TW202340185A - Ampk activators - Google Patents

Abstract

This disclosure is directed, at least in part, to AMPK activators useful for the treatment of conditions or disorders associated with AMPK. In some embodiments, the condition or disorder is associated with the gut-brain axis. In some embodiments, condition or disorder is associated with systemic infection and inflammation from having a leaky gut barrier. In some embodiments, the AMPK activators are gut-restricted compounds. In some embodiments, the AMPK activators are agonists, super agonists, full agonists, or partial agonists.

Description

AMPK activator

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) increases due to nutrient deprivation. Activated AMPK phosphorylates downstream substrates, thereby promoting catabolism and hindering anabolism, causing ATP production and energy recovery. AMPK activity can be altered by a variety of physiological factors, such as hormones, interleukins, and dietary nutrients, as well as pathological conditions, such as obesity, chronic inflammation, and type 2 diabetes. Activation of AMPK can cause reduced hepatic glucose production and lower plasma glucose levels. Therefore, AMPK is an attractive target for the treatment of various metabolic diseases.

In addition, AMPK has beneficial effects on intestinal health, such as enhancing intestinal absorption, improving barrier function, inhibiting colorectal cancer, and reducing intestinal inflammation and metabolism-related diseases, and is important for maintaining intestinal homeostasis. For example, AMPK activation enhances paracellular junctions, nutrient transporters, autophagy, and apoptosis, and inhibits inflammation and carcinogenesis in the intestine. Thus, AMPK is associated with maintaining tight junctions in the colon epithelium and controls the progression of colitis.

In various mouse models of colitis, treatment with direct AMPK activators has been shown to be effective in restoring intestinal barrier function (see, e.g., 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 using metformin, an indirect AMPK activator with other 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, especially in the heart. Chronic treatment with systemic, direct activators induces cardiac hypertrophy (accompanied by 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 abnormal electrocardiogram (ECG) (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 systemic AMPK activators is not suitable to address the problems of direct AMPK activators in the treatment of IBD, colitis, and other diseases with leaky intestinal barriers.

All reported direct AMPK activators that have been optimized and entered into clinical studies (e.g., PF-06409577 from Pfizer) or extensive preclinical evaluation (e.g., MK-3903 and MK-8722 from Merck) are systemic AMPK activators agents and their systemic effects have been studied, as reflected in the routes of administration and bioassays presented in patent applications and published manuscripts related to direct AMPK activators. Delayed release formulations have been studied to deliver higher concentrations of the indirect AMPK activator metformin to the large intestine for the treatment of IBD. However, metformin does not activate AMPK optimally, metformin has other activities, and this approach requires specific formulation development. Therefore, it is not the best solution to the problem.

This article describes the discovery and development of the first gut-restricted, direct AMPK activators that do not require complex formulations to reach target tissues and avoid systemic circulation.

In some embodiments, disclosed herein are adenosine 5'-monophosphate-activated protein kinase (5' AMP-activated protein kinase, AMPK) activators suitable for treating 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 caused by leaky intestinal barrier. In some embodiments, the AMPK activator is gut-restricted and selectively modulates 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 disorders, depression, mood disorders, schizophrenia, malaise, cognitive impairment, addiction, Autism, epilepsy, neurodegenerative disorders, Alzheimer's disease and Parkinson's disease, Lewy body dementia, intermittent cluster headache, migraine Headache, 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 non-alcoholic fat NASH; eating and nutritional disorders, including binge eating, cachexia, anorexia nervosa, short bowel syndrome, intestinal failure, intestinal insufficiency and other eating disorders; inflammatory conditions and autoimmune diseases, such as Inflammatory bowel disease, ulcerative colitis, Crohn's disease, colitis caused by checkpoint inhibitors, psoriasis, and celiac disease; necrotizing enterocolitis; caused by toxic insults such as radiation or chemotherapy gastrointestinal injury; diseases/conditions that impair gastrointestinal barrier function, including environmental intestinal dysfunction; spontaneous bacterial peritonitis; allergies, including food allergy, steatorrhea, and childhood allergy; graft-versus-host disease; functional gastrointestinal Tract conditions such as irritable bowel syndrome, functional dyspepsia, functional abdominal distension/distention, functional diarrhea, functional constipation and opioid-induced constipation; gastroparesis; nausea and vomiting; conditions related to microbial dysbiosis , and other conditions involving the gut-brain axis.

In some embodiments, disclosed herein are compounds of Formula (I): , ^where : X is -O-, -CH ₂ - or ^{-CHR 4} - ^; or X is -CH-, and L ¹ is connected to Each R ³ at each occurrence is independently selected from halogen, hydroxyl, C _{1 - 4} alkyl, -CN and C _{1 - 4} haloalkyl; each R ⁴ at each occurrence is independently selected from halogen, hydroxyl, C _{1 - 4} alkyl, -CN and C _{1 - 4} haloalkyl; or two R ⁴ together form a bond or C _{1 - 2} alkyl group; n is selected from 0, 1, 2, 3 and 4; o system is selected from 0, 1, 2, 3 and 4; p system is selected from 0, 1 and 2; q system is selected from 0, 1, 2, 3 and 4; R ⁵ system is selected from hydrogen and C _1-4 alkane base; R ⁶ is selected from hydrogen, halogen, C _1-4 alkyl and C _1-4 haloalkyl; L ¹ is a bond or -CH ₂ -; D is selected from -CO ₂ R ¹¹ , -P( O)(OR ¹¹ ) ₂ , -P(O)R ¹¹ (OR ¹¹ ), -S(O) ₂ OH and -L ² -K; L ² is selected from ^λ -(C(R ¹³ ) ₂ ) _r -, ^λ -O(C(R ¹³ ) ₂ ) _r -, ^λ -(C(R ¹³ ) ₂ ) _r O-, ^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 )- and 4 to 6 membered heterocycles, where ^λ represents the connection with 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 independently selected from one to six as appropriate: Substituent substitution: 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 carbocyclic rings and 3 to 10-membered _heterocyclic rings, wherein each C _{3-10 carbocyclic} ring and 3 to 10-membered heterocyclic rings are optionally substituted with one to six substituents independently selected from the following: halogen , C _{1 - 6} alkyl, -OR ¹⁴ , =O and -S(O) ₂ OH; and (ii) C _{3 - 10} carbocyclic rings and 3 to 10 membered heterocyclic rings, each of which has one to six independent rings as appropriate. Substituted with substituents selected from the following: 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 heterocyclyl, wherein each C _{1 - 10} alkyl and C _{1 - 10} heteroalkyl is independently selected from one to six as appropriate. Substituted from the following substituents: 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; R ¹¹ is independently selected at each occurrence from hydrogen, C _{1 - 4} alkyl and C _{1 - 4} haloalkyl; R ¹² at each occurrence is independently selected from hydrogen and optionally C _{1 - 4} substituted by halogen, -OH, -NH ₂ and -C(O)NH ₂ Alkyl; R ¹³ is independently selected at each occurrence from hydrogen, C _{1 - 4} alkyl, C _{1 - 4} haloalkyl and C _{1 - 4} hydroxyalkyl; each R ¹⁴ is independently selected at each occurrence From: hydrogen; optionally C _{1 - 10} alkyl and C _{1 - 10} heteroalkyl substituted by 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} carbocyclic rings and 3 to 10 membered heterocyclic rings, wherein each C _{3 - 10} carbocyclic ring and 3 to 10 membered heterocyclic rings are independently selected from one to six as appropriate, from the following Substituent substitution: 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 R ²¹ , -S(O) ₂ N(R ²¹ ) ₂ , =O and -CN; each R ¹⁵ is independently Selected from C _{1 - 4} alkyl; each R ¹⁶ is independently selected from hydrogen and C _{1 - 6} alkyl at each occurrence; each R ²¹ is independently selected from hydrogen and C _{1 - 6} alkyl at each occurrence , C _{1 - 6} haloalkyl, C _{1 - 6} hydroxyalkyl and C _{3 - 6} carbocyclic ring, wherein the C _{3 - 6} carbocyclic ring is optionally substituted by one to six substituents independently selected from the following: -OH, C _{1 - 6} alkyl, C _{1 - 6} haloalkyl, C _{1 - 6} hydroxyalkyl and =O.

In some embodiments, the compound is represented by Formula (II): , or its pharmaceutically acceptable salt.

In some embodiments, the compound is represented by formula (IIa) or (IIb): , or its pharmaceutically acceptable salt.

In some embodiments, the compound is represented by Formula (III): , or its pharmaceutically acceptable salt.

In some embodiments, the compound is represented by Formula (IIIa), Formula (IIIb) or Formula (IIIc): , or its pharmaceutically acceptable salt.

Any combination of the groups described above or below with respect to the various variables is contemplated herein. Throughout this specification, the selection of groups and their substituents to provide stable moieties and compounds is left to one skilled in the art.

In some embodiments, disclosed herein is a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof and at least one pharmaceutically acceptable Acceptable excipients.

In some embodiments, disclosed herein are methods for treating an adenosine 5'-monophosphate-activated protein kinase (AMPK)-related condition or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of The compounds disclosed herein or their pharmaceutically acceptable salts, solvates, stereoisomers or prodrugs. 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 caused by leaky intestinal barrier. In some embodiments, the condition or disorder is metabolic syndrome, obesity, type 2 diabetes, coronary artery disease, fatty liver, non-alcoholic steatohepatitis (NASH), cirrhosis, hepatic encephalopathy, fibrotic disorder ( including scleroderma), inflammatory bowel disease (including Crohn's disease, ulcerative colitis, and colitis caused by checkpoint inhibitors), psoriasis, celiac disease, necrotizing enterocolitis, inflammatory bowel diseases such as radiation or chemotherapy Gastrointestinal damage caused by toxic damage, environmental intestinal dysfunction, allergies (including food allergies, steatorrhea and childhood allergies), graft-versus-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 combinations thereof.

In some embodiments, also disclosed herein are methods for treating gastrointestinal damage caused by toxic insult, comprising administering to a subject a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof , solvate, stereoisomer or prodrug. In some embodiments, toxic damage is caused by radiation, chemotherapy, or combinations thereof. In some embodiments, toxic damage is induced by radiation. In some embodiments, toxic damage is induced by chemotherapy.

In some embodiments, also disclosed herein is the use of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, as a pharmaceutical.

In some embodiments, also disclosed herein is the use of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, for the treatment of an individual in need thereof. Adenosine 5'-monophosphate-activated protein kinase (AMPK)-related conditions or disorders. 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 caused by leaky intestinal barrier. In some embodiments, the condition or disorder is metabolic syndrome, obesity, type 2 diabetes, coronary artery disease, fatty liver, non-alcoholic steatohepatitis (NASH), cirrhosis, hepatic encephalopathy, fibrotic disorder ( including scleroderma), inflammatory bowel disease (including Crohn's disease, ulcerative colitis, and colitis caused by checkpoint inhibitors), psoriasis, celiac disease, necrotizing enterocolitis, inflammatory bowel diseases such as radiation or chemotherapy Gastrointestinal damage caused by toxic damage, environmental intestinal dysfunction, allergies (including food allergies, steatorrhea and childhood allergies), graft-versus-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 combinations thereof.

In some embodiments, also disclosed herein is the use of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, for the treatment of an individual in need thereof. Gastrointestinal damage caused by toxic damage. In some embodiments, toxic damage is caused by radiation, chemotherapy, or combinations thereof. In some embodiments, toxic damage is induced by radiation. In some embodiments, toxic damage is induced by chemotherapy.

In some embodiments, also disclosed herein is the use of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, for the preparation of a treatment for the treatment herein Remedies for the diseases revealed.

Cross-references to related applications

This application claims rights under U.S. Provisional Application No. 63/282,457, filed on November 23, 2021, which is incorporated herein by reference in its entirety.

The present invention relates, at least in part, to AMPK activators useful in the treatment of conditions or disorders involving the gut-brain axis. In some embodiments, the AMPK activator is a gut-restricted compound. In some embodiments, the AMPK activator is an agonist, a superagonist, a full agonist, or a partial agonist.

The compounds disclosed herein directly activate AMPK in the intestine without systemic effects. Preferred compounds are more potent, effective at lower doses, and have reduced systemic exposure than other previously known AMPK activators. definition

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 cells) and those skilled in the art Known equivalents, etc. When a range is used herein with respect to a physical property such as molecular weight or a chemical property such as chemical formula, all combinations and subcombinations of ranges and the specific examples thereof are intended to be included.

The term "about" when referring to a number or range of numbers means that the number or range of numbers mentioned is an approximation within experimental variability (or within statistical experimental error) and that therefore in some cases the number or range of numbers will be the same as that stated. The stated figures or ranges of figures vary by 1% to 15%.

The term "comprising" (and related terms such as "comprise or comprises" or "having" or "includes") is not intended to exclude other embodiments, such as those described herein. Any embodiment of a composition of matter, composition, method or process or the like "consists of" or "consists essentially of" the characteristics described.

Unless specified to the contrary, as used in the specification and accompanying claims, the following terms have the meanings indicated below:

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 denoted "C ₁ -C ₄ " indicates the presence of one to four carbon atoms in the moiety, that is, contains 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms of the group. Thus, by way of example only, "C ₁ -C ₄ alkyl" indicates that one to four carbon atoms are present in the alkyl group, i.e., the alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-propyl Butyl, isobutyl, secondary butyl and tertiary butyl.

"Alkyl" means an optionally substituted straight chain or optionally substituted branched chain saturated hydrocarbon monovalent group having one to about ten carbon atoms, or preferably one to six carbon atoms, wherein the alkyl residue The sp ³ -mixed carbon is connected 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 Base-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, secondary butyl, tertiary butyl, n-pentyl base, isopentyl, neopentyl, tertiary pentyl and hexyl, and longer alkyl groups such as heptyl, octyl and similar groups. Whenever used 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 Composed of 6 carbon atoms, but this definition also covers occurrences of the term "alkyl" without a specified numerical range. In some embodiments, alkyl is C ₁ -C ₁₀ alkyl, C ₁ -C ₉ alkyl, C ₁ -C ₈ alkyl, C ₁ -C ₇ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₅ alkyl, C ₁ -C ₄ alkyl, C ₁ -C ₃ alkyl, C ₁ -C ₂ alkyl or C ₁ alkyl. Unless otherwise specifically stated in this specification, an alkyl group is optionally substituted with one or more of the following substituents as described below: halo, cyano, nitro, pendant oxy, thione, imino, oxime group, trimethylsilyl group, -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 is 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.

"Alkenyl" means an optionally substituted straight chain or optionally substituted chain having one or more carbon-carbon double bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. A branched chain hydrocarbon monovalent group in which the sp ² -mixed carbon or sp ³ -mixed carbon of the alkenyl residue is connected to the rest of the molecule by a single bond. A group may be in the cis or trans configuration about a double bond and is understood to include both isomers. Examples include (but are not limited to) vinyl (-CH=CH ₂ ), n-propenyl (-CH=CHCH ₃ , -CH ₂ CH=CH ₂ ), isopropenyl (-C(CH ₃ )=CH ₂ ) , butenyl, 1,3-butadienyl and similar groups. Whenever used 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 , but this definition also covers occurrences of the term "alkenyl" without a specified numerical range. In some embodiments, the alkenyl group is C ₂ -C ₁₀ alkenyl, C ₂ -C ₉ alkenyl, C ₂ -C ₈ alkenyl, C ₂ -C ₇ alkenyl, C ₂ -C ₆ alkenyl, C ₂ -C ₅ alkenyl, C ₂ -C ₄ alkenyl, C ₂ -C ₃ alkenyl or C ₂ alkenyl. Unless otherwise specifically stated in the specification, alkenyl is optionally substituted as described below, for example by: pendant oxy, halogen, amine, nitrile, nitro, hydroxy, haloalkyl, alkoxy, Aryl, cycloalkyl, heterocycloalkyl, heteroaryl and similar groups. Unless otherwise specifically stated in this specification, an alkenyl group is optionally substituted with one or more of the following substituents as described below: halo, cyano, nitro, pendant oxy, thione, imine, Oxime group, trimethylsilyl group, -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 radical, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl.

"Alkynyl" refers to an optionally substituted straight chain or optionally substituted branched chain hydrocarbon monovalent group having one or more carbon-carbon bonds and having from two to about ten carbon atoms, more preferably From two to about six carbon atoms, the sp-mixed carbon or ^sp3 -mixed carbon of the alkynyl residue is connected 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 used 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 , but this definition also covers occurrences of the term "alkynyl" without a specified numerical range. In some embodiments, the alkynyl group is C ₂ -C ₁₀ alkynyl, C ₂ -C ₉ alkynyl, C ₂ -C ₈ alkynyl, C ₂ -C ₇ alkynyl, C ₂ -C ₆ alkynyl, C ₂ -C ₅ alkynyl, C ₂ -C ₄ alkynyl, C ₂ -C ₃ alkynyl or C ₂ alkynyl. Unless otherwise specifically stated in this specification, an alkynyl group is optionally substituted with one or more of the following substituents as described below: halo, cyano, nitro, pendant oxy, thione, imine, Oxime group, trimethylsilyl group, -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} independent is hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, and each R ^f is independently an alkyl, haloalkyl , cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl.

"Alkylene" or "alkylene chain" means a straight or branched divalent hydrocarbon chain that connects the rest of the molecule to a free radical, consists only of carbon and hydrogen, contains no unsaturation, and has from one to Twelve carbon atoms, such as methylene, ethyl, propyl, n-butyl and the like. The alkylene chain is connected to the rest of the molecule via a single bond and to the radical via a single bond. The point of attachment of the alkylene chain to the rest of the molecule and to the radical is via one carbon in the alkylene chain or via any two carbons in the chain. Unless otherwise specifically stated in this specification, an alkylene group is optionally substituted with one or more of the following substituents as described below: halo, cyano, nitro, pendant oxy, thione, imine , oxime group, trimethylsilyl group, -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 radical, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl.

"Alkenyl" or "alkenyl chain" means a chain that connects the rest of the molecule to the free radical, consists solely of carbon and hydrogen, contains at least one carbon-carbon double bond, and has from two to twelve carbon atoms. Straight or branched divalent hydrocarbon chain. The alkenylene chain is connected to the rest of the molecule via a single bond and to the radical via a single bond. Unless otherwise specifically stated in this specification, alkenylene groups are optionally substituted with one or more of the following substituents as described below: halo, cyano, nitro, pendant oxy, thione, imine , oxime group, trimethylsilyl group, -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, halo Alkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl.

"Alkynyl" or "alkynyl chain" means a straight or branched divalent hydrocarbon chain that connects the rest of the molecule to a free radical, consists solely of carbon and hydrogen, and contains at least one carbon-carbon bond. and have from two to twelve carbon atoms. The alkynyl chain is connected to the rest of the molecule via a single bond and to the radical via a single bond. Unless otherwise specifically stated in the specification, an alkynylene group is optionally substituted with one or more of the following substituents as described below: halo, cyano, nitro, pendant oxy, thione, imine , oxime group, trimethylsilyl group, -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 radical, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl.

"Alkoxy" or "alkoxyl" refers to a group bonded via an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.

"Aryl" refers to a group derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removal of a hydrogen atom from a ring carbon atom. Aromatic monocyclic or polycyclic hydrocarbon ring systems contain only hydrogen and carbon (6 to 18 carbon atoms), in which at least one ring in the ring system is completely unsaturated, that is, according to Hückel theory, It contains a cyclic, non-localized (4n+2) π electron system. Ring systems from which aryl groups are derived include, but are not limited to, groups such as benzene, benzene, indene, indene, tetralin, and naphthalene. In some embodiments, aryl is C ₆ -C ₁₀ aryl. In some embodiments, aryl is phenyl. Unless otherwise specifically stated in this specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is meant to include as described below optionally one or more independently selected from: Aryl substituted by substituents: alkyl, alkenyl, alkynyl, halo, haloalkyl, cyano, nitro, aryl, aralkyl, arylalkenyl, arylalkynyl, cycloalkyl, hetero Cycloalkyl, heteroaryl, heteroaralkyl, -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 -OR ^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 (as appropriate via one or Multiple halo substituted), aralkyl, heterocycloalkyl, heteroaryl or heteroaralkyl, R ^f is independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl ( optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroaralkyl, each R ^b is independently a direct bond or a linear or branched chain alkyl or alkylene base chain, and R ^c is a straight or branched alkylene or alkenyl chain.

"Aryl" refers to a divalent group derived from "aryl" that links the remainder of the molecule to a free radical as described above. The aryl group is connected to the rest of the molecule via a single bond and to the radical via a single bond. In some embodiments, the aryl group is phenyl. Unless otherwise specifically stated in this specification, aryl groups are optionally substituted as described above for aryl groups.

"Cycloalkyl" means a stable, partially or fully saturated monocyclic or polycyclic carbocyclic ring, which may include fused (when fused to an aryl or heteroaromatic ring, the cycloalkyl group is bonded via a non-aromatic ring atom knot) or bridged ring system. Representative cycloalkyl groups include, but are not limited to, those having three to fifteen carbon atoms (C ₃ -C ₁₅ cycloalkyl), three to ten carbon atoms (C 3 -C 10 cycloalkyl), three to eight carbon atoms (C ₃ -C ₁₀ cycloalkyl), carbon atoms (C ₃ -C ₈ cycloalkyl), three to six carbon atoms (C ₃ -C ₆ cycloalkyl), three to five carbon atoms (C ₃ -C ₅ cycloalkyl) or three to Cycloalkyl group with four carbon atoms (C ₃ -C ₄ cycloalkyl). In some embodiments, cycloalkyl is a 3-6 membered cycloalkyl. In some embodiments, cycloalkyl is 5- to 6-membered cycloalkyl. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Polycyclic cycloalkyl or carbocycles include, for example, adamantyl, norbornyl, decalinyl, bicyclo[1.1.1]pentyl, bicyclo[3.3.0]octyl, bicyclo[4.3.0]nonyl , cis-decahydronaphthyl, trans-decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.2]nonyl base, bicyclo[3.3.2]decyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl and their analogs. Unless otherwise specifically stated in this specification, the term "cycloalkyl" is meant to include cycloalkyl groups optionally substituted as described below with one or more substituents independently selected from: alkyl, alkenyl, alkyne Base, halo, haloalkyl, cyano, nitro, aryl, aralkyl, arylalkenyl, arylalkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroaralkyl, -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 -OR ^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) , wherein each R ^a is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl , heteroaryl or heteroaralkyl, 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 chain alkylene or alkenyl chain, and R ^c is a straight or branched chain alkylene. Or alkenyl chain.

"Cycloalkyl" refers to a divalent group derived from "cycloalkyl" that connects the remainder of the molecule to a free radical as described above. The cycloalkyl group is connected to the rest of the molecule via a single bond and to the radical via a single bond. Unless specifically stated otherwise in this specification, cycloalkyl groups are optionally substituted as described above for cycloalkyl groups.

"Halo" or "halogen" means bromine, chlorine, fluorine or iodine. In some embodiments, halogen is fluorine or chlorine. In some embodiments, the halogen is fluorine.

"Haloalkyl" refers to an alkyl group as defined above substituted by one or more halo groups, such as trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2- Trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl and the like.

"Fluoroalkyl" refers to an alkyl group as defined above substituted by one or more fluoro groups as defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2- Trifluoroethyl, 1-fluoromethyl-2-fluoroethyl and the like.

"Haloalkoxy" or "haloalkoxyl" refers to an alkoxy group as defined above substituted by one or more halo groups as defined above.

"Fluoroalkoxy" or "fluoroalkoxyl" refers to an alkoxy group as defined above substituted by one or more fluoro groups as defined above, such as trifluoromethoxy , difluoromethoxy, fluoromethoxy and their analogs.

"Heteroalkyl" refers to an alkyl group in which one or more backbone atoms are selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or combinations thereof of alkyl. The heteroalkyl group is attached to the rest of the molecule at the carbon atom of the heteroalkyl group. In one aspect, heteroalkyl is C ₁ -C ₆ heteroalkyl. In one aspect, the heteroalkyl group is polyethylene glycol (PEG). In some embodiments, C ₁ -C ₁₀ heteroalkyl groups contain 1 to 5 PEG groups. In some embodiments, C ₁ -C ₁₀ heteroalkyl groups contain 1 to 3 PEG groups.

"Hydroxyalkyl" refers to an alkyl group as defined above substituted by one or more hydroxyl groups as defined above, such as hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-hydroxypropyl , 3-hydroxypropyl, 1,2-dihydroxyethyl, 2,3-dihydroxypropyl, 2,3,4,5,6-pentahydroxyhexyl and their analogs.

"Heterocycloalkyl" refers to a stable 3- to 24-membered partially or fully saturated ring group containing 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Unless otherwise specifically stated in the specification, heterocycloalkyl may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused to an aryl or heteroaromatic ring, heterocycloalkyl bonded via non-aromatic ring atoms) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocycloalkyl group may be oxidized as appropriate; the nitrogen atoms may be quaternary ammonized as appropriate. In some embodiments, heterocycloalkyl is a 3- to 8-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is a 3-6 membered heterocycloalkyl. In some embodiments, heterocycloalkyl is a 5- to 6-membered heterocycloalkyl group. Examples of such heterocycloalkyl groups include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolinyl , imidazolinyl, imidazolidinyl, isothiazolidinyl, isothiazolidinyl, 𠰌linyl, octahydroindolyl, octahydroisoindolyl, 2-side oxypiperidine base, 2-side oxy Piperidinyl, 2-side oxypyrrolidinyl, oxazolidinyl, piperidinyl, piperidinyl, 4-piperidinonyl, pyrrolidinyl, pyrazolidinyl, Aldyl, thiazolidinyl, tetrahydrofuranyl, trithialkyl, tetrahydropyranyl, thioxanyl, thioxanyl, 1-side oxy-thioside, 1,1-biside Oxygen-thiothiobenzolinyl, 1,3-dihydroisobenzofuran-1-yl, 3-side oxy-1,3-dihydroisobenzofuran-1-yl, methyl-2- Pendant oxy-1,3-dioxol-4-yl and 2-Pendant oxy-1,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. More preferably, the heterocycloalkyl group has 2 to 10 carbons in the ring. It should be understood that when referring to the number of carbon atoms in a heterocycloalkyl group, the number of carbon atoms in the heterocycloalkyl group is related to the atoms (including heteroatoms) that make up the heterocycloalkyl group (i.e., the backbone of the heterocycloalkyl ring The total number of atoms) is not the same. Unless otherwise specifically stated in this specification, the term "heterocycloalkyl" is meant to include heterocycloalkyl as defined above optionally substituted with one or more substituents selected from: alkyl, alkenyl, Alkynyl, halo, fluoroalkyl, side oxygen, thione, cyano, nitro, aryl, aralkyl, arylalkenyl, arylalkynyl, cycloalkyl, heterocycloalkyl, heteroaryl group, heteroaralkyl group, -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 -OR ^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), wherein each R ^a is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo) , aralkyl, heterocycloalkyl, heteroaryl or heteroaralkyl, R ^f is independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally modified by one or more halo substituted), aralkyl, heterocycloalkyl, heteroaryl or heteroaralkyl, each R ^b is independently a direct bond or a straight or branched alkylene or alkenyl chain, and R ^c It is a straight or branched alkylene or alkenyl chain.

" N -Heterocycloalkyl" means a heterocycloalkyl group as defined above, which contains at least one nitrogen and wherein the point of attachment of the heterocycloalkyl group to the remainder of the molecule is via the nitrogen atom in the heterocycloalkyl group Realize. N -Heterocycloalkyl is optionally substituted as described above for heterocycloalkyl.

" C -Heterocycloalkyl" means a heterocycloalkyl group as defined above, wherein the point of attachment of the heterocycloalkyl group to the remainder of the molecule is via a carbon atom in the heterocycloalkyl group. C -Heterocycloalkyl is optionally substituted as described above for heterocycloalkyl.

"Heterocycloalkyl" refers to a divalent group derived from "heterocycloalkyl" as described above that connects the remainder of the molecule to the group. The heterocycloalkyl group is connected to the remainder of the molecule via a single bond and to the radical via a single bond. Unless specifically stated otherwise in this specification, heterocycloalkyl groups are optionally substituted as described above for heterocycloalkyl groups.

"Heteroaryl" refers to a group derived from a 5- to 18-membered aromatic ring group containing one to seventeen carbon atoms and one to six heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, heteroaryl is a monocyclic, bicyclic, tricyclic or tetracyclic ring system in which at least one of the rings in the ring system is fully unsaturated, that is, according to Huckel's theory, it contains a ring Nonlocal (4n+2) π electron system. In some embodiments, the heteroaryl group is 5-10 membered heteroaryl. In some embodiments, heteroaryl is a monocyclic heteroaryl or a monocyclic 5- or 6-membered heteroaryl. In some embodiments, the heteroaryl group is 6,5-fused bicyclic heteroaryl. Heteroatoms in heteroaryl groups are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl group is attached to the rest of the molecule through any atom of the ring. Unless otherwise specifically stated in this specification, the term "heteroaryl" is meant to include a heteroaryl group as defined above optionally substituted with one or more substituents selected from: alkyl, alkenyl, alkynyl , halo group, haloalkyl group, side oxygen group, thione group, cyano group, nitro group, aryl group, aralkyl group, arylalkenyl group, arylalkynyl group, cycloalkyl group, heterocycloalkyl group, heteroaryl group, Heteroaralkyl, -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 -OR ^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), aryl Alkyl, heterocycloalkyl, heteroaryl or heteroaralkyl, R ^f is independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally modified by one or more halogen (substituted), aralkyl, heterocycloalkyl, heteroaryl or heteroaralkyl, each R ^b is independently a direct bond or a straight or branched alkylene or alkenyl chain, and R ^c is a straight Chain or branched alkylene or alkenyl chain.

"Heteroaryl" refers to a divalent group derived from "heteroaryl" as described above that connects the remainder of the molecule to the group. The heteroaryl group is connected to the rest of the molecule via a single bond and to the radical via a single bond. Unless otherwise specifically stated in this specification, heteroaryl groups are optionally substituted as described above for heteroaryl groups.

The terms "as appropriate" or "as the case may be" mean that the subsequently described event or circumstance may or may not occur, and that the description includes circumstances in which the event or circumstance occurs and circumstances in which the event or circumstance does not occur . For example, "optionally substituted alkyl" means "alkyl" or "substituted alkyl" as defined above. Additionally, optionally substituted groups may be unsubstituted (e.g., _-CH2CH3 ) _, fully substituted ₍ e.g., _-CF2CF3 ) _, monosubstituted (e.g., _-CH2CH2F ), or Substituted to any degree between _fully substituted and monosubstituted (eg, _-CH2CHF2 , _-CH2CF3 , _{-CF2CH3 , -CFHCHF2 ,} etc.). Those skilled in the art will understand that with respect to any group containing one or more substituents, such groups are not intended to introduce any substitution or substitution pattern that is sterically impractical and/or synthetically unfeasible (e.g., Substituted alkyl includes optionally substituted cycloalkyl, which is defined to include optionally substituted alkyl, the possibilities being infinite).

The term "modulate" or "modulating" or "modulation" refers to an increase or decrease in the amount, quality or effect of a specific activity, function or molecule. By way of illustration and not limitation, activators, agonists, partial agonists, inverse agonists, antagonists, inhibitors and ectopic modulators of an enzyme are modulators of an enzyme.

As used herein, the term "agonist" refers to the activation of a receptor or enzyme by a modulator or agonist to cause a biological response.

As used herein, the term "agonist" or "activator" refers to a modulator that binds to a receptor or target enzyme and activates the receptor or enzyme to cause a biological response. As an example, "AMPK activator" may be used to refer to a compound that exhibits an _EC50 for AMPK activity of no more than about 100 μM as measured in a pAMPK1 kinase activation assay. In some embodiments, the term "agonist" includes superagonists, full agonists, or partial agonists.

As used herein, the term "superagonist" refers to a modulator that is capable of eliciting a maximal response that is greater than that of the endogenous agonist of the target receptor or enzyme and therefore has an efficacy of greater than 100%.

The term "full agonist" refers to a modulator that binds to and activates a receptor or target enzyme with the maximal response that the endogenous agonist can elicit at the receptor or enzyme.

The term "partial agonist" refers to a modulator that binds to and activates a receptor or target enzyme but has partial efficacy at the receptor or enzyme (i.e., less than a maximal response) relative to a full agonist.

The term "orthotopic modulator" refers to a modulator that binds to a site different from the orthotopic binding site and enhances or amplifies the effect of the agonist.

As used herein, the term "antagonism" or "inhibition" refers to the inactivation of a receptor or target enzyme by a modulator or antagonist. For example, receptor antagonism occurs when a molecule binds to the receptor or target enzyme and does not allow activity to occur.

As used herein, the term "antagonist" or "neutral antagonist" or "inhibitor" refers to a modulator that binds to a receptor or target enzyme and blocks a biological response. Antagonists are inactive in the absence of an agonist or inverse agonist, but block the activity of either without causing a change in the biological response.

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 that is opposite to that of the agonist (ie, a decrease in the biological response).

The term "negative ectopic modulator" refers to a modulator that binds to a site different from the orthotopic binding site and reduces or inhibits the effect of the agonist.

As used herein, " _EC50 " means the concentration of a substance (eg, compound or drug) required for 50% activation or enhancement of a biological process. In some cases, the _EC50 refers to the concentration of agonist that elicits half the response between baseline and maximal response in an in vitro assay. In some embodiments, as used herein, _EC50 refers to the concentration of activator (eg, AMPK activator) required for 50% activation of AMPK.

As used herein, " _IC50 " means the concentration of a substance (eg, compound or drug) required for 50% inhibition of a biological process. For example, IC ₅₀ refers to the half-maximal (50%) inhibitory concentration (IC) of a substance measured in a suitable analytical method. In some cases, the _IC50 is determined in an in vitro assay system. In some embodiments, as used herein, _IC50 refers to the concentration of modulator (eg, antagonist or inhibitor) required for 50% inhibition of a receptor or target enzyme.

The terms "subject", "individual" and "patient" are used interchangeably. These terms include mammals. Examples of mammals include, but are not limited to, any member of the class of mammals: humans, non-human primates such as chimpanzees and other ape and monkey species; farm animals such as cattle, horses, sheep, goats, pigs; domestic animals , such as rabbits, dogs and cats; laboratory animals, including rodents, such as rats, mice and guinea pigs, and the like.

As used herein, the term "gut-restricted" refers to compounds that are active primarily in the gastrointestinal system, such as AMPK activators. In some embodiments, the biological activity of a gut-limited compound, such as a gut-limited AMPK activator, is limited to the gastrointestinal system. In some embodiments, the gastrointestinal concentration of the gut-restricted modulator (e.g., a gut-restricted AMPK activator) is greater than the _IC50 of the gut-restricted modulator against its receptor or target enzyme (e.g., AMPK) value or _EC50 value, and the plasma level of the gut-restricted modulator (e.g., gut-restricted AMPK activator) is lower than the IC of the gut-restricted modulator against its receptor or target enzyme (e.g., AMPK) ₅₀ value or EC ₅₀ value. In some embodiments, a gut-restricted compound, such as a gut-restricted AMPK activator, is non-systemic. In some embodiments, a gut-limited compound, such as a gut-limited AMPK activator, is a non-absorbable compound. In other embodiments, a gut-limited compound, such as a gut-limited AMPK activator, is absorbed but rapidly metabolized to metabolites that are significantly less active at the target receptor or enzyme than the modulator itself, or In other words, it is a "soft drug". In other embodiments, gut-limited compounds, such as gut-limited AMPK activators, are minimally absorbed and rapidly metabolized to metabolites that are significantly less active at the target receptor or enzyme than the modulator itself . In some embodiments, gut-restricted AMPK activators have high efflux. In other embodiments, the intestinal-restricted AMPK activator is a substrate of one or more intestinal efflux transporters, such as P-gp (MDR1), BCRP, or MRP2.

In some embodiments, a gut-restricted modulator, such as a gut-restricted AMPK activator, is not systemic but instead localizes to the gastrointestinal system. For example, a modulator, such as a gut-limited AMPK activator, may be present at higher levels in the intestine but at lower levels in the serum. In some embodiments, the systemic exposure of a gut-limited modulator, such as a gut-limited AMPK activator, is, for example, less than 100, less than 50, less than 20, less than 10, or less than 5 nM (in serum, bound or unbound) . In some embodiments, the intestinal exposure of a gut-limited modulator, eg, a gut-limited AMPK activator, is greater than 1000, 5000, 10000, 50000, 100000, or 500000 nM, for example. In some embodiments, a modulator, such as a gut-limited AMPK activator, is gut-restricted due to poor absorption of the modulator itself or due to rapid metabolism of the absorbed modulator in the serum. Systemic circulation may be due to both poor absorption in the serum and rapid metabolism. In some embodiments, a modulator, such as a gut-restricted AMPK activator, is optionally covalently bonded to a kinetophore via a linker, thereby altering the pharmacokinetic profile of the modulator.

In other embodiments, the restrictive modulator is a soft drug. As used herein, the term "soft drug" refers to a compound that is biologically active but is rapidly metabolized into metabolites that are significantly less active at the target receptor than the modulator itself. In some embodiments, the intestinal restrictive modulator is a soft drug that is rapidly metabolized in the blood to a significantly less active metabolite. In some embodiments, the intestinal restrictive modulator is a soft drug that is rapidly metabolized in the liver to significantly less active metabolites. In some embodiments, the intestinal restrictive modulator is a soft drug that is rapidly metabolized in the blood and liver to significantly less active metabolites. In some embodiments, the intestinal restrictive modulator is a soft drug with low systemic exposure. In some embodiments, the biological activity of the metabolite is 10-fold, 20-fold, 50-fold, 100-fold, 500-fold, or 1000-fold less than the biological activity of the soft pharmaceutical intestinal restriction modulator.

As used herein, the term "kinetophore" refers to a structural unit tethered to a small molecule modulator (e.g., AMPK activator), optionally via a linker, which makes the overall molecule larger and increases the polar surface area , while maintaining the biological activity of small molecule regulators. Pharmacokinetics affect the pharmacokinetic properties (e.g., solubility, absorption, distribution, elimination rate, and the like) of small molecule modulators (e.g., AMPK activators) and the binding or association with receptors or target enzymes With minimal changes. The defining property of a pharmacokinetic is not its interaction with a target (eg, an enzyme), but its effect on the specific physiochemical characteristics of the modulator to which it is linked (eg, an AMPK activator). In some cases, pharmacokinetics are used to localize the modulator (eg, AMPK activator) to the intestine.

As used herein, the term "linkage" refers to a covalent linkage between a modulator (eg, AMPK activator) and a pharmacokinetic group. The connection can be via covalent bonds or via "linkers". As used herein, "linker" refers to one or more bifunctional molecules that can be used to covalently bond to a modulator (eg, AMPK activator) and a pharmacokinetic group. In some embodiments, the linker is attached to any part of the modulator (eg, AMPK activator) as 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 can be cleaved in the intestine. In some embodiments, cleavage of the linker releases a bioactive modulator, such as an AMPK activator, in the intestine.

As used herein, the term "gastrointestinal system" (GI system) or "gastrointestinal tract" (GI tract) refers to the organs and systems associated with the digestive process. The gastrointestinal tract includes the esophagus, stomach, small intestine (which includes the duodenum, jejunum, and ileum), and the large intestine (which includes the cecum, colon, and rectum). In some embodiments herein, the GI system refers to the "gut," which means the stomach, small intestine, and large intestine, or to the small intestine and large intestine, including, for example, the duodenum, jejunum, and/or colon. gut - brain axis

The gut-brain axis refers to the bidirectional biochemical communication connecting the gastrointestinal tract (GI tract) and the central nervous system (CNS) via the peripheral nervous system (PNS) and endocrine, immune, and metabolic pathways.

In some cases, the gut-brain axis includes 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 including the hypothalamus-pituitary gland -The neuroendocrine and neuroimmune systems of the adrenal axis (HPA axis). The gut-brain axis is important and regulated for maintaining body homeostasis, and regulates physiological functions through the central and peripheral nervous systems as well as endocrine, immune, and metabolic pathways.

The gut-brain axis regulates several important aspects of physiological function and behavior. Regulation through the gut-brain axis occurs via hormones and neural circuits. Key components of these hormonal and neural circuits of the gut-brain axis include hormone-releasing, highly specialized secretory intestinal cells (enteroendocrine cells or EECs), the autonomic nervous system (including the vagus nerve and enteric nervous system), and the central nervous system system. These systems work together in a highly coordinated manner to regulate physiological functions and behavior.

Defects in the gut-brain axis are associated with a variety of diseases, including those with significant unmet needs. Diseases and conditions affected by the gut-brain axis include central nervous system (CNS) disorders, including mood disorders, anxiety disorders, depression, mood disorders, schizophrenia, malaise, cognitive impairment, addiction, autism, Epilepsy, neurodegenerative disorders, Alzheimer's and Parkinson's diseases, Lewy body dementia, episodic cluster headache, migraine, pain; metabolic conditions, including diabetes and its complications, such as chronic Nephropathy/diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, cardiovascular disease, metabolic syndrome, obesity, dyslipidemia, and nonalcoholic steatohepatitis (NASH); eating and nutritional disorders, including overeating and cachexia , anorexia nervosa, short bowel syndrome, intestinal failure, intestinal insufficiency and other eating disorders; inflammatory conditions and autoimmune diseases such as inflammatory bowel disease, ulcerative colitis, Crohn's disease, examination Colitis, psoriasis, celiac disease, and enteritis caused by point inhibitors, including chemotherapy-induced enteritis or radiation-induced enteritis; necrotizing enterocolitis; gastrointestinal damage caused by toxic insults such as radiation or chemotherapy; gastrointestinal tract Barrier dysfunction diseases/conditions, including environmental intestinal dysfunction; spontaneous bacterial peritonitis; allergies, including food allergies, steatorrhea, and childhood allergies; graft-versus-host disease; functional gastrointestinal disorders, such as irritable bowel syndrome , functional dyspepsia, functional abdominal swelling/distention, functional diarrhea, functional constipation and opioid-induced constipation; gastroparesis; nausea and vomiting; conditions related to microbial dysbiosis, and other intestinal-brain involvement Symptoms of the axis. Adenosine 5'- monophosphate-activated protein kinase (AMPK) in the gut - brain axis

Adenosine 5'-monophosphate-activated protein kinase (AMPK) is a serine/threonine kinase and is evolutionarily conserved from yeast to mammals. In some cases, AMPK is a heterotrimeric protein complex formed from an alpha (alpha1 or alpha2), a beta (beta1 or beta2), and a gamma (gamma1, gamma2, or gamma3) subunits. Due to the presence of isoforms of AMPK's components, there are 12 versions of AMPK (AMPK1, AMPK2, ..., up to AMPK12). In some cases, 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) increases due to nutrient deprivation. In some cases, activated AMPK phosphorylates downstream substrates, thereby promoting catabolism and hindering anabolism, causing ATP production and energy recovery. In some cases, AMPK activity can be altered by a variety of physiological factors, such as hormones, interleukins, and dietary nutrients, as well as pathological conditions, such as obesity, chronic inflammation, and type 2 diabetes. In some cases, AMPK activation causes decreased hepatic glucose production and decreased plasma glucose levels. Thus, in some cases, AMPK activation may serve as a therapeutic agent for the treatment of various metabolic diseases.

In some cases, AMPK has beneficial effects on intestinal health, such as enhancing intestinal absorption, improving barrier function, inhibiting colorectal cancer, and reducing intestinal inflammation and metabolism-related diseases, and is important in maintaining intestinal homeostasis. . In some cases, AMPK is critical for proper intestinal health. In some cases, AMPK activation enhances paracellular junctions, nutrient transporters, autophagy, and apoptosis, and inhibits inflammation and carcinogenesis in the intestine.

In some embodiments, the invention provides AMPK activators that are broadly useful in a variety of AMPK-related conditions and disorders. 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 disorders, depression, mood disorders, schizophrenia, malaise, cognitive impairment, addiction, autism, Epilepsy, neurodegenerative disorders, Alzheimer's and Parkinson's diseases, Lewy body dementia, episodic cluster headache, migraine, pain; metabolic conditions, including diabetes and its complications, such as chronic Nephropathy/diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, cardiovascular disease, metabolic syndrome, obesity, dyslipidemia, and nonalcoholic steatohepatitis (NASH); eating and nutritional disorders, including overeating and cachexia , anorexia nervosa, short bowel syndrome, intestinal failure, intestinal insufficiency and other eating disorders; inflammatory conditions and autoimmune diseases such as inflammatory bowel disease, ulcerative colitis, Crohn's disease, examination Colitis, psoriasis, celiac disease, and enteritis caused by point inhibitors, including chemotherapy-induced enteritis or radiation-induced enteritis; necrotizing enterocolitis; gastrointestinal damage caused by toxic insults such as radiation or chemotherapy; gastrointestinal tract Barrier dysfunction diseases/conditions, including environmental intestinal dysfunction; spontaneous bacterial peritonitis; allergies, including food allergies, steatorrhea, and childhood allergies; graft versus host disease; functional gastrointestinal disorders, such as irritable bowel syndrome , functional dyspepsia, functional abdominal swelling/distention, functional diarrhea, functional constipation and opioid-induced constipation; gastroparesis; nausea and vomiting; conditions related to microbial dysbiosis, and other intestinal-brain involvement Symptoms of the 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, non-alcoholic steatotic hepatitis, 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 an 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 caused by toxic insults such as radiation or chemotherapy . In some embodiments, the condition or disorder is a disease/disorder of gastrointestinal barrier dysfunction, including environmental intestinal dysfunction; spontaneous bacterial peritonitis; allergies, including food allergies, steatorrhea, and childhood allergies; transplant Anti-host disease; functional gastrointestinal disorders such as irritable bowel syndrome, functional dyspepsia, functional abdominal distension/distention, functional diarrhea, functional constipation and opioid-induced constipation; gastroparesis; nausea and vomiting. In some embodiments, the condition or disorder is associated with systemic infection and inflammation caused by leaky intestinal barrier. In some embodiments, the condition or disorder is metabolic syndrome, obesity, type 2 diabetes, coronary artery disease, fatty liver, non-alcoholic steatohepatitis (NASH), cirrhosis, hepatic encephalopathy, fibrotic disorder ( Including scleroderma), inflammatory bowel disease (including Crohn's disease and ulcerative colitis), allergies (including food allergies, steatorrhea and childhood allergies), graft-versus-host disease, irritable bowel syndrome, idiopathic Bacterial peritonitis, ischemic colitis, sclerosing cholangitis, Alzheimer's disease, Parkinson's disease, cancer (including colorectal cancer), depression, autism, or combinations thereof. Adenosine 5'- monophosphate-activated protein kinase (AMPK) and intestinal barrier

In some cases, the intestinal mucosa maintains immunological constants under physiological circumstances by acting as a barrier that limits the passage of microorganisms, various microbial products, food antigens, and toxins in the intestinal lumen to the rest of the body. In some cases, the intestinal barrier consists of a monolayer of epithelial cells bound by cell-cell junctions, and a mucin layer covering the epithelium. In some cases, loosening of junctions induced by exogenous or endogenous stressors can damage the intestinal barrier and allow microorganisms and antigens to leak and conflict with the host immune system, thereby causing inflammation and systemic endotoxemia. disease. In some cases, damage to the intestinal barrier (e.g., leaky gut) is a major contributor to the initiation and/or progression of various chronic diseases, including (but not limited to) metabolic endotoxemia, metabolic endotoxemia, Type 2 diabetes, fatty liver disease, obesity, atherosclerosis, inflammatory bowel disease and cancer. In some cases, activation of AMPK, which is associated with maintaining tight junctions in the colon epithelium, controls the development of colitis. In some cases, the expression and assembly of tight junctions depend on AMPK activity.

In some embodiments, the present invention provides methods that can effectively strengthen/protect the intestinal barrier and reduce and/or prevent the development of chronic diseases. The intestinal barrier is an important boundary that separates the microorganisms and antigens in the intestinal lumen from the rest of the body; a damaged "leaky" intestinal barrier is often associated with systemic infection and inflammation, which is the cause of many chronic allergic conditions. , important contributors to infectious, metabolic and autoimmune diseases such as obesity, diabetes, inflammatory bowel disease, food allergies and metabolic endotoxemia.

In some embodiments, the invention provides AMPK activators that are broadly useful in a variety of AMPK-related conditions and disorders. In some embodiments, the condition or disorder is associated with systemic infection and inflammation caused by leaky intestinal barrier. In some embodiments, a leaky intestinal barrier can promote the development of a variety of chronic diseases, including (but not limited to): metabolic syndrome, obesity, type 2 diabetes, coronary artery disease, fatty liver disease, non-alcoholic Steatosis hepatitis (NASH), cirrhosis, hepatic encephalopathy, fibrotic disorders (including scleroderma), inflammatory bowel disease (including Crohn's disease, ulcerative colitis and colitis caused by checkpoint inhibitors) , Allergy (including food allergy, steatorrhea and childhood allergy), graft-versus-host disease, irritable bowel syndrome, spontaneous bacterial peritonitis, ischemic colitis, sclerosing cholangitis, Alzheimer's disease, Parkinson's disease disease, cancer (including colorectal cancer), depression, autism, or a combination thereof.

In some cases, intestinal mucosal injury is often a dose-limiting complication of radiation therapy and chemotherapy. Methods used to limit intestinal damage during radiation and chemotherapy have been largely ineffective. In some embodiments described herein, AMPK activators are suitable for treating gastrointestinal injury. In some embodiments, AMPK activators are suitable for treating gastrointestinal damage caused by toxic insults. In some embodiments, toxic damage is caused by radiation, chemotherapy, or combinations thereof. In some embodiments, toxic damage is induced by radiation. In some embodiments, toxic damage is induced by chemotherapy. Intestinal restriction modulator

In some cases, there are problems associated with systemic AMPK activation, such as AMPK activation in the heart. For example, in some cases, activating mutations in the AMPK gamma 2 subunit cause PRKAG2 cardiomyopathy. In other cases, systemic AMPK activation causes cardiac hypertrophy and increased cardiac glycogen. In some cases, tissue-selective AMPK activation is a noteworthy approach to the development of AMPK activators for the treatment of disease, given the potential association of side effects with systemic AMPK activation.

In some embodiments, the AMPK activator is intestinal restricted. In some embodiments, AMPK activators are designed to be substantially non-permeable or substantially non-bioavailable in the bloodstream. In some embodiments, AMPK activators are designed to activate AMPK activity in the intestine and are non-systemic in nature. In some embodiments, AMPK activators have low systemic exposure.

In some embodiments, gut-restricted AMPK activators have low oral bioavailability. In some embodiments, the 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.

In some embodiments, the plasma level of unbound gut-restricted AMPK activator is less than the _EC50 value of the AMPK activator for AMPK. In some embodiments, the plasma level of unbound gut-limited AMPK activator is significantly lower than the _EC50 value of the gut-limited AMPK activator for AMPK. In some embodiments, the plasma level of unbound AMPK activator is 2-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, or 100-fold lower than the EC ₅₀ value for AMPK of the gut-restricted AMPK activator. .

In some embodiments, gut-restricted AMPK activators have low systemic exposure. In some embodiments, the systemic exposure of a gut-limited 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 (in serum, bound or unbound). In some embodiments, the systemic exposure of a gut-limited 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 (in serum, bound or unbound) .

In some embodiments, gut-restricted AMPK activators have high gut exposure. In some embodiments, the intestinal exposure of the intestinal-limited AMPK activator is, for example, greater than 1, 5, 10, 50, 100, 250, or 500 μM.

In some embodiments, gut-restricted AMPK activators have high exposure in the large intestine. In some embodiments, the intestinal exposure of a gut-limited AMPK activator is, for example, greater than 1, 5, 10, 50, 100, 250, or 500 μM. In some embodiments, the intestinal exposure of a gut-limited AMPK activator is, for example, greater than 100 μM.

In some embodiments, the gut-restricted AMPK activator has low permeability. In some embodiments, intestinal-restricted AMPK activators have low intestinal permeability. In some embodiments, the gut-restricted AMPK activator has a permeability of, 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.

In some embodiments, gut-restricted AMPK activators have low absorption rates. In some embodiments, the intestinal-limited AMPK activator has an absorption rate of less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, or less than 1%.

In some embodiments, gut-restricted AMPK activators have high plasma clearance. In some embodiments, the gut-restricted AMPK activator is effective in less than 8 hours, less than 6 hours, less than 4 hours, less than 3 hours, less than 120 minutes, less than 90 minutes, less than 60 minutes, less than 45 minutes, less than 30 minutes, or Undetectable in plasma after less than 15 minutes.

In some embodiments, the gut-restricted AMPK activator is rapidly metabolized upon administration. In some embodiments, gut-restricted AMPK activators have a short half-life. In some embodiments, the gut-restricted AMPK activator has a half-life of less than 8 hours, less than 6 hours, less than 4 hours, less than 3 hours, less than 120 minutes, less than 90 minutes, less than 60 minutes, less than 45 minutes, less than 30 minutes or less than 15 minutes. In some embodiments, metabolites of intestinal-restricted AMPK activators have rapid clearance. In some embodiments, the metabolite of the gut-restricted AMPK activator is present in less than 8 hours, less than 6 hours, less than 4 hours, less than 3 hours, less than 120 minutes, less than 90 minutes, less than 60 minutes, less than 45 minutes, less than Undetectable after 30 minutes or less than 15 minutes. In some embodiments, metabolites of gut-restricted AMPK activators have low biological activity. In some embodiments, the EC ₅₀ value of the metabolite of the gut-limited AMPK activator is 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, higher than the EC ₅₀ value of the gut-limited AMPK activator for AMPK. 100x, 500x or 1000x. In some embodiments, metabolites of intestinal-restricted AMPK activators have rapid clearance and low biological activity.

In some embodiments, gut-restricted AMPK activators have high efflux. In some embodiments, the intestinal-restricted AMPK activator is a substrate of one or more intestinal efflux transporters, such as P-gp (MDR1), BCRP, or MRP2. In some embodiments, gut-restricted AMPK as measured by B-A/A-B ratio in cell lines such as Caco-2 or MDCK in the presence or absence of overexpression of one or more efflux transporters. The outflow amount of the activator is, for example, greater than 2, greater than 5, greater than 10, greater than 25 or greater than 50.

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 superagonist. In some embodiments, the AMPK activator is a gut-restricted AMPK full agonist. In some embodiments, the AMPK activator is a gut-restricted partial AMPK agonist. In some embodiments, the AMPK activator is covalently bonded to the pharmacokinetic group. In some embodiments, the AMPK activator is covalently bonded to the pharmacokinetic group via a linker. compound

In some embodiments, disclosed herein are compounds of Formula (I): , ^where : X is -O-, -CH ₂ - or ^{-CHR 4} - ^; or X is -CH-, and L ¹ is connected to Each R ³ at each occurrence is independently selected from halogen, hydroxyl, C _{1 - 4} alkyl, -CN and C _{1 - 4} haloalkyl; each R ⁴ at each occurrence is independently selected from halogen, hydroxyl, C _{1 - 4} alkyl, -CN and C _{1 - 4} haloalkyl; or two R ⁴ together form a bond or C _{1 - 2} alkyl group; n is selected from 0, 1, 2, 3 and 4; o system is selected from 0, 1, 2, 3 and 4; p system is selected from 0, 1 and 2; q system is selected from 0, 1, 2, 3 and 4; R ⁵ system is selected from hydrogen and C _1-4 alkane base; R ⁶ is selected from hydrogen, halogen, C _1-4 alkyl and C _1-4 haloalkyl; L ¹ is a bond or -CH ₂ -; D is selected from -CO ₂ R ¹¹ , -P( O)(OR ¹¹ ) ₂ , -P(O)R ¹¹ (OR ¹¹ ), -S(O) ₂ OH and -L ² -K; L ² is selected from ^λ -(C(R ¹³ ) ₂ ) _r -, ^λ -O(C(R ¹³ ) ₂ ) _r -, ^λ -(C(R ¹³ ) ₂ ) _r O-, ^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 )- and 4 to 6 membered heterocycles, where ^λ represents the connection with 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 independently selected from one to six as appropriate: Substituent substitution: 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 carbocyclic rings and 3 to 10-membered heterocyclic rings, wherein each C _{3-10 carbocyclic} ring and 3 to 10-membered _heterocyclic rings are optionally substituted with one to six substituents independently selected from the following: halogen , C _{1 - 6} alkyl, -OR ¹⁴ , =O and -S(O) ₂ OH; and (ii) C _{3 - 10} carbocyclic rings and 3 to 10 membered heterocyclic rings, each of which has one to six independent rings as appropriate. Substituted with substituents selected from the following: 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 independently selected from one to six as appropriate. Substituted from the following substituents: 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; R ¹¹ is independently selected at each occurrence from hydrogen, C _{1 - 4} alkyl and C _{1 - 4} haloalkyl; R ¹² at each occurrence is independently selected from hydrogen and optionally C _{1 - 4} substituted by halogen, -OH, -NH ₂ and -C(O)NH ₂ Alkyl; R ¹³ is independently selected at each occurrence from hydrogen, C _{1 - 4} alkyl, C _{1 - 4} haloalkyl and C _{1 - 4} hydroxyalkyl; each R ¹⁴ is independently selected at each occurrence From: hydrogen; optionally C _{1 - 10} alkyl and C _{1 - 10} heteroalkyl substituted by 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} carbocyclic rings and 3 to 10 membered heterocyclic rings, wherein each C _{3 - 10} carbocyclic ring and 3 to 10 membered heterocyclic rings are independently selected from one to six as appropriate, from the following Substituent substitution: 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 R ²¹ , -S(O) ₂ N(R ²¹ ) ₂ , =O and -CN; each R ¹⁵ is independently Selected from C _{1 - 4} alkyl; each R ¹⁶ is independently selected from hydrogen and C _{1 - 6} alkyl at each occurrence; each R ²¹ is independently selected from hydrogen and C _{1 - 6} alkyl at each occurrence , C _{1 - 6} haloalkyl, C _{1 - 6} hydroxyalkyl and C _{3 - 6} carbocyclic ring, wherein the C _{3 - 6} carbocyclic ring is optionally substituted by one to six substituents independently selected from the following: -OH, C _{1 - 6} alkyl, C _{1 - 6} haloalkyl, C _{1 - 6} hydroxyalkyl and =O.

For any and all embodiments, the substituents are selected from a subset of the enumerated alternatives. For example, in some embodiments, Y is ^CR6 . In some embodiments, ^R6 is hydrogen or halogen. In some embodiments, ^R6 is hydrogen or fluorine. 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.

In some embodiments, X is -O-. In some embodiments, X is _-CH2- . In some embodiments, X is ^-CHR4- . In some embodiments, X is -CHR ⁴ -, and R ⁴ is halogen, hydroxy, or methyl.

In some embodiments, X is -O- or _-CH2- ; or X is -CH-, and ^L1 is connected to X.

In some embodiments, X is -O-. In some embodiments, X is _-CH2- .

In some embodiments, ^L1 is a bond. In some embodiments, L ¹ is -CH ₂ -.

In some embodiments, X is O and ^L is a bond.

In some embodiments, the compound is represented by Formula (II): , or its pharmaceutically acceptable salt.

In some embodiments, the compound is represented by formula (IIa) or (IIb): , or its pharmaceutically acceptable salt.

In some embodiments, the compound is represented by Formula (IIa), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is represented by Formula (IIb), or a pharmaceutically acceptable salt thereof.

In some embodiments, X is -CH-, and L ¹ is connected to X. In some embodiments, ^L1 is a bond. In some embodiments, L ¹ is -CH ₂ -.

In some embodiments, the compound is represented by Formula (III): , or its pharmaceutically acceptable salt.

In some embodiments, the compound is represented by Formula (IIIa), Formula (IIIb) or Formula (IIIc): , or its pharmaceutically acceptable salt.

In some embodiments, the compound is represented by Formula (IIIa), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is represented by formula (IIIb), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is represented by Formula (IIIc), or a pharmaceutically acceptable salt thereof.

In some embodiments, ^R5 is hydrogen. In some embodiments _, R ⁵ is C _{1 -4} alkyl. In some embodiments, ^R5 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, and tertiary butyl. In some embodiments, ^R5 is methyl or ethyl. In some embodiments, ^R5 is methyl. In some embodiments, R ⁵ is ethyl.

In some embodiments, ^R5 is hydrogen, methyl, or ethyl. In some embodiments, ^R5 is hydrogen or methyl.

In some embodiments, the compound is represented by Formula (IV): , or its pharmaceutically acceptable salt.

In some embodiments, the compound is represented by Formula (IVa), Formula (IVb), Formula (IVc), Formula (IVd), or Formula (IVe): , or its pharmaceutically acceptable salt.

In some embodiments, the compound is represented by Formula (IVa), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is represented by Formula (IVb), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is represented by Formula (IVc), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is represented by Formula (IVd), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is represented by Formula (IVe), or a pharmaceutically acceptable salt thereof.

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.

In some _embodiments , each R ¹ at each occurrence is independently selected from halogen, hydroxyl, and C _{1 -4} alkyl. In some embodiments, ^each R at each occurrence is independently selected from F, Cl, hydroxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl and tertiary butyl. In some embodiments, each ^R1 is F, Cl, methyl, or hydroxyl. In some embodiments, each ^R1 is methyl. In some embodiments, each ^R1 is hydroxyl.

In some embodiments, R ¹ is hydroxyl and n is selected from 0 and 1.

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.

In some embodiments, each ^R at each _occurrence is independently selected from halogen, hydroxyl, and C _{1 -4} alkyl. In some embodiments, ^each R at each occurrence is independently selected from F, Cl, hydroxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl and tertiary butyl. In some embodiments, each ^R2 is F, Cl, methyl, or hydroxyl.

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.

In some _embodiments , each R ³ at each occurrence is independently selected from halogen, hydroxyl, and C _{1 -4} alkyl. In some embodiments, each ^R at each occurrence is independently selected from F, Cl, hydroxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl and tertiary butyl. In some embodiments, each ^R3 is halogen. In some embodiments, each ^R3 is F or Cl. In some embodiments, each ^R3 is F. In some embodiments, each ^R3 is Cl.

In some embodiments, ^R3 is halogen and p is selected from 0 and 1. In some embodiments, ^R3 is selected from fluorine and chlorine, and p is 1. In some embodiments, ^R3 is fluoro and p is 1. In some embodiments, ^R3 is chloro and p is 1.

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 zero. In some embodiments, q is 1. In some embodiments, q is 2.

In some embodiments, each R ⁴ at each occurrence _{is independently selected from halogen, hydroxyl, C 1 -4 alkyl , -CN} , and C _{1 -4} haloalkyl.

In some embodiments, each R ⁴ at each occurrence _{is independently selected from hydroxy, C 1 -4 alkyl , -CN} , and C _{1 -4} haloalkyl. In some embodiments, each R ⁴ at each occurrence is independently selected from hydroxyl and _{C 1 -4} alkyl. In some embodiments, each ^R at each occurrence is independently selected from hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, and tertiary butyl. base. In some embodiments, each R ⁴ is hydroxy or methyl.

In some embodiments, two R ^4's together form a bond or _a C _{1 -2} alkylene group. In some embodiments, two R ^4's together form a bond. In some _embodiments , two ^R4's taken together form _{a C1-2} alkylene group. In some embodiments, two ^R4 taken together form _-CH2- . In some embodiments, two ^R4 taken together _{form -CH2CH2-} .

In some embodiments _, R ⁶ is selected from hydrogen, halogen, and C _{1 -4} alkyl. In some embodiments, ^R6 is selected from hydrogen, F, Cl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, and tertiary butyl. In some embodiments, ^R6 is selected from hydrogen, F, Cl, and methyl. In some embodiments, ^R6 is selected from hydrogen and halogen. In some embodiments, ^R6 is selected from hydrogen, fluorine, and chlorine. In some embodiments, ^R6 is selected from hydrogen and fluorine. In some embodiments, ^R6 is hydrogen. In some embodiments, ^R6 is fluorine.

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.

In some embodiments, D is ^-L2 -K.

In some embodiments, L ² is ^λ -(C(R ¹³ ) ₂ ) _r -. In some embodiments, L ² is ^λ -O(C(R ¹³ ) ₂ ) _r -. In some embodiments, L ² is ^λ -(C(R ¹³ ) ₂ ) _r O-. In some embodiments, L ² is ^λ -N(R ¹² )(C(R ¹³ ) ₂ ) _s -. In some embodiments, L ² is ^λ -C(O)O-. In some embodiments, L ² is ^λ -C(O)N(R ¹² )-. In some embodiments, L ² is ^λ -N(R ¹² )C(O)-. In some embodiments, L ² is ^λ -N(R ¹² )S(O) ₂ -. In some embodiments, L ² is ^λ -S(O) ₂ N(R ¹² )-. In some embodiments, L ² is 4 to 6 membered heterocycloalkyl. In some embodiments, ^L2 is 5- to 6-membered heteroaryl.

In some embodiments, L ² 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 -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. L ² system 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 - and Triazolyl.

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.

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.

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.

In some embodiments, K is selected from (i) and (ii) _: (i) C _{1 -10} alkyl or C _{1 -10} heteroalkyl, each of which is independently selected from one to six, as appropriate _: Substituent substitution: halogen, -OR ¹⁴ , -N(R ¹⁴ ) ₂ , -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 , =O, -P(O)(OR ¹⁶ ) ₂ , -P(O)R ¹⁶ (OR ¹⁶ ), -S(O) ₂ OH; and 3 to 10 membered heterocycles, each of which is optionally substituted with one to six substituents independently selected from the following: halogen, C _{1 - 6} alkyl, -OR ¹⁴ , =O and -S(O) ₂ OH; (ii) C _{3 - 10} carbocyclic rings and 3 to 10 membered heterocyclic rings, each of which is optionally substituted with one to six substituents independently selected from the following: 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)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 by one _to six substituents independently selected from _the following: halogen , -OR ¹⁴ , -N(R ¹⁴ ) ₂ , -C(O)OR ¹⁴ , -P(O)(OR ¹⁶ ) ₂ , -S(O) ₂ OH, S(O) ₂ R ¹⁴ and =O .

In some embodiments, C _{1 -10} alkyl or C _{1 -10} heteroalkyl, each of which is optionally substituted with one to six substituents _{independently} selected from the following: halogen, -OR ¹⁴ , -N( _R ¹⁴ ) ₂ , -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 , =O, -P(O)(OR ¹⁶ ) ₂ , -P(O)R ¹⁶ (OR ¹⁶ ), -S(O) ₂ OH; and 3 to 10-membered heterocycles. In some embodiments, C _{1 -10} alkyl or C _{1 -10} heteroalkyl, each of which is optionally substituted with one to six substituents _{independently} selected from the following: halogen, -OR ¹⁴ , -N( _R ¹⁴ ) ₂ , -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 , =O, -P(O)(OR ¹⁶ ) ₂ , -P(O)R ¹⁶ (OR ¹⁶ ), -S(O) ₂ OH; and 3 to 10 membered heterocycles, each of which is subject to 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 and azetidine, optionally substituted with one to six substituents independently selected from: -OR ¹⁴ , S(O) ₂ R ¹⁴ and =O.

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 .

In some embodiments, K is selected from C _{1 -10} alkyl _, 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, 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 .

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 .

In some embodiments, K is selected from C _{3 -10} carbocyclic rings and 3 to 10 membered heterocyclic rings, each of which is optionally substituted with one _to six substituents independently selected from the following: 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)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, C _{3 - 10} carbocyclic rings and 3 to 10 membered heterocyclic rings are each optionally substituted with one to six substituents independently selected from the following: 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)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 by one to six substituents independently selected from the _{following :} Halogen, -OR ¹⁴ , -N(R ¹⁴ ) ₂ , -C(O)OR ¹⁴ , -P(O)(OR ¹⁶ ) ₂ , -S(O) ₂ OH, S(O) ₂ R ¹⁴ and = O.

In some embodiments, K is selected from C _{3 -10} carbocyclic rings and 3 to 10 membered heterocyclic rings, each of which is optionally substituted with one _to six substituents independently selected from the following: halogen, -OR ¹⁴ , -N (R ¹⁴ ) ₂ , =O and C _1-10 alkyl, wherein each C _{1 - 10} alkyl is optionally substituted by one to six substituents independently selected from the following: halogen, -OR ¹⁴ , -N(R ¹⁴ ) ₂ , -C(O)OR ¹⁴ , -P(O)(OR ¹⁶ ) ₂ , -S(O) ₂ OH and S(O) ₂ R ¹⁴ .

In some embodiments, K is selected from azetidines, which are optionally substituted with one to six substituents independently selected from C _{1 -10} alkyl, wherein each C _{1 -10} alkyl is optionally substituted with one to _six substituents _. Substituted with six substituents independently selected from: -OR ¹⁴ and S(O) ₂ R ¹⁴ .

In some embodiments, K is selected from piperidine, azetidine, and piperidine, each of which is optionally substituted with one to six substituents independently selected from: fluorine, -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 by one to six substituents independently selected from the following: fluorine, chlorine, -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.

In some embodiments, each R ¹⁴ at each occurrence is independently selected from hydrogen and optionally C _{1 - 10} alkyl substituted with one to six substituents independently selected from: halogen, -OR ²¹ , - N(R ²¹ ) ₂ , -P(O)(OR ¹⁶ ) ₂ , -S(O) ₂ OH and =O. In some embodiments, each R ¹⁴ at each occurrence is independently selected from hydrogen and optionally C _{1 - 10} alkyl substituted with one to six substituents independently selected from -OR ²¹ . In some embodiments, each R ¹⁴ at each occurrence is independently _selected from hydrogen and C _{1 -10} alkyl optionally substituted with one to six -OH substituents. In some _embodiments , each R ¹⁴ at each occurrence is independently selected from hydrogen and C _{1 -6} alkyl.

In some embodiments, _each R ²¹ at each occurrence is independently _{selected from} hydrogen, C _{1 -6} alkyl, C _{1 -6} haloalkyl, and C _{1 -6} hydroxyalkyl. In some _embodiments , each R ²¹ on each occurrence is independently selected from hydrogen and C _{1 -6} alkyl.

In some embodiments, the D-line is selected from: .

Any combination of the groups described above with respect to the various variables is contemplated herein. Throughout this specification, the selection of groups and their substituents to provide stable moieties and compounds is left to one skilled in the art.

In some embodiments, the compound is a compound in one of the following tables, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof. In some embodiments, the compound is not A - 1 , A - 2 , or A - 3 . Compound A - 1 as shown in Table 1 is Example 29 of International Patent Publication Application WO/2012/116145A1. Compound A - 2 as shown in Table 1 is Example 15 of International Patent Publication Application WO/2011/106273A1. Table 1. Compound number structure 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 twenty one twenty two 44 45 32 43 29 33 twenty four 34 49 48 26 37 28 46 30 31 42 52 53 54 55 56 57 58 59 60 A-1 A-2 A-3

The compounds in Table 1 are named: 1 : (1r,4r)-4-((6-chloro-5-(4'-((2-(2-hydroxyethoxy)ethoxy)methyl)- [1,1'-biphenyl]-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)cyclohexane-1-carboxylic acid; 2 : (2R,4S) -4-((6-chloro-5-(4'-(((2-(2-hydroxyethoxy)ethyl)amino)methyl)-[1,1'-biphenyl]-4- base)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)tetrahydro-2H-piran-2-carboxylic acid; 3 : (1r,4r)-4-((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)cyclohexane-1-carboxylic acid; 4 : (1r,4r)-4-((6-chloro-5-(4'-(( 4-(2-(2-Hydroxyethoxy)ethyl)piperidine-1-yl)methyl)-[1,1'-biphenyl]-4-yl)-1H-imidazo[4,5 -b]pyridin-2-yl)oxy)cyclohexane-1-carboxylic acid; 5 : (2R,4S)-4-((4,6-difluoro-5-(4'-((3-( (2-Hydroxyethoxy)methyl)azetidin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazole-2 -yl)oxy)tetrahydro-2H-piran-2-carboxylic acid; 6 : (2S,4R)-4-((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)tetrahydro-2H-piran-2-carboxylic acid; 7 : (1s,4s)-4-((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 base) cyclohexane-1-carboxylic acid; 8 : (1r,4r)-4-((4,6-difluoro-5-(4'-(2-(2-hydroxyethoxy)ethoxy) )methyl)-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)cyclohexane-1-carboxylic acid; 9 : (1r,4r )-4-((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)cyclohexane-1-carboxylic acid; 10 : (1r,4r)-4-(( 6-Chloro-5-(4'-((3-(2-methoxyethoxy)azetidin-1-yl)methyl)-[1,1'-biphenyl]-4- base)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)cyclohexane-1-carboxylic acid; 11 : (1r,4r)-4-((6-chloro-5-( 4'-((((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)methyl)-[1,1'-biphenyl]-4-yl )-1H-imidazo[4,5-b]pyridin-2-yl)oxy)cyclohexane-1-carboxylic acid; 12 : (2R,4S)-4-((6-chloro-5-(4) '-((((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)methyl)-[1,1'-biphenyl]-4-yl) -1H-imidazo[4,5-b]pyridin-2-yl)oxy)tetrahydro-2H-piran-2-carboxylic acid; 13 : (2R,4S)-4-((6-chloro-5 -(4'-((3-((2-hydroxyethoxy)methyl)azetidin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)- 1H-benzo[d]imidazol-2-yl)oxy)tetrahydro-2H-piran-2-carboxylic acid methyl ester; 14 : (2S,4R)-4-((6-chloro-5-(4) '-((3-((2-Hydroxyethoxy)methyl)azetidin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)-1H-benzene And [d]imidazol-2-yl)oxy)tetrahydro-2H-piran-2-carboxylic acid methyl ester; 15 : (2R,4S)-4-((6-chloro-5-(4'-( (3-((2-hydroxyethoxy)methyl)azetidin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)-1H-imidazo[4 ,5-b]pyridin-2-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid methyl ester; 16 : (2S,4R)-4-((6-chloro-5-(4'- ((3-((2-hydroxyethoxy)methyl)azetidin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)-1H-imidazo[ 4,5-b]pyridin-2-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid methyl ester; 17 : (2R,4S)-4-((6-chloro-5-(4'-((3-((2-hydroxyethoxy)methyl)azetidin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)-1H-benzo [d]imidazol-2-yl)oxy)tetrahydro-2H-piran-2-carboxylic acid; 18 : (2S,4R)-4-((6-chloro-5-(4'-((3- ((2-hydroxyethoxy)methyl)azetidin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazole- 2-yl)oxy)tetrahydro-2H-piran-2-carboxylic acid; 19 : (2R,4S)-4-((6-chloro-5-(4'-((3-((2-hydroxy Ethoxy)methyl)azetidin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)-1H-imidazo[4,5-b]pyridine-2 -yl)oxy)tetrahydro-2H-piran-2-carboxylic acid; 20 : (2S,4R)-4-((6-chloro-5-(4'-((3-((2-hydroxyethyl) Oxy)methyl)azetidin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)-1H-imidazo[4,5-b]pyridine-2- base)oxy)tetrahydro-2H-piran-2-carboxylic acid; 21 : (1r,4r)-4-((4,6-difluoro-5-(4'-((3-((methyl Sulfonyl)methyl)azetidin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy base) cyclohexane-1-carboxylic acid; 22 : (1r,4r)-4-((6-chloro-5-(4'-((2-(2-hydroxyethoxy)ethoxy)methyl) )-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)cyclohexane-1-carboxylic acid; 24 : 2-((1r,4r )-4-((6-chloro-5-(4'-(1-(2-(dimethylamino)ethyl)-1H-1,2,4-triazol-3-yl)-[ 1,1'-biphenyl]-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)cyclohexyl)acetic acid; 26 : 2-((1r,4r)- 4-((5-(4'-(1-(2-(azetidin-1-yl)ethyl)-1H-1,2,4-triazol-3-yl)-[1, 1'-biphenyl]-4-yl)-6-chloro-1H-imidazo[4,5-b]pyridin-2-yl)oxy)cyclohexyl)acetic acid; 28 : 2-((1r,4r )-4-((6-chloro-5-(4'-((2-(2-hydroxyethoxy)ethoxy)methyl)-[1,1'-biphenyl]-4-yl) -1H-imidazo[4,5-b]pyridin-2-yl)oxy)cyclohexyl)acetic acid; 29 : 2-((1r,4r)-4-((4,6-difluoro-5- (4'-((3-((methylsulfonyl)methyl)azetidin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)-1H- Benzo[d]imidazol-2-yl)oxy)cyclohexyl)acetic acid; 30 : 2-((1r,4r)-4-((5-(4'-(1-(2-(azacycle) Butan-1-yl)ethyl)-1H-1,2,4-triazol-3-yl)-[1,1'-biphenyl]-4-yl)-4,6-difluoro-1H -benzo[d]imidazol-2-yl)oxy)cyclohexyl)acetic acid; 31 : 2-((1r,4r)-4-((5-(4'-(1-(2-(dimethyl) ((amino)ethyl)-1H-1,2,4-triazol-3-yl)-[1,1'-biphenyl]-4-yl)-4,6-difluoro-1H-benzo [d]imidazol-2-yl)oxy)cyclohexyl)acetic acid; 32 : 2-((1r,4r)-4-((4,6-difluoro-5-(4'-(1-(2) ,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazole -2-yl)oxy)cyclohexyl)acetic acid; 33 : 2-((1r,4r)-4-((4,6-difluoro-5-(4'-((3-(2-methoxy) ethoxy)azetidin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy) Cyclohexyl)acetic acid; 34 : 2-((1r,4r)-4-((4,6-difluoro-5-(4'-(2-(2-hydroxyethoxy)ethoxy)methyl) base)-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)cyclohexyl)acetic acid; 37 : (1r,4r)-4-( (5-(4'-(1-(2-(azetidin-1-yl)ethyl)-1H-1,2,4-triazol-3-yl)-[1,1'- Biphenyl]-4-yl)-4,6-difluoro-1H-benzo[d]imidazol-2-yl)oxy)cyclohexane-1-carboxylic acid; 42 : (1r,4r)-4- ((5-(4'-(1-(2-(azetidin-1-yl)ethyl)-1H-1,2,4-triazol-3-yl)-[1,1' -Biphenyl]-4-yl)-6-chloro-1H-imidazo[4,5-b]pyridin-2-yl)oxy)cyclohexane-1-carboxylic acid; 43 : (1r,4r)- 4-((5-(4'-(1-(2-(dimethylamino)ethyl)-1H-1,2,4-triazol-3-yl)-[1,1'- Benzene]-4-yl)-4,6-difluoro-1H-benzo[d]imidazol-2-yl)oxy)cyclohexane-1-carboxylic acid; 44 : (1r,4r)-4-( (4,6-Difluoro-5-(4'-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-3-yl)-[1,1 '-Biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)cyclohexane-1-carboxylic acid; 45 : (1r,4r)-4-((4,6 -Difluoro-5-(4'-((3-(2-methoxyethoxy)azetidin-1-yl)methyl)-[1,1'-biphenyl]-4- base)-1H-benzo[d]imidazol-2-yl)oxy)cyclohexane-1-carboxylic acid; 46 : (1r,4r)-4-((4,6-difluoro-5-(4 '-((2-(2-Hydroxyethoxy)ethoxy)methyl)-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl) Oxy)cyclohexane-1-carboxylic acid; 48 : (1r,4r)-4-((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) Cyclohexane-1-carboxylic acid; 49 : 2-((1r,4r)-4-((6-chloro-5-(4'-((3-(trifluoromethoxy))azetidine- 1-yl)methyl)-[1,1'-biphenyl]-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)cyclohexyl)acetic acid; 52 : (1r,4r)-4-((4,6-difluoro-5-(4'-((3-(2-hydroxyethoxy)azetidin-1-yl)methyl)-[ 1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)cyclohexane-1-carboxylic acid; 53 : (1r,4r)-4-(( 4,6-Difluoro-5-(4'-((4-(2-(methylsulfonyl)ethyl)piperidine-1-yl)methyl)-[1,1'-biphenyl] -4-yl)-1H-benzo[d]imidazol-2-yl)oxy)cyclohexane-1-carboxylic acid; 54 : (1r,4r)-4-((6-chloro-5-(4) '-((4-(2-(methylsulfonyl)ethyl)piperidine-1-yl)methyl)-[1,1'-biphenyl]-4-yl)-1H-imidazo[ 4,5-b]pyridin-2-yl)oxy)cyclohexane-1-carboxylic acid; 55 : 2-((1r,4r)-4-((4,6-difluoro-5-(4'-((3-(2-Hydroxyethoxy)azetidin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazole -2-yl)oxy)cyclohexyl)acetic acid; 56 : 2-((1r,4r)-4-((4,6-difluoro-5-(4'-((4-(2-(methyl) (Sulfonyl)ethyl)piperidine-1-yl)methyl)-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy) Cyclohexyl)acetic acid; 57 : 2-((1r,4r)-4-((6-chloro-5-(4'-((4-(2-(methylsulfonyl)ethyl)ethyl)piperidine- 1-yl)methyl)-[1,1'-biphenyl]-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)cyclohexyl)acetic acid; 58 : (1r,4r)-4-((4,6-difluoro-5-(4'-((1r,3r)-3-hydroxycyclobutoxy)methyl)-[1,1'- Benzene]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)cyclohexane-1-carboxylic acid; 59 : (1r,4r)-4-((4,6-difluoro -5-(4'-(((1s,3s)-3-hydroxycyclobutoxy)methyl)-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazole -2-yl)oxy)cyclohexane-1-carboxylic acid; 60 : 2-((1s,4s)-4-((4,6-difluoro-5-(4'-((2-(2) -Hydroxyethoxy)ethoxy)methyl)-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)cyclohexyl)acetic acid; A-1 : (1r,4r)-4-((5-([1,1'-biphenyl]-4-yl)-6-chloro-1H-imidazo[4,5-b]pyridine-2 -yl)oxy)cyclohexane-1-carboxylic acid; A-2 : (1r,4r)-4-((5-([1,1'-biphenyl]-4-yl)-4,6- Difluoro-1H-benzo[d]imidazol-2-yl)oxy)cyclohexane-1-carboxylic acid; A-3 : 2-((1r,4r)-4-((5-([1, 1'-Biphenyl]-4-yl)-4,6-difluoro-1H-benzo[d]imidazol-2-yl)oxy)cyclohexyl)acetic acid.

In some embodiments, the compound is a pharmaceutically acceptable salt of a compound in Table 1. Table 2. Compound number structure twenty three 25 27 35 36 38 39 40 41 47 50 51

The compounds in Table 2 are named: 23 : 2-((1r,4r)-4-((6-chloro-5-(4'-((3-((methylsulfonyl)methyl)methyl)aza cyclobutan-1-yl)methyl)-[1,1'-biphenyl]-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)cyclohexyl) Acetic acid; 25 : 2-((1r,4r)-4-((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)cyclohexyl)acetic acid; 27 : 2-( (1r,4r)-4-((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)cyclohexyl)acetic acid; 35 : (1s,4s)- 4-((6-chloro-5-(4'-((3-((methylsulfonyl)methyl)azetidin-1-yl)methyl)-[1,1'-bis Benzene]-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)cyclohexane-1-carboxylic acid; 36 : (1s,4s)-4-((4, 6-Difluoro-5-(4'-((3-((methylsulfonyl)methyl)azetidin-1-yl)methyl)-[1,1'-biphenyl]- 4-yl)-1H-benzo[d]imidazol-2-yl)oxy)cyclohexane-1-carboxylic acid; 38 : (1r,4r)-4-((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)cyclohexane-1-carboxylic acid; 39 : (1r,4r)-4-((6-chloro-5-(4'-((3-( 2-methoxyethoxy)azetidin-1-yl)methyl)-[1,1'-biphenyl]-4-yl)-1H-imidazo[4,5-b]pyridine -2-yl)oxy)cyclohexane-1-carboxylic acid; 40 : (1r,4r)-4-((6-chloro-5-(4'-(1-(2-(dimethylamino) )ethyl)-1H-1,2,4-triazol-3-yl)-[1,1'-biphenyl]-4-yl)-1H-imidazo[4,5-b]pyridine-2 -yl)oxy)cyclohexane-1-carboxylic acid; 41 : (1r,4r)-4-((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)cyclohexane-1-carboxylic acid; 47 : (1r,4r)-4-((6-chloro-5-(4'-((3-(trifluoromethoxy))azetidine- 1-yl)methyl)-[1,1'-biphenyl]-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)cyclohexane-1-carboxylic acid ; 50 : 2-((1r,4r)-4-((6-chloro-5-(4'-((3-(2-(trifluoromethoxy)ethoxy)ethoxy)azetidine- 1-yl)methyl)-[1,1'-biphenyl]-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)cyclohexyl)acetic acid; 51 : 2-((1r,4r)-4-((6-chloro-5-(4'-((3-(2-(trifluoromethoxy)ethoxy)ethoxy)azetidin-1-yl )methyl)-[1,1'-biphenyl]-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)cyclohexyl)acetic acid.

In some embodiments, the compound is a pharmaceutically acceptable salt of a compound in Table 2. Other forms of compounds

Furthermore, in some embodiments, the compounds described herein exist as "geometric isomers." In some embodiments, compounds described herein have one or more double bonds. Compounds presented herein include all cis, trans, iso, trans, iso(E) and iso(Z) isomers and corresponding mixtures thereof. In some cases, compounds exist as tautomeric forms.

"Tautomer" refers to a molecule in which it is possible for a proton to be displaced from one atom of the molecule to another atom of the same molecule. In some embodiments, the compounds presented herein exist as tautomeric forms. In situations where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of tautomers depends on several factors, including physical state, temperature, solvent and pH. Some examples of tautomeric equilibrium include:

In some cases, the compounds described herein have one or more chiral centers, with each center existing in the ( R )-configuration or the ( S )-configuration. The compounds described herein include all diastereomers, enantiomers and epimeric forms as well as corresponding mixtures thereof. In other embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereomers resulting from a single preparation step, combination, or interconversion are suitable for the uses described herein. In some embodiments, the compounds described herein are prepared as optically pure enantiomers by chiral chromatography of racemic mixtures. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compounds with an optically active resolving agent to form a pair of diastereomeric compounds, and isolating the diastereomers. isomers and recover optically pure enantiomers. In some embodiments, dissociable complexes are preferred (eg, crystalline diastereomeric salts). In some embodiments, diastereomers have different physical properties (eg, melting point, boiling point, solubility, reactivity, etc.) and are separated using these dissimilarities. In some embodiments, diastereomeric systems are separated by chiral chromatography or preferably by separation/resolution techniques based on solubility differences. In some embodiments, the optically pure enantiomer is then recovered along with the resolving agent by any practical means that does not cause racemization.

The term "positional isomer" refers to structural isomers with respect to the central ring, such as ortho, meta and para isomers with respect to the benzene ring.

The methods and formulations described herein include the use of crystalline forms (also known as isomers) or pharmaceutically acceptable salts of the compounds described herein as well as active metabolites of such compounds having the same type of activity .

"Pharmaceutically acceptable salts" include acid addition salts and base addition salts. Pharmaceutically acceptable salts of any of the compounds described herein are 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.

"Pharmaceutically acceptable acid addition salt" means a salt which retains the biological effectiveness and properties of the free base, is not biologically or otherwise undesirable, and is prepared from an inorganic acid such as hydrochloric acid, hydrobromide Formed from acids, sulfuric acid, nitric acid, phosphoric acid, hydriodic acid, hydrofluoric acid, phosphorous acid and the like. Also included are salts formed from organic acids such as aliphatic monocarboxylic and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic Sulfonic acid, etc., and includes, 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, benzene Formic acid, cinnamic acid, mandelic acid, methane sulfonic acid, ethane sulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. Thus, exemplary salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monophosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, Chloride, bromide, iodide, acetate, trifluoroacetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberate, decanoate acid salt, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate Formate, benzenesulfonate, tosylate, phenylacetate, citrate, lactate, malate, tartrate, methanesulfonate and the like. Also encompassed are salts of amino acids such as arginates, gluconates and galacturonates (see, e.g., Berge SM 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 form with the desired acid in an amount sufficient to produce the salt.

"Pharmaceutically acceptable base addition salt" means a salt that retains the biological effectiveness and properties of the free acid and is not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to the free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed from 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 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 , such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine acid , arginine, histine, caffeine, procaine, N,N- diphenylmethylethylenediamine, chloroprocaine, hydrabamine, choline, Betaine, ethylenediamine, ethyldiphenylamine, N -methylglucamine, glucosamine, methylglucamine, theobromine, purine, piperidine, piperidine, N -ethylpiperidine, poly Amine resins and their analogues. See Berge et al., supra.

"Prodrug" is intended to refer to a compound that, in some embodiments, is converted under physiological conditions or by solvolysis to an active compound described herein. The term prodrug therefore refers to a pharmaceutically acceptable precursor of an active compound. Prodrugs are generally inactive when administered to an individual, but are converted to active compounds in vivo, such as by hydrolysis. Prodrug compounds often offer solubility, histocompatibility, or delayed release advantages in mammalian organisms (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam )).

Discussions of prodrugs are provided in Higuchi, T. et al., “Pro-drugs as Novel Delivery Systems,” A.C.S. Symposium Series, Volume 14, and Bioreversible Carriers in Drug Design, Edward B. Roche, eds., American Pharmaceutical Association and Pergamon Press, 1987.

The term "prodrug" is also meant to include any covalently bonded carrier that releases the active compound in vivo upon administration of such prodrug to a mammalian subject. Active compound precursors as described herein are prepared by modifying functional groups present in the active compound in such a manner that the modifications are cleaved to the parent active compound during routine procedures or in vivo. Prodrugs include compounds in which a hydroxyl, amine, carboxyl, or sulfhydryl group is bonded to any group that is cleaved to form a free hydroxyl, free amine, free, respectively, when the active compound prodrug is administered to a mammalian subject. Carboxyl group or free sulfhydryl group. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of the alcohol or amine functionality in the active compound, and the like.

"Pharmaceutically acceptable solvate" means a composition of substances in solvent addition form. In some embodiments, solvates contain stoichiometric or non-stoichiometric amounts of solvent and are formed during preparation from pharmaceutically acceptable solvents such as water, alcohols, and the like. A "hydrate" is formed when the solvent is water, or an "alcoholate" is formed when the solvent is alcohol. Solvates of the compounds described herein are suitably prepared or formed during the methods described herein. The compounds provided herein exist in unmiscible and miscible forms, as appropriate.

In some embodiments, the compounds disclosed herein are used in different enriched isotopic forms, such as to enrich the content of ^2H , ^3H , ^11C , ^13C , and/or ^14C . In some embodiments, the compound is deuterated at at least one position. Such deuterated forms can be prepared by the procedures described in US 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 metabolic stability and/or efficacy, thereby increasing the duration of drug action.

Unless otherwise stated, the structures depicted herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having structures of the present invention other than hydrogen replaced by deuterium or tritium or carbon replaced by carbon enriched in ¹³ C or ¹⁴ C are within the scope of the present invention.

The compounds of the present invention optionally contain unnatural proportions of atomic isotopes at one or more of the atoms that make up such compounds. For example, compounds can be isotopically labeled, such as deuterium ( ^2H ), tritium ( ^3H ), iodine-125 ( ^125I ), or carbon-14 ( ^14C ). Covered by ^2H , ^3H , ^11C , ^13C , ^14C , ^15C , ^12N , 13N, ^15N , ^{16N , 17O} , ^18O , ^14F , ^15F , ^16F , ^17F , All isotopes carried out by ¹⁸ F, ³³ S, ³⁴ S, ³⁵ S, ³⁶ S, ³⁵ Cl, ³⁷ Cl, ⁷⁹ Br, ⁸¹ Br, and ¹²⁵ I. All isotopic variations of the compounds of the invention (whether radioactive or not) are encompassed by the scope of the invention.

In some embodiments, some or all of the ¹ H atoms in the compounds disclosed herein are replaced with ² H atoms. Synthetic methods for deuterium-containing compounds are known in the art. In some embodiments, deuterium-substituted compounds are synthesized using various methods such as those described in: Dean, Dennis C., ed. Curr., Pharm. Des., 2000; 6(10)] 2000, page 110; 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.

In some embodiments, compounds described herein are labeled by other means, including, but not limited to, using chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof as described herein, is substantially pure because it contains less than about 5%, or less than about 1%, or less than about 0.1% of other small organic molecules, such as contaminating intermediates or by-products produced, for example, in one or more steps of a synthetic process. Preparation of compounds

Compounds described herein are synthesized using standard synthetic techniques or using methods known in the art and described herein.

Unless otherwise indicated, conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology were used.

Compounds are prepared using standard organic chemistry techniques, such as those described, for example, in March's Advanced Organic Chemistry, 6th Edition, John Wiley and Sons, Inc. Alternative reaction conditions for the synthetic transformations described herein may be used, such as changes in solvents, reaction temperatures, reaction times, and different chemical reagents and other reaction conditions.

In some embodiments, compounds described herein are prepared as outlined in the schemes below. Process 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. Removal of protecting groups and modification of substituents as appropriate

Briefly, nitropyridine (Y=N) or nitrophenyl (Y=CH or CR ⁶ ) compound A is reduced to diaminopyridine compound B. Compound B is treated with carbon dichlorosulfide or carbon disulfide or equivalent to give compound C. Compound C undergoes a methylation reaction followed by oxidation to give compound D. Compound D is protected with a suitable protecting group to obtain compound E. The aryl ester E undergoes a substitution reaction with a suitable alcohol to give the ester compound F (R ⁵ is, for example, C ₁ -C ₄ alkyl). Treatment of aryl iodide F under cross-coupling conditions, such as Suzuki cross-coupling, affords compound G. Ultimately, the protecting groups are removed and in some cases saponified, resulting in a final compound of formula (I) . In some cases, compound G is subjected to other chemical modifications, such as acylation or reductive amination, before final removal of the protecting group. In other embodiments, compounds of formula (I) are directly subjected to such modifications to obtain other compounds.

In some embodiments, compounds described herein are prepared as described, as outlined in the Examples. hospital composition

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 pharmaceutical acceptable excipients. 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, a physiologically suitable (or acceptable) excipients or physiologically suitable (or acceptable) carriers) based on the chosen route of administration (e.g., oral administration) and standard pharmaceutical practice. select.

Examples of aqueous and non-aqueous carriers suitable for use in 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. For example, proper flowability is maintained by using coating materials such as lecithin, by maintaining the desired particle size in the case of dispersions, and by using surfactants. combination therapy

In some embodiments, it is suitable 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.

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 for use in combination with the compounds described herein, or pharmaceutically acceptable salts, solvates, stereoisomers or prodrugs thereof, include, but are not limited to: aminosalicylates, such as Balsalazide, mesalamine, olsalazine and sulfalazine; corticosteroids such as budesonide, prednisone, prednisone prednisolone, methylprednisolone, dexamethasone, and betamethasone; anti-TNFα agents, such as infliximab, adalimumab , certolizumab pegol, golimumab, and PRX-106; anti-IL-12 and/or 23 agents, such as ustekinumab, guse guselkumab, brazikumab, mirikizumab, risankizumab, and PTG-200; anti-integrin agents such as natalizumab ( 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, gentian Acid, choline magnesium salicylate, choline magnesium salicylate, choline magnesium salicylate, choline salicylate, magnesium salicylate, sodium salicylate, and diflunisal; COX inhibition Agents such as carprofen, fenoprofen, fenoprofen calcium, fluorobiprofen, ibuprofen, ketoprofen, Nabumetone, ketorolac, ketorolac tromethamine, naproxen, oxaprozin, diclofenac, etodolac (etodolac), indomethacin, sulindac, tolmetin, meclofenamate, meclofenamate sodium, mefenamic acid (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-745 337 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: aminosalicylates, corticosteroids, Anti-TNFα agents, anti-IL-12 and/or 23 agents, anti-integrin agents, JAK inhibitors, S1P1R modulators, salicylates, COX inhibitors, COX-2 specific inhibitors, interleukin-22 ( IL-22) agent or combination thereof.

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 for use 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 (vildagliptin), saxagliptin (saxagliptin), linagliptin (linagliptin), gemigliptin (gemigliptin), teneligliptin (teneligliptin), alogliptin (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: hypoxia-inducible factor-prolinylhydroxy enzyme (HIF-PH) inhibitor, melanocortin-1 receptor (MC1R) agonist, enhancer of zeste homolog 2 (EZH2) inhibitor, or combinations thereof.

In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, is administered in combination with: glucagon-like peptide (GLP)-1 Agonist, GLP-2 agonist, GLP-1/2 co-agonist, peroxisome proliferator-activated receptor (PPAR) agonist, Farsnenoid X receptor (FXR) Agonist, TGR5 agonist, GPR40 agonist, GPR119 agonist, SSTR5 antagonist, SSTR5 reverse agonist, acetyl-CoA carboxylase (ACC) inhibitor, octadecyl-CoA Desaturase 1 (SCD-1) inhibitor, dipeptidyl peptidase 4 (DPP-4) inhibitor, or combinations thereof. In some embodiments, pharmaceutical compositions include one or more antidiabetic agents. In some embodiments, pharmaceutical compositions include one or more anti-obesity agents. In some embodiments, pharmaceutical compositions include one or more agents for treating nutritional disorders.

Examples of GLP-1 agonists for use in combination with the compounds described herein or their pharmaceutically acceptable salts, solvates, stereoisomers or prodrugs include: exenatide, Liraglutide, taspoglutide, lixisenatide, albiglutide, dulaglutide, semaglutide, OWL833 and ORMD0901.

Examples of GLP-2 agonists for use in combination with the compounds described herein, or pharmaceutically acceptable salts, solvates, stereoisomers, or prodrugs thereof include: tedaglutide, glepaglutide (ZP1848), elsiglutide (ZP1846), apraglutide (FE 203799), HM-15912, NB-1002, GX-G8, PE-0503 and SAN-134 and agonists described in the following documents: 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 or WO20080 28117.

Examples of GLP-1/2 co-agonists for use in combination with the compounds described herein, or pharmaceutically acceptable salts, solvates, stereoisomers or prodrugs thereof, include ZP-GG-72 and the following Co-agonists described in the literature: WO-2018104561, WO-2018104558, WO-2018103868, WO-2018104560, WO-2018104559, WO-2018009778, WO-2016066818 and WO-2014096440.

Examples of PPAR agonists for use in combination with a compound described herein or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof include: elafibranor (GFT505), elafibranor Lanifibranor, pioglitazone, rosiglitazone, saroglitazar, seladelpar and GW501516.

Examples of FXR agonists for use in combination with the compounds described herein, or pharmaceutically acceptable salts, solvates, stereoisomers or prodrugs thereof, include: obeticholic acid, NGM- 282, EYP001, GS-9674, tropifexor (LJN452) and LMB-763.

Examples of TGR5 agonists for use in combination with the compounds described herein, or pharmaceutically acceptable salts, solvates, stereoisomers or prodrugs thereof, include: INT-777, XL-475, SRX-1374 , RDX-8940, RDX-98940, SB-756050 and agonists disclosed in the following documents: WO-2008091540, WO-2010059853, WO-2011071565, WO-2018005801, WO-2010014739, WO-2018005794, WO-2016 054208 , WO-2015160772, WO-2013096771, WO-2008067222, WO-2008067219, WO-2009026241, WO-2010016846, WO-2012082947, WO-2012149236, WO-2008097976, WO-2 016205475、WO-2015183794、WO-2013054338、WO -2010059859、WO-2010014836、WO-2016086115、WO-2017147159、WO-2017147174、WO-2017106818、WO-2016161003、WO-2014100025、WO-2014100021、WO-2016 073767、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-2 014200349, WO-2017180577, WO-2014085474.

Examples of GPR40 agonists for use 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 agonists disclosed in the following documents: 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-2 009039942、WO-2009039943、WO-2009054390、WO -2009054423、WO-2009054468、WO-2009054479、WO-2009058237、WO-2010085522、WO-2010085525、WO-2010085528、WO-2010091176、WO-2010123016、WO-2010 123017、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-2 012111849、WO-2012147518、WO-2013025424、WO -2013057743、WO-2013104257、WO-2013122028、WO-2013122029、WO-2013128378、WO-2013144097、WO-2013154163、WO-2013164292、WO-2013178575、WO-2014 019186、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-2 015024448、WO-2015024526、WO-2015028960、WO -2015032328、WO-2015044073、WO-2015051496、WO-2015062486、WO-2015073342、WO-2015078802、WO-2015084692、WO-2015088868、WO-2015089809、WO-2015 097713、WO-2015105779、WO-2015105786、WO-2015119899 , WO-2015176267, WO-201600771, WO-2016019587, WO-2016022446, WO-2016022448, WO-2016022742, WO-2016032120, WO-2016057731, WO-2017025368, WO-20 17027309、WO-2017027310、WO-2017027312、WO -2017042121、WO-2017172505、WO-2017180571、WO-2018077699、WO-2018081047、WO-2018095877、WO-2018106518、WO-2018111012、WO-2018118670、WO-2018 138026、WO-2018138027、WO-2018138028、WO-2018138029 , WO-2018138030, WO-2018146008, WO-2018172727, WO-2018181847, WO-2018182050, WO-2018219204, WO-2019099315 and WO-2019134984.

Examples of GPR119 agonists for use in combination with the compounds described herein or their pharmaceutically acceptable salts, solvates, stereoisomers or prodrugs include: DS-8500a, HD-2355, LC34AD3, PSN -491, HM-47000, PSN-821, MBX-2982, GSK-1292263, APD597, DA-1241 and agonists disclosed in the following documents: 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-2 011138427、WO-2011140161、WO-2011061679、WO -2017175066、WO-2017175068、WO-2015080446、WO-2013173198、US-20120053180、WO-2011044001、WO-2010009183、WO-2012037393、WO-2009105715、WO-201 3074388、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-2 010048149、WO-2009105722、WO-2012103806、WO -2008025798、WO-2008097428、WO-2011146335、WO-2012080476、WO-2017106112、WO-2012145361、WO-2012098217、WO-2008137435、WO-2008137436、WO-2009 143049、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-2 014056938、WO-2007120689、WO-2016068453、WO -2007120702、WO-2013167514、WO-2011113947、WO-2007003962、WO-2011153435、WO-2018026890、WO-2011163090、WO-2011041154、WO-2008083238、WO-2008 070692, WO-2011150067 and WO-2009123992.

Examples of SSTR5 antagonists or inverse agonists for use in combination with the compounds described herein, or pharmaceutically acceptable salts, solvates, stereoisomers or prodrugs thereof, include the antagonists described in the following literature Or reverse agonists: WO-03104816, WO-2009050309, WO-2015052910, WO-2011146324, WO-2006128803, WO-2010056717, WO-2012024183 and WO-2016205032.

Examples of ACC inhibitors for use in combination with a compound described herein or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof include: firsocostat, GS-834356 and PF-05221304.

Examples of SCD-1 inhibitors for use in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, include aramchol.

Examples of DPP-4 inhibitors for use in combination with the compounds described herein or their pharmaceutically acceptable salts, solvates, stereoisomers or prodrugs include: sitagliptin, Vega Vildagliptin, saxagliptin, linagliptin, gemigliptin, teneligliptin, alogliptin, trotagliptin (trelagliptin), omarigliptin (omarigliptin), evogliptin (evogliptin), gosogliptin (gosogliptin) and dutogliptin (dutogliptin).

Examples of antidiabetic agents for use in combination with the compounds described herein, or pharmaceutically acceptable salts, solvates, stereoisomers, or prodrugs thereof, include: GLP-1 receptor agonists, such as excitin Natide, liraglutide, tasglutide, lixisenatide, albiglutide, dulaglutide, semaglutide, OWL833 and ORMD 0901; SGLT2 inhibitors such as dapagliflozin , canagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, remogliflozin, sergliflozin, sotagliflozin and tofogliflozin; biguanides, such as metformin; insulin and insulin analogs.

Examples of anti-obesity agents for use in combination with the compounds described herein, or pharmaceutically acceptable salts, solvates, stereoisomers or prodrugs thereof, include: GLP-1 receptor agonists, such as Laglutide, semaglutide; SGLT1/2 inhibitors, such as LIK066, pramlintide and other amyloid 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 total 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/Glycagon co-agonists such as cotadutide (MEDI0382), BI 456906, TT-401, G-49, H&D-001A, ZP-2929 and HM-12525A; GLP-1/ GIP/glucagon triple agonists, such as SAR-441255, HM-15211, and NN-9423; GLP-1/secretin co-agonists, such as GUB06-046; leptin analogs, such as metreleptin ( 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 (RG799 2), AKR-001, LLF-580, CVX-343, LY-2405319, BIO89-100 and BMS-986036; MC4 agonists such as setmelanotide; MetAP2 inhibitors such as ZGN-1061; brain-gut peptide receptor modulators , such as HM04 and AZP-531; and oxytocin analogs, such as carbetocin.

Examples of agents for use in nutritional disorders in combination with a compound described herein or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof include: GLP-2 receptor agonists, Such as tedallutide, gliglutide (ZP1848), isglutide (ZP1846), apraglutide (FE 203799), HM-15912, NB-1002, GX-G8, PE-0503, SAN- 134 and pharmaceuticals described in the following documents: WO-2011050174, WO-2012028602, WO-2013164484, WO-2019040399, WO-2018142363, WO-2019090209, WO-2006117565, WO-2019086559, WO-201 7002786、WO-2010042145、WO and GLP-1/G LP-2 receptor co-agonists such as ZP - GG-72 and co-agonists described in the following documents: WO-2018104561, WO-2018104558, WO-2018103868, WO-2018104560, WO-2018104559, WO-2018009778, WO-2016066818 and WO-2014096440.

In one embodiment, the therapeutic effectiveness of one of the compounds described herein is enhanced by administration of an adjuvant (i.e., an adjuvant that has minimal therapeutic benefit by itself, but in combination with another therapeutic agent, enhances overall therapeutic benefit to the patient). Alternatively, in some embodiments, the benefit experienced by the patient is increased by administering one of the compounds described herein and another agent that also has a therapeutic benefit (which also includes a treatment regimen).

In a 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 compounds described herein are Provided are the described compounds, or pharmaceutically acceptable salts, solvates, stereoisomers or prodrugs thereof, and the one or more additional therapeutic agents that modulate different aspects of the disease, disorder or condition being treated. Greater overall benefit than either therapeutic agent administered alone. In some embodiments, the one or more additional therapeutic agents are glucagon-like peptide (GLP)-1 agonists, GLP-2 agonists, GLP-1/2 co-agonists, peroxisome proliferators activating receptor (PPAR) agonist, farnesoid X receptor (FXR) agonist, stearyl-CoA desaturase 1 (SCD-1) inhibitor, dipeptidyl peptidase 4 (DPP) -4) Inhibitors or combinations thereof. In some embodiments, the second therapeutic agent is an anti-inflammatory agent. In some embodiments, the one or more additional therapeutic agents are an aminosalicylate, a corticosteroid, an anti-TNFa agent, an anti-IL-12 and/or 23 agent, an anti-integrin agent, a JAK inhibitor, an S1P1R modulator , salicylates, COX inhibitors, COX-2 specific inhibitors, IL-22 agents, or combinations thereof. In some embodiments, the second therapeutic agent is an agent that improves gastrointestinal barrier function. In some embodiments, the one or more additional therapeutic agents are HIF-PH inhibitors, MC1R agonists, EZH2 inhibitors, or combinations thereof.

In some embodiments, the overall benefit experienced by the patient is the additive effect of the two (or more) therapeutic agents. In other embodiments, patients experience synergistic benefits of two (or more) therapeutic agents.

In combination therapy, multiple therapeutic agents, one of which is one of the compounds described herein, are administered in any order or even simultaneously. By way of example only, if administered simultaneously, the multiple therapeutic agents are provided in a single, unified form, or in multiple forms (eg, as a single pill or as two separate pills).

The compounds described herein, or pharmaceutically acceptable salts, solvates, stereoisomers, or prodrugs thereof, and combination therapies are administered before, during, or after the onset of a disease or condition, and the administration contains the compound The timing of the composition is different. Thus, in one embodiment, the compounds described herein are used prophylactically and are administered continuously to an individual prone to developing a condition or disease in order to prevent the occurrence of the disease or condition. In another embodiment, compounds and compositions are administered to the subject during or as soon as possible after the onset of symptoms. In certain embodiments, a compound described herein is administered as soon as practicable after the onset of a disease or condition is detected or suspected, and for as long as necessary to treat the disease.

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 agents, analgesics, hormone blockade therapy, radiation therapy, monoclonal antibodies, or combinations thereof. Example List of abbreviations

As used above and throughout the specification of the invention, unless otherwise indicated, the following abbreviations shall be understood to have the following meanings: ACN or MeCN Acetonitrile AcOH or HOAc Acetate ADP Adenosine diphosphate AMP Adenosine monophosphate AMPK 5' AMP activation Protein kinase or adenosine 5'-monophosphate activated protein kinase ATP Adenosine triphosphate aq Aqueous BPD Bis(pinacolyl) diboron Boc Tertiary butoxycarbonyl CDI 1,1'-carbonyldiimidazole DBU 1,8-diazo Heterobicyclo[5.4.0]undec-7-ene DCM dichloromethane DIEA or DIPEA N,N -diisopropylethylamine DMA dimethylacetamide DMAP 4-dimethylaminopyridine DME dimethoxy Ethane DMF Dimethylformamide DMSO Dimethyl styrene eq Equivalent Et Ethyl EtOH Ethanol EtOAc or EA Ethyl acetate FA Formic acid Fmoc Benzylmethoxycarbonyl h, hr (s) Hour HATU Hexafluorophosphoric acid 3- 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridium oxide HPLC HPLC iPrOH Isopropyl alcohol KOAc Potassium acetate LCMS Liquid Chromatography-Mass Spectrometry mCPBA Meta-chloroperoxybenzoic acid Me Methyl MeOH Methanol MeI Methyl iodide min(s) minutes NaBH(OAc) _3Sodium triacetyloxyborohydride NCS N-chlorosuccinimide NIS N-iodosuccinimine NMR Oxone Potassium peroxosulfate PCy ₃ Pd G3 Methanesulfonic acid [(tricyclohexylphosphine)-2-(2'-aminobiphenyl)]palladium(II) Pd( dppf)Cl ₂ [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ [1,1'-bis(diphenyl) Phosphino)ferrocene]dichloropalladium (II) dichloromethane complex Pd (PPh ₃ ) ₄ (triphenylphosphine)palladium PE petroleum ether SEM 2-(trimethylsilyl)ethoxymethane Base SEM-Cl 2-(trimethylsilyl)ethoxymethyl chloride SFC Supercritical fluid chromatography rt or RT Room temperature Tf Trifluoromethanesulfonyl tBu Tertiary butyl TEA Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran TLC Thin Layer Chromatography I. Chemical Synthesis

Unless otherwise stated, reagents and solvents were used as received from commercial suppliers. Use anhydrous solvents and dry glassware for synthetic transformations that are sensitive to moisture and/or oxygen. Yield was not optimized. Reaction times are approximate and not optimized. Column chromatography and thin layer chromatography (TLC) were performed on silica unless otherwise stated. Example 1 : (1r,4r)-4-((6- chloro- 5-(4'-(2-(2- hydroxyethoxy ) ethoxy ) methyl )-[ 1,1'- Benzene ]-4- yl )-1H- imidazo [4,5-b] pyridin -2- yl ) oxy ) cyclohexanecarboxylic acid ( Compound 1)

Step 1 : 2-(2-((4- bromobenzyl ) oxy ) ethoxy ) ethanol (1-1) : At 0°C, add 2,2'-oxydiethanol (21 g, To a solution of 0.20 mol, 5 eq ) in THF (300 mL) was added NaH (16 g, 0.40 mol, 60% purity, 10 eq ). The mixture was stirred at 25°C for 30 min, then 1-bromo-4-(bromomethyl)benzene (10 g, 40 mmol, 1 eq ) was added at 0°C. The mixture was stirred at 70°C for 12 hours. The reaction mixture was quenched by adding saturated aqueous NH ₄ Cl (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 obtain 1-1 (9 g, 80% yield, 98%) as a yellow oil. purity). 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).

Step 2 : 2-[2-[[4-[4-(4,4,5,5- tetramethyl -1,3,2 -dioxaborolan -2- yl ) phenyl ] benzene Methoxy ] ethoxy ] ethanol (1-2) : To 1-1 (1 g, 3.6 mmol, 1 eq ) and 4,4,5,5 - tetramethyl-2-[4-( 4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3,2-dioxaborolane (1.8 To a solution of g, 5.5 mmol, 1.5 eq ) in dihexane (10 mL) and H ₂ O (1 mL) was added PCy ₃ Pd G ₃ (0.17 g, 0.25 mmol, 0.07 eq ) and Na ₂ CO ₃ ( 0.58 g, 5.5 mmol, 1.5 eq). The mixture was stirred at 80 °C under _N2 atmosphere for 12 h. The reaction mixture was partitioned between _H2O (50 mL) and ethyl acetate (30 mL×3). The organic layer was separated, washed with saturated brine (30 mL×2), dried over _Na2SO4 , filtered and concentrated under reduced pressure to _obtain a residue. The crude product was purified by reversed-phase HPLC (column: YMC Triart C18 250×50 mm×7 μm; mobile phase: A: water (0.1% FA), B: ACN]; B%: 56%-86%), 1-2 was obtained as a yellow oil (0.36 g, 19% yield, 76% purity). 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).

Step 3 : 5,6- Dichloro -3- nitropyridin -2- amine (1-3) : To 6-chloro-3-nitro-pyridin-2-amine (50 g, 0.29 mol, 1 eq) To a solution in AcOH (250 mL) was added NCS (46 g, 0.35 mmol, 1.2 eq). The mixture was stirred at 100°C for 3 hours. The mixture was cooled to room temperature and filtered. The filter cake was washed with ethanol (100 mL) and dried in vacuo to afford 1-3 as a yellow solid (48 g, crude material). LCMS (ES ⁺ ): m/z (M+H) ⁺ =207.9.

Step 4 : 5- Chloro -6- iodo -3- nitropyridin -2- amine (1-4) : To a solution of 1-3 (48 g, 0.23 mol, 1 eq) in AcOH (250 mL) NaI (73 g, 0.48 mol, 2.1 eq) was added. The mixture was stirred at 90°C for 12 hours. The mixture was poured into water (500 mL) and filtered. The filter cake was washed with water ( 200 mL) and dried in vacuo to afford 1-4 as a yellow solid (60 g, crude material). LCMS (ES ⁺ ): m/z (M+H) ⁺ =299.8.

Step 5 : 5- Chloro -6- iodopyridine -2,3- diamine (1-5) : To a solution of 1-4 (60 g, 0.20 mol, 1 eq) in EtOH (300 mL) was added SnCl ₂ ·2H ₂ O (0.18 kg, 0.80 mol, 4 eq). The mixture was stirred at 70°C for 0.5 hours. Water (450 mL) and KF (0.18 kg) were added to the mixture, and the mixture was stirred for 0.5 h, then extracted with ethyl acetate (2×100 mL). The organic phase was washed with saturated brine (2×50 mL) and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 2:1 to 0:1) to obtain 1-5 (41 g, 73% yield, 96% purity) as an off-white solid. ). LCMS (ES ⁺ ): m/z (M+H) ⁺ =269.9.

Step 6 : 6- Chloro -5- iodo - 1H - imidazo [4,5- b ] pyridine -2( 3H ) -thione (1-6) : ₀ °C under N To a solution of 1-5 (20 g, 74 mmol, 1 eq) and DMAP (26 g, 0.22 mol, 2.9 eq) in THF (400 mL) was added thiocarbonyldichloride (12 g, 0.10 mol, 8.0 mL, 1.4 eq). The mixture was stirred at room temperature for 24 hours. Ethyl acetate (2000 mL) and 2 N HCl aqueous solution (200 mL) were added to the reaction mixture. The organic layer was washed with saturated brine (2 × 300 mL) and concentrated in vacuo to afford 1-6 (17 g) as a yellow solid. LCMS (ES ⁺ ): m/z (M+H) ⁺ =311.8.

Step 7 : 6- Chloro -5- iodo -2-( methylthio ) -3H - imidazo [4,5- b ] pyridine (1-7) : 1-6 (22 g, 70 mmol, A solution of 1 eq) and KOH (4.7 g, 84 mmol, 1.2 eq) in EtOH (440 mL) was stirred at room temperature for 0.5 h. Mel (10.0 g, 70 mmol, 4.4 mL, 1 eq) was added and the reaction was stirred at room temperature for an additional 1 hour. The reaction mixture was concentrated in vacuo to give a residue, followed by the addition of ethyl acetate (300 mL) and 2 N aqueous HCl (50 mL). The organic layer was washed with saturated brine (2×50 mL) and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 5:1 to 1:1) to obtain 1-7 as a yellow solid (16 g, 48% yield, 68% purity ). The sum of m/z (M+H) ⁺ =325.8.

Step 8 : 6- Chloro -5- iodo -2-( methylsulfonyl ) -3H - imidazo [4,5- b ] pyridine (1-8) : To 1-7 (16 g, 49 To a solution of ACN (320 mL) and H ₂ O (320 mL) was added Oxone (66 g, 0.11 mmol, 2.2 eq). The mixture was stirred at room temperature for 12 hours. The mixture was extracted with ethyl acetate (3×400 mL). The combined organic layers were washed with saturated Na ₂ SO ₃ solution (2 × 200 mL) and brine (2 × 200 mL), and then concentrated in vacuo to obtain 1-8 (16 g) as a yellow solid, which was directly used. in the next step. LCMS (ES ⁺ ): m/z (M+H) ⁺ =357.8.

Step 9 : 6- Chloro -5- iodo -2-( methylsulfonyl )-1-((2-( trimethylsilyl ) ethoxy ) methyl ) -1H - imidazo [4 ,5- b ] pyridine (1-9) : SEM-Cl (7.3 g, 44 mmol, 7.7 mL, 1 eq) was added dropwise to 1-8 (16 g, 44 mmol) under nitrogen at 0 °C. , 1 eq) and TEA (6.6 g, 65 mmol, 9.1 mL, 1.5 eq) in THF (310 mL). The reaction mixture was stirred at room temperature for 0.5 hours. The mixture was poured into water (100 mL) and then extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with saturated brine (2×100 mL) and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 10:1 to 5:1) to obtain 1-9 as a yellow solid (12 g, 56% yield, 98% purity ). LCMS (ES ⁺ ): m/z (M+Na) ⁺ =510.0.

Step 10 : (1r,4r)-4-((6- chloro -5- iodo -1-((2-( trimethylsilyl ) ethoxy ) methyl )-1H- imidazo [4, 5-b] pyridin -2- yl ) oxy ) cyclohexanecarboxylic acid methyl ester (1-10) : to 1-9 (2 g, 4.1 mmol, 1 eq ) and trans - 4-hydroxycyclohexanecarboxylic acid To a solution of the methyl ester (1.3 g, 8.2 mmol, 2 eq ) in DMF (40 mL) was added DBU (1.9 g, 12 mmol, 1.85 mL, 3 eq). The mixture was stirred at 25°C for 12 hours. The solution was diluted with water (60 mL) and extracted with EA (80 mL×3). The combined organic layers were washed with saturated brine (150 mL×3), dried over anhydrous sodium sulfate (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO ₂ , PE:EA=100:0 to 10:1) to obtain 1-10 (1.2 g, 1.7 mmol, 42% yield, 84.52% purity) as yellow oil. ). LCMS: (ES+) m/z (M+H)+=566.2.

Step 11 : (1r,4r)-4-((6- chloro- 5-(4'-(2-(2- hydroxyethoxy ) ethoxy ) methyl )-[1,1'- linked Benzene ]-4- yl )-1-((2-( trimethylsilyl ) ethoxy ) methyl )-1H- imidazo [4,5-b] pyridin -2- yl ) oxy ) ring Hexaneformate methyl ester (1-11) : To 1-10 (0.55 g, 0.97 mmol, 1.0 eq) and 1-2 (0.43 g, 1.1 mmol, 1.1 eq) in H ₂ O (1.0 mL) and dimethacin To a solution in alkanes (5.0 mL) were added Na ₂ CO ₃ (0.24 g, 2.9 mmol, 3.0 eq) and Pd(dppf)Cl ₂ •CH ₂ Cl ₂ (0.16 g, 0.19 mmol, 0.2 eq). The mixture was degassed and purged with N ₃ times. The mixture was stirred at 80°C for 1 hour. The reaction solution was diluted with water (30 mL) and then extracted with EA (20 mL×3). The combined organic layers were washed with saturated brine (30 ml×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 10/1 to 1/1) to obtain 1-11 (0.37 mg, 25% yield, 47% purity) as a brown solid ). LCMS: (ES+) m/z (M) ⁺ =710.3.

Step 12 : (1r,4r)-4-((6- chloro- 5-(4'-(2-(2- hydroxyethoxy ) ethoxy ) methyl )-[1,1'- linked Benzene ]-4- yl )-1H- imidazo [4,5-b] pyridin -2- yl ) oxy ) cyclohexanecarboxylic acid methyl ester (1-12) : to 1-11 (0.37 g, 0.52 mmol To a solution of , 1.0 eq) in DCM (2.0 mL) was added TFA (0.31 g, 27 mmol, 2 mL, 52 eq). The mixture was stirred at 25°C for 1 hour. The reaction was filtered and concentrated under reduced pressure to afford 1-12 (0.30 g, crude material) as a brown oil. LCMS: (ES+) m/z (M) ⁺ =580.4.

Step 13 : (1r,4r)-4-((6- chloro- 5-(4'-(2-(2- hydroxyethoxy ) ethoxy ) methyl )-[1,1'- linked Benzene ]-4- yl )-1H- imidazo [4,5-b] pyridin -2- yl ) oxy ) cyclohexanecarboxylic acid ( Compound 1) : To 1-12 (0.3 g, 0.22 mmol, 42% Purity, 1.0 eq) To a solution of H ₂ O (2.0 mL) and propan-2-ol (4.0 mL) was added LiOH·H ₂ O (46 mg, 1.1 mmol, 5.0 eq). The mixture was stirred at 25°C for 24 hours. The mixture was concentrated under reduced pressure to obtain a residue. The residue was dissolved with DMF and analyzed by preparative HPLC (column: Phenomenex luna C18 150×25 mm×10 μm; mobile phase: [A: water (0.5% HCl aqueous solution), B: ACN]; B%: 29% -59%) was purified twice to obtain compound 1 as a yellow solid (40 mg, 29% yield, 94% purity, HCl salt). LCMS: (ES+) m/z (M+H) ⁺ =566.3. ¹ H NMR (400 MHz, methanol-d4) δ=8.23 (s, 1H), 7.90 - 7.81 (m, 2H), 7.80 - 7.76 (m, 2H), 7.74 (d, J= 8.0 Hz, 2H), 7.52 (d, J= 8.0 Hz, 2H), 5.22 -5.13 (m, 1H), 4.66 (s, 2H), 3.74 - 3.68 (m, 6H), 3.65 - 3.58 (m, 2H), 2.49 - 2.34 ( m, 3H), 2.20 - 2.12 (m, 2H), 1.80 - 1.63 (m, 4H). Example 2 : (2R,4S)-4-((6- chloro- 5-(4'-((2-(2- hydroxyethoxy ) ethyl ) amino ) methyl )-[1,1 ' -Biphenyl ]-4- yl )-1H- imidazo [4,5-b] pyridin -2- yl ) oxy ) tetrahydro -2H- piran -2- carboxylic acid ( compound 2)

Step 1 : 4- Pendantoxy -4H- piran -2- carboxylic acid methyl ester (2-1) : At 0°C, add 4-Pendantoxy-4H-piran-2-carboxylic acid (200 mg, 1.4 To a solution of _H2SO4 (73 mg, 0.74 mmol, 0.04 mL, 98% purity, 0.05 eq) in MeOH ₍ 4 mL) was added. The mixture was stirred at 65°C for 12 hours. The reaction mixture was diluted with saturated _aqueous NaHCO solution (100 mL) and extracted with EA (200 mL×3). The combined organic layers were washed with brine (100 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 100/0 to 1/1) to obtain 2-1 (0.21 g, 99%) as a yellow solid. LCMS: (ES ⁺ ) m/z (M+H) ⁺ =155.0. ¹ H NMR (400 MHz, CDCl ₃ -d) δ=7.83 (d, J =5.8 Hz, 1H), 7.11 (d, J =2.4 Hz, 1H), 6.45 (dd, J =2.4, 5.8 Hz, 1H ), 3.98 (s, 3H).

Step 2 : (2R,4S)-4- hydroxytetrahydro -2H- piran -2- carboxylic acid methyl ester (2-2) : 2-1 (23 g, 0.15 mol, 1 eq ) under _N atmosphere To a solution in MeOH (230 mL) was added Pd/C (2.3 g, 10% purity). The suspension was degassed and purged 3 times with _H2 . The mixture was stirred under _H2 (30 Psi) at 25°C for 72 hours. The solution was 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 obtain 2-2 as a yellow oil (10 g, 62 mmol, 42% yield) . ¹ H NMR (400 MHz, CDCl ₃ -d) δ=4.44 - 4.28 (m, 1H), 4.16 (m, 1H), 3.99 (dd, J =2.4, 11.4 Hz, 1H), 3.92 - 3.86 (m, 1H), 3.78 (s, 3H), 3.47 (dt, J =2.4, 11.8 Hz, 1H), 2.68 - 2.58 (m, 1H), 2.29 (m, 1H), 1.95 - 1.87 (m, 1H), 1.63 - 1.57 (m, 1H).

Step 3 : 2-(2-(((4'- bromo- [1,1'- biphenyl ]-4- yl ) methyl ) amino ) ethoxy ) ethanol (2-3) : To 4'-Bromo-[1,1'-biphenyl]-4-carbaldehyde (13 g, 49 mmol, 1 eq) and 2-(2-aminoethoxy)ethanol (7.8 g, 74 mmol, 7.5 mL, 1.5 eq) To a solution in THF (130 mL) was added AcOH (8.9 g, 0.15 mol, 8.5 mL, 3 eq). The mixture was stirred at 40°C for 1 hour, then NaBH(OAc) ₃ (21 g, 99 mmol, 2 eq) was added to the solution at 0°C. The mixture was stirred at 25°C for 11 hours. The solution was concentrated under reduced pressure to obtain 2-3 as a yellow oil (41 g, 73% yield, 96% purity). LCMS: (ES ⁺ ) m/z (M+H) ⁺ =349.9. ¹ H NMR (400 MHz, CDCl ₃ -d) δ=7.62 - 7.52 (m, 4H), 7.52 - 7.47 (m, 2H), 7.42 (d, J =8.8 Hz, 2H), 4.20 - 4.04 (m, 2H), 3.72 - 3.70 (m, 2H), 3.62 - 3.51 (m, 4H), 3.11 - 3.07 (m, 2H).

Step 4 : ((4'- bromo- [1,1'- biphenyl ]-4- yl ) methyl )(2-(2- hydroxyethoxy ) ethyl ) carbamic acid tertiary butyl ester (2 -4) : To a solution of 2-3 (17 g, 48 mmol, 1 eq) in THF (200 mL) was added DIEA (28 g, 0.22 mol, 38 mL, 4.5 eq) and Boc ₂ O (42 g , 0.2 mol, 45 mL, 4 eq). The mixture was stirred at 25°C for 2 hours. The solution was diluted with water (100 mL), then extracted with EA (100 mL×6). The combined organic layers were _washed with brine (100 mL×2), dried over _Na2SO4 , 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 obtain 2-4 as a yellow oil (22 g, 45 mmol, 93% yield, 92% purity). LCMS: (ES ⁺ ) m/z (M+H) ⁺ =450.1. ¹ H NMR (400 MHz, CDCl ₃ -d) δ=7.60 - 7.49 (m, 4H), 7.45 (d, J =8.4 Hz, 2H), 7.31 (br s, 2H), 4.55 (br s, 2H) , 3.67 - 3.24 (m, 6H), 1.60 - 1.38 (m, 9H).

Step 5 : (2-(2- hydroxyethoxy ) ethyl )((4'-(4,4,5,5- tetramethyl -1,3,2- dioxaborolane -2) - (yl )-[1,1'- biphenyl ]-4- yl ) methyl ) carbamic acid tertiary butyl ester (2-5) : To 2-4 (18 g, 40 mmol, 1 eq) in di To a solution in hexanes (400 mL) were added KOAc (12 g, 0.12 mol, 3 eq) and BPD (15 g, 60 mmol, 1.5 eq). The mixture was purged three times with _N2 , followed by the addition of Pd(dppf) _Cl2 • _CH2Cl2 (3.3 g, 4 mmol, 0.1 eq). The mixture was purged three times with _N2 and then stirred at 80 °C for 12 h. The solution was diluted with water (100 mL) and extracted with EA (100 mL×6). The combined organic layers were _washed with brine (100 mL×2), dried over _Na2SO4 , 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 obtain 2-5 as a yellow oil (17 g, 28 mmol, 71% yield, 82.6% purity). LCMS: (ES ⁺ ) m/z (M+H) ⁺ =498.1. ¹ H NMR (400 MHz, CDCl ₃ -d) δ=7.88 (d, J =8.0 Hz, 2H), 7.60 (br t, J =7.6 Hz, 4H), 7.31 (br s, 2H), 4.56 (d , J =8.2 Hz, 2H), 3.75 - 3.67 (m, 2H), 3.66 - 3.35 (m, 6H), 1.57 - 1.42 (m, 9H), 1.37 (s, 12H).

Step 6 : (2R,4S)-4-((6- chloro -5- iodo -1-((2-( trimethylsilyl ) ethoxy ) methyl )-1H- imidazo [4, 5-b] pyridin -2- yl ) oxy ) tetrahydro -2H- piran -2- carboxylic acid methyl ester (2-6) : to 6-chloro-5-iodo-2-(methylsulfonyl) )-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine 1-9 (2.7 g, 5 mmol, 1 eq) and 2 To a solution of -2 (0.9 g, 5.6 mmol, 1 eq) in DMF (30 mL) was added Cs ₂ CO ₃ (3.66 g, 11.24 mmol, 2 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×6). The combined organic layers were washed with brine (100 mL×5), dried over _Na2SO4 , 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 obtain 2-6 as a yellow solid (1 g, 0.88 mmol, 16% yield, 50% purity). LCMS: (ES ⁺ ) m/z (M+H) ⁺ =567.9.

Step 7 : (2R,4S)-4-((5-(4'-(( tertiary butoxycarbonyl )(2-(2- hydroxyethoxy ) ethyl ) amino ) methyl )- [1,1'- biphenyl ]-4- yl )-6- chloro -1-((2-( trimethylsilyl ) ethoxy ) methyl )-1H- imidazo [4,5-b ] pyridin -2- yl ) oxy ) tetrahydro -2H- piran -2- carboxylic acid methyl ester (2-7) : to 2-5 (900 mg, 1.6 mmol, 1 eq) and 2-6 (0.87 g , 1.7 mmol, 1.1 eq) To a solution of DME (20 mL) and H ₂ O (2 mL) was added Na ₂ CO ₃ (0.51 g, 4.8 mmol, 3 eq). The mixture was purged three times _{with N2} , then Pd(dppf) _Cl2 • _CH2Cl2 (0.13 g, 0.16 mmol, 0.1 eq) was added to the solution. The mixture was purged three times with _N2 , then the mixture was stirred at 90 °C for 3 h. The solution was diluted with water (50 mL), then extracted with EA (50 mL×6). _The combined organic layers were washed with brine (100 mL×1), dried over _Na2SO4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 100/0 to 0/1) to obtain 2-7 as a yellow oil (800 mg, 0.42 mmol, 27% yield, 43% purity). LCMS: (ES ⁺ ) m/z (M+H) ⁺ =811.3.

Step 8 : (2R,4S)-4-((6- chloro- 5-(4'-((2-(2- hydroxyethoxy ) ethyl ) amino ) methyl )-[1,1 ' -Biphenyl ]-4- yl )-1H- imidazo [4,5-b] pyridin -2- yl ) oxy ) tetrahydro -2H- pyran -2- carboxylic acid methyl ester (2-8) : To a solution of 2-7 (50 mg, 61 μmol, 1 eq) was added TFA (1.5 g, 14 mmol, 1 mL) and the mixture was stirred at 25 °C for 0.5 h. The solution was concentrated under reduced pressure to afford crude 2-8 as a black solid (30 mg, 51 μmol, 84% yield). LCMS: (ES ⁺ ) m/z (M+H) ⁺ =581.3.

Step 9 : (2R,4S)-4-((6- chloro- 5-(4'-((2-(2- hydroxyethoxy ) ethyl ) amino ) methyl )-[1,1 ' -Biphenyl ]-4- yl )-1H- imidazo [4,5-b] pyridin -2- yl ) oxy ) tetrahydro -2H- piran -2- carboxylic acid ( compound 2) : To 2- To a solution of 8 (0.3 g, 0.52 mmol, 1 eq), water (5 mL) and MeOH (5 mL) containing NaOH (82 mg, 2.1 mmol, 4 eq) were added. The mixture was stirred at 25°C for 5 minutes. The residue was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150×25 mm×10 μm; mobile phase: [A: water (0.1% FA), B: ACN]; B%: 10%-40%) And purified by preparative HPLC (column: YMC Triart C18 250×50 mm×7 μm; mobile phase: [A: water (0.1% FA), B: ACN]; B%: 22%-52%), Compound 2 was obtained as a white solid (31 mg, 48 μmol, 9% yield, 95.5% purity, FA salt). LCMS: (ES+) m/z (M+H) ⁺ =566.9. ¹ H NMR (400 MHz, CD ₃ OD-d4) δ=7.85 - 7.78 (m, 3H), 7.76 - 7.69 (m, 4H), 7.61 (d, J =8.4 Hz, 2H), 5.32 - 5.18 (m , 1H), 4.29 (s, 2H), 4.19 - 4.10 (m, 1H), 3.98 - 3.84 (m, 1H), 3.83 - 3.77 (m, 2H), 3.75 - 3.72 (m, 2H), 3.65 - 3.57 (m, 3H), 2.68 - 2.52 (m, 1H), 2.35 - 2.14 (m, 1H), 1.92 - 1.50 (m, 2H), 1.39 - 1.24 (m, 1H). Example 3 : 2-((1r,4r)-4-((5-(4'-(1-(2-( azetidin -1- yl ) ethyl ))-1H-1,2,4 -Triazol - 3- yl )-[1,1'- biphenyl ]-4- yl )-4,6- difluoro -1H- benzo [d] imidazol -2- yl ) oxy ) cyclohexyl ) Acetic acid ( compound 30) :

Step 1 : 3-(4- bromophenyl )-1-(2,2- dimethoxyethyl )-1H-1,2,4- triazole (3-1) : to 3-(4- Bromophenyl)-1H-1,2,4-triazole (18 g, 80 mmol, 1 eq) and 2-bromo-1,1-dimethoxy-ethane (136 g, 0.80 mol, 95 mL , 10 eq) to a solution in DMF (200 mL) was added Cs ₂ CO ₃ (79 g, 0.24 mol, 3 eq) and NaI (1.2 g, 8.0 mmol, 0.1 eq). The solution was stirred at 70°C for 6 hours. The solution was diluted with _H2O (500 mL) and extracted with EA (500 mL×3). The combined organic layers were washed with saturated brine (300 mL), dried over _Na2SO4 , filtered and concentrated under reduced _pressure to give a residue. By reversed-phase HPLC (column: Welch Ultimate XB_C18 40-60 μm, 120 A; mobile phase: [A: H ₂ O (0.1% TFA), B: ACN]; gradient: B: 10-50%, 25 min; 50%, 5 min) to purify the residue to obtain 3-1 (10 g, 29 mmol) as a yellow oil. LCMS: (ES+) m/z (M+H) ⁺ =314.0. ¹ H NMR (400 MHz, methanol-d ₄ ) δ=8.36 (s, 1H), 7.87 - 7.80 (m, 2H), 7.54 - 7.48 (m, 2H), 4.67 (t, J =5.2 Hz, 1H) , 4.27 (d, J =5.2 Hz, 2H), 3.31 (s, 6H)

Step 2 : 2-(3-(4- bromophenyl )-1H-1,2,4- triazol -1- yl ) ethane -1,1- diol (3-2) : 3-1 A solution of (3 g, 9.6 mmol, 1 eq ) in 4 M HCl/dioxane (20 mL) was stirred at 25 °C for 12 h. The mixture was then stirred at 35°C for 12 hours. The mixture was concentrated under reduced pressure to obtain 3-2 (2.5 g, crude material, hydrochloride) as a brown powder .

Step 3 : 1-(2-( azetidin -1- yl ) ethyl )-3-(4- bromophenyl )-1H-1,2,4- triazole (3-3) : To a solution of azetidine (2.2 g, 24 mmol, 2.6 mL, 3.1 eq, hydrochloride) in THF (20 mL) and DMSO (20 mL) was added KOAc (3.8 g, 39 mmol, 5 eq) . The mixture was stirred at 25°C for 1 h, then 3-2 (2.5 g, 7.8 mmol, 1 eq, HCl) was added. The mixture was stirred for a further 6 hours at 40°C, then NaBH(OAc) ₃ (5.0 g, 23 mmol, 3 eq ) was added portionwise at 0°C. The mixture was stirred at 25°C for 4 hours. The solution was diluted with H ₂ O (100 mL) and 28% ammonia (50 mL), and then extracted with EA (100 mL×3). The combined organic layers were washed with saturated brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 3-3 _{( 1} g , 2.7 mmol) as a yellow oil. LCMS: (ES+) m/z (M+H) ⁺ =309.0.

Step 4 : 1-(2-( azetidin -1- yl ) ethyl )-3-(4'-(4,4,5,5 -tetramethyl -1,3,2- dioxo Heteraborol- 2- yl )-[1,1'- biphenyl ]-4- yl )-1H-1,2,4- triazole (3-4) : To 3-3 (1 g, 3.3 mmol, 1 eq) and 1,4-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene (2.69 g, 8.14 mmol , 2.5 eq) To a solution of dioxane (10 mL) and H ₂ O (0.1 mL) was added Na ₂ CO ₃ (1.0 g, 9.8 mmol, 3 eq). The solution was degassed and purged 3 times with _N2 , then Pd(dppf) _Cl2 • _CH2Cl2 (0.27 g, 0.33 mmol, 0.1 eq) _was added. The mixture was stirred at 90 °C under _N2 atmosphere for 6 h. The solution was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , ethyl acetate:methanol=1/1) to obtain 3-4 (0.68 g, 1.4 mmol, 42% yield) as a yellow oil. LCMS: (ES+) m/z (M+H) ⁺ =431.3.

Step 5 : 3,5- Difluoro -2- nitroaniline ( 3-5 ): To 1,3,5-trifluoro-2-nitro-benzene (100 g, 0.56 mol, 66 mL, 1 eq) To a solution in EtOH (500 mL) was added NH ₃ ^. H ₂ O (460 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 obtain 3-5 as a red solid (98 g, crude material). LCMS: (ES ⁺ ) m/z (M+H) ⁺ =175.1.

Step 6 : 3,5- Difluoro -4- iodo -2- nitroaniline ( 3-6 ): To 3-5 (98 g, 0.45 mol, 80% purity, 1 eq) at 0°C To a solution in AcOH (800 mL) was added NIS (101 g, 0.45 mol, 1 eq). The mixture was stirred at 25°C for 2 hours. The solution was adjusted to pH=7 with saturated Na ₂ CO ₃ aqueous solution, and then the solution was extracted with EA (1 L × 4). The combined organic layers were dried over _Na2SO4 , filtered and concentrated under reduced pressure to afford 3-6 as _a yellow solid (130 g, 58% yield, 60% purity). LCMS: (ES ⁺ ) m/z (MH) ^- =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).

Step 7 : 3,5- Difluoro -4- iodobenzene -1,2- diamine ( 3-7 ): Add 3-6 (125 g, 0.42 mol, 1 eq) in EtOH (1.5 L) AcOH (113 g, 1.9 mol, 0.11 L, 4.5 eq) and Fe (116 g, 2.1 mol, 5 eq) were added to the solution. The mixture was stirred at 75°C for 12 hours. The solution was filtered and concentrated under reduced pressure to give a residue. The residue was then diluted with EA (3 L), and the organic layer was washed with Na ₂ CO ₃ solution, and then the solution was concentrated under reduced pressure to obtain 3-7 (80 g, 64% yield, 90% purity) as a black solid. ). LCMS: (ES ⁺ ) m/z (M+H) ⁺ =270.8.

Step 8 : 4,6- Difluoro -5- iodo - 1H- benzo [d] imidazole -2(3H) -thione ( 3-8 ): To 3-7 (80 g, 0.3 mol, 1 eq ) To a solution in EtOH (1 L) and water (1 L), add 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 4 N HCl, and then filtered to obtain 3-8 (144 g, crude material) as a white solid. LCMS: (ES ⁺ ) m/z (M+H) ⁺ =312.7.

Step 9 : 4,6- difluoro -5- iodo -2-( methylthio )-1H- benzo [d] imidazole ( 3-9 ): At 0°C, add 3-8 (57 g, To a solution of 0.18 mol, 1 eq) in EtOH (600 mL) was added KOH (12 g, 0.22 mol, 1.2 eq). The mixture was stirred at 0°C for 0.5 h, then Mel (26 g, 0.18 mol, 11 mL, 1 eq) was added to the solution and 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 _Na2SO4 , filtered and concentrated under reduced _pressure to obtain 3-9 as a black solid (60 g, crude material). LCMS: (ES ⁺ ) m/z (M+H) ⁺ =326.8.

Step 10 : 4,6- difluoro -5- iodo -2-( methylsulfonyl )-1H- benzo [d] imidazole ( 3-10 ): To 3-9 (50 g, 0.15 mol, 1 eq) To a solution of 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 obtain 3-10 (16 g, 48% product) as a yellow solid. rate, 68% purity). 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).

Step 11 : 4,6- Difluoro -5- iodo -2-( methylsulfonyl )-1-((2-( trimethylsilyl ) ethoxy ) methyl )-1H- benzo [d] Imidazole ( 3-11 ): To a solution of 3-10 (54 g, 0.15 mol, 1 eq) in THF (600 mL) at 0°C was added TEA (23 g, 0.22 mol, 31.48 mL , 1.5 eq) and SEM-Cl (30 g, 0.18 mol, 32 mL, 1.2 eq). The mixture was stirred at 25°C for 12 hours. The solution was diluted with 3 L of water and extracted with EA (2 L × 4). _The combined organic layers were washed with saturated brine (2L×3), dried over _Na2SO4 , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 100/1 to 5/1 ) to obtain 3-11 as a yellow oil (38 g, 50% yield, 97% purity ). LCMS: (ES ⁺ ) m/z (M+H) ⁺ =510.8. 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).

Step 12 : 2-((1r,4r)-4- hydroxycyclohexyl ) ethyl acetate ( 3-12 ): To 2-(4-side oxycyclohexyl)ethyl acetate (40 g) at -5°C To a solution of , 0.22 mol, 1 eq ) in EtOH (400 mL) was slowly added NaBH ₄ (16 g, 0.43 mol, 2 eq ), and the solution was stirred at -5 °C for 1 h. Quench the solution by adding 400 mL of saturated _NH4Cl . The solution was diluted with _H2O (300 mL) and extracted with EA (1 L×3). The combined organic layers were washed with 500 mL _of brine, then the organic layers were dried over _Na2SO4 , 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 obtain 3-12 (18 g, 98 mmol, 45% yield) as a colorless oil. ¹ H NMR (400 MHz, chloroform-d) δ=4.12 (dq, J =1.6, 7.2 Hz, 3H), 3.54 (tt, J =4.4, 10.8 Hz, 1H), 2.18 (d, J =6.8 Hz, 2H), 2.01 - 1.89 (m, 2H), 1.83 - 1.76 (m, 2H), 1.74 (br dd, J =3.6, 7.3 Hz, 1H), 1.34 - 1.25 (m, 5H), 1.13 - 0.96 (m , 2H).

Step 13 : 2-((1r,4r)-4-((4,6- difluoro -5- iodo -1-((2-( trimethylsilyl ) ethoxy ) methyl ))-1H -Benzo [d] imidazol -2- yl ) oxy ) cyclohexyl ) ethyl acetate ( 3-13 ): To 3-12 (4 g, 21 mmol, 1.2 eq ) and 2-[(4,6- Difluoro-5-iodo-2-methylsulfonyl-benzimidazol-1-yl)methoxy]ethyl-trimethyl-silane (8.7 g, 18 mmol, 1 eq ) in DMF (60 mL) was added Cs ₂ CO ₃ (17 g, 54 mmol, 3 eq ), and the mixture was stirred at 60°C for 6 hours. The solution was diluted with _H2O (300 mL) and extracted with EA (300 mL×3). The combined organic layers were washed with saturated brine (300 mL), dried over anhydrous _Na2SO4 , filtered and concentrated under _reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 19/1) to obtain 3-13 as a yellow oil (3.6 g, 5.1 mmol, 28% yield, 84% purity) .

Step 14 : 2-((1r,4r)-4-((5-(4'-(1-(2-( azetidin- 1- yl ) ethyl ))-1H-1,2,4 -Triazol -3- yl )-[1,1'- biphenyl ]-4- yl )-4,6- difluoro -1 - ((2-( trimethylsilyl ) ethoxy ) methyl )-1H- benzo [d] imidazol -2- yl ) oxy ) cyclohexyl ) ethyl acetate (3-14) : 2-[4-[4,6-difluoro-5-iodo-1 -(2-Trimethylsilylethoxymethyl)benzimidazol-2-yl]oxycyclohexyl]ethyl acetate (0.62 g, 0.82 mmol, 79% purity, 1.2 eq), 3-4 ( 0.34 g, 0.69 mmol, 87% purity, 1 eq), Na ₂ CO ₃ (0.22 g, 2.1 mmol, 3 eq) and Pd(dppf)Cl ₂ •CH ₂ Cl ₂ (56 mg, 0.69 mmol, 0.1 eq) The mixture in dihexane (5 mL) and _H2O (0.1 mL) was degassed and purged 3 times with _N2 , and then the mixture was stirred at 90 °C under _N2 atmosphere for 12 h. The solution was diluted with _H2O (50 mL) and extracted with EA (50 mL×3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous _Na2SO4 , filtered and concentrated under _reduced pressure to obtain a residue. By reversed-phase HPLC (Welch Ultimate XB_C18 40-60 μm, 120 A; mobile phase: [A: H ₂ O, B: ACN]; gradient: B: 10-50%, 15 min; 50%, 5 min) The residue was purified to afford 3-14 (88 mg, 0.10 mmol) as a yellow oil. LCMS: (ES+) m/z (M+H) ⁺ =771.4.

Step 15 : 2-((1r,4r)-4-((5-(4'-(1-(2-( azetidin- 1- yl ) ethyl ))-1H-1,2,4 -Triazol - 3- yl )-[1,1'- biphenyl ]-4- yl )-4,6- difluoro -1H- benzo [d] imidazol -2- yl ) oxy ) cyclohexyl ) Ethyl acetate (3-15) : To a solution of 3-12 (50 mg, 65 μmol, 1 eq ) in DCM (0.5 mL) was added TFA (1 mL) at 0 °C. The mixture was stirred at 25°C for 4 hours. The mixture was adjusted to pH=11 with 2 N aqueous LiOH solution at 0°C and concentrated in vacuo to afford 3-15 (35 mg, 55 μmol, crude material) as a yellow oil.

Step 16 : 2-((1r,4r)-4-((5-(4'-(1-(2-( azetidin- 1- yl ) ethyl ))-1H-1,2,4 -Triazol - 3- yl )-[1,1'- biphenyl ]-4- yl )-4,6- difluoro -1H- benzo [d] imidazol -2- yl ) oxy ) cyclohexyl ) Acetic acid ( Compound 30) : To a solution of 3-15 (0.2 g, 0.31 mmol, 1 eq) in MeOH (3 mL) and H ₂ O (3 mL) was added LiOH·H ₂ O ( 65 mg, 1.6 mmol, 5 eq). The mixture was stirred at 40°C for 2 hours. The mixture was adjusted to pH 4 with concentrated FA and concentrated to give a residue. By reversed-phase HPLC (Phenomenex luna C18 150×25 mm×10 μm; mobile phase: [A: H ₂ O (0.225% FA), B: ACN]; gradient: B: 20%, 5 min; 25-30 %, 15 min) to purify the residue to obtain compound 30 as an off-white solid (0.13 g, 0.2 mmol, 63% yield, 98.23% purity, FA). LCMS: (ES+) m/z (M+H) ⁺ =613.4. ¹ H NMR (400 MHz, methanol -d4) δ=8.54 (s, 1H), 8.17 (d, J =8.4 Hz, 2H), 7.93 - 7.71 (m, 4H), 7.55 (br d, J= 8.0 Hz , 2H), 7.02 (br d, J =9.2 Hz, 1H), 4.91 (br s, 1H), 4.47 (t, J =5.6 Hz, 2H), 3.83 (t, J=7.6 Hz, 4H), 3.48 (t, J =5.6 Hz, 2H), 2.41 - 2.32 (m, 2H), 2.32 - 2.25 (m, 2H), 2.23 (d, J =7.2 Hz, 2H), 1.99 - 1.90 (m, 2H), 1.84 (tdd, J =3.2, 11.1, 14.6 Hz, 1H), 1.65 - 1.49 (m, 2H), 1.37 - 1.16 (m, 2H). Example 4 : 2-((1r,4r)-4-((6- chloro -5-(4'-((4-(2-( methylsulfonyl ) ethyl) ethyl ) piperidine - 1- yl ) Methyl )-[1,1'- biphenyl ]-4- yl )-1H- imidazo [4,5-b] pyridin -2- yl ) oxy ) cyclohexyl ) acetic acid ( compound 57) :

Step 1 : 2-((1r,4r)-4-((6- chloro -5- iodo -1-((2-( trimethylsilyl ) ethoxy ) methyl )-1H- imidazo [ 4,5-b] pyridin -2- yl ) oxy ) cyclohexyl ) ethyl acetate ( 4-1 ): To 2-(4-hydroxycyclohexyl)ethyl acetate (6 g, 32 mmol, 1 eq) and 2-[(6-chloro-5-iodo-2-methylsulfonyl-imidazo[4,5-b]pyridin-1-yl)methoxy]ethyl- To a solution of trimethyl-silane (16 g, 32 mmol, 1 eq) in DMF (0.21 L) was added DBU (7.4 g, 48 mmol, 7.3 mL, 1.5 eq). The mixture was stirred at 40°C for 6 hours. The solution was diluted with _H2O (300 mL) and extracted with EA (1 L×2). The combined organic layers were washed with saturated brine (400 mL), dried over anhydrous _Na2SO4 , filtered and concentrated under reduced _pressure to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 9/1) to obtain 4-1 as brown oil (7.6 g, 35% yield, 88% purity). LCMS: (ES ⁺ ) m/z (M+H) ⁺ =594.2. HNMR: ¹ H NMR (400 MHz, methanol-d4) δ=7.84 - 7.76 (m, 1H), 5.50 - 5.39 (m, 2H), 5.03 (tt, J=4.4, 10.8 Hz, 1H), 4.85 (s , 4H), 4.18 - 4.06 (m, 2H), 3.73 - 3.62 (m, 2H), 2.35 - 2.24 (m, 4H), 2.01 (s, 1H), 1.97 - 1.88 (m, 2H), 1.85 (dt , J=3.6, 7.2 Hz, 1H), 1.69 - 1.56 (m, 2H), 1.31 - 1.25 (m, 3H), 1.24 - 1.18 (m, 2H), 0.96 - 0.87 (m, 2H), 0.00 - - 0.08 (m, 8H).

Step 2 : 2-((1r,4r)-4-((6- chloro -5-(4'- formyl- [1,1'- biphenyl ]-4- yl )-1-((2 -( Trimethylsilyl ) ethoxy ) methyl )-1H- imidazo [4,5-b] pyridin -2- yl ) oxy ) cyclohexyl ) ethyl acetate ( 4-2 ): To 4 -[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]benzaldehyde (0.93 g, 3.0 mmol, 1 eq) To a solution of 4-1 (1.8 g, 3.03 mmol, 1 eq) in dihexane (30 mL) and H ₂ O (3 mL) was added Na ₂ CO ₃ (0.96 g, 9.1 mmol, 3 eq). _The mixture was purged with _N2 3 times, then Pd( _dppf ) _Cl2.CH2Cl2 (123.74 mg, 0.15 mmol, 0.05 eq) was added to the solution and purged with _N2 3 times. The mixture was stirred at 80°C for 6 hours. The solution was diluted with _H2O (50 mL) and extracted with EA (50 mL×3). The combined organic layers were washed with saturated brine (60 mL), dried over anhydrous _Na2SO4 , filtered and concentrated under _reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 4/1) to obtain 4-2 as a brown solid (0.50 g, 24% yield, 94% purity). LCMS: (ES ⁺ ) m/z (M+H) ⁺ =648.3.

Step 3 : 2-((1r,4r)-4-((6- chloro -5-(4'-((4-(2-( methylsulfonyl ) ethyl) ethyl ) piperidine - 1- yl ) Methyl )-[1,1'- biphenyl ]-4- yl )-1-((2-( trimethylsilyl ) ethoxy ) methyl )-1H- imidazo [4,5-b ] Pyridin -2- yl ) oxy ) cyclohexyl ) ethyl acetate ( 4-3 ): To 1-(2-methylsulfonyl)piperdine (0.26 g, 1.2 mmol, 1.5 eq, HCl) To a solution in THF (4 mL) and DMSO (4 mL) was added KOAc (0.23 g, 2.3 mmol, 3 eq). The mixture was stirred at 25°C for 1 hour, then 4-2 (0.50 g, 0.77 mmol, 1 eq) was added and stirred at 40°C for a further 1 hour, then NaBH(OAc) ₃ (0.49 g, 0.49 g, 2.3 mmol, 3 eq) was added to the mixture and the solution was finally stirred at 25 °C for 6 h. The solution was diluted with _H2O (50 mL) and extracted with EA (50 mL×3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain 4-3 as brown oil (0.60 g, 0.68 mmol, 88% yield, 93% purity). LCMS: tR=0.535 min., (ES ⁺ ) m/z (M+H) ⁺ =824.3.

Step 4 : 2-((1r,4r)-4-((6- chloro -5-(4'-((4-(2-( methylsulfonyl ) ethyl ) ) piperidine -1- yl ) Methyl )-[1,1'- biphenyl ]-4- yl )-1H- imidazo [4,5-b] pyridin -2- yl ) oxy ) cyclohexyl ) ethyl acetate ( 4- 4 ) : To a solution of 4-3 (0.60 g, 0.68 mmol, 1 eq) in DCM (5 mL) at 0 °C was added HCl/dioxane (1.5 mL). The mixture was stirred at 25°C for 2 hours. The mixture was adjusted to pH=7 with 2 N LiOH solution at 0°C and concentrated to obtain 4-4 (0.50 g, crude material) as a brown solid.

Step 5 : 2-((1r,4r)-4-((6- chloro -5-(4'-((4-(2-( methylsulfonyl ) ethyl) ethyl ) piperidine - 1- yl ) Methyl )-[1,1'- biphenyl ]-4- yl )-1H- imidazo [4,5-b] pyridin -2- yl ) oxy ) cyclohexyl ) acetic acid ( compound 57) : at 0 To a solution of 4-4 (0.5 g, 0.72 mmol, 1 eq) in EtOH (3 mL) was added LiOH ^. H ₂ O (60 mg, 1.4 mmol, 2 eq) at 0 °C. The mixture was stirred at 25°C for 2 hours. The solution was diluted with _H2O (10 mL) and extracted with EA (10 mL×3). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous _Na2SO4 , filtered and concentrated under _reduced pressure to give a residue. The residue was purified by preparative HPLC (FA conditions; column: Phenomenex luna C18 150×25 mm×10 μm; mobile phase: [water (FA)-ACN]; B%: 12%-42%, 10 min) , Compound 57 was obtained as a white solid (0.10 g, 20% yield, 99% purity, FA). LCMS: (ES ⁺ ) m/z (M+H) ⁺ =666.5. ¹ H NMR (400 MHz, methanol-d4) δ=7.78 (s, 1H), 7.76 - 7.67 (m, 6H), 7.48 (d, J= 8.0 Hz, 2H), 5.02 - 4.94 (m, 1H), 3.79 (s, 2H), 3.30 - 3.27 (m, 2H), 3.05 (s, 3H), 2.88 (t, J =6.8 Hz, 2H), 2.75 (br s, 4H), 2.66 (br d, J = 2.0 Hz, 4H), 2.31 (br d, J =9.6 Hz, 2H), 2.23 (d, J= 7.2 Hz, 2H), 1.94 (br d, J =12.4 Hz, 2H), 1.84 (ddd, J = 3.6, 7.5, 11.2 Hz, 1H), 1.67 - 1.52 (m, 2H), 1.33 - 1.18 (m, 2H). Example 5 : (1r,4r)-4-((4,6- difluoro -5-(4'-((3-(2- hydroxyethoxy ) azetidin -1- yl ) methyl ) )-[1,1'- biphenyl ]-4- yl )-1H- benzo [d] imidazol -2- yl ) oxy ) cyclohexane -1- carboxylic acid ( compound 52) :

Step 1 : 3-(2-( Benzyloxy ) ethoxy ) azetidine -1- carboxylic acid tertiary butyl ester (5-1) : At 0°C, add to 3-hydroxyazetidine To a solution of tertiary butyl alkane-1-carboxylate (10 g, 58 mmol, 1 eq ) in DMF (100 mL) was added NaH (4.6 g, 0.12 mol, 60% purity, 2 eq ). The solution was stirred at 25 °C for 1 h, then a solution of 2-bromoethoxymethylbenzene (15 g, 69 mmol, 11 mL, 1.2 eq ) in DMF (100 mL) was added dropwise, and the mixture was added dropwise Stir at 25°C for 11 hours. The solution was quenched by adding saturated aqueous _NH4Cl (300 mL). The solution was diluted with saturated brine (200 mL) and extracted with EA (600 mL×3). The combined organic layers were dried _{over Na2SO4} , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 35/65) to obtain 5-1 as a colorless oil (17 g, 54 mmol, 93% yield, 97% purity) . ¹ H NMR (400 MHz, methanol-d ₄ ) δ=4.54 - 4.42 (m, 1H), 4.29 (dd, J =6.4, 11.7 Hz, 2H), 4.01 (br dd, J =5.2, 11.6 Hz, 2H ), 3.73 - 3.65 (m, 2H), 3.60 - 3.53 (m, 2H).

Step 2 : 3-(2- Hydroxyethoxy ) azetidine -1- carboxylic acid tertiary butyl ester ( 5-2 ): 5-1 (17 g, 55 mmol, 1 eq ) under _N To a solution in EtOH (170 mL) was added Pd(OH) ₂ (3.9 g, 2.8 mmol, 10% purity, 0.05 eq ) and Pd/C (1.0 g, 10% purity). The suspension was degassed in vacuum and purged several times with _H2 . The mixture was stirred under _H2 (15 psi) at 45°C for 2 hours. The solution was filtered and concentrated under reduced pressure to afford 5-2 as a colorless oil (8 g, 37 mmol, 67% yield). ¹ H NMR (400 MHz, methanol-d ₄ ) δ=4.32 (tt, J =4.0, 6.4 Hz, 1H), 4.17 - 4.03 (m, 2H), 3.82 (br dd, J =3.6, 9.3 Hz, 2H ), 3.70 - 3.65 (m, 2H), 3.52 - 3.45 (m, 2H), 1.45 (s, 9H).

Step 3 : 2-( azetidin -3- yloxy ) ethan -1- ol (5-3 ) : Dissolve 5-2 (5 g, 23 mmol, 1 eq ) in HCl (25 mL) and A solution in MeOH (25 mL) was stirred at 40 °C for 1 h. The solution was concentrated under reduced pressure to afford crude 5-3 as a colorless oil (4.0 g, 19 mmol, 84% yield, 75% purity, HCl).

Step 4 : (1r,4r)-4-((4,6- difluoro -5- iodo -1-((2-( trimethylsilyl ) ethoxy ) methyl )-1H- benzo [d] imidazol -2- yl ) oxy ) cyclohexane -1- carboxylic acid methyl ester (5-4 ) : at 0°C, to 2-[(4,6-difluoro-5-iodo-2 -methylsulfonyl-benzimidazol-1-yl)methoxy]ethyl-trimethyl-silane (5 g, 10 mmol, 1 eq ) and methyl 4-hydroxycyclohexanecarboxylate (3.2 g To a solution of , 20 mmol, 2 eq ) in DMF (80 mL) was added DBU (6.2 g, 41 mmol, 6.2 mL, 4 eq ). The mixture was stirred at 25°C for 24 hours. The solution was diluted with _H2O (150 mL) and extracted with EA (100 mL×3). The combined organic layers were washed with saturated brine (50 mL _× 3), dried over anhydrous _Na2SO4 , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 100/1 to 30/1) to obtain 5-4 as a colorless oil (3.3 g, 5.6 mmol, 55% yield, 96% purity). LCMS: (ES ⁺ ) m/z (M+Na) ⁺ =589.1.

Step 5 : (1r,4r)-4-((4,6- difluoro- 5-(4'- formyl- [1,1'- biphenyl ]-4- yl )-1-((2 -( Trimethylsilyl ) ethoxy ) methyl )-1H- benzo [d] imidazol -2- yl ) oxy ) cyclohexane -1- carboxylic acid methyl ester ( 5-5) : towards methyl 5-4 (0.7 g, 1.2 mmol, 1 eq ) and 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) To a solution of phenyl]benzaldehyde (0.57 g, 1.9 mmol, 1.5 eq ) in dihexane (13 mL) and H ₂ O (1.3 mL) was added Na ₂ CO ₃ (0.39 g, 3.7 mmol, 3 eq ) and Pd(dppf)Cl ₂ (90 mg, 0.12 mmol, 0.1 eq). The mixture was stirred at 90°C for 13 hours. The solution was diluted with _H2O (100 mL) and extracted with EA (50 mL×3). The combined organic _layers were washed with saturated brine (80 mL×3), dried over anhydrous _Na2SO4 , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 100/1 to 4/1) to obtain 5-5 as a yellow oil (0.51 g, 66% yield, 100% purity ). LCMS: (ES+) m/z (M+H)+=621.3.

Step 6 : (1r,4r)-4-((4,6- difluoro -5-(4'-((3-(2- hydroxyethoxy ) azetidin -1- yl ) methyl ) )-[1,1'- biphenyl ]-4- yl )-1-((2-( trimethylsilyl ) ethoxy ) methyl )-1H- benzo [d] imidazol -2- yl ) oxy ) cyclohexane -1- carboxylic acid methyl ester ( 5-6) : To a solution of 5-3 (91 mg, 0.77 mmol, 1.2 eq ) in DMSO (4 mL) and THF (2 mL) was added AcOK (0.19 g, 1.9 mmol, 3 eq). The mixture was stirred at 40°C for 1 hour. Then 5-5 (0.4 g, 0.64 mmol, 1 eq ) and AcOH (39 mg, 0.64 mmol, 37 μL, 1 eq ) were added and the mixture was stirred at 40°C for a further 1 hour. Next, NaBH(OAc) ₃ (0.41 g, 1.9 mmol, 3 eq ) was added at 0°C. The mixture was stirred at 25°C for 16 hours. The solution was diluted with _H2O (100 mL) and extracted with EA (50 mL×4). The combined organic layers were washed with saturated brine (50 mL _× 3), dried over anhydrous _Na2SO4 , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=100/1 to ethyl acetate/ethanol=2/3) to obtain 5-6 as colorless oil (0.45 g, 96% Yield, 99.5% purity). LCMS: (ES+) m/z (M+H)+=722.4.

Step 7 : (1r,4r)-4-((4,6- difluoro- 5-(4'-((3-(2-(2,2,2- trifluoroethyloxy ) ethoxy ) ) Azetidin -1- yl ) methyl )-[1,1'- biphenyl ]-4- yl ) -1H- benzo [d] imidazol -2- yl ) oxy ) cyclohexane- Methyl 1- formate (5-7 ) : To a solution of 5-6 (0.45 g, 0.62 mmol, 1 eq ) in DCM (5 mL) was added TFA (1 mL). The mixture was stirred at 25°C for 20 hours. The solution was diluted with saturated _aqueous NaHCO solution (50 mL) and extracted with EA (100 mL×3). The combined organic layers were washed with saturated brine (50 mL × 2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain crude 5-7 as a yellow oil (0.37 g, 55% yield, 64% purity).

Step 8 : (1r,4r)-4-((4,6-difluoro-5-(4'-((3-(2-hydroxyethoxy)azetidin-1-yl)methyl) )-[1,1'-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)cyclohexane-1-carboxylic acid ( compound 52 ): to 5-7 ( To a solution of 0.24 g, 0.34 mmol, 1 eq ) in THF (2 mL), H ₂ O (2 mL), and i-PrOH (2 mL) was added LiOH (83 mg, 3.4 mmol, 10 eq). The mixture was stirred at 25°C for 37 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. By reversed-phase HPLC (column: YMC Triart C18 250×50 mm×7 μm; mobile phase: [water (FA)-ACN]; B%: 25%-55%, 18 min) and (column: Waters xbridge 150×25 mm 10 μm; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 12%-42%, 9 min) purified the residue to obtain compound 52 as a white solid (25 mg , 13% yield, 100% purity). LCMS: (ES+) m/z (M+H)+=578.3. ¹ H NMR (400 MHz, methanol-d4) δ=7.78 (s, 1H), 7.76 - 7.67 (m, 6H), 7.48 (d, J =8.0 Hz, 2H), 5.02 - 4.94 (m, 1H), 3.79 (s, 2H), 3.30 - 3.27 (m, 2H), 3.05 (s, 3H), 2.88 (t, J =6.8 Hz, 2H), 2.75 (br s, 4H), 2.66 (br d, J = 2.0 Hz, 4H), 2.31 (br d, J =9.6 Hz, 2H), 2.23 (d, J =7.2 Hz, 2H), 1.94 (br d, J =12.4 Hz, 2H), 1.84 (ddd, J = 3.6, 7.5, 11.2 Hz, 1H), 1.67 - 1.52 (m, 2H), 1.33 - 1.18 (m, 2H). Example 6 : (1r,4r)-4-((4,6- difluoro -5-(4'-((1r,3r)-3- hydroxycyclobutoxy ) methyl )-[1,1 ' -Biphenyl ]-4- yl )-1H- benzo [d] imidazol -2- yl ) oxy ) cyclohexanecarboxylic acid ( compound 59) :

Step 1 : ((1s,3s)-3-((4- bromobenzyl ) oxy ) cyclobutoxy )( tertiary butyl ) dimethylsilane (6-1) : at 0°C, To (1s,3s)-3-((tertiary butyldimethylsilyl)oxy)cyclobutan-1-ol (1s,3s)-3-((tertiary butyldimethylsilyl) To a solution of oxy)cyclobutan-1-ol (1.0 g, 4.9 mmol, 1.0 eq) in DMF (10 mL) was added NaH (0.30 g, 7.4 mmol, 60% purity, 1.5 eq). The mixture was stirred at 25°C for 0.5 hours. Then a solution of 1-bromo-4-(bromomethyl)benzene (1.2 g, 4.9 mmol, 1.0 eq) in DMF (10 mL) was added dropwise. The mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched by adding water (100 mL), and then diluted with ethyl acetate (50 mL) and extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous _Na2SO4 , filtered and concentrated under _reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1:0 to 10:1) to obtain 6-1 as a white oil (1 g, 2.7 mmol, 54% yield) . ¹ H NMR (CD ₃ OD, 400 MHz) δ=7.51 (s, 1H), 7.48 (s, 1H), 7.27 (s, 1H), 7.24 (s, 1H), 4.37 (s, 2H), 4.95 - 3.89 (m, 1H), 3.88 - 3.63 (m, 1H), 2.67 - 2.62 (m, 2H), 1.91 - 1.86 (m, 2H), 0.80 (s, 9H), 0.05 (m, 6H).

Step 2 : Tertiary butyldimethyl ((1s,3s)-3-((4'-(4,4,5,5- tetramethyl -1,3,2 -dioxaborolane) -2- yl )-[1,1'- biphenyl ]-4- yl ) methoxy ) cyclobutoxy ) silane (6-2) : to 6-1 (1.0 g, 2.7 mmol, 1.0 eq) and 1,4-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene (0.89 g, 2.7 mmol, 1.0 eq) in di To a solution in ethane (10 mL) and H ₂ O (1 mL) were added Pd(dppf)Cl ₂ (0.20 g, 0.27 mmol, 0.1 eq) and K ₂ CO ₃ (0.74 g, 5.4 mmol, 2.0 eq) . The mixture was purged with N ₃ times. The mixture was stirred at 100 °C under _N2 for 12 h. The reaction mixture was quenched by adding water (20 mL), and then diluted with ethyl acetate (20 mL) and extracted with ethyl acetate (15 mL×3). _The combined organic layers were washed with saturated brine (10 mL), dried over _Na2SO4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1:0 to 10:1) to obtain 6-2 as a white oil (0.62 g, 1.3 mmol, 47% yield) . ¹ H NMR (CD ₃ OD, 400 MHz) δ=7.77 - 7.75 (d, J =8.0 Hz, 1H), 7.69 (s, 1H), 7.67 - 7.65 (m, 4H), 7.38 - 7.41 (m, 1H ), 7.40 (m, 1H), 4.39 (s, 1H), 3.82 - 3.89 (m, 1H), 3.62 - 3.59 (m, 1H), 2.63 - 2.58 (m, 2H), 1.79 - 1.76 (m, 2H ), 1.29 (s, 12H), 0.84 (d, 9H, J =1.3 Hz), 0.01 (s, 6H).

Step 3 : (1r,4r)-4-((5-(4'-((1s,3s)-3-(( tertiary butyldimethylsilyl ) oxy ) cyclobutoxy ) methyl base )-[1,1'- biphenyl ]-4- yl )-4,6- difluoro -1-((2-( trimethylsilyl ) ethoxy ) methyl )-1H- benzo [d] imidazol -2- yl ) oxy ) cyclohexane -1- carboxylic acid methyl ester ( 6-3) : to 6-2 (0.50 g, 1.0 mmol, 1.0 eq) and (1r,4r)-4- ((4,6-Difluoro-5-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)oxy ) cyclohexane-1-carboxylic acid methyl ester (0.57 g, 1.0 mmol, 1.0 eq) in DMSO (8 mL) was added Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (0.08 g, 0.10 mmol, 0.1 eq) and Na ₂ CO ₃ (0.32 g, 3.0 mmol, 3.0 eq). The _mixture was degassed and purged with N ₃ times and stirred at 110 °C under N for 16 h. The reaction mixture was quenched by adding water (20 mL), and then diluted with ethyl acetate (20 mL) and extracted with ethyl acetate (20 mL×3). _The combined organic layers were washed with saturated brine (10 mL), dried over _Na2SO4 , 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 3:1) to obtain 6-3 (70 mg, 8% yield, 97% purity) as a yellow oil. ). LCMS: (ES ⁺ ) m/z (M+H) ⁺ =808.8.

Step 4 : (1r,4r)-4-((4,6- difluoro -5-(4'-((1s,3s)-3- hydroxycyclobutoxy ) methyl )-[1,1 ' -Biphenyl ]-4- yl )-1H- benzo [d] imidazol - 2- yl ) oxy ) cyclohexane -1- carboxylic acid methyl ester ( 6-4) : at 0°C, to methyl To a solution of 6-3 (60 mg, 0.07 mmol, 1.0 eq) in THF (2 mL) was added TBAF (78 mg, 0.30 mmol, 4.0 eq). The mixture was stirred at 25°C for 13 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC (PE:EA=1:1) to obtain 6-4 as a yellow oil (25 mg, 57% yield, 96% purity). LCMS: (ES ⁺ ) m/z (M+H) ⁺ =563.3.

Step 5 : (1r,4r)-4-((4,6- difluoro -5-(4'-((1s,3s)-3- hydroxycyclobutoxy ) methyl )-[1,1 ' -Biphenyl ]-4- yl )-1H- benzo [d] imidazol -2- yl ) oxy ) cyclohexane -1- carboxylic acid ( Compound 59) : To 6-4 (25 mg, 44 μmol, To a solution of 1.0 eq) in H ₂ O (0.5 mL), THF (0.5 mL), and i-PrOH (0.5 mL) was added LiOH (3 mg, 0.13 mmol, 3.0 eq). The mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: Phenomenex C18 150×25 mm×10 μm; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 15%-45%, 8 min), Compound 59 was obtained as a white solid (7.63 mg, 31% yield, 98% purity). LCMS: (ES+) m/z (M+H)+=549.2. ¹ H NMR (DMSO- d ₆ , 400 MHz) δ=7.79 (s, 1H), 7.77 (s, 1H), 7.73 (s, 1H), 7.71 (s, 1H), 7.54 (s, 1H), 7.53 (s, 1H), 7.44 (s, 1H), 7.42 (s, 1H), 7.16 - 7.12 (m, 1H), 4.97 - 4.95 (m, 1H), 4.41 (s, 2H), 3.72 - 3.61 (m , 1H), 3.59 - 3.35 (m, 1H), 2.59 - 2.54 (m, 2H), 2.25 - 2.31 (m, 2H), 2.00 - 1.96 (m, 2H), 1.81 - 1.74 (m, 4H), 1.59 - 1.51 (m, 4H). Example 7 : 2-((1r,4r)-4-((4,6- difluoro - 5-(4'-((3-(( methylsulfonyl ) methyl )methyl ) azetidine- 1- yl ) methyl )-[1,1'- biphenyl ]-4- yl )-1H- benzo [d] imidazol -2- yl ) oxy ) cyclohexyl ) acetic acid ( compound 29) :

Step 1 : 3-(( Methylthio ) methyl ) azetidine -1- carboxylic acid tertiary butyl ester ( 7-1 ): add 3-(iodomethyl)azetidine to the solution Alkane-1-carboxylic acid tertiary butyl ester (14 g, 46 mmol, 1 eq) was added to MeOH (0.20 L) with sodium methylthioate (8.0 g, 0.11 mmol, 7.3 mL, 2.5 eq), and the mixture was incubated at 25 Stir for 2 hours at ℃. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with saturated _aqueous NaHCO solution (500 mL) and extracted with DCM (500 mL×3). The combined organic layers were washed with saturated brine (500 mL), dried over _Na2SO4 , filtered and concentrated under _reduced pressure to give 7-1 as a colorless oil (13 g, crude material).

Step 2 : 3-(( methylsulfonyl ) methyl ) azetidine -1- carboxylic acid tertiary butyl ester ( 7-2 ): add 7-1 (13 g, 59 mmol, To a solution of 1 eq ) in DCM (130 mL) was added m-CPBA (24 g, 0.12 mmol, 85% purity, 2 eq ), and the mixture was stirred at 25 °C for 12 h. The solution was diluted with _H2O (200 mL) and extracted with DCM (200 mL×3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous _Na2SO4 , filtered and concentrated under _reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 0/1) to obtain 7-2 (11 g, 44 mmol) as a light yellow oil.

Step 3 : 3-(( methylsulfonyl ) methyl ) azetidine ( 7-3) : 7-2 (11 g, 44 mmol, 1 eq ) in MeOH (55 HCl (55 mL) was added to the solution in mL). The mixture was stirred at 25°C for 6 hours. The solution was concentrated under reduced pressure to obtain 7-3 (7.9 g, crude material) as a white solid.

Step 4 : 4'- Bromo- [1,1'- biphenyl ]-4- carbaldehyde ( 7-4 ): Add (4-formylphenyl)boronic acid (30 g, 0.20 mmol, 1 eq ) and 1 To a solution of -bromo-4-iodo-benzene (57 g, 0.20 mmol, 1 eq ) in dihexane (500 mL) and H ₂ O (50 mL) was added Na ₂ CO ₃ (64 g, 0.60 mmol) ,3 eq). The mixture was purged 3 times with _N2 , then Pd( _dppf ) _Cl2.CH2Cl2 (1.6 g, 2.0 mmol, 0.01 eq ) was added, _the mixture was purged 2 times with _N2 , then the mixture was incubated at 90 ^° C Stir under _N2 atmosphere for 12 hours. The solution was diluted with _H2O (1 L) and extracted with EA (1 L×3). The combined organic layers were washed with saturated brine (1 L), dried over anhydrous _Na2SO4 , filtered and concentrated under reduced _pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , PE/EA=5:1) to obtain 7-4 (37 g, 0.14 mol) as a white solid.

Step 5 : 1-((4'- bromo- [1,1'- biphenyl ]-4- yl ) methyl )-3-(( methylsulfonyl ) methyl ) azetidine (7 -5) : To a solution of 7-3 (5.7 g, 31 mmol, 1 eq, HCl) in THF (70 mL) and DMSO (70 mL) was added KOAc (9.0 g, 92 mmol, 3 eq). The mixture was stirred at 25°C for 1 hour. Then 7-4 (8 g, 31 mmol, 1 eq ) and HOAc (1.8 g, 31 mmol, 1.75 mL, 1 eq ) were added. The mixture was stirred at 40°C for 1 hour. Next, NaBH(OAc) ₃ (20 g, 92 mmol, 3 eq ) was added at 0°C. The mixture was stirred at 25°C for 12 hours. The solution was diluted with _H2O (700 mL) and extracted with EA (500 mL×3). The combined organic layers were washed with saturated brine (500 mL), dried over anhydrous _Na2SO4 , filtered and concentrated under _reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , PE/EA=1:1) to obtain 7-5 (12 g, 29 mmol) as a yellow solid.

Step 6 : 3-(( methylsulfonyl ) methyl )-1-((4'-(4,4,5,5- tetramethyl -1,3,2 -dioxaborolane) -2- yl )-[1,1'- biphenyl ]-4- yl ) methyl ) azetidine (7-6) : To 7-5 (15 g, 38 mmol, 1 eq ) and bis To a solution of (pinacolyl)diboron (BPD) (15 g, 57 mmol, 1.5 eq ) in dioxane (200 mL) was added KOAc (11 g, 0.11 mol, 3 eq ), and the mixture was _N2 was purged 3 times, then Pd(dppf) _Cl2.CH2Cl2 (3.1 g, 3.8 mmol, ^0.1 eq ) was added, then _the mixture was purged with _N2 2 _times , then the mixture was incubated at 80 °C at Stir under _N2 atmosphere for 12 hours. The solution was diluted with _H2O (200 mL) and extracted with EA (200 mL×3). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous _Na2SO4 , filtered and concentrated under _reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , EA/MEOH=5:1) to obtain 7-6 (14 g, 32 mmol) as a yellow solid.

Step 7 : 2-((1r,4r)-4-((4,6- difluoro - 5-(4'-((3-(( methylsulfonyl ) methyl )methyl ) azetidine- 1- yl ) methyl )-[1,1'- biphenyl ]-4- yl )-1-((2-( trimethylsilyl ) ethoxy ) methyl )-1H- benzo [d ] imidazol -2- yl ) oxy ) cyclohexyl ) ethyl acetate (7-7) : At 25°C, 3-13 (2.7 g, 4.6 mmol, 1 eq ) and 7-6 (2.4 g, 5.5 mmol, 1.2 eq ), Na ₂ CO ₃ (1.5 g, 14 mmol, 3 eq ) in dioxane (30 mL) and H ₂ O (8 mL) was degassed and purged with N ₃ times, Then Pd(dppf) _Cl2 (0.33 g, 0.46 mmol, 0.1 eq ) was added to the solution, the mixture was purged with _N2 at 25°C three times, and the mixture was stirred at 100°C under _N2 atmosphere for 10 hours. The solution was diluted with _H2O (200 mL) and extracted with EA (200 mL×3). The combined organic layers were washed with saturated brine (400 mL), dried over anhydrous _Na2SO4 , filtered and concentrated under reduced _pressure to obtain a residue. The residue was purified by column chromatography (SiO ₂ , DCM/MeOH=90/10) to obtain 7-7 (3.0 g, 2.7 mmol) as a yellow solid. LCMS: tR=(ES+) m/z (M+H) ⁺ =782.9.

Step 8 : 2-((1r,4r)-4-((4,6- difluoro - 5-(4'-((3-(( methylsulfonyl ) methyl )methyl ) azetidine- 1- yl ) methyl )-[1,1'- biphenyl ]-4- yl )-1H- benzo [d] imidazol -2- yl ) oxy ) cyclohexyl ) ethyl acetate (7-8) : To a solution of 7-7 (3.0 g, 2.7 mmol, 70% purity, 1 eq ) in DMF (30 mL) was added CsF (6.1 g, 40 mmol, 1.48 mL, 15 eq ) at 25°C. The mixture was stirred at 100°C for 24 hours. The solution was diluted with _H2O (100 mL) and extracted with EA (100 mL×3). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain 7-8 as a yellow solid (1.5 g, crude material). LCMS: (ES+) m/z (M+H) ⁺ =652.1.

Step 9 : 2-((1r,4r)-4-((4,6- difluoro - 5-(4'-((3-(( methylsulfonyl ) methyl )methyl ) azetidine- 1- yl ) methyl )-[1,1'- biphenyl ]-4- yl )-1H- benzo [d] imidazol -2- yl ) oxy ) cyclohexyl ) acetic acid ( compound 29) : at 25 To a solution of 7-8 (1.5 g, 1.4 mmol, 62% purity, 1 eq ) in MeOH (10 mL) and H ₂ O (10 mL) was added LiOH ^. H ₂ O (0.30 g, 7 mmol) at °C. , 5 eq ), and the mixture was stirred at 25°C for 24 hours. The solution was concentrated under reduced pressure to obtain a mixture. The mixture was adjusted to pH=4 with concentrated FA, diluted with DMSO (10 mL), stirred at 25°C for 10 minutes, and then concentrated under reduced pressure to obtain a DMSO solution. Purified by reversed-phase HPLC (FA conditions; column: Phenomenex luna C18 150×25 mm×10 μm; mobile phase: [water (0.225% FA)-CAN]; B%: 13%-43%, 10 min) solution to obtain compound 29 as an off-white solid (0.89 g, 93% yield, 99% purity, FA). LCMS: (ES+) m/z (M+H) ⁺ =624.2. ¹ H NMR (400 MHz, methanol-d ₄ ) δ=8.37 (s, 1H), 7.78 (d, J =8.0 Hz, 2H), 7.74 (d, J =8.4 Hz, 2H), 7.53 (t, J =7.6 Hz, 4H), 7.01 (br d, J =9.2 Hz, 1H), 4.95 - 4.89 (m, 1H), 4.24 (s, 2H), 4.10 (br t, J =8.8 Hz, 2H), 3.95 - 3.81 (m, 2H), 3.54 (d, J =7.6 Hz, 2H), 3.41 - 3.33 (m, 1H), 3.00 (s, 3H), 2.34 - 2.26 (m, 2H), 2.23 (d, J =7.2 Hz, 2H), 1.94 (br d, J =12.4 Hz, 2H), 1.88 - 1.76 (m, 1H), 1.66 - 1.46 (m, 2H), 1.36 - 1.22 (m, 2H). Example 8 : 2-((1r,4r)-4-((4,6- difluoro - 5-(4'-((4-(2-( methylsulfonyl ) ethyl) ethyl ) piperidine ) - 1 -yl ) methyl )-[1,1'- biphenyl ]-4- yl )-1H- benzo [ d] imidazol -2- yl ) oxy ) cyclohexyl ) acetic acid ( compound 56) :

Step 1 : 4-(2-( methylsulfonyl ) ethyl ) piperidine - 1- carboxylic acid tertiary butyl ester (8-1) : piperazine-1-carboxylic acid tertiary butyl ester (1.8 g, 9.4 mmol , 1 eq ) and a solution of (methylsulfonyl)ethylene (1 g, 9.4 mmol, 0.83 mL, 1 eq ) in MeOH (10 mL). The mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated in vacuo to afford 8-1 (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).

Step 2 : 1-(2-( methylsulfonyl ) ethyl ) piperazine (8-2) : Dissolve 8-1 (0.3 g, 1.0 mmol, 1 eq ) in HCl/dioxane (3 mL, 4 mol/L) was stirred at 25°C for 4 hours. The reaction mixture was concentrated in vacuo to afford 8-2 (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).

Step 3 : 1-((4'- bromo- [1,1'- biphenyl ]-4- yl ) methyl )-4-(2-( methylsulfonyl ) ethyl ) piperidine ( 8- 3) : To 8-2 (26 g, 97 mmol, 1.2 eq, 2HCl) and 7-4 (21 g, 80 mmol, 1 eq ) in THF (200 mL) and DMSO (200 mL) at 25°C KOAc (24 g, 0.24 mol, 3 eq ) was added to the solution. The solution was stirred at 40°C for 1 hour. Then NaBH(OAc) ₃ (51 g, 0.24 mol, 3 eq ) was added portionwise at 0 °C. The mixture was stirred at 25°C for 4 hours. The solution was diluted with _H2O (800 mL) and extracted with EA (800 mL×3). The combined organic layers were washed with saturated brine (500 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain 8-3 (35 g, 64 mmol) as a white solid. LCMS: (ES+) m/z (M+H) ⁺ =439.1.

Step 4 : 1-(2-( methylsulfonyl ) ethyl )-4-((4'-(4,4,5,5- tetramethyl -1,3,2- dioxabora) Cyclopent -2- yl )-[1,1'- biphenyl ]-4- yl ) methyl ) piperdine (8-4) : At 25°C, add 8-3 (41 g, 94 mmol, 1 eq ) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) ( To a solution of 35 g, 0.14 mol, 1.5 eq ) in dioxane (1 L) was added KOAc (28 g, 0.28 mol, 3 eq ). The mixture was purged 3 times with _N2 , then Pd(dppf) _Cl2 (3.4 g, 4.7 mmol, 0.05 eq ) was added. The mixture was purged with N ₃ times and stirred at 100 °C for 6 h. The solution was diluted with _H2O (500 mL) and extracted with EA (500 mL×3). The combined organic layer was washed with saturated brine (500 mL), then the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO ₂ , DCM/MeOH=10/1) to obtain 8-4 (35 g, 48 mmol) as a white solid. LCMS: (ES+) m/z (M+H) ⁺ =485.2.

Step 5 : 2-((1r,4r)-4-((4,6- difluoro -5-(4'-( ( 4-(2-( methylsulfonyl ) ethyl) ethyl ) piperidine ) - 1 -yl ) methyl )-[1,1'- biphenyl ]-4- yl ) -1 -((2-( trimethylsilyl ) ethoxy ) methyl )-1H- benzo [d] Imidazol -2- yl ) oxy ) cyclohexyl ) ethyl acetate (8-5) : At 25°C, 8-4 (26 g, 36 mmol, 1.2 eq ), 2-[4-[4,6 -Ethyl difluoro-5-iodo-1-(2-trimethylsilylethoxymethyl)benzimidazol-2-yl]oxycyclohexyl]acetate (18 g, 30 mmol, 1 eq ) and Na ₂ CO ₃ (9.6 g, 91 mmol, 3 eq ) in dihexane (400 mL) and H ₂ O (40 mL) was degassed and purged with N ₃ times. Under _N2 , add Pd( _dppf ) _Cl2.CH2Cl2 (2.5 g, 3.0 mmol, 0.1 eq ) to the solution _at 25°C and stir at 100°C under _N2 atmosphere for 6 hours. The solution was diluted with _H2O (500 mL) and extracted with EA (500 mL×3). The combined organic layers were washed with saturated brine (300 mL), dried over anhydrous _Na2SO4 , filtered and concentrated under _reduced pressure to obtain a residue. The residue was purified by reversed-phase HPLC (FA conditions; mobile phase: Phenomenex luna C18 (250×70 mm, 10 μm) [water (0.225% FA)-CAN]; gradient: B% 35, 15 min) to obtain a 8-5 as yellow solid (8.4 g, 8.6 mmol). LCMS: (ES+) m/z (M+H) ⁺ =825.6.

Step 6 : 2-((1r,4r)-4-((4,6- difluoro -5-(4'-( ( 4-(2-( methylsulfonyl ) ethyl) ethyl ) piperidine ) - 1 -yl ) methyl )-[1,1'- biphenyl ]-4- yl )-1H- benzo [ d] imidazol -2- yl ) oxy ) cyclohexyl ) ethyl acetate (8-6) : To a solution of 8-5 (8.4 g, 8.6 mmol, 1 eq ) in DMF (80 mL) was added CsF (33 g, 0.22 mol, 7.97 mL, 25 eq ) at 25 °C. The solution was stirred at 100°C for 10 hours. The solution was diluted with _H2O (500 mL) and extracted with EA (500 mL×3). The combined organic layers were washed with saturated brine (500 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain 8-6 as a yellow solid (6 g, crude material).

Step 8 : 2-((1r,4r)-4-((4,6- difluoro - 5-(4'-((4-(2-( methylsulfonyl ) ethyl) ethyl ) piperidine ) - 1 -yl ) methyl )-[1,1'- biphenyl ]-4- yl )-1H- benzo [ d] imidazol -2- yl ) oxy ) cyclohexyl ) acetic acid ( compound 56) : at 25°C To a solution of 8-6 (6 g, 6.5 mmol, 1 eq) in i-PrOH (10 mL) and H ₂ O (10 mL) was added LiOH.H ₂ O (2.8 g, 66 mmol, 10 eq). The mixture was stirred at 50°C for 6 hours. The mixture was adjusted to pH=4 with concentrated FA and concentrated under reduced pressure to obtain a residue. By reversed-phase HPLC (FA conditions; column: Phenomenex luna C18 (250×70 mm, 10 μm); mobile phase: [water (0.225% FA)-ACN]; B%: 10%-45%, 22 min ) and purified the residue to obtain compound 56 as an off-white solid (3.4 g, 4.7 mmol, 70% yield, 97% purity, FA). LCMS: (ES+) m/z (M+H) ⁺ =667.5. ¹ H NMR (400 MHz, methanol-d4) δ=8.35 (s, 1H), 7.73 (dd, J =1.6, 8.3 Hz, 4H), 7.52 (dd, J =8.0, 11.6 Hz, 4H), 7.01 ( br d, J =9.2 Hz, 1H), 4.95 - 4.89 (m, 1H), 3.90 (s, 2H), 3.32 (br s, 1H), 3.29 (br s, 1H), 3.05 (s, 3H), 2.93 - 2.89 (m, 2H), 2.88 - 2.79 (m, 4H), 2.69 (br d, J =3.6 Hz, 4H), 2.34 - 2.25 (m, 2H), 2.23 (d, J =7.2 Hz, 2H ), 2.00 - 1.89 (m, 2H), 1.83 (ddd, J =3.6, 7.2, 10.8 Hz, 1H), 1.68 - 1.45 (m, 2H), 1.37 - 1.16 (m, 2H).

The following compounds were prepared according to the procedure described in the previous examples using appropriate intermediates. compound Characterization data 3 LCMS: (ES+) m/z (M+H)+ = 591.2. 1H NMR (400 MHz, CD ₃ OD-d4) δ = 7.83 - 7.77 (m, 3H), 7.75 (d, J = 2.4 Hz, 3H ), 7.55 (d, J = 8.4 Hz, 2H), 5.08 - 4.97 (m, 1H), 4.65 - 4.52 (m, 1H), 4.32 (s, 2H), 4.16 - 4.06 (m, 2H), 4.05 - 3.95 (m, 2H), 3.82 - 3.73 (m, 2H), 3.70 - 3.56 (m, 4H), 3.11 - 2.98 (m, 1H), 2.39 - 2.24 (m, 3H), 2.16 - 2.06 (m, 2H ), 1.74 - 1.55 (m, 4H). 4 LCMS: (ES ⁺ ) m/z (M+H) ⁺ = 634.5. ¹ H NMR (400 MHz, CD ₃ OD-d ₄ ) δ = 7.78 (s, 1H), 7.75 - 7.58 (m, 5H), 7.47 (d, J = 8.0 Hz, 2H), 5.09 - 4.94 (m, 1H), 3.80 - 3.71 (m, 4H), 3.70 - 3.64 (m, 2H), 3.60 - 3.52 (m, 2H), 3.16 - 2.91 (m, 6H), 2.88 - 2.61 (m, 4H), 2.42 - 2.20 (m, 3H), 2.17 - 2.00 (m, 2H), 1.74 - 1.52 (m, 4H), 1.37 - 1.25 (m, 1H ). 5 LCMS: (ES ⁺ ) m/z (M+H) ⁺ =594.2; 1H NMR (400 MHz, methanol-d4) δ = 7.75 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 8.4, 2H), 7.56 (d, J = 8.0, 2H), 7.50 - 7.40 (m, 2H), 7.00 (d, J = 9.2, 1H), 5.22 - 5.11 (m, 1H), 4.40 (s, 2H), 4.21 (t, J = 9.6, 2H), 4.16 - 4.03 (m, 3H), 3.92 (d, J = 10.0, 1H), 3.83 - 3.72 (m, 2H), 3.70 -3.51 (m, 5H), 3.09 (s, 1H), 2.70 - 2.59 (m, 1H), 2.27 - 2.15 (m, 1H), 1.77 - 1.58 (m, 2H). 6 LCMS: (ES ⁺ ) m/z (M+H) ⁺ =651.1; 1H NMR (400 MHz, methanol-d4) δ = 7.75 (d, J = 8.0, 2H), 7.65 (d, J = 8.4, 2H ), 7.56 (d, J = 8.0, 2H), 7.50 - 7.40 (m, 2H), 7.00 (d, J = 9.3, 1H), 5.22 - 5.11 (m, 1H), 4.40 (s, 2H), 4.21 (t, J = 9.6, 2H), 4.16 - 4.03 (m, 3H), 3.92 (d, J = 10.0, 1H), 3.83 - 3.72 (m, 2H), 3.70 -3.51 (m, 5H), 3.09 ( s, 1H), 2.70 - 2.59 (m, 1H), 2.27 - 2.15 (m, 1H), 1.77 - 1.58 (m, 2H). 7 LCMS: (ES ⁺ ) m/z (M+H) ⁺ = 609.2. ¹ H NMR (400 MHz, CD ₃ OD-d4) δ = 7.79 (d, J = 8.4 Hz, 3H), 7.75 (d, J = 2.4 Hz, 4H), 7.52 (d, J = 8.4 Hz, 2H), 5.09 - 4.98 (m, 1H), 4.21 (s, 2H), 4.12 - 3.98 (m, 2H), 3.90 - 3.76 (m, 2H), 3.53 (d, J = 7.6 Hz, 2H), 3.41 - 3.34 (m, 1H), 3.00 (s, 3H), 2.43 - 2.28 (m, 3H), 2.23 - 1.91 (m, 2H), 1.75 - 1.54 (m, 4H). 8 LCMS: (ES ⁺ ) m/z (M+H) ⁺ = 567.2. ¹ H NMR (400 MHz, CD ₃ OD-d ₄ ) δ = 7.71 (dd, J = 8.4, 12.6 Hz, 4H), 7.53 ( br d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.2 Hz, 2H), 7.13 - 6.92 (m, 1H), 5.01 - 4.90 (m, 1H), 4.63 (s, 2H), 3.81 - 3.62 (m, 6H), 3.62 - 3.52 (m, 2H), 2.32 (br d, J = 11.0 Hz, 3H), 2.11 (br d, J = 11 Hz, 2H), 1.84 - 1.49 (m, 4H) . 9 LCMS: (ES ⁺ ) m/z (M+H) ⁺ = 609.1. 1H NMR (400 MHz, CD ₃ OD-d4) δ = 7.79 (s, 1H), 7.77 - 7.69 (m, 6H), 7.46 ( d, J = 8.0 Hz, 2H), 5.09 - 4.97 (m, 1H), 3.96 (s, 2H), 3.84 (t, J = 8.4 Hz, 2H), 3.55 - 3.42 (m, 4H), 3.19 (s , 1H), 2.97 (s, 3H), 2.33 (br d, J = 8.0 Hz, 3H), 2.16 - 2.05 (m, 2H), 1.76 - 1.55 (m, 4H). 10 LCMS: (ES ⁺ ) m/z (M+H) ⁺ = 591.1. ¹ H NMR (400 MHz, CD ₃ OD-d4) δ = 7.79 (s, 2H), 7.77 - 7.70 (m, 5H), 7.48 (d, J = 8.4 Hz, 2H), 5.05 - 5.00 (m, 1H), 4.31 (m, 1H), 4.06 (s, 2H), 4.01 - 3.94 (m, 2H), 3.63 - 3.50 (m, 6H ), 3.36 (s, 3H), 2.38 - 2.27 (m, 3H), 2.16 - 2.07 (m, 2H), 1.73 - 1.56 (m, 4H). 11 LCMS: (ES+) m/z (M+H) ⁺ = 641.0, ¹ H NMR (400 MHz, methanol-d ₄ ) 7.71 - 7.51 (3, 1H), 7.49 - 7.29 (m, 4H), 7.49 - 7.29 (m, 4H), 7.28 - 6.79 (m, 4H), 3.88 - 3.62 (m, 4H), 3.61 - 3.36 (m, 4H), 3.35 - 7.20 (m, 2H), 2.74 - 2.30 (m, 2H) , 2.25 - 1.80 (m, 5H), 1.60 - 1.36 (m, 3H). 12 LCMS: (ES ⁺ ) m/z (M+H) ⁺ = 643.2. ¹ H NMR (400 MHz, methanol-d ₄ ) δ = 8.46 (d, J = 1.2 Hz, 1H), 7.93 (d, J = 8.4 Hz, 2H), 7.83 (dd, J = 8.4, 16.2 Hz, 4H ), 7.69 (d, J = 8.4 Hz, 2H), 5.57 - 5.43 (m, 1H), 4.42 - 4.08 (m, 5H), 3.87 (dd, J = 1.6, 4.8 Hz, 1H), 3.82 - 3.75 ( m, 1H), 3.74 - 3.62 (m, 4H), 3.28 - 3.18 (m, 2H), 2.79 - 2.63 (m, 1H), 2.38 - 2.27 (m, 1H), 2.02 - 1.84 (m, 2H). 13 LCMS: (ES+) m/z (M+H)+ = 606.2. ¹ H NMR (400 MHz, methanol-d ₄ ) δ = 7.66 (dd, J = 4.8, 8.0 Hz, 4H), 7.51 - 7.44 (m, 3H), 7.39 (d, J = 8.0 Hz, 2H), 7.31 (s, 1H), 5.24 - 5.14 (m, 1H), 4.28 - 4.15 (m, 2H), 3.74 (s, 3H), 3.73 (s, 2H), 3.71 - 3.65 (m, 3H), 3.60 (d , J = 6.4 Hz, 2H), 3.57 - 3.52 (m, 2H), 3.49 (t, J = 8.0 Hz, 2H), 3.20 (t, J = 7.2 Hz, 2H), 2.84-2.74 (m, 1H) , 2.66 - 2.52 (m, 1H), 2.29 - 2.17 (m, 1H), 1.91 - 1.73 (m, 2H). 14 LCMS: (ES+) m/z (M+H)+ = 606.2. ¹ H NMR (400 MHz, methanol-d ₄ ) δ = 7.67 (dd, J = 5.6, 8.0 Hz, 4H), 7.52 - 7.45 (m, 3H), 7.41 (br d, J = 8.0 Hz, 2H), 7.32 (s, 1H), 5.25 - 5.14 (m, 1H), 4.29 - 4.16 (m, 2H), 3.74 (s, 3H), 3.74 - 3.72 (m, 2H), 3.71 - 3.66 (m, 3H), 3.61 (d, J = 6.0 Hz, 2H), 3.57 - 3.53 (m, 2H), 3.51 (s, 2H), 3.26 - 3.19 (m, 2H), 2.87 - 2.74 (m, 1H), 2.66 - 2.53 ( m, 1H), 2.30 - 2.16 (m, 1H), 1.92 - 1.74 (m, 2H). 15 LCMS: (ES+) m/z (M+H) ⁺ = 607.4. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.94 (br s, 1H), 7.82 - 7.73 (m, 4H), 7.72 - 7.66 (m, 2H), 7.41 (d, J = 8.0 Hz, 2H), 5.38 - 5.27 (m, 1H), 4.28 (dd, J = 2.8, 10.5 Hz, 1H), 4.08 (td, J = 3.6, 11.5 Hz, 1H), 3.76 (br s, 2H), 3.66 (s, 3H), 3.61 (br dd, J = 9.6, 11.3 Hz, 2H), 3.55 (d, J = 6.8 Hz, 2H), 3.53 - 3.49 (m, 2H), 3.47 (br s, 1H), 3.45 - 3.43 (m, 2H), 3.43 - 3.40 (m, 2H), 3.13 (br d, J = 6.4 Hz, 2H), 2.73 - 2.65 ( m, 1H), 2.60 - 2.52 (m, 2H), 2.25 - 2.11 (m, 1H), 1.84 - 1.60 (m, 2H). 16 LCMS: (ES+) m/z (M+H) ⁺ = 607.5. ¹ H NMR (400 MHz, DMSO-d6) δ = 7.93 (s, 1H), 7.78 - 7.70 (m, 4H), 7.67 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 5.39 - 5.27 (m, 1H), 4.28 (dd, J = 2.8, 10.5 Hz, 1H), 4.08 (td, J ₁ = 3.6 Hz, J ₂ =11.6 Hz, 1H), 3.68 - 3.65 (m, 3H), 3.64 (br d, J = 2.4 Hz, 1H), 3.60 (s, 2H), 3.58 (br s, 1H), 3.55 (d, J = 6.8 Hz, 2H), 3.48 (d, J = 5.2 Hz, 2H), 3.41 (d, J = 5.2 Hz, 2H), 3.28 (s, 2H), 2.93 (t, J = 6.8 Hz , 2H), 2.65 - 2.58 (m, 1H), 2.58 - 2.52 (m, 2H), 2.27 - 2.12 (m, 1H), 1.82 - 1.63 (m, 2H). 17 LCMS: (ES+) m/z (M+H)+ = 592.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.35 - 11.99 (m, 1H), 7.68 (dd, J = 6.8, 16.4 Hz , 4H), 7.50 ( s, 3H), 7.38 (d, J = 8.0 Hz, 3H), 5.24 (dt, J = 4.8, 10.2 Hz, 1H), 4.06 (t, J = 8.0 Hz, 2H), 3.70 - 3.62 (m, 2H), 3.55 (d, J = 6.8 Hz, 3H), 3.51 - 3.47 (m, 2H), 3.46 - 3.39 (m, 3H), 3.32 (s, 5H), 3.07 - 2.95 (m , 2H), 2.17 (dd, J = 1.4, 10 Hz, 1H), 1.76 - 1.55 (m, 2H). 18 LCMS: (ES+) m/z (M+H)+ = 592.3. ¹ HNMR (400 MHz, DMSO-d ₆ ) δ = 12.34 - 12.00 (m, 1H), 7.68 ( dd, J = 8.0, 18.0 Hz, 4H), 7.60 - 7.45 (m, 3H), 7.38 (d, J = 8.0 Hz, 3H), 5.33 - 5.13 (m, 1H), 4.13 - 4.00 (m, 2H), 3.67 - 3.61 (m, 2H) , 3.55 (d, J = 6.8 Hz, 3H), 3.51 - 3.47 (m, 2H), 3.45 - 3.39 (m, 3H), 3.33 (d, J = 6.8Hz, 5H), 3.04 - 2.94 (m, 2H ), 2.22 - 2.13 (m, 1H), 1.74 - 1.52 (m, 2H). 19 LCMS: (ES+) m/z (M+H) ⁺ = 593.4. ¹ H NMR (400MHz, DMSO- d ₆ ) δ = 8.00 - 7.89 (m, 1H), 7.72 (s, 4H), 7.67 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 5.33 - 5.24 (m, 1H), 4.06 (dd, J ₁ = 2.0 Hz, J ₂ = 11.2 Hz, 2H), 3.67 ( s, 2H), 3.60 - 3.52 (m, 4H), 3.49 (d, J = 5.2 Hz, 2H), 3.42 - 3.36 (m, 4H), 3.02 (t, J = 6.4 Hz, 2H), 2.69 - 2.63 (m, 2H), 2.61 - 2.54 (m, 2H), 2.18 (d, J = 10.0 Hz, 1H), 1.83 - 1.44 (m, 2H). 20 LCMS: (ES+) m/z (M+H) ⁺ = 593.4. ¹ H NMR (400MHz, DMSO- d ₆ ) δ = 7.94 - 7.94 (m, 1H), 7.94 (s, 1H), 7.77 - 7.70 ( m, 4H), 7.68 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.3 Hz, 2H), 5.36 - 5.24 (m, 1H), 4.10 - 4.03 (m, 2H), 3.68 (s , 2H), 3.55 (d, J = 6.8 Hz, 4H), 3.49 (d, J = 5.2 Hz, 2H), 3.42 (d, J = 5.2 Hz, 2H), 3.37 (s, 2H), 3.03 (t , J = 6.4 Hz, 2H), 2.70 - 2.61 (m, 2H), 2.60 - 2.53 (m, 2H), 2.23 - 2.14 (m, 1H), 1.94 - 1.93 (m, 1H), 1.76 - 1.58 (m , 2H). twenty one LCMS: (ES+) m/z (M+H) ⁺ = 610.4. ¹ H NMR (400 MHz, methanol-d ₄ ) δ = 8.37 (s, 1H), 7.76 (dd, J = 8.4, 14.4 Hz, 4H), 7.53 (dd, J = 8.4, 16.4 Hz, 4H), 7.18 - 6.81 (m, 1H), 4.97 - 4.91 (m, 1H), 4.19 (s, 2H), 4.05 (br t, J = 9.2 Hz, 2H), 3.91 - 3.75 (m, 2H), 3.52 (d, J = 7.6 Hz, 2H), 3.00 (s, 3H), 2.42 - 2.24 (m, 3H), 2.12 (br d, J = 11.6 Hz, 2H), 1.75 - 1.55 (m, 4H), 1.34 - 1.28 ( m, 1H). twenty two LCMS: (ES+) m/z (M+H) + = 565.4; ¹ H NMR (400 MHz, methanol-d ₄ ) δ = 7.68 (d, J = 8.0 Hz, 4H), 7.48 (dd, J = 8.4 , 11.4 Hz, 5H), 7.37 - 7.19 (m, 1H), 4.90 (br d, J = 10.4 Hz, 1H), 4.62 (s, 2H), 3.74 - 3.63 (m, 6H), 3.62 - 3.55 (m , 2H), 2.41 - 2.26 (m, 3H), 2.18 - 2.05 (m, 2H), 1.76 - 1.54 (m, 4H). twenty four LCMS: (ES+) m/z (M+H)+ = 600.2 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 13.14 - 12.42 (m, 1H), 12.41 - 11.60 (m, 1H), 8.58 ( s, 1H), 8.10 (d, J = 8.0 Hz, 2H), 7.93 (br s, 1H), 7.88 - 7.79 (m, 4H), 7.79 - 7.70 (m, 2H), 5.03 - 4.90 (m, 1H ), 4.33 (t, J = 6.4 Hz, 2H), 2.71 (t, J = 6.4 Hz, 2H), 2.23 (br s, 2H), 2.20 (s, 6H), 2.16 (br d, J = 6.8 Hz , 2H), 1.83 (br d, J = 12.0 Hz, 2H), 1.78 - 1.67 (m, 1H), 1.59 - 1.43 (m, 2H), 1.25 - 1.09 (m, 2H). 26 LCMS: (ES+) m/z (M+H) ⁺ = 612.6, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.57 (s, 1H), 8.10 (d, J = 8.4 Hz, 2H), 7.90 (s, 1H), 7.87 - 7.81 (m, 4H), 7.78 - 7.74 (m, 2H), 5.01 - 4.92 (m, 1H), 4.17 (t, J = 6.0 Hz, 2H), 3.10 (t, J = 6.8 Hz, 4H), 2.80 (t, J = 5.6 Hz, 2H), 2.22 (m, 2H), 2.14 (d, J = 6.8 Hz, 2H), 1.96 - 1.89 (m, 2H), 1.83 ( d, J = 11.9 Hz, 2H), 1.77 - 1.68 (m, 1H), 1.55 - 1.46 (m, 2H), 1.20 - 1.11 (m, 2H). 28 LCMS: (ES+) m/z (M+H)+ = 580.2, 1H NMR (400 MHz, DMSO-d6) δ = 7.83 (s, 1H), 7.79 - 7.67 (m, 6H), 7.45 (d, J = 8.0 Hz, 2H), 5.25 (br s, 1H), 4.56 (s, 2H), 3.64 - 3.54 (m, 5H), 3.53 - 3.48 (m, 2H), 3.47 - 3.43 (m, 2H), 2.34 - 2.31 (m, 1H), 2.14 (br d, J = 6.8 Hz, 2H), 2.08 - 1.95 (m, 2H), 1.84 (dt, J = 4.0, 6.8 Hz, 1H), 1.71 (br t, J = 12.8 Hz, 2H), 1.65 - 1.55 (m, 2H), 1.42 - 1.27 (m, 2H) 31 LCMS: (ES ⁺ ) m/z (M+H) ⁺ = 601.3. ¹ H NMR (400 MHz, methanol-d4) δ = 8.57 - 8.40 (m, 1H), 8.13 (d, J = 8.4 Hz, 2H), 7.80 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H), 7.59 - 7.29 (m, 2H), 6.86 (d, J = 10.8 Hz, 1H), 4.85 - 4.60 (m, 1H), 4.41 (t, J = 6.4 Hz, 2H), 2.90 (t, J = 6.4 Hz, 2H), 2.33 (s, 6H), 2.28 - 2.19 (m, 2H), 2.11 (d, J = 7.2 Hz, 2H), 1.97 - 1.88 (m, 2H), 1.86 - 1.74 (m, 1H), 1.58 - 1.41 (m, 2H), 1.37 - 1.26 (m, 3H). 32 LCMS: (ES+) m/z (M+H)+ = 612.3. ¹ H NMR (400 MHz, MeOD-d4) δ = 8.65 (s, 1H), 8.16 (d, J = 8.4 Hz, 2H), 7.82 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H), 7.57 (br d, J = 8.4 Hz, 2H), 6.86 (d, J = 10.8 Hz, 1H), 5.17 ( d, J = 8.8 Hz, 2H), 4.83 - 4.70 (m, 1H), 2.32 - 2.19 (m, 2H), 2.11 (d, J = 7.2 Hz, 2H), 1.91 (br d, J = 13.2 Hz, 2H), 1.87 - 1.75 (m, 1H), 1.57 - 1.42 (m, 2H), 1.29 (br d, J = 3.2 Hz, 1H), 1.24 (br s, 1H). 33 LCMS: (ES+) m/z (M+H) ⁺ = 606.5. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.15 (s, 1H), 7.76 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.0 Hz, 2H), 7.52 (d, J = 7.6 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 7.09 (d, J = 6.4 Hz, 1H), 5.04 - 4.82 (m, 1H), 4.20 - 4.00 (m, 1H), 3.66 (s, 2H), 3.61 - 3.49 (m, 2H), 3.47 - 3.39 (m, 4H), 3.24 (s, 3H), 2.92 ( t, J = 6.4 Hz, 2H), 2.21 (d, J = 9.6 Hz, 2H), 2.16 (d, J = 6.8 Hz, 2H), 1.82 (d, J = 12.0 Hz, 2H), 1.76 - 1.65 ( m, 1H), 1.49 (d, J = 12.0 Hz, 2H), 1.28 - 1.10 (m, 2H) 34 LCMS: (ES+) m/z (M+H) ⁺ = 581.3. ¹ H NMR (400 MHz, methanol-d ₄ ) δ = 7.71 (d, J = 8.0, 12.2 Hz, 4H), 7.53 (d, J = 7.6 Hz, 2H), 7.47 (d, J = 7.6 Hz, 2H ), 7.14 - 6.89 (m, 1H), 5.02 - 4.91 (m, 1H), 4.63 (s, 2H), 3.70 (s, 4H), 3.68 (d, J = 5.2 Hz, 2H), 3.63 - 3.55 ( m, 2H), 2.30 (d, J = 11.2 Hz, 2H), 2.24 (d, J = 6.8 Hz, 2H), 1.94 (d, J = 13.2 Hz, 2H), 1.89 - 1.78 (m, 1H), 1.68 - 1.45 (m, 2H), 1.39 - 1.23 (m, 2H). 37 LCMS: (ES ⁺ ) m/z (M+H) ⁺ = 599. ¹ H NMR (400 MHz, methanol-d4) δ = 8.55 (s, 1H), 8.19 (d, J = 8.4 Hz, 2H), 7.83 (dd, J = 8.4, 11.9 Hz, 4H), 7.58 (d, J = 8.0 Hz, 2H), 7.17 - 6.93 (m, 1H), 5.03 - 4.93 (m, 1H), 4.45 (t, J = 5.6 Hz, 2H), 3.73 (br t, J = 7.2 Hz, 4H) , 3.39 (br t, J = 6.0 Hz, 2H), 2.49 - 2.25 (m, 5H), 2.19 - 2.07 (m, 2H), 1.81 - 1.52 (m, 4H) 42 LCMS: (ES ⁺ ) m/z (M+H) ⁺ =598.2. ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.51 (s, 1H), 8.49 (s, 3H), 8.15 (d, J = 8.4 Hz, 2H), 7.85 - 7.78 (m, 3H), 7.78 - 7.72 (m, 4H), 5.14 - 4.98 (m, 1H), 4.40 (br t, J = 5.6 Hz, 3H), 3.62 (br t, J = 7.6 Hz, 4H), 3.31 (br d, J = 1.6 Hz, 20H), 3.25 - 3.02 (m, 2H), 2.38 - 2.28 (m, 3H), 2.28 - 2.20 (m, 2H), 2.17 - 2.03 (m, 2H), 1.75 - 1.54 (m, 4H) 43 LCMS: (ES ⁺ ) m/z (M+H) ⁺ = 587.3. ¹ HNMR (400 MHz, methanol-d4) δ = 8.52 (s, 1H), 8.13 (d, J = 8.4 Hz, 2H), 7.80 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 8.4 Hz, 2H), 7.56 (br d, J = 8.0 Hz, 2H), 6.86 (d, J = 10.8 Hz, 1H), 4.86 - 4.76 (m, 1H), 4.41 (t, J = 6.4 Hz, 2H) , 2.90 (t, J = 6.4 Hz, 2H), 2.33 (s, 6H), 2.31 (br d, J = 4.0 Hz, 1H), 2.29 - 2.24 (m, 1H), 2.21 - 2.11 (m, 1H) , 2.09 - 1.98 (m, 2H), 1.83 - 1.57 (m, 2H), 1.56 - 1.41 (m, 2H). 44 LCMS: (ES+) m/z (M+H)+ =598.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.36 (s, 1H), 12.16 (s, 1H), 8.78 (s, 1H ), 8.13 (d, J = 8.4 Hz, 2H), 7.98 - 7.74 (m, 4H), 7.56 (d, J = 7.6 Hz, 2H), 7.10 (d, J = 9.6 Hz, 1H), 5.39 (q , J = 9.2 Hz, 2H), 4.97 (s, 1H), 2.38 - 2.27 (m, 1H), 2.23 (s, 2H), 2.00 (d, J = 4.4 Hz, 2H), 1.65 - 1.42 (m, 4H). 45 LCMS: (ES+) m/z (M+H) ⁺ = 592.5. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.19 (s, 1H), 7.76 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 8.0 Hz, 2H), 7.52 (br d, J = 8.0 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 7.26 - 7.00 (m, 1H), 5.04 - 4.86 ( m, 1H), 4.09 (t, J = 6.0 Hz, 1H), 3.63 (s, 2H), 3.52 (br dd, J = 6.0, 7.6 Hz, 3H), 3.42 (br d, J = 2.4 Hz, 4H ), 3.24 (s, 3H), 2.88 (br t, J = 6.8 Hz, 2H), 2.30 (br s, 1H), 2.23 (br s, 2H), 2.05 - 1.93 (m, 2H), 1.53 (br t, J = 9.8 Hz, 4H). 46 LCMS (ES+) m/z (M+H) ⁺ = 567.3. ¹ H NMR (400 MHz, DMSO-d6) δ = 7.82 - 7.76 (m, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 7.15 - 7.05 (m, 1H), 5.14 (s, 1H), 4.56 (s, 1H), 3.61 (s , 4H), 3.55 - 3.49 (m, 1H), 3.49 - 3.40 (m, 2H), 2.55 - 2.53 (m, 2H), 2.30 - 2.20 (m, 1H), 2.04 - 1.90 (m, 2H), 1.89 - 1.85 (m, 4H), 1.72 - 1.61 (m, 2H). 48 LCMS: (ES+) m/z (M+H) ⁺ = 645.4. ¹ H NMR (400 MHz, methanol-d4) δ = 7.79 (s, 1H), 7.78 - 7.71 (m, 5H), 7.71 (s, 1H), 7.46 (s, 1H), 7.44 (s, 1H), 5.06 - 4.99 (m, 1H), 4.30 (br t, J = 6.0 Hz, 1H), 4.19 - 4.09 (m, 2H), 3.94 (s, 2H), 3.89 - 3.81 (m, 2H), 3.72 - 3.65 (m, 2H), 3.42 (br d, J = 4.0 Hz, 2H), 2.43 - 2.25 (m, 3H), 2.18 - 2.04 (m, 2H), 1.74 - 1.56 (m, 4H). 49 LCMS: tR = (ES+) m/z (M+H) ⁺ = 615.1, ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 7.79-8.21 (m, 1H), 7.65-7.79 (m, 7H), 7.39 (d, J =8.0 Hz, 2H), 4.93-4.99 (m, 2H), 3.68 (s, 2H), 3.61-3.65 (m, 2H), 3.16-3.19 (m, 2H), 2.20-2.25 ( m, 2H), 2.14-2.18 (d, J = 6.8 Hz, 2H), 1.80-1.86 (m, 2H), 1.69-1.76 (m, 1H), 1.47-1.56 (m, 2H), 1.12-1.22 ( m, 2H). 53 LCMS: (ES+) m/z (M+H)+ = 653.3. ¹ H NMR (400 MHz, MeOD-d4) δ = 7.83 - 7.66 (m, 4H), 7.54 (t, J = 8.4 Hz, 4H) , 7.17 - 6.88 (m, 1H), 5.01 - 4.93 (m, 1H), 3.99 (s, 2H), 3.38 - 3.32 (m, 2H), 3.05 (s, 3H), 3.01 - 2.83 (m, 6H) , 2.81 - 2.52 (m, 4H), 2.45 - 2.36 (m, 1H), 2.36 - 2.27 (m, 2H), 2.12 (br d, J = 11.6 Hz, 2H), 1.81 - 1.52 (m, 4H). 54 LCMS: (ES+) m/z (M+H) ⁺ = 652.4, ¹ H NMR (400 MHz, methanol-d ₄ ) δ = 8.05 (s, 1H), 8.02 - 7.94 (m, 6H), 7.72 (d , J = 8.4 Hz, 2H), 5.35 - 5.27 (m, 1H), 3.94 (s, 2H), 3.76 - 3.63 (m, 2H), 3.31 (s, 3H), 3.12 (t, J = 6.4 Hz, 2H), 3.00 - 2.80 (m, 8H), 2.64 - 2.56 (m, 3H), 2.42 - 2.35 (m, 2H), 1.98 - 1.87 (m, 4H). 55 LCMS: (ES+) m/z (M+H)+ = 592.4. ¹ H NMR (400 MHz, MeOD-d4) δ = 7.81 (d, J = 8.4 Hz, 2H), 7.75 (d, J = 8.4 Hz , 2H), 7.56 (d, J = 8.0 Hz, 4H), 7.07 - 6.97 (m, 1H), 4.93 (br s, 1H), 4.51 - 4.42 (m, 1H), 4.42 - 4.37 (m, 2H) , 4.36 - 4.26 (m, 2H), 4.01 (dd, J = 4.4, 11.2 Hz, 2H), 3.76 - 3.66 (m, 2H), 3.63 - 3.52 (m, 2H), 2.29 (br dd, J = 2.4 , 11.8 Hz, 2H), 2.24 (d, J = 7.2 Hz, 2H), 2.08 - 1.90 (m, 2H), 1.89 - 1.78 (m, 1H), 1.73 - 1.48 (m, 2H), 1.38 - 1.20 ( m, 2H). 58 LCMS: (ES ⁺ ) m/z (M+H) ⁺ =549.3. ¹ H NMR (DMSO- d ₆ , 400 MHz) δ = 7.79 (s, 1H), 7.77 (s, 1H), 7.73 (s, 1H), 7.71 (s, 1H), 7.54 (s, 1H), 7.52 (s, 1H), 7.44 (s, 1H), 7.42 (s, 1H), 7.15 - 7.12 (m, 1H), 4.96 - 4.94 (m, 1H), 4.41 (s, 2H), 4.32 - 4.29 (m, 1H), 4.21 - 4.17 (m, 1H), 2.27 - 2.19 (m, 5H), 2.07 - 2.05 (m, 2H), 2.04 - 1.95 (m, 2H), 1.81 - 1.79 (m, 1H), 1.58 - 1.48 (m, 4H). 60 LCMS: (ES+) m/z (M+H) ⁺ = 579.3. ¹ H NMR (400 MHz, CD3OD, 0 K) δ (ppm) = 7.75 - 7.67 (m, 4H), 7.53 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 7.11 - 6.95 (m, 1H), 4.63 (s, 2H), 3.72 - 3.66 (m, 6H), 3.61 - 3.56 (m, 2H) , 2.46 - 2.06 (m, 5H), 1.98 - 1.90 (m, 1H), 1.81 - 1.67 (m, 3H), 1.60 - 1.43 (m, 2H), 1.40 - 1.13 (m, 1H). A-3 LCMS: (ES+) m/z (M+H)+ = 462.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 13.08 - 12.33 (m, 1H), 12.32 - 11.69 (m, 1H), 7.91 (br s, 1H), 7.83 - 7.63 (m, 6H), 7.59 - 7.45 (m, 2H), 7.44 - 7.34 (m, 1H), 5.03 - 4.88 (m, 1H), 2.22 (br d, J = 10.4 Hz, 2H), 2.16 (br d, J = 6.8 Hz, 2H), 1.83 (br d, J = 12.8 Hz, 2H), 1.73 (br d, J = 2.4 Hz, 1H), 1.58 - 1.42 (m , 2H), 1.24 - 1.09 (m, 2H). A-4 LCMS: (ES ⁺ ) m/z (M+H) ⁺ = 463.3. ¹ H NMR (400 MHz, methanol-d ₄ ) δ = 7.83 - 7.73 (m, 2H), 7.73 - 7.65 (m, 2H), 7.56 (br d, J = 8.4 Hz, 2H), 7.51 - 7.43 (m , 2H), 7.42 - 7.33 (m, 1H), 7.24 (dd, J = 1.2, 9.0 Hz, 1H), 4.97 - 4.93 (m, 1H), 2.34 (br d, J = 8.4 Hz, 2H), 2.27 (d, J = 7.2 Hz, 2H), 2.07 - 1.96 (m, 2H), 1.88 (dt, J = 4.0, 7.3 Hz, 1H), 1.80 - 1.64 (m, 2H), 1.35 - 1.27 (m, 2H ), -0.24 - -0.33 (m, 1H). II. Biological Assessment Example A-1 : In vitro pAMPK1 kinase activation assay

The effect of compounds on AMPK enzyme activation was determined using a 12-point concentration curve in a cell-free format. The phosphorylation of the SAMS peptide substrate was measured using the ADP-Glo detection system. Recombinant AMPK α1/β1/γ1 complexes were preactivated by phosphorylation with CAMKK2, followed by incubation with the compounds for 15 minutes, followed by incubation with the SAMS phosphorylation reaction. Activity curves and _EC50 values were fitted by interpolation to the ATP:ADP standard curve using Prism software as instructed by the ADP-Glo manufacturer.

Results for exemplary compounds are shown in Table A. Table A. compound EC ₅₀ (nM) 1 0.70 2 12.1 3 0.91 4 1.3 5 7.3 6 0.20 11 11.4 12 0.83 13 8.0 14 14.5 15 12.6 16 74.6 17 ＞10,000 18 4.6 19 20.3 20 2.9 twenty four 0.80 26 2.46 28 200 29 1.39 30 1.54 31 1.51 32 9.06 33 1.76 34 1.58 37 1.59 42 1.20 43 2.16 46 200 48 200 49 16.6 52 1.44 53 1.34 54 3.41 55 2.02 56 2.31 57 1.91 58 4.99 59 5.44 60 10.6 A-1 Example 29 in WO/2012/116145 30.1 A-2 Example 15 in WO/2011/106273 200 A-4 200 MK-8722 4.7

Claims (52)

A compound or pharmaceutically acceptable salt of formula (I): , ^where : X is -O-, -CH ₂ - or ^{-CHR 4} - ^; or X is -CH-, and L ¹ is connected to Each R ³ at each occurrence is independently selected from halogen, hydroxyl, C _{1 - 4} alkyl, -CN and C _{1 - 4} haloalkyl; each R ⁴ at each occurrence is independently selected from halogen, hydroxyl, C _{1 - 4} alkyl, -CN and C _{1 - 4} haloalkyl; or two R ⁴ together form a bond or C _{1 - 2} alkyl group; n is selected from 0, 1, 2, 3 and 4; o system is selected from 0, 1, 2, 3 and 4; p system is selected from 0, 1 and 2; q system is selected from 0, 1, 2, 3 and 4; R ⁵ system is selected from hydrogen and C _1-4 alkane base; R ⁶ is selected from hydrogen, halogen, C _1-4 alkyl and C _1-4 haloalkyl; L ¹ is a bond or -CH ₂ -; D is selected from -CO ₂ R ¹¹ , -P ( O)(OR ¹¹ ) ₂ , -P(O)R ¹¹ (OR ¹¹ ), -S(O) ₂ OH and -L ² -K; L ² is selected from ^λ -(C(R ¹³ ) ₂ ) _r -, ^λ -O(C(R ¹³ ) ₂ ) _r -, ^λ -(C(R ¹³ ) ₂ ) _r O-, ^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 )- and 4 to 6 membered heterocycles, where ^λ represents the connection with 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 independently selected from one to six as appropriate: Substituent substitution: 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 carbocyclic rings and 3 to 10-membered _heterocyclic rings, wherein each C _{3-10 carbocyclic} ring and 3 to 10-membered heterocyclic rings are optionally substituted with one to six substituents independently selected from the following: halogen , C _{1 - 6} alkyl, -OR ¹⁴ , =O and -S(O) ₂ OH; and (ii) C _{3 - 10} carbocyclic rings and 3 to 10 membered heterocyclic rings, each of which has one to six independent rings as appropriate. Substituted with substituents selected from the following: 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 independently selected from one to six as appropriate. Substituted from the following substituents: 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; R ¹¹ is independently selected at each occurrence from hydrogen, C _{1 - 4} alkyl and C _{1 - 4} haloalkyl; R ¹² at each occurrence is independently selected from hydrogen and optionally C _{1 - 4} substituted by halogen, -OH, -NH ₂ and -C(O)NH ₂ Alkyl; R ¹³ is independently selected at each occurrence from hydrogen, C _{1 - 4} alkyl, C _{1 - 4} haloalkyl and C _{1 - 4} hydroxyalkyl; each R ¹⁴ is independently selected at each occurrence. From: hydrogen; optionally C _{1 - 10} alkyl and C _{1 - 10} heteroalkyl substituted by 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} carbocyclic rings and 3 to 10 membered heterocyclic rings, wherein each C _{3 - 10} carbocyclic ring and 3 to 10 membered heterocyclic rings are independently selected from the following by one to six as appropriate. Substituent substitution: 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 R ²¹ , -S(O) ₂ N(R ²¹ ) ₂ , =O and -CN; each R ¹⁵ is independently Selected from C _{1 - 4} alkyl; each R ¹⁶ is independently selected from hydrogen and C _{1 - 6} alkyl at each occurrence; each R ²¹ is independently selected from hydrogen and C _{1 - 6} alkyl at each occurrence , C _{1 - 6} haloalkyl, C _{1 - 6} hydroxyalkyl and C _{3 - 6} carbocyclic ring, wherein the C _{3 - 6} carbocyclic ring is optionally substituted by one to six substituents independently selected from the following: -OH, C _{1 - 6} alkyl, C _{1 - 6} haloalkyl, C _{1 - 6} hydroxyalkyl and =O. Such as the compound or salt of claim 1, wherein X is O and L ¹ is a bond. Such as the compound or salt of claim 2, wherein the compound is represented by formula (II): , or its pharmaceutically acceptable salt. Such as the compound or salt of claim 3, wherein the compound is represented by formula (IIa) or (IIb): , or its pharmaceutically acceptable salt. The compound or salt of claim 1, wherein X is -CH-, and L ¹ is connected to X. Such as the compound or salt of claim 2, wherein the compound is represented by formula (III): , or its pharmaceutically acceptable salt. Such as the compound or salt of claim 6, wherein the compound is represented by formula (IIIa), formula (IIIb) or formula (IIIc): , or its pharmaceutically acceptable salt. The compound or salt of any one of claims 1 to 7, wherein n is 0. Such as the compound or salt of any one of claims 1 to 8, wherein o is 0. The compound or salt of any one of claims 1 to 9, wherein R ³ is halogen, and p is selected from 0 and 1. The compound or salt of claim 10, wherein R ³ is selected from fluorine and chlorine, and p is 1. The compound or salt of any one of claims 1 to 11, wherein q is 0. The compound or salt of any one of claims 1 to 12, wherein ^R5 is selected from hydrogen. The compound or salt of any one of claims 1 to 12, wherein R ⁵ is selected from C _{1 - 4} alkyl. The compound or salt of any one of claims 1 to 14, wherein Y is -CR ⁶ -, and R ⁶ is selected from hydrogen and halogen. The compound or salt of claim 15, wherein R ⁶ is selected from hydrogen and fluorine. The compound or salt of any one of claims 1 to 14, wherein Y is -N-. The compound or salt of any one of claims 1 to 17, wherein D is -L ² -K. The compound or salt of claim 18, wherein L ² 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 -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. The compound or salt of claim 19, wherein L ² 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 - and triazolyl. The compound or salt of any one of claims 1 to 20, wherein r is 1. The compound or salt of any one of claims 1 to 21, wherein s is 1. The compound or salt of any one of claims 19 to 22, wherein K is selected from (i) and (ii): (i) C _{1 - 10} alkyl or C _{1 - 10} heteroalkyl, each as appropriate Substituted with one to six substituents independently selected from: halogen, -OR ¹⁴ , -N(R ¹⁴ ) ₂ , -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 , =O, -P(O)(OR ¹⁶ ) ₂ , -P(O)R ¹⁶ ( OR ¹⁶ ), -S(O) ₂ OH; and 3 to 10 membered heterocycles, each of which is optionally substituted with one to six substituents independently selected from the following: halogen, C _{1 - 6} alkyl, -OR ¹⁴ , =O and -S(O) ₂ OH; (ii) C _{3 - 10} carbocyclic rings and 3 to 10 membered heterocyclic rings, each of which is optionally substituted with one to six substituents independently selected from the following: 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)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 has one to six independent Substituted with a substituent selected from the following: halogen, -OR ¹⁴ , -N(R ¹⁴ ) ₂ , -C(O)OR ¹⁴ , -P(O)(OR ¹⁶ ) ₂ , -S(O) ₂ OH, S(O) ₂ R ¹⁴ and =O. Such as the compound or salt of claim 23, wherein K is selected from C _{1 - 10} alkyl or C _{1 - 10} heteroalkyl, each of which is optionally substituted by one to six substituents independently selected from the following: halogen, - OR ¹⁴ , N(R ¹⁴ ) ₂ and azetidine, optionally substituted with one to six substituents independently selected from: -OR ¹⁴ , S(O) ₂ R ¹⁴ and =O. Such as the compound or salt of claim 23, wherein K is selected from C _{3 - 10} carbocyclic rings and 3 to 10 membered heterocyclic rings, each of which is optionally substituted with one to six substituents independently selected from the following: halogen, -OR ¹⁴ , -N(R ¹⁴ ) ₂ , =O and C _{1 - 10} alkyl, wherein each C _{1 - 10} alkyl is optionally substituted by one to six substituents independently selected from the following: halogen, -OR ¹⁴ , -N(R ¹⁴ ) ₂ , -C(O)OR ¹⁴ , -P(O)(OR ¹⁶ ) ₂ , -S(O) ₂ OH and S(O) ₂ R ¹⁴ . The compound or salt of claim 25, wherein K is selected from azetidines optionally substituted by one to six substituents independently selected from C _{1 - 10} alkyl, wherein each C _{1 - 10} alkyl group is optionally substituted. Cases are substituted with one to six substituents independently selected from: -OR ¹⁴ and S(O) ₂ R ¹⁴ . The compound or salt of any one of claims 1 to 26, wherein each R ¹⁴ at each occurrence is independently selected from hydrogen and optionally C _{1 - 10} substituted with one to six substituents independently selected from the following Alkyl group: halogen, -OR ²¹ , -N(R ²¹ ) ₂ , -P(O)(OR ¹⁶ ) ₂ , -S(O) ₂ OH and =O. The compound or salt of any one of claims 1 to 27, wherein each R ¹⁴ at each occurrence is independently selected from hydrogen and optionally C ₁ substituted by one to six substituents independently selected from -OR ²¹ _{- 10} alkyl. The compound or salt of any one of claims 1 to 28, wherein each R ²¹ at each occurrence is independently selected from hydrogen, C _{1 - 6} alkyl, C _{1 - 6} haloalkyl and C _{1 - 6} hydroxyl alkyl. The compound or salt of any one of claims 1 to 29, wherein _each R ²¹ at each occurrence is independently selected from hydrogen and C _{1 -6} alkyl. The compound or salt of any one of claims 1 to 17, wherein D is selected from: . Such as the compound or salt of claim 1, wherein the compound is represented by a structure selected from the group consisting of: , or its pharmaceutically acceptable salt. A pharmaceutical composition comprising a compound according to any one of claims 1 to 32 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. A method of treating adenosine 5'-monophosphate-activated protein kinase (AMPK)-related conditions or disorders in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of any one of claims 1 to 33 The compound of the item or its pharmaceutically acceptable salt. The method of claim 34, wherein the condition or disorder is related to the gut-brain axis. The method of claim 34 or claim 35, wherein the condition or disorder is a nutritional disorder. Such as claim 36, wherein the condition or disorder is short bowel syndrome, intestinal failure or intestinal insufficiency. The method of claim 34 or claim 35, wherein the condition or disorder is associated with systemic infection and inflammation caused by intestinal barrier leakage. The method of claim 34 or claim 35, wherein the condition or disorder is metabolic syndrome, obesity, type 2 diabetes, coronary artery disease, fatty liver, non-alcoholic steatotic hepatitis (NASH), cirrhosis, hepatic Encephalopathy, scleroderma, inflammatory bowel disease, Crohn's disease, ulcerative colitis, colitis caused by checkpoint inhibitors, psoriasis, celiac disease, necrotizing enterocolitis, Gastrointestinal injury caused by toxic insult, environmental intestinal dysfunction, allergy, food allergy, celiac sprue, childhood allergy, graft-versus-host disease, irritable bowel syndrome, spontaneous bacterial peritonitis, ischemic Colitis, sclerosing cholangitis, Alzheimer's disease, Parkinson's disease, cancer, colorectal cancer, depression, autism, or combinations thereof. A method for treating gastrointestinal damage caused by toxic damage, the method comprising administering to an individual a therapeutically effective amount of a compound of any one of claims 1 to 33 or a pharmaceutically acceptable salt or solvate thereof substances, stereoisomers or prodrugs. The method of claim 40, wherein the toxic damage is caused by radiation, chemotherapy, or a combination thereof. The method of claim 40 or claim 41, wherein the toxic damage is induced by chemotherapy. The use of a compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, as a pharmaceutical. Use of a compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, for the treatment of adenosine in an individual in need thereof 5'-monophosphate-activated protein kinase (AMPK) related conditions or disorders. The use of claim 44, wherein the condition or disorder is related to the gut-brain axis. Such use as claim 44 or claim 45, wherein the condition or disease is a nutritional disorder. For example, the use of claim 46, wherein the condition or disorder is short bowel syndrome, intestinal failure or intestinal insufficiency. The use of claim 44 or claim 45, wherein the condition or disorder is associated with systemic infection and inflammation caused by intestinal barrier leakage. For example, the use of claim 44 or claim 45, wherein the condition or disorder is metabolic syndrome, obesity, type 2 diabetes, coronary artery disease, fatty liver, non-alcoholic steatotic hepatitis (NASH), cirrhosis, hepatic Encephalopathy, scleroderma, inflammatory bowel disease, Crohn's disease, ulcerative colitis, colitis caused by checkpoint inhibitors, psoriasis, celiac disease, necrotizing enterocolitis, gastrointestinal damage caused by toxic insults , environmental intestinal dysfunction, allergies, food allergies, steatorrhea, childhood allergies, graft-versus-host disease, irritable bowel syndrome, spontaneous bacterial peritonitis, ischemic colitis, sclerosing cholangitis, Alzheimer's disease disease, Parkinson's disease, cancer, colorectal cancer, depression, autism, or a combination thereof. Use of a compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, for the preparation of a treatment for an individual in need Agents for gastrointestinal damage caused by toxic damage. The use of claim 50, wherein the toxic damage is caused by radiation, chemotherapy or a combination thereof. The use of claim 50 or claim 51, wherein the toxic damage is induced by chemotherapy.