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Title:
TRIAZOLE COMPOUNDS AND METHODS OF MAKING AND USING THE SAME
Document Type and Number:
WIPO Patent Application WO/2018/191682
Kind Code:
A1
Abstract:
The present invention provides triazole macrocyclic compounds useful as therapeutic agents. More particularly, these compounds are useful as anti-infective, anti-proliferative, anti-inflammatory, and prokinetic agents.

Inventors:
KANYO ZOLTAN F (US)
DUFFY ERIN M (US)
BHATTACHARJEE ASHOKE (US)
WU YUSHENG (US)
TANG YUANQING (US)
Application Number:
PCT/US2018/027601
Publication Date:
October 18, 2018
Filing Date:
April 13, 2018
Export Citation:
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Assignee:
MELINTA THERAPEUTICS INC (US)
International Classes:
C07H17/08; A61K31/7056; A61P31/04
Domestic Patent References:
WO2008106224A12008-09-04
WO2005085266A22005-09-15
WO2007025098A22007-03-01
WO2008106226A22008-09-04
WO2008143730A22008-11-27
Attorney, Agent or Firm:
SPENCER, William T. et al. (P.O. Box 1022Minneapolis, Minnesota, US)
Download PDF:
Claims:
What is claimed is:

1. A compound of Formula I having the structure:

or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof,

wherein

A is selected from (a) a C1-6 alkyl group, (b) a C2-6 alkenyl group, (c) a

C2-6 alkynyl group, (d) a C3-12 saturated, unsaturated, or aromatic carbocycle, (e) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more nitrogen, oxygen or sulfur atoms, (f) H, (g) -OH (h)–SH, (i) F, (j) Cl, (k) Br, (l) I, (m)– CF3, (n)–CN, (o)–N3 (p)–NO2, (q)–NR6(CR6R6)tR9, (r)–OR9, (s)–S(CR6R6)tR9, (t)– S(O)(CR6R6)tR9 ,(u)–S(O)2(CR6R6)tR9 (v)–C(O)(CR6R6)tR9, (w)–OC(O)(CR6R6)tR9, (x)–OC(O)O(CR6R6)tR9, (y)–SC(O)(CR6R6)tR9, (z)–C(O)O(CR6R6)tR9, (aa)–

NR6C(O)(CR6R6)tR9, (bb)–C(O)NR6(CR6R6)tR9, (cc)–C(=NR6)(CR6R6)tR9, (dd)– C(=NNR6R6)(CR6R6)tR9, (ee)–C[=NNR6C(O)R6](CR6R6)tR9, (ff)–

NR6C(O)O(CR6R6)tR9, (gg)–OC(O)NR6(CR6R6)tR9, (hh)–NR6C(O)NR6(CR6R6)tR9, (ii)–NR6S(O)p(CR6R6)tR9, (jj)–S(O)pNR6(CR6R6)tR9, (kk)–NR6R6, (ll)–

NR6(CR6R6)tR9, (mm)–SR6, (nn)–S(O)R6, (oo)–S(O)2R6, (pp)–NR6C(O)R6, (qq)– Si(R13)3, and (rr)–C(=O)H;

wherein (a)-(e) optionally are substituted with one or more R14 groups;

X is selected from–OR15 and–SR15,

R1 and R3 independently are selected from: (a) H, (b) a

C1-6 alkyl group, (c) a C2-6 alkenyl group, (d) a C2-6 alkynyl group, (e)–C(O)R5,

(f)–C(O)OR5, (g)–C(O)–NR4R4, (h)–C(S)R5, (i)–C(S)OR5, (j)–C(O)SR5, or (k)–C(S)- NR4R4; alternatively R1 and R3 are taken together with the oxygen to which R1 is attached, the nitrogen to which R3 is attached and the two intervening carbons to form a 5 or 6 membered ring, said ring being optionally substituted with one or more R5;

R2 is hydrogen or–OR12;

R4, at each occurrence, independently is selected from:

(a) H, (b) a C1-6 alkyl group, (c) a C2-6 alkenyl group, (d) a C2-6 alkynyl group, (e) a C6-10 saturated, unsaturated, or aromatic carbocycle, (f) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (g)–C(O)– C1-6 alkyl, (h)–C(O)–C2-6 alkenyl, (i)–C(O)–C2-6 alkynyl, (j)–C(O)–C6-10 saturated, unsaturated, or aromatic carbocycle, (k)–C(O)–3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (l)–C(O)O–C1-6 alkyl, (m)–C(O)O–C2-6 alkenyl, (n)–C(O)O–C2-6 alkynyl, (o)–C(O)O–C6-10 saturated, unsaturated, or aromatic carbocycle, p)– C(O)O–3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, and q)–C(O)NR6R6,

wherein any of (b)–(p) optionally is substituted with one or more R5 groups,

alternatively, NR6R6 forms a 3-7 membered saturated, unsaturated or aromatic ring including the nitrogen atom to which the R6 groups are attached, wherein said ring is optionally substituted at a position other than the nitrogen atom to which the R6 groups are attached, with one or more substituents selected from O, S(O)p, N, and NR8;

R5 is selected from:

(a) R7, (b) a C1-8 alkyl group, (c) a C2-8 alkenyl group, (d) a C2-8 alkynyl group, (e) a C3-12 saturated, unsaturated, or aromatic carbocycle, and (f) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, or two R5 groups, when present on the same carbon atom can be taken together with the carbon atom to which they are attached to form a spiro 3- 6 membered carbocyclic ring or heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur; wherein any of (b)–(f) immediately above optionally is substituted with one or more R7 groups;

R6, at each occurrence, independently is selected from:

(a) H, (b) a C1-6 alkyl group, (c) a C2-6 alkenyl group, (d) a C2-6 alkynyl group, (e) a C3-10 saturated, unsaturated, or aromatic carbocycle, and (f) a 3- 10 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur,

wherein any of (b)–(f) optionally is substituted with one or more moieties selected from:

(aa) a carbonyl group, (bb) a formyl group, (cc) F, (dd) Cl, (ee) Br, (ff) I, (gg) CN, (hh) NO2, (ii)–OR8,

(jj)–S(O)pR8, (kk)–C(O)R8, (ll)–C(O)OR8,

(mm)–OC(O)R8, (nn)–C(O)NR8R8,

(oo)–OC(O)NR8R8, (pp)–C(=NR8)R8,

(qq)–C(R8)(R8)OR8, (rr)–C(R8)2OC(O)R8,

(ss)–C(R8)(OR8)(CH2)rNR8R8, (tt)–NR8R8,

(uu)–NR8OR8, (vv)–NR8C(O)R8,

(ww)–NR8C(O)OR8, (xx)–NR8C(O)NR8R8,

(yy)–NR8S(O)rR8, (zz)–C(OR8)(OR8)R8,

(ab)–C(R8)2NR8R8, (ac) =NR8,

(ad)–C(S)NR8R8, (ae)–NR8C(S)R8,

(af)–OC(S)NR8R8, (ag)–NR8C(S)OR8,

(ah)–NR8C(S)NR8R8, (ai)–SC(O)R8,

(aj) a C1-8 alkyl group, (ak) a C2-8 alkenyl group, (al) a C2-8 alkynyl group, (am) a C1-8 alkoxy group, (an) a C1-8 alkylthio group, (ao) a C1-8 acyl group, (ap)–CF3,

(aq)–SCF3 , (ar) a C3-10 saturated, unsaturated, or aromatic carbocycle, and (as) a 3-10 membered saturated,

unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, alternatively, NR6R6 forms a 3-10 membered saturated, unsaturated or aromatic ring including the nitrogen atom to which the R6 groups are attached wherein said ring is optionally substituted at a position other than the nitrogen atom to which the R6 groups are bonded, with one or more moieties selected from O, S(O)p, N, and NR8; alternatively, CR6R6 forms a carbonyl group;

R7, at each occurrence, is selected from:

(a) H, (b) =O, (c) =S, (d) F, (e) Cl, (f) Br, (g) I, (h)–CF3,

(i)–CN, (j)–N3 (k)–NO2, (l)–NR6(CR6R6)tR9, (m)–OR9, (n)–

S(O)pC(R6R6)tR9, (o)–C(O)(CR6R6)tR9, (p)–OC(O)(CR6R6)tR9, (q)– SC(O)(CR6R6)tR9, (r)–C(O)O(CR6R6)tR9, (s)–NR6C(O)(CR6R6)tR9, (t)– C(O)NR6(CR6R6)tR9, (u)–C(=NR6)(CR6R6)tR9, (v)–

C(=NNR6R6)(CR6R6)tR9, (w)–C(=NNR6C(O)R6)(CR6R6)tR9, (x)– C(=NOR9)(CR6R6)tR9, (y)–NR6C(O)O(CR6R6)tR9, (z)–

OC(O)NR6(CR6R6)tR9, (aa)–NR6C(O)NR6(CR6R6)tR9, (bb)–

NR6S(O)p(CR6R6)tR9, (cc)–S(O)pNR6(CR6R6)tR9, (dd)–

NR6S(O)pNR6(CR6R6)tR9, (ee)–NR6R6, (ff)–NR6(CR6R6), (gg)–OH, (hh) –NR6R6, (ii)–OCH3, (jj)–S(O)pR6, (kk)–NC(O)R6, (ll) a C1-6 alkyl group, (mm) a C2-6 alkenyl group, (nn) a C2-6 alkynyl group, (oo)–C3-10 saturated, unsaturated, or aromatic carbocycle, and (pp) 3-10 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur,

wherein any of (ll)–(pp) optionally is substituted with one or more R9 groups;

alternatively, two R7 groups can form–O(CH2)uO–;

R8 is selected from:

(a) H, (b) a C1-6 alkyl group, (c) a C2-6 alkenyl group, (d) a C2-6 alkynyl group, (e) a C3-10 saturated, unsaturated, or aromatic carbocycle, (f) a 3-10 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (g)–C(O)– C1-6 alkyl, (h)–C(O)–C1-6 alkenyl, (i)–C(O)–C1-6 alkynyl, (j)–C(O)–C3-10 saturated, unsaturated, or aromatic carbocycle, and (k)–C(O)–3-10 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur,

wherein any of (c)–(k) optionally is substituted with one or more moieties selected from : (aa) H, (bb) F, (cc) Cl, (dd) Br, (ee) I, (ff) CN, (gg) NO2, (hh) OH, (ii) NH2, (jj) NH(C1-6 alkyl), (kk) N(C1-6 alkyl)2, (ll) a C1-6 alkoxy group, (mm) an aryl group, (nn) a substituted aryl group, (oo) a heteroaryl group, (pp) a substituted heteroaryl group, and qq) a C1-6 alkyl group optionally substituted with one or more moieties selected from an aryl group, a substituted aryl group, a heteroaryl group, a substituted heteroaryl group, F, Cl, Br, I, CN, NO2, CF3, SCF3, and OH;

R9, at each occurrence, independently is selected from:

(a) R10, (b) a C1-6 alkyl group, (c) a C2-6 alkenyl group, (d) a C2-6 alkynyl group, e) a C3-10 saturated, unsaturated, or aromatic carbocycle, and f) a 3-10 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein any of (b)–(f) optionally is substituted with one or more R10 groups;

R10, at each occurrence, independently is selected from:

(a) H, (b) =O, (c) F, (d) Cl, (e) Br, (f) I, (g)–CF3, (h)–CN, (i)–NO2, (j)– NR6R6, (k)–OR6, (l)–S(O)pR6, (m)–C(O)R6, (n)–C(O)OR6, (o)– OC(O)R6, (p) NR6C(O)R6, (q)–C(O)NR6R6, (r)–C(=NR6)R6, (s)– NR6C(O)NR6R6, (t)–NR6S(O)pR6, (u)–S(O)pNR6R6, (v)–

NR6S(O)pNR6R6, (w) a C1-6 alkyl group, (x) a C2-6 alkenyl group, (y) a C2-6 alkynyl group, (z) a C3-10 saturated, unsaturated, or aromatic carbocycle, and (aa) a 3-10 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur,

wherein any of (w)–(aa) optionally is substituted with one or more moieties selected from R6, F, Cl, Br, I, CN, NO2,–OR6,–NH2,– NH(C1-6 alkyl),–N(C1-6 alkyl)2, a C1-6 alkoxy group, a C1-6 alkylthio group, and a C1-6 acyl group;

R11 at each occurrence, independently is selected from:

(a) H, (b) F, (c) Cl, (d) Br, (e) I, (f) CN, (g) NO2, (h) OR8, (i)–S(O)pR8, (j) –C(O)R8, (k)–C(O)OR8, (l)–OC(O)R8, (m)–C(O)NR8R8, (n)–

OC(O)NR8R8,

(o)–C(=NR8)R8, (p)–C(R8)(R8)OR8, (q)–C(R8)2OC(O)R8,

(r)–C(R8)(OR8)(CH2)rNR8R8, (s)–NR8R8, (t)–NR8OR8, (u)–NR8C(O)R8, (v)–NR8C(O)OR8, (w)–NR8C(O)NR8R8, (x)–

NR8S(O)pR8, (y)–C(OR8)(OR8)R8, (z)–C(R8)2NR8R8, (aa)–C(S)NR8R8, (bb)–NR8C(S)R8, (cc)–OC(S)NR8R8, (dd)–NR8C(S)OR8, (ee)–

NR8C(S)NR8R8, (ff)–SC(O)R8, (gg) -N3, (hh)–Si(R13)3, (ii) a C1-8 alkyl group, (jj) a C2-8 alkenyl group, (kk) a C2-8 alkynyl group, (ll) a C3-10 saturated, unsaturated, or aromatic carbocycle, and (mm) a 3-10 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein (ii)-(mm) optionally are substituted with one or more R5 groups;

R12 is selected from:

(a) H, (b) a C1-6 alkyl group, (c) a C2-6 alkenyl group, (d) a C2-6 alkynyl group, (e)–C(O)R5, (f)–C(O)OR5, (g)–C(O)–NR4R4R4R4, (h)–C(S)R5, (i) –C(S)OR5, (j)–C(O)SR5, (k)–C(S)-NR4R4R4R4, (l) a C3-10 saturated, unsaturated, or aromatic carbocycle, or (m) a 3-10 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (n) a–(C1-6 alkyl)–C3-10 saturated, unsaturated, or aromatic carbocycle, or (o) a–(C1-6 alkyl)-3-10 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur,

wherein (a)–(d) and (l)–(o) optionally are substituted with one or more R5 groups;

each R13 is independently selected from (a) -C1-6 alkyl and (b)–O-(C1-6 alkyl); R14 at each occurrence is independently selected from:

(a) H, (b) F, (c) Cl, (d) Br, (e) I, (f) CN, (g) NO2, (h) OR8, (i)–S(O)pR8, (j) –C(O)R8, (k)–C(O)OR8, (l)–OC(O)R8, (m)–C(O)NR8R8, (n)–

OC(O)NR8R8, (o)–C(=NR8)R8, (p)–C(R8)(R8)OR8, (q)–C(R8)2OC(O)R8, (r)–C(R8)(OR8)(CH2)rNR8R8, (s)–NR8R8, (t)–NR8OR8,

(u)–NR8C(O)R8, (v)–NR8C(O)OR8, (w)–NR8C(O)NR8R8, (x)–

NR8S(O)pR8, (y)–C(OR8)(OR8)R8, (z)–C(R8)2NR8R8, (aa)–C(S)NR8R8, (bb)–NR8C(S)R8, (cc)–OC(S)NR8R8, (dd)–NR8C(S)OR8, (ee)–

NR8C(S)NR8R8, (ff)–SC(O)R8, (gg) -N3, (hh)–Si(R13)3, (ii) a C1-8 alkyl group, (jj) a C2-8 alkenyl group, (kk) a C2-8 alkynyl group, (ll) a C3-10 saturated, unsaturated, or aromatic carbocycle, and (mm) a 3-10 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein (ii)-(mm) optionally are substituted with one or more R5 groups;

alternatively two R14 groups are taken together to form (a) =O, (b) =S, (c) =NR8, (e) =NOR8;

R15 is selected from C1-6 alkyl, optionally substituted with from 1 to 13 fluorine atoms;

n at each occurrence is 0, 1, 2, 3, or 4;

p at each occurrence is 0, 1, or 2;

r at each occurrence is 0, 1, or 2;

t at each occurrence is 0, 1, or 2;

and u at each occurrence is 1, 2, 3, or 4; and

T is:

,

wherein:

M is–C(=NOR127)–;

R100 is selected from (a) H, (b) F, (c) Cl, (d) Br, (e)–SR114, and (f) C1-6 alkyl, wherein (f) optionally is substituted with one or more R115 groups;

R101 is selected from:

(a) H, (b) Cl, (c) F, (d) Br, (e) I, (f)–NR114R114, (g)–NR114C(O)R114, (h)– OR114,

(i)–OC(O)R114, (j)–OC(O)OR114, (k)–OC(O)NR114R114, (l)–O–C1-6 alkyl, (m)–OC(O)–C1-6 alkyl, (n)–OC(O)O–C1-6 alkyl, (o)–OC(O)NR114–C1- 6 alkyl,

(p) C1-6 alkyl, (q) C1-6 alkenyl, and (r) C1-6 alkynyl,

wherein any of (l)– (r) optionally is substituted with one or more R115 groups; R102 is H, (b) F, (c) Cl, (d) Br, (e)–SR114, (f) C1-6 alkyl, wherein (f) optionally is substituted with one or more R115 groups;

R103 is selected from:

(a) H, (b)–OR114, (c)–O–C1-6 alkyl–R115, (d)–OC((O)R114, (e)–OC(O)–C1-6 alkyl–R115, (f)–OC(O)OR114, (g)–OC(O)O–C1-6 alkyl– R115,

(h)–OC(O)NR114R114, (i)–OC(O)NR114–C1-6 alkyl–R115, and

alternatively, R102 and R103 taken together with the carbon to which they are attached form (a) a carbonyl group or (b) a 3-7 membered saturated, unsaturated or aromatic carbocyclic or heterocyclic ring which can optionally be substituted with one or more R114 groups;

alternatively, R101 and R103 taken together are a single bond between the respective carbons to which these two groups are attached thereby creating a double bond between the carbons to which R100 and R102 are attached;

alternatively, R101 and R103 taken together with the carbons to which they are attached form a 3-membered saturated, unsaturated or aromatic carbocyclic or heterocyclic ring which can optionally be substituted with one or more R114 groups;

R104 is selected from:

(a) H, (b) R114, (c)–C(O)R114(d)–C(O)OR114 (e)–C(O)NR114R114, (f)–C1-6 alkyl–K–R114, (g)–C2-6 alkenyl–K–R114, and (h)–C2-6 alkynyl–K–R114; K is selected from:

(a)–C(O)–, (b)–C(O)O–, (c)–C(O)NR114–, (d)–C(=NR114)–, (e)– C(=NR114)O–,

(f)–C(=NR114)NR114–, (g)–OC(O)–, (h)–OC(O)O–, (i)–OC(O)NR114–, (j)–NR114C(O)–, (k)–NR114C(O)O–, (l)–NR114C(O)NR114–, (m)–NR114C(=NR114)NR114–, and (o)–S(O)p–;

alternatively R103 and R104, taken together with the atoms to which they are bonded, form:

wherein R135 and R136 are selected from (a) hydrogen, (b) C1-6 alkyl, (c) C2-6 alkenyl, (d) C2-6 alkynyl, (d) C3-14 saturated, unsaturated or aromatic carbocycle, (e) 3-l4 membered saturated, unsaturated or aromatic heterocycle containing one or more oxygen, nitrogen, or sulfur atoms, (f) F, (g) Br, (h) I, (i) OH, (j)–N3, wherein (b) through (e) are optionally substituted with one or more R117; or alternatively, R135 and R136 are taken together to form =O, =S and =NR114, =NOR114, =NR114, and =N-NR114,R114 ],

wherein V is selected from(a)–(C4-alkyl)-, (b)-(C4-alkenyl)-, (c) O, (d) S, and (e) NR114, wherein (a) and (b) are optionally further substituted with one or more R117;

R105 is selected from:

(a) R114, (b)–OR114, (c)–NR114R114, (d)–O–C1-6 alkyl–R115, (e)–C(O)– R114,

(f)–C(O)–C1-6 alkyl–R115, (g)–OC(O)–R114, (h)–OC(O)–C1-6 alkyl–R115, (i)–OC(O)O–R114, (j)–OC(O)O–C1-6 alkyl–R115, (k)–OC(O)NR114R114, (l)–OC(O)NR114–C1-6 alkyl–R115, (m)–C(O)–C2-6 alkenyl–R115, and (n)–C(O)–C2-6 alkynyl–R115;

alternatively, R104 and R105, taken together with the atoms to which they are bonded, form

wherein

Q is CH or N, and R126 is–OR114,–NR114 or R114;

alternatively, R104 and R105, taken together with the atoms to which they are bonded, form:

wherein

i) R101 is as defined above;

ii) alternately, R101 and R109 can be taken together with the carbon to which they are attached to form a carbonyl group; iii) alternately, R101 and R109 can be taken together to form the group–O(CR116R116)uO–;

alternatively, R104 and R105, taken together with the atoms to which they are bonded, form:

wherein in the preceding structure the dotted line indicates an optional double bond i) R130 is–OH or R114,

ii) R131 is–OH or R114,

iii) alternately, R130 and R131 together with the carbons to which they are attached form a 3-7 membered saturated, unsaturated or aromatic carbocyclic or heterocyclic ring which can optionally be substituted with one or more R114 groups;

iv) alternatively, R130 and the carbon to which it is attached or R131 and the carbon to which it is attached are each independently–C(=O)-,

alternatively, R105, R132 and M, taken together with the atoms to which they are attached, form:

R106 is selected from:

(a)–OR114, (b)–C1-6 alkoxy–R115, (c)–C(O)R114, (d)–OC(O)R114, (e)– OC(O)OR114, (f)–OC(O)NR114R114, and (g)–NR114R114,

alternatively, R105 and R106 taken together with the atoms to which they are attached form a 5-membered ring by attachment to each other through a chemical moiety selected from:

(a)–OC(R115)2O–, (b)–OC(O)O–, (c)–OC(O)NR114–, (d)–NR114C(O)O–, (e)–OC(O)NOR114–, (f)–NOR114–C(O)O–, (g)–OC(O)NNR114R114–, (h)–NNR114R114–C(O)O–, (i)–OC(O)C(R115)2–, (j)–C(R115)2C(O)O–, (k) –OC(S)O–, (l)–OC((S)NR114–, (m)–NR114C(S)O–, (n)–OC(S)NOR114–, (o)–NOR114–C(S)O–, (p)–OC(S)NNR114R114–, (q)–NNR114R114–C(S)O–, (r)–OC(S)C(R115)2–, and (s)–C(R115)2C(S)O–;

alternatively, R105, R106, and R133 taken together with the atoms to which they are attached form:

, alternatively, M, R105, and R106 taken together with the atoms to which they are attached form:

bond, wherein in the preceding structure the dotted line indicates an optional double

,

wherein J1 and J2 are selected from hydrogen, Cl, F, Br, I, OH, -C1-6 alkyl, and -O(C1- 6alkyl) or are taken together to form =O, =S and =NR114, =NOR114, =NR114, and =N-NR114,R114; alternatively, M and R104 taken together with the atoms to which they are attached form:

wherein U is selected from(a)–(C4-alkyl)- and (b)-(C4-alkenyl)-, wherein (a) and (b) are optionally further substituted with one or more R117;

alternatively, M and R105 are taken together with the atoms to which they are attached to form:

,

R107 is selected from

(a) H, (b)–C1-4 alkyl, (c)–C2-4 alkenyl, which can be further substituted with C1-12 alkyl or one or more halogens, (d)–C2-4 alkynyl, which can be further substituted with C1-12 alkyl or one or more halogens, (e) aryl or heteroaryl, which can be further substituted with C1-12 alkyl or one or more halogens, (f)–C(O)H, (g)–COOH, (h)–CN, (i)–COOR114, (j) - C(O)NR114R114, (k)–C(O)R114, and (l)–C(O)SR114, wherein (b) is further substituted with one or more substituents selected from (aa)–OR114, (bb) halogen, (cc)–SR114, (dd) C1-12 alkyl, which can be further substituted with halogen, hydroxyl, C1-6 alkoxy, or amino, (ee)–OR114, (ff)–SR114, (gg)– NR114R114, (hh)–CN, (ii)-NO2, (jj)–NC(O)R114, (kk)–COOR114, (ll)–N3, (mm) =N-O-R114, (nn) =NR114, (oo) =N-NR114R114, (pp) =N-NH-C(O)R114, and (qq) =N-NH-C(O)NR114R114;

alternatively R106 and R107 are taken together with the atom to which they are attached to form an epoxide, a carbonyl, an olefin, or a substituted olefin, or a C3-C7 carbocyclic, carbonate, or carbamate, wherein the nitrogen of said carbamate can be further substituted with a C1-C6 alkyl;

R108 is selected from:

(a) C1-6 alkyl, (b) C2-6 alkenyl, and (c) C2-6 alkynyl,

wherein any of (a)–(c) optionally is substituted with one or more R114 groups;

R111 is selected from H and–C(O)R114;

R112 is selected from H, OH, and OR114;

R113 is selected from: (a) H, (b) R114, (c)–C1-6 alkyl–K–R114, (d)–C2-6 alkenyl–K–R114, and (e)–C2-6 alkynyl–K–R114,

wherein any of (c)-(e) optionally is substituted with one or more R115 groups;

R114, at each occurrence, independently is selected from:

(a) H, (b) C1-6 alkyl, (c) C2-6 alkenyl, (d) C2-6 alkynyl, (e) C6-10 saturated, unsaturated, or aromatic carbocycle, (f) 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (g)–C(O)–C1-6 alkyl, (h)– C(O)–C2-6 alkenyl, (i)–C(O)–C2-6 alkynyl, (j)–C(O)–C6-10 saturated, unsaturated, or aromatic carbocycle, (k)–C(O)–3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (l)–C(O)O–C1-6 alkyl, (m)– C(O)O–C2-6 alkenyl, (n)–C(O)O–C2-6 alkynyl, (o)–C(O)O–C6-10 saturated, unsaturated, or aromatic carbocycle, (p)–C(O)O–3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (q)–C(O)NR116R116, (r)– NR116CO-C2-6 alkyl, (s)–NR116CO-C6-10 saturated, unsaturated, or aromatic carbocycle, and (t)–NR116C(O)-3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur

wherein any of (b)–(t) optionally is substituted with one or more R115 groups, wherein one or more non-terminal carbon moieties of any of (b)–(d) optionally is replaced with oxygen, S(O)p, or–NR116, alternatively, NR114R114 forms a 3-7 membered saturated, unsaturated or aromatic ring including the nitrogen atom to which the R114 groups are bonded and optionally one or more moieties selected from O, S(O)p, N, and NR118;

R115 is selected from:

(a) R117, (b) C1-8 alkyl, (c) C2-8 alkenyl, (d) C2-8 alkynyl, (e) C3-12 saturated, unsaturated, or aromatic carbocycle, (f) 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur,

wherein any of (b)–(f) optionally is substituted with one or more R117 groups; R116, at each occurrence, independently is selected from:

(a) H, (b) C1-6 alkyl, (c) C2-6 alkenyl, (d) C2-6 alkynyl, (e) C3-10 saturated, unsaturated, or aromatic carbocycle, and (f) 3-10 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur,

wherein one or more non-terminal carbon moieties of any of (b)–(d) optionally is replaced with oxygen, S(O)p, or–NR114, wherein any of (b)– (f) optionally is substituted with one or more moieties selected from:

(aa) carbonyl, (bb) formyl, (cc) F, (dd) Cl, (ee) Br, (ff) I, (gg) CN, (hh) N3, (ii)NO2, (jj) OR118, (kk)–S(O)pR118, (ll)– C(O)R118, (mm)–C(O)OR118, (nn)–OC(O)R118, (oo)– C(O)NR118R118, (pp)–OC(O)NR118R118, (qq)–

C(=NR118)R118, (rr)–C(R118)(R118)OR118, (ss)–

C(R118)2OC(O)R118, (tt)–C(R118)(OR118)(CH2)rNR118R118, (uu)–NR118R118; (vv)–NR118OR118, (ww)–NR118C(O)R118, (xx)–NR118C(O)OR118, (yy)–NR118C(O)NR118R118, (zz)– NR118S(O)rR118, (ab)–C(OR118)(OR118)R118, (ac)–

C(R118)2NR118R118, (ad) =NR118, (ae)–C(S)NR118R118, (af)– NR118C(S)R118, (ag)–OC(S)NR118R118, (ah)–

NR118C(S)OR118, (ai)–NR118C(S)NR118R118, (aj)–

SC(O)R118, (ak) C1-8 alkyl, (al) C2-8 alkenyl, (am)

C2-8 alkynyl, (an) C1-8 alkoxy, (ao) C1-8 alkylthio, (ap) C1-8 acyl, (aq) saturated, unsaturated, or aromatic C3-10 carbocycle, and (ar) saturated, unsaturated, or aromatic 3-10 membered heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur,

alternatively, NR116R116 forms a 3-10 membered saturated, unsaturated or aromatic ring including the nitrogen atom to which the R116 groups are attached and optionally one or more moieties selected from O, S(O)p, N, and NR118;

alternatively, CR116R116 forms a carbonyl group;

R117, at each occurrence, is selected from:

(a) H, (b) =O, (c) F, (d) Cl, (e) Br, (f) I, (g) (CR116R116)rCF3, (h)

(CR116R116)rCN, (i) (CR116R116)rNO2, (j) (CR116R116)rNR116(CR116R116)tR119, (k) (CR116R116)rOR119,

(l) (CR116R116)rS(O)p(CR116R116)tR119, (m) (CR116R116)rC(O)(

CR116R116)tR119, (n) (CR116R116)rOC(O)( CR116R116)tR119,

(o) (CR116R116)rSC(O)( CR116R116)tR119,

(p) (CR116R116)rC(O)O(CR116R116)tR119, (q) (CR116R116)rNR116C(O)( CR116R116)tR119, (r) (CR116R116)rC(O)NR116(CR116R116)tR119, (s)

(CR116R116)rC(=NR116)( CR116R116)tR119,

(t) (CR116R116)rC(=NNR116R116)(CR116R116)tR119,

(u) (CR116R116)rC(=NNR116C(O)R116)( CR116R116)tR119,

(v) (CR116R116)rC(=NOR119)( CR116R116)tR119,

(w) (CR116R116)rNR116C(O)O(CR116R116)tR119,

(x) (CR116R116)rOC(O)NR116(CR116R116)tR119,

(y) (CR116R116)rNR116C(O)NR116(CR116R116)tR119,

(z) (CR116R116)rNR116S(O)p(CR116R116)tR119,

(aa) (CR116R116)rS(O)pNR116(CR116R116)tR119,

(bb) (CR116R116)rNR116S(O)pNR116(CR116R116)tR119,

(cc) (CR116R116)rNR116R116, (dd) C1-6 alkyl, (ee) C2-6 alkenyl,

(ff) C2-6 alkynyl, (gg) (CR116R116)r–C3-10 saturated, unsaturated, or aromatic carbocycle, and (hh) (CR116R116)r–3-10 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur,

wherein any of (dd)–(hh) optionally is substituted with one or more R119 groups;

alternatively, two R117 groups can form–O(CH2)uO–;

R118 is selected from:

(a) H, (b) C1-6 alkyl, (c) C2-6 alkenyl, (d) C2-6 alkynyl, (e) C3-10 saturated, unsaturated, or aromatic carbocycle, (f) 3-10 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (g)–C(O)–C1-6 alkyl, (h)– C(O)–C1-6 alkenyl, (g)–C(O)–C1-6 alkynyl, (i)–C(O)–C3-10 saturated, unsaturated, or aromatic carbocycle, and (j)–C(O)–3-10 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein any of (b)–(j) optionally is substituted with one or more moieties selected from : (aa) H, (bb) F, (cc) Cl, (dd) Br, (ee) I, (ff) CN, (gg) NO2, (hh) OH, (ii) NH2, (jj) NH(C1-6 alky(l), (kk)

N(C1-6 alky(l)2, (ll) C1-6 alkoxy, (mm) aryl, (nn) substituted aryl, (oo) heteroaryl, (pp) substituted heteroaryl, and (qq) C1-6 alkyl, optionally substituted with one or more moieties selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, F, Cl, Br, I, CN, NO2, and OH;

R119, at each occurrence, independently is selected from:

(a) R120, (b) C1-6 alkyl, (c) C2-6 alkenyl, (d) C2-6 alkynyl, (e) C3-10 saturated, unsaturated, or aromatic carbocycle, and (f) 3-10 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur,

wherein any of (b)–(f) optionally is substituted with one or more R119 groups;

R120, at each occurrence, independently is selected from:

(a) H, (b) =O, (c) F, (d) Cl, (e) Br, (f) I, (g) (CR116R116)rCF3, (h)

(CR116R116)rCN, (i) (CR116R116)rNO2, (j) (CR116R116)rNR116R116, (k) (CR116R116)rOR114, (l) (CR116R116)rS(O)pR116, (m) (CR116R116)rC(O)R116, (n) (CR116R116)rC(O)OR116, (o) (CR116R116)rOC(O)R116, (p)

(CR116R116)rNR116C(O)R116, (q) (CR116R116)rC(O)NR116R116, (r)

(CR116R116)rC(=NR116)R116, (s) (CR116R116)rNR116C(O)NR116R116,

(t) (CR116R116)rNR116S(O)pR116, (u) (CR116R116)rS(O)pNR116R116, (v) (CR116R116)rNR116S(O)pNR116R116, (w) C1-6 alkyl, (x) C2-6 alkenyl, (y) C2-6 alkynyl, (z) (CR116R116)r–C3-10 saturated, unsaturated, or aromatic carbocycle, and (aa) (CR116R116)r–3-10 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur,

wherein any of (w)–(aa) optionally is substituted with one or more moieties selected from R116, F, Cl, Br, I, CN, NO2,–OR116,–NH2,– NH(C1-6 alkyl),–N(C1-6 alkyl)2, C1-6 alkoxy, C1-6 alkylthio, and C1-6 acyl;

R121, at each occurrence, independently is selected from: (a) H, (b)–OR118, (c)–O–C1-6 alkyl–OC(O)R118, (d)–O–C1-6 alkyl– OC(O)OR118, (e)–O–C1-6 alkyl–OC(O)NR118R118, (f)–O–C1-6 alkyl– C(O)NR118R118, (g)–O–C1-6 alkyl–NR118C(O)R118, (h)–O–C1-6 alkyl– NR118C(O)OR118, (i)–O–C1-6 alkyl–NR118C(O)NR118R118, (j)–O–

C1-6 alkyl–NR118C(=N(H)NR118R118, (k)–O–C1-6 alkyl–S(O)pR118, (l)–O– C2-6 alkenyl–OC(O)R118, (m)–O–C2-6 alkenyl–OC(O)OR118, (n)–O–C2-6 alkenyl–OC(O)NR118R118, (o)–O–C2-6 alkenyl–C(O)NR118R118, (p)–O– C2-6 alkenyl–NR118C(O)R118, (q)–O–C2-6 alkenyl–NR118C(O)OR118, (r)– O–C2-6 alkenyl–NR118C(O)NR118R118, (s)–O–C2-6 alkenyl–

NR118C(=N(H)NR118R118, (t)–O–C2-6 alkenyl–S(O)pR118,

(u)–O–C2-6 alkynyl–OC(O)R118, (v)–O–C2-6 alkynyl–OC(O)OR118, (w)–O–C2-6 alkynyl–OC(O)NR118R118, (x)–O–C2-6 alkynyl–

C(O)NR118R118, (y)–O–C2-6 alkynyl–NR118C(O)R118, (z)–O–C2-6 alkynyl– NR118C(O)OR118, (aa)–O–C2-6 alkynyl–NR118C(O)NR118R118,

(bb)–O–C2-6 alkynyl–NR118C(=N(H)NR118R118, (cc)–O–C2-6 alkynyl– S(O)pR118; and (dd)–NR118R118;

alternatively, two R121 groups taken together form =O, =NOR118, or =NNR118R118; R122 is R115;

R123 is selected from:

(a) R116, (b) F, (c) Cl, (d) Br, (e) I, (f) CN, (g) NO2, and (h)–OR114;

alternatively, R122 and R123 taken together are–O(CH2)uO–;

R124, at each occurrence, independently is selected from:

(a) H, (b) F, (c) Cl, (d) Br, (e) I, (f) CN, (g)–OR114, (h)–NO2, (i)– NR114R114, (j) C1-6 alkyl, (k) C1-6 acyl, and (l) C1-6 alkoxy;

R125 is selected from:

(a) C1-6 alkyl, (b) C2-6 alkenyl, (c) C2-6 alkynyl, (d) C1-6 acyl, (e) C1-6 alkoxy, (f) C1-6 alkylthio, (g) saturated, unsaturated, or aromatic

C5-10 carbocycle, (h) saturated, unsaturated, or aromatic 5-10 membered heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (i)–O–C1-6 alkyl-saturated, unsaturated, or aromatic 5-10 membered heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (j)–NR114-C1-6 alkyl-saturated, unsaturated, or aromatic 5-10 membered heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur,

(k) saturated, unsaturated, or aromatic 10-membered bicyclic ring system optionally containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (l) saturated, unsaturated, or aromatic 13-membered tricyclic ring system optionally containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (m)–OR114,

(n)–NR114R114, (o)–S(O)pR114, and (p)–R124,

wherein any of (a)-(l) optionally is substituted with one or more R115 groups;

alternatively, R125 and one R124 group, taken together with the atoms to which they are bonded, form a 5-7 membered saturated or unsaturated carbocycle, optionally substituted with one or more R115 groups; or a 5-7 membered saturated or unsaturated heterocycle containing one or more atoms selected from nitrogen, oxygen, and sulfur, and optionally substituted with one or more R115 groups;

R126 at each occurrence, independently is selected from:

(a) hydrogen, (b) an electron-withdrawing group, (c) aryl, (d) substituted aryl, (e) heteroaryl, (f) substituted heteroaryl, and (g) C1-6 alkyl, optionally substituted with one or more R115 groups;

alternatively, any R126 and any R123, taken together with the atoms to which they are bonded, form a 5-7 membered saturated or unsaturated carbocycle, optionally substituted with one or more R115 groups; or a 5-7 membered saturated or unsaturated heterocycle containing one or more atoms selected from nitrogen, oxygen, and sulfur, and optionally substituted with one or more R115 groups;

R109 is H or F;

R127 is R114, a monosaccharide or disaccharide (including amino sugars and halo sugar(s),–(CH2)n-(O-CH2CH2-)m-O(CH2)pCH3 or–(CH2)n-(O-CH2CH2-)m-OH, R128 is R114;

R129 is R114;

R110 is R114;

alternatively, R109 and R110 taken together with the carbons to which they are attached form: alternately, R128 and R129 together with the carbons to which they are attached form a 3-6 membered saturated, unsaturated or aromatic carbocyclic or heterocyclic ring which can optionally be substituted with one or more R114 groups;

R132 , R133, and R134 are each independently selected from (a) H, (b) F, (c) Cl, (d) Br, (e)–OR114, (f)–SR114, (g)–NR114R114, and (h) C1-6 alkyl, wherein (h) optionally is substituted with one or more R115 groups;

alternatively, R132 and R133 are taken together to form a carbon-carbon double bond;

alternatively, R133 and R134 are taken together to form =O, =S, =NOR114, =NR114, and =N-NR114;

alternatively, R105 and R134 are taken together with the carbons to which they are attached to form a 3-membered ring, said ring optionally containing an oxygen or nitrogen atom, and said ring being optionally substituted with one or more R114 groups;

alternatively when M is a carbon moiety, R134 and M are taken together to form a carbon-carbon double bond;

k, at each occurrence is 0, 1, or 2;

m, at each occurrence is 0, 1, 2, 3, 4, or 5;

n, at each occurrence is 1, 2, or 3; and

provided that the compound is not a compound disclosed in PCT application No. WO2008/143730 or PCT application No. WO2008/106226.. 2. A compound according to claim 1 having the structure:

or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R1, R2, R3, R11, R15, A, T, and n are as described in claim 1.

3. A compound according to claim 1 having the structure:

or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R1, R2, R3, R11, R15, A, T, and n are as described in claim 1. 4. A compound according to any of claims 1-3, or a pharmaceutically acceptable salt, ester, N-oxide or prodrug thereof, wherein R15 is C1-3 alkyl, optionally substituted with from 1 to 7 fluorines. 5. A compound according to any of claims 1-3, or a pharmaceutically acceptable salt, ester, N-oxide or prodrug thereof, wherein R15 is C1-2 alkyl, optionally substituted with from 1 to 5 fluorines. 6. A compound according to any of claims 1-3, or a pharmaceutically acceptable salt, ester, N-oxide or prodrug thereof, wherein R15 is selected from–CH3, -CH2F, -CHF2, and –CF3. 7. A compound according to claim 6, or a pharmaceutically acceptable salt, ester, N- oxide or prodrug thereof, wherein R15 is–CH3. 8. A compound according to claim 1 having the structure:

or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R1, R2, R3, R11, A, T, and n are as described in claim 1. 9. A compound according to any of claims 1-8, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein n is 1 or 2. 10. A compound according to any of claims 1-8, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein n is 1. 11. A compound according to any of claims 1 to 10, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R11 is F. 12. A compound according to any of claims 1-8, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein n is 0. 13. A compound according to any of claims 1-12, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein A is selected from (a) a C1-6 alkyl group, (b) a C2-6 alkenyl group, (c) a C2-6 alkynyl group, (d) a C3-12 saturated, unsaturated, or aromatic carbocycle, (e) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more nitrogen, oxygen or sulfur atoms, (f)–CF3, (g)–NR6(CR6R6)tR9, (h)–OR9, (i)–S(CR6R6)tR9, (j)–S(O)(CR6R6)tR9 ,(k)–S(O)2(CR6R6)tR9 (l)–

C(O)(CR6R6)tR9, (m)–OC(O)(CR6R6)tR9, (n)–OC(O)O(CR6R6)tR9, (o)–

SC(O)(CR6R6)tR9, (p)–C(O)O(CR6R6)tR9, (q)–NR6C(O)(CR6R6)tR9, (r)–

C(O)NR6(CR6R6)tR9, (s)–C(=NR6)(CR6R6)tR9, (t)–C(=NNR6R6)(CR6R6)tR9, (u)– C[=NNR6C(O)R6](CR6R6)tR9, (v)–NR6C(O)O(CR6R6)tR9, (w)–OC(O)NR6(CR6R6)tR9, (x)–NR6C(O)NR6(CR6R6)tR9, (y)–NR6S(O)p(CR6R6)tR9, (z)–S(O)pNR6(CR6R6)tR9, (aa)–NR6R6, (bb)–NR6(CR6R6)tR9, (cc)–SR6, (dd)–S(O)R6, (ee)–S(O)2R6, and (ff)– NR6C(O)R6, wherein (a)-(e) optionally are substituted with one or more R14 groups. 14. A compound according to any of claims 1-12, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein A is selected from (a) a C1-6 alkyl group, (b) a C2-6 alkenyl group, (c) a C2-6 alkynyl group, (d) a C3-12 saturated, unsaturated, or aromatic carbocycle, (e) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more nitrogen, oxygen or sulfur atoms,;

wherein (a)-(e) optionally are substituted with one or more R14 groups. 15. A compound according to any of claims 1-12, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein A is selected (a)–NR6(CR6R6)tR9, (b)– OR9, (c)–S(CR6R6)tR9, (d)–S(O)(CR6R6)tR9 ,(e)–S(O)2(CR6R6)tR9 (f)–C(O)(CR6R6)tR9, (g)–OC(O)(CR6R6)tR9, (h)–OC(O)O(CR6R6)tR9, (i)–SC(O)(CR6R6)tR9, (j)–

C(O)O(CR6R6)tR9, (k)–NR6C(O)(CR6R6)tR9, (l)–C(O)NR6(CR6R6)tR9, (m)–

C(=NR6)(CR6R6)tR9, (n)–C(=NNR6R6)(CR6R6)tR9, (o)–C[=NNR6C(O)R6](CR6R6)tR9, (p)–NR6C(O)O(CR6R6)tR9, (q)–OC(O)NR6(CR6R6)tR9, (r)–NR6C(O)NR6(CR6R6)tR9, (s)–NR6S(O)p(CR6R6)tR9, (t)–S(O)pNR6(CR6R6)tR9, (u)–NR6R6, (v)–NR6(CR6R6)tR9, (w)–SR6, (x)–S(O)R6, (y)–S(O)2R6, and (z)–NR6C(O)R6. 16. A compound according to any of claims 1-14, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein A is a 3-12 (e.g., 5-6, 3.g., 6) membered saturated, unsaturated, or aromatic heterocycle containing one or more nitrogen, oxygen or sulfur atoms and optionally are substituted with one or more R14 groups (e.g., an aromatic heterocycle containing one or more nitrogen, oxygen or sulfur atoms, e.g., one or more nitrogen atoms; e.g., pyridyl, e.g., 3-pyridyl). 17. A compound according to any of claims 1-16, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein T is selected from:

, wherein M, R100, R101, R104, R105, R106, R107, R108, R109, R110, and R120 are as described in claim 9 and where the dotted lines indicate optional double bonds.

, , wherein M, R100, R101, R102, R104, R109, R114, R126 and R127 are as described in claim 9.

19. A compound according to any of claims 1-18, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein T is selected from:

, wherein M, R1, R2, R104, R114, R109 and R127 are as described in claim 16. 20. A compound according to any of claims 1-19, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein T is selected from T1 through T33:

21. A compound or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, selected from Table I:

. 22. A pharmaceutical composition comprising a compound according to any of claims 1-21, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, and a pharmaceutically acceptable carrier. 23. A method for treating or preventing a disease state in a mammal comprising administering to a mammal in need thereof an effective amount of a compound according to any of claims 1-21, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof. 24. A method of treating or preventing a microbial infection in a mammal comprising administering to the mammal an effective amount of a compound according to any of claims 1-21, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof. 25. A method according to claim 24 wherein said microbial infection is an

uncomplicated skin or soft tissue infection (uSSTI). 26. A method according to claim 24 wherein said microbial infection is a community acquired or community associated infection. 27. A method according to claim 26 wherein said microbial infection is an

uncomplicated skin or soft tissue infection (uSSTI). 28. A method of treating or preventing a fungal infection in a mammal comprising administering to the mammal an effective amount of a compound according to any of claims 1-21, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof . 29. A method of treating or preventing a parasitic disease in a mammal comprising administering to the mammal an effective amount of a compound according to any of claims 1-21, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.

30. A method of treating or preventing a proliferative disease in a mammal comprising administering to the mammal an effective amount of a compound according to any of claims 1-21, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof. 31. A method of treating or preventing a viral infection in a mammal comprising administering to the mammal an effective amount of a compound according to any one of claims 1-21, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof. 32. A method of treating or preventing an inflammatory disease in a mammal comprising administering to the mammal an effective amount of a compound according to any of claims 1-21, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof . 33. A method of treating or preventing a gastrointestinal motility disorder in a mammal comprising administering to the mammal an effective amount of a compound according to any of claims 1-21, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof. 34. A method of treating or preventing a disease state in a mammal caused or mediated by a nonsense or missense mutation comprising administering to a mammal in need thereof an effective amount of a compound according to any of claims 1-21, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, to suppress expression of the nonsense or missense mutation. 35. The method according to any of claims 23-34 wherein the compound is

administered orally, parentally, or topically. 36. A method of synthesizing a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, according to any of claims 1-21. 37. A medical device containing a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, according to any of claims 1-21.

38. The medical device according to claim 37, wherein the device is a stent.

Description:
TRIAZOLE COMPOUNDS AND

METHODS OF MAKING AND USING THE SAME PRIORITY CLAIM

This application claims the benefit of US Provisional Application No.64/485,909, filed on April 15, 2017, which is incorporated herein by reference in its entirety. FIELD OF THE INVENTION

The present invention relates generally to the field of anti-infective, anti- proliferative, anti-inflammatory, and prokinetic agents. More particularly, the invention relates to a family of triazole macrocyclic compounds that are useful as such agents. BACKGROUND

Since the discovery of penicillin in the 1920s and streptomycin in the 1940s, many new compounds have been discovered or specifically designed for use as antibiotic agents. It was once believed that infectious diseases could be completely controlled or eradicated with the use of such therapeutic agents. However, such beliefs have been shaken because strains of cells or microorganisms resistant to currently effective therapeutic agents continue to evolve. In fact, virtually every antibiotic agent developed for clinical use has ultimately encountered problems with the emergence of resistant bacteria. For example, resistant strains of Gram-positive bacteria such as methicillin-resistant staphylococci, penicillin-resistant streptococci, and vancomycin-resistant enterococci have developed. These resistant bacteria can cause serious and even fatal results for patients infected with such resistant bacteria. Bacteria that are resistant to macrolide antibiotics have emerged. Also, resistant strains of Gram-negative bacteria such as H. influenzae and M. catarrhalis have been identified. See, e.g., F.D. Lowry,“Antimicrobial Resistance: The Example of Staphylococcus aureus,” J. Clin. Invest., vol.111, no.9, pp.1265-1273 (2003); and Gold, H.S. and Moellering, R.C., Jr.,“Antimicrobial-Drug Resistance,” N. Engl. J. Med., vol. 335, pp.1445-53 (1996).

The problem of resistance is not limited to the area of anti-infective agents.

Resistance has also been encountered with anti-proliferative agents used in cancer chemotherapy. Therefore, the need exists for new anti-infective and anti-proliferative agents that are both effective against resistant bacteria and resistant strains of cancer cells. Despite the problem of increasing antibiotic resistance, no new major classes of antibiotics have been developed for clinical use since the approval in the United States in 2000 of the oxazolidinone ring-containing antibiotic, linezolid, which is sold under the trade name Zyvox ® . See, R.C. Moellering, Jr.,“Linezolid: The First Oxazolidinone Antimicrobial,” Annals of Internal Medicine, vol.138, no.2, pp.135-142 (2003).

Linezolid was approved for use as an anti-bacterial agent active against Gram-positive organisms. However, linezolid-resistant strains of organisms are already being reported. See, Tsiodras et al., Lancet, vol.358, p.207 (2001); Gonzales et al., Lancet, vol 357, p. 1179 (2001); Zurenko et al., Proceedings Of The 39 th Annual Interscience Conference On Antibacterial Agents And Chemotherapy (ICAAC), San Francisco, CA, USA (September 26-29, 1999).

Another class of antibiotics is the macrolides, so named for their characteristic 14- to 16-membered ring. The macrolides also often have one or more 6-membered sugar- derived rings attached to the main macrolide ring. The first macrolide antibiotic to be developed was erythromycin, which was isolated from a soil sample from the Philippines in 1952. Even though erythromycin has been one of the most widely prescribed antibiotics, its disadvantages are relatively low bioavailability, gastrointestinal side effects, and a limited spectrum of activity. Another macrolide is the compound, azithromycin, which is an azolide derivative of erythromycin incorporating a methyl-substituted nitrogen in the macrolide ring. Azithromycin is sold under the trade name Zithromax ® . A more recently introduced macrolide is telithromycin, which is sold under the trade name Ketek ® . Telithromycin is a semisynthetic macrolide in which a hydroxyl group of the macrolide ring has been oxidized to a ketone group. See Yong-Ji Wu, Highlights of Semi-synthetic Developments from Erythromycin A, Current Pharm. Design, vol.6, pp.181-223 (2000), and Yong-Ji Wu and Wei-uo Su, Recent Developments on Ketolides and Macrolides, Curr. Med. Chem., vol.8, no.14, pp.1727-1758 (2001).

In the search for new therapeutic agents, researchers have tried combining or linking various portions of antibiotic molecules to create multifunctional or hybrid compounds Other researches have tried making macrolide derivatives by adding further substituents to the large macrolide ring or associated sugar rings. However, this approach for making macrolide derivatives has also met with limited success.

Notwithstanding the foregoing, there is an ongoing need for new anti-infective and anti-proliferative agents. Furthermore, because many anti-infective and anti-proliferative agents have utility as anti-inflammatory agents and prokinetic agents, there is also an ongoing need for new compounds useful as anti-inflammatory and prokinetic agents. The present invention provides compounds that meet these needs. SUMMARY OF THE INVENTION

The invention provides compounds useful as anti-infective agents and/or anti- proliferative agents, for example, anti-biotic agents, anti-microbial agents, anti-bacterial agents, anti-fungal agents, anti-parasitic agents, anti-viral agents, and chemotherapeutic agents. The present invention also provides compounds useful as anti-inflammatory agents, and/or prokinetic (gastrointestinal modulatory) agents. The present invention also provides pharmaceutically acceptable salts, esters, N-oxides, or prodrugs thereof.

The present invention provides compounds having the structure:

or a stereoisomer, pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof. In the formula, variables A,T, X, R 1 , R 2 , R 3 , R 11 , and n can be selected from the respective groups of chemical moieties later defined in the detailed description. In addition, the invention provides methods of synthesizing the foregoing compounds. Following synthesis, a therapeutically effective amount of one or more of the compounds can be formulated with a pharmaceutically acceptable carrier for administration to a mammal, particularly humans, for use as an anti-cancer, anti-biotic, anti-microbial, anti-bacterial, anti-fungal, anti-parasitic or anti-viral agent, or to treat a proliferative disease, an inflammatory disease or a gastrointestinal motility disorder, or to suppress disease states or conditions caused or mediated by nonsense or missense mutations. Accordingly, the compounds or the formulations can be administered, for example, via oral, parenteral, or topical routes, to provide an effective amount of the compound to the mammal. The foregoing and other aspects and embodiments of the invention can be more fully understood by reference to the following detailed description and claims. DETAILED DESCRIPTION OF THE INVENTION The present invention provides a family of compounds that can be used as anti- proliferative agents and/or anti-infective agents. The compounds can be used without limitation, for example, as anti-cancer, anti-microbial, anti-bacterial, anti-fungal, anti- parasitic and/or anti-viral agents. Further, the present invention provides a family of compounds that can be used without limitation as anti-inflammatory agents, for example, for use in treating chronic inflammatory airway diseases, and/or as prokinetic agents, for example, for use in treating gastrointestinal motility disorders such as gastroesophageal reflux disease, gastroparesis (diabetic and post surgical), irritable bowel syndrome, and constipation. Further, the compounds can be used to treat or prevent a disease state in a mammal caused or mediated by a nonsense or missense mutation.

The compounds described herein can have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom can be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and can be isolated as a mixture of isomers or as separate isomeric forms. All chiral, diastereomeric, racemic, and geometric isomeric forms of a structure are intended, unless specific stereochemistry or isomeric form is specifically indicated. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention. All tautomers of shown or described compounds are also considered to be part of the present invention. 1. Definitions

The term“substituted,” as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., =O), then 2 hydrogens on the atom are replaced. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N).

The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.

When any variable (e.g., R 3 ) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with one or more R 3 moieties, then the group can optionally be substituted with one, two, three, four, five, or more R 3 moieties, and R 3 at each occurrence is selected independently from the definition of R 3 . Also, combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds.

A chemical structure showing a dotted line representation for a chemical bond indicates that the bond is optionally present. For example, a dotted line drawn next to a solid single bond indicates that the bond can be either a single bond or a double bond.

When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent can be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent can be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible, but only if such combinations result in stable compounds.

In cases wherein there are nitrogens in the compounds of the present invention, these can be converted to N-oxides by treatment with an oxidizing agent (e.g., MCPBA and/or hydrogen peroxides) to afford other compounds of the present invention. Thus, all shown and claimed nitrogens are considered to cover both the shown nitrogen and its N- oxide (N ^O) derivative.

As used herein, the term“anomeric carbon” means the acetal carbon of a glycoside. As used herein, the term“glycoside” is a cyclic acetal.

As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. C 1-6 alkyl is intended to include C 1 , C 2 , C 3 , C 4 , C 5 , and C 6 alkyl groups. C 1-8 alkyl is intended to include C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , and C 8 alkyl groups. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl, n-hexyl, n-heptyl, and n-octyl.

As used herein,“alkenyl" is intended to include hydrocarbon chains of either straight or branched configuration and one or more unsaturated carbon-carbon bonds that can occur in any stable point along the chain, such as ethenyl and propenyl. C 2-6 alkenyl is intended to include C 2 , C 3 , C 4 , C 5 , and C 6 alkenyl groups. C 2-8 alkenyl is intended to include C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , and C 8 alkenyl groups.

As used herein, "alkynyl" is intended to include hydrocarbon chains of either straight or branched configuration and one or more triple carbon-carbon bonds that can occur in any stable point along the chain, such as ethynyl and propynyl. C 2-6 alkynyl is intended to include C 2 , C 3 , C 4 , C 5 , and C 6 alkynyl groups. C 2-8 alkynyl is intended to include C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , and C 8 alkynyl groups.

Furthermore,“alkyl”,“alkenyl”, and“alkynyl” are intended to include moieties which are diradicals, i.e., having two points of attachment, an example of which in the present invention is when D is selected from these chemical groups. A nonlimiting example of such an alkyl moiety that is a diradical is–CH 2 CH 2 –, i.e., a C 2 alkyl group that is covalently bonded via each terminal carbon atom to the remainder of the molecule.

As used herein, the terms used to describe various carbon-containing moieties, including, for example,“alkyl,”“alkenyl,”“alkynyl,”“phenyl, and any variations thereof, are intended to include univalent, bivalent, or multivalent species. For example,“C 1-6 alkyl-R 3 ” is intended to represent a univalent C 1-6 alkyl group substituted with a R 3 group, and“O-C 1-6 alkyl-R 3 ” is intended to represent a bivalent C 1-6 alkyl group, i.e., an “alkylene” group, substituted with an oxygen atom and a R 3 group.

As used herein, "cycloalkyl" is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl. C 3-8 cycloalkyl is intended to include C 3 , C 4 , C 5 , C 6 , C 7 , and C 8 cycloalkyl groups.

As used herein, "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo.

"Counterion" is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, and sulfate.

As used herein, "haloalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example -C v F w where v = 1 to 3 and w = 1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl,

trichloromethyl, pentafluoroethyl, and pentachloroethyl.

As used herein,“alkoxy” refers to an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. C 1-6 alkoxy, is intended to include C 1 , C 2 , C 3 , C 4 , C 5 , and C 6 alkoxy groups. C 1-8 alkoxy, is intended to include C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , and C 8 alkoxy groups. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, s-pentoxy, n-heptoxy, and n-octoxy.

As used herein,“alkylthio” refers to an alkyl group as defined above with the indicated number of carbon atoms attached through an sulfur bridge. C 1-6 alkylthio, is intended to include C 1 , C 2 , C 3 , C 4 , C 5 , and C 6 alkylthio groups. C 1-8 alkylthio, is intended to include C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , and C 8 alkylthio groups.

As used herein, "carbocycle" or "carbocyclic ring" is intended to mean, unless otherwise specified, any stable 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12-membered monocyclic, bicyclic or tricyclic ring, any of which can be saturated, unsaturated (including partially and fully unsaturated), or aromatic, recognizing that rings with certain numbers of members cannot be bicyclic or tricyclic, e.g., a 3-membered ring can only be a monocyclic ring. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl,

[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl. As shown above, bridged rings are also included in the definition of carbocycle (e.g., [2.2.2]bicyclooctane). A bridged ring occurs when one or more carbon atoms link two non-adjacent carbon atoms. Preferred bridges are one or two carbon atoms. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the ring can also be present on the bridge. Fused (e.g., naphthyl and

tetrahydronaphthyl) and spiro rings are also included.

As used herein, the term "heterocycle" means, unless otherwise stated, a stable 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12-membered monocyclic, bicyclic or tricyclic ring (recognizing that rings with certain numbers of members cannot be bicyclic or tricyclic, e.g., a 3- membered ring can only be a monocyclic ring), which is saturated, unsaturated (including partially and fully unsaturated), or aromatic, and consists of carbon atoms and one or more ring heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, independently selected from nitrogen, oxygen, and sulfur, and including any bicyclic or tricyclic group in which any of the above-defined heterocyclic rings is fused to a second ring (e.g., a benzene ring). The nitrogen and sulfur heteroatoms can optionally be oxidized (i.e., N→O and S(O)p, where p = 1 or 2). When a nitrogen atom is included in the ring it is either N or NH, depending on whether or not it is attached to a double bond in the ring (i.e., a hydrogen is present if needed to maintain the tri-valency of the nitrogen atom). The nitrogen atom can be substituted or unsubstituted (i.e., N or NR wherein R is H or another substituent, as defined). The heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclic rings described herein can be substituted on carbon or on a nitrogen atom if the resulting compound is stable. A nitrogen in the heterocycle can optionally be quaternized. Bridged rings are also included in the definition of heterocycle. A bridged ring occurs when one or more atoms (i.e., C, O, N, or S) link two non-adjacent carbon or nitrogen atoms. Preferred bridges include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the ring can also be present on the bridge. Spiro and fused rings are also included.

As used herein, the term“aromatic heterocycle” or“heteroaryl” is intended to mean a stable 5, 6, 7, 8, 9, 10, 11, or 12-membered monocyclic or bicyclic aromatic ring (recognizing that rings with certain numbers of members cannot be a bicyclic aromatic, e.g., a 5-membered ring can only be a monocyclic aromatic ring),which consists of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, independently selected from nitrogen, oxygen, and sulfur. In the case of bicyclic heterocyclic aromatic rings, only one of the two rings needs to be aromatic (e.g., 2,3- dihydroindole), though both can be (e.g., quinoline). The second ring can also be fused or bridged as defined above for heterocycles. The nitrogen atom can be substituted or unsubstituted (i.e., N or NR wherein R is H or another substituent, as defined). The nitrogen and sulfur heteroatoms can optionally be oxidized (i.e., N→O and S(O)p, where p = 1 or 2). In some compounds, the total number of S and O atoms in the aromatic heterocycle is not more than 1.

Examples of heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,

benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,

dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl,

octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5- oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl,

phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl,

phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,

tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4- thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.

As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodide, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, and toluene sulfonic.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, USA, p.1445 (1990).

Since prodrugs are known to enhance numerous desirable qualities of

pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.) the compounds of the present invention can be delivered in prodrug form. Thus, the present invention is intended to cover prodrugs of the presently claimed compounds, methods of delivering the same and compositions containing the same. "Prodrugs" are intended to include any covalently bonded carriers that release an active parent drug of the present invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a mammalian subject, it cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention.

"Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

As used herein,“treating” or“treatment” means the treatment of a disease-state in a mammal, particularly in a human, and include: (a) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the disease- state but has not yet been diagnosed as having it; (b) inhibiting the disease-state, i.e., arresting its development; and/or (c) relieving the disease-state, i.e., causing regression of the disease state.

As used herein,“mammal” refers to human and non-human patients.

As used herein, the term "therapeutically effective amount" refers to a compound, or a combination of compounds, of the present invention present in or on a recipient in an amount sufficient to elicit biological activity, for example, anti-microbial activity, anti- fungal activity, anti-viral activity, anti-parasitic activity, and/or anti-proliferative activity. The combination of compounds is preferably a synergistic combination. Synergy, as described, for example, by Chou and Talalay, Adv. Enzyme Regul. vol.22, pp.27-55 (1984), occurs when the effect of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at sub-optimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased anti-proliferative and/or anti-infective effect, or some other beneficial effect of the combination compared with the individual components.

All percentages and ratios used herein, unless otherwise indicated, are by weight. Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes are described as having, including, or comprising specific process steps, it is contemplated that compositions of the present invention also consist essentially of, or consist of, the recited components, and that the processes of the present invention also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions are immaterial so long as the invention remains operable.

Moreover, two or more steps or actions can be conducted simultaneously. 2. Compounds of the Invention

The invention provides a compound having the structure of Formula I:

or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof,

wherein

A is selected from (a) a C 1-6 alkyl group, (b) a C 2-6 alkenyl group, (c) a

C 2-6 alkynyl group, (d) a C3-12 saturated, unsaturated, or aromatic carbocycle, (e) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more nitrogen, oxygen or sulfur atoms, (f) H, (g) -OH (h)–SH, (i) F, (j) Cl, (k) Br, (l) I, (m)– CF 3 , (n)–CN, (o)–N3 (p)–NO 2 , (q)–NR 6 (CR 6 R 6 ) t R 9 , (r)–OR 9 , (s)–S ( CR 6 R 6 ) t R 9 , (t)– S(O) ( CR 6 R 6 ) t R 9 ,(u)–S(O) 2 ( CR 6R6) t R9 (v)–C(O)(CR 6 R 6 ) t R 9 , (w)–OC(O)(CR 6 R 6 ) t R 9 , (x)–OC(O)O(CR 6 R 6 ) t R 9 , (y)–SC(O)(CR 6 R 6 ) t R 9 , (z)–C(O)O(CR 6 R 6 ) t R 9 , (aa)–

NR 6 C(O)(CR 6 R 6 ) t R 9 , (bb)–C(O)NR 6 (CR 6 R 6 ) t R 9 , (cc)–C(=NR 6 )(CR 6 R 6 ) t R 9 , (dd)– C(=NNR 6 R 6 )(CR 6 R 6 ) t R 9 , (ee)–C[=NNR 6 C(O)R 6 ](CR 6 R 6 ) t R 9 , (ff)–

NR 6 C(O)O(CR 6 R 6 ) t R 9 , (gg)–OC(O)NR 6 (CR 6 R 6 ) t R 9 , (hh)–NR 6 C(O)NR 6 (CR 6 R 6 ) t R 9 , (ii)–NR 6 S(O) p (CR 6 R 6 ) t R 9 , (jj)–S(O) p NR 6 (CR 6 R 6 ) t R 9 , (kk)–NR 6 R 6 , (ll)–

NR 6 (CR 6 R 6 )tR 9 , (mm)–SR 6 , (nn)–S(O)R 6 , (oo)–S(O) 2 R 6 , (pp)–NR 6 C(O)R 6 , (qq)– Si(R 13 ) 3 , and (rr)–C(=O)H;

wherein (a)-(e) optionally are substituted with one or more R 14 groups;

X is selected from–OR 15 and–SR 15 ,

R 1 and R 3 independently are selected from: (a) H, (b) a

C 1-6 alkyl group, (c) a C 2-6 alkenyl group, (d) a C 2-6 alkynyl group, (e)–C(O)R 5 ,

(f)–C(O)OR 5 , (g)–C(O)–NR 4 R 4 , (h)–C(S)R 5 , (i)–C(S)OR 5 , (j)–C(O)SR 5 , or (k)–C(S)- NR 4 R 4 ;

alternatively R 1 and R 3 are taken together with the oxygen to which R 1 is attached, the nitrogen to which R 3 is attached and the two intervening carbons to form a 5 or 6 membered ring, said ring being optionally substituted with one or more R 5 ; R 2 is hydrogen or–OR 12 ;

R 4 , at each occurrence, independently is selected from:

(a) H, (b) a C 1-6 alkyl group, (c) a C 2-6 alkenyl group, (d) a C 2-6 alkynyl group, (e) a C6-10 saturated, unsaturated, or aromatic carbocycle, (f) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (g)–C(O)– C1-6 alkyl, (h)–C(O)–C2-6 alkenyl, (i)–C(O)–C2-6 alkynyl, (j)–C(O)–C6-10 saturated, unsaturated, or aromatic carbocycle, (k)–C(O)–3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (l)–C(O)O–C 1-6 alkyl, (m)–C(O)O–C2-6 alkenyl, (n)–C(O)O–C2-6 alkynyl, (o)–C(O)O–C 6-10 saturated, unsaturated, or aromatic carbocycle, p)– C(O)O–3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, and q)–C(O)NR 6 R 6 ,

wherein any of (b)–(p) optionally is substituted with one or more R 5 groups,

alternatively, NR 6 R 6 forms a 3-7 membered saturated, unsaturated or aromatic ring including the nitrogen atom to which the R 6 groups are attached, wherein said ring is optionally substituted at a position other than the nitrogen atom to which the R 6 groups are attached, with one or more substituents selected from O, S(O)p, N, and NR 8 ;

R 5 is selected from:

(a) R 7 , (b) a C1-8 alkyl group, (c) a C2-8 alkenyl group, (d) a C2-8 alkynyl group, (e) a C3-12 saturated, unsaturated, or aromatic carbocycle, and (f) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, or two R 5 groups, when present on the same carbon atom can be taken together with the carbon atom to which they are attached to form a spiro 3- 6 membered carbocyclic ring or heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur;

wherein any of (b)–(f) immediately above optionally is substituted with one or more R 7 groups;

R 6 , at each occurrence, independently is selected from: (a) H, (b) a C1-6 alkyl group, (c) a C2-6 alkenyl group, (d) a C2-6 alkynyl group, (e) a C3-10 saturated, unsaturated, or aromatic carbocycle, and (f) a 3- 10 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur,

wherein any of (b)–(f) optionally is substituted with one or more moieties selected from:

(aa) a carbonyl group, (bb) a formyl group, (cc) F, (dd) Cl, (ee) Br, (ff) I, (gg) CN, (hh) NO2, (ii)–OR 8 ,

(jj)–S(O) p R 8 , (kk)–C(O)R 8 , (ll)–C(O)OR 8 ,

(mm)–OC(O)R 8 , (nn)–C(O)NR 8 R 8 ,

(oo)–OC(O)NR 8 R 8 , (pp)–C(=NR 8 )R 8 ,

(qq)–C(R 8 )(R 8 )OR 8 , (rr)–C(R 8 ) 2 OC(O)R 8 ,

(ss)–C(R 8 )(OR 8 )(CH 2 ) r NR 8 R 8 , (tt)–NR 8 R 8 ,

(uu)–NR 8 OR 8 , (vv)–NR 8 C(O)R 8 ,

(ww)–NR 8 C(O)OR 8 , (xx)–NR 8 C(O)NR 8 R 8 ,

(yy)–NR 8 S(O) r R 8 , (zz)–C(OR 8 )(OR 8 )R 8 ,

(ab)–C(R 8 )2NR 8 R 8 , (ac) =NR 8 ,

(ad)–C(S)NR 8 R 8 , (ae)–NR 8 C(S)R 8 ,

(af)–OC(S)NR 8 R 8 , (ag)–NR 8 C(S)OR 8 ,

(ah)–NR 8 C(S)NR 8 R 8 , (ai)–SC(O)R 8 ,

(aj) a C1-8 alkyl group, (ak) a C2-8 alkenyl group, (al) a C 2-8 alkynyl group, (am) a C 1-8 alkoxy group, (an) a C 1-8 alkylthio group, (ao) a C1-8 acyl group, (ap)–CF3,

(aq)–SCF3 , (ar) a C3-10 saturated, unsaturated, or aromatic carbocycle, and (as) a 3-10 membered saturated,

unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, alternatively, NR 6 R 6 forms a 3-10 membered saturated, unsaturated or aromatic ring including the nitrogen atom to which the R 6 groups are attached wherein said ring is optionally substituted at a position other than the nitrogen atom to which the R 6 groups are bonded, with one or more moieties selected from O, S(O)p, N, and NR 8 ;

alternatively, CR 6 R 6 forms a carbonyl group;

R 7 , at each occurrence, is selected from: (a) H, (b) =O, (c) =S, (d) F, (e) Cl, (f) Br, (g) I, (h)–CF 3 ,

(i)–CN, (j)–N3 (k)–NO 2 , (l)–NR 6 (CR 6 R 6 ) t R 9 , (m)–OR 9 , (n)–

S(O) p C(R 6R6) t R9 , (o)–C(O)(CR 6 R 6 ) t R 9 , (p)–OC(O)(CR 6 R 6 ) t R 9 , (q)– SC(O)(CR 6 R 6 ) t R 9 , (r)–C(O)O(CR 6 R 6 ) t R 9 , (s)–NR 6 C(O)(CR 6 R 6 ) t R 9 , (t)– C(O)NR 6 (CR 6 R 6 ) t R 9 , (u)–C(=NR 6 )(CR 6 R 6 ) t R 9 , (v)–

C(=NNR 6 R 6 )(CR 6 R 6 ) t R 9 , (w)–C(=NNR 6 C(O)R 6 )(CR 6 R 6 ) t R 9 , (x)– C(=NOR 9 )(CR 6 R 6 ) t R 9 , (y)–NR 6 C(O)O(CR 6 R 6 ) t R 9 , (z)–

OC(O)NR 6 (CR 6 R 6 ) t R 9 , (aa)–NR 6 C(O)NR 6 (CR 6 R 6 ) t R 9 , (bb)–

NR 6 S(O) p (CR 6 R 6 ) t R 9 , (cc)–S(O) p NR 6 (CR 6 R 6 ) t R 9 , (dd)–

NR 6 S(O) p NR 6 (CR 6 R 6 ) t R 9 , (ee)–NR 6 R 6 , (ff)–NR 6 (CR 6 R 6 ), (gg)–OH, (hh) –NR 6 R 6 , (ii)–OCH3, (jj)–S(O) p R 6 , (kk)–NC(O)R 6 , (ll) a C 1-6 alkyl group, (mm) a C 2-6 alkenyl group, (nn) a C 2-6 alkynyl group, (oo)–C 3-10 saturated, unsaturated, or aromatic carbocycle, and (pp) 3-10 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur,

wherein any of (ll)–(pp) optionally is substituted with one or more R 9 groups;

alternatively, two R 7 groups can form–O(CH2)uO–;

R 8 is selected from:

(a) H, (b) a C1-6 alkyl group, (c) a C2-6 alkenyl group, (d) a C 2-6 alkynyl group, (e) a C3-10 saturated, unsaturated, or aromatic carbocycle, (f) a 3-10 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (g)–C(O)– C1-6 alkyl, (h)–C(O)–C1-6 alkenyl, (i)–C(O)–C1-6 alkynyl, (j)–C(O)–C3-10 saturated, unsaturated, or aromatic carbocycle, and (k)–C(O)–3-10 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur,

wherein any of (c)–(k) optionally is substituted with one or more moieties selected from : (aa) H, (bb) F, (cc) Cl, (dd) Br, (ee) I, (ff) CN, (gg) NO2, (hh) OH, (ii) NH2, (jj) NH(C1-6 alkyl), (kk)

N(C 1-6 alkyl) 2 , (ll) a C 1-6 alkoxy group, (mm) an aryl group, (nn) a substituted aryl group, (oo) a heteroaryl group, (pp) a substituted heteroaryl group, and qq) a C1-6 alkyl group optionally substituted with one or more moieties selected from an aryl group, a substituted aryl group, a heteroaryl group, a substituted heteroaryl group, F, Cl, Br, I, CN, NO2, CF3, SCF3, and OH;

R 9 , at each occurrence, independently is selected from:

(a) R 10 , (b) a C 1-6 alkyl group, (c) a C 2-6 alkenyl group, (d) a C 2-6 alkynyl group, e) a C 3-10 saturated, unsaturated, or aromatic carbocycle, and f) a 3-10 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein any of (b)–(f) optionally is substituted with one or more R 10 groups;

R 10 , at each occurrence, independently is selected from:

(a) H, (b) =O, (c) F, (d) Cl, (e) Br, (f) I, (g)–CF 3 , (h)–CN, (i)–NO 2 , (j)– NR 6 R 6 , (k)–OR 6 , (l)–S(O) p R 6 , (m)–C(O)R 6 , (n)–C(O)OR 6 , (o)– OC(O)R 6 , (p) NR 6 C(O)R 6 , (q)–C(O)NR 6 R 6 , (r)–C(=NR 6 )R 6 , (s)– NR 6 C(O)NR 6 R 6 , (t)–NR 6 S(O) p R 6 , (u)–S(O) p NR 6 R 6 , (v)–

NR 6 S(O) p NR 6 R 6 , (w) a C 1-6 alkyl group, (x) a C 2-6 alkenyl group, (y) a C 2-6 alkynyl group, (z) a C3-10 saturated, unsaturated, or aromatic carbocycle, and (aa) a 3-10 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur,

wherein any of (w)–(aa) optionally is substituted with one or more moieties selected from R 6 , F, Cl, Br, I, CN, NO 2 ,–OR 6 ,–NH 2 ,– NH(C1-6 alkyl),–N(C1-6 alkyl)2, a C1-6 alkoxy group, a C1-6 alkylthio group, and a C 1-6 acyl group;

R 11 at each occurrence, independently is selected from:

(a) H, (b) F, (c) Cl, (d) Br, (e) I, (f) CN, (g) NO2, (h) OR 8 , (i)–S(O)pR 8 , (j) –C(O)R 8 , (k)–C(O)OR 8 , (l)–OC(O)R 8 , (m)–C(O)NR 8 R 8 , (n)–

OC(O)NR 8 R 8 ,

(o)–C(=NR 8 )R 8 , (p)–C(R 8 )(R 8 )OR 8 , (q)–C(R 8 )2OC(O)R 8 ,

(r)–C(R 8 )(OR 8 )(CH2)rNR 8 R 8 , (s)–NR 8 R 8 , (t)–NR 8 OR 8 ,

(u)–NR 8 C(O)R 8 , (v)–NR 8 C(O)OR 8 , (w)–NR 8 C(O)NR 8 R 8 , (x)–

NR 8 S(O)pR 8 , (y)–C(OR 8 )(OR 8 )R 8 , (z)–C(R 8 )2NR 8 R 8 , (aa)–C(S)NR 8 R 8 , (bb)–NR 8 C(S)R 8 , (cc)–OC(S)NR 8 R 8 , (dd)–NR 8 C(S)OR 8 , (ee)–

NR 8 C(S)NR 8 R 8 , (ff)–SC(O)R 8 , (gg) -N3, (hh)–Si(R 13 )3, (ii) a C1-8 alkyl group, (jj) a C 2-8 alkenyl group, (kk) a C 2-8 alkynyl group, (ll) a C 3-10 saturated, unsaturated, or aromatic carbocycle, and (mm) a 3-10 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein (ii)-(mm) optionally are substituted with one or more R 5 groups;

R 12 is selected from:

(a) H, (b) a C 1-6 alkyl group, (c) a C 2-6 alkenyl group, (d) a C 2-6 alkynyl group, (e)–C(O)R 5 , (f)–C(O)OR 5 , (g)–C(O)–NR 4 R 4 R 4 R 4 , (h)–C(S)R 5 , (i) –C(S)OR 5 , (j)–C(O)SR 5 , (k)–C(S)-NR 4 R 4 R 4 R 4 , (l) a C3-10 saturated, unsaturated, or aromatic carbocycle, or (m) a 3-10 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (n) a–(C1-6 alkyl)–C3-10 saturated, unsaturated, or aromatic carbocycle, or (o) a–(C1-6 alkyl)-3-10 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur,

wherein (a)–(d) and (l)–(o) optionally are substituted with one or more R 5 groups;

each R 13 is independently selected from (a) -C1-6 alkyl and (b)–O-(C1-6 alkyl); R 14 at each occurrence is independently selected from:

(a) H, (b) F, (c) Cl, (d) Br, (e) I, (f) CN, (g) NO 2, (h) OR 8 , (i)–S(O) p R 8 , (j) –C(O)R 8 , (k)–C(O)OR 8 , (l)–OC(O)R 8 , (m)–C(O)NR 8 R 8 , (n)–

OC(O)NR 8 R 8 ,

(o)–C(=NR 8 )R 8 , (p)–C(R 8 )(R 8 )OR 8 , (q)–C(R 8 ) 2 OC(O)R 8 ,

(r)–C(R 8 )(OR 8 )(CH 2 ) r NR 8 R 8 , (s)–NR 8 R 8 , (t)–NR 8 OR 8 ,

(u)–NR 8 C(O)R 8 , (v)–NR 8 C(O)OR 8 , (w)–NR 8 C(O)NR 8 R 8 , (x)–

NR 8 S(O) p R 8 , (y)–C(OR 8 )(OR 8 )R 8 , (z)–C(R 8 ) 2 NR 8 R 8 , (aa)–C(S)NR 8 R 8 , (bb)–NR 8 C(S)R 8 , (cc)–OC(S)NR 8 R 8 , (dd)–NR 8 C(S)OR 8 , (ee)–

NR 8 C(S)NR 8 R 8 , (ff)–SC(O)R 8 , (gg) -N3, (hh)–Si(R 13 )3, (ii) a C1-8 alkyl group, (jj) a C2-8 alkenyl group, (kk) a C2-8 alkynyl group, (ll) a C3-10 saturated, unsaturated, or aromatic carbocycle, and (mm) a 3-10 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein (ii)-(mm) optionally are substituted with one or more R 5 groups;

alternatively two R 14 groups are taken together to form (a) =O, (b) =S, (c) =NR 8 , (e) =NOR 8 ;

R 15 is selected from C1-6 alkyl, optionally substituted with from 1 to 13 fluorine atoms;

n at each occurrence is 0, 1, 2, 3, or 4;

p at each occurrence is 0, 1, or 2;

r at each occurrence is 0, 1, or 2;

t at each occurrence is 0, 1, or 2;

and u at each occurrence is 1, 2, 3, or 4;

T is

,

wherein:

M is–C(=NOR 127 )–;

R 100 is selected from (a) H, (b) F, (c) Cl, (d) Br, (e)–SR 114 , and (f) C1-6 alkyl, wherein (f) optionally is substituted with one or more R 115 groups;

R 101 is selected from:

(a) H, (b) Cl, (c) F, (d) Br, (e) I, (f)–NR 114 R 114 , (g)–NR 114 C(O)R 114 , (h)– OR 114 ,

(i)–OC(O)R 114 , (j)–OC(O)OR 114 , (k)–OC(O)NR 114 R 114 , (l)–O–C 1-6 alkyl, (m)–OC(O)–C1-6 alkyl, (n)–OC(O)O–C1-6 alkyl, (o)–OC(O)NR 114 –C1- 6 alkyl,

(p) C 1-6 alkyl, (q) C 1-6 alkenyl, and (r) C 1-6 alkynyl, wherein any of (l)– (r) optionally is substituted with one or more R 115 groups;

R 102 is H, (b) F, (c) Cl, (d) Br, (e)–SR 114 , (f) C 1-6 alkyl, wherein (f) optionally is substituted with one or more R 115 groups;

R 103 is selected from:

(a) H, (b)–OR 114 , (c)–O–C 1-6 alkyl–R 115 , (d)–OC((O)R 114 ,

(e)–OC(O)–C1-6 alkyl–R 115 , (f)–OC(O)OR 114 , (g)–OC(O)O–C1-6 alkyl– R 115 ,

(h)–OC(O)NR 114 R 114 , (i)–OC(O)NR 114 –C 1-6 alkyl–R 115 , and

alternatively, R 102 and R 103 taken together with the carbon to which they are attached form (a) a carbonyl group or (b) a 3-7 membered saturated, unsaturated or aromatic carbocyclic or heterocyclic ring which can optionally be substituted with one or more R 114 groups;

alternatively, R 101 and R 103 taken together are a single bond between the respective carbons to which these two groups are attached thereby creating a double bond between the carbons to which R 100 and R 102 are attached;

alternatively, R 101 and R 103 taken together with the carbons to which they are attached form a 3-membered saturated, unsaturated or aromatic carbocyclic or heterocyclic ring which can optionally be substituted with one or more R 114 groups ;

R 104 is selected from:

(a) H, (b) R 114 , (c)–C(O)R 114 (d)–C(O)OR 114 (e)–C(O)NR 114 R 114 , (f)–C1-6 alkyl–K–R 114 , (g)–C 2-6 alkenyl–K–R 114 , and (h)–C 2-6 alkynyl–K–R 114 ; K is selected from:

(a)–C(O)–, (b)–C(O)O–, (c)–C(O)NR 114 –, (d)–C(=NR 114 )–, (e)– C(=NR 114 )O–,

(f)–C(=NR 114 )NR 114 –, (g)–OC(O)–, (h)–OC(O)O–, (i)–OC(O)NR 114 –, (j)–NR 114 C(O)–, (k)–NR 114 C(O)O–, (l)–NR 114 C(O)NR 114 –,

(m)–NR 114 C(=NR 114 )NR 114 –, and (o)–S(O) p –; alternatively R 103 and R 104 , taken together with the atoms to which they are bonded, form:

wherein R 135 and R 136 are selected from (a) hydrogen, (b) C 1-6 alkyl, (c) C 2-6 alkenyl, (d) C2-6 alkynyl, (d) C3-14 saturated, unsaturated or aromatic carbocycle, (e) 3-l4 membered saturated, unsaturated or aromatic heterocycle containing one or more oxygen, nitrogen, or sulfur atoms, (f) F, (g) Br, (h) I, (i) OH, (j)–N 3 , wherein (b) through (e) are optionally substituted with one or more R 117 ; or alternatively, R 135 and R 136 are taken together to form =O, =S and =NR 114 , =NOR 114 , =NR 114 , and =N-NR 114 ,R 114 ],

wherein V is selected from(a)–(C 4 -alkyl)-, (b)-(C 4 -alkenyl)-, (c) O, (d) S, and (e) NR 114 , wherein (a) and (b) are optionally further substituted with one or more R 117 ;

R 105 is selected from:

(a) R 114 , (b)–OR 114 , (c)–NR 114 R 114 , (d)–O–C 1-6 alkyl–R 115 , (e)–C(O)– R 114 ,

(f)–C(O)–C1-6 alkyl–R 115 , (g)–OC(O)–R 114 , (h)–OC(O)–C1-6 alkyl–R 115 , (i)–OC(O)O–R 114 , (j)–OC(O)O–C 1-6 alkyl–R 115 , (k)–OC(O)NR 114 R 114 , (l)–OC(O)NR 114 –C 1-6 alkyl–R 115 , (m)–C(O)–C 2-6 alkenyl–R 115 , and (n)–C(O)–C2-6 alkynyl–R 115 ;

alternatively, R 104 and R 105 , taken together with the atoms to which they are bonded, form

wherein

Q is CH or N, and R 126 is–OR 114 ,–NR 114 or R 114 ;

alternatively, R 104 and R 105 , taken together with the atoms to which they are bonded, form:

wherein

i) R 101 is as defined above;

ii) alternately, R 101 and R 109 can be taken together with the carbon to which they are attached to form a carbonyl group; iii) alternately, R 101 and R 109 can be taken together to form the group–O(CR 116 R 116 )uO–;

alternatively, R 104 and R 105 , taken together with the atoms to which they are bonded, form:

wherein in the preceding structure the dotted line indicates an optional double bond i) R 130 is–OH, =C(O), or R 114 , ii) R 131 is–OH, =C(O), or R 114 ,

iii) alternately, R 130 and R 131 together with the carbons to which they are attached form a 3-7 membered saturated, unsaturated or aromatic carbocyclic or heterocyclic ring which can optionally be substituted with one or more R 114 groups;

iv) alternatively, R 130 and the carbon to which it is attached or R 131 and the carbon to which it is attached are each independently–C(=O)-,

alternatively, R 105 , R 132 and M, taken together with the atoms to which they are attached, form:

R 106 is selected from:

(a)–OR 114 , (b)–C1-6 alkoxy–R 115 , (c)–C(O)R 114 , (d)–OC(O)R 114 , (e)– OC(O)OR 114 , (f)–OC(O)NR 114 R 114 , and (g)–NR 114 R 114 ,

alternatively, R 105 and R 106 taken together with the atoms to which they are attached form a 5-membered ring by attachment to each other through a chemical moiety selected from:

(a)–OC(R 115 )2O–, (b)–OC(O)O–, (c)–OC(O)NR 114 –, (d)–NR 114 C(O)O–, (e)–OC(O)NOR 114 –, (f)–NOR 114 –C(O)O–, (g)–OC(O)NNR 114 R 114 –, (h)–NNR 114 R 114 –C(O)O–, (i)–OC(O)C(R 115 ) 2 –, (j)–C(R 115 ) 2 C(O)O–, (k) –OC(S)O–, (l)–OC((S)NR 114 –, (m)–NR 114 C(S)O–, (n)–OC(S)NOR 114 –, (o)–NOR 114 –C(S)O–, (p)–OC(S)NNR 114 R 114 –, (q)–NNR 114 R 114 –C(S)O–, (r)–OC(S)C(R 115 ) 2 –, and (s)–C(R 115 ) 2 C(S)O–;

alternatively, R 105 , R 106 , and R 133 taken together with the atoms to which they are attached form:

,

wherein J 1 and J 2 are selected from hydrogen, Cl, F, Br, I, OH, -C 1-6 alkyl, and -O(C 1- 6alkyl) or are taken together to form =O, =S and =NR 114 , =NOR 114 , =NR 114 , and =N-NR 114 ,R 114 ;

alternatively, M and R 104 taken together with the atoms to which they are attached form:

wherein U is selected from(a)–(C 4 -alkyl)- and (b)-(C 4 -alkenyl)-, wherein (a) and (b) are optionally further substituted with one or more R 117 ; alternatively, M and R 105 are taken together with the atoms to which they are attached to form:

,

R 107 is selected from

(a) H, (b)–C 1-4 alkyl, (c)–C 2-4 alkenyl, which can be further substituted with C 1-12 alkyl or one or more halogens, (d)–C 2-4 alkynyl, which can be further substituted with C1-12 alkyl or one or more halogens, (e) aryl or heteroaryl, which can be further substituted with C 1-12 alkyl or one or more halogens, (f)–C(O)H, (g)–COOH, (h)–CN, (i)–COOR 114 , (j) - C(O)NR 114 R 114 , (k)–C(O)R 114 , and (l)–C(O)SR 114 , wherein (b) is further substituted with one or more substituents selected from (aa)–OR 114 , (bb) halogen, (cc)–SR 114 , (dd) C 1-12 alkyl, which can be further substituted with halogen, hydroxyl, C1-6 alkoxy, or amino, (ee)–OR 114 , (ff)–SR 114 , (gg)– NR 114 R 114 , (hh)–CN, (ii)-NO2, (jj)–NC(O)R 114 , (kk)–COOR 114 , (ll)–N3, (mm) =N-O-R 114 , (nn) =NR 114 , (oo) =N-NR 114 R 114 , (pp) =N-NH-C(O)R 114 , and (qq) =N-NH-C(O)NR 114 R 114 ;

alternatively R 106 and R 107 are taken together with the atom to which they are attached to form an epoxide, a carbonyl, an olefin, or a substituted olefin, or a C 3 -C 7 carbocyclic, carbonate, or carbamate, wherein the nitrogen of said carbamate can be further substituted with a C1-C6 alkyl;

R 108 is selected from:

(a) C 1-6 alkyl, (b) C 2-6 alkenyl, and (c) C 2-6 alkynyl,

wherein any of (a)–(c) optionally is substituted with one or more R 114 groups;

R 111 is selected from H and–C(O)R 114 ;

R 112 is selected from H, OH, and OR 114 ; R 113 is selected from:

(a) H, (b) R 114 , (c)–C1-6 alkyl–K–R 114 , (d)–C2-6 alkenyl–K–R 114 , and (e)–C 2-6 alkynyl–K–R 114 ,

wherein any of (c)-(e) optionally is substituted with one or more R 115 groups;

R 114 , at each occurrence, independently is selected from:

(a) H, (b) C1-6 alkyl, (c) C2-6 alkenyl, (d) C2-6 alkynyl, (e) C6-10 saturated, unsaturated, or aromatic carbocycle, (f) 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (g)–C(O)–C 1-6 alkyl, (h)– C(O)–C2-6 alkenyl, (i)–C(O)–C2-6 alkynyl, (j)–C(O)–C6-10 saturated, unsaturated, or aromatic carbocycle, (k)–C(O)–3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (l)–C(O)O–C1-6 alkyl, (m)– C(O)O–C2-6 alkenyl, (n)–C(O)O–C2-6 alkynyl, (o)–C(O)O–C6-10 saturated, unsaturated, or aromatic carbocycle, (p)–C(O)O–3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (q)–C(O)NR 116 R 116 , (r)– NR 116 CO-C2-6 alkyl, (s)–NR 116 CO-C 6-10 saturated, unsaturated, or aromatic carbocycle, and (t)–NR 116 C(O)-3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur

wherein any of (b)–(t) optionally is substituted with one or more R 115 groups, wherein one or more non-terminal carbon moieties of any of (b)–(d) optionally is replaced with oxygen, S(O) p , or–NR 116 , alternatively, NR 114 R 114 forms a 3-7 membered saturated, unsaturated or aromatic ring including the nitrogen atom to which the R 114 groups are bonded and optionally one or more moieties selected from O, S(O) p , N, and NR 118 ;

R 115 is selected from:

(a) R 117 , (b) C1-8 alkyl, (c) C2-8 alkenyl, (d) C2-8 alkynyl, (e) C3-12 saturated, unsaturated, or aromatic carbocycle, (f) 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein any of (b)–(f) optionally is substituted with one or more R 117 groups;

R 116 , at each occurrence, independently is selected from:

(a) H, (b) C1-6 alkyl, (c) C2-6 alkenyl, (d) C2-6 alkynyl, (e) C3-10 saturated, unsaturated, or aromatic carbocycle, and (f) 3-10 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur,

wherein one or more non-terminal carbon moieties of any of (b)–(d) optionally is replaced with oxygen, S(O) p , or–NR 114 , wherein any of (b)– (f) optionally is substituted with one or more moieties selected from:

(aa) carbonyl, (bb) formyl, (cc) F, (dd) Cl, (ee) Br, (ff) I, (gg) CN, (hh) N 3 , (ii)NO 2, (jj) OR 118 , (kk)–S(O) p R 118 , (ll)– C(O)R 118 , (mm)–C(O)OR 118 , (nn)–OC(O)R 118 , (oo)– C(O)NR 118 R 118 , (pp)–OC(O)NR 118 R 118 , (qq)–

C(=NR 118 )R 118 , (rr)–C(R 118 )(R 118 )OR 118 , (ss)–

C(R 118 )2OC(O)R 118 , (tt)–C(R 118 )(OR 118 )(CH2)rNR 118 R 118 , (uu)–NR 118 R 118 ; (vv)–NR 118 OR 118 , (ww)–NR 118 C(O)R 118 , (xx)–NR 118 C(O)OR 118 , (yy)–NR 118 C(O)NR 118 R 118 , (zz)– NR 118 S(O)rR 118 , (ab)–C(OR 118 )(OR 118 )R 118 , (ac)–

C(R 118 )2NR 118 R 118 , (ad) =NR 118 , (ae)–C(S)NR 118 R 118 , (af)– NR 118 C(S)R 118 , (ag)–OC(S)NR 118 R 118 , (ah)–

NR 118 C(S)OR 118 , (ai)–NR 118 C(S)NR 118 R 118 , (aj)–

SC(O)R 118 , (ak) C1-8 alkyl, (al) C2-8 alkenyl, (am)

C 2-8 alkynyl, (an) C 1-8 alkoxy, (ao) C 1-8 alkylthio, (ap) C 1-8 acyl, (aq) saturated, unsaturated, or aromatic C 3-10 carbocycle, and (ar) saturated, unsaturated, or aromatic 3-10 membered heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur,

alternatively, NR 116 R 116 forms a 3-10 membered saturated, unsaturated or aromatic ring including the nitrogen atom to which the R 116 groups are attached and optionally one or more moieties selected from O, S(O) p , N, and NR 118 ;

alternatively, CR 116 R 116 forms a carbonyl group;

R 117 , at each occurrence, is selected from: (a) H, (b) =O, (c) F, (d) Cl, (e) Br, (f) I, (g) (CR 116 R 116 )rCF3, (h)

(CR 116 R 116 )rCN, (i) (CR 116 R 116 )rNO2,

(j) (CR 116 R 116 ) r NR 116 (CR 116 R 116 ) t R 119 , (k) (CR 116 R 116 ) r OR 119 ,

(l) (CR 116 R 116 )rS(O)p(CR 116 R 116 )tR 119 , (m) (CR 116 R 116 )rC(O)(

CR 116 R 116 )tR 119 , (n) (CR 116 R 116 )rOC(O)( CR 116 R 116 )tR 119 ,

(o) (CR 116 R 116 ) r SC(O)( CR 116 R 116 ) t R 119 ,

(p) (CR 116 R 116 )rC(O)O(CR 116 R 116 )tR 119 , (q) (CR 116 R 116 )rNR 116 C(O)( CR 116 R 116 )tR 119 , (r) (CR 116 R 116 )rC(O)NR 116 (CR 116 R 116 )tR 119 , (s)

(CR 116 R 116 ) r C(=NR 116 )( CR 116 R 116 ) t R 119 ,

(t) (CR 116 R 116 ) r C(=NNR 116 R 116 )(CR 116 R 116 ) t R 119 ,

(u) (CR 116 R 116 )rC(=NNR 116 C(O)R 116 )( CR 116 R 116 )tR 119 ,

(v) (CR 116 R 116 ) r C(=NOR 119 )( CR 116 R 116 ) t R 119 ,

(w) (CR 116 R 116 ) r NR 116 C(O)O(CR 116 R 116 ) t R 119 ,

(x) (CR 116 R 116 )rOC(O)NR 116 (CR 116 R 116 )tR 119 ,

(y) (CR 116 R 116 )rNR 116 C(O)NR 116 (CR 116 R 116 )tR 119 ,

(z) (CR 116 R 116 ) r NR 116 S(O) p (CR 116 R 116 ) t R 119 ,

(aa) (CR 116 R 116 )rS(O)pNR 116 (CR 116 R 116 )tR 119 ,

(bb) (CR 116 R 116 )rNR 116 S(O)pNR 116 (CR 116 R 116 )tR 119 ,

(cc) (CR 116 R 116 ) r NR 116 R 116 , (dd) C 1-6 alkyl, (ee) C 2-6 alkenyl,

(ff) C 2-6 alkynyl, (gg) (CR 116 R 116 ) r –C3-10 saturated, unsaturated, or aromatic carbocycle, and (hh) (CR 116 R 116 ) r –3-10 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur,

wherein any of (dd)–(hh) optionally is substituted with one or more R 119 groups;

alternatively, two R 117 groups can form–O(CH 2 ) u O–;

R 118 is selected from:

(a) H, (b) C 1-6 alkyl, (c) C 2-6 alkenyl, (d) C 2-6 alkynyl, (e) C 3-10 saturated, unsaturated, or aromatic carbocycle, (f) 3-10 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (g)–C(O)–C 1-6 alkyl, (h)– C(O)–C 1-6 alkenyl, (g)–C(O)–C 1-6 alkynyl, (i)–C(O)–C 3-10 saturated, unsaturated, or aromatic carbocycle, and (j)–C(O)–3-10 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur,

wherein any of (b)–(j) optionally is substituted with one or more moieties selected from : (aa) H, (bb) F, (cc) Cl, (dd) Br, (ee) I, (ff) CN, (gg) NO2, (hh) OH, (ii) NH2, (jj) NH(C1-6 alky(l), (kk)

N(C 1-6 alky(l) 2 , (ll) C 1-6 alkoxy, (mm) aryl, (nn) substituted aryl, (oo) heteroaryl, (pp) substituted heteroaryl, and (qq) C1-6 alkyl, optionally substituted with one or more moieties selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, F, Cl, Br, I, CN, NO 2 , and OH;

R 119 , at each occurrence, independently is selected from:

( a) R120, (b) C 1-6 alkyl, (c) C 2-6 alkenyl, (d) C 2-6 alkynyl, (e) C 3-10 saturated, unsaturated, or aromatic carbocycle, and (f) 3-10 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur,

wherein any of (b)–(f) optionally is substituted with one or more R 119 groups;

R 120 , at each occurrence, independently is selected from:

(a) H, (b) =O, (c) F, (d) Cl, (e) Br, (f) I, (g) (CR 116 R 116 ) r CF 3 , (h)

(CR 116 R 116 ) r CN, (i) (CR 116 R 116 ) r NO 2 , (j) (CR 116R116) r NR116 R 116 , (k) (CR 116 R 116 ) r OR 114 , (l) (CR 116 R 116 ) r S(O) p R 116 , (m) (CR 116 R 116 ) r C(O)R 116 , (n) (CR 116 R 116 ) r C(O)OR 116 , (o) (CR 116 R 116 ) r OC(O)R 116 , (p)

(CR 116 R 116 ) r NR 116 C(O)R 116 , (q) (CR 116 R 116 ) r C(O)NR 116 R 116 , (r)

(CR 116 R 116 ) r C(=NR 116 )R 116 , (s) (CR 116 R 116 ) r NR 116 C(O)NR 116 R 116 ,

(t) (CR 116 R 116 ) r NR 116 S(O) p R 116 , (u) (CR 116 R 116 ) r S(O) p NR 116 R 116 , (v) (CR 116 R 116 ) r NR 116 S(O) p NR 116 R 116 , (w) C 1-6 alkyl, (x) C 2-6 alkenyl, (y) C 2-6 alkynyl, (z) (CR 116 R 116 ) r –C3-10 saturated, unsaturated, or aromatic carbocycle, and (aa) (CR 116 R 116 ) r –3-10 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur,

wherein any of (w)–(aa) optionally is substituted with one or more moieties selected from R 116 , F, Cl, Br, I, CN, NO 2 ,–OR 116 ,–NH 2 ,– NH(C1-6 alkyl),–N(C1-6 alkyl)2, C1-6 alkoxy, C1-6 alkylthio, and C1-6 acyl;

R 121 , at each occurrence, independently is selected from:

(a) H, (b)–OR 118 , (c)–O–C1-6 alkyl–OC(O)R 118 , (d)–O–C1-6 alkyl– OC(O)OR 118 , (e)–O–C1-6 alkyl–OC(O)NR 118 R 118 , (f)–O–C1-6 alkyl– C(O)NR 118 R 118 , (g)–O–C 1-6 alkyl–NR 118 C(O)R 118 , (h)–O–C 1-6 alkyl– NR 118 C(O)OR 118 , (i)–O–C1-6 alkyl–NR 118 C(O)NR 118 R 118 , (j)–O–

C1-6 alkyl–NR 118 C(=N(H)NR 118 R 118 , (k)–O–C1-6 alkyl–S(O)pR 118 , (l)–O– C 2-6 alkenyl–OC(O)R 118 , (m)–O–C 2-6 alkenyl–OC(O)OR 118 , (n)–O–C 2-6 alkenyl–OC(O)NR 118 R 118 , (o)–O–C 2-6 alkenyl–C(O)NR 118 R 118 , (p)–O– C2-6 alkenyl–NR 118 C(O)R 118 , (q)–O–C2-6 alkenyl–NR 118 C(O)OR 118 , (r)– O–C 2-6 alkenyl–NR 118 C(O)NR 118 R 118 , (s)–O–C 2-6 alkenyl–

NR 118 C(=N(H)NR 118 R 118 , (t)–O–C 2-6 alkenyl–S(O) p R 118 ,

(u)–O–C2-6 alkynyl–OC(O)R 118 , (v)–O–C2-6 alkynyl–OC(O)OR 118 , (w)–O–C2-6 alkynyl–OC(O)NR 118 R 118 , (x)–O–C2-6 alkynyl–

C(O)NR 118 R 118 , (y)–O–C 2-6 alkynyl–NR 118 C(O)R 118 , (z)–O–C 2-6 alkynyl– NR 118 C(O)OR 118 , (aa)–O–C2-6 alkynyl–NR 118 C(O)NR 118 R 118 ,

(bb)–O–C2-6 alkynyl–NR 118 C(=N(H)NR 118 R 118 , (cc)–O–C2-6 alkynyl– S(O) p R 118 ; and (dd)–NR 118 R 118 ;

alternatively, two R 121 groups taken together form =O, =NOR 118 , or =NNR 118 R 118 ; R 122 is R 115 ;

R 123 is selected from:

(a) R 116 , (b) F, (c) Cl, (d) Br, (e) I, (f) CN, (g) NO2, and (h)–OR 114 ;

alternatively, R 122 and R 123 taken together are–O(CH2)uO–;

R 124 , at each occurrence, independently is selected from:

(a) H, (b) F, (c) Cl, (d) Br, (e) I, (f) CN, (g)–OR 114 , (h)–NO 2 , (i)– NR 114 R 114 , (j) C1-6 alkyl, (k) C1-6 acyl, and (l) C1-6 alkoxy;

R 125 is selected from:

(a) C 1-6 alkyl, (b) C 2-6 alkenyl, (c) C 2-6 alkynyl, (d) C 1-6 acyl, (e) C 1-6 alkoxy, (f) C1-6 alkylthio, (g) saturated, unsaturated, or aromatic

C 5-10 carbocycle, (h) saturated, unsaturated, or aromatic 5-10 membered heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (i)–O–C1-6 alkyl-saturated, unsaturated, or aromatic 5-10 membered heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (j)–NR 114 -C1-6 alkyl-saturated, unsaturated, or aromatic 5-10 membered heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (k) saturated, unsaturated, or aromatic 10-membered bicyclic ring system optionally containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (l) saturated, unsaturated, or aromatic 13-membered tricyclic ring system optionally containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (m)–OR 114 ,

(n)–NR 114 R 114 , (o)–S(O) p R 114 , and (p)–R 124 ,

wherein any of (a)-(l) optionally is substituted with one or more R 115 groups;

alternatively, R 125 and one R 124 group, taken together with the atoms to which they are bonded, form a 5-7 membered saturated or unsaturated carbocycle, optionally substituted with one or more R 115 groups; or a 5-7 membered saturated or unsaturated heterocycle containing one or more atoms selected from nitrogen, oxygen, and sulfur, and optionally substituted with one or more R 115 groups;

R 126 at each occurrence, independently is selected from:

(a) hydrogen, (b) an electron-withdrawing group, (c) aryl, (d) substituted aryl, (e) heteroaryl, (f) substituted heteroaryl, and (g) C1-6 alkyl, optionally substituted with one or more R 115 groups;

alternatively, any R 126 and any R 123 , taken together with the atoms to which they are bonded, form a 5-7 membered saturated or unsaturated carbocycle, optionally substituted with one or more R 115 groups; or a 5-7 membered saturated or unsaturated heterocycle containing one or more atoms selected from nitrogen, oxygen, and sulfur, and optionally substituted with one or more R 115 groups;

R 109 is H or F;

R 127 is R 114 , a monosaccharide or disaccharide (including amino sugars and halo sugar(s),–(CH 2 ) n -(O-CH 2 CH 2 -) m -O(CH 2 ) p CH 3 or–(CH 2 ) n -(O-CH 2 CH 2 -) m -OH R 128 is R 114 ;

R 129 is R 114 ;

R 110 is R 114 .

Alternatively, R 109 and R 110 taken together with the carbons to which they are attached form:

Alternately, R 128 and R 129 together with the carbons to which they are attached form a 3-6 membered saturated, unsaturated or aromatic carbocyclic or heterocyclic ring which can optionally be substituted with one or more R 114 groups;

R 132 , R 133 , and R 134 are each independently selected from (a) H, (b) F, (c) Cl, (d) Br, (e)–OR 114 , (f)–SR 114 , (g)–NR 114 R 114 , and (h) C1-6 alkyl, wherein (h) optionally is substituted with one or more R 115 groups;

alternatively, R 132 and R 133 are taken together to form a carbon-carbon double; alternatively, R 133 and R 134 are taken together to form =O, =S, =NOR 114 , =NR 114 , and =N-NR 114 ,R 114 ;

alternatively, R 105 and R 134 are taken together with the carbons to which they are attached to form a 3-membered ring, said ring optionally containing an oxygen or nitrogen atom, and said ring being optionally substituted with one or more R 114 groups;

alternatively when M is a carbon moiety, R 134 and M are taken together to form a carbon-carbon double bond;

k, at each occurrence is 0, 1, or 2;

m, at each occurrence is 0, 1, 2, 3, 4, or 5;

n, at each occurrence is 1, 2, or 3.

In certain embodiments, the compound is other than:

. In some embodiments, the compound is not a compound disclosed in PCT application No. WO2008/143730, PCT application No. WO2008/106226, PCT application No. WO2008/106224, PCT application No. WO2008/143729, PCT application No.

WO2008/106204, or PCT application No. WO2008/106225.

In some embodiments, the compound is not a compound disclosed in PCT application No. WO2008/143730 or PCT application No. WO2008/106226.

In further embodiments of the present invention, n is 1 or 2.

In further embodiments of the present invention, n is 1.

In further embodiments of the present invention, R 11 is F.

In further embodiments of the present invention, n is 0.

In further embodiments of the present invention, X is -OR 15 .

In further embodiments of the present invention, X is–SR 15 .

In further embodiments of the present invention, R 15 is C 1-3 alkyl, optionally substituted with from 1 to 7 fluorines.

In further embodiments of the present invention, R 15 is C1-2 alkyl, optionally substituted with from 1 to 5 fluorines.

In further embodiments of the present invention, R 15 is selected from–CH3, -

In further embodiments of the present invention, R 15 is–CH 3 .

In further embodiments of the present invention, A is selected from (a) a C 1-6 alkyl group, (b) a C 2-6 alkenyl group, (c) a C 2-6 alkynyl group, (d) a C3-12 saturated, unsaturated, or aromatic carbocycle, (e) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more nitrogen, oxygen or sulfur atoms, (f)–CF 3 , (g)– NR 6 (CR 6 R 6 ) t R 9 , (h)–OR 9 , (i)–S ( CR 6 R 6 ) t R 9 , (j)–S(O) ( CR 6 R 6 ) t R 9 ,(k)–S(O) 2 ( CR 6R6) t R9 (l)–C(O)(CR 6 R 6 ) t R 9 , (m)–OC(O)(CR 6 R 6 ) t R 9 , (n) OC(O)O(CR 6 R 6 ) t R 9 , (o)–

SC(O)(CR 6 R 6 ) t R 9 , (p)–C(O)O(CR 6 R 6 ) t R 9 , (q)–NR 6 C(O)(CR 6 R 6 ) t R 9 , (r)–

C(O)NR 6 (CR 6 R 6 ) t R 9 , (s)–C(=NR 6 )(CR 6 R 6 ) t R 9 , (t)–C(=NNR 6 R 6 )(CR 6 R 6 ) t R 9 , (u)– C[=NNR 6 C(O)R 6 ](CR 6 R 6 ) t R 9 , (v)–NR 6 C(O)O(CR 6 R 6 ) t R 9 , (w)–OC(O)NR 6 (CR 6 R 6 ) t R 9 , (x)–NR 6 C(O)NR 6 (CR 6 R 6 ) t R 9 , (y)–NR 6 S(O) p (CR 6 R 6 ) t R 9 , (z)–S(O) p NR 6 (CR 6 R 6 ) t R 9 , (aa)–NR 6 R 6 , (bb)–NR 6 (CR 6 R 6 )tR 9 , (cc)–SR 6 , (dd)–S(O)R 6 , (ee)–S(O) 2 R 6 , and (ff)– NR 6 C(O)R 6 ; wherein (a)-(e) optionally are substituted with one or more R 14 groups; In further embodiments of the present invention, A is selected from (a) a C 1-6 alkyl group, (b) a C 2-6 alkenyl group, (c) a C 2-6 alkynyl group, (d) a C3-12 saturated, unsaturated, or aromatic carbocycle, (e) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more nitrogen, oxygen or sulfur atoms; wherein (a)-(e) optionally are substituted with one or more R 14 groups.

In further embodiments of the present invention, A is selected (a)–

NR 6 (CR 6 R 6 ) t R 9 , (b)–OR 9 , (c)–S ( CR 6 R 6 ) t R 9 , (d)–S(O) ( CR 6 R 6 ) t R 9 ,(e)–S(O) 2 ( CR 6R6) t R9 (f)–C(O)(CR 6 R 6 ) t R 9 , (g)–OC(O)(CR 6 R 6 ) t R 9 , (h)–OC(O)O(CR 6 R 6 ) t R 9 , (i)–

SC(O)(CR 6 R 6 ) t R 9 , (j)–C(O)O(CR 6 R 6 ) t R 9 , (k)–NR 6 C(O)(CR 6 R 6 ) t R 9 , (l)–

C(O)NR 6 (CR 6 R 6 ) t R 9 , (m)–C(=NR 6 )(CR 6 R 6 ) t R 9 , (n)–C(=NNR 6 R 6 )(CR 6 R 6 ) t R 9 , (o)– C[=NNR 6 C(O)R 6 ](CR 6 R 6 ) t R 9 , (p)–NR 6 C(O)O(CR 6 R 6 ) t R 9 , (q)–OC(O)NR 6 (CR 6 R 6 ) t R 9 , (r)–NR 6 C(O)NR 6 (CR 6 R 6 ) t R 9 , (s)–NR 6 S(O) p (CR 6 R 6 ) t R 9 , (t)–S(O) p NR 6 (CR 6 R 6 ) t R 9 , (u)–NR 6 R 6 , (v)–NR 6 (CR 6 R 6 ) t R 9 , (w)–SR 6 , (x)–S(O)R 6 , (y)–S(O) 2 R 6 , and (z)–

NR 6 C(O)R 6 . In further embodiments of the present invention, A is a C 1-6 alkyl group, optionally substituted with one or more R 14 groups.

In further embodiments of the present invention, A is a C 2-6 alkenyl group, optionally substituted with one or more R 14 groups.

In further embodiments of the present invention, A is a C 2-6 alkynyl group, optionally substituted with one or more R 14 groups.

In further embodiments of the present invention, A is a C 3-12 saturated, unsaturated, or aromatic carbocycle, optionally are substituted with one or more R 14 groups.

In further embodiments of the present invention, A is a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more nitrogen, oxygen or sulfur atoms, optionally substituted with one or more R 14 groups. In certain embodiments, A is 5-10 (e.g., 5-6) membered aromatic heterocycle containing one or more nitrogen, oxygen or sulfur atoms, optionally substituted with one or more R 14 groups; e.g., 5-10 (e.g., 5-6) membered aromatic heterocycle containing one or more nitrogen atoms, optionally substituted with one or more R 14 groups; e.g., pyridyl, e.g., 3-pyridyl.

In further embodiments of the present invention, A is H.

In further embodiments of the present invention, A is–OH. In further embodiments of the present invention, A is–SH.

In further embodiments of the present invention, A is F.

In further embodiments of the present invention, A is Cl.

In further embodiments of the present invention, A is Br.

In further embodiments of the present invention, A is I.

In further embodiments of the present invention, A is–CF 3 .

In further embodiments of the present invention, A is–CN.

In further embodiments of the present invention, A is–N3.

In further embodiments of the present invention, A is–NO 2 .

In further embodiments of the present invention, A is–NR 6 (CR 6 R 6 ) t R 9 .

In further embodiments of the present invention, A is–OR 9 .

In further embodiments of the present invention, A is–S ( CR 6 R 6 ) t R 9 .

In further embodiments of the present invention, A is–S(O) ( CR 6 R 6 ) t R 9 .

In further embodiments of the present invention, A is–S(O) 2 ( CR 6R6) t R9 .

In further embodiments of the present invention, A is–C(O)(CR 6 R 6 ) t R 9 .

In further embodiments of the present invention, A is–OC(O)(CR 6 R 6 ) t R 9 .

In further embodiments of the present invention, A is–OC(O)O(CR 6 R 6 ) t R 9 . In further embodiments of the present invention, A is–SC(O)(CR 6 R 6 ) t R 9 .

In further embodiments of the present invention, A is–C(O)O(CR 6 R 6 ) t R 9 .

In further embodiments of the present invention, A is–NR 6 C(O)(CR 6 R 6 ) t R 9 . In further embodiments of the present invention, A is–C(O)NR 6 (CR 6 R 6 ) t R 9 . In further embodiments of the present invention, A is–C(=NR 6 )(CR 6 R 6 ) t R 9 . In further embodiments of the present invention, A is–C(=NNR 6 R 6 )(CR 6 R 6 ) t R 9 . In further embodiments of the present invention, A

is -C[=NNR 6 C(O)R 6 ](CR 6 R 6 ) t R 9 .

In further embodiments of the present invention, A is–NR 6 C(O)O(CR 6 R 6 ) t R 9 . In further embodiments of the present invention, A is–OC(O)NR 6 (CR 6 R 6 ) t R 9 . In further embodiments of the present invention, A is–NR 6 C(O)NR 6 (CR 6 R 6 ) t R 9 . In further embodiments of the present invention, A is–NR 6 S(O) p (CR 6 R 6 ) t R 9 . In further embodiments of the present invention, A is–S(O) p NR 6 (CR 6 R 6 ) t R 9 . In further embodiments of the present invention, A is–NR 6 R 6 . In further embodiments of the present invention, A is–NR 6 (CR 6 R 6 )tR 9 .

In further embodiments of the present invention, A is–SR 6 .

In further embodiments of the present invention, A is–S(O)R 6 .

In further embodiments of the present invention, A is–S(O) 2 R 6 .

In further embodiments of the present invention, A is–NR 6 C(O)R 6 .

In further embodiments of the present invention, A is–Si(R 13 ) 3 .

In further embodiments of the present invention, A is and–C(=O)H.

In further embodiments of the present invention, R 13 is selected from –CH3 and– OCH 3 .

In further embodiments of the present invention, R 13 is–CH 3 .

In further embodiments of the present invention, R 13 is–OCH3.

In further embodiments, the invention provides a compound having the structure:

or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R 1 , R 2 , R 3 , R 11 , R 15 , n A, and T, are as described herein.

In further embodiments, the invention provides a compound having the structure:

or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R 1 , R 2 , R 3 , R 11 , R 15 , n, A, and T, are as described herein.

In further embodiments, the invention provides a compound having the structure:

or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, wherein R 1 , R 2 , R 3 , R 11 , n A, and T, are as described herein.

In further embodiments of the present invention, T is selected from:

wherein M, R 100 , R 101 , R 104 , R 105 , R 106 , R 107 , R 108 , R 109 , R 110 , and R 120 are as described above and where the dotted lines indicate optional double bonds.

In certain embodiments, one of R 100 and R 101 is C 1-6 alkyl (e.g., CH 3 ), and the other is H.

In certain embodiments, R 104 is C 1-6 alkyl (e.g., CH3).

In certain embodiments, R 108 is C 1-6 alkyl (e.g., CH 2 CH 3 ).

In certain of the foregoing embodiments, each of R 105 and R 106 is an independently selected -OR 114 (e.g., each of R 105 and R 106 is -OH). In other of these embodiments, R 105 and R 106 taken together with the atoms to which they are attached form a 5-membered ring by attachment to each other through a chemical moiety selected from:

(a)–OC(R 115 )2O–, (b)–OC(O)O–, (c)–OC(O)NR 114 –, (d)–NR 114 C(O)O–, (e)–OC(O)NOR 114 –, (f)–NOR 114 –C(O)O–, (g)–OC(O)NNR 114 R 114 –, (h)–NNR 114 R 114 –C(O)O–, (i)–OC(O)C(R 115 )2–, (j)–C(R 115 )2C(O)O–, (k)– OC(S)O–, (l)–OC((S)NR 114 –, (m)–NR 114 C(S)O–, (n)–OC(S)NOR 114 –, (o)–NOR 114 – C(S)O–, (p)–OC(S)NNR 114 R 114 –, (q)–NNR 114 R 114 –C(S)O–, (r)–OC(S)C(R 115 )2–, and (s)–C(R 115 )2C(S)O–.

For example, R 105 and R 106 taken together with the atoms to which they are attached form a 5-membered ring by attachment to each other through a chemical moiety selected from (b)–OC(O)O–, (c)–OC(O)NR 114 –, and (d)–NR 114 C(O)O–.

In certain embodiments, R 127 is R 114 , e.g., R 114 can be selected from:

(a) H,

(b) C1-6 alkyl, optionally substituted with one or more R 115 groups, wherein one or more non-terminal carbon moieties is replaced with oxygen, S(O) p , or–NR 116 (e.g., oxygen); (c) C 2-6 alkenyl, (d) C 2-6 alkynyl, (e) C 6-10 saturated, unsaturated, or aromatic carbocycle; and

(f) 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, optionally substituted with one or more R 115 groups.

wherein M, R 100 , R 101 , R 102 , R 104 , R 109 , R 114 , R 126 and R 127 are as described above. In further embodiments of the present invention, T is selected from:

, , , wherein M, R 1 , R 2 , R 104 , R 114 , R 109 and R 127 are as described above.

In further embodiments of the resent invention T is selected from:

, and .

In the present invention, the macrolide,“T” is defined to include various 14- and 15-membered ring systems, which can contain one or more heteroatoms. Also, as defined herein, the macrolide,“T” is connected via a macrocyclic ring carbon atom”, which means that the connection or bond is made to a carbon atom on the 14- or 15-membered ring of the macrolide moiety. The macrolide can include further substituents, including ring substituents. For example, the substituent designated as R 103 can in certain embodiments be a sugar moiety, e.g. a cladinose sugar, or the substituents such as R 104 and R 105 are taken together in certain embodiments to form a bridged bicyclic ring system with the macrolide ring, or the substituents R 105 and R 106 ,are taken together in certain

embodiments to form a fused bicyclic ring system with the macrolide ring (supra), or the substituents or components M, R 105 , and R 106 are taken together to form a fused tricyclic ring system with the macrolide ring, etc. It is also recognized in the present invention that “T” is depicted as being connected to a 6-membered ring, for example in certain embodiments a desosamine sugar ring.

As is seen from the foregoing, the macrolide component of the compounds of the present invention can comprise a wide range of structures. Examples of such macrolide components and their syntheses are provided in the following documents, all of which are incorporated by reference in their entirety: PCT application No. WO 2005/118610, published December 15, 2005, to Rib-X Pharmaceuticals, Inc.; PCT application No. WO 2005/085266, published September 15, 2005, to Rib-X Pharmaceuticals, Inc.; PCT application No. WO 2005/049632, published June 2, 2005, to Rib-X Pharmaceuticals, Inc.; PCT application No. WO 2005/042554, published May 12, 2005, to Rib-X

Pharmaceuticals, Inc.; PCT application No. WO 2004/078770, published September 16, 2004, to Rib-X Pharmaceuticals, Inc.; PCT application No. WO 2004/029066, published April 8, 2004, to Rib-X Pharmaceuticals, Inc.; U.S. Patent No.; U.S. Patent No.6,992,069, to Gu et al., issued January 31, 2006; U.S. Patent No.6,953,782, to Phan et al., issued October 11, 2005; U.S. Patent No.6,939,861, to Ashley et al., issued September 6, 2005; U.S. Patent No., 6,927,057, to Khosla et al., issued August 9, 2005; U.S. Patent No.

6,794,366, to Chu et al., issued September 21,.2004; U.S. Patent No.6,762,168, to Chu, issued July 13, 2004; U.S. Patent No.6,756,359, to Chu et al, issued June 29, 2994; U.S. Patent No.6,750,205, to Ashley et al, issued June 15, 2004; U.S. Patent No.6,740,642, to Angehrn et al., issued May 25, 2004; U.S. Patent No.6,727,352, to Cheng et al., issued April 27, 2004; U.S. Patent Application Publication No. US 2006/0154881, to Or et al., published July 13, 2006; U.S. Patent Application Publication No. US 2006/0142215, to Tang et al., published June 29, 2006; U.S. Patent Application Publication No. US

2006/0142214, to Or et al, published June 29, 2006; U.S. Patent Application Publication No. US 2006/0122128, to Or et al., published June 8, 2006; U.S Patent Application Publication No. US 2006/0069048, to Or et al. published March 30, 2006; U.S. Patent Application Publication No. US 2005/0272672, to Li et al., published December 8, 2005; U.S. Patent Application Publication No US 2005/0009764, to Burger et al, published January 13, 2005; PCT application No. WO 2006/067589, to Pfizer Products Inc., published June 29, 2006; PCT application No. WO 2004/096823, to Chiron Corporation, published November 11, 2004; PCT application No. WO 2004/096822, to Chiron

Corporation, published November 11, 2004; PCT application No. WO 2004/080391, to Optimer Pharmaceuticals, Inc., published September 23, 2004; PCT application No. WO 2004/078771, to Taisho Pharmaceutical Co., Ltd., published September 16, 2004; PCT application no. WO 03/061671, to Kosan Biosciences, Inc. published July 31, 2003; and European Patent Document EP 1256587 B1, to the Kitasato Institute, granted March 29, 2006.

In some embodiments, the compound of Formula I is a compound selected from Table I, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof. For brevity, the structures in Table I depict the geometry of the major oxime isomer. Table I.

In some embodiments, the compound selected from Table I is not a compound disclosed in PCT application No. WO2008/143730, PCT application No.

WO2008/106226, PCT application No. WO2008/106224, PCT application No.

WO2008/143729, PCT application No. WO2008/106204, or PCT application No.

WO2008/106225.

In some embodiments, the compound selected from Table I is not a compound disclosed in PCT application No. WO2008/143730 or PCT application No.

WO2008/106226.

In some embodiments, the compound of Formula I is a compound selected from Table II, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof. Table II

In some embodiments, the compound is a compound selected from Table I and/or Table II. In some embodiments, the compound selected from Table I and/or Table II is not a compound disclosed in PCT application No. WO2008/143730, PCT application No. WO2008/106226, PCT application No. WO2008/106224, PCT application No.

WO2008/143729, PCT application No. WO2008/106204, or PCT application No.

WO2008/106225.

In some embodiments, the compound selected from Table I and/or Table II is not a compound disclosed in PCT application No. WO2008/143730 or PCT application No. WO2008/106226.

The invention also provides a compound having one of the following structures, or a harmaceuticall acce table salt ester N-oxide or rodru thereof:

.

(2) , (3), and (4).

The invention also provides a pharmaceutical composition that contains one or more of the compounds described above and a pharmaceutically acceptable carrier.

The invention also provides a method for treating or preventing a disease state in a mammal by administering to a mammal in need thereof an effective amount of one or more of the compounds described above.

The invention also provides a method of treating a microbial infection in a mammal by administering to the mammal an effective amount of one or more of the compounds described above. The invention also provides a method of treating a fungal infection in a mammal by administering to the mammal an effective amount of one or more of the compounds described above.

The invention also provides a method of treating a parasitic disease in a mammal by administering to the mammal an effective amount of one or more of the compounds described above.

The invention also provides a method of treating a proliferative disease in a mammal by administering to the mammal an effective amount of one or more of the compounds described above.

The invention also provides a method of treating a viral infection in a mammal by administering to the mammal an effective amount of one or more of the compounds described above.

The invention also provides a method of treating an inflammatory disease in a mammal by administering to the mammal an effective amount of one or more of the compounds described above.

The invention also provides a method of treating a gastrointestinal motility disorder in a mammal by administering to the mammal an effective amount of one or more of the compounds described above.

The invention also provides a method of treating or preventing a disease state in a mammal caused or mediated by a nonsense or missense mutation by administering to the mammal an effective amount of one or more of the compounds described above to suppress expression of the nonsense or missense mutation.

In the methods described herein, the compound or compounds are administered orally, parentally, or topically.

The invention also provides a method of synthesizing the compounds described above.

The invention also provides a medical device containing one or more of the compounds described above. For example, the device is a stent.

3. Synthesis of the Compounds of the Invention

The invention provides methods for making the compounds of the invention. The following schemes depict exemplary chemistries available for synthesizing the compounds of the invention.

Scheme 1 illustrates the synthesis of triazole compounds of type 5 and 6.

Erythromycin can be N-demethylated as described in the art (U.S. Patent No.3,725,385; Flynn et al. (1954) J. AM. CHEM. SOC.76: 3121; Ku et al. (1997) BIOORG. MED. CHEM. LETT.7: 1203; Stenmark et al. (2000) J. ORG. CHEM.65: 3875) to afford secondary amine 1. Alkylation of 1 with electrophiles of type 2 yields alkynes of type 3 containing an alkyl chain of appropriate length, generally between one and about four carbon atoms between the nitrogen atom and the alkyne group. Cycloaddition of azides of type 4 with alkynes 3 generates two regioisomeric triazole products. The reaction can be thermally catalyzed, or a number of catalysts could be added to facilitate the reaction (such as, but not limited to, copper (I) iodide: see Tornoe, C.W. et al. (2002) J. ORG. CHEM. 67: 3057). The major isomer (for steric reasons) is the“anti” isomer 5, a 1,4 disubstituted triazole. The minor component is the“syn” isomer 6, a 1,5 disubstituted triazole. Scheme 1

It is to be understood that other macrolide compounds such as, but not limited to, azithromycin and clarithromycin, could be N-demethylated and serve as starting materials for the chemistry exemplified in Scheme 1. Target compounds derived from such alternate macrolide precursors are to be considered within the scope of the present invention.

An alternate approach to derivatives of type 5 and 6 is illustrated by Scheme 2. Acetylenic alcohols of type 14 can be treated with azides 4 to yield intermediate alcohol 15 (along with a minor amount of the regioisomeric triazole). Tosylation of 15 will provide tosylates 16 which can serve as alkylating agents for macrolide amines of type 1 to afford targets 5 (and its isomer 6). It will be appreciated that other sulfonate derivatives or halides could be formed from intermediate alcohol 15, and these would be useful as electrophiles for the alkylation of macrolide amines such as 1 to afford compounds of the invention. Scheme 2

Other starting materials for the synthesis of compounds of the present invention are readily synthesizable. 4. Characterization of Compounds of the Invention

Compounds designed, selected and/or optimized by methods described above, once produced, can be characterized using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity. For example, the molecules can be characterized by conventional assays, including but not limited to those assays described below, to determine whether they have a predicted activity, binding activity and/or binding specificity.

Furthermore, high-throughput screening can be used to speed up analysis using such assays. As a result, it can be possible to rapidly screen the molecules described herein for activity, for example, as anti-cancer, anti-bacterial, anti-fungal, anti-parasitic or anti-viral agents. Also, it can be possible to assay how the compounds interact with a ribosome or ribosomal subunit and/or are effective as modulators (for example, inhibitors) of protein synthesis using techniques known in the art. General methodologies for performing high-throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No.5,763,263. High-throughput assays can use one or more different assay techniques including, but not limited to, those described below.

(1) Surface Binding Studies. A variety of binding assays can be useful in screening new molecules for their binding activity. One approach includes surface plasmon resonance (SPR) that can be used to evaluate the binding properties of molecules of interest with respect to a ribosome, ribosomal subunit or a fragment thereof.

SPR methodologies measure the interaction between two or more macromolecules in real-time through the generation of a quantum-mechanical surface plasmon. One device, (BIAcore Biosensor RTM from Pharmacia Biosensor, Piscataway, N.J.) provides a focused beam of polychromatic light to the interface between a gold film (provided as a disposable biosensor "chip") and a buffer compartment that can be regulated by the user. A 100 nm thick "hydrogel" composed of carboxylated dextran that provides a matrix for the covalent immobilization of analytes of interest is attached to the gold film. When the focused light interacts with the free electron cloud of the gold film, plasmon resonance is enhanced. The resulting reflected light is spectrally depleted in wavelengths that optimally evolved the resonance. By separating the reflected polychromatic light into its component wavelengths (by means of a prism), and determining the frequencies that are depleted, the BIAcore establishes an optical interface which accurately reports the behavior of the generated surface plasmon resonance. When designed as above, the plasmon resonance (and thus the depletion spectrum) is sensitive to mass in the evanescent field (which corresponds roughly to the thickness of the hydrogel). If one component of an interacting pair is immobilized to the hydrogel, and the interacting partner is provided through the buffer compartment, the interaction between the two components can be measured in real time based on the accumulation of mass in the evanescent field and its corresponding effects of the plasmon resonance as measured by the depletion spectrum. This system permits rapid and sensitive real-time measurement of the molecular interactions without the need to label either component.

(2) Fluorescence Polarization. Fluorescence polarization (FP) is a measurement technique that can readily be applied to protein-protein, protein-ligand, or RNA-ligand interactions in order to derive IC50s and Kds of the association reaction between two molecules. In this technique one of the molecules of interest is conjugated with a fluorophore. This is generally the smaller molecule in the system (in this case, the compound of interest). The sample mixture, containing both the ligand-probe conjugate and the ribosome, ribosomal subunit or fragment thereof, is excited with vertically polarized light. Light is absorbed by the probe fluorophores, and re-emitted a short time later. The degree of polarization of the emitted light is measured. Polarization of the emitted light is dependent on several factors, but most importantly on viscosity of the solution and on the apparent molecular weight of the fluorophore. With proper controls, changes in the degree of polarization of the emitted light depends only on changes in the apparent molecular weight of the fluorophore, which in-turn depends on whether the probe-ligand conjugate is free in solution, or is bound to a receptor. Binding assays based on FP have a number of important advantages, including the measurement of IC 50 s and Kds under true homogenous equilibrium conditions, speed of analysis and amenity to automation, and ability to screen in cloudy suspensions and colored solutions.

(3) Protein Synthesis. It is contemplated that, in addition to characterization by the foregoing biochemical assays, the compound of interest can also be characterized as a modulator (for example, an inhibitor of protein synthesis) of the functional activity of the ribosome or ribosomal subunit.

Furthermore, more specific protein synthesis inhibition assays can be performed by administering the compound to a whole organism, tissue, organ, organelle, cell, a cellular or subcellular extract, or a purified ribosome preparation and observing its pharmacological and inhibitory properties by determining, for example, its inhibition constant (IC50) for inhibiting protein synthesis. Incorporation of 3 H leucine or 35 S methionine, or similar experiments can be performed to investigate protein synthesis activity. A change in the amount or the rate of protein synthesis in the cell in the presence of a molecule of interest indicates that the molecule is a modulator of protein synthesis. A decrease in the rate or the amount of protein synthesis indicates that the molecule is a inhibitor of protein synthesis.

Furthermore, the compounds can be assayed for anti-proliferative or anti-infective properties on a cellular level. For example, where the target organism is a microorganism, the activity of compounds of interest can be assayed by growing the microorganisms of interest in media either containing or lacking the compound. Growth inhibition can be indicative that the molecule can be acting as a protein synthesis inhibitor. More specifically, the activity of the compounds of interest against bacterial pathogens can be demonstrated by the ability of the compound to inhibit growth of defined strains of human pathogens. For this purpose, a panel of bacterial strains can be assembled to include a variety of target pathogenic species, some containing resistance mechanisms that have been characterized. Use of such a panel of organisms permits the determination of structure-activity relationships not only in regards to potency and spectrum, but also with a view to obviating resistance mechanisms. The assays can be performed in microtiter trays according to conventional methodologies as published by The National Committee for Clinical Laboratory Standards (NCCLS) guidelines (NCCLS. M7-A5-Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard-Fifth Edition. NCCLS Document M100-S12/M7 (ISBN 1-56238-394-9)). 5. Formulation and Administration

The compounds of the invention can be useful in the prevention or treatment of a variety of human or other animal, including mammalian and non mammalian, disorders, including for example, bacterial infection, fungal infections, viral infections, parasitic diseases, and cancer. It is contemplated that, once identified, the active molecules of the invention can be incorporated into any suitable carrier prior to use. The dose of active molecule, mode of administration and use of suitable carrier will depend upon the intended recipient and target organism. The formulations, both for veterinary and for human medical use, of compounds according to the present invention typically include such compounds in association with a pharmaceutically acceptable carrier.

The carrier(s) should be "acceptable" in the sense of being compatible with the other ingredients of the formulations and not deleterious to the recipient.

Pharmaceutically acceptable carriers, in this regard, are intended to include any and all solvents, dispersion media, coatings, anti-bacterial and anti-fungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds (identified or designed according to the invention and/or known in the art) also can be incorporated into the compositions. The formulations can conveniently be presented in dosage unit form and can be prepared by any of the methods well known in the art of pharmacy/microbiology. In general, some formulations are prepared by bringing the compound into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.

A pharmaceutical composition of the invention should be formulated to be compatible with its intended route of administration. Examples of routes of administration include oral or parenteral, for example, intravenous, intradermal, inhalation, transdermal (topical), transmucosal, and rectal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following

components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.

Useful solutions for oral or parenteral administration can be prepared by any of the methods well known in the pharmaceutical art, described, for example, in Remington's Pharmaceutical Sciences, (Gennaro, A., ed.), Mack Pub., (1990). Formulations for parenteral administration can also include glycocholate for buccal administration, methoxysalicylate for rectal administration, or citric acid for vaginal administration. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Suppositories for rectal administration also can be prepared by mixing the drug with a non-irritating excipient such as cocoa butter, other glycerides, or other compositions which are solid at room temperature and liquid at body

temperatures. Formulations also can include, for example, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, and hydrogenated naphthalenes.

Formulations for direct administration can include glycerol and other compositions of high viscosity. Other potentially useful parenteral carriers for these drugs include ethylene- vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation administration can contain as excipients, for example, lactose, or can be aqueous solutions containing, for example, polyoxyethylene-9- lauryl ether, glycocholate and deoxycholate, or oily solutions for administration in the form of nasal drops, or as a gel to be applied intranasally. Retention enemas also can be used for rectal delivery.

Formulations of the present invention suitable for oral administration can be in the form of: discrete units such as capsules, gelatin capsules, sachets, tablets, troches, or lozenges, each containing a predetermined amount of the drug; a powder or granular composition; a solution or a suspension in an aqueous liquid or non-aqueous liquid; or an oil-in-water emulsion or a water-in-oil emulsion. The drug can also be administered in the form of a bolus, electuary or paste. A tablet can be made by compressing or moulding the drug optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing, in a suitable machine, the drug in a free-flowing form such as a powder or granules, optionally mixed by a binder, lubricant, inert diluent, surface active or dispersing agent. Moulded tablets can be made by moulding, in a suitable machine, a mixture of the powdered drug and suitable carrier moistened with an inert liquid diluent.

Oral compositions generally include an inert diluent or an edible carrier. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients. Oral compositions prepared using a fluid carrier for use as a mouthwash include the compound in the fluid carrier and are applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose; a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS). It should be stable under the conditions of manufacture and storage and should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as manitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin. Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filter sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation include vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

Formulations suitable for intra-articular administration can be in the form of a sterile aqueous preparation of the drug that can be in microcrystalline form, for example, in the form of an aqueous microcrystalline suspension. Liposomal formulations or biodegradable polymer systems can also be used to present the drug for both intra-articular and ophthalmic administration.

Formulations suitable for topical administration, including eye treatment, include liquid or semi-liquid preparations such as liniments, lotions, gels, applicants, oil-in-water or water-in-oil emulsions such as creams, ointments or pastes; or solutions or suspensions such as drops. Formulations for topical administration to the skin surface can be prepared by dispersing the drug with a dermatologically acceptable carrier such as a lotion, cream, ointment or soap. Particularly useful are carriers capable of forming a film or layer over the skin to localize application and inhibit removal. For topical administration to internal tissue surfaces, the agent can be dispersed in a liquid tissue adhesive or other substance known to enhance adsorption to a tissue surface. For example, hydroxypropylcellulose or fibrinogen/thrombin solutions can be used to advantage. Alternatively, tissue-coating solutions, such as pectin-containing formulations can be used.

For inhalation treatments, inhalation of powder (self-propelling or spray formulations) dispensed with a spray can, a nebulizer, or an atomizer can be used. Such formulations can be in the form of a fine powder for pulmonary administration from a powder inhalation device or self-propelling powder-dispensing formulations. In the case of self-propelling solution and spray formulations, the effect can be achieved either by choice of a valve having the desired spray characteristics (i.e., being capable of producing a spray having the desired particle size) or by incorporating the active ingredient as a suspended powder in controlled particle size. For administration by inhalation, the compounds also can be delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

Systemic administration also can be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants generally are known in the art, and include, for example, for transmucosal administration, detergents and bile salts.

Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds typically are formulated into ointments, salves, gels, or creams as generally known in the art.

The active compounds can be prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. Liposomal suspensions can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811.

Oral or parenteral compositions can be formulated in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals. Furthermore, administration can be by periodic injections of a bolus, or can be made more continuous by intravenous, intramuscular or intraperitoneal administration from an external reservoir (e.g., an intravenous bag).

Where adhesion to a tissue surface is desired the composition can include the drug dispersed in a fibrinogen-thrombin composition or other bioadhesive. The compound then can be painted, sprayed or otherwise applied to the desired tissue surface. Alternatively, the drugs can be formulated for parenteral or oral administration to humans or other mammals, for example, in therapeutically effective amounts, e.g., amounts that provide appropriate concentrations of the drug to target tissue for a time sufficient to induce the desired effect.

Where the active compound is to be used as part of a transplant procedure, it can be provided to the living tissue or organ to be transplanted prior to removal of tissue or organ from the donor. The compound can be provided to the donor host. Alternatively or, in addition, once removed from the donor, the organ or living tissue can be placed in a preservation solution containing the active compound. In all cases, the active compound can be administered directly to the desired tissue, as by injection to the tissue, or it can be provided systemically, either by oral or parenteral administration, using any of the methods and formulations described herein and/or known in the art. Where the drug comprises part of a tissue or organ preservation solution, any commercially available preservation solution can be used to advantage. For example, useful solutions known in the art include Collins solution, Wisconsin solution, Belzer solution, Eurocollins solution and lactated Ringer's solution.

The compounds of the present invention can be administered directly to a tissue locus by applying the compound to a medical device that is placed in contact with the tissue. An example of a medical device is a stent, which contains or is coated with one or more of the compounds of the present invention.

For example, an active compound can be applied to a stent at the site of vascular injury. Stents can be prepared by any of the methods well known in the pharmaceutical art. See, e.g., Fattori, R. and Piva, T.,“Drug Eluting Stents in Vascular Intervention,” Lancet, 2003, 361, 247-249; Morice, M. C.,“A New Era in the Treatment of Coronary Disease?” European Heart Journal, 2003, 24, 209-211; and Toutouzas, K. et al., “Sirolimus-Eluting Stents: A Review of Experimental and Clinical Findings,” Z. Kardiol., 2002, 91(3), 49-57. The stent can be fabricated from stainless steel or another bio- compatible metal, or it can be made of a bio-compatible polymer. The active compound can be linked to the stent surface, embedded and released from polymer materials coated on the stent, or surrounded by and released through a carrier which coats or spans the stent. The stent can be used to administer single or multiple active compounds to tissues adjacent to the stent.

Active compound as identified or designed by the methods described herein can be administered to individuals to treat disorders (prophylactically or therapeutically). In conjunction with such treatment, pharmacogenomics (i.e., the study of the relationship between an individual's genotype and that individual's response to a foreign compound or drug) can be considered. Differences in metabolism of therapeutics can lead to severe toxicity or therapeutic failure by altering the relation between dose and blood

concentration of the pharmacologically active drug. Thus, a physician or clinician can consider applying knowledge obtained in relevant pharmacogenomics studies in determining whether to administer a drug as well as tailoring the dosage and/or therapeutic regimen of treatment with the drug.

In therapeutic use for treating, or combating, bacterial infections in mammals, the compounds or pharmaceutical compositions thereof will be administered orally, parenterally and/or topically at a dosage to obtain and maintain a concentration, that is, an amount, or blood-level or tissue level of active component in the animal undergoing treatment which will be anti-microbially effective. Generally, an effective amount of dosage of active component will be in the range of from about 0.1 to about 100, more preferably from about 1.0 to about 50 mg/kg of body weight/day. The amount

administered will also likely depend on such variables as the type and extent of disease or indication to be treated, the overall health status of the particular patient, the relative biological efficacy of the compound delivered, the formulation of the drug, the presence and types of excipients in the formulation, and the route of administration. Also, it is to be understood that the initial dosage administered can be increased beyond the above upper level in order to rapidly achieve the desired blood-level or tissue level, or the initial dosage can be smaller than the optimum and the daily dosage can be progressively increased during the course of treatment depending on the particular situation. If desired, the daily dose can also be divided into multiple doses for administration, for example, two to four times per day.

Various disease states or conditions in humans and other mammals are found to be caused by or mediated by nonsense or missense mutations. These mutations cause or mediate the disease state or condition by adversely affecting, for example, protein synthesis, folding, trafficking and/or function. Examples of disease states or conditions in which an appreciable percentage of the disease or condition is believed to result from nonsense or missense mutations include hemophilia (factor VIII gene), neurofibromatosis (NF1 and NF2 genes), retinitis pigmentosa (human USH2A gene), bullous skin diseases like Epidermolysis bullosa pruriginosa (COL7A1 gene), cystic fibrosis (cystic fibrosis transmembrane regulator gene), breast and ovarian cancer (BRCA1 and BRCA2 genes), Duchenne muscular dystrophy (dystrophin gene), colon cancer (mismatch repair genes, predominantly in MLH1 and MSH2), and lysosomal storage disorders such as Neimann- Pick disease (acid sphingomyelinase gene). See Sanders CR, Myers JK. Disease-related misassembly of membrane proteins. Annu Rev Biophys Biomol Struct.2004;33:25-51; National Center for Biotechnology Information (U.S.) Genes and disease Bethesda, MD : NCBI, NLM ID: 101138560; and Raskó, István; Downes, C S Genes in medicine :

molecular biology and human genetic disorders 1st ed. London ; New York : Chapman & Hall, 1995. NLM ID: 9502404. The compounds of the present invention can be used to treat or prevent a disease state in a mammal caused or mediated by such nonsense or missense mutations by administering to a mammal in need thereof an effective amount of the present invention to suppress the nonsense or missense mutation involved in the disease state.

6. Examples Example 1: Compound Preparations

Nuclear magnetic resonance (NMR) spectra were obtained on a Bruker Avance 300 or Avance 500 spectrometer, or in some cases a GE-Nicolet 300 spectrometer.

Common reaction solvents were either high performance liquid chromatography (HPLC) grade or American Chemical Society (ACS) grade, and anhydrous as obtained from the manufacturer unless otherwise noted.“Chromatography” or“purified by silica gel” refers to flash column chromatography using silica gel (EM Merck, Silica Gel 60, 230-400 mesh) unless otherwise noted. Some of the abbreviations used in the following experimental details of the synthesis of the examples are defined below:

Ac = acetyl

hr = hour(s)

min = minute(s)

mol = mole(s)

mmol = millimole(s)

M = molar

^M = micromolar

g = gram(s) ^g = microgram(s)

rt = room temperature

L = liter(s)

mL = milliliter(s)

Et 2 O = diethyl ether

THF = tetrahydrofuran

DMSO = dimethyl sulfoxide

EtOAc = ethyl acetate

Et3N = triethylamine

i-Pr2NEt = diisopropylethylamine

CH 2 Cl 2 = methylene chloride

CHCl3 = chloroform

CDCl3 = deuterated chloroform

CCl 4 = carbon tetrachloride

MeOH = methanol

CD3OD = deuterated methanol

EtOH = ethanol

DMF = dimethylformamide

BOC = t-butoxycarbonyl

CBZ = benzyloxycarbonyl

TBS = t-butyldimethylsilyl

TBSCl = t-butyldimethylsilyl chloride TFA = trifluoroacetic acid

DBU = diazabicycloundecene

TBDPSCl = t-butyldiphenylchlorosilane Hunig’s Base = N,N-diisopropylethylamine DMAP = 4-dimethylaminopyridine CuI = copper (I) iodide

MsCl = methanesulfonyl chloride NaN 3 = sodium azide

Na2SO4 = sodium sulfate

NaHCO3 = sodium bicarbonate

NaOH = sodium hydroxide

MgSO4 = magnesium sulfate K2CO3 = potassium carbonate

KOH = potassium hydroxide

NH 4 OH = ammonium hydroxide

NH4Cl = ammonium chloride

SiO2 = silica

Pd-C = palladium on carbon

Pd(dppf)Cl2 = dichloro[1,1’-bis(diphenylphosphino)ferrocene] palladium (II) Exemplary compounds which can be synthesized in accordance with the invention are listed above. A bolded or dashed bond is shown to indicate a particular

stereochemistry at a chiral center, whereas a wavy bond indicates that the substituent can be in either orientation or that the compound is a mixture thereof. It should also be known that in the interest of space, the chemical structures for some compounds have been condensed, for example the methyl and ethyl group substituents are designated with just a carbon backbone representation, and the unsaturated bonds in the triazole rings might not always be visible. The compounds of the present invention can be prepared, formulated, and delivered as pharmaceutically acceptable salts, esters, and prodrugs. For convenience, the compounds are generally shown without indicating a particular salt, ester, or prodrug form. Compounds in which, for example, the–OCH 3 substituent is replaced with– OCH2F or–SCH3 can also be prepared and are contemplated as within the scope of the present invention.

In some embodiments,“A” is as defined in Table 1 below. Note that the fragments for“A” are drawn such that the fragment is bonded to the phenyl ring in the structure below via the bond on the left. For example, the first fragment,

Synthesis of the Compounds of the Present Invention

Compounds of the present invention can be made, for example, via a cycloaddition reaction of an alkynyl macrolide with an azide compound. In this cycloaddition reaction, the triazole functional group of the resulting compound is formed. Other compounds of the present invention are made by further chemically modifying the resulting compound from the cycloaddition reaction.

The cycloaddition reaction is generally run in the presence of a copper (I) salt such as copper iodide (CuI). A base can also be optionally used, such as Hunig’s base (N,N- diisopropylethylamine). The following general reaction scheme outlines the cycloaddition reaction of the alk n l macrolide and the azide com ound.

The time required for the reaction to proceed to completion is variable and is dependent upon several factors including: the specific alkynyl macrolide and azide compounds and their concentrations; the amount of Cu(I) salt used; and the presence or absence of base, such as Hunig’s Base( N,N-diisopropylethylamine). Reactions are monitored for the disappearance of the starting materials by TLC and/or LCMS and are typically allowed to run for between about 2 hours to about 72 hours. Reactions are generally stopped when analysis demonstrates that the starting alkynyl macrolide has been substantially consumed. The workup and purification protocols are standard.

Modifications to the described workup procedures can be used. Such modifications can include the use of different aqueous wash solutions, different organic solvents for extraction, the use of other anhydrous salts for the drying of organic extracts, and the employment of different solvent mixtures for the chromatographic purification of the compounds. The methods used for the workup of the reaction mixtures, the extraction of products, the drying of organic extracts, and for the isolation and purification of the title compounds are typical of procedures familiar to those trained in the art of organic synthesis. The isolated chemical yields for the synthesis of compounds can be variable and are indicated in Table 2. Most compounds of the present invention can be prepared from the desired alkynyl macrolide and azide compound under one of several similar reaction conditions as exemplified by Conditions A, B, C, and D below. Use of Conditions A and C, which do not include the step of degassing the reaction mixture, tend to result in the formation of iodinated side-products in addition to the desired product and thereby generally produced lower isolated yields. Additionally, reduction of the amount of copper iodide used in the reaction to 0.5 molar equivalents or less as in conditions B and D also tends to result in reduced formation of iodinated by-products. As demonstrated in Condition D, the presence of Hunig’s base is not essential for the success of the triazole formation step; however, it is found preferable that the base be included since it often results in a higher rate of reaction and correspondingly shorter reaction times. Condition A:

To a stirred solution of the alkynyl macrolide (0.04 mmol), the azide compound (0.07 mmol) and Hunig’s base (10 µL) in 0.5 mL tetrahydrofuran (THF) is added CuI (5 mg, 0.03 mmol). The mixture is stirred at ambient temperature for 16 hours then diluted with CH2Cl2 (10 mL) and washed with a 3:1 mixture of saturated aqueous NH4Cl and 28% aqueous NH4OH (10 mL) and with brine (10 mL) the aqueous washes are back-extracted with CH 2 Cl 2 (2 x 10 mL). The combined organic extracts are dried over K 2 CO 3 , filtered, and concentrated to afford 52 mg of crude product which is purified by chromatography on silica gel (elution with 40:12M NH3 in MeOH and CH2Cl2) to give the desired compound. Condition B:

A solution of alkynyl compound (0.10 mmol) and azide compound (0.12 mmol) and Hunig’s base in 0.4 mL THF are thoroughly degassed by alternately evacuating the reaction vessel and purging with dry argon. CuI is then added (2 mg, 0.01 mmol) and the mixture is further degassed. The mixture is stirred under argon for 6h then diluted with CH 2 Cl 2 (20 mL) and washed with a 3:1 mixture of saturated aqueous NH 4 Cl and 28% aqueous NH4OH (10 mL) and with brine (10 mL) the aqueous washes are back-extracted with CH2Cl2 (2 x 15 mL). The combined organic extracts were dried over K2CO3, filtered, and concentrated to afford 115 mg of crude product which is purified by chromatography on silica gel (eluted with 2M NH3 in MeOH (2.5%) and CH2Cl2 (97.5%), to give the desired compound. Condition C:

To a stirred solution of alkynyl compound (0.10 mmol) and Hunig’s base (0.2 mL) in 3 mL THF is added the azide compound (0.50 mmol) and CuI (20 mg, 0.10 mmol). The reaction mixture is stirred under argon for 60 hours then poured into saturated aqueous NH 4 Cl and extracted with CH 2 Cl 2 . The organic extracts are dried over Na 2 SO 4 , filtered, and concentrated to afford a crude residue which is purified by silica gel chromatography (eluted with 25:1:0.1 CH2Cl2:MeOH:NH4OH) and then by preparative TLC (elution with 25:1:0.1 CH 2 Cl 2 :MeOH:NH 4 OH) to afford the desired compound. Condition D

A solution of alkynyl compound (0.15 mmol) and the azide compound (0.25 mmol) in 2.7 mL THF are thoroughly degassed by alternately evacuating the reaction vessel and purging with dry argon. CuI is then added (10 mg, 0.05 mmol) and the mixture is further degassed. The mixture is stirred under argon for 4h then concentrated in vacuo, dissolved in CH 2 Cl 2 (1 mL) , and placed directly on a silica gel column. Elution with 2 molar (M) NH3 in MeOH (3%) and CH2Cl2 (97%) gives the desired compound. Synthesis of Compounds Wherein Substituent“A” Contains a Triazole Ring

These compounds are generally prepared from the cycloaddition reaction of the desired alkynyl macrolide and the nitro phenyl azide compound to form the resulting nitro phenyl macrolide compound. This nitro phenyl macrolide compound is then further transformed to yield the desired compound. The azide group is then reacted with an appropriately functionalized alkyne in a second cycloaddition reaction to form the desired compound.

Further detail for some of the compounds of the present invention are provided in Table 2, which lists azide compounds that can be used in the synthesis of the compounds of the present invention.

Nonlimiting examples of alkynyl macrolide compounds are separately shown below in Table 3.

Compounds can be prepared via a common nitro phenyl azide intermediate, X. The nitro group is further transformed after the cycloaddition reaction to produce the final desired product.

TABLE 2 Azide

T he alkynyl macrolide compounds that can be used in the synthesis of the compounds of the present invention are shown in the following Table 3. It is appreciated by one of skill in the art that these alkynyl macrolide compounds, M1 to M28, are non- limiting examples and that a wide variety of additional alkynyl macrolides can be used to prepare other compounds of the present invention.

Synthesis of Alkynyl Macrolides

The alkynyl macrolide compounds, such as alkynyl macrolide compounds M1 to M28, are generally made by the alkynylation (i.e. the addition of an alkynyl group) to a monomethyl amine macrolide compound. The monomethyl amine macrolide is generally made by the desmethylation of the corresponding macrolide compound. Depending on the macrolide compound and functional groups present, the desmethylation process can involve several steps, including various protection and deprotection steps. The desmethyl macrolide compound is alkynylated with the corresponding alkynyl compound, which is generally an alkynyl halide, tosylate, or mesylate. For the compounds of the present invention, 4-bromo-1-butyne, 4-iodo-1-butyne, or the tosylate or mesylate of 1-butyn-4-ol are generally used. Examples of synthetic procedures for preparing alkynyl macrolides are found in PCT Application No. WO 2005/085266, published September 15, 2005, to Rib-X Pharmaceuticals, Inc. The following general reaction scheme outlines this alkynylation process.

The following procedures outline the synthesis of various alkynyl macrolide compounds of the present invention.

Synthesis of Alkynyl Macrolide M1

Alkynyl macrolide M1 is made by selective demethylation of azithromycin 1 to produce 3’-N-desmethylazithromycin 2. This compound 2 is selectively alkylated with alkynyl tosylate 11 to produce alkynyl macrolide M1.

Synthesis of 3’-N-desmethylazithromycin 2

Azithromycin 1 (0.80 g, 1.02 mmol) and sodium acetate (NaOAc) (0.712 g, 8.06 mmol) were dissolved in 80% aqueous MeOH (25 mL). The solution was heated to 50 o C followed by addition of iodine (I 2 ) (0.272 g, 1.07 mmol) in three batches within 3 minutes. The reaction was maintained at a pH between 8 and 9 by adding 1N sodium hydroxide (NaOH) (1 mL) at 10 min and 45 minute intervals. The solution turned colorless within 45 minutes. Stirring was continued for 2 hours. TLC (CH 2 Cl 2 /MeOH/NH 4 OH 10:1:0.05) after 2 hours showed a single major product (Rf = 0.66). The reaction was cooled to room temperature, poured into H2O (75 mL) containing NH4OH (1.5 mL) and extracted with CHCl 3 (3 x 30 mL). The combined organic layers were washed with H 2 O (30 mL) containing NH4OH (1.5 mL), dried over Na2SO4 and the solvent evaporated to give a white residue. The crude was purified on a silica gel column eluting with

CH 2 Cl 2 /MeOH/NH 4 OH 18:1:0.05 to 10:1:0.05 to provide compound 2 (0.41 g, 55%).

Synthesis of alkynyl macrolide M1 A mixture of 3’-N-desmethylazithromycin 2 and tosylate 11 in Hunig’s base was stirred. The reaction mixture was diluted to EtOAc and washed with NaHCO 3 (aq) and with brine. The organic layer was dried over K2CO3 and the solvent was evaporated to give product. The crude product was purified on silica gel column to give M1 as a white solid.

Synthesis of 3’-N-desmethyl-clarithromycin 21

To a mixture of clarithromycin (1.00 g, 1.3 mmol) and NaOAc•3H20 (0.885 g, 6.5 mmol) was added MeOH-H 2 O (20 mL, 4:1), and the mixture heated to 55-60 o C. Iodine (0.330 g, 1.3 mmol) was added portion-wise and the reaction stirred at 55-60 o C for 3 h. The reaction mixture was poured into 50 mL CHCl3 containing 1 mL ammonium hydroxide. It was extracted with CHCl 3 (4 x 50 mL), washed with water (70 mL) containing 5 mL ammonium hydroxide, dried (anhydrous Na2SO4), concentrated, and purified by flash chromatography (silica gel, CHCl3:MeOH:NH4OH 100:10:0.1) to afford 21. Yield: 0.9g (92%). Synthesis of Alkynyl Macrolide M3 A mixture of 3’-N-desmethyl-clarithromycin 21 (5 g, 6.8 mmol) and Toluene-4- sulfonic acid but-3-ynyl ester 11 (3.05 g, 13.6 mmol) in Hunig’s base (15 ml) was heated at 110 o C for 16 h. The reaction mixture was poured into CH 2 Cl 2 , extracted with 2% aqueous NH4OH and saturated brine. The organic layer was dried over Na2SO4 and the solvent was evaporated away. The crude material was purified on a silica gel column to give M3 (3.5 g, 65%). Synthesis of Alkynyl Macrolide M14

Alkynyl macrolide M14 is made using a procedure analogous to that for making M3, starting from erythromycin A. The 3’-N-desmethyl-erythromycin A intermediate is made using a procedure described in U.S. Patent No.3,725,385, to Freiberg, issued April 3, 1973. Alkynyl macrolide M14 can further be used to prepare a variety of macrolides analogous to those already depicted for the clarithromycin core.

A mixture of 3’-N-desmethyl-erythromycin (1.0 g, 1.4 mmol) and the tosylate of 1- butyn-4-ol (1.25 g, 5.6 mmol) in anhydrous THF (15 mL) and Hunig’s base (2.2 mL, 11.9 mmol) was kept stirring at 55 o C for 48 hours. The reaction was poured into CH2Cl2 (50 mL), extracted with 2% aqueous NH4OH (3 x 30 mL) and saturated brine (1 x 30 mL). The organic layer was dried over Na 2 SO 4 and the solvent was evaporated away. The crude was purified on a silica gel column eluting with CH2Cl2/MeOH 10:1 to give alkynyl macrolide M14 (0.35 g, 32%). Synthesis of Alkynyl Macrolides M4, M9, M10, M11 and M12

The synthesis of alkynyl macrolides M4, M9, M10, M11 and M12 are depicted in the scheme below. Alkynyl macrolide M9 is prepared from the removal of the cladinose sugar of alkynyl macrolide M3 under acidic conditions. Alkynyl macrolide M10 is made by the acetylation of macrolide M9. Macrolide M4 is made by the oxidation of the hydroxyl group of macrolide M10. Alkynyl macrolides M11 and M12 are made by converting a keto group of alkynyl macrolide M4 to the desired oximes. The oxime functionality of alkynyl macrolides of precursors with substituted oxime functionality at the 9- osition of the macroc clic rin were re ared from alk ne M3 and as shown below.

Synthesis of alkynyl macrolide M9

Procedure 1: To the alkynyl macrolide M3 (0.700 g) was added 10 mL 0.9N HCl and the mixture was stirred for 4 h at room temperature. The reaction mixture was saturated with sodium chloride and was adjusted to pH 8 using aqueous NH4OH solution. The solution was extracted with ethyl acetate (3 x 30 mL), dried (with Na 2 SO 4 ), and concentrated under reduced pressure. Purification of the crude reaction mixture by flash chromatography (silica gel, 60% ethyl acetate in hexane) afforded 0.200 g (35% yield) of the descladinose alkynyl macrolide M9. Data for M9: 1 HNMR (300 MHz, CDCl 3, partial): δ 0.82 (t, 3H), 2.25 (s, 3H), 3.00 (s, 3H), 3.25 (dd, 1H), 3.55 (m, 2H), 3.70 (s, 1H), 3.85 (s, 1H), 3.95 (s, 1H), 4.40 (d, 1H), 5.15 (dd, 1H). Procedure 2: A suspension of M3 (23.9g) in 1N HCl-H 2 O (160 mL) was stirred at ambient temperature for 2h. An aliquot was taken out, neutralized with 1N NaOH and extracted with ethyl acetate. LCMS showed the presence of starting material. Another 100 mL 1N HCl-H 2 O was added and stirred for additional 2h. The aqueous acid part was extracted with ethyl acetate (3 x 200 mL) and then neutralized the aqueous layer with 1N NaOH to pH 11-12. Extracted with dichloromethane (3 x 200 mL), dried with anhydrous sodium sulphate and concentrated. The material (M9) thus obtained (14.0g, 74%) was used for the next step without further purification. 1 HNMR (300 MHz, CDCl3, partial): δ 0.82 (t, 3H), 2.25 (s, 3H), 3.00 (s, 3H), 3.25 (dd, 1H), 3.55 (m, 2H), 3.70 (s, 1H), 3.85 (s, 1H), 3.95 (s, 1H), 4.40 (d, 1H), 5.15 (dd, 1H).

Synthesis of alkynyl macrolide M10

Procedure 1: To a solution of alkynyl macrolide M9 (0.200 g, 0.32 mmol) in acetone (2 mL) was added acetic anhydride (0.050 mL, 0.5 mmol) and the mixture was stirred overnight at room temperature. The reaction was quenched with water and extracted with ethyl acetate (3 x 50 mL). The combined organic fractions were washed with saturated sodium bicarbonate (3 x 50 mL), dried (anhydrous Na2SO4), and concentrated under reduced pressure. The crude reaction mixture was purified by flash chromatography (silica gel, 50% ethyl acetate in hexane) to yield 0.100 g (50% yield) of acetate functionalized alkynyl macrolide M10. Data for M10: 1 HNMR(300 MHz, CDCl3, partial): δ 0.84 (t, 3H), 2.00 (s, 3H), 2.20 (s, 3H), 2.90 (s, 3H), 3.00 (q, 1H), 3.25 (s, 1H, 3.47 (m, 2H), 3.70 (bs, 1H), 3.82 (bs, 1H), 3.97 (s, 1H), 4.60 (d, 1H), 4.77 (dd, 1H), 5.15 (dd, 1H). Procedure 2: To a solution of M9 (14.0 g, 22.3 mmol) in dichloromethane (150 mL) was added acetic anhydride (3.16 mL, 33.5 mmol) and stirred at ambient temperature for 24h. Reaction was monitored with LCMS. Reaction was quenched with few pieces of ice and stirred for 1h. Then added water (50 mL) and stirred for additional 20 minutes. Diluted with dichloromethane (50 mL). The combined organic layer was washed with brine (3 x 200 mL) and dried with anhydrous sodium sulphate. The solution was filtered and evaporated to dryness. The crude material was dried under vacuum for 48h and used for the next step without further purification. Yield of M10:15g (100%). 1 HNMR(300 MHz, CDCl3, partial): δ 0.84 (t, 3H), 2.00 (s, 3H), 2.20 (s, 3H), 2.90 (s, 3H), 3.00 (q, 1H), 3.25 (s, 1H, 3.47 (m, 2H), 3.70 (bs, 1H), 3.82 (bs, 1H), 3.97 (s, 1H), 4.60 (d, 1H), 4.77 (dd, 1H), 5.15 (dd, 1H).

Synthesis of alkynyl macrolide M4

Procedure 1: To a solution of alkynyl macrolide M10 (0.090 g, 0.134 mmol), EDC•HCl (0.172 g, 0.90 mmol), and DMSO (0.171 mL, 2.41 mmol) in CH2Cl2 (1.5 mL) was added dropwise a solution of pyridinium trifluoroacetate (0.174 g, 0.90 mmol) in CH2Cl2 (1 mL) at 15 0 C. The reaction mixture was slowly warmed up to room temperature and stirred for 3 h. The reaction was quenched with water (2 mL), and allowed to stir for 30 min. The mixture was then poured into CHCl3 (50 mL), and the organic layer was washed with water (2 x 50 mL), dried (over anhydrous Na2SO4), and concentrated under reduced pressure. The crude material was purified by flash chromatography (silica gel, 30% ethyl acetate in hexane) to yield 0.070g (78%) of the alkynyl macrolide M4 (also commonly referred to as a ketolide). Data for M4:M4 MS (ESI) m/e 668 (M+H) + ; 1 HNMR (300 MHz, CDCl 3 , partial): δ 0.86 (t, 3H), 2.00 (s, 3H), 2.24 (s, 3H), 2.70 (s, 3H), 2.95-3.10 (m, 1H), 3.15-3.05 (m, 1H), 3.45-3.65 (m, 1H), 3.80 (q, 1H), 3.90 (s, 1H), 4.28 (d, 1H), 4.40 (d, 1H), 4.76 (dd, 1H), 5.10 (dd, 1H). Procedure 2: To a solution of M10 (34.3 g,51.19 mmol) in CH 2 Cl 2 (260 mL) at 0 o C was added EDCI (29.44g, 153.58 mmol), followed by DMSO (36.3 mL, 153.58 mmol). The resulted mixture was stirred at 0 0 C for 10 min. Pyridinium TFA (29.64g, 153.58 mmol) was added and stirred at 0 0 C for 2 h. Then slowly warmed up to room temperature and stirred for another 1h, quenched with water (300 mL). The organic layer was washed with water (200 mL) and brine (200 mL), dried over with anhydrous sodium sulphate, filtered and evaporated to dryness. The crude material was purified by flash chromatography over silica gel (0-50% ethyl acetate in hexanes). Yield of M4: 23.3 g (68%). MS (ESI) m/e 668 (M+H) + ; 1 HNMR (300 MHz, CDCl3, partial): δ 0.86 (t, 3H), 2.00 (s, 3H), 2.24 (s, 3H), 2.70 (s, 3H), 2.95-3.10 (m, 1H), 3.15-3.05 (m, 1H), 3.45-3.65 (m, 1H), 3.80 (q, 1H), 3.90 (s, 1H), 4.28 (d, 1H), 4.40 (d, 1H), 4.76 (dd, 1H), 5.10 (dd, 1H). Synthesis of Alkynyl Macrolide M5

A solution of alkynyl macrolide M4 (1g, 1.5mmol) in MeOH (30 mL) was refluxed for 12h. The solution was concentrated and the crude material was purified by flash chromatography over silica gel (50% ethyl acetate in hexane). Yield: 0.5g of M5 (53%). Synthesis of alkynyl macrolide M11

To a solution of M4 (2.0 g, 2.9 mmol) in MeOH (10 mL) was added (R)-N- Piperidin-3-yl-hydroxylamine hydrobromide (1.26 g, 4.4 mmol). The reaction mixture was stirred at rt for 14h. The mixture was then poured into (50 mL) and water (50 mL) the pH was adjusted to 11 by addition of NH4OH and the organic layer was separated and washed with brine (50 mL), dried (over anhydrous Na2SO4), and concentrated under reduced pressure. The crude material was purified by flash chromatography (silica gel, 12:1 CH 2 Cl 2 and 2M methanolic ammonia) to yield 2g (78%) of the oxime functionalized alkynyl macrolide M11 as a 1:1 mixture of E/Z isomers. Data for M11: MS (ESI) m/e 724.7 (M+H) + .

Synthesis of Alkynyl Macrolide M12

Alkynyl macrolide M12 was synthesized from alkynyl macrolide M4 and (R)-N- Pyrollidin-3-yl-hydroxylamine hydrobromide using the conditions described above for the synthesis of alkynyl macrolide M11. Data for M12: MS (ESI) m/e 710.6 (M+H) + . Synthesis of Alkynyl Macrolides M13, M16, M17, and M18

Alkynyl macrolides M13, M16, and M17 are also synthesized from alkynyl macrolide M4. Alkynyl macrolide M18 is synthesized from alkynyl macrolide M17. The syntheses are outlined in the following reaction scheme.

Synthesis of alkynyl macrolide M13 Alkynyl macrolide M13 was synthesized from alkynyl macrolide M4 and N-[2- dimethtylaminoethyl]-hydroxylamine hydrobromide using the conditions described above for the synthesis of oxime M11. Data for M13: MS (ESI) m/e 726.5 (M+H) + . Synthesis of alkynyl macrolide M16

Alkynyl macrolide M16 was synthesized from alkyne M4 and N-Piperidin-4-yl- hydroxylamine hydrobromide using the conditions described above for the synthesis of oxime M11. Data for M16: MS (ESI) m/e 724.6 (M+H) + . Synthesis of alkynyl macrolide M17

Alkynyl macrolide M17 was synthesized from alkyne M4 and cis-4- aminocylcohexyl-hydroxylamine hydrobromide using the conditions described above for the synthesis of oxime M11. Data for M17: MS (ESI) m/e 738.7 (M+H) + . Synthesis of alkynyl macrolide M18

To a solution of alkynyl macrolide M17 (20 mg, 0.02 mmol) in CHCl3 (0.2 mL) was added formaldehyde (5 mg of 37% aqueous solution, 0.06 mmol) and formic acid (6 mg, 0.12 mmol). The mixture was heated at 50 o C in a sealed tube for 12h. The reaction mixture was partitioned between aqueous NaHCO3 (10 mL) and chloroform (10 mL) the organic fraction was dried on K 2 CO 3 , filtered and concentrated to give alkynyl macrolide M18 as a white solid (18 mg). Data for M18: MS (ESI) m/e 766.7 (M+H) + . Synthesis of Alkynyl Macrolide M15

Telithromycin was selectively N-demethylated and then alkylated with the tosylate of 1-butyn-4-ol as described for azithromycin, erythromycin and clarithromycin above. Synthesis of 3’-N-Desmethyl telithromycin 30

To a solution of telithromycin 29 (3.0 g, 3.60 mmol) in anhydrous acetonitrile (70 mL) was added N-iodosuccinimide (NIS) (0.98 g, 4.32 mmol) in two portions within 30 min at 0 o C under argon atmosphere. The mixture was allowed to warm to rt and stirred overnight. CH2Cl2 (250 mL) and 5 % Na2S2O3 (80 mL) were added and the two layers separated. The organic layer was extracted with 5 % Na2S2O3 (1 X 80 mL), dilute NH4Cl (1 X 80 mL) and dried over Na 2 SO 4 . Solvent was evaporated and the crude was purified on silica gel eluting with 0– 8 % methanolic ammonia (2N NH3) in CH2Cl2 to give compound 30 as white solid (1.95 g, 68 %). MS (ESI) M/E; M+H + 798.6. Scheme 105 S nthesis of alk n l macrolide M15.

Synthesis of 3’-N-(but-3-ynyl) telithromycin, M15

Protocol A: A mixture of amine 30 (0.66 g, 0.83 mmol) and tosylate 11 (0.33 g, 1.49 mmol) in THF (15 mL) and Hunig’s base (3 mL) was heated at 90 o C for 5 days. The solvent was evaporated; the residue was dissolved in 1N HCl (50 mL) and kept stirring at room temperature for about 1h. CH2Cl2 (30 mL) was added and the two layers were separated. The aqueous layer was extracted with CH 2 Cl 2 (2 X 30 mL) and basified with NaOH (1N) to form a whitish-suspension. The suspension was extracted with CH 2 Cl 2 (3 X 30 mL) and the organic layer was dried over Na2SO4. Solvent was evaporated and the crude was purified on silica gel eluting with 0– 6 % methanolic ammonia (2N NH 3 ) in CH2Cl2 to give compound M15 as white solid (0.12 g, 17 %). MS (ESI) m/e 850.8 (M+H) + . Synthesis of 3’-N-(but-3-ynyl) telithromycin, M15

Protocol B: A mixture of amine 30 (0.66 g, 0.83 mmol), and tosylate 11 (0.40 g, 1.84 mmol) in acetonitrile (10 mL) and Hunig’s base (0.18 mL, 1.0 mmol) was microwave heated to 90 o C within 10 min and maintained at 90 o C for 1.5h. The reaction was vented within 15 min and solvent was evaporated. The residue was dissolved in 1N HCl (60 mL) and kept stirring at room temperature for about 2h. CH 2 Cl 2 (30 mL) was added and the two layers were separated. The aqueous layer was extracted with CH 2 Cl 2 (2 X 30 mL) and basified with 50 % KOH to form a whitish-suspension. The suspension was extracted with CH 2 Cl 2 (3 X 30 mL) and the organic layer was dried over Na 2 SO 4 . The solvent was evaporated and the crude was purified by preparative TLC (2000 micron plate) eluting with CH2Cl2/methanolic ammonia (2N NH3) 12:1 to give compound M15 as white solid (0.19 g, 27 %). MS (ESI) m/e 850.8 (M+H) + .

Synthesis of Alkynyl Macrolide M19.

Desmethyl telithromycin 30 was treated according to the procedures of US Patent No.6,124,269 to afford the 2-fluoro amine 30a. This was then alkylated with the tosylate of 1-butyn-4-ol under the conditions for making M15 to afford the fluorinated alkynyl macrolide M19. The reactions are outlined in the followin scheme.

Synthesis of Alkynyl Macrolides M20, M21, M22, and M23

Alkynyl macrolides M21, M22, and M23 are prepared according to the following reaction scheme from alkynyl macrolide M20. Alkynyl macrolide M20 is in turn made from alk n l macrolide M14.

Synthesis of alkynyl macrolide M20

To a mixture of alkynyl macrolide M14 (1g, 1.3 mmol) and hydroxylamine hydrochloride (0.4g, 6.4 mmol) was added methanol (15 mL) and triethylamine (3.2 mmol). The solution was refluxed for 72h. Cooled to ambient temperature, poured into water (50 mL) and adjusted pH to 11. The resulting solution was extracted with dichloromethane (4x 50 mL), dried and concentrated. The crude material was purified by flash chromatography over silica gel to yield M20 (C2Cl2:2N NH3-MeOH = 10:1). Yield: 0.6g (60%).

Synthesis of Alkynyl Macrolide M21

To a solution of alkynyl macrolide M20 (2.00g, 2.54mmol) in THF (17mL) at 0ºC was added Et3N (1.50mL, 10.67mmol), followed by addition of acetic anhydride (946µL, 9.91mmol), then, DMAP (34mg, 0.25mmol). The mixture was stirred at 0ºC for 3h, then, Et3N (150µL, 1.07mmol) and acetic anhydride (95µL, 0.99mmol) were added. The mixture was stirred for 3h, then, MeOH (2.0ml) was added. The reaction mixture was concentrated and EtOAc (100mL) was added, washed with saturated NaHCO 3 (30.0mL), then, brine (30.0mL), dried with Na2SO4, gave 2.28g of alkynyl macrolide M21. The residue was used for the next step without further purification. MS (ESI) m/e 913 (M + H) + . Synthesis of Alkynyl Macrolide M22

To a solution of triacetate alkynyl M21 (913mg, 1.00mmol, crude), 2-methylene- 1,3-propane-[bis-(tert-butyl)carbonate] (865mg, 3.00mmol) and 1,4- bis(diphenylphosphino)-butane (dppb) (305mg, 0.70mmol) in THF (10mL, degassed) was added Pd2(dba)3 (92mg, 0.10mmol) at room temperature. The mixture was refluxed for 12h , then, the reaction mixture was concentrated and EtOAc (100mL) was added. Washed with saturated NaHCO3 (30mL), brine (30mL), dried with Na2SO4, The residue was isolated by silica gel chromatography (CH2Cl2 to 2% MeOH in CH2Cl2 containing 0.2% NH 4 OH), gave 340mg of alkynyl macrolide M22 in 35% yield for two steps. MS (ESI) m/e 966 (M + H) + . Synthesis of Alkynyl Macrolide M23

Alkynyl macrolide M22 (330mg, 0.34mmol) in MeOH (6mL), was refluxed for 5 days. The residue was isolated by FC (CH2Cl2 to 2% MeOH in CH2Cl2 containing 0.2% NH4OH), gave 143mg of alkynyl macrolide M23 in 50% yield.

MS (ESI) m/e 839 (M + H) + . Synthesis of Alkynyl Macrolide M24

To a solution of alkynyl macrolide M4 (6.4g, 9.6 mmol) in pyridine (25 mL) was added methanesulfonic anhydride (4.0g, 22.9 mmol) at 10 0 C. The reaction was stirred at ambient temperature for 24h. The solution was concentrated and portioned between ethyl acetate (150 mL) and saturated NaHCO 3 solution (150 mL). Organic layer was separated and the aqueous layer was back extracted with ethyl acetate (2 x 100 mL). The combined organic layer was washed with brine (2 x 150 mL), dried and concentrated. The crude material was purified by flash chromatography over silica gel (50% ethyl acetate in hexane) to give 5.9g of M24 (83%). Synthesis of Alkynyl Macrolide M25

To a solution of alkynyl macrolide M24 (5.9 g, 7.9 mmol) in acetone (25 mL) was added diazabicycloundecene (DBU) (1.4 mL, 9.5 mmol) at ambient temperature. After stirring for 48h, the reaction was diluted with methylene chloride, washed with water, dried and concentrated in vacuo. The crude material was purified by flash chromatography over silica gel (40% ethyl acetate in hexanes). Yield 3.6 g M25 (70%). Synthesis of Alkynyl Macrolide M26

To a solution of M25 (3.3 g, 5.0 mmol) in methylene chloride (30 mL) was added DBU (1.0 mL, 6.5 mmol) at 0 0 C. Then was added carbonyldiimidazole (1.0g, 6.1 mmol) at once. After stirring for 3h, the reaction was diluted with methylene chloride, washed with water, dried and concentrated in vacuo. The crude material was purified by flash chromatography over silica gel (70% ethyl acetate in hexanes). Yield 3.4 g M26 (89%). Synthesis of Alkynyl Macrolide M27

Alkynyl macrolide M27 is made from alkynyl macrolide M23 by reduction of the oxime to the imine followed by acetylation of the compound, which is then oxidized to give the bridged ketone. The cladinose sugar is then hydrolyzed by treatment with dilute hydrochloric acid. Synthesis of Alkynyl Macrolide M28

Alkynyl macrolide M28 is made by refluxing alkynyl macrolide M27 with the following hydroxyl amine compound in methanol.

Synthesis of Alkynyl Macrolide M2

A mixture of M26 (1.48 g, 2.0 mmol) and hydrazine (0.65 mL, 20 mmol) in acetonitrile (40 mL) and water (6 mL) was heated to 50 0 C. After 5h the solution was concentrated and refluxed with MeOH (100 mL) for 20h. The solution was concentrated and the crude material was purified by flash chromatography over silica gel (60% ethyl acetate in hexane). Yield: 0.8g M2 (60%). Synthesis of Alkynyl Macrolides M6, M7, and M8

Alkynyl macrolides M6, M7, and M8 are made from M26 (using a procedure analogous to that for making M2, in which the hydrazine is replaced with methyl amine, ammonium hydroxide, and ethanol amine respectively. Synthesis of Azide Compounds

The organic azide compounds used in the synthesis of the compounds of the present invention are generally prepared from the iodo compound 2 or the boronic acid ester compound 3. Typically, the iodo or boronic acid functional groups provide a means for preparing a wide range of compounds using methods available to one skilled in the art.

The iodo compound 2, is prepared according to the following scheme from commercially available (1R,2R)-(-)-2-amino-1-(4-nitrophenyl)-1,3-propanediol. The boronic acid ester compound 3 is prepared from the iodo compound 2.

The following reaction scheme illustrates various azide compounds that can be made from iodo compound 2. R a , R b , R c , and R d represent various alkyl, substituted alkyl, aryl, and substituted aryl groups.

Synthesis of Azide A1 A mixture of 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2 - ylamine (0.4 g, 1.791 mmol), 1-(2-azido-3-fluoro-1-methoxy-propyl)-4-iodo-benzene (AI- 1, can be synthesized as shown above) (0.5 g, 1.4925 mmol), [1,1- bis(diphenylphosphino)ferrocene]palladium (II) chloride 1:1 complex with dichloromethane (61 mg, 0.075 mmol), potassium carbonate (621 mg, 4.5 mmol), dioxane (6 mL), ethanol (2 mL) and water (2 mL) was degassed and heated at 85 ºC for 5 h under argon atmosphere. After cooled to room temperature, the reaction mixture was diluted with ethyl acetate (50 ml) and washed with water (30 mL, twice) and brine (20 mL). The ethyl acetate solution was dried over MgSO 4 , filtered and concentrated. The crude product was purified by flash chromatography (silica, gradient from 0% to 80% ethyl acetate in hexane) to afford desired product A1 (250 mg, 56%). MS (ESI) m/e: 303 [M+H] + .

Synthesis of Compounds

As described above, compounds can be prepared from the cycloaddition reaction of the desired alkynyl macrolide and nitro phenyl azide to form a resulting nitro phenyl macrolide compound. This nitro phenyl macrolide is then further converted to an azide group, via reduction to an amine. The azide is a common intermediate which is then reacted with an appropriately functionalized alkyne in a second cycloaddition reaction to form the desired compound. Table 4, below shows representative alkynes used in the preparation of compounds. TMS-acetylene can be used as the alkyne and the TMS group is then subsequently removed under standard conditions. Table 4.

Alternatively, compounds can be synthesized via the cycloaddition of alkynyl macrolides and phenyl azide compounds. Preparations of the starting materials have been detailed in the preceding sections. Synthesis of C1

For example, compound C1 can be prepared via the cycloaddition between alkynyl macrolide M11 and azide A1 as shown below:

A mixture of the azide A1 (138 mg, 0.46 mmol) and alkynyl macrolide M11 (300 mg, 0.41 mmol), CuI (118 mg, 0.62 mmol), and THF (6 ml) was degassed. Hunig’s base (0.3 ml) was added to the above reaction mixture and stirred at room temperature under argon atmosphere for 7 h. The reaction mixture was quenched with saturated ammonium chloride solution containing 20% ammonium hydroxide solution (30 ml) and extracted with dichloromethane (30 ml, twice). The combined organic extract was washed with saturated ammonium chloride solution containing 20% ammonium hydroxide solution (100 ml). It was dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography over silica gel. (2N ammonia methanol in dichloromethane, 1:10) to afford desired product C1 (315 mg, 74%). MS (ESI) m/e: 514.1, [M/2+H] + . The following compounds can be prepared by the methods described herein;

molecular weights and LC/MS data are provided.

The compounds in Table 1 can be prepared using the same procedures as described above using the appropriate starting materials. Example 2 Susceptibility testing for bacteria (MIC) and Panel of Organisms

Method:

Antibacterial activity (MIC, in µg/mL) of compounds is determined using a microtiter-based liquid assay as described in by the Clinical and Laboratory Standards Institute (see: CLSI, Performance standards for antimicrobial susceptibility testing; sixteenth information supplement, in Clinical and Laboratory Standards Institute. 2006, Clinical and Laboratory Standards Institute, 940 West Valley Road, Suite 1400, Wayne, PA 19087-1898).

Table 2-1 summarizes the antibacterial activity (MIC, in µg/mL) of azithromycin, telithromycin, solithromycin, Compound 1, Compound 3, and Compound 4. Results

Table 2-1.

Compound C2 is evaluated in Examples 3 and 4. The structure of compound C2 is shown below:

Example 3 Bi-directional Permeability

Method

Studies were carried out at Absorption Systems, LP. (PA, USA). Confluent monolayers of Caco-2 cells (21-28 years old) comprised the assay system. Monolayer batch quality was assessed via a TEER measurement and by calculating Papp for control compounds. Test compounds were prepared at 5µM in HBSSg (Hanks’ balanced salts solution supplemented with glucose), with maximum DMSO concentration <1%. Receiver wells (Transwell ® ) were prepared with 1% BSA in HBSSg. Both apical and basolateral sides were held at pH 7.4±0.2. Two monolayers were dosed in each direction (N=2). Pre- incubation of cell monolayers was done for 30 minutes, both in the absence and in the presence of 10µM CSA (cyclosporine A, an efflux inhibitor). The apical side was dosed for A ^B assessment, while the basolateral side was dosed for B ^A evaluation. Both the apical and basolateral sides were sampled at 120 minutes. Concentrations of test compounds were determined using standard LC/MS/MS methods with a minimum 4-point calibration curve. Results

Bi-directional permeabilities in the presence and absence of efflux inhibitor cyclosporine A were measured for azithromycin, telithromycin, solithromycin, and C2 The results are summarized in Table 3-1, below.

Table 3-1

Example 4. Pharmacokinetic studies

Methods:

Rat Pharmacokinetics: Jugular-cannulated Sprague-Dawley ® rats were used, with 4 rats for each dosing regimen and 9 timepoints ranging from pre-dose to 24 hours. Dosage was set at 4 mg/Kg and 20 mg/Kg for intravenous and oral administration, respectively. Dosing was based on the free molecular weight of each compound. Blood (0.3 mL per timepoint) was sampled from the right jugular vein and added to lithium heparincoated microcentrifuge tubes. Samples were kept on-ice until centrifugation (within 30 minutes of sampling). Mouse Pharmacokinectics: Swiss-Webster mice (female, 25-30 g) were used, with 3 mice per timepoint and 8 timepoints between dose and 6 hours. Dosage was set at 5 mg/Kg and 25 mg/Kg for intravenous and oral adminstration, respectively. Dosing was based on the free molecular weight of each compound. Blood was collected via terminal cardiac puncture. Blood samples were kept in heparinized tubes on ice, centrifuged and separated within 30 minutes. Plasma samples were saved at -20 o C until analysis. Preparation of Plasma samples: Plasma samples (100 µL) were spiked with an internal standard solution before acetonitrile was added to precipitate protein. After centrifugation, a portion of the supernatant (200 µL) was transferred to a 96-well plate for LC-MS analysis. The linear range for the quantitation method covered 20-10000 ng/mL. Micromass Quattro Micro, a triple quadrupole mass spectrometer, was used in MRM mode with ESI for MS analysis. The LC system was a Waters Alliance HT 2795 with a reversed phase C18 (2.1 × 50 mm, 5 µM) column at room temperature.

Pharmacokinetic Analysis: Pharmacokinetic parameters were derived using WinNonlin version 5.1 (Pharsight Corporation, CA, USA). Non-compartmental methods were used. Oral bioavailability (F) was calculated as follows: %F = [AUC 0-∞ (PO)/Dose(IV)]/[AUC 0-∞ (IV)/Dose(PO)]×100 Results:

Rat oral pharmacokinetic data for azithromycin, telithromycin, clarithromycin, and C2 are shown in Table 4-1.

Table 4-1

Mouse oral pharmacokinetic data for azithromycin, telithromycin, clarithromycin, and C2 are shown in Table 4-2.

Table 4-2

INCORPORATION BY REFERENCE

The entire disclosure of each of the patent documents and scientific articles referred to herein is incorporated by reference for all purposes. EQUIVALENTS

The invention can be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting on the invention described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.