.07 (m, 9N) 4.21 - 4.48 (m, 4H) 4.66 - 5.14 (m, 2H) 6.86 - 7.08 (m, 2H) 7.22 - 7.34 (m, 3H);

B-123. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.53 - 1.53 (m, 46N) 1.56 - 2.18 (m, 13N) 2.42 - 2.85 (m, 5N) 2.91 - 3.16 (m, 5N) 3.20 - 3.47 (m, 2H) 3.47 - 3.94 (m, 2H) 3.96 - 4.46 (m, 2H) 4.66 - 4.88 (m, 2H) 4.92 - 5.02 (m, 1H) 6.58 - 6.72 (m, 3H) 6.83 - 7.06 (m, 6H);

B-124. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm. 0.46 - 1.55 (m, 40N) 1.59 - 2.32 (m, 15N) 2.43 - 3.43 (m, 9N) 3.67 - 3.92 (m, 3H) 3.97 - 4.13 (m, 2H) 4.13 - 4.52 (m, 3H) 4.63 - 4.83 (m, 3H) 4.90 - 5.10 (m, 1H) 6.35 - 6.56 (m, 2H) 6.59 - 6.73 (m, 2H) 7.75 - 7.91 (m, 1H) 7.99 - 8.17 (m, 2H) 8.56 - 8.72 (m, 1H) 8.78 - 8.90 (m, 1N);

B-125. ¹ H NMR (600 MHz, DMSO-d6) δ ppm 0.79 - 1.22 (m, 32H), 1.30 - 1.51 (m, 5H), 1.61 -1.88 (m, 5H), 1.90 (s, 1H, AcOH), 1.91 - 1.97 (m, 2H), 2.21 (br. d, 1H), 2.56 (br. d, 1H), 2.62 - 2.65 (m, 3H), 2.65 - 2.69 (m, 1H), 2.83 (lat. d, 1H), 3.03 (lat. dd, 1H), 3.14-3.19 (m, 1H), 3.24 (lat. dd, 1H), 3.32 (s, 3H), 3.49 (d, 1H), 3.63 - 3.65 (m, 3H), 3.67 (td, 1H), 3.71-3.78 (m, 3H), 4.15-4.18 (m, 1H), 4.40 (d, 1H), 4.44-4.47 (m, 1H), 4.49 (br. dd, 1H), 4.84 (dd, 1H), 4.88 (br. d, 1H), 4.98 (d, 1H), 6.39 (s, 2H), 6.58-6.62 (m, 2H), 6.70-6.74 (m, 2H);

B-126. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm. 0.77-1.5 (m, 42H), 1.6-2.4 (m, 12H) (including 1 proton of acetate salt), 2.6-2.8 (m, 11H), 3.13 (br s, 1H), 3.2-3.35 (m, 5H), 3.45 (br s, 1H), 3.65 (br s, 1H), 3.78 (br s, 2H), 4.09 (br s, 1H), 4.37-4.39 (m, 3H), 4.81-4.84 (m, 2H), 7.20 (br s, 2H), 7.53 (br s, 2H);

B-127. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.77-1.5 (m, 45H), 1.6-2.4 (m, 19H) (including 3 protons of acetate salt), 2.6-2.8 (m, 13H), 3.13 (br s, 3H), 3.32 (br s, 3H), 3.65 (br s, 2H), 3.79 (br s, 2H), 4.09 (br s, 1H), 4.37-4.40 (br s, 2H), 4.81-4.86 (m, 2H), 7.20 (br s, 2H), 7.53 (br s, 2H);

B-128. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm. 0.77-1.5 (m, 35H), 1.6-2.1 (m, 12H) (including 1 proton of acetate salt), 2.4-2.8 (m, 15H), 3.1-3.25 (m, 4H), 3.45 (br s, 3H), 3.65 (br s, 1H), 3.75 (br s, 2H), 4.09 (s, 1H), 4.32-4.37 (m, 2H), 4.80 (br s, 2H), 7.19 (br s, 2H), 7.44 (br s, 2H), 7.63-7.71 (m, 2H), 7.73-7.89 (m, 1H), 7.89(d, 2H, J=8 Hz);

B-129. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.77-1.5 (m, 35H), 1.6-2.1 (m, 9H), 2.4-2.8 (m, 13H), 3.1-3.25 (m, 6H), 3.45 (s, 1H), 3.65 (br s, 1H), 3.75 (br s, 3H), 4.09 (br s, 3H), 4.33-4.38 (m, 3H), 4.81-4.86 (m, 2H), 7.19 (br s, 2H), 7.50 (br s, 2H);

B-130. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.48 - 1.86 (m, 50H), 1.90 (s, 3H, AcOH), 2.03 (br. dd, 1H), 2.18 (br. d, 1H), 2.42 - 2.48 (m, 1H), 2.52 - 2.62 (m, 3H), 2.64 (s, 3H), 2.74 (lat dd, 2H), 3.22 (lat s, 1H), 3.39 (lat s, 1H), 3.41 (s, 3H), 3.74 (lat dd, 1H), 3.79 -3.90 (m, 1H), 3.99 (lat s, 1H), 4.16 (td, 1H), 4.37 - 4.46 (m, 1H), 4.67 (d, 1H), 4.79 (dd, 1H), 4.84 (br. d, 1H), 5.26 (dd, 1H), 6.20 (d, 1H), 6.83 (dd, 1H), 7.45 - 7.55 (m, 3H), 7.58 (d, 1H), 7.61 - 7.67 (m, 2H), 7.97 (dd, 1H);

B-131. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.52 - 1.84 (m, 49H), 1.90 (s, 2 H, AcOH), 1.99 (br dd, 1H), 2.16 (br d, 1H), 2.40 - 2.48 (m, 2H), 2.54 - 2.62 (m, 2H), 2.66 - 2.71 (m, 1H), 2.73 - 2.80 (m, 4H), 3.22 (br s, 1H), 3.37 (s, 3H), 3.42 (br d, 1 H), 3.67 (br d, 1H), 3.72 (s, 3H), 3.78 - 3.88 (m, 1H), 4.01 (br d, 1H), 4.06 - 4.16 (m, 1H), 4.22 (lat d, 1H), 4.41 (k, 1H), 4.71 (d, 1H), 4.79 (dd, 1H), 4.83 (lat d, 1H), 5.30 (dd, 1H), 6.48 (d, 1H), 6.89 (dd, 1H), 6.96 (d, 1H), 7.38 (s, 1H), 7.62 (ddd, 1H), 8.04 (dd, 1H);

B-132. ¹ H NMR (600 MHz, DMSO-d6) δ ppm 0.51 - 1.84 (m, 48H), 1.89 (s, 2 H, AcOH), 1.98 (br dd, 1H), 2.13 (br d, 1H), 2.41 - 2.48 (m, 2 H), 2.53 - 2.59 (m, 2H), 2.66 - 2.71 (m, 3H), 2.81 (br d, 1H), 3.24 (br d, 1H), 3.31 (br s, 3H), 3.46 - 3.50 (m, 2H), 3.66 (br d, 1H), 3.79 (s, 3H), 3.81 - 3.88 (m, 1H), 3.94 - 4.00 (m, 1H), 4.02 - 4.09 (m, 2H), 4.23 (lat. s, 1H), 4.36 - 4.42 (m, 1H), 4.55 - 4.62 (m, 1H), 4.65 (lat. d, 1H), 4.79 (lat. dd, 1H), 4.82 (lat. d, 1H), 6.51 - 6.57 (m, 2H), 7.01 (s, 1H), 7.27 (dd, 1H), 7.44 (s, 1H);

B-133. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.34 - 1.88 (m, 49H), 1.91 (s, 2H, AcOH), 2.03 (s, 2), 2.07 - 2.13 (m, 1H), 2.14 - 2.19 (m, 1H), 2.44 (s, 3H), 2.82 (br. d, 1H), 3.20 - 3.27 (m, 2H), 3.41 (s, 3H), 3.43 (br. s, 1H), 3.54 (ddd, 1H), 3.72 - 3.87 (m, 2H), 4.00 - 4.13 (m, 2H), 4.25 (br. s, 2H), 4.33 - 4.42 (m, 1H), 4.46 (k, 1H), 4.55 (s, 1H), 4.62 - 4.72 (m, 2H), 4.79 (br. dd, 1H), 4.85 (br. t, 1H), 4.90 (br. d, 1H), 6.86 (t, 1H), 6.98 - 7.04 (m, 1H), 7.04 -7.09 (m, 1H), 7.35 (br. d, 1H), 7.53 - 7.61 (m, 2H), 7.63 - 7.69 (m, 1H), 7.72 - 7.79 (m, 2H);

B-134. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.38 - 1.86 (m, 47H), 1.90 (s, 3H, AcOH), 1.96 (br. s, 1H), 2.11 - 2.18 (m, 1H), 2.40 - 2.48 (m, 2H), 2.53 - 2.58 (m, 2H), 2.62 (s, 3H), 2.70 (lat d, 1H), 2.82 (br d, 1H), 3.24 (br s, 1H), 3.37 (s, 3H), 3.45 (br d, 1H), 3.61 - 3.71 (m, 1H), 3.84 (s, 3H), 3.86 - 3.93 (m, 1H), 3.99 (width, 1H), 4.14 - 4.31 (m, 3H), 4.37 - 4.46 (m, 2H), 4.68 - 4.83 (m, 4H), 4.86 - 4.94 (m, 1H), 5.76 (s, 2H), 6.87 (t, 1H), 6.99 - 7.06 (m, 2H), 7.08 - 7.13 (m, 1H), 7.35 (br d, 1H), 7.42 (s, 1H);

B-135. ¹ H NMR (600 MHz, DMSO-d6) δ ppm 0.38 - 1.92 (m, 52H), 2.03 (wid dd, 1H), 2.16 (wid d, 1H), 2.41 - 2.47 (m, 2H), 2.53 - 2.61 (m, 2H), 2.62 - 2.65 (m, 2H), 2.66 - 2.76 (m, 2H), 3.21 (wid s, 1H), 3.39 - 3.41 (m, 3H), 3.60 (wid s, 1H), 3.85 (wid dd, 1H), 3.97 - 4.01 (m, 1H), 4.16 (td, 1H), 4.36 - 4.42 (m, 1H), 4.65 (wid d, 1H), 4.79 (lat dd, 1H), 4.83 (lat dd, 1H), 5.15 (lat dd, 1H), 6.22 (lat dd, 1H), 7.28 - 7.34 (m, 1H), 7.47 - 7.53 (m, 2H), 7.57 - 7.61 (m, 1H), 7.64 (ddd, 2H), 8.02 (d, 1H);

B-136. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.50 - 1.86 (m, 50H), 1.90 (br. s, 2H, AcOH), 1.97 (br. dd, 1H), 2.14 (br. d, 1H), 2.39 - 2.48 (m, 2H), 2.53 - 2.60 (m, 3H), 2.62 (s, 3H), 2.66 - 2.71 (m, 1 N), 2.82 (width, 1H), 3.25 (width, s, 2 N), 3.49 (width, 1 N), 3.66 (width, 1 N), 3.81 (s, 3H), 3.87 (width, dd, 1H), 4.03 (width, 1H), 4.06 - 4.16 (m, 2H), 4.18 - 4.28 (m, 1H), 4.40 (k, 1H), 4.70 (lat d, 1H), 4.79 (dd, 1 N), 4.82 (lat d, 1H), 6.93 (d, 2H), 7.02 (s, 1H), 7.20 (d, 2H), 7.44 (s, 1H);

B-137. ¹ H NMR (600 MHz, DMSO-d6) δ ppm 0.49 - 1.85 (m, 48H), 1.89 (s, 2H, AcOH), 1.99 (br.dd, 1H), 2.07 - 2.09 (m, 1H), 2.13 - 2.17 (m, 1H), 2.40 - 2.48 (m, 3H), 2.55 - 2.61 (m, 2H), 2.66 - 2.70 (m, 1H), 2.73 - 2.79 (m, 3H), 3.22 (lat d, 1H), 3.36 (lat s, 3H), 3.41 (lat d, 1H), 3.62 (lat d, 1H), 3.71 - 3.78 (m, 3H), 3.81 - 3.88 (m, 1H), 4.00 (lat. dd, 1H), 4.12 (lat. dd, 2H), 4.22 (lat. s, 1H), 4.37 - 4.43 (m, 1H), 4.71 (lat. d, 1H), 4.79 (lat. dd, 1H), 4.82 (lat. d, 1H), 5.21 (br.dd, 1H), 6.54 (d, 1H), 6.96 (d, 1H), 7.36 - 7.41 (m, 1H), 7.70 - 7.76 (m, 1H), 8.10 (d, 1H);

B-138. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.34 - 1.87 (m, 47H), 1.90 (s, 1H, AcOH), 2.10 (br dd, 1 H), 2.18 - 2.25 (m, 1 H), 2.55 (br dd, 2 H), 2.67 (s, 3 H), 2.79 (br t, 1H), 3.10 -3.25 (m, 4 H), 3.41 (s, 3H), 3.44 (br d, 1H), 3.63 - 3.84 (m, 3H), 3.95 (br d, 1H), 4.06 (br s, 1H), 4.15 - 4.32 (m, 3H), 4.43 - 4.51 (m, 1H), 4.63 - 4.69 (m, 1H), 4.81 (lat d, 1H), 4.97 (lat d, 1H), 6.57 - 6.79 (m, 1H), 7.02 (lat s, 1H), 7.14 (t, 1H), 7.28 (td, 1H), 7.52 -7.53 (m, 1H), 7.58 (width, 1 N), 7.66 (width, 2H), 7.73 (width, dd, 2 N), 7.82 (width, 2 N);

B-139. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.46 - 1.86 (m, 48H), 1.89 (s, 3H, AcOH), 1.97 (br dd, 1 H), 2.08 (s, 1H), 2.13 (br s, 1 H), 2.40 - 2.48 (m, 2H), 2.53 - 2.60 (m, 2H), 2.62 (d, 3H), 2.67 - 2.75 (m, 4H), 2.78 - 2.85 (m, 1H), 3.23 (br s, 1H), 3.35 (d, 3H), 3.50 (br d, 1H), 3.71 (br d, 1H), 3.81 (d, 3H), 3.86 - 3.93 (m, 1H), 4.03 (br s, 1H), 4.10 - 4.20 (m, 2H), 4.23 - 4.32 (m, 1H), 4.41 (k, 1H), 4.69 - 4.88 (m, 3H), 6.93 - 7.06 (m, 2H), 7.16 - 7.28 (m, 2H), 7.38 (td, 1H), 7.43 (d, 1H);

B-140. ¹ H NMR (600 MHz, DMSO-d6) δ ppm 0.77 - 1.20 (m, 37H), 1.27 - 1.50 (m, 7H), 1.61 -1.82 (m, 4H), 1.86 (lat, 1H), 1.90 (s, 3H, AcOH), 1.90 - 1.94 (m, 1H), 2.02 - 2.07 (m, 1H), 2.12 - 2.16 (m, 1H), 2.43 (dt, 1H), 2.55 - 2.59 (m, 1H), 2.62 (s, 3H), 2.63 - 2.68 (m, 2H), 2.83 (lat dt, 1H), 3.12-3.17 (m, 2H), 3.28 (s, 3H), 3.29 (br. d, 2H), 3.48 (br. d, 1H), 3.63 -3.76 (m, 3H), 4.11 (dd, 1H), 4.37 - 4.42 (m, 2H), 4.82 (dd, 1H), 4.86 (d, 1H), 6.39 (s, 2H);

B-141. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.8-1.5 (m, 41H), 1.6-1.9 (m, 5H), 2.1-2.4 (m, 3H), 2.6-2.8 (m, 5H), 3.1-3.5 (m, 5H), 3.6-4.0 (m, 5H), 4.1-4.5 (m, 5H), 4.6-4.8 (m, 3H), 6.9-7.2 (m, 5H), 7.23-7.26 (m, 1H), 7.30-7.33 (m, 4H), 7.43 (s, 1H), 8.1 (br s, 1H);

B-142. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.68 - 1.20 (m, 38H), 1.21 - 1.87 (m, 15H), 1.89 (s, 3 H, AcOH), 1.91 - 1.94 (m, 1H), 2.03 (br. dd, 1H), 2.11 - 2.18 (m, 1H), 2.40 - 2.48 (m, 2H), 2.52 - 2.73 (m, 5H), 2.78 - 2.85 (m, 1H), 3.05 (br. t, 2H), 3.13 - 3.22 (m, 2H), 3.26 (s, 3H), 3.46 (br. d, 1H), 3.60 - 3.75 (m, 3H), 4.09 (br. s, 1H), 4.34 - 4.42 (m, 2H), 4.79 - 4.87 (m, 2H), 7.59 (d, 2H), 7.83 (d, 2H);

B-143. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm. 0.76 - 1.44 (m, 37Н) 1.48 - 2.26 (m, 23Н) 2.54 - 3.13 (m, 8Н) 3.28 - 3.37 (m, 2Н) 3.39 - 3.49 (m, 2Н) 3.50 - 3.63 (m, 1Н) 3.78 - 3.97 (m, 1H) 4.12 - 4.21 (m, 1H) 4.30 - 4.47 (m, 1H) 4.49 - 4.61 (m, 1H) 4.62 - 4.90 (m, 1H) 4.95 - 5.06 (m, 1H) 6.74 - 6.97 (m, 1H) 6.83 - 6.87 (m, 1H) 6.93 (s, 1H) 7) 7.21 - 7.30 (m, 2H) 7.34 - 7.42 (m, 2H);

B-144. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm. 0.73 - 1.55 (m, 34N) 1.69 - 2.24 (m, 16N) 2.37 - 3.64 (m, 16N) 3.69 - 3.89 (m, 3H) 4.00 - 4.14 (m, 1H) 4.19 - 4.46 (m, 2H) 4.41 - 4.54 (m, 1H) 4.52 - 4.74 (m, 1H) 4.85 - 5.00 (m, 1H) 5.04 - 5.11 (m, 1H) 6.71 - 7.01 (m, 1H) 6.73 - 6.99 (m, 1H) 7.12 - 7.20 (m, 5H) 7.56 - 7.78 (m, 2H) 8.89 - 9.10 (m, 1H) 9.27 - 9.54 (m, 1H);

B-145. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm. 0.75 - 1.52 (m, 36N) 1.60 - 2.00 (m, 10N) 2.12 - 3.34 (m, 17N) 3.35 - 3.46 (m, 10N) 3.52 - 3.71 (m, 2H) 3.78 - 3.99 (m, 1H) 4.04 - 4.17 (m, 1H) 4.23 - 4.51 (m, 2H) 4.59 - 4.71 (m, 1H) 4.77 - 4.97 (m, 1H) 5.00 - 5.11 (m, 1H) 7.08 - 7.21 (m, 3H) 7.12 - 7.16 (m, 2H) 7.32 - 7.58 (m, 3H) 7.64 - 7.82 (m, 2H);

B-146. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.67 - 1.50 (m, 41Н) 1.56 - 2.15 (m, 9Н) 2.50 - 2.76 (m, 5Н) 2.99 - 3.57 (m, 12Н) 3.67 - 3.89 (m, 7Н) 4.04 - 4.49 (m, 6Н) 4.61 - 4.77 (m, 1H) 4.90 - 5.00 (m, 1H) 6.75 - 6.95 (m, 4H) 7.24 - 7.35 (m, 2H);

B-147. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm. 0.77 - 1.58 (m, 42N) 1.68 - 2.21 (m, 11N) 2.29 - 3.16 (m, 10N) 3.18 - 3.33 (m, 5N) 3.34 - 3.57 (m, 3H) 3.62 - 3.91 (m, 3H) 4.00 - 4.13 (m, 1H) 4.13 - 4.35 (m, 3H) 4.37 - 4.48 (m, 1H) 4.67 - 4.80 (m, 1H) 4.86 - 4.93 (m, 1H) 6.59 - 6.75 (m, 2H) 6.77 - 6.86 (m, 2H) 7.06 - 7.26 (m, 2H) 7.53 - 7.75 (m, 2H);

B-148. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm. 0.75 - 1.56 (m, 30N) 1.71 - 2.24 (m, 17N) 2.27 - 3.13 (m, 12N) 3.17 - 3.32 (m, 4N) 3.37 - 3.44 (m, 1H) 3.46 - 3.73 (m, 5N) 3.77 - 3.99 (m, 2H) 4.01 - 4.10 (m, 1H) 4.19 - 4.39 (m, 3H) 4.44 (lat. d, J=7.09 Hz, 1H) 4.75 (lat. d, J=8.80 Hz, 1H) 4.90 (lat. s, 1H) 6.65 - 6.77 (m, 4H) 7.30 - 7.39 (m, 2H) 7.40 - 7.52 (m, 1H) 7.67 -7.81 (m, 2H);

B-149. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.57 - 1.27 (m, 44H), 1.29 - 1.88 (m, 13H), 1.91 (s, 3H, AcOH), 1.93 - 2.04 (m, 2H), 2.16 (br.d, 1H), 2.53 - 2.58 (m, 1H), 2.60 - 2.71 (m, 3H), 2.72 - 2.78 (m, 1H), 2.84 - 3.01 (m, 4H), 3.22 (br. s, 1H), 3.27 (s, 3H), 3.42 (br. d, 1H), 3.57 - 3.66 (m, 2H), 3.82 (s, 3H), 4.03 (br. s, 1H), 4.33 - 4.42 (m, 2H), 4.72 (br. s, 1H), 4.80 - 4.90 (m, 2H), 7.03 (d, 2H), 7.74 (d, 2H);

B-150. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.58 - 1.27 (m, 45H), 1.28 - 1.89 (m, 14H), 1.91 (s, 3H, AcOH), 2.00 (br. d, 1H), 2.15 (br. d, 1H), 2.53 (br. d, 1H), 2.67 (br. d, 2H), 2.71 - 2.79 (m, 1H), 2.87 (lat d, 1H), 2.91 - 3.04 (m, 3H), 3.15 - 3.22 (m, 1H), 3.25 (s, 3H), 3.40 - 3.44 (m, 1H), 3.52 - 3.59 (m, 1H), 3.61 - 3.68 (m, 1H), 4.03 (br. s, 1H), 4.33 (br. d, 1H), 4.36-4.42 (m, 1H), 4.80 - 4.89 (m, 3H), 7.58-7.60 (m, 2H), 7.80 (d, 2H);

B-151. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.74 - 1.25 (m, 41Н) 1.30 - 1.54 (m, 8Н) 1.72 - 1.81 (m, 1Н) 1.84 - 2.24 (m, 11Н) 2.33 - 2.48 (m, 2Н) 2.53 - 2.82 (m, 8Н) 3.04 - 3.14 (m, 1H) 3.23 - 3.33 (m, 4H) 3.45 - 3.55 (m, 2H) 3.65 - 3.87 (m, 3H) 3.89 - 4.05 (m, 2H) 4.24 - 4.49 (m, 3H) 4.75 - 4.91 (m, 3H) 7.57 - 7.63 (m, 2H) 7.74-7.83 (m, 2H);

B-152. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.77 - 1.22 (m, 39N) 1.35 - 1.49 (m, N) 1.71 - 1.81 (m, 1H) 1.86 - 1.93 (m, 6N) 1.95 - 2.09 (m, 3H) 2.10 - 2.20 (m, 1H) 2.40 - 2.48 (m, 2H) 2.53 -2.63 (m, 3H) 2.64 - 2.74 (m, 6H) 2.87 - 2.96 (m, 1H) 3.04 - 3.13 (m, 1H) 3.28 - 3.31 (m, 4H) 3.46 - 3.54 (m, 2H) 3.66 - 3.74 (m, 1H) 3.76 - 3.89 (m, 2H) 3.95 - 4.02 (m, 1H) 4.34 - 4.47 (m, 2H) 4.75 - 4.81 (m, 1H) 4.82 - 4.89 (m, 2H) 7.57 - 7.64 (m, 2H) 7.74 - 7.82 (m, 2H);

B-153. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.76 - 1.20 (m, 36N) 1.22 - 1.54 (m, 8N) 1.72 - 1.81 (m, 1H) 1.88 - 1.92 (m, 6N) 1.99 - 2.18 (m, 4H) 2.17 - 2.22 (m, 3H) 2.32 - 2.38 (m, 1H) 2.43 - 2.49 (m, 1H) 2.58 - 2.73 (m, 7 N) 3.06 - 3.13 (m, 1H) 3.25 - 3.29 (m, 1H) 3.30 - 3.33 (m, 3H) 3.41 - 3.49 (m, 2H) 3.65 - 3.75 (m, 1H) 3.76 - 3.86 (m, 1H) 4.12 - 4.16 (m, 1H) 4.37 - 4.43 (m, 2H) 4.70 - 4.76 (m, 1H) 4.81 - 4.86 (m, 2H) 7.58 - 7.62 (m, 2H) 7.77 - 7.81 (m, 2H);

B-154. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.75 - 1.21 (m, 35H) 1.31 - 1.54 (m, 9H) 1.72 - 1.82 (m, 1H) 1.87 - 1.93 (m, 4H) 1.93 - 2.24 (m, 5H) 2.34 - 2.48 (m, 5H) 2.53 - 2.81 (m, 9H) 3.06 - 3.17 (m, 1H) 3.22 - 3.34 (m, 5H) 3.46 - 3.54 (m, 2H) 3.64 - 3.74 (m, 1H) 3.79 - 3.89 (m, 1H) 3.90 - 4.01 (m, 2H) 4.33 - 4.41 (m, 1H) 4.42 - 4.51 (m, 1H) 4.75 - 4.82 (m, 2H) 4.84 - 4.91 (m, 1H) 7.31 - 7.37 (m, 2H) 7.64 - 7.72 (m, 2H);

B-155. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.77 - 1.21 (m, 35N) 1.33 - 1.48 (m, 7H) 1.73 - 1.81 (m, 1H) 1.87 - 1.92 (m, 6N) 1.94 - 2.08 (m, 3H) 2.12 - 2.19 (m, 1H) 2.35 - 2.39 (m, 3H) 2.42 - 2.49 (m, 1H) 2.54 - 2.74 (m, 9H) 2.87 - 2.95 (m, 1H) 3.06 - 3.13 (m, 1H) 3.27 - 3.32 (m, 4H) 3.47 - 3.53 (m, 2H) 3.64 - 3.72 (m, 1H) 3.79 - 3.90 (m, 2H) 3.97 - 4.01 (m, 1H) 4.35 - 4.42 (m, 1H) 4.42 - 4.47 (m, 1H) 4.76 - 4.83 (m, 2H) 4.84 - 4.89 (m, 1H) 7.32 - 7.36 (m, 2H) 7.66 - 7.70 (m, 2H);

B-156. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.81 - 1.20 (m, 32Н) 1.22 - 1.55 (m, 7Н) 1.73 - 1.82 (m, 1Н) 1.87 - 1.93 (m, 6Н) 2.00 - 2.24 (m, 6Н) 2.32 - 2.39 (m, 4Н) 2.41 - 2.48 (m, 2H) 2.58 - 2.72 (m, 7H) 3.06 - 3.14 (m, 1H) 3.29 - 3.33 (m, 4H) 3.42 - 3.50 (m, 2H) 3.63 - 3.72 (m, 1H) 3.77 - 3.87 (m, 1H) 4.12 - 4.16 (m, 1H) 4.24 - 4.31 (m, 1H) 4.37 - 4.44 (m, 2H) 4.70 - 4.77 (m, 1H) 4.78 - 4.86 (m, 2H) 7.31 - 7.37 (m, 2H) 7.64 - 7.71 (m, 2H);

B-157. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.73 - 1.25 (m, 33H), 1.28 - 1.60 (m, 7H), 1.67 -1.81 (m, 2H), 1.91 (s, 2H, AcOH), 1.92 - 2.12 (m, 4H), 2.20 (br. d, 1H), 2.35 - 2.45 (m, 1Н), 2.59 (lat. d, 1Н), 2.63 (s, 3Н), 2.69 - 2.81 (m, 3Н), 3.01 (lat. dd, 1Н), 3.14 - 3.26 (m, 2Н), 3.31 (lat. s, 3Н), 3.49 - 3.53 (m, 2Н), 3.64 (s, 3H), 3.66 - 3.80 (m, 2H), 3.83 (s, 1H), 3.96 (lat d, 1H), 4.04 (br d, 1H), 4.31 (s, 1H), 4.43 (br d, 2H), 4.47 - 4.52 (m, 1H), 4.86 -4.91 (m, 3H), 6.41 (s, 2H), 6.60 (d, 2H), 6.69 - 6.75 (m, 2H);

B-158. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.74 - 1.23 (m, 36H), 1.23 - 1.85 (m, 12H), 1.91 (s, 3H, AcOH), 1.93-2.18 (m, 5H), 2.35 - 2.48 (m, 3H), 2.53 - 2.61 (m, 1H), 2.62 (s, 3H), 2.64 - 2.83 (m, 4H), 3.11 - 3.20 (m, 2H), 3.27 (s, 3H), 3.50 (lat d, 2H), 3.64 - 3.78 (m, 2H), 3.92 (lat d, 1H), 3.99 (lat d, 1H), 4.31 (broad s, 1H), 4.37 (k, 1H), 4.44 (width d, 1H), 4.78 (width d, 1H), 4.83 - 4.90 (m, 2 H), 6.40 (s, 2 H);

B-159. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.8-1.5 (m, 44H), 1.6-1.9 (m, 4H), 2.1-2.4 (m, 6H), 2.5-2.8 (m, 7H), 3.1-3.5 (m, 7H), 3.6-4.0 (m, 4H), 4.1-4.5 (m, 5H), 4.7-4.8 (m, 2H), 7.26 (br. s, 2H), 7.56-7.57 (m, 2H); B-160. No. NMR

B-161. ¹ H NMR (600 MHz, DMSO-d6) δ ppm 0.43 - 1.88 (m, 54H), 1.91 (s, 1H, AcOH), 1.97 -2.06 (m, 2H), 2.08 - 2.16 (m, 1H), 2.52 - 2.54 (m, 1H), 2.59 - 2.65 (m, 1H), 2.66 - 2.77 (m, 2H), 2.81 - 2.95 (m, 1H), 3.09 - 3.20 (m, 1H), 3.22 - 3.27 (m, 1H), 3.35 - 3.39 (m, 3H), 3.39 - 3.43 (m, 1H), 3.45 - 3.55 (m, 2H), 3.83 - 3.97 (m, 2H), 3.97 - 4.05 (m, 1H), 4.09 - 4.17 (m, 1H), 4.34 - 4.43 (m, 1H), 4.57 - 4.88 (m, 4H), 6.58 - 6.68 (m, 2H), 6.88 (td, 2H), 7.55 - 7.61 (m, 2H), 7.65 - 7.69 (m, 1H), 7.73 (br. d, 2 H);

B-162. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.8-1.5 (m, 44H), 1.6-1.9 (m, 5H), 2.1-2.4 (m, 6H), 2.5-2.8 (m, 7H), 3.1-3.5 (m, 5H), 3.6-4.0 (m, 6H), 4.1-4.5 (m, 4H), 4.7-4.8 (m, 3H), 6.9-7.1 (m, 5H), 7.43 (s, 1H);

S-1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.77-1.5 (m, 37H), 1.7-2.3 (m, 12H) (including 1 acetate salt proton), 2.4-2.8 (m, 13H), 3.13 (br s, 1H), 3.25-3.70 (m, 6H), 3.79 (br s, 2H), 3.85 (br s, 2H), 4.07 (br s, 1H), 4.40-4.44 (m, 2H), 4.81-4.85 (m, 3H), 7.60 (d, 2H, J=8 Hz), 7.78 (d, 2H, J=8 Hz);

S-2. ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 0.77-1.5 (m, 39H), 1.7-2.3 (m, 18H) (including 3 protons of acetate salt), 2.4-2.8 (m, 6H), 3.13 (br s, 1H), 3.25-3.50 (m, 8H), 3.79 (lat s, 1H), 3.80 (lat s, 1H), 4.06 (lat s, 1H), 4.34-4.41 (m, 2H), 4.79-4.81 (lat s, 3H), 7.60 (d, 2H, J=8 Hz), 7.78 (d, 2H, J=8 Hz);

S-3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.77-1.5 (m, 41H), 1.7-2.3 (m, 12H) (including 1 acetate salt proton), 2.4-2.8 (m, 7H), 3.13 (br s, 1H), 3.25-3.50 (m, 8H), 3.74-3.81 (m, 3H), 4.04 (br s, 1H), 4.31-4.50 (m, 3H), 4.81-4.84 (br s, 3H), 7.60 (d, 2H, J=8 Hz), 7.78 (d, 2H, J=8 Hz);

S-4. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.77-1.5 (m, 39H), 1.7-2.3 (m, 12H) (including 1 acetate salt proton), 2.4-2.8 (m, 13H), 3.13 (br. s, 1H), 3.25-3.70 (m, 6H), 3.75-3.82 (br s, 4H), 4.07 (br s, 1H), 4.42-4.46 (m, 2H), 4.81-4.84 (m, 3H), 7.60 (d, 2H, J=8 Hz), 7.77 (d, 2H, J=8 Hz);

C-5. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.77-1.5 (m, 35H), 1.7-2.3 (m, 12H) (including 1 acetate salt proton), 2.4-2.8 (m, 6H), 3.13 (br s, 1H), 3.25-3.50 (m, 5H), 3.79 (br s, 1H), 3.85 (br s, 1H), 4.10-4.23 (m, 4H), 4.35 (d, 2H, J=8 Hz), 4.49 (d, 2H, J=8 Hz), 4.85 (br s, 2H), 5.02 (s, 1H), 7.23 (s,1H), 7.60 (d, 2H, J=8 Hz), 7.68 (s, 1H), 7.78 (d, 2H, J=8 Hz);

S-6. ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm 0.77-1.5 (m, 37H), 1.7-2.3 (m, 18H) (including 3 proton of acetate salt), 2.4-2.8 (m, 13H), 3.13 (br s, 1H), 3.25-3.70 (m, 6H), 3.78 (br s, 2H), 3.85 (br s, 2H), 4.07 (br s, 1H), 4.40-4.44 (m, 2H), 4.81-4.83 (m, 3H), 7.60 (d, 2H, J=8 Hz), 7.77 (d, 2H, J=8 Hz);

S-1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.77-1.5 (m, 40H), 1.7-2.3 (m, 15H) (including 2 acetate salt protons), 2.4-2.8 (m, 13H), 3.13 (br s, 1H), 3.25-3.70 (m, 6H), 3.78 (br s, 2H), 3.85 (br s, 2H), 4.07 (br s, 1H), 4.41-4.44 (m, 2H), 4.81-4.84 (m, 3H), 7.60 (d, 2H, J=8 Hz), 7.77 (d, 2H, J=8 Hz);

C-8. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.77-1.5 (m, 35H), 1.7-2.3 (m, 15H) (including 2 protons of acetate salt), 2.4-2.8 (m, 6H), 3.13 (br s, 1H), 3.25-3.50 (m, 5H), 3.79 (br s, 1H), 3.81 (br s, 1H), 4.11 (br s, 1H), 4.34-4.39 (m, 4H), 4.49 (br s, 1H), 4.83 (br s, 2H), 4.92 (br s, 2H), 6.25 (s, 1H), 7.42 (s, 1H), 7.59 (d, 2H, J=8 Hz), 7.76-7.79 (m, 3H);

C-9. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.77-1.5 (m, 38H), 1.7-2.3 (m, 15H) (including 2 acetate salt protons), 2.4-2.8 (m, 6H), 3.13 (br s, 1H), 3.25-3.50 (m, 5H), 3.79 (br s, 1H), 3.85 (br s, 1H), 4.13 (br s, 1H), 4.33-4.49 (m, 2H), 4.61-4.65 (m, 1H), 4.79-4.86 (m, 2H), 4.97 (br s, 1H), 7.59 (d, 2H, J=8 Hz), 7.77 (d, 2H, J=8 Hz), 9.22 (s, 1H);

C-10. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.77-1.5 (m, 34H), 1.7-2.3 (m, 9H), 2.4-2.8 (m, 8H), 3.08 (br s, 1H), 3.29-3.40 (m, 4H), 3.71-3.85 (m, 6H), 4.09 (lat. s, 1H), 4.28-4.32 (lat. s, 2H), 4.41-4.47 (m, 3H), 4.82-4.87 (m, 3H), 5.04 (lat. s, 1H), 7.03-7.18 (m, 4H), 7.59 (d, 2H, J=8 Hz), 7.77 (d, 2H, J=8 Hz), 8.18 (d, 2H, J=8 Hz);

S-11. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.77-1.5 (m, 40H), 1.6-2.4 (m, 12H) (including 1 proton of acetate salt), 2.6-2.8 (m, 17H), 3.05-3.19 (m, 2H), 3.32 (br s, 2H), 3.52 (br s, 2H), 3.79 (br s, 2H), 4.06 (br s, 2H), 4.44-4.47 (m, 3H), 4.81-4.84 (m, 2H), 7.20 (br s, 2H), 7.52 (br s, 2H);

C-12. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.77-1.5 (m, 39H), 1.6-2.2 (m, 15H) (including 1 proton of acetate salt), 2.4-2.8 (m, 16H), 3.13 (br s, 1H), 3.25-3.35 (m, 5H), 3.45 (br s, 1H), 3.65 (br s, 1H), 3.75 (br s, 2H), 4.08 (br s, 1H), 4.44 (d, 2H, J=8 Hz), 4.85 (br s, 2H), 7.26 (d, 2H, J=8 Hz), 7.58 (d, 2H, J=8 Hz);

C-13. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.77-1.5 (m, 39H), 1.6-2.4 (m, 16H) (including 1 proton of acetate salt), 2.6-2.8 (m, 1H), 3.1-3.25 (m, 6H), 3.45 (br s, 1H), 3.65 (br s, 2H), 3.79 (br s, 2H), 4.09 (br s, 3H), 4.40 (d, 2H, J=8 Hz), 4.81-4.87 (m, 2H), 7.17 (br s, 2H), 7.50 (br s, 2H);

C-14. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.77-1.5 (m, 41H), 1.6-2.2 (m, 18H) (including 2 protons of acetate salt), 2.4-2.8 (m, 16H), 3.13 (br s, 1H), 3.25-3.35 (m, 5H), 3.45 (br s, 1H), 3.65 (br s, 1H), 3.75 (br s, 2H), 4.08 (br s, 1H), 4.40 (d, 2H, J=8 Hz), 4.86 (br s, 2H), 7.14 (br s, 2H), 7.48 (br s, 2H);

C-15. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.77-1.5 (m, 41H), 1.6-2.2 (m, 15H) (including 1 proton of acetate salt), 2.4-2.8 (m, 16H), 3.13 (br s, 1H), 3.25-3.35 (m, 5H), 3.45 (br s, 1H), 3.65 (br s, 1H), 3.75 (br s, 2H), 4.06 (br s, 1H), 4.41 (d, 2H, J=8 Hz), 4.82-4.86 (m, 2H), 7.25 (br s, 2H), 7.56 (br s, 2H);

C-16. ¹ H NMR (400 MHz, DMSO- _d6 ) δ ppm 0.68 - 1.55 (m, 48 N), 1.56 - 1.88 (m, 6 H), 1.89 (s, 3 H, AcOH), 1.91 - 1.96 (m, 1 H), 2.12 (br d, 1 H), 2.32 (width, 1 N), 2.52 (width, 1 N), 2.54 - 2.60 (m, 3 N), 2.64 - 2.69 (m, 1 N), 2.83 (width, 1 N), 3.11 - 3.18 (m, 1 N), 3.27 (s, 3 N), 3.32 (s, 1 N), 3.48 (width, 1 N), 3.67 - 3.83 (m, 3 N), 4.08 (lat. s, 1 N), 4.41 - 4.50 (m, 2 N), 4.80 -4.93 (m, 3 N), 6.39 (lat. s, 2 N);

C-17. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.74 - 1.23 (m, 28 N), 1.29 - 1.61 (m, 16 N), 1.63 -1.82 (m, 3 H), 1.91 (s, 3 H, AcOH), 1.93 - 2.16 (m, 3 H), 2.28 - 2.46 (m, 3 N), 2.56 (width, 3 N), 2.62 (s, 3 N), 2.65 - 2.83 (m, 3 N), 2.92 (width, 4 N), 3.15 (width, 1 N), 3.26 (s, 3 N), 3.49 (width, 2 N), 3.69 - 3.81 (m, 2 N), 3.87 - 4.00 (m, 2 N), 4.30 (lat. s, 1 N), 4.39 - 4.52 (m, 2 N), 4.76 (lat. d, 1 N), 4.85 (lat. s, 2 N), 6.39 (s, 2 N), 6.65 (s, 2 N);

C-18. ^1H NMR (400 MHz, CHLOROFORM-d) δ 0.78-0.86 (m, 3H), 0.88-0.92 (m, 5H), 1.01 (s, 3H), 1.04-1.15 (m, 12H), 1.17-1.28 (m, 7H), 1.30-1.60 (m, 12H), 1.74-1.97 (m, 5H), 2.04-2.30 (m, 4H), 2.37-2.50 (m, 2H), 2.51-2.72 (m, 9H), 3.03-3.11 (m, 2H), 3.16-3.25 (m, 2H), 3.30-3.35 (m, 3H), 3.39-3.44 (m, 1H), 3.50-3.57 (m, 1H), 3.78-3.89 (m, 1H), 3.98-4.12 (m, 2H), 4.43-4.51 (m, 1H), 4.51-4.57 (m, 1H), 4.69-4.79 (m, 1H), 4.83-4.91 (m, 1H), 7.60-7.69 (m, 2H), 7.89-7.96 (m, 2H);

C-19. ^1H NMR (400 MHz, CHLOROFORM-d) δ 0.77-0.85 (m, 3H), 0.89-0.97 (m, 6H), 0.99-1.04 (m, 3H), 1.05-1.17 (m, 12H), 1.18-1.64 (m, 18H), 1.69-1.89 (m, 2H), 1.90-1.95 (m, 3H), 1.95-2.20 (m, 5H), 2.21-2.71 (m, 10H), 2.75-2.84 (m, 1H), 3.10-3.24 (m, 2H), 3.29-3.35 (m, 3H), 3.45-3.50 (m, 1H), 3.52-3.58 (m, 1H), 3.74-3.84 (m, 1H), 3.95-4.08 (m, 2H), 4.42-4.50 (m, 1H), 4.52-4.57 (m, 1H), 4.79-4.88 (m, 3H), 7.07 (t, J=8.56 Hz, 2H), 7.77-7.85 (m, 2H);

S-20. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.8-1.5 (m, 48H), 1.6-1.9 (m, 16H) (including 3 protons of acetate salt), 2.1-2.4 (m, 6H), 2.5-2.8 (m, 8H), 3.1-3.5 (m, 7H), 3.6-4.0 (m, 6H), 4.43-4.48 (m, 2H), 4.7-4.9 (m, 2H), 7.0-7.3 (m, 5H);

S-21. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.8-1.5 (m, 51H), 1.6-1.9 (m, 15H) (including 3 protons of acetate salt), 2.1-2.4 (m, 7H), 2.6-2.8 (m, 8H), 3.1-3.5 (m, 6H), 3.6-4.0 (m, 5H), 4.3-4.5 (m, 3H), 4.8-4.9 (m, 2H), 6.9-7.0 (m, 1H), 7.09 (d, 2H, J=7.84 Hz), 7.22 (t, 2H, J=7.44 Hz);

C-22. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.8-1.5 (m, 55H), 1.6-1.9 (m, 10H) (including 1 proton of acetate salt), 2.1-2.4 (m, 5H), 2.6-2.8 (m, 8H), 3.0-3.1 (m, 1H), 3.28 (s, 3H), 3.40-3.42 (m, 1H), 3.6-3.8 (m, 4H), 4.08 (s, 1H), 4.4-4.5 (m, 2H), 4.81-4.84 (m, 2H), 7.08 (d, 2H, J=8.52 Hz), 7.26 (d, 2H, J=8.6 Hz);

S-23. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.8-1.5 (m, 47H), 1.6-1.9 (m, 12H) (including 2 acetate salt protons), 2.1-2.4 (m, 6H), 2.6-2.8 (m, 6H), 3.1-3.5 (m, 6H), 3.6-3.8 (m, 4H), 4.08 (s, 1H), 4.44-4.47 (m, 3H), 4.81-4.84 (m, 2H), 6.88-7.18 (m, 4H);

S-24. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.8-1.5 (m, 46H), 1.6-1.9 (m, 15H) (including 3 protons of acetate salt), 2.1-2.4 (m, 5H), 2.5-2.8 (m, 6H), 3.1-3.5 (m, JN), 3.6-3.8 (m, 4H), 4.09 (s, 1H), 4.4-4.5 (m, 2H), 4.82-4.85 (m, 2H), 6.39-6.41 (m, 1H), 6.61-6.65 (m, 2H), 7.02-7.04 (m, 1H);

S-25. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.8-1.5 (m, 46H), 1.6-1.9 (m, 18H) (including 3 protons of acetate salt), 2.1-2.5 (m, 5H), 2.6-2.9 (m, 15H), 3.1-3.4 (m, 7H), 3.6-3.7 (m, 2H), 4.39-4.41 (m, 2H), 4.78-4.80 (m, 2H), 6.37-6.40 (m, 2H), 6.47 (s, 1H), 7.00-7.03 (m, 1H);

S-26. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.8-1.5 (m, 47H), 1.6-1.9 (m, 14H) (including 2 acetate salt protons), 2.1-2.4 (m, 7H), 2.6-2.8 (m, 7H), 3.1-3.5 (m, 7H), 3.6-3.8 (m, 4H), 4.09 (s, 1H), 4.44-4.46 (m, 2H), 6.46-6.48 (m, 1H), 6.87-6.97 (m, 2H), 7.11 (t, W, J=7.66 Hz), 7.63 (s, 1H);

S-27. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.8-1.5 (m, 46H), 1.6-1.9 (m, 7H), 2.1-2.4 (m, 7H), 2.5-2.8 (m, 6H), 3.0-3.5 (m, 7H), 3.6-3.8 (m, 4H), 4.11 (s, 1H), 4.4-4.5 (m, 2H), 4.81-4.84 (m, 2H), 6.56 (d, 2H, J=8.36 Hz), 6.6-6.7 (m, 2H);

C-28. ^1H NMR (400 MHz, DMSO-d6) δ ppm 0.8-1.5 (m, 46H), 1.6-1.9 (m, 7H), 2.1-2.4 (m, 6H), 2.6-2.8 (m, 5H), 3.1-3.5 (m, 5H), 3.6-4.0 (m, 4H), 4.10 (s, 1H), 4.4-4.5 (m, 2H), 4.82-4.83 (m, 2H), 6.37 (s, 1H), 6.58 (dd, 1H, J=8.8 Hz, J=2.4 Hz), 6.87 (d, 1H, J=2.4 Hz), 7.08 (d, 1H, J=8.8 Hz);

S-29. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.8-1.5 (m, 46H), 1.6-1.9 (m, 11H) (including 2 protons of acetate salt), 2.1-2.4 (m, 5H), 2.5-2.8 (m, 9H), 3.0-3.5 (m, 8H), 3.6-3.8 (m, 3H), 4.08 (s, 1H), 4.43-4.47 (m, 2H), 4.81-4.83 (m, 2H), 7.07 (d, 2H, J=8.6 Hz), 7.42 (d, 2H, J=8.64 Hz);

S-30. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.8-1.5 (m, 46H), 1.6-1.9 (m, 11H) (including 2 acetate salt protons), 2.1-2.4 (m, 5H), 2.5-2.8 (m, 9H), 3.1-3.5 (m, 8H), 3.6-3.8 (m, 3H), 4.09 (s, 1H), 4.41-4.47 (m, 2H), 4.82-4.84 (m, 2H), 6.81 (d, 2H, J=8.4 Hz), 7.43 (d, 2H, J=8.44 Hz);

S-31. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.8-1.5 (m, 47H), 1.6-1.9 (m, 14H) (including 2 acetate salt protons), 2.1-2.4 (m, 5H), 2.6-2.8 (m, 6H), 3.1-3.5 (m, 7H), 3.6-3.8 (m, 3H), 4.08 (s, 1H), 4.41-4.47 (m, 2H), 4.82-4.83 (m, 2H), 7.07-7.33 (m, 3H);

S-32. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.8-1.5 (m, 48H), 1.6-1.9 (m, 11H) (including 1 proton of acetate salt), 2.1-2.4 (m, 8H), 2.6-2.9 (m, 8H), 3.0-3.4 (m, 6H), 4.02 (s, 1H), 4.39-4.41 (m, 2H), 4.77-4.81 (m, 2H), 7.04-7.05 (m, 4H);

S-33. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.8-1.5 (m, 47H), 1.6-1.9 (m, 12H) (including 2 protons of acetate salt), 2.1-2.4 (m, 12H), 2.5-2.8 (m, 8H), 3.0-3.5 (m, 6H), 3.6-3.8 (m, 3H), 4.08 (s, 1H), 4.43-4.45 (m, 2H), 4.82-4.84 (m, 2H), 6.86-6.88 (m, 1H), 6.96 (s, 1H), 7.00 (d, 1H, J=8.08 Hz);

S-34. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.5-1.5 (m, 48H), 1.6-1.9 (m, 8H), 2.1-2.4 (m, 6H), 2.5-2.8 (m, 4H), 3.2-3.5 (m, 7H), 3.7-3.9 (m, 3H), 4.1-4.4 (m, 4H), 4.8-4.9 (m, 2H), 6.66 (d, 1H, J=2.08 Hz), 6.86 (d, 1H, J=2.08 Hz);

S-35. ^1H NMR (400 MHz, DMSO-d6) δ ppm 0.8-1.5 (m, 45H), 1.6-1.9 (m, 9H), 2.1-2.4 (m, 5H), 2.5-2.8 (m, 8H), 3.0-3.5 (m, 10H), 3.6-3.8 (m, 3H), 3.9-4.1 (m, 2H), 4.4-4.5 (m, 3H), 4.83-4.88 (m, 3H);

S-36. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.8-1.5 (m, 48H), 1.6-1.9 (m, 15H) (including 3 protons of acetate salt), 2.1-2.4 (m, 7H), 2.5-2.8 (m, 8H), 3.1-3.5 (m, 8H), 3.7-4.0 (m, 5H), 4.44-4.46 (m, 2H), 4.7-4.9 (m, 2H), 6.84 (d, 2H, J=8.4 Hz), 7.26 (d, 2H, J=8.48 Hz);

C-37. ^1H NMR (400 MHz, CHLOROFORM-d) δ 0.71-0.86 (m, 3H), 0.88-0.98 (m, 5H), 0.98-1.06 (m, 3H), 1.06-1.18 (m, 11H), 1.18-1.28 (m, 4H), 1.28-1.55 (m, 11H), 1.56-1.67 (m, 1H), 1.69-1.89 (m, 3H), 1.93-1.97 (m, 3H), 2.05-2.19 (m, 2H), 2.37-2.49 (m, 2H), 2.53-2.78 (m, 6H), 2.85-2.91 (m, 3H), 3.08-3.38 (m, 12H), 3.40-3.46;

S-38. ^1H NMR (400 MHz, DMSO-d6) δ ppm 0.8-1.5 (m, 46H), 1.6-1.9 (m, 5H), 2.1-2.4 (m, 9H), 2.5-2.8 (m, 5H), 3.1-3.5 (m, 7H), 3.6-4.0 (m, 3H), 4.1-4.5 (m, 3H), 4.7-4.8 (m, 2H), 7.58 (d, 2H, J=8.36 Hz), 7.77 (d, 2H, J=8.32 Hz);

C-39. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.73 - 1.23 (m, 38 N), 1.30 - 1.85 (m, 18 H), 1.91 (s, 3 H, AcOH), 1.92 - 1.98 (m, 1 H), 2.11 (br d, 1 H), 2.32 (width, 1 N), 2.53 - 2.57 (m, 2 N), 2.64 - 2.70 (m, 1 N), 2.88 (width, 1 N), 3.17 (s, 3 N), 3.43 (width, 1 N), 3.60 - 3.74 (m, 2 N), 4.02 (width, s, 1 N), 4.26 - 4.52 (m, 6 N), 4.79 - 4.88 (m, 2 N), 7.10 - 7.26 (m, 3 N), 7.44 - 7.57 (m, 2 N), 7.65 - 7.72 (m, 1 N), 8.36 (dd, 1 N), 8.47 (s, 1 N);

C-40. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.71 - 1.29 (m, 39 N), 1.30 - 1.85 (m, 20 N), 1.91 (s, 2 H, AcOH), 1.94 (br d, 1 H), 2.13 (br d, 1 H), 2.31 - 2.37 (m, 1 N), 2.55 (lat, 2 N), 2.66 - 2.72 (m, 1 N), 2.90 - 2.97 (m, 1 N), 3.06 (lat, 2 N), 3.15 - 3.21 (m, 1 N), 3.25 (s, 3 N), 3.34 -3.38 (m, 1 N), 3.42 (lat. d, 1 N), 3.61 - 3.79 (m, 3 N), 3.99 (lat. s, 1 N), 4.39 - 4.46 (m, 1 N), 4.84 (lat. dd, 3 N), 7.34 - 7.40 (m, 2 N), 7.83 (d, 2 N);

C-41. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.68 - 1.29 (m, 38 N), 1.50 (br d, 20 N), 1.91 (s, 2 H, AcOH), 1.92 - 1.98 (m, 1 H), 2.13 (br d, 1 H), 2.31 - 2.37 (m, 1 N), 2.55 (width, 2 N), 2.66 - 2.73 (m, 1 N), 2.89 - 2.97 (m, 1 N), 2.98 - 3.04 (m, 2 N), 3.16 - 3.22 (m, 1 N), 3.27 (s, 3 N), 3.29 - 3.31 (m, 1 N), 3.37 (width s, 1 N), 3.43 (width d, 1 N), 3.61 - 3.74 (m, 2 N), 3.82 (s, 3 N), 4.00 (width s, 1 N), 4.44 (width dd, 2 N), 4.74 (width d, 1 N), 4.80 - 4.89 (m, 2 N), 7.00 - 7.07 (m, 2 N), 7.76 (d, 2 N);

C-42. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.69 - 1.28 (m, 42 N), 1.29 - 1.90 (m, 19 H), 1.91 (s, 2 H, AcOH), 2.12 (br d, 1 H), 2.33 (br d, 1 H), 2.52 - 2.57 (m, 2 N), 2.65 - 2.71 (m, 1 N), 2.89 - 3.07 (m, 4 N), 3.19 (lat. s, 1 N), 3.23 (lat. s, 3 N), 3.35 (lat. s, 1 N), 3.41 (lat. d, 1 N), 3.52 - 3.63 (m, 1 N), 3.71 (broad. dd, 1 N), 3.99 (lat. s, 1 N), 4.38 (lat. d, 1 N), 4.44 (lat. d, 1 N), 4.77 - 4.88 (m, 3 N), 7.59 (d, 3 N), 7.80 (d, 2 N);

C-43. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.70 - 1.27 (m, 42 N), 1.32 - 1.87 (m, 18 H), 1.91 (s, 3 H, AcOH), 1.92 - 1.95 (m, 1 H), 2.12 (br d, 1 H), 2.30 - 2.36 (m, 1 N), 2.52 - 2.57 (m, 3 N), 2.62 - 2.69 (m, 2 N), 2.83 - 3.02 (m, 4 N), 3.17 - 3.24 (m, 1 N), 3.25 (s, 3 N), 3.44 (lat. d, 1 N), 3.53 - 3.61 (m, 1 N), 3.66 - 3.73 (m, 1 N), 3.82 (s, 3 N), 4.03 (lat. s, 1 N), 4.39 (lat. d, 1 N), 4.45 (k, 2 N), 4.69 (lat. d, 1 N), 4.80 - 4.87 (m, 2 N), 7.03 (d, 2 N), 7.73 (d, 2 N);

C-44. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.62 - 1.27 (m, 43 N), 1.27-1.81 (m, 17 H), 1.83 -1.89 (m, 1 H), 1.91 (s, 2 H, AcOH), 1.93 (br d, 1 H), 2.12 (width, 1 N), 2.27 - 2.37 (m, 2 N), 2.55 (width, 2 N), 2.62 - 2.71 (m, 2 N), 2.81 - 3.01 (m, 4 N), 3.15 - 3.24 (m, 1 N), 3.26 (s, 3 N), 3.45 (width, 1 N), 3.63 - 3.71 (m, 1 N), 4.05 (lat s, 1 N), 4.36 - 4.50 (m, 3 N), 4.79 - 4.87 (m, 2 N), 7.18 - 7.32 (m, 2 N), 7.51 - 7.66 (m, 2 N); S-45.

C-46. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.66 - 1.27 (m, 38 H), 1.28 - 1.85 (m, 17 H), 1.91 (s, 3 H, AcOH), 1.93 (br d, 1 H), 2.29 - 2.37 (m, 2 H), 2.51 - 2.57 (m, 3 H), 2.63 - 2.73 (m, 2 H), 2.86 - 2.94 (m, 1 H), 3.16 - 3.23 (m, 1 H), 3.23 - 3.27 (m, 3 H), 3.43 (br d, 1 H), 3.61 - 3.71 (m, 1 H), 3.74 - 3.84 (m, 1 N), 4.02 (lat s, 1 N), 4.46 (lat dd, 2 N), 4.56 - 4.67 (m, 1 N), 4.70 -4.77 (m, 1 N), 4.80 - 4.87 (m, 2 N), 7.15 (lat s, 2 N), 7.43 - 7.56 (m, 2 N), 7.62 (lat, 1 N), 7.66 (d, 1 N);

C-47. ^1H NMR (400 MHz, CHLOROFORM-d) δ 0.86-0.94 (m, 3H), 0.97-1.04 (m, 5H), 1.08-1.14 (m, 3H), 1.15-1.26 (m, 10H), 1.26-1.36 (m, 4H), 1.37-1.40 (m, 3H), 1.41-1.72 (m, 10H), 1.85-2.07 (m, 7H), 1.86-2.08 (m, 6H), 2.20-2.28 (m, 2H), 2.68-2.82 (m, 7H), 3.17-3.23 (m, 3H), 3.27-3.34 (m, 3H), 3.40-3.46 (m, 3H), 3.49-3.53 (m, 1H), 3.64-3.70 (m, 1H), 3.87-4.00 (m, 1H), 4.08-4.21 (m, 2H), 4.51-4.61 (m, 1H), 4.61-4.67 (m, 1H), 4.85-4.91 (m, 1H), 4.91-4.98 (m, 1H), 7.89 (s, 2H), 7.95-8.08 (m, 2H);

C-48. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.30 - 1.87 (m, 44 N), 1.91 (s, 1 H), 2.08 (s, 1 H), 2.13 - 2.21 (m, 1 H), 2.32 - 2.40 (m, 1 H), 2.53 - 2.59 (m, 2 N), 2.63 (s, 3 N), 2.67 (lat s, 1 N), 2.87 - 2.99 (m, 1 N), 3.00 - 3.13 (m, 1 N), 3.18 (lat s, 1 N), 3.26 - 3.31 (m, 2 N), 3.41 (lat s, 3 N), 3.84 - 3.98 (m, 2 N), 4.14 - 4.25 (m, 1 N), 4.29 (width, 1 N), 4.44 (width, 1 N), 4.68 - 4.74 (m, 1 N), 4.78 - 4.85 (m, 2 N), 5.17 (width, dd, 1 N), 6.07 (lat, s, 1 N), 6.18 (d, 1 N), 7.28 - 7.32 (m, 3 N), 7.47 - 7.54 (m, 2 N), 7.57 - 7.61 (m, 3 N), 7.62 - 7.68 (m, 3 N), 8.01 (d, 1 N), 8.04 - 8.12 (m, 1 N);

C-49. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.44 - 1.89 (m, 54 N), 1.91 (s, 3 H), 2.08 - 2.15 (m, 1 N), 2.31 (br d, 1 H), 2.52 - 2.62 (m, 5 H), 2.73 (s, 3 N), 2.83 (width, 1 N), 3.22 - 3.27 (m, 1 N), 3.47 (width, 1 N), 3.70 - 3.78 (m, 1 N), 3.80 (s, 3 N), 3.91 - 4.02 (m, 2 N), 4.12 - 4.20 (m, 1 N), 4.26 (td, 1 N), 4.44 (k, 1 N), 4.48 - 4.55 (m, 1 N), 4.73 - 4.83 (m, 3 N), 6.73 (d, 2 N), 7.02 (d, 1 N), 7.45 (s, 1 N), 7.90 - 7.97 (m, 1 N);

S-50. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.8-1.5 (m, 45H), 1.6-1.9 (m, 7H) (including 1 proton of acetate salt), 2.1-2.4 (m, 5H), 2.5-2.8 (m, 7H), 3.0-3.5 (m, 5H), 3.6-3.8 (m, 6H), 4.0-4.4 (m, 4H), 4.6-4.8 (m, 5H), 6.66 (d, 2H, J=8.96 Hz), 6.81 (d, 2H, J=8.8 Hz), 7.02 (t, 1H, J=7.24 Hz), 7.13 (d, 2H, J=7.92 Hz), 7.27 (t, 2H, J=7.7 Hz), 9.80 (s, 1H);

S-51. ^1H NMR (400 MHz, DMSO-d6) δ ppm 0.5-1.5 (m, 46H), 1.6-2.3 (m, 16H) (including 2 protons of acetate salt), 2.4-2.8 (m, 9H), 2.9-3.5 (m, 8H), 3.8-4.1 (m, 4H), 4.4-4.8 (m, 3H), 6.84-7.03 (m, 5H), 7.11 (d, 2H, J=7.84 Hz), 7.25-7.29 (m, 2H);

S-52. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.5-1.5 (m, 40H), 1.6-2.3 (m, 13H) (including 1 proton of acetate salt), 2.4-2.6 (m, 6H), 2.8-3.3 (m, 8H), 3.4-3.8 (m, 3H), 3.9-4.8 (m, 11H), 6.83-6.87 (m, 3H), 7.01-7.26 (m, 7H), 9.82 (s, 1H);

C-53. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.40 - 1.84 (m, 53 N), 1.91 (s, 1 H), 2.15 (br d, 1 H), 2.33 - 2.39 (m, 1 H), 2.56 (br d, 3 H), 2.85 - 2.94 (m, 1 N), 3.27 (width, 2 N), 3.39 (s, 3 N), 3.45 (width, 1 N), 3.90 - 4.00 (m, 2 N), 4.04 - 4.18 (m, 3 N), 4.43 - 4.51 (m, 1 N), 4.71 (width, 1 N), 4.76 - 4.90 (m, 2 N), 6.59 (width, 2 N), 6.80 (width, 1 N), 7.02 - 7.11 (m, 2 N), 7.26 - 7.35 (m, 2 N), 7.55 - 7.62 (m, 3 N), 7.66 - 7.75 (m, 3 N);

S-54. ¹ H NMR (400 MHz, DMSO-d6)δm. d. 0.40 - 1.86 (m, 50 N), 1.91 (lat. s, 2 N), 2.11 -2.19 (m, 1 N), 2.31 - 2.40 (m, 1 N), 2.55 - 2.70 (m, 5 N), 2.76 - 2.84 (m, 1 N), 2.92 - 3.02 (m, 1 N), 3.29 (lat. s, 1 N), 3.37 (lat. s, 1 N), 3.39 (s, 3 N), 3.41 - 3.44 (m, 1 N), 3.86 - 4.19 (m, 5 N), 4.21 - 4.33 (m, 1 N), 4.41 - 4.50 (m, 1 N), 4.71 (lat d, 1 N), 4.78 - 4.85 (m, 2 N), 6.58 (lat d, 2 N), 6.83 - 6.92 (m, 2 N), 7.28 - 7.32 (m, 2 N), 7.56 - 7.61 (m, 3 N), 7.70 - 7.75 (m, 2 N);

C-55. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.34 - 1.88 (m, 46 N), 1.91 (s, 1 H, AcOH), 2.14 (br d, 1 H), 2.36 (br d, 1 H), 2.55 (br d, 2 H), 2.60 (s, 3 H), 2.61 - 2.70 (m, 2 N), 2.91 -3.01 (m, 1 N), 3.16 - 3.25 (m, 1 N), 3.25 - 3.31 (m, 2 N), 3.38 (s, 3 N), 3.41 (lat. s, 1 N), 3.85 -4.03 (m, 2 N), 4.12 - 4.32 (m, 2 N), 4.39 - 4.50 (m, 2 N), 4.70 - 4.85 (m, 3 N), 6.35 (broad d, 1 N), 6.47 (s, 1 N), 7.28 - 7.35 (m, 3 N), 7.55 - 7.63 (m, 4 N), 7.66 - 7.75 (m, 3 N), 7.84 (d, 1 N);

C-56. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.45 - 2.04 (m, 53 N), 2.12 (br d, 1 H), 2.31 (br d, 1 H), 2.52 - 2.58 (m, 3 H), 2.60 (s, 4 H), 2.85 (br d, 1 N), 3.27 (lat. s, 1 N), 3.33 (lat. s, 3 N), 3.50 (lat. d, 1 N), 3.82 (s, 3 N), 3.92 (lat. dd, 1 N), 3.98 - 4.07 (m, 2 N), 4.09 - 4.18 (m, 1 N), 4.29 (lat. s, 1 N), 4.47 (k, 1 N), 4.75 (lat, 1 N), 4.77 - 4.83 (m, 2 N), 6.88 - 7.05 (m, 5 N), 7.44 (s, 1 N);

S-57. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.8-1.5 (m, 48H), 1.6-1.9 (m, 12H) (including 2 protons of acetate salt), 2.1-2.4 (m, 7H), 2.5-2.7 (m, 7H), 3.1-3.4 (m, 6H), 3.7-3.8 (m, 3H), 4.13 (s, 1H), 4.2-4.5 (m, 3H), 4.7-4.8 (m, 2H), 7.0 (br s, 2H), 7.4 (br s, 2H);

S-58. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.8-1.5 (m, 50H), 1.6-1.9 (m, 12H) (including 2 protons of acetate salt), 2.1-2.4 (m, 6H), 2.6-2.8 (m, 8H), 3.1-3.5 (m, 6H), 3.6-4.0 (m, 6H), 4.3-4.5 (m, 3H), 4.8-4.9 (m, 2H), 7.05 (br. s, 2H), 7.42 (br. s, 2H);

D-1. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.75 - 1.22 (m, 36 N), 1.26 - 1.84 (m, 10 N), 1.91 (s, 3 H, AcOH), 1.93 - 1.98 (m, 1 H), 2.03 - 2.10 (m, 2 N), 2.14 - 2.20 (m, 1 N), 2.40 - 2.48 (m, 2 N), 2.52 - 2.56 (m, 1 N), 2.57 - 2.65 (m, 2 N), 2.67 (s, 3 N), 2.68 - 2.74 (m, 2 N), 2.87 (lat. d, 1 N), 3.25 (s, 3 N), 3.37 - 3.44 (m, 2 N), 3.75 (width, 1 N), 3.91 - 3.96 (m, 1 N), 3.98 (width, 1 N), 4.11 (dd, 1 N), 4.27 - 4.37 (m, 2 N), 4.81-4.87 (m, 2 N), 4.94 (d, 1 N);

D-2. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.68 - 1.25 (m, 40 N), 1.26 - 1.85 (m, 11 N), 1.91 (s, 3 H, AcOH), 2.02 - 2.08 (m, 2 H), 2.14 - 2.20 (m, 1 N), 2.32 - 2.41 (m, 1 N), 2.42 - 2.48 (m, 1 N), 2.52 - 2.56 (m, 1 N), 2.61 (width, 2 N), 2.67 (s, 3 N), 2.69 - 2.78 (m, 3 N), 3.23 (s, 3 N), 3.40 (width dd, 1 N), 3.46 (width, 2 N), 3.87 (width, 1 N), 3.93 - 3.99 (m, 1 N), 3.99 - 4.03 (m, 1 N), 4.11 (dd, 1 N), 4.27 - 4.34 (m, 2 N), 4.77 (width, 1 N), 4.90 (dd, 1 N), 4.99 (br. d, 1 N), 6.52 -6.89 (m, 1 N);

D-3. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.74 - 1.24 (m, 37 H), 1.25 - 1.58 (m, 9 H), 1.71 -1.89 (m, 2 H), 1.91 (s, 1 H, AcOH), 1.92 - 2.22 (m, 6 H), 2.34 - 2.48 (m, 3 H), 2.55 - 2.82 (m, 6 H), 3.24 (s, 3 H), 3.43 - 3.49 (m, 2 H), 3.59 (td, 1 H), 3.75 (s, 3 H), 3.86 (br d, 1 H), 3.92 (br s, 1 H), 4.01 (br d, 1 N), 4.07 - 4.24 (m, 3 N), 4.26 - 4.35 (m, 2 N), 4.77 (width, 1 N), 4.90 (dd, 1 N), 5.00 (width, 1 N), 6.91 (d, 2 N), 7.30 (d, 2 N);

D-4. ¹ H NMR (600 MHz, DMSO-d6) δ ppm 0.74 - 1.88 (m, 52 H), 1.91 (s, 1 H, AcOH), 1.95 (br s, 1 H), 2.13 (br d, 1 H), 2.86 (br s, 2 H), 2.94 (br d, 1 N), 3.06 (lat. s, 1 N), 3.25 (lat. s, 3 N), 3.47 (lat. s, 1 N), 3.70 - 3.72 (m, 3 N), 3.86 (lat. d, 1 N), 3.94 (width dd, 3 N), 4.40 (width dd, 1 N), 4.54 ( lat. d, 1 N), 4.69 - 4.78 (m, 1 N), 4.82 (lat dd, 1 N), 4.99 (lat s, 1 N), 5.31 - 5.39 (m, 1 N), 6.77 - 6.82 (m, 2 N), 7.27 (d, 2 N), 7.81 - 7.98 (m, 2 N);

D-5. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.63 - 1.87 (m, 49 N), 1.91 (s, 2 H, AcOH), 1.98 -2.04 (m, 1 H), 2.09 (br d, 1 H), 2.17 (br d, 1 H), 2.31 - 2.43 (m, 2 N), 2.52 - 2.58 (m, 2 N), 2.67 (s, 3 N), 2.70 - 2.81 (m, 5 N), 2.98 - 3.04 (m, 1 N), 3.24 (s, 3 N), 3.37 (lat. d, 1 N), 3.43 (lat. d, 1 N), 3.90 (width, 1 N), 4.01 (lat s, 1 N), 4.11 (lat dd, 1 N), 4.37 (k, 1 N), 4.83 -4.89 (m, 2 N), 4.99 (lat d, 1 N);

D-6. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.62 - 1.59 (m, 47 N), 1.66 - 2.24 (m, 8 N), 2.31 -2.43 (m, 2 H), 2.47 (br s, 1 H), 2.53 - 2.64 (m, 2 H), 2.67 (s, 3 N), 2.69 - 2.84 (m, 3 N), 3.23 (s, 3 N), 3.28 - 3.32 (m, 1 N), 3.35 - 3.41 (m, 1 N), 3.43 - 3.49 (m, 2 N), 3.84 (lat. d, 1 N), 4.03 (lat. d, 2 N), 4.11 (dd, 1 N), 4.25 (lat s, 1 N), 4.30 (s, 1 N), 4.36 (k, 1 N), 4.75 (lat s, 1 N), 4.90 (lat dd, 1 N), 5.03 (lat d, 1 N);

D-7. ¹ H NMR (600 MHz, DMSO-d6) δ ppm 0.70 - 1.89 (m, 44 H), 1.91 (s, 1 H, AcOH), 1.93 (br s, 1 H), 1.99 - 2.07 (m, 2 H), 2.15 - 2.26 (m, 1 H), 2.67 - 2.83 (m, 3 N), 2.99 - 3.13 (m, 3 N), 3.23 - 3.32 (m, 3 N), 3.39 - 3.51 (m, 2 N), 3.52 - 3.64 (m, 1 N), 3.68 - 3.73 (m, 1 N), 3.75 (s, 3 N), 3.76 - 3.84 (m, 1 N), 3.85 - 4.02 (m, 2 N), 4.08 - 4.25 (m, 4 N), 4.33 - 4.41 (m, 2 N), 4.84 - 4.93 (m, 3 N), 5.00 (broad d, 1 N), 5.13 (s, 1 N), 6.25 (broad s, 1 N), 6.89 - 6.94 (m, 2 N), 7.30 (d, 2 N);

A3-1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.77-1.5 (m, 38H), 1.7-2.3 (m, 9H), 2.4-2.8 (m, 6H), 3.13 (br s, 2H), 3.25-3.50 (m, 5H), 3.79 (br s, 1H), 3.85 (br s, 2H), 4.16 (br s, 1H), 4.37-4.49 (m, 2H), 4.83-4.85 (m, 3H), 4.97 (br s, 1H), 7.16 (t, 1H, J=8 Hz), 7.30 (t, 2H, J=8 Hz), 7.36 (d, 2H, J=8 Hz), 7.60 (d, 2H, J=8 Hz), 7.79 (d, 2H, J=8 Hz);

A4-1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.77-1.5 (m, 35H), 1.7-2.3 (m, 9H), 2.4-2.8 (m, 7H), 3.13 (br s, 1H), 3.25-3.50 (m, 5H), 3.62-3.85 (m, 4H), 4.10 (br s, 2H), 4.36-4.46 (m, 2H), 4.82-4.89 (m, 3H), 7.60 (d, 2H, J=8 Hz), 7.78 (d, 2H, J=8 Hz); and

A6-1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.77-1.5 (m, 35H), 1.7-2.3 (m, 12H), (including 1 proton of acetate salt), 2.4-2.8 (m, 8H), 3.13 (br. s, 1H), 3.25-3.50 (m, 8H), 3.82 (br s, 1H), 4.02 (br s, 2H), 4.35-4.46 (m, 2H), 4.54 (br s, 2H), 7.59 (d, 2H, J=8 Hz), 7.80 (d, 2H, J=8 Hz).

BIOLOGICAL EXPERIMENTS

Causal agents of BRD include, for example, Pasteurella multocida; Mannheimia haemolytica; Histophilus somni; and Mycoplasma bovis. There is debate as to whether M. bovis is the primary pathogen, a secondary agent, or a predisposing factor for other BRD agents. The polymicrobial nature of BRD makes it difficult to assign a specific pathogen(s) to an individual case of BRD, since affected animals typically have nonspecific clinical symptoms. The epidemiology of BRD is well established, with cases occurring within 6 to 10 days of arrival at the feedlot (Figure 1). Therefore, antimicrobial metaphylaxis is routine for arriving cattle considered at high risk for developing BRD. Parenteral metaphylaxis may also be initiated in low-risk cattle. Macrolides are typically the first choice antimicrobial agents for high-risk cattle.

The primary screening of the compounds of the invention included an assessment of the antibacterial activity of the analogs by determining the microbial inhibition concentration (MIC) in accordance with CLSI recommendations. The screening panel included relevant BRD pathogens: 1) M. haemolytica (e.g., 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, H. somni (A700025K) was also included in the screening panel. The AHDRCC strains were derived from the Zoetis BRD/SRD Surveillance Program and are part of the Animal Health Development and Research Culture Collection. In addition, S. aureus (ATCC 29213) as a representative Gram-positive isolate, E. faecalis (ATCC 19433) as a commensal Gram-positive gastrointestinal bacterium, and E. coli (ATCC 100, 3110, and 25922) were evaluated in the screening to assess efflux potential. The BRD pathogen screening panel was evaluated in determining the antibacterial activity of the compounds of formula (1).

All relevant BRD pathogens were initially screened at a peak concentration of 64 μg/mL of compound of formula (1) in an eleven-point dilution series. Analogs were then characterized based on their minimum inhibitory concentration (MIC) values for BRD pathogens with the goal of achieving a level >64 μg/mL for progression and being considered a non-antibiotic compound. Compounds of formula (1) were considered non-antibacterial if the MIC of the pathogen was >64 μg/mL for M. haemolytica and P. multocida strains. Additionally, if compounds of formula (1) were also tested against H. somni strain, to be considered non-antibacterial, the MIC was also >64 μg/mL. In general, when the analogs had an MIC >64 μg/mL for BRD pathogens, the reported MICs for S. aureus, E. faecalis, and E. coli were also >64 μg/mL. In most cases, compounds of the invention with an initial screening result of a BRD pathogen MIC >64 μg/mL were not tested beyond this maximum concentration because this MIC value was critical due to the lack of antibacterial activity. Additionally, it should be noted that some of the examples described in the tables and labeled as antibacterial (i.e., MIC ≤64 μg/mL) may in fact be non-antibacterial but may have potential residual antibacterial starting materials (i.e., tulathromycin epoxide, M9 epoxide, M8 epoxide, or azithromycin) that were used in their preparation. When the sample was further purified, 3MIC values increased by essentially two dilutions for all strains tested in the screening group.

In vitro model MIC

Compounds were assayed for antibacterial activity against a panel of animal health-specific Gram-positive and Gram-negative clinical strains by diluting compounds in DMSO to the appropriate stock concentration to determine the minimum inhibitory concentration (MIC) using a semiautomated broth microdilution assay (CLSI reference method) with quality control strains and antimicrobial agents. Specifically, bacteria were grown overnight on TSA agar plates with 5% w/w sheep blood and diluted in saline buffer to a McFarland standard of 0.5, then further diluted in cation-adjusted Mueller-Hinton broth to a final concentration of approximately 5 x ¹⁰⁵ CFU/mL. 100 µL of inoculated medium was added to 96-well plate(s) with 3 µL of serially diluted compound in each row. Depending on the strain (see CLSI reference method), bacteria were incubated for 18–22 hours at 35–37°C in atmospheric air, with 5% _CO2 , or under anaerobic conditions (up to 48 hours).

In-vitro immunoassay(s)

Whole blood assay. Fresh whole bovine blood samples were collected into heparinized vacutainer tubes. Assay plates were prepared with 25 μl of drug diluted in PBS at various concentrations in 96 round-bottomed wells, then 225 μl of blood were added and the plates were incubated at 37°C for 4 h. Cells were stimulated with LPS (or PBS for control) by adding 25 μl to the plates to a final concentration of 1 μg/ml and incubated at 37°C for 18 h.

To collect plasma, plates were centrifuged at 2000 x g for 10 min and 100 μl of the 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). The same MSD platform was used to assess cytokines in plasma collected directly from drug-treated animals.

Cytokine Detection. The MSD U-Plex Cytokine Assay was developed according to the MSD U-Plex Protocol Manual and included biotinylated capture antibodies against: bovine interleukin (IL)-1β (Biorad), bovine IL-6 (R&D Systems), and bovine tumor necrosis factor (TNF)-α (R&D Systems). The anti-IL-1β antibody was biotinylated using EZ-Link Sulfo-NHS-Biotin (Thermo Scientific) at a 1:20 infection ratio according to the manufacturer’s instructions. Assay calibrators (Kingfisher) were diluted to a concentration of 40,000 pg/mL in lithium heparin control plasma, followed by 4-fold serial dilutions in plasma. Detection antibodies were labeled with sulfo tags according to the MSD Quick Guide conjugation protocol using a 1:20 infection ratio. Antibodies were used at the following concentrations: anti-IL-1β at 1 μg/mL, anti-1L-6 at 1 μg/mL, and anti-TNF-α at 0.5 μg/mL. Cytokines were quantified according to the manufacturer’s instructions using a chemiluminescence assay. Briefly, 0.5 mL of total biotinylated antibodies were diluted to 10 μg/mL with diluent 100 and coupled to the appropriate linkers by adding 750 μL of the supplied linker solution and incubated for 30 min followed by the addition of stop solution for an additional 30 min. The coupled antibodies were then diluted 10-fold with stop solution. Plates were coated by adding 50 μl of antibody solutions per well and incubated with covering and shaking for 1 hour at room temperature. Plates were washed three times with PBS/Tween20 before adding samples or standards at 30 μl per well and incubated as above. Plates were washed three times before antibody detection, added with 2% goat and rabbit serum for blocking and incubated as above. Plates were washed three more times before adding 150 μl of 2X reading buffer and immediately read on an SI6000 instrument (MSD). The BCA protein assay (Thermofisher) was used to determine soluble protein levels. Cytokine concentrations (pg/ml) were normalized to total protein levels for each sample. [Bassel et al., BMC Veterinary Research (2020) 16:168]

CD163 expression by flow cytometry. Fresh bovine whole blood samples were collected into EDTA vacutainers, 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 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 an antibody master mix panel consisting of anti-CD14 (BioLegend #301854), anti-CD172a (BioRad #MCA2041C), anti-CD163 (Kingfisher #WSC0832B-100), and anti-CD16 (BioRad #MCA5665F) was added to the samples and returned to 4°C (protected from light) for 30 minutes. Single staining controls were included for use in fluorescence compensation arrays. Red blood cells were removed by adding 200 μl of lysis buffer and incubating for 10 minutes at heating temperature with shaking. The plate was then centrifuged at 270 x g for three minutes and the supernatant removed. This step was repeated until the supernatant was clear. 200 μl FACS buffer was added to each well to wash the cells, centrifuged as above, resuspended in 80 μl FACS buffer and immediately read on a FACS Canto II HTS digital flow cytometer (BD Bioscience). Data were analyzed using FlowJo software (BD Bioscience). Macrophage subpopulations were defined using CD172, CD14, CD16 markers and CD163 expression was assessed.

In vivo mouse lung infection model (murine)

The test organism was P. multocida 46572. The target inoculation concentration was 5 x 10 ² CFU/mouse. Isolated colonies grown overnight (37°C with 5% CO ₂ ) on trypticase soy agar (TSA II) blood plates (BHIB) were transferred to room temperature. The broth culture was incubated for 3.5 to 4 h to approximately mid-log growth as measured by forward light scatter at 600 nm (OD600, 0.200). The culture was centrifuged to collect the bacterial pellet. The pellet was resuspended in BHIB and adjusted to approximately 2.7 log ¹⁰ colony forming units (CFU) in 0.04 ml at the highest concentration. The concentration of the control inoculum was confirmed by serial dilutions of the inoculum for CFU enumeration. On day -5, female CD-I mice were obtained. Mice were fed standard rodent chow and water ad libitum. On day 0, each mouse (n=36) was intranasally challenged with a bacterial inoculum (0.04 ml). 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. Animals were observed from days 1-10. The study was terminated on day 10. In addition, samples were taken from some treatment groups at 6, 24 and 48 hours after bacterial challenge for lung tissue RNA sequencing analysis.

In vivo time course study

A clinical and genomic time-lapse study was conducted to mimic typical cattle management practices that lead to the development of BRD. The study design included extensive longitudinal genomic sampling, including the respiratory tract, and a comprehensive clinical assessment to link disease mechanism to clinical phenotype. The study resulted in a 20% incidence of classic BRD by standard clinical assessment criteria. To facilitate data analysis, animals were stratified into phenotypic groups based on clinical signs, lung lesions, and treatment qualifications according to feedlot standards. The study provided a basis for interpreting the biological processes that led to healthy, subclinical, and diseased animals at a typical feedlot arrival point. For example, comparison of whole-transcriptome RNA sequencing data from nasopharyngeal swabs collected at a time similar to feedlot arrival (when drug administration often occurs but before full BRD occurs) could be consistent with the known clinical outcome derived from the study results.

The study demonstrated that, contrary to dogma, there is an activation of innate inflammatory pathways associated with the stress experienced by cattle at risk for BRD during shipping and upon arrival at the feedlot following shipping. This heightened inflammatory state is observed in virtually all animals, regardless of the final clinical outcome. Further analysis of the comprehensive data showed that animals that progressed to BRD continued to have elevated innate inflammatory pathway signatures expressed in the airways, while healthy and subclinical animals (healthy cohort) showed a self-limited reduction in inflammatory signals over several days as illustrated in Figure 2. Following weaning, cattle are transported to market barns and then to the feedlot. Prior to arrival at the feedlot, animals experience stress, some of which may recover while others develop disease.

3The initial presentation is the presence of an unresolved inflammatory flare state on days 4-6 in the BRD cohort, leading to differential bacterial challenge with H.somni and M.haemolytica and progression to full BRD disease complex. RNA sequence analysis confirmed that both healthy and diseased cohorts have similar viral and bacterial challenge from day -1 to day 4. The healthy cohort (non-disease and subclinical) was able to resolve the inflammatory state early on, either day 0 or day 1. In the BRD cohort, the pathological inflammation did not resolve and progressed to full BRD complex. 3A significant increase in typical BRD-associated organisms (M. bovis, H. somni, and M. haemolytica) was not observed until the innate inflammatory pathways had resolved on days 4-6. It is believed that it is the unresolved inflammatory process that transforms into a chronic process that ensures progression into the full complex of BRD.

This interim study identified pathways of intervention. These included TLR-4 pattern recognition receptor (PRR) activation, inflammatory signaling, NF-κB and STAT transcription, which were aimed at reducing the pathological innate inflammatory cascade prior to disease onset. Some key inflammatory cytokines included IL-1β, IL-6, IL-8, IL-17, IL-36, IFN-γ and TNF-α, many of which were further validated using in vitro cellular assays and an ex vivo bovine challenge model. The study also identified biomarkers that correlate with disease severity (CD163, IL-6 and haptoglobin).

Plasma samples were collected from at-risk calves upon arrival at the feedlot and assessed for cytokine levels. Data were correlated with final disease (BRD) as assessed by a clinical score within seven days. Of the cohort, 14 animals were healthy and 24 were diagnosed with BRD. As predicted from the etiology and pathogenesis of BRD, NF-κB mediated cytokines, including IL-6, were highest in animals that developed clinical BRD. Interestingly, there was a correlation between higher IFN-γ levels in animals upon arrival associated with animals that did not develop clinical BRD (Figure 3). These data also confirm 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 with elevated levels of IFN-γ, a cytokine associated with pathogen clearance, are associated with continued health and lack of progression to BRD.

In vitro studies

The compounds of the present invention had MIC values for a variety of pathogenic bacterial strains, including BRDM. haemolytica yl P. multocida, as well as other pathogenic bacterial strains, including E. coli, S. aureus, and E. faecalis, which were considered non-antibacterial (i.e., MIC >64 μg/mL). The 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) and S. aureus (A29213K/T). K and T represent a specific strain at two different sites of the study. With the exception of a few compounds of the present invention, most of them had MIC values >64 μg/mL for pathogenic BRD strains (i.e., non-antibacterial) as well as for non-BRD strains.

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

Thus, the non-antibacterial compounds in Tables A–D demonstrated no in vitro activity against clinically significant BRD pathogen strains (M. haemolytica and P. multocidd) and no clinically significant MIC values against other zoonotic bacterial strains.

The compounds of the invention share the most frequently described immune effects with the parent class of macrolides, including modulation of proinflammatory cytokine production and granulocyte trafficking/fate. Decreases in IL-1β, IL-6, and TNFα were observed with the compounds of the invention, which were associated with positive clinical outcome (mouse). Thus, the primary mechanism of action of the compounds of the invention appears to be modulation of a broad spectrum of the innate inflammatory response.

Early in vitro systems using single cell types had limited success in their ability to demonstrate the immunomodulatory effects of compounds, suggesting that a more complex multicellular system was needed to recapitulate the immunological pathways involved. Therefore, a fresh whole bovine blood assay was developed using LPS as the stimulator (TLR-4 agonist) and IL-1β and TNF-α as indicators. Compounds of the invention were evaluated against a positive control for their ability to inhibit LPS-induced IL-1β and TNF-α as a general assessment of relative activity and modulation of target pathways.

A second in vitro immunomodulation assay assessed the ability of compounds of the invention (250 μM or 500 μM) to induce phospholipidosis in bovine alveolar macrophages. The phospholipidosis assay is a convenient method for assessing cellular uptake. This assay utilized the commercially available Invitrogen LipidTox HCS detection kit with the Incucyte real-time fluorescence reader to observe changes in _EC50 and phospholipidosis profiles with compound concentrations (Table 2). Murine intraperitoneal macrophages were also used in the same assay to assess species variation for potential correlation with mouse efficacy results. The combination of the bovine whole blood assay and the phospholipidosis assay provided a streamlined ranking for progression to in vivo testing in a mouse challenge model.

The results presented in Table 2 demonstrate 3A significant increase in TNFα inhibition for the test compounds compared to M9 at a drug concentration of 250 μM. For M9, the maximum dose of 500 μM was not high enough to detect excessive IL-1β stimulation, which was reported as not applicable (NA). An enhanced response indicates an increased IL-1β cytokine concentration at a given drug concentration. This is typically seen when compounds are outside the acceptable range (high concentration) and stimulate a cellular toxicity signal. Additional data supporting this hypothesis include mouse studies using P. multocida infection in mice. For example, M9 was clinically effective when airway tissues were collected longitudinally and assessed by transcriptomic analysis. Using these results, specific transcriptional expression corresponding to some key BRD pathways (PRR, cytokines, STAT) was demonstrated and cellular crosstalk activity was assessed.

TNFα is a cell signaling protein, a cytokine, which plays a key role in both acute and chronic inflammation. In an in vitro screening assay in bovine whole blood, inhibition of TNFa induced by lipopolysaccharide (LPS) stimulation and measured by half-maximal inhibitory concentration (IC ₅₀ ) is a key 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 processes including proliferation, differentiation and apoptosis. IL-1β is also released upon cellular stress, cytotoxicity or upon TLR stimulation. In the bovine whole blood assay, stimulation of IL-1β release with increasing concentrations of a test compound is considered a potential signal of cellular toxicity induced by the test compound. The difference between the IC ₅₀ of TNFα (immunomodulatory efficacy) and the perceived concentration of cellular toxicity (IL-1β release or overstimulation) was used to estimate the therapeutic index using an in vitro assay. A lower IC ₅₀ of TNFα would indicate a lower total mg/kg dose in vivo, provided that the therapeutic index was >2. Since the in vitro assay index approaches 1, it is expected that the balance between immunomodulation and cytotoxicity would be too narrow to achieve an effective dose in vivo.

Screening assays used to identify compounds are used because of their ability to recapitulate key components of BRD. Activation of pathways including TLRs and the downstream transcription factor NFKB have been associated with disease state in BRD. Regulation or attenuation of these pathways has been associated with disease protection, and therefore inhibition of markers of pathway activation has been used to identify compounds of interest. Lipopolysaccharide (LPS) is a bacterial membrane component (including M. haemolytica and P. multocida, where it is associated with virulence) that binds to and signals through CD14 and Toll-like receptor 4 (TLR4). These receptors are expressed on macrophages, which are a cell type that express CD163 (a BRD disease marker) and are relevant to the pathobiology of BRD. Following LPS binding, NFkB signaling results in upregulation of cytokines including IL-1, IL-6, and TNF-α, which has been implicated in many different diseases, including BRD. Decreased NFkB-regulated cytokines are often implicated in diseases with an inflammatory component to the pathobiology. An emerging understanding is that inflammation, and in particular IL-1β, IL-6, and TNFa, is a component of the etiology of BRD.

Study on mice

Compounds of the invention were selected to achieve potency in mice or greater based on 3 Significant increases in MIC (target >64 μg/mL) for all bacterial strains in the screening panel. This assessment was coupled with in vitro immunomodulatory potency equal to or greater than that of M9, TNF-α, and IL-1β, IC ₅₀ -250 μM for both cytokines, and an EC ₅₀ for phospholipidosis <3.74 mM.

The mouse efficacy model (P.multocida challenge) was optimized and the treatment group size was increased such that statistically significant improvements 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 pooled within a cage, with each treatment group equally represented within the cages. Mortality was the primary variable. Mortality data were analyzed using a generalized mixed model with a fixed effect of treatment and a random effect of block. Survival times were also analyzed using the SAS PHREG procedure (survival analysis) to test whether there were 3significant differences between the treatment and control groups. Numerous compounds of the invention and M9 (positive control) were tested in this model at a dose of 20 mg/kg (Table 3). Typical survival percentages in the absence of a treatment control are in the range of 0-20% based on a study examining variations in the challenge inoculum and the rate of challenge. The tested analogues had MIC compared to the control strain ≥64 μg/ml compared to M9 at (8 μg/ml). The survival rate of mice for M9 was about 90-100%, which further confirms its residual antibacterial properties against the bacterial strain. Harmonized (% survival relative to the vehicle (“-” control) and M9 (“+” control) survival data are taken into account. “*” o3Starts MIC ≤64 μg/ml for the control strain P.multocida (46572K); and the survival could also be partly related to the antibacterial activity.

Table 3. Mouse survival rate (murine)

In one study of intranasal challenge of mice with P. multocida, mice were given tulathromycin (16 mg/kg; T02), M9 (32 mg/kg; TO3), or ceftiofur (9 mg/kg; T04) by subcutaneous injection 18 hours after bacterial challenge ( ^5x103 CFU/mouse) for lung tissue RNA-seq analysis. Survival at day 7 was approximately 80%, 50%, and 90% for T02, T03, and T04, respectively, compared to placebo at 0%. Differential gene expression inferred from total lung tissue RNA-seq analysis revealed that at least 226 unique genes were significantly up- or downregulated in T03. Ingenious analyses of these unique genes allowed prediction of key regulators of the pathways involved. The data were analyzed based on the number of genes modulated in the same direction and associated with a given upstream regulator. An activation z-score of 2 or greater is considered 3On, and a reversal of direction is considered 3On+ (activated) or 3On+ (inhibited). The top 5 directions were: IL-9 signaling, glucocorticoid receptor signaling, prolactin signaling, JAK STAT signaling, and IL-17 signaling. The top 6 upstream regulators (activation z-score) were: lipopolysaccharide (-6.725), TNF (-4.669), IFNγ (-5.759), IL-1β (-5.947), STAT1 (-2.787), and poly rl:rC-RNA (-5.289). Although this study was performed in a mouse model, the upstream regulators identified as modulated by M9 almost universally overlap with pathways identified in natural disease studies as key mediators in BRD and therefore modulate highly important pathways in BRD.

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 the compounds of the invention. Whole blood contains a variety of immune cell types, including both myeloid (e.g., neutrophils and macrophages) and lymphoid (e.g., T and B cells) cells, as well as further differentiated cell type-specific subsets. Cells with transcriptional similarity were grouped together and identity was predicted based on reference lists of markers that were cross-checked with the most differentially expressed genes against our established bovine antibody marker panels. Samples were sequenced at 30 min, 4 h, and 20 h stimulation (LPS, as described above), with relatively greater changes observed at 20 h. Among the genes with the highest differential expression values were, but were not limited to, cytokines such as IL-1β, chemokines such as CXCL2 and CXCL8, and members of the interferon-stimulated gene (ISG) family (data not shown).

By focusing on cell clusters identified in drug-induced correlations, lists of 3 significantly modulated genes (adjusted p<0.05 and absolute log(fold change)>0.25) were used to identify predicted upstream regulators of associated pathways. These regulators include, but are not limited to, components central to putative BRD pathological pathways such as TNFα, LPS (TLR4 agonist), NFkB, IL-1β, and IL-6. As described previously, attenuation of these inflammatory pathways that are upregulated in BRD correlates with positive clinical outcome. In this experimental system, LPS was administered to activate inflammatory pathways observed in calves at risk for BRD, and whole transcriptome sequencing was used to determine the effect of the drug on these key pathways. In myeloid cell populations, the neutrophil/activated macrophage cluster, and the monocyte cluster, the drug attenuated the activation of most of the inflammatory pathways described above. In B cell populations, the drug attenuated LPS-induced activation of almost all of the identified major pathway regulators. This result makes sense because the PRR-related pathways described here are consistently expressed between 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, so the pathways affected by the drug are less affected in this cell type. Interestingly, the group of pathway regulators upregulated by the drug in the context of stimulation (within myeloid and T cell clusters) are pathways often associated with immunity against viral pathogens, interferons, and STATs (a signaling molecule of the interferon family). This finding extends the mechanism of action described above, where the drug attenuates innate proinflammatory pathways associated with bacterial pathobiology and may also enhance immune defense against viral pathogens, which are known to be a major component of BRD.

A metabolite of desmethyltulathromycin M9 with reduced antimicrobial activity was used in a study of natural bovine respiratory disease. The primary clinical efficacy endpoint was treatment failure/success over a 14-day observation period. Clinically normal beef calves (150-200 kg) at moderate risk for developing BRD were dosed on arrival at the feedlot. Animals (N=114/group) received saline (T01), 5 mg/kg M9 (T02), or 10 mg/kg M9 (T03); or zactran (T04). 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 MIC values were assessed (Table 4). In a separate pharmacokinetic study, the peak plasma concentration after a 10 mg/kg dose was 5 μg/mL. Based on the observed MIC values (Table 4) and peak plasma concentration, it was hypothesized that residual MIC activity of M9 was not responsible for the observed overall outcome and that the efficacy was primarily due to the immunomodulatory effects of M9. M9 demonstrated efficacy in a BRD natural infection study with statistical superiority demonstrated over untreated controls in reducing lung lesions and treatment failures (position, rectal temperature, respiratory rate/effort, and nasal/ocular discharge). However, as can be seen for some BRD bacterial isolates, M9 has antibacterial (i.e., MIC <64 μg/mL) properties.

To evaluate the effects of immunomodulation and potential biomarkers, a study was completed in bovine M. haemolytica (strain: OSU-012103-BHI) in a lung intratracheal challenge model using M9 treatment with and without bacterial challenge and Draxxin® as a comparator. Importantly, the MIC for M9 for the control strain is >64 μg/mL, indicating that the observed effects were primarily due to immunomodulation rather than reduction in bacterial challenge. Animals were administered 0.05 mL/kg saline (T01), 10 mg/kg M9 (T02); 2.5 mg/kg Draxxin (T03), and 10 mg/kg M9 (T04) subcutaneously on day -1. Dosing was based on body weight. Animals were tested on day 0 except T04. Blood was collected throughout the study for the biomarker assessment cohort (e.g., IL-6 and CD163), including two pre-treatment baseline samples. The study results are presented in Table 5 and Fig. 4. Fig. 4A shows the area under the curve of IL-6 protein concentration for individual animals versus percent lung injury score, and Fig. 4B shows the area under the curve of CD163 fold change for individual animals versus percent lung injury score. Data are presented as percent lung injury scores relative to the area under the curve (AUC) for IL-6 protein (assay expressed in pg/mL) and CD163 (flow cytometry mean fluorescence intensity (MFI) per fold change from baseline). A two-fold change is generally considered relevant for both assays.

IL-6 levels were elevated and correlated with higher rectal temperature (data not shown) and mortality. M9 and Draxxin®® 3 significantly reduced IL-6 levels, which also correlated with overall animal survival or disease progression. CD163 receptor expression followed initial innate inflammatory cascade signaling in animals that developed clinical signs of BRD within days. Increased CD163 expression on monocytes/macrophages correlates with clinical disease progression in longitudinal whole blood sampling. M9 attenuates the pathological increase in CD163 expression.

In conclusion, M9 demonstrated statistically significant efficacy in both natural BRD infection and the saline (T01) M. haemolytica challenge model. In a separate study, 10 mg/kg M9 demonstrated statistical superiority over saline control in reducing lung lesions (20% vs. 31%, p=0.023) and mortality (13% vs. 38.9%, p=0.025). In addition, a reduction in biomarkers 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 profile of a non-antibiotic immunomodulator (>64 μg/mL).

Drug binding partners as potential biological targets

The data presented herein regarding the immunomechanical activity of the compounds of the invention are consistent with the pathways presented herein that have been found to be important in the pathobiology of BRD. Key pathways associated with natural disease onset include NFκB, TLR4 (often represented by its agonist such as LPS), JAK-STAT, TNFa, and IL-16. Subsequent signaling of these pathways results in the induction of proinflammatory cytokines such as TNFα and IL-1β, as well as IL-6 and chemokines such as CXCL8. These same pathways and their respective components are modulated by these compounds both in vitro and in vivo. In addition, cell types known to participate in these pathways, including macrophages, neutrophils, and lymphocytes, have been used in a whole blood LPS stimulation format (both in vitro and ex vivo) to demonstrate drug-induced changes in gene expression, cytokine expression, and cell surface receptor activation. In addition to classical immune cells, tissue-resident epithelial and endothelial cells can express innate immune receptors and activate the canonical pathway.

Claims (139)

1. Compound of formula (1) where W is a compound of formula (A) where X is -(CH ₂ ) _m NR ⁵ R ⁶ ; R is H, phenyl, or a 5- or 6-membered monocyclic heteroaryl ring, wherein the heteroaryl ring contains one N or S heteroatom; and wherein each phenyl and heteroaryl ring is substituted with (R ⁹ ) _n ; each R ^a , R ⁰ and R ¹ independently represents H or C ₁ -C ₆ alkyl; or R ¹ is benzyl optionally substituted with (R ⁹ ) _n ; or R ¹ is -CH ₂ Het, wherein Het is a 6-membered heteroaryl ring containing one N heteroatom; and wherein the heteroaryl ring is optionally substituted with (R ⁹ ) _n ; or R ¹ is C ₃ -C ₆ cycloalkyl optionally substituted with (R ⁹ ) _n ; R ^b is H, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₀ -C ₃ alkylphenyl, C ₃ -C ₆ cycloalkyl, C ₀ -C ₃ alkylheterocycle, C ₀ -C ₃ alkylheteroaryl; wherein the heterocycle is a 6-membered saturated or partially saturated monocyclic ring; the heteroaryl is a 5- or 6-membered monocyclic ring; and wherein each of the heterocyclic and heteroaryl rings contains one or two N heteroatoms; and wherein the phenyl, heterocyclic and heteroaryl rings are each substituted with (R ⁹ ) _n ; R ^c is C ₁ -C ₄ alkyl; R ² is C ₁ -C ₆ alkyl, -R ^c OR ^b , C ₁ -C ₆ haloalkyl, C ₀ -C ₃ alkylC ₃ -C ₆ cycloalkyl, -R ^c NR ^a R ^b , -R ^c S(O) _p R ⁸ , -NR ^a R ^b , -NR ^b R ^b , C ₀ -C ₃ alkylphenyl, C ₀ -C ₃ alkylheterocycle which is a 5- or 6-membered saturated or partially saturated heterocyclic ring; C ₀ -C ₃ alkylheteroaryl, wherein heteroaryl is a 5- or 6-membered heteroaryl ring; and wherein each of the heterocyclic and heteroaryl rings contains one or two heteroatoms selected from N, O and S; and wherein each phenyl, heterocyclic and heteroaryl ring is substituted with (R ⁹ ) _n , and wherein each ring is optionally fused with Y; or R and R ² join to form a bond to form a fused dioxo-oxathiazole ring, which is R ⁵ and R ⁶ are each independently selected from H; C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, -R ^c NR ^a C(O)R ⁸ , -R ^c C(O)NR ^a R ^b , -R ^c S(O) _p R ⁸ , -R ^c NR ^a R ^b , -R ^c OR ^b , -S(O) _p R ⁸ or -R ^c S(O) _p NR ^a R ^b ; or C ₀ -C ₄ alkylphenyl, C ₀ -C ₄ alkyl, _{C 3} -C ₆ cycloalkyl, C ₀ -C ₄ alkyl heterocycle and C ₀ -C ₄ alkyl heteroaryl; wherein the heterocyclic and heteroaryl rings are a 5- or 6-membered monocyclic ring, each containing one or two heteroatoms selected from the group consisting of N, O and S; and wherein each phenyl, heterocyclic and heteroaryl ring is substituted with (R ⁹ ) _n ; or R ⁵ and R ⁶ , taken together with the nitrogen atom to which they are attached, form a ring B which is a 4-6 membered heterocyclic ring or a 5-membered heteroaryl ring, each of which optionally contains one, two or three additional heteroatoms selected from N, O and S; and wherein each ring is optionally substituted with (R ⁹ ) _n , and wherein each ring is optionally fused with Y; R ⁸ is C ₁ -C ₆ alkyl, -NR ^a R ^b or phenyl; R ⁹ is independently selected from the group consisting of C ₁ -C ₆ alkyl optionally substituted with hydroxy; C ₁ -C ₆ alkoxy, halogen, oxo, nitro, cyano, -NR ^a R ^b , C ₁ -C ₆ haloalkyl, -S(O) _p R ⁸ , -SF ₅ , phenyl; a 5- or 6-membered heterocyclic or heteroaryl ring, each containing one or two heteroatoms selected from the group consisting of N and O; and wherein the heteroaryl ring is further optionally substituted with -CF ₃ ; Y represents phenyl, pyridinyl or thiophenyl; m is equal to the integer 1; n is an integer 0, 1, or 2; and p is equal to the integer 1 or 2; or its pharmaceutically acceptable salts. 2. A compound of formula (1) according to claim 1, characterized in that W is formula (A), which is formula (A1) and wherein R ⁰ is H, methyl, ethyl or propyl; and pharmaceutically acceptable salts thereof. 3. A compound of formula (1) according to claim 2, which is a compound of formula (1-A1) and its pharmaceutically acceptable salts. 4. A compound of formula (1-A1) according to claim 3, characterized in that R ⁰ is H, methyl, ethyl or propyl; R is H or phenyl or pyridinyl, each of which is substituted by (R ⁹ ) _n ; R ¹ is C ₁ -C ₆ alkyl or cyclohexyl; or R ¹ is benzyl or -CH ₂ pyridinyl, each of which is substituted with (R ⁹ ) _n ; R ² is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, n-butyl, -CH ₂ OCH ₃ , -(CH ₂ ) ₂ OCH ₃ , -CH ₂ CF ₃ , -CF ₃ , -NHR ^b , -NCH ₂ R ^b , where R ^b is methyl, cyclohexyl, phenyl or pyridinyl, and wherein the phenyl and pyridinyl rings are optionally substituted with F, Cl, cyano or -CF ₃ ; or R ² is cyclopropyl, -CH ₂ cyclopropyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, phenyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, pyridinyl or pyrimidinyl, each of which is substituted with (R ⁹ ) _n ; or R ² is phenyl or pyridinyl, each of which is substituted with morpholine; R ⁵ is H or C ₁ -C ₆ alkyl; and R ⁶ represents H; C ₁ -C ₆ alkyl, optionally substituted with hydroxy; C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, -OCF ₃ , -R ^c S(O) _p R ⁸ , -R ^c NR ^a R ^b , -R ^c OR ^b or -S(O) _p R ⁸ ; or C ₀ -C ₃ alkylphenyl, C ₀ -C ₃ alkylC ₃ -C ₆ cycloalkyl, oxazolidinyl, C ₀ -C ₃ alkylpyrrolidinyl, C ₀ -C ₃ alkylpiperidinyl, C ₀ -C ₃ alkylpiperazinyl, C ₀ -C ₃ alkylmorpholinyl, C ₀ -C ₃ alkyltetrahydropyranyl, tetrahydrofuranyl, pyrazolyl, imidazolyl, pyridazinyl, C ₀ -C ₃ alkylpyridinyl, pyrimidinyl, C ₀ -C ₃ alkylthiazolyl or pyrazinyl, each of which is substituted with (R ⁹ ) _n ; and each R ⁹ is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, -NH ₂ , -N(CH ₃ ) ₂ , -CF ₃ , -CHF ₂ , -OCHF ₂ , -S(O) ₂ NH ₂ , -S(O)CH ₃ and -S(O) ₂ CH ₃ ; and its pharmaceutically acceptable salts. 5. A compound of formula (1-A1) according to claim 4, characterized in that R ¹ is methyl; R ² is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, n-butyl, -CH ₂ OCH ₃ , -(CH ₂ ) ₂ OCH ₃ , -CH ₂ CF ₃ , -CF ₃ , -NHR ^b , -NCH ₂ R ^b , wherein R ^b is methyl, cyclohexyl, phenyl or pyridinyl, and wherein the phenyl and pyridinyl rings are optionally substituted with F, Cl, cyano or -CF ₃ ; or R ² is cyclopropyl, -CH ₂ cyclopropyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, phenyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, pyridinyl or pyrimidinyl, each of which is substituted with (R ⁹ ) _n ; or R ² is phenyl or pyridinyl, each of which is substituted with morpholine; and R⁶represents H; C₁-C₆alkyl, methoxy, ethoxy, C₁-C₆haloalkyl, -CH₂OCF₃, -(CH₂)₂OCF₃, -R^cS(O)_pCH₃; -R^cS(O)_pNR^aR^b; -R^cS(O)_pphenyl, -R^cNR^aR^bor R^cOR^b; where each R^aand R^bindependently represents H, methyl and ethyl; or R⁶represents or C₀-C₃alkylphenyl, C₀-C₃alkylC₃-C₆cycloalkyl, C₀-C₃alkylpyrrolidinyl, C₀-C₃alkylpiperidinyl, piperazinyl, morpholinyl, C₀-C₃alkyltetrahydropyranyl, pyrazolyl, imidazolyl, pyridazinyl, C₀-C₃alkylpyridinyl or C₀-C₃alkylthiazolyl, each of which is substituted (R⁹)_n; in this case, each R⁹independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, -NH₂, -N(CH₃)₂, -CF₃, -CHF₂, -S(O)₂NH₂, -S(O)CH₃and -S(O)₂CH₃; and its pharmaceutically acceptable salts. 6. A compound of formula (1-A1) according to claim 5, which is a compound selected from the group consisting of the following: N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N,4-dimethylbenzenesulfonamide; (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-[[(4-chlorophenyl)methyl-methylsulfamoyl]methylamino]-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one; (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl(phenylsulfamoyl)amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane; (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-[[cyclohexyl(methyl)sulfamoyl]methylamino]-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one; (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane; 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(((3-(piperidin-1-yl)propyl)amino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide; 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide; N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)ox an-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(4-fluorophenoxy)-6-methyloxan-4-yl]-N,1-dimethylimidazol-2-sulfonamide; (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[methyl-[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one; and N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-(4-methoxybenzyl)benzenesulfonamide, and pharmaceutically acceptable salts thereof. 7. The compound according to claim 3, which is represented by a compound of formula (1-A1a) where R ⁰ represents H; R is H or phenyl or pyridinyl, each of which is substituted by (R ⁹ ) _n ; R ¹ is methyl; R ² is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, n-butyl, -CH ₂ OCH ₃ , -(CH ₂ ) ₂ OCH ₃ , -CH ₂ CF ₃ , -CF ₃ , -NHR ^b , -NCH ₂ R ^b , where R ^b is methyl, cyclohexyl, phenyl or pyridinyl, and wherein the phenyl and pyridinyl rings are optionally substituted with F, Cl, cyano or -CF ₃ ; or R ² is cyclopropyl, -CH ₂ cyclopropyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, phenyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, pyridinyl or pyrimidinyl, each of which is substituted with (R ⁹ ) _n ; or R ² is phenyl or pyridinyl, each of which is substituted with morpholine; Ring B is azetidinyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, imidazolyl, azathianyl or tetrazolyl, each of which is substituted with (R ⁹ ) _n ; and pharmaceutically acceptable salts thereof. 8. A compound of formula (1-A1a) according to claim 7, which is 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide or (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, and pharmaceutically acceptable salts. 9. A compound of formula (1) according to claim 1, characterized in that R and R ² are joined to form a bond to form a dioxo-oxathiazolyl ring, which is represented by formula (2-A1) where R ⁰ is H, methyl, ethyl or propyl; R ¹ is C ₁ -C ₆ alkyl; or R ¹ is benzyl or -CH ₂ pyridinyl, each of which is substituted with (R ⁹ ) _n ; R ⁵ is H, methyl, ethyl or propyl; R ⁶ is H, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -CF ₃ , -R ^c S(O) _p R ⁸ , -R ^c NR ^a R ^b , -R ^c OR ^b or -S(O) _p R ⁸ ; or R ⁶ is 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 alkylmorpholinyl, C ₁ -C ₂ alkyltetrahydropyranyl, C ₁ -C ₂ alkyltetrahydrofuranyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, C ₁ -C ₂ alkylpyrazolyl, _C1 - _C2 alkylimidazolyl, _C1 - _C2 alkylpyridinyl, _C1 - _C2 alkylpyrimidinyl or _C1 - _C2 alkylpyrazinyl, each of which is substituted with ( ^R9 ) _n ; each R ^a and R ^b independently represents H, methyl or ethyl; R ^c represents methyl, ethyl or propyl; R ⁸ is methyl or ethyl; or R ⁸ is phenyl; or R ⁵ and R ⁶ , taken together with the nitrogen atom to which they are attached, form a ring B which is azetidinyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, imidazolyl, azathianyl, tetrazolyl or 3,4-dihydroisoquinolinyl, each of which is substituted with (R ⁹ ) _n ; R ⁹ is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, n-butyl, t-butyl, methoxy, F, Cl, Br, I, oxo, cyano, NH ₂ , -N(CH ₃ ) ₂ , -CF ₃ , -CHF ₂ , -OCHF ₂ , -S(O) ₂ NH ₂ , -S(O)CH ₃ and -S(O) ₂ CH ₃ ; and its pharmaceutically acceptable salt. 10. A compound of formula (1) according to claim 1, which is a compound selected from the group consisting of the following: N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N,4-dimethylbenzenesulfonamide; (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-[[(4-chlorophenyl)methyl-methylsulfamoyl]methylamino]-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one; (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl(phenylsulfamoyl)amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane; (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-[[cyclohexyl(methyl)sulfamoyl]methylamino]-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one; (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane; 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(((3-(piperidin-1-yl)propyl)amino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide; 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide; N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)ox an-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(4-fluorophenoxy)-6-methyloxan-4-yl]-N,1-dimethylimidazol-2-sulfonamide; (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[methyl-[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one; N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-(4-methoxybenzyl)benzenesulfonamide; 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide; and (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, and pharmaceutically acceptable salts thereof. 11. A pharmaceutical composition having the activity of modulating the production of proinflammatory cytokines selected from TNFα, IL-1β and IL-6, which contains a therapeutically effective amount of a compound selected from the group consisting of: N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-ox o-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-(4-methoxyphenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide; N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N,4-dimethylbenzenesulfonamide; (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-[[(4-chlorophenyl)methyl-methylsulfamoyl]methylamino]-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one; (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl(phenylsulfamoyl)amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane; (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-[[cyclohexyl(methyl)sulfamoyl]methylamino]-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one; (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane; 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(((3-(piperidin-1-yl)propyl)amino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide; 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide; N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxa n-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(4-fluorophenoxy)-6-methyloxan-4-yl]-N,1-dimethylimidazol-2-sulfonamide; (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[methyl-[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one; N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-(4-methoxybenzyl)benzenesulfonamide; 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide; and (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-11-[(2 S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, or a pharmaceutically acceptable salt thereof, characterized in that said composition additionally contains a pharmaceutically acceptable carrier. 12. A method for treating or preventing an inflammatory response involving proinflammatory cytokines selected from TNFα, IL-1β and IL-6 in an animal by administering to said animal in need thereof a therapeutically effective amount of a compound selected from the group consisting of: N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-ox o-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-(4-methoxyphenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide; N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N,4-dimethylbenzenesulfonamide; (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-[[(4-chlorophenyl)methyl-methylsulfamoyl]methylamino]-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one; (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl(phenylsulfamoyl)amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane; (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-[[cyclohexyl(methyl)sulfamoyl]methylamino]-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one; (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane; 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(((3-(piperidin-1-yl)propyl)amino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide; 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide; N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxa n-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(4-fluorophenoxy)-6-methyloxan-4-yl]-N,1-dimethylimidazol-2-sulfonamide; (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[methyl-[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one; N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-(4-methoxybenzyl)benzenesulfonamide; 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide; and (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-11-[(2 S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, or a pharmaceutically acceptable salt thereof; and wherein said treating or preventing an inflammatory response in an animal prevents or mitigates the progression of a respiratory disease or disorder in the animal. 13. Use of a compound selected from the group consisting of: N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10,13-tetrahydroxy-3,5,8,10,12,14-hexamethyl-15-ox o-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-(4-methoxyphenoxy)-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide; N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N,4-dimethylbenzenesulfonamide; (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-[[(4-chlorophenyl)methyl-methylsulfamoyl]methylamino]-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one; (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl(phenylsulfamoyl)amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane; (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-[[cyclohexyl(methyl)sulfamoyl]methylamino]-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one; (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane; 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(((3-(piperidin-1-yl)propyl)amino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide; 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide; N-[(2S,3R,4S,6R)-2-[[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxa n-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadec-11-yl]oxy]-3-(4-fluorophenoxy)-6-methyloxan-4-yl]-N,1-dimethylimidazol-2-sulfonamide; (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(propylaminomethyl)oxan-2-yl]oxy-11-[(2S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[methyl-[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one; N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-((propylamino)methyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-(4-methoxybenzyl)benzenesulfonamide; 4-chloro-N-((2S,3R,4S,6R)-2-(((2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-(((2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)tetrahydro-2H-pyran-2-yl)oxy)-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecan-11-yl)oxy)-3-hydroxy-6-methyltetrahydro-2H-pyran-4-yl)-N-methylbenzenesulfonamide; and (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyl-5-(piperidin-1-ylmethyl)oxan-2-yl]oxy-11-[(2 S,3R,4S,6R)-3-hydroxy-6-methyl-4-[methyl-[[4-(trifluoromethyl)phenyl]sulfamoyl]amino]oxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-15-oxo-1-oxa-6-azacyclopentadecane, or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment or prevention of an inflammatory response involving proinflammatory cytokines TNFα, IL-1β and IL-6 in an animal, wherein the treatment or prevention of an inflammatory response in an animal prevents or mitigates the progression of a respiratory disease or disorder in the animal.