# Patent

## Title
Pyridyl substituted ketolide antibiotics

## Abstract

Antimicrobial macrolide and ketolide compounds are provided having formulas XII:




as well as pharmaceutically acceptable salts, esters or prodrugs thereof; pharmaceutical compositions comprising such compounds; methods of treating bacterial infections by the administration of such compounds; and processes for the preparation of the compounds.

## Background
This application claims priority to U.S. Provisional Application Ser. No. 60/465,294 filed on Apr. 25, 2003. The disclosure of the above provisional application is herein incorporated by reference in its entirety and for all purposes as if fully set forth herein.


FIELD OF THE INVENTION
This invention relates to novel semi-synthetic macrolides, ketolides, and pyridyl substituted ketolides having antibacterial activity. In another aspect, the present invention relates to pharmaceutical compositions comprising these compounds and to a medical method of treatment employing these compositions. More particularly, this invention concerns C12 modified erythromycin macrolides and ketolide derivatives, such as pyridyl substituted ketolides, compositions containing these compounds, methods of producing the compounds and methods of treating bacterial infections.
BACKGROUND OF THE INVENTION
Erythromycins A through D, represented by formula (I),














(I)








 









Erythromycin
R1
R2





A
—OH
—CH3


B
—H
—CH3


C
—OH
—H


D
—H
—H









are well-known and potent antibacterial agents, used widely to treat and prevent bacterial infection. As with other antibacterial agents, however, bacterial strains having resistance or insufficient susceptibility to erythromycin have been identified. Also, erythromycin A has only weak activity against Gram-negative bacteria. Therefore, there is a continuing need to identify new erythromycin derivative compounds which possess improved antibacterial activity, which have less potential for developing resistance, which possess Gram-negative activity, or which possess unexpected selectivity against target microorganisms. Consequently, numerous investigators have prepared chemical derivatives of erythromycin in an attempt to obtain analogs having modified or improved profiles of antibiotic activity. For example, the compound 6-OMe erythromycin A, or clarithromycin, has found widespread use. However, even this compound is beginning to lose its effectiveness and other erythromycin derivatives having improved activity are needed. Other 6-O-substituted erythromycin compounds have also been proposed for this purpose. For example, PCT application WO 92/09614, published Jun. 11, 1992, discloses tricyclic 6-O-methylerythromycin A derivatives. U.S. Pat. No. 5,444,051 discloses 6-O-substituted-3-oxoerythromycin A derivatives in which the substituents are selected from alkyl, —CONH2, —CONHC(O)alkyl and —CONHSO2 alkyl. PCT application WO 97/10251, published Mar. 20, 1997, discloses 6-O-methyl 3-descladinose erythromycin derivatives. European Patent Application 596802, published May 11, 1994, discloses bicyclic 6-O-methyl-3-oxoerythromycin A derivatives.

More recently, a class of 3-O ketolide erythromycin derivatives have been disclosed in U.S. Pat. Nos. 6,147,197 and 5,635,485. Representative lead compounds in this class include, for example ABT-773 disclosed in U.S. Pat. No. 6,147,197 and telithromycin disclosed in U.S. Pat. No. 5,635,485. The structures of these compounds are as follows:




Other modifications that have shown promise include modifications at C2, including, for example, those shown in U.S. Pat. No. 6,124,269 and International Application Publication No. WO 00/69875, the disclosures of which are incorporated herein by reference.
Despite much activity in designing 14-membered macrolide derivatives, few examples of modifications at C12 exist, especially with regards to the C12-C21 bond. U.S. Pat. No. 4,857,641 (Hauske) discloses that when the C9-C11 erythromycin positions are protected as cyclic thiocarbonates, the C12 OH can be selectively activated and eliminated over the C6 OH to give an exocyclic double bond, and the thiocarbonate protecting group can then be removed reductively with NaBH4. Stereoselective dihydroxylation is disclosed as the sole olefin modification. U.S. Pat. No. 5,217,960 (Lartey), discloses that the above C12 exocyclic alkene formation of Hauske can also be effected with a protected amino group at C9 and a formate ester at C11. However, elimination at C6 did occur, suggesting that the C9 amino substituent does not provide as great a steric impediment to C6 OH activation as does the Hauske C9 thiocarbonate. The desired C12 olefin could be separated and isolated, and is disclosed as participating in stereoselective epoxidation, dihydroxylation, and hydroboration reactions, wherein all reagents attack the same face of the olefin (top face if the macrolide is drawn as shown above). Of these products, only the epoxide is disclosed as being derivatized by ring opening with alkyl amines. (Ring opening with other nucleophiles is suggested, but only generally, and no specific examples are given). It should be noted that the C12 modified compounds of Hauske and Lartey exhibit minimal antibacterial activity.




Efficient strategies for synthetic modifications involving the C12-C21 bond rely, in part, on the ability to selectively differentiate between the aglycon alcohols of erythromycin A. The differentiation appears to be dependent upon the identity of the C9 substituent, although the order and degree of selectivity can be difficult to predict without further experimentation. For example, the reactivity of the aglycon alcohols generally decrease when comparing C11 to C6 to C12. However as seen in the Hauske and Lartey examples above, the C12 OH can become more reactive than the C6 OH if the C9 ketone is modified in a particular manner. Alternatively when the C9 ketone is functionalized as various oximes (see U.S. Pat. No. 6,147,195), the C6 OH can be selectively alkylated over both C12 and C11. Finally, it has been shown that when erythromycin A is treated with NaBH4 to form a bis-erythromycin A borate ester followed by alkylation with MeI, selective methylation occurs at C12 over both C11 and C6 (JOC, 1999, p. 2107).
Macrolides and ketolides containing non-methyl C12 group have been disclosed in WO 03/004509, which is incorporated by reference herein.
SUMMARY OF THE INVENTION
The present invention provides novel 14 membered macrolide and ketolide antibiotics containing C12 modifications, useful common intermediates for introducing C12 modifications, methods for their synthesis, and methods of use of the compounds for the treatment and/or prophylaxis of diseases, especially bacterial infections.
In one embodiment, the present invention provides a compound of the following formula (II):




or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein

    A. V is —OCORx, carbonyl, or a cladinose moiety of the formula:






    
    
        wherein Rx is H, C1-C12-alkyl, —O—C1-C12-alkyl, —N(H)—C1-C12-alkyl, or —N(C1-C12-alkyl)2;
    
    
    B. either Y and Z taken together define a group X, wherein X is selected from the group consisting of
    
        (1) ═O,
        (2) ═N—OH,
        (3) ═N—O—R1, wherein R1 is selected from the group consisting of
        
            (a) C1-C12-alkyl,
            (b) C1-C12-alkyl substituted with alkylalkoxy,
            (c) C1-C12-alkyl substituted with aryl,
            (d) C1-C12-alkyl substituted with substituted aryl,
            (e) C1-C12-alkyl substituted with heteroaryl,
            (f) C1-C12-alkyl substituted with substituted heteroaryl,
            (g) C3-C12-cycloalkyl, and
            (h) —Si—(R2)(R3)(R4), wherein R2, R3, R4 are each independently selected from C1-C12-alkyl and aryl; and
        
        
        (4) ═N—O—C(R5)(R6)—O—R1, wherein R1 is as previously defined and R5 and R6 may be the same or different and are each independently selected from the group consisting of
        
            (a) hydrogen,
            (b) C1-C12-alkyl,
            (c) C1-C12-alkyl substituted with aryl,
            (d) C1-C12-alkyl substituted with substituted aryl,
            (e) C1-C12-alkyl substituted with heteroaryl, and
            (f) C1-C12-alkyl substituted with substituted heteroaryl;
            or R5 and R6 taken together with the atoms to which they are attached form a C3-C12-cycloalkyl ring; or
        
        
        Y and Z are ═N— when taken together with T to form a moiety of the structure
    
    






    
    
         or
        one of Y and Z is hydrogen and the other is selected from a group consisting of
        (1) hydroxy,
        (2) protected hydroxy, and
        (3) —NR7R8, wherein R7 and R8 are independently selected from hydrogen and C1-C12-alkyl, substituted C1-C12-alkyl, or R7 and R8 are taken with the nitrogen atom to which they are connected to form a 3- to 7-membered ring which, when the ring is a 5- to 7-membered ring, may optionally contain a hetero function selected from the group consisting of —O—, —NH—, —N(C1-C6-alkyl)-, —N(aryl)-, —N(aryl-C1-C6-alkyl-)-, —N(substituted-aryl-C1-C6-alkyl-)-, —N(heteroaryl)-, —N(heteroaryl-C1-C6-alkyl-)-, —N(substituted-heteroaryl-C1-C6-alkyl-)-, and —S— or —S(O)n— wherein n is 1 or 2;
    
    
    C. T is selected from the group consisting of —O-Rg, —O—, —NH—, —N(W-Rf)-, and —CH(W-Rf)-, wherein
    
        (1) W is absent or is selected from the group consisting of —O—, —NH—C(O)—, —N═CH—, —NH—, and —CH2—; and
        (2) Rf is selected from the group consisting of
        
            (a) hydrogen,
            (b) C1-C12-alkyl, C2-C12-alkenyl, or C2-C12-alkynyl,
            (c) C1-C12-alkyl, C2-C12-alkenyl, or C2-C12-alkynyl substituted with one or more substituents selected from the group consisting of
            
                (i) aryl,
                (ii) substituted aryl,
                (iii) heteroaryl,
                (iv) substituted heteroaryl,
                (v) hydroxy,
                (vi) C1-C6-alkoxy,
                (vii) —NR7R8, wherein R7 and R8 are as defined previously, and
                (viii)-M-R9, wherein M is selected from the group consisting of:
                
                    (a) —C(O)—NH—,
                    (b) —NH—C(O)—,
                    (c) —NH—,
                    (d) —N═,
                    (e) —N(CH3)—,
                    (f) —NH—C(O)—O—,
                    (g) —NH—C(O)—NH—,
                    (h) —O—C(O)—NH—,
                    (i) —O—C(O)—O—,
                    (j) —O—,
                    (k) —S(O)n—, wherein n is 0, 1, or 2,
                    (l) —C(O)—O—,
                    (m) —O—C(O)—,
                    (n) —C(O)—; and
                
                
                and R9 is selected from the group consisting of:
                
                    (a) C1-C12-alkyl optionally substituted with a substituent selected from the group consisting of
                     (aa) aryl,
                     (bb) substituted aryl,
                     (cc) heteroaryl, and
                     (dd) substituted heteroaryl,
                    (b) aryl,
                    (c) substituted aryl,
                    (d) heteroaryl,
                    (e) substituted heteroaryl, and
                    (f) heterocycloalkyl,
                
                
            
            
        
        
    
    
    D. R is selected from the group consisting of
    
        (1) hydrogen;
        (2) methyl substituted with a moiety selected from the group consisting of
        
            (a) —CN,
            (b) —F,
            (c) —CO2R10, wherein R10 is C1-C3-alkyl or aryl substituted C1-C3-alkyl, or heteroaryl substituted C1-C3-alkyl,
            (d) —S(O)nR10—, wherein n is 0, 1, or 2 and R10 is as previously defined,
            (e) —NH—C(O)R10, wherein R10 is as previously defined,
            (f) —NH—C(O)NR11R12, wherein R11 and R12 are independently selected from hydrogen, C1-C3-alkyl, C1-C3-alkyl substituted with aryl, substituted aryl, heteroaryl, and substituted heteroaryl,
            (g) aryl,
            (h) substituted aryl,
            (i) heteroaryl, and
            (j) substituted heteroaryl;
        
        
        (3) alkyl;
        (4) C2-C12-alkyl substituted with one or more substituents selected from the group consisting of
        
            (a) halogen,
            (b) hydroxy,
            (c) C1-C3-alkoxy,
            (d) C1-C3-alkoxy-C1-C3-alkoxy,
            (e) oxo,
            (f) —O—SO2—(substituted C1-C6-alkyl),
            (g) —N3,
            (h) —CHO,
            (i) —NR13R14, wherein R13 and R14 may be the same or different and are independently selected from the group consisting of
            
                (i) hydrogen,
                (ii) C1-C12-alkyl,
                (iii) substituted C1-C12-alkyl,
                (iv) C2-C12-alkenyl,
                (v) substituted C2-C12-alkenyl,
                (vi) C2-C12-alkynyl,
                (vii) substituted C2-C12-alkynyl,
                (viii) aryl,
                (ix) C3-C8-cycloalkyl,
                (x) substituted C3-C8-cycloalkyl,
                (xi) substituted aryl,
                (xii) heterocycloalkyl,
                (xiii) substituted heterocycloalkyl,
                (xiv) C1-C12-alkyl substituted with aryl,
                (xv) C1-C12-alkyl substituted with substituted aryl,
                (xvi) C1-C12-alkyl substituted with heterocycloalkyl,
                (xvii) C1-C12-alkyl substituted with substituted heterocycloalkyl,
                (xviii) C1-C12-alkyl substituted with C3-C8-cycloalkyl,
                (xix) C1-C12-alkyl substituted with substituted C3-C8-cycloalkyl,
                (xx) heteroaryl,
                (xxi) substituted heteroaryl,
                (xxii) C1-C12-alkyl substituted with heteroaryl, and
                (xxiii) C1-C12-alkyl substituted with substituted heteroaryl;
            
            
            or R13 and R14 are taken together with the atom to which they are attached to form a 3- to 10-membered heterocycloalkyl ring which may optionally be substituted with one or more substituents independently selected from the group consisting of
            
                (i) halogen,
                (ii) hydroxy,
                (iii) C1-C3-alkoxy,
                (iv) C1-C3-alkoxy-C1-C3-alkoxy,
                (v) oxo,
                (vi) C1-C3-alkyl,
                (vii) halo-C1-C3-alkyl, and
                (viii) C1-C3-alkoxy-C1-C3-alkyl;
            
            
            (j) —CO2R10, wherein R10 is as previously defined,
            (k) —C(O)NR11R12, wherein R11 and R12 are as previously defined,
            (l) ═N—O—R10, wherein R10 is as previously defined,
            (m) —CN,
            (n) —O—S(O)nR10, wherein n is 0, 1, or 2 and R10 is as previously defined,
            (o) aryl,
            (p) substituted aryl,
            (q) heteroaryl,
            (r) substituted heteroaryl,
            (s) C3-C8-cycloalkyl,
            (t) substituted C3-C8-cycloalkyl,
            (u) C1-C12-alkyl substituted with heteroaryl,
            (v) heterocycloalkyl,
            (w) substituted heterocycloalkyl,
            (x) —NH—C(O)R10, wherein R10 is as previously defined,
            (y) —NH—C(O)NR11R12, wherein R11 and R12 are as previously defined,
            (z) ═N—NR13R14, wherein R13 and R14 are as previously defined,
            (aa) ═N—R9, wherein R9 is as previously defined,
            (bb) ═N—NH—C(O)R10, wherein R10 is as previously defined, and
            (cc) ═N—NH—C(O)NR11R12, wherein R11 and R12 are as previously defined;
        
        
        (5) C3-alkenyl substituted with a moiety selected from the group consisting of
        
            (a) halogen,
            (b) —CHO,
            (c) —CO2R10, wherein R10 is as previously defined,
            (d) —C(O)NR11R12, wherein R11 and R12 are as previously defined,
            (e) —C(O)R9, wherein R9 is as previously defined,
            (f) —CN,
            (g) aryl,
            (h) substituted aryl,
            (i) heteroaryl,
            (j) substituted heteroaryl,
            (k) C3-C8-cycloalkyl, and
            (l) C1-C12-alkyl substituted with heteroaryl;
        
        
        (6) C4-C10-alkenyl;
        (7) C4-C10-alkenyl substituted with one or more substituents selected from the group consisting of
        
            (a) halogen,
            (b) C1-C3-alkoxy,
            (c) oxo,
            (d) —CHO,
            (e) —CO2R10, wherein R10 is as previously defined,
            (f) —C(O)NR11R12, wherein R11 and R12 are as previously defined,
            (g) —NR13R14, wherein R13 and R14 are as previously defined,
            (h) ═N—O—R10, wherein R10 is as previously defined,
            (i) —CN,
            (j) —O—S(O)nR10, wherein n is 0, 1, or 2 and R10 is as previously defined,
            (k) aryl,
            (l) substituted aryl,
            (m) heteroaryl,
            (n) substituted heteroaryl,
            (o) C3-C8-cycloalkyl,
            (p) C1-C12-alkyl substituted with substituted heteroaryl,
            (q) —NH—C(O)R10, wherein R10 is as previously defined,
            (r) —NH—C(O)NR11R12, wherein R11 and R12 are as previously defined,
            (s) ═N—NR13R14, wherein R13 and R14 are as previously defined,
            (t) ═N—R9, wherein R9 is as previously defined,
            (u) ═N—NH—C(O)R10, wherein R10 is as previously defined, and
            (v) ═N—NH—C(O)NR11R12, wherein R11 and R12 are as previously defined;
        
        
        (8) C3-C10-alkynyl;
        (9) C3-C10-alkynyl substituted with one or more substituents selected from the group consisting of
        
            (a) trialkylsilyl,
            (b) aryl,
            (c) substituted aryl,
            (d) heteroaryl, and
            (e) substituted heteroaryl; and
        
        
        (10) —C(O)NR7R8 where R7 and R8 are previously defined;
    
    
    E. Ra is selected from a group consisting of
    
        (1) hydrogen;
        (2) C1 alkyl further substituted with a one or more substituents selected from a group consisting of
        
            (a) hydroxyl,
            (b) halogen,
            (c) thiol, which can be further substituted with and alkyl or substituted alkyl group
            (d) C1-C12-alkyl, which can be further substituted by halogen, hydroxyl alkoxy, or amino,
            (e) C1-C3-alkoxy,
            (f) C1-C3-thioalkoxy,
            (g) amino,
            (h) alkylamino,
            (i) dialkylamino,
            (j) —CN,
            (k) —NO2,
            (l) —CONH2,
            (m) —COOH,
            (n) —CO2R10, wherein R10 is as previously defined,
            (o) —N3,
            (p) ═N—O—R10, wherein R10 is as previously defined,
            (q) ═N—R9, wherein R9 is as previously defined,
            (r) ═N—NR13R14, wherein R13 and R14 are as previously defined,
            (s) ═N—NH—C(O)R10, wherein R10 is as previously defined, and
            (t) ═N—NH—C(O)NR11R12, wherein R11 and R12 are as previously defined;
        
        
        (3) C2-C4-alkenyl, which can be further substituted with C1-C12-alkyl and one or more halo groups;
        (4) C2-C4-alkynyl, which can be further substituted with C1-C12-alkyl and one or more halo groups;
        (5) aryl, which can be further substituted with C1-C12-alkyl and one or more halo groups;
        (6) —CHO;
        (7) —CO2H;
        (8) —CN;
        (9) —CO2R10, wherein R10 is as previously defined;
        (10) —C(O)NR11R12, wherein R11 and R12 are as previously defined;
        (11) —C(O)R9 wherein R9 is as previously defined; and
        (12) thioester;
        with the proviso that in formula II, when Z is amino or substituted amino, then Ra can not be —CH2OH, —NR4R6, or —(CH2)nNR4R6, wherein R4 and R6 are selected from the group consisting of hydrogen, loweralkyl, and arylalkyl;
    
    
    F. Rb is hydrogen, halogen, or C1-C12-alkyl, which can be further substituted by one or more halo groups, or Rb can be taken together with V to form a double bond;
    G. Rc is hydrogen or a hydroxy protecting group;
    H. Rd is selected from the group consisting of
    
        (1) C1-C12-alkyl,
        (2) C1-C12-alkyl substituted with one or more substituents selected from the group consisting of (a) halogen, (b) hydroxy, and (c) C1-C3-alkoxy,
        (3) C3-C7-cycloalkyl,
        (4) C2-C4-alkenyl, and
        (5) C2-C4-alkynyl;
    
    
    I. Re is hydroxyl, amino, or alkylamino; or Re and Ra may be taken together to form an epoxide, a carbonyl, an olefin, or a substituted olefin; or Re and Ra when taken together with the atom to which they are attached form a spiro ring consisting of C3-C7-carbocyclic, carbonate or carbamate wherein the nitrogen atom can be unsubstituted or substituted with an alkyl group; or Re and T when taken together with the carbon atoms to which they are attached form a ring of the structure






    
    
        wherein L is methylene or carbonyl and P is —O—, —NH— or —NR1—, wherein R1 is as previously defined; provided that when L is methylene, T is —O— and P is —O—;
    
    
    J. Rg is hydrogen or R, wherein R is as previously defined; or Rg may be taken together with Y, seperated by a linker of the formula —C(═O)— or —C(CH3)2—, to form a cyclic moiety;
    K. Rh is selected from the group consisting of
    
        (1) hydrogen,
        (2) —ORj, wherein Rj is hydrogen or a hydroxy protecting group,
        (3) halogen,
        (4) OC(O)NHRi, wherein Ri is selected from a group consisting of
        
            (a) C1-C4 alkyl,
            (b) C1-C4 aminoalkyl, wherein the amino group is substituted with one or two groups independently selected from
            
                (i) C1-C4 alkyl,
                (ii) C1-C4 alkyl substituted with halogen,
                (iii) C1-C4 alkyl substituted with alkoxy,
                (iv) C1-C4 alkyl substituted with hydroxyl,
                (v) C1-C4 alkyl substituted with aryl,
                (vi) C1-C4 alkyl substituted with substituted aryl,
                (vii) C1-C4 alkyl substituted with heteroaryl,
                (viii) C1-C4 alkyl substituted with substituted heteroaryl,
                (ix) C3-C6 cycloalkyl; and
            
            
        
        
    
    
    L. A, B, D, and E are independently selected from the group consisting of
    
        (1) hydrogen;
        (2) C1-C6-alkyl optionally substituted with one or more substituents selected from the group consisting of
        
            (a) aryl,
            (b) substituted aryl,
            (c) heteroaryl,
            (d) substituted heteroaryl,
            (e) heterocycloalkyl,
            (f) hydroxy,
            (g) C1-C6-alkoxy,
            (h) halogen selected from the group consisting of Br, Cl, F, and I, and
            (i) —NR7R8, wherein R7 and R8 are as previously defined;
        
        
        (3) C3-C7-cycloalkyl;
        (4) aryl;
        (5) substituted aryl;
        (6) heteroaryl;
        (7) substituted heteroaryl;
        (8) heterocycloalkyl; and
        (9) a group selected from option (L)(2) above further substituted with -M-R9, wherein M and R9 are as previously defined; or any one pair of substituents, consisting of AB, AD, AE, BD, BE, or DE, is taken together with the atom or atoms to which they are attached to form a 3- to 7-membered ring optionally containing a hetero function selected from the group consisting of —O—, —NH—, —N(C1-C6-alkyl-)-, —N(aryl-C1-C6-alkyl-)-, —N(substituted-aryl-C1-C6-alkyl-)-, —N(heteroaryl-C1-C6-alkyl-)-, —N(substituted-heteroaryl-C1-C6-alkyl-)-, —S— or —S(O)n—, wherein n is 1 or 2, —C(O)—NH, —C(O)—NR12, wherein R12 is as previously defined, —NH—C(O)—, —NR12—C(O)—, wherein R12 is as previously defined, and —C(═NH)—NH—; with the provision that at least two of A, B, D, and E are hydrogen.
    
    


In another embodiment, the present invention provides a compound of formula (II) above having the structure of the following formula (III):




or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein Y, Z, R, Ra, Rc, Rd, Re, Rg, and Rh have the meanings defined above.

In another embodiment, the present invention provides a compound of formula (II) above having the structure of the following formula (IV):




or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein Y, Z, R, Ra, Rb, Rc, Rd, Re, and Rg have the meanings defined above.

In another embodiment, the present invention provides a compound of formula (II) above having the structure of the following formula (V):




or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein L, P, T, Y, Z, R, Ra, Rc, Rd, and Rh have the meanings defined above.

In another embodiment, the present invention provides a compound of formula (II) above having the structure of the following formula (VI):




or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein L, P, T, R, Ra, Rb, Rc, and Rd have the meanings defined above.

In another embodiment, the present invention provides a compound of formula (II) above having the structure of the following formula (VII):




or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein A, B, D, E, R, Ra, Rb, Rc, and Rd have the meanings defined above.

In another embodiment, the present invention provides a compound of formula (II) above having the structure of the following formula (VIII):




or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein L, P, T, R, Ra, Rc, and Rd have the meanings defined above.

In yet another embodiment, the present invention provides a compound of the following formula (XII):




or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein

    A. R is selected from the group consisting of
    
        (1) hydrogen;
        (2) methyl substituted with a moiety selected from the group consisting of
        
            (a) —CN,
            (b) —F,
            (c) —CO2R10, wherein R10 is C1-C3-alkyl or aryl substituted with C1-C3-alkyl, or heteroaryl substituted with C1-C3-alkyl,
            (d) —S(O)nR10—, wherein n is 0, 1, or 2 and R10 is as previously defined,
            (e) —NH—C(O)R10, wherein R10 is as previously defined,
            (f) —NH—C(O)NR11R12, wherein R11 and R12 are independently selected from hydrogen, C1-C3-alkyl, C1-C3-alkyl substituted with aryl, substituted aryl, heteroaryl, and substituted heteroaryl,
            (g) aryl,
            (h) substituted aryl,
            (i) heteroaryl, and
            (j) substituted heteroaryl;
        
        
        (3) C1-C12 alkyl;
        (4) C2-C12-alkyl substituted with one or more substituents selected from the group consisting of
        
            (a) halogen,
            (b) hydroxy,
            (c) C1-C3-alkoxy,
            (d) C1-C3-alkoxy-C1-C3-alkoxy,
            (e) oxo,
            (f) —O—SO2—(substituted C1-C6-alkyl),
            (g) —N3,
            (h) —CHO,
            (i) —NR13R14, wherein R13 and R14 are selected from the group consisting of
            
                (i) hydrogen,
                (ii) C1-C12-alkyl,
                (iii) substituted C1-C12-alkyl,
                (iv) C2-C12-alkenyl,
                (v) substituted C2-C12-alkenyl,
                (vi) C2-C12-alkynyl,
                (vii) substituted C2-C12-alkynyl,
                (viii) aryl,
                (ix) C3-C8-cycloalkyl,
                (x) substituted C3-C8-cycloalkyl,
                (xi) substituted aryl,
                (xii) C3-C12-heterocycloalkyl,
                (xiii) substituted C3-C12-heterocycloalkyl,
                (xiv) C1-C12-alkyl substituted with aryl,
                (xv) C1-C12-alkyl substituted with substituted aryl,
                (xvi) C1-C12-alkyl substituted with C3-C12-heterocycloalkyl,
                (xvii) C1-C12-alkyl substituted with substituted C3-C12-heterocycloalkyl,
                (xviii) C1-C12-alkyl substituted with C3-C8-cycloalkyl,
                (xix) C1-C12-alkyl substituted with substituted C3-C8-cycloalkyl,
                (xx) heteroaryl,
                (xxi) substituted heteroaryl,
                (xxii) C1-C12-alkyl substituted with heteroaryl, and
                (xxiii) C1-C12-alkyl substituted with substituted heteroaryl;
                
                    or R13 and R14 are taken together with the atom to which they are attached to form a 3- to 10-membered heterocycloalkyl ring which may optionally be substituted with one or more substituents independently selected from the group consisting of
                    (i) halogen,
                    (ii) hydroxy,
                    (iii) C1-C3-alkoxy,
                    (iv) C1-C3-alkoxy-C1-C3-alkoxy,
                    (v) oxo,
                    (vi) C1-C3-alkyl,
                    (vii) halo-C1-C3-alkyl, and
                    (viii) C1-C3-alkoxy-C1-C3-alkyl;
                
                
            
            
            (j) —CO2R10, wherein R10 is as previously defined,
            (k) —C(O)NR11R12, wherein R11 and R12 are as previously defined,
            (l) ═N—O—R10, wherein R10 is as previously defined,
            (m) —CN,
            (n) —O—S(O)nR10 wherein n is 0, 1, or 2 and R10 is as previously defined,
            (o) aryl,
            (p) substituted aryl,
            (q) heteroaryl,
            (r) substituted heteroaryl,
            (s) C3-C8-cycloalkyl,
            (t) substituted C3-C8-cycloalkyl,
            (u) C1-C12-alkyl substituted with heteroaryl,
            (v) C3-C12-heterocycloalkyl,
            (w) substituted C3-C12-heterocycloalkyl,
            (x) —NH—C(O)R10, wherein R10 is as previously defined,
            (y) —NH—C(O)NR11R12, wherein R11 and R12 are as previously defined,
            (z) ═N—NR13R14, wherein R13 and R14 are as previously defined,
            (aa) ═N—R9, wherein R9 is selected from the group consisting of:
            
                (i) C1-C12-alkyl optionally substituted with a substituent selected from the group consisting of
                
                    (a) aryl,
                    (b) substituted aryl,
                    (c) heteroaryl, and
                    (d) substituted heteroaryl,
                    (ii) aryl,
                    (iii) substituted aryl,
                    (iv) heteroaryl,
                    (v) substituted heteroaryl, and
                    (vi) C3-C12-heterocycloalkyl,
                
                
            
            
            (bb) ═N—NH—C(O)R10, wherein R10 is as previously defined, and
            (cc) ═N—NH—C(O)NR11R12, wherein R11 and R12 are as previously defined;
        
        
        (5) C3-alkenyl substituted with a moiety selected from the group consisting of
        
            (a) hydrogen,
            (b) halogen,
            (c) —CHO,
            (d) —CO2R10, wherein R10 is as previously defined,
            (e) —C(O)NR11R12, wherein R11 and R12 are as previously defined,
            (f) —C(O)R9, wherein R9 is as previously defined,
            (g) —CN,
            (h) aryl,
            (i) substituted aryl,
            (j) heteroaryl,
            (k) substituted heteroaryl,
            (l) —C3-C8-cycloalkyl, and
            (m) —C1-C12-alkyl substituted with heteroaryl;
        
        
        (6) C4-C10-alkenyl;
        (7) C4-C10-alkenyl substituted with one or more substituents selected from the group consisting of
        
            (a) halogen,
            (b) —C1-C3-alkoxy,
            (c) oxo,
            (d) —CHO,
            (e) —CO2R10, wherein R10 is as previously defined,
            (f) —C(O)NR11R12, wherein R11 and R12 are as previously defined,
            (g) —NR13R14, wherein R13 and R14 are as previously defined,
            (h) ═N—O—R10, wherein R10 is as previously defined,
            (i) —CN,
            (j) —O—S(O)nR10, wherein n is 0, 1, or 2 and R10 is as previously defined,
            (k) aryl,
            (l) substituted aryl,
            (m) heteroaryl,
            (n) substituted heteroaryl,
            (o) —C3-C8-cycloalkyl,
            (p) —C1-C12-alkyl substituted with substituted heteroaryl,
            (q) —NH—C(O)R10, wherein R10 is as previously defined,
            (r) —NH—C(O)NR11R12, wherein R11 and R12 are as previously defined,
            (s) ═N—NR13R14, wherein R13 and R14 are as previously defined,
            (t) ═N—R9, wherein R9 is as previously defined,
            (u) ═N—NH—C(O)R10, wherein R10 is as previously defined, and
            (v) ═N—NH—C(O)NR11R12, wherein R11 and R12 are as previously defined;
        
        
        (8) C3-C10-alkynyl;
        (9) C3-C10-alkynyl substituted with one or more substituents selected from the group consisting of
        
            (a) C1-C12-trialkylsilyl,
            (b) aryl,
            (c) substituted aryl,
            (d) heteroaryl, and
            (e) substituted heteroaryl; and
        
        
        (10) C(O)NR7R8, wherein R7 and R8 are independently selected from hydrogen, C1-C12-alkyl, and substituted C1-C12-alkyl, or R7 and R8 are taken with the nitrogen atom to which they are connected to form a 3- to 7-membered ring which, when the ring is a 5- to 7-membered ring, may optionally contain a hetero function selected from the group consisting of —O—, —NH, —N(C11-C6-alkyl)-, —N(aryl)-, —N(aryl-C1-C6-alkyl-)-, —N(substituted aryl-C1-C6-alkyl-)-, —N(heteroaryl)-, —N(heteroaryl-C1-C6-alkyl-)-, —N(substituted heteroaryl-C1-C6-alkyl-)-, and —S— or —S(O)n— wherein n is 1 or 2;
    
    
    B. Ra is selected from the group consisting of
    
        (1) hydrogen;
        (2) C1 alkyl further substituted with one or more substituents selected from the group consisting of
        
            (a) hydroxyl,
            (b) halogen,
            (c) thiol, which can be further substituted with an C1-C12-alkyl or substituted C1-C12-alkyl group,
            (d) C1-C12-alkyl, which can be further substituted by halogen, hydroxyl, C1-C12-alkoxy, or amino,
            (e) C1-C3-alkoxy,
            (f) C1-C3-thioalkoxy,
            (g) amino,
            (h) C1-C12-alkylamino,
            (i) C1-C12-dialkylamino,
            (j) —CN,
            (k) —NO2,
            (l) —CONH2,
            (m) —COOH,
            (n) —CO2R10, wherein R10 is as previously defined,
            (o) —N3,
            (p) ═N—O—R10, wherein R10 is as previously defined,
            (q) ═N—R9, wherein R9 is as previously defined,
            (r) ═N—NR13R14, wherein R13 and R14 are as previously defined,
            (s) ═N—NH—C(O)R10, wherein R10 is as previously defined, and
            (t) ═N—NH—C(O)NR11R12, wherein R11 and R12 are as previously defined;
        
        
        (3) C2-C4-alkenyl, which can be further substituted with C1-C12-alkyl and one or more halogen groups;
        (4) C2-C4-alkynyl, which can be further substituted with C1-C12-alkyl and one or more halogen groups;
        (5) aryl, which can be further substituted with C1-C12-alkyl and one or more halogen groups;
        (6) —CHO;
        (7) —CO2H;
        (8) —CN;
        (9) —CO2R10, wherein R10 is as previously defined;
        (10) —C(O)NR11R12, wherein R11 and R12 are as previously defined;
        (11) —C(O)R9, wherein R9 is as previously defined; and
        (12) thioester;
    
    
    C. Rb is hydrogen, halogen, C1-C12 alkyl, substituted C1-C12-alkyl, or C1-C12-alkyl further substituted with one or more halogen groups;
    D. Each R32 is independently selected from the group consisting of a free, salified, esterified and amidified
    
        (1) carboxyl, hydroxyl, halogen, —NO2, —CN, C1-C12-alkyl, C3-C12-cycloalkyl, C2-C12-alkenyl, C2-C12-alkynyl, O-alkyl, O-alkenyl, O-alkynyl, S-alkyl, S-alkenyl, S-alkynyl, N-alkyl, N-alkenyl, and N-alkynyl of up to 12 carbon atoms optionally substituted by one or more halogens;
        (2) —NR21(R22), wherein R21 and R22 are individually hydrogen or C1-C12-alkyl;
        (3) —C(O)R23, wherein R23 is C1-C12-alkyl; and
        (4) optionally substituted heteroaryl, O-aryl, S-aryl, and O-substituted-C1-C12 alkyl, or S-substituted-C1-C12 alkyl;
    
    
    E. q is 0, 1, 2, 3, or 4; and
    F. R33 and R34 are independently selected from the group consisting of hydrogen, halogen, C1-C12 alkyl, and substituted C1-C12-alkyl;


with the proviso that when q is 0, then R33 and R34 are not both hydrogen;
with the proviso that when Ra is ethyl, and R33 and R34 are hydrogen, then R32 is not 6-fluoro; and
with the proviso that when Ra is —CH═CH2, and R33 and R34 are hydrogen, then R32 is not 6-methyl.
The present invention also provides pharmaceutical compositions which comprise a therapeutically effective amount of a compound as defined above in combination with a pharmaceutically acceptable carrier.
The invention further provides a method of treating bacterial infections in a patient in need thereof comprising administering a therapeutically effective amount of a compound of the invention as defined above to the patient, together with a pharmaceutically acceptable carrier. Patients include mammals such as humans, cats, or dogs.
The invention also provides for the use of a compound of the invention as described above in the manufacture of a medicament for the treatment or prophylaxis of bacterial infections.
In a further aspect of the present invention are provided processes for the preparation of macrolide derivatives of Formulas (II), (III), (IV), (V), (VI), (VII), (VIII) and (XII), above.


DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
Abbreviations
Abbreviations which have been used in the descriptions of the scheme and the examples that follow are: Ac for acetyl; AcOH for acetic acid; AIBN for azobisisobutyronitrile; Bu3SnH for tributyltin hydride; CDI for carbonyldiimidazole; DBU for 1,8-diazabicyclo[5.4.0]undec-7-ene; DCM for dichloromethane; DEAD for diethylazodicarboxylate; DMF for dimethylformamide; DMP for 2,2-dimethoxypropane DMSO for dimethylsulfoxide; DPPA for diphenylphosphoryl azide; Et for ethyl; Et3N for triethylamine; EtOAc for ethyl acetate; Et2O for diethyl ether; EtOH for ethanol; HOAc for acetic acid; LiHMDS or LiN(TMS)2 for lithium bis(trimethylsilyl)amide; MCPBA for meta-chloroperbenzoic acid; Me for methyl; MeOH for methanol; MsCl for methanesulfonyl chloride; NaHMDS or NaN(TMS)2 for sodium bis(trimethylsilyl)amide; NMO for N-methylmorpholine N-oxide; SOCl2 for thionyl chloride; PPTS for pyridium p-toluene sulfonate; Py for pyridine; TEA for triethylamine; THF for tetrahydrofuran; TMSCl for trimethylsilyl chloride; TMSCF3 for trimethyl(trifluoromethyl)-silane; TPP for triphenylphosphine; TPAP for tetra-n-propylammonium perruthenate; DMAP for 4-dimethylamino pyridine, TsOH for p-toluene sulfonic acid.
In one embodiment, the present invention provides a compound of the following formula (II):




or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein

    A. V is —OCORx, carbonyl, or a cladinose moiety of the formula:






    
    
        wherein Rx is H, C1-C12-alkyl, —O—C1-C12-alkyl, —N(H)—C1-C12-alkyl, or —N(C1-C12-alkyl)2;
    
    
    B. either Y and Z taken together define a group X, wherein X is selected from the group consisting of
    
        (1) ═O,
        (2) ═N—OH,
        (3) ═N—O—R1, wherein R1 is selected from the group consisting of
        
            (a) C1-C12-alkyl,
            (b) C1-C12-alkyl substituted with alkylalkoxy,
            (c) C1-C12-alkyl substituted with aryl,
            (d) C1-C12-alkyl substituted with substituted aryl,
            (e) C1-C12-alkyl substituted with heteroaryl,
            (f) C1-C12-alkyl substituted with substituted heteroaryl,
            (g) C3-C12-cycloalkyl, and
            (h) —Si—(R2)(R3)(R4), wherein R2, R3, R4 are each independently selected from C1-C12-alkyl and aryl; and
        
        
        (4) ═N—O—C(R5)(R6)—O—R1, wherein R1 is as previously defined and R5 and R6 may be the same or different and are each independently selected from the group consisting of
        
            (a) hydrogen,
            (b) C1-C12-alkyl,
            (c) C1-C12-alkyl substituted with aryl,
            (d) C1-C12-alkyl substituted with substituted aryl,
            (e) C1-C12-alkyl substituted with heteroaryl, and
            (f) C1-C12-alkyl substituted with substituted heteroaryl;
            or R5 and R6 taken together with the atoms to which they are attached form a C3-C12-cycloalkyl ring; or
        
        
        Y and Z are ═N— when taken together with T to form a moiety of the structure
    
    






    
    
         or
        one of Y and Z is hydrogen and the other is selected from a group consisting of
        (1) hydroxy,
        (2) protected hydroxy, and
        (3) —NR7R8, wherein R7 and R8 are independently selected from hydrogen and C1-C12-alkyl, substituted C1-C12-alkyl, or R7 and R8 are taken with the nitrogen atom to which they are connected to form a 3- to 7-membered ring which, when the ring is a 5- to 7-membered ring, may optionally contain a hetero function selected from the group consisting of —O—, —NH—, —N(C1-C6-alkyl)-, —N(aryl)-, —N(aryl-C1-C6-alkyl-)-, —N(substituted-aryl-C1-C6-alkyl-)-, —N(heteroaryl)-, —N(heteroaryl-C1-C6-alkyl-)-, —N(substituted-heteroaryl-C1-C6-alkyl-)-, and —S— or —S(O)n— wherein n is 1 or 2;
    
    
    C. T is selected from the group consisting of —O-Rg, —O—, —NH—, —N(W-Rf)-, and —CH(W-Rf)-, wherein
    
        (1) W is absent or is selected from the group consisting of —O—, —NH—C(O)—, —N═CH—, —NH—, and —CH2—; and
        (2) Rf is selected from the group consisting of
        
            (a) hydrogen,
            (b) C1-C12-alkyl, C2-C12-alkenyl, or C2-C12-alkynyl,
            (c) C1-C12-alkyl, C2-C12-alkenyl, or C2-C12-alkynyl substituted with one or more substituents selected from the group consisting of
            
                (i) aryl,
                (ii) substituted aryl,
                (iii) heteroaryl,
                (iv) substituted heteroaryl,
                (v) hydroxy,
                (vi) C1-C6-alkoxy,
                (vii) —NR7R8, wherein R7 and R8 are as defined previously, and
                (viii)-M-R9, wherein M is selected from the group consisting of:
                
                    (a) —C(O)—NH—,
                    (b) —NH—C(O)—,
                    (c) —NH—,
                    (d) —N═,
                    (e) —N(CH3)—,
                    (f) —NH—C(O)—O—,
                    (g) —NH—C(O)—NH—,
                    (h) —O—C(O)—NH—,
                    (i) —O—C(O)—O—,
                    (j) —O—,
                    (k) —S(O)n—, wherein n is 0, 1, or 2,
                    (l) —C(O)—O—,
                    (m) —O—C(O)—,
                    (n) —C(O)—; and
                
                
                and R9 is selected from the group consisting of:
                
                    (a) C1-C12-alkyl optionally substituted with a substituent selected from the group consisting of
                     (aa) aryl,
                     (bb) substituted aryl,
                     (cc) heteroaryl, and
                     (dd) substituted heteroaryl,
                    (b) aryl,
                    (c) substituted aryl,
                    (d) heteroaryl,
                    (e) substituted heteroaryl, and
                    (f) heterocycloalkyl,
                
                
            
            
        
        
    
    
    D. R is selected from the group consisting of
    
        (1) hydrogen;
        (2) methyl substituted with a moiety selected from the group consisting of
        
            (a) —CN,
            (b) —F,
            (c) —CO2R10, wherein R10 is C1-C3-alkyl or aryl substituted C1-C3-alkyl, or heteroaryl substituted C1-C3-alkyl,
            (d) —S(O)nR10—, wherein n is 0, 1, or 2 and R10 is as previously defined,
            (e) —NH—C(O)R10, wherein R10 is as previously defined,
            (f) —NH—C(O)NR11R12, wherein R11 and R12 are independently selected from hydrogen, C1-C3-alkyl, C1-C3-alkyl substituted with aryl, substituted aryl, heteroaryl, and substituted heteroaryl,
            (g) aryl,
            (h) substituted aryl,
            (i) heteroaryl, and
            (j) substituted heteroaryl;
        
        
        (3) alkyl;
        (4) C2-C12-alkyl substituted with one or more substituents selected from the group consisting of
        
            (a) halogen,
            (b) hydroxy,
            (c) C1-C3-alkoxy,
            (d) C1-C3-alkoxy-C1-C3-alkoxy,
            (e) oxo,
            (f) —O—SO2—(substituted C1-C6-alkyl),
            (g) —N3,
            (h) —CHO,
            (i) —NR13R14, wherein R13 and R14 may be the same or different and are independently selected from the group consisting of
            
                (i) hydrogen,
                (ii) C1-C12-alkyl,
                (iii) substituted C1-C12-alkyl,
                (iv) C2-C12-alkenyl,
                (v) substituted C2-C12-alkenyl,
                (vi) C2-C12-alkynyl,
                (vii) substituted C2-C12-alkynyl,
                (viii) aryl,
                (ix) C3-C8-cycloalkyl,
                (x) substituted C3-C8-cycloalkyl,
                (xi) substituted aryl,
                (xii) heterocycloalkyl,
                (xiii) substituted heterocycloalkyl,
                (xiv) C1-C12-alkyl substituted with aryl,
                (xv) C1-C12-alkyl substituted with substituted aryl,
                (xvi) C1-C12-alkyl substituted with heterocycloalkyl,
                (xvii) C1-C12-alkyl substituted with substituted heterocycloalkyl,
                (xviii) C1-C12-alkyl substituted with C3-C8-cycloalkyl,
                (xix) C1-C12-alkyl substituted with substituted C3-C8-cycloalkyl,
                (xx) heteroaryl,
                (xxi) substituted heteroaryl,
                (xxii) C1-C12-alkyl substituted with heteroaryl, and
                (xxiii) C1-C12-alkyl substituted with substituted heteroaryl;
            
            
            or R13 and R14 are taken together with the atom to which they are attached to form a 3- to 10-membered heterocycloalkyl ring which may optionally be substituted with one or more substituents independently selected from the group consisting of
            
                (i) halogen,
                (ii) hydroxy,
                (iii) C1-C3-alkoxy,
                (iv) C1-C3-alkoxy-C1-C3-alkoxy,
                (v) oxo,
                (vi) C1-C3-alkyl,
                (vii) halo-C1-C3-alkyl, and
                (viii) C1-C3-alkoxy-C1-C3-alkyl;
            
            
            (j) —CO2R10, wherein R10 is as previously defined,
            (k) —C(O)NR11R12, wherein R11 and R12 are as previously defined,
            (l) ═N—O—R10, wherein R10 is as previously defined,
            (m) —CN,
            (n) —O—S(O)nR10, wherein n is 0, 1, or 2 and R10 is as previously defined,
            (o) aryl,
            (p) substituted aryl,
            (q) heteroaryl,
            (r) substituted heteroaryl,
            (s) C3-C8-cycloalkyl,
            (t) substituted C3-C8-cycloalkyl,
            (u) C1-C12-alkyl substituted with heteroaryl,
            (v) heterocycloalkyl,
            (w) substituted heterocycloalkyl,
            (x) —NH—C(O)R10, wherein R10 is as previously defined,
            (y) —NH—C(O)NR11R12, wherein R11 and R12 are as previously defined,
            (z) ═N—NR13R14, wherein R13 and R14 are as previously defined,
            (aa) ═N—R9, wherein R9 is as previously defined,
            (bb) ═N—NH—C(O)R10, wherein R10 is as previously defined, and
            (cc) ═N—NH—C(O)NR11R12, wherein R11 and R12 are as previously defined;
        
        
        (5) C3-alkenyl substituted with a moiety selected from the group consisting of
        
            (a) halogen,
            (b) —CHO,
            (c) —CO2R10, wherein R10 is as previously defined,
            (d) —C(O)NR11R12, wherein R11 and R12 are as previously defined,
            (e) —C(O)R9, wherein R9 is as previously defined,
            (f) —CN,
            (g) aryl,
            (h) substituted aryl,
            (i) heteroaryl,
            (j) substituted heteroaryl,
            (k) C3-C8-cycloalkyl, and
            (l) C1-C12-alkyl substituted with heteroaryl;
        
        
        (6) C4-C10-alkenyl;
        (7) C4-C10-alkenyl substituted with one or more substituents selected from the group consisting of
        
            (a) halogen,
            (b) C1-C3-alkoxy,
            (c) oxo,
            (d) —CHO,
            (e) —CO2R10, wherein R10 is as previously defined,
            (f) —C(O)NR11R12, wherein R11 and R12 are as previously defined,
            (g) —NR13R14, wherein R13 and R14 are as previously defined,
            (h) ═N—O—R10, wherein R10 is as previously defined,
            (i) —CN,
            (j) —O—S(O)nR10, wherein n is 0, 1, or 2 and R10 is as previously defined,
            (k) aryl,
            (l) substituted aryl,
            (m) heteroaryl,
            (n) substituted heteroaryl,
            (o) C3-C8-cycloalkyl,
            (p) C1-C12-alkyl substituted with substituted heteroaryl,
            (q) —NH—C(O)R10, wherein R10 is as previously defined,
            (r) —NH—C(O)NR11R12, wherein R11 and R12 are as previously defined,
            (s) ═N—NR13R14, wherein R13 and R14 are as previously defined,
            (t) ═N—R9, wherein R9 is as previously defined,
            (u) ═N—NH—C(O)R10, wherein R10 is as previously defined, and
            (v) ═N—NH—C(O)NR11R12, wherein R11 and R12 are as previously defined;
        
        
        (8) C3-C10-alkynyl;
        (9) C3-C10-alkynyl substituted with one or more substituents selected from the group consisting of
        
            (a) trialkylsilyl,
            (b) aryl,
            (c) substituted aryl,
            (d) heteroaryl, and
            (e) substituted heteroaryl; and
        
        
        (10) —C(O)NR7R8 where R7 and R8 are previously defined;
    
    
    E. Ra is selected from a group consisting of
    
        (1) hydrogen;
        (2) C1 alkyl further substituted with a one or more substituents selected from a group consisting of
        
            (a) hydroxyl,
            (b) halogen,
            (c) thiol, which can be further substituted with and alkyl or substituted alkyl group
            (d) C1-C12-alkyl, which can be further substituted by halogen, hydroxyl alkoxy, or amino,
            (e) C1-C3-alkoxy,
            (f) C1-C3-thioalkoxy,
            (g) amino,
            (h) alkylamino,
            (i) dialkylamino,
            (j) —CN,
            (k) —NO2,
            (l) —CONH2,
            (m) —COOH,
            (n) —CO2R10, wherein R10 is as previously defined,
            (o) —N3,
            (p) ═N—O—R10, wherein R10 is as previously defined,
            (q) ═N—R9, wherein R9 is as previously defined,
            (r) ═N—NR13R14, wherein R13 and R14 are as previously defined,
            (s) ═N—NH—C(O)R10, wherein R10 is as previously defined, and
            (t) ═N—NH—C(O)NR11R12, wherein R11 and R12 are as previously defined;
        
        
        (3) C2-C4-alkenyl, which can be further substituted with C1-C12-alkyl and one or more halo groups;
        (4) C2-C4-alkynyl, which can be further substituted with C1-C12-alkyl and one or more halo groups;
        (5) aryl, which can be further substituted with C1-C12-alkyl and one or more halo groups;
        (13) —CHO;
        (14) —CO2H;
        (15) —CN;
        (16) —CO2R10, wherein R10 is as previously defined;
        (17) —C(O)NR11R12, wherein R11 and R12 are as previously defined;
        (18) —C(O)R9 wherein R9 is as previously defined; and
        (19) thioester;
        with the proviso that in formula II, when Z is amino or substituted amino, then Ra can not be —CH2OH, —NR4R6, or —(CH2)nNR4R6, wherein R4 and R6 are selected from the group consisting of hydrogen, loweralkyl, and arylalkyl;
    
    
    F. Rb is hydrogen, halogen, or C1-C12-alkyl, which can be further substituted by one or more halo groups, or Rb can be taken together with V to form a double bond;
    G. Rc is hydrogen or a hydroxy protecting group;
    H. Rd is selected from the group consisting of
    
        (1) C1-C12-alkyl,
        (2) C1-C12-alkyl substituted with one or more substituents selected from the group consisting of
        
            (a) halogen,
            (b) hydroxy, and
            (c) C1-C3-alkoxy,
        
        
        (3) C3-C7-cycloalkyl,
        (4) C2-C4-alkenyl, and
        (5) C2-C4-alkynyl;
    
    
    I. Re is hydroxyl, amino, or alkylamino; or Re and Ra may be taken together to form an epoxide, a carbonyl, an olefin, or a substituted olefin; or Re and Ra when taken together with the atom to which they are attached form a spiro ring consisting of C3-C7-carbocyclic, carbonate or carbamate wherein the nitrogen atom can be unsubstituted or substituted with an alkyl group; or Re and T when taken together with the carbon atoms to which they are attached form a ring of the structure






    
    
        wherein L is methylene or carbonyl and P is —O—, —NH— or —NR1—, wherein R1 is as previously defined; provided that when L is methylene, T is —O— and P is —O—;
    
    
    J. Rg is hydrogen or R, wherein R is as previously defined; or Rg may be taken together with Y, seperated by a linker of the formula —C(═O)— or —C(CH3)2—, to form a cyclic moiety;
    K. Rh is selected from the group consisting of
    
        (1) hydrogen,
        (2) —ORj, wherein Rj is hydrogen or a hydroxy protecting group,
        (3) halogen,
        (4) OC(O)NHRi, wherein Ri is selected from a group consisting of
        
            (a) C1-C4 alkyl,
            (b) C1-C4 aminoalkyl, wherein the amino group is substituted with one or two groups independently selected from
            
                (i) C1-C4 alkyl,
                (ii) C1-C4 alkyl substituted with halogen,
                (iii) C1-C4 alkyl substituted with alkoxy,
                (iv) C1-C4 alkyl substituted with hydroxyl,
                (v) C1-C4 alkyl substituted with aryl,
                (vi) C1-C4 alkyl substituted with substituted aryl,
                (vii) C1-C4 alkyl substituted with heteroaryl,
                (viii) C1-C4 alkyl substituted with substituted heteroaryl,
                (ix) C3-C6 cycloalkyl; and
            
            
        
        
    
    
    L. A, B, D, and E are independently selected from the group consisting of
    
        (1) hydrogen;
        (2) C1-C6-alkyl optionally substituted with one or more substituents selected from the group consisting of
        
            (a) aryl,
            (b) substituted aryl,
            (c) heteroaryl,
            (d) substituted heteroaryl,
            (e) heterocycloalkyl,
            (f) hydroxy,
            (g) C1-C6-alkoxy,
            (h) halogen selected from the group consisting of Br, Cl, F, and I, and
            (i) —NR7R8, wherein R7 and R8 are as previously defined;
        
        
        (3) C3-C7-cycloalkyl;
        (4) aryl;
        (5) substituted aryl;
        (6) heteroaryl;
        (7) substituted heteroaryl;
        (8) heterocycloalkyl; and
        (9) a group selected from option (L)(2) above further substituted with -M-R9, wherein M and R9 are as previously defined; or any one pair of substituents, consisting of AB, AD, AE, BD, BE, or DE, is taken together with the atom or atoms to which they are attached to form a 3- to 7-membered ring optionally containing a hetero function selected from the group consisting of —O—, —NH—, —N(C1-C6-alkyl-)-, —N(aryl-C1-C6-alkyl-)-, —N(substituted-aryl-C1-C6-alkyl-)-, —N(heteroaryl-C1-C6-alkyl-)-, —N(substituted-heteroaryl-C1-C6-alkyl-)-, —S— or —S(O)n—, wherein n is 1 or 2, —C(O)—NH, —C(O)—NR12, wherein R12 is as previously defined, —NH—C(O)—, —NR12—C(O)—, wherein R12 is as previously defined, and —C(═NH)—NH—; with the provision that at least two of A, B, D, and E are hydrogen.
    
    


In another embodiment, the present invention provides a compound of formula (II) above having the structure of the following formula (III):




or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein Y, Z, R, Ra, Rc, Rd, Re, Rg, and Rh have the meanings defined above.

In another embodiment, the present invention provides a compound of formula (II) above having the structure of the following formula (IV):




or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein Y, Z, R, Ra, Rb, Rc, Rd, Re, and Rg have the meanings defined above.

In another embodiment, the present invention provides a compound of formula (II) above having the structure of the following formula (V):




or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein L, P, T, Y, Z, R, Ra, Rc, Rd, and Rh have the meanings defined above.

In another embodiment, the present invention provides a compound of formula (II) above having the structure of the following formula (VI):




or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein L, P, T, R, Ra, Rb, Rc, and Rd have the meanings defined above. In another embodiment, an illustrative compound of formula (VI) has the structure of formula (VIa):





or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein W, Rf, R, Ra, Rc, and Rd have the meanings defined above. Illustrative, but nonlimiting examples include, without limitation, a compound of formula (VIa(1)):





wherein R is H, ethyl, ethynyl, or vinyl, and R′ is H or F;

a compound of formula (VIa(2)):





wherein R is H, ethyl, ethynyl, or vinyl, R′ is H or F, and Y is H, halogen, amino, C1-C4 alkyl, hydroxy, alkoxy, alkylamino, cyano, or substituted C1-C4 alkyl;

compounds of formula (VIa(3)):





wherein R is H, CF3, ethyl, ethynyl, or vinyl, and R′ is H or F;

a compound of formula (VIa(4)):





wherein R is H, CF3, ethyl, ethynyl, or vinyl, and R′ is H or F; and

a compound of formula (VIa(5)):





wherein R is H, CF3, ethyl, ethynyl, or vinyl, and R′ is H or F.

In another embodiment, the present invention provides a compound of formula (II) above having the structure of the following formula (VII):




or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein A, B, D, E, R, Ra, Rb, Rc, and Rd have the meanings defined above.

In another embodiment, the present invention provides a compound of formula (II) above having the structure of the following formula (VIII):




or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein L, P, T, R, Ra, Rc, and Rd have the meanings defined above.

In yet another embodiment, the present invention provides a compound having the structure of the following formula (XII):




or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein

    A. R is selected from the group consisting of
    
        (1) hydrogen;
        (2) methyl substituted with a moiety selected from the group consisting of
        
            (a) —CN,
            (b) —F,
            (c) —CO2R10, wherein R10 is C1-C3-alkyl or aryl substituted with C1-C3-alkyl, or heteroaryl substituted with C1-C3-alkyl,
            (d) —S(O)nR10—, wherein n is 0, 1, or 2 and R10 is as previously defined,
            (e) —NH—C(O)R10, wherein R10 is as previously defined,
            (f) —NH—C(O)NR11R12, wherein R11 and R12 are independently selected from hydrogen, C1-C3-alkyl, C1-C3-alkyl substituted with aryl, substituted aryl, heteroaryl, and substituted heteroaryl,
            (g) aryl,
            (h) substituted aryl,
            (i) heteroaryl, and
            (j) substituted heteroaryl;
        
        
        (3) C1-C12 alkyl;
        (4) C2-C12-alkyl substituted with one or more substituents selected from the group consisting of
        
            (a) halogen,
            (b) hydroxy,
            (c) C1-C3-alkoxy,
            (d) C1-C3-alkoxy-C1-C3-alkoxy,
            (e) oxo,
            (f) —O—SO2—(substituted C1-C6-alkyl),
            (g) —N3,
            (h) —CHO,
            (i) —NR13R14, wherein R13 and R14 are selected from the group consisting of
            
                (i) hydrogen,
                (ii) C1-C12-alkyl,
                (iii) substituted C1-C12-alkyl,
                (iv) C2-C12-alkenyl,
                (v) substituted C2-C12-alkenyl,
                (vi) C2-C12-alkynyl,
                (vii) substituted C2-C12-alkynyl,
                (viii) aryl,
                (ix) C3-C8-cycloalkyl,
                (x) substituted C3-C8-cycloalkyl,
                (xi) substituted aryl,
                (xii) C3-C12-heterocycloalkyl,
                (xiii) substituted C3-C12-heterocycloalkyl,
                (xiv) C1-C12-alkyl substituted with aryl,
                (xv) C1-C12-alkyl substituted with substituted aryl,
                (xvi) C1-C12-alkyl substituted with C3-C12-heterocycloalkyl,
                (xvii) C1-C12-alkyl substituted with substituted C3-C12-heterocycloalkyl,
                (xviii) C1-C12-alkyl substituted with C3-C8-cycloalkyl,
                (xix) C1-C12-alkyl substituted with substituted C3-C8-cycloalkyl,
                (xx) heteroaryl,
                (xxi) substituted heteroaryl,
                (xxii) C1-C12-alkyl substituted with heteroaryl, and
                (xxiii) C1-C12-alkyl substituted with substituted heteroaryl;
                
                    or R13 and R14 are taken together with the atom to which they are attached to form a 3- to 10-membered heterocycloalkyl ring which may optionally be substituted with one or more substituents independently selected from the group consisting of
                    (i) halogen,
                    (ii) hydroxy,
                    (iii) C1-C3-alkoxy,
                    (iv) C1-C3-alkoxy-C1-C3-alkoxy,
                    (v) oxo,
                    (vi) C1-C3-alkyl,
                    (vii) halo-C1-C3-alkyl, and
                    (viii) C1-C3-alkoxy-C1-C3-alkyl;
                
                
            
            
            (j) —CO2R10, wherein R10 is as previously defined,
            (k) —C(O)NR11R12, wherein R11 and R12 are as previously defined,
            (l) ═N—O—R10, wherein R10 is as previously defined,
            (m) —CN,
            (n) —O—S(O)nR10 wherein n is 0, 1, or 2 and R10 is as previously defined,
            (o) aryl,
            (p) substituted aryl,
            (q) heteroaryl,
            (r) substituted heteroaryl,
            (s) C3-C8-cycloalkyl,
            (t) substituted C3-C8-cycloalkyl,
            (u) C1-C12-alkyl substituted with heteroaryl,
            (v) C3-C12-heterocycloalkyl,
            (w) substituted C3-C12-heterocycloalkyl,
            (x) —NH—C(O)R10, wherein R10 is as previously defined,
            (y) —NH—C(O)NR11R12, wherein R11 and R12 are as previously defined,
            (z) ═N—NR13R14, wherein R13 and R14 are as previously defined,
            (aa) ═N—R9, wherein R9 is selected from the group consisting of:
            
                (i) C1-C12-alkyl optionally substituted with a substituent selected from the group consisting of
                
                    (a) aryl,
                    (b) substituted aryl,
                    (c) heteroaryl, and
                    (d) substituted heteroaryl,
                    (ii) aryl,
                    (iii) substituted aryl,
                    (iv) heteroaryl,
                    (v) substituted heteroaryl, and
                    (vi) C3-C12-heterocycloalkyl,
                
                
            
            
            (bb) ═N—NH—C(O)R10, wherein R10 is as previously defined, and
            (cc) ═N—NH—C(O)NR11R12, wherein R11 and R12 are as previously defined;
        
        
        (5) C3-alkenyl substituted with a moiety selected from the group consisting of
        
            (a) hydrogen,
            (b) halogen,
            (c) —CHO,
            (d) —CO2R10, wherein R10 is as previously defined,
            (e) —C(O)NR11R12, wherein R11 and R12 are as previously defined,
            (f) —C(O)R9, wherein R9 is as previously defined,
            (g) —CN,
            (h) aryl,
            (i) substituted aryl,
            (j) heteroaryl,
            (k) substituted heteroaryl,
            (l) —C3-C8-cycloalkyl, and
            (m) —C1-C12-alkyl substituted with heteroaryl;
        
        
        (6) C4-C10-alkenyl;
        (7) C4-C10-alkenyl substituted with one or more substituents selected from the group consisting of
        
            (a) halogen,
            (b) —C1-C3-alkoxy,
            (c) oxo,
            (d) —CHO,
            (e) —CO2R10, wherein R10 is as previously defined,
            (f) —C(O)NR11R12, wherein R11 and R12 are as previously defined,
            (g) —NR13R14, wherein R13 and R14 are as previously defined,
            (h) ═N—O—R10, wherein R10 is as previously defined,
            (i) —CN,
            (j) —O—S(O)nR10, wherein n is 0, 1, or 2 and R10 is as previously defined,
            (k) aryl,
            (l) substituted aryl,
            (m) heteroaryl,
            (n) substituted heteroaryl,
            (o) C3-C8-cycloalkyl,
            (p) C1-C12-alkyl substituted with substituted heteroaryl,
            (q) —NH—C(O)R10, wherein R10 is as previously defined,
            (r) —NH—C(O)NR11R12, wherein R11 and R12 are as previously defined,
            (s) ═N—NR13R14, wherein R13 and R14 are as previously defined,
            (t) ═N—R9, wherein R9 is as previously defined,
            (u) ═N—NH—C(O)R10, wherein R10 is as previously defined, and
            (v) ═N—NH—C(O)NR11R12, wherein R11 and R12 are as previously defined;
        
        
        (8) C3-C10-alkynyl;
        (9) C3-C10-alkynyl substituted with one or more substituents selected from the group consisting of
        
            (a) C1-C12-trialkylsilyl,
            (b) aryl,
            (c) substituted aryl,
            (d) heteroaryl, and
            (e) substituted heteroaryl; and
        
        
        (10) C(O)NR7R8, wherein R7 and R8 are independently selected from hydrogen, C1-C12-alkyl, and substituted C1-C12-alkyl, or R7 and R8 are taken with the nitrogen atom to which they are connected to form a 3- to 7-membered ring which, when the ring is a 5- to 7-membered ring, may optionally contain a hetero function selected from the group consisting of —O—, —NH, —N(C11-C6-alkyl)-, —N(aryl)-, —N(aryl-C1-C6-alkyl-)-, —N(substituted aryl-C1-C6-alkyl-)-, —N(heteroaryl)-, —N(heteroaryl-C1-C6-alkyl-)-, —N(substituted heteroaryl-C1-C6-alkyl-)-, and —S— or —S(O)n— wherein n is 1 or 2;
    
    
    B. Ra is selected from the group consisting of
    
        (1) hydrogen;
        (2) C1 alkyl further substituted with one or more substituents selected from the group consisting of
        
            (a) hydroxyl,
            (b) halogen,
            (c) thiol, which can be further substituted with an C1-C12-alkyl or substituted C1-C12-alkyl group,
            (d) C1-C12-alkyl, which can be further substituted by
            halogen, hydroxyl, C1-C12-alkoxy, or amino,
            (e) C1-C3-alkoxy,
            (f) C1-C3-thioalkoxy,
            (g) amino,
            (h) C1-C12-alkylamino,
            (i) C1-C12-dialkylamino,
            (j) —CN,
            (k) —NO2,
            (l) —CONH2,
            (m) —COOH,
            (n) —CO2R10, wherein R10 is as previously defined,
            (o) —N3,
            (u) ═N—O—R10, wherein R10 is as previously defined,
            (v) ═N—R9, wherein R9 is as previously defined,
            (w) ═N—NR13R14, wherein R13 and R14 are as previously defined,
            (x) ═N—NH—C(O)R10, wherein R10 is as previously defined, and
            (y) ═N—NH—C(O)NR11R12, wherein R11 and R12 are as previously defined;
        
        
        (3) C2-C4-alkenyl, which can be further substituted with C1-C12-alkyl and one or more halogen groups;
        (4) C2-C4-alkynyl, which can be further substituted with C1-C12-alkyl and one or more halogen groups;
        (5) aryl, which can be further substituted with C1-C12-alkyl and one or more halogen groups;
        (6) —CHO;
        (7) —CO2H;
        (8) —CN;
        (9) —CO2R10, wherein R10 is as previously defined;
        (10) —C(O)NR11R12, wherein R11 and R12 are as previously defined;
        (11) —C(O)R9, wherein R9 is as previously defined; and
        (12) thioester;
    
    
    C. Rb is hydrogen, halogen, C1-C12 alkyl, substituted C1-C12-alkyl, or C1-C12-alkyl further substituted with one or more halogen groups;
    D. Each R32 is independently selected from the group consisting of a free, salified, esterified and amidified
    
        (1) carboxyl, hydroxyl, halogen, —NO2, —CN, C1-C12-alkyl, C3-C12-cycloalkyl, C2-C12-alkenyl, C2-C12-alkynyl, O-alkyl, O-alkenyl, O-alkynyl, S-alkyl, S-alkenyl, S-alkynyl, N-alkyl, N-alkenyl, and N-alkynyl of up to 12 carbon atoms optionally substituted by one or more halogens;
        (2) —NR21(R22),
        
            wherein R21 and R22 are individually hydrogen or C1-C12-alkyl;
        
        
        (3) —C(O)R23,
        
            wherein R23 is C1-C12-alkyl; and
        
        
        (4) optionally substituted heteroaryl, O-aryl, S-aryl, and O-substituted-C1-C12 alkyl, or S-substituted-C1-C12 alkyl;
    
    
    E. q is 0, 1, 2, 3, or 4; and
    F. R33 and R34 are independently selected from the group consisting of hydrogen, halogen, C1-C12 alkyl, and substituted C1-C12-alkyl;


with the proviso that when q is 0, then R33 and R34 are not both hydrogen;
with the proviso that when Ra is ethyl, and R33 and R34 are hydrogen, then R32 is not 6-fluoro; and
with the proviso that when Ra is —CH═CH2, and R33 and R34 are hydrogen, then R32 is not 6-methyl.

    
    
        A) R is methyl;
        B) Ra is selected from the group consisting of hydrogen, —CH2CH3, —CH═CH2, and —C≡CH,
        C) Rb is hydrogen or halogen;
        D) Each R32 is independently selected from the group consisting of halogen, C1-C12-alkyl, C1-C12-alkoxy, C1-C12-alkylalkoxy, and N -substituted-C1-C12-alkyl; and
        E) R33 and R34 are independently selected from the group consisting of hydrogen or C1-C12-alkyl.
    
    


In some embodiments, the invention provides compounds of formula XII wherein R is methyl.
In still other embodiments, the invention provides compounds of formula XII wherein Ra is —CH2CH3.
In still other embodiments, the invention provides compounds of formula XII wherein Ra is —CH═CH2.
In still other embodiments, the invention provides compounds of formula XII wherein Ra is —C≡CH.
In still other embodiments, the invention provides compounds of formula XII wherein Rb is hydrogen.
In still other embodiments, the invention provides compounds of formula XII wherein Rb is fluorine.
In some embodiments, the invention provides compounds of formula XII wherein each R32 is independently selected from the group consisting of halogen, C1-C12-alkyl, C1-C12-alkoxy, C1-C12-alkylalkoxy, amino, and —NR21(R22). In some particular embodiments, the invention provides compounds of formula XII wherein at least one of R32 is 2-chloro, 6-chloro, 2-fluoro, or 6-fluoro. In other embodiments, the invention provides compounds of formula XII wherein R32 is methyl. In yet other embodiments, the invention provides compounds of formula XII wherein at least one of R32 is 5-methyl or 6-methyl.
In some further embodiments, the invention provides compounds of formula XII wherein at least one of R32 is methoxy or ethoxy. In some particular embodiments, the invention provides compounds of formula XII wherein at least one of R32 is 4-methoxy, 6-methoxy, or 4-ethoxy.
In still some further embodiments, the invention provides compounds of formula XII wherein at least one of R32 is amino, methylamino, or dimethylamino. In some particular embodiments, the invention provides compounds of formula XII wherein at least one of R32 is 6-amino, 6-methylamino, or 6-dimethylamino.
In other embodiments, the invention provides compounds of formula XII wherein R33 is methyl.
In other embodiments, the invention provides compounds of formula XII wherein R33 and R34 are independently selected from the group consisting of hydrogen and C1-C12-alkyl.
In still other embodiments, the invention provides compounds of formula XII wherein R34 is methyl.
In still other embodiments, the invention provides compounds having the formula (XIII):




In still other embodiments, the invention provides compounds having the formula (XIV):




or a pharmaceutically acceptable salt, ester or prodrug thereof.

In still other embodiments, the invention provides compounds having the formula (XV):




or a pharmaceutically acceptable salt, ester or prodrug thereof.

In still other embodiments, the invention provides compounds having the formula (XVI)




or a pharmaceutically acceptable salt, ester or prodrug thereof.

In still other embodiments, the invention provides compounds having the formula (XVII)




or a pharmaceutically acceptable salt, ester or prodrug thereof.

In still other embodiments, the invention provides compounds having the formula (XVIII)
In still other embodiments, the invention provides compounds having the formula




or a pharmaceutically acceptable salt, ester or prodrug thereof.

In still other embodiments, the invention provides compounds having the formula (XIX)




or a pharmaceutically acceptable salt, ester or prodrug thereof.

In still other embodiments, the invention provides compounds having the formula (XX)




or a pharmaceutically acceptable salt, ester or prodrug thereof.

In still other embodiments, the invention provides compounds having the formula (XXI)




or a pharmaceutically acceptable salt, ester or prodrug thereof.

In still other embodiments, the invention provides compounds having the formula (XXII)




or a pharmaceutically acceptable salt, ester or prodrug thereof

In still other embodiments, the invention provides compounds having the formula (XXIII)




or a pharmaceutically acceptable salt, ester or prodrug thereof.

In still other embodiments, the invention provides compounds having the formula (XXIV)




or a pharmaceutically acceptable salt, ester or prodrug thereof.

In still other embodiments, the invention provides compounds having the formula (XXV)




or a pharmaceutically acceptable salt, ester or prodrug thereof.

In still other embodiments, the invention provides compounds having the formula (XXVI)




or a pharmaceutically acceptable salt, ester or prodrug thereof.

In still other embodiments, the invention provides compounds having the formula (XXVII):
In still other embodiments, the invention provides compounds having the formula




or a pharmaceutically acceptable salt, ester or prodrug thereof.

In still other embodiments, the invention provides compounds having the formula (XXVIII)




or a pharmaceutically acceptable salt, ester or prodrug thereof.

In still other embodiments, the invention provides compounds having the formula (XXIX)




or a pharmaceutically acceptable salt, ester or prodrug thereof.

In still other embodiments, the invention provides compounds having the formula (XXX):




or a pharmaceutically acceptable salt, ester or prodrug thereof.

In still other embodiments, the invention provides compounds having the formula (XXXI)




or a pharmaceutically acceptable salt, ester or prodrug thereof.

In still other embodiments, the invention provides compounds having the formula (XXXII)




or a pharmaceutically acceptable salt, ester or prodrug thereof.

In still other embodiments, the invention provides compounds having the formula (XXXIII)




or a pharmaceutically acceptable salt, ester or prodrug thereof.

In still other embodiments, the invention provides compounds having the formula (XXXIV)




or a pharmaceutically acceptable salt, ester or prodrug thereof.

In still other embodiments, the invention provides compounds having the formula (XXXV)




or a pharmaceutically acceptable salt, ester or prodrug thereof.

In still other embodiments, the invention provides compounds having the formula (XXXVI)




or a pharmaceutically acceptable salt, ester or prodrug thereof.

In still other embodiments, the invention provides compounds having the formula (XXXVII)




or a pharmaceutically acceptable salt, ester or prodrug thereof.

In still other embodiments, the invention provides compounds having the formula (XXXVIII)




or a pharmaceutically acceptable salt, ester or prodrug thereof.

In some embodiments, the invention provides compounds of formula XII wherein

    q is 1, R33 is hydrogen, R34 is hydrogen, and R32 is 6-methyl; or
    q is 1, R33 is hydrogen, R34 is hydrogen, and R32 is 6-fluoro; or
    q is 1, R33 is hydrogen, R34 is hydrogen, and R32 is 6-chloro; or
    q is 1, R33 is hydrogen, R34 is hydrogen, and R32 is 6-methoxy; or
    q is 1, R33 is hydrogen, R34 is hydrogen, and R32 is 6-ethoxy; or
    q is 1, R33 is hydrogen, R34 is hydrogen, and R32 is 6-amino; or
    q is 1, R33 is hydrogen, R34 is hydrogen, and R32 is 6-methylamino; or
    q is 1, R33 is hydrogen, R34 is hydrogen, and R32 is 6-dimethylamino; or
    q is 1, R33 is hydrogen, R34 is hydrogen, and R32 is 4-chloro; or
    q is 1, R33 is hydrogen, R34 is hydrogen, and R32 is 4-methoxy; or
    q is 1, R33 is hydrogen, R34 is hydrogen, and R32 is 2-chloro; or
    q is 1, R33 is hydrogen, R34 is hydrogen, and R32 is 2-methoxy; or
    q is 2, R33 is hydrogen, R34 is hydrogen, one of R32 is 5-methyl, and the other of R32 is 6-chloro; or
    q is 1, R33 is methyl, R34 is hydrogen, and R32 is 6-methoxy; or
    q is 1, R33 is methyl, R34 is hydrogen, and R32 is 6-chloro; or
    q is 1, R33 is hydrogen, R34 is methyl, and R32 is 6-methoxy; or
    q is 1, R33 is hydrogen, R34 is methyl, and R32 is 6-chloro.


In yet another embodiment, the invention provides for a pharmaceutical composition comprising the compounds presented herein, pharmaceutically acceptable salts, esters, or prodrugs thereof, and a pharmaceutically acceptable carrier.
In yet another embodiment, the invention provides for a method of treating bacterial infection in a patient in need thereof comprising administering to said patient a therapeutically effecting amount of a pharmaceutical composition comprising a therapeutically effective amount of a compound presented herein, or a pharmaceutically acceptable salt, ester, or prodrug thereof, and a pharmaceutically acceptable carrier. In one embodiment, the patient is a mammal. In another embodiment the patient is a human.
In still another embodiment, the invention also provides for the use of the compounds presented herein in the manufacture of a medicament for the treatment or prophylaxis of bacterial infections.
In certain aspects, representative compounds of formulas II, III, IV, V, VI, VII, VIII, or XII are provided which include, but are not limited to, compounds in which Ra is hydrogen, substituted or unsubstituted C1-C12-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, aryl, or thioester; X is ═O; L is —CO; P is ═O; T is —NH— or —N(W—Rf), wherein W is as previously defined and Rf is an alkyl or substituted alkyl group, which may be further substituted by a heteroaryl selected from but not limited to










A, B, D, and E are H; and R is methyl, allyl, propyl, —CH2CHO, —CH2CH═NOH, —CH2CN, —CH2CH2NH2, —CH2CH2NHCH2-phenyl, —CH2CH2NHCH2CH2-phenyl, —CH2CH2—NHCH—(CO2CH3)CH2-phenyl, —CH2CH2NHCH2(4-pyridyl), —CH2CH2NHCH2—(4-quinolyl), —CH2CH═CH-phenyl, —CH2CH2CH2-phenyl, —CH2CH═CH—(4-methoxyphenyl), —CH2CH═CH—(4-chlorophenyl), —CH2CH═CH—(3-quinolyl), —CH2CH2CH2OH, —CH2C(O)OH, —CH2CH2CH═CHCH3, —CH2CH2NHCH2OH, —CH2CH2N(CH3)2, —CH2CH2—(1-morpholinyl), —CH2C(O)NH2, —CH2NHC(O)NH2, —CH2NHC(O)CH3, —CH2F, —CH2CH2OCH3, —CH2CH3, —CH2CH═C(CH3)2, —CH2CH2CH(CH3)CH3, —CH2CH2OCH2CH2OCH3, —CH2SCH3, -cyclopropyl, —CH2OCH3, —CH2CH2F, —CH2-cyclopropyl, —CH2CH2CHO, —C(O)CH2CH2CH3, —CH2—(4-nitrophenyl), —CH2-(4-chlorophenyl), —CH2—(4-methoxyphenyl), —CH2—(4-cyanophenyl), —CH2CH═CHC(O)OCH3, —CH2CH═CH—C(O)OCH2CH3, —CH2CH═CHCH3, —CH2CH═CHCH2CH3, —CH2CH═CHCH2CH2CH3, —CH2CH═CHSO2-phenyl, —CH2C═C—Si(CH3)3, —CH2C═CCH2CH2CH2CH2CH2CH3, —CH2C═CCH3, —CH2—(2-pyridyl), —CH2-(3-pyridyl), —CH2—(4-pyridyl), —CH2—(4-quinolyl), —CH2NO2, —CH2C(O)OCH3, —CH2C(O)-phenyl, —CH2C(O)CH2CH3, —CH2Cl, —CH2S(O)2-phenyl, —CH2CH═CHBr, —CH2CH═CH-(4-quinolyl), —CH2CH2CH2—(4-quinolyl), —CH2CH═CH-(5-quinolyl), —CH2CH2CH2-(5-quinolyl), —CH2CH═CH—(4-benzoxazolyl), —CH2CH═CH—(7-benzimidazolyl), —CH2-(3-iodophenyl), —CH2—(2-naphthyl), —CH2—CH═CH—(4-fluorophenyl), —CH2—CH(OH)—CN, —CH2CH═CH—(quinoxalin-6-yl), —CH2CH═CH—([1,8]-naphthyridin-3-yl), —CH2CH═CH-([1,5]-naphthyridin-3-yl), —CH2CH═CH—(5-pyridin-2-yl-thiophen-2-yl), —CH2CH═CH—(5-pyridin-3-yl-thiophen-2-yl), —CH2CH═CH—(5-(6-methylpyridin-3-yl)-thiophen-2-yl), —CH2CH═CH—(5-thiazol-2-yl-thiophen-2-yl), —CH2CH═CH—(5-thiazol-5-yl-thiophen-2-yl), —CH2CH═CH—(5-pyrimidin-2-yl-thiophen-2-yl), —CH2CH═CH—(5-pyrazin-2-yl-thiophen-2-yl), —CH2C—C—(quinolin-3-yl), —CH2C—C—(quinoxalin-6-yl), —CH2C≡C—([1,8]-naphthyridin-3-yl), —CH2C≡C—([1,5]-naphthyridin-3-yl), —CH2C≡C—(5-pyridin-2-yl-thiophen-2-yl), —CH2C≡C—(5-pyridin-3-yl-thiophen-2-yl), —CH2C≡C—(5-(6-methylpyridin-3-yl)-thiophen-2-yl), —CH2C≡C—(5-thiazol-2-yl-thiophen-2-yl), —CH2C≡C—(5-thiazol-5-yl-thiophen-2-yl), —CH2C═-C-(5-pyrimidin-2-yl-thiophen-2-yl), or —CH2C≡C—(5-pyrazin-2-yl-thiophen-2-yl).
Definitions
As used throughout this specification and the appended claims, the following terms have the meanings specified.
The term “alkyl” refers to saturated, straight, or branched chain hydrocarbon groups that do not contain heteroatoms. Thus the phrase includes straight chain alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, and the like. The phrase also includes branched chain isomers of straight chain alkyl groups, including but not limited to, the following which are provided by way of example: —CH(CH3)2, —CH(CH3)(CH2CH3), —CH(CH2CH3)2, —C(CH3)3, —C(CH2CH3)3, —CH2CH(CH3)2, —CH2CH(CH3)(CH2CH3), —CH2CH(CH2CH3)2, —CH2C(CH3)3, —CH2C(CH2CH3)3, —CH(CH3)CH(CH3)(CH2CH3), —CH2CH2CH(CH3)2, —CH2CH2CH(CH3)(CH2CH3), —CH2CH2CH(CH2CH3)2, —CH2CH2C(CH3)3, —CH2CH2C(CH2CH3)3, —CH(CH3)CH2CH(CH3)2, —CH(CH3)CH(CH3)CH(CH3)2, —CH(CH2CH3)CH(CH3)CH(CH3)(CH2CH3), and others. Alkyl also includes cyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl and such rings substituted with straight and branched chain alkyl groups as defined above. Thus the phrase alkyl groups includes primary alkyl groups, secondary alkyl groups, and tertiary alkyl groups. Preferred alkyl groups include straight and branched chain alkyl groups and cyclic alkyl groups having 1 to 12 carbon atoms.
The phrase “substituted alkyl” refers to an alkyl group as defined above in which one or more bonds to a carbon(s) or hydrogen(s) are replaced by a bond to non-hydrogen and non-carbon atoms such as, but not limited to, a halogen atom such as F, Cl, Br, and I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, aryloxy groups, and ester groups; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; a silicon atom in groups such as in trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl groups; and other heteroatoms in various other groups. Substituted alkyl groups also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom is replaced by a higher-order bond (e.g., a double- or triple-bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; nitrogen in groups such as imines, oximes, hydrazones, and nitriles. Substituted alkyl groups further include alkyl groups in which one or more bonds to a carbon(s) or hydrogen(s) atoms is replaced by a bond to an aryl, heterocyclyl group, or cycloalkyl group. Preferred substituted alkyl groups include, among others, alkyl groups in which one or more bonds to a carbon or hydrogen atom is/are replaced by one or more bonds to fluorine atoms. Another preferred substituted alkyl group is the trifluoromethyl group and other alkyl groups that contain the trifluoromethyl group. Other preferred substituted alkyl groups include those in which one or more bonds to a carbon or hydrogen atom is replaced by a bond to an oxygen atom such that the substituted alkyl group contains a hydroxyl, alkoxy, or aryloxy group. Still other preferred substituted alkyl groups include alkyl groups that have an amine, or a substituted or unsubstituted alkylamine, dialkylamine, arylamine, (alkyl)(aryl)amine, diarylamine, heterocyclylamine, diheterocyclylamine, (alkyl)(heterocyclyl)amine, or (aryl)(heterocyclyl)amine group.
The terms “C1-C3-alkyl”, “C1-C6-alkyl”, and “C1-C12-alkyl” as used herein refer to saturated, straight, or branched chain hydrocarbon radicals derived from a hydrocarbon moiety containing between one and three, one and six, and one and twelve carbon atoms, respectively, by removal of a single hydrogen atom. Examples of C1-C3-alkyl radicals include methyl, ethyl, propyl, and isopropyl; examples of C1-C6-alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, and n-hexyl. Examples of C1-C12-alkyl radicals include, but are not limited to, all the foregoing examples as well as n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-docecyl.
The term “C1-C6-alkoxy” as used herein refers to a C1-C6-alkyl group, as previously defined, attached to the parent molecular moiety through an oxygen atom. Examples of C1-C6-alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, neopentoxy, and n-hexoxy.
The term “C2-C12-alkenyl” denotes a monovalent group derived from a hydrocarbon moiety containing from two to twelve carbon atoms and having at least one carbon-carbon double bond. Alkenyl groups include, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like.
The term “C2-C12-alkynyl” as used herein refers to a monovalent group derived from a hydrocarbon moiety containing from two to twelve carbon atoms and having at least one carbon-carbon triple bond. Representative alkynyl groups include ethynyl, propynyl, and the like.
The term 14-member macrolide antibiotics used herein include the natural products erythromycin, narbomycin, lakamycin, and oleandomycin, as well as derivatives such as roxithromycin, clarithromycin, dirithromycin, flurithromycin, and the ketolides (telithromycin, HMR 3004, TE-802, TE-810, ABT 773).
The term “alkylene” denotes a divalent group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms, for example methylene, 1,2-ethylene, 1,1-ethylene, 1,3-propylene, 2,2-dimethyl-propylene, and the like.
The term “C1-C3-alkylamino” as used herein refers to one or two C1-C3-alkyl groups, as previously defined, attached to the parent molecular moiety through a nitrogen atom. Examples of C1-C3-alkylamino include, but are not limited to methylamino, dimethylamino, ethylamino, diethylamino, and propylamino.
The term “oxo” denotes a group wherein two hydrogen atoms on a single carbon atom in an alkyl group as defined above are replaced with a single oxygen atom (i.e., a carbonyl group).
The term “aryl” as used herein refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl, and the like. Representative aryl groups comprise from 3 to 12 carbon atoms. Preferable aryl groups include, but are not limited to, aryl groups of C3-C12, such as C4-C10 and C6-C8. Aryl groups (including bicyclic aryl groups) can be unsubstituted or substituted with one, two, or three substituents independently selected from loweralkyl, substituted loweralkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, acylamino, cyano, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl, and carboxamide. In addition, substituted aryl groups include tetrafluorophenyl and pentafluorophenyl.
The term “C3-C12-cycloalkyl” denotes a monovalent group derived from a monocyclic or bicyclic saturated carbocyclic ring compound. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl, and bicyclo[2.2.2]octyl.
The terms “halo” and “halogen” as used herein refer to an atom selected from fluorine, chlorine, bromine, and iodine.
The term “alkylamino” refers to a group having the structure —NHR′, wherein R′ is alkyl as previously defined. Examples of alkylamino include, but are not limited to, methylamino, ethylamino, and iso-propylamino.
The term “dialkylamino” refers to a group having the structure —NR′R′′, wherein R′ and R′′ are independently selected from alkyl as previously defined. Additionally, R′ and R′′ taken together may optionally be —(CH2)k—, wherein k is an integer from 2 to 6. Examples of dialkylamino include, but are not limited to, dimethylamino, diethylamino, diethylaminocarbonyl, methylethylamino, methyl-propylamino, and piperidino.
The term “haloalkyl” denotes an alkyl group, as defined above, having one, two, or three halogen atoms attached thereto and is exemplified by such groups as chloromethyl, bromoethyl, trifluoromethyl, and the like.
The term “alkoxycarbonyl” represents an ester group; i.e., an alkoxy group, attached to the parent molecular moiety through a carbonyl group, such as methoxycarbonyl, ethoxycarbonyl, and the like.
The term “thioalkoxy” refers to an alkyl group as previously defined attached to the parent molecular moiety through a sulfur atom.
The term “carboxaldehyde” as used herein refers to a group of formula —CHO.
The term “carboxy” as used herein refers to a group of formula —CO2H.
The term “carboxamide” as used herein refers to a group of formula —CONHR′R′′, wherein R′ and R′′ are independently selected from hydrogen or alkyl, or R′ and R′′ taken together may optionally be —(CH2)k—, wherein k is an integer from 2 to 6.
The term “heteroaryl”, as used herein, refers to a cyclic or bicyclic aromatic radical having from five to ten ring atoms in each ring of which one atom of the cyclic or bicyclic ring is selected from S, O, and N; zero, one or two ring atoms are additional heteroatoms independently selected from S, O, and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms, such as, for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, and naphthyridinyl. Representative heteroaryl groups comprise from 3 to 12 carbon atoms. Preferable heteroaryl groups include, but are not limited to, aryl groups of C3-C12, such as C4-C10 and C6-C8. Representative examples of heteroaryl moieties include, but not limited to, pyridin-3-yl-1H-imidazol-1-yl, phenyl-1H-imidazol-1-yl, 3H-imidazo[4,5-b]pyridin-3-yl, quinolin-4-yl, 4-pyridin-3-yl-1H-imidazol-1-yl, quinolin-4-yl, quinolin-2-yl, 2-methyl-4-pyridin-3-yl-1H-imidazol-1-yl, 5-methyl-4-pyridin-3-yl-1H-imidazol-1-yl, 1H-imidazo[4,5-b]pyridin-1-yl, pyridin-3-ylmethyl, 3H-imidazo[4,5-b]pyridin-3-yl, 4-pyrimidin-5-yl-1H-imidazol-1-yl, 4-pyrazin-2-yl-1H-imidazol-1-yl, 4-pyridin-3-yl-1H-imidazol-1-yl, 4-pyridin4-yl-1H-imidazol-1-yl, 4-(6-methylpyridin-3-yl)-1H-imidazol-1-yl, 4-(6-fluoropyridin-3-yl)-1H-imidazol-1-yl, 5-(3-aminophenyl)-1,3-thiazol-2-yl, 3-pyridin-3-ylphenoxy, 4-pyridin-3-ylphenoxy, 3H-imidazo[4,5-b]pyridin-3-yl, 4-phenyl-1H-imidazol-1-yl, 1H-pyrrolo[3,2-b]pyridin-1-yl, quinolin-3-yl, 2-methylquinolin-4-yl, trifluoromethyl)quinolin-4-yl, 8-(trifluoromethyl)-quinolin-4-yl, 2-phenoxyethoxy, 4-pyridin-3-ylphenoxy, 3-pyridin-3-ylphenoxy, 5-phenyl-1,3-thiazole, 5-(2,4-difluorophenyl)-1,3-thiazol-2-yl, 5-(3-aminophenyl)-1,3-thiazol-2-yl, (3,3′-bipyridin-5-ylmethyl)(methyl)amino, (6-methylpyridin-3-yl)-1H-imidazol-1-yl, methyl(quinolin-3-ylmethyl)amino, 3-phenylisoxazol-5-yl, 3-(4-methylphenyl)isoxazol-5-yl, and the like.
The term “heterocycloalkyl” as used herein, refers to a non-aromatic partially unsaturated or fully saturated 3- to 10-membered ring system, which includes single rings of 3 to 8 atoms in size and bi- or tri-cyclic ring systems which may include aromatic six-membered aryl or heteroaryl rings fused to a non-aromatic ring. These heterocycloalkyl rings include those having from one to three heteroatoms independently selected from oxygen, sulfur, and nitrogen, in which the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
Representative heterocycles include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.
The term “heteroarylalkyl” as used herein, refers to a heteroaryl group as defined above attached to the parent molecular moiety through an alkylene group wherein the alkylene group is of one to four carbon atoms.
“Hydroxy-protecting group”, as used herein, refers to an easily removable group which is known in the art to protect a hydroxyl group against undesirable reaction during synthetic procedures and to be selectively removable. The use of hydroxy-protecting groups is well known in the art for protecting groups against undesirable reactions during a synthetic procedure and many such protecting groups are known, cf., for example, T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley & Sons, New York (1991). Examples of hydroxy-protecting groups include, but are not limited to, methylthiomethyl, tert-dimethylsilyl, tert-butyldiphenylsilyl, ethers such as methoxymethyl, and esters including acetyl, benzoyl, and the like.
The term “ketone protecting group”, as used herein, refers to an easily removable group which is known in the art to protect a ketone group against undesirable reaction during synthetic procedures and to be selectively removable. The use of ketone-protecting groups is well known in the art for protecting groups against undesirable reaction during a synthetic procedure and many such protecting groups are known, cf., for example, T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley & Sons, New York (1991). Examples of ketone-protecting groups include, but are not limited to, ketals, oximes, O-substituted oximes for example O-benzyl oxime, O-phenylthiomethyl oxime, 1-isopropoxycyclohexyl oxime, and the like.
The term “protected-hydroxy” refers to a hydroxy group protected with a hydroxy protecting group, as defined above, including benzoyl, acetyl, trimethylsilyl, triethylsilyl, and methoxymethyl groups, for example.
The term “substituted aryl” as used herein refers to an aryl group as defined herein substituted by independent replacement of one, two, or three of the hydrogen atoms thereon with Cl, Br, F, I, OH, CN, C1-C3-alkyl, C1-C6-alkoxy, C1-C6-alkoxy substituted with aryl, haloalkyl, thioalkyl, thioalkoxy, amino, alkylamino, dialkylamino, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl, and carboxamide. In addition, any one substituent may be an aryl, heteroaryl, or heterocycloalkyl group.
The term “substituted heteroaryl” as used herein refers to a heteroaryl group as defined herein substituted by independent replacement of one, two, or three of the hydrogen atoms thereon with Cl, Br, F, I, OH, CN, C1-C3-alkyl, C1-C6-alkoxy, C1-C6-alkoxy substituted with aryl, haloalkyl, thioalkoxy, amino, alkylamino, dialkylamino, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl, and carboxamide. In addition, any one substituent may be an aryl, heteroaryl, or heterocycloalkyl group.
The term “substituted heterocycloalkyl” as used herein, refers to a heterocycloalkyl group, as defined above, substituted by independent replacement of one, two or three of the hydrogen atoms thereon with Cl, Br, F, I, OH, CN, C1-C3-alkyl, C1-C6-alkoxy, C1-C6-alkoxy substituted with aryl, haloalkyl, thioalkyl, thioalkoxy, amino, alkylamino, dialkylamino, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide. In addition, any one substituent may be an aryl, heteroaryl, or heterocycloalkyl group.
Numerous asymmetric centers may exist in the compounds of the present invention. Except where otherwise noted, the present invention contemplates the various stereoisomers and mixtures thereof. Accordingly, whenever a bond is represented by a wavy line, it is intended that a mixture of stereo-orientations or an individual isomer of assigned or unassigned orientation may be present.
As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977), incorporated herein by reference. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
As used herein, the term “pharmaceutically acceptable ester” refers to esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic COOH, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Representative examples of particular esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.
The term “pharmaceutically acceptable prodrugs” as used herein refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term “prodrug” refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
Synthetic Methods
Synthesis of the compounds of the invention can be broadly summarized as follows. 1) The free alcohols on the sugars and the reduced C9 ketone are protected in a fashion that allows for the relatively efficient elimination of the C12 hydroxy group (i.e., without burdensome competing side products) to form an alkene intermediate. 2) The alkene intermediate is converted to an epoxide, diol, or ketone intermediate. 3) The epoxide, diol, and ketone is then used to introduce new C12 substituents. 4) Further manipulations are then carried out as needed to generate the desired final products.
1. Useful intermediates for producing useful C12 olefins. The above-described disclosure of the Lartey patent (U.S. Pat. No. 5,217,960) is limited, because the C9 amine disclosed therein cannot be converted to a ketone to access C9-keto analogs combined with C12 modifications. The unavailability of this option is unfortunate in view of the fact that compounds lacking the C9-keto group generally show weak antibacterial activity. Alternatively the disclosure of the Hauske patent (U.S. Pat. No. 4,857,641) typically leads to a complex mixture of products. Thus, Hauske does not show or suggest synthetically reasonable routes to address the deficiencies of Lartey.
Thus, in one aspect, the invention provides macrolide and ketolide synthesis procedures having advantages over the prior teachings of Hauske and Lartey. Surprisingly, the inventors have found that the C9 and C11-diols, when protected as acid labile acetonides or base labile carbonates, provide relatively efficient elimination at C12 over C6. Moreover, the inventors have discovered that the elimination reaction to form the C12 alkene can be more efficiently carried out when acetates are not used to protect the 2′ and 4′′ positions of the associated sugars as is taught by the prior art. Representative protecting groups used in the novel and surprisingly effective synthesis methodologies provided by the present invention include, but are not limited to, benzyl (Bz) esters and TMS ethers. This invention also provides still other alternative protecting groups that lead to useful C12 alkene intermediates. For example, the five illustrative compounds below have been found to be useful precursors for the elimination reaction to form the corresponding C12 alkenes.







2. New macrolide and ketolide antibiotics arising from an epoxide intermediate. In one aspect, this invention provides means for functionalizing the macrolide C12 methyl group with optionally substituted alkyl, alkenyl, alkynyl, and aryl groups to give a new, monosubstituted C12 methyl group. It has been found that the alkyl and aryl cuprates LiMe2Cu and LiPh2Cu can be efficiently added to a C12 epoxide to produce, effectively, the respective ethyl and benzyl substituents at C12. This invention also contemplates a number of novel substituents at C12 that may be similarly introduced via the reagents shown below.




In addition to the above carbanion equivalents, nucleophiles (such as azides and thiolates) known to react with epoxides are also included with the methods and compounds provided by the invention.
3. New C12 ketone intermediate. In other aspects, the present invention relates to methods for introducing a ketone at the C12 position. In this aspect, a C12 olefin can undergo ozonolysis to form the corresponding ketone. This procedure can be efficiently carried out if the amino group on the desosamine sugar is preferably protonated to minimize generating unwanted side products. This invention also contemplates other methods for producing a ketone at C12 such as treatment of the alkene with RuO4 or dihydoxylating the precursor olefin followed by diol cleavage with NaIO4.
4. Method for generating new macrolides and ketolides from ketone intermediate. A. Addition of nucleophiles from top face. Unlike the epoxide route that only allows access to monosubstituted C12 methyl groups, this procedure further relates to methods for replacing the C12 methyl group entirely with substituents such as H or CF3. such as shown in Scheme A, below.




B. Introduction of a tertiary amine at C12. The C12 ketone moiety is useful in the synthesis of derivatives with a C12 amine. The following “reverse carbamate” analog containing a 4′′ benzoate has been synthesized.




5. Representative examples of other C12 modified compounds. Further examples of analogs that may be synthesized using the above methods are described in the following section.










Scheme 1a illustrates one embodiment of the invention, whereby novel C12 modifications may be introduced via an epoxide intermediate. Starting with compound 1, the free hydroxyl groups on the sugar moieties may be protected as benzyl (Bz) esters followed by stereoselective reduction of the C9 ketone to give compound 2. After protecting the two remaining secondary alcohols as their formate esters, the C12 tertiary alcohol 3 may be treated with thionyl chloride and an amine base to form the exocyclic alkene 4. The formate protecting groups may then be removed by treatment with MeOH. These conditions may also result in deprotection of the benzyl esters, which can be overcome by an additional protection step to reinstall the benzyl protecting groups, if necessary. Olefin 5 may then be epoxidized and the resulting C9 alcohol 6 selectively reoxidized back to the ketone 7. Ring opening of epoxide 7 with a nucleophile to give 8 followed by global removal of the sugar protecting groups furnishes analog 9 with a new C21 substituent.







A similar reaction sequence shown in Scheme 1b has also been carried out where an acetonide, rather than formate, is used to protect the C9-C11, diol of 2 to give compound 10. Treatment of alcohol 10 with SOCl2/Et3N gives the C12 olefin 11 that is then epoxidized. The epoxide ring opening may be successfully carried out with LiMe2Cu and LiPh2Cu. The resulting intermediates are useful for accessing C12 telithromycin analogs and demonstrate the viability of cuprate mediated C12 epoxide openings.

















In another embodiment of the invention, the C12 modification can be introduced via a ketone intermediate. In this embodiment, olefin 11 is converted to ketone 12 under ozonolytic conditions, as shown in Scheme 2a, above. H or CF3 can be added to the ketone product. The resulting C12 alcohol of 13 may be inverted via a four-step process involving the initial steps of activating the alcohol to give 14 and then removing the acetonide. Here, two options are possible. The sugar moiety at C3 may also be removed during the acetonide deprotection if 10% HCl/MeCN or PPTS (EtOH, 90° C.) is used; use of HOAc/H2O/MeOH removes only the acetonide (Scheme 2b). The C3 and C9 alcohols of 15 are regioselectively oxidized to 16 and the inversion step is next effected under basic conditions to give 17. During this process, a C10-C11 alkene also forms that can be refunctionalized by an intramolecular michael addition as taught in U.S. Pat. No. 5,635,485. More specifically, an activated carbamate at C12 of 18, formed by condensation of the alcohol 17 with carbonyl diimidazole may be coupled to a variety of alkyl amines. The resulting intermediate then cyclizes in situ to form the cyclic carbamate 19. Removal of the remaining protecting groups yields the novel ketolides 20. A similar route as utilized for the C12-hydrogen series, is outline in Scheme 3 for the C12-trifluoromethyl series.











These manipulations may also be carried out on erythromycin as shown in Scheme 4 above. These transformations parallel those shown in the above example (Scheme 1, epoxide route) but are applied to a more demanding case wherein the intermediates contain a free C6 tertiary alcohol. Acetonide and carbonate protecting groups are useful in directing olefin formation at C12 over C6. Representative sugar protecting groups for this purpose include, for example, TMS and benzyl esters.







With alkene 30 successfully in hand, epoxidation or ozonolysis can lead to useful intermediates for generating novel compounds containing a modified C12 substituent. Scheme 5a shows the process to prepare C12-derivatives by way of C12,21-epoxide. Scheme 5b outlines modifications of C12-ketone.




Greater diversity at C12 can also be attained by conversion of the C12 ketone to an imine prior to the introduction of nucleophiles as shown in Scheme 6.








Dihydroxylation of alkene 30 can lead to useful intermediates for generating novel compounds containing modified C12 substituents as depicted in Scheme 7. Upon deprotection of the C9-C12 acetonide the C12 exocyclic olefin can be dihydroxylated yielding a tetraol that can be selectively protected at the primary C21 alcohol as the acetate. Selective oxidation of the C9 hydroxyl and mesylation of the C11 hydroxyl followed by elimination yields the C9-C11 enone. Removal of the cladinose and acetate yields a triol that can be bis oxidized to give a C12 formyl substituent. A Wittig reaction coverts this to the C12 vinyl substituent and then following in the manner described already the cyclic carbamate is installed.




Further modification of dihydroxylated derived compound A can lead to further C12 modified macrolides, as described in Scheme 8. Selective silyl protection of the primary alcohol in A, followed by C3 oxidation, conversion to the cyclic carbamate in the usual fashion and disilylation yields the C12 hydroxymethyl macrolide. The C21 hydroxyl can be sulfonylated to form the C21 mesylate as depicted. The C12 hydroxymethyl can also be oxidized to form the C12 formyl macrolide. Wittig reaction on the C12 formyl, or reaction with organometallics, followed by oxidation yields the C12 alkenyl and C12 acteyl macrolides respectively as depicted.
Scheme 9 outlines the synthetic method to make novel C12 anhydrolides 308. Route 1 shows that novel C12 enone-ol 305 can be converted to 11,12-cyclic carbamate 306 in a similar manner as shown in Scheme 2b. Further modifications include removal of cladinose under acidic condition, activating 3-hydroxy as mesylate, and elimination under basic condition to give desired anhydrolide 308. Alternatively, C2, C3 double bond can be formed prior to the formation of C11, C12-cyclic carbamate as shown in Route 2.











Scheme 10 depicts representative methods used to construct side chains incorporated into the macrolides of the invention.
In the foregoing reaction schemes and other synthesis methods disclosed herein, diol protecting groups for the C9-C11 diol, wherein both alcohols are linked to form a 6-8 membered ring, may include, but are not limited to, those described in Greene and Wuts (1991), supra. Exemplary groups include cyclic acetals, such as methylene, ethylidene, 2,2,2-trichloroethylidene, benzylidene, p-methoxybenzylidene, 2,4-dimethoxybenzylidene, 3,4-dimethoxybenzylidene, 2-nitrobenzylidene; ketals such as 1-t-butylethylidene, 1-phenylethylidene, and (4-methoxyphenyl)ethylidene, acetonide, cyclopentylidene, cyclohexylidene, and cycloheptylidene; cyclic ortho esters such as methoxymethylene, ethoxymethylene, dimethoxymethylene, 1-methoxyethylidene, 1-ethoxyethylidine, 1,2-dimethoxyethylidene, a-methoxybenzylidene, 1-(N,N-dimethylamino)ethylidene, a-(N,N-dimethylamino)benzylidene, 2-oxacyclopentylidene; cyclic silyl ethers such as di-t-butylsilylene, 1,3-(1,1,3,3-tetraisopropyldisiloxanylidene), tetra-t-butoxy-disiloxane-1,2-diylidene; cyclic carbonates; and cyclic boronates such as ethyl, phenyl, their polymeric versions, and boronates linking two or more macrolides. Additionally, the diol as well as the sugar alcohols may be individually and independently protected with suitable alcohol blocking groups familiar to those skilled in the art. Exemplary protecting groups include but are not limited to silyl ethers such t-butyldimethyl-chlorosilyl, trimethylchlorosilyl, triisopropylchlorosilyl, triethylchlorosilyl, diphenylmethylsilyl, and triphenylsilyl; optionally substituted ethers such as triphenylmethyl, methoxymethyl, methythiomethyl, benzyloxymethyl, t-butoxymethyl, 2-methoxyethoxymethyl, tetrahydropyranyl, 1-ethoxyethyl ether, allyl, benzyl, p-methoxybenzyl, and nitrobenzyl; aryl and alkyl esters such as benzoylformate, formate, acetate, trichloroacetate, trifluoracetate, and pivaloate; and carbonates such as methyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, vinyl, allyl, p-nitrophenyl, benzyl, and p-methoxybenzyl.
Pharmaceutical Compositions
Pharmaceutical compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers. As used herein, the term “pharmaceutically acceptable carrier” means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. The pharmaceutical compositions of this invention can be administered to humans and other mammals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, or as an oral or nasal spray, or a liquid aerosol or dry powder formulation for inhalation.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.
The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form may be accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations may also be prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, acetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise one or more buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise one or more buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulations, ear drops, and the like are also contemplated as being within the scope of this invention.
The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
Compositions of the invention may also be formulated for delivery as a liquid aerosol or inhalable dry powder. Liquid aerosol formulations may be nebulized predominantly into particle sizes that can be delivered to the terminal and respiratory bronchioles where bacteria reside in patients with bronchial infections, such as chronic bronchitis and pneumonia. Pathogenic bacteria are commonly present throughout airways down to bronchi, bronchioli and lung parenchema, particularly in terminal and respiratory bronchioles. During exacerbation of infection, bacteria can also be present in alveoli. Liquid aerosol and inhalable dry powder formulations are preferably delivered throughout the endobronchial tree to the terminal bronchioles and eventually to the parenchymal tissue.
Aerosolized formulations of the invention may be delivered using an aerosol forming device, such as a jet, vibrating porous plate or ultrasonic nebulizer, preferably selected to allow the formation of a aerosol particles having with a mass medium average diameter predominantly between 1 to 5 microns. Further, the formulation preferably has balanced osmolarity ionic strength and chloride concentration, and the smallest aerosolizable volume able to deliver effective dose of the compounds of the invention to the site of the infection. Additionally, the aerosolized formulation preferably does not impair negatively the functionality of the airways and does not cause undesirable side effects.
Aerosolization devices suitable for administration of aerosol formulations of the invention include, for example, jet, vibrating porous plate, ultrasonic nebulizers and energized dry powder inhalers, that are able to nebulize the formulation of the invention into aerosol particle size predominantly in the size range from 1-5 microns. Predominantly in this application means that at least 70% but preferably more than 90% of all generated aerosol particles are within 1-5 micron range. A jet nebulizer works by air pressure to break a liquid solution into aerosol droplets. Vibrating porous plate nebulizers work by using a sonic vacuum produced by a rapidly vibrating porous plate to extrude a solvent droplet through a porous plate. An ultrasonic nebulizer works by a piezoelectric crystal that shears a liquid into small aerosol droplets. A variety of suitable devices are available, including, for example, AeroNeb and AeroDose vibrating porous plate nebulizers (AeroGen, Inc., Sunnyvale, Calif.), Sidestream nebulizers (Medic-Aid Ltd., West Sussex, England), Pari LC and Pari LC Star jet nebulizers (Pari Respiratory Equipment, Inc., Richmond, Va.), and Aerosonic (DeVilbiss Medizinische Produkte (Deutschland) GmbH, Heiden, Germany) and UltraAire (Omron Healthcare, Inc., Vernon Hills, Ill.) ultrasonic nebulizers.
Compounds of the invention may also be formulated for use as topical powders and sprays that can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.
Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
According to the methods of treatment of the present invention, bacterial infections are treated or prevented in a patient such as a human or lower mammal by administering to the patient a therapeutically effective amount of a compound of the invention, in such amounts and for such time as is necessary to achieve the desired result. By a “therapeutically effective amount” of a compound of the invention is meant a sufficient amount of the compound to treat bacterial infections, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.
The total daily dose of the compounds of this invention administered to a human or other mammal in single or in divided doses can be in amounts, for example, from 0.01 to 50 mg/kg body weight or more usually from 0.1 to 25 mg/kg body weight. Single dose compositions may contain such amounts or submultiples thereof to make up the daily dose. In general, treatment regimens according to the present invention comprise administration to a patient in need of such treatment from about 10 mg to about 2000 mg of the compound(s) of this invention per day in single or multiple doses.
Characterization and Purification Methods
Referring to the examples that follow, compounds of the present invention were characterized by high performance liquid chromatography (HPLC) using a Waters Millenium chromatography system with a 2690 Separation Module (Milford, Mass.). The analytical columns were Alltima C-18 reversed phase, 4.6×250 mm from Alltech (Deerfield, Ill.). A gradient elution was used, typically starting with 5% acetonitrile/95% water and progressing to 100% acetonitrile over a period of 40 minutes. All solvents contained 0.1% trifluoroacetic acid (TFA). Compounds were detected by ultraviolet light (UV) absorption at either 220 or 254 nm. HPLC solvents were from Burdick and Jackson (Muskegan, Mich.), or Fisher Scientific (Pittsburg, Pa.). In some instances, purity was assessed by thin layer chromatography (TLC) using glass or plastic backed silica gel plates, such as, for example, Baker-Flex Silica Gel IB2-F flexible sheets. TLC results were readily detected visually under ultraviolet light, or by employing well known iodine vapor and other various staining techniques.
Mass spectrometric analysis was performed on one of two LCMS instruments: a Waters System (Alliance HT HPLC and a Micromass ZQ mass spectrometer; Column: Eclipse XDB-C18, 2.1×50 mm; Solvent system: 5-95% (or 35-95% , or 65-95% or 95-95%) acetonitrile in water with 0.05% TFA; Flow rate 0.8 ml/min; Molecular weight range 500-1500; Cone Voltage 20 V; Column temperature 40° C.) or a Hewlett Packard System (Series 100 HPLC; Column: Eclipse XDB-C18, 2.1×50 mm; Solvent system: 1-95% acetonitrile in water with 0.05% TFA; Flow rate 0.4 ml/min; Molecular weight range 150-850; Cone Voltage 50 V; Column temperature 30° C.). All masses are reported as those of the protonated parent ions.
GCMS analysis was performed on a Hewlet Packard instrument (HP6890 Series gas chromatograph with a Mass Selective Detector 5973; Injector volume: 1 μL; Initial column temperature 50° C.; Final column temperature: 30° C.; Ramp time: 20 minutes; Gas flow rate: 1 ml/min; Column: 5% Phenyl Methyl Siloxane, Model #HP 190915-443, Dimensions: 30.0 m×25 m×0.25 m).
Nuclear magnetic resonance (NMR) analysis was performed with a Varian 300 MHz NMR (Palo Alto, Calif.). The spectral reference was either TMS or the known chemical shift of the solvent. Some compound samples were run at elevated temperatures (i.e., 75° C.) to promote increased sample solubility.
The purity of some of the invention compounds was assessed by elemental analysis (Desert Analytics, Tuscon, Ariz.)
Melting points were determined on a Laboratory Devices MeI-Temp apparatus (Holliston, Mass.).
Preparative separations were carried out using a Flash 40 chromatography system and KP-Sil, 60A (Biotage, Charlottesville, Va.), or by flash column chromatography using silica gel (230-400 mesh) packing material, or by HPLC using a C-18 reversed phase column. Typical solvents employed for the Flash 40 Biotage system and flash column chromatography were dichloromethane, methanol, ethyl acetate, hexane, acetone, aqueous hydroxyamine and triethyl amine. Typical solvents employed for the reverse phase HPLC were varying concentrations of acetonitrile and water with 0. 1% trifluoroacetic acid.
The foregoing may be better understood by reference to the following examples which are presented for illustration and not to limit the scope of the inventive concepts.
EXAMPLE 1
SYNTHESIS of 12,21-ANHYDRO-9-DIHYDRO ERYTHROMYCIN A VIA BIS TMS 9,11-CARBONATE







To a THF solution (0.15 M) of bis TMS 9-dihydro erythronolide A triol (prepared according to known procedures) was added CDI (1.1 eq) and K2CO3 (4.2 eq). After 3 h, EtOAc and sat. NaHCO3 were added. The organic layer was washed with 5% KH2PO4, water and brine, dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (25% to 50% EtOAc in Hx gradient) gave the desired carbonate as a white foam. MS m/z 906.9 (MH+).
To a 0° C. EtOAc solution (0.06 M) of the above carbonate was added Et3N (4.0 eq) followed by SOCl2 (1.2 eq). After 1 h, the reaction was quenched with saturated NaHCO3 and the organic layer was washed with 5% KH2PO4 (3×), water, and brine, dried over Na2SO4, and concentrated. Purification by silica gel chromatography (20% EtOAc in Hx with 2% Et3N) gave the desired elimination product. MS m/z 888.9 (MH+).
The C12 alkene was combined with a 10% HCOOH in iPrOH to give a 0.35 M solution. After 1 h, 1 M K2CO3 was added until the pH was approximately 8-9. The reaction was then diluted with EtOAc and the organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated to give the crude product as a white foam. MS m/z 744.6 (MH+). The crude product was then suspended in MeOH (0.3 M) and to this was added 1 M K2CO3 (1.5 eq). The reaction was be monitored by TLC and after 2.5 h, 5% KH2PO4 and EtOAc was added. The aqueous layer was extracted with more EtOAc (2×) and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated. Purification by crystallization from MeCN gave the desired product. MS m/z 718.6 (MH+).
EXAMPLE 2 
SYNTHESIS of 12,21-ANHYDRO-9-DIHYDRO ERYTHROMYCIN A VIA BIS TMS 9,11-ACETONIDE







To a 1:1 acetone:2,2-dimethoxypropane solution (0.22 M) containing 9-dihydro erythronolide A was added PPTS (3 eq) and the resulting solution was refluxed. The reaction was monitored by TLC to watch for cleavage of the cladinose sugar. After approximately 1.5 h the reaction was cooled, quenched with Et3N, and concentrated. The residue was suspended in CHCl3, washed with 5% KH2PO4, 1N NH4OH, and brine. The organic extracts were then dried over Na2SO4, and concentrated. Purification by silica gel chromatography (3% MeOH in CHCl3 with 0.5% NH4OH to 10% MeOH in CHCl3 with 0.5% NH4OH) gave the desired acetonide product. MS m/z 776 (MH+).
To an EtOAc solution (0.13 M) of the acetonide was added dropwise via cannula an EtOAc (0.8 M) solution containing TMSCl (1.5 eq) and TMSIm (1.5 eq). After 2 hours, saturated NaHCO3 was added and the organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated. Purification by silica gel chromatography (25% to 50% EtOAc in Hx gradient) gave the desired bis TMS acetonide as a white foam.
To a 0° C. EtOAc solution (0.06 M) of the above bis TMS acetonide was added Et3N (4.0 eq) followed by SOCl2 (1.2 eq). After 1.5 h, the reaction was quenched with saturated NaHCO3 and the organic layer was washed with 5% KH2PO4 (3×), water, and brine, dried over Na2SO4, and concentrated to give the desired elimination alkene product as a white foam.
To a 1:1 AcOH/MeOH solution (0.24 M) containing the alkene above was added H2O (12 eq) and the solution was refluxed for 2 h. The reaction was then cooled and concentrated. The residue was suspended in CHCl3 and washed with pH 10 NH4OH solution (2×), water, and brine, dried over Na2SO4, and concentrated. Purification by silica gel chromatography chromatography (5% MeOH in CHCl3 with 0.5% NH4OH to 7.5% MeOH in CHCl3 with 0.5% NH4OH) followed by crystallization from MeCN gave the desired product (12,21-anhydro-9-dihydro erythromycin A). MS m/z 718.6 (MH+).
EXAMPLE 3 
C12 ANALOGS VIA BIS BENZOATE 9,11 FORMATES OR 9,11 ACETONIDE




EXAMPLE 3(A)
Synthesis of Compound 2
To a solution of anhydrous methylene chloride (0.13 M) containing azeotropically dried compound 1 and DMAP (5 eq) was added anhydrous triethylamine (5 eq), and benzoic anhydride (5 eq). After stirring over night, the reaction was poured into ice-cold sat. sodium bicarbonate solution. The aqueous layer was extracted with methylene chloride (3×) and the combined organic layers were washed with 1 M NaH2PO4, brine, dried over Na2SO4, filtered, and concentrated. Purification by silica gel chromatography (8% MeOH/1% NH4OH/91% DCM) followed by recrystallization from acetonitrile gave the desired dibenzoate product. ES/MS m/z 956.6 (MH+).
To a THF solution of compound obtained from the above step was added ethanol (0.06 M 11:1 EtOH:THF) followed by fresh sodium borohydride (3.3 eq). The slightly cloudy mixture was monitored by LC/MS and stirred for 24 h at room temperature. Triethanolamine (7.8 eq) was added to the mixture and stirred for 8 h. The reaction mixture was then concentrated to a thick residue and to this was carefully added 10% aqueous NaH2PO4 followed by vigorous stirring for 20 min. The pH of the aqueous layer was corrected to approximately 9 with K2CO3 (if needed) and an equal volume of ethyl acetate was added. The organic layer was separated and the aqueous layer extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude material (compound 2) may be recrystallized from acetonitrile or purified by silica gel chromatography (4:1 hexane:acetone with 1% TEA). ES/MS 958.6 (MH+).
EXAMPLE 3(B)
Synthesis of Compound 3 
To a 0° C. CH2Cl2 solution (0.12 M) of compound 2 was added DMAP (2 eq) followed by dropwise addition of FAA (3 eq; for formyl acetic acid FAA synthesis, see reference: Krimen, L. I. Organic Synthesis, 1970, vol. 50, p. 1.). The reaction was then warmed to room temperature and stirred for 18 h. Over the course of approximately 3 days additional DMAP (2 eq) and FAA (3 eq) were periodically added (about every 24 h) at 0° C. followed by warming to room temperature (RT), until LC/MS showed >90% formation of the desired product. The reaction was quenched by pouring into cold NaHCO3 (aq. layer has approximate pH 9). The solution was next extracted with CH2Cl2 and concentrated in vacuo. The residue was re-dissolved in DCM, washed with 10% HCl aq., brine, and concentrated in vacuo to give a white foam (>90%) that can be used in the next step without further purification or may be recrystallized form CH3CN. ES/MS 1014 (MH+).
EXAMPLE 3(C)
Synthesis of Compound 4 
To a 0° C. EtOAc solution of compound 3 was added anhydrous Et3N (4 eq) followed by rapid addition of thionyl chloride (1.7 eq). A pink precipitate forms immediately. The reaction was stirred for another 2 h at 0° C. then quenched with ice-cold saturated NaHCO3. The aqueous layer was extracted with CH2Cl2 (3×) and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated. Recrystallization from acetonitrile yielded the pure product (compound 4). ES/MS 996 (MH+).
EXAMPLE 3(D)
Synthesis of Compound 10 
To a 1.75:1 acetone:2,2-dimethoxypropane (0.02 M) solution containing azeotropically dried triol 2 was added pyridinium p-toluenesulfonate (PPTS, 3 eq) and the resulting solution was heated to reflux for 3.5 h. Reaction progress can be monitored by TLC (4:1, hexane:acetone, approximately 1% Et3N, Rf=0.27) by quenching an aliquot from the reaction pot with CH2Cl2 containing Et3N. Upon consumption of starting material, the reaction mixture was cooled to room temperature and Et3N (5.8 eq) was added to quench the PPTS. The solvents were removed under reduced pressure and the resulting foam was redissolved in CH2Cl2 and washed with 5% aqueous NaH2PO4 (2×), water (2×), and brine. The organic layer was dried with Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography (4:1 hexane:acetone, with 1% Et3N) gave the desired acetonide 10. MS m/z 998.7 (MH+).
EXAMPLE 3(E)
Synthesis of Compound 11
To a 0° C. solution of dry ethyl acetate (0.05 M) containing acetonide 10 was added anhydrous triethylamine (4.3 eq) followed by slow addition of thionyl chloride (1.4 eq) over 15 minutes. A pink precipitate forms immediately. The reaction was monitored by LC/MS stirred for another 1.5 h at 0° C. The reaction mixture was then poured over ice and saturated NaHCO3. The aqueous layer was extracted with CH2Cl2 (2×) and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. Purification by silica gel chromatography (15% acetone/hexane and 1% Et3N) gave the alkene 11. MS m/z 980.6 (MH+)
EXAMPLE 4 
C12 ANALOGS VIA EPOXIDE RING OPENING
EXAMPLE 4(A)
Synthesis of Scheme 1A Compound 5 
Referring to Scheme 1a, above, Et3N (4 eq.) was added to a 0.06 M MeOH solution of 4 and the mixture was refluxed for 14 h. An additional Et3N (1 eq) was then added and refluxing was continued for an additional 5 h. The solution was cooled to room temperature and concentrated in vacuo to give an approximately 1.2:1 ratio of 2′-OH:2′′-OBz. The crude intermediate was next suspended in CH2Cl2 (0.14 M) and treated with Bz2O (3 eq). After stirring overnight at room temperature, more Bz2O (1 eq) and CH2Cl2 were added. After stirring for 23 h, CH2Cl2 was added and the reaction was quenched with sat. NaHCO3 (aq.). The aqueous layer was extracted with CH2Cl2 (2×) and the combined organic layers were dried over MgSO4, filtered, and concentrated. Purification by silica gel chromatography (5:1 hexanes: acetone with 1% Et3N) gave the desired diol product 5. ES/MS m/z 941 (MH+), C52H77NO14=940 g/mol.
EXAMPLE 4(B)
Synthesis of Compound 6 
To a 0.05 M CH2Cl2 solution of alkene 5 at 0° C. was added mCPBA (4 eq). The reaction was then warmed to room temperature and stirred for overnight. Additional mCPBA (1 eq) and CH2Cl2 were added and stirred for 5 h. The reaction was quenched by adding cyclohexene (3 eq) and stirring for 1 h. 3 M NaHSO3 (aq) was next added to reduce the desosamine N-oxide. After stirring overnight, the solution was extracted with NaHCO3 and CH2Cl2. The organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated. Purification by silica gel chromatography (2:1 hexane/acetone with 1% Et3N) gave the product 6. ES/MS m/z 957 (MH+), C52H77NO15=956 g/mol.
EXAMPLE 4(C)
Synthesis of Compound 7 
To a solution of the epoxide 6 in 0.1 M CH2Cl2 at 0° C. was added the Dess-Martin periodinane (1.2 eq). After 1 h, the reaction was warmed to room temperature, stirred for 6 h, diluted with CH2Cl2, filtered through celite, and concentrated. Purification by silica gel chromatography (6:1 to 4:1 hexanes:acetone gradient with 1% Et3N) gave the ketone 7. ES/MS m/z 955 (MH+), C52H75NO15=954 g/mol.
EXAMPLE 4(D)
Synthesis of Compound 8




To 0.05 M DMF solution of epoxide 7 was added LiClO4 (2 eq) and NaN3 (6 eq). After heating at 60° C. for 2 days, the reaction was quenched with NaHCO3 (aq) and extracted with CH2Cl2. The organic extracts were washed with water, brine, dried over MgSO4, filtered, concentrated, and purified by silica gel chromatography (7:1 to 5:1 hexanes:acetone with 1% Et3N gradient) give the desired product 8a. ES/MS m/z 997.5 (MH+), C52H76N4O15=996.5 g/mol. Ring opening of the epoxide with NaSMe was performed in a similar matter (reaction stirred at room temperature for 2 h) to give the thiol ether 8b. ES/MS m/z 1002.5 (MH+), C53H79NO15=1001.5 g/mol.
EXAMPLE 4(E)
Synthesis of Compound 9




A 0.02 M MeOH solution containing 8 was heated at 65° C. for 16 h and cooled to room temperature. K2CO3 was next added and heated to 40° C. for 46 h. The solution was diluted with CH2Cl2 and washed with aq. NaHCO3. The aq layer was extracted with CH2Cl2 and the combined organic extracts were washed with brine, dried over MgSO4, filtered, concentrated, and purified by silica gel chromatography (3:1 to 2:1 hexanes:acetone with 1% Et3N gradient) to give the final product. 9a: ES/MS m/z 789 (MH+), C38H68N4O13=788 g/mol. 9b: ES/MS m/z 794 (MH+), C39H71NO13S=793 g/mol.
EXAMPLE 5 
C12 ANALOGS VIA EPOXIDE (SCHEME 1B)




Referring to Scheme 1b, above, to a 0° C. dichloromethane solution (0.13 M) containing 2′,4′′ OBz, C9,C11-dimethylketal, C12,21 alkene macrolide (Example 3, compound 11) was added 3-chloroperoxybenzoic acid (4.4 eq). After stirring for 30 minutes, the ice bath was removed and the solution was stirred for 4 hours. Cyclohexene (3.9 eq) was added and the solution was stirred for an additional 15 minutes. The solution was then diluted with dichloromethane and washed with sat. NaHCO3, brine, dried over MgSO4, filtered, and concentrated. Purification by silica gel chromatography (2.5-5-10% MeOH/CH2Cl2 gradient with 0.1% triethylamine) yielded the product epoxide, N-oxide as a white solid.




To a 0° C. dichloromethane solution (0.1 M) containing the epoxide was added 2-propanol (4 eq.), 4 angstrom powdered mol sieves and (tetrapropyl)ammonium perruthenate (0.05 eq). After stirring for 2 h, the ice bath was removed and the solution was stirred for an additional 2 h. The reaction mixture was purified directly by column chromatography (15% acetone/CH2Cl2 with 0.1% triethylamine) yielding the product epoxide as a white solid. MS m/z 996.4 (MH+).




An oven dried 2-neck flask equipped with a 14/20 side arm connection to the manifold was cooled under Ar. An internal thermocouple was inserted and CuBr dimethyl sulfide complex (5 eq) was added. The system was evacuated under high vacuum and purged with Ar three times. Diethyl ether (0.05 M in CuBr) was added and the heterogeneous solution was cooled in a −78° C. bath. Methyl lithium (10 eq) was added via syringe with the internal temperature<−60° C. The solution was held in the −78° C. bath for 10 minutes and then the bath was removed. Upon warming to −20° C., a homogeneous solution resulted. The solution was then held at −30° C. An oven dried 2-neck flask equipped with a 14/20 side arm connection to the manifold was cooled under Ar. C12,C21 epoxide was added and the system was evacuated under high vacuum and purged with Ar three times. Diethyl ether was added (0.07 M) and the epoxide was stirred and heated gently to dissolve everything. Upon cooling, the epoxide solution was added via syringe to the cuprate solution (at −30° C.; a diethyl ether rinse was also included). The internal temperature during the addition was ≦−10° C. The resultant light yellow heterogeneous solution was held at 0° C. for 6 h with stirring. Sat. NH4Cl (40 ml) was added to stop the reaction, with the internal temp ≦10° C. The reaction was diluted with ethyl acetate and washed with sat. NH4Cl (2×), brine, dried over MgSO4, filtered and concentrated. Purification by silica gel chromatography (15% acetone/hexanes with 0.1% triethylamine) yielded the C12 ethyl, hydroxy macrolide as a white solid. MS m/z 1012.4 (MH+).




An oven dried 2-neck flask equipped with a 14/20 side arm connection to the manifold was cooled under Ar. An internal thermocouple was inserted and CuBr dimethyl sulfide complex (5 eq) was added. The system was evacuated under high vacuum and purged with Ar three times. Diethyl ether (0.05 M in CuBr) was added and the heterogeneous solution was cooled in a −78° C. bath. Phenyl lithium (9.6 eq) was added via syringe with the internal temperature ≦5° C. The solution was then held in the 0° C. bath for 45 minutes. An oven dried 2-neck flask equipped with a 14/20 side arm connection to the manifold was cooled under Ar. C12,C21 epoxide was added and the system was evacuated under high vacuum and purged with Ar three times. Diethyl ether was added (0.07 M) and the epoxide was stirred and heated gently to dissolve everything. Upon cooling, the epoxide solution was added via syringe to the cuprate solution (at 0° C.; 2× diethyl ether rinses were included). The internal temperature during the addition was ≦5° C. The resultant heterogeneous solution was stirred at 0° C. for 2.5 h and than at room temperature for 5 h. The solution was cooled to 0° C., and sat. NH4Cl was added to stop the reaction, with the internal temp ≦10° C. The reaction was diluted with ethyl acetate and washed with sat. NH4Cl, brine, dried over MgSO4, filtered, and concentrated. Purification by silica gel chromatography (15% acetone/hexanes with 0.1% triethylamine) yielded the C12 phenyl, hydroxy macrolide as a white solid. MS m/z 1074.5 (MH+).




To C9, C11 ketal C12 ethyl, C12 hydroxy macrolide in 2:1 acetonitrile/water (0.1 M) was added pyridinium p-toluenesulfonate (5 eq). The solution was heated in a 68° C. oil bath for 46 hours. Upon cooling, the reaction was diluted with ethyl acetate, washed with sat. NaHCO3, brine, dried over MgSO4, filtered, and concentrated. Purification by flash chromatography (15% acetone/hexanes with 0.1% triethylamine) yielded the C12 ethyl, C9,C11,C12 triol macrolide as a white solid. MS m/z 972.4 (MH+).




To C9, C11 ketal C12 phenyl, C12 hydroxy macrolide (obtained as described above) in 2:1 acetonitrile/water (0.09 M) was added pyridinium p-toluenesulfonate (5 eq). The solution was heated in a 68° C. oil bath for 21 hours. Upon cooling, the reaction was diluted with ethyl acetate and washed with sat. NaHCO3, brine, dried over MgSO4, filtered, and concentrated. Purification by flash chromatography (20% acetone/hexanes with 0.1% triethylamine) yielded the C12 phenyl, C9,C11,C12 triol macrolide as a white solid. MS m/z 1034.4 (MH+).




To C12 ethyl, C9, C11, C12 triol macrolide (obtained as described above) in dichloromethane (0.05 M) at −5° C. was added Dess-Martin periodinane (1.3 eq). The solution was stirred for 5 minutes and then was placed in a −10° C. refrigerator. After standing for 22 h, more Dess-Martin periodinane (0.22 eq) was added and the solution stood in the −10° C. refrigerator for an additional 8 hours. The solution was diluted with ethyl acetate and washed with 1:1 10% Na2S2O3/sat. NaHCO3. The combined aqueous layers were back extracted with ethyl acetate and the combined organic layers were then washed with brine, dried over MgSO4, filtered, and concentrated. Purification by flash chromatography (15% acetone/hexanes with 0.1% triethylamine) yielded the C12 ethyl C9 keto, C11, C12 diol macrolide as a white solid. MS m/z 970.5 (MH+).




To C12 phenyl, C9, C11, C12 triol macrolide (obtained as described above) in dichloromethane (0.05 M) at −5° C. was added Dess-Martin periodinane (1.1 eq). The solution was stirred for 5 minutes and then was placed in a −10° C. refrigerator. After standing for 40 h, more Dess-Martin periodinane (0.68 eq) was added and the solution stood in the −1° C. refrigerator for an additional 8 h. The solution was diluted with dichloromethane and washed with 1:1 10% Na2S2O3/NaHCO3, brine, dried over MgSO4, filtered, and concentrated. Purification by flash chromatography (15% acetone/hexanes with 0.1% triethylamine) yielded the C12 phenyl C9 keto, C11, C12 diol macrolide as a white solid. MS m/z 1032.3 (MH+)
C12 BENZYL C9 KETO, C11 OMS, C12 OH MACROLIDE




To C12 benzyl, C9 keto, C11, C12 diol macrolide (1 eq) in pyridine at 0° C. was added methanesulfonyl chloride (5 eq) via syringe over 5 minutes. The solution was stirred for 20 hours as the solution warmed to room temperature. Upon concentrating, the material was taken up in ethyl acetate and washed with NaHCO3 (sat.), with NaCl (sat.), dried over MgSO4, filtered, and concentrated. Purification by flash chromatography (25% acetone/hexanes with 0.1% triethylamine) yielded the C12 benzyl C9 keto, C11 OMs, C12 hydroxy macrolide (90% yield) as a white solid. MH+(1110.5)
C12 BENZYL C9, C10, C11 ENONE, C12 OH DIOL MACROLIDE 




To C12 benzyl, C9, C11 OMs, C12 OH macrolide (1 eq) in acetone was added DBU (1.5 eq). The solution was stirred for 16 hours at room temperature and then for 26 hours at 60° C. The solution was diluted with ethyl acetate, washed with H2O, with NaCl (sat.), dried over MgSO4, filtered, and concentrated yielding the C12 benzyl C9, C10, C11 enone, C12 OH macrolide (81% yield) as an off white solid. MH+(1014.5)
C12 BENZYL C9, C10, C11 ENONE, C3, C12 DIOL MACROLIDE




To C12 benzyl, C9, C10, C11 enone C12 OH macrolide (1 eq) in acetonitrile was added 3 M HC (aq.) (10%). After standing for 22 hours the solution was diluted with ethyl acetate and washed with NaHCO3 (sat.), with NaCl (sat.), dried over MgSO4, filtered and concentrated. Purification by flash chromatography (30% acetone/hexanes with 0.1% triethylamine) yielded the C12 benzyl C9, C10, C11 enone, C3, C12 diol macrolide (76% yield) as a white solid. MH+(752.4)
C12 Benzyl C9, C10, C11 ENONE, C3 OXO, C12 OH Macrolide




To C12 benzyl, C9, C10, C11 enone, C3, C12 diol macrolide (1 eq) in dichloromethane was added Dess-Martin periodinane (1.3 eq). After stirring for 4 hours, the solution was diluted with ethyl acetate and washed with 1:1 10% Na2S2O3/NaHCO3 (sat.), with NaCl (sat.), dried over MgSO4, filtered, and concentrated. Purification by flash chromatography (30% acetone/hexanes with 0.1% triethylamine) yielded the C12 benzyl C9, C10, C11 enone, C3 oxo, C12 OH macrolide (96% yield) as a white solid. MH+(750.5)
C9, C10, C11 ENONE, C3 OXO, C12 BENZYL, C12 OCOIM MACROLIDE




To a solution of C12 benzyl, C9, C10, C11 enone, C3 oxo, C12 OH macrolide (1 eq) and carbonyldiimidazole (3 eq) in tetrahydrofuran at 0° C. was added sodium hydride (2 eq). The solution was stirred at 0° C. for 4.5 hours, and then ethyl acetate was added. While still at 0° C., NaHCO3 (sat.) was added. The mixture was then diluted with ethyl acetate and was washed with NaHCO3 (sat.). with NaCl (sat.), dried over MgSO4, filtered, concentrated, and pumped on yielding crude C12 benzyl C9, C10, C11 enone, C3 oxo, C12 OCOIm macrolide. The crude material was used in the next step without further purification.
EXAMPLE 6 
SYNTHESIS OF (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a-BENZYL-4-ETHYL-11-METHOXY-7,9,11,13,15-PENTAMETHYL-2,6,8,14-TETRAOXO-1-[4-(4-PYRIDIN-3-YL-1H-IMIDAZOL-1-YL)BUTYL]TETRADECAHYDRO-2H-OXACYCLOTETRADECINO[4,3-D][1,3]OXAZOL-10-YL-3,4,6-TRIDEOXY-3-(DIMETHYLAMINO)-D-XYLO-HEXOPYRANOSIDE




A solution of crude C12 benzyl, C9, C10, C11 enone, C3 oxo, C12 OCOIm macrolide (1 eq) in acetonitrile (1.5 ml) was added to 4-(4-(3-pyridyl)imidazolyl)butylamine (10 eq), and water (10%) was added. The solution was heated at 60° C. for 21 hours. Upon cooling the reaction was diluted with ethyl acetate and washed with NaHCO3 (sat.), NaCl (sat.), dried over MgSO4, filtered, and concentrated. To the crude material was added methanol (10 ml) and the solution was heated at reflux for 18 hours. Upon concentrating, the material was purified silica gel chromatography (0-3-5-10% methanol/dichloromethane with 0.1% triethylamine) and than by RP HPLC yielding (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a-benzyl-4-ethyl-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-1-[4-(4-pyridin-3-yl-1H-imidazol-1-yl)butyl]tetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside (35% yield) as a white solid. MH+(888.5)
C12 ETHYL ANALOGS
EXAMPLE 7-EXAMPLE 43
EXAMPLE 7 
SYNTHESIS OF C12 ETHYL C9 KETO, C11 OMS, C12 HYDROXY MACROLIDE




To 0° C. 0.2 M pyridine solution containing the C12 ethyl, C9 keto, C11, C12 diol macrolide of Example 5 (1 eq) was added methanesulfonyl chloride (5 eq) via syringe over 5 minutes. The solution was stirred for 18 hours as the solution warmed to room temperature. Upon concentrating, the material was taken up in ethyl acetate and washed with sat. NaHCO3 (2×). The combined aqueous layers were back extracted with ethyl acetate and the combined organic layers were then washed with brine, dried over MgSO4, filtered, and concentrated. Purification by flash chromatography (20-25% acetone/hexanes with 0.1% triethylamine) yielded the C12 ethyl C9 keto, C11 OMs, C12 hydroxy macrolide as a white solid. MH+(1048.5)
EXAMPLE 8 
SYNTHESIS OF C12 ETHYL C9, C10, C11 ENONE, C12 OH MACROLIDE




To C12 ethyl, C9, C11 OMs, C12 OH macrolide of Example 6 (1 eq) in acetone (0.07 M) was added DBU (1.2 eq). The solution was stirred for 6 hours at room temperature and then for 14 hours at 61° C. The solution was diluted with ethyl acetate, washed with H2O, sat. NaHCO3, brine, dried over MgSO4, filtered, and concentrated to yield the C12 ethyl C9, C10, C11 enone, C12 OH macrolide as an off white solid. MH+(952.5)
EXAMPLE 9 
SYNTHESIS OF C12 ETHYL C9, C10, C11 ENONE, C3, C12 DIOL MACROLIDE




To C12 ethyl, C9, C10, C11 enone, C12 OH macrolide of Example 7 (1 eq) in acetonitrile (0.08 M) was added 3 M HCl (aq.) (19 eq). After standing for 22 hours the solution was diluted with ethyl acetate and washed with sat. NaHCO3, brine, dried over MgSO4, filtered, and concentrated. Purification by flash chromatography (30% acetone/hexanes with 0.1% triethylamine) yielded the C12 ethyl C9, C10, C11 enone, C3, C12 diol macrolide as a white solid. MH+(690.4).
EXAMPLE 10
SYNTHESIS OF C12 ETHYL C9, C10, C11 ENONE, C3 OXO, C12 OH MACROLIDE




To C12 ethyl, C9, C10, C11 enone, C3, C12 diol macrolide of Example 8 (1 eq) in dichloromethane (0.04 M) was added Dess-Martin periodinane (1.5 eq). After stirring for 1 hour, the solution was diluted with ethyl acetate and washed with 1:1 10% Na2S2O3/NaHCO3, brine, dried over MgSO4, filtered, and concentrated. Purification by flash chromatography (30% acetone/hexanes with 0.1% triethylamine) yielded the C12 ethyl C9, C10, C11 enone, C3 oxo, C12 OH macrolide as a white solid. MH+(688.5).
EXAMPLE 11 
SYNTHESIS OF C12 ETHYL C9, C10, C11 ENONE, C3 OXO, C12 OCOIM MACROLIDE




To a solution of C12 ethyl, C9, C10, C11 enone, C3 oxo, C12 OH macrolide of Example 10 (1 eq) and carbonyldiimidazole (3 eq) in tetrahydrofuran (0.1 M) at −15° C. was added sodium hydride (2 eq). The solution was stirred for 5 minutes at −15° C. and then was placed in a 0° C. ice bath. After stirring for 4 hours, ethyl acetate was added. While still at 0° C., NaHCO3 (sat.) was added. The mixture was then diluted with ethyl acetate and was washed with sat. NaHCO3 (2×), brine, dried over MgSO4, filtered, concentrated, and dried under high vacuum to yield the crude C12 ethyl C9, C10, C11 enone, C3 oxo, C12 OCOIm macrolide that was used in the next example without further purification. MH+(782.5)
EXAMPLE 12 
SYNTHESIS OF (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-DIETHYL-11-METHOXY-7,9,11,13,15-PENTAMETHYL-2,6,8,14-TETRAOXO-1-[4-(4-PYRIDIN-3-YL-1H-IMIDAZOL-1-YL)BUTYL]TETRADECAHYDRO-2H-OXACYCLOTETRADECINO[4,3-D][1,3]OXAZOL-10-YL-3,4,6-TRIDEOXY-3-(DIMETHYLAMINO)-D-XYLO-HEXOPYRANOSIDE




A solution of crude C12 ethyl, C9, C10, C11 enone, C3 oxo, C12 OCOIm macrolide of Example 11 (1 eq) in acetonitrile was added to 4-(4-(3-pyridyl)imidazolyl)butylamine (8 eq), and water was added. The solution was heated at 60° C. for 20 hours. Upon cooling the reaction was diluted with ethyl acetate and washed with NaHCO3 (sat.), NaCl (sat.), dried over MgSO4, filtered and concentrated. To the crude material was added methanol and the solution was heated at reflux for 19 hours. Upon concentrating, the material was purified by RP HPLC. The combined product fractions coming off the HPLC were diluted with ethyl acetate and washed with NaHCO3 (sat.). The aqueous layer was back extracted with ethyl acetate and the combined organic layers were then washed with NaCl (sat.), dried over MgSO4, filtered, concentrated, dissolved in acetonitrile/water, and lyophilized yielding (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-1-[4-(4-pyridin-3-yl-1H-imidazol-1-yl)butyl]-tetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside (44% yield) as a white solid. MH+(826.5)
EXAMPLE 13 
SYNTHESIS OF (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-DIETHYL-11-METHOXY-7,9,11,13,15-PENTAMETHYL-2,6,8,14-TETRAOXO-1-[4-(4-PHENYL-1H-IMIDAZOL-1-YL)BUTYL]TETRADECAHYDRO-2H-OXACYCLOTETRADECINO[4,3-D][1,3]OXAZOL-10-YL-3,4,6-TRIDEOXY-3-(DIMETHYLAMINO)-D-XYLO-HEXOPYRANOSIDE




A solution of crude C12 ethyl, C9, C10, C11 enone, C3 oxo, C12 OCOIm macrolide of Example 11 (1 eq) in acetonitrile was added to 4-(4-phenyl-imidazol-1-yl)butylamine (4 eq), and water was added. The solution was heated at 60° C. for 60 hours. Upon cooling the reaction was diluted with ethyl acetate and washed with NaHCO3 (sat.), NaCl (sat.), dried over MgSO4, filtered, and concentrated. To the crude material was added methanol and the solution was heated at reflux for 19 hours. Upon concentrating, the material was purified by RP HPLC. The combined product fractions coming off the HPLC were diluted with ethyl acetate and washed with NaHCO3 (sat.). The aqueous layer was back extracted with ethyl acetate and the combined organic layers were then washed with NaCl (sat.), dried over MgSO4, filtered, concentrated, dissolved in acetonitrile/water, and lyophilized yielding (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-1-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-1-[4-(4-phenyl-1H-imidazol-1-yl)butyl]tetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside (42% yield) as a white solid. MH+(825.5)
EXAMPLE 14 
SYNTHESIS OF (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-DIETHYL-1-[4-(3H-IMIDAZO[4,5-B]PYRIDIN-3-YL)BUTYL]-11-METHOXY-7,9,11,13,15-PENTAMETHYL-2,6,8,14-TETRAOXOTETRADECAHYDRO-2H-OXACYCLOTETRADECINO[4,3-D][1,3]OXAZOL-10-YL-3,4,6-TRIDEOXY-3-(DIMETHYLAMINO)-D-XYLO-HEXOPYRANOSIDE




C12 ethyl, C9, C10, C11 enone, C3 oxo, C12 OCOIm macrolide of Example 11 (1 eq) was added to 4-imidazo[4,5-b]pyridin-3-yl-butylamine (2.5 eq); acetonitrile and water were added. The solution was heated at 65° C. for 20 hours. Upon cooling, the reaction was diluted with ethyl acetate and washed with NaHCO3 (sat.), NaCl (sat.), dried over MgSO4, filtered and concentrated. To the crude material was added methanol and the solution was heated at 60° C. for 19 hours. Upon concentrating, the material was purified by RP HPLC. The combined product fractions coming off the HPLC were diluted with ethyl acetate and NaHCO3 was added. The aqueous layer was separated and the organic layer was washed with NaCl (sat.), dried over MgSO4, filtered, concentrated, dissolved in acetonitrile/water, and lyophilized yielding (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-1-[4-(3H-imidazo[4,5-b]pyridin-3-yl)butyl]-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside (38%) as a white solid. MH+(800.00)
EXAMPLE 15 
SYNTHESIS OF (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-DIETHYL-11-METHOXY-7,9,11,13,15-PENTAMETHYL-2,6,8,14-TETRAOXO-1-(4-QUINOLIN-4-YLBUTYL)TETRADECAHYDRO-2H-OXACYCLOTETRADECINO[4,3-D][1,3]OXAZOL-10-YL-3,4,6-TRIDEOXY-3-(DIMETHYLAMINO)-D-XYLO-HEXOPYRANOSIDE




C12 ethyl, C9, C10, C11 enone, C3 oxo, C12 OCOIm macrolide of Example 11 (1 eq) was added to 4-quinolin-4-yl-butylamine (4 eq); acetonitrile and water were added. The solution was heated at 65° C. for 20 hours. Upon cooling, the reaction was diluted with ethyl acetate and washed with NaHCO3 (sat.). NaCl (sat.), dried over MgSO4, filtered, and concentrated. Purification by RP HPLC yielded the pure benzoylated ketolide and a mixture of benzoylated ketolide and (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-1-(4-quinolin-4-ylbutyl)tetradecahydro-2H-oxacyclo-tetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside. To the mixture of benzoylated ketolide and product, was added methanol and the solution was heated at 60° C. for 19 hours. Upon concentrating, the material was purified by column chromatography (0-2-5-10% MeOH/CH2Cl2 with 0.1% triethylamine), and lyophilized from MeCN:H2O to provide (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-1-(4-quinolin-4-ylbutyl)tetradecahydro-2H-oxacyclo-tetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside (46% yield) as a white solid. MH+(810.05)
EXAMPLE 16 
SYNTHESIS OF (3aS,4R,7S,9R,10R,11R,13R,15R,15aR)-3a,4-DIETHYL-7-FLUORO-11-METHOXY-7,9,11,13,15-PENTAMETHYL-2,6,8,14-TETRAOXO-1-[4-(4-PYRIDIN-3-YL-1H-IMIDAZOL-1-YL)BUTYL]TETRADECAHYDRO-2H-OXACYCLOTETRADECINO[4,3-D][1,3]OXAZOL-10-YL-3,4,6-TRIDEOXY-3-(DIMETHYLAMINO)-D-XYLO-HEXOPYRANOSIDE




To 2′ benzoylated (6S,1R,2R,4R,7R,8R,10R,13R)-7-[(4S,2R,3R,6R)-4-(dimethylamino)-3-hydroxy-6-methyl(2H-3,4,5,6-tetrahydropyran-2-yl)oxy]-17-aza-13,14-diethyl-6-methoxy-2,4,6,8,10-pentamethyl-12,15-dioxa-17-(4-(4-quinolyl)-butyl)bicyclo[12.3.0]heptadecane-3,9,11,16-tetraone in DMF at 0° C. was added 60% NaH (2 eq). After stirring for 1 hour at 0° C., N-fluorobenzenesulfonimide (1 eq) was added. After stirring for an additional hour at 0° C., the solution was diluted with ethyl acetate and NaHCO3 (sat.) was added cautiously to quench. The reaction was then added to ethyl acetate and was washed with NaHCO3 (sat.), NaCl (sat.), dried over MgSO4, filtered, concentrated and purified by RP HPLC. The combined product fractions coming off the HPLC were diluted with ethyl acetate and NaHCO3 was added. The aqueous layer was separated and the organic layer was washed with NaCl (sat.), dried over MgSO4, filtered, and concentrated to provide the benzoylated 2-fluoroketolide. Methanol was added and the solution was heated at 60° C. for 19 hours. Upon concentrating, the material was purified by column chromatography (0-2-5-10% MeOH/CH2Cl2 with 0.1% triethylamine), and lyophilized from MeCN:H20 providing (3aS,4R,7S,9R,10R,11R,13R,15R,15aR)-3a,4-diethyl-7-fluoro-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-1-[4-(4-pyridin-3-yl-1H-imidazol-1-yl)butyl]tetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside (62% yield) as a white solid. MH+(844.50)
EXAMPLE 17 
SYNTHESIS OF (3aS,4R,7S,9R,10R,11S,13R,15R,15aR)-3a,4-DIETHYL-7-FLUORO-11-METHOXY-7,9,11,13,15-PENTAMETHYL-2,6,8,14-TETRAOXO-1-(4-QUINOLIN-4-YLBUTYL)TETRADECAHYDRO-2H-OXACYCLOTETRADECINO[4,3-D][1,3]OXAZOL-10-YL-3,4,6-TRIDEOXY-3-(DIMETHYLAMINO)-D-XYLO-HEXOPYRANOSIDE




To 2′ benzoylated (6S,1R,2R,4R,7R,8R,10R,13R)-7-[(4S,2R,3R,6R)-4-(dimethylamino)-3-hydroxy-6-methyl(2H-3,4,5,6-tetrahydropyran-2-yl)oxy]-17-aza-13,14-diethyl-6-methoxy-2,4,6,8,10-pentamethyl-12,15-dioxa-17-(4-(4-quinolyl)-butyl)bicyclo[12.3.0heptadecane-3,9,11,16-tetraone (1 eq) in DMF at 0° C. was added 60% NaH (2 eq). After stirring for 1 hour at 0° C., N-fluorobenzenesulfonimide (1.1 eq) was added. After stirring for an additional hour at 0° C., the solution was diluted with ethyl acetate followed by addition of NaHCO3 (sat.) to quench the reaction. The reaction mixture was then added to ethyl acetate and was washed with NaHCO3 (sat.), NaCl (sat.), dried over MgSO4, filtered, concentrated, and purified by RP HPLC. The combined product fractions coming off the HPLC were diluted with ethyl acetate and NaHCO3 was added. The aqueous layer was separated and the organic layer was washed with NaCl (sat.), dried over MgSO4, filtered, and concentrated yielding the benzoylated 2-fluoroketolide. Methanol was added and the solution was heated at 60° C. for 19 hours. Upon concentrating, the material was purified by column chromatography (0-2-5-10% MeOH/CH2Cl2 with 0.1% triethylamine), and lyophilized from MeCN:H2O to give (3aS,4R,7S,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-7-fluoro-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-1-(4-quinolin-4-ylbutyl)tetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside (57% yield) as a white solid. MH+(828.50)
EXAMPLE 18
SYNTHESIS OF (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-DIETHYL-11-METHOXY-7,9,11,13,15-PENTAMETHYL-2,6,8,14-TETRAOXO-1-(4-QUINOLIN-2-YLBUTYL)TETRADECAHYDRO-2H-OXACYCLOTETRADECINO[4,3-D][1,3]OXAZOL-10-YL-3,4,6-TRIDEOXY-3-(DIMETHYLAMINO)-D-XYLO-HEXOPYRANOSIDE




C12 ethyl, C9, C10, C11 enone, C3 oxo, C12 OCOIm macrolide of Example 11 (1 eq) was added to 4-quinolin-2-yl-butylamine (4 eq); acetonitrile and water was added. The solution was heated at 65° C. for 24 hours. Upon cooling, the reaction was diluted with ethyl acetate and washed with NaHCO3 (sat.), NaCl (sat.), dried over MgSO4, filtered, and concentrated. Purification by RP HPLC yielded the benzoylated ketolide. To the benzoylated ketolide was added methanol and the solution was heated at 60° C. for 19 hours. Upon concentrating, the material was purified by column chromatography (0-2-5-10% MeOH/CH2Cl2 with 0.1% triethylamine), and lyophilized from MeCN:H2O providing (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-1-(4-quinolin-2-ylbutyl)tetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside (40% yield) as a white solid. MH+(810.50)
EXAMPLE 19 
SYNTHESIS OF (3aS,4R,7S,9R,10R,11S,13R,15R,15aR)-3a,4-DIETHYL-7-FLUORO-11-METHOXY-7,9,11,13,15-PENTAMETHYL-2,6,8,14-TETRAOXO-1-(4-QUINOLIN-2-YLBUTYL)TETRADECAHYDRO-2H-OXACYCLOTETRADECINO[4,3-D][1,3]OXAZOL-10-YL-3,4,6-TRIDEOXY-3-(DIMETHYLAMINO)-D-XYLO-HEXOPYRANOSIDE




Using the procedure described above for the preparation of (3aS,4R,7S,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-7-fluoro-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-1-(4-quinolin-4-ylbutyl)tetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside, utilizing 2′ benzoylated (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-1-(4-quinolin-2-ylbutyl)tetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl 3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside as starting material, (3aS,4R,7S,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-7-fluoro-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-1-(4-quinolin-2-ylbutyl)tetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside was attained (52% yield) as a white solid. MH+(828.50)
EXAMPLE 20
SYNTHESIS OF (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-DIETHYL-11-METHOXY-7,9,11,13,15-PENTAMETHYL-1-[4-(2-METHYL-4-PYRIDIN-3-YL-1H-IMIDAZOL-1-YL)BUTYL]-2,6,8,14-TETRAOXOTETRADECAHYDRO-2H-OXACYCLOTETRADECINO[4,3-D][1,3]OXAZOL-10-YL-3,4,6-TRIDEOXY-3-(DIMETHYLAMINO)-D-XYLO-HEXOPYRANOSIDE




C12 ethyl, C9, C10, C11 enone, C3 oxo, C12 OCOIm macrolide of Example 11 (1 eq) was added to 4-(2-methyl-4-pyridin-3-yl-imidazol-1-yl)-butylamine (4 eq), acetonitrile, and water. The solution was heated at 65° C. for 48 hours. Upon cooling, the reaction was diluted with ethyl acetate and washed with NaHCO3 (sat.), NaCl (sat.), dried over MgSO4, filtered, and concentrated. To the crude material was added methanol and the solution was heated at 60° C. for 24 hours. Upon concentrating, the material was purified by column chromatography (0-5-10% MeOH/CH2Cl2 with 0.1% triethylamine) and than RP HPLC. The combined product fractions coming off the HPLC were diluted with ethyl acetate and NaHCO3 was added. After mixing, the aqueous layer was separated and the organic layer was washed with NaCl (sat.), dried over MgSO4, filtered, concentrated, dissolved in acetonitrile/water and lyophilized to provide (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-11-methoxy-7,9,11,13,15-pentamethyl-1-[4-(2-methyl-4-pyridin-3-yl-1H-imidazol-1-yl)butyl]-2,6,8,14-tetraoxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside (28% yield) as a white solid product. MH+(840.50)
EXAMPLE 21 
SYNTHESIS OF (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-DIETHYL-11-METHOXY-7,9,11,13,15-PENTAMETHYL-1-[4-(5-METHYL-4-PYRIDIN-3-YL-1H-IMIDAZOL-1-YL)BUTYL]-2,6,8,14-TETRAOXOTETRADECAHYDRO-2H-OXACYCLOTETRADECINO[4,3-D][1,3]OXAZOL-10-YL-3,4,6-TRIDEOXY-3-(DIMETHYLAMINO)-D-XYLO-HEXOPYRANOSIDE




C12 ethyl, C9, C10, C11 enone, C3 oxo, C12 OCOIm macrolide of Example 11 (1 eq) was added to 4-(5-methyl-4-pyridin-3-yl-imidazol-1-yl)-butylamine (4 eq), acetonitrile, and water. The solution was heated at 65° C. for 20 hours. Upon cooling, the reaction was diluted with ethyl acetate and washed with NaHCO3 (sat.), NaCl (sat.), dried over MgSO4, filtered, and concentrated. To the crude material was added methanol and the solution was heated at 60° C. for 24 hours. Upon concentrating, the material was purified by column chromatography (0-5-10% MeOH/CH2Cl2 with 0.1% triethylamine) and than RP HPLC. The combined product fractions coming off the HPLC were diluted with ethyl acetate and NaHCO3 was added. After mixing, the aqueous layer was separated and the organic layer was washed with NaCl (sat.), dried over MgSO4, filtered, concentrated, dissolved in acetonitrile/water, and lyophilized yielding (3aS,4R,7R,9R,10R,11S,13R,15R15aR)-3a,4-diethyl-11-methoxy-7,9,11,13,15-pentamethyl-1-[4-(5-methyl-4-pyridin-3-yl-1H-imidazol-1-yl)butyl]-2,6,8,14-tetraoxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside (37% yield) as a white solid. MH+(840.50)
EXAMPLE 22
SYNTHESIS OF (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-DIETHYL-1-[4-(1H-IMIDAZO[4,5-B]PYRIDIN-1-YL)BUTYL]-11-METHOXY-7,9,11,13,15-PENTAMETHYL-2,6,8,14-TETRAOXOTETRADECAHYDRO-2H-OXACYCLOTETRADECINO[4,3-D][1,3]OXAZOL-10-YL-3,4,6-TRIDEOXY-3-(DIMETHYLAMINO)-D-XYLO-HEXOPYRANOSIDE




C12 ethyl, C9, C10, C11 enone, C3 oxo, C12 OCOIM macrolide of Example 11 (1 eq) was added to 4-imidazo[4,5-b]pyridin-1-yl-butylamine (6 eq), acetonitrile, and water. The solution was heated at 65° C. for 20 hours. Upon cooling the reaction was diluted with ethyl acetate (350 ml) and washed with NaHCO3 (sat.), NaCl (sat.), dried over MgSO4, filtered, and concentrated. To the crude material was added methanol and the solution was heated at 60° C. for 19 hours. Upon concentrating, the material was purified by RP HPLC. The combined product fractions coming off the HPLC were diluted with ethyl acetate and NaHCO3 was added. The aqueous layer was separated and the organic layer was washed with NaCl (sat.), dried over MgSO4, filtered, concentrated, dissolved in acetonitrile/water, and lyophilized providing (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-1-[4-(1H-imidazo[4,5-b]pyridin-1-yl)butyl]-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside (31% yield) as a white solid. MH+(800.00)
EXAMPLE 23
SYNTHESIS OF (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-DIETHYL-1-METHOXY-7,9,11,13,15-PENTAMETHYL-1-{2-[METHYL(PYRIDIN-3-YLMETHYL)AMINO]ETHYL)-2,6,8,14-TETRAOXOTETRADECAHYDRO-2H-OXACYCLOTETRADECINO[4,3-D][1,3]OXAZOL-10-YL-3,4,6-TRIDEOXY-3-(DIMETHYLAMINO)-D-XYLO-HEXOPYRANOSIDE




C12 ethyl, C9, C10, C11 enone, C3 oxo, C12 OCOIm macrolide of Example 11 (1 eq) was added to N1-methyl-N1-pyridin-3-ylmethyl-ethane-1,2-diamine (6 eq); acetonitrile (3 ml) and water (10%). The reaction conditions are the same as described previously for (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-1-[4-(1H-imidazo[4,5-b]pyridin-1-yl)butyl]-1-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside. (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-11-methoxy-7,9,11,13,15-pentamethyl-1-{2-[methyl(pyridin-3-ylmethyl)amino]ethyl}-2,6,8,14-tetra-oxotetradecahydro-2H-oxacyclotetradecino[4,3-d]([1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside was attained (47% yield) as a white solid. MH+(775.50)
EXAMPLE 24




Using the procedure described above for the preparation of (3aS,4R,7S,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-7-fluoro-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-1-(4-quinolin-4-ylbutyl)tetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside, utilizing 2′ benzoylated (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-1-[4-(3H-imidazo[4,5-b]pyridin-3-yl)butyl]-1-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexo-pyranoside as starting material, (3aS,4R,7S,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-7-fluoro-1-[4-(3H-imidazo[4,5-b]pyridin-3-yl)butyl]-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside was obtained (49% yield) as a white solid. MH+(818.50)
EXAMPLE 25 
SYNTHESIS OF (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-DIETHYL-11-METHOXY-7,9,11,13,15-PENTAMETHYL-2,6,8,14-TETRAOXO-1-[4-(4-PYRIMIDIN-5-YL-1H-IMIDAZOL-1-YL)BUTYL]TETRADECAHYDRO-2H-OXACYCLOTETRADECINO[4,3-D][1,3]OXAZOL-10-YL-3,4,6-TRIDEOXY-3-(DIMETHYLAMINO)-D-XYLO-HEXOPYRANOSIDE




C12 ethyl, C9, C10, C11 enone, C3 oxo, C12 OCOIm macrolide of Example 11 (1 eq) was added to 4-(4-pyrimidin-5-yl-imidazol-1-yl)-butylamine (4 eq), acetonitrile, and water (10%). The reaction conditions are the same as described previously for (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-1-[4-(1H-imidazo[4,5-b]pyridin-1-yl)butyl]-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside. (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-1-[4-(4-pyrimidin-5-yl-1H-imidazol-1-yl)butyl]tetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside was attained (27% yield) as a white solid. MH+(827.50)
EXAMPLE 26
SYNTHESIS OF (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-DIETHYL-11-METHOXY-7,9,11,13,15-PENTAMETHYL-2,6,8,14-TETRAOXO-1-[4-(4-PYRAZIN-2-YL-1H-IMIDAZOL-1-YL)BUTYL]TETRADECAHYDRO-2H-OXACYCLOTETRADECINO[4,3-D][1,3]OXAZOL-10-YL-3,4,6-TRIDEOXY-3-(DIMETHYLAMINO)-D-XYLO-HEXOPYRANOSIDE




C12 ethyl, C9, C10, C11 enone, C3 oxo, C12 OCOIm macrolide of Example 11 (1 eq) was added to 4-(4-pyrazin-2-yl-imidazol-1-yl)-butylamine (6 eq), acetonitrile and water (10%). The reaction conditions are the same as described previously for (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-11-[4-(1H-imidazo[4,5-b]pyridin-1-yl)butyl]-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside. The product (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-1-[4-(4-pyrazin-2-yl-1H-imidazol-1-yl)butyl]tetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside was attained (29% yield) as a white solid. MM+(827.50)
EXAMPLE 27
SYNTHESIS OF (3aS,4R,7S,9R,10R,11S,13R,15R,15aR)-3a,4-DIETHYL-7-FLUORO-1-[4-(1H-IMIDAZO[4,5-B]PYRIDIN-1-YL)BUTYL]-11-METHOXY-7,9,11,13,15-PENTAMETHYL-2,6,8,14-TETRAOXOTETRADECAHYDRO-2H-OXACYCLOTETRADECINO[4,3-D][1,3]OXAZOL-10-YL-3,4,6-TRIDEOXY-3-(DIMETHYLAMINO)-D-XYLO-HEXOPYRANOSIDE




Using the procedure previously described for the preparation of (3aS,4R,7S,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-7-fluoro-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-1-(4-quinolin-4-ylbutyl)tetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside, utilizing 2′ benzoylated (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-1-[4-(1H-imidazo[4,5-b]pyridin-1-yl)butyl]-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxotetradecahydro-2H-oxacyclotetra-decino[4,3-d][1,3]oxazol-10-yl3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexo-pyranoside as starting material, the product (3aS,4R,7S,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-7-fluoro-1-[4-(1H-imidazo[4,5-b]pyridin-1-yl)butyl]-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside was attained (31% yield) as a white solid. MH+(818.50)
EXAMPLE 28
SYNTHESIS OF (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-DIETHYL-11-METHOXY-7,9,11,13,15-PENTAMETHYL-2,6,8,14-TETRAOXO-1-[4-(4-PYRIDIN-4-YL-1H-IMIDAZOL-1-YL)BUTYL]TETRADECAHYDRO-1H-OXACYCLOTETRADECINO[4,3-D][1,3]OXAZOL-10-YL-3,4,6-TRIDEOXY-3-(DIMETHYLAMINO)-D-XYLO-HEXOPYRANOSIDE




C12 ethyl, C9, C10, C11 enone, C3 oxo, C12 OCOIm macrolide of Example 11 (1 eq) was added to 4-(4-pyridin-4-yl-imidazol-1-yl)-butylamine (5 eq); acetonitrile and water (10%). The reaction conditions are the same as described previously for (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-1-[4-(1H-imidazo[4,5-b]pyridin-1-yl)butyl]-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside. The product (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-1-[4-(4-pyridin-4-yl-1H-imidazol-1-yl)butyl]tetradecahydro-1H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-tri-deoxy-3-(dimethylamino)-D-xylo-hexopyranoside was attained (31% yield) as a white solid. MH+(826.50)
EXAMPLE 29
SYNTHESIS OF (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-DIETHYL-11-METHOXY-7,9,11,13,15-PENTAMETHYL-1-{4-[4-(6-METHYLPYRIDIN-3-YL)-1H-IMIDAZOL-1-YL]BUTYL}-2,6,8,14-TETRAOXOTETRADECAHYDRO-1H-OXACYCLOTETRADECINO[4,3-D][1,3]OXAZOL-10-YL-3,4,6-TRIDEOXY-3-(DIMETHYLAMINO)-D-XYLO-HEXOPYRANOSIDE




C12 ethyl, C9, C10, C11 enone, C3 oxo, C12 OCOIm macrolide of Example 11 (1 eq) was added to 4-[4-(6-methyl-pyridin-3-yl)-imidazol-1-yl]-butylamine (3 eq), acetonitrile, and water (10%). The reaction conditions are the same as described previously for (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-1-[4-(1H-imidazo[4,5-b]pyridin-1-yl)butyl]-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside. The product (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-11-methoxy-7,9,11,13,15-pentamethyl-1-{4-[4-(6-methylpyridin-3-yl)-1H-imidazol-1-yl]butyl}-2,6,8,14-tetraoxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside was attained (44% yield) as a white solid. MH+(840.50)
EXAMPLE 30
SYNTHESIS OF (3aS,4R,7S,9R,10R,11S,13R,15R,15aR)-3a,4-DIETHYL-7-FLUORO-11-METHOXY-7,9,11,13,15-PENTAMETHYL-1-{4-[4-(6-METHYLPYRIDIN-3-YL)-1H-IMIDAZOL-1-YL]BUTYL}-2,6,8,14-TETRAOXOTETRADECAHYDRO-1H-OXACYCLOTETRADECINO[4,3-D]-[1,3]OXAZOL-10-YL-3,4,6-TRIDEOXY-3-(DIMETHYLAMINO)-D-XYLO-HEXOPYRANOSIDE




Using the procedure previously described for the preparation of (3aS,4R,7S,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-7-fluoro-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-1-(4-quinolin-4-ylbutyl)tetradecahydro-1H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside, utilizing 2′ benzoylated (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-11-methoxy-7,9,11,13,15-pentamethyl-1-{4-[4-(6-methylpyridin-3-yl)-1H-imidazol-1-yl]butyl)-2,6,8,14-tetraoxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside as starting material, the product (3aS,4R,7S,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-7-fluoro-11-methoxy-7,9,11,13,15-pentamethyl-1-{4-[4-(6-methylpyridin-3-yl)-1H-imidazol-1-yl]butyl}-2,6,8,14-tetraoxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl 3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside was attained (61% yield) as a white solid. MH+(858.50)
EXAMPLE 31
SYNTHESIS OF (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-DIETHYL-11-METHOXY-7,9,11,13,15-PENTAMETHYL-1-[4-METHYL-4-(4-PYRIDIN-3-YL-1H-IMIDAZOL-1-YL)PENTYL]-2,6,8,14-TETRAOXOTETRADECAHYDRO-1H-OXACYCLOTETRADECINO[4,3-D][1,3]OXAZOL-10-YL-3,4,6-TRIDEOXY-3-(DIMETHYLAMINO)-D-XYLO-HEXOPYRANOSIDE




C12 ethyl, C9, C10, C11 enone, C3 oxo, C12 OCOIm macrolide of Example 11 (1 eq) was added to 4-methyl-4-(4-pyridin-3-yl-imidazol-1-yl)-pentylamine (3 eq); acetonitrile and water. The reaction conditions are the same as described previously for (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-1-[4-(1H-imidazo[4,5-b]pyridin-1-yl)butyl]-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside. The product (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-11-methoxy-7,9,11,13,15-pentamethyl-1-[4-methyl-4-(4-pyridin-3-yl-1H-imidazol-1-yl)pentyl]-2,6,8,14-tetraoxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside was attained (40% yield) as a white solid. MH+(958.50)
EXAMPLE 32
SYNTHESIS OF (3aS,4R,7S,9R,10R,11S,13R,15R,15aR)-3a,4-DIETHYL-7-FLUORO-11-METHOXY-7,9,11,13,15-PENTAMETHYL-1-[4-METHYL-4-(4-PYRIDIN-3-YL-1H-IMIDAZOL-1-YL)PENTYL]-2,6,8,14-TETRAOXOTETRADECAHYDRO-1H-OXACYCLOTETRADECINO[4,3-D][1,3]OXAZOL-10-YL-3,4,6-TRIDEOXY-3-(DIMETHYLAMINO)-D-XYLO-HEXOPYRANOSIDE




Using the procedure previously described for the preparation of (3aS,4R,7S,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-7-fluoro-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-1-(4-quinolin-4-ylbutyl)tetradecahydro-1H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside, utilizing 2′ benzoylated (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-11-methoxy-7,9,11,13,15-pentamethyl-1-[4-methyl-4-(4-pyridin-3-yl-1H-imidazol-1-yl)pentyl]-2,6,8,14-tetraoxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl 3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside as starting material, the product (3aS,4R,7S,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-7-fluoro-11-methoxy-7,9,11,13,15-pentamethyl-1-[4-methyl-4-(4-pyridin-3-yl-1H-imidazol-1-yl)pentyl]-2,6,8,14-tetraoxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside was attained (42% yield) as a white solid. MH+(872.50)
EXAMPLE 33
SYNTHESIS OF (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-DIETHYL-1-14-[4-(6-FLUOROPYRIDIN-3-YL)-1H-IMIDAZOL-1-YL]BUTYL}-11-METHOXY-7,9,11,13,15-PENTAMETHYL-2,6,8,14-TETRAOXOTETRADECAHYDRO-1H-OXACYCLOTETRADECINO[4,3-D][1,3]OXAZOL-10-YL-3,4,6-TRIDEOXY-3-(DIMETHYLAMINO)-D-XYLO-HEXOPYRANOSIDE




C12 ethyl, C9, C10, C11 enone, C3 oxo, C12 OCOIm macrolide of Example 11 (1 eq) was added to 4-[4-(6-fluoro-pyridin-3-yl)-imidazol-1-yl]-butylamine (4 eq), acetonitrile and water (10%). The reaction conditions are the same as described previously for (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-1-[4-(1H-imidazo[4,5-b]pyridin-1-yl)butyl]-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl 3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside. The product (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-1-14-[4-(6-fluoropyridin-3-yl)-1H-imidazol-1-yl]butyl)-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside was attained (79% yield) as a white solid. MH+(844.50)
EXAMPLE 34
SYNTHESIS OF (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-1-{4-[5-(3-AMINOPHENYL)-1,3-THIAZOL-2-YL]BUTYL}-3a,4-DIETHYL-11-METHOXY-7,9,11,13,15-PENTAMETHYL-2,6,8,14-TETRAOXOTETRADECAHYDRO-1H-OXACYCLOTETRADECINO[4,3-D][1,3]OXAZOL-10-YL 3,4,6-TRIDEOXY-3-(DIMETHYLAMINO)-D-XYLO-HEXOPYRANOSIDE




C12 ethyl, C9, C10, C11 enone, C3 oxo, C12 OCOIm macrolide of Example 11 (1 eq) was added to 3-[2-(4-amino-butyl)-thiazol-5-yl]-phenylamine (4 eq), acetonitrile, and water (10%). The reaction conditions are the same as described previously for (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-1-[4-(1H-imidazo[4,5-b]pyridin-1-yl)butyl]-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside. The product (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-1-{4-[5-(3-aminophenyl)-1,3-thiazol-2-yl]butyl}-3a,4-diethyl-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside was attained (12% yield) as a white solid. MH+(857.50)
EXAMPLE 35
SYNTHESIS OF (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-DIETHYL-11-METHOXY-7,9,11,13,15-PENTAMETHYL-2,6,8,14-TETRAOXO-1-[3-(3-PYRIDIN-3-YLPHENOXY)PROPYL]TETRADECAHYDRO-1H-OXACYCLOTETRADECINO[4,3-D][1,3]OXAZOL-10-YL-3,4,6-TRIDEOXY-3-(DIMETHYLAMINO)-D-XYLO-HEXOPYRANOSIDE




C12 ethyl, C9, C10, C11 enone, C3 oxo, C12 OCOIm macrolide of Example 11 (1 eq) was added to 3-(3-pyridin-3-yl-phenoxy)-propylamine (3 eq), acetonitrile, and water. The reaction conditions are the same as described previously for (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-1-[4-(1H-imidazo[4,5-b]-pyridin-1-yl)butyl]-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxotetradeca-hydro-1H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethyl-amino)-D-xylo-hexopyranoside. The product (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-1-[3-(3-pyridin-3-ylphenoxy)propyl]tetradecahydro-1H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside was attained (30% yield) as a white solid. MM+(838.50)
EXAMPLE 36
SYNTHESIS OF (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-DIETHYL-1-METHOXY-7,9,11,13,15-PENTAMETHYL-2,6,8,14-TETRAOXO-1-[3-(4-PYRIDIN-3-YLPHENOXY)PROPYL]TETRADECAHYDRO-1H-OXACYCLOTETRADECINO[4,3-D][1,3]OXAZOL-10-YL-3,4,6-TRIDEOXY-3-(DIMETHYLAMINO)-D-XYLO-HEXOPYRANOSIDE




C12 ethyl, C9, C10, C11 enone, C3 oxo, C12 OCOIm macrolide of Example 11 (1 eq) was added to 3-(4-pyridin-3-yl-phenoxy)-propylamine (3 eq), acetonitrile, and water (10%). The reaction conditions are the same as described previously for (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-1-[4-(1H-imidazo[4,5-b]pyridin-1-yl)butyl]-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside. The product (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-1-[3-(4-pyridin-3-ylphenoxy)propyl]tetradecahydro-1H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside was attained (31% yield) as a white solid. MH+(838.50)
EXAMPLE 37
SYNTHESIS OF (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-DIETHYL-1-[4-(1H-IMIDAZO[4,5-B]PYRIDIN-1-YL)-4-METHYLPHENYL -11-METHOXY-7,9,11,13,15-PENTAMETHYL-2,6,8,14-TETRAOXOTETRADECAHYDRO-1H-OXACYCLOTETRADECINO[4,3-D][1,3]OXAZOL-10-YL-3,4,6-TRIDEOXY-3-(DIMETHYLAMINO)-D-XYLO-HEXOPYRANOSIDE




C12 ethyl, C9, C10, C11 enone, C3 oxo, C12 OCOIm macrolide of Example 11 (1 eq) was added to 4-imidazo[4,5-b]pyridin-1-yl-4-methyl-pentylamine(4 eq), acetonitrile, and water (10%). The reaction conditions are the same as described previously for (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-1-[4-(1H-imidazo[4,5-b]pyridin-1-yl)butyl]-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside. The product (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-1-[4-(1H-imidazo[4,5-b]pyridin-1-yl)-4-methylpentyl]-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside was attained (22% yield) as a white solid. MH+(828.50)
EXAMPLE 38
SYNTHESIS OF (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-DIETHYL-1-[4-(3H-IMIDAZO[4,5-B]PYRIDIN-3-YL)-4-METHYLPENTYL]-11-METHOXY-7,9,11,13,15-PENTAMETHYL-2,6,8,14-TETRAOXOTETRADECAHYDRO-1H-OXACYCLOTETRADECINO[4,3-D][1,3]OXAZOL-10-YL-3,4,6-TRIDEOXY-3-(DIMETHYLAMINO)-D-XYLO-HEXOPYRANOSIDE




C12 ethyl, C9, C10, C11 enone, C3 oxo, C12 OCOIm macrolide of Example 11 (1 eq) was added to 4-imidazo[4,5-b]pyridin-3-yl-4-methyl-pentylamine (3.8 eq), acetonitrile, and water (10%). The reaction conditions are the same as described previously for (3aS,4R,7R,9R,10R,1S,13R,15R,15aR)-3a,4-diethyl-1-[4-(1H-imidazo[4,5-b]pyridin-1-yl)butyl]-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside. The product (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-1-[4-(3H-imidazo[4,5-b]pyridin-3-yl)-4-methylpentyl]-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside was attained (76% yield) as a white solid. MH+(828.50)
EXAMPLE 39
SYNTHESIS OF (3aS,4R,7S,9R,10R,11S,13R,15R,15aR)-3a,4-DIETHYL-7-FLUORO-1-[4-(1H-IMIDAZO[4,5-B]PYRIDIN-1-YL)-4-METHYLPENTYL]-11-METHOXY-7,9,11,13,15-PENTAMETHYL-2,6,8,14-TETRAOXOTETRADECAHYDRO-1H-OXACYCLOTETRADECINO[4,3-D][1,3]OXAZOL-10-YL-3,4,6-TRIDEOXY-3-(DIMETHYLAMINO)-D-XYLO-HEXOPYRANOSIDE




Using the procedure previously described for the preparation of (3aS,4R,7S,9R,10R,11S,13R,15R,15aR)-3 a,4-diethyl-7-fluoro-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-1-(4-quinolin-4-ylbutyl)tetradecahydro-1H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside, utilizing 2′ benzoylated (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-1-[4-(1H-imidazo[4,5-b]pyridin-1-yl)-4-methylpentyl]-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxotetradecahydro-2H-oxacyclo-tetradecino[4,3-d][1,3]oxazol-10-yl 3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside as starting material, the product (3aS,4R,7S,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-7-fluoro-1-[4-(1H-imidazo[4,5-b]pyridin-1-yl)-4-methylpentyl]-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside was attained (58% yield) as a white solid. MH+(846.50)
EXAMPLE 40
SYNTHESIS OF (3aS,4R,7S,9R,10R,11S,13R,15R,15aR)-3a,4-DIETHYL-7-FLUORO-1-[4-(3H-IMIDAZO[4,5-B]PYRIDIN-3-YL)-4-METH-YLPENTYL]-11-METHOXY-7,9,11,13,15-PENTAMETHYL-2,6,8,14-TETRAOXOTETRADECAHYDRO-1H-OXACYCLOTETRADECINO[4,3-D][1,3]OXAZOL-10-YL-3,4,6-TRIDEOXY-3-(DIMETHYLAMINO)-D-XYLO-HEXOPYRANOSIDE




Using the procedure previously described for the preparation of (3aS,4R,7S,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-7-fluoro-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-1-(4-quinolin-4-ylbutyl)tetradecahydro-1H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside, utilizing 2′ benzoylated (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-1-[4-(3H-imidazo[4,5-b]pyridin-3-yl)-4-methylpentyl]-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxotetradecahydro-2H-oxacyclo-tetradecino[4,3-d][1,3]oxazol-10-yl 3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexo-pyranoside as starting material, the product (3aS,4R,7S,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-7-fluoro-1-[4-(3H-imidazo[4,5-b]pyridin-3-yl)-4-methylpentyl]-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside was attained (63% yield) as a white solid. MH+(846.50)
EXAMPLE 41
SYNTHESIS OF (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-DIETHYL-11-METHOXY-7,9,11,13,15-PENTAMETHYL-1-{2-[METHYL(QUINOLIN-2-YLMETHYL)AMINO]ETHYL)-2,6,8,14-TETRAOXOTETRADECAHYDRO-1H-OXACYCLOTETRADECINO[4,3-D][1,3]OXAZOL-10-YL-3,4,6-TRIDEOXY-3-(DIMETHYLAMINO)-D-XYLO-HEXOPYRANOSIDE




C12 ethyl, C9, C10, C11 enone, C3 oxo, C12 OCOIm macrolide of Example 11 (1 eq) was added to N1-methyl-N1-quinolin-2-ylmethyl-ethane-1,2-diamine (6 eq); acetonitrile, and water (10%). The reaction conditions are the same as described previously for (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-1-[4-(1H-imidazo[4,5-b]pyridin-1-yl)butyl]-111-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside. The product (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-11-methoxy-7,9,11,13,15-pentamethyl-1-{2-[methyl(quinolin-2-yl methyl)amino]ethyl}-2,6,8,14-tetraoxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside was attained in a 13% yield. MH+(825.50)
EXAMPLE 42
SYNTHESIS OF (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-DIETHYL-11-METHOXY-7,9,11,13,15-PENTAMETHYL-1-2-[METHYL(QUINOLIN4-YLMETHYL)AMINO]ETHYL}-2,6,8,14-TETRAOXOTETRADECAHYDRO-1H-OXACYCLOTETRADECINO[4,3-D][1,3]OXAZOL-10-YL-3,4,6-TRIDEOXY-3-(DIMETHYLAMINO)-D-XYLO-HEXOPYRANOSIDE




C12 ethyl, C9, C10, C11 enone, C3 oxo, C12 OCOIm macrolide of Example 11 (1 eq) was added to N1-methyl-N1-quinolin-4-ylmethyl-ethane-1,2-diamine (6 eq), acetonitrile, and water (10%). The reaction conditions are the same as described previously for (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-1-[4-(1H-imidazo[4,5-b]pyridin-1-yl)butyl]-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethyl amino)-D-xylo-hexopyranoside, yielding (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-11-methoxy-7,9,11,13,15-pentamethyl-1-{2-[methyl(quinolin-4-ylmethyl)amino]ethyl}-2,6,8,14-tetraoxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside (18% yield) as an off white solid. MH+(825.50)
EXAMPLE 43
SYNTHESIS OF (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-1-{2-[(3,3′-BIPYRIDIN-5-YLMETHYL)(METHYL)AMINO]ETHYL}-3a,4-DIETHYL-11-METHOXY-7,9,11,13,15-PENTAMETHYL-2,6,8,14-TETRAOXOTETRADECAHYDRO-1H-OXACYCLOTETRADECINO[4,3-D][1,3]OXAZOL-10-YL-3,4,6-TRIDEOXY-3-(DIMETHYLAMINO)-D-XYLO-HEXOPYRANOSIDE




C12 ethyl, C9, C10, C11 enone, C3 oxo, C12 OCOIm macrolide of Example 11 (1 eq) was added to N1-[3,3′]bipyridinyl-5-ylmethyl-N1-methyl-ethane-1,2-diamine (3 eq), acetonitrile, and water (10%). The reaction conditions are the same as described previously for (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-1-[4-(1H-imidazo[4,5-b]pyridin-1-yl)butyl]-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside, yielding the product (3aS,4R,7R,9R,10R,1S,13R,15R,15aR)-1-{2-[(3,3′-bipyridin-5-ylmethyl)(methyl)amino]ethyl)-3a,4-diethyl-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxotetradecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside (27% yield) as a white solid. MM+(852.50).
EXAMPLE 44
SYNTHESIS OF (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-DIETHYL-11-METHOXY-7,9,11,13,15-PENTAMETHYL-1-{2-[METHYL(QUINOLIN-3-YLMETHYL)AMINO]ETHYL}-2,6,8,14-TETRAOXOTETRADECAHYDRO-1H-OXACYCLOTETRADECINO[4,3-D][1,3]OXAZOL-10-YL 3,4,6-TRIDEOXY-3-(DIMETHYLAMINO)-D-XYLO-HEXOPYRANOSIDE




C12 ethyl, C9, C10, C11 enone, C3 oxo, C12 OCOIm macrolide of Example 11 (1 eq) was added to N1-methyl-N1-quinolin-3-ylmethyl-ethane-1,2-diamine (6 eq); acetonitrile and water (10:1), respectively, were added. The solution was heated at 65° C. for 20 hours. Upon cooling the reaction was diluted with ethyl acetate and washed with NaHCO3 (sat.), NaCl (sat.), dried over MgSO4, filtered and concentrated. To the crude material was added methanol and the solution was heated at 65° C. for 18 hours. Upon concentrating, the material was purified using flash chromatography (5% methanol/dichloromethane with 0.1% triethylamine), followed by further purification by RP HPLC. The combined product fractions coming off the HPLC were diluted with ethyl acetate and NaHCO3 was added. The aqueous layer was separated and the organic layer was washed with NaCl (sat.), dried over MgSO4, filtered, concentrated, dissolved in acetonitrile/water, and lyophilized yielding the product (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-11-methoxy-7,9,11,13,15-pentamethyl-1-{2-[methyl(quinolin-3-ylmethyl)amino]ethyl}-2,6,8,14-tetra-oxotetradecahydro-1H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside (35% yield) as an off white solid. MH+(825.50)
EXAMPLE 45
SYNTHESIS OF (3aS,4R,7R,9R,10R,11S,13R,15R,5aR)-3a,4-DIETHYL-11-METHOXY-7,9,11,13,15-PENTAMETHYL-2,6,8,14-TETRAOXO-1-[4-(3-PHENYLISOXAZOL-5-YL)BUTYL]TETRADECAHYDRO-1H-OXACYCLOTETRADECINO[4,3-D][1,3]OXAZOL-10-YL-3,4,6-TRIDEOXY-3-(DIMETHYLAMINO)-D-XYLO-HEXOPYRANOSIDE




C12 ethyl, C9, C10, C11 enone, C3 oxo, C12 OCOIm macrolide of Example 11 (1 eq) was added to 4-(3-phenyl-isoxazol-5-yl)-butylamine (6 eq). The reaction conditions are described in Example 44. The product (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-1-[4-(3-phenyl isoxazol-5-yl)butyl]tetradecahydro-1H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside was obtained as an off white solid in a 50% yield. MH+(826.50)
EXAMPLE 46
SYNTHESIS OF (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-DIETHYL-11-METHOXY-7,9,11,13,15-PENTAMETHYL-1-{4-[3-(4-METHYLPHENYL)ISOXAZOL-5-YL]BUTYL}-2,6,8,14-TETRAOXOTETRADECAHYDRO-1H-OXACYCLOTETRADECINO[4,3-D][1,3]OXAZOL-10-YL-3,4,6-TRIDEOXY-3-(DIMETHYLAMINO)-D-XYLO-HEXOPYRANOSIDE




C12 ethyl, C9, C10, C11 enone, C3 oxo, C12 OCOIm macrolide of Example 11 (1 eq) was added to 4-(3-p-tolyl-isoxazol-5-yl)-butylamine (6 eq). The reaction conditions were as described in Example 44. The product (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-11-methoxy-7,9,11,13,15-pentamethyl-1-{4-[3-(4-methylphenyl)isoxazol-5-yl]butyl}-2,6,8,14-tetraoxotetra-decahydro-1H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside was obtained as an off white solid in a 73% yield. MH+(840.06)
EXAMPLE 47
SYNTHESIS OF C12 VINYL MACROLIDES (SCHEME 7)
EXAMPLE 47(A)
C12 ALKENE, C9,C11 DIOL MACROLIDE




To 2′,4′′ OBz, C9, C11-dimethylketal C12, 21 alkene macrolide (1 eq) in 2:1 acetonitrile/water was added pyridinium p-toluenesulfonate (5 eq). The solution was heated in a 68° C. oil bath for 17 hours. Upon cooling, the solution was diluted with ethyl acetate, and solid NaHCO3 was added (12 eq). The organic layer was then diluted with ethyl acetate, washed with NaHCO3 (sat.), and NaCl (sat.). The combined aqueous layers were back extracted with ethyl acetate, and the combined organic layers dried over MgSO4, filtered and concentrated to yield C12 alkene, C9, C11 diol as a white solid (90% yield). The material is used as is for the next step. MH+(940.4)
EXAMPLE 47(B)
C12, C21, C11, C9 TETRAOL MACROLIDE




To C12 alkene, C9, C11 diol macrolide (1 eq) in 9:1 acetone/water was added N-methyl morpholine N-oxide mono-hydrate (2 eq), followed by 0.08 M osmium tetroxide in tert-butanol. The solution was allowed to stir at room temperature for 4 hours. The solution was then diluted with ethyl acetate and cooled to 0° C. Upon cooling Na2SO3 (sat.) was added and the solution was allowed to stir for 10 minutes. The reaction was then warmed to room temperature, diluted with ethyl acetate, and washed with NaHCO3 (sat.), and NaCl (sat.). The combined aqueous layers were back extracted with ethyl acetate, and the combined organic layers were dried with MgSO4, filtered and concentrated. Diethyl ether was added and the slurry was allowed to stir for 17 hours, then filtered and rinsed with diethyl ether to yield the C9, C11, C12, C21 tetraol macrolide (82% yield) as an off-white solid. MH+(974.5)
EXAMPLE 47(C)
C21 ACETATE C9, C11, C12 TRIOL MACROLIDE




To C9, C11, C12, C21 tetraol macrolide (1 eq) in dichloromethane at 0° C. under argon was added acetic anhydride (1.1 eq), diisopropylethylamine (1.1 eq), and dimethylaminopyridine (0.1 eq). After stirring for 15 minutes, the solution was cooled at −10° for 17 hours. The solution was diluted with ethyl acetate, and washed with NaHCO3 (sat.), NaCl (sat.), dried over MgSO4, filtered, and concentrated to yield the C21 acetate, C12, C11, C9 triol macrolide as an off white solid in quantitative yield. The material is used as is for the next step.
EXAMPLE 47(D)
C21 ACETATE C9 KETO, C11, C12 DIOL MACROLIDE




To C21 acetate, C9, C11, C12 triol macrolide (1 eq) in dichloromethane at 0° C. was added Dess-Martin periodinane (1.2 eq). The solution was stirred at 0° C. for 14 hours. The reaction was diluted with ethyl acetate, and 1:1 10% Na2S2O3/NaHCO3 (sat.) was added. The bilayer solution was stirred vigorously for 1 hour. The layers were separated and the organic layer was washed with NaCl(sat), dried over MgSO4, filtered and concentrated yielding the C21 acetate, C9 keto, C11, C12 diol macrolide (99% yield) as an off white solid. The material is used as is for the next step. MH+(1014.5)
EXAMPLE 47(E)
C21 ACETATE C9 KETO, C10 MS, C12 OH MACROLIDE




To C21 acetate, C9 keto, C11, C12 diol macrolide (1 eq) in pyridine at 0° C. was added methanesulfonyl chloride (5 eq) via syringe. The solution was stirred for 18 hours as the solution warmed to room temperature. After concentrating the reaction mixture, water was added and the slurry was stirred vigorously for 17 hours; the slurry was filtered and dried to afford the C21 acetate C9 keto, C11 OMs, C12 hydroxy macrolide (100% yield) as a yellow solid. MH+(1092.4)
EXAMPLE 47(F)
C21 ACETATE C9, C10, C11 ENONE, C12 OH DIOL MACROLIDE




To C21 acetate, C9keto, C11 OMs, C12 OH macrolide (1 eq) in acetone was added DBU (2 eq). The solution was stirred for 5 hours at room temperature and then for 40 hours at 68° C. The solution was diluted with ethyl acetate, washed with H2O, NaHCO3 (sat.), with NaCl (sat.), dried over MgSO4, filtered, and concentrated yielding the C21 acetone C9, C10, C11 enone, C12 OH macrolide (90% yield) as an off white solid. MH+(996.4)
EXAMPLE 47(G)
C9, C10, C11 ENONE, C3, C12, C21 TRIOL MACROLIDE




To C21 acetate, C9, C10, C11 enone C12 OH macrolide (1 eq) in acetonitrile was added 3 M HCl(aq). The solution was heated at 40° C. for 22 hours; upon cooling, the solution was diluted with ethyl acetate and solid NaHCO3 was added. The solution was washed with NaHCO3 (sat.), with NaCl (sat.), dried over MgSO4, filtered, and concentrated to yield an off white solid. Purification through flash chromatography (35% acetone/hexanes with 0.1% triethylamine) yielded crude product as a white solid. The material was further purified by triturating from diethyl ether/hexanes to yield C9, C10, C11 enone, C3, C12, C21 triol macrolide (24%). MH+(690.4)
EXAMPLE 47(H)
C3, C21 OXO, C9, C10, C11 ENONE-12-OL MACROLIDE




To N-chlorosuccinimide (1 eq) in dichloromethane at 0° C. was added methyl sulfide (1.2 eq). After stirring for 5 minutes, the solution was cooled to −20° C. To this solution was added C21,C3 hydroxy macrolide (0.4 eq) in dichloromethane. The resulting solution was stirred at −23° C. for 95 minutes at which time triethylamine (1 eq) was added dropwise. After stirring at −20° C. for 5 minutes, the solution was allowed to warm to room temperature. The solution was than added to ethyl acetate, washed with NaHCO3 (sat.), with NaCl (sat.), dried over MgSO4, filtered, and concentrated to yield an off white solid. Purification through flash chromatography (15-20% acetone/hexanes with 0.1% triethylamine) yielded the C3, C21 oxo, C9, C10, C11 enone-12-ol macrolide (75% yield) as a white solid. MH+(688.4)
EXAMPLE 47(I)
C12 VINYL, C3, OXO, C9, C10, C11 ENONE-12-OL MACROLIDE




To methyl triphenylphosphonium bromide (1 eq) in tetrahydrofuran at −78° C. was added potassium bis(trimethylsilyl)amide/0.5 M in toluene (1 eq). The cooling bath was removed and the anion solution was stirred for 1 hour. After cooling the anion solution back to −78° C., C21 aldehyde macrolide (0.5 eq) in tetrahydrofuran was added. The cooling bath was removed and the anion solution was stirred for 4 hours at which time ethyl acetate and NH4Cl (sat.) were added. After two layers formed, the reaction was added to ethyl acetate and NH4Cl (sat.). Upon mixing and separating off the aqueos layer, the organic layer was washed with NaHCO3 (sat.), with NaCl (sat.), dried over MgSO4, filtered, and concentrated. Purification through flash chromatography (15-20% acetone/hexanes with 0.1% triethylamine) yielded the C12-vinyl, C3-oxo, C9, C10, C11 enone-12-ol macrolide (50% yield) as a white solid. MH+(686.4)
EXAMPLE 47(J)
C12 VINYL C10, C11 ENONE, C3 OXO, C12 OCOIM MACROLIDE




To a solution of C12 vinyl, C9, C10, C11 enone, C3 OXO, C12 OH macrolide (1 eq) and carbonyldiimidazole (3 eq) in tetrahydrofuran at 0° C. was added sodium hydride (2 eq). After stirring for 6 hours, ethyl acetate was added. While still at 0° C., NaHCO3 (sat.) was added cautiously. The mixture was then diluted with ethyl acetate and was washed with NaHCO3 (sat.), with NaCl (sat.), dried over MgSO4, filtered, concentrated, and pumped on yielding crude C12 vinyl C9, C10, C11 enone, C3 oxo, C12 OCOIm macrolide. The crude material was used in the next step without further purification. MH+(780.5, and hydrolyzed 686.5)
EXAMPLE 48
SYNTHESIS OF (3aS,4R,7R,9R,10R,11R,13R,15R,15aR)-4-ETHYL-11-METHOXY-7,9,11,13,15-PENTAMETHYL-2,6,8,14-TETRAOXO-1-[4-(4-PYRIDIN-3-YL-1H-IMIDAZOL-1-YL)BUTYL]-3a-VINYLTETRADECAHYDRO-1H-OXACYCLOTETRADECINO[4,3-D][1,3]OXAZOL-10-YL-3,4,6-TRIDEOXY-3-(DIMETHYLAMINO)-D-XYLO-HEXOPYRANOSIDE




C12 vinyl, C9, C10, C11 enone, C3 oxo, C12 OCOIm macrolide (1 eq) was added to 4-(4-(3-pyridyl)imidazolyl)butylamine (4 eq); acetonitrile and water were added. The solution was heated at 65° C. for 14 hours. Upon cooling, the reaction was diluted with ethyl acetate and washed with NaHCO3 (sat.), NaCl (sat.), dried over MgSO4, filtered, and concentrated. To the crude material was added dichloromethane, benzoic anhydride, triethylamine, and dimethylaminopyridine. After standing for 12 hours the solution was concentrated and purified by RP HPLC. The combined product fractions coming off the HPLC were diluted with ethyl acetate and NaHCO3 was added. After mixing, the aqueous layer was separated and the organic layer was washed with NaCl (sat.), dried over MgSO4, filtered, and concentrated, yielding benzoylated (3aS,4R,7R,9R,10R,11R,13R,15R,15aR)-4-ethyl-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-1-[4-(4-pyridin-3-yl-1H-imidazol-1-yl)butyl]-3a-vinyltetradecahydro-1H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside (35% yield) as a white solid. To the benzoylated compound was added methanol and the solution was heated at 65° C. for 16 hours. Upon concentrating, the material was purified by RP HPLC. The combined product fractions coming off the HPLC were diluted with ethyl acetate and NaHCO3 was added. After mixing, the aqueous layer was separated and the organic layer was washed with NaCl (sat.), dried over MgSO4, filtered, concentrated, dissolved in acetonitrile/water, and lyophilized yielding (3aS,4R,7R,9R,10R,1R,13R,15R,15aR)-4-ethyl-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-1-[4-(4-pyridin-3-yl-1H-imidazol-1-yl)butyl]-3a-vinyltetradecahydro-1H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside (83% yield) as a white solid. MH+ (824.50)
EXAMPLE 49
SYNTHESIS OF (3aS,4R,7S,9R,10R,11S,13R,15R,15aR)-4-ETHYL-7-FLUORO-11-METHOXY-7,9,11,13,15-PENTAMETHYL-2,6,8,14-TETRAOXO-1-[4-(4-PYRIDIN-3-YL-1H-IMIDAZOL-1-YL)BUTYL]-3a-VINYLTETRADECAHYDRO-1H-OXACYCLOTETRADECINO[4,3-D][1,3]OXAZOL-10-YL 3,4,6-TRIDEOXY-3-(DIMETHYLAMINO)-D-XYLO-HEXOPYRANOSIDE




To benzoylated (3aS,4R,7R,9R,10R,11R,13R,15R,15aR)-4-ethyl-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-1-[4-(4-pyridin-3-yl-1H-imidazol-1-yl)butyl]-3a-vinyltetradecahydro-1H-oxacyclotetradecino[4,3-d]-[1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside (1 eq) in DMF (5.3 ml) at 0° C. was added 60% NaH (2 eq). After stirring for 1 hour at 0° C., N-fluorobenzenesulfonimide (1 eq) was added. After stirring for an additional hour at 0° C., the solution was diluted with ethyl acetate and NaHCO3 (sat.) was added cautiously to quench. The reaction was then added to ethyl acetate and was washed with NaHCO3 (sat.), NaCl (sat.), dried over MgSO4, filtered, concentrated, and purified by RP HPLC. The combined product fractions coming off the HPLC were diluted with ethyl acetate and NaHCO3 was added. The aqueous layer was separated and the organic layer was washed with NaCl (sat.), dried over MgSO4, filtered, and concentrated. Methanol was added and the solution was heated at 60° C. for 15 hours. Upon concentrating, the material was purified by RP HPLC. The combined product fractions coming off the HPLC were diluted with ethyl acetate and NaHCO3 was added. The aqueous layer was separated and the organic layer was washed with NaCl (sat.) dried over MgSO4, filtered, concentrated, and lyophilized from MeCN:H2O yielding (3aS,4R,7S,9R,10R,11S,13R,15R,15aR)-4-ethyl-7-fluoro-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-1-[4-(4-pyridin-3-yl-1H-imidazol-1-yl)butyl]-3a-vinyltetradecahydro-1H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside (47% yield) as a white solid. MH+ (842.50)
EXAMPLE 50
SYNTHESIS OF (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-4-ETHYL-11-METHOXY-7,9,11,13,15-PENTAMETHYL-1-[4-METHYL-4-(4-PYRIDIN-3-YL-1H-IMIDAZOL-1-YL)PENTYL]-2,6,8,14-TETRAOXO-3a-VINYLTETRADECAHYDRO-1H-OXACYCLOTETRADECINO[4,3-D][1,3]OXAZOL-10-YL 3,4,6-TRIDEOXY-3-(DIMETHYLAMINO)-D-XYLO-HEXOPYRANOSIDE




C12 vinyl, C9, C10, C11 enone, C3 oxo, C12 OCOIm macrolide (1 eq) was added to 4-Methyl-4-(4-pyridin-3-yl-imidazol-1-yl)-pentylamine (3 eq); acetonitrile and water (10%). The solution was heated at 65° C. for 16 hours. Upon cooling the reaction was diluted with ethyl acetate and washed with NaHCO3 (sat.), NaCl (sat.), dried over MgSO4, filtered, and concentrated. To the crude material was added dichloromethane, benzoic anhydride, triethylamine (10%), and dimethylaminopyridine (2%). After standing for 17 hours the solution was concentrated and purified by RP HPLC. The combined product fractions coming off the HPLC were diluted with ethyl acetate and NaHCO3 was added. After mixing, the aqueous layer was separated and the organic layer was washed with NaCl (sat.), dried over MgSO4, filtered, and concentrated, affording the 2′ benzoylated product (21% yield). Methanol was added, and the solution was heated at 65° C. for 16 hours. Upon concentrating, the material was purified by RP HPLC. The combined product fractions coming off the HPLC were diluted with ethyl acetate and NaHCO3 was added. After mixing, the aqueous layer was separated and the organic layer was washed with NaCl (sat.), dried over MgSO4, filtered, concentrated, dissolved in acetonitrile/water, and lyophilized affording (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-4-ethyl-11-methoxy-7,9,11,13,15-pentamethyl-1-[4-methyl-4-(4-pyridin-3-yl-1H-imidazol-1-yl)pentyl]-2,6,8,14-tetraoxo-3a-vinyltetradecahydro-1H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside (73% yield) as a white solid. MH+(852.50).
EXAMPLE 51
SYNTHESIS OF C12 VINYL ANALOGS (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-4-ETHYL-1-[4-(3H-IMIDAZO[4,5-B]PYRIDIN-3-YL)BUTYL]-11-METHOXY-7,9,11,13,15-PENTAMETHYL-2,6,8,14-TETRAOXO-3a-VINYLTETRADECAHYDRO-1H-OXACYCLOTETRADECINO[4,3-D[1,3]OXAZOL-10-YL 3,4,6-TRIDEOXY-3-(DIMETHYLAMINO)-D-XYLO-HEXOPYRANOSIDE




C12 vinyl, C9, C10, C11 enone, C3 oxo, C12 OCOIm macrolide of Example 47 (1 eq) was added to 4-imidazo[4,5-b]pyridin-3-yl-butylamine (5 eq). The reaction conditions are described in Example 44. The product (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-4-ethyl-1-[4-(3H-imidazo[4,5-b]pyridin-3-yl)butyl]-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-3a-vinyltetradecahydro-1H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside was obtained as an off white solid in a 70% yield. MH+ (798.00)
EXAMPLE 52
SYNTHESIS OF (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-4-ETHYL-1-[4-(1H-IMIDAZO[4,5-B]PYRIDIN-1-YL)BUTYL]-11-METHOXY-7,9,11,13,15-PENTAMETHYL-2,6,8,14-TETRAOXO-3 a-VINYLTETRADECAHYDRO-1H-OXACYCLOTETRADECINO[4,3-D][1,3]OXAZOL-10-YL-3,4,6-TRIDEOXY-3-(DIMETHYLAMINO)-D-XYLO-HEXOPYRANOSIDE




C12 vinyl, C9, C10, C11 enone, C3 oxo, C12 OCOIm macrolide of Example 47 (1 eq) was added to 4-imidazo[4,5-b]pyridin-1-yl-butylamine (6 eq). The reaction conditions are described in Example 44. The product (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-4-ethyl-1-[4-(1H-imidazo[4,5-b]pyridin-1-yl)butyl]-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-3a-vinyltetradecahydro-1H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside was obtained as an off white solid in a 26% yield. MH+(798.00)
EXAMPLE 53
SYNTHESIS OF (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-4-ETHYL-11-METHOXY-7,9,11,13,15-PENTAMETHYL-1-14-[4-(6-METHYLPYRIDIN-3-YL)-1H-IMIDAZOL-1-YL]BUTYL )-2,6,8,14-TETRAOXO-3a-VINYLTETRADECAHYDRO-1H-OXACYCLOTETRADECINO[4,3-D][1,3]OXAZOL-10-YL-3,4,6-TRIDEOXY-3-(DIMETHYLAMINO)-D-XYLO-HEXOPYRANOSIDE




C12 vinyl, C9, C10, C11 enone, C3 oxo, C12 OCOIm macrolide of Example 47(1 eq) was added to 4-[4-(6-methyl-pyridin-3-yl)-imidazol-1-yl]-butylamine (3 eq). The reaction conditions are described in Example 44. The resulting product (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-4-ethyl-11-methoxy-7,9,11,13,15-pentamethyl-1-{4-[4-(6-methylpyridin-3-yl)-1H-imidazol-1-yl]butyl}-2,6,8,14-tetraoxo-3a-vinyltetradecahydro-1H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside was obtained as an off white solid in a 25% yield. MH+(838.05)
EXAMPLE 54
SYNTHESIS OF (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-1-{2-[(3,3′-BIPYRIDIN-5-YLMETHYL)(METHYL)AMINO]ETHYL}-4-ETHYL-11-METHOXY-7,9,11,13,15-PENTAMETHYL-2,6,8,14-TETRAOXO-3a-VINYLTETRADECAHYDRO-1H-OXACYCLOTETRADECINO[4,3-D][1,3]OXAZOL-10-YL-3,4,6-TRIDEOXY-3-(DIMETHYLAMINO)-D-XYLO-HEXOPYRANOSIDE




C12 vinyl, C9, C10, C11 enone, C3 oxo, C12 OCOIm macrolide of Example 47 (1 eq) was added to N1-[3,3′]bipyridinyl-5-ylmethyl-N1-methyl-ethane-1,2-diamine (5 eq). The reaction conditions are described in Example 44. The product (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-1-12-[(3,3′-bipyridin-5-ylmethyl)(methyl)-amino]ethyl}-4-ethyl-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-3a-vinyltetradecahydro-1H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside was obtained as an off white solid in a 27% yield. MH+(850.50)
EXAMPLE 55 
SYNTHESIS OF (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-4-ETHYL-11-METHOXY-7,9,11,13,15-PENTAMETHYL-2,6,8,14-TETRAOXO-1-[4-(4-PYRAZIN-2-YL-1H-IMIDAZOL-1-YL)BUTYL]-3a-VINYLTETRADECAHYDRO-1H-OXACYCLOTETRADECINO[4,3-D][1,3]OXAZOL-10-YL-3,4,6-TRIDEOXY-3-(DIETHYLAMINO)-D-XYLO-HEXOPYRANOSIDE




C12 vinyl, C9, C10, C11 enone, C3 oxo, C12 OCOIm macrolide of Example 47 (1 eq) was added to 4-(4-pyrazin-2-yl-imidazol-1-yl)-butylamine (4 eq) The reaction conditions are described in Example 44. The reaction product (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-4-ethyl-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-1-[4-(4-pyrazin-2-yl-1H-imidazol-1-yl)butyl]-3a-vinyltetradecahydro-1H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside was obtained as an off white solid in a 12% yield. MH+(825.01)
EXAMPLE 56 
SYNTHESIS OF (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-4-ETHYL-11-METHOXY-7,9,11,13,15-PENTAMETHYL-2,6,8,14-TETRAOXO-1-[4-(4-PYRIMIDIN-5-YL-1H-IMIDAZOL-1-YL)BUTYL]-3a-VINYLTETRADECAHYDRO-1H-OXACYCLOTETRADECINO[4,3-D][1,3]OXAZOL-10-YL-3,4,6-TRIDEOXY-3-(DIMETHYLAMINO)-D-XYLO-HEXOPYRANOSIDE




C12 vinyl, C9, C10, C11 enone, C3 oxo, C12 OCOIm macrolide of Example 47 (1 eq) was added to 4-(4-pyrimidin-5-yl-imidazol-1-yl)-butylamine (4 eq). The reaction conditions are described in Example 44. The reaction product (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-4-ethyl-11-methoxy-7,9,11,13,15-penta-methyl-2,6,8,14-tetraoxo-1-[4-(4-pyrimidin-5-yl-1H-imidazol-1-yl)butyl]-3a-vinyl-tetradecahydro-1H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside was obtained as an off white solid in a 16% yield. MH+(825.01)
EXAMPLE 57 
SYNTHESIS OF (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-4-ETHYL-1-[4-(1H-IMIDAZO[4,5-B]PYRIDIN-1-YL)-4-METHYLPENTYL]-11-METHOXY-7,9,11,13,15-PENTAMETHYL-2,6,8,14-TETRAOXO-3a-VINYLTETRADECAHYDRO-1H-OXACYCLOTETRADECINO[4,3-D][1,3]OXAZOL-10-YL-3,4,6-TRIDEOXY-3-(DIMETHYLAMINO)-D-XYLO-HEXOPYRANOSIDE




C12 vinyl, C9, C10, C11 enone, C3 oxo, C12 OCOIm macrolide of Example 47 (1 eq) was added to 4-imidazo[4,5-b]pyridin-1-yl-4-methyl-pentylamine (4 eq). The reaction conditions are described in Example 44. The resulting product (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-4-ethyl-1-[4-(1H-imidazo[4,5-b]pyridin-1-yl)-4-methylpentyl]-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-3a-vinyltetradecahydro-1H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside was obtained as an off white solid in a 16% yield. MH+(826.04)
EXAMPLE 58 
SYNTHESIS OF (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-4-ETHYL-11-METHOXY-7,9,11,13,15-PENTAMETHYL-2,6,8,14-TETRAOXO-1-(4-QUINOLIN-4-YLBUTYL)-3a-VINYLTETRADECAHYDRO-1H-OXACYCLOTETRADECINO[4,3-D][1,3]OXAZOL-10-YL-3,4,6-TRIDEOXY-3-(DIMETHYLAMINO)-D-XYLO-HEXOPYRANOSIDE




C12 vinyl, C9, C10, C11 enone, C3 oxo, C12 OCOIm macrolide of Example 47 (1 eq) was added to 4-quinolin-4-yl-butylamine (20 eq). The reaction conditions are described in Example 44. The resulting product (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-4-ethyl-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-1-(4-quinolin-4-ylbutyl)-3a-vinyltetradecahydro-1H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside was obtained as an off white solid in a 19% yield. MH+(808.50)
EXAMPLE 59 
SYNTHESIS OF C12 SUBSTITUTED MACROLIDES (SCHEME 8)
EXAMPLE 59(A)
C3 Hydroxy, C21 OTBMDS, C9, C10, C11 Enone-12-OL Macrolide




Referring to Scheme 8, to C21, C3 hydroxy macrolide (1 eq) in 10 ml of dimethylformamide was added imidazole (4 eq) and tert-butyldimethylsilyl chloride (1.3 eq). After stirring for 14 hours, more tert-butyldimethylsilyl chloride (1.3 eq) was added. After stirring for an additional 2 hours, the reaction was added to ethyl acetate, was washed with NaHCO3 (sat.), with H2O, with NaCl (sat.), dried over MgSO4, filtered and concentrated. Purification by flash chromatography (30% acetone/hexanes with 0.1% triethylamine) afforded the C3 hydroxy, C21 OTBDMS, C9, C10, C11 enone-12-ol macrolide (77% yield) as a white solid. MH+(806.5)
EXAMPLE 59(B)
C21 OTBDMS, C9, C10, C11 ENONE, C3 OXO, C12 OH MACROLIDE




To C21 OTBDMS, C9, C10, C11 enone, C3, C12 diol macrolide (1 eq) in dichloromethane was added Dess-Martin periodinane (2 eq). After stirring for 2 hours, the solution was diluted with ethyl acetate and washed with 1:1 10% Na2S2O3/NaHCO3 (sat.), with NaCl (sat.), dried over MgSO4, filtered, and concentrated. Purification by flash chromatography (15-20% acetone/hexanes with 0.1% triethylamine) afforded the C2OTBDMS, C9, C10, C11 enone, C3 oxo, C12 OH macrolide (59% yield) as a white solid. MH+(804.5)
EXAMPLE 59(C)
C21 OTBDMS, C10, C11 ENONE, C3 OXO, C12 OCOIM MACROLIDE




To a solution of C21 OTBDMS, C9, C10, C11 enone, C3 oxo, C12 OH macrolide (1 eq) and carbonyldiimidazole (3 eq) in tetrahydrofuran at 0° C. was added sodium hydride (2 eq). After stirring for 10 hours at 0° C., ethyl acetate was added. While still at 0° C., NaHCO3 (sat.) was added cautiously. The mixture was then diluted with ethyl acetate and was washed with NaHCO3 (sat.), with NaCl (sat.), dried over MgSO4, filtered, concentrated, and pumped yielding crude C21 OTBDMS, C9, C10, C11 enone, C3 oxo, C12 OCOIm macrolide. The crude material was used in the next step without further purification. MH+(898.5)
EXAMPLE 60 
SYNTHESIS OF (3aR,4R,7R,9R,10R,11R,13R,15R,15aR)-3a-({[TERT-BUTYL(DIMETHYL)SILYL]OXY}METHYL)-4-ETHYL-11-METHOXY-7,9,11,13,15-PENTAMETHYL-2,6,8,14-TETRAOXO-1-[4-(4-PYRIDIN-3-YL-1H-IMIDAZOL-1-YL)BUTYL]TETRADECAHYDRO-1H-OXACYCLOTETRADECINO[4,3-D][1,3]OXAZOL-10-YL-3,4,6-TRIDEOXY-3-(DIMETHYLAMINO)-D-XYLO-HEXOPYRANOSIDE




C21 OTBDMS, C9, C10, C11 enone, C3 oxo, C12 OCOIm macrolide (1 eq) was added to 4-(4-(3-pyridyl)imidazolyl)butylamine (6 eq); acetonitrile and water were added. The solution was heated at 60° C. for 3 days. Upon cooling the reaction was diluted with ethyl acetate and washed with NaHCO3 (sat.), NaCl (sat.), dried over MgSO4, filtered, and concentrated. To the crude material was added dichloromethane, benzoic anhydride, triethylamine, and dimethylaminopyridine, 1:20:3:1, respectively. After standing for 12 hours, the solution was concentrated and purified by RP HPLC. The combined product fractions coming off the HPLC were diluted with ethyl acetate and NaHCO3 was added. After mixing, the aqueous layer was separated and the organic layer was washed with NaCl (sat.), dried over MgSO4, filtered, and concentrated, yielding benzoylated (3aR,4R,7R,9R,10R,11R,13R,15R,15aR)-3a-({[tert-butyl(dimethyl)silyl]oxy}-methyl)-4-ethyl-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-1-[4-(4-pyridin-3-yl-1H-imidazol-1-yl)butyl]tetradecahydro-1H-oxacyclotetradecino[4,3-d]-[1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside (41% yield) as a white solid. To benzoylated (3aR,4R,7R,9R,10R,11R,13R,15R,15aR)-3a-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-ethyl-11-methoxy-7,9,11,13,15-penta-methyl-2,6,8,14-tetraoxo-1-[4-(4-pyridin-3-yl-1H-imidazol-1-yl)butyl]tetradeca-hydro-1H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethyl-amino)-D-xylo-hexopyranoside (1 eq) was added methanol and the solution was heated at 65° C. for 16 hours. Upon concentrating, the material was purified by RP HPLC. The combined product fractions coming off the HPLC were diluted with ethyl acetate and NaHCO3 was added. After mixing, the aqueous layer was separated and the organic layer was washed with NaCl (sat.), dried over MgSO4, filtered, concentrated, dissolved in acetonitrile/water, and lyophilized yielding (3aR,4R,7R,9R,10R,1R,13R,15R,15aR)-3a-({[tert-butyl(dimethyl)silyl]oxy}-methyl)-4-ethyl-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-1-[4-(4-pyridin-3-yl-1H-imidazol-1-yl)butyl]tetradecahydro-1H-oxacyclotetradecino[4,3-d]-[1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside (72% yield) as a white solid. MH+(942.60)
EXAMPLE 61 
SYNTHESIS OF (3aR,4R,7R,9R,10R,11R,13R,15R,15aR)-4-ETHYL-3a-(HYDROXYMETHYL)-11-METHOXY-7,9,11,13,15-PENTAMETHYL-2,6,8,14-TETRAOXO-1-[4-(4-PYRIDIN-3-YL-1H-IMIDAZOL-1-YL)BUTYL]TETRADECAHYDRO-1H-OXACYCLOTETRADECINO[4,3-D][1,3]OXAZOL-10-YL-3,4,6-TRIDEOXY-3-(DIMETHYLAMINO)-D-XYLO-HEXOPYRANOSIDE




To (3aR,4R,7R,9R,10R,11R,13R,15R,15aR)-3a-(([tert-butyl(dimethyl)silyl]oxy}methyl)-4-ethyl-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-1-[4-(4-pyridin-3-yl-1H-imidazol-1-yl)butyl]tetradecahydro-1H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3 ,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside (1 eq) in tetrahydrofuran was added acetic acid (2 eq) and tetrabutylammonium fluoride/1.0 M in tetrahydrofuran (2 eq). After standing for 48 hours, ethyl acetate was added and the solution was washed with NaHCO3 (sat.), NaCl (sat.), dried over MgSO4, filtered, and concentrated. Purification by RP HPLC afforded (3aR,4R,7R,9R,10R,11R,13R,15R,15aR)-4-ethyl-3a-(hydroxymethyl)-1-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-1-[4-(4-pyridin-3-yl-1H-imidazol-1-yl)butyl]tetradecahydro-1H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside (48% yield) as a white solid. MH+(828.50)
EXAMPLE 62 
SYNTHESIS OF [(3aR,4R,7R,9R,10R,11R,13R,15R,15aR)-4-ETHYL-11-METHOXY-7,9,11,13,15-PENTAMETHYL-2,6,8,14-TETRAOXO-1-[4-(4-PYRIDIN-3-YL-1H-IMIDAZOL-1-YL)BUTYL]-10-{[3,4,6-TRIDEOXY-3-(DIMETHYLAMINO)-D-XYLO-HEXOPYRANOSYL]OXY}DODECAHYDRO-2H-OXACYCLOTETRADECINO[4,3-D][1,3]OXAZOL-3a (4H)-YL]METHYL METHANESULFONATE




To benzoylated (3aR,4R,7R,9R,10R,11R,13R,15R,15aR)-4-ethyl-3a-(hydroxymethyl)-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-1-[4-(4-pyridin-3-yl-1H-imidazol-1-yl)butyl]tetradecahydro-1H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside (1 eq) in pyridine was methanesulfonyl chloride (5 eq). After standing for 5 hours, the solution was concentrated, taken up in DMSO and purified by RP HPLC affording benzoylated [(3aR,4R,7R,9R,10R,11R,13R,15R,15aR)-4-ethyl-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-1-[4-(4-pyridin-3-yl-1H-imidazol-1-yl)butyl]-10-[3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranosyl]oxy)dodecahydro-1H-oxacyclotetradecino[4,3-d][1,3]oxazol-3a(4H)-yl]methyl methanesulfonate (81% yield) as a white solid. To benzoylated [(3aR,4R,7R,9R,10R,11R,13R,15R,15aR)-4-ethyl-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-1-[4-(4-pyridin-3-yl-1H-imidazol-1-yl)butyl]-10-{[3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexo-pyranosyl]oxy}dodecahydro-1H-oxacyclotetradecino[4,3-d][1,3]oxazol-3a(4H)-yl]methyl methanesulfonate (0.03 mmoles) was added methanol and the solution was heated at 65° C. for 17 hours. Upon cooling the solution was concentrated and purified by RP HPLC yielding [(3aR,4R,7R,9R,10R,11R,13R,15R,15aR)-4-ethyl-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-1-[4-(4-pyridin-3-yl-1H-imidazol-1-yl)butyl]-10-{[3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranosyl]-oxy}dodecahydro-1H-oxacyclotetradecino[4,3-d][1,3]oxazol-3a(1H)-yl]methyl methanesulfonate (55% yield) as a white solid. MH+(906.50)
EXAMPLE 63 
SYNTHESIS OF (3aS,4R,7R,9R,10R,11R,13R,5R,15aR)-4-ETHYL-3a-FORMYL-11-METHOXY-7,9,11,13,15-PENTAMETHYL-2,6,8,14-TETRAOXO-1-[4-(4-PYRIDIN-3-YL-1H-IMIDAZOL-1-YL)BUTYL]TETRADECAHYDRO-1H-OXACYCLOTETRADECINO[4,3-D][1,3]OXAZOL-10-YL-3,4,6-TRIDEOXY-3-(DIMETHYLAMINO)-D-XYLO-HEXOPYRANOSIDE




To (3aR,4R,7R,9R,10R,11R,13R,15R,15aR)-4-ethyl-3a-(hydroxymethyl)-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-1-[4-(4-pyridin-3-yl-1H-imidazol-1-yl)butyl]tetradecahydro-1H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside (1 eq) in dichloromethane was added Dess-Martin periodinane (1.1 eq). After stirring for 3 hours, more Dess-Martin periodinane (1 eq) was added. After stirring for an additional 15 hours, the solution was diluted with ethyl acetate and was washed with 1:1 10% Na2S2O3/NaHCO3 (sat.), with NaCl (sat.), dried over MgSO4, filtered, and concentrated. Purification by RP HPLC yielded (3aS,4R,7R,9R,10R,11R,13R,15R,15aR)-4-ethyl-3a-formyl-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-1-[4-(4-pyridin-3-yl-1H-imidazol-1-yl)butyl]tetradecahydro-1H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside (19% yield) as a white solid. MH+(826.5)
EXAMPLE 64
SYNTHESIS OF (3aS,4R,7R,9R,10R,11R,13R,15R,15aR)-3a-ACETYL4-ETHYL-11-METHOXY-7,9,11,13,15-PENTAMETHYL-2,6,8,14-TETRAOXO-1-[4-(4-PYRIDIN-3-YL-1H-IMIDAZOL-1-YL)BUTYL]TETRADECAHYDRO-1H-OXACYCLOTETRADECINO[4,3-D][1,3]OXAZOL-10-YL-3,4,6-TRIDEOXY-3-(DIMETHYLAMINO)-D-XYLO-HEXOPYRANOSIDE




To benzoylated (3aR,4R,7R,9R,10R,11R,13R,15R,15aR)-4-ethyl-3a-(hydroxymethyl)-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-1-[4-(4-pyridin-3-yl-1H-imidazol-1-yl)butyl]tetradecahydro-1H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside (1 eq) in dichloromethane was added Dess-Martin periodinane (2 eq). After stirring for 2.5 hours the solution was diluted with ethyl acetate and was washed with 1:1 10% Na2S2O3/NaHCO3 (sat.), with NaCl (sat.), dried over MgSO4, filtered, and concentrated yielding C21 aldehyde (94%). To the aldehyde (1 eq) in tetrahydrofuran (2 ml) at −78° C. was added methyl lithium (0.5 eq). After stirring for 30 minutes at −78° C., acetone was added. The cooling bath was removed, NaHCO3 (sat.) was added and upon warming to room temperature the solution was diluted with ethyl acetate, washed with NaHCO3 (sat.), with NaCl (sat.), dried over MgSO4, filtered and concentrated. Purification by RP HPLC yielded C12 hydroxyethyl macrolide (50%). To this material in dichloromethane was added Dess-Martin periodinane (1 eq). After stirring for 2 hours, the solution was diluted with ethyl acetate and was washed with 1:1 10% Na2S2O3/NaHCO3 (sat.), with NaCl (sat.), dried over MgSO4, filtered and concentrated yielding C12 acetyl macrolide (99%). Methanol was added and the solution was heated at 65° C. for 19 hours. Upon cooling the solution was concentrated and purified by RP HPLC yielding (3aS,4R,7R,9R,10R,11R,13R,15R,15aR)-3a-acetyl-4-ethyl-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-1-[4-(4-pyridin-3-yl-1H-imidazol-1-yl)butyl]-tetradecahydro-1H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside (16.4 mg, 51% yield) as a white solid. MH+(840.5)
EXAMPLE 65
SYNTHESIS OF (3aS,4R,7S,9R,10R,11S,13R,15R,15aR)-3a,4-DIETHYL-7-FLUORO-11-METHOXY-7,9,11,13,15-PENTAMETHYL-2,6,8,14-TETRAOXO-1-(4-QUINOLIN-2-YLBUTYL)TETRADECAHYDRO-2H-OXACYCLOTETRADECINO[4,3-D][1,3]OXAZOL-10-YL-3,4,6-TRIDEOXY-3-(DIMETHYLAMINO)-D-XYLO-HEXOPYRANOSIDE AND (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-4-ETHYL-11-METHOXY-7,9,11,13,15-PENTAMETHYL-2,6,8,14-TETRAOXO-3a-[(1E)-PROP-1-ENYL]-1-[4-(4-PYRIDIN-3-YL-1H-IMIDAZOL-1-YL)BUTYL]TETRADECAHYDRO-1H-OXACYCLOTETRADECINO[4,3-D][1,3]OXAZOL-10-YL 3,4,6-TRIDEOXY-3-(DIMETHYLAMINO)-D-XYLO-HEXOPYRANOSIDE




To ethyl triphenylphosphonium bromide (1 eq) in tetrahydrofuran at −78° C. was added lithium bis(trimethylsilyl)amide/1.0 M in tetrahydrofuran (1 eq). The cooling bath was removed and the solution was stirred for 1 hour. After cooling the solution back to −78° C., C2, aldehyde macrolide (3 eq) in tetrahydrofuran was added. The cooling bath was removed and the solution was stirred for 64 hours at which time ethyl acetate was added. The solution was washed with NaHCO3 (sat.), with NaCl (sat.), dried over MgSO4, filtered and concentrated. Purification through flash chromatography (0-3-5-10% methanol/dichloromethane with 0.1% triethylamine) and subsequently by preparatory RP HPLC, yielded the Z-C12-prenyl macrolide (smaller retention time, 23% yield) as a white solid and E-C12 prenyl macrolide (larger retention time, 10% yield) as a white solid. To the benzoylated isomers (1 eq) was added methanol and the solution was heated at 65° C. for 14 hours. Upon concentrating, the material was purified by RP HPLC. The combined product fractions coming off the HPLC were diluted with ethyl acetate and NaHCO3 was added. After mixing, the aqueous layer was separated and the organic layer was washed with NaCl (sat.), dried over MgSO4, filtered, concentrated, dissolved in acetonitrile/water and lyophilized yielding the products (3aS,4R,7S,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-7-fluoro-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-1-(4-quinolin-2-ylbutyl)tetradecahydro-1H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside and (3aS,4R,7R,9R,10R,11S,13R,15R,15aR)-4-ethyl-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-3a-[(1E)-prop-1-enyl]-1-[4-(4-pyridin-3-yl-1H-imidazol-1-yl)butyl]tetradecahydro-1H-oxacyclotetradecino[4,3-d]-[1,3]oxazol-10-yl 3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside (71% yield) as white solids. MH+(838.04)
EXAMPLE 66
SYNTHESIS OF (3aS,4R,7S,9R,10R,11S,13R,15R,15aR)-4-ETHYL-7-FLUORO-11-METHOXY-7,9,11,13,15-PENTAMETHYL-2,6,8,14-TETRAOXO-3a-[(1Z)-PROP-1-ENYL]-1-[4-(4-PYRIDIN-3-YL-1H-IMIDAZOL-1-YL)BUTYL]TETRADECAHYDRO-1H-OXACYCLOTETRADECINO[4,3-D][1,3]OXAZOL-10-YL-3,4,6-TRIDEOXY-3-(DIMETHYLAMINO)-D-XYLO-HEXOPYRANOSIDE




To benzoylated (3aS,4R,7S,9R,10R,11S,13R,15R,15aR)-3a,4-diethyl-7-fluoro-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-11-(4-quinolin-2-yl-butyl)tetradecahydro-1H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside (1 eq) in DMF at 0° C. was added 60% NaH (2 eq). After stirring for 1 hour at 0° C., N-fluorobenzenesulfonimide (1.1 eq) was added. After stirring for an additional hour at 0° C., the solution was diluted with ethyl acetate and NaHCO3 (sat.) was added cautiously to quench. The reaction was then added to ethyl acetate and was washed with NaHCO3 (sat.), NaCl (sat.), dried over MgSO4, filtered, and concentrated. Methanol was added and the solution was heated at 60° C. for 15 hours. Upon concentrating, the material was purified by silica gel chromatographly (0-5-10% methanol/dichloromethane with 0.1% triethylamine) and than by RP BPLC. The combined product fractions coming off the HIPLC were diluted with ethyl acetate and NaHCO3 was added. The aqueous layer was separated and the organic layer was washed with NaCl (sat.), dried over MgSO4, filtered, concentrated and lyophilized from MeCN:H2O yielding (3aS,4R,7S,9R,10R,11S,13R,15R,15aR)-4-ethyl-7-fluoro-11-methoxy-7,9,11,13,15-pentamethyl-2,6,8,14-tetraoxo-3a-[(1Z)-prop-1-enyl]-1-[4-(4-pyridin-3-yl-1H-imidazol-1-yl)butyl]tetradecahydro-1H-oxacyclotetradecino[4,3-d][1,3]oxazol-10-yl-3,4,6-trideoxy-3-(dimethylamino)-D-xylo-hexopyranoside (40% yield) as a white solid. MH+(856.50)
EXAMPLE 67
C12 MODIFICATION VIA KETONE INTERMEDIATE TO GENERATE KETOLIDES (SCHEME 2A, R=H)
EXAMPLE 67(A)
Synthesis of Compound 12
Referring to Scheme 2a, to a −78° C. 0.02 M CH2Cl2:MeOH (19:1 v/v) solution containing the alkene 11 (Example 3) and 1.2 eq TsOH.H2O (both azeotropically dried with benzene before use) was bubbled in 03 until a medium blue color appeared. The reaction was stirred for an additional 10 minutes and then sparged with N2 until the solution became colorless. After adding dimethyl sulfide (3.0 eq), the solution was stirred for 10 min, treated with Et3N (5 eq), warmed to room temperature, and concentrated. Purification by silica gel chromatography (7:1 hexane:acetone with 1% Et3N) gave the ketone product 12. ES/MS m/z 982.5 (MH+), C54H79NO15=981.5 g/mol.
EXAMPLE 67(B)
Synthesis of Compound 13
NaBH4 (4 eq) was added to a 0.2 M EtOH solution of ketone 12. After stirring at room temperature for 20 h, the reaction was poured into 4:1 CH2Cl2:NaHCO3 (aq.) and stirred vigorously for 1 h. The aq. layer was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was the resuspended in MeOH and stirred overnight. After removing the MeOH in vacuo, the residue was dissolved in EtOAc. The resulting solution was washed with NaHCO3 (aq.), water, and brine, dried over MgSO4, filtered, and concentrated to give the crude product 13. ES/MS m/z 985 (MH+), C54H81NO15=984 g/mol.
EXAMPLE 67(C)
Synthesis of Compound 14
To a 0° C. 0.2 M CH2Cl2 solution containing alcohol 13 and DMAP (0.5 eq) was added Et3N (3 eq) followed by addition of MsCl (1.5 eq) over a 0.5 h period. After 15 min, the reaction was quenched with sat. NaHCO3 (aq.) and poured into EtOAc. The organic layer was washed with water and brine, dried, filtered, and concentrated to give the crude product 14. ES/MS m/z 1063 (M′+), C55H183NO17S=1062 g/mol.
EXAMPLE 67(D)
Synthesis of Compound 15
To a 0.08 M MeCN solution of acetonide 14 was added 10% HCl (aq) to give a 2:1 (v/v) MeCN:H2O mixture. After stirring for 14 h, 1N NaOH was added until an approximate pH 9 solution persisted. The organic solvent was then removed in vacuo and the remaining solution was extracted with CH2Cl2 (2×). The organic extracts were washed with brine, dried, filtered, concentrated, and purified by silica gel chromatography (3:1 to 2:1 hexanes:acetone with 1% Et3N gradient) to give the triol 15. ES/MS m/z 760 (MH+), C37H16NO13S=759 g/mol.
EXAMPLE 67(E)
Synthesis of Compound 16
To a 0.1 M CH2Cl2 solution of triol 6 at 0° C. was added the Dess-Martin periodinane (2.1 eq). After 26 h, the reaction was quenched with sat. NaHCO3 (aq.) diluted with CH2Cl2, filtered through celite, washed with brine, dried over MgSO4, filtered, and concentrated. Purification by silica gel chromatography (4:1 hexanes:acetone with 1% Et3N) gave the diketone 16. ES/MS m/z 756 (MH+), C37H57NO13S=755 g/mol.
EXAMPLE 67(F)
Synthesis of Compound 17
DBU (2 eq) was quickly added to a 0.1 M acetone solution of alcohol 16 and stirred overnight at room temperature. The mixture was then concentrated and the residue was purified by silica gel chromatography (4:1 hexanes:acetone with 1% Et3N) to give enone 17. ES/MS m/z 660 (MH+), C36H53NO10=659 g/mol.
EXAMPLE 67(G)
Synthesis of Compound 18
To a −15° C. 0.2M THF solution of alcohol 17 and carbonyl diimidazole (2 eq) was added NaH (1.2 eq). After stirring for 15 min., the solution was warmed to 0° C., diluted with EtOAc, and quenched with sat. NaHCO3 (aq.). The aq. layer was extracted with EtOAc (2×) and the extracts were washed with water and brine, dried over MgSO4, filtered, and concentrated to give the crude carbamate 18.
EXAMPLE 67(H)
Synthesis of Compound 19




A 0.2M MeCN:H2O (9:1 v/v) solution containing carbamate 18 and ammonia (4 eq) was heated at 70° C. for 23 h. The reaction was then poured into EtOAc and washed with NaHCO3, water, and brine, dried over MgSO4, filtered, and concentrated. Purification by silica gel chromatography (1:1 to 1:2 hexanes:acetone with 1% Et3N gradient) gave the cyclic carbamate 19. 19a: R′ =H, ES/MS m/z 703 (MH+), C37H54N2O11=702 g/mol.
Compounds with variations in the R′ were obtained by following the procedure for the synthesis of 19a and substituting the appropriate amine in place of ammonia. The requisite amine starting materials are set forth in Table 1 below to give the following analogs:







TABLE 1







AMINE STARTING MATERIALS













ES/MS


ID
Amine
R′
(MH+)





19b
4-(4-phenyl-imidazol-1-yl)-
4-(4-phenyl-imidazol-1-yl)-butyl
901



butylamine


19c
4-quinolin-4-yl-butylamine
4-quinolin-4-yl-butyl
886


19d
4-imidazo[4,5-b]pyridin-3-yl-
4-imidazo[4,5-b]pyridin-3-yl-butyl
876



butylamine


19e
4-imidazo[4,5-b]pyridin-1-yl-
4-imidazo[4,5-b]pyridin-1-yl-butyl
876



butylamine


19f
4-(4-phenyl-imidazol-1-yl)-propyl
4-(4-phenyl-imidazol-1-yl)-propyl
887



amine


19g
4-imidazo[4,5-b]pyridin-1-yl-
4-imidazo[4,5-b]pyridin-1-yl-propyl
862



propylamine


19h
4-imidazo[4,5-b]pyridin-3-yl-
4-imidazo[4,5-b]pyridin-3-yl-propyl
862



propylamine


19i
4-indol-1-yl-butylamine
4-indol-1-yl-butyl
874


19j
4-(2-quinolyl)butylamine
4-(2-quinolyl)butyl
887


19k
4-(4-(3-pyridyl)imidazolyl)butyl
4-(4-(3-pyridyl)imidazolyl)butyl
903



amine


19l
4-(4-(4-pyridyl)imidazolyl)butyl
4-(4-(4-pyridyl)imidazolyl)butyl
903



amine


19m
4-pyrrolo[3,2-b]pyridinylbutyl
4-pyrrolo[3,2-b]pyridinylbutyl
876



amine


19n
4-(3-quinolyl)butylamine
4-(3-quinolyl)butyl
887


19o
4-(2-methyl-4-quinolyl)butyl
4-(2-methyl-4-quinolyl)butyl
901



amine


19p
4-[2-(trifluoromethyl)-4-
4-[2-(trifluoromethyl)-4-quinolyl]butyl
955



quinolyl]butylamine


19q
4-[8-(trifluoromethyl)-4-
4-[8-(trifluoromethyl)-4-quinolyl]butyl
955



quinolyl]butylamine


19r
3-(4-(3-pyridyl)phenoxy)propyl
3-(4-(3-pyridyl)phenoxy)propyl
915



amine


19s
3-(3-(3-pyridyl)phenoxy)propyl
3-(3-(3-pyridyl)phenoxy)propyl
915



amine


19t
4-(5-phenyl-1,3-thiazol-2-yl)butyl
4-(5-phenyl-1,3-thiazol-2-yl)butyl
919



amine


19u
4-[5-(2,4-difluorophenyl)-1,3-
4-[5-(2,4-difluorophenyl)-1,3-thiazol-2-
955



thiazol-2-yl]butylamine
yl]butyl


19v
4-[5-(3-aminophenyl)-1,3-thiazol-
4-[5-(3-aminophenyl)-1,3-thiazol-2-
934



2-yl]butylamine
yl]butyl


19w
oxy(2-phenoxyethyl)amine
R′NH2 = oxy(2-phenoxyethyl)amine
840









EXAMPLE 67(I)
Synthesis of Compound 20




A 0.06 M MeOH solution of each of 19a-19w was heated at 70° C. for 23 h. The solvent was the removed in vacuo and the residue was purified by silica gel chromatography (2:3 hexanes:acetone with 2% Et3N) to give the desired product 20a-20w as shown in Table 2 below:











TABLE 2





Compound

ES/MS

MS


ID
R′
(MH+)
Formula
(g/mol)







20a
H
599
C30H50N2O10
598


20b
4-(4-phenyl-imidazol-1-yl)-butyl
797
C43H64N4O10
796


20c
4-quinolin-4-yl-butyl
782
C43H63N3O10
781


20d
4-imidazo[4,5-b]pyridin-3-yl-butyl
772
C40H61N5O10
771


20e
4-imidazo[4,5-b]pyridin-1-yl-butyl
772
C40H61N5O10
771


20f
4-(4-phenyl-imidazol-1-yl)-propyl
783
C42H62N4O10
782


20g
4-imidazo[4,5-b]pyridin-1-yl-propyl
758
C39H56N5O10
757


20h
4-imidazo[4,5-b]pyridin-3-yl-propyl
758
C39H56N5O10
757


20i
4-indol-1-yl-butyl
770
C42H63N3O10
769


20j
4-(2-quinolyl)butyl
783
C43H63N3O10
782


20k
4-(4-(3-pyridyl)imidazolyl)butyl
799
C42H63N5O10
798


20l
4-(4-(4-pyridyl)imidazolyl)butyl
799
C42H63N5O10
798


20m
4-pyrrolo[3,2-b]pyridinylbutyl,
772
C41H62N4O10
771


20n
4-(3-quinolyl)butyl,
783
C43H63N3O10
782


20o
4-(2-methyl-4-quinolyl)butyl
797
C44H65N3O10
796


20p
4-[2-(trifluoromethyl)-4-quinolyl]butyl
851
C44H62F3N3O10
850


20q
4-[8-(trifluoromethyl)-4-quinolyl]butyl
851
C44H62F3N3O10
850


20r
3-(4-(3-pyridyl)phenoxy)propyl
811
C44H63N3O11
810


20s
3-(3-(3-pyridyl)phenoxy)propyl
811
C44H63N3O11
810


20t
4-(5-phenyl-1,3-thiazol-2-yl)butyl
815
C43H63N3O10S
814


20u
4-[5-(2,4-difluorophenyl)-1,3-thiazol-2-
851
C43H61F2N3O10S
850



yl]butyl


20v
4-[5-(3-aminophenyl)-1,3-thiazol-2-
830
C43H64N4O10S
829



yl]butyl


20w
R′NH2 = oxy(2-phenoxyethyl)amine
736
C38H58N2O12
735









EXAMPLE 68
C12 MODIFICATION VIA KETONE INTERMEDIATE TO GENERATE ANALOGS WITH A C3 SUGAR (SCHEME 2B)
EXAMPLE 68(A)
Synthesis of Compound 21
Referring to Scheme 2b, an aqueous solution of acetic acid (84 eq) was added to acetonide 14 (Example 67(c)) in MeCN to give a 0.08 M MeCN:H2O solution (2:1 v/v). The reaction was stirred for 16 h at 65-70° C. and then concentrated from toluene/iPrOH (2×) and toluene (1×). Purification by silica gel chromatography (4:1 hexanes:acetone with 1% Et3N gradient) gave diol 21. ES/MS m/z 1022.5 (MH+), C52H79NO17S=1021.5 g/mol.
EXAMPLE 68(B)
Synthesis of Compound 22
To a 0.1 M CH2Cl2 solution of diol 21 at 0° C. was added the Dess-Martin periodinane (1.05 eq) and the resulting mixture was warmed to room temperature over 1.5 h. After 3 h, an additional periodinane (0.1 eq) was added and stirring was continued for 2 h. The reaction was quenched with sat. NaHCO3 (aq.) followed with EtOAc. After vigorously stirring for 15 min, the solution was filtered through celite with additional EtOAc. The organic layer was washed with NaHCO3 (aq.) and brine, dried over MgSO4, filtered, and concentrated. Purification by silica gel chromatography (6:1 hexanes:acetone with 1% Et3N) gave the ketone 22. ES/MS m/z 1020 (MH+), C52H77NO17 S=1019 g/mol.
EXAMPLE 68(C)
Synthesis of Compound 23
DBU (3.3 eq) was quickly added to a 0.08 M acetone solution of alcohol 22, stirred for 23 h, and then concentrated. The residue was suspended in EtOAc, washed with NaHCO3 (aq.) and brine, dried over MgSO4, filtered, and concentrated again. Purification by silica gel chromatography (4:1 hexanes:acetone with 1% Et3N) gave the enone 23. ES/MS m/z 924 (MH+), C51H73NO14=923 g/mol.
EXAMPLE 68(D)
Synthesis of Compound 24
To a −15° C. 0.2 M THF solution of alcohol 23 and carbonyl diimidazole (2 eq) was added NaH (1.2 eq). After stirring for 0.5 h, the solution was warmed to 0° C. and stirred for an additional 2 h. The reaction was next diluted with EtOAc and quenched with sat. NaHCO3 (aq.). The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated to give the crude carbamate 24.
EXAMPLE 68(E)
Synthesis of Compound 25




To a 0.1 M MeCN:THF (5:1) solution of carbamate 24 was added NH4OH (20 eq) and heated at 50° C. for 23 h. The reaction was then poured into CH2Cl2 and washed with brine, dried over MgSO4, filtered, and concentrated. Purification by silica gel chromatography (7:2 hexanes:acetone with 1% Et3N) gave the cyclic carbamate 25a. ES/MS m/z 967.5 (MH+), C52H74N2O15=966.5 g/mol. Cyclic carbamate formation using 4-(4-phenyl-imidazol-1-yl)-butylamine was performed in a similar fashion to give compound 25b. ES/MS m/z 1166 (MH+), C65H88N4O15=1165 g/mol.
EXAMPLE 68(F)
Synthesis of Compound 26




A 0.05 M MeOH solution of 25a was heated at 75° C. for 24 h. The solvent was the removed in vacuo and the residue was purified by silica gel chromatography (3:1 hexanes:acetone with 1% Et3N) to give the desired product 26. ES/MS m/z 863 (MH+), C45H70N2O14=862 g/mol.
EXAMPLE 69 
ERYTHROMYCIN C12 ALKENE FORMATION (SCHEME 4)
EXAMPLE 69(A)
Synthesis of Compound 28
Referring to Scheme 4, 0.07 M CH2Cl2:dimethoxypropane (2:1) solution containing 9-dihydroerythromycin A 27 and PPTS (2 eq) was heated at 50-55° C. for 2.5 h. The reaction was cooled to room temperature, quenched with Et3N (2.1 eq), and diluted with CH2Cl2. The solution was next washed with sat. NaHCO3 (aq.), water, and brine, dried over MgSO4, filtered, and concentrated. Purification by silica gel chromatography (2:1 hexanes:acetone with 1% Et3N) gave the desired acetonide 28. ES/MS m/z 776 (MH+), C40H73NO13=775 g/mol.
EXAMPLE 69(B)
Synthesis of Compound 29
A 0.15 M EtOAc solution containing compound 28 (azeotropically dried with benzene), DMAP (4 eq, azeotropically dried with benzene), Bz2O (4 eq), and Et3N (4 eq) was stirred for 20 h, after which time the solution was diluted with EtOAc and quenched with sat. NaHCO3 (aq). The organic layer was then washed with brine, dried, filtered, and concentrated. Purification by silica gel chromatography (8:1 hexanes:acetone with 1% Et3N) gave the benzoate 29. ES/MS m/z 985 (MH+), C54H81NO15=984 g/mol.
EXAMPLE 69(C)
Synthesis of Compound 30 
To a 0° C. 0.1 M EtOAc solution of compound 29 was quickly added Et3N (4 eq.) followed by SOCl2 (1.1 eq). The reaction was stirred for 80 min, then quenched with sat. NaHCO3 (aq.) and poured into EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. Purification by silica gel chromatography (3:2 hexanes:ethyl actetate with 1% Et3N) gave the alkene product 30. ES/MS m/z 967 (MH+), C54H79NO14=966 g/mol.
EXAMPLE 70 
SYNTHESIS OF 6-O-ALKYL KETOLIDE ANALOGS (SCHEME 5A)
EXAMPLE 70(A)
Synthesis of Compound 300 (R=ME)
Step 1. Referring to Scheme 5a, to a 0° C. 0.1 M CH2Cl2 solution containing 30 was added mCPBA (5 eq). Warmed the reaction to room temperature and stirred for 16 h. Added cyclohexene (4 eq) and continued stirring for another 16 h. Poured into cold NaHCO3 aq. and extracted with CH2Cl2 (3×). The organic extracts were washed with saturated NaHCO3 aq. (6×) and brine (2×), dried with Na2SO4 and concentrated in vacuo to give the N-oxide epoxide intermediate. This intermediate was dissolved in CH2Cl2 (0.1 M). To this solution at 0° C. was added sequentially isoproponol (2 eq) and tetra-n-propylammonium perruthenate (5 mol% ). Warmed to room temperature and stirred for 16 h. Concentrated in vacuo to give a black residue. Purification by silica gel chromatography (5:1 hexane:acetone with 1% Et3N) gave the epoxide product . ES/MS m/z 982.5 (MH+), C54H79NO15=981.5 g/mol.
Step 2. A solution (0.1 M in anhydrous diethyl ether) of compound obtained from step 1 was added to dimethyl lithium cuprate (LiMe2Cu) solution (0.1 M in anhydrous diethyl ether, 5 eq) at −78° C. The mixture was warmed to 0° C. and stirred under this temperature for 8 h, poured into cold NH4Cl (aq.) and the pH of aqueous was approximately 7, and extracted with ether and CH2Cl2. The organic extracts were combined, washed with brine, dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (5:1 hexane:acetone with 1% Et3N) to give the C12-ethyl intermediate. ES/MS m/z 999 (MH+), C55H83NO15=998 g/mol.
Step 3. An aqueous solution of acetic acid (100 eq) was added to acetonide from step 2 in MeCN to give a 0.08 M MeCN:H2O solution (2:1 v/v). The reaction was stirred for 70 h at 65-70° C. and neutralized with saturated NaHCO3 (aq.). The reaction was extracted with CH2Cl2, and the organic layer was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography (4:1 hexanes:acetone with 1% Et3N) to afford 9,11-diol. ES/MS m/z 959 (MH+), C52H79NO15=958 g/mol.
Step 4. To a 0° C. CH2Cl2 solution (0.2 M) of product obtained from step 3 was added tetra-n-propylammonium perruthenate (5 mol%), N-methylmorpholine N-oxide (1.2 eq) and 3 A molecular sieves (100 wt.%). The reaction was stirred under argon at 0° C. for 16 h. Diluted with EtOAc and filtered through a celite pad. The filtrate was concentrated in vacuo to give a residue which was purified by flash column chromatography (2:1 hexane/EtOAc+1% Et3N). Compound 300 (R=Me) was obtained as white foam. ES/MS m/z 956 (MH+), C52H77NO15=955 g/mol.
EXAMPLE 70(B)
Synthesis of 301 (R=ME)
Step 1. A 50% (w/w) aqueous solution of hydroxylamine (13 eq) was added to a 0.5 M solution of compound 300 in 2-propanol. Glacial acetic acid (4.2 eq) was added. The mixture was stirred at 50° C. for 18 h and then returned to ambient temperature. The reaction mixture was poured into dichloromethane and saturated aqueous sodium bicarbonate. The pH of the aqueous layer was adjusted to 9 with 6N sodium hydroxide, and the layers were separated. The organic phase was washed with brine, dried over magnesium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography over silica gel (2:1 hexanes:acetone +2% triethylamine) to give the desired product. ES/MS m/z 868 (M+H+), C45H74N2O14=867 g/mol.
Step 2. A 0.3 M solution of the compound from step 1 in dichloromethane was cooled to 0° C. 2,2-dimethoxypropane (10 eq) and pyridinium p-toluenesulfonate (2 eq) were added. After 0.5 h, the reaction was brought to ambient temperature. The mixture was stirred for 48 h and poured into dichloromethane and saturated aqueous sodium bicarbonate. The layers were separated. The organic phase was washed with water then brine, dried over magnesium sulfate, filtered, and concentrated. The crude material was re-dissolved in toluene and concentrated. The material was used without further purification. ES/MS m/z 940 (M+H+), C49H82N2O15=939 g/mol.
Step 3. Benzoic anhydride (1.5 eq) was added to a 0.2 M solution of the compound from step 2 in EtOAc. The mixture was stirred at ambient temperature for 6 h and then poured into EtOAc and saturated sodium bicarbonate. The layers were separated. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography over silica gel (eluting with 6:1 hexanes:acetone +1% TEA) to give compound 301. ES/MS m/z 1044 (M+H+), C56H86N2O16=1043 g/mol.
EXAMPLE 70(C)
Synthesis of 302 (R=ME)
Step 1. 6-O-alkylation.
A. Allylation (O-Z=O-allyl). A 0.1M solution of compound 301 in 1:1 THF:DMSO was cooled to 5° C. Freshly distilled allyl bromide (4 eq) was added. A 0.5 M solution of potassium tert-butoxide in 1:1 THF:DMSO (3 eq) was added over 2 h while keeping the reaction mixture at 5-7° C. The mixture was poured into EtOAc and saturated sodium bicarbonate. The layers were separated. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered, and concentrated. The crude material was used without further purification. ES/MS m/z 1084 (M+H+), C59H90N2O16=1083 g/mol.
B. Propargylation (O-Z=O-propargyl). A 0.15 M solution of compound 301 in 2:1 THF:DMSO was cooled to 10° C. 3-Bromo-1-(trimethylsilyl)propyne (6 eq) was added. A 0.67 M solution of potassium tert-butoxide in 2:1 THF:DMSO (5 eq) was added over 2 h while keeping the reaction mixture at 12-15° C. The mixture was poured into EtOAc and saturated sodium bicarbonate. The layers were separated. The organic layer was washed sequentially with water and brine, dried over magnesium sulfate, filtered, and concentrated. The crude material was used without further purification. ES/MS m/z 1140 (M+H+), C61H94N2O16Si=1139 g/mol.
Step 2. A 0.1 M solution of compound from step 1 in 2:1:1 acetonitrile:water:HOAc was stirred overnight at ambient temperature. Toluene and 2-propanol were added, and the mixture was concentrated under reduced pressure. The residue was re-dissolved in toluene and concentrated under reduced pressure. The crude material was used without further purification. ES/MS m/z 1012 (M+H+), C55H82N2O15=1011 g/mol.
A. For the propargyl compound only. Potassium carbonate (2 eq) was added to a 0.05M solution of the compound from Step 2. The mixture was stirred at ambient temperature for 2 h and then poured into ethyl acetate and saturated sodium bicarbonate. The layers were separated. The organic layer was washed sequentially with water and brine, dried over magnesium sulfate, filtered, and concentrated. The crude material was used without further purification. ES/MS m/z 1010 (M+H+), C59H80N2O15=1009 g/mol.
Step 3. A 0.1 M solution of compound from step 2 in 1:1 EtOH:water was treated with sodium hydrosulfite (5.5 eq) and formic acid (4.7 eq). The mixture was stirred at 80° C. for 6 h and then returned to ambient temperature. The reaction was quenched by addition of sodium bicarbonate and extracted with EtOAc. The combined extracts were washed sequentially with sodium bicarbonate, water, and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography over silica gel to give compound 302 (O-Z=O-allyl). ES/MS m/z 997 (M+H+), C55H81NO15=996 g/mol.
EXAMPLE 70(D)
SYNTHESIS OF 303 (R=ME, O-Z=O-ALLYL)
Step 1. A 0.3 M solution of the compound 302 in pyridine was cooled to 0° C. and treated with methanesulfonyl chloride (6 eq). The reaction was brought to ambient temperature and stirred overnight. The reaction mixture was poured into EtOAc and saturated sodium bicarbonate. The layers were separated. The organic layer was washed sequentially with water and brine, dried over magnesium sulfate, filtered, and concentrated. The crude material was used without further purification. ES/MS m/z 1075 (M+H+), C56H83NO17S=1074 g/mol.
Step 2. A 0.2 M solution of the compound from step 1 in acetone was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (5.0 eq). The reaction was brought to ambient temperature and stirred overnight. The reaction mixture was poured into EtOAc and saturated sodium bicarbonate. The layers were separated. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography over silica gel to give the desired compound. ES/MS m/z 979 (M+H+), C55H79NO14=978 g/mol.
Step 3. A 0.05 M solution of the compound from step 2 in 2:1 acetonitrile:3 N aqueous HCl was stirred overnight at ambient temperature. The mixture was cooled to 0° C. and neutralized with 6 N aqueous sodium hydroxide. Volatiles were removed under reduced pressure, and the resulting syrup was extracted with EtOAc. The combined extracts were washed sequentially with sodium bicarbonate, water, and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography over silica gel to give the desired compound. ES/MS m/z 717 (M+H+), C40H61NO10=716 g/mol.
Step 4. A 0.1 M solution of the compound from step 3 was cooled to 0° C. and treated with Dess-Martin periodinane (1.5 eq). The solution was stirred for 3 h and poured into EtOAc and saturated sodium bicarbonate. The layers were separated. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography over silica gel to give the desired compound. ES/MS m/z 715 (M+H+), C40H59NO10=714 g/mol.
Step 5. A 0.1 M solution of the compound from step 4 and 1,1-carbonyldiimidazole (3.0 eq) in tetrahydrofuran was cooled to −15° C. Sodium hydride (60% dispersion in mineral oil, 2 eq) was added. The mixture was stirred at −15° C. for 20 min. The solution was stirred at ambient temperature for an additional 1 h and poured into EtOAc and saturated sodium bicarbonate. The layers were separated. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered, and concentrated. The crude material was used without further purification. ES/MS m/z 809 (M+H+), C44H61N3O11=808 g/mol.
Step 6. Ammonium hydroxide (90 eq) was added to a 0.15 M solution of the compound from step 5 in 10:1 acetonitrile:tetrahydrofuran. The mixture was stirred at ambient temperature for 4 days. The reaction mixture was poured into EtOAc and saturated sodium bicarbonate. The layers were separated. The organic layer is washed with water and brine, dried over magnesium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography over silica gel (4:1 hexanes:acetone+1% TEA) to give compound 303. ES/MS m/z 757 (M+H+), C41H60N2O11=756 g/mol.
EXAMPLE 70(E)
Synthesis of 304 (R=ME)
Step 1. Coupling of heterocycle.
A. Heck coupling. Tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (0.25 eq) and tri-O-tolylphosphine (1.0 eq) were added to a degassed 0.1 M solution of compound V (1.0 eq), 3-bromoquinoline (10 eq), and triethylamine (2.0 eq) in acetonitrile. The mixture was stirred at 75° C. for 42 h and returned to ambient temperature. The reaction mixture was poured into EtOAc and saturated sodium bicarbonate. The layers were separated. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered through Celite, and concentrated. The crude material was purified by flash chromatography over silica gel (3:1 hexanes:acetone+2% TEA) to give the desired compound. ES/MS m/z 884 (M+H+), C50H65N3O11=883 g/mol.




B. Sonogashira. Tetrakis(triphenylphosphine)palladium(0) (0.25 eq) and copper(I) iodide (0.25 eq) are added to a degassed 0.1 M solution of compound V, 3-bromoquinoline (10 eq), and triethylamine (2.0 eq) in N,N-dimethylformamide. The mixture is stirred at 80° C. for 16 h and returned to ambient temperature. The reaction mixture is poured into EtOAc and saturated sodium bicarbonate. The layers are separated. The organic layer is washed with water and brine, dried over magnesium sulfate, filtered through Celite, and concentrated. The crude material is purified by flash chromatography over silica gel to give the desired compound.




Step 2. A 0.05 M solution of the compound from step 1A was refluxed in methanol for 20 h. The mixture was returned to ambient temperature, and volatiles were removed under reduced pressure. Purification by flash chromatography over silica gel (1:1 hexanes:acetone +2% TEA) gave compound 304. ES/MS m/z 780 (M+H+), C43H61N3O10=779 g/mol.




Compounds having general structure 304a, below, are made following the above scheme. ArX (where X is I, Br, or Cl) are used in the step of Heck reaction. Compounds having general structure 304b are made following the above scheme. ArX (where X is I, Br, or Cl) are used in the step of Sonogashira reaction.
General Structure:




where Ar is 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl, 1-naphthyl, 2-naphthyl,





where Y is H, and X is F, Cl, OH, CN, NO2, NH2, pyridyl, OR, or Ac; or X is H, and Y is NO2, NH2, CH3, or CF3;





where Ar′ is pyridyl, substituted-pyridyl, phenyl, substituted phenyl, thiophene, substituted thiophene, furanyl, substituted furanyl, thiazole, substituted thiazole, imidazole, substituted imidazole, pyrimidinyl, pyrazinyl, or pyridazinyl.

EXAMPLE 71
SYNTHESIS OF 6-O-ALKYLATED, 12-H DERIVATIVES
(SCHEME 5B)
EXAMPLE 71(A)
Synthesis of Compound II, Scheme 5B
Step 1. Removal of the C3-cladinose. Referring to Scheme 5b, above, 2′,4′′-OBz-9,11-dimethylketal-12,21-ene macrolide (I) (1 eq) was dissolved in 1:1 CH3CN/HCl (6 M) and the reaction mixture was stirred at room temperature for 24 h. The reaction was diluted with CH2Cl2 and poured into NaHCO3 (sat.), neutralized with K2CO3 (sat.) until a pH of approximately 8 was obtained. The product was separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with brine and dried over Na2SO4, filtered, and concentrated in vacuo. The crude foam was taken on to the subsequent step without further purification. ES/MS m/z found 664.9(M+H)+, exact mass for C36H58NO10 (M+H)+=664.85
Step 2. Reinstallation of the 9,11-acetonide. To the crude product from step 1 (above) in CH2Cl2 (0.02 M) was added PPTS (4 eq) and DMP (23 eq). The reaction mixture was heated to reflux for 4 h. After cooling to room temperature, the reaction mixture was washed with NaHCO3 (sat.) and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The foam was chromatographed over silica gel (4:1, hexane/acetone, with 0.1% triethylamine) to yield the desired product, as a white solid. ES/MS m/z found 705.0 (M+H)+, exact mass for C39H62NO10 (M+H)+=704.91
Step 3. C3-Silylether formation. The alcohol obtained in step 2 (above) was dissolved in CH2Cl2 (0.1 M) and imidiazole (5 eq) was added in one portion, followed by TMSCl (1.8 eq) via syringe, at 0° C. . The reaction mixture was stirred for 1 h after which time NaHCO3 (sat.) was added, the layers separated, and the organic layer was washed with brine. The product was dried over Na2SO4, filtered and concentrated in vacuo. The crude material was chromatographed over silica gel (5:1, hexane/acetone, with 0.2% triethylamine) to yield the Compound II as a white foam (98%). ES/MS m/z found 705.0 (M+H)+, exact mass for C39H62NO10 (M+H)+=704.9 1.
EXAMPLE 71(B)
Synthesis of III, Scheme 5B
6-O-Allylation of compound II. To Compound II in dry THF (0.1 M) was added allyl methyl carbonate (1.6 eq) and the solution was degassed with a steady flow of argon for 10 minutes. Pd(OAc)2 (0.05 mol eq) and PPh3 (0.1 mol eq) were placed in a bomb, suspended in THF and subsequently degassed with argon for 10 minutes. The solution containing the carbonate and Compound 1 was transferred to the bomb via syringe and the reaction mixture was heated to 90° C. overnight. After work-up with sat. NaHCO3, the organic layer was separated, and washed with brine, and dried over Na2SO4. Upon concentration, the product was purified over silica gel (4:1, hexane/acetone with 0.1% TEA) to afford the desired allylated product, Compound III. Removal of the TMS group was accomplished with prolonged stirring upon aqueous work-up. For R=TMS: ES/MS m/z found 816.8(M+H+), exact mass for C45H74NO10Si (M+H)+=817.16. For R=H: ES/MS m/z found 744.9 (M+H+), exact mass for C42H66N10(M+H)+=744.97
EXAMPLE 71(C)
Synthesis of IV, Scheme 5B
Step 1. Ozonolytic Cleavage of Compound III. Compound III and TsOH (1.2 eq) is dissolved in EtOAc (0.04 M) and cooled to −78° C. Ozone is bubbled through the solution until a blue color persists. The excess ozone is displaced with nitrogen and the reaction quenched with DMS (3 eq), followed by the addition of TEA (4 eq). The reaction mixture is washed with NaHCO3 (sat.) and brine, dried over Na2SO4, and upon concentration, is purified via column chromatography.
Step 2. Olefination of Aldehyde. To a solution of methyl triphenylphosphonium bromide (2 eq) in THF (0.45 M) is added KN(TMS)2 (1.9 eq of 0.5 M solution in toluene) at −78° C. After ylide formation is complete, the aldehyde from step 1 is added to the ylide as a solution in THF (0.2 M) at −78° C. The reaction mixture is allowed to stir for 4 hours, warming to room temperature over this time. To the solution is added NH4Cl and diluted with EtOAc. The two layers are separated, and the organic layer is washed with NaHCO3 (sat.) and brine. The organic layer is dried with Na2SO4, concentrated under reduced pressure, and chromatographed over silica gel to obtain the title compound IV.
EXAMPLE 71(D)
Synthesis of V, Scheme 5B
Step 1. Reduction of 12-Keto. Compound IV is dissolved in absolute ethanol (0.2 M) followed by the addition of NaBH4 (3 eq). The reaction mixture is stirred under argon for 16 h at ambient temperature. The solution is then diluted with EtOAc and neutralized with NaHCO3 (sat.) with vigorous stirring for 2 h. The two phases were separated and the organic layer is washed with water, and then brine. The organic phase is dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product is then subjected to mesylation without further purification.
Step 2. Mesylation 12-Hydroxy. A 0.3 M solution of the compound from step 1 in pyridine is cooled to 0° C. and treated with methanesulfonyl chloride (7 eq). The reaction is brought to ambient temperature and stirred overnight. The reaction mixture is poured into EtOAc and saturated sodium bicarbonate. The layers are separated. The organic layer is washed with water and brine, dried over sodium sulfate, filtered, and concentrated. The crude material is purified by flash chromatography over silica gel to give the desired compound.
Step 3. Removal of Acetonide and 3-O-Protecting Group. A 0.02 M solution of the compound from step 2 in 1:1 acetonitrile:3 N aqueous HCl is stirred for two hours at ambient temperature. The mixture is cooled to 0° C. and neutralized with NaHCO3 (sat.). Volatiles are removed under reduced pressure, and the resulting syrup is extracted with EtOAc. The combined extracts are washed sequentially with sodium bicarbonate, water, and brine. The organic layer is dried over sodium sulfate, filtered, and concentrated. The crude material is purified by flash chromatography over silica gel to give the desired compound.
Step 4. Corey-Kim Oxidation. Methyl sulfide (3.5 eq) is added to a 0.1 M solution of N-chlorosuccinimide (3.0 eq) in dichloromethane at −10° C. The mixture is stirred for 15 min. A 0.1 M solution of the compound from step 3 (1.0 eq) in dichloromethane is added dropwise over 10 min. The mixture is stirred an additional 30 min and then quenched with triethylamine (2.0 eq). The reaction is brought to 0° C. over 30 min and then poured into EtOAc and saturated sodium bicarbonate. The layers are separated. The organic layer is washed with water and brine, dried over magnesium sulfate, filtered, and concentrated. The crude material is purified by flash chromatography over silica gel to give the desired compound.
Step 5. Elimination. A 0.3 M solution of the compound from step 3 in acetone is cooled to 0° C. and treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (5.0 eq). The reaction is brought to ambient temperature and stirred for 5 h. The reaction mixture is poured into EtOAc and saturated sodium bicarbonate. The layers are separated. The organic layer is washed with water and brine, dried over magnesium sulfate, filtered, and concentrated. The crude material is purified by flash chromatography over silica gel to give compound V.
EXAMPLE 71(E)
Synthesis of VI, Scheme 5B
Step 1. Imidazole carbamate. A 0.2 M solution of the compound from step 4 and 1,1-carbonyldiimidazole (2.0 eq) in tetrahydrofuran is cooled to −15° C. Sodium hydride (60% dispersion in mineral oil, 1.2 eq) is added. The mixture is stirred at −15° C. for 15 min and at 0° C. for an additional 10 min. The reaction is diluted with ethyl acetate and quenched with saturated aqueous sodium bicarbonate. The layers are separated. The organic layer is washed with water and brine, dried over magnesium sulfate, filtered, and concentrated. The crude material is used without further purification.
Step 2. Cyclic carbamate. Ammonium hydroxide (90 eq) is added to a 0.15 M solution of the compound from step 5 in 10:1 acetonitrile:tetrahydrofuran. The mixture is stirred at 50° C. for 16 h and then returned to ambient temperature. The reaction mixture is poured into EtOAc and saturated sodium bicarbonate. The layers are separated. The organic layer is washed with water and brine, dried over magnesium sulfate, filtered, and concentrated. The crude material is purified by flash chromatography over silica gel to give compound V.
Step 3. Coupling of heterocycle: Heck coupling. Tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (0.25 eq) is added to a degassed 0.1 M solution of compound V, tri-O-tolylphosphine (1.0 eq), 3-bromoquinoline (10 eq), and triethylamine (2.0 eq) in acetonitrile. The mixture is stirred at 70° C. for 30 h and returned to ambient temperature. The reaction mixture is poured into EtOAc and saturated sodium bicarbonate. The layers are separated. The organic layer is washed with water and brine, dried over magnesium sulfate, filtered through Celite, and concentrated. The crude material is purified by flash chromatography over silica gel to give the desired compound.
Step 4. Deprotection. A 0.05 M solution of the compound from step 1 is stirred in methanol at 70° C. for 16 h. The mixture is returned to ambient temperature, and volatiles are removed under reduced pressure. Purification by flash chromatography over silica gel gives compound VI.
Compounds having following structure VIa are made following the above scheme. ArX (X=I, Br, Cl) are used in the step of Heck reaction.




Where Ar is as described in Example 70(e) for C12-ethyl, 06-allyl/propargy derivatives (above).
EXAMPLE 72
SYNTHESIS OF C12-TRIFLUOROMETHYL DERIVATIVES 208A-C, SCHEME 3 
EXAMPLE 72(A)
Synthesis of 202A-C, Scheme 3
Step 1. CF3 addition, R=TMS. Referring to synthesis Scheme 3, above, to ketone 12, (1 eq) in dry THF (0.4 M) at 0° C. was added dry KF (0.25 eq) and TMSCF3 (2 eq). After stirring for 10 minutes at 0° C., several drops of potassium t-butoxide (1.0 M solution in THF) was slowly added. An exotherm was observed and the solution turned from colorless to golden-yellow. The ice bath was removed and after 15 min, the reaction was complete by both TLC and LCMS. The reaction was quenched with NaHCO3 (sat.) and the product extracted with dichloromethane (3×) and the combined organic layers were dried over Na2SO4, filtered and concentrated iii vacuo. Purification by column chromatography (5:1, hexane/acetone, with 0.5% triethylamine) yielded the product 12-trifluoroemethyl-12-trimethylsilylether 202a as a white solid. LCMS (ES) (M+H)=1125.3; exact mass for C58H89F3NO15Si (M+H)=1124.60.
Step 2. Desilylation, R=H. The trifluoromethyl-silylether (202a) from step 1, above, (1 eq) was dissolved in THF (0.14 M) and TBAF (2-3 eq) was added at 0° C. The ice bath was removed and the reaction mixture stirred for 1.5 h. Complete deprotection of the silylether was observed by analysis of the LCMS and TLC data. Brine was added to reaction vessel, and diluted with methylene chloride. The layers were separated and the aqueous layer back extracted with methylene chloride (2×). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified over silica gel (4:1, hexane/acetone, with 0.2% triethylamine) to yield the product, 12-trifluoroemethyl-12-OH-clarithromycin derivative 202b, as a white solid. LCMS (ES) (M+H)=1052.9; exact mass for C55H81F3NO15 (M+H)=1052.56.
Step 3. Mesylation, R=Ms. The alcohol obtained in Step 2 (202b) was dissolved (1 eq) in dry THF (0.4 M), cooled to 0° C., and lithium bis(trimethylsilyl)amide (3-4 eq of 1 M LiHMDS in THF) was added via syringe. After stirring for 20 minutes at 0° C., methanesulfonyl chloride was added (2 eq) dropwise. A temperature of 0° C. was maintained for 1 hour after which time the reaction was complete. Excess base was quenched with NaHCO3 (sat.) and the product extracted with dichloromethane (4×30 ml) and the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Purification by column chromatography (4:1, hexane/acetone, with 0.5% triethylamine) yielded the product 12-trifluoroemethyl-12-mesylate clarithromycin derivative 202c as a white solid. LCMS (ES) (M+H)=1130.9; exact mass for C38H61F3NO13S (M+H)=1130.53
EXAMPLE 72(B)
Synthesis of 203, Scheme 3
Step 1. Deprotection of acetonide. To C12-trifluoromethyl-C12-mesylate clarithromycin 202c (1 eq) in acetonitrile (0.02 M) was added 3 N hydrochloric acid (aq.), (to make a 3:1 CH3CN to 3 N HCl) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured over ice and NaHCO3 (sat.), the product was extracted with ethyl acetate, dried over Na2SO4, filtered and concentrated in vacuo. The titled compound 203 was obtained as a white foam which was taken on crude, without purification. LCMS (ES): Mass found (M+H)=1091.2; exact mass for C53H79F3NO17S (M+H)=1090.50.
Step 2. Oxidation of C9. To the crude product obtained in step 1, above (1 eq) in methylene chloride (0.02 M) was added Dess-Martin periodinane (1.5 eq) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour. The reaction was quenched with NaHCO3 (sat.), the layers separated, the organic layer was then washed with Na2S2O3 (aq.), and followed by brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude foam was purified over silica gel (3:1, hexane/acetone, with 0.5% TEA) to give the titled C9-ketone, compound 203.
EXAMPLE 72(C)
Synthesis of 204, Scheme 3 
Inversion of C12 enone formation. To compound 203 in acetone (0.1 M) was added DBU (3 equiv) at room temperature. The reaction mixture was heated to 60° C. for 48 hours. A single product was observed by TLC and LCMS, no starting material remained after this time. The solvent was removed under reduced pressure and the residue was dissolved in methylene chloride, washed with NaHCO3 (sat), followed by a brine wash. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude foam was purified over silica gel (3:1, hexane/acetone, with 0.5% TEA) to give the desired enone, compound 204. LCMS (ES): Mass found (M+H)=992.9; Exact mass for C52H73F3NO14+(M+H)=992.50. 13C NMR: the C9 signal appears at 205 ppm, and new vinyl signal for C110 at 143 ppm.
EXAMPLE 72(D)
Synthesis of 205, Scheme 3 
C12-carbonate formation. To compound 204 in THF (0.08 M) was added LiHMDS (5 eq) at 0° C. The reaction mixture was stirred for 1 hour, followed by the addition of (4-nitrophenyl)-chloroformate (4 equiv). Stirring was continued for another 1 hour, allowing reaction vessel to slowly warm from 0° C. to room temperature. The reaction was quenched with NaHCO3 (sat.), diluted with EtOAc, separated, and the organic layer was washed with water (5×) and brine. The product was dried over Na2SO4, filtered, and concentrated in vacuo and the crude foam, compound 205, was used immediately in the following step. LCMS (ES): Mass found (M+H)=1157.8; Exact mass for C59H76F3N2O18+(M+H)=1157.50.
EXAMPLE 72(E)
Synthesis of 206, Scheme 3
11,12-cyclic carbamate general procedure. To a solution of compound 205 (from above) in a 4:1, acetonitrile/water was added the alkyl-aryl amine (5-10 eq) as described for specific examples. The reaction was heated to 60° C. for 2 hours, after which time conversion to the carbamate was complete according to both TLC and LCMS data. The reaction was quenched with NaHCO3 (sat.), diluted with EtOAc, separated, and the organic layer was washed with water (8×) and brine. The product was dried over Na2SO4, filtered and concentrated in vacuo and the crude foam was chromatographed over silica gel (5:4, hexane/acetone, and 1% TEA) to give the desired products, 206a-c. All products were observed as the (M+2H)/2 ion as opposed to the usual M+H in the LCMS data.
Compound 206a: alkyl is butyl, and aryl is imidazole-3-phenyl. LCMS (ES); Mass found [(M+2H)/2]=617.7 Exact mass for C66H89F3N4O152+[(M+2H)/2]=617.32.
Compound 206b: alkyl is butyl, and aryl is imidazole-3-pyridyl. LCMS (ES); Mass found [(M+2H)/2]=618.3 Exact mass for C65H88F3N5O152+[(M+2H)/2]=617.81.
Compound 206c: alkyl is butyl, and aryl is 4-quinolyl. LCMS (ES); Mass found [(M+2H)/2]=610.1 Exact mass for C66H88F3N3O152+[(M+2H)/2]=609.81
EXAMPLE 72(F)
Synthesis of 207, Scheme 3 
C3-ketolides. Compound 206 in CH3CN and 6 N HCl (3:1, CH3CN/6N HCl) was stirred for 3 hours at room temperature, after which time hydrolysis was complete. With vigorous stirring, the reaction mixture was poured over NaHCO3 (sat.), diluted with EtOAc, and K2CO3(s) was added until a pH 8 had been attained. The layers were separated and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude foam was dissolved in CH2Cl2 (3.0 ml) followed by the addition of Dess-Martin periodinane (2.5 eq) at 0° C. and allowed to warm to room temperature over 1.5 hours. Complete conversion to the 3-keto product was determined by both TLC and LCMS. The reaction was quenched with 1:1 NaHCO3 (aq.)/Na2S2O3 (aq.) and stirred for 10 minutes. The layers were separated, washed with brine, and dried over Na2SO4. Upon concentration, the foam was purified over silica gel (3:2, hexane/acetone, with 0.5% TEA) to give the desired 3-keto products 207a-c.
Compound 207a: alkyl is butyl, and aryl is imidazole-3-phenyl. LCMS (ES); Mass found [(M+2H)/2]=486.4; exact mass for C51H69F3N4O112+[(M+1H)/2]=485.25.
Compound 207b: alkyl is butyl, and aryl is imidazole-3-pyridyl. LCMS (ES); Mass found [(M+2H)/2]=486.1; exact mass for C43H64F3N5O102+[(M+2H)/2]=485.75.
Compound 207c: alkyl is butyl, and aryl is 4-quinolyl. LCMS (ES); Mass found [(M+2H)/2]=478.0; exact mass for C51H68F3N3O112+[(M+2H)/2]=477.74.
EXAMPLE 72(G)
Synthesis of 208, Scheme 3
Compound 207 was dissolved in MeOH (0.01 M) and the reaction mixture was refluxed over night. The MeOH was removed under reduced pressure and the crude foam was then purified over silica gel (1:1, hexane/acetone, with 0.5% TEA) to give the titled compounds, 208a-c.
Compound 208a: alkyl is butyl, and aryl is imidazole-3-phenyl. LCMS (ES); Mass found (M+H)=865.8; Exact mass for C44H64F3N4O10+2 (M+H)=865.46.
Compound 208b: alkyl is butyl, and aryl is imidazole-3-pyridyl. LCMS (ES); Mass found (M+H)=434.3; Exact mass for C43H643N4O10+2 [(M+H)/2]=434.00.
Compound 208c: alkyl is butyl, and aryl is 4-quinolyl. LCMS (ES); Mass found (M+H)=426.1; Exact mass for C44H64F3N3O10+2 [(M+H)/2]=425.50.
EXAMPLE 73
GENERAL SCHEME TO 12-CF3 11,12-CARBAZATE ZETOLIDES




EXAMPLE 73(A)
Synthesis of 209, Carbazate Formation
The carbazate is formed directly from the nitrophenyl carbonate 205 (obtained from Example 72(a)), by addition of hydrazine (approximately 10 eq) to the same reaction pot following the formation of the carbonate, and prior to work-up. The reaction mixture was then warmed to room temperature and stirred for 2.5 h. Both TLC and LCMS indicated that carbonate had been consumed and formation of the carbazate was complete. The reaction was quenched with NaHCO3 (sat.), diluted with EtOAc, separated, and the organic layer was washed with water, and then with brine. The product was dried over Na2SO4, filtered, concentrated in vacuo, and the crude foam was chromatographed over silica gel (4:1, hexane/acetone, and 0.1% TEA) to give the titled compound, 209. LCMS (ES); Mass found (M+H)=1051.1; Exact mass for C53H75F3N3O15+(M+H)=1050.52
Synthesis of 210a, Scheme 2d. To compound 209 in methanol (0.1 M) was added 4-(3-propanal)-quinoline (2 eq), and glacial acetic acid (4 eq) at room temperature. After 4 hours, NaCNBH3 (5.3 eq) was added to the reaction vessel and the reaction mixture was stirred overnight at room temperature. The reaction was quenched with NaHCO3 (sat.), diluted with EtOAc, separated, and the organic layer was washed with brine. The product was dried over Na2SO4, filtered, concentrated in vacuo, and the crude foam was chromatographed over silica gel (4:1, hexane/acetone, and 0.1% TEA) to give 210a. LCMS (ES); Mass found [(M+2H)/2]=610.1; Exact mass for C65H87F3N4O152+[(M+2H)/2]=610.31
EXAMPLE 73(B)
Synthesis of 210B
To carbazate 209 in glacial acetic acid (0.05 M) was added 4-(3-pyridyl)-imidazole (8 eq) and acrolein (1.2 eq) at room temperature. After 2 hours, the reaction was quenched with NaHCO3 (sat.), the imine extracted with EtOAc, and concentrated under reduced pressure. The crude intermediate was dissolved in MeOH (0.02 M), 2 drops of HOAc was added, followed by NaCNBH3 (10 eq), and the reaction mixture was stirred for 8 h at room temperature. The reaction was quenched with NaHCO3 (sat.), diluted with EtOAc, separated, and the organic layer was washed with brine. The crude carbazate product 210b was taken on to the next step without further purification. LCMS (ES); Mass found [(M+2H)/2]=618.6; Exact mass for C64H87F3N6O152+[(M+2H)/2]=618.70
EXAMPLE 73(C)
Synthesis of 211A-B
Step 1. Removal of C3-sugar, general procedure: The carbazate 210 was dissolved in CH3CN/HCl (6 N) (1.5:1) at room temperature. After 2 hours, TLC indicated that hydrolysis of the cladinose sugar was complete. The reaction was quenched with NaHCO3 (sat.), diluted with EtOAc, and the pH was adjusted to approximately 8 with K2CO3 (s). The layers were separated, and the aqueous layer was extracted with EtOAC (3×), the combined organic layers were washed with brine. The product was dried over Na2SO4, filtered, concentrated in vacuo, and the crude foam was carried on to the next step without further purification.
Step 2. Oxidation of the C3—OH, general procedure: To the crude 11,12-carbazate from step 1 (above), in CH2Cl2 (0.01 M) was added Dess-Martin periodinane (2 equiv) at 0° C. The reaction mixture was warmed to room temperature over 2 h, after which time oxidation was complete. The reaction was quenched with a 1:1 solution of NaHCO3 (sat.) and Na2S2O3 (1 M). The layers were separated, and the aqueous layer extracted with additional CH2Cl2 (2×). The combined organic layers were then washed with brine and dried over Na2SO4, filtered, concentrated in vacuo, and the crude foam was purified over silica gel (4:1, hexane/acetone with 0.1% TEA) to give the pure ketolide.
Step 3. Deprotection of 2′ Benzoate, general procedure: The ketolide, from Step 2 (above), was dissolved in MeOH (0.01 M) and refluxed overnight. The methanol was removed under reduced pressure and the crude foam was chromatographed over silica gel (3:1 to 1:1, hexane/acetone with 0.1% TEA), to give the final carbazate derivatives, 211a-b.
Compound 211a: aryl is 4-quinolyl. LCMS (ES); Mass found [(M+2H)/2]=426.8; Exact mass for C43H63F3N4O102+[(M+2H)/2]=426.49.
Compound 211b: aryl is imidazole-3-pyridyl. LCMS (ES); Mass found [(M+2H)/2]=434.6; Exact mass for C49H67F3N6O112+[(M+2H)/2]=434.49.
EXAMPLE 74
SYNTHESIS OF C11-C12 “REVERSE” CARBAMATE (SYNTHESIS SCHEME 6)




To 2′,4′′-OBz-9,11-dimethylketal-12-keto-macrolide in EtOH (0.04 M) was added Et3N (9.5 eq), followed by hydroxylamine hydrochloride (4.7 eq). The reaction mixture was stirred at room temperature overnight after which time complete conversion to the oxime was observed. The solvent was removed under reduced pressure and the residue taken up in CH2Cl2 and washed with NaHCO3 (sat.). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The 12-oxime-derivative was purified by column chromatography over silica gel (2:1, hexane/acetone, with 0.5% triethylamine) to give the desired 12-oxime-9,11-acetonide as a white solid. The crude product may be taken on to the reduction step directly. ES/MS 997.6 (MH+).
To 2′,4′′-OBz-9,11-dimethylketal-12-oxime-macrolide in EtOH (0.02 M) was added NH3 (2 M in ethanol; 33 eq), followed by the addition of NaCNBH3 (7.9 eq). The reaction mixture was cooled to 0° C. and TiC13 (5 eq) was added dropwise over 5 minutes. The ice bath was removed and stirring continued at room temperature. Reaction progress was monitored by TLC and LCMS; both indicated that the reduction to the amine had reached completion after 30 minutes. At this point, the acetonide at the 9 and 11 positions was still intact. Deprotection was accomplished by the slow addition of HCl (6 M; 70 eq) at 0° C. The blue slurry was poured over ice and the pH was adjusted to approximately 10 with dry NaHCO3. The grey slury was diluted with water to decrease the emulsion during the extraction process. The product was extract from the aqueous layer with CHCl3 (5×) and the combined organic layers were dried over Na2SO4. Concentration in vacuo followed by purification over silica gel (2% MeOH/97% CH2Cl2 and 1% triethylamine) gave the single isomer 12-amino-9,11-diol as a white solid. The structure and stereochemistry at C-12 was confirmed by X-ray analysis. ES/MS 943.2 (MH+). The intermediate acetonide can also be isolated if the deprotection step is omitted. ES/MS 983.5 (MH+).
To 2′,4′′-OBz-9,11-hydroxy-12-amino-macrolide in CH2Cl2 (0.05 M) was added TEA (2.2 eq) and triphosgene (1.1 eq) at 0° C. The reaction vessel was warmed to room temperature and stirred for 15 minutes after which time no starting material remained. Aqueous NaHCO3 (sat.) was added to reaction mixture, and the layers were separated. The product was further extracted from the aqueous layer with additional CH2Cl2 (3×). The combined organic layers then dried over Na2SO4, filtered, and concentrated in vacuo. Purification over silica gel (5:1, hexane/acetone and 0.5% triethylamine) gave the 9-hydroxy-11,12-oxazolidonone derivative as a white solid. Structure confirmed by X-ray analysis. ES/MS 969.5 (MH+).
To 2′,4′′-OBz-9-hydroxy-11,12-oxazolidinone-macrolide in CH2C2 (0.1 M) was added Dess-Martin periodinane (1.2 eq) at 0° C. The reaction vessel was warmed to room temperature and stirred for 30 minutes after which time no starting material remained. Aqueous NaHCO3 (sat.) was added to reaction mixture, and the layers separated. The aqueous layer was extracted with CH2Cl2 (3×). The combined organic layers then dried over Na2SO4, filtered, and concentrated in vacuo. Purification over silica gel (5:1 hexane:acetone and 0.5% triethylamine) gave the 9-keto-11,12-oxazolidonone derivative as a white solid. ES/MS 967.4 (MH+).
The 2′,4′′-OBz-9-keto-11,12-oxazolidinone-macrolide was dissolved in MeOH (0.01 M) and heated to reflux for 3 days. The solvent removed in vacuo, followed by purification over silica gel (3:1, hexane/acetone and 0.5% triethylamine) to give the 9-keto-11,12-oxazolidonone derivative as a white solid. ES/MS 863.6 (MH+).
EXAMPLE 75
2-FLUORO ANALOGS




To a −15° C. (MeOH/ice bath) 0.15 M THF solution containing the 10, 11 anhydroketolide (17, Example 67) was added KO-tBu (1.15 eq, 1.0 M in THF). After 5 min, N-fluorobenzenesulfonimide (1.2 eq) was added and the solution was stirred for 10 min before being warmed to 0° C. over 0.5 h. The reaction was next diluted with EtOAc and quenched with sat. NaHCO3. The organic layer was washed with water and brine, dried over MgSO4, filtered, and concentrated. Purification by silica gel chromatography (4:1 hexanes:acetone with 1% Et3N) gave the desired halo product 45. ESMS m/z 678 (MH+), C36H52FNO10=677 g/mol
To a −15° C. (MeOH/ice bath) 0.18 M THF solution containing the C2 fluorine 45 and CDI (2 eq) was added NaH (60% , 1.2 eq). After stirring for 10 min, the solution was warmed to −5° C. over 10 min. The reaction was next diluted with EtOAc and quenched with sat. NaHCO3. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated. The product 46 was used without further purification.
The crude carbamate product 46 was added to a 0.25 M MeCN solution containing the appropriate amine R1NH2 (4 eq) and stirred at room temperature for 2 h before being heated to 70° C. for 16 h. The reaction was next diluted with EtOAc and quenched with sat. NaHCO3. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated. Purification by silica gel chromatography (5:2 hexanes:acetone with 2% Et3N) gave the desired cyclic carbamate product. 47a: R′=4-quinolin-4-yl-butyl, ESMS m/z 904 (MH+), C50H66FN3O11=903 g/mol. 47b: R′=4-(4-phenyl-imidazol-1-yl)-butyl, ESMS m/z 919 (MH+), C5OH67FN4O11=918 g/mol. 47c: R′=4-quinolin-4-yl-butyl, ESMS m/z 904 (MH+). 47d: R′=4-(4-(3-pyridyl)imidazolyl)butyl, ESMS m/z 920.5.
A 0.05 M MeOH solution containing the benzoate was heated to 70° C. for 3 h and then concentrated. Purification by silica gel chromatography (1:1 hexane:acetone with 2% Et3N) gave the desired products. 48a: R′=4-quinolin-4-yl-butyl, ESMS m/z 800 (MH+), C43H62FN3O10=799 g/mol. 48b: R′=4-(4-phenyl-imidazol-1-yl)-butyl, ESMS m/z 815 (MH+), C43H63FN4O10=814 g/mol. 48c: R′=4-(2-quinolyl)butyl, ESMS m/z 800 (MH+). 48d: R′=4-(4-(3-pyridyl)imidazolyl)butyl, ESMS m/z 816.5.
EXAMPLE 76
SYNTHESIS OF 2-F ACROLEIN PYRIDYL-IMIDAZOLE CARBAZATE




Compound 51 was prepared as described in Example 80 for the analogous 2-H compound except using compound 46 (Example 75) as the starting material. ES/MS m/z 369 [(M+2H+)/2], C37H54FN3O11=736 g/mol.
Compound 52 was prepared from 51 as described in Example 80 for the analogous 2-H compound. ES/MS m/z 461 [(M+2H+)/2], C48H65FN6O11=921 g/mol.
Compound 53 was prepared from 52 as described in Example 80 for the analogous 2-H compound. ES/MS m/z 409 [(M+2H+)/2], C41H61FN6O10=817 g/mol.
EXAMPLE 77
SYNTHESIS OF 2-F QUINOLYL CARBAZATE




Starting material 51 (Example 76, 1.0 eq) and 4-quinolinecarboxaldehyde (1.2 eq) were dissolved in methanol. Glacial acetic acid (4.0 eq) was added. The solution was stirred at ambient temperature for 5.5 h. Sodium cyanoborohydride (2.0 eq) was added. The mixture was stirred overnight. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate and then poured into EtOAc. The phases were separated. The organic layer was washed with brine and then dried over Na2SO4, filtered, and concentrated. Column chromatography (1:1 hexanes:EtOAc+2% Et3N) gave the desired product 61. ES/MS m/z 906 (MH+), C49H65FN4O11=905 g/mol.
A 0.05 M solution of starting material 61 in methanol was refluxed for 15 h. The mixture was brought to ambient temperature and concentrated. Column chromatography (2:3 hexanes:EtOAc+2% Et3N) gave the desired product 62. ES/MS m/z 401 [(M+2H+)/2], C48H67N5O11=801 g/mol.
EXAMPLE 78
SYNTHESIS OF 2-F CROTONALDEHYDE PYRIDYL-IMIDAZOLE CARBAZATE




Compound 71 was obtained as described in Step 1 of Example 82 for: the analogous 2-H compound except using compound 51 (Example 76) as the starting material. ES/MS m/z 468 [(M+2H+)/2], C49H67FN6O11=935 g/mol.
Compound 72 was obtained as described in Step 2 of Example 82 for the analogous 2-H compound except using compound 71 as the starting material. ES/MS m/z 416 [(M+2H+)/2], C42H63FN6O10=831 g/mol.
EXAMPLE 79




The previously described crude carbamate intermediate 18 (Example 67) was added to a 0.22 M MeCN solution containing the appropriate amine (2 eq [ethylene diamine; (S)-(−)-1,2-diaminopropane 2HCl]) and stirred at room temperature for 2 h to overnight. The reaction was next diluted with EtOAc and quenched with water (2×), brine, dried over Na2SO4, filtered, and concentrated. The products were purified by silica gel chromatography where necessary and redissolved in 0.2 M MeCN containing Et3N (10 eq) and heated at 55-60° C. for 15-39 h before being concentrated and chromatographed (silica gel, 1:1 hexane:acetone with 2% Et3N). 74a: R′=H, ESMS m/z 746 (MH+), C39H59N3O11=745 g/mol. 74b: R′=Me, ESMS m/z 760 (MH+), C40H61N3O11=759 g/mol.
To a 0.05 M toluene solution containing the carbamate 74 and benzoic acid or pivalic acid (2 eq) was stirred at 70° C. for 3 days then at to 80° C. for an additional 2 days. Purification by silica gel chromatography (2:1 hexanes:acetone with 2% Et3N) gave the cyclic imine product. 75a: R′=H, ESMS m/z 728 (MH+), C39H57N3O10=727 g/mol. 75b: R′=Me, ESMS m/z 742 (MH+), C40H59N3O10=741 g/mol.
A 0.05 M MeOH solution containing the benzoate 75 was heated to 70° C. for 3 h and then concentrated. Purification by silica gel chromatography (1:2 hexanes:acetone with 2% Et3N) gave the desired product. 76a: R′=H, ESMS m/z 624 (MH+), C32H53N3O9=623 g/mol. 76b: R′=Me, ESMS m/z 638 (MH+), C33H55N3O9=637 g/mol.
EXAMPLE 80
SYNTHESIS OF 2-H ACROLEIN PYRIDYL-IMIDAZOLE CARBAZATE ANALOG




Compound 18 of Example 67 (1.00 eq) was dissolved in DMF. Hydrazine hydrate (4.0 eq) was added. The solution was stirred at ambient temperature for 3 h. The reaction mixture was poured into EtOAc and washed sequentially with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. Column chromatography (5:2 hexanes:EtOAc+2% Et3N) gave the cyclic carbazide 77, ES/MS m/z 360 [(M+2H+)/2], C37H55N3O11=718 g/mol.
The cyclic carbazate 77 (1.0 eq) and 4-(3-pyridyl)-imidazole (3.0 eq) was dissolved in HOAc. Freshly distilled acrolein (1.2 eq) was added. The solution was stirred at ambient temperature for 16 h; and sodium triacetoxyborohydride (8.0 eq) was added. The solution was stirred for an additional 8.5 h. The reaction mixture was poured into EtOAc and quenched by the addition of 6 N aqueous sodium hydroxide and saturated aqueous sodium bicarbonate. The layers were separated; and the organic layer was washed with brine then dried over Na2SO4, filtered, and concentrated. Column chromatography (2:1 hexanes:acetone+2% Et3N to 1:2 hexanes:acetone+2% Et3N) gave 78. ES/MS m/z 452 [(M+2H+)/2], C48H66N6O11=903 g/mol.
A 0.05 M solution of 78 in methanol was refluxed for 15 h. The mixture was brought to ambient temperature and concentrated. Column chromatography (94:5:1 CHCl3:MeOH:NH4OH) gave 79. ES/MS m/z 400 [(M+2H+)/2], C41H62N6O10=799 g/mol.
EXAMPLE 81
SYNTHESIS OF 2-H QUINOLYL CARBAZATE




The cyclic carbazate 77 (Example 80, 1.0 eq) and 4-quinolinecarboxaldehyde (1.2 eq) were dissolved in methanol. Glacial acetic acid (4.0 eq) was added. The solution was stirred at ambient temperature for 5 h. Sodium cyanoborohydride (2.0 eq) was added. The mixture was stirred overnight. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate and then poured into EtOAc. The phases were separated. The organic layer was washed with brine and then dried over Na2SO4, filtered, and concentrated. Column chromatography (1:1 hexanes:EtOAc+2% Et3N) gave the desired product 81 (78.3%). ES/MS m/z 888 (MH+), C49H66N4O11=887 g/mol.
A 0.05 M solution of 81 in methanol was refluxed for 15 h. The mixture was brought to ambient temperature and concentrated. Column chromatography (2:3 hexanes:EtOAc+2% Et3N) gave the desired 2-H quinolyl carbazate 82. ES/MS m/z 392 [(M+2H+)/2], C48H67N5O11=783 g/mol.
EXAMPLE 82
SYNTHESIS OF 2-H CROTONALDEHYDE PYRIDYL-IMIDAZOLE CARBAZATE




Compound 77 (Example 80) was converted to compound 83 as described in Example 80 for the analogous acrolein-derived compound except using crotonaldehyde in place of acrolein. ES/MS m/z 459 [(M+2H+)/2], C49H68N6O11=917.
Compound 83 was converted to compound 84 as described in Example 80 for the analogous acrolein-derived compound. ES/MS m/z 407 [(M+2H+)/2], C41H62N6O10=813 g/mol
EXAMPLE 83
SYNTHESIS OF 2-GEM-DIMETHYL CARBAMATE




Compound 18 from Example 67 (1.0 eq) and the appropriate butanamine were dissolved in acetonitrile. The reaction was stirred at 70° C. for 14 h. The mixture was brought to ambient temperature, diluted with EtOAc, and washed sequentially with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. Column chromatography (3:2 hexanes:EtOAc+2% Et3N) gave 85. ES/MS m/z 439 [(M+2H+)/2], C47H65N5O11=876 g/mol.
Compound 85 (1.0 eq) was dissolved in 1:1 THF:DMSO and cooled to 0° C. A solution of MeBr in ether (3.0 eq) was added. A solution of potassium tert-butoxide in THF was added dropwise over 20 min. The reaction was stirred at 0° C. for 2.5 h. The mixture was diluted with EtOAc, and washed sequentially with saturated sodium bicarbonate, water, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. Column chromatography (3:2 hexanes:EtOAc+2% Et3N) gave the product 86. ES/MS nm/z 446 [(M+2H+)/2], C48H67N5O11=890 g/mol.
A 0.05 M solution of 86 in methanol was refluxed for 15 h. The mixture was brought to ambient temperature and concentrated. Column chromatography (2:3 hexanes:EtOAc+2% Et3N) gave the desired 2-gem-dimethyl carbamate 87. ES/MS m/z 394 [(M+2H+)/2], C48H67N5O11=786 g/mol.
EXAMPLE 84




Step 1. To a stirred solution of aldehyde 97 (R1=4-(4-(3-pyridyl)imidazolyl)butyl, 97 is synthesized using the product of Example 63 as the starting material: To a solution of the starting material in methylene chloride (0.2 M) is added benzoic anhydride (2 eq). The mixture is stirred under argon at room temperature until the starting material disappears, poured into sat. NaHCO3 (aq.) and extracted with EtOAc. The organic portions are combined, washed with brine, dried with MgSO4 and concentrated in vacuo. The crude material is purified by flash column chromatography (silica gel, hexane/acetone to give compound 9.) in CH2Cl2 (0.1 M) at 0° C. under argon is added triphenylphosphine (2.3 eq). The mixture is stirred for 10 min and carbon tetra-bromide (1.15 eq) is added. The mixture is kept at 0° C. with stirring until complete conversion of the starting material, diluted with water, and extracted with CH2Cl2. The combined extracts are dried with MgSO4 and concentrated under reduced pressure. The resulting residue is purified by flash column chromatography (silica gel) to give 1,1-dibromo-olefin intermediate.
Step 2. To a stirred solution of material obtained from step 1 in anhydrous THF (0.1 M) at −78° C. under argon is added n-BuLi solution (1.6 M in hexane, 2.1 eq). The mixture is kept at −78° C. until complete conversion of the starting material, quenched with ammonium chloride aqueous solution, and extracted with CH2Cl2. The combined extracts are dried with MgSO4 and concentrated under reduced pressure. The resulting residue is purified by flash column chromatography (silica gel) to give 12-alkyne (R2=H) intermediate.
Step 3. A 0.05 M solution of the compound from step 2 is stirred in methanol at 70° C. for 16 h. The mixture is returned to ambient temperature, and volatiles are removed under reduced pressure. Purification by flash chromatography over silica gel gives compound 98.
The following compounds are made according to the procedure described above. 98b: R1=4-(4-Phenyl-imidazol-1-yl)-butyl; 98c: R1=4-Quinolin-4-yl-butyl; 98d: R1=4-Imidazo[4,5-b]pyridin-3-yl-butyl; 98e: R1=4-Imidazo[4,5-b]pyridin-1-yl-butyl; and 98f: R1=4-(2-quinolyl)butyl.
EXAMPLE 85




Step 1. A solution of aldehyde 97 (R1=4-(4-(3-pyridyl)imidazolyl)butyl, 0.1 M, Example 84), powdered activated Zn (16 eq) and bromodifluoromethyl[tris(dimethylamino)]phosphonium bromide (8 eq, made from dibromodifluoromethane and hexamethylphosphorous triamide according to procedure by Houlton, S. J. et al, Tetrahedron 1993, 8087) in anhydrous THF is heated to 50° C. under argon until complete conversion of the starting material. The reaction is cooled to room temperature. The solid is filtered off and the filtrate is partitioned between CHCl3 and NaHCO3 (aq.). The organic layer is separated, washed with brine, dried with MgSO4, and concentrated under reduced pressure. The resulting residue is purified by flash column chromatography (silica gel) to give 1,1-difluoro-olefin intermediate.
Step 2. A 0.05 M solution of the compound from step 1 is stirred in methanol at 70° C. for 16 h. The mixture is returned to ambient temperature, and volatiles are removed under reduced pressure. Purification by flash chromatography over silica gel gives compound 99.
The following compounds are made according to the procedure described above. 99b: R1=4-(4-phenyl-imidazol-1-yl)-butyl; 99c: R1=4-quinolin-4-yl-butyl; 99d: R1=4-imidazo[4,5-b]pyridin-3-yl-butyl; 99e: R1=4-imidazo[4,5-b]pyridin-1-yl-butyl; and 99f: R1=4-(2-quinolyl)butyl.
EXAMPLE 86




Step 1. To a solution of aldehyde 97 (R1=4-(4-(3-pyridyl)imidazolyl)butyl, 0.1 M, (Example 84)) and fluoroiodomethyltriphenylphosphonium iodide (1.2 eq, synthesized using commercially available materials according to the procedure by Burton and Greenlimb, J. Org. Chem., 1975, 40, 2796) in anhydrous DMF at 0° C. is added zinc-copper couple (1.5 eq) under argon. The mixture is stirred at 0° C., then at elevated temperature (5-25° C.) until complete conversion of the starting material. The solid is filtered off and the filtrate is partitioned between CHCl3 and NaHCO3 (aq.). The organic layer is separated, washed with brine, dried with MgSO4, and concentrated under reduced pressure. The resulting residue is purified by flash column chromatography (silica gel) to give fluoro-olefin intermediate as a mixture of E/Z isomers.
Step 2. A 0.05 M solution of the compound from step 1 is stirred in methanol at 70° C. for 16 h. The mixture is returned to ambient temperature, and volatiles are removed under reduced pressure. Purification by flash chromatography over silica gel gives compound 100.
The following compounds are made according to the procedure described above. 10b: R1=4-(4-phenyl-imidazol-1-yl)-butyl; 100c: R1=4-quinolin-4-yl-butyl; 100d: R1=4-imidazo[4,5-b]pyridin-3-yl-butyl; 10e: R1=4-imidazo[4,5-b]pyridin-1-yl-butyl; and 100f: R1=4-(2-quinolyl)butyl.
EXAMPLE 87




Step 1. Molecular sieves (4 angstrom powder) is added to a 1M solution of tetrabutylammonium fluoride in THF (10 eq), and the mixture is stirred at room-temperature overnight under argon. To the mixture is added a solution of aldehyde 97 (R1=4-(4-(3-pyridyl)imidazolyl)butyl, 0.2 M, Example 84) and 2,2,2-trifluoroethyldiphenylphosphine oxide (2 eq, synthesized using commercially available materials according to the procedure by Ishibashi, H. et al, J. Org. Chem., 2002, 67, 3156) in THF. After the mixture is stirred for 1 h, molecular sieves is removed by filtration. Water is added to the filtrate, and the whole is extracted with EtOAc. The organic extract is washed with brine, dried with MgSO4 and concentrated under reduced pressure. The resulting residue is purified by flash column chromatography (silica gel) to give trifluoromethyl-olefin intermediate as a mixture of E/Z isomers.
Step 2. A 0.05 M solution of the compound from step 1 is stirred in methanol at 70° C. for 16 h. The mixture is returned to ambient temperature, and volatiles are removed under reduced pressure. Purification by flash chromatography over silica gel gives compound 101.
The following compounds are made according to the procedure described above. 101b: R1=4-(4-phenyl-imidazol-1-yl)-butyl; 101c: R1=4-quinolin-4-yl-butyl; 101d: R1=4-imidazo[4,5-b]pyridin-3-yl-butyl; 101e: R1=4-imidazo[4,5-b]pyridin-1-yl-butyl; and 101f: R1=4-(2-quinolyl)butyl.
EXAMPLE 88




Step 1. To a stirred suspension of NaH (60% dispersion in oil, 1.2 eq) in dry DMSO (0.3 M) at 0° C. is added trimethylsulfoxonium iodide (1.2 eq). After 15 min, compound 97 (R1=4-(4-(3-pyridyl)imidazolyl)butyl, 1 eq, Example 84) in DMSO (0.2 M) is introduced. The reaction is stirred for 30 min (or until complete conversion of the starting material) at room temperature, diluted with water, and extracted with EtOAc. The organic layer is washed with brine, dried with MgSO4 and concentrated under reduced pressure. The resulting residue is purified by flash column chromatography (silica gel) to give 12-epoxy intermediate.
Step 2. A 0.05 M solution of the compound from step 1 is stirred in methanol at 70° C. for 16 h. The mixture is returned to ambient temperature, and volatiles are removed under reduced pressure. Purification by flash chromatography over silica gel gives compound 102.
The following compounds are made according to the procedure described above. 102b: R1=4-(4-phenyl-imidazol-1-yl)-butyl; 102c: R1=4-quinolin-4-yl-butyl; 102d: R1=4-imidazo[4,5-b]pyridin-3-yl-butyl; 102e: R1=4-imidazo[4,5-b]pyridin-1-yl-butyl; and 102f: R1=4-(2-quinolyl)butyl.
EXAMPLE 89
SYNTHESIS OF ANHYDROLIDE DERIVATIVES (SCHEME 9)
EXAMPLE 89(A)
Preparation of Compound 305
R1=H, R2=OMe, compound 23 in Example 68(c).
R1=CF3, R2=OMe, compound 204 in Example 72(c).
R1=Et, R2=OMe, product of Example 8.
R1=Et, R2=O-allyl, see compound obtained from step 4 for making 303 in Example 70(d).
EXAMPLE 89(B)
Preparation of Compound 306
R1=H, R2=OMe
Step 1. Same as synthesis of 24 in Example 68(d).
Step 2. R3-W=4-(4-phenyl-imidazol-1-yl)-butyl. Same as synthesis of 25b in Example 68(e).
EXAMPLE 89(C)
Preparation of Compound 307
R1=Et, R2=O-allyl or O-propargyl
Step 1. Compound 305 is dissolved in a mixture of acetonitrile/3 N HCl aqueous (2:1) (0.1 M). The mixture is stirred under argon until the starting material disappears, poured into sat. NaHCO3 (aq.) and extracted with EtOAc. The organic portions are combined, washed with brine, dried with MgSO4, and concentrated in vacuo. The crude material is purified by flash column chromatography (silica gel, hexane/acetone).
Step 2. To material obtained from step 1 in dichloromethane (0.1 M) at 0° C. is added triethylamine (2 eq) and methanesulfonyl chloride (1.1 eq). The mixture is stirred at 25° C. until complete conversion of the starting material (monitored by TLC and LC/MS), poured into sat. NaHCO3 (aq.) and extracted with EtOAc. The organic portions are combined, washed with brine, dried with MgSO4, and concentrated in vacuo. The crude material is purified by flash column chromatography (silica gel, hexane/acetone).
Step 3. To material obtained from step 2 in THF (0.1 M) at 0° C. is added sodium hydride (2.2 eq). The mixture is stirred at room temperature until complete conversion of the starting material (monitored by TLC and LC/MS), poured into sat. NaHCO3 (aq.) and extracted with EtOAc. The organic portions are combined, washed with brine, dried with MgSO4, and concentrated in vacuo. The crude material is purified by flash column chromatography (silica gel, hexane/acetone) to give compound 307.
EXAMPLE 89(D)
Preparation of Compound 308 (Route 1)
R1=H, R2=OMe, R3-W=4-(4-phenyl-imidazol-1-yl)-butyl
Step 1. Compound 306 is dissolved in a mixture of acetonitrile/3 N HCl aqueous (2:1). The mixture is stirred under argon until the starting material disappears, poured into sat. NaHCO3 (aq.) and extracted with EtOAc. The organic portions are combined, washed with brine, dried with MgSO4, and concentrated in vacuo. The crude material is purified by flash column chromatography (silica gel, hexane/acetone).
Step 2. To material obtained from step 1 in dichloromethane at 0° C. was added triethylamine (2 eq) and methanesulfonyl chloride (1.1 eq). The mixture is stirred at room temperature until complete conversion of the starting material (monitored by TLC and LC/MS), poured into sat. NaHCO3 (aq.) and extracted with EtOAc. The organic portions are combined, washed with brine, dried with MgSO4, and concentrated in vacuo. The crude material is purified by flash column chromatography (silica gel, hexane/acetone).
Step 3. To material obtained from step 2 in THF at 0° C. is added sodium hydride (1.2 eq). The mixture is stirred at room temperature until complete conversion of the starting material (monitored by TLC and LC/MS), poured into sat. NaHCO3 (aq.) and extracted with EtOAc. The organic portions are combined, washed with brine, dried with MgSO4, and concentrated in vacuo. The crude material is purified by flash column chromatography (silica gel, hexane/acetone).
Step 4. The solution of material obtained from step 3 in MeOH (0.05 M) is heated to 60° C. until the starting material disappears. The solvent is removed under reduced pressure. Purification using flash chromatography (silica gel, hexane/acetone) then gives the desired material 308.
EXAMPLE 89(E)
Preparation of Compound 308 (Route 2)
R1=Et, R3-W=H
Step 1. A 0.2 M solution of the compound 307 and 1,1-carbonyldiimidazole (2.0 eq) in tetrahydrofuran is cooled to −15° C. Sodium hydride (60% dispersion in mineral oil, 1.2 eq) is added. The mixture is stirred at −15° C. for 15 min and at 0° C. for an additional 10 min. The reaction is diluted with ethyl acetate and quenched with saturated aqueous sodium bicarbonate. The layers are separated. The organic layer is washed with water and brine, dried over magnesium sulfate, filtered, and concentrated. The crude material is used without further purification.
Step 2. Ammonium hydroxide (90 eq) is added to a 0.15 M solution of the compound from step 1 in 10:1 acetonitrile:tetrahydrofuran. The mixture is stirred at 50° C. for 16 h and then returned to ambient temperature. The reaction mixture is poured into EtOAc and saturated sodium bicarbonate. The layers are separated. The organic layer is washed with water and brine, dried over magnesium sulfate, filtered, and concentrated. The crude material is purified by flash chromatography over silica gel.
R2=(2E)-3-(3-quinolyl)prop-2-en-1-oxy
Step 3. Heck reaction: Tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (0.25 eq) is added to a degassed 0.1 M solution of compound obtained from step 2, tri-O-tolylphosphine (1.0 eq), 3-bromoquinoline (10 eq), and triethylamine (2.0 eq) in acetonitrile. The mixture is stirred at 70° C. for 30 h and returned to ambient temperature. The reaction mixture is poured into EtOAc and saturated sodium bicarbonate. The layers are separated. The organic layer is washed with water and brine, dried over magnesium sulfate, filtered through Celite, and concentrated. The crude material is purified by flash chromatography over silica gel to give the desired compound.
R2=3-(5-(2-pyridyl)-2-thienyl)prop-2-yn-1-oxy
Step 3. Sonogashira reaction: Tetrakis(triphenylphosphine)palladium(0) (0.25 eq) and copper(I) iodide (0.25 eq) are added to a degassed 0.1 M solution of compound obtained from step 2, 5-bromo-2-(2-pyridyl)thiophene (10 eq), and triethylamine (2.0 eq) in N,N-dimethylformamide. The mixture is stirred at 80° C. for 16 h and returned to ambient temperature. The reaction mixture is poured into EtOAc and saturated sodium bicarbonate. The layers are separated. The organic layer is washed with water and brine, dried over magnesium sulfate, filtered through Celite, and concentrated. The crude material is purified by flash chromatography over silica gel to give the desired compound.
Step 4. A 0.05 M solution of the compound from step 3 is stirred in methanol at 70° C. for 16 h. The mixture is returned to ambient temperature, and volatiles are removed under reduced pressure. Purification by flash chromatography over silica gel gives compound 308.
Compounds having general structure 308a are made following the above scheme. ArX (X=I, Br, or Cl) are used in the step of Heck reaction. Compounds having general structure 308b are made following the above scheme. ArX (X=I, Br, or Cl) are used in the step of Sonogashira reaction.




General Structure
wherein Ar is 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl, 1-naphthyl, 2-naphthyl,




wherein when Y is H, X is F, Cl, OH, CN, NO2, NH2, pyridyl, OR, or Ac; and when X=H, Y=NO2, NH2, CH3, CF3,





wherein Ar′ is pyridyl, substituted-pyridyl, phenyl, or substituted phenyl.

EXAMPLE 90
SYNTHESIS OF 4-IODO-1-TRITYL-1H-IMIDAZOLE




To a solution of 4-iodoimidazole (1 eq) in DMF at room temperature was added triphenylmethyl chloride (1.2 eq). After stirring at room temperature for 24 h, the solution was poured into ice water and left stirring for 30 min. The solid was filtered and pumped on for several hours to yield the crude compound. Ethyl ether was added to the crude compound and the solution was filtered to yield 4-iodo-1-trityl-1H-imidazole (92%) as a white solid. MH+(437).
EXAMPLE 91
SYNTHESIS OF 5-(1H-IMIDAZOL-4-YL)-2-METHYL-PYRIDINE




To a solution of 4-iodo-1-trityl-1H-imidazole (1 eq) in THF at room temperature was added ethylmagnesium bromide (1.2 eq) under dry conditions. After stirring for 90 minutes, zinc chloride (1.2 eq) was added to the reaction mixture. After stirring for another 90 minutes, tetrakis(triphenylphosphine)palladium (10%) and 5-bromo-2-methylpyridine (1.2 eq) were added to the reaction mixture. Following that, the reaction mixture was heated in a 70° C. oil bath overnight. Upon cooling, the reaction was diluted with dichloromethane and washed with a EDTA buffer (at approximately pH 9), NaCl, dried over sodium sulfate, filtered and concentrated. The crude product was disolved in ethanol and concentrated HCl was added to the solution at room temperature. The reaction mixture was heated in a 50° C. oil bath for 2 hours. Upon cooling, the reaction was filtered and washed with ethyl ether to yield 5-(1H-imidazol-4-yl)-2-methyl-pyridine (63%). MH+(160)
EXAMPLE 92
SYNTHESIS OF ISOINDOLE-1,3-DIONES
EXAMPLE 92(A)
SYNTHESIS OF 2-[4-(6-METHYL-PYRIDIN-3-YL)-IMIDAZOL-1-YLMETHYL]-ISOINDOLE-1,3-DIONE




To a solution of 5-(1H-imidazol-4-yl)-2-methyl-pyridine (1 eq) in DMF was added potassium carbonate (4 eq) at room temperature under dry conditions. After heating the reaction mixture in a 80° C. oil bath for 1 hour, N-(4-bromobutyl)phtalimide (3.9 eq) was added to the mixture. The solution was left stirring in a 80° C. oil bath for 24 hours. Upon cooling, the reaction was filtered and the solid was washed with ethyl acetate. The filterate was diluted with ethyl acetate and washed with NH4Cl (sat.), H2O, NaCl (sat.), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography using an initial solvent gradient of 97% DCM, 3% MeOH, and 0.1% TEA (1 L) to afford the product (37%). MH+(361)
EXAMPLE 92(B)
SYNTHESIS OF 2-FLUORO-5-(1-TRITYL-1H-IMIDAZOL-4-YL)-PYRIDINE




To a solution of 4-iodo-1-trityl-1H-imidazole (1 eq) in THF at room temperature was added ethylmagnesium bromide (1.2 eq) under dry conditions. After stirring for 90 minutes, zinc chloride (1.2 eq) was added to the reaction mixture. After stirring for another 90 minutes, tetrakis(triphenylphosphine)palladium (10%) and 5-bromo-2-fluoropyridine (1.2 eq) were added to the reaction mixture. Subsequent reaction conditions and work up are as described previously, in Example 73 to afford the solid 2-fluoro-5-(1H-imidazol-4-yl)-pyridine (46%). MH+(164)
EXAMPLE 92(C)
SYNTHESIS OF 2-{4-[4-(6-FLUORO-PYRIDIN-3-YL)-IMIDAZOL-1-YLMETHYL]-BUTYL}-ISOINDOLE-1,3-DIONE




To a solution of 2-fluoro-5-(1H-imidazol-4-yl)-pyridine (1 eq) in DMF was added potassium carbonate (5 eq) at room temperature under dry conditions. After heating the reaction mixture in a 80° C. oil bath for 1 hour, N-(4-bromobutyl)phtalimide (4 eq) was added to the mixture. The solution was left stirring in a 80° C. oil bath for 24 hours. Upon cooling, the reaction was filtered and the solid was washed with ethyl acetate. The filterate was diluted with ethyl acetate and washed with NH4Cl (sat.), H2O, NaCl (sat.), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography using an initial solvent gradient of 97% DCM, 3% MeOH, and 0.1% TEA (1 L) to yield 2-{4-[4-(6-fluoro-pyridin-3-yl)-imidazol-1-ylmethyl]-butyl}-isoindole-1,3-dione (55%). MH+(365)
EXAMPLE 92(D)
SYNTHESIS OF 5-(1-TRITYL-1H-IMIDAZOL-4-YL)-PYRIMIDINE (A)




To a solution of 4-iodo-1-trityl-1H-imidazole (A) (1 eq) in THF (100 ml) at room temperature was added ethylmagnesium bromide (1.2 eq) under dry conditions. After stirring for 90 minutes, zinc chloride (1.2 eq) was added to the reaction mixture. After stirring for another 90 minutes, tetrakis (triphenylphosphine)palladium (10%) and 5-bromopyrimidine (1.2 eq) were added to the reaction mixture. Subsequent reaction conditions and work up are as described previously in Example 73, the resulting solid 5-(1H-imidazol-4-yl)-pyrimidine (46%) was collected by filtration and used without further purification. MH+(147)
EXAMPLE 92(E)
SYNTHESIS OF 2-[4-(4-PYRIMIDIN-5-YL-IMIDAZOL-1-YL)-BUTYL]-ISOINDOLE-1,3-DIONE




Synthesis was performed as in Example 74, to yield 2-[4-(4-pyrimidin-5-yl-imidazol-1-yl)-butyl]-isoindole-1,3-dione (48%). MH+(348)
EXAMPLE 92(F)
SYNTHESIS OF 2-(1H-IMIDAZOL-4-YL)-PYRAZINE




To a solution of 4-iodo-1-trityl-1H-imidazole (1 eq) in THF at room temperature was added ethylmagnesium bromide (1.2 eq) under dry conditions. After stirring for 90 minutes, zinc chloride (1.2 eq) was added to the reaction mixture. After stirring for another 90 minutes, tetrakis(triphenylphosphine) palladium (10%) and 5-bromopyrazine (1.3 eq) were added to the reaction mixture. Subsequent reaction conditions and work up are as described previously in Example 73, the resulting solid 2-(1H-imidazol-4-yl)-pyrazine (37%) was collected by filtration. MH+(147)
EXAMPLE 92(G)
SYNTHESIS OF 2-[4-(4-PYRAZIN-2-YL-IMIDAZOL-1-YL)-BUTYL]-ISOINDOLE-1,3-DIONE




Synthesis was performed as in Example 74, to yield 2-[4-(4-pyrazin-2-yl-imidazol-1-yl)-butyl]-isoindole-1,3-dione (A) (48%). MH+(348)
EXAMPLE 92(H)
SYNTHESIS OF 2-METHOXY-5-(1-TRITYL-1H-IMIDAZOL-4-YL)-PYRIDINE




To a solution of 4-iodo-1-trityl-1H-imidazole (A) (1 eq) in THF at room temperature was added ethylmagnesium bromide (1.2 eq) under dry conditions. After stirring for 90 minutes, zinc chloride (1.2 eq) was added to the reaction mixture. After stirring for another 90 minutes, tetrakis(triphenylphosphine)palladium (10%) and 5-bromo-2-methoxypyridine (1.2 eq) were added to the reaction mixture. Upon cooling, the reaction was diluted with dichloromethane and washed with a EDTA buffer (at approximate pH 9), NaCl (sat.), dried over sodium sulfate, filtered, and concentrated. MH+(418)
EXAMPLE 92(I)
SYNTHESIS OF 3-(5-METHYL-1-TRITYL-1H-IMIDAZOL-4-YL)-PYRIDINE




To a solution of 4-iodo-5-methyl-1-trityl-1H-imidazole (1 eq) in THF at room temperature was added ethylmagnesium bromide (1.2 eq) under dry conditions. After stirring for 90 minutes, zinc chloride (1.2 eq) was added to the reaction mixture. After stirring for another 90 minutes, tetrakis(triphenylphosphine)palladium (10%) and 3-bromopyridine (1.2 eq) were added to the reaction mixture. Subsequent reaction conditions were performed as in Example 73 to give 3-(5-methyl-1H-imidazol-4-yl)-pyridine (92%). MH+(160)
EXAMPLE 92(J)
SYNTHESIS OF 2-[4-(5-METHYL-4-PYRIDIN-3-YL-IMIDAZOL-1-YL)-BUTYL]-ISOINDOLE-1,3-DIONE (A), AND 2-[4-(4-METHYL-5-PYRIDIN-3-YL-IMIDAZOL-1-YL)-BUTYL]-ISOINDOLE-1,3-DIONE (B)




To a solution of sodium hydride (4.5 eq) in DMF was added slowly a solution of 3-(5-methyl-1H-imidazol-4-yl)-pyridine (1 eq) in DMF. Once the reaction mixture was left stirring at room temperature for 30 minutes, N-(4-bromobutyl)phtalimide (2 eq) was added to the mixture. The solution was left stirring in a 80° C. oil bath for 90 minutes. Upon cooling, the reaction was diluted with ethyl acetate and washed with NH4Cl (sat.), H2O, NaCl (sat.), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography (97% DCM, 3% MeOH and 0.1% TEA) to yield a 6 to 1 mixture of (A) and (B) (28%). MH+(361)
EXAMPLE 92(K)
SYNTHESIS OF 3-(2-METHYL-1-TRITYL-1H-IMIDAZOL-4-YL)-PYRIDINE




To a solution of 4-iodo-3-methyl-1-trityl-1H-imidazole (1 eq) in THF at room temperature was added ethylmagnesium bromide (1.2 eq) under dry conditions. After stirring for 90 minutes, zinc chloride (1.2 eq) was added to the reaction mixture. After stirring for another 90 minutes, tetrakis(triphenylphosphine)palladium (10%) and 3-bromopyridine (1.1 eq) were added to the reaction mixture. Subsequent reaction conditions were performed as in Example 91(b) to provide 3-(2-methyl-1H-imidazol-4-yl)-pyridine (88%). MH+(160)
EXAMPLE 92(L)
SYNTHESIS OF 2-METHYL-2-(4-PYRIDIN-3-YL-IMIDAZOL-1-YL)-PROPIONIC ACID ETHYL ESTER




To a solution of 3-(1H-imidazol-4-yl)-pyridine (1 eq) in DMF was added potassium carbonate (2 eq) under dry condition. After stirring for 1 hour, ethyl 2-bromoisobutyrate (5 eq) was added to the mixture. The solution was left stirring over 36 hours at room temperature. The reaction solvent was removed in vacuo and the solid was diluted with ethyl acetate washed with H2O, NaCl (sat.), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography using a solvent gradient of 97% DCM, 3% MeOH, and 0.1% TEA to yield 2-methyl-2-(4-pyridin-3-yl-imidazol-1-yl)-propionic acid ethyl ester (33%). MH+(260)
EXAMPLE 92(M)
SYNTHESIS OF 2-METHYL-2-(4-PYRIDIN-3-YL-IMIDAZOL-1-YL)-PROPIONALDEHYDE




To a solution of 2-methyl-2-(4-pyridin-3-yl-imidazol-1-yl)-propionic acid ethyl ester (1 eq) in DCM at −78° C. was added diisobutylaluminum hydride (4 eq). After leaving the reaction mixture stir at −78° C. for 3 hours, methanol (4 eq) was added to the reaction mixture at −78° C. and the solution was warmed to room temperature over 60 minutes. Ethyl acetate was added to the solution and after 30 minutes the solution was filtered and concentrated to give 2-methyl-2-(4-pyridin-3-yl-imidazol-1-yl)-propionaldehyde (70%). MH++H2O (234)
EXAMPLE 92(N)
SYNTHESIS OF 4-METHYL-4-(4-PYRIDIN-3-YL-IMIDAZOL-1-YL)PENTANOIC ACID METHYL ESTER




To a solution of sodium hydride (1.2 eq) in THF was added slowly methyl diethylphosphonoacetate (1.2 eq) at 0° C. under dry conditions and the mixture was stirred at room temperature for 30 minutes. A solution of 2-methyl-2-(4-pyridin-3-yl-imidazol-1-yl)-propionaldehyde (1 eq), in THF was added dropwise at room temperature and the mixture was stirred for 1 hour at the same temperature. The mixture was poured into H2O and the whole was extracted with ethyl acetate. The organic layer was washed with NaCl (sat.), dried over sodium sulfate, filtered, and concentrated. To a solution of the residue in ethyl acetate, was added palladium, 10 wt. % on activated carbon and left stirring under 1 atm hydrogen overnight. After the catalyst was filtered off, the filtrate was purified by flash chromatography using a solvent gradient 97% DCM, 3% MeOH, and 0.1% TEA to yield 4-methyl-4-(4-pyridin-3-yl-imidazol-1-yl)pentanoic acid methyl ester (75%). MH+(274)
EXAMPLE 92(O)
SYNTHESIS OF 4-METHYL-4-(4-PYRIDIN-3-YL-IMIDAZOL-1-YL)-PENTAN-1-OL




To a solution of 4-methyl-4-(4-pyridin-3-yl-imidazol-1-yl)pentanoic acid methyl ester (1 eq) in ethanol was added sodium borohydride (4 eq) at room temperature. The reaction mixture was heated in a 50° C. oil bath for 60 minutes and then quenched by addition of H2O. Once the reaction solvent was removed in vacuo, a solution of the residue in dichloromethane was washed with NaCl (sat.), dried over sodium sulfate, filtered and concentrated to give 4-methyl-4-(4-pyridin-3-yl-imidazol-1-yl)-pentan-1-ol (68%). MH+(246)
EXAMPLE 92(P)
SYNTHESIS OF 2-[4-METHYL-4-(4-PYRIDIN-3-YL-IMIDAZOL-1-YL)-PENTYL]-ISOINDOLE-1,3-DIONE




To a solution of 4-methyl-4-(4-pyridin-3-yl-imidazol-1-yl)-pentan-1-ol (1 eq) in THF (20 ml) was added dropwise diethyl azodicarboxylate (1.1 eq), triphenyl phosphine (1.1 eq), and pthalimide (1.1 eq). The yellow solution was stirred at room temperature overnight and the solution was concentrated. The crude product was directly purified by flash chromatography using a solvent gradient of 97% DCM, 3% MeOH, and 0.1% TEA to yield 2-[4-methyl-4-(4-pyridin-3-yl-imidazol-1-yl)-pentyl]-isoindole-1,3-dione (66%). MH+(375)
EXAMPLE 92(Q)
2-IMIDAZO[4,5-B]PYRIDIN-1-YL-2-METHYL-PROPIONIC ACID ETHYL ESTER (1) AND 2-IMIDAZO[4,5-B]PYRIDIN-3-YL-2-METHYL-PROPIONIC ACID ETHYL ESTER (2)




To a solution of 4-azabenzidimazole (1 eq) in DMF was added potassium carbonate (2 eq) under dry condition. After stirring for 1 hour, ethyl 2-bromoisobutyrate (5 eq) was added to the mixture. The solution was left stirring for 7 days at room temperature. The reaction solvent was removed in vacuo and the solid was diluted with dichloromethane, washed with H2O, NaCl (sat.), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography using a solvent gradient of 98% DCM, 2% MeOH, and 0. 1% TEA to afford 2-imidazo[4,5-b]pyridin-3-yl-2-methyl-propionic acid ethyl ester (1) (33%), and subsequently 2-imidazo[4,5-b]pyridin-1-yl-2-methyl-propionic acid ethyl ester (2) (66%) as the later spot. MH+(234)
EXAMPLE 93
2-IMIDAZO[4,5-B]PYRIDIN-1-YL-2-METHYL-PROPAN-1-OL




To a solution of 2-imidazo[4,5-b]pyridin-1-yl-2-methyl-propionic acid ethyl ester (1 eq) in ethanol was added sodium borohydride (4 eq) at room temperature. The reaction mixture was left stirring at room temperature overnight and then quenched by addition of H2O. Once the reaction solvent was removed in vacuo, the residue was dissolved in dichloromethane, washed with NaCl (sat.), dried over sodium sulfate, filtered, and concentrated to give compound 2-imidazo[4,5-b]pyridin-1-yl-2-methyl-propan-1-ol (92%) MH+(192)
EXAMPLE 94
4-IMIDAZO[4,5-B]PYRIDIN-1-YL-4-METHYL-PENT-2-ENOIC ACID METHYL ESTER




To a −78° C. cooled stirred solution of oxalyl chloride (1 eq) in dichloromethane was added dimethyl sulfoxide (2 eq). After an additional 5 minutes, 2-imidazo[4,5-b]pyridin-1-yl-2-methyl-propan-1-ol (1 eq) dissolved in dichloromethane was added to the cooled solution via cannula. The resulting heterogeneous mixture was stirred at −78° C. for 30 minutes, and triethylamine (5 eq) was added to produce a thick white slurry. After stirring at −78° C. for 15 minutes, the mixture was allowed to warm slowly to 0° C., diluted with dichloromethane, washed with NaCl (sat.), dried over sodium sulfate, filtered, and concentrated. Following this, to a solution of sodium hydride (1 eq) in THF was added methyl diethylphosphonoacetate (1 eq) at 0° C. The mixture was stirred at room temperature for 30 minutes and a solution of the latter concentrated residue dissolved in THF was added dropwise to the mixture. The solution was stirred for 1 hour at the same temperature and then poured into H2O, followed by an extraction with ethyl acetate. The organic layer was washed with NaCl (sat.), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography using a solvent gradient of 97% DCM, 3% MeOH, and 0.1% TEA to yield 4-imidazo[4,5-b]pyridin-1-yl-4-methyl-pent-2-enoic acid methyl ester (93%). MH+(246)
EXAMPLE 95
2-(4-IMIDAZO[4,5-B]PYRIDIN-1-YL-4-METHYL-PENTYL)-ISOINDOLE-1,3-DIONE




To a solution of 4-imidazo[4,5-b]pyridin-1-yl-4-methyl-pent-2-enoic acid methyl ester (1 eq) was added palladium, 10 wt. % on activated carbon, (10%) and left stirring under an atmospheric pressure of hydrogen for 2 days. After the catalyst was filtered off, the mixture was concentrated and dissolved in ethanol. To this solution was added sodium borohydride (4 eq) at room temperature. The reaction mixture was heated in a 50° C. oil bath for 60 minutes and then quenched by addition of H2O. Once the solvent was removed in vacuto, a solution of the residue in dichloromethane was washed with NaCl (sat.), dried over sodium sulfate, filtered, and concentrated. To a solution of the residue in THF was added dropwise diethyl azodicarboxylate (1 eq), triphenyl phosphine (1 eq), and phtalimide (1 eq). The yellow solution was stired at room temperature overnight and the solution was concentrated. The crude solid was treated with 3 N HCl and ethyl acetate. Once the aqueous layer was seperated, it was added to ethyl acetate and treated with sodium bicarbonate under vigorous stirring to obtain an approximate basic pH 7. The organic phase was seperated and washed with NaCl (sat.), dried over sodium sulfate, filtered, and concentrated to give 2-(4-imidazol[4,5-b]pyridin-1-yl-4-methyl-pentyl)-isoindole-1,3-dione (40%). MH+(349)
EXAMPLE 95(A)
2-IMIDAZO[4,5-B]PYRIDIN-3-YL-2-METHYL-PROPAN-1-OL




Reduction performed as in Example 93, to give compound 2-imidazo[4,5-b]pyridin-3-yl-2-methyl-propan-1-ol (A) (16.53 g, 80.7%). MH+(192)
EXAMPLE 95(B)
4-IMIDAZO[4,5-B]PYRIDIN-3-YL-4-METHYL-PENT-2-ENOIC ACID METHYL ESTER




Reaction carried out as in Example 94, to yield 4-imidazo[4,5-b]pyridin-3-yl-4-methyl-pent-2-enoic acid methyl ester (A) (15.8 g, 75%). MH+(246)
EXAMPLE 95(C)
2-(4-IMIDAZO[4,5-B]PYRIDIN-3-YL-4-METHYL-PENTYL)-ISOINDOLE-1,3-DIONE




Protection carried out as in Example 95 to give 2-(4-imidazo[4,5-b]pyridin-3-yl-4-methyl-pentyl)-isoindole-1,3-dione (13.9 g, 77%). MH+(349)
EXAMPLE 95(D)
2-[2-(METHYL-PYRIDIN-3-YL-METHYL-AMINO)-ETHYL]-ISOINDOLE-1,3-DIONE




To a solution of 2-(2-methylamino-ethyl)-isoindole-1,3-dione (1 eq) in dichloromethane was added nicotinaldehyde (1.5 eq), sodium acetoborohydride (4.5 eq) and acetic acid (1.5 eq). After stirring at room temperature for 1 h, NaHCO3 (sat.) was added to the reaction mixture followed by an extraction with dichloromethane. The organic phase was washed with H2O, NaCl (sat.) (50 ml), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography using a solvent gradient of 97% DCM, 3% MeOH, and 0.1% TEA (2L) to yield 2-[2-methyl-pyridin-3-ylmethyl-amino)-ethyl]-isoindole-1,3-dione (57%). MH+(296)
EXAMPLE 95(E)
[3,3′]BIPYRIDINYL-5-COOH ETHYL ESTER




To a solution of 5-bromo-nicotinic acid ethyl ester (1 eq) in THF was added diethyl(3-pyridyl)borane (2 eq), tetrakis(triphenylphosphine)palladium (10%), potassium carbonate (3 eq) and H2O. The solution was left stirring in a 80° C. oil bath for 60 hours. Upon cooling, the reaction was filtered and concentrated. The crude solid was treated with 3 N HCl and ethyl acetate. Once the aqueous layer was seperated, it was added to ethyl acetate and the whole was treated with sodium bicarbonate under vigorous stirring to obtain an approximate basic pH 7. The organic phase was seperated and washed with NaCl (sat.) dried over sodium sulfate, filtered, and concentrated to give [3,3′]bipyridinyl-5-COOH ethyl ester (82%). MH+(229)
EXAMPLE 95(F)
[3,3′]BIPYRIDINYL-5-YL-METHANOL




To a solution of [3,3′]bipyridinyl-5-COOH ethyl ester (1 eq) in ethanol was added sodium borohydride (2 eq) at room temperature. The reaction mixture was heated in a 50° C. oil bath for 60 minutes and then quenched by addition of H2O. Once the reaction solvent was removed in vacuo, a solution of the residue in dichloromethane was washed with NaCl (sat.), dried over sodium sulfate, filtered, and concentrated. The crude solid was purified by flash chromatography using a solvent gradient of 95% DCM, 5% MeOH, and 0.1% TEA to yield [3,3′]bipyridinyl-5-yl-methanol (34%). MH+(187)
EXAMPLE 95(G)
2-[2-(2,3′]BIPYRIDINYL-5-YLMETHYL-METHYL-AMINO)-ETHYL]-ISOINDOLE-1,3-DIONE




Reaction carried out as in Example 95 to yield 2-[2-(2,3′]bipyridinyl-5-ylmethyl-methyl-amino)-ethyl]-isoindole-1,3-dione (A) (48%). MH+(373)
EXAMPLE 96
2-(2-METHYLAMINO-ETHYL)-ISOINDOLE-1,3-DIONE




To the HCl salt of 2-(2-methylamino-ethyl)-isoindole-1,3-dione (1 eq) in dichloromethane was added quinoline-2-carbaldehyde (1.2 eq), sodium triacetoxyborohydride (2 eq), and acetic acid (1.2 eq) at room temperature. The solution was allowed to stir for 16 hours. After concentration, the solution was diluted with ethyl acetate, washed with NaHCO3 (sat.), NaCl (sat.). dried over MgSO4 filtered, concentrated, and pumped on. The yellow oil was then purified using flash chromatography (2% methanol/dichloromethane with 0.1% triethylamine) to yield 2-[2-(methyl-quinolin-2-ylmethyl-amino)-ethyl]-isoindole-1,3-dione as a green solid. MH+(346)
EXAMPLE 96(A)
2-[2-(METHYL-QUINOLIN-2-YLMETHYL-AMINO)-ETHYL]-ISOINDOLE-1,3-DIONE




To 2-[2-(methyl-quinolin-2-ylmethyl-amino)-ethyl]-isoindole-1,3-dione (1 eq) in ethanol was added hydrazine (2 eq). A reflux condenser was attached and the solution was heated 65° C. for 19 hours. The solution was then filtered, concentrated, and co-evaporated from toluene to yield N1-methyl-N1-quinolin-2-ylmethyl-ethane-1,2-diamine in quantitative yield as a dark oil. MH+(216)
EXAMPLE 96(B)
2-(2-METHYLAMINO-ETHYL)-ISOINDOLE-1,3-DIONE




Reaction carried out as in Example 96, to yield 2-[2-(methyl-quinolin-4-ylmethyl-amino)-ethyl]-isoindole-1,3-dione as an off-white solid. MH+(346)
EXAMPLE 96(C)
2-[2-(METHYL-QUINOLIN-4-YLMETHYL-AMINO)-ETHYL]-ISOINDOLE-1,3-DIONE




Deprotection was carried out as in Example 96 to yield N1-methyl-N1-quinolin-4-ylmethyl-ethane-1,2-diamine in quantitative yield as a dark oil. MH+(216)
EXAMPLE 97(A)
QUINOLINES




Step 1: A mixture of N-(3-buten-1-yl)phthalimide (1 eq), 4-chloroquinaldine (1 eq), dicyclohexylmethylamine (1.1 eq), and t-Bu3P (0.200 M solution in 1,4-dioxane) in 1,4-dioxane was degassed for 15 min. Tris(dibenzylidene-acetone)dipalladium(0) (15%) was added. The mixture was stirred at 90° C. for 46 h, cooled to room temperature, and diluted with ethyl acetate. The mixture was filtered through a pad of silica gel, concentrated, and purified by silica gel chromatography (eluting with 1:1 EtOAc:hexanes) to afford quinaldine 309a (63%).
Step 2: A solution of compound 309a (1 eq) in EtOH and 10% Pd/C was stirred under H2 (1.0 atm) for 17 h and filtered through Celite. The filtrate was concentrated to give crude 2 (quantitative yields).
Step 3: The crude material 309b (1 eq) was suspended in EtOH. To this mixture was added hydrazine hydrate (2 eq). The mixture was heated to 90° C. for 5 h, cooled to ambient temperature, and filtered through Celite. The filtrate was concentrated in vacuo to give a residue. To the residue was added 2 N NaOH (aq.) solution, extracted with dichloromethane, washed with brine, dried over Na2SO4 and concentrated in vacuo to yield product 309c as a brown oil (79%). ES/MS m/z 215 (MH+), C14H18N2=214 g/mol.




Amine 310 was synthesized in the same manner as described above. In step 1, 4-chloro-2-trifluoromethylquinoline was used as the starting material. ES/MS m/z 269 (MH+), C14H15F3N2=268.12 g/mol.




Amine 311 was synthesized in the same manner as described above. In step 1, 4-chloro-8-trifluoromethylquinoline was used as the starting material. ES/MS m/z 269 (MH+), C14H15F3N2=268.12 g/mol.
EXAMPLE 97(B)
THIAZOLES (SYNTHESIS OF 312)







Step 1: A mixture of phthalimide (1 eq); triphenylphosphine (1 eq); and 3-butyn-1-ol (1 eq) in THF was cooled to 0° C. A solution of diethylazodicarboxylate (1 eq) in THF was added over 25 min. The solution was stirred for 5 heat ambient temperature and then poured into 1:1 EtOAc:ether. The solution was washed with water then brine then dried over MgSO4, filtered, and concentrated. The solid was purified by silica gel chromatography (eluting with 1:1 DCM:hexanes) followed by recrystallization from EtOAc/hexanes/DCM to give compound 312a.
Step 2: Only degassed solvents were used under anhydrous conditions. A mixture of 312a (1.5 eq), 2,5-dibromothiazole (1 eq), bis(triphenylphosphine)-palladium(II)chloride (3%), and Cul (3%) in 2:1 THF:TEA was stirred at 70° C. for 5 h, cooled to ambient temperature, filtered through a pad of silica gel, concentrated, and purified by silica gel chromatography (eluting with 3:1:1 hexanes:EtOAc:DCM) to afford 312b (55%).
Step 3: Only degassed solvents were used under anhydrous conditions. A mixture of 312b (1 eq), phenylboronic acid (1 eq), and 10% tetrakis(triphenylphosphine)-palladium(0) in 2:1 THF:2 M Na2CO3 (aq.) was stirred at 70° C. for 4 h and then cooled to ambient temperature. Volatiles were removed under reduced pressure. The residue was suspended in DCM, washed sequentially with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated. The crude material was purified by silica gel chromatography (eluting with 2:1:1 hexanes:EtOAc:DCM) to give a 58% yield of 312c and a recovery of 20% of unreacted 312b.
Step 4: A solution of compound 312c (1 eq) in EtOH and 10% Pd/C (412 mg) was stirred under H2 (1.0 atm) for 48 h filtered through Celite and the filtrate was concentrated to give crude 312d (97%).
Step 5: The crude material 312d (obtained from step 4, 1 eq) was suspended in EtOH. To this mixture was added hydrazine hydrate (2 eq). The mixture was heated at 70° C. for 5 h, cooled to ambient temperature and filtered through Celite. The filtrate was concentrated in vacuo to give a residue. The residue was re-suspended in 1:1 EtOAc:DCM, filtered through Celite, and concentrated. The residue was concentrated from toluene and left under high-vacuum for 24 h to yield the desired product (312) as a yellow solid (quantitative yields). ES/MS m/z 233 (MH+), C13H16N2S=232 g/mol.
EXAMPLE 98
PYRIDYL-SUBSTITUTED AMINES
EXAMPLE 98(A)
SYNTHESIS OF 4-IODO-1-TRITYL-1H-IMIDAZOLE




To a solution of 4-iodoimidazole (50 g, 258 mmoles) in DMF (500 ml) was added triethyl amine (37.7 ml, 270.6 mmoles) and than triphenylmethyl chloride (69.7 g, 250 mmoles). After stirring at room temperature for 48 hours, the solution was poured into ice water (2.5 L). The solid was filtered and pumped on for several hours to yield the crude compound. Ethyl ether (200 ml) was added to the crude compound and the solution was filtered to yield 4-iodo-1-trityl-]H-imidazole (104.1, 93%) as a white solid. MH+(437)
EXAMPLE 98(B)
4-[4-(6-METHYL-3-PYRIDYL)IMIDAZOLYL]BUTYLAMINE




A. 5-(1H-imidazol-4-yl)-2-methyl-pyridine. To a solution of 4-iodo-1-trityl-1H-imidazole (15.0 g, 34 mmoles) in THF (150 ml) at room temperature was added ethylmagnesium bromide (41 ml, 40.7 mmoles) under dry conditions. After stirring for 90 minutes, zinc chloride (5.6 g, 40.7 mmoles) was added to the reaction mixture. After stirring for another 90 minutes, tetrakis(triphenylphosphine)palladium (4.0 g, 3.43 mmoles) and 5-bromo-2-methylpyridine (7.0 g, 40.7 mmoles) were added to the reaction mixture. Following that, the reaction mixture was heated in a 70° C. oil bath overnight. Upon cooling, the reaction was diluted with dichloromethane and washed with an EDTA buffer (at approimate pH 9) (2×300 ml), NaCl (sat.) (300 ml), dried over sodium sulfate, filtered, and concentrated. The crude product was dissolved in ethanol (250 ml) and concentrated HCl (13.6 ml) was added to the solution at room temperature. The reaction mixture was heated in a 50° C. oil bath for 2 hours. Upon cooling, the reaction was filtered and washed with ethyl ether (25 ml) to yield 5-(1H-imidazol-4-yl)-2-methyl-pyridine (5.815 g, 63%). MH+(160).




B. 2-[4-(6-Methyl-pyridin-3-yl)-imidazol-1-ylmethyl]-isoindole-1,3-dione. To a solution of 5-(1H-Imidazol-4-yl)-2-methyl-pyridine (2.185 g, 9.46 mmoles) in DMF (20 ml) was added potassium carbonate (6.54 g, 47.3 mmoles) at room temperature under dry conditions. After heating the reaction mixture in an 80° C. oil bath for 1 hour, N-(4-bromobutyl)phthalimide (10.63 g, 37.8 mmoles) was added to the mixture. The solution was left stirring in an 80° C. oil bath for 24 hours. Upon cooling, the reaction was filtered and the solid was washed with ethyl acetate (25 ml). The filtrate was diluted with ethyl acetate and washed with NH4Cl (sat.) (50 ml), H2O (50 ml), NaCl (sat.) (75 ml), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash 40 chromatography using an initial solvent gradient of 99% DCM, 1% MeOH, and 0.1% TEA (1 L), then a solvent gradient of 97% DCM, 3% MeOH, and 0.1% TEA (1 L) to yield 2-[4-(6-methyl-pyridin-3-yl)-imidazol-1-ylmethyl]-isoindole-1,3-dione (1.275 g, 37%). MH+(361)




C. 4-[4-(6-methyl-3-pyridyl)imidazolyl]butylamine. To a solution of 2-[4-(6-methyl-pyridin-3-yl)-imidazol-1-ylmethyl]-isoindole-1,3-dione (1.5 g, 4.17 mmoles) in ethanol (42 ml) was added hydrazine (0.26 ml, 8.33 mmoles). After heating the reaction mixture in a 65° C. oil bath for 15 hours, the solution was cooled, filtered, and concentrated. The resulting oil was taken up in dichloromethane (150 ml) and was washed with 1M NaOH (15 ml). The aqueous layer was extracted further with dichloromethane (2×150 ml), the combined organics were dried over MgSO4, filtered and concentrated yielding 4-[4-(6-methyl-3-pyridyl)imidazolyl]butylamine (917 mg, 95%). MH+(231)
EXAMPLE 98(C)
4-[4-(6-FLUORO-3-PYRIDYL)IMIDAZOLYL]BUTYLAMINE




A. 2-fluoro-5-(1-trityl-1H-imidazol-4-yl)-pyridine. To a solution of 4-iodo-1-trityl-1H-imidazole (10.0 g, 23 mmoles) in THF (100 ml) at room temperature was added ethylmagnesium bromide (28 ml, 27.5 mmoles) under dry conditions. After stirring for 90 minutes, zinc chloride (3.8 g, 27.5 mmoles) was added to the reaction mixture. After stirring for another 90 minutes, tetrakis(triphenylphosphine)palladium (2.6 g, 2.3 mmoles) and 5-bromo-2-fluoropyridine (5.0 g, 27.5 mmoles) were added to the reaction mixture. Following that, the reaction mixture was heated in a 70° C. oil bath overnight. Upon cooling, the reaction was diluted with dichloromethane and washed with an EDTA buffer (at approximate pH 9) (2×300 ml), NaCl (sat.) (300 ml), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash 40 chromatography using an initial solvent gradient of 99.5% DCM, 0.5% MeOH, and 0.1% TEA (1 L), then a solvent gradient of 99% DCM, 1% MeOH, and 0.1% TEA (1 L) to yield 2-fluoro-5-(1-trityl-1H-imidazol-4-yl)-pyridine (6.4 g, 69%). MH+(406)




B. 2-Fluoro-5-(1H-imidazol-4-yl)-pyridine. To a solution of 2-fluoro-5-(1-trityl-1H-imidazol-4-yl)-pyridine (6.4 g, 15.8 mmoles) in ethanol (100 ml) was added concentrated HCl (7 ml) at room temperature. The reaction mixture was heated in a 50° C. oil bath for 90 minutes. Upon cooling, the reaction was concentrated in vacuo to about half the original amount of solvent. Ethyl ether (75 ml) was added to the mixture and the product precipitated slowly. After 90 minutes, the resulting solid 2-fluoro-5-(1H-imidazol-4-yl)-pyridine (1.72 g, 46%) was collected by filtration. MH+(164)




C. 2-14-[4-(6-fluoro-pyridin-3-yl)-imidazol-1-ylmethyl]-butyl)-isoindole-1,3-dione. To a solution of 2-fluoro-5-(1H-imidazol-4-yl)-pyridine (1.72 g, 7.3 mmoles) in DMF (15 ml) was added potassium carbonate (5.0 g, 36.4 mmoles) at room temperature under dry conditions. After heating the reaction mixture in a 80° C. oil bath for 1 hour, N-(4-bromobutyl)phthalimide (8.2 g, 29.2 mmoles) was added to the mixture. The solution was left stirring in an 80° C. oil bath for 24 hours. Upon cooling, the reaction was filtered and the solid was washed with ethyl acetate (25 ml). The filterate was diluted with ethyl acetate and washed with NH4Cl (sat.) (50 ml), H2O (50 ml), NaCl (sat.) (75 ml), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash 40 chromatography using an initial solvent gradient of 99% DCM, 1% MeOH, and 0.1% TEA (1 L), then a solvent gradient of 97% DCM, 3% MeOH, and 0.1% TEA (1 L) to yield 2-{4-[4-(6-fluoro-pyridin-3-yl)-imidazol-1-ylmethyl]-butyl}-isoindole-1,3-dione (1.476 g, 55%). MH+(365)




D. 4-[4-(6-fluoro-3-pyridyl)imidazolyl]butylamine. To a solution of 2-[4-(6-fluoro-pyridin-3-yl)-imidazol-1-ylmethyl]-isoindole-1,3-dione (1.12 g, 3.07 mmoles) in ethanol (31 ml) was added hydrazine (0.2 ml, 6.14 mmoles). After heating the reaction mixture in a 65° C. oil bath for 15 hours, the solution was cooled, filtered and concentrated. The resulting oil was taken up in dichloromethane (150 ml) and was washed with 1M NaOH (15 ml). The aqueous layer was extracted further with dichloromethane (2×150 ml), the combined organics were dried over MgSO4, filtered and concentrated yielding 4-[4-(6-fluoro-3-pyridyl)imidazolyl]butylamine (717 mg, 99%). MH+(235)
EXAMPLE 98(D)
4-[4-(6-METHOXY-3-PYRIDYL)IMIDAZOLYL]BUTYLAMINE




A. 5-imidazol-4-yl-2-methoxypyridine. To a solution of 4-iodo-1-trityl-1H-imidazole (25 g, 57.2 mmoles) in THF (150 ml) at room temperature was added ethylmagnesium bromide (69 ml, 68.7 mmoles) under dry conditions. After stirring for 90 minutes, zinc chloride (9.4 g, 68.6 mmoles) was added to the reaction mixture. After stirring for another 90 minutes, tetrakis(triphenylphosphine)palladium (6.6 g, 5.72 mmoles) and 5-bromo-2-methoxypyridine (8.9 ml, 68.7 mmoles) were added to the reaction mixture. Following that, the reaction mixture was heated in a 70° C. oil bath overnight. Upon cooling, the reaction was diluted with dichloromethane (500 ml) and washed with a 30% NaOH solution containing an added 20 g of EDTA (3×200 ml), with NaCl (sat.) (200 ml), dried over MgSO4, filtered, and concentrated. To the crude material was added dichloromethane (200 ml) and trifluoroactetic acid (40 ml, 410 mmoles). After standing for 6 hours, the reaction was concentrated and pumped on overnight. The crude material was purified by flash chromatography using 0-5% MeOH/CH2Cl2 with 0.1% triethylamine yielding 5-imidazol-4-yl-2-methoxypyridine (7.0 g, 70%). MH+(176)




B. 2-{4-[4-(6-methoxy-pyridin-3-yl)-imidazol-1-yl]-butyl}-isoindole-1,3-dione. To a solution of 5-(1H-imidazol-4-yl)-2-methoxy-pyridine (6.7 g, 38.3 mmoles) in DMF (80 ml) was added potassium carbonate (26.5 g, 192 mmoles) and N-(4-bromobutyl)phthalimide (43.0 g, 153 mmoles) at room temperature under dry conditions. The solution was left stirring at room temperature for 36 hours. The reaction was filtered and the solid was washed with ethyl acetate (25 ml). The filtrate was diluted with ethyl acetate and washed with NH4Cl (sat.) (50 ml), H20 (50 ml), NaCl (sat.) (75 ml), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash 40 chromatography using an initial solvent gradient of 99% DCM, 1% MeOH, and 0.1% TEA (1 L), then a solvent gradient of 97% DCM, 3% MeOH, and 0.1% TEA (1 L) to yield 2-14-[4-(6-methoxy-pyridin-3-yl)-imidazol-1-yl]-butyl)-isoindole-1,3-dione (10.09 g, 70%). MH+(377).




C. 4-[4-(6-methoxy-3-pyridyl)imidazolyl]butylamine. To a solution of 2-[4-(6-methoxy-pyridin-3-yl)-imidazol-1-ylmethyl]-isoindole-1,3-dione (10 g, 26.6 mmoles) in ethanol (265 ml) was added hydrazine (1.67 ml, 53.2 mmoles). After heating the reaction mixture in a 60° C. oil bath for 15 hours, the solution was cooled, filtered and concentrated. The resulting oil was taken up in dichloromethane (400 ml) and was washed with 1M NaOH (50 ml). The aqueous layer was extracted further with dichloromethane (2×400 ml), the combined organics were dried over MgSO4, filtered and concentrated yielding 4-[4-(6-methoxy-3-pyridyl)imidazolyl]butylamine (6.46 g, 98%). MH+(247)
EXAMPLE 98(E)
4-[4-(6-CHLORO-3-PYRIDYL)IMIDAZOLYL]BUTYLAMINE




A. 5-(1H-imidazol-4-yl)-2-chloro-pyridine. To a solution of 4-iodo-1-trityl-1H-imidazole (72.8 g, 166 mmoles) in THF (400 ml) at room temperature was added ethylmagnesium bromide (200 ml, 200 mmoles) under dry conditions. After stirring for 90 minutes, zinc chloride (27.2 g, 200 mmoles) was added to the reaction mixture. After stirring for another 90 minutes, tetrakis(triphenylphosphine)palladium (20 g, 16.6 mmoles) and 5-bromo-2-chloropyridine (38.48 g, 200 mmoles) were added to the reaction mixture. Following that, the reaction mixture was heated in a 70° C. oil bath overnight. Upon cooling, the reaction was diluted with dichloromethane (1 L) and washed with a 30% NaOH solution containing an added 40 g of EDTA (3×400 ml), with NaCl (sat.) (300 ml), dried over MgSO4, filtered, and concentrated. To the crude material was added dichloromethane (600 ml) and trifluoroactetic acid (180 ml). After standing for 1 hour, the reaction was concentrated and pumped on overnight. To the resulting oily tar was added 1M HCl (100 ml) and the mixture was sonicated for 30 minutes and than filtered. The aqueous filtrate was washed with diethyl ether (400 ml). The ether layer was back extracted with 1M HCl (2×20 ml). The combined aqueous layers were washed with diethyl ether (2×200 ml). The aqueous layer was cooled in an ice bath and the pH was adjusted by addition of a 30% NaOH solution until the pH was around 9-10. The resulting solid was filtered, rinsed with cold water (20 ml), rinsed with diethyl ether (20 ml), and pumped on yielding 5-(1H-imidazol-4-yl)-2-chloro-pyridine (12.90 g, 43%). MH+(180)




B. 2-(4-[4-(6-chloro-pyridin-3-yl)-imidazol-1-yl]-butyl)-isoindole-1,3-dione. To a solution of 5-(1H-imidazol-4-yl)-2-chloro-pyridine (15.14 g, 84.1 mmoles) in DMF (336 ml) was added potassium carbonate (58.1 g, 420.6 mmoles) and N-(4-bromobutyl)phthalimide (59.3 g, 210.3 mmoles) at room temperature under dry conditions. The solution was left stirring at room temperature for 48 hours. The reaction was filtered and the resulting clear solution was dumped onto ice (1.5 L). The precipitate was filtered and rinsed with water (2×500 ml) and was pumped on for 1 hour. The material was than rinsed with diethyl ether (15×500 ml) and than was pumped on to yield 2-14-[4-(6-chloro-pyridin-3-yl)-imidazol-1-yl]-butyl)-isoindole-1,3-dione (25.16 g, 78%). MH+(381)




C. 4-[4-(6-chloro-3-pyridyl)imidazolyl]butylamine. To a solution of 2-[4-(6-chloro-pyridin-3-yl)-imidazol-1-ylmethyl]-isoindole-1,3-dione (13.9 g, 36.6 mmoles) in ethanol (365 ml) was added hydrazine (2.3 ml, 73.16 mmoles). After heating the reaction mixture in a 65° C. oil bath for 15 hours, the solution was cooled, filtered, and concentrated. The resulting oil was taken up in dichloromethane (600 ml) and was washed with 1M NaOH (100 ml). The aqueous layer was extracted further with dichloromethane (3×400 ml), the combined organics were dried over MgSO4, filtered, and concentrated yielding 4-[4-(6-chloro-3-pyridyl)imidazolyl]butylamine (7.83 g, 85.6%). MH+(251)
EXAMPLE 98(F)
4-[4-(6-ETHOXY-3-PYRIDYL)IMIDAZOLYL]BUTYLAMINE




To a solution of 4-[4-(6-chloro-3-pyridyl)imidazolyl]butylamine (825 mg, 3.3 mmoles) in ethanol (15 ml) was added sodium ethoxide (2.24 g, 33 mmoles). The reaction mixture was heated in a sealed vessel in a 130° C. oil bath for 48 hours; upon cooling more sodium ethoxide was added (1.0 g) and the closed vessel was heated at 150° C. for 48 hours more. Upon cooling the reaction mixture was concentrated and than was taken up in dichloromethane (200 ml) and was washed with water (50 ml). The aqueous layer was extracted further with dichloromethane (2×200 ml), the combined organics were dried over MgSO4, filtered, and concentrated yielding 4-[4-(6-ethoxy-3-pyridyl)imidazolyl]butylamine (747 mg, 87%). MH+(261)
EXAMPLE 98(G)
{5-[1-(4-AMINOBUTYL)IMIDAZOL-4-YL](2-PYRIDYL)}DIMETHYLAMINE




To a solution of 4-[4-(6-chloro-3-pyridyl)imidazolyl]butylamine (1.0 g, 4.0 mmoles) was added dimethylamine, 5.6 M in ethanol (15 ml, 84 mmoles). The reaction mixture was heated in a sealed vessel in a 150° C. oil bath for 73 hours. Upon cooling the reaction mixture was concentrated and then was taken up in dichloromethane (200 ml) and was washed with 1M NaOH (20 ml). The aqueous layer was extracted further with dichloromethane (2×200 ml), the combined organics were dried over MgSO4, filtered, and concentrated yielding {5-[1-(4-aminobutyl)imidazol-4-yl](2-pyridyl)}dimethylamine (1.04mg, 100%). MH+(260)
EXAMPLE 98(H)
{5-[1-(4-AMINOBUTYL)IMIDAZOL-4-YL](2-PYRIDYL)}METHYLAMINE




To a solution of 4-[4-(6-chloro-3-pyridyl)imidazolyl]butylamine (1.0 g, 4.0 mmoles) was added methylamine, 8.0 M in ethanol (15 ml, 120 mmoles). The reaction mixture was heated in a sealed vessel in a 150° C. oil bath for 73 hours. Upon cooling the reaction mixture was concentrated and then was taken up in dichloromethane (200 ml) and was washed with 1M NaOH (20 ml). The aqueous layer was extracted further with dichloromethane (2×200 ml), the combined organics were dried over MgSO4, filtered, and concentrated yielding {5-[1-(4-aminobutyl)imidazol-4-yl](2-pyridyl)}methylamine (766 mg, 78%). MH+(246)
EXAMPLE 98(I)
4-[4-(6-CHLORO-3-PYRIDYL)IMIDAZOLYL]BUTYLAMINE




A. 4-Chloro-3-(1H-imidazol-4-yl)-pyridine. To a solution of 4-iodo-1-trityl-1H-imidazole (13 g, 30.3 mmoles) in THF (150 ml) at room temperature was added ethylmagnesium bromide (43 ml, 33 mmoles) under dry conditions. After stirring for 90 minutes, zinc chloride (4.5 g, 33 mmoles) was added to the reaction mixture. After stirring for another 90 minutes, tetrakis(triphenylphosphine)palladium (3.5 g, 3 mmoles) and 5-bromo-2-chloropyridine (7.0 g, 36 mmoles) were added to the reaction mixture. Following that, the reaction mixture was heated in a 70° C. oil bath overnight. Upon cooling, the reaction was diluted with dichloromethane and washed with an EDTA buffer (at approximate pH 9) (300 ml), NaCl (sat.) (150 ml), dried over sodium sulfate, filtered, and concentrated. To the crude material in DCM (250 ml) at room temperature was added trifluoroacetic acid (60 ml, 780 mmoles). After stirring for 90 minutes, the excess TFA and DCM were removed in vacuo. The crude product was left under high vacuum pump overnight. To the crude product was added 60 ml of 3 N HCl and the mixture was left in the sonicator for 120 minutes. Once recovered from the sonicator, the mixture was filtered and the aqueous solution was washed with diethyl ether until the organic phase was no more UV active. The aqueous solution was cooled to 0° C. and 30% NaOH solution was added until an approximate pH 7-8 was obtained. The obtained solid product was filtered and dried over night under high vacuum pump to yield 4-chloro-3-(1H-imidazol-4-yl)-pyridine (3.32 g, 61%). MH+(180)




B. 2-{4-[4-(4-chloro-3-pyridyl)imidazolyl]butyl} isoindole-1,3-dione. To a solution of 4-(4-chloro-3-pyridyl)imidazole (3.32 g, 18.54 mmoles) in DMF (74 ml) was added potassium carbonate (12.8 g, 92.7 mmoles) and N-(4-bromobutyl)phthalimide (10.5 g, 37.1 mmoles) at room temperature under dry conditions. The solution was left stirring at room temperature for 96 hours. The reaction was filtered and the resulting clear solution was dumped onto ice (500 ml). The precipitate was filtered and the solid was dissolved in DCM. The organic solution was dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography using a solvent gradient of 0-1-3% MeOH in CH2Cl2 with 0.1% TEA to yield 2-(4-[4-(4-chloro-3-pyridyl)imidazolyl]butyl) isoindole-1,3-dione (2.82 g, 40%). MH+(381)




C. 4-[4-(6-chloro-3-pyridyl)imidazolyl]butylamine. To a solution of 2-[4-(4-chloro-pyridin-3-yl)-imidazol-1-ylmethyl]-isoindole-1,3-dione (2.82 g, 7.42 mmoles) in ethanol (75 ml) was added hydrazine (0.58 ml, 18.6 mmoles). After heating the reaction mixture in a 65° C. oil bath for 15 hours, the solution was cooled, filtered, and concentrated. The resulting oil was taken up in dichloromethane (200 ml) and was washed with 1M NaOH (250 ml). The aqueous layer was extracted further with dichloromethane (2×200 ml), the combined organics were dried over MgSO4, filtered, and concentrated yielding 4-[4-(4-chloro-3-pyridyl)imidazolyl]butylamine (1.74 g, 94%). MH+(251)
EXAMPLE 98(J)
4-[4-(4-METHOXY-3-PYRIDYL)IMIDAZOLYL]BUTYLAMINE




To a solution of 4-[4-(4-chloro-3-pyridyl)imidazolyl]butylamine (400 mg, mmoles) was added sodium methoxide, 5.3 M in methanol (10 ml, 53 mmoles). The reaction mixture was heated at 70° C. for 2 hours. Upon cooling the reaction mixture was concentrated to around 4 ml and then was taken up in dichloromethane (125 ml) and was washed with water (20 ml). The aqueous layer was extracted further with dichloromethane (125 ml), the combined organics were dried over MgSO4, filtered, and concentrated yielding 4-[4-(4-methoxy-3-pyridyl)imidazolyl]butylamine (379 mg, 96%). MH+(247)
EXAMPLE 98(K)
4-[4-(2-CHLORO-3-PYRIDYL)IMIDAZOLYL]BUTYLAMINE




A. 4-(2-chloro-3-pyridyl)imidazole. To a solution of 4-iodo-1-trityl-1H-imidazole (25 g, 57.3 mmoles) in THF (285 ml) at room temperature was added ethylmagnesium bromide (69 ml, 68.8 mmoles) under dry conditions. After stirring for 90 minutes, zinc chloride (9.37 g, 68.8 mmoles) was added to the reaction mixture. After stirring for another 90 minutes, tetrakis(triphenylphosphine)palladium (5 g, 4.3 mmoles) and 3-bromo-2-chloropyridine (13.2 g, 68.8 mmoles) were added to the reaction mixture. Following that, the reaction mixture was heated in a 70° C. oil bath overnight. Upon cooling, the reaction was diluted with dichloromethane (1 L) and washed with a 30% NaOH solution containing an added 40 g of EDTA (3×400 ml), with NaCl (sat.) (300 ml), dried over MgSO4, filtered, and concentrated. To the crude material was added dichloromethane (200 ml) and trifluoroactetic acid (60 ml). After standing for 1 hour, the reaction was concentrated and pumped on overnight. To the resulting oily tar was added 1M HCl (60 ml) and the mixture was sonicated for 30 minutes and than filtered. The aqueous filtrate was washed with diethyl ether (2×100 ml). The aqueous layer was cooled in an ice bath and the pH was adjusted by addition of a 30% NaOH solution until the pH was approximately 9-10. The resulting solid was filtered, rinsed with cold water (20 ml), rinsed with diethyl ether (20 ml), and pumped on yielding 4-(2-chloro-3-pyridyl)imidazole (8.43 g, 82%). MH+(180)




B. 2-{4-[4-(2-chloro-3-pyridyl)imidazolyl]butyl) isoindole-1,3-dione. To a solution of 4-(2-chloro-3-pyridyl)imidazole (8.43 g, 47.1 mmoles) in DMF (188 ml) was added potassium carbonate (32.6 g, 235.5 mmoles) and N-(4-bromobutyl)phthalimide (26.6 g, 94.2 mmoles) at room temperature under dry conditions. The solution was left stirring at room temperature for 72 hours. The reaction was filtered and the resulting clear solution was dumped onto ice (500 ml). The precipitate was filtered and the solid was dissolved in DCM. The organic solution was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography using a solvent gradient of 0-1-3% MeOH in CH2Cl2 with 0.1% TEA to yield 2-{4-[4-(2-chloro-3-pyridyl)imidazolyl]butyl}isoindole-1,3-dione (3.47 g, 19%). MH+(381)




C. 4-[4-(2-chloro-3-pyridyl)imidazolyl]butylamine. To a solution of 2-{4-[4-(2-chloro-3-pyridyl)imidazolyl]butyl}isoindole-1,3-dione (2.0 g, 5.26 mmoles) in ethanol (53 ml) was added hydrazine (0.5 ml, 15.8 mmoles). After heating the reaction mixture in a 80° C. oil bath for 2.5 hours, the solution was cooled, filtered, and concentrated. The resulting oil was taken up in dichloromethane (400 ml) and was washed with 1M NaOH (20 ml). The aqueous layer was extracted further with dichloromethane (2×200 ml), the combined organics were dried over MgSO4, filtered and concentrated yielding 4-[4-(2-chloro-3-pyridyl)imidazolyl]butylamine (1.09 g, 83%). MH+(251)
EXAMPLE 98(L)
4-[4-(6-CHLORO-5-METHYL-3-PYRIDYL)IMIDAZOLYL]BUTYLAMINE




A. 4-(6-chloro-5-methyl-3-pyridyl)imidazole. To a solution of 4-iodo-1-trityl-1H-imidazole (25 g, 57.3 mmoles) in THF (250 ml) at room temperature was added ethylmagnesium bromide (69 ml, 69 mmoles) under dry conditions. After stirring for 90 minutes, zinc chloride (9.4 g, 68.6 mmoles) was added to the reaction mixture. After stirring for another 90 minutes, tetrakis(triphenylphosphine)palladium (6.6 g, 5.72 mmoles) and 5-bromo-3-methyl-2-chloropyridine (14.2 g, 68.6 mmoles) were added to the reaction mixture. Following that, the reaction mixture was heated in a 70° C. oil bath overnight. Upon cooling, the reaction was diluted with dichloromethane and washed with an EDTA buffer (at approximate pH 9) (300 ml), NaCl (sat.) (150 ml), dried over sodium sulfate, filtered, and concentrated. To the crude material in DCM (250 ml) at room temperature was added trifluoroacetic acid (115 ml, 1.5 moles). After stirring for 90 minutes, the excess TFA and DCM were removed in vacuo. The crude product was left under high vacuum pump overnight. To the crude product was added 60 ml of 3 N HCl and the mixture was left in the sonicator for 120 minutes. Once recovered from the sonicator, the mixture was filtered and the aqueous solution was washed with diethyl ether until the organic phase was no more UV active. The aqueous solution was cooled to 0° C. and 30% NaOH solution was added until an approximate pH 7-8 was obtained. The obtained solid product was filtered and dried over night under high vacuum pump to yield 2-chloro-5-(1H-imidazol-4-yl)-3-methyl-pyridine (8.156 g, 74%). MH+(194)




B. 2-{4-[4-(6-Chloro-5-methyl-pyridin-3-yl)-imidazol-1-yl]-butyl}-isoindole-1,3-dione. To a solution of 2-chloro-5-(1H-imidazol-4-yl)-3-methyl-pyridine (8.2 g, 42.3 mmoles) in DMF (80 ml) was added potassium carbonate (29 g, 212 mmoles) and N-(4-bromobutyl)phthalimide (30 g, 106 mmoles) at room temperature under dry conditions. The solution was left stirring at room temperature overnight. The reaction was filtered and the resulting clear solution was dumped onto ice (1 L). The precipitate was filtered and the solid was dissolved in DCM. The organic solution was dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography using first a solvent gradient of 99% DCM, 1% MeOH, and 0.1% TEA, then 97% DCM, 3% MeOH, and 0.1% TEA to yield 2-14-[4-(6-chloro-5-methyl-pyridin-3-yl)-imidazol-1-yl]-butyl)-isoindole-1,3-dione (4.0 g, 27%). MH+(395)




C. 4-[4-(6-chloro-5-methyl-3-pyridyl)imidazolyl]butylamine. To a solution of 2-{4-[4-(6-chloro-5-methyl-pyridin-3-yl)-imidazol-1-yl]-butyl}-isoindole-1,3-dione (3.97 g, 10.07 mmoles) in ethanol (100 ml) was added hydrazine (0.95 ml, 30.22 mmoles). After heating the reaction mixture in a 80° C. oil bath for 3 hours, the solution was cooled, filtered, and concentrated. The resulting oil was taken up in dichloromethane (400 ml) and was washed with 1M NaOH (20 ml). The aqueous layer was extracted further with dichloromethane (3×200 ml), the combined organics were dried over MgSO4, filtered, and concentrated yielding 4-[4-(6-chloro-5-methyl-3-pyridyl)imidazolyl]butylamine (2.14 g, 86%). MH+(265)
EXAMPLE 98(M)
4-[4-(6-CHLORO(3-PYRIDYL))-5-METHYLIMIDAZOLYL]BUTYLAMINE




A. 2-Chloro-5-(5-methyl-1H-imidazol-4-yl)-pyridine. To a solution of 4-iodo-5-methyl-1-trityl-1H-imidazole (25.0 g, 56 mmoles) in THF (250 ml) at room temperature was added ethylmagnesium bromide (61 ml, 61 mmoles) under dry conditions. After stirring for 90 minutes, zinc chloride (8.3 g, 6 mmoles) was added to the reaction mixture. After stirring for another 90 minutes, tetrakis(triphenylphosphine)palladium (6.0 g, 61 mmoles) and 5-bromo-2-chloropyridine (12.8 g, 66.7 mmoles) were added to the reaction mixture. Following that, the reaction mixture was heated in a 70° C. oil bath overnight. Upon cooling, the reaction was filtered and the filtrate was diluted with dichloromethane (500 ml) and washed with an EDTA buffer (at approximate pH 9) (300 ml), NaCl (sat.) (300 ml), dried over sodium sulfate, filtered, and concentrated. To a solution of crude 2-chloro-5-(5-methyl-1-trityl-1H-imidazol-4-yl)-pyridine (24 g, 55.6 mmoles) in DCM (250 ml) at room temperature was added trifluoroacetic acid (60 ml, 780 moles). After stirring for 90 minutes, the excess TFA and DCM were removed in vacuo. The crude product was left under high vacuum pump overnight. To the crude product was added 60 ml of 3N HCl and the mixture was left in the sonicator for 120 minutes. Once recovered from the sonicator, the mixture was filtered and the aqueous solution was washed with diethyl ether until the organic phase was no more UV active. The aqueous solution was cooled to 0° C. and 30% NaOH solution was added until an approximate pH 7-8 was obtained. The obtained solid product was filtered and dried over night under high vacuum pump to yield 2-chloro-5-(5-methyl-1H-imidazol-4-yl)-pyridine (5.56 g, 52%). MH+(194)




B. 2-{4-[4-(6-chloro(3-pyridyl))-5-methylimidazolyl]butyl}-isoindole-1,3-dione. To a solution of 4-(6-chloro(3-pyridyl))-5-methylimidazole (2.22 g, 11.44 mmoles) in DMF (45 ml) was added potassium carbonate (7.9 g, 57.2 mmoles) and N-(4-bromobutyl)phthalimide (6.5 g, 22.9 mmoles) at room temperature under dry conditions. The solution was left stirring at room temperature for 48 hours. The reaction was filtered and the resulting clear solution was dumped onto ice (300 ml). The precipitate was filtered and the solid was dissolved in DCM. The organic solution was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography using first a solvent gradient of 99% DCM, 1% MeOH, and 0.1% TEA, then 97% DCM, 3% MeOH, and 0.1% TEA to yield 2-{4-[4-(6-chloro(3-pyridyl))-5-methylimidazolyl]butyl}-isoindole-1,3-dione (415 mg, 9%). MH+(396)




C. 4-[4-(6-chloro(3-pyridyl))-5-methylimidazolyl]butylamine. To a solution of 2-{4-[4-(6-chloro(3-pyridyl))-5-methylimidazolyl]butyl}isoindole-1,3-dione (405 g, 1.05 mmoles) in ethanol (10 ml) was added hydrazine (0.14 ml, 4.2 mmoles). After heating the reaction mixture in a 65° C. oil bath for 15 hours, the solution was cooled, filtered, and concentrated. The resulting oil was taken up in dichloromethane (100 ml) and was washed with 1M NaOH (5 ml). The aqueous layer was extracted further with dichloromethane (3×100 ml), the combined organics were dried over MgSO4, filtered, and concentrated yielding 4-[4-(6-chloro(3-pyridyl))-5-methylimidazolyl]butylamine (214 mg, 76%). MH+(266)
EXAMPLE 98(N)
4-[4-(6-METHOXY(3-PYRIDYL))-5-METHYLIMIDAZOLYL]BUTYLAMINE




A. 2-methoxy-5-(5-methylimidazol-4-yl)pyridine. To a solution of 4-iodo-5-methyl-1-trityl-1H-imidazole (25.0 g, 56 mmoles) in THF (250 ml) at room temperature was added ethylmagnesium bromide (61 ml, 61 mmoles) under dry conditions. After stirring for 90 minutes, zinc chloride (8.3 g, 6 mmoles) was added to the reaction mixture. After stirring for another 90 minutes, tetrakis(triphenylphosphine)palladium (6.0 g, 61 mmoles) and 5-bromo-2-methoxypyridine (8.62 ml, 66.7 mmoles) were added to the reaction mixture. Following that, the reaction mixture was heated in a 65° C. oil bath overnight. Upon cooling, the reaction was diluted with dichloromethane (1 L) and washed with a 30% NaOH+10% EDTA solution (3×200 ml), washed with NaCl (sat.) (300 ml), dried over sodium sulfate, filtered, and concentrated. To the crude material (16.1 g) in dichloromethane (250 ml) at room temperature was added trifluoroacetic acid (27.8 ml, 373.3 moles). After stirring for 24 hours, the excess TFA and DCM were removed in vacuo. The crude product was left under high vacuum pump overnight. To the crude product was added 60 ml of 3 N HCl and the mixture was sonicated for 120 minutes. Once recovered from the sonicator, the mixture was filtered and the aqueous solution was washed with diethyl ether until the organic phase was no longer UV active. The aqueous solution was cooled to 0° C. and 30% NaOH solution was added until an approximate pH 7-8 was obtained. The obtained solid product was filtered and dried over night under high vacuum pump to yield 2-methoxy-5-(5-methylimidazol-4-yl)pyridine (3.9 g, 55%). MH+(190)




B. 2-{4-[4-(6-methoxy(3-pyridyl))-5-methylimidazolyl]butyl}-isoindole-1,3-dione. To a solution of sodium hydride, 60% dispersion (1.8 g, 44.75 mmoles) in DMF (9 ml) at 0° C. was added a solution of 2-methoxy-5-(5-methylimidazol-4-yl)pyridine (3.4 g, 17.9+mmoles) in DMF (18 ml) dropwise. A solution of N-(4-bromobutyl)phthalimide (7.6 g, 26.9 mmoles) in DMF (12 ml) was than added. The reaction was held at 0° C. for 22 hours, at which time it was dumped onto ice (400 g). The precipitate was filtered and the solid was dissolved in DCM. The organic solution was dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography using a solvent gradient of 0-1-3% MeOH in CH2Cl2 with 0.1% TEA to yield 2-{4-[4-(6-methoxy(3-pyridyl))-5-methylimidazolyl]butyl-isoindole-1,3-dione (1.6 g, 24%). MH+(391)




C. 4-[4-(6-methoxy(3-pyridyl))-5-methylimidazolyl]butylamine. To a solution of 2-{4-[4-(6-methoxy(3-pyridyl))-5-methylimidazolyl]butyl}isoindole-1,3-dione (664 mg, 1.7 mmoles) in ethanol (17 ml) was added hydrazine (0.16 ml, 5.1 mmoles). After heating the reaction mixture in a 80° C. oil bath for 3 hours, the solution was cooled, filtered, and concentrated. The resulting oil was taken up in dichloromethane (100 ml) and was washed with 1M NaOH (15 ml). The aqueous layer was extracted further with dichloromethane (2×100ml), the combined organics were dried over MgSO4, filtered, and concentrated yielding 4-[4-(6-4-[4-(6-methoxy(3-pyridyl))-5-methylimidazolyl]butylamine (287 mg, 65%). MH+(261)
EXAMPLE 98(N)
4-[4-(6-METHOXY(3-PYRIDYL))-2-METHYLIMIDAZOLYL]BUTYLAMINE




A. 2-methoxy-5-(2-methylimidazol-4-yl)pyridine. To a solution of 4-iodo-2-methyl-1-trityl-1H-imidazole (31.5 g, 70 mmoles) in THF (300 ml) at room temperature was added ethylmagnesium bromide (84 ml, 84 mmoles) under dry conditions. After stirring for 90 minutes, zinc chloride (11.44 g, 84 mmoles) was added to the reaction mixture. After stirring for another 90 minutes, tetrakis(triphenylphosphine)palladium (8.1 g, 7.0 mmoles) and 5-bromo-2-methoxypyridine (10.9 ml, 84 mmoles) were added to the reaction mixture. Following that, the reaction mixture was heated in a 65° C. oil bath overnight. Upon cooling, the reaction was diluted with dichloromethane (1 L) and washed with a 30% NaOH+10% EDTA solution (3×200 ml), washed with NaCl (sat.) (300 ml), dried over sodium sulfate, filtered, and concentrated. To the crude material in dichloromethane (250 ml) at room temperature was added trifluoroacetic acid (27.8 ml, 373.3 moles). After stirring for 24 hours, the excess TFA and DCM were removed in vacuo. The crude product was left under high vacuum pump overnight. To the crude product was added 60 ml of 3N HCl and the mixture was sonicated for 120 minutes. Once recovered from the sonicator, the mixture was filtered and the aqueous solution was washed with diethyl ether until the organic phase was no longer UV active. The aqueous solution was cooled to 0° C. and 30% NaOH solution was added until an approximate pH 7-8 was obtained. The obtained solid product was filtered and dried over night under high vacuum pump to yield 2-methoxy-5-(2-methylimidazol-4-yl)pyridine (5.0 g, 38%). MH+(190)




B. 2-{4-[4-(6-methoxy(3-pyridyl))-2-methylimidazolyl]butyl}-isoindole-1,3-dione. To a solution of 2-methoxy-5-(2-methylimidazol-4-yl)pyridine (5.0 g, 26.4 mmoles) in DMF (100 ml) was added potassium carbonate (18.3 g, 132 mmoles) and N-(4-bromobutyl)phthalimide (8.97 g, 31.7 mmoles) at room temperature under dry conditions. The solution was left stirring at room temperature for 72 hours. The reaction was filtered and the resulting clear solution was dumped onto ice (1 L). The precipitate was filtered and rinsed with water (2×200 ml) and was pumped on for 1 hour. The material was than rinsed with diethyl ether (7×200 ml) and than was pumped on to yield to yield 2-14-[4-(6-methoxy(3-pyridyl))-2-methylimidazolyl]butyl}-isoindole-1,3-dione (4.1 g, 48%). MH+(391)




C. 4-[4-(6-methoxy(3-pyridyl))-2-methylimidazolyl]butylamine. To a solution of 2-{4-[4-(6-methoxy(3-pyridyl))-2-methylimidazolyl]butyl}-isoindole-1,3-dione (900 mg, 2.3 mmoles) in ethanol (23 ml) was added hydrazine (0.22 ml, 6.9 mmoles). After heating the reaction mixture in a 80° C. oil bath for 3 hours, the solution was cooled, filtered, and concentrated. The resulting oil was taken up in dichloromethane (100 ml) and was washed with 1M NaOH (15 ml). The aqueous layer was extracted further with dichloromethane (2×100 ml), the combined organics were dried over MgSO4, filtered, and concentrated yielding 4-[4-(6-methoxy(3-pyridyl))-2-methylimidazolyl]butylamine (600 mg, 100%). MH+(261)
EXAMPLE 98(P)
4-[4-(6-CHLORO(3-PYRIDYL))-2-METHYLIMIDAZOLYL]BUTYLAMINE




A. 2-chloro-5-(2-methylimidazol-4-yl)pyridine. To a solution of 4-iodo-2-methyl-1-trityl-1H-imidazole (25.9 g, 57.6 mmoles) in THF (20 ml) at room temperature was added ethylmagnesium bromide (69 ml, 69 mmoles) under dry conditions. After stirring for 90 minutes, zinc chloride (9.4 g, 69 mmoles) was added to the reaction mixture. After stirring for another 90 minutes, tetrakis(triphenylphosphine)palladium (6.66 g, 5.76 mmoles) and 5-bromo-2-chloropyridine (13.3 g, 69.0 mmoles) were added to the reaction mixture. Following that, the reaction mixture was heated in a 65° C. oil bath overnight. Upon cooling, the reaction was diluted with dichloromethane (1 L) and washed with a 30% NaOH+10% EDTA solution (3×200 ml), washed with NaCl (sat.) (300 ml), dried over sodium sulfate, filtered and concentrated. To the crude material (16.1 g) in dichloromethane (250 ml) at room temperature was added trifluoroacetic acid (27.8 ml, 373.3 mmoles). After stirring for 24 hours, the excess TFA and DCM were removed in vacuo. The crude product was left under high vacuum pump overnight. To the crude product was added 60 ml of 3N HCl and the mixture was sonicated for 120 minutes. Once recovered from the sonicator, the mixture was filtered and the aqueous solution was washed with diethyl ether until the organic phase was no longer UV active. The aqueous solution was cooled to 0° C. and 30% NaOH solution was added until an approximate pH 7-8 was obtained. The obtained solid product was filtered and dried over night under high vacuum pump to yield 2-chloro-5-(2-methylimidazol-4-yl)pyridine (3.5 g, 31%). MH+(194)




B. 2-{4-[4-(6-chloro(3-pyridyl))-2-methylimidazolyl]butyl}-isoindole-1,3-dione. To a solution of 2-chloro-5-(2-methylimidazol-4-yl)pyridine (3.5 g, 18 mmoles) in DMF (50 ml) was added potassium carbonate (12.4 g, 90 mmoles) and N-(4-bromobutyl)phthalimide (15.4 g, 54 mmoles) at room temperature under dry conditions. The solution was left stirring at room temperature for 48 hours. The reaction was filtered and the resulting clear solution was dumped onto ice (0.5 L). The precipitate was filtered and rinsed with water (2×200 ml) and was pumped on for I hour. The crude product was rinsed with diethyl ether(4×200 ml) and was purified than by flash chromatography using a solvent gradient of 0-1-3% MeOH in CH2Cl2 with 0.1% TEA to yield 2-{4-[4-(6-chloro(3-pyridyl))-2-methylimidazolyl]butyl}-isoindole-1,3-dione (4.3 g, 61%). MH+(395)




C. 4-[4-(6-chloro(3-pyridyl))-2-methylimidazolyl]butylamine. To a solution of 2-{4-[4-(6-chloro(3-pyridyl))-2-methylimidazolyl]butyl}-isoindole-1,3-dione (1.0 g, 2.54 mmoles) in ethanol (25 ml) was added hydrazine (0.24 ml, 7.6 mmoles). After heating the reaction mixture in a 80° C. oil bath for 3 hours, the solution was cooled, filtered, and concentrated. The resulting oil was taken up in dichloromethane (100 ml) and was washed with 1M NaOH (15 ml). The aqueous layer was extracted further with dichloromethane (2×100 ml), the combined organics were dried over MgSO4, filtered, and concentrated yielding 4-[4-(6-4-[4-(6-chloro(3-pyridyl))-5-methylimidazolyl]butylamine (500 mg, 75%). MH+(265).
EXAMPLE 99
C12 ALKYNE KETOLIDE ENONE-OL




The C12 formyl ketolide (synthesis described in PCT WO 03/004509 A2, the disclosure of which is incorporated herein by reference) (3.87 g, 5.63 mmoles, 1.00 eq) was added to a 0° C. solution of Seyferth-Gilbert reagent, (MeO)2PC(O)CHN2, (1.01 g, 6.75 mmoles, 1.20 eq) in dry MeOH (50 ml). Potassium carbonate (1.55 g, 11.2 mmoles, 2.00 eq) was added. The solution was stiffed at 0° C. for 1.5 h and then brought up to ambient temperature for 1 h. The reaction mixture was poured into EtOAc (200 ml) and washed sequentially with water and brine (40 ml each). The organic layer was dried over MgSO4, filtered, and concentrated. Column chromatography (4:1 hexanes:acetone+1% Et3N) gave the desired C12 alkyne (2.30 g, 59.8%) and some recovered starting material. MH+(684).
EXAMPLE 100
C12 ALKYNE IMIDAZOLYL CARBAMATE KETOLIDE ENONE




A 0.2M solution of C12 alkyne ketolide enone-C12-ol (1.50 g, 2.19 mmol, 1.00 eq) and 1,1-carbonyldiimidazole (719 mg, 4.39 mmol, 2.00 eq) in tetrahydrofuran (11 ml) is cooled to −15° C. Sodium hydride (60% dispersion in mineral oil, 105 mg, 2.63 mmol, 1.2 eq) is added. The mixture is stirred at −15° C. for 15 min and at ambient temperature for an additional 45 min. The reaction is diluted with ethyl acetate (100 ml) and quenched with saturated aqueous sodium bicarbonate (20 ml). The layers are separated. The organic layer is washed with water (2×20 ml) and brine (20 ml), dried over sodium sulfate, filtered, and concentrated. The crude imidazolyl carbamate was used without further purification.
EXAMPLE 101
Synthesis of Compound XIII




Procedure A: A 0.25M solution of C12 ethyl imidazolyl carbamate ketolide (1 equivalent)—(synthesis described in PCT WO 03/004509 A2, the disclosure of which is incorporated herein by reference)— and 4-[4-(6-Methyl-pyridin-3-yl)-imidazol-1-yl]-butylamine (2.0 eq) in 10:1 acetonitrile:water was heated in a 65° C. oil bath for 12 hours. Upon cooling the reaction was diluted with ethyl acetate and washed with NaHCO3 (sat.) (3×), NaCl (sat.) (1×), dried over MgSO4, filtered, and concentrated. A 0.05 M solution of the crude material in methanol was heated at 65° C. for 16 hours. Upon concentrating, the material was purified by RP HPLC and/or silica chromatography and a white solid was obtained (31% yield). MH+(840.05)
EXAMPLE 102
Synthesis of Compound XIV




C12 ethyl, C9, C10, C11 enone, C3 oxo, C12 OCOIm ketolide (811 mg, 1.04 mmoles) was added to 4-[4-(6-methyl-pyridin-3-yl)-imidazol-1-yl]-butylamine (716 mg, 3.11 mmoles); acetonitrile (3 ml) and water (0.3 ml) were added. The solution was heated at 65° C. for 17 hours. Upon cooling the reaction was diluted with ethyl acetate (400 ml) and washed with NaHCO3 (sat.) (2×100 ml), NaCl (sat.) (100 ml), dried over MgSO4, filtered, and concentrated. To the crude material (615 mg) was added dichloromethane (5 ml), benzoic anhydride (300 mg), triethylamine (0.3 ml), and dimethylaminopyridine (2 mg). After standing for 18 hours the solution was concentrated and purified by RP HPLC. The combined product fractions coming off the HPLC were diluted with ethyl acetate (650 ml) and NaHCO3 (10 g) was added. After mixing, the aqueous layer was separated and the organic layer was washed with NaCl (sat.) (150 ml), dried over MgSO4, filtered, and concentrated, yielding benzoylated XIII (470 mg, 48% yield) as a white solid. To benzoylated XIII (265 mg, 0.28 mmoles) in DMF (4 ml) at 0° C. was added 60% NaH (22.5 mg, 0.56 mmoles). After stirring for 1 hour at 0° C., N-fluorobenzenesulfonimide (93 mg, 0.296 mmoles) were added. After stirring for an additional hour at 0° C., the solution was diluted with ethyl acetate (10 ml) and NaHCO3 (sat.) (1 ml) was added cautiously to quench. The reaction was then added to ethyl acetate (200 ml) and was washed with NaHCO3 (sat.) (2×50 ml), NaCl (sat.) (50 ml), dried over MgSO4, filtered, concentrated, and purified by RP HPLC. The combined product fractions coming off the HPLC were diluted with ethyl acetate (300 ml) and NaHCO3 (10 g) was added. The aqueous layer was separated and the organic layer was washed with NaCl (sat.) (100 ml), dried over MgSO4, filtered, and concentrated. Methanol (10 ml) was added and the solution was heated at 60° C. for 15 hours. Upon concentrating, the material was purified by RP HPLC. The combined product fractions coming off the HPLC were diluted with ethyl acetate (350 ml) and NaHCO3 (10 g) was added. The aqueous layer was separated and the organic layer was washed with NaCl (sat.) (100 ml), dried over MgSO4, filtered, concentrated, lyophilized from MeCN:H2O, and obtained (148 mg, 61% yield) a white solid.
EXAMPLE 103
Synthesis of Compound XV




Following Procedure A using the C12 ethyl imidazolyl carbamate ketolide and 4-[4-(6-fluoro-pyridin-3-yl)-imidazol-1-yl]-butylamine, a white solid was obtained (27% yield). MH+(844.02). 1H NMR (CDC13, referenced at 7.26 ppm on 300 MHz NMR, J=coupling constants in Hertz) 8.55(1H, d, J=2.1), 8.18(1H, td, J=8.4, 2.4), 7.52(1H,s) 7.28(1H,d, J=1.2), 6.94(1H, dd, J=8.4, 2.4), 4.93(1H,dd, J=11.1, 2.4), 4.32(1H, d, J=7.2), 4.24(1H, d, J=8.7), 4.0 (1H,t, J=7.2), 3.85(1H,q, J=6.6), 3.53-3.78(3H, m), 3.67(1H,s), 3.32(1H,dd, J=9.9, 7.2), 3.2(1H, q, J=6.6), 3.0-3.1(1H, m), 2.74-2.84(1H, m), 2.60(3H,s), 2.53-2.58(1H, m), 2.51(6H,s), 1.47-2.10(14H, m), 1.35(3H, d, J=6.6), 1.23-1.32(12H, m), 1.17(3H,d, J=6.9), 1.01(3H,d, J=6.9), 0.83(3H,t, J=7.5).
EXAMPLE 104 
Synthesis of Compound XVI




Following Procedure A using the C12 vinyl imidazolyl carbamate ketolide (synthesis described in PCT WO 03/004509 A2, the disclosure of which is incorporated herein by reference) and 4-[4-(6-methyl-pyridin-3-yl)-imidazol-1-yl]-butylamine, a white solid was obtained (39% yield). MH+(838.05). 1H NMR (CDCl3, referenced at 7.26 ppm on 300 MHz NMR, J=coupling constants in Hertz) 8.83(1H, d, J=1.8), 7.97(1H, dd, J=7.8, 2.1), 7.53(1H,d, J=1.2) 7.27(1H,d, J=1.2), 7.15(1H, d, J=8.1), 5.95(1H, dd, J=16.8, 10.8), 5.71(1H, dd, J=17.1, 1.5), 5.55(1H, dd, J=11.1,1.5), 4.95(1H,dd, J=10.5, 2.4), 4.28(1H, d, J=7.2), 4.23(1H, d, J=9.0), 4.0 (2H,t, J=7.2), 3.89(1H,q, J=6.9), 3.62-3.78(2H, m), 3.71(1H,s), 3.5-3.62(1H,m), 3.22(1H,dd, J=9.9, 7.2), 3.06-3.16(2H,m), 2.61(3H,s), 2.55-2.58(1H, m) 2.55(3H,s), 2.35(6H,s), 1.54-1.93(12H, m), 1.36(3H, d, J=6.9), 1.33 (3H,s), 1.31(3H, d, J=7.5), 1.25(3H, s, J=6.3), 1.10(3H,d, J=6.9), 0.84(3H,d, J=6.9), 0.79(3H,t, J=7.2).
EXAMPLE 105
Synthesis of Compound XVII




Following Procedure A using the C12 ethyl imidazolyl carbamate ketolide and 4-[4-(6-methoxy-pyridin-3-yl)-imidazol-1-yl]-butylamine, a white solid was obtained (33% yield). MH+(856.06)
EXAMPLE 106
Synthesis of Compound XVIII




Following Procedure A using the C12 vinyl imidazolyl carbamate ketolide and 4-[4-(6-methoxy-pyridin-3-yl)-imidazol-1-yl]-butylamine, a white solid was obtained (36% yield). MH+(854.05). 1H NMR (CDCl3, referenced at 7.26 ppm on 300 MHz NMR, J=coupling constants in Hertz) 8.51(1H, d, J=3.0), 7.97(1H, dd, J=8.7, 3.3), 7.51(1H,d, J=0.9) 7.18(1H,d, J=1.2), 6.75(1H, d, J=8.4), 5.95(1H, dd, J=16.8, 10.8), 5.71(1H, dd, J=17.1, 1.5), 5.55(1H, dd, J=11.1,1.5), 4.95(1H,dd, J=10.5, 2.4), 4.28(1H, d, J=7.2), 4.23(1H, d, J=9.0), 4.0 (1H,t, J=7.2), 3.95(3H,s), 3.89(1H,q, J=6.9), 3.62-3.78(2H, m), 3.71 (1H,s), 3.5-3.62(1H,m), 3.22(1H,dd, J=9.9, 7.2), 3.06-3.16(2H, m), 2.61(3H,s), 2.50-2.58(1H,m), 2.32(6H,s), 1.54-1.93(12H, m), 1.36(3H, d, J=6.9), 1.33 (3H,s), 1.31(3H, d, J=7.8), 1.25(3H, s, J=6.0), 1.10(3H,d, J=7.2), 0.84(3H,d, J=6.9), 0.79(3H,t, J=7.5).
EXAMPLE 107 
Synthesis of Compound XIX




Following Procedure A using the C12 vinyl imidazolyl carbamate ketolide and 4-[4-(6-fluoro-pyridin-3-yl)-imidazol-1-yl]-butylamine, a white solid was obtained (38% yield). MH+(842.01). 1H NMR (CDCl3, referenced at 7.26 ppm on 300 MHz NMR, J=coupling constants in Hertz) 8.55(1H, d, J=2.4), 8.18(1H, td, J=8.4, 2.4), 7.53(1H,d, J=1.2) 7.30(1H,d, J=1.2), 6.94(1H, dd, J=8.4, 2.4), 5.95(1H, dd, J=17.4, 11.1), 5.71(1H, dd, J=17.4, 1.5), 5.55(1H, dd, J=11.1,1.5), 4.95(1H,dd, J=10.8, 2.4), 4.28(1H, d, J=7.2), 4.23(1H, d, J=9.0), 4.0 (1H,t, J=7.2), 3.89(1H,q, J=6.9), 3.62-3.78(2H, m), 3.71(1H,s), 3.5-3.62(1H,m), 3.22(1H,dd, J=10.2, 7.2), 3.06-3.16(2H, m), 2.60(3H,s), 2.50-2.58(1H, m), 2.33(6H,s), 1.42-1.93(12H, m), 1.36(3H, d, J=6.6), 1.33 (3H,s), 1.31(3H, d, J=7.8), 1.25(3H, s, J=6.3), 1.10(3H,d, J=7.2), 0.84(3H,d, J=6.9), 0.78(3H,t, J=7.5).
EXAMPLE 108
Synthesis of Compound XX




Following Procedure A using the C12 vinyl imidazolyl carbamate ketolide and 4-[4-(6-chloro-pyridin-3-yl)-imidazol-1-yl]-butylamine, a white solid was obtained (37% yield). MH+(858.47). 1H NMR (CDCl3, referenced at 7.26 ppm on 300 MHz NMR, J=coupling constants in Hertz) 8.73(1H, d, J=2.1), 8.06(1H, dd, J=8.1, 2.4), 7.54(1H,s) 7.34(1H,d, J=0.9), 7.32(1H, d, J=8.4), 5.95(1H, dd, J=16.8, 10.8), 5.71(1H, dd, J=17.1, 1.5), 5.55(1H, dd, J=11.1,1.5), 4.94(1H,dd, J=10.5, 2.4), 4.28(1H, d, J=7.2), 4.23(1H, d, J=9.0), 4.0 (1H,t, J=7.2), 3.89(1H,q, J=6.9), 3.62-3.78(2H, m), 3.71(1H,s), 3.5-3.62(1H,m), 3.22(1H,dd, J=10.2, 7.2), 3.06-3.16(2H, m), 2.60(3H,s), 2.50-2.58(1H, m), 2.27(6H,s), 1.42-1.93(12H, m), 1.36(3H, d, J=6.9), 1.33 (3H,s), 1.31(3H, d, J=7.8), 1.25(3H, s, J=6.0), 1.10(3H,d, J=7.2), 0.84(3H,d, J=6.9), 0.78(3H,t, J=7.5).
EXAMPLE 109
Synthesis of Compound XXI




Following Procedure A using the C12 ethyl imidazolyl carbamate ketolide and 4-[4-(6-chloro-pyridin-3-yl)-imidazol-1-yl]-butylamine, a white solid was obtained (14% yield). MH+(860.40)
EXAMPLE 110
Synthesis of Compound XXII




Following Procedure A using the C12 vinyl imidazolyl carbamate ketolide and 4-[4-(6-ethoxy-pyridin-3-yl)-imidazol-1-yl]-butylamine, a white solid was obtained (32% yield). MH+(868.08)
EXAMPLE 111
Synthesis of Compound XXIII




Following Procedure A using the C12 vinyl imidazolyl carbamate ketolide and {5-[1-(4-aminobutyl)imidazol-4-yl](2-pyridyl)}methylamine, a white solid was obtained (37% yield). MH+(853.06). 1H NMR (CDCl3, referenced at 7.26 ppm on 300 MHz NMR, J=coupling constants in Hertz) 8.46(1H, d, J=2.1), 7.87(1H, dd, J=8.7, 2.4), 7.48(1H,d, J=0.9) 7.10(1H,d, J=1.2), 6.43(1H, d, J=8.4), 5.95(1H, dd, J=17.1, 10.8), 5.71(1H, dd, J=17.1, 1.2), 5.55(1H, dd, J=11.1,1.2), 4.96(1H,dd, J=10.8, 2.4), 4.53(1H, q, J=5.1), 4.26(1H, t, J=9.6), 3.97 (2H,t, J=7.2), 3.89(1H,q, J=6.9), 3.5-3.78(3H, m), 3.72(1H,s), 3.18(1H,dd, J=10.2, 7.2), 3.03-3.13(2H, m), 2.93 (3H, d, J=5.4), 2.63(3H,s), 2.4-2.48(1H, m), 2.26(6H,s), 1.42-1.93(12H, m), 1.37(3H, d, J=6.9), 1.34 (3H,s), 1.31(3H, d, J=7.5), 1.24(3H, d, J=6.0), 1.10(3H,d, J=6.9), 0.84(3H,d, J=6.9), 0.79(3H,t, J=7.5).
EXAMPLE 112 
Synthesis of Compound XXIV




Following Procedure A using the C12 vinyl imidazolyl carbamate ketolide and 15-[1-(4-aminobutyl)imidazol-4-yl](2-pyridyl)}dimethylamine, a white solid was obtained (27% yield). MH+(867.07). 1H NMR (CDCl3, referenced at 7.26 ppm on 300 MHz NMR, J=coupling constants in Hertz) 8.52(1H, d, J=2.4), 7.89(1H, dd, J=8.7, 2.4), 7.49(1H,s) 7.09(1H,s), 6.55(1H, d, J=8.7), 5.95(1H, dd, J=17.1, 10.8), 5.71(1H, dd, J=17.1, 1.2), 5.55(1H, dd, J=11.1,1.2), 4.96(1H,dd, J=10.8, 2.4), 4.28(1H, d, J=7.5), 4.24 (1H, d, J=9), 3.97 (2H,t, J=7.2), 3.89(1H,q, J=6.9), 3.5-3.78(3H, m), 3.72(1H,s), 3.16-3.24(1H, m), 3.1(6H, s), 3.04-3.14(1H, m), 2.63 (3H, s), 2.4-2.48(1H, m), 2.31(6H,s), 1.42-1.93(12H, m), 1.37(3H, d, J=6.9), 1.34 (3H,s), 1.31(3H, d, J=7.5), 1.25(3H, d, J=6.3), 1.10(3H,d, J=6.9), 0.85(3H,d, J=6.6), 0.80(3H,t, J=7.5).
EXAMPLE 113
Synthesis of Compound XXV




Procedure B: A 0.25M solution of C12 hydrogen imidazolyl carbamate ketolide (synthesis described in PCT WO 03/004509 A2, the disclosure of which is incorporated herein by reference) in ACN was stirred with 4-[4-(6-methyl-pyridin-3-yl)-imidazol-1-yl]-butylamine (4 equivalents) at 60° C. for 14 h. The mixture was brought to ambient temperature and concentrated. Column chromatography (3:2 hexanes:acetone+2% Et3N) gave the desired benzoylated product. A 0.05M solution of benzoylated ketolide in methanol was refluxed for 15 h. The mixture was brought to ambient temperature and concentrated. Column chromatography (80:20:9:1 Et2O:CHCl3:MeOH:NH4OH) yielded a white solid (38%). MH+(812.01)
EXAMPLE 114
Synthesis of Compound XXVI




Following Procedure A using the C12 vinyl imidazolyl carbamate ketolide and 4-[4-(6-methoxy(3-pyridyl))-5-methylimidazolyl]butylamine, a white solid was obtained (38% yield). MH+(868.07). 1H NMR (CDCl3, referenced at 7.26 ppm on 300 MHz NMR, J=coupling constants in Hertz) 8.35(1H, d, J=2.4), 7.91(1H, dd, J=8.7, 2.4), 7.49(1H, s), 6.79(1H, d, J=8.7), 5.95(1H, dd, J=16.8, 10.8), 5.71(1H, dd, J=17.1, 1.5), 5.55(1H, dd, J=11.1,1.5), 4.95(1H,dd, J=10.8, 2.1), 4.30(1H, d, J=7.5), 4.24(1H, d, J=9.0), 3.96(3H, s), 3.89-4.0(3H,m), 3.62-3.78(2H, m), 3.73(1H,s), 3.5-3.62(1H,m), 3.29(1H,dd, J=9.9, 7.5), 3.06-3.16(2H, m), 2.63(3H,s), 2.50-2.65(1H, m), 2.43(6H,s), 2.34(3H, s), 1.41-1.93(12H, m), 1.36(3H, d, J=6.9), 1.34 (3H,s), 1.31(3H, d, J=7.2), 1.26(3H, s, J=6.0), 1.11(3H,d, J=7.2), 0.85(3H,d, J=7.2), 0.80(3H,t, J=7.2).
EXAMPLE 115
Synthesis of Compound XXVII




Following Procedure A using the C12 vinyl imidazolyl carbamate ketolide and 4-[4-(6-methoxy(3-pyridyl))-2-methylimidazolyl]butylamine, a white solid was obtained (38% yield). MH+(868.07)
EXAMPLE 116
Synthesis of Compound XXIX




Following Procedure B using the C12 hydrogen imidazolyl carbamate ketolide and 4-[4-(6-chloro-pyridin-3-yl)-imidazol-1-yl]-butylamine, a white solid was obtained (30% yield). MH+(832.43)
EXAMPLE 117
Synthesis of Compound XXIX




Following Procedure A using the C12 vinyl imidazolyl carbamate ketolide and 4-[4-(6-chloro-(3-pyridyl))-2-methylimidazolyl]butylamine, a white solid was obtained (27% yield). MH+(872.49)
EXAMPLE 118
Synthesis of Compound XXX




Following Procedure A using the C12 vinyl imidazolyl carbamate ketolide and 4-[4-(4-chloro-3-pyridyl)imidazolyl]butylamine, a white solid was obtained (50% yield). MH+(858.47). 1H NMR (CDCl3, referenced at 7.26 ppm on 300 MHz NMR, J=coupling constants in Hertz) 9.32(1H, s), 8.33(1H, d, J=5.1), 7.67(1H,s) 7.58(1H,s), 7.31(1H, d, J=4.8), 5.95(1H, dd, J=16.8, 10.8), 5.71(1H, dd, J=17.1, 1.5), 5.55(1H, dd, J=11.1,1.5), 4.95(1H,dd, J=10.5, 2.4), 4.29(1H, d, J=7.2), 4.24(1H, d, J=9.3), 4.0 (1H,t, J=7.2), 3.89(1H,q, J=6.9), 3.62-3.78(2H, m), 3.72(1H,s), 3.5-3.62(1H,m), 3.24(1H,dd, J=10.2, 7.2), 3.06-3.16(2H, m), 2.63(3H,s), 2.50-2.60(1H, m), 2.37(6H,s), 1.40-1.93(12H, m), 1.38(3H, d, J=6.9), 1.34 (3H,s), 1.31(3H, d, J=7.8), 1.26(3H, s, J=6.0), 1.11 (3H,d, J=6.9), 0.85(3H,d, J=6.9), 0.79(3H,t, J=7.5).
EXAMPLE 119
Synthesis of Compound XXXI




Procedure C: A 0.25M solution of C12 alkynyl imidazolyl carbamate ketolide in 10:1 ACN:H2O was stirred with 4-[4-(6-fluoro-pyridin-3-yl)-imidazol-1-yl]-butylamine (2 eq) at 70° C. for 14 h. The mixture was brought to ambient temperature and concentrated. Column chromatography (3:2 hexanes:acetone+2% Et3N) gave the desired benzoylated product. A 0.05M solution of benzoylated ketolide in methanol was refluxed for 15 h. The mixture was brought to ambient temperature and concentrated. Column chromatography (80:20:9:1 Et2O:CHCl3:MeOH:NH4OH) yielded a white solid (25%). MH+(840.00)
EXAMPLE 120
Synthesis of Compound XXXII




Following Procedure C using the C12 alkynyl imidazolyl carbamate ketolide and 4-[4-(6-methoxy-pyridin-3-yl)-imidazol-1-yl]-butylamine, a white solid was obtained (25% yield). MH+(852.03)
EXAMPLE 121
Synthesis of Compound XXXIII




Following Procedure C using the C12 alkynyl imidazolyl carbamate ketolide and 4-[4-(6-methyl-pyridin-3-yl)-imidazol-1-yl]-butylamine, a white solid was obtained (25% yield). MH+(836.03)
EXAMPLE 122
Synthesis of Compound XXXIV




Following Procedure C using the C12 alkynyl imidazolyl carbamate ketolide and 4-[4-(6-chloro-pyridin-3-yl)-imidazol-1-yl]-butylamine, a white solid was obtained (25% yield). MH+(856.45)
EXAMPLE 123
Synthesis of Compound XXXV




Following Procedure A using the C12 vinyl imidazolyl carbamate ketolide and 4-[4-(4-methoxy-3-pyridyl)imidazolyl]butylamine, a white solid was obtained (33% yield). MH+(854.05). 1H NMR (CDCl3, referenced at 7.26 ppm on 300 MHz NMR, J=coupling constants in Hertz) 9.27(1H, s), 8.39(1H, d, J=5.7), 7.55(1H,d, J=1.2) 7.49(1H,d, J=1.2), 6.85(1H, d, J=5.7), 5.95(1H, dd, J=16.8, 10.8), 5.71(1H, dd, J=17.1, 1.5), 5.55(1H, dd, J=11.1,1.5), 4.95(1H,dd, J=10.5, 2.4), 4.29(1H, d, J=7.5), 4.24(1H, d, J=9.3), 4.0 (1H,t, J=7.2), 4.0(3H,s), 3.88(1H,q, J=6.9), 3.62-3.78(2H, m), 3.72(1H,s), 3.5-3.62(1H,m), 3.24(1H,dd, J=9.9, 7.2), 3.06-3.16(2H, m), 2.63(3H,s), 2.50-2.58(1H, m), 2.37(6H,s), 1.54-1.93(12H, m), 1.36(3H, d, J=6.6), 1.34 (3H,s), 1.32(3H, d, J=7.5), 1.26(3H, s, J=6.0), 1.11(3H,d, J=7.2), 0.85(3H,d, J=7.2), 0.80(3H,t, J=7.5).
EXAMPLE 124
Synthesis of Compound XXXVI




Following Procedure A using the C12 vinyl imidazolyl carbamate ketolide and 4-[4-(2-chloro-3-pyridyl)imidazolyl]butylamine, a white solid was obtained (24% yield). MH+(854.05)
EXAMPLE 125
Synthesis of Compound XXXVII




Following Procedure A using the C12 vinyl imidazolyl carbamate ketolide and 4-[4-(6-chloro (3-pyridyl))-5-methylimidazolyl]butylamine, a white solid was obtained (17% yield). MH+(872.49). 1H NMR (CDCl3, referenced at 7.26 ppm on 300 MHz NMR, J=coupling constants in Hertz) 8.62(1H, d, J=1.8), 8.01(1H, dd, J=8.1, 2.1), 7.65(1H,s) 7.37(1H,d, J=8.4), 5.95(1H, dd, J=16.8, 10.8), 5.71(1H, dd, J=17.1, 1.5), 5.55(1H, dd, J=11.1,1.5), 4.94(1H,dd, J=10.5, 2.4), 4.38(1H, d, J=6.9), 4.23(1H, d, J=8.7), 3.97 (2H,t, J=7.2), 3.87(1H,q, J=6.9), 3.71 (1H,s), 3.5-3.80(3H,m), 3.24-3.38(1H, m), 3.06-3.16(2H, m), 2.84(6H,s), 2.59(3H, s), 2.50-2.58(1H, m), 2.39(3H, s), 1.42-1.93(12H, m), 1.25-1.35(12H, m), 1.13(3H,d, J=6.9), 0.85(3H,d, J=6.9), 0.78(3H,t, J=7.2).
EXAMPLE 126
Synthesis of Compound XXXVIII




Following Procedure A using the C12 vinyl imidazolyl carbamate ketolide and 4-[4-(6-chloro-5-methyl-3-pyridyl)imidazolyl]butylamine, a white solid was obtained (20% yield). MH+(872.49). 1H NMR (CDCl3, referenced at 7.26 ppm on 300 MHz NMR, J=coupling constants in Hertz) 8.54(1H, d, J=2.1), 7.98(1H, d, J=2.4), 7.53(1H,d, J=1.2) 7.31(1H,d, J=1.2), 5.95(1H, dd, J=16.8, 10.8), 5.71(1H, dd, J=17.1, 1.5), 5.55(1H, dd, J=11.1,1.5), 4.94(1H,dd, J=10.5, 2.4), 4.28(1H, d, J=7.2), 4.23(1H, d, J=9.0), 4.0 (1H,t, J=7.2), 3.89(1H,q, J=6.9), 3.62-3.78(2H, m), 3.71(1H,s), 3.5-3.62(1H,m), 3.24(1H,dd, J=10.2, 7.2), 3.06-3.16(2H, m), 2.60(3H,s), 2.50-2.58(1H, m), 2.40(3H, s), 2.36(6H,s), 1.42-1.93(12H, m), 1.36(3H, d, J=6.9), 1.32 (3H,s), 1.31(3H, d, J=7.8), 1.25(3H, s, J=6.0), 1.11(3H,d, J=7.2), 0.84(3H,d, J=6.9), 0.78(3H,t, J=7.2).
EXAMPLE 127
Antibacterial Activity
Representative compounds of the present invention, listed in Table 3, were assayed in vitro for antibacterial activity, shown in Table 5, against the bacterial isolates listed in Table 4 as follows:
Strains. The bacterial isolates listed in Table 4 were cultivated from −70° C. frozen stocks by two consecutive overnight passages (P1, P2) at 35° C. on 5% blood agar (Remel, Lenexa, Kans.). Chocolate agar (Remel) is used for Haemophilus influenzae. H. influenzae and Streptococcus pneumoniae are incubated in 5-10% CO2 
Drug Stock Preparation. To determine the amount of solvent to be used to give the desired final concentration, the formula “weight obtained in mg/final concentration in mg/ml” will be used. It will give the amount of solvent in ml needed to be added to give the desired concentration. For example, if 2.5 mg/ml is the desired concentration and the weight of compound is 13.7 mg, then the amount of solvent to be added is 3.94 ml (13.7 mg/2.5 mg/ml=3.94 ml). Methanol is used as the solvent to dissolve the test compounds. Further dilution of stock is done in sterile, deionized water. Drug stocks are kept frozen at −70° C., protected from light.
Susceptibility Testing. MICs are determined by the broth microdilution method in accordance with the NCCLS guidelines. In brief, organism suspensions are adjusted to a 0.5 McFarland standard to yield a final inoculum between 3×105 and 7×105 CFU/ml. Drug dilutions and inocula are made in sterile, cation adjusted Mueller-Hinton Broth (CAMHB) (Remel) for all but S. pneumoniae [CAMHB with 2-5% lysed horse blood (Remel)] and H. influenzae [Haemophilus Test Medium (Remel)]. An inoculum volume of 100 μl is added to wells containing 100 μl of broth with 2-fold serial dilutions of drug. All inoculated microdilution trays are incubated in ambient air at 35° C. for 18-24 hours, except for S. pneumoniae, and H. influenzae (both at 5-10% CO2).
Following appropriate incubation, the MIC is determined and the MIC is defined as the lowest concentration of the drug that prevented visible growth. The results of this assay, shown below in Table 5, demonstrate the antibacterial activity of representative compounds of the invention against the organism strain panel shown in Table 4.







TABLE 3







REPRESENTATIVE COMMPOUNDS










Cmd.

Cmd.



No.
Structure
No.
Structure





5960




4710






 


6220




4711






 


6221




4713






 


6222




4714






 


6223




4716






 


4265




4717






 


4266




7280






 


7281




7282






 


7283




















TABLE 4







STRAINS TESTED











Strain



Strains Tested
ID







S. epidermidis Step_14990
A



S. epidermidis Step_f50654 Pen S
B



E. faecalis Enfa_29212
C



S. pyogenes Stpy_8668
D



S. pneumoniae Stpn_49619
E



S. pneumoniae Stpn_297-749 Pen R
F



S. pneumoniae Stpn_280-962 Pen S
G



S. pneumoniae Stpn_Erm 6849
H



S. pneumoniae Stpn_Erm S 4297
I



S. pneumoniae Stpn_Mef 5654
J



S. pneumoniae Stpn_Mef S 3427
K



H. influenzae Hain_49247
L



E. coli Esco_25922
M

















TABLE 5







COMPOUND ACTIVITY









Strain ID




















Cmpd
A
B
C
D
E
F
G
H
I
J
K
L
M























Clar.
0.2
0.2
0.78
=0.05
=0.05
=0.05
=0.05
>50
>50
6.25
1.56
12.5
50


5960
0.2
0.2
=0.05
=0.05
=0.05
=0.05
=0.05
25
0.1
0.2
=0.05
3.13
25


6220
0.1
0.1
=0.05
=0.05
=0.05
=0.05
=0.05
3.13
0.1
0.4
=0.5
1.56
6.25


6221
0.1
0.1
=0.05
=0.05
=0.05
=0.05
=0.05
0.1
=0.05
0.4
=0.05
3.13
25


6222
1.56
1.56
0.4
0.2
0.2
0.4
0.2
>50
>50
0.78
0.4
25
50


6223
1.56
3.13
0.78
0.2
0.2
0.2
0.2
>50
>50
0.78
0.4
>50
50


4265
3.13
6.25
3.13
0.4
0.2
0.1
=0.5
25
1.56
1.56
0.4
>50
>50


4266
3.13
3.13
1.56
0.1
0.2
=0.05
=0.05
>50
>50
0.2
0.1
25
>50


4710
0.1
0.2
=0.05
=0.5
=0.5
=0.5
=0.5
0.2
=0.05
0.2
=0.5
3.13
50


4711
0.1
0.1
=0.05
=0.5
=0.5
=0.5
=0.5
6.25
0.2
0.1
=0.5
1.56
50


4713
0.4
0.4
0.1
=0.5
=0.5
=0.5
=0.5
0.78
0.1
3.13
0.4
3.13
50


4714
6.25
6.25
0.4
0.1
=0.5
=0.5
=0.5
>50
6.25
0.4
0.1
>50
>50


4716
6.25
12.5
0.78
0.1
=0.5
=0.5
=0.5
>50
25
0.78
0.4
25
>50


4717
0.2
0.4
0.1
=0.5
=0.5
=0.5
=0.5
6.25
0.4
0.2
=0.05
6.25
>50


7280
0.2
0.2
0.1
=0.05
=0.05
=0.05
=0.05
0.4
=0.05
0.4
0.1
6.25
25


7281
0.2
0.1
0.1
=0.05
=0.05
=0.05
=0.05
0.2
=0.05
0.4
=0.05
3.13
25


7282
0.4
0.2
0.1
=0.05
=0.05
=0.05
=0.05
0.78
0.2
0.4
0.1
3.13
12.5


7283
0.2
0.2
0.1
=0.05
=0.05
=0.05
=0.05
0.4
0.1
0.4
=0.05
3.13
12.5









The foregoing procedure is repeated using the strain panel shown in Table 6 demonstrating the antibacterial activity of representative compounds of the invention as shown in Table 7.







TABLE 6







STRAINS TESTED











Strain



Strains Tested
ID







S. aureus Stau_29213
A



S. epidermidis Step_14990
B



S. epidermidis Step_f50654
C



E. faecalis Enfa_29212
D



S. pyogenes Stpy_8668
E



S. pneumoniae Stpn_49619
F



S. pneumoniae Stpn_297-749
G



S. pneumoniae Stpn_280-962
H



S. pneumoniae Stpn_Erm 6849
I



S. pneumoniae Stpn_Erm S
J



4297



S. pneumoniae Stpn_Mef 5654
K



S. pneumoniae Stpn_Mef S
L



3427



H. influenzae Hain_49247
M

















TABLE 7







COMPOUND ACTIVITY









Strain ID




















Cmpd Ex.
A
B
C
D
E
F
G
H
I
J
K
L
M























14
0.4
0.2
0.2
0.1
=0.05
=0.05
=0.05
=0.05
0.4
0.1
0.4
=0.05
3.13


65 (1)
0.2
0.2
0.2
0.1
=0.05
=0.05
=0.05
=0.05
=0.05
=0.05
0.2
=0.05
3.13


15
0.4
0.2
0.4
0.1
=0.05
=0.05
=0.05
=0.05
1.56
0.1
0.2
=0.05
3.13


20
0.2
0.1
0.2
0.1
=0.05
=0.05
=0.05
=0.05
=0.5
=0.05
0.4
=0.05
6.25


48
0.2
0.2
0.2
0.1
=0.05
=0.05
=0.05
=0.05
0.4
=0.05
0.78
0.1
3.13


49
0.2
0.2
0.2
0.1
=0.05
=0.05
=0.05
=0.05
0.1
=0.05
0.78
=0.05
6.25


67/20m
0.2
0.1
0.2
=0.05
=0.05
=0.05
=0.05
=0.05
0.2
=0.05
0.2
=0.05
1.56


67/20w
3.13
1.56
3.13
0.2
=0.05
=0.05
=0.05
=0.05
12.5
3.13
0.4
0.1
50


25
0.4
0.2
0.2
0.1
=0.05
=0.05
=0.05
=0.05
0.1
0.1
0.4
0.1
3.13


27
0.1
0.1
0.1
0.05
=0.025
=0.025
=0.025
=0.025
3.13
0.1
0.4
0.1
1.56


67/20r
3.13
3.13
1.56
1.56
0.4
0.1
0.1
0.1
25
25
1.56
0.1
50


67/20s
0.78
0.78
0.4
0.2
=0.05
=0.05
=0.05
=0.05
12.5
0.2
0.78
=0.05
3.13


29
0.4
0.2
0.4
0.2
=0.05
=0.05
=0.05
=0.05
1.56
0.2
0.78
0.2
6.25


30
0.2
0.2
0.4
0.2
=0.05
=0.05
=0.05
=0.05
0.4
0.1
0.78
0.1
6.25


33
0.4
0.2
0.2
0.1
=0.05
3.13
=0.05
=0.05
=0.05
0.4
0.1
0.4
0.1


34
0.4
0.2
0.2
0.1
=0.05
3.13
=0.05
=0.05
=0.05
12.5
0.2
0.4
0.1


37
0.4
0.2
0.2
0.1
=0.05
=0.05
=0.05
=0.05
0.4
0.1
1.56
0.2
6.25


50
0.4
0.4
0.2
0.2
=0.05
=0.05
=0.05
=0.05
0.1
=0.05
0.4
0.1
6.25


38
0.2
0.2
0.2
0.1
=0.05
=0.05
=0.05
=0.05
0.4
0.1
0.78
0.1
6.25


39
0.2
0.1
0.4
0.1
=0.05
=0.05
=0.05
=0.05
0.1
=0.05
0.78
0.2
3.13


22
0.4
0.4
0.4
0.2
=0.05
=0.05
=0.05
=0.05
0.2
0.1
0.78
0.2
3.13


23
1.56
0.78
0.78
0.2
=0.05
=0.05
=0.05
=0.05
0.78
0.2
0.4
0.1
6.25


17
0.4
0.4
0.4
0.2
0.1
=0.05
=0.05
=0.05
0.78
0.2
0.4
0.1
3.13


18
0.78
0.4
0.78
0.1
0.1
=0.05
=0.05
=0.05
3.13
0.2
0.4
=0.05
3.13


19
0.4
0.4
0.4
0.4
0.1
=0.05
=0.05
=0.05
0.78
0.2
0.4
0.1
6.25


21
0.4
0.4
0.4
0.1
=0.05
=0.05
=0.05
=0.05
0.2
0.1
0.78
0.1
12.5


67/20n
0.4
0.2
0.4
0.1
=0.05
=0.05
=0.05
=0.05
0.4
0.1
0.2
0.1
6.25


67/20o
0.2
0.2
0.2
0.1
=0.05
=0.05
=0.05
=0.05
1.56
0.1
0.2
0.1
3.13


26
0.2
0.2
0.2
0.2
=0.05
=0.05
=0.05
=0.05
0.2
=0.05
0.4
0.1
3.13


65 (2)
3.13
3.13
3.13
0.78
0.2
=0.05
=0.05
=0.05
0.78
0.4
0.78
0.2
25


66
0.2
0.2
0.2
.01
=0.05
=0.05
=0.05
=0.05
0.2
0.1
0.4
0.1
6.25


28
0.4
0.4
0.4
0.1
=0.05
=0.05
=0.05
=0.05
>50
0.4
0.78
0.2
3.13


67/20t
0.78
0.78
0.4
0.4
0.2
=0.05
=0.05
=0.05
25
1.56
1.56
0.1
12.5


67/20u
0.78
0.78
0.4
0.4
0.4
0.1
0.1
0.1
25
12.5
1.56
0.2
25


67/20v
0.4
0.4
0.2
0.2
=0.05
=0.05
=0.05
=0.05
50
0.4
0.78
=0.05
6.25


31
0.2
0.4
0.4
0.2
=0.05
=0.05
=0.05
=0.05
0.4
0.2
0.78
0.2
6.25


32
0.2
0.4
0.4
.02
=0.05
=0.05
=0.05
=0.05
0.2
=0.05
0.78
0.2
6.25


35
0.78
0.78
0.78
0.2
0.2
6.25
=0.05
=0.05
=0.05
3.13
0.78
0.78
0.2


36
6.25
1.56
0.78
0.78
0.4
25
0.1
0.1
0.1
12.5
12.5
0.78
0.2


40
0.2
0.2
0.2
0.1
=0.05
=0.05
=0.05
=0.05
0.2
=0.05
0.78
0.2
6.25


67/20p
0.4
0.2
0.4
0.2
0.1
0.1
=0.05
0.1
6.25
0.78
0.78
0.2
6.25


67/20q
0.4
0.2
0.4
0.1
=0.05
=0.05
=0.05
=0.05
1.56
0.2
0.4
0.1
12.5









EXAMPLE 128
ANTIBACTERIAL ACTIVITY OF PYRIDYL SUBSTITUTED KETOLIDES
Representative compounds of the present invention, listed in Table 9, were assayed in vitro for antibacterial activity, shown in Table 10, against the bacterial isolates listed in Table 8 as follows:
Strains. The bacterial isolates listed in Table 8 were cultivated from −70° C. frozen stocks by two consecutive overnight passages (P1, P2) at 35° C. on 5% blood agar (Remel, Lenexa, Kans.). Chocolate agar (Remel) is used for Haemophilus influenzae. H. influenzae and Streptococcus pneumoniae are incubated in 5-10% CO2 
Drug Stock Preparation. To determine the amount of solvent to be used to give the desired final concentration, the formula “weight obtained in mg/final concentration in mg/ml” will be used. It will give the amount of solvent in ml needed to be added to give the desired concentration. For example, if 2.5 mg/ml is the desired concentration and the weight of compound is 13.7 mg, then the amount of solvent to be added is 3.94 ml (13.7 mg/2.5 mg/ml=3.94 ml). Methanol is used as the solvent to dissolve the test compounds. Further dilution of stock is done in sterile, deionized water. Drug stocks are kept frozen at −70° C., protected from light.
Susceptibility Testing. MICs are determined by the broth microdilution method in accordance with the NCCLS guidelines. In brief, organism suspensions are adjusted to a 0.5 McFarland standard to yield a final inoculum between 3×105 and 7×105 CFU/ml. Drug dilutions and inocula are made in sterile, cation adjusted Mueller-Hinton Broth (CAMHB) (Remel) for all but S. pneumoniae [CAMHB with 2-5% lysed horse blood (Remel)] and H. influenzae [Haemophilus Test Medium (Remel)]. An inoculum volume of 100 μl is added to wells containing 100 μl of broth with 2-fold serial dilutions of drug. All inoculated microdilution trays are incubated in ambient air at 35° C. for 18-24 hours, except for S. pneumoniae, and H. influenzae (both at 5-10% CO2).
Following appropriate incubation, the MIC is determined and the MIC is defined as the lowest concentration of the drug that prevented visible growth. The results of this assay, shown below in Table 10, demonstrate the antibacterial activity of representative compounds of the invention shown in Table 9 against the organism strain panel shown in Table 8. Antibacterial activity of representative compounds of the invention were compared against telitromycin.







TABLE 8







STRAINS TESTED











Strain



Strains Tested
ID







Staphylococcus aureus Stau_29213
A



Staphylococcus aureus Stau_33591
B



Staphylococcus epidermidis Step_14990
C



Staphylococcus epidermidis Step_f50654
D



Enterococcus faecalis Enfa_29212
E



Enterococcus faecalis Enfa_bc 11148-2
F



Streptococcus pyogenes Stpy_8668
G



Haemophilus influenzae Hain_49247
H



Haemophilus influenzae Hain_960730503-3
I



Haemophilus influenzae Hain_960820544-3
J



Haemophilus influenzae Hain_953460299-3
K



Haemophilus influenzae Hain_2762
L



Streptococcus pneumoniae Stpn_49619
M



Streptococcus pneumoniae Stpn_297-749
N



Streptococcus pneumoniae Stpn_280-962
O



Streptococcus pneumoniae Stpn_Mef 5654
P



Streptococcus pneumoniae Stpn_Mef S 3427
Q



Streptococcus pneumoniae Stpn_Erm S 4297
R

















TABLE 9







REPRESENTATIVE COMPOUNDS








Compound No.
Structure





XIII






 


XIV






 


XV






 


XVI






 


XVII






 


XVIII






 


XIX






 


XX






 


XXI






 


XXII






 


XXIII






 


XXIV






 


XXV






 


XXVI






 


XXVII






 


XXVIII






 


XXIX






 


XXX






 


XXXI






 


XXXII






 


XXXIII






 


XXXIV






 


XXXV






 


XXXVI






 


XXXVII




















TABLE 10(A)







COMPOUND ACTIVITY














STRAIN









ID
Telithromycin
XVI
XIII
XIV
XV
XVII
XVIII

















A
0.1-0.2
0.2
0.4
0.2
0.4
0.2
0.2


B
>50
>50
>50
>50
>50
>50
>50


C
0.1-0.2
0.2
0.2
0.2
0.2
0.4
0.2


D
0.1-0.2
0.2
0.4
0.4
0.2
0.2
0.2


E
0.1-0.2
0.1
0.2
0.2
0.1
0.1
0.1


F
 0.4-0.78
0.78
3.13
1.56
0.78
3.13
0.78


G
=0.05
=0.05
=0.05
=0.05
=0.05
=0.05
=0.05


H
3.13
6.25
6.25
6.25
3.13
6.25
6.25


I
3.13-6.25
6.25
6.25
6.25
6.25
6.25
6.25


J
3.13-6.25
6.25
6.25
6.25
6.25
12.5
6.25


K
3.13-6.25
6.25
6.25
6.25
3.13
12.5
6.25


L
0.78-1.56
1.56
1.56
1.56
0.78
1.56
1.56


M
=0.05
=0.05
=0.05
=0.05
=0.05
=0.05
=0.05


N
=0.05
=0.05
=0.05
=0.05
=0.05
=0.05
=0.05


O
=0.05
=0.05
=0.05
=0.05
=0.05
=0.05
=0.05


P
 0.2-0.78
0.78
0.78
0.78
0.4
0.78
0.78


Q
0.1-0.2
0.1
0.2
0.1
0.1
0.2
0.2


R
=0.1
=0.05
0.2
0.1
0.1
0.2
0.1
















TABLE 10(B)







COMPOUND ACTIVITY















Telithro-








STRAIN ID
mycin
XIX
XX
XXI
XXII
XXVI
XXVII

















A
0.1-0.2
0.1
=0.05
0.1
0.4
0.2
0.2


B
>50
>50
>50
>50
>50
>50
>50


C
0.1-0.2
0.1
=0.05
0.1
0.4
0.1
0.2


D
0.1-0.2
0.1
=0.05
0.1
0.4
0.4
0.2


E
0.1-0.2
0.1
=0.05
=0.05
0.2
0.2
0.2


F
 0.4-0.78
0.4
0.1
1.56
25
1.56
6.25


G
=0.05
=0.05
=0.05
=0.05
0.1
0.1
0.1


H
3.13
3.13
3.13
3.13
6.25
6.25
6.25


I
3.13-6.25
12.5
3.13
6.25
6.25
12.5
12.5


J
3.13-6.25
6.25
3.13
6.25
3.13
12.5
6.25


K
3.13-6.25
6.25
6.25
6.25
12.5
12.5
12.5


L
0.78-1.56
1.56
0.78
0.78
1.56
1.56
1.56


M
=0.05
=0.05
=0.05
=0.05
=0.05
=0.05
=0.05


N
=0.05
=0.05
=0.05
=0.05
=0.05
=0.05
=0.05


O
=0.05
=0.05
=0.05
=0.05
=0.05
=0.05
=0.05


P
 0.2-0.78
0.4
0.2
0.78
0.78
1.56
1.56


Q
0.1-0.2
0.1
=0.05
0.2
0.78
0.2
0.2


R
=0.1
=0.05
=0.05
0.1
1.56
N/A
N/A
















TABLE 10(C)







COMPOUND ACTIVITY














STRAIN ID
Telithromycin
XXVIII
XXIX
XXX
XXXI
XXXII
XXXIII

















A
0.1-0.2
0.2
0.2
0.2
0.2
0.2
0.2


B
>50
>50
>50
>50
>50
>50
>50


C
0.1-0.2
0.1
0.1
0.2
0.1
0.1
0.2


D
0.1-0.2
0.2
0.2
0.1
0.2
0.2
0.2


E
0.1-0.2
=0.05
0.1
=0.05
0.1
0.1
0.1


F
 0.4-0.78
0.4
3.13
0.4
0.78
1.56
6.25


G
=0.05
=0.05
=0.05
=0.05
=0.05
=0.05
=0.05


H
3.13
6.25
6.25
3.13
6.25
6.25
6.25


I
3.13-6.25
6.25
6.25
6.25
6.25
12.5
12.5


J
3.13-6.25
6.25
6.25
6.25
12.5
12.5
12.5


K
3.13-6.25
12.5
12.5
3.13
6.25
12.5
12.5


L
0.78-1.56
1.56
1.56
0.78
1.56
1.56
3.13


M
=0.05
=0.05
=0.05
=0.05
=0.05
=0.05
=0.05


N
=0.05
=0.05
=0.05
=0.05
=0.05
=0.05
=0.05


O
=0.05
=0.05
=0.05
=0.05
=0.05
=0.05
=0.05


P
 0.2-0.78
0.78
0.78
0.4
0.4
0.78
1.56


Q
0.1-0.2
0.1
=0.05
=0.05
0.2
0.2
0.4


R
=0.1
N/A
N/A
N/A
N/A
N/A
N/A
















TABLE 10(D)







COMPOUND ACTIVITY














STRAIN ID
Telithromycin
XXXIV
XXXV
XXXVI
XXXVII
XXXVIII
XXXIII

















A
0.1-0.2
0.1
0.2
0.2
0.2
0.1
0.1


B
>50
>50
>50
>50
>50
>50
>50


C
0.1-0.2
0.1
0.1
0.1
0.2
0.1
0.2


D
0.1-0.2
0.1
0.1
0.2
0.2
0.4
0.1


E
0.1-0.2
=0.05
0.1
0.1
0.1
0.1
0.1


F
 0.4-0.78
0.4
0.78
1.56
0.78
3.13
0.78


G
=0.05
=0.05
=0.05
=0.05
=0.05
=0.05
=0.05


H
3.13
3.13
6.25
3.13
6.25
3.13
3.13


I
3.13-6.25
6.25
6.25
6.25
12.5
6.25
6.25


J
3.13-6.25
6.25
6.25
6.25
6.25
12.5
6.25


K
3.13-6.25
6.25
6.25
6.25
6.25
12.5
6.25


L
0.78-1.56
0.78
1.56
1.56
1.56
1.56
0.78


M
=0.05
=0.05
=0.05
=0.05
=0.05
=0.05
=0.05


N
=0.05
=0.05
=0.05
=0.05
=0.05
=0.05
=0.05


O
=0.05
=0.05
=0.05
=0.05
=0.05
=0.05
=0.05


P
 0.2-0.78
0.4
0.78
0.78
0.78
0.2
1.56


Q
0.1-0.2
0.1
0.2
0.1
0.2
0.2
0.2


R
=0.1
N/A
N/A
N/A
N/A
N/A
N/A
















TABLE 10(E)







COMPOUND ACTIVITY












STRAIN ID
Telithromycin
XXIV
XXV
















A
0.1-0.2
0.2
0.2



B
>50
>50
>50



C
0.1-0.2
0.2
0.2



D
0.1-0.2
0.2
0.2



E
0.1-0.2
0.1
0.1



F
 0.4-0.78
0.78
3.13



G
=0.05
=0.05
=0.05



H
3.13
12.5
3.13



I
3.13-6.25
12.5
6.25



J
3.13-6.25
6.25
6.25



K
3.13-6.25
12.5
6.25



L
0.78-1.56
1.56
1.56



M
=0.05
=0.05
=0.05



N
=0.05
=0.05
=0.05



O
=0.05
=0.05
=0.05



P
 0.2-0.78
1.56
1.56



Q
0.1-0.2
0.4
.04



R
=0.1
N/A
N/A










EXAMPLE 129
IN VIVO PHARMACOKINETIC STUDIES OF PYRIDYL SUBSTITUTED KETOLIDES
Animal Models. A total of 54 male Sprague-Dawley rats, weighing 200 grams in average, were evaluated for pharmacokinetic studies of representative pyridyl substituted ketolides. Rats were under overnight food restriction and received water ad libitum. Rats were acclimated for approximately 5 days before antibiotic administration.
Antibiotic Administration. Rats were given bolus administration through (IV) and oral (PO) routes. Representative pyridyl substituted ketolides and telithromycin, for comparison, were diluted in 0.85% saline to a concentration of 15.0 mg/ml, and the resulting pH was adjusted using 1N acetic acid until the compound was in solution. Approximately 200 microliters of the compound solution was administered to the rats. The target dose for IV and PO administration was 5 mg/kg and 15 mg/kg, respectively.
Sample Collection. Plasma and whole lung samples were collected from the rats. Plasma samples were obtained from blood samples by centrifugation at 3000 RPM for 10 min. Heparin was added in the plasma as an anticoagulant. Whole lung samples were homogenized in deionized water. Samples were stored at −80° C. A total of 9 time points were collected in triplicate at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hrs. Ketolide concentrations in plasma and lung were determined by well-established non-GLP LC-MS-MS methods. PK parameters were estimated from the raw bioanalytical data using WinNolin software (Version 4.0, Pharsight Corporation, CA). The results of this phannacokinetic assay, shown below in Table 11, demonstrate the antibacterial activity of representative compounds of the invention in rat animal models. All representative compounds were compared to telithromycin.







TABLE 11







COMPARISON OF PK PARAMETERS OF REPRESENTATIVE


KETOLIDES IN RAT ANIMAL MODEL









PK parameter

















AUC,
L/P ratio,


t1/2, IV
t1/2, IV
F,



Dose
IV
IV
CL
Vss
Plasma
Lung
PO









Units
















mg/kg
μg · h/ml
—
ml/min/kg
L/kg
h
h
%



















Telithromycin
IV = 5
2.5
16
100
 5
1.0
1.3
11



PO = 15


Compound
IV = 15
3.3
83
 70
13
2.3
3.6
43


XIV
PO = 15


Compound
IV = 5
2.1
80
115
14
1.6
3.4
35


XVI
PO = 15


Compound
IV = 5
2.6
110 
 91
11
1.7
3.1
51


XVIII
PO = 15


Compound
IV = 5
2.3
94
107
12
1.3
1.4
26


XX
PO = 15


Compound
IV = 5
2.1
75
121
 8
1.0
1.2
21


XXX
PO = 15









While the preferred embodiment of the invention has been illustrated and described, it will be appreciated that various changes can be made therein without departing from the spirit and scope of the invention.

## Claims

1. A compound having the formula XII:



or a pharmaceutically acceptable salt or ester thereof, wherein
A) R is selected from the group consisting of
(1) hydrogen;
(2) methyl substituted with a moiety selected from the group consisting of
(a) —CN,
(b) —F,
(c) —CO2R10, wherein R10 is C1-C3-alkyl or aryl substituted with C1-C3-alkyl, or heteroaryl substituted with C1-C3-alkyl,
(d) —S(O)nR10—, wherein n is 0, 1, or 2 and R10 is as previously defined,
(e) —NH—C(O)R10, wherein R10 is as previously defined,
(f) —NH—C(O)NR11R12, wherein R11 and R12 are independently selected from hydrogen, C1-C3-alkyl, C1-C3-alkyl substituted with aryl, substituted aryl, heteroaryl, and substituted heteroaryl,
(g) aryl,
(h) substituted aryl,
(i) heteroaryl, and
(j) substituted heteroaryl;

(3) C1-C12 alkyl;
(4) C2-C12-alkyl substituted with one or more substituents selected from the group consisting of
(a) halogen,
(b) hydroxy,
(c) C1-C3-alkoxy,
(d) C1-C3-alkoxy-C1-C3-alkoxy,
(e) oxo,
(f) —O—SO2—(substituted C1-C6-alkyl),
(g) —N3,
(h) —CHO,
(i) —NR13R14, wherein R13 and R14 are selected from the group consisting of
(i) hydrogen,
(ii) C1-C12-alkyl,
(iii) substituted C1-C12-alkyl,
(iv) C2-C12-alkenyl,
(v) substituted C2-C12-alkenyl,
(vi) C2-C12-alkynyl,
(vii) substituted C2-C12-alkynyl,
(viii) aryl,
(ix) C3-C8-cycloalkyl,
(x) substituted C3-C8-cycloalkyl,
(xi) substituted aryl,
(xii) C3-C12-heterocycloalkyl,
(xiii) substituted C3-C12-heterocycloalkyl,
(xiv) C1-C12-alkyl substituted with aryl,
(xv) C1-C12-alkyl substituted with substituted aryl,
(xvi) C1-C12-alkyl substituted with C3-C12-heterocycloalkyl,
(xvii) C1-C12-alkyl substituted with substituted C3-C12-heterocycloalkyl,
(xviii) C1-C12-alkyl substituted with C3-C8-cycloalkyl,
(xix) C1-C12-alkyl substituted with substituted C3-C8-cycloalkyl,
(xx) heteroaryl,
(xxi) substituted heteroaryl,
(xxii) C1-C12-alkyl substituted with heteroaryl, and
(xxiii) C1-C12-alkyl substituted with substituted heteroaryl;
 or R13 and R14 are taken together with the atom to which they are attached to form a 3- to 10-membered heterocycloalkyl ring which may optionally be substituted with one or more substituents independently selected from the group consisting of
 (i) halogen,
 (ii) hydroxy,
 (iii) C1-C3-alkoxy,
 (iv) C1-C3-alkoxy-C1-C3-alkoxy,
 (v) oxo,
 (vi) C1-C3-alkyl,
 (vii) halo-C1-C3-alkyl, and
 (viii) C1-C3-alkoxy-C1-C3-alkyl;

(j) —CO2R10, wherein R10 is as previously defined,
(k) —C(O)NR11R12, wherein R11 and R12 are as previously defined,
(l) ═N—O—R10, wherein R10 is as previously defined,
(m) —CN,
(n) —O—S(O)nR10 wherein n is 0, 1, or 2 and R10 is as previously defined,
(o) aryl,
(p) substituted aryl,
(q) heteroaryl,
(r) substituted heteroaryl,
(s) C3-C8-cycloalkyl,
(t) substituted C3-C8-cycloalkyl,
(u) C1-C12-alkyl substituted with heteroaryl,
(v) C3-C12-heterocycloalkyl,
(w) substituted C3-C12-heterocycloalkyl,
(x) —NH—C(O)R10, wherein R10 is as previously defined,
(y) —NH—C(O)NR11R12, wherein R11 and R12 are as previously defined,
(z) ═N—NR13R14, wherein R13 and R14 are as previously defined,
(aa) ═N—R9, wherein R9 is selected from the group consisting of:
(i) C1-C12-alkyl optionally substituted with a substituent selected from the group consisting of
 (a) aryl,
 (b) substituted aryl,
 (c) heteroaryl, and
 (d) substituted heteroaryl,
 (ii) aryl,
 (iii) substituted aryl,
 (iv) heteroaryl,
 (v) substituted heteroaryl, and
 (vi) C3-C12-heterocycloalkyl,

(bb) ═N—NH—C(O)R10, wherein R10 is as previously defined, and
(cc) ═N—NH—C(O)NR11R12, wherein R11 and R12 are as previously defined;

(5) C3-alkenyl substituted with a moiety selected from the group consisting of
(a) hydrogen,
(b) halogen,
(c) —CHO,
(d) —CO2R10, wherein R10 is as previously defined,
(e) —C(O)NR11R12, wherein R11 and R12 are as previously defined,
(f) —C(O)R9, wherein R9 is as previously defined,
(g) —CN,
(h) aryl,
(i) substituted aryl,
(j) heteroaryl,
(k) substituted heteroaryl,
(l) —C3-C8-cycloalkyl, and
(m) —C1-C12-alkyl substituted with heteroaryl;

(6) C4-C10-alkenyl;
(7) C4-C10-alkenyl substituted with one or more substituents selected from the group consisting of
(a) halogen,
(b) —C1-C3-alkoxy,
(c) oxo,
(d) —CHO,
(e) —CO2R10, wherein R10 is as previously defined,
(f) —C(O)NR11R12, wherein R11 and R12 are as previously defined,
(g) —NR13R14, wherein R13 and R14 are as previously defined,
(h) ═N—O—R10, wherein R10 is as previously defined,
(i) —CN,
(j) —O—S(O)nR10, wherein n is 0, 1, or 2 and R10 is as previously defined,
(k) aryl,
(l) substituted aryl,
(m) heteroaryl,
(n) substituted heteroaryl,
(o) —C3-C8-cycloalkyl,
(p) —C1-C12-alkyl substituted with substituted heteroaryl,
(q) —NH—C(O)R10, wherein R10 is as previously defined,
(r) —NH—C(O)NR11R12, wherein R11 and R12 are as previously defined,
(s) ═N—NR13R14, wherein R13 and R14 are as previously defined,
(t) ═N—R9, wherein R9 is as previously defined,
(u) ═N—NH—C(O)R10, wherein R10 as is previously defined, and
(v) ═N—NH—C(O)NR11R12, wherein R11 and R12 are as previously defined;

(8) C3-C10-alkynyl;
(9) C3-C10-alkynyl substituted with one or more substituents selected from the group consisting of
(a) C1-C12-trialkylsilyl,
(b) aryl,
(c) substituted aryl,
(d) heteroaryl, and
(e) substituted heteroaryl; and

(10) C(O)NR7R8, wherein R7 and R8 are independently selected from hydrogen, C1-C12-alkyl, and substituted C1-C12-alkyl, or R7 and R8 are taken with the nitrogen atom to which they are connected to form a 3- to 7-membered ring which, when the ring is a 5- to 7-membered ring, may optionally contain a hetero function selected from the group consisting of —O—, —NH, —N(C1-C6-alkyl)-, —N(aryl)-, —N(aryl-C1-C6-alkyl-)-, —N(substituted aryl-C1-C6-alkyl-)-, —N(heteroaryl)-, —N(heteroaryl-C1-C6-alkyl-)-, —N(substituted heteroaryl-C1-C6-alkyl-)-, and —S— or —S(O)n— wherein n is 1 or 2;

B) Ra is selected from the group consisting of
(1) hydrogen;
(2) C1 alkyl further substituted with one or more substituents selected from the group consisting of
(a) hydroxyl,
(b) halogen,
(c) thiol, which can be further substituted with an C1-C12-alkyl or substituted C1-C12-alkyl group,
(d) C1-C12-alkyl, which can be further substituted by halogen, hydroxyl, C1-C12-alkoxy, or amino,
(e) C1-C3-alkoxy,
(f) C1-C3-thioalkoxy,
(g) amino,
(h) C1-C12-alkylamino,
(i) C1-C12-dialkylamino,
(j) —CN,
(k) —NO2,
(l) —CONH2,
(m) —COOH,
(n) —CO2R10, wherein R10 is as previously defined,
(o) —N3,
(p) ═N—O—R10, wherein R10 is as previously defined,
(q) ═N—R9, wherein R9 is as previously defined,
(r) ═N—NR13R14, wherein R13 and R14 are as previously defined,
(s) ═N—NH—C(O)R10, wherein R10 is as previously defined, and
(t) ═N—NH—C(O)NR11R12, wherein R11 and R12 are as previously defined;

(3) C2-C4-alkenyl, which can be further substituted with C1-C12-alkyl and one or more halogen groups;
(4) C2-C4-alkynyl, which can be further substituted with C1-C12-alkyl and one or more halogen groups;
(5) aryl, which can be further substituted with C1-C12-alkyl and one or more halogen groups;
(6) —CHO;
(7) —CO2H;
(8) —CN;
(9) —CO2R10, wherein R10 is as previously defined;
(10) —C(O)NR11R12, wherein R11 and R12 are as previously defined;
(11) —C(O)R9, wherein R9 is as previously defined; and
(12) thioester;

C) Rb is hydrogen, halogen, C1-C12 alkyl, substituted C1-C12-alkyl, or C1-C12-alkyl further substituted with one or more halogen groups;
D) Each R32 is independently selected from the group consisting of a free, salified, esterified and amidified
(1) carboxyl, hydroxyl, halogen, —NO2, —CN, C1-C12-alkyl, C3-C12-cycloalkyl, C2-C12-alkenyl, C2-C12-alkynyl, O-alkyl, O-alkenyl, O-alkynyl, S-alkyl, S-alkenyl, S-alkynyl, N-alkyl, N-alkenyl, and N-alkynyl of up to 12 carbon atoms optionally substituted by one or more halogens;
(2) —NR21(R22),
wherein R21 and R22 are individually hydrogen or C1-C12-alkyl;

(3) —C(O)R23,
wherein R23 is C1-C12-alkyl; and

(4) optionally substituted heteroaryl, O-aryl, S-aryl, and O-substituted-C1-C12 alkyl, or S-substituted-C1-C12 alkyl;
E) q is 0, 1, 2, 3, or 4; and

F) R33 and R34 are independently selected from the group consisting of hydrogen, halogen, C1-C12 alkyl, and substituted C1-C12-alkyl;
with the proviso that when q is 0, then R33 and R34 are not both hydrogen;
with the proviso that when Ra is ethyl, and R33 and R34 are hydrogen, then R32 is not 6-fluoro; and
with the proviso that when Ra is —CH═CH2, and R33 and R34 are hydrogen, then R32 is not 6-methyl.

2. The compound of claim 1, wherein
A) R is methyl;
B) Ra is selected from the group consisting of hydrogen, —CH2CH3, —CH═CH2, and —C≡CH,
C) Rb is hydrogen or halogen;
D) Each R32 is independently selected from the group consisting of halogen, C1-C12-alkyl, C1-C12-alkoxy, C1-C12-alkylalkoxy, and N-substituted-C1-C12-alkyl; and
E) R33 and R34 are independently selected from the group consisting of hydrogen or C1-C12-alkyl.

3. The compound of claim 1, wherein R is methyl.

4. The compound of claim 1, wherein Ra is —CH2CH3.

5. The compound of claim 1, wherein Ra is —CH═CH2.

6. The compound of claim 1, wherein Ra is —C≡CH.

7. The compound of claim 1, wherein Rb is hydrogen.

8. The compound of claim 1, wherein Rb is fluorine.

9. The compound of claim 1, wherein each R32 is independently selected from the group consisting of halogen, C1-C12-alkyl, C1-C12-alkoxy, C1-C12-alkylalkoxy, amino, and —NR21(R22).

10. The compound of claim 9, wherein at least one of R32 is 2-chloro, 6-chloro, 2-fluoro, or 6-fluoro.

11. The compound of claim 9, wherein at least one of R32 is methyl.

12. The compound of claim 10, wherein at least one of R32 is 5-methyl or 6-methyl.

13. The compound of claim 9, wherein at least one of R32 is methoxy or ethoxy.

14. The compound of claim 13, wherein at least one of R32 is 4-methoxy, 6-methoxy, 4-ethoxy, or 6-ethoxy.

15. The compound of claim 9, wherein at least one of R32 is amino, methylamino, or dimethylamino.

16. The compound of claim 15, wherein as least one of R32 is 6-amino, 6-methylamino, or 6-dimethylamino.

17. The compound of claim 1, wherein R33 and R34 are independently selected from the group consisting of hydrogen and C1-C12-alkyl.

18. The compound of claim 17, wherein R33 is methyl.

19. The compound of claim 17, wherein R34 is methyl.

20. The compound of claim 1 wherein
q is 1, R33 is hydrogen, R34 is hydrogen, and R32 is 6-methyl; or
q is 1, R33 is hydrogen, R34 is hydrogen, and R32 is 6-fluoro; or
q is 1, R33 is hydrogen, R34 is hydrogen, and R32 is 6-chloro; or
q is 1, R33 is hydrogen, R34 is hydrogen, and R32 is 6-methoxy; or
q is 1, R33 is hydrogen, R34 is hydrogen, and R32 is 6-ethoxy; or
q is 1, R33 is hydrogen, R34 is hydrogen, and R32 is 6-amino; or
q is 1, R33 is hydrogen, R34 is hydrogen, and R32 is 6-methylamino; or
q is 1, R33 is hydrogen, R34 is hydrogen, and R32 is 6-dimethylamino; or
q is 1, R33 is hydrogen, R34 is hydrogen, and R32 is 4-chloro; or
q is 1, R33 is hydrogen, R34 is hydrogen, and R32 is 4-methoxy; or
q is 1, R33 is hydrogen, R34 is hydrogen, and R32 is 2-chloro; or
q is 1, R33 is hydrogen, R34 is hydrogen, and R32 is 2-methoxy; or
q is 2, R33 is hydrogen, R34 is hydrogen, one of R32 is 5-methyl, and the other of R32 is 6-chloro; or
q is 1, R33 is methyl, R34 is hydrogen, and R32 is 6-methoxy; or
q is 1, R33 is methyl, R34 is hydrogen, and R32 is 6-chloro; or
q is 1, R33 is hydrogen, R34 is methyl, and R32 is 6-methoxy; or
q is 1, R33 is hydrogen, R34 is methyl, and R32 is 6-chloro.

21. The compound of claim 1 having the formula (XIII):



or a pharmaceutically acceptable salt or ester thereof.

22. The compound of claim 1 having the formula (XIV):



or a pharmaceutically acceptable salt or ester thereof.

23. The compound of claim 1 having the formula (XVII):



or a pharmaceutically acceptable salt or ester thereof.

24. The compound of claim 1 having the formula (XVIII):



or a pharmaceutically acceptable salt or ester thereof.

25. The compound of claim 1 having the formula (XIX):



or a pharmaceutically acceptable salt or ester thereof.

26. The compound of claim 1 having the formula (XX):



or a pharmaceutically acceptable salt or ester thereof.

27. The compound of claim 1 having the formula (XXI):



or a pharmaceutically acceptable salt or ester thereof.

28. The compound of claim 1 having the formula (XXII):



or a pharmaceutically acceptable salt or ester thereof.

29. The compound of claim 1 having the formula (XXIII):



or a pharmaceutically acceptable salt or ester thereof.

30. The compound of claim 1 having the formula (XXIV):



or a pharmaceutically acceptable salt or ester thereof.

31. The compound of claim 1 having the formula (XXV):



or a pharmaceutically acceptable salt or ester thereof.

32. The compound of claim 1 having the formula (XXVI):



or a pharmaceutically acceptable salt or ester thereof.

33. The compound of claim 1 having the formula (XXVII):



or a pharmaceutically acceptable salt or ester thereof.

34. The compound of claim 1 having the formula (XXVIII):



or a pharmaceutically acceptable salt or ester thereof.

35. The compound of claim 1 having the formula (XXIX):



or a pharmaceutically acceptable salt or ester thereof.

36. The compound of claim 1 having the formula (XXX):



or a pharmaceutically acceptable salt or ester thereof.

37. The compound of claim 1 having the formula (XXXI):



or a pharmaceutically acceptable salt or ester thereof.

38. The compound of claim 1 having the formula (XXXII):



or a pharmaceutically acceptable salt or ester thereof.

39. The compound of claim 1 having the formula (XXXIII):



or a pharmaceutically acceptable salt or ester thereof.

40. The compound of claim 1 having the formula (XXXIV):



or a pharmaceutically acceptable salt or ester thereof.

41. The compound of claim 1 having the formula (XXXV):



or a pharmaceutically acceptable salt or ester thereof.

42. The compound of claim 1 having the formula (XXXVI):



or a pharmaceutically acceptable salt or ester thereof.

43. The compound of claim 1 having the formula (XXXVII):



or a pharmaceutically acceptable salt or ester thereof.

44. The compound of claim 1 having the formula (XXXVIII):



or a pharmaceutically acceptable salt or ester thereof.

45. A pharmaceutical composition comprising a therapeutically effective amount of a compound any one of claims 1, 2, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, or 44 and a pharmaceutically acceptable carrier.

46. A method of treating bacterial infection in a patient in need thereof comprising administering to said patient a therapeutically effecting amount of a pharmaceutical composition comprising a compound any one of claims 1, 2, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, or 44 and a pharmaceutically acceptable carrier.