G protein-coupled receptor modulators

Abstract

To provide a compound that acts as an agonist at a GLP-1 receptor.SOLUTION: This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt and / or hydrate and / or a prodrug of the compound) that modulate (e.g., agonize or partially agonize or antagonize) a glucagon-like peptide-1 receptor ("GLP-1R") and / or a gastric inhibitory polypeptide receptor ("GIPR"). The chemical entities are useful, e.g., for treating a subject (e.g., a human) having a disease, a disorder, or a condition in which modulation (e.g., agonism, partial agonism or antagonism) of GLP-1R and / or GIPR activities is beneficial for the treatment or prevention of the underlying pathology and / or symptoms and / or progression of the disease, the disorder, or the condition.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Claim of priority This application claims the benefit of U.S. Provisional Application No. 62 / 647,604, filed March 23, 2018, which is incorporated herein by reference in its entirety.

[0002] Sequence List This application includes a sequence listing, which has been submitted electronically in ASCII format and is incorporated herein by reference in its entirety. The ASCII copy, created on March 22, 2019, is named 41517-0002WO1_SL.txt and has a size of 39,811 bytes.

[0003] Technical field This disclosure features chemical entities (e.g., compounds, or pharmaceutically acceptable salts and / or hydrates and / or prodrugs) that modulate (e.g., stimulate, partially stimulate, or antagonize) the glucagon-like peptide 1 receptor ("GLP-1R") and / or gastric suppressor polypeptide receptor ("GIPR"). These chemical entities are useful, for example, for treating subjects (e.g., humans) having a disease, disorder, or condition, where the modulation (e.g., agonism, partial agonism, or antagonism) of GLP-1R and / or GIPR activity is beneficial for treating or preventing the underlying pathophysiology and / or symptoms and / or progression of the disease, disorder, or condition. In some embodiments, the modulation improves (e.g., increases) the current level (e.g., normal level or below normal level) of GLP-1R and / or GIPR activity (e.g., signaling). In some embodiments, the chemical entities described herein further modulate (e.g., attenuate, uncouple) β-arrestin signaling relative to that observed with the natural ligand. This disclosure also features compositions, as well as other methods for using and preparing the chemical entities. [Background technology]

[0004] background Type 2 diabetes mellitus (Type 2 diabetes) is characterized by high blood glucose levels and insulin resistance. In the United States alone, tens of millions of people have Type 2 diabetes or conditions that are complications or sequelae of Type 2 diabetes. In many cases, Type 2 diabetes is associated with obesity.

[0005] Non-alcoholic steatohepatitis (NASH) is inflammation and damage of the liver caused by fat accumulation in the liver. It is part of a group of conditions called non-alcoholic fatty liver disease (NAFLD). NASH and NAFLD tend to occur in patients with one of the following risk factors: obesity, dyslipidemia, and impaired glucose tolerance, and appear to be associated with insulin resistance (as with obesity or metabolic syndrome, for example).

[0006] Incretin hormones are hormones that control blood glucose in response to food intake. Gastric suppressor polypeptide ("GIP") and glucagon-like peptide 1 ("GLP-1") are primary incretin hormones secreted from L cells and K cells, respectively, in the small intestine upon ingestion of glucose or nutrients, in order to stimulate insulin secretion from pancreatic β cells. GIP and GLP-1 are rapidly degraded by dipeptidyl peptidase 4 (DPP-4) and lose their biological activity (see, for example, Y. Sieno, et. al, Journal of Diabetes Investigation 2013, 4, 108-130 (Non-Patent Literature 1)).

[0007] The actions of GIP and GLP-1 are thought to be mediated by their specific receptors, the GIP receptor (GIPR) and the GLP-1 receptor (GLP-1R), respectively. Both receptors belong to the G protein-coupled receptor family and are expressed in pancreatic β-cells as well as in various tissues and organs. GLP-1 activity includes, but is not limited to, stimulation of insulin synthesis and secretion, inhibition of glucagon secretion, and inhibition of food intake. GIP activity includes, but is not limited to, stimulation of glucose-dependent insulin secretion, increase in β-cell volume, stimulation of glucagon secretion, and decrease in gastric acid secretion. See, for example, WO 2016 / 131893 (Patent Document 1).

[0008] GLP-1 and GLP-1 analogs that act as agonists at the GLP-1 receptor have been shown to be effective in controlling blood glucose levels, for example, in type 2 diabetes. See, for example, WO 2016 / 131893. In addition to their insulin secretion effects, GIP and GLP-1 are thought to be involved in various biological processes in different tissues and organs that express GIPR and GLP-1R, including, for example, the pancreas, fat, bone, brain, heart, kidney, eye, nerve, and liver. For example, studies using mice lacking GIPR and / or GLP-1R, as well as mice lacking DPP-4, have shown that GIP and GLP-1 are involved in diverse biological activities. The results of these studies suggest that GIP and GLP-1 are involved in the treatment and / or prevention of diabetes-related microvascular complications (e.g., retinopathy, nephropathy, and neuropathy) and macrovascular complications (e.g., coronary artery disease, peripheral artery disease, and cerebrovascular disease), as well as diabetes-related comorbidities (e.g., obesity, non-alcoholic fatty liver disease, fractures, and cognitive impairment). See, for example, page 108 of Sieno. [Prior art documents] [Patent Documents]

[0009] [Patent Document 1] WO 2016 / 131893 [Non-patent literature]

[0010] [Non-Patent Document 1] Y. Sieno, et. al, Journal of Diabetes Investigation 2013, 4, 108-130 [Overview of the project]

[0011] overview This disclosure features chemical entities (e.g., compounds, or pharmaceutically acceptable salts and / or hydrates and / or prodrugs) that modulate (e.g., stimulate, partially stimulate, or antagonize) the glucagon-like peptide 1 receptor ("GLP-1R") and / or gastric suppressor polypeptide receptor ("GIPR"). These chemical entities are useful, for example, for treating subjects (e.g., humans) having a disease, disorder, or condition, where the modulation (e.g., agonism, partial agonism, or antagonism) of GLP-1R and / or GIPR activity is beneficial for treating or preventing the underlying pathophysiology and / or symptoms and / or progression of the disease, disorder, or condition. In some embodiments, the modulation improves (e.g., increases) the current level (e.g., normal level or below normal level) of GLP-1R and / or GIPR activity (e.g., signaling). In some embodiments, the chemical entities described herein further modulate (e.g., attenuate, uncouple) β-arrestin signaling relative to that observed with the natural ligand. This disclosure also features compositions, as well as other methods for using and preparing the chemical entities.

[0012] GLP-1R "agonists" include compounds that directly bind to or modify GLP-1R at the protein level, such that GLP-1R activity is increased compared to GLP-1R activity in the absence of the ligand, for example, by activation, stabilization, alteration of distribution, or in other ways.

[0013] Certain compounds described herein (partial agonists) that stimulate GLP-1R to a smaller degree than a complete GLP-1R agonist (e.g., natural GLP-1) may function as antagonists and agonists in assays. These compounds antagonize the activation of GLP-1R by a complete GLP-1R agonist by preventing the full effect of the GLP-1R interaction. However, these compounds also activate some GLP-1R activity on their own, usually in smaller amounts than the corresponding GLP-1R complete agonist. These compounds are sometimes referred to herein as “GLP-1R partial agonists.”

[0014] GLP-1R "antagonists" include compounds that directly bind to or modify GLP-1R at the protein level such that GLP-1R activity is reduced compared to GLP-1R activity in the absence of the ligand, for example, by inhibiting, blocking, or attenuating the agonist-mediated response, altering its distribution, or otherwise.

[0015] In some embodiments, the compounds described herein are agonists (e.g., complete agonists) of GLP-1R. In other embodiments, the compounds described herein are partial agonists or antagonists of GLP-1R.

[0016] GIPR "agonists" include compounds that directly bind to or modify GIPR at the protein level such that GIPR activity is increased compared to GIPR activity in the absence of the ligand, for example, by activation, stabilization, alteration of distribution, or in other ways.

[0017] Certain compounds described herein that stimulate GIPR to a smaller degree than natural GIP (a complete agonist) may function as both antagonists and agonists. These compounds are partial antagonists because they reduce the activation of GIPR by natural GIP, thereby diminishing the complete effect of natural GIP. However, these compounds also activate some GIPR activity on their own, usually in amounts less than the corresponding amount of natural GIP. These compounds may be referred to herein as “GIPR partial agonists.”

[0018] GIPR "antagonists" include compounds that directly bind to or modify GIPR at the protein level such that GIPR activity is reduced compared to GIPR activity in the absence of the ligand, for example, by inhibiting, blocking, or attenuating the agonist-mediated response, altering its distribution, or otherwise.

[0019] In some embodiments, the compounds described herein are agonists (e.g., complete agonists) of GIPR. In other embodiments, the compounds described herein are partial agonists of GIPR. In yet another embodiment, the compounds described herein are antagonists of GIPR.

[0020] In some embodiments, the compounds described herein are complete agonists of both GLP-1R and GIPR. In some embodiments, the compounds described herein are partial agonists of both GLP-1R and GIPR. The disclosure also assumes a chemical entity that (i) stimulates one of GLP-1R and GIPR (e.g., GLP-1R); and antagonizes the other of GLP-1R and GIPR (e.g., GIPR). For example, the disclosure assumes a chemical entity that (i) completely stimulates one of GLP-1R and GIPR (e.g., GLP-1R); and partially stimulates or antagonizes the other of GLP-1R and GIPR (e.g., GIPR). In certain embodiments, the chemical entity is a complete agonist of GLP-1R and a partial agonist or antagonist of GIPR; or a partial agonist or antagonist of GLP-1R and a complete agonist of GIPR.

[0021] Generally, receptors exist in both an active (Ra) and an inactive (Ri) conformation. Certain compounds that affect receptors can alter the Ra / Ri ratio. For example, a full agonist increases the Ra / Ri ratio and can cause a "maximal" saturation effect. A partial agonist, upon binding to the receptor, gives a lower response than a full agonist (e.g., an endogenous agonist). Therefore, the Ra / Ri ratio of a partial agonist is smaller than that of a full agonist. However, the potency of a partial agonist may or may not be greater than that of a full agonist.

[0022] In some embodiments, the chemical entities described herein further modulate (e.g., reduce, attenuate, interfere with, or inhibit) β-arrestin coupling and / or β-arrestin signaling, as well as the internal translocation of GLP-1R and / or GIPR. In certain embodiments, the chemical entities described herein modulate (e.g., reduce, attenuate, interfere with, or inhibit) β-arrestin recruitment to G protein-coupled receptors (e.g., GLP-1R). In certain embodiments, the chemical entities described herein modulate (e.g., reduce, attenuate, interfere with, or inhibit) the formation (e.g., "coupling") of a complex (e.g., a signaling complex) between β-arrestin and a G protein-coupled receptor (e.g., GLP-1R or GIPR). The effects of the chemical entities described herein on β-arrestin signaling and related downstream processes (e.g., processes described above) can be evaluated using conventional methods, such as the PathHunter β-arrestin assay for determining β-arrestin coupling (see the Examples section). For example, β-arrestin (GLP-1R) EC50 values ​​of less than 1 μM in the above assay indicate compounds that induce β-arrestin recruitment to GLP-1R. GLP-1, the natural ligand of GLP-1R, and its therapeutic analog, such as liraglutide, are potent recruiters of β-arrestin. Another example is β-arrestin (GLP-1R) EC50 values ​​greater than 1 μM (e.g., greater than 10 μM). 50The values ​​indicate compounds that do not substantially induce β-arrestin recruitment to GLP-1R. Therapeutic agents that modulate G protein-coupled receptors (e.g., GLP-1R and / or GIPR) can produce a range of effects on β-arrestin-based signaling that depend on the degree of cAMP activation. β-arrestin coupling has been shown to be a key trap in receptor internalization and subsequent desensitization and attenuation of signaling. Both GLP-1 (and liraglutide analogues) and GIP have been shown to induce rapid receptor internalization. Therefore, compounds that activate cAMP signaling of GLP-1R and / or GIPR but are not substantially coupled with β-arrestin show the potential to prolong receptor signaling and extend pharmacological benefits. In some embodiments, the chemical entities described herein exhibit relatively potent GLP-1R and / or GIPR-mediated cAMP activation with minimal or undetectable β-arrestin coupling. In some embodiments, the chemical entities described herein exhibit relatively potent GLP-1R-mediated cAMP activation with minimal or undetectable β-arrestin conjugation and little to no GIPR-mediated cAMP activation.

[0023] In some embodiments, the compounds described herein exhibit reduced activity in rodent aversion models while maintaining relatively high potency in glucose clearance assays. Aversion models, such as conditioned taste aversion, are commonly used to identify compounds that exhibit adverse effects such as nausea. Nausea inducers such as Exendin-4 and liraglutide are known to exhibit potent signals in conditioned taste aversion models. Therefore, advantageously, some of the chemical entities described herein are expected to exhibit a reduced likelihood of causing undesirable side effects, such as nausea, while maintaining their full pharmacological benefits when administered to patients.

[0024] Therefore, in one aspect, the present disclosure features peptide-based chemical entities (e.g., N-protected peptide-based chemical entities; e.g., peptide-based chemical entities having 30-50 amino acids, 30-45 amino acids, 30-40 amino acids, 35-40 amino acids; e.g., N-protected peptide-based chemical entities having 30-50 amino acids, 30-45 amino acids, 30-40 amino acids, 35-40 amino acids). As described herein, the peptide-based chemical entities modulate (e.g., stimulate, partially stimulate, or antagonize) the glucagon-like peptide 1 receptor ("GLP-1R") and / or gastric suppressor polypeptide receptor ("GIPR"), and further, optionally, modulate (e.g., uncouple, attenuate) β-arrestin signaling and / or aversion.

[0025] In some embodiments, peptide-based chemical entities stimulate or partially stimulate GLP-1R.

[0026] In some embodiments, peptide chemical entities stimulate, partially stimulate, or antagonize GIPR.

[0027] In some embodiments, the peptide chemical entity reduces (e.g., uncouples, attenuates, or inhibits) β-arrestin signaling, reduces (e.g., uncouples, attenuates, or inhibits) the recruitment of β-arrestin to G protein-coupled receptors (e.g., GLP-1R), and reduces (e.g., attenuates, interferes with, or inhibits) the formation of a complex (e.g., a signaling complex) between β-arrestin and a G protein-coupled receptor (e.g., GLP-1R).

[0028] In certain embodiments, peptide-based chemical entities • Stimulate or partially stimulate GLP-1R; • To stimulate, partially stimulate, or antagonize GIPR; • Reduce β-arrestin signaling (e.g., uncoupling, attenuating, inhibiting), reduce β-arrestin recruitment to G protein-coupled receptors (e.g., GLP-1R and / or GIPR) (e.g., attenuating, interfering, inhibiting), reduce the formation of complexes (e.g., signaling complexes) between β-arrestin and G protein-coupled receptors (e.g., GLP-1R and / or GIPR) (e.g., attenuating, interfering, inhibiting); and • Stimulates glucose clearance in vivo (GTT test) without causing aversion.

[0029] In some embodiments, the peptide chemical entities exhibit cAMP(GLP1R)EC50 values ​​of less than approximately 10 nM, less than approximately 5 nM, or less than approximately 1 nM (e.g., less than approximately 1 nM).

[0030] In some embodiments, the peptide chemical entities exhibit cAMP(GIPR)EC50 values ​​of less than approximately 100 nm, less than approximately 50 nM, or less than approximately 10 nM (e.g., less than approximately 10 nM).

[0031] In some embodiments, peptide-based chemical entities inhibit GIP-induced cAMP production (GIPR antagonistism).

[0032] In some embodiments, the compounds described herein exhibit a β-arrestin (GLP1R)EC50 value greater than 1 μM.

[0033] In some embodiments, the peptide chemical entity • Indicates a cAMP(GLP1R)EC50 value of less than approximately 10 nM, less than approximately 5 nM, or less than approximately 1 nM (e.g., less than approximately 1 nM); • Exhibits a cAMP(GIPR)EC50 value of less than approximately 100 nm, less than approximately 50 nM, or less than approximately 10 nM (e.g., less than approximately 10 nM), or is a GIPR antagonist; • Shows a β-arrestin (GLP1R) EC50 value greater than 1 μM; and • Stimulates glucose clearance in vivo (GTT test) without causing aversion (nausea).

[0034] In one aspect, the characteristic peptide chemical entities include compounds of formula (IAA) or pharmaceutically acceptable salts thereof: TIFF0007933830000001.tif36128In formula, rings A, G, L, W, R 1 , R 2 , R 2' , and R 4 This may be defined as any other part of this specification.

[0035] In one aspect, the present invention relates to a pharmaceutical composition comprising a chemical entity described herein (for example, a compound generally or specifically described herein or a pharmaceutically acceptable salt thereof, or a composition containing the same) and one or more pharmaceutically acceptable excipients.

[0036] In one aspect, a method for modulating (e.g., stimulating, partially stimulating, or antagonizing) GLP-1R and / or GIPR activity is characterized by a step of contacting GLP-1R and / or GIPR with a chemical entity described herein (e.g., a compound generally or specifically described herein or a pharmaceutically acceptable salt thereof, or a composition containing thereof). Methods include in vitro methods, such as contacting a sample containing one or more cells, each independently containing one or more of GLP-1R and / or GIPR, with the chemical entity. Methods also include in vivo methods, such as administering the chemical entity to an subject (e.g., a human) having a disease, disorder, or condition, where the modulation of GLP-1R and / or GIPR signaling is beneficial for treating the underlying pathophysiology and / or symptoms and / or progression of the disease, disorder, or condition (e.g., diabetes mellitus; e.g., NASH; e.g., obesity). In vivo methods include, but are not limited to, regulating (e.g., increasing) insulin levels and regulating (e.g., decreasing) glucose levels in a subject (e.g., a human). In some of the above embodiments, the regulatory method is achieved without substantially stimulating β-arrestin signaling, for example, without stimulating the recruitment of β-arrestin to a G protein-coupled receptor (e.g., GLP-1R), and for example, without stimulating the formation of a complex (e.g., a signaling complex) between β-arrestin and a G protein-coupled receptor (e.g., GLP-1R). In some of the above embodiments, the regulatory method is achieved without causing aversion or nausea.

[0037] A further aspect is a method for treating a disease, disorder, or condition in which modulation of GLP-1R and / or GIPR signaling is beneficial for treating the underlying pathology and / or symptoms and / or progression of the disease, disorder, or condition. The method comprises the step of administering an effective amount of the chemical entities described herein (e.g., compounds, pharmaceutically acceptable salts thereof, or compositions thereof) to a subject requiring such treatment.

[0038] In another aspect, the present disclosure features a method for treating a subject having a disease, disorder, or condition in which modulation of GLP-1R and / or GIPR signaling is beneficial for treating the underlying pathology and / or symptoms and / or progression of the disease, disorder, or condition. The method includes the step of administering a chemical entity described herein (e.g., a compound, a pharmaceutically acceptable salt thereof, or a composition comprising the same) in an amount effective for treating the disease, disorder, or condition.

[0039] In a further context, the treatment method is characterized by a step of administering to a subject a chemical entity described herein (e.g., a compound, a pharmaceutically acceptable salt thereof, or a composition comprising the same, either generally or specifically described herein). The method comprises a step of administering the chemical entity in an amount effective for treating a disease, disorder, or condition, wherein the modification of GLP-1R and / or GIPR is beneficial for treating the underlying pathology and / or symptoms and / or progression of the disease, disorder, or condition.

[0040] In another situation, the treatment method (i) The step of administering a first therapeutic agent that modulates (e.g., stimulates, partially stimulates, or antagonizes) GLP-1R and / or GIPR to a subject as defined anywhere in this specification; (ii) The step of determining that the subject is suffering from one or more adverse reactions (e.g., nausea, vomiting); and (iii) The administration of the first therapeutic agent may further include the step of discontinuing administration of the first therapeutic agent and administering a chemical entity described herein (e.g., a compound having formula (IAA), (IA), or (I)).

[0041] Non-limiting examples of the aforementioned diseases, disorders, and conditions include metabolic syndrome; diabetes mellitus (e.g., type 2 diabetes mellitus); obesity; obesity-related disorders; impaired glucose tolerance; insulin resistance; non-alcoholic steatohepatitis (NASH); fatty liver disease; steatohepatitis; and other forms of inflammation in metabolically important tissues, including the liver, fat, pancreas, kidneys, and intestines.

[0042] Other non-limiting examples of the aforementioned diseases, disorders, and conditions include cerebral insulin resistance, mild cognitive impairment (MCI), Alzheimer's disease (AD), Parkinson's disease (PD), anxiety, dementia (e.g., senile dementia), traumatic brain injury, Huntington's disease, tardive dyskinesia, hyperkinesia, mania, Morbus Parkinson's disease, Steele-Richard syndrome, Down syndrome, myasthenia gravis, neurological injury, traumatic brain injury, vascular amyloidosis, cerebral hemorrhage with amyloidosis, encephalitis, Friedreich's ataxia, acute confusional disorder, amyotrophic lateral sclerosis (ALS), glaucoma, and neurological disorders, including apoptosis-mediated degenerative diseases of the central nervous system (e.g., Creutzfeldt-Jakob disease, bovine spongiform encephalopathy (mad cow disease), and chronic wasting syndrome).

[0043] Further, non-limiting examples of the aforementioned diseases, disorders, and conditions include bone disorders characterized by changes in bone metabolism, such as osteoporosis including postmenopausal osteoporosis, decreased bone density, osteopenia, Paget's disease, osteolytic metastases in cancer patients, malformations in liver disease, and changes in bone metabolism caused by renal failure or hemodialysis, fractures, bone surgery, aging, pregnancy, protection against fractures, and malnutrition.

[0044] In certain aspects, the disease, disorder, or condition is diabetes.

[0045] In other embodiments, the disease, disorder, or condition is NASH.

[0046] In yet another aspect, the disease, disorder, or condition is obesity.

[0047] In other embodiments, the disease, disorder, or condition is Alzheimer's disease (AD) or Parkinson's disease (PD).

[0048] In other embodiments, disease, disorder, or condition is a bone disorder characterized by changes in bone metabolism, such as osteoporosis including postmenopausal osteoporosis, decreased bone density, osteopenia, Paget's disease, osteolytic metastases in cancer patients, osteogenesis imperfecta in liver disease, and changes in bone metabolism caused by renal failure or hemodialysis, fracture, bone surgery, aging, or pregnancy.

[0049] In certain embodiments, the chemical entities described herein are useful for protection against fractures.

[0050] The methods described herein may further include treating one or more conditions that are comorbidities, complications, or sequelae of any one or more conditions described herein. In non-limiting examples, the methods may further include treating one or more conditions that are comorbidities or sequelae of diabetes mellitus (e.g., type 2 diabetes mellitus), such as obesity, obesity-related disorders, metabolic syndrome, impaired glucose tolerance, insulin resistance, cardiovascular risk factors (e.g., coronary artery disease, peripheral artery disease, cerebrovascular disease, hypertension, and uncontrolled cholesterol and / or lipid levels, and / or risk factors associated with inflammation), retinopathy, nephropathy, neuropathy, NASH, fractures, and cognitive impairment.

[0051] In another aspect, the present disclosure comprises a method for screening candidate compounds for the treatment of a disease, disorder, or condition, the method comprising the following steps, wherein the modulation of GLP-1R and / or GIPR is beneficial for treating the underlying pathology and / or symptoms and / or progression of the disease, disorder, or condition: (a) The step of contacting the candidate compound with (i) a β-arrestin-coupled GPCR receptor signaling complex, or (ii) one or more GPCR receptor signaling complexes that are not complexed with β-arrestin (e.g., uncoupled GLP-1R and / or uncoupled GIPR); and (b) (i) a step of detecting the disruption of the β-arrestin-coupled complex; or (ii) a step of detecting the formation of a signaling complex in the absence of β-arrestin coupling, wherein the candidate compound modulates (e.g., stimulates, partially stimulates) GLP-1R and / or GIPR.

[0052] In certain embodiments, the method further includes the step of selecting candidate compounds exhibiting a β-arrestin (GLP-1R) EC50 value greater than 1 μM.

[0053] This method may further include a step of identifying the target.

[0054] This method may further include the step of administering one or more other therapeutic agents (for example, in combination with the chemical entities described herein).

[0055] The embodiment may include one or more of the following advantageous characteristics:

[0056] In some embodiments, the compounds described herein exhibit an AUC score of 0–25% relative to the vehicle, which corresponds to the finding that blood glucose fluctuations are maximally reduced compared to the control.

[0057] In some embodiments, the compounds described herein exhibit a cAMP(GLP-1R)EC50 value of less than approximately 1 nM, indicating that the compounds are relatively potent GLP-1R agonists.

[0058] In some embodiments, the compounds described herein exhibit cAMP(GLP-1R)Emax values ​​greater than approximately 80%, indicating that these compounds are agonists capable of fully activating GLP-1R.

[0059] In some embodiments, the compounds described herein are cAMP(GIPR)EC23 50 The values ​​shown indicate that this compound is a relatively potent GIPR agonist.

[0060] In some embodiments, the compounds described herein are cAMP(GIPR)EC23 50 The values ​​shown indicate that this compound is a relatively potent GIPR antagonist.

[0061] GLP-1 and GIP are readily degraded rapidly by dipeptidyl peptidase IV (DPP-IV) (see, e.g., Deacon, et al. Journal of Clinical Endocrinology & Metabolism, 1995, 80, 952-957). Therefore, GLP-1 and GIP have been shown to exhibit relatively short half-lives in humans due to degradation by DPP-IV. Advantageously, the compounds described herein exhibit relatively longer half-lives compared to GLP-1 and GIP in the presence of DPP-IV.

[0062] In some embodiments, the compounds described herein exhibit a β-arrestin-conjugated (GLP-1R) EC50 value greater than 1 μM in a β-arrestin (GLP1R) assay that measures the formation of a complex between GLP-1R and β-arrestin in cells. A β-arrestin (GLP1R) EC50 value greater than 1 μM indicates a compound that does not substantially induce β-arrestin recruitment to GLP-1R.

[0063] In some embodiments, the compounds described herein exhibit a conditioned taste aversion ("CTA") value of 0.6–1.0, which indicates no measurable aversion to the compound and is desirable. A CTA value of 0.0–0.6 indicates significant aversion to the compound. In a conditioned taste aversion assay, palatability to a dilute saccharin solution associated with compound administration is measured.

[0064] In some embodiments, the compounds described herein exhibit a reduced likelihood of causing undesirable side effects when administered to patients. A non-limiting example of these side effects is nausea.

[0065] [Invention 1001] A compound having formula (IAA), or a pharmaceutically acceptable salt thereof: TIFF0007933830000002.tif36128 In the formula, Ring A is (i) a saturated or unsaturated monocyclic ring comprising 3 to 8 ring atoms (including G and the labeled nitrogen atom N * ); or (ii) a saturated or unsaturated bicyclic or tricyclic ring comprising 6 to 14 ring atoms (including G and the labeled nitrogen atom N * ) ; wherein · G is C(O), S(O), or SO2; · The circular dotted line connecting G and N * is a divalent group comprising 1 to 6 ring atoms; wherein (a) 0 to 2 ring atoms of the divalent group are ring heteroatoms, each independently selected from the group consisting of N, N(R a ), O, S, and SO2; (b) 1 to 6 ring atoms of the divalent group are ring carbon atoms, each independently selected from the group consisting of C, CH, CH2, CR b , C(R b )2, and CHR b ; wherein (1) When Ring A is a monocyclic ring, each of the 1 to 6 ring carbon atoms of the divalent group is independently selected from the group consisting of CH, CH2, CR b , C(R b )2, and CHR b ; (2) When Ring A is a bicyclic or tricyclic ring, the following (A) or (B) applies: (A) 2 or 3 adjacent ring carbon atoms of the divalent group are each independently selected from the group consisting of C, CH, CH2, CR b , C(R b )2, and CHR b , and (a) C which may be substituted with 1 to 5 independently selected R c aryl optionally substituted 6~10 ; (b) A heteroaryl compound containing 5 to 10 ring atoms, wherein 1 to 4 ring atoms are independently N, N(R) a R is selected from the group consisting of ), O, and S, and the heteroaryl is selected from 1 to 3 independently. c A heteroaryl that may be substituted with; (c) 1 to 4 independently selected R d Even if replaced by C 3~10 Cycloalkyl; (d) A heterocycline containing 3 to 10 ring atoms, wherein 1 to 3 ring atoms are independently N(R) a R is selected from the group consisting of ), O, and S, and the heterocyclyl is selected in a manner in which 1 to 4 independent individuals are selected. d Heterocyclines may be replaced by It is condensed with a second ring selected from the group consisting of; or, (B) One of the ring carbon atoms of the divalent group is C, and (a) 1 to 4 independently selected R d Even if replaced by C 3~10 Cycloalkyl; (b) A heterocycline containing 3 to 10 ring atoms, wherein 1 to 3 ring atoms are independently N(R) a R is selected from the group consisting of ), O, and S, and the heterocyclyl is selected in a manner in which 1 to 4 independent individuals are selected. d Heterocyclines may be replaced by It is spiro-condensed with a second ring selected from the group consisting of; L is (i) -(CH2) m -X 1 -(CH2) n -X 2 -(CH2) p -(Equation VIII), where m is between 1 and 6; n is between 0 and 2; and p is between 0 and 8. (ii) -C(O)-(CH2) n -X 3 -(CH2) p -(Equation IX), where n is between 0 and 2; p is between 0 and 8; (iii) -(CH2) q -, in the formula, q is between 1 and 10; (iv) -C(O)-; or (v) -(CH2) m -X 1 -(CH2) p -(Equation VIII), where m is between 1 and 6; p is between 0 and 8. and; X 1 is -C(O)-; -N(R')C(O)-; -C(O)N(R')-; or -N(R')C(O)NR')-; where each existence of R' is independently of H and C 1~4 Selected from the group consisting of alkyl groups; X 2 teeth, (i) -O-; (ii) -S-; (iii) -S(O) t -, where t is 1 or 2; (iv) -C(Q 1 )(Q 2 )-, in the formula, Q 1 and Q 2 H and C are independent of each other. 1~4 Selected from the group consisting of alkyl groups; or Q 1 and Q 2 Each of them, together with the carbon atoms to which it is bonded, becomes C 3~10 A cycloalkyl group is formed, and the cycloalkyl group consists of 1 to 4 independently selected R d It may be substituted with phenyl, or condensed with phenyl; (v) 1 to 5 independently selected R c Even if replaced by C 6~10 Ariren; (vi) A heteroarylene containing 5 to 10 ring atoms, wherein 1 to 4 ring atoms are independently N, N(R) a R is selected from the group consisting of ), O, and S, and the heteroarylene is selected from 1 to 5 independently. c Heteroarylenes which may be substituted with; (vii) 1 to 4 independently selected R d Even if replaced by C 3~10 Cycloalkylene; (viii) A heterocycloalkylene containing 3 to 10 ring atoms, wherein 1 to 3 ring atoms are independently N(R) a R is selected from the group consisting of ), O, and S, and the heterocycloalkylene is selected in a group of 1 to 5 independent elements. d Heterocycloalkylenes, which may be substituted with; (ix) 1-2 R e C2-C4 alkenylenes which may be substituted with; or (x) 1 to 2 R e C2-C4 alkynylenes may be substituted with and; X 3 is -O-; -S-; or -S(O) t - and in the formula t is 1 or 2; R 1 , R 2 , and R 4 These are H and unsubstituted C, respectively, independently. 1~3 Selected from the group consisting of alkyl groups; R 2' The definition is as follows: (AA) or (BB): (AA) R 2' teeth TIFF0007933830000003.tif25128, and in the formula, R 3 -C(O)OH, -C(O)OR 31 It is -CH(C(O)OH)2, or a carboxylic acid isoster (e.g., amide or tetrazolyl); a is between 0 and 5; a' is either 0 or 1; R 3a and R 3b Each is independently H or C 1~3 It is alkyl; (BB) R 2' and R4 together with the atoms connecting them, form a ring comprising 5 to 8 ring atoms, wherein 3 to 7 are each ring carbon atoms substituted with 1 to 2 substituents independently selected from H, halo, hydroxy, oxo, and C 1~3 alkyl; 0 to 1 is a heteroatom (other than N bonded to R 1~3 selected from O, -NH, -N(C 1 alkyl), and S (for example, R 4 and R 3 together with the atoms to which they are each bonded, form a ring comprising 5 to 8 ring atoms); R 31 is (i) C e alkyl, which is optionally substituted with 1 to 2 independently selected R 1~6 groups; (ii) -(C 0~3 alkylene)-C 3~10 cycloalkyl, wherein the cycloalkyl is optionally substituted with 1 to 4 independently selected R d groups; (iii) -(C 0~3 alkylene)-heterocyclyl comprising 3 to 10 ring atoms, wherein 1 to 3 ring atoms are each independently selected from the group consisting of N(R a ), O, and S, and the heterocyclyl is optionally substituted with 1 to 4 independently selected R d groups; (iv) -(C 0~3 alkylene)-C 6~10 aryl, wherein the aryl is optionally substituted with 1 to 5 independently selected R c groups; or (v) -(C 0~3 alkylene)-heteroaryl comprising 5 to 10 ring atoms, wherein 1 to 4 ring atoms are each independently selected from the group consisting of N, N(R a ), O, and S, and the heteroaryl is optionally substituted with 1 to 3 independently selected R c groups and; R a Each of the entities is independent of H; C 1~4 Alkyl; C 3~6 Cycloalkyl; -C(=O)(C 1~6 alkyl); -C(=O)O(C 1~6 alkyl); and -S(O) 1~2 (C 1~6 Selected from the group consisting of alkyl groups; R b Each existence of R is independent. 31 ; C 1~4 Haloalkyl; -OH; Oxo; -F; -N(R) a )(R''); C 1~4 Alkoxy; C 1~4 Haloalkoxy; -C(=O)(C 1~4 alkyl); -C(=O)O(C 1~6 alkyl); -C(=O)OH; -C(=O)N(R''')(R''''); -S(O) 1~2 (C 1~6 Selected from the group consisting of alkyl and cyano; R c Each existence is independently selected from 1 to 2 independently selected R e Even if replaced by C 1~6 Alkyl; C 3~6 Cycloalkyl; C 1~4 Haloalkyl; -OH; -halo; -NO2; N3; -N(R) a )(R''); C 1~4 Alkoxy; C 1~4 Thioalkoxy; C 1~4 Haloalkoxy; -OC(=O)(C 1~6 alkyl); -C(=O)(C 1~6 alkyl); -C(=O)O(C 1~6 alkyl); -C(=O)OH; -C(=O)N(R''')(R''''); -S(O) 1~2 (C 1~6 Selected from the group consisting of alkyl and cyano; R d Each existence is independently selected from 1 to 2 independently selected R eEven if replaced by C 1~6 Alkyl; C 1~4 Haloalkyl; -OH; -F; Cl; -N(R) a )(R''); Oxo; C 1~4 Alkoxy; C 1~4 Haloalkoxy; -OC(=O)(C 1~6 alkyl); -C(=O)(C 1~6 alkyl); -C(=O)O(C 1~6 alkyl); -C(=O)OH; -C(=O)N(R''')(R''''); -S(O) 1~2 (C 1~6 Selected from the group consisting of alkyl and cyano; R e Each existence of -OH; -N(R a )(R''); C 1~4 Alkoxy; C 1~4 Haloalkoxy; -OC(=O)(C 1~6 alkyl); -C(=O)O(C 1~6 alkyl); -C(=O)OH; -C(=O)N(R''')(R''''); -S(O) 1~2 (C 1~6 Selected from the group consisting of alkyl and cyano; The existence of R'', R''', and R'''' is independent of H and C 1~6 Selected from the group consisting of alkyl groups; W is given by the formula W'-R 5 It is a peptide having, where W' is a sequence of 5 to 60 amino acids, and R 5 This is a C-terminal amino acid, amino acid ester, or amino acid amide, which may be substituted with 1-2 modifying groups (e.g., 1-2 groups selected from acyl and PEG groups). However, one or more of the compound provisions detailed herein shall apply. [Invention 1002] Compounds of the present invention 1001 having formula (IA), or pharmaceutically acceptable salts thereof: TIFF0007933830000004.tif38128In formula, Ring A is, (i) 3 to 8 ring atoms (G), and a labeled nitrogen atom N * A saturated or unsaturated monocyclic ring containing (including); or (ii) 6 to 14 ring atoms (G, and labeled nitrogen atoms N) * (including) saturated or unsaturated bicyclic or tricyclic And; here G is C(O), S(O), or SO2; G and N * The circular dotted lines connecting them represent divalent groups containing 1 to 6 ring atoms; here (a) The divalent group has 0 to 2 ring atoms which are ring heteroatoms, each independently of N, N(R) a Selected from the group consisting of ), O, S, and SO2; (b) The 1 to 6 ring atoms of the divalent group are ring carbon atoms, and each is independently C, CH, CH2, CR b , C(R b )2, and CHR b Selected from the group consisting of; Here (1) If ring A is a monoring, each of the 1 to 6 ring carbon atoms of the divalent group can independently be CH, CH2, or CR. b , C(R b )2, and CHR b Selected from the group consisting of; (2) If ring A is biring or triring, then (A) or (B) below applies: (A) Two or three adjacent ring carbon atoms of the divalent group are, independently, C, CH, and CR. b Selected from the group consisting of, (a) 1 to 5 independently selected R c Even if replaced by C 6~10 Ariel; (b) A heteroaryl compound containing 5 to 10 ring atoms, wherein 1 to 4 ring atoms are independently N, N(R) a R is selected from the group consisting of ), O, and S, and the heteroaryl is selected from 1 to 3 independently. c A heteroaryl that may be substituted with; (c) 1 to 4 independently selected R d Even if replaced by C 3~10 Cycloalkyl; (d) A heterocycline containing 3 to 10 ring atoms, wherein 1 to 3 ring atoms are independently N(R) a R is selected from the group consisting of ), O, and S, and the heterocyclyl is selected in a manner in which 1 to 4 independent individuals are selected. d Heterocyclines may be replaced by It is condensed with a second ring selected from the group consisting of; or, (B) One of the ring carbon atoms of the divalent group is C, and (a) 1 to 4 independently selected R d Even if replaced by C 3~10 Cycloalkyl; (b) A heterocycline containing 3 to 10 ring atoms, wherein 1 to 3 ring atoms are independently N(R) a R is selected from the group consisting of ), O, and S, and the heterocyclyl is selected in a manner in which 1 to 4 independent individuals are selected. d Heterocyclines may be replaced by It is spiro-condensed with a second ring selected from the group consisting of; L is (i) -(CH2) m -X 1 -(CH2) n -X 2 -(CH2) p -(Equation VIII), where m is between 1 and 6; n is between 0 and 2; and p is between 0 and 8. (ii) -C(O)-(CH2) n -X 3 -(CH2) p -(Equation IX), where n is between 0 and 2; p is between 0 and 8; (iii) -(CH2) q -, in the formula, q is between 1 and 10; (iv) -C(O)-; or (v) -(CH2) m -X 1 -(CH2) p-(Equation VIII), where m is between 1 and 6; p is between 0 and 8. and; X 1 is -C(O)-; -N(R')C(O)-; -C(O)N(R')-; or -N(R')C(O)NR')-; where each existence of R' is independently of H and C 1~4 Selected from the group consisting of alkyl groups; X 2 teeth, (i) -O-; (ii) -S-; (iii) -S(O) t -, where t is 1 or 2; (iv) -C(Q 1 )(Q 2 )-, in the formula, Q 1 and Q 2 H and C are independent of each other. 1~4 Selected from the group consisting of alkyl groups; or Q 1 and Q 2 Each of them, together with the carbon atoms to which it is bonded, becomes C 3~10 A cycloalkyl group is formed, and the cycloalkyl group consists of 1 to 4 independently selected R d It may be substituted with phenyl, or condensed with phenyl; (v) 1 to 5 independently selected R c Even if replaced by C 6~10 Ariren; (vi) A heteroarylene containing 5 to 10 ring atoms, wherein 1 to 4 ring atoms are independently N, N(R) a R is selected from the group consisting of ), O, and S, and the heteroarylene is selected from 1 to 5 independently. c Heteroarylenes which may be substituted with; (vii) 1 to 4 independently selected R d Even if replaced by C 3~10 Cycloalkylene; (viii) A heterocycloalkylene containing 3 to 10 ring atoms, wherein 1 to 3 ring atoms are independently N(R) aR is selected from the group consisting of ), O, and S, and the heterocycloalkylene is selected in a group of 1 to 5 independent elements. d Heterocycloalkylenes, which may be substituted with; (ix) 1-2 R e C2-C4 alkenylenes which may be substituted with; or (x) 1 to 2 R e C2-C4 alkynylenes may be substituted with and; X 3 is -O-; -S-; or -S(O) t - and in the formula t is 1 or 2; R 1 , R 2 , and R 4 These are H and unsubstituted C, respectively, independently. 1~3 Selected from the group consisting of alkyl groups; R 3 -C(O)OH, -C(O)OR 31 It is -CH(C(O)OH)2, or a carboxylic acid isoster (e.g., amide or tetrazolyl); a is between 0 and 5; a' is either 0 or 1; R 3a and R 3b Each is independently H or C 1~3 It is alkyl; R 31 teeth, (i) 1 to 2 independently selected R e Even if replaced by C 1~6 alkyl; (ii) -(C 0~3 Alkylene)-C 3~10 A cycloalkyl group, wherein the cycloalkyl group consists of 1 to 4 independently selected R d A cycloalkyl group which may be substituted with; (iii) Contains 3 to 10 ring atoms - (C 0~3 Alkylene)-heterocyclyl, in which 1 to 3 ring atoms are independently N(R) aR is selected from the group consisting of ), O, and S, and the heterocyclyl is selected in a manner in which 1 to 4 independent individuals are selected. d A heterocycline that may be substituted with; (iv) -(C 0~3 Alkylene)-C 6~10 An aryl, wherein the aryl is composed of 1 to 5 independently selected R c The aryl may be replaced by; or (v) Contains 5 to 10 ring atoms - (C 0~3 Alkylene)-heteroaryl, where 1 to 4 ring atoms are independently N, N(R) a R is selected from the group consisting of ), O, and S, and the heteroaryl is selected from 1 to 3 independently. c Heteroaryls may be substituted with and; R a Each of the entities is independent of H; C 1~4 Alkyl; C 3~6 Cycloalkyl; -C(=O)(C 1~6 alkyl); -C(=O)O(C 1~6 alkyl); and -S(O) 1~2 (C 1~6 Selected from the group consisting of alkyl groups; R b Each existence of R is independent. 31 ; C 1~4 Haloalkyl; -OH; Oxo; -F; -N(R) a )(R''); C 1~4 Alkoxy; C 1~4 Haloalkoxy; -C(=O)(C 1~4 alkyl); -C(=O)O(C 1~6 alkyl); -C(=O)OH; -C(=O)N(R''')(R''''); -S(O) 1~2 (C 1~6 Selected from the group consisting of alkyl and cyano; R c Each existence is independently selected from 1 to 2 independently selected R e Even if replaced by C 1~6 Alkyl; C 3~6Cycloalkyl; C 1~4 Haloalkyl; -OH; -halo; -NO2; N3; -N(R) a )(R''); C 1~4 Alkoxy; C 1~4 Thioalkoxy; C 1~4 Haloalkoxy; -OC(=O)(C 1~6 alkyl); -C(=O)(C 1~6 alkyl); -C(=O)O(C 1~6 alkyl); -C(=O)OH; -C(=O)N(R''')(R''''); -S(O) 1~2 (C 1~6 Selected from the group consisting of alkyl and cyano; R d Each existence is independently selected from 1 to 2 independently selected R e Even if replaced by C 1~6 Alkyl; C 1~4 Haloalkyl; -OH; -F; Cl; -N(R) a )(R''); Oxo; C 1~4 Alkoxy; C 1~4 Haloalkoxy; -OC(=O)(C 1~6 alkyl); -C(=O)(C 1~6 alkyl); -C(=O)O(C 1~6 alkyl); -C(=O)OH; -C(=O)N(R''')(R''''); -S(O) 1~2 (C 1~6 Selected from the group consisting of alkyl and cyano; R e Each existence of -OH; -N(R a )(R''); C 1~4 Alkoxy; C 1~4 Haloalkoxy; -OC(=O)(C 1~6 alkyl); -C(=O)O(C 1~6 alkyl); -C(=O)OH; -C(=O)N(R''')(R''''); -S(O) 1~2 (C 1~6 Selected from the group consisting of alkyl and cyano; The existence of R'', R''', and R'''' is independent of H and C 1~6 Selected from the group consisting of alkyl groups; W is given by the formula W'-R 5 It is a peptide having, where W' is a sequence of 5 to 60 amino acids, and R 5 This is a C-terminal amino acid, amino acid ester, or amino acid amide, which may be substituted with 1-2 modifying groups (e.g., 1-2 groups selected from acyl and PEG groups). However, one or more of the compound provisions detailed herein shall apply. [Invention 1003] A compound having formula (I), any of the compounds 1001 to 1002 of the present invention, or a pharmaceutically acceptable salt thereof: TIFF0007933830000005.tif36128In formula, Ring A is, (i) 3 to 8 ring atoms (G), and a labeled nitrogen atom N * A saturated or unsaturated monocyclic ring containing (including); or (ii) 6 to 14 ring atoms (G, and labeled nitrogen atoms N) * (including) saturated or unsaturated bicyclic or tricyclic And; here G is C(O), S(O), or SO2; G and N * The circular dotted lines connecting them represent divalent groups containing 1 to 6 ring atoms; here (a) The divalent group has 0 to 2 ring atoms which are ring heteroatoms, each independently of N, N(R) a Selected from the group consisting of ), O, S, and SO2; (b) The 1 to 6 ring atoms of the divalent group are ring carbon atoms, and each is independently C, CH, CH2, CR b , C(R b )2, and CHR b Selected from the group consisting of; Here (1) If ring A is a monoring, each of the 1 to 6 ring carbon atoms of the divalent group can independently be CH, CH2, or CR. b, C(R b )2, and CHR b Selected from the group consisting of; (2) If ring A is biring or triring, then (A) or (B) below applies: (A) Two or three adjacent ring carbon atoms of the divalent group are, independently, C, CH, and CR. b Selected from the group consisting of, (a) 1 to 5 independently selected R c Even if replaced by C 6~10 Ariel; (b) A heteroaryl compound containing 5 to 10 ring atoms, wherein 1 to 4 ring atoms are independently N, N(R) a R is selected from the group consisting of ), O, and S, and the heteroaryl is selected from 1 to 3 independently. c A heteroaryl that may be substituted with; (c) 1 to 4 independently selected R d Even if replaced by C 3~10 Cycloalkyl; (d) A heterocycline containing 3 to 10 ring atoms, wherein 1 to 3 ring atoms are independently N(R) a R is selected from the group consisting of ), O, and S, and the heterocyclyl is selected in a manner in which 1 to 4 independent individuals are selected. d Heterocyclines may be replaced by It is condensed with a second ring selected from the group consisting of; or, (B) One of the ring carbon atoms of the divalent group is C, and (a) 1 to 4 independently selected R d Even if replaced by C 3~10 Cycloalkyl; (b) A heterocycline containing 3 to 10 ring atoms, wherein 1 to 3 ring atoms are independently N(R) a R is selected from the group consisting of ), O, and S, and the heterocyclyl is selected in a manner in which 1 to 4 independent individuals are selected. d Heterocyclines may be replaced by It is spiro-condensed with a second ring selected from the group consisting of; L is (i) -(CH2) m -X 1 -(CH2) n -X 2 -(CH2) p -(Equation VIII), where m is between 1 and 6; n is between 0 and 2; and p is between 0 and 8. (ii) -C(O)-(CH2) n -X 3 -(CH2) p -(Equation IX), where n is between 0 and 2; p is between 0 and 8; (iii) -(CH2) q -, in the formula, q is between 1 and 10; (iv) -C(O)-; or (v) -(CH2) m -X 1 -(CH2) p -(Equation VIII), where m is between 1 and 6; p is between 0 and 8. and; X 1 is -C(O)-; -N(R')C(O)-; -C(O)N(R')-; or -N(R')C(O)NR')-; where each existence of R' is independently of H and C 1~4 Selected from the group consisting of alkyl groups; X 2 teeth, (i) -O-; (ii) -S-; (iii) -S(O) t -, where t is 1 or 2; (iv) -C(Q 1 )(Q 2 )-, in the formula, Q 1 and Q 2 H and C are independent of each other. 1~4 Selected from the group consisting of alkyl groups; or Q 1 and Q 2 Each of them, together with the carbon atoms to which it is bonded, becomes C 3~10 A cycloalkyl group is formed, and the cycloalkyl group consists of 1 to 4 independently selected R dIt may be substituted with phenyl, or condensed with phenyl; (v) 1 to 5 independently selected R c Even if replaced by C 6~10 Ariren; (vi) A heteroarylene containing 5 to 10 ring atoms, wherein 1 to 4 ring atoms are independently N, N(R) a R is selected from the group consisting of ), O, and S, and the heteroarylene is selected from 1 to 5 independently. c Heteroarylenes which may be substituted with; (vii) 1 to 4 independently selected R d Even if replaced by C 3~10 Cycloalkylene; (viii) A heterocycloalkylene containing 3 to 10 ring atoms, wherein 1 to 3 ring atoms are independently N(R) a R is selected from the group consisting of ), O, and S, and the heterocycloalkylene is selected in a group of 1 to 5 independent elements. d Heterocycloalkylenes, which may be substituted with; (ix) 1-2 R e C2-C4 alkenylenes which may be substituted with; or (x) 1 to 2 R e C2-C4 alkynylenes may be substituted with and; X 3 is -O-; -S-; or -S(O) t - and in the formula t is 1 or 2; R 1 , R 2 , and R 4 These are H and unsubstituted C, respectively, independently. 1~3 Selected from the group consisting of alkyl groups; R 3 -C(O)OH, -C(O)OR 31 , or a carboxylic acid isoster; where R 31 teeth, (i) 1 to 2 independently selected R e Even if replaced by C 1~6alkyl; (ii) -(C 0~3 Alkylene)-C 3~10 A cycloalkyl group, wherein the cycloalkyl group consists of 1 to 4 independently selected R d A cycloalkyl group which may be substituted with; (iii) Contains 3 to 10 ring atoms - (C 0~3 Alkylene)-heterocyclyl, in which 1 to 3 ring atoms are independently N(R) a R is selected from the group consisting of ), O, and S, and the heterocyclyl is selected in a manner in which 1 to 4 independent individuals are selected. d A heterocycline that may be substituted with; (iv) -(C 0~3 Alkylene)-C 6~10 An aryl, wherein the aryl is composed of 1 to 5 independently selected R c The aryl may be replaced by; or (v) Contains 5 to 10 ring atoms - (C 0~3 Alkylene)-heteroaryl, where 1 to 4 ring atoms are independently N, N(R) a R is selected from the group consisting of ), O, and S, and the heteroaryl is selected from 1 to 3 independently. c Heteroaryls may be substituted with and; a is between 0 and 5; R a Each of the entities is independent of H; C 1~4 Alkyl; C 3~6 Cycloalkyl; -C(=O)(C 1~6 alkyl); -C(=O)O(C 1~6 alkyl); and -S(O) 1~2 (C 1~6 Selected from the group consisting of alkyl groups; R b Each existence of R is independent. 31 ; C 1~4 Haloalkyl; -OH; Oxo; -F; -N(R) a )(R''); C 1~4 Alkoxy; C 1~4 Haloalkoxy; -C(=O)(C1~4 alkyl); -C(=O)O(C 1~6 alkyl); -C(=O)OH; -C(=O)N(R''')(R''''); -S(O) 1~2 (C 1~6 Selected from the group consisting of alkyl and cyano; R c Each existence is independently selected from 1 to 2 independently selected R e Even if replaced by C 1~6 Alkyl; C 3~6 Cycloalkyl; C 1~4 Haloalkyl; -OH; -halo; -NO2; N3; -N(R) a )(R''); C 1~4 Alkoxy; C 1~4 Thioalkoxy; C 1~4 Haloalkoxy; -OC(=O)(C 1~6 alkyl); -C(=O)(C 1~6 alkyl); -C(=O)O(C 1~6 alkyl); -C(=O)OH; -C(=O)N(R''')(R''''); -S(O) 1~2 (C 1~6 Selected from the group consisting of alkyl and cyano; R d Each existence is independently selected from 1 to 2 independently selected R e Even if replaced by C 1~6 Alkyl; C 1~4 Haloalkyl; -OH; -F; Cl; -N(R) a )(R''); Oxo; C 1~4 Alkoxy; C 1~4 Haloalkoxy; -OC(=O)(C 1~6 alkyl); -C(=O)(C 1~6 alkyl); -C(=O)O(C 1~6 alkyl); -C(=O)OH; -C(=O)N(R''')(R''''); -S(O) 1~2 (C 1~6 Selected from the group consisting of alkyl and cyano; R e Each existence of -OH; -N(Ra )(R''); C 1~4 Alkoxy; C 1~4 Haloalkoxy; -OC(=O)(C 1~6 alkyl); -C(=O)O(C 1~6 alkyl); -C(=O)OH; -C(=O)N(R''')(R''''); -S(O) 1~2 (C 1~6 Selected from the group consisting of alkyl and cyano; The existence of R'', R''', and R'''' is independent of H and C 1~6 Selected from the group consisting of alkyl groups; W is given by the formula W'-R 5 It is a peptide having, where W' is a sequence of 5 to 60 amino acids, and R 5 This is a C-terminal amino acid, amino acid ester, or amino acid amide, which may be substituted with 1-2 modifying groups (e.g., 1-2 groups selected from acyl and PEG groups). However, one or more of the compound provisions detailed herein shall apply. [Invention 1004] Formula (IIA) A compound according to any of invention 1001 to 1002, having TIFF0007933830000006.tif38128. [Invention 1005] A compound of any of the present inventions 1001 to 1004, wherein G is C(O). [Invention 1006] A compound from any of the inventions 1001 to 1004, wherein G is S(O) or SO2. [Invention 1007] A compound according to any of the invention 1001 to 1006, wherein ring A is a saturated or unsaturated monocycle containing 3 to 8 (e.g., 4 to 8) ring atoms. [Invention 1008] A compound according to any of the present invention 1001 to 1007, wherein ring A is a saturated monocycle containing 3 to 8 (e.g., 4 to 8) ring atoms. [Invention 1009] A compound according to any of the inventions 1001 to 1008, wherein ring A is a saturated monocycle containing 5 to 7 ring atoms. [Invention 1010] A compound of any of the present inventions 1001, 1002, 1004, 1005, and 1007-1009, wherein ring A has the following formula (III): TIFF0007933830000007.tif33128In formula, A1 is a bond, A 1A -A 1B , C(O), CH2, CHR b , or C(R b )2; A 1A and A 1B These are C(O), CH2, and CHR, respectively, and are independent of each other. b , or C(R b )2; A2 is C(O), CH2, CHR b , or C(R b )2; A3 is C(O), CH2, CHR b , or C(R b )2; O; S; SO2; or N(R a ) and; A4 is C(O), CH2, CHR b , or C(R b )2; O; S; or N(R a ) and however, A3 and A4 are both O; S; or N(R a ); or it cannot be a combination of those. [Invention 1011] A1 is C(O), CH2, CHR b , or C(R b The compound of the present invention 1010, wherein ring A is a 6-membered ring. [Invention 1012] A1 is CH2, CHR b , or C(R b )2, the compound of the present invention 1010 or 1011. [Invention 1013] A compound of any of the inventions 1010 to 1012, wherein A1 is CH2. [Invention 1014] A compound of the present invention 1010 or 1011, wherein A1 is C(O). [Invention 1015] A2 is CH2, CHR b , or C(R b )2, any of the compounds 1010 to 1014 of the present invention. [Invention 1016] A compound of any of the inventions 1010 to 1015, wherein A2 is CH2. [Invention 1017] A3 is CH2, CHR b , or C(R b )2, any of the compounds 1010 to 1016 of the present invention. [Invention 1018] A compound of any of the present invention 1010 to 1017, wherein A3 is CH2. [Invention 1019] A3 is O; S; SO2; or N(R) a A compound of any of the present invention 1010 to 1016, which is ). [Invention 1020] A4 is CH2, CHR b , or C(R b )2, which is any of the compounds 1010 to 1019 of the present invention. [Invention 1021] A compound of any of the present inventions 1010 to 1020, wherein A4 is CH2. [Invention 1022] A2, A3, and A4 are independent of each other, CH2, CHR b , and C(R b A compound of the present invention 1010 or 1011, selected from the group consisting of )2. [Invention 1023] One or two of A2, A3, and A4 are independently CHR b and C(R b A compound of the present invention 1022, selected from the group consisting of )2, wherein the other is CH2. [Invention 1024] A compound of the present invention 1022, wherein A2, A3, and A4 are each CH2. [Invention 1025] A1, A2, A3, and A4 are independent of each other, CH2, CHR b , and C(R b A compound of the present invention 1010 or 1011, selected from the group consisting of )2. [Invention 1026] One or two of A1, A2, A3, and A4 independently become CHR b and C(R b A compound of the present invention 1025, selected from )2, the other being CH2. [Invention 1027] A compound of the present invention 1026, wherein A1, A2, A3, and A4 are each CH2. [Invention 1028] A1 is a bond, and ring A is given by the following formula A compound of the present invention 1010 having TIFF0007933830000008.tif28128. [Invention 1029] A compound of the present invention 1028, wherein A2 is C (=O). [Invention 1030] A3 is O; S; or N(R) e ) and A4 is CH2, CHR b , or C(R b The compound of the present invention 1029, which is 2. [Invention 1031] A compound of the present invention 1030, wherein A3 is S. [Invention 1032] A3 is N(R) a A compound of the present invention 1030, which is (for example, A3 is NH). [Invention 1033] A compound of any of the inventions 1030 to 1032, wherein A4 is CH2. [Invention 1034] A4 is CHR b or C(R b )2, any of the compounds 1030 to 1032 of the present invention. [Invention 1035] A3 and A4 are independently CH2 and CHR b , or C(R b A compound of the present invention 1029, selected from )2. [Invention 1036] A compound of the present invention 1035, wherein A3 and A4 are each CH2. [Invention 1037] One of A3 and A4 is CH2, and the other of A3 and A4 is CHR b or C(R b )2, the compound of the present invention 1035. [Invention 1038] A3 and A4 are independently CHR b or C(R b A compound of the present invention 1035, selected from )2. [Invention 1039] A2 is CH2, CHR b , or C(R b The compound of the present invention 1028, which is 2. [Invention 1040] A compound of the present invention 1039, wherein A2 is CH2. [Invention 1041] A3 and A4 are independently CH2 and CHR b , or C(R b A compound of the present invention 1039 or 1040, selected from 2 (for example, A3 and A4 are each CH2). [Invention 1042] A 1 is A 1A -A 1B The compound of the present invention 1010. [Invention 1043] A 1A and A 1B These are CH2 and CHR, respectively, operating independently. b , or C(R b The compound of the present invention 1042, which is 2. [Invention 1044] A 1A and A 1BA compound of the present invention 1043, wherein each of the components is independently CH2. [Invention 1045] A 2 CH2, CHR b , or C(R b )2, any of the compounds 1042 to 1044 of the present invention. [Invention 1046] A 2 A compound of the present invention 1045, wherein the compound is CH2. [Invention 1047] A 3 CH2, CHR b , or C(R b )2, any of the compounds 1042 to 1046 of the present invention. [Invention 1048] A 3 A compound of the present invention 1047, wherein the compound is CH2. [Invention 1049] A 4 CH2, CHR b , or C(R b )2, any of the compounds 1042 to 1048 of the present invention. [Invention 1050] A 4 A compound of the present invention 1049, wherein the compound is CH2. [Invention 1051] A compound according to any of the present invention 1001 to 1006, wherein ring A is an unsaturated monocycle containing 3 to 8 (e.g., 4 to 8) ring atoms. [Invention 1052] A compound according to any of invention 1001-1006 and 1051, wherein ring A is an unsaturated monocycle containing 5-6 ring atoms. [Invention 1053] A compound according to any of the present invention 1001-1006, 1051, and 1052, wherein ring A is an unsaturated monoring containing six ring atoms. [Invention 1054] A compound of any of the present inventions 1051 to 1053, wherein ring A has formula (IV): TIFF0007933830000009.tif33128In formula, A6 and A7 are independently CH and CR b More selected; A5 and A8 are independently N, CH, or CR. b That is the case. [Invention 1055] A5, A6, A7, and A8 are each independently CH and CR b A more selected compound of the present invention 1054. [Invention 1056] One or two of A5, A6, A7, and A8 are independently selected in the CR. b Compounds of the present invention 1054 or 1055, wherein the other is CH. [Invention 1057] Compound 1054 of the present invention, wherein A5, A6, A7, and A8 are each CH. [Invention 1058] A5, A6, and A7 are independently CH and CR b A more selected compound of the present invention 1054, wherein A8 is N. [Invention 1059] A5 is N; A6, A7, and A8 are independently CH and CR, respectively. b More likely to be selected (for example, one of A6, A7, and A8 is CR) b A compound of the present invention 1054 (for example, C-OH). [Invention 1060] R b Each of the entities is independent, R 31 -OH; -N(R a )(R''); C 1~4 Alkoxy; and C 1~4 A compound selected from the group consisting of haloalkoxys, any of compounds 1054-1056 and 1058-1059 of the present invention. [Invention 1061] R b Each of these beings exists independently, (i) 1 to 2 independently selected R e Even if replaced by C 1~6 alkyl; (ii) -(C0~3 Alkylene)-C 6~10 An aryl, wherein the aryl is composed of 1 to 5 independently selected R c Arial may be replaced by; (iii) Contains 5 to 10 ring atoms - (C 0~3 Alkylene)-heteroaryl, where 1 to 4 ring atoms are independently N, N(R) a R is selected from the group consisting of ), O, and S, and the heteroaryl is selected from 1 to 3 independently. c A heteroaryl that may be substituted with; (iv) -OH; (v) -N(R a )(R''); (vi) C 1~4 Alkoxy; (vii) C 1~4 Haloalkoxy; and (viii) -F A compound selected from the group consisting of 1054-1056 and 1058-1059 of the present invention. [Invention 1062] R b Each of the entities is independent, R 31 -OH; -N(R a )(R''); C 1~4 Alkoxy; and C 1~4 A compound selected from the group consisting of haloalkoxys, any of the compounds 1010 to 1050 of the present invention. [Invention 1063] R b Each of these beings exists independently, (i) 1 to 2 independently selected R e Even if replaced by C 1~6 alkyl; (ii) -(C 0~3 Alkylene)-C 6~10 An aryl, wherein the aryl is composed of 1 to 5 independently selected R c Arial may be replaced by; (iii) Contains 5 to 10 ring atoms - (C 0~3Alkylene)-heteroaryl, where 1 to 4 ring atoms are independently N, N(R) a R is selected from the group consisting of ), O, and S, and the heteroaryl is selected from 1 to 3 independently. c A heteroaryl that may be substituted with; (iv) -OH; (v) -N(R a )(R''); (vi) C 1~4 Alkoxy; (vii) C 1~4 Haloalkoxy; and (viii) -F A compound selected from the group consisting of any of the compounds 1010 to 1050 of the present invention. [Invention 1064] R b Each of these beings exists independently, (I C 1~6 alkyl; (iv) -OH; (v) -N(R a )(R''); (vi) C 1~4 Alkoxy; (vii) C 1~4 Haloalkoxy; and (viii) -F A compound selected from the group consisting of any of the compounds 1010 to 1050 of the present invention. [Invention 1065] A compound according to any one of the invention 1001 to 1006, wherein ring A is a saturated or unsaturated bicyclic or tricyclic ring containing 6 to 14 (e.g., 8 to 10) ring atoms. [Invention 1066] A compound according to any of the invention 1001 to 1006, wherein ring A is an unsaturated bicyclic or tricyclic ring containing 6 to 14 (e.g., 8 to 10) ring atoms. [Invention 1067] Compounds of the present invention 1065 or 1066 to which (A) applies. [Invention 1068] A compound according to any one of the present invention 1065 to 1067, wherein ring A may be further substituted with one oxo. [Invention 1069] Ring A is given by equation (VI) A compound of any of the present invention 1065 to 1068 having TIFF0007933830000010.tif35128. [Invention 1070] The condensed ring B is selected from 1 to 5 independently selected R c Even if substituted, the condensed C 6~10 A compound of the present invention 1069, which is aryl. [Invention 1071] The condensed ring B is selected from 1 to 5 independently selected R c A compound of the present invention 1069 or 1070, which is a condensed phenyl that may be substituted with . [Invention 1072] A compound of any of the inventions 1069 to 1071, wherein ring A has formula (VI-A): TIFF0007933830000011.tif35128In formula, R c' is H or R c (For example C 1~6 It is an alkyl group (for example, CH3). [Invention 1073] Ring B is selected from 1 to 5 independently selected R c Condensed C may be substituted (for example, not substituted) 10 A compound according to any of the inventions 1069 to 1070, which is an aryl compound. [Invention 1074] Ring B is a condensed heteroaryl containing 5 to 10 (e.g., 6) ring atoms, where 1 to 4 (e.g., 1) ring atoms are independently N, N(R) a R is selected from the group consisting of ), O, and S, and the heteroaryl is selected from 1 to 3 independently. c A compound of the present invention 1069, which is a heteroaryl compound that may be substituted with [a specific compound]. [Invention 1075] Ring A is as follows: A compound selected from one of TIFF0007933830000012.tif35139, which is any of the compounds 1065 to 1068 of this invention. [Invention 1076] Each condensed ring B independently has the following properties: A condensed heteroaryl containing 5 to 10 (e.g., 6) ring atoms, wherein 1 to 4 (e.g., 1) ring atoms are independently N, N(R) a R is selected from the group consisting of ), O, and S, and the heteroaryl is selected from 1 to 3 independently. c Heteroaryls which may be substituted with; and 1 to 5 (for example, 1 to 2) independently selected R c Even if substituted, the condensed C 6~10 (e.g., C6) aryl A more selected compound of the present invention 1075. [Invention 1077] Each condensed ring B independently selects 1 to 5 (e.g., 1 to 2) R rings. c Even if substituted, the condensed C 6~10 A compound of the present invention 1075, which is (for example, C6)aryl. [Invention 1078] A compound according to any of the present invention 1001 to 1006, wherein ring A is a saturated bicyclic or tricyclic ring containing 8 to 10 ring atoms. [Invention 1079] Compound 1078 of the present invention to which (A) applies. [Invention 1080] Compounds of the present invention 1078 or 1079, wherein ring A may be further substituted with one oxo. [Invention 1081] Ring A is given by equation (VI) A compound of any of the present invention 1078 to 1080 having TIFF0007933830000013.tif35128. [Invention 1082] The condensed ring B is selected from 1 to 4 independently selected R d Even if substituted, the condensed C 3~10 A cycloalkyl compound according to the present invention 1081. [Invention 1083] The condensed ring B is selected from 1 to 4 independently selected R d (For example C 1~3 Condensed C may be substituted with alkyl. 3~6 Cycloalkyl (e.g., C 3~4 A compound of the present invention 1081 or 1082, which is a cycloalkyl compound. [Invention 1084] Compound 1078 of the present invention to which (B) applies. [Invention 1085] A compound of the present invention 1084, wherein ring A contains 5 to 6 ring atoms and may be further substituted with one oxo. [Invention 1086] Ring A is given by equation (VII) Compound 1084 or 1085 of the present invention having TIFF0007933830000014.tif41128. [Invention 1087] Spiro-condensed ring B is selected from 1 to 4 independently selected R d Spirocondensation C may be substituted with 3~10 A cycloalkyl compound according to the present invention 1086. [Invention 1088] Spiro-condensed ring B is selected from 1 to 4 independently selected R d (For example C 1~3 Spirocondensation C may be substituted with alkyl. 3~6 Cycloalkyl (e.g., C 3~4 A compound of any of the present invention 1084 to 1087 that is a cycloalkyl compound. [Invention 1089] L is given by equation (VIII): -(CH2) m -X 1 -(CH2) n -X 2 -(CH2) p A compound having - any of the compounds 1001 to 1088 of the present invention. [Invention 1090] A compound of the present invention 1089, wherein m is 2 to 6. [Invention 1091] Compounds of the present invention 1089 or 1090, wherein m is 2. [Invention 1092] Compound 1089 of the present invention, wherein m is 1. [Invention 1093] X 1 A compound according to any of the inventions 1089 to 1092, wherein the compound is -N(R')C(O)-. [Invention 1094] X 1 A compound according to any of the inventions 1089 to 1093, wherein the compound is -N(H)C(O)-. [Invention 1095] A compound from any of the inventions 1089 to 1094, wherein n + p ≥ 2. [Invention 1096] A compound according to any of Invention 1089 to 1094, wherein n + p = 2 (for example, n and p are each 1). [Invention 1097] A compound from any of the inventions 1089 to 1094, wherein n + p < 2. [Invention 1098] A compound according to any of Invention 1089 to 1094, wherein n + p = 0. [Invention 1099] X 2 -O-; -S-; or -S(O) t -A compound of any of the inventions 1089 to 1098, wherein t is 1 or 2 in the formula. [Invention 1100] X 2 A compound according to any of the inventions 1089 to 1099, wherein the compound is -S-. [Invention 1101] X 2 -C(Q 1 )(Q 2 )- A compound of any of the invention 1089 to 1098. [Invention 1102] Q 1 and Q 2 H and C are independent of each other. 1~4 A compound of the present invention 1101, which is alkyl. [Invention 1103] Q 1 and Q 2 A compound of the present invention 1101, wherein each of these is H. [Invention 1104] Q 1 and Q 2 Each of these is independently selected C 1~4 A compound of the present invention 1101, which is alkyl. [Invention 1105] Q 1 H is Q 2 C 1~4 A compound of the present invention 1102, which is alkyl. [Invention 1106] Q 1 and Q 2 However, each of them, together with the carbon atoms to which they are bonded, becomes C 3~10 A cycloalkyl group is formed, and the cycloalkyl group consists of 1 to 4 independently selected R d The compound of the present invention 1101, which may be substituted with or condensed with phenyl. [Invention 1107] Q 1 and Q 2 However, each of them, together with the carbon atoms to which they are bonded, becomes C 3~6 A cycloalkyl group is formed, and the cycloalkyl group consists of 1 to 4 independently selected R d The compound of the present invention 1106, which may be substituted with or condensed with phenyl. [Invention 1108] Q 1 and Q 2 However, each of them, together with the carbon atoms to which they are bonded, becomes C 4~6 (For example, C4) forms a cycloalkyl group, and the cycloalkyl group consists of 1 to 2 independently selected R d Compounds of the present invention 1107, which may be substituted with [Invention 1109] X 2 but, (v) 1 to 5 independently selected R c Even if replaced by C 6~10 Ariren; (vi) A heteroarylene containing 5 to 10 ring atoms, wherein 1 to 4 ring atoms are independently N, N(R) a R is selected from the group consisting of ), O, and S, and the heteroarylene is selected from 1 to 5 independently. c Heteroarylenes which may be substituted with; (vii) 1 to 4 independently selected R d Even if replaced by C 3~10 Cycloalkylene; or (viii) A heterocycloalkylene containing 3 to 10 ring atoms, wherein 1 to 3 ring atoms are independently N(R) a R is selected from the group consisting of ), O, and S, and the heterocycloalkylene is selected in a group of 1 to 5 independent elements. d Heterocycloalkylenes may be substituted with A compound according to any of the invention 1089 to 1098. [Invention 1110] X 2 but, (v) 1 to 5 independently selected R c Even if replaced by C 6~10 Arirene; or (vii) 1 to 4 independently selected R d Even if replaced by C 3~10 Cycloalkylene A compound according to any of the invention 1089 to 1098. [Invention 1111] X 2 but, (viii) A heterocycloalkylene containing 3 to 10 ring atoms, wherein 1 to 3 ring atoms are independently N(R) a R is selected from the group consisting of ), O, and S, and the heterocycloalkylene is selected in a group of 1 to 5 independent elements. d Heterocycloalkylenes may be substituted with The compound of the present invention 1109. [Invention 1112] X 2 but, (viii) A heterocycloalkylene containing 4 to 6 (e.g., 4) ring atoms, wherein 1 to 3 (e.g., 1) ring atoms are each independently N(R) a R is selected from the group consisting of ), O, and S, and the heterocycloalkylene is selected in a group of 1 to 5 independent elements. d Heterocycloalkylenes may be substituted with (For example, X 2 but Compound 1111 of the present invention (possibly TIFF0007933830000015.tif7128). [Invention 1113] m is between 2 and 6; n + p ≥ 2; X 2 -O-; -S-; -S(O) t -; or CH2, A compound according to any of the invention 1001 to 1089. [Invention 1114] Compound 1113 of the present invention, wherein m is 2. [Invention 1115] X 1 is -N(R')C(O)- (for example X 1 A compound of the present invention 1113 or 1114, wherein (the compound is -N(H)C(O)-). [Invention 1116] A compound from any of the inventions 1113 to 1115, wherein n + p > 2. [Invention 1117] A compound according to any of the inventions 1113 to 1115, wherein n + p = 2 (for example, n and p are each 1). [Invention 1118] X 2 A compound according to any of the inventions 1113 to 1117, wherein the parent compound is -S-. [Invention 1119] m is between 2 and 6; n + p < 2; X 2 but, (i) -C(Q 1 )(Q 2 )-, in the formula, Q1 and Q 2 Each of these is independently selected C 1~4 It is alkyl; or, Q 1 and Q 2 Each of them, together with the carbon atoms to which it is bonded, becomes C 3~10 A cycloalkyl group is formed, and the cycloalkyl group consists of 1 to 4 independently selected R d It may be substituted with phenyl, or condensed with phenyl; (v) 1 to 5 independently selected R c Even if replaced by C 6~10 Ariren; (vi) A heteroarylene containing 5 to 10 ring atoms, wherein 1 to 4 ring atoms are independently N, N(R) a R is selected from the group consisting of ), O, and S, and the heteroarylene is selected from 1 to 5 independently. c Heteroarylenes which may be substituted with; (vii) 1 to 4 independently selected R d Even if replaced by C 3~10 Cycloalkylene; or, (viii) A heterocycloalkylene containing 3 to 10 ring atoms, wherein 1 to 3 ring atoms are independently N(R) a R is selected from the group consisting of ), O, and S, and the heterocycloalkylene is selected in a group of 1 to 5 independent elements. d Heterocycloalkylenes may be substituted with A compound according to any of the invention 1001 to 1089. [Invention 1120] Compound 1119 of the present invention, wherein m is 2. [Invention 1121] X 1 A compound of the present invention 1119 or 1120, wherein is -N(R')C(O)- (for example, -N(H)C(O)-). [Invention 1122] A compound according to any of the inventions 1119 to 1121, wherein n + p = 0. [Invention 1123] X 2 -C(Q 1 )(Q 2 )- A compound of any of the inventions 1119 to 1122. [Invention 1124] Q 1 and Q 2 A compound of the present invention 1123, wherein each of these is H. [Invention 1125] Q 1 C 1~4 A compound of the present invention 1123, which is alkyl. [Invention 1126] Q 2 C 1~4 A compound of the present invention 1125, which is alkyl. [Invention 1127] Q 1 and Q 2 However, each of them, together with the carbon atoms to which they are bonded, becomes C 3~6 A cycloalkyl group is formed, and the cycloalkyl group consists of 1 to 4 independently selected R d A compound according to any of the invention 1119 to 1122, which may be substituted with or condensed with phenyl. [Invention 1128] X 2 but, (v) 1 to 5 independently selected R c Even if replaced by C 6~10 Arirene; or (vii) 1 to 4 independently selected R d Even if replaced by C 3~10 Cycloalkylene A compound according to any of the inventions 1119 to 1122. [Invention 1129] X 2 but, (viii) A heterocycloalkylene containing 4 to 6 (e.g., 4) ring atoms, wherein 1 to 3 (e.g., 1) ring atoms are each independently N(R) a R is selected from the group consisting of ), O, and S, and the heterocycloalkylene is selected in a group of 1 to 5 independent elements. dHeterocycloalkylenes may be substituted with (For example, X 2 but A compound of any of the inventions 1119 to 1122 (possibly TIFF0007933830000016.tif7128). [Invention 1130] m is 1; n + p ≤ 2; X 2 -O-; -S-; -S(O) t -; or C(Q 1 )(Q 2 ) A compound according to any of the invention 1001 to 1089. [Invention 1131] The compound of the present invention 1130, wherein n + p = 2. [Invention 1132] X 2 A compound of the present invention 1131, wherein the genotype is -S-. [Invention 1133] A compound of the present invention 1130, wherein n + p < 2 (for example, n + p = 0; or n + p = 1). [Invention 1134] X 2 is C(Q 1 )(Q 2 The compound of the present invention 1133, which is ). [Invention 1135] Q 1 and Q 2 A compound of the present invention 1134, wherein each of these is H. [Invention 1136] Q 1 and Q 2 Each is C 1~4 A compound of the present invention 1134, which is alkyl. [Invention 1137] Q 1 H is Q 2 C 1~4 A compound of the present invention 1134, which is alkyl. [Invention 1138] L is given by equation (IX): -C(O)-(CH2) n -X 3 -(CH2) p A compound having - any of the compounds 1001 to 1089 of the present invention. [Invention 1139] The compound of Invention 1138, wherein n + p ≥ 2. [Invention 1140] A compound of the present invention 1138 or 1139, wherein n + p = 2 (for example, n and p are each 1). [Invention 1141] X 3 A compound according to any of the present inventions 1138 to 1140, wherein the compound is -S-. [Invention 1142] R 1 A compound according to any of the inventions 1001 to 1141, wherein the element is H. [Invention 1143] R 2 A compound according to any of the inventions 1001 to 1142, wherein the element is H. [Invention 1144] R 4 A compound according to any of the inventions 1001 to 1143, wherein the element is H. [Invention 1145] R 1 , R 2 , and R 4 A compound according to any of the inventions 1001 to 1144, wherein each of the elements is H. [Invention 1146] R 2 is non-substituted C 1~3 A compound according to any of the present invention 1001 to 1142, which is alkyl (e.g., methyl). [Invention 1147] R 1 and R 4 A compound of the present invention 1146, wherein each of these is H. [Invention 1148] R 2' A compound of any of the present invention 1001 and 1005-1147, as defined by (AA). [Invention 1149] A compound from any of the present inventions 1001-1002 and 1004-1148, wherein a' is 1. [Invention 1150] R 3a and R 3b A compound from any of the present inventions 1001-1002 and 1004-1149, wherein each of these is H. [Invention 1151] R 3a and R 3b Each is C 1~3 A compound of any of the present invention 1001, 1002, and 1004-1149, which is alkyl (e.g., methyl). [Invention 1152] A compound of any of the present inventions 1001, 1002, and 1004-1148, wherein a' is 0. [Invention 1153] R 3 A compound according to any of the inventions 1001 to 1152, wherein -C(O)OH. [Invention 1154] R 3 A compound according to any of the inventions 1001 to 1152, wherein is a carboxylic acid isoster. [Invention 1155] R 3 However, tetrazolyl, amide, or isoxazolyl may be substituted. A compound of any of the present invention 1001-1152 and 1154, which is TIFF0007933830000017.tif14128. [Invention 1156] A compound according to any of the inventions 1001 to 1155, wherein a is 0, 1, 2, or 3 (for example, a = 0; or a = 1; or a = 2). [Invention 1157] A compound of the present invention 1157 in which a is 1. [Invention 1158] A compound according to any of the present invention 1001 to 1157, wherein W is a sequence of 25 to 45 amino acids (for example, 30 to 45). [Invention 1159] A compound according to any of the invention 1001 to 1158, wherein W is a sequence of 36 amino acids. [Invention 1160] W is in equation (X): -GTF-W''-R 5 A compound according to any of the present invention 1001 to 1158, wherein the formula has a sequence of 30 to 40 amino acids (e.g., 31 to 36 or 33). [Invention 1161] A compound according to any of the present inventions 1001 to 1158 and 1160, wherein W is represented by one of SEQ IDs 1 to 34 (e.g., SEQ IDs 5 to 27; e.g., SEQ IDs 5 to 29; (e.g., SEQ ID 6); e.g., SEQ IDs 28 to 29; e.g., SEQ IDs 30 to 34). [Invention 1162] R 5 A compound according to any of the present invention 1001 to 1161, wherein the C-terminal amino acid amide may be substituted with 1 to 2 modifying groups (e.g., 1 to 2 groups selected from an acyl group and a PEG group). [Invention 1163] R 5 A compound according to any of the present invention 1001 to 1162, wherein the C-terminal lysylamide residue may be substituted with 1 to 2 modifying groups (e.g., 1 to 2 groups selected from an acyl group and a PEG group). [Invention 1164] R 5 A compound according to any of the present invention 1001 to 1163, wherein the C-terminal L-lysylamide residue may be substituted with 1 to 2 modifying groups (e.g., 1 to 2 groups selected from an acyl group and a PEG group). [Invention 1165] R 5 A compound of any of the present inventions 1001 to 1164 having formula (XI): TIFF0007933830000018.tif68128In formula, R * is either H or a modifying group (e.g., an acyl group and a PEG group). [Invention 1166] W is a compound of any of the inventions 1001 to 1165 having formula (XII): In formula TIFF0007933830000019.tif68128, W'' is a sequence of 30-40 amino acids (e.g., 31-36, 33), and R * is either H or a modifying group (e.g., an acyl group and a PEG group). [Invention 1167] R 5 A compound according to any of the present invention 1001 to 1161, wherein is a C-terminal amino acid and may be substituted with 1 to 2 modifying groups (e.g., 1 to 2 groups selected from an acyl group and a PEG group). [Invention 1168] R 5 A compound according to any of the present inventions 1001 to 1161 and 1167, wherein the C-terminal lysine is substituted with 1 to 2 modifying groups (e.g., 1 to 2 groups selected from an acyl group and a PEG group). [Invention 1169] R 5 A compound according to any of the present invention 1001-1161 and 1167-1168, wherein the C-terminal L-lysine is substituted with 1-2 modifying groups (e.g., 1-2 groups selected from acyl and PEG groups). [Invention 1170] R 5 A compound from any of the inventions 1001-1161 and 1168-1169 having the formula (XI-OH): TIFF0007933830000020.tif71128 formula, R * is either H or a modifying group (e.g., an acyl group and a PEG group). [Invention 1171] A compound from any of the inventions 1001-1161 and 1168-1170, wherein W has the formula (XII-OH): In formula TIFF0007933830000021.tif71128, W'' is a sequence of 30-40 amino acids (e.g., 31-36, 33), and R * is either H or a modifying group (e.g., an acyl group and a PEG group). [Invention 1172] R *A compound according to any of the inventions 1165-1166 and 1170-1171, wherein the compound is H. [Invention 1173] R * However, 1-2 independently selected R f Even if replaced by C 2~30 (For example C 2~20 ) is an acyl group; here R f Each existence is -C(=O)(OH); -C(=O)(C 2~20 alkyl); -C(=O)O(C 2~20 Alkyl); -S(O) 1~2 (C 1~6 Alkyl; Oxo; F; C 1~10 Alkoxy; C 1~10 Haloalkoxy; and -N(R g )(R h Selected from the group consisting of; R g and R h Each of the entities is independent of H; C 1~4 Alkyl; -C(=O)(C 2~20 alkyl); -C(=O)O(C 2~20 alkyl); and -S(O) 1~2 (C 1~6 A compound selected from the group consisting of alkyl groups, any of the compounds 1165-1166 and 1170-1171 of the present invention. [Invention 1174] R * However, 1-2 independently selected R f C replaced by 2~30 (For example C 2~20 ) A compound of any of the present invention 1165-1166, 1170-1171, and 1173, which is an acyl group. [Invention 1175] R f Each of these entities exists independently of -C(=O)(OH) and -N(R g )(R h A compound of the present invention 1174, selected from the group consisting of ). [Invention 1176] R * but, A compound of any of the present invention 1165-1166, 1170-1171, and 1173-1175, which is TIFF0007933830000022.tif36143. [Invention 1177] R * but, The compound of the present invention 1176, which is TIFF0007933830000023.tif35128. [Invention 1178] R * but, The compound of the present invention 1176, which is TIFF0007933830000024.tif10128. [Invention 1179] R 5 A compound of any of the present invention 1001 to 1161, wherein the C-terminal amino acid is selected from serine, glycine, and arginine. [Invention 1180] R 5 The compound is one of the compounds 1001 to 1161 of the present invention, which is a C-terminal amino acid amide selected from selinylamide, glycylamide, and argininylamide. [Invention 1181] Having the formula (IA-A), (IA-AA), or (IA-AB); Ring A is a saturated monoring containing 3 to 8 ring atoms (e.g., 4 to 8, 4 to 7, 5 to 6); L is given by equation (VIII): -(CH2) m -X 1 -(CH2) n -X 2 -(CH2) p - has, A compound according to any of the present inventions 1001-1002 and 1162-1180. [Invention 1182] A compound according to any of the present inventions 1001-1002 and 1162-1181, wherein W is represented by one of the formulas (X), (XII), (XIII), (XIV-AA), (XIV), (XIV-A), (XIV-B), (XV), or SEQ ID 1-34. [Invention 1183] A compound according to any of the present inventions 1001-1002 and 1162-1182, wherein W is represented by one of the SEQ IDs 5-29. [Invention 1184] A compound from any of the present inventions 1001-1002 and 1162-1183, wherein W is represented by SEQ ID 6. [Invention 1185] (i) m is 2 to 6 (for example, 2), X 1 is -N(R')C(O)- (for example, -N(H)C(O)-), n + p = 2 (for example, n and p are each 1), X 2 is -S-; or, (ii) m is 2 to 6 (for example, 2), X 1 is -N(R')C(O)- (for example, -N(H)C(O)-), n + p = 0, and X 2 -C(Q 1 )(Q 2 )- and Q 1 and Q 2 However, each of them, together with the carbon atoms to which they are bonded, becomes C 3~6 A cycloalkyl group is formed, and the cycloalkyl group consists of 1 to 4 independently selected R d It may be substituted with, or condensed with phenyl; or, (iii) m is 2 to 6 (for example, 2), X 1 is -N(R')C(O)- (for example, -N(H)C(O)-), n + p = 0, and X 2 -C(Q 1 )(Q 2 )- and Q 1 and Q 2 However, C is selected independently. 1~4 It is alkyl (e.g., CH3); or, (iv) m is 2 to 6 (for example, 2), X 1 is -N(R')C(O)- (for example, -N(H)C(O)-), n + p = 0, and X 2 but (v) 1 to 5 independently selected R c Even if replaced by C 6~10Arirenes (e.g., phenylene); or (vii) 1 to 4 independently selected R d Even if replaced by C 3~10 Cycloalkylene That is, A compound according to any of the present inventions 1001-1002 and 1162-1184. [Invention 1186] (iv) m is 2 to 6 (for example, 2), X 1 is -N(R')C(O)- (for example, -N(H)C(O)-), n + p = 0, and X 2 However, it is a heterocycloalkylene containing 4 to 6 (for example, 4) ring atoms, where 1 to 3 (for example, 1) ring atoms are each independently N(R) a R is selected from the group consisting of ), O, and S, and the heterocycloalkylene is selected in a group of 1 to 5 independent elements. d It is a heterocycloalkylene that may be substituted with (e.g., X 2 but (Possibly TIFF0007933830000025.tif7128), A compound according to any of the present inventions 1001-1002 and 1162-1184. [Invention 1187] m is 2 to 6 (for example, 2), X 1 is -N(R')C(O)- (for example, -N(H)C(O)-), n + p = 2 (for example, n and p are each 1), X 2 A compound according to any of the inventions 1001-1002 and 1162-1185, wherein the compound is -S-. [Invention 1188] A compound of any of the present inventions 1001-1002, 1162-1184, and 1187, wherein L is -CH2CH2NHC(O)CH2SCH2-. [Invention 1189] A compound according to any of the present inventions 1001-1002 and 1162-1188, wherein ring A has formula (III). [Invention 1190] A compound according to any of Inventions 1001-1002 and 1162-1189, wherein ring A is defined as in any of Inventions 1011-1027. [Invention 1191] A compound according to any of the present inventions 1001-1002 and 1162-1189, wherein ring A has formula (III-A). [Invention 1192] A compound according to any of the inventions 1001-1002, 1162-1188, and 1190, wherein ring A is defined as any of the inventions 1029-1041. [Invention 1193] A compound according to any of the inventions 1001-1002 and 1162-1189, wherein ring A is defined as in any of the inventions 1042-1050. [Invention 1194] R 1 , R 2 , and R 4 A compound according to any of the present inventions 1001-1002 and 1162-1193, wherein one, two, or three of the atoms are H. [Invention 1195] R 1 , R 2 , and R 4 A compound according to any of the present invention 1001-1002 and 1162-1194, wherein one, two, or three of the atoms are H. [Invention 1196] R 3 A compound from any of the present inventions 1001-1002 and 1162-1195, wherein the compound is -C(O)OH. [Invention 1197] a' is 1; R 3a and R 3b A compound according to any of the present invention 1001-1002 and 1162-1196, wherein each of them is independently H. [Invention 1198] A compound according to any of the present inventions 1001 and 1162-1197, wherein a is 0, 1, or 2 (e.g., 1). [Invention 1199] R 1 , R 2 , and R4 H is H, a is 0, 1, or 2 (for example, 1), R 3 A compound from any of the present inventions 1001-1002 and 1162-1198, wherein -C(O)OH. [Invention 1200] A compound of the present invention 1001, selected from the group consisting of the compounds shown in Figure 1. [Invention 1201] A pharmaceutical composition comprising any compound or salt of Invention 1001 to 1200 and one or more pharmaceutically acceptable excipients. [Invention 1202] A method for modulating GLP-1R and / or GIPR activity, comprising the step of contacting GLP-1R and / or GIPR with any compound of the present invention 1001 to 1200. [Invention 1203] A method of the present invention 1202, comprising regulating GLP-1R and / or GIPR. [Invention 1204] The method of the present invention 1202, wherein the modulation includes partially stimulating or antagonizing GLP-1R and / or GIPR. [Invention 1205] Any of the methods described in 1202 to 1204 of this invention, performed in vitro. [Invention 1206] Any of the methods described in 1202 to 1204 of this invention, performed in vivo. [Invention 1207] A method for modulating GLP-1R and / or GIPR-induced aversion, nausea, and / or vomiting, comprising the step of contacting GLP-1R and / or GIPR with any compound of the present invention 1001 to 1200. [Invention 1208] A method for regulating (e.g., increasing) insulin levels in a subject requiring regulation (e.g., increase), comprising the step of administering an effective amount of any compound 1001 to 1200 of the present invention to the subject. [Invention 1209] A method for adjusting (e.g., reducing) glucose levels in a subject requiring adjustment (e.g., reduction) of glucose levels, comprising the step of administering an effective amount of any compound 1001 to 1200 of the present invention to the subject. [Invention 1210] A method for treating a disease, disorder, or condition, comprising the step of administering an effective amount of any compound 1001 to 1200 of the present invention to a subject in need thereof, wherein modulation of GLP-1R and / or GIPR signaling can alter the pathogenesis and / or symptoms and / or progression of the disease, disorder, or condition. [Invention 1211] The method of the present invention 1210, wherein the disease, disorder, or condition or disorder is diabetes. [Invention 1212] The method of the present invention 1210, wherein the disease, disorder, or condition or disorder is NASH. [Invention 1213] The method of the present invention 1210, wherein the disease, disorder, or condition or disorder is obesity. [Invention 1214] The method of the present invention 1210, wherein the disease, disorder, or condition or disorder is fatty liver disease. [Invention 1215] The method of the present invention 1210, wherein the disease, disorder, or condition or disorder is fatty liver disease. [Invention 1216] Any method of the present invention 1210 to 1215, further comprising the step of identifying the target. [Invention 1217] Any method according to invention 1210 to 1216, wherein the subject is a human. [Invention 1218] A method for treating a disease, disorder, or condition, comprising the step of administering an effective amount of any compound 1001-1200 of the present invention to a subject in need thereof, wherein modulation of GLP-1R and / or GIPR signaling causes aversion, nausea, or vomiting. Other embodiments include those described in the detailed description, drawings, and / or claims. [Brief explanation of the drawing]

[0066] [Figure 1-1] Representative compounds of formula (IAA) are shown. [Figure 1-2] Representative compounds of formula (IAA) are shown. [Figure 1-3] Representative compounds of formula (IAA) are shown. [Figure 1-4] Representative compounds of formula (IAA) are shown. [Figure 1-5] Representative compounds of formula (IAA) are shown. [Figure 1-6] Representative compounds of formula (IAA) are shown. [Figure 1-7] Representative compounds of formula (IAA) are shown. [Figure 1-8] Representative compounds of formula (IAA) are shown. [Figure 1-9] Representative compounds of formula (IAA) are shown. [Figure 1-10] Representative compounds of formula (IAA) are shown. [Figure 1-11] Representative compounds of formula (IAA) are shown. [Figure 1-12] Representative compounds of formula (IAA) are shown. [Figure 1-13] Representative compounds of formula (IAA) are shown. [Figure 1-14] Representative compounds of formula (IAA) are shown. [Figure 1-15] Representative compounds of formula (IAA) are shown. [Figure 1-16] Representative compounds of formula (IAA) are shown. [Figure 1-17] Representative compounds of formula (IAA) are shown. [Figure 1-18] Representative compounds of formula (IAA) are shown. [Figure 1-19] Representative compounds of formula (IAA) are shown. [Figure 1-20] Representative compounds of formula (IAA) are shown. [Figure 1-21]Representative compounds of formula (IAA) are shown. [Figure 1-22] Representative compounds of formula (IAA) are shown. [Figure 1-23] Representative compounds of formula (IAA) are shown. [Figure 1-24] Representative compounds of formula (IAA) are shown. [Figure 1-25] Representative compounds of formula (IAA) are shown. [Figure 1-26] Representative compounds of formula (IAA) are shown. [Figure 1-27] Representative compounds of formula (IAA) are shown. [Figure 1-28] Representative compounds of formula (IAA) are shown. [Figure 1-29] Representative compounds of formula (IAA) are shown. [Figure 1-30] Representative compounds of formula (IAA) are shown. [Figure 1-31] Representative compounds of formula (IAA) are shown. [Figure 1-32] Representative compounds of formula (IAA) are shown. [Figure 1-33] Representative compounds of formula (IAA) are shown. [Figure 1-34] Representative compounds of formula (IAA) are shown. [Figure 1-35] Representative compounds of formula (IAA) are shown. [Figure 1-36] Representative compounds of formula (IAA) are shown. [Figure 1-37] Representative compounds of formula (IAA) are shown. [Figure 1-38] Representative compounds of formula (IAA) are shown. [Figure 1-39] Representative compounds of formula (IAA) are shown. [Figure 1-40] Representative compounds of formula (IAA) are shown. [Figure 1-41] Representative compounds of formula (IAA) are shown. [Figure 1-42] Representative compounds of formula (IAA) are shown. [Figure 1-43] Representative compounds of formula (IAA) are shown. [Figure 1-44]Representative compounds of formula (IAA) are shown. [Figure 1-45] Representative compounds of formula (IAA) are shown. [Figure 1-46] Representative compounds of formula (IAA) are shown. [Figure 1-47] Representative compounds of formula (IAA) are shown. [Figure 1-48] Representative compounds of formula (IAA) are shown. [Figure 1-49] Representative compounds of formula (IAA) are shown. [Figure 1-50] Representative compounds of formula (IAA) are shown. [Figure 1-51] Representative compounds of formula (IAA) are shown. [Figure 1-52] Representative compounds of formula (IAA) are shown. [Figure 1-53] Representative compounds of formula (IAA) are shown. [Figure 1-54] Representative compounds of formula (IAA) are shown. [Figure 1-55] Representative compounds of formula (IAA) are shown. [Figure 1-56] Representative compounds of formula (IAA) are shown. [Figure 1-57] Representative compounds of formula (IAA) are shown. [Figure 1-58] Representative compounds of formula (IAA) are shown. [Figure 1-59] Representative compounds of formula (IAA) are shown. [Figure 1-60] Representative compounds of formula (IAA) are shown. [Figure 1-61] Representative compounds of formula (IAA) are shown. [Figure 1-62] Representative compounds of formula (IAA) are shown. [Figure 1-63] Representative compounds of formula (IAA) are shown. [Figure 1-64] Representative compounds of formula (IAA) are shown. [Figure 1-65] Representative compounds of formula (IAA) are shown. [Figure 1-66] Representative compounds of formula (IAA) are shown. [Figure 1-67]Representative compounds of formula (IAA) are shown. [Figure 1-68] Representative compounds of formula (IAA) are shown. [Figure 1-69] Representative compounds of formula (IAA) are shown. [Figure 1-70] Representative compounds of formula (IAA) are shown. [Figure 1-71] Representative compounds of formula (IAA) are shown. [Figure 1-72] Representative compounds of formula (IAA) are shown. [Figure 1-73] Representative compounds of formula (IAA) are shown. [Figure 1-74] Representative compounds of formula (IAA) are shown. [Figure 1-75] Representative compounds of formula (IAA) are shown. [Figure 1-76] Representative compounds of formula (IAA) are shown. [Figure 1-77] Representative compounds of formula (IAA) are shown. [Figure 1-78] Representative compounds of formula (IAA) are shown. [Figure 1-79] Representative compounds of formula (IAA) are shown. [Figure 1-80] Representative compounds of formula (IAA) are shown. [Figure 1-81] Representative compounds of formula (IAA) are shown. [Figure 1-82] Representative compounds of formula (IAA) are shown. [Figure 1-83] Representative compounds of formula (IAA) are shown. [Figure 1-84] Representative compounds of formula (IAA) are shown. [Figure 1-85] Representative compounds of formula (IAA) are shown. [Figure 1-86] Representative compounds of formula (IAA) are shown. [Figure 1-87] Representative compounds of formula (IAA) are shown. [Figure 1-88] Representative compounds of formula (IAA) are shown. [Figure 1-89] Representative compounds of formula (IAA) are shown. [Figure 1-90]Representative compounds of formula (IAA) are shown. [Figure 1-91] Representative compounds of formula (IAA) are shown. [Figure 1-92] Representative compounds of formula (IAA) are shown. [Figure 1-93] Representative compounds of formula (IAA) are shown. [Figure 1-94] Representative compounds of formula (IAA) are shown. [Figure 1-95] Representative compounds of formula (IAA) are shown. [Figure 1-96] Representative compounds of formula (IAA) are shown. [Figure 1-97] Representative compounds of formula (IAA) are shown. [Figure 1-98] Representative compounds of formula (IAA) are shown. [Figure 1-99] Representative compounds of formula (IAA) are shown. [Figure 1-100] Representative compounds of formula (IAA) are shown. [Figure 1-101] Representative compounds of formula (IAA) are shown. [Figure 1-102] Representative compounds of formula (IAA) are shown. [Figure 1-103] Representative compounds of formula (IAA) are shown. [Figure 1-104] Representative compounds of formula (IAA) are shown. [Figure 1-105] Representative compounds of formula (IAA) are shown. [Figure 1-106] Representative compounds of formula (IAA) are shown. [Figure 1-107] Representative compounds of formula (IAA) are shown. [Figure 1-108] Representative compounds of formula (IAA) are shown. [Figure 1-109] Representative compounds of formula (IAA) are shown. [Figure 1-110] Representative compounds of formula (IAA) are shown. [Figure 1-111] Representative compounds of formula (IAA) are shown. [Figure 1-112] Representative compounds of formula (IAA) are shown. [Figure 1-113]Representative compounds of formula (IAA) are shown. [Figure 1-114] Representative compounds of formula (IAA) are shown. [Figure 1-115] Representative compounds of formula (IAA) are shown. [Figure 1-116] Representative compounds of formula (IAA) are shown. [Figure 1-117] Representative compounds of formula (IAA) are shown. [Figure 1-118] Representative compounds of formula (IAA) are shown. [Figure 1-119] Representative compounds of formula (IAA) are shown. [Figure 1-120] Representative compounds of formula (IAA) are shown. [Figure 1-121] Representative compounds of formula (IAA) are shown. [Figure 1-122] Representative compounds of formula (IAA) are shown. [Figure 1-123] Representative compounds of formula (IAA) are shown. [Figure 1-124] Representative compounds of formula (IAA) are shown. [Figure 1-125] Representative compounds of formula (IAA) are shown. [Figure 1-126] Representative compounds of formula (IAA) are shown. [Figure 1-127] Representative compounds of formula (IAA) are shown. [Figure 1-128] Representative compounds of formula (IAA) are shown. [Figure 1-129] Representative compounds of formula (IAA) are shown. [Figure 1-130] Representative compounds of formula (IAA) are shown. [Figure 1-131] Representative compounds of formula (IAA) are shown. [Figure 1-132] Representative compounds of formula (IAA) are shown. [Figure 1-133] Representative compounds of formula (IAA) are shown. [Figure 1-134] Representative compounds of formula (IAA) are shown. [Figure 1-135] Representative compounds of formula (IAA) are shown. [Figure 1-136]Representative compounds of formula (IAA) are shown. [Figure 1-137] Representative compounds of formula (IAA) are shown. [Figure 1-138] Representative compounds of formula (IAA) are shown. [Figure 1-139] Representative compounds of formula (IAA) are shown. [Figure 1-140] Representative compounds of formula (IAA) are shown. [Figure 1-141] Representative compounds of formula (IAA) are shown. [Figure 1-142] Representative compounds of formula (IAA) are shown. [Figure 1-143] Representative compounds of formula (IAA) are shown. [Figure 1-144] Representative compounds of formula (IAA) are shown. [Figure 1-145] Representative compounds of formula (IAA) are shown. [Figure 1-146] Representative compounds of formula (IAA) are shown. [Figure 1-147] Representative compounds of formula (IAA) are shown. [Figure 1-148] Representative compounds of formula (IAA) are shown. [Figure 1-149] Representative compounds of formula (IAA) are shown. [Figure 1-150] Representative compounds of formula (IAA) are shown. [Figure 1-151] Representative compounds of formula (IAA) are shown. [Figure 1-152] Representative compounds of formula (IAA) are shown. [Figure 1-153] Representative compounds of formula (IAA) are shown. [Figure 1-154] Representative compounds of formula (IAA) are shown. [Figure 1-155] Representative compounds of formula (IAA) are shown. [Figure 1-156] Representative compounds of formula (IAA) are shown. [Figure 1-157] Representative compounds of formula (IAA) are shown. [Figure 1-158] Representative compounds of formula (IAA) are shown. [Figure 1-159]Representative compounds of formula (IAA) are shown. [Figure 1-160] Representative compounds of formula (IAA) are shown. [Figure 1-161] Representative compounds of formula (IAA) are shown. [Figure 1-162] Representative compounds of formula (IAA) are shown. [Figure 1-163] Representative compounds of formula (IAA) are shown. [Figure 1-164] Representative compounds of formula (IAA) are shown. [Figure 1-165] Representative compounds of formula (IAA) are shown. [Figure 1-166] Representative compounds of formula (IAA) are shown. [Figure 1-167] Representative compounds of formula (IAA) are shown. [Figure 1-168] Representative compounds of formula (IAA) are shown. [Figure 1-169] Representative compounds of formula (IAA) are shown. [Figure 1-170] Representative compounds of formula (IAA) are shown. [Figure 1-171] Representative compounds of formula (IAA) are shown. [Figure 1-172] Representative compounds of formula (IAA) are shown. [Figure 1-173] Representative compounds of formula (IAA) are shown. [Figure 1-174] Representative compounds of formula (IAA) are shown. [Figure 1-175] Representative compounds of formula (IAA) are shown. [Figure 1-176] Representative compounds of formula (IAA) are shown. [Figure 1-177] Representative compounds of formula (IAA) are shown. [Figure 1-178] Representative compounds of formula (IAA) are shown. [Figure 1-179] Representative compounds of formula (IAA) are shown. [Figure 1-180] Representative compounds of formula (IAA) are shown. [Figure 1-181] Representative compounds of formula (IAA) are shown. [Figure 1-182]Representative compounds of formula (IAA) are shown. [Figure 1-183] Representative compounds of formula (IAA) are shown. [Figure 1-184] Representative compounds of formula (IAA) are shown. [Figure 1-185] Representative compounds of formula (IAA) are shown. [Figure 1-186] Representative compounds of formula (IAA) are shown. [Figure 1-187] Representative compounds of formula (IAA) are shown. [Figure 1-188] Representative compounds of formula (IAA) are shown. [Figure 1-189] Representative compounds of formula (IAA) are shown. [Figure 1-190] Representative compounds of formula (IAA) are shown. [Figure 1-191] Representative compounds of formula (IAA) are shown. [Figure 1-192] Representative compounds of formula (IAA) are shown. [Figure 1-193] Representative compounds of formula (IAA) are shown. [Figure 1-194] Representative compounds of formula (IAA) are shown. [Figure 1-195] Representative compounds of formula (IAA) are shown. [Figure 1-196] Representative compounds of formula (IAA) are shown. [Figure 1-197] Representative compounds of formula (IAA) are shown. [Figure 1-198] Representative compounds of formula (IAA) are shown. [Figure 1-199] Representative compounds of formula (IAA) are shown. [Figure 1-200] Representative compounds of formula (IAA) are shown. [Figure 1-201] Representative compounds of formula (IAA) are shown. [Figure 1-202] Representative compounds of formula (IAA) are shown. [Figure 1-203] Representative compounds of formula (IAA) are shown. [Figure 1-204] Representative compounds of formula (IAA) are shown. [Figure 1-205]Representative compounds of formula (IAA) are shown. [Figure 1-206] Representative compounds of formula (IAA) are shown. [Figure 1-207] Representative compounds of formula (IAA) are shown. [Figure 1-208] Representative compounds of formula (IAA) are shown. [Figure 1-209] Representative compounds of formula (IAA) are shown. [Figure 1-210] Representative compounds of formula (IAA) are shown. [Figure 1-211] Representative compounds of formula (IAA) are shown. [Figure 1-212] Representative compounds of formula (IAA) are shown. [Figure 1-213] Representative compounds of formula (IAA) are shown. [Figure 1-214] Representative compounds of formula (IAA) are shown. [Figure 1-215] Representative compounds of formula (IAA) are shown. [Figure 1-216] Representative compounds of formula (IAA) are shown. [Figure 1-217] Representative compounds of formula (IAA) are shown. [Figure 1-218] Representative compounds of formula (IAA) are shown. [Figure 1-219] Representative compounds of formula (IAA) are shown. [Figure 1-220] Representative compounds of formula (IAA) are shown. [Figure 1-221] Representative compounds of formula (IAA) are shown. [Figure 1-222] Representative compounds of formula (IAA) are shown. [Figure 1-223] Representative compounds of formula (IAA) are shown. [Figure 1-224] Representative compounds of formula (IAA) are shown. [Figure 1-225] Representative compounds of formula (IAA) are shown. [Figure 1-226] Representative compounds of formula (IAA) are shown. [Figure 1-227] Representative compounds of formula (IAA) are shown. [Figure 1-228]Representative compounds of formula (IAA) are shown. [Figure 1-229] Representative compounds of formula (IAA) are shown. [Figure 1-230] Representative compounds of formula (IAA) are shown. [Figure 1-231] Representative compounds of formula (IAA) are shown. [Figure 1-232] Representative compounds of formula (IAA) are shown. [Figure 1-233] Representative compounds of formula (IAA) are shown. [Figure 1-234] Representative compounds of formula (IAA) are shown. [Figure 1-235] Representative compounds of formula (IAA) are shown. [Figure 1-236] Representative compounds of formula (IAA) are shown. [Figure 1-237] Representative compounds of formula (IAA) are shown. [Figure 1-238] Representative compounds of formula (IAA) are shown. [Figure 1-239] Representative compounds of formula (IAA) are shown. [Figure 1-240] Representative compounds of formula (IAA) are shown. [Figure 1-241] Representative compounds of formula (IAA) are shown. [Figure 1-242] Representative compounds of formula (IAA) are shown. [Figure 1-243] Representative compounds of formula (IAA) are shown. [Figure 1-244] Representative compounds of formula (IAA) are shown. [Figure 1-245] Representative compounds of formula (IAA) are shown. [Figure 1-246] Representative compounds of formula (IAA) are shown. [Figure 1-247] Representative compounds of formula (IAA) are shown. [Figure 1-248] Representative compounds of formula (IAA) are shown. [Figure 1-249] Representative compounds of formula (IAA) are shown. [Figure 1-250] Representative compounds of formula (IAA) are shown. [Figure 1-251]Representative compounds of formula (IAA) are shown. [Modes for carrying out the invention]

[0067] Further definition To facilitate understanding of the disclosures contained herein, several further terms are defined below. In general, the nomenclature used herein, as well as the experimental methods in organic chemistry, medicinal chemistry, and pharmacology described herein, are well known and commonly used in the art. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as those commonly understood by those skilled in the art to which this disclosure belongs. Patents, applications, publications, and other publications referenced throughout this specification and its appendices are incorporated herein by reference in their entirety.

[0068] As used herein, the term "GLP-1R" is intended to include, in no particular way, its nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide chains, complementary sequences, peptides, polypeptides, proteins, homologous and / or orthologous GLP-1R molecules, isoforms, precursors, variants, variants, derivatives, splice variants, alleles, different species, and active fragments.

[0069] As used herein, the term "GIPR" is intended to include, in no particular way, nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide chains, complementary sequences, peptides, polypeptides, proteins, homologous and / or orthologous GIPR molecules, isoforms, precursors, variants, variants, derivatives, splice variants, alleles, different species, and active fragments.

[0070] As used herein, the term “acceptable” with respect to a formulation, composition, or component means that there is no sustained adverse effect on the systemic health of the subject being treated.

[0071] "API" stands for "Pharmaceutical Active Ingredient."

[0072] The terms "IC50" or "EC50" refer to the amount, concentration, or dose of a compound required to achieve 50% inhibition or 50% activation of the maximum response observed with respect to the compound (or, in some cases, the maximum response of a reference compound) in an assay measuring the maximum response.

[0073] As used herein, the terms “effective dose” or “therapeutic effective dose” mean an amount of a chemical entity administered (e.g., a compound, a pharmaceutically acceptable salt thereof, or a composition containing thereof, as generally or specifically described herein) that is sufficient to alleviate to some extent one or more symptoms of the disease or condition being treated. Results include a reduction and / or mitigation of the signs, symptoms, or causes of the disease, or any other desired change in the biological system. For example, “effective dose” in therapeutic use means the amount of a composition containing a compound disclosed herein that is necessary to achieve a clinically significant reduction in disease symptoms. The appropriate “effective” dose for any individual case is determined using any preferred technique, such as a dose-escalation study.

[0074] The terms “excipient” or “pharmaceutically acceptable excipient” mean a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In one embodiment, each component is “pharmaceutically acceptable” in the sense that it is compatible with the other components of a pharmaceutical preparation, suitable for use in contact with human and animal tissues or organs, free from excessive toxicity, irritation, allergic reactions, immunogenicity, or other problems or complications, and corresponding to a reasonable benefit-risk ratio. For example, Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

[0075] The term "pharmaceutically acceptable salt" means a formulation of a compound that does not cause significant irritation to the organism to which it is administered and does not inhibit the biological activity and biological properties of the compound. In certain cases, pharmaceutically acceptable salts are obtained by reacting the compounds described herein with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. In some cases, pharmaceutically acceptable salts are obtained by reacting the acidic group compounds described herein with alkali metal salts such as ammonium salts, sodium salts, or potassium salts; alkaline earth metal salts such as calcium salts, or magnesium salts; salts of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, and tris(hydroxymethyl)methylamine; and salts with amino acids such as arginine and lysine; or by other methods already established. Pharmacologically acceptable salts are not particularly limited as long as they are usable in pharmaceuticals. Examples of salts formed by the compounds described herein with bases include: salts of the compounds with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts of the compounds with organic bases such as methylamine, ethylamine, and ethanolamine; salts of the compounds with basic amino acids such as lysine and ornithine; and ammonium salts. The salts may be acid addition salts, with specific examples being acid addition salts with: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.

[0076] The term "pharmaceutical composition" means a mixture of the compounds described herein with other chemical components such as carriers, stabilizers, diluents, dispersants, suspending agents, and / or thickeners (collectively referred to herein as "excipients"). Pharmaceutical compositions facilitate the administration of the compounds to living organisms. There are several techniques in the art for administering the compounds, including but not limited to rectal administration, oral administration, intravenous administration, aerosol administration, parenteral administration, intraocular administration, intrapulmonary administration, and topical administration.

[0077] The term "subject" means animals including, but not limited to, primates (e.g., humans), monkeys, cows, pigs, sheep, goats, horses, dogs, cats, rabbits, rats, or mice. In this specification, the terms "subject" and "patient" are used interchangeably with respect to mammalian subjects, such as humans.

[0078] In the context of treating a disease, disorder, or condition, the terms “treat,” “treat,” and “treat” are intended to include reducing or suppressing one or more symptoms of the disorder, disorder, or condition, or one or more symptoms associated therewith; or slowing the progression, metastasis, or worsening of the disease, disorder, or condition, or one or more symptoms thereof.

[0079] The term "halo" refers to fluoro(F), chloro(Cl), bromo(Br), or iodine(I).

[0080] The term "alkyl" refers to a hydrocarbon chain that contains a specified number of carbon atoms and can be either linear or branched. For example, C 1~10 This indicates that the group may contain between 1 and 10 carbon atoms. Non-limiting examples include methyl, ethyl, isopropyl, tert-butyl, and n-hexyl.

[0081] The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by independently selected halos.

[0082] The term "alkoxy" refers to an -O-alkyl group (e.g., -OCH3).

[0083] The term "haloalkoxy" refers to an -O-haloalkyl group (e.g., -OCH3).

[0084] The term "alkylene" refers to a divalent branched or unbranched alkyl group (e.g., -CH2-).

[0085] Terms like "arirene" refer to the form of a divalent ring system, in this case, a divalent aryl.

[0086] The term "alkenyl" refers to a hydrocarbon chain that can be straight or branched, having one or more carbon-carbon double bonds. The alkenyl portion contains the indicated number of carbon atoms. For example, C 2~6 This indicates that the group may contain two to six carbon atoms.

[0087] The term "alkynyl" refers to a hydrocarbon chain that can be straight or branched, having one or more carbon-carbon triple bonds. The alkynyl portion contains the indicated number of carbon atoms. For example, C 2~6 This indicates that the group may contain two to six carbon atoms.

[0088] The term "aryl" refers to an aromatic ring system of 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic structures, where 0, 1, 2, 3, or 4 atoms in each ring may be substituted with substituents, the ring containing the monocyclic group is an aromatic ring, and at least one fused ring containing the bicyclic or tricyclic group is an aromatic ring, such as tetrahydronaphthyl. Examples of aryl groups include phenyl and naphthyl.

[0089] As used herein, the term "cycloalkyl" includes a saturated cyclic hydrocarbon group having 3 to 10 carbon atoms, preferably 3 to 8 carbon atoms, and more preferably 3 to 6 carbon atoms, which may be substituted. Preferred cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

[0090] The term "heteroaryl" means an aromatic ring system of 5-8 member monocyclic, 8-12 member bicyclic, or 11-14 member tricyclic forms, having 1-3 heteroatoms in the case of monocyclic, 1-6 heteroatoms in the case of bicyclic, or 1-9 heteroatoms in the case of tricyclic, wherein the heteroatoms are selected from O, N, or S (e.g., carbon atoms and, in the case of monocyclic, bicyclic, or tricyclic, 1-3, 1-6, or 1-9 N, O, or S heteroatoms, respectively), and 0, 1, 2, 3, or 4 atoms in each ring may be substituted with substituents, the ring containing the monocyclic group is an aromatic ring, and at least one fused ring containing the bicyclic or tricyclic group is an aromatic ring (however, the ring containing heteroatoms does not have to be, e.g., tetrahydroisoquinolinyl), and thus an aromatic ring system. Examples of heteroaryl groups include pyridyl, furyl or furanyl, imidazolyl, benzimidazolyl, pyrimidinyl, thiophenyl or thienyl, quinolinyl, indolyl, and thiazolyl.

[0091] The term "heterocyclyl" refers to an aromatic ring system of 5-8 member monocyclic, 8-12 member bicyclic, or 11-14 member tricyclic rings, having 1-3 heteroatoms in the case of monocyclic, 1-6 heteroatoms in the case of bicyclic, or 1-9 heteroatoms in the case of tricyclic, where the heteroatoms are selected from O, N, or S (e.g., carbon atoms and, in the case of monocyclic, bicyclic, or tricyclic, 1-3, 1-6, or 1-9 N, O, or S heteroatoms, respectively), and where 0, 1, 2, or 3 atoms in each ring may be substituted with substituents. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, and tetrahydrofuranyl.

[0092] Furthermore, the atoms constituting the compounds of this embodiment are intended to include all isotopic forms of the atom. The isotopes used herein include atoms with the same atomic number but different mass numbers. As a general and non-limiting example, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include... 13 C and 14 C is one example.

[0093] Details of one or more embodiments of the present invention are described below in the description and drawings. Other features and advantages will also be apparent from the claims.

[0094] Detailed explanation This disclosure features chemical entities (e.g., compounds, or pharmaceutically acceptable salts and / or hydrates and / or prodrugs) that modulate (e.g., stimulate, partially stimulate, or antagonize) the glucagon-like peptide 1 receptor ("GLP-1R") and / or gastric suppressor polypeptide receptor ("GIPR"). These chemical entities are useful, for example, for treating subjects (e.g., humans) having a disease, disorder, or condition, where the modulation (e.g., agonism, partial agonism, or antagonism) of GLP-1R and / or GIPR activity is beneficial for treating or preventing the underlying pathophysiology and / or symptoms and / or progression of the disease, disorder, or condition. In some embodiments, the modulation improves (e.g., increases) the current level (e.g., normal level or below normal level) of GLP-1R and / or GIPR activity (e.g., signaling). In some embodiments, the chemical entities described herein further modulate (e.g., attenuate, uncouple) β-arrestin signaling relative to that observed with the natural ligand. This disclosure also features compositions, as well as other methods for using and preparing the chemical entities.

[0095] In one aspect, this disclosure provides compounds having formula (IAA) or pharmaceutically acceptable salts thereof: TIFF0007933830000026.tif36128In formula, Ring A is, (i) 3 to 8 ring atoms (G), and a labeled nitrogen atom N * A saturated or unsaturated monocyclic ring containing (including); or (ii) 6 to 14 ring atoms (G, and labeled nitrogen atoms N) * (including) saturated or unsaturated bicyclic or tricyclic And; here G is C(O), S(O), or SO2; G and N * The circular dotted lines connecting them represent divalent groups containing 1 to 6 ring atoms; here (a) The divalent group has 0 to 2 ring atoms which are ring heteroatoms, each independently of N, N(R) a Selected from the group consisting of ), O, S, and SO2; (b) The 1 to 6 ring atoms of the divalent group are ring carbon atoms, and each is independently C, CH, CH2, CR b , C(R b )2, and CHR b Selected from the group consisting of; Here (1) If ring A is a monoring, each of the 1 to 6 ring carbon atoms of the divalent group can independently be CH, CH2, or CR. b , C(R b )2, and CHR b Selected from the group consisting of; (2) If ring A is biring or triring, then (A) or (B) below applies: (A) Two or three adjacent ring carbon atoms of a divalent group are independently C, CH, CH2, CR b , C(R b )2, and CHR b Selected from the group consisting of, (a) 1 to 5 independently selected R c Even if replaced by C 6~10 Ariel; (b) A heteroaryl compound containing 5 to 10 ring atoms, wherein 1 to 4 ring atoms are independently N, N(R) a R is selected from the group consisting of ), O, and S, and the heteroaryl is selected from 1 to 3 independently. c A heteroaryl that may be substituted with; (c) 1 to 4 independently selected R d Even if replaced by C 3~10 Cycloalkyl; (d) A heterocycline containing 3 to 10 ring atoms, wherein 1 to 3 ring atoms are independently N(R) a R is selected from the group consisting of ), O, and S, and the heterocyclyl is selected in a manner in which 1 to 4 independent individuals are selected. d Heterocyclines may be replaced by It is condensed with a second ring selected from the group consisting of; or, (B) One of the ring carbon atoms of the divalent group is C, and (a) 1 to 4 independently selected R d Even if replaced by C 3~10 Cycloalkyl; (b) A heterocycline containing 3 to 10 ring atoms, wherein 1 to 3 ring atoms are independently N(R) a R is selected from the group consisting of ), O, and S, and the heterocyclyl is selected in a manner in which 1 to 4 independent individuals are selected. d Heterocyclines may be replaced by It is spiro-condensed with a second ring selected from the group consisting of; L is (i) -(CH2) m -X 1 -(CH2) n -X 2 -(CH2) p -(Equation VIII), where m is between 1 and 6; n is between 0 and 2; and p is between 0 and 8. (ii) -C(O)-(CH2) n -X 3 -(CH2) p -(Equation IX), where n is between 0 and 2; p is between 0 and 8; (iii) -(CH2) q -, in the formula, q is between 1 and 10; (iv) -C(O)-; or (v) -(CH2) m -X 1 -(CH2) p -(Equation VIII), where m is between 1 and 6; p is between 0 and 8. and; X 1 is -C(O)-; -N(R')C(O)-; -C(O)N(R')-; or -N(R')C(O)NR')-; where each existence of R' is independently of H and C 1~4 Selected from the group consisting of alkyl groups; X 2 teeth, (i) -O-; (ii) -S-; (iii) -S(O) t -, where t is 1 or 2; (iv) -C(Q 1 )(Q 2 )-, in the formula, Q 1 and Q 2 H and C are independent of each other. 1~4 Selected from the group consisting of alkyl groups; or Q 1 and Q 2 Each of them, together with the carbon atoms to which it is bonded, becomes C 3~10 A cycloalkyl group is formed, and the cycloalkyl group consists of 1 to 4 independently selected R d It may be substituted with phenyl, or condensed with phenyl; (v) 1 to 5 independently selected R c Even if replaced by C 6~10 Ariren; (vi) A heteroarylene containing 5 to 10 ring atoms, wherein 1 to 4 ring atoms are independently N, N(R) a R is selected from the group consisting of ), O, and S, and the heteroarylene is selected from 1 to 5 independently. c Heteroarylenes which may be substituted with; (vii) 1 to 4 independently selected R d Even if replaced by C 3~10 Cycloalkylene; (viii) A heterocycloalkylene containing 3 to 10 ring atoms, wherein 1 to 3 ring atoms are independently N(R) a R is selected from the group consisting of ), O, and S, and the heterocycloalkylene is selected in a group of 1 to 5 independent elements. d Heterocycloalkylenes, which may be substituted with; (ix) 1-2 R e C2-C4 alkenylenes which may be substituted with; or (x) 1 to 2 R e C2-C4 alkynylenes may be substituted with and; X 3is -O-; -S-; or -S(O) t -, wherein t is 1 or 2; R 1 , R 2 , and R 4 are each independently selected from the group consisting of H and unsubstituted C 1~3 alkyl; R 2' is as defined by (AA) or (BB) below: (AA) R 2' is TIFF0007933830000027.tif25128, wherein R 3 is -C(O)OH, -C(O)OR 31 , -CH(C(O)OH)2, or a carboxylic acid isostere (e.g., amide or tetrazolyl); a is 0 to 5; a' is 0 or 1; R 3a and R 3b are each independently H or C 1~3 alkyl; (BB) R 2' and R 4 together with the atoms connecting them form a ring comprising 5 to 8 ring atoms, wherein 3 to 7 are ring carbon atoms each substituted with 1 to 2 substituents independently selected from H, halo, hydroxy, oxo, and C 1~3 alkyl; 0 to 1 is a heteroatom (other than the N bonded to R) selected from O, -NH, -N(C 1~3 alkyl), and S (for example, R 1 and R 4 together with the atoms to which they are each bonded form a ring comprising 5 to 8 ring atoms); 3 R 31 is (i) C optionally substituted with 1 to 2 independently selected R e 1~6 alkyl; ​​(ii) -(C 0~3 alkylene)-C 3~10 cycloalkyl, wherein said cycloalkyl is optionally substituted with 1 to 4 independently selected R d groups; cycloalkyl; (iii) -(C comprising 3 to 10 ring atoms 0~3 alkylene)-heterocyclyl, wherein 1 to 3 ring atoms are each independently selected from the group consisting of N(R a ), O, and S, and said heterocyclyl is optionally substituted with 1 to 4 independently selected R d groups; heterocyclyl; (iv) -(C 0~3 alkylene)-C 6~10 aryl, wherein said aryl is optionally substituted with 1 to 5 independently selected R c groups; aryl; or (v) -(C comprising 5 to 10 ring atoms 0~3 alkylene)-heteroaryl, wherein 1 to 4 ring atoms are each independently selected from the group consisting of N, N(R a ), O, and S, and said heteroaryl is optionally substituted with 1 to 3 independently selected R c groups; heteroaryl and; R a each occurrence of is independently selected from the group consisting of H; C 1~4 alkyl; C 3~6 cycloalkyl; -C(=O)(C 1~6 alkyl); -C(=O)O(C 1~6 alkyl); and -S(O) 1~2 (C 1~6 alkyl); R b each occurrence of is independently R 31 ; C 1~4 haloalkyl; -OH; oxo; -F; -N(R a )(R''); C 1~4 alkoxy; C 1~4 haloalkoxy; -C(=O)(C 1~4 alkyl); -C(=O)O(C 1~6alkyl); -C(=O)OH; -C(=O)N(R''')(R''''); -S(O) 1~2 (C 1~6 Selected from the group consisting of alkyl and cyano; R c Each existence is independently selected from 1 to 2 independently selected R e Even if replaced by C 1~6 Alkyl; C 3~6 Cycloalkyl; C 1~4 Haloalkyl; -OH; -halo; -NO2; N3; -N(R) a )(R''); C 1~4 Alkoxy; C 1~4 Thioalkoxy; C 1~4 Haloalkoxy; -OC(=O)(C 1~6 alkyl); -C(=O)(C 1~6 alkyl); -C(=O)O(C 1~6 alkyl); -C(=O)OH; -C(=O)N(R''')(R''''); -S(O) 1~2 (C 1~6 Selected from the group consisting of alkyl and cyano; R d Each existence is independently selected from 1 to 2 independently selected R e Even if replaced by C 1~6 Alkyl; C 1~4 Haloalkyl; -OH; -F; Cl; -N(R) a )(R''); Oxo; C 1~4 Alkoxy; C 1~4 Haloalkoxy; -OC(=O)(C 1~6 alkyl); -C(=O)(C 1~6 alkyl); -C(=O)O(C 1~6 alkyl); -C(=O)OH; -C(=O)N(R''')(R''''); -S(O) 1~2 (C 1~6 Selected from the group consisting of alkyl and cyano; R e Each existence of -OH; -N(R a )(R''); C 1~4 Alkoxy; C1~4 Haloalkoxy; -OC(=O)(C 1~6 alkyl); -C(=O)O(C 1~6 alkyl); -C(=O)OH; -C(=O)N(R''')(R''''); -S(O) 1~2 (C 1~6 Selected from the group consisting of alkyl and cyano; The existence of R'', R''', and R'''' is independent of H and C 1~6 Selected from the group consisting of alkyl groups; W is given by the formula W'-R 5 It is a peptide having, where W' is a sequence of 5 to 60 amino acids, and R 5 This is a C-terminal amino acid, amino acid ester, or amino acid amide, which may be substituted with one or two modifying groups (e.g., one or two groups selected from an acyl group and a PEG group).

[0096] In some embodiments, the compound has the formula (IIAA). TIFF0007933830000028.tif36128

[0097] In some embodiments, the compound has the formula (IIAA-B). TIFF0007933830000029.tif36128

[0098] In some embodiments, the compound has formula (IA): TIFF0007933830000030.tif38128In formula, Ring A is, (i) 3 to 8 ring atoms (G), and a labeled nitrogen atom N * A saturated or unsaturated monocyclic ring containing (including); or (ii) 6 to 14 ring atoms (G, and labeled nitrogen atoms N) * (including) saturated or unsaturated bicyclic or tricyclic And; here G is C(O), S(O), or SO2; G and N *The circular dotted line connecting the two represents a divalent group containing 1 to 6 ring atoms; where (a) 0 to 2 of the ring atoms of the divalent group are ring heteroatoms, each independently selected from the group consisting of N, N(R a ), O, S, and SO2; (b) 1 to 6 of the ring atoms of the divalent group are ring carbon atoms, each independently selected from the group consisting of C, CH, CH2, CR b , C(R b )2, and CHR b ; where (1) When Ring A is a monocyclic ring, each of the 1 to 6 ring carbon atoms of the divalent group is independently selected from the group consisting of CH, CH2, CR b , C(R b )2, and CHR b ; (2) When Ring A is a bicyclic or tricyclic ring, the following (A) or (B) applies: (A) 2 or 3 adjacent ring carbon atoms of the divalent group are each independently selected from the group consisting of C, CH, and CR b , and (a) C aryl which may be substituted with 1 to 5 independently selected R c ; 6~10 ; (b) Heteroaryl containing 5 to 10 ring atoms, wherein 1 to 4 ring atoms are each independently selected from the group consisting of N, N(R a ), O, and S, and the heteroaryl may be substituted with 1 to 3 independently selected R c ; (c) C cycloalkyl which may be substituted with 1 to 4 independently selected R d ; 3~10 ; (d) Heterocyclyl containing 3 to 10 ring atoms, wherein 1 to 3 ring atoms are each independently selected from the group consisting of N(R a ), O, and S, and the heterocyclyl may be substituted with 1 to 4 independently selected R d ; It is condensed with a second ring selected from the group consisting of; or, (B) One of the ring carbon atoms of the divalent group is C, and (a) 1 to 4 independently selected R d Even if replaced by C 3~10 Cycloalkyl; (b) A heterocycline containing 3 to 10 ring atoms, wherein 1 to 3 ring atoms are independently N(R) a R is selected from the group consisting of ), O, and S, and the heterocyclyl is selected in a manner in which 1 to 4 independent individuals are selected. d Heterocyclines may be replaced by It is spiro-condensed with a second ring selected from the group consisting of; L is (i) -(CH2) m -X 1 -(CH2) n -X 2 -(CH2) p -(Equation VIII), where m is between 1 and 6; n is between 0 and 2; and p is between 0 and 8. (ii) -C(O)-(CH2) n -X 3 -(CH2) p -(Equation IX), where n is between 0 and 2; p is between 0 and 8; (iii) -(CH2) q -, in the formula, q is between 1 and 10; (iv) -C(O)-; or (v) -(CH2) m -X 1 -(CH2) p -(Equation VIII), where m is between 1 and 6; p is between 0 and 8. and; X 1 is -C(O)-; -N(R')C(O)-; -C(O)N(R')-; or -N(R')C(O)NR')-; where each existence of R' is independently of H and C 1~4 Selected from the group consisting of alkyl groups; X 2 teeth, (i) -O-; (ii) -S-; (iii) -S(O) t -, where t is 1 or 2; (iv) -C(Q 1 )(Q 2 )-, in the formula, Q 1 and Q 2 H and C are independent of each other. 1~4 Selected from the group consisting of alkyl groups; or Q 1 and Q 2 Each of them, together with the carbon atoms to which it is bonded, becomes C 3~10 A cycloalkyl group is formed, and the cycloalkyl group consists of 1 to 4 independently selected R d It may be substituted with phenyl, or condensed with phenyl; (v) 1 to 5 independently selected R c Even if replaced by C 6~10 Ariren; (vi) A heteroarylene containing 5 to 10 ring atoms, wherein 1 to 4 ring atoms are independently N, N(R) a R is selected from the group consisting of ), O, and S, and the heteroarylene is selected from 1 to 5 independently. c Heteroarylenes which may be substituted with; (vii) 1 to 4 independently selected R d Even if replaced by C 3~10 Cycloalkylene; (viii) A heterocycloalkylene containing 3 to 10 ring atoms, wherein 1 to 3 ring atoms are independently N(R) a R is selected from the group consisting of ), O, and S, and the heterocycloalkylene is selected in a group of 1 to 5 independent elements. d Heterocycloalkylenes, which may be substituted with; (ix) 1-2 R e C2-C4 alkenylenes which may be substituted with; or (x) 1 to 2 R e C2-C4 alkynylenes may be substituted with and; X 3is -O-; -S-; or -S(O) t - and in the formula t is 1 or 2; R 1 , R 2 , and R 4 These are H and unsubstituted C, respectively, independently. 1~3 Selected from the group consisting of alkyl groups; R 3 -C(O)OH, -C(O)OR 31 It is -CH(C(O)OH)2, or a carboxylic acid isoster (e.g., amide or tetrazolyl); a is between 0 and 5; a' is either 0 or 1; R 3a and R 3b Each is independently H or C 1~3 It is alkyl; R 31 teeth, (i) 1 to 2 independently selected R e Even if replaced by C 1~6 alkyl; (ii) -(C 0~3 Alkylene)-C 3~10 A cycloalkyl group, wherein the cycloalkyl group consists of 1 to 4 independently selected R d A cycloalkyl group which may be substituted with; (iii) Contains 3 to 10 ring atoms - (C 0~3 Alkylene)-heterocyclyl, in which 1 to 3 ring atoms are independently N(R) a R is selected from the group consisting of ), O, and S, and the heterocyclyl is selected in a manner in which 1 to 4 independent individuals are selected. d A heterocycline that may be substituted with; (iv) -(C 0~3 Alkylene)-C 6~10 An aryl, wherein the aryl is composed of 1 to 5 independently selected R c The aryl may be replaced by; or (v) Contains 5 to 10 ring atoms - (C 0~3 Alkylene)-heteroaryl, where 1 to 4 ring atoms are independently N, N(R)a R is selected from the group consisting of ), O, and S, and the heteroaryl is selected from 1 to 3 independently. c Heteroaryls may be substituted with and; R a Each of the entities is independent of H; C 1~4 Alkyl; C 3~6 Cycloalkyl; -C(=O)(C 1~6 alkyl); -C(=O)O(C 1~6 alkyl); and -S(O) 1~2 (C 1~6 Selected from the group consisting of alkyl groups; R b Each existence of R is independent. 31 ; C 1~4 Haloalkyl; -OH; Oxo; -F; -N(R) a )(R''); C 1~4 Alkoxy; C 1~4 Haloalkoxy; -C(=O)(C 1~4 alkyl); -C(=O)O(C 1~6 alkyl); -C(=O)OH; -C(=O)N(R''')(R''''); -S(O) 1~2 (C 1~6 Selected from the group consisting of alkyl and cyano; R c Each existence is independently selected from 1 to 2 independently selected R e Even if replaced by C 1~6 Alkyl; C 3~6 Cycloalkyl; C 1~4 Haloalkyl; -OH; -halo; -NO2; N3; -N(R) a )(R''); C 1~4 Alkoxy; C 1~4 Thioalkoxy; C 1~4 Haloalkoxy; -OC(=O)(C 1~6 alkyl); -C(=O)(C 1~6 alkyl); -C(=O)O(C 1~6 alkyl); -C(=O)OH; -C(=O)N(R''')(R''''); -S(O) 1~2 (C1~6 Selected from the group consisting of alkyl and cyano; R d Each existence is independently selected from 1 to 2 independently selected R e Even if replaced by C 1~6 Alkyl; C 1~4 Haloalkyl; -OH; -F; Cl; -N(R) a )(R''); Oxo; C 1~4 Alkoxy; C 1~4 Haloalkoxy; -OC(=O)(C 1~6 alkyl); -C(=O)(C 1~6 alkyl); -C(=O)O(C 1~6 alkyl); -C(=O)OH; -C(=O)N(R''')(R''''); -S(O) 1~2 (C 1~6 Selected from the group consisting of alkyl and cyano; R e Each existence of -OH; -N(R a )(R''); C 1~4 Alkoxy; C 1~4 Haloalkoxy; -OC(=O)(C 1~6 alkyl); -C(=O)O(C 1~6 alkyl); -C(=O)OH; -C(=O)N(R''')(R''''); -S(O) 1~2 (C 1~6 Selected from the group consisting of alkyl and cyano; The existence of R'', R''', and R'''' is independent of H and C 1~6 Selected from the group consisting of alkyl groups; W is given by the formula W'-R 5 It is a peptide having, where W' is a sequence of 5 to 60 amino acids, and R 5 This is a C-terminal amino acid, amino acid ester, or amino acid amide, which may be substituted with one or two modifying groups (e.g., one or two groups selected from an acyl group and a PEG group).

[0099] In some embodiments, the compound has formula (IIA). TIFF0007933830000031.tif38128

[0100] In some embodiments, the compound has formula (I): TIFF0007933830000032.tif36128In formula, Ring A is, (i) 3 to 8 ring atoms (G), and a labeled nitrogen atom N * A saturated or unsaturated monocyclic ring containing (including); or (ii) 6 to 14 ring atoms (G, and labeled nitrogen atoms N) * (including) saturated or unsaturated bicyclic or tricyclic And; here G is C(O), S(O), or SO2; G and N * The circular dotted lines connecting them represent divalent groups containing 1 to 6 ring atoms; here (a) The divalent group has 0 to 2 ring atoms which are ring heteroatoms, each independently of N, N(R) a Selected from the group consisting of ), O, S, and SO2; (b) The 1 to 6 ring atoms of the divalent group are ring carbon atoms, and each is independently C, CH, CH2, CR b , C(R b )2, and CHR b Selected from the group consisting of; Here (1) If ring A is a monoring, each of the 1 to 6 ring carbon atoms of the divalent group can independently be CH, CH2, or CR. b , C(R b )2, and CHR b Selected from the group consisting of; (2) If ring A is biring or triring, then (A) or (B) below applies: (A) Two or three adjacent ring carbon atoms of the divalent group are, independently, C, CH, and CR. b Selected from the group consisting of, (a) 1 to 5 independently selected R c Even if replaced by C 6~10Ariel; (b) A heteroaryl compound containing 5 to 10 ring atoms, wherein 1 to 4 ring atoms are independently N, N(R) a R is selected from the group consisting of ), O, and S, and the heteroaryl is selected from 1 to 3 independently. c A heteroaryl that may be substituted with; (c) 1 to 4 independently selected R d Even if replaced by C 3~10 Cycloalkyl; (d) A heterocycline containing 3 to 10 ring atoms, wherein 1 to 3 ring atoms are independently N(R) a R is selected from the group consisting of ), O, and S, and the heterocyclyl is selected in a manner in which 1 to 4 independent individuals are selected. d Heterocyclines may be replaced by It is condensed with a second ring selected from the group consisting of; or, (B) One of the ring carbon atoms of the divalent group is C, and (a) 1 to 4 independently selected R d Even if replaced by C 3~10 Cycloalkyl; (b) A heterocycline containing 3 to 10 ring atoms, wherein 1 to 3 ring atoms are independently N(R) a R is selected from the group consisting of ), O, and S, and the heterocyclyl is selected in a manner in which 1 to 4 independent individuals are selected. d Heterocyclines may be replaced by It is spiro-condensed with a second ring selected from the group consisting of; L is (i) -(CH2) m -X 1 -(CH2) n -X 2 -(CH2) p -(Equation VIII), where m is between 1 and 6; n is between 0 and 2; and p is between 0 and 8. (ii) -C(O)-(CH2) n -X 3 -(CH2) p-(Equation IX), where n is between 0 and 2; p is between 0 and 8; (iii) -(CH2) q -, in the formula, q is between 1 and 10; (iv) -C(O)-; or (v) -(CH2) m -X 1 -(CH2) p -(Equation VIII), where m is between 1 and 6; p is between 0 and 8. and; X 1 is -C(O)-; -N(R')C(O)-; -C(O)N(R')-; or -N(R')C(O)NR')-; where each existence of R' is independently of H and C 1~4 Selected from the group consisting of alkyl groups; X 2 teeth, (i) -O-; (ii) -S-; (iii) -S(O) t -, where t is 1 or 2; (iv) -C(Q 1 )(Q 2 )-, in the formula, Q 1 and Q 2 H and C are independent of each other. 1~4 Selected from the group consisting of alkyl groups; or Q 1 and Q 2 Each of them, together with the carbon atoms to which it is bonded, becomes C 3~10 A cycloalkyl group is formed, and the cycloalkyl group consists of 1 to 4 independently selected R d It may be substituted with phenyl, or condensed with phenyl; (v) 1 to 5 independently selected R c Even if replaced by C 6~10 Ariren; (vi) A heteroarylene containing 5 to 10 ring atoms, wherein 1 to 4 ring atoms are independently N, N(R) a R is selected from the group consisting of ), O, and S, and the heteroarylene is selected from 1 to 5 independently. cHeteroarylenes which may be substituted with; (vii) 1 to 4 independently selected R d Even if replaced by C 3~10 Cycloalkylene; (viii) A heterocycloalkylene containing 3 to 10 ring atoms, wherein 1 to 3 ring atoms are independently N(R) a R is selected from the group consisting of ), O, and S, and the heterocycloalkylene is selected in a group of 1 to 5 independent elements. d Heterocycloalkylenes, which may be substituted with; (ix) 1-2 R e C2-C4 alkenylenes which may be substituted with; or (x) 1 to 2 R e C2-C4 alkynylenes may be substituted with and; X 3 is -O-; -S-; or -S(O) t - and in the formula t is 1 or 2; R 1 , R 2 , and R 4 These are H and unsubstituted C, respectively, independently. 1~3 Selected from the group consisting of alkyl groups; R 3 -C(O)OH, -C(O)OR 31 , or a carboxylic acid isoster; where R 31 teeth, (i) 1 to 2 independently selected R e Even if replaced by C 1~6 alkyl; (ii) -(C 0~3 Alkylene)-C 3~10 A cycloalkyl group, wherein the cycloalkyl group consists of 1 to 4 independently selected R d A cycloalkyl group which may be substituted with; (iii) Contains 3 to 10 ring atoms - (C 0~3 Alkylene)-heterocyclyl, in which 1 to 3 ring atoms are independently N(R) aR is selected from the group consisting of ), O, and S, and the heterocyclyl is selected in a manner in which 1 to 4 independent individuals are selected. d A heterocycline that may be substituted with; (iv) -(C 0~3 Alkylene)-C 6~10 An aryl, wherein the aryl is composed of 1 to 5 independently selected R c The aryl may be replaced by; or (v) Contains 5 to 10 ring atoms - (C 0~3 Alkylene)-heteroaryl, where 1 to 4 ring atoms are independently N, N(R) a R is selected from the group consisting of ), O, and S, and the heteroaryl is selected from 1 to 3 independently. c Heteroaryls may be substituted with and; a is between 0 and 5; R a Each of the entities is independent of H; C 1~4 Alkyl; C 3~6 Cycloalkyl; -C(=O)(C 1~6 alkyl); -C(=O)O(C 1~6 alkyl); and -S(O) 1~2 (C 1~6 Selected from the group consisting of alkyl groups; R b Each existence of R is independent. 31 ; C 1~4 Haloalkyl; -OH; Oxo; -F; -N(R) a )(R''); C 1~4 Alkoxy; C 1~4 Haloalkoxy; -C(=O)(C 1~4 alkyl); -C(=O)O(C 1~6 alkyl); -C(=O)OH; -C(=O)N(R''')(R''''); -S(O) 1~2 (C 1~6 Selected from the group consisting of alkyl and cyano; R c Each existence is independently selected from 1 to 2 independently selected R e Even if replaced by C 1~6Alkyl; C 3~6 Cycloalkyl; C 1~4 Haloalkyl; -OH; -halo; -NO2; N3; -N(R) a )(R''); C 1~4 Alkoxy; C 1~4 Thioalkoxy; C 1~4 Haloalkoxy; -OC(=O)(C 1~6 alkyl); -C(=O)(C 1~6 alkyl); -C(=O)O(C 1~6 alkyl); -C(=O)OH; -C(=O)N(R''')(R''''); -S(O) 1~2 (C 1~6 Selected from the group consisting of alkyl and cyano; Each R d Each existence is independently selected from 1 to 2 independently selected R e Even if replaced by C 1~6 Alkyl; C 1~4 Haloalkyl; -OH; -F; Cl; -N(R) a )(R''); Oxo; C 1~4 Alkoxy; C 1~4 Haloalkoxy; -OC(=O)(C 1~6 alkyl); -C(=O)(C 1~6 alkyl); -C(=O)O(C 1~6 alkyl); -C(=O)OH; -C(=O)N(R''')(R''''); -S(O) 1~2 (C 1~6 Selected from the group consisting of alkyl and cyano; Each R e Each existence of -OH; -N(R a )(R''); C 1~4 Alkoxy; C 1~4 Haloalkoxy; -OC(=O)(C 1~6 alkyl); -C(=O)O(C 1~6 alkyl); -C(=O)OH; -C(=O)N(R''')(R''''); -S(O) 1~2 (C 1~6 Selected from the group consisting of alkyl and cyano; The existences of R'', R''', and R'''' are, independently of each other, H and C 1~6 Selected from the group consisting of alkyl groups; W is given by the formula W'-R 5 It is a peptide having, where W' is a sequence of 5 to 60 amino acids, and R 5 This is a C-terminal amino acid, amino acid ester, or amino acid amide, which may be substituted with one or two modifying groups (e.g., one or two groups selected from an acyl group and a PEG group).

[0101] In some embodiments, one or more of the compound conditions described herein (for example, those described in the following sections) are applied.

[0102] Compound conditions In some embodiments, the compound is other than CAS RN 1401463-49-7; and / or CAS RN 1116465-43-0; and / or CAS RN 1614237-35-2, and / or CAS RN 1614237-36-3; and / or CAS RN 1353718-57-6; and / or CAS Registry No. 1083307-90-7, where each registered chemical structure is incorporated herein by reference.

[0103] In some embodiments, the compound is not one of the compounds disclosed in Nacheva et al., Organic & Biomolecular Chemistry, 2012, 10 (38), 7840-7846, Chopra et al., Bioconjugate Chemistry, 2009, 20 (2), 231-240, and PCT application publication number WO 2013 / 148579, which are incorporated by reference, respectively.

[0104] In some embodiments, ring A is other than unsubstituted maleimido-1-yl, i.e., other than the following formula. TIFF0007933830000033.tif40128

[0105] In certain embodiments, when L is -(CH2)2-, -(CH2)5-C(O)NH-CH2-, or -(CH2)2-C(O)NH-(CH2)6-, ring A is not unsubstituted maleimido-1-yl.

[0106] In certain embodiments, when L is -(CH2)2-, -(CH2)5-C(O)NH-CH2-, or -(CH2)2-C(O)NH-(CH2)6-, and a is 1, ring A is not unsubstituted maleimido-1-yl.

[0107] In some embodiments, ring A is other than substituted maleimido-1-yl (e.g., other than 3,4-bis(2,4-difluorophenyl)-maleimido-1-yl, i.e., other than the formula below). TIFF0007933830000034.tif35128

[0108] In certain embodiments, when L is -(CH2)3-, ring A is other than substituted maleimido-1-yl (e.g., other than 3,4-bis(2,4-difluorophenyl)-maleimido-1-yl).

[0109] In certain embodiments, when L is -(CH2)3- and a is 1, ring A is other than substituted maleimido-1-yl (e.g., other than 3,4-bis(2,4-difluorophenyl)-maleimido-1-yl).

[0110] In some embodiments, ring A is other than N-[2-(1,3-dioxo-1H-benzo[de]isoquinoline-2(3H)-yl, which may be substituted (for example, other than unsubstituted N-[2-(1,3-dioxo-1H-benzo[de]isoquinoline-2(3H)-yl, i.e., other than the formula below). TIFF0007933830000035.tif35128

[0111] In certain embodiments, when L is -(CH2)3-, ring A is other than N-[2-(1,3-dioxo-1H-benzo[de]isoquinoline-2(3H)-yl, which may be substituted (for example, other than unsubstituted N-[2-(1,3-dioxo-1H-benzo[de]isoquinoline-2(3H)-yl).

[0112] In certain embodiments, when L is -(CH2)3- and a is 0, ring A is other than substituted N-[2-(1,3-dioxo-1H-benzo[de]isoquinoline-2(3H)-yl) (for example, other than unsubstituted N-[2-(1,3-dioxo-1H-benzo[de]isoquinoline-2(3H)-yl).

[0113] In some embodiments, ring A is (i) Unsubstituted maleimido-1-yl; and (ii) Anything other than substituted maleimido-1-yl (e.g., 3,4-bis(2,4-difluorophenyl)-maleimido-1-yl).

[0114] In some embodiments, ring A is (i) Unsubstituted maleimido-1-yl; (ii) Substituted maleimido-1-yl (e.g., 3,4-bis(2,4-difluorophenyl)-maleimido-1-yl); and (iii) Any compound other than N-[2-(1,3-dioxo-1H-benzo[de]isoquinoline-2(3H)-yl) which may be substituted (e.g., unsubstituted N-[2-(1,3-dioxo-1H-benzo[de]isoquinoline-2(3H)-yl)).

[0115] In some cases, (i) If L is -(CH2)2-, -(CH2)5-C(O)NH-CH2-, or -(CH2)2-C(O)NH-(CH2)6-, then ring A is not unsubstituted maleimido-1-yl; (ii) If L is -(CH2)3-, then ring A is not substituted maleimido-1-yl (e.g., not 3,4-bis(2,4-difluorophenyl)-maleimido-1-yl).

[0116] In some cases, (i) If L is -(CH2)2-, -(CH2)5-C(O)NH-CH2-, or -(CH2)2-C(O)NH-(CH2)6-, and a is 1, then ring A is not unsubstituted maleimido-1-yl; (ii) If L is -(CH2)3- and a is 1, then ring A is not substituted maleimido-1-yl (e.g., not 3,4-bis(2,4-difluorophenyl)-maleimido-1-yl).

[0117] In some cases, (i) If L is -(CH2)2-, -(CH2)5-C(O)NH-CH2-, or -(CH2)2-C(O)NH-(CH2)6-, then ring A is not unsubstituted maleimido-1-yl; (ii) If L is -(CH2)3-, then ring A is not substituted maleimido-1-yl (e.g., not 3,4-bis(2,4-difluorophenyl)-maleimido-1-yl); (iii) If L is -(CH2)3-, then ring A is any other than N-[2-(1,3-dioxo-1H-benzo[de]isoquinoline-2(3H)-yl, which may be substituted (for example, any other than unsubstituted N-[2-(1,3-dioxo-1H-benzo[de]isoquinoline-2(3H)-yl).

[0118] In some cases, (i) If L is -(CH2)2-, -(CH2)5-C(O)NH-CH2-, or -(CH2)2-C(O)NH-(CH2)6-, and a is 1, then ring A is not unsubstituted maleimido-1-yl; (ii) If L is -(CH2)3- and a is 1, then ring A is not substituted maleimido-1-yl (e.g., not 3,4-bis(2,4-difluorophenyl)-maleimido-1-yl); (iii) If L is -(CH2)3- and a is 0, then ring A is any other than N-[2-(1,3-dioxo-1H-benzo[de]isoquinoline-2(3H)-yl, which may be substituted (for example, any other than unsubstituted N-[2-(1,3-dioxo-1H-benzo[de]isoquinoline-2(3H)-yl).

[0119] In some embodiments, the first three amino acids in W' must be glycine-threonine-phenylalanine (GTF).

[0120] In some embodiments, W' must contain 11 or more amino acids (for example, 12 or more, 13 or more, 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, 19 or more, 20 or more, 25 or more, or 30 or more amino acids).

[0121] In some embodiments, the first three amino acids in W' must be glycine-threonine-phenylalanine (GTF), and W' must contain 11 or more amino acids (e.g., 12 or more, 13 or more, 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, 19 or more, 20 or more, 25 or more, 30 or more amino acids).

[0122] In some of these embodiments, one or more of the following apply: Ring A is unsubstituted maleimido-1-yl and L is -(CH2)2-, -(CH2)5-C(O)NH-CH2-, or -(CH2)2-C(O)NH-(CH2)6- (in some cases, a is 1). Ring A is substituted maleimido-1-yl (e.g., 3,4-bis(2,4-difluorophenyl)-maleimido-1-yl) and L is -(CH2)3- (in some cases, a is 1). Ring A is optionally substituted N-[2-(1,3-dioxo-1H-benzo[de]isoquinoline-2(3H)-yl) (e.g., unsubstituted N-[2-(1,3-dioxo-1H-benzo[de]isoquinoline-2(3H)-yl) (in some cases, a is 0).

[0123] In certain embodiments, L is (CH2) q In this case, q is not 3. In certain embodiments, ring A has two R b Substituted with R b If neither group is o,p-(difluoro)phenyl, or if ring A is substituted with two o,p-(difluoro)phenyl groups, the first amino acid in sequence W' is not valine; or if ring A is substituted with two o,p-(difluoro)phenyl groups, L is not (CH2)3; or if L is (CH2)3, the first amino acid in sequence W' is not valine.

[0124] In certain embodiments, L is -(CH2) m -X 1 -(CH2) n -X 2 -(CH2) p - and m is 5, X 1 The expression is -C(O)NH-, and n and p are both 0, X 2 CQ 1 Q 2 If Q 1 and Q 2 At least one of them is not H. In certain embodiments, L is -(CH2) m -X 1 -(CH2) n -X 2 -(CH2) p - and m is 5, X 1 The expression is -C(O)NH-, and n and p are both 0, X 2 If is CH2, then ring A is not -N-maleimide. In certain embodiments, L is -(CH2) m -X 1 -(CH2) n -X 2 -(CH2) p - and m is 5, X 1 The expression is -C(O)NH-, and n and p are both 0, X 2 If the molecule is CH2 and ring A is -N-maleimide, then the first amino acid in sequence W' is not glycine.

[0125] In certain embodiments, L is -(CH2) m -X 1 -(CH2) n -X 2 -(CH2) p - and m is 2, X 1 The expression is -C(O)NH-, and the sum of n and p is 5, X 2 CQ 1 Q 2 If Q 1 and Q 2 At least one of them is not H. In certain embodiments, L is -(CH2) m -X 1 -(CH2) n -X 2 -(CH2) p - and m is 2, X 1 The expression is -C(O)NH-, and the sum of n and p is 5, X 2 If is CH2, then ring A is not -N-maleimide. In certain embodiments, L is -(CH2) m -X 1 -(CH2) n -X 2 -(CH2) p - and m is 2, X 1 The expression is -C(O)NH-, and the sum of n and p is 5, X 2 If the first amino acid is CH2 and ring A is -N-maleimide, then the first amino acid in sequence W' is not alanine.

[0126] In certain embodiments, L is (CH2) q If L is (CH2)2, then q is not 2; or, if L is (CH2)2, then ring A is not -N-maleimide; or, if L is (CH2)2 and ring A is -N-maleimide, then the first amino acid in sequence W' is not alanine.

[0127] Ring A In some embodiments, G is C(O). Non-limiting examples of such compounds include those of formula (IA), (I-AA), and (I-AB). TIFF0007933830000036.tif156128

[0128] Further non-limiting examples include compounds having the formulas (IA-A), (IA-AA), or (IA-AB). TIFF0007933830000037.tif146128

[0129] In some embodiments, G is S(O) or SO2. Non-limiting examples of such compounds include those of formula (IB), (I-BA), or (I-BB). TIFF0007933830000038.tif141128

[0130] Further non-limiting examples include compounds having the formulas (IA-B), (IA-BA), or (IA-BB). TIFF0007933830000039.tif147128

[0131] In some embodiments, ring A is a saturated or unsaturated monoring containing 3 to 8 ring atoms (e.g., 4 to 8, 4 to 7, or 5 to 6).

[0132] In some of these embodiments, ring A is a saturated ring. In other embodiments, ring A is an unsaturated ring. In some of these embodiments, ring A contains 4 to 7 ring atoms or 5 to 6 ring atoms.

[0133] In certain embodiments, ring A is a saturated monoring containing 3 to 8 ring atoms (e.g., 4 to 8, 4 to 7, or 5 to 6).

[0134] In certain embodiments, ring A is a saturated monoring containing 5 to 7 ring atoms.

[0135] In certain embodiments, ring A is a saturated monoring containing 5 to 6 ring atoms.

[0136] In certain embodiments, ring A has the following formula (III): TIFF0007933830000040.tif34128In formula, A1 is a bond, A 1A -A 1B , C(O), CH2, CHR b , or C(R b )2; A 1A and A 1B These are C(O), CH2, and CHR, respectively, and are independent of each other. b , or C(R b )2; A2 is C(O), CH2, CHR b , or C(R b )2; A3 is C(O), CH2, CHR b , or C(R b )2; O; S; SO2; or N(R a ) and; A4 is C(O), CH2, CHR b , or C(R b )2; O; S; or N(R a ) However, if A3 and A4 are both O; S; or N(R a ); or it cannot be a combination of those.

[0137] In certain embodiments, ring A has formula (III): TIFF0007933830000041.tif33128In formula, A1 represents a bond, C(O), CH2, CHR b , or C(R b )2; A2 is C(O), CH2, CHR b , or C(R b )2; A3 is C(O), CH2, CHR b , or C(R b )2; O; S; SO2; or N(R a ) and; A4 is CH2, CHR b , or C(R b )2; O; S; or N(R a) However, if A3 and A4 are both O; S; or N(R a ); or it cannot be a combination of those.

[0138] In certain aspects of formula (III), A1 is not a bond (i.e., A1 is C(O), CH2, CHR). b , or C(R b )2) and ring A contains 6 ring atoms (i.e., ring A is a 6-membered ring).

[0139] In a specific form of the six-membered ring of formula (III), A1 is CH2, CHR b , or C(R b )2. For example, A1 can be CH2. In other embodiments, A1 is C(O).

[0140] In a specific form of the six-membered ring of formula (III), A2 is CH2, CHR b , or C(R b )2. For example, A2 can be CH2.

[0141] In a specific form of the six-membered ring of formula (III), A3 is CH2, CHR b , or C(R b )2. For example, A3 can be CH2. In other embodiments, A3 can be O; S; SO2; or N(R a )

[0142] In a specific form of the six-membered ring of formula (III), A4 is CH2, CHR b , or C(R b )2. For example, A4 can be CH2. In other embodiments, A4 is O; S; or N(R a )

[0143] In a specific six-membered ring configuration of formula (III), A2, A3, and A4 are independently CH2, CHR b , or C(R b Selected from the group consisting of )2.

[0144] In certain embodiments, one or two of A2, A3, and A4 (e.g., one) independently constitute CHR b and C(R b ) Selected from the group consisting of 2, the rest are CH2.

[0145] In a specific six-membered ring configuration of formula (III), A2, A3, and A4 are each CH2.

[0146] In a specific six-membered ring configuration of formula (III), A2 and A4 are independently CH2 and CHR, respectively. b , and C(R b ) Selected from the group consisting of 2; A3 is O; S; SO2; or N(R a ) In some of these embodiments, one or two of A2 and A4 (e.g., one) independently constitute CHR b and C(R b ) is selected from the group consisting of 2, and the others (if applicable) are CH2. In other embodiments, both A2 and A4 are CH2. In some of these embodiments, A3 is N(R a ) (for example, A3 can be NH). In another embodiment, A3 is O. In yet another embodiment, A3 is SO2.

[0147] In a specific six-membered ring configuration of formula (III), A2 and A3 are independently CH2 and CHR, respectively. b , and C(R b ) Selected from the group consisting of 2; A4 is O; S; or N(R a ) In some of these embodiments, one or two of A2 and A3 (e.g., one) independently constitute CHR b and C(R b ) is selected from the group consisting of 2, and the others (if applicable) are CH2. In other embodiments, both A2 and A3 are CH2. In some of these embodiments, A4 is N(R a ) (for example, A4 can be NH). In other embodiments, A4 is O.

[0148] In a specific six-membered ring configuration of formula (III), A1, A2, A3, and A4 are independently CH2, CHR b , or C(R b Selected from the group consisting of )2.

[0149] In a particular embodiment of the six-membered ring of formula (III), one or two of A1, A2, A3, and A4 (e.g., one) independently constitute CHR b and C(R b ) Selected from the group consisting of 2, the rest are CH2.

[0150] In a specific six-membered ring configuration of formula (III), A1, A2, A3, and A4 are each CH2.

[0151] In a specific six-membered ring configuration of formula (III), A1, A2, and A4 are independently CH2, CHR b , and C(R b ) Selected from the group consisting of 2; A3 is O; S; SO2; or N(R a ) In some of these embodiments, one or two of A2 and A4 (e.g., one) independently constitute CHR b and C(R b ) is selected from the group consisting of 2, and the others (if applicable) are CH2. In other embodiments, both A2 and A3 are CH2. In some of these embodiments, A1 is CH2. In some of these embodiments, A3 is N(R a ) (for example, A3 can be NH). In another embodiment, A3 is O. In yet another embodiment, A3 is SO2.

[0152] In a specific six-membered ring configuration of formula (III), A1, A2, and A3 are independently CH2, CHR b , and C(R b ) Selected from the group consisting of 2; A4 is O; S; or N(R a ) In some of these embodiments, one or two of A2 and A4 (e.g., one) independently constitute CHR b and C(Rb ) is selected from the group consisting of 2, and the others (if applicable) are CH2. In other embodiments, both A2 and A3 are CH2. In some of these embodiments, A1 is CH2. In some of these embodiments, A4 is N(R a ) (for example, A4 can be NH). In other embodiments, A4 is O.

[0153] In a specific six-membered ring configuration of formula (III), A1 is C(O); A2, A3, and A4 are independently CH2 and CHR, respectively. b , or C(R b ) Selected from the group consisting of 2. In some of these embodiments, one or two (e.g., one) of A2, A3, and A4 are independently CHR b and C(R b ) Selected from the group consisting of 2, the rest are CH2.

[0154] In a specific six-membered ring configuration of formula (III), A1 is C(O); A2, A3, and A4 are each CH2.

[0155] In a specific six-membered ring configuration of formula (III), A1 is C(O); A2 and A4 are independently CH2 and CHR, respectively. b , and C(R b ) Selected from the group consisting of 2; A3 is O; S; SO2; or N(R a ) In some of these embodiments, one or two of A2 and A4 (e.g., one) independently constitute CHR b and C(R b ) is selected from the group consisting of 2, and the others (if applicable) are CH2. In other embodiments, both A2 and A4 are CH2. In some of these embodiments, A3 is N(R a ) (for example, A3 can be NH). In another embodiment, A3 is O. In yet another embodiment, A3 is SO2.

[0156] In a specific six-membered ring configuration of formula (III), A1 is C(O); A2 and A3 are independently CH2 and CHR, respectively. b , and C(R b ) Selected from the group consisting of 2; A4 is O; S; or N(R a ) In some of these embodiments, one or two of A2 and A3 (e.g., one) independently constitute CHR b and C(R b ) is selected from the group consisting of 2, and the others (if applicable) are CH2. In other embodiments, both A2 and A3 are CH2. In some of these embodiments, A4 is N(R a ) (for example, A4 can be NH). In other embodiments, A4 is O.

[0157] In a particular embodiment of formula (III), A1 is a bond, ring A contains five ring atoms (i.e., ring A is a five-membered ring), and ring A has formula (III-A). TIFF0007933830000042.tif28128

[0158] In a specific form of equation (III-A), A2 is C (=O). In other forms, A2 is CH2, CHR b , or C(R b ) is 2; for example, A2 can be CH2.

[0159] In a specific form of equation (III-A), A3 is O; S; or N(R e ) For example, A3 can be S. Another example is A3 is N(R a ) can be (for example, A3 can be NH).

[0160] In a specific form of formula (III-A), A4 is CH2, CHR b , or C(R b )2. For example, A4 is CHR b or C(R b ) could be 2. As another example, A4 could be CH2.

[0161] In a particular form of equation (III-A), A2 is C (=O); A3 is O; S; or N(R) e ) and; A4 is CH2, CHR b , or C(R b )2. In some of these embodiments, A3 is S. In other embodiments, A3 is N(R a ) (for example, A3 is NH). In some of these embodiments, A4 is CH2. In other embodiments, A4 is CHR b or C(R b )2.

[0162] In a specific form of equation (III-A), A2 is C (=O); and A3 and A4 are independently CH2 and CHR, respectively. b , or C(R b )2 is selected. In some of these embodiments, A3 and A4 are each CH2. In other embodiments, one of A3 and A4 is CH2 and the other of A3 and A4 is CHR b or C(R b )2. In another embodiment, A3 and A4 are independently CHR b or C(R b ) Selected from 2.

[0163] In a specific form of equation (III-A), A2 is CH2, CHR b , or C(R b )2, for example A2 may be CH2; A3 and A4 are independently CH2 and CHR, respectively. b , or C(R b ) Selected from 2 (for example, A3 and A4 are CH2 respectively).

[0164] In some of the forms of equation (III), A 1 is A 1A -A 1B That is the case.

[0165] In some of the embodiments of equation (III) above, A 1A and A 1BThese are CH2 and CHR, respectively, and are independent of each other. b , or C(R b )2. As a non-restrictive example, A 1A and A 1B Each of these can independently be CH2.

[0166] In some of the forms of equation (III), (A 1 is A 1A -A 1B If A 2 CH2, CHR b , or C(R b )2. As a non-restrictive example, A 2 It could be CH2.

[0167] In some of the forms of equation (III), (A 1 is A 1A -A 1B If A 3 CH2, CHR b , or C(R b )2. As a non-restrictive example, A 3 It could be CH2.

[0168] In some of the forms of equation (III), (A 1 is A 1A -A 1B If A 4 CH2, CHR b , or C(R b )2. As a non-restrictive example, A 4 It is CH2.

[0169] In some of the embodiments of equations (III) and (III-A) above, R b Each existence is independently selected from the following group: (i) 1 to 2 independently selected R e Even if replaced by C 1~6 alkyl; (ii) -(C 0~3 Alkylene)-C 6~10 An aryl, wherein the aryl is composed of 1 to 5 independently selected Rc Arial may be replaced by; (iii) Contains 5 to 10 ring atoms - (C 0~3 Alkylene)-heteroaryl, where 1 to 4 ring atoms are independently N, N(R) a R is selected from the group consisting of ), O, and S, and the heteroaryl is selected from 1 to 3 independently. c A heteroaryl that may be substituted with; (iv) -OH; (v) -N(R a )(R''); (vi) C 1~4 Alkoxy; (vii) C 1~4 Haloalkoxy; and (viii) -F.

[0170] In some of the embodiments of equations (III) and (III-A), R b Each existence is independently selected from the following group: (I C 1~6 alkyl; (iv) -OH; (v) -N(R a )(R''); (vi) C 1~4 Alkoxy; (vii) C 1~4 Haloalkoxy; and (viii) -F.

[0171] In some of the embodiments of equation (III) above, R b Each existence is independently selected from the following group: 1 to 2 independently selected R e Even if replaced by C 1~6 Alkyl; 1 to 5 independently selected R c Phenyl may be substituted with -OH; -F; -N(R) a )(R''); and C 1~4 Alkoxy.

[0172] Non-restrictive examples of ring A parts having formula (III) or (III-A) are shown in tabular form in Table 1 below.

[0173] (Table 1) TIFF0007933830000043.tif68153

[0174] In some embodiments, ring A is an unsaturated monoring containing 4 to 8 (e.g., 4 to 7, 5 to 6) ring atoms.

[0175] In certain embodiments, ring A is an unsaturated monoring containing 4 to 7 ring atoms.

[0176] In certain embodiments, ring A is an unsaturated monoring containing 5 to 6 ring atoms.

[0177] In certain embodiments, ring A is an unsaturated monoring containing six ring atoms.

[0178] In certain embodiments, ring A is not an unsaturated monoring containing five ring atoms (e.g., not a maleimide, e.g., not an unsubstituted or disubstituted maleimide).

[0179] In some of these embodiments, ring A has equation (IV): TIFF0007933830000044.tif33128In formula, A6 and A7 are independently CH and CR b More selected; A5 and A8 are independently N, CH, or CR. b That is the case.

[0180] In some of these embodiments, ring A has equation (IV): TIFF0007933830000045.tif33128In formula, A5, A6, and A7 are independently CH and CR. b More selected; A8 is N, CH, or CR b That is the case.

[0181] In a particular aspect of formula (IV), A5, A6, A7, and A8 are independently CH and CR. b More selections are made. For example, one or two of A5, A6, A7, and A8 are selected independently in the CR. b And the others are CH. As another example, A5, A6, A7, and A8 are each CH.

[0182] In other forms of formula (IV), A5, A6, and A7 are independently CH and CR, respectively. b A8 is selected from among the more selected ones, and A8 is N. For example, one or two of A5, A6, and A7 are independently selected CR. b And the others are CH. As another example, A5, A6, and A7 are each CH.

[0183] Furthermore, in other aspects of equation (IV), A5 is N; A6, A7, and A8 are independently CH and CR, respectively. b More selections (for example, one of A6, A7, and A8 is CR) b (For example, C-OH)

[0184] In some of the embodiments of equation (IV) above, R b Each existence is independently selected from the group consisting of: R 31 ; C 1~4 Haloalkyl; -OH; -N(R) a )(R''); C 1~4 Alkoxy; and C 1~4 Haloalkoxy.

[0185] In some of the embodiments of equation (IV) above, R b Each existence is independently selected from the group consisting of: R 31 -OH; -N(R a )(R''); C 1~4 Alkoxy; and C 1~4 Haloalkoxy.

[0186] In some of the embodiments of equation (IV) above, R b Each existence is independently selected from the following group: (i) 1 to 2 independently selected R e Even if replaced by C 1~6 alkyl; (ii) -(C 0~3 Alkylene)-C 6~10 An aryl, wherein the aryl is composed of 1 to 5 independently selected R c Arial may be replaced by; (iii) Contains 5 to 10 ring atoms - (C 0~3 Alkylene)-heteroaryl, where 1 to 4 ring atoms are independently N, N(R) a R is selected from the group consisting of ), O, and S, and the heteroaryl is selected from 1 to 3 independently. c A heteroaryl that may be substituted with; (iv) -OH; (v) -N(R a )(R''); (vi) C 1~4 Alkoxy; (vii) C 1~4 Haloalkoxy; and (viii) -F.

[0187] In some of these embodiments, ring A has equation (V): TIFF0007933830000046.tif35128In formula, A6 and A7 are independently CH and CR b More selected; A8 is N, CH, or CR b That is the case.

[0188] In other forms of equation (V), A6 and A7 are each CH. In other forms of equation (IV), both A6 and A7 cannot be CH.

[0189] In a particular form of formula (V), one of A6 and A7 is CR bAnd of A6 and A7, the other is CH.

[0190] In other forms of equation (IV), A6 and A7 are independently selected CR b In other forms of equation (IV), both A6 and A7 are independently selected in the CR. b This is not possible. In some of these embodiments, A6 and A7 are selected independently of each other. b If so, both R b The substituents are 1 to 5 independently selected R c C replaced by 6~10 It cannot be an aryl (e.g., phenyl). As another example, both R b The substituents are 1 to 3 or 1 to 2 independently selected R c C replaced by 6~10 It cannot be an aryl (e.g., phenyl). For example, both R's b The substituents are C, which are substituted with 1 to 5 independently selected halos (e.g., fluoroes). 6~10 It cannot be an aryl (e.g., phenyl). As another example, both R b The substituents are C, which are substituted with 1 to 3 or 1 to 2 independently selected halos (e.g., fluoroes). 6~10 It cannot be an aryl (e.g., phenyl). For example, both R's b The substituent cannot be a difluorophenyl, such as o,p-(difluoro)phenyl.

[0191] In some embodiments, ring A is a saturated or unsaturated bicyclic or tricyclic ring containing 7 to 9 (e.g., 7 to 8, e.g., 7) ring atoms.

[0192] In some of these embodiments, (A) applies (for example, the three adjacent ring carbon atoms of a divalent group are each independently C, CH, CR b CH2, C(R b )H, C(R b (Selected from the group consisting of 2, and condensed with the second ring).

[0193] In some of these embodiments, ring A has the following equation: In formula TIFF0007933830000047.tif31128, D is as follows: (c) 1 to 4 independently selected R d Even if replaced by C 3~10 Cycloalkyl; or (d) A heterocycline containing 4 to 10 ring atoms, wherein 1 to 3 ring atoms are independently N(R) a R is selected from the group consisting of ), O, and S, and the heterocyclyl is selected in a manner in which 1 to 4 independent individuals are selected. d A heterocycline that may be substituted with [another compound].

[0194] As a non-limiting example of the above embodiment, ring A is It could be TIFF0007933830000048.tif17128.

[0195] In some embodiments, ring A is a saturated or unsaturated bicyclic or tricyclic ring containing 8 to 10 ring atoms.

[0196] In some of these embodiments, ring A is a saturated ring. In other embodiments, ring A is an unsaturated ring.

[0197] In some of these embodiments, (A) applies (for example, two adjacent ring carbon atoms of a divalent group are independently C, CH, and CR). b (Selected from the group consisting of and condensed with the second ring). In other embodiments, (B) applies.

[0198] In certain embodiments, ring A is an unsaturated bicyclic or tricyclic ring containing 8 to 10 ring atoms. In some of these embodiments, (A) applies. In some of these embodiments, ring A may be further substituted with one oxo.

[0199] In certain embodiments, (A) applies, and ring A may be further substituted with one oxo, and ring A has formula (VI). TIFF0007933830000049.tif35128

[0200] In some of these embodiments, the condensed ring B is composed of 1 to 5 independently selected R c Even if substituted, the condensed C 6~10 It is aryl. For example, fused ring B is composed of 1 to 5 independently selected R c It may be a condensed phenyl which may be substituted with . As a further example, ring A may have formula (VI-A): TIFF0007933830000050.tif35128In formula, R c' is H or R c (For example C 1~6 It is an alkyl group (for example, CH3).

[0201] In some aspects of equation (VI), ring B is composed of 1 to 5 independently selected R c Condensed C may be substituted (for example, not substituted) 10 It is Ariel.

[0202] In some aspects of formula (VI), ring B is a condensed heteroaryl containing 5 to 10 (e.g., 6) ring atoms, where 1 to 4 (e.g., 1) ring atoms are independently N, N(R) a R is selected from the group consisting of ), O, and S, and the heteroaryl is selected from 1 to 3 independently. c It is a heteroaryl that may be substituted with [another compound].

[0203] In certain embodiments, ring A is selected from one of the following: TIFF0007933830000051.tif35138

[0204] In some of the above embodiments, each condensed ring B is independently selected from the following: A condensed heteroaryl containing 5 to 10 (e.g., 6) ring atoms, wherein 1 to 4 (e.g., 1) ring atoms are independently N, N(R) aR is selected from the group consisting of ), O, and S, and the heteroaryl is selected from 1 to 3 independently. c Heteroaryls which may be substituted with; and 1 to 5 (for example, 1 to 2) independently selected R c Even if substituted, the condensed C 6~10 (For example, C6) aryl.

[0205] As a non-restrictive example, each condensed ring B can independently select 1 to 5 (e.g., 1 to 2) independently R rings. c Even if substituted, the condensed C 6~10 (For example, C6) It can be an aryl group.

[0206] In certain embodiments, ring A is a saturated bicyclic or tricyclic ring containing 8 to 10 ring atoms. In some of these embodiments, (A) applies. In other embodiments, (B) applies. In some of these embodiments, ring A may be further substituted with one oxo.

[0207] In certain embodiments, (A) applies, and ring A may be further substituted with one oxo, and ring A has formula (VI). TIFF0007933830000052.tif35128

[0208] In some of these embodiments, the condensed ring B is composed of 1 to 4 independently selected R d Even if substituted, the condensed C 3~10 It is a cycloalkyl group. For example, the condensed ring B consists of 1 to 4 independently selected R groups. d Even if substituted, the condensed C 3~6 Cycloalkyl (e.g., C 3~4 (Cycloalkyl) can be (for example, R d is C 1~3 (It can be alkyl.)

[0209] In other embodiments, (B) applies, and ring A may be further substituted with one oxo, and ring A has formula (VII). TIFF0007933830000053.tif41128

[0210] In some of these embodiments, the spiro-condensed ring B is composed of 1 to 4 independently selected R d Spirocondensation C may be substituted with 3~10 It is a cycloalkyl group. For example, the spirocondensed ring B consists of 1 to 4 independently selected R groups. d Spirocondensation C may be substituted with 3~6 Cycloalkyl (e.g., C 3~4 (Cycloalkyl) (e.g., R d is C 1~3 (It can be alkyl.)

[0211] Variable element L In some embodiments, L is given by equation (VIII): -(CH2) m -X 1 -(CH2) n -X 2 -(CH2) p - has.

[0212] In certain aspects of equation (VIII), m is between 2 and 6 (for example, m can be 2).

[0213] In a particular form of equation (VIII), m is 1.

[0214] In a particular form of equation (VIII), X 1 is -N(R')C(O)- (for example X 1 (It can be -N(H)C(O)-).

[0215] In certain aspects of equation (VIII), n + p ≥ 2. For example, n + p = 2 (for example, n and p are each 1). Another example is n + p > 2 (for example, n + p = 3, 4, 5, 6, 7, 8, 9, or 10).

[0216] In another embodiment, n + p < 2.

[0217] In yet another embodiment, n + p = 0.

[0218] In a particular form of equation (VIII), X 2 is -O-; -S-; or -S(O) t - and in the formula, t is either 1 or 2. For example, X 2 It can be -S-.

[0219] In a particular form of equation (VIII), X 2 -C(Q 1 )(Q 2 )-is.

[0220] In some of these configurations, Q 1 and Q 2 H and C are independent of each other. 1~4 Selected from the group consisting of alkyl groups. For example, Q 1 and Q 2 One of them can be H, and Q 1 and Q 2 Of these, the other is C 1~4 It can be an alkyl group (e.g., CH3). For example, Q 1 can be H; Q 2 is C 1~4 It can be alkyl. Another example is Q 1 and Q 2 Each of these can be H. As a further example, Q 1 and Q 2 Each of these is independently selected C 1~4 It could be alkyl.

[0221] In other forms, Q 1 and Q 2 Each of them, together with the carbon atoms to which it is bonded, becomes C 3~10 A cycloalkyl group is formed, and the cycloalkyl group consists of 1 to 4 independently selected R d It may be substituted with, or condensed with phenyl. For example, Q 1 and Q 2 Each of them, together with the carbon atoms to which it is bonded, becomes C 3~6A cycloalkyl group is formed, and the cycloalkyl group consists of 1 to 4 independently selected R d It may be substituted with or condensed with phenyl.

[0222] In some of the above configurations, Q 1 and Q 2 Each of them, together with the carbon atoms to which it is bonded, becomes C 4~6 (For example, C4) forms a cycloalkyl group, and the cycloalkyl group consists of 1-2 independently selected R d It may be replaced with .

[0223] In a particular form of equation (VIII), X 2 The following is true: (v) 1 to 5 independently selected R c Even if replaced by C 6~10 Ariren; (vi) A heteroarylene containing 5 to 10 ring atoms, wherein 1 to 4 ring atoms are independently N, N(R) a R is selected from the group consisting of ), O, and S, and the heteroarylene is selected from 1 to 5 independently. c Heteroarylenes which may be substituted with; (vii) 1 to 4 independently selected R d Even if replaced by C 3~10 Cycloalkylene; or (viii) A heterocycloalkylene containing 3 to 10 ring atoms, wherein 1 to 3 ring atoms are independently N(R) a R is selected from the group consisting of ), O, and S, and the heterocycloalkylene is selected in a group of 1 to 5 independent elements. d A heterocycloalkylene which may be substituted with [another compound].

[0224] For example, X 2 teeth, (v) 1 to 5 independently selected R c Even if replaced by C 6~10 Arirene; or (vii) 1 to 4 independently selected R d Even if replaced by C 3~10 Cycloalkylene It is possible.

[0225] As another example, X 2 teeth, (v) 1 to 5 independently selected R elements (e.g., 1 to 3, 1 to 2, 1) c Phenylene may be substituted with; or (vii) 1 to 4 independently selected R d Even if replaced by C 3~6 Cycloalkylene (e.g., C 3~4 Cycloalkylene) (e.g., R d is C 1~3 (Possibly alkyl) It is possible.

[0226] In a particular form of equation (VIII), X 2 (viii) A heterocycloalkylene containing 3 to 10 ring atoms, wherein 1 to 3 ring atoms are each independently N(R) a R is selected from the group consisting of ), O, and S, and the heterocycloalkylene is selected in a group of 1 to 5 independent elements. d It is a heterocycloalkylene that may be substituted with [another compound].

[0227] In a particular form of equation (VIII), X 2 (viii) A heterocycloalkylene containing 4 to 6 (e.g., 4) ring atoms, wherein 1 to 3 (e.g., 1) ring atoms are each independently N(R a R is selected from the group consisting of ), O, and S, and the heterocycloalkylene is selected in a group of 1 to 5 independent elements. d It is a heterocycloalkylene that may be substituted with (e.g., X 2 teeth (Possible filename: TIFF0007933830000054.tif7128).

[0228] In some embodiments, L is given by equation (IX): -C(O)-(CH2) n -X 3 -(CH2) p - has. In some of these embodiments, n + p ≥ 2. For example, n + p = 2 (for example, n and p are each 1). Another example is n + p > 2. In some of these embodiments, X 3 It is -S-.

[0229] Non-restrictive combinations of L [1] In a particular form of equation (VIII), m is between 2 and 6; n + p ≥ 2; X 2 is -O-; -S-; or -S(O) t - is

[0230] In some of these embodiments, m is 2.

[0231] In some of these configurations, X 1 This is -N(R')C(O)- (for example, -N(H)C(O)-).

[0232] In some of these embodiments, n + p > 2.

[0233] In some of these embodiments, n + p = 2 (for example, n and p are each 1).

[0234] In some of these configurations, X 2 It is -S-.

[0235] In some of these embodiments, m is 2 to 6 (for example, 2), and X 1 The expression is -N(R')C(O)- (for example, -N(H)C(O)-), and n + p > 2.

[0236] In some of these embodiments, m is 2 to 6 (for example, 2), and X 1is -N(R')C(O)- (for example, -N(H)C(O)-), n + p>2, and X 2 It is -S-.

[0237] In some of these embodiments, m is 2 to 6 (for example, 2), and X 1 The expression is -N(R')C(O)- (for example, -N(H)C(O)-) and n + p = 2 (for example, n and p are each 1).

[0238] In some of these embodiments, m is 2 to 6 (for example, 2), and X 1 is -N(R')C(O)- (for example, -N(H)C(O)-), where n + p = 2 (for example, n and p are each 1), X 2 It is -S-.

[0239] For example, L could be -CH2CH2NHC(O)CH2SCH2-.

[0240] [2] In a particular form of equation (VIII), m is between 2 and 6; n + p < 2; X 2 teeth, (i) -C(Q 1 )(Q 2 )-, in the formula, Q 1 and Q 2 Each of these is independently selected C 1~4 It is alkyl; or, Q 1 and Q 2 Each of them, together with the carbon atoms to which it is bonded, becomes C 3~10 A cycloalkyl group is formed, and the cycloalkyl group consists of 1 to 4 independently selected R d It may be substituted with phenyl, or condensed with phenyl; (v) 1 to 5 independently selected R c Even if replaced by C 6~10 Ariren; (vi) A heteroarylene containing 5 to 10 ring atoms, wherein 1 to 4 ring atoms are independently N, N(R) a R is selected from the group consisting of ), O, and S, and the heteroarylene is selected from 1 to 5 independently. c Heteroarylenes which may be substituted with; (vii) 1 to 4 independently selected R d Even if replaced by C 3~10 Cycloalkylene; or (viii) A heterocycloalkylene containing 3 to 10 ring atoms, wherein 1 to 3 ring atoms are independently N(R) a R is selected from the group consisting of ), O, and S, and the heterocycloalkylene is selected in a group of 1 to 5 independent elements. d Heterocycloalkylenes may be substituted with That is the case.

[0241] In some of these embodiments, m is 2.

[0242] In some of these configurations, X 1 This is -N(R')C(O)- (for example, -N(H)C(O)-).

[0243] In some of these embodiments, n + p = 0.

[0244] In some of these configurations, X 2 -C(Q 1 )(Q 2 )-is.

[0245] In some of these configurations, Q 1 and Q 2 These are H.

[0246] In some of these configurations, Q 1 is C 1~4 It is alkyl.

[0247] In some of these configurations, Q2 is C 1~4 It is alkyl.

[0248] In some of these configurations, Q 1 and Q 2 Each of these is independently selected C 1~4 It is an alkyl group (for example, CH3).

[0249] In some of these configurations, Q 1 and Q 2 Each of them, together with the carbon atoms to which it is bonded, becomes C 3~6 A cycloalkyl group is formed, and the cycloalkyl group consists of 1 to 4 independently selected R d It may be substituted with or condensed with phenyl.

[0250] In some of these configurations, X 2 teeth, (v) 1 to 5 independently selected R c Even if replaced by C 6~10 Arirene; or (vii) 1 to 4 independently selected R d Even if replaced by C 3~10 Cycloalkylene That is the case.

[0251] In some of these configurations, X 2 (viii) A heterocycloalkylene containing 4 to 6 (e.g., 4) ring atoms, wherein 1 to 3 (e.g., 1) ring atoms are each independently N(R a R is selected from the group consisting of ), O, and S, and the heterocycloalkylene is selected in a group of 1 to 5 independent elements. d It is a heterocycloalkylene that may be substituted with (e.g., X 2 teeth (Possible filename: TIFF0007933830000055.tif7128).

[0252] In some of these embodiments, m is 2 to 6 (for example, 2), and X1 It is -N(R')C(O)- (for example, -N(H)C(O)-) and n + p = 0.

[0253] In some of these embodiments, m is 2 to 6 (for example, 2), and X 1 is -N(R')C(O)- (for example, -N(H)C(O)-), n + p = 0, and X 2 -C(Q 1 )(Q 2 )- and Q 1 and Q 2 Each of them, together with the carbon atoms to which it is bonded, becomes C 3~6 A cycloalkyl group is formed, and the cycloalkyl group consists of 1 to 4 independently selected R d It may be substituted with or condensed with phenyl.

[0254] In some of these embodiments, m is 2 to 6 (for example, 2), and X 1 is -N(R')C(O)- (for example, -N(H)C(O)-), n + p = 0, and X 2 -C(Q 1 )(Q 2 )- and Q 1 and Q 2 C is selected independently 1~4 It is an alkyl group (for example, CH3).

[0255] In some of these embodiments, m is 2 to 6 (for example, 2), and X 1 is -N(R')C(O)- (for example, -N(H)C(O)-), n + p = 0, and X 2 (v) 1 to 5 independently selected R c Even if replaced by C 6~10 Arylene (e.g., phenylene); or (vii) 1 to 4 independently selected R d Even if replaced by C 3~10 It is a cycloalkylene.

[0256] [3] In certain aspects of equation (IX), n + p = 2 (for example, n and p are each 1), X 3 It is -S-.

[0257] [4] In a particular form of equation (VIII), m is 1; n + p ≤ 2; X 2 -O-; -S-; -S(O) t -; or C(Q 1 )(Q 2 )

[0258] In some of these embodiments, n + p = 2.

[0259] In some of these configurations, X 2 It is -S-.

[0260] In some of these embodiments, n + p < 2 (for example, n + p = 0; or n + p = 1).

[0261] In some of these embodiments, X 2 is C(Q 1 )(Q 2 )

[0262] In some of these configurations, Q 1 and Q 2 These are H.

[0263] In some of these configurations, Q 1 and Q 2 These are C 1~4 It is alkyl.

[0264] In some of these configurations, Q 1 is H; Q 2 is C 1~4 It is alkyl.

[0265] Variable element R 1 、R 2 、R 2' , and R 4 In some embodiments, R 1 H is H. In some embodiments, R 2 H is H. In some embodiments, R 4 H is H.

[0266] In some embodiments, R 1 , R 2 , and R 4 Two of them are H.

[0267] In some embodiments, R 1 , R 2 , and R 4 These are H.

[0268] In some embodiments, R 2 is non-substituted C 1~3 It is an alkyl group (for example, methyl).

[0269] In some embodiments, R 1 and R 4 H is H.

[0270] In some embodiments, R 2' This is as defined by (AA).

[0271] In certain embodiments, a' is 1.

[0272] In some of these embodiments, R 3a and R 3b These are H.

[0273] In some of these embodiments, R 3a and R 3b These are C 1~3 It is an alkyl group (for example, methyl).

[0274] In other embodiments, a' is 0.

[0275] In some embodiments, R 3 is -C(O)OH. In other embodiments, R 3 R is a carboxylic acid isostere. Non-limiting examples of carboxylic acid isosteres include non-carbon acyclic acids, e.g., phosphonic acids / phosphinic acids and sulfonic acids / sulfinic acids, as well as sulfonamides; modified carbon acids, e.g., hydroxamic acids, hydroxamic acid esters, acylureas, acylsulfonamides, and sulfonylureas; heteroaryl and heterocyclyl isosteres that may be substituted, e.g., tetrazoles, oxadiazole-5(4H)-thione, thiadiazole-5(4H)-one, oxathiadiazole, and their oxidized forms, isoxazole, thiazolidinedione, oxazolidinedione, tetramic acid, and isosteres based on their derivatives; and cycloalkyl and aryl isosteres that may be substituted, e.g., cyclopentan-1,3-dione, phenol, and squalic acid, and isosteres based on their derivatives (e.g., tetrazolyl or amide). In certain embodiments, R 3 is an amide. In certain embodiments, R 3 is a tetrazolyl that may be substituted (e.g., unsubstituted tetrazolyl). In certain embodiments, R 3 isoxazolyl may be substituted (for example, isoxazolyl substituted with hydroxyl). This is TIFF0007933830000056.tif14128).

[0276] In some embodiments, a is between 1 and 5 (e.g., 1 to 4, 1 to 3, 1 to 2). In some embodiments, a is 0. In some embodiments, a is 0, 1, or 2. In a particular embodiment, a is 1. In other embodiments, a is 2. In yet another embodiment, a is 0. In some embodiments, a is 0, 1, 2, or 3 (e.g., a = 0; or a = 1; or a = 2).

[0277] Variable elements W, W', and R 5 W is given by the formula W'-R 5 It is a peptide having, where W' is a sequence of 5 to 60 amino acids, and R 5 The C-terminal amino acid, amino acid ester, or amino acid amide may be substituted with one or two modifying groups (e.g., one or two groups selected from acyl and PEG groups). As used herein, "peptide" means a peptide with an N-terminus at each end (NR in formula (IAA), (IA), or (I)). 4 ) and C-terminal amino acid residue (R 5 The term peptide refers to a chain of amino acid monomers (sometimes called "residues") linked by peptide (amide) bonds (or their isostere substitutions), having a peptide (amide) bond. The term peptide also includes modified peptides, for example, that contain any one or more of the modifications described herein.

[0278] Constituent amino acids and their modifications In some embodiments, W includes one or more native amino acids found, for example, in polypeptides and / or proteins produced by living organisms, such as Ala(A), Val(V), Leu(L), Ile(I), Pro(P), Phe(F), Trp(W), Met(M), Gly(G), Ser(S), Thr(T), Cys(C), Tyr(Y), Asn(N), Gln(Q), Asp(D), Glu(E), Lys(K), Arg(R), and His(H).

[0279] In some embodiments, W comprises one or more independently selected modifiers present in the so-called modified peptide. These modifiers include, but are not limited to, (i) the incorporation of lactam crosslinks; (ii) head-to-tail cyclization; (iii) one or more alternative or non-natural (D- or L-) amino acids, such as synthetic non-natural amino acids, substituted amino acids, and D-amino acids; (iv) peptide bond substitutions; (v) targeting groups. In certain embodiments, W comprises the W' component or R 5The component contains one modifier. In other embodiments, W is the W' component / or R 5 In the components (for example, only the W' component; or R 5 Only the component; or W' component and R 5 It includes two or more independently selected modifiers occurring in both components (for example, two independently selected modifiers, three independently selected modifiers, four independently selected modifiers, five independently selected modifiers, six independently selected modifiers, seven independently selected modifiers, eight independently selected modifiers, nine independently selected modifiers, or ten independently selected modifiers).

[0280] Non-exclusive examples of substitute or non-natural amino acids include D-amino acids; β-amino acids; homocysteine, phosphoserine, phosphothreonine, phosphotyrosine, hydroxyproline, γ-carboxyglutamic acid; hippuric acid, octahydroindole-2-carboxylic acid, statins, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine (3-mercapto-D-valine), ornithine, citrulline, α-methylalanine, para-benzoylphenylalanine, para-aminophenylalanine, para-fluorophenylalanine, phenylglycine, propargylglycine, sarcosine, and tert-butylglycine), diaminobutyric acid, 7-hydroxytetrahydroisoquinolinecarboxylic acid, naphthylalanine, biphenylalanine, cyanopropyl alcohol (7-hydroxytetrahydroisoquinoline), sulfate (7-hydroxytetrahydroisoquinoline), sulfate (7-hydroxytetrahydroisoquinoline), sulfate (7-hydroxy- Examples include chlorohexylalanine, aminoisobutyric acid, norvaline, norleucine, tert-leucine, tetrahydroisoquinoline carboxylic acid, pipecolic acid, phenylglycine, homophenylalanine, cyclohexylglycine, dehydroleucine, 2,2-diethylglycine, 1-amino-1-cyclopentanecarboxylic acid, 1-amino-1-cyclohexanecarboxylic acid, aminobenzoic acid, aminonaphthoic acid, γ-aminobutyric acid, difluorophenylalanine, nipecoic acid, α-aminobutyric acid, thienylalanine, t-butylglycine, trifluorovaline; hexafluoroleucine; fluorinated analogs; azide-modified amino acids; alkyne-modified amino acids; cyano-modified amino acids; and their derivatives (each of which may be independently a D-amino acid or an L-amino acid, where appropriate).

[0281] Non-limiting examples of peptide bond substitutions include urea, thiourea, carbamates, sulfonylurea, trifluoroethylamine, ortho-(aminoalkyl)-phenylacetic acid, para-(aminoalkyl)-phenylacetic acid, meta-(aminoalkyl)-phenylacetic acid, thioamides, tetrazoles, boronic acid esters, olefin groups, and their derivatives.

[0282] Other non-limiting examples of modifications and / or moieties include PEGylation; glycosylation; HESation; ELPation; lipidation; acetylation; amidation; end-binding modifications (e.g., amidation at the C-terminus, introduction of C-terminal alcohol, aldehyde, ester, and thioester moieties); cyano groups; phosphorylation; cyclization and binding with targeted moieties and / or targeting agents (e.g., agents such as cellulose, fatty acids, polyethylene glycol (PEG), or combinations thereof) to increase retention in the body; and incorporation of retroinversopeptide motifs (i.e., peptides with reversal of the direction of peptide bonds at at least one position).

[0283] In certain embodiments, W comprises only natural amino acids. In other embodiments, W comprises only substitute or non-natural amino acids. In yet another embodiment, W comprises one or more natural amino acids and one or more substitute or non-natural amino acids. In some of the above embodiments, W comprises only L-amino acids; or W comprises both D-amino acids and L-amino acids; or W comprises only D-amino acids. While it is undesirable to be bound by theory, it is thought that the incorporation of D-amino acids can improve the in vivo or intracellular stability of the compounds described herein.

[0284] In some embodiments, W comprises an amino acid residue of formula XAA, or its C-terminal amino acid, amino acid ester, or amino acid amide: TIFF0007933830000057.tif25128 formula, R aa1 and R aa2 Each is independently selected from the following: (a) H; (b) 1 to 3 R ba Even if replaced by C 1~6 alkyl; (c) 1 to 4 R ba It may be replaced with (C 0~3 Alkylene)-C 3~10 Cycloalkyl; (d) Contains 3 to 10 ring atoms - (C 0~3 Alkylene)-heterocyclyl, in which 1 to 3 ring atoms are independently N(R) da A heteroatom selected from the group consisting of ), O, and S, wherein one or more heterocyclyl ring carbon atoms are independently selected from 1 to 4. ba A heterocycline that may be substituted with; (e) 1 to 4 R ca It may be replaced with (C 0~3 Alkylene)-C6~C 10 Ariel; (f) Contains 5 to 10 ring atoms - (C 0~3 Alkylene)-heteroaryl, where 1 to 4 ring atoms are independently N, N(R) da A heteroatom selected from the group consisting of ), O, and S, and one or more heteroaryl ring carbon atoms, 1 to 4 independently selected R ca A heteroaryl that may be substituted with; or, (g) -C(=O)CR aa1 (R aa2 )N(R da )-R in the base aa1 and R da Together, they form a ring containing 5 to 8 ring atoms, (a) H and C 1~3 1 to 6 ring carbon atoms (CR) each substituted with 1 to 2 substituents independently selected from alkyl groups. aa1 (R aa2 (b) In addition to (b), N(R da ), 0 to 3 ring heteroatoms (R) selected from the group consisting of O and S da It forms a ring containing (other than the nitrogen atom bonded to it); R ba Each existence is -C(=O)(OH); -C(=O)(C 2~20 Alkyl); -C(=O)NR'R''; -NHC(=NR')NR'R''; -C(=O)O(C 2~20 Alkyl); -S(O) 0~2 (C 1~6Alkyl; Oxo; F; C 1~10 Alkoxy; C 1~10 Haloalkoxy; Azide; -N(R) ga )(R ha Selected from the group consisting of; R ca Each of these entities is independent of -OH; -SH; -F; -Cl; -Br; -NR'R''; C 1~4 Alkyl; C 1~4 Haloalkyl; C 1~4 Alkoxy; C 1~4 Haloalkoxy; -C(=O)O(C 1~4 alkyl); -C(=O)(C 1~4 alkyl); -C(=O)OH; -CON(R')(R''); -S(O) 1~2 (NR'R''); -S(O) 0~2 (C 1~4 Alkyl; Cyano; -NR'C(=NR')NR'R''; Halo, C 1~4 Alkyl, and C 1~4 The C may be substituted with 1 to 4 substituents independently selected from the haloalkyl group. 6~10 Aryl; and 1 to 4 independently selected C 1~4 C may be substituted with alkyl. 3~6 Selected from the group consisting of cycloalkyl groups; R da Each of the entities is independent of H; C 1~6 Alkyl; C 3~6 Cycloalkyl; -C(O)(C 1~4 alkyl); -C(O)O(C 1~4 alkyl); -CON(R')(R''); -S(O) 1~2 (NR'R''); -S(O) 1~2 (C 1~4 alkyl); -OH; and C 1~4 Selected from the group consisting of alkoxys; or -C(=O)CR aa1 (R aa2 )N(R da )-R in the base aa1 and R da Together, they form a ring containing 5 to 8 ring atoms as defined above; R ga and R ha Each of the entities is independent of H; C 1~4 Alkyl; -C(=O)O(C 2~20 alkyl); and -S(O) 1~2 (C 1~6 Selected from the group consisting of alkyl groups; The existence of R' and R'' independently determines H and C 1~4 Selected from the group consisting of alkyl groups; or, R' and R'' together with the nitrogen atom to which they are bonded, form a ring containing 3 to 8 ring atoms, (a) H and C 1~3 (b) 1 to 7 ring carbon atoms each substituted with 1 to 2 substituents independently selected from alkyl groups; and (b) each independently forming a ring containing 0 to 3 ring heteroatoms (other than nitrogen atoms bonded to R' and R'') selected from the group consisting of N(H), O, and S.

[0285] In some embodiments, W comprises 25 to 45 amino acid residues of formula XAA, or its C-terminal amino acid, amino acid ester, or amino acid amide, where R aa2 H is H.

[0286] In some of these embodiments, R aa1 The group is selected from the following: ·H; C1-C6 alkyl groups that may be substituted with one or two substituents selected from -NH2, -OH, -SH, -SMe, -NH(C=NH)NH2, CO2H, and CO2NH2; (C1-C6 alkylene)-phenyl, which may be substituted with 1-2 -OH groups; (C1-C6 alkylene)-indolyl; and (C1~C6 alkylene)-imidazolyl; or, ·-CH(R aa1 )N(R da )-R in the base aa1 and R da These combine to form a pyrrolidine ring.

[0287] As a non-limiting example of the above embodiments, W may include 25 to 45 natural amino acids found, for example, in polypeptides and / or proteins produced by living organisms, such as Ala(A), Val(V), Leu(L), Ile(I), Pro(P), Phe(F), Trp(W), Met(M), Gly(G), Ser(S), Thr(T), Cys(C), Tyr(Y), Asn(N), Gln(Q), Asp(D), Glu(E), Lys(K), Arg(R), and His(H); or their amino acid esters or amino acid amides.

[0288] In certain embodiments, W comprises one to two (e.g., one) amino acid residues of formula XAA, or its C-terminal amino acid, amino acid ester, or amino acid amide, where R aa2 is H; R aa1 is 1-2 Rs (for example, 1) ba C replaced by 1~6 Alkyl; R ba Each existence is independently -N(R ga )(R ha ) will be selected from.

[0289] As a non-limiting example of the above embodiment, W may include an amino acid residue selected from the following, or its C-terminal amino acid, amino acid ester, or amino acid amide: TIFF0007933830000058.tif19135

[0290] In certain embodiments, W comprises one to two (e.g., one) amino acid residues of formula XAA, or its C-terminal amino acid, amino acid ester, or amino acid amide, where R aa2 is C 1~3 It is alkyl (e.g., methyl); R aa1 It is anything other than H.

[0291] Non-limiting examples include TIFF0007933830000059.tif36128; or its C-terminal amino acid, amino acid ester, or amino acid amide.

[0292] Variable element W' In some embodiments, W' is a sequence of 20 to 60 amino acids (e.g., 20 to 55, 20 to 50, 20 to 45, 20 to 40, 20 to 30, 20 to 35).

[0293] In some embodiments, W' is a sequence of 30 to 60 amino acids (e.g., 30 to 55, 30 to 50, 30 to 45, 30 to 40). In certain embodiments, W' is a sequence of 25 to 45 amino acids (e.g., 30 to 45). In certain embodiments, W' is a sequence of 30 to 50 amino acids. For example, W' can be a sequence of 30 to 45 amino acids or 30 to 40 amino acids. In certain embodiments, W' can be 34, 35, 36, 37, 38, or 39 amino acids; for example, 36 or 37 amino acids; for example, a sequence of 36 amino acids. In certain embodiments, W' can be 25 to 28 amino acids; for example, a sequence of 26 or 27 amino acids.

[0294] Variable element R 5 In some embodiments, R 5 is a C-terminal amino acid amide which may be substituted with 1-2 modifying groups. In other embodiments, R 5 This is a C-terminal amino acid that may be substituted with one or two modifying groups.

[0295] In certain aspects, R 5 This is a C-terminal lysyl residue, such as a lysylamide residue, which may be substituted with one or two modifying groups. For example, R 5 This can be a C-terminal L-lysylamide residue which may be substituted with 1-2 modifying groups. In certain embodiments, R 5 has equation (XI): TIFF0007933830000060.tif68128In formula, R *is H or a modifying group. In some of these embodiments, formula (XI) is L. In other embodiments, formula (XI) is D.

[0296] In certain aspects, R * H is H.

[0297] In certain embodiments, modifying groups (e.g., R * ) is an acyl group. For example, the acyl group is one or two independently selected R f Even if replaced by C 2~30 (For example C 2~20 , C 2~10 , C 2~6 ) It can be an acyl group. R f Each existence is -C(=O)(OH); -C(=O)(C 2~20 alkyl); -C(=O)O(C 2~20 Alkyl); -S(O) 1~2 (C 1~6 Alkyl; Oxo; F; C 1~10 Alkoxy; C 1~10 Haloalkoxy; and -N(R g )(R h Selected from the group consisting of ). g and R h Each of the entities is independent of H; C 1~4 Alkyl; -C(=O)(C 2~20 alkyl); -C(=O)O(C 2~20 alkyl); and -S(O) 1~2 (C 1~6 Selected from the group consisting of alkyl groups.

[0298] In certain embodiments, modifying groups (e.g., R * ) are 1-2 (e.g., 2) independently selected R f C replaced by 2~30 (For example C 2~20 , C 2~10 , C 2~6 ) is an acyl group. In certain embodiments, R f Each of these entities exists independently of -C(=O)(OH) and -N(R g )(R h) can be selected from the group consisting of ). For example, R g and R h One of them is independent, -C(=O)(C 2~20 alkyl); -C(=O)O(C 2~20 alkyl); and -S(O) 1~2 (C 1~6 Alkyl), for example, -C(=O)(C 2~20 Selected from the group consisting of alkyl groups. For example, modifying groups (e.g., R * ) could be the following: TIFF0007933830000061.tif43128

[0299] As a further example, R * The following are possible: TIFF0007933830000062.tif36142

[0300] In some embodiments, R 5 is a C-terminal amino acid and may be substituted with 1-2 modifying groups (e.g., 1-2 groups selected from acyl and PEG groups).

[0301] In certain aspects, R 5 R is a C-terminal lysine, which may be substituted with 1-2 modifying groups (e.g., 1-2 groups selected from acyl and PEG groups). For example, R 5 The C-terminal L-lysine may be substituted with one or two modifying groups (e.g., one or two groups selected from an acyl group and a PEG group).

[0302] In certain aspects, R 5 It has the formula (XI-OH): TIFF0007933830000063.tif71128In formula, R * is H or a modifying group (e.g., an acyl group and a PEG group). In some of these embodiments, formula (XI-OH) is L. In other embodiments, formula (XI-OH) is D.

[0303] In certain aspects of formulas (XI) and (XI-OH), R* H is H.

[0304] In certain embodiments, modifying groups (e.g., R * ) is an acyl group. For example, the acyl group is one or two independently selected R f Even if replaced by C 2~30 (For example C 2~20 , C 2~10 , C 2~6 ) It can be an acyl group. R f Each existence is -C(=O)(OH); -C(=O)(C 2~20 alkyl); -C(=O)O(C 2~20 Alkyl); -S(O) 1~2 (C 1~6 Alkyl; Oxo; F; C 1~10 Alkoxy; C 1~10 Haloalkoxy; and -N(R g )(R h Selected from the group consisting of ). g and R h Each of the entities is independent of H; C 1~4 Alkyl; -C(=O)(C 2~20 alkyl); -C(=O)O(C 2~20 alkyl); and -S(O) 1~2 (C 1~6 Selected from the group consisting of alkyl groups.

[0305] In certain embodiments, modifying groups (e.g., R * ) are 1-2 (e.g., 2) independently selected R f C replaced by 2~30 (For example C 2~20 , C 2~10 , C 2~6 ) is an acyl group. In certain embodiments, R f Each of these entities is independently -C(=O)(OH) and -N(R g )(R h ) can be selected from the group consisting of ). For example, R g and R h One of them is independently -C(=O)(C 2~20 alkyl); -C(=O)O(C 2~20alkyl); and -S(O) 1~2 (C 1~6 Alkyl), for example, -C(=O)(C 2~20 Selected from the group consisting of alkyl groups. For example, modifying groups (e.g., R * ) could be the following: TIFF0007933830000064.tif43128

[0306] As a further example, R * The following are possible: TIFF0007933830000065.tif36143

[0307] Other non-restrictive representative examples of acyl modification groups are listed, for example, in Table 2.

[0308] In other embodiments, the modifying group is PEG. As used herein, the general terms “polyethylene glycol” or “PEG” refer to a polyethylene glycol of the general formula H(OCH2CH2) where n is at least 9. n This term refers to a mixture of branched or straight-chain ethylene oxide and water condensation polymers represented by OH. Unless further characterized, the term is intended to include polymers of ethylene glycol having a total average molecular weight selected from the range of 5,000 to 40,000 Daltons. "Polyethylene glycol" or "PEG" is used in combination with a numerical suffix indicating its approximate average molecular weight. For example, PEG-5,000 means polyethylene glycol with a total average molecular weight of approximately 5,000. As used herein, the term "PEGylated" or similar terms refers to a compound modified from its natural state by linking a PEG chain to a peptide. A "PEGylated peptide" is a peptide that has a PEG chain covalently bonded to the peptide itself.

[0309] In certain aspects, R 5 It is a C-terminal amino acid selected from serine, glycine, and arginine.

[0310] In certain aspects, R 5It is a C-terminal amino acid amide selected from selinylamide, glycylamide, and argininylamide.

[0311] In certain aspects, R 5 This is a C-terminal glycyl residue (e.g., C-terminal glycine or C-terminal glycylamide).

[0312] In certain aspects, R 5 This is a C-terminal arginine residue (e.g., C-terminal arginine or C-terminal arginineamide).

[0313] In certain aspects, R 5 This is a C-terminal selinyl residue (e.g., C-terminal serine or C-terminal selinylamide).

[0314] Non-restrictive examples of W In some embodiments, the amino acid sequence present in W is or includes a sequence present in natural GLP-1-OH or GLP-1-NH2. In other embodiments, the amino acid sequence present in W is or includes a sequence present in natural GIP. In yet another embodiment, the amino acid sequence present in W is or includes a hybrid sequence having one or more fragments (e.g., a functional fragment) present in natural GLP-1-OH or GLP-1-NH2 and one or more fragments (e.g., a functional fragment) present in natural GIP. The disclosure further envisions variations of the above embodiments, for example, W being or including a conservatively substituted variation of the above embodiments, i.e., one or more amino acid residues of the original peptide being replaced with different residues, and the conservatively substituted peptide retains the desired biological activity. Examples of conservative substitutions include substitutions of amino acids that tend not to change the secondary and / or tertiary structure of the compounds described herein, substitutions that do not change the overall or local hydrophobicity, substitutions that do not change the overall or local charge, substitutions with residues of equivalent side chain size, or substitutions with side chains having similar reactive groups.

[0315] A given amino acid can be replaced with a residue having similar physiological and chemical properties, for example, one aliphatic residue can be replaced with another (e.g., Ile, Val, Leu, or Ala with each other), or one polar residue can be replaced with another (e.g., between Lys and Arg; between Glu and Asp; or between Gln and Asn). Other such conservative substitutions, such as the substitution of an entire region having similar hydrophobicity, or the substitution of residues having similar side-chain volume, are also within the scope of this disclosure.

[0316] Amino acids can be classified according to the similarity of their side chain properties (AL Lehninger, in Biochemistry, second ed., pp. 73-75, Worth Publishers, New York (1975)): (1) Nonpolar: Ala(A), Val(V), Leu(L), Ile(I), Pro(P), Phe(F), Trp(W), Met(M); (2) Uncharged polar: Gly(G), Ser(S), Thr(T), Cys(C), Tyr(Y), Asn(N), Gln(Q); (3) Acidic: Asp(D), Glu(E); (4) Basic: Lys(K), Arg(R), His(H). Alternatively, native residues can be classified based on common side-chain properties: (1) Hydrophobic: norleucine, Met, Ala, Val, Leu, Ile, Phe, Trp; (2) Neutral hydrophilic: Cys, Ser, Thr, Asn, Gln, Ala, Tyr, His, Pro, Gly; (3) Acidic: Asp, Glu; (4) Basic: His, Lys, Arg; (5) Residues affecting chain orientation: Gly, Pro; (6) Aromatic: Trp, Tyr, Phe, Pro, His, or hydroxyproline. Non-conservative substitutions would involve exchanging a member belonging to one of these classes for another.

[0317] In certain embodiments, the conservative substitutions used in the variants described herein are: Ala to Gly or Ser; Arg to Lys; Asn to Gln or His; Asp to Glu or Asn; Cys to Ser; Gln to Asn; Glu to Asp; Gly to Ala or Pro; His to Asn or Gln; Ile to Leu or Val; Leu to Ile or Val; Lys to Arg, Gln, or Glu; Met to Leu, Tyr, or Ile; Phe to Met, Leu, or Tyr; Ser to Thr; Thr to Ser; Trp to Tyr or Phe; Tyr to Phe or Trp; and / or Phe to Val, Tyr, Ile, or Leu. Generally, conservative substitutions include the exchange of residues with similar physicochemical properties (i.e., replacing a hydrophobic residue with another hydrophobic amino acid).

[0318] In yet another embodiment, the amino acid sequence present in W is at least 0.01% of the GLP-1 receptor activating activity of natural GLP-1, for example, at least 0.1%, 0.2%, 0.5%, 0.8%, 1%, 3%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99% of the GLP-1 receptor activating activity of natural GLP-1-OH or GLP-1-NH2. The sequence is present in, contains, or is based on, a peptide exhibiting %, and / or at least 0.01% of the GIP receptor activating activity of GIP, for example, at least 0.1%, 0.2%, 0.5%, 0.8%, 1%, 3%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% of the GIP receptor activating activity of native GIP.

[0319] As used herein, the term “natural GLP-1” means a peptide containing the sequence of human GLP-1 (7-36, or 7-37), and the term “natural GIP” means a peptide containing the sequence of human GIP (1-42). Any general reference to “GLP-1” or “GIP” used herein, in the absence of further indication, is intended to mean natural GLP-1 or natural GIP, respectively.

[0320] In some embodiments, W is given by equation (X): -GTF-W''-R 5 The formula has the following characteristics, where W'' is a sequence of 30 to 40 amino acids (e.g., 31 to 36 or 33).

[0321] In certain embodiments, W has equation (XII): In formula TIFF0007933830000066.tif68128, W'' is a sequence of 30-40 amino acids (e.g., 31-35, e.g., 33), R * is H or a modifying group (e.g., an acyl group, and the PEG group described herein).

[0322] In certain embodiments, W has the formula (XII-OH): In formula TIFF0007933830000067.tif71128, W'' is a sequence of 30-40 amino acids (e.g., 31-35, e.g., 33), and R * is H or a modifying group (e.g., an acyl group, and the PEG group described herein).

[0323] In some embodiments, W has equation (XIII): -GTF-W'''-GPSSGAPPPS-R 5 (SEQ ID NO: 1) In the formula, W''' represents a sequence of 20 to 30 amino acids (for example, 21 to 25, or 23).

[0324] In some embodiments, W has the equation (XIV-AA): TIFF0007933830000068.tif19151 (SEQ ID NO: 2A, listed as SEQ ID NO: 35 in the sequence listing); During the ceremony, Xaa3 is F; Xaa4 is T or I (for example, T); Xaa7 is Y, V, L, or K * (For example, Y) Xaa9 is I or S (e.g., I); Xaa10 is Y, Y * , Q, A, or (Aib) (e.g., Y); Xaa11 is L, M, or L * (For example, L) Xaa12 is D or E (for example, D); Xaa13 is K, G, R, or E (for example, K); Xaa14 is Q or I (for example, Q); Xaa15 is A, H, or R (for example, A); Xaa16 is A, Q, or V (for example, A); Xaa17 is A, (Aib), K * , K, or Q (e.g., (Aib)); Xaa18 is A, D, E, (Aib), or L (e.g., A, D, E, or L (e.g., E)); Xaa19 is F, or A (for example, F); Xaa20 is V or I (for example, V); Xaa21 is N, A, Q, K * , or E (e.g., N); Xaa24 is I, L, or V (for example, L); Xaa25 is A, K, or I (for example, A); Xaa26 is QR, GRGK * , Q, or G (for example, G); Xaa36 is either S or non-existent (e.g., S).

[0325] In some embodiments (for example, when W has the equation (XIV-AA)), W has the equation (XIV): TIFF0007933830000069.tif12151In formula, Xaa4 is T or I (for example, T); Xaa7 is Y, V, or L (for example, Y); Xaa9 is I or S (e.g., I); Xaa10 is Y, Q, or A (for example, Y); Xaa11 is L, M, or L * (For example, L) Xaa12 is D or E (for example, D); Xaa13 is K, G, or E (for example, K); Xaa16 is A or V (for example, A); Xaa17 is (Aib) or K (e.g., (Aib)); Xaa18 is E or L (for example, E); Xaa20 is V or I (for example, V); Xaa21 is N, A, or E (for example, N); Xaa24 is L or V (for example, L); Xaa25 is A or K (for example, A).

[0326] In certain embodiments, W has the equation (XIV-A): In formula TIFF0007933830000070.tif12152, each "Xaa" variable element is defined with respect to formula (XIV). In some of these embodiments, R 5 may be defined anywhere in this specification (for example, formula (XI); for example, formula D or L may have formula (XI), R * (This may be defined as any other part of this specification.)

[0327] In certain embodiments, W has the equation (XIV-B): TIFF0007933830000071.tif5145. In some of these embodiments, R 5may be defined anywhere in this specification (for example, formula (XI); for example, formula D or L may have formula (XI), R * (This may be defined as any other part of this specification.)

[0328] As used herein, "(Aib)" means 2-aminoisobutyric acid (also known as α-aminoisobutyric acid, α-methylalanine, or 2-methylalanine).

[0329] Y as used herein * L means 2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid (e.g., (S)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid). * This refers to 2-amino-2-methylpentanoic acid (e.g., (S)-2-amino-2-methylpentanoic acid), or its C-terminal amino acid, amino acid ester, or amino acid amide.

[0330] K used herein * This refers to a lysine residue substituted with a modifying group, or its C-terminal amino acid, amino acid ester, or amino acid amide.

[0331] K * Non-limiting examples include amino acid residues selected from the following, or their C-terminal amino acids, amino acid esters, or amino acid amides. TIFF0007933830000072.tif19132

[0332] In some embodiments, W is represented by one of the following equations: (X), (XII), (XIII), (XIV-AA), (XIV), (XIV-A), (XIV-B), (XV), or SEQ IDs 1 to 34.

[0333] For example, W may have any one of the sequences listed in Table 2.

[0334] (Table 2) TIFF0007933830000073.tif136168TIFF0007933830000074.tif218168TIFF0007933830000075.tif216168TIFF0007933830 000076.tif178168TIFF0007933830000077.tif153168TIFF0007933830000078.tif215168TIFF0007933830000079.tif93168

[0335] In some embodiments, W is represented by one of the SEQ IDs 1-34 (e.g., SEQ IDs 5-27; e.g., SEQ IDs 5-29; (e.g., SEQ ID 6); e.g., SEQ IDs 28-29; e.g., SEQ IDs 30-34).

[0336] In some embodiments, W is represented by one of the SEQ IDs 1 to 27 (e.g., SEQ IDs 5 to 27; e.g., SEQ ID 6).

[0337] In some embodiments, W is represented by one of the SEQ IDs 28-29 (e.g., 28, 29).

[0338] In certain embodiments, W has the sequence of SEQ ID 6.

[0339] Non-restrictive combinations of formulas (IAA), (IA), and (I) [1] In some embodiments, the compound has formula (IA), (I-AA), or (I-AB), where ring A is a saturated or unsaturated monoring containing 3 to 8 ring atoms (e.g., 4 to 8, 4 to 7, 5 to 6), and L is of formula (VIII): -(CH2) m -X 1 -(CH2) n -X 2 -(CH2) p - has. In certain embodiments, R 1 , R 2 , and R 4One, two, or three of them are H. In certain embodiments, R 3 is -C(O)OH. In certain embodiments, a is 0, 1, or 2 (e.g., 1). In certain embodiments, R 1 , R 2 , and R 4 H is H, a is 0, 1, or 2 (for example, 1), and R 3 It is -C(O)OH.

[0340] [1A] In some embodiments, the compound has the formula (IA-A), (IA-AA), or (IA-AB), where ring A is a saturated or unsaturated monoring containing 3 to 8 ring atoms (e.g., 4 to 8, 4 to 7, or 5 to 6), and L is of the formula (VIII): -(CH2) m -X 1 -(CH2) n -X 2 -(CH2) p - has. In certain embodiments, R 1 , R 2 , and R 4 One, two, or three of them are H. In certain embodiments, R 3 is -C(O)OH. In certain embodiments, a is 0, 1, or 2 (e.g., 1). In certain embodiments, R 1 , R 2 , and R 4 H is H, a is 0, 1, or 2 (for example, 1), and R 3 is -C(O)OH. In certain embodiments, a' is 1; R 3a and R 3b These are H.

[0341] [2] In some embodiments, the compound has the formula (IA), (I-AA), or (I-AB), (IA), (I-AA), or (I-AB), where ring A is a saturated monoring containing 3 to 8 ring atoms (e.g., 4 to 8, 4 to 7, 5 to 6), and L is of the formula (VIII): -(CH2) m -X 1 -(CH2) n -X 2 -(CH2) p - has. In certain embodiments, R1 , R 2 , and R 4 One, two, or three of them are H. In certain embodiments, R 3 is -C(O)OH. In certain embodiments, a is 0, 1, or 2 (e.g., 1). In certain embodiments, R 1 , R 2 , and R 4 H is H, a is 0, 1, or 2 (for example, 1), and R 3 It is -C(O)OH.

[0342] [2A] In some embodiments, the compound has the formula (IA-A), (IA-AA), or (IA-AB), (IA-B), (IA-BA), or (IA-BB), where ring A is a saturated monoring containing 3 to 8 ring atoms (e.g., 4 to 8, 4 to 7, 5 to 6), and L is of the formula (VIII): -(CH2) m -X 1 -(CH2) n -X 2 -(CH2) p - has. In certain embodiments, R 1 , R 2 , and R 4 One, two, or three of them are H. In certain embodiments, R 3 is -C(O)OH. In certain embodiments, a is 0, 1, or 2 (e.g., 1). In certain embodiments, R 1 , R 2 , and R 4 H is H, a is 0, 1, or 2 (for example, 1), and R 3 is -C(O)OH. In certain embodiments, a' is 1; R 3a and R 3b These are H.

[0343] [3] In some embodiments, the compound has formula (IA), (I-AA), or (I-AB), where ring A is a saturated six-membered monoring having formula (III) (i.e., A 1 (This is not a combination), L is in equation (VIII): -(CH2) m -X 1 -(CH2) n-X 2 -(CH2) p - has. In certain embodiments, R 1 , R 2 , and R 4 One, two, or three of them are H. In certain embodiments, R 3 is -C(O)OH. In certain embodiments, a is 0, 1, or 2 (e.g., 1). In certain embodiments, R 1 , R 2 , and R 4 H is H, a is 0, 1, or 2 (for example, 1), and R 3 It is -C(O)OH.

[0344] [3A] In some embodiments, the compound has the formula (IA-A), (IA-AA), or (IA-AB), where ring A is a saturated six-membered monoring having the formula (III) (i.e., A 1 (This is not a combination), L is in equation (VIII): -(CH2) m -X 1 -(CH2) n -X 2 -(CH2) p - has. In certain embodiments, R 1 , R 2 , and R 4 One, two, or three of them are H. In certain embodiments, R 3 is -C(O)OH. In certain embodiments, a is 0, 1, or 2 (e.g., 1). In certain embodiments, R 1 , R 2 , and R 4 H is H, a is 0, 1, or 2 (for example, 1), and R 3 is -C(O)OH. In certain embodiments, a' is 1; R 3a and R 3b These are H.

[0345] [4] In some embodiments, the compound has the formula (IA), (I-AA), or (I-AB), where ring A is a saturated five-membered monoring having the formula (III-A) (i.e., A in formula (III) 1 ( is a combination), and L is in equation (VIII): -(CH2)m -X 1 -(CH2) n -X 2 -(CH2) p - has. In certain embodiments, R 1 , R 2 , and R 4 One, two, or three of them are H. In certain embodiments, R 3 is -C(O)OH. In certain embodiments, a is 0, 1, or 2 (e.g., 1). In certain embodiments, R 1 , R 2 , and R 4 H is H, a is 0, 1, or 2 (for example, 1), and R 3 It is -C(O)OH.

[0346] [4A] In some embodiments, the compound has the formula (IA-A), (IA-AA), or (IA-AB), where ring A is a saturated five-membered monoring having the formula (III-A) (i.e., A in formula (III)). 1 ( is a combination), and L is in equation (VIII): -(CH2) m -X 1 -(CH2) n -X 2 -(CH2) p - has. In certain embodiments, R 1 , R 2 , and R 4 One, two, or three of them are H. In certain embodiments, R 3 is -C(O)OH. In certain embodiments, a is 0, 1, or 2 (e.g., 1). In certain embodiments, R 1 , R 2 , and R 4 H is H, a is 0, 1, or 2 (for example, 1), and R 3 is -C(O)OH. In certain embodiments, a' is 1; R 3a and R 3b These are H.

[0347] [5] In some embodiments, the compound has the formula (IA), (I-AA), or (I-AB), where ring A is a saturated or unsaturated bicyclic or tricyclic ring containing 6 to 14 (e.g., 8 to 10) ring atoms, and L is of the formula (VIII): -(CH2) m -X 1 -(CH2) n -X 2 -(CH2) p - has. In certain embodiments, R 1 , R 2 , and R 4 One, two, or three of them are H. In certain embodiments, R 3 is -C(O)OH. In certain embodiments, a is 0, 1, or 2 (e.g., 1). In certain embodiments, R 1 , R 2 , and R 4 H is H, a is 0, 1, or 2 (for example, 1), and R 3 It is -C(O)OH.

[0348] [5A] In some embodiments, the compound has the formula (IA-A), (IA-AA), or (IA-AB), where ring A is a saturated or unsaturated bicyclic or tricyclic ring containing 6 to 14 (e.g., 8 to 10) ring atoms, and L is of the formula (VIII): -(CH2) m -X 1 -(CH2) n -X 2 -(CH2) p - has. In certain embodiments, R 1 , R 2 , and R 4 One, two, or three of them are H. In certain embodiments, R 3 is -C(O)OH. In certain embodiments, a is 0, 1, or 2 (e.g., 1). In certain embodiments, R 1 , R 2 , and R 4 H is H, a is 0, 1, or 2 (for example, 1), and R 3 is -C(O)OH. In certain embodiments, a' is 1; R 3a and R 3b These are H.

[0349] [6] In some embodiments, the compound has the formula (IA), (I-AA), or (I-AB), where ring A is a saturated or unsaturated monoring containing 3 to 8 ring atoms (e.g., 4 to 8, 4 to 7, or 5 to 6), and L is of the formula (VIII): -(CH2) m -X 1 -(CH2) n -X 2 -(CH2) p - has, where W is represented by any one of the formulas (X), (XII), (XIII), (XIV), (XIV-A), (XIV-B), or SEQ IDs 1 to 27 (e.g., SEQ IDs 5 to 27, e.g., SEQ ID 6). In certain embodiments, R 1 , R 2 , and R 4 One, two, or three of them are H. In certain embodiments, R 3 is -C(O)OH. In certain embodiments, a is 0, 1, or 2 (e.g., 1). In certain embodiments, R 5 has equation (XI). In certain embodiments, R 1 , R 2 , and R 4 H is H, a is 0, 1, or 2 (for example, 1), and R 3 is -C(O)OH, and R 5 has equation (XI).

[0350] [6A] In some embodiments, the compound has the formula (IA-A), (IA-AA), or (IA-AB), where ring A is a saturated or unsaturated monoring containing 3 to 8 ring atoms (e.g., 4 to 8, 4 to 7, or 5 to 6), and L is of the formula (VIII): -(CH2) m -X 1 -(CH2) n -X 2 -(CH2) p- has, and W is represented by any one of the following formulas: (X), (XII), (XIII), (XIV-AA), (XIV), (XIV-A), (XIV-B), (XV), or SEQ IDs 1-34 (e.g., SEQ IDs 5-27; e.g., SEQ IDs 5-29; (e.g., SEQ ID 6); e.g., SEQ IDs 28-29; e.g., SEQ IDs 30-34). In certain embodiments, R 1 , R 2 , and R 4 One, two, or three of them are H. In certain embodiments, R 3 is -C(O)OH. In certain embodiments, a is 0, 1, or 2 (e.g., 1). In certain embodiments, R 5 has equation (XI). In certain embodiments, R 1 , R 2 , and R 4 H is H, a is 0, 1, or 2 (for example, 1), and R 3 is -C(O)OH, and R 5 has equation (XI). In a particular embodiment, a' is 1; R 3a and R 3b These are H.

[0351] [7] In some embodiments, the compound has the formula (IA), (I-AA), or (I-AB), where ring A is a saturated monoring containing 3 to 8 ring atoms (e.g., 4 to 8, 4 to 7, 5 to 6), and L is of the formula (VIII): -(CH2) m -X 1 -(CH2) n -X 2 -(CH2) p - has, and W is represented by any one of (X), (XII), (XIII), (XIV), (XIV-A), (XIV-B), or SEQ ID 1 to 27 (e.g., SEQ ID 5 to 27, e.g., SEQ ID 6). In certain embodiments, R 1 , R 2 , and R 4 One, two, or three of them are H. In certain embodiments, R 3is -C(O)OH. In certain embodiments, a is 0, 1, or 2 (e.g., 1). In certain embodiments, R 5 has equation (XI). In certain embodiments, R 1 , R 2 , and R 4 H is H, a is 0, 1, or 2 (for example, 1), and R 3 is -C(O)OH, and R 5 has equation (XI).

[0352] [7A] In some embodiments, the compound has formula (IA), (I-AA), or (I-AB), where ring A is a saturated monoring containing 3 to 8 ring atoms (e.g., 4 to 8, 4 to 7, 5 to 6), and L is of formula (VIII): -(CH2) m -X 1 -(CH2) n -X 2 -(CH2) p - has, and W is represented by any one of the following formulas: (X), (XII), (XIII), (XIV-AA), (XIV), (XIV-A), (XIV-B), (XV), or SEQ IDs 1-34 (e.g., SEQ IDs 5-27; e.g., SEQ IDs 5-29; (e.g., SEQ ID 6); e.g., SEQ IDs 28-29; e.g., SEQ IDs 30-34). In certain embodiments, R 1 , R 2 , and R 4 One, two, or three of them are H. In certain embodiments, R 3 is -C(O)OH. In certain embodiments, a is 0, 1, or 2 (e.g., 1). In certain embodiments, R 5 has equation (XI). In certain embodiments, R 1 , R 2 , and R 4 H is H, a is 0, 1, or 2 (for example, 1), and R 3 is -C(O)OH, and R 5 has equation (XI). In a particular embodiment, a' is 1; R 3a and R 3b These are H.

[0353] [8] In some embodiments, the compound has formula (IA), (I-AA), or (I-AB), where ring A is a saturated six-membered monoring having formula (III) (i.e., A 1 (This is not a combination), L is in equation (VIII): -(CH2) m -X 1 -(CH2) n -X 2 -(CH2) p - has, where W is represented by any one of the formulas (X), (XII), (XIII), (XIV), (XIV-A), (XIV-B), or SEQ IDs 1 to 27 (e.g., SEQ IDs 5 to 27, e.g., SEQ ID 6). In certain embodiments, R 1 , R 2 , and R 4 One, two, or three of them are H. In certain embodiments, R 3 is -C(O)OH. In certain embodiments, a is 0, 1, or 2 (e.g., 1). In certain embodiments, R 5 has equation (XI). In certain embodiments, R 1 , R 2 , and R 4 H is H, a is 0, 1, or 2 (for example, 1), and R 3 is -C(O)OH, and R 5 has equation (XI).

[0354] [8A] In some embodiments, the compound has the formula (IA-A), (IA-AA), or (IA-AB), where ring A is a saturated six-membered monoring having the formula (III) (i.e., A 1 (This is not a combination), L is in equation (VIII): -(CH2) m -X 1 -(CH2) n -X 2 -(CH2) p- has, and W is represented by any one of the following formulas: (X), (XII), (XIII), (XIV-AA), (XIV), (XIV-A), (XIV-B), (XV), or SEQ IDs 1-34 (e.g., SEQ IDs 5-27; e.g., SEQ IDs 5-29; (e.g., SEQ ID 6); e.g., SEQ IDs 28-29; e.g., SEQ IDs 30-34). In certain embodiments, R 1 , R 2 , and R 4 One, two, or three of them are H. In certain embodiments, R 3 is -C(O)OH. In certain embodiments, a is 0, 1, or 2 (e.g., 1). In certain embodiments, R 5 has equation (XI). In certain embodiments, R 1 , R 2 , and R 4 H is H, a is 0, 1, or 2 (for example, 1), and R 3 is -C(O)OH, and R 5 has equation (XI). In a particular embodiment, a' is 1; R 3a and R 3b These are H.

[0355] [9] In some embodiments, the compound has the formula (IA), (I-AA), or (I-AB), where ring A is a saturated five-membered monoring having the formula (III-A) (i.e., A in formula (III) 1 ( is a combination), and L is in equation (VIII): -(CH2) m -X 1 -(CH2) n -X 2 -(CH2) p - has, where W is represented by any one of the formulas (X), (XII), (XIII), (XIV), (XIV-A), (XIV-B), or SEQ IDs 1 to 27 (e.g., SEQ IDs 5 to 27, e.g., SEQ ID 6). In certain embodiments, R 1 , R 2 , and R 4 One, two, or three of them are H. In certain embodiments, R 3is -C(O)OH. In certain embodiments, a is 0, 1, or 2 (e.g., 1). In certain embodiments, R 5 has equation (XI). In certain embodiments, R 1 , R 2 , and R 4 H is H, a is 0, 1, or 2 (for example, 1), and R 3 is -C(O)OH, and R 5 has equation (XI).

[0356] [9A] In some embodiments, the compound has the formula (IA-A), (IA-AA), or (IA-AB), where ring A is a saturated five-membered monoring having the formula (III-A) (i.e., A in formula (III)). 1 ( is a combination), and L is in equation (VIII): -(CH2) m -X 1 -(CH2) n -X 2 -(CH2) p - has, and W is represented by any one of the following formulas: (X), (XII), (XIII), (XIV-AA), (XIV), (XIV-A), (XIV-B), (XV), or SEQ IDs 1-34 (e.g., SEQ IDs 5-27; e.g., SEQ IDs 5-29; (e.g., SEQ ID 6); e.g., SEQ IDs 28-29; e.g., SEQ IDs 30-34). In certain embodiments, R 1 , R 2 , and R 4 One, two, or three of them are H. In certain embodiments, R 3 is -C(O)OH. In certain embodiments, a is 0, 1, or 2 (e.g., 1). In certain embodiments, R 5 has equation (XI). In certain embodiments, R 1 , R 2 , and R 4 H is H, a is 0, 1, or 2 (for example, 1), and R 3 is -C(O)OH, and R 5 has equation (XI). In a particular embodiment, a' is 1; R 3a and R 3b These are H.

[0357]

[10] In some embodiments, the compound has the formula (IA), (I-AA), or (I-AB), where ring A is a saturated or unsaturated bicyclic or tricyclic ring containing 6 to 14 (e.g., 8 to 10) ring atoms, and L is of the formula (VIII): -(CH2) m -X 1 -(CH2) n -X 2 -(CH2) p - has, where W is represented by any one of the formulas (X), (XII), (XIII), (XIV), (XIV-A), (XIV-B), or SEQ IDs 1 to 27 (e.g., SEQ IDs 5 to 27, e.g., SEQ ID 6). In certain embodiments, R 1 , R 2 , and R 4 One, two, or three of them are H. In certain embodiments, R 3 is -C(O)OH. In certain embodiments, a is 0, 1, or 2 (e.g., 1). In certain embodiments, R 5 has equation (XI). In certain embodiments, R 1 , R 2 , and R 4 H is H, a is 0, 1, or 2 (for example, 1), and R 3 is -C(O)OH, and R 5 has equation (XI).

[0358] [10A] In some embodiments, the compound has the formula (IA-A), (IA-AA), or (IA-AB), where ring A is a saturated or unsaturated bicyclic or tricyclic ring containing 6 to 14 (e.g., 8 to 10) ring atoms, and L is of the formula (VIII): -(CH2) m -X 1 -(CH2) n -X 2 -(CH2) p- has, and W is represented by any one of the following formulas: (X), (XII), (XIII), (XIV-AA), (XIV), (XIV-A), (XIV-B), (XV), or SEQ IDs 1-34 (e.g., SEQ IDs 5-27; e.g., SEQ IDs 5-29; (e.g., SEQ ID 6); e.g., SEQ IDs 28-29; e.g., SEQ IDs 30-34). In certain embodiments, R 1 , R 2 , and R 4 One, two, or three of them are H. In certain embodiments, R 3 is -C(O)OH. In certain embodiments, a is 0, 1, or 2 (e.g., 1). In certain embodiments, R 5 has equation (XI). In certain embodiments, R 1 , R 2 , and R 4 H is H, a is 0, 1, or 2 (for example, 1), and R 3 is -C(O)OH, and R 5 has equation (XI). In a particular embodiment, a' is 1; R 3a and R 3b These are H.

[0359]

[11] In some embodiments, The compound has the formula (IA), (I-AA), or (I-AB); Ring A is a saturated monoring containing 3 to 8 ring atoms (e.g., 4 to 8, 4 to 7, 5 to 6); L is given by equation (VIII): -(CH2) m -X 1 -(CH2) n -X 2 -(CH2) p - has; W is represented by any one of the following equations: (X), (XII), (XIII), (XIV), (XIV-A), (XIV-B), or SEQ IDs 1 through 27 (e.g., SEQ IDs 5 through 27, e.g., SEQ ID 6); m is 2 to 6 (for example, 2), X 1is -N(R')C(O)- (for example, -N(H)C(O)-), where n + p = 2 (for example, n and p are each 1), X 2 is -S-; or, m is 2 to 6 (for example, 2), X 1 is -N(R')C(O)- (for example, -N(H)C(O)-), n + p = 0, and X 2 -C(Q 1 )(Q 2 )- and Q 1 and Q 2 Each of them, together with the carbon atoms to which it is bonded, becomes C 3~6 A cycloalkyl group is formed, and the cycloalkyl group consists of 1 to 4 independently selected R d It may be substituted with, or condensed with phenyl; or, m is 2 to 6 (for example, 2), X 1 is -N(R')C(O)- (for example, -N(H)C(O)-), n + p = 0, and X 2 -C(Q 1 )(Q 2 )- and Q 1 and Q 2 C is selected independently 1~4 It is alkyl (e.g., CH3); or, m is 2 to 6 (for example, 2), X 1 is -N(R')C(O)- (for example, -N(H)C(O)-), n + p = 0, and X 2 (v) 1 to 5 independently selected R c Even if replaced by C 6~10 Arylene (e.g., phenylene); or (vii) 1 to 4 independently selected R d Even if replaced by C 3~10 It is a cycloalkylene.

[0360] In certain aspects, R 1 , R 2 , and R 4 One, two, or three of them are H. In certain embodiments, R 3is -C(O)OH. In certain embodiments, a is 0, 1, or 2 (e.g., 1). In certain embodiments, R 5 has equation (XI). In certain embodiments, R 1 , R 2 , and R 4 H is H, a is 0, 1, or 2 (for example, 1), and R 3 is -C(O)OH, and R 5 has equation (XI).

[0361] In some of these embodiments, m is 2 to 6 (for example, 2), and X 1 is -N(R')C(O)- (for example, -N(H)C(O)-) and n + p = 2 (for example, n and p are each 1), X 2 is -S-. For example, L can be -CH2CH2NHC(O)CH2SCH2-.

[0362] In some of these configurations, one of the SEQ IDs 5-27 (for example, SEQ ID 6) represents W.

[0363] [11A] In some embodiments, The compounds have the formula (IA-A), (IA-AA), or (IA-AB); Ring A is a saturated monoring containing 3 to 8 ring atoms (e.g., 4 to 8, 4 to 7, 5 to 6); L is given by equation (VIII): -(CH2) m -X 1 -(CH2) n -X 2 -(CH2) p - has, W is represented by one of the following equations: (X), (XII), (XIII), (XIV-AA), (XIV), (XIV-A), (XIV-B), (XV), or SEQ IDs 1-34 (e.g., SEQ IDs 5-27; SEQ IDs 5-29; (e.g., SEQ ID 6); SEQ IDs 28-29; SEQ IDs 30-34).

[0364] In certain embodiments, m is 2 to 6 (for example, 2), and X 1 is -N(R')C(O)- (for example, -N(H)C(O)-), where n + p = 2 (for example, n and p are each 1), X 2 is -S-; or, m is 2 to 6 (for example, 2), X 1 is -N(R')C(O)- (for example, -N(H)C(O)-), n + p = 0, and X 2 -C(Q 1 )(Q 2 )- and Q 1 and Q 2 Each of them, together with the carbon atoms to which it is bonded, becomes C 3~6 A cycloalkyl group is formed, and the cycloalkyl group consists of 1 to 4 independently selected R d It may be substituted with, or condensed with phenyl; or, m is 2 to 6 (for example, 2), X 1 is -N(R')C(O)- (for example, -N(H)C(O)-), n + p = 0, and X 2 -C(Q 1 )(Q 2 )- and Q 1 and Q 2 C is selected independently 1~4 It is alkyl (e.g., CH3); or, m is 2 to 6 (for example, 2), X 1 is -N(R')C(O)- (for example, -N(H)C(O)-), n + p = 0, and X 2 (v) 1 to 5 independently selected R c Even if replaced by C 6~10 Arylene (e.g., phenylene); or (vii) 1 to 4 independently selected R d Even if replaced by C 3~10 It is a cycloalkylene.

[0365] In certain embodiments, m is 2 to 6 (for example, 2), and X 1is -N(R')C(O)- (for example, -N(H)C(O)-), n + p = 0, and X 2 This is a heterocycloalkylene containing 4 to 6 (e.g., 4) ring atoms, where 1 to 3 (e.g., 1) ring atoms are each independently N(R) a R is selected from the group consisting of ), O, and S, and the heterocycloalkylene is selected in a group of 1 to 5 independent elements. d It is a heterocycloalkylene that may be substituted with (e.g., X 2 teeth (Possibly TIFF0007933830000080.tif7128).

[0366] In certain aspects, R 1 , R 2 , and R 4 One, two, or three of them are H. In certain embodiments, R 3 is -C(O)OH. In certain embodiments, a is 0, 1, or 2 (e.g., 1). In certain embodiments, R 5 has equation (XI). In certain embodiments, R 1 , R 2 , and R 4 H is H, a is 0, 1, or 2 (for example, 1), and R 3 is -C(O)OH, and R 5 has equation (XI). In a particular embodiment, a' is 1; R 3a and R 3b These are H.

[0367] In some of these embodiments, m is 2 to 6 (for example, 2), and X 1 is -N(R')C(O)- (for example, -N(H)C(O)-), where n + p = 2 (for example, n and p are each 1), X 2 is -S-. For example, L can be -CH2CH2NHC(O)CH2SCH2-.

[0368] In some of these embodiments, one of the SEQ IDs 5-34 (for example, SEQ ID 6) represents W.

[0369]

[12] In some embodiments, The compound has the formula (IA), (I-AA), or (I-AB); Ring A is a saturated 6-membered monoring having formula (III) (i.e., A 1 (This is not a combination); L is given by equation (VIII): -(CH2) m -X 1 -(CH2) n -X 2 -(CH2) p - has; W is represented by any one of the following equations: (X), (XII), (XIII), (XIV), (XIV-A), (XIV-B), or SEQ IDs 1 through 27 (e.g., SEQ IDs 5 through 27, e.g., SEQ ID 6); m is 2 to 6 (for example, 2), X 1 is -N(R')C(O)- (for example, -N(H)C(O)-), where n + p = 2 (for example, n and p are each 1), X 2 is -S-; or, m is 2 to 6 (for example, 2), X 1 is -N(R')C(O)- (for example, -N(H)C(O)-), n + p = 0, and X 2 -C(Q 1 )(Q 2 )- and Q 1 and Q 2 Each of them, together with the carbon atoms to which it is bonded, becomes C 3~6 A cycloalkyl group is formed, and the cycloalkyl group consists of 1 to 4 independently selected R d It may be substituted with, or condensed with phenyl; or, m is 2 to 6 (for example, 2), X 1 is -N(R')C(O)- (for example, -N(H)C(O)-), n + p = 0, and X 2 -C(Q 1 )(Q 2 )- and Q 1 and Q 2 C is selected independently 1~4It is alkyl (e.g., CH3); or, m is 2 to 6 (for example, 2), X 1 is -N(R')C(O)- (for example, -N(H)C(O)-), n + p = 0, and X 2 (v) 1 to 5 independently selected R c Even if replaced by C 6~10 Arylene (e.g., phenylene); or (vii) 1 to 4 independently selected R d Even if replaced by C 3~10 It is a cycloalkylene.

[0370] In certain aspects, R 1 , R 2 , and R 4 One, two, or three of them are H. In certain embodiments, R 3 is -C(O)OH. In certain embodiments, a is 0, 1, or 2 (e.g., 1). In certain embodiments, R 5 has equation (XI). In certain embodiments, R 1 , R 2 , and R 4 H is H, a is 0, 1, or 2 (for example, 1), and R 3 is -C(O)OH, and R 5 has equation (XI).

[0371] In some of these embodiments, m is 2 to 6 (for example, 2), and X 1 is -N(R')C(O)- (for example, -N(H)C(O)-), where n + p = 2 (for example, n and p are each 1), X 2 is -S-. For example, L can be -CH2CH2NHC(O)CH2SCH2-.

[0372] In some of these configurations, one of the SEQ IDs 5-27 (for example, SEQ ID 6) represents W.

[0373] In a specific six-membered ring configuration of formula (III), A1, A2, A3, and A4 are independently CH2, CHRb , or C(R b Selected from the group consisting of )2.

[0374] In a particular form of the six-membered ring of formula (III), one or two of A1, A2, A3, and A4 (e.g., one) independently form CHR b and C(R b ) Selected from the group consisting of 2, the rest are CH2.

[0375] In a specific six-membered ring configuration of formula (III), A1, A2, A3, and A4 are each CH2.

[0376] In a specific six-membered ring configuration of formula (III), A1, A2, and A4 are independently CH2, CHR b , and C(R b ) Selected from the group consisting of 2; A3 is O; S; SO2; or N(R a ) In some of these embodiments, one or two of A2 and A4 (e.g., one) independently perform CHR b and C(R b ) is selected from the group consisting of 2, and the others (if applicable) are CH2. In other embodiments, both A2 and A3 are CH2. In some of these embodiments, A1 is CH2. In some of these embodiments, A3 is N(R a ) (for example, A3 can be NH). In another embodiment, A3 is O. In yet another embodiment, A3 is SO2.

[0377] In a specific six-membered ring configuration of formula (III), A1, A2, and A3 are independently CH2, CHR b , and C(R b ) Selected from the group consisting of 2; A4 is O; S; or N(R a ) In some of these embodiments, one or two of A2 and A4 (e.g., one) independently perform CHR b and C(R b) is selected from the group consisting of 2, and the others (if applicable) are CH2. In other embodiments, both A2 and A3 are CH2. In some of these embodiments, A1 is CH2. In some of these embodiments, A4 is N(R a ) (for example, A4 can be NH). In other embodiments, A4 is O.

[0378] In a specific six-membered ring configuration of formula (III), A1 is C(O); A2, A3, and A4 are independently CH2 and CHR, respectively. b , or C(R b ) Selected from the group consisting of 2. In some of these embodiments, one or two (e.g., one) of A2, A3, and A4 are independently CHR b and C(R b ) Selected from the group consisting of 2, the rest are CH2.

[0379] In a specific six-membered ring configuration of formula (III), A1 is C(O); A2, A3, and A4 are each CH2.

[0380] In a specific six-membered ring configuration of formula (III), A1 is C(O); A2 and A4 are independently CH2 and CHR, respectively. b , and C(R b ) Selected from the group consisting of 2; A3 is O; S; SO2; or N(R a ) In some of these embodiments, one or two of A2 and A4 (e.g., one) independently perform CHR b and C(R b ) is selected from the group consisting of 2, and the others (if applicable) are CH2. In other embodiments, both A2 and A4 are CH2. In some of these embodiments, A3 is N(R a ) (for example, A3 can be NH). In another embodiment, A3 is O. In yet another embodiment, A3 is SO2.

[0381] In a specific six-membered ring configuration of formula (III), A1 is C(O); A2 and A3 are independently CH2 and CHR, respectively. b , and C(R b ) Selected from the group consisting of 2; A4 is O; S; or N(R a ) In some of these embodiments, one or two of A2 and A3 (e.g., one) independently perform CHR b and C(R b ) is selected from the group consisting of 2, and the others (if applicable) are CH2. In other embodiments, both A2 and A3 are CH2. In some of these embodiments, A4 is N(R a ) (for example, A4 can be NH). In other embodiments, A4 is O. In certain embodiments of the 6-membered ring of formula (III), A1, A2, A3, and A4 are independently CH2, CHR b , or C(R b Selected from the group consisting of )2.

[0382] [12A] In some embodiments, The compounds have the formula (IA-A), (IA-AA), or (IA-AB); Ring A is a saturated 6-membered monoring having formula (III) (i.e., A 1 (This is not a combination); L is given by equation (VIII): -(CH2) m -X 1 -(CH2) n -X 2 -(CH2) p - has; W is represented by one of the following equations: (X), (XII), (XIII), (XIV-AA), (XIV), (XIV-A), (XIV-B), (XV), or SEQ IDs 1-34 (e.g., SEQ IDs 5-27; SEQ IDs 5-29; (e.g., SEQ ID 6); SEQ IDs 28-29; SEQ IDs 30-34).

[0383] In certain embodiments, m is 2 to 6 (for example, 2), and X 1is -N(R')C(O)- (for example, -N(H)C(O)-), where n + p = 2 (for example, n and p are each 1), X 2 is -S-; or, m is 2 to 6 (for example, 2), X 1 is -N(R')C(O)- (for example, -N(H)C(O)-), n + p = 0, and X 2 -C(Q 1 )(Q 2 )- and Q 1 and Q 2 Each of them, together with the carbon atoms to which it is bonded, becomes C 3~6 A cycloalkyl group is formed, and the cycloalkyl group consists of 1 to 4 independently selected R d It may be substituted with, or condensed with phenyl; or, m is 2 to 6 (for example, 2), X 1 is -N(R')C(O)- (for example, -N(H)C(O)-), n + p = 0, and X 2 -C(Q 1 )(Q 2 )- and Q 1 and Q 2 C is selected independently 1~4 It is alkyl (e.g., CH3); or, m is 2 to 6 (for example, 2), X 1 is -N(R')C(O)- (for example, -N(H)C(O)-), n + p = 0, and X 2 (v) 1 to 5 independently selected R c Even if replaced by C 6~10 Arylene (e.g., phenylene); or (vii) 1 to 4 independently selected R d Even if replaced by C 3~10 It is a cycloalkylene.

[0384] In certain embodiments, m is 2 to 6 (for example, 2), and X 1 is -N(R')C(O)- (for example, -N(H)C(O)-), n + p = 0, and X 2This is a heterocycloalkylene containing 4 to 6 (e.g., 4) ring atoms, where 1 to 3 (e.g., 1) ring atoms are each independently N(R) a R is selected from the group consisting of ), O, and S, and the heterocycloalkylene is selected in a group of 1 to 5 independent elements. d It is a heterocycloalkylene that may be substituted with (e.g., X 2 teeth (Possible filename: TIFF0007933830000081.tif7128).

[0385] In certain aspects, R 1 , R 2 , and R 4 One, two, or three of them are H. In certain embodiments, R 3 is -C(O)OH. In certain embodiments, a is 0, 1, or 2 (e.g., 1). In certain embodiments, R 5 has equation (XI). In certain embodiments, R 1 , R 2 , and R 4 H is H, a is 0, 1, or 2 (for example, 1), and R 3 is -C(O)OH, and R 5 has equation (XI). In a particular embodiment, a' is 1; R 3a and R 3b These are H.

[0386] In some of these embodiments, m is 2 to 6 (for example, 2), and X 1 is -N(R')C(O)- (for example, -N(H)C(O)-) and n + p = 2 (for example, n and p are each 1), X 2 is -S-. For example, L can be -CH2CH2NHC(O)CH2SCH2-.

[0387] In some of these embodiments, one of the SEQ IDs 5-34 (for example, SEQ ID 6) represents W.

[0388] In a specific six-membered ring configuration of formula (III), A1, A2, A3, and A4 are independently CH2, CHR b , or C(R b Selected from the group consisting of )2.

[0389] In a particular form of the six-membered ring of formula (III), one or two of A1, A2, A3, and A4 (e.g., one) independently form CHR b and C(R b ) Selected from the group consisting of 2, the rest are CH2.

[0390] In a specific six-membered ring configuration of formula (III), A1, A2, A3, and A4 are each CH2.

[0391] In a specific six-membered ring configuration of formula (III), A1, A2, and A4 are independently CH2, CHR b , and C(R b ) Selected from the group consisting of 2; A3 is O; S; SO2; or N(R a ) In some of these embodiments, one or two of A2 and A4 (e.g., one) independently perform CHR b and C(R b ) is selected from the group consisting of 2, and the others (if applicable) are CH2. In other embodiments, both A2 and A3 are CH2. In some of these embodiments, A1 is CH2. In some of these embodiments, A3 is N(R a ) (for example, A3 can be NH). In another embodiment, A3 is O. In yet another embodiment, A3 is SO2.

[0392] In a specific six-membered ring configuration of formula (III), A1, A2, and A3 are independently CH2, CHR b , and C(R b ) Selected from the group consisting of 2; A4 is O; S; or N(R a ) In some of these embodiments, one or two of A2 and A4 (e.g., one) independently perform CHR b and C(Rb ) is selected from the group consisting of 2, and the others (if applicable) are CH2. In other embodiments, both A2 and A3 are CH2. In some of these embodiments, A1 is CH2. In some of these embodiments, A4 is N(R a ) (for example, A4 can be NH). In other embodiments, A4 is O.

[0393] In a specific six-membered ring configuration of formula (III), A1 is C(O); A2, A3, and A4 are independently CH2 and CHR, respectively. b , or C(R b ) Selected from the group consisting of 2. In some of these embodiments, one or two (e.g., one) of A2, A3, and A4 are independently CHR b and C(R b ) Selected from the group consisting of 2, the rest are CH2.

[0394] In a specific six-membered ring configuration of formula (III), A1 is C(O); A2, A3, and A4 are each CH2.

[0395] In a specific six-membered ring configuration of formula (III), A1 is C(O); A2 and A4 are independently CH2 and CHR, respectively. b , and C(R b ) Selected from the group consisting of 2; A3 is O; S; SO2; or N(R a ) In some of these embodiments, one or two of A2 and A4 (e.g., one) independently perform CHR b and C(R b ) is selected from the group consisting of 2, and the others (if applicable) are CH2. In other embodiments, both A2 and A4 are CH2. In some of these embodiments, A3 is N(R a ) (for example, A3 can be NH). In another embodiment, A3 is O. In yet another embodiment, A3 is SO2.

[0396] In a specific six-membered ring configuration of formula (III), A1 is C(O); A2 and A3 are independently CH2 and CHR, respectively. b , and C(R b ) Selected from the group consisting of 2; A4 is O; S; or N(R a ) In some of these embodiments, one or two of A2 and A3 (e.g., one) independently perform CHR b and C(R b ) is selected from the group consisting of 2, and the others (if applicable) are CH2. In other embodiments, both A2 and A3 are CH2. In some of these embodiments, A4 is N(R a ) (for example, A4 can be NH). In other embodiments, A4 is O. In certain embodiments of the 6-membered ring of formula (III), A1, A2, A3, and A4 are independently CH2, CHR b , or C(R b Selected from the group consisting of )2.

[0397]

[13] In some embodiments, The compounds have the formula (IA-A), (IA-AA), or (IA-AB); Ring A is a saturated five-membered monoring having formula (III-A) (i.e., A in formula (III) 1 (This is a combination). L is given by equation (VIII): -(CH2) m -X 1 -(CH2) n -X 2 -(CH2) p - has; W is represented by any one of the following equations: (X), (XII), (XIII), (XIV), (XIV-A), (XIV-B), or SEQ IDs 1 through 27 (e.g., SEQ IDs 5 through 27, e.g., SEQ ID 6); m is 2 to 6 (for example, 2), X 1 is -N(R')C(O)- (for example, -N(H)C(O)-), where n + p = 2 (for example, n and p are each 1), X 2 is -S-; or, m is 2 to 6 (for example, 2), X 1 is -N(R')C(O)- (for example, -N(H)C(O)-), n + p = 0, and X 2 -C(Q 1 )(Q 2 )- and Q 1 and Q 2 Each of them, together with the carbon atoms to which it is bonded, becomes C 3~6 A cycloalkyl group is formed, and the cycloalkyl group consists of 1 to 4 independently selected R d It may be substituted with, or condensed with phenyl; or, m is 2 to 6 (for example, 2), X 1 is -N(R')C(O)- (for example, -N(H)C(O)-), n + p = 0, and X 2 -C(Q 1 )(Q 2 )- and Q 1 and Q 2 C is selected independently 1~4 It is alkyl (e.g., CH3); or, m is 2 to 6 (for example, 2), X 1 is -N(R')C(O)- (for example, -N(H)C(O)-), n + p = 0, and X 2 (v) 1 to 5 independently selected R c Even if replaced by C 6~10 Arylene (e.g., phenylene); or (vii) 1 to 4 independently selected R d Even if replaced by C 3~10 It is a cycloalkylene.

[0398] In certain aspects, R 1 , R 2 , and R 4 One, two, or three of them are H. In certain embodiments, R 3 is -C(O)OH. In certain embodiments, a is 0, 1, or 2 (e.g., 1). In certain embodiments, R 5 has equation (XI). In certain embodiments, R 1 , R 2 , and R4 H is H, a is 0, 1, or 2 (for example, 1), and R 3 is -C(O)OH, and R 5 has equation (XI).

[0399] In some of these embodiments, m is 2 to 6 (for example, 2), and X 1 is -N(R')C(O)- (for example, -N(H)C(O)-), where n + p = 2 (for example, n and p are each 1), X 2 is -S-. For example, L can be -CH2CH2NHC(O)CH2SCH2-.

[0400] In some of these configurations, one of the SEQ IDs 5-27 (for example, SEQ ID 6) represents W.

[0401] [13A] In some embodiments, The compounds have the formula (IA-A), (IA-AA), or (IA-AB); Ring A is a saturated five-membered monoring having formula (III-A) (i.e., A in formula (III) 1 (This is a combination). L is given by equation (VIII): -(CH2) m -X 1 -(CH2) n -X 2 -(CH2) p - has, W is represented by one of the following equations: (X), (XII), (XIII), (XIV-AA), (XIV), (XIV-A), (XIV-B), (XV), or SEQ IDs 1-34 (e.g., SEQ IDs 5-27; SEQ IDs 5-29; (e.g., SEQ ID 6); SEQ IDs 28-29; SEQ IDs 30-34).

[0402] In certain embodiments, m is 2 to 6 (for example, 2), and X 1 is -N(R')C(O)- (for example, -N(H)C(O)-), where n + p = 2 (for example, n and p are each 1), X2 is -S-; or, m is 2 to 6 (for example, 2), X 1 is -N(R')C(O)- (for example, -N(H)C(O)-), n + p = 0, and X 2 -C(Q 1 )(Q 2 )- and Q 1 and Q 2 Each of them, together with the carbon atoms to which it is bonded, becomes C 3~6 A cycloalkyl group is formed, and the cycloalkyl group consists of 1 to 4 independently selected R d It may be substituted with, or condensed with phenyl; or, m is 2 to 6 (for example, 2), X 1 is -N(R')C(O)- (for example, -N(H)C(O)-), n + p = 0, and X 2 -C(Q 1 )(Q 2 )- and Q 1 and Q 2 C is selected independently 1~4 It is alkyl (e.g., CH3); or, m is 2 to 6 (for example, 2), X 1 is -N(R')C(O)- (for example, -N(H)C(O)-), n + p = 0, and X 2 (v) 1 to 5 independently selected R c Even if replaced by C 6~10 Arylene (e.g., phenylene); or (vii) 1 to 4 independently selected R d Even if replaced by C 3~10 It is a cycloalkylene.

[0403] In certain embodiments, m is 2 to 6 (for example, 2), and X 1 is -N(R')C(O)- (for example, -N(H)C(O)-), n + p = 0, and X 2 This is a heterocycloalkylene containing 4 to 6 (e.g., 4) ring atoms, where 1 to 3 (e.g., 1) ring atoms are each independently N(R) aR is selected from the group consisting of ), O, and S, and the heterocycloalkylene is selected in a group of 1 to 5 independent elements. d It is a heterocycloalkylene that may be substituted with (e.g., X 2 teeth (Possible filename: TIFF0007933830000082.tif7128).

[0404] In certain aspects, R 1 , R 2 , and R 4 One, two, or three of them are H. In certain embodiments, R 3 is -C(O)OH. In certain embodiments, a is 0, 1, or 2 (e.g., 1). In certain embodiments, R 5 has equation (XI). In certain embodiments, R 1 , R 2 , and R 4 H is H, a is 0, 1, or 2 (for example, 1), and R 3 is -C(O)OH, and R 5 has equation (XI). In a particular embodiment, a' is 1; R 3a and R 3b These are H.

[0405] In some of these embodiments, m is 2 to 6 (for example, 2), and X 1 is -N(R')C(O)- (for example, -N(H)C(O)-) and n + p = 2 (for example, n and p are each 1), X 2 is -S-. For example, L can be -CH2CH2NHC(O)CH2SCH2-.

[0406] In some of these embodiments, one of the SEQ IDs 5-34 (for example, SEQ ID 6) represents W.

[0407] The combinations [1] to

[13] may include any one or more features described in the detailed description and / or claims.

[0408] The combinations [1A] to [13A] may include any one or more features described in the detailed description and / or claims.

[0409] Those skilled in the art will recognize that some of the chemical structures described herein may be represented in one or more other resonance forms on paper, or may exist in one or more other tautomers even when dynamically present, and that these tautomers represent only a small fraction of the samples of these compounds. Although these resonance forms or tautomers are not explicitly shown herein, it is assumed that these compounds are within the scope of this disclosure.

[0410] Pharmaceutical composition and administration general In some embodiments, a chemical entity (e.g., a compound, or a pharmaceutically acceptable salt and / or hydrate and / or prodrug) that modulates (e.g., stimulates, partially stimulates, or antagonizes) the glucagon-like peptide 1 receptor ("GLP-1R") and / or gastric suppressor polypeptide receptor ("GIPR") is administered as a pharmaceutical composition comprising the chemical entity, one or more pharmaceutically acceptable excipients, and optionally one or more further therapeutic agents as described herein.

[0411] In some embodiments, the chemical entity can be administered in combination with one or more conventional pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, self-emulsifying drug delivery systems (SEDDS) such as alumina, aluminum stearate, lecithin, d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutically active formulations such as Tween, poloxamer, or other similar polymer delivery matrices, serum proteins such as human serum albumin, phosphates, buffers such as Tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block copolymers, and lanolin. Furthermore, chemically modified derivatives such as cyclodextrins including α-, β-, and γ-cyclodextrins, or hydroxyalkylcyclodextrins including 2- and 3-hydroxypropyl-β-cyclodextrin, or other solubilized derivatives, can be used to improve the delivery of the compounds described herein. Dosage forms or compositions can be prepared containing the chemical entities described herein in an amount ranging from 0.005% to 100%, with the remainder consisting of non-toxic excipients. The envisioned compositions may contain 0.001% to 100%, 0.1 to 95% in one embodiment, 75 to 85% in another embodiment, and 20 to 80% in yet another embodiment, of the chemical entities provided herein. Practical methods for preparing these dosage forms are known to or will be obvious to those skilled in the art. For example, Remington: The Science and Practice of Pharmacy, 22 nd See Edition (Pharmaceutical Press, London, UK. 2012).

[0412] Route of administration and compositional components In some embodiments, the chemical entities or pharmaceutically active compositions described herein may be administered to subjects requiring them via any acceptable route of administration. Acceptable routes of administration include buccal, skin, intracervical, endosinusial, intratracheal, intraintestinal, epidural, interstitial, intraperitoneal, intraarterial, intrabronchial, intrasacral, intracerebral, intracisional, intracoronal, intradermal, intratubular, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intraguanal, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, and intrasinusial. Routes of administration include, but are not limited to, asinal, intraspinal, intrabursal, intratesticular, subarachnoid, intratubular, intratumoral, intrauterine, intravascular, intravenous, intranasal, transnasogastric, oral, parenteral, percutaneous, epidural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, tracheal, ureter, urethra, and vaginal. In certain embodiments, the preferred route of administration is parenteral (e.g., intratumoral).

[0413] The compositions can be formulated for parenteral administration, for example, for injection via intravenous, intramuscular, subcutaneous, or even intraperitoneal routes. Typically, these compositions can be prepared as injectable solutions or suspensions, and a solid form suitable for use in preparing solutions or suspensions can also be prepared by adding liquid before injection; the formulations can also be emulsified. In light of this disclosure, methods for preparing these formulations will be apparent to those skilled in the art.

[0414] Suitable pharmaceutical forms for injection include sterile aqueous solutions or aqueous dispersions; formulations containing sesame oil, peanut oil, or aqueous propylene glycol; and sterile powders for the immediate preparation of sterile injectable solutions or dispersions. In general, the form must be sterile and fluid enough to be easily injected. The form should also be stable under manufacturing and storage conditions and protected from contamination by microorganisms such as bacteria and fungi.

[0415] Furthermore, the carrier may be a solvent or dispersion medium, for example, containing water, ethanol, polyols (e.g., glycerin, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. Appropriate fluidity can be maintained by the use of coatings such as lecithin, maintaining the required particle size in the case of dispersions, and using surfactants. Inhibition of microbial action can be achieved by various antimicrobial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and thimerosal. In many cases, it is preferable to include isotonic agents, such as sugars or sodium chloride. Long-term absorption of the injectable composition can be achieved by the use of absorption retarders in the composition, such as aluminum monostearate and gelatin.

[0416] Sterile injectable solutions are prepared by incorporating the required amount of active compound into a suitable solvent, along with various other components as listed above as needed, and then performing sterilization by filtration. Generally, dispersions are prepared by incorporating various sterilizing active ingredients into a sterilizing vehicle containing a basic dispersion medium and other necessary components from those listed above. For sterilizing powders for the preparation of sterilizing injectable solutions, preferred preparation methods are vacuum drying and freeze-drying techniques, which produce a powder of the active ingredient and any further desired components from the already sterilized filtered solution.

[0417] Pharmacologically acceptable excipients that can be used in rectal compositions as gels, creams, enemas, or rectal suppositories include cocoa butter glycerides, polyvinylpyrrolidone, synthetic polymers such as PEG (like PEG ointment), glycerin, glycerinated gelatin, hydrogenated vegetable oils, poloxamer, mixtures of polyethylene glycols of various molecular weights and polyethylene glycol fatty acid esters, petrolatum, anhydrous lanolin, shark liver oil, sodium saccharate, menthol, sweet almond oil, sorbitol, sodium benzoate, and anoxide. SBN, vanilla essential oil, aerosol, phenoxyethanol contains one or more of the following: parabens, sodium methyl p-oxybenzoate, sodium propyl p-oxybenzoate, diethylamine, carbomer, Carbopol, methyl oxybenzoate, macrogol cetostearyl ether, cocoyl caprylocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metabites, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methylsulfonylmethane (MSM), lactic acid, glycine, vitamins such as vitamins A and E, and potassium acetate.

[0418] In certain embodiments, suppositories can be prepared by mixing the chemical entities described herein with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or suppository wax, which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum to release the active compound. In other embodiments, the rectal administration composition is in the form of an enema.

[0419] In other embodiments, the compounds or pharmaceutically active compositions described herein are suitable for local delivery to the gastrointestinal tract or digestive tract by oral administration (e.g., in solid or liquid dosage forms).

[0420] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the chemical entity is mixed with one or more pharmaceutically acceptable excipients such as sodium citrate or dicalcium phosphate, and / or a) fillers or bulking agents such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and gum arabic; c) hydrating agents such as glycerin; d) disintegrants such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) dissolution retarders such as paraffin; f) absorption enhancers such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin clay and bentonite clay; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, and sodium lauryl sulfate, as well as combinations thereof. In the case of capsules, tablets, and pills, the dosage form may include a buffer. Similar types of solid compositions may be used as fillers in soft-filled and hard-filled gelatin capsules using excipients such as lactose or lactose and high molecular weight polyethylene glycol.

[0421] In one embodiment, the composition may take the form of a unit dosage form such as a pill or tablet, and thus the composition may include, along with the chemical entities provided herein, diluents such as lactose, sucrose, and dicalcium phosphate; lubricants such as magnesium stearate; and binders such as starch, gum arabic, polyvinylpyrrolidine, gelatin, cellulose, and cellulose derivatives. In another solid dosage form, a powder, marume, solution, or suspension (e.g., in propylene carbonate, vegetable oil, PEG, poloxamer 124, or triglycerides) is encapsulated in a capsule (gelatin or cellulosic capsule). Unit dosage forms in which one or more chemical entities or further active ingredients provided herein are physically separated, such as capsules having granules (or tablets in capsules) of each drug; two-layer tablets; two-compartment gel capsules, etc. Enteric-coated oral dosage forms or delayed-release oral dosage forms are also conceivable.

[0422] Other physiologically acceptable compounds include wetting agents, emulsifiers, dispersants, or preservatives particularly useful for preventing the growth or action of microorganisms. Various preservatives are well known, such as phenol and ascorbic acid.

[0423] In certain embodiments, excipients are sterile and generally free of undesirable substances. These compositions can be sterilized by conventional, well-known sterilization techniques. Sterility is not required for excipients in various oral dosage forms such as tablets and capsules; USP / NF standards are usually sufficient.

[0424] The eye drop composition may, in no particular way, contain one or more of the following: viscogens (e.g., carboxymethylcellulose, glycerin, polyvinylpyrrolidone, polyethylene glycol); stabilizers (e.g., Pluronic (ternary block copolymer), cyclodextrin); preservatives (e.g., benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloro complex; Allergan, Inc.)).

[0425] Topical compositions include ointments and creams. Ointments are semi-solid formulations, usually based on petrolatum or other petroleum derivatives. Creams, usually containing the selected active ingredient, are often oil-in-water or water-in-oil liquid or semi-solid emulsions. Cream bases are usually washable with water and comprise an oil phase, an emulsifier, and an aqueous phase. The oil phase, sometimes called the "internal" phase, generally consists of petrolatum and fatty alcohols such as cetyl or stearyl alcohol, while the aqueous phase, though not always, usually exceeds the oil phase in volume and generally contains a water-retaining agent. Generally, emulsifiers in cream formulations are nonionic, anionic, cationic, or amphoteric surfactants. Like other carriers or vehicles, ointment bases should be inert, stable, non-irritating, and non-sensitizing.

[0426] In any of the above embodiments, the pharmaceutical compositions described herein may comprise one or more of the following: lipids, bilayer-crosslinked multilayer vesicles, biodegradable poly(D,L-lactic acid-co-glycolic acid) [PLGA]-based or polyanhydride-based nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers.

[0427] Dosage The dosage may vary depending on the patient's needs, the severity of the condition being treated, and the specific compound used. The appropriate dosage in a particular situation can be determined by those skilled in the medical field. In some cases, the total daily dose may be divided and administered in several doses throughout the day, or by means of continuous delivery.

[0428] In some embodiments, the compounds described herein are present in concentrations of approximately 0.0002 mg / kg to approximately 100 mg / kg (e.g., approximately 0.0002 mg / kg to approximately 50 mg / kg; approximately 0.0002 mg / kg to approximately 25 mg / kg; approximately 0.0002 mg / kg to approximately 10 mg / kg; approximately 0.0002 mg / kg to approximately 5 mg / kg; approximately 0.0002 mg / kg to approximately 1 mg / kg; approximately 0.0002 mg / kg to approximately 0.5 mg / kg; approximately 0.0002 mg / kg to approximately 0.1 mg / kg; approximately 0.001 mg / kg to approximately 50 mg / kg; approximately 0.001 mg / kg to approximately 25 mg / kg; approximately 0.001 mg / kg to approximately 10 mg / kg; About 0.001mg / Kg~about 5mg / Kg; About 0.001mg / Kg~about 1mg / Kg; About 0.001mg / Kg~about 0.5mg / Kg; About 0.001mg / Kg~about 0.1mg / Kg; About 0.01mg / Kg~about 50mg / Kg; Approx. 0.01mg / Kg~Approx. 25mg / Kg; Approx. 0.01mg / Kg~Approx. 10mg / Kg; Approx. 0.01mg / Kg~Approx. 5mg / Kg; Approx. 0.01mg / Kg~Approx. 1mg / Kg; Approx. 0.01mg / Kg~Approx. 0.5mg / Kg; Approx. 0.01mg / Kg~Approx. 0.1mg / Kg; Approx. 0.1mg / Kg~Approx. 50mg / Kg; It is administered in doses of approximately 0.1 mg / kg to 25 mg / kg; approximately 0.1 mg / kg to 10 mg / kg; approximately 0.1 mg / kg to 5 mg / kg; approximately 0.1 mg / kg to 1 mg / kg; and approximately 0.1 mg / kg to 0.5 mg / kg.

[0429] regimen The above dosage can be administered daily (for example, as one dose or two or more divided doses), or not daily (for example, every other day, every two days, every three days, once a week, twice every few weeks, once every two weeks, or once a month).

[0430] In some embodiments, the duration of administration of the compounds described herein is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer. In further embodiments, the period of discontinuation of administration may be 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer. In one embodiment, the therapeutic compound is administered to an individual for one period, followed by another period. In another embodiment, the therapeutic compound is administered for a first period, followed by a second period following the first period, with administration discontinued during the second period, followed by commencement of administration of the therapeutic compound in a third period, and then discontinued in a fourth period following the third period. In one aspect of this embodiment, the period of administration of the therapeutic compound and the subsequent period of discontinuation of administration are repeated for a predetermined or indefinite period. In a further embodiment, the administration period is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer. In a further embodiment, the period of discontinuation of administration may be 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer.

[0431] Treatment method This disclosure features methods for treating subjects (e.g., humans) having a disease, disorder, or condition, wherein modulation of GLP-1R and / or GIPR activity (e.g., suppressed or impaired and / or elevated or undesirable GLP-1R and / or GIPR signaling) is beneficial for treating the underlying pathology and / or symptoms and / or progression of the disease, disorder, or condition. In particular embodiments, the methods described herein may include, or further include, treating one or more conditions that are comorbidities, complications, or sequelae of any one or more conditions described herein.

[0432] In certain embodiments, the chemical entities described herein induce a decrease in blood glucose levels (e.g., reduce blood glucose levels), promote insulin synthesis, stimulate insulin secretion, increase β-cell mass, regulate gastric acid secretion, regulate gastric emptying, and / or decrease glucagon production. In certain embodiments, the chemical entities described herein stabilize serum glucose and serum insulin levels.

[0433] Indications obesity In some aspects, a condition, disease, or disorder is obesity and obesity-related conditions, diseases, or disorders. Non-exclusive examples of obesity and obesity-related conditions include symptomatic obesity, simple obesity, childhood obesity, morbid obesity, and abdominal obesity (central obesity characterized by abdominal fat accumulation). Non-exclusive examples of symptomatic obesity include endocrine obesity (e.g., Cushing's syndrome, hypothyroidism, insulinoma, obesity-type 2 diabetes, pseudohypoparathyroidism, hypogonadism), hypothalamic obesity, hereditary obesity (e.g., Prader-Willi syndrome, Laurence Moon-Beadle syndrome), and drug-induced obesity (e.g., steroid-induced obesity, phenothiazine-induced obesity, insulin-induced obesity, sulfonylurea-induced obesity, or beta-blocker-induced obesity).

[0434] In some embodiments, conditions, diseases, or disorders are associated with obesity. Examples of these conditions, diseases, or disorders include, but are not limited to, impaired glucose tolerance, diabetes mellitus (e.g., type 2 diabetes, obese diabetes), dyslipidemia, hyperlipidemia, hypertension, heart failure, hyperuricemia, gout, fatty liver (including non-alcoholic steatohepatitis (NASH)), coronary heart disease (e.g., myocardial infarction, angina pectoris), stroke (e.g., cerebral thrombosis, transient ischemic attack), bone or joint diseases (e.g., osteoarthritis of the knee, osteoarthritis of the hip, spondylitis degeneratively, lower back pain), sleep apnea syndrome, obesity hypoventilation syndrome (Pickwick's syndrome), menstrual disorders (e.g., menstrual cycle abnormalities, menstrual flow / menstrual cycle abnormalities, amenorrhea, paramenorrhea), visceral obesity syndrome, and metabolic syndrome. In certain embodiments, the chemical entities described herein may be used to treat subjects exhibiting symptoms of both obesity and insulin deficiency.

[0435] diabetes In some aspects, the condition, disease, or disorder is diabetes mellitus. Non-specific examples of diabetes mellitus include type 1 diabetes, type 2 diabetes (e.g., diet-assisted type 2 diabetes, sulfonylurea-assisted type 2 diabetes, acute type 2 diabetes, long-term insulin-assisted type 2 diabetes), diabetes mellitus (e.g., non-insulin-dependent diabetes mellitus, insulin-dependent diabetes mellitus), gestational diabetes, obesity-related diabetes, autoimmune diabetes, and prediabetes.

[0436] In some aspects, a condition, disease, or disorder is associated with diabetes (e.g., diabetic complications). Non-limiting examples of disorders associated with diabetes include obesity, obesity-related disorders, metabolic syndrome, neuropathy, nephropathy (e.g., diabetic nephropathy), retinopathy, diabetic cardiomyopathy, cataracts, macrovascular complications, osteopenia, hyperosmolar diabetic coma, infectious diseases (e.g., respiratory infections, urinary tract infections, gastrointestinal infections, skin and soft tissue infections, lower extremity infections), diabetic gangrene, dry mouth, hearing loss, cerebrovascular disorders, diabetic cachexia, delayed wound healing, diabetic dyslipidemia, peripheral circulatory disorders, cardiovascular risk factors (e.g., coronary artery disease, peripheral artery disease, cerebrovascular disease, hypertension, and risk factors associated with uncontrolled cholesterol and / or lipid levels, and / or inflammation), NASH, fractures, and cognitive impairment.

[0437] Other non-limiting examples of diabetes-related disorders include prediabetes, hyperlipidemia (e.g., hypertriglyceridemia, hypercholesterolemia, hyper-LDL cholesterolemia, hypo-HDL cholesterolemia, postprandial hyperlipidemia), metabolic syndrome (e.g., metabolic disorders in which GLP-1R activation is beneficial, metabolic syndrome X), hypertension, impaired glucose tolerance (IGT), insulin resistance, and sarcopenia.

[0438] In some embodiments, the condition, disease, or disorder is diabetes and obesity. In certain embodiments, the compounds described herein are also useful in improving the therapeutic efficacy of metformin.

[0439] Damage to metabolically important tissues In some aspects, a condition, disease, or disorder is a disorder of metabolically important tissues.

[0440] In some aspects, a condition, disease, or disorder is a fatty liver disease. Fatty liver diseases include, but are not limited to, non-alcoholic fatty liver disease (NAFLD), steatohepatitis, non-alcoholic steatohepatitis (NASH), fatty liver disease caused by hepatitis, fatty liver disease caused by obesity, fatty liver disease caused by diabetes, fatty liver disease caused by insulin resistance, fatty liver disease caused by hypertriglyceridemia, abetalipoproteinemia, glycogen storage disease, Weber-Christian disease, Wolmann disease, acute fatty liver of pregnancy, and lipodystrophy.

[0441] Non-alcoholic fatty liver disease (NAFLD) is a set of disorders that occur in the absence of alcohol abuse and are usually characterized by the presence of fatty liver (fat in the liver). NAFLD is thought to be associated with various conditions, such as metabolic syndrome (including obesity, diabetes, and hypertriglyceridemia) and insulin resistance. It can cause liver disease in adults and children and can eventually lead to cirrhosis (Skelly et al., J Hepatol 2001; 35: 195-9; Chitturi et al., Hepatology 2002; 35(2):373-9). The severity of NAFLD ranges from relatively benign, mainly macrodrip localized fatty liver (i.e., non-alcoholic fatty liver or NAFL) to non-alcoholic steatohepatitis (NASH) (Angulo et al., J Gastroenterol Hepatol 2002; 17 Suppl:S186-90). In certain aspects, the target audience is children (e.g., 6-16 years old; or 6-12 years old; or 6-10 years old). In certain aspects, the target audience is adults.

[0442] Other non-limiting examples of disorders in metabolically important tissues include joint disorders (e.g., osteoarthritis, secondary osteoarthritis), fatty liver (e.g., in the liver); gallstones; gallbladder disorders; gastroesophageal reflux disease; sleep apnea; hepatitis; fatty liver; bone disorders characterized by changes in bone metabolism, such as osteoporosis including postmenopausal osteoporosis, decreased bone density, osteopenia, Paget's disease, osteolytic metastases in cancer patients, osteogenesis imperfecta in liver disease, and changes in bone metabolism caused by renal failure or hemodialysis, fractures, bone surgery, aging, pregnancy, protection against fractures, and malnutrition; polycystic ovary syndrome; kidney diseases (e.g., chronic renal failure, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end-stage renal disease); Examples include muscular dystrophy, angina pectoris, acute or chronic diarrhea, testicular dysfunction, respiratory dysfunction, frailty, sexual dysfunction (e.g., erectile dysfunction), and geriatric syndromes. In certain embodiments, the chemical entities described herein can be used to treat surgical trauma by improving postoperative recovery and / or preventing catabolic reactions caused by surgical trauma.

[0443] cardiovascular disease In some aspects, a condition, disease, or disorder is a cardiovascular disease. Non-limiting examples of cardiovascular diseases include congestive heart failure, atherosclerosis, arteriosclerosis, coronary heart disease, or peripheral artery disease, stroke, coronary artery disease, congestive heart failure, coronary heart disease, hypertension, heart failure, cerebrovascular disease (e.g., cerebral infarction), vascular dysfunction, myocardial infarction, hypertension (e.g., ≥130 / 85 mmHg), and prothrombotic conditions (indicated by elevated blood levels of fibrinogen or plasminogen activator inhibitors).

[0444] Neurological diseases In some aspects, the condition, disease, or disorder is a neurological disorder (e.g., neurodegenerative disorder) or a psychiatric disorder. Non-limiting examples of neurological disorders include cerebral insulin resistance, mild cognitive impairment (MCI), Alzheimer's disease (AD), Parkinson's disease (PD), anxiety, dementia (e.g., senile dementia), traumatic brain injury, Huntington's disease, tardive dyskinesia, hyperkinesia, mania, Morbus Parkinson's disease, Steele-Richard syndrome, Down syndrome, myasthenia gravis, neurotrauma, traumatic brain injury, vascular amyloidosis, hemorrhagic brain injury with amyloidosis, encephalitis, Friedreich's ataxia, acute confusional disorder, amyotrophic lateral sclerosis (ALS), glaucoma, and apoptosis-mediated degenerative diseases of the central nervous system (e.g., Creutzfeldt-Jakob disease, bovine spongiform encephalopathy (mad cow disease), chronic wasting syndrome). See, for example, US20060275288A1.

[0445] Non-specific examples of mental disorders include drug dependence / addiction (narcotics and amphetamines) and attention deficit hyperactivity disorder (ADHD). The chemical entities described herein may be useful in improving behavioral responses to addictive substances, reducing drug dependence, preventing relapses of substance abuse, and alleviating anxiety caused in the absence of a given addictive substance. See, for example, US20120021979A1.

[0446] In certain embodiments, the chemical entities described herein are useful in improving learning and memory by enhancing neuronal plasticity and promoting cell differentiation, and in preserving dopamine neurons and motor function in Parkinson's disease.

[0447] Insulin-related In some embodiments, the condition, disease, or disorder is an abnormal fasting blood glucose level (IFG), a hyperglycemia (IFG), hyperglycemia, insulin resistance (abnormal glucose homeostasis), hyperinsulinemia, elevated blood fatty acids or glycerols, hypoglycemic state, insulin resistance syndrome, paresthesia caused by hyperinsulinemia, hyperlipidemia, hypercholesterolemia, poor wound healing, leptin resistance, impaired glucose tolerance, elevated fasting blood glucose, dyslipidemia (e.g., atherosclerotic dyslipidemia characterized by hyperlipidemia, high triglyceride levels and low HDL cholesterol levels), glucagonoma, hyperuricemia, hypoglycemia (e.g., nocturnal hypoglycemia), and insulin-related concomitant coma endpoints.

[0448] In certain embodiments, the chemical entities described herein can reduce or delay the progression from prediabetes, fasting blood glucose abnormalities, or fasting hyperglycemia to diabetes.

[0449] Autoimmune disorders In some aspects, a condition, disease, or disorder is an autoimmune disorder. Non-exclusive examples of autoimmune disorders include multiple sclerosis, experimental autoimmune encephalomyelitis, autoimmune disorders associated with immune rejection, graft-versus-host disease, uveitis, optic neuropathy, optic neuritis, transverse myelitis, inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, myasthenia gravis, and Graves' disease. See, for example, US20120148586A1.

[0450] Stomach and intestinal disorders In some aspects, a condition, disease, or disorder is a disorder relating to the stomach or intestines. Non-limiting examples of these disorders include ulcers of any etiology (e.g., peptic ulcers, Zollinger-Ellison syndrome, drug-induced ulcers, ulcers associated with infection or other pathogens), digestive disorders, malabsorption, short bowel syndrome, duct-blind syndrome, inflammatory bowel disease (Crohn's disease and ulcerative colitis), celiac disease, hypogammaglobulinemia, chemotherapy and / or radiotherapy-induced mucositis and diarrhea, gastroenteritis, short bowel syndrome, ulcerative colitis (colitis ulcerosa), gastric mucosal injury (e.g., gastric mucosal injury caused by aspirin), small intestinal mucosal injury, and cachexia (e.g., cancer cachexia, tuberculous cachexia, cachexia associated with hematological disorders, cachexia associated with endocrine disorders, cachexia associated with infectious diseases, cachexia caused by acquired immunodeficiency syndrome).

[0451] body weight In some embodiments, the chemical entities described herein can be used to reduce body weight (e.g., excess weight), prevent weight gain, induce weight loss, reduce body fat, or reduce food intake in a subject (e.g., a subject that requires it). In certain embodiments, weight gain in a subject may be due to excessive or unbalanced food intake, or to concomitant medications (e.g., insulin resistance improvers exhibiting PPARγ agonist-like activity, such as troglitazone, rosiglitazone, englitazone, siglitazone, pioglitazone, etc.). Alternatively, weight gain may be pre-obese weight gain or weight gain in an obese subject. Weight gain may be drug-induced weight gain or weight gain after quitting smoking.

[0452] In some aspects, the condition, disorder, or impairment is an eating disorder, such as polyphagia, bulimia, binge eating, or forced eating.

[0453] inflammatory diseases In some aspects, a condition, disease, or disorder is an inflammatory disorder. Non-exclusive examples of inflammatory disorders include rheumatoid arthritis, spondylitis degenerative, osteoarthritis, low back pain, gout, postoperative or post-traumatic inflammation, abdominal distension, neuralgia, pharyngitis, cystitis, pneumonia, pancreatitis, colitis, inflammatory bowel disease (including inflammatory bowel disease), inflammation in metabolically important tissues including the liver, fat, pancreas, kidneys, and intestines, as well as pro-inflammatory conditions (e.g., elevated blood levels of inflammatory cytokines or inflammatory C-reactive protein markers).

[0454] cancer In some aspects, the condition, disease, or disorder is cancer. Preferred examples of cancer include breast cancer (e.g., invasive ductal carcinoma, non-invasive ductal carcinoma, inflammatory breast cancer), prostate cancer (e.g., hormone-dependent prostate cancer, hormone-independent prostate cancer), pancreatic cancer (e.g., pancreatic ductal carcinoma), gastric cancer (e.g., papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous cell carcinoma), lung cancer (e.g., non-small cell lung cancer, small cell lung cancer, malignant mesothelioma), colon cancer (e.g., gastrointestinal stromal tumor), and rectal cancer (e.g., gastrointestinal stromal tumor). Stromas), colorectal cancer (e.g., familial colorectal cancer, hereditary nonpolyposis colorectal cancer, gastrointestinal stromal tumors), small intestine cancer (e.g., non-Hodgkin lymphoma, gastrointestinal stromal tumors), esophageal cancer, duodenal cancer, tongue cancer, pharyngeal cancer (e.g., nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer), salivary gland cancer, brain tumors (e.g., pineal astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma), schwannoma, liver cancer (e.g., Primary liver cancer, extrahepatic cholangiocarcinoma, kidney cancer (e.g., renal cell carcinoma, ureteral transitional cell carcinoma), bile duct cancer, endometrial cancer, cervical cancer, ovarian cancer (e.g., ovarian epithelial carcinoma, extragonadal germ cell tumor, ovarian germ cell tumor, low-grade ovarian tumor), bladder cancer, urethral cancer, skin cancer (e.g., intraocular melanoma, Merkel cell carcinoma), hemangioma, malignant lymphoma, malignant melanoma, thyroid cancer (e.g., medullary thyroid carcinoma), parathyroid These include cancer, nasal cavity cancer, paranasal sinus cancer, bone tumors (e.g., osteosarcoma, Ewing's sarcoma, uterine sarcoma, soft tissue sarcoma), angiofibroma, retinal sarcoma, penile cancer, testicular tumors, pediatric solid tumors (e.g., Wilms' tumor, pediatric renal tumors), Kaposi's sarcoma, Kaposi's sarcoma caused by AIDS, maxillary trunk tumors, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, and leukemia (e.g., acute myeloid leukemia, acute lymphoblastic leukemia).

[0455] Combination therapy This disclosure envisions both monotherapy regimens and combination therapy regimens.

[0456] In some embodiments, the methods described herein may further include the step of administering one or more further treatments (e.g., one or more further therapeutic agents and / or one or more therapeutic regimens) in combination with the administration of the compounds described herein.

[0457] In some embodiments, the methods described herein include administering the compounds described herein in combination with one or more of the following: dietary therapy (e.g., diabetic diet), exercise therapy, blood glucose monitoring, and dietary modifications.

[0458] In some embodiments, the compounds described herein can be administered in combination with one or more further therapeutic agents.

[0459] Representative additional therapeutic agents include, but are not limited to, anti-obesity agents, diabetes medications, diabetic complication medications, hyperlipidemia medications, antihypertensive agents, diuretics, chemotherapy agents, immunotherapies, anti-inflammatory drugs, antithrombotic agents, antioxidants, osteoporosis medications, vitamins, anti-dementia drugs, erectile dysfunction medications, medications for frequent urination or urinary incontinence, NAFLD medications, and medications for urinary disorders.

[0460] In some embodiments, one or more further therapeutic agents include, for example, therapeutic agents useful as anti-obesity agents. Non-limiting examples include: • Monoamine reuptake inhibitors (e.g., tramadol, phentermine, sibutramine, mazindol, fluoxetine, tesofensine); • Serotonin 2C receptor agonists (e.g., lorcaserin); • Serotonin 6 receptor antagonist; • Histamine H3 receptor modulators; GABAergic modulators (e.g., topiramate), including GABA receptor agonists (e.g., gabapentin, pregabalin); • Neuropeptide Y antagonists (e.g., berneperito); • Cannabinoid receptor antagonists (e.g., rimonabant, taranabant); Grelin's Antagonist; • Ghrelin receptor antagonist; Ghrelin acylate inhibitors; • Opioid receptor antagonists (e.g., GSK-1521498); • Orexin receptor antagonist; • Melanocortin 4 receptor agonist; • 11β-hydroxysteroid dehydrogenase inhibitors (e.g., AZD-4017, BVT-3498, INCB-13739); • Pancreatic lipase inhibitors (e.g., orlistat, cetilistat); • β3 agonist (e.g., N-5984); • Diacylglycerol acyltransferase 1 (DGAT1) inhibitors; • Acetyl-CoA carboxylase (ACC) inhibitors; • Stearoyl-CoA desaturates inhibitors; • Microsomal triglyceride transport protein inhibitors (e.g., R-256918); • Sodium-glucose cotransporter 2 (SGLT-2) inhibitors (e.g., JNJ-28431754, dapagliflozin, AVE2268, TS-033, YM543, TA-7284, ASP1941, remogliflozin); • NFK inhibitors (e.g., HE-3286); • PPAR agonists (e.g., GFT-505, DRF-11605, gemfibrozil, and fenofibrate); • Phosphotyrosine phosphatase inhibitors (e.g., sodium vanadate, trodusquemin); • GPR119 agonists (e.g., PSN-821, MBX-2982, APD597); • Glucokinase activators (e.g., compounds described in W0006 / 112549, W0007 / 028135, W0008 / 047821, W0008 / 050821, W0008 / 136428, and W0008 / 156757); • Leptin, leptin derivatives (e.g., metreleptin), and leptin resistance improvers; • CNTF (Ciliary Neurotrophic Factor); • BDNF (brain-derived neurotrophic factor); • Cholecystokinin agonists, amylin preparations (e.g., Pramulintide, AC-2307); • Neuropeptide Y agonists (e.g., PYY3-36, PYY3-36 derivatives, obineptide, TM-30339, TM-30335); • Oxintomodulin (OXM) preparations; • Appetite suppressants (e.g., ephedrine); • FGF21 preparations (e.g., animal FGF21 preparations extracted from bovine or porcine pancreas; human FGF21 preparations genetically synthesized using E. coli or yeast; fragments or derivatives of FGF21); and • Anorexia-inducing agents (e.g., P-57).

[0461] In some embodiments, one or more further therapeutic agents include, for example, therapeutic agents useful as antidiabetic agents. Non-limiting examples include: • Insulin and insulin preparations (e.g., animal insulin preparations extracted from bovine or porcine pancreas; human insulin preparations genetically synthesized using E. coli or yeast; zinc insulin; protamine zinc insulin; insulin fragments or derivatives (e.g., INS-1), oral insulin preparations, synthetic human insulin); • Insulin resistance improving agents (e.g., pioglitazone or its salts); • Biguanides (e.g., metformin, buformin, or their salts (e.g., hydrochloride, fumarate, succinate)); • Glucagon analogs (e.g., any of the glucagon analogs described, for example, in WO 2010 / 011439); Agents that antagonize the action of glucagon or reduce glucagon secretion; • Sulfonylurea drugs (e.g., chlorpropamide, trazamide, gliclazide, glimepiride, tolbutamide, glibenclamide, gliclazide, acetohexamide, glyclopyramide, glibzol, glibrid); • Thiazolidinedione preparations (e.g., rosiglitazone or pioglitazone); • Alpha-glucosidase inhibitors (e.g., voglibose, acarbose, miglitol, emiglitate); • Insulin secretagogues, such as postprandial blood glucose regulators (sometimes called "short-acting secretagogues"), such as meglitinide (e.g., repaglinide and nateglinide); • Cholinesterase inhibitors (e.g., donepezil, galantamine, rivastigmine, tacrine); • NMDA receptor antagonist; • Dual GLP-1 / GIP receptor agonists (e.g., LBT-2000, ZPD1-70); • GLP-1R agonists (e.g., exenatide, liraglutide, albiglutide, dulaglutide, AVE-0010, S4P, and Boc5); and • Dipeptidyl peptidase IV (DPP-4) inhibitors (e.g., vildagliptin, dutogliptin, gemigliptin, alogliptin, saxagliptin, sitagliptin, linagliptin, berberine, alogliptin, BI1356, GRC8200, MP-513, PF-00734200, PHX1149, SK-0403, ALS2-0426, TA-6666, TS-021, KRP-104, trelagliptin).

[0462] In some embodiments, one or more further therapeutic agents include those useful for treating, for example, NAFL and NASH. Non-limiting examples include glycyrrhizin, Schisandra extract, ascorbic acid, glutathione, silymarin, lipoic acid, and d-α-tocopherol, ascorbic acid, glutathione, vitamin B complex, glitazone / thiazolidinediones (e.g., troglitazone, rosiglitazone, pioglitazone), metformin, cysteamine, sulfonylurea, α-glucosidase inhibitors, meglitinide, vitamin E, tetrahydrolipustatin, milk thistle protein, antiviral agents, and antioxidants.

[0463] In some embodiments, one or more additional therapeutic agents include, for example, those useful for treating diabetic complications. Non-limiting examples include: Aldose reductase inhibitors (e.g., torrestat, epalrestat, zopolrestat, fidarestat, CT-112, ranirestat, lidorestat); • Neurotrophic factors and their proliferators (e.g., NGF, NT-3, BDNF, neurotrophic factor production / secretion promoters described in WO01 / 14372 (e.g., 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxyl)propyl]oxazole), compounds described in WO2004 / 039365); • PKC inhibitors (e.g., ruboxystaurine mes...

Claims

1. A method for synthesizing a compound having formula (IAA) or a pharmaceutically acceptable salt thereof: During the ceremony, Ring A is given by equation (III): It has, in the formula, A 1 CH 2 And, A 2 CH 2 And, A 3 CH 2 And, A 4 CH 2 And, L is -CH 2 CH 2 NHC(O)CH 2 SCH 2 -; R 1 , R 2 , and R 4 Each of these is H; R 2' teeth And in the formula, R 3 is -C(O)OH; a is 2; a' is 0; R 3a and R 3b Each is independently H or C 1～3 It is alkyl; W is given by equation (XIV-B): GTFTSDYSIYLDKQAA(Aib)EFVNWLLAGGPSSGAPPPS-R 5 (SEQ ID NO: 4, XIV-B) It has, in the formula, (Aib) is structure: It has R 5 This is a C-terminal lysylamide residue, The above method involves the following steps: (i) Piperidine-2-one: Reacting with (2-bromoethoxy)(tert-butyl)dimethylsilane yields 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidine-2-one (I-244): The process of generating (ii) React 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidine-2-one (I-244) with HCl in MeOH to obtain 1-(2-hydroxyethyl)piperidine-2-one (I-245): The process of generating (iii) 1-(2-hydroxyethyl)piperidine-2-one (I-245) as phthalimide: Reacting with 2-(2-(2-oxopiperidine-1-yl)ethyl)isoindoline-1,3-dione (I-246): The process of generating (iv) 2-(2-(2-oxopiperidine-1-yl)ethyl)isoindoline-1,3-dione (I-246) NH 2 NH 2 Reacting with 1-(2-aminoethyl)piperidine-2-one (I-247): The process of generating (v) 1-(2-aminoethyl)piperidine-2-one (I-247): Alternatively, react a salt thereof with thiodiglycolic acid anhydride to obtain 2-((2-oxo-2-((2-(2-oxopiperidine-1-yl)ethyl)aminoethyl)thio)acetic acid (I-248): The process of generating (vi) Formula R-1: A step of treating a link amide resin with 20% v / v piperidine / DMF, wherein sequence Aa contains the sequence SEQ ID NO: 37, and (vii) The product of step (vi) is 2-((2-oxo-2-((2-(2-oxopiperidine-1-yl)ethyl)aminoethyl)thio)acetic acid (I-248): The process of reacting with Methods that include...

2. R 5 However, equation (XI): It has, in the formula, R * The method according to claim 1, wherein is H or a modifying group, and the modifying group is an acyl group.

3. R * but, The method according to claim 2.

4. R * but, The method according to claim 2.

5. Formula E-153: A method for synthesizing a compound of or a pharmaceutically acceptable salt thereof, The above method involves the following steps: (i) Piperidine-2-one: Reacting with (2-bromoethoxy)(tert-butyl)dimethylsilane yields 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidine-2-one (I-244): The process of generating (ii) React 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidine-2-one (I-244) with HCl in MeOH to obtain 1-(2-hydroxyethyl)piperidine-2-one (I-245): The process of generating (iii) 1-(2-hydroxyethyl)piperidine-2-one (I-245) as phthalimide: Reacting with 2-(2-(2-oxopiperidine-1-yl)ethyl)isoindoline-1,3-dione (I-246): The process of generating (iv) 2-(2-(2-oxopiperidine-1-yl)ethyl)isoindoline-1,3-dione (I-246) NH 2 NH 2 Reacting with 1-(2-aminoethyl)piperidine-2-one (I-247): The process of generating (v) 1-(2-aminoethyl)piperidine-2-one (I-247): Alternatively, react a salt thereof with thiodiglycolic acid anhydride to obtain 2-((2-oxo-2-((2-(2-oxopiperidine-1-yl)ethyl)aminoethyl)thio)acetic acid (I-248): The process of generating (vi) Formula R-1: A step of treating a link amide resin with 20% v / v piperidine / DMF, wherein sequence Aa contains the sequence SEQ ID NO: 37, and (vii) The product of step (vi) is 2-((2-oxo-2-((2-(2-oxopiperidine-1-yl)ethyl)aminoethyl)thio)acetic acid (I-248): The process of reacting with Methods that include...

6. The method according to claim 1 or 5, wherein step (vii) comprises reacting 2-((2-oxo-2-((2-(2-oxopiperidine-1-yl)ethyl)aminoethyl)thio)acetic acid with a coupling reagent.

7. The method according to claim 6, wherein the coupling reagent is 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU).

8. 2-((2-oxo-2-((2-(2-oxopiperidine-1-yl)ethyl)amino)ethyl)thio)acetic acid (I-248): A method for synthesizing, The above method involves the following steps: (i) Piperidine-2-one: Reacting with (2-bromoethoxy)(tert-butyl)dimethylsilane yields 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidine-2-one (I-244): The process of generating (ii) React 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)piperidine-2-one (I-244) with HCl in MeOH to obtain 1-(2-hydroxyethyl)piperidine-2-one (I-245): The process of generating (iii) 1-(2-hydroxyethyl)piperidine-2-one (I-245) as phthalimide: Reacting with 2-(2-(2-oxopiperidine-1-yl)ethyl)isoindoline-1,3-dione (I-246): The process of generating (iv) 2-(2-(2-oxopiperidine-1-yl)ethyl)isoindoline-1,3-dione (I-246) NH 2 NH 2 Reacting with 1-(2-aminoethyl)piperidine-2-one (I-247): The process of generating, (v) 1-(2-aminoethyl)piperidine-2-one (I-247): Alternatively, react a salt thereof with thiodiglycolic acid anhydride to obtain 2-((2-oxo-2-((2-(2-oxopiperidine-1-yl)ethyl)aminoethyl)thio)acetic acid (I-248): The process of generating Methods that include...

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