Triazole compounds and methods of making and using the same

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. These compounds are represented by the following formula (I): wherein R 1 , R 2 , etc. are defined as in claim 1.

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.