Conjugate Compounds and Compositions

Abstract

Provided herein are novel compounds of formula I, pharmaceutical compositions, and methods of use that relate to membrane-bound proteins such as GPR40. 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] This application claims the benefit of priority to International Application No. PCT / CN2023 / 074733, filed February 7, 2023, and U.S. Provisional Application No. 63 / 527,807, filed July 19, 2023, the contents of each of which are incorporated herein by reference in their entirety.

[0002] The present disclosure relates generally, in various embodiments, to novel compounds, pharmaceutical compositions, and methods of use thereof for treating 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 focus on: (1) hepatic glucose production (biguanides such as phenformin and metformin), (2) insulin resistance (PPAR agonists such as rosiglitazone, troglitazone, engliazone, balaglitazone, netoglitazone, T-131, LY-300512, LY-818, and pioglitazone), (3) insulin secretion (sulfonylureas such as tolbutamide, glipizide, and glimepiride), and (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 provided 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. Novel GPR40 agonists with pharmacokinetic and pharmacodynamic properties suitable for use as human pharmaceuticals are needed. Novel ligands for other membrane-bound proteins, such as other GPCRs, with pharmacokinetic and pharmacodynamic properties suitable for use as human pharmaceuticals are also needed. Summary of the Invention

[0006] Provided herein are compounds, pharmaceutical compositions, and methods of use related to membrane-bound proteins such as 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: JPEG2026504319000002.jpg20170, where the variables are defined herein. In some embodiments, D may be D-1, as defined herein (e.g., D-1-A, D-1-B, D-1-A-1, D-1-A-2, D-1-A-3, D-1-A-4, D-1-A-5, D-1-A-6, D-1-A-7, D-1-A-8, D-1-A-9, or D-1-A-10, etc.). In some embodiments, D may be D-2-A, as defined herein (e.g., D-2-A-1, D-2-A-2, or D-2-A-3). In some embodiments, D may be D-2-B, as defined herein (e.g., D-2-B-1, D-2-B-2, or D-2-B-3). In some embodiments, D may be D-3-A (e.g., D-3-A-1, D-3-A-2, or D-3-A-3), as defined herein. In some embodiments, D may be D-3-B (e.g., D-3-B-1, D-3-B-2, or D-3-B-3), as defined herein. In some embodiments, a compound of Formula I can have a subformula according to Formula I-1, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-G-1, I-1-G-2, I-1-G-3, I-1-G-4, I-1-G-5, I-1-G-6, I-1-G-7, I-1-G-8, I-1-G-9, I-1-H, I-1-I, I-1-A-1, I-1-B-1, I-1-C-1, I-1-D-1, I-1-E-1, I-1-F-1, I-1-H-1, or I-1-I-1, as defined herein.

[0008] In some embodiments, the present disclosure also provides a compound selected from Table 1 herein, or a pharmaceutically acceptable salt or ester thereof. In some embodiments, the present disclosure also provides a compound selected from Examples 1-36 herein, or a pharmaceutically acceptable salt or ester thereof.

[0009] In some embodiments, the present disclosure provides a pharmaceutical composition 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-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-G-1, I-1-G-2, I-1-G-3, I-1-G-4, I-1-G-5, I-1-G-6, I-1-G-7, I-1-G-8, I-1-G-9, I-1-H, I-1-I ... The pharmaceutical composition may comprise a compound of formula (I-A-1, I-1-B-1, I-1-C-1, I-1-D-1, I-1-E-1, I-1-F-1, I-1-H-1, or I-1-I-1), or any of the compounds listed in Table 1 herein, any of the compounds according to Examples 1-36 herein, or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable excipient. The pharmaceutical composition may 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.

[0010] 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 a compound of Formula I (e.g., Formulas I-1, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-G-1, I-1-G-2, I-1-G-3, I-1-G-4, I-1-G-5, I-1-G-6, I-1-G-7, I-1-G-8, I-1-G-9, I-1-H, I-1-I ... In some embodiments, the method comprises administering a compound of formula I-1-A-1, I-1-B-1, I-1-C-1, I-1-D-1, I-1-E-1, I-1-F-1, I-1-H-1, or I-1-I-1), or any of the compounds listed in Table 1 herein, any of the compounds according to Examples 1-36 herein, or a pharmaceutically acceptable salt or ester thereof, or a pharmaceutical composition comprising same. In some embodiments, the administration is oral.

[0011] In some embodiments, the present disclosure provides methods 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 a compound of Formula I (e.g., Formulas I-1, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-G-1, I-1-G-2, I-1-G-3, I-1-G-4, I-1-G-5, I-1-G-6, I-1-G-7, I-1-G-8, I-1-G-9, I-1-H, I-1-I, In some embodiments, the method comprises administering a compound of formula I-1-A-1, I-1-B-1, I-1-C-1, I-1-D-1, I-1-E-1, I-1-F-1, I-1-H-1, or I-1-I-1), or any of the compounds listed in Table 1 herein, any of the compounds according to Examples 1-36 herein, or a pharmaceutically acceptable salt or ester thereof, or a pharmaceutical composition comprising same. In some embodiments, the administration is oral.

[0012] 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 agonist, or a PPARα / δ partial agonist. 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 / 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 antibodies, GPR119 agonists, TGR5 agonists, SSTR2 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 antibodies or inhibitors, ANGPTL3 / 8 antibody, ANGPTL4 inhibitor, oxyntomodulin, (xi) anti-amyloid beta antibody, (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, anti-IL-12 / IL-23 antibodies, (xiii) anti-integrin antibodies or small molecule inhibitors of integrins including α4β7, α4,β7, MAdCAM-1, αvβ6, and αvβ1.

[0013] 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. [Brief explanation of the drawings]

[0014] [Figure 1] 1 is a graph showing the change in blood glucose concentration over time after treating mice with the exemplary compounds of Examples 17, 18, and 19, or a control. [Figure 2] 1 is a bar graph showing the relative AUC of blood glucose concentrations from 0 to 120 minutes after treatment with the exemplary compounds of Examples 17, 18, and 19 compared to the control. DETAILED DESCRIPTION OF THE INVENTION

[0015] In various embodiments, the present disclosure provides compounds useful for modulating membrane-bound proteins such as GPCRs, particularly 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 above-described compounds and methods of using them, such as for treating type 2 diabetes. As shown in the Examples section herein, exemplary compounds were shown to be active in oral glucose tolerance tests with minimal systemic exposure. The oral bioavailability (F%) of all tested compounds (see Biological Example 2) was less than 1%, with most being less than 0.5%.

[0016] compound

[0017] 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.

[0018] International Application No. PCT / CN2023 / 071833, filed January 12, 2023, now published as WO2023 / 134712 (the entire contents of which are incorporated herein by reference), describes that when certain GPR40 agonists are covalently attached to a polar group via a hydrophobic linker of sufficient chain length, the resulting compounds can be highly potent GPR40 agonists with EC50 values ​​of less than 50 nM, less than 10 nM, or less than 1 nM when tested according to the methods described herein.

[0019] In a broad sense, the compounds described herein can be considered to have one or more ligands of a membrane-bound protein, such as a GPR40 agonist, covalently bound to a hydrophilic group via a linker. Typically, the compounds described herein have one GPR40 agonist covalently bound to a hydrophilic group via a linker: (GPR40 agonist)-linker-hydrophilic group. In some embodiments, the linker and hydrophilic group together can be considered to be the residue of a surfactant, such as an anionic surfactant, a cationic surfactant, a zwitterionic surfactant, or a nonionic surfactant. For example, in some embodiments, the linker and hydrophilic group can be such that when the compounds described herein bind to a membrane-bound protein, such as GPR40, the hydrophobic linker binds to the cell membrane, but the hydrophilic group does not.

[0020] In more specific embodiments, the compound typically comprises a residue of a GPR40 agonist. JPEG2026504319000003.jpg32170JPEG2026504319000004.jpg103170, linker L A via the hydrophilic group T A where the variables are as described and preferred herein. 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 have residues 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 A compound is said to be within the scope of a genus of compounds if all of the D-1, D-2-A, D-2-B, D-3-A, or D-3-B variables are within the respective definitions of that genus of compounds herein. Typically, the variables D-1, D-2-A, D-2-B, D-3-A, or D-3-B are such that at least one of the corresponding compounds according to 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: JPEG2026504319000005.jpg81170JPEG2026504319000006.jpg82170E 2 is E 2A or L N -E 2A and E 1 or E 2A is hydrogen, C 1-4 Alkyl, N3, JPEG2026504319000007.jpg29170E 3 is E 3A or L N -E 3A and E 3A is hydrogen, C 1-4 Alkyl, N3, JPEG2026504319000008.jpg28170, L N is defined here (empty (null) or C 1-6 In a preferred embodiment, residues D-1, D-2-A, D-2-B, D-3-A, or D-3-B are hydrophilic groups T A Compounds herein covalently bound to have similar (e.g., within 3-fold) or lower EC50 values ​​compared to at least one (preferably all) of the corresponding compounds of formula GPR-1, GPR-2, GPR-2B, GPR-3, or GPR-3B.

[0021] In some embodiments, the present disclosure provides a compound of Formula I, or a pharmaceutically acceptable salt or ester thereof: JPEG2026504319000009.jpg19170In formula, D is a residue of a ligand of a membrane-bound protein such as a GPCR, preferably D is a residue of a GPR40 agonist; q is an integer of 1 to 10, preferably 1 or 2; L A is a hydrophobic linker, and T A is a group characterized as having one or more (e.g., 1, 2, or 3) hydrophilic polar groups, preferably T A is a group characterized as having one or more (e.g., 1, 2, or 3) charged groups, e.g., one or more quaternary amines, one or more carboxylic acids, one or more phosphoric acids, and / or one or more sulfonic acids; wherein the compound is charge-balanced as needed. As used herein, the term "polar group" refers to a functional group containing at least one heteroatom selected from N, O, P, and S. In some embodiments, a "polar group" can be a charged group, which refers to a functional group containing at least one charge, such as at least one positive charge, at least one negative charge, or both positive and negative charges in the case of zwitterions, at pH 7. As used herein, a "hydrophilic" organic group refers to a functional group containing (i) at least one, preferably at least two or at least three neutral hydrophilic groups (e.g., O, OH, etc.) per five carbons, and / or (ii) at least one, preferably at least two, at least three, or at least four charged hydrophilic groups (e.g., charged amine groups such as quaternary amine groups, chargeable amine groups, COOH groups, SOH groups, etc.) per seven carbons. In some embodiments, a "hydrophilic" organic group is characterized as having a ratio of (total number of nitrogen and oxygen atoms) / (total number of carbon atoms) of 4:1 to 1:4, e.g., 3:1, 2:1, 1:1, 1:2, 1:3, or 1:4, or any range or value between the recited values. As used herein, a "hydrophobic" molecule generally refers to a molecule having a cLogP of at least 3.

[0022] In Formula I, the integer q is typically 1, and the compound has the formula I-1: It can have a structure according to JPEG2026504319000010.jpg9170. Hydrophilic group T A

[0023] As set forth herein and in part in PCT / CN2023 / 071833, when D represents a residue of a GPCR ligand, the inventors have found that several factors are important for a compound of Formula I to be a potent GPCR ligand, such as a GPR40 agonist. For example, one factor that can determine whether a compound of Formula I (e.g., I-1) can be a potent GPCR ligand, such as a GPR40 agonist, is T A hydrophilic or polar, but T AThe exact chemical structure of is not critical.

[0024] In some preferred embodiments, T A contains a quaternary nitrogen atom, a positively charged group such as CO2 - , 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, will be 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.

[0025] In some embodiments, T A is a group characterized as having one or more (e.g., 1, 2, or 3) quaternary amines, one or more (e.g., 1, 2, or 3) carboxylic acids, one or more (e.g., 1, 2, or 3) phosphoric acids, and / or one or more (e.g., 1, 2, or 3) sulfonic acids. For example, in some embodiments, T A contains one or more, e.g., one, two, or three, quaternary amine groups. In some embodiments, T A contains one or more, for example, one, two, or three, carboxylic acid groups. A contains one or more zwitterions.

[0026] In some embodiments, T A is the corresponding T A They can be characterized as having a particular hydrophilicity as indicated by the cLogP value of the molecules they contain. For example, in some embodiments, T A L Awherein (1) if the terminal atom is an N of a basic primary or secondary amine group, the corresponding compound T A -(C(O)-CH3) q has a cLogP less than 0, preferably less than -1, -C(O)-CH3 is bonded to the terminal N atom, and (2) when the terminal atom is the N of a basic tertiary amine group, the corresponding compound [T A -CH3] + has a cLogP less than 0, preferably less than -1, and -CH3 is bonded to the terminal N atom; (3) if the terminal atom is a C in 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 (4) if the terminal atom is S in the SO2 group, the corresponding compound T A -(OH) q has a cLogP less than 1, and -OH is bonded to the terminal S atom, or (5) if (1) to (4) do not apply, the corresponding compound T A -H q has a cLogP less than 1.

[0027] The terms "end atom(s)", "terminal atom(s)", and the like refer to the L A or T A When used herein in connection with a structure such as -(CH2), 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 end / terminal atoms are non-hydrogen atoms. 10 An alkylene chain of - is to be understood as having two terminal carbon atoms.

[0028] In some embodiments, T A L A wherein the terminal N atom is an N atom of a basic primary or secondary amine group, and the corresponding compound T A-(C(O)-CH3) q has a cLogP of less than 0, preferably less than −1 (e.g., less than −2, less than −3, less than −3.5, less than −4, or even less), where —C(O)—CH is attached to the terminal N atom. In some embodiments, q is 1, and the corresponding compound T A -C(O)-CH3 has a cLogP of less than 0, preferably less than -1 (e.g., less than -2, less than -3, less than -3.5, less than -4, or even lower), where -C(O)-CH3 is attached to the terminal N atom.

[0029] In some embodiments, q is 1 and T A L A is a hydrophilic group having a terminal N atom covalently bonded to the first terminal atom of the corresponding compound [T A -CH3] + has a cLogP of less than 0, preferably less than −1 (e.g., less than −2, less than −3, less than −3.5, less than −4, or even less), where —CH3 is attached to the terminal N atom.

[0030] 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 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), where -OH is attached to the terminal C atom. In some embodiments, q is 1, and the corresponding compound T A The -OH has a cLogP of less than 0, preferably less than -1 (eg, less than -2, less than -3, less than -3.5, less than -4, or even less), where the -OH is attached to the terminal C atom.

[0031] In some embodiments, the terminal atom is S in the SO group, and T A is the corresponding compound T A -(OH) qhas 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), where -OH is attached to the terminal S atom. In some embodiments, q is 1, and the corresponding compound T A The -OH has a cLogP of less than 0, preferably less than -1 (eg, less than -2, less than -3, less than -3.5, less than -4, or even less), where the -OH is attached to the terminal S atom.

[0032] 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 In some embodiments, q is 1 and the corresponding compound T A -H has a cLogP of less than 0, preferably less than -1 (eg, less than -2, less than -3, less than -3.5, less than -4, or even lower).

[0033] In some embodiments, q is 1 and T A has a formula according to M-1 or M-2: JPEG2026504319000011.jpg20170In formula, L in each occurrence B and L C each independently represents a divalent group; Here, in M-1, (i)G A and G B is hydrogen or C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, or a 3- to 14-membered ring, each of which is optionally substituted; G A and G B the other is a moiety having the structure M-2, M-3, or M-4 as defined herein; or (ii) G A and G B are joined together with the nitrogen atom to which they are both attached to form an optionally substituted 4- to 14-membered ring, or (iii) G A and G B each independently represents a moiety having the structure M-2, M-3, or M-4 as defined herein; In M-2, (i)G A1 , G B1 , and G C1 are each independently 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, a 3- to 14-membered ring, or a structure of M-3 or M-4; 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 each of the alkynyl and the 3- to 14-membered ring is optionally substituted; (ii) G A1 and G B1 are joined together with the nitrogen atom to which they are both attached to form an optionally substituted 4- to 14-membered ring, and G C1 is as defined in (i), or (iii) G A1 , G B1 , and G C1 are all joined together with the nitrogen atom to which they are attached to form an optionally substituted 5- to 14-membered ring, M-3 is JPEG2026504319000012.jpg12170 structure, and M-4 is It has the structure JPEG2026504319000013.jpg11170, During the ceremony, L D is null or represents a divalent group, A represents a moiety having an anionic group or its conjugate acid, and preferably the anionic group is COO - , SO3 - , HPO3 - or PO32- and Cat represents a moiety having a cationic group that is positively charged regardless of pH or capable of being positively charged at pH 7; preferably, the cationic group is a quaternary amine. In this specification, a "3- to 14-membered ring," a "4- to 14-membered ring," or a "5- to 14-membered ring" can be either (1) a monocyclic ring, typically having 3 to 8 ring atoms, where the monocyclic ring (i) may be saturated, partially unsaturated, or aromatic, and (ii) contains 0 to 4 heteroatoms independently selected from N, S, O, and P, or (2) a fused, spiro, and / or bridged structure having two or more rings, typically having a total of 5 to 14 ring atoms, where each ring independently (i) may be saturated, partially unsaturated, or aromatic, and (ii) contains 0 to 4 heteroatoms independently selected from N, S, O, and P. The ring heteroatoms N, S, and P may exist in different oxidation states. For example, S can be present as S, SO, or SO, etc., and it should also be understood that nitrogen ring atoms may optionally be oxidized or quaternized. Unless otherwise specified, ring structures herein should be understood to include ring structures having different designations for the number of ring members.

[0034] In some embodiments, T A has a formula according to M-1. In some embodiments, G A and G B One of the two is hydrogen or C 1-4 is alkyl, G A and G B The other has the structure according to M-2. A and G B Each of G is independently a structure according to M-2. A and G B One of the two is hydrogen or C 1-4 is alkyl, G A and G B The other has a structure according to M-3. A and G B One of the two is hydrogen or C1-4 is alkyl, G A and G B The other has a structure according to M-4. A and G B Each of G is independently a structure according to M-3. A and G B Each of G is independently a structure according to M-4. A and G B are joined together with the nitrogen atom to which they are both attached to form an optionally substituted 4- to 14-membered ring, e.g., a monocyclic 4- to 8-membered ring, or a 5- to 14-membered ring structure having two or more member rings as defined and exemplified herein. For example, in some embodiments, a compound of Formula I can have a structure according to Formula I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, or I-1-F, balanced as needed: JPEG2026504319000014.jpg112170, where the variables are defined herein. For clarity, in formulas I-1-B, I-1-D, and I-1-F, variables with the same identifier, such as two "A"s in formula I-1-D or two "Cat"s in formula I-1-F, may be the same or different.

[0035] In some embodiments, T A has a formula according to M-2. In some embodiments, G A1 and G B1 are joined together with the nitrogen atom to which they are both attached to form an optionally substituted 3- to 14-membered ring, and G C1 is C 1-4 In some embodiments, G is alkyl. A1 , G B1 , and G C1 may be joined together with the nitrogen atom to which they are all attached to form an optionally substituted 5- to 14-membered ring, typically a ring structure having two or more member rings as defined and exemplified herein, e.g., a fused or bridged bicyclic ring structure. In some embodiments, G A1 , G B1 , and G C1are each independently 1-4 In some embodiments, the compound of formula I can have a structure according to formula I-1-G, I-1-G-1, I-1-G-2, I-1-G-3, I-1-G-4, I-1-G-5, I-1-G-6, or I-1-G-7, optionally balanced: JPEG2026504319000015.jpg137170 where the variables are defined herein.

[0036] In some embodiments, T A may also have the formula according to M-3 or M-4 as defined herein, where L D is L A For example, in some embodiments, a compound of Formula I can have a structure according to Formula I-1-H or I-1-I: JPEG2026504319000016.jpg15170 where the variables are defined herein.

[0037] The bivalent linker L in M-1, M-2, M-3, or M-4 of the present specification B , L C , and L D Where applicable, for example, in any of the applicable subformulas of Formula I-1, is not particularly limited and may be a null, acyclic, or cyclic divalent structure, and may optionally contain heteroatoms (e.g., 1 to 4 heteroatoms).

[0038] In some embodiments, L B L B1 or L B1 -L B2 where L B1 is not allowed A G B binds to L B1 is empty (null), optionally substituted alkylene, optionally substituted C 1-6 heteroalkylene, an optionally substituted 3- to 14-membered ring, or an optionally substituted ring / chain structure; B2is null, C(O), NH, —SO—, or a moiety selected from the following: JPEG2026504319000017.jpg23170 where R in each occurrence 100 , R 101 and R 102 are independently hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl, and either of the attachment points is B1 In some embodiments, L B is L B1 In some embodiments, L B is L B1 In some embodiments, L B is L B1 For example, in some embodiments, L B or L B1 is empty (null). In some embodiments, L B or L B1 is an optionally substituted alkylene, for example, an optionally substituted C 1-6 In some embodiments, L is alkylene. B or L B1 is an optionally substituted heteroalkylene, e.g., an optionally substituted C alkyl group having 1 or 2 heteroatoms independently selected from N, O, P, and S. 1-6 heteroalkylene, where S and P are optionally oxidized. For example, L B or L B1 may be -CH2-CH2-O-, -CH2-CH2-NH-, -CH2-CH2-N(CH3)-, -CH2-CH2-O-CH2-CH2-NH-, -CH2-CH2-CH2-NH-, -CH2-CH2-S-CH2-CH2-NH-, -CH2-CH2-SO2-NH-CH2-CH2-NH-, etc. In some embodiments, one or more CH2 of the heteroalkylene may be optionally substituted with an oxo group. For example, an optionally substituted -CH2-CH2-CH2-NH- includes structures such as -CH2-CH2-C(O)-NH-. In some embodiments, L B or L B1is an optionally substituted divalent ring structure that is attached to the remainder of the molecule through two points of attachment on the divalent ring structure, e.g., through one ring atom or two ring atoms. B or L B1 is an optionally substituted divalent ring chain structure that is attached to the rest of the molecule through one chain atom and one ring atom. B If it contains L B are independently selected.

[0039] In some embodiments, L of M-2 C , or L as a variable C Any of the subformulas of formula I having L C1 or L C1 -L C2 where L C1 is the quaternary nitrogen [NG A1 G B1 G C1 ] + binds to L C1 is empty (null), optionally substituted alkylene, optionally substituted C 1-6 heteroalkylene, an optionally substituted 3- to 14-membered ring, or an optionally substituted ring / chain structure; C2 is null, C(O), NH, —SO—, or a moiety selected from the following: JPEG2026504319000018.jpg24170 where R in each occurrence 100 , R 101 and R 102 are independently hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl, and either of the attachment points is C1 In some embodiments, L C is L C1 In some embodiments, L C is L C1 In some embodiments, L C is L C1 In some embodiments, L Cor L C1 is empty (null). In some embodiments, L C or L C1 is an optionally substituted alkylene, for example, an optionally substituted C 1-6 In some embodiments, L is alkylene. C or L C1 is an optionally substituted heteroalkylene, e.g., an optionally substituted C alkyl group having 1 or 2 heteroatoms independently selected from N, O, P, and S. 1-6 heteroalkylene, where S or P is optionally oxidized, e.g., L C or L C1 can be -CH2-CH2-O-, -CH2-CH2-NH-, -CH2-CH2-N(CH3)-, -CH2-CH2-O-CH2-CH2-NH-, -CH2-CH2-CH2-NH-, -CH2-CH2-S-CH2-CH2-NH-, -CH2-CH2-SO2-NH-CH2-CH2-NH-, etc. In some embodiments, one or more CH2 of the heteroalkylene can be optionally substituted with an oxo group. In some embodiments, L C or L C1 is an optionally substituted divalent ring structure that is attached to the remainder of the molecule through two points of attachment on the divalent ring structure, e.g., through one ring atom or two ring atoms. C or L C1 is an optionally substituted divalent ring chain structure that is attached to the rest of the molecule through one chain atom and one ring atom. C If it contains L C are independently selected.

[0040] In some embodiments, L in M-3 or M-4 D , or L as a variable D Any of the subformulas of formula I having L D1 or L D1 -L D2 where L D1 binds to A or Cat, and L D1is empty (null), optionally substituted alkylene, optionally substituted C 1-6 heteroalkylene, an optionally substituted 3- to 14-membered ring, or an optionally substituted ring / chain structure; D2 is null, C(O), NH, —SO—, or a moiety selected from the following: JPEG2026504319000019.jpg22170 where R in each occurrence 100 , R 101 and R 102 are independently hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl, and either of the attachment points is D1 In some embodiments, L D is L D1 In some embodiments, L D is L D1 In some embodiments, L D is L D1 In some embodiments, L D or L D1 is empty (null). In some embodiments, L D or L D1 is an optionally substituted alkylene, for example, an optionally substituted C 1-6 In some embodiments, L is alkylene. D or L D1 is an optionally substituted heteroalkylene, e.g., an optionally substituted C alkyl group having 1 or 2 heteroatoms independently selected from N, O, P, and S. 1-6 In some embodiments, L is a heteroalkylene, and P or S is optionally oxidized. In some embodiments, one or more CH2 of the heteroalkylene may be optionally substituted with an oxo group. D or L D1 is an optionally substituted divalent ring structure that is attached to the remainder of the molecule through two points of attachment on the divalent ring structure, e.g., one ring atom or two ring atoms. In some embodiments, L D or L D1is an optionally substituted divalent ring chain structure that is attached to the rest of the molecule through one chain atom and one ring atom. D If it contains L D are independently selected.

[0041] In some embodiments, M-2 or G as a variable A1 , G B1 , and G C1 In any of the subformulas of formula I having A1 , G B1 , and G C1 can all be joined together with the nitrogen atom to which they are attached to form an optionally substituted 5- to 14-membered ring having 0-4 ring heteroatoms in addition to the nitrogen atom. The additional ring heteroatoms, if present, are independently selected from N, S, and O, where the nitrogen can be optionally oxidized or quaternized, and the sulfur can be optionally oxidized. Typically, the 5- to 14-membered ring is a ring structure having two or more member rings. For example, the 5- to 14-membered ring can have a fused ring structure, a bridged ring structure, and / or a spiro ring structure, where each member ring is independently a saturated or partially unsaturated heterocyclic ring, typically having 4-8 ring members. For example, in some embodiments, the 5- to 14-membered ring is a bridged bicyclic ring, e.g., a 1,1,1-bridged (e.g., JPEG2026504319000020.jpg18170), 2,2,2-bridged (e.g., JPEG2026504319000021.jpg21170), 3,2,1-bridged, 3,3,3-bridged rings, etc. In some embodiments, the 5- to 14-membered ring may be a fused bicyclic ring. For example, in some preferred embodiments, G A1 , G B1 , and G C1 are bonded together with the nitrogen atom to which they are all attached, The structure of JPEG2026504319000022.jpg29170 can be formed, where Q A is an optionally substituted C such as methyl1-4 In some preferred embodiments, G A1 , G B1 , and G C1 are bonded together with the nitrogen atom to which they are all attached, JPEG2026504319000023.jpg24170. The compound of formula I has two or more sets of G A1 , G B1 , and G C1 where each set of variables is independently selected.

[0042] In some embodiments, in M-3 or any of the subformulas of Formula I having A as a variable, A in each occurrence is independently COO - , SO3 - , HPO3 - or PO3 2- or a group containing its conjugate acid. In some embodiments, when more than one A appears as a variable in a formula, each A can be the same or different. For example, in some embodiments, when more than one A appears in a formula herein, all A's are the same, e.g., all A's are COO - or COOH.

[0043] In some embodiments, in M-4, or any of the subformulas of Formula I having Cat as a variable, Cat at each occurrence is independently an amine-containing, preferably a quaternary amine-containing, structure. For example, in some preferred embodiments, Cat at each occurrence is JPEG2026504319000024.jpg29170 is a quaternary amine having the structure Q A is an optionally substituted C such as methyl 1-4 In some embodiments, Cat is alkyl. JPEG2026504319000025.jpg24170. In some embodiments, Cat may be NH. In some embodiments, Cat may be NH—(CH) 2-5In some embodiments, Cat may be —NH, for example, NH—(CH)—NH. JPEG2026504319000026.jpg18170[N(CH3)3] + , or [N(CH2CH3)3] + In some embodiments, when more than two Cats appear as variables in a formula, each Cat may be the same or different, and preferably all Cats are the same.

[0044] In some preferred embodiments, T of formula I-1 A teeth, JPEG2026504319000027.jpg44170, where Q A is an optionally substituted C such as methyl 1-4 It is alkyl.

[0045] In some preferred embodiments, T of formula I-1 A teeth, Represents JPEG2026504319000028.jpg40170.

[0046] In some preferred embodiments, T of formula I-1 A teeth, Represents JPEG2026504319000029.jpg42170.

[0047] In some preferred embodiments, T of formula I-1 A teeth, Represents JPEG2026504319000030.jpg48170.

[0048] In some embodiments, T of formula I-1 A teeth JPEG2026504319000031.jpg26170, where Cat is defined herein, for example, in some embodiments, Cat is JPEG2026504319000032.jpg23170[N(CH3)3] + , or [N(CH2CH3)3]+ is.

[0049] In some embodiments, T of formula I-1 A teeth JPEG2026504319000033.jpg26170, where Cat is defined herein, for example, in some embodiments, Cat is JPEG2026504319000034.jpg21170, [N(CH3)3] + , or [N(CH2CH3)3] + is.

[0050] In some preferred embodiments, T of formula I-1 A teeth In some preferred embodiments, T in formula I-1 A teeth Represents JPEG2026504319000036.jpg35170.

[0051] In some preferred embodiments, T of formula I-1 A teeth, JPEG2026504319000037.jpg19170[N(CH3)3] + , or [N(CH2CH3)3] + Represents.

[0052] In some preferred embodiments, T of formula I-1 A represents one of the following structures: JPEG2026504319000038.jpg59170JPEG2026504319000039.jpg65170

[0053] In some preferred embodiments, T of formula I-1 A teeth, Represents JPEG2026504319000040.jpg46170.

[0054] In some preferred embodiments, T of formula I-1 A teeth, JPEG2026504319000041.jpg27170[N(CH3)3] + , [N(CH2CH3)3] + , Represents JPEG2026504319000042.jpg19170. Linker L A

[0055] When D represents a residue of a GPCR ligand, another factor that can determine whether a compound of Formula I can be a potent GPCR ligand, such as a GPR40 agonist, is the molecular weight of the linker (e.g., L A As shown in PCT / CN2023 / 071833, when the linker length is below a certain threshold, the EC50 value as a GPR40 agonist can be significantly increased. Therefore, the present inventors have proposed a method for reducing the length of 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: JPEG2026504319000043.jpg14170Here, Q 1 is T A L bonded to the terminal atom of A represents the first terminal non-hydrogen atom of 2 is the L bonded to the attachment point of D. 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 2Under 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, the -(CH) 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 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- the maximum length between the two terminal carbon atoms of (ii) -(CH2) 50 - the maximum length between the two terminal carbon atoms.

[0056] Another factor that can determine whether a compound of Formula I can be a potent GPCR ligand, such as a 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., where each -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.

[0057] In some embodiments, in Formula I (e.g., Formula I-1), L A is the formula (X) m X in each occurrence can be independently selected from CR, C(=O), -C(R)=C(R)-, JPEG2026504319000044.jpg11170SiR2, O, S, SO, 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 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 a linear structure linked to two other X groups (excluding two X groups directly linked to D), 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 JPEG2026504319000045.jpg24170. A "ring structure" or a "3- to 10-membered ring structure" is not limited to a 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 JPEG2026504319000046.jpg26170 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, X may be a cycloalkyl, a 5- or 6-membered heteroaryl such as a triazole ring, or the like. In some embodiments, two consecutive Xs 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. In some embodiments, X in each occurrence is independently selected from the group consisting of -CR2, -C(R)=C(R)-, JPEG2026504319000047.jpg10170 or a 3- to 10-membered ring, and R in each occurrence is independently hydrogen or C 1-4 More preferably, X at each occurrence is independently CR2 and R at each occurrence is independently hydrogen or C 1-4 Typically, one of the terminal X groups is linked to T via a carbon atom. A Connect to 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.

[0058] 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)-, JPEG2026504319000048.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 Characterized in that -COOH 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. "m-1" should be understood as the integer m minus 1 and should not be mistaken for another designated variable. In some embodiments, X in each occurrence independently represents CR2, -C(R)=C(R)-, JPEG2026504319000049.jpg11170 or a 3- to 10-membered ring, and R in each occurrence is independently hydrogen or C 1-4More preferably, X at each occurrence is independently CR2 and R at each occurrence is independently hydrogen or C 1-4 It is alkyl.

[0059] In some embodiments, L A (X) m wherein X in each occurrence is independently CR, C(=O), -C(R)=C(R)-, JPEG2026504319000050.jpg11170SiR2, O, S, SO2, NR, [NR2] + or a ring structure, preferably a 3- to 10-membered ring structure, with the proviso 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. In some embodiments, X in each occurrence is independently selected from C—R, —C(R)═C(R)—, JPEG2026504319000051.jpg11170 or a 3- to 10-membered ring, wherein R in each occurrence is independently hydrogen or C 1-4 More preferably, X at each occurrence is independently CR2 and R at each occurrence is independently hydrogen or C 1-4 It is alkyl.

[0060] 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: Therefore, 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.

[0061] 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)-, JPEG2026504319000053.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. In some embodiments, X at each occurrence is independently selected from the group consisting of CR, -C(R)=C(R)-, JPEG2026504319000054.jpg11170 or a 3- to 10-membered ring, and R in each occurrence is independently hydrogen or C 1-4 More preferably, X at each occurrence is independently CR2 and R at each occurrence is independently hydrogen or C 1-4 It is alkyl.

[0062] In some embodiments, L A -X 12-30 -C(O)- (e.g., -X 14 -C(O)-, -X 16 -C(O)-, -X 18 -C(O)-, -X 20 -C(O)-, -X 24 -C(O)-, -X 14-30 -C(O)-, -X 16-30-C(O)-, -X 18-30 -C(O)-, etc.), where C(O) is T A and X in each occurrence is independently CR2, C(=O), -C(R)=C(R)-, JPEG2026504319000055.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 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. In some embodiments, X in each occurrence is independently selected from CR2, -C(R)=C(R)-, JPEG2026504319000056.jpg11170 or a 3- to 10-membered ring, and R in each occurrence is independently hydrogen or C 1-4 More preferably, X at each occurrence is independently CR2 and R at each occurrence is independently hydrogen or C 1-4 It is alkyl.

[0063] 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 12-30Unsubstituted -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.

[0064] 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 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.

[0065] In some preferred embodiments, L A teeth, JPEG2026504319000057.jpg33170, 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 that binds to D 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 maximum chain length of is at least -(CH2) 12 -, e.g., at least -(CH2) 14- maximum chain length of at least -(CH2) 16 - the longest chain length is at least -(CH2) 18 - is the longest chain length. A The hydrophobicity of the corresponding compound JPEG2026504319000058.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., 14-30, 14-50, 16-50, 18-100, 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.

[0066] In some embodiments, L A teeth, It can be characterized as having a structure according to JPEG2026504319000059.jpg30170. A1 and L A2 are each independently a bond, -C1-30 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 L that binds to D 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 D 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.

[0067] In some embodiments, L A teeth, It can be characterized as having a structure according to JPEG2026504319000060.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-. The sulfur atom, if present, is optionally oxidized. L bonded to D 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 JPEG2026504319000061.jpg31170 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, LA1 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.

[0068] In some embodiments, L A teeth, It can be characterized as having a structure according to JPEG2026504319000062.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-. The sulfur atom, if present, is optionally oxidized. L bonded to D 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 JPEG2026504319000063.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. L A -T A Example of

[0069] 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.

[0070] In some embodiments, the compound of formula I-1 can have a structure according to any of the following: JPEG2026504319000064.jpg98170JPEG2026504319000065.jpg103170In the formula, The integer m1 is at least 10, e.g., at least 12, at least 14, at least 16, at least 18, at least 20, or at least 50, e.g., from 12 to 50, from 16 to 50, etc.; Other variables are defined and preferred herein. The charges appearing in the above formula are counterbalanced with counterions as necessary, making the compound overall neutral.

[0071] In some embodiments, L B1 is an arbitrarily substituted C 1-6 alkylene (e.g., ethylene, n-propylene, n-butylene, etc.), or optionally substituted C having 1 or 2 heteroatoms independently selected from N, O, P, and S; 1-6 It is heteroalkylene, and P or S is optionally oxidized. Preferably, the atom bonded to the amide NH in the above formula I-1-A-1, I-1-B-1, I-1-C-1, I-1-D-1, I-1-E-1, or I-1-F-1 is not a heteroatom.

[0072] In some embodiments, L C1 is an arbitrarily substituted C 1-6 alkylene (e.g., ethylene, n-propylene, n-butylene, etc.), or optionally substituted C having 1 or 2 heteroatoms independently selected from N, O, P, and S; 1-6 It is heteroalkylene, and P or S is optionally oxidized. Preferably, the atom bonded to the amide NH in formula I-1-G-9 is not a heteroatom.

[0073] In some preferred embodiments, in formula I-1-A-1, I-1-B-1, I-1-G-8, or I-1-G-9, G A1 , G B1 , and G C1are bonded together with the nitrogen atom to which they are all attached, JPEG2026504319000066.jpg30170, where Q A is an optionally substituted C such as methyl 1-4 In some preferred embodiments, G A1 , G B1 , and G C1 are bonded together with the nitrogen atom to which they are all attached, JPEG2026504319000067.jpg26170. In some preferred embodiments, A1 , G B1 , and G C1 together with the nitrogen atoms to which they are all attached. JPEG2026504319000068.jpg23170[N(CH3)3] + , or [N(CH2CH3)3] + Represents.

[0074] In some embodiments, in formula I-1-A-1, I-1-B-1, or I-1-G-8, L C is an arbitrarily substituted C 1-6 In some embodiments, in Formula I-1-G-8, L is an alkylene (e.g., ethylene, n-propylene, n-butylene, etc.). C is empty (null).

[0075] In some embodiments, X at each occurrence is independently selected from the group consisting of CR, -C(R)=C(R)-, JPEG2026504319000069.jpg11170 or a 3- to 10-membered ring, and R in each occurrence is independently hydrogen or C 1-4 More preferably, X at each occurrence is independently CR2 and R at each occurrence is independently hydrogen or C 1-4In some embodiments, at most one X is a 3- to 10-membered ring. In some embodiments, no X contains a heteroatom. In some embodiments, all X are independently CR2, and R at each occurrence is independently hydrogen or methyl, provided that at most 10 R (e.g., 1, 2, 3, 4, 5, or 6 R) are methyl groups.

[0076] In some embodiments, -(X) in formula I-1-A-1, I-1-B-1, I-1-C-1, I-1-D-1, I-1-E-1, or I-1-F-1, or I-1-G-9 m1 The hydrophobicity of -C(O)- is similar to that of the corresponding compound H-(X) m1 The -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.), such as 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.

[0077] In some embodiments, -(X) m1 - is an optionally substituted linear C 10-50 Alkylene, e.g., optionally substituted straight chain C 10-30 Alkylene (e.g., linear C 10 , C 12 , C 14 , C 16 , C 18 , C 20 , C 22 , or C 24 In some embodiments, 1 to 10 (e.g., 1, 2, 3, 4, 5, or 6) CH2 in the linear alkylene chain may be substituted, e.g., each of the 1 to 10 CH2 may be independently substituted with one or two methyl groups. In some embodiments, -(X) m1- may also be a group derived by replacing 1 to 10 (e.g., 1, 2, 3, 4, 5, or 6) CH2 in the aforementioned linear alkylene chain with a double bond. For example, when one CH2 in a C10 alkylene is replaced with a double bond, the resulting group is a C11 alkenyl having one double bond.

[0078] In some embodiments, D is a residue having the formula D-1, D-2-A, D-2-B, D-3-A, or D-3-B, or a subformula thereof, as defined herein. Residues of the ligand of a membrane-bound protein

[0079] In Formula I, D is typically a residue of a ligand for a GPCR, although residues of ligands for other membrane-bound proteins are also suitable. In some particular embodiments, D is a residue of a GPR40 agonist.

[0080] In some embodiments, D is a residue having the formula D-1: JPEG2026504319000070.jpg29170In 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 C3-6 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; and J3 is an optionally substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl ring.

[0081] Variable L in Equation D-1 10 , J 1 , J 2 , J 3 , R A , R B However, in a preferred embodiment, the variables of formula D-1 are represented by the formula GPR-1, At least one corresponding compound (E 1 is hydrogen, C 1-4 Alkyl, N3, JPEG2026504319000072.jpg28170), are preferably such that they are GPR40 agonists with an EC50 of less than 100 nM when measured according to Biological Example 1 herein.

[0082] Typically, p1 in formula D-1 is 0.

[0083] In some embodiments, p1 in formula D-1 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.

[0084] Typically, p2 in formula D-1 is 0.

[0085] In some embodiments, p2 in formula D-1 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.

[0086] In some preferred embodiments, L 10 is optionally substituted ethylene. When substituted, the ethylene is typically each independently 1-4 Alkyl or C 3-6 For example, in some embodiments, L is substituted with one or two substituents that are cycloalkyl. 10 teeth JPEG2026504319000073.jpg25170, R 10 is hydrogen or C 1-4 In some preferred embodiments, formula D-1 can be characterized as having the following formula D-1-A: JPEG2026504319000074.jpg30170R 10 is hydrogen or C 1-4 alkyl (preferably methyl), J 1 , J 2 , and J 3 is defined herein.

[0087] In some embodiments, J of Formula D-1 (e.g., Formula D-1-A) 1 -C 1-6 Alkylene-N(R 100 )-, for example, -CH2-N(C 1-4 Typically, in formula D-1, J 1 is a 4-12 membered optionally substituted heterocycle having one or two ring nitrogen atoms. In some embodiments, J of Formula D-1 (e.g., Formula D-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), JPEG2026504319000075.jpg21170 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.

[0088] In some embodiments, J of Formula D-1 (e.g., Formula D-1-A) 1 may 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 linkage): JPEG2026504319000076.jpg23170

[0089] In some embodiments, J of Formula D-1 (e.g., Formula D-1-A) 2 is a linear or branched C 1-4 alkylene, optionally substituted with 1 to 3 fluorines. For example, in some embodiments, J 2 is CH2 or -CH(CH3)-.

[0090] J in Formula D-1 (for example, Formula D-1-A) 3 is typically 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, C1-6 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 optionally substituted with one or more (e.g., 1, 2, or 3) substituents, including F, —OH, protected hydroxyl, oxo (if applicable), NH, protected amino, NH(C 1-4 alkyl) or its protected derivatives, N(C 1-4 Alkyl ((C 1-4 alkyl), C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 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, cycloalkoxy, phenyl, heteroaryl, and heterocyclyl is independently selected from 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.

[0091] In some embodiments, J of Formula D-1 (e.g., Formula D-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 3-6The 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. 1-4 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.

[0092] In some embodiments, J of Formula D-1 (e.g., Formula D-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.

[0093] For example, in some embodiments, J of Formula D-1 (e.g., Formula D-1-A) 3 is selected from: JPEG2026504319000077.jpg31170In 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 1-4 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 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.

[0094] In some embodiments, J of Formula D-1 (e.g., Formula D-1-A) 3 is selected from: JPEG2026504319000078.jpg57170 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 cycloalkoxy, wherein alkyl, heteroalkyl, cycloalkyl, alkoxy, or cycloalkoxy is C optionally substituted with F, —OH, F1-4 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.

[0095] In some embodiments, J of Formula D-1 (e.g., Formula D-1-A) 3 is selected from: JPEG2026504319000079.jpg58170 Each of these is C optionally substituted with F, Cl, CN, OH, 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 orthogonal to

[0096] In some embodiments, D is characterized as having the following formula D-1-A-1, D-1-A-2, D-1-A-3, D-1-A-4, or D-1-A-5: JPEG2026504319000080.jpg32170JPEG2026504319000081.jpg39170JPEG2026504319000082.jpg37170In the formula, R 20 is C 1-6 Alkyl or fluorine substituted C 1-6 alkyl, and R 21is 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 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.

[0097] In some embodiments, D is characterized as having the formula D-1-A-6, D-1-A-7, D-1-A-8, D-1-A-9, or D-1-A-10: JPEG2026504319000083.jpg118170In 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 20is 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.

[0098] In some embodiments, D of Formula I (e.g., I-1) is a residue having the following formula D-2-A or D-2-B: JPEG2026504319000084.jpg26170JPEG2026504319000085.jpg42170In the formula, 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 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, 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 C3-6 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, p2 is 0, 1, 2, or 3, and R 13 is hydrogen, optionally substituted phenyl, or optionally substituted heteroaryl.

[0099] In some embodiments, D has a structure according to formula D-2-A:

[0100] In some embodiments, D has a structure according to formula D-2-B:

[0101] In some embodiments according to formula D-2-A or D-2-B, L N is null. That is, L Ais directly linked to the phenyl ring depicted in formula D-2-A or the HET ring of D-2-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

[0102] In some embodiments according to formula D-2-A or D-2-B, L N is a branched or linear C 1-6 Alkylene, for example JPEG2026504319000086.jpg22170(L A is shown to indicate the direction of linkage. In some embodiments according to formula D-2-A or D-2-B, L N teeth, JPEG2026504319000087.jpg23170(L A is shown to indicate the direction of linkage), where G A10 are independently hydrogen or optionally substituted C 1-4 Alkyl or two G A10 are linked to form a 3- to 6-membered ring, such as a cyclopropyl or cyclobutyl ring. In some preferred embodiments, G A10 is methyl.

[0103] In some embodiments according to formula D-2-A or D-2-B, L N is a branched or linear C with one or two oxygen atoms 1-6 Heteroalkylene, e.g. JPEG2026504319000088.jpg22170(L A is shown to indicate the direction of linkage. In some embodiments according to formula D-2-A or D-2-B, L N teeth, JPEG2026504319000089.jpg27170(L A is shown to indicate the connection direction), where G A10 are independently hydrogen or optionally substituted C 1-4 Alkyl or two G A10 may be linked to form a 3- to 6-membered ring, such as a cyclopropyl or cyclobutyl ring. B10 are independently hydrogen or optionally substituted C 1-4 alkyl or two G B10 or one G A10 and one G B10 are linked to form a 3- to 6-membered ring such as a cyclopropyl or cyclobutyl ring. C10 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 A10 In some preferred embodiments, G at each occurrence is methyl. B10 is hydrogen. In some preferred embodiments, G C10 is hydrogen or methoxy, etc. 1-4 It is an alkoxy.

[0104] In some embodiments, formula D-2-A can be characterized as having formula D-2-A-1: JPEG2026504319000090.jpg34170 where the variables are defined herein.

[0105] In some embodiments, formula D-2-B can be characterized as having formula D-2-B-1: JPEG2026504319000091.jpg34170 where the variables are defined herein.

[0106] Variable L in formula D-2-A or D-2-B 10 , R 11 , R 12 , R 13 , R A , R C However, in a preferred embodiment, the variables of formula D-2-A or D-2-B are selected from the group consisting of the formula GPR-2, JPEG2026504319000092.jpg58170, wherein E 2 is E 2A or L N -E 2A where E 2A is hydrogen, N3, JPEG2026504319000093.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.

[0107] Typically, p1 in formula D-2-A or D-2-B is 0.

[0108] In some embodiments, p1 of formula D-2-A or D-2-B is 1.

[0109] 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.

[0110] Typically, p2 in formula D-2-A or D-2-B is 0.

[0111] In some embodiments, p2 of formula D-2-A or D-2-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.

[0112] In formula D-2-A or D-2-B, Y is typically CH.

[0113] Preferably, Z in formula D-2-A or D-2-B is O.

[0114] In some embodiments, R 11 and R 12 are both hydrogen.

[0115] In some preferred embodiments, L 10 teeth, JPEG2026504319000094.jpg19170, 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 1-4is 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 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.

[0116] For example, in some embodiments, L 10 teeth JPEG2026504319000095.jpg25170, where R 10 is hydrogen or C such as methyl 1-4 It is alkyl.

[0117] R in formula D-2-A or D-2-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 D-2-A or D-2-B is 13 may also be hydrogen.

[0118] In some embodiments, R 13 is optionally substituted phenyl. In some embodiments, R 13 is an unsubstituted phenyl ring. In some embodiments, R 13are 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 F 1-4 It is optionally substituted with one or more (eg, 1, 2, or 3) substituents independently selected from alkyl.

[0119] 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 JPEG2026504319000096.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.

[0120] In some preferred embodiments, formula D-2-A or D-2-B can be characterized as having formula D-2-A-2 or formula D-2-B-2: JPEG2026504319000097.jpg39170JPEG2026504319000098.jpg39170In 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 linked 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; L N are described herein and are preferred. For example, in some embodiments, L N is null. In some embodiments, L N teeth, JPEG2026504319000099.jpg21170(LA (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.

[0121] In some preferred embodiments, D has a structure according to formula D-2-A-3 or D-2-B-3: JPEG2026504319000100.jpg73170L N are described herein and are preferred. For example, in some embodiments, L N is null. In some embodiments, L N teeth, JPEG2026504319000101.jpg22170(L A is shown to indicate the linkage direction) 1-6 It is alkylene.

[0122] In some embodiments, D in formula I (e.g., I-1) can have a structure according to formula D-3-A or D-3-B: JPEG2026504319000102.jpg84170In formula, Y is CH, CR A , or N, Z is O, S, NH, or N(C1-4 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, 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 C3-6 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, p2 is 0, 1, 2, or 3, and R 18 is optionally substituted phenyl or optionally substituted heteroaryl.

[0123] In some embodiments, D has a structure according to formula D-3-A:

[0124] In some embodiments, D has a structure according to formula D-3-B:

[0125] In some embodiments, D has a structure according to formula D-3-A-1 or D-3-B-1: JPEG2026504319000103.jpg84170

[0126] In some embodiments according to formula D-3-A or D-3-B, L N is null. That is, L A (in Formula I) is directly linked to the amide nitrogen atom shown in Formula D-3-A or D-3-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

[0127] In some embodiments according to formula D-3-A or D-3-B, L N is a branched or linear C 1-6 Alkylene, for example JPEG2026504319000104.jpg22170(L A is shown to indicate the direction of linkage. In some embodiments according to formula D-3-A or D-3-B, L N teeth, JPEG2026504319000105.jpg22170(L A is shown to indicate the direction of linkage), where G A10 are independently hydrogen or optionally substituted C 1-4 Alkyl or two G A10 are linked to form a 3- to 6-membered ring, such as a cyclopropyl or cyclobutyl ring. In some preferred embodiments, G A10 is methyl.

[0128] Variable L in formula D-3-A or D-3-B 10 , R 11 , R 12 , R 18 , R A , R C However, in a preferred embodiment, the variables of formula D-3-A or D-3-B are each a group selected from the group consisting of the formula GPR-3, JPEG2026504319000106.jpg36170 or formula GPR-3B, JPEG2026504319000107.jpg35170 (in the formula, E 3 is E 3A or L N -E 3A and E 3A is hydrogen, N3, JPEG2026504319000108.jpg29170, L N is defined herein (e.g., null or C 1-6alkylene)) is such that at least one corresponding compound is a GPR40 agonist, preferably having an EC50 of less than 100 nM as measured according to Biological Example 1 herein.

[0129] Typically, p1 in formula D-3-A or D-3-B is 0.

[0130] In some embodiments, p1 in formula D-3-A or D-3-B is 1.

[0131] 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.

[0132] Typically, p2 in formula D-3-A or D-3-B is 0.

[0133] In some embodiments, p2 in formula D-3-A or D-3-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.

[0134] In formula D-3-A, Y is typically N.

[0135] Preferably, Z in formula D-3-A is O.

[0136] In some embodiments, R 11 and R 12 are both hydrogen.

[0137] In some preferred embodiments, L 10 teeth, JPEG2026504319000109.jpg20170, where CR 16R 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 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.

[0138] For example, in some embodiments, L10 teeth JPEG2026504319000110.jpg25170, where R 10 is hydrogen or C such as methyl 1-4 It is alkyl.

[0139] R in formula D-3-A or D-3-B 18 is typically an optionally substituted phenyl or an optionally substituted 5- or 6-membered heteroaryl having 1 to 4 ring heteroatoms.

[0140] 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 JPEG2026504319000111.jpg13170, 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 1-4 alkyl), 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, JPEG2026504319000112.jpg17170, 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 3-6cycloalkoxy, 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.

[0141] Ring A of formula D-3-A or D-3-B is a nitrogen-containing heterocyclic structure, with at least one nitrogen bonded to the phenyl ring shown in formula D-3-A or D-3-B.

[0142] In some embodiments, ring A of formula D-3-A or D-3-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: JPEG2026504319000113.jpg18170 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 1-4 alkyl or C optionally substituted with 1 to 3 fluorines 1-4 Optionally substituted with 1 to 2 substituents independently selected from alkoxy.

[0143] In some embodiments, ring A of formula D-3-A or D-3-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.

[0144] In some preferred embodiments, D has a structure according to formula D-3-A-2 or D-3-B-2: JPEG2026504319000114.jpg52170JPEG2026504319000115.jpg51170In 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 linked to form a 3- to 7-membered ring having 0, 1, or 2 heteroatoms selected from O, N, or S; R in 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; L N are described herein and are preferred. For example, in some embodiments, L N is null. In some embodiments, L N teeth, JPEG2026504319000116.jpg20170(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.

[0145] In some preferred embodiments, D has a structure according to formula D-3-A-3 or D-3-B-3: JPEG2026504319000117.jpg49170JPEG2026504319000118.jpg48170L N are described herein and are preferred. For example, in some embodiments, L N is null. In some embodiments, L N teeth, JPEG2026504319000119.jpg21170(L A (The symbol is shown to indicate the linkage direction) 1-6 It is alkylene.

[0146] JPEG2026504319000120.jpg36170JPEG2026504319000121.jpg36170JPEG2026504319000122.jpg161170JPEG2026504319000123.jpg219170J PEG2026504319000124.jpg236170JPEG2026504319000125.jpg228170JPEG2026504319000126.jpg232170JPEG2026504319000127.jpg106170

[0147] In some embodiments, any one of the compounds in Table 1 can be present in the form of a pharmaceutically acceptable salt.

[0148] 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.

[0149] In some embodiments, the present disclosure also provides a compound according to any of Examples 1-36, or a pharmaceutically acceptable salt thereof. A compound according to any of Examples 1-36 should be understood as the same compound depicted in Examples 1-36, without regard to its salt form and / or counterion. The compound may exist in different salt forms and / or contain different counterions.

[0150] In some embodiments, to the extent applicable, the genus of compounds in this disclosure includes: This does not include any compounds that have been specifically prepared and disclosed prior to the present disclosure, such as any of the compounds described in International Application Nos. PCT / CN2021 / 109496 and PCT / CN2023 / 071833, such as JPEG2026504319000128.jpg27170, or pharmaceutically acceptable salts or esters thereof.

[0151] 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.

[0152] 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 employed by one of ordinary skill in the art to synthesize other compounds of the present disclosure.

[0153] As exemplified herein, the compounds of the present disclosure can be typically prepared by coupling reaction of a membrane-bound protein ligand residue, such as a GPCR, particularly a GPR40 agonist, with a hydrophilic molecule. Suitable coupling reactions are not particularly limited, but depend on the structural characteristics of the compound.

[0154] In some embodiments, amide coupling can be used to link a residue of a GPR40 agonist with a hydrophilic molecule. For example, a compound of formula I-1-A-1, where D is D-1, D-2, or D-3, can be prepared according to the synthetic sequence shown in Scheme A-1, A-2, or A-3, and the acid S-1, S-3, or S-4 can be reacted with the amine S-2 under amide coupling conditions, followed by deprotection to obtain a compound of formula I-1-A-1-D2, I-1-A-1-D3, or I-1-A-1-D1, respectively. Although not shown, it should be understood that the amine S-2 and the compound of formula I-1-A-1-D2, I-1-A-1-D3, or I-1-A-1-D1 are charge-balanced as necessary to make the entire molecule neutral. Pg in S-1, S-3, or S-4 1 refers to a carboxylic acid protecting group, such as a tert-butyl group. The variables shown in the schemes are preferred as described herein for each such variable. JPEG2026504319000129.jpg76170JPEG2026504319000130.jpg81170JPEG2026504319000131.jpg73170

[0155] Other compounds of Formula I can be prepared similarly to those shown in Schemes A-1, A-2, and A-3. Illustrated procedures are also provided in the Examples section herein.

[0156] 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, and A-3, 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 some embodiments, the present disclosure provides novel synthetic intermediates shown in the Examples section herein, which, where applicable, may exist in any salt form and / or have different counterions, similar to those shown in the Examples section herein.

[0157] As will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting particular functional groups, are well known in the art. For example, numerous protecting groups are described in "Protective Groups in Organic Synthesis," 4 th ed. PGM Wuts; TW Greene, John Wiley, 2007, and the references cited therein. The reagents for the reactions described herein are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the reagents are commercially available from Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), They are available from commercial suppliers such as Sigma (St. Louis, Missouri, USA). Others are published in Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplemental (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), and March's Advanced Organic Chemistry, (Wiley, 7 th These compounds can be prepared either by procedures described in standard reference texts such as "The American Journal of Biological Chemistry," ... Pharmaceutical Composition

[0158] Certain embodiments are directed to pharmaceutical compositions comprising one or more compounds of the present disclosure.

[0159] The pharmaceutical composition can optionally contain a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of the present disclosure (e.g., a compound of Formula I (e.g., Formula I-1, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-G-1, I-1-G-2, I-1-G-3, I-1-G-4, I-1-G-5, I-1-G-6, I-1-G-7, I-1-G-8, I-1-G-9, I-1-H, I-1-I, I-1-J ... The pharmaceutical composition of the present invention includes a compound of formula (I-I, I-1-A-1, I-1-B-1, I-1-C-1, I-1-D-1, I-1-E-1, I-1-F-1, I-1-H-1, or I-1-I-1), or any of the compounds listed in Table 1 herein, any of the compounds according to Examples 1-36 herein, or a pharmaceutically acceptable salt or ester thereof), and a pharmaceutically acceptable excipient. Pharmaceutically acceptable excipients are well known in the art. Non-limiting examples of suitable excipients include, for example, encapsulating materials or additives such as antioxidants, binders, buffers, carriers, coating agents, colorants, diluents, disintegrants, emulsifiers, bulking agents, fillers, flavoring agents, wetting agents, lubricants, fragrances, preservatives, propellants, release agents, sterilizing agents, sweeteners, solubilizing agents, wetting agents, and mixtures thereof. See also Remington's The Science and Practice of Pharmacy, 21st Edition, A.R. Gennaro (Lippincott, Williams & Wilkins, Baltimore, Md., 2005; incorporated herein by reference), which discloses various excipients used in formulating pharmaceutical compositions and known techniques for their preparation.

[0160] The pharmaceutical composition can include any one or more of the compounds of the present disclosure. For example, in some embodiments, the pharmaceutical composition can include a compound of Formula I (e.g., Formulas I-1, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-G-1, I-1-G-2, I-1-G-3, I-1-G-4, I-1-G-5, I-1-G-6, I-1-G-7, I-1-G-8, I-1-G-9, I-1-H, I-1-I ... The pharmaceutical composition may comprise a therapeutically effective amount of a compound of formula (I), (I-1-A-1), (I-1-B-1), (I-1-C-1), (I-1-D-1), (I-1-E-1), (I-1-F-1), (I-1-H-1), or (I-1-I-1), or any of the compounds listed in Table 1 herein, any of the compounds according to Examples 1-36 herein, or a pharmaceutically acceptable salt or ester thereof, for example. In any of the embodiments described herein, the pharmaceutical composition may comprise a therapeutically effective amount of a compound selected from the compounds listed in Table 1 herein, or a pharmaceutically acceptable salt or ester thereof. In any of the embodiments described herein, the pharmaceutical composition may comprise a therapeutically effective amount of a compound according to Examples 1-36 herein, or a pharmaceutically acceptable salt or ester thereof.

[0161] In some embodiments, pharmaceutical compositions can be prepared for oral administration.Typically, pharmaceutical compositions are administered to subjects who need to deliver an effective amount of GPR40 agonist to the gastrointestinal tract, with minimal or no absorption of GPR40 agonist in systemic circulation.Oral formulations can be provided in individual units such as capsules, pills, oblates, lozenges, each containing a predetermined amount of active compound, as powder or granules, as a solution or suspension in aqueous or non-aqueous liquid, or as oil-in-water or water-in-oil emulsion.Excipients for preparing compositions for oral administration are known in the art. Non-limiting examples of suitable excipients include agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butylene glycol, carbomer, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, crospovidone, diglycerides, ethanol, ethyl cellulose, ethyl laurate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerin, peanut oil, hydroxypropyl methylcellulose, isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, potassium phosphate salts, potato starch, povidone, propylene glycol, Ringer's solution, safflower oil, sesame oil, sodium carboxymethylcellulose, sodium phosphate salts, sodium lauryl sulfate, sodium sorbitol sorbitol), soybean oil, stearic acid, stearyl fumarate, sucrose, surfactants, talc, tragacanth, tetrahydrofurfuryl alcohol, triglycerides, water, and mixtures thereof.

[0162] The compounds of the present disclosure can be used alone or in combination with each other, or in combination with one or more additional therapeutic agents, such as 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 a 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 agonist, or a PPARα / δ partial agonist. 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 / 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 antibodies, GPR119 agonists, TGR5 agonists, SSTR2 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 antibodies or inhibitors, ANGPTL3 / 8 antibody, ANGPTL4 inhibitor, oxyntomodulin, (xi) anti-amyloid beta antibody, (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, anti-IL-12 / IL-23 antibodies, (xiii) anti-integrin antibodies or small molecule inhibitors of integrins including α4β7, α4,β7, MAdCAM-1, αvβ6, and αvβ1.These additional therapeutic agents are known in the art, some of which are exemplified in the background section. Additional examples can be found in various patent documents, such as those described in U.S. Published Application No. 20190367495, the contents of which are incorporated herein by reference.

[0163] When used in combination with one or more additional therapeutic agents, the compounds of the present disclosure or pharmaceutical compositions herein can be administered to a subject simultaneously with such additional therapeutic agents or sequentially in any order. In some embodiments, a pharmaceutical composition can contain one or more compounds of the present disclosure and one or more additional therapeutic agents in a single composition. In some embodiments, a pharmaceutical composition containing one or more compounds of the present disclosure can be included in a kit that also contains a separate pharmaceutical composition containing one or more additional therapeutic agents.

[0164] Pharmaceutical compositions can contain varying amounts of the compounds of the present disclosure, depending on various factors, such as the intended use and the potency and selectivity of the compound. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present disclosure. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the present disclosure and a pharmaceutically acceptable excipient. As used herein, a therapeutically effective amount of a compound of the present disclosure is an amount effective to treat a disorder, condition, or disease described herein, such as type 1 or type 2 diabetes, obesity, and / or an eating disorder, and can depend on the person being treated, the disorder, condition, or disease being treated and its severity, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the potency of the compound, its clearance rate, and whether another drug is being co-administered.

[0165] Method of Treatment / Use

[0166] The compounds of the present disclosure have a variety of utilities. For example, the compounds of the present disclosure can be used as therapeutically active substances for the treatment and / or prevention of disorders, conditions, or diseases associated with G protein-coupled receptor 40 ("GPR40"). Accordingly, some embodiments of the present disclosure are also directed to methods of using one or more compounds of the present disclosure or pharmaceutical compositions herein to treat or prevent disorders, conditions, or diseases that may respond to agonism of G protein-coupled receptor 40 ("GPR40") in a subject in need thereof, for example, to treat type 1 or type 2 diabetes mellitus, obesity, and / or eating disorders in a subject in need thereof.

[0167] In some embodiments, the present disclosure provides a method of treating or preventing a disorder, condition, or disease responsive to agonism of G protein-coupled receptor 40 ("GPR40") in a subject in need thereof. In some embodiments, the method comprises administering to a subject an effective amount of a compound of the present disclosure (e.g., a compound of Formula I (e.g., Formulas I-1, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-G-1, I-1-G-2, I-1-G-3, I-1-G-4, I-1-G-5, I-1-G-6, I-1-G-7, I-1-G-8, I-1-G-9, I-1-H, I-1-I, In some embodiments, the disorder, condition, or disease responsive to agonism of GPR40 is selected from the group consisting of: I-1-A-1, I-1-B-1, I-1-C-1, I-1-D-1, I-1-E-1, I-1-F-1, I-1-H-1, or I-1-I-1), any of the compounds listed in Table 1 herein, any of the compounds according to Examples 1-36 herein, or a pharmaceutically acceptable salt or ester thereof, or an effective amount of a pharmaceutical composition described herein. In some embodiments, the disorder, condition, or disease responsive to agonism of GPR40 is selected from the group consisting of: 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 retinopathy, sexual dysfunction, dermatitis, dyspepsia, hypoglycemia, cancer, edema, non-alcoholic steatohepatitis (NASH), lipodystrophy, Prader-Willi syndrome, inflammatory bowel disease 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.

[0168] In some embodiments, the present disclosure also provides a method of treating type 2 diabetes mellitus in a subject in need thereof. In some embodiments, the method includes administering to a subject an effective amount of a compound of the present disclosure (e.g., a compound of Formula I (e.g., Formula I-1, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-G-1, I-1-G-2, I-1-G-3, I-1-G-4, I-1-G-5, I-1-G-6, I-1-G-7, I-1-G-8, I-1-G-9, I-1-H, I-1-I, I-1-I, I-1-I). The present invention also includes administering to a patient a compound of formula (I-1-A-1, I-1-B-1, I-1-C-1, I-1-D-1, I-1-E-1, I-1-F-1, I-1-H-1, or I-1-I-1), or any of the compounds listed in Table 1 herein, any of the compounds according to Examples 1-36 herein, or a pharmaceutically acceptable salt or ester thereof), or an effective amount of a pharmaceutical composition described herein.

[0169] The administration in the methods herein is not limited. In some embodiments, the administration is oral.

[0170] As discussed herein, the compounds of the present disclosure can be used as monotherapy or in combination therapy. In some embodiments according to the methods described herein, the compounds of the present disclosure can be administered as the sole active ingredient.

[0171] In some embodiments according to the methods described herein, a compound of the present disclosure can be administered to a subject in need thereof simultaneously with an additional therapeutic agent, or sequentially in any order. In some embodiments, the additional therapeutic agent can 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 agonist, or a PPARα / γ agonist. 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, amylases analogs, GPR119 agonists, TGR5 agonists, SSTR2 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 antibodies or inhibitors, AN (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 or small molecule inhibitors, including α4β7, α4, β7, MAdCAM-1, αvβ6, and αvβ1.

[0172] Dosage regimens, including dosages, for the methods described herein can be varied and adjusted, and can depend on the person being treated, the disorder, condition, or disease being treated and its severity, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the potency of the compound, its clearance rate, and whether another drug is being co-administered.

[0173] definition

[0174] It is to be understood that appropriate atomic valences are maintained for all moieties and combinations thereof.

[0175] When a variable or structure is defined herein as containing a charged group, such as one containing a quaternary nitrogen atom, it should be understood that a compound containing such a variable or structure is overall neutral. In other words, the charge associated with the variable or structure is balanced with a counterion as needed to maintain the overall electronic neutrality of the compound, regardless of whether a counterion is explicitly drawn or described. Furthermore, if the charge of a variable or structure is balanced by an internal salt (or zwitterionic structure), such that the variable or structure is overall neutral, it should be understood that a counterion is not required to maintain electronic neutrality. In such cases, it should be understood that no counterion is present, even if such a counterion is explicitly drawn or described.

[0176] Suitable counterions are not particularly limited, but preferably, the counterions herein are pharmaceutically acceptable counterions, e.g., pharmaceutically acceptable anions, and can be monovalent (e.g., containing one formal negative charge) or multivalent (e.g., containing two or more formal negative charges), such as divalent or trivalent. Non-limiting exemplary suitable counterions include halide ions (e.g., F - , Cl - , Br - , I - ), NO3 - , ClO4 - , O.H. - , H2PO4 -, HSO4 - , sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate, acid-2-sulfonate), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, tartrate, citrate, fumarate, maleate, maleic acid, etc.), malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, etc.), BF4 - , PF4 - , PF6 - , AsF6 - , SbF6 - , B[3,5-(CF3)2C6H3]4] - , BPh4 - , Al(OC(CF3)3)4 - , carborane anions (e.g., CB11 H 12 - or (HCB 11 Me5Br6) - ), CO3 2- , HPO4 2- , PO4 3- , B4O7 2- , SO4 2- , S2O3 2- Includes:

[0177] It is also to be understood that a particular embodiment of a variable moiety herein may be the same as or different from another particular embodiment having the same identifier.

[0178] Suitable groups in the compounds of Formula I or its subformulas are independently selected, where applicable. The described embodiments of the present disclosure can be combined. Such combinations are contemplated and within the scope of the present disclosure. For example, q, T of Formula I A , L A , and any one or more of the definitions of D, q, T, A , L A and D may be combined with any one or more other definitions, and compounds resulting from such combinations are considered to be within the scope of the present disclosure. Other combinations of variables in other formulas are to be understood as well. For clarity, with respect to any formula herein, it should be understood that, unless specified otherwise or contradicted by context, the definition and preferred definition of a variable appearing in the formula may be any of the respective definitions and preferred definitions set forth herein for the variable in relation to the parent formula (or any subformula of the parent formula) or any other formula indicated as applicable. For example, unless specified otherwise or contradicted by context, a variable appearing in formula I-1-A may have the definition defined for that variable in relation to formula I or any other subformula (e.g., I-1, I-1-B, etc.). As a further example, unless specified otherwise or contradicted by context, L in relation to any formula herein may have the definition defined for that variable in relation to formula I or any other subformula (e.g., I-1, I-1-B, etc.). A and / or T AThe definitions and preferred definitions of L associated with any formula herein are generally applicable to all other formulae herein. A and / or T A Preferred definitions of also include those given for specific compounds prepared herein, such as Examples 1-36.

[0179] Symbols displayed perpendicular to (or across) a bond indicates the point at which the indicated moiety is attached to the remainder of the molecule. In some chemical diagrams herein, one or more groups that are directly linked are represented by the symbol , to indicate the direction of the bond, as will be understood by those skilled in the art. Note that JPEG2026504319000132.jpg8170 is shown above.

[0180] Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are listed in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th In addition, general principles of organic chemistry, as well as specific functional groups and reactivities, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5 th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3 rdEdition, Cambridge University Press, Cambridge, 1987. The present disclosure is not intended to be limited in any way by the exemplary list of substituents set forth herein.

[0181] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various isomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts. Alternatively, preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725(1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., University of Notre Dame Press, Notre Dame, IN 1972). The present disclosure further encompasses the compounds described herein as individual isomers substantially free of other isomers or as mixtures of various isomers, including racemic mixtures. Where stereochemistry is specifically depicted, unless the context contradicts, with respect to that particular chiral center or axial chirality, the compound may exist predominantly as the stereoisomer as depicted, with less than 20%, less than 10%, less than 5%, less than 1%, etc., or undetectable amounts of other stereoisomers by weight, by HPLC area, or both.In some preferred embodiments, the compounds herein can exist predominantly as the depicted stereoisomer, having an enantiomeric excess ("ee") of at least 70%, e.g., at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% ee, or alternatively, the other enantiomer is undetectable. The presence and / or amount of stereoisomers can be determined by one of skill in the art in light of the present disclosure, including by use of chiral HPLC or other methods.

[0182] When a range of values ​​is listed, it is intended to encompass each value and subrange within the range. For example, "C 1-6 ” is C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 is intended to include.

[0183] As used herein, the term "compounds of the disclosure" refers to compounds of Formula I (e.g., Formulas I-1, I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-G-1, I-1-G-2, I-1-G-3, I-1-G-4, I-1-G-5, I-1-G-6, I-1-G-7, I-1-G-9, I-1-G-10, I-1-G-11, I-1-G-12, I-1-G-13, I-1-G-14, I-1-G-15, I-1-G-16, I-1-G-17, I-1-G-18, I-1-G-19, I-1-G-20, I-1-G-21, I-1-G-22, , I-1-G-8, I-1-G-9, I-1-H, I-1-I, I-1-A-1 (e.g., I-1-A-1-D1, I-1-A-1-D2, I-1-A-1-D3), I-1-B-1, I-1-C-1, I-1-D-1, I-1-E-1, I-1-F-1, I-1-H-1, or I-1-I-1) according to the present invention. " refers to any of the compounds described in the specification, or any of the compounds listed in Table 1 herein, any of the compounds according to Examples 1-36 herein, its isotopically labeled compounds (such as deuterated analogs in which at least one of the hydrogen atoms is replaced with a deuterium atom in an abundance greater than its natural abundance), possible regioisomers, possible stereoisomers (including diastereoisomers, enantiomers, and racemic mixtures), tautomers, conformers, pharmaceutically acceptable esters, zwitterionic structures, and / or possible pharmaceutically acceptable salts (e.g., acid addition salts such as HCl salts or base addition salts such as Na salts). Hydrates and solvates of the compounds of the present disclosure are considered compositions of the present disclosure, wherein the compound is combined with water or a solvent, respectively. For clarity, as used herein, a compound according to Examples 1-36 herein, or a pharmaceutically acceptable salt thereof, should be understood to encompass any compound having the structure of any of Examples 1-36 shown in the Examples section herein, or a pharmaceutically acceptable salt thereof, except that the counterion and / or salt form may be different. For example, a compound according to Example 1, or a pharmaceutically acceptable salt thereof, should be understood to encompass the base form of Example 1, a pharmaceutically acceptable salt thereof (including but not limited to the HCl addition salt), or any combination thereof. Similarly, a compound according to Example 3, or a pharmaceutically acceptable salt thereof, should be understood to encompass any compound having the structure of any of Examples 1-36 shown in the Examples section herein, or a pharmaceutically acceptable salt thereof, in which the counterion of the quaternary nitrogen is Cl. -or any other pharmaceutically acceptable counterion or internal counterion, a pharmaceutically acceptable salt thereof (HCl addition salt with counterion Cl of the quaternary nitrogen). - It should be understood that the term "aromatic" refers to a compound of formula (I), (II), (III), (IV ...

[0184] The compounds of the present disclosure may exist in isotopically labeled or isotopically enriched forms containing one or more atoms with an atomic mass or mass number different from the atomic mass or mass number most abundantly found in nature. The isotopes may be radioactive or non-radioactive. Isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine, and iodine are 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 32 P, 35 S, 18 F, 36 Cl, and 125 Compounds containing other isotopes of these and / or other atoms are within the scope of this invention, including, but not limited to, I.

[0185] As used herein, the phrase "administration" of a compound, "administering" a compound, or other variations thereof, means providing a compound or a prodrug of a compound to an individual in need of treatment.

[0186] As used herein, the term "alkyl," when used by itself or as part of another group, refers to a straight or branched chain aliphatic saturated hydrocarbon. In some embodiments, alkyl refers to an alkyl group having 1 to 12 carbon atoms (i.e., C 1-12 In one embodiment, an alkyl group can be a straight chain C 1-10 Alkyl group (or linear C 1-10 In another embodiment, the alkyl group is a branched C 3-10In another embodiment, the alkyl group is a straight-chain C 1-6 In another embodiment, the alkyl group is a branched C 3-6 In another embodiment, the alkyl group is a straight-chain C 1-4 It is an alkyl group. For example, C 1-4 Alkyl groups include methyl, ethyl, propyl (n-propyl), isopropyl, butyl (n-butyl), sec-butyl, tert-butyl, and iso-butyl. As used herein, the term "alkylene," when used by itself or as part of another group, refers to a divalent radical derived from an alkyl group. For example, non-limiting straight chain alkylene groups include -CH-CH-CHCH-, -CH-CH-CH-, -CH-CH-, and the like.

[0187] As used herein, the term "alkenyl," by itself or as part of another group, refers to a straight or branched chain aliphatic hydrocarbon containing one or more, e.g., one, two, or three, carbon-carbon double bonds. In one embodiment, an alkenyl group is a C 2-6 In another embodiment, the alkenyl group is C 2-4 Alkenyl groups. Non-limiting exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.

[0188] As used herein, the term "alkynyl," by itself or as part of another group, refers to a straight or branched chain aliphatic hydrocarbon containing one or more, e.g., one to three, carbon-carbon triple bonds. In one embodiment, an alkynyl has one carbon-carbon triple bond. In one embodiment, an alkynyl group is C 2-6 In another embodiment, the alkynyl group is C 2-4 Alkynyl groups. Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl groups.

[0189] As used herein, the term "alkoxy" when used by itself or as part of another group refers to a group of the formula OR a1 refers to the radical of R a1 is alkyl.

[0190] As used herein, the term "cycloalkoxy" when used by itself or as part of another group refers to a group of the formula OR a1 refers to the radical of R a1 is cycloalkyl.

[0191] As used herein, the term "haloalkyl," when used by itself or as part of another group, refers to an alkyl substituted with one or more fluorine, chlorine, bromine, and / or iodine atoms. In preferred embodiments, a haloalkyl is an alkyl group substituted with one, two, or three fluorine atoms. In one embodiment, a haloalkyl group is selected from the group consisting of C 1-10 In one embodiment, the haloalkyl group is C 1-6 In one embodiment, the haloalkyl group is C 1-4 It is a haloalkyl group.

[0192] As used herein, the term "heteroalkyl," by itself or in combination with another term, means, unless otherwise specified, a stable straight- or branched-chain alkyl group, e.g., having 2 to 14 carbons, e.g., 2 to 10 carbons, in the chain, one or more of which are replaced by a heteroatom selected from S, O, P, and N; the nitrogen, phosphine, and sulfur atoms can be optionally oxidized; and the nitrogen heteroatom can be optionally quaternized. The heteroatoms S, O, P, and N can be placed at any position within the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. For example, C 1-4Heteroalkyl includes, but is not limited to, C4 heteroalkyl such as -CH2-CH2-N(CH3)-CH3, C3 heteroalkyl such as -CH2-CH2-O-CH3, CH2-CH2-NH-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, and CH2-CH2-S(O)2-CH3, C2 heteroalkyl such as -O-CH2-CH3, and C1 heteroalkyl such as O-CH3. For clarity, when a heteroalkyl is referred to as xx-membered, the number of carbons and heteroatoms forming the heteroalkyl should be counted together, but potential oxidation should not be counted. For example, sulfur oxides and N-oxides are counted as one member. For example, -CH2-CH2-N(CH3)-CH3 or CH2-[N(CH3)3] +can be considered a 5-membered heteroalkyl. Further, by way of example, 4-membered heteroalkyls include -CH-CH-O-CH, CH-CH-NH-CH, -CH-S-CH-CH, -CH-CH-S(O)-CH, and CH-CH-S(O)-CH; 3-membered heteroalkyls include -O-CH-CH, and 2-membered heteroalkyls include -O-CH. Similarly, for purposes of this specification, oxygen atoms from potential oxidation are not counted when counting the number of heteroatoms in a heteroalkyl group. Thus, -CH-S-CH-CH, -CH-CH-S(O)-CH, and CH-CH-S(O)-CH would all be considered 4-membered C heteroalkyls having one heteroatom, S, where S is optionally oxidized. Similarly, the term "heteroalkylene" by itself or as part of another substituent means a divalent radical derived from heteroalkyl, exemplified by, but not limited to, -CH-CH-O-CHCH- and -O-CH-CH-NH-CH-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. When a "heteroalkyl" is recited followed by -NR'R '' When specific heteroalkyl groups such as -NR'R'' are recited, it will be understood that the terms heteroalkyl and -NR'R'' are not overlapping or mutually exclusive. Rather, specific heteroalkyl groups are recited to add clarity. Thus, the term "heteroalkyl" refers to -NR'R''. '' The term should not be construed as excluding certain heteroalkyl groups such as:

[0193] "Carbocyclyl" or "carbocyclic," when used by itself or as part of another group, refers to a ring system having at least three carbon atoms, e.g., 3 to 10 ring carbon atoms ("C3-10 "Carbocyclyl" refers to the radical of a non-aromatic cyclic hydrocarbon group having 1 or more heteroatoms, such as aryl, aryl(s), or aryl(s) ("carbocyclyl"), and zero heteroatoms. A carbocyclyl group can be monocyclic ("monocyclic carbocyclyl") or contain fused, bridged, or spiro ring systems, such as bicyclic systems ("bicyclic carbocyclyl"), and can be saturated or partially unsaturated. "Carbocyclyl" also includes ring systems in which a carbocyclic ring, as defined above, is fused to one or more aryl or heteroaryl groups, and the point of attachment is on the carbocyclic ring; in such cases, the number of carbons still refers to the number of carbons in the carbocyclic ring system. Non-limiting exemplary carbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclopentenyl, and cyclohexenyl. As used herein, the term "carbocyclylene," when used by itself or as part of another group, refers to a divalent radical derived from a carbocyclyl group, as defined herein.

[0194] In some embodiments, a "carbocyclyl" is fully saturated and is also referred to as a cycloalkyl. In some embodiments, a cycloalkyl can have from 3 to 10 ring carbon atoms ("C 3-10 In preferred embodiments, the cycloalkyl is a monocyclic ring. As used herein, the term "cycloalkylene" when used by itself or as part of another group refers to a cycloalkyl group, such as It refers to a divalent radical derived from JPEG2026504319000133.jpg19170, etc.

[0195] "Heterocyclyl" or "heterocyclic," by itself or as part of another group, refers to a radical of three or more members, such as a 3- to 14-membered non-aromatic ring system having ring carbon atoms and at least one ring heteroatom, such as 1 to 4 ring heteroatoms, each heteroatom being independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, as valence permits. Heterocyclyl groups may be monocyclic ("monocyclic heterocyclyl"), or fused, bridged, or spiro ring systems, such as bicyclic ring systems ("bicyclic heterocyclyl"), and may be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocycle, as defined above, is fused to one or more carbocyclyl groups, with the point of attachment being on the heterocycle, or in which a heterocycle, as defined above, is fused to one or more aryl or heteroaryl groups, with the point of attachment being on the heterocycle; in such cases, the number of ring members still refers to the number of ring members in the heterocycle system. As used herein, the term "heterocyclylene," when used by itself or as part of another group, refers to a divalent radical derived from a heterocyclyl group, as defined herein. For example, a piperidinylene group is a ring system in which a piperidine ring is fused to one or more aryl or heteroaryl groups. JPEG2026504319000134.jpg18170. The heterocyclyl or heterosilylene can optionally be linked to the remainder of the molecule through a carbon or nitrogen atom.

[0196] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C aryl ring (also referred to herein as a 5,6-bicyclic heterocycle) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocycle) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0197] "Aryl," when used by itself or as part of another group, refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic arrangement) having 6 to 14 ring carbon atoms and 0 heteroatoms provided in the aromatic ring system ("C 6-14 In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl", e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 aryl," e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C 14 "Aryl", e.g., anthracyl). "Aryl" also includes ring systems in which an aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups, and the radical or point of attachment is on the aryl ring; in such cases, the number of carbon atoms still refers to the number of carbon atoms in the aryl ring system. As used herein, the term "arylene", when used by itself or as part of another group, refers to a divalent radical derived from an aryl group, as defined herein. For example, a phenylene group can be fused to a benzene ring, e.g., 1,3-phenylene, 1,4-phenylene: Contains two join points from JPEG2026504319000135.jpg19170, etc.

[0198] "Aralkyl," when used by itself or as part of another group, refers to an alkyl substituted with one or more aryl groups, preferably one aryl group. Examples of aralkyls include benzyl, phenethyl, and the like. When an aralkyl is said to be optionally substituted, either the alkyl or aryl portion of the aralkyl can be optionally substituted.

[0199] "Heteroaryl," when used by itself or as part of another group, refers to a radical of a 5-14-membered monocyclic, bicyclic, or tricyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π-electrons shared in the cyclic arrangement) having ring carbon atoms and at least one, preferably 1 to 4, ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-14-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be to a carbon or nitrogen atom, valence permitting. Heteroaryl bicyclic ring systems can contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more carbocyclyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring; in such cases, the number of ring members still refers to the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused with one or more aryl groups, and the point of attachment is on either the aryl or heteroaryl ring; in such cases, the number of ring members refers to the number of ring members in the fused (aryl / heteroaryl) ring system. In the case of bicyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, etc.), the point of attachment can be on either ring, i.e., the ring containing the heteroatom (e.g., 2-indolyl) or the ring not containing the heteroatom (e.g., 5-indolyl). As used herein, the term "heteroarylene," when used by itself or as part of another group, refers to a divalent radical derived from a heteroaryl group, as defined herein. For example, a pyridinylene group is a pyridine ring, e.g., 2,4-pyridinylene, 2,5-pyridinylene: JPEG2026504319000136.jpg20170 or It contains two attachment points from etc.

[0200] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing 1 heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl.Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0201] "Heteroaralkyl," by itself or as part of another group, refers to an alkyl substituted with one or more heteroaryl groups, preferably one heteroaryl group. When a heteroaralkyl is said to be optionally substituted, either the alkyl or the heteroaryl portion of the heteroaralkyl can be optionally substituted.

[0202] "Optionally substituted" groups, such as optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl groups, refer to the respective groups, whether unsubstituted or substituted. Generally, the term "substituted," whether preceded by the term "optionally," means that at least one hydrogen atom present on the group (e.g., a carbon or nitrogen atom) is replaced with an acceptable substituent, e.g., a substituent that, upon substitution, results in a stable compound, e.g., a compound that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, or other reaction. Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group; when more than one position in any structure is substituted, the substituents may be the same or different at each position. Typically, when substituted, an optionally substituted group herein can be substituted with 1 to 5 substituents. The substituent may be a carbon atom, nitrogen atom, oxygen atom, or sulfur atom, where applicable. Any two of the substituents may combine to form an optionally substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl ring. Substitutions may occur at any available carbon, oxygen, or nitrogen atom, forming a spirocyclic ring. Typically, substitutions herein do not result in OO, ON, SS, SN (excluding SO-N bonds), heteroatom-halogen, or -C(O)-S bonds, or three or more consecutive heteroatoms, except for O-SO-O, O-SO-N, and N-SO-N. However, some of such bonds or linkages may be tolerated in a stable aromatic system.

[0203] In a broad aspect, the permissible substituents herein include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, heteroatoms such as nitrogen can have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valences of the heteroatoms. Substituents can include any substituent described herein, for example, halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxy, cycloalkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonyl, heterocyclyl, aralkyl, aryl, or heteroaryl, each of which can be substituted where appropriate.

[0204] Exemplary substituents are alkyl, alkenyl, alkynyl, aryl, heteroaryl, -alkylene-aryl, -arylene-alkyl, -alkylene-heteroaryl, -alkenylene-heteroaryl, -alkynylene-heteroaryl, -OH, hydroxyalkyl, haloalkyl, -O-alkyl, -O-haloalkyl, -alkylene-O-alkyl, -O-aryl, -O-alkylene-aryl, acyl, -C(O)-aryl, halo, -NO, -CN, -SF, -C(O)OH, -C(O)O-alkyl, -C(O)O-aryl, -C(O)O-alkylene-aryl, -S(O)-alkyl, -S(O)-alkyl, -S(O)-aryl, -S(O) Examples include, but are not limited to, -aryl, -S(O)-heteroaryl, -S(O)-heteroaryl, -S-alkyl, -S-aryl, -S-heteroaryl, -S-alkylene-aryl, -S-alkylene-heteroaryl, -S(O)-alkylene-aryl, -S(O)-alkylene-heteroaryl, cycloalkyl, heterocycloalkyl, -OC(O)-alkyl, -OC(O)-aryl, -OC(O)-cycloalkyl, -C(=N-CN)-NH, -C(=NH)-NH, -C(=NH)-NH(alkyl), -N(Y)(Y), -alkylene-N(Y)(Y), -C(O)N(Y)(Y) and -S(O)N(Y)(Y). wherein Y1 and Y2 may be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, and -alkylene-aryl.

[0205] Some examples of suitable substituents are (C1-C8) alkyl groups, (C2-C8) alkenyl groups, (C2-C8) alkynyl groups, (C3-C 10) cycloalkyl groups, halogens (F, Cl, Br, or I), halogenated (C1-C8) alkyl groups (such as, but not limited to, —CF3)—O—(C1-C8) alkyl groups, —OH, —S—(C1-C8) alkyl groups, —SH, —NH(C1-C8) alkyl groups, —N((C1-C8) alkyl) groups, —NH2, —C(O)NH2, —C(O)NH(C1-C8) alkyl groups, —C(O)N((C1-C8) alkyl)2, —NHC(O)H, —NHC(O)(C1-C8) alkyl groups, —NHC(O)(C3-C8) cycloalkyl groups, —N((C1- C8) alkyl)C(O)H, -N((C1-C8) alkyl)C(O)(C1-C8) alkyl group, -NHC(O)NH2, -NHC(O)NH(C1-C8) alkyl group, -N((C1-C8) alkyl)C(O)NH2 group, -NHC(O)N((C1-C8) alkyl)2 group, -N((C1-C8) alkyl)C(O)N((C1-C8) alkyl)2 group, -N((C1-C8) alkyl)C(O)NH((C1-C8) alkyl), -C(O)H, -C(O)(C1-C8) alkyl group, -CN, -NO2, -S(O)(C1-C8) alkyl group, -S(O)2(C1-C8) alkyl group, -S(O)2N((C1-C8) alkyl)2 group, -S(O)2NH(C1-C8) alkyl group, -S(O)2NH(C3-C8) cycloalkyl group, -S(O)2NH2 group, -NHS(O)2(C1-C8) alkyl group, -N((C1-C8) alkyl)S(O)2(C1-C8) alkyl group, -(C1-C8) alkyl-O-(C1-C8) alkyl group, -O-(C1-C8) alkyl-O-(C1-C8) alkyl group, -C(O)OH, -C(O)O(C1-C8) alkyl group, NHOH, NHO(C1-C 8) alkyl groups, -O-halogenated (C1-C8) alkyl groups (such as, but not limited to, -OCF3)-S(O)2-halogenated (C1-C8) alkyl groups (such as, but not limited to, -S(O)2CF3)-S-halogenated (C1-C8) alkyl groups (such as, but not limited to, -SCF3)-(C1-C6)heterocycles (such as, but not limited to, pyrrolidine, tetrahydrofuran, pyran, or morpholine)-(C1-C6)heteroaryls (such as, but not limited to, tetrazole, imidazole, furan, pyrazine, or pyrazole), -phenyl,These include, but are not limited to, -NHC(O)O-(C1-C6)alkyl groups, -N((C1-C6)alkyl)C(O)O-(C1-C6)alkyl groups, -C(=NH)-(C1-C6)alkyl groups, -C(=NOH)-(C1-C6)alkyl groups, or -C(=NO-(C1-C6)alkyl)-(C1-C6)alkyl groups.

[0206] Exemplary carbon atom substituents are halogen, -CN, -NO2, -N3, hydroxyl, alkoxy, cycloalkoxy, aryloxy, amino, monoalkylamino, dialkylamino, amido, sulfonamido, thiol, acyl, carboxylic acid, ester, sulfone, sulfoxide, alkyl, haloalkyl, alkenyl, alkynyl, C 3-10 Carbocyclyl, C 6-10 Examples of carbon atom substituents include, but are not limited to, aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, etc. For example, exemplary carbon atom substituents are F, Cl, —CN, —SOH, —SOH, —OH, —OC 1-6 Alkyl, -NH2, -N(C 1-6 alkyl)2, -NH(C 1-6 alkyl), -SH, -SC 1-6 Alkyl, -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6alkyl)2, -SO2NH(C 1-6 alkyl), -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclyl, C 6-10 It can include aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or two geminal substituents can join to form =0.

[0207] Nitrogen atoms may be substituted or unsubstituted, where valence allows, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents are hydrogen, acyl groups, esters, sulfones, sulfoxides, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14Examples of suitable substituents include, but are not limited to, aryl, and 5- to 14-membered heteroaryl. Alternatively, two substituents attached to the nitrogen atom may be joined to form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring. Each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl may be further substituted as defined herein. In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to as an amino protecting group). Nitrogen protecting groups are well known in the art and include those described in detail in Protective Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference. Exemplary nitrogen protecting groups include, but are not limited to, those that form carbamates such as a carbobenzyloxy (Cbz) group, a p-methoxybenzylcarbonyl (Moz or MeOZ) group, a tert-butyloxycarbonyl (BOC) group, a Troc group, a 9-fluorenylmethyloxycarbonyl (Fmoc) group, those that form amides such as acetyl, benzoyl, those that form benzylamines such as benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, those that form sulfonamides such as tosyl, nosyl, and others such as p-methoxyphenyl.

[0208] Exemplary oxygen atom substituents are acyl groups, esters, sulfonates, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14

[0023] Examples of the aryl group include, but are not limited to, aryl and 5- to 14-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl can be further substituted as defined herein. In certain embodiments, the oxygen atom substituent present on the oxygen atom is an oxygen protecting group (also called a hydroxyl protecting group). Oxygen protecting groups are well known in the art and include those described in detail in Protective Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, 3rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference. Exemplary oxygen protecting groups include, but are not limited to, those that form alkyl ethers or substituted alkyl ethers such as methyl, allyl, benzyl, substituted benzyl (such as 4-methoxybenzyl, methoxylmethyl (MOM), benzyloxymethyl (BOM), 2-methoxyethoxymethyl (MEM)), etc.; those that form silyl ethers such as trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBDMS); those that form acetals or ketals such as tetrahydropyranyl (THP); those that form esters such as formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate; and those that form carbonates or sulfonates such as methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0209] Unless expressly stated to the contrary, combinations of substituents and / or variables are permissible only if such combinations are chemically permissible and result in stable compounds. A "stable" compound is one that can be prepared and isolated and whose structure and properties remain essentially unchanged, or can remain essentially unchanged, for a period of time sufficient to use the compound for the purposes described herein (e.g., therapeutic administration to a subject).

[0210] In some embodiments, the "optionally substituted" alkyl, alkylene, alkenyl, alkynyl, carbocycle, carbocyclylene, cycloalkyl, cycloalkylene, alkoxy, cycloalkoxy, heterocyclyl, or heterocyclylene herein are each independently unsubstituted or substituted with F, Cl, -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 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 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, cycloalkoxy, phenyl, heteroaryl, and heterocyclyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from 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 In some embodiments, the "optionally substituted" aryl, arylene, heteroaryl, or heteroarylene groups herein are each independently unsubstituted or substituted with one, two, or three substituents selected from F, Cl, -OH, -CN, NH, protected amino, NH(C 1-4 alkyl) or its protected derivatives, N(C 1-4 Alkyl ((C 1-4alkyl), -S(=O)(C 1-4 alkyl), -SO2(C 1-4 alkyl), C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 and 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, cycloalkoxy, phenyl, heteroaryl, and heterocyclyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from F, —OH, oxo (where applicable), C 1-4 Alkyl, Fluoro-substituted C 1-4 Alkyl, C 1-4 Alkoxy and Fluoro Substituted C 1-4 Optionally substituted with 1, 2, or 3 substituents independently selected from alkoxy.

[0211] "Halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0212] The term "leaving group" is given its ordinary meaning in the field of synthetic organic chemistry and refers to an atom or group that can be displaced by a nucleophile. See, e.g., Smith, March, Advanced Organic Chemistry 6 thed. (501-502). Examples of suitable leaving groups include, but are not limited to, halogen (such as F, Cl, Br, or I (iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, N,O-dimethylhydroxylamino, pixyl, and haloformate.

[0213] The terms "pharmaceutically acceptable salt," "pharmaceutically acceptable anion," or "pharmaceutically acceptable cation" refer to salts, anions, or cations that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts, anions, or cations are well known in the art.

[0214] The term "pharmaceutically acceptable ester" refers to an ester that, within the scope of sound medical judgment, is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable esters are well known in the art and include, for example, C esters, such as ethyl esters. 1-4 It is an alkyl ester.

[0215] The term "tautomer" or "tautomerism" refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valence (e.g., from a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of tautomers varies depending on several factors, including temperature, solvent, and pH. Tautomerization (i.e., the reaction that provides a tautomeric pair) can be catalyzed by acid or base. Exemplary tautomerizations include keto to enol, amide to imide, lactam to lactim, enamine to imine, and enamine to (different enamine) tautomerization.

[0216] The term "subject" (also referred to herein as "patient"), as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.

[0217] As used herein, the terms "treat," "treating," "treatment," and the like refer to relieving, alleviating, or ameliorating a disease or condition and / or its associated symptoms. Although not excluded, treating a disease or condition does not require complete elimination of the disease, condition, or its associated symptoms. As used herein, the terms "treat," "treating," "treatment," and the like can include "prophylactic treatment," which refers to reducing the likelihood of recurrence of a disease or condition, or the likelihood of a previously controlled disease or condition recurring, in a subject who does not have, but is at risk of, or susceptible to, recurrence of the disease or condition or recurrence of the disease or condition. The term "treat" and cognate terms contemplate administering a therapeutically effective amount of a compound described herein to a subject in need of such treatment.

[0218] As used herein, the singular forms "a," "an," and "the" include plural references unless expressly stated or clearly clear from the context that this is not intended.

[0219] The term "and / or" as used herein in phrases such as "A and / or B" is intended to include both A and B, A or B, A alone, and B alone. Similarly, the term "and / or" as used in phrases such as "A, B, and / or C" is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A alone; B alone; and C alone.

[0220] Headings and subheadings are used for convenience and / or formal compliance only, do not limit the subject technology, and should not be referenced in connection with interpreting the description of the subject technology. Features described under one heading or one subheading of this disclosure may be combined with features described under other headings or subheadings in various embodiments. Furthermore, not all features under a single heading or a single subheading may be used together in an embodiment. <Example>

[0221] The various starting materials, intermediates, and compounds of the preferred embodiments can be isolated and purified using conventional techniques, such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography, as appropriate. Characterization of these compounds can be performed using conventional methods, such as melting point, mass spectrometry, nuclear magnetic resonance, and various other spectroscopic analyses. Exemplary embodiments of steps for carrying out the synthesis of the products described herein are described in more detail below. The examples are for illustrative purposes only and are not intended to limit the claimed invention in any way. Additionally, in the structures shown in the Examples section herein, salt forms and / or counterions may be shown associated with the particular structure (stoichiometry may or may not be shown, and charge on the counterion may or may not be shown). However, it should be understood that the examples and / or intermediates herein are not limited to any of the specific salt forms and / or counterions shown; for example, the examples and / or intermediates herein may exist in the form of internal and / or external salts with pharmaceutically acceptable counterions.

[0222] Abbreviations used in the Examples section should be understood to have their ordinary meaning in the art unless otherwise specified or clearly contradicted by the context. Below is a list of some of the abbreviations used in the Examples section and their ordinary meaning in the art: AIBN Azobisisobutyronitrile ACN Acetonitrile Bn Benzyl DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCM dichloromethane DEAD Diethyl azodicarboxylate DHP 3,4-dihydropyran DIBAL-H Diisobutylaluminum hydride DMF Dimethylformamide DMP Dess-Martin Periodinane DMSO dimethyl sulfoxide DPPA Diphenylphosphoryl azide Dppf 1,1'-bis(diphenylphosphino)ferrocene EA or EtOAc Ethyl acetate EDCI N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide HMDS Hexamethyldisilazane IPA Isopropyl Alcohol LAH Lithium Aluminum Hydride LDA Lithium diisopropylamide MTBE Methyl tertiary-butyl ether NMP N-methylpyrrolidinone NBS N-Bromosuccinimide NIS N-iodosuccinimide O / N overnight PCC Pyridinium Chlorochromate PE Petroleum Ether PPTS Pyridinium p-toluenesulfonate Rt retention time (e.g., when describing an HPLC peak) RT Room temperature (describes the reaction state) TBAF Tetra-n-butylammonium fluoride TBS tert-butyldimethylsilyl (or TBDMS) TBDPS tert-butyldiphenylsilyl TEA Triethylamine TFA trifluoroacetic acid THF tetrahydrofuran THP tetrahydropyran TMS trimethylsilyl TPP Triphenylphosphine TLC thin layer chromatography TsOH p-toluenesulfonic acid (or PTSA) Z Benzyloxycarbonyl (benzyl chloroformate (Z-Cl)) JPEG2026504319000137.jpg138170

[0223] Step 1. To a solution of compound (1) 2-chloroisonicotinonitrile (10 g, 0.072 mol) in DMF (200 mL) was added NaH (4.32 g, 0.108 mol) at 0 °C, followed by a solution of (2) tert-butyl 4-(hydroxyethyl)piperidine-1-carboxylate (15.5 g, 0.072 mol) in DMF (100 mL). The mixture was stirred at 0 °C for 2 hours. The mixture was diluted with EA and water and extracted with EA. The organic layer was separated, washed with brine, dried over Na2SO4, and concentrated in vacuo to give a white powder. The powder was collected by filtration, washed with PE, and dried to give (3) tert-butyl 4-(((4-cyanopyridin-2-yl)oxy)methyl)piperidine-1-carboxylate, 1-1 (11 g, 48% yield) as a white powder. 1 H NMR(300 MHz, CDCl3): δ 8.28(d, J = 5.1 Hz, 1H), 7.06(d, J = 5.1 Hz, 1H), 6.98(s, 1H), 4.18-4.10 (m, 4H), 2.74(t, J = 12.1 Hz, 2H), 2.04-1.89(m, 1H), 1.79(d, J = 12.6 Hz, 2H), 1.46(s, 9H), 1.27-1.23(m, 2H).

[0224] Step 2. To a solution of 1-1 (16.7 g, 0.053 mol) in THF (100 mL) was added dropwise cyclopropylmagnesium bromide (1 M in THF, 100, 0.106 mol) at room temperature. The mixture was stirred at the same temperature for 2 h. The resulting mixture was slowly quenched with 1N aqueous HCl below 10 °C and extracted with EA at this temperature. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated in vacuo to give tert-butyl 4-(((4-(cyclopropanecarbonyl)pyridin-2-yl)oxy)methyl)piperidine-1-carboxylate, 1-2, (16.7 g, crude product) as a brown oil, which was used in the next reaction without further purification. MS (ESI) m / z 361.2 [M+]+.

[0225] Step 3. To a suspension of NaH (3.4 g, 0.087 mol) in THF (50 mL) was added ethyl 2-(diethoxyphosphoryl)acetate (20 g, 0.087 mol) at 0 °C and stirred for 30 min. To the mixture was added a solution of 1-2 (15.6 g, 0.043 mol) in THF (50 mL) and stirred at 80 °C for 3 h. The reaction mixture was poured into saturated aqueous NH4Cl (50 mL), and the mixture was extracted with EA. The organic layer was separated, washed with brine, dried over Na2SO4, and concentrated in vacuo to give tert-butyl (E / Z)-4-(((4-(1-cyclopropyl-3-ethoxy-3-oxoprop-1-en-1-yl)pyridin-2-yl)oxy)methyl)piperidine-1-carboxylate, 1-3 (17.5 g, crude product) as a brown oil, which was used in the next reaction without further purification. MS (ESI) m / z 431.3 [M+] + .

[0226] Step 4. Zinc powder (15.8 g, 0.24 mol) was added portionwise to a solution of 1-3 (17.5 g, 0.041 mol) in HOAc (80 mL) at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo. The residue was basified with NaHCO3 and extracted with EtOAc. The organic layer was separated, washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (PE / EA=5 / 1) to give tert-butyl 4-(((4-(1-cyclopropyl-3-ethoxy-3-oxopropyl)pyridin-2-yl)oxy)methyl)-piperidine-1-carboxylate, 1-4, (13.2 g, 75% yield) as a pale yellow oil. MS (ESI) m / z 433.3 [M+] + . 1H NMR (300 MHz, CDCl3): δ 8.08-8.07 (m, 1H), 6.80-6.78(m, 1H), 6.64 (s, 1H), 4.17-4.07 (m, 6H), 2.83-2.73 (m, 4H), 2.35-2.32 (m, 1H), 1.87-1.82 (m, 2H), 1.50 (s, 9H), 1.32-1.19(m, 5H), 1.03-1.00 (m, 1H), 0.65-0.62(m, 1H), 0.52-0.48 (m, 1H), 0.35-0.30 (m, 1H), 0.22-0.19 (m, 1H).

[0227] Step 5. To a mixture of 1-4 (13.2 g, 0.031 mol) in MeOH / HO (50 mL / 30 mL) was added NaOH (4.89 g, 0.122 mol) at room temperature. After stirring at ambient temperature for 2 h, the mixture was concentrated in vacuo to remove MeOH. The residue was diluted with HO and washed with EA. The aqueous phase was acidified with 1N HCl to a pH of 4-5. The solid was collected by filtration, washed with PE, and dried in vacuo to give 3-(2-((1-(tert-butoxycarbonyl)piperidin-4-yl)methoxy)pyridin-4-yl)-3-cyclopropylpropanoic acid, 1-5, (9.9 g, 79% yield) as a white powder. MS (ESI) m / z 405.3 [M+] + .

[0228] Step 6. To a solution of 1-5 (9.9 g, 0.025 mol) in EtOH (100 mL), (S)-1-(p-tolyl)ethanamine (3.375 g, 0.025 mol) in EA (30 mL) was added. After stirring at ambient temperature for 12 h, the mixture was filtered, and the filter cake was washed with EtOH / EA (v:v = 1 / 2, 30 mL x 3). The solid was dissolved in EtOH / hexane (v:v = 1 / 2, 350 mL) at 70 °C. After cooling to room temperature, the solid was collected by filtration. The solid was suspended in ethyl acetate (50 mL), and a solution of 1 N HCl (99 mL) was added dropwise at 0 °C and stirred for 30 min. The mixture was extracted with EA and EA / THF (v:v = 1 / 1). The combined organic phase was dried and concentrated in vacuo to give (S)-3-(2-((1-(tert-butoxycarbonyl)piperidin-4-yl)methoxy)pyridin-4-yl)-3-cyclopropylpropanoic acid, 1-6, (4 g, 40% yield) as a white solid. Chiral HPLC analysis: ee 96.5%. Method information: Column: Chiralpak IA, Mobile phase: Hex:IPA:TFA=90:10:0.2, Peak 1, Rt = 7.493; Peak 2, Rt = 9.199.

[0229] Step 7. To a mixture of 1-6 (11 g, 27.2 mmol) in DCM (100 mL) was added TFA (25 mL) dropwise at 0 °C. After the addition, the resulting mixture was stirred at room temperature for 1.5 h. The solvent was removed, and the residue was co-evaporated twice with toluene to give crude (S)-3-cyclopropyl-3-(2-(piperidin-4-ylmethoxy)pyridin-4-yl)propanoic acid, 1-7, (TFA salt, 20 g crude) as a pale yellow gum. MS (ESI) m / z = 305.2 [M+H]+.

[0230] Step 8. To a mixture of 1-7 (TFA salt, 20 g crude, 0.0272 mmol) and TEA (13.9 g, 0.136 mol) in THF (150 mL) was added CbzOSu (8.13 g, 0.0326 mol) portionwise at 0 °C. After the addition, the resulting suspension was stirred at room temperature for 12 h. The reaction mixture became clear. The solvent was removed, and the residue was diluted with water (100 mL), extracted with EA (60 mL x 3), dried, and concentrated. The residue was purified by flash chromatography (20%-35% in PE) to give (S)-3-(2-((1-((benzyloxy)carbonyl)piperidin-4-yl)methoxy)-pyridin-4-yl)-3-cyclopropylpropanoic acid, 1-8, (10.2 g, yield: 85%) as a colorless gum. MS (ESI) m / z = 439.2 [M+H]+. 1 H NMR (400 MHz, DMSO-d6) δ 12.01 (s, 1H), 8.02-8.01 (d, 1H), 7.39-7.29 (m, 5H), 6.91-6.89 (d, 1H), 6.69 (s, 1H), 5.07 (s, 2H), 4.09-4.00 (m, 2H), 2.90-2.76 (m, 2H), 2.68-2.65 (m, 2H), 2.25-2.21 (m, 1H), 1.98-1.92 (m, 1H), 1.78-1.72 (m, 2H), 1.24-1.12 (m, 2H), 1.04-0.94 (m, 1H), 0.54-0.47 (m, 1H), 0.35-0.23 (m, 2H), 0.18-0.13 (m, 1H).

[0231] Step 9. To a mixture of 1-8 (10.2 g, 0.0233 mol) in tBuOH (110 mL) was added BocO (10.1 g, 0.0466 mol) and DMAP (850 mg, 6.98 mmol). After the addition, the resulting mixture was stirred at 35 °C for 2 h. LCMS showed the reaction was complete. The solvent was removed, and the residue was purified by flash chromatography (10% EA in PE) to give (S)-benzyl 4-(((4-(3-(tert-butoxy)-1-cyclopropyl-3-oxopropyl)pyridin-2-yl)oxy)methyl)piperidine-1-carboxylate, 1-9, (7.5 g, yield: 65%) as a colorless gum. MS (ESI) m / z = 439.1 [M+H] + .

[0232] Step 10. A flask containing 1-9 (7.5 g, 15.15 mmol) and Pd / C (wet, ∼1.4 g) in isopropyl alcohol (120 mL) was evacuated and filled with hydrogen using a balloon. The resulting mixture was then hydrogenated at room temperature for 1.5 h. LCMS showed the reaction was complete. The mixture was filtered through Celite, and the filter cake was washed with EA / MeOH. The combined filtrate was concentrated to give tert-butyl (S)-3-cyclopropyl-3-(2-(piperidin-4-ylmethoxy)pyridin-4-yl)propanoate, Intermediate 1, (5.5 g, 100% yield) as a colorless gum. MS (ESI) m / z = 361.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.02-8.01 (d, 1H), 6.89-6.87 (dd, 1H), 6.67 (s, 1H), 4.06-4.04 (d, 2H), 2.95-2.92 (m, 2H), 2.69-2.62 (m, 2H), 2.45-2.41 (m, 2H), 2.25-2.15 (m, 1H), 1.83-1.77 (m, 1H), 1.66-1.63 (m, 2H), 1.26 (s, 9H), 1.17-1.07 (m, 2H), 1.02-0.96 (m, 1H), 0.54-0.48 (m, 1H), 0.37-0.22 (m, 2H), 0.17-0.13 (m, 1H). JPEG2026504319000138.jpg118170

[0233] Step 1. To a solution of icosane diacid (6.9 g, 20.2 mmol) in THF (300 mL) was added LiAlH (3.07 g, 80.8 mmol) in small portions at 0 °C. The mixture was stirred overnight at 80 °C under N. Water (3.1 mL) was added to the reaction at 0 °C, followed by NaOH (15% solution, 3.1 mL) and more water (9.3 mL). The resulting mixture was diluted with THF, dried over NaSO, and the filtrate was concentrated to give icosane-1,20-diol, 2-1, (10.2 g, 81% yield) as a white solid. H NMR (400 MHz, CDCl) δ 3.64 (t, 4H), 1.57 (br, 4H), 1.43-1.25 (m, 32H).

[0234] Step 2. To a solution of 2-1 (8.38 g, 26.7 mmol) in toluene (60 mL), HBr (9.01 g, 53.4 mmol) was added. The reaction mixture was stirred overnight at 110 °C under N2. The reaction mixture was concentrated under reduced pressure to remove excess reagents and solvent. The crude product was purified by column chromatography (PE / EA = 4 / 1) to give 20-bromoicosan-1-ol, 2-2, (4.4 g, 44% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 3.64 (t, 2H), 3.41 (t, 2H), 1.85 (m, 2H), 1.44-1.40 (m, 2H), 1.40-1.26 (m, 32H).

[0235] Step 3. To a solution of 2-2 (4.4 g, 11.75 mmol) in THF (20 mL) was added NaH (338.8 mg, 23.49 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h, followed by the dropwise addition of BnBr (4.01 g, 23.4 mmol). The reaction mixture was further stirred at room temperature overnight. The reaction mixture was quenched with saturated aqueous NH4Cl (1 mL) at 0 °C. The resulting solution was extracted with EA (20 mL × 3), dried over Na2SO4, and filtered. The filtrate was concentrated, and the crude product was purified on a silica gel column (PE / EA = 10 / 1) to give (((20-bromoicosyl)oxy)methyl)-benzene, 2-3 (3.6 g, 66% yield) as an orange-yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.35-7.26 (m, 4H), 7.30-7.25 (m, 1H), 4.50 (s, 2H), 3.46 (t, 2H), 3.41 (t, 2H), 1.85 (m, 2H), 1.61 (m, 2H), 1.41-1.26 (m, 32H).

[0236] Step 4. To a solution of ethyl isobutyrate (2.02 g, 17.47 mmol) in THF (50 mL) was added LDA (8.7 mL, 17.47 mmol) dropwise at −78° C. under N. The reaction mixture was stirred at −78° C. for 1 h. To the mixture was added 2-3 (3.6 g, 13.3 mmol) dropwise at −78° C. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was quenched with saturated aqueous NH4Cl (10 mL) at 0° C. The resulting solution was extracted with EA (50 mL × 3), dried over Na2SO4, and filtered. The filtrate was concentrated, and the crude product was chromatographed on silica gel (PE / EA = 10 / 1) to give ethyl 22-(benzyloxy)-2,2-dimethyldocosanoate, 2-4, (4.3 g, 97% yield) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.34-7.26 (m, 4H), 7.30-7.25 (m, 1H), 4.50 (s, 2H), 4.11 (q, 2H), 3.46 (t, 2H), 1.63-1.57 (m, 2H), 1.51-1.47 (m, 2H), 1.37-1.22 (m, 37H), 1.15 (s, 6H).

[0237] Step 5. To a solution of 2-4 (4.3 g, 7.56 mmol) in THF / MeOH / HO (20 mL / 20 mL / 10 mL) was added NaOH (7.84 g, 196 mmol). The reaction mixture was stirred at 60 °C overnight. The reaction mixture was concentrated under reduced pressure to remove MeOH and THF. The residue was diluted with solvent and poured into water. The aqueous phase was acidified with aqueous HCl and extracted with EA (50 mL × 4). The combined organic layers were dried over NaSO and concentrated. The crude product was chromatographed on silica gel (PE / EA = 1 / 1) to give 22-(benzyloxy)-2,2-dimethyldocosanoic acid, 2-5 (2.55 g, 71% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.34-7.29 (m, 4H), 7.30-7.25 (m, 1H), 4.50 (s, 2H), 3.46 (t, 2H), 1.61-1.49 (m, 4H), 1.31-1.25 (m, 34H), 1.19 (s, 6H).

[0238] Step 6. To a solution of 2-5 (2.55 g, 5.4 mmol) in dry DCM (15 mL) was added (COCl) (1.02 g, 8.1 mmol) and DMF (0.5 mL) under a N atmosphere at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to give 22-(benzyloxy)-2,2-dimethyldocosanoyl chloride, 2-6, as a yellow oil.

[0239] Step 7. To a solution of 6-methylpyridin-2-amine (2.5 g, 23.2 mmol) and TEA (3.55 g, 34.8 mmol) in THF (25 mL) was added dropwise a solution of 2-6 (5.72 g, 11.6 mmol) in THF (25 mL). The reaction mixture was stirred overnight at room temperature under N2. The reaction mixture was extracted with EA (50 mL × 4). The combined organic layers were dried over Na2SO4 and concentrated. The crude product was chromatographed on silica gel (PE / EA = 10 / 1) to give 22-(benzyloxy)-2,2-dimethyl-N-(6-methylpyridin-2-yl)docosanamide, 2-7, (6.3 g, 97% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 11.2 Hz, 1H), 7.90 (brs, 1H), 7.58 (t, J = 10.4 Hz, 1H), 7.35-7.26 (m, 5H), 6.88 (d, J = 10.0 Hz, 1H), 4.50 (s, 2H), 3.46 (t, J = 8.8 Hz, 2H), 2.45 (s, 3H), 1.63-1.57 (m, 6H), 1.28 (s, 6H), 1.28-1.24 (m, 32H).

[0240] Step 8. To a solution of 2-7 (1.23 mg, 2.2 mmol) in THF (10 mL) was added LiAlH (836 mg, 22 mmol) in small portions at room temperature. The mixture was stirred overnight at 60 °C under N. Completion of the reaction was detected by TLC. To the reaction mixture was added HO (0.8 mL) at 0 °C. Then, 15% aqueous NaOH (0.8 mL) and water (2.4 mL) were added. The resulting mixture was diluted with THF, dried over NaSO, filtered, and the filtrate was concentrated to give N-(22-(benzyloxy)-2,2-dimethyldocosyl)-6-methylpyridin-2-amine, 2-8 (1.2 g, crude product) as a pale green oil. 1 H NMR (400 MHz, CDCl3) δ 7.36-7.26 (m, 6H), 6.41 (d, J = 9.6 Hz, 1H), 6.21 (d, J = 11.2 Hz, 1H), 4.50 (s, 2H), 3.46 (t, J = 8.8 Hz, 2H), 2.98 (d, J = 8.0 Hz, 2H), 2.36 (s, 3H), 1.69-1.57 (m, 6H), 1.43-1.25 (m, 32H), 0.94 (s, 6H).

[0241] Step 9. To a solution of 2-8 (1.2 g, 2.1 mmol) and TEA (636.3 mg, 6.3 mmol) in THF (10 mL) was added a solution of 2-fluoro-4-methoxybenzoyl chloride in THF (10 mL). The reaction mixture was stirred at 40 °C for 4 h. The reaction mixture was quenched with HO (40 mL) and extracted with EA (50 mL × 2). The combined organic layers were dried over NaSO and concentrated. The crude product was chromatographed on silica gel (PE / EA = 10 / 1) to give N-(22-(benzyloxy)-2,2-dimethyldocosyl)-2-fluoro-4-methoxy-N-(6-methylpyridin-2-yl)benzamide, 2-9, (1.2 g, 70% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.35-7.31(m, 4H), 7.29-7.25 (m, 1H), 7.25-7.23(m, 1H), 7.11(t, 1H), 6.85-6.83 (d, 1H), 6.60-6.58 (d, 1H), 6.54-6.51(dd, 1H), 6.40-6.36 (dd, 1H), 4.50 (s, 2H), 4.13(s, 2H), 3.73 (s, 3H), 3.48-3.46 (t, 2H), 2.47(s, 3H), 1.62-1.57 (m, 2H), 1.41-0.97 (m, 36H), 0.83 (s, 6H).

[0242] Step 10. To a solution of 2-9 (1.2 g, 1.7 mmol) in MeOH (12 mL) was added Pd / C (120 mg) and Pd(OH) (120 mg). The reaction mixture was stirred under H at room temperature overnight. The mixture was filtered, and the filtrate was concentrated to give 2-fluoro-N-(22-hydroxy-2,2-dimethyldocosyl)-4-methoxy-N-(6-methylpyridin-2-yl)benzamide, 2-10, (930 mg, 89% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ: 7.46 (t, J = 7.6 Hz, 1H), 7.07 (t, J = 8.0 Hz, 1H), 6.97 (d, J = 7.2 Hz, 1H), 6.74 (d, J = 7.6 Hz, 1H), 6.67-6.62 (m, 2H), 4.30 (br, 1H), 3.98 (s, 2H), 3.70 (s, 3H), 3.36 (t, J = 6.4 Hz, 2H), 2.35 (s, 3H), 1.39 (t, J = 6.8 Hz, 2H), 1.29-0.87 (m, 36H), 0.77 (m, 6H). MS (ESI) m / z 613.5 [M+1] +.

[0243] Step 11. To a solution of 2-10 (930 mg, 1.51 mmol) in acetone (10 mL) was added Jones reagent (3.7 mL, 7.55 mmol) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 1 h. The mixture was quenched with HO (30 mL) and extracted with EA (50 mL × 3). The combined organic layers were dried and concentrated to give the crude product. The crude product was purified on a silica gel column (PE / EA = 3 / 1) to give 22-(2-fluoro-4-methoxy-N-(6-methylpyridin-2-yl)benzamido)-21,21-dimethyldocosanoic acid, 2-11, (750 mg, 78% yield) as a yellow oil. 1H NMR (300 MHz, DMSO-d6) δ:11.94 (s, 1H), 7.49 (t, J = 7.8 Hz, 1H), 7.10 (t, J = 8.1 Hz, 1H), 6.98-6.96 (d, J = 7.8 Hz, 1H), 6.74-6.72 (d, J = 7.8 Hz, 1H), 6.70-6.66 (m, 2H), 3.98 (s, 2H), 3.70 (s, 3H), 2.34 (s, 3H), 2.18 (t, J = 7.2 Hz, 1H), 1.50-1.45 (m, 2H), 1.26-0.99 (m, 34 H), 0.77 (m, 6H). MS (ESI) m / z 627.3 [M+1] +.

[0244] Step 12. To a solution of 2-11 (550 mg, 0.88 mmol) and intermediate 1 (622 mg, 1.75 mmol) in DMF (1 mL) was added Cs2CO3 (860 mg, 2.64 mmol) and TBA (65 mg, 0.076 mmol). The reaction mixture was stirred at 110 °C for 3 days. The reaction mixture was acidified to pH = 5 and extracted with EA (30 mL x 3). The combined organic layers were dried and concentrated to give the crude product. The crude product was purified on a silica gel column (PE / EA / HOAc=10 / 1 / 0.001) to give (S)-22-(2-(4-(((4-(3-(tert-butoxy)-1-cyclopropyl-3-oxopropyl)pyridin-2-yl)oxy)methyl)piperidin-1-yl)-4-methoxy-N-(6-methylpyridin-2-yl)benzamido)-21,21-dimethyldocosanoic acid, intermediate 2, (210 mg, 24% yield) as a yellow oil. 1H NMR (300 MHz, DMSO-d6): 8.05-8.03 (d, 1H), 7.28-7.24(t, 1H), 7.10-7.08 (d, 1H), 6.91-6.90 (d, 1H), 6.85-6.83 (m, 1H), 6.69 (s, 1H), 6.52-6.49 (dd, 1H), 6.43 (br, 1H), 6.22 (s, 1H), 4.20-4.10 (m, 2H), 4.10-3.98 (m, 2H), 3.68 (s, 3H), 2.65-2.61(m, 2H), 2.36 (s, 3H), 2.22-2.15 (m, 3H), 1.72 (br, 1H), 1.68-1.61 (m, 2H), 1.50-1.82 (m, 2H), 1.29-1.05 (m, 32H), 1.02-0.85 (m, 5H), 0.80-0.68 (m, 6H), 0.57-0.48 (m, 1H), 0.36-0.23 (m, 2H), 0.18-0.12 (m, 1H). MS (ESI) m / z 484.2 [M / 2+1] +.

[0245] The following intermediates were prepared in the same manner as intermediate 2: JPEG2026504319000139.jpg34170

[0246] MS (ESI) m / z 317.2 [M+] + . 1 H NMR (400 MHz, DMSO-d6): 8.04-8.03 (d, 1H), 7.27-7.25(t, 1H), 7.10-7.08 (d, 1H), 6.91-6.89 (d, 1H), 6.85-6.83 (m, 1H), 6.69 (s, 1H), 6.52-6.49 (dd, 1H), 6.42 (br, 1H), 6.22 (s, 1H), 4.17-4.12 (m, 2H), 4.05-3.96 (m, 2H), 3.68 (s, 3H), 2.65-2.61(m, 2H), 2.36 (s, 3H), 2.22-2.15 (m, 3H), 1.72 (br, 1H), 1.68-1.61 (m, 2H), 1.50-1.82 (m, 2H), 1.29-1.05 (m, 34H), 1.02-0.88 (m, 5H), 0.80-0.68 (m, 6H), 0.57-0.48 (m, 1H), 0.36-0.23 (m, 2H), 0.18-0.12 (m, 1H). JPEG2026504319000140.jpg37170

[0247] MS (ESI) m / z 317.2 [M+] + . 1H NMR (400 MHz, DMSO-d6): 8.05-8.03 (d, 1H), 7.26-7.23(t, 1H), 7.10-7.08 (d, 1H), 6.91-6.89 (d, 1H), 6.85-6.83 (m, 1H), 6.69 (s, 1H), 6.52-6.49 (dd, 1H), 6.42 (br, 1H), 6.22 (s, 1H), 4.17-4.12 (m, 2H), 4.05-3.96 (m, 2H), 3.68 (s, 3H), 2.65-2.61(m, 2H), 2.36 (s, 3H), 2.22-2.15 (m, 3H), 1.72 (br, 1H), 1.68-1.61 (m, 2H), 1.50-1.82 (m, 2H), 1.29-1.05 (m, 36H), 1.02-0.88 (m, 5H), 0.80-0.68 (m, 6H), 0.57-0.48 (m, 1H), 0.36-0.23 (m, 2H), 0.18-0.12 (m, 1H). JPEG2026504319000141.jpg36170

[0248] MS (ESI) m / z 317.2 [M+] + . 1H NMR (400 MHz, DMSO-d6): 8.05-8.03 (d, 1H), 7.28-7.25(t, 1H), 7.10-7.08 (d, 1H), 6.91-6.90 (d, 1H), 6.85-6.84 (m, 1H), 6.69 (s, 1H), 6.52-6.49 (dd, 1H), 6.42 (br, 1H), 6.22 (s, 1H), 4.17-4.12 (m, 2H), 4.05-3.96 (m, 2H), 3.68 (s, 3H), 2.65-2.61(m, 2H), 2.36 (s, 3H), 2.22-2.15 (m, 3H), 1.72 (br, 1H), 1.68-1.61 (m, 2H), 1.50-1.46 (m, 2H), 1.29-1.15 (m, 28H), 1.02-0.88 (m, 5H), 0.76-0.68 (m, 6H), 0.57-0.48 (m, 1H), 0.36-0.23 (m, 2H), 0.18-0.12 (m, 1H). JPEG2026504319000142.jpg66170

[0249] Step 1. To a mixture of tert-butyl (2-aminoethyl)carbamate (20 g, 0.125 mol) and TEA (18.95 g, 0.187 mol) in DCM (200 mL) was added 2-bromoacetyl bromide (30 g, 0.15 mol) in DCM (30 mL) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 12 h, followed by the addition of water (100 mL) and extraction with DCM. The combined organic phase was dried and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 5:1 → 2:1) to give tert-butyl (2-(2-bromoacetamido)-ethyl)carbamate, 6-1 (9.5 g, yield: 27%) as a pale yellow solid. MS (ESI) m / z 303.1 [M+Na]. 1 H NMR (400 MHz, DMSO-d6): 8.26 (s, 1H), 6.80 (s, 1H), 3.83 (s, 2H), 3.12-3.07 (m, 2H), 3.00-2.96 (m, 2H), 1.38 (s, 9H).

[0250] Step 2. A mixture of 6-1 (9.1 g, 32.5 mmol), benzyl (2-aminoethyl)carbamate (2.4 g, 12.3 mmol), and DIEA (6.68 g, 51.3 mmol) in MeCN (100 mL) was heated at 70 °C for 16 h. The product (11-(2-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-2-oxoethyl)-2,2-dimethyl-4,9-dioxo-3-oxa-5,8,11-triazatridecan-13-yl)benzyl carbamate, 6-2, was collected by filtration as a white solid (5.6 g, 76% yield). MS (ESI) m / z 595.4 [M+H]. 1 H NMR (400 MHz, DMSO-d6): 8.03 (s, 2H), 7.35-7.30 (m, 5H), 7.21 (s, 1H), 6.80 (s, 2H), 5.01 (s, 2H), 3.18 (s, 4H), 3.11-3.08 (m, 4H), 3.01-2.98 (m, 4H), 2.55-2.53 (m, 2H), 1.37 (s, 18H).

[0251] Step 3. A flask containing 6-2 (520 mg, 0.85 mmol) and Pd / C (wet, ∼100 mg) in isopropyl alcohol (25 mL) was evacuated and filled with hydrogen using a balloon. The resulting mixture was then hydrogenated at room temperature for 1.5 h. The mixture was filtered through Celite and washed with EA and IPA. The combined filtrate was concentrated to give crude di-tert-butyl (((2,2'-((2-aminoethyl)azanediyl)bis(acetyl))bis(azanediyl))bis(ethane-2,1-diyl))dicarbamate, Intermediate 6 (490 mg, crude) as a pale yellow gum, which was used directly in the next step. JPEG2026504319000143.jpg35170

[0252] Step 1. A pressure tube containing 6-2 (500 mg) and MeI (2 mL, 32 mmol) in ACN (7 mL) was sealed and heated at 60 °C for 20 h. The reaction mixture was concentrated, and the residue was purified by prep-HPLC to give, after lyophilization, N-(2-(((benzyloxy)carbonyl)amino)ethyl)-2-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-N-(2-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-2-oxoethyl)-N-methyl-2-oxoethan-1-aminium 2,2,2-trifluoroacetate, 7-1, (490 mg, 81%) as a white solid. MS (ESI) m / z 609.3 [M+]. 1 H NMR (400 MHz, DMSO-d6): 8.64 (t, 2H), 7.58 (s, tH), 7.39-7.32 (m, 5H), 6.84 (mt, 2H), 5.05 (s, 2H), 4.29 (s, 4H), 3.79-3.75 (m, 2H), 3.51-3.46 (m, 2H), 3.34 (s, 3H), 3.13-3.10 (m, 4H), 3.03-3.00 (m, 4H), 1.37(s, 18H).

[0253] Step 2. A flask containing 7-1 (520 mg, 0.85 mmol) and Pd / C (wet, ∼100 mg) in isopropyl alcohol (25 mL) was degassed and filled with hydrogen using a balloon. The resulting mixture was then hydrogenated at room temperature for 1.5 h. The mixture was filtered through Celite and washed with EA and IPA. The combined filtrate was concentrated to give crude N-(2-aminoethyl)-2-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-N-(2-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-2-oxoethyl)-N-methyl-2-oxoethan-1-aminium 2,2,2-trifluoroacetate, Intermediate 7, (490 mg, crude) as a pale yellow gum, which was used directly in the next step. Note: TFA (200 mg, 1.75 mmol) was added to stabilize the product before hydrogenation. JPEG2026504319000144.jpg52170

[0254] Step 1. To a mixture of (2-amino-ethyl)-carbamic acid tert-butyl ester (8 g, 0.005 mol) and TEA (15.3 g, 0.15 mol) in DCM (120 mL) at 0 °C, acryloyl chloride (6.787 g, 0.075 mol, CAUTION!) was added dropwise over 5 min. After the addition, the resulting mixture was stirred for 16 h, and the temperature was gradually raised to room temperature. The reaction mixture was quenched with aqueous NaHCO3, separated, and extracted with DCM (50 mL x 2). The combined organic phases were dried and concentrated. The residue was purified by flash chromatography (60% EA in PE) to give (2-acryloylamino-ethyl)-carbamic acid tert-butyl ester, 8-1 (5.5 g, yield: 51%) as a pale yellow solid. 1 H NMR (400 MHz, CDCl3): δ = 6.46 (br, 1H), 6.28-6.24 (d, J = 16.8 Hz, 1H), 6.13-6.07 (dd, J = 16.8 Hz, 10.4 Hz, 1H), 5.65-5.62 (d, J = 10.4 Hz, 1H), 4.98 (br,1H), 3.46-3.42 (m, 2H), 3.33-3.29 (m, 2H), 1.43 (s, 9H).

[0255] Step 2. A pressure tube containing (2-amino-ethyl)-carbamic acid benzyl ester (500 mg, 2.577 mmol) and 8-1 (2.76 g, 12.886 mmol) in saturated aqueous HBO3 (5 mL) was sealed and heated at 100 °C for 2 days. The reaction mixture was diluted with water (10 mL), extracted with DCM (30 mL x 4), and concentrated. The residue was purified by flash chromatography (10% MeOH in DCM at 214 nm) to give (2-{bis-[2-(2-tert-butoxycarbonylamino-ethylcarbamoyl)-ethyl]-amino}-ethyl)-carbamic acid benzyl ester, 8-2 (550 mg, 35% yield) as a white solid. MS (ESI) m / z 623.1 [M+H]+ .

[0256] Step 3. A flask containing 8-2 (550 mg, 0.884 mmol) and Pd / C (~270 mg, 50 wt%) in MeOH (50 mL) was evacuated and filled with hydrogen using a balloon. The resulting mixture was then hydrogenated at 25 °C for 16 h. The reaction was filtered through Celite and concentrated. The residue was purified by flash chromatography (28% MeOH, 0.5% NH3.HO in DCM) to give [2-(3-{(2-amino-ethyl)-[2-(2-tert-butoxycarbonylamino-ethylcarbamoyl)-ethyl]-amino}-propionylamino)-ethyl]-carbamic acid tert-butyl ester, intermediate 88 (330 mg, yield: 76%) as a pale yellow solid. MS (ESI) m / z 489.5 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ = 7.99 (br, NH, 2H), 6.86 (br, NH, 2H), 3.11-3.07 (m, 4H), 3.03-2.99 (m, 4H), 2.66-2.62 (m, 6H), 2.45-2.40 (m, 2H), 2.24-2.20 (m, 4H), 1.42 (s, 18H). JPEG2026504319000145.jpg37170

[0257] Step 1. A pressure tube containing a suspension of benzyl (12-(3-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-3-oxopropyl)-2,2-dimethyl-4,9-dioxo-3-oxa-5,8,12-triazatetradecan-14-yl)carbamate, 8-2, (500 mg, 0.80 mmol) and MeI (2 mL, 32 mmol) in ACN (5 mL) was sealed and heated at 60° C. for 20 h. The reaction mixture was concentrated and the residue was purified by prep-HPLC to give N-(2-(((benzyloxy)carbonyl)amino)ethyl)-3-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-N-(3-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-3-oxopropyl)-N-methyl-3-oxopropan-1-aminium 2,2,2-trifluoroacetate, 9-1, (450 mg, 97% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6): 8.15 (t, 1H), 7.60-7.55(t, 1H), 7.39-7.31(m, 5H), 6.83-6.80 (t, 2H), 5.06 (s, 2H), 3.58-3.54 (m, 4H), MS (ESI) m / z 637.4 [M+].

[0258] Step 2. A flask containing 9-1 (450 mg, 0.71 mmol) and Pd / C (wet, ∼100 mg) in MeOH (25 mL) was evacuated and filled with hydrogen using a balloon. The resulting mixture was hydrogenated at room temperature for 2 h. The mixture was filtered through Celite and washed with EA and MeOH. The combined filtrate was concentrated to give the crude product of N-(2-aminoethyl)-3-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-N-(3-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-3-oxopropyl)-N-methyl-3-oxopropan-1-aminium 2,2,2-trifluoroacetate, intermediate 9, (300 mg, 84% yield) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6): 8.18 (t, 2H), 6.82 (t, 2H), 3.58-3.54 (m, 4H), 3.36-3.30 (m, 2H), 3.16-3.10 (m, 2H), 3.09-3.06 (m, 4H), 3.03 (s, 3H), 3.01-2.97 (m, 4H), 2.64-2.61 (m, 4H), 1.37 (m, 18H). MS (ESI) m / z 503.4 [M+]. JPEG2026504319000146.jpg61170

[0259] Step 1. A mixture of (2-amino-ethyl)-carbamic acid benzyl ester (10 g, 0.043 mol), 4-bromo-butyric acid ethyl ester (42 g, 0.217 mmol), and DIEA (33 g, 0.258 mol) in MeCN (150 mL) was heated at 70 °C for 16 h. The solvent was removed, and the residue was purified by silica gel column chromatography (PE / EA = 2:1) to give 4-[(2-benzyloxycarbonylamino-ethyl)-(3-ethoxycarbonyl-propyl)-amino]-butyric acid ethyl ester, 10-1, (14.5 g, yield: 79%) as a yellow oil. MS (ESI) m / z 423.2 [M+H] + .

[0260] Step 2. To a mixture of 10-1 (14.5 g, 0.034 mol) in MeOH (50 mL) and HO (10 mL) was added NaOH (6.9 g, 0.171 mol). The resulting mixture was stirred at room temperature for 24 h. The mixture was diluted with HCl (1 M) until the pH reached 2-3 and concentrated. The residue was treated with MeOH (40 mL) and filtered. The filtrate was concentrated in vacuo to give a residue, which was purified by chromatography to give 4-[(2-benzyloxycarbonylamino-ethyl)-(3-carboxy-propyl)-amino]-butyric acid, 10-2, (9 g, yield: 72%) as a white solid. MS (ESI) m / z 367.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): 7.38-7.29 (m, 5H), 7.14 (t, J = 5.6 Hz, 1H), 5.00 (s, 2H), 3.06-3.01 (m, 2H), 2.45-2.37 (m, 6H), 2.16 (t, J = 7.2 Hz, 4H), 1,61-1.54 (m, 4H).

[0261] Step 3. To a suspension of 10-2 (1 g, 2.729 mmol) in DCM (10 mL) was added (COCl) (0.9 mL, 10.917 mmol) and DMF (2 drops) at 0 °C. After the addition, the resulting mixture was stirred at room temperature for 16 h. The solvent was removed to give the crude product {2-[bis-(3-chlorocarbonyl-propyl)-amino]-ethyl}-carbamic acid benzyl ester, 10-3, (1.2 g, crude) as a yellow oil.

[0262] Step 4. To a mixture of (2-amino-ethyl)-carbamic acid tert-butyl ester (1.1 g, 2.727 mmol) and TEA (1.1 g, 10.91 mmol) in DCM was added 10-3 (1.2 g, crude product, 10.91 mmol) at 0 °C. After the addition, the resulting mixture was stirred at room temperature for 12 h. The solvent was removed, and the residue was purified by silica gel column chromatography (DCM / MeOH = 15:1) and slurred with MeCN to give (2-{bis-[3-(2-tert-butoxycarbonylamino-ethylcarbamoyl)-propyl]-amino}-ethyl)-carbamic acid benzyl ester, 10-4, (500 mg, yield: 28%) as a white solid. MS (ESI) m / z 651.5 [M+H] + . 1 H NMR (400 MHz, CDCl3): 7.36-7.26 (m, 5H), 6.71 (br s, 2H), 5.53 (br s, 1H), 5.24 (br s, 2H), 5.10 (s, 2H), 3.32-3.30 (m, 4H), 3.22-3.20 (m, 6H), 2.49-2.46 (m, 2H), 2.37 (t, J = 6.4 Hz, 4H), 2.18 (t, J = 7.2 Hz, 4H), 1.74-1.67 (m, 4H), 1.42 (s, 18H).

[0263] Step 5. A flask containing 10-4 (200 mg, 0.31 mmol) and Pd / C (wet, ∼50 mg) in isopropyl alcohol (10 mL) was evacuated and filled with hydrogen using a balloon. The resulting mixture was then hydrogenated at 30 °C for 2 h. The mixture was filtered through Celite and washed with EA and IPA. The combined filtrate was concentrated to give the crude product of [2-(4-{(2-amino-ethyl)-[3-(2-tert-butoxycarbonylamino-ethylcarbamoyl)-propyl]-amino}-butyrylamino)-ethyl]-carbamic acid tert-butyl ester, Intermediate 10 (150 mg, 94% yield) as a white gum. MS (ESI) m / z 517.3 [M+H] + . JPEG2026504319000147.jpg33170

[0264] Step 1. A pressure tube containing compound 10-4 (200 mg, 0.31 mmol) and MeI (1 mL, 16 mmol) in ACN (3 mL) was sealed and heated to 70 °C for 20 h. The reaction mixture was concentrated, and the residue was purified by prep-HPLC to give N-(2-(((benzyloxy)carbonyl)amino)ethyl)-4-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-N-(4-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-4-oxobutyl)-N-methyl-4-oxobutan-1-aminium, 11-1 (140 mg, yield: 68%) as a white gum after lyophilization. MS (ESI) m / z 665.4 [M+] + . 1 H NMR (400 MHz, DMSO-d6): 7.96 (t, J = 5.6 Hz, 2H), 7.56 (s, 1H), 7.39-7.30 (m, 5H), 6.80 (t, J = 5.2 Hz, 2H), 5.05 (s, 2H), 3.45-3.42 (m, 2H), 3.32 (br, 2H), 3.28-3.24 (m, 4H), 3.08-3.04 (m, 4H), 3.20 (s, 3H), 3.00-2.96 (m, 4H), 2.14 (t, J = 6.4 Hz, 4H), 1.90-1.86 (m, 4H), 1.37 (s, 18H).

[0265] Step 2. A flask containing 11-1 (140 mg, 0.21 mmol) and Pd / C (wet, ∼30 mg) in isopropyl alcohol (10 mL) was evacuated and filled with hydrogen using a balloon. The mixture was then hydrogenated at 30 °C for 2 h. The mixture was filtered through Celite and washed with EA and IPA. The combined filtrate was concentrated to give the crude product of N-(2-aminoethyl)-4-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-N-(4-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-4-oxobutyl)-N-methyl-4-oxobutan-1-aminium, intermediate 11 (90 mg, 81% yield) as a white gum. MS (ESI) m / z 531.3 [M+] + . JPEG2026504319000148.jpg56170

[0266] Step 1. To a mixture of tert-butyl (2-aminoethyl)carbamate (20 g, 0.125 mol) and TEA (18.95 g, 0.187 mol) in DCM (200 mL) was added 2-bromoacetyl bromide (30 g, 0.15 mol) in DCM (30 mL) dropwise at 0 °C. The mixture was stirred at room temperature for 12 h, quenched with water (100 mL), and extracted with DCM. The combined organic phase was dried and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 5:1 → 2:1) to give tert-butyl (2-(2-bromoacetamido)ethyl)carbamate, 12-1 (9.5 g, yield: 27%) as a pale yellow solid. MS (ESI) m / z 181.1 [M+H-100] + . 1 H NMR (400 MHz, DMSO-d6): 8.26 (s, 1H), 6.80 (s, 1H), 3.83 (s, 2H), 3.12-3.07 (m, 2H), 3.00-2.96 (m, 2H), 1.37 (s, 9H).

[0267] Step 2. A mixture of 12-1 (5 g, 17.79 mmol), (3-amino-propyl)-carbamic acid benzyl ester (1.5 g, 6.15 mmol), and DIEA (4.0 g, 30.7 mmol) in MeCN (100 mL) was heated at 70 °C for 16 h. The reaction was cooled to room temperature. The product (3-{bis-[(2-tert-butoxycarbonylamino-ethylcarbamoyl)-methyl]-amino}-propyl)-carbamic acid benzyl ester, 12-2, was collected by filtration as a pale yellow solid (2.3 g, yield: 61%). MS (ESI) m / z 609.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): 8.06 (t, J = 5.6 Hz, 2H), 7.37-7.28 (m, 5H), 7.23-7.20 (m, 1H), 6.79 (t, J = 5.2 Hz, 2H), 4.99 (s, 2H), 3.12-3.09 (m, 4H), 3.03-2.98 (m, 10H), 2.49-2.43 (m, 2H), 1.55-1.51 (m, 2H), 1.36 (s, 18H).

[0268] Step 3. A flask containing 12-2 (500 mg, 0.821 mmol) and Pd / C (wet, ∼100 mg) in isopropyl alcohol (30 mL) was evacuated and filled with hydrogen using a balloon. The mixture was then hydrogenated at 25 °C for 2 h. The mixture was filtered through Celite and washed with EA and IPA. The combined filtrate was concentrated to give the crude product of [2-(4-{(2-amino-ethyl)-[3-(2-tert-butoxycarbonylamino-ethylcarbamoyl)-propyl]-amino}-butyrylamino)-ethyl]-carbamic acid tert-butyl ester, intermediate 12 (390 mg, ∼100% yield) as a white gum. MS (ESI) m / z 475.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6): 8.13 (t, NH, 2H), 6.84 (t, NH, 2H), 3.17-3.10 (m, 4H), 3.03 (s, 4H), 3.00-2.97 (m, 4H), 2.58-2.55 (m, 2H), 2.50-2.45 (m, 2H), 1.49-1.45 (m, 2H), 1.30 (s, 18H). JPEG2026504319000149.jpg35170

[0269] Step 1. A pressure tube containing 12-2 (600 mg, 0.985 mmol) and MeI (2 mL, 32 mmol) in ACN (7 mL) was sealed and heated at 60 °C for 20 h. The reaction mixture was concentrated, and the residue was purified by prep-HPLC to give 3-(((benzyloxy)carbonyl)amino)-N,N-bis(2-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-2-oxoethyl)-N-methylpropan-1-aminium, 13-1 (450 mg, 73% yield) as a white gum after lyophilization. MS (ESI) m / z 623.3 [M+] + . 1 H NMR (400 MHz, DMSO-d6): 8.65 (t, J = 5.6 Hz, 2H), 7.41-7.31 (m, 5H), 6.84 (t, J = 5.6 Hz, 2H), 5.02 (s, 2H), 4.23 (s, 4H), 3.68-3.63 (m, 2H), 3.29 (s, 3H), 3.13-2.91 (m, 10H), 1.89-1.85 (m, 2H), 1.37 (s, 18H).

[0270] Step 2. A flask containing 13-1 (250 mg, 0.21 mmol) and Pd / C (wet, ∼50 mg) in isopropyl alcohol (20 mL) was evacuated and filled with hydrogen using a balloon. The mixture was then hydrogenated at 30 °C for 2 h. The mixture was filtered through Celite and washed with EA and IPA. The combined filtrate was concentrated to give crude 3-amino-N,N-bis(2-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-2-oxoethyl)-N-methylpropan-1-aminium, Intermediate 13 (190 mg, 97% yield) as a white gum. MS (ESI) m / z 489.3 [M+] + . 1 H NMR (400 MHz, DMSO-d6): 8.76 (t, J = 5.6 Hz, 2H), 8.00 (brs, 2H), 6.87-6.82 (m, 2H), 4.30-4.22 (m, 4H), 3.77-3.73 (m, 2H), 3.31 (s, 3H), 3.15-3.12 (m, 4H), 3.05-3.00 (m, 4H), 2.90-2.86 (m, 2H), 2.07-1.99 (m, 2H), 1.37 (s, 18H). JPEG2026504319000150.jpg37170

[0271] Step 1. To a mixture of (3-amino-propyl)-carbamic acid benzyl ester (HCl salt, 500 mg, 2.409 mmol) and DIEA (1.05 g, 8 mmol) in MeCN (40 mL) was added bromo-acetic acid tert-butyl ester (1.0 g, 5.12 mmol) dropwise at room temperature. After the addition, the resulting mixture was heated at 75 °C for 16 h. The solvent was removed, and the residue was diluted with EA (20 mL), washed with water and brine, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 8:1 → 4:1) to give [(3-benzyloxycarbonylamino-propyl)-tert-butoxycarbonylmethyl-amino]-acetic acid tert-butyl ester, 14-1 (700 mg, yield: 78.4%) as a brown gum. MS (ESI) m / z 437.2 [M+H]+ . 1 H NMR (400 MHz, DMSO-d6) 7.35-7.29 (m, 5H), 7.17 (t, J = 5.6 Hz, 1H), 4.99 (s, 2H), 3.33 (s, 4H), 3.05-3.01 (m, 2H), 2.59 (t, J = 7.2 Hz, 2H), 1.53-1.49 (m, 2H), 1.39 (s, 18H).

[0272] Step 2. A flask containing 14-1 (790 mg, 0.821 mmol) and Pd / C (wet, ∼200 mg) in isopropyl alcohol (50 mL) was evacuated and filled with hydrogen using a balloon. The mixture was then hydrogenated at 25 °C for 2 h. The mixture was filtered through Celite and washed with EA and IPA. The combined filtrate was concentrated to give the crude product of [(3-amino-propyl)-tert-butoxycarbonylmethyl-amino]-acetic acid tert-butyl ester, intermediate 14 (540 mg, yield: 98%) as a pale yellow gum. MS (ESI) m / z 303.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) 3.33 (s, 4H), 2.61 (t, J = 6.8 Hz, 2H), 2.54-2.50 (m, 2H), 1.46-1.42 (m, 2H), 1.40 (s, 18H). JPEG2026504319000151.jpg38170

[0273] Step 1. A pressure tube containing 14-1 (260 mg, 0.595 mmol) and MeI (1 mL, 16 mmol) in ACN (2 mL) was sealed and heated at 60 °C for 20 h. The reaction mixture was concentrated, and the residue was purified by prep-HPLC to give 3-(((benzyloxy)carbonyl)amino)-N,N-bis(2-(tert-butoxy)-2-oxoethyl)-N-methylpropan-1-aminium, 15-1 (130 mg, 48% yield) as a yellow gum after lyophilization. MS (ESI) m / z 451.3 [M+] + .1 H NMR (400 MHz, DMSO-d6): 7.41-7.31 (m, 6H), 5.01 (s, 2H), 4.46 (s, 4H), 3.62-3.58 (m, 2H), 3.29 (s, 3H), 3.09-3.05 (m, 2H), 1.87-1.83 (m, 2H), 1.46 (s, 18H).

[0274] Step 2. A flask containing 15-1 (180 mg, 0.399 mmol) and Pd / C (wet, ∼50 mg) in isopropyl alcohol (20 mL) was evacuated and filled with hydrogen using a balloon. The resulting mixture was then hydrogenated at 30 °C for 2 h. LCMS showed the reaction was complete. The mixture was filtered through Celite and washed with EA and IPA. The combined filtrate was concentrated to give the crude product of 3-amino-N,N-bis(2-(tert-butoxy)-2-oxoethyl)-N-methylpropan-1-aminium, Intermediate 15 (120 mg, 95% yield) as a white gum. MS (ESI) m / z 317.2 [M+] + . 1 H NMR (400 MHz, DMSO-d6): 7.82 (br, 2H), 4.50 (s, 4H), 3.69-3.64 (m, 2H), 3.29 (s, 3H), 2.85 (t, J = 6.8 Hz, 2H), 2.01-1.97 (m, 2H), 1.47 (s, 18H). JPEG2026504319000152.jpg47170

[0275] Step 1. To a mixture of (3-aminopropyl)benzylcarbamate (hydrogen chloride, 1,2.77 g, 11.3 mmol, 2.0 eq) in 20 mL ACN was added DIEA (2.93 g, 22.64 mmol, 4.0 eq) and tert-butyl (2-(2-bromoacetamido)ethyl)carbamate (1.59 g, 5.66 mmol, 1.0 eq) at room temperature. The reaction mixture was stirred at 40 °C for 15 h. The reaction mixture was concentrated, and the residue was diluted with water and extracted with EA. The combined organic layers were dried and concentrated. The residue was purified by silica column chromatography (DCM / MeOH=20 / 1) to give benzyl (2,2-dimethyl-4,9-dioxo-3-oxa-5,8,11-triazatetradecan-14-yl)carbamate, 16-1 (3,1.28 g, yield=38.3%) as a yellow solid. MS (ESI) m / z 409.3 [M+1] + . 1 H NMR (400 MHz, DMSO-d6): δ = 7.80 (t, J = 5.6 Hz, 1H), 7.38-7.29 (m, 5H), 7.22 (t, J = 5.6 Hz, 1H), 6.81 (t, J = 4.8 Hz, 1H), 5.00 (s, 2H), 3.14-3.10 (m, 2H), 3.07-3.02 (m, 4H), 3.00-2.96 (m, 2H), 2.45 (t, J = 6.8 Hz, 2H), 1.57-1.50 (m, 2H), 1.37 (s, 9H).

[0276] Step 2. To a solution of 16-1 (3, 1.28 g, 3.13 mmol, 1.0 eq) was added 1.2 g of HOAc and HCHO (40% aq, 0.188 g, 6.27 mmol, 2.0 eq). The reaction mixture was stirred at room temperature for 30 min. NaBHCN (0.394 g, 6.27 mmol, 2.0 eq) was added to the mixture in batches. The reaction mixture was stirred at room temperature overnight. The reaction was quenched with aqueous NaHCO and extracted with DCM. The combined organic layers were dried and concentrated. The residue was purified by silica column chromatography (DCM / MeOH = 20 / 1) to give benzyl (2,2,11-trimethyl-4,9-dioxo-3-oxa-5,8,11-triazatetradecan-14-yl)carbamate, 16-2 (4,348 mg, yield = 26.3%) as a white solid. MS (ESI) m / z 423.3[M+1] + . 1 H NMR (400 MHz, DMSO-d6): δ = 7.71 (t, J = 4.4 Hz, 1H), 7.36-7.30 (m, 5H), 7.23 (t, J = 5.2 Hz, 1H), 6.80 (t, J = 4.4 Hz, 1H), 5.01 (s, 2H), 3.14-3.10 (m, 2H), 3.06-2.97 (m, 2H), 2.85 (s, 2H), 2.34 (t, J = 7.2 Hz, 2H), 2.14 (s, 3H), 1.57-1.52 (m, 2H), 1.36 (s, 9H).

[0277] Step 3. To a mixture of 16-2 (4,112 mg, 0.265 mmol, 1.0 eq) in IPA (2 mL) was added Pd / C (wet, ∼30 mg). The reaction mixture was degassed and charged with hydrogen using a balloon. The resulting mixture was then hydrogenated at room temperature for 2 h. The mixture was filtered through Celite, and the filtrate was concentrated to give tert-butyl (2-(2-((3-aminopropyl)(methyl)amino)acetamido)ethyl)carbamate, intermediate 16 (5, Tail 32, 50 mg, yield: 65.7%) as a colorless oil. MS (ESI) m / z 282.3 [M+1] + . 1H NMR (400 MHz, DMSO-d6): δ = 7.85 (m, 1H), 6.83 (t, 1H), 3.15-3.10 (m, 2H), 3.02-2.97 (m, 2H), 2.86 (s, 2H), 2.56 (t, J = 6.8 Hz, 2H), 2.36 (t, J = 7.2 Hz, 2H), 2.16 (s, 3H), 1.52-1.45 (m, 2H), 1.37 (s, 9H). JPEG2026504319000153.jpg24170

[0278] Step 1. A pressure tube containing 16-2 (236 mg, 0.559 mmol, 1.0 eq) and MeI (1.5 mL) in ACN (5 mL) was sealed. The reaction mixture was then heated at 50 °C for 18 h. The reaction was monitored by LCMS. The solvent was removed, and the residue was purified by prep-HPLC (5% to 95% TFA, C8) to give 3-(((benzyloxy)carbonyl)amino)-N-(2-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-2-oxoethyl)-N,N-dimethylpropan-1-aminium, 17-1 (TFA salt, 327 mg, crude) as a colorless oil. MS (ESI) m / z 437.3 [M + ]. 1 H NMR (400 MHz, DMSO-d6): δ = 8.59 (t, J = 4.8 Hz, 1H), 7.40-7.32 (m, 5H), 6.86 (s, 1H), 5.02 (s, 2H), 5.02 (brs, 1H), 3.98 (s, 2H), 3.48-3.44 (m, 2H), 3.16 (s, 6H), 3.16-3.14 (m, 2H), 3.08-3.02 (m, 4H), 1.87-1.83 (m, 2H), 1.38 (s, 9H).

[0279] Step 2. To a mixture of 17-1 (327 mg, 0.559 mmol, 1.0 eq) in IPA (5 mL) was added Pd / C (50 mg). The reaction mixture was degassed and filled with hydrogen using a balloon. The resulting mixture was then hydrogenated at room temperature for 3 h. LCMS showed the reaction was complete. The mixture was filtered through Celite and concentrated to give 3-amino-N-(2-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-2-oxoethyl)-N,N-dimethylpropan-1-aminium, intermediate 17 (Tail 33, TFA salt, 180 mg, yield: 77% for 2 steps) as a colorless oil. MS (ESI) m / z 303.2 [M + ]. 1 H NMR (400 MHz, DMSO-d6): δ = 8.67 (t, NH, 1H), 7.48 (brs, 3H), 6.88 (t, NH, 1H), 4.34-4.33 (d, 1H), 4.01 (s, 2H), 3.56-3.51 (m, 2H), 3.18 (s, 6H), 3.18-3.13 (m, 2H), 3.06-3.01 (m, 2H), 2.86-2.82 (t, 2H), 1.98-1.94 (m, 2H), 1.38 (s, 9H). JPEG2026504319000154.jpg43170

[0280] Step 1. To a solution of benzyl (3-hydroxypropyl)carbamate (10 g, 48 mmol) in DCM (120 mL) was added CBr (31.8 g, 96 mmol) and triphenylphosphine (25.2 g, 96 mmol) under a N atmosphere. The resulting mixture was stirred at room temperature for 2 h. The solvent was removed, and the residue was purified by column chromatography (PE or PE:EA = 10:1) to give benzyl (3-bromopropyl)carbamate, 18-1 (12.2 g, yield: 93.7%) as a yellow oil. 1H NMR (400 MHz, DMSO-d6): 7.38-7.28 (m, 5H), 5.01 (s, 2H), 3.51 (t, J = 6.8 Hz, 2H), 3.14-3.09 (m, 2H), 1.98-1.91 (m, 2H).

[0281] Step 2. A mixture of compound 18-1 (0.7 g, 2.6 mmol) and 1,4-diazabicyclo[2.2.2]octane (0.58 g, 5.2 mmol) in ACN (20 mL) was stirred at room temperature for 2 h. The solvent was removed to give a thick residue, which was washed with EA (5 mL x 5) to give 1-(3-(((benzyloxy)carbonyl)amino)propyl)-1,4-diazabicyclo[2.2.2]octan-1-ium bromide, 18-2 (1.1 g, mixed with DABCO, yield: 110%) as a yellow gum. MS (ESI) m / z 304.2 [M] +. 1 H NMR (400 MHz, DMSO-d6): 7.37-7.32 (m, 5H), 5.03 (s, 2H), 3.28-3.18 (m, 8H), 3.09-3.06 (m, 2H), 3.03-2.99 (m, 6H), 1.85-1.81 (m, 2H).

[0282] Step 3. A flask containing 18-2 and Pd / C (wet, ca. 50 mg) in IPA (10 mL) was evacuated and filled with hydrogen using a balloon. The resulting mixture was then hydrogenated at room temperature for 40 h. LC-MS showed the reaction was complete. The reaction mixture was then filtered through Celite and concentrated to give the crude product of 1-(3-aminopropyl)-1,4-diazabicyclo[2.2.2]octan-1-ium bromide, intermediate 18 (contaminated with some DABCO, yield: 80.4%) as a yellow gum. MS (ESI) m / z 170.2 [M] +. 1 H NMR (400 MHz, DMSO-d6): 3.28-3.22 (m, 10H), 3.04-3.00 (m, 6H), 1.77-1.70 (m, 2H). JPEG2026504319000155.jpg53170

[0283] Step 1. To a mixture of 1,3-dibromopropane (2.73 g, 13.5 mmol) in DMF (10 mL) was added potassium 1,3-dioxoisoindolin-2-ide (0.5 g, 2.7 mmol). The resulting mixture was then stirred at room temperature for 16 h. DMF was removed in vacuo, and the residue was purified by column chromatography (PE to PE:EA = 10:1) to give crude 2-(3-bromopropyl)isoindoline-1,3-dione 2, 19-1 (610 mg, impure, mixed with dimer, yield: 85%) as a white gum. MS (ESI) m / z 268.0 [M+H] +

[0284] Step 2. A mixture of crude product 19-1 (610 mg, 2.2 mmol) and 1,4-diazabicyclo[2.2.2]octane (0.5 g, 4.4 mmol) in ACN (20 mL) was stirred at room temperature for 3 h. The solvent was removed, and the residue was triturated and washed three times with EA (10 mL) to give 1-(3-(((benzyloxy)carbonyl)amino)propyl)-1,4-diazabicyclo[2.2.2]octan-1-ium bromide, 19-2 (510 mg, 60% yield over two steps) as a white solid. MS (ESI) m / z 300.2 [M+] +. 1H NMR (400 MHz, DMSO-d6): 7.92-7.83 (m, 4H), 3.67 (t, J = 6.0 Hz, 2H), 3.31-3.22 (m, 8H), 3.01-2.97 (m, 6H), 2.08-1.99 (m, 2H).

[0285] Step 3. A pressure tube containing 19-2 (100 mg, 0.3 mmol) and MeI (0.1 mL, excess) in ACN (0.8 mL) / HO (0.2 mL) was sealed and heated at 60 °C for 20 h. The solvent was removed and the residue was treated twice with MeCN to give 1-(3-(1,3-dioxoisoindolin-2-yl)propyl)-4-methyl-1,414-diazabicyclo[2.2.2]octan-1-ium salt, 19-3 (70 mg, yield: 44.8%) as a brown solid. MS (ESI) m / z 314.2 [M-] +. 1H NMR (400 MHz, DMSO-d6): 7.92-7.86 (m, 4H), 3.83-3.78 (m, 12H), 3.69 (t, J = 6.4 Hz, 2H), 3.59-3.55 (m, 2H), 3.25 (s, 3H), 2.09-2.06 (m, 2H).

[0286] Step 4. A mixture of 19-3 (1.0 g, 1.92 mmol) and hydrazinium hydroxide (85%, 500 mg, 7.66 mmol) in EtOH (6 mL) and water (1 mL) was heated to reflux (85 °C) for 20 h. The mixture was cooled and filtered. The filtrate was concentrated, and the residue was dissolved in water (4 mL) and washed three times with EA. The aqueous phase was lyophilized to give 1-(3-aminopropyl)-4-methyl-1,4-diazabicyclo[2.2.2]octane-1,4-diium salt, intermediate 19 (crude product, 600 mg, mixed with hydrazine hydrate and a small amount of phthalhydrazide) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6): 3.99-3.89 (br, 12H), 3.62-3.58 (m, 2H), 3.31 (s, 3H), 2.65 (t, J = 6.4 Hz, 2H), 1.83-1.75 (m, 2H). JPEG2026504319000156.jpg90170

[0287] Step 1. A mixture of 5-bromo-2-(trifluoromethoxy)benzaldehyde (3.0 g, 11.15 mmol), ethane-1,2-diol (1.3 g, 20.96 mmol), and PTSA.HO (420 mg, 2.19 mmol) in toluene (80 mL) was heated at 100 °C for 10 h under a N atmosphere. The solvent was removed, and the residue was purified by flash chromatography (PE to 5% EA in PE) to give 2-(5-bromo-2-(trifluoromethoxy)phenyl)-1,3-dioxolane, 20-1 (3.1 g, 88.7% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 2.4 Hz, 1H), 7.52-7.49 (m, 1H), 7.15-7.13 (m, 1H), 6.03 (s, 1H), 4.16-4.13 (m, 2H), 4.07-4.03 (m, 2H).

[0288] Step 2. A flask containing Pd(PPh3)2Cl2 (219 mg, 0.312 mmol) and CuI (59 mg, 0.312 mmol) was degassed and backfilled with N2. Next, a solution of 20-1 (1.0 g, 3.12 mmol) and methyl icos-19-ynoate (1.77 g, 5.75 mmol) in TEA (5 mL) and THF (50 mL) was added via syringe. After the addition, the resulting mixture was heated at 60 °C for 6 h. The brown reaction mixture was then concentrated. The residue was purified by flash chromatography (PE to 6% EA in PE) to give methyl 20-(3-(1,3-dioxolan-2-yl)-4-(trifluoromethoxy)phenyl)icos-19-ynoate, 20-2 (1.2 g, mixed with 3, purity ∼20%, yield: 13.9%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.44-7.42 (m, 2H), 7.15-7.16 (m, 1H), 6.04 (s, 1H), 4.16-4.14 (m, 2H), 4.06-4.03 (m, 2H), 3.66 (s, 3H), 2.60 (t, J = 7.6 Hz, 2H), 2.30 (t, J = 7.6 Hz, 2H), 1.65-1.56 (m, 4H), 1.30-1.25 (m, 26H).

[0289] Step 3. A flask containing 20-2 (1.2 g, purity ∼20%, 0.433 mmol) and Pd / C (wet, ∼300 mg) in EA (10 mL) and MeOH (10 mL) was evacuated and filled with hydrogen using a balloon. The resulting mixture was then hydrogenated at 40 °C for 14 h. It was filtered through Celite and concentrated. The residue was purified by flash chromatography (PE:EA = 40:1 to 5:1) to give methyl 20-(3-(hydroxymethyl)-4-(trifluoromethoxy)phenyl)icosanoate, 20-3 (160 mg, yield: 71.7%) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 7.33 (s, 1H), 7.12-7.11 (m, 2H), 4.75 (s, 2H), 3.66 (s, 3H), 2.60 (t, J = 7.6 Hz, 2H), 2.29 (t, J = 7.6 Hz, 2H), 1.61-1.56 (m, 4H), 1.30-1.25 (m, 30H).

[0290] Step 4. To a mixture of methyl 20-3 (160 mg, 0.31 mmol) in DCM (10 mL) was added Dess-Martin periodinane (263 mg, 0.62 mmol) portionwise at room temperature. The resulting mixture was stirred at room temperature for 10 hours. The reaction mixture was filtered and washed with DCM (5 mL x 5), and the organic phases were combined and concentrated. The residue was purified by prep-TLC (PE:EA = 10:1) to give methyl 20-(3-formyl-4-(trifluoromethoxy)phenyl)icosanoate, 20-4 (130 mg, yield: 81.7%) as a pale yellow solid.1 H NMR (400 MHz, CDCl3) δ 10.35 (s, 1H), 7.75 (d, J = 2.0 Hz, 1H), 7.46-7.43 (m, 1H), 7.26-7.24 (m, 1H), 3.66 (s, 3H), 2.65 (t, J = 7.6 Hz, 2H), 2.29 (t, J = 7.6 Hz, 2H), 1.63-1.59 (m, 4H), 1.33-1.24 (m, 30H).

[0291] Step 5. A mixture of 20-4 (130 mg, 0.253 mmol) and LiOH.HO (32 mg, 0.758 mmol) in THF (5 mL), MeOH (1 mL), and water (1 mL) was heated at 40 °C for 12 h. The mixture was acidified with 1 M HCl until the pH reached 3 and concentrated. The residue was purified by prep-TLC (DCM) to give 20-(3-formyl-4-(trifluoromethoxy)phenyl)icosanoic acid, 20-5 (80 mg, yield: 63.5%) as a white solid. MS (ESI) m / z 501.3 [M+H] + .

[0292] Step 6. To a mixture of 20-5 (70 mg, 0.14 mmol) and (2S,3R)-3-cyclopropyl-2-methyl-3-((R)-2-(piperidin-4-yl)chroman-7-yl)propanoate (20-6, see Intermediate 1 in WO2023134712) (40 mg, 0.12 mmol) in MeOH (3 mL) and DCM (3 mL) was added ZnCl (38 mg, 0.28 mmol) and NaBHCN (26 mg, 0.42 mmol). The resulting mixture was heated at 40 °C for 20 h. The solvent was removed and the residue was purified by prep-TLC (DCM:MeOH=10:1) to give 20-(3-((4-((R)-7-((1R,2S)-1-cyclopropyl-3-methoxy-2-methyl-3-oxopropyl)chroman-2-yl)piperidin-1-yl)methyl)-4-(trifluoromethoxy)phenyl)icosanoic acid, intermediate 20 (25 mg, yield: 26.9%) as a yellow gum. MS (ESI) m / z 422.0 [M / 2+H]+ . JPEG2026504319000157.jpg73170

[0293] Step 1. Intermediate 21-1 was prepared in a similar manner to Intermediate 2-10 (500 mg, 0.78 mmol). (S)-ethyl 3-cyclopropyl-3-(2-(piperidin-4-ylmethoxy)pyridin-4-yl)propanoate (390 mg, 1.17 mmol), CsCO (635 mg, 1.95 mmol), and TBAI (29 mg, 0.078 mmol) in DMF (1.2 mL) were sealed and heated at 110 °C under N for 48 h. The mixture was cooled, diluted with water (15 mL), acidified with 1 M HCl to pH 3, and extracted with EA (20 mL x 3). The combined organic phase was dried and concentrated. The residue was purified by pre-TLC (DCM / MeOH=10:1) to give (S)-3-cyclopropyl-3-(2-((1-(2-((24-hydroxy-2,2-dimethyltetracosyl)(6-methylpyridin-2-yl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)pyridin-4-yl)propanoic acid, 21-2, as a brown gum. MS (ESI) m / z 463.5 [M / 2+H] + . 1 H NMR (400 MHz, DMSO-d6): 11.95 (br, 1H), 8.04-8.02 (m, 1H), 7.28-7.24(m, 1H), 6.91-6.82 (m, 2H), 6.70 (s, 1H), 6.51-6.49 (m, 1H), 6.33 (br, 1H), 6.23 (s, 1H), 4.21-3.95 (m, 4H), 3.69 (s, 3H), 3.38-3.34 (m, 2H), 2.74-2.32 (m, 7H), 2.36 (s, 3H), 2.27-2.19 (m, 1H), 1.80-1.35 (m, 5H), 1.29-0.85 (m, 42H), 0.80-0.68 (m, 6H), 0.53-0.48 (m, 1H), 0.37-0.24 (m, 2H), 0.18-0.14 (m, 1H).

[0294] Step 2. To a mixture of 21-2 (3,140 mg, 0.151 mmol) in MeOH (2 mL) / DCM (8 mL) at 0 °C, TMSCHN (2.0 M in hexanes, 0.22 mL) was added dropwise. After the addition, the resulting mixture was stirred at room temperature for 2 h. The solvent was removed to give the crude product of (S)-3-cyclopropyl-3-(2-((1-(2-((24-hydroxy-2,2-dimethyltetracosyl)(6-methylpyridin-2-yl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)pyridin-4-yl)methyl propanoate, 21-3, as a yellow solid. MS (ESI) m / z 470.5 [M / 2+H] + .

[0295] Step 3. To a solution of 21-3 (150 mg, 0.16 mmol) in DCM (3 mL) was added 4-methylbenzenesulfonyl chloride (46 mg, 0.23 mmol), TEA (49 mg, 0.48 mmol), and DMAP (1.9 mg, 0.016 mmol). The reaction mixture was then stirred at 30 °C for 14 h. The reaction mixture was quenched with water and extracted with DCM (5 mL x 3). The combined organic layer was washed with water (5 mL x 2) and brine (5 mL) and dried over Na2SO4. The organic layer was concentrated to give the crude product. The crude product was purified by prep-TLC (DCM / MeOH=20 / 1) to give methyl (S)-3-cyclopropyl-3-(2-((1-(2-((2,2-dimethyl-24-(tosyloxy)tetracosyl)(6-methylpyridin-2-yl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)pyridin-4-yl)propanoate, intermediate 21, as a yellow gum. MS (ESI) m / z 547.5 [M / 2+H]+. JPEG2026504319000158.jpg37170

[0296] Intermediate 22 was prepared in a similar manner to intermediate 21. MS (ESI) m / z 526.4 [(M+2H] / 2]. JPEG2026504319000159.jpg73170JPEG2026504319000160.jpg48170

[0297] Step 1. To a solution of hex-5-enoic acid (2.03 g, 17.8 mmol) in DMF (30 mL) was added K2CO3 (7.37 g, 53.4 mmol) and BnBr (3.66 g, 21.4 mmol) at 0 °C. The reaction mixture was stirred overnight at 40 °C under N2. The reaction mixture was quenched with water and extracted with EA (20 mL × 4). The combined organic layers were dried over Na2SO4 and concentrated. The crude product was chromatographed on silica gel (petroleum ether / EtOAc 1:0 → 20:1 → 10:1) to give benzyl hex-5-enoate, 23-1, as a colorless liquid. MS (ESI) m / z 205.2 [M+H]+. 1 H NMR (300 MHz, CDCl3) δ 7.40-7.26 (m, 5H), 5.84-5.70 (m, 1H), 5.12 (s, 2H), 5.04-4.96 (m, 2H), 2.37 (t, J = 7.5 Hz, 2H), 2.13-2.05 (m, 2H), 1.75 (qt, J = 7.4 Hz, 2H).

[0298] Step 2. To a solution of 23-1 (3.0 g, 14.7 mmol) and TMSCl (2.39 g, 22.1 mmol) in THF (30 mL) was added LDA (2 M, 8.8 mL, 17.6 mmol) dropwise at −78 °C under a N atmosphere. The reaction mixture was stirred at −78 °C for 4 h. Then, NBS (3.13 g, 17.6 mmol) in THF (40 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was quenched at 0 °C by the addition of saturated aqueous NaHCO solution. The resulting solution was extracted with EA (20 mL × 3), dried over NaSO, and filtered. The filtrate was concentrated and the crude product was chromatographed on silica gel (petroleum ether / EtOAc 20:1→10:1→4:1) to give benzyl 2-bromohex-5-enoate, 23-2, as an orange liquid. 1H NMR (300 MHz, CDCl3) δ 7.37-7.26 (m, 5H), 5.78-5.66 (m, 1H), 5.20 (s, 2H), 5.12-5.00 (m, 2H), 4.27 (t, J = 6.6 Hz, 1H), 2.24-2.08 (m, 4H).

[0299] Step 3. To a solution of 23-2 (4.06 g, 14.3 mmol) in DCM (40 mL) was added propane-1,3-diamine (3.17 g, 42.9 mmol) at room temperature. The reaction mixture was stirred overnight at 30 °C under N2. The reaction mixture was diluted with solvent and extracted with DCM (20 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated. The crude product was chromatographed on silica gel (petroleum ether / EtOAc 10:1 → MeOH / DCM 10:1 → 4:1) to give benzyl 2-((3-aminopropyl)amino)hex-5-enoate, 23-3, as an orange liquid. MS (ESI) m / z 277.2 [M+H]+. 1 H NMR (300 MHz, CDCl3) δ 7.40-7.26 (m, 5H), 5.82-5.68 (m, 1H), 5.17 (d, J = 3.9 Hz, 2H), 5.02-4.95 (m, 2H), 3.29 (t, J = 6.8 Hz, 1H), 2.86 (t, J = 6.2 Hz, 2H), 2.71-2.63 (m, 1H), 2.61-2.55 (m, 1H), 2.09 (q, J = 7.3 Hz, 2H), 1.82-1.64 (m, 4H).

[0300] Step 4. To a solution of 23-3 (2.42 g, 8.8 mmol) and TEA (2.67 g, 26.4 mmol) in DCM (20 mL) was added (Boc)O (11.51 g, 52.8 mmol) at 0 °C. The reaction mixture was stirred overnight at 30 °C under N. The reaction mixture was concentrated under reduced pressure to remove DCM and TEA. The crude product was chromatographed on silica gel (petroleum ether / EtOAc 0 → 5 → 10 → 30%) to give benzyl 2-((tert-butoxycarbonyl)(3-((tert-butoxycarbonyl)amino)propyl)amino)hex-5-enoate, 23-4, as an orange liquid. MS (ESI) m / z 499.3 [M+Na]+. 1 H NMR (300 MHz, CDCl3) δ 7.34-7.26 (m, 5H), 5.82-5.71 (m, 1H), 5.29-5.09 (m, 2H), 5.06-5.00 (m, 2H), 3.87-3.10 (m, 2H), 3.10-2.96 (m, 3H), 2.13-2.07 (m, 3H), 1.67-1.61 (m, 3H), 1.43 (s, 18H).

[0301] Step 5. To a mixture of 23-4 (1.15 g, 2.6 mmol) in THF (15 mL) cooled to 0 °C, BH3 (2.0 M in THF, 5.3 mL, 10.6 mmol) was added dropwise under N2. The reaction mixture was stirred at 30 °C for 6 h. To the reaction mixture, NaOAc (3.3 mL) and H2O2 (3.3 mL) were added at 0 °C. The reaction mixture was stirred at 30 °C overnight under N2. The reaction mixture was diluted with EA (30 mL) and washed with Na2S2O3 (15 mL × 2) and brine (15 mL × 2). The combined organic layers were dried over Na2SO4 and concentrated. The crude product was chromatographed on silica gel (petroleum ether / EtOAc 10→20→100%) to give benzyl 2-((tert-butoxycarbonyl)(3-((tert-butoxycarbonyl)amino)propyl)amino)-6-hydroxyhexanoate, 23-5, as a colorless gum. MS (ESI) m / z 495.3 [M+H]+.

[0302] Step 6. To a mixture of 23-5 (292 mg, 0.6 mmol) in dry DCM (10 mL) was added DMP (382 mg, 0.9 mmol). The reaction mixture was stirred overnight at 30 °C under N. The reaction mixture was washed with NaHCO (10 mL x 2), NaSO (10 mL x 2), and brine (10 mL x 2). The combined organic layers were dried over NaSO and concentrated. The crude product was chromatographed on silica gel (petroleum ether / EtOAc 10 → 20 → 50 → 100) to give benzyl 2-((tert-butoxycarbonyl)(3-((tert-butoxycarbonyl)amino)propyl)amino)-6-oxohexanoate, 23-6, as a pale yellow gum. MS (ESI) m / z 515.3 [M+Na]. 1 H NMR (400 MHz, CDCl3) δ 9.76 (s, 1H), 7.33-7.26 (m, 5H), 5.15-5.09 (m, 2H), 4.11-4.09 (m, 1H), 2.63-2.47 (m, 8H), 2.29-2.20 (m, 4H), 1.43 (s, 18H).

[0303] Step 7. To a solution of 23-6 (443 mg, 0.9 mmol), di-tert-butyl (azanediylbis(propane-3,1-diyl)dicarbamate (398 mg, 1.2 mmol) in MeOH (10 mL) was added NaBHCN (76 mg, 1.2 mmol) and AcOH (1 drop). The reaction mixture was stirred under N at 30 °C for 12 h. The reaction mixture was concentrated under reduced pressure to remove MeOH. The crude product was chromatographed on silica gel (petroleum ether / EtOAc 10 → 20 → 100%) to give benzyl N-(tert-butoxycarbonyl)-N,N,N-tris(3-((tert-butoxycarbonyl)amino)propyl)lysinate, 23-7, as a pale yellow solid. MS (ESI) m / z 808.6 [M+H]. 1H NMR (300 MHz, CDCl3) δ 7.34-7.26 (m, 5H), 5.30 (s, 2H), 4.11-4.09 (m, 1H), 3.80-4.72 (m, 4H), 3.20-2.98 (m, 10H), 1.80-1.32 (m, 12H), 1.43 (s, 36H).

[0304] Step 8. To a solution of 23-7 (471 mg, 0.6 mmol) in MeOH (5 mL), THF (5 mL), and HO (5 mL) was added NaOH (72 mg, 1.8 mmol) at room temperature. The reaction mixture was stirred at room temperature for 10 hours. The reaction mixture was concentrated under reduced pressure to remove MeOH and THF. The residue was acidified with 1 M HCl until the pH reached 3–4. The mixture was then extracted with DCM (15 mL × 4). The combined organic layers were dried over NaSO and concentrated. The residue (in MeOH) was purified by preparative HPLC to give N-(tert-butoxycarbonyl)-N,N,N-tris(3-((tert-butoxycarbonyl)amino)propyl)lysine, 23-8, as a pale yellow gum. MS (ESI) m / z 716.5 [M−H].

[0305] Step 9. To a solution of 23-8 (227 mg, 0.316 mmol), DIEA (194 mg, 1.48 mmol), and HATU (148 mg, 0.39 mmol) in DMF (7.5 mL) was added benzyl (2-aminoethyl)carbamate (126 mg, 0.65 mmol) at room temperature. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL × 4). The combined organic layer was dried over Na2SO4 and concentrated. The residue (in MeOH) was purified by preparative HPLC to give tert-butyl (3-((tert-butoxycarbonyl)amino)propyl)(14-(3-((tert-butoxycarbonyl)amino)propyl)-21,21-dimethyl-3,8,19-trioxo-1-phenyl-2,20-dioxa-4,7,14,18-tetraazadocosan-9-yl)carbamate, 23-9, as a pale yellow gum. MS (ESI) m / z 894.6 [M+H]+.

[0306] Step 10. A mixture of 23-9 (70 mg, 0.08 mmol) and Pd / C (wet, ∼500 mg) in MeOH (10 mL) was hydrogenated using a balloon at 30 °C for 14 h. The mixture was filtered through a pad of Celite and concentrated to give crude tert-butyl (18-amino-9-(3-((tert-butoxycarbonyl)amino)propyl)-2,2-dimethyl-4,15-dioxo-3-oxa-5,9,16-triazaoctadecan-14-yl)(3-((tert-butoxycarbonyl)amino)propyl)carbamate, 23-10, as a pale yellow gum. MS (ESI) m / z 760.6 [M+H]+.

[0307] Step 11. A mixture of crude product 23-10 (65 mg, 0.1 mmol), TEA (15 mg, 0.15 mmol), and 2,5-dioxopyrrolidin-1-yl icos-19-ynoate (45 mg, 0.11 mmol) in THF (5 mL) was heated at 40° C. for 16 hours. The solvent was removed, and the residue (in MeOH) was purified by preparative HPLC to give tert-butyl (3-((tert-butoxycarbonyl)amino)propyl)(9-(3-((tert-butoxycarbonyl)amino)propyl)-2,2-dimethyl-4,15,20-trioxo-3-oxa-5,9,16,19-tetraazanonatriacont-38-yn-14-yl)carbamate, intermediate 23, as a yellow gum. MS (ESI) m / z 1051.9 [M+H]+. 1 H NMR (400 MHz, d6-DMSO): δ = 7.55 (br, 2H), 6.73 (s, 2H), 3.43-3.02 (m, 12H), 2.92-2.86 (m, 6H), 2.71 (s, 1H), 2.37-2.31 (m, 5H), 2.14-2.12 (m, 2H), 2.02 (t, J = 7.0 Hz, 2H), 1.61-1.41 (m, 12H), 1.36 (s, 36H), 1.25-1.08 (m, 24H). JPEG2026504319000161.jpg57170

[0308] Step 1. To a mixture of CBr4 (6 g, 18 mmol) and triphenylphosphine (4.72 g, 18 mmol) in 30 mL of THF was added (4-hydroxybutyl)benzyl carbamate (2 g, 9.0 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. The solvent was concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH 20 / 1 to 10 / 1) to give (4-bromobutyl)benzyl carbamate, 24-1, as a yellow oil. 1 H-NMR (400 MHz, DMSO-d6): 7.38-7.28 (m, 6H), 5.05-5.03 (m, 2H), 3.53 (t, J = 7.6, 2H), 3.02 (q, J = 6.4, 2H), 1.83-1.75 (m, 2H), 1.55-1.48 (m, 2H).

[0309] Step 2. To a stirred solution of 24-1 (400 mg, 1.4 mmol) in ACN (8 mL) at room temperature, 1,4-diazabicyclo[2.2.2]octane (172.5 mg, 1.54 mmol) was added. The mixture was stirred at room temperature for 16 h. The solvent was concentrated, and the residue was washed with EA (10 mL). EA was decanted, and the insoluble gum was dried under vacuum to give crude 1-(4-(((benzyloxy)carbonyl)amino)butan-1-ylium-1-yl)-1,4-diazabicyclo[2.2.2]octan-1-ium bromide, 24-2, as a yellow gum. MS (ESI) m / z 318.2 [M+]+.

[0310] Step 3. A flask containing 24-2 (620 mg, crude, 1.4 mmol) and Pd / C (wet, approximately 300 mg) in IPA (10 mL) was evacuated and filled with hydrogen using a balloon. The resulting mixture was then hydrogenated at room temperature for 40 h. The reaction mixture was then filtered through Celite and concentrated to give crude 1-(4-aminobutan-1-ylium-1-yl)-1,4-diazabicyclo[2.2.2]octan-1-ium bromide, intermediate 24, as a yellow gum. MS (ESI) m / z 185.2 [M+H] +. JPEG2026504319000162.jpg29170

[0311] Step 1. A pressure tube containing a mixture of benzyl (4-bromobutyl)carbamate, 24-1 (400 mg, 1.398 mmol) and trimethylamine (2.0 M in EtOH, 10 mL, 20 mmol) was sealed and heated at 80 °C for 16 h. The mixture was cooled to room temperature and concentrated. The residue was triturated with EA (8 mL x 3). The insoluble sticky material was collected and dried in vacuo to give crude 4-(((benzyloxy)carbonyl)amino)-N,N,N-trimethylbutan-1-aminium bromide, 25-1, as a yellow gum. MS (ESI) m / z 265.2 [M+].

[0312] Step 2. A flask containing 25-1 (490 mg, 1.398 mmol) and Pd / C (wet, ∼200 mg) in isopropyl alcohol (30 mL) was evacuated and filled with hydrogen using a balloon. The resulting mixture was then hydrogenated at 30 °C for 16 h. The mixture was filtered through Celite and washed with EA and IPA. The combined filtrate was concentrated to give crude 4-amino-N,N,N-trimethylbutan-1-aminium bromide, Intermediate 25, as a pale yellow oil. MS (ESI) m / z 131.2 [M+]+.

[0313] JPEG2026504319000163.jpg30170

[0314] Intermediate 26 was prepared in a similar manner to intermediate 25. MS: m / z 173.2 [M+].

[0315] The syntheses of the following examples were all carried out by coupling the corresponding acid and amine intermediates with HATU in a manner similar to that described in Example 11 unless otherwise specified. JPEG2026504319000164.jpg34170

[0316] MS (ESI) m / z 1183.0[M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 8.36 (t, NH, 2H), 8.12 (t, NH, 1H), 8.04-8.03 (d, 1H), 7.81 (br, NH3, 6H), 7.29-7.26 (m, 1H), 7.11-7.08 (d, 1H), 6.92-6.91 (d, 1H), 6.86-6.84 (d, 1H), 6.71 (s, 1H), 6.52-6.50 (d, 1H), 6.44 (br, 1H), 6.28 (br, 1H), 4.12 (m, 4H), 3.69 (s, 3H), 3.41-3.37 (m, 6H), 3.33-3.28 (m, 4H), 3.20-3.16 (m, 2H), 2.89-2.85 (m, 4H), 2.62-2.60 (d, 2H), 2.59-2.56 (m, 4H), 2.36 (s, 3H), 2.27-2.21 (m, 1H), 2.10-2.06 (t, 2H), 1.75 (br, 1H), 1.68-1.66 (m, 2H), 1.49-1.46 (m, 4H), 1.30-1.12 (m, 30H), 1.02-1.97 (m, 5H), 0.75 (s, 6H), 0.54-0.49 (m, 1H), 0.35-0.25 (m, 2H), 0.18-0.15 (m, 1H). JPEG2026504319000165.jpg33170

[0317] MS (ESI) m / z 1155.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 8.39 (t, NH, 2H), 8.04-8.03 (d, 1H), 7.93 (br, NH, 1H), 7.82 (br, NH3, 6H), 7.26-7.24 (br, 1H), 7.10-7.08 (d, 1H), 6.92-6.91 (d, 1H), 6.86-6.84 (d, 1H), 6.70 (s, 1H), 6.52-6.50 (d, 1H), 6.44-6.43 (br, 1H), 6.22 (s, 1H), 4.13-4.11 (m, 4H), 3.68 (s, 3H), 3.53-3.50 (s, 4H), 3.36-3.31 (m, 6H), 3.26-3.20 (m, 2H), 2.90-2.88 (m, 4H), 2.69-2.67 (d, 2H), 2.36 (s, 3H), 2.26-2.22 (m, 1H), 2.08-2.04 (t, 2H), 1.76-1.74 (m, 1H), 1.68-1.65 (m, 2H), 1.46-1.40 (m, 4H), 1.30-1.12 (m, 30H), 1.02-0.97 (m, 5H), 0.75 (s, 6H), 0.52-0.49 (m, 1H), 0.35-0.25 (m, 2H), 0.18-0.15 (m, 1H). JPEG2026504319000166.jpg34170

[0318] MS (ESI) m / z 1198.1 [M]+. 1H NMR (400 MHz, DMSO-d6): δ 8.38 (t, NH, 2H), 8.15 (t, NH, 1H), 8.04-8.03 (d, 1H), 7.89 (br, NH3, 6H), 7.27 (br, 1H), 7.10-7.08 (d, 1H), 6.92-6.91 (d, 1H), 6.86-6.84 (d, 1H), 6.71 (s, 1H), 6.52-6.51 (d, 1H), 6.50 (br, 1H), 6.22 (s, 1H), 4.14-4.12 (m, 4H), 3.68 (s, 3H), 3.59-3.56 (m, 4H), 3.46-3.44 (m, 2H), 3.33-3.24 (m, 6H), 3.03 (s, 3H), 2.90-2.85 (m, 4H), 2.69-2.67 (m, 6H), 2.36 (s, 3H), 2.27-2.20 (m, 1H), 2.10-2.06 (t, 2H), 1.75 (br, 1H), 1.68-1.65 (m, 2H), 1.49-1.46 (m, 4H), 1.35-1.14 (m, 30H), 1.02-0.97(m, 5H), 0.75 (s, 6H), 0.53-0.49 (m, 1H), 0.35-0.25 (m, 2H), 0.18-0.15 (m, 1H). JPEG2026504319000167.jpg34170

[0319] MS (ESI) m / z 1026.8 [(M+H) / 2]+. 1H NMR (400 MHz, DMSO-d6): δ 8.92 (t, NH, 2H), 8.21 (t, NH, 1H), 8.04-8.03 (d, 1H), 7.93 (br, NH3, 6H), 7.28-7.25 (br, 1H), 7.11-7.08 (d, 1H), 6.92-6.91 (d, 1H), 6.86-6.84 (d, 1H), 6.71 (s, 1H), 6.52-6.50 (d, 1H), 6.44-6.43 (br, 1H), 6.23 (s, 1H), 4.36 (s, 4H), 4.14-4.05 (m, 4H), 3.75-3.70 (m, 2H), 3.69 (s, 3H), 3.53-3.50 (m, 2H), 3.38 (s, 3H), 3.38-3.35 (m, 4H), 2.94-2.89 (m, 4H), 2.71-2.67 (m, 2H), 2.36 (s, 3H), 2.27-2.21 (m, 1H), 2.10-2.06 (t, 2H), 1.75 (br, 1H), 1.68-1.65 (m, 2H), 1.49-1.46 (m, 4H), 1.35-1.14 (m, 30H), 1.02-0.97(m, 5H), 0.75 (s, 6H), 0.53-0.49 (m, 1H), 0.35-0.25 (m, 2H), 0.18-0.15 (m, 1H). JPEG2026504319000168.jpg33170

[0320] MS (ESI) m / z 1167.5 [M+H] + . 1H NMR (400 MHz, DMSO-d6): δ 8.82 (t, NH, 2H), 8.05-8.03 (d, 1H), 7.87 (br, NH3, 6H), 7.29-7.24 (br, 1H), 7.11-7.08 (d, 1H), 6.92-6.91 (d, 1H), 6.86-6.84 (d, 1H), 6.71 (s, 1H), 6.52-6.50 (d, 1H), 6.43 (br, 1H), 6.23 (s, 1H), 4.14-4.12 (d, 2H), 4.12 (br, 2H), 3.81 (br, 4H), 3.69 (s, 3H), 3.38-3.34 (m, 4H), 3.06-2.98 (m, 4H), 2.92-2.88 (m, 4H), 2.69-2.67 (d, 2H), 2.36 (s, 3H), 2.27-2.23 (m, 1H), 2.07-1,97 (m, 2H), 1.77-1.66 (m, 5H), 1.46-1.34 (m, 4H), 1.25-1.12 (m, 30H), 1.04-0.96 (m, 5H), 0.75 (s, 6H), 0.53-0.49 (m, 1H), 0.32-0.25 (m, 2H), 0.23-0.18 (m, 1H). JPEG2026504319000169.jpg33170

[0321] MS (ESI) m / z 1181.6 [M] + . 1H NMR (400 MHz, DMSO-d6): δ 8.85 (t, NH, 2H), 7.95 (t, NJ, 1H), 8.05-8.03 (d, 1H), 7.86 (br, NH3, 6H), 7.27-7.23 (br, 1H), 7.10-7.08 (d, 1H), 6.92-6.91 (d, 1H), 6.86-6.84 (d, 1H), 6.71 (s, 1H), 6.52-6.50 (d, 1H), 6.43 (br, 1H), 6.23 (s, 1H), 4.32-4.26 (m, 4H), 4.16-4.12 (m, 4H), 3.69 (s, 3H), 3.65-3.61 (m, 2H), 3.38-3.33 (m, 4H), 3.31 (s, 3H), 3.10-3.05 (m, 2H), 2.92-2.88 (m, 4H), 2.69-2.67 (d, 2H), 2.36 (s, 3H), 2.27-2.23 (m, 1H), 2.07-1,97 (m, 2H), 1.87-1.82 (m, 2H), 1.79-1.66 (m, 3H), 1.46-1.34 (m, 4H), 1.25-1.12 (m, 30H), 1.04-0.96 (m, 5H), 0.75 (s, 6H), 0.54-0.50 (m, 1H), 0.32-0.25 (m, 2H), 0.23-0.18 (m, 1H). JPEG2026504319000170.jpg36170

[0322] MS (ESI) m / z 1139.5 [M] + . 1H NMR (400 MHz, DMSO-d6): δ 8.92 (t, NH, 2H), 8.20 (t, NH, 1H), 8.05-8.03 (d, 1H), 7.93 (br, NH3, 6H), 7.28 (br, 1H), 7.11-7.09 (d, 1H), 6.92-6.91 (d, 1H), 6.86-6.84 (d, 1H), 6.71 (s, 1H), 6.52-6.50 (d, 1H), 6.50 (br, 1H), 6.23 (br, 1H), 4.36 (s, 4H), 4.14-4.12 (d, 2H), 4.12 (br, 2H), 3.75-3.72 (m, 2H), 3.69 (s, 3H), 3.53-3.50 (m, 2H), 3.38 (s, 3H), 3.38-3.34 (m, 4H), 2.94-2.89 (m, 4H), 2.69-2.67 (d, 2H), 2.36 (s, 3H), 2.26-2.22 (m, 1H), 2.10-2.06 (t, 2H), 1.81-1.66 (m, 3H), 1.46-1.34 (m, 4H), 1.25-1.12 (m, 26H), 1.04-0.96 (m, 5H), 0.75 (s, 6H), 0.55-0.51 (m, 1H), 0.32-0.25 (m, 2H), 0.23-0.18 (m, 1H). JPEG2026504319000171.jpg32170

[0323] MS (ESI) m / z 1209.6 [M+H] + . 1H NMR (400 MHz, DMSO-d6): δ 8.17 (t, NH, 2H), 8.12 (t, NH, 1H), 8.05-8.03 (d, 1H), 7.84 (br, NH3, 6H), 7.28 (br, 1H), 7.11-7.09 (d, 1H), 6.92-6.91 (d, 1H), 6.86-6.84 (d, 1H), 6.72 (s, 1H), 6.52-6.50 (d, 1H), 6.50 (br, 1H), 6.23 (br, 1H), 4.13-4.12 (d, 2H), 4.12 (br, 2H), 3.69 (s, 3H), 3.41-3.38 (m, 2H), 3.31-3.25 (m, 4H), 3.15-3.12 (m, 6H), 2.92-2.88 (m, 4H), 2.69-2.67 (d, 2H), 2.36 (s, 3H), 2.27-2.20 (m, 5H), 2.10-2.06 (t, 2H), 1.86-1.82 (m, 4H), 1.81-1.66 (m, 3H), 1.46-1.34 (m, 4H), 1.25-1.12 (m, 30H), 1.04-0.96 (m, 5H), 0.75 (s, 6H), 0.53-0.48 (m, 1H), 0.32-0.25 (m, 2H), 0.23-0.18 (m, 1H). JPEG2026504319000172.jpg33170

[0324] MS (ESI) m / z 1223.6 [M] + . 1H NMR (400 MHz, DMSO-d6): δ 8.19(t, NH, 2H), 8.15 (t, NH, 1H), 8.06-8.04 (d, 1H), 7.90 (br, NH3, 6H), 7.28 (br, 1H), 7.11-7.09 (d, 1H), 6.94-6.93 (d, 1H), 6.86-6.84 (d, 1H), 6.71 (s, 1H), 6.53-6.50 (dd, 1H), 6.4 (br, 1H), 6.24 (br, 1H), .15-4.13 (d, 2H), 4.10 (br, 2H), 3.69 (s, 3H), 3.48-3.45 (m, 2H), 3.32-3.27 (m, 10H), 3.02 (s, 3H), 2.89-2.85 (m, 4H), 2.70-2.67 (m, 2H), 2.36 (s, 3H), 2.28-2.18 (m, 5H), 2.10-2.06 (t, 2H), 1.92-1.88 (m, 2H), 1.81-1.66 (m, 3H), 1.50-1.34 (m, 4H), 1.25-1.12 (m, 30H), 1.04-0.96 (m, 5H), 0.75 (s, 6H), 0.53-0.48 (m, 1H), 0.32-0.25 (m, 2H), 0.23-0.18 (m, 1H). JPEG2026504319000173.jpg37170

[0325] MS (ESI) m / z 1182.7 [M+H] + . 1H NMR (400 MHz, DMSO-d6): δ 8.89 (t, NH, 2H), 8.20 (t, NH, 1H), 8.04-8.03 (d, 1H), 7.91 (br, NH3, 6H), 7.26 (br, 1H), 7.10-7.08 (d, 1H), 6.92-6.91 (d, 1H), 6.86-6.84 (d, 1H), 6.71 (s, 1H), 6.52-6.49 (d, 1H), 6.44 (br, 1H), 6.23 (br, 1H), 4.35 (s, 4H), 4.14-4.12 (d, 2H), 4.09 (br, 2H), 3.75-3.71 (m, 2H), 3.68 (s, 3H), 3.53-3.50 (m, 2H), 3.38 (s, 3H), 3.38-3.34 (m, 4H), 2.93-2.86 (m, 4H), 2.69-2.67 (d, 2H), 2.36 (s, 3H), 2.26-2.22 (m, 1H), 2.10-2.06 (t, 2H), 1.81-1.66 (m, 3H), 1.46-1.34 (m, 4H), 1.25-1.12 (m, 32H), 1.04-0.96 (m, 5H), 0.75 (s, 6H), 0.53-0.49 (m, 1H), 0.32-0.25 (m, 2H), 0.23-0.18 (m, 1H). JPEG2026504319000174.jpg75170

[0326] Step 1. To a solution of intermediate 4 (100 mg, 0.10 mmol) in THF (2 mL) were added HATU (76.4 mg, 0.20 mmol), TEA (30.5 mg, 0.30 mmol), and intermediate 7 (95.5 mg, 0.20 mmol). The mixture was stirred at room temperature for 12 h, then quenched with water and extracted with EA. The organic phase was washed with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give (S)—N-(2-(24-(2-(4-(((4-(3-(tert-butoxy)-1-cyclopropyl-3-oxopropyl)pyridin-2-yl)oxy)methyl)piperidin-1-yl)-4-methoxy-N-(6-methylpyridin-2-yl)benzamido)-23,23-dimethyltetracosanamido)ethyl)-2-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-N-(2-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-2-oxoethyl)-N-methyl-2-oxoethanaminium salt, E11-1 (98 mg, crude product) as a yellow gum. MS (ESI) m / z 726.7 [M / 2+H]+.

[0327] Step 2. To a solution of E11-1 (98 mg, 0.068 mmol) in DCM (2 mL) was added TFA / DCM (1 mL / 1 mL) at 0° C., and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and purified by prep-HPLC to give (S)-2-((2-aminoethyl)amino)-N-(2-((2-aminoethyl)amino)-2-oxoethyl)-N-(2-(24-(2-(4-(((4-(2-carboxy-1-cyclopropylethyl)pyridin-2-yl)oxy)methyl)piperidin-1-yl)-4-methoxy-N-(6-methylpyridin-2-yl)benzamido)-23,23-dimethyltetracosanamido)ethyl)-N-methyl-2-oxoethanaminium trifluoroacetate, Example 11, as a white gum. MS (ESI) m / z 1195.6 [M]+. 1H NMR (400 MHz, DMSO-d6): δ 8.85 (t, NH, 2H), 8.17 (t, NH, 1H), 8.04-8.03 (d, 1H), 7.84 (br, NH3, 6H), 7.27 (br, 1H), 7.10-7.08 (d, 1H), 6.92-6.91 (d, 1H), 6.86-6.84 (d, 1H), 6.70 (s, 1H), 6.52-6.50 (d, 1H), 6.43 (br, 1H), 6.23 (br, 1H), 4.34 (s, 4H), 4.14-4.12 (d, 2H), 4.09 (br, 2H), 3.74-3.71 (m, 2H), 3.68 (s, 3H), 3.52-3.48 (m, 2H), 3.38 (s, 3H), 3.36-3.33 (m, 4H), 2.93-2.88 (m, 4H), 2.69-2.67 (d, 2H), 2.36 (s, 3H), 2.26-2.22 (m, 1H), 2.10-2.06 (t, 2H), 1.81-1.66 (m, 3H), 1.46-1.34 (m, 4H), 1.25-1.12 (m, 34H), 1.04-0.96 (m, 5H), 0.75 (s, 6H), 0.53-0.49 (m, 1H), 0.32-0.25 (m, 2H), 0.23-0.18 (m, 1H). JPEG2026504319000175.jpg38170

[0328] MS (ESI) m / z 577.3 [(M+H) / 2] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.86 (t, NH, 2H), 7.96 (t, NH, 1H), 8.05-8.03 (d, 1H), 7.86 (br, NH3, 6H), 7.29-7.25 (br, 1H), 7.11-7.08 (d, 1H), 6.92-6.91 (d, 1H), 6.86-6.84 (d, 1H), 6.71 (s, 1H), 6.52-6.50 (d, 1H), 6.43 (br, 1H), 6.23 (s, 1H), 4.31-4.22 (q, 4H), 4.16-4.12 (m, 4H), 3.69 (s, 3H), 3.64-3.60 (m, 2H), 3.38-3.33 (m, 4H), 3.31 (s, 3H), 3.10-3.05 (m, 2H), 2.92-2.88 (m, 4H), 2.69-2.67 (d, 2H), 2.36 (s, 3H), 2.27-2.23 (m, 1H), 2.07-1,97 (m, 2H), 1.88-1.84 (m, 2H), 1.79-1.66 (m, 3H), 1.49-1.34 (m, 4H), 1.25-1.12 (m, 26H), 1.04-0.96 (m, 5H), 0.75 (s, 6H), 0.53-0.48 (m, 1H), 0.32-0.25 (m, 2H), 0.23-0.18 (m, 1H). JPEG2026504319000176.jpg32170

[0329] MS (ESI) m / z 1084.4 [M+H] + . 1H NMR (400 MHz, DMSO-d6): δ 8.04-8.03 (d, 1H), 7.81 (t, NH, 1H), 7.27-7.25 (br, 1H), 7.11-7.08 (d, 1H), 6.92-6.91 (d, 1H), 6.86-6.84 (d, 1H), 6.71 (s, 1H), 6.52-6.50 (d, 1H), 6.43 (br, 1H), 6.23 (s, 1H), 4.14-4.12 (d, 2H), 4.12 (br, 2H), 3.95 (br, 4H), 3.69 (s, 3H), 3.08-3.03 (m, 4H), 2.69-2.67 (d, 2H), 2.36 (s, 3H), 2.27-2.23 (m, 1H), 2.07-1,97 (m, 2H), 1.77-1.66 (m, 5H), 1.48-1.34 (m, 4H), 1.25-1.12 (m, 30H), 1.04-0.96 (m, 5H), 0.75 (s, 6H), 0.53-0.48 (m, 1H), 0.32-0.25 (m, 2H), 0.23-0.18 (m, 1H). JPEG2026504319000177.jpg33170

[0330] MS (ESI) m / z 1098.4 [M+H] + . 1H NMR (400 MHz, DMSO-d6): δ 8.04-8.03 (d, 1H), 7.87 (t, NH, 1H), 7.27-7.25 (br, 1H), 7.11-7.08 (d, 1H), 6.92-6.90 (d, 1H), 6.86-6.84 (d, 1H), 6.70 (s, 1H), 6.52-6.50 (d, 1H), 6.43 (br, 1H), 6.23 (s, 1H), 4.46 (s, 4H), 4.14-4.12 (d, 2H), 4.12 (br, 2H), 3.69 (s, 3H), 3.69-3.62 (m, 2H), 3.30 (s, 3H), 3.10-3.06 (m, 2H), 2.69-2.67 (d, 2H), 2.38 (s, 3H), 2.27-2.22 (m, 1H), 2.05-2.00 (m, 2H), 1.86-1.78 (m, 3H), 1.68-1.64 (m, 2H), 1.49-1.46 (m, 4H), 1.25-1.12 (m, 30H), 1.04-0.96 (m, 5H), 0.75 (s, 6H), 0.78-0.74 (m, 1H), 0.32-0.25 (m, 2H), 0.23-0.18 (m, 1H). JPEG2026504319000178.jpg33170

[0331] MS (ESI) m / z 1081.5 [M+H] + . 1H NMR (400 MHz, DMSO-d6): δ 8.82 (t, NH, 1H), 8.04-8.03 (d, 1H), 8.00 (br, NH3, 3H), 7.97-7.94 (t, NH, 1H), 7.24 (t, 1H), 7.11-7.09 (d, 1H), 6.92-6.90 (d, 1H), 6.84-6.82 (d, 1H), 6.71 (s, 1H), 6.51-6.49 (d, 1H), 6.41 (br, 1H), 6.22 (br, 1H, 4.13-4.11 (d, 2H), 4.10 (br, 2H), 3.93-3.87 (br, 2H), 3.68 (s, 3H), 3.42-3.37 (m, 2H), 3.08-3.06 (m, 2H), 2.95-2.90 (m, 4H), 2.80 (s, 3H), 2.69-2.67 (d, 2H), 2.35 (s, 3H), 2.25-2.23 (m, 1H), 2.06-2.02 (t, 2H), 1.79-1.75 (m, 3H), 1.68-1.65 (m, 2H), 1.48-1.45 (m, 2H), 1.38-1.36 (m, 2H), 1.25-1.10 (m, 30H), 1.04-0.96 (m, 5H), 0.75 (s, 6H), 0.52-0.48 (m, 1H), 0.36-0.25 (m, 2H), 0.23-0.18 (m, 1H). JPEG2026504319000179.jpg34170

[0332] MS (ESI) m / z 548.4 [(M+H) / 2] + . 1H NMR (400 MHz, DMSO-d6): δ 8.91 (t, NH, 1H), 8.05-8.04 (d, 1H), 7.97 (br, NH3, 3H), 7.96-7.94 (t, NH, 1H), 7.26 (t, 1H), 7.11-7.09 (d, 1H), 6.93-6.92 (d, 1H), 6.86-6.84 (d, 1H), 6.72 (s, 1H), 6.53-6.50 (d, 1H), 6.43 (br, 1H), 6.23 (br, 1H), 4.14-4.12 (d, 2H),4.10 (br, 2H), 4.05 (br, 2H), 3.69 (s, 3H), 3.48-3.44 (m, 2H), 3.40-3.36 (m, 2H), 3.18 (s, 6H), 3.11-3.07 (m, 2H), 2.95-2.91 (m, 2H), 2.69-2.68 (d, 2H), 2.36 (s, 3H), 2.25-2.23 (m, 1H), 2.07-2.03 (t, 2H), 1.80-1.70 (m, 3H), 1.68-1.64 (m, 2H), 1.52-1.49 (m, 2H), 1.38 (m, 2H), 1.25-1.10 (m, 30H), 1.04-0.90 (m, 5H), 0.74 (s, 6H), 0.53-0.48 (m, 1H), 0.36-0.25 (m, 2H), 0.23-0.18 (m, 1H). JPEG2026504319000180.jpg36170

[0333] MS (ESI) m / z 1195.4 [M] + . 1H NMR (400 MHz, DMSO-d6): δ 8.18(t, NH, 2H), 8.15 (t, NH, 1H), 8.05-8.04 (d, 1H), 7.87 (br, NH3, 6H), 7.28 (br, 1H), 7.11-7.09 (d, 1H), 6.93-6.91 (dd, 1H), 6.86-6.84 (d, 1H), 6.72 (s, 1H), 6.53-6.50 (dd, 1H), 6.4 (br, 1H), 6.23 (br, 1H), 4.13-4.12 (d, 2H), 4.10 (br, 2H), 3.69 (s, 3H), 3.48-3.44 (m, 2H), 3.32-3.27 (m, 10H), 3.02 (s, 3H), 2.89-2.84 (m, 4H), 2.69-2.67 (m, 2H), 2.36 (s, 3H), 2.27-2.18 (m, 5H), 2.10-2.06 (t, 2H), 1.91-1.87 (m, 2H), 1.77-1.66 (m, 3H), 1.49-1.37 (m, 4H), 1.25-1.12 (m, 26H), 1.02-0.96 (m, 5H), 0.75 (s, 6H), 0.54-0.49 (m, 1H), 0.32-0.25 (m, 2H), 0.21-0.17 (m, 1H). JPEG2026504319000181.jpg72170

[0334] Step 1. To a mixture of intermediate 5 (60 mg, 0.066 mmol) and intermediate 18 (29 mg, 0.165 mmol) in THF (2 mL) was added HATU (30 mg, 0.079 mmol) and TEA (20 mg, 0.198 mmol). The resulting mixture was stirred at room temperature for 12 hours. The solvent was removed and the residue was treated with EA (20 mL), washed with water and brine, dried and concentrated to give crude (S)-1-(3-(20-(2-(4-(((4-(1-cyclopropyl-3-ethoxy-3-oxopropyl)pyridin-2-yl)oxy)methyl)piperidin-1-yl)-4-methoxy-N-(6-methylpyridin-2-yl)benzamido)-19,19-dimethylicosanamido)propyl)-1,4-diazabicyclo[2.2.2]octan-1-ium salt (90 mg, crude) as a yellow oil. MS (ESI) m / z 532.0 [(M+H) / 2]+.

[0335] Step 2. A mixture of (S)-1-(3-(20-(2-(4-(((4-(1-cyclopropyl-3-ethoxy-3-oxopropyl)pyridin-2-yl)oxy)methyl)piperidin-1-yl)-4-methoxy-N-(6-methylpyridin-2-yl)benzamido)-19,19-dimethylicosanamido)propyl)-1,4-diazabicyclo[2.2.2]octan-1-ium salt (90 mg, 0.078 mmol) and LiOH.HO (14 mg, 0.333 mmol) in HO (1 mL), MeOH (1.5 mL), and THF (1.5 mL) was stirred at room temperature for 14 h. The solvent was removed and the residue was purified by prep-HPLC to give (S)-1-(3-(20-(2-(4-(((4-(2-carboxy-1-cyclopropylethyl)pyridin-2-yl)oxy)methyl)piperidin-1-yl)-4-methoxy-N-(6-methylpyridin-2-yl)benzamido)-19,19-dimethylicosanamido)propyl)-1,4-diazabicyclo[2.2.2]octan-1-ium TFA salt, Example 18, as a yellow gum. MS (ESI) m / z 1034.4 [M] + . 1H NMR (400 MHz, DMSO-d6): δ 8.05-8.03 (d, 1H), 7.88 (t, NH, 1H), 7.27-7.25 (br, 1H), 7.11-7.08 (d, 1H), 6.93-6.91 (d, 1H), 6.86-6.84 (d, 1H), 6.71 (s, 1H), 6.52-6.50 (d, 1H), 6.45 (br, 1H), 6.23 (s, 1H), 4.14-4.10 (m, 4H), 3.69 (s, 3H), 3.35-3.30 (m, 8H), 3.22-3.17 (m, 2H), 3.15-3.06 (m, 6H), 2.67-2.65 (d, 2H), 2.36 (s, 3H), 2.27-2.23 (m, 1H), 2.07-2.03 (m, 2H), 1.83-1.78 (m, 3H), 1.69-1.63 (m, 2H), 1.49-1.46 (m, 4H), 1.27-1.22 (m, 26H), 1.04-0.96 (m, 5H), 0.75 (s, 6H), 0.52-0.48 (m, 1H), 0.35-0.25 (m, 2H), 0.22-0.18 (m, 1H). JPEG2026504319000182.jpg34170

[0336] MS (ESI) m / z 524.9 [M / 2] + . 1H NMR (400 MHz, DMSO-d6): δ 8.05-8.03 (d, 1H), 7.95 (t, NH, 1H), 7.29-7.25 (br, 1H), 7.11-7.09 (d, 1H), 6.92-6.91 (dd, 1H), 6.86-6.84 (d, 1H), 6.71 (s, 1H), 6.52-6.50 (dd, 1H), 6.43 (br, 1H), 6.23 (s, 1H), 4.14-4.10 (m, 4H), 3.85-3.77 (m, 12H), 3.69 (s, 3H), 3.48-3.44 (m, 2H), 3.26 (s, 3H), 3.13-3.08 (, m, 2H), 2.69-2.67 (d, 2H), 2.36 (s, 3H), 2.26-2.20 (m, 1H), 2.08-2.04 (m, 2H), 1.85-1.77 (m, 3H), 1.68-1.66 (m, 2H), 1.49-1.46 (m, 4H), 1.25-1.12 (m, 26H), 1.02-0.96 (m, 5H), 0.75 (s, 6H), 0.52-0.48 (m, 1H), 0.35-0.25 (m, 2H), 0.22-0.18 (m, 1H). JPEG2026504319000183.jpg36170

[0337] MS (ESI) m / z 1099.5 [M+] + . 1H NMR (400 MHz, DMSO-d6) δ 8.92 (m, 2H), 7.99-7.90 (m, 7H), 7.61 (s, 1H), 7.43-7.40 (m, 2H), 7.00-6.97 (m, 1H), 6.66 (d, 1H), 6.52 (s, 1H), 4.37-4.33 (m, 2H), 4.31 (s, 4H), 3.83-3.80 (m, 1H), 3.67-3.63 (m, 2H), 3.38-3.33 (m, 6H), 3.31 (s, 3H), 3.13-3.09 (m, 4H), 2.91-2.87 (m, 4H), 2.77-2.59 (m. 5H), 2.10-2.00 (t, 2H), 2.00-1.78 (m, 8H), 1.73-1.55 (m, 4H), 1.55-1.39 (m, 2H), 1.35-0.95 (m, 30H), 1.08-1.04 (m, 1H), 0.81 (d, 3H), 0.52-0.49 (m, 1H), 0.27-0.23 (m, 2H), -0.07 ~ -0.12 (m, 1H). JPEG2026504319000184.jpg79170

[0338] Step 1. To a solution of intermediate 21 (80 mg, 0.077 mmol) in EtOH (2.5 mL), 1,4-diazabicyclo[2.2.2]octane (13 mg, 0.116 mmol) was added. The reaction mixture was stirred at 80° C. for 16 hours. The reaction mixture was concentrated, and the residue was purified by prep-TLC (DCM / MeOH=10 / 1) to give (S)-1-(24-(2-(4-(((4-(1-cyclopropyl-3-methoxy-3-oxopropyl)pyridin-2-yl)oxy)methyl)piperidin-1-yl)-4-methoxy-N-(6-methylpyridin-2-yl)benzamido)-23,23-dimethyltetracosyl)-1,4-diazabicyclo[2.2.2]octan-1-ium, E21-1, as a yellow gum. MS (ESI) m / z 517.5 [M / 2+H] + .

[0339] Step 5. To a solution of E21-1 (70 mg, 0.067 mmol) in MeOH / HO (2 mL / 1 mL) was added LiOH.HO (13.8 mg, 0.338 mmol). The reaction mixture was stirred at room temperature for 16 hours. LCMS showed the reaction was complete. The reaction mixture was then acidified with 1 M HCl until the pH reached 3-4 and concentrated. The residue was purified by prep-HPLC to give (S)-1-(24-(2-(4-(((4-(2-carboxy-1-cyclopropylethyl)pyridin-2-yl)oxy)methyl)piperidin-1-yl)-4-methoxy-N-(6-methylpyridin-2-yl)benzamido)-23,23-dimethyltetracosyl)-1,4-diazabicyclo[2.2.2]octan-1-ium, Example 21, as a yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ = 8.05-8.03 (d, 1H), 7.29-7.26 (br, 1H), 7.11-7.09 (d, 1H), 6.92-6.91 (d, 1H), 6.86-6.84 (d, 1H), 6.71 (s, 1H), 6.52-6.50 (d, 1H), 6.44 (br, 1H), 6.23 (s, 1H), 4.14-4.12 (d, 2H), 4.12 (br, 2H), 3.69 (s, 3H), 3.40-3.34 (m, 6H), 3.24-3.14 (m, 8H), 2.69-2.67 (d, 2H), 2.36 (s, 3H), 2.27-2.21 (m, 1H), 1.76 (br, 1H), 1.68-1.60 (m, 4H), 1.46-1.36 (m, 2H), 1.27-1.22 (m, 36H), 1.04-0.97 (m, 5H), 0.75 (s, 6H), 0.52-0.49 (m, 1H), 0.35-0.25 (m, 2H), 0.22-0.18 (m, 1H). JPEG2026504319000185.jpg36170

[0340] Example 22 was prepared in a similar manner as described for Example 21. MS (ESI) m / z 963.5 [M+] + .1 H NMR (400 MHz, DMSO-d6) δ 8.05-8.03 (d, 1H), 7.29-7.26 (br, 1H), 7.11-7.09 (d, 1H), 6.92-6.91 (d, 1H), 6.86-6.84 (d, 1H), 6.71 (s, 1H), 6.52-6.50 (d, 1H), 6.44 (br, 1H), 6.23 (s, 1H), 4.13-4.12 (d, 2H), 4.12 (br, 2H), 3.69 (s, 3H), 3.37-3.34 (m, 6H), 3.24-3.17 (m, 8H), 2.69-2.67 (d, 2H), 2.36 (s, 3H), 2.27-2.21 (m, 1H), 1.76 (br, 1H), 1.68-1.62 (m, 4H), 1.46-1.36 (m, 2H), 1.27-1.22 (m, 28H), 1.04-0.97 (m, 5H), 0.75 (s, 6H), 0.52-0.49 (m, 1H), 0.35-0.25 (m, 2H), 0.22-0.18 (m, 1H). JPEG2026504319000186.jpg44170JPEG2026504319000187.jpg72170

[0341] Step 1. A mixture of (S)-3-cyclopropyl-3-(2-((1-(2-((2,2-dimethyl-20-oxoicosyl)(6-methylpyridin-2-yl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)pyridin-4-yl)ethyl propanoate, E23-1, (400 mg, 0.447 mmol) and ammonium acetate (103 mg, 1.342 mmol) in dry MeOH (20 mL) was stirred at 30° C. for 50 minutes. Then, NaBHCN (86 mg, 1.342 mmol) was added in small portions. After the addition, the resulting mixture was stirred at 50° C. for an additional 16 hours. The mixture was filtered, and the filtrate was concentrated. The residue was purified by pre-TLC (PE / EA=1:1) to give (S)-ethyl 3-(2-((1-(2-((20-amino-2,2-dimethylicosyl)(6-methylpyridin-2-yl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)pyridin-4-yl)-3-cyclopropylpropanoate, E23-2, as a yellow gum. MS (ESI) m / z 896.6 [M+H].

[0342] Step 2. To a mixture of E23-2 (270 mg, 0.301 mmol) and TEA (45 mg, 0.45 mmol) in dry DCM was added chloroacetyl chloride (41 mg, 0.36 mmol) dropwise at 0 °C. After the addition, the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water and extracted twice with DCM. The organic phases were combined, dried, and concentrated. The residue was purified by pre-TLC (DCM / MeOH = 10:1) to give (S)-ethyl 3-(2-((1-(2-((20-(2-chloroacetamido)-2,2-dimethylicosyl)(6-methylpyridin-2-yl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)pyridin-4-yl)-3-cyclopropylpropanoate, E23-3, as a yellow gum. MS(ESI) m / z 972.6[M+H]+.

[0343] Step 3. A mixture of E23-3 (165 mg, 0.172 mmol) and DABCO (98 mg, 0.874 mmol) in EtOH (6 mL) was heated to reflux (80 °C) for 16 hours. The solvent was removed, and the residue was purified by pre-TLC (DCM / MeOH = 10:1) to give (S)-1-(2-((20-(2-(4-(((4-(1-cyclopropyl-3-ethoxy-3-oxopropyl)pyridin-2-yl)oxy)methyl)piperidin-1-yl)-4-methoxy-N-(6-methylpyridin-2-yl)benzamido)-19,19-dimethylicosyl)amino)-2-oxoethyl)-1,4-diazabicyclo[2.2.2]octan-1-ium, E23-4, as a yellow gum. MS (ESI) m / z 1048.8 [M+]+.

[0344] Step 4. To a solution of E23-4 (35 mg, 0.033 mmol) in MeOH / THF / HO (1.5 mL / 1.5 mL / 0.5 mL) was added LiOH.HO (7 mg, 0.167 mmol). The reaction mixture was stirred at room temperature for 14 h. LCMS showed the reaction was complete. The reaction mixture was then acidified with 1 M HCl until a pH of 2 was reached and concentrated. The residue was purified by prep-HPLC to give (S)-1-(2-((20-(2-(4-(((4-(2-carboxy-1-cyclopropylethyl)pyridin-2-yl)oxy)methyl)piperidin-1-yl)-4-methoxy-N-(6-methylpyridin-2-yl)benzamido)-19,19-dimethylicosyl)amino)-2-oxoethyl)-1,4-diazabicyclo[2.2.2]octan-1-ium trifluoroacetate, Example 23, as a white solid. MS (ESI) m / z 1019.6 [M+] +. MS (ESI) m / z 1020.5 [M+] + . 1H NMR (400 MHz, DMSO-d6) δ 8.64-8.63 (d, 1H), 8.05-8.04 (d, 1H), 7.29-7.26 (br, 1H), 7.11-7.09 (d, 1H), 6.93-6.92 (d, 1H), 6.86-6.84 (d, 1H), 6.72 (s, 1H), 6.52-6.50 (d, 1H), 6.45 (br, 1H), 6.23 (s, 1H), 4.13-4.12 (d, 2H), 4.12 (br, 4H), 3.72-3.70 (m, 6H), 3.69 (s, 3H), 3.37-3.34 (m, 6H), 3.13-3.08 (m, 8H), 2.69-2.67 (d, 2H), 2.36 (s, 3H), 2.27-2.21 (m, 1H), 1.76 (br, 1H), 1.69-1.66 (m, 2H), 1.46-1.36 (m, 2H), 1.27-1.22 (m, 28H), 1.04-0.97 (m, 5H), 0.75 (s, 6H), 0.52-0.49 (m, 1H), 0.35-0.25 (m, 2H), 0.22-0.18 (m, 1H). JPEG2026504319000188.jpg35170

[0345] Example 24 was prepared in a similar manner as described for Example 21. MS (ESI) m / z 483.4 [(M+H] / 2] + . 1H NMR (400 MHz, DMSO-d6) δ 8.06-8.04 (d, 1H), 7.29-7.26 (br, 1H), 7.11-7.09 (d, 1H), 6.94-6.92 (d, 1H), 6.86-6.84 (d, 1H), 6.73 (s, 1H), 6.53-6.50 (d, 1H), 6.44 (br, 1H), 6.24 (s, 1H), 4.15-4.13 (d, 2H), 4.10 (br, 2H), 3.69 (br, 7H), 3.63 (br, 4H), 3.47 (br, 2H), 3.18 (s, 3H), 2.89 (s, 3H), 2.70-2.68 (d, 2H), 2.37 (s, 3H), 2.28-2.22 (m, 1H), 1.77-1.75 (br, 1H), 1.74-1.67 (m, 4H), 1.46-1.36 (m, 2H), 1.27-1.22 (m, 28H), 1.04-0.97 (m, 5H), 0.75 (s, 6H), 0.52-0.49 (m, 1H), 0.35-0.25 (m, 2H), 0.22-0.18 (m, 1H). JPEG2026504319000189.jpg36170

[0346] Example 25 was prepared in a similar manner as described for Example 21. MS (ESI) m / z 910.5 [M+] + . 1H NMR (400 MHz, DMSO-d6) δ 8.05-8.04 (d, 1H), 7.26 (br, 1H), 7.11-7.09 (d, 1H), 6.93-6.92 (d, 1H), 6.85-6.84 (d, 1H), 6.72 (s, 1H), 6.52-6.50 (d, 1H), 6.43 (br, 1H), 6.23 (s, 1H), 4.14-4.12 (d, 2H), 4.11 (br, 2H), 3.69 (s, 3H), 3.27-3.23 (m, 2H), 3.03 (s, 9H), 2.69-2.67 (d, 2H), 2.36 (s, 3H), 2.27-2.23 (m, 1H), 1.77(br, 1H), 1.74-1.67 (m, 4H), 1.46-1.36 (m, 2H), 1.27-1.22 (m, 28H), 1.04-0.97 (m, 5H), 0.75 (s, 6H), 0.52-0.49 (m, 1H), 0.35-0.25 (m, 2H), 0.22-0.18 (m, 1H). JPEG2026504319000190.jpg35170

[0347] Example 26 was prepared in a similar manner as described for Example 21. MS (ESI) m / z 476.8 [(M+H) / 2] + . 1H NMR (400 MHz, DMSO-d6) δ 8.05-8.04 (d, 1H), 7.26 (br, 1H), 7.11-7.08 (d, 1H), 6.93-6.91 (d, 1H), 6.86-6.84 (d, 1H), 6.71 (s, 1H), 6.52-6.50 (d, 1H), 6.45 (br, 1H), 6.23 (s, 1H), 4.14-4.12 (d, 2H), 4.11 (br, 2H), 3.69 (s, 3H), 3.24-3.19 (q, 6H), 3.11-3.07 (m, 2H), 2.69-2.67 (d, 2H), 2.36 (s, 3H), 2.27-2.23 (m, 1H), 1.79(br, 1H), 1.74-1.67 (m, 4H), 1.46-1.36 (m, 2H), 1.27-1.10 (m, 37H), 1.04-0.97 (m, 5H), 0.75 (s, 6H), 0.52-0.49 (m, 1H), 0.35-0.25 (m, 2H), 0.22-0.18 (m, 1H). JPEG2026504319000191.jpg35170

[0348] MS (ESI) m / z 1320.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.04-8.03 (d, 1H), 8.00 (br, 9H), 7.94 (br, 2H), 7.29-7.26 (br, 1H), 7.15-7.13 (d, 1H), 6.93-6.92 (d, 1H), 6.86-6.84 (d, 1H), 6.71 (s, 1H), 6.53-6.50 (dd, 1H), 6.46-6.45 (br, 1H), 6.213 (s, 1H), 4.34-4.30 (t, 2H), 4.18 (br, 4H), 4.13-4.11(d, 2H), 3.75-3.72 (m, 1H), 3.69 (s, 3H), 3.12-3.05 (m, 10H), 3.02-3.00 (m, 2H), 2.90-2.86 (m, 6H), 2.69-2.67 (d, 2H), 2.35 (s, 3H), 2.26-2.21 (m, 1H), 2.06-2.03 (m, 2H), 1.98-1.87 (m, 6H), 1.80-1.76 (m, 3H), 1.65-1.62 (m, 6H), 1.46-1.36 (m, 2H), 1.27-1.22 (m, 28H), 1.04-0.97 (m, 1H), 0.75 (s, 6H), 0.52-0.49 (m, 1H), 0.35-0.25 (m, 2H), 0.22-0.18 (m, 1H). JPEG2026504319000192.jpg34170

[0349] MS (ESI) m / z 525.0[(M+H) / 2] + . 1H NMR (400 MHz, DMSO-d6) δ 8.05-8.03 (d, 1H), 7.80 (t, NH, 1H), 7.28-7.25 (br, 1H), 7.11-7.08 (d, 1H), 6.93-6.91 (d, 1H), 6.86-6.84 (d, 1H), 6.71 (s, 1H), 6.52-6.50 (d, 1H), 6.44 (br, 1H), 6.23 (s, 1H), 4.14-4.10 (m, 4H), 3.69 (s, 3H), 3.38-3.28 (m, 6H), 3.26-3.22 (m, 2H), 3.19-3.15 (m, 6H), 3.09-3.04 (m, 2H), 2.69-2.67 (d, 2H), 2.36 (s, 3H), 2.27-2.21 (m, 1H), 2.07-2.03 (m, 2H), 1.83-1.78 (m, 1H), 1.69-1.63 (m, 4H), 1.49-1.38 (m, 6H), 1.27-1.22 (m, 26H), 1.04-0.96 (m, 5H), 0.75 (s, 6H), 0.52-0.48 (m, 1H), 0.35-0.25 (m, 2H), 0.22-0.18 (m, 1H). JPEG2026504319000193.jpg38170

[0350] MS (ESI) m / z 995.5 [M+] + . 1H NMR (400 MHz, DMSO-d6) δ 8.05-8.04 (d, 1H), 7.83 (t, NH, 1H), 7.29-7.25 (br, 1H), 7.11-7.09 (d, 1H), 6.94-6.93 (d, 1H), 6.86-6.84 (d, 1H), 6.74 (s, 1H), 6.53-6.50 (dd, 1H), 6.44 (br, 1H), 6.24 (s, 1H), 4.14-4.10 (m, 4H), 3.69 (s, 3H), 3.30-3.27 (m, 2H), 3.09-3.02 (m, 11H), 2.70-2.68 (d, 2H), 2.36 (s, 3H), 2.28-2.22 (m, 1H), 2.06-2.02 (m, 2H), 1.78 (br, 1H), 1.70-1.62 (m, 4H), 1.49-1.46 (m, 2H), 1.43-1.35 (m, 4H), 1.27-1.22 (m, 26H), 1.04-0.96 (m, 5H), 0.75 (s, 6H), 0.52-0.48 (m, 1H), 0.35-0.25 (m, 2H), 0.22-0.18 (m, 1H). JPEG2026504319000194.jpg37170

[0351] MS (ESI) m / z 519.3 [(M+H) / 2] + . 1H NMR (400 MHz, DMSO-d6) δ 8.05-8.03 (d, 1H), 7.81 (t, NH, 1H), 7.30-7.25 (br, 1H), 7.11-7.08 (d, 1H), 6.93-6.91 (d, 1H), 6.86-6.84 (d, 1H), 6.72 (s, 1H), 6.53-6.49 (dd, 1H), 6.44 (br, 1H), 6.23 (s, 1H), 4.14-4.10 (m, 4H), 3.69 (s, 3H), 3.24-3.17 (q, C), 3.14-3.04 (m, 4H), 2.69-2.67 (d, 2H), 2.36 (s, 3H), 2.27-2.22 (m, 1H), 2.06-2.02 (m, 2H), 1.80 (br, 1H), 1.76-1.66 (m, 2H), 1.56-1.53 (m, 2H), 1.46-1.38 (m, 4H), 1.27-1.22 (m, 35H), 1.04-0.96 (m, 5H), 0.75 (s, 6H), 0.52-0.48 (m, 1H), 0.35-0.25 (m, 2H), 0.22-0.18 (m, 1H). JPEG2026504319000195.jpg37170

[0352] MS (ESI) m / z 972.5 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.04-8.03 (d, 1H), 7.30-7.20 (m, 6H), 7.10-7.08 (d, 1H), 6.92-6.90 (dd, 1H), 6.86-6.84 (d, 1H), 6.70 (s, 1H), 6.52-6.50 (d, 1H), 6.43 (br, 1H), 6.23 (s, 1H), 4.25-4.24 (d, 2H), 4.22-4.00 (m, 4H), 3.69 (s, 3H), 2.67-2.65 (d, 2H), 2.36 (s, 3H), 2.26-2.21 (m, 1H), 2.13-2.10 (m, 2H), 1.73-1.62 (m, 3H), 1.52-1.37 (m, 4H), 1.27-1.22 (m, 26H), 1.04-0.96 (m, 5H), 0.75 (s, 6H), 0.52-0.48 (m, 1H), 0.35-0.25 (m, 2H), 0.22-0.18 (m, 1H). JPEG2026504319000196.jpg36170

[0353] MS (ESI) m / z 938.5 [M+] + . 1H NMR (400 MHz, DMSO-d6) δ 8.04-8.03 (d, 1H), 7.29-7.25 (m, 1H), 7.11-7.08 (d, 1H), 6.92-6.91 (d, 1H), 6.86-6.84 (d, 1H), 6.70 (s, 1H), 6.52-6.50 (dd, 1H), 6.44 (br, 1H), 6.23 (s, 1H), 4.14-4.06 (m, 4H), 3.69 (s, 3H), 3.03-2.98 (q, 2H), 2.67-2.63 (d, 2H), 2.36 (s, 3H), 2.26-2.20 (m, 1H), 2.03-2.00 (m, 2H), 1.76 (br, 1H), 1.68-1.65 (m, 2H), .50-1.45 (m, 4H), 1.38-1.32 (m, 2H), 1.30-1.20 (m, 28H), 1.04-0.96 (m, 5H), 0.80 (t, 3H), 0.75 (s, 6H), 0.52-0.48 (m, 1H), 0.35-0.25 (m, 2H), 0.22-0.18 (m, 1H). JPEG2026504319000197.jpg35170

[0354] Example 33 is the same as that of WO2023 / 134712 Intermediate 59 is. JPEG2026504319000198.jpg36170

[0355] Example 34 was synthesized in the same manner as Example 18, starting from Example 33. MS (ESI) m / z 1131.5 [M+] + . 11H NMR (400 MHz, DMSO-d6) δ 8.05 - 8.04 (d, 1H), 7.93 - 7.90 (t, 1H), 7.68 (s, 1H), 7.30 - 7.26 (br, 1H), 7.16 - 6.14 (d, 1H), 6.93 - 6.91 (d, 1H), 6.86 - 6.84 (d, 1H), 6.72 (s, 1H), 6.54 - 6.51 (dd, 1H), 6.45 (br, 1H), 6.21 (s, 1H), 4.35 - 4.30 (t, 2H), 4.20 (br, 2H), 4.13 - 4.12 (d, 2H), 3.69 (s, 3H), 3.45 - 3.41 (m, 6H), 3.27 - 3.24 (m, 8H), 3.12 - 3.08 (m, 2H), 2.69 - 2.67 (d, 2H), 2.58 - 2.55 (t, 2H), 2.36 (s, 3H), 2.27 - 2.21 (m, 1H), 2.07 - 2.04 (t, 2H), 1.84 - 1.70 (m, 3H), 1.69 - 1.63 (m, 4H), 1.60 - 1.45 (m, 4H), 1.38 - 1.25 (br, 2H), 1.30 - 1.20 (m, 26H), 1.02 - 0.99 (m, 1H), 0.78 (s, 6H), 0.52 - 0.49 (m, 1H), 0.36 - 0.25 (m, 2H), 0.17 - 0.13 (m, 1H). JPEG2026504319000199.jpg37170

[0356] 〈Example 35〉 MS (ESI) m / z 535.3 [(M + 2H] / 2]. 11H NMR (400 MHz, DMSO-d6) δ 8.05 - 8.03 (d, 1H), 7.88 (t, NH, 1H), 7.29 - 7.26 (m, 1H), 7.11 - 7.09 (d, 1H), 6.93 - 6.91 (d, 1H), 6.86 - 6.84 (d, 1H), 6.71 (s, 1H), 6.52 - 6.50 (dd, 1H), 6.44 (br, 1H), 6.23 (s, 1H), 4.46 (s, 4H), 4.14 - 4.07 (m, 4H), 3.69 (s, 3H), 3.66 - 3.62 (q, 2H), 3.31 (s, 3H), 3.10 - 3.05 (m, 2H), 2.69 - 2.67 (d, 2H), 2.36 (s, 3H), 2.26 - 2.20 (m, 1H), 2.05 - 2.00 (m, 2H), 1.88 - 1.75 (m, 3H), 1.69 - 1.65 (m, 2H), 1.50 - 1.40 (m, 4H), 1.25 - 1.15 (m, 26H), 1.04 - 0.96 (m, 5H), 0.75 (s, 6H), 0.52 - 0.48 (m, 1H), 0.35 - 0.25 (m, 2H), 0.22 - 0.18 (m, 1H). JPEG2026504319000200.jpg39170

[0357] <Example 36> MS (ESI) m / z 545.4 [(M + 2H] / 2]. 1H NMR (400 MHz, DMSO-d6) δ 8.05-8.04 (d, 1H), 7.87 (t, NH, 1H), 7.30-7.27 (m, 1H), 7.11-7.09 (d, 1H), 6.94-6.92 (dd, 1H), 6.86-6.85 (d, 1H), 6.73 (s, 1H), 6.53-6.50 (dd, 1H), 6.44 (br, 1H), 6.23 (s, 1H), 4.14-4.09 (m, 4H), 3.69 (s, 3H), 3.42-3.39 (m, 2H), 3.25-3.21 (m, 2H), 3.12-3.07 (m, 2H), 3.00 (s, 6H), 2.69-2.67 (d, 2H), 2.54-2.50 (m, 2H), 2.36 (s, 3H), 2.26-2.20 (m, 1H), 2.08-2.04 (m, 2H), 2.01-1.93 (m, 2H), 1.82-1.75 (m, 3H), 1.69-1.65 (m, 2H), 1.50-1.39 (m, 4H), 1.25-1.15 (m, 26H), 1.04-0.96 (m, 5H), 0.75 (s, 6H), 0.52-0.48 (m, 1H), 0.35-0.25 (m, 2H), 0.22-0.18 (m, 1H). Biological Example 1: Materials and General Methods

[0358] Compound potency was assessed using an IP1 accumulation assay. HEK293 cells stably expressing GPR40 were cultured in maintenance medium (Dulbecco's modified Eagle's medium containing 4.5 g / L glucose, 10% fetal bovine serum, 100 μg / mL hygromycin, and penicillin (100 U / mL) / streptomycin (100 μg / mL)) in a 5% CO2 incubator (ThermoFisher) until 100% confluency was reached. Freshly harvested cells were spun down at 300 × g for 5 min and resuspended in prewarmed 1× stimulation buffer from the Cisbio IP-One HTRF Detection Kit (Cisbio). The cell density was adjusted to 2.0 × 10 6The concentration of cells / mL was adjusted. DMSO was used as a blank control, and AMG-1638 (CAS No.: 1142214-62-7) was used as a positive control. Compounds were prepared at 10 mM in DMSO, and 5 nL of 3x serially diluted compounds (10 concentrations) were added to each well of a 384-LDV assay plate (Corning) using an ECHO 550 (Labcyte). 5 μL of cells in suspension were transferred to each well using a Multidrop Combi reagent dispenser (ThermoFisher). The assay plate was then sealed and incubated at 37°C for 2 hours. IP-d2 and anti-IP1 reagents were prepared according to the manual (Cisbio). 5 μL of IP1-d2 and then 5 μL of anti-IP1 antibody were added sequentially to each well. The assay plate was incubated at room temperature for 60 minutes and then read at 665 nm / 615 nm on an Envision plate reader (PerkinElmer). The ratio of the values ​​obtained at 665 nm and 615 nm was used to calculate IP1 accumulation: % effect = (ratio サンプル -ratio ブランク ) / (ratio AMG-1638 -ratio ブランク ) × 100. Dose curves were fitted and the EC 50 was calculated.

[0359] All exemplified compounds of the present disclosure, i.e., Examples 1-36, were tested according to Biological Example 1 and showed EC 50 Values ​​were <50 nM. Additional exemplary data tested according to Biological Example 1 are shown in the table below: JPEG2026504319000201.jpg81170〈Biological Example 2〉Pharmacokinetics In-life PK assay

[0360] Male ICR (CD-1) mice (n = 3), approximately 4-6 weeks old and weighing approximately 25 grams, were purchased from VT-River (Zhejiang Province, China). After 1 week of acclimation, the animals were administered the exemplified compounds intravenously at 1 mpk or orally at 10 mpk (0.5% methylcellulose in PBS as the vehicle for both administration routes). Blood samples (30 μL) were collected by saphenous vein puncture at 5 (IV only), 15, 30, 60, 120, 240, 480, and 1440 minutes post-dose. Blood samples were stored in 0.5 M K2EDTA-coated tubes and centrifuged at 4,600 rpm for 5 minutes at 4°C. Plasma samples were collected and stored at -80°C until PK analysis. LC-MS / MS PK analysis:

[0361] Ten microliters of K2EDTA-treated plasma samples from CD-1 mice were collected, and 200 μL of precipitation solution containing an internal standard (5 ng / mL terfenadine in MeOH / ACN) was added. The mixture was mixed well by vortexing at room temperature for 1 minute, followed by centrifugation at 4000 rpm for 15 minutes at 4°C. The supernatant was saved as the injection solution for LC-MS / MS quantification of the example compounds in the mouse plasma samples.

[0362] A standard curve should be prepared before and after each analytical batch, with quality control samples at low, medium, and high concentrations. The number of quality control samples should be at least six, greater than or equal to the number of samples in each batch, and should be interspersed among the sample measurements. The standard curve and quality control samples for each batch must meet the acceptance criteria.

[0363] Exemplary data obtained according to Biological Example 2 are shown in the table below: JPEG2026504319000202.jpg55170JPEG2026504319000203.jpg21170〈Biological Example 3〉oGTT study

[0364] Male C57BL / 6 mice were purchased from Zhejiang Vital River Laboratories Co., Ltd. (a subsidiary of Charles River Laboratories) at approximately 7–8 weeks of age (n = 8). Animals were housed at room temperature under a regular light / dark cycle (12 h light: 12 h dark, LD) and provided with free access to regular chow and tap water in the facility for at least one week. On the day of the study, food was removed at 7:00 AM and the animals were fasted. Blood glucose levels were measured by tail blood sampling using a blood glucose meter (Roche) at 9:00 AM, and mice were classified into treatment groups based on the mean blood glucose level (-240 min). Vehicle (0.5% methylcellulose) or a solution of the exemplified compound (30 mpk dose) was thoroughly mixed and orally administered (dose volume = 10 mL / kg body weight). Blood glucose levels were measured using a blood glucose meter at 1:00 PM (0 min). Next, animals were orally administered 5 g / kg of glucose for an oral glucose tolerance test. Blood glucose levels were then measured using a blood glucose meter at 20, 40, 60, and 120 minutes. At the end of the study, 50 μl of tail blood was collected from each treatment group and mixed with 4% sodium citrate (vol 9:1). The tubes were centrifuged at 8,000 RPM for 10 minutes at 4°C in a tabletop centrifuge. Plasma samples were separated and stored in a -80°C freezer for PK analysis by LC-MS / MS.

[0365] The test results are shown in Figures 1 and 2. The following table also shows the percent change in AUC and drug concentration relative to the vehicle at 6 hours post-dose: JPEG2026504319000204.jpg23170

[0366] The Overview and Abstract sections are not intended to limit the scope of the invention and the appended claims in any way, as they describe one or more, but not all, exemplary embodiments of the invention as contemplated by the inventors.

[0367] The present invention has been described above with the aid of functional building blocks illustrating the implementation of certain functions and relationships thereof. The boundaries of these functional building blocks have been arbitrarily defined herein for the convenience of the description. Alternative boundaries may be defined so long as the certain functions and relationships thereof are appropriately performed.

[0368] For aspects of the invention described as genus, all individual species are considered individually as separate aspects of the invention. When an aspect of the invention is described as "comprising" a feature, it is contemplated that the embodiment also "consists of" or "consists essentially of" that feature.

[0369] The foregoing description of specific embodiments sufficiently clarifies the general nature of the present invention so that others, by applying knowledge within the skill of the art, can readily modify and / or adapt such specific embodiments for various uses without undue experimentation and without departing from the general concept of the present invention. Such adaptations and modifications are therefore intended to be within the meaning and range of equivalents of the disclosed embodiments, based on the teaching and guidance presented herein. It is to be understood that the phrases or terminology herein are intended to be descriptive rather than limiting, as the terms or phrases herein would be interpreted by one of ordinary skill in the art in light of the teaching and guidance.

[0370] The breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments.

[0371] All of the various aspects, embodiments, and options described herein can be combined in any and all variations.

[0372] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. If the meaning or definition of a term in this document conflicts with the meaning or definition of the same term in a document incorporated by reference, the meaning or definition assigned to that term in this document shall control.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt or ester thereof, During the ceremony, D is a residue of a ligand for a membrane-bound protein such as a GPCR, preferably D is a residue of a GPR40 agonist; q is an integer from 1 to 10, preferably 1 or 2; L A is a hydrophobic linker, and T A is a group characterized as having one or more (e.g., 1, 2, or 3) hydrophilic polar groups, preferably T A is a group characterized as having one or more (e.g., 1, 2, or 3) charged groups, e.g., one or more quaternary amines, one or more carboxylic acids, one or more phosphoric acids, and / or one or more sulfonic acids; The compound is an optionally charge-balanced compound of Formula I or a pharmaceutically acceptable salt or ester thereof.

2. 2. The compound of claim 1, or a pharmaceutically acceptable salt or ester thereof, wherein q is 1.

3. T A L A wherein (1) if the terminal atom is an N of a basic primary or secondary amine group, the corresponding compound T A -(C(O)-CH 3 ) q has a cLogP less than 0, preferably less than -1, and -C(O)-CH 3 is bonded to the terminal N atom, and (2) when the terminal atom is N of a basic tertiary amine group, the corresponding compound [T A -CH 3 ] + has a cLogP less than 0, preferably less than -1, and -CH 3 is bonded to the terminal N atom, and (3) if the terminal atom is C in 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 (4) 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 (5) if (1) to (4) do not apply, the corresponding compound T A -H q 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt or ester thereof, having a cLogP of less than 1.

4. T A L A wherein the terminal N atom is an N atom of a basic primary or secondary amine group, and the corresponding compound T A -(C(O)-CH 3 ) q has a cLogP less than 0, preferably less than -1, and -C(O)-CH 3 is attached to the terminal N atom, or a pharmaceutically acceptable salt or ester thereof.

5. T A L A wherein the terminal N atom is an N atom of a basic tertiary amine group, and the corresponding compound [T A -CH 3 ] + has a cLogP less than 0, preferably less than -1, and -CH 3 is attached to the terminal N atom, or a pharmaceutically acceptable salt or ester thereof.

6. 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 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 6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt or ester thereof, wherein -H has a cLogP of at least 3.

7. L A where only one terminal atom is C in C(O) or S in SO2 group, the corresponding compound HL A 6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or ester thereof, wherein -OH has a cLogP of at least 3, preferably at least 4, and -OH is bonded to a C(O) or SO group.

8. T A and the terminal atoms of L A or a pharmaceutically acceptable salt or ester thereof, according to claims 1 to 7, wherein the covalent bond between the first terminal atom of

9. 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

10. 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 -, preferably at least -(CH 2 ) 14 -, more preferably at least -(CH 2 ) 16 10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt or ester thereof, characterized in that the maximum length between the two terminal carbon atoms is -.

11. L A L A The maximum length between the two terminal atoms of (i)-(CH 2 ) 12 -, and (ii) -(CH 2 ) 50 - the maximum length between the two terminal carbon atoms of the compound or its pharmaceutically acceptable salt or ester according to any one of claims 1 to 9.

12. T A has a formula according to M-1 or M-2, During the ceremony, L in each occurrence B and L C each independently represents a divalent group; In M-1, (i)G A and G B is hydrogen or C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, or a 3- to 14-membered ring, each of which is optionally substituted; G A and G B the other of which is a moiety having the structure M-2, M-3, or M-4 as defined in this claim; or (ii) G A and G B are joined together with the nitrogen atom to which they are both attached to form an optionally substituted 4- to 14-membered ring; or (iii) G A and G B each independently represents a moiety having the structure M-2, M-3, or M-4 as defined in this claim; In M-2, (i)G A1 , G B1 , and G C1 are each independently 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, a 3- to 14-membered ring, or a structure of M-3 or M-4; C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 each of the alkynyl and 3- to 14-membered ring is optionally substituted; (ii) G A1 and G B1 are joined together with the nitrogen atom to which they are both attached to form an optionally substituted 4- to 14-membered ring, and G C1 is as defined in (i), or (iii) G A1 , G B1 , and G C1 are joined together with the nitrogen atom to which they are all attached to form an optionally substituted 5- to 14-membered ring; M-3 is having the structure M-4 is having the structure where: L D is null or represents a divalent group, A represents a moiety having an anionic group or its conjugate acid, and preferably the anionic group is COO - , SO 3 - , HPO 3 - or P.O. 3 2- is selected from 12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt or ester thereof, wherein Cat represents a moiety having a cationic group that is positively charged regardless of pH or capable of being positively charged at pH 7, preferably the cationic group is a quaternary amine.

13. T A has a formula according to M-1, and G A and G B One of the two is hydrogen or C 1-4 is alkyl, G A and G B or a pharmaceutically acceptable salt or ester thereof.

14. L B The compound according to claim 12 or 13, or a pharmaceutically acceptable salt or ester thereof, wherein is null.

15. L B is C 1-6 alkylene or C having 1 or 2 heteroatoms independently selected from N, O, P, and S 1-6 14. The compound of claim 12 or 13, or a pharmaceutically acceptable salt or ester thereof, wherein P is heteroalkylene and P or S is optionally oxidized.

16. T A 13. The compound of claim 12, or a pharmaceutically acceptable salt or ester thereof, having the formula according to M-2:

17. G A1 and G B1 are joined together with the nitrogen atom to which they are both attached to form an optionally substituted 3- to 14-membered ring, and G C1 is C 1-4 alkyl, for example, 17. The compound according to any one of claims 12 to 16, wherein:

18. G A1 , G B1 , and G C1 may be joined together with the nitrogen atom to which they are all attached to form an optionally substituted 5- to 14-membered ring, preferably a fused or bridged bicyclic ring, such as 17. The compound according to any one of claims 12 to 16, wherein:

19. L C is null, or a pharmaceutically acceptable salt or ester thereof.

20. L C is C 1-6 alkylene or C having 1 or 2 heteroatoms independently selected from N, O, P, and S 1-6 19. The compound of any one of claims 12 to 18, or a pharmaceutically acceptable salt or ester thereof, wherein P is heteroalkylene and P or S is optionally oxidized.

21. M-2 is or M-2 represents [N(CH 3 ) 3 ] + , or [N(CH 2 CH 3 ) 3 ] + or a pharmaceutically acceptable salt or ester thereof.

22. T A teeth, or T A teeth and Cat represents [N(CH 3 ) 3 ] + , or [N(CH 2 CH 3 ) 3 ] + 12. The compound according to any one of claims 1 to 11, wherein:

23. T A represents one of the following structures: T A teeth, represents, or T A teeth, [N(CH 3 ) 3 ] + 、N(CH 2 CH 3 ) 3 ] + 、 or a pharmaceutically acceptable salt or ester thereof.

24. L A (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 24. The compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt or ester thereof, wherein m is 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.

25. L A Ha-(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 C(O) or SO 2 and 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 24. The compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt or ester thereof, characterized in that -COOH has a cLogP of at least 3, for example between 3 and 15, preferably at least 4.

26. X in each occurrence independently represents a CR 2 , -C(R)=C(R)-, or a 3- to 10-membered ring, and R in each occurrence is independently hydrogen or C 1-4 alkyl, and more preferably, X at each occurrence is independently CR 2 and R in each occurrence is independently hydrogen or C 1-4 26. The compound of claim 24 or 25, or a pharmaceutically acceptable salt or ester thereof, wherein:

27. L A -C 12-30 Alkylene- or -C 12-30 alkylene-C(O)-, where -C 12-30 24. The compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt or ester thereof, wherein alkylene- is optionally substituted, and said optional substituents can optionally be joined together to form a double bond, a triple bond, or a ring structure.

28. 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, wherein the sulfur atom, if present, is optionally oxidized, and wherein any substituents can be optionally joined to form a double bond, a triple bond, or a ring structure, or a pharmaceutically acceptable salt or ester thereof.

29. D is a residue having the formula D-1: 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 29. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt or ester thereof, wherein: is an optionally substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl ring.

30. 30. The compound of claim 29, or a pharmaceutically acceptable salt or ester thereof, wherein p1 is 0.

31. p1 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 31. The compound of claim 29 or 30, or a pharmaceutically acceptable salt or ester thereof, which is alkoxy.

32. 32. The compound of any one of claims 29 to 31, or a pharmaceutically acceptable salt or ester thereof, wherein p2 is 0.

33. p2 is 1 or 2, and R in each occurrence B are independently F, OH, and 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 32. The compound of any one of claims 29 to 31, or a pharmaceutically acceptable salt or ester thereof, which is alkoxy.

34. D has the formula according to D-1-A: In the formula, R 10 is hydrogen or C 1-4 30. The compound of claim 29, or a pharmaceutically acceptable salt or ester thereof, which is alkyl (preferably methyl).

35. J 1 is an optionally substituted 4-12 membered heterocycle having one or two ring nitrogen atoms, or a pharmaceutically acceptable salt or ester thereof.

36. J 1 is a 4-8 membered optionally substituted monocyclic saturated heterocycle having 1 or 2 ring heteroatoms independently selected from S, O, and N, with the proviso that at least one of the ring heteroatoms is nitrogen, or a pharmaceutically acceptable salt or ester thereof.

37. J 1 is selected from the following: 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 37. The compound of claim 36, or a pharmaceutically acceptable salt or ester thereof, optionally substituted with 1 to 2 substituents independently selected from alkoxy.

38. J 1 is 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, with the proviso that at least one of the ring heteroatoms is nitrogen, or a pharmaceutically acceptable salt or ester thereof.

39. J 2 is a straight or branched C optionally substituted with 1 to 3 fluorines 1-4 39. The compound of any one of claims 29 to 38, or a pharmaceutically acceptable salt or ester thereof, which is alkylene.

40. J 2 is CH 2 or -CH(CH 3 40. The compound of any one of claims 29 to 39, wherein:

41. J 3 is an aryl or heteroaryl ring, each of which is unsubstituted or substituted with one or more (e.g., 1, 2, or 3) substituents independently selected from the following 1) and 2): 1) halogen, CN, -CF 3 , 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- to 8-membered heterocycloalkyl having 1 or 2 ring heteroatoms independently selected from N, O, and S, each of which is optionally substituted with one or more (e.g., 1, 2, or 3) substituents, such as F, —OH, protected hydroxyl, oxo (if applicable), NH 2 , protected amino, NH(C 1-4 alkyl) or its protected derivatives, N(C 1-4 Alkyl ((C 1-4 alkyl), C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 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, cycloalkoxy, phenyl, heteroaryl, and heterocyclyl is independently selected from 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 41. The compound of any one of claims 29 to 40, or a pharmaceutically acceptable salt or ester thereof, optionally substituted with 1, 2, or 3 substituents independently selected from alkoxy.

42. J 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 a phenyl ring substituted with 1 to 3 substituents independently selected from alkyl, heteroalkyl, cycloalkyl, alkoxy, or cycloalkoxy, wherein the alkyl, heteroalkyl, cycloalkyl, alkoxy, or cycloalkoxy is optionally substituted with one or more (e.g., 1, 2, or 3) substituents, the substituents being F, —OH, C optionally substituted with F, 1-4 Alkoxy, oxo (where applicable), NH 2 , NH(C 1-4 alkyl), N(C 1-4 Alkyl ((C 1-4 alkyl), C optionally substituted with F 1-4 42. The compound of any one of claims 29 to 41, or a pharmaceutically acceptable salt or ester thereof, wherein:

43. J 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 a 5-10 membered monocyclic or bicyclic heteroaryl ring substituted with 1 to 3 substituents independently selected from cycloalkoxy, wherein said alkyl, heteroalkyl, cycloalkyl, alkoxy, or cycloalkoxy is optionally substituted with one or more (e.g., 1, 2, or 3) substituents, said substituents being F, —OH, C optionally substituted with F. 1-4 Alkoxy, oxo (where applicable), NH 2 , NH(C 1-4 alkyl), N(C 1-4 Alkyl ((C 1-4 alkyl), C optionally substituted with F 1-4 42. The compound of any one of claims 29 to 41, or a pharmaceutically acceptable salt or ester thereof, wherein:

44. J 3 is selected from the following: In 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 and optionally substituted with 1 to 3 substituents independently selected from alkyl, heteroalkyl, cycloalkyl, alkoxy, or cycloalkoxy, wherein said alkyl, heteroalkyl, cycloalkyl, alkoxy, or cycloalkoxy is optionally substituted with one or more (e.g., 1, 2, or 3) substituents, and said substituents are selected from 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), C optionally substituted with F 1-4 42. The compound of any one of claims 29 to 41, or a pharmaceutically acceptable salt or ester thereof, wherein:

45. J 3 is selected from the following: Each of these 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 and optionally substituted with 1 to 3 substituents independently selected from alkyl, heteroalkyl, cycloalkyl, alkoxy, or cycloalkoxy, wherein said alkyl, heteroalkyl, cycloalkyl, alkoxy, or cycloalkoxy is optionally substituted with one or more (e.g., 1, 2, or 3) substituents, and said substituents are selected from C optionally substituted with F, —OH, —C 1-4 Alkoxy, oxo (where applicable), NH 2 , NH(C 1-4 alkyl), N(C 1-4 Alkyl ((C 1-4 alkyl), C optionally substituted with F 1-4 42. The compound of any one of claims 29 to 41, or a pharmaceutically acceptable salt or ester thereof, wherein:

46. J 3 is selected from the following: Each of these is optionally substituted with F, Cl, CN, OH, F 1-6 Alkyl (e.g., CF 3 ), cyclopropyl, cyclobutyl, C optionally substituted with F 1-6 Alkoxy (e.g., -O-CF 3 ), or C 3-6 46. ​​The compound of claim 45, or a pharmaceutically acceptable salt or ester thereof, optionally substituted with 1 to 3 substituents independently selected from cycloalkoxy.

47. D is characterized as having a structure according to formula D-1-A-1, D-1-A-2, D-1-A-3, D-1-A-4, or D-1-A-5: During the ceremony, R 20 is C 1-6 Alkyl or Fluoro 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 Fluoro Substituted C 1-6 Alkyl or C 3-6 30. The compound of claim 29, or a pharmaceutically acceptable salt or ester thereof, which is cycloalkyl.

48. D is characterized as having a structure according to formula D-1-A-6, D-1-A-7, D-1-A-8, D-1-A-9, or D-1-A-10: During the ceremony, R 20 is C 1-6 Alkyl or Fluoro 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 Fluoro Substituted C 1-6 Alkyl or C 3-6 30. The compound of claim 29, or a pharmaceutically acceptable salt or ester thereof, which is cycloalkyl.

49. D is a residue having the formula D-2-A or D-2-B: 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, p2 is 0, 1, 2, or 3, and R 13 29. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt or ester thereof, wherein: is hydrogen, optionally substituted phenyl, or optionally substituted heteroaryl.

50. 50. The compound of claim 49, wherein D is a residue having the formula D-2-A-1 or D-2-B-1, or a pharmaceutically acceptable salt or ester thereof:

51. L N is (i) empty (null), (ii) (L A (The symbol is shown to indicate the linkage direction) 1-6 alkylene, or (iii) (L A Branched or linear C alkyl groups with one or two oxygen atoms, such as 1-6 51. The compound of claim 49 or 50, or a pharmaceutically acceptable salt or ester thereof, which is heteroalkylene.

52. L N teeth, where G in each occurrence A10 are independently hydrogen or optionally substituted C 1-4 alkyl, or two G A10 are linked to form a 3- to 6-membered ring such as a cyclopropyl or cyclobutyl ring, and preferably, G in each occurrence A10 is methyl and G in each occurrence B10 are independently hydrogen or optionally substituted C 1-4 alkyl, or two G B10 or one G A10 and one G B10 are linked to form a 3- to 6-membered ring, such as a cyclopropyl or cyclobutyl ring, or a pharmaceutically acceptable salt or ester thereof.

53. p1 is 0 or p1 is 1, and 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 53. The compound of any one of claims 49 to 52, or a pharmaceutically acceptable salt or ester thereof, which is alkoxy.

54. 54. The compound of any one of claims 49 to 53, or a pharmaceutically acceptable salt or ester thereof, wherein p2 is 0.

55. 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 54. The compound of any one of claims 49 to 53, or a pharmaceutically acceptable salt or ester thereof, which is alkoxy.

56. 56. The compound of any one of claims 49 to 55, or a pharmaceutically acceptable salt or ester thereof, wherein Y is CH.

57. 57. The compound of any one of claims 49 to 56, or a pharmaceutically acceptable salt or ester thereof, wherein Z is O.

58. R 11 and R 12 or a pharmaceutically acceptable salt or ester thereof.

59. 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 said alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heteroaryl, and heterocyclyl is optionally substituted with 1, 2, or 3 substituents, said substituents being F, —OH, oxo (if 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 R is 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, or a pharmaceutically acceptable salt or ester thereof.

60. R 13 is a phenyl ring, unsubstituted or substituted with 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 said alkyl, heteroalkyl, cycloalkyl, alkoxy, or cycloalkoxy is optionally substituted with one or more (e.g., 1, 2, or 3) substituents, and said substituents are selected from the group consisting of F, —OH, C optionally substituted with F, —C 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 60. The compound of any one of claims 49 to 59, or a pharmaceutically acceptable salt or ester thereof, wherein:

61. R 13 is a 6-membered heteroaryl ring, such as a pyridyl ring, which is unsubstituted or is 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 said alkyl, heteroalkyl, cycloalkyl, alkoxy, or cycloalkoxy is optionally substituted with one or more (e.g., 1, 2, or 3) substituents, and said substituents are selected from the group consisting of F, —OH, C optionally substituted with F, —C 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 60. The compound of any one of claims 49 to 59, or a pharmaceutically acceptable salt or ester thereof, wherein:

62. D has a structure according to formula D-2-A-2 or formula D-2-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 said alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heteroaryl, and heterocyclyl is optionally substituted with 1, 2, or 3 substituents, said substituents being F, —OH, oxo (if 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 R is 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, 53. The compound of any one of claims 49 to 52, or a pharmaceutically acceptable salt or ester thereof, wherein p3 is 0, 1, 2, or 3.

63. R 16 and R 17 are both hydrogen or R 16 and R 17 is hydrogen and R 16 and R 17 or a pharmaceutically acceptable salt or ester thereof.

64. 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 64. The compound of claim 62 or 63, or a pharmaceutically acceptable salt or ester thereof, which is cycloalkyl.

65. R 14 and R 15 is combined to C 3-6 64. The compound of claim 62 or 63, or a pharmaceutically acceptable salt or ester thereof, which forms a cycloalkyl.

66. 53. The compound of any one of claims 49-52, wherein D has a structure according to formula D-2-A-3 or D-2-B-3, or a pharmaceutically acceptable salt or ester thereof:

67. D has a structure according to formula D-3-A or D-3-B: 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, p2 is 0, 1, 2, or 3, and R 18 29. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt or ester thereof, wherein: is optionally substituted phenyl or optionally substituted heteroaryl.

68. 68. The compound of claim 67, wherein D has a structure according to formula D-3-A-1 or D-3-B-1, or a pharmaceutically acceptable salt or ester thereof:

69. L N is either (i) empty (null), or (ii) (L A (The symbol is shown to indicate the linkage direction) 1-6 69. The compound of claim 67 or 68, or a pharmaceutically acceptable salt or ester thereof, which is alkylene.

70. L N teeth where G in each occurrence A10 are independently hydrogen or optionally substituted C 1-4 alkyl, or two G A10 are linked to form a 3- to 6-membered ring such as a cyclopropyl or cyclobutyl ring, and preferably, G in each occurrence A10 69. The compound of claim 67 or 68, or a pharmaceutically acceptable salt or ester thereof, wherein is methyl.

71. p1 is 0 or p1 is 1, and 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 71. The compound of any one of claims 67 to 70, or a pharmaceutically acceptable salt or ester thereof, which is alkoxy.

72. 72. The compound of any one of claims 67 to 71, or a pharmaceutically acceptable salt or ester thereof, wherein p2 is 0.

73. 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 73. The compound of any one of claims 67 to 72, or a pharmaceutically acceptable salt or ester thereof, which is alkoxy.

74. 74. The compound of any one of claims 67 to 73, or a pharmaceutically acceptable salt or ester thereof, wherein Y is N.

75. 75. The compound of any one of claims 67 to 74, or a pharmaceutically acceptable salt or ester thereof, wherein Z is O.

76. R 11 and R 12 and n is 0 or 1; and n is 1 or 2. The compound of any one of claims 67 to 75, or a pharmaceutically acceptable salt or ester thereof, wherein

77. L 10 teeth and CR 16 R 17 is bonded to the COOH group, where: 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 said alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heteroaryl, and heterocyclyl is optionally substituted with 1, 2, or 3 substituents, said substituents being F, —OH, oxo (if 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 R is 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, or a pharmaceutically acceptable salt or ester thereof.

78. R 18 represents a 6-membered heteroaryl ring, e.g., and 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 said alkyl, heteroalkyl, cycloalkyl, alkoxy, or cycloalkoxy is optionally substituted with one or more (e.g., 1, 2, or 3) substituents, and said substituents are selected from 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 78. The compound of any one of claims 67 to 77, or a pharmaceutically acceptable salt or ester thereof, wherein:

79. 79. The compound of any one of claims 67 to 78, or a pharmaceutically acceptable salt or ester thereof, wherein Ring A 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.

80. 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 80. The compound of claim 79, or a pharmaceutically acceptable salt or ester thereof, optionally substituted with 1 to 2 substituents independently selected from alkoxy.

81. 79. The compound of any one of claims 67-78, or a pharmaceutically acceptable salt or ester thereof, wherein Ring A is a bicyclic or polycyclic 6-12 membered optionally substituted saturated heterocycle having 1 or 2 ring heteroatoms independently selected from S, O, and N, with the proviso that at least one of the ring heteroatoms is nitrogen.

82. D has a structure according to formula D-3-A-2 or D-3-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 said alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heteroaryl, and heterocyclyl is optionally substituted with 1, 2, or 3 substituents, said substituents being F, —OH, oxo (if 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 R is 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, 80. The compound of any one of claims 67 to 79, or a pharmaceutically acceptable salt or ester thereof, wherein p3 is 0, 1, 2, or 3.

83. R 16 and R 17 are both hydrogen or R 16 and R 17 is hydrogen and R 16 and R 17 or a pharmaceutically acceptable salt or ester thereof.

84. 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 84. The compound of claim 82 or 83, or a pharmaceutically acceptable salt or ester thereof, which is cycloalkyl.

85. R 14 and R 15 is combined to C 3-6 84. The compound of claim 82 or 83, or a pharmaceutically acceptable salt or ester thereof, which forms a cycloalkyl.

86. 71. The compound of any one of claims 67-70, wherein D has a structure according to formula D-3-A-3 or D-3-B-3, or a pharmaceutically acceptable salt or ester thereof:

87. A compound selected from any of the compounds in Table 1 herein, or a compound according to Examples 1-36 herein, or a pharmaceutically acceptable salt or ester thereof.

88. 88. A pharmaceutical composition comprising a compound according to any one of claims 1 to 87 or a pharmaceutically acceptable salt or ester thereof, and optionally a pharmaceutically acceptable carrier.

89. 88. A method for treating or preventing a disorder, condition, or disease responsive to agonism of G protein-coupled receptor 40 in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 87 or a pharmaceutically acceptable salt or ester thereof, or a pharmaceutical composition of claim 88.

90. 89. A method of treating type 2 diabetes mellitus in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 87 or a pharmaceutically acceptable salt or ester thereof, or a pharmaceutical composition of claim 88.

91. 91. The method of claim 89 or 90, further comprising administering to the subject one or more additional therapeutic agents.

92. 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 agonist, an 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 / 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, GPR11 9 agonists, TGR5 agonists, SSTR2 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 antibodies or inhibitors, ANGPTL3 / 8 antibodies, ANGP 92. The method of claim 91, wherein the therapeutic agent is selected from the group consisting of: (i) a TL4 inhibitor, oxyntomodulin, (ii) an anti-amyloid beta antibody, (iii) an anti-inflammatory drug, including but not limited to a PDE4 inhibitor, a JAK inhibitor, a TYK2 inhibitor, an S1P receptor modulator, an NLRP3 inhibitor, a BTK inhibitor, an IRAK1 inhibitor, an IRAK4 inhibitor, a glucocorticoid, an anti-TNFα antibody, an anti-IL-12 / IL-23 antibody, and (iv) an anti-integrin antibody or a small molecule inhibitor of an integrin, including α4β7, α4, β7, MAdCAM-1, αvβ6, and αvβ1.

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