TRIAZOLE COMPOUNDS AND METHODS OF MAKING AND USING THE SAME

1 . A compound having the structure:

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

wherein

T is a 14- or 15-membered macrolide connected via a macrocyclic ring carbon atom;

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 ;

R 2 is hydrogen or —OR 12 ;

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 C 3-12 saturated, unsaturated, or aromatic carbocycle, (e) a 3-12 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein

i) 0-2 carbon atoms in any of (a)-(c) of A immediately above optionally is replaced by a moiety selected from 0, S(O) p , and NR 5 , and

ii) each of the groups (a)-(e) immediately above optionally is substituted with one or more R 5 groups;

G is selected from: (a) —B′ and (b) —B′—Z—B″, wherein

i) each B′ and B″ is independently selected from (aa) an aryl group, (bb) a heteroaryl group, (cc) a biaryl group, (dd) a fused bicyclic or tricyclic saturated, unsaturated or aromatic ring system optionally containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (ee) a 3-10 membered saturated or unsaturated heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, and (ff) a 3-10 membered saturated, or unsaturated carbocycle, wherein each (aa)-(ff) optionally is substituted with one or more R 11 or R 11a groups; and

ii) Z is selected from

(aa) a single bond, (bb) a C 1-6 alkyl group, (cc) a C 2-6 alkenyl group, (dd) a C 2-6 alkynyl group, (ee) —C(O)—, (ff) —C(O)O—, (gg) —C(O)NR 4 —, (hh) —C(═NR 4 )—, (ii) —C(═NR 4 )O—, (jj) —C(═NR 4 )NR 4 —, (kk) —S(O) p —, (ll) —OC(O)—, (mm) —C(S)—, (nn) —C(S)NR 4 —, (oo) —C(NR 4 )S—, (pp) —C(O)S—, (qq) —O—, (rr) —NR 4 —, (ss) —NR 4 C(O)—, (tt) —OC(NR 4 )—, (uu) —NC(NR 4 )—, (vv) —C(S)O—, (ww) —SC(O)—, (xx) —OC(S)—, and (yy) —S(O) p —;

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 C 6-10 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)—C 1-6 alkyl, (h) —C(O)—C 2-6 alkenyl, (i) —C(O)—C 2-6 alkynyl, (j) —C(O)—C 6-10 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—C 2-6 alkenyl, (n) —C(O)O—C 2-6 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 bonded, 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 ;

R 5 is selected from:

(a) R 7 , (b) a C 1-8 alkyl group, (c) a C 2-8 alkenyl group, (d) a C 2-8 alkynyl group, (e) a C 3-12 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) 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 3-7 membered carbocyclic ring or heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (h) two R 5 groups, when present on the same nitrogen atom, can be taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclic ring optionally containing one or more additional heteroatoms selected from nitrogen, oxygen, and sulfur, (i) two R 5 groups, when present on different carbon atoms, can be taken together with the carbon atoms to which they are attached to form a 3-7 membered carbocyclic ring or heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (j) two R 5 groups, when present on a carbon and a-nitrogen atom, can be taken together with the carbon and nitrogen atoms to which they are attached to form a 3-7 membered heterocyclic ring optionally containing one or more additional heteroatoms selected from nitrogen, oxygen, and sulfur, and (k) two R 5 groups, when present on different nitrogen atoms, can be taken together with the nitrogen atoms to which they are attached to form a 3-7 membered heterocyclic ring optionally containing one or more additional heteroatoms selected from nitrogen, oxygen, and sulfur;

wherein any of (b)-(k) 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 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 moieties selected from:

(aa) a carbonyl group, (bb) a formyl group, (cc) F, (dd) Cl, (ee) Br,

(ff) I, (gg) CN, (hh) NO 2 , (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 , (v) —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 ) 2 NR 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 C 1-8 alkyl group, (ak) a C 2-8 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 C 1-9 acyl group, (ap) —CF 3 ,

(aq) —SCF 3 —, (ar) a C 3-10 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) F, (d) Cl, (e) Br, (f) I, (g) —CF 3 ,

(h) —CN, (i) —N 3 , (j) —NO 2 , (k) —NR 6 (CR 6 R 6 ) t R 9 , (l) —OR 9 ,

(m) —S(O) p C(R 6 R 6 ) t R 9 , (n) —C(O)(CR 6 R 6 ) t R 9 , (o) —OC(O)(CR 6 R 6 ) t R 9 ,

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

(s) —C(O)NR 6 (CR 6 R 6 ) t R 9 , (t) —C(═NR 6 )(CR 6 R 6 ) t R 9 , (u) —C(═NNR 6 R 6 )(CR 6 R 6 ) t R 9 ,

(v) —C(═NNR 6 C(O)R 6 )(CR 6 R 6 ) t R 9 , (w) —C(═NOR 9 )(CR 6 R 6 ) t R 9 ,

(x) —NR 6 C(O)O(CR 6 R 6 ) t R 9 , (y) —OC(O)NR 6 (CR 6 R 6 ) t R 9 ,

(z) —NR 6 C(O)NR 6 (CR 6 R 6 ) t R 9 , (aa) —NR 6 S(O) p (CR 6 R 6 ) t R 9 ,

(bb) —S(O)pNR 6 (CR 6 R 6 ) t R 9 , (cc) —NR 6 S(O)pNR 6 (CR 6 R 6 ) t R 9 , (dd) —NR 6 R 6 ,

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

wherein any of (kk)-(oo) optionally is substituted with one or more R 9 groups;

alternatively, two R 7 groups can form —O(CH 2 ) u O—;

R 8 is selected from:

(a) R 5 , (b) H, (c) a C 1-6 alkyl group, (d) a C 2-6 alkenyl group, (e) a C 2-6 alkynyl group, (f) a C 3-10 saturated, unsaturated, or aromatic carbocycle, (g) a 3-10 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (h) —C(O)—C 1-6 alkyl, (i) —C(O)—C 1-6 alkenyl, (j) —C(O)—C 1-6 alkynyl, (k) —C(O)—C 3-10 saturated, unsaturated, or aromatic carbocycle, and (l) —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) NO 2 , (hh) OH, (ii) NH 2 , (jj) NH(C 1-6 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 C 1-6 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, NO 2 , CF 3 , SCF 3 , 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)pR 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)pR 6 , (u) —S(O)pNR 6 R 6 , (v) —NR 6 S(O)pNR 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 C 3-10 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(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , a C 1-6 alkoxy group, a C 1-6 alkylthio group, and a C 1-6 acyl group;

R 11 and R 11a at each occurrence, independently is selected from:

(a) a carbonyl group, (b) a formyl group, (c) F, (d) Cl, (e) Br, (f) I, (g) CN, (h) NO 2 , (i) OR 8 , (j) —S(O) p R 8 , (k) —C(O)R 8 , (l) —C(O)OR 8 ,

(m) —OC(O)R 8 , (n) —C(O)NR 8 R 8 , (o) —OC(O)NR 8 R 8 ,

(p) —C(═NR 8 )R 8 , (q) —C(R 8 )(R 8 )OR 8 , (r) —C(R 8 ) 2 OC(O)R 8 ,

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

(v) —NR 8 C(O)R 8 , (w) —NR 8 C(O)OR 8 , (x) —NR 8 C(O)NR 8 R 8 , (y) —NR 8 S(O)pR 8 , (z) —C(OR 8 )(OR 8 )R 8 , (aa) —C(R 8 ) 2 NR 8 R 8 , (bb)═NR 8 , (cc) —C(S)NR 8 R 8 , (dd) —NR 8 C(S)R 8 , (ee) —OC(S)NR 8 R 8 , (ff) —NR 8 C(S)OR 8 , (gg) —NR 8 C(S)NR 8 R 8 , (hh) —SC(O)R 8 , (ii) —N 3 , (jj) —Si(CH 3 ) 3 , (kk) —O—Si(CH 3 ) 3 , (ll) —Si(C 2 H 5 ) 2 CH 3 , (mm) —O—Si(C 2 H 5 ) 2 CH 3 , (nn) a C 1-8 alkyl group, (oo) a C 2-8 alkenyl group,

(pp) a C 2-8 alkynyl group, (qq) a C 1-9 alkoxy group, (rr) a C 1-9 alkylthio group, (ss) a C 1-8 acyl group, (tt) a C 3-10 saturated, unsaturated, or aromatic carbocycle, and (uu) a 3-10 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein (nn)-(pp) 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 , (h) —C(S)R 5 , (i) —C(S)OR 5 , (j) —C(O)SR 5 , (k) —C(S)—NR 4 R 4 , (l) a C 3-10 saturated, unsaturated, or aromatic carbocycle, (m) a 3-10 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, (n) a —(C 1-6 alkyl) —C 3-10 saturated, unsaturated, or aromatic carbocycle, and (o) a —(C 1-6 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;

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

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

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

2 . A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof and a pharmaceutically acceptable carrier.

3 . 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 claim 1 , or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.

4 . A method of treating a microbial infection in a mammal comprising administering to the mammal an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.

5 . A method according to claim 4 wherein said microbial infection is an uncomplicated skin or soft tissue infection (uSSTI).

6 . A method according to claim 4 wherein said microbial infection is a community acquired or community associated infection.

7 . A method according to claim 6 wherein said microbial infection is an uncomplicated skin or soft tissue infection (uSSTI).

8 . A method of treating a fungal infection in a mammal comprising administering to the mammal an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.

9 . A method of treating a parasitic disease in a mammal comprising administering to the mammal an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt, ester, JV-oxide, or prodrug thereof.

10 . A method of treating a proliferative disease in a mammal comprising administering to the mammal an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.

11 . A method of treating a viral infection in a mammal comprising administering to the mammal an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.

12 . A method of treating an inflammatory disease in a mammal comprising administering to the mammal an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.

13 . A method of treating a gastrointestinal motility disorder in a mammal comprising administering to the mammal an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof.

14 . 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 claim 1 , or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, to suppress expression of the nonsense or missense mutation.

15 . The method according to claim 3 , wherein the compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof is administered orally, parentally, or topically.

16 . A method of synthesizing a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof according to claim 1 .

17 . A medical device containing a compound, or a pharmaceutically acceptable salt, ester, N-oxide, or prodrug thereof, according to claim 1 .

18 . The medical device according to claim 17 , wherein the device is a stent.