BACKGROUND OF THE INVENTION

Adenosine 5′-monophosphate-activated protein kinase (AMPK) is a serine/threonine kinase and is evolutionarily conserved from yeast to mammals. AMPK acts as an energy sensor and is activated by upstream enzymes when the cellular ratio of adenosine 5′—monophosphate (AMP) to adenosine triphosphate (ATP) is elevated due to nutrient deprivation. Activated AMPK phosphorylates downstream substrates to promote catabolism and impede anabolism, leading to ATP production and energy restoration. AMPK activity can be altered due to numerous physiological factors, such as hormones, cytokines and dietary nutrients, as well as pathological conditions such as obesity, chronic inflammation and type 2 diabetes. AMPK activation can lead to lower hepatic glucose production and plasma glucose levels. Thus, AMPK is an attractive target to treat various metabolic diseases.

Additionally, AMPK has beneficial effects for gut health, such as enhancing intestinal absorption, improving barrier function, suppressing colorectal carcinogenesis, and reducing intestinal inflammation and metabolic-related disease, and is important for the maintenance of intestinal homeostasis. For example, AMPK activation enhances paracellular junctions, nutrient transporters, autophagy and apoptosis, and suppresses inflammation and carcinogenesis in the intestine. Accordingly, AMPK is associated with the maintenance of tight junctions in colonic epithelium and controls the progression of colitis.

In various mouse models of colitis, treatment with a direct AMPK activator has been shown to be efficacious at restoring gut barrier function (see, for example, WO 2018/189683; Sun, X., et al. (2017), Cell Death and Differentiation, 24(5), 819-831; Xue, Y., et al. (2016), PLoS ONE, 11(12), 1-18; and Sun, X., et al. (2017), Open Biology, 7(8). This effect has also been recapitulated with metformin, which is an indirect AMPK activator having additional biological activities (see, for example, WO 2018/161077; and Di Fusco, D., et al. (2018), Clinical Science, 132(11). However, there are safety concerns with sustained direct AMPK activation, particularly in the heart. Chronic treatment with systemic, direct activators can lead to cardiac hypertrophy (concomitant with increased cardiac glycogen) in rodents and non-human primates (See, Myers, R. W., et al. (2017),

Science, 357(6350), 507-511). Additionally, human genetic polymorphisms in AMPK are associated with cardiac glycogen deposition, cardiac hypertrophy and Wolff-Parkinson-White syndrome, a condition characterized by electrocardiogram (ECG) abnormalities (see, Burwinkel, B., et al. (2005), Am Journal of Human Genetics, 76(6), 1034-1049). Due to this risk of cardiac hypertrophy, treatment with known AMPK activators, which are systemic in nature, is unsuitable to address the problem of treating IBD, colitis, and other diseases with a leaky gut barrier with a direct AMPK activator.

Direct AMPK activation in the intestine without systemic engagement has never been demonstrated or proposed until the instant disclosure. All reported direct AMPK activators which have been optimized and entered clinical studies (for example, PF-06409577 from Pfizer) or extensive preclinical evaluation (for example, MK-3903 and MK-8722 from Merck) are systemic AMPK activators and have been developed for systemic engagement, as is reflected in the routes of administration and biological assays present in patent applications and published manuscripts relating to direct AMPK activators. A delayed-release formulation has been investigated to deliver higher concentrations of the indirect AMPK activator metformin to the colon for treatment of IBD. However, metformin does not optimally activate AMPK, metformin has other activities, and this approach requires specific formulation development. Thus it is not an optimal solution to the problem.

Disclosed herein is the discovery and development of the first gut-restricted, direct AMPK activators that do not require sophisticated formulations to reach the target tissue and avoid systemic circulation.

BRIEF SUMMARY OF THE INVENTION

Disclosed herein, in some embodiments, are adenosine 5′-monophosphate-activated protein kinase (5′ AMP-activated protein kinase, 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, the 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 or selectively modulate AMPK located in the gut. In some embodiments, the condition is selected from the group consisting of: central nervous system (CNS) disorders including mood disorders, anxiety, depression, affective disorders, schizophrenia, malaise, cognition disorders, addiction, autism, epilepsy, neurodegenerative disorders, Alzheimer's disease, and Parkinson's disease, Lewy Body dementia, episodic cluster headache, migraine, pain; metabolic conditions including diabetes and its complications such as chronic kidney disease/diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, cardiovascular disease, metabolic syndrome, obesity, dyslipidemia, and nonalcoholic steatohepatitis (NASH); eating and nutritional disorders including hyperphagia, cachexia, anorexia nervosa, short bowel syndrome, intestinal failure, intestinal insufficiency and other eating disorders; inflammatory disorders and autoimmune diseases such as inflammatory bowel disease, ulcerative colitis, Crohn's disease, checkpoint inhibitor-induced colitis, psoriasis and celiac disease; necrotizing enterocolitis; gastrointestinal injury resulting from toxic insults such as radiation or chemotherapy; diseases/disorders of gastrointestinal barrier dysfunction including environmental enteric dysfunction; spontaneous bacterial peritonitis; allergy including food allergy, celiac sprue, and childhood allergy; graft vs. host disease; functional gastrointestinal disorders such as irritable bowel syndrome, functional dyspepsia, functional abdominal bloating/distension, functional diarrhea, functional constipation, and opioid-induced constipation; gastroparesis; nausea and vomiting; disorders related to microbiome dysbiosis, and other conditions involving the gut-brain axis.

Disclosed herein, in some embodiments, is a compound of Formula (I):


or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein: X is —O—, —S—, —NR3—, —C(O)—, —C(O)O—**, —C(O)NR3—**, —NR3C(O)—**, —SO2—, or —SO2NR3—**;

wherein ** indicates the attachment point to G;

Y is N, CH, or CR2;

G is C1-C5alkyl, —(CH2)j-(C3-C10cycloalkyl), —(CH2)j-(C4-10Cycloalkenyl), —(CH2)j-(aryl), —(CH2)j-(heteroaryl), —(CH2)j-(3- to 10-membered heterocycloalkyl), or —(CH2)j-(5- to 10-membered heterocycloalkenyl), which is substituted with 1, 2, 3, or 4 substituents selected from —(CH2)h—C(O)OR7, —(CH2)h—P(O)(R7)OR7, —(CH2)h—P(O)(OR7)2, —(CH2)h—S(O)2OR7, —and —(CH2)hOH; and is further optionally substituted with 1, 2, 3, or 4 substituents selected from C1-C6alkyl, C3-C6cycloalkyl, C1-C6hydroxyalkyl, C1-C6fluoroalkyl, —O—(C1-C6alkyl), ═O and ═S;



is aryl, heteroaryl, or absent; wherein if



is —C≡C—or absent, then p is 0;



is aryl, heteroaryl, cycloalkyl, heterocycloalkyl, C5-10Cycloalkenyl, or 5- to 10-membered heterocycloalkenyl;

D is K, -Z-NR5R6, or Rc;

Z is —(CH2)r—, —(CH(CH3)—, *—(CH2)r-C(═O)—, or *—(CH2)r—S(═O)2—, where * represents

attachment to



K is —SO2OH, —S(O)OH, —P(O)(OH)(Rd), —P(O)(OH)(ORd), —CH2P(O)(OH)(ORd), —B(ORd)(OH), —NHC(O)H, —N(Rd)C(O)NHSO2(Rd), —C(O)NHSO2(Rd), —SO2NHC(O)(Rd), —NHC(O)NH(Rd),

—N(Rd)C(═N(Rd)N(Rd)2, —N(Rd)C(═NH)NHC(═NH)NH2,



each Raand Rbis independently halogen, —CN, —OH, —OR13, —NR14R14, —C(O)R13, —C(O)OR13, —C(O)OR14, —OC(O)R13, —C(O)NR14R14, —NR14C(O)R14, —NR14C(O)NR14R14, —OC(O)NR14R14, —NR14C(O)OR14, —OC(O)OR14, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 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;

Rcis C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, c1-10alkoxyl, or —[(C(Rd)2)s-V]t—R9; wherein each V is independently —C(Rd)2O—, —C(Rd)2NRd—, —C(Rd)2N+(Rd)2—, —N(Rd)—C(O)—N(Rd)—, —C(O)N(Rd)—, —C(Rd)2SO2—, or —C(Rd)2S(O)—; and wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and alkoxyl is substituted by 1-6 groups selected from —N(Re)3+, K, and -Z-NR5R6; or wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and alkoxyl is substituted by 2-6 groups selected from —CO2H, —OH, and —N(Rd)2;

each Rdis independently hydrogen, C1-6alkyl or C3-6cycloalkyl; wherein the alkyl and cycloalkyl are unsubstituted or substituted by 1-3 halogen or —OH groups;

each Reis independently C1-6alkyl or C3-6cycloalkyl; wherein the alkyl and cycloalkyl are unsubstituted or substituted by 1-3 halogen or —OH groups;

R1is hydrogen or C1-Cb 4alkyl;

each R2is independently halogen, —CN, C1-C4alkyl, C1-C4fluoroalkyl, or C3-C6cycloalkyl;

R3is hydrogen or C1-C4alkyl;

R5is C6-C10alkyl that is substituted by 5 to 9 —OH groups;

or R5is C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10Cycloalkyl, C5-10cycloalkenyl, 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(Re)3+and K; or wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl is substituted by 2-6 groups selected from —CO2H, —OH, and —N(Rd)2; and wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl is optionally further substituted by 1, 2, or 3 Rfgroups;

each Rfis independently halogen, —CN, —OH, —OR13, —NR14R14, —C(O)R13, —C(O)OR14, —OC(O)R13, —C(O)NR14R14, —NR14C(O)R14, —NR14C(O)NR14R14, —OC(O)NR14R14, —NR14C(O)OR14, —OC(O)OR14, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 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 R5is —[(C(Rd)2)s—V]t—R9; wherein each V is independently —C(Rd)2O—, —C*Rd)2NRd—, —C(Rd)2—, —N(Rd)—2- —N(Rd)—C(O)—N(Rd)—, —C(O)N(Rd)—, C(Rd)2SO2—, or —C(Rd)2S(O)-;

or R5is —(C1-C6alkylene)—aryl, or —(C1-C6alkylene)-heteroaryl; wherein the aryl or heteroaryl is substituted by 1-6 groups selected from —CO2H, —OH, —N(Rd)2, —N(Re)3+, and K; and wherein the alkylene is unsubstituted or substituted by 1, 2, or 3 Rfgroups; R6is hydrogen, C1-6alkyl, or C3-6cycloalkyl; wherein the alkyl and cycloalkyl are unsubstituted or substituted by 1-3 groups independently selected from halogen, —CN, —OH, —OR13, —NR14R14, —C(O)R13, —C(O)OR14, —OC(O)R13, —C(O)NR14R14, —NR14C(O)R14—NR14C(O)NR14R14, —OC(O)NR14R14, —NR14C(O)OR14, —OC(O)OR14, or —P(O)(OR14)2;

or R5and R6are 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 —CH3, —CH2OH, —CH2NH2, —CH2CH2OH, —CH2OCH2CH2OH, —N(Re)3+, and K; or with 2-6 groups selected from —CO2H, —OH, —CH2OH, —CH2NH2, —CH2CH2OH, —CH2OCH2CH2OH, and —N(Rd)2;

each R7is independently hydrogen or C1-C4alkyl;

R9is hydrogen, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, C5-8cycloalkenyl, 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, —CO2H, —N(Re)2, —N(Re)3+, and K;

each R—is independently C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or monocyclic heteroaryl; and

each R14is independently hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or monocyclic heteroaryl; or two R14on 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.

Any combination of the groups described above or below for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds.

In some embodiments, Y is N or CH; R1is hydrogen or methyl; and each R2is independently —F, —Cl, —CN, methyl, ethyl, isopropyl, or —CF3. In some embodiments, Y is N; R1is hydrogen; R2is —F, —Cl, or —CN; and n is 1.

In some embodiments,


is aryl or heteroaryl; and


is aryl, heteroaryl, cycloalkyl, heterocycloalkyl, C5-10Cycloalkenyl, or 5- to 10-membered heterocycloalkenyl. In some embodiments,


is phenyl or 5- or 6-membered monocyclic heteroaryl; and


is phenyl, 5- or 6-membered monocyclic heteroaryl, C3-C6cycloalkyl, 3- to 8-membered heterocycloalkyl, or 5- to 10-membered heterocycloalkenyl.

In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is a compound of Formula (II):


or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:


is phenyl, C3-C6cycloalkyl, 3- to 8-membered heterocycloalkyl, or 5- to 10-membered bicyclic heterocycloalkenyl.

In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is a compound of Formula (III):



or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof

In some embodiments, each Raand Rbis independently halogen, —CN, —OH, —OR13, —NR14R14, —C(O)OR14, —C(O)NR14R14, C1-C6alkyl, or C1-C6fluoroalkyl; p is 0 or 1; and q is 0 or 1. In some embodiments, p is 0; and q is 0.

In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is a compound of Formula (IV):

or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.

In some embodiments, X is —O—, —S—, —NR3—, —C(O)NR3—**, —NR3C(O)—**, or —SO2NR3—**; wherein ** indicates the attachment point to G; and R3is hydrogen or methyl. In some embodiments, X is —O—or —S—. In some embodiments, X is —O—.

In some embodiments, G is C1-C5alkyl, C3-C10Cycloalkyl, —CH2—(C3—C10cycloalkyl), aryl, 3-to 10-membered heterocycloalkyl, or 5- to 10-membered heterocycloalkenyl, which is substituted with 1, 2, 3, or 4 substituents selected from —(CH2)h-C(O)OR7, —(CH2)h—P(O)(R7)OR7, —(CH2)h—P(O)(OR7)2, —(CH2)h—S(O)2OR7, -and —(CH2)hOH; and is further optionally substituted with 1, 2, 3, or 4 substituents selected from C1-C6alkyl, C3-C6cycloalkyl, C1-C6hydroxyalkyl, C1-C6fluoroalkyl, and —O—(C1-C6alkyl); each R7is independently hydrogen, methyl, or ethyl; and h is 0-1. In some embodiments, G is C1-C5alkyl, C3-C10Cycloalkyl, —CH2—(C3-C10cycloalkyl), 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, —CH2C(O)OH, —P(O)(Me)OH, —P(O)(OH)2, —S(O)2OH, —OH, and —CH2OH; and is further optionally substituted with 1, 2, 3, or 4 substituents selected from C1-C6alkyl, C3-C6cycloalkyl, C1-C6hydroxyalkyl, C1-C6fluoroalkyl, and —O-(C1-C6alkyl). In some embodiments, G is 3- to 10-membered heterocycloalkyl, which is substituted with 1, 2, 3, or 4 substituents selected from —C(O)OH, —CH2C(O)OH, —P(O)(Me)OH, —P(O)(OH)2, - S(O)2OH, —OH, and —CH2OH. In some embodiments, 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, —CH2C(O)OH, —P(O)(Me)OH, —P(O)(OH)2, —S(O)2OH, —OH, and —CH2OH. In some embodiments, 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, —CH2C(O)OH, —P(O)(Me)OH, —P(O)(OH)2, —S(O)2OH, —OH, and —CH2OH. In some embodiments, G is C1-C5alkyl, C3-C6cycloalkyl, —CH2-(C3-C6cycloalkyl), or phenyl, which is substituted with 1, 2, 3, or 4 substituents selected from —C(O)OH, —CH2C(O)OH, —P(O)(Me)OH, —P(O)(OH)2, —S(O)2OH, —OH, and —CH2OH; and is further optionally substituted with 1 or 2 substituents selected from C1-C6alkyl, C3-C6cycloalkyl, and C1-C6hydroxyalkyl.

In some embodiments, —X—G is selected from:



In some embodiments, D is K or -Z-NR5R6.

In some embodiments, D is K. In some embodiments, K is —SO2OH, —P(O)(OH)(Rd), —P(O)(OH)(ORd), —CH2P(O)(OH)(ORd), —C(O)NHSO2(Rd), or —SO2NHC(O)(Rd); and each Rdis independently hydrogen or C1-6alkyl. In some embodiments, K is —SO2OH, —P(O)(OH)2, —CH2P(O)(OH)2, —P(O)(OH)(Me), —P(O)(OH)(H), or —P(O)(OH)(OMe).

In some embodiments, D is -Z-NR5R6. In some embodiments, Z is —(CH2)—, —(CH(CH3)—, —C(═O)—, or —S(═O)2—. In some embodiments, R5is C6-C10alkyl that is substituted by 5 to 9 —OH groups; and R6is hydrogen or C1-6alkyl. In some embodiments, R5is C1-10alkyl which is substituted by 1-6 groups selected from —N(Re)3+and K; or with 2-6 groups selected from —CO2H, —OH, and —N(Rd)2; and is optionally further substituted by 1, 2, or 3 Rfgroups; each Rfis independently halogen, —CN, —OH, —OR13, NR14R14, —C(O)OR14, —C(O)NR14R14, —NR14C(O)R14, —NR14C(O)NR14R14, C1-C6alkyl, C3-C6cycloalkyl, or phenyl, wherein the alkyl, cycloalkyl, or phenyl, is unsubstituted or substituted by 1, 2, or 3 halogen or —OH groups; and R6is hydrogen or C1-6alkyl, which is unsubstituted or substituted by 1-3 groups independently selected from halogen, —CN, —OH, —OR13, —NR14R14, C(O)OR14, C(O)NR14R14, —NR14C(O)R14, —NR14C(O)NR14R14, or —P(O)(OR14)2. In some embodiments, R5is —[(C(Rd)2)s—V]t—R9; wherein each V is independently —C(Rd)2O—, —C(Rd)2NRd—, —N(Rd)—C(O)—N(Rd)—, or —C(O)N(Rd)—; each Rdis independently hydrogen or C1-6alkyl; R6is hydrogen or C1-6alkyl; and R9is hydrogen, C1-8alkyl, phenyl, or naphthyl, wherein the alkyl, phenyl, or naphthyl is unsubstituted or substituted by 1-6 groups selected from —OH, —CO2H, —N(Re)2, —N(Re)3+, and K. In some embodiments, R5is —(C1-C6alkylene)—aryl, or —(C1-C6alkylene)—heteroaryl; wherein the aryl or heteroaryl is substituted by 1-6 groups selected from —CO2H, —OH, —N(Rd)2, —N(Re)3+, and K; and wherein the alkylene is unsubstituted or substituted by 1, 2, or 3 Rfgroups; and R6is hydrogen or C1-6alkyl. In some embodiments, R5and R6are 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 —CH3, —CH2OH, —CH2NH2, —CH2CH2OH, —CH2OCH2CH2OH, —N(Re)3+, and K; or with 2-6 groups selected from —CO2H, —OH, —CH2OH, —CH2NH2, —CH2CH2OH, —CH2OCH2CH2OH, and —N(Rd)2. In some embodiments, K is —SO2OH, —P(O)(OH)(Rd), —P(O)(OH)(ORd), —CH2P(O)(OH)(ORd), —C(O)NHSO2(Rd), or —SO2NHC(O)(Rd); and each Rdis independently hydrogen or C1-6alkyl. In some embodiments, K is —SO2OH, —P(O)(OH)2, —CH2P(O)(OH)2, —P(O)(OH)(Me), —P(O)(OH)(H), or —P(O)(OH)(OMe).

In some embodiments, D is



In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is a compound of Formula (V):


or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
R2is —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, —CH2C(O)OH, —P(O)(Me)OH, —P(O)(OH)2, —S(O)2OH, —OH, and —CH2OH;
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, —CH2C(O)OH, —P(O)(Me)OH, —P(O)(OH)2, —S(O)2OH, —OH, and —CH2OH;
D is K or -Z-NR5R6.

In some embodiments, D is K; K is —SO2OH, —P(O)(OH)(Rd), —P(O)(OH)(ORd), —CH2P(O)(OH)(ORd), —C(O)NHSO2(Rd), or —SO2NHC(O)(Rd); and each Rdis independently hydrogen or C1-6alkyl.

In some embodiments, D is -Z-NR5R6; Z is —(CH2)—, —(CH(CH3)—, —C(═O)—, or —S(═O)2-; and R5is C6-C10alkyl that is substituted by 5 to 9 —OH groups; or R5is C1-10alkyl which is substituted by 1-6 groups selected from —N(Re)3+and K; or with 2-6 groups selected from —CO2H, —OH, and —N(Rd)2; and is optionally further substituted by 1, 2, or 3 Rfgroups; or R5is —[(C(Rd)2)s—V]t—R9; wherein each V is independently —C(Rd)2O—, —C(Rd)2NRd—, —N(Rd)—C(O)—N(Rd)—, or —C(O)N(Rd)—; each Rdis independently hydrogen or C1-6alkyl; R9is hydrogen, C1-8alkyl, phenyl, or naphthyl, wherein the alkyl, phenyl, or naphthyl is unsubstituted or substituted by 1-6 groups selected from —OH, —CO2H, —N(Re)2, —N(Re)3+, and K; or R5is —(C1-C6alkylene)—aryl, or —(C1-C6alkylene)—heteroaryl; wherein the aryl or heteroaryl is substituted by 1-6 groups selected from —CO2H, —OH, —N(Rd)2, —N(Re)3+, and K; and wherein the alkylene is unsubstituted or substituted by 1, 2, or 3 Rfgroups; R6is hydrogen or C1-6alkyl, which is unsubstituted or substituted by 1-3 groups independently selected from halogen, —CN, —OH, —OR13, —NR14R14, —C(O)OR14, —C(O)NR14R14, —NR14C(O)R14, —NR14C(O)NR14R14, or —P(O)(OR14)2; and or R5and R6are 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 —CH3, —CH2OH, —CH2NH2, —CH2CH2OH, —CH2OCH2CH2OH, —N(Re)3+, and K; or with 2-6 groups selected from —CO2H, —OH, —CH2OH, —CH2NH2, —CH2CH2OH, —CH2OCH2CH2OH, and —N(Rd)2; each Rfis independently halogen, —CN, —OH, —OR13, —NR14R14, —C(O)OR14, —C(O)NR14R14, —NR14C(O)R14, —NR14C(O)NR14R14, C1-C6alkyl, C3-C6cycloalkyl, or phenyl, wherein the alkyl, cycloalkyl, or phenyl, is unsubstituted or substituted by 1, 2, or 3 halogen or —OH groups. In some embodiments, R5is C6-C10alkyl that is substituted by 5 to 9 —OH groups; and R6is hydrogen or C1-6alkyl.

In some embodiments, D is



Also disclosed herein, in some embodiment is 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, —CH2C(O)OH, —P(O)(Me)OH, —P(O)(OH)2, —S(O)2OH, —OH, and —CH2OH; 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, —CH2C(O)OH, —P(O)(Me)OH, —P(O)(OH)2, —S(O)2OH, —OH, and —CH2OH;

D is K or -Z-NR5R6;

Z is —(CH2)—, —(CH(CH3)—, —C(═O)—, or —S(═O)2-;

K is —SO2OH, —S(O)OH, —P(O)(OH)(Rd), —P(O)(OH)(ORd), —CH2P(O)(OH)(ORd), —B(ORd)(OH), —NHC(O)H, —N(Rd)C(O)NHSO2(Rd), —C(O)NHSO2(Rd), —SO2NHC(O)(Rd), —NHC(O)NH(Rd),

—N(Rd)C(═N(Rd)N(Rd)2, —N(Rd)C(═NH)NHC(═NH)NH2,



Raand Rbare each independently halogen, —CN, —OH, —OR13, —NR14R14, —C(O)OR14, —C(O)NR14R14, C1-C6alkyl, or C1-C6fluoroalkyl;

each Rdis independently hydrogen or C1-6alkyl;

each Reis independently C1-6alkyl;

each R2is independently halogen, —CN, C1-C4alkyl, C1-C4fluoroalkyl, or C3-C6cycloalkyl;

R5is C6-C10alkyl that is substituted by 5 to 9 —OH groups;

or R5is C1-10alkyl which is substituted by 1-6 groups selected from —N(Re)3+and K; or with 2-6 groups selected from —CO2H, —OH, and —N(Rd); and is optionally further substituted by 1, 2, or 3 Rfgroups;

each Rfis independently halogen, —CN, —OH, —OR13, —NR14R14, —C(O)OR14, —C(O)NR14R14, —NR14C(O)R14, —NR14C(O)NR14R14, C1-C6alkyl, C3-C6cycloalkyl, or phenyl, wherein the alkyl, cycloalkyl, or phenyl, is unsubstituted or substituted by 1, 2, or 3 halogen or —OH groups;

or R5is —[(C(Rd)2)s—V]t—R9; wherein each V is independently —C(Rd)2O—, —C(Rd)2NRd—, —N(Rd)—C(O)—N(Rd)—, or —C(O)N(Rd)—;

or R5is —(C1-C6alkylene)—aryl, or —(C1-C6alkylene)—heteroaryl; wherein the aryl or heteroaryl is substituted by 1-6 groups selected from —CO2H, —OH, —N(Rd)2, —N(Re)3+, and K; and wherein the alkylene is unsubstituted or substituted by 1, 2, or 3 Rfgroups;

R6is hydrogen or C1-6alkyl;

or R5and R6are 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 —CH3, —CH2OH, —CH2NH2, —CH2CH2OH, —CH2OCH2CH2OH, —N(Re)3+, and K; or with 2-6 groups selected from —CO2H, —OH, —CH2OH, —CH2NH2, —CH2CH2OH, —CH2OCH2CH2OH, and —N(Rd)2;

R9is hydrogen, C1-8alkyl, phenyl, or naphthyl, wherein the alkyl, phenyl, or naphthyl is unsubstituted or substituted by 1-6 groups selected from —OH, —CO2H, —N(Re)2, —N(Re)3+, and K;

each R13is independently c1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, 0-C6fluoroalkyl, C3-C6cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or monocyclic heteroaryl; and

each R14is independently hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, or monocyclic heteroaryl;

or two R14on 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.

In some embodiments, R2is —F, —Cl, or —CN; rais —F, —Cl, —CN, —OH, —OCH3, —OCF3, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, —CH2F, —CHF2, or —CF3; and Rbis —F, —Cl, —CN, —OH, —OCH3, —OCF3, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, —CH2F, —CHF2, or —CF3.

In some embodiments, the compound of Formula (III), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is a compound of Formula (IV):



or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.

In some embodiments, X is —O—.

In some embodiments, 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, —CH2C(O)OH, —P(O)(Me)OH, —P(O)(OH)2, —S(O)2OH, —OH, and —CH2OH. In some embodiments, 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, —CH2C(O)OH, —P(O)(Me)OH, —P(O)(OH)2, —S(O)2OH, —OH, and —CH2OH.

In some embodiments, —X—G is selected from:



In some embodiments, Y is N. In some embodiments, Y is CH.

In some embodiments, D is K; and K is —SO2OH, —P(O)(OH)(Rd), —P(O)(OH)(ORd), —CH2P(O)(OH)(ORd), —C(O)NHSO2(Rd), or —SO2NHC(O)(Rd).

In some embodiments, D is -Z-NR5R6. In some embodiments, Z is —(CH2)—, —C(═O)—, or —S(═O)2—. In some embodiments, R5is C6-C10alkyl that is substituted by 5 to 9 —OH groups. In some embodiments, R5is C1-10alkyl which is substituted by 1-6 groups selected from —N(Re)3+and K; or with 2-6 groups selected from —CO2H, —OH, and —N(Rd)2; and is optionally further substituted by 1, 2, or 3 Rfgroups; and each Rfis independently halogen, —CN, —OH, —OR13, NR14R14, —C(O)OR14, —C(O)NR14R14R14, —NR14C(O)R14, —NR14C(O)NR14R14, C1-C6alkyl, C3-C6cycloalkyl, or phenyl, wherein the alkyl, cycloalkyl, or phenyl, is unsubstituted or substituted by 1, 2, or 3 halogen or —OH groups. In some embodiments, R5is —[(C(Rd)2)s—V]t—R9; wherein each V is independently —C(Rd)2O—, —C(Rd)2NRd—, —N(Rd)—C(O)—N(Rd)—, or —C(O)N(Rd)—; each Rdis independently hydrogen or C1-6alkyl; R6is hydrogen or C1-6alkyl; and R9is hydrogen, C1-8alkyl, phenyl, or naphthyl, wherein the alkyl, phenyl, or naphthyl is unsubstituted or substituted by 1-6 groups selected from —OH, —CO2H, —N(Re)2, —N(Re)3+, and K. In some embodiments, R5and R6are 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 —CH3, —CH2OH, —CH2NH2, —CH2CH2OH, —CH2OCH2CH2OH, —N(Re)3+, and K; or with 2-6 groups selected from —CO2H, —OH, —CH2OH, —CH2NH2, —CH2CH2OH, —CH2OCH2CH2OH, and —N(Rd)2. In some embodiments, R5and R6are 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 —CH2OH. In some embodiments, R5is C6-C10alkyl that is substituted by 5 to 9 —OH groups; or R5is C1-10alkyl which is substituted by 1-6 groups selected from —N(Re)3+and K; or with 2-6 groups selected from —CO2H, —OH, and —N(Rd)2; and is optionally further substituted by 1, 2, or 3 Rfgroups. In some embodiments, K is —SO2OH, —P(O)(OH)(Rd), —P(O)(OH)(ORd), —CH2P(O)(OH)(ORd), —C(O)NHSO2(Rd), or —SO2NHC(O)(Rd). In some embodiments, K is —SO2OH, —P(O)(OH)2, —CH2P(O)(OH)2, —P(O)(OH)(Me), —P(O)(OH)(H), or —P(O)(OH)(OMe). In some embodiments, K is —SO2OH or —P(O)(OH)2.

In some embodiments, D is



Disclosed herein, in some embodiments, are pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, and at least one pharmaceutically acceptable excipient.

Disclosed herein, in some embodiments, are methods 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 disclosed herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof. In some embodiments, the condition or disorder involves the gut-brain axis. In some embodiments, the condition or disorder is a nutritional disorder. In some embodiments, the condition or disorder is short bowel syndrome, intestinal failure, or intestinal insufficiency. In some embodiments, the condition or disorder is associated with systemic infection and inflammation from having a leaky gut barrier. In some embodiments, 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.

Also disclosed herein, in some embodiments, are methods of treating gastrointestinal injury resulting from toxic insult, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof. In some embodiments, the toxic insult is from radiation, chemotherapy, or a combination thereof. In some embodiments, the toxic insult is radiation-induced. In some embodiments, the toxic insult is chemotherapy-induced.

Also disclosed herein, in some embodiments, is the use of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, as a medicine.

Also disclosed herein, in some embodiments, is the use of a compound disclosed herein, 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. In some embodiments, the condition or disorder involves the gut-brain axis. In some embodiments, the condition or disorder is a nutritional disorder. In some embodiments, the condition or disorder is short bowel syndrome, intestinal failure, or intestinal insufficiency. In some embodiments, the condition or disorder is associated with systemic infection and inflammation from having a leaky gut barrier. In some embodiments, 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.

Also disclosed herein, in some embodiments, is the use of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, for the treatment of gastrointestinal injury resulting from toxic insult in a subject in need thereof. In some embodiments, the toxic insult is from radiation, chemotherapy, or a combination thereof. In some embodiments, the toxic insult is radiation-induced. In some embodiments, the toxic insult is chemotherapy-induced.

Also disclosed herein, in some embodiments, is the use of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, for the preparation of a medicament for the treatment of the diseases disclosed herein.

