US2022340599A1PendingUtilityA1
Ampk activators
Est. expiryJun 26, 2040(~14 yrs left)· nominal 20-yr term from priority
C07F 9/6561A61P 1/00C07D 519/00A61P 3/10C07D 493/04
70
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Claims
Abstract
This disclosure is directed, at least in part, to AMPK activators useful for the treatment of conditions or disorders associated with AMPK. In some embodiments, the condition or disorder is associated with the gut-brain axis. In some embodiments, condition or disorder is associated with systemic infection and inflammation from having a leaky gut barrier. In some embodiments, the AMPK activators are gut-restricted compounds. In some embodiments, the AMPK activators are agonists, super agonists, full agonists, or partial agonists.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of Formula (III):
or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
X is —O— or —S—;
Y is N or CH;
G is monocyclic 3- to 6-membered heterocycloalkyl containing 1 oxygen atom, which is substituted with 1 or 2 substituents selected from —C(O)OH, —CH 2 C(O)OH, —P(O)(Me)OH, —P(O)(OH) 2 , —S(O) 2 OH, —OH, and —CH 2 OH;
or G is bicyclic 8- to 10-membered heterocycloalkyl containing 2 oxygen atoms, which is substituted with 1 or 2 substituents selected from —C(O)OH, —CH 2 C(O)OH, —P(O)(Me)OH, —P(O)(OH) 2 , —S(O) 2 OH, —OH, and —CH 2 OH;
D is K or —Z—NR 5 R 6 ;
Z is —(CH 2 )—, —(CH(CH 3 ))—, —C(═O)—, or —S(═O) 2 —;
K is —SO 2 OH, —S(O)OH, —P(O)(OH)(R d ), —P(O)(OH)(OR d ), —CH 2 P(O)(OH)(OR d ), —B(OR d )(OH), —NHC(O)H, —N(R d )C(O)NHSO 2 (R d ), —C(O)NHSO 2 (R d ), —SO 2 NHC(O)(R d ), —NHC(O)NH(R d ), —N(R d )C(═N(R d ))N(R d ) 2 , —N(R d )C(═NH)NHC(═NH)NH 2 ,
R a and R b are each independently halogen, —CN, —OH, —OR 13 , —NR 14 R 14 , —C(O)OR 14 , —C(O)NR 14 R 14 , C 1 -C 6 alkyl, or C 1 -C 6 fluoroalkyl;
each R d is independently hydrogen or C 1-6 alkyl;
each R e is independently C 1-6 alkyl;
each R 2 is independently halogen, —CN, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, or C 3 -C 6 cycloalkyl;
R 5 is C 6 -C 10 alkyl that is substituted by 5 to 9 —OH groups;
or R 5 is C 1-10 alkyl which is substituted by 1-6 groups selected from —N(R e ) 3 + and K; or with 2-6 groups selected from —CO 2 H, —OH, and —N(R d ) 2 ; and is optionally further substituted by 1, 2, or 3 R groups;
each R f is independently halogen, —CN, —OH, —OR 13 , —NR 14 R 14 , —C(O)OR 14 , —C(O)NR 14 R 14 , —NR 14 C(O)R 14 , —NR 14 C(O)NR 14 R 14 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or phenyl, wherein the alkyl, cycloalkyl, or phenyl, is unsubstituted or substituted by 1, 2, or 3 halogen or —OH groups;
or R 5 is —[(C(R d ) 2 ) s —V] t —R 9 ; wherein each V is independently —C(R d ) 2 O—, —C(R d ) 2 NR d —, —N(R d )—C(O)—N(R d )—, or —C(O)N(R d )—;
or R 5 is —(C 1 -C 6 alkylene)-aryl, or —(C 1 -C 6 alkylene)-heteroaryl; wherein the aryl or heteroaryl is substituted by 1-6 groups selected from —CO 2 H, —OH, —N(R d ) 2 , —N(R e ) 3 + , and K; and wherein the alkylene is unsubstituted or substituted by 1, 2, or 3 R f groups;
R 6 is hydrogen or C 1-6 alkyl;
or R 5 and R 6 are taken together with the nitrogen to which they are attached to form a 3- to 6-membered N-heterocycloalkyl which is unsubstituted or substituted with 1-6 groups selected from —CH 3 , —CH 2 OH, —CH 2 NH 2 , —CH 2 CH 2 OH, —CH 2 OCH 2 CH 2 OH, —N(R e ) 3 + , and K; or with 2-6 groups selected from —CO 2 H, —OH, —CH 2 OH, —CH 2 NH 2 , —CH 2 CH 2 OH, —CH 2 OCH 2 CH 2 OH, and —N(R d ) 2 ;
R 9 is hydrogen, C 1-8 alkyl, phenyl, or naphthyl, wherein the alkyl, phenyl, or naphthyl is unsubstituted or substituted by 1-6 groups selected from —OH, —CO 2 H, —N(R e ) 2 , —N(R e ) 3 + , and K;
each R 13 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 fluoroalkyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or monocyclic heteroaryl; and
each R 14 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 fluoroalkyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or monocyclic heteroaryl;
or two R 14 on the same nitrogen atom are taken together with the nitrogen to which they are attached to form a 3- to 6-membered N-heterocycloalkyl;
p is 0 or 1;
q is 0 or 1;
each s is independently 1-6; and
each t is independently 1-6.
2 . The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
R 2 is —F, —Cl, or —CN; R a is —F, —Cl, —CN, —OH, —OCH 3 , —OCF 3 , methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, —CH 2 F, —CHF 2 , or —CF 3 ; and R b is —F, —Cl, —CN, —OH, —OCH 3 , —OCF 3 , methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, —CH 2 F, —CHF 2 , or —CF 3 .
3 . The compound of claim 1 , having the structure of Formula (IV):
or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.
4 . The compound of any one of claims 1 - 3 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
X is —O—.
5 . The compound of any one of claims 1 - 4 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
G is monocyclic 3- to 6-membered heterocycloalkyl containing 1 oxygen atom, which is substituted with 1 or 2 substituents selected from —C(O)OH, —CH 2 C(O)OH, —P(O)(Me)OH, —P(O)(OH) 2 , —S(O) 2 OH, —OH, and —CH 2 OH.
6 . The compound of any one of claims 1 - 4 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
G is bicyclic 8- to 10-membered heterocycloalkyl containing 2 oxygen atoms, which is substituted with 1 or 2 substituents selected from —C(O)OH, —CH 2 C(O)OH, —P(O)(Me)OH, —P(O)(OH) 2 , —S(O) 2 OH, —OH, and —CH 2 OH.
7 . The compound of any one of claims 1 - 3 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
—X-G is selected from:
8 . The compound of any one of claims 1 - 7 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
Y is N.
9 . The compound of any one of claims 1 - 7 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
Y is CH.
10 . The compound of any one of claims 1 - 9 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
D is K; and K is —SO 2 OH, —P(O)(OH)(R d ), —P(O)(OH)(OR d ), —CH 2 P(O)(OH)(OR d ), —C(O)NHSO 2 (R d ), or —SO 2 NHC(O)(R d ).
11 . The compound of any one of claims 1 - 9 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
D is —Z—NR 5 R 6 .
12 . The compound of claim 11 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
Z is —(CH 2 )—, —C(═O)—, or —S(═O) 2 —.
13 . The compound of claim 11 or claim 12 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
R 5 is C 6 -C 10 alkyl that is substituted by 5 to 9 —OH groups.
14 . The compound of claim 11 or claim 12 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
R 5 is C 1-10 alkyl which is substituted by 1-6 groups selected from —N(R e ) 3 + and K; or with 2-6 groups selected from —CO 2 H, —OH, and —N(R d ) 2 ; and is optionally further substituted by 1, 2, or 3 R f groups; and
each R f is independently halogen, —CN, —OH, —OR 13 , —NR 14 R 14 , —C(O)OR 14 , —C(O)NR 14 R 14 , —NR 14 C(O)R 14 , —NR 14 C(O)NR 14 R 14 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or phenyl, wherein the alkyl, cycloalkyl, or phenyl, is unsubstituted or substituted by 1, 2, or 3 halogen or —OH groups.
15 . The compound of claim 11 or claim 12 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
R 5 is —[(C(R d ) 2 ) s —V] t —R 9 ; wherein each V is independently —C(R d ) 2 O—, —C(R d ) 2 NR d —, —N(R d )—C(O)—N(R d )—, or —C(O)N(R d )—;
each R d is independently hydrogen or C 1-6 alkyl;
R 6 is hydrogen or C 1-6 alkyl; and
R 9 is hydrogen, C 1-8 alkyl, phenyl, or naphthyl, wherein the alkyl, phenyl, or naphthyl is unsubstituted or substituted by 1-6 groups selected from —OH, —CO 2 H, —N(R e ) 2 , —N(R e ) 3 + , and K.
16 . The compound of claim 11 or claim 12 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
R 5 and R 6 are taken together with the nitrogen to which they are attached to form a 3- to 6-membered N-heterocycloalkyl which is unsubstituted or substituted with 1-6 groups selected from —CH 3 , —CH 2 OH, —CH 2 NH 2 , —CH 2 CH 2 OH, —CH 2 OCH 2 CH 2 OH, —N(R e ) 3 + , and K; or with 2-6 groups selected from —CO 2 H, —OH, —CH 2 OH, —CH 2 NH 2 , —CH 2 CH 2 OH, —CH 2 OCH 2 CH 2 OH, and —N(R d ) 2 .
17 . The compound of claim 11 or claim 12 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
R 5 and R 6 are taken together with the nitrogen to which they are attached to form a 4- to 6-membered N-heterocycloalkyl which is substituted with 2-4 groups selected from —OH and —CH 2 OH.
18 . The compound of claim 11 or claim 12 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
R 5 is C 6 -C 10 alkyl that is substituted by 5 to 9 —OH groups;
or R 5 is C 1-10 alkyl which is substituted by 1-6 groups selected from —N(R e ) 3 + and K; or with 2-6 groups selected from —CO 2 H, —OH, and —N(R d ) 2 ; and is optionally further substituted by 1, 2, or 3 R groups.
19 . The compound of any one of claims 11 - 18 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
K is —SO 2 OH, —P(O)(OH)(R d ), —P(O)(OH)(OR d ), —CH 2 P(O)(OH)(OR d ), —C(O)NHSO 2 (R d ), or —SO 2 NHC(O)(R d ).
20 . The compound of any one of claims 10 - 19 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
K is —SO 2 OH, —P(O)(OH) 2 , —CH 2 P(O)(OH) 2 , —P(O)(OH)(Me), —P(O)(OH)(H), or —P(O)(OH)(OMe).
21 . The compound of any one of claims 10 - 20 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
K is —SO 2 OH or —P(O)(OH) 2 .
22 . The compound of any one of claims 1 - 9 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
D is
23 . A compound of Formula (I):
or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
X is —O—, —S—, —NR 3 —, —C(O)—, —C(O)O—**, —C(O)NR 3 —**, —NR 3 C(O)—**, —SO 2 —, or —SO 2 NR 3 —**; wherein ** indicates the attachment point to G;
Y is N, CH, or CR 2 ;
G is C 1 -C 5 alkyl, —(CH 2 ) j —(C 3 -C 10 cycloalkyl), —(CH 2 ) j —(C 4-10 cycloalkenyl), —(CH 2 ) j -(aryl), —(CH 2 ) j -(heteroaryl), —(CH 2 ) j -(3- to 10-membered heterocycloalkyl), or —(CH 2 ) j -(5- to 10-membered heterocycloalkenyl), which is substituted with 1, 2, 3, or 4 substituents selected from —(CH 2 ) h —C(O)OR 7 , —(CH 2 ) h —P(O)(R 7 )OR 7 , —(CH 2 ) h —P(O)(OR 7 ) 2 , —(CH 2 ) h —S(O) 2 OR 7 , -and —(CH 2 ) h OH; and is further optionally substituted with 1, 2, 3, or 4 substituents selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 fluoroalkyl, —O—(C 1 -C 6 alkyl), ═O and ═S;
is aryl, heteroaryl, —C≡C—, or absent; wherein if
is —C≡C— or absent, then p is 0;
is aryl, heteroaryl, cycloalkyl, heterocycloalkyl, C 5-10 cycloalkenyl, or 5- to 10-membered heterocycloalkenyl;
D is K, —Z—NR 5 R 6 , or R c ;
Z is —(CH 2 ) r —, —(CH(CH 3 ))—, *—(CH 2 ) r —C(═O)—, or *—(CH 2 ) r —S(═O) 2 —, where * represents attachment to
K is —SO 2 OH, —S(O)OH, —P(O)(OH)(R d ), —P(O)(OH)(OR d ), —CH 2 P(O)(OH)(OR d ), —B(OR d )(OH), —NHC(O)H, —N(R d )C(O)NHSO 2 (R d ), —C(O)NHSO 2 (R d ), —SO 2 NHC(O)(R d ), —NHC(O)NH(R d ), —N(R d )C(═N(R d ))N(R d ) 2 , —N(R d )C(═NH)NHC(═NH)NH 2 ,
each R a and R b is independently halogen, —CN, —OH, —OR 13 , —NR 14 R 14 , —C(O)R 13 , —C(O)OR 14 , —OC(O)R 13 , —C(O)NR 14 R 14 , —NR 14 C(O)R 14 , —NR 14 C(O)NR 14 R 14 , —OC(O)NR 14 R 14 , —NR 14 C(O)OR 14 , —OC(O)OR 14 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, or monocyclic heteroaryl, wherein the alkyl, alkenyl, akynyl, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl are unsubstituted or substituted by 1, 2, or 3 halogen or —OH groups;
R c is C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 1-10 alkoxyl, or —[(C(R d ) 2 ) s —V] t —R 9 ; wherein each V is independently —C(R d ) 2 O—, —C(R d ) 2 NR d —, —C(R d ) 2 N + (R d ) 2 —, —N(R d )—C(O)—N(R d )—, —C(O)N(R d )—, —C(R d ) 2 SO 2 —, or —C(R d ) 2 S(O)—; and wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and alkoxyl is substituted by 1-6 groups selected from —N(R e ) 3 + , K, and —Z—NR 5 R 6 ; or wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and alkoxyl is substituted by 2-6 groups selected from —CO 2 H, —OH, and —N(R d ) 2 ;
each R d is independently hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl; wherein the alkyl and cycloalkyl are unsubstituted or substituted by 1-3 halogen or —OH groups;
each R e is independently C 1-6 alkyl or C 3-6 cycloalkyl; wherein the alkyl and cycloalkyl are unsubstituted or substituted by 1-3 halogen or —OH groups;
R 1 is hydrogen or C 1 -C 4 alkyl;
each R 2 is independently halogen, —CN, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, or C 3 -C 6 cycloalkyl;
R 3 is hydrogen or C 1 -C 4 alkyl;
R 5 is C 6 -C 10 alkyl that is substituted by 5 to 9 —OH groups;
or R 5 is C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 cycloalkyl, C 5-10 cycloalkenyl, 3- to 8-membered heterocycloalkyl, or 5- to 10-membered heterocycloalkenyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl is substituted by 1-6 groups selected from —N(R e ) 3 + and K; or wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl is substituted by 2-6 groups selected from —CO 2 H, —OH, and —N(R d ) 2 ; and wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl is optionally further substituted by 1, 2, or 3 R f groups;
each R f is independently halogen, —CN, —OH, —OR 13 , —NR 14 R 14 , —C(O)R 13 , —C(O)OR 14 , —OC(O)R 13 , —C(O)NR 14 R 14 , —NR 14 C(O)R 14 , —NR 14 C(O)NR 14 R 14 , —OC(O)NR 14 R 14 , —NR 14 C(O)OR 14 , —OC(O)OR 14 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, or monocyclic heteroaryl, wherein the alkyl, alkenyl, akynyl, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl are unsubstituted or substituted by 1, 2, or 3 halogen or —OH groups;
or R 5 is —[(C(R d ) 2 ) s —V] t —R 9 ; wherein each V is independently —C(R d ) 2 O—, —C(R d ) 2 NR d —, —C(R d ) 2 N + (R d ) 2 —, —N(R d )—C(O)—N(R d )—, —C(O)N(R d )—, —C(R d ) 2 SO 2 —, or —C(R d ) 2 S(O)—;
or R 5 is —(C 1 -C 6 alkylene)-aryl, or —(C 1 -C 6 alkylene)-heteroaryl; wherein the aryl or heteroaryl is substituted by 1-6 groups selected from —CO 2 H, —OH, —N(R d ) 2 , —N(R e ) 3 + , and K; and wherein the alkylene is unsubstituted or substituted by 1, 2, or 3 R f groups;
R 6 is hydrogen, C 1-6 alkyl, or C 3-6 cycloalkyl; wherein the alkyl and cycloalkyl are unsubstituted or substituted by 1-3 groups independently selected from halogen, —CN, —OH, —OR 13 , —NR 14 R 14 , —C(O)R 13 , —C(O)OR 14 , —OC(O)R 13 , —C(O)NR 14 R 14 , —NR 14 C(O)R 14 , —NR 14 C(O)NR 14 R 14 , —OC(O)NR 14 R 14 , —NR 14 C(O)OR 14 , —OC(O)OR 14 , or —P(O)(OR 14 ) 2 ;
or R 5 and R 6 are taken together with the nitrogen to which they are attached to form a 3- to 6-membered N-heterocycloalkyl which is unsubstituted or substituted with 1-6 groups selected from —CH 3 , —CH 2 OH, —CH 2 NH 2 , —CH 2 CH 2 OH, —CH 2 OCH 2 CH 2 OH, —N(R e ) 3 + , and K; or with 2-6 groups selected from —CO 2 H, —OH, —CH 2 OH, —CH 2 NH 2 , —CH 2 CH 2 OH, —CH 2 OCH 2 CH 2 OH, and —N(R d ) 2 ;
each R 7 is independently hydrogen or C 1 -C 4 alkyl;
R 9 is hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, C 5-8 cycloalkenyl, 3- to 8-membered heterocycloalkyl, phenyl, naphthyl, monocyclic heteroaryl, or bicyclic heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl phenyl, naphthyl, monocyclic heteroaryl, or bicyclic heteroaryl is unsubstituted or substituted by 1-6 groups selected from —OH, —CO 2 H, —N(R e ) 2 , —N(R e ) 3 + , and K;
each R 13 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 fluoroalkyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or monocyclic heteroaryl; and
each R 14 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 fluoroalkyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or monocyclic heteroaryl;
or two R 14 on the same nitrogen atom are taken together with the nitrogen to which they are attached to form a 3- to 6-membered N-heterocycloalkyl;
each h is independently 0-4;
j is 0-4;
n is 0-2;
p is 0-3;
q is 0-3;
r is 0-3;
each s is independently 1-6; and
each t is independently 1-6.
24 . The compound of claim 23 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
Y is N or CH; R 1 is hydrogen or methyl; and each R 2 is independently —F, —Cl, —CN, methyl, ethyl, isopropyl, or —CF 3 .
25 . The compound of claim 23 or claim 24 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
Y is N;
R 1 is hydrogen;
R 2 is —F, —Cl, or —CN; and
n is 1.
26 . The compound of any one of claims 23 - 25 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
is aryl or heteroaryl; and
is aryl, heteroaryl, cycloalkyl, heterocycloalkyl, C 5-10 cycloalkenyl, or 5- to 10-membered heterocycloalkenyl.
27 . The compound of claim 26 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
is phenyl or 5- or 6-membered monocyclic heteroaryl; and
is phenyl, 5- or 6-membered monocyclic heteroaryl, C 3 -C 6 cycloalkyl, 3- to 8-membered heterocycloalkyl, or 5- to 10-membered heterocycloalkenyl.
28 . The compound of claim 23 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, having the structure of Formula (II):
or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
is phenyl, C 3 -C 6 cycloalkyl, 3- to 8-membered heterocycloalkyl, or 5- to 10-membered bicyclic heterocycloalkenyl.
29 . The compound of claim 23 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, having the structure of Formula (III):
or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.
30 . The compound of any one of claims 23 - 29 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
each R a and R b is independently halogen, —CN, —OH, —OR 13 , —NR 14 R 14 , —C(O)OR 14 , —C(O)NR 14 R 14 , C 1 -C 6 alkyl, or C 1 -C 6 fluoroalkyl; p is 0 or 1; and q is 0 or 1.
31 . The compound of any one of claims 23 - 29 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
p is 0; and q is 0.
32 . The compound of claim 23 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, having the structure of Formula (IV):
or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.
33 . The compound of any one of claims 23 - 32 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
X is —O—, —S—, —NR 3 —, —C(O)NR 3 —**, —NR 3 C(O)—**, or —SO 2 NR 3 —**; wherein ** indicates the attachment point to G; and R 3 is hydrogen or methyl.
34 . The compound of any one of claims 23 - 33 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
X is —O— or —S—.
35 . The compound of any one of claims 23 - 34 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
X is —O—.
36 . The compound of any one of claims 23 - 35 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
G is C 1 -C 5 alkyl, C 3 -C 10 cycloalkyl, —CH 2 —(C 3 -C 10 cycloalkyl), aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heterocycloalkenyl, which is substituted with 1, 2, 3, or 4 substituents selected from —(CH 2 ) h —C(O)OR 7 , —(CH 2 ) h —P(O)(R 7 )OR 7 , —(CH 2 ) h —P(O)(OR 7 ) 2 , —(CH 2 ) h —S(O) 2 OR 7 , -and —(CH 2 ) h OH; and is further optionally substituted with 1, 2, 3, or 4 substituents selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 fluoroalkyl, and —O—(C 1 -C 6 alkyl); each R 7 is independently hydrogen, methyl, or ethyl; and h is 0-1.
37 . The compound of any one of claims 23 - 36 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
G is C 1 -C 5 alkyl, C 3 -C 10 cycloalkyl, —CH 2 —(C 3 -C 10 cycloalkyl), aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heterocycloalkenyl, which is substituted with 1, 2, 3, or 4 substituents selected from —C(O)OH, —CH 2 C(O)OH, —P(O)(Me)OH, —P(O)(OH) 2 , —S(O) 2 OH, —OH, and —CH 2 OH; and is further optionally substituted with 1, 2, 3, or 4 substituents selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 fluoroalkyl, and —O—(C 1 -C 6 alkyl).
38 . The compound of claim 37 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
G is 3- to 10-membered heterocycloalkyl, which is substituted with 1, 2, 3, or 4 substituents selected from —C(O)OH, —CH 2 C(O)OH, —P(O)(Me)OH, —P(O)(OH) 2 , —S(O) 2 OH, —OH, and —CH 2 OH.
39 . The compound of claim 38 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
G is monocyclic 3- to 6-membered heterocycloalkyl containing 1 oxygen atom, which is substituted with 1 or 2 substituents selected from —C(O)OH, —CH 2 C(O)OH, —P(O)(Me)OH, —P(O)(OH) 2 , —S(O) 2 OH, —OH, and —CH 2 OH.
40 . The compound of claim 38 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
G is bicyclic 8- to 10-membered heterocycloalkyl containing 2 oxygen atoms, which is substituted with 1 or 2 substituents selected from —C(O)OH, —CH 2 C(O)OH, —P(O)(Me)OH, —P(O)(OH) 2 , —S(O) 2 OH, —OH, and —CH 2 OH.
41 . The compound of claim 37 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
G is C 1 -C 5 alkyl, C 3 -C 6 cycloalkyl, —CH 2 —(C 3 -C 6 cycloalkyl), or phenyl, which is substituted with 1, 2, 3, or 4 substituents selected from —C(O)OH, —CH 2 C(O)OH, —P(O)(Me)OH, —P(O)(OH) 2 , —S(O) 2 OH, —OH, and —CH 2 OH; and is further optionally substituted with 1 or 2 substituents selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and C 1 -C 6 hydroxyalkyl.
42 . The compound of any one of claims 23 - 32 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
X-G is selected from:
43 . The compound of any one of claims 23 - 42 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
D is K or —Z—NR 5 R 6 .
44 . The compound of any one of claims 23 - 43 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
D is K.
45 . The compound of claim 44 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
K is —SO 2 OH, —P(O)(OH)(R d ), —P(O)(OH)(OR d ), —CH 2 P(O)(OH)(OR d ), —C(O)NHSO 2 (R d ), or —SO 2 NHC(O)(R d ); and each R d is independently hydrogen or C 1-6 alkyl.
46 . The compound of claim 44 or claim 45 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
K is —SO 2 OH, —P(O)(OH) 2 , —CH 2 P(O)(OH) 2 , —P(O)(OH)(Me), —P(O)(OH)(H), or —P(O)(OH)(OMe).
47 . The compound of any one of claims 23 - 43 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
D is —Z—NR 5 R 6 .
48 . The compound of claim 47 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
Z is —(CH 2 )—, —(CH(CH 3 ))—, —C(═O)—, or —S(═O) 2 —.
49 . The compound of claim 47 or claim 48 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
R 5 is C 6 -C 10 alkyl that is substituted by 5 to 9 —OH groups; and
R 6 is hydrogen or C 1-6 alkyl.
50 . The compound of claim 47 or claim 48 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
R 5 is C 1-10 alkyl which is substituted by 1-6 groups selected from —N(R e ) 3 + and K; or with 2-6 groups selected from —CO 2 H, —OH, and —N(R d ) 2 ; and is optionally further substituted by 1, 2, or 3 R f groups;
each R f is independently halogen, —CN, —OH, —OR 13 , —NR 14 R 14 , —C(O)OR 14 , —C(O)NR 14 R 14 , —NR 14 C(O)R 14 , —NR 14 C(O)NR 14 R 14 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or phenyl, wherein the alkyl, cycloalkyl, or phenyl, is unsubstituted or substituted by 1, 2, or 3 halogen or —OH groups; and
R 6 is hydrogen or C 1-6 alkyl, which is unsubstituted or substituted by 1-3 groups independently selected from halogen, —CN, —OH, —OR 13 , —NR 14 R 14 , —C(O)OR 14 , —C(O)NR 14 R 14 , —NR 14 C(O)R 14 , —NR 14 C(O)NR 14 R 14 , or —P(O)(OR 14 ) 2 .
51 . The compound of claim 47 or claim 48 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
R 5 is —[(C(R d ) 2 ) s —V] t —R 9 ; wherein each V is independently —C(R d ) 2 O—, —C(R d ) 2 NR d —, —N(R d )—C(O)—N(R d )—, or —C(O)N(R d )—;
each R d is independently hydrogen or C 1-6 alkyl;
R 6 is hydrogen or C 1-6 alkyl; and
R 9 is hydrogen, C 1-8 alkyl, phenyl, or naphthyl, wherein the alkyl, phenyl, or naphthyl is unsubstituted or substituted by 1-6 groups selected from —OH, —CO 2 H, —N(R e ) 2 , —N(R e ) 3 + , and K.
52 . The compound of claim 47 or claim 48 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
R 5 is —(C 1 -C 6 alkylene)-aryl, or —(C 1 -C 6 alkylene)-heteroaryl; wherein the aryl or heteroaryl is substituted by 1-6 groups selected from —CO 2 H, —OH, —N(R d ) 2 , —N(R e ) 3 + , and K; and wherein the alkylene is unsubstituted or substituted by 1, 2, or 3 R groups; and
R 6 is hydrogen or C 1-6 alkyl.
53 . The compound of claim 47 or claim 48 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
R 5 and R 6 are taken together with the nitrogen to which they are attached to form a 3- to 6-membered N-heterocycloalkyl which is unsubstituted or substituted with 1-6 groups selected from —CH 3 , —CH 2 OH, —CH 2 NH 2 , —CH 2 CH 2 OH, —CH 2 OCH 2 CH 2 OH, —N(R e ) 3 + , and K; or with 2-6 groups selected from —CO 2 H, —OH, —CH 2 OH, —CH 2 NH 2 , —CH 2 CH 2 OH, —CH 2 OCH 2 CH 2 OH, and —N(R d ) 2 .
54 . The compound of any one of claims 47 - 53 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
K is —SO 2 OH, —P(O)(OH)(R d ), —P(O)(OH)(OR d ), —CH 2 P(O)(OH)(OR d ), —C(O)NHSO 2 (R d ), or —SO 2 NHC(O)(R d ); and each R d is independently hydrogen or C 1-6 alkyl.
55 . The compound of any one of claims 31 - 38 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
K is —SO 2 OH, —P(O)(OH) 2 , —CH 2 P(O)(OH) 2 , —P(O)(OH)(Me), —P(O)(OH)(H), or —P(O)(OH)(OMe).
56 . The compound of any one of claims 23 - 42 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
D is
57 . The compound of claim 23 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, having the structure of Formula (V):
or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
R 2 is —F, —Cl, or —CN;
X is O or S;
G is monocyclic 3- to 6-membered heterocycloalkyl containing 1 oxygen atom, which is substituted with 1 or 2 substituents selected from —C(O)OH, —CH 2 C(O)OH, —P(O)(Me)OH, —P(O)(OH) 2 , —S(O) 2 OH, —OH, and —CH 2 OH;
or G is bicyclic 8- to 10-membered heterocycloalkyl containing 2 oxygen atoms, which is substituted with 1 or 2 substituents selected from —C(O)OH, —CH 2 C(O)OH, —P(O)(Me)OH, —P(O)(OH) 2 , —S(O) 2 OH, —OH, and —CH 2 OH;
D is K or —Z—NR 5 R 6 .
58 . The compound of claim 57 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
D is K; K is —SO 2 OH, —P(O)(OH)(R d ), —P(O)(OH)(OR d ), —CH 2 P(O)(OH)(OR d ), —C(O)NHSO 2 (R d ), or —SO 2 NHC(O)(R d ); and each R d is independently hydrogen or C 1-6 alkyl.
59 . The compound of claim 57 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
D is —Z—NR 5 R 6 ; Z is —(CH 2 )—, —(CH(CH 3 ))—, —C(═O)—, or —S(═O) 2 —; and R 5 is C 6 -C 10 alkyl that is substituted by 5 to 9 —OH groups; or R 5 is C 1-10 alkyl which is substituted by 1-6 groups selected from —N(R e ) 3 + and K; or with 2-6 groups selected from —CO 2 H, —OH, and —N(R d ) 2 ; and is optionally further substituted by 1, 2, or 3 R f groups; or R 5 is —[(C(R d ) 2 ) s —V] t —R 9 ; wherein each V is independently —C(R d ) 2 O—, —C(R d ) 2 NR d —, —N(R d )—C(O)—N(R d )—, or —C(O)N(R d )—;
each R d is independently hydrogen or C 1-6 alkyl;
R 9 is hydrogen, C 1-8 alkyl, phenyl, or naphthyl, wherein the alkyl, phenyl, or naphthyl is unsubstituted or substituted by 1-6 groups selected from —OH, —CO 2 H, —N(R e ) 2 , —N(R e ) 3 + , and K;
or R 5 is —(C 1 -C 6 alkylene)-aryl, or —(C 1 -C 6 alkylene)-heteroaryl; wherein the aryl or heteroaryl is substituted by 1-6 groups selected from —CO 2 H, —OH, —N(R d ) 2 , —N(R e ) 3 + , and K; and wherein the alkylene is unsubstituted or substituted by 1, 2, or 3 R f groups; R 6 is hydrogen or C 1-6 alkyl, which is unsubstituted or substituted by 1-3 groups independently selected from halogen, —CN, —OH, —OR 13 , —NR 14 R 14 , —C(O)OR 14 , —C(O)NR 14 R 14 , —NR 14 C(O)R 14 , —NR 14 C(O)NR 14 R 14 , or —P(O)(OR 14 ) 2 ; and or R 5 and R 6 are taken together with the nitrogen to which they are attached to form a 4- to 6-membered N-heterocycloalkyl which is unsubstituted or substituted with 1-6 groups selected from —CH 3 , —CH 2 OH, —CH 2 NH 2 , —CH 2 CH 2 OH, —CH 2 OCH 2 CH 2 OH, —N(R e ) 3 ′, and K; or with 2-6 groups selected from —CO 2 H, —OH, —CH 2 OH, —CH 2 NH 2 , —CH 2 CH 2 OH, —CH 2 OCH 2 CH 2 OH, and —N(R d ) 2 ; each R f is independently halogen, —CN, —OH, —OR 13 , —NR 14 R 14 , —C(O)OR 14 , —C(O)NR 14 R 14 , —NR 14 C(O)R 14 , —NR 14 C(O)NR 14 R 14 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or phenyl, wherein the alkyl, cycloalkyl, or phenyl, is unsubstituted or substituted by 1, 2, or 3 halogen or —OH groups.
60 . The compound of claim 59 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
R 5 is C 6 -C 10 alkyl that is substituted by 5 to 9 —OH groups; and R 6 is hydrogen or C 1-6 alkyl.
61 . The compound of any claim 57 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
D is
62 . A compound selected from:
1: 4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-N-((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)-[1,1′-biphenyl]-4-carboxamide; 2: (4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)phosphonic acid; 3: 4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-N-((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)-[1,1′-biphenyl]-4-sulfonamide; 4: (2R,3R,4R,5S)-6-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)hexane-1,2,3,4,5-pentaol; 5: 2-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-carboxamido)ethane-1-sulfonic acid; 6: 3-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-carboxamido)propane-1-sulfonic acid; 7: 3-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-carboxamido)-2-(4-chlorophenyl)propane-1-sulfonic acid; 8: 2-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-N-methyl-[1,1′-biphenyl]-4-carboxamido)ethane-1-sulfonic acid; 9: 2-(N-(2-amino-2-oxoethyl)-4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-carboxamido)ethane-1-sulfonic acid; 10: 5-((2-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-carboxamido)ethyl)amino)naphthalene-1-sulfonic acid; 11: 4-(2-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-carboxamido)ethyl)benzenesulfonic acid; 12: (4′-(6-chloro-2-(((3R,5S,6R)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)phosphonic acid; 13: (2-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-carboxamido)ethyl)phosphonic acid; 14: (3-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-carboxamido)propyl)phosphonic acid; 15: 3-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-N-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)-[1,1′-biphenyl]-4-carboxamido)propane-1-sulfonic acid; 16: (4-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)-1-hydroxybutane-1,1-diyl)bis(phosphonic acid); 17: (2-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)-2,3-dihydro-1H-inden-2-yl)phosphonic acid; 18: (S)-2-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)-3-(4-(phosphonomethyl)phenyl)propanoic acid; 19: N-((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-N-(phosphonomethyl)glycine; 20: 3-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)pentanedioic acid; 21: 2-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)-4-(hydroxy(methyl)phosphoryl)butanoic acid; 22: 3-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)-2-hydroxypropanoic acid; 23: ((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-L-aspartic acid; 24: (2R,3R,4R,5S)-6-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)methyl)(methyl)amino)hexane-1,2,3,4,5-pentaol; 25: (2R,3R,4R,5S)-1-((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-(hydroxymethyl)piperidine-3,4,5-triol; 26: (4-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-carboxamido)butyl)phosphonic acid; 27: ((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-carboxamido)methyl)phosphonic acid; 28: ((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-N-(phosphonomethyl)-[1,1′-biphenyl]-4-carboxamido)methyl)phosphonic acid; 29: 2-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-carboxamido)-N,N,N-trimethylethan-1-aminium; 30: 4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-N-((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)-[1,1′-biphenyl]-4-carboxamide; 31: 4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-N-(2-(2-hydroxyethoxy)ethyl)-[1,1′-biphenyl]-4-carboxamide; 32: 1-(2-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-carboxamido)ethyl)-1,4-diazabicyclo[2.2.2]octan-1-ium; 33: 1-(3-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-carboxamido)propyl)-1,4-diazabicyclo[2.2.2]octan-1-ium; 34: 4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-N-(2-(3-(1,3-dihydroxypropan-2-yl)ureido)ethyl)-[1,1′-biphenyl]-4-carboxamide; 35: 4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-N-(2-(3-(2-hydroxyethyl)ureido)ethyl)-[1,1′-biphenyl]-4-carboxamide; 36: 2-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)-2-(hydroxymethyl)propane-1,3-diol; 37: 4-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)-N-(2-hydroxyethyl)butanamide; 38: 4-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)-N-(1,3-dihydroxypropan-2-yl)butanamide; 39: 2-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)(methyl)amino)-N,N,N-trimethylethan-1-aminium; 40: 2-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)propane-1,3-diol; 41: 1-(2-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)ethyl)-3-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)urea; 42: (1R,2S,3R,5R)-3-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)-5-(hydroxymethyl)cyclopentane-1,2-diol; 43: (2R,3R)-2-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)butane-1,3-diol; 44: 2-(2-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)ethyl)guanidine; 45: (4′-(6-chloro-2-(((3S,4R,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)phosphonic acid; 46: 2-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)-N-(2-(dimethylamino)ethyl)-2-methylpropanamide; 48: 4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-N-(2-(2-hydroxyethoxy)ethyl)-N-methyl-[1,1′-biphenyl]-4-carboxamide; 49: (3R,3aR,6R,6aR)-6-((6-chloro-5-(4′-(piperazin-1-ylmethyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol; 50: (3R,3aR,6R,6aR)-6-((6-chloro-5-(4′-((3-((2-hydroxyethoxy)methyl)azetidin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol; 51: (3R,3aR,6R,6aR)-6-((6-chloro-5-(4′-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol; 52: (1-((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)methyl)azetidine-3,3-diyl)dimethanol; 53: 2-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)-2-(hydroxymethyl)propane-1,3-diol; 54: (1-((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)methyl)piperidine-4,4-diyl)dimethanol; 55: (3R,3aR,6R,6aR)-6-((6-chloro-5-(4′-((4-(hydroxymethyl)piperidin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol; 56: (3R,3aR,6R,6aR)-6-((6-chloro-5-(4′-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol; 57: (3R,3aR,6R,6aR)-6-((6-chloro-5-(4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol; 58: (3R,3aR,6R,6aR)-6-((6-chloro-5-(4′-(((2-(2-hydroxyethoxy)ethyl)amino)methyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol; 59: (R)-1-((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)pyrrolidin-3-ol; 60: (1-((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)piperidine-4,4-diyl)dimethanol; 61: (3S,4R)-1-((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)pyrrolidine-3,4-diol; 62: (3R,3aR,6R,6aR)-6-((6-chloro-5-(4′-(((2-(2-hydroxyethoxy)ethyl)(methyl)amino)methyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol; 63: (3R,3aR,6R,6aR)-6-((6-chloro-5-(4′-((3-(hydroxymethyl)azetidin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol; 64: (3S,4S)-1-((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)pyrrolidine-3,4-diol; 65: (2R,3R,4R,5S)-6-(((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)amino)hexane-1,2,3,4,5-pentaol; 66: (1-((4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)azetidine-3,3-diyl)dimethanol; 67: (3R,3aR,6R,6aR)-6-((5-(4′-((3-(aminomethyl)azetidin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol; 68: (4′-(6-chloro-2-(((3R,4S,5S)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)phosphonic acid; 69: 4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-sulfonic acid; 70: 4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-N-(2-(2-hydroxyethoxy)ethyl)-[1,1′-biphenyl]-4-sulfonamide; 71: 4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-N-((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)-[1,1′-biphenyl]-4-sulfonamide; 72: 4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-N-(2-(2-hydroxyethoxy)ethyl)-N-methyl-[1,1′-biphenyl]-4-sulfonamide; 73: (2R,3R,4R,5S)-6-((1-(4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-imidazo[4,5-b]pyridin-5-yl)-[1,1′-biphenyl]-4-yl)ethyl)amino)hexane-1,2,3,4,5-pentaol; 74: (3R,3aR,6R,6aR)-6-((6-chloro-5-(2′-hydroxy-4′-(((2-(2-hydroxyethoxy)ethyl)amino)methyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-ol; and 75: 4′-(6-chloro-2-(((3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-2-hydroxy-N-(2-(2-hydroxyethoxy)ethyl)-[1,1′-biphenyl]-4-carboxamide; or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.
63 . A pharmaceutical composition comprising a compound of any one of claims 1 - 62 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, and at least one pharmaceutically acceptable excipient.
64 . A method of treating an adenosine 5′-monophosphate-activated protein kinase (AMPK) associated condition or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 - 62 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.
65 . The method of claim 64 , wherein the condition or disorder involves the gut-brain axis.
66 . The method of claim 64 or claim 65 , wherein the condition or disorder is a nutritional disorder.
67 . The method of claim 66 , wherein the condition or disorder is short bowel syndrome, intestinal failure, or intestinal insufficiency.
68 . The method of claim 64 or claim 65 , wherein the condition or disorder is associated with systemic infection and inflammation from having a leaky gut barrier.
69 . The method of claim 48 or claim 49 , wherein the condition or disorder is metabolic syndrome, obesity, type 2 diabetes, coronary artery disease, fatty liver, nonalcoholic steatohepatitis (NASH), cirrhosis, hepatic encephalopathy, fibrotic disorders including scleroderma, inflammatory bowel disease including Crohn's disease, ulcerative colitis, and checkpoint inhibitor-induced colitis, psoriasis, celiac disease, necrotizing enterocolitis, gastrointestinal injury resulting from toxic insults such as radiation or chemotherapy, environmental enteric dysfunction, allergy including food allergy, celiac sprue, and childhood allergy, graft vs. host disease, irritable bowel syndrome, spontaneous bacterial peritonitis, ischemic colitis, sclerosing cholangitis, Alzheimer's disease, Parkinson's disease, cancer including colorectal cancer, depression, autism, or a combination thereof.
70 . A method of treating gastrointestinal injury resulting from toxic insult, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 - 62 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.
71 . The method of claim 70 , wherein the toxic insult is from radiation, chemotherapy, or a combination thereof.
72 . The method of claim 70 or claim 71 , wherein the toxic insult is radiation-induced.
73 . The method of claim 70 or claim 70 , wherein the toxic insult is chemotherapy-induced.
74 . Use of a compound of any one of claims 1 - 62 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, as a medicine.
75 . Use of a compound of any one of claims 1 - 62 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, for the treatment of an adenosine 5′-monophosphate-activated protein kinase (AMPK) associated condition or disorder in a subject in need thereof.
76 . The use of claim 75 , wherein the condition or disorder involves the gut-brain axis.
77 . The use of claim 75 or claim 76 , wherein the condition or disorder is a nutritional disorder.
78 . The use of claim 77 , wherein the condition or disorder is short bowel syndrome, intestinal failure, or intestinal insufficiency.
79 . The use of claim 75 or claim 76 , wherein the condition or disorder is associated with systemic infection and inflammation from having a leaky gut barrier.
80 . The use of claim 75 or claim 76 , wherein the condition or disorder is metabolic syndrome, obesity, type 2 diabetes, coronary artery disease, fatty liver, nonalcoholic steatohepatitis (NASH), cirrhosis, hepatic encephalopathy, fibrotic disorders including scleroderma, inflammatory bowel disease including Crohn's disease, ulcerative colitis, and checkpoint inhibitor-induced colitis, psoriasis, celiac disease, necrotizing enterocolitis, gastrointestinal injury resulting from toxic insults such as radiation or chemotherapy, environmental enteric dysfunction, allergy including food allergy, celiac sprue, and childhood allergy, graft vs. host disease, irritable bowel syndrome, spontaneous bacterial peritonitis, ischemic colitis, sclerosing cholangitis, Alzheimer's disease, Parkinson's disease, cancer including colorectal cancer, depression, autism, or a combination thereof.
81 . Use of a compound of any one of claims 1 - 62 , or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, for the preparation of a medicament for the treatment of gastrointestinal injury resulting from toxic insult in a subject in need thereof.
82 . The use of claim 81 , wherein the toxic insult is from radiation, chemotherapy, or a combination thereof.
83 . The use of claim 81 or claim 82 , wherein the toxic insult is radiation-induced.
84 . The use of claim 81 or claim 82 , wherein the toxic insult is chemotherapy-induced.Cited by (0)
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