WO2023097189A1 - Activateurs de l'ampk - Google Patents

Activateurs de l'ampk Download PDF

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Publication number
WO2023097189A1
WO2023097189A1 PCT/US2022/080264 US2022080264W WO2023097189A1 WO 2023097189 A1 WO2023097189 A1 WO 2023097189A1 US 2022080264 W US2022080264 W US 2022080264W WO 2023097189 A1 WO2023097189 A1 WO 2023097189A1
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compound
alkyl
independently selected
salt
optionally substituted
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PCT/US2022/080264
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English (en)
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Iyassu Sebhat
Shuwen He
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Kallyope, Inc.
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Publication of WO2023097189A1 publication Critical patent/WO2023097189A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/26—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • Adenosine 5 '-monophosphate-activated protein kinase is a serine/threonine kinase and is evolutionarily conserved from yeast to mammals. AMPK acts as an energy sensor and is activated by upstream enzymes when the cellular ratio of adenosine 5 '-monophosphate (AMP) to adenosine triphosphate (ATP) is elevated due to nutrient deprivation. Activated AMPK phosphorylates downstream substrates to promote catabolism and impede anabolism, leading to ATP production and energy restoration.
  • AMP adenosine 5 '-monophosphate-activated protein kinase
  • ATP adenosine triphosphate
  • AMPK activity can be altered due to numerous physiological factors, such as hormones, cytokines and dietary nutrients, as well as pathological conditions such as obesity, chronic inflammation and type 2 diabetes. AMPK activation can lead to lower hepatic glucose production and plasma glucose levels. Thus, AMPK is an attractive target to treat various metabolic diseases.
  • AMPK has beneficial effects for gut health, such as enhancing intestinal absorption, improving barrier function, suppressing colorectal carcinogenesis, and reducing intestinal inflammation and metabolic-related disease, and is important for the maintenance of intestinal homeostasis.
  • AMPK activation enhances paracellular junctions, nutrient transporters, autophagy and apoptosis, and suppresses inflammation and carcinogenesis in the intestine.
  • AMPK is associated with the maintenance of tight junctions in colonic epithelium and controls the progression of colitis.
  • adenosine 5 '-monophosphate-activated protein kinase (5' AMP-activated protein kinase, AMPK) activators useful for the treatment of conditions or disorders associated with AMPK.
  • the condition or disorder is associated with the gut-brain axis.
  • the condition or disorder is associated with systemic infection and inflammation from having a leaky gut barrier.
  • the AMPK activators are gut-restricted or selectively modulate AMPK located in the gut.
  • the condition is selected from the group consisting of: central nervous system (CNS) disorders including mood disorders, anxiety, depression, affective disorders, schizophrenia, malaise, cognition disorders, addiction, autism, epilepsy, neurodegenerative disorders, Alzheimer’s disease, and Parkinson’s disease, Lewy Body dementia, episodic cluster headache, migraine, pain; metabolic conditions including diabetes and its complications such as chronic kidney disease/diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, cardiovascular disease, metabolic syndrome, obesity, dyslipidemia, and nonalcoholic steatohepatitis (NASH); eating and nutritional disorders including hyperphagia, cachexia, anorexia nervosa, short bowel syndrome, intestinal failure, intestinal insufficiency and other eating disorders; inflammatory disorders and autoimmune diseases such as inflammatory bowel disease, ulcerative colitis, Crohn’s disease, checkpoint inhibitor-induced colitis, psoriasis and celiac disease; necrotizing enterocolitis; gastrointestinal injury resulting from toxic insults such
  • CNS
  • X is -O-, -CH2-, or -CHR 4 -; or X is -CH-, and L 1 is atached to X;
  • Y is -N- or -CR 6 -;
  • R 1 , R 2 , and R 3 are each independently selected at each occurrence from halogen, hydroxyl, C 1-4 alkyl, -CN, and C 1 -4 haloalky 1; each R 4 is independently selected at each occurrence from halogen, hydroxyl, C 1-4 alkyl, - CN, and C 1-4 haloalkyl; or two R 4 are taken together to form a bond or a C1-2 alkylene; n is selected from 0, 1, 2, 3, and 4; o is selected from 0, 1, 2, 3, and 4; p is selected from 0, 1, and 2; q is selected from 0, 1, 2, 3, and 4;
  • R 5 is selected from hydrogen and C 1-4 alkyl
  • R 6 is selected from hydrogen, halogen, C alkyl, and C 1-4 haloalkyl
  • L 1 is a bond or -CH2-
  • D is selected from -CO2R 11 , -P(O)(OR n ) 2 , -P(O)R 11 (OR 11 ), -S(O) 2 OH, and -L 2 -K;
  • L 2 is selected from -(C(R 13 ) 2 )r-, -O(C(R 13 ) 2 )r-, -(C(R 13 ) 2 )rO-, ⁇ -N(R 12 )(C(R 13 ) 2 ) S -, '- C(O)O-, ⁇ -OC(O)-, ⁇ -C(O)N(R 12 )-, ⁇ -N(R 12 )C(O)-, ⁇ -N(R 12 )S(O) 2 -, ⁇ -S(O) 2 N(R 12 )-, and 4- to 6-membered heterocycle, wherein 1 denotes the connection to K; r is selected from 1, 2, and 3; s is selected from 0, 1, 2, and 3;
  • K is selected from (i) and (ii): (i) Ci-io alkyl or Ci-io heteroalkyl, each of which is optionally substituted with one to six substituents independently selected from: halogen, -OR 14 , -SR 14 , -N(R 14 )2, - N + (R 15 ) 3 , -C(O)R 14 , -C(O)OR 14 , -OC(O)R 14 , -OC(O)N(R 14 ) 2 , -C(O)N(R 14 ) 2 , - N(R 14 )C(O)R 14 , -N(R 14 )C(O)OR 14 , -N(R 14 )C(O)N(R 14 ) 2 , -N(R 14 )S(O) 2 (R 14 ), - S(O)R 14 , -S(O) 2 R 14 , -S(O) 2 N(R 14 )
  • R 11 is independently selected at each occurrence from hydrogen, C 1-4 alkyl, and C 1-4 haloalkyl;
  • R 12 is independently selected at each occurrence from hydrogen and C 1-4 alkyl optionally substituted with halogen, -OH, -NH 2 and -C(0)NH 2 ;
  • R 13 is independently selected at each occurrence from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, and Ci -4 hydroxy alkyl; each R 14 is independently selected at each occurrence from: hydrogen;
  • the compound is represented by Formula (II): or a pharmaceutically acceptable salt thereof.
  • the compound is represented by Formula (Ila) or (lib) : or a pharmaceutically acceptable salt thereof.
  • the compound is represented by Formula (III): or a pharmaceutically acceptable salt thereof.
  • the compound is represented by Formula (Illa), Formula (Illb), or Formula (IIIc): or a pharmaceutically acceptable salt thereof.
  • compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, and at least one pharmaceutically acceptable excipient.
  • AMPK adenosine 5'- monophosphate-activated protein kinase
  • the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.
  • the condition or disorder involves the gut-brain axis.
  • the condition or disorder is a nutritional disorder.
  • the condition or disorder is short bowel syndrome, intestinal failure, or intestinal insufficiency.
  • the condition or disorder is associated with systemic infection and inflammation from having a leaky gut barrier.
  • the condition or disorder is metabolic syndrome, obesity, type 2 diabetes, coronary artery disease, fatty liver, nonalcoholic steatohepatitis (NASH), cirrhosis, hepatic encephalopathy, fibrotic disorders including scleroderma, inflammatory bowel disease including Crohn’s disease, ulcerative colitis, and checkpoint inhibitor-induced colitis, psoriasis, celiac disease, necrotizing enterocolitis, gastrointestinal injury resulting from toxic insults such as radiation or chemotherapy, environmental enteric dysfunction, allergy including food allergy, celiac sprue, and childhood allergy, graft vs.
  • metabolic syndrome obesity, type 2 diabetes, coronary artery disease, fatty liver, nonalcoholic steatohepatitis (NASH), cirrhosis, hepatic encephalopathy, fibrotic disorders including scleroderma, inflammatory bowel disease including Crohn’s disease, ulcerative colitis, and checkpoint inhibitor-induced colitis, psoriasis, cel
  • irritable bowel syndrome spontaneous bacterial peritonitis, ischemic colitis, sclerosing cholangitis, Alzheimer’s disease, Parkinson’s disease, cancer including colorectal cancer, depression, autism, or a combination thereof.
  • the toxic insult is from radiation, chemotherapy, or a combination thereof.
  • the toxic insult is radiation-induced.
  • the toxic insult is chemotherapy -induced.
  • a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof for the treatment of an adenosine 5 '-monophosphate-activated protein kinase (AMPK) associated condition or disorder in a subject in need thereof.
  • AMPK adenosine 5 '-monophosphate-activated protein kinase
  • the condition or disorder involves the gut-brain axis.
  • the condition or disorder is a nutritional disorder.
  • the condition or disorder is short bowel syndrome, intestinal failure, or intestinal insufficiency.
  • the condition or disorder is associated with systemic infection and inflammation from having a leaky gut barrier.
  • the condition or disorder is metabolic syndrome, obesity, type 2 diabetes, coronary artery disease, fatty liver, nonalcoholic steatohepatitis (NASH), cirrhosis, hepatic encephalopathy, fibrotic disorders including scleroderma, inflammatory bowel disease including Crohn’s disease, ulcerative colitis, and checkpoint inhibitor -induced colitis, psoriasis, celiac disease, necrotizing enterocolitis, gastrointestinal injury resulting from toxic insults such as radiation or chemotherapy, environmental enteric dysfunction, allergy including food allergy, celiac sprue, and childhood allergy, graft vs.
  • metabolic syndrome obesity, type 2 diabetes, coronary artery disease, fatty liver, nonalcoholic steatohepatitis (NASH), cirrhosis, hepatic encephalopathy, fibrotic disorders including scleroderma, inflammatory bowel disease including Crohn’s disease, ulcerative colitis, and checkpoint inhibitor -induced colitis, psoriasis
  • irritable bowel syndrome spontaneous bacterial peritonitis, ischemic colitis, sclerosing cholangitis, Alzheimer’s disease, Parkinson’s disease, cancer including colorectal cancer, depression, autism, or a combination thereof.
  • a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof for the treatment of gastrointestinal injury resulting from toxic insult in a subject in need thereof.
  • the toxic insult is from radiation, chemotherapy, or a combination thereof.
  • the toxic insult is radiation-induced.
  • the toxic insult is chemotherapy-induced.
  • a compound disclosed herein or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, for the preparation of a medicament for the treatment of the diseases disclosed herein.
  • AMPK activators useful for the treatment of conditions or disorders involving the gut-brain axis.
  • the AMPK activators are gut-restricted compounds.
  • the AMPK activators are agonists, super agonists, full agonists, or partial agonists.
  • Compounds disclosed herein directly activate AMPK in the intestine without systemic engagement.
  • the preferred compounds are more potent, efficacious at lower doses, and have decreased systemic exposure compared to other previously-known AMPK activators.
  • Ci-C x includes C1-C2, C1-C3 . . . Ci-C x .
  • a group designated as “C1-C4” indicates that there are one to four carbon atoms in the moiety, i.e., groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms.
  • C1-C4 alkyl indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, Ao-propyl, //-butyl, isobutyl, ec-butyl, and /-butyl.
  • Alkyl refers to an optionally substituted straight-chain, or optionally substituted branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, or more preferably, from one to six carbon atoms, wherein an sp 3 -hybridized carbon of the alkyl residue is attached to the rest of the molecule by a single bond.
  • Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-l -propyl, 2-methyl-2-propyl, 2-methyl- 1-butyl, 3 -methyl- 1 -butyl, 2-methyl-3 -butyl, 2,2-dimethyl-l-propyl, 2-methyl-l -pentyl, 3- methyl-1 -pentyl, 4-methyl-l -pentyl, 2-methyl-2 -pentyl, 3 -methyl-2 -pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l -butyl, 3,3-dimethyl-l-butyl, 2-ethyl-l -butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl
  • a numerical range such as “Ci-Ce alkyl” means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated.
  • the alkyl is a C1-C10 alkyl, a C1-C9 alkyl, a Ci-C 8 alkyl, a C1-C7 alkyl, a Ci-C 6 alkyl, a Ci-C 5 alkyl, a C1-C4 alkyl, a C1-C3 alkyl, a C1-C2 alkyl, or a Ci alkyl.
  • an alkyl group is optionally substituted as described below by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , - SR a , -OC(O)R a , -OC(O)-OR f , -N(R a ) 2 , -N + (R a ) 3 , -C(O)R a , -C(O)OR a , -C(O)N(R a ) 2 , - N(R a )C(O)OR f , -OC(O)-N(R a ) 2 , -N(R a )C(O)R a , -N(R a )S(O) t R f (where t is 1 or 2), -S
  • Alkenyl refers to an optionally substituted straight-chain, or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms, wherein an sp 2 -hybridized carbon or an sp 3 -hybridized carbon of the alkenyl residue is attached to the rest of the molecule by a single bond.
  • C 2 -C 6 alkenyl means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated.
  • the alkenyl is a C 2 -C 10 alkenyl, a C 2 -C 9 alkenyl, a C 2 -C 8 alkenyl, a C 2 -C 7 alkenyl, a C 2 -C 6 alkenyl, a C 2 -C 5 alkenyl, a C 2 -C 4 alkenyl, a C 2 -C 3 alkenyl, or a C2 alkenyl.
  • an alkenyl group is optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • an alkenyl group is optionally substituted as described below by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)-R f , -OC(O)-OR f , -N(R a ) 2 , -N + (R a ) 3 , -C(O)R a , -C(O)OR a , -C(O)N(R a ) 2 , - N(R a )C(O)OR f , -OC(O)-N(R a ) 2 , -N(R a )C(O)R f , -N(R a )S(O) t R f (where t is 1 or 2), -
  • Alkynyl refers to an optionally substituted straight-chain or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms, wherein an sp-hybridized carbon or an sp 3 -hybridized carbon of the alkynyl residue is attached to the rest of the molecule by a single bond. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like.
  • C 2 -C 6 alkynyl means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated.
  • the alkynyl is a C 2 -C 10 alkynyl, a C 2 -C 9 alkynyl, a C 2 -C 8 alkynyl, a C 2 -C 7 alkynyl, a C 2 -C 6 alkynyl, a C 2 -C 5 alkynyl, a C 2 -C 4 alkynyl, a C 2 -C 3 alkynyl, or a C 2 alkynyl.
  • an alkynyl group is optionally substituted as described below by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)R a , -OC(O)-OR f , - N(R a ) 2 , -N + (R a ) 3 , -C(O)R a , -C(O)OR a , -C(O)N(R a ) 2 , -N(R a )C(O)OR f , -OC(O)-N(R a ) 2 , - N(R a )C(O)R f , -N(R a )S(O)tR f (where t is 1 or 2), -S
  • Alkylene or “alkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, ⁇ -butylene, and the like.
  • the alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • the points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon in the alkylene chain or through any two carbons within the chain.
  • an alkylene group is optionally substituted as described below by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)R a , -OC(O)-OR f , -N(R a ) 2 , -N + (R a ) 3 , -C(O)R a , -C(O)OR a , -C(O)N(R a ) 2 , -N(R a )C(O)OR f , -OC(O)-N(R a ) 2 , -N(R a )C(O)R f , -N(R a )S(O) t R f (where t is 1 or 2), -S(
  • alkenylene or “alkenylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms.
  • the alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • an alkenylene group is optionally substituted as described below by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)-R f , -OC(O)-OR f , -N(R a ) 2 , -N + (R a ) 3 , -C(O)R a , -C(O)OR a , - C(O)N(R a ) 2 , -N(R a )C(O)OR f , -OC(O)-N(R a ) 2 , -N(R a )C(O)R f , -N(R a )S(O) t R f (where t is 1 or 2), -
  • Alkynylene or “alkynylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and having from two to twelve carbon atoms.
  • the alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • an alkynylene group is optionally substituted as described below by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, - OR a , -SR a , -OC(O)R a , -OC(O)-OR f , -N(R a ) 2 , -N + (R a ) 3 , -C(O)R a , -C(O)OR a , -C(O)N(R a ) 2 , - N(R a )C(O)OR f , -OC(O)-N(R a ) 2 , -N(R a )C(O)R f , -N(R a )S(O) t R f (where t is 1 or 2), -
  • Alkoxy or “alkoxyl” refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.
  • Aryl refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom.
  • the aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from 6 to 18 carbon atoms, where at least one of the rings in the ring system is fully unsaturated, /. ⁇ ., it contains a cyclic, delocalized (4n+2) ⁇ -electron system in accordance with the Hiickel theory.
  • the ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene.
  • the aryl is a Ce-Cio aryl. In some embodiments, the aryl is a phenyl.
  • the term “aryl” or the prefix “ar-“ is meant to include aryl radicals optionally substituted as described below by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroaryl alkyl, -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
  • arylene refers to a divalent radical derived from an “aryl” group as described above linking the rest of the molecule to a radical group.
  • the arylene is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • the arylene is a phenylene.
  • an arylene group is optionally substituted as described above for an aryl group.
  • Cycloalkyl refers to a stable, partially or fully saturated, monocyclic or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems.
  • Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C3-C15 cycloalkyl), from three to ten carbon atoms (C3-C10 cycloalkyl), from three to eight carbon atoms (C3-C8 cycloalkyl), from three to six carbon atoms (C3-C6 cycloalkyl), from three to five carbon atoms (C3-C5 cycloalkyl), or three to four carbon atoms (C3-C4 cycloalkyl).
  • the cycloalkyl is a 3 - to 6-membered cycloalkyl.
  • the cycloalkyl is a 5- to 6-membered cycloalkyl.
  • Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyls or carbocycles include, for example, adamantyl, norbomyl, decalinyl, bicyclofl.1.1 ]pentyl, bicyclo[3.3.0]octyl, bicyclo[4.3.0]nonyl, cis-decalyl, trans-decalyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.2]decyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, and the like.
  • cycloalkyl is meant to include cycloalkyl radicals optionally substituted as described below by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -R b -OR a , -R b -SR a , -R b -OC(O)-R a , -R b - OC(O)-OR f , -R b -OC(O)-N(R a ) 2 , -R b -N(R a ) 2 , -R b -N + (R a ) 3 , -R b -C(
  • a “cycloalkylene” refers to a divalent radical derived from a “cycloalkyl” group as described above linking the rest of the molecule to a radical group.
  • the cycloalkylene is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • a cycloalkylene group is optionally substituted as described above for a cycloalkyl group.
  • Halo or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
  • Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3 -bromo-2 -fluoropropyl, 1,2-dibromoethyl, and the like.
  • halo radicals e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3 -bromo-2 -fluoropropyl, 1,2-dibromoethyl, and the like.
  • Fluoroalkyl refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1 -fluoromethyl -2 -fhioroethyl, and the like.
  • Haloalkoxy or “haloalkoxyl” refers to an alkoxyl radical, as defined above, that is substituted by one or more halo radicals, as defined above.
  • Fluoroalkoxy or “fluoroalkoxyl” refers to an alkoxy radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethoxy, difluoromethoxy, fluoromethoxy, and the like.
  • Heteroalkyl refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N(alkyl)-), sulfur, or combinations thereof.
  • a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a Ci-Ce heteroalkyl.
  • a heteroalkyl is a polyethylene glycol (PEG).
  • PEG polyethylene glycol
  • a Ci-Cio heteroalkyl comprises from 1 to 5 PEG groups.
  • a Ci-Cio heteroalkyl comprises from 1 to 3 PEG groups.
  • “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyl radicals, as defined above, e.g., hydroxymethyl, 1 -hydroxy ethyl, 2- hydroxyethyl, 2-hydroxypropyl, 3 -hydroxypropyl, 1,2-dihydroxy ethyl, 2,3-dihydroxypropyl, 2,3,4,5,6-pentahydroxyhexyl, and the like.
  • Heterocycloalkyl refers to a stable 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.
  • the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized.
  • the heterocycloalkyl is a 3- to 8-membered heterocycloalkyl.
  • the heterocycloalkyl is a 3- to 6- membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl.
  • heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidin
  • heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. More preferably, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e., skeletal atoms of the heterocycloalkyl ring).
  • heterocycloalkyl is meant to include heterocycloalkyl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -R b - OR a , -R b -SR a , -R b -OC(O)-R a , -R b -OC(O)-OR f , -R b -OC(O)-N(R a ) 2 , -R b -N(R a ) 2 , -R b -N + (R a
  • A-heterocycloalkyl refers to a heterocycloalkyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocycloalkyl radical to the rest of the molecule is through a nitrogen atom in the heterocycloalkyl radical.
  • An A- heterocycloalkyl radical is optionally substituted as described above for heterocycloalkyl radicals.
  • C-heterocycloalkyl refers to a heterocycloalkyl radical as defined above and where the point of attachment of the heterocycloalkyl radical to the rest of the molecule is through a carbon atom in the heterocycloalkyl radical.
  • a C-heterocycloalkyl radical is optionally substituted as described above for heterocycloalkyl radicals.
  • a “heterocycloalkylene” refers to a divalent radical derived from a “heterocycloalkyl” group as described above linking the rest of the molecule to a radical group.
  • the heterocycloalkylene is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • a heterocycloalkylene group is optionally substituted as described above for a heterocycloalkyl group.
  • Heteroaryl refers to a radical derived from a 5- to 18-membered aromatic ring radical that comprises one to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur.
  • the heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, z.e., it contains a cyclic, delocalized (4n+2) ⁇ -electron system in accordance with the Hiickel theory.
  • the heteroaryl is a 5- to 10-membered heteroaryl.
  • the heteroaryl is a monocyclic heteroaryl, or a monocyclic 5- or 6- membered heteroaryl. In some embodiments, the heteroaryl is a 6,5-fused bicyclic heteroaryl.
  • the heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized.
  • the heteroaryl is attached to the rest of the molecule through any atom of the ring(s).
  • heteroaryl is meant to include heteroaryl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, oxo, thioxo, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -R b -0R 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 ,
  • a “heteroarylene” refers to a divalent radical derived from a “heteroaryl” group as described above linking the rest of the molecule to a radical group.
  • the heteroarylene is attached to the rest of the molecule through a single bond and to the radical group through a single bond. Unless stated otherwise specifically in the specification, a heteroarylene group is optionally substituted as described above for a heteroaryl group.
  • an optionally substituted group may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.).
  • substituted alkyl includes optionally substituted cycloalkyl groups, which in turn are defined as including optionally substituted alkyl groups, potentially ad infinitum
  • substitution or substitution patterns e.g., substituted alkyl includes optionally substituted cycloalkyl groups, which in turn are defined as including optionally substituted alkyl groups, potentially ad infinitum
  • modulate refers to an increase or decrease in the amount, quality, or effect of a particular activity, function or molecule.
  • activators, agonists, partial agonists, inverse agonists, antagonists, inhibitors, and allosteric modulators of an enzyme are modulators of the enzyme.
  • agonism refers to the activation of a receptor or enzyme by a modulator, or agonist, to produce a biological response.
  • agonist refers to a modulator that binds to a receptor or target enzyme and activates the receptor or enzyme to produce a biological response.
  • AMPK activator can be used to refer to a compound that exhibits an EC50 with respect to AMPK activity of no more than about 100 pM, as measured in the pAMPKl kinase activation assay.
  • agonist includes super agonists, full agonists or partial agonists.
  • super agonist refers to a modulator that is capable of producing a maximal response greater than the endogenous agonist for the target receptor or enzyme, and thus has an efficacy of more than 100%.
  • full agonist refers to a modulator that binds to and activates a receptor or target enzyme with the maximum response that an endogenous agonist can elicit at the receptor or enzyme.
  • partial agonist refers to a modulator that binds to and activates a receptor or target enzyme, but has partial efficacy, that is, less than the maximal response, at the receptor or enzyme relative to a full agonist.
  • the term “positive allosteric modulator” refers to a modulator that binds to a site distinct from the orthosteric binding site and enhances or amplifies the effect of an agonist.
  • the term “antagonism” or “inhibition” as used herein refers to the inactivation of a receptor or target enzyme by a modulator, or antagonist. Antagonism of a receptor, for example, is when a molecule binds to the receptor or target enzyme and does not allow activity to occur.
  • the term “antagonist” or “neutral antagonist” or “inhibitor” as used herein refers to a modulator that binds to a receptor or target enzyme and blocks a biological response. An antagonist has no activity in the absence of an agonist or inverse agonist but can block the activity of either, causing no change in the biological response.
  • inverse agonist refers to a modulator that binds to the same receptor or target enzyme as an agonist but induces a pharmacological response opposite to that agonist, i.e., a decrease in biological response.
  • negative allosteric modulator refers to a modulator that binds to a site distinct from the orthosteric binding site and reduces or dampens the effect of an agonist.
  • EC50 is intended to refer to the concentration of a substance (e.g., a compound or a drug) that is required for 50% activation or enhancement of a biological process. In some instances, EC50 refers to the concentration of agonist that provokes a response halfway between the baseline and maximum response in an in vitro assay. In some embodiments as used herein, EC50 refers to the concentration of an activator (e.g., an AMPK activator) that is required for 50% activation of AMPK.
  • an activator e.g., an AMPK activator
  • IC50 is intended to refer to the concentration of a substance (e.g., a compound or a drug) that is required for 50% inhibition of a biological process.
  • IC50 refers to the half maximal (50%) inhibitory concentration (IC) of a substance as determined in a suitable assay.
  • an IC50 is determined in an in vitro assay system.
  • IC50 refers to the concentration of a modulator (e.g., an antagonist or inhibitor) that is required for 50% inhibition of a receptor or a target enzyme.
  • a modulator e.g., an antagonist or inhibitor
  • mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
  • gut-restricted refers to a compound, e.g., an AMPK activator, that is predominantly active in the gastrointestinal system.
  • the biological activity of the gut-restricted compound e.g., a gut-restricted AMPK activator, is restricted to the gastrointestinal system.
  • gastrointestinal concentration of a gut-restricted modulator is higher than the IC50 value or the EC50 value of the gut-restricted modulator against its receptor or target enzyme, e.g., AMPK, while the plasma levels of said gut-restricted modulator, e.g., gut-restricted AMPK activator, are lower than the IC50 value or the EC50 value of the gut-restricted modulator against its receptor or target enzyme, e.g., AMPK.
  • the gut-restricted compound e.g., a gut- restricted AMPK activator, is non-systemic.
  • the gut-restricted compound e.g., a gut-restricted AMPK activator
  • the gut-restricted compound is a non-absorbed compound.
  • the gut-restricted compound e.g., a gut-restricted AMPK activator
  • the gut-restricted compound e.g., a gut-restricted AMPK activator
  • the gut-restricted AMPK activator has high efflux. In other embodiments, the gut-restricted AMPK activator is a substrate for one or more intestinal efflux transporters such as P-gp (MDR1), BCRP, or MRP2.
  • the gut-restricted modulator e.g., a gut-restricted AMPK activator
  • the modulator e.g., a gut-restricted AMPK activator
  • the systemic exposure of a gut-restricted modulator, e.g., a gut-restricted AMPK activator is, for example, less than 100, less than 50, less than 20, less than 10, or less than 5 nM, bound or unbound, in blood serum.
  • the intestinal exposure of a gut-restricted modulator is, for example, greater than 1000, 5000, 10000, 50000, 100000, or 500000 nM.
  • a modulator e.g., a gut-restricted AMPK activator
  • a modulator e.g., a gut-restricted AMPK activator
  • a modulator is covalently bonded to a kinetophore, optionally through a linker, which changes the pharmacokinetic profile of the modulator.
  • the gut-restricted modulator is a soft drug.
  • soft drug refers to a modulator that is biologically active but is rapidly metabolized to metabolites that are significantly less active than the modulator itself toward the target receptor.
  • the gut-restricted modulator is a soft drug that is rapidly metabolized in the blood to significantly less active metabolites.
  • the gut-restricted modulator is a soft drug that is rapidly metabolized in the liver to significantly less active metabolites.
  • the gut-restricted modulator is a soft drug that is rapidly metabolized in the blood and the liver to significantly less active metabolites.
  • the gut-restricted modulator is a soft drug that has low systemic exposure.
  • the biological activity of the metabolite(s) is/are 10-fold, 20-fold, 50-fold, 100-fold, 500-fold, or 1000-fold lower than the biological activity of the soft drug gut-restricted modulator.
  • kinetophore refers to a structural unit tethered to a small molecule modulator, e.g., an AMPK activator, optionally through a linker, which makes the whole molecule larger and increases the polar surface area while maintaining biological activity of the small molecule modulator.
  • the kinetophore influences the pharmacokinetic properties, for example solubility, absorption, distribution, rate of elimination, and the like, of the small molecule modulator, e.g., an AMPK activator, and has minimal changes to the binding to or association with a receptor or target enzyme.
  • a kinetophore is not its interaction with the target, for example an enzyme, but rather its effect on specific physiochemical characteristics of the modulator to which it is attached, e.g., an AMPK activator.
  • kinetophores are used to restrict a modulator, e.g., an AMPK activator, to the gut.
  • the term “linked” as used herein refers to a covalent linkage between a modulator, e.g., an AMPK activator, and a kinetophore.
  • the linkage can be through a covalent bond, or through a “linker.”
  • “linker” refers to one or more bifunctional molecules which can be used to covalently bonded to the modulator, e.g., an AMPK activator, and kinetophore.
  • the linker is attached to any part of the modulator, e.g., an AMPK activator, so long as the point of attachment does not interfere with the binding of the modulator to its receptor or target enzyme.
  • the linker is non-cleavable. In some embodiments, the linker is cleavable. In some embodiments, the linker is cleavable in the gut. In some embodiments, cleaving the linker releases the biologically active modulator, e.g., an AMPK activator, in the gut.
  • the biologically active modulator e.g., an AMPK activator
  • GI system refers to the organs and systems involved in the process of digestion.
  • the gastrointestinal tract includes the esophagus, stomach, small intestine, which includes the duodenum, jejunum, and ileum, and large intestine, which includes the cecum, colon, and rectum.
  • the GI system refers to the “gut,” meaning the stomach, small intestines, and large intestines or to the small and large intestines, including, for example, the duodenum, jejunum, and/or colon.
  • the gut-brain axis refers to the bidirectional biochemical signaling that connects the gastrointestinal tract (GI tract) with the central nervous system (CNS) through the peripheral nervous system (PNS) and endocrine, immune, and metabolic pathways.
  • the gut-brain axis comprises the GI tract; the PNS including the dorsal root ganglia (DRG) and the sympathetic and parasympathetic arms of the autonomic nervous system including the enteric nervous system and the vagus nerve; the CNS; and the neuroendocrine and neuroimmune systems including the hypothalamic-pituitary-adrenal axis (HPA axis).
  • the gut-brain axis is important for maintaining homeostasis of the body and is regulated and modulates physiology through the central and peripheral nervous systems and endocrine, immune, and metabolic pathways.
  • the gut-brain axis modulates several important aspects of physiology and behavior. Modulation by the gut-brain axis occurs via hormonal and neural circuits. Key components of these hormonal and neural circuits of the gut-brain axis include highly specialized, secretory intestinal cells that release hormones (enteroendocrine cells or EECs), the autonomic nervous system (including the vagus nerve and enteric nervous system), and the central nervous system. These systems work together in a highly coordinated fashion to modulate physiology and behavior.
  • Defects in the gut-brain axis are linked to a number of diseases, including those of high unmet need.
  • Diseases and conditions affected by the gut-brain axis include central nervous system (CNS) disorders including mood disorders, anxiety, depression, affective disorders, schizophrenia, malaise, cognition disorders, addiction, autism, epilepsy, neurodegenerative disorders, Alzheimer’s disease, and Parkinson’s disease, Lewy Body dementia, episodic cluster headache, migraine, pain; metabolic conditions including diabetes and its complications such as chronic kidney disease/diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, cardiovascular disease, metabolic syndrome, obesity, dyslipidemia, and nonalcoholic steatohepatitis (NASH); eating and nutritional disorders including hyperphagia, cachexia, anorexia nervosa, short bowel syndrome, intestinal failure, intestinal insufficiency and other eating disorders; inflammatory disorders and autoimmune diseases such as inflammatory bowel disease, ulcerative colitis, Crohn’s disease, checkpoint inhibitor-induced colitis
  • Adenosine 5'-Monophosphate-Activated Protein Kinase (AMPK) in the Gut-Brain Axis is a serine/threonine kinase and is evolutionarily conserved from yeast to mammals.
  • AMPK is a heterotrimeric protein complex that is formed by one a (al or a2), one P (Pl or P2), and one y (yl, y2, or y3) subunit. Due to the presence of isoforms of its components, there are 12 versions of AMPK (AMPK1, AMPK2, etc., through AMPK 12).
  • AMPK acts as an energy sensor and is activated by upstream enzymes when the cellular ratio of adenosine 5'- monophosphate (AMP) to adenosine triphosphate (ATP) is elevated due to nutrient deprivation.
  • activated AMPK phosphorylates downstream substrates to promote catabolism and impede anabolism, leading to ATP production and energy restoration.
  • AMPK activity can be altered due to numerous physiological factors, such as hormones, cytokines and dietary nutrients, as well as pathological conditions such as obesity, chronic inflammation and type 2 diabetes.
  • AMPK activation leads to lower hepatic glucose production and plasma glucose levels.
  • AMPK activation can act as a therapeutic agent to treat various metabolic diseases.
  • AMPK has beneficial effects for gut health, such as enhancing intestinal absorption, improving barrier function, suppressing colorectal carcinogenesis, and reducing intestinal inflammation and metabolic-related disease, and is important for the maintenance of intestinal homeostasis.
  • AMPK is essential for proper intestinal health.
  • AMPK activation enhances paracellular junctions, nutrient transporters, autophagy and apoptosis, and suppresses inflammation and carcinogenesis in the intestine.
  • this disclosure provides AMPK activators that can be broadly used for multiple conditions and disorders associated with AMPK.
  • the condition or disorder is associated with the gut-brain axis.
  • the condition or disorder is a central nervous system (CNS) disorder including mood disorders, anxiety, depression, affective disorders, schizophrenia, malaise, cognition disorders, addiction, autism, epilepsy, neurodegenerative disorders, Alzheimer’s disease, and Parkinson’s disease, Lewy Body dementia, episodic cluster headache, migraine, pain; metabolic conditions including diabetes and its complications such as chronic kidney disease/diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, cardiovascular disease, metabolic syndrome, obesity, dyslipidemia, and nonalcoholic steatohepatitis (NASH); eating and nutritional disorders including hyperphagia, cachexia, anorexia nervosa, short bowel syndrome, intestinal failure, intestinal insufficiency and other eating disorders; inflammatory disorders and autoimmune diseases such as inflammatory bowel disease, ulcerative colitis, Crohn’s disease, checkpoint inhibitor-induced colitis, psoriasis, celiac disease, and enteritis, including chemotherapy-induced enteritis or radiation-induced enteritis; necrot
  • CNS
  • the condition or disorder is a metabolic disorder.
  • the condition or disorder is type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia, nonalcoholic steatohepatitis, or hypertension.
  • the condition or disorder is a nutritional disorder.
  • the condition or disorder is short bowel syndrome, intestinal failure, or intestinal insufficiency.
  • the condition or disorder is inflammatory bowel disease including ulcerative colitis, Crohn’s disease and checkpoint inhibitor-induced colitis.
  • the condition or disorder is celiac disease, enteritis including chemotherapy -induced enteritis or radiation-induced enteritis, necrotizing enterocolitis; or gastrointestinal injury resulting from toxic insults such as radiation or chemotherapy.
  • the condition or disorder is diseases/disorders of gastrointestinal barrier dysfunction including environmental enteric dysfunction, spontaneous bacterial peritonitis; allergy including food allergy, celiac sprue, and childhood allergy; graft vs.
  • the condition or disorder is associated with systemic infection and inflammation from having a leaky gut barrier.
  • the condition or disorder is metabolic syndrome, obesity, type 2 diabetes, coronary artery disease, fatty liver, nonalcoholic steatohepatitis (NASH), cirrhosis, hepatic encephalopathy, fibrotic disorders including scleroderma, inflammatory bowel disease including Crohn’s disease and ulcerative colitis, allergy including food allergy, celiac sprue, and childhood allergy, graft vs. host disease, irritable bowel syndrome, spontaneous bacterial peritonitis, ischemic colitis, sclerosing cholangitis, Alzheimer’s disease, Parkinson’s disease, cancer including colorectal cancer, depression, autism, or a combination thereof.
  • NASH nonalcoholic steatohepatitis
  • fibrotic disorders including scleroderma, inflammatory bowel disease including Crohn’s disease and ulcerative colitis
  • allergy including food allergy, celiac sprue, and childhood allergy
  • graft vs. host disease irritable bowel syndrome, spontaneous
  • the gut mucosa maintains immune homeostasis under physiological circumstances by serving as a barrier that restricts access of microbes, diverse microbial products, food antigens and toxins in the lumen of the gut to rest of the body.
  • the gut barrier is comprised of a single layer of epithelial cells, bound by cell-cell junctions, and a layer of mucin that covers the epithelium.
  • an impaired gut barrier e.g. a leaky gut
  • AMPK which is associated with the maintenance of tight junction in colonic epithelium, controls the progression of colitis.
  • expression and assembly of tight junctions is dependent on AMPK activity.
  • the present disclosure provides methods effective to strengthen/protect the gut barrier and reduce and/or prevent the progression of chronic diseases.
  • the gut barrier is a critical frontier that separates microbes and antigens in the lumen of the gut from the rest of the body; a compromised “leaky” gut barrier is frequently associated with systemic infection and inflammation, which is a key contributor to many chronic allergic, infectious, metabolic and autoimmune diseases such as obesity, diabetes, inflammatory bowel diseases, food allergy, and metabolic endotoxemia.
  • this disclosure provides AMPK activators that can be broadly used for multiple conditions and disorders associated with AMPK.
  • the condition or disorder is associated with systemic infection and inflammation from having a leaky gut barrier.
  • a leaky gut barrier can fuel the progression of multiple chronic diseases, including but not limited to: metabolic syndrome, obesity, type 2 diabetes, coronary artery disease, fatty liver, nonalcoholic steatohepatitis (NASH), cirrhosis, hepatic encephalopathy, fibrotic disorders including scleroderma, inflammatory bowel disease including Crohn’s disease, ulcerative colitis, checkpoint inhibitor-induced colitis, allergy including food allergy, celiac sprue, and childhood allergy, graft vs.
  • metabolic syndrome including obesity, type 2 diabetes, coronary artery disease, fatty liver, nonalcoholic steatohepatitis (NASH), cirrhosis, hepatic encephalopathy, fibrotic disorders including scleroderma, inflammatory bowel disease including Crohn’s disease,
  • irritable bowel syndrome spontaneous bacterial peritonitis, ischemic colitis, sclerosing cholangitis, Alzheimer’s disease, Parkinson’s disease, cancer including colorectal cancer, depression, autism, or a combination thereof.
  • AMPK activators are useful for the treatment of gastrointestinal injury.
  • AMPK activators are useful for the treatment of gastrointestinal injury resulting from toxic insult.
  • the toxic insult is from radiation, chemotherapy, or a combination thereof.
  • the toxic insult is radiation- induced.
  • the toxic insult is chemotherapy -induced.
  • systemic AMPK activation for example, AMPK activation in the heart.
  • activating mutations in the AMPK y2-subunit lead to PRKAG2 cardiomyopathy.
  • systemic AMPK activation results in cardiac hypertrophy and increased cardiac glycogen.
  • tissue selective AMPK activation is an attractive approach for developing AMPK activators to treat disease.
  • the AMPK activator is gut-restricted. In some embodiments, the AMPK activator is designed to be substantially non-permeable or substantially non- bioavailable in the blood stream. In some embodiments, the AMPK activator is designed to activate AMPK activity in the gut and is substantially non-systemic. In some embodiments, the AMPK activator has low systemic exposure.
  • a gut-restricted AMPK activator has low oral bioavailability. In some embodiments, a gut-restricted AMPK activator has ⁇ 40% oral bioavailability, ⁇ 30% oral bioavailability, ⁇ 20% oral bioavailability, ⁇ 10% oral bioavailability, ⁇ 8% oral bioavailability, ⁇ 5% oral bioavailability, ⁇ 3% oral bioavailability, or ⁇ 2% oral bioavailability. [0087] In some embodiments, the unbound plasma levels of a gut-restricted AMPK activator are lower than the EC50 value of the AMPK activator against AMPK.
  • the unbound plasma levels of a gut-restricted AMPK activator are significantly lower than the EC50 value of the gut-restricted AMPK activator against AMPK. In some embodiments, the unbound plasma levels of the AMPK activator are 2-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, or 100-fold lower than the EC50 value of the gut-restricted AMPK activator against AMPK.
  • a gut-restricted AMPK activator has low systemic exposure.
  • the systemic exposure of a gut-restricted AMPK activator is, for example, less than 500, less than 200, less than 100, less than 50, less than 20, less than 10, or less than 5 nM, bound or unbound, in blood serum.
  • the systemic exposure of a gut- restricted AMPK activator is, for example, less than 500, less than 200, less than 100, less than 50, less than 20, less than 10, or less than 5 ng/mL, bound or unbound, in blood serum.
  • a gut-restricted AMPK activator has high intestinal exposure.
  • the intestinal exposure of a gut-restricted AMPK activator is, for example, greater than 1, 5, 10, 50, 100, 250 or 500 pM.
  • a gut-restricted AMPK activator has high exposure in the colon.
  • the colon exposure of a gut-restricted AMPK activator is, for example, greater than 1, 5, 10, 50, 100, 250 or 500 pM.
  • the colon exposure of a gut-restricted AMPK activator is, for example, greater than 100 pM.
  • a gut-restricted AMPK activator has low permeability. In some embodiments, a gut-restricted AMPK activator has low intestinal permeability. In some embodiments, the permeability of a gut-restricted AMPK activator is, for example, less than 5.0* 10' 6 cm/s, less than 2.0* 10' 6 cm/s, less than 1.5* 10' 6 cm/s, less than 1.0* 10' 6 cm/s, less than 0.75* 10' 6 cm/s, less than 0.50* 10' 6 cm/s, less than 0.25* 10' 6 cm/s, less than O. lOx lO' 6 cm/s, or less than 0.05* 10' 6 cm/s.
  • a gut-restricted AMPK activator has low absorption. In some embodiments, the absorption of a gut-restricted AMPK activator is less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, or less than 1%.
  • a gut-restricted AMPK activator has high plasma clearance. In some embodiments, a gut-restricted AMPK activator is undetectable in plasma in less than 8 hours, less than 6 hours, less than 4 hours, less than 3 hours, less than 120 min, less than 90 min, less than 60 min, less than 45 min, less than 30 min, or less than 15 min.
  • a gut-restricted AMPK activator is rapidly metabolized upon administration.
  • a gut-restricted AMPK activator has a short half-life.
  • the half-life of a gut-restricted AMPK activator is less than less than 8 hours, less than 6 hours, less than 4 hours, less than 3 hours, less than 120 min, less than 90 min, less than 60 min, less than 45 min, less than 30 min, or less than 15 min.
  • the metabolites of a gut-restricted AMPK activator have rapid clearance.
  • the metabolites of a gut-restricted AMPK activator are undetectable in less than 8 hours, less than 6 hours, less than 4 hours, less than 3 hours, less than 120 min, less than 90 min, less than 60 min, less than 45 min, less than 30 min, or less than 15 min.
  • the metabolites of a gut-restricted AMPK activator have low bioactivity.
  • the EC50 value of the metabolites of a gut-restricted AMPK activator is 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 100-fold, 500-fold, or 1000-fold higher than the EC50 value of the gut-restricted AMPK activator against AMPK.
  • the metabolites of a gut-restricted AMPK activator have rapid clearance and low bioactivity.
  • the gut-restricted AMPK activator has high efflux.
  • the gut-restricted AMPK activator is a substrate for one or more intestinal efflux transporters such as P-gp (MDR1), BCRP, or MRP2.
  • the efflux of the gut-restricted AMPK activator as measured by the B-A/A-B ratio in a cell line such as Caco-2 or MDCK with or without over-expression of one or more efflux transporters is, for example, greater than 2, greater than 5, greater than 10, greater than 25, or greater than 50.
  • the AMPK activator is gut- restricted. In some embodiments, the AMPK activator is a gut-restricted AMPK agonist. In some embodiments, the AMPK activator is a gut-restricted AMPK super agonist. In some embodiments, the AMPK activator is a gut-restricted AMPK full agonist. In some embodiments, the AMPK activator is a gut-restricted AMPK partial agonist. In some embodiments, the AMPK activator is covalently bonded to a kinetophore. In some embodiments, the AMPK activator is covalently bonded to a kinetophore through a linker.
  • X is -O-, -CH2-, or -CHR 4 -; or X is -CH-, and L 1 is atached to X;
  • Y is -N- or -CR 6 -;
  • R 1 , R 2 , and R 3 are each independently selected at each occurrence from halogen, hydroxyl, C1-4 alkyl, -CN, and C i -4 haloalky 1;
  • each R 4 is independently selected at each occurrence from halogen, hydroxyl, C 1-4 alkyl, - CN, and C 1-4 haloalkyl; or two R 4 are taken together to form a bond or a C1-2 alkylene;
  • n is selected from 0, 1, 2, 3, and 4;
  • o is selected from 0, 1, 2, 3, and 4;
  • p is selected from 0, 1, and 2;
  • q is selected from 0, 1, 2, 3, and 4;
  • R 5 is selected from hydrogen and C 1-4 alkyl
  • R 6 is selected from hydrogen, halogen, C 1-4 alkyl, and C 1-4 haloalkyl;
  • L 1 is a bond or -CH2-
  • D is selected from -CO2R 11 , -P(O)(OR n ) 2 , -P(O)R 11 (OR 11 ), -S(O) 2 OH, and -L 2 -K;
  • L 2 is selected from -(C(R 13 ) 2 )r-, -O(C(R 13 ) 2 )r-, -(C(R 13 ) 2 )rO-, ⁇ -N(R 12 )(C(R 13 ) 2 ) S -, '- C(O)O-, -OC(O)-, ⁇ -C(O)N(R 12 )-, ⁇ -N(R 12 )C(O)-, ⁇ -N(R 12 )S(O) 2 -, ⁇ -S(O) 2 N(R 12 )-, and 4- to 6-membered heterocycle, wherein 1 denotes the connection to K; r is selected from 1, 2, and 3; s is selected from 0, 1, 2, and 3;
  • K is selected from (i) and (ii):
  • R 11 is independently selected at each occurrence from hydrogen, C 1-4 alkyl, and C 1-4 haloalkyl;
  • R 12 is independently selected at each occurrence from hydrogen and C 1-4 alkyl optionally substituted with halogen, -OH, -NH 2 and -C(O)NH 2 ;
  • R 13 is independently selected at each occurrence from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, and C 1 -4 hydroxy alkyl; each R 14 is independently selected at each occurrence from: hydrogen;
  • substituents are selected from among a subset of the listed alternatives.
  • Y is CR 6 .
  • R 6 is hydrogen or halogen.
  • R 6 is hydrogen or fluoro.
  • Y is N, CH, or CF.
  • Y is N.
  • Y is CH.
  • Y is CF.
  • X is -O-. In some embodiments, X is -CH 2 -. In some embodiments, X is -CHR 4 -. In some embodiments, X is -CHR 4 -, and R 4 is halogen, hydroxyl, or methyl.
  • X is -O- or -CH 2 -; or X is -CH-, and L 1 is attached to X.
  • X is -O-. In some embodiments, X is -CH 2 -. [00102] In some embodiments, L 1 is bond. In some embodiments, L 1 is -CH 2- .
  • X is O
  • L 1 is a bond
  • the compound is represented by Formula (II): or a pharmaceutically acceptable salt thereof.
  • the compound is represented by Formula (Ila) or (lib) : or a pharmaceutically acceptable salt thereof.
  • the compound is represented by Formula (Ila), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is represented by Formula (lib), or a pharmaceutically acceptable salt thereof.
  • X is -CH-, and L 1 is attached to X.
  • L 1 is bond.
  • L 1 is -CH 2- .
  • the compound is represented by Formula (III): or a pharmaceutically acceptable salt thereof.
  • the compound is represented by Formula (Illa), Formula (Illb), or Formula (IIIc): or a pharmaceutically acceptable salt thereof.
  • the compound is represented by Formula (Illa), or a pharmaceutically acceptable salt thereof.
  • the compound is represented by Formula (Illb), or a pharmaceutically acceptable salt thereof.
  • the compound is represented by Formula (IIIc), or a pharmaceutically acceptable salt thereof.
  • R 5 is hydrogen. In some embodiments, R 5 is C 1-4 alkyl. In some embodiments, R 5 is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, and tert-butyl. In some embodiments, R 5 is methyl or ethyl. In some embodiments, R 5 is methyl. In some embodiments, R 5 is ethyl.
  • R 5 is hydrogen, methyl, or ethyl. In some embodiments, R 5 is hydrogen or methyl.
  • the compound is represented by Formula (IV): or a pharmaceutically acceptable salt thereof.
  • the compound is represented by Formula (IVa), Formula (Va), Formula (Va), Formula (IVa), Formula (IVa), Formula (IVa), Formula (IVa), Formula (IVa), Formula (IVa), Formula (IVa), Formula (IVa), Formula (IVa), Formula (IVa), Formula (IVa), Formula (IVa), Formula (IVa), Formula (IVa), Formula (IVa), Formula (IVa), Formula (IVa), Formula (IVa), Formula (IVa), Formula
  • the compound is represented by Formula (IVa), or a pharmaceutically acceptable salt thereof.
  • the compound is represented by Formula (IVb), or a pharmaceutically acceptable salt thereof.
  • the compound is represented by Formula (IVc), or a pharmaceutically acceptable salt thereof.
  • the compound is represented by Formula (IVd), or a pharmaceutically acceptable salt thereof.
  • the compound is represented by Formula (IVe), or a pharmaceutically acceptable salt thereof.
  • 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.
  • each R 1 is independently selected at each occurrence from halogen, hydroxyl, and C 1-4 alkyl. In some embodiments, each R 1 is independently selected at each occurrence from F, Cl, hydroxyl, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec- butyl, and tert-butyl. In some embodiments, each R 1 is F, Cl, methyl, or hydroxyl. In some embodiments, each R 1 is methyl. In some embodiments, each R 1 is hydroxyl.
  • R 1 is hydroxyl
  • n is selected from 0 and 1.
  • 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.
  • each R 2 is independently selected at each occurrence from halogen, hydroxyl, and C 1-4 alkyl. In some embodiments, each R 2 is independently selected at each occurrence from F, C1, hydroxyl, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec- butyl, and tert-butyl. In some embodiments, each R 2 is F, C1, methyl, or hydroxyl.
  • 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.
  • each R 3 is independently selected at each occurrence from halogen, hydroxyl, and C 1-4 alkyl. In some embodiments, each R 3 is independently selected at each occurrence from F, Cl, hydroxyl, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec- butyl, and tert-butyl. In some embodiments, each R 3 is halogen. In some embodiments, each R 3 is F or Cl. In some embodiments, each R 3 is F. In some embodiments, each R 3 is Cl.
  • R 3 is halogen, and p is selected from 0 and 1. In some embodiments, R 3 is selected from fluoro and chloro, and p is 1. In some embodiments, R 3 is fluoro, and p is 1. In some embodiments, R 3 is chloro, and p is 1.
  • q is selected from 0 and 1. In some embodiments, q is selected from 1 and 2. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2.
  • each R 4 is independently selected at each occurrence from halogen, hydroxyl, C 1-4 alkyl, -CN, and C 1-4 haloalkyl.
  • each R 4 is independently selected at each occurrence from hydroxyl, C 1-4 alkyl, -CN, and C 1 -4 haloalky 1. In some embodiments, each R 4 is independently selected at each occurrence from hydroxyl and C 1-4 alkyl. In some embodiments, each R 4 is independently selected at each occurrence from hydroxyl, methyl, ethyl, n-propyl, i-propyl, n- butyl, i-butyl, sec-butyl, and tert-butyl. In some embodiments, each R 4 is hydroxyl or methyl. [00127] In some embodiments, two R 4 are taken together to form a bond or a C 1-2 alkylene.
  • two R 4 are taken together to form a bond. In some embodiments, two R 4 are taken together to form a C 1-2 alkylene. In some embodiments, two R 4 are taken together to form a -CH 2 -. In some embodiments, two R 4 are taken together to form a -CH 2 CH 2- .
  • R 6 is selected from hydrogen, halogen, and C 1-4 alkyl. In some embodiments, R 6 is selected from hydrogen, F, Cl, methyl, ethyl, n-propyl, i-propyl, n-butyl, i- butyl, sec-butyl, and tert-butyl. In some embodiments, R 6 is selected from hydrogen, F, Cl, and methyl. In some embodiments, R 6 is selected from hydrogen and halogen. In some embodiments, R 6 is selected from hydrogen, fluoro, and chloro. In some embodiments, R 6 is selected from hydrogen and fluoro. In some embodiments, R 6 is hydrogen. In some embodiments, R 6 is fluoro.
  • D is selected from -P(O)(OR 11 ) 2 , -P(O)R 11 (OR 11 ), and - S(O) 2 OH.
  • 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.
  • D is selected from -P(O)(OH) 2 , - P(O)Me(OH), and -S(O) 2 OH.
  • D is -L 2 -K.
  • L 2 is -(C(R 13 )2)r-. In some embodiments, L 2 is -O(C(R 13 ) 2 )r-. In some embodiments, L 2 is -(C(R 13 )2)rO-. In some embodiments, L 2 is ⁇ -N(R 12 )(C(R 13 )2) S -. In some embodiments, L 2 is ⁇ -C(O)O-. In some embodiments, L 2 is ⁇ -C(O)N(R 12 )-. In some embodiments, L 2 is ⁇ -N(R 12 )C(O)-.
  • L 2 is ⁇ -N(R 12 )S(O) 2 -. In some embodiments, L 2 is ⁇ -S(O)2N(R 12 )-. In some embodiments, L 2 is 4- to 6-membered heterocycloalkyl. In some embodiments, L 2 is 5- to 6-membered heteroaryl.
  • L 2 is selected from -(C(R 13 )2)r-, -O(C(R 13 )2)r-, N(R 12 )(C(R 13 ) 2 ) S -, ⁇ -C(O)O-, ⁇ -N(R 12 )C(O)-, ⁇ -N(R 12 )S(O) 2 -, ⁇ -S(O) 2 N(R 12 )-, 4- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl.
  • L 2 is selected from -(C(R 13 )2)r-, O(C(R 13 ) 2 )r-, ⁇ -N(R 12 )(C(R 13 ) 2 ) S -, and triazolyl.
  • 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.
  • 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.
  • L is selected from 4- to 6-membered heterocycloalkyl and 5- to 6-membered heteroaryl.
  • L is selected from piperidinyl, azetidinyl, pyrazolyl, and triazolyl.
  • L is selected from piperidinyl and azetidinyl.
  • L is selected from pyrazolyl and triazolyl.
  • K is selected from (i) and (ii):
  • K is selected from C1-10 alkyl or C1-10 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 .
  • K is selected from C1-6 alkyl or C1-6 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 .
  • K is selected from C1-10 alkyl, which is optionally substituted with one to six substituents independently selected from halogen, -OR 14 , -N(R 14 ) 2 , and - S(O) 2 R 14 .
  • K is selected from C1-6 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 .
  • K is selected from C1-10 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 .
  • K is selected from C1-6 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 .
  • K is selected from azetidine optionally substituted with one to six substituents independently selected from Ci-io alkyl, wherein each Ci-io alkyl is optionally substituted with one to six substituents independently selected from -OR 14 , and S(O) 2 R 14 .
  • each R 14 is independently selected at each occurrence from hydrogen and CMO alkyl optionally substituted with one to six substituents independently selected from -OR 21 .
  • each R 14 is independently selected at each occurrence from hydrogen and Ci-io alkyl optionally substituted with one to six -OH substituents.
  • each R 14 is independently selected at each occurrence from hydrogen and C 1-6 alkyl.
  • each R 21 is independently selected at each occurrence from hydrogen, C 1-6 alkyl, Ci-e haloalkyl, and Ci -6 hydroxy alkyl. In some embodiments, each R 21 is independently selected at each occurrence from hydrogen and C 1-6 alkyl.
  • the compound is a compound in one of the following tables, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.
  • the compound is not A-l, A-2, or A-3.
  • the compound A-l as shown in Table 1 is Example 29 in the published international patent application WO/2012/116145A1.
  • the compound A-2 as shown in Table 1 is Example 15 in the published international patent application WO/2011/106273 Al.
  • A-3 2-((lr,4r)-4-((5-([l,l'-biphenyl]-4-yl)-4,6-difluoro-lH-benzo[d]imidazol-2- yl)oxy)cyclohexyl)acetic acid.
  • the compound is a pharmaceutically acceptable salt of a compound in Table 1.
  • the compound is a pharmaceutically acceptable salt of a compound in Table 2.
  • the compounds described herein exist as “geometric isomers.” In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti,
  • Z) isomers as well as the corresponding mixtures thereof. In some situations, compounds exist as tautomers.
  • a “tautomer” refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible.
  • the compounds presented herein exist as tautomers.
  • a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH.
  • the compounds described herein possess one or more chiral centers and each center exists in the (R)- configuration or (5)- configuration.
  • the compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof.
  • mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein.
  • the compounds described herein are prepared as optically pure enantiomers by chiral chromatographic resolution of the racemic mixture.
  • the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers.
  • dissociable complexes are preferred (e.g., crystalline diastereomeric salts).
  • the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities.
  • the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
  • positional isomer refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring.
  • compositions described herein include the use of crystalline forms (also known as polymorphs), or pharmaceutically acceptable salts of compounds described herein, as well as active metabolites of these compounds having the same type of activity.
  • “Pharmaceutically acceptable salt” includes both acid and base addition salts.
  • a pharmaceutically acceptable salt of any one of the compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms.
  • Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.
  • acetic acid trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, -toluenesulfonic acid, salicylic acid, and the like.
  • Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like.
  • salts of amino acids such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Science, 66: 1- 19 (1997).
  • Acid addition salts of basic compounds are prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt.
  • “Pharmaceutically acceptable base addition salt” refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N- dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, 7V-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, 7V-ethylpiperidine, polyamine resins and the like.
  • prodrug is meant to indicate a compound that is, in some embodiments, converted under physiological conditions or by solvolysis to an active compound described herein.
  • prodrug refers to a precursor of an active compound that is pharmaceutically acceptable.
  • a prodrug is typically inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis.
  • the prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam).
  • prodrugs are also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs of an active compound, as described herein are prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound.
  • Prodrugs include compounds wherein a hydroxy, amino, carboxy, or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino, free carboxy, or free mercapto group, respectively.
  • Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol or amine functional groups in the active compounds and the like.
  • solvates refers to a composition of matter that is the solvent addition form.
  • solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of making with pharmaceutically acceptable solvents such as water, ethanol, and the like.
  • “Hydrates” are formed when the solvent is water, or “alcoholates” are formed when the solvent is alcohol.
  • Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. The compounds provided herein optionally exist in either unsolvated as well as solvated forms.
  • the compounds disclosed herein are used in different enriched isotopic forms, e.g., enriched in the content of 2 H, 3 H, n C, 13 C and/or 14 C.
  • the compound is deuterated in at least one position.
  • deuterated forms can be made by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.
  • structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13 C- or 14 C-enriched carbon are within the scope of the present disclosure.
  • the compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds.
  • the compounds may be labeled with isotopes, such as for example, deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C).
  • isotopes such as for example, deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C).
  • Isotopic substitution with 2 H, 3 H, n C, 13 C, 14 C, 15 C, 12 N, 13 N, 15 N, 16 N, 17 O, 18 O, 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 C1, 37 C1, 79 Br, 81 Br, 125 I are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of
  • the compounds disclosed herein have some or all of the 3 H atoms replaced with 2 H atoms.
  • the methods of synthesis for deuterium-containing compounds are known in the art.
  • deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.
  • the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • the compounds described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, as described herein are substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0. 1%, of other organic small molecules, such as contaminating intermediates or by-products that are created, for example, in one or more of the steps of a synthesis method.
  • Compound C undergoes a methylation reaction following by oxidation to afford compound D.
  • Compound D is protected with a suitable protecting group to afford compound E.
  • Aryl sulfone E undergoes a substitution reaction with a suitable alcohol to afford ester compound F (R 5 is, for example, C1-C4 alkyl).
  • Aryl iodide F is treated under cross-coupling conditions, for example Suzuki cross-coupling, to arrive at compound G.
  • protecting group removal and in some cases saponification yields final Compounds of Formula (I).
  • additional chemical modification such as amide formation or reductive amination, is performed on compound G before final deprotection. In other embodiments, such modifications are performed directly on the Compounds of Formula (I) to afford additional compounds.
  • compositions described herein are prepared as described as outlined in the Examples.
  • a pharmaceutical composition comprising an AMPK activator described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, and at least one pharmaceutically acceptable excipient.
  • the AMPK activator is combined with a pharmaceutically suitable (or acceptable) carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration, e.g., oral administration, and standard pharmaceutical practice.
  • aqueous and non-aqueous carriers examples 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.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate and cyclodextrins.
  • Proper fluidity is maintained, for example, by the use of coating materials, such as lecithin; by the maintenance of the required particle size, in the case of dispersions; and by the use of surfactants.
  • 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.
  • anti-inflammatory agents include, but are not limited to: aminosalicylates such as balsalazide, mesalamine, olsalazine, and sulfalazine; corticosteroids such as budesonide, prednisone, prednisolone, methylprednisolone, dexamethasone, and betamethasone; anti-TNF alpha agents such as infliximab, adalimumab, certolizumab pegol, golimumab, and PRX-106; anti-IL-12 and/or 23 agents such as ustekinumab, guse
  • a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof is administered in combination with a aminosalicylate, a corticosteroid, an anti-TNF alpha agent, an anti-IL-12 and/or 23 agent, an anti-integrin agent, a JAK inhibitor, a S1P1R modulator, a salicylate, a COX inhibitor, a COX-2 specific inhibitor, an interleukin-22 (IL-22) agent, or a combination thereof.
  • 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.
  • agents that improve gastrointestinal barrier function to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof include, but are not limited to: HIF-PH inhibitors such as DS-1093, TRC-160334, and GB-004; MC1R agonists such as PL-8177; EZH2 inhibitors such as IMU-856; and DPP -4 inhibitors such as sitagliptin, vildagliptin, saxagliptin, linagliptin, gemigliptin, teneligliptin, alogliptin, trelagliptin, omarigliptin, evogliptin, gosogliptin, and dutogliptin.
  • HIF-PH inhibitors such as DS-1093, TRC-160334, and GB-004
  • MC1R agonists such as PL-8177
  • EZH2 inhibitors
  • a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof is administered in combination with a hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor, a melanocortin-1 receptor (MC1R) agonist, an enhancer of zeste homolog 2 (EZH2) inhibitor, or combinations thereof.
  • HIF-PH hypoxia-inducible factor-prolyl hydroxylase
  • M1R melanocortin-1 receptor
  • EZH2 enhancer of zeste homolog 2
  • a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof is administered in combination with a glucagon- like peptide (GLP)-l agonist, a GLP-2 agonist, a GLP-1/2 co-agonist, a peroxisome proliferator- activator receptor (PPAR) agonist, a Farsnenoid X receptor (FXR) agonist, a TGR5 agonist, a GPR40 agonist, a GPR119 agonist, an SSTR5 antagonist, an SSTR5 inverse agonist, an acetyl- CoA carboxylase (ACC) inhibitor, a stearoyl-CoA desaturase 1 (SCD-1) inhibitor, a dipeptidyl peptidase 4 (DPP -4) inhibitor, or combinations thereof.
  • the pharmaceutical composition comprises one or more anti-diabetic agents.
  • the pharmaceutical composition comprises one or
  • Examples of a GLP-1 agonist to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof include: exenatide, liraglutide, taspoglutide, lixisenatide, albiglutide, dulaglutide, semaglutide, OWL833 and ORMD 0901.
  • Examples of a GLP-2 agonist to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof include: tedaglutide, glepaglutide (ZP1848), elsiglutide (ZP1846), apraglutide (FE 203799), HM-15912, NB-1002, GX-G8, PE-0503, and SAN-134, and those described in WO-2011050174, WO- 2012028602, WO-2013164484, WO-2019040399, WO-2018142363, WO-2019090209, WO- 2006117565, WO-2019086559, WO-2017002786, WO-2010042145, WO-2008056155, WO- 2007067828, WO-2018229252, WO-2013040093, WO-2002066511, WO-2005067368, WO- 2009739031, WO-200963
  • Examples of a GLP-1/2 co-agonist to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, include ZP-GG-72 and those described in WO-2018104561, WO-2018104558, WO- 2018103868, WO-2018104560, WO-2018104559, WO-2018009778, WO-2016066818, and WO-2014096440..
  • Examples of a PPAR agonist to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof include: elafibranor (GFT505), lanifibranor, pioglitazone, rosiglitazone, saroglitazar, seladelpar, and GW501516.
  • Examples of a FXR agonist to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, include: obeticholic acid, NGM-282, EYP001, GS-9674, tropifexor (LJN452), and LMB-763.
  • Examples of a TGR5 agonist to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof include: INT-777, XL-475, SRX-1374, RDX-8940, RDX-98940, SB-756050, and those disclosed in WO-2008091540, WO-2010059853, WO-2011071565, WO-2018005801, WO-2010014739, WO-2018005794, WO-2016054208, WO-2015160772, WO-2013096771, WO-2008067222, WO-2008067219, WO-2009026241, WO-2010016846, WO-2012082947, WO-2012149236, WO-2008097976, WO-2016205475, WO-2015183794, WO-2013054338, WO-2010059859, WO-2010014836, WO-20160
  • Examples of a GPR40 agonist to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof include: fasiglifam, MR-1704, SCO-267, SHR-0534, HXP-0057-SS, LY-2922470, P-11187, JTT-851, ASP-4178, AMG-837, ID-11014A, HD-C715, CNX-011-67, JNJ-076, TU-5113, HD-6277, MK-8666, LY-2881835, CPL-207-280, ZYDG-2, and those described in US-07750048, WO- 2005051890, WO-2005095338, WO-2006011615, WO-2006083612, WO-2006083781, WO- 2007088857, WO-2007123225, WO-2007136572, WO-2008054674, WO-20080546
  • Examples of a GPR119 agonist to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof include: DS-8500a, HD-2355, LC34AD3, PSN-491, HM-47000, PSN-821, MBX-2982, GSK-1292263, APD597, DA-1241, and those described in WO-2009141238, WO-2010008739, WO- 2011008663, WO-2010013849, WO-2012046792, WO-2012117996, WO-2010128414, WO- 2011025006, WO-2012046249, WO-2009106565, WO-2011147951, WO-2011127106, WO- 2012025811, WO-2011138427, WO-2011140161, WO-2011061679, WO-2017175066, WO- 2017175068, WO-2015080446, WO-20131
  • Examples of a SSTR5 antagonist or inverse agonist to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, include those described in: WO-03104816, WO-2009050309, WO- 2015052910, WO-2011146324, WO-2006128803, WO-2010056717, WO-2012024183, and WO-2016205032.
  • Examples of an ACC inhibitor to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, include: firsocostat, GS-834356, and PF-05221304.
  • Examples of a SCD-1 inhibitor to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, include aramchol.
  • Examples of a DPP -4 inhibitor to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof include: sitagliptin, vildagliptin, saxagliptin, linagliptin, gemigliptin, teneligliptin, alogliptin, trelagliptin, omarigliptin, evogliptin, gosogliptin, and dutogliptin.
  • anti-diabetic agents examples include: GLP-1 receptor agonists such as exenatide, liraglutide, taspoglutide, lixisenatide, albiglutide, dulaglutide, semaglutide, OWL833 and ORMD 0901; SGLT2 inhibitors such as dapagliflozin, canagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, remogliflozin, sergliflozin, sotagliflozin, and tofogliflozin; biguinides such as metformin; insulin and insulin analogs.
  • GLP-1 receptor agonists such as exenatide, liraglutide, taspoglutide, lixisenatide, albiglutide, dulaglutide, semaglutide, OWL833 and ORMD 0901
  • SGLT2 inhibitors such as
  • anti-obesity agents examples include: GLP-1 receptor agonists such as liraglutide, semaglutide; SGLT1/2 inhibitors such as LIK066, pramlintide and other amylin analogs such as AM-833, AC2307, and BI 473494; PYY analogs such as NN-9747, NN-9748, AC-162352, AC-163954, GT-001, GT-002, GT-003, and RHS-08; GIP receptor agonists such as APD-668 and APD-597; GLP-l/GIP co-agonists such as tirzepatide (LY329176), BHM-089, LBT-6030, CT-868, SCO-094, NNC-0090-2746, RG-7685, NN-9709, and SAR-438335; GLP-l
  • agents for nutritional disorders to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, include: GLP-2 receptor agonists such as tedaglutide, glepaglutide (ZP1848), elsiglutide (ZP1846), apraglutide (FE 203799), HM-15912, NB-1002, GX-G8, PE-0503, SAN- 134, and those described in WO-2011050174, WO-2012028602, WO-2013164484, WO- 2019040399, WO-2018142363, WO-2019090209, WO-2006117565, WO-2019086559, WO- 2017002786, WO-2010042145, WO-2008056155, WO-2007067828, WO-2018229252, WO- 2013040093, WO-2002066511, WO-2005067368, WO-200973
  • the therapeutic effectiveness of one of the compounds described herein is enhanced by administration of an adjuvant (i.e., by itself the adjuvant has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced).
  • an adjuvant i.e., by itself the adjuvant has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced.
  • the benefit experienced by a patient is increased by administering one of the compounds described herein with another agent (which also includes a therapeutic regimen) that also has therapeutic benefit.
  • a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof is co-administered with one or more additional therapeutic agents, wherein the compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, and the additional therapeutic agent(s) modulate different aspects of the disease, disorder or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone.
  • the additional therapeutic agent(s) is a glucagon-like peptide (GLP)-l agonist, a GLP-2 agonist, a GLP-1/2 co-agonist, a peroxisome proliferator-activator receptor (PPAR) agonist, a Farsnenoid X receptor (FXR) agonist, a stearoyl-CoA desaturase 1 (SCD-1) inhibitor, a dipeptidyl peptidase 4 (DPP -4) inhibitor, or a combination thereof.
  • the second therapeutic agent is an anti-inflammatory agent.
  • the additional therapeutic agent(s) is an aminosalicylate, a corticosteroid, an anti-TNF alpha agent, an anti-IL- 12 and/or 23 agent, an anti-integrin agent, a JAK inhibitor, a S1P1R modulator, a salicylate, a COX inhibitor, a COX-2 specific inhibitor, an IL-22 agent, or a combination thereof.
  • the second therapeutic agent is an agent that improves gastrointestinal barrier function.
  • the additional therapeutic agent(s) is a HIF-PH inhibitor, an MC1R agonist, an EZH2 inhibitor, or a combination thereof.
  • the overall benefit experienced by the patient is additive of the two (or more) therapeutic agents. In other embodiments, the patient experiences a synergistic benefit of the two (or more) therapeutic agents.
  • the multiple therapeutic agents are administered in any order or even simultaneously. If administration is simultaneous, the multiple therapeutic agents are, by way of example only, provided in a single, unified form, or in multiple forms (e.g., as a single pill or as two separate pills).
  • the compounds described herein, or pharmaceutically acceptable salts, solvates, stereoisomers, or prodrugs thereof, as well as combination therapies, are administered before, during or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound varies.
  • the compounds described herein are used as a prophylactic and are administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition.
  • the compounds and compositions are administered to a subject during or as soon as possible after the onset of the symptoms.
  • a compound described herein is administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease.
  • a compound described herein, or a pharmaceutically acceptable salt thereof is administered in combination with anti-inflammatory agent, anti-cancer agent, immunosuppressive agent, steroid, non-steroidal anti-inflammatory agent, antihistamine, analgesic, hormone blocking therapy, radiation therapy, monoclonal antibodies, or combinations thereof.
  • Step 1 2-(2-((4-bromobenzyl)oxy)ethoxy)ethanol (1-1): To a solution of 2,2'- oxydiethanol (21 g, 0.20 mol, 5 eq) in THF (300 mL) was added NaH (16 g, 0.40 mol, 60% purity, 10 eq) at 0 °C. The mixture was stirred at 25 °C for 30 min, then was added l-bromo-4- (bromomethyl)benzene (10 g, 40 mmol, 1 eq at 0 °C. The mixture stirred at 70 °C for 12 hours.
  • Step 2 2-[2-[[4-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl]phenyl]methoxy]ethoxy]ethanol (1-2): To a solution of 1-1 (1 g, 3.6 mmol, 1 eq) and 4,4,5,5-tetramethyl-2-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]-l,3,2- dioxaborolane (1.8 g, 5.5 mmol, 1.5 eq) in dioxane (10 mL) and H2O (1 mL) was added PCys Pd G3 (0.17 g, 0.25 mmol, 0.07 eq) and Na2COs (0.58 g, 5.5 mmol, 1.5 eq).
  • the mixture was stirred at 80 °C for 12 hours under N2 atmosphere.
  • the reaction mixture was partitioned between H2O (50 mL) and ethyl acetate (30 mLx3).
  • the organic phase was separated, washed with saturated brine (30 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • the crude product was purified by reversed-phase HPLC (column: YMC Triart Cl 8 250 x 50mm x 7um; mobile phase: A: water (0.1% FA), B: ACN]; B%: 56%-86%) to give 1-2 (0.36 g, 19% yield, 76% purity) as yellow oil.
  • Step 5 5-chloro-6-iodopyridine-2,3-diamine (1-5): To a solution 1-4 of (60 g, 0.20 mol, 1 eq) in EtOH (300 mL) was added SnCL 2H2O (0.18 kg, 0.80 mol, 4 eq). The mixture was stirred at 70 °C for 0.5 hr. To the mixture was added water (450 mL) and KF (0.18 kg), and the mixture was stirred for 0.5 h, then extracted with ethyl acetate (2 x 100 mL). The organic phase was washed with saturated brine (2 x 50 mL), then concentrated in vacuo.
  • Step 6 6-chloro-5-iodo-l//-iinidazo
  • LCMS (ES + ): m/z (M+H) + 311.8.
  • Step 7 6-chloro-5-iodo-2-(methylthio)-3//-iniidazo
  • 1-6 22 g, 70 mmol, 1 eq
  • KOH 4.7 g, 84 mmol, 1.2 eq
  • EtOH 440 mL
  • Mel 10.0 g, 70 mmol, 4.4 mL, 1 eq
  • Step 8 6-chloro-5-iodo-2-(methylsulfonyl)-3Z7-imidazo [4,5-6] pyridine (1-8): To a solution of 1-7 (16 g, 49 mmol, 1 eq) in ACN (320 mL) and H2O (320 mL) was added Oxone (66 g, 0.11 mmol, 2.2 eq). The mixture was stirred at room temperature for 12 hrs. The mixture was extracted with ethyl acetate (3 x 400 mL).
  • Step 9 6-chloro-5-iodo-2-(methylsulfonyl)-l-((2-(trimethylsilyl)ethoxy)methyl)- IH-imidazo [4,5-6] pyridine (1-9): SEM-C1 (7.3 g, 44 mmol, 7.7 mL, 1 eq) was added dropwise to a THF (310 mL) solution of 1-8 (16 g, 44 mmol, 1 eq) and TEA (6.6 g, 65 mmol, 9.1 mL, 1.5 eq) at 0 °C under nitrogen. The reaction mixture was stirred at room temperature for 0.5 hr.
  • Step 10 (lr,4r)-methyl 4-((6-chloro-5-iodo-l-((2-(trimethylsilyl)ethoxy)methyl)- lH-imidazo[4,5-b]pyridin-2-yl)oxy)cyclohexanecarboxylate (1-10): To a solution of 1-9 (2 g, 4.1 mmol, 1 eq) and methyl /ra//.s-4-hydroxy cyclohexanecarboxylate (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).
  • Step 11 (lr,4r)-methyl 4-((6-chloro-5-(4'-((2-(2-hydroxyethoxy)ethoxy)methyl)- [l,l'-biphenyl]-4-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-2- yl)oxy)cyclohexanecarboxylate
  • 1-11) To a solution of 1-10 (0.55 g, 0.97 mmol, 1.0 eq) and 1- 2 (0.43 g, 1.1 mmol, 1.1 eq) in FLO (1.0 mL) and dioxane (5.0 mL) was added Na2COs (0.24 g, 2.9 mmol, 3.0 eq) and Pd ⁇ ppfJCL’CEECL (0.16 g, 0.19 mmol, 0.2 eq).
  • Step 12 (lr,4r)-methyl 4-((6-chloro-5-(4'-((2-(2-hydroxyethoxy)ethoxy)methyl)- [l,l'-biphenyl]-4-yl)-lH-imidazo[4,5-b]pyridin-2-yl)oxy)cyclohexanecarboxylate
  • 1-12 To a solution of 1-11 (0.37 g, 0.52 mmol, 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 give 1-12 (0.30 g, crude) as a brown oil.
  • LCMS: (ES+) m/z (M) + 580.4.
  • Step 13 (lr,4r)-4-((6-chloro-5-(4'-((2-(2-hydroxyethoxy)ethoxy)methyl)-[l,l'- biphenyl]-4-yl)-lH-imidazo[4,5-b]pyridin-2-yl)oxy)cyclohexanecarboxylic acid (Compound 1): To a solution of 1-12 (0.3 g, 0.22 mmol, 42% purity, 1.0 eq) in H2O (2.0 mL) and propan-2 - ol (4.0 mL) was added LiOH»H2O (46 mg, 1.1 mmol, 5.0 eq). The mixture was stirred at 25 °C for 24 hours.
  • Step 1 methyl 4-oxo-4H-pyran-2-carboxylate (2-1): To a solution of 4-oxo-4H- pyran-2-carboxylic acid (200 mg, 1.4 mmol, 1 eq) in MeOH (4 mL) was added H2SO4 (73 mg, 0.74 mmol, 0.04 mL, 98% purity, 0.05 eq) at 0 °C. The mixture was stirred 65 °C for 12 hours. The reaction mixture was diluted with saturated aqueous NaHCOs (100 mL) solution and extracted with EA (200 mL x 3).
  • Step 2 (2R,4S)-methyl 4-hydroxytetrahydro-2H-pyran-2-carboxylate (2-2): To a solution of 2-1 (23 g, 0.15 mol, 1 eq) in MeOH (230 mL) was added Pd/C (2.3 g, 10% purity) under N2 atmosphere. The suspension was degassed and purged with H2 3 times. The mixture was stirred under H2 (30 Psi) at 25 °C for 72 h. The solution was filtered and concentrated under reduced pressure to give a residue.
  • Step 3 2-(2-(((4'-bromo-[l,l'-biphenyl]-4-yl)methyl)amino) ethoxy)ethanol (2-3):
  • Step 4 tert-butyl ((4'-bromo-[l,l'-biphenyl]-4-yl)methyl)(2-(2- hydroxyethoxy)ethyl)carbamate (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 BOC2O (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 x 6).
  • Step 5 tert-butyl (2-(2-hydroxyethoxy)ethyl)((4'-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-[l,l'-biphenyl]-4-yl)methyl)carbamate (2-5): To a solution of 2-4 (18 g, 40 mmol, 1 eq) in dioxane (400 mL) was added KOAc (12 g, 0.12 mol, 3 eq) and BPD (15 g, 60 mmol, 1.5 eq).
  • Step 6 (2R,4S)-methyl 4-((6-chloro-5-iodo-l-((2-(trimethylsilyl)ethoxy)methyl)- lH-imidazo[4,5-b]pyridin-2-yl)oxy)tetrahydro-2H-pyran-2-carboxylate (2-6): To a solution of 6-chloro-5-iodo-2-(methylsulfonyl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5- b]pyridine 1-9 (2.7 g, 5 mmol, 1 eq) and 2-2 (0.9 g, 5.6 mmol, 1 eq) in DMF (30 mL) was added CS2CO3 (3.66 g, 11.24 mmol, 2 eq).
  • Step 7 (2R,4S)-methyl 4-((5-(4'-(((tert-butoxycarbonyl)(2-(2- hydroxyethoxy)ethyl)amino)methyl)-[l,l'-biphenyl]-4-yl)-6-chloro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-2-yl)oxy)tetrahydro-2H-pyran-2- carboxylate (2-7): To a solution of 2-5 (900 mg, 1.6 mmol, 1 eq) and 2-6 (0.87 g, 1.7 mmol, 1.1 eq) in DME (20 mL) and H2O (2 mL) was added Na2COs (0.51 g, 4.8 mmol, 3 eq).
  • Step 8 (2R,4S)-methyl 4-((6-chloro-5-(4'-(((2-(2- hydroxyethoxy)ethyl)amino)methyl)-[l,l'-biphenyl]-4-yl)-lH-imidazo[4,5-b]pyridin-2- yl)oxy)tetrahydro-2H-pyran-2-carboxylate (2-8): To a solution of 2-7 (50 mg, 61 umol, 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 give crude 2-8 (30 mg, 51 umol, 84% yield) as a black solid.
  • LCMS: (ES + ) m/z (M+H) + 581.3.
  • Step 9 (2R,4S)-4-((6-chloro-5-(4'-(((2-(2-hydroxyethoxy)ethyl)amino)methyl)- [l,l'-biphenyl]-4-yl)-lH-imidazo[4,5-b]pyridin-2-yl)oxy)tetrahydro-2H-pyran-2-carboxylic acid
  • Compound 2 To a solution of 2-8 (0.3 g, 0.52 mmol, 1 eq) was added NaOH (82 mg, 2.1 mmol, 4 eq) in water (5 mL) and MeOH (5 mL). The mixture was stirred at 25 °C for 5 min.
  • Step 1 3-(4-bromophenyl)-l-(2,2-dimethoxyethyl)-lH-l,2,4-triazole (3-1): To a solution of 3-(4-bromophenyl)-lH-l,2,4-triazole (18 g, 80 mmol, 1 eq) and 2-bromo-l,l- dimethoxy-ethane (136 g, 0.80 mol, 95 mL, 10 eq) in DMF (200 mL) was added CS2CO3 (79 g, 0.24 mol, 3 eq) and Nal (1.2 g, 8.0 mmol, 0.1 eq).
  • Step 2 2-(3-(4-bromophenyl)-lH-l,2,4-triazol-l-yl)ethane-l,l-diol (3-2): A solution of 3-1 (3 g, 9.6 mmol, 1 eq in 4M HCl/dioxane (20 mL) was stirred at 25 °C for 12 h. Then the mixture was stirred at 35 °C for 12 h. The mixture was concentrated under reduced pressure to give 3-2 (2.5 g, crude, HC1 salt) as a brown powder.
  • Step 3 l-(2-(azetidin-l-yl)ethyl)-3-(4-bromophenyl)-lH-l,2,4-triazole (3-3): To a solution of azetidine (2.2 g, 24 mmol, 2.6 mL, 3.1 eq, HC1 salt) 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, HC1) was added.
  • Step 4 l-(2-(azetidin-l-yl)ethyl)-3-(4'-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-[l,l'-biphenyl]-4-yl)-lH-l,2,4-triazole (3-4): To a solution of 3-3 (1 g, 3.3 mmol, 1 eq) and l,4-bis(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzene (2.69 g, 8.14 mmol, 2.5 eq) in dioxane (10 mL) and H2O (0.1 mL) was added Na2COs (1.0 g, 9.8 mmol, 3 eq).
  • Step 7 3,5-difluoro-4-iodobenzene-l,2-diamine (3-7): To a solution of 3-6 (125 g, 0.42 mol, 1 eq) in EtOH (1.5 L) was added AcOH (113 g, 1.9 mol, 0.11 L, 4.5 eq) and Fe (116 g, 2.1 mol, 5 eq). The mixture was stirred at 75 °C for 12 hours. The solution was filtered and concentrated under reduced pressure to give a residue. Then the residue was diluted with EA (3 L), the organic layers were washed with Na2CO3 solution, then the solution was concentrated under reduced pressure to give 3-7 (80 g, 64% yield, 90% purity) as a black solid.
  • Step 9 4,6-difluoro-5-iodo-2-(methylthio)-lH-benzo[d]imidazole (3-9): To a solution of 3-8 (57 g, 0.18 mol, 1 eq) in EtOH (600 mL) was added KOH (12 g, 0.22 mol, 1.2 eq) at 0 °C. The mixture was stirred at 0 °C for 0.5 h, then Mel (26 g, 0.18 mol, 11 mL, 1 eq) was added into the solution, the mixture was stirred at 25 °C for 1 h. The solution was diluted with water (500 mL), extracted with EA (500 mL x 10).
  • Step 10 4,6-difluoro-5-iodo-2-(methylsulfonyl)-lH-benzo[d]imidazole (3-10): To a solution of 3-9 (50 g, 0.15 mol, 1 eq) in ACN (500 mL) and water (500 mL) was added Oxone (141 g, 0.23 mol, 1.5 eq). The mixture was stirred at 25 °C for 12 hours. The solution was diluted with water (500 mL), extracted with EA (500 mL x 10).
  • Step 11 4,6-difluoro-5-iodo-2-(methylsulfonyl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazole (3-11): To a solution of 3-10 (54 g, 0.15 mol, 1 eq) in THF (600 mL) was added TEA (23 g, 0.22 mol, 31.48 mL, 1.5 eq) and SEM- C1 (30 g, 0.18 mol, 32 mL, 1.2 eq) at 0 °C. The mixture was stirred at 25 °C for 12 hours.
  • Step 12 ethyl 2-((lr,4r)-4-hydroxycyclohexyl)acetate (3-12): To a solution of ethyl 2-(4-oxocyclohexyl)acetate (40 g, 0.22 mol, 1 eq) in EtOH (400 mL) was added NaBEU (16 g, 0.43 mol, 2 eq) slowly at -5 °C, then the solution was stirred at -5 °C for 1 h. The solution was quenched by addition saturated NEUCl 400 mL. The solution was diluted with ELO (300 mL) and extracted with EA (1 Lx 3).
  • Step 13 ethyl 2-((lr,4r)-4-((4,6-difluoro-5-iodo-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-2-yl)oxy)cyclohexyl)acetate (3-13): To a solution of 3-12 (4 g, 21 mmol, 1.2 eq and 2-[(4,6-difhioro-5-iodo-2-methylsulfonyl- benzimidazol-l-yl)methoxy]ethyl-trimethyl-silane (8.7 g, 18 mmol, 1 eq) in DMF (60 mL) was added CS2CO3 (17 g, 54 mmol, 3 eq), the mixture was stirred at 60 °C for 6 hr.
  • Step 14 ethyl 2-((lr,4r)-4-((5-(4'-(l-(2-(azetidin-l-yl)ethyl)-lH-l,2,4-triazol-3-yl)- [l,l'-biphenyl]-4-yl)-4,6-difluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- benzo [d]imidazol-2-yl)oxy)cyclohexyl)acetate (3-14): A mixture of ethyl 2-[4-[4,6-difluoro-5- iodo-l-(2-trimethylsilylethoxymethyl)benzimidazol-2-yl]oxycyclohexyl]acetate (0.62 g, 0.82 mmol, 79% purity, 1.2 eq), 3-4 (0.34 g, 0.69 mmol, 87% purity, 1 e
  • Step 15 ethyl 2-((lr,4r)-4-((5-(4'-(l-(2-(azetidin-l-yl)ethyl)-lH-l,2,4-triazol-3-yl)- [1 , 1 '-biphenyl] -4-yl)-4,6-difluoro- IH-benzo [d] imidazol-2-yl)oxy)cyclohexyl)acetate (3- 15) : To a solution of 3-12 (50 mg, 65 umol, 1 eq) in DCM (0.5 mL) was added TFA (1 mL) at 0 °C.
  • Step 16 2-((lr,4r)-4-((5-(4'-(l-(2-(azetidin-l-yl)ethyl)-lH-l,2,4-triazol-3-yl)-[l,l'- biphenyl]-4-yl)-4,6-difluoro-lH-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 H2O (3 mL) was added LiOH»H2O (65 mg, 1.6 mmol, 5 eq) at 25 °C.
  • Example 4 2-((lr,4r)-4-((6-chloro-5-(4'-((4-(2-(methylsulfonyl)ethyl)piperazin-l- yl)methyl)-[l,l'-biphenyl]-4-yl)-lH-imidazo[4,5-b]pyridin-2-yl)oxy)cyclohexyl)acetic acid
  • Step 1 ethyl 2-((lr,4r)-4-((6-chloro-5-iodo-l-((2-(trimethylsilyl)ethoxy)methyl)- lH-imidazo[4,5-b]pyridin-2-yl)oxy)cyclohexyl)acetate (4-1): To a solution of ethyl 2-(4- hydroxycyclohexyl)acetate (6 g, 32 mmol, 1 eq) and 2-[(6-chloro-5-iodo-2-methylsulfonyl- imidazo[4,5-b]pyridin-l-yl)methoxy]ethyl-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) at 0 °C.
  • Step 2 ethyl 2-((lr,4r)-4-((6-chloro-5-(4'-formyl-[l,l'-biphenyl]-4-yl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5-b]pyridin-2-yl)oxy)cyclohexyl)acetate (4-2): To a solution of 4-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]benzaldehyde (0.93 g, 3.0 mmol, 1 eq) and 4-1 (1.8 g, 3.03 mmol, 1 eq) in dioxane (30 mL) and H2O (3 mL) was added Na2CC>3 (0.96 g, 9.1 mmol, 3 eq).
  • Step 3 ethyl 2-((lr,4r)-4-((6-chloro-5-(4'-((4-(2-(methylsulfonyl)ethyl)piperazin- l-yl)methyl)-[l,l'-biphenyl]-4-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazo[4,5- b]pyridin-2-yl)oxy)cyclohexyl)acetate (4-3): To a solution of l-(2- methylsulfonylethyl)piperazine (0.26 g, 1.2 mmol, 1.5 eq, HC1) in THF (4 mL) and DMSO (4 mL) was added KOAc (0.23 g, 2.3 mmol, 3 eq).
  • Step 1 tert-butyl 3-(2-(benzyloxy)ethoxy)azetidine-l-carboxylate (5-1): To a solution of tert-butyl 3 -hydroxyazetidine-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) at 0 °C.
  • Step 2 tert-butyl 3-(2-hydroxyethoxy)azetidine-l-carboxylate (5-2): To a solution of 5-1 (17 g, 55 mmol, 1 eq) 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) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 psi) at 45 °C for 2 hrs. The solution was filtered and concentrated under reduced pressure to give 5-2 (8 g, 37 mmol, 67% yield) as a colourless oil.
  • Step 3 2-(azetidin-3-yloxy)ethan-l-ol (5-3): A solution of 5-2 (5 g, 23 mmol, 1 eq in HC1 (25 mL) and MeOH (25 mL) was stirred at 40 °C for 1 hr. The solution was concentrated under reduced pressure to give a crude 5-3 (4.0 g, 19 mmol, 84% yield, 75% purity, HC1) as a colourless oil.
  • Step 4 methyl (lr,4r)-4-((4,6-difluoro-5-iodo-l-((2-
  • Step 5 methyl (lr,4r)-4-((4,6-difluoro-5-(4'-formyl-[l,l'-biphenyl]-4-yl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-2-yl)oxy)cyclohexane-l-carboxylate (5-5): To a solution of methyl 5-4 (0.7 g, 1.2 mmol, 1 eq and 4-[4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl]benzaldehyde (0.57 g, 1.9 mmol, 1.5 eq) in dioxane (13 mL) and H2O (1.3 mL) was added Na2COs (0.39 g, 3.7 mmol, 3 eq) and Pd(dppf)C12 (90 mg, 0.12
  • Step 6 methyl (lr,4r)-4-((4,6-difluoro-5-(4'-((3-(2-hydroxyethoxy)azetidin-l- yl)methyl)-[l,l'-biphenyl]-4-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol- 2-yl)oxy)cyclohexane-l-carboxylate (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).
  • Step 7 methyl (lr,4r)-4-((4,6-difluoro-5-(4'-((3-(2-(2,2,2- trifluoroacetoxy)ethoxy)azetidin-l-yl)methyl)-[l,l'-biphenyl]-4-yl)-lH-benzo[d]imidazol-2- yl)oxy)cyclohexane-l-carboxylate (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 hrs.
  • Step 8 (lr,4r)-4-((4,6-difluoro-5-(4'-((3-(2-hydroxyethoxy)azetidin-l-yl)methyl)- [1, l'-biphenyl]-4-yl)-lH-benzo[d]imidazol -2 -yl)oxy)cyclohexane-l -carboxylic acid (Compound 52): To a solution of 5-7 (0.24 g, 0.34 mmol, 1 eq) in THF (2 mL) , H2O (2 mL) and i-PrOH (2 mL) was added Li OH (83 mg, 3.4 mmol, 10 eq).
  • Step 1 ((ls,3s)-3-((4-bromobenzyl)oxy)cyclobutoxy)(tert-butyl)dimethylsilane (6- 1): To a solution of (ls,3s)-3-((tert-butyldimethylsilyl)oxy)cyclobutan-l-ol(ls,3s)-3-((tert- butyldimethylsilyl)oxy)cyclobutan-l-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) at 0 °C.
  • Step 2 tert-butyldimethyl((ls,3s)-3-((4'-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)-[l,l'-biphenyl]-4-yl)methoxy)cyclobutoxy)silane (6-2): To a solution of 6-1 (1.0 g, 2.7 mmol, 1.0 eq) and l,4-bis(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzene (0.89 g, 2.7 mmol, 1.0 eq) in dioxane (10 mL) and H2O (1 mL) was added Pd(dppf)C12 (0.20 g, 0.27 mmol, 0.1 eq) and K2CO3 (0.74 g, 5.4 mmol, 2.0 eq).
  • Step 3 methyl (lr,4r)-4-((5-(4'-(((ls,3s)-3-((tert- butyldimethylsilyl)oxy)cyclobutoxy)methyl)-[l,l'-biphenyl]-4-yl)-4,6-difluoro-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-2-yl)oxy)cyclohexane-l-carboxylate
  • Step 4 methyl (lr,4r)-4-((4,6-difluoro-5-(4'-(((ls,3s)-3- hydroxycyclobutoxy)methyl)-[l,l'-biphenyl]-4-yl)-lH-benzo[d]imidazol-2- yl)oxy)cyclohexane-l-carboxylate (6-4): To a solution of methyl 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) at 0 °C. The mixture was stirred at 25 °C for 13 hours.
  • Step 5 (lr,4r)-4-((4,6-difluoro-5-(4'-(((ls,3s)-3-hydroxycyclobutoxy)methyl)- [l,l'-biphenyl]-4-yl)-lH-benzo[d]imidazol-2-yl)oxy)cyclohexane-l-carboxylic acid
  • Step 1 tert-butyl 3-((methylthio)methyl)azetidine-l-carboxylate (7-1): To a solution of tert-butyl 3 -(iodomethyl)azetidine-l -carboxylate (14 g, 46 mmol, 1 eq) in MeOH (0.20 L) was added methyl sulfanyl sodium (8.0 g, 0.11 mmol, 7.3 mL, 2.5 eq) , then the mixture was stirred at 25 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure to remove solvent.
  • Step 2 tert-butyl 3-((methylsulfonyl)methyl)azetidine-l-carboxylate (7-2): To a solution of 7-1 (13 g, 59 mmol, 1 eq) in DCM (130 mL) was added m-CPBA (24 g, 0.12 mmol, 85% purity, 2 eq) at 0 °C, then the mixture was stirred at 25 °C for 12 hrs. The solution was diluted with H2O (200 mL) and extracted with DCM (200 mL x 3).
  • Step 3 3-((methylsulfonyl)methyl)azetidine (7-3): To a solution of 7-2 (11 g, 44 mmol, 1 eq) in MeOH (55 mL) was added HC1 (55 mL) at 0 °C. The mixture was stirred at 25 °C for 6 hrs. The solution was concentrated under reduced pressure to give 7-3 (7.9 g, crude) as a white solid.
  • Step 4 4'-bromo-[l,l'-biphenyl]-4-carbaldehyde (7-4): To a solution of (4- formylphenyl)boronic acid (30 g, 0.20 mmol, 1 eq) and l-bromo-4-iodo-benzene (57 g, 0.20 mmol, 1 eq) in dioxane (500 mL) and H2O (50 mL) was added Na2COs (64 g, 0.60 mmol, 3 eq).
  • Step 5 l-((4'-bromo-[l,l'-biphenyl]-4-yl)methyl)-3-
  • Step 6 3-((methylsulfonyl)methyl)-l-((4'-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)-[l,l'-biphenyl]-4-yl)methyl)azetidine (7-6): To a solution of 7-5 (15 g, 38 mmol, 1 eq) and bis(pinacolato)diboron (BPD) (15 g, 57 mmol, 1.5 eq) in dioxane (200 mL) was added KOAc (11 g, 0.11 mol, 3 eq), then the mixture was purged with N2 3 times, then the Pd(dppf)C12 CH2Q2 (3.1 g, 3.8 mmol, 0.1 eq) was added, then the mixture was purged with N2 2 times, then the mixture was stirred at 80°C for 12 hrs under N2 atmosphere.
  • BPD bis(pinacolato)d
  • Step 7 ethyl 2-((lr,4r)-4-((4,6-difluoro-5-(4'-((3-
  • Step 8 ethyl 2-((lr,4r)-4-((4,6-difluoro-5-(4'-((3-
  • Step 9 2-((lr,4r)-4-((4,6-difluoro-5-(4'-((3-((methylsulfonyl)methyl)azetidin-l- yl)methyl)-[l,l'-biphenyl]-4-yl)-lH-benzo[d]imidazol-2-yl)oxy)cyclohexyl)acetic acid
  • Compound 29 To a solution of 7-8 (1.5 g, 1.4 mmol, 62% purity, 1 eq) in MeOH (10 mL) and H2O (10 mL) was added LiOHTLO (0.30 g, 7 mmol, 5 eq) at 25 °C, then the mixture was stirred at 25 °C for 24 h.
  • Example 8 2-((lr,4r)-4-((4,6-difluoro-5-(4'-((4-(2-(methylsulfonyl)ethyl)piperazin-l- yl)methyl)-[l,l'-biphenyl]-4-yl)-lH-benzo[d]imidazol-2-yl)oxy)cyclohexyl)acetic acid (Compound 56):
  • Step 1 tert-butyl 4-(2-(methylsulfonyl) ethyl) piperazine-l-carboxylate (8-1): To a solution of tert-butyl piperazine-l-carboxylate (1.8 g, 9.4 mmol, 1 eq and
  • Step 2 l-(2-(methylsulfonyl) ethyl) piperazine (8-2): A solution of 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 vacuum to give a 8-2 (0.2, crude) as a white solid.
  • Step 3 l-((4'-bromo-[l,l'-biphenyl]-4-yl)methyl)-4-(2- (methylsulfonyl)ethyl)piperazine (8-3): To a solution of 8-2 (26 g, 97 mmol, 1.2 eq, 2HC1) and 7-4 (21 g, 80 mmol, 1 eq) in THF (200 mL) and DMSO (200 mL) was added KO Ac (24 g, 0.24 mol, 3 eq) at 25 °C. The solution was stirred at 40 °C for 1 hr.
  • Step 4 l-(2-(methylsulfonyl)ethyl)-4-((4'-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)-[l,l'-biphenyl]-4-yl)methyl)piperazine (8-4): To a solution of 8-3 (41 g, 94 mmol, 1 eq) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (35 g, 0.14 mol, 1.5 eq) in dioxane (1 L) was added KOAc (28 g, 0.28 mol, 3 eq) at 25 °C.
  • Step 5 ethyl 2-((lr,4r)-4-((4,6-difluoro-5-(4'-((4-(2- (methylsulfonyl)ethyl)piperazin-l-yl)methyl)-[l,l'-biphenyl]-4-yl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-benzo[d]imidazol-2-yl)oxy)cyclohexyl)acetate (8-5): A mixture of 8-4 (26 g, 36 mmol, 1.2 eq , ethyl 2-[4-[4,6-difluoro-5-iodo-l-(2- trimethylsilylethoxymethyl)benzimidazol-2-yl]oxycyclohexyl]acetate (18 g, 30 mmol, 1 eq and Na2CC>3 (9.6 g, 91 mmol, 3 e
  • Step 6 ethyl 2-((lr,4r)-4-((4,6-difluoro-5-(4'-((4-(2- (methylsulfonyl)ethyl)piperazin-l-yl)methyl)-[l,l'-biphenyl]-4-yl)-lH-benzo[d]imidazol-2- yl)oxy)cyclohexyl)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.
  • Step 8 2-((lr,4r)-4-((4,6-difluoro-5-(4'-((4-(2-(methylsulfonyl)ethyl)piperazin-l- yl)methyl)-[l,l'-biphenyl]-4-yl)-lH-benzo[d]imidazol-2-yl)oxy)cyclohexyl)acetic acid
  • Compound 56 To a solution of 8-6 (6 g, 6.5 mmol, 1 eq) in i-PrOH (10 mL) and H2O (10 mL) was added LiOH.H ⁇ O (2.8 g, 66 mmol, 10 eq) at 25 °C.
  • Example A-l In Vitro pAMPKl Kinase Activation Assay
  • Compound effect on AMPK enzyme activation was determined in a cell-free format with a 12-point concentration curve.
  • the ADP-Glo detection system was used to determine phosphorylation of a SAMS peptide substrate.
  • Recombinant AMPK al/pi/yl complex was preactivated by phosphorylation with CAMKK2 followed by incubated with compound for 15 minutes prior to the SAMS phosphorylation reaction.
  • Activity curves and EC50 values were fitted by interpolation to an ATP:ADP standard curve as indicated by the ADP-Glo manufacturer using Prism software.

Abstract

La présente invention concerne, au moins en partie, des activateurs de l'AMPK utiles pour le traitement d'états pathologiques ou de troubles associés à l'AMPK. Dans certains modes de réalisation, l'état pathologique ou le trouble est associé à l'axe intestin-cerveau. Dans certains modes de réalisation, l'état pathologique ou le trouble est associé à une infection et à une inflammation systémiques dues à une barrière intestinale perméable. Dans certains modes de réalisation, les activateurs de l'AMPK sont des composés restreints à l'intestin. Dans certains modes de réalisation, les activateurs de l'AMPK sont des agonistes, des superagonistes, des agonistes complets ou des agonistes partiels.
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US11851429B2 (en) 2020-05-19 2023-12-26 Kallyope, Inc. AMPK activators

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WO2012116145A1 (fr) * 2011-02-25 2012-08-30 Merck Sharp & Dohme Corp. Nouveaux dérivés d'azabenzimidazole cyclique utiles en tant qu'agents antidiabétiques
US20120309736A1 (en) * 2010-02-25 2012-12-06 Merck Sharp & Donme Corp Novel cyclic benzimidazole derivatives useful anti-diabetic agents
US20140194420A1 (en) * 2011-07-15 2014-07-10 Shionogi & Co., Ltd. Azabenzimidazole derivative having ampk-activating activity
US20190183866A1 (en) * 2016-05-20 2019-06-20 Shionogi & Co., Ltd. 5-substituted benzimidazole and 5-substituted azabenzimidazole derivative both having ampk activation effect
WO2021263039A1 (fr) * 2020-06-26 2021-12-30 Kallyope, Inc. Activateurs d'ampk

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US20120309736A1 (en) * 2010-02-25 2012-12-06 Merck Sharp & Donme Corp Novel cyclic benzimidazole derivatives useful anti-diabetic agents
WO2012116145A1 (fr) * 2011-02-25 2012-08-30 Merck Sharp & Dohme Corp. Nouveaux dérivés d'azabenzimidazole cyclique utiles en tant qu'agents antidiabétiques
US20140194420A1 (en) * 2011-07-15 2014-07-10 Shionogi & Co., Ltd. Azabenzimidazole derivative having ampk-activating activity
US20190183866A1 (en) * 2016-05-20 2019-06-20 Shionogi & Co., Ltd. 5-substituted benzimidazole and 5-substituted azabenzimidazole derivative both having ampk activation effect
WO2021263039A1 (fr) * 2020-06-26 2021-12-30 Kallyope, Inc. Activateurs d'ampk

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11851429B2 (en) 2020-05-19 2023-12-26 Kallyope, Inc. AMPK activators

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