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.

What is claimed is: 
     
         1 . A compound having the structure: 
       
         
           
           
               
               
           
         
         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 C 3-12  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) —N 3 , (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 6 R 6 ) t R 9  (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 ) t R 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;
 T is a 14- or 15-membered macrolide connected via a macrocyclic ring carbon atom; 
 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′, (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 , and (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 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 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 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, 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 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 , (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) p 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 1-8  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) ═S, (d) F, (e) Cl, (f) Br, (g) I, (h) —CF 3 , (i) —CN, (j) —N 3 , (k) —NO 2 , (l) —NR 6 (CR 6 R 6 ) t R 9 , (m) —OR 9 , (n) —S(O) p C(R 6 R 6 ) t R 9 , (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) —OCH 3 , (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 taken together form —O(CH 2 ) u O—; 
 R 8  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, (f) a 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, (i) —C(O)—C 1-6  alkynyl, (j) —C(O)—C 3-10  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) 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) 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 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  at each occurrence, independently is 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) —N 3 , (hh) —Si(R 13 ) 3 , (ii) a C 1-8  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 , (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; 
 
 
 R 13  at each occurrence, is independently selected from (a) —C 1-6  alkyl and (b) —O—(C 1-6  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 )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 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) —N 3 , (hh) —Si(R 13 ) 3 , (ii) a C 1-8  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; 
 
 
         alternatively two R 14  groups are taken together to form (a) ═O, (b) ═S, (c) ═NR 8 , (e) ═NOR 8 ; 
         R 15  is C 1-6  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.