CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of US Provisional Application No. 63/282,373 filed on November 23, 2021, which is incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

[0002] 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.

[0003] 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.

[0004] 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.

[0005] 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. [0006] 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

[0007] 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. [0008] Disclosed herein, in some embodiments, is a compound of Formula (I): or pharmaceutically acceptable salt thereof, wherein: X is -O- or -S-; Y is -N- or -CR ⁶ -; R ¹ , R ² , R ³ , and R ⁴ , are each independently selected at each occurrence from halogen, hydroxyl, C _1-4 alkyl, -CN, and C _1-4 haloalkyl; n is selected from 0, 1, 2, 3, and 4; o is selected from 0, 1, 2, 3, and 4; p is selected from 0, 1, and 2; q is selected from 0, 1, 2, 3, and 4; R ⁵ is selected from hydrogen and C _1-4 alkyl; R ⁶ is selected from hydrogen, halogen, C _1-4 alkyl, and C _1-4 haloalkyl; D is selected from -P(O)(OR ¹¹ ) ₂ , -P(O)R ¹¹ (OR ¹¹ ), -S(O) ₂ OH, and -L-K; L is selected from ^λ -(C(R ¹³ ) ₂ ) _r -, ^λ -O(C(R ¹³ ) ₂ ) _r -, ^λ -N(R ¹² )(C(R ¹³ ) ₂ ) _s -, ^λ -C(O)O-, ^λ -OC(O)-, ^λ - C(O)N(R ¹² )-, ^λ -N(R ¹² )C(O)-, ^λ -N(R ¹² )S(O) ₂ -, ^λ -S(O) ₂ N(R ¹² )-, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, wherein ^λ denotes the connection to K; r is selected from 1, 2, and 3; s is selected from 0, 1, 2, and 3; K is selected from (i) and (ii): (i) C _1-10 alkyl or C _1-10 heteroalkyl, each of which is optionally substituted with one to six substituents independently selected from: halogen, -OR ¹⁴ , -SR ¹⁴ , -N(R ¹⁴ ) ₂ , - N ⁺ (R ¹⁵ ) ₃ , -C(O)R ¹⁴ , -C(O)OR ¹⁴ , -OC(O)R ¹⁴ , -OC(O)N(R ¹⁴ ) ₂ , -C(O)N(R ¹⁴ ) ₂ , - N(R ¹⁴ )C(O)R ¹⁴ , -N(R ¹⁴ )C(O)OR ¹⁴ , -N(R ¹⁴ )C(O)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )S(O) ₂ (R ¹⁴ ), - S(O)R ¹⁴ , -S(O) ₂ R ¹⁴ , -S(O) ₂ N(R ¹⁴ ) ₂ , =O, -CN, -P(O)(OR ¹⁶ ) ₂ , -P(O)R ¹⁶ (OR ¹⁶ ), - S(O) ₂ OH, C _3-10 carbocycle and 3- to 10-membered heterocycle, wherein each C _3-10 carbocycle and 3- to 10-membered heterocycle is optionally substituted with one to six substituents independently selected from halogen, C _1-6 alkyl, -OR ¹⁴ , =O, and -S(O) ₂ OH; and (ii) C _3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one to six substituents independently selected from halogen, -OR ¹⁴ , - SR ¹⁴ , -N(R ¹⁴ ) ₂ , -N ⁺ (R ¹⁵ ) ₃ , -C(O)R ¹⁴ , -C(O)OR ¹⁴ , -OC(O)R ¹⁴ , -OC(O)N(R ¹⁴ ) ₂ , - C(O)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )C(O)R ¹⁴ , -N(R ¹⁴ )C(O)OR ¹⁴ , -N(R ¹⁴ )C(O)N(R ¹⁴ ) ₂ , - N(R ¹⁴ )S(O) ₂ R ¹⁴ , -S(O)R ¹⁴ , -S(O) ₂ R ¹⁴ , -S(O) ₂ N(R ¹⁴ ) ₂ , -P(O)(OR ¹⁶ ) ₂ , -P(O)R ¹⁶ (OR ¹⁶ ), -S(O) ₂ OH, =O, -CN, C _1-10 alkyl, and C _1-10 heteroalkyl, wherein each C _1-10 alkyl and C _1-10 heteroalkyl is optionally substituted with one to six substituents independently selected from halogen, -OR ¹⁴ , -SR ¹⁴ , - N(R ¹⁴ ) ₂ , -N ⁺ (R ¹⁵ ) ₃ , -C(O)OR ¹⁴ , -P(O)(OR ¹⁶ ) ₂ , -P(O)R ¹⁶ (OR ¹⁶ ), -S(O) ₂ R ¹⁶ , - S(O) ₂ OH, and =O; R ¹¹ is independently selected at each occurrence from hydrogen, C _1-4 alkyl and C _1-4 haloalkyl; R ¹² is independently selected at each occurrence from hydrogen and C _1-4 alkyl optionally substituted with halogen, -OH, -NH ₂ and -C(O)N(H) ₂ ; R ¹³ is independently selected at each occurrence from hydrogen, C _1-4 alkyl, C _1-4 haloalkyl, and C _1-4 hydroxyalkyl; R ¹⁴ is independently selected at each occurrence from: hydrogen; and C _1-10 alkyl and C _1-10 heteroalkyl optionally substituted with one to six substituents independently selected from halogen, -OR ²¹ , -SR ²¹ , -N(R ²¹ ) ₂ , -N ⁺ (R ¹⁵ ) ₃ , -C(O)R ²¹ , - C(O)OR ²¹ , -OC(O)R ²¹ , -OC(O)N(R ²¹ ) ₂ , -C(O)N(R ²¹ ) ₂ , -N(R ²¹ )C(O)R ²¹ , - P(O)(OR ¹⁶ ) ₂ , -P(O)R ¹⁶ (OR ¹⁶ ), -S(O) ₂ OH, =O, and -CN; and C _3-10 carbocycle and 3- to 10-membered heterocycle, wherein each C _3-10 carbocycle and 3- to 10-membered heterocycle is optionally substituted with one to six substituents independently selected from halogen, C _1-6 alkyl, -OR ²¹ , -N ⁺ (R ¹⁵ ) ₃ , -S(O)R ²¹ , -P(O)(OR ¹⁶ ) ₂ , - P(O)R ¹⁶ (OR ¹⁶ ), -S(O) ₂ OH,-S(O) ₂ N(R ²¹ ) ₂ , =O, and -CN; R ¹⁵ are each is selected from C _1-4 alkyl; R ¹⁶ is independently selected at each occurrence from hydrogen and C _1-6 alkyl; R ²¹ is independently selected at each occurrence from hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, and C _3-6 carbocycle, wherein the C _3-6 carbocycle is optionally substituted with one to six substituents independently selected from -OH, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, and =O. [0009] 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. [0010] 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. [0011] 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, scleroderma, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, checkpoint inhibitor-induced colitis, psoriasis, celiac disease, necrotizing enterocolitis, gastrointestinal injury resulting from toxic insults, environmental enteric dysfunction, allergy, food allergy, celiac sprue, childhood allergy, graft vs. host disease, irritable bowel syndrome, spontaneous bacterial peritonitis, ischemic colitis, sclerosing cholangitis, Alzheimer’s disease, Parkinson’s disease, cancer, colorectal cancer, depression, autism, or a combination thereof. [0012] 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. [0013] 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. [0014] 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.

[0015] 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.

[0016] 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.

DETAILED DESCRIPTION OF THE INVENTION

[0017] This disclosure is directed, at least in part, to AMPK activators useful for the treatment of conditions or disorders involving the gut-brain axis. 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.

[0018] Compounds disclosed herein directly activate AMPK in the intestine without systemic engagement. The preferred compounds are more potent, efficacious at lower doses, and have decreased systemic exposure compared to other previously-known AMPK activators. Definitions [0019] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes a plurality of such agents, and reference to “the cell” includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulas, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. [0020] The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. [0021] The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that in other embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, “consist of” or “consist essentially of” the described features. [0022] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below: [0023] As used herein, C ₁ -C _x includes C ₁ -C ₂ , C ₁ -C ₃ ... C ₁ -C _x . By way of example only, a group designated as “C ₁ -C ₄ ” indicates that there are one to four carbon atoms in the moiety, i.e., groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way of example only, “C ₁ -C4 alkyl” indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, iso- butyl, sec-butyl, and t-butyl. [0024] “Alkyl” refers to an optionally substituted straight-chain, or optionally substituted branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, or more preferably, from one to six carbon atoms, wherein an sp ³ -hybridized carbon of the alkyl residue is attached to the rest of the molecule by a single bond. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl- 1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3- methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl, and the like. Whenever it appears herein, a numerical range such as “C ₁ -C ₆ alkyl” means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a C ₁ -C ₁₀ alkyl, a C ₁ -C ₉ alkyl, a C ₁ -C ₈ alkyl, a C ₁ -C ₇ alkyl, a C ₁ -C ₆ alkyl, a C ₁ -C ₅ alkyl, a C ₁ -C ₄ alkyl, a C ₁ -C ₃ alkyl, a C ₁ -C ₂ alkyl, or a C ₁ alkyl. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted as described below by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR ^a , - SR ^a , -OC(O)R ^a , -OC(O)-OR ^f , -N(R ^a ) ₂ , -N ⁺ (R ^a ) ₃ , -C(O)R ^a , -C(O)OR ^a , -C(O)N(R ^a ) ₂ , - N(R ^a )C(O)OR ^f , -OC(O)-N(R ^a ) ₂ , -N(R ^a )C(O)R ^a , -N(R ^a )S(O) _t R ^f (where t is 1 or 2), -S(O) _t OR ^a (where t is 1 or 2), -S(O) _t R ^f (where t is 1 or 2) and -S(O) _t N(R ^a ) ₂ (where t is 1 or 2) where each R ^a is independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, and each R ^f is independently alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl. [0025] “Alkenyl” refers to an optionally substituted straight-chain, or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms, wherein an sp ² -hybridized carbon or an sp ³ -hybridized carbon of the alkenyl residue is attached to the rest of the molecule by a single bond. The group may be in either the cis or trans conformation about the double bond(s), and should be understood to include both isomers. Examples include, but are not limited to ethenyl (-CH=CH ₂ ), n-propenyl (-CH=CHCH ₃ , -CH ₂ CH=CH ₂ ), isopropenyl (-C(CH ₃ )=CH ₂ ), butenyl, 1,3-butadienyl and the like. Whenever it appears herein, a numerical range such as “C ₂ -C ₆ alkenyl” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. In some embodiments, the alkenyl is a C ₂ -C ₁₀ alkenyl, a C ₂ -C ₉ alkenyl, a C ₂ -C ₈ alkenyl, a C ₂ -C ₇ alkenyl, a C ₂ -C ₆ alkenyl, a C ₂ -C ₅ alkenyl, a C ₂ -C ₄ alkenyl, a C ₂ -C ₃ alkenyl, or a C ₂ alkenyl. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted as described below by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR ^a , -SR ^a , -OC(O)-R ^f , -OC(O)-OR ^f , -N(R ^a ) ₂ , -N ⁺ (R ^a ) ₃ , -C(O)R ^a , -C(O)OR ^a , -C(O)N(R ^a ) ₂ , - N(R ^a )C(O)OR ^f , -OC(O)-N(R ^a ) ₂ , -N(R ^a )C(O)R ^f , -N(R ^a )S(O) _t R ^f (where t is 1 or 2), -S(O) _t OR ^a (where t is 1 or 2), -S(O) _t R ^f (where t is 1 or 2) and -S(O) _t N(R ^a ) ₂ (where t is 1 or 2) where each R ^a is independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, and each R ^f is independently alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl. [0026] “Alkynyl” refers to an optionally substituted straight-chain or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms, wherein an sp-hybridized carbon or an sp ³ -hybridized carbon of the alkynyl residue is attached to the rest of the molecule by a single bond. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like. Whenever it appears herein, a numerical range such as “C ₂ -C ₆ alkynyl” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated. In some embodiments, the alkynyl is a C ₂ -C ₁₀ alkynyl, a C ₂ -C ₉ alkynyl, a C ₂ -C ₈ alkynyl, a C ₂ -C ₇ alkynyl, a C ₂ -C ₆ alkynyl, a C ₂ -C ₅ alkynyl, a C ₂ -C ₄ alkynyl, a C ₂ -C ₃ alkynyl, or a C2 alkynyl. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted as described below by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR ^a , -SR ^a , -OC(O)R ^a , -OC(O)-OR ^f , - N(R ^a ) ₂ , -N ⁺ (R ^a ) ₃ , -C(O)R ^a , -C(O)OR ^a , -C(O)N(R ^a ) ₂ , -N(R ^a )C(O)OR ^f , -OC(O)-N(R ^a ) ₂ , - N(R ^a )C(O)R ^f , -N(R ^a )S(O) _t R ^f (where t is 1 or 2), -S(O) _t OR ^a (where t is 1 or 2), -S(O) _t R ^f (where t is 1 or 2) and -S(O) _t N(R ^a ) ₂ (where t is 1 or 2) where each R ^a is independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, and each R ^f is independently alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl. [0027] “Alkylene” or “alkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon in the alkylene chain or through any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkylene group is optionally substituted as described below by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR ^a , -SR ^a , -OC(O)R ^a , -OC(O)-OR ^f , -N(R ^a ) ₂ , -N ⁺ (R ^a ) ₃ , -C(O)R ^a , -C(O)OR ^a , -C(O)N(R ^a ) ₂ , -N(R ^a )C(O)OR ^f , -OC(O)-N(R ^a ) ₂ , -N(R ^a )C(O)R ^f , -N(R ^a )S(O) _t R ^f (where t is 1 or 2), -S(O) _t OR ^a (where t is 1 or 2), -S(O) _t R ^f (where t is 1 or 2) and -S(O) _t N(R ^a ) ₂ (where t is 1 or 2) where each R ^a is independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, and each R ^f is independently alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl. [0028] “Alkenylene” or “alkenylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. Unless stated otherwise specifically in the specification, an alkenylene group is optionally substituted as described below by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR ^a , -SR ^a , -OC(O)-R ^f , -OC(O)-OR ^f , -N(R ^a ) ₂ , -N ⁺ (R ^a ) ₃ , -C(O)R ^a , -C(O)OR ^a , -C(O)N(R ^a ) ₂ , - N(R ^a )C(O)OR ^f , -OC(O)-N(R ^a ) ₂ , -N(R ^a )C(O)R ^f , -N(R ^a )S(O) _t R ^f (where t is 1 or 2), -S(O) _t OR ^a (where t is 1 or 2), -S(O) _t R ^f (where t is 1 or 2) and -S(O) _t N(R ^a ) ₂ (where t is 1 or 2) where each R ^a is independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, and each R ^f is independently alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl. [0029] “Alkynylene” or “alkynylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and having from two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. Unless stated otherwise specifically in the specification, an alkynylene group is optionally substituted as described below by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, - OR ^a , -SR ^a , -OC(O)R ^a , -OC(O)-OR ^f , -N(R ^a ) ₂ , -N ⁺ (R ^a ) ₃ , -C(O)R ^a , -C(O)OR ^a , -C(O)N(R ^a ) ₂ , - N(R ^a )C(O)OR ^f , -OC(O)-N(R ^a ) ₂ , -N(R ^a )C(O)R ^f , -N(R ^a )S(O) _t R ^f (where t is 1 or 2), -S(O) _t OR ^a (where t is 1 or 2), -S(O) _t R ^f (where t is 1 or 2) and -S(O) _t N(R ^a ) ₂ (where t is 1 or 2) where each R ^a is independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, and each R ^f is independently alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl. [0030] “Alkoxy” or “alkoxyl” refers to a radical bonded through an oxygen atom of the formula –O–alkyl, where alkyl is an alkyl chain as defined above. [0031] “Aryl” refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from 6 to 18 carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) π–electron system in accordance with the Hückel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. In some embodiments, the aryl is a C ₆ -C ₁₀ aryl. In some embodiments, the aryl is a phenyl. Unless stated otherwise specifically in the specification, the term “aryl” or the prefix “ar-“ (such as in “aralkyl”) is meant to include aryl radicals optionally substituted as described below by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -R ^b -OR ^a , -R ^b -SR ^a , -R ^b -OC(O)-R ^a , -R ^b -OC(O)-OR ^f , -R ^b -OC(O)-N(R ^a ) ₂ , -R ^b -N(R ^a ) ₂ , -R ^b -N ⁺ (R ^a ) ₃ , -R ^b -C(O)R ^a , -R ^b - C(O)OR ^a , -R ^b -C(O)N(R ^a ) ₂ , -R ^b -O-R ^c -C(O)N(R ^a ) ₂ , -R ^b -N(R ^a )C(O)OR ^f , -R ^b -N(R ^a )C(O)R ^a , -R ^b - N(R ^a )S(O) _t R ^f (where t is 1 or 2), -R ^b -S(O) _t OR ^a (where t is 1 or 2), -R ^b -S(O) _t R ^f (where t is 1 or 2) and -R ^b -S(O) _t N(R ^a ) ₂ (where t is 1 or 2), where each R ^a is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, R ^f is independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, each R ^b is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R ^c is a straight or branched alkylene or alkenylene chain. [0032] An “arylene” refers to a divalent radical derived from an “aryl” group as described above linking the rest of the molecule to a radical group. The arylene is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In some embodiments, the arylene is a phenylene. Unless stated otherwise specifically in the specification, an arylene group is optionally substituted as described above for an aryl group. [0033] “Cycloalkyl” refers to a stable, partially or fully saturated, monocyclic or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C ₃ -C ₁₅ cycloalkyl), from three to ten carbon atoms (C ₃ -C ₁₀ cycloalkyl), from three to eight carbon atoms (C ₃ -C ₈ cycloalkyl), from three to six carbon atoms (C ₃ -C ₆ cycloalkyl), from three to five carbon atoms (C ₃ -C ₅ cycloalkyl), or three to four carbon atoms (C ₃ -C ₄ cycloalkyl). In some embodiments, the cycloalkyl is a 3- to 6-membered cycloalkyl. In some embodiments, the cycloalkyl is a 5- to 6-membered cycloalkyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls or carbocycles include, for example, adamantyl, norbornyl, decalinyl, bicyclo[1.1.1]pentyl, bicyclo[3.3.0]octyl, bicyclo[4.3.0]nonyl, cis-decalyl, trans-decalyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, and the like. Unless otherwise stated specifically in the specification, the term “cycloalkyl” is meant to include cycloalkyl radicals optionally substituted as described below by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -R ^b -OR ^a , -R ^b -SR ^a , -R ^b -OC(O)-R ^a , -R ^b - OC(O)-OR ^f , -R ^b -OC(O)-N(R ^a ) ₂ , -R ^b -N(R ^a ) ₂ , -R ^b -N ⁺ (R ^a ) ₃ , -R ^b -C(O)R ^a , -R ^b -C(O)OR ^a , -R ^b - C(O)N(R ^a ) ₂ , -R ^b -O-R ^c -C(O)N(R ^a ) ₂ , -R ^b -N(R ^a )C(O)OR ^f , -R ^b -N(R ^a )C(O)R ^a , -R ^b -N(R ^a )S(O) _t R ^f (where t is 1 or 2), -R ^b -S(O) _t OR ^a (where t is 1 or 2), -R ^b -S(O) _t R ^f (where t is 1 or 2) and -R ^b - S(O) _t N(R ^a ) ₂ (where t is 1 or 2), where each R ^a is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, R ^f is independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, each R ^b is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R ^c is a straight or branched alkylene or alkenylene chain. [0034] A “cycloalkylene” refers to a divalent radical derived from a “cycloalkyl” group as described above linking the rest of the molecule to a radical group. The cycloalkylene is attached to the rest of the molecule through a single bond and to the radical group through a single bond. Unless stated otherwise specifically in the specification, a cycloalkylene group is optionally substituted as described above for a cycloalkyl group. [0035] “Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro. [0036] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. [0037] “Fluoroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. [0038] “Haloalkoxy” or “haloalkoxyl” refers to an alkoxyl radical, as defined above, that is substituted by one or more halo radicals, as defined above. [0039] “Fluoroalkoxy” or “fluoroalkoxyl” refers to an alkoxy radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethoxy, difluoromethoxy, fluoromethoxy, and the like. [0040] “Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N(alkyl)-), sulfur, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C ₁ -C ₆ heteroalkyl. In one aspect, a heteroalkyl is a polyethylene glycol (PEG). In some embodiments, a C ₁ -C ₁₀ heteroalkyl comprises from 1 to 5 PEG groups. In some embodiments, a C ₁ -C ₁₀ heteroalkyl comprises from 1 to 3 PEG groups. [0041] “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyl radicals, as defined above, e.g., hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1,2-dihydroxyethyl, 2,3-dihydroxypropyl, 2,3,4,5,6- pentahydroxyhexyl, and the like. [0042] “Heterocycloalkyl” refers to a stable 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 6- membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3- dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. More preferably, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e., skeletal atoms of the heterocycloalkyl ring). Unless stated otherwise specifically in the specification, the term “heterocycloalkyl” is meant to include heterocycloalkyl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -R ^b - OR ^a , -R ^b -SR ^a , -R ^b -OC(O)-R ^a , -R ^b -OC(O)-OR ^f , -R ^b -OC(O)-N(R ^a ) ₂ , -R ^b -N(R ^a ) ₂ , -R ^b -N ⁺ (R ^a ) ₃ , -R ^b - C(O)R ^a , -R ^b -C(O)OR ^a , -R ^b -C(O)N(R ^a ) ₂ , -R ^b -O-R ^c -C(O)N(R ^a ) ₂ , -R ^b -N(R ^a )C(O)OR ^f , -R ^b - N(R ^a )C(O)R ^a , -R ^b -N(R ^a )S(O) _t R ^f (where t is 1 or 2), -R ^b -S(O) _t OR ^a (where t is 1 or 2), -R ^b - S(O) _t R ^f (where t is 1 or 2) and -R ^b -S(O) _t N(R ^a ) ₂ (where t is 1 or 2), where each R ^a is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, R ^f is independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, each R ^b is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R ^c is a straight or branched alkylene or alkenylene chain. [0043] “N-heterocycloalkyl” refers to a heterocycloalkyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocycloalkyl radical to the rest of the molecule is through a nitrogen atom in the heterocycloalkyl radical. An N-heterocycloalkyl radical is optionally substituted as described above for heterocycloalkyl radicals. [0044] “C-heterocycloalkyl” refers to a heterocycloalkyl radical as defined above and where the point of attachment of the heterocycloalkyl radical to the rest of the molecule is through a carbon atom in the heterocycloalkyl radical. A C-heterocycloalkyl radical is optionally substituted as described above for heterocycloalkyl radicals. [0045] A “heterocycloalkylene” refers to a divalent radical derived from a “heterocycloalkyl” group as described above linking the rest of the molecule to a radical group. The heterocycloalkylene is attached to the rest of the molecule through a single bond and to the radical group through a single bond. Unless stated otherwise specifically in the specification, a heterocycloalkylene group is optionally substituted as described above for a heterocycloalkyl group. [0046] “Heteroaryl” refers to a radical derived from a 5- to 18-membered aromatic ring radical that comprises one to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, the heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) π–electron system in accordance with the Hückel theory. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a monocyclic heteroaryl, or a monocyclic 5- or 6- membered heteroaryl. In some embodiments, the heteroaryl is a 6,5-fused bicyclic heteroaryl. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Unless stated otherwise specifically in the specification, the term “heteroaryl” is meant to include heteroaryl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, oxo, thioxo, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -R ^b -OR ^a , -R ^b -SR ^a , -R ^b -OC(O)-R ^a , -R ^b -OC(O)-OR ^f , -R ^b -OC(O)- N(R ^a ) ₂ , -R ^b -N(R ^a ) ₂ , -R ^b -N ⁺ (R ^a ) ₃ , -R ^b -C(O)R ^a , -R ^b -C(O)OR ^a , -R ^b -C(O)N(R ^a ) ₂ , -R ^b -O-R ^c - C(O)N(R ^a ) ₂ , -R ^b -N(R ^a )C(O)OR ^f , -R ^b -N(R ^a )C(O)R ^a , -R ^b -N(R ^a )S(O) _t R ^f (where t is 1 or 2), -R ^b - S(O) _t OR ^a (where t is 1 or 2), -R ^b -S(O) _t R ^f (where t is 1 or 2) and -R ^b -S(O)tN(R ^a ) ₂ (where t is 1 or 2), where each R ^a is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, R ^f is independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, each R ^b is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R ^c is a straight or branched alkylene or alkenylene chain. [0047] A “heteroarylene” refers to a divalent radical derived from a “heteroaryl” group as described above linking the rest of the molecule to a radical group. The heteroarylene is attached to the rest of the molecule through a single bond and to the radical group through a single bond. Unless stated otherwise specifically in the specification, a heteroarylene group is optionally substituted as described above for a heteroaryl group. [0048] The term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above. Further, an optionally substituted group may be unsubstituted (e.g., -CH ₂ CH ₃ ), fully substituted (e.g., -CF ₂ CF ₃ ), mono- substituted (e.g., -CH ₂ CH ₂ F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH ₂ CHF ₂ , -CH ₂ CF ₃ , -CF ₂ CH ₃ , -CFHCHF ₂ , etc.). It will be understood by those skilled in the art with respect to any group containing one or more substituents that such groups are not intended to introduce any substitution or substitution patterns (e.g., substituted alkyl includes optionally substituted cycloalkyl groups, which in turn are defined as including optionally substituted alkyl groups, potentially ad infinitum) that are sterically impractical and/or synthetically non-feasible. [0049] The term “modulate” or “modulating” or “modulation” refers to an increase or decrease in the amount, quality, or effect of a particular activity, function or molecule. By way of illustration and not limitation, activators, agonists, partial agonists, inverse agonists, antagonists, inhibitors, and allosteric modulators of an enzyme are modulators of the enzyme. [0050] The term “agonism” as used herein refers to the activation of a receptor or enzyme by a modulator, or agonist, to produce a biological response. [0051] The term “agonist” or “activator” as used herein refers to a modulator that binds to a receptor or target enzyme and activates the receptor or enzyme to produce a biological response. By way of example, “AMPK activator” can be used to refer to a compound that exhibits an EC ₅₀ with respect to AMPK activity of no more than about 100 μM, as measured in the pAMPK1 kinase activation assay. In some embodiments, the term “agonist” includes super agonists, full agonists or partial agonists. [0052] The term “super agonist” as used herein refers to a modulator that is capable of producing a maximal response greater than the endogenous agonist for the target receptor or enzyme, and thus has an efficacy of more than 100%. [0053] The term “full agonist” refers to a modulator that binds to and activates a receptor or target enzyme with the maximum response that an endogenous agonist can elicit at the receptor or enzyme. [0054] The term “partial agonist” refers to a modulator that binds to and activates a receptor or target enzyme, but has partial efficacy, that is, less than the maximal response, at the receptor or enzyme relative to a full agonist. [0055] The term “positive allosteric modulator” refers to a modulator that binds to a site distinct from the orthosteric binding site and enhances or amplifies the effect of an agonist. [0056] The term “antagonism” or “inhibition” as used herein refers to the inactivation of a receptor or target enzyme by a modulator, or antagonist. Antagonism of a receptor, for example, is when a molecule binds to the receptor or target enzyme and does not allow activity to occur. [0057] The term “antagonist” or “neutral antagonist” or “inhibitor” as used herein refers to a modulator that binds to a receptor or target enzyme and blocks a biological response. An antagonist has no activity in the absence of an agonist or inverse agonist but can block the activity of either, causing no change in the biological response. [0058] The term “inverse agonist” refers to a modulator that binds to the same receptor or target enzyme as an agonist but induces a pharmacological response opposite to that agonist, i.e., a decrease in biological response. [0059] The term “negative allosteric modulator” refers to a modulator that binds to a site distinct from the orthosteric binding site and reduces or dampens the effect of an agonist. [0060] As used herein, “EC ₅₀ ” is intended to refer to the concentration of a substance (e.g., a compound or a drug) that is required for 50% activation or enhancement of a biological process. In some instances, EC ₅₀ refers to the concentration of agonist that provokes a response halfway between the baseline and maximum response in an in vitro assay. In some embodiments as used herein, EC ₅₀ refers to the concentration of an activator (e.g., an AMPK activator) that is required for 50% activation of AMPK. [0061] As used herein, “IC ₅₀ ” is intended to refer to the concentration of a substance (e.g., a compound or a drug) that is required for 50% inhibition of a biological process. For example, IC ₅₀ refers to the half maximal (50%) inhibitory concentration (IC) of a substance as determined in a suitable assay. In some instances, an IC ₅₀ is determined in an in vitro assay system. In some embodiments as used herein, IC ₅₀ refers to the concentration of a modulator (e.g., an antagonist or inhibitor) that is required for 50% inhibition of a receptor or a target enzyme. [0062] The terms “subject,” “individual,” and “patient” are used interchangeably. These terms encompass mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. [0063] The term “gut-restricted” as used herein refers to a compound, e.g., an AMPK activator, that is predominantly active in the gastrointestinal system. In some embodiments, the biological activity of the gut-restricted compound, e.g., a gut-restricted AMPK activator, is restricted to the gastrointestinal system. In some embodiments, gastrointestinal concentration of a gut-restricted modulator, e.g., a gut-restricted AMPK activator, is higher than the IC ₅₀ value or the EC ₅₀ value of the gut-restricted modulator against its receptor or target enzyme, e.g., AMPK, while the plasma levels of said gut-restricted modulator, e.g., gut-restricted AMPK activator, are lower than the IC ₅₀ value or the EC ₅₀ value of the gut-restricted modulator against its receptor or target enzyme, e.g., AMPK. In some embodiments, the gut-restricted compound, e.g., a gut-restricted AMPK activator, is non-systemic. In some embodiments, the gut-restricted compound, e.g., a gut-restricted AMPK activator, is a non-absorbed compound. In other embodiments, the gut- restricted compound, e.g., a gut-restricted AMPK activator, is absorbed, but is rapidly metabolized to metabolites that are significantly less active than the modulator itself toward the target receptor or enzyme, i.e., a “soft drug.” In other embodiments, the gut-restricted compound, e.g., a gut-restricted AMPK activator, is minimally absorbed and rapidly metabolized to metabolites that are significantly less active than the modulator itself toward the target receptor or enzyme. In some embodiments, the gut-restricted AMPK activator has high efflux. In other embodiments, the gut-restricted AMPK activator is a substrate for one or more intestinal efflux transporters such as P-gp (MDR1), BCRP, or MRP2. [0064] In some embodiments, the gut-restricted modulator, e.g., a gut-restricted AMPK activator, is non-systemic but is instead localized to the gastrointestinal system. For example, the modulator, e.g., a gut-restricted AMPK activator, may be present in high levels in the gut, but low levels in serum. In some embodiments, the systemic exposure of a gut-restricted modulator, e.g., a gut-restricted AMPK activator, is, for example, less than 100, less than 50, less than 20, less than 10, or less than 5 nM, bound or unbound, in blood serum. In some embodiments, the intestinal exposure of a gut-restricted modulator, e.g., a gut-restricted AMPK activator, is, for example, greater than 1000, 5000, 10000, 50000, 100000, or 500000 nM. In some embodiments, a modulator, e.g., a gut-restricted AMPK activator, is gut-restricted due to poor absorption of the modulator itself, or because of absorption of the modulator which is rapidly metabolized in serum resulting in low systemic circulation, or due to both poor absorption and rapid metabolism in the serum. In some embodiments, a modulator, e.g., a gut-restricted AMPK activator, is covalently bonded to a kinetophore, optionally through a linker, which changes the pharmacokinetic profile of the modulator. [0065] In other embodiments, the gut-restricted modulator is a soft drug. The term “soft drug” as used herein refers to a modulator that is biologically active but is rapidly metabolized to metabolites that are significantly less active than the modulator itself toward the target receptor. In some embodiments, the gut-restricted modulator is a soft drug that is rapidly metabolized in the blood to significantly less active metabolites. In some embodiments, the gut-restricted modulator is a soft drug that is rapidly metabolized in the liver to significantly less active metabolites. In some embodiments, the gut-restricted modulator is a soft drug that is rapidly metabolized in the blood and the liver to significantly less active metabolites. In some embodiments, the gut-restricted modulator is a soft drug that has low systemic exposure. In some embodiments, the biological activity of the metabolite(s) is/are 10-fold, 20-fold, 50-fold, 100-fold, 500-fold, or 1000-fold lower than the biological activity of the soft drug gut-restricted modulator. [0066] The term “kinetophore” as used herein refers to a structural unit tethered to a small molecule modulator, e.g., an AMPK activator, optionally through a linker, which makes the whole molecule larger and increases the polar surface area while maintaining biological activity of the small molecule modulator. The kinetophore influences the pharmacokinetic properties, for example solubility, absorption, distribution, rate of elimination, and the like, of the small molecule modulator, e.g., an AMPK activator, and has minimal changes to the binding to or association with a receptor or target enzyme. The defining feature of a kinetophore is not its interaction with the target, for example an enzyme, but rather its effect on specific physiochemical characteristics of the modulator to which it is attached, e.g., an AMPK activator. In some instances, kinetophores are used to restrict a modulator, e.g., an AMPK activator, to the gut. [0067] The term “linked” as used herein refers to a covalent linkage between a modulator, e.g., an AMPK activator, and a kinetophore. The linkage can be through a covalent bond, or through a “linker.” As used herein, “linker” refers to one or more bifunctional molecules which can be used to covalently bonded to the modulator, e.g., an AMPK activator, and kinetophore. In some embodiments, the linker is attached to any part of the modulator, e.g., an AMPK activator, so long as the point of attachment does not interfere with the binding of the modulator to its receptor or target enzyme. In some embodiments, the linker is non-cleavable. In some embodiments, the linker is cleavable. In some embodiments, the linker is cleavable in the gut. In some embodiments, cleaving the linker releases the biologically active modulator, e.g., an AMPK activator, in the gut. [0068] The term “gastrointestinal system” (GI system) or “gastrointestinal tract” (GI tract) as used herein, refers to the organs and systems involved in the process of digestion. The gastrointestinal tract includes the esophagus, stomach, small intestine, which includes the duodenum, jejunum, and ileum, and large intestine, which includes the cecum, colon, and rectum. In some embodiments herein, the GI system refers to the “gut,” meaning the stomach, small intestines, and large intestines or to the small and large intestines, including, for example, the duodenum, jejunum, and/or colon. Gut-Brain Axis [0069] The gut-brain axis refers to the bidirectional biochemical signaling that connects the gastrointestinal tract (GI tract) with the central nervous system (CNS) through the peripheral nervous system (PNS) and endocrine, immune, and metabolic pathways. [0070] In some instances, the gut-brain axis comprises the GI tract; the PNS including the dorsal root ganglia (DRG) and the sympathetic and parasympathetic arms of the autonomic nervous system including the enteric nervous system and the vagus nerve; the CNS; and the neuroendocrine and neuroimmune systems including the hypothalamic–pituitary–adrenal axis (HPA axis). The gut-brain axis is important for maintaining homeostasis of the body and is regulated and modulates physiology through the central and peripheral nervous systems and endocrine, immune, and metabolic pathways. [0071] The gut-brain axis modulates several important aspects of physiology and behavior. Modulation by the gut-brain axis occurs via hormonal and neural circuits. Key components of these hormonal and neural circuits of the gut-brain axis include highly specialized, secretory intestinal cells that release hormones (enteroendocrine cells or EECs), the autonomic nervous system (including the vagus nerve and enteric nervous system), and the central nervous system. These systems work together in a highly coordinated fashion to modulate physiology and behavior. [0072] Defects in the gut-brain axis are linked to a number of diseases, including those of high unmet need. Diseases and conditions affected by the gut-brain axis, include 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, celiac disease, and enteritis, including chemotherapy-induced enteritis or radiation-induced enteritis; 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. Adenosine 5'–Monophosphate–Activated Protein Kinase (AMPK) in the Gut-Brain Axis [0073] Adenosine 5'–monophosphate–activated protein kinase (AMPK) is a serine/threonine kinase and is evolutionarily conserved from yeast to mammals. In some instances, AMPK is a heterotrimeric protein complex that is formed by one α (α1 or α2), one β (β1 or β2), and one γ (γ1, γ2, or γ3) subunit. Due to the presence of isoforms of its components, there are 12 versions of AMPK (AMPK1, AMPK2, etc., through AMPK12). In some instances, 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. In some instances, activated AMPK phosphorylates downstream substrates to promote catabolism and impede anabolism, leading to ATP production and energy restoration. In some instances, 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. In some instances, AMPK activation leads to lower hepatic glucose production and plasma glucose levels. Thus, in some instances, AMPK activation can act as a therapeutic agent to treat various metabolic diseases. [0074] In some instances, 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. In some instances, AMPK is essential for proper intestinal health. In some instances, AMPK activation enhances paracellular junctions, nutrient transporters, autophagy and apoptosis, and suppresses inflammation and carcinogenesis in the intestine. [0075] In some embodiments, this disclosure provides AMPK activators that can be broadly used for multiple conditions and 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 a central nervous system (CNS) disorder 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, celiac disease, and enteritis, including chemotherapy-induced enteritis or radiation-induced enteritis; 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. In some embodiments, the condition or disorder is a metabolic disorder. In some embodiments, the condition or disorder is type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia, nonalcoholic steatohepatitis, or hypertension. 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 inflammatory bowel disease including ulcerative colitis, Crohn’s disease and checkpoint inhibitor-induced colitis. In some embodiments, the condition or disorder is celiac disease, enteritis including chemotherapy-induced enteritis or radiation-induced enteritis, necrotizing enterocolitis; or gastrointestinal injury resulting from toxic insults such as radiation or chemotherapy. In some embodiments, the condition or disorder is 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, opioid-induced constipation; gastroparesis; or nausea and vomiting. 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, scleroderma, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, checkpoint inhibitor-induced colitis, psoriasis, celiac disease, necrotizing enterocolitis, gastrointestinal injury resulting from toxic insults, environmental enteric dysfunction, allergy, food allergy, celiac sprue, childhood allergy, graft vs. host disease, irritable bowel syndrome, spontaneous bacterial peritonitis, ischemic colitis, sclerosing cholangitis, Alzheimer’s disease, Parkinson’s disease, cancer, colorectal cancer, depression, autism, or a combination thereof. Adenosine 5'–Monophosphate–Activated Protein Kinase (AMPK) and the Gut Barrier [0076] In some instances, the gut mucosa maintains immune homeostasis under physiological circumstances by serving as a barrier that restricts access of microbes, diverse microbial products, food antigens and toxins in the lumen of the gut to rest of the body. In some instances, the gut barrier is comprised of a single layer of epithelial cells, bound by cell-cell junctions, and a layer of mucin that covers the epithelium. In some instances, loosening of the junctions induced either by exogenous or endogenous stressors, compromises the gut barrier and allows microbes and antigens to leak through and encounter the host immune system, thereby generating inflammation and systemic endotoxemia. In some instances, an impaired gut barrier (e.g. a leaky gut) is a major contributor to the initiation and/or progression of various chronic diseases including, but not limited to, metabolic endotoxemia, type 2 diabetes, fatty liver disease, obesity, atherosclerosis, inflammatory bowel diseases, and cancers. In some instances, activation of AMPK, which is associated with the maintenance of tight junction in colonic epithelium, controls the progression of colitis. In some instances, expression and assembly of tight junctions is dependent on AMPK activity.

[0077] In some embodiments, the present disclosure provides methods effective to strengthen/protect the gut barrier and reduce and/or prevent the progression of chronic diseases. The gut barrier is a critical frontier that separates microbes and antigens in the lumen of the gut from the rest of the body; a compromised “leaky” gut barrier is frequently associated with systemic infection and inflammation, which is a key contributor to many chronic allergic, infectious, metabolic and autoimmune diseases such as obesity, diabetes, inflammatory bowel diseases, food allergy, and metabolic endotoxemia.

[0078] In some embodiments, this disclosure provides AMPK activators that can be broadly used for multiple conditions and disorders associated with AMPK. In some embodiments, the condition or disorder is associated with systemic infection and inflammation from having a leaky gut barrier. In some embodiments, a leaky gut barrier can fuel the progression of multiple chronic diseases, including but not limited to: 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, checkpoint inhibitor-induced colitis, 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.

[0079] In some instances, injury to the intestinal mucosa is frequently a dose-limiting complication of radiotherapy and chemotherapy. Approaches to limit the damage to the intestine during radiation and chemotherapy have been largely ineffective. In some embodiments described herein, AMPK activators are useful for the treatment of gastrointestinal injury. In some embodiments, AMPK activators are useful for the treatment of gastrointestinal injury resulting from toxic insult. 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.

Gut-Restricted Modulators

[0080] In some instances, there are concerns associated with systemic AMPK activation, for example, AMPK activation in the heart. For example, in some instances, activating mutations in the AMPK γ2-subunit lead to PRKAG2 cardiomyopathy. In other instances, systemic AMPK activation results in cardiac hypertrophy and increased cardiac glycogen. In some instances, given the potential association of adverse effects with systemic AMPK activation, tissue selective AMPK activation is an attractive approach for developing AMPK activators to treat disease. [0081] In some embodiments, the AMPK activator is gut-restricted. In some embodiments, the AMPK activator is designed to be substantially non-permeable or substantially non-bioavailable in the blood stream. In some embodiments, the AMPK activator is designed to activate AMPK activity in the gut and is substantially non-systemic. In some embodiments, the AMPK activator has low systemic exposure. [0082] In some embodiments, a gut-restricted AMPK activator has low oral bioavailability. In some embodiments, a gut-restricted AMPK activator has <40% oral bioavailability, <30% oral bioavailability, <20% oral bioavailability, < 10% oral bioavailability, < 8% oral bioavailability, < 5% oral bioavailability, < 3% oral bioavailability, or < 2% oral bioavailability. [0083] In some embodiments, the unbound plasma levels of a gut-restricted AMPK activator are lower than the EC ₅₀ value of the AMPK activator against AMPK. In some embodiments, the unbound plasma levels of a gut-restricted AMPK activator are significantly lower than the EC ₅₀ value of the gut-restricted AMPK activator against AMPK. In some embodiments, the unbound plasma levels of the AMPK activator are 2-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, or 100-fold lower than the EC ₅₀ value of the gut-restricted AMPK activator against AMPK. [0084] In some embodiments, a gut-restricted AMPK activator has low systemic exposure. In some embodiments, the systemic exposure of a gut-restricted AMPK activator is, for example, less than 500, less than 200, less than 100, less than 50, less than 20, less than 10, or less than 5 nM, bound or unbound, in blood serum. In some embodiments, the systemic exposure of a gut- restricted AMPK activator is, for example, less than 500, less than 200, less than 100, less than 50, less than 20, less than 10, or less than 5 ng/mL, bound or unbound, in blood serum. [0085] In some embodiments, a gut-restricted AMPK activator has high intestinal exposure. In some embodiments, the intestinal exposure of a gut-restricted AMPK activator is, for example, greater than 1, 5, 10, 50, 100, 250 or 500 µM. [0086] In some embodiments, a gut-restricted AMPK activator has high exposure in the colon. In some embodiments, the colon exposure of a gut-restricted AMPK activator is, for example, greater than 1, 5, 10, 50, 100, 250 or 500 µM. In some embodiments, the colon exposure of a gut-restricted AMPK activator is, for example, greater than 100 µM. [0087] In some embodiments, a gut-restricted AMPK activator has low permeability. In some embodiments, a gut-restricted AMPK activator has low intestinal permeability. In some embodiments, the permeability of a gut-restricted AMPK activator is, for example, less than 5.0×10 ^-6 cm/s, less than 2.0×10 ^-6 cm/s, less than 1.5×10 ^-6 cm/s, less than 1.0×10 ^-6 cm/s, less than 0.75×10 ^-6 cm/s, less than 0.50×10 ^-6 cm/s, less than 0.25×10 ^-6 cm/s, less than 0.10×10 ^-6 cm/s, or less than 0.05×10 ^-6 cm/s. [0088] In some embodiments, a gut-restricted AMPK activator has low absorption. In some embodiments, the absorption of a gut-restricted AMPK activator is less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, or less than 1%. [0089] In some embodiments, a gut-restricted AMPK activator has high plasma clearance. In some embodiments, a gut-restricted AMPK activator is undetectable in plasma in less than 8 hours, less than 6 hours, less than 4 hours, less than 3 hours, less than 120 min, less than 90 min, less than 60 min, less than 45 min, less than 30 min, or less than 15 min. [0090] In some embodiments, a gut-restricted AMPK activator is rapidly metabolized upon administration. In some embodiments, a gut-restricted AMPK activator has a short half-life. In some embodiments, the half-life of a gut-restricted AMPK activator is less than less than 8 hours, less than 6 hours, less than 4 hours, less than 3 hours, less than 120 min, less than 90 min, less than 60 min, less than 45 min, less than 30 min, or less than 15 min. In some embodiments, the metabolites of a gut-restricted AMPK activator have rapid clearance. In some embodiments, the metabolites of a gut-restricted AMPK activator are undetectable in less than 8 hours, less than 6 hours, less than 4 hours, less than 3 hours, less than 120 min, less than 90 min, less than 60 min, less than 45 min, less than 30 min, or less than 15 min. In some embodiments, the metabolites of a gut-restricted AMPK activator have low bioactivity. In some embodiments, the EC ₅₀ value of the metabolites of a gut-restricted AMPK activator is 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 100-fold, 500-fold, or 1000-fold higher than the EC ₅₀ value of the gut-restricted AMPK activator against AMPK. In some embodiments, the metabolites of a gut-restricted AMPK activator have rapid clearance and low bioactivity. [0091] In some embodiments, the gut-restricted AMPK activator has high efflux. In some embodiments, the gut-restricted AMPK activator is a substrate for one or more intestinal efflux transporters such as P-gp (MDR1), BCRP, or MRP2. In some embodiments, the efflux of the gut-restricted AMPK activator as measured by the B-A/A-B ratio in a cell line such as Caco-2 or MDCK with or without over-expression of one or more efflux transporters is, for example, greater than 2, greater than 5, greater than 10, greater than 25, or greater than 50. [0092] In some embodiments of the methods described herein, the AMPK activator is gut- restricted. In some embodiments, the AMPK activator is a gut-restricted AMPK agonist. In some embodiments, the AMPK activator is a gut-restricted AMPK super agonist. In some embodiments, the AMPK activator is a gut-restricted AMPK full agonist. In some embodiments, the AMPK activator is a gut-restricted AMPK partial agonist. In some embodiments, the AMPK activator is covalently bonded to a kinetophore. In some embodiments, the AMPK activator is covalently bonded to a kinetophore through a linker. Compounds [0093] Disclosed herein, in some embodiments, is a compound of Formula (I): or pharmaceutically acceptable salt thereof, wherein: X is -O- or -S-; Y is -N- or -CR ⁶ -; R ¹ , R ² , R ³ , and R ⁴ , are each independently selected at each occurrence from halogen, hydroxyl, C _1-4 alkyl, -CN, and C _1-4 haloalkyl; n is selected from 0, 1, 2, 3, and 4; o is selected from 0, 1, 2, 3, and 4; p is selected from 0, 1, and 2; q is selected from 0, 1, 2, 3, and 4; R ⁵ is selected from hydrogen and C _1-4 alkyl; R ⁶ is selected from hydrogen, halogen, C _1-4 alkyl, and C _1-4 haloalkyl; D is selected from -P(O)(OR ¹¹ ) ₂ , -P(O)R ¹¹ (OR ¹¹ ), -S(O) ₂ OH, and -L-K; L is selected from ^λ -(C(R ¹³ ) ₂ ) _r -, ^λ -O(C(R ¹³ ) ₂ ) _r -, ^λ -N(R ¹² )(C(R ¹³ ) ₂ ) _s -, ^λ -C(O)O-, ^λ -OC(O)-, ^λ - C(O)N(R ¹² )-, ^λ -N(R ¹² )C(O)-, ^λ -N(R ¹² )S(O) ₂ -, ^λ -S(O) ₂ N(R ¹² )-, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, wherein ^λ denotes the connection to K; r is selected from 1, 2, and 3; s is selected from 0, 1, 2, and 3; K is selected from (i) and (ii): (i) C _1-10 alkyl or C _1-10 heteroalkyl, each of which is optionally substituted with one to six substituents independently selected from: halogen, -OR ¹⁴ , -SR ¹⁴ , -N(R ¹⁴ ) ₂ , - N ⁺ (R ¹⁵ ) ₃ , -C(O)R ¹⁴ , -C(O)OR ¹⁴ , -OC(O)R ¹⁴ , -OC(O)N(R ¹⁴ ) ₂ , -C(O)N(R ¹⁴ ) ₂ , - N(R ¹⁴ )C(O)R ¹⁴ , -N(R ¹⁴ )C(O)OR ¹⁴ , -N(R ¹⁴ )C(O)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )S(O) ₂ (R ¹⁴ ), - S(O)R ¹⁴ , -S(O) ₂ R ¹⁴ , -S(O) ₂ N(R ¹⁴ ) ₂ , =O, -CN, -P(O)(OR ¹⁶ ) ₂ , -P(O)R ¹⁶ (OR ¹⁶ ), - S(O) ₂ OH, C _3-10 carbocycle and 3- to 10-membered heterocycle, wherein each C _3-10 carbocycle and 3- to 10-membered heterocycle is optionally substituted with one to six substituents independently selected from halogen, C _1-6 alkyl, -OR ¹⁴ , =O, and -S(O) ₂ OH; and (ii) C _3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one to six substituents independently selected from halogen, -OR ¹⁴ , - SR ¹⁴ , -N(R ¹⁴ ) ₂ , -N ⁺ (R ¹⁵ ) ₃ , -C(O)R ¹⁴ , -C(O)OR ¹⁴ , -OC(O)R ¹⁴ , -OC(O)N(R ¹⁴ ) _2, - C(O)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )C(O)R ¹⁴ , -N(R ¹⁴ )C(O)OR ¹⁴ , -N(R ¹⁴ )C(O)N(R ¹⁴ ) ₂ , - N(R ¹⁴ )S(O) ₂ (R ¹⁴ ), -S(O)R ¹⁴ , -S(O) ₂ R ¹⁴ , -S(O) ₂ N(R ¹⁴ ) ₂ , -P(O)(OR ¹⁶ ) ₂ , - P(O)R ¹⁶ (OR ¹⁶ ), -S(O) ₂ OH, =O, -CN, C _1-10 alkyl, and C _1-10 heteroalkyl, wherein each C _1-10 alkyl and C _1-10 heteroalkyl is optionally substituted with one to six substituents independently selected from halogen, -OR ¹⁴ , -SR ¹⁴ , - N(R ¹⁴ ) ₂ , -N ⁺ (R ¹⁵ ) ₃ , -C(O)OR ¹⁴ , -P(O)(OR ¹⁶ ) ₂ , -P(O)R ¹⁶ (OR ¹⁶ ), -S(O) ₂ R ¹⁶ , - S(O) ₂ OH, and =O; R ¹¹ is independently selected at each occurrence from hydrogen, C _1-4 alkyl and C _1-4 haloalkyl; R ¹² is independently selected at each occurrence from hydrogen and C _1-4 alkyl optionally substituted with halogen, -OH, -NH ₂ and -C(O)N(H) ₂ ; R ¹³ is independently selected at each occurrence from hydrogen, C _1-4 alkyl, C _1-4 haloalkyl, and C _1-4 hydroxyalkyl; R ¹⁴ is independently selected at each occurrence from: hydrogen; and C _1-10 alkyl and C _1-10 heteroalkyl optionally substituted with one to six substituents independently selected from halogen, -OR ²¹ , -SR ²¹ , -N(R ²¹ ) ₂ , -N ⁺ (R ¹⁵ ) ₃ , -C(O)R ²¹ , - C(O)OR ²¹ , -OC(O)R ²¹ , -OC(O)N(R ²¹ ) ₂ , -C(O)N(R ²¹ ) ₂ , -N(R ²¹ )C(O)R ²¹ , - P(O)(OR ¹⁶ ) ₂ , -P(O)R ¹⁶ (OR ¹⁶ ), -S(O) ₂ OH, =O, and -CN; and C _3-10 carbocycle and 3- to 10-membered heterocycle, wherein each C _3-10 carbocycle and 3- to 10-membered heterocycle is optionally substituted with one to six substituents independently selected from halogen, C _1-6 alkyl, -OR ²¹ , -N ⁺ (R ¹⁵ ) ₃ , -S(O)R ²¹ , -P(O)(OR ¹⁶ ) ₂ , - P(O)R ¹⁶ (OR ¹⁶ ), -S(O) ₂ OH,-S(O) ₂ N(R ²¹ ) ₂ , =O, and -CN; R ¹⁵ are each is selected from C _1-4 alkyl; R ¹⁶ is independently selected at each occurrence from hydrogen and C _1-6 alkyl; R ²¹ is independently selected at each occurrence from hydrogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, and C _3-6 carbocycle, wherein the C _3-6 carbocycle is optionally substituted with one to six substituents independently selected from -OH, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, and =O. [0094] For any and all of the embodiments, substituents are selected from among a subset of the listed alternatives. For example, in some embodiments, Y is CR ⁶ . In some embodiments, R ⁶ is hydrogen or halogen. In some embodiments, Y is N, CH, or CF. In some embodiments, Y is N. In some embodiments, Y is CH. In some embodiments, Y is CF. [0095] In some embodiments, n is selected from 0 and 1. In some embodiments, n is selected from 1 and 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. [0096] In some embodiments, each R ¹ is independently selected at each occurrence from halogen, hydroxyl, and C _1-4 alkyl. In some embodiments, each R ¹ is independently selected at each occurrence from F, Cl, hydroxyl, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec- butyl, and tert-butyl. In some embodiments, each R ¹ is F, Cl, methyl, or hydroxyl. In some embodiments, each R ¹ is methyl. In some embodiments, each R ¹ is hydroxyl. [0097] In some embodiments, R ¹ is hydroxyl, and n is selected from 0 and 1. [0098] In some embodiments, o is selected from 0 and 1. In some embodiments, o is selected from 1 and 2. In some embodiments, o is 0. In some embodiments, o is 1. In some embodiments, o is 2. [0099] In some embodiments, each R ² is independently selected at each occurrence from halogen, hydroxyl, and C _1-4 alkyl. In some embodiments, each R ² is independently selected at each occurrence from F, Cl, hydroxyl, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec- butyl, and tert-butyl. In some embodiments, each R ² is F, Cl, methyl, or hydroxyl. [00100] In some embodiments, p is selected from 0 and 1. In some embodiments, p is selected from 1 and 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. [00101] In some embodiments, each R ³ is independently selected at each occurrence from halogen, hydroxyl, and C _1-4 alkyl. In some embodiments, each R ³ is independently selected at each occurrence from F, Cl, hydroxyl, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec- butyl, and tert-butyl. In some embodiments, each R ³ is halogen. In some embodiments, each R ³ is F or Cl. In some embodiments, each R ³ is F. In some embodiments, each R ³ is Cl. [00102] In some embodiments, R ³ is halogen, and p is selected from 0 and 1. In some embodiments, R ³ is selected from fluoro and chloro, and p is 1. In some embodiments, R ³ is fluoro, and p is 1. In some embodiments, R ³ is chloro, and p is 1. [00103] In some embodiments, q is selected from 0 and 1. In some embodiments, q is selected from 1 and 2. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. [00104] In some embodiments, each R ⁴ is independently selected at each occurrence from halogen, C _1-4 alkyl, -CN, and C _1-4 haloalkyl. In some embodiments, each R ⁴ is independently selected at each occurrence from halogen and C _1-4 alkyl. In some embodiments, each R ⁴ is independently selected at each occurrence from F, Cl, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, and tert-butyl. In some embodiments, each R ⁴ is F, Cl, or methyl. In some embodiments, each R ⁴ is Cl or methyl. In some embodiments, each R ⁴ is methyl. In some embodiments, each R ¹ is fluoro. In some embodiments, each R ¹ is chloro. [00105] In some embodiments, R ⁴ is selected from halogen and C _1-4 alkyl, and q is selected from 0 and 1. In some embodiments, R ⁴ is selected from chloro and methyl, and q is 1. [00106] In some embodiments, R ⁵ is hydrogen. In some embodiments, R ⁵ is C _1-4 alkyl. In some embodiments, R ⁵ is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, and tert- butyl. In some embodiments, R ⁵ is methyl or ethyl. In some embodiments, R ⁵ is methyl. In some embodiments, R ⁵ is ethyl. [00107] In some embodiments, R ⁵ is hydrogen, methyl, or ethyl. In some embodiments, R ⁵ is hydrogen or methyl. [00108] In some embodiments, R ⁶ is selected from hydrogen, halogen, and C _1-4 alkyl. In some embodiments, R ⁶ is selected from hydrogen, F, Cl, methyl, ethyl, n-propyl, i-propyl, n- butyl, i-butyl, sec-butyl, and tert-butyl. In some embodiments, R ⁶ is selected from hydrogen, F, Cl, and methyl. In some embodiments, R ⁶ is selected from hydrogen and halogen. In some embodiments, R ⁶ is selected from hydrogen, fluoro, and chloro. In some embodiments, R ⁶ is selected from hydrogen and fluoro. In some embodiments, R ⁶ is hydrogen. In some embodiments, R ⁶ is fluoro. [00109] In some embodiments, X is -O-. In some embodiments, X is -S-. [00110] In some embodiments, D is selected from -P(O)(OR ¹¹ ) ₂ , -P(O)R ¹¹ (OR ¹¹ ), and - S(O) ₂ OH. In some embodiments, D is selected from -P(O)(OH) ₂ , -P(O)(OMe) ₂ , -P(O)Me(OMe), -P(O)Me(OH), and -S(O) ₂ OH. In some embodiments, D is selected from -P(O)(OH) ₂ , - P(O)Me(OH), and -S(O) ₂ OH. [00111] In some embodiments, D is -L-K. [00112] In some embodiments, L is ^λ -(C(R ¹³ ) ₂ ) _r -. In some embodiments, L is ^λ -O(C(R ¹³ ) ₂ ) _r -. In some embodiments, L is ^λ -N(R ¹² )(C(R ¹³ ) ₂ ) _s -. In some embodiments, L is ^λ -C(O)O-. In some embodiments, L is ^λ -C(O)N(R ¹² )-. In some embodiments, L is ^λ -N(R ¹² )C(O)-. In some embodiments, L is ^λ -N(R ¹² )S(O) ₂ -. In some embodiments, L is ^λ -S(O) ₂ N(R ¹² )-. In some embodiments, L is 4- to 6-membered heterocycloalkyl. In some embodiments, L is 5- to 6- membered heteroaryl. [00113] In some embodiments, L is selected from ^λ -(C(R ¹³ ) ₂ ) _r -, ^λ -O(C(R ¹³ ) ₂ ) _r -, ^λ - N(R ¹² )(C(R ¹³ ) ₂ ) _s -, ^λ -C(O)O-, ^λ -C(O)N(R ¹² )-, ^λ -N(R ¹² )C(O)-, ^λ -N(R ¹² )S(O) ₂ -, ^λ -S(O) ₂ N(R ¹² )-, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl. In some embodiments, L is selected from ^λ -(C(R ¹³ ) ₂ ) _r -, ^λ -O(C(R ¹³ ) ₂ ) _r -, and ^λ -N(R ¹² )(C(R ¹³ ) ₂ ) _s -. [00114] In some embodiments, r is selected from 1 and 2. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3. [00115] In some embodiments, s is selected from 0, 1, and 2. In some embodiments, s is 0. In some embodiments, s is 1. In some embodiments, s is 2. In some embodiments, s is 3. [00116] In some embodiments, L is selected from 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl. In some embodiments, L is selected from piperidinyl, azetidinyl, pyrazolyl, and triazolyl. In some embodiments, L is selected from piperidinyl and azetidinyl. In some embodiments, L is selected from pyrazolyl and triazolyl. [00117] In some embodiments, K is selected from (i) and (ii): (i) C _1-10 alkyl or C _1-10 heteroalkyl, each of which is optionally substituted with one to six substituents independently selected from: halogen, -OR ¹⁴ , -N(R ¹⁴ ) ₂ , -N ⁺ (R ¹⁵ ) ₃ , - C(O)OR ¹⁴ , -OC(O)R ¹⁴ , -C(O)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )C(O)R ¹⁴ , -S(O) ₂ R ¹⁴ , -P(O)(OR ¹⁶ ) ₂ , - P(O)R ¹⁶ (OR ¹⁶ ), -S(O) ₂ OH, =O, C _3-10 carbocycle, and 3- to 10-membered heterocycle, wherein each C _3-10 carbocycle and 3- to 10-membered heterocycle is optionally substituted with one to six substituents independently selected from halogen, C _1-6 alkyl, -OR ¹⁴ , =O, and -S(O) ₂ OH; and (ii) C _3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one to six substituents independently selected from halogen, -OR ¹⁴ , - N(R ¹⁴ ) ₂ , -N ⁺ (R ¹⁵ ) ₃ , -C(O)R ¹⁴ , -C(O)OR ¹⁴ , -OC(O)R ¹⁴ , -C(O)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )C(O)R ¹⁴ , - S(O)R ¹⁴ , -S(O) ₂ R ¹⁴ , -P(O)(OR ¹⁶ ) ₂ , -P(O)R ¹⁶ (OR ¹⁶ ), -S(O) ₂ OH, =O, C _1-10 alkyl, and C _1-10 heteroalkyl, wherein each C _1-10 alkyl and C _1-10 heteroalkyl is optionally substituted with one to six substituents independently selected from halogen, -OR ¹⁴ , -SR ¹⁴ , -N(R ¹⁴ ) ₂ , - N ⁺ (R ¹⁵ ) ₃ , -C(O)OR ¹⁴ , -P(O)(OR ¹⁶ ) ₂ , -P(O)R ¹⁶ (OR ¹⁶ ), -S(O) ₂ R ¹⁶ , -S(O) ₂ OH, and =O. [00118] In some embodiments, K is selected from C _1-10 alkyl or C _1-10 heteroalkyl, each of which is optionally substituted with one to six substituents independently selected from: halogen, -OR ¹⁴ , -N(R ¹⁴ ) ₂ , -N ⁺ (R ¹⁵ ) ₃ , -C(O)OR ¹⁴ , -OC(O)R ¹⁴ , -C(O)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )C(O)R ¹⁴ , - S(O) ₂ R ¹⁴ , -P(O)(OR ¹⁶ ) ₂ , -P(O)R ¹⁶ (OR ¹⁶ ), -S(O) ₂ OH, =O, and 3- to 10-membered heterocycle. In some embodiments, K is selected from C _1-10 alkyl or C _1-10 heteroalkyl, each of which is optionally substituted with one to six substituents independently selected from: halogen, -OR ¹⁴ , - N(R ¹⁴ ) ₂ , -N ⁺ (R ¹⁵ ) ₃ , -C(O)OR ¹⁴ , -OC(O)R ¹⁴ , -C(O)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )C(O)R ¹⁴ , -S(O) ₂ R ¹⁴ , - P(O)(OR ¹⁶ ) ₂ , -P(O)R ¹⁶ (OR ¹⁶ ), -S(O) ₂ OH, =O, and 3- to 10-membered heterocycle, wherein each C _3-10 carbocycle and 3- to 10-membered heterocycle is optionally substituted with one to six substituents independently selected from halogen, C _1-6 alkyl, -OR ¹⁴ , =O, and -S(O) ₂ OH. In some embodiments, K is selected from C _1-10 alkyl or C _1-10 heteroalkyl, each of which is optionally substituted with one to six substituents independently selected from halogen, -OR ¹⁴ , -N(R ¹⁴ ) ₂ , - N ⁺ (R ¹⁵ ) ₃ , -C(O)OR ¹⁴ , -C(O)N(R ¹⁴ ) ₂ , -S(O) ₂ R ¹⁴ , -P(O)(OR ¹⁶ ) ₂ , --S(O) ₂ OH,C _3-10 carbocycle and 3- to 10-membered heterocycle, wherein each C _3-10 carbocycle and 3- to 10-membered heterocycle is optionally substituted with one to six substituents independently selected from halogen, -OR ¹⁴ , =O, and -S(O) ₂ OH. [00119] In some embodiments, K is selected from C _1-10 alkyl or C _1-10 heteroalkyl, each of which is optionally substituted with one to six substituents independently selected from halogen, -OR ¹⁴ , -N(R ¹⁴ ) ₂ , and -S(O) ₂ R ¹⁴ . In some embodiments, K is selected from C _1-6 alkyl or C _1-6 heteroalkyl, each of which is optionally substituted with one to six substituents independently selected from halogen, -OH, -OMe, -NH ₂ , -N(CH ₃ ) ₂ , and -S(O) ₂ CH ₃ . [00120] In some embodiments, K is selected from C _1-10 alkyl, which is optionally substituted with one to six substituents independently selected from halogen, -OR ¹⁴ , -N(R ¹⁴ ) ₂ , and - S(O) ₂ R ¹⁴ . In some embodiments, K is selected from C _1-6 alkyl, which is optionally substituted with one to six substituents independently selected from halogen, -OH, -OMe, -NH ₂ , -N(CH ₃ ) ₂ , and -S(O) ₂ CH ₃ . [00121] In some embodiments, K is selected from C _1-10 heteroalkyl, each of which is optionally substituted with one to six substituents independently selected from halogen, -OR ¹⁴ , - N(R ¹⁴ ) ₂ , and -S(O) ₂ R ¹⁴ . In some embodiments, K is selected from C _1-6 heteroalkyl, each of which is optionally substituted with one to six substituents independently selected from halogen, -OH, -OMe, -NH ₂ , -N(CH ₃ ) ₂ , and -S(O) ₂ CH ₃ . [00122] In some embodiments, K is selected from C _3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one to six substituents independently selected from halogen, -OR ¹⁴ , -N(R ¹⁴ ) ₂ , -N ⁺ (R ¹⁵ ) ₃ , -C(O)R ¹⁴ , -C(O)OR ¹⁴ , -OC(O)R ¹⁴ , - C(O)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )C(O)R ¹⁴ , - S(O)R ¹⁴ , -S(O) ₂ R ¹⁴ , -P(O)(OR ¹⁶ ) ₂ , -P(O)R ¹⁶ (OR ¹⁶ ), - S(O) ₂ OH,=O, C _1-10 alkyl, and C _1-10 heteroalkyl. In some embodiments, K is selected from C _3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one to six substituents independently selected from halogen, -OR ¹⁴ , -N(R ¹⁴ ) ₂ , -N ⁺ (R ¹⁵ ) ₃ , -C(O)R ¹⁴ , - C(O)OR ¹⁴ , -OC(O)R ¹⁴ , -C(O)N(R ¹⁴ ) ₂ , -N(R ¹⁴ )C(O)R ¹⁴ , - S(O)R ¹⁴ , -S(O) ₂ R ¹⁴ , -P(O)(OR ¹⁶ ) ₂ , - P(O)R ¹⁶ (OR ¹⁶ ), -S(O) ₂ OH,=O, C _1-10 alkyl, and C _1-10 heteroalkyl, wherein each C _1-10 alkyl and C _1-10 heteroalkyl is optionally substituted with one to six substituents independently selected from halogen, -OR ¹⁴ , -SR ¹⁴ , -N(R ¹⁴ ) ₂ , -N ⁺ (R ¹⁵ ) ₃ , -C(O)OR ¹⁴ , -P(O)(OR ¹⁶ ) ₂ , -P(O)R ¹⁶ (OR ¹⁶ ), - S(O) ₂ OH, -S(O) ₂ R ¹⁴ , and =O. [00123] In some embodiments, K is selected from C _3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one to six substituents independently selected from halogen, -OR ¹⁴ , -N(R ¹⁴ ) ₂ , -C(O)R ¹⁴ , -C(O)N(R ¹⁴ ) ₂ , =O, C _1-10 alkyl, and C _1-10 heteroalkyl, wherein each C _1-10 alkyl and C _1-10 heteroalkyl is optionally substituted with one to six substituents independently selected from halogen, -OR ¹⁴ , -N(R ¹⁴ ) ₂ , -C(O)OR ¹⁴ , - P(O)(OR ¹⁶ ) ₂ , -P(O)R ¹⁶ (OR ¹⁶ ), -S(O) ₂ OH, and -S(O) ₂ R ¹⁴ . [00124] In some embodiments, K is selected from piperidine, azetidine, and piperazine, each of which is optionally substituted with one to six substituents independently selected from halogen, -OR ¹⁴ , -N(R ¹⁴ ) ₂ , -C(O)R ¹⁴ , -C(O)N(R ¹⁴ ) ₂ , =O, C _1-10 alkyl, and C _1-10 heteroalkyl, wherein each C _1-10 alkyl and C _1-10 heteroalkyl is optionally substituted with one to six substituents independently selected from halogen, -OR ¹⁴ , -N(R ¹⁴ ) ₂ , -C(O)OR ¹⁴ , -P(O)(OR ¹⁶ ) ₂ , - P(O)R ¹⁶ (OR ¹⁶ ), -S(O) ₂ R ¹⁶ , and -S(O) ₂ OH,. [00125] In some embodiments, K is selected from piperidine, azetidine, and piperazine, each of which is optionally substituted with one to six substituents independently selected from fluoro, -OH, -OMe, -NH ₂ , -N(CH ₃ ) ₂ , -C(O)Me, -C(O)NH ₂ , -C(O)N(CH ₃ ) ₂ , =O, C _1-6 alkyl, and C _1-6 heteroalkyl, wherein each C _1-6 alkyl and C _1-6 heteroalkyl is optionally substituted with one to six substituents independently selected from fluoro, chloro, -OH, -OMe, -NH ₂ , -N(CH ₃ ) ₂ , - C(O)OH, -C(O)OMe, -P(O)(OH) ₂ , -P(O)Me(OH), -S(O) ₂ OH, and -S(O) ₂ Me. [00126] In some embodiments, K is selected from piperidine, azetidine, and piperazine, each of which is optionally substituted with one or two substituents independently selected from fluoro, -OH, -OMe, -NH ₂ , -N(CH ₃ ) ₂ , -C(O)Me, -C(O)NH ₂ , -C(O)N(CH ₃ ) ₂ , C _1-6 alkyl, and C _1-6 heteroalkyl, wherein each C _1-6 alkyl and C _1-6 heteroalkyl is optionally substituted with one to six substituents independently selected from fluoro, chloro, -OH, -OMe, -NH ₂ , -N(CH ₃ ) ₂ , -C(O)OH, -C(O)OMe, -P(O)(OH) ₂ , -P(O)Me(OH), -S(O) ₂ OH, and -S(O) ₂ Me. [00127] In some embodiments, K is selected from piperidine, azetidine, and piperazine, each of which is substituted with one or two substituents independently selected from C _1-6 alkyl and C _1-6 heteroalkyl, wherein each C _1-6 alkyl and C _1-6 heteroalkyl is optionally substituted with one to six substituents independently selected from fluoro, -OH, -OMe, -C(O)OH, and -S(O) ₂ Me. [00128] In some embodiments, each R ¹⁴ is independently selected at each occurrence from hydrogen; C _1-10 alkyl optionally substituted with one to six substituents independently selected from, -OR ²¹ , -N(R ²¹ ) ₂ , -P(O)(OR ¹⁶ ) ₂ , -S(O) ₂ OH; and C _3-10 carbocycle optionally substituted with one to six substituents independently selected from -P(O)(OR ¹⁶ ) ₂ , -S(O) ₂ OH, and =O. In some embodiments, each R ¹⁴ is independently selected at each occurrence from hydrogen and C _1-6 alkyl. [00129] In some embodiments, each R ²¹ is independently selected at each occurrence from hydrogen, C _1-6 alkyl, C _1-6 hydroxyalkyl, and C _1-6 haloalkyl. In some embodiments, each R ²¹ is independently selected at each occurrence from hydrogen and C _1-6 alkyl. [00130] In some embodiments, D is selected from: , , , , ,

[00131] Any combination of the groups described above 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.

[00132] In some embodiments, the compound is a compound in one of the following tables, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.

Table 1.

[00133] Compounds in Table 1 are named: 1: methyl 5-((6-chloro-5-(4'-((2-(2-hydroxyethoxy)ethoxy)methyl)-[1,1' -biphenyl]-4-yl)-1H- benzo[d]imidazol-2-yl)oxy)-2-methylbenzoate; 2: 5-((6-chloro-5-(4'-((2-(2-hydroxyethoxy)ethoxy)methyl)-[1,1' -biphenyl]-4-yl)-1H- benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 4: 5-((6-chloro-5-(4'-((2-(2-hydroxyethoxy)ethoxy)methyl)-[1,1' -biphenyl]-4-yl)-1H- imidazo[4,5-b]pyridin-2-yl)oxy)-2-methylbenzoic acid; 5: 5-((4,6-difluoro-5-(4'-((2-(2-hydroxyethoxy)ethoxy)methyl)-[ 1,1'-biphenyl]-4-yl)-1H- benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 6: methyl 5-((4,6-difluoro-5-(4'-((2-(2-hydroxyethoxy)ethoxy)methyl)-[ 1,1'-biphenyl]-4-yl)-1H- benzo[d]imidazol-2-yl)oxy)-2-methylbenzoate; 7: 5-((6-chloro-5-(4'-((3-(((1,3-dihydroxypropan-2-yl)amino)met hyl)azetidin-1-yl)methyl)-[1,1'- biphenyl]-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)-2-methylb enzoic acid; 8: 5-((6-chloro-5-(4'-((((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhe xyl)amino)methyl)-[1,1'- biphenyl]-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)-2-methylb enzoic acid; 9: 5-((5-(4'-((4,4-bis(hydroxymethyl)piperidin-1-yl)methyl)-[1, 1'-biphenyl]-4-yl)-6-chloro-1H- imidazo[4,5-b]pyridin-2-yl)oxy)-2-methylbenzoic acid; 10: 2-chloro-5-((6-chloro-5-(2'-hydroxy-4'-((((2S,3R,4R,5R)-2,3, 4,5,6- pentahydroxyhexyl)amino)methyl)-[1,1'-biphenyl]-4-yl)-1H-imi dazo[4,5-b]pyridin-2- yl)oxy)benzoic acid; 11: 5-((5-(4'-((3,3-bis(hydroxymethyl)azetidin-1-yl)methyl)-[1,1 '-biphenyl]-4-yl)-6-chloro-1H- imidazo[4,5-b]pyridin-2-yl)oxy)-2-methylbenzoic acid; 12: 2-chloro-5-((6-chloro-5-(4'-((((2S,3R,4R,5R)-2,3,4,5,6-penta hydroxyhexyl)amino)methyl)- [1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)benzoic acid; 13: 5-((6-chloro-5-(4'-((3-(((1,3-dihydroxy-2-(hydroxymethyl)pro pan-2- yl)amino)methyl)azetidin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)- 1H-imidazo[4,5-b]pyridin-2- yl)oxy)-2-methylbenzoic acid; 14: 5-((6-chloro-5-(4'-(((1,3-dihydroxy-2-(hydroxymethyl)propan- 2-yl)amino)methyl)-[1,1'- biphenyl]-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)-2-methylb enzoic acid; 15: methyl 2-chloro-5-((6-chloro-5-(4'-(((2-(2-hydroxyethoxy)ethyl)amin o)methyl)-[1,1'- biphenyl]-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)benzoate; 16: 2-chloro-5-((6-chloro-5-(4'-(((2-(2-hydroxyethoxy)ethyl)amin o)methyl)-[1,1'-biphenyl]-4- yl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)benzoic acid; 17: methyl 5-((6-chloro-5-(4'-(((2-(2-hydroxyethoxy)ethyl)amino)methyl) -[1,1'-biphenyl]-4-yl)- 1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoate; 18: 5-((6-chloro-5-(4'-(((2-(2-hydroxyethoxy)ethyl)amino)methyl) -[1,1'-biphenyl]-4-yl)-1H- benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 19: methyl 5-((6-chloro-5-(4'-(((2-(2-hydroxyethoxy)ethyl)amino)methyl) -[1,1'-biphenyl]-4-yl)- 1H-imidazo[4,5-b]pyridin-2-yl)oxy)-2-methylbenzoate; 20: 5-((6-chloro-5-(4'-(((2-(2-hydroxyethoxy)ethyl)amino)methyl) -[1,1'-biphenyl]-4-yl)-1H- imidazo[4,5-b]pyridin-2-yl)oxy)-2-methylbenzoic acid; 21: methyl 5-((4,6-difluoro-5-(4'-(((2-(2-hydroxyethoxy)ethyl)amino)met hyl)-[1,1'-biphenyl]-4- yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoate; 22: 5-((4,6-difluoro-5-(4'-(((2-(2-hydroxyethoxy)ethyl)amino)met hyl)-[1,1'-biphenyl]-4-yl)-1H- benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 23: 5-((6-fluoro-5-(4'-((4-(2-(2-hydroxyethoxy)ethyl)piperazin-1 -yl)methyl)-[1,1'-biphenyl]-4- yl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)-2-methylbenzoic acid; 24: methyl 5-((6-fluoro-5-(4'-((4-(2-(2-hydroxyethoxy)ethyl)piperazin-1 -yl)methyl)-[1,1'- biphenyl]-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)-2-methylb enzoate; 25: methyl 5-((6-chloro-5-(4'-((4-(2-(2-hydroxyethoxy)ethyl)piperazin-1 -yl)methyl)-[1,1'- biphenyl]-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)-2-methylb enzoate; 26: 5-((6-chloro-5-(4'-((4-(2-(2-hydroxyethoxy)ethyl)piperazin-1 -yl)methyl)-[1,1'-biphenyl]-4- yl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)-2-methylbenzoic acid; 27: methyl 5-((6-chloro-5-(4'-((4-(2-(2-hydroxyethoxy)ethyl)piperazin-1 -yl)methyl)-[1,1'- biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoa te; 28: 5-((6-chloro-5-(4'-((4-(2-(2-hydroxyethoxy)ethyl)piperazin-1 -yl)methyl)-[1,1'-biphenyl]-4- yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 29: 5-((5-(4'-((3-((2,2-difluoroethyl)amino)azetidin-1-yl)methyl )-[1,1'-biphenyl]-4-yl)-4,6- difluoro-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 30: 5-((4,6-difluoro-5-(4'-((3-((methylsulfonyl)methyl)azetidin- 1-yl)methyl)-[1,1'-biphenyl]-4- yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 31: 5-((4,6-difluoro-5-(4'-((4-((methylsulfonyl)methyl)piperidin -1-yl)methyl)-[1,1'-biphenyl]-4- yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 32: 5-((4,6-difluoro-5-(4'-((3-(2-methoxyethoxy)azetidin-1-yl)me thyl)-[1,1'-biphenyl]-4-yl)-1H- benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 33: (S)-5-((4,6-difluoro-5-(4'-(1-(2-methoxyethyl)piperidin-3-yl )-[1,1'-biphenyl]-4-yl)-1H- benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 34: (R)-5-((4,6-difluoro-5-(4'-(1-(2-methoxyethyl)piperidin-3-yl )-[1,1'-biphenyl]-4-yl)-1H- benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 35: 5-((4,6-difluoro-5-(4'-(1-(2,2,2-trifluoroethyl)piperidin-4- yl)-[1,1'-biphenyl]-4-yl)-1H- benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 36: 5-((4,6-difluoro-5-(4'-(1-(2-methoxyethyl)piperidin-4-yl)-[1 ,1'-biphenyl]-4-yl)-1H- benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 37: 5-((5-(4'-((3-(ethylcarbamoyl)azetidin-1-yl)methyl)-[1,1'-bi phenyl]-4-yl)-4,6-difluoro-1H- benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 38: 5-((5-(4'-((3-carbamoylazetidin-1-yl)methyl)-[1,1'-biphenyl] -4-yl)-4,6-difluoro-1H- benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 39: 5-((4,6-difluoro-5-(4'-((2-oxo-4-(2,2,2-trifluoroethyl)piper azin-1-yl)methyl)-[1,1'-biphenyl]- 4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 40: 5-((4,6-difluoro-5-(4'-((3-((2-hydroxyethoxy)methyl)azetidin -1-yl)methyl)-[1,1'-biphenyl]- 4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 41: 5-((4,6-difluoro-5-(4'-((4-(2,2-difluoroethyl)piperazin-1-yl )methyl)-[1,1'-biphenyl]-4-yl)- 1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 45: 5-((4,6-difluoro-5-(4'-((4-(2,2,2-trifluoroethyl)piperazin-1 -yl)methyl)-[1,1'-biphenyl]-4-yl)- 1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 46: ((4,6-difluoro-5-(4'-((3-(trifluoromethoxy)azetidin-1-yl)met hyl)-[1,1'-biphenyl]-4-yl)-1H- benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 47: 5-((5-(4'-((4-(aminomethyl)piperidin-1-yl)methyl)-[1,1'-biph enyl]-4-yl)-4,6-difluoro-1H- benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 48: 5-((4,6-difluoro-5-(4'-((4-(methoxymethyl)piperidin-1-yl)met hyl)-[1,1'-biphenyl]-4-yl)-1H- benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 49: 5-((4,6-difluoro-5-(4'-((3-(methoxymethyl)azetidin-1-yl)meth yl)-[1,1'-biphenyl]-4-yl)-1H- benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 50: 5-((4,6-difluoro-5-(4'-((4-(2-methoxyethyl)piperazin-1-yl)me thyl)-[1,1'-biphenyl]-4-yl)-1H- benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 51: 5-((5-(4'-((4-acetylpiperazin-1-yl)methyl)-[1,1'-biphenyl]-4 -yl)-4,6-difluoro-1H- benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 52: 5-((5-(4'-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-[1,1'-biphenyl] -4-yl)-4,6-difluoro-1H- benzo[d]imidazol-2-yl)oxy)-2-chlorobenzoic acid; 53: 5-((4,6-difluoro-5-(4'-(1-(2-(2-hydroxyethoxy)ethyl)-1H-pyra zol-3-yl)-[1,1'-biphenyl]-4-yl)- 1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 54: 5-((4,6-difluoro-5-(4'-(1-(2-(2-hydroxyethoxy)ethyl)-1H-1,2, 4-triazol-5-yl)-[1,1'-biphenyl]- 4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 55: 5-((4,6-difluoro-5-(4'-(1-(2-(2-hydroxyethoxy)ethyl)-1H-1,2, 4-triazol-3-yl)-[1,1'-biphenyl]- 4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 56: 5-((5-(4'-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-3-yl)-[1,1' -biphenyl]-4-yl)-4,6-difluoro- 1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 57: 5-((4,6-difluoro-5-(4'-(1-(2-methoxyethyl)-1H-1,2,4-triazol- 3-yl)-[1,1'-biphenyl]-4-yl)-1H- benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 58: 5-((5-(4'-(1-(2-aminoethyl)-1H-1,2,4-triazol-3-yl)-[1,1'-bip henyl]-4-yl)-4,6-difluoro-1H- benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 59: 5-((5-(4'-(1-(2-(dimethylamino)ethyl)-1H-1,2,4-triazol-3-yl) -[1,1'-biphenyl]-4-yl)-4,6- difluoro-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 60: 5-((5-(4'-(1-(2-(dimethylamino)ethyl)-1H-1,2,4-triazol-5-yl) -[1,1'-biphenyl]-4-yl)-4,6- difluoro-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 61: 5-((5-(4'-(1-(2-aminoethyl)-1H-1,2,4-triazol-5-yl)-[1,1'-bip henyl]-4-yl)-4,6-difluoro-1H- benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 62: 5-((5-(4'-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-[1,1'-biphenyl] -4-yl)-4,6-difluoro-1H- benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 63: 5-((4,6-difluoro-5-(4'-(1-(2-methoxyethyl)-1H-1,2,4-triazol- 5-yl)-[1,1'-biphenyl]-4-yl)-1H- benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 64: 5-((4,6-difluoro-5-(4'-(1-(2-methoxyethyl)-1H-pyrazol-3-yl)- [1,1'-biphenyl]-4-yl)-1H- benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 65: 5-((4,6-difluoro-5-(4'-(1-(2,2,2-trifluoroethyl)-1H-pyrazol- 3-yl)-[1,1'-biphenyl]-4-yl)-1H- benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 66: 5-((4,6-difluoro-5-(4'-(1-(2-methoxyethyl)-1H-pyrazol-5-yl)- [1,1'-biphenyl]-4-yl)-1H- benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 67: 5-((4,6-difluoro-5-(4'-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-tr iazol-3-yl)-[1,1'-biphenyl]-4-yl)- 1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 68: 5-((5-(4'-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-[1,1'-biphenyl] -4-yl)-6-chloro-1H- benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 69: 5-((5-(4'-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-5-yl)-[1,1' -biphenyl]-4-yl)-4,6-difluoro- 1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 70: 2-chloro-5-((4,6-difluoro-5-(4'-((2-(2-hydroxyethoxy)ethoxy) methyl)-[1,1'-biphenyl]-4-yl)- 1H-benzo[d]imidazol-2-yl)oxy)benzoic acid; 71: 5-((6-chloro-5-(4'-((3-(((2-hydroxyethyl)amino)methyl)azetid in-1-yl)methyl)-[1,1'- biphenyl]-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)-2-methylb enzoic acid; 72: 5-((4,6-difluoro-5-(4'-((4-(2-(methylsulfonyl)ethyl)piperazi n-1-yl)methyl)-[1,1'-biphenyl]-4- yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 73: 5-((4,6-difluoro-5-(4'-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-tr iazol-5-yl)-[1,1'-biphenyl]-4-yl)- 1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 74: 5-((5-(4'-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-[1,1'-biphenyl] -4-yl)-6-chloro-1H- imidazo[4,5-b]pyridin-2-yl)oxy)-2-methylbenzoic acid; 75: 5-((6-fluoro-5-(4'-((2-(2-hydroxyethoxy)ethoxy)methyl)-[1,1' -biphenyl]-4-yl)-1H- imidazo[4,5-b]pyridin-2-yl)oxy)-2-methylbenzoic acid; 76: 5-((5-(4'-((3-(aminomethyl)azetidin-1-yl)methyl)-[1,1'-biphe nyl]-4-yl)-4,6-difluoro-1H- benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 77: 5-((6-chloro-5-(4'-((3-(2-methoxyethoxy)azetidin-1-yl)methyl )-[1,1'-biphenyl]-4-yl)-1H- imidazo[4,5-b]pyridin-2-yl)oxy)-2-methylbenzoic acid; 78: 5-((6-chloro-5-(4'-((3-((methylsulfonyl)methyl)azetidin-1-yl )methyl)-[1,1'-biphenyl]-4-yl)- 1H-imidazo[4,5-b]pyridin-2-yl)oxy)-2-methylbenzoic acid; 79: 2-chloro-5-((4,6-difluoro-5-(4'-((2-(2-hydroxyethoxy)ethoxy) methyl)-[1,1'-biphenyl]-4-yl)- 1H-benzo[d]imidazol-2-yl)oxy)benzoic acid; 80: 2-chloro-5-((6-chloro-5-(4'-((((2S,3R,4R,5R)-2,3,4,5,6-penta hydroxyhexyl)amino)methyl)- [1,1'-biphenyl]-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)thio)ben zoic acid; 81: 5-((6-chloro-5-(4'-((3-((((2S,3R,4R,5R)-2,3,4,5,6- pentahydroxyhexyl)amino)methyl)azetidin-1-yl)methyl)-[1,1'-b iphenyl]-4-yl)-1H-imidazo[4,5- b]pyridin-2-yl)oxy)-2-methylbenzoic acid; 82: 2-chloro-5-((6-chloro-5-(4'-((((2S,3R,4R,5R)-2,3,4,5,6-penta hydroxyhexyl)amino)methyl)- [1,1'-biphenyl]-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)benz oic acid; 83: methyl 2-chloro-5-((6-chloro-5-(4'-((4-(2-(2-hydroxyethoxy)ethyl)pi perazin-1-yl)methyl)- [1,1'-biphenyl]-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)benz oate; 84: 2-chloro-5-((6-chloro-5-(4'-((4-((hydroxymethoxy)methyl)pipe razin-1-yl)methyl)-[1,1'- biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)benzoic acid; 85: methyl 2-chloro-5-((6-chloro-5-(4'-((2-(2-hydroxyethoxy)ethoxy)meth yl)-[1,1'-biphenyl]-4- yl)-1H-benzo[d]imidazol-2-yl)oxy)benzoate; 86: 2-chloro-5-((6-chloro-5-(4'-((2-(2-hydroxyethoxy)ethoxy)meth yl)-[1,1'-biphenyl]-4-yl)-1H- benzo[d]imidazol-2-yl)oxy)benzoic acid; 87: methyl 2-chloro-5-((6-chloro-5-(4'-((3-((2-hydroxyethoxy)methyl)aze tidin-1-yl)methyl)- [1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)benzoate; 88: 2-chloro-5-((6-chloro-5-(4'-((3-((2-hydroxyethoxy)methyl)aze tidin-1-yl)methyl)-[1,1'- biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)benzoic acid; 89: 2-chloro-5-((6-chloro-5-(4'-((4-(2-(2-hydroxyethoxy)ethyl)pi perazin-1-yl)methyl)-[1,1'- biphenyl]-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)benzoic acid; 90: methyl 2-chloro-5-((6-chloro-5-(4'-((3-((2-hydroxyethoxy)methyl)aze tidin-1-yl)methyl)- [1,1'-biphenyl]-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)benz oate; 91: 2-chloro-5-((6-chloro-5-(4'-((3-((2-hydroxyethoxy)methyl)aze tidin-1-yl)methyl)-[1,1'- biphenyl]-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)benzoic acid; 92: 5-((6-chloro-5-(4'-((3-((2-hydroxyethoxy)methyl)azetidin-1-y l)methyl)-[1,1'-biphenyl]-4- yl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)-2-methylbenzoic acid; 93: methyl 5-((6-chloro-5-(4'-((3-((2-hydroxyethoxy)methyl)azetidin-1-y l)methyl)-[1,1'- biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoa te; 94: 5-((6-chloro-5-(4'-((3-((2-hydroxyethoxy)methyl)azetidin-1-y l)methyl)-[1,1'-biphenyl]-4- yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 95: 2-chloro-5-((4,6-difluoro-5-(4'-((4-(2-(2-hydroxyethoxy)ethy l)piperazin-1-yl)methyl)-[1,1'- biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)benzoic acid; 96: 5-((4,6-difluoro-5-(4'-((4-(2-(2-hydroxyethoxy)ethyl)piperaz in-1-yl)methyl)-[1,1'-biphenyl]- 4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 97: 2-chloro-5-((4,6-difluoro-5-(4'-((3-((2-hydroxyethoxy)methyl )azetidin-1-yl)methyl)-[1,1'- biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)benzoic acid; 98: 5-((4,6-difluoro-5-(4'-((3-((2-hydroxyethoxy)methyl)azetidin -1-yl)methyl)-[1,1'-biphenyl]- 4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 99: 2-chloro-5-((6-chloro-5-(4'-(1-(2,2,2-trifluoroethyl)-1H-1,2 ,4-triazol-3-yl)-[1,1'-biphenyl]-4- yl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)benzoic acid; 100: 5-((5-(4'-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-[1,1'-biphenyl] -4-yl)-4,6-difluoro-1H- benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 101: 5-((6-chloro-5-(4'-((3-(2-hydroxyethoxy)azetidin-1-yl)methyl )-[1,1'-biphenyl]-4-yl)-1H- imidazo[4,5-b]pyridin-2-yl)oxy)-2-methylbenzoic acid; 110: 5-((6-chloro-5-(4'-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazo l-3-yl)-[1,1'-biphenyl]-4-yl)-1H- imidazo[4,5-b]pyridin-2-yl)oxy)-2-methylbenzoic acid; 112: 5-((4,6-difluoro-5-(4'-(1-(2,2,2-trifluoroethyl)-1H-pyrazol- 5-yl)-[1,1'-biphenyl]-4-yl)-1H- benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 114: 5-((4,6-difluoro-5-(4'-((3-((2,2,2-trifluoroethyl)amino)azet idin-1-yl)methyl)-[1,1'- biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoi c acid; 123: 5-((6-chloro-5-(4'-((3-(trifluoromethoxy)azetidin-1-yl)methy l)-[1,1'-biphenyl]-4-yl)-1H- imidazo[4,5-b]pyridin-2-yl)oxy)-2-methylbenzoic acid; 124: 5-((4,6-difluoro-5-(4'-((3-((2-hydroxyethyl)amino)azetidin-1 -yl)methyl)-[1,1'-biphenyl]-4- yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 125: 5-((5-(4'-((3-((2-aminoethyl)amino)azetidin-1-yl)methyl)-[1, 1'-biphenyl]-4-yl)-4,6- difluoro-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 126: 5-((4,6-difluoro-5-(4'-((2-hydroxyethoxy)methyl)-[1,1'-biphe nyl]-4-yl)-1H- benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 127: 5-((5-(4'-((2-(carboxymethoxy)ethoxy)methyl)-[1,1'-biphenyl] -4-yl)-4,6-difluoro-1H- benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 128: 5-((5-(4'-((carboxymethoxy)methyl)-[1,1'-biphenyl]-4-yl)-4,6 -difluoro-1H- benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 129: ethyl 5-((4,6-difluoro-5-(4'-((4-(2-(methylsulfonyl)ethyl)piperazi n-1-yl)methyl)-[1,1'- biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoa te; 130: 4'-(2-(3-carboxy-4-methylphenoxy)-4,6-difluoro-1H-benzo[d]im idazol-5-yl)-[1,1'- biphenyl]-4-carboxylic acid. [00134] In some embodiments, the compound is a pharmaceutically acceptable salt of a compound in Table 1. Table 2.

[00135] Compounds in Table 2 are named: 102: 5-((4,6-difluoro-5-(4'-(1-(2-(2-hydroxyethoxy)ethyl)-1H-pyra zol-5-yl)-[1,1'-biphenyl]-4- yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 103: methyl 5-((4,6-difluoro-5-(4'-((4-(2-(2-hydroxyethoxy)ethyl)piperaz in-1-yl)methyl)-[1,1'- biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoa te; 104: methyl 2-chloro-5-((4,6-difluoro-5-(4'-((4-(2-(2-hydroxyethoxy)ethy l)piperazin-1- yl)methyl)-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)ox y)benzoate; 105: methyl 5-((4,6-difluoro-5-(4'-((3-((2-hydroxyethoxy)methyl)azetidin -1-yl)methyl)-[1,1'- biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoa te; 106: methyl 2-chloro-5-((4,6-difluoro-5-(4'-((3-((2-hydroxyethoxy)methyl )azetidin-1- yl)methyl)-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)ox y)benzoate; 107: 5-((4,6-difluoro-5-(4'-(((2-(2-hydroxyethoxy)ethyl)amino)met hyl)-[1,1'-biphenyl]-4-yl)- 1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 108: 2-chloro-5-((4,6-difluoro-5-(4'-((3-((2-hydroxyethoxy)methyl )azetidin-1-yl)methyl)-[1,1'- biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)benzoic acid; 109: 5-((6-chloro-5-(4'-((2-(2-hydroxyethoxy)ethoxy)methyl)-[1,1' -biphenyl]-4-yl)-1H- imidazo[4,5-b]pyridin-2-yl)oxy)-2-methylbenzoic acid; 111: 5-((5-(4'-((4-(2,2-difluoroethyl)piperazin-1-yl)methyl)-[1,1 '-biphenyl]-4-yl)-4,6-difluoro- 1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 113: 5-((4,6-difluoro-5-(4'-(1-(2-(2-hydroxyethoxy)ethyl)-1H-pyra zol-5-yl)-[1,1'-biphenyl]-4- yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 115: 5-((5-(4'-((3-(2-aminoethoxy)azetidin-1-yl)methyl)-[1,1'-bip henyl]-4-yl)-4,6-difluoro-1H- benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 116: methyl 5-((6-chloro-5-(4'-(((2-(2-hydroxyethoxy)ethyl)amino)methyl) -[1,1'-biphenyl]-4- yl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)-2-methylbenzoate; 117: 5-((5-(4'-((3-(aminomethyl)azetidin-1-yl)methyl)-[1,1'-biphe nyl]-4-yl)-4,6-difluoro-1H- benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 118: 5-((4,6-difluoro-5-(4'-((2-(2-hydroxyethoxy)ethoxy)methyl)-[ 1,1'-biphenyl]-4-yl)-1H- benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 119: 2-chloro-5-((4,6-difluoro-5-(4'-((2-(2-hydroxyethoxy)ethoxy) methyl)-[1,1'-biphenyl]-4-yl)- 1H-benzo[d]imidazol-2-yl)oxy)benzoic acid; 120: 5-((4,6-difluoro-5-(4'-((3-(2-methoxyethoxy)azetidin-1-yl)me thyl)-[1,1'-biphenyl]-4-yl)- 1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 121: 5-((6-chloro-5-(4'-((3-(2-methoxyethoxy)azetidin-1-yl)methyl )-[1,1'-biphenyl]-4-yl)-1H- benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid; 122: 5-((6-chloro-5-(4'-((3-(2-(trifluoromethoxy)ethoxy)azetidin- 1-yl)methyl)-[1,1'-biphenyl]-4- yl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)-2-methylbenzoic acid. [00136] In some embodiments, the compound is a pharmaceutically acceptable salt of a compound in Table 2. Further Forms of Compounds [00137] Furthermore, in some embodiments, the compounds described herein exist as “geometric isomers.” In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, compounds exist as tautomers. [00138] A “tautomer” refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. In some embodiments, the compounds presented herein exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

[00139] In some situations, the compounds described herein possess one or more chiral centers and each center exists in the (R)- configuration or (S)- configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as optically pure enantiomers by chiral chromatographic resolution of the racemic mixture. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred (e.g., crystalline diastereomeric salts). In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization. [00140] The term “positional isomer” refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring. [00141] The methods and formulations described herein include the use of crystalline forms (also known as polymorphs), or pharmaceutically acceptable salts of compounds described herein, as well as active metabolites of these compounds having the same type of activity. [00142] “Pharmaceutically acceptable salt” includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. [00143] “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Science, 66:1- 19 (1997). Acid addition salts of basic compounds are prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt. [00144] “Pharmaceutically acceptable base addition salt” refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N- dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al., supra. [00145] “Prodrug” is meant to indicate a compound that is, in some embodiments, converted under physiological conditions or by solvolysis to an active compound described herein. Thus, the term prodrug refers to a precursor of an active compound that is pharmaceutically acceptable. A prodrug is typically inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam).

[00146] A discussion of prodrugs is provided in Higuchi, T., et al., “Pro-drugs as Novel Delivery Systems,” A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergam on Press, 1987. [00147] The term “prodrug” is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of an active compound, as described herein, are prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound. Prodrugs include compounds wherein a hydroxy, amino, carboxy, or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino, free carboxy, or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol or amine functional groups in the active compounds and the like.

[00148] “Pharmaceutically acceptable solvate” refers to a composition of matter that is the solvent addition form. In some embodiments, solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of making with pharmaceutically acceptable solvents such as water, ethanol, and the like. “Hydrates” are formed when the solvent is water, or “alcoholates” are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. The compounds provided herein optionally exist in either unsolvated as well as solvated forms. [00149] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of ² H, ³ H, ¹¹ C, ¹³ C and/or ¹⁴ C. In some embodiments, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos.5,846,514 and 6,334,997. As described in U.S. Patent Nos.5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs. [00150] Unless otherwise stated, structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by ¹³ C- or ¹⁴ C-enriched carbon are within the scope of the present disclosure. [00151] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium ( ² H), tritium ( ³ H), iodine-125 ( ¹²⁵ I) or carbon-14 ( ¹⁴ C). Isotopic substitution with ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ C, ¹² N, ¹³ N, ¹⁵ N, ¹⁶ N, ¹⁷ O, ¹⁸ O, ¹⁴ F, ¹⁵ F, ¹⁶ F, ¹⁷ F, ¹⁸ F, ³³ S, ³⁴ S, ³⁵ S, ³⁶ S, ³⁵ Cl, ³⁷ Cl, ⁷⁹ Br, ⁸¹ Br, ¹²⁵ I are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention. [00152] In some embodiments, the compounds disclosed herein have some or all of the ¹ H atoms replaced with ² H atoms. The methods of synthesis for deuterium-containing compounds are known in the art. In some embodiments deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32. [00153] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. [00154] In some embodiments, the compounds described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, as described herein are substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as contaminating intermediates or by-products that are created, for example, in one or more of the steps of a synthesis method. Preparation of the Compounds [00155] Compounds described herein are synthesized using standard synthetic techniques or using methods known in the art in combination with methods described herein. [00156] Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are employed. [00157] Compounds are prepared using standard organic chemistry techniques such as those described in, for example, March’s Advanced Organic Chemistry, 6th Edition, John Wiley and Sons, Inc. Alternative reaction conditions for the synthetic transformations described herein may be employed such as variation of solvent, reaction temperature, reaction time, as well as different chemical reagents and other reaction conditions. [00158] In some embodiments, compounds described herein are prepared as outlined in the Schemes below. Scheme 1. PG is a suitable protecting group; a. SnCl ₂ -2H ₂ O or Fe/NH ₄ Cl; b. C(S)Cl ₂ or CS ₂ /KOH; c. CH ₃ I; d. [ox]; e. protection; f. base; g. R ^A -B(OR) ₂ , cross-coupling conditions; h. deprotection and optional substituent modification [00159] Briefly, nitropyridine (Y=N) or nitrophenyl (Y=CH or CR ⁶ ) compound A is reduced to diaminopyridine compound B. Compound B is treated with thiophosgene or carbon disulfide or an equivalent to afford compound C. Compound C undergoes a methylation reaction following by oxidation to afford compound D. Compound D is protected with a suitable protecting group to afford compound E. Aryl sulfone E underdgoes a substitution reaction with a suitable phenol to afford ester compound F (R ⁵ is, for example, C ₁ -C ₄ alkyl). Aryl iodide F is treated under cross-coupling conditions, for example Suzuki cross-coupling, to arrive at compound G. Finally, protecting group removal and in some cases saponification yields final Compounds of Formula (I). In some instances, additional chemical modification, such as amide formation or reductive amination, is performed on compound G before final deprotection. In other embodiments, such modifications are performed directly on the Compounds of Formula (I) to afford additional compounds. Scheme 2. Z is a suitable leaving group; PG is a suitable protecting group; R ⁵ is, for example, C ₁ -C ₄ alkyl; a. Ar-I; b. pinacolato diboron; c. cross-coupling conditions; d. deprotection; e. amine, NaBH(OAc) ₃ [00160] Briefly, aryl boronate H is treated under cross-coupling conditions, for example Suzuki cross-coupling, to arrive at compound J. Compound J is converted to boronate K. Aryl iodide F is treated with boronate compound K under cross-coupling conditions, for example Suzuki cross-coupling, to arrive at compound L. Protecting group removal and saponification yields aldehyde M. Finally, aldehyde M undergoes reductive amination to yield final Compounds of Formula (I). In some instances, additional chemical modification, such as amide formation, is performed on Compounds of Formula (I) to afford additional compounds. [00161] In some embodiments, compounds described herein are prepared as described as outlined in the Examples.

Pharmaceutical Compositions

[00162] In some embodiments, disclosed herein is a pharmaceutical composition comprising an AMPK activator described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, and at least one pharmaceutically acceptable excipient. In some embodiments, the AMPK activator is combined with a pharmaceutically suitable (or acceptable) carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration, e.g., oral administration, and standard pharmaceutical practice.

[00163] Examples of suitable aqueous and non-aqueous carriers which are employed in the pharmaceutical compositions include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof; vegetable oils, such as olive oil; and injectable organic esters, such as ethyl oleate and cyclodextrins. Proper fluidity is maintained, for example, by the use of coating materials, such as lecithin; by the maintenance of the required particle size, in the case of dispersions; and by the use of surfactants.

Combination Therapies

[00164] In some embodiments, it is appropriate to administer at least one compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, in combination with one or more other therapeutic agents.

[00165] In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered in combination with one or more anti-inflammatory agents. Examples of anti-inflammatory agents to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, include, but are not limited to: aminosalicylates such as balsalazide, mesalamine, olsalazine, and sulfalazine; corticosteroids such as budesonide, prednisone, prednisolone, methylprednisolone, dexamethasone, and betamethasone; anti-TNF alpha agents such as infliximab, adalimumab, certolizumab pegol, golimumab, and PRX-106; anti-IL-12 and/or 23 agents such as ustekinumab, guselkumab, brazikumab, mirikizumab, risankizumab, and PTG-200; anti-integrin agents such as natalizumab, vedolizumab, etrolizumab, SHP 647 (PF-00547659), alicaforsen, abrilumab, AJM300, and PTG-100; JAK inhibitors such as tofacitinib, filgotinib, peficitinib, itacitinib, ABT-494, and TD-1473; S1P1R modulators such as ozanimod, amiselimod, etrasimod, and CBP-307; salicylates such as aspirin, salicylic acid, gentisic acid, choline magnesium salicylate, choline salicylate, choline magnesium salicylate, choline salicylate, magnesium salicylate, sodium salicylate, and diflunisal; COX inhibitors such as carprofen, fenoprofen, fenoprofen calcium, fluorobiprofen, ibuprofen, ketoprofen, nabutone, ketolorac, ketorolac tromethamine, naproxen, oxaprozin, diclofenac, etodolac, indomethacin, sulindac, tolmetin, meclofenamate, meclofenamate sodium, mefenamic acid, piroxicam, and meloxicam; COX-2 specific inhibitors such as, but not limited to, celecoxib, rofecoxib, valdecoxib, parecoxib, etoricoxib, lumiracoxib, CS-502, JTE-522, L- 745337, and NS398; and IL-22 agents such as RG-7880. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered in combination with a aminosalicylate, a corticosteroid, an anti-TNF alpha agent, an anti-IL-12 and/or 23 agent, an anti-integrin agent, a JAK inhibitor, a S1P1R modulator, a salicylate, a COX inhibitor, a COX-2 specific inhibitor, an interleukin-22 (IL-22) agent, or a combination thereof. [00166] In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered in combination with one or more agents that improve gastrointestinal barrier function. Examples of agents that improve gastrointestinal barrier function to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, include, but are not limited to: HIF-PH inhibitors such as DS-1093, TRC-160334, and GB-004; MC1R agonists such as PL-8177; EZH2 inhibitors such as IMU-856; and DPP-4 inhibitors such as sitagliptin, vildagliptin, saxagliptin, linagliptin, gemigliptin, teneligliptin, alogliptin, trelagliptin, omarigliptin, evogliptin, gosogliptin, and dutogliptin. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered in combination with a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor, a melanocortin-1 receptor (MC1R) agonist, an enhancer of zeste homolog 2 (EZH2) inhibitor, or combinations thereof. [00167] In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered in combination with a glucagon-like peptide (GLP)-1 agonist, a GLP-2 agonist, a GLP-1/2 co-agonist, a peroxisome proliferator-activator receptor (PPAR) agonist, a Farsnenoid X receptor (FXR) agonist, a TGR5 agonist, a GPR40 agonist, a GPR119 agonist, an SSTR5 antagonist, an SSTR5 inverse agonist, an acetyl-CoA carboxylase (ACC) inhibitor, a stearoyl-CoA desaturase 1 (SCD-1) inhibitor, a dipeptidyl peptidase 4 (DPP-4) inhibitor, or combinations thereof. In some embodiments, the pharmaceutical composition comprises one or more anti-diabetic agents. In some embodiments, the pharmaceutical composition comprises one or more anti-obesity agents. In some embodiments, the pharmaceutical composition comprises one or more agents to treat nutritional disorders. [00168] Examples of a GLP-1 agonist to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, include: exenatide, liraglutide, taspoglutide, lixisenatide, albiglutide, dulaglutide, semaglutide, OWL833 and ORMD 0901. [00169] Examples of a GLP-2 agonist to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, include: tedaglutide, glepaglutide (ZP1848), elsiglutide (ZP1846), apraglutide (FE 203799), HM-15912, NB-1002, GX-G8, PE-0503, and SAN-134, and those described in WO-2011050174, WO- 2012028602, WO-2013164484, WO-2019040399, WO-2018142363, WO-2019090209, WO- 2006117565, WO-2019086559, WO-2017002786, WO-2010042145, WO-2008056155, WO- 2007067828, WO-2018229252, WO-2013040093, WO-2002066511, WO-2005067368, WO- 2009739031, WO-2009632414, and WO2008028117 [00170] Examples of a GLP-1/2 co-agonist to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, include ZP-GG-72 and those described in WO-2018104561, WO-2018104558, WO- 2018103868, WO-2018104560, WO-2018104559, WO-2018009778, WO-2016066818, and WO-2014096440.. [00171] Examples of a PPAR agonist to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, include: elafibranor (GFT505), lanifibranor, pioglitazone, rosiglitazone, saroglitazar, seladelpar, and GW501516. [00172] Examples of a FXR agonist to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, include: obeticholic acid, NGM-282, EYP001, GS-9674, tropifexor (LJN452), and LMB-763. [00173] Examples of a TGR5 agonist to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, include: INT-777, XL-475, SRX-1374, RDX-8940, RDX-98940, SB-756050, and those disclosed in WO-2008091540, WO-2010059853, WO-2011071565, WO-2018005801, WO-2010014739, WO-2018005794, WO-2016054208, WO-2015160772, WO-2013096771, WO-2008067222, WO-2008067219, WO-2009026241, WO-2010016846, WO-2012082947, WO-2012149236, WO-2008097976, WO-2016205475, WO-2015183794, WO-2013054338, WO-2010059859, WO-2010014836, WO-2016086115, WO-2017147159, WO-2017147174, WO-2017106818, WO-2016161003, WO-2014100025, WO-2014100021, WO-2016073767, WO-2016130809, WO-2018226724, WO-2018237350, WO-2010093845, WO-2017147137, WO-2015181275, WO-2017027396, WO-2018222701, WO-2018064441, WO-2017053826, WO-2014066819, WO-2017079062, WO-2014200349, WO-2017180577, WO-2014085474.

[00174] Examples of a GPR40 agonist to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, include: fasiglifam, MR-1704, SCO-267, SHR-0534, HXP-0057-SS, LY-2922470, P-11187, JTT-851, ASP-4178, AMG-837, ID-11014A, HD-C715, CNX-011-67, JNJ-076, TU-5113, HD-6277, MK-8666, LY-2881835, CPL-207-280, ZYDG-2, and those described in US-07750048, WO- 2005051890, WO-2005095338, WO-2006011615, WO-2006083612, WO-2006083781, WO- 2007088857, WO-2007123225, WO-2007136572, WO-2008054674, WO-2008054675, WO- 2008063768, WO-2009039942, WO-2009039943, WO-2009054390, WO-2009054423, WO- 2009054468, WO-2009054479, WO-2009058237, WO-2010085522, WO-2010085525, WO- 2010085528, WO-2010091176, WO-2010123016, WO-2010123017, WO-2010143733, WO- 2011046851, WO-2011052756, WO-2011066183, WO-2011078371, WO-2011161030, WO- 2012004269, WO-2012004270, WO-2012010413, WO-2012011125, WO-2012046869, WO- 2012072691, WO-2012111849, WO-2012147518, WO-2013025424, WO-2013057743, WO- 2013104257, WO-2013122028, WO-2013122029, WO-2013128378, WO-2013144097, WO- 2013154163, WO-2013164292, WO-2013178575, WO-2014019186, WO-2014073904, WO- 2014082918, WO-2014086712, WO-2014122067, WO-2014130608, WO-2014146604,WO- 2014169817, WO-2014170842,WO-2014187343, WO-2015000412, WO-2015010655, WO- 2015020184, WO-2015024448, WO-2015024526, WO-2015028960, WO-2015032328, WO- 2015044073, WO-2015051496, WO-2015062486, WO-2015073342, WO-2015078802, WO- 2015084692, WO-2015088868, WO-2015089809, WO-2015097713, WO-2015105779, WO- 2015105786, WO-2015119899, WO-2015176267, WG-201600771, WO-2016019587, WO- 2016022446, WO-2016022448, WO-2016022742, WO-2016032120, WO-2016057731, WO- 2017025368, WO-2017027309, WO-2017027310, WO-2017027312, WO-2017042121, WO- 2017172505, WO-2017180571, WO-2018077699, WO-2018081047, WO-2018095877, WO- 2018106518, WO-2018111012, WO-2018118670, WO-2018138026, WO-2018138027, WO- 2018138028, WO-2018138029, WO-2018138030, WO-2018146008, WO-2018172727, WO- 2018181847, WO-2018182050, WO-2018219204, WO-2019099315, and WO-2019134984. [00175] Examples of a GPR119 agonist to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, include: DS-8500a, HD-2355, LC34AD3, PSN-491, HM-47000, PSN-821, MBX-2982, GSK-1292263, APD597, DA-1241, and those described in WO-2009141238, WO-2010008739, WO-2011008663, WO-2010013849, WO-2012046792, WO-2012117996, WO-2010128414, WO-2011025006, WO-2012046249, WO-2009106565, WO-2011147951, WO-2011127106, WO-2012025811, WO-2011138427, WO-2011140161, WO-2011061679, WO-2017175066, WO-2017175068, WO-2015080446, WO-2013173198, US-20120053180, WO-2011044001, WO-2010009183, WO-2012037393, WO-2009105715, WO-2013074388, WO-2013066869, WO-2009117421, WO-201008851, WO-2012077655, WO-2009106561, WO-2008109702, WO-2011140160, WO-2009126535, WO-2009105717, WO-2013122821, WO-2010006191, WO-2009012275, WO-2010048149, WO-2009105722, WO-2012103806, WO-2008025798, WO-2008097428, WO-2011146335, WO-2012080476, WO-2017106112, WO-2012145361, WO-2012098217, WO-2008137435, WO-2008137436, WO-2009143049, WO-2014074668, WO-2014052619, WO-2013055910, WO-2012170702, WO-2012145604, WO-2012145603, WO-2011030139, WO-2018153849, WO-2017222713, WO-2015150565, WO-2015150563, WO-2015150564, WO-2014056938, WO-2007120689, WO-2016068453, WO-2007120702, WO-2013167514, WO-2011113947, WO-2007003962, WO-2011153435, WO-2018026890, WO-2011163090, WO-2011041154, WO-2008083238, WO-2008070692, WO-2011150067, and WO-2009123992. [00176] Examples of a SSTR5 antagonist or inverse agonist to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, include those described in: WO-03104816, WO-2009050309, WO- 2015052910, WO-2011146324, WO-2006128803, WO-2010056717, WO-2012024183, and WO-2016205032. [00177] Examples of an ACC inhibitor to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, include: firsocostat, GS-834356, and PF-05221304. [00178] Examples of a SCD-1 inhibitor to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, include aramchol. [00179] Examples of a DPP-4 inhibitor to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, include: sitagliptin, vildagliptin, saxagliptin, linagliptin, gemigliptin, teneligliptin, alogliptin, trelagliptin, omarigliptin, evogliptin, gosogliptin, and dutogliptin. [00180] Examples of anti-diabetic agents to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, include: GLP-1 receptor agonists such as exenatide, liraglutide, taspoglutide, lixisenatide, albiglutide, dulaglutide, semaglutide, OWL833 and ORMD 0901; SGLT2 inhibitors such as dapagliflozin, canagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, remogliflozin, sergliflozin, sotagliflozin, and tofogliflozin; biguinides such as metformin; insulin and insulin analogs. [00181] Examples of anti-obesity agents to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, include: GLP-1 receptor agonists such as liraglutide, semaglutide; SGLT1/2 inhibitors such as LIK066, pramlintide and other amylin analogs such as AM-833, AC2307, and BI 473494; PYY analogs such as NN-9747, NN-9748, AC-162352, AC-163954, GT-001, GT-002, GT-003, and RHS-08; GIP receptor agonists such as APD-668 and APD-597; GLP-1/GIP co- agonists such as tirzepatide (LY329176), BHM-089, LBT-6030, CT-868, SCO-094, NNC-0090- 2746, RG-7685, NN-9709, and SAR-438335; GLP-1/glucagon co-agonist such as cotadutide (MEDI0382), BI 456906, TT-401, G-49, H&D-001A, ZP-2929, and HM-12525A; GLP- 1/GIP/glucagon triple agonist such as SAR-441255, HM-15211, and NN-9423; GLP-1/secretin co-agonists such as GUB06-046; leptin analogs such as metreleptin; GDF15 modulators such as those described in WO2012138919, WO2015017710, WO2015198199, WO-2017147742 and WO-2018071493; FGF21 receptor modulators such as NN9499, NGM386, NGM313, BFKB8488A (RG7992), AKR-001, LLF-580, CVX-343, LY-2405319, BIO89-100, and BMS- 986036; MC4 agonists such as setmelanotide; MetAP2 inhibitors such as ZGN-1061; ghrelin receptor modulators such as HM04 and AZP-531; and oxytocin analogs such as carbetocin. [00182] Examples of agents for nutritional disorders to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, include: GLP-2 receptor agonists such as tedaglutide, glepaglutide (ZP1848), elsiglutide (ZP1846), apraglutide (FE 203799), HM-15912, NB-1002, GX-G8, PE-0503, SAN- 134, and those described in WO-2011050174, WO-2012028602, WO-2013164484, WO- 2019040399, WO-2018142363, WO-2019090209, WO-2006117565, WO-2019086559, WO- 2017002786, WO-2010042145, WO-2008056155, WO-2007067828, WO-2018229252, WO- 2013040093, WO-2002066511, WO-2005067368, WO-2009739031, WO-2009632414, and WO2008028117; and GLP-1/GLP-2 receptor co-agonists such as ZP-GG-72 and those described in WO-2018104561, WO-2018104558, WO-2018103868, WO-2018104560, WO-2018104559, WO-2018009778, WO-2016066818, and WO-2014096440. [00183] In one embodiment, the therapeutic effectiveness of one of the compounds described herein is enhanced by administration of an adjuvant (i.e., by itself the adjuvant has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Or, in some embodiments, the benefit experienced by a patient is increased by administering one of the compounds described herein with another agent (which also includes a therapeutic regimen) that also has therapeutic benefit. [00184] In one specific embodiment, a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is co-administered with one or more additional therapeutic agents, wherein the compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, and the additional therapeutic agent(s) modulate different aspects of the disease, disorder or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone. In some embodiments, the additional therapeutic agent(s) is a glucagon-like peptide (GLP)-1 agonist, a GLP-2 agonist, a GLP-1/2 co-agonist, a peroxisome proliferator-activator receptor (PPAR) agonist, a Farsnenoid X receptor (FXR) agonist, a stearoyl-CoA desaturase 1 (SCD-1) inhibitor, a dipeptidyl peptidase 4 (DPP-4) inhibitor, or a combination thereof. In some embodiments, the second therapeutic agent is an anti-inflammatory agent. In some embodiments, the additional therapeutic agent(s) is an aminosalicylate, a corticosteroid, an anti-TNF alpha agent, an anti-IL- 12 and/or 23 agent, an anti-integrin agent, a JAK inhibitor, a S1P1R modulator, a salicylate, a COX inhibitor, a COX-2 specific inhibitor, an IL-22 agent, or a combination thereof. In some embodiments, the second therapeutic agent is an agent that improves gastrointestinal barrier function. In some embodiments, the additional therapeutic agent(s) is a HIF-PH inhibitor, an MC1R agonist, an EZH2 inhibitor, or a combination thereof. [00185] In some embodiments, the overall benefit experienced by the patient is additive of the two (or more) therapeutic agents. In other embodiments, the patient experiences a synergistic benefit of the two (or more) therapeutic agents. [00186] In combination therapies, the multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order or even simultaneously. If administration is simultaneous, the multiple therapeutic agents are, by way of example only, provided in a single, unified form, or in multiple forms (e.g., as a single pill or as two separate pills). [00187] The compounds described herein, or pharmaceutically acceptable salts, solvates, stereoisomers, or prodrugs thereof, as well as combination therapies, are administered before, during or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound varies. Thus, in one embodiment, the compounds described herein are used as a prophylactic and are administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition. In another embodiment, the compounds and compositions are administered to a subject during or as soon as possible after the onset of the symptoms. In specific embodiments, a compound described herein is administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease. [00188] In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is administered in combination with anti-inflammatory agent, anti-cancer agent, immunosuppressive agent, steroid, non-steroidal anti-inflammatory agent, antihistamine, analgesic, hormone blocking therapy, radiation therapy, monoclonal antibodies, or combinations thereof. EXAMPLES List of Abbreviations [00189] As used above, and throughout the description of the invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings: ACN or MeCN acetonitrile AcOH or HOAc acetic acid ADP adenosine diphosphate AMP adenosine monophosphate AMPK 5' AMP-activated protein kinase or adenosine 5'–monophosphate– activated protein kinase ATP adenosine triphosphate aq aqueous BPD bis(pinacolato)diboron Boc tert-butyloxycarbonyl CDI 1,1'-carbonyldiimidazole DCM dichloromethane DEA diethylamine DIEA or DIPEA N,N-diisopropylethylamine DMA dimethylacetamide DME dimethoxyethane DMF dimethylformamide DMF-DMA N,N-dimethylformamide dimethyl acetal DMSO dimethyl sulfoxide eq equivalent(s) Et ethyl EtOH ethanol EtOAc or EA ethyl acetate FA formic acid Fmoc fluorenylmethoxycarbonyl h, hr(s) hour(s) HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxide hexafluorophosphate HPLC high performance liquid chromatography iPrOH, IPA iso-propanol KOAc potassium acetate LCMS liquid chromatography-mass spectrometry mCPBA meta-chloroperoxybenzoic acid Me methyl MeOH methanol MeI methyl iodide min(s) minute(s) NaBH(OAc) ₃ sodium triacetoxyborohydride NIS N-iodosuccinimide NMR nuclear magnetic resonance Oxone potassium peroxysulfate PCy ₃ Pd G3 [(tricyclohexylphosphine)-2-(2'-aminobiphenyl)]palladium(II) methanesulfonate Pd(dppf)Cl ₂ [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex Pd(PPh3)4 palladium-tetrakis(triphenylphosphine) PE petroleum ether SEM 2-(trimethylsilyl)ethoxymethyl SEM-Cl 2-(trimethylsilyl)ethoxymethyl chloride SFC supercritical fluid chromatography rt or RT room temperature Tf trifluoromethylsulfonyl tBu tert-butyl TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography I. Chemical Synthesis [00190] Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Anhydrous solvents and oven-dried glassware were used for synthetic transformations sensitive to moisture and/or oxygen. Yields were not optimized. Reaction times are approximate and were not optimized. Column chromatography and thin layer chromatography (TLC) were performed on silica gel unless otherwise noted. Example 1: methyl 5-((6-chloro-5-(4'-((2-(2-hydroxyethoxy)ethoxy)methyl)-[1,1' -biphenyl]- 4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoate (Compound 1) & 5-((6-chloro-5-(4'- ((2-(2-hydroxyethoxy)ethoxy)methyl)-[1,1'-biphenyl]-4-yl)-1H -benzo[d]imidazol-2-yl)oxy)- 2-methylbenzoic acid (Compound 2):

[00191] Step 1: 5-chloro-4-iodo-2-nitroaniline (1-1): To a solution of 5-chloro-2- nitroaniline (100 g, 0.58 mol, 1 eq) in AcOH (1 L) was added NIS (130 g, 0.58 mol, 1 eq). The mixture was stirred at 65 °C for 4 hr. The reaction mixture was filtered, and the residue was washed with H ₂ O to give the crude product. The crude product was dried in vacuo to give 1-1 (149 g, 86% yield) as yellow solid. LCMS: (ES+) m/z (M+H) ⁺ =299.0. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.17 - 7.28 (1 H, m) 7.56 (2 H, br s) 8.20 - 8.39 (1 H, m). [00192] Step 2: 4-chloro-5-iodo-benzene-1,2-diamine (1-2): To a solution of 1-1 (149 g, 0.49 mol, 1 eq) in EtOH (800 mL) and H ₂ O (800 mL) was added Fe (279 g, 5.0 mol, 10 eq) and NH ₄ Cl (214 g, 4.0 mol, 8 eq). The mixture was stirred at 50 °C for 12 hr. The solution was filtered to give a solution. The solution was extracted with EA (500 mL×10), then the combined organic layers were dried over by Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give to give 1-2 (110 g, 79% yield, 96% purity) as off-white solid. LCMS: (ES ⁺ ) m/z (M+H) ⁺ = 268.9. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.28-6.05 (m, 1 H), 6.73 - 6.68 (m, 1 H), 5.54 - 4.25 (m, 4 H). [00193] Step 3: 5-chloro-6-iodo-1,3-dihydrobenzimidazole-2-thione (1-3): To a solution of 1-2 (110 g, 0.41 mol, 1 eq) in EtOH (800 mL) and H ₂ O (800 mL) was added CS ₂ (37 g, 0.49 mol, 30 mL, 1.2 eq) and KOH (28 g, 0.49 mol, 1.2 eq). The mixture was stirred at 70 °C for 19 hours. The pH of the reaction solution was adjusted to 1 with 4 M aqueous HCl. The solid was precipitated, collected, and dried in vacuo to give 1-3 (150 g, 71% yield, 60% purity) as off- white solid. LCMS: (ES ⁺ ) m/z (M+H) ⁺ = 310.8. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.65 (s, 1 H), 7.37 (s, 1 H). [00194] Step 4: 6-chloro-5-iodo-2-methylsulfanyl-1H-benzimidazole (1-4): To a solution of 1-3 (100 g, 0.32 mol, 1 eq) in EtOH (1.2 L) was added KOH (22 g, 0.39 mol, 1.2 eq) at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. Then to the mixture was added MeI (46 g, 0.32 mol, 20 mL, 1 eq) at 0 °C. The mixture was stirred at 25 °C for 2.5 hours. The reaction mixture was quenched by addition of saturated aqueous NH ₄ Cl solution (1 L) at 0 °C. The solid was precipitated, collected and dried in vacuo to give 1-4 (95 g, crude) as an off-white solid. LCMS: (ES ⁺ ) m/z (M+H) ⁺ = 324.7. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.05 (s, 1 H), 7.76 (s, 1 H), 2.77 (s, 3 H). [00195] Step 5: 6-chloro-5-iodo-2-methylsulfonyl-1H-benzimidazole (1-5): To a solution of 1-4 (95 g, 0.29 mol, 1 eq) in ACN (300 mL) and H ₂ O (300 mL) was added Oxone (396 g, 0.64 mol, 2.2 eq) at 0 °C. The mixture was stirred at 25 °C for 12 hours. The reaction mixture was quenched by addition of saturated aqueous Na ₂ SO ₃ solution (800 mL) at 0 °C, and then diluted with H ₂ O (1 L) and extracted with ethyl acetate (1 L×3). The combined organic layers were washed with saturated brine (450 mL×2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 1-5 (56 g, 38% yield, 71% purity) as an off-white solid. LCMS: (ES ⁺ ) m/z (M+H) ⁺ = 356.7. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.28 (br s, 1 H), 7.96 (br s, 1 H), 3.52 (s, 3 H). [00196] Step 6 : 2-[(6-chloro-5-iodo-2-methylsulfonyl-benzimidazol-1-yl)metho xy]ethyl- trimethylsilane (1-6): To a solution of 1-5 (10 g, 28 mmol, 1 eq) in THF (200 mL), was added SEMCl (5.6 g, 34 mmol, 1.2 eq) and TEA (3.4 g, 34 mmol, 1.2 eq) at 0 °C. The mixture was stirred at 25 °C for 1 hr. The reaction mixture was diluted with H ₂ O (400 mL) and extracted with ethyl acetate (200 mL×3). The combined organic layers were washed with saturated aqueous NaCl (200 mL×2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=19/1) to give 1-6 (9.8 g, 67% yield, 94% purity) as white solid. LCMS: (ES ⁺ ) m/z (M+H) ⁺ = 428.8. [00197] Step 7: methyl 5-((6-chloro-5-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- benzo[d]imidazol-2-yl)oxy)-2-methylbenzoate (1-7): To a solution of 1-6 (5 g, 10.27 mmol, 1 eq) and methyl 5-hydroxy-2-methylbenzoate (1.9 g, 11 mmol, 1.1 eq) in DMF (50 mL) was added Cs ₂ CO ₃ (6.69 g, 20.54 mmol, 2 eq), and the mixture was stirred at 25 °C for 12 hrs. The solution was diluted with water (60 mL) and extracted with EA (60 mL × 3). The combined organic layers were washed with brine (150 mL×6), dried over by anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , PE:EA=100:0) to give 1-7 (6.07 g, 89% yield, 87% purity) as yellow oil, LCMS: (ES ⁺ ) m/z (M+H) ⁺ = 573.2. [00198] Step 8: 2-(2-((4-bromobenzyl)oxy)ethoxy)ethanol (1-8): To a solution of 2,2'- oxydiethanol (21 g, 0.20 mol, 5 eq) in THF (300 mL) was added NaH (16 g, 0.40 mol, 60% purity, 10 eq) at 0 °C. The mixture was stirred at 25 °C for 30 min, then was added 1-bromo-4- (bromomethyl)benzene (10 g, 40 mmol, 1 eq) at 0 °C. The mixture stirred at 70 °C for 12 hours. The reaction mixture was quenched by addition of saturated NH ₄ Cl solution (1.5 L) at 0 °C, then diluted with H ₂ O (1 L) and extracted with ethyl acetate (800 mL×3). The combined organic layers were washed with saturated brine (600 mL × 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 1-8 (9 g, 80% yield, 98% purity) as yellow oil. LCMS: (ES ⁺ ) m/z (M+Na) ⁺ = 298.9. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.52 (d, J = 8.4 Hz, 2 H), 7.28 (d, J = 8.24 Hz, 2 H), 4.46 (s, 2 H), 3.56 (s, 4 H), 3.51 (q, J = 4.88 Hz, 2 H), 3.46 - 3.42 (m, 2 H). [00199] Step 9 : 2-[2-[[4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]phenyl]methoxy]ethoxy]ethanol (1-9): To a solution of 1-8 (1 g, 3.6 mmol, 1 eq) and 4,4,5,5-tetramethyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxabor olan-2-yl)phenyl]-1,3,2- dioxaborolane (1.8 g, 5.5 mmol, 1.5 eq) in dioxane (10 mL) and H ₂ O (1 mL) was added PCy ₃ Pd G3 (0.17 g, 0.25 mmol, 0.07 eq) and Na ₂ CO ₃ (0.58 g, 5.5 mmol, 1.5 eq). And then the mixture was stirred at 80 °C for 12 hours under N ₂ atmosphere. The reaction mixture was partitioned between H ₂ O (50 mL) and ethyl acetate (30 mL×3). The organic phase was separated, washed with saturated brine (30 mL × 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (column: YMC Triart C18250×50mm×7um; mobile phase: [A: water (0.1% FA), B: ACN]; B%: 56%- 86%) to give 1-9 (0.36 g, 19% yield, 76% purity) as yellow oil. LCMS: (ES ⁺ ) m/z (M+H) ⁺ = 292.9. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.79 - 7.72 (m, 2 H), 7.70 - 7.65 (m, 4 H), 7.42 (d, J = 8.00 Hz, 2 H), 4.54 (s, 2 H), 3.58 (s, 4 H), 3.51 - 3.48 (m, 2 H), 3.46 - 3.43 (m, 2 H), 3.16 (s, 1 H), 1.31 (s, 12 H). [00200] Step 10: methyl 5-((6-chloro-5-(4'-((2-(2-hydroxyethoxy)ethoxy)methyl)-[1,1' - biphenyl]-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benz o[d]imidazol-2-yl)oxy)-2- methylbenzoate (1-10): To a solution of 1-7 (600 mg, 1.1 mmol, 1 eq) and 1-9 (760 mg, 1.3 mmol, 66% purity, 1.2 eq) in H ₂ O (2 mL) and DME (10 mL) was added Na ₂ CO ₃ (280 mg, 2.6 mmol, 2.5 eq). The mixture was purged with N ₂ 3 times, then Pd(dppf)Cl ₂ •CH ₂ Cl ₂ (86 mg, 105 umol, 0.1 eq) was added. The mixture was purged with N ₂ 2 times, then the mixture was stirred at 90 °C for 12 hours under N ₂ atmosphere. The reaction solution was diluted with water (60 mL) and extracted with EA (50 mL×3). The combined organic layers were washed with saturated brine (100 mL), dried over by anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , PE: EA=100:0 to 60:40) to give 1-10 (700 mg, 87% yield, 94% purity) as a yellow oil. LCMS: (ES+) m/z (M+H)+ = 717.2. [00201] Step 11: methyl 5-((6-chloro-5-(4'-((2-(2-hydroxyethoxy)ethoxy)methyl)-[1,1' - biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoa te (Compound 1): A solution of 1-10 (700 mg, 0.98 mmol, 1 eq) in HCl/dioxane (4 M, 7 mL) at 0 °C was stirred at 25 °C for 12 hours. The reaction solution was concentrated under reduced pressure to give 560 mg crude. A 110-mg portion was purified by prep-HPLC (column: Welch Xtimate C18 150×25mm×5um; mobile phase: [A: water (0.5% aqueous HCl), B: ACN]; B%: 42%-72%) to give Compound 1 (25 mg, 20% yield, 95% purity, HCl salt). LCMS: (ES+) m/z (M+H)+ = 587.3. ¹ H NMR (400 MHz, CD ₃ OD) δ = 7.99 (d, J = 2.4 Hz, 1H), 7.76 - 7.67 (m, 4H), 7.63 (s, 1H), 7.60 - 7.55 (m, 1H), 7.55 - 7.42 (m, 6H), 4.63 (s, 2H), 3.91 (s, 3H), 3.76 - 3.66 (m, 6H), 3.63 - 3.55 (m, 2H), 2.65 (s, 3H). [00202] Step 12: 5-((6-chloro-5-(4'-((2-(2-hydroxyethoxy)ethoxy)methyl)-[1,1' -biphenyl]- 4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid (Compound 2): To a solution of Compound 1 (450 mg, 0.72 mmol, 1 eq) in H ₂ O (1 mL), THF (1 mL) and i-PrOH (1 mL) was added LiOH (43 mg, 1.8 mmol, 2.5 eq). The mixture was stirred at 25 °C for 3 hours. The solution was diluted with water (15 mL) and extracted with EA (20 mL). The aqueous phase was acidified to a pH of 3 with 1M aqueous HCl solution, then extracted with EA (20 mL×3). The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18150 ×25 mm× 5 um;mobile phase: [A: water (0.5% aqueous HCl), B: ACN]; B%: 30%-60%) to give Compound 2 (45 mg, 10% yield, 95% purity, HCl salt) as an off-white solid. LCMS: (ES+) m/z (M+H)+ = 573.2. ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.02 (d, J = 2.8 Hz, 1H), 7.75 - 7.66 (m, 4H), 7.64 (s, 1H), 7.58 - 7.54 (m, 1H), 7.55 (d, J = 2.8 Hz, 1H), 7.54 - 7.45 (m, 6H), 4.63 (s, 2H), 3.72 - 3.69 (m, 4H), 3.69 - 3.67 (m, 2H), 3.61 - 3.57 (m, 2H), 2.66 (s, 1H), 2.71 - 2.64 (m, 1H). [00203] The following compounds were prepared according to the procedures described in Example 1 using the appropriate intermediates. Example 2: 5-((4,6-difluoro-5-(4'-((2-(2-hydroxyethoxy)ethoxy)methyl)-[ 1, 1'-biphenyl]-4- yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid (Compound 5): [00204] Step 1: 3,5-difluoro-2-nitroaniline (5-1): To a solution of 1,3,5-trifluoro-2-nitro- benzene (100 g, 0.56 mol, 66 mL, 1 eq) in EtOH (500 mL) was added NH ₃ ·H ₂ O (455 g, 3.9 mol, 500 mL, 30% purity, 6.9 eq). The mixture was stirred at 25 °C for 4 hours. The solution was concentrated under reduced pressure to give 5-1 (98 g, crude) as a red solid. LCMS: (ES ⁺ ) m/z (M+H) ⁺ =149.0. [00205] Step 2: 3,5-difluoro-4-iodo-2-nitroaniline (5-2): To a solution of 5-1 (98 g, 0.45 mol, 80% purity, 1 eq) in AcOH (800 mL) was added NIS (101 g, 0.45 mol, 1 eq) at 0 °C. The mixture was stirred at 25 °C for 2 hours. The solution was adjusted to pH 7 with saturated aqueous Na ₂ CO ₃ solution, then extracted with EA (500 mL × 10). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 5-2 (130 g, 58% yield, 60% purity) as a yellow solid. LCMS: (ES ⁺ ) m/z (M-H) - =298.9. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) = 7.35 (s, 2H), 6.66 (dd, J = 2.0, 10.4 Hz, 1H). [00206] Step 3: 3,5-difluoro-4-iodobenzene-1,2-diamine (5-3): To a solution of 5-2 (125 g, 0.42 mol, 1 eq) in EtOH (1.5 L) was added AcOH (113 g, 1.9 mol, 107 mL, 4.5 eq) and Fe (116 g, 2.1 mol, 5 eq). The mixture was stirred at 75 °C for 12 hours. The solution was filtered and concentrated under reduced pressure to give a residue. Then the residue was diluted with EA (3 L). The organic layer was washed with Na ₂ CO ₃ solution, then concentrated under reduced pressure to give 5-3 (80 g, 64% yield, 90% purity) as a black solid. LCMS: (ES ⁺ ) m/z (M+H) ⁺ =270.8. [00207] Step 4: 4,6-difluoro-5-iodo-1H-benzo[d]imidazole-2(3H)-thione (5-4): To a solution of 5-3 (80 g, 0.3 mol, 1 eq) in EtOH (1 L) and water (1 L) was added CS ₂ (68 g, 0.89 mol, 54 mL, 3 eq) and KOH (25 g, 0.44 mol, 1.5 eq). The mixture was stirred at 70 °C for 12 hours. The solution was adjusted to pH 1 with 4N aqueous HCl, then filtered to give 5-4 (144 g, crude) as a white solid. LCMS: (ES ⁺ ) m/z (M+H) ⁺ =312.7. [00208] Step 5: 4,6-difluoro-5-iodo-2-(methylthio)-1H-benzo[d]imidazole (5-5): To a solution of 5-4 (57 g, 0.18 mol, 1 eq) in EtOH (600 mL) was added KOH (12 g, 0.22 mol, 1.2 eq) at 0 °C. The mixture was stirred at 0 °C for 0.5 h, then MeI (26 g, 0.18 mol, 11 mL, 1 eq) was added. The mixture was stirred at 25 °C for 1 h. The solution was diluted with water (500 mL) and extracted with EA (500 mL × 10). The combined organic layers were washed with saturated brine (1 L × 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 5-5 (60 g, crude) as a black solid. LCMS: (ES ⁺ ) m/z (M+H) ⁺ =326.8. [00209] Step 6: 4,6-difluoro-5-iodo-2-(methylsulfonyl)-1H-benzo[d]imidazole (5-6): To a solution of 5-5 (50 g, 0.15 mol, 1 eq) in ACN (500 mL) and water (500 mL) was added Oxone (141 g, 0.23 mol, 1.5 eq). The mixture was stirred at 25 °C for 12 hours. The solution was diluted with water (500 mL) and extracted with EA (500 mL × 10). The combined organic layers were washed with saturated Na ₂ SO ₃ solution (1 L × 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 5-6 (16 g, 48% yield, 68% purity) as a yellow solid. LCMS: (ES ⁺ ) m/z (M+H) ⁺ =358.8. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) = 13.14 (dd, J = 3.20, 5.6 Hz, 2H), 6.92 (d, J = 7.20 Hz, 1H). [00210] Step 7: 4,6-difluoro-5-iodo-2-(methylsulfonyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole (5-7): To a solution of 5-6 (54 g, 0.15 mol, 1 eq) in THF (600 mL) was added TEA (22.89 g, 0.22 mol, 31.48 mL, 1.5 eq) and SEM-Cl (30.17 g, 0.18 mol, 32 mL, 1.2 eq) at 0 °C. The mixture was stirred at 25 °C for 12 hours. The solution was diluted with water (500 mL) and extracted with EA (500 mL × 10). The combined organic layers were washed with saturated brine (1L × 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=100/1 to 5/1) to give 5-7 (38 g, 50% yield, 97% purity) as a yellow oil. LCMS: (ES ⁺ ) m/z (M+H) ⁺ =551.8. ¹ H NMR (400 MHz, CDCl ₃ -d) δ = 7.40 (d, J = 7.4 Hz, 1H), 7.27 (s, 2H), 6.04 - 5.84 (m, 2H), 3.73 - 3.61 (m, 2H), 3.60 - 3.48 (m, 3H), 1.56 (s, 3H), 0.93 (m, 2H), 0.01 - 0.08 (m, 9H). [00211] Step 8: methyl 5-((4,6-difluoro-5-iodo-1-((2-(trimethylsilyl)ethoxy)methyl) -1H- benzo[d]imidazol-2-yl)oxy)-2-methylbenzoate (5-8): To a solution of 5-7 (30 g, 0.06 mmol, 1 eq) in DMF (400 mL) was added Cs ₂ CO ₃ (40 g, 0.12 mol, 2 eq) and methyl 5-hydroxy-2- methyl-benzoate (11 g, 0.07 mol, 1.1 eq). The mixture was stirred at 25 °C for 12 hours. The solution was diluted with water (500 mL), extracted with EA (500 mL × 10). The combined organic layers were washed with saturated brine (1 L × 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=100/1 to 5/1) to give 5-8 (28 g, 60% yield, 76% purity) as a yellow oil. LCMS: (ES ⁺ ) m/z (M+Na) ⁺ =575.2. [00212] Step 9: methyl 5-((4,6-difluoro-5-(4'-((2-(2-hydroxyethoxy)ethoxy)methyl)-[ 1,1'- biphenyl]-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benz o[d]imidazol-2-yl)oxy)-2- methylbenzoate (5-9): To a solution of 5-8 (0.50 g, 0.87 mmol, 1 eq.) and 1-9 (0.38 g, 0.96 mmol, 1.10 eq.) in dioxane (8 mL) and H ₂ O (0.5 mL) was added Pd(dppf)Cl ₂ (64 mg, 87 umol, 0.10 eq.) and Na ₂ CO ₃ (0.28 g, 2.6 mmol, 3.00 eq.). The mixture was degassed, purged with N ₂ 2 times, and then stirred at 90 °C for 5 hours under N ₂ atmosphere. The reaction mixture was quenched by addition H ₂ O (30 mL) and then extracted with EA (40 mL × 3). The combined organic layers were washed with saturated brine (40 mL × 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 10/1 to 1/1) to give 5-9 (0.36 g, 46% yield, 80% purity) as a yellow oil. LCMS: (ES ⁺ ) m/z (M+H) ⁺ =719.4. [00213] Step 10: methyl 5-((4,6-difluoro-5-(4'-((2-(2-hydroxyethoxy)ethoxy)methyl)- [1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methyl benzoate (Compound 6): To a solution of 5-9 (0.35 mg, 0.39 mmol, 80% purity, 1.0 eq) in DCM (2.5 mL) was added HCl/dioxane (4 M, 5 mL) at 0 °C. The mixture was stirred at 25 °C for 2 hrs. The mixture was concentrated in vacuum to remove solvent. The mixture was purified by prep-HPLC (column: Phenomenex Luna C18100 × 30 mm × 5 um; mobile phase: [A: water (0.1% FA), B: ACN]; B%: 47% - 77%) to give 5-10 (28 mg, 12% yield, 99% purity) as a yellow solid. LCMS: (ES+) m/z (M+H)+ =589.1. ¹ H NMR (400 MHz, DMSO-d ₆ ,) δ (ppm) = 7.82 - 7.75 (m, 3H), 7.72 (d, J = 8.0 Hz, 2H), 7.59 - 7.51 (m, 3H), 7.48 - 7.42 (m, 3H), 7.25 (d, J = 9.6 Hz, 1H), 4.67 - 4.57 (m, 1H), 4.55 (s, 2H), 3.84 (s, 3H), 3.60 (s, 4H), 3.53 - 3.49 (m, 2H), 3.47 - 3.43 (m, 2H), 2.54 (s, 3H). [00214] Step 11: 5-((4,6-difluoro-5-(4'-((2-(2-hydroxyethoxy)ethoxy)methyl)-[ 1,1'- biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoi c acid (Compound 5): To a solution of Compound 6 (0.45 g, 0.76 mmol, 1.00 eq.) in THF (8 mL) and H ₂ O (2 mL) was added LiOH (55 mg, 2.3 mmol, 3 eq.). The mixture was stirred at 25 °C for 2 hrs. The mixture was concentrated in vacuum to remove solvent. The mixture was purified by prep-HPLC (column: Phenomenex luna C18150 × 25 mm × 10 um; mobile phase: [A: water (0.1% FA), B: ACN]; B%: 43% - 73%) to give Compound 5 (79 mg, 17% yield, 96% purity) as a yellow solid. LCMS: (ES+) m/z (M+H) ⁺ =575.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ (ppm) = 7.81 - 7.76 (m, 3H), 7.72 (d, J = 8.4 Hz, 2H), 7.58 - 7.49 (m, 3H), 7.48 - 7.38 (m, 3H), 7.26 (d, J = 9.6 Hz, 1H), 4.67 - 4.58 (m, 1H), 4.55 (s, 2H), 3.60 (s, 4H), 3.52 - 3.48 (m, 2H), 3.47 - 3.42 (m, 3H), 2.55 (s, 3H). [00215] The following compounds were prepared according to the procedures described in Example 2 using the appropriate intermediates. Example 3: 5-((6-chloro-5-(4'-((3-(((1,3-dihydroxypropan-2-yl)amino)met hyl)azetidin-1- yl)methyl)-[1,1'-biphenyl]-4-yl)-1H-imidazo[4,5-b]pyridin-2- yl)oxy)-2-methylbenzoic acid (Compound 7)

[00216] Step 1: 4'-bromo-[1,1'-biphenyl]-4-carbaldehyde (7-1): To a solution of (4- formylphenyl)boronic acid (10 g, 67 mmol, 1 eq) and 1-bromo-4-iodobenzene (19 g, 67 mmol, 1 eq) in toluene (100 mL), EtOH (50 mL) and H ₂ O (100 mL) was added Pd(PPh3)4 (0.77 g, 67 mmol, 0.01 eq) and K ₂ CO ₃ (28 g, 0.20 mol, 3 eq). The suspension was degassed under vacuum and purged with N ₂ several times. The mixture was stirred at 90 °C for 12 hours. The mixture was poured into H ₂ O (300 mL) and extracted with ethyl acetate (300 mL × 3). The combined organic phase was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 100/1 to 80/20) to give 7-1 (12 g, 44 mmol, 66% yield) as a yellow solid. LCMS: (ES ⁺ ) m/z (M+H) ⁺ = 263.2. [00217] Step 2: 4'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphe nyl]-4-carb aldehyde (7-2): To a mixture of 7-1 (12 g, 44 mmol, 1 eq) and BPD (13 g, 53 mmol, 1.2 eq) in dioxane (200 mL) was added Pd(dppf)Cl ₂ •CH ₂ Cl ₂ (1.8 g, 2.2 mmol, 0.05 eq) and KOAc (13 g, 13 mmol, 3 eq) under N ₂ . The mixture was stirred at 80 °C for 12 hours. The mixture was poured into H ₂ O (200 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic phase was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=100/1 to 0/1) to give 7-2 (13 g, 41 mmol, 92% yield) as a yellow solid. LCMS: (ES ⁺ ) m/z (M+H) ⁺ = 309.2. [00218] Step 3: methyl 5-((6-chloro-5-(4'-formyl-[1,1'-biphenyl]-4-yl)-1-((2- (trimethylsilyl)ethoxy) methyl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)-2-methylbenzoate (7- 3): To a solution of methyl 5-((6-chloro-5-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- imidazo[4,5-b]pyridin-2-yl)oxy)-2-methylbenzoate (1.0 g, 1.8 mmol, 1 eq; prepared via similar procedures to compound 1-7) and 7-2 (0.65 g, 2.1 mmol, 1.2 eq) in dioxane (12 mL) and H ₂ O (2.4 mL) was added Pd(dppf)Cl ₂ •CH ₂ Cl ₂ (0.29 g, 0.35 mmol, 0.2 eq) and Na ₂ CO ₃ (0.56 g, 5.3 mmol, 3 eq). The suspension was degassed under vacuum and purged with N ₂ several times. The mixture was stirred at 90 °C for 12 hours. The mixture was poured into water (20 mL) and then extracted with ethyl acetate (2 × 20 mL). The combine organic layers were washed with saturated brine (2 × 20 mL) and concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 100:1 to 0:1) to give 7-3 (0.95 g, 1.5 mmol, 86% yield) as a yellow solid. LCMS: (ES ⁺ ) m/z (M+H) ⁺ = 325.8. [00219] Step 4: methyl 5-((6-chloro-5-(4'-formyl-[1,1'-biphenyl]-4-yl)-1H-imidazo[4 ,5- b]pyridine-2-yl)oxy)-2-methylbenzoate (7-4): A mixture of 7-3 (0.9 g, 1.4 mmol, 1 eq) in HCl/dioxane (4 M, 9 mL) was stirred at 35 °C for 2 hrs. The reaction mixture was concentrated in vacuo to give 7-4 (0.85 g, crude) as a yellow solid. LCMS: (ES ⁺ ) m/z (M+H) ⁺ = 497.9. [00220] Step 5: 5-((6-chloro-5-(4'-formyl-[1,1'-biphenyl]-4-yl)-1H-imidazo[4 ,5- b]pyridine-2 -yl)oxy)-2-methylbenzoic acid (7-5): A solution of 7-4 (0.85 g, 1.7 mmol, 1 eq) and NaOH (0.41 g, 10 mmol, 6 eq) in THF (2 mL), H ₂ O (2 mL) and MeOH (2 mL) was stirred at 40 °C for 2 hr. The mixture was acidified with 4N aqueous HCl to pH 6~7, filtered to give a clear solution and then concentrated under reduced pressure to give 7-5 (0.45 g, crude) as a white solid. LCMS: (ES ⁺ ) m/z (M+Na) ⁺ = 484.0. [00221] Step 6: tert-butyl 3-(((1,3-dihydroxypropan-2-yl)amino)methyl)azetidine-1- carboxylate (7-6): To a solution of tert-butyl 3-formylazetidine-1-carboxylate (3 g, 16.20 mmol, 1 eq) and 2-aminopropane-1,3-diol (1.8 g, 19 mmol, 1.2 eq) in EtOH (30 mL) was added Pd/C (0.5 g, 10% purity) under Ar atmosphere. The suspension was degassed and purged with H ₂ (40 Psi) 3 times. The mixture was stirred under H ₂ (40 Psi) at 25 °C for 24 hours The insoluble matter was removed by filtration and washed with EtOH, and the filtrate was concentrated under reduced pressure to give 7-6 (4 g, crude) as yellow oil. [00222] Step 7: tert-butyl 3-(((((9H-fluoren-9-yl)methoxy)carbonyl)(1,3- dihydroxypropan-2-yl)amino)methyl)azetidine-1-carboxylate (7-7): To a solution of 7-6 (4 g, 15 mmol, 1 eq) and NaHCO ₃ (2.6 g, 31 mmol, 1.2 mL, 2 eq) in dioxane (24 mL) and H ₂ O (20 mL) was added 9-fluorenylmethyl chloroformate (4.8 g, 18 mmol, 1.2 eq), and the mixture was stirred at 25 °C for 12 hours. The reaction mixture was diluted with H ₂ O (30 mL) and extracted with EA (30 mL×3). The combined organic layers were filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=80/20 to 70/30) to give 7-7 (3 g, 40% yield, 98% purity) as a yellow solid. LCMS: (ES ⁺ ) m/z (M+H) ⁺ =483.2. [00223] Step 8: (9H-fluoren-9-yl)methyl (azetidin-3-ylmethyl)(1,3-dihydroxypropan-2- yl)carbamate (7-8): 7-7 (1 g, 2.1 mmol, 1 eq) was added to a mixture of 12 N aqueous HCl solution (5 mL) and MeOH (5 mL) at 25 °C. The resulting mixture was stirred at 25 °C for 2 hours. The reaction mixture was diluted with water (50 mL) and concentrated under reduced pressure to give 7-4. (0.5 g, crude) as a yellow solid. LCMS: (ES ⁺ ) m/z (M+H) ⁺ =383.2. [00224] Step 9: 5-((6-chloro-5-(4'-((3-(((1,3-dihydroxypropan-2- yl)amino)methyl)azetidin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)- 1H-imidazo[4,5-b]pyridin-2- yl)oxy)-2-methylbenzoic acid (Compound 7): To a solution of 7-5 (0.4 g, 0.83 mmol, 1 eq) and 7-8 (0.47 g, 1.2 mmol, 1.5 eq) in THF (2 mL) and DMSO (2 mL) was added AcOH (0.15 g, 2.5 mmol, 0.15 mL, 3 eq) and KOAc (0.24 g, 2.5 mmol, 3 eq). The mixture was stirred at 25 °C for 1 hour. Then NaBH(OAc) ₃ (0.35 g, 1.7 mmol, 2 eq) was added into the mixture at 0 °C. The solution was stirred at 25 °C for 12 hours. The reaction mixture was adjusted to pH 6 by addition of FA, then concentrated under vacuum to give a residue. The residue was purified by prep-HPLC (column: YMC Triart C18250 × 50mm × 7um; mobile phase: [A: water (0.5% aqueous HCl), B: MeOH]; B%: 40%-70%) to give Compound 7 (78 mg, 14% yield, 96.35% purity) as a white solid. LCMS: (ES ⁺ ) m/z (M+H) ⁺ = 628.3; HPLC: Rt = 1.434 min, 96.35 % purity.1H NMR (400 MHz, CD ₃ OD) δ ppm 8.44 (s, 1 H) 8.03 (d, J=2.8 Hz, 1 H) 7.89 (s, 1 H) 7.85 - 7.88 (m, 2 H) 7.84 (s, 1 H) 7.76 - 7.82 (m, 2 H) 7.68 (t, J=7.6 Hz, 2 H) 7.56 (dd, J=8.4, 2.75 Hz, 1 H) 7.45 (d, J=8.4 Hz, 1 H) 4.54 (d, J=7.6 Hz, 2 H) 4.35 - 4.47 (m, 1 H) 4.17 - 4.33 (m, 2 H) 4.12 (br dd, J=12, 5.25 Hz, 1 H) 3.82 - 3.93 (m, 2 H) 3.71 - 3.81 (m, 2 H) 3.63 (br d, J=7.2 Hz, 1 H) 3.56 (br d, J=6.8 Hz, 1 H) 3.33 - 3.43 (m, 2 H) 2.64 (s, 3 H). [00225] The following compounds were prepared according to the procedures described in Example 3 using the appropriate intermediates.

Example 4: 5-((6-fluoro-5-(4'-((4-(2-(2-hydroxyethoxy)ethyl)piperazin-1 -yl)methyl)-[1,1'- biphenyl]-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)-2-methylb enzoic acid (Compound 23)

[00226] Step 1: 5-fluoro-3-nitropyridin-2-amine (23-1): A solution of 2-chloro-5-fluoro-3- nitropyridine (10 g, 57 mmol, 1 eq) in THF (80 mL) and NH ₃ •H ₂ O (54 g, 0.57 mol, 59 mL, 37% purity, 10 eq) was stirred at 60 °C for 24 hours. The solution was concentrated under reduced pressure to give 23-1 (8.5 g, 51 mmol, 90% yield, 94% purity) as a black solid. LCMS: (ES ⁺ ) m/z (M+H) ⁺ =149.0. [00227] Step 2: 5-fluoropyridine-2, 3-diamine (23-2): To a solution of 23-1 (8 g, 51mmol, 1 eq) in EtOH (100 mL) was added SnCl ₂ •2H ₂ O (23 g, 0.1 mol, 2 eq), then the mixture was stirred at 70 °C for 0.5 hour. The solution was diluted with KF solution (KF: 28 g, water 300 mL). Then the solution was extracted with EA (400 mL × 5). The combined organic phase was washed with brine (500 mL × 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC (column: Welch Ultimate XB_C1873mm × 300mm × 20-40μm; mobile phase: [A: H ₂ O (0.1% FA); B: ACN] B%: 66%) to give 23-2 (5 g, 37 mmol, 73% yield, 95% purity) as a black solid. LCMS: (ES ⁺ ) m/z (M+H) ⁺ =128.1. [00228] Step 3: 6-fluoro-1H-imidazo[4,5-b]pyridin-2(3H)-one (23-3): To a solution of 23- 2 (3.6 g, 28 mmol, 1 eq) in MeCN (150 mL) was added CDI (9.2 g, 56 mmol, 2 eq). The mixture was stirred at 80 °C for 24 hours. The solution was concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC (column: Welch Ultimate XB_C18 73mm × 300mm × 20-40μm; mobile phase: [A: H ₂ O (0.1% FA); B: ACN]; B%: 44%) to give 23-3 (3 g, 19 mmol, 68% yield, 98.8% purity) as a white solid. LCMS: (ES ⁺ ) m/z (M+H) ⁺ =154.0. [00229] Step 4: 5-bromo-6-fluoro-1H-imidazo[4,5-b]pyridin-2(3H)-one (23-4): To a solution of 23-3 (2.8 g, 18 mmol, 1 eq) in HOAc (30 mL) was added Br ₂ (3.5 g, 22 mmol, 1.1 mL, 1.2 eq) and NaOAc (3 g, 36 mmol, 2 eq), and the mixture was stirred at 90 °C for 2 hours. The reaction mixture was diluted with water (500 mL) and extracted with EA (500 mL × 4). The combined organic layers were washed with brine (300 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 23-4 (3.5 g, 11 mmol, 61% yield, 74% purity) as an off-white solid. LCMS: (ES ⁺ ) m/z (M+H) ⁺ =234.0. [00230] Step 5: 5-bromo-2-chloro-6-fluoro-1H-imidazo[4,5-b]pyridine (23-5): To POCl ₃ (35 mL) was added 23-4 (3.5 g, 15 mmol, 1 eq). The mixture was stirred at 90 °C for 6 h. The solution was concentrated under reduced pressure to give 23-5 (3 g, 4.8 mmol, 32% yield, 40% purity) as a yellow solid. LCMS: (ES ⁺ ) m/z (M+H) ⁺ =251.8. [00231] Step 6: 5-bromo-2-chloro-6-fluoro-1-((2-(trimethylsilyl)ethoxy)methy l)-1H- imidazo[4,5-b]pyridine (23-6): To a solution of 23-5 (1.2 g, 4.8 mmol, 1 eq) in THF (12 mL) was added TEA (0.72 g, 7.2 mmol, 1.00 mL, 1.5 eq) and SEM-Cl (0.96 g, 5.8 mmol, 1 mL, 1.2 eq) at 0 °C. The mixture was stirred at 25 °C for 1.5 hours. The solution was diluted with water (50 mL) and extracted with EA (50 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 23- 6 (1.2 g, crude) as a yellow oil. LCMS: (ES ⁺ ) m/z (M+H) ⁺ =323.9. [00232] Step 7: methyl 5-((5-bromo-6-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H - imidazo[4,5-b]pyridin-2-yl)oxy)-2-methylbenzoate (23-7): To a solution of 23-6 (1.2 g, 3.2 mmol, 1 eq) in DMF (10 mL) was added Cs ₂ CO ₃ (2.1 g, 6.3 mmol, 2 eq) and methyl 5-hydroxy- 2-methyl-benzoate (0.68 g, 4.1 mmol, 1.3 eq). The mixture was stirred at 25 °C for 12 hours. The solution was diluted with water (50 mL), then extracted with EA (50 mL × 3). The combined organic layers were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=100/1 to 10/1) to give 23-7 (1 g, 1.6 mmol, 49% yield, 79% purity) as a yellow solid. LCMS: (ES ⁺ ) m/z (M+H) ⁺ =511.9. [00233] Step 8: 2-(2-(4-((4'-bromo-[1,1'-biphenyl]-4-yl)methyl)piperazin-1- yl)ethoxy)ethanol (23-8): A solution of 4-(4-bromophenyl)benzaldehyde (4 g, 15 mmol, 1 eq), 2-(2-piperazin-1-ylethoxy)ethanol (2.7 g, 15 mmol, 2.5 mL, 1 eq) and AcOH (1.8 g, 31 mmol, 1.8 mL, 2 eq) in THF (40 mL) was stirred at 40 °C for 1 hr, and then NaBH(OAc) ₃ (8.1 g, 38 mmol, 2.5 eq) was added to the mixture at 25 °C. The mixture was stirred at 25 °C for 11 hrs. The reaction mixture was concentrated in vacuum to give a residue that was then diluted with EA (100 mL), filtered and concentrated under reduced pressure to give 23-8 (7.6 g, crude) as a yellow solid LCMS: (ES ⁺ ) m/z (M+H) ⁺ =419.1. [00234] Step 9: 2-(2-(4-((4'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[ 1,1'-biphenyl]- 4-yl)methyl)piperazin-1-yl)ethoxy)ethanol (23-9): To a solution of 23-8 (7.6 g, 18 mmol, 1 eq) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborola n-2-yl)-1,3,2-dioxaborolane (5.1 g, 20 mmol, 1.1 eq) in dioxane (76 mL) was added KOAc (5.3 g, 54 mmol, 3 eq). The mixture was purged with N ₂ 3 times, then Pd(dppf)Cl ₂ (0.67 g, 0.91 mmol, 0.05 eq) was added. The mixture was purged with N ₂ 3 times, then stirred at 80 °C for 12 h. The reaction mixture was concentrated in vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , EtOH : EA = 0:100 to 10:90) to give 23-9 (6 g, 61% yield, 86% purity) as a yellow solid. LCMS: (ES ⁺ ) m/z (M+H) ⁺ =467.2. [00235] Step 10: methyl 5-((6-fluoro-5-(4'-((4-(2-(2-hydroxyethoxy)ethyl)piperazin-1 - yl)methyl)-[1,1'-biphenyl]-4-yl)-1-((2-(trimethylsilyl)ethox y)methyl)-1H-imidazo[4,5- b]pyridin-2-yl)oxy)-2-methylbenzoate (23-10): To a solution of 23-9 (0.6 g, 1.3 mmol, 1.1 eq) and 23-7 (0.6 g, 1.2 mmol, 1 eq) in dioxane (10 mL) and water (1 mL) was added Pd(dppf)Cl ₂ •CH ₂ Cl ₂ (95 mg, 0.12 mmol, 0.1 eq) and K ₂ CO ₃ (0.49 g, 3.5 mmol, 3 eq). The mixture was purged with N ₂ 3 times, then stirred at 130 °C for 1 hour under microwave. The solution was filtered and concentrated under reduced pressure to give a residue. The solution was purified by column chromatography (SiO ₂ , DCM/MeOH=100/0 to 10/1) to give 23-10 (0.5 g, 39% yield, 70.8% purity) as a black solid. LCMS: (ES ⁺ ) m/z (M+H) ⁺ =770.3. [00236] Step 11: methyl 5-((6-fluoro-5-(4'-((4-(2-(2-hydroxyethoxy)ethyl)piperazin-1 - yl)methyl)-[1,1'-biphenyl]-4-yl)-1H-imidazo[4,5-b]pyridin-2- yl)oxy)-2-methylbenzoate (Compound 24): To a solution of 23-10 (0.15 g, 0.19 mmol, 1 eq) in DCM (1 mL) was added TFA (4.6 g, 41 mmol, 3 mL, 208 eq) at 0 °C. The mixture was stirred at 25 °C for 2 hours. The solution was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 × 25mm × 10um; mobile phase: [A: water (0.1% FA), B: ACN]; B%: 20%-50%) and further purified by prep-HPLC (Waters xbridge 150 × 25mm × 10um; mobile phase: [A: water (10 mM NH ₄ HCO ₃ ), B: ACN]; B%: 31%-61%) to give 23-11 (10 mg, 53% yield, 90% purity) as a yellow solid. LCMS: (ES ⁺ ) m/z (M+H) ⁺ =640.3. ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.01 (d, J = 8.4 Hz, 2H), 7.90 (br s, 1H), 7.74 (d, J = 7.2 Hz, 2H), 7.68 (d, J = 6.8 Hz, 2H), 7.65 - 7.57 (m, 1H), 7.54 - 7.47 (m, 1H), 7.46 - 7.36 (m, 3H), 3.89 (d, J = 0.8 Hz, 3H), 3.69 - 3.58 (m, 6H), 3.53 (d, J = 3.6 Hz, 2H), 2.86 - 2.46 (m, 13H). [00237] Step 12: 5-((6-fluoro-5-(4'-((4-(2-(2-hydroxyethoxy)ethyl)piperazin-1 -yl)methyl)- [1,1'-biphenyl]-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)-2-m ethylbenzoic acid (Compound 23): To a solution of Compound 24 (0.4 g, 0.62 mmol, 1 eq) in THF (2 mL), water (2 mL) and i-PrOH (2 mL) was added LiOH (0.15 g, 6.3 mmol, 10 eq). The mixture was stirred at 25 °C for 2 hours. The mixture was purified by prep-HPLC (Phenomenex Luna C18150 × 25mm × 10um; mobile phase: [A: water (0.1% FA), B: ACN]; B%: 13%-43%) to give Compound 23 (114 mg, 0.17 mmol, 27% yield, 98.65% purity, FA salt) as a yellow solid. LCMS: (ES ⁺ ) m/z (M+H) ⁺ =626.5. ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.17 (d, J = 9.6 Hz, 1H), 8.05 (d, J = 2.4 Hz, 1H), 7.99 (d, J = 7.2 Hz, 2H), 7.88 (d, J = 8.0 Hz, 4H), 7.79 (d, J = 8.4 Hz, 2H), 7.57 (dd, J = 2.8, 8.4 Hz, 1H), 7.53 - 7.40 (m, 1H), 4.60 (s, 2H), 4.02 - 3.87 (m, 4H), 3.85 - 3.67 (m, 8H), 3.66 - 3.61 (m, 2H), 3.57 (br s, 2H), 2.65 (s, 3H). [00238] The following compounds were prepared according to the procedures described in Example 4 using the appropriate intermediates.

Example 5: 5-((5-(4'-((3-((2,2-difluoroethyl)amino)azetidin-1-yl)methyl )-[1,1'-biphenyl]-4- yl)-4,6-difluoro-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzo ic acid (Compound 29) [00239] Step 1: tert-butyl 3-((2,2-difluoroethyl)amino)azetidine-1-carboxylate (29-1): To a solution of tert-butyl 3-aminoazetidine-1-carboxylate (1.0 g, 5.8 mmol, 1.0 eq) in DMF (10 mL) was added Cs ₂ CO ₃ (3.8 g, 12 mmol, 2.0 eq) and 2,2-difluoroethyl trifluoromethanesulfonate (1.5 g, 7.0 mmol, 1.2 eq). The mixture was stirred at 25 °C for 16 hours. The reaction mixture was quenched by addition H ₂ O (20 mL) and then extracted with EA (20 mL ×3). The combined organic layers were washed with saturated brine (20 mL × 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 29-1 (1.4 g, crude) as yellow liquid which was used into the next step without further purification. ¹ H NMR (400 MHz, methanol-d4) δ = 6.07 - 5.59 (m, 1H), 4.14 - 4.02 (m, 2H), 3.69 - 3.58 (m, 3H), 2.98 - 2.84 (m, 2H), 1.43 (s, 9H). [00240] Step 2: tert-butyl 3-((((9H-fluoren-9-yl)methoxy)carbonyl)(2,2- difluoroethyl)amino)azetidine-1-carboxylate (29-2): To a solution of 29-1 (0.40 g, 1.7 mmol, 1.0 eq) in H ₂ O (4 mL) and dioxane (4 mL) was added Fmoc-Cl (0.53 g, 2.0 mmol, 1.2 eq) and NaHCO ₃ (0.43 g, 5.0 mmol, 0.20 mL, 3.0 eq). The mixture was stirred at 25 °C for 16 hours. The reaction mixture was quenched by addition H ₂ O (50 mL) and then extracted with EA (40 mL ×3). The combined organic layers were washed with saturated brine (30 mL × 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=5/1 to 1/1) to afford 29-2 (0.40 g, 52% yield) as a yellow liquid. ¹ H NMR (400 MHz, methanol-d ₄ ) δ = 7.80 (br d, J = 7.2 Hz, 2H), 7.59 (br d, J = 7.2 Hz, 2H), 7.46 - 7.36 (m, 2H), 7.36 - 7.28 (m, 2H), 5.48 (s, 1H), 4.70 (br d, J = 3.6 Hz, 2H), 4.24 (br s, 2H), 4.08 - 3.84 (m, 3H), 3.60 (br s, 2H), 3.19 (br d, J = 5.2 Hz, 1H), 1.42 (s, 9H). [00241] Step 3: (9H-fluoren-9-yl)methyl azetidin-3-yl(2,2-difluoroethyl)carbamate (29- 3): To a solution of 29-2 (0.40 g, 0.87 mmol, 1.0 eq) in MeOH (4 mL) was added HCl in methanol (12 M, 3.6 mL, 50 eq) at 0°C. After addition, the mixture was stirred at 25 °C for 4 hours. The reaction mixture was concentrated under reduced pressure to give 29-3 (0.36 g, crude, HCl salt) as a white solid. [00242] Step 4: 5-((5-(4'-((3-((((9H-fluoren-9-yl)methoxy)carbonyl)(2,2- difluoroethyl)amino)azetidin-1-yl)methyl)-[1,1'-biphenyl]-4- yl)-4,6-difluoro-1H- benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid (29-5): To a solution of 29-3 (0.34 g, 0.87 mmol, 1.2 eq, HCl salt) in THF (5 mL) and DMSO (1 mL) was added KOAc (0.14 g, 1.4 mmol, 2.0 eq), and the mixture was stirred at 25°C for 0.5 hour. Then to the mixture was added HOAc (130 mg, 2.2 mmol, 0.124 mL, 3.0 eq) and 5-((4,6-difluoro-5-(4'-formyl-[1,1'-biphenyl]-4-yl)- 1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid 29-4 (0.35 g, 0.72 mmol, 1.0 eq; prepared via similar procedures to compound 7-5). After addition, the mixture was stirred at 40 °C for 0.5 hour, then to the mixture was added NaBH(OAc) ₃ (0.46 g, 2.2 mmol, 3.0 eq). The reaction mixture was stirred at 25 °C for 15 hours. The reaction mixture was concentrated under reduced pressure to give 29-5 (0.55 g, crude) as a yellow liquid, which was used next step directly without further purification. [00243] Step 5: 5-((5-(4'-((3-((2,2-difluoroethyl)amino)azetidin-1-yl)methyl )-[1,1'- biphenyl]-4-yl)-4,6-difluoro-1H-benzo[d]imidazol-2-yl)oxy)-2 -methylbenzoic acid (Compound 29): To a solution of 29-5 (0.55 g, 0.67 mmol, 1.0 eq) in DCM (8 mL) was added piperidine (0.85 g, 10 mmol, 0.99 mL, 15 eq). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Phenomenex Luna C18200 × 40 mm × 10 um; mobile phase: [A: water (0.1% FA), B: ACN]; B%: 20%-50%) to give Compound 29 (78 mg, 0.15 mmol, 23% yield, 92% purity) as a white solid. LCMS: (ES+) m/z (M+H) ⁺ =605.1. ¹ H NMR (400 MHz, methanol-d ₄ ) δ = 7.76 (d, J = 8.0 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 2.4 Hz, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.49 (br d, J = 8.4 Hz, 2H), 7.34 - 7.27 (m, 2H), 7.07 (d, J = 9.2 Hz, 1H), 6.05 - 5.66 (m, 1H), 4.30 (s, 2H), 4.21 - 4.14 (m, 2H), 3.83 - 3.73 (m, 3H), 2.98 (dt, J = 3.6, 16.0 Hz, 2H), 2.58 - 2.54 (m, 3H) Example 6: 5-((4,6-difluoro-5-(4'-((3-((methylsulfonyl)methyl)azetidin- 1-yl)methyl)-[1,1'- biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoi c acid (Compound 30) [00244] Step 1: tert-butyl 3-((methylthio)methyl)azetidine-1-carboxylate (30-1): To a solution of tert-butyl 3-(iodomethyl)azetidine-1-carboxylate (0.80 g, 2.7 mmol, 1.0 eq) in MeOH (20 mL) was added NaSMe (0.47 g, 6.8 mmol, 0.43 mL, 2.5 eq). The mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with saturated aqueous NaHCO ₃ solution (20 mL) and extracted with DCM (15 mL × 3). The combined organic layers were washed with saturated brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 30-1 (0.58 g, crude) as yellow liquid, which was used into the next step without further purification. [00245] Step 2: tert-butyl 3-((methylsulfonyl)methyl)azetidine-1-carboxylate (30-2): To a solution of 30-1 (0.55 g, 2.5 mmol, 1.0 eq) in DCM (10 mL) was added m-CPBA (0.87 g, 80% purity, 4.0 mmol, 1.6 eq). The mixture was stirred at 25 °C for 16 hours. The reaction mixture was quenched by addition H ₂ O (10 mL) and then extracted with DCM (10 mL × 3). The combined organic layers were washed with aqueous Na ₂ SO ₃ (15 mL × 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue, then the residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=10/1 to 0/1) to afford 30-2 (0.24 g, 0.93 mmol, 38 % yield) as a yellow oil. ¹ H NMR (400 MHz, methanol-d ₄ ) δ = 4.12 (t, J = 8.4 Hz, 2H), 3.86 - 3.77 (m, 2H), 3.48 (d, J = 7.6 Hz, 2H), 3.20 - 3.09 (m, 1H), 2.96 (s, 3H), 1.44 (s, 9H). [00246] Step 3: 3-((methylsulfonyl)methyl)azetidine (30-3): To a solution of 30-2 (0.24 g, 96 umol, 1.0 eq) in MeOH (3 mL) was added HCl in methanol (12 M, 1.2 mL, 15 eq) at 0 °C. Then the mixture was warmed to 25 °C and stirred at 25 °C for 2 hour. The mixture was concentrated under reduced pressure to give 30-3 (180 mg, crude, HCl salt) as a yellow oil. [00247] Step 4: 5-((4,6-difluoro-5-(4'-formyl-[1,1'-biphenyl]-4-yl)-1H-benzo [d]imidazol- 2-yl)oxy)-2 methylbenzoic acid (Compound 30): To a solution of 30-3 (153 mg, 825 umol, 2.0 eq, HCl salt) in DMSO (0.2 mL) and THF (4 mL) was added NaBH(OAc) ₃ (87 mg, 413 umol, 1 eq), and the mixture was stirred at 25 °C for 0.5 hour. Then to the mixture was added KOAc (81 mg, 826 umol, 2.0 eq) and 29-4 (0.20 g, 0.41 mmol, 1.0 eq). After addition, the mixture was stirred at 40 °C for 0.5 hour, then HOAc (74 mg, 1.2 mmol, 71 uL, 3.0 eq) was added. The mixture was stirred at 25 °C for 15 hours. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was dissolved in DMF and then purified by prep-HPLC (column: Phenomenex luna C18150 × 25 mm × 10 um; mobile phase: [A: water (0.1% FA), B: ACN]; B%: 17%-47%) to give Compound 30 (49.67 mg, 19.09% yield, 98% purity) as a white solid. LCMS: (ES+) m/z (M+H) ⁺ =618.3. ¹ H NMR (400 MHz, DEUTERIUM OXIDE) δ = 8.42 (s, 1H), 7.27 (s, 4H), 7.17 - 7.12 (m, 3H), 7.10 - 7.06 (m, 2H), 6.93 (dd, J = 2.8, 8.3 Hz, 1H), 6.78 (br d, J = 7.6 Hz, 2H), 3.13 (br d, J = 12.8 Hz, 4H), 2.83 (br d, J = 6.8 Hz, 2H), 2.77 - 2.67 (m, 3H), 2.64 - 2.51 (m, 3H), 2.30 (s, 3H). [00248] The following compounds were prepared according to the procedures described in Example 6 using the appropriate intermediates.

Example 7: (S)-5-((4,6-difluoro-5-(4'-(1-(2-methoxyethyl)piperidin-3-yl )-[1,1'-biphenyl]-4- yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid (Compound 33) [00249] Step 1: 3-(4-bromophenyl)-1-(2-methoxyethyl)piperidine (33-1): To a solution of 3-(4-bromophenyl)piperidine (0.5 g, 2.1 mmol, 1 eq) and 1-bromo-2-methoxyethane (0.58 g, 4.2 mmol, 0.39 mL, 2 eq) in DMF (10 mL) was added K ₂ CO ₃ (0.86 g, 6.3 mmol, 3 eq). The mixture was stirred at 25 °C for 2 hours. The reaction mixture was partitioned between EA (100 mL × 3) and water (100 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, EA/PE= 1: 0) to give 33-1 (0.50 mg, 1.7 mmol, 81% yield) as a yellow solid. LCMS: (ES ⁺ ) m/z (M+H) ⁺ =299.0. [00250] Step 2: 1-(2-methoxyethyl)-3-(4'-(4,4,5,5-tetramethyl-1,3,2-dioxabor olan-2-yl)- [1,1'-biphenyl]-4-yl)piperidine (33-2): To a solution of 33-1 (0.3 g, 1.0 mmol, 1 eq) and 4,4,5,5-tetramethyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxabor olan-2-yl)phenyl]-1,3,2- dioxaborolane (0.66 g, 2.0 mmol, 2 eq) in dioxane (10 mL) and H ₂ O (1 mL) was added Na ₂ CO ₃ (0.16 g, 1.5 mmol, 1.5 eq). The mixture was purged with N ₂ 3 times, then [2-(2- aminophenyl)phenyl]methylsulfonyloxy-palladium;dichlorometha ne;tricyclohexylphosphane (52 mg, 70 umol, 0.07 eq) was added. The mixture was purged with N ₂ 2 times, then stirred at 80 °C for 12 hours under N ₂ atmosphere. The reaction mixture was partitioned between EA (100 mL × 3) and water (100 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , MeOH/EA= 1: 10) to give 33-2 (0.24 g, 0.57 mmol, 57% yield) as a yellow solid. LCMS: (ES+) m/z (M+H) ⁺ =422.2. [00251] Step 3: methyl 5-((4,6-difluoro-5-(4'-(1-(2-methoxyethyl)piperidin-3-yl)-[1 ,1'- biphenyl]-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benz o[d]imidazol-2-yl)oxy)-2- methylbenzoate (33-3): To a solution of 5-8 (0.22 g, 0.38 mmol, 1 eq) and 33-2 (0.24 g, 0.57 mmol, 1.5 eq) in dioxane (3 mL) and H ₂ O (0.3 mL) was added Na ₂ CO ₃ (80.49 mg, 0.76 mmol, 2 eq). The mixture was purged with N ₂ 3 times, then Pd(dppf)Cl ₂ •CH ₂ Cl ₂ (46 mg, 57 umol, 0.15 eq) was added. The mixture was purged with N ₂ 2 times and stirred at 90 °C for 12 hours under N ₂ atmosphere. The reaction mixture was partitioned between EA (50 mL × 3) and water (50 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , MEOH/EA= 1: 10) to give 33-3 (0.33 g, crude) as a yellow oil. LCMS: (ES ⁺ ) m/z (M+H) ⁺ =742.4. [00252] Step 4: methyl 5-((4,6-difluoro-5-(4'-(1-(2-methoxyethyl)piperidin-3-yl)-[1 ,1'- biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoa te (33-4): To a solution of 33-3 (0.33 g, 0.44 mmol, 1 eq) in HCOOH (4 mL) was added KHSO ₄ (61 mg, 0.44 mmol, 26 uL, 1 eq). The mixture was stirred at 25 °C for 12 hrs. The reaction mixture was partitioned between EA (50 mL × 3) and water (50 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by prep-HPLC (Waters xbridge 150 × 25 mm × 10um; mobile phase: [A: water (10 mM NH ₄ HCO ₃ ), B: ACN]; B%: 65%-95%) to give 33-4 (87 mg, 95% purity, 32% yield) as a white solid. [00253] Step 5: methyl (S)-5-((4,6-difluoro-5-(4'-(1-(2-methoxyethyl)piperidin-3-yl )-[1,1'- biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoa te (33-5B): 33-4 (87 mg) was further separated by SFC (column: Daicel Chiralpak AD 250 mm × 30 mm, 10 um; mobile phase: [A: CO ₂ , B: 0.1% NH ₄ OH in IPA]; B%: 35%-35%) to give 33-5A (45 mg) and 33-5B (40 mg) as a white solid. LCMS: (ES+) m/z (M+H) ⁺ =612.5. [00254] Step 6: (S)-5-((4,6-difluoro-5-(4'-(1-(2-methoxyethyl)piperidin-3-yl )-[1,1'- biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoi c acid (Compound 33): To a solution of 33-5B (40 mg, 65.39 umol, 1 eq) in H ₂ O (0.1 mL), THF (0.1 mL) and i-PrOH (0.1 mL) was added LiOH•H ₂ O (8.2 mg, 0.20 mmol, 3 eq). The mixture was stirred at 25 °C for 16 hours. The solution was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Phenomenex luna C18150 × 25 mm× 10 um; mobile phase: [A: water (0.5% aqueous HCl), B: ACN]; B%: 26%-56%) to give Compound 33 (17 mg, 26 umol, 40% yield, 99% purity, HCl salt) as a white solid. LCMS: (ES ⁺ ) m/z (M+H) ⁺ = 598.4. 1H NMR (400 MHz, CD ₃ OD) δ = 7.89 (d, J = 2.4 Hz, 1H), 7.72 (dd, J = 2.4, 8.2 Hz, 4H), 7.54 (br d, J = 8.0 Hz, 2H), 7.50 - 7.30 (m, 4H), 7.11 (d, J = 9.2 Hz, 1H), 3.76 (br t, J = 4.0 Hz, 2H), 3.73 - 3.58 (m, 2H), 3.43 (s, 3H), 3.39 (br s, 2H), 3.19 - 2.98 (m, 3H), 2.63 (s, 3H), 2.10 (br d, J = 17.2 Hz, 2H), 2.01 - 1.73 (m, 2H). [00255] The following compounds were prepared according to the procedures described in Example 7 using the appropriate intermediates. Example 8: 5-((5-(4'-((3-(ethylcarbamoyl)azetidin-1-yl)methyl)-[1,1'-bi phenyl]-4-yl)-4,6- difluoro-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid (Compound 37) [00256] Step 1: benzyl 3-(ethylcarbamoyl)azetidine-1-carboxylate (37-1): To a solution of 1-benzyloxycarbonylazetidine-3-carboxylic acid (1 g, 4.3 mmol, 1 eq) in DMF (10 mL) was added HATU (2.4 g, 6.4 mmol, 1.5 eq), DIPEA (2.8 g, 21 mmol, 3.7 mL, 5 eq) and ethanamine hydrochloride (3.5 g, 43 mmol, 10 eq). The mixture was stirred at 25 °C for 12 hours. The reaction mixture was partitioned between EA (100 mL × 3) and water (100 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , EA/PE= 1: 1) to give 37-1 (2.1 g crude) as a yellow oil. LCMS: (ES+) m/z (M+H) ⁺ =263.1. [00257] Step 2: N-ethylazetidine-3-carboxamide (37-2): To a solution of 37-1 (1 g, 3.8 mmol, 1 eq) in MeOH (10 mL) was added Pd/C (0.2 g, 5% purity) under N ₂ . The suspension was degassed under vacuum and purged with H ₂ several times. The mixture was stirred under H ₂ (7.7 mg, 3.8 mmol, 1 eq) (15 psi) at 25 °C for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure to give 37-2 (0.45 g, crude) as a colorless oil. ¹ H NMR (400 MHz, CD ₃ OD) δ = 3.49 (s, 1H), 2.98-2.96 (d, J = 6 Hz 2H), 2.89 (s, 2H), 2.81 (s, 2H), 1.34-1.33(m, 3H). [00258] Step 3: 5-((5-(4'-((3-(ethylcarbamoyl)azetidin-1-yl)methyl)-[1,1'-bi phenyl]-4-yl)- 4,6-difluoro-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid (Compound 37): To a solution of 29-4 (200 mg, 0.41 mmol, 1 eq) in THF (2 mL) and DMSO (1 mL) was added 37-2 (0.16 g, 1.24 mmol, 3 eq) and CH ₃ COOH (50 mg, 0.83 mmol, 47 uL, 2 eq) at 0 °C. The mixture was stirred at 40 °C for 0.5 hour. Then NaBH(OAc) ₃ (0.18 g, 0.83 mmol, 2 eq) was added, and the mixture was stirred at 25 °C for 16 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18200 × 40 mm ×10 um; mobile phase: [A: water (0.1% FA), B: ACN]; B%: 20%-50%) to give Compound 37 (20.57 mg, 7.5% yield, 96.8% purity, FA salt) as a white solid. LCMS: (ES ⁺ ) m/z (M+H) ⁺ =597.0. ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.13 - 8.07 (m, 1H), 7.81 (dd, J = 3.8, 8.2 Hz, 4H), 7.72 - 7.63 (m, 3H), 7.62 - 7.56 (m, 3H), 7.37 (d, J = 7.9 Hz, 1H), 4.59 - 4.48 (m, 2H), 4.41 - 4.17 (m, 4H), 3.76 - 3.62 (m, 1H), 3.28 - 3.21 (m, 2H), 2.68 (s, 3H), 1.19 - 1.09 (m, 3H). [00259] The following compounds were prepared according to the procedures described in Example 8 using the appropriate intermediates.

Example 9: 5-((4,6-difluoro-5-(4'-((2-oxo-4-(2,2,2-trifluoroethyl)piper azin-1-yl)methyl)- [1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methyl benzoic acid (Compound 39) [00260] Step 1: tert-butyl 4-(4-bromobenzyl)-3-oxopiperazine-1-carboxylate (39-1): To a solution of tert-butyl 3-oxopiperazine-1-carboxylate (2.0 g, 10 mmol, 1 eq) in DMF (30 mL) was added NaH (0.80 g,20 mmol, 60% purity, 2 eq) at 0°C. The mixture was stirred at 0 °C for 0.5 hour. Then to the mixture was added 1-bromo-4-(bromomethyl)benzene (7.5 g, 30 mmol, 3 eq) at 0 °C. The mixture was stirred at 60 °C for 12 hours. The reaction mixture was quenched by addition H ₂ O (50 mL) and extracted with EA (60 mL × 5). The combined organic layers were washed with saturated brine (100 mL × 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=5/1 to 1/1) to give 39-1 (2.1 g, 57% yield) as a yellow oil. (ES ⁺ ) m/z (M+H) ⁺ = 369.25. ¹ H NMR (400 MHz, methanol-d ₄ ) δ = 7.22 - 7.16 (m, 2H), 6.91 (d, J = 8.4 Hz, 2H), 4.28 (s, 2H), 3.83 - 3.76 (m, 2H), 3.04 - 2.99 (m, 4H), 1.16 (s, 9H). [00261] Step 2: 1-(4-bromobenzyl)piperazin-2-one (39-2): A solution of 39-1 (2.1 g, 6 mmol, 1 eq) in HCl/dioxane (4 M, 22 mL, 15 eq) was stirred at 25 °C for 2 hours. The mixture was concentrated under reduced pressure to give 39-2 (1.5 g, 6 mmol, 96% yield) as a yellow solid. (ES+) m/z (M+H) ⁺ = 269.0. [00262] Step 3: 1-(4-bromobenzyl)-4-(2,2,2-trifluoroethyl)piperazin-2-one (39-3): To a solution of 39-2 (1.5 g, 5 mmol, 1 eq) in DMF (15 mL) was added NaH (441 mg, 11 mmol, 60% purity, 2 eq) at 0 °C. The mixture was stirred at 0 °C for 0.5 hour. Then 1,1,1-trifluoro-2- iodoethane (6.4 g, 28 mmol, 5 eq) was added at 0 °C. The mixture was stirred at 25 °C for 12 hours. The reaction mixture was quenched by addition saturated aqueous H ₂ O (100 mL), and extracted with EA (200 mL × 3). The combined organic layers were washed with saturated brine (200 mL × 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=2/1 to 1/1) to give 39-3 (0.63 g, 31% yield, 95% purity) as a yellow solid, (ES ⁺ ) m/z (M+H) ⁺ =351.0. [00263] Step 4: 1-((4'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-b iphenyl]-4- yl)methyl)-4-(2,2,2-trifluoroethyl)piperazin-2-one (39-4): A mixture of 39-3 (0.54 g, 1.5 mmol, 94% purity, 1 eq) ,1,4-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene (723 mg, 2 mmol, 1.5 eq), Na ₂ CO ₃ (464 mg, 4.4mmol, 3 eq), and [2-(2-aminophenyl)phenyl]- methylsulfonyloxypalladium;dichloromethane;tricyclohexylphos phane (75 mg, 102 umol, 0.07 eq) in dioxane (15 mL) and H ₂ O (1.5 mL) was degassed and purged with N ₂ 3 times. The mixture was stirred at 80 °C for 12 hrs under N ₂ atmosphere. The reaction mixture was quenched by addition of H ₂ O (100 mL) and extracted with EA (100 mL × 3). The combined organic layers were washed with saturated brine (100 mL × 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=5/1 to 1/1) to give 39-4 (0.43 g, 29% yield, 47% purity) as a white solid, (ES ⁺ ) m/z (M+H) ⁺ =475.1. [00264] Step 5: methyl 5-((4,6-difluoro-5-(4'-((2-oxo-4-(2,2,2-trifluoroethyl)piper azin-1- yl)methyl)-[1,1'-biphenyl]-4-yl)-1-((2-(trimethylsilyl)ethox y)methyl)-1H-benzo[d]imidazol- 2-yl)oxy)-2-methylbenzoate (39-5): A mixture of 39-4 (0.38 g, 0.38 mmol, 47% purity, 1 eq), 5-8 (0.22 g, 0.38 mmol, 1 eq), and Na ₂ CO ₃ (0.12 g, 1 mmol, 3 eq) in dioxane (6 mL) and H ₂ O (0.6 mL) was degassed and purged with N ₂ 3 times. To the mixture was added Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (62 mg, 75umol, 0.2 eq). The reaction mixture was degassed and purged with N ₂ 3 times, then stirred at 90 °C for 12 hours under N ₂ atmosphere. The reaction mixture was quenched by addition H ₂ O (100 mL) and extracted with EA (100 mL × 3). The combined organic layers were washed with saturated brine (100 mL × 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=3/1 to 1/1) to give 39-5 (0.40 g, 72% yield, 54% purity) as a white solid. (ES ⁺ ) m/z (M+H) ⁺ =795.6. [00265] Step 6: methyl 5-((4,6-difluoro-5-(4'-((2-oxo-4-(2,2,2-trifluoroethyl)piper azin-1- yl)methyl)-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)ox y)-2-methylbenzoate (39-6): To a solution of 39-5 (0.35 g, 0.44 mmol, 1 eq) in HCOOH (5 mL) was added KHSO ₄ (60 mg, 0.44 mmol, 26 uL, 1 eq). The mixture was stirred at 25 °C for 12 hours. The mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with H ₂ O (10 mL), then adjusted to pH 8 with saturated aqueous NaHCO ₃ solution and extracted with EA (10 mL × 3). The combined organic layers were washed with saturated brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 39-6 (0.34 g, 51% yield, 44% purity) as a white solid. (ES ⁺ ) m/z (M+H) ⁺ =665.3. [00266] Step 7: 5-((4,6-difluoro-5-(4'-((2-oxo-4-(2,2,2-trifluoroethyl)piper azin-1- yl)methyl)-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)ox y)-2-methylbenzoic acid (Compound 39): To a solution of 39-6 (0.33 g, 0.50 mmol, 1 eq) in THF (2 mL) and H ₂ O (2 mL) was added LiOH•H ₂ O (63 mg, 1.5 mmol, 3 eq). The mixture was stirred at 25 °C for 12 hours. The mixture was adjusted to pH 6 with FA and concentrated under reduced pressure to give a residue. The crude product was purified by prep-HPLC (column: Phenomenex luna C18 150 × 25 mm × 10 um; mobile phase: [A: water (0.1% FA), B: ACN]; B%: 48%-78%) to give Compound 39 (30 mg, 8% yield, 97% purity, FA salt) as a white solid, (ES ⁺ ) m/z (M+H) ⁺ = 651.2. ¹ H NMR (400 MHz, methanol-d ₄ ) δ = 7.75 (br d, J = 8.0 Hz, 2H), 7.65 (br d, J = 8.4 Hz, 2H), 7.56 (br d, J = 8.0 Hz, 2H), 7.50 - 7.40 (m, 2H), 7.00 (brd, J = 9.3 Hz, 1H), 5.22 - 5.11 (m, 1H), 4.40 (s, 2H), 4.21 (br t, J = 9.6 Hz, 2H), 4.16 - 4.03 (m, 3H), 3.92 (br d, J = 10.0 Hz, 1H), 3.83 - 3.72 (m, 2H), 3.70 -3.51 (m, 5H), 3.09 (br s, 1H), 2.70 - 2.59 (m, 1H), 2.27 - 2.15 (m, 1H), 1.77 - 1.58 (m, 2H). Example 10: methyl 5-((4,6-difluoro-5-(4'-((3-(2-hydroxyethoxy)azetidin-1-yl)me thyl)-[1,1'- biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoi c acid (Compound 40)

[00267] Step 1: tert-butyl 3-(2-benzyloxyethoxy)azetidine-1-carboxylate (40-1): To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (1.0 g, 5.8 mmol, 1 eq) in DMF (25 mL) was added NaH (0.35 g, 8.7 mmol, 60% purity, 1.5 eq) at 0 °C. The mixture was stirred at 0 °C for 0.5 hour. Then 2-bromoethoxymethylbenzene (1.5 g, 6.9 mmol, 1.1 mL, 1.2 eq) was added, and the mixture was stirred at 25 °C for 16 hours. The resulting solution was quenched by addition of saturated aqueous NH ₄ Cl (50 mL) and extracted with EA (50 mL × 3). The combined organic phases were washed with water (50 mL) and saturated brine (50 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=100/1 to 1/1) to give 40-1 (0.86 g, 38% yield, 79% purity) as a yellow oil. LCMS: (ES+) m/z (M+Na) ⁺ =330.1. ¹ H NMR (400 MHz, methanol-d ₄ ) δ ppm 1.43 (9 H, s) 3.47 - 3.59 (2 H, m) 3.61 (2 H, s) 3.77 (2 H, br dd, J=9.2, 3.88 Hz) 3.99 - 4.08 (2 H, m) 4.22 - 4.34 (1 H, m) 4.54 (2 H, s) 7.20 - 7.29 (1 H, m) 7.30 (1 H, br s) 7.33 - 7.43 (3 H, m). [00268] Step 2: tert-butyl 3-(2-hydroxyethoxy)azetidine-1-carboxylate (40-2): To a solution of 40-1 (0.86 g g, 2.8 mmol, 1 eq) in MeOH (10 mL) was added Pd/C (0.20 g, 50% purity, 1.0 eq). The mixture was purged with H ₂ 3 times and then stirred at 25 °C for 48 hours under H ₂ (50 psi). TLC analysis showed no reaction had happened. Pd(OH) ₂ (0.18 g, 1.3 mmol, 0.5 eq) was added, and the reaction mixture was stirred at 25 °C for another 24 hours under H ₂ (50 psi). The solution was filtered, and the filtrate was concentrated under reduced pressure to give 40-2 (0.50 g, crude) as a yellow oil. ¹ H NMR (400 MHz, methanol-d ₄ ) δ ppm 1.44 (9 H, s) 3.48 (2 H, t, J=4.80 Hz) 3.66 (2 H, t, J=4.80 Hz) 3.80 (2 H, br dd, J=9.20, 3.50 Hz) 3.98 - 4.18 (2 H, m) 4.23 - 4.38 (1 H, m). [00269] Step 3: 2-(azetidin-3-yloxy)ethanol (40-3): A solution of 40-2 (0.50 g, crude) in MeOH (2 mL) and 12 M HCl in methanol (2 mL) was stirred at 25 °C for 24 hours. The reaction mixture was concentrated under reduced pressure to remove solvent to give 40-3 (0.25 g, crude). ¹ HNMR (400 MHz, methanol-d ₄ ) δ ppm 3.44 - 3.62 (2 H, m) 3.63 - 3.80 (2 H, m) 4.02 (2 H, br d, J=6.40 Hz) 4.17 - 4.40 (2 H, m) 4.42 - 4.62 (1 H, m). [00270] Step 4: 5-((4,6-difluoro-5-(4'-((3-(2-hydroxyethoxy)azetidin-1-yl)me thyl)-[1,1'- biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoi c acid (Compound 40): To a solution of 29-4 (0.20 g, 0.30 mmol, 72% purity, 1 eq) and 40-3 (0.25 g, crude) in THF (5 mL) and DMSO (2 mL) was added AcOH (0.02 g, 0.30 mmol, 17.00 uL, 1 eq) and KOAc (0.09 g, 0.90 mmol, 3 eq). The mixture was stirred at 40 °C for 1 hour. Then NaBH(OAc) ₃ (0.19 g, 0.89 mmol, 3 eq) was added at 0 °C. The mixture was stirred at 25 °C for 24 hours. The mixture was adjusted to pH 2 by addition of 2N aqueous HCl, then filtered. The filtrate was purified by prep- HPLC (column: Phenomenex Luna C18200 × 40 mm × 10 um; mobile phase: [A: water (0.1% FA), B: ACN]; B%: 18%-48%) to give Compound 40 (0.06 g, 0.06 mmol, 19 % yield, 99.5% purity, FA salt) as a white solid. LCMS: (ES+) m/z (M+H) ⁺ =586.2. ¹ H NMR (400 MHz, methanol-d ₄ ) δ ppm 2.69 (3 H, s) 3.52 - 3.64 (2 H, m) 3.65 - 3.73 (2 H, m) 4.03 - 4.18 (2 H, m) 4.36 - 4.46 (2 H, m) 4.46 - 4.60 (3 H, m) 7.36 (1 H, d, J=8.40 Hz) 7.52 - 7.62 (3 H, m) 7.62 - 7.72 (3 H, m) 7.81 (4 H, dd, J=8.40, 3.75 Hz) 8.06 - 8.15 (1 H, m). Example 11: 5-((4,6-difluoro-5-(4'-((4-(2,2-difluoroethyl)piperazin-1-yl )methyl)-[1,1'- biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoi c acid (Compound 41) [00271] Step 1: tert-butyl 4-(2,2-difluoroethyl)piperazine-1-carboxylate (41-1): To a solution of tert-butyl piperazine-1-carboxylate (0.5 g, 2.7 mmol, 1 eq) in THF (10 mL) was added K ₂ CO ₃ (1.1 g, 8.1 mmol, 3 eq) and 2,2-difluoroethyl trifluoromethanesulfonate (0.86 g, 4.0 mmol, 1.5 eq). The mixture was stirred at 25 °C for 12 hours. The mixture was filtered and concentrated under reduced pressure to give 41-1 (0.8 g, crude) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ = 6.17 - 5.77 (m, 1H), 3.46 - 3.40 (m, 4H), 2.77 (dt, J = 4.4, 15.2 Hz, 2H), 2.59 - 2.53 (m, 4H), 1.45 (s, 9H). [00272] Step 2: 1-(2,2-difluoroethyl)piperazine (41-2): To a solution of 41-1 (0.5 g, 2.0 mmol, 1 eq) in DCM (3 mL) was added HCl/dioxane (4 M, 0.5 mL, 1 eq). The mixture was stirred at 25 °C for 12 hours. The mixture was concentrated under reduced pressure to give 41-2 (0.33 g, crude) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ = 6.43 - 6.04 (m, 1H), 3.66 (s, 2H), 3.48 - 3.41 (m, 3H), 3.39 (d, J = 4.0 Hz, 1H), 3.36 - 3.31 (m, 4H). [00273] Step 3: 5-((4,6-difluoro-5-(4'-((4-(2,2-difluoroethyl)piperazin-1-yl )methyl)-[1,1'- biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoi c acid (Compound 41): To a solution of 29-4 (0.3 g, 0.6 mmol, 1 eq) in THF (3 mL) and DMSO (1.5 mL) was added 41-2 (0.19 g, 0.10 mmol, 1.6 eq, HCl salt) and HOAc (75 mg, 1.2 mmol, 71 uL, 2 eq) and KOAc (61 mg, 0.62 mmol, 1 eq) at 0 °C. The mixture was stirred at 40 °C for 0.5 hr. Then NaBH(OAc) ₃ (0.3 g, 1.2 mmol, 2 eq) was added. The mixture was stirred at 25 °C for 12 hours, then concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 × 25 mm × 10 um; mobile phase: [A: water (0.1% FA), B: ACN]; B%: 20%-50%) to give Compound 41 (12 mg, 18 umol, 3% yield, 95% purity, FA salt) as a white solid. LCMS: (ES ⁺ ) m/z (M+H) ⁺ =619.4.1H NMR (400 MHz, CD ₃ OD) δ = 8.12 - 8.08 (m, 1H), 7.88 - 7.77 (m, 6H), 7.68 (dd, J = 2.8, 8.6 Hz, 1H), 7.64 - 7.56 (m, 3H), 7.40 - 7.32 (m, 1H), 6.70 - 6.34 (m, 1H), 4.63 (s, 2H), 4.00 - 3.84 (m, 6H), 3.83 - 3.77 (m, 4H), 2.68 (s, 3H). [00274] The following compounds were prepared according to the previous procedures using the appropriate intermediates. Example 12: 5-((4,6-difluoro-5-(4'-((4-(2-(methylsulfonyl)ethyl)piperazi n-1-yl)methyl)- [1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methyl benzoic acid (Compound 72) [00275] Step 1: tert-butyl 4-(2-(methylsulfonyl)ethyl)piperazine-1-carboxylate (72-1): A solution of tert-butyl piperazine-1-carboxylate (1.8 g, 9.4 mmol, 1 eq) and (methylsulfonyl)ethene (1 g, 9.4 mmol, 826 uL, 1 eq) in MeOH (10 mL) was stirred at 25 °C for 2 hours. The reaction mixture was concentrated in vacuum to give 72-1 (2.3 g, crude) as a yellow oil. ¹ H NMR (400 MHz, CD ₃ OD) δ = 3.76 - 3.63 (m, 4H), 3.58 - 3.55 (m, 2H), 3.31 (s, 3H), 3.11 (t, J = 6.8 Hz, 2H), 2.77 - 2.67 (m, 4H), 1.71 (s, 9H). [00276] Step 2: 1-(2-(methylsulfonyl)ethyl)piperazine (72-2): A solution of 72-1 (0.3 g, 1.0 mmol, 1 eq) in HCl/dioxane (4 M, 3 mL) was stirred at 25 °C for 4 hours. The reaction mixture was concentrated in vacuum to give a 72-2 (0.2, crude) as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ = 3.47 (m, J = 6.8 Hz, 2H), 3.39 - 3.33 (m, 4H), 3.17 (d, J = 3.6 Hz, 2H), 3.08 (s, 3H), 3.04 (s, 4H). [00277] Step 3: 5-((4,6-difluoro-5-(4'-((4-(2-(methylsulfonyl)ethyl)piperazi n-1- yl)methyl)-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)ox y)-2-methylbenzoic acid (Compound 72): To a solution of 29-4 (0.25 g, 0.52 mmol, 1 eq) and 72-2 (0.15 g, 0.77 mmol, 1.5 eq) in THF (3 mL) and DMSO (1 mL) was added KOAc (0.10 g, 1.0 mmol, 2 eq) and NaBH(OAc) ₃ (0.44 g, 2.1 mmol, 4 eq). Then the mixture was stirred 40 °C for 1 hour. Then CH ₃ COOH (62 mg, 1.0 mmol, 59 uL, 2 eq) was added to the mixture at 0 °C. The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated in vacuum to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18100 × 30 mm × 5 um; mobile phase: [A: water (0.1% FA), B: ACN]; B%: 14%-44%) to give Compound 72 (26 mg, 7% yield, 98% purity) as a yellow solid. LCMS: (ES ⁺ ) m/z (M+H) ⁺ = 661.4. ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.39 - 8.35 (m, 1H), 7.81 - 7.65 (m, 5H), 7.52 (m, 4H), 7.35 (d, J = 1.6 Hz, 2H), 7.09 (d, J = 9.6 Hz, 1H), 3.88 (s, 2H), 3.30 - 3.18 (m, 1H), 3.17 - 2.98 (m, 4H), 2.89 (t, J = 6.8 Hz, 3H), 2.84 (d, J = 1.2 Hz, 3H), 2.76 - 2.61 (m, 4H), 2.58 (s, 3H). [00278] The following compounds were prepared according to the procedures described in Example 12 using the appropriate intermediates.

Example 13: 5-((4,6-difluoro-5-(4'-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-tr iazol-5-yl)-[1,1'- biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoi c acid (Compound 73) [00279] Step 1: (E)-4-bromo-N-(dimethylaminomethylene)benzamide (73-1): A solution of 4-bromobenzamide (10 g, 50 mmol, 1 eq) in DMF-DMA (100 mL) was stirred to 100 °C for 12 hours. The resulting mixture was cooled to room temperature and diluted with hexane (650 mL), then filtered to give 73-1 (10.2 g, 31.2 mmol, 62.38% yield, 78% purity) as a white solid. LCMS: (ES+) m/z (M+H) ⁺ =257.0. [00280] Step 2: 5-(4-bromophenyl)-1-(2,2,2-trifluoroethyl)-1,2,4-triazole (73-2): A solution of 73-1 (1.0 g, 3.1 mmol, 1 eq) and 2,2,2-trifluoroethylhydrazine (0.69 g, 6.1 mmol, 2 eq) in AcOH (20 mL) was stirred at 90 °C for 3 hours. The reaction solution was diluted with H ₂ O (50 mL) and extracted with EA (50 mL×3). The combined organic layers were washed with saturated brine (50 mL×2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150 × 25 mm × 10 um; mobile phase: [A: water (0.1% FA), B: ACN]; B%: 48%-78%) to give 73-2 (0.45 g, 44% yield, 92% purity) as a white solid. LCMS: (ES+) m/z (M+H) ⁺ =305.9. ¹ H NMR (400 MHz, methanol-d ₄ ) δ ppm 5.07 (2 H, q, J=8.4 Hz) 7.53 - 7.63 (2 H, m) 7.71 - 7.83 (2 H, m) 8.12 (1 H, s). [00281] Step 3: 5-[4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl] phenyl]-1- (2,2,2-trifluoroethyl)-1,2,4-triazole (73-3): To a solution of 73-2 (0.40 g, 1.31 mmol, 1 eq) and 4,4,5,5-tetramethyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxabor olan-2-yl)phenyl]-1,3,2- dioxaborolane (0.86 g, 2.6 mmol, 2 eq) in dioxane (10 mL) and H ₂ O (1 mL) was added Na ₂ CO ₃ (0.21 g, 2.0 mmol, 1.5 eq). Then the mixture was purged with N ₂ 3 times and [2-(2- aminophenyl)phenyl]-methylsulfonyloxy-palladium;dichlorometh ane;tricyclohexylphosphane (0.07 g, 0.09 mmol, 0.07 eq) was added. The mixture was purged with N ₂ 3 times and stirred at 80 °C for 48 hours. The reaction mixture was diluted with water (100 mL) and extracted with EA (150 mL× 3). The combine organic layers were washed with saturated brine (50mL×3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=100/1 to 3/1) to give 73-3 (0.52 g, 80% yield, 86% purity) as a yellow oil. LCMS: (ES+) m/z (M+H) ⁺ =429.8. [00282] Step 4: methyl 5-[4,6-difluoro-5-[4-[4-[2-(2,2,2-trifluoroethyl)-1,2,4-tria zol-3- yl]phenyl]phenyl]-1-(2-trimethylsilylethoxymethyl)benzimidaz ol-2-yl]oxy-2-methyl- benzoate (73-4): To a solution of 5-8 (0.69 g, 1.2 mmol, 1 eq) and 73-3 (0.52 g, 1.2 mmol, 1 eq) in dioxane (10 mL) and H ₂ O (1 mL) was added Na ₂ CO ₃ (0.38 g, 3.62 mmol, 3 eq). Then the mixture was purged with N ₂ 3 times and Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (0.15 g, 0.18 mmol, 0.15 eq) was added under N ₂ atmosphere. The mixture was stirred at 90 °C for 12 hours. The reaction mixture was diluted with H ₂ O (150 mL) and extracted with EA (150 mL× 3). The combined organic layers were washed with saturated brine (100 mL×2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 100/1 to 1/1) to give 73-4 (0.65 g, 47% yield, 66% purity) as a yellow oil. LCMS: (ES+) m/z (M+H) ⁺ =750.2. [00283] Step 5: methyl 5-[[4,6-difluoro-5-[4-[4-[2-(2,2,2-trifluoroethyl)-1,2,4-tri azol-3- yl]phenyl]phenyl]-1H-benzimidazol-2-yl]oxy]-2-methyl-benzoat e (73-5): A solution of 73-4 (0.65 g, 0.57 mmol, 66% purity) in HCl/dioxane (4 M, 5 mL) and DCM (5 mL) was stirred at 25 °C for 12 h. The reaction solution was concentrated under reduced pressure to give 73-5 (500 mg, crude) as a brown oil. LCMS: (ES+) m/z (M+H) ⁺ =620.1. [00284] Step 6: 5-((4,6-difluoro-5-(4'-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-tr iazol-5-yl)-[1,1'- biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoi c acid (Compound 73): To a solution of 73-5 (500 mg, crude) in THF (3 mL), H ₂ O (3 mL) and i-PrOH (3 mL) was added LiOH•H ₂ O (0.17 g, 4.04 mmol, 5 eq). The mixture was stirred at 25 °C for 12 h. The mixture was adjusted to pH 5 by addition of 4M aqueous HCl, then filtered. The filtrate was purified by prep-HPLC (column: Phenomenex Luna C18200 × 40 mm × 10 um; mobile phase: [A: water (0.1% FA), B: ACN]; B%: 46%-76%) to give Compound 73 (30 mg, 5.5% yield, 95% purity, FA salt) as an off-white solid. LCMS: (ES+) m/z (M+H) ⁺ =606.2. ¹ H NMR (400 MHz, methanol-d ₄ ) δ ppm 8.15 (1 H, s) 7.95 (2 H, d, J=8.4 Hz) 7.89 - 7.81 (3 H, m) 7.78 (2 H, d, J=8.4 Hz) 7.60 (2 H, d, J=8.0 Hz) 7.50 - 7.34 (2 H, m) 7.11 (1 H, d, J=9.2 Hz) 5.13 (2 H, q, J=8.4 Hz) 2.62 (3 H, s). Example 14: 5-((5-(4'-((3-(2-aminoethoxy)azetidin-1-yl)methyl)-[1,1'-bip henyl]-4-yl)-4,6- difluoro-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid (Compound 125)

[00285] Step 1: benzyl 3-(2-((tert-butoxycarbonyl)amino)ethoxy)azetidine-1-carboxyl ate (125-1): To a solution of benzyl 3-hydroxyazetidine-1-carboxylate (0.20 g, 0.97 mmol, 1 eq) in DMF (3 mL) was added NaH (46 mg, 1.2 mmol, 60% purity, 1.2 eq) at 0 °C. The mixture was stiired at 0 °C for 30 min, then tert-butyl 2,2-dioxooxathiazolidine-3-carboxylate (0.26 g, 1.2 mmol, 1.2 eq) was added at 0 °C. The mixture was stirred at 25 °C for 6 h. The solution was quenched by addition of saturated aqueous NH ₄ Cl solution (3 mL), diluted with H ₂ O (10 mL) and extracted with EA (10 mL × 3). The combined organic layers were washed with saturated brine (10 mL), then the organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 65/35) to give 125-1 (0.11 g, 0.30 mmol) as a colorless oil. ¹ H NMR (400 MHz, methanol-d ₄ ) δ = 9.15 (s, 1H), 8.38 (dd, J = 2.0, 8.2 Hz, 1H), 8.28 (d, J = 8.0 Hz, 1H), 7.73 (s, 1H), 7.66 - 7.60 (m, 1H), 7.60 - 7.53 (m, 1H), 7.28 (s, 1H), 4.83 - 4.80 (m, 3H), 4.58 (s, 1H), 2.76 (d, J = 7.6 Hz, 2H), 1.27 (s, 3H). [00286] Step 2: tert-butyl (2-(azetidin-3-yloxy)ethyl)carbamate (125-2): To a solution of 125-1 (0.11 g, 0.31 mmol, 1 eq) in MeOH (3 mL) was added 5% Pd/C (0.1 g, 0.31 mmol, 1.00 eq) under N ₂ atmosphere. The suspension was degassed and purged with H ₂ 3 times. The mixture was stirred under H ₂ (15 psi) at 25 °C for 2 h. The solution was filtered. The filtrate was concentrated under reduced pressure to give 125-2 (67 mg, 0.29 mmol) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 4.36 - 4.25 (m, 1H), 3.73 - 3.65 (m, 2H), 3.62 - 3.53 (m, 2H), 3.41 - 3.34 (m, 2H), 3.31 - 3.21 (m, 2H), 1.43 (s, 9H). [00287] Step 3: methyl 5-((5-(4'-((3-(2-((tert-butoxycarbonyl)amino)ethoxy)azetidin -1- yl)methyl)-[1,1'-biphenyl]-4-yl)-4,6-difluoro-1-((2-(trimeth ylsilyl)ethoxy)methyl)-1H- benzo[d]imidazol-2-yl)oxy)-2-methylbenzoate (125-3): To a solution of 125-2 (67 mg, 0.31 mmol, 1 eq) in THF (0.2 mL) and DMSO (0.2 mL) was added KOAc (91 mg, 0.93 mmol, 3 eq), and the mixture was stirred at 25 °C for 1 h. Then methyl 5-[4,6-difluoro-5-[4-(4- formylphenyl)phenyl]-1-(2-trimethylsilylethoxymethyl)benzimi dazol-2-yl]oxy-2-methyl- benzoate (0.19 g, 0.31 mmol, 1 eq) and HOAc (19 mg, 0.31 mmol, 18 uL, 1 eq) was added, and the solution was stirred at 40 °C for another 1 h. Then NaBH(OAc) ₃ (0.20 g, 0.93 mmol, 3 eq) was added at 0 °C. The mixture was stirred at 25 °C for 6 h. The solution was filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed- phase HPLC (column: Phenomenex luna C18150 × 25 mm × 10 um; mobile phase: [A: water (0.1% FA), B: ACN]; gradient: B% 10-50%, 25 min; 50%, 5 min) to give 125-3 (0.11 g, 0.16 mmol) as a yellow oil. [00288] Step 4: methyl 5-((5-(4'-((3-(2-aminoethoxy)azetidin-1-yl)methyl)-[1,1'- biphenyl]-4-yl)-4,6-difluoro-1H-benzo[d]imidazol-2-yl)oxy)-2 -methylbenzoate (125-4): To a solution of 125-3 (93 mg, 0.13 mmol, 1 eq) in DCM (1 mL) was added TFA (0.2 mL) at 0 °C, and the mixture was stirred at 25 °C for 2 h. The mixture was adjusted to pH = 11 with 2 N aqueous LiOH solution at 0 °C, then concentrated to give 125-4 (75 mg) as a yellow oil. [00289] Step 5: 5-((5-(4'-((3-(2-aminoethoxy)azetidin-1-yl)methyl)-[1,1'-bip henyl]-4-yl)- 4,6-difluoro-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid (Compound 125): To a solution of 125-4 (75 mg, 0.13 mmol, 1 eq) in EtOH (1 mL) and H ₂ O (0.25 mL) was added LiOH•H ₂ O (53 mg, 1.3 mmol, 10 eq). The mixture was stirred at 25 °C for 6 h. The solution was filtered and concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC (column: Phenomenex luna C18150 × 25 mm × 10 um; mobile phase: [A: water (0.1% FA), B: ACN]; gradient: B% 10-30%, 25min; 35%, 5 min) to give Compound 125 (70 mg, 89 % yield, 100% purity, FA) as a white solid. LCMS: (ES+) m/z (M+H) ⁺ = 585.2. ¹ H NMR (400 MHz, METHANOL-d4) δ = 7.70 - 7.59 (m, 5H), 7.51 - 7.42 (m, 4H), 7.35 - 7.27 (m, 2H), 7.06 (d, J = 9.6 Hz, 1H), 4.35 (br t, J = 5.2 Hz, 1H), 4.08 (s, 2H), 3.98 (br dd, J = 6.0, 10.2 Hz, 2H), 3.73 - 3.55 (m, 4H), 3.16 - 3.10 (m, 2H), 2.56 (s, 3H). Example 15: 5-((5-(4'-((2-(carboxymethoxy)ethoxy)methyl)-[1,1'-biphenyl] -4-yl)-4,6- difluoro-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid (Compound 127)

[00290] Step 1: 2-((4-bromobenzyl)oxy)ethanol (127-1): To a solution of NaH (1.9 g, 48 mmol, 60% purity, 6 eq) in THF (50 mL) was added dropwise a solution of ethylene glycol (1.5 g, 24 mmol, 1.3 mL, 3 eq) in THF (10 mL) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. Then a solution of 1-bromo-4-(bromomethyl)benzene (2 g, 8.0 mmol, 1 eq) in THF (10 mL) was added dropwise at 0 °C. The mixture was stirred at 70 °C for another 15 h. The solution was diluted with H ₂ O (150 mL) and extracted with EA (100 mL × 3). The combined organic layers were washed with saturated brine (50 mL × 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=100/1 to 5/1) to give 127-1 (1.1 g, 4.9 mmol, 61% yield) as a colorless oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.60 - 7.46 (m, 2H), 7.35 - 7.22 (m, 2H), 4.45 (s, 2H), 3.60 - 3.52 (m, 2H), 3.51 - 3.40 (m, 2H). [00291] Step 2: tert-butyl 2-(2-((4-bromobenzyl)oxy)ethoxy)acetate (127-2): To a solution of NaH (0.23 g, 5.9 mmol, 60% purity, 1.2 eq) in THF (25 mL) was added a solution of 127-1 (1.1 g, 4.9 mmol, 1 eq) in THF (5 mL) at 0°C. The mixture was stirred at 0 °C for 0.5 h, then a solution of tert-butyl 2-bromoacetate (1.9 g, 9.8 mmol, 1.5 mL, 2 eq) in THF (5 mL) was added dropwise into the solution. The mixture was stirred at 70 °C for 15 h. The solution was diluted with H ₂ O (150 mL) and extracted with EA (100 mL × 3). The combined organic layers were washed with saturated brine (50 mL × 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=100/1 to 1/1) to give 127-2 (0.50 g, 1.5 mmol, 31% yield) as a colorless oil. ¹ H NMR (400 MHz, methanol-d ₄ ) δ = 7.53 - 7.43 (m, 2H), 7.28 (br d, J = 8.4 Hz, 2H), 4.55 - 4.47 (m, 2H), 4.36 - 4.28 (m, 1H), 4.25 - 4.19 (m, 1H), 4.03 (s, 2H), 3.76 - 3.69 (m, 2H), 3.68 - 3.60 (m, 2H), 1.52 - 1.41 (m, 9H). [00292] Step 3: tert-butyl 2-(2-((4'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1 '- biphenyl]-4-yl)methoxy)ethoxy)acetate (127-3): To a solution of 127-2 (0.50 g, 1.5 mmol, 1 eq) and 4,4,5,5-tetramethyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxabor olan-2-yl)phenyl]-1,3,2- dioxaborolane (0.96 g, 2.9 mmol, 2 eq) in dioxane (14 mL) and H ₂ O (1 mL) was added Na ₂ CO ₃ (0.46 mg, 4.4 mmol, 3 eq) and Pd(dppf)Cl ₂ •CH ₂ Cl ₂ (0.24 g, 0.29 mol, 0.2 eq). The mixture was stirred at 90 °C for 15 hrs. The solution was diluted with H ₂ O (80 mL) and extracted with EA (50 mL × 3). The combined organic layers were washed with saturated brine (50 mL × 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=100/1 to 1/1) to give 127-3 (0.28 g, 16% yield, 40% purity) as a yellow oil. LCMS: (ES ⁺ ) m/z (M+H) ⁺ =469.1. [00293] Step 4: methyl 5-((5-(4'-((2-(2-(tert-butoxy)-2-oxoethoxy)ethoxy)methyl)-[1 ,1'- biphenyl]-4-yl)-4,6-difluoro-1-((2-(trimethylsilyl)ethoxy)me thyl)-1H-benzo[d]imidazol-2- yl)oxy)-2-methylbenzoate (127-4): To a solution of 127-3 (0.26 g, 0.56 mmol, 1 eq) and methyl 5-[4,6-difluoro-5-iodo-1-(2-trimethylsilylethoxymethyl)benzi midazol-2-yl]oxy-2-methyl- benzoate (0.32 g, 0.56 mol, 1 eq) in dioxane (6 mL) and H ₂ O (0.6 mL) was added Na ₂ CO ₃ (0.18 g, 1.7 mmol, 3 eq) and Pd(dppf)Cl ₂ •CH ₂ Cl ₂ (0.091 g, 111.02 umol, 0.2 eq). The mixture was stirred at 90 °C for 15 hrs. The solution was diluted with H ₂ O (50 mL) and extracted with EA (50 mL × 3). The combined organic layers were washed with saturated brine (50 mL × 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=100/1 to 1/1) to give 127-4 (0.30 g, 36% yield, 54% purity) as a yellow oil. LCMS: (ES ⁺ ) m/z (M+H) ⁺ =789.4. [00294] Step 5: 2-(2-((4'-(4,6-difluoro-2-(3-(methoxycarbonyl)-4-methylpheno xy)-1H- benzo[d]imidazol-5-yl)-[1,1'-biphenyl]-4-yl)methoxy)ethoxy)a cetic acid (127-5): To a solution of 127-4 (0.29 g, 0.37 mmol, 1 eq) in CH ₂ Cl ₂ (0.5 mL) was added HCl/dioxane (4 M, 2.5 mL, 27 eq). The mixture was stirred at 25 °C for 4.5 hr. The mixture was diluted with saturated aqueous NaHCO ₃ solution (20 mL) and extracted with EA (20 mL × 3). The combined organic layers were washed with saturated brine (50 mL × 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give compound 5 (0.18 g) as yellow oil. LCMS: (ES ⁺ ) m/z (M+H) ⁺ =603.1. [00295] Step 6: 5-((5-(4'-((2-(carboxymethoxy)ethoxy)methyl)-[1,1'-biphenyl] -4-yl)-4,6- difluoro-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid (Compound 127): To a solution of 127-5 (0.14 g, 0.23 mol, 1 eq) in THF (1 mL), i-PrOH (1 mL) and H ₂ O (1 mL) was added LiOH•H ₂ O (0.56 g, 1.3 mmol, 5.7 eq). The mixture was stirred at 25 °C for 17 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC [column: Phenomenex luna C18150 × 25 mm × 10 um; mobile phase: [A: water (0.1% FA), B: ACN]; B%: 37%-67%, 10 min] to give a residue. The residue was purified by prep-HPLC [column: Waters xbridge 150 × 25 mm × 10 um; mobile phase: [A: water (10 mM NH ₄ HCO ₃ ), B: ACN]; B%: 7%-37%, 9 min] to give Compound 127 (17 mg, 28 umol, 12% yield, 95.87% purity) as a white solid. LCMS: (ES ⁺ ) m/z (M+H) ⁺ =589.3. ¹ H NMR (400 MHz, methanol-d ₄ ) δ = 7.73 (d, J = 8.3 Hz, 2H), 7.71 - 7.65 (m, 3H), 7.53 (br d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 1.3 Hz, 2H), 7.09 (d, J = 9.3 Hz, 1H), 4.63 (s, 2H), 4.02 (s, 2H), 3.73 (br d, J = 1.0 Hz, 4H), 2.57 (s, 3H). [00296] The following compounds were prepared according to the procedures described in Example 15 by using the appropriate intermediates. [00297] The following compounds were prepared according to the previous procedures using the appropriate intermediates. II. Biological Evaluation Example A-1: In Vitro pAMPK1 Kinase Activation Assay [00298] Compound effect on AMPK enzyme activation was determined in a cell-free format with a 12-point concentration curve. The ADP-Glo detection system was used to determine phosphorylation of a SAMS peptide substrate. Recombinant AMPK α1/β1/γ1 complex was pre- activated by phosphorylation with CAMKK2 followed by incubated with compound for 15 minutes prior to the SAMS phosphorylation reaction. Activity curves and EC ₅₀ values were fitted by interpolation to an ATP:ADP standard curve as indicated by the ADP-Glo manufacturer using Prism software. [00299] Results for exemplary compounds are shown in Table A. Table A. ^{a Compound A-1 is 5-((5-([1,1'-biphenyl]-4-yl)-6-fluoro-1H-benzo[d]imidazol-2- yl)oxy)-2-} methylbenzoic acid, which is Example 365 in WO/2010/036613 and does not comprise the kinetophore group found in the compounds disclosed herein. Compound A-1 has the following structure: Example A-2: Pharmacokinetic Assays Oral Bioavailability [00300] Compounds were tested for pharmacokinetics in C57BL/6 mice. Compounds were dosed IV at 1 mg/kg as a formulation of 0.5 mg/mL in 5% DMSO + 30% PEG400+ 65% water and PO at 30 mg/kg as a formulation of 6 mg/mL in 0.25% MC + 5% Tween 80 + 0.02% SDS. [00301] Results for exemplary compounds are shown in Table B. Compounds 30, 32, 40, 59, 72 and 96 were shown to have PO Cmax values between 1.13 and 3.97 μM, PO AUC values between 1.38 annd 8.66 μM•h and oral bioavailabilities of 4% to 7%. Compound A-1 was found to have a PO Cmax of 16.8 μM, PO AUC of 27.8 μM•h and oral bioavailability of 41%. [00302] The compounds in Table B therefore have a greater degree of gut restriction compared to Compound A-1. Table B.