Antidiabetic Compounds and Compositions

Abstract

Provided herein are novel compounds related to GPR40 (e.g., Formula I, II, II-B, III, or III-B), pharmaceutical compositions, and methods of use. The compounds herein are typically GPR40 agonists and can be used to treat a variety of disorders, conditions, or diseases, such as type 2 diabetes.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to International Application No. PCT / CN2022 / 071974, filed January 14, 2022, the entire contents of which are incorporated herein by reference.

[0002] In various embodiments, the present disclosure relates generally to novel antidiabetic compounds, pharmaceutical compositions, and methods of use thereof, such as for the treatment of type 2 diabetes mellitus. [Background technology]

[0003] Type 2 diabetes mellitus is a form of diabetes characterized by hyperglycemia, insulin resistance, and a relative deficiency of insulin. There are several available treatments for type 2 diabetes, each with its own limitations and potential risks. Pharmacological treatments for diabetes primarily target: (1) hepatic glucose production (biguanides such as phenformin and metformin), (2) insulin resistance (PPAR agonists such as rosiglitazone, troglitazone, engliazone, balaglitazone, MCC-555, netoglitazone, T-131, LY-300512, LY-818, and pioglitazone), (3) insulin secretion (sulfonylureas such as tolbutamide, glipizide, and glimepiride), and (4) incretin hormones. (4) incretin hormone mimetics (GLP-1 / GIP derivatives and analogs such as exenatide, liraglutide, dulaglutide, semaglutide, lixisenatide, albiglutide, taspoglutide, and tirzepatide), (5) inhibitors of incretin hormone degradation (DPP-4 inhibitors such as sitagliptin, alogliptin, vildagliptin, linagliptin, denagliptin, and saxagliptin), and (6) SGLT2 inhibitors (canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin).

[0004] G protein-coupled receptor 40 (GPR40) is a cell-surface GPCR that is highly expressed in human (and rodent) pancreatic islets and insulin-secreting cell lines. The human G protein-coupled receptor hGPR40 is primarily localized in pancreatic β cells and enteroendocrine cells. GPR40 has also been reported to be expressed in the brain (hippocampus and hypothalamus), hepatocytes, and macrophages. Medium- to long-chain fatty acids (FFAs) are endogenous ligands for GPR40. Upon binding to GPR40, FFAs trigger a signaling cascade that results in the increase of [Ca] in β cells. 2+ ] levels increase, subsequently stimulating insulin secretion. In the intestine, FFAs also stimulate the secretion of incretins, including glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), cholecystokinin (CCK), and peptide YY (PYY). The recent recognition of the function of GPR40 in regulating insulin secretion has provided insight into the regulation of carbohydrate and lipid metabolism in vertebrates and also provides a target for the development of therapeutics for metabolic disorders such as obesity, diabetes, cardiovascular disease, and dyslipidemia.

[0005] Agonists of G protein-coupled receptor 40 (GPR40) have been shown to be useful in the treatment of type 2 diabetes mellitus, obesity, hypertension, dyslipidemia, cancer and metabolic syndrome, as well as cardiovascular diseases such as myocardial infarction and stroke. There is a need for novel GPR40 agonists with pharmacokinetic and pharmacodynamic properties suitable for use as human pharmaceuticals. Summary of the Invention

[0006] Provided herein are compounds, pharmaceutical compositions, and methods of use related to GPR40. The compounds herein are typically GPR40 agonists, and are useful in treating type 1 or type 2 diabetes, obesity, hyperglycemia, impaired glucose tolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, myocardial infarction, stroke, hypertriglyceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, renal disease, diabetic kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinal disease, and the like. The compounds may be used to treat disorders, conditions, or diseases such as inflammatory bowel diseases including, but not limited to, rheumatoid arthritis, sexual dysfunction, dermatoses, dyspepsia, hypoglycemia, cancer, edema, non-alcoholic steatohepatitis (NASH), lipodystrophy, Prader-Willi syndrome, inflammatory bowel diseases including Crohn's disease and ulcerative colitis, irritable bowel syndrome, short bowel syndrome, lymphocytic colitis, rare microscopic colitis, and / or neurodegenerative diseases including, but not limited to, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.

[0007] Some embodiments of the present disclosure are directed to compounds of formula I, or pharmaceutically acceptable salts or esters thereof: JPEG2025502110000002.jpg34170, where the variables are defined herein. In some embodiments, a compound of Formula I can have a subformula according to Formula I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-1-A, I-4-A, I-4-B, I-4-C, I-5-A, I-5-B, I-5-C, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, or I-1-A-10, as defined herein.

[0008] Some embodiments of the present disclosure are directed to a compound of formula II, or a pharmaceutically acceptable salt or ester thereof: JPEG2025502110000003.jpg37170 wherein the variables are defined herein. In some embodiments, the compound of Formula II can have a subformula according to Formula II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-9, II-1-A, II-4-A, II-5-A, or II-1-A-1, as defined herein.

[0009] Some embodiments of the present disclosure are directed to a compound of formula II-B, or a pharmaceutically acceptable salt or ester thereof: JPEG2025502110000004.jpg37170, where the variables are defined herein. In some embodiments, the compound of Formula II-B can have a sub-formula according to Formula II-B-1, II-B-2, or II-B-3, as defined herein.

[0010] In some embodiments, the disclosure provides a compound of formula III, or a pharmaceutically acceptable salt or ester thereof: JPEG2025502110000005.jpg45170, where the variables are defined herein. In some embodiments, the compound of Formula III can have a sub-formula according to Formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-1-A, III-4-A, III-5-A, or III-1-A-1, as defined herein.

[0011] In some embodiments, the present disclosure provides a compound of formula III-B, or a pharmaceutically acceptable salt or ester thereof: JPEG2025502110000006.jpg44170, where the variables are defined herein. In some embodiments, the compound of Formula III-B can have a sub-formula according to Formula III-B-1, III-B-2, or III-B-3, as defined herein.

[0012] In some embodiments, the present disclosure also provides a compound selected from Table 1 herein, or a pharmaceutically acceptable salt or ester thereof.

[0013] In some embodiments, the present disclosure provides pharmaceutical compositions comprising one or more compounds of the present disclosure, and optionally a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of Formula I (e.g., Formula I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-1-A, I-4-A, I-4-B, I-4-C, I-5-A, I-5-B, I-5-C, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, or I-1-A-10), a compound of Formula II (e.g., Formula II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-9, II-1-A, II-4-A, II-5-A, or II ... 1), a compound of Formula II-B (e.g., Formula II-B-1, II-B-2, or II-B-3), Formula III (e.g., Formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-1-A, III-4-A, III-5-A, or III-1-A-1), Formula III-B (e.g., III-B-1, III-B-2, or III-B-3), or any of the compounds listed in Table 1 herein, any of the compounds according to Examples 1 to 221 herein, or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable excipient. The pharmaceutical composition can typically be formulated for oral administration. In some embodiments, the pharmaceutical composition is administered to a subject in need of delivering an effective amount of a GPR40 agonist to the gastrointestinal tract with minimal or no absorption of the GPR40 agonist in the systemic circulation.

[0014] In some embodiments, the present disclosure provides methods for treating or preventing a disorder, condition, or disease responsive to activation of GPR40 in a subject in need thereof. In some embodiments, the method comprises administering to the subject an effective amount of one or more compounds of the present disclosure or a pharmaceutical composition herein. In some embodiments, the method comprises administering to the subject an effective amount of one or more compounds of Formula I (e.g., Formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-1-A, I-4-A, I-4-B, I-4-C, I-5-A, I-5-B, I-5-C, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I-1 -A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, or I-1-A-10), Formula II (e.g., Formula II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-9, II-1-A, II-4-A, II-5-A, or II-1-A-1), Formula The present invention includes administering to a subject a compound of II-B (e.g., Formula II-B-1, II-B-2, or II-B-3), Formula III (e.g., Formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-1-A, III-4-A, III-5-A, or III-1-A-1), Formula III-B (e.g., III-B-1, III-B-2, or III-B-3), or any of the compounds listed in Table 1 herein, any of the compounds according to Examples 1-221 herein, or a pharmaceutically acceptable salt or ester thereof, or a pharmaceutical composition comprising same. In some embodiments, the administration is oral.

[0015] In some embodiments, the present disclosure provides a method of treating type 2 diabetes mellitus in a subject in need thereof. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of one or more compounds of the present disclosure or a pharmaceutical composition herein. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of one or more compounds of Formula I (e.g., Formulas I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-1-A, I-4-A, I-4-B, I-4-C, I-5-A, I-5-B, I-5-C, I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, I- I-1-A-5, I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, or I-1-A-10), Formula II (e.g., Formula II-1, II-2, II-3, II-4, II-5, II-6, II-7, II-8, II-9, II-1-A, II-4-A, II-5-A, or II-1-A-1), The present invention includes administering to a subject a compound of Formula II-B (e.g., Formula II-B-1, II-B-2, or II-B-3), Formula III (e.g., Formula III-1, III-2, III-3, III-4, III-5, III-6, III-7, III-8, III-9, III-1-A, III-4-A, III-5-A, or III-1-A-1), Formula III-B (e.g., III-B-1, III-B-2, or III-B-3), or any of the compounds listed in Table 1 herein, any of the compounds according to Examples 1-221 herein, or a pharmaceutically acceptable salt or ester thereof, or a pharmaceutical composition comprising same. In some embodiments, the administration is oral.

[0016] In some embodiments, the methods herein further comprise administering to the subject an additional therapeutic agent, which may be PPARγ agonists and partial agonists, biguanides, protein tyrosine phosphatase 1B (PTP-1B) inhibitors, dipeptidyl peptidase IV (DPP-IV) inhibitors, insulin or insulin mimetics, sulfonylureas, α-glucosidase inhibitors, or agents that improve the patient's lipid profile.The drug may be (i) an HMG-CoA reductase inhibitor, (ii) a bile acid sequestrant, (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) a PPARα agonist, (v) a cholesterol absorption inhibitor, (vi) an acyl-CoA: cholesterol acyltransferase (ACAT) inhibitor, (vii) a CETP inhibitor, (viii) a PCSK9 inhibitor or antibody, (ix) an apolipoprotein inhibitor, (x) a phenolic antioxidant, a PPARα / γ dual agonist, a PPARδ agonist, a PPARα / δ Partial agonists, anti-obesity compounds, ileal bile acid transporter inhibitors, anti-inflammatory agents, glucagon receptor antagonists, glucokinase activators, GLP-1 and GLP-1 analogs, GLP-1 receptor agonists (peptides and small molecules), GLP-1 / GIP receptor dual agonists, GLP-1 / glucagon receptor dual agonists, GLP-1 / GIP / insulin receptor triple agonists, GLP-1 / GIP / glucagon receptor triple agonists, GIP receptor antibodies, GLP-1 analogs / GIP receptor antibodies, PYY analogs, amylin analogs, GPR119 agonists, TGR5 agonists, SSTR3 and / or SSTR5 antagonists or inverse agonists, THRβ agonists, HSD-1 inhibitors, HSD-17 inhibitors and degraders, PNPLA3 inhibitors and degraders, SGLT-2 inhibitors, SGLT-1 / SGLT-2 inhibitors, intestinal α-glucosidase inhibitors, FXR agonists, DGAT1 and / or DGAT2 inhibitors, FGF19 and analogs, FGF21 and analogs, GDF15 and analogs, ANGPTL (xi) anti-amyloid beta antibodies, (xii) anti-inflammatory drugs including, but not limited to, PDE4 inhibitors, JAK inhibitors, TYK2 inhibitors, S1P receptor modulators, NLRP3 inhibitors, BTK inhibitors, IRAK1 inhibitors, IRAK4 inhibitors, glucocorticoids, anti-TNFα antibodies, and anti-IL-12 / IL-23 antibodies, and (xiii) anti-integrin antibodies including anti-α4β7, anti-α4, anti-β7, and anti-MAdCAM-1.

[0017] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention herein. DETAILED DESCRIPTION OF THE INVENTION

[0018] In various embodiments, the present disclosure provides compounds useful for modulating GPR40. The compounds herein typically have no or reduced systemic exposure, and are therefore expected to have reduced side effects due to such systemic exposure. In some embodiments, the present disclosure also provides pharmaceutical compositions comprising the compounds and methods of using them, such as for treating type 2 diabetes. compound

[0019] International Application No. PCT / CN2021 / 109496, filed July 30, 2021 (the entire contents of which are incorporated herein by reference), describes various conjugates of GPR40 agonists covalently linked to a carrier. As described in the '496 application, without wishing to be bound by theory, it is believed that conjugates of GPR40 agonists, when administered, may have advantages such as modulating GPR40 without side effects or with reduced side effects due to reduced systemic exposure.

[0020] The present disclosure is based, in part, on the discovery that when certain GPR40 agonists are covalently attached to a polar group via a linker of sufficient chain length, the resulting compounds, such as compounds of Formula I, II, II-B, III, or III-B described herein, can be highly potent GPR40 agonists, having EC50 values ​​of less than 50 nM, less than 10 nM, or less than 1 nM when tested according to Biological Example 1 herein.

[0021] In a broader sense, the compounds described herein (e.g., of Formula I, II, II-B, III, or III-B) can be considered to have one or more GPR40 agonists covalently attached to a hydrophilic group via a linker. Typically, the compounds described herein have one GPR40 agonist covalently attached to a hydrophilic group via a linker: (GPR40 agonist)-linker-hydrophilic group. In some more specific embodiments, the compounds typically have a residue of a GPR40 agonist JPEG2025502110000007.jpg59170JPEG2025502110000008.jpg101170JPEG2025502110000009.jpg78170, as in the linker L A via the hydrophilic group T A and may be considered to be linked to each other. The variables include any of the preferred ones described herein, in any combination. For clarity, the analysis of compounds as residues of a GPR40 agonist, linkers, and hydrophilic groups is merely for the convenience of the discussion herein and does not in any way limit the compounds herein. For example, even in the same compound, a particular structural fragment may be linked to a residue of a GPR40 agonist, L A , or T A For purposes herein, in such a situation, under any method of assignment, the GPR40 agonist residue of the compound, L A , and T A are within the respective definitions of a genus of compounds herein. Typically, the variables GPR-1-R, GPR-2-R, GPR-2-R', GPR-2B-R, GPR-2B-R', GPR-3-R, GPR-3-R', GPR-3B-R, or GPR-3B-R' are such that at least one of the corresponding compounds according to the formula GPR-1, GPR-2, GPR-2B, GPR-3, or GPR-3B is a GPR40 agonist, preferably with an EC50 of less than 100 nM as measured according to Biological Example 1 herein: JPEG2025502110000010.jpg157170E 2 is E 2A or L N -E 2A and E 1 or E 2A is hydrogen, C 1-4 Alkyl, N3, JPEG2025502110000011.jpg30170E 3 is E 3A or L N -E 3A and E 3A is hydrogen, C 1-4 Alkyl, N3, JPEG2025502110000012.jpg31170L N is defined here (empty (null) or C 1-6 In a preferred embodiment, the residues GPR-1-R, GPR-2-R, GPR-2B-R, GPR-3-R, or GPR-3B-R are hydrophilic groups T A The compounds herein covalently bound to have a similar EC50 value (e.g., within 3-fold) or a lower EC50 value compared to at least one (preferably all) of the corresponding compounds of formula GPR-1, GPR-2, GPR-2B, GPR-3, or GPR-3B. Using formula I-1 or II-1 described herein below as an example, in a preferred embodiment, L in formula I-1 or II-1 A -T A N3 or JPEG2025502110000013.jpg11170 results in a GPR40 agonist that is equally or less active. In other words, in such embodiments, the compound of formula I-1 or II-1 has an EC50 that is equal to or less than the EC50 of the corresponding compound of formula GPR-1 or GPR-2, and 1 or E 2 N3 or JPEG2025502110000014.jpg12170 and EC50 is determined according to Biological Example 1 herein. Formula I

[0022] In some embodiments, the disclosure provides a compound of Formula I, or a pharmaceutically acceptable salt or ester thereof: JPEG2025502110000015.jpg33170In formula, L 10 is alkylene (e.g., C 1-6 alkylene), halogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 1-6 Alkoxy, optionally substituted C 3-6 optionally substituted with 1 to 3 substituents independently selected from cycloalkoxy, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two substituents joined to form an optionally substituted ring system; R at each occurrence A are independently selected from halogen, CN, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 1-6 Alkoxy or optionally substituted C 3-6 cycloalkoxy or two R A are linked to form an optionally substituted ring structure, and p1 is 0, 1, or 2; R at each occurrence B are independently selected from halogen, hydroxyl, amino, substituted amino, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 1-6 Alkoxy or optionally substituted C 3-6 cycloalkoxy or two R B are linked to form an optionally substituted ring structure, and p2 is 0, 1, 2, 3, or 4; J 1is a bond, an optionally substituted aryl or heteroaryl ring, -C 1-6 Alkylene-N(R 100 )-, a 3- to 14-membered optionally substituted heterocyclylene containing at least one ring nitrogen atom, or -C 1-6 alkylene-(3- to 14-membered optionally substituted heterocyclylene containing at least one ring nitrogen atom)-; R 100 is hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl; J 2 is a bond or alkylene, halogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 1-6 Alkoxy, optionally substituted C 3-6 optionally substituted with 1 to 3 substituents independently selected from cycloalkoxy, or two substituents joined to form an optionally substituted ring structure; J 3 is an optionally substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl ring; During the ceremony, q is an integer of 1 to 10, preferably 1 or 2; T A is a hydrophilic group, and L A is a linker. In a preferred embodiment, T A L A wherein (1) if the terminal atom is N of a basic amine group, the corresponding compound T A -(C(O)-CH3) q has a cLogP less than 1, -C(O)-CH3 is bonded to the terminal N atom, and (2) if the terminal atom is the C of the C(O) group, the corresponding compound TA -(OH) q has a cLogP less than 1, -OH is bonded to the terminal C atom, and (3) if the terminal atom is S in the SO2 group, T A -(OH) q has a cLogP less than 1, -OH is bonded to the terminal S atom, or (4) if (1) to (3) do not apply, T A -H q has a cLogP less than 1, L A L A The maximum length between the two terminal atoms of is at least -(CH2) 10 a linker characterized in that the maximum length between the two terminal carbon atoms of A If both terminal atoms of the compound are C in a C(O) or S in an SO group, the corresponding compound is HO-L A -OH has a cLogP of at least 3, each -OH is bonded to a terminal C(O) or SO2 group, (2) L A If only one terminal atom of is C in C(O) or S in SO2 group, the corresponding compound HL A -OH has a cLogP of at least 3, -OH is bonded to a C(O) or SO2 group, or (3) if neither (1) nor (2) applies, the corresponding compound HL A -H has a cLogP of at least 3.

[0023] The terms "end atom(s)", "terminal atom(s)", and the like refer to L, for Formula I, II, or III herein. A or T A When used herein in connection with a structure such as -(CH), it should be understood as the point (atom) of attachment of the structure to the rest of the molecule, and therefore, by this definition, these terminal atoms are non-hydrogen atoms. For example, -(CH) 10 An alkylene chain of - is to be understood as having two terminal carbon atoms.

[0024] In some embodiments, q of formula I is 1, and the compound of formula I can be characterized as having formula I-1: JPEG2025502110000016.jpg35170 Variable T A , L A , L 10 , J 1 , J 2 , J 3 , R A , R B , p1, and p2 include any of the preferred definitions described herein, in any combination, i.e., each definition and preferred definition of a variable may be any of those described herein for each variable, which may be combined in any possible way with any one or more other definitions (e.g., preferred definitions) of any variable herein. Linker L A

[0025] As shown herein, the present inventors have discovered that several factors are important for a compound of Formula I to be a potent GPR40 agonist. One factor that can determine whether a compound of Formula I can be a potent GPR40 agonist is the molecular weight of the linker (e.g., L), rather than the exact chemical structure of the linker. A As shown in the Examples section of the specification, the EC50 value can be significantly increased when the linker length is below a certain threshold. Therefore, the present inventors have found that the linker L in Formula I A The maximum length between the two terminal atoms of the alkylene chain -(CH2) 10 - should be the maximum length between the two terminal carbon atoms of L. A The longest chain length is the alkylene chain -(CH2) 10 In further detail, the linker L A can be considered to have the following structure with two terminal atoms: JPEG2025502110000017.jpg14170Here, Q 1 is T AL bonded to the terminal atom of A represents the first terminal non-hydrogen atom of 2 is J 3 L bonded to the attachment point of A represents the second terminal non-hydrogen atom of 1 and Q 2 are linked via a chain or ring / chain structure. A The maximum distance between two terminals of A Two connection points Q in 1 and Q 2 Under the above definition, the alkylene chain -(CH2) 10 - should be equal to or greater than the maximum length between the two terminal carbons of L. A Two connection points Q in 1 and Q 2 The maximum distance between A Ga-(CH2) 10 Unless otherwise specified or clearly contradicted by the context, in this specification, -(CH2) 10 Alkylene chains such as -(CH2) are not cyclic structures. 10 The maximum length between the two terminal carbons of - can be estimated by computer modeling by measuring the distance between the two terminal carbons when the alkylene chain is fully extended in one direction. A Q in 1 and Q 2 The maximum length between A Q when the chain is fully extended in one direction 1 and Q 2 Using this method, linear alkylene chains with more than 10 carbons in the chain can be estimated by computer modeling by measuring the distance between -(CH2) 10 Similarly, linear saturated chain structures with more than 10 non-hydrogen atoms in the chain are also found to have a maximum length greater than the maximum length of -(CH2). 10 In some embodiments, L A L AThe maximum length between the two terminal atoms of is at least -(CH2) 12 - the maximum length between the two terminal carbon atoms, preferably at least -(CH2) 14 -, more preferably at least -(CH2) 16 In some embodiments, L A L A The maximum length between the two terminal atoms of (i)-(CH2) 12 - the maximum length between the two terminal carbon atoms of (ii) -(CH2) 50 - the maximum length between the two terminal carbon atoms.

[0026] In some embodiments, in Formula I (e.g., Formula I-1), L A (X) m where X in each occurrence is independently CR, C(=O), -C(R)=C(R)-, JPEG2025502110000018.jpg11170SiR2, O, S, SO, SO2, NR, [NR2] + or a ring structure, preferably a 3- to 10-membered ring structure. R in each occurrence is independently hydrogen, halogen, optionally substituted C 1-4 Alkyl or optionally substituted C 1-4 Alkoxy, typically hydrogen or C 1-4 The integer m is at least 10, e.g., at least 12, at least 14, at least 16, at least 18, at least 20, at least 50, e.g., 12 to 50, 16 to 50, etc. For clarity, the formula (X) m is a group in which each X has two terminal X groups (T A or J 3(the two X groups directly linked to each other) (i.e., -XXX-...-X-), and the total number of X is m. When X is a ring structure, preferably a 3- to 10-membered ring structure, it should be understood that the ring structure is bonded to two adjacent X units via one or two ring atoms, for example, X is JPEG2025502110000019.jpg24170. As used herein, a "ring structure" or a "3- to 10-membered ring structure" is not limited to any particular ring system and can include a substituted or unsubstituted carbocyclic ring, a heterocyclic ring, an aromatic ring, a heteroaryl ring, or a combination thereof. For example, a "3- to 10-membered ring structure" can be monocyclic, bicyclic, or tricyclic, and can include fused, spiro, or bridged ring systems. For clarity, two ring systems linked via a single bond should be considered separate ring systems, each of which can occupy one X unit herein. For example, A structure such as JPEG2025502110000020.jpg33170 can be viewed as two X units linked together, one X being cyclohexylene and the other X being phenylene. Typically, L A In the formula, 0, 1, or 2 instances of X are ring structures, preferably 3- to 10-membered ring structures (C such as cyclopropyl). 3-6 In some embodiments, two consecutive X's may be -C(O)O- or -C(O)NR-. In some embodiments, one instance of X may be a cyclopropane, cyclobutane, or bicyclobutane [1.1] ring. In some embodiments, one instance of X may be a 5- or 6-membered heteroaryl, such as a triazole ring. In some embodiments, one instance of X may be a cyclopentane, cyclohexane, or cycloheptane ring. Typically, one of the terminal X groups is connected to T via a carbon atom. A L AThe total number of non-hydrogen atoms may typically be between 10 and 100, for example, 12 to 30, 14 to 50, 16 to 50, 18 to 100, etc.

[0027] Another factor that can determine whether a compound of Formula I can be a potent GPR40 agonist is the molecular weight of the linker (e.g., L) rather than the exact chemical structure of the linker. A ) is hydrophobic. Generally, L A should be a hydrophobic moiety. In some embodiments, L A Both terminal atoms of L are C in a C(O) or S in a SO group. A The hydrophobicity of the corresponding compound HO-L is typically A The -OH may be characterized as having a cLogP of at least 3, e.g., between 3 and 15, preferably at least 4 (e.g., at least 4.5, at least 5, at least 5.5, at least 6, at least 6.5, at least 7, etc.), e.g., 3 to 10, 4 to 12, 4.5 to 9, 5 to 11, 5.5 to 10.5, 6 to 14, 6.5 to 13, etc., and each of the -OH is bonded to a terminal C(O) or SO2 group. A Only one terminal atom of L is C in C(O) or S in SO group. A The hydrophobicity of the corresponding compound HL is typically A The -OH has a cLogP of at least 3, e.g., between 3 and 15, preferably at least 4 (e.g., at least 4.5, at least 5, at least 5.5, at least 6, at least 6.5, at least 7, etc.), e.g., 3 to 10, 4 to 12, 4.5 to 9, 5 to 11, 5.5 to 10.5, 6 to 14, 6.5 to 13, etc., and can be characterized in that the -OH is bonded to a terminal C(O) or SO2 group. A None of the terminal atoms of L is a C of a C(O) or an S of a SO group. A The hydrophobicity of the corresponding compound HL A-H has a cLogP of at least 3, e.g., between 3 and 15, preferably at least 4 (e.g., at least 4.5, at least 5, at least 5.5, at least 6, at least 6.5, at least 7, etc.), and can be characterized as having a cLogP of, for example, 3 to 10, 4 to 12, 4.5 to 9, 5 to 11, 5.5 to 10.5, 6 to 14, 6.5 to 13, etc.

[0028] For example, in some embodiments, L A (X) m-1 -C(O)-, where the C(O) terminus is T A X in each occurrence is independently CR2, C(=O), -C(R)=C(R)-, JPEG2025502110000021.jpg12170SiR2, O, S, SO2, NR, [NR2] + or a ring structure, preferably a 3- to 10-membered ring structure, provided that the terminal X group (i.e., L A The X group furthest from the C(O) end in the formula (X) is not C(O) or SO2. R in each occurrence is independently hydrogen, halogen, optionally substituted C 1-4 Alkyl or optionally substituted C 1-4 Alkoxy, typically hydrogen or C 1-4 The integer m is at least 10, for example, at least 12, at least 14, at least 16, at least 18, at least 20, or at least 50, for example, 12 to 50, 16 to 50, etc. -(X) m-1 The hydrophobicity of -C(O)- is similar to that of the corresponding compound H-(X) m-1 -COOH should have a cLogP of at least 3, for example, between 3 and 15, preferably at least 4 (e.g., at least 4.5, at least 5, at least 5.5, at least 6, at least 6.5, at least 7, etc.), characterized by a cLogP of, for example, 3 to 10, 4 to 12, 4.5 to 9, 5 to 11, 5.5 to 10.5, 6 to 14, 6.5 to 13, etc. "m-1" should be understood as the integer m minus 1 and should not be mistaken for a different designated variable.

[0029] In some embodiments, L A (X) m wherein X in each occurrence is independently CR, C(=O), -C(R)=C(R)-, JPEG2025502110000022.jpg11170SiR2, O, S, SO2, NR, [NR2] + or a ring structure, preferably a 3- to 10-membered ring structure, provided that none of the terminal X groups is C(O) or SO2. R in each occurrence is independently hydrogen, halogen, optionally substituted C 1-4 Alkyl or optionally substituted C 1-4 Alkoxy, typically hydrogen or C 1-4 The integer m is at least 10, for example, at least 12, at least 14, at least 16, at least 18, at least 20, at least 50, for example, 12 to 50, 16 to 50, etc., and the corresponding compound H-(X) m -H should have a cLogP of at least 3, e.g., between 3 and 15, preferably at least 4 (e.g., at least 4.5, at least 5, at least 5.5, at least 6, at least 6.5, at least 7, etc.), e.g., 3 to 10, 4 to 12, 4.5 to 9, 5 to 11, 5.5 to 10.5, 6 to 14, 6.5 to 13, etc.

[0030] As will be appreciated by those skilled in the art, the term cLogP (or CLogP) refers to calculated LogP. For purposes of this application, cLogP values ​​can be obtained using PerkinElmer's ChemDraw Professional software, version 20.0.0.41, or equivalent software using the same calculation method. Below are examples of cLogP values ​​for several compounds using the ChemDraw Professional software mentioned above: JPEG2025502110000023.jpg73170JPEG2025502110000024.jpg30170Thus, a compound with a cLogP of at least 3 should be about as hydrophobic as or more hydrophobic than octanoic acid. A compound with a cLogP of at least 4 should be about as hydrophobic as or more hydrophobic than decanoic acid. A compound with a cLogP of at least 5 should be about as hydrophobic as or more hydrophobic than lauric acid.

[0031] In some embodiments, L A -X 12-30 -(e.g., -X 14 -, -X 16 -, -X 18 -, -X 20 -, -X 24 -, -X 14-30 -, -X 16-30 -, -X 18-30 X in each occurrence is independently CR2, C(=O), -C(R)=C(R)-, JPEG2025502110000025.jpg10170SiR2, O, S, SO2, NR, [NR2] + or a ring structure, preferably a 3- to 10-membered ring structure, provided that none of the terminal X groups is C(O) or SO2. R in each occurrence is independently hydrogen, halogen, optionally substituted C 1-4 Alkyl or optionally substituted C 1-4 Alkoxy, typically hydrogen or C 1-4 It is alkyl. A The hydrophobicity of the corresponding compound HL A -H may be characterized as having a cLogP of at least 3, e.g., between 3 and 15, preferably at least 4 (e.g., at least 4.5, at least 5, at least 5.5, at least 6, at least 6.5, at least 7, etc.), e.g., 3 to 10, 4 to 12, 4.5 to 9, 5 to 11, 5.5 to 10.5, 6 to 14, 6.5 to 13, etc. In some embodiments, L AThe total number of non-hydrogen atoms in is between 12 and 100, e.g., 12, 14, 16, 18, 20, 24, 30, 40, 50, 100, or any range between the recited values, e.g., 12-30, 14-50, 16-50, 18-100, etc. In some embodiments, two consecutive Xs can represent -C(O)O- or -C(O)NR-. In some embodiments, one or more (e.g., one or two) instances of X can be a ring structure selected from cyclopropane, cyclobutane, bicyclobutane [1.1], cyclopentane, cyclohexane, or cycloheptane. In some embodiments, one or more (e.g., one) instances of X can be a ring structure selected from phenyl, or a 5- or 6-membered heteroaryl, such as triazole. In some embodiments, R is hydrogen.

[0032] In some embodiments, L A -X 12-30 -C(O)-, where C(O) is T A X in each occurrence is independently CR2, C(=O), -C(R)=C(R)-, JPEG2025502110000026.jpg11170SiR2, O, S, SO2, NR, [NR2] + or a ring structure, preferably a 3- to 10-membered ring structure, provided that the terminal X group is not C(O) or SO2. R in each occurrence is independently hydrogen, halogen, optionally substituted C 1-4 Alkyl or optionally substituted C 1-4 Alkoxy, typically hydrogen or C 1-4 It is alkyl. A The hydrophobicity of the corresponding compound HX 12-30 -C(O)-OH may be characterized as having a cLogP of at least 3, e.g., between 3 and 15, preferably at least 4 (e.g., at least 4.5, at least 5, at least 5.5, at least 6, at least 6.5, at least 7, etc.), e.g., 3 to 10, 4 to 12, 4.5 to 9, 5 to 11, 5.5 to 10.5, 6 to 14, 6.5 to 13, etc. In some embodiments, L AThe total number of non-hydrogen atoms in is between 14 and 100, e.g., 14, 16, 18, 20, 24, 30, 40, 50, 100, or any range between the recited values, e.g., 14-30, 14-50, 16-50, 18-100, etc. In some embodiments, two consecutive Xs may be -C(O)O- or -C(O)NR-. In some embodiments, one or more (e.g., one or two) instances of X may be a ring structure selected from cyclopropane, cyclobutane, bicyclobutane [1.1], cyclopentane, cyclohexane, or cycloheptane. In some embodiments, one or more (e.g., one) instances of X may be a ring structure selected from phenyl, or a 5- or 6-membered heteroaryl such as triazole. In some embodiments, R is hydrogen.

[0033] In some preferred embodiments, L A Ha-C 12-30 Alkylene- or -C 12-30 alkylene-C(O)-, where -C 12-30 The alkylene- is optionally substituted, and the optional substituents can be optionally joined together to form a double bond, a triple bond, or a ring structure (typically a 3- to 10-membered ring structure). 12-30 The terminal carbon atom of alkylene- is not substituted with oxo (=O). A The maximum chain length of is at least -(CH2) 12 -, e.g., at least -(CH2) 14 - maximum chain length of at least -(CH2) 16 - maximum chain length of at least -(CH2) 18 - is the longest chain length. A The hydrophobicity of the corresponding compound HC 12-30 Alkylene-H or HC 12-30The alkylene -C(O)-OH may be characterized as having a cLogP of at least 3, e.g., between 3 and 15, preferably at least 4 (e.g., at least 4.5, at least 5, at least 5.5, at least 6, at least 6.5, at least 7, etc.), e.g., 3 to 10, 4 to 12, 4.5 to 9, 5 to 11, 5.5 to 10.5, 6 to 14, 6.5 to 13, etc. In some embodiments, L A The total number of non-hydrogen atoms in L is between 14 and 100, e.g., 14, 16, 18, 20, 24, 30, 40, 50, 100, or any range between the listed values, e.g., 14 to 30, 14 to 50, 16 to 50, 18 to 100, etc. A is a linear or branched chain C 12-30 Unsubstituted -C such as alkylene 12-30 In some embodiments, L A is unsubstituted -C 12-30 alkylene-C(O)-, where C 12-30 Alkylene may be linear or branched. In some preferred embodiments, L A Ha-C 12-30 Alkylene- or -C 12-30 alkylene-C(O)-, where C 12-30 Alkylene is a straight-chain unsubstituted -C 12-30 It is alkylene.

[0034] In some embodiments, L A is a 12- to 30-membered heteroalkylene or -(12- to 30-membered heteroalkylene)-C(O)-, where the 12- to 30-membered heteroalkylene is optionally substituted and contains 1 to 6 heteroatoms independently selected from O, N, and S. The sulfur atom, if present, is optionally oxidized. The optional substituents can optionally be bonded together to form a double bond, a triple bond, or a ring structure (typically a 3- to 10-membered ring structure). The terminal atom of the 12- to 30-membered heteroalkylene is not the C of C(O) or the S of an SO group. L A The maximum chain length of is at least -(CH2) 12 -, e.g., at least -(CH2)14 - maximum chain length of at least -(CH2) 16 - maximum chain length of at least -(CH2) 18 - is the longest chain length. A The hydrophobicity of L can be characterized by the corresponding compound H--(12-30 membered heteroalkylene)-H or H--(12-30 membered heteroalkylene)-C(O)-OH having a cLogP of at least 3, e.g., between 3 and 15, preferably at least 4 (e.g., at least 4.5, at least 5, at least 5.5, at least 6, at least 6.5, at least 7, etc.), e.g., 3-10, 4-12, 4.5-9, 5-11, 5.5-10.5, 6-14, 6.5-13, etc. A The total number of non-hydrogen atoms in L is between 14 and 100, e.g., 14, 16, 18, 20, 24, 30, 40, 50, 100, or any range between the listed values, e.g., 14 to 30, 14 to 50, 16 to 50, 18 to 100, etc. A is unsubstituted 12- to 30-membered heteroalkylene, for example, straight-chain or branched-chain 12- to 30-membered heteroalkylene. In some embodiments, L A is an unsubstituted -(12- to 30-membered heteroalkylene)-C(O)-, where the 12- to 30-membered heteroalkylene may be linear or branched. In some preferred embodiments, L A is a 12- to 30-membered heteroalkylene or -(12- to 30-membered heteroalkylene)-C(O)-, wherein the 12- to 30-membered heteroalkylene is linear and unsubstituted. In some embodiments, the 12- to 30-membered heteroalkylene contains 1, 2, 3, 4, or 5 heteroatoms independently selected from O, S, and N.

[0035] In some preferred embodiments, L A teeth, JPEG2025502110000027.jpg33170, where the carbonyl is T A It is directly bonded to L A1 and L A2each independently represents a bond, an optionally substituted -C 1-30 alkylene- or optionally substituted -C containing 1 to 6 heteroatoms independently selected from O, N, and S; 1-30 Heteroalkylene-. The sulfur atom, if present, is optionally oxidized. The optional substituents can optionally be joined together to form a double bond, a triple bond, or a ring structure. T A or J 3 L binds to A1 and L A2 The terminal atom of is not, where applicable, the C of C(O) or the S of an SO2 group. A The maximum chain length of is at least -(CH2) 12 -, e.g., at least -(CH2) 14 - maximum chain length of at least -(CH2) 16 - maximum chain length of at least -(CH2) 18 - is the longest chain length. A The hydrophobicity of the corresponding compound JPEG2025502110000028.jpg30170 can be characterized as having a cLogP of at least 3, e.g., between 3 and 15, preferably at least 4 (e.g., at least 4.5, at least 5, at least 5.5, at least 6, at least 6.5, at least 7, etc.), e.g., 3 to 10, 4 to 12, 4.5 to 9, 5 to 11, 5.5 to 10.5, 6 to 14, 6.5 to 13, etc. In some embodiments, L A The total number of non-hydrogen atoms in L is between 14 and 100, e.g., 14, 16, 18, 20, 24, 30, 40, 50, 100, or any range between the listed values, e.g., 14 to 30, 14 to 50, 16 to 50, 18 to 100, etc. A1 is C 1-20 Alkylene, for example, straight chain alkylene, (CH2) 1-20 In some embodiments, L A1 is -O-(C 1-10 C with 1 to 3 oxygen atoms, such as alkylene)- 1-10 In some embodiments, L is heteroalkylene. A2is a bond. In some embodiments, L A2 is C 1-20 Alkylene, for example, straight chain alkylene, (CH2) 1-20 In some embodiments, L A2 is -O-(C 1-10 C with 1 to 3 oxygen atoms, such as alkylene)- 1-10 It is heteroalkylene.

[0036] In some embodiments, L A teeth, It can be characterized as having a structure according to JPEG2025502110000029.jpg29170. A1 and L A2 are each independently a bond, -C 1-30 alkylene- or -C containing 1 to 6 heteroatoms independently selected from O, N, and S 1-30 Heteroalkylene-. Sulfur atoms, if present, are optionally oxidized. T A or J 3 L binds to A1 and L A2 The terminal atom of is not the C of a C(O) or the S of an SO2 group, if applicable. A The total number of non-hydrogen atoms in L is between 15 and 50, e.g., 18, 20, 25, 30, 35, 40, 45, or 50, or any range between the listed values. A The maximum chain length of is at least -(CH2) 12 -, e.g., at least -(CH2) 14 - maximum chain length of at least -(CH2) 16 - maximum chain length of at least -(CH2) 18 - is the longest chain length. A The hydrophobicity of the corresponding compound HL A-H may be characterized as having a cLogP of at least 3, e.g., between 3 and 15, preferably at least 4 (e.g., at least 4.5, at least 5, at least 5.5, at least 6, at least 6.5, at least 7, etc.), e.g., 3 to 10, 4 to 12, 4.5 to 9, 5 to 11, 5.5 to 10.5, 6 to 14, 6.5 to 13, etc. In some embodiments, L A1 is a bond (i.e., absent, the triazole nitrogen atom is J 3 or T A In some embodiments, L A2 is a bond. In some embodiments, L A1 is C 1-20 Alkylene, for example, straight chain alkylene, (CH2) 1-20 In some embodiments, L A1 is -O-(C 1-10 C with 1 to 3 oxygen atoms, such as alkylene)- 1-10 In some embodiments, L is heteroalkylene. A2 is C 1-20 Alkylene, for example, straight chain alkylene, (CH2) 1-20 In some embodiments, L A2 is -O-(C 1-10 C with 1 to 3 oxygen atoms, such as alkylene)- 1-10 It is heteroalkylene.

[0037] In some embodiments, L A teeth, It can be characterized as having a structure according to JPEG2025502110000030.jpg34170. A1 and L A2 are each independently a bond, -C 1-30 alkylene- or -C containing 1 to 6 heteroatoms independently selected from O, N, and S 1-30 Heteroalkylene-. Sulfur atoms, if present, are optionally oxidized. J 3 L binds to A2 The terminal atom of is not the C of C(O) or the S of an SO2 group.A The total number of non-hydrogen atoms in L is between 15 and 50, e.g., 18, 20, 25, 30, 35, 40, 45, or 50, or any range between the listed values. A The maximum chain length of is at least -(CH2) 12 -, e.g., at least -(CH2) 14 - maximum chain length of at least -(CH2) 16 - maximum chain length of at least -(CH2) 18 - is the longest chain length. A The hydrophobicity of the corresponding compound JPEG2025502110000031.jpg32170 can be characterized as having a cLogP of at least 3, e.g., between 3 and 15, preferably at least 4 (e.g., at least 4.5, at least 5, at least 5.5, at least 6, at least 6.5, at least 7, etc.), e.g., between 3 and 10, 4 and 12, 4.5 and 9, 5 and 11, 5.5 and 10.5, 6 and 14, 6.5 and 13, etc. In some embodiments, L A1 is a bond. In some embodiments, L A2 is a bond. In some embodiments, L A1 is C 1-20 Alkylene, for example, straight chain alkylene, (CH2) 1-20 In some embodiments, L A1 is -O-(C 1-10 C with 1 to 3 oxygen atoms, such as alkylene)- 1-10 In some embodiments, L is heteroalkylene. A2 is C 1-20 Alkylene, for example, straight chain alkylene, (CH2) 1-20 In some embodiments, L A2 is -O-(C 1-10 C with 1 to 3 oxygen atoms, such as alkylene)- 1-10 It is heteroalkylene.

[0038] In some embodiments, L A teeth, It can be characterized as having a structure according to JPEG2025502110000032.jpg33170. A1 and L A2 are each independently a bond, -C 1-30 alkylene- or -C containing 1 to 6 heteroatoms independently selected from O, N, and S 1-30 Heteroalkylene-. Sulfur atoms, if present, are optionally oxidized. J 3 L binds to A1 The terminal atom of is not the C of C(O) or the S of an SO2 group. A The total number of non-hydrogen atoms in L is between 15 and 50, e.g., 18, 20, 25, 30, 35, 40, 45, or 50, or any range between the listed values. A The maximum chain length of is at least -(CH2) 12 -, e.g., at least -(CH2) 14 - maximum chain length of at least -(CH2) 16 - maximum chain length of at least -(CH2) 18 - is the longest chain length. A The hydrophobicity of the corresponding compound JPEG2025502110000033.jpg33170 can be characterized as having a cLogP of at least 3, e.g., between 3 and 15, preferably at least 4 (e.g., at least 4.5, at least 5, at least 5.5, at least 6, at least 6.5, at least 7, etc.), e.g., 3 to 10, 4 to 12, 4.5 to 9, 5 to 11, 5.5 to 10.5, 6 to 14, 6.5 to 13, etc. In some embodiments, L A1 is a bond. In some embodiments, L A2 is a bond. In some embodiments, L A1 is C 1-20 Alkylene, for example, straight chain alkylene, (CH2) 1-20 In some embodiments, L A1 is -O-(C 1-10 C with 1 to 3 oxygen atoms, such as alkylene)- 1-10 In some embodiments, L is heteroalkylene.A2 is a straight chain alkylene, (CH2) 1-20 C etc. 1-20 In some embodiments, L is alkylene. A2 is -O-(C 1-10 C with 1 to 3 oxygen atoms, such as alkylene)- 1-10 It is heteroalkylene. Hydrophilic group T A

[0039] Another factor that can determine whether a compound of Formula I can be a potent GPR40 agonist is T A hydrophilic or polar, but T A The exact chemical structure of is not critical. A L A wherein (1) when the terminal atom is N of a basic amine group, the corresponding compound T A -(C(O)-CH3) q has a cLogP less than 1, -C(O)-CH3 is bonded to the terminal N atom, and (2) if the terminal atom is the C of the C(O) group, the corresponding compound T A -(OH) q has a cLogP less than 1, -OH is bonded to the terminal C atom, and (3) if the terminal atom is S in the SO2 group, the corresponding compound T A -(OH) q has a cLogP less than 1, -OH is bonded to the terminal S atom, or (4) if (1) to (3) do not apply, T A -H q has a cLogP of less than 1. In some embodiments, the terminal atom is the N of the basic amine group, and T A is the corresponding compound T A -(C(O)-CH3) qis less than 0 (e.g., less than -1, less than -2, less than -3, less than -3.5, less than -4, or even less). As used herein, a basic amine group refers to any amine group that has a pKa in water (based on its conjugate acid at room temperature) of at least 5. In other words, T A In embodiments where the terminal atom of is an N of a basic primary or secondary amine group, [T A -H2] + has an aqueous pKa of 5 or greater for the terminal nitrogen atom in question. In some embodiments, the terminal atom is the C of a C(O) group, and T A is the corresponding compound T A -(OH) q is less than 0 (e.g., less than -1, less than -2, less than -3, less than -3.5, less than -4, or even less). In some embodiments, the terminal atom is S in an SO group, and T A is the corresponding compound T A -(OH) q is less than 0 (e.g., less than -1, less than -2, less than -3, less than -3.5, less than -4, or even less). In some embodiments, the terminal atom is not N of a basic amine group, C of a C(O) group, or S of a SO group, but is T A is the corresponding compound T A -H q is less than 0 (e.g., less than -1, less than -2, less than -3, less than -3.5, less than -4, or even less).

[0040] In some preferred embodiments, T A contains a quaternary nitrogen atom, a positively charged group such as SO3 - The compound may contain negatively charged groups such as , or charged groups containing zwitterionic structures. AIt should be understood that when contains a charged group, a counterion, preferably a pharmaceutically acceptable anion or cation, is present if necessary to balance the charge so that the compound of Formula I is overall neutral. Pharmaceutically acceptable anions are known in the art and are typically pharmaceutically acceptable acids, e.g., Cl. - It is derived from Na + Pharmaceutically acceptable cations, such as alkaline cations such as are also known in the art.

[0041] In some embodiments, T A are characterized as having charged groups (including zwitterionic structures) or groups that can be charged at pH 7, such as primary amines, secondary amines, tertiary amines, quaternary amines, carboxylic acids, etc.

[0042] In some embodiments, T A is characterized as having at least two hydrogen bond donors.

[0043] In some embodiments, T A is characterized as having at least two hydrogen bond acceptors.

[0044] In some embodiments, T A is T A1 , T A1 -L B -, T A1 -L B -(heteroalkylene), or T A1 -L B -(heteroalkylene)-L B - and L in each occurrence B are independently -SO2-, -C(=O)-, or a moiety selected from: JPEG2025502110000034.jpg25170 R in each occurrence 100 , R 101 and R 102 are independently hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl; TA1 teeth, JPEG2025502110000035.jpg31170 is characterized as having the structure G 1 are independently hydrogen, halogen, or optionally substituted C 1-4 Alkyl or optionally substituted C 1-4 heteroalkyl (such as optionally substituted C1-4 alkoxy) or two gem-G 1 The groups may be bonded to form =O, =NH, or =N(C 1-4 alkyl) or two or more G 1 the groups can be linked to form a ring structure; the integer r is 1 to 10, such as 1 or 2; G in each occurrence 2 are independently hydrogen, G 10 , C(O)-G 10 , SO2G 10 , C(O)-NH-G 10 , or SO2NHG 10 , C(O)-OG 10 , or SO2OG 10 and G 10 are independently optionally substituted alkyl, optionally substituted heteroalkyl, or an optionally substituted 3- to 10-membered ring structure which may be carbocyclic, heterocyclic, aromatic, heteroaromatic, or combinations thereof; G 3 is hydrogen or optionally substituted alkyl (e.g., C 1-4 alkyl), Or two Gs 2 , or one G 2 and one G 1 , or one G 1 and G 3 can be linked to form ring structures such as 3- to 10-membered ring structures, and the fragments JPEG2025502110000036.jpg28170 is (i)NG 3 Next to the CG 1 G 1 If the group is not C(=O), the corresponding compound JPEG2025502110000037.jpg29170 has a cLogP of less than 1, preferably less than 0 (e.g., less than −1, less than −2, less than −3, less than −3.5, less than −4, or less), or (ii) NG 3 Next to the CG 1 G 1 When the group is C(=O), the corresponding compound JPEG2025502110000038.jpg26170 is further characterized in that it has a cLogP of less than 1, preferably less than 0 (e.g., less than −1, less than −2, less than −3, less than −3.5, less than −4, or even less); Fragment JPEG2025502110000039.jpg17170 is (i) when the nitrogen is a basic nitrogen, the corresponding compound (G 2 )N—C(O)—CH has a cLogP of less than 1, preferably less than 0 (e.g., less than −1, less than −2, less than −3, less than −3.5, less than −4, or less), or (ii) if the nitrogen is a non-basic nitrogen, the corresponding compound (G 2 )2N-H has a cLogP of less than 1, preferably less than 0 (e.g., less than -1, less than -2, less than -3, less than -3.5, less than -4, or even less). 3 is hydrogen. In some preferred embodiments, T A is T A1 or T A1 -L B In some embodiments, T A is T A1 -L B -(heteroalkylene) or T A1 -L B -(heteroalkylene)-L B - and the heteroalkylene may be a glycol chain, such as a polyethylene glycol chain.

[0045] In some embodiments, T A is T A1 In some embodiments, T A is T A1In some embodiments, T A1 teeth, JPEG2025502110000040.jpg20170. In some embodiments, T A1 teeth, JPEG2025502110000041.jpg15170. In some embodiments, the G 2 is, independently, JPEG2025502110000042.jpg13170, where n is an integer of 0 to 100, preferably 0 to 10 (for example, 0 to 4, 1 to 5, or 2 to 6), and Z 1 are CH2, C(O), SO, SO2, CH(C 1-4 alkyl), C(C 1-4 Alkyl)(C 1-4 alkyl) or a 3- to 10-membered ring structure. 2 are independently CH2, O, S, SO, SO2, C(O), CH(C 1-4 alkyl), C(C 1-4 Alkyl)(C 1-4 alkyl), NH, N(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 alkyl)] + Or a 3- to 10-membered ring structure. 3 is H, C 1-4 Alkyl, OH, SO3H, COOH, NH2, NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, SO2NH2, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), or SO2N(C 1-4 Alkyl)(C 1-4C 1-4 Each alkyl is independently selected and optionally includes, for example, 1 to 3 G as defined herein. 20 In some embodiments, Z is substituted with a group. 2 In some embodiments, none of Z 2 One or more examples of the formula include 3-10 membered ring structures such as nitrogen-containing rings, e.g., JPEG2025502110000043.jpg24170. In some embodiments, Z 3 Directly connect to Z 2 is a 3- to 10-membered ring structure such as a nitrogen-containing ring, for example, JPEG2025502110000044.jpg25170, etc. Preferably, Z 2 Up to two instances of G are 3- to 10-membered ring structures. 2 are independently hydrogen, optionally substituted C 1-6 Alkyl or optionally substituted C 1-6 For example, when substituted, C 1-6 Alkyl is OH, NH2, oxo (=O), NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, C(O)OH, SO2NH2, SO3H, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), and SO2N(C 1-4 Alkyl)(C 1-4 C can be substituted with 1 to 3 substituents independently selected from alkyl. 1-4 Each alkyl is independently selected and optionally includes, for example, 1 to 3 G as defined herein. 20 Each occurrence of G herein is substituted with a group. 20The groups are OH, NH2, oxo (=O), NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, C(O)OH, SO2NH2, SO3H, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), SO2N(C 1-4 Alkyl)(C 1-4 alkyl), or a 3- to 10-membered ring structure. 1-4 Each alkyl is independently selected and optionally includes, for example, 1 to 3 G as defined herein. 21 Each occurrence of G herein is substituted with a group. 21 The groups are OH, NH2, oxo (=O), NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, C(O)OH, SO2NH2, SO3H, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), SO2N(C 1-4 Alkyl)(C 1-4 alkyl) or a 3- to 10-membered ring structure. 2 One or more examples of 1-4 alkylene)-NH2 or CONH-(C 1-4 alkylene)-[N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] +C optionally substituted with an amide derivative such as 1-4 For example, in some embodiments, G 2 One or two examples of -(C 1-4 alkylene)-COOH, and G 2 Any remaining instance of C 1-4 In some embodiments, G is alkyl. 2 One or two examples of JPEG2025502110000045.jpg20170 etc. -(C 1-4 alkylene)-CONH-(C 1-4 alkylene)-NH2, and G 2 Any remaining instance of C 1-4 In some embodiments, G is alkyl. 2 One or two examples of JPEG2025502110000046.jpg17170 etc. -(C 1-4 alkylene)-CONH-(C 1-4 alkylene)-[N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + and G 2 Any remaining instance of C 1-4 In some embodiments, T A1 teeth, JPEG2025502110000047.jpg42170. In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000048.jpg42170. In some embodiments, T A1 teeth, JPEG2025502110000049.jpg39170. In some embodiments, T A1 teeth, JPEG2025502110000050.jpg33170. In some embodiments, T A1is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000051.jpg62170. In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), For example, in some embodiments, T A1 teeth JPEG2025502110000053.jpg54170. In some embodiments, T A1 teeth JPEG2025502110000054.jpg32170. In some embodiments, T A1 teeth JPEG2025502110000055.jpg39170. In some embodiments, T A1 teeth JPEG2025502110000056.jpg27170. In some embodiments, T A1 teeth JPEG2025502110000057.jpg24170. In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000058.jpg24170. In some embodiments, T A1 teeth JPEG2025502110000059.jpg25170. In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000060.jpg23170. In some embodiments, T A1 teeth It could also be JPEG2025502110000061.jpg20170.

[0046] In some embodiments, T A is T A1 , T A1 -L B -, T A1 -L B -(heteroalkylene), or T A1 -L B -(heteroalkylene)-L B - and L in each occurrence B are independently -SO2-, -C(=O)-, or a moiety selected from: JPEG2025502110000062.jpg25170 R in each occurrence 100 , R 101 and R 102 are independently hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl; T A1 teeth, charge-balanced with counterions (e.g., those described herein) as needed, i.e., to maintain overall electronic neutrality of the compound; JPEG2025502110000063.jpg24170 is characterized as having a structure of G 1 are independently hydrogen, halogen, or optionally substituted C 1-4 Alkyl or optionally substituted C 1-4 Heteroalkyl (optionally substituted C 1-4 alkoxy, etc.) or two gem-G 1 The groups may be bonded to form =O, =NH, or =N(C 1-4 alkyl), or two or more G 1 The groups can be linked to form a ring structure. the integer r is 1 to 10, such as 1 or 2; G 3 is hydrogen or optionally substituted alkyl (e.g., C 1-4 alkyl), G in each occurrence 4 are independently hydrogen or G 10 and G 10are independently an optionally substituted alkyl, an optionally substituted heteroalkyl, or an optionally substituted 3- to 10-membered ring structure which may be carbocyclic, heterocyclic, aromatic, heteroaromatic, or a combination thereof; or two G 4 , or one G 4 and one G 1 , or one G 1 and G 3 can be linked to form an optionally substituted 3- to 10-membered ring structure, and the fragment JPEG2025502110000064.jpg23170 is (i) the CG next to NH 1 G 1 If the group is not C(=O), the corresponding compound JPEG2025502110000065.jpg26170 has a cLogP of less than 1, preferably less than 0 (e.g., less than −1, less than −2, less than −3, less than −3.5, less than −4, or less), or (ii) a CG next to NH 1 G 1 When the group is C(=O), the corresponding compound JPEG2025502110000066.jpg25170 has a cLogP less than 1, preferably less than 0 (e.g., less than -1, less than -2, less than -3, less than -3.5, less than -4, or less). 3 is hydrogen. In some preferred embodiments, T A is T A1 or T A1 -L B In some embodiments, T A is T A1 -L B -(heteroalkylene) or T A1 -L B -(heteroalkylene)-L B - and the heteroalkylene may be a glycol chain, such as a polyethylene glycol chain.

[0047] In some embodiments, T A is T A1 In some embodiments, T A is TA1 In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000067.jpg20170. In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000068.jpg17170. In some embodiments, the G 4 is, independently, JPEG2025502110000069.jpg13170 structure, where n is an integer of 0 to 100, preferably 0 to 10 (for example, 0 to 4, 1 to 5, or 2 to 6). 1 are CH2, C(O), SO2, CH(C 1-4 alkyl), or C(C 1-4 Alkyl)(C 1-4 (alkyl). Z in each occurrence 2 are independently CH2, O, S, SO, SO2, C(O), CH(C 1-4 alkyl), C(C 1-4 Alkyl)(C 1-4 alkyl), NH, N(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 alkyl)] + Or a 3- to 10-membered ring structure. 3 is H, C 1-4 Alkyl, OH, SO3H, COOH, NH2, NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, SO2NH2, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4alkyl), SO2NH(C 1-4 alkyl), or SO2N(C 1-4 Alkyl)(C 1-4 C 1-4 Each alkyl is independently selected and optionally includes, for example, 1 to 3 G as defined herein. 20 Preferably, Z 2 Up to two instances of Z are 3- to 10-membered ring structures. 2 In some embodiments, none of Z 2 One example of the ring structure is a 3-10 membered ring structure such as a nitrogen-containing ring, for example: JPEG2025502110000070.jpg22170. In some embodiments, 4 are independently hydrogen, optionally substituted C 1-6 Alkyl or optionally substituted C 1-6 For example, when substituted, C 1-6 Alkyl is OH, NH2, oxo (=O), NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, C(O)OH, SO2NH2, SO3H, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), and SO2N(C 1-4 Alkyl)(C 1-4 C can be substituted with 1 to 3 substituents independently selected from alkyl. 1-4 Each alkyl is independently selected and optionally includes, for example, 1 to 3 G as defined herein. 20 Each occurrence of G herein is substituted with a group. 20 The groups are OH, NH2, oxo (=O), NH(C 1-4 alkyl), N(C 1-4Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, C(O)OH, SO2NH2, SO3H, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), SO2N(C 1-4 Alkyl)(C 1-4 alkyl), or a 3- to 10-membered ring structure. 1-4 Each alkyl is independently selected and optionally includes, for example, 1 to 3 G as defined herein. 21 Each occurrence of G herein is substituted with a group. 21 The groups are OH, NH2, oxo (=O), NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, C(O)OH, SO2NH2, SO3H, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), SO2N(C 1-4 Alkyl)(C 1-4 alkyl) or a 3- to 10-membered ring structure. 4 One or more examples of C, such as methyl 1-4 In some embodiments, G is alkyl. 4 One or more examples of 1-4 alkylene)-NH2 or CONH-(C 1-4 alkylene)-[N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] +C optionally substituted with an amide derivative such as 1-4 For example, in some embodiments, G 4 One or two examples of -(C 1-4 alkylene)-COOH, and G 4 Any remaining instance of C 1-4 In some embodiments, G is alkyl. 4 One or two examples of JPEG2025502110000071.jpg20170 etc. -(C 1-4 alkylene)-CONH-(C 1-4 alkylene)-NH2, and G 4 Any remaining instance of C 1-4 In some embodiments, G is alkyl. 4 One or two examples of JPEG2025502110000072.jpg16170 etc. -(C 1-4 alkylene)-CONH-(C 1-4 alkylene)-[N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + and G 4 Any remaining instance of C 1-4 In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000073.jpg41170JPEG2025502110000074.jpg51170. In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000075.jpg39170. In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000076.jpg29170. In some embodiments, TA1 is optionally charge balanced with a counterion (e.g., as described herein), For example, in some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000078.jpg49170. In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000079.jpg32170. In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000080.jpg24170. In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000081.jpg23170. In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000082.jpg32170. In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000083.jpg27170. In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000084.jpg23170. In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000085.jpg31170. In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000086.jpg17170. In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000087.jpg33170. In some embodiments, T A1 teeth It could also be JPEG2025502110000088.jpg16170.

[0048] In some preferred embodiments, T A is T A1 or T A1 -L B - and T A1 teeth, JPEG2025502110000089.jpg153170JPEG2025502110000090.jpg189170, R at each occurrence 100 , R 101 , and R 102 are independently hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl; T A is optionally charge balanced with a counterion (eg, as described herein). L A -T A Example of

[0049] L A and T A The covalent bond formed between T A and the terminal atoms of L A The covalent bond between the terminal carbon or nitrogen atom of T is an amide bond.A and the terminal atoms of L A The covalent bond between the terminal atoms of is a non-amide carbon-nitrogen bond, an ester bond, a non-ester carbon-oxygen bond, a carbon-carbon bond, or a carbon-sulfur bond.

[0050] In some preferred embodiments, the compounds of formula I can be characterized as having formula I-2, I-3, I-4, I-5, I-6, I-7, I-8, or I-9. JPEG2025502110000091.jpg203170JPEG2025502110000092.jpg128170In the formula, X in each occurrence is independently CR, C(=O), -C(R)=C(R)-, JPEG2025502110000093.jpg11170SiR2, O, S, SO2, NR, [NR2] + or a ring structure, preferably a 3- to 10-membered ring structure, wherein R in each occurrence is independently hydrogen, halogen, optionally substituted C 1-4 Alkyl or optionally substituted C 1-4 is an alkoxy; The integer m1 is at least 12, for example, 12 to 50 (eg, 12, 14, 16, 18, 20, 22, 24, 30, 40, 50, or any range or value between the listed values). (X) m1 The hydrophobicity of is (i) H-(X) when neither of the two terminal X groups is C(O) or SO2. m1 -H has a cLogP of at least 3, for example, between 3 and 15, preferably at least 4 (e.g., at least 4.5, at least 5, at least 5.5, at least 6, at least 6.5, at least 7, etc.), for example, 3 to 10, 4 to 12, 4.5 to 9, 5 to 11, 5.5 to 10.5, 6 to 14, 6.5 to 13, etc.; (ii) when one terminal X group is C(O) or SO2 and the other is not C(O) or SO2, the corresponding compound H-(X) m1-OH has a cLogP of at least 3, e.g., between 3 and 15, preferably at least 4 (e.g., at least 4.5, at least 5, at least 5.5, at least 6, at least 6.5, at least 7, etc.), e.g., 3 to 10, 4 to 12, 4.5 to 9, 5 to 11, 5.5 to 10.5, 6 to 14, 6.5 to 13, etc., and the OH is bonded to C(O) or SO2; or (iii) when both terminal X groups are C(O) or SO2, the corresponding compound HO-(X) m1 The -OH has a cLogP of at least 3, for example, between 3 and 15, preferably at least 4 (e.g., at least 4.5, at least 5, at least 5.5, at least 6, at least 6.5, at least 7, etc.), for example, a cLogP of 3 to 10, 4 to 12, 4.5 to 9, 5 to 11, 5.5 to 10.5, 6 to 14, 6.5 to 13, etc., and is characterized in that the OH is bonded to C(O) or SO2. G in each occurrence 1 are independently hydrogen, halogen, or optionally substituted C 1-4 Alkyl or optionally substituted C 1-4 heteroalkyl (such as optionally substituted C1-4 alkoxy) or two gem-G 1 The groups may be bonded to form =O, =NH, or =N(C 1-4 alkyl), or two or more G 1 The groups can be linked to form a ring structure. The integer r is 1 to 10, such as 1 or 2. G in each occurrence 2 are independently hydrogen, G 10 , C(O)-G 10 , SO2G 10 , C(O)-NH-G 10 , or SO2NHG 10 , C(O)-OG 10 , or SO2OG 10 and G 10are independently optionally substituted alkyl, optionally substituted heteroalkyl, or an optionally substituted 3- to 10-membered ring structure that may be carbocyclic, heterocyclic, aromatic, heteroaromatic, or combinations thereof. G 3 is hydrogen or optionally substituted alkyl (e.g., C 1-4 alkyl), G in each occurrence 4 are independently hydrogen or G 10 and G 10 are independently optionally substituted alkyl, optionally substituted heteroalkyl, or an optionally substituted 3- to 10-membered ring structure that may be carbocyclic, heterocyclic, aromatic, heteroaromatic, or combinations thereof. Or two Gs 2 , or one G 2 and one G 1 , or one G 1 and G 3 can be linked to form a ring structure, such as a 3- to 10-membered ring structure, Or two Gs 4 , or one G 4 and one G 1 , or one G 1 and G 3 can be linked to form an optionally substituted 3- to 10-membered ring structure. JPEG2025502110000094.jpg10170 is a counterion, preferably a pharmaceutically acceptable anion, required to balance the overall charge of the compound. Fragment JPEG2025502110000095.jpg25170 is (i)NG 3 Next to the CG 1 G 1 If the group is not C(=O), the corresponding compound JPEG2025502110000096.jpg28170 has a cLogP of less than 1, preferably less than 0 (e.g., less than −1, less than −2, less than −3, less than −3.5, less than −4, or less), or (ii) NG 3 Next to the CG1 G 1 When the group is C(=O), the corresponding compound JPEG2025502110000097.jpg26170 is further characterized in that it has a cLogP of less than 1, preferably less than 0 (e.g., less than -1, less than -2, less than -3, less than -3.5, less than -4, or even less). Fragment JPEG2025502110000098.jpg23170 is (i) the CG next to NH 1 G 1 If the group is not C(=O), the corresponding compound JPEG2025502110000099.jpg24170 has a cLogP of less than 1, preferably less than 0 (e.g., less than −1, less than −2, less than −3, less than −3.5, less than −4, or less), or (ii) a CG next to NH 1 G 1 When the group is C(=O), the corresponding compound JPEG2025502110000100.jpg23170 is characterized as having a cLogP of less than 1, preferably less than 0 (e.g., less than -1, less than -2, less than -3, less than -3.5, less than -4, or even less). Variable T A , L 10 , J 1 , J 2 , J 3 , R A , R B , p1, and p2 include any of the preferred ones described herein, in any combination. 1 is hydrogen. In some embodiments, G 1 One or more examples of C, such as methyl 1-4 In some embodiments, the integer r is 1, 2, 3, 4, or 5. In some embodiments, G 2 One or more instances of It can have a structure of JPEG2025502110000101.jpg14170, where n is an integer of 0 to 100, preferably 0 to 10 (for example, 0 to 4, 1 to 5, or 2 to 6). 1 are CH2, C(O), SO, SO2, CH(C 1-4 alkyl), C(C 1-4 Alkyl)(C 1-4 alkyl), or a 3- to 10-membered ring structure. 2 are independently CH2, O, S, SO, SO2, C(O), CH(C 1-4 alkyl), C(C 1-4 Alkyl)(C 1-4 alkyl), NH, N(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 alkyl)] + Or a 3- to 10-membered ring structure. 3 is H, C 1-4 Alkyl, OH, SO3H, COOH, NH2, NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, SO2NH2, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), or SO2N(C 1-4 Alkyl)(C 1-4 C 1-4 Each alkyl is independently selected and optionally includes, for example, 1 to 3 G as defined herein. 20 In some embodiments, Z is substituted with a group. 2 In some embodiments, none of Z 2 One or more examples of the formula include 3-10 membered ring structures such as nitrogen-containing rings, e.g., JPEG2025502110000102.jpg26170. In some embodiments, Z 3 Directly connect to Z 2 is a 3- to 10-membered ring structure such as a nitrogen-containing ring, for example, JPEG2025502110000103.jpg24170, etc. Preferably, Z 2 Up to two instances of G are 3- to 10-membered ring structures. 2 are independently hydrogen, optionally substituted C 1-6 Alkyl or optionally substituted C 1-6 For example, when substituted, C 1-6 Alkyl is OH, NH2, oxo (=O), NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, C(O)OH, SO2NH2, SO3H, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), and SO2N(C 1-4 Alkyl)(C 1-4 C can be substituted with 1 to 3 substituents independently selected from alkyl. 1-4 Each alkyl is independently selected and optionally includes, for example, 1 to 3 G as defined herein. 20 In some embodiments, each occurrence of G is substituted with a group. 4 is, independently, JPEG2025502110000104.jpg14170, where n is an integer of 0 to 100, preferably 0 to 10 (for example, 0 to 4, 1 to 5, or 2 to 6). 1 are CH2, C(O), SO2, CH(C 1-4 alkyl), or C(C 1-4 Alkyl)(C 1-4(alkyl). Z in each occurrence 2 are independently CH2, O, S, SO, SO2, C(O), CH(C 1-4 alkyl), C(C 1-4 Alkyl)(C 1-4 alkyl), NH, N(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 alkyl)] + Or a 3- to 10-membered ring structure. 3 is H, C 1-4 Alkyl, OH, SO3H, COOH, NH2, NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, SO2NH2, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), or SO2N(C 1-4 Alkyl)(C 1-4 C 1-4 Each alkyl is independently selected and optionally includes, for example, 1 to 3 G as defined herein. 20 Preferably, Z 2 Up to two instances of Z are 3- to 10-membered ring structures. 2 In some embodiments, none of Z 2 One example of the ring structure is a 3-10 membered ring structure such as a nitrogen-containing ring, for example: JPEG2025502110000105.jpg24170. In some embodiments, 4 are independently hydrogen, optionally substituted C 1-6 Alkyl or optionally substituted C 1-6 For example, when substituted, C 1-6 Alkyl is OH, NH2, oxo (=O), NH(C1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, C(O)OH, SO2NH2, SO3H, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), and SO2N(C 1-4 Alkyl)(C 1-4 C can be substituted with 1 to 3 substituents independently selected from alkyl. 1-4 Each alkyl is independently selected and optionally includes, for example, 1 to 3 G as defined herein. 20 Each occurrence of G herein is substituted with a group. 20 The groups are OH, NH2, oxo (=O), NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, C(O)OH, SO2NH2, SO3H, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), SO2N(C 1-4 Alkyl)(C 1-4 alkyl), or a 3- to 10-membered ring structure. 1-4 Each alkyl is independently selected and optionally includes, for example, 1 to 3 G as defined herein. 21 Each occurrence of G herein is substituted with a group. 21 The groups are OH, NH2, oxo (=O), NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, C(O)OH, SO2NH2, SO3H, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), SO2N(C 1-4 Alkyl)(C 1-4 alkyl) or a 3- to 10-membered ring structure. 4 One or more examples of C, such as methyl 1-4 In some embodiments, G is alkyl. 4 One or more examples of 1-4 alkylene)-NH2 or CONH-(C 1-4 alkylene)-[N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + C optionally substituted with an amide derivative such as 1-4 For example, in some embodiments, G 4 One or two examples of -(C such as -CH2COOH 1-4 alkylene)-COOH, and G 4 Any remaining instance of C 1-4 In some embodiments, G is alkyl. 4 One or two examples of JPEG2025502110000106.jpg18170 etc. -(C 1-4 alkylene)-CONH-(C 1-4 alkylene)-NH2, and G 4 Any remaining instance of C 1-4 In some embodiments, G is alkyl. 4 One or two examples of JPEG2025502110000107.jpg18170 etc. -(C 1-4 alkylene)-CONH-(C 1-4 alkylene)-[N(C1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + and G 4 Any remaining instance of C 1-4 In a preferred embodiment, G 3 is hydrogen. In some embodiments, X at each occurrence is independently CH2, CHCH3, or C(CH3)2. In some embodiments, X at each occurrence is CH2. In some embodiments, up to 6 (e.g., 1, 2, 3, 4, 5, or 6) instances of X are O, and the remaining X are CH2, CHCH3, or C(CH3)2. In some embodiments, up to 10 instances of X are -CH=CH-, and the remaining X are CH2, CHCH3, or C(CH3)2. In some embodiments, (X) m1 The moiety has one or more structural features selected from the following: (i) two consecutive X's together form -C(O)O- or -C(O)NR- (e.g., C(O)NH or C(O)NCH3); (ii) one or more instances of X can have a ring structure selected from cyclopropane, cyclobutane, bicyclobutane [1.1], cyclopentane, cyclohexane, or cycloheptane; and (iii) one or more instances of X can have a ring structure selected from phenyl, or a 5- or 6-membered heteroaryl, such as triazole. In some embodiments, (X) m1 Within the moiety, there can be 0, 1, or 2 instances of a ring structure, preferably a 3- to 10-membered ring structure. In some embodiments, (X) m1 For example, in some embodiments, one triazole ring is present within the (X) moiety. m1 The moiety is as defined herein and is preferred For example, in some embodiments, L A1 and L A2 are each independently a bond, -C 1-30 alkylene- or -C containing 1 to 6 heteroatoms independently selected from O, N, and S1-30 heteroalkylene-, where the sulfur atom, if present, is optionally oxidized, (X) m1 The total number of non-hydrogen atoms in L is between 15 and 50, e.g., 18, 20, 25, 30, 35, 40, 45, or 50, or any range between the listed values. A1 is a bond. In some embodiments, L A1 is a straight chain alkylene, (CH2) 1-20 C etc. 1-20 In some embodiments, L is alkylene. A1 is -O-(C 1-10 C with 1 to 3 oxygen atoms, such as alkylene)- 1-10 In some embodiments, L is heteroalkylene. A2 is a bond. In some embodiments, L A2 is a straight chain alkylene, (CH2) 1-20 C etc. 1-20 In some embodiments, L is alkylene. A2 is -O-(C 1-10 C with 1 to 3 oxygen atoms, such as alkylene)- 1-10 Heteroalkylene. A1 and L A2 Both of these are J in the above formulas I-2 to I-9. 3 can be combined with Residues of GPR40 agonists

[0051] The variable L in Equation I 10 , J 1 , J 2 , J 3 ,R A , R B However, in a preferred embodiment, the variables of formula I are represented by the formula GPR-1, JPEG2025502110000109.jpg23170 (GPR-1) 1 is hydrogen, C 1-4 Alkyl, N3, JPEG2025502110000110.jpg29170), are preferably such that they are GPR40 agonists with an EC50 of less than 100 nM when measured according to Biological Example 1 herein.

[0052] Typically, p1 in Formula I is 0.

[0053] In some embodiments, p1 of Formula I is 1 and R A is F, Cl, CN, C optionally substituted with 1 to 3 fluorines 1-4 alkyl or C optionally substituted with 1 to 3 fluorines 1-4 It is an alkoxy.

[0054] Typically, p2 in Formula I is 0.

[0055] In some embodiments, p2 in Formula I is 1 or 2, and R B are independently F, OH, NH2, NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), C optionally substituted with 1 to 3 fluorines 1-4 alkyl or C optionally substituted with 1 to 3 fluorines 1-4 It is an alkoxy.

[0056] In some preferred embodiments, L 10 is optionally substituted ethylene. When substituted, ethylene is typically substituted with one or two substituents, each independently 1-4 Alkyl or C 3-6 For example, in some embodiments, L 10 teeth JPEG2025502110000111.jpg25170, where R 10 is hydrogen or C 1-4 In some preferred embodiments, the compounds of formula I-1 can be characterized as having the following formula I-1-A: JPEG2025502110000112.jpg32170In formula, R 10 is hydrogen or C 1-4 alkyl (preferably methyl), J 1 , J 2 , J 3 , L A , and T A includes any of those described herein in any combination.

[0057] In some embodiments, J of Formula I (e.g., Formula I-1 or I-1-A) 1 is -CH2-N(C 1-4 -C such as alkyl)- 1-6 Alkylene-N(R 100 Typically, in Formula I, J 1 is a 4-12 membered optionally substituted heterocycle having one or two ring nitrogen atoms. In some embodiments, J of Formula I (e.g., Formula I-1 or I-1-A) 1 is a 4-12 membered optionally substituted heterocycle having one or two ring nitrogen atoms. For example, in some embodiments, J 1 is a 4-8 (e.g., 4, 5, 6, or 7) membered monocyclic, optionally substituted saturated heterocycle having one or two ring heteroatoms independently selected from S, O, and N, provided that at least one of the ring heteroatoms is nitrogen. In some embodiments, J 1 is selected from the following (J 2 is included to indicate the direction of the link), JPEG2025502110000113.jpg23170 Each of them is F, OH, NH2, NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), C optionally substituted with 1 to 3 fluorines 1-4 Alkyl and C optionally substituted with 1 to 3 fluorines 1-4 Optionally substituted with 1 to 2 substituents independently selected from alkoxy.

[0058] In some embodiments, J of Formula I (e.g., Formula I-1 or I-1-A)1 can also be a bicyclic or polycyclic 6-12 membered, optionally substituted saturated heterocycle having one or two ring heteroatoms independently selected from S, O, and N, provided that at least one of the ring heteroatoms is nitrogen. For example, in some embodiments, J 1 is selected from the following (J 2 is included to indicate the direction of the link). JPEG2025502110000114.jpg26170

[0059] In some embodiments, J of Formula I (e.g., Formula I-1 or I-1-A) 2 is a straight or branched chain C optionally substituted with 1 to 3 fluorines 1-4 For example, in some embodiments, J 2 is CH2 or -CH(CH3)-.

[0060] J of Formula I (e.g., Formula I-1 or I-1-A) 3 is an aryl (e.g., phenyl) or heteroaryl ring (e.g., pyridyl), each of which is unsubstituted or substituted with one or more (e.g., 1, 2, or 3) substituents independently selected from 1) and 2) below: 1) halogen, CN, —CF3, OH, amino, substituted amino, ester, amide, carbonate, or carbamate; 2) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkoxy, aryl, heteroaryl, 3-8 membered heterocycloalkyl having 1 or 2 ring heteroatoms independently selected from N, O, and S, each of which is selected from F, —OH, protected hydroxyl, oxo (where applicable), NH, protected amino, NH(C 1-4 alkyl) or its protected derivatives, N(C 1-4 Alkyl ((C 1-4 alkyl), C 1-4Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 and optionally substituted with one or more (e.g., 1, 2, or 3) substituents independently selected from cycloalkoxy, phenyl, 5- or 6-membered heteroaryl containing 1, 2, or 3 ring heteroatoms independently selected from O, S, and N, and 3- to 7-membered heterocyclyl containing 1 or 2 ring heteroatoms independently selected from O, S, and N, wherein each of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkoxyphenyl, heteroaryl, and heterocyclyl is optionally substituted with one or more (e.g., 1, 2, or 3) substituents independently selected from F, —OH, oxo (if applicable), C 1-4 Alkyl, Fluoro-substituted C 1-4 Alkyl (e.g., CF3), C 1-4 Alkoxy and Fluoro Substituted C 1-4 Optionally substituted with 1, 2, or 3 substituents independently selected from alkoxy.

[0061] In some embodiments, J of Formula I (e.g., Formula I-1 or I-1-A) 3 are F, Cl, CN, OH, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy or C 3-6 The alkyl, heteroalkyl, cycloalkyl, alkoxy or cycloalkoxy is a C optionally substituted with F, —OH, F. 1-4 Alkoxy, oxo (where applicable), NH2, NH(C 1-4 alkyl), N(C 1-4 Alkyl ((C 1-4 alkyl), C optionally substituted with F 1-4 The phenyl ring is optionally substituted with one or more (e.g., 1, 2, or 3) substituents independently selected from alkyl. For example, in some embodiments, the phenyl ring is optionally substituted with fluorine, such as CF. 1-4C optionally substituted with alkyl and methoxy, ethoxy, isopropoxy, or fluorine such as O-CF 1-6 It may be substituted with one or two substituents independently selected from alkoxy.

[0062] In some embodiments, J of Formula I (e.g., Formula I-1 or I-1-A) 3 are F, Cl, CN, OH, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy or C 3-6 and cycloalkoxy. The alkyl, heteroalkyl, cycloalkyl, alkoxy, or cycloalkoxy is a C alkyl group optionally substituted with F, —OH, or F. 1-4 Alkoxy, oxo (where applicable), NH2, NH(C 1-4 alkyl), N(C 1-4 Alkyl ((C 1-4 alkyl), C optionally substituted with F 1-4 It is optionally substituted with one or more (eg, 1, 2, or 3) substituents independently selected from alkyl.

[0063] For example, in some embodiments, J of Formula I (e.g., Formula I-1 or I-1-A) 3 is selected from: JPEG2025502110000115.jpg32170In the formula, Ring represents an aromatic or non-aromatic ring structure, Each of the phenyl, pyridyl, or fused ring structures may be selected from the group consisting of F, Cl, CN, OH, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy or C 3-6 cycloalkoxy, wherein alkyl, heteroalkyl, cycloalkyl, alkoxy, or cycloalkoxy is C optionally substituted with F, —OH, F 1-4Alkoxy, oxo (where applicable), NH2, NH(C 1-4 alkyl), N(C 1-4 Alkyl ((C 1-4 alkyl), C optionally substituted with F 1-4 For example, in some embodiments, the phenyl, pyridyl, or fused ring structure is optionally substituted with one or more (e.g., 1, 2, or 3) substituents independently selected from alkyl, C substituted with fluorine, such as CF . 1-4 C optionally substituted with alkyl and methoxy, ethoxy, isopropoxy, or fluorine such as O-CF 1-6 It may be substituted with one or two substituents independently selected from alkoxy.

[0064] In some embodiments, J of Formula I (e.g., Formula I-1 or I-1-A) 3 is selected from: JPEG2025502110000116.jpg68170 These are F, Cl, CN, OH, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy or C 3-6 and optionally substituted with 1 to 3 substituents independently selected from alkyl, heteroalkyl, cycloalkyl, alkoxy, or cycloalkoxy, wherein alkyl, heteroalkyl, cycloalkyl, alkoxy, or cycloalkoxy is C optionally substituted with F, —OH, F. 1-4 Alkoxy, oxo (where applicable), NH2, NH(C 1-4 alkyl), N(C 1-4 Alkyl ((C 1-4 alkyl), C optionally substituted with F 1-4 It is optionally substituted with one or more (eg, 1, 2, or 3) substituents independently selected from alkyl.

[0065] In some embodiments, J of Formula I (e.g., Formula I-1 or I-1-A) 3 is selected from: JPEG2025502110000117.jpg61170 Each is C optionally substituted with F, Cl, CN, OH, or F 1-6 C optionally substituted with alkyl (e.g., CF), cyclopropyl, cyclobutyl, F 1-6 Alkoxy (e.g., -O-CF3), or C 3-6 For example, in some embodiments, the phenyl, benzofuran, benzothiophene, benzoxazole, or benzothiazole ring is optionally substituted with 1 to 3 substituents independently selected from C alkyl optionally substituted with fluorine, such as CF, and C alkyl optionally substituted with fluorine, such as methoxy, ethoxy, isopropoxy, or O-CF. 1-6 The alkyl group may be substituted with one or two substituents independently selected from alkoxy. Preferably, one substituent is J 2 It is an orthogonal to the

[0066] In some embodiments, the compound of Formula I is characterized as having the following formula I-1-A-1, I-1-A-2, I-1-A-3, I-1-A-4, or I-1-A-5: JPEG2025502110000118.jpg133170In formula, R 20 is C 1-6 Alkyl or fluorine substituted C 1-6 alkyl, and R 21 is hydrogen or C 1-6 alkyl, and R 22 are hydrogen, halogens, CN, C 1-6 Alkyl or fluorine substituted C 1-6 Alkyl or C 3-6 It is cycloalkyl. A and T A includes any of those described herein in any combination. In some embodiments, R 20 is methyl, ethyl, n-propyl, isopropyl, or CF. In some embodiments, R 21 is hydrogen, methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 20is CF3 and R 21 is hydrogen or methyl. In some embodiments, R 20 is CH3 and R 21 is hydrogen or methyl. In some embodiments, R 22 is hydrogen. In some embodiments, R 22 is methyl. In some embodiments, R 22 is cyclopropyl.

[0067] In some embodiments, the compound of Formula I is characterized as having the following formula I-1-A-6, I-1-A-7, I-1-A-8, I-1-A-9, or I-1-A-10: JPEG2025502110000119.jpg137170In formula, R 20 is C 1-6 Alkyl or fluorine substituted C 1-6 alkyl, and R 21 is hydrogen or C 1-6 alkyl, and R 22 is hydrogen, halogen, CN, C 1-6 Alkyl or Fluorine Substituted C 1-6 Alkyl or C 3-6 It is cycloalkyl. A and T A includes any of those described herein in any combination. In some embodiments, R 20 is methyl, ethyl, n-propyl, isopropyl, or CF. In some embodiments, R 21 is hydrogen, methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R 20 is CF3 and R 21 is hydrogen or methyl. In some embodiments, R 20 is CH3 and R 21 is hydrogen or methyl. In some embodiments, R 22 is hydrogen. In some embodiments, R 22 is methyl. In some embodiments, R 22 is cyclopropyl.

[0068] In a preferred embodiment, L of formulas I-1-A-1 to I-1-A-10 A -X 12-30 It may also be -C(O)-, where C(O) is T A X in each occurrence is independently CR2, -C(R)=C(R)-, JPEG2025502110000120.jpg10170SiR2, C(O), O, NR, S, SO2, or a ring structure, preferably a 3- to 10-membered ring structure. R in each occurrence is independently hydrogen, halogen, optionally substituted C 1-4 Alkyl or optionally substituted C 1-4 Alkoxy, typically hydrogen or C 1-4 It is alkyl. A The maximum chain length of is at least -(CH2) 12 The maximum chain length is, for example, at least -(CH2) 14 The longest chain length is at least -(CH2) 16 The longest chain length is at least -(CH2) 18 The longest chain length is L A The hydrophobicity of the corresponding compound HX 12-30 The -C(O)-OH may be characterized as having a cLogP of at least 3, e.g., between 3 and 15, preferably at least 4 (e.g., at least 4.5, at least 5, at least 5.5, at least 6, at least 6.5, at least 7, etc.), e.g., 3 to 10, 4 to 12, 4.5 to 9, 5 to 11, 5.5 to 10.5, 6 to 14, 6.5 to 13, etc. Preferably, the terminal X group is not C(=O) or SO2. Preferably, L A The total number of non-hydrogen atoms in is between 15 and 50, e.g., 18, 20, 25, 30, 35, 40, 45, or 50, or any range between the recited values. In some preferred embodiments, none of the X groups is a ring structure. In some preferred embodiments, one instance of X is a ring structure, preferably a 3- to 10-membered ring structure. For example, in some embodiments, one instance of X is triazole, and the remaining X groups are each independently selected from C—R, —C(R)═C(R)—, JPEG2025502110000121.jpg12170 or O, and R at each occurrence is independently hydrogen or C alkyl. In some embodiments, no X group is a ring structure, and each X is independently CR, -C(R)=C(R)-, JPEG2025502110000122.jpg12170 or O, and R at each occurrence is independently hydrogen or C alkyl (preferably methyl). In some embodiments, all instances of X are CR, and R at each occurrence is independently hydrogen or C alkyl (preferably methyl). In some embodiments, up to six (e.g., 1, 2, 3, 4, 5, or 6) instances of X may be O. In some embodiments, one or two instances of X are O and all other instances of X are CR, where R at each occurrence is independently hydrogen or C alkyl (preferably methyl). In some embodiments, one or two instances of X are O, one X is triazole, and all other instances of X are CR, where R at each occurrence is independently hydrogen or C alkyl (preferably methyl). In some embodiments, R is hydrogen.

[0069] In some preferred embodiments, T of formulas I-1-A-1 to I-1-A-10 A teeth JPEG2025502110000123.jpg24170. G in each occurrence 1 are independently hydrogen, halogen, or optionally substituted C 1-4 Alkyl or optionally substituted C 1-4 Heteroalkyl (optionally substituted C 1-4 alkoxy, etc.) or two gem-G 1 The groups may be bonded to form =O, =NH, or =N(C 1-4 alkyl), or two or more G 1 The groups can be linked to form a ring structure. The integer r is 1 to 10, such as 1 or 2. G in each occurrence 2are independently hydrogen, G 10 , C(O)-G 10 , SO2G 10 , C(O)-NH-G 10 , or SO2NHG 10 , C(O)-OG 10 , or SO2OG 10 At each occurrence, G 10 are independently optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl or an optionally substituted 3- to 10-membered ring structure that can be carbocyclic, heterocyclic, aromatic, heteroaromatic, or a combination thereof. The fragments are (i) a CG group next to an NH group. 1 G 1 If the group is not C(=O), the corresponding compound JPEG2025502110000124.jpg27170 has a cLogP less than 1, preferably less than 0 (e.g., less than -1, less than -2, less than -3, less than -3.5, less than -4, or less), or (ii) a CG next to NH 1 G 1 When the group is C(=O), the corresponding compound JPEG2025502110000125.jpg25170 is further characterized by having a cLogP less than 1, preferably less than 0 (e.g., less than -1, less than -2, less than -3, less than -3.5, less than -4, or even less).

[0070] In some preferred embodiments, T of formulas I-1-A-1 to I-1-A-10 A teeth, JPEG2025502110000126.jpg20170. In some embodiments, G 2 Examples of one or both of It can have a structure of JPEG2025502110000127.jpg13170. n is an integer of 0 to 100, preferably 0 to 10 (for example, 0 to 4, 1 to 5, or 2 to 6). Z 1 are CH2, C(O), SO, SO2, CH(C 1-4alkyl), C(C 1-4 Alkyl)(C 1-4 alkyl) or a 3- to 10-membered ring structure. 2 are independently CH2, O, S, SO, SO2, C(O), CH(C 1-4 alkyl), C(C 1-4 Alkyl)(C 1-4 alkyl), NH, N(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 alkyl)] + Or a 3- to 10-membered ring structure. 3 is H, C 1-4 Alkyl, OH, SO3H, COOH, NH2, NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, SO2NH2, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), or SO2N(C 1-4 Alkyl)(C 1-4 C 1-4 Each alkyl is independently selected and optionally includes, for example, 1 to 3 G as defined herein. 20 In some embodiments, Z is substituted with a group. 2 In some embodiments, none of Z 2 One or more examples of the formula include 3-10 membered ring structures such as nitrogen-containing rings, e.g., JPEG2025502110000128.jpg22170. In some embodiments, Z 3 Directly connect to Z 2 is a 3- to 10-membered ring structure such as a nitrogen-containing ring, for example, JPEG2025502110000129.jpg23170, etc. Preferably, Z 2Up to two instances of G are 3- to 10-membered ring structures. 2 are independently hydrogen, optionally substituted C 1-6 Alkyl or optionally substituted C 1-6 For example, when substituted, C 1-6 Alkyl is OH, NH2, oxo (=O), NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, C(O)OH, SO2NH2, SO3H, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), and SO2N(C 1-4 Alkyl)(C 1-4 C can be substituted with 1 to 3 substituents independently selected from alkyl. 1-4 Each alkyl is independently selected and optionally includes, for example, 1 to 3 G as defined herein. 20 Each occurrence of G herein is substituted with a group. 20 The groups are OH, NH2, oxo (=O), NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, C(O)OH, SO2NH2, SO3H, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), SO2N(C 1-4 Alkyl)(C 1-4 alkyl), or a 3- to 10-membered ring structure. 1-4Each alkyl is independently selected and optionally includes, for example, 1 to 3 G as defined herein. 21 Each occurrence of G herein is substituted with a group. 21 The groups are OH, NH2, oxo (=O), NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, C(O)OH, SO2NH2, SO3H, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), SO2N(C 1-4 Alkyl)(C 1-4 alkyl) or a 3- to 10-membered ring structure. 2 One or more examples of 1-4 alkylene)-NH2 or CONH-(C 1-4 alkylene)-[N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + C optionally substituted with an amide derivative such as 1-4 For example, in some embodiments, G 2 One or two examples of -(C 1-4 alkylene)-COOH, and G 2 Any remaining instance of C 1-4 In some embodiments, G is alkyl. 2 One or two examples of JPEG2025502110000130.jpg18170 etc. -(C 1-4 alkylene)-CONH-(C 1-4 alkylene)-NH2, and G 2 Any remaining instance of C 1-4 In some embodiments, G is alkyl. 2One or two examples of JPEG2025502110000131.jpg17170 etc. -(C 1-4 alkylene)-CONH-(C 1-4 alkylene)-[N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + and G 2 Any remaining instance of C 1-4 In some embodiments, T A teeth, JPEG2025502110000132.jpg42170. In some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000133.jpg40170. In some embodiments, T A teeth, JPEG2025502110000134.jpg41170. In some embodiments, T A teeth, JPEG2025502110000135.jpg29170. In some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000136.jpg63170. In some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000137.jpg50170JPEG2025502110000138.jpg52170. In some embodiments, T A teeth, For example, in some embodiments, T A teeth JPEG2025502110000140.jpg52170. In some embodiments, T A teeth JPEG2025502110000141.jpg34170. In some embodiments, T A teeth JPEG2025502110000142.jpg38170. In some embodiments, T A teeth JPEG2025502110000143.jpg25170. In some embodiments, T A teeth JPEG2025502110000144.jpg24170. In some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000145.jpg24170. In some embodiments, T A teeth JPEG2025502110000146.jpg23170. In some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000147.jpg24170. In some embodiments, T A teeth It could also be JPEG2025502110000148.jpg21170.

[0071] In some preferred embodiments, T of formulas I-1-A-1 to I-1-A-10 A teeth, Optionally, the charge is balanced with a counterion (e.g., as described herein); JPEG2025502110000149.jpg27170 can be characterized as having the structure G 1 are independently hydrogen, halogen, or optionally substituted C 1-4Alkyl or optionally substituted C 1-4 Heteroalkyl (optionally substituted C 1-4 alkoxy, etc.) or two gem-G 1 The groups may be bonded to form =O, =NH, or =N(C 1-4 alkyl), or two or more G 1 The groups can be linked to form a ring structure. The integer r is 1 to 10, such as 1 or 2. G in each occurrence 4 are independently hydrogen or G 10 At each occurrence, G 10 are independently optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl or an optionally substituted 3- to 10-membered ring structure that can be carbocyclic, heterocyclic, aromatic, heteroaromatic, or a combination thereof. JPEG2025502110000150.jpg25170 is (i) the CG next to NH 1 G 1 If the group is not C(=O), the corresponding compound JPEG2025502110000151.jpg24170 has a cLogP of less than 1, preferably less than 0 (e.g., less than −1, less than −2, less than −3, less than −3.5, less than −4, or less), or (ii) a CG next to NH 1 G 1 When the group is C(=O), the corresponding compound JPEG2025502110000152.jpg23170 is characterized as having a cLogP of less than 1, preferably less than 0 (e.g., less than -1, less than -2, less than -3, less than -3.5, less than -4, or even less).

[0072] In some preferred embodiments, T of formulas I-1-A-1 to I-1-A-10 A teeth, JPEG2025502110000153.jpg20170. In some embodiments, G 4One or more instances of JPEG2025502110000154.jpg11170, where n is an integer of 0 to 100, preferably 0 to 10 (for example, 0 to 4, 1 to 5, or 2 to 6). 1 are CH2, C(O), SO2, CH(C 1-4 alkyl), or C(C 1-4 Alkyl)(C 1-4 (alkyl). Z in each occurrence 2 are independently CH2, O, S, SO, SO2, C(O), CH(C 1-4 alkyl), C(C 1-4 Alkyl)(C 1-4 alkyl), NH, N(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 alkyl)] + Or a 3- to 10-membered ring structure. 3 is H, C 1-4 Alkyl, OH, SO3H, COOH, NH2, NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, SO2NH2, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), or SO2N(C 1-4 Alkyl)(C 1-4 C 1-4 Each alkyl is independently selected and optionally includes, for example, 1 to 3 G as defined herein. 20 Preferably, Z 2 Up to two instances of Z are 3- to 10-membered ring structures. 2 In some embodiments, none of Z 2 One example of is a 3-10 membered ring structure such as a nitrogen-containing ring, e.g., JPEG2025502110000155.jpg22170. In some embodiments, 4 are independently hydrogen, optionally substituted C 1-6 Alkyl or optionally substituted C 1-6 For example, when substituted, C 1-6 Alkyl is OH, NH2, oxo (=O), NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, C(O)OH, SO2NH2, SO3H, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), and SO2N(C 1-4 Alkyl)(C 1-4 C can be substituted with 1 to 3 substituents independently selected from alkyl. 1-4 Each alkyl is independently selected and optionally includes, for example, 1 to 3 G as defined herein. 20 Each occurrence of G herein is substituted with a group. 20 The groups are OH, NH2, oxo (=O), NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, C(O)OH, SO2NH2, SO3H, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), SO2N(C 1-4 Alkyl)(C 1-4 alkyl), or a 3- to 10-membered ring structure.1-4 Each alkyl is independently selected and optionally includes, for example, 1 to 3 G as defined herein. 21 Each occurrence of G herein is substituted with a group. 21 The groups are OH, NH2, oxo (=O), NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, C(O)OH, SO2NH2, SO3H, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), SO2N(C 1-4 Alkyl)(C 1-4 alkyl) or a 3- to 10-membered ring structure. 4 One or more examples of C, such as methyl 1-4 In some embodiments, G is alkyl. 4 One or more examples of 1-4 alkylene)-NH2 or CONH-(C 1-4 alkylene)-[N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + C optionally substituted with an amide derivative such as 1-4 For example, in some embodiments, G 4 One or two examples of -(C 1-4 alkylene)-COOH, and G 4 Any remaining instance of C 1-4 In some embodiments, G is alkyl. 4 One or two examples of JPEG2025502110000156.jpg18170 etc. -(C 1-4 alkylene)-CONH-(C 1-4alkylene)-NH2, and G 4 Any remaining instance of C 1-4 In some embodiments, G is alkyl. 4 One or two examples of JPEG2025502110000157.jpg18170 etc. -(C 1-4 alkylene)-CONH-(C 1-4 alkylene)-[N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + and G 4 Any remaining instance of C 1-4 In some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000158.jpg83170. In some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000159.jpg44170. In some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000160.jpg28170. In some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), For example, in some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000162.jpg50170. In some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000163.jpg34170. In some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000164.jpg24170. In some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000165.jpg23170. In some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000166.jpg32170. In some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000167.jpg25170. In some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000168.jpg24170. In some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000169.jpg30170. In some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000170.jpg16170. In some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000171.jpg54170

[0073] In some preferred embodiments, the disclosure also provides a compound of formula I-4-A, I-4-B, I-4-C, I-5-A, I-5-B, or I-5-C, or a pharmaceutically acceptable salt or ester thereof. JPEG2025502110000172.jpg190170JPEG2025502110000173.jpg111170In formula, X, m1, G 1 , G 2 , G 4 , r, and JPEG2025502110000174.jpg10170 includes any of the preferred structures described herein, e.g., any of the preferred structures described in connection with formula I-4 or I-5, in any combination. For example, X in each occurrence is independently selected from C—R, —C(R)═C(R)—, JPEG2025502110000175.jpg10170SiR2, C(O), O, NR, S, SO2, or a ring structure, preferably a 3- to 10-membered ring structure. R in each occurrence is independently hydrogen, halogen, optionally substituted C 1-4 Alkyl or optionally substituted C 1-4 Alkoxy, typically hydrogen or C 1-4 Preferably, (X) is alkyl. m1 The terminal X group of the moiety is not C(=O) or SO2. In some embodiments, the integer m1 may be 12 to 50, such as 14 to 50, 16 to 30, etc. Preferably, (X) m1 The total number of non-hydrogen atoms in the moiety is between 15 and 50, e.g., 18, 20, 25, 30, 35, 40, 45, or 50, or any range between the recited values. In some preferred embodiments, none of the X groups is a ring structure. In some preferred embodiments, one instance of X is a ring structure, preferably a 3- to 10-membered ring structure. For example, in some embodiments, one instance of X is triazole, and the remaining X groups are each independently selected from the group consisting of -CR2, -C(R)=C(R)- ... JPEG2025502110000176.jpg10170 or O, more preferably CR2 or O, and R at each occurrence is independently hydrogen or C1-4 alkyl. In some embodiments, no X group is a ring structure, and each X is independently CR2, -C(R)=C(R)-, JPEG2025502110000177.jpg10170 or O, more preferably CR2 or O, where R at each occurrence is independently hydrogen or C1-4 alkyl. In some embodiments, up to six (e.g., 1, 2, 3, 4, 5, or 6) instances of X may be O. In some embodiments, all instances of X are CR2, and R at each occurrence is independently hydrogen or C1-4 alkyl (preferably methyl). In some embodiments, one or two instances of X are O, and all other instances of X are CR2, where R at each occurrence is independently hydrogen or C1-4 alkyl (preferably methyl). In some embodiments, one or two instances of X are O, one X is triazole, and all other instances of X are CR2, where R at each occurrence is independently hydrogen or C1-4 alkyl (preferably methyl). In some embodiments, R is hydrogen. G 1 , G 2 , G 4 , r, and The definition and preferred definition of JPEG2025502110000178.jpg10170 are also described herein, including any of their corresponding definitions set forth in any of the compounds listed in Table 1 herein or any of the compounds according to Examples 1 to 221. Formula II and II-B

[0074] In some embodiments, the present disclosure provides a compound of formula II or II-B, or a pharmaceutically acceptable salt or ester thereof: JPEG2025502110000179.jpg73170In formula, Y is CH, CR A , or N, Z is O, S, NH, or N(C 1-4alkyl), HET ring represents an optionally substituted heteroaryl ring (e.g., a 5- or 6-membered heteroaryl such as a triazole ring); R 11 and R 12 are each independently hydrogen or C 1-4 is alkyl, L N is empty (null), an arbitrarily substituted C 1-6 Alkylene or optionally substituted C having 1 to 3 heteroatoms 1-6 is heteroalkylene, L 10 is alkylene (e.g., C 1-6 alkylene), halogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 1-6 Alkoxy, optionally substituted C 3-6 optionally substituted with 1 to 3 substituents independently selected from cycloalkoxy, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two substituents joined to form an optionally substituted ring system; R at each occurrence A are independently selected from halogen, CN, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 1-6 Alkoxy or optionally substituted C 3-6 cycloalkoxy or two R A are linked to form an optionally substituted ring structure, and p1 is 0, 1, or 2; R at each occurrence C are independently selected from halogen, CN, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C1-6 Alkoxy or optionally substituted C 3-6 cycloalkoxy or two R C are linked to form an optionally substituted ring structure, and p2 is 0, 1, 2, or 3; R 13 is hydrogen, optionally substituted phenyl, or optionally substituted heteroaryl; where: q is an integer of 1 to 10, preferably 1 or 2; T A is a hydrophilic group, and L A is a linker. In a preferred embodiment, T A L A wherein (1) if the terminal atom is N of a basic amine group, the corresponding compound T A -(C(O)-CH3) q has a cLogP less than 1, -C(O)-CH3 is bonded to the terminal N atom, and (2) if the terminal atom is the C of the C(O) group, the corresponding compound T A -(OH) q has a cLogP less than 1, -OH is bonded to the terminal C atom, and (3) if the terminal atom is S in the SO2 group, T A -(OH) q has a cLogP less than 1, -OH is bonded to the terminal S atom, or (4) if (1) to (3) do not apply, T A -H q has a cLogP less than 1, L A L A The maximum length between the two terminal atoms of is at least -(CH2) 10 a linker characterized in that the maximum length between the two terminal carbon atoms of A If both terminal atoms of the compound are C in a C(O) or S in an SO group, the corresponding compound is HO-L A -OH has a cLogP of at least 3, each -OH is bonded to a terminal C(O) or SO2 group, (2) L AIf only one terminal atom of is C in C(O) or S in SO2 group, the corresponding compound HL A -OH has a cLogP of at least 3, -OH is bonded to a C(O) or SO2 group, or (3) if neither (1) nor (2) applies, the corresponding compound HL A -H has a cLogP of at least 3.

[0075] In some embodiments, the compound has a structure according to Formula II.

[0076] In some embodiments, the compound has a structure according to formula II-B.

[0077] In some embodiments according to Formula II or II-B, L N is null. That is, L A is directly linked to the phenyl ring depicted in Formula II or the HET ring of II-B. For clarity, for purposes of this specification, L as null will be used. N In such an embodiment, the definition of L A is the L described herein N This should not be construed as meaning that the fragment cannot contain fragments that fit one or more of the definitions of L. N If is defined as empty (null), then the variable L A L N In an embodiment where L is not empty (null), N -L A can have any of the definitions described herein for

[0078] In some embodiments according to Formula II or II-B, L N is a branched or linear C 1-6 Alkylene, for example JPEG2025502110000180.jpg22170(L A is shown to indicate the direction of linkage. In some embodiments according to Formula II or II-B, L N teeth JPEG2025502110000181.jpg26170, (L A is shown to indicate the linkage direction), where G A are independently hydrogen or optionally substituted C 1-4 Alkyl or two G A are linked to form a 3- to 6-membered ring, such as a cyclopropyl or cyclobutyl ring. A is methyl.

[0079] In some embodiments according to Formula II or II-B, L N is a branched or linear C with one or two oxygen atoms 1-6 Heteroalkylene, for example JPEG2025502110000182.jpg26170(L A is shown to indicate the direction of linkage. In some embodiments according to Formula II or II-B, L N teeth, JPEG2025502110000183.jpg26170(L A is shown to indicate the connection direction), where G A are independently hydrogen or optionally substituted C 1-4 Alkyl or two G A may be linked to form a 3- to 6-membered ring, such as a cyclopropyl or cyclobutyl ring. B are independently hydrogen or optionally substituted C 1-4 alkyl or two G B or one G A and one G B are linked to form a 3- to 6-membered ring such as a cyclopropyl or cyclobutyl ring. C is hydrogen, optionally substituted C 1-4 Alkyl or optionally substituted C 1-4 Heteroalkyl (e.g., C 1-4 In some preferred embodiments, each occurrence of G is AIn some preferred embodiments, G at each occurrence is methyl. B is hydrogen. In some preferred embodiments, G C is hydrogen or methoxy, etc. 1-4 It is an alkoxy.

[0080] In some embodiments, q in Formula II is 1, and the compound of Formula II can be characterized as having formula II-1: JPEG2025502110000184.jpg33170In the formula, variable T A , L A , L N , L 10 , R 11 , R 12 , R 13 , R A , R C , Y, Z, p1, and p2 are as defined herein, including any of the preferred ones described herein, in any combination.

[0081] In some embodiments, q of Formula II-B is 1, and the compound of Formula II-B can be characterized as having the formula II-B-1: JPEG2025502110000185.jpg35170In the formula, variable T A , L A , L N , L 10 , R 11 , R 12 , R 13 , R A , Y, p1, and Z are defined herein. Linker L A

[0082] As shown herein, the inventors have discovered that several factors are important for a compound of Formula II or II-B to be a potent GPR40 agonist. One factor that can determine whether a compound of Formula II or II-B can be a potent GPR40 agonist is the molecular weight of the linker (e.g., L), rather than the exact chemical structure of the linker. A) is the length of the linker. As shown in the Examples section of the specification, if the linker length is below a certain threshold, the EC50 value can be significantly increased. Therefore, the inventors have found that the linker L in Formula II or II-B, similar to that described above in relation to Formula I, A The maximum length between the two terminal atoms of the alkylene chain -(CH2) 10 - should be the maximum length between the two terminal carbon atoms of L. A The longest chain length is the alkylene chain -(CH2) 10 The maximum chain length of the linker L discussed above for Formula I should be equal to or greater than the maximum chain length of A The meaning and determination of the maximum distance between the two terminal non-hydrogen atoms of also applies to Formula II or II-B. A L A The maximum length between the two terminal atoms is at least -(CH2) 12 - the maximum length between the two terminal carbon atoms, preferably at least -(CH2) 14 -, more preferably at least -(CH2) 16 In some embodiments, L A L A The maximum length between the two terminal atoms of (i)-(CH2) 12 - the maximum length between the two terminal carbon atoms of (ii) -(CH2) 50 - the maximum length between the two terminal carbon atoms.

[0083] In some embodiments, in Formula II (e.g., Formula II-1) or II-B (e.g., Formula II-B-1), L A is (X) m where X in each occurrence is independently CR, C(=O), -C(R)=C(R)-, JPEG2025502110000186.jpg12170SiR2, O, S, SO2, NR, [NR2] +or a ring structure, preferably a 3- to 10-membered ring structure. R in each occurrence is independently hydrogen, halogen, optionally substituted C 1-4 Alkyl or optionally substituted C 1-4 Alkoxy, typically hydrogen or C 1-4 The integer m is at least 10, e.g., at least 12, at least 14, at least 16, at least 18, at least 20, at least 50, e.g., 12 to 50, 16 to 50, etc. Suitable X groups for Formula II also include any of those described and preferred herein in connection with Formula I. Typically, L A In the formula, 0, 1, or 2 instances of X are ring structures, preferably 3- to 10-membered ring structures (C such as cyclopropyl). 3-6 In some embodiments, two consecutive X's may be -C(O)O- or -C(O)NR-. In some embodiments, one instance of X may be a cyclopropane, cyclobutane, or bicyclobutane [1.1] ring. In some embodiments, one instance of X may be a 5- or 6-membered heteroaryl, such as a triazole ring. In some embodiments, one instance of X may be a cyclopentane, cyclohexane, or cycloheptane ring. Typically, one of the terminal X groups is connected to T via a carbon atom. A L A The total number of non-hydrogen atoms may typically be between 10 and 100, for example, 12 to 30, 14 to 50, 16 to 50, 18 to 100, etc.

[0084] Another factor that can determine whether a compound of Formula II or II-B can be a potent GPR40 agonist is the molecular weight of the linker (e.g., L) rather than the exact chemical structure of the linker. A ) is hydrophobic. Generally, L A should be a hydrophobic moiety. In some embodiments, L A Both terminal atoms of L are C in a C(O) or S in a SO group. A The hydrophobicity of the corresponding compound HO-L is typically AThe -OH has a cLogP of at least 3, e.g., between 3 and 15, preferably at least 4 (e.g., at least 4.5, at least 5, at least 5.5, at least 6, at least 6.5, at least 7, etc.), and can be characterized as having a cLogP of, e.g., 3 to 10, 4 to 12, 4.5 to 9, 5 to 11, 5.5 to 10.5, 6 to 14, 6.5 to 13, etc., where each of the -OH is bonded to a terminal C(O) or SO2 group. A Only one terminal atom of L is C in C(O) or S in SO group. A The hydrophobicity of the corresponding compound HL is typically A The -OH has a cLogP of at least 3, e.g., between 3 and 15, preferably at least 4 (e.g., at least 4.5, at least 5, at least 5.5, at least 6, at least 6.5, at least 7, etc.), and can be characterized as having a cLogP of 3 to 10, 4 to 12, 4.5 to 9, 5 to 11, 5.5 to 10.5, 6 to 14, 6.5 to 13, etc., where the -OH is attached to a terminal C(O) or SO2 group. A None of the terminal atoms of L is a C of a C(O) or an S of a SO group. A The hydrophobicity of the corresponding compound HL A -H has a cLogP of at least 3, e.g., between 3 and 15, preferably at least 4 (e.g., at least 4.5, at least 5, at least 5.5, at least 6, at least 6.5, at least 7, etc.), and can be characterized as having a cLogP of, for example, 3 to 10, 4 to 12, 4.5 to 9, 5 to 11, 5.5 to 10.5, 6 to 14, 6.5 to 13, etc.

[0085] For example, in some embodiments, L A is (X) m-1 -C(O)-, where the C(O) terminus is T A X in each occurrence is independently CR2, C(=O), -C(R)=C(R)-, JPEG2025502110000187.jpg12170SiR2, O, S, SO2, NR, [NR2] + or a ring structure, preferably a 3- to 10-membered ring structure, provided that the terminal X group (i.e., the L furthest from the (O) terminal) A X in each occurrence is not C(O) or SO2. R is independently hydrogen, halogen, optionally substituted C 1-4 Alkyl or optionally substituted C 1-4 Alkoxy, typically hydrogen or C 1-4 The integer m is at least 10, for example, at least 12, at least 14, at least 16, at least 18, at least 20, or at least 50, for example, 12 to 50, 16 to 50, etc. -(X) m-1 The hydrophobicity of -C(O)- is similar to that of the corresponding compound H-(X) m-1 -COOH has a cLogP of at least 3, for example, between 3 and 15, preferably at least 4 (e.g., at least 4.5, at least 5, at least 5.5, at least 6, at least 6.5, at least 7, etc.), for example, 3 to 10, 4 to 12, 4.5 to 9, 5 to 11, 5.5 to 10.5, 6 to 14, 6.5 to 13, etc. "m-1" should be understood as the integer m minus 1 and should not be mistaken for another designated variable.

[0086] In some embodiments, L A (X) m wherein X in each occurrence is independently CR, C(=O), -C(R)=C(R)-, JPEG2025502110000188.jpg12170SiR2, O, S, SO2, NR, [NR2] + or a ring structure, preferably a 3- to 10-membered ring structure, provided that none of the terminal X groups is C(O) or SO2. R in each occurrence is independently hydrogen, halogen, optionally substituted C 1-4 Alkyl or optionally substituted C 1-4 Alkoxy, typically hydrogen or C 1-4The integer m is at least 10, for example, at least 12, at least 14, at least 16, at least 18, at least 20, at least 50, for example, 12 to 50, 16 to 50, etc., and the corresponding compound H-(X) m -H should have a cLogP of at least 3, e.g., between 3 and 15, preferably at least 4 (e.g., at least 4.5, at least 5, at least 5.5, at least 6, at least 6.5, at least 7, etc.), e.g., 3 to 10, 4 to 12, 4.5 to 9, 5 to 11, 5.5 to 10.5, 6 to 14, 6.5 to 13, etc.

[0087] In some embodiments, L A -X 12-30 -(e.g., -X 14 -, -X 16 -, -X 18 -, -X 20 -, -X 24 -, -X 14-30 -, -X 16-30 -, -X 18-30 -, etc.), where X in each occurrence is independently CR2, C(=O), -C(R)=C(R)-, JPEG2025502110000189.jpg12170SiR2, O, S, SO2, NR, [NR2] + or a ring structure, preferably a 3- to 10-membered ring structure, provided that none of the terminal X groups is C(O) or SO2. R in each occurrence is independently hydrogen, halogen, optionally substituted C 1-4 Alkyl or optionally substituted C 1-4 Alkoxy, typically hydrogen or C 1-4 It is alkyl. A The hydrophobicity of the corresponding compound HL A-H may be characterized as having a cLogP of at least 3, e.g., between 3 and 15, preferably at least 4 (e.g., at least 4.5, at least 5, at least 5.5, at least 6, at least 6.5, at least 7, etc.), e.g., 3 to 10, 4 to 12, 4.5 to 9, 5 to 11, 5.5 to 10.5, 6 to 14, 6.5 to 13, etc. In some embodiments, L A The total number of non-hydrogen atoms in is between 12 and 100, e.g., 12, 14, 16, 18, 20, 24, 30, 40, 50, 100, or any range between the recited values, e.g., 12-30, 14-50, 16-50, 18-100, etc. In some embodiments, two consecutive Xs can represent -C(O)O- or -C(O)NR-. In some embodiments, one or more (e.g., one or two) instances of X can be a ring structure selected from cyclopropane, cyclobutane, bicyclobutane [1.1], cyclopentane, cyclohexane, or cycloheptane. In some embodiments, one or more (e.g., one) instances of X can be a ring structure selected from phenyl, or a 5- or 6-membered heteroaryl, such as triazole. In some embodiments, R is hydrogen.

[0088] In some embodiments, L A -X 12-30 -C(O)-, where C(O) is T A X in each occurrence is independently CR2, C(=O), -C(R)=C(R)-, JPEG2025502110000190.jpg12170SiR2, O, S, SO2, NR, [NR2] + or a ring structure, preferably a 3- to 10-membered ring structure, provided that the terminal X group (i.e., the L furthest from the C(O) terminal) A X in each occurrence is not C(O) or SO2. R is independently hydrogen, halogen, optionally substituted C 1-4 Alkyl or optionally substituted C 1-4 Alkoxy, typically hydrogen or C 1-4 It is alkyl. AThe hydrophobicity of the corresponding compound HX 12-30 -C(O)-OH may be characterized as having a cLogP of at least 3, e.g., between 3 and 15, preferably at least 4 (e.g., at least 4.5, at least 5, at least 5.5, at least 6, at least 6.5, at least 7, etc.), e.g., 3 to 10, 4 to 12, 4.5 to 9, 5 to 11, 5.5 to 10.5, 6 to 14, 6.5 to 13, etc. In some embodiments, L A The total number of non-hydrogen atoms in is between 14 and 100, e.g., 14, 16, 18, 20, 24, 30, 40, 50, 100, or any range between the recited values, e.g., 14-30, 14-50, 16-50, 18-100, etc. In some embodiments, two consecutive Xs may be -C(O)O- or -C(O)NR-. In some embodiments, one or more (e.g., one or two) instances of X may be a ring structure selected from cyclopropane, cyclobutane, bicyclobutane [1.1], cyclopentane, cyclohexane, or cycloheptane. In some embodiments, one or more (e.g., one) instances of X may be a ring structure selected from phenyl, or a 5- or 6-membered heteroaryl such as triazole. In some embodiments, R is hydrogen.

[0089] In some preferred embodiments, L A Ha-C 12-30 Alkylene- or -C 12-30 alkylene-C(O)-, where -C 12-30 The alkylene- is optionally substituted, and the optional substituents can be optionally joined together to form a double bond, a triple bond, or a ring structure (typically a 3- to 10-membered ring structure). 12-30 The terminal carbon atom of alkylene- is not substituted with oxo (=O). A The maximum chain length of is at least -(CH2) 12 -, e.g., at least -(CH2) 14 - maximum chain length of at least -(CH2) 16 - maximum chain length of at least -(CH2) 18 - is the longest chain length.A The hydrophobicity of the corresponding compound HC 12-30 Alkylene-H or HC 12-30 The alkylene -C(O)-OH may be characterized as having a cLogP of at least 3, e.g., between 3 and 15, preferably at least 4 (e.g., at least 4.5, at least 5, at least 5.5, at least 6, at least 6.5, at least 7, etc.), e.g., 3 to 10, 4 to 12, 4.5 to 9, 5 to 11, 5.5 to 10.5, 6 to 14, 6.5 to 13, etc. In some embodiments, L A The total number of non-hydrogen atoms in L is between 14 and 100, e.g., 14, 16, 18, 20, 24, 30, 40, 50, 100, or any range between the listed values, e.g., 14-30, 14-50, 16-50, 18-100, etc. A is a linear or branched chain C 12-30 Unsubstituted -C such as alkylene 12-30 In some embodiments, L A is unsubstituted -C 12-30 alkylene-C(O)-, where C 12-30 Alkylene may be linear or branched. In some preferred embodiments, L A Ha-C 12-30 Alkylene- or -C 12-30 alkyleneC(O)-, where C 12-30 Alkylene- is a linear unsubstituted -C 12-30 It is alkylene.

[0090] In some preferred embodiments, L of Formula II (e.g., Formula II-1) or II-B (e.g., Formula II-B-1) A or L N -L A teeth, You can select from the structure JPEG2025502110000191.jpg26170, where C 10-26 Alkylene is optionally substituted and each occurrence of G A are independently hydrogen or optionally substituted C 1-4 Alkyl or two GA are linked to form a 3- to 6-membered ring, such as a cyclopropyl or cyclobutyl ring. In some preferred embodiments, G A is methyl. In some embodiments, C 10-26 Alkylene is unsubstituted, for example, a straight or branched chain C 10-26 In some preferred embodiments, C 10-26 Alkylene is a linear unsubstituted C 10-26 It is alkylene.

[0091] In some embodiments, L A is a 12- to 30-membered heteroalkylene or -(12- to 30-membered heteroalkylene)-C(O)-, where the 12- to 30-membered heteroalkylene is optionally substituted and contains 1 to 6 heteroatoms independently selected from O, N, and S. The sulfur atom, if present, is optionally oxidized. The optional substituents can optionally be bonded together to form a double bond, a triple bond, or a ring structure (typically a 3- to 10-membered ring structure). The terminal atom of the 12- to 30-membered heteroalkylene is not the C of C(O) or the S of an SO group. L A The maximum chain length of is at least -(CH2) 12 -, e.g., at least -(CH2) 14 - maximum chain length of at least -(CH2) 16 - maximum chain length of at least -(CH2) 18 - is the longest chain length. A The hydrophobicity of L can be characterized by the corresponding compound H--(12-30 membered heteroalkylene)-H or H--(12-30 membered heteroalkylene)-C(O)-OH having a cLogP of at least 3, e.g., between 3 and 15, preferably at least 4 (e.g., at least 4.5, at least 5, at least 5.5, at least 6, at least 6.5, at least 7, etc.), e.g., 3-10, 4-12, 4.5-9, 5-11, 5.5-10.5, 6-14, 6.5-13, etc. In some embodiments, L AThe total number of non-hydrogen atoms in L is between 14 and 100, e.g., 14, 16, 18, 20, 24, 30, 40, 50, 100, or any range between the listed values, e.g., 14 to 30, 14 to 50, 16 to 50, 18 to 100, etc. A is an unsubstituted 12- to 30-membered heteroalkylene, such as a straight or branched chain 12- to 30-membered heteroalkylene. A is an unsubstituted -(12- to 30-membered heteroalkylene)-C(O)-, where the 12- to 30-membered heteroalkylene may be linear or branched. In some preferred embodiments, L A is a 12- to 30-membered heteroalkylene or -(12- to 30-membered heteroalkylene)-C(O)-, wherein the 12- to 30-membered heteroalkylene is linear and unsubstituted. In some embodiments, the 12- to 30-membered heteroalkylene contains 1, 2, 3, 4, or 5 heteroatoms independently selected from O, S, and N.

[0092] Alkylene In some preferred embodiments, L of Formula II (e.g., Formula II-1) or II-B (e.g., Formula II-B-1) A or L N -L A teeth, You can choose from JPEG2025502110000192.jpg68170. 10-26 Alkylene is optionally substituted and each occurrence of G A are independently hydrogen or optionally substituted C 1-4 Alkyl or two G A are linked to form a 3- to 6-membered ring, such as a cyclopropyl or cyclobutyl ring, and G in each occurrence B are independently hydrogen or optionally substituted C 1-4 alkyl or two G B or one G A and one G B are linked to form a 3- to 6-membered ring, such as a cyclopropyl or cyclobutyl ring. In some preferred embodiments, G AIn some preferred embodiments, G at each occurrence is methyl. B In some preferred embodiments, L of Formula II (e.g., Formula II-1) or II-B (e.g., Formula II-B-1) is hydrogen. A or L N -L A teeth, JPEG2025502110000193.jpg64170. In some embodiments, C 10-26 Alkylene is unsubstituted, for example, a straight or branched chain C 10-26 In some preferred embodiments, C 10-26 Alkylene is a linear unsubstituted C 10-26 It is alkylene.

[0093] In some preferred embodiments, L A teeth, JPEG2025502110000194.jpg35170, where the carbonyl is T A It is directly bonded to L A1 and L A2 each independently represents a bond, an optionally substituted -C 1-30 alkylene or optionally substituted —C containing 1 to 6 heteroatoms independently selected from O, N, and S; 1-30 Heteroalkylene. The sulfur atom, if present, is optionally oxidized. The optional substituents can optionally be joined together to form a double bond, a triple bond, or a ring structure. T A or L N L binds to A1 and L A2 The terminal atom of is not, where applicable, the C of C(O) or the S of an SO2 group. A The maximum chain length of is at least -(CH2) 12 -, e.g., at least -(CH2) 14 - maximum chain length of at least -(CH2) 16 - maximum chain length of at least -(CH2) 18 - is the longest chain length. AThe hydrophobicity of the corresponding compound JPEG2025502110000195.jpg32170 can be characterized as having a cLogP of at least 3, e.g., between 3 and 15, preferably at least 4 (e.g., at least 4.5, at least 5, at least 5.5, at least 6, at least 6.5, at least 7, etc.), e.g., 3 to 10, 4 to 12, 4.5 to 9, 5 to 11, 5.5 to 10.5, 6 to 14, 6.5 to 13, etc. In some embodiments, L A The total number of non-hydrogen atoms in L is between 14 and 100, e.g., 14, 16, 18, 20, 24, 30, 40, 50, 100, or any range between the listed values, e.g., 14 to 30, 14 to 50, 16 to 50, 18 to 100, etc. A1 is C 1-20 Alkylene, for example, straight chain alkylene, (CH2) 1-20 In some embodiments, L A1 is -O-(C 1-10 C with 1 to 3 oxygen atoms, such as alkylene)- 1-10 In some embodiments, L is heteroalkylene. A2 is a bond. In some embodiments, L A2 is C 1-20 Alkylene, for example, straight chain alkylene, (CH2) 1-20 In some embodiments, L A2 is -O-(C 1-10 C with 1 to 3 oxygen atoms, such as alkylene)- 1-10 It is heteroalkylene.

[0094] In some embodiments, L A teeth, It can be characterized as having a structure according to JPEG2025502110000196.jpg29170. A1 and L A2 are each independently a bond, -C 1-30 alkylene- or -C containing 1 to 6 heteroatoms independently selected from O, N, and S 1-30Heteroalkylene-. Sulfur atoms, if present, are optionally oxidized. T A or L N L binds to A1 and L A2 If the terminal atom (LN) of formula II is empty (null), the applicable terminal atom is R 13 or HET of formula II-B) is not the C of C(O) or the S of an SO group, where applicable. A The total number of non-hydrogen atoms in L is between 15 and 50, e.g., 18, 20, 25, 30, 35, 40, 45, or 50, or any range between the listed values. A The maximum chain length of is at least -(CH2) 12 -, e.g., at least -(CH2) 14 - maximum chain length of at least -(CH2) 16 - maximum chain length of at least -(CH2) 18 - is the longest chain length. A The hydrophobicity of the corresponding compound HL A -H may be characterized as having a cLogP of at least 3, e.g., between 3 and 15, preferably at least 4 (e.g., at least 4.5, at least 5, at least 5.5, at least 6, at least 6.5, at least 7, etc.), e.g., 3 to 10, 4 to 12, 4.5 to 9, 5 to 11, 5.5 to 10.5, 6 to 14, 6.5 to 13, etc. In some embodiments, L A1 is a bond (i.e., absent, the triazole nitrogen atom is T A or L N In some embodiments, L A2 is a bond. In some embodiments, L A1 is C 1-20 Alkylene, for example, straight chain alkylene, (CH2) 1-20 In some embodiments, L A1 is -O-(C 1-10 C with 1 to 3 oxygen atoms, such as alkylene)- 1-10 In some embodiments, L is heteroalkylene. A2is C 1-20 Alkylene, for example, straight chain alkylene, (CH2) 1-20 In some embodiments, L A2 is -O-(C 1-10 C with 1 to 3 oxygen atoms, such as alkylene)- 1-10 It is heteroalkylene.

[0095] In some embodiments, L A teeth, It can be characterized as having a structure according to JPEG2025502110000197.jpg34170. A1 and L A2 are each independently a bond, -C 1-30 alkylene- or -C containing 1 to 6 heteroatoms independently selected from O, N, and S 1-30 Heteroalkylene-is. The sulfur atom, if present, is optionally oxidized. L N L binds to A2 The terminal atom of is not the C of C(O) or the S of an SO2 group. A The total number of non-hydrogen atoms in L is between 15 and 50, e.g., 18, 20, 25, 30, 35, 40, 45, or 50, or any range between the listed values. A The maximum chain length of is at least -(CH2) 12 -, e.g., at least -(CH2) 14 - maximum chain length of at least -(CH2) 16 - maximum chain length of at least -(CH2) 18 - is the longest chain length. A The hydrophobicity of the corresponding compound JPEG2025502110000198.jpg32170 can be characterized as having a cLogP of at least 3, e.g., between 3 and 15, preferably at least 4 (e.g., at least 4.5, at least 5, at least 5.5, at least 6, at least 6.5, at least 7, etc.), e.g., 3 to 10, 4 to 12, 4.5 to 9, 5 to 11, 5.5 to 10.5, 6 to 14, 6.5 to 13, etc. In some embodiments, L A1is a bond. In some embodiments, L A2 is a bond. In some embodiments, L A1 is C 1-20 Alkylene, for example, straight chain alkylene, (CH2) 1-20 In some embodiments, L A1 is -O-(C 1-10 C with 1 to 3 oxygen atoms, such as alkylene)- 1-10 In some embodiments, L is heteroalkylene. A2 is C 1-20 Alkylene, for example, straight chain alkylene, (CH2) 1-20 In some embodiments, L A2 is -O-(C 1-10 C with 1 to 3 oxygen atoms, such as alkylene)- 1-10 It is heteroalkylene.

[0096] In some embodiments, L A teeth, It can be characterized as having a structure according to JPEG2025502110000199.jpg33170. A1 and L A2 are each independently a bond, -C 1-30 alkylene- or -C containing 1 to 6 heteroatoms independently selected from O, N, and S 1-30 Heteroalkylene-. Sulfur atoms, if present, are optionally oxidized. L N L binds to A1 The terminal group of is not C of C(O) or S of SO2 group. A The total number of non-hydrogen atoms in L is between 15 and 50, e.g., 18, 20, 25, 30, 35, 40, 45, or 50, or any range between the listed values. A The maximum chain length of is at least -(CH2) 12 -, e.g., at least -(CH2) 14 - maximum chain length of at least -(CH2) 16 - maximum chain length of at least -(CH2) 18 - is the longest chain length. A The hydrophobicity of the corresponding compound JPEG2025502110000200.jpg30170 can be characterized as having a cLogP of at least 3, e.g., between 3 and 15, preferably at least 4 (e.g., at least 4.5, at least 5, at least 5.5, at least 6, at least 6.5, at least 7, etc.), e.g., 3 to 10, 4 to 12, 4.5 to 9, 5 to 11, 5.5 to 10.5, 6 to 14, 6.5 to 13, etc. In some embodiments, L A1 is a bond. In some embodiments, L A2 is a bond. In some embodiments, L A1 is C 1-20 Alkylene, for example, straight chain alkylene, (CH2) 1-20 In some embodiments, L A1 is -O-(C 1-10 C with 1 to 3 oxygen atoms, such as alkylene)- 1-10 In some embodiments, L is heteroalkylene. A2 is C 1-20 Alkylene, for example, straight chain alkylene, (CH2) 1-20 In some embodiments, L A2 is -O-(C 1-10 C with 1 to 3 oxygen atoms, such as alkylene)- 1-10 It is heteroalkylene.

[0097] In some preferred embodiments, L of Formula II (e.g., Formula II-1) or II-B (e.g., Formula II-B-1) A or L N -L A You can choose from the following structures: JPEG2025502110000201.jpg22170JPEG2025502110000202.jpg231170Here, C 0-26 Alkylene, C 0-27 Alkylene, C 1-25 Alkylene, C 1-26 Alkylene, or C 1-30 The alkylene is optionally substituted. Aare independently hydrogen or optionally substituted C 1-4 Alkyl or two G A may be linked to form a 3- to 6-membered ring, such as a cyclopropyl or cyclobutyl ring. B are independently hydrogen or optionally substituted C 1-4 Alkyl or two G B or one G A and one G B are linked to form a 3- to 6-membered ring such as a cyclopropyl or cyclobutyl ring. C is hydrogen, optionally substituted C 1-4 Alkyl or optionally substituted C 1-4 Heteroalkyl (e.g., C 1-4 In some preferred embodiments, each occurrence of G is A In some preferred embodiments, G at each occurrence is methyl. B is hydrogen. In some embodiments, C 0-26 Alkylene, C 0-27 Alkylene, C 1-25 Alkylene, C 1-26 Alkylene, or C 1-30 The alkylene is unsubstituted and is a straight or branched chain alkylene. In some embodiments, C 0-26 Alkylene, C 0-27 Alkylene, C 1-25 Alkylene, C 1-26 Alkylene, or C 1-30 Alkylene is a straight-chain unsubstituted alkylene. For clarity, as used herein, C alkylene should be understood to be absent. For example, In the structure of JPEG2025502110000203.jpg19170, C 0-26 When alkylene is a C0 alkylene, the structure is It should be understood as JPEG2025502110000204.jpg18170.

[0098] In some preferred embodiments, L of Formula II (e.g., Formula II-1) or II-B (e.g., Formula II-B-1)A or L N -L A You can choose from the following structures: JPEG2025502110000205.jpg133170JPEG2025502110000206.jpg18170C 0-26 Alkylene, C 0-27 Alkylene, C 1-25 Alkylene, C 1-26 Alkylene, or C 1-30 The alkylene is optionally substituted. In some embodiments, C 0-26 Alkylene, C 0-27 Alkylene, C 1-25 Alkylene, C 1-26 Alkylene, or C 1-30 The alkylene is unsubstituted and is a straight or branched chain alkylene. In some embodiments, C 0-26 Alkylene, C 0-27 Alkylene, C 1-25 Alkylene, C 1-26 Alkylene, or C 1-30 Alkylene is a straight chain unsubstituted alkylene.

[0099] In some preferred embodiments, L of Formula II (e.g., Formula II-1) or II-B (e.g., Formula II-B-1) A or L N -L A You can choose from the following structures: JPEG2025502110000207.jpg76170JPEG2025502110000208.jpg111170JPEG2025502110000209.jpg49170Here, C 0-26 Alkylene, C 0-27 Alkylene, C 1-25 Alkylene, C 1-26 Alkylene, or C 1-30 Alkylene is optionally substituted and each occurrence of G A are independently hydrogen or optionally substituted C 1-4 Alkyl or two G A are linked to form a 3- to 6-membered ring, such as a cyclopropyl or cyclobutyl ring, and G in each occurrenceB are independently hydrogen or optionally substituted C 1-4 Alkyl or two G B or one G A and one G B are linked to form a 3- to 6-membered ring, such as a cyclopropyl or cyclobutyl ring. In some preferred embodiments, G A In some preferred embodiments, G at each occurrence is methyl. B is hydrogen. In some embodiments, C 0-26 Alkylene, C 0-27 Alkylene, C 1-25 Alkylene, C 1-26 Alkylene, or C 1-30 The alkylene is unsubstituted and is a straight or branched chain alkylene. In some embodiments, C 0-26 Alkylene, C 0-27 Alkylene, C 1-25 Alkylene, C 1-26 Alkylene, or C 1-30 Alkylene is a straight chain unsubstituted alkylene.

[0100] In some preferred embodiments, L of Formula II (e.g., Formula II-1) or II-B (e.g., Formula II-B-1) A or L N -L A You can choose from the following structures: JPEG2025502110000210.jpg114170JPEG2025502110000211.jpg139170Here, C 0-26 Alkylene, C 0-27 Alkylene, C 1-25 Alkylene, C 1-26 Alkylene, or C 1-30 The alkylene is optionally substituted. In some embodiments, C 0-26 Alkylene, C 0-27 Alkylene, C 1-25 Alkylene, C 1-26 Alkylene, or C 1-30 The alkylene is unsubstituted and is a straight or branched chain alkylene. In some embodiments, C 0-26Alkylene, C 0-27 Alkylene, C 1-25 Alkylene, C 1-26 Alkylene, or C 1-30 Alkylene is a straight chain unsubstituted alkylene. Hydrophilic group T A

[0101] Similar to compounds of Formula I, another factor that can determine whether a compound of Formula II or II-B can be a potent GPR40 agonist is T A hydrophilic or polar, but T A The exact chemical structure of is not critical. Preferred T suitable for formula II or II-B are A includes any of those described and preferred in relation to formula I. In formula II or II-B, T A L A wherein (1) when the terminal atom is N of a basic amine group, the corresponding compound T A -(C(O)-CH3) q has a cLogP less than 1, -C(O)-CH3 is bonded to the terminal N atom, and (2) if the terminal atom is the C of the C(O) group, the corresponding compound T A -(OH) q has a cLogP less than 1, -OH is bonded to the terminal C atom, and (3) if the terminal atom is S in the SO2 group, the corresponding compound T A -(OH) q has a cLogP less than 1, -OH is bonded to the terminal S atom, or (4) if (1) to (3) do not apply, T A -H q has a cLogP of less than 1. In some embodiments, the terminal atom is the N of the basic amine group, and T A is the corresponding compound T A -(C(O)-CH3) q is less than 0 (e.g., less than -1, less than -2, less than -3, less than -3.5, less than -4, or even less). In some embodiments, the terminal atom is the C of a C(O) group, and TA is the corresponding compound T A -(OH) q is less than 0 (e.g., less than -1, less than -2, less than -3, less than -3.5, less than -4, or even less). In some embodiments, the terminal atom is S in an SO group, and T A is the corresponding compound T A -(OH) q is less than 0 (e.g., less than -1, less than -2, less than -3, less than -3.5, less than -4, or even less). In some embodiments, the terminal atom is not N of a basic amine group, C of a C(O) group, or S of a SO group, but is T A is the corresponding compound T A -H q is less than 0 (e.g., less than -1, less than -2, less than -3, less than -3.5, less than -4, or even less).

[0102] In some preferred embodiments, T A contains a quaternary nitrogen atom, a positively charged group such as SO3 - The compound may contain negatively charged groups such as , or charged groups containing zwitterionic structures. A It should be understood that when contains a charged group, a counterion, preferably a pharmaceutically acceptable anion or cation, is present if necessary to balance the charge so that the compound of Formula II or II-B is overall neutral.

[0103] In some embodiments, T A are characterized as having charged groups (including zwitterionic structures) or groups that can be charged at pH 7, such as primary amines, secondary amines, tertiary amines, quaternary amines, carboxylic acids, etc.

[0104] In some embodiments, T A is characterized as having at least two hydrogen bond donors.

[0105] In some embodiments, TA is characterized as having at least two hydrogen bond acceptors.

[0106] In some embodiments, T A is T A1 , T A1 -L B -, T A1 -L B -(heteroalkylene), or T A1 -L B -(heteroalkylene)-L B - and L in each occurrence B are independently -SO2-, -C(=O)-, or a moiety selected from: JPEG2025502110000212.jpg24170 R in each occurrence 100 , R 101 and R 102 are independently hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl; T A1 teeth, JPEG2025502110000213.jpg28170 is characterized as having the structure G 1 are independently hydrogen, halogen, or optionally substituted C 1-4 Alkyl or optionally substituted C 1-4 heteroalkyl (such as optionally substituted C1-4 alkoxy) or two gem-G 1 The groups may be bonded to form =O, =NH, or =N(C 1-4 alkyl) or two or more G 1 the groups can be linked to form a ring structure; the integer r is 1 to 10, such as 1 or 2; G in each occurrence 2 are independently hydrogen, G 10 , C(O)-G 10 , SO2G 10 , C(O)-NH-G 10 , or SO2NHG 10 , C(O)-OG 10 , or SO2OG 10and G 10 are independently optionally substituted alkyl, optionally substituted heteroalkyl, or an optionally substituted 3- to 10-membered ring structure which may be carbocyclic, heterocyclic, aromatic, heteroaromatic, or combinations thereof; G 3 is hydrogen or optionally substituted alkyl (e.g., C 1-4 alkyl), Or two Gs 2 , or one G 2 and one G 1 , or one G 1 and G 3 can be linked to form a ring structure, such as a 3- to 10-membered ring structure, Fragment JPEG2025502110000214.jpg26170 is (i)NG 3 Next to the CG 1 G 1 If the group is not C(=O), the corresponding compound JPEG2025502110000215.jpg28170 has a cLogP of less than 1, preferably less than 0 (e.g., less than −1, less than −2, less than −3, less than −3.5, less than −4, or less), or (ii) NG 3 Next to the CG 1 G 1 When the group is C(=O), the corresponding compound JPEG2025502110000216.jpg27170 is further characterized in that it has a cLogP of less than 1, preferably less than 0 (e.g., less than −1, less than −2, less than −3, less than −3.5, less than −4, or even less); Fragment JPEG2025502110000217.jpg19170 is (i) when the nitrogen is a basic nitrogen, the corresponding compound (G 2 )N—C(O)—CH has a cLogP of less than 1, preferably less than 0 (e.g., less than −1, less than −2, less than −3, less than −3.5, less than −4, or less), or (ii) if the nitrogen is a non-basic nitrogen, the corresponding compound (G 2)2N-H has a cLogP of less than 1, preferably less than 0 (e.g., less than -1, less than -2, less than -3, less than -3.5, less than -4, or even less). 3 is hydrogen. In some preferred embodiments, T A is T A1 or T A1 -L B In some embodiments, T A is T A1 -L B -(heteroalkylene) or T A1 -L B -(heteroalkylene)-L B -, and the heteroalkylene may be a glycol chain, such as a polyethylene glycol chain.

[0107] In some embodiments, T A is T A1 In some embodiments, T A is T A1 In some embodiments, T A1 teeth, JPEG2025502110000218.jpg19170. In some embodiments, T A1 teeth, JPEG2025502110000219.jpg15170. In some embodiments, the G 2 is, independently, It can have a structure of JPEG2025502110000220.jpg12170, where n is an integer of 0 to 100, preferably 0 to 10 (for example, 0 to 4, 1 to 5, or 2 to 6). 1 are CH2, C(O), SO, SO2, CH(C 1-4 alkyl), C(C 1-4 Alkyl)(C 1-4 alkyl) or a 3- to 10-membered ring structure. 2 are independently CH2, O, S, SO, SO2, C(O), CH(C 1-4alkyl), C(C 1-4 Alkyl)(C 1-4 alkyl), NH, N(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 alkyl)] + Or a 3- to 10-membered ring structure. 3 is H, C 1-4 Alkyl, OH, SO3H, COOH, NH2, NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, SO2NH2, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), or SO2N(C 1-4 Alkyl)(C 1-4 C 1-4 Each alkyl is independently selected and optionally includes, for example, 1 to 3 G as defined herein. 20 In some embodiments, Z is substituted with a group. 2 In some embodiments, none of Z 2 One or more examples of the formula include 3-10 membered ring structures such as nitrogen-containing rings, e.g., JPEG2025502110000221.jpg25170. In some embodiments, Z 3 Directly connect to Z 2 is a 3- to 10-membered ring structure such as a nitrogen-containing ring, for example, JPEG2025502110000222.jpg25170, etc. Preferably, Z 2 Up to two instances of G are 3- to 10-membered ring structures. 2 are independently hydrogen, optionally substituted C 1-6 Alkyl or optionally substituted C 1-6 For example, when substituted, C1-6 Alkyl is OH, NH2, oxo (=O), NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, C(O)OH, SO2NH2, SO3H, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), and SO2N(C 1-4 Alkyl)(C 1-4 C can be substituted with 1 to 3 substituents independently selected from alkyl. 1-4 Each alkyl is independently selected and optionally includes, for example, 1 to 3 G as defined herein. 20 Each occurrence of G herein is substituted with a group. 20 The groups are OH, NH2, oxo (=O), NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, C(O)OH, SO2NH2, SO3H, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), SO2N(C 1-4 Alkyl)(C 1-4 alkyl), or a 3- to 10-membered ring structure. 1-4 Each alkyl is independently selected and optionally includes, for example, 1 to 3 G as defined herein. 21 Each occurrence of G herein is substituted with a group. 21 The groups are OH, NH2, oxo (=O), NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, C(O)OH, SO2NH2, SO3H, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), SO2N(C 1-4 Alkyl)(C 1-4 alkyl) or a 3- to 10-membered ring structure. 2 One or more examples of 1-4 alkylene)-NH2 or CONH-(C 1-4 alkylene)-[N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + C optionally substituted with an amide derivative such as 1-4 For example, in some embodiments, G 2 One or two examples of -(C 1-4 alkylene)-COOH, and G 2 Any remaining instance of C 1-4 In some embodiments, G is alkyl. 2 One or two examples of JPEG2025502110000223.jpg17170 etc. -(C 1-4 alkylene)-CONH-(C 1-4 alkylene)-NH2, and G 2 Any remaining instance of C 1-4 In some embodiments, G is alkyl. 2 One or two examples of JPEG2025502110000224.jpg19170 etc. -(C 1-4 alkylene)-CONH-(C 1-4 alkylene)-[N(C 1-4 Alkyl)(C 1-4 Alkyl)(C1-4 alkyl)] + and G 2 Any remaining instance of C 1-4 In some embodiments, T A1 teeth, JPEG2025502110000225.jpg42170. In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000226.jpg44170. In some embodiments, T A1 teeth, JPEG2025502110000227.jpg40170. In some embodiments, T A1 teeth, JPEG2025502110000228.jpg29170. In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000229.jpg63170. In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), For example, in some embodiments, T A1 teeth JPEG2025502110000231.jpg51170. In some embodiments, T A1 teeth JPEG2025502110000232.jpg35170. In some embodiments, T A1 teeth JPEG2025502110000233.jpg40170. In some embodiments, T A1 teeth JPEG2025502110000234.jpg25170. In some embodiments, T A1 teeth JPEG2025502110000235.jpg25170. In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000236.jpg25170. In some embodiments, T A1 teeth JPEG2025502110000237.jpg23170. In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000238.jpg25170. In some embodiments, T A1 teeth It could also be JPEG2025502110000239.jpg22170.

[0108] In some embodiments, T A is T A1 , T A1 -L B -, T A1 -L B -(heteroalkylene), or T A1 -L B -(heteroalkylene)-L B - and L in each occurrence B are independently -SO2-, -C(=O)-, or a moiety selected from: JPEG2025502110000240.jpg24170 R in each occurrence 100 , R 101 and R 102 are independently hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl; T A1 teeth, Optionally, the charge is balanced with a counterion (e.g., as described herein); JPEG2025502110000241.jpg24170. 1are independently hydrogen, halogen, or optionally substituted C 1-4 Alkyl or optionally substituted C 1-4 Heteroalkyl (optionally substituted C 1-4 alkoxy, etc.) or two gem-G 1 The groups may be bonded to form =O, =NH, or =N(C 1-4 alkyl), or two or more G 1 The groups can be linked to form a ring structure. The integer r is 1 to 10, such as 1 or 2. G 3 is hydrogen or optionally substituted alkyl (e.g., C 1-4 alkyl). G in each occurrence 4 are independently hydrogen or G 10 and G 10 are independently an optionally substituted alkyl, an optionally substituted heteroalkyl, or an optionally substituted 3- to 10-membered ring structure which may be carbocyclic, heterocyclic, aromatic, heteroaromatic, or a combination thereof; or two G 4 , or one G 4 and one G 1 , or one G 1 and G 3 can be linked to form an optionally substituted 3- to 10-membered ring structure. Fragment JPEG2025502110000242.jpg24170 is (i) the CG next to NH 1 G 1 If the group is not C(=O), the corresponding compound JPEG2025502110000243.jpg26170 has a cLogP of less than 1, preferably less than 0 (e.g., less than −1, less than −2, less than −3, less than −3.5, less than −4, or less), or (ii) a CG next to NH 1 G 1 When the group is C(=O), the corresponding compound JPEG2025502110000244.jpg24170 has a cLogP of less than 1, preferably less than 0 (e.g., less than -1, less than -2, less than -3, less than -3.5, less than -4, or less than or equal to 0). 3 is hydrogen. In some preferred embodiments, T A is T A1 or T A1 -L B In some embodiments, T A is T A1 -L B -(heteroalkylene) or T A1 -L B -(heteroalkylene)-L B -, and the heteroalkylene may be a glycol chain, such as a polyethylene glycol chain.

[0109] In some embodiments, T A is T A1 In some embodiments, T A is T A1 In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000245.jpg19170. In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), In some embodiments, the G 4 is, independently, It can have a structure of JPEG2025502110000247.jpg15170, where n is an integer of 0 to 100, preferably 0 to 10 (for example, 0 to 4, 1 to 5, or 2 to 6). 1 are CH2, C(O), SO2, CH(C 1-4 alkyl), or C(C1-4 Alkyl)(C 1-4 (alkyl). Z in each occurrence 2 are independently CH2, O, S, SO, SO2, C(O), CH(C 1-4 alkyl), C(C 1-4 Alkyl)(C 1-4 alkyl), NH, N(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 alkyl)] + Or a 3- to 10-membered ring structure. 3 is H, C 1-4 Alkyl, OH, SO3H, COOH, NH2, NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, SO2NH2, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), or SO2N(C 1-4 Alkyl)(C 1-4 C 1-4 Each alkyl is independently selected and optionally includes, for example, 1 to 3 G as defined herein. 20 Preferably, Z 2 Up to two instances of Z are 3- to 10-membered ring structures. 2 In some embodiments, none of Z 2 One example of is a 3-10 membered ring structure such as a nitrogen-containing ring, e.g., JPEG2025502110000248.jpg23170. In some embodiments, 4 are independently hydrogen, optionally substituted C 1-6 Alkyl or optionally substituted C 1-6 For example, when substituted, C 1-6Alkyl is OH, NH2, oxo (=O), NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, C(O)OH, SO2NH2, SO3H, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), and SO2N(C 1-4 Alkyl)(C 1-4 C can be substituted with 1 to 3 substituents independently selected from alkyl. 1-4 Each alkyl is independently selected and optionally includes, for example, 1 to 3 G as defined herein. 20 Each occurrence of G herein is substituted with a group. 20 The groups are OH, NH2, oxo (=O), NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, C(O)OH, SO2NH2, SO3H, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), SO2N(C 1-4 Alkyl)(C 1-4 alkyl), or a 3- to 10-membered ring structure. 1-4 Each alkyl is independently selected and optionally includes, for example, 1 to 3 G as defined herein. 21 Each occurrence of G herein is substituted with a group. 21 The groups are OH, NH2, oxo (=O), NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, C(O)OH, SO2NH2, SO3H, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), SO2N(C 1-4 Alkyl)(C 1-4 alkyl) or a 3- to 10-membered ring structure. 4 One or more examples of C, such as methyl 1-4 In some embodiments, G is alkyl. 4 One or more examples of 1-4 alkylene)-NH2 or CONH-(C 1-4 alkylene)-[N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + C optionally substituted with an amide derivative such as 1-4 For example, in some embodiments, G 4 One or two examples of -(C 1-4 alkylene)-COOH, and G 4 Any remaining instance of C 1-4 In some embodiments, G is alkyl. 4 One or two examples of JPEG2025502110000249.jpg19170 etc. -(C 1-4 alkylene)-CONH-(C 1-4 alkylene)-NH2, and G 4 Any remaining instance of C 1-4 In some embodiments, G is alkyl. 4 One or two examples of JPEG2025502110000250.jpg17170 etc. -(C 1-4 alkylene)-CONH-(C 1-4alkylene)-[N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + and G 4 Any remaining instance of C 1-4 In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000251.jpg84170. In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000252.jpg43170. In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000253.jpg30170. In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), For example, in some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000255.jpg47170. In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000256.jpg35170. In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000257.jpg25170. In some embodiments, T A1is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000258.jpg22170. In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000259.jpg31170. In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000260.jpg23170. In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000261.jpg24170. In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000262.jpg30170. In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000263.jpg16170. In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000264.jpg32170. In some embodiments, T A1 teeth It could also be JPEG2025502110000265.jpg16170.

[0110] In some preferred embodiments, T A is T A1 or T A1 -L B - and T A1 teeth, JPEG2025502110000266.jpg231170JPEG2025502110000267.jpg81170L B is —SO—, —C(═O)—, or a moiety selected from: JPEG2025502110000268.jpg25170 where R in each occurrence 100 , R 101 , and R 102 are independently hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl; T A is optionally charge balanced with a counterion (eg, as described herein). L A -T A Example of

[0111] L A and T A The covalent bond formed between T A and the terminal atoms of L A The covalent bond between the terminal carbon or nitrogen atom of T is an amide bond. A and the terminal atoms of L A The covalent bond between the terminal atoms of is a non-amide carbon-nitrogen bond, an ester bond, a non-ester carbon-oxygen bond, a carbon-carbon bond, or a carbon-sulfur bond.

[0112] In some preferred embodiments, the compound of formula II can be characterized as having formula II-2, II-3, II-4, II-5, II-6, II-7, II-8, or II-9. JPEG2025502110000269.jpg49170JPEG2025502110000270.jpg235170JPEG2025502110000271.jpg108170In the formula, X in each occurrence is independently CR, C(=O), -C(R)=C(R)-, JPEG2025502110000272.jpg11170SiR2, O, S, SO2, NR, [NR2] + or a ring structure, preferably a 3- to 10-membered ring structure, wherein R in each occurrence is independently hydrogen, halogen, optionally substituted C 1-4 Alkyl or optionally substituted C 1-4 It is an alkoxy. The integer m1 is at least 12, for example, 12 to 50 (eg, 12, 14, 16, 18, 20, 22, 24, 30, 40, 50, or any range or value between the listed values). (X) m1 The hydrophobicity of is (i) H-(X) when neither of the two terminal X groups is C(O) or SO2. m1 -H has a cLogP of at least 3, for example, between 3 and 15, preferably at least 4 (e.g., at least 4.5, at least 5, at least 5.5, at least 6, at least 6.5, at least 7, etc.), for example, 3 to 10, 4 to 12, 4.5 to 9, 5 to 11, 5.5 to 10.5, 6 to 14, 6.5 to 13, etc.; (ii) when one terminal X group is C(O) or SO2 and the other is not C(O) or SO2, the corresponding compound H-(X) m1 -OH has a cLogP of at least 3, e.g., between 3 and 15, preferably at least 4 (e.g., at least 4.5, at least 5, at least 5.5, at least 6, at least 6.5, at least 7, etc.), e.g., 3 to 10, 4 to 12, 4.5 to 9, 5 to 11, 5.5 to 10.5, 6 to 14, 6.5 to 13, etc., and the OH is bonded to C(O) or SO2; or (iii) when both terminal X groups are C(O) or SO2, the corresponding compound HO-(X) m1 The -OH has a cLogP of at least 3, for example, between 3 and 15, preferably at least 4 (e.g., at least 4.5, at least 5, at least 5.5, at least 6, at least 6.5, at least 7, etc.), for example, a cLogP of 3 to 10, 4 to 12, 4.5 to 9, 5 to 11, 5.5 to 10.5, 6 to 14, 6.5 to 13, etc., and is characterized in that the OH is bonded to C(O) or SO2. G in each occurrence 1 are independently hydrogen, halogen, or optionally substituted C 1-4 Alkyl or optionally substituted C 1-4 heteroalkyl (such as optionally substituted C1-4 alkoxy) or two gem-G 1 The groups may be bonded to form =O, =NH, or =N(C 1-4 alkyl), or two or more G 1 The groups can be linked to form a ring structure. The integer r is 1 to 10, such as 1 or 2. G in each occurrence 2 are independently hydrogen, G 10 , C(O)-G 10 , SO2G 10 , C(O)-NH-G 10 , or SO2NHG 10 , C(O)-OG 10 , or SO2OG 10 and G 10 is independently an optionally substituted alkyl, an optionally substituted heteroalkyl, or an optionally substituted 3- to 10-membered ring structure that may be carbocyclic, heterocyclic, aromatic, heteroaromatic, or combinations thereof. G 3 is hydrogen or optionally substituted alkyl (e.g., C 1-4 alkyl). G in each occurrence 4 are independently hydrogen or G 10 and G 10 is independently an optionally substituted alkyl, an optionally substituted heteroalkyl, or an optionally substituted 3- to 10-membered ring structure that may be carbocyclic, heterocyclic, aromatic, heteroaromatic, or combinations thereof. Or two Gs 2 , or one G 2 and one G 1 , or one G 1 and G 3 can be linked to form a ring structure such as a 3- to 10-membered ring structure. Or two Gs 4 , or one G 4 and one G 1 , or one G 1 and G 3 can be linked to form an optionally substituted 3- to 10-membered ring structure. JPEG2025502110000273.jpg12170 is an anion. Fragment JPEG2025502110000274.jpg26170 is (i)NG 3 Next to the CG 1 G 1 If the group is not C(=O), the corresponding compound JPEG2025502110000275.jpg31170 has a cLogP of less than 1, preferably less than 0 (e.g., less than −1, less than −2, less than −3, less than −3.5, less than −4, or less), or (ii) NG 3 Next to the CG 1 G 1 When the group is C(=O), the corresponding compound JPEG2025502110000276.jpg27170 is further characterized in that it has a cLogP of less than 1, preferably less than 0 (e.g., less than -1, less than -2, less than -3, less than -3.5, less than -4, or even less). Fragment JPEG2025502110000277.jpg24170 is (i) the CG next to NH 1 G 1 If the group is not C(=O), the corresponding compound JPEG2025502110000278.jpg27170 has a cLogP of less than 1, preferably less than 0 (e.g., less than −1, less than −2, less than −3, less than −3.5, less than −4, or less), or (ii) a CG 1 G 1 When the group is C(=O), the corresponding compound JPEG2025502110000279.jpg23170 is characterized as having a cLogP of less than 1, preferably less than 0 (e.g., less than -1, less than -2, less than -3, less than -3.5, less than -4, or even less). Variable T A , L N , L 10 , R 11 , R 12 , R 13 , R A , R C , Y, Z, p1, and p2 are as defined herein, including any of the preferred ones described herein, in any combination. N is null. In some embodiments, L N is null, and the two instances of X attached to the phenyl ring are JPEG2025502110000280.jpg21170 (where X is shown to indicate the concatenation direction), with the remaining instances of X as defined herein. N teeth, Branched or linear C such as JPEG2025502110000281.jpg22170 (X is shown to indicate the linkage direction) 1-6 In some embodiments, each occurrence of G is alkylene. 1 is hydrogen. In some embodiments, G 1 One or more examples of C, such as methyl 1-4 In some embodiments, the integer r is 1, 2, 3, 4, or 5. In some embodiments, one or more instances of G 2 teeth, JPEG2025502110000282.jpg13170, where n is an integer of 0 to 100, preferably 0 to 10 (for example, 0 to 4, 1 to 5, or 2 to 6). 1 are CH2, C(O), SO, SO2, CH(C 1-4 alkyl), C(C 1-4 Alkyl)(C 1-4alkyl) or a 3- to 10-membered ring structure. 2 are independently CH2, O, S, SO, SO2, C(O), CH(C 1-4 alkyl), C(C 1-4 Alkyl)(C 1-4 alkyl), NH, N(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 alkyl)] + Or a 3- to 10-membered ring structure. 3 is H, C 1-4 Alkyl, OH, SO3H, COOH, NH2, NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, SO2NH2, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), or SO2N(C 1-4 Alkyl)(C 1-4 C 1-4 Each alkyl is independently selected and optionally includes, for example, 1 to 3 G as defined herein. 20 In some embodiments, Z is substituted with a group. 2 In some embodiments, none of Z 2 One or more examples of the formula include 3-10 membered ring structures such as nitrogen-containing rings, e.g., JPEG2025502110000283.jpg25170. In some embodiments, Z 3 Directly connect to Z 2 is a 3- to 10-membered ring structure such as a nitrogen-containing ring, for example, JPEG2025502110000284.jpg25170, etc. Preferably, Z 2 Up to two instances of G are 3- to 10-membered ring structures. 2are independently hydrogen, optionally substituted C 1-6 Alkyl or optionally substituted C 1-6 For example, when substituted, C 1-6 Alkyl is OH, NH2, oxo (=O), NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, C(O)OH, SO2NH2, SO3H, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), and SO2N(C 1-4 Alkyl)(C 1-4 C can be substituted with 1 to 3 substituents independently selected from alkyl. 1-4 Each alkyl is independently selected and optionally includes, for example, 1 to 3 G as defined herein. 20 In some embodiments, each occurrence of G is substituted with a group. 4 is, independently, JPEG2025502110000285.jpg14170, where n is an integer of 0 to 100, preferably 0 to 10 (for example, 0 to 4, 1 to 5, or 2 to 6). 1 are CH2, C(O), SO2, CH(C 1-4 alkyl), or C(C 1-4 Alkyl)(C 1-4 (alkyl). Z in each occurrence 2 are independently CH2, O, S, SO, SO2, C(O), CH(C 1-4 alkyl), C(C 1-4 Alkyl)(C 1-4 alkyl), NH, N(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 alkyl)] + Or a 3- to 10-membered ring structure. 3is H, C 1-4 Alkyl, OH, SO3H, COOH, NH2, NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, SO2NH2, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), or SO2N(C 1-4 Alkyl)(C 1-4 C 1-4 Each alkyl is independently selected and optionally includes, for example, 1 to 3 G as defined herein. 20 Preferably, Z 2 Up to two instances of Z are 3- to 10-membered ring structures. 2 In some embodiments, none of Z 2 One example of is a 3-10 membered ring structure such as a nitrogen-containing ring, e.g., JPEG2025502110000286.jpg24170. In some embodiments, 4 are independently hydrogen, optionally substituted C 1-6 Alkyl or optionally substituted C 1-6 For example, when substituted, C 1-6 Alkyl is OH, NH2, oxo (=O), NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, C(O)OH, SO2NH2, SO3H, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4alkyl), SO2NH(C 1-4 alkyl), and SO2N(C 1-4 Alkyl)(C 1-4 C can be substituted with 1 to 3 substituents independently selected from alkyl. 1-4 Each alkyl is independently selected and optionally includes, for example, 1 to 3 G as defined herein. 20 Each occurrence of G herein is substituted with a group. 20 The groups are OH, NH2, oxo (=O), NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, C(O)OH, SO2NH2, SO3H, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), SO2N(C 1-4 Alkyl)(C 1-4 alkyl), or a 3- to 10-membered ring structure. 1-4 Each alkyl is independently selected and optionally includes, for example, 1 to 3 G as defined herein. 21 Each occurrence of G herein is substituted with a group. 21 The groups are OH, NH2, oxo (=O), NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, C(O)OH, SO2NH2, SO3H, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), SO2N(C 1-4 Alkyl)(C 1-4alkyl) or a 3- to 10-membered ring structure. 4 One or more examples of C, such as methyl 1-4 In some embodiments, G is alkyl. 4 One or more examples of 1-4 alkylene)-NH2 or CONH-(C 1-4 alkylene)-[N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + C optionally substituted with an amide derivative such as 1-4 For example, in some embodiments, G 4 One or two examples of -(C 1-4 alkylene)-COOH, and G 4 Any remaining instance of C 1-4 In some embodiments, G is alkyl. 4 One or two examples of JPEG2025502110000287.jpg17170 etc. -(C 1-4 alkylene)-CONH-(C 1-4 alkylene)-NH2, and G 4 Any remaining instance of C 1-4 In some embodiments, G is alkyl. 4 One or two examples of JPEG2025502110000288.jpg17170 etc. -(C 1-4 alkylene)-CONH-(C 1-4 alkylene)-[N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + and G 4 Any remaining instance of C 1-4 In a preferred embodiment, G 3is hydrogen. In some embodiments, X at each occurrence is independently CH2, CHCH3, or C(CH3)2. In some embodiments, X at each occurrence is CH2. In some embodiments, up to 6 (e.g., 1, 2, 3, 4, 5, or 6) instances of X are O, and the remaining X are CH2, CHCH3, or C(CH3)2. In some embodiments, up to 10 instances of X are -CH=CH-, and the remaining X are CH2, CHCH3, or C(CH3)2. In some embodiments, (X) m1 The moiety has one or more structural features selected from the following: (i) two consecutive X's together form -C(O)O- or -C(O)NR- (e.g., C(O)NH or C(O)NCH3); (ii) one or more instances of X can have a ring structure selected from cyclopropane, cyclobutane, bicyclobutane [1.1], cyclopentane, cyclohexane, or cycloheptane; and (iii) one or more instances of X can have a ring structure selected from phenyl, or a 5- or 6-membered heteroaryl, such as triazole. In some embodiments, (X) m1 Within the moiety, there can be 0, 1, or 2 instances of a ring structure, preferably a 3- to 10-membered ring structure. In some embodiments, (X) m1 For example, in some embodiments, one triazole ring is present within the (X) moiety. m1 The moiety is as defined herein and is preferred For example, in some embodiments, L A1 and L A2 are each independently a bond, -C 1-30 alkylene- or -C containing 1 to 6 heteroatoms independently selected from O, N, and S 1-30 heteroalkylene-, where the sulfur atom, if present, is optionally oxidized, (X) m1 The total number of non-hydrogen atoms in L is between 15 and 50, e.g., 18, 20, 25, 30, 35, 40, 45, or 50, or any range between the listed values.A1 is a bond. In some embodiments, L A1 is C 1-20 Alkylene, for example, straight chain alkylene, (CH2) 1-20 In some embodiments, L A1 is -O-(C 1-10 C with 1 to 3 oxygen atoms, such as alkylene)- 1-10 In some embodiments, L is heteroalkylene. A2 is a bond. In some embodiments, L A2 is C 1-20 Alkylene, for example, straight chain alkylene, (CH2) 1-20 In some embodiments, L A2 is -O-(C 1-10 C with 1 to 3 oxygen atoms, such as alkylene)- 1-10 Heteroalkylene. A1 and L A2 Any of the above formulas II-2 to II-9 is L N (This means that L N It should be clear that this does not require that L actually exists. N If is empty (null), L A1 or L A2 is R in the above formulas II-2 to II-9 13 It should be understood that the phenyl ring may be directly attached to the ortho ring relative to the phenyl ring. Residues of GPR40 agonists

[0113] Variable L of Formula II or II-B 10 , R 11 , R 12 , R 13 , R A , R C However, in a preferred embodiment, the variables of formula II or II-B are selected from the group consisting of the formula GPR-2, JPEG2025502110000290.jpg29170(GPR-2), or formula GPR-2B, JPEG2025502110000291.jpg30170 (GPR-2B) 2 is E 2A or L N -E 2A where E 2A is hydrogen, N3, JPEG2025502110000292.jpg30170, L N is defined herein (e.g., null, or C 1-6 Alkylene)) is preferably such that it is a GPR40 agonist with an EC50 of less than 100 nM as measured according to Biological Example 1 herein.

[0114] Typically, p1 in formula II or II-B is 0.

[0115] In some embodiments, p1 of formula II or II-B is 1.

[0116] Typically, R in each occurrence A are independently F, Cl, CN, C optionally substituted with 1 to 3 fluorines 1-4 alkyl or C optionally substituted with 1 to 3 fluorines 1-4 It is an alkoxy.

[0117] Typically, p2 in formula II or II-B is 0.

[0118] In some embodiments, p2 of Formula II or II-B is 1 and R C is F, Cl, CN, C optionally substituted with 1 to 3 fluorines 1-4 alkyl or C optionally substituted with 1 to 3 fluorines 1-4 It is an alkoxy.

[0119] In formula II or II-B, Y is typically CH.

[0120] Preferably, Z in formula II or II-B is O.

[0121] In some embodiments, R 11 and R 12 are both hydrogen.

[0122] In some preferred embodiments, L 10 teeth, JPEG2025502110000293.jpg22170, where CR 16 R 17 is bonded to the COOH group, R 14 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 cycloalkyl, phenyl, 5- or 6-membered heteroaryl, or 3- to 7-membered heterocyclyl, wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heteroaryl, and heterocyclyl is optionally substituted with F, —OH, oxo (where applicable), C 1-4 Alkyl, Fluoro-substituted C 1-4 Alkyl (e.g., CF3), C 1-4 Alkoxy and Fluoro Substituted C 1-4 optionally substituted with 1, 2, or 3 substituents independently selected from alkoxy; R 15 , R 16 and R 17 are each independently hydrogen or C 1-4 alkyl, or R 14 and R 15 are joined to form a 3-7 membered ring having 0, 1, or 2 heteroatoms selected from O, N, or S. In some embodiments, R 16 and R 17 are both hydrogen or R 16 and R 17 is hydrogen and R 16 and R 17 The other of R is methyl. 14 and R 15 is hydrogen and R 14 and R15 The other is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, or C 3-6 In some embodiments, R 14 and R 15 combines to form C 3-6 Forms a cycloalkyl.

[0123] For example, in some embodiments, L 10 teeth JPEG2025502110000294.jpg26170, where R 10 is hydrogen or C such as methyl 1-4 It is alkyl.

[0124] R of Formula II or II-B 13 is typically an optionally substituted phenyl or an optionally substituted 5- or 6-membered heteroaryl having 1 to 4 ring heteroatoms. In some embodiments, R of Formula II or II-B 13 may also be hydrogen.

[0125] In some embodiments, R 13 is optionally substituted phenyl. In some embodiments, R 13 is an unsubstituted phenyl ring. In some embodiments, R 13 are F, Cl, CN, OH, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy or C 3-6 and a phenyl ring substituted with 1 to 3 substituents independently selected from alkyl, heteroalkyl, cycloalkyl, alkoxy, or cycloalkoxy, wherein alkyl, heteroalkyl, cycloalkyl, alkoxy, or cycloalkoxy is a C substituted with F, —OH, or C 1-4 Alkoxy, oxo (where applicable), NH2, NH(C 1-4 alkyl), N(C 1-4 Alkyl ((C 1-4 alkyl), and C optionally substituted with F1-4 It is optionally substituted with one or more (eg, 1, 2, or 3) substituents independently selected from alkyl.

[0126] In some embodiments, R 13 is an optionally substituted 6-membered heteroaryl ring. In some embodiments, R 13 are F, Cl, CN, OH, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy or C 3-6 a pyridyl ring optionally substituted with 1 to 3 substituents independently selected from cycloalkoxy; 6-membered heteroaryl rings such as JPEG2025502110000295.jpg13170, wherein alkyl, heteroalkyl, cycloalkyl, alkoxy or cycloalkoxy is C optionally substituted with F, —OH, F. 1-4 Alkoxy, oxo (where applicable), NH2, NH(C 1-4 alkyl), N(C 1-4 Alkyl ((C 1-4 alkyl), and C optionally substituted with F 1-4 It is optionally substituted with one or more (eg, 1, 2, or 3) substituents independently selected from alkyl.

[0127] In some preferred embodiments, the compounds of formula II or II-B can be characterized as having formula II-1-A or II-B-2, respectively: JPEG2025502110000296.jpg81170In formula, R 14 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 cycloalkyl, phenyl, 5- or 6-membered heteroaryl, or 3- to 7-membered heterocyclyl, wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heteroaryl, and heterocyclyl is optionally substituted with F, —OH, oxo (where applicable), C1-4 Alkyl, Fluoro-substituted C 1-4 Alkyl (e.g., CF3), C 1-4 Alkoxy and Fluoro Substituted C 1-4 optionally substituted with 1, 2, or 3 substituents independently selected from alkoxy; 15 , R 16 and R 17 are each independently hydrogen or C 1-4 alkyl, or R 14 and R 15 are joined together to form a 3- to 7-membered ring having 0, 1, or 2 heteroatoms selected from O, N, or S; R at each occurrence D are independently F, Cl, C optionally substituted with 1 to 3 F 1-4 alkyl, or C optionally substituted with 1 to 3 F 1-4 is an alkoxy, p3 is 0, 1, 2, or 3; Variable T A , L N , and L A includes any of the preferred ones described herein, in any combination. For example, in some embodiments, L N is null. In some embodiments, L N teeth, JPEG2025502110000297.jpg21170(L A (The symbol is shown to indicate the linkage direction) 1-6 In some embodiments, R 16 and R 17 are both hydrogen. In some embodiments, R 16 and R 17 is hydrogen and R 16 and R 17 The other of R is methyl. 14 and R 15 is hydrogen and R 14 and R 15 The other is C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, or C 3-6 In some embodiments, R 14 and R 15 combines to form C 3-6 Forms a cycloalkyl.

[0128] In some preferred embodiments, the compounds of formula II or II-B can be characterized as having formula II-1-A-1 or II-B-3, respectively: JPEG2025502110000298.jpg81170 variable T A , L N , and L A includes any of the preferred ones described herein, in any combination. For example, in some embodiments, L N is null. In some embodiments, L N teeth, JPEG2025502110000299.jpg22170(L A (The symbol is shown to indicate the linkage direction) 1-6 It is alkylene.

[0129] In a preferred embodiment, L of formula II-1-A (e.g., II-1-A-1), II-B-2, or II-B-3 A -X 12-30 It may also be -C(O)-, where C(O) is T A X in each occurrence is independently CR2, -C(R)=C(R)-, JPEG2025502110000300.jpg10170SiR2, C(O), O, NR, S, SO2, or a ring structure, preferably a 3- to 10-membered ring structure. R in each occurrence is independently hydrogen, halogen, optionally substituted C 1-4 Alkyl or optionally substituted C 1-4 Alkoxy, typically hydrogen or C 1-4 It is alkyl. A The maximum chain length of is at least -(CH2) 12 The maximum chain length is, for example, at least -(CH2)14 The longest chain length is at least -(CH2) 16 The longest chain length is at least -(CH2) 18 The longest chain length is L A The hydrophobicity of the corresponding compound HX 12-30 The -C(O)-OH has a cLogP of at least 3, for example, between 3 and 15, preferably at least 4 (e.g., at least 4.5, at least 5, at least 5.5, at least 6, at least 6.5, at least 7, etc.), and can be characterized as having a cLogP of, for example, 3 to 10, 4 to 12, 4.5 to 9, 5 to 11, 5.5 to 10.5, 6 to 14, 6.5 to 13, etc. Preferably, the terminal X group (i.e., the L furthest from the C(O) terminus) is A The X group in L is not C(=O) or SO. A The total number of non-hydrogen atoms in is between 15 and 50, e.g., 18, 20, 25, 30, 35, 40, 45, or 50, or any range between the recited values. In some preferred embodiments, none of the X groups is a ring structure. In some preferred embodiments, one instance of X is a ring structure, preferably a 3- to 10-membered ring structure. For example, in some embodiments, one instance of X is triazole, and the remaining X groups are each independently selected from C—R, —C(R)═C(R)—, JPEG2025502110000301.jpg12170 or O, and R at each occurrence is independently hydrogen or C alkyl. In some embodiments, no X group is a ring structure, and each X is independently CR, -C(R)=C(R)-, JPEG2025502110000302.jpg11170 or O, and R at each occurrence is independently hydrogen or C alkyl (preferably methyl). In some embodiments, all instances of X are CR, and R at each occurrence is independently hydrogen or C alkyl (preferably methyl). In some embodiments, up to six (e.g., 1, 2, 3, 4, 5, or 6) instances of X may be O. In some embodiments, one or two instances of X are O and all other instances of X are CR, where R at each occurrence is independently hydrogen or C alkyl (preferably methyl). In some embodiments, one or two instances of X are O, one X is triazole, and all other instances of X are CR, where R at each occurrence is independently hydrogen or C alkyl (preferably methyl). In some embodiments, R is hydrogen.

[0130] In some preferred embodiments, T of formula II-1-A (e.g., II-1-A-1), II-B-2, or II-B-3 A teeth JPEG2025502110000303.jpg26170. G in each occurrence 1 are independently hydrogen, halogen, or optionally substituted C 1-4 Alkyl or optionally substituted C 1-4 Heteroalkyl (optionally substituted C 1-4 alkoxy, etc.) or two gem-G 1 The groups may be bonded to form =O, =NH, or =N(C 1-4 alkyl), or two or more G 1 The groups can be linked to form a ring structure. The integer r is 1 to 10, such as 1 or 2. G in each occurrence 2 are independently hydrogen, G 10 , C(O)-G 10 , SO2G 10 , C(O)-NH-G 10 , or SO2NHG 10, C(O)-OG 10 , or SO2OG 10 At each occurrence, G 10 are independently optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl or an optionally substituted 3- to 10-membered ring structure that can be carbocyclic, heterocyclic, aromatic, heteroaromatic, or a combination thereof. The fragments are (i) a CG group next to an NH group. 1 G 1 If the group is not C(=O), the corresponding compound JPEG2025502110000304.jpg26170 has a cLogP less than 1, preferably less than 0 (e.g., less than -1, less than -2, less than -3, less than -3.5, less than -4, or less), or (ii) a CG next to NH 1 G 1 When the group is C(=O), the corresponding compound JPEG2025502110000305.jpg24170 is further characterized by having a cLogP less than 1, preferably less than 0 (e.g., less than -1, less than -2, less than -3, less than -3.5, less than -4, or even less).

[0131] In some preferred embodiments, T of formula II-1-A (e.g., II-1-A-1), II-B-2, or II-B-3 A teeth, JPEG2025502110000306.jpg21170. In some embodiments, G 2 Examples of one or both of JPEG2025502110000307.jpg13170, where n is an integer of 0 to 100, preferably 0 to 10 (for example, 0 to 4, 1 to 5, or 2 to 6). 1 are CH2, C(O), SO, SO2, CH(C 1-4 alkyl), C(C 1-4 Alkyl)(C 1-4 alkyl) or a 3- to 10-membered ring structure. 2are independently CH2, O, S, SO, SO2, C(O), CH(C 1-4 alkyl), C(C 1-4 Alkyl)(C 1-4 alkyl), NH, N(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 alkyl)] + Or a 3- to 10-membered ring structure. 3 is H, C 1-4 Alkyl, OH, SO3H, COOH, NH2, NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, SO2NH2, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), or SO2N(C 1-4 Alkyl)(C 1-4 C 1-4 Each alkyl is independently selected and optionally includes, for example, 1 to 3 G as defined herein. 20 In some embodiments, Z is substituted with a group. 2 In some embodiments, none of Z 2 One or more examples of the formula include 3-10 membered ring structures such as nitrogen-containing rings, e.g., JPEG2025502110000308.jpg23170. In some embodiments, Z 3 Directly connect to Z 2 is a 3- to 10-membered ring structure such as a nitrogen-containing ring, for example, JPEG2025502110000309.jpg22170, etc. Preferably, Z 2 Up to two instances of G are 3- to 10-membered ring structures. 2 are independently hydrogen, optionally substituted C 1-6Alkyl or optionally substituted C 1-6 For example, when substituted, C 1-6 Alkyl is OH, NH2, oxo (=O), NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, C(O)OH, SO2NH2, SO3H, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), and SO2N(C 1-4 Alkyl)(C 1-4 C can be substituted with 1 to 3 substituents independently selected from alkyl. 1-4 Each alkyl is independently selected and optionally includes, for example, 1 to 3 G as defined herein. 20 Each occurrence of G herein is substituted with a group. 20 The groups are OH, NH2, oxo (=O), NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, C(O)OH, SO2NH2, SO3H, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), SO2N(C 1-4 Alkyl)(C 1-4 alkyl), or a 3- to 10-membered ring structure. 1-4 Each alkyl is independently selected and optionally includes, for example, 1 to 3 G as defined herein. 21 Each occurrence of G herein is substituted with a group. 21The groups are OH, NH2, oxo (=O), NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, C(O)OH, SO2NH2, SO3H, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), SO2N(C 1-4 Alkyl)(C 1-4 alkyl) or a 3- to 10-membered ring structure. 2 One or more examples of 1-4 alkylene)-NH2 or CONH-(C 1-4 alkylene)-[N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + C optionally substituted with an amide derivative such as 1-4 For example, in some embodiments, G 2 One or two examples of -(C 1-4 alkylene)-COOH, and G 2 Any remaining instance of C 1-4 In some embodiments, G is alkyl. 2 One or two examples of JPEG2025502110000310.jpg19170 etc. -(C 1-4 alkylene)-CONH-(C 1-4 alkylene)-NH2, and G 2 Any remaining instance of C 1-4 In some embodiments, G is alkyl. 2 One or two examples of JPEG2025502110000311.jpg18170 etc. -(C 1-4 alkylene)-CONH-(C1-4 alkylene)-[N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + and G 2 Any remaining instance of C 1-4 In some embodiments, T A teeth, JPEG2025502110000312.jpg47170. In some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000313.jpg42170. In some embodiments, T A teeth, JPEG2025502110000314.jpg39170. In some embodiments, T A teeth, JPEG2025502110000315.jpg28170. In some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000316.jpg32170JPEG2025502110000317.jpg34170. In some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), For example, in some embodiments, T A teeth JPEG2025502110000319.jpg49170. In some embodiments, T A teeth JPEG2025502110000320.jpg33170. In some embodiments, T A teeth JPEG2025502110000321.jpg40170. In some embodiments, TA teeth JPEG2025502110000322.jpg24170. In some embodiments, T A teeth JPEG2025502110000323.jpg25170. In some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000324.jpg23170. In some embodiments, T A teeth JPEG2025502110000325.jpg23170. In some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000326.jpg23170. In some embodiments, T A teeth It could also be JPEG2025502110000327.jpg19170.

[0132] In some preferred embodiments, T of formula II-1-A (e.g., II-1-A-1), II-B-2, or II-B-3 A teeth, JPEG2025502110000328.jpg24170 can be characterized as having the structure G 1 are independently hydrogen, halogen, or optionally substituted C 1-4 Alkyl or optionally substituted C 1-4 Heteroalkyl (optionally substituted C 1-4 alkoxy, etc.) or two gem-G 1 The groups may be bonded to form =O, =NH, or =N(C 1-4 alkyl), or two or more G 1 The groups can be linked to form a ring structure. The integer r is 1 to 10, such as 1 or 2. G in each occurrence4 are independently hydrogen or G 10 At each occurrence, G 10 are independently optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl or an optionally substituted 3- to 10-membered ring structure that can be carbocyclic, heterocyclic, aromatic, heteroaromatic, or a combination thereof. JPEG2025502110000329.jpg23170 is (i) the CG next to NH 1 G 1 If the group is not C(=O), the corresponding compound JPEG2025502110000330.jpg26170 has a cLogP of less than 1, preferably less than 0 (e.g., less than −1, less than −2, less than −3, less than −3.5, less than −4, or less), or (ii) a CG next to NH 1 G 1 When the group is C(=O), the corresponding compound JPEG2025502110000331.jpg22170 is characterized as having a cLogP of less than 1, preferably less than 0 (e.g., less than -1, less than -2, less than -3, less than -3.5, less than -4, or even less).

[0133] In some preferred embodiments, T of formula II-1-A (e.g., II-1-A-1), II-B-2, or II-B-3 A teeth, JPEG2025502110000332.jpg21170. In some embodiments, G 4 One or more instances of JPEG2025502110000333.jpg15170, where n is an integer of 0 to 100, preferably 0 to 10 (for example, 0 to 4, 1 to 5, or 2 to 6). 1 are CH2, C(O), SO2, CH(C 1-4 alkyl), or C(C 1-4 Alkyl)(C 1-4 (alkyl). Z in each occurrence2 are independently CH2, O, S, SO, SO2, C(O), CH(C 1-4 alkyl), C(C 1-4 Alkyl)(C 1-4 alkyl), NH, N(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 alkyl)] + Or a 3- to 10-membered ring structure. 3 is H, C 1-4 Alkyl, OH, SO3H, COOH, NH2, NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, SO2NH2, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), or SO2N(C 1-4 Alkyl)(C 1-4 C 1-4 Each alkyl is independently selected and optionally includes, for example, 1 to 3 G as defined herein. 20 Preferably, Z 2 Up to two instances of Z are 3- to 10-membered ring structures. 2 In some embodiments, none of Z 2 One example of is a 3-10 membered ring structure such as a nitrogen-containing ring, e.g., JPEG2025502110000334.jpg24170. In some embodiments, 4 are independently hydrogen, optionally substituted C 1-6 Alkyl or optionally substituted C 1-6 For example, when substituted, C 1-6 Alkyl is OH, NH2, oxo (=O), NH(C 1-4 alkyl), N(C1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, C(O)OH, SO2NH2, SO3H, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), and SO2N(C 1-4 Alkyl)(C 1-4 C can be substituted with 1 to 3 substituents independently selected from alkyl. 1-4 Each alkyl is independently selected and optionally includes, for example, 1 to 3 G as defined herein. 20 Each occurrence of G herein is substituted with a group. 20 The groups are OH, NH2, oxo (=O), NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, C(O)OH, SO2NH2, SO3H, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), SO2N(C 1-4 Alkyl)(C 1-4 alkyl), or a 3- to 10-membered ring structure. 1-4 Each alkyl is independently selected and optionally includes, for example, 1 to 3 G as defined herein. 21 Each occurrence of G herein is substituted with a group. 21 The groups are OH, NH2, oxo (=O), NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4Alkyl)(C 1-4 alkyl)] + , C(O)NH2, C(O)OH, SO2NH2, SO3H, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), SO2N(C 1-4 Alkyl)(C 1-4 alkyl) or a 3- to 10-membered ring structure. 4 One or more examples of C, such as methyl 1-4 In some embodiments, G is alkyl. 4 One or more examples of 1-4 alkylene)-NH2 or CONH-(C 1-4 alkylene)-[N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + C optionally substituted with an amide derivative such as 1-4 For example, in some embodiments, G 4 One or two examples of -(C 1-4 alkylene)-COOH, and G 4 Any remaining instance of C 1-4 In some embodiments, G is alkyl. 4 One or two examples of JPEG2025502110000335.jpg19170 etc. -(C 1-4 alkylene)-CONH-(C 1-4 alkylene)-NH2, and G 4 Any remaining instance of C 1-4 In some embodiments, G is alkyl. 4 One or two examples of JPEG2025502110000336.jpg17170 etc. -(C 1-4 alkylene)-CONH-(C 1-4 alkylene)-[N(C 1-4 Alkyl)(C 1-4Alkyl)(C 1-4 alkyl)] + and G 4 Any remaining instance of C 1-4 In some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000337.jpg42170JPEG2025502110000338.jpg45170. In some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000339.jpg39170. In some embodiments, the TA is optionally charge balanced with a counterion (e.g., as described herein). JPEG2025502110000340.jpg27170. In some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), For example, in some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000342.jpg48170. In some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000343.jpg33170. In some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000344.jpg24170. In some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000345.jpg25170. In some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000346.jpg32170. In some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000347.jpg25170. In some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000348.jpg24170. In some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000349.jpg31170. In some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000350.jpg16170. In some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000351.jpg31170. In some embodiments, T A teeth It could also be JPEG2025502110000352.jpg16170.

[0134] In some preferred embodiments, the present disclosure also provides compounds of formula II-4-A or II-5-A, or pharmaceutically acceptable salts or esters thereof: JPEG2025502110000353.jpg107170In formula, X, m1, L N , G 1 , G2 , G 4 , r, and JPEG2025502110000354.jpg9170 is defined herein and includes any of the preferred ones described herein with respect to Formula II (e.g., II-1, II-4, II-5, II-1-A, II-1-A-1, etc.), in any combination. For example, in some embodiments, L N teeth, Branched or linear C, such as JPEG2025502110000355.jpg22170 (X is shown to indicate the linkage direction) 1-6 In some embodiments, L is alkyl. N In some embodiments, X in each occurrence is independently selected from the group consisting of CR, -C(R)=C(R)-, JPEG2025502110000356.jpg11170SiR2, C(O), O, NR, S, SO2, or a ring structure, preferably a 3- to 10-membered ring structure. R in each occurrence is independently hydrogen, halogen, optionally substituted C 1-4 Alkyl or optionally substituted C 1-4 Alkoxy, typically hydrogen or C 1-4 Preferably, (X) is alkyl. m1 The terminal X group of the moiety is not C(=O) or SO2. In some embodiments, the integer m1 may be 12 to 50, e.g., 14 to 50, 16 to 30, etc. Preferably, (X) m1 The total number of non-hydrogen atoms in the moiety is between 15 and 50, e.g., 18, 20, 25, 30, 35, 40, 45, or 50, or any range between the recited values. In some preferred embodiments, none of the X groups is a ring structure. In some preferred embodiments, one instance of X is a ring structure, preferably a 3- to 10-membered ring structure. For example, in some embodiments, one instance of X is triazole, and the remaining X groups are each independently selected from the group consisting of -CR2, -C(R)=C(R)- ... JPEG2025502110000357.jpg10170 or O, more preferably CR2 or O, and R at each occurrence is independently hydrogen or C1-4 alkyl. In some embodiments, no X group is a ring structure, and each X is independently CR2, -C(R)=C(R)-, JPEG2025502110000358.jpg10170 or O, more preferably CR2 or O, where R at each occurrence is independently hydrogen or C1-4 alkyl. In some embodiments, up to six (e.g., 1, 2, 3, 4, 5, or 6) instances of X may be O. In some embodiments, all instances of X are CR2, and R at each occurrence is independently hydrogen or C1-4 alkyl (preferably methyl). In some embodiments, one or two instances of X are O, and all other instances of X are CR2, where R at each occurrence is independently hydrogen or C1-4 alkyl (preferably methyl). In some embodiments, one or two instances of X are O, one X is triazole, and all other instances of X are CR2, where R at each occurrence is independently hydrogen or C1-4 alkyl (preferably methyl). In some embodiments, R is hydrogen. G 1 , G 2 , G 4 , r, and The definition and preferred definition of JPEG2025502110000359.jpg10170 are also described herein and include any of their corresponding definitions set forth for any of the compounds listed in Table 1 herein or any of the compounds according to Examples 1 to 221. Formula III and III-B

[0135] In some embodiments, the present disclosure provides a compound of formula III or III-B, or a pharmaceutically acceptable salt or ester thereof: JPEG2025502110000360.jpg43170JPEG2025502110000361.jpg47170In the formula, Y is CH, CR A , or N, Z is O, S, NH, or N(C 1-4 alkyl), R 11 and R 12 are each independently hydrogen or C 1-4 is alkyl, Ring A is an optionally substituted 4- to 12-membered nitrogen-containing ring; Ring B is an optionally substituted monocyclic heteroaryl or bicyclic aryl or heteroaryl ring such as a benzofuran ring; L N is empty (null), an arbitrarily substituted C 1-6 Alkylene or optionally substituted C having 1 to 3 heteroatoms 1-6 is heteroalkylene, L 10 is alkylene (e.g., C 1-6 alkylene), halogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 1-6 Alkoxy, optionally substituted C 3-6 optionally substituted with 1 to 3 substituents independently selected from cycloalkoxy, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two substituents joined to form an optionally substituted ring system; R at each occurrence A are independently selected from halogen, CN, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 1-6 Alkoxy or optionally substituted C 3-6 cycloalkoxy or two R A are linked to form an optionally substituted ring structure, and p1 is 0, 1, or 2; R at each occurrence Care independently selected from halogen, CN, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 1-6 Alkoxy or optionally substituted C 3-6 cycloalkoxy or two R C are linked to form an optionally substituted ring structure, and p2 is 0, 1, 2, or 3; R 18 is an optionally substituted phenyl or an optionally substituted heteroaryl; During the ceremony, q is an integer of 1 to 10, preferably 1 or 2; T A is a hydrophilic group, and L A is a linker. In a preferred embodiment, T A L A wherein (1) if the terminal atom is N of a basic amine group, the corresponding compound T A -(C(O)-CH3) q has a cLogP less than 1, -C(O)-CH3 is bonded to the terminal N atom, and (2) if the terminal atom is the C of the C(O) group, the corresponding compound T A -(OH) q has a cLogP less than 1, -OH is bonded to the terminal C atom, and (3) if the terminal atom is S in the SO2 group, T A -(OH) q has a cLogP less than 1, -OH is bonded to the terminal S atom, or (4) if (1) to (3) do not apply, T A -H q has a cLogP less than 1, L A L A The maximum length between the two terminal atoms of is at least -(CH2) 10 a linker characterized in that the maximum length between the two terminal carbon atoms of A Only one terminal atom of AC of C(O) or S of SO2 group bonded to the corresponding compound HL A -OH has a cLogP of at least 3, -OH is bonded to a terminal C(O) or SO2 group, or (2) L A Neither terminal atom of the compound is C in C(O) or S in the SO2 group, and the corresponding compound HL A -H has a cLogP of at least 3.

[0136] In some embodiments, the compound has a structure according to Formula III.

[0137] In some embodiments, the compound has a structure according to Formula III-B.

[0138] In some embodiments according to Formula III or III-B, L N is null. That is, L A is directly linked to the amide nitrogen atom shown in formula III or III-B. For clarity, for purposes of this specification, L as null N In such an embodiment, the definition of L A is the L described herein N This should not be construed as meaning that the fragment cannot contain fragments that fit one or more of the definitions of L. N If is defined as empty (null), then the variable L A L N In an embodiment where L is not empty (null), N -L A can have any of the definitions described herein for

[0139] In some embodiments according to Formula III or III-B, L N is a branched or linear C 1-6 Alkylene, for example JPEG2025502110000362.jpg24170(L Ais shown to indicate the direction of linkage. In some embodiments according to Formula III or III-B, L N teeth JPEG2025502110000363.jpg25170(L A is shown to indicate the direction of linkage), where G A are independently hydrogen or optionally substituted C 1-4 Alkyl or two G A are linked to form a 3- to 6-membered ring, such as a cyclopropyl or cyclobutyl ring. A is methyl.

[0140] In some embodiments, q of Formula III or III-B is 1, and the compound of Formula III can be characterized as having the formula III-1 or III-B-1: JPEG2025502110000364.jpg89170In the formula, variable T A , L A , L N , L 10 , R 11 , R 12 , R 18 , R A , R C , rings A, Y, Z, p1, and p2 are as defined herein, including any of the preferred ones described herein, in any combination. Linker L A

[0141] Similar to Formulas I and II discussed herein, one factor that can determine whether a compound of Formula II or II-B can be a potent GPR40 agonist is the molecular weight of the linker (e.g., L), rather than the exact chemical structure of the linker. A ) is the length of the linker. As shown in the Examples section of the specification, if the linker length is below a certain threshold, the EC50 value can be significantly increased. Therefore, the inventors have proposed a method for determining the length of the linker L in Formula III or III-B, similar to that described above in relation to Formula I. AThe maximum length between the two terminal atoms of the alkylene chain -(CH2) 10 - should be the maximum length between the two terminal carbon atoms of L. A The longest chain length is the alkylene chain -(CH2) 10 The maximum chain length of the linker L discussed above for Formula I or II should be equal to or greater than the maximum chain length of A The meaning and determination of the maximum distance between the two terminal non-hydrogen atoms of also applies to Formula III. A L A The maximum length between the two terminal atoms of is at least -(CH2) 12 - the maximum length between the two terminal carbon atoms, preferably at least -(CH2) 14 -, more preferably at least -(CH2) 16 In some embodiments, L A L A The maximum length between the two terminal atoms of (i)-(CH2) 12 - and (ii) -(CH2) 50 - the maximum length between the two terminal carbon atoms.

[0142] In some embodiments, in Formula III (e.g., Formula III-1) or III-B (e.g., Formula III-B-1), L A is (X) m where X in each occurrence is independently CR, C(=O), -C(R)=C(R)-, JPEG2025502110000365.jpg12170SiR2, O, S, SO2, NR, [NR2] + or a ring structure, preferably a 3- to 10-membered ring structure. R in each occurrence is independently hydrogen, halogen, optionally substituted C 1-4 Alkyl or optionally substituted C 1-4 Alkoxy, typically hydrogen or C 1-4The integer m is at least 10, e.g., at least 12, at least 14, at least 16, at least 18, at least 20, at least 50, e.g., 12-50, 16-50, etc. One terminal X group is L N Because it is bonded to (L N is null, it should be understood that a covalent bond is formed with the amide nitrogen atom of Formula III or III-B, the terminal X group of which is preferably CR2 or a ring structure, preferably a 3- to 10-membered ring structure as described herein, more preferably CR2, such as CH2. Thus, in any of the embodiments described herein with reference to Formula III or III-B, unless otherwise specified or contrary to context, L N The terminal X group (L N is null, it should be understood that a covalent bond is formed with the amide nitrogen atom of Formula III (e.g., Formula III-1) or III-B (e.g., Formula III-B-1). L of Formula III or III-B (e.g., Formula III-B-1) may be CR, such as CH. A Suitable X groups for L also include any of those described and preferred herein in relation to formula I or II. A In the formula, 0, 1, or 2 instances of X are ring structures, preferably 3- to 10-membered ring structures (C such as cyclopropyl). 3-6 In some embodiments, two consecutive X's may be -C(O)O- or -C(O)NR-. In some embodiments, one instance of X may be a cyclopropane, cyclobutane, or bicyclobutane [1.1] ring. In some embodiments, one instance of X may be a 5- or 6-membered heteroaryl, such as a triazole ring. In some embodiments, one instance of X may be a cyclopentane, cyclohexane, or cycloheptane ring. Typically, one of the terminal X groups is connected to T via a carbon atom. A L AThe total number of non-hydrogen atoms may typically be between 10 and 100, for example, 12 to 30, 14 to 50, 16 to 50, 18 to 100, etc.

[0143] Another factor that can determine whether a compound of formula III or III-B can be a potent GPR40 agonist is the molecular weight of the linker (e.g., L) rather than the exact chemical structure of the linker. A ) is hydrophobic. Generally, L A should be a hydrophobic moiety. In some embodiments, L A Only one terminal atom of L is C in C(O) or S in SO group. A The hydrophobicity of the corresponding compound HL is typically A The -OH has a cLogP of at least 3, e.g., between 3 and 15, preferably at least 4 (e.g., at least 4.5, at least 5, at least 5.5, at least 6, at least 6.5, at least 7, etc.), and can be characterized as having a cLogP of 3 to 10, 4 to 12, 4.5 to 9, 5 to 11, 5.5 to 10.5, 6 to 14, 6.5 to 13, etc., where the -OH is attached to a terminal C(O) or SO2 group. A Neither of the two terminal atoms of L is a C of a C(O) or an S of a SO group. A The hydrophobicity of the corresponding compound HL A -H has a cLogP of at least 3, e.g., between 3 and 15, preferably at least 4 (e.g., at least 4.5, at least 5, at least 5.5, at least 6, at least 6.5, at least 7, etc.), and can be characterized as having a cLogP of, for example, 3 to 10, 4 to 12, 4.5 to 9, 5 to 11, 5.5 to 10.5, 6 to 14, 6.5 to 13, etc.

[0144] For example, in some embodiments, L A is (X) m-1 -C(O)-, where the C(O) terminus is T A X in each occurrence is independently CR2, C(=O), -C(R)=C(R)-, JPEG2025502110000366.jpg11170SiR2, O, S, SO2, NR, [NR2] + or a ring structure, preferably a 3- to 10-membered ring structure, provided that the terminal X group (i.e., the L furthest from the (O) terminal) A X in each occurrence is not C(O) or SO2. R is independently hydrogen, halogen, optionally substituted C 1-4 Alkyl or optionally substituted C 1-4 Alkoxy, typically hydrogen or C 1-4 The integer m is at least 10, for example, at least 12, at least 14, at least 16, at least 18, at least 20, or at least 50, for example, 12 to 50, 16 to 50, etc. -(X) m-1 The hydrophobicity of -C(O)- is similar to that of the corresponding compound H-(X) m-1 -COOH has a cLogP of at least 3, for example, between 3 and 15, preferably at least 4 (e.g., at least 4.5, at least 5, at least 5.5, at least 6, at least 6.5, at least 7, etc.), for example, 3 to 10, 4 to 12, 4.5 to 9, 5 to 11, 5.5 to 10.5, 6 to 14, 6.5 to 13, etc. "m-1" should be understood as the integer m minus 1 and should not be mistaken for another designated variable.

[0145] In some embodiments, L A (X) m wherein X in each occurrence is independently CR, C(=O), -C(R)=C(R)-, JPEG2025502110000367.jpg10170SiR2, O, S, SO2, NR, [NR2] + or a ring structure, preferably a 3- to 10-membered ring structure, provided that none of the terminal X groups is C(O) or SO2. R in each occurrence is independently hydrogen, halogen, optionally substituted C 1-4 Alkyl or optionally substituted C 1-4 Alkoxy, typically hydrogen or C 1-4The integer m is at least 10, for example, at least 12, at least 14, at least 16, at least 18, at least 20, at least 50, for example, 12 to 50, 16 to 50, etc., and the corresponding compound H-(X) m -H should have a cLogP of at least 3, e.g., between 3 and 15, preferably at least 4 (e.g., at least 4.5, at least 5, at least 5.5, at least 6, at least 6.5, at least 7, etc.), e.g., 3 to 10, 4 to 12, 4.5 to 9, 5 to 11, 5.5 to 10.5, 6 to 14, 6.5 to 13, etc.

[0146] In some embodiments, L A -X 12-30 -(e.g., -X 14 -, -X 16 -, -X 18 -, -X 20 -, -X 24 -, -X 14-30 -, -X 16-30 -, -X 18-30 -, etc.), where X in each occurrence is independently selected from C—R, C(═O), —C(R)═C(R)—, JPEG2025502110000368.jpg11170SiR2, O, S, SO2, NR, [NR2] + or a ring structure, preferably a 3- to 10-membered ring structure, provided that none of the terminal X groups is C(O) or SO2. R in each occurrence is independently hydrogen, halogen, optionally substituted C 1-4 Alkyl or optionally substituted C 1-4 Alkoxy, typically hydrogen or C 1-4 It is alkyl. A The hydrophobicity of the corresponding compound HL A-H may be characterized as having a cLogP of at least 3, e.g., between 3 and 15, preferably at least 4 (e.g., at least 4.5, at least 5, at least 5.5, at least 6, at least 6.5, at least 7, etc.), e.g., 3 to 10, 4 to 12, 4.5 to 9, 5 to 11, 5.5 to 10.5, 6 to 14, 6.5 to 13, etc. In some embodiments, L A The total number of non-hydrogen atoms in is between 12 and 100, e.g., 12, 14, 16, 18, 20, 24, 30, 40, 50, 100, or any range between the recited values, e.g., 12-30, 14-50, 16-50, 18-100, etc. In some embodiments, two consecutive Xs can represent -C(O)O- or -C(O)NR-. In some embodiments, one or more (e.g., one or two) instances of X can be a ring structure selected from cyclopropane, cyclobutane, bicyclobutane [1.1], cyclopentane, cyclohexane, or cycloheptane. In some embodiments, one or more (e.g., one) instances of X can be a ring structure selected from phenyl, or a 5- or 6-membered heteroaryl, such as triazole. In some embodiments, R is hydrogen.

[0147] In some embodiments, L A -X 12-30 -C(O)-, where C(O) is T A X in each occurrence is independently CR2, C(=O), -C(R)=C(R)-, JPEG2025502110000369.jpg11170SiR2, O, S, SO2, NR, [NR2] + or a ring structure, preferably a 3- to 10-membered ring structure, provided that the terminal X group (i.e., the L furthest from the C(O) terminal) A The X group in the formula (I) is CR2 or a ring structure, preferably a 3- to 10-membered ring structure. R in each occurrence is independently hydrogen, halogen, optionally substituted C 1-4 Alkyl or optionally substituted C 1-4 Alkoxy, typically hydrogen or C 1-4 It is alkyl.A The hydrophobicity of the corresponding compound HX 12-30 -C(O)-OH may be characterized as having a cLogP of at least 3, e.g., between 3 and 15, preferably at least 4 (e.g., at least 4.5, at least 5, at least 5.5, at least 6, at least 6.5, at least 7, etc.), e.g., 3 to 10, 4 to 12, 4.5 to 9, 5 to 11, 5.5 to 10.5, 6 to 14, 6.5 to 13, etc. In some embodiments, L A The total number of non-hydrogen atoms in is between 14 and 100, e.g., 14, 16, 18, 20, 24, 30, 40, 50, 100, or any range between the recited values, e.g., 14-30, 14-50, 16-50, 18-100, etc. In some embodiments, two consecutive Xs can represent -C(O)O- or -C(O)NR-. In some embodiments, one or more (e.g., one or two) instances of X can be a ring structure selected from cyclopropane, cyclobutane, bicyclobutane [1.1], cyclopentane, cyclohexane, or cycloheptane. In some embodiments, one or more (e.g., one) instances of X can be a ring structure selected from phenyl, or a 5- or 6-membered heteroaryl such as triazole. In some embodiments, R is hydrogen.

[0148] In some preferred embodiments, L A Ha-C 12-30 Alkylene- or -C 12-30 alkylene-C(O)-, where -C 12-30 The alkylene- is optionally substituted, and the optional substituents can be optionally joined together to form a double bond, a triple bond, or a ring structure (typically a 3- to 10-membered ring structure). 12-30 The terminal carbon atom of alkylene- is not substituted with oxo (=O). A The maximum chain length of is at least -(CH2) 12 -, e.g., at least -(CH2) 14 - maximum chain length of at least -(CH2) 16 - maximum chain length of at least -(CH2) 18- is the longest chain length. A The hydrophobicity of the corresponding compound HC 12-30 Alkylene-H or HC 12-30 The alkylene -C(O)-OH may be characterized as having a cLogP of at least 3, e.g., between 3 and 15, preferably at least 4 (e.g., at least 4.5, at least 5, at least 5.5, at least 6, at least 6.5, at least 7, etc.), e.g., 3 to 10, 4 to 12, 4.5 to 9, 5 to 11, 5.5 to 10.5, 6 to 14, 6.5 to 13, etc. In some embodiments, L A The total number of non-hydrogen atoms in L is between 14 and 100, e.g., 14, 16, 18, 20, 24, 30, 40, 50, 100, or any range between the listed values, e.g., 14-30, 14-50, 16-50, 18-100, etc. A is a linear or branched chain C 12-30 Unsubstituted -C such as alkylene 12-30 In some embodiments, L A is unsubstituted -C 12-30 alkylene-C(O)-, where C 12-30 Alkylene may be linear or branched. In some preferred embodiments, L A Ha-C 12-30 Alkylene- or -C 12-30 alkylene-C(O)-, where C 12-30 Alkylene is a straight-chain unsubstituted -C 12-30 It is alkylene.

[0149] In some preferred embodiments, L of Formula III (e.g., Formula III-1) or III-B (e.g., Formula III-B-1) A or L N -L A teeth, You can select from the structure JPEG2025502110000370.jpg18170, where C 10-26 Alkylene is optionally substituted and each occurrence of G A are independently hydrogen or optionally substituted C 1-4Alkyl or two G A are linked to form a 3- to 6-membered ring, such as a cyclopropyl or cyclobutyl ring. In some preferred embodiments, G A is methyl. In some embodiments, C 10-26 Alkylene is unsubstituted, for example, a straight or branched chain C 10-26 In some preferred embodiments, C 10-26 Alkylene is a linear unsubstituted C 10-26 It is alkylene.

[0150] In some embodiments, L A is a 12- to 30-membered heteroalkylene or -(12- to 30-membered heteroalkylene)-C(O)-, where the 12- to 30-membered heteroalkylene is optionally substituted and contains 1 to 6 heteroatoms independently selected from O, N, and S. The sulfur atom, if present, is optionally oxidized. The optional substituents can optionally be joined together to form a double bond, a triple bond, or a ring structure (typically a 3- to 10-membered ring structure). L N The terminal atom (L) of 12-30 membered heteroalkylene that forms a covalent bond with N When L is null, it should be understood that a covalent bond is formed with the amide nitrogen atom of formula III or III-B, and L is the carbon atom of a non-carbonyl group. A The maximum chain length of is at least -(CH2) 12 -, e.g., at least -(CH2) 14 - maximum chain length of at least -(CH2) 16 - maximum chain length of at least -(CH2) 18 - is the longest chain length. AThe hydrophobicity of L can be characterized by the corresponding compound H--(12-30 membered heteroalkylene)-H or H--(12-30 membered heteroalkylene)-C(O)-OH having a cLogP of at least 3, e.g., between 3 and 15, preferably at least 4 (e.g., at least 4.5, at least 5, at least 5.5, at least 6, at least 6.5, at least 7, etc.), e.g., 3-10, 4-12, 4.5-9, 5-11, 5.5-10.5, 6-14, 6.5-13, etc. In some embodiments, L A The total number of non-hydrogen atoms in L is between 14 and 100, e.g., 14, 16, 18, 20, 24, 30, 40, 50, 100, or any range between the listed values, e.g., 14 to 30, 14 to 50, 16 to 50, 18 to 100, etc. A is unsubstituted 12- to 30-membered heteroalkylene, for example, straight-chain or branched-chain 12- to 30-membered heteroalkylene. In some embodiments, L A is an unsubstituted -(12- to 30-membered heteroalkylene)-C(O)-, where the 12- to 30-membered heteroalkylene may be linear or branched. In some preferred embodiments, L A is a 12- to 30-membered heteroalkylene or -(12- to 30-membered heteroalkylene)-C(O)-, wherein the 12- to 30-membered heteroalkylene is linear and unsubstituted. In some embodiments, the 12- to 30-membered heteroalkylene contains 1, 2, 3, 4, or 5 heteroatoms independently selected from O, S, and N.

[0151] In some preferred embodiments, L A teeth, It can be characterized as having the structure according to JPEG2025502110000371.jpg34170, where the carbonyl is T A It is directly bonded to L A1 and L A2 each independently represents a bond, an optionally substituted -C 1-30 alkylene- or optionally substituted -C containing 1 to 6 heteroatoms independently selected from O, N, and S;1-30 Heteroalkylene-. The sulfur atom, if present, is optionally oxidized. The optional substituents can optionally be joined together to form a double bond, a triple bond, or a ring structure. T A Forms a covalent bond with L A1 or L A2 The terminal atom of is not C in C(O) or S in SO2 group, but L N Forms a covalent bond with L A1 or L A2 The terminal atom (L N When L is null, it should be understood that a covalent bond is formed with the amide nitrogen atom of formula III or III-B, and L is the carbon atom of a non-carbonyl group. A The maximum chain length of is at least -(CH2) 12 -, e.g., at least -(CH2) 14 - maximum chain length of at least -(CH2) 16 - maximum chain length of at least -(CH2) 18 - is the longest chain length. A The hydrophobicity of the corresponding compound JPEG2025502110000372.jpg32170 can be characterized as having a cLogP of at least 3, e.g., between 3 and 15, preferably at least 4 (e.g., at least 4.5, at least 5, at least 5.5, at least 6, at least 6.5, at least 7, etc.), e.g., 3 to 10, 4 to 12, 4.5 to 9, 5 to 11, 5.5 to 10.5, 6 to 14, 6.5 to 13, etc. In some embodiments, L A The total number of non-hydrogen atoms in L is between 14 and 100, e.g., 14, 16, 18, 20, 24, 30, 40, 50, 100, or any range between the listed values, e.g., 14 to 30, 14 to 50, 16 to 50, 18 to 100, etc. A1 is C 1-20 Alkylene, for example, straight chain alkylene, (CH2) 1-20 In some embodiments, L A1 is a C with 1 to 3 oxygen atoms 1-10 In some embodiments, L is heteroalkylene.A2 is a bond. In some embodiments, L A2 is C 1-20 Alkylene, for example, straight chain alkylene, (CH2) 1-20 In some embodiments, L A2 is -O-(C 1-10 C with 1 to 3 oxygen atoms, such as alkylene)- 1-10 It is heteroalkylene.

[0152] In some embodiments, L A teeth, JPEG2025502110000373.jpg31170, where L A1 and L A2 are each independently a bond, -C 1-30 alkylene- or -C containing 1 to 6 heteroatoms independently selected from O, N, and S; 1-30 heteroalkylene-, and the sulfur atom, if present, is optionally oxidized. A Forms a covalent bond with L A1 or L A2 The terminal atom of is not C in C(O) or S in SO2 group, but L N Forms a covalent bond with L A1 or L A2 The terminal atom (L N It should be understood that when L is null, a covalent bond is formed with the amide nitrogen atom of formula III or III-B, and L is the carbon atom of a non-carbonyl group. A The total number of non-hydrogen atoms in L is between 15 and 50, e.g., 18, 20, 25, 30, 35, 40, 45, or 50, or any range between the listed values. A The maximum chain length of is at least -(CH2) 12 -, e.g., at least -(CH2) 14 - maximum chain length of at least -(CH2) 16 - maximum chain length of at least -(CH2) 18 - is the longest chain length. A The hydrophobicity of the corresponding compound HL A-H has a cLogP of at least 3, for example, between 3 and 15, preferably at least 4 (e.g., at least 4.5, at least 5, at least 5.5, at least 6, at least 6.5, at least 7, etc.), and can be characterized as having a cLogP of, for example, 3 to 10, 4 to 12, 4.5 to 9, 5 to 11, 5.5 to 10.5, 6 to 14, 6.5 to 13, etc. Preferably, L A1 is not a bond. However, L A1 is a bond, the triazole nitrogen atom is T A In some embodiments, L A2 is a bond. In some embodiments, L A1 is C 1-20 Alkylene, for example, straight chain alkylene, (CH2) 1-20 In some embodiments, L A1 is a C with 1 to 3 oxygen atoms 1-10 In some embodiments, L is heteroalkylene. A2 is C 1-20 Alkylene, for example, straight chain alkylene, (CH2) 1-20 In some embodiments, L A2 is -O-(C 1-10 C with 1 to 3 oxygen atoms, such as alkylene)- 1-10 It is heteroalkylene.

[0153] In some embodiments, L A teeth, It can be characterized as having a structure according to JPEG2025502110000374.jpg33170. A1 and L A2 are each independently a bond, -C 1-30 alkylene- or -C containing 1 to 6 heteroatoms independently selected from O, N, and S 1-30 Heteroalkylene-. Sulfur atoms, if present, are optionally oxidized. L N Forms a bond with L A2 The terminal atom (L NWhen L is null, it should be understood that a covalent bond is formed with the amide nitrogen atom. L is the carbon atom of the non-carbonyl group. A The total number of non-hydrogen atoms in L is between 15 and 50, e.g., 18, 20, 25, 30, 35, 40, 45, or 50, or any range between the listed values. A The maximum chain length of is at least -(CH2) 12 -, e.g., at least -(CH2) 14 - maximum chain length of at least -(CH2) 16 - maximum chain length of at least -(CH2) 18 - is the longest chain length. A The hydrophobicity of the corresponding compound JPEG2025502110000375.jpg31170 can be characterized as having a cLogP of at least 3, for example, between 3 and 15, preferably at least 4 (e.g., at least 4.5, at least 5, at least 5.5, at least 6, at least 6.5, at least 7, etc.), for example, 3 to 10, 4 to 12, 4.5 to 9, 5 to 11, 5.5 to 10.5, 6 to 14, 6.5 to 13, etc. Preferably, L A1 is not a bond. In some embodiments, L A2 is a bond. In some embodiments, L A1 is C 1-20 Alkylene, for example, straight chain alkylene, (CH2) 1-20 In some embodiments, L A1 is a C with 1 to 3 oxygen atoms 1-10 In some embodiments, L is heteroalkylene. A2 is a straight chain alkylene, (CH2) 1-20 C etc. 1-20 In some embodiments, L is alkylene. A2 is a C with 1 to 3 oxygen atoms 1-10 heteroalkylene and the like.

[0154] In some embodiments, L A teeth, It can be characterized as having a structure according to JPEG2025502110000376.jpg34170. A1 and L A2 are each independently a bond, -C 1-30 alkylene- or -C containing 1 to 6 heteroatoms independently selected from O, N, and S 1-30 Heteroalkylene-. Sulfur atoms, if present, are optionally oxidized. L N Forms a bond with L A1 The terminal atom (L N When L is null, it should be understood that a covalent bond is formed with the amide nitrogen atom. L is the carbon atom of the non-carbonyl group. A The total number of non-hydrogen atoms in L is between 15 and 50, e.g., 18, 20, 25, 30, 35, 40, 45, or 50, or any range between the listed values. A The maximum chain length of is at least -(CH2) 12 -, e.g., at least -(CH2) 14 - maximum chain length of at least -(CH2) 16 - maximum chain length of at least -(CH2) 18 - is the longest chain length. A The hydrophobicity of the corresponding compound JPEG2025502110000377.jpg31170 can be characterized as having a cLogP of at least 3, for example, between 3 and 15, preferably at least 4 (e.g., at least 4.5, at least 5, at least 5.5, at least 6, at least 6.5, at least 7, etc.), for example, 3 to 10, 4 to 12, 4.5 to 9, 5 to 11, 5.5 to 10.5, 6 to 14, 6.5 to 13, etc. Preferably, L A1 is not a bond. In some embodiments, L A2 is a bond. In some embodiments, L A1 is C 1-20 Alkylene, for example, straight chain alkylene, (CH2) 1-20 In some embodiments, L A1 is a C with 1 to 3 oxygen atoms 1-10In some embodiments, L is heteroalkylene. A2 is C 1-20 Alkylene, for example, straight chain alkylene, (CH2) 1-20 In some embodiments, L A2 is -O-(C 1-10 C with 1 to 3 oxygen atoms, such as alkylene)- 1-10 It is heteroalkylene.

[0155] In some preferred embodiments, L of Formula III (e.g., Formula III-1) or III-B (e.g., Formula III-B-1) A or L N -L A You can choose from the following structures: JPEG2025502110000378.jpg44170JPEG2025502110000379.jpg48170Here, C 0-26 Alkylene, or C 1-30 Alkylene is optionally substituted and each occurrence of G A are independently hydrogen or optionally substituted C 1-4 Alkyl or two G A are linked to form a 3- to 6-membered ring, such as a cyclopropyl or cyclobutyl ring. In some preferred embodiments, G A is methyl. In some embodiments, C 0-26 Alkylene or C 1-30 The alkylene is unsubstituted and is a straight or branched chain alkylene. In some embodiments, C 0-26 Alkylene or C 1-30 Alkylene is a straight chain unsubstituted alkylene.

[0156] In some preferred embodiments, L of Formula III (e.g., Formula III-1) or III-B (e.g., Formula III-B-1) A or L N -L A You can choose from the following structures: JPEG2025502110000380.jpg84170 where C 0-26 Alkylene or C1-30 The alkylene is optionally substituted. In some embodiments, C 0-26 Alkylene or C 1-30 The alkylene is unsubstituted and is a straight or branched chain alkylene. In some embodiments, C 0-26 Alkylene or C 1-30 Alkylene is a straight chain unsubstituted alkylene. Hydrophilic group T A

[0157] Similar to compounds of Formula I and II, another factor that can determine whether a compound of Formula III or III-B can be a potent GPR40 agonist is T A hydrophilic or polar, but T A The exact chemical structure of is not critical. Preferred T suitable for formula III or III-B are A includes any of those described and preferred in relation to formula I or II. In formula III or III-BI, T A L A wherein (1) when the terminal atom is N of a basic amine group, the corresponding compound T A -(C(O)-CH3) q has a cLogP less than 1, -C(O)-CH3 is bonded to the terminal N atom, and (2) if the terminal atom is the C of the C(O) group, the corresponding compound T A -(OH) q has a cLogP less than 1, -OH is bonded to the terminal C atom, and (3) if the terminal atom is S in the SO2 group, the corresponding compound T A -(OH) q has a cLogP less than 1, -OH is bonded to the terminal S atom, or (4) if (1) to (3) do not apply, T A -H q has a cLogP of less than 1. In some embodiments, the terminal atom is the N of the basic amine group, and T A is the corresponding compound T A -(C(O)-CH3) qis less than 0 (e.g., less than -1, less than -2, less than -3, less than -3.5, less than -4, or even less). In some embodiments, the terminal atom is the C of a C(O) group, and T A is the corresponding compound T A -(OH) q is less than 0 (e.g., less than -1, less than -2, less than -3, less than -3.5, less than -4, or even less). In some embodiments, the terminal atom is S in an SO group, and T A is the corresponding compound T A -(OH) q is less than 0 (e.g., less than -1, less than -2, less than -3, less than -3.5, less than -4, or even less). In some embodiments, the terminal atom is not N of a basic amine group, C of a C(O) group, or S of a SO group, but is T A is the corresponding compound T A -H q is less than 0 (e.g., less than -1, less than -2, less than -3, less than -3.5, less than -4, or even less).

[0158] In some preferred embodiments, T A contains a quaternary nitrogen atom, a positively charged group such as SO3 - The compound may contain negatively charged groups such as , or charged groups containing zwitterionic structures. A It should be understood that when contains a charged group, a counterion, preferably a pharmaceutically acceptable anion or cation, is present if necessary to balance the charge so that the compound of formula III or III-B is overall neutral.

[0159] In some embodiments, T A are characterized as having charged groups (including zwitterionic structures) or groups that can be charged at pH 7, such as primary amines, secondary amines, tertiary amines, quaternary amines, carboxylic acids, etc.

[0160] In some embodiments, T Ais characterized as having at least two hydrogen bond donors.

[0161] In some embodiments, T A is characterized as having at least two hydrogen bond acceptors.

[0162] In some embodiments, T A is T A1 , T A1 -L B -, T A1 -L B -(heteroalkylene), or T A1 -L B -(heteroalkylene)-L B - and L in each occurrence B are independently -SO2-, -C(=O)-, or a moiety selected from: JPEG2025502110000381.jpg24170 R in each occurrence 100 , R 101 and R 102 are independently hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl; T A1 teeth, JPEG2025502110000382.jpg28170. 1 are independently hydrogen, halogen, or optionally substituted C 1-4 Alkyl or optionally substituted C 1-4 heteroalkyl (such as optionally substituted C1-4 alkoxy) or two gem-G 1 The groups may be bonded to form =O, =NH, or =N(C 1-4 alkyl) or two or more G 1 The groups can be linked to form a ring structure. The integer r is 1 to 10, such as 1 or 2. G in each occurrence 2 are independently hydrogen, G 10 , C(O)-G 10 , SO2G 10, C(O)-NH-G 10 , or SO2NHG 10 , C(O)-OG 10 , or SO2OG 10 and G 10 is independently an optionally substituted alkyl, an optionally substituted heteroalkyl, or an optionally substituted 3- to 10-membered ring structure that may be carbocyclic, heterocyclic, aromatic, heteroaromatic, or combinations thereof. G 3 is hydrogen or optionally substituted alkyl (e.g., C 1-4 alkyl). Or two Gs 2 , or one G 2 and one G 1 , or one G 1 and G 3 can be linked to form a ring structure such as a 3- to 10-membered ring structure. Fragment JPEG2025502110000383.jpg25170 is (i)NG 3 Next to the CG 1 G 1 If the group is not C(=O), the corresponding compound JPEG2025502110000384.jpg29170 has a cLogP of less than 1, preferably less than 0 (e.g., less than −1, less than −2, less than −3, less than −3.5, less than −4, or less), or (ii) NG 3 Next to the CG 1 G 1 When the group is C(=O), the corresponding compound JPEG2025502110000385.jpg26170 is further characterized in that it has a cLogP of less than 1, preferably less than 0 (e.g., less than -1, less than -2, less than -3, less than -3.5, less than -4, or even less). Fragment JPEG2025502110000386.jpg18170 shows that (i) when the nitrogen is a basic nitrogen, the corresponding compound (G 2)N—C(O)—CH has a cLogP of less than 1, preferably less than 0 (e.g., less than −1, less than −2, less than −3, less than −3.5, less than −4, or less), or (ii) if the nitrogen is a non-basic nitrogen, the corresponding compound (G 2 )2N-H has a cLogP of less than 1, preferably less than 0 (e.g., less than -1, less than -2, less than -3, less than -3.5, less than -4, or even less). 3 is hydrogen. In some preferred embodiments, T A is T A1 or T A1 -L B In some embodiments, T A is T A1 -L B -(heteroalkylene) or T A1 -L B -(heteroalkylene)-L B -, and the heteroalkylene may be a glycol chain, such as a polyethylene glycol chain.

[0163] In some embodiments, T A is T A1 In some embodiments, T A is T A1 In some embodiments, T A1 teeth, JPEG2025502110000387.jpg19170. In some embodiments, T A1 teeth, JPEG2025502110000388.jpg16170. In some embodiments, the G 2 is, independently, It can have a structure of JPEG2025502110000389.jpg12170, where n is an integer of 0 to 100, preferably 0 to 10 (for example, 0 to 4, 1 to 5, or 2 to 6). 1 are CH2, C(O), SO, SO2, CH(C 1-4 alkyl), C(C1-4 Alkyl)(C 1-4 alkyl) or a 3- to 10-membered ring structure. 2 are independently CH2, O, S, SO, SO2, C(O), CH(C 1-4 alkyl), C(C 1-4 Alkyl)(C 1-4 alkyl), NH, N(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 alkyl)] + Or a 3- to 10-membered ring structure. 3 is H, C 1-4 Alkyl, OH, SO3H, COOH, NH2, NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, SO2NH2, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), or SO2N(C 1-4 Alkyl)(C 1-4 C 1-4 Each alkyl is independently selected and optionally includes, for example, 1 to 3 G as defined herein. 20 In some embodiments, Z is substituted with a group. 2 In some embodiments, none of Z 2 One or more examples of the formula include 3-10 membered ring structures such as nitrogen-containing rings, e.g., JPEG2025502110000390.jpg23170. In some embodiments, Z 3 Directly connect to Z 2 is a 3- to 10-membered ring structure such as a nitrogen-containing ring, for example, JPEG2025502110000391.jpg25170, etc. Preferably, Z 2Up to two instances of G are 3- to 10-membered ring structures. 2 are independently hydrogen, optionally substituted C 1-6 Alkyl or optionally substituted C 1-6 For example, when substituted, C 1-6 Alkyl is OH, NH2, oxo (=O), NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, C(O)OH, SO2NH2, SO3H, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), and SO2N(C 1-4 Alkyl)(C 1-4 C can be substituted with 1 to 3 substituents independently selected from alkyl. 1-4 Each alkyl is independently selected and optionally includes, for example, 1 to 3 G as defined herein. 20 Each occurrence of G herein is substituted with a group. 20 The groups are OH, NH2, oxo (=O), NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, C(O)OH, SO2NH2, SO3H, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), SO2N(C 1-4 Alkyl)(C 1-4 alkyl), or a 3- to 10-membered ring structure. 1-4Each alkyl is independently selected and optionally includes, for example, 1 to 3 G as defined herein. 21 Each occurrence of G herein is substituted with a group. 21 The groups are OH, NH2, oxo (=O), NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, C(O)OH, SO2NH2, SO3H, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), SO2N(C 1-4 Alkyl)(C 1-4 alkyl) or a 3- to 10-membered ring structure. 2 One or more examples of 1-4 alkylene)-NH2 or CONH-(C 1-4 alkylene)-[N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + C optionally substituted with an amide derivative such as 1-4 For example, in some embodiments, G 2 One or two examples of -(C 1-4 alkylene)-COOH, and G 2 Any remaining instance of C 1-4 In some embodiments, G is alkyl. 2 One or two examples of JPEG2025502110000392.jpg18170 etc. -(C 1-4 alkylene)-CONH-(C 1-4 alkylene)-NH2, and G 2 Any remaining instance of C 1-4 In some embodiments, G is alkyl. 2One or two examples of JPEG2025502110000393.jpg19170 etc. -(C 1-4 alkylene)-CONH-(C 1-4 alkylene)-[N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + and G 2 Any remaining instance of C 1-4 In some embodiments, T A1 teeth JPEG2025502110000394.jpg41170. In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000395.jpg41170. In some embodiments, T A1 teeth, JPEG2025502110000396.jpg43170. In some embodiments, T A1 teeth, JPEG2025502110000397.jpg31170. In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000398.jpg61170. In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), For example, in some embodiments, T A1 teeth JPEG2025502110000400.jpg50170. In some embodiments, T A1 teeth JPEG2025502110000401.jpg32170. In some embodiments, T A1 teeth JPEG2025502110000402.jpg37170. In some embodiments, T A1 teeth JPEG2025502110000403.jpg24170. In some embodiments, T A1 teeth JPEG2025502110000404.jpg24170. In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000405.jpg25170. In some embodiments, T A1 teeth JPEG2025502110000406.jpg24170. In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000407.jpg25170. In some embodiments, T A1 teeth It could also be JPEG2025502110000408.jpg21170.

[0164] In some embodiments, T A is T A1 , T A1 -L B -, T A1 -L B -(heteroalkylene), or T A1 -L B -(heteroalkylene)-L B - and L in each occurrence B are independently -SO2-, -C(=O)-, or a moiety selected from: JPEG2025502110000409.jpg30170 R in each occurrence 100 , R 101 and R 102 are independently hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl; T A1 teeth, Optionally, the charge is balanced with a counterion (e.g., as described herein); JPEG2025502110000410.jpg26170. 1 are independently hydrogen, halogen, or optionally substituted C 1-4 Alkyl or optionally substituted C 1-4 Heteroalkyl (optionally substituted C 1-4 alkoxy, etc.) or two gem-G 1 The groups may be bonded to form =O, =NH, or =N(C 1-4 alkyl), or two or more G 1 The groups can be linked to form a ring structure. The integer r is 1 to 10, such as 1 or 2. G 3 is hydrogen or optionally substituted alkyl (e.g., C 1-4 alkyl). G in each occurrence 4 are independently hydrogen or G 10 and G 10 are independently an optionally substituted alkyl, an optionally substituted heteroalkyl, or an optionally substituted 3- to 10-membered ring structure which may be carbocyclic, heterocyclic, aromatic, heteroaromatic, or a combination thereof; or two G 4 , or one G 4 and one G 1 , or one G 1 and G 3 can be linked to form an optionally substituted 3- to 10-membered ring structure. Fragment JPEG2025502110000411.jpg24170 is (i) the CG next to NH 1 G 1 If the group is not C(=O), the corresponding compound JPEG2025502110000412.jpg25170 has a cLogP of less than 1, preferably less than 0 (e.g., less than −1, less than −2, less than −3, less than −3.5, less than −4, or less), or (ii) a CG 1 G 1 When the group is C(=O), the corresponding compound JPEG2025502110000413.jpg27170 is characterized by having a cLogP of less than 1, preferably less than 0 (e.g., less than -1, less than -2, less than -3, less than -3.5, less than -4, or less). 3 is hydrogen. In some preferred embodiments, T A is T A1 or T A1 -L B In some embodiments, T A is T A1 -L B -(heteroalkylene) or T A1 -L B -(heteroalkylene)-L B -, and the heteroalkylene may be a glycol chain, such as a polyethylene glycol chain.

[0165] In some embodiments, T A is T A1 In some embodiments, T A is T A1 In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000414.jpg21170. In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), In some embodiments, the G 4 is, independently, JPEG2025502110000416.jpg13170, where n is an integer of 0 to 100, preferably 0 to 10 (for example, 0 to 4, 1 to 5, or 2 to 6). 1 are CH2, C(O), SO2, CH(C 1-4 alkyl), or C(C 1-4 Alkyl)(C 1-4 (alkyl). Z in each occurrence 2 are independently CH2, O, S, SO, SO2, C(O), CH(C 1-4 alkyl), C(C 1-4 Alkyl)(C 1-4 alkyl), NH, N(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 alkyl)] + Or a 3- to 10-membered ring structure. 3 is H, C 1-4 Alkyl, OH, SO3H, COOH, NH2, NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, SO2NH2, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), or SO2N(C 1-4 Alkyl)(C 1-4 C 1-4 Each alkyl is independently selected and optionally includes, for example, 1 to 3 G as defined herein. 20 Preferably, Z 2 Up to two instances of Z are 3- to 10-membered ring structures. 2 In some embodiments, none of Z 2 One example of is a 3-10 membered ring structure such as a nitrogen-containing ring, e.g., JPEG2025502110000417.jpg24170. In some embodiments, 4 are independently hydrogen, optionally substituted C 1-6 Alkyl or optionally substituted C 1-6 For example, when substituted, C 1-6 Alkyl is OH, NH2, oxo (=O), NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, C(O)OH, SO2NH2, SO3H, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), and SO2N(C 1-4 Alkyl)(C 1-4 C can be substituted with 1 to 3 substituents independently selected from alkyl. 1-4 Each alkyl is independently selected and optionally includes, for example, 1 to 3 G as defined herein. 20 Each occurrence of G herein is substituted with a group. 20 The groups are OH, NH2, oxo (=O), NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, C(O)OH, SO2NH2, SO3H, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), SO2N(C 1-4 Alkyl)(C 1-4 alkyl), or a 3- to 10-membered ring structure. 1-4Each alkyl is independently selected and optionally includes, for example, 1 to 3 G as defined herein. 21 Each occurrence of G herein is substituted with a group. 21 The groups are OH, NH2, oxo (=O), NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, C(O)OH, SO2NH2, SO3H, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), SO2N(C 1-4 Alkyl)(C 1-4 alkyl) or a 3- to 10-membered ring structure. 4 One or more examples of C, such as methyl 1-4 In some embodiments, G is alkyl. 4 One or more examples of 1-4 alkylene)-NH2 or CONH-(C 1-4 alkylene)-[N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + C optionally substituted with an amide derivative such as 1-4 For example, in some embodiments, G 4 One or two examples of -(C 1-4 alkylene)-COOH, and G 4 Any remaining instance of C 1-4 In some embodiments, G is alkyl. 4 One or two examples of JPEG2025502110000418.jpg17170 etc. -(C 1-4 alkylene)-CONH-(C 1-4 alkylene)-NH2, and G4 Any remaining instance of C 1-4 In some embodiments, G is alkyl. 4 One or two examples of JPEG2025502110000419.jpg20170 etc. -(C 1-4 alkylene)-CONH-(C 1-4 alkylene)-[N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + and G 4 Any remaining instance of C 1-4 In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000420.jpg80170. In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000421.jpg41170. In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000422.jpg29170. In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), For example, in some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000424.jpg49170. In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000425.jpg33170. In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000426.jpg26170. In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000427.jpg25170. In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000428.jpg32170. In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000429.jpg25170. In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000430.jpg23170. In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000431.jpg31170. In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000432.jpg18170. In some embodiments, T A1 is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000433.jpg33170. In some embodiments, T A1 teeth It could also be JPEG2025502110000434.jpg17170.

[0166] In some preferred embodiments, T A is T A1 or T A1 -L B - and T A1 teeth, JPEG2025502110000435.jpg160170JPEG2025502110000436.jpg161170L B is —SO—, —C(═O)—, or a moiety selected from: JPEG2025502110000437.jpg24170 where R in each occurrence 100 , R 101 , and R 102 are independently hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl; T A is optionally charge balanced with a counterion (eg, as described herein). L A -T A Example of

[0167] L A and T A The covalent bond formed between T A and the terminal atoms of L A The covalent bond between the terminal carbon or nitrogen atom of T is an amide bond. A and the terminal atoms of L A The covalent bond between the terminal atoms of is a non-amide carbon-nitrogen bond, an ester bond, a non-ester carbon-oxygen bond, a carbon-carbon bond, or a carbon-sulfur bond.

[0168] In some preferred embodiments, the compound of formula III can be characterized as having formula III-2, III-3, III-4, III-5, III-6, III-7, III-8, or III-9. JPEG2025502110000438.jpg168170JPEG2025502110000439.jpg210170JPEG2025502110000440.jpg56170In the formula, X in each occurrence is independently CR, C(=O), -C(R)=C(R)-, JPEG2025502110000441.jpg12170SiR2, O, S, SO2, NR, [NR2] + or a ring structure, preferably a 3- to 10-membered ring structure. R in each occurrence is independently hydrogen, halogen, optionally substituted C 1-4 Alkyl or optionally substituted C 1-4 Alkoxy, provided that L N X group (L N is empty (null), it should be understood that a covalent bond is formed with the amide nitrogen atom of Formulae III-2 to III-9) is CR2 or a ring structure, preferably a 3- to 10-membered ring structure. The integer m1 is at least 12, for example, 12 to 50 (eg, 12, 14, 16, 18, 20, 22, 24, 30, 40, 50, or any range or value between the listed values). (X) m1 The hydrophobicity of the corresponding compound H-(X) is: (i) if one terminal X group is C(O) or SO2; m1 -OH has a cLogP of at least 3, e.g., between 3 and 15, preferably at least 4 (e.g., at least 4.5, at least 5, at least 5.5, at least 6, at least 6.5, at least 7, etc.), e.g., 3 to 10, 4 to 12, 4.5 to 9, 5 to 11, 5.5 to 10.5, 6 to 14, 6.5 to 13, etc., and the OH is bonded to C(O) or SO2, or (ii) the corresponding compound H-(X) m1-H has a cLogP of at least 3, for example, between 3 and 15, preferably at least 4 (e.g., at least 4.5, at least 5, at least 5.5, at least 6, at least 6.5, at least 7, etc.), for example, 3 to 10, 4 to 12, 4.5 to 9, 5 to 11, 5.5 to 10.5, 6 to 14, 6.5 to 13, etc. G in each occurrence 1 are independently hydrogen, halogen, or optionally substituted C 1-4 Alkyl or optionally substituted C 1-4 heteroalkyl (such as optionally substituted C1-4 alkoxy) or two gem-G 1 The groups may be bonded to form =O, =NH, or =N(C 1-4 alkyl), or two or more G 1 The groups can be linked to form a ring structure. the integer r is 1 to 10, such as 1 or 2; G in each occurrence 2 are independently hydrogen, G 10 , C(O)-G 10 , SO2G 10 , C(O)-NH-G 10 , or SO2NHG 10 , C(O)-OG 10 , or SO2OG 10 and G 10 is independently an optionally substituted alkyl, an optionally substituted heteroalkyl, or an optionally substituted 3- to 10-membered ring structure that may be carbocyclic, heterocyclic, aromatic, heteroaromatic, or combinations thereof. G 3 is hydrogen or optionally substituted alkyl (e.g., C 1-4 alkyl). G in each occurrence 4 are independently hydrogen or G 10 and G 10is independently an optionally substituted alkyl, an optionally substituted heteroalkyl, or an optionally substituted 3- to 10-membered ring structure that may be carbocyclic, heterocyclic, aromatic, heteroaromatic, or combinations thereof. Or two Gs 2 , or one G 2 and one G 1 , or one G 1 and G 3 can be linked to form a ring structure such as a 3- to 10-membered ring structure. Or two Gs 4 , or one G 4 and one G 1 , or one G 1 and G 3 can be linked to form an optionally substituted 3- to 10-membered ring structure. JPEG2025502110000442.jpg10170 is a counterion, preferably a pharmaceutically acceptable anion, required to balance the overall charge of the compound. Fragment JPEG2025502110000443.jpg26170 is (i)NG 3 Next to the CG 1 G 1 If the group is not C(=O), the corresponding compound JPEG2025502110000444.jpg27170 has a cLogP less than 1, preferably less than 0 (e.g., less than −1, less than −2, less than −3, less than −3.5, less than −4, or less), or (ii) NG 3 Next to the CG 1 G 1 When the group is C(=O), the corresponding compound JPEG2025502110000445.jpg28170 is further characterized in that it has a cLogP of less than 1, preferably less than 0 (e.g., less than -1, less than -2, less than -3, less than -3.5, less than -4, or even less). Fragment JPEG2025502110000446.jpg23170 is (i) the CG next to NH 1 G1 If the group is not C(=O), the corresponding compound JPEG2025502110000447.jpg26170 has a cLogP less than 1, preferably less than 0 (e.g., less than -1, less than -2, less than -3, less than -3.5, less than -4, or less), or (ii) a CG next to NH 1 G 1 When the group is C(=O), the corresponding compound JPEG2025502110000448.jpg24170 is characterized as having a cLogP of less than 1, preferably less than 0 (e.g., less than -1, less than -2, less than -3, less than -3.5, less than -4, or even less). Variable T A , L 10 , L N , R 11 , R 12 , R 18 , R A , R C , rings A, Y, Z, p1, and p2 are as defined herein, including any of the rings described and preferred herein, in any combination. N is null. In some embodiments, L N is empty (null), and the two examples of X attached to the amide nitrogen atom in formulas III-2 to III-9 are C, such as JPEG2025502110000449.jpg23170 (X's are shown to indicate the concatenation direction) 1-6 and the remainder of X are as defined herein. N teeth, Branched or linear C such as JPEG2025502110000450.jpg23170 (X is shown to indicate the linkage direction) 1-6 In some embodiments, each occurrence of G is alkylene. 1 is hydrogen. In some embodiments, G 1 One or more examples of C, such as methyl 1-4In some embodiments, the integer r is 1, 2, 3, 4, or 5. In some embodiments, G 2 One or more instances of It may have a structure of JPEG2025502110000451.jpg16170, where n is an integer of 0 to 100, preferably 0 to 10 (for example, 0 to 4, 1 to 5, or 2 to 6). 1 are CH2, C(O), SO, SO2, CH(C 1-4 alkyl), C(C 1-4 Alkyl)(C 1-4 alkyl) or a 3- to 10-membered ring structure. 2 are independently CH2, O, S, SO, SO2, C(O), CH(C 1-4 alkyl), C(C 1-4 Alkyl)(C 1-4 alkyl), NH, N(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 alkyl)] + Or a 3- to 10-membered ring structure. 3 is H, C 1-4 Alkyl, OH, SO3H, COOH, NH2, NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, SO2NH2, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), or SO2N(C 1-4 Alkyl)(C 1-4 C 1-4 Each alkyl is independently selected and optionally includes, for example, 1 to 3 G as defined herein. 20 In some embodiments, Z is substituted with a group. 2 In some embodiments, none of Z 2One or more examples of the formula include 3-10 membered ring structures such as nitrogen-containing rings, e.g., JPEG2025502110000452.jpg26170. In some embodiments, Z 3 Directly connect to Z 2 is a 3- to 10-membered ring structure such as a nitrogen-containing ring, for example, JPEG2025502110000453.jpg24170, etc. Preferably, Z 2 Up to two instances of G are 3- to 10-membered ring structures. 2 are independently hydrogen, optionally substituted C 1-6 Alkyl or optionally substituted C 1-6 For example, when substituted, C 1-6 Alkyl is OH, NH2, oxo (=O), NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, C(O)OH, SO2NH2, SO3H, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), and SO2N(C 1-4 Alkyl)(C 1-4 C can be substituted with 1 to 3 substituents independently selected from alkyl. 1-4 Each alkyl is independently selected and optionally includes, for example, 1 to 3 G as defined herein. 20 In some embodiments, each occurrence of G is substituted with a group. 4 is, independently, JPEG2025502110000454.jpg14170, where n is an integer of 0 to 100, preferably 0 to 10 (for example, 0 to 4, 1 to 5, or 2 to 6). 1 are CH2, C(O), SO2, CH(C 1-4alkyl), or C(C 1-4 Alkyl)(C 1-4 (alkyl). Z in each occurrence 2 are independently CH2, O, S, SO, SO2, C(O), CH(C 1-4 alkyl), C(C 1-4 Alkyl)(C 1-4 alkyl), NH, N(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 alkyl)] + Or a 3- to 10-membered ring structure. 3 is H, C 1-4 Alkyl, OH, SO3H, COOH, NH2, NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, SO2NH2, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), or SO2N(C 1-4 Alkyl)(C 1-4 C 1-4 Each alkyl is independently selected and optionally includes, for example, 1 to 3 G as defined herein. 20 Preferably, Z 2 Up to two instances of Z are 3- to 10-membered ring structures. 2 In some embodiments, none of Z 2 One example of is a 3-10 membered ring structure such as a nitrogen-containing ring, e.g., JPEG2025502110000455.jpg25170. In some embodiments, 4 are independently hydrogen, optionally substituted C 1-6 Alkyl or optionally substituted C 1-6 For example, when substituted, C1-6 Alkyl is OH, NH2, oxo (=O), NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, C(O)OH, SO2NH2, SO3H, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), and SO2N(C 1-4 Alkyl)(C 1-4 C can be substituted with 1 to 3 substituents independently selected from alkyl. 1-4 Each alkyl is independently selected and optionally includes, for example, 1 to 3 G as defined herein. 20 Each occurrence of G herein is substituted with a group. 20 The groups are OH, NH2, oxo (=O), NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, C(O)OH, SO2NH2, SO3H, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), SO2N(C 1-4 Alkyl)(C 1-4 alkyl), or a 3- to 10-membered ring structure. 1-4 Each alkyl is independently selected and optionally includes, for example, 1 to 3 G as defined herein. 21 Each occurrence of G herein is substituted with a group. 21 The groups are OH, NH2, oxo (=O), NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, C(O)OH, SO2NH2, SO3H, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), SO2N(C 1-4 Alkyl)(C 1-4 alkyl) or a 3- to 10-membered ring structure. 4 One or more examples of C, such as methyl 1-4 In some embodiments, G is alkyl. 4 One or more examples of 1-4 alkylene)-NH2 or CONH-(C 1-4 alkylene)-[N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + C optionally substituted with an amide derivative such as 1-4 For example, in some embodiments, G 4 One or two examples of -(C 1-4 alkylene)-COOH, and G 4 Any remaining instance of C 1-4 In some embodiments, G is alkyl. 4 One or two examples of JPEG2025502110000456.jpg18170 etc. -(C 1-4 alkylene)-CONH-(C 1-4 alkylene)-NH2, and G 4 Any remaining instance of C 1-4 In some embodiments, G is alkyl. 4 One or two examples of JPEG2025502110000457.jpg18170 etc. -(C 1-4 alkylene)-CONH-(C1-4 alkylene)-[N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + and G 4 Any remaining instance of C 1-4 In a preferred embodiment, G 3 is hydrogen. In some embodiments, X at each occurrence is independently CH2, CHCH3, or C(CH3)2. In some embodiments, X at each occurrence is CH2. In some embodiments, up to 6 (e.g., 1, 2, 3, 4, 5, or 6) instances of X are O, and the remaining X are CH2, CHCH3, or C(CH3)2. In some embodiments, up to 10 instances of X are -CH=CH-, and the remaining X are CH2, CHCH3, or C(CH3)2. In some embodiments, (X) m1 The moiety has one or more structural features selected from the following: (i) two consecutive X's together form -C(O)O- or -C(O)NR- (e.g., C(O)NH or C(O)NCH3); (ii) one or more instances of X can have a ring structure selected from cyclopropane, cyclobutane, bicyclobutane [1.1], cyclopentane, cyclohexane, or cycloheptane; and (iii) one or more instances of X can have a ring structure selected from phenyl, or a 5- or 6-membered heteroaryl, such as triazole. In some embodiments, (X) m1 Within the moiety, there can be 0, 1, or 2 instances of a ring structure, preferably a 3- to 10-membered ring structure. In some embodiments, (X) m1 For example, in some embodiments, one triazole ring is present within the (X) moiety. m1 The moiety is as defined herein and is preferred For example, in some embodiments, L A1 and L A2 are each independently a bond, -C 1-30alkylene- or -C containing 1 to 6 heteroatoms independently selected from O, N, and S 1-30 heteroalkylene-, where the sulfur atom, if present, is optionally oxidized, (X) m1 The total number of non-hydrogen atoms in L is between 15 and 50, e.g., 18, 20, 25, 30, 35, 40, 45, or 50, or any range between the listed values. A1 is a bond. In some embodiments, L A1 is C 1-20 Alkylene, for example, straight chain alkylene, (CH2) 1-20 In some embodiments, L A1 is a C with 1 to 3 oxygen atoms 1-10 In some embodiments, L is heteroalkylene. A2 is a bond. In some embodiments, L A2 is C 1-20 Alkylene, for example, straight chain alkylene, (CH2) 1-20 In some embodiments, L A2 is -O-(C 1-10 C with 1 to 3 oxygen atoms, such as alkylene)- 1-10 Heteroalkylene. A1 and L A2 Either L N can be bonded to (L N When is null, it should be understood that a covalent bond is formed with the amide nitrogen atom of Formulas III-2 to III-9 above. Residues of GPR40 agonists

[0169] Variable L of Formula III or III-B 10 , R 11 , R 12 , R 18 , R A , R C , ring A, ring B, Y, Z, p1, and p2 are not particularly limited. However, in a preferred embodiment, the variables of formula III or III-B are represented by formula GPR-3, JPEG2025502110000459.jpg35170(GPR-3), or formula GPR-3B, JPEG2025502110000460.jpg36170 (GPR-3B) 3 is E 3A or L N -E 3A and E 3A is hydrogen, N3, JPEG2025502110000461.jpg30170, L N is defined herein (empty (null) or C 1-6 Alkylene, etc.)) are preferably such that they are GPR40 agonists with an EC50 of less than 100 nM as measured according to Biological Example 1 herein.

[0170] Typically, p1 in formula III or III-B is 0.

[0171] In some embodiments, p1 of formula III or III-B is 1.

[0172] Typically, R in each occurrence A are independently F, Cl, CN, C optionally substituted with 1 to 3 fluorines 1-4 alkyl or C optionally substituted with 1 to 3 fluorines 1-4 It is an alkoxy.

[0173] Typically, p2 in formula III or III-B is 0.

[0174] In some embodiments, p2 of formula III or III-B is 1 and R C is F, Cl, CN, C optionally substituted with 1 to 3 fluorines 1-4 alkyl or C optionally substituted with 1 to 3 fluorines 1-4 It is an alkoxy.

[0175] In formula III, Y is typically N.

[0176] Preferably, Z in formula III is O.

[0177] In some embodiments, R 11 and R 12 are both hydrogen.

[0178] In some preferred embodiments, L 10 teeth, JPEG2025502110000462.jpg21170, where CR 16 R 17 is bonded to the COOH group, R 14 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 cycloalkyl, phenyl, 5- or 6-membered heteroaryl, or 3- to 7-membered heterocyclyl, wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heteroaryl, and heterocyclyl is optionally substituted with F, —OH, oxo (where applicable), C 1-4 Alkyl, Fluoro-substituted C 1-4 Alkyl (e.g., CF3), C 1-4 Alkoxy and Fluoro Substituted C 1-4 optionally substituted with 1, 2, or 3 substituents independently selected from alkoxy; 15 , R 16 and R 17 are each independently hydrogen or C 1-4 alkyl, or R 14 and R 15 are joined to form a 3-7 membered ring having 0, 1, or 2 heteroatoms selected from O, N, or S. In some embodiments, R 16 and R 17 are both hydrogen or R 16 and R 17 is hydrogen and R 16 and R 17 The other of R is methyl. 14 and R15 is hydrogen and R 14 and R 15 The other is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, or C 3-6 In some embodiments, R 14 and R 15 combines to form C 3-6 Forms a cycloalkyl.

[0179] For example, in some embodiments, L 10 teeth JPEG2025502110000463.jpg28170, where R 10 is hydrogen or C such as methyl 1-4 It is alkyl.

[0180] R of Formula III or III-B 18 is typically an optionally substituted phenyl or an optionally substituted 5- or 6-membered heteroaryl having 1 to 4 ring heteroatoms.

[0181] In some embodiments, R 18 is an optionally substituted 6-membered heteroaryl ring. In some embodiments, R 18 is a pyridyl ring, 6-membered heteroaryl rings such as JPEG2025502110000464.jpg14170, and containing F, Cl, CN, OH, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy or C 3-6 cycloalkoxy, wherein alkyl, heteroalkyl, cycloalkyl, alkoxy, or cycloalkoxy is C optionally substituted with F, —OH, F 1-4 Alkoxy, oxo (where applicable), NH2, NH(C 1-4 alkyl), N(C 1-4 Alkyl ((C 1-4alkyl), and C optionally substituted with F 1-4 In some embodiments, R is optionally substituted with one or more (e.g., 1, 2, or 3) substituents independently selected from alkyl. 18 teeth, JPEG2025502110000465.jpg16170, and each of them is F, Cl, CN, OH, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy or C 3-6 cycloalkoxy, wherein alkyl, heteroalkyl, cycloalkyl, alkoxy, or cycloalkoxy is C optionally substituted with F, —OH, F 1-4 Alkoxy, oxo (where applicable), NH2, NH(C 1-4 alkyl), N(C 1-4 Alkyl ((C 1-4 alkyl), and C optionally substituted with F 1-4 It is optionally substituted with one or more (eg, 1, 2, or 3) substituents independently selected from alkyl.

[0182] Ring A of formula III or III-B is a nitrogen-containing heterocyclic structure, with at least one nitrogen bonded to the phenyl ring shown in formula III or III-B.

[0183] In some embodiments, ring A of formula III or III-B is a 4-8 membered, optionally substituted, monocyclic, saturated heterocycle having 1 or 2 ring heteroatoms independently selected from S, O, and N, provided that at least one of the ring heteroatoms is nitrogen. For example, in some embodiments, ring A is selected from: JPEG2025502110000466.jpg20170 These are F, OH, NH2, NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), C optionally substituted with 1 to 3 fluorines 1-4alkyl or C optionally substituted with 1 to 3 fluorines 1-4 Optionally substituted with 1 to 2 substituents independently selected from alkoxy.

[0184] In some embodiments, ring A of formula III or III-B can be a bicyclic or polycyclic 6- to 12-membered, optionally substituted saturated heterocycle having 1 or 2 ring heteroatoms independently selected from S, O, and N, provided that at least one of the ring heteroatoms is nitrogen.

[0185] In some preferred embodiments, the compounds of formula III or III-B can be characterized as having formula III-1-A or III-B-2, respectively: JPEG2025502110000467.jpg100170JPEG2025502110000468.jpg10170In the formula, R 14 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 cycloalkyl, phenyl, 5- or 6-membered heteroaryl, or 3- to 7-membered heterocyclyl, wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heteroaryl, and heterocyclyl is optionally substituted with F, —OH, oxo (where applicable), C 1-4 Alkyl, Fluoro-substituted C 1-4 Alkyl (e.g., CF3), C 1-4 Alkoxy and Fluoro Substituted C 1-4 optionally substituted with 1, 2, or 3 substituents independently selected from alkoxy; 15 , R 16 and R 17 are each independently hydrogen or C 1-4 alkyl, or R 14 and R 15 are joined together to form a 3- to 7-membered ring having 0, 1, or 2 heteroatoms selected from O, N, or S; R at each occurrence Dare independently F, Cl, C optionally substituted with 1 to 3 F 1-4 alkyl, or C optionally substituted with 1 to 3 F 1-4 is an alkoxy, p3 is 0, 1, 2, or 3; Variable T A , L N , and L A includes any of the preferred ones described herein, in any combination. For example, in some embodiments, L N is null. In some embodiments, L N teeth, JPEG2025502110000469.jpg21170(L A (The symbol is shown to indicate the linkage direction) 1-6 In some embodiments, R 16 and R 17 are both hydrogen. In some embodiments, R 16 and R 17 is hydrogen and R 16 and R 17 The other of R is methyl. 14 and R 15 is hydrogen and R 14 and R 15 The other is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, or C 3-6 In some embodiments, R 14 and R 15 combines to form C 3-6 Forms a cycloalkyl.

[0186] In some preferred embodiments, the compounds of formula III or III-B can be characterized as having formula III-1-A-1 or III-B-3, respectively: JPEG2025502110000470.jpg45170JPEG2025502110000471.jpg61170Variable T A , L N , and LA includes any of the preferred ones described herein, in any combination. For example, in some embodiments, L N is null. In some embodiments, L N teeth, JPEG2025502110000472.jpg22170(L A (The symbol is shown to indicate the linkage direction) 1-6 It is alkylene.

[0187] In a preferred embodiment, L of formula III-1-A (e.g., III-1-A-1), III-B-2, or III-B-3 A -X 12-30 It may also be -C(O)-, where C(O) is T A and X in each occurrence is independently CR2, -C(R)=C(R)-, JPEG2025502110000473.jpg12170SiR2, C(O), O, NR, S, SO2, or a ring structure, preferably a 3- to 10-membered ring structure, provided that the terminal X group (i.e., L N X group directly bonded to L N When X is null, it is understood that X is directly bonded to the amide nitrogen atom of formula III or III-B. R is CR or a ring structure, preferably a 3- to 10-membered ring structure. R in each occurrence is independently hydrogen, halogen, optionally substituted C 1-4 Alkyl or optionally substituted C 1-4 Alkoxy, typically hydrogen or C 1-4 It is alkyl. A The maximum chain length of is at least -(CH2) 12 -, e.g., at least -(CH2) 14 - maximum chain length of at least -(CH2) 16 - maximum chain length of at least -(CH2) 18 - is the longest chain length. A The hydrophobicity of the corresponding compound HX 12-30The -C(O)-OH has a cLogP of at least 3, e.g., between 3 and 15, preferably at least 4 (e.g., at least 4.5, at least 5, at least 5.5, at least 6, at least 6.5, at least 7, etc.), and can be characterized as having a cLogP of, e.g., 3 to 10, 4 to 12, 4.5 to 9, 5 to 11, 5.5 to 10.5, 6 to 14, 6.5 to 13, etc. Preferably, the terminal X group is CR2, such as CH2. Preferably, L A The total number of non-hydrogen atoms in is between 15 and 50, e.g., 18, 20, 25, 30, 35, 40, 45, or 50, or any range between the recited values. In some preferred embodiments, none of the X groups is a ring structure. In some preferred embodiments, one instance of X is a ring structure, preferably a 3- to 10-membered ring structure. For example, in some embodiments, one instance of X is triazole, and the remaining X groups are each independently selected from C—R, —C(R)═C(R)—, JPEG2025502110000474.jpg11170 or O, and R at each occurrence is independently hydrogen or C alkyl. In some embodiments, no X group is a ring structure, and each X is independently CR, -C(R)=C(R)-, JPEG2025502110000475.jpg11170 or O, and R at each occurrence is independently hydrogen or C alkyl (preferably methyl). In some embodiments, all instances of X are CR, and R at each occurrence is independently hydrogen or C alkyl (preferably methyl). In some embodiments, up to six (e.g., 1, 2, 3, 4, 5, or 6) instances of X may be O. In some embodiments, one or two instances of X are O and all other instances of X are CR, where R at each occurrence is independently hydrogen or C alkyl (preferably methyl). In some embodiments, one or two instances of X are O, one X is triazole, and all other instances of X are CR, where R at each occurrence is independently hydrogen or C alkyl (preferably methyl). In some embodiments, R is hydrogen.

[0188] In some preferred embodiments, T of formula III-1-A (e.g., III-1-A-1), III-B-2, or III-B-3 A teeth, JPEG2025502110000476.jpg27170, where G 1 are independently hydrogen, halogen, or optionally substituted C 1-4 Alkyl or optionally substituted C 1-4 Heteroalkyl (optionally substituted C 1-4 alkoxy, etc.) or two gem-G 1 The groups may be bonded to form =O, =NH, or =N(C 1-4 alkyl), or two or more G 1 The groups can be linked to form a ring structure. The integer r is 1 to 10, such as 1 or 2. G in each occurrence 2 are independently hydrogen, G 10 , C(O)-G 10 , SO2G 10 , C(O)-NH-G 10 , or SO2NHG 10 , C(O)-OG 10 , or SO2OG 10 At each occurrence, G 10 are independently optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl or an optionally substituted 3- to 10-membered ring structure that can be carbocyclic, heterocyclic, aromatic, heteroaromatic, or a combination thereof. The fragments are (i) a CG group next to an NH group. 1 G 1 If the group is not C(=O), the corresponding compound JPEG2025502110000477.jpg30170 has a cLogP of less than 1, preferably less than 0 (e.g., less than −1, less than −2, less than −3, less than −3.5, less than −4, or less), or (ii) a CG next to NH 1 G 1 When the group is C(=O), the corresponding compound JPEG2025502110000478.jpg23170 is further characterized in that it has a cLogP of less than 1, preferably less than 0 (e.g., less than -1, less than -2, less than -3, less than -3.5, less than -4, or even less).

[0189] In some preferred embodiments, T of formula III-1-A (e.g., III-1-A-1), III-B-2, or III-B-3 A teeth, JPEG2025502110000479.jpg19170. In some embodiments, G 2 Examples of one or both of JPEG2025502110000480.jpg14170, where n is an integer of 0 to 100, preferably 0 to 10 (for example, 0 to 4, 1 to 5, or 2 to 6). 1 are CH2, C(O), SO, SO2, CH(C 1-4 alkyl), C(C 1-4 Alkyl)(C 1-4 alkyl) or a 3- to 10-membered ring structure. 2 are independently CH2, O, S, SO, SO2, C(O), CH(C 1-4 alkyl), C(C 1-4 Alkyl)(C 1-4 alkyl), NH, N(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 alkyl)] + Or a 3- to 10-membered ring structure. 3 is H, C 1-4 Alkyl, OH, SO3H, COOH, NH2, NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, SO2NH2, CONH(C 1-4 alkyl), CON(C 1-4Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), or SO2N(C 1-4 Alkyl)(C 1-4 C 1-4 Each alkyl is independently selected and optionally includes, for example, 1 to 3 G as defined herein. 20 In some embodiments, Z is substituted with a group. 2 In some embodiments, none of Z 2 One or more examples of the formula include 3-10 membered ring structures such as nitrogen-containing rings, e.g., JPEG2025502110000481.jpg25170. In some embodiments, Z 3 Directly connect to Z 2 is a 3- to 10-membered ring structure such as a nitrogen-containing ring, for example, JPEG2025502110000482.jpg26170, etc. Preferably, Z 2 Up to two instances of G are 3- to 10-membered ring structures. 2 are independently hydrogen, optionally substituted C 1-6 Alkyl or optionally substituted C 1-6 For example, when substituted, C 1-6 Alkyl is OH, NH2, oxo (=O), NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, C(O)OH, SO2NH2, SO3H, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), and SO2N(C 1-4 Alkyl)(C 1-4 C can be substituted with 1 to 3 substituents independently selected from alkyl. 1-4Each alkyl is independently selected and optionally includes, for example, 1 to 3 G as defined herein. 20 Each occurrence of G herein is substituted with a group. 20 The groups are OH, NH2, oxo (=O), NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, C(O)OH, SO2NH2, SO3H, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), SO2N(C 1-4 Alkyl)(C 1-4 alkyl), or a 3- to 10-membered ring structure. 1-4 Each alkyl is independently selected and optionally includes, for example, 1 to 3 G as defined herein. 21 Each occurrence of G herein is substituted with a group. 21 The groups are OH, NH2, oxo (=O), NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, C(O)OH, SO2NH2, SO3H, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), SO2N(C 1-4 Alkyl)(C 1-4 alkyl) or a 3- to 10-membered ring structure. 2 One or more examples of 1-4 alkylene)-NH2 or CONH-(C 1-4alkylene)-[N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + C optionally substituted with an amide derivative such as 1-4 For example, in some embodiments, G 2 One or two examples of -(C 1-4 alkylene)-COOH, and G 2 Any remaining instance of C 1-4 In some embodiments, G is alkyl. 2 One or two examples of JPEG2025502110000483.jpg20170 etc. -(C 1-4 alkylene)-CONH-(C 1-4 alkylene)-NH2, and G 2 Any remaining instance of C 1-4 In some embodiments, G is alkyl. 2 One or two examples of JPEG2025502110000484.jpg19170 etc. -(C 1-4 alkylene)-CONH-(C 1-4 alkylene)-[N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + and G 2 Any remaining instance of C 1-4 In some embodiments, T A teeth, JPEG2025502110000485.jpg43170. In some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000486.jpg45170. In some embodiments, T A teeth, JPEG2025502110000487.jpg43170. In some embodiments, T A teeth, JPEG2025502110000488.jpg28170. In some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000489.jpg60170. In some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), For example, in some embodiments, T A teeth JPEG2025502110000491.jpg51170. In some embodiments, T A teeth JPEG2025502110000492.jpg34170. In some embodiments, T A teeth JPEG2025502110000493.jpg38170. In some embodiments, T A teeth JPEG2025502110000494.jpg24170. In some embodiments, T A teeth JPEG2025502110000495.jpg23170. In some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000496.jpg23170. In some embodiments, T A teeth JPEG2025502110000497.jpg27170. In some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000498.jpg24170. In some embodiments, T A teeth It could also be JPEG2025502110000499.jpg19170.

[0190] In some preferred embodiments, the T of III-1-A (e.g., III-1-A-1), III-B-2, or III-B-3 A teeth, JPEG2025502110000500.jpg25170 can be characterized as having the structure G 1 are independently hydrogen, halogen, or optionally substituted C 1-4 Alkyl or optionally substituted C 1-4 Heteroalkyl (optionally substituted C 1-4 alkoxy, etc.) or two gem-G 1 The groups may be bonded to form =O, =NH, or =N(C 1-4 alkyl), or two or more G 1 The groups can be linked to form a ring structure. The integer r is 1 to 10, such as 1 or 2. G in each occurrence 4 are independently hydrogen or G 10 At each occurrence, G 10 are independently optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl or an optionally substituted 3- to 10-membered ring structure that can be carbocyclic, heterocyclic, aromatic, heteroaromatic, or a combination thereof. JPEG2025502110000501.jpg24170 is (i) the CG next to NH 1 G 1 If the group is not C(=O), the corresponding compound JPEG2025502110000502.jpg27170 has a cLogP of less than 1, preferably less than 0 (e.g., less than -1, less than -2, less than -3, less than -3.5, less than -4, or less), or (ii) a CG next to NH 1 G 1 When the group is C(=O), the corresponding compound JPEG2025502110000503.jpg23170 is characterized as having a cLogP of less than 1, preferably less than 0 (e.g., less than -1, less than -2, less than -3, less than -3.5, less than -4, or even less).

[0191] In some preferred embodiments, T of formula III-1-A (e.g., III-1-A-1), III-B-2, or III-B-3 A teeth, JPEG2025502110000504.jpg20170. In some embodiments, G 4 One or more instances of It may have a structure of JPEG2025502110000505.jpg15170, where n is an integer of 0 to 100, preferably 0 to 10 (for example, 0 to 4, 1 to 5, or 2 to 6). 1 are CH2, C(O), SO2, CH(C 1-4 alkyl), or C(C 1-4 Alkyl)(C 1-4 (alkyl). Z in each occurrence 2 are independently CH2, O, S, SO, SO2, C(O), CH(C 1-4 alkyl), C(C 1-4 Alkyl)(C 1-4 alkyl), NH, N(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 alkyl)] + Or a 3- to 10-membered ring structure. 3 is H, C 1-4 Alkyl, OH, SO3H, COOH, NH2, NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, SO2NH2, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4alkyl), SO2NH(C 1-4 alkyl), or SO2N(C 1-4 Alkyl)(C 1-4 C 1-4 Each alkyl is independently selected and optionally includes, for example, 1 to 3 G as defined herein. 20 Preferably, Z 2 Up to two instances of Z are 3- to 10-membered ring structures. 2 In some embodiments, none of Z 2 One example of the ring structure is a 3-10 membered ring structure such as a nitrogen-containing ring, for example: JPEG2025502110000506.jpg24170. In some embodiments, 4 are independently hydrogen, optionally substituted C 1-6 Alkyl or optionally substituted C 1-6 For example, when substituted, C 1-6 Alkyl is OH, NH2, oxo (=O), NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, C(O)OH, SO2NH2, SO3H, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), and SO2N(C 1-4 Alkyl)(C 1-4 C can be substituted with 1 to 3 substituents independently selected from alkyl. 1-4 Each alkyl is independently selected and optionally includes, for example, 1 to 3 G as defined herein. 20 Each occurrence of G herein is substituted with a group. 20 The groups are OH, NH2, oxo (=O), NH(C 1-4 alkyl), N(C 1-4Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, C(O)OH, SO2NH2, SO3H, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), SO2N(C 1-4 Alkyl)(C 1-4 alkyl), or a 3- to 10-membered ring structure. 1-4 Each alkyl is independently selected and optionally includes, for example, 1 to 3 G as defined herein. 21 Each occurrence of G herein is substituted with a group. 21 The groups are OH, NH2, oxo (=O), NH(C 1-4 alkyl), N(C 1-4 Alkyl)(C 1-4 alkyl), [N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + , C(O)NH2, C(O)OH, SO2NH2, SO3H, CONH(C 1-4 alkyl), CON(C 1-4 Alkyl)(C 1-4 alkyl), SO2NH(C 1-4 alkyl), SO2N(C 1-4 Alkyl)(C 1-4 alkyl) or a 3- to 10-membered ring structure. 4 One or more examples of C, such as methyl 1-4 In some embodiments, G is alkyl. 4 One or more examples of 1-4 alkylene)-NH2 or CONH-(C 1-4 alkylene)-[N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] +C optionally substituted with an amide derivative such as 1-4 For example, in some embodiments, G 4 One or two examples of -(C 1-4 alkylene)-COOH, and G 4 Any remaining instance of C 1-4 In some embodiments, G is alkyl. 4 One or two examples of JPEG2025502110000507.jpg19170 etc. -(C 1-4 alkylene)-CONH-(C 1-4 alkylene)-NH2, and G 4 Any remaining instance of C 1-4 In some embodiments, G is alkyl. 4 One or two examples of JPEG2025502110000508.jpg19170 etc. -(C 1-4 alkylene)-CONH-(C 1-4 alkylene)-[N(C 1-4 Alkyl)(C 1-4 Alkyl)(C 1-4 alkyl)] + and G 4 Any remaining instance of C 1-4 In some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000509.jpg83170. In some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000510.jpg40170. In some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000511.jpg29170. In some embodiments, T Ais optionally charge balanced with a counterion (e.g., as described herein), For example, in some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000513.jpg48170. In some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000514.jpg33170. In some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000515.jpg24170. In some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000516.jpg26170. In some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000517.jpg31170. In some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000518.jpg23170. In some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000519.jpg23170. In some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000520.jpg31170. In some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000521.jpg16170. In some embodiments, T A is optionally charge balanced with a counterion (e.g., as described herein), JPEG2025502110000522.jpg34170. In some embodiments, T A teeth It could also be JPEG2025502110000523.jpg16170.

[0192] In some preferred embodiments, the present disclosure also provides a compound of formula III-4-A or III-5-A, or a pharmaceutically acceptable salt or ester thereof: JPEG2025502110000524.jpg115170In formula, X, m1, L N , G 1 , G 2 , G 4 , r, and JPEG2025502110000525.jpg9170 is defined herein and includes any of the preferred groups described herein with respect to Formula III (e.g., III-1, III-4, III-5, III-1-A, III-1-A-1, etc.), in any combination. For example, in some embodiments, L N teeth, Branched or linear C such as JPEG2025502110000526.jpg23170 (X is shown to indicate the linkage direction) 1-6 In some embodiments, L is alkyl. N In some embodiments, X in each occurrence is independently selected from the group consisting of CR, -C(R)=C(R)-, JPEG2025502110000527.jpg11170SiR2, C(O), O, NR, S, SO2, or a ring structure, preferably a 3- to 10-membered ring structure, N X group (L N When R is null, it should be understood that a covalent bond is formed with the amide nitrogen atom of formula III-4-A or III-5-A. R is CR, or a ring structure, preferably a 3- to 10-membered ring structure, more preferably CR, such as CH. R in each occurrence is independently hydrogen, halogen, optionally substituted C. 1-4 Alkyl or optionally substituted C 1-4 Alkoxy, typically hydrogen or C 1-4 In some embodiments, the integer m1 may be 12 to 50, for example, 14 to 50, 16 to 30, etc. Preferably, (X) m1 The total number of non-hydrogen atoms in the moiety is between 15 and 50, e.g., 18, 20, 25, 30, 35, 40, 45, or 50, or any range between the recited values. In some preferred embodiments, none of the X groups is a ring structure. In some preferred embodiments, one instance of X is a ring structure, preferably a 3- to 10-membered ring structure. For example, in some embodiments, one instance of X is triazole, and the remaining X groups are each independently selected from the group consisting of -CR2, -C(R)=C(R)- ... JPEG2025502110000528.jpg12170 or O, more preferably CR2 or O, and R at each occurrence is independently hydrogen or C1-4 alkyl. In some embodiments, no X group is a ring structure, and each X is independently CR2, -C(R)=C(R)-, JPEG2025502110000529.jpg10170 or O, more preferably CR2 or O, where R at each occurrence is independently hydrogen or C1-4 alkyl. In some embodiments, up to six (e.g., 1, 2, 3, 4, 5, or 6) instances of X may be O. In some embodiments, all instances of X are CR2, and R at each occurrence is independently hydrogen or C1-4 alkyl (preferably methyl). In some embodiments, one or two instances of X are O, and all other instances of X are CR2, where R at each occurrence is independently hydrogen or C1-4 alkyl (preferably methyl). In some embodiments, one or two instances of X are O, one X is triazole, and all other instances of X are CR2, where R at each occurrence is independently hydrogen or C1-4 alkyl (preferably methyl). In some embodiments, R is hydrogen. G 1 , G 2 , G 4 , r, and The definition and preferred definition of JPEG2025502110000530.jpg10170 are also described herein, including any of the corresponding definitions set forth for any of the compounds listed in Table 1 herein, or any of the compounds according to Examples 1 to 221.

[0193] In some embodiments, the present disclosure also provides a compound selected from Table 1 below, or a pharmaceutically acceptable salt or ester thereof, wherein A - is a counter ion, preferably Cl - It is apparent that under certain conditions, the compounds shown in Table 1 may exist as internal salts, i.e., zwitterionic structures, in which case A - may not be necessary to balance the charge shown. As used herein, the compounds shown in Table 1 (A - Inner salts derivable from the compounds shown in Table 1, with or without (within the formula (I)), are within the definition of a compound shown in Table 1 or a pharmaceutically acceptable salt thereof. JPEG2025502110000531.jpg48170JPEG2025502110000532.jpg218170JPEG2025502110000533.jpg232170JPEG2025 502110000534.jpg229170JPEG2025502110000535.jpg216170JPEG2025502110000536.jpg214170JPEG20255021100 00537.jpg233170JPEG2025502110000538.jpg221170JPEG2025502110000539.jpg224170JPEG2025502110000540.j pg222170JPEG2025502110000541.jpg219170JPEG2025502110000542.jpg218170JPEG2025502110000543.jpg215170 JPEG2025502110000544.jpg216170JPEG2025502110000545.jpg209170JPEG2025502110000546.jpg210170JPEG202 5502110000547.jpg212170JPEG2025502110000548.jpg213170JPEG2025502110000549.jpg231170JPEG2025502110 000550.jpg215170JPEG2025502110000551.jpg233170JPEG2025502110000552.jpg234170JPEG2025502110000553. jpg243170JPEG2025502110000554.jpg223170JPEG2025502110000555.jpg218170JPEG2025502110000556.jpg70170

[0194] In some embodiments, any one of the compounds in Table 1 can be present in the form of a pharmaceutically acceptable salt.

[0195] In some embodiments, any one of the compounds in Table 1 can be present in the form of a pharmaceutically acceptable ester, or a pharmaceutically acceptable salt thereof.

[0196] In some embodiments, the present disclosure also provides a compound according to any of Examples 1-221, or a pharmaceutically acceptable salt thereof. A compound according to any of Examples 1-221 should be understood as the same compound depicted in Examples 1-221, without regard to its salt form and / or counterion. The compound may exist in different salt forms and / or contain different counterions.

[0197] In some embodiments, the present disclosure also provides a compound according to any of GPR-1, GPR-2, GPR-2B, GPR-3, or GPR-3B, or a pharmaceutically acceptable salt or ester thereof.

[0198] As discussed herein, the inventors have A and T A cLogP and L A It is believed that the length of the L, rather than their exact identity, is important in achieving potent GPR40 agonist activity. Tables A-1a, A-1b, A-2a, A-2b, A-3a, A-3b, A-4a, A-4b, A-5a, A-5b, A-6a, A-6b, A-7, and A-8 below show the L for representative compounds of the present disclosure. A and T A Further support for the role of cLogP in L A When the cLogP of GPR40 falls below a certain point, the activity of GPR40 decreases significantly (as indicated by a significant increase in the EC50 value). The EC50 values ​​in the table were obtained by the following method described in Biological Example 1.

[0199] JPEG2025502110000557.jpg121170

[0200] JPEG2025502110000558.jpg74170JPEG2025502110000559.jpg62170

[0201] JPEG2025502110000560.jpg60170* L NIt should be noted that the designation is only one way of subdividing the molecule and is not limiting; the same applies to L N It should also be understood that other tables in this specification also carry the designation L. N L A It is clear that the cLogP values ​​may change when included as part of the JPEG2025502110000561.jpg44170

[0202] JPEG2025502110000562.jpg64170JPEG2025502110000563.jpg53170

[0203] JPEG2025502110000564.jpg113170

[0204] JPEG2025502110000565.jpg113170

[0205] JPEG2025502110000566.jpg101170

[0206] JPEG2025502110000567.jpg100170

[0207] JPEG2025502110000568.jpg62170JPEG2025502110000569.jpg44170

[0208] JPEG2025502110000570.jpg122170

[0209] JPEG2025502110000571.jpg110170

[0210] JPEG2025502110000572.jpg65170JPEG2025502110000573.jpg47170

[0211] JPEG2025502110000574.jpg107170

[0212] JPEG2025502110000575.jpg119170

[0213] JPEG2025502110000576.jpg120170JPEG2025502110000577.jpg250170JPEG2025502110000578.jpg254170JPEG2025502110000579.jpg231170

[0214] The compounds herein can be prepared by one of ordinary skill in the art in light of the present disclosure. Exemplary syntheses, such as those shown in the schemes in the Examples section, are provided in the Examples section that can be adapted by one of ordinary skill in the art to synthesize other compounds of the present disclosure.

[0215] As exemplified herein, the compounds of the present disclosure can typically be prepared by coupling a residue of a GPR40 agonist with a hydrophilic molecule. Suitable coupling reactions are not particularly limited, but depend on the structural characteristics of the compound.

[0216] For example, in some embodiments, the compound contains a triazole and can be synthesized by coupling an azide-containing compound with an alkyne-containing compound under click chemistry conditions. Click chemistry is well known in the art, and suitable reaction conditions include those known in the art and those exemplified herein. Using compounds of formula II-5 or III-5 as an example, when one instance of X is a triazole, the compound can be synthesized by coupling an appropriate alkyne with an azide under click chemistry conditions to form a target compound of formula II-5 or III-5 (see Scheme A-1 or B-1 below). For example, in Scheme A-1, compound S-1 can be coupled with compound S-2 under click chemistry conditions, where J10 is an alkyne and J11 is N3, or J10 is N3 and J11 is an alkyne, to form a compound of formula II-5. One instance of X is triazole, and a+b+1 is equal to m1. The variable L in Scheme A-1 10 , L N , R 11 , R 12 , R 13 , R A , R C , X, Y, Z, G 1 , G 3 , G 4 , A - , r, m1, p1, and p2 include any of the preferred ones described herein in relation to Formula II, in any combination, provided that one example of X in Formula II-5 is J 10 and J 11 Similarly, in Scheme B-1, compound S-3 can be coupled with compound S-2 under click chemistry conditions, where J 10 is an alkyne and J 11 is N3 or J 10 is N3 and J11 is an alkyne, forming a compound of formula III-5. One example of X is triazole, and a+b+1 is equal to m1. The variable L in Scheme B-1 10, L N , R 11 , R 12 , R 18 , R A , R C , ring A, X, Y, Z, G 1 , G 3 , G 4 , A - , r, m1, p1, and p2 include any of the preferred ones described herein in relation to Formula III, in any combination, provided that one example of X in Formula III-5 is J 10 and J 11 is a triazole formed by coupling of JPEG2025502110000580.jpg103170JPEG2025502110000581.jpg93170

[0217] In some embodiments, amide coupling can be used to link the residue of a GPR40 agonist with a hydrophilic molecule. For example, the compound of formula II-4 can be prepared according to the synthetic sequence shown in Scheme A-2, in which the acid of S-4 can be converted to the amine of S-5 under amide coupling conditions, followed by deprotection to obtain the compound of formula II-4. Pg in S-4 1 refers to a carboxylic acid protecting group, such as a tert-butyl group. Similarly, as shown in Scheme A-3, compounds of formula II-5 can be prepared by coupling the acid of S-4 with the amine of S-6 under amide coupling conditions, followed by deprotection to give compounds of formula II-5. The variable L in Scheme A-2 or A-3 can be 10 , L N , R 11 , R 12 , R 13 , R A , R C , X, Y, Z, G 1 , G 2 , G 3 , G 4 , A -, r, m1, p1, and p2 include any of the preferred ones described herein in connection with Formula II, in any combination. JPEG2025502110000582.jpg79170JPEG2025502110000583.jpg86170

[0218] For example, compound III-4 can be prepared according to the synthetic sequence shown in Scheme B-2, in which the acid of S-7 can be converted to the amine of S-5 under amide coupling conditions, followed by deprotection to give compound III-4. 1 refers to a carboxylic acid protecting group, such as a tert-butyl group. Similarly, as shown in Scheme B-3, compounds of formula III-5 can be prepared by coupling the acid of S-8 with the amine of S-6 under amide coupling conditions, followed by deprotection to give compounds of formula III-5. The variable L in Scheme B-2 or B-3 10 , L N , R 11 , R 12 , R 18 , R A , R C , ring A, X, Y, Z, G 1 , G 2 , G 3 , G 4 , A - , r, m1, p1, and p2 include any of the preferred ones described herein in connection with Formula III, in any combination. JPEG2025502110000584.jpg87170JPEG2025502110000585.jpg89170

[0219] Similarly, the compound of formula I can be prepared through click chemistry or amide coupling reaction. For example, as shown in Scheme C-1, the compound of formula I-5 can be prepared by coupling the compound of S-2 with the compound of S-9 under click chemistry conditions. Here, J10 is an alkyne and J11 is N3, or J10 is N3 and J11 is an alkyne. One example of X in formula I-5 is triazole, and a+b+1 is equal to m1. The variable L in Scheme C-1 10 , J 1 , J 2 , J 3 , R A , R B , G 1 , G 3 , G 4 , A - , r, m1, p1, and p2 include any of the preferred ones described herein in connection with Formula I, in any combination, except that one example of X in Formula I-5 is a triazole formed by coupling J10 with J11. As shown in Scheme C-2, in some embodiments, compounds of Formula I-5 can be prepared by coupling an acid of S-10 with an amine of S-6 under amide coupling conditions, followed by deprotection to obtain compounds of Formula I-5. Pg of S-10 1 refers to a carboxylic acid protecting group such as a tert-butyl group. 10 , J 1 , J 2 , J 3 , R A , R B , G 1 , G 3 , G 4 , A - , r, m1, p1, and p2 include any of the preferred ones described herein in connection with Formula I, in any combination. JPEG2025502110000586.jpg77170JPEG2025502110000587.jpg75170

[0220] Other compounds of Formula I, II, II-B, III, or III-B can be prepared similarly to those shown in Schemes A-1, A-2, A-3, B-1, B-2, B-3, C-1, and C-2. Illustrated procedures are also provided in the Examples section herein.

[0221] In some embodiments, the present disclosure also provides synthetic intermediates and methods according to any of those described herein, such as those shown in Schemes A-1, A-2, A-3, B-1, B-2, B-3, C-1, and C-2, and those shown in the schemes in the Examples section. For clarity, synthetic intermediates shown in the Examples section having different salt forms and / or different counterions are within the scope of the present disclosure. In...

Claims

1. A compound of formula III or III-B, or a pharmaceutically acceptable salt or ester thereof: During the ceremony, Y is CH, CR A , or N, Z is O, S, NH, or N(C 1-4 alkyl), R 11 and R 12 are each independently hydrogen or C 1-4 is alkyl, Ring A is an optionally substituted 4- to 12-membered nitrogen-containing ring; Ring B is an optionally substituted monocyclic heteroaryl or bicyclic aryl or heteroaryl ring such as a benzofuran ring; L N is an empty (null) or an arbitrarily substituted C 1-6 alkylene or optionally substituted C having 1 to 3 heteroatoms 1-6 is heteroalkylene, L 10 is alkylene, halogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 1-6 Alkoxy, optionally substituted C 3-6 optionally substituted with 1 to 3 substituents independently selected from cycloalkoxy, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two substituents joined to form an optionally substituted ring system; R at each occurrence A are independently selected from halogen, CN, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 1-6 Alkoxy or optionally substituted C 3-6 cycloalkoxy or two R A are linked to form an optionally substituted ring structure, and p1 is 0, 1, or 2; R at each occurrence C are independently selected from halogen, CN, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 1-6 Alkoxy or optionally substituted C 3-6 cycloalkoxy or two R C are linked to form an optionally substituted ring structure, and p2 is 0, 1, 2, or 3; R 18 is an optionally substituted phenyl or an optionally substituted heteroaryl; where: q is an integer from 1 to 10, preferably 1 or 2; T A L A wherein (1) if the terminal atom is N of a basic amine group, the corresponding compound T A -(C(O)-CH 3 ) q has a cLogP less than 1 and -C(O)-CH 3 is bonded to the terminal N atom, and (2) if the terminal atom is C of a C(O) group, the corresponding compound T A -(OH) q has a cLogP less than 1, -OH is bonded to the terminal C atom, and (3) the terminal atom is SO 2 When the group S is the corresponding compound T A -(OH) q has a cLogP less than 1, and -OH is bonded to the terminal S atom, or (4) if (1) to (3) do not apply, the corresponding compound T A -H q has a cLogP less than 1, L A L A The maximum length between the two terminal non-hydrogen atoms of 2 ) 10 a linker characterized in that the maximum length between the two terminal carbon atoms of L is A Only one terminal atom of A C(O)C or SO 2 group S and the corresponding compound HL A -OH has a cLogP of at least 3 and -OH is a terminal C(O) or SO 2 or (2) L A Either of the terminal atoms is C(O)C or SO 2 Not the group S, but the corresponding compound HL A -H has a cLogP of at least 3.

2. (1) q is 1, (2) L N is either (i) empty (null), or (ii) (L A (The symbol is shown to indicate the linkage direction) 1-6 (3) p1 is 0 or p1 is 1; and (4) R A are independently F, Cl, CN, C optionally substituted with 1 to 3 fluorines 1-4 alkyl or C optionally substituted with 1 to 3 fluorines 1-4 (5) p2 is 0 or p2 is 1, and R C is F, Cl, CN, C optionally substituted with 1 to 3 fluorines 1-4 alkyl or C optionally substituted with 1 to 3 fluorines 1-4 (6) Y is N; (7) Z is O; and / or (8) R 11 and R 12 and R are both hydrogen, or a pharmaceutically acceptable salt or ester thereof.

3. (1)L 10 teeth and CR 16 R 17 binds to the COOH group, R 14 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 cycloalkyl, phenyl, 5- or 6-membered heteroaryl, or 3- to 7-membered heterocyclyl, wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heteroaryl, and heterocyclyl is optionally substituted with F, —OH, oxo (where applicable), C 1-4 Alkyl, Fluoro-substituted C 1-4 Alkyl (e.g., CF 3 ), C 1-4 Alkoxy and Fluoro Substituted C 1-4 optionally substituted with 1, 2, or 3 substituents independently selected from alkoxy; 15 , R 16 and R 17 are each independently hydrogen or C 1-4 alkyl, or R 14 and R 15 are joined to form a 3- to 7-membered ring having 0, 1, or 2 heteroatoms selected from O, N, or S; (2)R 18 are F, Cl, CN, OH, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy or C 3-6 a 6-membered heteroaryl ring optionally substituted with 1 to 3 substituents independently selected from cycloalkoxy, e.g., wherein alkyl, heteroalkyl, cycloalkyl, alkoxy or cycloalkoxy is C optionally substituted with F, —OH, F 1-4 Alkoxy, oxo (where applicable), NH 2 , NH(C 1-4 alkyl), N(C 1-4 Alkyl ((C 1-4 alkyl), and C optionally substituted with F 1-4 and / or (3) Ring A is a 4- to 8-membered, optionally substituted, monocyclic, saturated heterocycle having one or two ring heteroatoms independently selected from S, O, and N, provided that at least one of the ring heteroatoms is nitrogen; and optionally, Ring A is selected from: Each of these is F, OH, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) (C 1-4 alkyl), C optionally substituted with 1 to 3 fluorines 1-4 alkyl or C optionally substituted with 1 to 3 fluorines 1-4 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt or ester thereof, optionally substituted with 1 to 2 substituents independently selected from alkoxy.

4. having formula III-1-A or III-B-2, During the ceremony, R 14 is hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 cycloalkyl, phenyl, 5- or 6-membered heteroaryl, or 3- to 7-membered heterocyclyl, wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heteroaryl, and heterocyclyl is optionally substituted with F, —OH, oxo (where applicable), C 1-4 Alkyl, Fluoro-substituted C 1-4 Alkyl (e.g., CF 3 ), C 1-4 Alkoxy and Fluoro Substituted C 1-4 optionally substituted with 1, 2, or 3 substituents independently selected from alkoxy; 15 , R 16 and R 17 are each independently hydrogen or C 1-4 alkyl, or R 14 and R 15 are joined to form a 3- to 7-membered ring having 0, 1, or 2 heteroatoms selected from O, N, or S; R at each occurrence D are independently F, Cl, C optionally substituted with 1 to 3 F 1-4 alkyl or C optionally substituted with 1 to 3 F 1-4 is an alkoxy, p3 is 0, 1, 2, or 3, and optionally (i)R 16 and R 17 are both hydrogen or R 16 and R 17 is hydrogen and R 16 and R 17 the other is methyl, and / or (ii)R 14 and R 15 is hydrogen and R 14 and R 15 The other is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, or C 3-6 4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt or ester thereof, which is cycloalkyl.

5. 10. The compound of claim 1, or a pharmaceutically acceptable salt or ester thereof, wherein q is 1 and the compound has the formula III-1-A-1 or III-B-3.

6. L A L A The maximum length between the two terminal atoms of is at least -(CH 2 ) 12 The maximum length between the two terminal carbon atoms of - is preferably at least -(CH 2 ) 14 The maximum length between the two terminal carbon atoms of -, more preferably at least -(CH 2 ) 16 -, and optionally, L A Only one terminal atom of T A C(O)C or SO 2 The base is S, L A is the corresponding compound HL A -OH has a cLogP of at least 4 and -OH is a terminal C(O) or SO 2 or L A is the corresponding compound HL A -OH has a cLogP of 3 to 15, and -OH is a terminal C(O) or SO 2 6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or ester thereof, which is bound to a group.

7. (1) The terminal atom is N of a basic amine group, and T A is the corresponding compound T A -(C(O)-CH 3 ) q (2) the terminal atom is a C of a C(O) group; and T A is the corresponding compound T A -(OH) q (3) the terminal atom has a cLogP of less than 0 (e.g., less than -1, less than -2, less than -3, less than -3.5, less than -4, or less), and 2 The base is S and T A is the corresponding compound T A -(OH) q or (4) the terminal atom is an N of a basic amine group, a C of a C(O) group, or an SO 2 T, not S A is the corresponding compound T A -H q 7. The compound of claim 1, or a pharmaceutically acceptable salt or ester thereof, wherein the compound has a cLogP of less than 0 (e.g., less than -1, less than -2, less than -3, less than -3.5, less than -4, or even less).

8. (1)T A is T A1 , T A1 -L B -, T A1 -L B -(heteroalkylene), or T A1 -L B -(heteroalkylene)-L B - and L in each occurrence B independently, -SO 2 -, -C(=O)-, or a moiety selected from: R at each occurrence 100 , R 101 , and R 102 are independently hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl; T A1 is characterized as having the following structure: G in each occurrence 1 are independently hydrogen, halogen, or optionally substituted C 1-4 Alkyl or optionally substituted C 1-4 heteroalkyl (such as optionally substituted C1-4 alkoxy) or two gem-G 1 The groups may be bonded to form =O, =NH, or =N(C 1-4 alkyl), or two or more G 1 the groups can be linked to form a ring structure; the integer r is 1 to 10, such as 1 or 2; G in each occurrence 2 are independently hydrogen, G 10 , C(O)-G 10 , SO 2 G 10 , C(O)-NH-G 10 , or SO 2 NHG 10 , C(O)-OG 10 , or SO 2 OG 10 and G at each occurrence 10 are independently optionally substituted alkyl, optionally substituted heteroalkyl, or an optionally substituted 3- to 10-membered ring structure which may be carbocyclic, heterocyclic, aromatic, heteroaromatic, or combinations thereof; G 3 is hydrogen or optionally substituted alkyl (e.g., C 1-4 alkyl), Or two Gs 2 , or one G 2 and one G 1 , or one G 1 and G 3 can be linked to form a ring structure, such as a 3- to 10-membered ring structure; Fragment (i)NG 3 The CG next to 1 G 1 If the group is not C(=O), the corresponding compound has a cLogP of less than 1, preferably less than 0 (e.g., less than -1, less than -2, less than -3, less than -3.5, less than -4, or less), or (ii) NG 3 The CG next to 1 G 1 When the group is C(=O), the corresponding compound is further characterized by having a cLogP of less than 1, preferably less than 0 (e.g., less than -1, less than -2, less than -3, less than -3.5, less than -4, or even less); Fragment (i) If the nitrogen is a basic nitrogen, the corresponding compound (G 2 ) 2 N-C(O)-CH 3 has a cLogP of less than 1, preferably less than 0 (e.g., less than −1, less than −2, less than −3, less than −3.5, less than −4, or less), or (ii) if the nitrogen is a non-basic nitrogen, the corresponding compound (G 2 ) 2 NH has a cLogP of less than 1, preferably less than 0 (e.g., less than -1, less than -2, less than -3, less than -3.5, less than -4, or even less); or (2)T A is T A1 , T A1 -L B -, T A1 -L B -(heteroalkylene), or T A1 -L B -(heteroalkylene)-L B - and L in each occurrence B independently, -SO 2 -, -C(=O)-, or a moiety selected from: R at each occurrence 100 , R 101 , and R 102 are independently hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl; T A1 is characterized as having the following structure: optionally charge-balanced with counterions (e.g., those described herein); G in each occurrence 1 are independently hydrogen, halogen, or optionally substituted C 1-4 Alkyl or optionally substituted C 1-4 Heteroalkyl (optionally substituted C 1-4 alkoxy, etc.), or two gem-G 1 The groups may be bonded to form =O, =NH, or =N(C 1-4 alkyl), or two or more G 1 the groups can be linked to form a ring structure; the integer r is 1 to 10, such as 1 or 2; G 3 is hydrogen or optionally substituted alkyl (e.g., C 1-4 alkyl), G in each occurrence 4 are independently hydrogen or G 10 and G at each occurrence 10 are independently an optionally substituted alkyl, an optionally substituted heteroalkyl, or an optionally substituted 3- to 10-membered ring structure which may be carbocyclic, heterocyclic, aromatic, heteroaromatic, or a combination thereof; or two G 4 , or one G 4 and one G 1 , or one G 1 and G 3 can be linked to form an optionally substituted 3- to 10-membered ring structure; Fragment (i) CG next to NH 1 G 1 If the group is not C(=O), the corresponding compound has a cLogP of less than 1, preferably less than 0 (e.g., less than -1, less than -2, less than -3, less than -3.5, less than -4, or less), or (ii) a CG 1 G 1 When the group is C(=O), the corresponding compound or a pharmaceutically acceptable salt or ester thereof, wherein the compound has a cLogP of less than 1, preferably less than 0 (e.g., less than -1, less than -2, less than -3, less than -3.5, less than -4, or even less).

9. G 3 is hydrogen, and / or G at each occurrence 1 9. The compound of claim 8, or a pharmaceutically acceptable salt or ester thereof, wherein is hydrogen.

10. T A and the terminal atoms of L A is an amide bond; or T A and the terminal atoms of L A or a pharmaceutically acceptable salt or ester thereof, wherein the covalent bond between the first terminal atom of

11. (1)L A is (X) m and X in each occurrence is independently 2 , C(=O), -C(R)=C(R)-, SiR 2 , O, S, SO 2 ,NR,[NR 2 ] ＋ or a ring structure, preferably a 3- to 10-membered ring structure, wherein R in each occurrence is independently hydrogen, halogen, optionally substituted C 1-4 Alkyl or optionally substituted C 1-4 alkoxy, typically R is hydrogen or C 1-4 alkyl, and the integer m is at least 10, for example, at least 12, at least 14, at least 16, at least 18, at least 20, at least 50, such as 12 to 50, 16 to 50, and preferably L N is null, the X group directly bonded to the amide nitrogen in formula III or III-B is CR 2 , preferably CH 2 and (2)L A -(X) m-1 -C(O)-, with the C(O) terminus being T A and X in each occurrence independently binds to CR 2 , C(=O), -C(R)=C(R)-, SiR 2 , O, S, SO 2 ,NR,[NR 2 ] ＋ or a ring structure, preferably a 3- to 10-membered ring structure, provided that the terminal X group is CR 2 or a ring structure, preferably a 3- to 10-membered ring structure, wherein R in each occurrence is independently hydrogen, halogen, optionally substituted C 1-4 Alkyl or optionally substituted C 1-4 alkoxy, typically R is hydrogen or C 1-4 alkyl, and the integer m is at least 10, e.g., at least 12, at least 14, at least 16, at least 18, at least 20, at least 50, such as 12 to 50, 16 to 50, and -(X) m-1 The hydrophobicity of -C(O)- is similar to that of the corresponding compound H-(X) m-1 -COOH has a cLogP of at least 3, for example between 3 and 15, preferably at least 4, and preferably L N is null, the X group directly bonded to the amide nitrogen in formula III or III-B is CR 2 , preferably CH 2 and (3)L A -C 12-30 Alkylene- or -C 12-30 Alkylene-C(O)-, -C 12-30 Alkylene- is optionally substituted, and the optional substituents can optionally be joined together to form a double bond, a triple bond, or a ring structure, preferably -C 12-30 The terminal carbon atom of alkylene is not substituted with (=O) (4)L A or L N -L A teeth, It has the structure of C 10-26 Alkylene is optionally substituted and each occurrence of G A are independently hydrogen or optionally substituted C 1-4 Alkyl or two G A are linked to form a 3- to 6-membered ring such as a cyclopropyl or cyclobutyl ring, and preferably A is methyl, and (5)L A is a 12- to 30-membered heteroalkylene or -(12- to 30-membered heteroalkylene)-C(O)-, wherein said 12- to 30-membered heteroalkylene is optionally substituted and contains 1 to 6 heteroatoms independently selected from O, N, and S, said sulfur atom, if present, is optionally oxidized, and any substituents can optionally be joined together to form a double bond, a triple bond, or a ring structure, preferably L N The terminal atom of the 12- to 30-membered heteroalkylene that forms a covalent bond with N is a carbon atom of a non-carbonyl group, and when is null, it is understood that a covalent bond is formed with the amide nitrogen atom of formula III or III-B. (6)L A teeth and the carbonyl end is T A Combines with L A1 and L A2 each independently represents a bond, an optionally substituted -C 1-30 alkylene- or optionally substituted -C containing 1 to 6 heteroatoms independently selected from O, N, and S 1-30 heteroalkylene-, wherein the sulfur atom, if present, is optionally oxidized, and the optional substituents can optionally be joined together to form a double bond, a triple bond, or a ring structure, provided that L A The maximum chain length of is at least -(CH 2 ) 12 -, for example, at least -(CH 2 ) 14 -, the maximum chain length is at least -(CH 2 ) 16 -, the maximum chain length is at least -(CH 2 ) 18 - the longest chain length is preferably T A Forms a covalent bond with L A1 or L A2 The terminal atom of the C(O) group is not the C or S of the SO2 group, but L. N Forms a covalent bond with L A1 or L A2 The terminal atom (L N is null, it should be understood that a covalent bond is formed with the amide nitrogen atom of formula III or III-B) is a carbon atom of a non-carbonyl group, or (7)L A or L N -L A teeth, having the structure C 0-26 Alkylene, or C 1-30 Alkylene is optionally substituted and each occurrence of G A are independently hydrogen or optionally substituted C 1-4 Alkyl or two G A or a pharmaceutically acceptable salt or ester thereof, of any one of claims 1 to 10, wherein:

12. T A is T A1 or T A1 -C(O)-, T A1 teeth, and T A is optionally charge balanced with a counterion (e.g., as described herein), or a pharmaceutically acceptable salt or ester thereof.

13. A compound of formula I, or a pharmaceutically acceptable salt or ester thereof, or a compound of formula II or II-B, or a pharmaceutically acceptable salt or ester thereof: During the ceremony, L 10 is alkylene (e.g., C 1-6 alkylene), halogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 1-6 Alkoxy, optionally substituted C 3-6 optionally substituted with 1 to 3 substituents independently selected from cycloalkoxy, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two substituents joined to form an optionally substituted ring system; R at each occurrence A are independently selected from halogen, CN, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 1-6 Alkoxy or optionally substituted C 3-6 cycloalkoxy or two R A are linked to form an optionally substituted ring structure, and p1 is 0, 1, or 2; R at each occurrence B are independently selected from halogen, hydroxyl, amino, substituted amino, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 1-6 Alkoxy or optionally substituted C 3-6 cycloalkoxy or two R B are linked to form an optionally substituted ring structure, and p2 is 0, 1, 2, 3, or 4; J 1 is a bond, an optionally substituted aryl or heteroaryl ring, -C 1-6 Alkylene-N(R 100 )-, a 3- to 14-membered optionally substituted heterocyclylene containing at least one ring nitrogen atom, or -C 1-6 alkylene-(3- to 14-membered optionally substituted heterocyclylene containing at least one ring nitrogen atom)-; R 100 is hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl; J 2 is a bond or alkylene, halogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 1-6 Alkoxy, optionally substituted C 3-6 optionally substituted with 1 to 3 substituents independently selected from cycloalkoxy, or two substituents joined to form an optionally substituted ring structure; J 3 is an optionally substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl ring; where: q is an integer from 1 to 10, preferably 1 or 2; T A L A wherein (1) if the terminal atom is N of a basic amine group, the corresponding compound T A -(C(O)-CH 3 ) q has a cLogP less than 1 and -C(O)-CH 3 is bonded to the terminal N atom, and (2) if the terminal atom is C of a C(O) group, the corresponding compound T A -(OH) q has a cLogP less than 1, -OH is bonded to the terminal C atom, and (3) the terminal atom is SO 2 When the group S is the corresponding compound T A -(OH) q has a cLogP less than 1, and -OH is bonded to the terminal S atom, or (4) if (1) to (3) do not apply, the corresponding compound T A -H q has a cLogP less than 1, L A L A The maximum length between the two terminal atoms of is at least -(CH 2 ) 10 a linker characterized in that the maximum length between the two terminal carbon atoms of L is A If both terminal atoms are C in a C(O) or S in a SO2 group, the corresponding compound is HO-L A -OH has a cLogP of at least 3, each -OH is bonded to a terminal C(O) or SO2 group, (2) L A Only one terminal atom of C(O)C or SO 2 If the group S, the corresponding compound HL A -OH has a cLogP of at least 3, -OH is bonded to a C(O) or SO2 group, or (3) if neither (1) nor (2) applies, the corresponding compound HL A -H has a cLogP of at least 3. During the ceremony, Y is CH, CR A , or N, Z is O, S, NH, or N(C 1-4 alkyl), HET ring represents an optionally substituted heteroaryl ring (e.g., a 5- or 6-membered heteroaryl such as a triazole ring); R 11 and R 12 are each independently hydrogen or C 1-4 is alkyl, L N is an empty (null) or an arbitrarily substituted C 1-6 alkylene or optionally substituted C having 1 to 3 heteroatoms 1-6 is heteroalkylene, L 10 is alkylene, halogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 1-6 Alkoxy, optionally substituted C 3-6 optionally substituted with 1 to 3 substituents independently selected from cycloalkoxy, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two substituents joined to form an optionally substituted ring system; R at each occurrence A are independently selected from halogen, CN, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 1-6 Alkoxy or optionally substituted C 3-6 cycloalkoxy or two R A are linked to form an optionally substituted ring structure, and p1 is 0, 1, or 2; R at each occurrence C are independently selected from halogen, CN, optionally substituted C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 1-6 Alkoxy or optionally substituted C 3-6 cycloalkoxy or two R C are linked to form an optionally substituted ring structure, and p2 is 0, 1, 2, or 3; R 13 is hydrogen, optionally substituted phenyl, or optionally substituted heteroaryl; where: q is an integer from 1 to 10, preferably 1 or 2; T A L A wherein (1) if the terminal atom is N of a basic amine group, the corresponding compound T A -(C(O)-CH 3 ) q has a cLogP less than 1 and -C(O)-CH 3 is bonded to the terminal N atom, and (2) if the terminal atom is C of a C(O) group, the corresponding compound T A -(OH) q has a cLogP less than 1, -OH is bonded to the terminal C atom, and (3) the terminal atom is SO 2 When the group S is the corresponding compound T A -(OH) q has a cLogP less than 1, and -OH is bonded to the terminal S atom, or (4) if (1) to (3) do not apply, the corresponding compound T A -H q has a cLogP less than 1, L A L A The maximum length between the two terminal atoms of is at least -(CH 2 ) 10 wherein (1) L is a linker having a maximum length between the two terminal carbon atoms of A If both terminal atoms are C in a C(O) or S in a SO2 group, the corresponding compound is HO-L A -OH has a cLogP of at least 3, each -OH is bonded to a terminal C(O) or SO2 group, (2) L A If only one terminal atom of the C(O) is C or S of the SO2 group, the corresponding compound HL A -OH has a cLogP of at least 3, -OH is bonded to a C(O) or SO2 group, or (3) if neither (1) nor (2) applies, the corresponding compound HL A -H has a cLogP of at least 3.

14. A compound selected from any of the compounds in Table 1 herein, or a pharmaceutically acceptable salt or ester thereof. - represents the counterion:

15. 15. Use of a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt or ester thereof, or a pharmaceutical composition comprising a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt or ester thereof, in a method for treating or preventing a disorder, condition or disease responsive to agonism of G protein-coupled receptor 40, preferably type 2 diabetes mellitus, in a subject in need thereof, comprising administering a therapeutically effective amount of said compound or a pharmaceutically acceptable salt or ester thereof Optionally, the method further comprises administering to the subject one or more additional therapeutic agents; Optionally, the one or more additional therapeutic agents are selected from PPARγ agonists and partial agonists, biguanides, protein tyrosine phosphatase 1B (PTP-1B) inhibitors, dipeptidyl peptidase IV (DPP-IV) inhibitors, insulin or insulin mimetics, sulfonylureas, α-glucosidase inhibitors, and agents that improve the lipid profile of the patient; The drug may be (i) an HMG-CoA reductase inhibitor, (ii) a bile acid sequestrant, (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) a PPARα agonist, (v) a cholesterol absorption inhibitor, (vi) an acyl-CoA: cholesterol acyltransferase (ACAT) inhibitor, (vii) a CETP inhibitor, (viii) a PCSK9 inhibitor or antibody, (ix) an apolipoprotein inhibitor, (x) a phenolic antioxidant, a PPARα / γ dual agonist, a PPARδ agonist, a PPARα / δ Partial agonists, anti-obesity compounds, ileal bile acid transporter inhibitors, anti-inflammatory agents, glucagon receptor antagonists, glucokinase activators, GLP-1 and GLP-1 analogs, GLP-1 receptor agonists (peptides and small molecules), GLP-1 / GIP receptor dual agonists, GLP-1 / glucagon receptor dual agonists, GLP-1 / GIP / insulin receptor triple agonists, GLP-1 / GIP / glucagon receptor triple agonists, GIP receptor antibodies, GLP-1 analogs / GIP receptor antibodies, PYYs analogs, amylin analogs, GPR119 agonists, TGR5 agonists, SSTR3 and / or SSTR5 antagonists or inverse agonists, THRβ agonists, HSD-1 inhibitors, HSD-17 inhibitors and degraders, PNPLA3 inhibitors and degraders, SGLT-2 inhibitors, SGLT-1 / SGLT-2 inhibitors, intestinal α-glucosidase inhibitors, FXR agonists, DGAT1 and / or DGAT2 inhibitors, FGF19 and analogs, FGF21 and analogs, GDF15 and analogs, ANGPTL3 inhibitors (xi) anti-amyloid beta antibodies; (xii) anti-inflammatory drugs, including but not limited to PDE4 inhibitors, JAK inhibitors, TYK2 inhibitors, S1P receptor modulators, NLRP3 inhibitors, BTK inhibitors, IRAK1 inhibitors, IRAK4 inhibitors, glucocorticoids, anti-TNFα antibodies, and anti-IL-12 / IL-23 antibodies; and (xiii) anti-integrin antibodies, including anti-α4β7, anti-α4, anti-β7, and anti-MAdCAM-1.

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