Antimicrobial compounds and methods of making and using the same
View Patent ↗The present invention relates generally to the field of antimicrobial compounds and to methods of making and using them. These compounds are useful for treating, preventing, and reducing the risk of microbial infections in humans and animals.
1. A compound having the formula:
or a tautomer thereof, or a pharmaceutically acceptable salt, ester, or prodrug of said compound or tautomer, wherein
X 1 is CR 1 or N; X 2 is CR 2 or N; X 3 is CR 3 or N; X 4 is CR 4 or N; X 5 is CR 5 or N; with the proviso that X 1 , X 2 , X 3 , X 4 , and X 5 are not all N;
Y 6 is CR 6 or N; Y 7 is CR 7 or N; Y 8 is CR 8 or N; Y 9 is CR 9 or N; Y 10 is CR 10 or N; with the proviso that Y 6 , Y 7 , Y 8 , Y 9 , and Y 10 are not all N; wherein
R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 and R 10 are each independently selected from (a) hydrogen, (b) F, (c) Cl, (d) Br, (e) I, (f) —CF 3 , (g) —CF 2 H, (h) —CFH 2 , (i) —OCF 3 , (j) —OCF 2 H, (k) —OCFH 2 , (l) —OCH 3 , (m) —CN, (n) —N 3 , (o) —NO 2 , (p) —NR 11 R 11 , (q) —NR 11 C(O)R 11 , (r) —C(O)NR 11 R 11 , (s) —OR 11 , (t) —COH, (u) —CO(C 1 -C 8 alkyl), (v) —COR 11 , (w) —NR 11 (CNR 11 )NR 11 R 11 , (x) —S(O) p R 11 , (y) —NR 11 S(O) p R 11 , (z) —SR 11 , (aa) —SCF 3 , (bb) —C(CF 3 )H—NH—CHR 11 R 11 , (cc) —COOR 11 , (dd) —(OCH 2 CH 2 ) t R 11 , (ee) —(OCH 2 CH 2 ) t OR 11 , (ff) —C 1 -C 8 alkyl, (gg) —C 2 -C 8 alkenyl, (hh) —C 2 -C 8 alkynyl, (ii) —(C 1 -C 8 alkyl)-(3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur), (jj) —(C 1 -C 8 alkyl)-(3-14 membered saturated, unsaturated, or aromatic carbocycle), (kk) -haloalkyl, (ll) -3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, (mm) -3-14 membered saturated, unsaturated, or aromatic carbocycle, and (nn) —CHR 11 —NH-(3-14 membered saturated, unsaturated, or aromatic heterocycle containing one of more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur);
wherein each (ff) through (nn) is optionally substituted with one or more R 12 ;
alternatively, wherein two substituents selected from R 6 , R 7 , and R 8 are taken together with the carbon atom to which they are attached to form (a) -3-7 membered saturated or unsaturated carbocyclic or (b) -3-7 membered saturated or unsaturated heterocyclic ring containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; wherein each (a) through (b) is optionally substituted with one or more R 12 ;
each R 11 is independently selected from (a) hydrogen, (b) halogen, (c) —OH, (d) —SH, (e) —(C 1 -C 8 alkyl)OH, (f) —OCF 3 , (g) —OCF 2 H, (h) —OCFH 2 , (i) —OCH 3 , (j) —OR 12 , (k) —COR 12 , (l) —CN, (m) —NO 2 , (n) —CONH 2 , (o) —CONR 12 R 12 , (p) —COCH 3 , (q) —S(O) p CH 3 , (r) —S(O) p NR 12 R 12 , (s) —SR 12 , (t) —C(O)OH, (u) —C(O)OR 12 , (v) —N 3 , (w) —NH 2 , (x) —NR 12 C(O)R 12 , (y) —NH(C 1 -C 8 alkyl), (z) —N(C 1 -C 8 alkyl) 2 , (aa) —C 1 -C 8 alkyl, (bb) —C 2 -C 8 alkenyl, (cc) —C 2 -C 8 alkynyl, (dd) -haloalkyl, (ee) —(C 1 -C 8 alkyl)-(3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur), (ff) —(C 1 -C 8 alkyl)-(3-14 membered saturated, unsaturated, or aromatic carbocycle), (gg) —3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, (hh) —3-14 membered saturated, unsaturated, or aromatic carbocycle, and (ii) —(C═NH)NR 12 R 12 ;
wherein each (y) through (hh) is optionally substituted with one or more R 12 ;
alternatively two R 11 substituents are taken together to form (a) -3-7 membered saturated or unsaturated carbocyclic or (b) -3-7 membered saturated or unsaturated heterocyclic ring containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, wherein each (a) through (b) is optionally substituted with one or more R 12 ;
R 3 is selected from:
wherein R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R 3h , R 3i , R 3j , R 3k , and R 3l are each independently selected from (a) hydrogen, (b) halogen, (c) —CN, (d) —N 3 , (e) —NO 2 , (f) —OCF 3 , (g) —OCF 2 H, (h) —OCFH 2 , (i) —OCH 3 , (j) —OR 11 , (k) —C(O)R 11 , (l) —C(O)NR 11 R 11 , (m) —NH 2 , (n) —NR 11 R 11 , (o) —NR 11 C(O)R 11 , (p) —S(O) p R 11 , (q) —C(O)OH, (r) —C(O)OR 11 , (s) —C 1 -C 8 alkyl, (t) —C 2 -C 8 alkenyl, (u) —C 2 -C 8 alkynyl, (v) haloalkyl, (w) -3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and (x) -3-14 membered saturated, unsaturated, or aromatic carbocycle;
wherein each (s) through (x) is optionally substituted with one or more R 12 ;
alternatively, one or more pairs of substituents selected from R 3a and R 3b , R 3c and R 3d , R 3e and R 3f , R 3g and R 3h , R 3i and R 3j , and R 3k and R 3l are taken together with the carbon atom to which they are attached to form (a) -3-7 membered saturated or unsaturated carbocyclic, (b) -3-7 membered saturated or unsaturated heterocyclic ring containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, (c) an exo carbon-carbon double bond, (d) carbonyl group, or (e) thiocarbonyl group;
wherein each (a) through (b) is optionally substituted with one or more R 12 ;
alternatively, wherein two substituents selected from R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R 3h , R 3i , R 3j , R 3k , and R 3l on different carbon atoms are taken together with the intervening atoms to which they are attached to form (a) -3-7 membered saturated or unsaturated carbocyclic or (b) -3-7 membered saturated or unsaturated heterocyclic ring containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur;
wherein each (a) through (b) is optionally substituted with one or more R 12 ;
alternatively, wherein two substituents selected from R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R 3h , R 3i , R 3j , R 3k , and R 3l on two adjacent carbon atoms are taken together with the bond between said adjacent carbon atoms to form a substituted or unsubstituted carbon-carbon double bond, or wherein four substituents selected from R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R 3h , R 3i , R 3j , R 3k , and R 3l on two adjacent carbon atoms are taken together with the bond between said adjacent carbon atoms to form a carbon-carbon triple bond;
U is selected from —O—, —S(O) p —, —NR 11 —, —(C═O)—, —NR 11 (C═O)—, —(C═O)NR 11 —, —S(O) p NR 11 —, —NR 11 S(O) p —, —NR 11 S(O) p NR 11 —, and —NR 11 C(O)NR 11 —;
T is selected from —NR 11 R 11 , —NR 11 (C═O)OR 11 , —NR 11 (C═NR 11 )NR 11 R 11 , and OR 11 ;
alternatively, one R 11 and one substituent selected from R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R 3h , R 3i , R 3j , R 3k , and R 3l are taken together with the intervening atoms to which they are attached to form (a) -3-7 membered saturated or unsaturated carbocyclic or (b) -3-7 membered saturated or unsaturated heterocyclic ring containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur;
wherein each (a) through (b) is optionally substituted with one or more R 12 ;
R 9 is selected from:
wherein R 9k , R 9l , R 9m , R 9n , R 9o , R 9p , R 9q , R 9r , R 9s , and R 9t are each independently selected from (a) hydrogen, (b) halogen, (c) —CN, (d) —N 3 , (e) —NO 2 , (f) —OCF 3 , (g) —OCH 3 , (h) —OCF 2 H, (i) —OCFH 2 , (j) —OR 11 , (k) —NH 2 , (l) —NR 11 R 11 , (m) —C(O)R 11 , (n) —C(O)OR 11 , (o) —C(O)NR 11 R 11 , (p) —NR 11 C(O)R 11 , (q) —S(O) p R 11 , (r) —C 1 -C 8 alkyl, (s) —C 2 -C 8 alkenyl, (t) —C 1 -C 8 alkynyl, (u) haloalkyl, (v) -3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and (w) -3-14 membered saturated, unsaturated, or aromatic carbocycle;
wherein each (r) through (w) is optionally substituted with one or more R 12 ;
alternatively, one or more pairs of substituents selected from R 9k and R 9l , R 9m and R 9n , R 9o and R 9p , R 9q and R 9r , and R 9s and R 9t are taken together with the carbon atom to which they are attached to form (a) 3-7 membered saturated or unsaturated carbocyclic, (b) 3-7 membered saturated or unsaturated heterocyclic ring containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, (c) an exo carbon-carbon double bond, (d) carbonyl group, or (e) thiocarbonyl group;
wherein each (a) through (c) is optionally substituted with one or more R 12 ;
alternatively, two substituents selected from R 9k , R 9l , R 9m , R 9n , R 9o , R 9p , R 9q , R 9r , R 9s , and R 9t on different carbon atoms are taken together with the intervening atoms to which they are attached to form (a) -3-7 membered saturated or unsaturated carbocyclic or (b) -3-7 membered saturated or unsaturated heterocyclic ring containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur;
wherein each (a) through (b) is optionally substituted with one or more R 12 ;
alternatively, two substituents selected from R 9k , R 9l , R 9m , R 9n , R 9o , R 9p , R 9q , R 9r , R 9s , and R 9t on two adjacent carbon atoms are taken together with the bond between said adjacent carbon atoms form a substituted or unsubstituted carbon-carbon double bond, or four substituents selected from R 9k , R 9l , R 9m , R 9n , R 9o , R 9p , R 9q , R 9r , R 9s , and R 9t on two adjacent carbon atoms are taken together with the bond between said adjacent carbon atoms form a carbon-carbon triple bond;
Z is selected from —O—, —S(O) p —, —NR 11 —, —(C═O)—, —NR 11 (C═O)—, —(C═O)NR 11 —, —S(O) p NR 11 —, —NR 11 S(O) p —, —NR 11 S(O) p NR 11 —, and —NR 11 C(O)NR 11 —;
W is selected from —NR 11 R 11 , —NR 11 (CO)OR 11 , —NR 11 (C═NR 11 )NR 11 R 11 , and —OR 11 ;
alternatively, one R 11 and one substituent selected from R 9k , R 9l , R 9m , R 9n , R 9o , R 9p , R 9q , R 9r , R 9s , and R 9t are taken together with the intervening atoms to which they are attached to form (a) -3-7 membered saturated or unsaturated carbocyclic or (b) -3-7 membered saturated or unsaturated heterocyclic ring containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur;
wherein each (a) through (b) is optionally substituted with one or more R 12 ;
R 12 is independently selected from (a) hydrogen, (b) halogen, (c) —OH, (d) —SH, (e) —(C 1 -C 8 alkyl)OH, (f) —OCF 3 , (g) —OCH 3 , (h) —OCF 2 H, (i) —OCFH 2 , (j) —O(C 1 -C 8 alkyl), (k) —CN, (l) —NO 2 , (m) —CONH 2 , (n) C(O)NH(C 1 -C 8 alkyl), (o) C(O)N(C 1 -C 8 alkyl) 2 , (p) —COH, (q) —COCH 3 , (r) —S(O) p CH 3 , (s) —S(O) p N(C 1 -C 8 alkyl) 2 , (t) —S(C 1 -C 8 alkyl), (u) —C(O)OH, (v) —C(O)O(C 1 -C 8 alkyl), (w) —N 3 , (x) —NHC(O)(C 1 -C 8 alkyl), (y) —N(C 1 -C 8 alkyl)C(O)(C 1 -C 8 alkyl), (z) —NH 2 , (aa) —NH(C 1 -C 8 alkyl), (bb) —N(C 1 -C 8 alkyl) 2 , (cc) —C 1 -C 8 alkyl, (dd) —C 2 -C 8 alkenyl, (ee) —C 2 -C 8 alkynyl, (ff) -haloalkyl, (gg) —(C 1 -C 8 alkyl)-(3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur), (hh) —(C 1 -C 8 alkyl)-(3-14 membered saturated, unsaturated, or aromatic carbocycle), (ii) -3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, (jj) -3-14 membered saturated, unsaturated, or aromatic carbocycle, (kk) —(C═NH)NH 2 , (ll) —C(═NH)NH 2 , (mm) —C(O)R 13 , (nn) ═O, and (oo) ═NR 13 ;
wherein each (aa) through (jj) is optionally substituted with one or more R 13 ;
R 13 is independently selected from (a) hydrogen, (b) halogen, (c) —C 1 -C 8 alkyl, (d) —C 2 -C 8 alkenyl, (e) —C 2 -C 8 alkynyl, (f) -haloalkyl, (g) —OH, (h) —OC 1 -C 8 alkyl, (i) —OC 2 -C 8 alkenyl, (j) —OC 2 -C 8 alkynyl, (k) —OCF 3 , (l) —OCH 3 , (m) —OCF 2 H, (n) —OCFH 2 , (o) —NH 2 , (p) —CN, (q) —N 3 , (r) —S(O) p C 1 -C 8 alkyl, (s) -3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and (t) -3-14 membered saturated, unsaturated, or aromatic carbocycle;
p is 0, 1, or 2; and
t is 0, 1, or 2.
2. The compound according to claim 1 having the formula:
or a tautomer thereof, or a pharmaceutically acceptable salt, ester, or prodrug of said compound or tautomer.
3. The compound according to claim 2 having the formula:
or a tautomer thereof, or a pharmaceutically acceptable salt, ester, or prodrug of said compound or tautomer.
4. The compound according to claim 3 having a formula selected from:
or a tautomer thereof, or a pharmaceutically acceptable salt, ester, or prodrug of said compound or tautomer.
5. The compound according to claim 3 having a formula selected from:
or a tautomer thereof, or a pharmaceutically acceptable salt, ester, or prodrug of said compound or tautomer.
6. The compound or a tautomer thereof, or a pharmaceutically acceptable salt, ester, or prodrug of said compound or tautomer, according to claim 1 , wherein at least one substituent selected from R 9k , R 9l , R 9m , R 9n , R 9o , R 9p , R 9q , R 9r , R 9s , and R 9t is not hydrogen.
7. The compound or a tautomer thereof, or a pharmaceutically acceptable salt, ester, or prodrug of said compound or tautomer, according to claim 2 wherein R 1 , R 2 , R 4 , and R 5 are each hydrogen.
8. The compound or a tautomer thereof, or a pharmaceutically acceptable salt, ester, or prodrug of said compound or tautomer, according to claim 3 , wherein R 3a and R 3b are each independently selected from (a) hydrogen, (b) F, (c) Cl, (d) —CH 3 , (e) —CF 3 , (f) —CF 2 H, (g) —CFH 2 , (h) —OCF 3 , (i) —OCF 2 H, (j) —OCFH 2 , (k) —OCH 3 , and (l) —OH.
9. The compound or a tautomer thereof, or a pharmaceutically acceptable salt, ester, or prodrug of said compound or tautomer, according to claim 1 , wherein R 10 is selected from hydrogen, F and Cl.
10. The compound or a tautomer thereof, or a pharmaceutically acceptable salt, ester, or prodrug of said compound or tautomer, according to claim 1 , wherein R 6 and R 7 are each independently selected from (a) F, (b) Cl, (c) —CF 3 , (d) —CF 2 H, (e) —CFH 2 , (f) —OCF 3 , (g) —OCF 2 H, (h) —OCFH 2 , (i) —OCH 3 , (j) —CN, (k) —OR 11 , (l) —S(O) p R 11 , (m) —SCF 3 , (n) —C 1 -C 8 alkyl, (o) -3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, (p) -3-14 membered saturated, unsaturated, or aromatic carbocycle, (q) —CHCHCN and (r) —CHCH—C(O)NH-t-butyl.
11. The compound or a tautomer thereof, or a pharmaceutically acceptable salt, ester, or prodrug of said compound or tautomer, according to claim 1 , wherein R 9k , R 9l , R 9m , R 9n , R 9o , R 9p , R 9q , R 9r , R 9s , and R 9t are each independently selected from (a) hydrogen, (b) halogen, (c) —CF 3 , (d) —CF 2 H, (e) —CFH 2 , (f) —OCF 3 , (g) —OCH 3 , (h) —OCF 2 H, (i) —OCFH 2 , (j) —OR 11 , (k) —C 1 -C 8 alkyl, (l) haloalkyl, (m) -3-14 membered saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and (n) -3-14 membered saturated, unsaturated, or aromatic carbocycle;
alternatively, one or more of pairs of substituents selected from R 9k and R 9l , R 9m and R 9n , R 9o and R 9p , R 9q and R 9r , and R 9s and R 9t are taken together with the carbon atom to which they are attached to form (a) -3-7 membered saturated or unsaturated carbocyclic or (b) -3-7 membered saturated or unsaturated heterocyclic ring containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; and
at least one substituent selected from R 9k , R 9l , R 9m , R 9n , R 9o , R 9p , R 9q , R 9r , R 9s , and R 9t is not hydrogen.
12. The compound or a tautomer thereof, or a pharmaceutically acceptable salt, ester, or prodrug of said compound or tautomer, according to claim 11 wherein R 9k , R 9l , R 9m , R 9n , R 9o , R 9p , R 9q , R 9r , R 9s , and R 9t are each independently selected from (a) hydrogen, (b) halogen, (d) —CF 3 , (e) —CF 2 H, (f) —CFH 2 , (g) —OCF 3 , (h) —OCH 3 , (i) —OCF 2 H, (j) —OCFH 2 , (k) —OH, (c) —OCH 3 , (l) methyl, (m) ethyl, (n) isopropyl, and (o) t-butyl; and
at least one substituent selected from R 9k , R 9l , R 9m , R 9n , R 9o , R 9p , R 9q , R 9r , R 9s , and R 9t is not hydrogen.
13. The compound according to claim 1 having a formula selected from:
or a tautomer thereof, or a pharmaceutically acceptable salt, ester, or prodrug of said compound or tautomer.
14. The compound or a tautomer thereof, or a pharmaceutically acceptable salt, ester, or prodrug of said compound or tautomer, according to claim 13 , wherein R 9o , R 9p , R 9q , and R 9r are each independently selected from —C 1 -C 6 alkyl and hydrogen;
R 6 and R 8 are each independently selected from hydrogen, F, Cl, Br, I, —C 1 -C 6 alkyl, —CH 2 F, —CHF 2 , and —CF 3 ;
R 7 is selected from hydrogen, F, Cl, Br, I, —C 1 -C 6 alkyl, —CH 2 F, —CHF 2 , —CF 3 , —OC 1 -C 6 alkyl, —S(O) p —C 1 -C 6 alkyl, —OCH 2 F, —OCHF 2 , —OCF 3 , —S(O) p —CH 3 , —S(O) p —CH 2 F, and —S(O) p —CF 3 ; and
R 3a is selected from halogen and C 1 -C 6 alkyl; and
p is 0, 1, or 2.
15. The compound or a tautomer thereof, or a pharmaceutically acceptable salt, ester, or prodrug of said compound or tautomer, according to claim 13 , wherein R 9o , R 9p , R 9q , and R 9r are each independently selected from C 1 -C 6 alkyl and hydrogen;
R 6 is selected from hydrogen, F, Cl, Br, I, —C 1 -C 6 alkyl, —CH 2 F, —CHF 2 , and —CF 3 ;
R 7 is selected from hydrogen, F, Cl, Br, I, —C 1 -C 6 alkyl, —CH 2 F, —CHF 2 , —CF 3 , —OC 1 -C 6 alkyl, —S(O) p —C 1 -C 6 alkyl, —OCH 2 F, —OCHF 2 , —OCF 3 , —S(O) p —CH 3 , —S(O) p —CH 2 F, and —S(O) p —CF 3 ;
R 8 is hydrogen;
R 3a is selected from halogen and —C 1 -C 6 alkyl; and
p is 0, 1, or 2.
16. The compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt, ester, or prodrug of said compound or tautomer selected from:
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17. A pharmaceutical composition comprising a compound according to claim 1 or a tautomer thereof, or a pharmaceutically acceptable salt, ester, or prodrug of said compound or tautomer, and a pharmaceutically acceptable carrier.