GPR40 agonists

Abstract

This disclosure is directed, at least in part, to GPR40 agonists useful for the treatment of conditions or disorders involving the gut-brain axis. In some embodiments, the GPR40 agonists are gut-restricted compounds. In some embodiments, the GPR40 agonists are full agonists or partial agonists. In some embodiments, the condition or disorder is a metabolic disorder, such as diabetes, obesity, nonalcoholic steatohepatitis (NASH), or a nutritional disorder such as short bowel syndrome.

Description

GPR40 AGONISTS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of US Provisional Application No.63 / 611,881 filed on December 19, 2023, which is incorporated herein by reference in its entirety. BRIEF SUMMARY OF THE INVENTION

[0002] Disclosed herein, in certain embodiments, are free fatty acid receptor 1 (GPR40) agonists useful for the treatment of conditions or disorders involving the gut-brain axis. In some embodiments, the GPR40 agonists are gut-restricted or selectively modulate GPR40 located in the gut. In some embodiments, the condition is selected from the group consisting of: central nervous system (CNS) disorders including mood disorders, anxiety, depression, affective disorders, schizophrenia, malaise, cognition disorders, addiction, autism, epilepsy, neurodegenerative disorders, Alzheimer’s disease, and Parkinson’s disease, Lewy Body dementia, episodic cluster headache, migraine, pain; metabolic conditions including diabetes and its complications such as chronic kidney disease / diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, and 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, psoriasis and celiac disease; necrotizing enterocolitis; gastrointestinal injury resulting from toxic insults such as radiation or chemotherapy; diseases / disorders of gastrointestinal barrier dysfunction including environmental enteric dysfunction, spontaneous bacterial peritonitis; functional gastrointestinal disorders such as irritable bowel syndrome, functional dyspepsia, functional abdominal bloating / distension, functional diarrhea, functional constipation, and opioid-induced constipation; gastroparesis; nausea and vomiting; disorders related to microbiome dysbiosis, and other conditions involving the gut-brain axis.

[0003] Disclosed herein, in certain embodiments, is a compound of Formula (I):Formula (I)or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R1is C1-C10fluoroalkyl, C1-C10fluoroalkoxy, C3-C12cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10aryl, 5- to 9-membered heteroaryl, or -C(=O)N(R11)2; wherein each fluoroalkyl, fluoroalkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, C1-C6alkyl, C3-C6cycloalkyl, C1-C6fluoroalkyl, C1-C6hydroxyalkyl, -CN, -OH, -O-(C1-C6alkyl), and -O-(C1-C6fluoroalkyl); R2is hydrogen, C1-C6alkyl, or C3-C6cycloalkyl; each R3, R4, and R5are each independently hydrogen, halogen, or C1-C6alkyl; R6is C1-C6alkyl; R7is hydrogen or C1-C6alkyl; Y is CH, CR8, or N; each R8is independently halogen, -CN, -OH, -O-(C1-C6alkyl), -O–(C1-C6fluoroalkyl), - NH2, -NH-(C1-C6alkyl), -N(C1-C6alkyl)2, C1-C6alkyl, or C1-C6fluoroalkyl; each R9is independently halogen, C1-C6alkyl, or C1-C6fluoroalkyl; each R10is independently halogen, -CN, -OH, -O-(C1-C6alkyl), -O–(C1-C6fluoroalkyl), - NH2, -NH-(C1-C6alkyl), -N(C1-C6alkyl)2, C1-C6alkyl, or C1-C6fluoroalkyl; n is 0, 1, or 2; m is 0, 1, 2, 3, or 4; p is 0, 1, or 2; each R11is independently hydrogen, C1-C10alkyl, C2-C10alkenyl, C2-C10alkynyl, C3-C10cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl, or monocyclic heteroaryl; wherein each alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, -CN, -OH, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6hydroxyalkyl, -O-(C1-C6alkyl), and -O-(C1-C6fluoroalkyl); or two R11on the same nitrogen atom are taken together with the nitrogen to which they are attached to form a 3- to 10-membered N-heterocycloalkyl; wherein the heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, -CN, -OH, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6hydroxyalkyl, -O-(C1-C6alkyl), and -O-(C1-C6fluoroalkyl).

[0004] Any combination of the groups described above or below for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds.

[0005] In some embodiments, the compound is a compound of Formula (II):Formula (II) or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.

[0006] In some embodiments, the compound is a compound of Formula (III):Formula (III) or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.

[0007] In some embodiments, the compound is a compound of Formula (IV):Formula (IV) or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.

[0008] Disclosed herein, in certain embodiments, are pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, and at least one pharmaceutically acceptable excipient.

[0009] Disclosed herein, in certain embodiments, are methods of treating a condition or disorder involving the gut-brain axis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof. In some embodiments, the condition or disorder is associated with GPR40 activity. In some embodiments,the condition or disorder is a metabolic disorder. In some embodiments, the metabolic disorder is type 2 diabetes. In some embodiments, the metabolic disorder is obesity. In some embodiments, the condition or disorder is type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia, nonalcoholic steatohepatitis, or hypertension. In some embodiments, the condition or disorder is a nutritional disorder. In some embodiments, the condition or disorder is short bowel syndrome, intestinal failure, or intestinal insufficiency. In some embodiments, the nutritional disorder is short bowel syndrome. In some embodiments, the condition or disorder is an eating disorder. In some embodiments, the eating disorder is hyperphagia or binge eating disorder. In some embodiments, the eating disorder is binge eating disorder. In some embodiments, the condition or disorder is addiction. In some embodiments, the addiction is alcohol addiction, cocaine addiction, methamphetamine addiction, nicotine addiction, or opioid addiction. In some embodiments, the compound disclosed herein is gut-restricted. In some embodiments, the compound disclosed herein has low systemic exposure.

[0010] In some embodiments, the methods disclosed herein further comprise administering one or more additional therapeutic agents to the subject. In some embodiments, the one or more additional therapeutic agents are selected from a TGR5 agonist, a GPR119 agonist, an SSTR5 antagonist, an SSTR5 inverse agonist, a CCK1 agonist, a PDE4 inhibitor, a DPP-4 inhibitor, a GLP-1 receptor agonist, a GOAT inhibitor, metformin, or combinations thereof. In some embodiments, the TGR5 agonist, GPR119 agonist, SSTR5 antagonist, SSTR5 inverse agonist or CCK1 agonist is gut-restricted.

[0011] Other objects, features and advantages of the compounds, methods and compositions described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the instant disclosure will become apparent to those skilled in the art from this detailed description. As will be realized, the present disclosure is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, all without departing from the disclosure. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive. INCORPORATION BY REFERENCE

[0012] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent publications and patents or patent applications incorporated by reference contradict thedisclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such contradictory material. DETAILED DESCRIPTION OF THE INVENTION

[0013] This disclosure is directed, at least in part, to GPR40 agonists useful for the treatment of conditions or disorders involving the gut-brain axis. In some embodiments, the GPR40 agonists are gut-restricted compounds. In some embodiments, the GPR40 agonists are full agonists or partial agonists. Definitions

[0014] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes a plurality of such agents, and reference to “the cell” includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulas, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included.

[0015] The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range.

[0016] The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, “consist of” or “consist essentially of” the described features.

[0017] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below:

[0018] As used herein, C1-Cxincludes C1-C2, C1-C3... C1-Cx. By way of example only, 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. Thus, by way of example only, “C1-C4alkyl” indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, iso- butyl, sec-butyl, and t-butyl.

[0019] “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 sp3-hybridized carbon of the alkyl residue is attached to the rest of the molecule by a single bond. Examples include, but are notlimited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1- butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl- 1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2- dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n- pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl, and the like. Whenever it appears herein, a numerical range such as “C1-C6alkyl” means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a C1-C10alkyl, a C1-C9alkyl, a C1-C8alkyl, a C1-C7alkyl, a C1-C6alkyl, a C1-C5alkyl, a C1-C4alkyl, a C1-C3alkyl, a C1-C2alkyl, or a C1alkyl. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted as described below by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, - OC(O)Ra, -OC(O)-ORf, -N(Ra)2, -N+(Ra)3, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORf, - OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRf(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), - S(O)tRf(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, and each Rfis independently alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl.

[0020] “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 sp2-hybridized carbon or an sp3-hybridized carbon of the alkenyl residue is attached to the rest of the molecule by a single bond. The group may be in either the cis or trans conformation about the double bond(s), and should be understood to include both isomers. Examples include, but are not limited to ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl (-C(CH3)=CH2), butenyl, 1,3-butadienyl and the like. Whenever it appears herein, a numerical range such as “C2-C6alkenyl” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. In some embodiments, the alkenyl is a C2-C10alkenyl, a C2-C9alkenyl, a C2-C8alkenyl, a C2-C7alkenyl, a C2-C6alkenyl, a C2-C5alkenyl, a C2-C4alkenyl, a C2-C3alkenyl, or aC2alkenyl. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. Unlessstated otherwise specifically in the specification, an alkenyl group is optionally substituted as described below by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Rf, -OC(O)-ORf, -N(Ra)2, -N+(Ra)3, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORf, -OC(O)-N(Ra)2, -N(Ra)C(O)Rf, -N(Ra)S(O)tRf(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRf(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, and each Rfis independently alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl.

[0021] “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 sp3-hybridized carbon of the alkynyl residue is attached to the rest of the molecule by a single bond. Examples include, but are not limited to ethynyl, 2- propynyl, 2-butynyl, 1,3-butadiynyl and the like. Whenever it appears herein, a numerical range such as “C2-C6alkynyl” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated. In some embodiments, the alkynyl is a C2-C10alkynyl, a C2-C9alkynyl, a C2-C8alkynyl, a C2-C7alkynyl, a C2-C6alkynyl, a C2-C5alkynyl, a C2-C4alkynyl, a C2-C3alkynyl, or a C2alkynyl. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted as described below by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)Ra, -OC(O)-ORf, -N(Ra)2, -N+(Ra)3, -C(O)Ra, - C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORf, -OC(O)-N(Ra)2, -N(Ra)C(O)Rf, -N(Ra)S(O)tRf(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRf(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, and each Rfis independently alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl.

[0022] “Alkylene” or “alkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon in the alkylene chain or through any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkylene group is optionally substituted asdescribed below by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)Ra, -OC(O)-ORf, -N(Ra)2, -N+(Ra)3, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORf, -OC(O)-N(Ra)2, -N(Ra)C(O)Rf, -N(Ra)S(O)tRf(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRf(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, and each Rfis independently alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl.

[0023] “Alkenylene” or “alkenylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. Unless stated otherwise specifically in the specification, an alkenylene group is optionally substituted as described below by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, - SRa, -OC(O)-Rf, -OC(O)-ORf, -N(Ra)2, -N+(Ra)3, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - N(Ra)C(O)ORf, -OC(O)-N(Ra)2, -N(Ra)C(O)Rf, -N(Ra)S(O)tRf(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRf(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, and each Rfis independently alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl.

[0024] “Alkynylene” or “alkynylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and having from two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. Unless stated otherwise specifically in the specification, an alkynylene group is optionally substituted as described below by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, - SRa, -OC(O)Ra, -OC(O)-ORf, -N(Ra)2, -N+(Ra)3, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, - N(Ra)C(O)ORf, -OC(O)-N(Ra)2, -N(Ra)C(O)Rf, -N(Ra)S(O)tRf(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRf(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, and each Rfis independently alkyl, haloalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl.

[0025] “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.

[0026] The term “aromatic” refers to a planar ring having a delocalized p-electron system containing 4n+2 p electrons, where n is an integer. The term “aromatic” includes both carbocyclic aryl (“aryl”, e.g., phenyl) and heterocyclic aryl (or “heteroaryl” or “heteroaromatic”) groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups.

[0027] “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 atoms unless otherwise specified (i.e., from 6 to 18 carbon atoms), where at least one of the rings in the ring system is fully unsaturated, (i.e., it contains a cyclic, delocalized (4n+2) ^–electron system in accordance with the Hückel theory). The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. In some embodiments, the aryl is a C6-C10aryl. In some embodiments, the aryl is a phenyl. Unless stated otherwise specifically in the specification, the term “aryl” or the prefix “ar-“ (such as in “aralkyl”) is meant to include aryl radicals optionally substituted as described below by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -Rb-ORa, -Rb-SRa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORf, -Rb-OC(O)- N(Ra)2, -Rb-N(Ra)2, -Rb-N+(Ra)3, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc- C(O)N(Ra)2, -Rb-N(Ra)C(O)ORf, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRf(where t is 1 or 2), -Rb- S(O)tORa(where t is 1 or 2), -Rb-S(O)tRf(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, Rfis independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain.

[0028] An “arylene” refers to a divalent radical derived from an “aryl” group as described above linking the rest of the molecule to a radical group. The arylene is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In some embodiments, the arylene is a phenylene. Unless stated otherwise specifically in the specification, an arylene group is optionally substituted as described above for an aryl group.

[0029] The term “carbocyclic” or “carbocycle” refers to a ring or ring system where the atoms forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocyclic from “heterocyclic” rings or “heterocycles” in which the ring backbone contains atleast one atom which is different from carbon. In some embodiments, at least one of the two rings of a bicyclic carbocycle is aromatic. In some embodiments, both rings of a bicyclic carbocycle are aromatic. Carbocycles include aryls and cycloalkyls.

[0030] “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-C15cycloalkyl), from three to ten carbon atoms (C3-C10cycloalkyl), from three to eight carbon atoms (C3-C8cycloalkyl), from three to six carbon atoms (C3-C6cycloalkyl), from three to five carbon atoms (C3-C5cycloalkyl), or three to four carbon atoms (C3-C4cycloalkyl). In some embodiments, the cycloalkyl is a 3- to 6-membered cycloalkyl. In some embodiments, the cycloalkyl is a 5- to 6-membered cycloalkyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls or carbocycles include, for example, adamantyl, norbornyl, decalinyl, bicyclo[1.1.1]pentyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, the term “cycloalkyl” is meant to include cycloalkyl radicals optionally substituted as described below by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -Rb-ORa, -Rb-SRa, -Rb-OC(O)-Ra, -Rb- OC(O)-ORf, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-N+(Ra)3, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb- C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORf, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRf(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2), -Rb-S(O)tRf(where t is 1 or 2) and -Rb- S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, Rfis independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain.

[0031] A “cycloalkylene” refers to a divalent radical derived from a “cycloalkyl” group as described above linking the rest of the molecule to a radical group. The cycloalkylene is attached to the rest of the molecule through a single bond and to the radical group through a single bond.Unless stated otherwise specifically in the specification, a cycloalkylene group is optionally substituted as described above for a cycloalkyl group.

[0032] “Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0033] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxy radicals, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0034] “Fluoroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.

[0035] “Haloalkoxy” or “haloalkoxyl” refers to an alkoxyl radical, as defined above, that is substituted by one or more halo radicals, as defined above.

[0036] “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.

[0037] “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2- hydroxypropyl, 3-hydroxypropyl, 1,2-dihydroxyethyl, 2,3-dihydroxypropyl, 2,3,4,5,6- pentahydroxyhexyl, and the like.

[0038] The term "heterocycle" or “heterocyclic” refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings containing one to four heteroatoms in the ring(s), where each heteroatom in the ring(s) is selected from O, S and N, wherein each heterocyclic group has from 3 to 10 atoms in its ring system, and with the proviso that any ring does not contain two adjacent O or S atoms. Non-aromatic heterocyclic groups (also known as heterocycloalkyls) include rings having 3 to 10 atoms in its ring system and aromatic heterocyclic groups include rings having 5 to 10 atoms in its ring system. The heterocyclic groups include benzo-fused ring systems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6- tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3- azabicyclo[4.1.0]heptanyl, 3H-indolyl, indolin-2-onyl, isoindolin-1-onyl, isoindoline-1,3-dionyl,3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl, isoindoline-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, 1H-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups are either C-attached (or C-linked) or N-attached where such is possible. For instance, a group derived from pyrrole includes both pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). Further, a group derived from imidazole includes imidazol-1-yl or imidazol-3-yl (both N- attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-attached). The heterocyclic groups include benzo-fused ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (=O) moieties, such as pyrrolidin-2-one. In some embodiments, at least one of the two rings of a bicyclic heterocycle is aromatic. In some embodiments, both rings of a bicyclic heterocycle are aromatic.

[0039] “Heterocycloalkyl” refers to a stable 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 6- membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3- dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited tothe monosaccharides, the disaccharides and the oligosaccharides. More preferably, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e., skeletal atoms of the heterocycloalkyl ring). Unless stated otherwise specifically in the specification, the term “heterocycloalkyl” is meant to include heterocycloalkyl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -Rb- ORa, -Rb-SRa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORf, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-N+(Ra)3, -Rb- C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORf, -Rb- N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRf(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2), -Rb-S(O)tRf(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, Rfis independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain.

[0040] “N-heterocycloalkyl” refers to a heterocycloalkyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocycloalkyl radical to the rest of the molecule is through a nitrogen atom in the heterocycloalkyl radical. An N-heterocycloalkyl radical is optionally substituted as described above for heterocycloalkyl radicals.

[0041] “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.

[0042] A “heterocycloalkylene” refers to a divalent radical derived from a “heterocycloalkyl” group as described above linking the rest of the molecule to a radical group. The heterocycloalkylene is attached to the rest of the molecule through a single bond and to the radical group through a single bond. Unless stated otherwise specifically in the specification, a heterocycloalkylene group is optionally substituted as described above for a heterocycloalkyl group.

[0043] “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 selectedfrom nitrogen, oxygen and sulfur. As used herein, the heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ^–electron system in accordance with the Hückel theory. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a monocyclic heteroaryl, or a monocyclic 5- or 6- membered heteroaryl. In some embodiments, the heteroaryl is a 6,5-fused bicyclic heteroaryl. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Unless stated otherwise specifically in the specification, the term “heteroaryl” is meant to include heteroaryl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, oxo, thioxo, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -Rb-ORa, -Rb-SRa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORf, -Rb-OC(O)- N(Ra)2, -Rb-N(Ra)2, -Rb-N+(Ra)3, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc- C(O)N(Ra)2, -Rb-N(Ra)C(O)ORf, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRf(where t is 1 or 2), -Rb- S(O)tORa(where t is 1 or 2), -Rb-S(O)tRf(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, Rfis independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain.

[0044] 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.

[0045] The term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above. Further, an optionally substituted group may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), mono- substituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.). It will be understood by those skilled in the art with respect to any group containing one or more substituents that suchgroups are not intended to introduce any substitution or substitution patterns (e.g., substituted alkyl includes optionally substituted cycloalkyl groups, which in turn are defined as including optionally substituted alkyl groups, potentially ad infinitum) that are sterically impractical and / or synthetically non-feasible.

[0046] The term “modulate” or “modulating” or “modulation” refers to an increase or decrease in the amount, quality, or effect of a particular activity, function or molecule. By way of illustration and not limitation, agonists, partial agonists, inverse agonists, antagonists, and allosteric modulators of a G protein-coupled receptor are modulators of the receptor.

[0047] The term “agonism” as used herein refers to the activation of a receptor or enzyme by a modulator, or agonist, to produce a biological response.

[0048] The term “agonist” as used herein refers to a modulator that binds to a receptor or target enzyme and activates the receptor or enzyme to produce a biological response. By way of example, “GPR40 agonist” can be used to refer to a compound that exhibits an EC50with respect to GPR40 activity of no more than about 100 μM, as measured in the as measured in the inositol phosphate accumulation assay. In some embodiments, the term “agonist” includes full agonists or partial agonists.

[0049] The term “full agonist” refers to a modulator that binds to and activates a receptor or target enzyme with the maximum response that an agonist can elicit at the receptor or enzyme.

[0050] The term “partial agonist” refers to a modulator that binds to and activates a receptor or target enzyme, but has partial efficacy, that is, less than the maximal response, at the receptor or enzyme relative to a full agonist.

[0051] 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.

[0052] The term “antagonism” 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.

[0053] The term “antagonist” or “neutral antagonist” as used herein refers to a modulator that binds to a receptor or target enzyme and blocks a biological response. By way of example, “SSTR5 antagonist” can be used to refer to a compound that exhibits an IC50with respect to SSTR5 activity of no more than about 100 μM, as measured in the as measured in the inositol phosphate accumulation assay. 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.

[0054] The term “inverse agonist” refers to a modulator that binds to the same receptor or target enzyme as an agonist but induces a pharmacological response opposite to that agonist, i.e., a decrease in biological response.

[0055] The term “negative allosteric modulator” refers to a modulator that binds to a site distinct from the orthosteric binding site and reduces or dampens the effect of an agonist.

[0056] As used herein, “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, EC50refers 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, EC50refers to the concentration of an agonist (e.g., a GPR40 agonist) that is required for 50% activation of a receptor or target enzyme (e.g., GPR40).

[0057] As used herein, “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. For example, IC50refers to the half maximal (50%) inhibitory concentration (IC) of a substance as determined in a suitable assay. In some instances, anIC50is determined in an in vitro assay system. In some embodiments as used herein, IC50refers to the concentration of a modulator (e.g., an antagonist or inhibitor) that is required for 50% inhibition of a receptor, for example, SSTR5, or an enzyme, for example, DPP-4, or PDE4.

[0058] The terms “subject,” “individual,” and “patient” are used interchangeably. These terms encompass mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.

[0059] The term “gut-restricted” as used herein refers to a compound, e.g., a GPR40 agonist, that is predominantly active in the gastrointestinal system. In some embodiments, the biological activity of the gut-restricted compound, e.g., a gut-restricted GPR40 agonist, is restricted to the gastrointestinal system. In some embodiments, gastrointestinal concentration of a gut-restricted modulator, e.g., a gut-restricted GPR40 agonist, is higher than the IC50value or the EC50value of the gut-restricted modulator against its receptor or target enzyme, e.g., GPR40, while the plasma levels of said gut-restricted modulator, e.g., gut-restricted GPR40 agonist, are lower than the IC50value or the EC50value of the gut-restricted modulator against its receptor or target enzyme, e.g., GPR40. In some embodiments, the gut-restricted compound, e.g., a gut-restricted GPR40 agonist, is non-systemic. In some embodiments, the gut-restricted compound, e.g., a gut-restricted GPR40 agonist, is a non-absorbed compound. In other embodiments, the gut-restricted compound, e.g., a gut-restricted GPR40 agonist, is absorbed, but is rapidly metabolized to metabolites that are significantly less active than the modulator itself toward the target receptor or enzyme, i.e., a “soft drug.” In other embodiments, the gut-restricted compound, e.g., a gut-restricted GPR40agonist, is minimally absorbed and rapidly metabolized to metabolites that are significantly less active than the modulator itself toward the target receptor or enzyme.

[0060] In some embodiments, the gut-restricted modulator, e.g., a gut-restricted GPR40 agonist, is non-systemic but is instead localized to the gastrointestinal system. For example, the modulator, e.g., a gut-restricted GPR40 agonist, may be present in high levels in the gut, but low levels in serum. In some embodiments, the systemic exposure of a gut-restricted modulator, e.g., a gut-restricted GPR40 agonist, is, for example, less than 100, less than 50, less than 20, less than 10, or less than 5 nM, bound or unbound, in blood serum. In some embodiments, the intestinal exposure of a gut-restricted modulator, e.g., a gut-restricted GPR40 agonist, is, for example, greater than 1000, 5000, 10000, 50000, 100000, or 500000 nM. In some embodiments, a modulator, e.g., a GPR40 agonist, is gut-restricted due to poor absorption of the modulator itself, or because of absorption of the modulator which is rapidly metabolized in serum resulting in low systemic circulation, or due to both poor absorption and rapid metabolism in the serum. In some embodiments, a modulator, e.g., a GPR40 agonist, is covalently bonded to a kinetophore, optionally through a linker, which changes the pharmacokinetic profile of the modulator.

[0061] In particular embodiments, the gut-restricted GPR40 agonist is a soft drug. The term “soft drug” as used herein refers to a compound that is biologically active but is rapidly metabolized to metabolites that are significantly less active than the compound itself toward the target receptor. In some embodiments, the gut-restricted GPR40 agonist is a soft drug that is rapidly metabolized in the blood to significantly less active metabolites. In some embodiments, the gut-restricted GPR40 agonist is a soft drug that is rapidly metabolized in the liver to significantly less active metabolites. In some embodiments, the gut-restricted GPR40 agonist is a soft drug that is rapidly metabolized in the blood and the liver to significantly less active metabolites. In some embodiments, the gut-restricted GPR40 agonist is a soft drug that has low systemic exposure. In some embodiments, the biological activity of the metabolite(s) is / are 10- fold, 20-fold, 50-fold, 100-fold, 500-fold, or 1000-fold lower than the biological activity of the soft drug gut-restricted GPR40 agonist.

[0062] The term “kinetophore” as used herein refers to a structural unit tethered to a small molecule modulator, e.g., a GPR40 agonist, 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., a GPR40 agonist, and has minimal changes to the binding to or association with a receptor or target enzyme. The defining feature of a kinetophore is not its interaction with the target, for example a receptor, but rather its effect on specific physiochemicalcharacteristics of the modulator to which it is attached, e.g., a GPR40 agonist. In some instances, kinetophores are used to restrict a modulator, e.g., a GPR40 agonist, to the gut.

[0063] The term “linked” as used herein refers to a covalent linkage between a modulator, e.g., a GPR40 agonist, and a kinetophore. The linkage can be through a covalent bond, or through a “linker.” As used herein, “linker” refers to one or more bifunctional molecules which can be used to covalently bond to the modulator, e.g., a GPR40 agonist, and kinetophore. In some embodiments, the linker is attached to any part of the modulator, e.g., a GPR40 agonist, so long as the point of attachment does not interfere with the binding of the modulator to its receptor or target enzyme. In some embodiments, the linker is non-cleavable. In some embodiments, the linker is cleavable. In some embodiments, the linker is cleavable in the gut. In some embodiments, cleaving the linker releases the biologically active modulator, e.g., a GPR40 agonist, in the gut.

[0064] The term “gastrointestinal system” (GI system) or “gastrointestinal tract” (GI tract) as used herein, refers to the organs and systems involved in the process of digestion. The gastrointestinal tract includes the esophagus, stomach, small intestine, which includes the duodenum, jejunum, and ileum, and large intestine, which includes the cecum, colon, and rectum. In some embodiments herein, the GI system refers to the “gut,” meaning the stomach, small intestines, and large intestines or to the small and large intestines, including, for example, the duodenum, jejunum, and / or colon. Gut-Brain Axis

[0065] 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.

[0066] In some instances, the gut-brain axis comprises the GI tract; the PNS including the dorsal root ganglia (DRG) and the sympathetic and parasympathetic arms of the autonomic nervous system including the enteric nervous system and the vagus nerve; the CNS; and the neuroendocrine and neuroimmune systems including the hypothalamic–pituitary–adrenal axis (HPA axis). The gut-brain axis is important for maintaining homeostasis of the body and is regulated and modulates physiology through the central and peripheral nervous systems and endocrine, immune, and metabolic pathways.

[0067] 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.

[0068] 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, and cardiovascular disease, metabolic syndrome, obesity, dyslipidemia, and nonalcoholic steatohepatitis (NASH); eating and nutritional disorders including hyperphagia, cachexia, anorexia nervosa, binge eating disorder, 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, psoriasis, and celiac disease; necrotizing enterocolitis; gastrointestinal injury resulting from toxic insults such as radiation or chemotherapy; diseases / disorders of gastrointestinal barrier dysfunction including environmental enteric dysfunction, spontaneous bacterial peritonitis; functional gastrointestinal disorders such as irritable bowel syndrome, functional dyspepsia, functional abdominal bloating / distension, functional diarrhea, functional constipation, and opioid-induced constipation; gastroparesis; nausea and vomiting; disorders related to microbiome dysbiosis, other conditions involving the gut-brain axis. In some embodiments, the condition is a metabolic disorder. In some embodiments, the metabolic disorder is type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia, or nonalcoholic steatohepatitis. In some embodiments, the metabolic disorder is diabetes. In other embodiments, the metabolic disorder is obesity. In other embodiments, the metabolic disorder is nonalcoholic steatohepatitis. In some embodiments, the condition involving the gut-brain axis is a nutritional disorder. In some embodiments, the nutritional disorder is short bowel syndrome, intestinal failure, or intestinal insufficiency. In some embodiments, the nutritional disorder is short bowel syndrome. In some embodiments, the condition involving the gut-brain axis is weight loss or preventing weight gain or weight regain. In some embodiments, the condition involving the gut-brain axis is weight loss or preventing weight gain or weight regain post-bariatric surgery. In some embodiments, the condition involving the gut-brain axis is weight loss or preventing weight gain or weight regain, wherein the subject has had bariatric surgery. GPR40 in the Gut-Brain Axis

[0069] Free fatty acid receptor 1 (FFA1, FFAR1), also known as GPR40, is a class A G- protein coupled receptor. This membrane protein binds free fatty acids, acting as a nutrient sensor for regulating energy homeostasis. In some instances, GPR40 is expressed in enteroendocrine cells and pancreatic islet β cells. In some instances, GPR40 is expressed in enteroendocrine cells. Several naturally-occurring medium to long-chain fatty acids act as ligands for GPR40. GPR40 agonists or partial agonists may be useful in the treatment of metabolic diseases such as obesity, diabetes, and NASH, and other diseases involving the gut-brain axis.

[0070] In some instances, modulators of GPR40, for example, GPR40 agonists or partial agonists, induce insulin secretion. In some instances, modulators of GPR40, for example, GPR40 agonists or partial agonists, induce an increase in cytosolic Ca2+. In some instances, modulators of GPR40, for example, GPR40 agonists or partial agonists, induce higher levels of intracellular cAMP. In some instances, GPR40 modulation is in enteroendocrine cells. In some instances, modulators of GPR40, for example, GPR40 agonists or partial agonists, induce the secretion of GLP-1, GLP-2, GIP, PYY, CCK, or other hormones. In some instances, modulators of GPR40, for example, GPR40 agonists, induce the secretion of GLP-1, GIP, CCK or PYY. In some instances, modulators of GPR40, for example, GPR40 agonists, induce the secretion of GLP-1.

[0071] Described herein is a method of treating a condition or disorder involving the gut- brain axis in an individual in need thereof, the method comprising administering to the individual a GPR40 receptor modulator. In some embodiments, the GPR40 receptor modulator is a GPR40 agonist or partial agonist. In some embodiments, the GPR40 receptor modulator is a GPR40 agonist. In some embodiments, the GPR40 receptor modulator is a GPR40 partial agonist. In some embodiments, the GPR40 receptor modulator is a GPR40 positive allosteric modulator. In some embodiments, the GPR40 modulator is a gut-restricted GPR40 modulator. In some embodiments, the GPR40 modulator is a soft drug.

[0072] In some embodiments, the condition or disorder involving the gut-brain axis 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, and cardiovascular disease, metabolic syndrome, obesity, dyslipidemia, and nonalcoholic steatohepatitis (NASH); eating and nutritional disorders including hyperphagia, cachexia, anorexia nervosa, binge eating disorder, 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,psoriasis, and celiac disease; necrotizing enterocolitis; gastrointestinal injury resulting from toxic insults such as radiation or chemotherapy; diseases / disorders of gastrointestinal barrier dysfunction including environmental enteric dysfunction, spontaneous bacterial peritonitis; functional gastrointestinal disorders such as irritable bowel syndrome, functional dyspepsia, functional abdominal bloating / distension, functional diarrhea, functional constipation, and opioid-induced constipation; gastroparesis; nausea and vomiting; disorders related to microbiome dysbiosis, other conditions involving the gut-brain axis. In some embodiments, the condition is a metabolic disorder. In some embodiments, the metabolic disorder is type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia, or nonalcoholic steatohepatitis. In some embodiments, the metabolic disorder is diabetes. In other embodiments, the metabolic disorder is obesity. In other embodiments, the metabolic disorder is nonalcoholic steatohepatitis. In some embodiments, the condition involving the gut-brain axis is a nutritional disorder. In some embodiments, the nutritional disorder is short bowel syndrome, intestinal failure, or intestinal insufficiency. In some embodiments, the nutritional disorder is short bowel syndrome. In some embodiments, the condition involving the gut-brain axis is an eating disorder. In some embodiments, the eating disorder is hyperphagia or binge eating disorder. In some embodiments, the eating disorder is binge eating disorder. In some embodiments, the condition involving the gut-brain axis is weight loss or preventing weight gain or weight regain. In some embodiments, the condition involving the gut-brain axis is weight loss or preventing weight gain or weight regain post-bariatric surgery. In some embodiments, the condition involving the gut- brain axis is weight loss or preventing weight gain or weight regain, wherein the subject has had bariatric surgery.

[0073] Emerging clinical evidence (e.g., Nat Commun 15, 4548 (2024); Nicotine Tob Res 2021 Aug 29;23(10):1682-1690) and the results of multiple preclinical studies (e.g., eBioMedicine 2023;93: 104642; JCI Insight 2023 Jun 22;8(12):e170671) suggest the potential for GLP-1 analogs in substance use disorder. There is also evidence that other gut hormones (e.g., CCK) are involved in substance use disorder. In some instances as discussed above, GPR40 agonists robustly stimulate the secretion of GLP-1, CCK, and multiple other gut hormones. In some embodiments, the condition or disorder involving the gut-brain axis which is treated by the GPR40 agonists described herein is addiction. In some embodiments, the addiction is alcohol addiction, cocaine addiction, methamphetamine addiction, nicotine addiction, or opioid addiction. Gut-Restricted Modulators

[0074] In some instances, differentiation of systemic effects of a GPR40 agonist from beneficial, gut-driven effects would be critical for the development of a GPR40 agonist for the treatment of disease.

[0075] In some instances, activation of GPR40 by a GPR40 agonist recapitulates the lipotoxicity of free fatty acids on pancreatic beta-cells. In some instances, activation of GPR40 by a GPR40 agonist leads to beta-cell degeneration, islet insulin depletion, glucose intolerance and hyperglycemia. In some instances, the detrimental effects on beta-cells by a GPR40 agonist may be mediated through ER stress and NF-kB signaling pathways. In some instances, differentiation of deleterious systemic effects of a GPR40 agonist on beta-cell function and viability from beneficial, gut-driven effects would be critical for the development of a GPR40 agonist for the treatment of disease.

[0076] In some embodiments, the GPR40 agonist is gut restricted. In some embodiments, the GPR40 agonist is designed to be substantially non-permeable or substantially non-bioavailable in the blood stream. In some embodiments, the GPR40 agonist is designed to activate GPR40 activity in the gut and is substantially non-systemic. In some embodiments, the GPR40 agonist has low systemic exposure.

[0077] In some embodiments, a gut-restricted GPR40 agonist has low oral bioavailability. In some embodiments, a gut-restricted GPR40 agonist 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.

[0078] In some embodiments, the unbound plasma levels of a gut-restricted GPR40 agonist are lower than the EC50value of the GPR40 agonist against GPR40. In some embodiments, the unbound plasma levels of a gut-restricted GPR40 agonist are significantly lower than the EC50value of the gut-restricted GPR40 agonist against GPR40. In some embodiments, the unbound plasma levels of the GPR40 agonist are 2-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, or 100- fold lower than the EC50value of the gut-restricted GPR40 agonist against GPR40. In some embodiments, the unbound plasma levels of the GPR40 agonist are greater than 2-fold, greater than 10-fold, greater than 20-fold, greater than 30-fold, greater than 40-fold, greater than 50-fold, or greater than 100-fold lower than the EC50value of the gut-restricted GPR40 agonist against GPR40.

[0079] In some embodiments, a gut-restricted GPR40 agonist has low systemic exposure. In some embodiments, the systemic exposure of a gut-restricted GPR40 agonist is, for example, less than 500, less than 200, less than 100, less than 50, less than 20, less than 10, or less than 5 nM, bound or unbound, in blood serum. In some embodiments, the systemic exposure of a gut-restricted GPR40 agonist 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.

[0080] In some embodiments, a gut-restricted GPR40 agonist has low pancreatic exposure. In some embodiments, the pancreatic exposure of a gut-restricted GPR40 agonist is, for example, less than 500, less than 200, less than 100, less than 50, less than 20, less than 10, or less than 5 nM in the pancreas. In some embodiments, the pancreatic exposure of a gut-restricted GPR40 agonist is, for example, less than 500, less than 200, less than 100, less than 50, less than 20, less than 10, or less than 5 ng / mL in the pancreas.

[0081] In some embodiments, a gut-restricted GPR40 agonist has low permeability. In some embodiments, a gut-restricted GPR40 agonist has low intestinal permeability. In some embodiments, the permeability of a gut-restricted GPR40 agonist is, for example, less than 5.0×10-6cm / s, less than 2.0×10-6cm / s, less than 1.5×10-6cm / s, less than 1.0×10-6cm / s, less than 0.75×10-6cm / s, less than 0.50×10-6cm / s, less than 0.25×10-6cm / s, less than 0.10×10-6cm / s, or less than 0.05×10-6cm / s.

[0082] In some embodiments, a gut-restricted GPR40 agonist has low absorption. In some embodiments, the absorption of a gut-restricted GPR40 agonist is less than less than 40%, less than 30%, less than 20%, or less than 10%, less than 5%, or less than 1%.

[0083] In some embodiments, a gut-restricted GPR40 agonist has high plasma clearance. In some embodiments, a gut-restricted GPR40 agonist 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.

[0084] In some embodiments, a gut-restricted GPR40 agonist is rapidly metabolized upon administration. In some embodiments, the internal ester of the compounds described herein is rapidly cleaved upon administration. In some embodiments, a gut-restricted GPR40 agonist has a short half-life. In some embodiments, the half-life of a gut-restricted GPR40 agonist is less than less than 8 hours, less than 6 hours, less than 4 hours, less than 3 hours, less than 120 min, less than 90 min, less than 60 min, less than 45 min, less than 30 min, or less than 15 min. In some embodiments, the metabolites of a gut-restricted GPR40 agonist have rapid clearance. In some embodiments, the metabolites of a gut-restricted GPR40 agonist are undetectable in less than 8 hours, less than 6 hours, less than 4 hours, less than 3 hours, less than 120 min, less than 90 min, less than 60 min, less than 45 min, less than 30 min, or less than 15 min. In some embodiments, the metabolites of a gut-restricted GPR40 agonist have low bioactivity. In some embodiments, the EC50value of the metabolites of a gut-restricted GPR40 agonist is 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 100-fold, 500-fold, or 1000-fold higher than the EC50value of the gut-restrictedGPR40 agonist against GPR40. In some embodiments, the metabolites of a gut-restricted GPR40 agonist have rapid clearance and low bioactivity.

[0085] In some embodiments of the methods described herein, the GPR40 modulator is gut- restricted. In some embodiments, the GPR40 modulator is a gut-restricted GPR40 agonist. In some embodiments, the GPR40 agonist is a gut-restricted GPR40 full agonist. In some embodiments, the GPR40 agonist is a gut-restricted GPR40 partial agonist. In some embodiments, the GPR40 agonist is covalently bonded to a kinetophore. In some embodiments, the GPR40 agonist is covalently bonded to a kinetophore through a linker. Peptide Hormones of the Gut-Brain Axis

[0086] Incretins are a group of metabolic hormones released in the gut that stimulate a decrease in blood glucose levels in a glucose-dependent manner. Incretins include the peptide hormones GLP-1 and GIP. In some instances, incretin hormones are released in enteroendocrine cells after eating. In some instances, incretin hormones augment the secretion of insulin released from pancreatic beta cells of the islets of Langerhans by a blood glucose-dependent mechanism. In some instances, incretin hormones (such as GLP-1) also inhibit glucagon release from the alpha cells of the islets of Langerhans. Beside insulinotropic effects, GLP-1 has been associated with numerous regulatory and protective effects. GLP-1 inhibits gastric emptying, acid secretion, motility, decreases appetite and promotes satiety. GLP-1 receptor activation has been linked with neurotrophic effects including neurogenesis and neuroprotective effects including reduced necrotic and apoptotic signalling and cell death. GLP-1 receptor agonist treatment is associated with protection against a range of experimental disease models such as Parkinson's disease, Alzheimer's disease, stroke, traumatic brain injury, and multiple sclerosis. Other peptide hormones released in the gut include CCK, PYY, GLP-2, oxyntomdulin, gastrin, secretin, vasoactive intestinal peptide (VIP), motilin, ghrelin, bombesin, calcitonin gene-related peptide (CGRP), chromogranin A, enkephalins, enteroglucagon, galanin, ghrelin, growth factors, growth hormone-releasing factor, leptin, motilin, amylin, neuropeptide Y (NPY), neurotensin, pancreatic polypeptide, somatostatin, substance P and trefoil peptides. These peptides regulate a wide variety of processes including food intake, metabolic rate, glucose homeostasis, gastric emptying, gut motility, gall bladder contraction, pancreatic secretion, intestinal mucosal growth, muscosal protection and repair, pain, cell proliferation and differentiation, water and electrolyte secretion, and intestinal blood flow.

[0087] In some instances, modulating the activity of the GPCRs described herein, e.g., GPR40 and GPR119 increases peptide hormone secretion. In some instances, the biological effect of peptide hormones is in enteroendocrine cells. In some instances, peptide hormones, (e.g., GLP-1 and GIP), stimulate insulin release in a glucose dependent manner. In someinstances, GLP-1, for example, is necessary for normal glucose homeostasis. In some instances, peptide hormones, (e.g., GLP-1, GLP-2 and GIP), contribute to beneficial effects for the treatment of diseases or conditions involving the gut-brain axis (e.g., diabetes, obesity or short bowel syndrome), including 1) increased insulin secretion, 2) increased glucose disposal, 3) suppression in glucose production, 4) reduced gastric emptying, 5) reduction in food intake, 6) body mass reduction, 7) increased cAMP levels, 8) increased nutrient absorption, 9) increased small intestinal length, 10) increased small intestinal weight, 11) increased villus height, and 12) increased villus height / crypt depth ratio. Compounds

[0088] Disclosed herein, in certain embodiments, is a compound of Formula (I):Formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R1is C1-C10fluoroalkyl, C1-C10fluoroalkoxy, C3-C12cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10aryl, 5- to 9-membered heteroaryl, or -C(=O)N(R11)2; wherein each fluoroalkyl, fluoroalkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, C1-C6 alkyl,C3-C6cycloalkyl, C1-C6fluoroalkyl, C1-C6hydroxyalkyl, -CN, -OH, -O-(C1-C6alkyl), and -O-(C1-C6fluoroalkyl); R2is hydrogen, C1-C6alkyl, or C3-C6cycloalkyl; each R3, R4, and R5are each independently hydrogen, halogen, or C1-C6alkyl; R6is C1-C6alkyl; R7is hydrogen or C1-C6alkyl; Y is CH, CR8, or N; each R8is independently halogen, -CN, -OH, -O-(C1-C6alkyl), -O–(C1-C6fluoroalkyl), - NH2, -NH-(C1-C6alkyl), -N(C1-C6alkyl)2, C1-C6alkyl, or C1-C6fluoroalkyl; each R9is independently halogen, C1-C6alkyl, or C1-C6fluoroalkyl; each R10is independently halogen, -CN, -OH, -O-(C1-C6alkyl), -O–(C1-C6fluoroalkyl), - NH2, -NH-(C1-C6alkyl), -N(C1-C6alkyl)2, C1-C6alkyl, or C1-C6fluoroalkyl; n is 0, 1, or 2;m is 0, 1, 2, 3, or 4; p is 0, 1, or 2; each R11is independently hydrogen, C1-C10alkyl, C2-C10alkenyl, C2-C10alkynyl, C3-C10cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl, or monocyclic heteroaryl; wherein each alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, -CN, -OH, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6hydroxyalkyl, -O-(C1-C6alkyl), and -O-(C1-C6fluoroalkyl); or two R11on the same nitrogen atom are taken together with the nitrogen to which they are attached to form a 3- to 10-membered N-heterocycloalkyl; wherein the heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, -CN, -OH, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6hydroxyalkyl, -O-(C1-C6alkyl), and -O-(C1-C6fluoroalkyl).

[0089] For any and all of the embodiments, substituents are selected from among a subset of the listed alternatives. For example, in some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, R2is C1-C6alkyl or C3-C6cycloalkyl; and each R3, R4, and R5are each independently hydrogen, F, Cl, or C1-C4alkyl. In some embodiments, R2is C1-C6alkyl or C3-C6cycloalkyl; and each R3, R4, and R5areeach independently hydrogen, F, or C1-C4 alkyl. In some embodiments, R2 is C1-C4 alkyl or C3-C6cycloalkyl; and each R3, R4, and R5are each independently hydrogen, F, or C1-C4alkyl. In some embodiments, R2is C1-C4alkyl or C3-C6cycloalkyl; and each R3, R4, and R5are each independently hydrogen, F, -CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2. In some embodiments, R2is -CH3, -CH2CH3, or C3-C6cycloalkyl; and each R3, R4, and R5are each independently hydrogen, F, -CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2. In some embodiments, R2is C3-C6cycloalkyl; and each R3, R4, and R5are each independently hydrogen, F, -CH3, -CH2CH3, or -CH(CH3)2. In some embodiments, R2is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; and each R3, R4, and R5are each independently hydrogen, F, or -CH3. In some embodiments, R2is cyclopropyl; and each R3, R4, and R5are each independently hydrogen, F, or -CH3. In some embodiments, R2is cyclopropyl; and each R3, R4, and R5are each hydrogen.

[0090] In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, R2is C1-C6alkyl or C3-C6cycloalkyl. In some embodiments, R2is C1-C4alkyl or C3-C6cycloalkyl. In some embodiments, R2is -CH3, - CH2CH3, or C3-C6cycloalkyl. In some embodiments, R2is C3-C6cycloalkyl. In someembodiments, R2is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R2is cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R2is cyclopropyl or cyclobutyl. In some embodiments, R2is cyclopropyl.

[0091] In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, each R3, R4, and R5are each independently hydrogen, F, Cl, or C1-C4alkyl. In some embodiments, each R3, R4, and R5are each independently hydrogen, F, or C1-C4alkyl. In some embodiments, each R3, R4, and R5are each independently hydrogen, F, -CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2. In some embodiments, each R3, R4, and R5are each independently hydrogen, F, -CH3, or -CH2CH3. In some embodiments, each R3, R4, and R5are each independently hydrogen, F, or -CH3. In some embodiments, each R3, R4, and R5are each independently hydrogen or F. In some embodiments, each R3, R4, and R5are hydrogen.

[0092] In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, R2is C3-C6cycloalkyl; each R3, R4, and R5are each independently hydrogen, F, Cl, or C1-C6alkyl; R6is C1-C6alkyl; and R7is H or C1-C3alkyl. In some embodiments, R2is C3-C6cycloalkyl; each R3, R4, and R5are each independently hydrogen, F, Cl, -CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2; R6is C1-C4alkyl; and R7is H, - CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2. In some embodiments, R2is C3-C6cycloalkyl; each R3, R4, and R5are each independently hydrogen, F, -CH3, or -CH2CH3; R6is C1-C4alkyl;and R7 is H. In some embodiments, R2 is C3-C6 cycloalkyl; each R3, R4, and R5 are eachindependently hydrogen, F, -CH3, or -CH2CH3; R6is C1-C4alkyl; and R7is H. In some embodiments, R2is C3-C6cycloalkyl; each R3, R4, and R5are each independently hydrogen, F or -CH3; R6is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, or - C(CH3)3; and R7is H. In some embodiments, R2is C3-C6cycloalkyl; each R3, R4, and R5are each independently hydrogen, F or -CH3; R6is -CH3, -CH2CH3, or -CH(CH3)2; and R7is H. In some embodiments, R2is C3-C6cycloalkyl; each R3, R4, and R5are each hydrogen; R6is -CH3, - CH2CH3, or -CH(CH3)2; and R7is H. In some embodiments, R2is C3-C6cycloalkyl; each R3, R4, and R5are each hydrogen; R6is -CH3or -CH2CH3; and R7is H. In some embodiments, R2is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; each R3, R4, and R5are each hydrogen; R6is -CH3; and R7is H. In some embodiments, R2is cyclopropyl; each R3, R4, and R5are each hydrogen; R6is -CH3; and R7is H.

[0093] In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, R6is C1-C6alkyl. In some embodiments, R6is C1-C4alkyl. In some embodiments, R6is -CH3, -CH2CH3, -CH2CH2CH3, - CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, or -C(CH3)3. In some embodiments, R6is -CH3, -CH2CH3, or -CH(CH3)2. In some embodiments, R6is -CH3or -CH2CH3. In some embodiments, R6is -CH3.

[0094] In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, R7is H or C1-C3alkyl. In some embodiments, R7is H, -CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2. In some embodiments, R7is H, -CH3, or -CH2CH3. In some embodiments, R7is H.

[0095] In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, Y is CH, CR8, or N. In some embodiments, Y is CH or CR8. In some embodiments, Y is CR8. In some embodiments, Y is CH or N. In some embodiments, is CH. In some embodiments, Y is N.

[0096] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is a compound of Formula (II):Formula (II) or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.

[0097] In some embodiments, of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, R6is C1-C6alkyl. In some embodiments, R6is C1-C4alkyl. In some embodiments, R6is -CH3, -CH2CH3, - CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, or -C(CH3)3. In some embodiments, R6is -CH3, -CH2CH3, or -CH(CH3)2. In some embodiments, R6is -CH3or - CH2CH3. In some embodiments, R6is -CH3.

[0098] In some embodiments, of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, each R3, R4, and R5are each independently hydrogen, F, Cl, or C1-C4alkyl. In some embodiments, each R3, R4, and R5are each independently hydrogen, F, or C1-C4alkyl. In some embodiments, each R3, R4, and R5are each independently hydrogen, F, -CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2. In some embodiments, each R3, R4, and R5are each independently hydrogen, F, -CH3, or -CH2CH3. In some embodiments, each R3, R4, and R5are each independently hydrogen, F, or -CH3. In some embodiments, each R3, R4, and R5are each independently hydrogen or F. In some embodiments, each R3, R4, and R5are hydrogen.

[0099] In some embodiments, the compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is a compound of Formula (III):or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.

[0100] In some embodiments, the compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, each R8is independently halogen, -O-(C1-C6alkyl), -O-(C1-C6fluoroalkyl), -NH-(C1-C6alkyl), -N(C1-C6alkyl)2, C1-C6alkyl, or C1-C6fluoroalkyl; each R10is independently halogen, -O-(C1-C6alkyl), - O-(C1-C6fluoroalkyl), -NH-(C1-C6alkyl), -N(C1-C6alkyl)2, C1-C6alkyl, or C1-C6fluoroalkyl; n is 0, 1, or 2; m is 0, 1, 2, 3, or 4; and p is 0, 1, or 2. In some embodiments, each R8is independently halogen, -O-(C1-C6alkyl), -O-(C1-C6fluoroalkyl), -NH-(C1-C6alkyl), -N(C1-C6alkyl)2, C1-C6alkyl, or C1-C6fluoroalkyl; each R10is independently halogen, -O-(C1-C6alkyl), - O-(C1-C6fluoroalkyl), -NH-(C1-C6alkyl), -N(C1-C6alkyl)2, C1-C6alkyl, or C1-C6fluoroalkyl; nis 0 or 1; m is 0, 1, or 2; and p is 0 or 1. In some embodiments, each R8 is independently F , Cl, -O-(C1-C6alkyl), -O-(C1-C6fluoroalkyl), -NH-(C1-C6alkyl), -N(C1-C6alkyl)2, C1-C6alkyl, or C1- C6fluoroalkyl; each R10is independently F, Cl, -O-(C1-C6alkyl), -O-(C1-C6fluoroalkyl), -NH- (C1-C6alkyl), -N(C1-C6alkyl)2, C1-C6alkyl, or C1-C6fluoroalkyl; n is 0 or 1; m is 0, 1, or 2; and p is 0 or 1. In some embodiments, each R8is independently F, Cl, -O-(C1-C6alkyl), -O-(C1-C6fluoroalkyl), -NH-(C1-C6alkyl), -N(C1-C6alkyl)2, C1-C6alkyl, or C1-C6fluoroalkyl; each R10is independently F, Cl, -O-(C1-C6alkyl), -O-(C1-C6fluoroalkyl), -NH-(C1-C6alkyl), -N(C1-C6alkyl)2, C1-C6alkyl, or C1-C6fluoroalkyl; n is 0 or 1; m is 0; and p is 0 or 1. In some embodiments, each R8is independently F, Cl, –O–(C1-C4alkyl), –O–(C1-C4fluoroalkyl), -CH3, - CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), - CH2F, -CHF2, -CF3, -CH2CF3, -CH(CF3)2, or -CF2CF3; each R10is independently F, Cl, –O–(C1- C4 alkyl), –O–(C1-C4fluoroalkyl), -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, - CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -CH2F, -CHF2, -CF3, -CH2CF3, - CH(CF3)2, or -CF2CF3; n is 0 or 1; m is 0; and p is 0 or 1. In some embodiments, each R8is independently F, Cl, –OCH3, –OCH2F, –OCHF2, –OCF3, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CF3, or -CF2CF3; each R10is independently F, Cl, –OCH3, –OCH2F, –OCHF2, –OCF3, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CF3, or -CF2CF3; n is 0 or 1; m is 0; and p is 0 or 1.

[0101] In some embodiments, the compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, each R8is independently halogen, -O-(C1-C6alkyl), -O-(C1-C6fluoroalkyl), -NH-(C1-C6alkyl), -N(C1-C6alkyl)2, C1-C6alkyl, or C1-C6fluoroalkyl. In some embodiments, each R8is independently F , Cl, -O-(C1-C6alkyl), -O-(C1-C6fluoroalkyl), -NH-(C1-C6alkyl), -N(C1-C6alkyl)2, C1-C6alkyl, or C1-C6fluoroalkyl. In some embodiments, each R8is independently F, Cl, –O–(C1-C4alkyl), –O– (C1-C4fluoroalkyl), -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, - CH2CH(CH3)2, -CH(CH3)(CH2CH3), -CH2F, -CHF2, -CF3, -CH2CF3, -CH(CF3)2, or -CF2CF3. In some embodiments, each R8is independently F, Cl, –OCH3, –OCH2F, –OCHF2, –OCF3, -CH3, - CH2CH3, -CH2F, -CHF2, -CF3, -CH2CF3, or -CF2CF3.

[0102] In some embodiments, the compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, each R9is independently F, Cl, C1-C4alkyl, or C1-C4fluoroalkyl. In some embodiments, each R9is independently F, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -CH2F, -CHF2, -CF3, -CH2CF3, -CH(CF3)2, or -CF2CF3. In some embodiments, each R9is independently F, -CH3, -CH2F, -CHF2, or -CF3. In some embodiments, each R9is independently F or -CH3.

[0103] In some embodiments, the compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, each R10is independently halogen, -O-(C1-C6alkyl), -O-(C1-C6fluoroalkyl), -NH-(C1-C6alkyl), -N(C1-C6alkyl)2, C1-C6alkyl, or C1-C6fluoroalkyl. In some embodiments, each R10is independently F , Cl, -O-(C1-C6alkyl), -O-(C1-C6fluoroalkyl), -NH-(C1-C6alkyl), -N(C1-C6alkyl)2, C1-C6alkyl, or C1-C6fluoroalkyl. In some embodiments, each R10is independently F, Cl, –O–(C1-C4alkyl), –O– (C1-C4fluoroalkyl), -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, - CH2CH(CH3)2, -CH(CH3)(CH2CH3), -CH2F, -CHF2, -CF3, -CH2CF3, -CH(CF3)2, or -CF2CF3. In some embodiments, each R10is independently F, Cl, –OCH3, –OCH2F, –OCHF2, –OCF3, -CH3, - CH2CH3, -CH2F, -CHF2, -CF3, -CH2CF3, or -CF2CF3.

[0104] In some embodiments, the compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 1 or 2.

[0105] In some embodiments, the compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, m is 0, 1, 2 or 3. In some embodiments, m is 1, 2, 3, or 4. In some embodiments, m is 1, 2, or 3. In someembodiments, m is 0, 1, or 2. In some embodiments, m is 1 or 2. In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0106] In some embodiments, the compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, p is 0 or 1. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 1 or 2.

[0107] In some embodiments, the compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, n is 0 or 1; and p is 0 or 1. In some embodiments, n is 0; and p is 0 or 1. In some embodiments, n is 0 or 1; and p is 0. In some embodiments, n is 1; and p is 1. In some embodiments, n is 0; and p is 0.

[0108] In some embodiments, the compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, n is 0 or 1; m is 0, 1, 2, or 3; and p is 0 or 1. In some embodiments, n is 0 or 1; m is 0, 1, or 2; and p is 0 or 1. In some embodiments, n is 0 or 1; m is 0 or 1; and p is 0 or 1. In some embodiments, n is 0 or 1; m is 0; and p is 0 or 1. In some embodiments, n is 1; m is 0, 1, or 2; and p is 0 or 1. In some embodiments, n is 0 or 1; m is 0, 1, or 2; and p is 1. In some embodiments, n is 1; m is 0; and p is 0. In some embodiments, n is 0; m is 0; and p is 1. In some embodiments, n is 0; m is 0; and p is 0.

[0109] In some embodiments, the compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is a compound of Formula (IV):Formula (IV) or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.

[0110] In some embodiments, the compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, R1is C1-C10fluoroalkyl, C1-C10fluoroalkoxy, C3-C12cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10aryl, 5- to 9-membered heteroaryl, or -C(=O)N(R11)2; wherein each fluoroalkyl, fluoroalkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, C1-C6alkyl, C3-C6cycloalkyl, C1-C6fluoroalkyl, C1-C6hydroxyalkyl, -CN, -OH, -O-(C1-C6alkyl), and -O-(C1-C6fluoroalkyl). In some embodiments, R1is C3-C12cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10aryl, or 5- to 9-membered heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, C1-C6alkyl, C3-C6cycloalkyl, C1-C6fluoroalkyl, C1-C6hydroxyalkyl, -CN, -OH, -O-(C1-C6alkyl), and -O-(C1-C6fluoroalkyl). In some embodiments, R1is C3-C8cycloalkyl, 4- to 9-membered heterocycloalkyl, C6-C10aryl, or 5- to 6-membered heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, C1-C6alkyl, C3-C6cycloalkyl, C1-C6fluoroalkyl, C1-C6hydroxyalkyl, -CN, -OH, -O-(C1-C6alkyl), and -O-(C1-C6fluoroalkyl). In some embodiments, R1is C3-C8cycloalkyl, 4- to 9-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl; wherein each cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C1-C6alkyl, C3-C6cycloalkyl, C1-C6fluoroalkyl, C1-C6hydroxyalkyl, -CN, -OH, -O- (C1-C6alkyl), and -O-(C1-C6fluoroalkyl). In some embodiments, R1is C3-C8cycloalkyl, 4- to 9- membered heterocycloalkyl, or 5- to 6-membered heteroaryl; wherein each cycloalkyl, heterocycloalkyl, and heteroaryl is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C1-C6alkyl, C3-C6cycloalkyl, C1-C6fluoroalkyl, C1-C6hydroxyalkyl, -CN, -OH, -O-(C1-C6alkyl), and -O-(C1-C6fluoroalkyl).

[0111] In some embodiments, the compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, R1is C6-C10aryl or 5- to 6-membered heteroaryl; wherein the aryl and heteroaryl is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C1-C6alkyl, C3-C6cycloalkyl, -CN, -OH, and -O-(C1-C6alkyl). In some embodiments, R1is phenyl or 5- to 6-membered heteroaryl; wherein the phenyl and heteroaryl is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C1-C6alkyl, C3-C6cycloalkyl, -CN, -OH, and -O-(C1-C6alkyl). In some embodiments, R1is phenyl; wherein the phenyl is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C1-C6alkyl, C3-C6cycloalkyl, -CN, -OH, and -O-(C1-C6alkyl). In some embodiments, R1is phenyl; wherein the phenyl is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, -CH3, -CH2CH3, - CH2CH2CH3, -CH(CH3)2, C3-C6cycloalkyl, -CN, -OH, -OCH3, -OCH2CH3, -OCH2CH2CH3, and -OCH(CH3)2. In some embodiments, R1is 5- to 6-membered heteroaryl; wherein the heteroaryl isindependently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C1-C6alkyl, C3-C6cycloalkyl, -CN, -OH, and -O-(C1-C6alkyl). In some embodiments, R1is 5- to 6-membered heteroaryl; wherein the heteroaryl is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, C3-C6cycloalkyl, -CN, -OH, -OCH3, -OCH2CH3, -OCH2CH2CH3, and -OCH(CH3)2. In some embodiments, R1is 5- to 6-membered heteroaryl; wherein the heteroaryl is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of F, Cl, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, -CN, -OH, -OCH3, -OCH2CH3, -OCH2CH2CH3, and -OCH(CH3)2.

[0112] In some embodiments, the compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, R1is selected from, , , , , , , ,and. In some embodiments, R1is selected from, and. In some embodiments, R1is selected fromand . I 1n some embodiments, R is selected from

[0113] In some embodiments, the compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, R1is C3-C8cycloalkyl or 4- to 9-membered heterocycloalkyl; wherein each cycloalkyl and heterocycloalkyl is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, C1-C6alkyl, C3-C6cycloalkyl, -CN, -OH, and -O-(C1-C6alkyl). In some embodiments, R1is C3-C8cycloalkyl; wherein the cycloalkyl is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, C1-C6alkyl, C3-C6cycloalkyl, -CN, -OH, and -O- (C1-C6alkyl). In some embodiments, R1is C3-C8cycloalkyl; wherein the cycloalkyl is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C1-C6alkyl, C3-C6cycloalkyl, -CN, -OH, and -O-(C1-C6alkyl). In some embodiments, R1is 4- to 9-membered heterocycloalkyl; wherein the heterocycloalkyl is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, C1-C6alkyl, C3-C6cycloalkyl, -CN, -OH, and -O-(C1-C6alkyl). In some embodiments, R1is 4- to 9-membered heterocycloalkyl; wherein the heterocycloalkyl is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C1-C6alkyl, C3-C6cycloalkyl, -CN, -OH, and -O-(C1-C6alkyl). In some embodiments, R1is C3-C8cycloalkyl or 4- to 9-membered heterocycloalkyl; wherein each cycloalkyl and heterocycloalkyl is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C1-C6alkyl, C3-C6cycloalkyl, -CN, -OH, and -O-(C1-C6alkyl). In some embodiments, R1is C3-C8cycloalkyl or 4- to 9-membered heterocycloalkyl; wherein each cycloalkyl and heterocycloalkyl is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, -CH3, -CH2CH3, - CH2CH2CH3, -CH(CH3)2, C3-C6cycloalkyl, -CN, -OH, and -OCH3, -OCH2CH3, -OCH2CH2CH3, and -OCH(CH3)2. In some embodiments, R1is C3-C8cycloalkyl or 4- to 9-membered heterocycloalkyl; wherein each cycloalkyl and heterocycloalkyl is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of F, Cl,-CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, C3-C6cycloalkyl, -CN, -OH, and -OCH3, - OCH2CH3, -OCH2CH2CH3, and -OCH(CH3)2. In some embodiments, R1is C3-C8cycloalkyl or 4- to 9-membered heterocycloalkyl; wherein each cycloalkyl and heterocycloalkyl is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of F, Cl, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CN, -OH, and - OCH3, -OCH2CH3, -OCH2CH2CH3, and -OCH(CH3)2. In some embodiments, R1is C3-C8cycloalkyl; wherein the cycloalkyl is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of F, Cl, -CH3, -CH2CH3, - CH2CH2CH3, -CH(CH3)2, -CN, -OH, and -OCH3, -OCH2CH3, -OCH2CH2CH3, and -OCH(CH3)2. In some embodiments, R1is 4- to 9-membered heterocycloalkyl; wherein the heterocycloalkyl is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of F, Cl, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CN, -OH, and - OCH3, -OCH2CH3, -OCH2CH2CH3, and -OCH(CH3)2.

[0114] In some embodiments, the compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, R1some embodiments, R1is selected from, , , , ,, , , , , , , ,, and. In some embodiments, R1is selected, , ,, , , , and 1. In some embodiments, R is selectedand. In some embo 1diments, R isselectedand. some embodiments, R1is selected from, and. In some1embodiments, R is selected from, and

[0115] In some embodiments, the compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, R1is C1-C6fluoroalkyl or C1-C6fluoroalkoxy. In some embodiments, R1is C1-C6fluoroalkyl. In some embodiments, R1is C1-C6fluoroalkoxy. In some embodiments, R1is C1-C4fluoroalkyl or C1-C4fluoroalkoxy. In some embodiments, R1is C1-C4fluoroalkyl. In some embodiments, R1is C1-C4fluoroalkoxy. In some embodiments, R1is -CH2F, -CHF2, -CF3, -CH2CF3, -CH(CF3)2, - CF2CF3, -OCH2F, -OCHF2, -OCF3, -OCH2CF3, or -OCH(CF3)2. In some embodiments, R1is - CH2F, -CHF2, -CF3, -CH2CF3, -OCH2F, -OCHF2, or -OCF3. In some embodiments, R1is selected from -CF2H, -CF3, and -OCF2H. In some embodiments, R1is selected from -CF2H and -CF3. In some embodiments, R1is selected from -CF2H and -OCF2H. In some embodiments, R1is selected from -CF3and -OCF2H.

[0116] In some embodiments, the compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, R1is -C(=O)N(R11)2. In some embodiments, R1is -C(=O)N(R11)2; and each R11is independently hydrogen, C1-C10alkyl, C3-C10cycloalkyl, 4- to 9-membered heterocycloalkyl, phenyl, or 5- to 6- membered heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, -CN, -OH, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6hydroxyalkyl, -O-(C1-C6alkyl), and -O-(C1-C6fluoroalkyl); or two R11on the same nitrogen atom are taken together with the nitrogen to which they are attached to form a 3- to 10-membered N-heterocycloalkyl; wherein the heterocycloalkyl is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, -CN, -OH, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6hydroxyalkyl, -O-(C1-C6alkyl), and -O-(C1-C6fluoroalkyl). In some embodiments, R1is -C(=O)N(R11)2; and each R11is independently hydrogen, C1-C6alkyl, C3-C6cycloalkyl, phenyl, or 5- to 6-membered heteroaryl; wherein each alkyl, cycloalkyl, phenyl, and heteroaryl is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, -CN, -OH, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6hydroxyalkyl, -O-(C1-C6alkyl), and -O-(C1-C6fluoroalkyl); or two R11on the same nitrogen atom are taken together with the nitrogen to which they are attached to form a 3- to 10-membered N-heterocycloalkyl; wherein the heterocycloalkyl is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, -CN, -OH, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6hydroxyalkyl, -O-(C1-C6alkyl), and -O-(C1-C6fluoroalkyl). In some embodiments, R1is -C(=O)N(R11)2; and each R11is independently hydrogen, C1-C6alkyl, C3-C6cycloalkyl, phenyl, or 5- to 6-membered heteroaryl; wherein each alkyl, cycloalkyl, phenyl, and heteroaryl is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of F, Cl, –O–(C1-C4alkyl), –O–(C1-C4fluoroalkyl), -CH3, - CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -CH2F, -CHF2, -CF3, -CH2CF3, -CH(CF3)2, and -CF2CF3; or two R11 on the same nitrogen atomare taken together with the nitrogen to which they are attached to form a 3- to 10-membered N- heterocycloalkyl; wherein the heterocycloalkyl is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting F, Cl, –O–(C1-C4alkyl), –O–(C1- C4 fluoroalkyl), -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, - CH(CH3)(CH2CH3), -CH2F, -CHF2, -CF3, -CH2CF3, -CH(CF3)2, and -CF2CF3. In some embodiments, R1is. In some embodiments, R1is. In some embodiments, R1is

[0117] In some embodiments, the compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, each R11is independently hydrogen, C1-C10alkyl, C3-C10cycloalkyl, 4- to 9-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl; wherein each alkyl, cycloalkyl,heterocycloalkyl, phenyl, and heteroaryl is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, -CN, -OH, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6hydroxyalkyl, -O-(C1-C6alkyl), and -O-(C1-C6fluoroalkyl); or two R11on the same nitrogen atom are taken together with the nitrogen to which they are attached to form a 3- to 10-membered N-heterocycloalkyl; wherein the heterocycloalkyl is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, -CN, -OH, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6hydroxyalkyl, -O-(C1-C6alkyl), and -O-(C1-C6fluoroalkyl). In some embodiments, each R11is independently hydrogen, C1-C6alkyl, C3-C6cycloalkyl, phenyl, or 5- to 6-membered heteroaryl; wherein each alkyl, cycloalkyl, phenyl, and heteroaryl is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, -CN, -OH, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6hydroxyalkyl, -O-(C1-C6alkyl), and -O-(C1-C6fluoroalkyl); or two R11on the same nitrogen atom are taken together with the nitrogen to which they are attached to form a 3- to 10-membered N-heterocycloalkyl; wherein the heterocycloalkyl is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, -CN, -OH, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6hydroxyalkyl, -O-(C1-C6alkyl), and - O-(C1-C6fluoroalkyl). In some embodiments, each R11is independently hydrogen, C1-C6alkyl, C3-C6cycloalkyl, phenyl, or 5- to 6-membered heteroaryl; wherein each alkyl, cycloalkyl, phenyl, and heteroaryl is independently unsubstituted or substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of F, Cl, –O–(C1-C4 alkyl), –O–(C1-C4fluoroalkyl), -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, - CH(CH3)(CH2CH3), -CH2F, -CHF2, -CF3, -CH2CF3, -CH(CF3)2, and -CF2CF3; or two R11on the same nitrogen atom are taken together with the nitrogen to which they are attached to form a 3- to 10-membered N-heterocycloalkyl; wherein the heterocycloalkyl is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting F, Cl, –O–(C1-C4alkyl), –O–(C1-C4fluoroalkyl), -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, - CH2CH(CH3)2, -CH(CH3)(CH2CH3), -CH2F, -CHF2, -CF3, -CH2CF3, -CH(CF3)2, and -CF2CF3. In some embodiments, each R11is independently hydrogen, C1-C6alkyl, C3-C6cycloalkyl, phenyl, or 5- to 6-membered heteroaryl; wherein each alkyl, cycloalkyl, phenyl, and heteroaryl is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of F, Cl, –O–(C1-C4alkyl), –O–(C1-C4fluoroalkyl), -CH3, -CH2CH3, - CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -CH2F, - CHF2, -CF3, -CH2CF3, -CH(CF3)2, and -CF2CF3; or two R11on the same nitrogen atom are taken together with the nitrogen to which they are attached to form a 3- to 8-membered N- heterocycloalkyl; wherein the heterocycloalkyl is unsubstituted or substituted with 1, 2, or 3substituents independently selected from the group consisting F, Cl, –O–(C1-C4alkyl), –O–(C1- C4 fluoroalkyl), -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, - CH(CH3)(CH2CH3), -CH2F, -CHF2, -CF3, -CH2CF3, -CH(CF3)2, and -CF2CF3. In some embodiments, each R11is independently hydrogen, C1-C6alkyl, C3-C6cycloalkyl; wherein each alkyl and cycloalkyl is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of F, Cl, –O–(C1-C4alkyl), –O–(C1-C4fluoroalkyl), -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, - CH(CH3)(CH2CH3), -CH2F, -CHF2, -CF3, -CH2CF3, -CH(CF3)2, and -CF2CF3; or two R11on the same nitrogen atom are taken together with the nitrogen to which they are attached to form a 3- to 8-membered N-heterocycloalkyl; wherein the heterocycloalkyl is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting F, Cl, –O–(C1-C4alkyl), –O–(C1-C4fluoroalkyl), -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, - CH2CH(CH3)2, -CH(CH3)(CH2CH3), -CH2F, -CHF2, -CF3, -CH2CF3, -CH(CF3)2, and -CF2CF3.

[0118] In some embodiments, the compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, each R11is independently hydrogen, C1-C10alkyl, C3-C10cycloalkyl, 4- to 9-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, -CN, -OH, C1-C6alkyl, C1-C6 fluoroalkyl, C1-C6 hydroxyalkyl, -O-(C1-C6 alkyl), and -O-(C1-C6 fluoroalkyl). Insome embodiments, each R11is independently hydrogen, C1-C6alkyl, C3-C6cycloalkyl, phenyl, or 5- to 6-membered heteroaryl; wherein each alkyl, cycloalkyl, phenyl, and heteroaryl is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, -CN, -OH, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6hydroxyalkyl, -O-(C1-C6alkyl), and -O-(C1-C6fluoroalkyl). In some embodiments, each R11is independently hydrogen, C1-C6alkyl, C3-C6cycloalkyl, phenyl, or 5- to 6-membered heteroaryl; wherein each alkyl, cycloalkyl, phenyl, and heteroaryl is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of F, Cl, –O–(C1-C4alkyl), –O–(C1-C4fluoroalkyl), -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, - CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -CH2F, -CHF2, -CF3, -CH2CF3, - CH(CF3)2, and -CF2CF3. In some embodiments, each R11is independently hydrogen, C1-C6alkyl, C3-C6cycloalkyl; wherein each alkyl and cycloalkyl is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of F, Cl, –O–(C1-C4alkyl), –O–(C1-C4fluoroalkyl), -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, - CH2CH(CH3)2, -CH(CH3)(CH2CH3), -CH2F, -CHF2, -CF3, -CH2CF3, -CH(CF3)2, and -CF2CF3.

[0119] In some embodiments, the compound of Formula (I), Formula (II), Formula (III), or Formula (IV), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, two R11on the same nitrogen atom are taken together with the nitrogen to which they are attached to form a 3- to 10-membered N-heterocycloalkyl; wherein the heterocycloalkyl is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, -CN, -OH, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6hydroxyalkyl, -O-(C1-C6alkyl), and -O-(C1-C6fluoroalkyl). In some embodiments, two R11on the same nitrogen atom are taken together with the nitrogen to which they are attached to form a 3- to 8-membered N- heterocycloalkyl; wherein the heterocycloalkyl is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, -CN, -OH, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6hydroxyalkyl, -O-(C1-C6alkyl), and -O-(C1-C6fluoroalkyl). In some embodiments, two R11on the same nitrogen atom are taken together with the nitrogen to which they are attached to form a 3- to 8-membered N-heterocycloalkyl; wherein the heterocycloalkyl is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting F, Cl, –O–(C1-C4alkyl), –O–(C1-C4fluoroalkyl), -CH3, -CH2CH3, -CH2CH2CH3, - CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3), -CH2F, -CHF2, -CF3, - CH2CF3, -CH(CF3)2, and -CF2CF3. In some embodiments, two R11on the same nitrogen atom are taken together with the nitrogen to which they are attached to form a 3- to 6-membered N- heterocycloalkyl; wherein the heterocycloalkyl is unsubstituted or substituted with 1, 2, or 3substituents independently selected from the group consisting F, Cl, –O–(C1-C4 alkyl), –O–(C1-C4 fluoroalkyl), -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, - CH(CH3)(CH2CH3), -CH2F, -CHF2, -CF3, -CH2CF3, -CH(CF3)2, and -CF2CF3.

[0120] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds.

[0121] In some embodiments, the compound of Formula (I), Formula (II), Formula(III), or Formula (IV), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, selected from: ,or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.

[0122] In some embodiments, the compound of Formula (I), Formula (II), Formula(III), or Formula (IV), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, selected from:, andor a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.

[0123] In some embodiments, the compound of Formula (I), Formula (II), Formula(III), or Formula (IV), or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, selected from:, and ; or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof. Further Forms of Compounds

[0124] Furthermore, in some embodiments, the compounds described herein exist as “geometric isomers.” In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, compounds exist as tautomers.

[0125] A “tautomer” refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. In certain embodiments, the compounds presented herein exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

[0126] In some situations, the compounds described herein possess one or more chiral centers and each center exists in the (R)- configuration or (S)- configuration. The compoundsdescribed herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as optically pure enantiomers by chiral chromatographic resolution of the racemic mixture. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred (e.g., crystalline diastereomeric salts). In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation / resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.

[0127] The term “positional isomer” refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring.

[0128] The methods and formulations described herein include the use of N-oxides (if appropriate), 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.

[0129] “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.

[0130] “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonicacid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Science, 66:1-19 (1997). Acid addition salts of basic compounds are prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt.

[0131] “Pharmaceutically acceptable base addition salt” refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N- methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al., supra.

[0132] “Prodrug” is meant to indicate a compound that is, in some embodiments, converted under physiological conditions or by solvolysis to an active compound described herein. Thus, the term prodrug refers to a precursor of an active compound that is pharmaceutically acceptable. A prodrug is typically inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp.7-9, 21-24 (Elsevier, Amsterdam).

[0133] A discussion of prodrugs is provided in Higuchi, T., et al., “Pro-drugs as Novel Delivery Systems,” A.C.S. Symposium Series, Vol.14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

[0134] The term “prodrug” is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of an active compound, as described herein, are prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound. Prodrugs include compounds wherein a hydroxy, amino, carboxy, or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino, free carboxy, or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol or amine functional groups in the active compounds and the like.

[0135] “Pharmaceutically acceptable solvate” refers to a composition of matter that is the solvent addition form. In some embodiments, solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of making with pharmaceutically acceptable solvents such as water, ethanol, and the like. “Hydrates” are formed when the solvent is water, or “alcoholates” are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. The compounds provided herein optionally exist in either unsolvated as well as solvated forms.

[0136] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of2H,3H,11C,13C and / or14C. In some embodiments, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos.5,846,514 and 6,334,997. As described in U.S. Patent Nos.5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.

[0137] Unless otherwise stated, structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by13C- or14C-enriched carbon are within the scope of the present disclosure.

[0138] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H),iodine-125 (125I) or carbon-14 (14C). Isotopic substitution with2H,3H,11C,13C,14C,15C,12N,13N,15N,16N,17O,18O,14F,15F,16F,17F,18F,33S,34S,35S,36S,35Cl,37Cl,79Br,81Br,125I are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0139] In certain embodiments, the compounds disclosed herein have some or all of the1H atoms replaced with2H atoms. The methods of synthesis for deuterium-containing compounds are known in the art. In some embodiments deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0140] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0141] In certain embodiments, the compounds described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, as described herein are substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as contaminating intermediates or by-products that are created, for example, in one or more of the steps of a synthesis method. Preparation of the Compounds

[0142] Compounds described herein are synthesized using standard synthetic techniques or using methods known in the art in combination with methods described herein.

[0143] Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are employed.

[0144] Compounds are prepared using standard organic chemistry techniques such as those described in, for example, March’s Advanced Organic Chemistry, 6th Edition, John Wiley and Sons, Inc. Alternative reaction conditions for the synthetic transformations described herein may be employed such as variation of solvent, reaction temperature, reaction time, as well as different chemical reagents and other reaction conditions.

[0145] In some embodiments, compounds described herein are prepared as described as outlined in the Examples.Pharmaceutical Compositions

[0146] In some embodiments, disclosed herein is a pharmaceutical composition comprising a herein GPR40 agonist described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, and a pharmaceutically acceptable excipient. In some embodiments, the GPR40 agonist 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 as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21stEd. Mack Pub. Co., Easton, PA (2005)).

[0147] Accordingly, provided herein is a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable excipient.

[0148] Examples of suitable aqueous and non-aqueous carriers which are employed in the pharmaceutical compositions include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins. Proper fluidity is maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Combination Therapies

[0149] In certain embodiments, it is appropriate to administer the compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, as described herein in combination with one or more additional therapeutic agents. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is administered in combination with a TGR5 agonist, a GPR119 agonist, an SSTR5 antagonist, an SSTR5 inverse agonist, a CCK1 agonist, a PDE4 inhibitor, a DPP-4 inhibitor, a GLP-1 receptor agonist, a ghrelin O-acyltransferase (GOAT) inhibitor, metformin, or combinations thereof. In certain embodiments, the pharmaceutical composition further comprises one or more anti-diabetic agents. In certain embodiments, the pharmaceutical composition further comprises one or more anti-obesity agents. In certain embodiments, the pharmaceutical composition further comprises one or more agents to treat nutritional disorders. In certain embodiments, the combination therapies described herein are administered in combination with a DPP-4 inhibitor, a GLP-1 receptor agonist, metformin, or combinations thereof. In some embodiments, the combination therapies described herein are administered in combination with a DPP-4 inhibitor. In some embodiments, the combination therapies described herein are administered incombination with a GLP-1 receptor agonist. In some embodiments, the combination therapies described herein are administered in combination with metformin.

[0150] Examples of a TGR5 agonist to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, include: INT-777, XL-475, SRX-1374, RDX-8940, RDX-98940, SB-756050, and those disclosed in WO- 2008091540, WO-2010059853, WO-2011071565, WO-2018005801, WO-2010014739, WO- 2018005794, WO-2016054208, WO-2015160772, WO-2013096771, WO-2008067222, WO- 2008067219, WO-2009026241, WO-2010016846, WO-2012082947, WO-2012149236, WO- 2008097976, WO-2016205475, WO-2015183794, WO-2013054338, WO-2010059859, WO- 2010014836, WO-2016086115, WO-2017147159, WO-2017147174, WO-2017106818, WO- 2016161003, WO-2014100025, WO-2014100021, WO-2016073767, WO-2016130809, WO- 2018226724, WO-2018237350, WO-2010093845, WO-2017147137, WO-2015181275, WO- 2017027396, WO-2018222701, WO-2018064441, WO-2017053826, WO-2014066819, WO- 2017079062, WO-2014200349, WO-2017180577, WO-2014085474.

[0151] 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: K-833, DS-8500a, HD-2355, LC34AD3, PSN-491, HM-47000, PSN-821, MBX-2982, GSK- 1292263, APD597, DA-1241, and those described in WO-2009141238, WO-2010008739, WO- 2011008663, WO-2010013849, WO-2012046792, WO-2012117996, WO-2010128414, WO- 2011025006, WO-2012046249, WO-2009106565, WO-2011147951, WO-2011127106, WO- 2012025811, WO-2011138427, WO-2011140161, WO-2011061679, WO-2017175066, WO- 2017175068, WO-2015080446, WO-2013173198, US-20120053180, WO-2011044001, WO- 2010009183, WO-2012037393, WO-2009105715, WO-2013074388, WO-2013066869, WO- 2009117421, WO-201008851, WO-2012077655, WO-2009106561, WO-2008109702, WO- 2011140160, WO-2009126535, WO-2009105717, WO-2013122821, WO-2010006191, WO- 2009012275, WO-2010048149, WO-2009105722, WO-2012103806, WO-2008025798, WO- 2008097428, WO-2011146335, WO-2012080476, WO-2017106112, WO-2012145361, WO- 2012098217, WO-2008137435, WO-2008137436, WO-2009143049, WO-2014074668, WO- 2014052619, WO-2013055910, WO-2012170702, WO-2012145604, WO-2012145603, WO- 2011030139, WO-2018153849, WO-2017222713, WO-2015150565, WO-2015150563, WO- 2015150564, WO-2014056938, WO-2007120689, WO-2016068453, WO-2007120702, WO- 2013167514, WO-2011113947, WO-2007003962, WO-2011153435, WO-2018026890, WO- 2011163090, WO-2011041154, WO-2008083238, WO-2008070692, WO-2011150067, and WO-2009123992.

[0152] 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.

[0153] Examples of a CCK1 agonist to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, include: A-70874, A-71378, A-71623, A-74498, CE-326597, GI-248573, GSKI-181771X, NN-9056, PD- 149164, PD-134308, PD-135158, PD-170292, PF-04756956, SR-146131, SSR-125180, and those described in EP-00697403, US-20060177438, WO-2000068209, WO-2000177108, WO- 2000234743, WO-2000244150, WO-2009119733, WO-2009314066, WO-2009316982, WO- 2009424151, WO-2009528391, WO-2009528399, WO-2009528419, WO-2009611691, WO- 2009611940, WO-2009851686, WO-2009915525, WO-2005035793, WO-2005116034, WO- 2007120655, WO-2007120688, WO-2008091631, WO-2010067233, WO-2012070554, and WO-2017005765.

[0154] Examples of a PDE4 inhibitor to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, include: apremilast, cilomilast, crisaborole, diazepam, luteolin, piclamilast, and roflumilast.

[0155] 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.

[0156] Examples of a GLP-1 receptor agonist to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, include: albiglutide, dulaglutide, exenatide, extended-release exenatide, liraglutide, lixisenatide, semaglutide, ECC-5004, CT-996, PF-522, MDR-001, TERN-601, danuglipron, GSBR-1290, GL-0034, ecnoglutide, and orforglipron.

[0157] Examples of a GOAT inhibitors to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, include: T-3525770 (RM-852), GLWL-01, BOS-704, and those described in US-08013015, US- 09340578, WO-2019149959, US-20170056373, WO-2018035079, WO-2016044467, WO- 2010039461, WO-2018024653, WO-2019149660, WO-2019149659, WO-2015073281, WO- 2019149658, WO-2016168225, WO-2016168222, WO-2019149657, WO-2013125732, and WO-2019152889.

[0158] Examples of anti-diabetic agents to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof,include: GLP-1 receptor agonists such as exenatide, liraglutide, taspoglutide, lixisenatide, albiglutide, dulaglutide, semaglutide, orforglipron (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.

[0159] Examples of anti-obesity agents to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, include: GLP-1 receptor agonists such as liraglutide, semaglutide, ECC-5004, CT-996, PF-522, MDR-001, TERN-601, danuglipron, GSBR-1290, GL-0034, ecnoglutide, and orforglipron; SGLT1 / 2 inhibitors such as LIK066, pramlintide and other amylin analogs such as AM-833, AC2307, BI 473494, ZP8396 and AZD6234; PYY analogs such as NN-9747, NN-9748, AC- 162352, AC-163954, GT-001, GT-002, GT-003, and RHS-08; GIP receptor agonists such as APD-668 and APD-597; GLP-1 / GIP co-agonists such as tirzepatide (LY329176), BHM-089, LBT-6030, CT-868, SCO-094, NNC-0090-2746, RG-7685, NN-9709, SAR-438335, CT-388, GMA-106, VK-2735, HRS-9531, RAY-1225, and maridebart cafraglutide; GLP-1 / glucagon co- agonist such as cotadutide (MEDI0382), survodutide (BI 456906), TT-401, G-49, H&D-001A, ZP-2929, HM-12525A, DD-01, pemvidutide, and mazdutide; GLP-1 / GIP / glucagon triple agonist such as SAR-441255, HM-15211, NN-9423, and retatrutide; GLP-1 / secretin co-agonists such as GUB06-046; GLP-1 / amylin co-agonists such as amycretin and cagrisema; leptin analogs such as metreleptin; leptin sensitizers such as ERX-1000; GDF15 modulators such as CIN-109 and those described in WO2012138919, WO2015017710, WO2015198199, WO-2017147742 and WO- 2018071493; FGF21 receptor modulators such as NN9499, NGM386, NGM313, BFKB8488A (RG7992), AKR-001, LLF-580, CVX-343, LY-2405319, BIO89-100, and BMS-986036; MC4 agonists such as setmelanotide; MetAP2 inhibitors such as ZGN-1061; ghrelin receptor modulators such as HM04 and AZP-531; and oxytocin analogs such as carbetocin.

[0160] Examples of agents for nutritional disorders to be used in combination with a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, include: GLP-2 receptor agonists such as tedaglutide, glepaglutide (ZP1848), elsiglutide (ZP1846), apraglutide (FE 203799), HM-15912, NB-1002, GX-G8, PE-0503, SAN- 134, and those described in WO-2011050174, WO-2012028602, WO-2013164484, WO- 2019040399, WO-2018142363, WO-2019090209, WO-2006117565, WO-2019086559, WO- 2017002786, WO-2010042145, WO-2008056155, WO-2007067828, WO-2018229252, WO- 2013040093, WO-2002066511, WO-2005067368, WO-2009739031, WO-2009632414, and WO2008028117; and GLP-1 / GLP-2 receptor co-agonists such as ZP-GG-72, dapiglutide, andthose described in WO-2018104561, WO-2018104558, WO-2018103868, WO-2018104560, WO-2018104559, WO-2018009778, WO-2016066818, and WO-2014096440.

[0161] In one embodiment, the therapeutic effectiveness of one of the compounds described herein is enhanced by administration of an adjuvant (i.e., by itself the adjuvant has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Or, in some embodiments, the benefit experienced by a patient is increased by administering one of the compounds described herein with another agent (which also includes a therapeutic regimen) that also has therapeutic benefit.

[0162] In one specific embodiment, a compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, is co-administered with one or more additional therapeutic agents, wherein the compound described herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, and the additional therapeutic agent(s) modulate different aspects of the disease, disorder or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone. In some embodiments, the additional therapeutic agent(s) is a TGR5 agonist, a GPR119 agonist, an SSTR5 antagonist, an SSTR5 inverse agonist, a CCK1 agonist, a PDE4 inhibitor, a DPP-4 inhibitor, a GOAT inhibitor, a GLP-1 receptor agonist, metformin, or combinations thereof. In some embodiments, the additional therapeutic agent is an anti-diabetic agent. In some embodiments, the additional therapeutic agent is an anti-obesity agent. In some embodiments, the additional therapeutic agent is an agent to treat nutritional disorders.

[0163] In combination therapies, the multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order or even simultaneously. If administration is simultaneous, the multiple therapeutic agents are, by way of example only, provided in a single, unified form, or in multiple forms (e.g., as a single pill or as two separate pills).

[0164] The compounds described herein, or pharmaceutically acceptable salts, solvates, stereoisomers, or prodrugs thereof, as well as combination therapies, are administered before, during or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound varies. Thus, in one embodiment, the compounds described herein are used as a prophylactic and are administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition. In another embodiment, the compounds and compositions are administered to a subject during or as soon as possible after the onset of the symptoms. In specific embodiments, a compound described herein is administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease.

[0165] In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is administered in combination with anti-inflammatory agent, anti-cancer agent, immunosuppressive agent, steroid, non-steroidal anti-inflammatory agent, antihistamine, analgesic, hormone blocking therapy, radiation therapy, monoclonal antibodies, or combinations thereof. EXAMPLES

[0166] The following example are included for illustrative purposes only and are not intended to limit the scope of the disclosure. List of Abbreviations

[0167] As used above, and throughout the description of the invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings: ACN or MeCN acetonitrile AIBN azobisisobutyronitrile Aq. aqueous BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl BPO benzoyl peroxide Boc or BOC tert-butyloxycarbonyl Bn benzyl BnBr benzyl bromide DCC N,N'-dicyclohexylcarbodiimide DCM dichloromethane (CH2Cl2) DEA diethylamine DIAD diisopropyl azodicarboxylate DIBAL-H diisobutylaluminum hydride DIPEA or DIEA diisopropylethylamine DMAP 4-dimethylaminopyridine DME 1,2,-dimethoxyethane DMF dimethylformamide DMP Dess-Martin periodinane DMSO dimethylsulfoxide EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide eq equivalent(s) Et ethylEtOH ethanol EA ethyl acetate EtOAc ethyl acetate FA formic acid h, hr(s) hour(s) HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate HPLC high performance liquid chromatography IPA isopropanol IPAM isopropylamine LDA lithium diisopropylamide LCMS liquid chromatography-mass spectrometry Me methyl MeOH methanol MS mass spectroscopy Ms methanesulfonyl (mesyl) MsCl methanesulfonyl chloride (mesyl chloride) NBS N-bromosuccinimide NMR nuclear magnetic resonance PE petroleum ether Py pyridine Rt or RT room temperature Sat. saturated SFC supercritical fluid chromatography TEA triethylamine Tf trifluoromethylsulfonyl (triflyl) TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography TMAD tetramethylazodicarboxamide TMS trimethylsilyl Tol or tol toluene tR retention time Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxantheneI. Chemical Synthesis

[0168] Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Anhydrous solvents and oven-dried glassware were used for synthetic transformations sensitive to moisture and / or oxygen. Yields were not optimized. Reaction times are approximate and were not optimized. Column chromatography and thin layer chromatography (TLC) were performed on silica gel unless otherwise noted. Example 1: ((S)-2-cyclopropyl-2-(3-(((1r,4S)-4-(2-(difluoromethyl)-5- methoxyphenyl)cyclohexyl)methoxy)phenyl)ethyl)(methyl)phosphinic acid (Compound 1):

[0169] Step 1: 2-(1-cyclopropylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1-1): To a solution of ethynylcyclopropane (50 g, 0.76 mol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2- dioxaborolane) (0.21 kg, 0.83 mmol) in toluene (1500 mL) was added Pd(OAc)2(8.5 g, 38 mmol), 2,2,2-trifluoroethanol (0.15 kg, 1.5 mol), PCy3(21 g, 76 mmol) and bromobenzene (0.12 kg, 0.76 mol). The mixture was degassed and purged with N23 times, then stirred at 80 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue. Theresidue was purified by column chromatography (SiO2, Petroleum ether : Ethyl acetate = 1 : 0 to 1 : 1) to give 1-1 (72 g, 0.37 mol, 49% yield) as a yellow oil.1H NMR (400 MHz, CDCl3): δ 5.57 (d, J = 3.2 Hz, 1H), 5.42 (s, 1H), 1.29~1.26 (m, 1H), 1.19 (s, 11H), 0.64~0.58 (m, 2H), 0.54~0.48 (m, 2H).

[0170] Step 2: 1-(benzyloxy)-3-(1-cyclopropylvinyl)benzene (1-2): To a solution of 2-(1- cyclopropylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 1-1 (72 g, 0.37 mol) and 1- (benzyloxy)-3-bromobenzene (75 g, 0.29 mol) in dioxane (750 mL) and H2O (150 mL) was added Pd(dppf)Cl2•CH2Cl2(12 g, 14 mmol) and K3PO4(0.12 kg, 0.57 mol). The mixture was degassed and purged with N23 times, then stirred at 80 °C for 12 hours. The reaction mixture was quenched by addition of water (500 mL), and then diluted with ethyl acetate (300 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with sat. brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether : Ethyl acetate = 1 : 0 to 1 : 1) to give 1-2 (64 g, 0.24 mol, 86% yield) as a yellow oil.1H NMR (400 MHz, CDCl3): δ 7.40~7.32 (m, 2H), 7.29 (t, J = 7.3 Hz, 2H), 7.26~7.20 (m, 1H), 7.19~7.07 (m, 3H), 6.83~6.78 (m, 1H), 5.18 (s, 1H), 4.98 (s, 2H), 4.84 (s, 1H), 1.60~1.48 (m, 1H), 0.78~0.66 (m, 2H), 0.54~0.40 (m, 2H).

[0171] Step 3: 2-(3-(benzyloxy)phenyl)-2-cyclopropylethanol (1-3): To a solution of 1- (benzyloxy)-3-(1-cyclopropylvinyl)benzene 1-2 (14 g, 56 mmol, 1 eq) in THF (150 mL) wasadded BH3•THF (1 M in THF, 0.17 L, 3 eq) at 0 °C for 30 min. Then NaOH (6 M in water, 56mL, 6 eq) and H2O2(130 g, 1.1 mol, 107 mL, 30% purity, 20 eq) was added at 0 °C. The mixture was stirred at 25 °C for 1.5 hours. The mixture was quenched with water (50 mL) and extracted with ethyl acetate (200 mL × 2). The combined organic phase was washed with sat. brine (50 mL × 2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether : Ethyl acetate = 20 : 1 to 3 : 1) to give 1-3 (11 g, 70% yield, 94% purity) as a colorless oil.1H-NMR (CDCl3, 400 MHz): δ = 7.35 - 7.30 (m, 2H), 7.27 (s, 2H), 7.24 - 7.18 (m, 1H), 7.14 (t, J = 8 Hz, 1H), 6.81 - 6.78 (m, 1H), 6.77 - 6.73 (m, 2H), 4.94 (s, 2H), 3.86 - 3.63 (m, 2H), 1.91 - 1.84 (m, 1H), 1.44 (s, 1H), 0.93 - 0.82 (m, 1H), 0.56 - 0.45 (m, 1H), 0.38 - 0.28 (m, 1H), 0.22 - 0.15 (m, 1H), 0.02 – 0.05 (m, 1H).

[0172] Step 4: (S)-2-(3-(benzyloxy)phenyl)-2-cyclopropylethan-1-ol (1-3-S): 2-(3- (benzyloxy)phenyl)-2-cyclopropylethan-1-ol 1-3 (9.1 g) was separated by SFC (column: DAICEL CHIRALPAK AD (250mm × 50 mm, 10 um); mobile phase: [A: CO2; B: 0.1% NH3•H2O in MeOH]; B%: 45%-45%, 5.4 min; 130 min) to give 1-3-S (4.2 g, 45% yield) as a colourless oil. tR = 1.767 min on SFC. [Note: R-isomer, tR = 2.407 min].

[0173] Step 5: (S)-1-(benzyloxy)-3-(1-cyclopropyl-2-iodoethyl)benzene (1-4): Triphenylphosphane (22 g, 84 mmol, 1.5 eq) and imidazole (5.7 g, 83 mmol, 1.5 eq) were dissolved in dichloromethane (150 mL) and the solution was stirred for 0.1 hr. Then molecular iodine (21 g, 83 mmol, 17 mL, 1.5 eq) was added to the mixture, and the mixture was stirred for 0.1 hr. A solution of (S)-2-(3-(benzyloxy)phenyl)-2-cyclopropylethan-1-ol 1-3-S (15 g, 56 mmol, 1 eq) in dichloromethane (50 mL) was added dropwise to the mixture, and the mixture was stirred at 25 °C for 1 hr. The reaction mixture was quenched with water (300 ml) and then extracted with ethyl acetate (150 mL × 3). The combined organic phase was washed with saturated brine (150 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 220 g Sepa Flash ® Silica Flash Column, Eluent of 0~15% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to give 1-4 (20 g, 90% yield) as a colorless oil.1H NMR (400 MHz, CDCl3) δ = 7.32 - 7.25 (m, 2H), 7.25 - 7.22 (m, 1H), 7.19 - 7.13 (m, 1H), 7.09 (t, J = 7.8 Hz, 1H), 6.72 (br d, J = 8.4 Hz, 1H), 6.69 - 6.60 (m, 2H), 4.90 (s, 2H), 3.45 - 3.36 (m, 1H), 3.35 - 3.24 (m, 1H), 2.01 - 1.79 (m, 1H), 0.99 - 0.81 (m, 1H), 0.58 - 0.45 (m, 1H), 0.39 - 0.26 (m, 1H), 0.16 (qd, J = 4.9, 9.6 Hz, 1H), -0.03 (qd, J = 5.0, 9.6 Hz, 1H).

[0174] Step 6: diethyl (S)-(2-(3-(benzyloxy)phenyl)-2-cyclopropylethyl)phosphonate (1-5): A mixture of (S)-1-(benzyloxy)-3-(1-cyclopropyl-2-iodoethyl)benzene 1-4 (20 g, 53 mmol, 1 eq) in triethyl phosphite (141 g, 846 mmol, 145 mL, 16 eq) was stirred at 130 °C for 12 hrs under N2atmosphere. The reaction mixture was purified by reversed phase HPLC (column: 120 g Flash Column Welch Ultimate XB_C1820-40 μm; mobile phase: [A: water (0.1% ammonia) B: ACN], B%: 5-45, 18 min; B%: 45, 5 min.) to give 1-5 (13 g, 63% yield, 99% purity) as a colorless oil.1H NMR (400 MHz, CDCl3) δ = 7.49 - 7.42 (m, 2H), 7.39 (t, J = 7.4 Hz, 2H), 7.36 - 7.29 (m, 1H), 7.22 (t, J = 7.8 Hz, 1H), 6.91 - 6.75 (m, 3H), 5.07 (s, 2H), 4.06 - 3.80 (m, 3H), 3.75 (td, J = 7.4, 9.8 Hz, 1H), 2.41 - 2.09 (m, 3H), 1.21 (t, J = 7.2 Hz, 3H), 1.13 (t, J = 7.2 Hz, 3H), 1.06 (br dd, J = 4.3, 8.4 Hz, 1H), 0.67 - 0.52 (m, 1H), 0.46 - 0.25 (m, 2H), 0.15 (br dd, J = 4.8, 9.4 Hz, 1H).

[0175] Step 7: ethyl hydrogen ((S)-2-(3-(benzyloxy)phenyl)-2-cyclopropylethyl)phosphonate (1-6): To a solution of diethyl (S)-(2-(3-(benzyloxy)phenyl)-2-cyclopropylethyl)phosphonate 1-5 (13 g, 33 mmol, 1 eq) in pyridine (150 mL) was added NaI (15 g, 100 mmol, 3 eq). The mixture was stirred at 120 °C for 12 hrs. The reaction mixture was adjusted to pH 2 with 4 M aqueous HCl solution, then extracted with ethyl acetate (200 mL × 3). The combined organic phase was washed with saturated brine (200 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 1-6 (12 g, crude) as a brown oil. LCMS: (ES+) m / z (M+H)+= 361.0.

[0176] Step 8: ethyl ((S)-2-(3-(benzyloxy)phenyl)-2-cyclopropylethyl)phosphonochloridate (1-7): To a solution of ethyl hydrogen ((S)-2-(3-(benzyloxy)phenyl)-2- cyclopropylethyl)phosphonate 1-6 (12 g, 33.30 mmol, 1 eq) in dichloromethane (150 mL) was added oxalyl dichloride (21 g, 166 mmol, 15 mL, 5 eq) and DMF (24 mg, 333 μmol, 27 μL, 0.01 eq) under N2atmosphere at 25°C. The mixture was stirred at 25°C for 0.5 hr under N2atmosphere. The reaction mixture was directly concentrated under reduced pressure to give 1-7 (12.5 g, crude) as a colorless oil.

[0177] Step 9: ethyl ((S)-2-(3-(benzyloxy)phenyl)-2-cyclopropylethyl)(methyl)phosphinate (1-8): To a solution of ethyl ((S)-2-(3-(benzyloxy)phenyl)-2- cyclopropylethyl)phosphonochloridate 1-7 (12.5 g, 33.00 mmol, 1 eq) in tetrahydrofuran (130 mL) was added bromo(methyl)magnesium (3 M in THF, 33 mL, 3 eq) at -78 °C dropwise under N2atmosphere. The reaction was allowed to warm to 25 °C and stirred at 25 °C for 1 hr under N2atmosphere. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (100 mL) at 0 °C and then extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with saturated brine (100 mL), dried and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 80g SepaFlash ® Silica Flash Column, Eluent of 0~30% Ethyl acetate / Petroleum ether gradient @ 100mL / min) to give 1-8 (8.5 g, 71% yield, 99% purity) as a colorless oil. LCMS: (ES+) m / z (M+H)+= 359.1.1H NMR (400 MHz, CDCl3) δ = 7.46 - 7.22 (m, 6H), 6.93 - 6.76 (m, 3H), 5.07 (s, 2H), 4.05 - 3.74 (m, 2H), 2.42 - 2.12 (m, 3H), 1.34 - 1.18 (m, 4H), 1.13 - 0.87 (m, 3H), 0.71 - 0.54 (m, 1H), 0.43 (dt, J = 4.4, 8.8 Hz, 1H), 0.38 - 0.28 (m, 1H), 0.25 - 0.15 (m, 1H).

[0178] Step 10: ethyl ((S)-2-cyclopropyl-2-(3-hydroxyphenyl)ethyl)(methyl)phosphinate (1- 9-S): To a solution of ethyl ((S)-2-(3-(benzyloxy)phenyl)-2- cyclopropylethyl)(methyl)phosphinate 1-8 (8.5 g, 24 mmol, 1 eq) in methanol (130 mL) was added Pd / C (1.26 g, 1.19 mmol, 10% purity, 0.05 eq) under N2atmosphere. The mixture was stirred at 25 °C for 12 hrs under H2(50 psi) atmosphere. The insoluble matter was removed by filtration and washed with methanol (50 mL). The filtrate was concentrated under vacuum to give 1-9-S (6 g, crude) as a colorless oil. LCMS: (ES+) m / z (M+H)+= 269.1.1H NMR (400 MHz, CD3OD) δ = 7.13 (dt, J = 4.4, 7.8 Hz, 1H), 6.75 (t, J = 7.4 Hz, 1H), 6.71 (td, J = 2.2, 4.2 Hz, 1H), 6.68 - 6.61 (m, 1H), 4.03 - 3.74 (m, 2H), 2.41 - 2.24 (m, 2H), 2.19 - 2.03 (m, 1H), 1.27 - 1.15 (m, 4H), 1.15 - 1.08 (m, 1H), 1.03 (d, J = 14.0 Hz, 2H), 0.67 - 0.56 (m, 1H), 0.47 - 0.35 (m, 1H), 0.30 (td, J = 4.6, 7.4 Hz, 1H), 0.17 (td, J = 4.6, 9.4 Hz, 1H).

[0179] Step 11: 2-bromo-1-(difluoromethyl)-4-methoxybenzene (1-10): To a mixture of 2- bromo-4-methoxy-benzaldehyde (2.0 g, 9.3 mmol, 1 eq) in DAST (8 mL) was added MeOH (0.29 g, 9.3 mmol, 370 μL, 1 eq). The mixture was stirred at 25 °C for 12 hours. The reactionmixture was quenched by sat. aq. NaHCO3solution (80 mL) at 0 °C and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with saturated aqueous sodium chloride solution (30 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to give 1-10 (1.35 g, 54% yield) as a yellow oil.1H NMR (400 MHz, CD3OD) δ = 7.55 (d, J = 8.6 Hz, 1H), 7.26 - 7.13 (m, 1H), 7.03 – 7.00 (m, 1H), 6.89 (t, J = 55.2 Hz, 1H), 3.82 (s, 3H).

[0180] Step 12: ethyl 2'-(difluoromethyl)-5'-methoxy-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4- carboxylate (1-11): A mixture of 2-bromo-1-(difluoromethyl)-4-methoxybenzene 1-10 (1.4 g, 6.0 mmol, 1 eq), ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate (2.4 g, 8.5 mmol, 1.5 eq), K2CO3(2.4 g, 17 mmol, 3 eq), and Pd(dppf)Cl2•CH2Cl2(470 mg, 570 μmol, 0.1 eq) in dioxane (15 mL) and H2O (1.5 mL) was degassed and purged with N23 times. The mixture was stirred at 80 °C for 12 hours under N2atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The reaction mixture was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~40% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to give 1-11 (1.8 g, 92% yield) as a colorless oil.1H NMR (400 MHz, CD3OD) δ = 7.52 (d, J = 8.8 Hz, 1H), 6.91 (dd, J = 8.8, 2.4 Hz, 1H), 6.84 – 6.56 (m, 2H), 5.61 (br s, 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.81 (s, 3H), 2.83 - 2.61 (m, 1H), 2.47 - 2.31 (m, 4H), 2.16 - 2.05 (m, 1H), 1.97 - 1.83 (m, 1H), 1.27 (t, J = 7.2 Hz, 3H).

[0181] Step 13: (2'-(difluoromethyl)-5'-methoxy-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4- yl)methanol (1-12): A mixture of ethyl 2'-(difluoromethyl)-5'-methoxy-2,3,4,5-tetrahydro-[1,1'- biphenyl]-4-carboxylate 1-11 (1.6 g, 5.2 mmol, 1 eq) in THF (16 mL) and MeOH (4 mL) was degassed and purged with N23 times, and then NaBH4 (2.0 g, 52 mmol, 10 eq) was added in portions at 0 °C. The resulting mixture was stirred at 25 °C for 12 hours. The reaction mixture was quenched by saturated aqueous ammonium chloride solution (10 mL), then extracted with ethyl acetate (20 mL× 3). The combined organic layers were washed with saturated aqueous sodium chloride solution (20 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~20% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to give 1-12 (1.23 g, 95% yield) as a colorless oil. LCMS: (ES+) m / z (M+H)+= 269.3.

[0182] Step 14: (4-(2-(difluoromethyl)-5-methoxyphenyl)cyclohexyl)methanol (1-13): To a solution of (2'-(difluoromethyl)-5'-methoxy-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methanol 1- 12 (500 mg, 1.9 mmol, 1 eq) in THF (5 mL) was added Pd / C (100 mg, 5% purity) under N2atmosphere. The suspension was degassed and purged with H23 times. The mixture was stirred under H2(15 Psi) at 25 °C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated to give 1-13 (465 mg, 83% yield) as colorless oil.1H NMR (400 MHz, CD3OD) δ = 7.41 (d, J = 8.6 Hz, 1H), 7.00 – 6.73 (m, 3H), 3.81 (s, 3H), 3.71 (d, J = 7.6 Hz, 1H), 3.42 (d, J = 6.4 Hz, 1H), 2.97 - 2.87 (m, 1H), 2.00 - 1.80 (m, 4H), 1.67 - 1.54 (m, 4H).

[0183] Step 15: ((1r,4r)-4-(2-(difluoromethyl)-5-methoxyphenyl)cyclohexyl)methanol (1- 13T): The mixture of (4-(2-(difluoromethyl)-5-methoxyphenyl)cyclohexyl)methanol 1-13 (450 mg) was purified by normal phase chiral HPLC (column: DAICEL CHIRALCEL OJ (250 mm × 50 mm, 10 um); mobile phase: [A: hexane, B: IPA (0.1% IPAM)]; B%: 20%, isocratic elution mode) to give 1-13T (179 mg, 39% yield) as a colorless gum. Chiral HPLC: RT=2.949 min. [Note: RT of cis isomer = 3.799 min].

[0184] Step 16: ethyl ((S)-2-cyclopropyl-2-(3-(((1r,4S)-4-(2-(difluoromethyl)-5- methoxyphenyl)cyclohexyl)methoxy)phenyl)ethyl)(methyl)phosphinate (1-14): To a solution of TMAD (120 mg, 680 μmol, 2.3 eq) in THF (1 mL) was added dropwise tributylphosphane (150 mg, 740 μmol, 180 μL, 2.5 eq) at 0 °C. After addition, the mixture was stirred at 0 °C for 0.25 hours, and then ((1r,4r)-4-(2-(difluoromethyl)-5-methoxyphenyl)cyclohexyl)methanol 1-13T (80 mg, 290 μmol, 1 eq) and ethyl ((S)-2-cyclopropyl-2-(3- hydroxyphenyl)ethyl)(methyl)phosphinate 1-9-S (80 mg, 290 μmol, 1 eq) in THF (1 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 40 °C for 12 hours. The residue was quenched with water (3 mL), then extracted with ethyl acetate (5 mL × 3). The combined organic layers were washed with saturated aqueous sodium chloride solution (3 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reverse phase HPLC (column Santai Technologies SepaFlash® cartridge 184 × 21.4 mm 40-60 μm [A: water (0.1% HCl), B: ACN]; B: 0~50%) to give 1-14 (105 mg, 66% yield) as a colorless oil. LCMS: (ES+) m / z (M-20+H)+= 501.2.

[0185] Step 17: ((S)-2-cyclopropyl-2-(3-(((1r,4S)-4-(2-(difluoromethyl)-5- methoxyphenyl)cyclohexyl)methoxy)phenyl)ethyl)(methyl)phosphinic acid (Compound 1): To a solution of ethyl ((S)-2-cyclopropyl-2-(3-(((1r,4S)-4-(2-(difluoromethyl)-5- methoxyphenyl)cyclohexyl)methoxy)phenyl)ethyl)(methyl)phosphinate 1-14 (100 mg, 200 μmol, 1 eq) in H2O (0.5 mL) and EtOH (0.5 mL) was added NaOH (40 mg, 1.01 mmol, 5 eq). The mixture was stirred at 40 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150×25mm× 5um; mobile phase: [A: water (0.1% NH3•H2O), B: ACN]; gradient: 17%-47% B over 12 min) to give Compound 1 (27 mg, 26% yield, NH3) as a white solid. LCMS: (ES+) m / z (2M+H)+= 985.6.1H NMR (400 MHz, CD3OD) δ = 7.42 (d, J = 8.6 Hz, 1H), 7.18 (t, J = 8.2 Hz,1H), 6.94 (s, 1H), 6.89 (t, J = 55.6 Hz, 1H), 6.86 - 6.84 (m, 2H), 6.75 - 6.73 (2, 2H), 3.84 (br dd, J = 6.2, 1.8 Hz, 2H), 3.82 (s, 3H), 2.93 (br t, J = 12.0 Hz, 1H), 2.22 (br dd, J = 9.6, 4.6 Hz, 1H), 2.11 - 1.99 (m, 4H), 1.89 (br d, J = 11.4 Hz, 3H), 1.60 (dq, J = 12.6, 2.6Hz, 2H), 1.35 - 1.26 (m, 2H), 1.14 - 0.99 (m, 1H), 0.72 (d, J = 13.6 Hz, 3H), 0.62 - 0.47 (m, 1H), 0.41 - 0.29 (m, 2H), 0.20 - 0.06 (m, 1H). Example 2: ((S)-2-cyclopropyl-2-(3-(((1r,4S)-4-(5-methoxy-2- (trifluoromethyl)phenyl)cyclohexyl)methoxy)phenyl)ethyl)(methyl)phosphinic acid (Compound 2):

[0186] Step 1: ethyl 5'-methoxy-2'-(trifluoromethyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4- carboxylate (2-1): To a solution of 2-bromo-4-methoxy-1-(trifluoromethyl)benzene (1 g, 3.9 mmol, 1 eq) and ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1- carboxylate (1.7 g, 5.9 mmol, 1.5 eq) in dioxane (10 mL) and H2O (2 mL) was added K2CO3(1.6 g, 11 mmol, 3 eq) and Pd(dppf)Cl2•CH2Cl2(0.32 g, 0.04 mmol, 0.1 eq). The reaction mixture was degassed and purged with N23 times, then stirred at 80 °C for 12 hrs. The reaction mixture was diluted with H2O (30 mL) and extracted with EA (30 mL × 3). The combined organic layers were washed with saturated brine (30 mL × 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~10% Ethyl acetate / Petroleum ether gradient @ 60 mL / min,) to give 2-1 (1.1 g, 93% yield) as a yellow oil.1H NMR (400 MHz, CDCl3) δ = 7.59 - 7.49 (m, 1H), 6.83 (br d, J = 8.8 Hz, 1H), 6.69 (s, 1H), 5.60 (br s, 1H), 4.19 - 4.11 (m, 2H), 3.84 (s, 3H), 2.46 - 2.27 (m, 5H), 2.16 - 2.10 (m, 1H), 1.93 - 1.81 (m, 1H), 1.27 (s, 3H).

[0187] Step 2: (5'-methoxy-2'-(trifluoromethyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4- yl)methanol (2-2): To a solution of ethyl 5'-methoxy-2'-(trifluoromethyl)-2,3,4,5-tetrahydro-[1,1'- biphenyl]-4-carboxylate 2-1 (1.1 g, 3.35 mmol, 1 eq) in THF (9 mL) and MeOH (3 mL) was added NaBH4 (1.3 g, 33 mmol, 10 eq) portionwise at 0 °C under N2.The mixture was stirred at 25°C for 12 hrs under N2. The reaction mixture was quenched with saturated aqueous NH4Cl solution (40 mL) and extracted with EA (40 mL × 3). The combined organic layers were washed with saturated brine (40 mL × 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~29% Ethyl acetate / Petroleum ether gradient @ 60 mL / min) to give 2-2 (0.7 g, 66% yield) as a colorless oil.1H NMR (400 MHz, CDCl3) δ = 7.55 (d, J = 8.8 Hz, 1H), 6.82 (br d, J = 8.8 Hz, 1H), 6.70 (s, 1H), 5.59 (br s, 1H), 3.84 (s, 3H), 3.72 - 3.58 (m, 2H), 2.37 - 2.24 (m, 3H), 1.97 - 1.85 (m, 2H), 1.71 - 1.53 (m, 2H).

[0188] Step 3: (4-(5-methoxy-2-(trifluoromethyl)phenyl)cyclohexyl)methanol (2-3): To a solution of Pd / C (0.9 g, 0.08 mol, 10% purity, 0.4 eq) in MeOH (6 mL) was added (5'-methoxy- 2'-(trifluoromethyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methanol 2-2 (0.7 g, 2.1 mmol, 1 eq) under N2atmosphere. The suspension was degassed and purged with H23 times. The mixture was stirred under H2(50 Psi) at 40 °C for 48 hrs. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give 2-3 (0.42 g, crude) a colorless oil.1H NMR (400 MHz, CDCl3) δ = 7.53 (d, J = 8.8 Hz, 1H), 7.01 - 6.79 (m, 1H), 6.79 - 6.67 (m, 1H), 3.83 (s, 3H), 3.59 - 3.41 (m, 2H), 3.01 - 2.80 (m, 1H), 2.02 - 1.76 (m, 6H), 1.71 - 1.52 (m, 3H).

[0189] Step 4: ((1r,4r)-4-(5-methoxy-2-(trifluoromethyl)phenyl)cyclohexyl)methanol (2- 3T): (4-(5-methoxy-2-(trifluoromethyl)phenyl)cyclohexyl)methanol 2-3 (0.42 g) was purified by normal phase chiral HPLC (column: DAICEL CHIRALPAK IE (50 × 250 mm × 10 μm); mobile phase: [A: hexane, B: IPA(0.1%IPAM)]; B%: 5, isocratic elution mode) to give 2-3T (0.12 g, 28% yield). Chiral HPLC: 1.585 min. [Note: RT of cis isomer: 1.464 min].

[0190] Step 5: ethyl ((S)-2-cyclopropyl-2-(3-(((1r,4S)-4-(5-methoxy-2- (trifluoromethyl)phenyl)cyclohexyl)methoxy)phenyl)ethyl)(methyl)phosphinate (2-4): To a solution of TMAD (0.17g, 0.96 mmol, 2.3 eq) in THF (1 mL) was added dropwise tributylphosphane (0.2 g, 1.04 mmol, 0.26 mL, 2.5 eq) at 0°C. After addition, the mixture was stirred at this temperature for 15 min, and then ((1r,4r)-4-(5-methoxy-2- (trifluoromethyl)phenyl)cyclohexyl)methanol 2-3T (0.12 g, 0.04 mol, 1 eq) and ethyl ((S)-2- cyclopropyl-2-(3-hydroxyphenyl)ethyl)(methyl)phosphinate 1-9-S (0.11 g, 0.04 mol, 1 eq) in THF (1 mL) was added dropwise at 0 °C. The mixture was stilled at 40 °C for 12 hrs. The reaction mixture was concentrated under reduced pressure to remove THF. The crude product was purified by reversed phase HPLC (Santai Technologies SepaFlash® cartridge 184.4 × 26.7mm × 40-60 μm; mobile phase: [A: water (0.1% FA)-B: ACN], gradient: 0-75% B over 35 min) to give 2-4 (0.13 g, 57% yield). LCMS: (ES+) m / z (M+H)+= 539.

[0191] Step 6: ((S)-2-cyclopropyl-2-(3-(((1r,4S)-4-(5-methoxy-2- (trifluoromethyl)phenyl)cyclohexyl)methoxy)phenyl)ethyl)(methyl)phosphinic acid (Compound2): To a solution of ethyl ((S)-2-cyclopropyl-2-(3-(((1r,4S)-4-(5-methoxy-2- (trifluoromethyl)phenyl)cyclohexyl)methoxy)phenyl)ethyl)(methyl)phosphinate 2-4 (100 mg, 0.2 mol, 1 eq) in EtOH (0.5 mL) and H2O (0.5 mL) was added NaOH (37 mg, 0.9 mol, 5 eq). The mixture was stirred at 80 °C for 3 hrs. The reaction mixture filtered. The filtrate was purified by reversed-phase HPLC (column: Waters xbridge 150 × 25mm × 10um; mobile phase: [A: water (0.1% NH4HCO3), B: ACN]; gradient:30%-60% B over 10 min) to give Compound 2 (42 mg, 44% yield) as a white solid. LCMS: (ES+) m / z (M+H)+= 511.1.1H NMR (400 MHz, CD3OD) δ = 7.55 (d, J = 8.8 Hz, 1H), 7.20 (t, J = 8.2 Hz, 1H), 7.03 (s, 1H), 6.86 (br s, 3H), 6.77 (br d, J = 8.2 Hz, 1H), 3.85 (s, 5H), 2.92 (br t, J = 11.4 Hz, 1H), 2.24 - 2.12 (m, 3H), 2.06 (br d, J = 12.8 Hz, 2H), 1.96 - 1.83 (m, 3H), 1.63 (q, J = 12.2 Hz, 2H), 1.34 - 1.23 (m, 2H), 1.15 - 1.04 (m, 1H), 0.92 - 0.84 (m, 3H), 0.63 - 0.55 (m, 1H), 0.44 - 0.29 (m, 2H), 0.22 - 0.13 (m, 1H). Example 3: ((S)-2-(3-(((1r,4S)-4-(2-cyclobutyl-5- methoxyphenyl)cyclohexyl)methoxy)phenyl)-2-cyclopropylethyl)(methyl)phosphinic acid (Compound 3):

[0192] Step 1: 1-(2-bromo-4-methoxyphenyl)cyclobutan-1-ol (3-1): A mixture of 2-bromo- 1-iodo-4-methoxybenzene (3 g, 9.59 mmol, 1 eq) in THF (30 mL) was added i-PrMgCl•LiCl (1.3 M in THF, 6.64 mL, 0.9 eq) at -40 °C dropwise under N2. The mixture was stirred at -40 °C for 0.5 h under N2. Then cyclobutanone (0.67 g, 9.59 mmol, 716.35 μL, 1 eq) in THF (6 mL) was added to the mixture at -40 °C dropwise under N2. The mixture was stirred at -20 °C for additional 2 h under N2. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (50 mL) at 0 °C and then extracted with EA (60 mL × 3). The combinedorganic layers were washed with saturated aqueous sodium chloride solution (50 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~20% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to give 3-1 (1 g, 38% yield) as a yellow oil.1H NMR (400 MHz, CD3OD) δ (ppm) = 7.34 (d, J = 8.6 Hz, 1H), 7.14 (d, J = 2.6 Hz, 1H), 6.88 (dd, J = 2.6, 8.6 Hz, 1H), 3.78 (s, 3H), 2.72 - 2.61 (m, 2H), 2.48 - 2.39 (m, 2H), 2.19 - 2.05 (m, 1H), 1.71 - 1.60 (m, 1H).

[0193] Step 2: 2-bromo-1-cyclobutyl-4-methoxybenzene (3-2): A mixture of 1-(2-bromo-4- methoxyphenyl)cyclobutan-1-ol 3-1 (1 g, 3.69 mmol, 1 eq), Et3SiH (3.95 g, 33.99 mmol, 5.43 mL, 9.2 eq), and TFA (4.09 g, 35.84 mmol, 2.66 mL, 9.7 eq) in DCM (10 mL) was degassed and purged with N23 times, and then the mixture was stirred at 25 °C for 4 h under N2atmosphere. The reaction mixture was directly concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~10% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give 3-2 (0.93 g, 99% yield) as a white solid.1H NMR (400 MHz, CD3OD) δ (ppm) = 7.26 (d, J = 8.6 Hz, 1H), 7.07 (d, J = 2.6 Hz, 1H), 6.88 (dd, J = 2.6, 8.6 Hz, 1H), 3.76 (s, 3H), 3.69 (quin, J = 8.8 Hz, 1H), 2.42 - 2.31 (m, 2H), 2.13 - 1.94 (m, 3H), 1.85 - 1.74 (m, 1H).

[0194] Step 3: ethyl 2'-cyclobutyl-5'-methoxy-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4- carboxylate (3-3): A mixture of 2-bromo-1-cyclobutyl-4-methoxybenzene 3-2 (0.83 g, 3.27 mmol, 1 eq), ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate (1.83 g, 6.54 mmol, 2 eq), Pd(dppf)Cl2•CH2Cl2(0.27 g, 0.33 mmol, 0.1 eq), and K2CO3(1.36 g, 9.81 mmol, 3 eq) in dioxane (10 mL) and H2O (1 mL) was degassed and purged with N23 times, and then the mixture was stirred at 80 °C for 12 h under N2atmosphere. The reaction was quenched by H2O (30 mL) and then extracted with EA (20 ml × 3) The combined organic phase was washed with saturated brine (50 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash®Silica Flash Column, Eluent of 0~10% Ethyl acetate / Petroleum ether gradient @ 60 mL / min) to give 3-3 (1.2 g, 99% yield) as a white solid.1H NMR (400 MHz, CD3OD) δ (ppm) = 7.24 (d, J = 8.6 Hz, 1H), 6.78 (dd, J = 2.8, 8.6 Hz, 1H), 6.53 (d, J = 2.8 Hz, 1H), 5.46 (br s, 1H), 4.18 (q, J = 7.0 Hz, 2H), 3.74 (s, 3H), 3.66 - 3.48 (m, 1H), 2.80 - 2.62 (m, 1H), 2.62 - 2.41 (m, 1H), 2.40 - 2.31 (m, 2H), 2.30 - 2.24 (m, 2H), 2.23 - 2.17 (m, 2H), 2.14 - 2.02 (m, 3H), 2.00 - 1.94 (m, 1H), 1.93 - 1.73 (m, 2H), 1.28 (t, J = 7.2 Hz, 3H).

[0195] Step 4: (2'-cyclobutyl-5'-methoxy-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methanol (3-4): A solution of ethyl 2'-cyclobutyl-5'-methoxy-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-carboxylate 3-3 (1 g, 2.70 mmol, 1 eq) in THF (10 mL) and MeOH (4 mL) was added NaBH4 (1.02 g, 27.03 mmol, 10 eq) in portions at 0 °C. The mixture was stirred at 25 °C for 12 hrs under N2atmosphere. The mixture was quenched by saturated aqueous ammonium chloride solution (50 mL), then extracted with EA (50 mL × 3). The combined organic layers were washed with saturated aqueous sodium chloride solution (20 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash®Silica Flash Column, Eluent of 0~30% Ethyl acetate / Petroleum ether gradient @ 80 mL / min) to give 3-4 (0.54 g, 66% yield) as a white solid.1H NMR (400 MHz, CD3OD) δ (ppm) = 7.23 (d, J = 8.6 Hz, 1H), 6.77 (dd, J = 2.8, 8.6 Hz, 1H), 6.53 (d, J = 2.8 Hz, 1H), 5.45 (br d, J = 2.4 Hz, 1H), 3.74 (s, 3H), 3.67 - 3.58 (m, 1H), 3.52 (dd, J = 2.6, 6.0 Hz, 2H), 2.28 (br d, J = 4.8 Hz, 3H), 2.22 - 2.15 (m, 2H), 2.14 - 2.03 (m, 2H), 1.99 - 1.90 (m, 2H), 1.89 - 1.81 (m, 2H), 1.81 - 1.73 (m, 1H), 1.51 - 1.36 (m, 1H).

[0196] Step 5: (4-(2-cyclobutyl-5-methoxyphenyl)cyclohexyl)methanol (3-5): To a solution of (2'-cyclobutyl-5'-methoxy-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methanol 3-4 (0.5 g, 1.65 mmol, 1 eq) in MeOH (5 mL) was added Pd / C (0.35 g, 0.17 mmol, 10% purity, 0.1 eq) under N2atmosphere. The suspension was degassed and purged with H23 times. The mixture was stirred under H2(15 Psi.) at 25 °C for 12 hrs. Palladium on carbon was removed by filtration, and the filtrate was concentrated under reduced pressure to give 3-5 (0.44 g, crude) as a white solid.1H NMR (400 MHz, CD3OD,) δ (ppm) = 7.15 (d, J = 8.4 Hz, 1H), 6.76 - 6.66 (m, 2H), 3.75 (s, 3H), 3.71 - 3.63 (m, 2H), 3.42 (d, J = 6.4 Hz, 1H), 2.79 - 2.64 (m, 1H), 2.52 - 2.51 (m, 1H), 2.35 - 2.21 (m, 2H), 2.15 - 1.97 (m, 3H), 1.96 - 1.85 (m, 3H), 1.85 - 1.72 (m, 2H), 1.71 - 1.58 (m, 2H), 1.57 - 1.46 (m, 3H).

[0197] Step 6: ((1r,4r)-4-(2-cyclobutyl-5-methoxyphenyl)cyclohexyl)methanol (3-5T): (4- (2-cyclobutyl-5-methoxyphenyl)cyclohexyl)methanol 3-5 (0.44 g, crude) was separated by SFC: ((Column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm); mobile phase: [A: CO2, B: MeOH]; B%: 25, isocratic elution mode) to give 3-5T (50 mg, 10.80% yield). RT_SFC = 1.125 min. [Note: RT of cis isomer = 1.220 min].1H NMR (400 MHz, CD3OD) δ (ppm) = 7.15 (d, J = 8.6 Hz, 1H), 6.78 - 6.56 (m, 2H), 3.75 (s, 3H), 3.70 - 3.59 (m, 1H), 3.42 (d, J = 6.4 Hz, 2H), 2.69 (br t, J = 11.8 Hz, 1H), 2.35 - 2.23 (m, 2H), 2.16 - 1.98 (m, 3H), 1.96 - 1.88 (m, 2H), 1.85 - 1.73 (m, 3H), 1.57 - 1.39 (m, 3H), 1.18 - 1.07 (m, 2H).

[0198] Step 7: ethyl ((S)-2-(3-(((1r,4S)-4-(2-cyclobutyl-5- methoxyphenyl)cyclohexyl)methoxy)phenyl)-2-cyclopropylethyl)(methyl)phosphinate (3-6): To a solution of (3E)-3-(dimethylcarbamoylimino)-1,1-dimethyl-urea (72.17 mg, 0.42 mmol, 2.3 eq) in tetrahydrofuran (0.5 mL) was added dropwise tributylphosphane (92.17 mg, 0.46 mmol, 0.11 mL, 2.5 eq) at 0 °C. The mixture was stirred at 0 °C for 0.25 h, and then ((1r,4r)-4-(2-cyclobutyl-5-methoxyphenyl)cyclohexyl)methanol 3-5T (50 mg, 0.18 mmol, 1 eq) and ethyl ((S)-2- cyclopropyl-2-(3-hydroxyphenyl)ethyl)(methyl)phosphinate 1-9-S (48.89 mg, 0.18 mmol, 1 eq) in tetrahydrofuran (0.5 mL) were added dropwise at 0 °C. The resulting mixture was stirred at 40 °C for 12 h under N2atmosphere. The reaction mixture was concentrated under reduced pressure. The crude product was purified by reversed phase (Column: Daisogel SP ODS RPS 150 × 25 mm × 5 um; mobile phase: [A: water (0.1% FA), B: ACN]; gradient: 80%-100% B over 10 min) to give 3-6 (30 mg, 31% yield) as a white solid.1H NMR (400 MHz, CD3OD) δ (ppm) = 7.17 - 7.10 (m, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.77 (br d, J = 7.6 Hz, 2H), 6.73 - 6.68 (m, 1H), 6.67 - 6.65 (m, 1H), 6.61 (dd, J = 2.6, 8.4 Hz, 1H), 3.88 - 3.79 (m, 1H), 3.76 (d, J = 6.6 Hz, 2H), 3.66 (s, 3H), 2.71 - 2.57 (m, 1H), 2.34 - 2.16 (m, 4H), 2.11 - 1.90 (m, 6H), 1.82 - 1.65 (m, 4H), 1.62 - 1.29 (m, 3H), 1.26 - 1.16 (m, 3H), 1.15 - 1.00 (m, 5H), 0.99 - 0.84 (m, 2H), 0.60 - 0.47 (m, 1H), 0.32 (br dd, J = 4.6, 8.0 Hz, 1H), 0.22 (td, J = 4.6, 9.2 Hz, 1H), 0.10 (br dd, J = 4.6, 9.2 Hz, 1H).

[0199] Step 8: ((S)-2-(3-(((1r,4S)-4-(2-cyclobutyl-5- methoxyphenyl)cyclohexyl)methoxy)phenyl)-2-cyclopropylethyl)(methyl)phosphinic acid (Compound 3): A mixture of ethyl ((S)-2-(3-(((1r,4S)-4-(2-cyclobutyl-5- methoxyphenyl)cyclohexyl)methoxy)phenyl)-2-cyclopropylethyl)(methyl)phosphinate (30 mg, 56.61 μmol, 1 eq) and NaOH (22.64 mg, 0.57 mmol, 10 eq) in EtOH (0.5 mL) and H2O (0.5 mL) was degassed and purged with N23 times. The mixture was stirred at 60 °C for 2 hr under N2atmosphere. The reaction residue was purified by prep-HPLC (Column: Daisogel SP ODS RPS150 × 25 mm × 5 um; mobile phase: [A: water (0.1% NH4HCO3), B: ACN]; gradient: 36%-66%B over 10 min) to give Compound 3 (6.5 mg.23% yield) as a white solid. LCMS: (ES+) m / z (M+H)+= 497.4.1H NMR (400 MHz, CD3OD) δ (ppm) = 7.21 (t, J = 7.8 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 6.86 (br d, J = 5.0 Hz, 2H), 6.81 - 6.74 (m, 2H), 6.70 (br d, J = 8.6 Hz, 1H), 3.85 (d, J = 6.2 Hz, 2H), 3.75 (s, 3H), 3.72 - 3.62 (m, 1H), 2.74 (br t, J = 12.2 Hz, 1H), 2.30 (q, J = 7.2 Hz, 2H), 2.26 - 2.16 (m, 3H), 2.15 - 2.08 (m, 2H), 2.07 - 2.05 (m, 1H), 2.02 (br s, 1H), 1.91 - 1.74 (m, 4H), 1.59 - 1.48 (m, 2H), 1.47 - 1.17 (m, 3H), 1.11 (br dd, J = 3.6, 7.8 Hz, 1H), 0.90 (d, J = 14.0 Hz, 3H), 0.65 - 0.54 (m, 1H), 0.43 - 0.28 (m, 2H), 0.17 (qd, J = 4.6, 9.2 Hz, 1H).

[0200] The compounds in Table 1 were prepared according to the procedures described above using the appropriate intermediates and reagents.Table 1.II. Biological Evaluation Example A-1: In Vitro Activity Assay Cell Lines Expressing GPR40 / FFAR1

[0201] CHO-K1 cells expressing human GPR40 were purchased from DiscoverX (95- 1005C2). HEK293 cells expressing mouse FFAR1 were prepared using a mouse FFAR1 carrying plasmid purchased from OriGene Technologies (MR222997). The cells were transfected using Lipofectamine 2000 using manufacturer instructions and stable cell line was established from a single cell using geneticine selection. Assay ready frozen (ARF) cells were prepared and used throughout the study. Inositol Phosphate Accumulation Assay

[0202] The assay was performed in a 384-well plate format using IP1 assay kit from Cis-Bio. ARF cells expressing FFAR1 (mouse and human) were thawed, washed and then plated in theappropriate medium (F12 based medium for CHO hFFAR1 and DMEM based medium for HEK293 mFFAR1 – both were supplemented with 10% FBS and penicillin / streptomycin).20 μL of 3.5×105cells / mL were plated on a Poly D-Lysine coated 384-well white plate. The cells were then incubated for 16 hr at 37 °C / 5 % CO2. After 16 hr the medium was removed and 15 µL of stimulation buffer containing the test compounds was added to the cells. The plates were then incubated for 90 min at 37 °C / 5 % CO2.5 µL of detection buffer (prepared as described in the IP-one kit) was added to each well and the plates were incubated at RT for 1hr.

[0203] RT-FRET was measured using ClarioSTAR plate reader, calculating the ratio between emissions at 665 nm and 620 nm (HTRF ratio). HTRF ratio for positive (Max) and negative (Min) controls were used to normalize HTRF data and generate values for % activity. EC50and Max activity values were determined using a standard 4-parameter fit.

[0204] Results for exemplary compounds are shown in Table 2. Table 2.A ≤ 25 nM; 25 nM < B ≤ 50 nM; 50 nM < C ≤ 500 nM; D > 500 nM.

[0205] Ref. A is ((S)-2-cyclopropyl-2-(3-(((1r,4S)-4-(5-methoxy-2-(trifluoromethyl)pyridin- 3-yl)cyclohexyl)methoxy)phenyl)ethyl)(methyl)phosphinic acid:.

[0206] Ref. B is ((S)-2-cyclopropyl-2-(3-(((1s,4R)-4-(2-(difluoromethyl)-5- methoxyphenyl)cyclohexyl)methoxy)phenyl)ethyl)(methyl)phosphinic acid:.

[0207] Ref. C is ((S)-2-cyclopropyl-2-(3-(((1r,4S)-4-(5-methoxy-2-(trifluoromethyl)pyridin- 3-yl)cyclohexyl)methoxy)phenyl)ethyl)(methyl)phosphinic acid:.

[0208] While preferred embodiments of the present disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. It is not intended that the disclosure be limited by the specific examples provided within the specification. While the disclosure has been described with reference to the aforementioned specification, the descriptions and illustrations of the embodiments herein are not meant to be construed in a limiting sense. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the disclosure. Furthermore, it shall be understood that all aspects of the disclosure are not limited to the specific depictions, configurations or relative proportions set forth herein which depend upon a variety of conditions and variables. It should be understood that various alternatives to the embodiments of the disclosure described herein may be employed in practicing the disclosure. It is therefore contemplated that the invention shall also cover any such alternatives, modifications, variations or equivalents. It is intended that the following claims define the scope of the disclosure and that methods and structures within the scope of these claims and their equivalents be covered thereby. - 80 -

Claims

CLAIMS What is Claimed is:

1. A compound of Formula (I):Formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R1is C1-C10fluoroalkyl, C1-C10fluoroalkoxy, C3-C12cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10aryl, 5- to 9-membered heteroaryl, or -C(=O)N(R11)2; wherein each fluoroalkyl, fluoroalkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, C1-C6alkyl, C3-C6cycloalkyl, C1-C6fluoroalkyl, C1-C6hydroxyalkyl, -CN, -OH, -O-(C1-C6alkyl), and -O-(C1-C6fluoroalkyl); R2is hydrogen, C1-C6alkyl, or C3-C6cycloalkyl; each R3, R4, and R5 are each independently hydrogen, halogen, or C1-C6 alkyl;R6is C1-C6alkyl; R7is hydrogen or C1-C6alkyl; Y is CH, CR8, or N; each R8is independently halogen, -CN, -OH, -O-(C1-C6alkyl), -O–(C1-C6fluoroalkyl), - NH2, -NH-(C1-C6alkyl), -N(C1-C6alkyl)2, C1-C6alkyl, or C1-C6fluoroalkyl; each R9is independently halogen, C1-C6alkyl, or C1-C6fluoroalkyl; each R10is independently halogen, -CN, -OH, -O-(C1-C6alkyl), -O–(C1-C6fluoroalkyl), - NH2, -NH-(C1-C6alkyl), -N(C1-C6alkyl)2, C1-C6alkyl, or C1-C6fluoroalkyl; n is 0, 1, or 2; m is 0, 1, 2, 3, or 4; p is 0, 1, or 2; each R11is independently hydrogen, C1-C10alkyl, C2-C10alkenyl, C2-C10alkynyl, C3-C10cycloalkyl, 3- to 10-membered heterocycloalkyl, phenyl, or monocyclic heteroaryl; wherein each alkyl, alkenyl, alkynyl, phenyl, heteroaryl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, -CN, -OH,C1-C6alkyl, C1-C6fluoroalkyl, C1-C6hydroxyalkyl, -O-(C1-C6alkyl), and -O-(C1-C6fluoroalkyl); or two R11on the same nitrogen atom are taken together with the nitrogen to which they are attached to form a 3- to 10-membered N-heterocycloalkyl; wherein the heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, -CN, -OH, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6hydroxyalkyl, -O-(C1-C6alkyl), and -O-(C1-C6fluoroalkyl). The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein: R2is C3-C6cycloalkyl; each R3, R4, and R5are each independently hydrogen, F, -CH3, or -CH2CH3; R6is C1-C4alkyl; and R7is H. The compound of claim 1, having the structure of Formula (III):or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein: each R8is independently F, Cl, -O-(C1-C6alkyl), -O-(C1-C6fluoroalkyl), -NH-(C1-C6alkyl), -N(C1-C6alkyl)2, C1-C6alkyl, or C1-C6fluoroalkyl; each R10is independently F, Cl, -O-(C1-C6alkyl), -O-(C1-C6fluoroalkyl), -NH-(C1-C6alkyl), -N(C1-C6alkyl)2, C1-C6alkyl, or C1-C6fluoroalkyl; n is 0 or 1; m is 0; and p is 0 or 1. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein: n is 0; and p is 0.The compound of any one of claims 1-5, having the structure of Formula (IV):Formula (IV) or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof wherein: R1is C1-C10fluoroalkyl, C1-C10fluoroalkoxy, C3-C12cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10aryl, 5- to 9-membered heteroaryl, or -C(=O)N(R11)2; wherein each fluoroalkyl, fluoroalkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, C1-C6alkyl, C3-C6cycloalkyl, C1-C6fluoroalkyl, C1-C6hydroxyalkyl, -CN, -OH, -O-(C1-C6alkyl), and -O-(C1-C6fluoroalkyl). The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein: R1is C3-C12cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C10aryl, or 5- to 9- membered heteroaryl; wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, C1-C6alkyl, C3-C6cycloalkyl, C1-C6fluoroalkyl, C1-C6hydroxyalkyl, -CN, -OH, -O-(C1-C6alkyl), and - O-(C1-C6fluoroalkyl). The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein: R1is 5- to 6-membered heteroaryl; wherein the heteroaryl is independently unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C1-C6alkyl, C3-C6cycloalkyl, -CN, -OH, and -O-(C1-C6alkyl). The compound of any one of claims 1-9, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:R1is selected from, , , , ,andThe compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein: R1is C3-C8cycloalkyl or 4- to 9-membered heterocycloalkyl; wherein each cycloalkyl and heterocycloalkyl is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, C1-C6alkyl, C3-C6cycloalkyl, -CN, -OH, and -O-(C1-C6alkyl). The compound of any one of claims 1-8 or 11, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein: R1is selected from, , , , , , ,, , , , , , ,, and. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein: R1is C1-C4fluoroalkyl or C1-C4fluoroalkoxy. The compound of any one of claims 1-7 or 13, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein: R1is selected from -CF2H, -CF3, and -OCF2H.

15. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein: R1is -C(=O)N(R11)2.

16. The compound of any one of claims 1-7 or 15, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein: R1is17. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, selected from:pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.

18. A pharmaceutical composition comprising a compound of any one of claims 1-17, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, and at least one pharmaceutically acceptable excipient.

19. A method of treating a condition or disorder involving the gut-brain axis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-17, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof.

20. The method of claim 19, wherein the condition or disorder is associated with GPR40 activity.

21. The method of claim 19 or claim 20, wherein the condition or disorder is a metabolic disorder.

22. The method of claim 21, wherein the condition or disorder is type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia, nonalcoholic steatohepatitis, or hypertension.

23. The method of claim 19 or claim 20, wherein the condition or disorder is a nutritional disorder.

24. The method of claim 23, wherein the condition or disorder is short bowel syndrome, intestinal failure, or intestinal insufficiency.

25. The method of claim 19 or claim 20, wherein the condition or disorder is an eating disorder.

26. The method of claim 25, wherein the eating disorder is hyperphagia or binge eating disorder.

27. The method of claim 19 or claim 20, wherein the condition or disorder is addiction.

28. The method of claim 27, wherein the addiction is alcohol addiction, cocaine addiction, methamphetamine addiction, nicotine addiction, or opioid addiction.

29. The method of any one of claims 19-28, wherein the compound is gut restricted.

30. The method of claim 29, wherein the compound has low systemic exposure.

31. The method of any one of claims 19-30, further comprising administering one or more additional therapeutic agents to the subject.

32. The method of claim 31, wherein the one or more additional therapeutic agents are selected from a TGR5 agonist, a GPR119 agonist, an SSTR5 antagonist, an SSTR5 inverse agonist, a CCK1 agonist, a PDE4 inhibitor, a DPP-4 inhibitor, a GLP-1 receptor agonist, a GOAT inhibitor, and metformin, or combinations thereof.

33. The method of claim 32, wherein the TGR5 agonist, GPR119 agonist, SSTR5 antagonist, SSTR5 inverse agonist or CCK1 agonist is gut-restricted.

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