Compounds and compositions for treating conditions associated with APJ receptor activity

Abstract

To provide chemical entities (e.g., a compound or a pharmaceutically acceptable salt and / or hydrate and / or prodrug of the compound) that modulate the apelin receptor.SOLUTION: For example, 6-bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine represented by the following formula is illustrated. The chemical entity is useful for treating a subject having a disease, disorder, or condition in which a decrease in APJ receptor activity (e.g., repressed or impaired APJ receptor signaling; e.g., repressed or impaired apelin-APJ receptor signaling) or downregulation of endogenous apelin contributes to the pathology and / or symptoms and / or progression of the disease, disorder, or condition.SELECTED DRAWING: None

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of U.S. Provisional Application No. 62 / 742,218, filed Oct. 5, 2018, which is hereby incorporated by reference in its entirety.

[0002] Technical Field The present disclosure features chemical entities (e.g., compounds, or pharmaceutically acceptable salts and / or hydrates and / or prodrugs thereof) that modulate (e.g., stimulate) the apelin receptor (also referred to herein as the APJ receptor; gene symbol “APLNR”). The present disclosure also features compositions containing the same, as well as other methods of using and making the same. For example, the chemical entity is useful for treating a subject (e.g., a human) having a disease, disorder, or condition in which a decrease in APJ receptor activity (e.g., suppression or deficiency of APJ receptor signaling; e.g., suppression or deficiency of apelin - APJ receptor signaling) or down - regulation of endogenous apelin contributes to the pathophysiology and / or symptoms and / or progression of the disease, disorder, or condition. Non - limiting examples of such diseases, disorders, or conditions include (i) cardiovascular diseases; (ii) metabolic disorders; (iii) diseases, disorders, and conditions associated with vascular pathologies; and (iv) organ failure; (v) diseases, disorders, and conditions associated with infectious diseases (e.g., microbial infections); and (vi) diseases, disorders, or conditions that are sequelae or comorbidities associated with any of the foregoing or any disclosed herein. More specific non - limiting examples of such diseases, disorders, or conditions include pulmonary hypertension (e.g., PAH); heart failure; type II diabetes; renal failure; sepsis; and systemic hypertension.

Background Art

[0003] Background Pulmonary arterial hypertension (PAH) is a severe cardiorespiratory disorder characterized by pulmonary arteriolar vascular remodeling, including the formation of plexiform lesions and concentric lesions composed of proliferative vascular cells. PAH is thought to be caused by cell proliferation and fibrosis of small pulmonary arteries. Clinically, PAH leads to an increase in pulmonary artery pressure and subsequently right ventricular failure, which is one of the main causes of morbidity and death. The mortality rate remains very high, with mortality rates of 15%, 30%, and 45% at 1 year, 2 years, and 3 years after diagnosis, respectively. See, for example, Kim, J., Mol. Cells 2014; 37(3): 196-201 (Non-Patent Document 1) and Lau, E.M.T., Nature Reviews, 2017, 1-12 (Non-Patent Document 2).

[0004] True type 2 diabetes (type 2 diabetes) is characterized by high blood glucose levels and insulin resistance. Tens of millions of people in the United States alone are affected by type 2 diabetes and conditions that are co-morbidities or sequelae of type 2 diabetes. In many cases, type 2 diabetes is associated with obesity.

[0005] The apelin receptor or APJ receptor is a G protein-coupled receptor containing seven hydrophobic transmembrane domains (see, for example, the Kim paper cited above). Apelin (also known as APLN) is a 36-amino acid peptide encoded by the APLN gene in humans and is the endogenous ligand of the APJ receptor (see, for example, O'Carroll, A-M., et al., J Endocrinol 2013, 219, R13-R35 (Non-Patent Document 3)).

[0006] The apelin / APJ system is present in many tissues such as the heart, kidney, pancreas, lung, vascular structures, central nervous system, liver, adipose tissue, gastrointestinal tract, brain, adrenal glands, endothelium, and human plasma.

[0007] Furthermore, there is evidence indicating that both apelin and APJ are regulators of central and peripheral responses to multiple homeostatic disturbances, such as cardiovascular control and cardiovascular function; angiogenesis; fluid homeostasis; water balance; hypothalamic-pituitary-adrenal (HPA) axis control; metabolic homeostasis; energy metabolism; and renal function. For example, evidence has emerged showing that APJ-apelin signaling plays a role in maintaining pulmonary vascular homeostasis (see, e.g., Kim, supra). Also, evidence shows an association between the apelinergic system (e.g., apelin receptor and APJ receptor) and the treatment of conditions such as sepsis, septic shock, and renal failure (see, e.g., Coquerel, D., et al., Critical Care 2018, 22: 10 (Non-Patent Document 4)). As another example, apelin, which is synthesized and secreted by adipocytes, has been described as a beneficial adipokine with respect to obesity, and furthermore, there is evidence regarding the potential role of apelin receptor and APJ receptor in glucose metabolism and energy metabolism (see, e.g., O'Carroll, supra).

Prior Art Documents

Non-Patent Documents

[0008]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Summary of the Invention

[0009] Summary The present disclosure features chemical entities (e.g., compounds, or pharmaceutically acceptable salts and / or hydrates and / or prodrugs thereof) that modulate (e.g., stimulate) the apelin receptor (also referred to herein as the APJ receptor; gene symbol “APLNR”). The present disclosure also features compositions containing the same, as well as other methods of using and making the same. For example, the chemical entity is useful for treating a subject (e.g., a human) having a disease, disorder, or condition in which a decrease in APJ receptor activity (e.g., inhibition or loss of APJ receptor signaling; e.g., inhibition or loss of apelin-APJ receptor signaling) or downregulation of endogenous apelin contributes to the pathogenesis and / or symptoms and / or progression of the disease, disorder, or condition. Non-limiting examples of such diseases, disorders, or conditions include (i) cardiovascular diseases; (ii) metabolic disorders; (iii) diseases, disorders, and conditions associated with vasculopathies; and (iv) organ failure; (v) diseases, disorders, and conditions associated with infectious diseases (e.g., microbial infections); and (vi) diseases, disorders, or conditions that are sequelae or comorbidities associated with any of the foregoing or any disclosed herein. More specific non-limiting examples of such diseases, disorders, or conditions include pulmonary hypertension (e.g., PAH); heart failure; type II diabetes; renal failure; sepsis; systemic hypertension; idiopathic pulmonary fibrosis (IPF); and systemic sclerosis.

[0010] An “agonist” of the APJ receptor includes a compound that directly binds to or modifies the APJ receptor at the protein level such that APJ receptor activity is increased, e.g., by activation, stabilization, change in distribution, or otherwise.

[0011] Certain chemical entities described herein that stimulate the APJ receptor to a lesser extent than a full agonist of the APJ receptor can function as antagonists as well as agonists in an assay. These chemical entities antagonize the activation of the APJ receptor by a full agonist of the APJ receptor, since they prevent the full effect of the APJ receptor interaction. However, these chemical entities also, by themselves, activate some APJ receptor activity, usually at less than the corresponding amount of a full agonist of the APJ receptor. These chemical entities are sometimes referred to herein as "partial agonists of the APJ receptor".

[0012] In some embodiments, the chemical entities described herein are agonists (e.g., full agonists) of the APJ receptor. In other embodiments, the chemical entities described herein are partial agonists of the APJ receptor.

[0013] In other embodiments, the chemical entities described herein modulate (e.g., stimulate) the APJ receptor pathway specifically. Thus, the disclosure also features chemical entities that exhibit activity as ligand-biased modulators (e.g., ligand-biased agonists). APJ receptor activity can modulate (e.g., modify or bias) the competing levels of downstream G-protein signaling (activation) and β-arrestin recruitment. β-Arrestin-mediated APJ receptor signaling has been shown to mediate dilated cardiomyopathy. See, e.g., Scimia, M.C., et al., Nature 2012, 488, 394-398. In certain embodiments, the chemical entities described herein modulate (e.g., decrease, e.g., attenuate, interfere with, inhibit) β-arrestin signaling. In certain embodiments, the chemical entities described herein modulate (e.g., decrease, e.g., attenuate, interfere with, inhibit) β-arrestin recruitment.

[0014] In certain embodiments, the chemical entities described herein activate or increase the level of downstream G-protein signaling.

[0015] In certain embodiments, the chemical entities described herein inhibit or reduce the level of β-arrestin mobilization.

[0016] In certain embodiments, the chemical entities described herein activate or increase the level of β-arrestin mobilization.

[0017] In certain embodiments, the chemical entities described herein selectively modulate (e.g., increase) one pathway over another. For example, the chemical entities described herein can activate or increase the level of downstream G-protein signaling and inhibit or reduce the level of β-arrestin mobilization.

[0018] In other embodiments, the chemical entities described herein can activate or increase the level of downstream G-protein signaling and activate or increase the level of β-arrestin mobilization. For example, the chemical entities described herein can fully stimulate the signaling pathways of both β-arrestin and G-protein.

[0019] Generally, receptors exist in an active conformation (Ra) and an inactive conformation (Ri). Certain compounds that affect the receptor can change the Ra to Ri ratio (Ra / Ri). For example, full agonists are those that increase the Ra / Ri ratio and can cause a "maximal" saturating effect. Partial agonists, when binding to the receptor, give a response lower than that induced by a full agonist (e.g., an endogenous agonist). Thus, the Ra / Ri of a partial agonist is smaller than that of a full agonist. However, the potency of a partial agonist can be greater than or less than that of a full agonist.

[0020] In one aspect, the characteristic chemical entity is of formula I: a compound of TIFF2025081550000001.tif30128, or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , A1 , X 1 , X 2 , X 3 , and X 4 may be as defined anywhere in this specification.

[0021] In one aspect, a pharmaceutical composition is provided that comprises a chemical entity described herein (e.g., a compound described generally or specifically herein or a pharmaceutically acceptable salt thereof, or a composition containing the same) and one or more pharmaceutically acceptable excipients.

[0022] In one aspect, a method for modulating (e.g., stimulating, partially stimulating) APJ receptor activity is provided, the method comprising contacting an APJ receptor with a chemical entity described herein (e.g., a compound described generally or specifically herein or a pharmaceutically acceptable salt thereof, or a composition containing the same). The method can include an in vitro method, e.g., contacting a sample containing one or more cells each independently containing one or more APJ receptors with the chemical entity. An in vivo method can also be provided. The method can include, for example, administering the chemical entity to a subject (e.g., a human) having a disease, disorder, or condition (e.g., PAH; heart failure; type II diabetes; sepsis; renal failure; and systemic hypertension) in which a decrease in APJ receptor activity (e.g., suppression or deficiency of APJ receptor signaling; e.g., suppression or deficiency of apelin-APJ receptor signaling) or downregulation of endogenous apelin contributes to the pathophysiology and / or symptoms and / or progression of the disease, disorder, or condition. The in vivo method can include, but is not limited to, modulating (e.g., decreasing) right ventricular afterload; modulating (e.g., decreasing) mean pulmonary artery pressure; modulating (e.g., increasing) insulin levels; and modulating (e.g., decreasing) glucose levels in a subject (e.g., a human).

[0023] In a further aspect, there is provided a method of treating a disease, disorder, or condition, wherein a decrease in APJ receptor activity (e.g., inhibition or deficiency of APJ receptor signaling; e.g., inhibition or deficiency of apelin-APJ receptor signaling) or downregulation of endogenous apelin contributes to the pathogenesis and / or symptoms and / or progression of the disease, disorder, or condition. The method comprises administering to a subject in need thereof an effective amount of a chemical entity described herein (e.g., a compound described generally or specifically herein, a pharmaceutically acceptable salt thereof, or a composition comprising the same).

[0024] In another aspect, the present disclosure provides a method of treating a subject having a disease, disorder, or condition, wherein a decrease in APJ receptor activity (e.g., inhibition or deficiency of APJ receptor signaling; e.g., inhibition or deficiency of apelin-APJ receptor signaling) or downregulation of endogenous apelin contributes to the pathogenesis and / or symptoms and / or progression of the disease, disorder, or condition. The method comprises administering a chemical entity described herein (e.g., a compound described generally or specifically herein, a pharmaceutically acceptable salt thereof, or a composition comprising the same) in an amount effective to treat the disease, disorder, or condition.

[0025] In a further aspect, there is provided a method of treatment comprising administering to a subject a chemical entity described herein (e.g., a compound described generally or specifically herein, a pharmaceutically acceptable salt thereof, or a composition comprising the same). The method comprises treating the disease, disorder, or condition by administering the chemical entity in an amount effective to treat a disease, disorder, or condition, wherein a decrease in APJ receptor activity (e.g., inhibition or deficiency of APJ receptor signaling; e.g., inhibition or deficiency of apelin-APJ receptor signaling) or downregulation of endogenous apelin contributes to the pathogenesis and / or symptoms and / or progression of the disease, disorder, or condition.

[0026] Non-limiting examples of the diseases, disorders, and conditions include PAH. In some embodiments, PAH is idiopathic. In other embodiments, PAH is hereditary PAH, toxic or drug-induced PAH, or PAH associated with one or more of the following: congenital heart disease, connective tissue disorders (such as scleroderma, systemic lupus erythematosus, systemic sclerosis, Hashimoto's thyroiditis, Sjogren's syndrome, and antiphospholipid antibody syndrome), portal hypertension, BMPR2 mutations, schistosomiasis, and HIV infection.

[0027] Another non-limiting examples of the diseases, disorders, and conditions include cardiovascular diseases, such as coronary artery disease and heart failure. In certain embodiments, the cardiovascular disease is heart failure; such as systolic heart failure, diastolic heart failure, diabetic heart failure, and heart failure with preserved ejection fraction, cardiomyopathy, myocardial infarction, left ventricular dysfunction including left ventricular dysfunction after myocardial infarction, right ventricular dysfunction, right ventricular failure, cardiac hypertrophy, myocardial remodeling including post-infarction or post-cardiac surgery myocardial remodeling, and valvular heart disease.

[0028] Still another non-limiting examples of the diseases, disorders, and conditions include metabolic disorders, such as metabolic syndrome; diabetes (such as type 2 diabetes); obesity; obesity-related disorders; impaired glucose tolerance; and insulin resistance.

[0029] Other non-limiting examples of the diseases, disorders, and conditions include sepsis, septic shock, renal failure, systemic hypertension, idiopathic pulmonary fibrosis (IPF), and systemic sclerosis.

[0030] Further non-limiting examples include non-CAD atherosclerotic conditions including coronary artery disease (CAD), peripheral vascular disease (PVD), aortic atherosclerotic arteriosclerosis, and cerebral arteriosclerosis, diabetic retinopathy, ischemia-reperfusion injury, emphysema, radiation-induced organ / tissue damage, luteal regression, scleroderma, systemic sclerosis, and immunoregulatory disorders.

[0031] In one aspect, the present disclosure features methods for identifying and / or selecting a subject (e.g., a human) for whom the methods described herein are likely to be beneficial, as well as methods for determining whether a subject (e.g., a human) is responding to the methods. In certain embodiments, a biological sample, which can be, for example, but not limited to, breath, sputum, tissue, plasma or serum sample, urine, is obtained from the subject, the level of a particular parameter in the sample is determined, and compared to a control value. In some cases, the control value may be determined from one or more normal individuals who do not have the disease, disorder, or condition being treated. In other cases, the control value may be determined from a sample already obtained from the subject. Generally, a measured parameter level that is high (or elevated) compared to a control value determined from a normal, non-afflicted individual or population indicates that the methods described herein are beneficial to the subject. Generally, a level that is low compared to the control value indicates that the patient is responding to treatment or, for a subject not receiving the treatment, that the treatment may not be as beneficial to the subject.

[0032] In some of the above embodiments, the subject has or is at risk of having PAH. Non-limiting and exemplary parameters associated with PAH are described below.

[0033] In certain embodiments, the parameter is the LTB4 level. For example, the baseline value or reference value of LTB4 can be 100 pg / mL or more, 200 pg / mL or more, 300 pg / mL or more, 400 pg / mL or more, 500 pg / mL or more, 600 pg / mL or more, or 100 pg / mL or more. In certain embodiments, the provided treatment is effective if the endpoint LTB4 level of the subject decreases from the baseline or reference LTB4 level after the treatment is initiated. For example, the endpoint LTB4 level of the subject decreases to 600 pg / mL or less, 500 pg / mL or less, 400 pg / mL or less, 300 pg / mL or less, 200 pg / mL or less, or 100 pg / mL or less. In certain embodiments, the provided treatment is effective if the endpoint LTB4 level is 30 pg / mg tissue or less, 20 pg / mg tissue or less, 10 pg / mg tissue or less, 7.5 pg / mg tissue or less, or 5 pg / mg tissue or less after the treatment is initiated. In other embodiments, the provided treatment is effective if the endpoint LTB4 level is at least 2-fold, at least 3-fold, at least 4-fold, or at least 5-fold lower than the baseline LTB4 level after the treatment is initiated.

[0034] In certain embodiments, the parameter is pulmonary vascular resistance (PVR). The baseline or reference PVR level is 200 dynsec / cm 5 or more, 240 dynsec / cm 5 or more, 300 dynsec / cm 5 or more, 400 dynsec / cm 5 or more, 500 dynsec / cm 5 or more, 600 dynsec / cm 5 or more, 700 dynsec / cm 5 or more, or 800 dynsec / cm 5 or more. In certain embodiments, the provided treatment is effective if the endpoint PVR level of the subject is 70 dynsec / cm 5 or more, 100 dynsec / cm 5 or more, 130 dynsec / cm 5 or more, or 160 dynsec / cm 5It is effective when it decreases as described above.

[0035] In certain embodiments, the parameter is pulmonary artery pressure (PAP). The baseline or reference PAP level can be 20 mmHg or more, 25 mmHg or more, 30 mmHg or more, 35 mmHg or more, 40 mmHg or more, 45 mmHg or more, 50 mmHg or more, 60 mmHg or more, or 70 mmHg or more. In certain embodiments, the provided treatment is effective when the endpoint PAP level of the subject decreases by 0.5 mmHg or more, 1 mmHg or more, 1.5 mmHg or more, 5 mmHg or more, 10 mmHg or more, 20 mmHg or more, 30 mmHg or more, 40 mmHg or more, or 50 mmHg from the baseline or reference PAP level after the treatment is initiated. In certain embodiments, the subject exhibits a mean pulmonary artery pressure of more than 25 mmHg.

[0036] In certain embodiments, the parameter is cardiac index (CI). The baseline or reference CI level can be 5 L / min / m.sup.2 or less, 2.5 L / min / m.sup.2 or less, 2 L / min / m.sup.2 or less, 1.5 L / min / m.sup.2 or less, or 1 L / min / m.sup.2 or less. In certain embodiments, the provided treatment is effective when the endpoint CI level increases by 0.1 or more, 0.2 or more, 0.3 or more, 0.4 or more, 0.5 or more, 1 or more, or 2 or more from the baseline or reference CI level after the treatment is initiated.

[0037] In certain embodiments, the parameter is pulmonary capillary wedge pressure (PCWP). The baseline or reference PCWP level can be 36 mmHg or less, 24 mmHg or less, 18 mmHg or less, 10 mmHg, or 5 mmHg or less. In certain embodiments, the provided treatment is effective when the endpoint PCWP level increases by 0.2 mmHg or more, 0.3 mmHg or more, 0.4 mmHg or more, 0.5 mmHg or more, 0.6 mmHg or more, 1 mmHg or more, or 5 mmHg or more from the baseline or reference PCWP level after the treatment is initiated.

[0038] In certain embodiments, the parameter is right atrial pressure (RAP). The baseline or reference RAP level can be 4 mmHg or more, 6 mmHg or more, 8 mmHg or more, 10 mmHg or more, 12 mmHg or more, 16 mmHg or more, 20 mmHg or more, or 25 mmHg or more. In certain embodiments, the provided treatment is effective if, after the treatment is initiated, the subject's endpoint RAP level decreases by 5 mmHg or more, 2.5 mmHg or more, 1 mmHg or more, 0.5 mmHg or more, or 0.2 mmHg or more from the baseline or reference RAP level.

[0039] In certain embodiments, the parameter is the six-minute walk distance (6MWD). The baseline or reference 6MWD can be 50 m or less, 100 m or less, 200 m or less, 300 m or less, 400 m or less, or 500 m or less. In certain embodiments, the provided treatment is effective if, after the treatment is initiated, the subject's endpoint 6MWD increases by 10 m or more, 15 m or more, 20 m or more, 25 m or more, 30 m or more, or 50 m or more from the baseline or reference 6MWD. Alternatively, or furthermore, the treatment provided in the present invention is effective if, after the treatment is initiated, the subject's endpoint 6MWD increases by 3% or more, 4% or more, 5% or more, 10% or more, or 20% or more from the baseline level.

[0040] In certain embodiments, the parameter is the level of brain natriuretic peptide (BNP). The baseline or reference BNP level can be 60 pg / mL or more, 80 pg / mL or more, 100 pg / mL or more, 120 pg / mL or more, 140 pg / mL or more, 200 pg / mL or more, 500 pg / mL or more, or 1000 pg / mL or more. In certain embodiments, the provided treatment is effective if, after the treatment is initiated, the subject's endpoint BNP level decreases from the baseline or reference BNP level. For example, the subject's endpoint BNP level can decrease by 1 pg / mL or more, 2 pg / mL or more, 5 pg / mL or more, 10 pg / mL or more, 20 pg / mL or more, 100 pg / mL or more, 500 pg / mL or more, or 1000 pg / mL or more.

[0041] In certain embodiments, the parameter is atrial natriuretic peptide (ANP) level. The baseline or reference ANP level can be 60 pg / mL or greater, 80 pg / mL or greater, 100 pg / mL or greater, 120 pg / mL or greater, 140 pg / mL or greater, 200 pg / mL or greater, 500 pg / mL or greater, or 1000 pg / mL or greater. In certain embodiments, the provided treatment is effective if the endpoint ANP level of the subject decreases from the baseline or reference ANP level after the treatment is initiated. For example, the endpoint ANP level of the subject can decrease by 1 pg / mL or greater, 2 pg / mL or greater, 5 pg / mL or greater, 10 pg / mL or greater, 20 pg / mL or greater, 100 pg / mL or greater, 500 pg / mL or greater, or 1000 pg / mL or greater.

[0042] In certain embodiments, the parameter is the pulmonary diffusing capacity (DLCO), or the diffusing capacity of CO, and may be used in this method as a parameter for determining effectiveness. The baseline or reference DLCO can be 90% or less, 80% or less, 70% or less, 50% or less, 45% or less, or 40% or less. In certain embodiments, the provided treatment is effective if the endpoint DLCO increases from the baseline level after the treatment is initiated. For example, the endpoint DLCO can increase by 1% or greater, 5% or greater, 10% or greater, 15% or greater, 20% or greater, or 50% or greater than the baseline or reference DLCO.

[0043] In another aspect, the present disclosure is a method for reducing the risk of right ventricular failure in a subject in need thereof, the method comprising administering to the subject an effective amount of a chemical entity described herein.

[0044] The methods described herein may further comprise treating one or more conditions that are complications, comorbidities, or sequelae of any one or more of the conditions described herein.

[0045] For example, the method may further include treating one or more conditions that are comorbidities, complications, or sequelae of PAH, such as coronary heart disease or heart failure. In certain embodiments, the cardiovascular disease includes heart failure, such as systolic heart failure, diastolic heart failure, diabetic heart failure, and heart failure with preserved ejection fraction, cardiomyopathy, myocardial infarction, left ventricular dysfunction including left ventricular dysfunction after myocardial infarction, right ventricular dysfunction, right ventricular failure, cardiac hypertrophy, myocardial remodeling including post-infarction or post-cardiac surgery myocardial remodeling, and valvular heart disease.

[0046] As another example, the method may further include treating one or more conditions that are comorbidities or sequelae of diabetes (e.g., type 2 diabetes), 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 risk factors associated with unregulated cholesterol levels and / or lipid levels and / or inflammation), retinopathy, nephropathy, neuropathy, NASH, fractures, and cognitive impairment.

[0047] The method may further include administering one or more other therapeutic agents (e.g., in combination with the chemical entities described herein).

[0048] Embodiments may include one or more of the following advantageous properties.

[0049] Aperin peptides are unstable, and thus only the acute pharmacodynamic effects of aperin peptides are observable. In some embodiments, the compounds described herein exhibit relatively high metabolic stability that allows for the observation of non-acute pharmacodynamic effects.

[0050] In some embodiments, the compounds described herein can lower atrial pressure in addition to increasing cardiac output.

[0051] In some embodiments, the compounds described herein can reduce the tachyphylaxis often associated with the administration of potent agonists by selectively activating the G protein pathway through the APJ receptor. Thus, in certain embodiments, the compounds described herein can reduce apelin-related cardiac hypertrophy.

[0052] In some embodiments, the compounds described herein may exhibit pleiotropic properties (e.g., potent cardiovascular dilation activity, cardiorenal protection, and regulation of body fluid homeostasis).

[0053] Other embodiments include those described in the detailed description and / or the claims.

[0054] Further Definitions To facilitate understanding of the disclosure described herein, some additional terms are defined below. Generally, 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 commonly understood by one of ordinary skill in the technical field to which this disclosure belongs. Patents, applications, published applications, and other publications referred to throughout this specification and the appendices are hereby incorporated by reference in their entirety.

[0055] As used herein, the term "APJ receptor" is intended to non-limitingly include its nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide strands, complementary sequences, peptides, polypeptides, proteins, homologous and / or ortholog APJ molecules or APJ receptor molecules, isoforms, precursors, variants, mutants, derivatives, splice variants, alleles, different species, and active fragments.

[0056] As used herein, the term "acceptable" with respect to a formulation, composition, or ingredient means that there are no continuing adverse effects on the overall health of the subject being treated.

[0057] "API" means an active pharmaceutical ingredient.

[0058] The term "IC50" or "EC50" means the amount, concentration, or dose of a compound required for 50% inhibition or activation of the maximal response in an assay measuring the maximal response.

[0059] As used herein, the term "effective amount" or "therapeutically effective amount" means an amount of an administered chemical entity (e.g., a compound described generally or specifically herein, a pharmaceutically acceptable salt thereof, or a composition containing the same) sufficient to alleviate to some extent one or more symptoms of a disease or condition being treated. The results include a decrease and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition containing a compound disclosed herein necessary to achieve a clinically significant decrease in disease symptoms. The appropriate "effective" amount in any individual case is determined using any suitable technique, such as a dose escalation study.

[0060] The term "excipient" or "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In one aspect, each component is "pharmaceutically acceptable" in the sense that it is compatible with the other components of the pharmaceutical formulation and suitable for use in contact with human and animal tissues or organs without undue toxicity, irritation, allergic response, immunogenicity, or other problems or complications and is commensurate with a reasonable benefit / risk ratio. See, e.g., 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.

[0061] 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 properties of the compound. In certain cases, pharmaceutically acceptable salts can be 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, salicylic acid, etc. In some cases, pharmaceutically acceptable salts can be obtained by reacting a compound having an acidic group described herein with a base to form salts such as ammonium salts, alkali metal salts such as 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, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine and lysine, or by other established methods. Pharmaceutically acceptable salts are not particularly limited as long as they can be used in pharmaceuticals. Examples of salts formed by the compounds described herein with bases include: its salts with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; its salts with organic bases such as methylamine, ethylamine, and ethanolamine; its salts with basic amino acids such as lysine and ornithine; and ammonium salts. The salts can 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.

[0062] The term "pharmaceutical composition" means a mixture of a compound described herein and 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 present compound to a living being. There are multiple techniques in the art for administering the compound, including but not limited to rectal administration, oral administration, intravenous administration, aerosol administration, parenteral administration, intraocular administration, pulmonary administration, and topical administration.

[0063] The term "subject" means an animal including but not limited to primates (e.g., humans), monkeys, female 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.

[0064] The terms "treat", "treating", and "treatment" in the context of treating a disease, disorder, or condition are intended to include reducing or suppressing the disorder, disease, or condition, or one or more symptoms associated with the disorder, disease, or condition; or delaying the progression, metastasis, or worsening of the disease, disorder, or condition, or one or more of its symptoms.

[0065] The term "halo" means fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

[0066] The term "alkyl" means a hydrocarbon chain that can be straight-chain or branched-chain and contains the indicated number of carbon atoms. For example, C 1~10 indicates that the group can have from 1 to 10 carbon atoms therein. Non-limiting examples include methyl, ethyl, isopropyl, tert-butyl, and n-hexyl.

[0067] The term "haloalkyl" means an alkyl in which one or more hydrogen atoms are independently replaced by a halo selected therefrom.

[0068] The term "alkoxy" means an -O-alkyl group (e.g., -OCH 3 ).

[0069] The term "haloalkoxy" means an -O-haloalkyl group (e.g., -OCH 3 ).

[0070] The term "alkylene" means a divalent branched or unbranched alkyl (e.g., -CH 2 -).

[0071] Terms such as "arylene" mean a divalent ring system, herein meaning a divalent aryl.

[0072] The term "alkenyl" means a hydrocarbon chain that can be straight or branched and has one or more carbon-carbon double bonds. The alkenyl moiety contains the indicated number of carbon atoms. For example, C 2~6 indicates that the group can have from 2 to 6 carbon atoms therein.

[0073] The term "alkynyl" means a hydrocarbon chain that can be straight or branched and has one or more carbon-carbon triple bonds. The alkynyl moiety contains the indicated number of carbon atoms. For example, C 2~6 indicates that the group can have from 2 to 6 carbon atoms therein.

[0074] The term "aryl" means a 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system, where 0, 1, 2, 3, or 4 atoms of 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. Also, examples of aryl groups include phenyl, naphthyl, and the like.

[0075] As used herein, the term "cycloalkyl" includes optionally substituted saturated cyclic hydrocarbon groups having 3 to 10 carbons, preferably 3 to 8 carbons, more preferably 3 to 6 carbons. Preferred cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

[0076] The term "heteroaryl" means a 5- to 8-membered monocyclic, 8- to 12-membered bicyclic, or 11- to 14-membered tricyclic aromatic ring system having 1 to 3 heteroatoms in the monocyclic case, 1 to 6 heteroatoms in the bicyclic case, or 1 to 9 heteroatoms in the tricyclic case, where the heteroatoms are selected from O, N, or S (e.g., carbon atoms, and, in the monocyclic, bicyclic, or tricyclic cases, 1 to 3, 1 to 6, or 1 to 9 N, O, or S heteroatoms, respectively), 0, 1, 2, 3, or 4 atoms of each ring may be substituted with substituents, the ring containing the monocyclic group is an aromatic ring, and at least one fused ring containing a bicyclic group or a tricyclic group is an aromatic ring (however, a ring containing a heteroatom, such as tetrahydroisoquinolinyl, is not required), meaning an aromatic ring system. Exemplary heteroaryl systems are derived from, but not limited to, the following ring systems: pyrrole, furan, thiophene, imidazole, pyrazole, oxazole (= [1,3]oxazole), isoxazole (= [1,2]oxazole), thiazole (= [1,3]thiazole), isothiazole (= [1,2]thiazole), [1,2,3]triazole, [1,2,4]triazole, [1,2,4]oxadiazole, [1,3,4]oxadiazole, [1,2,4]thiadiazole, [1,3,4]thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, [1,2,3]triazine, [1,2,4]triazine, [1,3,5]triazine, indole, isoindole, benzofuran, benzothiophene, [1,3]benzoxazole, [1,3]benzothiazole, benzimidazole, indazole, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, different naphthyridines, such as [1,8]naphthyridine, different thienopyridines, such as thieno[2,3-b]pyridine, and purine.

[0077] The term "heterocyclyl" means a 5- to 8-membered monocyclic, 8- to 12-membered bicyclic, or 11- to 14-membered tricyclic aromatic ring system having 1 to 3 heteroatoms in the monocyclic case, 1 to 6 heteroatoms in the bicyclic case, or 1 to 9 heteroatoms in the tricyclic case, wherein the heteroatoms are selected from O, N, or S (e.g., carbon atoms, and 1 to 3, 1 to 6, or 1 to 9 N, O, or S heteroatoms in the monocyclic, bicyclic, or tricyclic cases, respectively), and 0, 1, 2, or 3 atoms of each ring may be substituted with substituents. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like.

[0078] Furthermore, the atoms constituting the compounds of this aspect are intended to include all isotopic forms of the atoms. Isotopes as used herein include atoms having the same atomic number but different mass numbers. By way of general and non-limiting example, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include 13 C and 14 C.

[0079] The compounds provided herein may encompass various stereochemical forms. The compounds also include diastereomers and optical isomers, e.g., mixtures of enantiomers (including atropisomers) including racemic mixtures, as well as individual enantiomers and diastereomers, resulting from structural asymmetry in a particular compound. Separation of individual isomers or selective synthesis of individual isomers is achieved by application of various methods well known to those skilled in the art. Unless otherwise indicated, when a disclosed compound is named or illustrated by one structure without specifying the stereochemical structure and has one or more chiral centers, the disclosed compound is understood to represent all possible stereoisomers of the compound. For example, -S(O)(=NH)-R 4 are enantiomers TIFF2025081550000002.tif10128 and enantiomer TIFF2025081550000003.tif10128, and is intended to include its compounds, and mixtures thereof (e.g., racemic mixtures).

[0080] [The present invention 1001] Formula (I): a compound of TIFF2025081550000004.tif30128, or a pharmaceutically acceptable salt thereof, wherein A 1 is CH or N; X 1 , X 2 , X 3 , and X 4 each independently is selected from the group consisting of N and CR 3 ; R 1 is as follows: (i) -(Y 1 ) n -Y 2 , where ·n is 0 or 1; ·Y 1 is C a alkylene which may be substituted with 1 to 6 R 1~6 ; and ·Y 2 is as follows: (a) C b cycloalkyl which may be substituted with 1 to 4 R 3~10 ; (b) C c aryl which may be substituted with 1 to 4 R 6~10 ; (c) heteroaryl containing 5 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S, and one or more of the heteroaryl ring carbon atoms may be substituted with 1 to 4 independently selected R c ; or (d) Heterocyclyl containing 3 to 10 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), and O, and one or more of the heterocyclyl ring carbon atoms are optionally substituted with 1 to 4 independently selected R b ; Heterocyclyl; Or (ii) -Z 1 -Z 2 -Z 3 where ·Z 1 is C a alkylene optionally substituted with 1 to 4 R 1~3 ; ·Z 2 is -N(H)-, -N(R d )-, -O-, or -S-; and ·Z 3 is C a alkyl optionally substituted with 1 to 4 R 2~7 ; Or (iii) C a alkyl optionally substituted with 1 to 6 independently selected R 3~10 ; Or (iv) -Z 4 -Z 5 -Z 6 -Y 2 where ·Z 4 is C a alkylene optionally substituted with 1 to 4 R 1~3 ; ·Z 5 is -N(H)-, -N(R d )-, -O-, or -S-; ·Z 6 is C a alkylene optionally substituted with 1 to 4 R 1~4 ; and ·Y 2 is as defined above ; R 2is as follows: (i) C which may be further substituted with 1 to 4 R c aryl; 6~10 (ii) heteroaryl containing 5 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S, and one or more of the heteroaryl ring carbon atoms may be substituted with 1 to 4 independently selected R c heteroaryl; (iii) C b cycloalkyl which may be substituted with 1 to 4 R 3~10 ; (iv) heterocyclyl containing 3 to 10 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), and O, and one or more of the heterocyclyl ring carbon atoms may be substituted with 1 to 4 independently selected R b heterocyclyl; or (v) C a alkyl which may be substituted with 1 to 6 independently selected R 1~10 ; wherein; each occurrence of R 3 is independently selected from the group consisting of -L 4 -R 4 , H, and R c '; each occurrence of L 4 is independently as follows: (i) a single bond; (ii) N(H), N(R d ), or N(R 4 ); (iii) -N(H)S(O) 1~2 - or -N(R d )S(O) 1~2 -; (iv) -S(O) 1~2 N(H)- or -S(O) 1~2 N(R d ); ​(v) -O-; (vi) -S(O) 0~2 -; (vii) -C(O)NH- or -C(O)N(R d ); (viii) -N(H)C(O)- or -N(R d )C(O)-; (ix) -C≡C; (x) -N(H)S(O)(=NH)-, -N(R d )S(O)(=NH), -N(H)S(O)(=NR d )-, or -N(R d )S(O)(=NR d )-; (xi) -S(O)(=NH)NH-, -S(O)(=NR d )NH-, -S(O)(=NH)NR d -, or -S(O)(=NR d )NR d -; (xii) -S(O)(=NH)- or -S(O)(=NR d ); and (xiii) -N(H)S(O) 1~2 N(H)-, -N(R d )S(O) 1~2 N(H)-, -N(H)S(O) 1~2 N(R d )-, or -N(R d )S(O) 1~2 N(R d )- selected from the group consisting of; R 4 each occurrence of which is independently, the following: (i) -(Y 3 ) p -Y 4 where ·p is 0 or 1; ·Y 3 is C a alkylene or C 1~6 alkenylene which may each be substituted with 1 to 6 R 1~6 s; and ·Y 4 is the following: (a) C which may be substituted with 1 to 4 R b cycloalkyl; 3~6 (b) C which may be substituted with 1 to 4 R c aryl; 6~10 (c) heteroaryl containing 5 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S, and one or more of the heteroaryl ring carbon atoms may be substituted with 1 to 4 independently selected R c heteroaryl; or (d) heterocyclyl containing 3 to 10 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), and O, and one or more of the heterocyclyl ring carbon atoms may be substituted with 1 to 4 independently selected R b heterocyclyl; or (ii) C a alkyl, C 1~10 alkenyl, or C 1~10 alkynyl 1~10 each of which may be substituted with 1 to 6 independently selected R ; Each occurrence of R a is independently -OH; -F; -Cl; -Br; -NR e R f ; 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) 1~2 (C 1~4 alkyl); cyano; and C 1~4 alkyl which may be substituted with 1 to 4 independently selected C 3~6 ​​selected from the group consisting of cycloalkyl; R b each occurrence of which is independently, C 1~6 alkyl; C 1~4 haloalkyl; -OH; oxo; -F; -Cl; -Br; -NR e R f ; C 1~4 alkoxy; C 1~4 haloalkoxy; -C(=O)(C 1~4 alkyl); -C(=O)O(C 1~4 alkyl); -C(=O)OH; -C(=O)N(R')(R''); -S(O) 1~2 (NR'R''); -S(O) 1~2 (C 1~4 alkyl); cyano; and 1 to 4 independently selected C 1~4 cycloalkyl optionally substituted with alkyl; 3~6 selected from the group consisting of cycloalkyl; R c each occurrence of which is independently, the following: (i) halo; (ii) cyano; (iii) C 1~6 alkyl; (iv) C 2~6 alkenyl; (v) C 2~6 alkynyl; (vi) C 1~4 haloalkyl; (vii) C 1~4 alkoxy; (viii) C 1~4 haloalkoxy; (ix) 1 to 4 independently selected C 1~4 cycloalkyl optionally substituted with alkyl; 0~3 -(C 3~6 alkylene)-C (x) -S(O) 1~2 (C 1~4 alkyl); (xi) -NR e R f ; (xii) -OH; (xiii) -S(O) 1~2 (NR'R''); (xiv) -C 1~4 Thioalkoxy; (xv) -NO 2 ; (xvi) -C(=O)(C 1~4 Alkyl); (xvii) -C(=O)O(C 1~4 Alkyl); (xviii) -C(=O)OH; (xix) -C(=O)N(R')(R''); and (xx) C 3~6 Cycloalkoxy selected from the group consisting of; Each occurrence of R c ' is independently one of the following: (i) Halo; (ii) Cyano; (iii) -OH; (iv) -NO 2 ; (v) -C(=O)(C 1~4 Alkyl); (vi) -C(=O)O(C 1~4 Alkyl); (vii) -C(=O)OH; and (viii) -NH 2 selected from the group consisting of; R d is 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 alkoxy; R e and each occurrence of R f is independently H; C 1~6 Alkyl; C 3~6Cycloalkyl; -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 alkoxy, or R e and R f together with the nitrogen atom to which each is attached form a ring containing 3 to 8 ring atoms, the ring having (a) 1 to 7 ring carbon atoms each substituted with 1 to 2 substituents independently selected from H and C 1~3 alkyl; and (b) 0 to 3 ring heteroatoms (other than the nitrogen atom to which R' and R'' are attached) independently selected from the group consisting of N(R d ), O, and S; each occurrence of R' and R'' is independently selected from the group consisting of H and C 1~4 alkyl, or R' and R'' together with the nitrogen atom to which each is attached form a ring containing 3 to 8 ring atoms, the ring having (a) 1 to 7 ring carbon atoms each substituted with 1 to 2 substituents independently selected from H and C 1~3 alkyl; and (b) 0 to 3 ring heteroatoms (other than the nitrogen atom to which R' and R'' are attached) independently selected from the group consisting of N(R d ), O, and S, provided that when the compound is a compound of formula (I-1): TIFF2025081550000005.tif35128, R 1 is other than unsubstituted phenyl, p-dimethylaminophenyl, p-aminosulfonylphenyl, and unsubstituted 4-pyridinyl; when the compound is a compound of formula (I-2): TIFF2025081550000006.tif34128, R 1 is other than unsubstituted phenyl; provided that the compound is of formula (I-3): Not the compound of TIFF2025081550000007.tif34128; However, when the compound is of formula (I-4): TIFF2025081550000008.tif34128, R 1 is other than p-fluorophenyl; However, when the compound is of formula (I-5): TIFF2025081550000009.tif34128, R 3 is other than trifluoromethyl; However, when the compound is of formula (I-6): TIFF2025081550000010.tif34128, R 2 is as follows: (i) Unsubstituted phenyl; (ii) TIFF2025081550000011.tif10128; (iii) TIFF2025081550000012.tif20128; (iv) Unsubstituted pyridinyl; (v) TIFF2025081550000013.tif12128 where Q 1 , Q 2 , Q 3 , and Q 4 are each independently selected from N and CH; or (vi) Heteroaryl containing 9 to 10 ring atoms, wherein 1 to 2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S, and one or more of the heteroaryl ring carbon atoms may be substituted with 1 to 2 independently selected R c , heteroaryl excluding, a compound of formula (I), or a pharmaceutically acceptable salt thereof. [Invention 1002] X 1 , X 2 , X 3 , and X4 One or two of which are independently N; and X 1 X 2 X 3 and X 4 Two to three of which are each independently selected CR 3 The compound of the present invention 1001, which is [The present invention 1003] Formula (I-a): The compound of the present invention 1001, which is the compound of TIFF2025081550000014.tif30128, or a pharmaceutically acceptable salt thereof. [The present invention 1004] Formula (I-a1): The compound of any one of the present inventions 1001 to 1003, which is the compound of TIFF2025081550000015.tif34128, or a pharmaceutically acceptable salt thereof. [The present invention 1005] Formula (I-a2): The compound of any one of the present inventions 1001 to 1003, which is the compound of TIFF2025081550000016.tif34128, or a pharmaceutically acceptable salt thereof. [The present invention 1006] Formula (I-b): The compound of the present invention 1001, which is the compound of TIFF2025081550000017.tif30128, or a pharmaceutically acceptable salt thereof. [The present invention 1007] Formula (I-b1): The compound of any one of the present inventions 1001 and 1006, which is the compound of TIFF2025081550000018.tif34128, or a pharmaceutically acceptable salt thereof. [The present invention 1008] Formula (I-c) or (I-d): The compound of the present invention 1001, which is the compound of TIFF2025081550000019.tif30128, or a pharmaceutically acceptable salt thereof. [The present invention 1009] Formula (I-c1) or (I-d1): The compound of TIFF2025081550000020, or a pharmaceutically acceptable salt thereof, which is any one of Compounds 1001 and 1008 of the present invention. [Invention 1010] R 1 is -(Y 1 ) n -Y 2 and is any one of Compounds 1001 to 1009 of the present invention. [Invention 1011] where n is 0, and is any one of Compounds 1001 to 1010 of the present invention. [Invention 1012] where n is 1, and is any one of Compounds 1001 to 1010 of the present invention. [Invention 1013] Y 1 is C 1~3 alkylene, and is the compound of Invention 1012. [Invention 1014] Y 2 is heteroaryl containing 5 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S, and one or more of the heteroaryl ring carbon atoms may be substituted with 1 to 4 independently selected R c , and is any one of Compounds 1001 to 1013 of the present invention. heteroaryl [Invention 1015] Y 2 is heteroaryl containing 5 to 6 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S, and one or more of the heteroaryl ring carbon atoms may be substituted with 1 to 4 independently selected R c , and is any one of Compounds 1001 to 1014 of the present invention. heteroaryl [Invention 1016] Y 2 is A heteroaryl containing 6 ring atoms, wherein 1 to 2 ring atoms are N, and one or more of the heteroaryl ring carbon atoms are 1 to 4 independently selected R c heteroaryl, which may be substituted with is a compound of any one of the present inventions 1001 to 1015. [Present Invention 1017] Y 2 is pyridyl (e.g., 2-pyridyl or 6-pyridyl) in which one or more of the ring carbon atoms may be substituted with 1 to 4 independently selected R c is a compound of the present invention 1016. [Present Invention 1018] [Present Invention 1018] Y 2 is pyridyl (e.g., 2-pyridyl or 6-pyridyl) in which one or more of the ring carbon atoms may be substituted with 1 independently selected R c is a compound of the present invention 1017. is a compound of the present invention 1017. [Present Invention 1019] Y 2 is a heteroaryl containing 5 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S, and one or more of the heteroaryl ring carbon atoms may be substituted with 1 to 3 independently selected R c heteroaryl, which may be substituted with is a compound of any one of the present inventions 1001 to 1015. [Present Invention 1020] Y 2 is furanyl in which one or more of the ring carbon atoms may be substituted with 1 to 2 (e.g., 1) independently selected R c is a compound of the present invention 1019. is a compound of the present invention 1019. [Present Invention 1021] R c Each occurrence of is independently as follows: (iii) C1~6 Alkyl; (iv) C 2~6 Alkenyl; (v) C 2~6 Alkynyl; (vi) C 1~4 Haloalkyl; (vii) C 1~4 Alkoxy; (viii) C 1~4 Haloalkoxy; (ix) 1 to 4 independently selected C 1~4 Optionally substituted with alkyl-(C 0~3 Alkylene)-C 3~6 Cycloalkyl; (xiv) -C 1~4 Thioalkoxy; and (xx) C 3~6 Cycloalkoxy A compound according to any one of the present invention 1014 to 1020, selected from the group consisting of. [The present invention 1022] R c Each occurrence of is independently as follows: (vii) C 1~4 Alkoxy; (viii) C 1~4 Haloalkoxy (e.g., OCH 2 CF 3 Or OCF 3 ); (xiv) -C 1~4 Thioalkoxy; and (xx) C 3~6 Cycloalkoxy (e.g., cyclopropoxy) A compound according to any one of the present invention 1014 to 1020, selected from the group consisting of. [The present invention 1023] R c Each occurrence of is independently selected C 1~4 Alkoxy (e.g., -OCH 3 , -OCH 2 CH 3 ) and is a compound according to any one of the present invention 1014 to 1020. [The present invention 1024] Rc Each occurrence of C is independently selected 1~6 A compound of any one of the present inventions 1014 to 1020, which is alkyl (e.g., methyl). [Present Invention 1025] A compound of any one of the present inventions 1014 to 1024, wherein n is 0. [Present Invention 1026] R 1 is A compound of any one of the present inventions 1001 to 1011, 1014 to 1018, and 1021 to 1023, which is TIFF2025081550000021.tif14128. [Present Invention 1027] R 1 is A compound of any one of the present inventions 1001 to 1011, 1014 to 1018, 1021, and 1024, which is TIFF2025081550000022.tif15128. [Present Invention 1028] R 1 is A compound of any one of the present inventions 1001 to 1011, 1014 to 1015, 1019 to 1021, and 1024, which is TIFF2025081550000023.tif11128. [Present Invention 1029] R 2 is C which may be substituted with 1 to 4 R c 6~10 A compound of any one of the present inventions 1001 to 1028, which is aryl. [Present Invention 1030] R 2 is phenyl which may be substituted with 1 to 4 R c A compound of any one of the present inventions 1001 to 1029. [Present Invention 1031] R 2 is phenyl which may be substituted with 1 to 2 R c A compound of any one of the present inventions 1001 to 1030. [Present Invention 1032] R 2 is phenyl substituted with 2 R c ​A compound of any one of the present inventions 1001 to 1031, which may be phenyl substituted. [The present invention 1033] R c Each occurrence of is independently one of the following: (i) Halo (e.g., F); (vi) C 1~4 Haloalkyl (e.g., CF 3 ); (vii) C 1~4 Alkoxy; (viii) C 1~4 Haloalkoxy; and (xiv) -C 1~4 Thioalkoxy A compound of any one of the present inventions 1029 to 1032, selected from the group consisting of [The present invention 1034] R c Each occurrence of is independently selected from halo, C 1~4 Alkoxy, and C 1~4 Haloalkyl, a compound of any one of the present inventions 1029 to 1033. [The present invention 1035] R c Each occurrence of is independently -OCH 3 , CF 3 , or F, a compound of any one of the present inventions 1029 to 1034. [The present invention 1036] R 2 is TIFF2025081550000024.tif17128, for example, R 2 is TIFF2025081550000025.tif16128, a compound of any one of the present inventions 1001 to 1035. [The present invention 1037] R 2 is A heteroaryl containing 5 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S, and one or more of the heteroaryl ring carbon atoms are one or more independently selected Rc heteroaryl, which may be substituted A compound according to any one of the present inventions 1001 to 1028 [Present Invention 1038] R 2 is heteroaryl containing 6 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), and N(R d ), and one or more of the heteroaryl ring carbon atoms are optionally substituted with 1 to 4 independently selected R c heteroaryl, which may be substituted A compound according to any one of the present inventions 1001 to 1028 and 1037 [Present Invention 1039] R 2 is pyridinyl optionally substituted with 1 to 2 independently selected R c A compound according to any one of the present inventions 1001 to 1028 and 1037 to 1038 [Present Invention 1040] Each R c is independently selected from the following: (i) halo; (vi) C 1~4 haloalkyl (e.g., CF 3 ); (vii) C 1~4 alkoxy; (viii) C 1~4 haloalkoxy; and (xiv) -C 1~4 thioalkoxy A compound according to any one of the present inventions 1001 to 1028 and 1037 to 1039 [Present Invention 1041] Each R c is independently C 1~4 alkoxy (e.g., methoxy) A compound according to any one of the present inventions 1001 to 1028 and 1037 to 1039 [Present Invention 1042] R 2 is The compound of any one of the present inventions 1001 to 1028 and 1037 to 1041, which is TIFF2025081550000026.tif17128. [The present invention 1043] R 2 is The compound of any one of the present inventions 1001 to 1028 and 1037 to 1041, which is TIFF2025081550000027.tif17128. [The present invention 1044] R 3 One occurrence of is -L 4 -R 4 The compound of any one of the present inventions 1001 to 1043, which is. [The present invention 1045] R 3 One occurrence of is H or R c '(for example, R c ' may be halo, such as Br or Cl; or R c ' may be -OH or NH 2 ). The compound of any one of the present inventions 1001 to 1044, which is. [The present invention 1046] R 3 One occurrence of is H. The compound of any one of the present inventions 1001 to 1045, which is. [The present invention 1047] R 3 One occurrence of is -L 4 -R 4 and; and each of the remaining occurrences of R 3 is independently selected from the group consisting of H and R c '(for example, R c ' may be halo, such as Br or Cl; or R c ' may be NH 2 ). The compound of any one of the present inventions 1001 to 1046, which is. [The present invention 1048] R 3 One occurrence of is -L 4 -R 4 and, and each of the remaining occurrences of R 3 is H. The compound of any one of the present inventions 1001 to 1047, which is. [The present invention 1049] R 3 One occurrence of is -L 4 -R 4 and one occurrence of R 3 is R c '(for example, R c ' may be a halo, such as Br or Cl (for example, R c' may be Cl)), a compound of any one of the present inventions 1001 to 1047. [The present invention 1050] R 3 One occurrence of is -L 4 -R 4 and one occurrence of R 3 is H, a compound of any one of the present inventions 1001 to 1049. [The present invention 1051] R 3 Two occurrences of are independently selected -L 4 -R 4 a compound of any one of the present inventions 1001 to 1043. [The present invention 1052] R 3 Any remaining occurrences of are selected from the group consisting of H and R c' a compound of any one of the present inventions 1001 to 1043 and 1051. [The present invention 1053] R 3 Any remaining occurrences of are H, a compound of any one of the present inventions 1001 to 1043 and 1051 to 1052. [The present invention 1054] L 4 is -N(H)S(O) 1~2 - or -N(R d )S(O) 1~2 (for example N(C 1~3 alkyl)S(O) 2 ), a compound of any one of the present inventions 1001 to 1053. [The present invention 1055] L 4 is -N(H)S(O) 2 -, a compound of any one of the present inventions 1001 to 1054. [The present invention 1056] L 4 is -N(H)C(O)- or -N(R d )C(O), a compound of any one of the present inventions 1001 to 1053. [The present invention 1057] L 4 is -N(H)C(O)-, a compound of any one of the present inventions 1001 to 1053 and 1056. [The present invention 1058] L 4 is -C(O)NH- or -C(O)N(R d )-, a compound of any one of the present inventions 1001 to 1053. [The present invention 1059] L 4 is -N(H)-, -N(R d )-, or -N(R 4 )-, a compound of any one of the present inventions 1001 to 1053. [The present invention 1060] L 4 is a single bond, a compound of any one of the present inventions 1001 to 1053. [The present invention 1061] L 4 is C≡C, a compound of any one of the present inventions 1001 to 1053. [The present invention 1062] L 4 is -O-, a compound of any one of the present inventions 1001 to 1053. [The present invention 1063] L 4 is -N(H)S(O) 1~2 N(H)-, -N(R d )S(O) 1~2 N(H)-, -N(H)S(O) 1~2 N(R d )-, and -N(R d )S(O) 1~2 N(R d )-, selected from the group consisting of, a compound of any one of the present inventions 1001 to 1053. [The present invention 1064] L 4 is -N(H)S(O) 1~2N(H)-(for example, -N(H)S(O) 2 A compound of any one of the compounds of the present invention 1001 to 1053 and 1063, which is N(H)-). [The present invention 1065] L 4 is -N(H)S(O) 1~2 N(R d )-(for example, -N(H)S(O) 2 N(R d )-, for example, -N(H)S(O) 2 N(C 1~3 alkyl)-), a compound of any one of the compounds of the present invention 1001 to 1053 and 1063. [The present invention 1066] R 4 is -(Y 3 ) p -Y 4 A compound of any one of the compounds of the present invention 1001 to 1065, which is. [The present invention 1067] A compound of any one of the compounds of the present invention 1001 to 1066, where p is 1. [The present invention 1068] Y 3 is C 1~3 alkylene, a compound of any one of the compounds of the present invention 1001 to 1067. [The present invention 1069] Y 3 is CH 2 or CH 2 -CH 2 A compound of any one of the compounds of the present invention 1001 to 1068, which is. [The present invention 1070] A compound of any one of the compounds of the present invention 1001 to 1066, where p is 0. [The present invention 1071] Y 4 is C c aryl which may be substituted with 1 to 4 R 6~10 A compound of any one of the compounds of the present invention 1001 to 1070. [The present invention 1072] Y 4 is phenyl which may be substituted with 1 to 2 (for example, 1) R c A compound of any one of the compounds of the present invention 1001 to 1071. [The present invention 1073] R c Each occurrence of is independently one of the following: (i) halo; (ii) cyano; (iii) C 1~6 alkyl; (iv) C 2~6 alkenyl; (v) C 2~6 alkynyl; (vi) C 1~4 haloalkyl; (vii) C 1~4 alkoxy; (viii) C 1~4 haloalkoxy; (ix) -(C 1~4 alkylene)-C 0~3 which may be substituted with 1 to 4 independently selected C 3~6 cycloalkyl; (xiv) -C 1~4 thioalkoxy; and (xx) C 3~6 cycloalkoxy A compound of the present invention 1071 or 1072 selected from the group consisting of [The present invention 1074] R c Each occurrence of is independently one of the following: (i) halo; (iii) C 1~6 alkyl; (vi) C 1~4 haloalkyl; (vii) C 1~4 alkoxy; and (viii) C 1~4 haloalkoxy A compound of the present invention 1071 or 1072 selected from the group consisting of [The present invention 1075] R c Each occurrence of is independently one of the following: (vii) C 1~4 alkoxy; (viii) C 1~4Haloalkoxy; and (xiv) -C 1~4 Thioalkoxy The compound of the present invention 1071 or 1072 selected from the group consisting of [The present invention 1076] Y 4 is unsubstituted C 6~10 aryl (e.g., phenyl), the compound of any one of the present inventions 1001 to 1072. [The present invention 1077] Y 4 is C b which may be substituted with 1 to 4 R 3~6 (e.g., C 3~4 or C 6 ) cycloalkyl, the compound of any one of the present inventions 1001 to 1070. [The present invention 1078] Y 4 is cyclopropyl or cyclobutyl which may be substituted with 1 to 2 R b , the compound of any one of the present inventions 1001 to 1070 and 1077. [The present invention 1079] Y 4 is C b cycloalkyl (e.g., cyclohexyl) which may be substituted with 1 to 2 R 6 , the compound of any one of the present inventions 1001 to 1070 and 1077. [The present invention 1080] R b Each occurrence of is independently selected from the group consisting of -F, C 1~6 alkyl, C 1~4 haloalkyl, and -OH (e.g., R b may be OH; and / or R b may be C 1~6 alkyl, e.g., methyl), the compound of any one of the present inventions 1001 to 1070 and 1077 to 1079. [The present invention 1081] Y 4 is unsubstituted C 3~6 (e.g., C 3~4 or C 6A compound of any one of the present inventions 1001 to 1070 and 1077, which is cycloalkyl. [Present Invention 1082] Y 4 A compound of the present invention 1081, wherein Y is unsubstituted cyclopropyl or unsubstituted cyclobutyl (for example, unsubstituted cyclopropyl). [Present Invention 1083] Y 4 is heteroaryl containing 5 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S, and one or more of the heteroaryl ring carbon atoms may be substituted with 1 to 4 independently selected R c , and is a compound of any one of the present inventions 1001 to 1070. [Present Invention 1084] Y 4 is heteroaryl containing 6 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), and N(R d ), and one or more of the heteroaryl ring carbon atoms may be substituted with 1 to 4 independently selected R c , and is a compound of any one of the present inventions 1001 to 1070 and 1083. [Present Invention 1085] Y 4 is pyridinyl (for example, 2-pyridinyl, 3-pyridinyl, or 4-pyridinyl), pyrimidinyl (for example, 2-pyrimidinyl or 5-pyrimidinyl), or pyrazinyl, each of which may be substituted with 1 to 2 independently selected R c , and is a compound of any one of the present inventions 1001 to 1070 and 1083 to 1084. [Present Invention 1086] R c Each occurrence of is independently as follows: (i) halo; (ii) cyano; ​​(iii) C 1~6 alkyl; (iv) C 2~6 alkenyl; (v) C 2~6 alkynyl; (vi) C 1~4 haloalkyl; (vii) C 1~4 alkoxy; (viii) C 1~4 haloalkoxy; (ix) 1 to 4 independently selected C 1~4 alkyl optionally substituted with -(C 0~3 alkylene)-C 3~6 cycloalkyl; (xii) OH; (xiv) -C 1~4 thioalkoxy; and (xx) C 3~6 cycloalkoxy a compound of any one of the compounds of the present invention 1083 to 1085 selected from the group consisting of. [The present invention 1087] R c each occurrence of is independently the following: (i) halo (e.g., F, Cl); (iii) C 1~6 alkyl (e.g., methyl); and (xii) OH a compound of the present invention 1086 selected from the group consisting of. [The present invention 1088] Y 4 is unsubstituted pyridinyl, pyrimidinyl, or pyrazinyl, a compound of any one of the present inventions 1001 to 1070 and 1083 to 1085. [The present invention 1089] Y 4 is heterocyclyl containing 3 to 10 ring atoms, 1 to 3 of the ring atoms being heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), and O, and one or more of the heterocyclyl ring carbon atoms being 1 to 4 independently selected Rb heterocyclyl which may be substituted A compound according to any one of the present inventions 1001 to 1070. [Present Invention 1090] Y 4 is heterocyclyl containing 4 to 6 ring atoms, wherein 1 to 2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), and O, and one or more of the heterocyclyl ring carbon atoms are optionally substituted with 1 to 4 independently selected R b heterocyclyl which may be substituted A compound according to any one of the present inventions 1001 to 1070 and 1089. [Present Invention 1091] Y 4 is heterocyclyl containing 4 ring atoms, wherein 1 ring atom is a heteroatom, independently selected from the group consisting of N, N(H), N(R d ), and O, and one or more of the heterocyclyl ring carbon atoms are optionally substituted with 1 to 2 independently selected R b heterocyclyl which may be substituted A compound according to any one of the present inventions 1001 to 1070 and 1089 to 1090. [Present Invention 1092] Y 4 is oxetanyl (e.g., unsubstituted oxetanyl) which may be substituted with 1 to 2 independently selected R b A compound according to any one of the present inventions 1001 to 1070 and 1089 to 1091. [Present Invention 1093] Y 4 is azetidinyl (e.g., azetidinyl substituted with 1 R b ) which may be substituted with 1 to 2 independently selected R b A compound according to any one of the present inventions 1001 to 1070 and 1089 to 1091. [Present Invention 1094] Y 4 is A heterocyclyl containing 6 ring atoms, wherein 1 to 2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), and O, and one or more of the heterocyclyl ring carbon atoms may be substituted with 1 to 4 independently selected R b s, and is a heterocyclyl which is a compound of any one of the present inventions 1001 to 1070 and 1089 to 1090. [Present Invention 1095] Y 4 is selected from the group consisting of tetrahydropyranyl, piperidinyl, piperazinyl, and morpholinyl, each of which may be substituted with 1 to 2 independently selected R b s, and is a compound of any one of the present inventions 1001 to 1070, 1089 to 1090, and 1094. [Present Invention 1096] Y 4 is selected from the group consisting of tetrahydropyranyl, piperidinyl, and morpholinyl, each of which may be substituted with 1 to 2 independently selected R b s, and is a compound of any one of the present inventions 1001 to 1070, 1089 to 1090, and 1094 to 1095. [Present Invention 1097] R b each occurrence of which is independently selected from the group consisting of -F, C 1~6 alkyl, C 1~4 haloalkyl, oxo, and -OH, and is a compound of any one of the present inventions 1089 to 1096. [Present Invention 1098] R b each occurrence of which is independently selected from the group consisting of -F, C 1~6 alkyl, C 1~4 haloalkyl, and -OH (for example, R b may be OH), and is a compound of any one of the present inventions 1089 to 1096. [Present Invention 1099] R 4 is as follows: A compound of any of the compounds of the present invention 1001 - 1069 and 1071 - 1076 selected from the group consisting of TIFF2025081550000028.tif50137. [The present invention 1100] R 4 is as follows: A compound of any of the compounds of the present invention 1001 - 1069 and 1071 - 1076 selected from the group consisting of TIFF2025081550000029.tif30128. [The present invention 1101] R 4 is A compound of any of the compounds of the present invention 1001 - 1066, 1070, and 1071 - 1076 which is TIFF2025081550000030.tif17128. [The present invention 1102] R 4 is A compound of any of the compounds of the present invention 1001 - 1066, 1070, and 1071 - 1076 which is TIFF2025081550000031.tif21128. [The present invention 1103] R 4 is as follows: A compound of any of the compounds of the present invention 1001 - 1069 and 1077 - 1082 selected from the group consisting of TIFF2025081550000032.tif14128. [The present invention 1104] R 4 is as follows: A compound of any of the compounds of the present invention 1001 - 1069 and 1077 - 1082 selected from the group consisting of TIFF2025081550000033.tif14128. [The present invention 1105] R 4 is as follows: A compound of any of the compounds of the present invention 1001 - 1066, 1070, and 1077 - 1082 selected from the group consisting of TIFF2025081550000034.tif24128. [The present invention 1106] R 4 is as follows: A compound of any one of the present inventions 1001 to 1069 and 1083 to 1088 selected from the group consisting of TIFF2025081550000035.tif52156. [Present Invention 1107] R 4 is as follows: A compound of any one of the present inventions 1001 to 1069 and 1083 to 1088 selected from the group consisting of TIFF2025081550000036.tif15128. [Present Invention 1108] R 4 is as follows: A compound of any one of the present inventions 1001 to 1066, 1070, and 1083 to 1088 selected from the group consisting of TIFF2025081550000037.tif15128. [Present Invention 1109] R 4 is as follows: A compound of any one of the present inventions 1001 to 1066, 1070, and 1083 to 1088 selected from the group consisting of TIFF2025081550000038.tif15128. [Present Invention 1110] R 4 is as follows: A compound of any one of the present inventions 1001 to 1069 and 1089 to 1098 selected from the group consisting of TIFF2025081550000039.tif26128. [Present Invention 1111] R 4 is A compound of any one of the present inventions 1001 to 1069 and 1089 to 1098 which is TIFF2025081550000040.tif24128. [Present Invention 1112] R 4 is as follows: A compound of any one of the present inventions 1001 to 1066, 1070, and 1089 to 1098 selected from the group consisting of TIFF2025081550000041.tif24138. [Present Invention 1113] R 4 is as follows: A compound of any one of 1001 - 1066, 1070, and 1089 - 1098 of the present invention, selected from the group consisting of TIFF2025081550000042.tif24128. [The present invention 1114] R 4 wherein R is C which may be substituted with 1 - 6 independently selected R a alkyl, a compound of any one of 1001 - 1065 of the present invention. 1~10 [The present invention 1115] R 4 wherein R is C which may be substituted with 1 - 6 independently selected R a alkyl, a compound of any one of 1001 - 1065 and 1114 of the present invention. 1~6 [The present invention 1116] R 4 wherein R is C which may be substituted with 1 - 2 independently selected R a alkyl, a compound of any one of 1001 - 1065 and 1114 - 1115 of the present invention. 1~6 [The present invention 1117] R a each occurrence of which is independently selected from the group consisting of -F; -OH; C 1~4 alkoxy; and C 1~4 haloalkoxy, a compound of any one of 1001 - 1065 and 1114 - 1116 of the present invention. [The present invention 1118] R a each occurrence of which is independently -OH, a compound of any one of 1001 - 1065 and 1114 - 1117 of the present invention. [The present invention 1119] R 4 is methyl, ethyl, selected from TIFF2025081550000043.tif14128, a compound of any one of 1001 - 1065 and 1114 - 1118 of the present invention. [The present invention 1120] R 4 is methyl and ​​​A compound selected from TIFF2025081550000044.tif and being any one of Compounds 1001 - 1065 and 1114 - 1118 of the present invention. [Compound 1121 of the present invention] R 4 is C which may be substituted with 1 - 6 (e.g., 1 - 3) independently selected R a and is optionally substituted with 2~10 (e.g., C 2~4 ) alkynyl (e.g., unsubstituted C such as TIFF2025081550000045.tif8128 2~4 alkynyl), being any one of Compounds 1001 - 1065 of the present invention. [Compound 1122 of the present invention] R 4 is C which may be substituted with 1 - 6 (e.g., 1 - 3) independently selected R a and is optionally substituted with 2~10 (e.g., C 2~4 ) alkenyl (e.g., unsubstituted C such as vinyl 2~4 alkenyl), being any one of Compounds 1001 - 1065 of the present invention. [Compound 1123 of the present invention] -L 4 is selected from the group consisting of -N(H)S(O) 2 -, C≡C, single bond, -C(O)N(H)-, -N(H)-, -N(R 4 )-, -N(R d )-, and -N(H)C(O)-; and R 4 is as follows: (i) C a alkyl which may be substituted with 1 - 2 R 1~6 ; and (ii) -(Y 3 ) p -Y 4 selected from the group consisting of, being any one of Compounds 1001 - 1053 of the present invention. [Compound 1124 of the present invention] -L 4 is -N(H)S(O) 2 -, single bond, -NH-, -N(R 4) selected from the group consisting of -NH- and -N(H)C(O)-; and R 4 is as follows: (i) C a alkyl optionally substituted with 1 to 2 R 1~6 ; and (ii) -(Y 3 ) p -Y 4 selected from the group consisting of, any compound of the present invention 1001 to 1053 and 1123. [Invention 1125] -L 4 is -N(H)S(O) 2 -,-N(H)S(O) 2 N(H)-,-N(H)S(O) 2 N(R d )-C≡C, single bond, -C(O)N(H)-, -N(H)-, -N(R 4 )-,-N(R d )- and -N(H)C(O)-; and R 4 is as follows: (i) C a alkyl optionally substituted with 1 to 2 R 1~6 ; (ii) -(Y 3 ) p -Y 4 ; and (iii) C a alkenyl or C 2~10 alkynyl each optionally substituted with 1 to 3 independently selected R 2~10 selected from the group consisting of, any compound of the present invention 1001 to 1053. from [Invention 1126] -L 4 is selected from the group consisting of -N(H)S(O) 2 -,-N(H)S(O) 2 N(H)-, and -N(H)S(O) 2 N(R d )-; and R 4 is as follows: (i) 1 to 2 R's a optionally substituted with 1~6 alkyl; (ii) -(Y 3 ) p -Y 4 ; and (iii) 1 to 3 independently selected R's a each optionally substituted with 2~10 alkenyl or C 2~10 alkynyl A compound according to any one of inventions 1001 - 1053 and 1125, selected from the group consisting of [Invention 1127] -L 4 is -N(H)S(O) 2 - of a compound according to any one of inventions 1123 - 1126. [Invention 1128] -L 4 is -N(H)S(O) 2 N(H)- or -N(H)S(O) 2 N(R d )- of a compound according to any one of inventions 1125 - 1126. [Invention 1129] -L 4 is a single bond of a compound according to any one of inventions 1123 - 1125. [Invention 1130] -L 4 is -NH- or -N(R 4 )- of a compound according to any one of inventions 1123 - 1125. [Invention 1131] -L 4 is -N(H)C(O)- of a compound according to any one of inventions 1123 - 1125. [Invention 1132] R 4 is C a alkyl optionally substituted with 1 to 2 R's 1~6 of a compound according to any one of inventions 1123 - 1131. [Invention 1133] R 4 is 1 to 3 independently selected R'sa C which may be each substituted with 2~10 alkenyl or C 2~10 The compound according to any one of the present inventions 1123 to 1131, which is alkynyl. [The present invention 1134] R 4 is C which may be substituted with 1 to 3 independently selected R a 2~10 (for example, C 2~5 ) alkynyl (for example unsubstituted C such as TIFF2025081550000046.tif8128 2~5 alkynyl), the compound of the present invention 1133. [The present invention 1135] R 4 is - (Y 3 ) p -Y 4 The compound according to any one of the present inventions 1123 to 1131. [The present invention 1136] Y 4 is C aryl which may be substituted with 1 to 4 R c 6~10 The compound of the present invention 1135. [The present invention 1137] Y 4 is phenyl which may be substituted with 1 to 2 (for example, 1) R c [The present invention 1138] Y 4 is C b which may be substituted with 1 to 4 R 3~6 (for example, C 3~4 or C 6 ) cycloalkyl, the compound of the present invention 1135. [The present invention 1139] Y 4 is C b cycloalkyl or C 3~4 cycloalkyl, each of which may be substituted with 1 to 2 R 6 (for example, R b may be -OH), the compound of the present invention 1138. [The present invention 1140]​​​ Y 4 is a heterocyclyl containing 4 to 6 ring atoms, 1 to 3 of which are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), and O, and one or more of the heterocyclyl ring carbon atoms may be substituted with 1 to 2 independently selected R b , a heterocyclyl which is the compound of the present invention 1135 [Present Invention 1141] Y 4 is a heterocyclyl containing 6 ring atoms, 1 to 3 of which are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), and O, and one or more of the heterocyclyl ring carbon atoms may be substituted with 1 to 2 independently selected R b , a heterocyclyl which is (for example, Y 4 may be tetrahydropyranyl, piperidinyl, or morpholinyl each optionally substituted with 1 to 2 independently selected R b ), the compound of the present invention 1140 [Present Invention 1142] Y 4 is a heterocyclyl containing 4 ring atoms, 1 to 3 of which are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), and O, and one or more of the heterocyclyl ring carbon atoms may be substituted with 1 to 2 independently selected R b , a heterocyclyl which is (for example, Y 4 may be oxetanyl; or Y 4 may be azetidinyl), the compound of the present invention 1140 [Present Invention 1143] Y 4 is A heteroaryl containing 6 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), and N(R d ), and one or more of the heteroaryl ring carbon atoms may be substituted with 1 to 4 independently selected R c , the heteroaryl is the compound of the present invention 1135. [The present invention 1144] Y 4 is pyridinyl (e.g., 2-pyridinyl, 3-pyridinyl, or 4-pyridinyl), pyrimidinyl (e.g., 2-pyrimidinyl or 5-pyrimidinyl), or pyrazinyl, each optionally substituted with 1 to 2 independently selected R c , the compound of the present invention 1143. [The present invention 1145] For any compound of the present invention 1135 to 1144, p is 0. [The present invention 1146] For any compound of the present invention 1135 to 1144, p is 1. [The present invention 1147] Y 3 is C 1~3 alkylene (e.g., CH 2 , CH 2 -CH 2 ), the compound of the present invention 1146. [The present invention 1148] R 3 is as follows: Selected from the group consisting of TIFF2025081550000047.tif63143, any compound of the present invention 1001 to 1043. [The present invention 1149] R 3 is as follows: Selected from the group consisting of TIFF2025081550000048.tif35128, the compound of the present invention 1148. [The present invention 1150] R 3 is as follows: A compound of any one of the compounds 1001 to 1043 of the present invention selected from the group consisting of TIFF2025081550000049.tif31128. [Invention 1151] R 3 is as follows: A compound of any one of the compounds 1001 to 1043 of the present invention selected from the group consisting of TIFF2025081550000050.tif27128. [Invention 1152] R 3 is as follows: A compound of any one of the compounds 1001 to 1043 of the present invention selected from the group consisting of TIFF2025081550000051.tif24128. [Invention 1153] R 3 is as follows: A compound of any one of the compounds 1001 to 1043 of the present invention selected from the group consisting of TIFF2025081550000052.tif22140. [Invention 1154] R 3 is as follows: A compound of any one of the compounds 1001 to 1043 of the present invention selected from the group consisting of TIFF2025081550000053.tif20128. [Invention 1155] R 3 is as follows: A compound of any one of the compounds 1001 to 1043 of the present invention selected from the group consisting of TIFF2025081550000054.tif19128. [Invention 1156] R 3 is as follows: A compound of any one of the compounds 1001 to 1043 of the present invention selected from the group consisting of TIFF2025081550000055.tif34140. [Invention 1157] R 3 is as follows: A compound of any one of the compounds 1001 to 1043 of the present invention selected from the group consisting of TIFF2025081550000056.tif42141. [Invention 1158] R 3 is as follows: Any compound of the present invention from 1001 to 1043 selected from the group consisting of TIFF2025081550000057.tif18128. [The present invention 1159] R 3 is as follows: Any compound of the present invention from 1001 to 1043 selected from the group consisting of TIFF2025081550000058.tif19134. [The present invention 1160] R 3 is as follows: Any compound of the present invention from 1001 to 1043 selected from the group consisting of TIFF2025081550000059.tif19148. [The present invention 1161] R 3 is as follows: Any compound of the present invention from 1001 to 1043 selected from the group consisting of TIFF2025081550000060.tif40150. [The present invention 1162] R 3 is as follows: Any compound of the present invention from 1001 to 1043 selected from the group consisting of TIFF2025081550000061.tif17128, NHMe, and NMe 2 from the group consisting of. [The present invention 1163] R 3 is as follows: Any compound of the present invention from 1001 to 1043 selected from the group consisting of TIFF2025081550000062.tif15128. [The present invention 1164] R 3 is as follows: Any compound of the present invention from 1001 to 1043 selected from the group consisting of TIFF2025081550000063.tif15128. [The present invention 1165] R 3 One occurrence of The compound of the present invention 1162 or 1163, which is TIFF2025081550000064.tif12128. [The present invention 1166] R 1 is -(Y 1 ) n -Y 2 ; and R 2 is C c aryl which may be substituted with 1 to 4 R 6~10 . The compound of the present invention 1001. [The present invention 1167] The compound of the present invention 1166, wherein n is 0. [The present invention 1168] X 1 , X 2 , X 3 , and X 4 Among them, 1 to 2 are N; and X 1 , X 2 , X 3 , and X 4 Among them, 2 to 3 are each independently selected CR 3 . [The present invention 1169] X 1 , X 2 , X 3 , and X 4 Among them, 1 is N; and the remaining X 1 , X 2 , X 3 , and X 4 Each of them is independently selected CR 3 ; or X 1 , X 2 , X 3 , and X 4 Among them, 2 are N; and the remaining X 1 , X 2 , X 3 , and X 4 Each of them is independently selected CR 3 . The compound of the present invention 1168. [The present invention 1170] X 2 and X 3 One to two of them are each independently selected CR 3 For example, X 2 and X 3 Both are each independently selected CR 3 A compound according to any one of the present inventions 1168 to 1169. [Present invention 1171] R 3 One occurrence of is -L 4 -R 4 and R 4 is -(Y 3 ) p -Y 4 or R 4 is C a alkyl which may be substituted with one to six independently selected R 1~10 A compound according to any one of the present inventions 1168 to 1170. [Present invention 1172] R 4 is (Y 3 ) p -Y 4 and p is 1, a compound according to the present invention 1171. [Present invention 1173] R 4 is (Y 3 ) p -Y 4 and p is 0, a compound according to the present invention 1171. [Present invention 1174] R 3 Each of the remaining occurrences of is independently selected from the group consisting of H and R c '(for example, each of the remaining occurrences of R 3 is H), a compound according to any one of the present inventions 1171 to 1173. [Present invention 1175] R 3 One occurrence of is -L 4 -R 4 and R 3 One occurrence of is R c' , for example halo, a compound according to any one of the present inventions 1171 to 1174. [The present invention 1176] R 3 One occurrence of which is R c' (such as Br or Cl, such as Cl); and each of the remaining occurrences of R 3 is H, a compound of any one of the present inventions 1166 - 1169. [The present invention 1177] Y 2 is as defined in any one of the present inventions 1014 - 1020 and 1026 - 1028; and each R c , if present, is independently as defined in any one of the present inventions 1021 - 1024, a compound of any one of the present inventions 1166 - 1176. [The present invention 1178] Y 2 is as defined in any one of the present inventions 1014 - 1018; and each R c , if present, is as defined in any one of the present inventions 1021 - 1023, a compound of any one of the present inventions 1166 - 1176. [The present invention 1179] Y 2 is as defined in any one of the present inventions 1016 - 1018; and each R c , if present, is as defined in any one of the present inventions 1021 - 1023, a compound of any one of the present inventions 1166 - 1176. [The present invention 1180] R 1 is TIFF2025081550000065.tif14128, for example, R 1 is TIFF2025081550000066.tif13128, a compound of any one of the present inventions 1166 - 1176. [The present invention 1181] R 2 is C c aryl which may be substituted with 1 - 4 R 6~10 , for example, phenyl which may be substituted with 1 - 4 R c or 1 - 2 R c or 2 R c ; and R cis, when present, a compound of any one of the present invention 1166 - 1180 as defined in any one of the present invention 1033 - 1035. [The present invention 1182] R 2 is phenyl which may be substituted with two Rs c , for example, R 2 is TIFF2025081550000067.tif17128; and R c is, when present, a compound of any one of the present invention 1166 - 1181 as defined in any one of the present invention 1033 - 1035. [The present invention 1183] R 2 is heteroaryl containing 5 - 10 (for example 6) ring atoms, 1 - 4 (for example 1 - 3) of which are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S (for example the group consisting of N, N(H), and N(R d )), and one or more of the heteroaryl ring carbon atoms may be substituted with 1 - 4 independently selected Rs c , heteroaryl , for example, R 2 is pyridinyl which may be substituted with 1 - 2 independently selected Rs c , or for example, R 2 is TIFF2025081550000068.tif17128; and R c is, when present, a compound of any one of the present invention 1166 - 1180 as defined in any one of the present invention 1040 - 1041. [The present invention 1184] R 2 is TIFF2025081550000069.tif17128, a compound of any one of the present invention 1166 - 1180. [The present invention 1185] -L 4 is as follows: ·-N(H)S(O)1~2 - or -N(R d )S(O) 1~2 (e.g., N(C 1~3 alkyl)S(O) 2 ), e.g., L 4 is -N(H)S(O) 2 -; · -N(H)C(O)- or -N(R d )C(O), e.g., L 4 is -N(H)C(O)-; · -C(O)NH- or -C(O)N(R d )-; · -N(H)-, -N(R d )-, or -N(R 4 )-; · single bond; · C≡C; · -O-; and · -N(H)S(O) 1~2 N(H)-, -N(R d )S(O) 1~2 N(H)-, -N(H)S(O) 1~2 N(R d )-, and -N(R d )S(O) 1~2 N(R d )-, e.g., L 4 is -N(H)S(O) 1~2 N(H)-(e.g., -N(H)S(O) 2 N(H)-), or L 4 is -N(H)S(O) 1~2 N(R d )-(e.g., -N(H)S(O) 2 N(R d )-(e.g., -N(H)S(O) 2 N(C 1~3 alkyl)-)) A compound according to any one of claims 1171 - 1184 of the present invention, selected from the group consisting of [Inventive item 1186] -L 4 is as follows: · -N(H)S(O) 1~2 - or -N(R d )S(O) 1~2 (e.g., N(C1~3 (alkyl)S(O) 2 )、for example, L 4 is -N(H)S(O) 2 -; · -N(H)C(O)- or -N(R d )C(O), for example, L 4 is -N(H)C(O)-; · -C(O)NH- or -C(O)N(R d )-; · -N(H)-, -N(R d )-, or -N(R 4 )-; · single bond; and · C≡C Any compound of the present invention from 1171 to 1184 selected from the group consisting of [The present invention 1187] -L 4 is as follows: · N(H)S(O) 2 -; · -N(H)C(O)-; and · -N(H)-, -N(R d )-, or -N(R 4 )- Any compound of the present invention from 1171 to 1184 selected from the group consisting of [The present invention 1188] -L 4 is as follows: -N(H)S(O) 1~2 - or -N(R d )S(O) 1~2 (for example N(C 1~3 alkyl)S(O) 2 )), for example, L 4 is -N(H)S(O) 2 -; and -N(H)S(O) 1~2 N(H)-, -N(R d )S(O) 1~2 N(H)-, -N(H)S(O) 1~2 N(R d )-, and -N(R d )S(O) 1~2 N(R d)-, for example, L 4 is -N(H)S(O) 1~2 N(H)-(for example -N(H)S(O) 2 N(H)-), or L 4 is -N(H)S(O) 1~2 N(R d )-(for example -N(H)S(O) 2 N(R d )-(for example -N(H)S(O) 2 N(C 1~3 alkyl)-)) A compound according to any one of the compounds of the present invention 1171 to 1184, selected from the group consisting of [The present invention 1189] -L 4 is -N(H)S(O) 2 -, a compound according to any one of the compounds of the present invention 1171 to 1188. [The present invention 1190] Y 4 is C c aryl which may be substituted with 1 to 4 R 6~10 s, for example phenyl which may be substituted with 1 to 2 (for example 1) R c s, or Y 4 is unsubstituted C 6~10 aryl, for example unsubstituted phenyl; and R c , when present, is as defined in any one of the present invention 1073 to 1075, a compound according to any one of the compounds of the present invention 1171 to 1189. [The present invention 1191] Y 4 is C c aryl which may be substituted with 1 to 4 R 6~10 s, for example phenyl which may be substituted with 1 to 4 R c s; and each occurrence of R c , when present, is independently, as follows: (vii) C 1~4 alkoxy; (viii) C 1~4 haloalkoxy; and (xiv) -C 1~4 thioalkoxy A compound according to any one of the compounds of the present invention from 1171 to 1189, selected from the group consisting of [The present invention 1192] Y 4 is as defined in any one of the present invention 1077, 1078, 1079, 1081, and 1082; and R b when present, is as defined in the present invention 1080, a compound according to any one of the compounds of the present invention from 1171 to 1189. [The present invention 1193] Y 4 is as defined in any one of the present invention 1077 to 1079; and R b when present, is as defined in the present invention 1080, a compound according to any one of the compounds of the present invention from 1171 to 1189. [The present invention 1194] Y 4 is as defined in any one of the present invention 1083 to 1085 and 1088; and R c when present, is as defined in any one of the present invention 1086 to 1087, a compound according to any one of the compounds of the present invention from 1171 to 1189. [The present invention 1195] Y 4 is as defined in any one of the present invention 1083 to 1085 and 1088, a compound according to any one of the compounds of the present invention from 1171 to 1189. [The present invention 1196] Y 4 is as defined in any one of the present invention 1089 to 1096; and R b when present, is as defined in any one of the present invention 1097 to 1098, a compound according to any one of the compounds of the present invention from 1171 to 1189. [The present invention 1197] Y 4 is as defined in any one of the present invention 1089 to 1092, 1094, and 1096; and R b when present, is as defined in the present invention 1098, a compound according to any one of the compounds of the present invention from 1171 to 1189. [The present invention 1198] R 4is a compound of any one of the present invention 1171-1189 selected from the group consisting of the structures of the present invention 1099-1113. [The present invention 1199] R 4 is a compound of any one of the present invention 1171-1189 selected from the group consisting of the structures of the present invention 1100, 1101, 1104-1105, 1107, 1109, 1111, and 1113. [The present invention 1200] ·R 4 is C alkyl which may be substituted with 1 to 6 independently selected Rs a ; or 1~10 ·R 4 is C alkyl which may be substituted with 1 to 6 independently selected Rs a 1~6 ; or ·R 4 is C alkyl which may be substituted with 1 to 2 independently selected Rs a 1~6 and, for example, R 4 is selected from the group consisting of methyl, ethyl, TIFF2025081550000070.tif14128 (for example methyl and TIFF2025081550000071.tif12128); or ·R 4 is C alkynyl (for example C alkynyl) which may be substituted with 1 to 6 (for example 1 to 3) independently selected Rs a 2~10 2~4 2~4 such as unsubstituted C alkynyl such as TIFF2025081550000072.tif8128); or ·R 4 is C alkenyl (for example C alkenyl) which may be substituted with 1 to 6 (for example 1 to 3) independently selected Rs a 2~10 2~4 2~4 such as unsubstituted C alkenyl such as vinyl); ​​​​​​​​​​Here, each R a , when present, is independently selected from the group consisting of -F; -OH; C 1~4 alkoxy; and C 1~4 haloalkoxy, for example, each occurrence of R a is independently -OH, a compound of any one of the present invention 1171 and 1174 - 1189. [the present invention 1201] ·R 4 is C a alkyl which may be substituted with 1 to 6 independently selected R 1~10 ; or ·R 4 is C a alkyl which may be substituted with 1 to 6 independently selected R 1~6 ; or ·R 4 is C a alkyl which may be substituted with 1 to 2 independently selected R 1~6 , for example methyl and TIFF2025081550000073.tif12128; here, each R a , when present, is independently selected from the group consisting of -OH etc., -F; -OH; C 1~4 alkoxy; and C 1~4 haloalkoxy, a compound of any one of the present invention 1171 and 1174 - 1189. [the present invention 1202] -L 4 is selected from the group consisting of -N(H)S(O) 2 -,-N(H)S(O) 2 N(H)-,-N(H)S(O) 2 N(R d )-、C≡C、single bond, -C(O)N(H)-、-N(H)-、-N(R 4 )-、-N(R d )-、and -N(H)C(O)-; and R 4 is as follows: (i) 1 to 2 R aC which may be replaced 1~6 alkyl; (ii) -(Y 3 ) p -Y 4 ; and (iii) C alkenyl or C alkynyl, each optionally substituted with 1 to 3 independently selected Rs a selected from the group consisting of, a compound of any one of 1171 to 1184 of the present invention. 2~10 2~10 4 alkynyl selected from the group consisting of, a compound of any one of 1171 to 1184 of the present invention. [Present Invention 1203] -L 4 is selected from the group consisting of -N(H)S(O)-, -N(H)S(O)N(H)-, and -N(H)S(O)N(R 2 -N(H)S(O) 2 N(H)-, and -N(H)S(O) 2 N(R d )); and R 4 is as follows: (i) C alkyl optionally substituted with 1 to 2 Rs a 1~6 3 alkyl; (ii) -(Y 3 ) p -Y 4 ; and (iii) C alkenyl or C alkynyl, each optionally substituted with 1 to 3 independently selected Rs a 2~10 2~10 3 3 alkynyl selected from the group consisting of, a compound of any one of 1171 to 1184 of the present invention. [Present Invention 1204] R 3 is selected from the group consisting of the structures of 1148 to 1165 of the present invention; or R 3 is selected from the group consisting of the structures of 1148 to 1149, 1151, 1153, 1155 to 1156, 1158, 1160, 1162, and 1165 of the present invention, a compound of any one of 1171 to 1189 of the present invention. [Present Invention 1205] X 2 and each of X 3 is independently selected CR3 and X 1 and X 4 A compound according to any one of the present invention 1166 - 1169, wherein each of X is N. [The present invention 1206] Each R 3 is independently selected from -L 4 -R 4 A compound according to the present invention 1205. [The present invention 1207] -L 4 -R 4 One occurrence of -R 4 is (i.e., one occurrence of L 4 is a bond), a compound according to the present invention 1206. [The present invention 1208] -L 4 The other occurrences of are as follows: · -N(H)S(O) 1~2 - or -N(R d )S(O) 1~2 (e.g., N(C 1~3 alkyl)S(O) 2 ), for example, L 4 is -N(H)S(O) 2 -; · -N(H)C(O)- or -N(R d )C(O), for example, L 4 is -N(H)C(O)-; · -C(O)NH- or -C(O)N(R d )-; · -N(H)-, -N(R d )-, or -N(R 4 )-; · A single bond; · C≡C; · -O-; and · -N(H)S(O) 1~2 N(H)-, -N(R d )S(O) 1~2 N(H)-, -N(H)S(O) 1~2 N(R d )-, and -N(R d )S(O) 1~2 N(R d )-, for example, L 4-N(H)S(O) 1~2 N(H)-(e.g., -N(H)S(O) 2 N(H)-), or L 4 is -N(H)S(O) 1~2 N(R d )-(e.g., -N(H)S(O) 2 N(R d )-(e.g., -N(H)S(O) 2 N(C 1~3 alkyl)-)) A compound according to any one of inventions 1205 - 1207, selected from the group consisting of [Invention 1209] -L 4 Other occurrences of are as follows: · -N(H)S(O) 1~2 - or -N(R d )S(O) 1~2 (e.g., N(C 1~3 alkyl)S(O) 2 ), e.g., L 4 is -N(H)S(O) 2 -; · -N(H)C(O)- or -N(R d )C(O), e.g., L 4 is -N(H)C(O)-; · -C(O)NH- or -C(O)N(R d )-; · -N(H)-, -N(R d )-, or -N(R 4 )-; · A single bond; and · C≡C A compound according to any one of inventions 1205 - 1207, selected from the group consisting of [Invention 1210] -L 4 Other occurrences of are as follows: · -N(H)S(O) 2 -; · -N(H)C(O)-; and · -N(H)-, -N(R d )-, or -N(R 4 )- Selected from the group consisting of, e.g., -L4 Other occurrences of 2 - are a compound of any one of 1205 - 1207 of the present invention. [1211 of the present invention] -L 4 Other occurrences of · -N(H)S(O) 1~2 - or -N(R d )S(O) 1~2 (e.g., N(C 1~3 alkyl)S(O) 2 )), for example, L 4 is -N(H)S(O) 2 -; and · -N(H)S(O) 1~2 N(H)-, -N(R d )S(O) 1~2 N(H)-, -N(H)S(O) 1~2 N(R d )-, and -N(R d )S(O) 1~2 N(R d )-, for example, L 4 is -N(H)S(O) 1~2 N(H)-(e.g., -N(H)S(O) 2 N(H)-), or L 4 is -N(H)S(O) 1~2 N(R d )-(e.g., -N(H)S(O) 2 N(R d )-(e.g., -N(H)S(O) 2 N(C 1~3 alkyl)-)) A compound of any one of 1205 - 1207 of the present invention, selected from the group consisting of. [1212 of the present invention] R 3 One occurrence of 4 -R 4 is (e.g., L 4 is N(H)S(O) 2 -); and the other occurrences of R 3 are R c '(e.g., halo, e.g., -Cl), a compound of 1205 of the present invention. [1213 of the present invention] Formula (I-a1-a): A compound of any one of Compounds 1001 to 1004 of the present invention, which is the compound of TIFF2025081550000074.tif38128 or a pharmaceutically acceptable salt thereof. [Invention 1214] Formula (I-a1-a1), (I-a1-a2), or (I-a1-a3): A compound of Invention 1213, which is the compound of TIFF2025081550000075.tif43128 or a pharmaceutically acceptable salt thereof. [Invention 1215] The compound of formula (I-a1-a) is of formula (I-a1-a5): A compound of Invention 1213, which is the compound of TIFF2025081550000076.tif38128 or a pharmaceutically acceptable salt thereof. [Invention 1216] R c' For the compound of Invention 1215, R is halo (e.g., -Cl). [Invention 1217] L 4 For the compounds of any one of Inventions 1215 to 1216, L is -NHS(O) 2 -. [Invention 1218] L 4 For the compounds of any one of Inventions 1215 to 1216, L is -N(H)S(O) 2 N(H)- or -N(H)S(O) 2 N(R d )-. [Invention 1219] The compound of formula (I-a1-a) is of formula (I-a1-a6): A compound of TIFF2025081550000077.tif38128 or a pharmaceutically acceptable salt thereof, and wherein each of L 4A and L 4B is independently selected L 4 ; and each of R 4A and R 4B is independently selected R 4 . The compound of the present invention 1213. [The present invention 1220] L 4B is a bond, the compound of the present invention 1219. [The present invention 1221] L 4A is -NHS(O) 2 -, the compound of any one of the present inventions 1219 to 1220. [The present invention 1222] L 4A is -N(H)S(O) 2 N(H)- or -N(H)S(O) 2 N(R d )-, the compound of any one of the present inventions 1219 to 1220. [The present invention 1223] Formula (I-a1-a7), (I-a1-a8), or (I-a1-a9): The compound of TIFF2025081550000078.tif47137, or a pharmaceutically acceptable salt thereof, wherein R d' is H or R d (for example, H or C 1~3 alkyl), The compound of the present invention 1213. [The present invention 1224] Formula (I-a1-b): The compound of TIFF2025081550000079.tif34128, or a pharmaceutically acceptable salt thereof, any one of the present inventions 1001 to 1004. [The present invention 1225] Formula (I-a1-b1) or formula (I-a1-b2): TIFF2025081550000080.tif38128 (for example, L 4 is N(H)SO 2 , -N(H)-, or NHC(O)) The compound of, or a pharmaceutically acceptable salt thereof, the present invention 1224. [The present invention 1226] Formula (I-a2-a): The compound of TIFF2025081550000081.tif34128, or a pharmaceutically acceptable salt thereof, which is any one of the compounds of the present invention 1001 to 1003 and 1005. [The present invention 1227] Formula (I-a2-a1): The compound of TIFF2025081550000082.tif43128, or a pharmaceutically acceptable salt thereof, which is the compound of the present invention 1226. [The present invention 1228] Formula (I-b1-a): The compound of TIFF2025081550000083.tif34128, or a pharmaceutically acceptable salt thereof, which is any one of the compounds of the present invention 1001 and 1006 to 1007. [The present invention 1229] Formula (I-b1-a1): The compound of TIFF2025081550000084.tif43128, or a pharmaceutically acceptable salt thereof, which is the compound of the present invention 1228. [The present invention 1230] Formula (I-b1-a3): The compound of TIFF2025081550000085.tif51128, or a pharmaceutically acceptable salt thereof, wherein R d' is H or R d (for example, H or C 1~3 alkyl), which is the compound of the present invention 1228. [The present invention 1231] Formula (I-c1-a): The compound of TIFF2025081550000086.tif34128, or a pharmaceutically acceptable salt thereof, which is any one of the compounds of the present invention 1001 and 1008 to 1009. [The present invention 1232] Formula (I-c1-a1): The compound of TIFF2025081550000087.tif43128, or a pharmaceutically acceptable salt thereof, which is the compound of the present invention 1231. [The present invention 1233] Formula (I-d1-a): The compound of TIFF2025081550000088, or a pharmaceutically acceptable salt thereof, which is any one of Compounds 1001 and 1008 - 1009 of the present invention. [Invention 1234] Formula (I - d1 - a1): The compound of TIFF2025081550000089, or a pharmaceutically acceptable salt thereof, which is the compound of Invention 1233. [Invention 1235] R 4 is as follows: (i) C a alkyl which may be substituted with 1 to 6 independently selected R 1~10 ; (ii) -(Y 3 ) p -Y 4 ; and (iii) C a alkenyl or C 2~10 alkynyl each of which may be substituted with 1 to 3 independently selected R 2~10 ; A compound selected from the group consisting of any one of Compounds 1213 - 1234 of the present invention. [Invention 1236] R 4 is -(Y 3 ) p -Y 4 ; A compound selected from any one of Compounds 1213 - 1235 of the present invention. [Invention 1237] Y 4 is C c aryl which may be substituted with 1 to 4 R 6~10 , for example, phenyl which may be substituted with 1 to 2 (for example, 1) R c ; or Y 4 is unsubstituted C 6~10 aryl, for example, unsubstituted phenyl; and R c , if present, is as defined in any one of Inventions 1073 - 1075; A compound selected from any one of Compounds 1205 - 1236 of the present invention. [Invention 1238] Y4 is C which may be substituted with 1 to 4 R c aryl, for example phenyl which may be substituted with 1 to 4 R 6~10 ; and each occurrence of R, when present, is independently selected from the following: c ; and each occurrence of R, when present, is independently selected from the following: c the compounds of any one of 1205 - 1236 of the present invention selected from the group consisting of: (vii) C 1~4 alkoxy; (viii) C 1~4 haloalkoxy; and (xiv) -C 1~4 thioalkoxy Any compound of the present invention from 1205 to 1236, wherein Y is as defined in any one of 1077, 1078, 1079, 1081, and 1082 of the present invention; and R, when present, is as defined in 1080 of the present invention. [Present Invention 1239] Y 4 is as defined in any one of 1077, 1078, 1079, 1081, and 1082 of the present invention; and R, when present, is as defined in 1080 of the present invention, any compound of the present invention from 1205 to 1236. b Any compound of the present invention from 1205 to 1236, wherein Y is as defined in any one of 1077 - 1079 of the present invention; and R, when present, is as defined in 1080 of the present invention. [Present Invention 1240] Y 4 is as defined in any one of 1077 - 1079 of the present invention; and R, when present, is as defined in 1080 of the present invention, any compound of the present invention from 1205 to 1236. b Any compound of the present invention from 1205 to 1236, wherein Y is as defined in any one of 1083 - 1085 and 1088 of the present invention; and R, when present, is as defined in any one of 1086 - 1087 of the present invention. [Present Invention 1241] Y 4 is as defined in any one of 1083 - 1085 and 1088 of the present invention; and R, when present, is as defined in any one of 1086 - 1087 of the present invention, any compound of the present invention from 1205 to 1236. c Any compound of the present invention from 1205 to 1236, wherein Y is as defined in any one of 1083 - 1085 and 1088 of the present invention. [Present Invention 1242] Y 4 is as defined in any one of 1083 - 1085 and 1088 of the present invention; and R, when present, is as defined in any one of 1086 - 1087 of the present invention, any compound of the present invention from 1205 to 1236. [Present Invention 1243] Y 4 is as defined in any one of 1089 - 1096 of the present invention; and R, when present, is as defined in any one of 1086 - 1087 of the present invention, any compound of the present invention from 1205 to 1236. bis, when present, a compound of any one of the present invention 1205-1236 as defined in any one of the present invention 1097-1098. [The present invention 1244] Y 4 is as defined in any one of the present invention 1089-1092, 1094, and 1096; and R b is, when present, a compound of any one of the present invention 1205-1236 as defined in the present invention 1098. [The present invention 1245] a compound of any one of the present invention 1235-1244, where p is 0. [The present invention 1246] a compound of any one of the present invention 1235-1244, where p is 1. [The present invention 1247] Y 3 is C 1~3 alkylene, for example CH 2 or CH 2 -CH 2 is a compound of the present invention 1244. [The present invention 1248] R 4 is a compound of any one of the present invention 1205-1236, selected from the group consisting of the structures of the present invention 1099-1113. [The present invention 1249] Each R 4 is a compound of any one of the present invention 1205-1236, selected from the group consisting of the structures of the present invention 1100, 1101, 1104-1105, 1107, 1109, 1111, and 1113. [The present invention 1250] ·R 4 is C a alkyl which may be substituted with 1 to 6 independently selected R 1~10 ; or ·R 4 is C a alkyl which may be substituted with 1 to 6 independently selected R 1~6 ; or ·R 4 is C a alkyl which may be substituted with 1 to 2 independently selected RC which may be replaced 1~6 is alkyl, for example, R 4 is methyl, ethyl, TIFF2025081550000090.tif14128 (for example, methyl and TIFF2025081550000091.tif12128) and is selected from the group consisting of; or ·R 4 is C which may be independently substituted with 1 to 6 (for example, 1 to 3) R a which may be replaced 2~10 alkynyl (for example, C 2~4 alkynyl) (for example TIFF2025081550000092.tif8128 such as unsubstituted C 2~4 alkynyl); or ·R 4 is C which may be independently substituted with 1 to 6 (for example, 1 to 3) R a which may be replaced 2~10 alkenyl (for example, C 2~4 alkenyl) (for example, unsubstituted C 2~4 alkenyl such as vinyl); wherein each R a , when present, is independently selected from the group consisting of -F; -OH; C 1~4 alkoxy; and C 1~4 haloalkoxy, for example, each occurrence of R a is independently -OH, any compound of the present invention from 1205 to 1235. [Invention 1251] ·R 4 is C which may be independently substituted with 1 to 6 R a which may be replaced 1~10 alkyl; or ·R 4 is C which may be independently substituted with 1 to 6 R a which may be replaced 1~6 alkyl; or ·R 4 is C which may be independently substituted with 1 to 2 R a which may be replaced1~6 Alkyl, such as methyl and is TIFF2025081550000093.tif12128; where each R a , when present, is independently selected from the group consisting of -F; -OH; C 1~4 alkoxy; and C 1~4 haloalkoxy, any compound of the present invention from 1205 to 1235. [The present invention 1252] R 1 is -(Y 1 ) n -Y 2 is any compound of the present invention from 1205 to 1251. [The present invention 1253] Y 2 is as defined in any of the present invention 1014 to 1020; and each R c , when present, is independently as defined in any of the present invention 1021 to 1024, any compound of the present invention from 1205 to 1252. [The present invention 1254] Y 2 is as defined in any of the present invention 1014 to 1018 and 1026; and each R c , when present, is as defined in any of the present invention 1021 to 1023, any compound of the present invention from 1205 to 1253. [The present invention 1255] Y 2 is as defined in any of the present invention 1016 to 1018; and each R c , when present, is as defined in any of the present invention 1021 to 1023, any compound of the present invention from 1205 to 1252. [The present invention 1256] R 1 is TIFF2025081550000094.tif14128, for example is TIFF2025081550000095.tif13128, any compound of the present invention from 1205 to 1252. [The present invention 1257] A compound according to any one of the present inventions 1250 to 1256, wherein n is 0. [The present invention 1258] R 2 is C which may be substituted with 1 to 4 R c aryl, for example, 1 to 4 R 6~10 or 1 to 2 R c or 2 R c substituted phenyl; and R c when present, is as defined in any one of the present inventions 1033 to 1035, a compound according to any one of the present inventions 1205 to 1257. c A compound according to any one of the present inventions 1205 to 1257, wherein R [The present invention 1259] R 2 is phenyl which may be substituted with 2 R c , for example, R 2 is TIFF2025081550000096.tif17128; and R c when present, is as defined in any one of the present inventions 1033 to 1035, a compound according to any one of the present inventions 1205 to 1257. [The present invention 1260] R 2 is heteroaryl containing 5 to 10 (for example, 6) ring atoms, 1 to 4 (for example, 1 to 3) of which are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S (for example, the group consisting of N, N(H), N(R d ), and O), and one or more of the heteroaryl ring carbon atoms may be substituted with 1 to 4 independently selected R c , heteroaryl , for example, R 2 is pyridinyl which may be substituted with 1 to 2 independently selected R c , or for example, R 2 is TIFF2025081550000097.tif17128; and Rc a compound of any one of the present invention 1205 - 1257, which, if present, is as defined in any one of the present invention 1040 - 1041. [The present invention 1261] R 2 is a compound of any one of the present invention 1205 - 1257, which is TIFF2025081550000098.tif17128. [The present invention 1262] R 1 is -(Y 1 ) n -Y 2 ; and R 2 is C c aryl which may be substituted with 1 - 4 R 6~10 s. a compound of any one of the present invention 1213 - 1251. [The present invention 1263] a compound of the present invention 1262, wherein n is 0. [The present invention 1264] Y 2 is a heteroaryl containing 6 ring atoms, wherein 1 - 2 ring atoms are N, and one or more of the heteroaryl ring carbon atoms may be substituted with 1 - 4 independently selected R c s, the heteroaryl being a compound of any one of the present invention 1262 - 1263. [The present invention 1265] Y 2 is pyridyl (e.g., 2 - pyridyl or 6 - pyridyl) in which one or more of the ring carbon atoms may be substituted with 1 - 4 (e.g., 1) independently selected R c s, the being a compound of any one of the present invention 1262 - 1264. [The present invention 1266] R c each occurrence of which is independently selected C 1~4 alkoxy (e.g., -OCH 3 , -OCH 2 CH 3A compound of any one of the present inventions 1262 to 1265, which is as follows. [The present invention 1267] R 1 is A compound of any one of the present inventions 1262 to 1266, which is TIFF2025081550000099.tif13128. [The present invention 1268] R 2 is phenyl which may be substituted with 1 to 4 Rs c A compound of any one of the present inventions 1262 to 1267. [The present invention 1269] R 2 is phenyl which may be substituted with 2 Rs c A compound of any one of the present inventions 1262 to 1268. [The present invention 1270] R 2 is A compound of the present invention 1269, which is TIFF2025081550000100.tif16128. [The present invention 1271] R 1 is TIFF2025081550000101.tif13128; and R 2 is TIFF2025081550000102.tif16128. A compound of any one of the present inventions 1205 to 1251. [The present invention 1272] Formula (I-a1-a4): A compound of any one of the present inventions 1213, 1235 to 1251, and 1271, which is a compound of TIFF2025081550000103.tif50128. [The present invention 1273] R 3 is H. A compound of the present invention 1272. [The present invention 1274] R 3 is R c' , for example, halo (e.g., Cl). A compound of the present invention 1272. [The present invention 1275] Formula (I-b1-a2): The compound of TIFF2025081550000104.tif52128, any compound of the present invention 1228, 1235 - 1251, and 1271. [The present invention 1276] L 4 is NHS(O) 2 Any compound of the present invention 1272 - 1275. [The present invention 1277] The following table: The compound in TIFF2025081550000105.tif72153 TIFF2025081550000106.tif205153 TIFF2025081550000107.tif204153 TIFF2025081550000108.tif198153 TIFF2025081550000109.tif208153 TIFF2025081550000110.tif215153 TIFF2025081550000111.tif191153 TIFF2025081550000112.tif200153 TIFF2025081550000113.tif189153 TIFF2025081550000114.tif213153 TIFF2025081550000115.tif204153 TIFF2025081550000116.tif210153 TIFF2025081550000117.tif211153 TIFF2025081550000118.tif214153 TIFF2025081550000119.tif213153 TIFF2025081550000120.tif212153 TIFF2025081550000121.tif209153 TIFF2025081550000122.tif203153 TIFF2025081550000123.tif213153 TIFF2025081550000124.tif219153 TIFF2025081550000125.tif199153 TIFF2025081550000126.tif194153 TIFF2025081550000127.tif185153 TIFF2025081550000128.tif102153, and the compound of the present invention 1001 selected from the group consisting of its pharmaceutically acceptable salts. [Invention 1278] A pharmaceutical composition comprising a compound or salt according to any one of Inventions 1001 to 1277 and one or more pharmaceutically acceptable excipients. [Invention 1279] A method for modulating APJ receptor activity, the method comprising contacting an APJ receptor with a compound according to any one of Inventions 1001 to 1277. [Invention 1280] The method of Invention 1279, wherein said modulating comprises stimulating the APJ receptor. [Invention 1281] The method of Invention 1279 or 1280, which is performed in vitro. [Invention 1282] The method of Invention 1279 or 1280, which is performed in vivo. [Invention 1283] A method for modulating (e.g., decreasing) pulmonary vascular resistance in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of Inventions 1001 to 1277. [Invention 1284] A method for modulating (e.g., decreasing) right ventricular afterload in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of Inventions 1001 to 1277. [Invention 1285] A method for modulating (e.g., decreasing) mean pulmonary artery pressure in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of Inventions 1001 to 1277. [Invention 1286] The method of Invention 1285, wherein the subject exhibits a mean pulmonary artery pressure of more than 25 mmHg. [Invention 1287] A method for reducing the risk of right ventricular failure in a subject in need thereof, the method comprising administering to the subject an effective amount of any one of Compounds 1001 to 1277 of the present invention. [Compound 1288 of the present invention] A method for treating a disease, disorder, or condition in which suppression or deficiency of APJ receptor signaling or downregulation of endogenous apelin contributes to the pathophysiology and / or symptoms and / or progression of the disease, disorder, or condition, the method comprising administering to a subject in need thereof an effective amount of any one of Compounds 1001 to 1277 of the present invention. [Compound 1289 of the present invention] The method of Compound 1288 of the present invention, wherein the disease, disorder, or condition is pulmonary arterial hypertension ("PAH"). [Compound 1290 of the present invention] The method of Compound 1289 of the present invention, wherein the PAH is idiopathic. [Compound 1291 of the present invention] The method of Compound 1289 of the present invention, wherein the PAH is hereditary PAH, toxic or drug-induced PAH, or associated with one or more of the following: Congenital heart disease, connective tissue disorders (e.g., scleroderma, systemic lupus erythematosus, systemic sclerosis, Hashimoto's thyroiditis, Sjogren's syndrome, and antiphospholipid antibody syndrome), portal hypertension, BMPR2 mutations, schistosomiasis, and HIV infection The method of Compound 1289 of the present invention, wherein the PAH is associated with one or more of the above. [Compound 1292 of the present invention] The method of Compound 1288 of the present invention, wherein the disease, disorder, or condition is fibrosis. [Compound 1293 of the present invention] The method of Compound 1292 of the present invention, wherein the fibrosis is associated with an organ or tissue selected from the group consisting of lung, liver, heart, mediastinum, bone marrow, retroperitoneum, skin, intestine, joint, genitalia, and combinations thereof. [Compound 1294 of the present invention] The methods of Compounds 1288 and 1292 of the present invention, wherein the disease, disorder, or condition is idiopathic pulmonary fibrosis (IPF). [Compound 1295 of the present invention] The method of Compound 1288 of the present invention, wherein the disease, disorder, or condition is a connective tissue disorder. [The present invention 1296] The method of the present invention 1295, wherein the connective tissue disorder is selected from the group consisting of dermatomyositis, systemic lupus erythematosus, systemic sclerosis, Hashimoto's thyroiditis, Sjogren's syndrome, and antiphospholipid antibody syndrome. [The present invention 1297] Any method of the present invention 1288 and 1295-1296, wherein the disease, disorder, or condition is systemic sclerosis. [The present invention 1298] Any method of the present invention 1279-1297, further comprising the step of identifying a subject. [The present invention 1299] Said identifying comprises determining, in the subject, one or more of the following parameters: Leukotriene B4 level, pulmonary vascular resistance, pulmonary artery pressure, cardiac index, pulmonary capillary wedge pressure, right atrial pressure, 6-minute walk distance, brain natriuretic peptide level, atrial natriuretic peptide level, and lung diffusing capacity The method of the present invention 1298, comprising determining the levels of. [The present invention 1300] Any method of the present invention 1279-1299, wherein the subject is human. [The present invention 1301] Any method of the present invention 1279-1300, further comprising the step of administering one or more additional therapeutic agents. [The present invention 1302] Any method of the present invention 1279-1301, further comprising treating one or more diseases, disorders, or conditions that are secondary or co-existing conditions of PAH. Details of one or more aspects of the present invention are described in the following description and the accompanying appendices, which are expressly considered to be part of the present disclosure. Other features and advantages will be apparent from the claims.

Modes for Carrying Out the Invention

[0081] Detailed Description The present disclosure features chemical entities (e.g., compounds, or pharmaceutically acceptable salts and / or hydrates and / or prodrugs thereof) that modulate (e.g., stimulate) the apelin receptor (also referred to herein as the APJ receptor; gene symbol “APLNR”). The present disclosure also features compositions containing the same, as well as other methods of using and making the same. For example, the chemical entity is useful for treating a subject (e.g., a human) having a disease, disorder, or condition in which a decrease in APJ receptor activity (e.g., suppression or deficiency of APJ receptor signaling; e.g., suppression or deficiency of apelin-APJ receptor signaling) or downregulation of endogenous apelin contributes to the pathophysiology and / or symptoms and / or progression of the disease, disorder, or condition. Non-limiting examples of such diseases, disorders, or conditions include (i) cardiovascular diseases; (ii) metabolic disorders; (iii) diseases, disorders, and conditions associated with vasculopathies; and (iv) organ failure; (v) diseases, disorders, and conditions associated with infections (e.g., microbial infections); and (vi) diseases, disorders, or conditions that are sequelae or comorbidities associated with any of the foregoing or any disclosed herein. More specific non-limiting examples of such diseases, disorders, or conditions include pulmonary hypertension (e.g., PAH); heart failure; type II diabetes; renal failure; sepsis; and systemic hypertension.

[0082] Compounds of formula (I) In one aspect, the present disclosure provides a compound of formula (I): TIFF2025081550000129.tif30128, or a pharmaceutically acceptable salt thereof, wherein A 1 is CH or N; X 1 , X 2 , X 3 , and X 4 are each independently selected from the group consisting of N and CR 3 ; R 1 is as follows: (i) -(Y 1 )n -Y 2 、where ·n is 0 or 1; ·Y 1 is C alkylene which may be substituted with 1 to 6 Rs; and a is C alkylene which may be substituted with 1 to 6 Rs; and 1~6 ·Y is as follows: 2 is as follows: (a) C cycloalkyl which may be substituted with 1 to 4 Rs; b is C cycloalkyl which may be substituted with 1 to 4 Rs; 3~10 cycloalkyl; (b) C aryl which may be substituted with 1 to 4 Rs; c is C aryl which may be substituted with 1 to 4 Rs; 6~10 aryl; (c) heteroaryl containing 5 to 10 ring atoms, where 1 to 4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S, and one or more of the heteroaryl ring carbon atoms may be substituted with 1 to 4 independently selected Rs, heteroaryl; or c is C alkylene which may be substituted with 1 to 4 Rs; (d) heterocyclyl containing 3 to 10 ring atoms, where 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), and O, and one or more of the heterocyclyl ring carbon atoms may be substituted with 1 to 4 independently selected Rs, heterocyclyl; b is C alkylene which may be substituted with 1 to 4 Rs; alternatively (ii) -Z 1 -Z 2 -Z 3 、where ·Z 1 is C alkylene which may be substituted with 1 to 4 Rs; a is C alkylene which may be substituted with 1 to 4 Rs; 1~3 alkylene; ·Z 2 is -N(H)-, -N(R d ), -O-, or -S-; and ·Z 3 is C alkyl which may be substituted with 1 to 4 Rs; a is C alkyl which may be substituted with 1 to 4 Rs; 2~7 alkyl; Alternatively (iii) C optionally substituted with 1 to 6 independently selected R a alkyl; 3~10 alkyl; Alternatively (iv) -Z 4 -Z 5 -Z 6 -Y 2 , where ·Z 4 is C alkylene optionally substituted with 1 to 4 R a alkyl; 1~3 and is alkylene; ·Z 5 is -N(H)-, -N(R d ), -O-, or -S-; ·Z 6 is C alkylene optionally substituted with 1 to 4 R a alkyl; and 1~4 is alkylene; and ·Y 2 is as defined above and is; R 2 is as follows: (i) C aryl optionally further substituted with 1 to 4 R c alkyl; 6~10 aryl; (ii) heteroaryl containing 5 to 10 ring atoms, where 1 to 4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S, and one or more of the heteroaryl ring carbon atoms are optionally substituted with 1 to 4 independently selected R c alkyl; heteroaryl; (iii) C cycloalkyl optionally substituted with 1 to 4 R b alkyl; 3~10 cycloalkyl; (iv) heterocyclyl containing 3 to 10 ring atoms, where 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), and O, and one or more of the heterocyclyl ring carbon atoms are optionally substituted with 1 to 4 independently selected R bheterocyclyl, which may be replaced; or (v) C alkyl which may be independently substituted with 1 to 6 selected R a ; 1~10 alkyl ; R 3 each occurrence of which is independently selected from the group consisting of -L 4 -R 4 , H, and R c '; L 4 each occurrence of which is independently one of the following: (i) single bond; (ii) N(H), N(R d ), or N(R 4 ); (iii) -N(H)S(O) 1~2 - or -N(R d )S(O) 1~2 -; (iv) -S(O) 1~2 N(H)- or -S(O) 1~2 N(R d ); (v) -O-; (vi) -S(O) 0~2 -; (vii) -C(O)NH- or -C(O)N(R d ); (viii) -N(H)C(O)- or -N(R d )C(O)-; (ix) -C≡C; (x) -N(H)S(O)(=NH)-, -N(R d )S(O)(=NH), -N(H)S(O)(=NR d ), or -N(R d )S(O)(=NR d ); (xi) -S(O)(=NH)NH-, -S(O)(=NR d )NH-, -S(O)(=NH)NR d -, or -S(O)(=NR d )NR d -; (xii) -S(O)(=NH)- or -S(O)(=NRd ); and (xiii) -N(H)S(O) 1~2 N(H)-, -N(R d )S(O) 1~2 N(H)-, -N(H)S(O) 1~2 N(R d )-, or -N(R d )S(O) 1~2 N(R d )- selected from the group consisting of; R 4 each occurrence of which is independently, the following: (i) -(Y 3 ) p -Y 4 where ·p is 0 or 1; ·Y 3 is C a alkylene or C 1~6 alkenylene which may each be substituted with 1 to 6 R 1~6 ; and ·Y 4 is the following: (a) C b cycloalkyl which may be substituted with 1 to 4 R 3~6 ; (b) C c aryl which may be substituted with 1 to 4 R 6~10 ; (c) heteroaryl containing 5 to 10 ring atoms, 1 to 4 of which are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S, and one or more of the heteroaryl ring carbon atoms may be substituted with 1 to 4 independently selected R c ; or (d) heterocyclyl containing 3 to 10 ring atoms, 1 to 3 of which are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), and O, and one or more of the heterocyclyl ring carbon atoms may be substituted with 1 to 4 independently selected R bheterocyclyl, which may be replaced; or (ii) C alkyl, C alkenyl, or C alkynyl, each of which may be replaced by 1 to 6 independently selected R; a alkyl, C alkenyl, or C alkynyl, each of which may be replaced by 1 to 6 independently selected R; 1~10 alkyl, C alkenyl, or C alkynyl 1~10 alkyl, C alkenyl, or C alkynyl 1~10 alkynyl ; R a each occurrence of which is independently selected from the group consisting of -OH; -F; -Cl; -Br; -NRR; C alkoxy; C haloalkoxy; -C(=O)O(C alkyl); -C(=O)(C alkyl); -C(=O)OH; -CON(R')(R''); -S(O)(NR'R''); -S(O)(C alkyl); cyano; and C cycloalkyl optionally substituted with 1 to 4 independently selected C alkyl; e R f ; 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) 1~2 (C 1~4 alkyl); cyano; and C cycloalkyl optionally substituted with 1 to 4 independently selected C alkyl; 1~4 alkyl, C alkenyl, or C alkynyl, each of which may be replaced by 1 to 6 independently selected R; 3~6 ; R b each occurrence of which is independently selected from the group consisting of C alkyl; C haloalkyl; -OH; oxo; -F; -Cl; -Br; -NRR; C alkoxy; C haloalkoxy; -C(=O)(C alkyl); -C(=O)O(C alkyl); -C(=O)OH; -C(=O)N(R')(R''); -S(O)(NR'R''); -S(O)(C alkyl); cyano; and C cycloalkyl optionally substituted with 1 to 4 independently selected C alkyl; 1~6 alkyl; C 1~4 haloalkyl; -OH; oxo; -F; -Cl; -Br; -NR e R f ; C 1~4 alkoxy; C 1~4 haloalkoxy; -C(=O)(C 1~4 alkyl); -C(=O)O(C 1~4 alkyl); -C(=O)OH; -C(=O)N(R')(R''); -S(O) 1~2 (NR'R''); -S(O) 1~2 (C 1~4 alkyl); cyano; and C cycloalkyl optionally substituted with 1 to 4 independently selected C alkyl; 1~4 alkyl, C alkenyl, or C alkynyl, each of which may be replaced by 1 to 6 independently selected R; 3~6 ; R c each occurrence of which is independently selected from the following: (i) halo; (ii) cyano; (iii) C 1~6 alkyl; (iv) C 2~6 alkenyl; (v) C 2~6 alkynyl; (vi) C 1~4 haloalkyl; (vii) C 1~4 alkoxy; (viii) C 1~4 haloalkoxy; (ix) one to four independently selected C 1~4 alkyl optionally substituted with -(C 0~3 alkylene)-C 3~6 cycloalkyl; (x) -S(O) 1~2 (C 1~4 alkyl); (xi) -NR e R f ; (xii) -OH; (xiii) -S(O) 1~2 (NR'R''); (xiv) -C 1~4 thioalkoxy; (xv) -NO 2 ; (xvi) -C(=O)(C 1~4 alkyl); (xvii) -C(=O)O(C 1~4 alkyl); (xviii) -C(=O)OH, (xix) -C(=O)N(R')(R''), and (xx) C 3~6 cycloalkoxy selected from the group consisting of; Each occurrence of R c ' is independently, as follows: (i) halo; (ii) cyano; (iii) -OH; (iv) -NO 2 ; (v) -C(=O)(C 1~4 alkyl); (vi) -C(=O)O(C 1~4 alkyl); (vii) -C(=O)OH; and (viii) -NH 2 selected from the group consisting of; R d is 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 alkoxy selected from the group consisting of; R e and R f each occurrence of is independently 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 alkoxy selected from the group consisting of, or R e and R f together with the nitrogen atom to which each is attached form a ring containing 3 to 8 ring atoms, the ring having (a) 1 to 7 ring carbon atoms each substituted with 1 to 2 substituents independently selected from H and C 1~3 alkyl; and (b) 0 to 3 ring heteroatoms (other than the nitrogen atoms bonded to R' and R'') each independently selected from the group consisting of N(R d ), O, and S; each occurrence of R' and R'' is independently H and C 1~4Selected from the group consisting of alkyl, or R' and R'' together with the nitrogen atom to which each is attached form a ring containing 3 to 8 ring atoms, and the ring is (a) H and C 1~3 1 to 7 ring carbon atoms each substituted with 1 to 2 substituents independently selected from alkyl; and (b) 0 to 3 ring heteroatoms (other than the nitrogen atoms to which R' and R'' are attached) each independently selected from the group consisting of N(R d ), O, and S.

[0083] In some embodiments, the present disclosure features a compound of formula (I): TIFF2025081550000130.tif30128, or a pharmaceutically acceptable salt thereof, wherein, A 1 is CH or N; X 1 , X 2 , X 3 , and X 4 are each independently selected from the group consisting of N and CR 3 (e.g., X 1 and X 4 are each independently CH or N; X 2 and X 3 are each independently CR 3 or N), provided that 1 to 3 of X 1 , X 2 , X 3 , and X 4 are N; R 1 is as follows: (i) -(Y 1 ) n -Y 2 , where ·n is 0 or 1; ·Y 1 is C a alkylene which may be substituted with 1 to 6 R 1~6 ; and ·Y 2 is as follows: (a) 1 to 4 Rb C which may be substituted 3~10 Cycloalkyl; (b) C which may be substituted with 1 to 4 R c C which may be substituted 6~10 Aryl; (c) Heteroaryl containing 5 to 10 ring atoms, 1 to 4 of which are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S, and one or more of the heteroaryl ring carbon atoms are 1 to 4 independently selected R c substituted heteroaryl; or (d) Heterocyclyl containing 3 to 10 ring atoms, 1 to 3 of which are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), and O, and one or more of the heterocyclyl ring carbon atoms are 1 to 4 independently selected R b substituted heterocyclyl; or (ii) -Z 1 -Z 2 -Z 3 where ·Z 1 is C alkylene which may be substituted with 1 to 4 R a C which may be substituted 1~3 is alkylene; ·Z 2 is -N(H)-, -N(R d ), -O-, or -S-; and ·Z 3 is C alkyl which may be substituted with 1 to 4 R a C which may be substituted 2~7 is alkyl; or (iii) C alkyl which may be substituted with 1 to 6 independently selected R a C which may be substituted 3~10 is alkyl; or (iv) -Z 4 -Z 5 -Z 6 -Y 2 where ·Z 4 is C alkylene which may be substituted with 1 to 4 R a ; 1~3 ·Z is -N(H)-, -N(R 5 )-, -O-, or -S-; d and ·Z 6 is C alkylene which may be substituted with 1 to 4 R a ; and 1~4 ·Y is as defined above 2 ; R is as follows: 2 (i) C aryl which may be further substituted with 1 to 4 R c ; 6~10 (ii) heteroaryl containing 5 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S, and one or more of the heteroaryl ring carbon atoms may be substituted with 1 to 4 independently selected R c ; (iii) C cycloalkyl which may be substituted with 1 to 4 R b ; 3~10 (iv) heterocyclyl containing 3 to 10 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), and O, and one or more of the heterocyclyl ring carbon atoms may be substituted with 1 to 4 independently selected R b ; or (v) C alkyl which may be substituted with 1 to 6 independently selected R a ; 1~10 and each occurrence of R 3 is independently, -L 4 -R 4 , H, and R c ​​​​selected from the group consisting of; L 4 each occurrence of is independently, as follows: (i) a single bond; (ii) N(H), N(R d ), or N(R 4 ); (iii) -N(H)S(O) 1~2 - or -N(R d )S(O) 1~2 -; (iv) -S(O) 1~2 N(H)- or -S(O) 1~2 N(R d )-; (v) -O-; (vi) -S(O) 0~2 -; (vii) -C(O)NH- or -C(O)N(R d ); (viii) -N(H)C(O)- or -N(R d )C(O)-; (ix) -C≡C; (x) -N(H)S(O)(=NH)-, -N(R d )S(O)(=NH), -N(H)S(O)(=NR d ), or -N(R d )S(O)(=NR d ); and (xi) -S(O)(=NH)NH-, -S(O)(=NR d )NH-, -S(O)(=NH)NR d -, or -S(O)(=NR d )NR d -; and (xii) -S(O)(=NH)- or -S(O)(=NR d ) selected from the group consisting of; R 4 each occurrence of is independently, as follows: (i) -(Y 3 ) p -Y 4 where · p is 0 or 1; · Y 3is C which may be replaced by 1 to 6 R's respectively a and is alkylene or C 1~6 alkenylene; and 1~6 ·Y is as follows: 4 : (a) C b which may be replaced by 1 to 4 R's respectively 3~6 cycloalkyl; (b) C c which may be further replaced by 1 to 4 R's respectively 6~10 aryl; (c) heteroaryl containing 5 to 10 ring atoms, 1 to 4 of which are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S, and one or more of the heteroaryl ring carbon atoms are optionally replaced by 1 to 4 independently selected R c ; or (d) heterocyclyl containing 3 to 10 ring atoms, 1 to 3 of which are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), and O, and one or more of the heterocyclyl ring carbon atoms are optionally replaced by 1 to 4 independently selected R b ; or (ii) C a which may be replaced by 1 to 6 independently selected R's respectively 1~10 alkyl, C 1~10 alkenyl, or C 1~10 alkynyl ; Each occurrence of R a is independently -OH; -F; -Cl; -Br; -NR e R f ; 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) 1~2 (C 1~4 alkyl); cyano; and 1 to 4 independently selected C 1~4 cycloalkyl which may be substituted with C 3~6 alkyl, selected from the group consisting of; R b each occurrence of which is independently C 1~6 alkyl; C 1~4 haloalkyl; -OH; oxo; -F; -Cl; -Br; -NR e R f ; C 1~4 alkoxy; C 1~4 haloalkoxy; -C(=O)(C 1~4 alkyl); -C(=O)O(C 1~4 alkyl); -C(=O)OH; -C(=O)N(R')(R''); -S(O) 1~2 (NR'R''); -S(O) 1~2 (C 1~4 alkyl); cyano; and 1 to 4 independently selected C 1~4 cycloalkyl which may be substituted with C 3~6 alkyl, selected from the group consisting of; R c each occurrence of which is independently the following: (i) halo; (ii) cyano; (iii) C 1~6 alkyl; (iv) C 2~6 alkenyl; (v) C 2~6 alkynyl; (vi) C 1~4 haloalkyl; (vii) C 1~4 alkoxy; (viii) C 1~4 haloalkoxy; (ix) 1 to 4 independently selected C 1~4 cycloalkyl which may be substituted with C 0~3 alkylene)-C 3~6 cycloalkyl; (x) -S(O) 1~2 (C 1~4 alkyl); (xi) -NR e R f ; (xii) -OH; (xiii) -S(O) 1~2 (NR'R''); (xiv) -C 1~4 thioalkoxy; (xv) -NO 2 ; (xvi) -C(=O)(C 1~4 alkyl); (xvii) -C(=O)O(C 1~4 alkyl); (xviii) -C(=O)OH; (xix) -C(=O)N(R')(R''); and (xx) C 3~6 cycloalkoxy selected from the group consisting of; Each occurrence of R c ' is independently one of the following: (i) halo; (ii) cyano; (iii) -OH; (iv) -NO 2 ; (v) -C(=O)(C 1~4 alkyl); (vi) -C(=O)O(C 1~4 alkyl); (vii) -C(=O)OH; and (viii) -NH 2 selected from the group consisting of; R d is 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 1~4alkyl); -OH; and C 1~4 is selected from the group consisting of alkoxy; R e and R f each occurrence of is independently 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 is selected from the group consisting of alkoxy, or R e and R f together with the nitrogen atom to which each is attached form a ring containing 3 to 8 ring atoms, the ring having (a) 1 to 7 ring carbon atoms each substituted with 1 to 2 substituents independently selected from H and C 1~3 alkyl; and (b) 0 to 3 ring heteroatoms (other than the nitrogen atoms to which R' and R'' are attached) independently selected from the group consisting of N(R d ), O, and S; each occurrence of R' and R'' is independently selected from the group consisting of H and C 1~4 alkyl, or R' and R'' together with the nitrogen atom to which each is attached form a ring containing 3 to 8 ring atoms, the ring having (a) 1 to 7 ring carbon atoms each substituted with 1 to 2 substituents independently selected from H and C 1~3 alkyl; and (b) 0 to 3 ring heteroatoms (other than the nitrogen atoms to which R' and R'' are attached) independently selected from the group consisting of N(R d ), O, and S.

[0084] In some embodiments, the compound is of formula (I-1): When the compound of TIFF2025081550000131.tif34128, R 1It shall be other than unsubstituted phenyl, p-dimethylaminophenyl, p-aminosulfonylphenyl, and unsubstituted 4-pyridinyl.

[0085] In some embodiments, the compound is of formula (I-1): When the compound is the compound of TIFF2025081550000132.tif34128, R 1 shall be other than unsubstituted phenyl, p-monosubstituted phenyl, and unsubstituted pyridinyl.

[0086] In some embodiments, the compound is of formula (I-2): When the compound is the compound of TIFF2025081550000133.tif34128, R 1 shall be other than unsubstituted phenyl.

[0087] In some embodiments, the compound is other than the compound of formula (I-1) or formula (I-2): TIFF2025081550000134.tif34128.

[0088] In some embodiments, the compound is of formula (I-3): It shall not be the compound of TIFF2025081550000135.tif34128.

[0089] In some embodiments, when the compound is of formula (I-4): TIFF2025081550000136.tif34128, R 1 shall be other than p-monosubstituted phenyl (e.g., p-fluorophenyl).

[0090] In some embodiments, when the compound is of formula (I-5): TIFF2025081550000137.tif34128, R 3 shall be other than trifluoromethyl.

[0091] In some embodiments, the compound is of formula (I-6): When it is the compound of TIFF2025081550000138, R 2 is as follows: (i) Unsubstituted phenyl; (ii) TIFF2025081550000139.tif10128; (iii) TIFF2025081550000140.tif20128; (iv) Unsubstituted pyridinyl; (v) TIFF2025081550000141.tif12128 where Q 1 、Q 2 、Q 3 、and Q 4 are each independently selected from N and CH; or (vi) Heteroaryl containing 9 to 10 ring atoms, where 1 to 2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S, and one or more of the heteroaryl ring carbon atoms may be substituted with one or two independently selected R c , excluding heteroaryl .

[0092] In some embodiments, the compound excludes one or more of the following: TIFF2025081550000142.tif79128. TIFF2025081550000143.tif30128.

[0093] In some embodiments, the compound excludes one or more of the following: TIFF2025081550000144.tif32141.

[0094] In certain embodiments, the compound is other than the compounds disclosed in European Journal of Medicinal Chemistry (2014), 86, 270-278. In certain embodiments, the compound is other than the compounds disclosed in Tetrahedron Letters (2012), 53(25), 3126-3130. In certain embodiments, the compound is other than the compounds disclosed in Organic Letters (2011), 13(24), 6516-6519. In certain embodiments, the compound is other than the compounds disclosed in U.S. Patent Application Publication No. 2012 / 0095037 and / or U.S. Patent No. 8,362,019.

[0095] In certain embodiments, the compound is other than the compounds disclosed in Angewandte Chemie, International Edition (2018), 57(5), 1399-1403. In certain embodiments, the compound is other than the compounds disclosed in Organic Letters (2017), 19(19), 5118-5121. In certain embodiments, the compound is other than the compounds disclosed in Tetrahedron (2009), 65(44), 8930-8939. In certain embodiments, the compound is other than the compounds disclosed in Organic Letters (2016), 18(13), 3250-3253. In certain embodiments, the compound is other than the compounds disclosed in Organic & Biomolecular Chemistry (2015), 13(21), 6047-6058. In certain embodiments, the compound is other than the compounds disclosed in Chemistry - A European Journal (2013), 19(49), 16760-16771. In certain embodiments, the compound is other than the compounds disclosed in Organic & Biomolecular Chemistry (2013), 11(18), 3064-3072. In certain embodiments, the compound is other than the compounds disclosed in Organic Letters (2011), 13(24), 6516-6519. In certain embodiments, the compound is other than the compounds disclosed in Bioorganic & Medicinal Chemistry Letters (2004), 14(13), 3595-3599. In certain embodiments, the compound is other than the compounds disclosed in International Patent Application Publication No. 2015 / 073528. In certain embodiments, the compound is other than the compounds disclosed in International Patent Application Publication No. 2012 / 146667. In certain embodiments, the compound is other than the compounds disclosed in International Patent Application Publication No. 2001 / 030778. In certain embodiments, the compound is other than the compounds disclosed in US Patent Application Publication No. 2012 / 0095037.

[0096] In certain embodiments, the compound is other than the compounds disclosed in Journal of Medicinal Chemistry (2012), 55(11), 5291-5310. In certain embodiments, the compound is other than the compounds disclosed in Tetrahedron Letters (2000), 41(28), 5383-5386. In certain embodiments, the compound is other than the compounds disclosed in International Patent Application Publication No. WO 2017 / 171234. In certain embodiments, the compound is other than the compounds disclosed in International Patent Application Publication No. WO 2016 / 176460. In certain embodiments, the compound is other than the compounds disclosed in JP 2013-018771 and / or U.S. Patent No. 5,959,330. In certain embodiments, the compound is other than the compounds disclosed in International Patent Application Publication No. WO 2011 / 153310. In certain embodiments, the compound is other than the compounds disclosed in International Patent Application Publication No. WO 2011 / 082270. In certain embodiments, the compound is other than the compounds disclosed in Australian Patent Application Publication No. AU 2010 / 331175 and / or U.S. Patent Application Publication No. US 2012 / 0258951 and / or U.S. 2014 / 0194407. In certain embodiments, the compound is other than the compounds disclosed in International Patent Application Publication No. WO 2010 / 051245 and / or U.S. Patent Application Publication No. US 2011 / 0207750. In certain embodiments, the compound is other than the compounds disclosed in WO 2010 / 030360. In certain embodiments, the compound is other than the compounds disclosed in European Patent Application No. EP 1878724 and / or U.S. Patent No. 8,188,282. In certain embodiments, the compound is other than the compounds disclosed in International Patent Application No. WO 2007 / 075629. In certain embodiments, the compound is other than the compounds disclosed in JP 2000-302754 and / or U.S. Patent No. 6,358,634.

[0097] Variable element A 1 and X 1 ~X 4 In some embodiments, A 1 is N.

[0098] In other embodiments, A 1 is CH.

[0099] In some embodiments, X 1 and X 4 are each independently selected from CH and N.

[0100] In some embodiments, one to two of X 1 , X 2 , X 3 , and X 4 are independently N.

[0101] In certain embodiments, one to two of X 1 , X 2 , X 3 , and X 4 are independently N; two to three of X 1 , X 2 , X 3 , and X 4 are each independently selected CR 3 .

[0102] In certain embodiments, one to two of X 1 , X 2 , X 3 , and X 4 are independently N; X 1 and X 4 are each independently N or CH.

[0103] In some embodiments, two of X 1 , X 2 , X 3 , and X 4 are independently N; the other two of X 1 , X 2 , X 3 , and X 4 are independently selected from N and CR 3 .

[0104] In certain embodiments, the compound of formula (I) is of formula (I-a): The compound of TIFF2025081550000145.tif30128, or a pharmaceutically acceptable salt thereof.

[0105] In certain embodiments, the compound of formula (I) is of formula (I-b): The compound of TIFF2025081550000146.tif30128, or a pharmaceutically acceptable salt thereof.

[0106] In some of the above embodiments, X 1 , X 2 , X 3 , and X 4 When two of them are independently N, X 1 , X 2 , X 3 , and X 4 The other two of them are independently selected CR 3 .

[0107] In certain embodiments, the compound of formula (I) is of formula (I-a1): The compound of TIFF2025081550000147.tif34128, or a pharmaceutically acceptable salt thereof.

[0108] In certain embodiments, the compound of formula (I) is of formula (I-a2): The compound of TIFF2025081550000148.tif34128, or a pharmaceutically acceptable salt thereof.

[0109] In certain embodiments, the compound of formula (I) is of formula (I-b1): The compound of TIFF2025081550000149.tif34128, or a pharmaceutically acceptable salt thereof.

[0110] In some embodiments, one of X 1 , X 2 , X 3 , and X 4 is independently N; X 1 , X 2 , X 3 , and X 4Of the other three, they are independently N and CR 3 selected from

[0111] In certain embodiments, the compound of formula (I) is of formula (I-c): the compound of TIFF2025081550000150.tif30128, or a pharmaceutically acceptable salt thereof.

[0112] In certain embodiments, the compound of formula (I) is of formula (I-d): the compound of TIFF2025081550000151.tif30128, or a pharmaceutically acceptable salt thereof.

[0113] In some of the above embodiments, when one of X 1 , X 2 , X 3 , and X 4 is independently N, the other three of X 1 , X 2 , X 3 , and X 4 are independently selected CR 3 .

[0114] In certain embodiments, the compound of formula (I) is of formula (I-c1): the compound of TIFF2025081550000152.tif34128, or a pharmaceutically acceptable salt thereof.

[0115] In certain embodiments, the compound of formula (I) is of formula (I-d1): the compound of TIFF2025081550000153.tif35128, or a pharmaceutically acceptable salt thereof.

[0116] In certain embodiments, the compound of formula (I-d1) has the following formula: TIFF2025081550000154.tif32128, and wherein one R 3 is independently -L 4 -R 4 and R cselected from '; the other R 3 is independently H, -L 4 -R 4 , and R c selected from '; R 1 is (i) -(Y 1 ) n -Y 2 where ·n is 0; ·Y 2 is as follows: (a) Partially unsaturated C b which may be substituted with 1 to 4 R 3~10 cycloalkyl; (b) C c which may be substituted with 1 to 4 R 6~10 aryl; (c) Heteroaryl containing 5 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S, and one or more of the heteroaryl ring carbon atoms may be substituted with 1 to 4 independently selected R c ; or (d) Partially unsaturated heterocyclyl containing 3 to 10 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), and O, and one or more of the heterocyclyl ring carbon atoms may be substituted with 1 to 4 independently selected R b ; and R 2 is as follows: (i) C c aryl which may be further substituted with 1 to 4 R 6~10 ; (ii) Heteroaryl containing 5 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d) selected from the group consisting of O, O, and S, wherein one or more of the heteroaryl ring carbon atoms are one to four independently selected R c heteroaryl, which may be substituted with; (iii) one to four R b optionally substituted with partially unsaturated C 3~10 cycloalkyl; or (iv) a partially unsaturated heterocyclyl containing 3 to 10 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), and O, and one or more of the heterocyclyl ring carbon atoms are one to four independently selected R b optionally substituted with partially unsaturated heterocyclyl is.

[0117] Variable element R 1 In some embodiments, R 1 is -(Y 1 ) n -Y 2 is.

[0118] In some embodiments, n is 0.

[0119] In other embodiments, n is 1. In some of these embodiments, Y 1 is C 1~3 alkylene.

[0120] In some embodiments, Y 2 is a heteroaryl containing 5 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S, and one or more of the heteroaryl ring carbon atoms are one to four independently selected R c optionally substituted with heteroaryl. In some of the above embodiments, n is 0.

[0121] In some embodiments, Y2 is a heteroaryl containing 6 ring atoms, where 1 to 4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S, and one or more of the heteroaryl ring carbon atoms are substituted with 1 to 4 independently selected R c ; or a heteroaryl containing 5 or 9 to 10 ring atoms, where 1 to 4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S, and one or more of the heteroaryl ring carbon atoms may be substituted with 1 to 4 independently selected R c . In some of the above embodiments, n is 0.

[0122] In certain embodiments, Y 2 is a heteroaryl containing 5 to 6 ring atoms, where 1 to 4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S, and one or more of the heteroaryl ring carbon atoms may be substituted with 1 to 4 independently selected R c . In some of these embodiments, n is 0.

[0123] In certain embodiments, Y 2 is a heteroaryl containing 6 ring atoms, where 1 to 2 ring atoms are N, and one or more of the heteroaryl ring carbon atoms may be substituted with 1 to 4 independently selected R c . For example, Y 2 may be pyridyl (e.g., 2-pyridyl or 6-pyridyl) in which one or more of the ring carbon atoms may be substituted with 1 to 4 (e.g., 1, 2, 3, or 4) independently selected R c (e.g., Y 2 is such that one or more of the ring carbon atoms are substituted with 1 independently selected R cIt may be replaced by pyridyl (e.g., 2-pyridyl or 6-pyridyl). In some of these embodiments, n is 0.

[0124] In certain embodiments, Y 2 is heteroaryl containing 5 ring atoms, 1 to 4 of which are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S, and one or more of the heteroaryl ring carbon atoms may be substituted with 1 to 2 independently selected R c . For example, Y 2 is heteroaryl in which any replaceable nitrogen atom may be substituted with R d , and one or more of the ring carbon atoms may be substituted with 1 to 2 independently selected R c . It may be pyrazolyl, oxazolyl, or thiazolyl. In some of these embodiments, n is 0.

[0125] In certain embodiments, Y 2 is heteroaryl containing 5 ring atoms, 1 to 3 of which are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S, and one or more of the heteroaryl ring carbon atoms may be substituted with 1 to 3 independently selected R c . In some of these embodiments, n is 0.

[0126] In some of these embodiments, Y 2 is furanyl in which one or more of the ring carbon atoms may be substituted with 1 to 2 (e.g., 1) independently selected R c . In some of these embodiments, n is 0.

[0127] In some of the above embodiments, when Y 2 is heteroaryl, each occurrence of R c is independently selected from the group consisting of: (iii) C 1~6 Alkyl; (iv) C 2~6 Alkenyl; (v) C 2~6 Alkynyl; (vi) C 1~4 Haloalkyl; (vii) C 1~4 Alkoxy; (viii) C 1~4 Haloalkoxy; (ix) 1 to 4 independently selected C 1~4 Optionally substituted with alkyl-(C 0~3 Alkylene)-C 3~6 Cycloalkyl; (xiv) -C 1~4 Thioalkoxy; And (xx) C 3~6 Cycloalkoxy.

[0128] In some of the above embodiments, when Y 2 is heteroaryl, each occurrence of R c is independently selected from the group consisting of: (vii) C 1~4 Alkoxy; (viii) C 1~4 Haloalkoxy (e.g., OCH 2 CF 3 or OCF 3 ); (xiv) -C 1~4 Thioalkoxy; and (xx) C 3~6 Cycloalkoxy (e.g., cyclopropoxy).

[0129] For example, each occurrence of R c is independently selected C 1~4 Alkoxy (e.g., -OCH 3 , -OCH 2 CH 3 ).

[0130] As another example, R cEach occurrence of C is independently selected to be 1~6 alkyl (e.g., methyl).

[0131] In some of the above embodiments, when Y 2 is heteroaryl, each occurrence of R d is independently selected to be C 1~6 alkyl.

[0132] In some of the above embodiments, when Y 2 is heteroaryl and n is 0, R 1 is as follows: It may be selected from the group consisting of TIFF2025081550000155.tif26143.

[0133] In some of the above embodiments, when Y 2 is heteroaryl and n is 0, R 1 is as follows: It may be selected from the group consisting of TIFF2025081550000156.tif13128.

[0134] As a non-limiting example of the above embodiments, when Y 2 is heteroaryl and n is 0, R 1 may be TIFF2025081550000157.tif14128.

[0135] In certain embodiments, when Y 2 is heteroaryl and n is 0, R 1 may be TIFF2025081550000158.tif15128.

[0136] In certain embodiments, when Y 2 is heteroaryl and n is 0, R 1 may be TIFF2025081550000159.tif11128.

[0137] In some embodiments, Y 2 is a C b cycloalkyl which may be substituted with 1 to 4 R 3~10 . In some of these embodiments, n is 0.

[0138] In some embodiments, Y 2 is a C c aryl which may be substituted with 1 to 4 R 6~10 .

[0139] In certain embodiments, Y 2 is phenyl substituted with 1 to 4 R c . In certain embodiments, Y 2 is phenyl; when the ring carbon atom para to the point of attachment to Y 1 is substituted with R c , one or more other ring carbon atoms may be substituted with 1 to 3 R c .

[0140] In some embodiments, R 1 is -Z 1 -Z 2 -Z 3 .

[0141] In some embodiments, Z 1 is CH 2 .

[0142] In some embodiments, Z 2 is -O- or -S-. For example, Z 2 may be -O-.

[0143] In some embodiments, Z 3 is C 2~3 alkylene.

[0144] In certain embodiments, Z 1 is CH 2 , and Z 2 is -O- or -S- (e.g., -O-).

[0145] In certain embodiments, Z 2 is -O- or -S- (e.g., -O-), and Z 3 is C 2~3 alkylene.

[0146] In certain embodiments, Z 1 is CH 2 and Z 2 is -O- or -S- (e.g., -O-), and Z 3 is C 2~3 alkylene.

[0147] In some of the above embodiments, when R 1 is -Z 1 -Z 2 -Z 3 , R 1 is TIFF2025081550000160.tif6128.

[0148] Variable element R 2 In some embodiments, R 2 is as follows: (i) C c aryl, which may be further substituted with 1 to 4 R 6~10 ; (ii) heteroaryl containing 5 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S, and one or more of the heteroaryl ring carbon atoms may be substituted with 1 to 4 independently selected R c ; (iii) partially unsaturated C b cycloalkyl, which may be substituted with 1 to 4 R 3~10 ; or (iv) partially unsaturated heterocyclyl containing 3 to 10 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d) and selected from the group consisting of O, and one or more of the heterocyclic ring carbon atoms are 1 to 4 independently selected R b Optionally substituted partially unsaturated heterocyclyl.

[0149] In some embodiments, R 2 is C c aryl which may be substituted with 1 to 4 R 6~10 s.

[0150] In certain embodiments, R 2 is phenyl which may be substituted with 1 to 4 R c s. In some of the above embodiments, R 2 may be phenyl which may be substituted with 1 to 2 R c s. By way of non-limiting example, R 2 may be phenyl which may be substituted with 2 R c s.

[0151] In some of the above embodiments, when R 2 is aryl (e.g., phenyl), each occurrence of R c is independently selected from the group consisting of: (i) halo (e.g., F); (vi) C 1~4 haloalkyl (e.g., CF 3 ); (vii) C 1~4 alkoxy; (viii) C 1~4 haloalkoxy; and (xiv) -C 1~4 thioalkoxy.

[0152] By way of non-limiting example, each occurrence of R c may be independently selected from halo, C 1~4 alkoxy, and C 1~4 haloalkyl (e.g., each occurrence of R c is independently -OCH 3 , CF 3 , or F).

[0153] In some of the above embodiments, R 2 is aryl (e.g., phenyl), R 2 is the following formula (A): TIFF2025081550000161.tif25128, and wherein R 2a , R 2b , R 2c , R 2d , and R 2e are each independently selected from the group consisting of H and R c .

[0154] In a particular embodiment, four of R 2a , R 2b , R 2c , R 2d , and R 2e are each independently selected R c , and the others are H.

[0155] In a particular embodiment, three of R 2a , R 2b , R 2c , R 2d , and R 2e are each independently selected R c , and the others are H.

[0156] In a particular embodiment, two of R 2a , R 2b , R 2c , R 2d , and R 2e are each independently selected R c , and the others are H. In some of these embodiments, R 2a and R 2e are each independently selected R c (e.g., C 1~4 alkoxy; C 1~4 haloalkoxy; -C 1~4 thioalkoxy; C 1~4 haloalkyl; and halo), for example, each occurrence of R c is independently selected C1~4 is an alkoxy (e.g., -OCH 3 ). For example, R 2a and R 2e are each OCH 3 .

[0157] In certain embodiments, R 2 is TIFF2025081550000162.tif18128.

[0158] In some of the above embodiments, when R 2 is aryl (e.g., phenyl), R 2 has the formula (B): TIFF2025081550000163.tif18128.

[0159] In some embodiments, R 2 is aryl (e.g., phenyl); when R 2 has the following formula (A): TIFF2025081550000164.tif25128, 1 to 4 of R 2a , R 2b , R 2d , and R 2e are independently selected R c .

[0160] In some of the above embodiments, each R c is independently selected from the following: (i) -F; (ii) cyano; (iii) C 1~3 alkyl, C 5~6 alkyl, n-butyl, sec-butyl, isobutyl; (iv) C 2~6 alkenyl; (v) C 2~6 alkynyl; (vi) C 1~4 haloalkyl; (vii) C 1~4 alkoxy; (viii) C1~4 Haloalkoxy; (ix) 1 to 4 independently selected C 1~4 optionally substituted with alkyl- (C 0~3 alkylene)-C 3~6 cycloalkyl; (x) -S(O) 1~2 (C 1~4 alkyl); (xii) -OH; (xiv) -C 1~4 thioalkoxy; (xv) -NO 2 ; (xvi) -C(=O)(C 1~4 alkyl); (xvii) -C(=O)O(C 1~4 alkyl); (xviii) -C(=O)OH; (xix) -C(=O)N(R')(R''); and (xx) C 3~6 cycloalkoxy.

[0161] In some embodiments, R 2 is heteroaryl containing 5 to 10 ring atoms, 1 to 4 of which are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S, and one or more of the heteroaryl ring carbon atoms may be substituted with 1 to 4 independently selected R c , heteroaryl.

[0162] In some of the above embodiments, R 2 is heteroaryl containing 6 ring atoms, 1 to 3 of which are heteroatoms, each independently selected from the group consisting of N, N(H), and N(R d ), and one or more of the heteroaryl ring carbon atoms may be substituted with 1 to 4 independently selected R c , heteroaryl.

[0163] As a non-limiting example, R2 is optionally substituted with one or two independently selected R c and may be pyridinyl which may be substituted.

[0164] In some of the above embodiments, when R 2 is the heteroaryl defined above (for example, R 2 is heteroaryl containing 5 to 10 ring atoms, 1 to 4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S, and one or more of the heteroaryl ring carbon atoms are optionally substituted with one or two independently selected R c ), each R c is independently selected from the following: (i) halo; (vi) C 1~4 haloalkyl (for example CF 3 ); (vii) C 1~4 alkoxy; (viii) C 1~4 haloalkoxy; and (xiv) -C 1~4 thioalkoxy.

[0165] As a non-limiting example, each R c may independently be C 1~4 alkoxy (for example methoxy).

[0166] In some of the above embodiments, when R 2 is heteroaryl, R 2 is TIFF2025081550000165.tif17128.

[0167] In some of the above embodiments, when R 2 is heteroaryl, R 2 is TIFF2025081550000166.tif17128.

[0168] In some embodiments (e.g., when the compound has Formula I-d1), R 2 when is a heteroaryl as defined elsewhere herein, R 2 is selected from the following: (a) A heteroaryl containing 5 ring atoms, wherein 1 to 2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S, and one or more of the heteroaryl ring carbon atoms may be substituted with 1 to 4 independently selected R c ; heteroaryl (b) TIFF2025081550000167.tif12128 Here, Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 are each independently selected from N, CH, and CR c , provided that ·Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 1 to 4 of are independently CR c ; ·Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 one or more of are independently N; and ·Q 5 when is CR c , Q 1 , Q 2 , Q 3 , and Q 4 one or more of are CR c ; and (c) A heteroaryl containing 9 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d) Selected from the group consisting of O, O, and S, where one or more of the heteroaryl ring carbon atoms are R selected independently from 1 to 4 c substituted heteroaryl; where R c each occurrence is independently selected from the following: (i) -F; (ii) cyano; (iii) C 2~6 alkyl; (iv) C 2~6 alkenyl; (v) C 2~6 alkynyl; (vi) C 1~4 haloalkyl; (vii) C 1~4 alkoxy; (viii) C 1~4 haloalkoxy; (ix) -(C 1~4 alkylene)-C 0~3 optionally substituted with 1 to 4 independently selected C 3~6 cycloalkyl; (x) -S(O) 1~2 (C 1~4 alkyl); (xi) -NR e R f ; (xiii) -S(O) 1~2 (NR'R''); (xiv) -C 1~4 thioalkoxy; (xv) -NO 2 ; (xvi) -C(=O)(C 1~4 alkyl); (xvii) -C(=O)O(C 1~4 alkyl); (xviii) -C(=O)OH; (xix) -C(=O)N(R')(R''); and (xx) C 3~6 cycloalkoxy.

[0169] Variable element R3 In some embodiments, one or more occurrences of R 3 are each independently selected from R c' and -L 4 -R 4 More preferably.

[0170] In some embodiments, one occurrence of R 3 is -L 4 -R 4 is.

[0171] In some of the above embodiments, when one occurrence of R 3 is -L 4 -R 4 is, each of the remaining occurrences of R 3 is independently selected from the group consisting of H and R c '(for example, R c ' may be halo, such as Br or Cl; or R c ' may be -OH or NH 2 ). For example, each of the remaining occurrences of R 3 may be H.

[0172] In some embodiments, one occurrence of R 3 is -L 4 -R 4 and one occurrence of R 3 is H or R c '(for example, R c ' may be halo, such as Br or Cl; or R c ' may be NH 2 ).

[0173] In some embodiments, one occurrence of R 3 is -L 4 -R 4 and one occurrence of R 3 is R c '(for example, R c ' may be halo, such as Br or Cl (for example, R c' may be Cl)).

[0174] In some embodiments, one occurrence of R 3 is -L 4 -R 4 and one occurrence of R 3 is H.

[0175] In some embodiments, two occurrences of R 3 are independently selected -L 4 -R 4 .

[0176] In some of the above embodiments, any remaining occurrences of R 3 are selected from the group consisting of H and R c' . For example, any remaining occurrences of R 3 may be H.

[0177] As a non-limiting example of the above embodiments, X 2 and X 3 may each be CR 3 where each R 3 is independently selected -L 4 -R 4 (in certain embodiments, X 1 and X 4 are each independently CH or N).

[0178] In some embodiments, one occurrence of R 3 is H or R c ' (for example, R c ' may be halo, such as Br or Cl; or R c ' may be -OH or NH 2 ).

[0179] In certain embodiments, if one occurrence of R 3 is R c ', each of the remaining occurrences of R 3 is independently H or R c '. For example, each of the remaining occurrences of R 3 may be H.

[0180] In certain embodiments, R 3 one occurrence of is R c ', when the remaining R 3 one or more occurrences of are independently -L 4 -R 4 and R c' is selected from.

[0181] In some embodiments, R 3 one occurrence of is H.

[0182] X 1 ~X 4 and R 3 non-limiting combinations of In some embodiments, the portion TIFF2025081550000168.tif18128 (the structure originally shown in U.S. Provisional Application No. 62 / 742,218, redrawn for greater clarity of connection points TIFF2025081550000169.tif14128) is TIFF2025081550000170.tif23128 (the structure originally shown in U.S. Provisional Application No. 62 / 742,218, redrawn for greater clarity of connection points TIFF2025081550000171.tif19128), where * indicates the point of attachment to NR 2 ; TIFF2025081550000172.tif3128 indicates the point of attachment to A 1 .

[0183] In certain embodiments, R 3B is -L 4 -R 4 ; R 3C is H (e.g., -L 4 may be NHS(O) 2 ).

[0184] In certain embodiments, R 3B is -L 4 -R 4 ; R 3C is Rc' is (e.g., R c' may be a halo, e.g., -Cl; and / or, -L 4 may be NHS(O) 2 ).

[0185] In certain embodiments, R 3B is -L 4 -R 4 ; R 3C is independently selected -L 4 -R 4 . In some of the above embodiments, the -L of R 3B is different from the -L of R 4 . As a non-limiting example, the -L of R 3C may be NHS(O) 4 ; the -L of R 3B may be a bond 4 . 2 . 3C 4 .

[0186] In certain embodiments, R 3B is H; R 3C is -L 4 -R 4 (e.g., -L 4 may be NHS(O) 2 ).

[0187] In certain embodiments, R 3B is R c' ; R 3C is -L 4 -R 4 (e.g., -L 4 may be NHS(O) 2 ).

[0188] In certain embodiments, R 3B is H; R 3C is R c' .

[0189] In some embodiments, the moiety ​TIFF2025081550000173.tif18128 (redrawn for clearer connection points, the structure originally shown in U.S. Provisional Application No. 62 / 742,218) TIFF2025081550000174.tif14128 (redrawn) TIFF2025081550000175.tif23128 (redrawn for clearer connection points, the structure originally shown in U.S. Provisional Application No. 62 / 742,218) TIFF2025081550000176.tif19128 (redrawn), where * indicates the junction point to NR 2 ; TIFF2025081550000177.tif3128 indicates the junction point to A 1 ;

[0190] In certain embodiments, R 3A is H

[0191] In some of the above embodiments, R 3B is -L 4 -R 4 (e.g., -L 4 may be NHS(O) 2 ).

[0192] In some embodiments, the portion TIFF2025081550000178.tif18128 (redrawn for clearer connection points, the structure originally shown in U.S. Provisional Application No. 62 / 742,218) TIFF2025081550000179.tif15128 (redrawn) TIFF2025081550000180.tif23128 (redrawn for clearer connection points, the structure originally shown in U.S. Provisional Application No. 62 / 742,218) TIFF2025081550000181.tif19128 (redrawn), where * indicates the junction point to NR 2 ; TIFF2025081550000182.tif3128 indicates the junction point to A 1Indicates the junction point to

[0193] In certain embodiments, R 3A is H.

[0194] In some of the above embodiments, R 3B is -L 4 -R 4 (for example, -L 4 may be NHS(O) 2 ).

[0195] In some of the above embodiments, R 3B is -L 4 -R 4 (for example, -L 4 may be NHS(O) 2 ); R 3C is H.

[0196] In some of the above embodiments, R 3B is -L 4 -R 4 (for example, -L 4 may be NHS(O) 2 ); R 3C is R c' .

[0197] In some of the above embodiments, R 3B is -L 4 -R 4 (for example, -L 4 may be NHS(O) 2 ); R 3C is independently selected -L 4 -R 4 . In some of the above embodiments, R 3B 's -L 4 is different from R 3C 's -L 4 . As a non-limiting example, R 3B 's -L 4 may be NHS(O) 2 ; R 3C 's -L 4 may be a bond.

[0198] In some embodiments, the moiety TIFF2025081550000183.tif18128 (the structure originally shown in U.S. Provisional Application No. 62 / 742,218 redrawn for greater clarity of connection points) TIFF2025081550000184.tif15128 redrawn) is TIFF2025081550000185.tif23128 (the structure originally shown in U.S. Provisional Application No. 62 / 742,218 redrawn for greater clarity of connection points) TIFF2025081550000186.tif19128 redrawn), where * indicates a point of attachment to NR 2 and the point of attachment to; TIFF2025081550000187.tif3128 indicates a point of attachment to A 1 and the point of attachment to.

[0199] In certain embodiments, R 3D is H.

[0200] In some of the above embodiments, R 3B is -L 4 -R 4 (e.g., -L 4 may be NHS(O) 2 ).

[0201] In some of the above embodiments, R 3B is -L 4 -R 4 and (e.g., -L 4 may be NHS(O) 2 ); R 3C is H.

[0202] In some of the above embodiments, R 3B is -L 4 -R 4 and (e.g., -L 4 may be NHS(O) 2 ); R 3C is R c' ).

[0203] In some of the above embodiments, R 3B is -L 4 -R 4 (for example, -L 4 may be NHS(O) 2 ); R 3C is independently selected -L 4 -R 4 In some of the above embodiments, R 3B 's -L 4 is different from R 3C 's -L 4 As a non-limiting example, R 3B 's -L 4 may be NHS(O) 2 ; R 3C 's -L 4 may be a bond.

[0204] Variable element L 4 In some embodiments, -L 4 is -N(H)S(O) 1~2 - or -N(R d )S(O) 1~2 (e.g., N(C 1~3 alkyl)S(O) 2 )

[0205] In some of the above embodiments, -L 4 is -N(H)S(O) 2 -

[0206] In some embodiments, -L 4 is -N(H)S(O)(=NH)-, -N(R d )S(O)(=NH), N(H)S(O)(=NR d )-, or -N(R d )S(O)(=NR d )-

[0207] In some of the above embodiments, -L 4 is -N(H)S(O)(=NH)-

[0208] In some embodiments, -L 4 is -S(O)(=NH)NH-, -S(O)(=NR d )NH-, -S(O)(=NH)NR d -, or -S(O)(=NR d )NR d -.

[0209] In some of the above embodiments, -L 4 is -S(O)(=NH)NH-.

[0210] In some embodiments, -L 4 is -S(O) 1~2 N(H)- or -S(O) 1~2 N(R d ).

[0211] In some of the above embodiments, -L 4 is -S(O) 2 N(H)-.

[0212] In some embodiments, -L 4 is -N(H)C(O)- or -N(R d ).C(O).

[0213] In some of the above embodiments, -L 4 is -N(H)C(O)-.

[0214] In some embodiments, L 4 is -C(O)NH- or -C(O)N(R d ).

[0215] In some embodiments, -L 4 is -N(H)-, -N(R d ), or -N(R 4 ).

[0216] In certain embodiments, -L 4 is -N(H)- or -N(R 4 ).

[0217] In some embodiments, -L 4 is a single bond.

[0218] In some embodiments, -L 4 is C≡C.

[0219] In some embodiments, -L 4 is -O-.

[0220] In some embodiments, L 4 is -N(H)S(O) 1~2 N(H)-, -N(R d )S(O) 1~2 N(H)-, -N(H)S(O) 1~2 N(R d )-, and -N(R d )S(O) 1~2 N(R d )- selected from the group consisting of.

[0221] In some embodiments, L 4 is -N(H)S(O) 1~2 N(H)-(e.g., -N(H)S(O) 2 N(H)-).

[0222] In some embodiments, L 4 is -N(H)S(O) 1~2 N(R d )-(e.g., -N(H)S(O) 2 N(R d )-, e.g., -N(H)S(O) 2 N(C 1~3 alkyl)-).

[0223] In some embodiments, -L 4 is -N(H)S(O) 2 -, C≡C, single bond, -C(O)N(H)-, -N(H)-, -N(R 4 )-, -N(R d )-, and -N(H)C(O)- selected from the group consisting of.

[0224] In some of the above embodiments, -L 4-N(H)S(O) 2 -, a single bond, -NH-, -N(R 4 )-, and -N(H)C(O)- selected from the group consisting of.

[0225] In some embodiments, -L 1 is selected from the following: (i) a bond (in certain embodiments, -L 4 is a bond; R 4 is -(Y 3 ) p -Y 4 is, p is 1); (ii) N(R 4 ); (iii) -N(H)S(O) 1~2 - or -N(R d )S(O) 1~2 -; (iv) -S(O) 1~2 N(H)- or -S(O) 1~2 N(R d )-; (vi) -S(O) 1~2 -; (viii) -N(H)C(O)- or -N(R d )C(O)-; (ix) -C≡C; (x) -N(H)S(O)(=NH)-, -N(R d )S(O)(=NH), -N(H)S(O)(=NR d )-, or -N(R d )S(O)(=NR d )-; (xi) -S(O)(=NH)NH-, -S(O)(=NR d )NH-, -S(O)(=NH)NR d -, or -S(O)(=NR d )NR d -; and (xii) -S(O)(=NH)- or -S(O)(=NR d )。

[0226] Variable element R 4 In some embodiments, R 4 is -(Y 3 ) p -Y 4 .

[0227] In some embodiments, p is 0.

[0228] In other embodiments, p is 1. In some of these embodiments, Y 3 is C 1~3 alkylene. For example, Y 3 may be CH 2 or CH 2 -CH 2 .

[0229] In some embodiments, Y 4 is C c aryl optionally substituted with 1 to 4 R 6~10 .

[0230] In some embodiments, Y 4 is phenyl optionally substituted with 1 to 2 (e.g., 1) R c .

[0231] In certain embodiments, when Y 4 is C c aryl optionally substituted with 1 to 4 R 6~10 (e.g., when Y 4 is phenyl optionally substituted with 1 to 2 (e.g., 1) R c ), each occurrence of R c is independently selected from the group consisting of: (i) halo; (ii) cyano; (iii) C 1~6 alkyl; (iv) C 2~6 alkenyl; (v) C 2~6 alkynyl; (vi) C 1~4 haloalkyl; (vii) C 1~4 alkoxy; (viii) C 1~4 Haloalkoxy; (ix) 1 to 4 independently selected C 1~4 alkyl optionally substituted with -(C 0~3 alkylene)-C 3~6 cycloalkyl; (xiv) -C 1~4 thioalkoxy; and (xx) C 3~6 cycloalkoxy.

[0232] In certain embodiments, Y 4 is C c aryl optionally substituted with 1 to 4 R 6~10 (e.g., when Y 4 is phenyl optionally substituted with 1 to 2 (e.g., 1) R c ), each occurrence of R c is independently selected from the group consisting of: (i) Halo; (iii) C 1~6 alkyl; (vi) C 1~4 haloalkyl; (vii) C 1~4 alkoxy; and (viii) C 1~4 haloalkoxy.

[0233] In certain embodiments, Y 4 is C 6~10 aryl, each occurrence of R c is independently selected from the group consisting of: (vii) C 1~4 alkoxy; (viii) C 1~4 haloalkoxy; and (xiv) -C 1~4 thioalkoxy.

[0234] In certain embodiments, Y 4 is unsubstituted C 6~10 aryl (e.g., phenyl).

[0235] In certain embodiments, p = 1 and Y 4 is C 6~10 When aryl, R 4 is as follows: Selected from the group consisting of TIFF2025081550000188.tif58138.

[0236] In certain embodiments, p = 1 and Y 4 is C 6~10 When aryl, R 4 is as follows: Selected from the group consisting of TIFF2025081550000189.tif30128.

[0237] In certain embodiments, p = 0 and Y 4 is C 6~10 When aryl, R 4 is TIFF2025081550000190.tif21128.

[0238] In certain embodiments, p = 0 and Y 4 is C 6~10 When aryl, R 4 is TIFF2025081550000191.tif17128.

[0239] In some embodiments, Y 4 is C which may be substituted with 1 to 4 R b s 3~6 (e.g., C 3~4 or C 6 ) cycloalkyl.

[0240] In some of the above embodiments, Y 4 is cyclopropyl which may be substituted with 1 to 2 R b s. For example, Y 4 is unsubstituted cyclopropyl.

[0241] In some embodiments, Y 4 is C which may be substituted with 1 to 2 Rb C which may be replaced 6 is cycloalkyl (e.g., cyclohexyl).

[0242] In some of the above aspects, Y 4 is cycloalkyl which may be substituted with 1 to 4 Rs b in which each occurrence of R is independently selected from the group consisting of -F, C b alkyl, C 1~6 haloalkyl, and -OH (e.g., R 1~4 may be OH; and / or, R b may be C b alkyl, e.g., methyl). 1~6

[0243] In a specific aspect, p = 1 and Y 4 is cycloalkyl which may be substituted with 1 to 4 Rs b in which R is as follows: 3~6 is selected from the group consisting of TIFF2025081550000192.tif14128 4

[0244] In a specific aspect, p = 1 and Y 4 is cycloalkyl which may be substituted with 1 to 4 Rs b in which R is as follows: 3~6 is selected from the group consisting of TIFF2025081550000193.tif13128 4

[0245] In a specific aspect, p = 0 and Y 4 is cycloalkyl which may be substituted with 1 to 4 Rs b in which R is as follows: 3~6 is selected from the group consisting of TIFF2025081550000194.tif24128 4

[0246] In a specific aspect, Y​​​​​​​4 is unsubstituted C 3~6 (e.g., C 3~4 or C 6 ) is a cycloalkyl.

[0247] In some of these embodiments, Y 4 is unsubstituted cyclopropyl or unsubstituted cyclobutyl (e.g., unsubstituted cyclopropyl).

[0248] In some embodiments, Y 4 is heteroaryl containing 5 to 10 ring atoms, 1 to 4 of which are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S, and one or more of the heteroaryl ring carbon atoms may be substituted with 1 to 4 independently selected R c and is heteroaryl.

[0249] In some of the above embodiments, Y 4 is heteroaryl containing 6 ring atoms, 1 to 4 of which are heteroatoms, each independently selected from the group consisting of N, N(H), and N(R d ), and one or more of the heteroaryl ring carbon atoms may be substituted with 1 to 4 independently selected R c and is heteroaryl.

[0250] As a non-limiting example of the above embodiments, Y 4 may be pyridinyl (e.g., 2-pyridinyl, 3-pyridinyl, or 4-pyridinyl), pyrimidinyl (e.g., 2-pyrimidinyl or 5-pyrimidinyl), or pyrazinyl, each optionally substituted with 1 to 2 independently selected R c .

[0251] For example, Y 4 may be pyridinyl, pyrimidinyl, or pyrazinyl, each unsubstituted.

[0252] In certain embodiments, Y4 is a heteroaryl optionally substituted with one or more independently selected R as defined above c when it is, each occurrence of R is independently selected from the group consisting of: c : (i) halo; (ii) cyano; (iii) C 1~6 alkyl; (iv) C 2~6 alkenyl; (v) C 2~6 alkynyl; (vi) C 1~4 haloalkyl; (vii) C 1~4 alkoxy; (viii) C 1~4 haloalkoxy; (ix) -(C 1~4 alkylene)-C 0~3 cycloalkyl optionally substituted with one to four independently selected C 3~6 alkyl; (xii) OH; (xiv) -C 1~4 thioalkoxy; and (xx) C 3~6 cycloalkoxy.

[0253] In some of these embodiments, each occurrence of R is independently selected from the group consisting of: c : (i) halo (e.g., F, Cl); (iii) C 1~6 alkyl (e.g., methyl); and (xii) OH.

[0254] In certain embodiments, p = 1 and when Y 4 is heteroaryl, R 4 is selected from the group consisting of: TIFF2025081550000195.tif52159.

[0255] In certain embodiments, p = 1 and; Y 4 when Y is heteroaryl, R 4 is as follows: selected from the group consisting of TIFF2025081550000196.tif14128.

[0256] In certain embodiments, p = 0 and; Y 4 when Y is heteroaryl, R 4 is as follows: selected from the group consisting of TIFF2025081550000197.tif15128.

[0257] In certain embodiments, p = 0 and; Y 4 when Y is heteroaryl, R 4 is as follows: selected from the group consisting of TIFF2025081550000198.tif15128.

[0258] In some embodiments, Y 4 is a heterocyclyl containing 3 to 10 ring atoms, 1 to 3 of which are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), and O, and one or more of the heterocyclyl ring carbon atoms may be substituted with 1 to 4 independently selected R b .

[0259] In some of the above embodiments, Y 4 is a heterocyclyl containing 4 to 6 ring atoms, 1 to 2 of which are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), and O, and one or more of the heterocyclyl ring carbon atoms may be substituted with 1 to 4 independently selected R b .

[0260] In certain embodiments, Y 4is a heterocyclyl containing 4 ring atoms, wherein 1 ring atom is a heteroatom, independently selected from the group consisting of N, N(H), N(R d ), and O, and one or more of the heterocyclyl ring carbon atoms may be substituted with 1 to 2 independently selected R b .

[0261] As a non-limiting example, Y 4 may be oxetanyl (e.g., unsubstituted oxetanyl) which may be substituted with 1 to 2 independently selected R b .

[0262] As another non-limiting example, Y 4 may be azetidinyl (e.g., azetidinyl substituted with 1 R b ) which may be substituted with 1 to 2 independently selected R b .

[0263] In some embodiments, Y 4 is a heterocyclyl containing 6 ring atoms, wherein 1 to 2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), and O, and one or more of the heterocyclyl ring carbon atoms may be substituted with 1 to 4 independently selected R b .

[0264] As a non-limiting example, Y 4 may be selected from the group consisting of tetrahydropyranyl, piperidinyl, piperazinyl, and morpholinyl, each of which may be substituted with 1 to 2 independently selected R b .

[0265] As a non-limiting example, Y 4 may be selected from tetrahydropyranyl, piperidinyl, and morpholinyl, each of which may be substituted with 1 to 2 independently selected R b .

[0266] In some of the above aspects, Y 4 is a heterocyclyl which may be substituted with 1 to 4 independently selected R b , each occurrence of R b is independently selected from the group consisting of -F, C 1~6 alkyl, C 1~4 haloalkyl, oxo, and -OH.

[0267] In some of the above aspects, Y 4 is a heterocyclyl which may be substituted with 1 to 4 independently selected R b , each occurrence of R b is independently selected from the group consisting of -F, C 1~6 alkyl, C 1~4 haloalkyl, and -OH (for example, R b may be OH).

[0268] In a particular aspect, p = 1; and when Y 4 is a heterocyclyl which may be substituted with 1 to 4 independently selected R b , R 4 is as follows: Selected from the group consisting of TIFF2025081550000199.tif26128.

[0269] In a particular aspect, p = 1; and when Y 4 is a heterocyclyl which may be substituted with 1 to 4 independently selected R b , R 4 is TIFF2025081550000200.tif24128.

[0270] In a particular aspect, p = 0; and when Y 4 is a heterocyclyl which may be substituted with 1 to 4 independently selected R b , R 4 is as follows: It is selected from the group consisting of TIFF2025081550000201.tif24140.

[0271] In certain embodiments, p = 0; and Y 4 is a heterocyclyl which may be substituted with 1 to 4 independently selected R b wherein R 4 is as follows: It is selected from the group consisting of TIFF2025081550000202.tif24128.

[0272] In some embodiments, R 4 is a C a alkyl which may be substituted with 1 to 6 independently selected R 1~10 and is.

[0273] In certain embodiments, R 4 is a C a alkyl which may be substituted with 1 to 6 independently selected R 1~6 and is.

[0274] In certain embodiments, R 4 is a C a alkyl which may be substituted with 1 to 2 independently selected R 1~6 For example, R 4 may be methyl.

[0275] In some of the above embodiments, when R 4 is C 1~6 alkyl, each occurrence of R a is independently selected from the group consisting of -F; -OH; C 1~4 alkoxy; and C 1~4 haloalkoxy.

[0276] In certain embodiments, each occurrence of R a is -OH independently. For example, R 4 is TIFF2025081550000203.tif12128.

[0277] In some embodiments, R 4 is selected from the group consisting of methyl, ethyl, TIFF2025081550000204.tif14128.

[0278] In some embodiments, R 4 is methyl and TIFF2025081550000205.tif12128.

[0279] In some embodiments, R 4 is C a optionally substituted with 1 to 6 (e.g., 1 to 3) independently selected R 2~10 (e.g., C 2~4 ) alkynyl (e.g., TIFF2025081550000206.tif8128 such as unsubstituted C 2~4 ) alkynyl).

[0280] In some embodiments, R 4 is C a optionally substituted with 1 to 6 (e.g., 1 to 3) independently selected R 2~10 (e.g., C 2~4 ) alkenyl (e.g., unsubstituted C 2~4 ) alkenyl such as vinyl).

[0281] In some embodiments (e.g., when -L 4 is a bond or -O-), R 4 is C a alkyl optionally substituted with 1 to 6 independently selected R 2~10 ; or methyl optionally substituted with 1 to 2 independently selected R a .

[0282] In certain embodiments (e.g., when -L 4 is a bond or -O-), R 4 is C a optionally substituted with 1 to 6 independently selected R 2~10alkyl; or methyl substituted with 1 or 2 independently selected R a is methyl substituted with a .

[0283] -L 4 and R 4 non-limiting combinations of non-limiting combination [A] In some embodiments, -L 4 is selected from the group consisting of -N(H)S(O)-, -N(H)S(O)N(H)-, -N(H)S(O)N(R 2 -N(H)S(O)-, -N(H)S(O)N(H)-, -N(H)S(O)N(R 2 N(H)-, -N(H)S(O)N(R 2 N(R d ), -C≡C, a single bond, -C(O)N(H)-, -N(H)-, -N(R 4 ), -N(R d ), and -N(H)C(O)-; R 4 is selected from the group consisting of: (i) C a alkyl optionally substituted with 1 or 2 R 1~6 ; (ii) -(Y 3 ) p -Y 4 ; and (iii) C a alkenyl or C 2~10 alkynyl each optionally substituted with 1 to 3 independently selected R 2~10 .

[0284] In certain embodiments, -L 4 is selected from the group consisting of -N(H)S(O)-, -N(H)S(O)N(H)-, and -N(H)S(O)N(R 2 -N(H)S(O)-, -N(H)S(O)N(H)-, and -N(H)S(O)N(R 2 N(H)-, and -N(H)S(O)N(R 2 N(R d ); R 4 is selected from the group consisting of: (i) C a alkyl optionally substituted with 1 or 2 R 1~6 ; (ii) -(Y 3 ) p -Y4 ; and (iii) one to three independently selected Rs a optionally each substituted with a C 2~10 alkenyl or C 2~10 alkynyl.

[0285] In some embodiments, -L 4 is selected from the group consisting of -N(H)S(O) 2 -, C≡C, a single bond, -C(O)N(H)-, -N(H)-, -N(R 4 ), -, -N(R d ), and -N(H)C(O)-; R 4 is selected from the group consisting of: (i) C a alkyl optionally substituted with one or two Rs 1~6 ; and (ii) -(Y 3 ) p -Y 4 .

[0286] In certain embodiments, -L 4 is selected from the group consisting of -N(H)S(O) 2 (ii) a single bond, -NH-, -N(R 4 ), and -N(H)C(O)-; R 4 is selected from the group consisting of: (i) C a alkyl optionally substituted with one or two Rs 1~6 ; and (ii) -(Y 3 ) p -Y 4 .

[0287] In certain embodiments, -L 4 is -N(H)S(O) 2 -; R 4 is selected from the group consisting of: (i) C a alkyl optionally substituted with one or two Rs 1~6 ; and (ii) -(Y 3 ) p -Y 4 。

[0288] In certain embodiments, -L 4 is a single bond; R 4 is selected from the group consisting of: (i) C a alkyl optionally substituted with 1 to 2 R 1~6 ; and (ii) -(Y 3 ) p -Y 4 。

[0289] In certain embodiments, -L 4 is -NH- or -N(R 4 )-; R 4 is selected from the group consisting of: (i) C a alkyl optionally substituted with 1 to 2 R 1~6 ; and (ii) -(Y 3 ) p -Y 4 。

[0290] In certain embodiments, -L 4 is -N(H)C(O)-; R 4 is selected from the group consisting of: (i) C a alkyl optionally substituted with 1 to 2 R 1~6 ; and (ii) -(Y 3 ) p -Y 4 。

[0291] In some of these embodiments, -L 4 is -N(H)S(O) 2 N(H)- or -N(H)S(O) 2 N(R d )-; R 4 is selected from the group consisting of: (i) 1 to 2 Ra C which may be replaced 1~6 alkyl; and (ii) -(Y 3 ) p -Y 4 .

[0292] In certain embodiments, -L 4 is -N(H)S(O) 2 -; and R 4 is selected from the group consisting of: R 4 is selected from the group consisting of: (i) C a alkyl which may be substituted with 1 to 2 R 1~6 ; (ii) -(Y 3 ) p -Y 4 ; and (iii) C a alkenyl or C 2~10 alkynyl, each of which may be substituted with 1 to 3 independently selected R 2~10 .

[0293] In certain embodiments, -L 4 is a single bond; and R 4 is selected from the group consisting of: R 4 is selected from the group consisting of: (i) C a alkyl which may be substituted with 1 to 2 R 1~6 ; (ii) -(Y 3 ) p -Y 4 ; and (iii) C a alkenyl or C 2~10 alkynyl, each of which may be substituted with 1 to 3 independently selected R 2~10 .

[0294] In certain embodiments, -L 4 is -NH- or -N(R 4 )-; and R 4is selected from the group consisting of: R 4 is selected from the group consisting of: (i) C alkyl which may be substituted with 1 to 2 R a ; 1~6 alkyl; (ii) -(Y 3 ) p -Y 4 ; and (iii) C alkenyl or C alkynyl which may each be substituted with 1 to 3 independently selected R a ; 2~10 alkenyl or C 2~10 alkynyl.

[0295] In certain embodiments, -L 4 is -N(H)C(O)-; R 4 is selected from the group consisting of: R 4 is selected from the group consisting of: (i) C alkyl which may be substituted with 1 to 2 R a ; 1~6 alkyl; (ii) -(Y 3 ) p -Y 4 ; and (iii) C alkenyl or C alkynyl which may each be substituted with 1 to 3 independently selected R a ; 2~10 alkenyl or C 2~10 alkynyl.

[0296] In certain embodiments, -L 4 is -N(H)S(O) 2 N(H)- or -N(H)S(O) 2 N(R d )-; R 4 is selected from the group consisting of: (i) C alkyl which may be substituted with 1 to 2 R a ; 1~6 alkyl; (ii) -(Y 3 ) p -Y 4 ; and (iii) 1 to 3 independently selected Rs a optionally each substituted with C 2~10 alkenyl or C 2~10 alkynyl.

[0297] In some embodiments of [A], R 4 is C optionally substituted with 1 to 2 Rs a alkyl. 1~6

[0298] In some embodiments of [A], R 4 is C alkenyl or C optionally substituted with 1 to 3 independently selected Rs a alkynyl each 2~10 substituted with 2~10

[0299] In some of these embodiments, R 4 is C alkynyl (such as unsubstituted C a optionally substituted with 1 to 3 independently selected Rs 2~10 (e.g., C 2~5 ) alkynyl (e.g., TIFF2025081550000207.tif8128 etc.) 2~5

[0300] In some embodiments of [A], R 4 is -(Y 3 ) p -Y 4 In certain embodiments, Y 4 is aryl C optionally substituted with 1 to 4 Rs c For example, Y 6~10 may be phenyl optionally substituted with 1 to 2 (e.g., 1) Rs 4 c

[0301] In some embodiments of [A], when R 4 is -(Y 3 ) p -Y 4 then Y 4is C which may be substituted with 1 to 4 R b cycloalkyl (for example, C 3~6 or C 3~4 ). In certain embodiments, Y 6 is C cycloalkyl which may each be substituted with 1 to 2 R 4 (for example, R b may be -OH). 3~4 cycloalkyl or C 6 cycloalkyl (for example, R b may be -OH).

[0302] In some embodiments of [A], R 4 is -(Y 3 ) p -Y 4 . In certain embodiments, Y 4 is a heterocyclyl containing 4 to 6 ring atoms, 1 to 3 of which are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), and O, and one or more of the heterocyclyl ring carbon atoms may be substituted with 1 to 2 independently selected R b . In certain embodiments, Y 4 is a heterocyclyl containing 6 ring atoms, 1 to 3 of which are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), and O, and one or more of the heterocyclyl ring carbon atoms may be substituted with 1 to 2 independently selected R b (for example, Y 4 may be tetrahydropyranyl, piperidinyl, or morpholinyl which may each be substituted with 1 to 2 independently selected R b ). In certain embodiments, Y 4 is a heterocyclyl containing 4 ring atoms, 1 to 3 of which are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), and O, and one or more of the heterocyclyl ring carbon atoms may be substituted with 1 to 2 independently selected R bwhich may be replaced by, and is heterocyclic (e.g., Y 4 may be oxetanyl; or Y 4 may be azetidinyl).

[0303] In some embodiments of [A], R 4 is -(Y 3 ) p -Y 4 . In certain embodiments, Y 4 is heteroaryl containing 6 ring atoms, 1 to 4 of which are heteroatoms, each independently selected from the group consisting of N, N(H), and N(R d ), and one or more of the heteroaryl ring carbon atoms may be substituted with 1 to 4 independently selected R c , and is heteroaryl. In certain embodiments, Y 4 is pyridinyl (e.g., 2-pyridinyl, 3-pyridinyl, or 4-pyridinyl), pyrimidinyl (e.g., 2-pyrimidinyl or 5-pyrimidinyl), or pyrazinyl, each optionally substituted with 1 to 2 independently selected R c .

[0304] In some of the above embodiments of [A], when R 4 is -(Y 3 ) p -Y 4 , p = 0.

[0305] In other embodiments of [A], when R 4 is -(Y 3 ) p -Y 4 , p = 1. In some of these embodiments, Y 3 is C 1~3 alkylene (e.g., CH 2 , CH 2 -CH 2 ).

[0306] In some embodiments, when R 3 is -L 4 -R 4 , then R3 is as follows: selected from the group consisting of TIFF2025081550000208.tif64132.

[0307] In some embodiments, R 3 is -L 4 -R 4 If so, R 3 is as follows: selected from the group consisting of TIFF2025081550000209.tif35128.

[0308] In some embodiments, R 3 is -L 4 -R 4 If so, R 3 is as follows: selected from the group consisting of TIFF2025081550000210.tif31128.

[0309] In some embodiments, R 3 is -L 4 -R 4 If so, R 3 is as follows: selected from the group consisting of TIFF2025081550000211.tif27128.

[0310] In some embodiments, R 3 is -L 4 -R 4 If so, R 3 is as follows: selected from the group consisting of TIFF2025081550000212.tif24128.

[0311] In some embodiments, R 3 is -L 4 -R 4 If so, R 3 is as follows: selected from the group consisting of TIFF2025081550000213.tif21147.

[0312] In some embodiments, R 3 is -L4 -R 4 When it is 3 R is as follows: Selected from the group consisting of TIFF2025081550000214.tif20128.

[0313] In some embodiments, R 3 is -L 4 -R 4 When it is 3 R is as follows: Selected from the group consisting of TIFF2025081550000215.tif19128.

[0314] In some embodiments, R 3 is -L 4 -R 4 When it is 3 R is as follows: Selected from the group consisting of TIFF2025081550000216.tif35140.

[0315] In some embodiments, R 3 is -L 4 -R 4 When it is 3 R is as follows: Selected from the group consisting of TIFF2025081550000217.tif42147.

[0316] In some embodiments, R 3 is -L 4 -R 4 When it is 3 R is as follows: Selected from the group consisting of TIFF2025081550000218.tif18128.

[0317] In some embodiments, R 3 is -L 4 -R 4 When it is 3 R is as follows: Selected from the group consisting of TIFF2025081550000219.tif19140.

[0318] In some embodiments, R 3 is -L 4 -R 4 If so, R 3 is as follows: selected from the group consisting of TIFF2025081550000220.tif19148.

[0319] In some embodiments, R 3 is -L 4 -R 4 If so, R 3 is as follows: selected from the group consisting of TIFF2025081550000221.tif40150.

[0320] In some embodiments, R 3 is -L 4 -R 4 If so, R 3 is as follows: selected from the group consisting of TIFF2025081550000222.tif17128, NHMe, and NMe 2 from the group consisting of.

[0321] In some embodiments, R 3 is -L 4 -R 4 If so, R 3 is as follows: selected from the group consisting of TIFF2025081550000223.tif15128.

[0322] In some embodiments, R 3 is -L 4 -R 4 If so, R 3 is as follows: selected from the group consisting of TIFF2025081550000224.tif15128.

[0323] In some of the above embodiments, R 3 is TIFF2025081550000225.tif12128.

[0324] Variable element R c' In some embodiments, R c each occurrence of'is independently selected from the group consisting of: (i) halo (e.g., -F, Cl); (ii) cyano; (iii) -OH; (iv) -NO 2 ; (v) -C(=O)(C 1~4 alkyl); (vi) -C(=O)O(C 1~4 alkyl); (vii) -C(=O)OH; and (viii) -NH 2 。

[0325] In certain embodiments, R c each occurrence of'is independently selected from the group consisting of: (i) halo (e.g., -F, Cl); (iii) -OH; (iv) -NO 2 ; (v) -C(=O)(C 1~4 alkyl); and (vi) -C(=O)O(C 1~4 alkyl).

[0326] In certain embodiments, R c each occurrence of'is independently selected from halo (e.g., -F, Cl).

[0327] In certain embodiments, R c each occurrence of'is independently selected from OH and NH 2 。

[0328] Non-limiting combinations Non-limiting combination [1] In some embodiments, R 1 is -(Y 1 ) n -Y2 and; R 2 is C aryl which may be substituted with 1 to 4 Rs. c which may be substituted with 1 to 4 Rs. 6~10 is C aryl which may be substituted with 1 to 4 Rs.

[0329] In some of these embodiments, n is 0.

[0330] In some of the above embodiments of [1], one to two of X 1 , X 2 , X 3 , and X 4 are N; two to three of X 1 , X 2 , X 3 , and X 4 are each independently selected CR 3 .

[0331] In some of the above embodiments of [1], one of X 1 , X 2 , X 3 , and X 4 is N; the remaining X 1 , X 2 , X 3 , and X 4 are each independently selected CR 3 ; or two of X 1 , X 2 , X 3 , and X 4 are N; the remaining X 1 , X 2 , X 3 , and X 4 are each independently selected CR 3 .

[0332] In certain embodiments, one to two of X 2 and X 3 are independently CR 3 , for example, both X 2 and X 3 are each independently selected CR 3is as follows. In some of the above aspects, X 1 and X 4 are each independently CH or N (for example, X 1 and X 4 are each N).

[0333] In some of the above aspects of [1], one occurrence of R 3 is -L 4 -R 4 .

[0334] In some of the above aspects of [1], R 4 is -(Y 3 ) p -Y 4 .

[0335] In some of the above aspects, when R 4 is (Y 3 ) p -Y 4 , p = 1. In other aspects, p = 0.

[0336] In some of the above aspects of [1], R 4 is C a alkyl which may be substituted with 1 to 6 independently selected R 1~10 .

[0337] In some of the above aspects of [1], each of the remaining occurrences of R 3 is independently selected from the group consisting of H and R c '. For example, each of the remaining occurrences of R 3 may independently be H.

[0338] In some of the above aspects of [1], when one occurrence of R 3 is -L 4 -R 4 , one occurrence of R 3 is H.

[0339] In some of the above aspects of [1], when one occurrence of R 3 is -L4 -R 4 When it is, R 3 One occurrence of is R c' (For example, halo (for example, Br or Cl, for example, Cl)).

[0340] In some embodiments of [1], R 3 One occurrence of is R c' (For example, Br or Cl, for example, Cl); Each R 3 of the remaining occurrences is H.

[0341] In some embodiments of [1], Y 2 is as defined in any one of claims 14 to 20 and 26 to 28; Each R c , when present, is independently as defined in any one of claims 21 to 24.

[0342] In some embodiments of [1], Y 2 is as defined in any one of claims 14 to 18; Each R c , when present, is as defined in any one of claims 21 to 23.

[0343] In some embodiments of [1], Y 2 is as defined in any one of claims 16 to 18; Each R c , when present, is as defined in any one of claims 21 to 23.

[0344] In some embodiments of [1], Y 2 is as defined in claim 18; Each R c , when present, is as defined in claim 23.

[0345] In a particular embodiment of [1], R 1 is TIFF2025081550000226.tif15128, for example TIFF2025081550000227.tif13128.

[0346] In some embodiments of [1], R 1 is as defined in any one of claims 10 to 23 of US 62 / 742,218 filed on October 5, 2018. In some of the above embodiments, R 1 is as defined in any one of claims 16 to 23 of US 62 / 742,218 filed on October 5, 2018. For example, R 1 may be as defined in claim 23 of US 62 / 742,218 filed on October 5, 2018. In some embodiments of [1], R 2 is C c optionally substituted with 1 to 4 R 6~10 aryl, for example phenyl optionally substituted with 1 to 4 R c or 1 to 2 R c or 2 R c ; R c , when present, is as defined in any one of claims 33 to 35.

[0347] In some embodiments of [1], R 2 is as defined in any one of claims 24 to 31 of US 62 / 742,218 filed on October 5, 2018. In some of the above embodiments, R 2 is phenyl optionally substituted with 2 R c , for example, R 2 is TIFF2025081550000228.tif16128, TIFF2025081550000229.tif17128; R c , when present, is as defined in any one of claims 33 to 35.

[0348] In certain embodiments of [1], R 2 is as defined in any one of claims 27 to 31 of US 62 / 742,218 filed on October 5, 2018. For example, R 2 is It may be 16128 for TIFF2025081550000230.tif.

[0349] In some embodiments of [1], R 2 is heteroaryl containing 5 to 10 (e.g., 6) ring atoms, 1 to 4 (e.g., 1 to 3) of which are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S (e.g., the group consisting of N, N(H), and N(R d )), and one or more of the heteroaryl ring carbon atoms may be substituted with 1 to 4 independently selected R c , and is heteroaryl, for example, R 2 is pyridinyl which may be substituted with 1 to 2 independently selected R c , or for example, R 2 is 17128 for TIFF2025081550000231.tif; R c , if present, is as defined in any one of claims 40 to 41.

[0350] In certain embodiments of [1], R 2 is 17128 for TIFF2025081550000232.tif.

[0351] In some embodiments of [1], R 2 is as defined in any one of claims 32 to 37 of US 62 / 742,218 filed on October 5, 2018. In some of the above embodiments, R 2 is as defined in any one of claims 34 to 37 of US 62 / 742,218 filed on October 5, 2018. For example, R 2 may be as defined in claim 37 of US 62 / 742,218 filed on October 5, 2018.

[0352] In some embodiments of [1], one occurrence of R 3 is -L 4 -R4 when it is -L 4 is selected from the group consisting of: · -N(H)S(O) 1~2 - or -N(R d )S(O) 1~2 (e.g., N(C 1~3 alkyl)S(O) 2 ), for example, L 4 is -N(H)S(O) 2 -; · -N(H)C(O)- or -N(R d )C(O), for example, L 4 is -N(H)C(O)-; · -C(O)NH- or -C(O)N(R d )-; · -N(H)-, -N(R d )-, or -N(R 4 )-; · single bond; · C≡C; · -O-; and · -N(H)S(O) 1~2 N(H)-, -N(R d )S(O) 1~2 N(H)-, -N(H)S(O) 1~2 N(R d )-, and -N(R d )S(O) 1~2 N(R d )-, for example, L 4 is -N(H)S(O) 1~2 N(H)-(e.g., -N(H)S(O) 2 N(H)-), or L 4 is -N(H)S(O) 1~2 N(R d )-(e.g., -N(H)S(O) 2 N(R d )-(e.g., -N(H)S(O) 2 N(C 1~3 alkyl)-)), and and is as defined in any one of claims 48 to 55 of US 62 / 742,218 filed on October 5, 2018.

[0353] ​In some embodiments of [1], one occurrence of R 3 is -L 4 -R 4 and, when -L 4 is selected from the group consisting of: · -N(H)S(O) 1~2 - or -N(R d )S(O) 1~2 (e.g., N(C 1~3 alkyl)S(O) 2 ), for example, L 4 is -N(H)S(O) 2 -; · -N(H)C(O)- or -N(R d )C(O), for example, L 4 is -N(H)C(O)-; · -C(O)NH- or -C(O)N(R d )-; · -N(H)-, -N(R d )-, or -N(R 4 )-; · a single bond; and · C≡C.

[0354] In some embodiments of [1], one occurrence of R 3 is -L 4 -R 4 and, when -L 4 is selected from the group consisting of: · N(H)S(O) 2 -; · -N(H)C(O)-; and · -N(H)-, -N(R d )-, or -N(R 4 )-.

[0355] In certain embodiments of [1], -L 4 is as defined in any one of claims 49, 51, and 53 of US 62 / 742,218, filed Oct. 5, 2018. For example, L 4 may be as defined in claim 49 of US 62 / 742,218, filed Oct. 5, 2018. In some embodiments of [1], R 3One occurrence of -L 4 -R 4 is the case, -L 4 is -NHS(O)(=NH)-.

[0356] In some embodiments of [1], R 3 One occurrence of -L 4 -R 4 is the case, -L 4 is selected from the group consisting of: · -N(H)S(O) 1~2 - or -N(R d )S(O) 1~2 (e.g., N(C 1~3 alkyl)S(O) 2 ), for example, L 4 is -N(H)S(O) 2 -; and · -N(H)S(O) 1~2 N(H)-, -N(R d )S(O) 1~2 N(H)-, -N(H)S(O) 1~2 N(R d )-, and -N(R d )S(O) 1~2 N(R d ), for example, L 4 is -N(H)S(O) 1~2 N(H)-(e.g., -N(H)S(O) 2 N(H)-), or L 4 is -N(H)S(O) 1~2 N(R d )(e.g., -N(H)S(O) 2 N(R d )(e.g., -N(H)S(O) 2 N(C 1~3 alkyl)-)).

[0357] In some embodiments of [1], R 3 One occurrence of -L 4 -R 4 is the case; R 4 is (Y 3 ) p -Y 4 is the case, Y 4is C which may be substituted by 1 to 4 Rs c aryl, for example phenyl which may be substituted by 1 to 2 (for example 1) Rs 6~10 or Y c is unsubstituted C 4 aryl, for example unsubstituted phenyl; R 6~10 when present, is as defined in any one of claims 73 to 75. c

[0358] In some embodiments of [1], one occurrence of R 3 is -L 4 -R 4 wherein; R 4 when (Y 3 ) p -Y 4 is the case, Y 4 is C c aryl which may be substituted by 1 to 4 Rs 6~10 for example phenyl which may be substituted by 1 to 4 Rs; R c each occurrence of, when present, is independently selected from the group consisting of: c (vii) C 1~4 alkoxy; (viii) C 1~4 haloalkoxy; and (xiv) -C 1~4 thioalkoxy.

[0359] In some embodiments of [1], one occurrence of R 3 is -L 4 -R 4 wherein; R 4 when (Y 3 ) p -Y 4 is the case, Y 4 is as defined in any one of claims 77, 78, 79, 81, and 82; R b when present, is as defined in claim 80. 3

[0360] In some embodiments of [1], R 3 ​One occurrence of -L 4 -R 4 and; R 4 is (Y 3 ) p -Y 4 then Y 4 is as defined in any one of claims 77 to 79; R b is, if present, as defined in claim 80.

[0361] In some embodiments of [1], one occurrence of R 3 is -L 4 -R 4 and; R 4 is (Y 3 ) p -Y 4 then Y 4 is as defined in any one of claims 83 to 85 and 88; R c is, if present, as defined in any one of claims 86 to 87.

[0362] In some embodiments of [1], one occurrence of R 3 is -L 4 -R 4 and; R 4 is (Y 3 ) p -Y 4 then Y 4 is as defined in any one of claims 83 to 85 and 88.

[0363] In some embodiments of [1], one occurrence of R 3 is -L 4 -R 4 and; R 4 is (Y 3 ) p -Y 4 then Y 4 is as defined in any one of claims 89 to 96; R b is, if present, as defined in any one of claims 97 to 98.

[0364] In some embodiments of [1], R 3 one occurrence of is -L 4 -R 4 and; R 4 is (Y 3 ) p -Y 4 when, Y 4 is as defined in any one of claims 89-92, 94, and 96; and R b , when present, is as defined in claim 98.

[0365] In some embodiments of [1], R 4 is selected from the group consisting of the structures recited in claims 99-113.

[0366] In some embodiments of [1], R 4 is selected from the group consisting of the structures recited in claims 100, 101, 104-105, 107, 109, 111, and 113.

[0367] In some embodiments of [1], R 3 one occurrence of is -L 4 -R 4 when, ·R 4 is C a alkyl which may be substituted with 1 to 6 independently selected R 1~10 ; or ·R 4 is C a alkyl which may be substituted with 1 to 6 independently selected R 1~6 ; or ·R 4 is C a alkyl which may be substituted with 1 to 2 independently selected R 1~6 , for example, R 4 is methyl, ethyl, TIFF2025081550000233.tif14128 (for example methyl and TIFF2025081550000234.tif12128) and is selected from the group consisting of; or ·R4 is C optionally substituted with 1 to 6 (e.g., 1 to 3) independently selected R a ; or 2~10 is C alkynyl (e.g., C 2~4 alkynyl) (e.g., non-substituted C alkynyl such as TIFF2025081550000235.tif8128; or 2~4 is C alkynyl); or ·R 4 is C optionally substituted with 1 to 6 (e.g., 1 to 3) independently selected R a ; or 2~10 is C alkenyl (e.g., C 2~4 alkenyl) (e.g., non-substituted C alkenyl such as vinyl 2~4 alkenyl); wherein each R a , when present, is independently selected from the group consisting of -F; -OH; C 1~4 alkoxy; and C 1~4 haloalkoxy, e.g., each occurrence of R a is independently -OH.

[0368] In some embodiments of [1], when one occurrence of R 3 is -L 4 -R 4 , ·R 4 is C alkyl optionally substituted with 1 to 6 independently selected R a ; or 1~10 ·R is C alkyl optionally substituted with 1 to 6 independently selected R 4 ; or a ·R 1~6 is C alkyl optionally substituted with 1 to 2 independently selected R ; e.g., methyl and 4 is C alkyl optionally substituted with 1 to 2 independently selected R a ; e.g., TIFF2025081550000236.tif12128; 1~6 wherein each R , when present, is independently selected from the group consisting of -F; -OH; C such as -OH; a ; etc.1~4 alkoxy; and C 1~4 is selected from the group consisting of haloalkoxy.

[0369] In some embodiments of [1], one occurrence of R 3 is -L 4 -R 4 If so, R 4 is as defined in any one of claims 56-60 and 61-63 of US 62 / 742,218, filed October 5, 2018.

[0370] In some embodiments of [1], one occurrence of R 3 is -L 4 -R 4 If so, R 4 is as defined in any one of claims 56-60 and 64-67 of US 62 / 742,218, filed October 5, 2018.

[0371] In some embodiments of [1], one occurrence of R 3 is -L 4 -R 4 If so, R 4 is as defined in any one of claims 56-60 and 68-71 of US 62 / 742,218, filed October 5, 2018.

[0372] In some embodiments of [1], one occurrence of R 3 is -L 4 -R 4 If so, R 4 is as defined in any one of claims 56-60 and 72-78 of US 62 / 742,218, filed October 5, 2018.

[0373] In some embodiments of [1], one occurrence of R 3 is -L 4 -R 4 If so, R 4 is as defined in any one of claims 56-60 and 79-86 of US 62 / 742,218, filed October 5, 2018.

[0374] In some embodiments of [1], R 3 one occurrence of is -L 4 -R 4 If so, R 4 is as defined in any one of claims 56-60 and 87-92 of US 62 / 742,218, filed October 5, 2018.

[0375] In certain embodiments of [1], -L 4 is -N(H)S(O) 2 -, -N(H)S(O) 2 N(H)-, -N(H)S(O) 2 N(R d )-, C≡C, a single bond, -C(O)N(H)-, -N(H)-, -N(R 4 )-, -N(R d )-, and -N(H)C(O)-; R 4 is selected from the group consisting of: (i) C a alkyl optionally substituted with 1-2 R 1~6 ; (ii) -(Y 3 ) p -Y 4 ; and (iii) C a alkenyl or C 2~10 alkynyl, each optionally substituted with 1-3 independently selected R 2~10 .

[0376] In certain embodiments of [1], -L 4 is -N(H)S(O) 2 -, -N(H)S(O) 2 N(H)-, and -N(H)S(O) 2 N(R d )-; R 4 is selected from the group consisting of: (i) C a alkyl optionally substituted with 1-2 R 1~6Alkyl; (ii) -(Y 3 ) p -Y 4 ; and (iii) C alkenyl or C alkynyl, each optionally substituted with 1 to 3 independently selected R. a 2~10 2~10

[0377] In some embodiments of [1], R is selected from the group consisting of the structures recited in claims 148 - 165; or R is selected from the group consisting of the structures recited in claims 148 - 149, 151, 153, 155 - 156, 158, 160, 162, and 165. 3 3

[0378] In some embodiments of [1], R is as defined in any one of claims 113 - 122 of US 62 / 742,218, filed October 5, 2018. 3

[0379] [1 - 1] In some embodiments of [1], X and X are each independently selected CR; X and X are each independently N or CH. In some of these embodiments, X and X are each N. In some of the above embodiments, each R is independently selected -L -R. 2 3 3 1 4 1 4 3 4 4

[0380] In some embodiments of [1 - 1], one occurrence of -L -R is -R (i.e., one occurrence of L is a bond). 4 4 4 4

[0381] In some of these embodiments, -L 4 other occurrences are selected from the group consisting of: · -N(H)S(O) 1~2 - or -N(R d )S(O) 1~2 (e.g., N(C 1~3 alkyl)S(O) 2 ), e.g., L 4 is -N(H)S(O) 2 -; · -N(H)C(O)- or -N(R d )C(O), e.g., L 4 is -N(H)C(O)-; · -C(O)NH- or -C(O)N(R d )-; · -N(H)-, -N(R d )-, or -N(R 4 )-; · single bond; · C≡C; · -O-; and · -N(H)S(O) 1~2 N(H)-, -N(R d )S(O) 1~2 N(H)-, -N(H)S(O) 1~2 N(R d )-, and -N(R d )S(O) 1~2 N(R d )-, e.g., L 4 is -N(H)S(O) 1~2 N(H)-(e.g., -N(H)S(O) 2 N(H)-) or L 4 is -N(H)S(O) 1~2 N(R d )-(e.g., -N(H)S(O) 2 N(R d )-(e.g., -N(H)S(O) 2 N(C 1~3 alkyl)-))

[0382] In certain embodiments, other occurrences of -L 4 are selected from the group consisting of: · -N(H)S(O)1~2 -or -N(R d )S(O) 1~2 (e.g., N(C 1~3 alkyl)S(O) 2 ), e.g., L 4 is -N(H)S(O) 2 -; · -N(H)C(O)- or -N(R d )C(O), e.g., L 4 is -N(H)C(O)-; · -C(O)NH- or -C(O)N(R d )-; · -N(H)-, -N(R d )-, or -N(R 4 )-; · single bond; and · C≡C.

[0383] In certain embodiments, the other occurrences of -L 4 are selected from the group consisting of: · -N(H)S(O) 2 -; · -N(H)C(O)-; and · -N(H)-, -N(R d )-, or -N(R 4 )-, e.g., the other occurrences of -L 4 are N(H)S(O) 2 -.

[0384] In certain embodiments, the other occurrences of -L 4 are selected from the group consisting of: -N(H)S(O) 1~2 - or -N(R d )S(O) 1~2 (e.g., N(C 1~3 alkyl)S(O) 2 ), e.g., L 4 is -N(H)S(O) 2 -; and -N(H)S(O) 1~2 N(H)-, -N(R d )S(O) 1~2 N(H)-, -N(H)S(O) 1~2 N(Rd )-, and -N(R d )S(O) 1~2 N(R d )-, for example, L 4 is -N(H)S(O) 1~2 N(H)-(for example -N(H)S(O) 2 N(H)-), or L 4 is -N(H)S(O) 1~2 N(R d )-(for example -N(H)S(O) 2 N(R d )-(for example -N(H)S(O) 2 N(C 1~3 alkyl)-)).

[0385] In some of the above embodiments, -L 4 's other occurrences are as defined in any one of claims 48 - 55 of US 62 / 742,218 filed on October 5, 2018. For example, -L 4 's other occurrences may be as defined in any one of claims 49, 51, and 53 (for example claim 49) of US 62 / 742,218 filed on October 5, 2018.

[0386] In some embodiments of [1 - 1], each R 4 is independently as defined in any one of claims 56 - 60 and 61 - 63 of US 62 / 742,218 filed on October 5, 2018.

[0387] In some embodiments of [1 - 1], each R 4 is independently as defined in any one of claims 56 - 60 and 64 - 67 of US 62 / 742,218 filed on October 5, 2018.

[0388] In some embodiments of [1 - 1], each R 4 is independently as defined in any one of claims 56 - 60 and 68 - 71 of US 62 / 742,218 filed on October 5, 2018.

[0389] In some embodiments of [1-1], each R 4 is independently as defined in any one of claims 56-60 and 72-78 of US 62 / 742,218, filed October 5, 2018.

[0390] In some embodiments of [1-1], each R 4 is independently as defined in any one of claims 79-86 of US 62 / 742,218, filed October 5, 2018.

[0391] In some embodiments of [1-1], each R 4 is independently as defined in any one of claims 87-92 of US 62 / 742,218, filed October 5, 2018.

[0392] In some embodiments of [1-1], R 1 is as defined in any one of claims 10-23 of US 62 / 742,218, filed October 5, 2018.

[0393] In some embodiments of [1-1], R 1 is as defined in any one of claims 16-23 of US 62 / 742,218, filed October 5, 2018.

[0394] In some embodiments of [1-1], R 1 is as defined in claim 23 of US 62 / 742,218, filed October 5, 2018.

[0395] In some embodiments of [1-1], R 2 is as defined in any one of claims 24-31 of US 62 / 742,218, filed October 5, 2018.

[0396] In some embodiments of [1-1], R 2 is as defined in any one of claims 27-31 of US 62 / 742,218, filed October 5, 2018.

[0397] In some embodiments of [1-1], R 2 is as defined in any one of claims 32 to 37 (e.g., 34 to 37) of US 62 / 742,218 filed on October 5, 2018.

[0398] [1-2] In some embodiments of [1], X 2 and X 3 are each independently selected CR 3 ; X 1 and X 4 are each independently N or CH. In some of these embodiments, X 1 and X 4 are each N.

[0399] In some embodiments of [1-2], one occurrence of R 3 is -L 4 -R 4 (e.g., -L 4 is as defined in claim 49); and the other occurrences of R 3 are R c ' (e.g., R c' may be halo, e.g., -Cl).

[0400] In some of these embodiments, -L 4 is selected from the group consisting of: · -N(H)S(O) 1~2 - or -N(R d )S(O) 1~2 (e.g., N(C 1~3 alkyl)S(O) 2 ), e.g., L 4 is -N(H)S(O) 2 -; · -N(H)C(O)- or -N(R d )C(O), e.g., L 4 is -N(H)C(O)-; · -C(O)NH- or -C(O)N(R d )-; · -N(H)-, -N(Rd )-, or -N(R 4 )-; · Single bond; · C≡C; · -O-; and · -N(H)S(O) 1~2 N(H)-, -N(R d )S(O) 1~2 N(H)-, -N(H)S(O) 1~2 N(R d )-, and -N(R d )S(O) 1~2 N(R d )-, for example, L 4 is -N(H)S(O) 1~2 N(H)-(for example -N(H)S(O) 2 N(H)-), or L 4 is -N(H)S(O) 1~2 N(R d )-(for example -N(H)S(O) 2 N(R d )-(for example -N(H)S(O) 2 N(C 1~3 alkyl)-)).

[0401] In certain embodiments, -L 4 is selected from the group consisting of: · -N(H)S(O) 1~2 - or -N(R d )S(O) 1~2 (for example N(C 1~3 alkyl)S(O) 2 ), for example, L 4 is -N(H)S(O) 2 -; · -N(H)C(O)- or -N(R d )C(O), for example, L 4 is -N(H)C(O)-; · -C(O)NH- or -C(O)N(R d )-; · -N(H)-, -N(R d )-, or -N(R 4 )-; · Single bond; and · C≡C.

[0402] In certain embodiments, -L 4 is selected from the group consisting of: · -N(H)S(O) 2 -; · -N(H)C(O)-; and · -N(H)-, -N(R d )-, or -N(R 4 )-, for example, other occurrences of -L 4 are N(H)S(O) 2 -.

[0403] In certain embodiments, -L 4 is selected from the group consisting of: · -N(H)S(O) 1~2 - or -N(R d )S(O) 1~2 (e.g., N(C 1~3 alkyl)S(O) 2 ), for example, L 4 is -N(H)S(O) 2 -; and · -N(H)S(O) 1~2 N(H)-, -N(R d )S(O) 1~2 N(H)-, -N(H)S(O) 1~2 N(R d )-, and -N(R d )S(O) 1~2 N(R d ), for example, L 4 is -N(H)S(O) 1~2 N(H)-(e.g., -N(H)S(O) 2 N(H)-), or L 4 is -N(H)S(O) 1~2 N(R d )-(e.g., -N(H)S(O) 2 N(R d )-(e.g., -N(H)S(O) 2 N(C 1~3 alkyl)-)).

[0404] In some of the above embodiments, -L 4Other occurrences are as defined in any one of claims 48 to 55 of US 62 / 742,218 filed on October 5, 2018. For example, -L 4 Other occurrences may also be as defined in any one of claims 49, 51, and 53 (e.g., claim 49) of US 62 / 742,218 filed on October 5, 2018.

[0405] In some embodiments of [1-2], each R 4 is independently as defined in any one of claims 56 to 60 and 61 to 63 of US 62 / 742,218 filed on October 5, 2018.

[0406] In some embodiments of [1-2], each R 4 is independently as defined in any one of claims 56 to 60 and 64 to 67 of US 62 / 742,218 filed on October 5, 2018.

[0407] In some embodiments of [1-2], each R 4 is independently as defined in any one of claims 56 to 60 and 68 to 71 of US 62 / 742,218 filed on October 5, 2018.

[0408] In some embodiments of [1-2], each R 4 is independently as defined in any one of claims 56 to 60 and 72 to 78 of US 62 / 742,218 filed on October 5, 2018.

[0409] In some embodiments of [1-2], each R 4 is independently as defined in any one of claims 79 to 86 of US 62 / 742,218 filed on October 5, 2018.

[0410] In some embodiments of [1-2], each R 4 is independently as defined in any one of claims 87 to 92 of US 62 / 742,218 filed on October 5, 2018.

[0411] In some embodiments of [1-2], R 1 is as defined in any one of claims 10-23 of US 62 / 742,218 filed on October 5, 2018.

[0412] In some embodiments of [1-2], R 1 is as defined in any one of claims 16-23 of US 62 / 742,218 filed on October 5, 2018.

[0413] In some embodiments of [1-2], R 1 is as defined in claim 23 of US 62 / 742,218 filed on October 5, 2018.

[0414] In some embodiments of [1-2], R 2 is as defined in any one of claims 24-31 of US 62 / 742,218 filed on October 5, 2018.

[0415] In some embodiments of [1-2], R 2 is as defined in any one of claims 27-31 of US 62 / 742,218 filed on October 5, 2018.

[0416] In some embodiments of [1-2], R 2 is as defined in any one of claims 32-37 (e.g., 34-37) of US 62 / 742,218 filed on October 5, 2018.

[0417] Non-limiting combination [2] In some embodiments, the compound of formula (I) is of formula (I-a1-a): the compound of TIFF2025081550000237.tif39128, or a pharmaceutically acceptable salt thereof.

[0418] In some embodiments of [2], -L 4 is selected from the group consisting of: ·-N(H)S(O) 1~2 - or -N(R d )S(O) 1~2 (e.g., N(C 1~3 alkyl)S(O) 2 ), for example, L 4 is -N(H)S(O) 2 -; and ·-N(H)S(O) 1~2 N(H)-, -N(R d )S(O) 1~2 N(H)-, -N(H)S(O) 1~2 N(R d )-, and -N(R d )S(O) 1~2 N(R d )-, for example, L 4 is -N(H)S(O) 1~2 N(H)-(e.g., -N(H)S(O) 2 N(H)-), or L 4 is -N(H)S(O) 1~2 N(R d )-(e.g., -N(H)S(O) 2 N(R d )-(e.g., -N(H)S(O) 2 N(C 1~3 alkyl)-)).

[0419] [2] In certain embodiments, the compound of formula (I-a1-a) is of formula (I-a1-a1): The compound of TIFF2025081550000238.tif43128, or a pharmaceutically acceptable salt thereof.

[0420] [2] In certain embodiments, the compound of formula (I-a1-a) is of formula (I-a1-a2): The compound of TIFF2025081550000239.tif43128, or a pharmaceutically acceptable salt thereof.

[0421] [2] In certain embodiments, the compound of formula (I-a1-a) is of formula (I-a1-a3): TIFF2025081550000240.tif43128 (e.g., R c'is a halo, for example, -Cl) or a pharmaceutically acceptable salt thereof.

[0422] In some of the above embodiments of [2], R 1 is as defined in any one of claims 10 to 23 of US 62 / 742,218 filed on October 5, 2018; and / or, R 2 is as defined in any one of claims 24 to 37 of US 62 / 742,218 filed on October 5, 2018; and / or, R 4 is as defined in any one of claims 56 to 92 of US 62 / 742,218 filed on October 5, 2018.

[0423] In a specific embodiment of [2], the compound of formula (I-a1-a) is of formula (I-a1-a4): TIFF2025081550000241.tif50128 (for example, R 3 is R c' ; or R 3 is -L 4 -R 4 )( or a pharmaceutically acceptable salt thereof.

[0424] In a specific embodiment of formula (I-a1-a4), L 3 is NHS(O) 2 .

[0425] In a specific embodiment of formula (I-a1-a4), R 3 is H.

[0426] In a specific embodiment of formula (I-a1-a4), R 3 is R c' , for example, halo (for example, -Cl).

[0427] In a specific embodiment of formula (I-a1-a4), R 3 is -L 4 -R 4 .

[0428] In some of the above aspects of [2] (for example, when the compound has the formula (I-a1-a4)), L 4 is as defined in any one of claims 48 to 55 of US 62 / 742,218 filed on October 5, 2018; and / or, R 4 is as defined in claims 56 to 60 of US 62 / 742,218 filed on October 5, 2018 and claims 61 to 63 of US 62 / 742,218 filed on October 5, 2018; or claims 56 to 60 of US 62 / 742,218 filed on October 5, 2018 and claims 64 to 67 of US 62 / 742,218 filed on October 5, 2018; or claims 56 to 60 of US 62 / 742,218 filed on October 5, 2018 and claims 68 to 71 of US 62 / 742,218 filed on October 5, 2018; or claims 56 to 60 of US 62 / 742,218 filed on October 5, 2018 and claims 72 to 78 of US 62 / 742,218 filed on October 5, 2018; or claims 79 to 86 of US 62 / 742,218 filed on October 5, 2018; or claims 87 to 92 of US 62 / 742,218 filed on October 5, 2018, as defined in any one of these claims.

[0429] [2-1] In some aspects of [2], the compound of formula (I-a1-a) is of formula (I-a1-a5): The compound of TIFF2025081550000242.tif38128, or a pharmaceutically acceptable salt thereof.

[0430] In some aspects of [2-1], R c' is halo (e.g., -Cl).

[0431] In some aspects of [2-1], R 1 is as defined in any one of claims 10 to 23 of US 62 / 742,218 filed on October 5, 2018.

[0432] In some aspects of [2-1], R 2It is as defined in any one of claims 24 to 37 (for example, claims 24 to 31) of US 62 / 742,218 filed on October 5, 2018.

[0433] In some embodiments of [2-1], R 4 is as defined in any one of claims 56 to 92 (for example, claims 87 to 92) of US 62 / 742,218 filed on October 5, 2018. In some embodiments of [2-1], L 4 is -NHS(O) 2 -.

[0434] In some embodiments of [2-1], L 4 is -N(H)S(O) 2 N(H)- or -N(H)S(O) 2 N(R d )-.

[0435] [2-2] In some embodiments of [2], the compound of formula (I-a1-a) is a compound of formula (I-a1-a6): TIFF2025081550000243.tif38128, or a pharmaceutically acceptable salt thereof, wherein each of L 4A and L 4B is independently selected L 4 ; Each of R 4A and R 4B is independently selected R 4 .

[0436] In some embodiments of [2-2], L 4B is a bond.

[0437] In some embodiments of [2-2], R 1 is as defined in any one of claims 10 to 23 of US 62 / 742,218 filed on October 5, 2018.

[0438] In some embodiments of [2-2], R 2is as defined in any one of claims 24 to 37 (for example, claims 24 to 31) of US 62 / 742,218 filed on October 5, 2018.

[0439] In some embodiments of [2-2], R 4A is as defined in any one of claims 56 to 92 of US 62 / 742,218 filed on October 5, 2018.

[0440] In some embodiments of [2-2], L 4A is -NHS(O) 2 -.

[0441] In some embodiments of [2-2], L 4 is -N(H)S(O) 2 N(H)- or -N(H)S(O) 2 N(R d )-.

[0442] In some embodiments of [2-2], R 4B is as defined in any one of claims 56 to 92 (for example, claims 56 to 60 and 64 to 67) of US 62 / 742,218 filed on October 5, 2018.

[0443] [2-3] In some embodiments of [2], the compound of formula (I-a1-a) is a compound of formula (I-a1-a7), (I-a1-a8), or (I-a1-a9): TIFF2025081550000244.tif47143's compound, or a pharmaceutically acceptable salt thereof, wherein R d' is H or R d (for example, H or C 1~3 alkyl).

[0444] Non-limiting combination [3] In some embodiments, the compound of formula (I) is of formula (I-a1-b): It is a compound of TIFF2025081550000245.tif34128, or a pharmaceutically acceptable salt thereof.

[0445] In certain embodiments of [3], the compound of formula (I-a1-b) is of formula (I-a1-b1) or formula (I-a1-b2): TIFF2025081550000246.tif39128 (e.g., L 4 is N(H)SO 2 , -N(H)-, or NHC(O)) It is a compound of, or a pharmaceutically acceptable salt thereof.

[0446] In some embodiments of [3], -L 4 is selected from the group consisting of: -N(H)S(O) 1~2 - or -N(R d )S(O) 1~2 (e.g., N(C 1~3 alkyl)S(O) 2 ), e.g., L 4 is -N(H)S(O) 2 -; and -N(H)S(O) 1~2 N(H)-, -N(R d )S(O) 1~2 N(H)-, -N(H)S(O) 1~2 N(R d )-, and -N(R d )S(O) 1~2 N(R d )-, e.g., L 4 is -N(H)S(O) 1~2 N(H)-(e.g., -N(H)S(O) 2 N(H)-), or L 4 is -N(H)S(O) 1~2 N(R d )-(e.g., -N(H)S(O) 2 N(R d )-(e.g., -N(H)S(O) 2 N(C 1~3 alkyl)-)).

[0447] In some of the above embodiments of [3], R 1 is as defined in any one of claims 10 to 23 of US 62 / 742,218 filed on October 5, 2018; and / or, R 2 is as defined in any one of claims 24 to 37 of US 62 / 742,218 filed on October 5, 2018; and / or, R 4 is as defined in any one of claims 56 to 92 of US 62 / 742,218 filed on October 5, 2018.

[0448] In some of the above embodiments of [3], R c ' is halo (e.g., Cl, Br), -OH, and NH 2 selected from.

[0449] Non-limiting combination [4] In some embodiments, the compound of formula (I) is a compound of formula (I-a2-a): the compound of TIFF2025081550000247.tif34128, or a pharmaceutically acceptable salt thereof.

[0450] In a particular embodiment of [4], the compound of formula (I-a2-a1) is a compound of formula (I-a2-a1): the compound of TIFF2025081550000248.tif43128, or a pharmaceutically acceptable salt thereof.

[0451] In some of the above embodiments of [4], R 1 is as defined in any one of claims 10 to 23 of US 62 / 742,218 filed on October 5, 2018; and / or, R 2 is as defined in any one of claims 24 to 37 of US 62 / 742,218 filed on October 5, 2018; and / or, R 4 is as defined in any one of claims 56 to 92 of US 62 / 742,218 filed on October 5, 2018.

[0452] In certain embodiments of [4], the compound of formula (I-a2-a) is of formula (I-a1-a2): TIFF2025081550000249.tif50128 (e.g., L 4 is NHS(O) 2 (i.e.) the compound of, or a pharmaceutically acceptable salt thereof.

[0453] In some of the above embodiments of [4] (e.g., when the compound has formula (I-a2-a2)), L 4 is as defined in any one of claims 48 - 55 (e.g., 49) of US 62 / 742,218 filed on October 5, 2018; and / or R 4 is as defined in claims 56 - 60 of US 62 / 742,218 filed on October 5, 2018 and claims 61 - 63 of US 62 / 742,218 filed on October 5, 2018; or claims 56 - 60 of US 62 / 742,218 filed on October 5, 2018 and claims 64 - 67 of US 62 / 742,218 filed on October 5, 2018; or claims 56 - 60 of US 62 / 742,218 filed on October 5, 2018 and claims 68 - 71 of US 62 / 742,218 filed on October 5, 2018; or claims 56 - 60 of US 62 / 742,218 filed on October 5, 2018 and claims 72 - 78 of US 62 / 742,218 filed on October 5, 2018; or claims 79 - 86 of US 62 / 742,218 filed on October 5, 2018; or claims 87 - 92 of US 62 / 742,218 filed on October 5, 2018, as defined in any one of these claims.

[0454] Non-limiting combination [5] In some embodiments, the compound of formula (I) is of formula (I-b1-a): TIFF2025081550000250.tif34128 the compound of, or a pharmaceutically acceptable salt thereof.

[0455] In certain embodiments of [5], the compound of formula (I-b1-a) is of formula (I-b1-a1): The compound of TIFF2025081550000251.tif43128, or a pharmaceutically acceptable salt thereof.

[0456] [5] In some of the above embodiments, R 1 is as defined in any one of claims 10 to 23 of US 62 / 742,218 filed on October 5, 2018; and / or, R 2 is as defined in any one of claims 24 to 37 of US 62 / 742,218 filed on October 5, 2018; and / or, R 4 is as defined in any one of claims 56 to 92 of US 62 / 742,218 filed on October 5, 2018.

[0457] [5] In a particular embodiment, the compound of formula (I-b1-a) is of formula (I-b1-a3): The compound of TIFF2025081550000252.tif51128, or a pharmaceutically acceptable salt thereof, wherein R d' is H or R d (e.g., H or C 1~3 alkyl).

[0458] [5] In a particular embodiment, the compound of formula (I-b1-a) is of formula (I-b1-a2): The compound of TIFF2025081550000253.tif52128 (e.g., L 4 is NHS(O) 2 )( ), or a pharmaceutically acceptable salt thereof.

[0459] In a particular embodiment of formula (I-b1-a2), L 4 is NHS(O) 2 .

[0460] [5] In some of the above embodiments (e.g., when the compound has formula (I-b1-a2)), L 4is as defined in any one of claims 48 - 55 (e.g., 49) of US 62 / 742,218 filed on October 5, 2018; and / or R 4 is as defined in any one of claims 56 - 60 of US 62 / 742,218 filed on October 5, 2018 and claims 61 - 63 of US 62 / 742,218 filed on October 5, 2018; or claims 56 - 60 of US 62 / 742,218 filed on October 5, 2018 and claims 64 - 67 of US 62 / 742,218 filed on October 5, 2018; or claims 56 - 60 of US 62 / 742,218 filed on October 5, 2018 and claims 68 - 71 of US 62 / 742,218 filed on October 5, 2018; or claims 56 - 60 of US 62 / 742,218 filed on October 5, 2018 and claims 72 - 78 of US 62 / 742,218 filed on October 5, 2018; or claims 79 - 86 of US 62 / 742,218 filed on October 5, 2018; or claims 87 - 92 of US 62 / 742,218 filed on October 5, 2018.

[0461] Non-limiting combination [6] In some embodiments, the compound of formula (I) is of formula (I - c1 - a): the compound of TIFF2025081550000254.tif34128, or a pharmaceutically acceptable salt thereof.

[0462] In certain embodiments of [6], the compound of formula (I - c1 - a) is of formula (I - c1 - a1): the compound of TIFF2025081550000255.tif43128, or a pharmaceutically acceptable salt thereof.

[0463] In some of the above embodiments of [6], R 1 is as defined in any one of claims 10 - 23 of US 62 / 742,218 filed on October 5, 2018; and / or R 2is as defined in any one of claims 24 to 37 of US 62 / 742,218 filed on October 5, 2018; and / or R 4 is as defined in any one of claims 56 to 92 of US 62 / 742,218 filed on October 5, 2018.

[0464] In certain embodiments of [6], the compound of formula (I-c1-a) is of formula (I-c1-a2): TIFF2025081550000256.tif50128 (e.g., L 4 is NHS(O) 2 (where) or a pharmaceutically acceptable salt thereof.

[0465] In some of the above embodiments of [6] (e.g., when the compound has formula (I-c1-a2)), L 4 is as defined in any one of claims 48 to 55 (e.g., 49) of US 62 / 742,218 filed on October 5, 2018; and / or R 4 is as defined in claims 56 to 60 and claims 61 to 63 of US 62 / 742,218 filed on October 5, 2018; or claims 56 to 60 and claims 64 to 67 of US 62 / 742,218 filed on October 5, 2018; or claims 56 to 60 and claims 68 to 71 of US 62 / 742,218 filed on October 5, 2018; or claims 56 to 60 and claims 72 to 78 of US 62 / 742,218 filed on October 5, 2018; or claims 79 to 86 of US 62 / 742,218 filed on October 5, 2018; or claims 87 to 92 of US 62 / 742,218 filed on October 5, 2018.

[0466] Non-limiting combination [7] In some embodiments, the compound of formula (I) is a compound of formula (I-d1-a): the compound of TIFF2025081550000257.tif34128, or a pharmaceutically acceptable salt thereof.

[0467] In certain embodiments of [7], the compound of formula (I-d1-a) is a compound of formula (I-d1-a1): the compound of TIFF2025081550000258.tif43128, or a pharmaceutically acceptable salt thereof.

[0468] In certain embodiments of [7], R 1 is as defined in any one of claims 10 to 23 of US 62 / 742,218 filed on October 5, 2018; and / or, R 2 is as defined in any one of claims 24 to 37 of US 62 / 742,218 filed on October 5, 2018; and / or, R 4 is as defined in any one of claims 56 to 92 of US 62 / 742,218 filed on October 5, 2018.

[0469] In certain embodiments of [7], the compound of formula (I-d1-a) is a compound of formula (I-d1-a2): TIFF2025081550000259.tif50128 (for example, L 4 is NHS(O) 2 )( the compound of, or a pharmaceutically acceptable salt thereof.

[0470] In some of the above embodiments of [7] (for example, when the compound has formula (I-c1-a2)), L 4 is as defined in any one of claims 48 to 55 (for example 49) of US 62 / 742,218 filed on October 5, 2018; and / or, R 4is as defined in any one of claims 56 to 60 of US 62 / 742,218 filed on October 5, 2018 and claims 61 to 63 of US 62 / 742,218 filed on October 5, 2018; or claims 56 to 60 of US 62 / 742,218 filed on October 5, 2018 and claims 64 to 67 of US 62 / 742,218 filed on October 5, 2018; or claims 56 to 60 of US 62 / 742,218 filed on October 5, 2018 and claims 68 to 71 of US 62 / 742,218 filed on October 5, 2018; or claims 56 to 60 of US 62 / 742,218 filed on October 5, 2018 and claims 72 to 78 of US 62 / 742,218 filed on October 5, 2018; or claims 79 to 86 of US 62 / 742,218 filed on October 5, 2018; or claims 87 to 92 of US 62 / 742,218 filed on October 5, 2018.

[0471] [1-1], [1-2], [2], [2-1], [2-2], [2-3], [3], [4], [5], [6], and [7], in certain embodiments related to any one or more thereof, R 4 is selected from the group consisting of: (i) C a alkyl optionally substituted with 1 to 6 independently selected R 1~10 ; (ii) -(Y 3 ) p -Y 4 ; and (iii) C a alkenyl or C 2~10 alkynyl, each optionally substituted with 1 to 3 independently selected R 2~10 .

[0472] [1-1], [1-2], [2], [2-1], [2-2], [2-3], [3], [4], [5], [6], and [7], in certain embodiments related to any one or more thereof, R 4 is -(Y 3 ) p -Y 4 .

[0473] In certain embodiments relating to any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3], [3], [4], [5], [6], and [7], R 4 is -(Y 3 ) p -Y 4 wherein Y 4 is C c aryl which may be substituted with 1 to 4 R 6~10 s, for example phenyl which may be substituted with 1 to 2 (for example 1) R c s, or Y 4 is unsubstituted C 6~10 aryl, for example unsubstituted phenyl; and R c , when present, is as defined in any one of claims 73 to 75 (for example claim 75).

[0474] In certain embodiments relating to any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3], [3], [4], [5], [6], and [7], R 4 is -(Y 3 ) p -Y 4 wherein Y 4 is C c aryl which may be substituted with 1 to 4 R 6~10 s, for example phenyl which may be substituted with 1 to 4 R c s; and each occurrence of R c , when present, is independently selected from the group consisting of: (vii) C 1~4 alkoxy; (viii) C 1~4 haloalkoxy; and (xiv) -C 1~4 thioalkoxy.

[0475] In certain embodiments relating to any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3], [3], [4], [5], [6], and [7], R4 is -(Y 3 ) p -Y 4 in the case of, Y 4 is as defined in any one of claims 77, 78, 79, 81, and 82; R b is, when present, as defined in claim 80.

[0476] In a particular aspect related to any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3], [3], [4], [5], [6], and [7], R 4 is -(Y 3 ) p -Y 4 in the case of, Y 4 is as defined in any one of claims 77 to 79; R b is, when present, as defined in claim 80.

[0477] In a particular aspect related to any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3], [3], [4], [5], [6], and [7], R 4 is -(Y 3 ) p -Y 4 in the case of, Y 4 is as defined in any one of claims 83 to 85 and 88; R c is, when present, as defined in any one of claims 86 to 87.

[0478] In a particular aspect related to any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3], [3], [4], [5], [6], and [7], R 4 is -(Y 3 ) p -Y 4 in the case of, Y 4 is as defined in any one of claims 83 to 85 and 88.

[0479] In certain embodiments related to any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3], [3], [4], [5], [6], and [7], R 4 is -(Y 3 ) p -Y 4 where Y 4 is as defined in any one of claims 89 to 96; and R b , if present, is as defined in any one of claims 97 to 98.

[0480] In certain embodiments related to any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3], [3], [4], [5], [6], and [7], R 4 is -(Y 3 ) p -Y 4 where Y 4 is as defined in any one of claims 89 to 92, 94, and 96; and R b , if present, is as defined in claim 98.

[0481] In certain embodiments related to any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3], [3], [4], [5], [6], and [7], R 4 is -(Y 3 ) p -Y 4 in which case p is 0.

[0482] In other embodiments, p is 1. In some of these embodiments, Y 3 is C 1~3 alkylene, such as CH 2 or CH 2 -CH 2 .

[0483] In certain embodiments related to any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3], [3], [4], [5], [6], and [7], R4 is selected from the group consisting of the structures described in claims 99 to 113.

[0484] [1-1], [1-2], [2], [2-1], [2-2], [2-3], [3], [4], [5], [6], and [7], in certain embodiments related to any one or more of them, each R 4 is selected from the group consisting of the structures described in claims 100, 101, 104 to 105, 107, 109, 111, and 113.

[0485] [1-1], [1-2], [2], [2-1], [2-2], [2-3], [3], [4], [5], [6], and [7], in certain embodiments related to any one or more of them, ·R 4 is C a alkyl which may be substituted with 1 to 6 independently selected R 1~10 ; or ·R 4 is C a alkyl which may be substituted with 1 to 6 independently selected R 1~6 ; or ·R 4 is C a alkyl which may be substituted with 1 to 2 independently selected R 1~6 and, for example, R 4 is selected from the group consisting of methyl, ethyl, TIFF2025081550000260.tif14128 (for example methyl and TIFF2025081550000261.tif12128); or ·R 4 is C a alkynyl which may be substituted with 1 to 6 (for example 1 to 3) independently selected R 2~10 and, for example, C 2~4 alkynyl (for example TIFF2025081550000262.tif8128 such as unsubstituted C 2~4 alkynyl); or ·R 4is 1 to 6 (e.g., 1 to 3) independently selected R a C which may be substituted with 2~10 Alkenyl (e.g., C 2~4 alkenyl) (e.g. unsubstituted C 2~4 alkenyl); Here, each R a are, if present, independently: -F; -OH; C 1~4 Alkoxy; and C 1~4 haloalkoxy, for example, R a Each occurrence of is independently -OH.

[0486] In certain embodiments relating to any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3], [3], [4], [5], [6], and [7], ·R 4 is 1 to 6 independently selected R a C which may be substituted with 1~10 is alkyl; or ·R 4 is 1 to 6 independently selected R a C which may be substituted with 1~6 is alkyl; or ·R 4 is one or two independently selected R a C which may be substituted with 1~6 Alkyl, such as methyl and TIFF2025081550000263.tif12128; Here, each R a When present, they are independently: -OH, -F; -OH; C 1~4 Alkoxy; and C 1~4 haloalkoxy.

[0487] In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3], [3], [4], [5], [6], and [7], R 1 Is -(Y 1 )n -Y 2 is as follows.

[0488] In some of these aspects, Y 2 is as defined in any one of claims 14 to 20; each R c , when present, is independently as defined in any one of claims 21 to 24.

[0489] In a specific aspect related to any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3], [3], [4], [5], [6], and [7], R 1 is -(Y 1 ) n -Y 2 is the case, Y 2 is as defined in any one of claims 14 to 18 and 26; each R c , when present, is as defined in any one of claims 21 to 23.

[0490] In a specific aspect related to any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3], [3], [4], [5], [6], and [7], R 1 is -(Y 1 ) n -Y 2 is the case, Y 2 is as defined in any one of claims 16 to 18; each R c , when present, is as defined in any one of claims 21 to 23.

[0491] In a specific aspect related to any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3], [3], [4], [5], [6], and [7], R 1 is -(Y 1 ) n -Y 2 is the case, n is 0.

[0492] In certain embodiments related to any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3], [3], [4], [5], [6], and [7], R 1 is -(Y 1 ) n -Y 2 and when it is, R 1 is TIFF2025081550000264.tif15128. As a non-limiting example, R 1 may be TIFF2025081550000265.tif13128.

[0493] In certain embodiments related to any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3], [3], [4], [5], [6], and [7], R 2 is C c aryl which may be substituted with 1 to 4 R 6~10 , for example phenyl which may be substituted with 1 to 4 R c or 1 to 2 R c or 2 R c ; R c , when present, is as defined in any one of claims 33 to 35.

[0494] In certain embodiments related to any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3], [3], [4], [5], [6], and [7], R 2 is phenyl which may be substituted with 2 R c , for example, R 2 is TIFF2025081550000266.tif17128; R c , when present, is as defined in any one of claims 33 to 35.

[0495] In certain embodiments related to any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3], [3], [4], [5], [6], and [7], R 2 is heteroaryl containing 5 to 10 (e.g., 6) ring atoms, wherein 1 to 4 (e.g., 1 to 3) ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R d ), O, and S (e.g., the group consisting of N, N(H), N(R d ), and O), and one or more of the heteroaryl ring carbon atoms may be substituted with 1 to 4 independently selected R c ; for example, R 2 is pyridinyl which may be substituted with 1 to 2 independently selected R c ; or for example, R 2 is TIFF2025081550000267.tif17128; R c , if present, is as defined in any one of claims 40 to 41.

[0496] In certain embodiments related to any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3], [3], [4], [5], [6], and [7], R 2 is TIFF2025081550000268.tif17128.

[0497] In certain embodiments related to any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3], [3], [4], [5], [6], and [7], R 1 is -(Y 1 ) n -Y 2 ; R 2 is C c aryl which may be substituted with 1 to 4 R 6~10 .

[0498] In some of these embodiments, n is 0.

[0499] In certain embodiments relating to any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3], [3], [4], [5], [6], and [7], R 1 is -(Y 1 ) n -Y 2 wherein Y 2 is heteroaryl containing 6 ring atoms, 1 to 2 of the ring atoms being N, and one or more of the heteroaryl ring carbon atoms being optionally substituted with 1 to 4 independently selected R c and is heteroaryl.

[0500] In certain embodiments relating to any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3], [3], [4], [5], [6], and [7], R 1 is -(Y 1 ) n -Y 2 wherein Y 2 is pyridyl (such as 2-pyridyl or 6-pyridyl) optionally substituted with 1 to 4 (e.g., 1) independently selected R c on one or more of the ring carbon atoms.

[0501] In certain embodiments relating to any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3], [3], [4], [5], [6], and [7], R 1 is -(Y 1 ) n -Y 2 wherein; when Y 2 is heteroaryl such as pyridyl optionally substituted with 1 to 4 independently selected R c as defined above, each occurrence of R c is independently selected C 1~4 alkoxy (such as -OCH 3 , -OCH 2 CH 3 ).

[0502] As a non-limiting example, R 1 is TIFF2025081550000269.tif13128.

[0503] In certain embodiments related to any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3], [3], [4], [5], [6], and [7] (where R 1 is -(Y 1 )) n -Y 2 ), R 2 is a C c aryl which may be substituted with 1 to 4 R 6~10 s. For example, R 2 is a phenyl which may be substituted with 1 to 4 R c s.

[0504] In some of these embodiments, R 2 is a phenyl which may be substituted with 2 R c s. For example, R 2 may be TIFF2025081550000270.tif15128.

[0505] In certain embodiments related to any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3], [3], [4], [5], [6], and [7], R 1 is TIFF2025081550000271.tif13128; R 2 is TIFF2025081550000272.tif16128.

[0506] This specification ends with 302 claims. For ease of explanation, certain variable provisions are referred to by one or more specific claim numbers, and thus the entire subject matter of each claim referred to is understood to be incorporated by reference in its entirety into the part of the present disclosure to which it is referred. To avoid doubt, and by way of non-limiting example, the use of phrases such as "Y 4 is as defined in any one of claims 77, 78, 79, 81, and 82" is intended to represent a shorthand description of the following set of provisions. Y 4 is C b optionally substituted with 1 to 4 R 3~6 (e.g., C 3~4 or C 6 ) cycloalkyl. Y 4 is cyclopropyl or cyclobutyl optionally substituted with 1 to 2 R b . Y 4 is C b cycloalkyl (e.g., cyclohexyl) optionally substituted with 1 to 2 R 6 . Y 4 is unsubstituted C 3~6 (e.g., C 3~4 or C 6 ) cycloalkyl. Y 4 is unsubstituted cyclopropyl or unsubstituted cyclobutyl (e.g., unsubstituted cyclopropyl). Y 4 is C b cycloalkyl optionally substituted with 1 to 4 R 3~6 (e.g., C 3~4 or C 6 ); cyclopropyl or cyclobutyl optionally substituted with 1 to 2 R b ; C b cycloalkyl (e.g., cyclohexyl) optionally substituted with 1 to 2 R 6 ; unsubstituted C 3~6 (e.g., C 3~4 or C 6)It is selected from the group consisting of cycloalkyl; and unsubstituted cyclopropyl or unsubstituted cyclobutyl (such as unsubstituted cyclopropyl).

[0507] This also applies to the claims incorporated by reference from the priority document US 62 / 742,218, filed on October 5, 2018.

[0508] Pharmaceutical compositions and administration General In some embodiments, a chemical entity (such as a compound, or a pharmaceutically acceptable salt and / or hydrate and / or prodrug of the compound) that modulates (such as stimulates) the APJ receptor is administered as a pharmaceutical composition comprising the chemical entity, one or more pharmaceutically acceptable excipients, and optionally one or more additional therapeutic agents described herein.

[0509] In some embodiments, the chemical entity can be administered in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-α-tocopherol polyethylene glycol 1000 succinate, Tween, poloxamer, or other similar polymeric delivery matrices surfactants used in pharmaceutical dosage forms, serum proteins such as human serum albumin, buffering substances such as phosphates, Tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, protamine sulfate, sodium hydrogen phosphate, potassium hydrogen phosphate, salts or electrolytes such as sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, wax, polyethylene-polyoxypropylene block copolymers, and lanolin, but are not limited thereto. Also, cyclodextrins such as α-, β-, and γ-cyclodextrins, or hydroxyalkyl cyclodextrins including 2- and 3-hydroxypropyl-β-cyclodextrin, or other chemical modification derivatives such as solubilizing derivatives can be used to improve the delivery of the compounds described herein. Dosage forms or compositions can be prepared that contain the chemical entity described herein in the range of 0.005% to 100%, with the balance consisting of non-toxic excipients. The contemplated compositions can contain from 0.001% to 100%, in one embodiment from 0.1 to 95%, in another embodiment from 75 to 85%, and in a further embodiment from 20 to 80% of the chemical entity provided herein. The actual methods for preparing these dosage forms are known to those of skill in the art or will be apparent to those of skill in the art. See, for example, Remington: The Science and Practice of Pharmacy, 22 nd nd Edition (Pharmaceutical Press, London, UK. 2012).

[0510] Route of administration and composition components In some embodiments, the chemical entities described herein, or pharmaceutical compositions thereof, are administrable to a subject in need thereof by any acceptable route of administration. Acceptable routes of administration include, but are not limited to, buccal, dermal, intracervical, endosinusial, intratracheal, enteral, epidural, interstitial, intraperitoneal, intraarterial, intratracheobronchial, intracapsular, intracerebral, intrathecal, intracoronal, intradermal, intraluminal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intramuscular, intramesenteric, intramyeloid, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratesticular, intrathecal, intratumoral, intrauterine, intravascular, intravenous, intranasal, nasogastric, oral, parenteral, percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral, and intravaginal.

[0511] The compositions can be formulated for parenteral administration and can be formulated, for example, for injection by intravenous, intramuscular, subcutaneous, and even intraperitoneal routes. Typically, these compositions can be prepared as injectable solutions or suspensions, and solid forms suitable for use in preparing solutions or suspensions by the addition of a liquid prior to injection can also be prepared, and the formulations can also be emulsified. In light of the present disclosure, methods for preparing these formulations will be apparent to those skilled in the art.

[0512] Pharmaceutical forms suitable 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 must be fluid to the extent that easy syringability exists. In addition, the form should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.

[0513] In addition, the carrier can be a solvent or a dispersion medium, for example, including water, ethanol, polyols (such as glycerin, propylene glycol, and liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils. Appropriate fluidity can be maintained, for example, by the use of coatings such as lecithin, maintaining the required particle size in the case of dispersion agents, and the use of surfactants. The action of microorganisms can be inhibited by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc. In many cases, it is preferred to contain an isotonic agent, such as sugar or sodium chloride. The long-term absorption of the injectable composition can be achieved by the use of absorption delaying agents in the composition, such as aluminum monostearate and gelatin.

[0514] The sterile injectable solution is prepared by incorporating the required amount of the active compound into a suitable solvent, together with various other components listed above as required, and then performing filtration sterilization. Generally, the dispersion agent is prepared by incorporating various sterilized active ingredients into a sterile medium containing a basic dispersion medium and the other necessary components among those listed above. In the case of a sterile powder for the preparation of a sterile injectable solution, the preferred preparation methods are vacuum drying and lyophilization techniques that produce a powder of the active ingredient and any additional desired components from its already sterile-filtered solution.

[0515] 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 (such as PEG ointments), glycerin, glycerinated gelatin, hardened vegetable oils, poloxamer, mixtures of polyethylene glycols of various molecular weights and polyethylene glycol fatty acid esters, petrolatum, anhydrous lanolin, shark liver oil, sodium saccharinate, menthol, sweet almond oil, sorbitol, sodium benzoate, Anoxid SBN, vanilla essential oil, aerosol, parabens in phenoxyethanol, sodium methyl p - hydroxybenzoate, sodium propyl p - hydroxybenzoate, diethylamine, carbomer, Carbopol, methyl p - hydroxybenzoate, macrogol cetostearyl ether, cocoil caprylocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy - methyl bisulfite, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methylsulfonylmethane (MSM), lactic acid, glycine, vitamins such as vitamin A and E, and potassium acetate, among one or more of them but not limited thereto.

[0516] 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 thus melts in the rectum to release the active compound. In other embodiments, the rectal administration composition is in the form of an enema.

[0517] In other embodiments, the compounds described herein, or their pharmaceutical compositions, are suitable for local delivery to the gastrointestinal or alimentary tract by oral administration (e.g., solid or liquid dosage forms).

[0518] Examples of solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the chemical entity is combined 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 carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and gum arabic, c) humectants such as glycerin, d) disintegrants such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) dissolution retardants such as paraffin, f) absorption promoters 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, and combinations and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may contain a buffering agent. Similar types of solid compositions may be used as fillers in soft-fill and hard-fill gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0519] In one aspect, the composition is in 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, dicalcium phosphate; lubricants such as magnesium stearate; and binders such as starch, gum arabic, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives, etc. In another solid dosage form, powders, marume, solutions or suspensions (e.g., in propylene carbonate, vegetable oil, PEG, poloxamer 124, or triglycerides) are encapsulated in capsules (gelatin or cellulose-based capsules). Capsule dosage forms having one or more of the chemical entities provided herein or additional active agents in physically separated unit dosage forms, such as granules of each drug (or tablets in capsules); bilayer tablets; two-compartment gel capsule dosage forms, etc. are also envisioned. Enteric-coated oral dosage forms or extended-release oral dosage forms are also envisioned.

[0520] Other physiologically acceptable compounds include wetting agents, emulsifying agents, dispersing agents, or preservatives that are particularly useful for preventing the growth or action of microorganisms. Various preservatives are well known, for example, phenol and ascorbic acid.

[0521] In certain aspects, the excipients are sterile and generally do not contain undesirable substances. These compositions can be sterilized by conventional well-known sterilization techniques. Sterility is not required for the excipients of various oral dosage forms such as tablets and capsules. USP / NF standards are usually sufficient.

[0522] The ophthalmic composition may non - limitatively contain any one or more of the following: viscogens (e.g., carboxymethyl cellulose, 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 oxy - chloro complex; Allergan, Inc.)).

[0523] Examples of topical compositions include ointments and creams. An ointment is a semi - solid preparation usually based on petrolatum or other petroleum derivatives. Usually, a cream containing a selected active agent is often an oil - in - water or water - in - oil liquid or semi - solid emulsion. A cream base is usually washable with water and contains an oil phase, an emulsifier, and an aqueous phase. The oil phase, sometimes also called the "inner" phase, is generally composed of petrolatum and fatty alcohols such as cetyl or stearyl alcohol, and the aqueous phase, although not necessarily, usually exceeds the oil phase in amount and generally contains a humectant. Generally, the emulsifier in a cream formulation is a non - ionic, anionic, cationic, or amphoteric surfactant. Similar to other carriers or vehicles, an ointment base should be inert, stable, non - irritating, and non - sensitizing.

[0524] In any of the above - mentioned embodiments, the pharmaceutical compositions described herein may contain one or more of the following: lipids, inter - bilayer cross - linked multilamellar vesicles, biodegradable poly(D,L - lactic - co - glycolic acid) [PLGA] - based or polyanhydride - based nanoparticles or microparticles, and nanoporous particle - supported lipid bilayers.

[0525] Dosage The dosage may vary depending on the patient's requirements, the severity of the condition being treated, and the particular compound being used. The appropriate dosage in a particular situation can be determined by those skilled in the medical art. In some cases, the total daily dose can be divided and administered in several portions throughout the day or by means of continuous delivery.

[0526] In some embodiments, the compounds described herein are administered at a dosage of about 0.001 mg / Kg to about 500 mg / Kg (e.g., about 0.001 mg / Kg to about 200 mg / Kg; about 0.01 mg / Kg to about 200 mg / Kg; about 0.01 mg / Kg to about 150 mg / Kg; about 0.01 mg / Kg to about 100 mg / Kg; about 0.01 mg / Kg to about 50 mg / Kg; about 0.01 mg / Kg to about 10 mg / Kg; about 0.01 mg / Kg to about 5 mg / Kg; about 0.01 mg / Kg to about 1 mg / Kg; about 0.01 mg / Kg to about 0.5 mg / Kg; about 0.01 mg / Kg to about 0.1 mg / Kg; about 0.1 mg / Kg to about 200 mg / Kg; about 0.1 mg / Kg to about 150 mg / Kg; about 0.1 mg / Kg to about 100 mg / Kg; about 0.1 mg / Kg to about 50 mg / Kg; about 0.1 mg / Kg to about 10 mg / Kg; about 0.1 mg / Kg to about 5 mg / Kg; about 0.1 mg / Kg to about 1 mg / Kg; about 0.1 mg / Kg to about 0.5 mg / Kg).

[0527] Regimen The above dosages can be administered daily (e.g., as a single dose or in two or more divided doses) or not daily (e.g., every other day, every two days, every three days, once a week, twice every few weeks, once every two weeks, once a month).

[0528] In some embodiments, the administration period 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 more. In a further embodiment, the period during which administration is discontinued 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 more. 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 and a second period following the first period, administration is discontinued during the second period, and then administration of the therapeutic compound is initiated during a third period, and administration is discontinued during a fourth period following the third period. In one aspect of this embodiment, the administration period of the therapeutic compound and the period during which administration is subsequently discontinued are repeated for a predetermined period or an 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 more. In a further embodiment, the period during which administration is discontinued 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 more.

[0529] Treatment method The present disclosure features methods for treating a subject (e.g., a human) having a disease, disorder, or condition in which a decrease in APJ receptor activity (e.g., inhibition or deficiency of APJ receptor signaling; e.g., inhibition or deficiency of apelin-APJ receptor signaling) or downregulation of endogenous apelin contributes to the pathophysiology and / or symptoms and / or progression of the disease, disorder, or condition. In certain embodiments, the methods described herein may or further include treating one or more conditions that are complications, comorbidities, or sequelae of any one or more of the conditions described herein.

[0530] In some embodiments, the method further includes identifying a subject. In some embodiments, identifying includes determining the level of one or more of the following parameters in the subject: leukotriene B4 level, pulmonary vascular resistance, pulmonary artery pressure, cardiac index, pulmonary capillary wedge pressure, right atrial pressure, six-minute walk distance, brain natriuretic peptide level, atrial natriuretic peptide, and lung diffusing capacity.

[0531] In certain embodiments, the chemical entities described herein modulate (e.g., decrease) pulmonary vascular resistance, modulate (e.g., decrease) right ventricular afterload, and modulate (e.g., decrease) mean pulmonary artery pressure. In certain embodiments, the chemical entities described herein decrease the risk of right ventricular failure.

[0532] In certain embodiments, the chemical entities described herein modulate vasotension, modulate fluid homeostasis, modulate renal function, modulate energy metabolism, modulate the inflammatory response, and modulate thrombosis.

[0533] Indications Pulmonary hypertension In some embodiments, the condition, disease, or disorder is pulmonary arterial hypertension (PAH). Non-limiting examples of PAH and related conditions include idiopathic PAH, hereditary PAH (e.g., BMPR2 mutations and other mutations), drug- or toxin-induced PAH, and PAH associated with connective tissue disease (CTD) (e.g., dermatomyositis, systemic lupus erythematosus, systemic sclerosis, Hashimoto's thyroiditis, Sjogren's syndrome, and antiphospholipid antibody syndrome), HIV infection, portal hypertension, congenital heart disease, and schistosomiasis.

[0534] In some embodiments, the PAH is idiopathic.

[0535] In other embodiments, the PAH is hereditary PAH, toxin- or drug-induced PAH, or PAH associated with one or more of the following: congenital heart disease, connective tissue disorders (e.g., dermatomyositis, systemic lupus erythematosus, systemic sclerosis, Hashimoto's thyroiditis, Sjogren's syndrome, and antiphospholipid antibody syndrome), portal hypertension, BMPR2 mutations, schistosomiasis, and HIV infection.

[0536] In some embodiments, the condition, disease, or disorder is pulmonary hypertension other than PAH. Examples of such conditions include pulmonary hypertension due to left heart disease (e.g., left ventricular systolic dysfunction, left ventricular diastolic dysfunction, valvular heart disease, and congenital / acquired left heart inflow / outflow tract obstruction and congenital cardiomyopathy), pulmonary disease and / or hypoxia (e.g., chronic obstructive pulmonary disease, interstitial lung disease, other pulmonary diseases with a mixed restrictive and obstructive pattern, sleep disordered breathing, alveolar hypoventilation disorder, chronic exposure to high altitude, and developmental lung disease), chronic thromboembolic pulmonary hypertension and other pulmonary arterial occlusive diseases (e.g., chronic thromboembolic pulmonary hypertension, other pulmonary arterial occlusive diseases), and pulmonary hypertension due to unclear multifactorial mechanisms (e.g., hematologic disorders, systemic disorders, metabolic disorders, etc.).

[0537] Cardiovascular condition, cardiovascular disease, or cardiovascular disorder In some embodiments, the condition, disease, or disorder is a cardiovascular condition, cardiovascular disease, or cardiovascular disorder. Non-limiting examples of cardiovascular conditions, cardiovascular diseases, or cardiovascular disorders include coronary heart disease, acute coronary syndrome, peripheral vascular disease, angina, stroke, cerebrovascular accident, transient ischemic attack, heart failure, cardiomyopathy, myocardial infarction, myocardial remodeling after heart surgery, valvular heart disease, hypertension (e.g., systemic hypertension, essential hypertension, pulmonary hypertension, portal hypertension, systolic hypertension), aortic aneurysm (e.g., abdominal aortic aneurysm), atrial fibrillation, arrhythmia, atherosclerosis, Brugada syndrome, ischemic cardiovascular disease, peripheral arterial disease, preeclampsia, ventricular tachycardia, and myocardial fibrosis.

[0538] In some embodiments, the cardiovascular condition, cardiovascular disease, or cardiovascular disorder is heart failure. Non-limiting examples of heart failure include chronic heart failure, systolic heart failure, diastolic heart failure, diabetic heart failure, congestive heart failure, heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, left ventricular dysfunction (e.g., left ventricular dysfunction after myocardial infarction), right ventricular dysfunction, cardiac hypertrophy, myocardial remodeling, and acute decompensated heart failure (ADHF).

[0539] In some embodiments, the cardiovascular condition, cardiovascular disease, or cardiovascular disorder is a condition, disease, or disorder associated with vascular pathology (e.g., associated with increased vascular permeability and vascular non-functionality). Non-limiting examples of such conditions, diseases, or disorders include vascular hypertrophy, vascular remodeling (e.g., arteriosclerosis), atherosclerosis, peripheral arterial occlusive disease (PAOD), restenosis (e.g., angioplasty restenosis), thrombosis and vascular permeability disorders, and ischemia and / or reperfusion disorders (e.g., ischemia and / or reperfusion disorders of the heart, kidney, and retina). In some embodiments, the condition, disease, or disorder is vein-related. Non-limiting examples of such conditions, diseases, or disorders include hemangioma, venous insufficiency, stasis, or thrombosis.

[0540] In some embodiments, the chemical entities described herein can improve cardiac contractility (e.g., cardiac relaxation), ventriculoarterial coupling, inotropic function, or lusitropic function in a subject suffering from a cardiovascular condition. In some embodiments, the chemical entities described herein can increase the ejection fraction in a subject suffering from a cardiovascular condition.

[0541] Metabolic and homeostatic dysfunctions, and related conditions, diseases, or disorders In some embodiments, the condition, disease, or disorder is related to a metabolic dysfunction. Non-limiting examples of such conditions, diseases, or disorders include metabolic dysfunction, obesity, diabetes (e.g., type II diabetes, gestational diabetes), diabetic complications (e.g., metabolic syndrome, insulin resistance, microvascular or macrovascular organ damage, e.g., macrovascular and microvascular disorders, diabetic neuropathy, diabetic retinopathy, cardiac autonomic neuropathy), kidney diseases (e.g., chronic kidney disease), edema, dyslipidemia, anorexia, bulimia, polyphagia, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, growth hormone disorders (e.g., gigantism, acromegaly), galactorrhea, and cardiac cachexia.

[0542] In some embodiments, the condition, disease, or disorder is related to syndrome of inappropriate antidiuretic hormone secretion (SIADH). Non-limiting examples of such conditions, diseases, or disorders include neurogenic diabetes (e.g., diabetic complications such as diabetic nephropathy, diabetic neuropathy, diabetic retinopathy), lung cancer, septic shock, and thirst trouble.

[0543] In some embodiments, the condition, disease, or disorder is associated with systemic inflammation. Non-limiting examples of the condition, disease, or disorder include systemic inflammatory response syndrome (SIRS), sepsis (e.g., severe sepsis), and septic shock. In some embodiments, the condition, disease, or disorder is associated with sepsis (e.g., a complication, comorbidity, or sequela of sepsis). Non-limiting examples of conditions, diseases, or disorders associated with sepsis include septic cardiomyopathy, sepsis-associated inflammatory response (e.g., systemic inflammation), sepsis-associated hemodynamic changes, decreased blood volume, sepsis-associated organ failure (e.g., multiple organ failure, renal failure), acute kidney injury, vasoplegia, lung injury, syndrome of inappropriate antidiuretic hormone secretion, persistent hypertension associated with systemic vasodilation, refractory muscle contractile response, massive capillary leak syndrome, coagulation / fibrinolysis imbalance, and metabolic disorders characterized by elevated blood lactate levels. See, e.g., Coquerel et al. Critical Care (2018) 22:10.

[0544] In some embodiments, the chemical entities described herein can regulate arginine vasopressin (AVP) receptors or angiotensin receptors.

[0545] In some embodiments, the condition, disease, or disorder is associated with disorders of fluid homeostasis by CNS-dependent and non-dependent actions. Non-limiting examples of the condition, disease, or disorder include renal failure (e.g., acute and chronic renal failure), renal perfusion, renal dysfunction (e.g., polycystic kidney disease), water diuresis, and polyuria.

[0546] Dementia and related conditions, diseases, or disorders In some embodiments, the condition, disease, or disorder is dementia. Non-limiting examples of the condition, disease, or disorder include senile dementia, vascular dementia, dementia due to systemic degeneration, degenerative diseases (such as Alzheimer's disease, Parkinson's disease, Pick's disease, Huntington's disease, etc.), dementia due to infectious diseases (such as late-onset viral infections such as Creutzfeldt-Jakob disease), endocrine diseases, metabolic diseases, or dementia associated with poisoning (such as hypothyroidism, vitamin B12 deficiency, alcohol dependence, poisoning caused by various drugs, metals, or organic compounds), dementia caused by tumors (such as brain tumors), and dementia due to traumatic diseases (such as chronic subdural hematoma), depression, attention deficit hyperactivity disorder (ADHD), disturbance of consciousness, anxiety disorder, schizophrenia, and phobia.

[0547] Connective tissue disorders In some embodiments, the condition, disease, or disorder is a connective tissue disorder. In certain embodiments, the connective tissue disorder is selected from the group consisting of scleroderma, systemic lupus erythematosus, systemic sclerosis, Hashimoto's thyroiditis, Sjogren's syndrome, and antiphospholipid antibody syndrome. In certain embodiments, the condition, disease, or disorder is systemic sclerosis.

[0548] Fibrosis In some embodiments, the condition, disease, or disorder is fibrosis. In certain embodiments, the fibrosis is associated with an organ or tissue selected from the group consisting of the lung, liver, heart, mediastinum, bone marrow, retroperitoneum, skin, intestine, joint, genitalia, and combinations thereof. In certain embodiments, the fibrosis is idiopathic pulmonary fibrosis (IPF). In certain embodiments, the fibrosis is liver fibrosis. In certain embodiments, the fibrosis is associated with non-alcoholic fatty liver disease (NAFLD).

[0549] Other conditions, diseases, or disorders In some embodiments, the condition, disease, or disorder is a liver disease. Non-limiting examples of the condition, disease, or disorder include alcoholic liver disease, toxic liver disease, viral liver disease, and cirrhosis.

[0550] In some embodiments, the condition, disease, or disorder is a pulmonary disease. Non-limiting examples of the condition, disease, or disorder include chronic obstructive pulmonary disease (COPD), asthma, acute respiratory distress syndrome (ARDS), and amyotrophic lateral sclerosis. In some embodiments, the condition, disease, or disorder is a retinopathy (e.g., macular degeneration).

[0551] In some embodiments, the condition, disease, or disorder is HIV infection, HIV neurodegeneration, neurodegenerative disease, cancer (e.g., breast cancer, lymphocytic leukemia, bladder cancer, ovarian cancer, prostate cancer, etc.), asthma, burns (e.g., sunburn), traumatic brain injury, pancreatitis, Turner syndrome, neurosis, rheumatoid arthritis, spinal cord injury, immune function, inflammation, spinocerebellar degeneration, fracture, wound, atopic dermatitis, osteoporosis, asthma, epilepsy, and infertility.

[0552] Activating stem cells Also, the chemical entities described herein can be used to activate stem cells (e.g., cardiac stem cells such as endogenous cardiac stem cells). In some embodiments, the chemical entities described herein are used for regrowing tissue, assisting functional recovery after transplantation of cells (e.g., cells with bone marrow-derived mesenchymal stem cells), improving cardiac stem cell proliferation (e.g., in patients suffering from myocardial infarction), reducing infarct size, promoting cardiac repair, activating stem cells and progenitor cells in a subject after myocardial infarction, or reducing reperfusion injury (e.g., during surgery such as cardiac bypass surgery or heart transplantation surgery).

[0553] Combination therapy The present disclosure contemplates both monotherapy regimens and combination therapy regimens.

[0554] In some embodiments, the methods described herein may further comprise administering one or more additional treatments (e.g., one or more additional therapeutic agents and / or one or more treatment regimens) in combination with the administration of the compounds described herein.

[0555] In some embodiments, the compounds described herein can be administered in combination with one or more additional therapeutic agents.

[0556] Representative additional therapeutic agents include, but are not limited to, agents for treating PAH, pulmonary hypertension, heart failure (e.g., ADHF, chronic heart failure), hypertension (e.g., systemic hypertension), amyotrophic lateral sclerosis, arrhythmia, asthma, atherosclerosis, atrial fibrillation, Brugada syndrome, burns (e.g., sunburn), cancer, cardiac fibrosis, cardiomyopathy, cerebrovascular accident, diabetes (e.g., gestational diabetes), septic shock, sepsis, renal failure, dyslipidemia, HIV neurodegeneration, inflammation, ischemic cardiovascular disease, liver disease, metabolic disorders, neurodegenerative diseases, obesity, peripheral arterial disease, preeclampsia, restenosis, transient ischemic attack, traumatic brain injury, ventricular tachycardia, edema, or immunomodulatory agents.

[0557] In some embodiments, the one or more additional therapeutic agents include agents that are useful, for example, as PAH therapeutic agents. Non-limiting examples include the following: · Prostacyclin analogs (e.g., epoprostenol, treprostinil, iloprost); · Prostacyclin IP receptor (e.g., selexipag); · Endothelin receptor antagonists (e.g., bosentan, ambrisentan, macitentan); · PDE5 inhibitors (e.g., sildenafil, tadalafil); · Soluble guanylate cyclase stimulators (e.g., riociguat); · Agents for treating mitochondrial dysfunction (e.g., bardoxolone methyl); · Anti-inflammatory agents (e.g., rituximab, tocilizumab, ubenimex); and · Agents that modulate oxidative stress (e.g., dimethyl fumarate, intravenous iron).

[0558] In some embodiments, the one or more additional therapeutic agents include agents that are useful, for example, as therapeutic agents for heart failure or hypertension. Non-limiting examples include the following: · Alpha blockers (e.g., doxazosin, prazosin, tamsulosin, terazosin); · Beta blockers (e.g., acebutolol, acetutolol, atenolol, bisoprolol, bupranolol, carteolol, carvedilol, celiprolol, esmolol, mepindolol, metoprolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol, taliprolol); · Calcium channel blockers including but not limited to dihydropyridine (DHP) (e.g., amlodipine, felodipine, isradipine, lacidipine, nicardipine, nifedipine, nigulpidine, nilutipine, nimodiphine, nisoldipine, nitrendipine, nivaldipine, ryosidine) and non-DHP (e.g., anipamil, diltiazem, fendiline, flunarizine, gallpamil, mibefradil, prenylamine, tiapamil, verapamil); · Diuretics (e.g., amiloride, chlorothalidon, chlorothiazide, hydrochlorothiazide, and methylchlorothiazide and other thiazide derivatives not limited thereto); · Agents for central hypertension (e.g., clonidine, guanabenz, guanfacine, methyldopa); · Angiotensin-converting enzyme (ACE) inhibitors (alaceptril, benazepril, benazaprilat, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, lisinopril, moexipiril, moveltopril, perindopril, quinapril, quinaprilat, ramipril, ramiprilat, spriapril, temocapril, trandolapril, and zofenopril) and dual ACE / NEP inhibitors (e.g., omapatrilat, fasidotril, and fasidotrilat); · Angiotensin receptor blockers (ARBs) (e.g., candesartan, eprosartan, irbesartan, losartan, olmesartan, tasosartan, telmisartan, valsartan) and dual ARB / NEP inhibitors (e.g., a combination of valsartan and sacubitril); · Neutral endopeptidase (NEP) inhibitors (e.g., sacubitril); · Aldosterone synthase inhibitors (e.g., anastrozole, fadrozole, exemestane); · Endothelin antagonists (e.g., bosentan, enrasentan, atrasentan, darusentan, macitentan, sitaxentan, tezosentan); · If current inhibitors (e.g., ivabradine); · Myosin activators (e.g., cardiac myosin activators); · Sodium diuretics; · Thiazide diuretics; · Vasodilators / vasorelaxants (e.g., nitrates) · Mineralocorticoid receptor antagonists; · Renin inhibitors; · Digitalis compounds; · Inotropic agents and β-receptor agonists; · Anti-hyperlipidemic agents, · Plasma HDL elevators; · Anti-hypercholesterolemic agents; · Cholesterol biosynthesis inhibitors (e.g., HMG CoA reductase inhibitors) · LXR agonists; · Probucol; · Raloxifene; · Nicotinic acid; · Niacinamide; · Cholesterol absorption inhibitors; · Bile acid sequestrants (e.g., anion exchange resins, or quaternary amines such as cholestyramine or colestipol); · Low density lipoprotein receptor inducers; · Clofibrate; · Fenofibrate; · Bezafibrate; · Ciprofibrate; · Gemfibrozil; · Vitamins (e.g., vitamin B 6 、vitamin B 12 、antioxidant vitamins); · Platelet aggregation inhibitors; · Fibrinogen receptor antagonists; · Aspirin; and · Fibrinic acid derivatives.

[0559] In some embodiments, one or more additional therapeutic agents include therapeutic agents useful, for example, in treating diabetes. Non-limiting examples include the following: · Sulfonylureas (e.g., chlorpropamide, tolbutamide, acetohexamide, tolazamide, glibenclamide, glipizide, gliclazide, glimepiride, glibendamide); · Biguanides (e.g., metformin); · Thiazolidinediones (e.g., ciglitazone, pioglitazone, troglitazone, rosiglitazone) · Insulin sensitizers related to the above (e.g., selective and non-selective activators of PPAR-α, PPAR-β, and PPAR-γ); · Dehydroepiandrosterone (DHEA or its conjugated sulfate DHEA-SO4 also known as); · anti-glucocorticoid; · TNF-α inhibitor, · dipeptidyl peptidase IV (DPP4) inhibitor (e.g., sitagliptin, saxagliptin); · GLP-1 agonist or analog (e.g., exenatide); · α-glucosidase inhibitor (e.g., acarbose, miglitol, and voglibose); · pramlintide (synthetic analog of human hormone amylin); · other insulin secretagogues (e.g., repaglinide, glyquidone, and nateglinide); and · insulin.

[0560] In some embodiments, one or more additional therapeutic agents include therapeutic agents useful, for example, for treating obesity. Non-limiting examples include phenylpropanolamine, phentermine, diethylpropion, mazindol, fenfluramine, dexfenfluramine, phentermine, β3-adrenergic receptor agonist agent, sibutramine, gastrointestinal lipase inhibitor (e.g., orlistat), leptin, neuropeptide Y, enterostatin, cholecystokinin, bombesin, amylin, histamine H 3 receptor, dopamine D 2 receptor modulator, melanocyte-stimulating hormone, corticotropin-releasing factor, galanin, and gamma-aminobutyric acid (GABA).

[0561] Other additional therapeutic agents include the following: · anti-atherosclerotic agent; · anti-dyslipidemic agent; · anti-hyperinsulinemic agent; · antithrombotic agent; · anti-retinopathy agent; · anti-neuropathy agent; · anti-nephropathy agent; · anti-ischemic agent; · anti-hyperlipidemic agent, · anti-hypertriglyceridemic agent; · Anti - hypercholesterolemia agent; · Anti - restenosis agent; · Anti - pancreatic agent; · Hypo - appetite agent; · Memory enhancer; · Anti - dementia agent; · Cognition promoter; · Appetite suppressant; · Agent for treating peripheral arterial disease; · Agent for treating malignant tumor; · Anti - inflammatory agent; · Diuretic; · Digoxin; · Nitric oxide donor; · Hydralazine; · Inotropic agent; · Vasopressin receptor antagonist; · Statin; · Anti - arrhythmic agent; · Phosphodiesterase inhibitor (e.g., PDE5 inhibitor); and · Renal protective agent.

[0562] As a non - limiting example of additional therapeutic agents, the therapeutic agents described in US9156796B2, which is incorporated herein by reference, can also be mentioned.

[0563] In certain embodiments, the second therapeutic agent or treatment regimen is administered to the subject before contacting or administering the chemical entity (e.g., about 1 hour before, or about 6 hours before, or about 12 hours before, or about 24 hours before, or about 48 hours before, or about 1 week before, or about 1 month before).

[0564] In other embodiments, the second therapeutic agent or treatment regimen is administered to the subject substantially simultaneously with contacting or administering the chemical entity. For example, the second therapeutic agent or treatment regimen and the chemical entity are simultaneously administered to the subject in the same dosage form. As another example, the second therapeutic agent or treatment regimen and the chemical entity are simultaneously administered to the subject in separate dosage forms.

[0565] In yet other embodiments, a second therapeutic agent or treatment regimen is administered to the subject after contact with or administration of the chemical entity (e.g., after about 1 hour, or about 6 hours, or about 12 hours, or about 24 hours, or about 48 hours, or about 1 week, or about 1 month).

[0566] Compound preparation and biological assays As will be appreciated by those skilled in the art, methods for synthesizing the compounds of the formulas herein will be apparent to those skilled in the art. Synthetic chemical transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and RGM. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), as well as their subsequent editions.

[0567] In some embodiments, intermediates useful for preparing the compounds described herein can be prepared using the chemical reactions described in any one or more of the following schemes and non-limiting examples.

[0568] Compound preparation Schemes 1 to 4 show general methods for preparing the compounds and intermediates provided herein for illustrative purposes. For a more detailed description of the individual reaction steps, see the section on Synthetic Examples below. Those skilled in the art will recognize that other synthetic routes can be used to synthesize the compounds of the present invention. Specific starting materials and reagents are shown in the schemes and described below, but can be readily substituted with other starting materials and reagents to obtain various derivatives and / or reaction conditions. Furthermore, many of the compounds prepared by the methods described below can be further modified in light of the present disclosure using conventional chemical reactions well known to those skilled in the art.

[0569] Scheme 1 TIFF2025081550000273.tif62150 With respect to Scheme 1, the compounds of formula (I) (shown as I-6 and I-7) can be prepared from Compounds I-1, I-2, and I-4 where R 1 and R 2 are as defined herein. By reacting aminopyrazine I-1 with carboxylic acid I-2 under standard conditions (e.g., in the presence of oxalyl chloride to convert I-2 to an acyl chloride or in the presence of a peptide coupling reagent), amide I-3 (wherein X is halo, e.g., bromo or chloro) can be obtained. Next, a reaction between I-3 and amine I-4 under S N Ar or metal-catalyzed cross-coupling conditions (e.g., Buchwald-Hartwig coupling using xanthphos and Pd(OAc) 2 ) gives Compound I-5. By condensing the carbonyl moiety in I-5 with an amino group, I-6, which is a compound of formula (I), can be obtained.

[0570] Alternatively, I-3 can also be obtained through coupling between I-1 and an ester of I-2 (e.g., an alkyl ester, e.g., a methyl or ethyl ester) under appropriate conditions (e.g., in the presence of AlMe 3 ).

[0571] In some cases, by converting the X moiety in I-6 to another R 3 group, I-7, which is another compound of formula (I), can be obtained. As a non-limiting example regarding the conversion between I-6 and I-7, compound I-8 (see Scheme 1 above) can be obtained by reacting I-6 with a sulfonamide under Ullmann coupling conditions.

[0572] The following starting materials can be used in place of I-1 and subjected to the sequence shown in Scheme 1. TIFF2025081550000274.tif14128

[0573] Scheme 2 TIFF2025081550000275.tif92151Regarding Scheme 2, the compounds of formula (I) in Scheme 2 (shown as compounds II-7 to II-9) can be prepared from compound II-1, where R 1 is as defined elsewhere in this specification and X is a halo (e.g., Br) group or a pseudohalo (e.g., OTf) group. Compound II-2 can be obtained by subjecting II-1 to a Sonogashira coupling with a protected acetylene (e.g., TMS-acetylene) or a corresponding reaction. Subsequently, II-3 can be obtained by removing the alkyne protecting group, and compound II-5 can be obtained by coupling this with a pyrazine derivative II-4. Compound II-6 can be obtained by cyclizing the amino group in II-5 to the alkynyl moiety, and this can be subjected to a cross-coupling (e.g., under Chan-Lam coupling conditions) with a boronic acid of the formula R 2 as defined elsewhere in this specification of formula R 2 -B(OH) 2 to obtain compound II-7, which is a compound of formula (I). Further, by functionalizing compound II-7, compound II-8, which is also a compound of formula (I), can be obtained.

[0574] As a non-limiting example regarding the conversion from II-7 to II-8, II-7 and R 4Formula H as defined elsewhere in this specification 2 NS(O) 2 R 4 By coupling with a compound of (e.g., under Ullmann coupling conditions), compound II-9, a non-limiting example of compound II-8, can be obtained.

[0575] Scheme 3 TIFF2025081550000276.tif72151 For Scheme 3, the compound of formula (I) (shown as compounds III-5 to III-7 in Scheme 3) can be prepared from compound III-1 where R 1 is as defined elsewhere in this specification. By coupling between III-1 and III-2 (e.g., in the presence of a Lewis acid such as AlMe 3 ), compound III-3 can be obtained, which is subjected to cross-coupling with a compound of formula R 2 is as defined elsewhere in this specification, formula R 2 NH 2 to obtain compound III-4. By cyclizing the amino group in III-4 to an amide moiety (e.g., under heating, in the presence of P(O)Cl 3 ), III-5, a compound of formula (I), can be obtained. By functionalizing III-5, III-6, also a compound of formula (I), can be obtained.

[0576] As a non-limiting example of the conversion from III-5 to III-6, by coupling II-5 with a compound of formula H 4 is as defined elsewhere in this specification 2 NS(O) 2 R 4 (e.g., under Ullmann coupling conditions), compound III-7, a non-limiting example of compound III-6, can be obtained.

[0577] Scheme 4 For Scheme 4, the compound of formula (I) (shown as compounds IV-6 to IV-8 in Scheme 4) can be prepared from pyridazine derivative IV-1. IV-3 can be obtained by sequentially treating IV-1 with ammonium hydroxide and bromine, and then IV-4 can be obtained by coupling IV-3 with R 1 CO 2 H (wherein R 1 is as defined elsewhere in this specification). IV-5 can be obtained by subjecting IV-4 to coupling with R 2 wherein R is as defined elsewhere in this specification and R 2 NH 2 (for example, under Buchwald-Hartwig coupling conditions), and by cyclizing this (for example, under heating and / or microwave irradiation), IV-6, which is the compound of formula (I), can be obtained. By functionalizing compound IV-6, IV-7, which is also the compound of formula (I), can be obtained.

[0578] As a non-limiting example of the conversion from IV-6 to IV-7, by coupling IV-6 with a compound of formula H 4 wherein R is as defined elsewhere in this specification and 2 NS(O) 2 R 4 (for example, under Ullmann coupling conditions), compound IV-8, which is a non-limiting example of compound IV-7, can be obtained.

[0579] Scheme 5 For Scheme 5, the compounds of formula (I) (shown as V-6 and V-7) can be prepared from compounds V-1, V-2, and V-4 wherein R 1 and R 2 are as defined in this specification. Amide V-3 (wherein X is halo, for example bromo or chloro) can be obtained by reacting aminopyrazine V-1 with carboxylic acid V-2 under standard conditions. Next, the S between V-3 and amine V-4N The reaction under Ar or metal catalyst cross-coupling conditions (e.g., Buchwald-Hartwig coupling using xanthophos and Pd(OAc) 2 can be used to obtain compound V-5. By condensing the carbonyl moiety in V-5 with an amino group, V-6, which is a compound of formula (I), can be obtained.

[0580] Alternatively, V-3 can also be obtained through coupling between V-1 and an ester of V-2 (e.g., an alkyl ester, such as a methyl or ethyl ester) under appropriate conditions (e.g., in the presence of AlMe 3 .

[0581] In some cases, by converting the X moiety in V-6 to another R 3 group, I-7, which is another compound of formula (I), can be obtained. As a non-limiting example regarding the conversion between V-6 and V-7, compound V-8 (see Scheme 5 above) can be obtained by reacting V-6 with a sulfonamide under Ullmann coupling conditions.

[0582] General procedure Reactions highly sensitive to moisture or air were carried out under nitrogen or argon using anhydrous solvents and reagents. The progress of the reaction was determined by analytical thin-layer chromatography (TLC), usually performed using Sanpont pre-coated TLC plates, silica gel GF-254, layer thickness 0.25 mm, or liquid chromatography-mass spectrometry (LC-MS).

[0583] Generally, the LC-MS system used was composed of an Agilent 6120 platform with electrospray ionization in positive ion detection mode, equipped with an Agilent 1260 series HPLC with an autosampler. The column was usually Agilent Poroshell C18, 3.0 x 50 mm, 2.7 μm. The flow rate was set at 0.6 mL / min and the injection volume was 5 μL. UV detection was carried out in the range of 190 - 400 nm. The mobile phase consisted of solvent A (water + 0.1% TFA) and solvent B (acetonitrile + 0.05% TFA). A gradient from 90% solvent A to 95% solvent B was changed over 1.7 minutes, maintained for 1.8 minutes, then reversed back to 90% solvent A over 0.1 minute and maintained for 1.4 minutes.

[0584] Preparative HPLC purification was usually performed using a Waters 2555 - 2767 system equipped with a 2489 UV detector. The column was Welch C-18, 21.2 x 150 mm, 5 μm. The mobile phase consisted of a mixture of acetonitrile (5 - 95%) in water containing 0.05% TFA. The flow rate was maintained at 20 mL / min, the injection volume was 1800 μL, and two channels 254 nm and 280 nm were used in the UV detector. The mobile phase gradient was optimized for each individual compound.

[0585] Reactions carried out using microwave irradiation were usually performed using a Biotage Initiator. Concentration of the solution was carried out under reduced pressure on a rotary evaporator. Flash chromatography was usually performed using a Biotage flash chromatography apparatus (Dyax Corp.) on silica gel (40 - 63 mM, pore size 60 Å) in a prepacked cartridge of the size described. Unless otherwise stated, 1 H NMR spectra were obtained in CDCl 3 solution using a 400 MHz spectrometer. Chemical shifts were reported in parts per million (ppm). Tetramethylsilane (TMS) was used as an internal standard in CD 3 Cl solution, and the residual CH 3 OH peak or TMS in CD 3It was used as an internal standard in the OD solution. The coupling constant (J) was reported in Hertz (Hz). Chiral analysis chromatography was performed on one of the Chiralpak AS, Chiralpak AD, Chiralcel OD, Chiralcel IA, or Chiralcel OJ columns (250x4.6 mm) (Daicel Chemical Industries, Ltd.) using the described ratio of ethanol - hexane solution (%Et / Hex) or isopropanol - heptane solution (%IPA / Hep) as a gradient - free solvent system. Chiral preparative chromatography was performed on one of the Chiralpak AS, Chiralpak AD, Chiralcel OD, Ciralcel IA, or Chiralcel OJ columns (20x250 mm) (Daicel Chemical Industries, Ltd.) using the desired gradient - free solvent system identified by chiral analysis chromatography or under supercritical fluid (SFC) conditions.

[0586] Abbreviations -C(O)CH 3 (Ac); acetic acid (AcOH); -OC(O)CH 3 (OAc); aqueous solution (aq); Cbz (benzyloxycarbonyl); N,N - diisopropylethylamine (DIEA); N,N - dimethylformamide (DMF); 1 - ethyl - 3 - (3 - dimethylaminopropyl)carbodiimide (EDCI); ethyl acetate (EtOAc); diethyl ether (ether or Et 2 O); petroleum ether (PE); gram (g); hour (h or hr); 2 - propanol (IPA); mass spectrum (ms or MS); microliter (μL); milligram (mg); milliliter (mL); millimole (mmol); minute (min); methyl t - butyl ether (MTBE); (benzotriazol - 1 - yloxy)tripyrrolidino - phosphonium hexafluorophosphate (PyBOP); retention time (R t); room temperature (rt or RT); saturated aqueous sodium chloride solution (brine); trifluoroacetic acid (TFA); tetrahydrofuran (THF); flash chromatography (FC); liquid chromatography (LC); liquid chromatography-mass spectrometry (LCMS or LC-MS); supercritical fluid chromatography (SFC); tert-butyloxycarbonyl (Boc or BOC); diethylaminosulfur trifluoride (DAST); dichloromethane (DCM); dimethylacetamide (DMA; DMAC); dimethyl sulfoxide (DMSO); 1,3-bis(diphenylphosphino)propane (DPPP); acetic acid (HOAc); 3-chloroperoxybenzoic acid (m-CPBA); methyl (Me); methanol (MeOH); N-bromosuccinimide (NBS); thin layer chromatography (TLC).

Example

[0587] Synthesis examples The following are representative procedures for the preparation of compounds used in the following examples that may not be commercially available, or compounds that can replace the compounds used in the following examples.

[0588] Method A TIFF20...

Claims

1. Formula (I): or a pharma- ceutically acceptable salt thereof, During the ceremony, A 1 is CH or N; X 1 , X 2 , X 3 , and X 4 Each of the formulas is independently N and CR 3 selected from the group consisting of; R 1 is the following: (i) -(Y 1 ) n -Y 2 , where n is 0 or 1; ・Y 1 is 1 to 6 R a C which may be substituted with 1～6 alkylene; and ・Y 2 is: (a) 1 to 4 R b C which may be substituted with 3～10 Cycloalkyl; (b) 1 to 4 R c C which may be substituted with 6～10 Aryl; (c) Heteroaryl containing 5 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O, and S, and one or more of the heteroaryl ring carbon atoms are selected from 1 to 4 independently selected R c heteroaryl, optionally substituted with (d) heterocyclyl containing 3 to 10 ring atoms, in which 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), and O, wherein one or more of the heterocyclyl ring carbon atoms are selected from 1 to 4 independently selected R b heterocyclyl, optionally substituted by or (ii) -Z 1 -Z 2 -Z 3 , where ・Z 1 is 1 to 4 R a C which may be substituted with 1～3 is alkylene; ・Z 2 -N(H)-, -N(R d )-, -O-, or -S-; and ・Z 3 is 1 to 4 R a C which may be substituted with 2～7 is alkyl; or (iii) 1 to 6 independently selected R a C which may be substituted with 3～10 Alkyl; or (iv) -Z 4 -Z 5 -Z 6 -Y 2 , where ・Z 4 is 1 to 4 R a C which may be substituted with 1～3 is alkylene; ・Z 5 -N(H)-, -N(R d )-, -O-, or -S-; ・Z 6 is 1 to 4 R a C which may be substituted with 1～4 alkylene; and ・Y 2 is as defined above and; R 2 is the following: (i) 1 to 4 R c C which may be further substituted 6～10 Aryl; (ii) Heteroaryl containing 5 to 10 ring atoms, of which 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O, and S, and one or more of the heteroaryl ring carbon atoms are selected from 1 to 4 independently selected R c heteroaryl, optionally substituted with (iii) 1 to 4 R b C which may be substituted with 3～10 Cycloalkyl; (iv) heterocyclyl containing 3 to 10 ring atoms, of which 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), and O, wherein one or more of the heterocyclyl ring carbon atoms are selected from 1 to 4 independently selected R b heterocyclyl, optionally substituted by (v) 1 to 6 independently selected R a C which may be substituted with 1～10 Alkyl and; R 3 Each occurrence of is independently -L 4 -R 4 , H, and R c ' selected from the group consisting of; L 4 Each occurrence of may independently be: (i) a single bond; (ii) N(H), N(R d ), or N(R 4 ); (iii) -N(H)S(O) 1～2 -or-N(R d )S(O) 1～2 -; (iv) -S(O) 1～2 N(H)- or -S(O) 1～2 N(R d )-; (v) -O-; (vi) -S(O) 0～2 -; (vii) -C(O)NH-または-C(O)N(R d ); (viii) -N(H)C(O)-または-N(R d )COLOR)-; (ix) -C≡C; (x) -N(H)S(O)(=NH)-、-N(R d )S(O)(=NH)、-N(H)S(O)(=NR d )-、or-N(R d )S(O)(=NR d )-; (xi) -S(O)(=NH)NH-, -S(O)(=NR d )NH-, -S(O)(=NH)NR d - or -S(O)(=NR d )NR d -; (xii) -S(O)(=NH)- or -S(O)(=NR d ); and (xiii) -N(H)S(O) 1～2 N(H)-、-N(R d )S(O) 1～2 N(H)-、-N(H)S(O) 1～2 N(R d )-、または-N(R d )S(O) 1～2 N(R d )- selected from the group consisting of; R 4 Each occurrence of may independently be: (i) -(Y 3 ) p -Y 4 , where p is 0 or 1; ・Y 3 is 1 to 6 R a C, each of which may be substituted with 1～6 Alkylene or C 1～6 alkenylene; and ・Y 4 is: (a) 1 to 4 R b C which may be substituted with 3～6 Cycloalkyl; (b) 1 to 4 R c C which may be substituted with 6～10 Aryl; (c) Heteroaryl containing 5 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O, and S, and one or more of the heteroaryl ring carbon atoms are selected from 1 to 4 independently selected R c heteroaryl, optionally substituted with (d) heterocyclyl containing 3 to 10 ring atoms, in which 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), and O, wherein one or more of the heterocyclyl ring carbon atoms are selected from 1 to 4 independently selected R b heterocyclyl, optionally substituted by or (ii) 1 to 6 independently selected R a C, each of which may be substituted with 1～10 Alkyl, C 1～10 Alkenyl, or C 1～10 Alkynyl and; R a Each occurrence of is independently -OH; -F; -Cl; -Br; -NR e R f ; 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) 1～2 (C 1～4 alkyl; cyano; and 1 to 4 independently selected C 1～4 C optionally substituted with alkyl 3～6 cycloalkyl; R b Each occurrence of is independently 1～6 Alkyl; C 1～4 Haloalkyl; -OH; oxo; -F; -Cl; -Br; -NR e R f ; C 1～4 Alkoxy; C 1～4 Haloalkoxy; -C(=O)(C 1～4 alkyl); -C(=O)O(C 1～4 alkyl); -C(=O)OH; -C(=O)N(R')(R''); -S(O) 1～2 (NR'R''); -S(O) 1～2 (C 1～4 alkyl; cyano; and 1 to 4 independently selected C 1～4 C optionally substituted with alkyl 3～6 cycloalkyl; R c Each occurrence of may independently be: (i) Halo; (ii) cyano; (iii) C 1～6 Alkyl; (iv) C 2～6 Alkenyl; (v) C 2～6 Alkynyl; (vi) C 1～4 Haloalkyl; (vii) C 1～4 Alkoxy; (viii) C 1～4 Haloalkoxy; (ix) 1 to 4 independently selected C 1～4 Optionally substituted with alkyl -(C 0～3 Alkylene)-C 3～6 Cycloalkyl; (x) -S(O) 1～2 (C 1～4 alkyl); (xi) -NR e R f ; (xii) -OH; (xiii) −S(O) 1～2 (NR'R''); (xiv) -C 1～4 Thioalkoxy; (xv) -NO 2 ; (xvi) -C(=O)(C 1～4 alkyl); (xvii) -C(=O)O(C 1～4 alkyl); (xviii) -C(=O)OH; (xix) -C(=O)N(R')(R''); and (xx) C 3～6 Cycloalkoxy selected from the group consisting of; R c Each occurrence of ' is independently: (i) Halo; (ii) cyano; (iii) -OH; (iv) -NO 2 ; (v) -C(=O)(C 1～4 alkyl); (vi) -C(=O)O(C 1～4 alkyl); (vii) -C(=O)OH; and (viii) -NH 2 selected from the group consisting of; R d is 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 alkoxy; R e and R f Each occurrence of is independently 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 alkoxy; or R e and R f together with the nitrogen atom to which each is attached form a ring containing 3 to 8 ring atoms, the ring being selected from the group consisting of (a) H and C 1～3 (b) 1 to 7 ring carbon atoms, each substituted with 1 to 2 substituents independently selected from alkyl; and (b) N(R d ), O, and S; Each occurrence of R' and R'' is independently H and C 1～4 alkyl, or R' and R'' taken together with the nitrogen atom to which they are each attached form a ring containing 3 to 8 ring atoms, the ring being selected from the group consisting of: (a) H and C 1～3 (b) 1 to 7 ring carbon atoms, each substituted with 1 to 2 substituents independently selected from alkyl; and (b) N(R d ), O, and S; However, the compound has the formula (I-1): If the compound is R 1 is other than unsubstituted phenyl, p-dimethylaminophenyl, p-aminosulfonylphenyl, and unsubstituted 4-pyridinyl; The compound has the formula (I-2): If the compound is R 1 is other than unsubstituted phenyl; However, the compound has the formula (I-3): rather than a compound of; However, the compound has the formula (I-4): If the compound is R 1 is other than p-fluorophenyl; However, the compound has the formula (I-5): If the compound is R 3 is other than trifluoromethyl; However, the compound has the formula (I-6): If the compound is R 2 is the following: (i) unsubstituted phenyl; (ii) ; (iii) ; (iv) unsubstituted pyridinyl; (v) Here, Q 1 , Q 2 , Q 3 , and Q 4 are each independently selected from N and CH; or (vi) Heteroaryl containing 9 to 10 ring atoms, wherein 1 to 2 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O, and S, and one or more of the heteroaryl ring carbon atoms are selected from 1 to 2 independently selected R c Heteroaryl, optionally substituted with Except, A compound of formula (I), or a pharma- ceutically acceptable salt thereof.

2. X 1 , X 2 , X 3 , and X 4 1-2 of are independently N; and X 1 , X 2 , X 3 , and X 4 Two or three of these are independently selected CR 3 2. The compound of claim 1, wherein

3. Formula (Ia):

2. The compound of claim 1, which is a compound of the formula:

4. Formula (I-a1): or a pharma- ceutically acceptable salt thereof.

5. Formula (I-a2): or a pharma- ceutically acceptable salt thereof.

6. Formula (Ib):

2. The compound of claim 1, which is a compound of the formula:

7. Formula (I-b1):

7. The compound of claim 1, wherein the compound is:

8. Formula (Ic) or (Id):

2. The compound of claim 1, which is a compound of the formula:

9. Formula (I-c1) or (I-d1):

9. The compound of claim 1, wherein the compound is:

10. R 1 -(Y 1 ) n -Y 2 10. The compound of any one of claims 1 to 9, wherein

11. The compound of any one of claims 1 to 10, wherein n is 0.

12. The compound of any one of claims 1 to 10, wherein n is 1.

13. Y 1 C 1～3 13. The compound of claim 12 which is an alkylene.

14. Y 2 but, Heteroaryl containing 5 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O, and S, and one or more of the heteroaryl ring carbon atoms are selected from 1 to 4 independently selected R c Heteroaryl, optionally substituted with 14. The compound of any one of claims 1 to 13, wherein

15. Y 2 but, Heteroaryl containing 5 to 6 ring atoms, of which 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O, and S, and one or more of the heteroaryl ring carbon atoms are selected from 1 to 4 independently selected R c Heteroaryl, optionally substituted with 15. The compound of any one of claims 1 to 14, wherein

16. Y 2 but, Heteroaryl containing 6 ring atoms, wherein 1-2 ring atoms are N and one or more of the heteroaryl ring carbon atoms are selected from 1-4 independently selected R c Heteroaryl, optionally substituted with 16. The compound of any one of claims 1 to 15, wherein

17. Y 2 but, One or more of the ring carbon atoms are independently selected from 1 to 4 R c pyridyl (e.g. 2-pyridyl or 6-pyridyl), optionally substituted with 17. The compound of claim 16, wherein

18. Y 2 but, One or more of the ring carbon atoms is selected from the group consisting of an independently selected R c pyridyl (e.g. 2-pyridyl or 6-pyridyl), optionally substituted with 18. The compound of claim 17, wherein

19. Y 2 but, Heteroaryl containing 5 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O, and S, and one or more of the heteroaryl ring carbon atoms are selected from 1 to 3 independently selected R c Heteroaryl, optionally substituted with 16. The compound of any one of claims 1 to 15, wherein

20. Y 2 but, One or more of the ring carbon atoms may be selected from 1 to 2 (e.g., 1) independently selected R c Optionally substituted furanyl 20. The compound of claim 19, wherein

21. R c Each occurrence of independently: (iii) C 1～6 Alkyl; (iv) C 2～6 Alkenyl; (v) C 2～6 Alkynyl; (vi) C 1～4 Haloalkyl; (vii) C 1～4 Alkoxy; (viii) C 1～4 Haloalkoxy; (ix) 1 to 4 independently selected C 1～4 Optionally substituted with alkyl -(C 0～3 Alkylene)-C 3～6 Cycloalkyl; (xiv) -C 1～4 Thioalkoxy; and (xx) C 3～6 Cycloalkoxy The compound of any one of claims 14 to 20, selected from the group consisting of:

22. R c Each occurrence of independently: (vii) C 1～4 Alkoxy; (viii) C 1～4 Haloalkoxy (e.g. OCH 2 CF 3 or OCF 3 ); (xiv) -C 1～4 Thioalkoxy; and (xx) C 3～6 Cycloalkoxy (e.g. cyclopropoxy) The compound of any one of claims 14 to 20, selected from the group consisting of:

23. R c Each occurrence of is selected independently 1～4 Alkoxy (e.g. -OCH 3 , -OCH 2 CH 3 21. The compound according to any one of claims 14 to 20, wherein

24. R c Each occurrence of is selected independently 1～6 21. The compound of any one of claims 14 to 20, which is alkyl (e.g. methyl).

25. The compound of any one of claims 14 to 24, wherein n is 0.

26. R 1 but 24. The compound of any one of claims 1 to 11, 14 to 18, and 21 to 23, wherein

27. R 1 but 25. The compound of any one of claims 1 to 11, 14 to 18, 21, and 24, wherein

28. R 1 but 25. The compound of any one of claims 1 to 11, 14 to 15, 19 to 21, and 24, wherein

29. R 2 But 1 to 4 R c C which may be substituted with 6～10 29. The compound of any one of claims 1 to 28, which is aryl.

30. R 2 But 1 to 4 R c 30. The compound of any one of claims 1 to 29, wherein the phenyl is optionally substituted with

31. R 2 But 1-2 R c 31. The compound of any one of claims 1 to 30, wherein the phenyl is optionally substituted with

32. R 2 But two R c 32. The compound of any one of claims 1 to 31, wherein the phenyl is optionally substituted with

33. R c Each occurrence of independently: (i) Halo (e.g. F); (vi) C 1～4 Haloalkyl (e.g., CF 3 ); (vii) C 1～4 Alkoxy; (viii) C 1～4 haloalkoxy; and (xiv) -C 1～4 Thioalkoxy The compound of any one of claims 29 to 32, selected from the group consisting of:

34. R c Each occurrence of is independently halo, C 1～4 Alkoxy, and C 1～4 34. The compound of any one of claims 29 to 33, selected from haloalkyl.

35. R c Each occurrence of -OCH 3 , C.F. 3 or F.

36. R 2 but For example, R 2 but 36. The compound of any one of claims 1 to 35, wherein

37. R 2 but, Heteroaryl containing 5 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O, and S, and one or more of the heteroaryl ring carbon atoms are selected from 1 to 4 independently selected R c Heteroaryl, optionally substituted with 29. The compound of any one of claims 1 to 28, wherein

38. R 2 but, Heteroaryl containing 6 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), and N(R d ), wherein one or more of the heteroaryl ring carbon atoms are selected from 1 to 4 independently selected R c Heteroaryl, optionally substituted with 40. The compound of any one of claims 1 to 28 and 37, wherein

39. R 2 is one to two independently selected R c The compound of any one of claims 1-28 and 37-38, wherein the compound is pyridinyl optionally substituted with

40. Each R c but independently: (i) Halo; (vi) C 1～4 Haloalkyl (e.g., CF 3 ); (vii) C 1～4 Alkoxy; (viii) C 1～4 haloalkoxy; and (xiv) -C 1～4 Thioalkoxy The compound according to any one of claims 1 to 28 and 37 to 39, selected from:

41. Each R c C 1～4 The compound of any one of claims 1 to 28 and 37 to 39, which is alkoxy (e.g., methoxy).

42. R 2 but The compound of any one of claims 1 to 28 and 37 to 41, wherein

43. R 2 but The compound of any one of claims 1 to 28 and 37 to 41, wherein

44. R 3 One occurrence of -L 4 -R 4 44. The compound of any one of claims 1 to 43, wherein

45. R 3 One occurrence of H or R c ' (e.g., R c ' may be halo, e.g., Br or Cl; or R c ' is -OH or NH 2 45. The compound of claim 1,

46. R 3 The compound of any one of claims 1-45, wherein one occurrence of is H.

47. R 3 One occurrence of -L 4 -R 4 and R 3 each of the remaining occurrences of independently selects H and R c ' (e.g., R c ' may be halo, e.g., Br or Cl; or R c ' is NH 2 47. The compound of any one of claims 1 to 46,

48. R 3 One occurrence of -L 4 -R 4 and R 3 48. The compound of any one of claims 1-47, wherein each remaining occurrence of is H.

49. R 3 One occurrence of -L 4 -R 4 and R 3 One occurrence of R c ' (e.g., R c ' may be halo, e.g., Br or Cl (e.g., R c' 48. The compound of any one of claims 1 to 47, wherein

50. R 3 One occurrence of -L 4 -R 4 and R 3 50. The compound of any one of claims 1-49, wherein one occurrence of is H.

51. R 3 Two occurrences of are selected independently -L 4 -R 4 44. The compound of any one of claims 1 to 43, wherein

52. R 3 Any remaining occurrences of H and R c' 52. The compound of any one of claims 1 to 43 and 51, selected from the group consisting of:

53. R 3 The compound of any one of claims 1-43 and 51-52, wherein any remaining occurrences of are H.

54. L 4 -N(H)S(O) 1～2 -or-N(R d )S(O) 1～2 (For example, N(C 1～3 Alkyl)S(O) 2 54. The compound of any one of claims 1 to 53, wherein

55. L 4 -N(H)S(O) 2 55. The compound of any one of claims 1 to 54, wherein:

56. L 4 is -N(H)C(O)- or -N(R d 54. The compound of any one of claims 1 to 53, wherein:

57. L 4 57. The compound of any one of claims 1-53 and 56, wherein is -N(H)C(O)-.

58. L 4 -C(O)NH- or -C(O)N(R d 54. The compound of any one of claims 1 to 53, wherein:

59. L 4 -N(H)-, -N(R d )- or -N(R 4 54. The compound of any one of claims 1 to 53, wherein:

60. L 4 The compound of any one of claims 1 to 53, wherein is a single bond.

61. L 4 The compound of any one of claims 1 to 53, wherein is C≡C.

62. L 4 The compound of any one of claims 1-53, wherein is -O-.

63. L 4 -N(H)S(O) 1～2 N(H)-, -N(R d )S(O) 1～2 N(H)-, -N(H)S(O) 1～2 N(R d )- and -N(R d )S(O) 1～2 N(R d 54. The compound of any one of claims 1 to 53, selected from the group consisting of -.

64. L 4 -N(H)S(O) 1～2 N(H)- (e.g. -N(H)S(O) 2 64. The compound of any one of claims 1 to 53 and 63, wherein N(H)-.

65. L 4 -N(H)S(O) 1～2 N(R d )-(e.g. -N(H)S(O) 2 N(R d )-, for example -N(H)S(O) 2 N(C 1～3 64. The compound of any one of claims 1 to 53 and 63, wherein said compound is alkyl)-.

66. R 4 -(Y 3 ) p -Y 4 66. The compound of any one of claims 1 to 65, wherein

67. 67. The compound of any one of claims 1 to 66, wherein p is 1.

68. Y 3 C 1～3 68. The compound of any one of claims 1 to 67, which is an alkylene.

69. Y 3 CH 2 or CH 2 -CH 2 69. The compound of any one of claims 1 to 68, wherein

70. The compound of any one of claims 1 to 66, wherein p is 0.

71. Y 4 But 1 to 4 R c C which may be substituted with 6～10 71. The compound of any one of claims 1 to 70, which is aryl.

72. Y 4 But there are 1-2 (for example, 1) R c 72. The compound of any one of claims 1-71, wherein the phenyl is optionally substituted with

73. R c Each occurrence of independently: (i) Halo; (ii) cyano; (iii) C 1～6 Alkyl; (iv) C 2～6 Alkenyl; (v) C 2～6 Alkynyl; (vi) C 1～4 Haloalkyl; (vii) C 1～4 Alkoxy; (viii) C 1～4 Haloalkoxy; (ix) 1 to 4 independently selected C 1～4 Optionally substituted with alkyl -(C 0～3 Alkylene)-C 3～6 Cycloalkyl; (xiv) -C 1～4 Thioalkoxy; and (xx) C 3～6 Cycloalkoxy 73. The compound of claim 71 or 72, selected from the group consisting of:

74. R c Each occurrence of independently: (i) Halo; (iii) C 1～6 Alkyl; (vi) C 1～4 Haloalkyl; (vii) C 1～4 Alkoxy; and (viii) C 1～4 Haloalkoxy 73. The compound of claim 71 or 72, selected from the group consisting of:

75. R c Each occurrence of independently: (vii) C 1～4 Alkoxy; (viii) C 1～4 haloalkoxy; and (xiv) -C 1～4 Thioalkoxy 73. The compound of claim 71 or 72, selected from the group consisting of:

76. Y 4 is non-substituted C 6～10 73. The compound of any one of claims 1 to 72, which is aryl (e.g., phenyl).

77. Y 4 But 1 to 4 R b C which may be substituted with 3～6 (For example, C 3～4 or C 6 71. The compound of any one of claims 1 to 70, wherein:

78. Y 4 But 1-2 R b 80. The compound of any one of claims 1-70 and 77, wherein said cyclopropyl or cyclobutyl is optionally substituted with.

79. Y 4 But 1-2 R b C which may be substituted with 6 80. The compound of any one of claims 1 to 70 and 77, which is cycloalkyl (e.g., cyclohexyl).

80. R b Each occurrence of is independently -F, C 1～6 Alkyl, C 1～4 haloalkyl, and —OH (e.g., R b may be OH; and / or R b C 1～6 80. The compound of any one of claims 1 to 70 and 77 to 79, wherein the aryl group is aryl, and the aryl group is aryl, and the aryl group is aryl.

81. Y 4 is non-substituted C 3～6 (For example, C 3～4 or C 6 ) cycloalkyl.

82. Y 4 82. The compound of claim 81, wherein is unsubstituted cyclopropyl or unsubstituted cyclobutyl (e.g., unsubstituted cyclopropyl).

83. Y 4 but, Heteroaryl containing 5 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O, and S, and one or more of the heteroaryl ring carbon atoms are selected from 1 to 4 independently selected R c Heteroaryl, optionally substituted with 71. The compound of any one of claims 1 to 70, wherein

84. Y 4 but, Heteroaryl containing 6 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), and N(R d ), wherein one or more of the heteroaryl ring carbon atoms are selected from 1 to 4 independently selected R c Heteroaryl, optionally substituted with 84. The compound of any one of claims 1 to 70 and 83, wherein

85. Y 4 is one to two independently selected R c The compound of any one of claims 1-70 and 83-84, which is pyridinyl (e.g., 2-pyridinyl, 3-pyridinyl, or 4-pyridinyl), pyrimidinyl (e.g., 2-pyrimidinyl or 5-pyrimidinyl), or pyrazinyl, each of which may be substituted with.

86. R c Each occurrence of independently: (i) Halo; (ii) cyano; (iii) C 1～6 Alkyl; (iv) C 2～6 Alkenyl; (v) C 2～6 Alkynyl; (vi) C 1～4 Haloalkyl; (vii) C 1～4 Alkoxy; (viii) C 1～4 Haloalkoxy; (ix) 1 to 4 independently selected C 1～4 Optionally substituted with alkyl -(C 0～3 Alkylene)-C 3～6 Cycloalkyl; (xii) OH; (xiv) -C 1～4 Thioalkoxy; and (xx) C 3～6 Cycloalkoxy 86. The compound of any one of claims 83 to 85, selected from the group consisting of:

87. R c Each occurrence of independently: (i) Halo (e.g. F, Cl); (iii) C 1～6 Alkyl (e.g., methyl); and (xii) OH 87. The compound of claim 86, selected from the group consisting of:

88. Y 4 The compound of any one of claims 1-70 and 83-85, wherein is pyridinyl, pyrimidinyl, or pyrazinyl, each of which is unsubstituted.

89. Y 4 but, Heterocyclyl containing 3 to 10 ring atoms, of which 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), and O, wherein one or more of the heterocyclyl ring carbon atoms are selected from 1 to 4 independently selected R b Heterocyclyl, optionally substituted by 71. The compound of any one of claims 1 to 70, wherein

90. Y 4 but, Heterocyclyl containing 4 to 6 ring atoms, of which 1 to 2 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), and O, wherein one or more of the heterocyclyl ring carbon atoms are selected from 1 to 4 independently selected R b Heterocyclyl, optionally substituted by 90. The compound of any one of claims 1 to 70 and 89, wherein

91. Y 4 but, Heterocyclyl containing 4 ring atoms, one ring atom of which is a heteroatom, and independently selected from N, N(H), N(R d ), and O, wherein one or more of the heterocyclyl ring carbon atoms are selected from 1 to 2 independently selected R b Heterocyclyl, optionally substituted by The compound of any one of claims 1 to 70 and 89 to 90,

92. Y 4 is one to two independently selected R b The compound of any one of claims 1 to 70 and 89 to 91, which is an oxetanyl optionally substituted with (e.g., unsubstituted oxetanyl).

93. Y 4 is one to two independently selected R b Azetidinyl optionally substituted with (e.g., one R b 92. The compound of any one of claims 1-70 and 89-91, wherein the compound is azetidinyl substituted with

94. Y 4 but, Heterocyclyl containing 6 ring atoms, 1 to 2 of which are heteroatoms, each independently selected from N, N(H), N(R d ), and O, wherein one or more of the heterocyclyl ring carbon atoms are selected from 1 to 4 independently selected R b Heterocyclyl, optionally substituted by The compound of any one of claims 1 to 70 and 89 to 90,

95. Y 4 is one to two independently selected R b 95. The compound of any one of claims 1-70, 89-90, and 94, wherein the compound is selected from the group consisting of tetrahydropyranyl, piperidinyl, piperazinyl, and morpholinyl, each of which is optionally substituted with:

96. Y 4 is one to two independently selected R b The compound of any one of claims 1-70, 89-90, and 94-95, wherein the compound is selected from the group consisting of tetrahydropyranyl, piperidinyl, and morpholinyl, each of which is optionally substituted with:

97. R b Each occurrence of is independently -F, C 1～6 Alkyl, C 1～4 97. The compound of any one of claims 89-96, wherein the compound is selected from the group consisting of haloalkyl, oxo, and -OH.

98. R b Each occurrence of is independently -F, C 1～6 Alkyl, C 1～4 haloalkyl, and —OH (e.g., R b and optionally OH.

99. R 4 But below: The compound of any one of claims 1 to 69 and 71 to 76, selected from the group consisting of:

100. R 4 But below: The compound of any one of claims 1 to 69 and 71 to 76, selected from the group consisting of:

101. R 4 but The compound of any one of claims 1 to 66, 70, and 71 to 76, wherein

102. R 4 but The compound of any one of claims 1 to 66, 70, and 71 to 76, wherein

103. R 4 But below: The compound of any one of claims 1 to 69 and 77 to 82, selected from the group consisting of:

104. R 4 But below: The compound of any one of claims 1 to 69 and 77 to 82, selected from the group consisting of:

105. R 4 But below: The compound of any one of claims 1 to 66, 70, and 77 to 82, selected from the group consisting of:

106. R 4 But below: The compound of any one of claims 1 to 69 and 83 to 88, selected from the group consisting of:

107. R 4 But below: The compound of any one of claims 1 to 69 and 83 to 88, selected from the group consisting of:

108. R 4 But below: The compound of any one of claims 1 to 66, 70, and 83 to 88, selected from the group consisting of:

109. R 4 But below: The compound of any one of claims 1 to 66, 70, and 83 to 88, selected from the group consisting of:

110. R 4 But below: The compound of any one of claims 1 to 69 and 89 to 98, selected from the group consisting of:

111. R 4 but The compound of any one of claims 1 to 69 and 89 to 98, wherein

112. R 4 But below: The compound of any one of claims 1 to 66, 70, and 89 to 98, selected from the group consisting of:

113. R 4 But below: The compound of any one of claims 1 to 66, 70, and 89 to 98, selected from the group consisting of:

114. R 4 is 1 to 6 independently selected R a C which may be substituted with 1～10 66. The compound of any one of claims 1 to 65, which is alkyl.

115. R 4 is 1 to 6 independently selected R a C which may be substituted with 1～6 The compound of any one of claims 1 to 65 and 114, which is alkyl.

116. R 4 is one to two independently selected R a C which may be substituted with 1～6 The compound of any one of claims 1-65 and 114-115, which is alkyl.

117. R a Each occurrence of is independently -F; -OH; C 1～4 Alkoxy; and C 1～4 The compound of any one of claims 1-65 and 114-116, selected from the group consisting of haloalkoxy.

118. R a The compound of any one of claims 1-65 and 114-117, wherein each occurrence of is independently -OH.

119. R 4 Methyl, ethyl, The compound of any one of claims 1 to 65 and 114 to 118, selected from:

120. R 4 Methyl and The compound of any one of claims 1 to 65 and 114 to 118, selected from:

121. R 4 is 1 to 6 (e.g., 1 to 3) independently selected R a C which may be substituted with 2～10 (For example, C 2～4 ) alkynyl (e.g. Non-substituted C such as 2～4 66. The compound of any one of claims 1 to 65, wherein said compound is selected from the group consisting of aryl, aryloxy ...

122. R 4 is 1 to 6 (e.g., 1 to 3) independently selected R a C which may be substituted with 2～10 (For example, C 2～4 ) alkenyl (e.g., unsubstituted C such as vinyl 2～4 66. The compound of any one of claims 1 to 65, wherein said compound is selected from the group consisting of aryl, ... and alkenyl.

123. -L 4 -N(H)S(O) 2 -, C≡C, single bond, -C(O)N(H)-, -N(H)-, -N(R 4 )-, -N(R d )-, and -N(H)C(O)-; and R 4 But below: (i) 1 to 2 R a C which may be substituted with 1～6 Alkyl; and (ii) -(Y 3 ) p -Y 4 54. The compound of any one of claims 1 to 53, selected from the group consisting of:

124. -L 4 -N(H)S(O) 2 -, single bond, -NH-, -N(R 4 )-, and -N(H)C(O)-; and R 4 But below: (i) 1 to 2 R a C which may be substituted with 1～6 Alkyl; and (ii) -(Y 3 ) p -Y 4 The compound of any one of claims 1 to 53 and 123, selected from the group consisting of:

125. -L 4 -N(H)S(O) 2 -, -N(H)S(O) 2 N(H)-, -N(H)S(O) 2 N(R d )-, C≡C, single bond, -C(O)N(H)-, -N(H)-, -N(R 4 )-, -N(R d )-, and -N(H)C(O)-; and R 4 But below: (i) 1 to 2 R a C which may be substituted with 1～6 Alkyl; (ii) -(Y 3 ) p -Y 4 and (iii) 1 to 3 independently selected R a C, each of which may be substituted with 2～10 Alkenyl or C 2～10 Alkynyl 54. The compound of any one of claims 1 to 53, selected from the group consisting of:

126. -L 4 -N(H)S(O) 2 -, -N(H)S(O) 2 N(H)- and -N(H)S(O) 2 N(R d )-; and R 4 But below: (i) 1 to 2 R a C which may be substituted with 1～6 Alkyl; (ii) -(Y 3 ) p -Y 4 and (iii) 1 to 3 independently selected R a C, each of which may be substituted with 2～10 Alkenyl or C 2～10 Alkynyl The compound of any one of claims 1 to 53 and 125, selected from the group consisting of:

127. -L 4 -N(H)S(O) 2 The compound of any one of claims 123 to 126, wherein

128. -L 4 -N(H)S(O) 2 N(H)- or -N(H)S(O) 2 N(R d 127. The compound of any one of claims 125 to 126, wherein

129. -L 4 The compound of any one of claims 123-125, wherein is a single bond.

130. -L 4 -NH- or -N(R 4 126. The compound of any one of claims 123 to 125, wherein

131. -L 4 The compound of any one of claims 123-125, wherein is -N(H)C(O)-.

132. R 4 But 1-2 R a C which may be substituted with 1～6 The compound of any one of claims 123-131, which is alkyl.

133. R 4 is one to three independently selected R a C, each of which may be substituted with 2～10 Alkenyl or C 2～10 132. The compound of any one of claims 123-131, which is alkynyl.

134. R 4 is one to three independently selected R a C which may be substituted with 2～10 (For example, C 2～5 ) alkynyl (e.g. Non-substituted C such as 2～5 alkynyl).

135. R 4 -(Y 3 ) p -Y 4 The compound of claims 123-131,

136. Y 4 But 1 to 4 R c C which may be substituted with 6～10 136. The compound of claim 135, which is aryl.

137. Y 4 But there are 1-2 (for example, 1) R c 137. The compound of claim 136, which is phenyl optionally substituted with.

138. Y 4 But 1 to 4 R b C which may be substituted with 3～6 (For example, C 3～4 or C 6 ) cycloalkyl.

139. Y 4 But 1-2 R b C, each of which may be substituted with 3～4 Cycloalkyl or C 6 Cycloalkyl (e.g., R b may be -OH.

140. Y 4 but, Heterocyclyl containing 4 to 6 ring atoms, of which 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), and O, wherein one or more of the heterocyclyl ring carbon atoms are selected from 1 to 2 independently selected R b Heterocyclyl, optionally substituted by 136. The compound of claim 135,

141. Y 4 but, Heterocyclyl containing 6 ring atoms, 1 to 3 of which are heteroatoms, each independently selected from N, N(H), N(R d ), and O, wherein one or more of the heterocyclyl ring carbon atoms are selected from 1 to 2 independently selected R b Heterocyclyl, optionally substituted by (For example, Y 4 is one to two independently selected R b 141. The compound of claim 140, wherein the aryl group is tetrahydropyranyl, piperidinyl, or morpholinyl, each of which may be optionally substituted with.

142. Y 4 but, Heterocyclyl containing 4 ring atoms, 1 to 3 of which are heteroatoms, each independently selected from N, N(H), N(R d ), and O, wherein one or more of the heterocyclyl ring carbon atoms are selected from 1 to 2 independently selected R b Heterocyclyl, optionally substituted by (For example, Y 4 may be oxetanyl; or Y 4 141. The compound of claim 140, wherein

143. Y 4 but, Heteroaryl containing 6 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), and N(R d ), wherein one or more of the heteroaryl ring carbon atoms are selected from 1 to 4 independently selected R c Heteroaryl, optionally substituted with 136. The compound of claim 135,

144. Y 4 is one to two independently selected R c 144. The compound of claim 143, which is pyridinyl (e.g., 2-pyridinyl, 3-pyridinyl, or 4-pyridinyl), pyrimidinyl (e.g., 2-pyrimidinyl or 5-pyrimidinyl), or pyrazinyl, each of which is optionally substituted with:

145. The compound of any one of claims 135-144, wherein p is 0.

146. The compound of any one of claims 135-144, wherein p is 1.

147. Y 3 C 1～3 Alkylene (e.g. CH 2 , C.H. 2 -CH 2 147. The compound of claim 146, wherein

148. R 3 But below:

44. The compound of any one of claims 1 to 43, selected from the group consisting of:

149. R 3 But below: The compound of claim 148, selected from the group consisting of:

150. R 3 But below:

44. The compound of any one of claims 1 to 43, selected from the group consisting of:

151. R 3 But below:

44. The compound of any one of claims 1 to 43, selected from the group consisting of:

152. R 3 But below:

44. The compound of any one of claims 1 to 43, selected from the group consisting of:

153. R 3 But below:

44. The compound of any one of claims 1 to 43, selected from the group consisting of:

154. R 3 But below:

44. The compound of any one of claims 1 to 43, selected from the group consisting of:

155. R 3 But below:

44. The compound of any one of claims 1 to 43, selected from the group consisting of:

156. R 3 But below:

44. The compound of any one of claims 1 to 43, selected from the group consisting of:

157. R 3 But below:

44. The compound of any one of claims 1 to 43, selected from the group consisting of:

158. R 3 But below:

44. The compound of any one of claims 1 to 43, selected from the group consisting of:

159. R 3 But below:

44. The compound of any one of claims 1 to 43, selected from the group consisting of:

160. R 3 But below:

44. The compound of any one of claims 1 to 43, selected from the group consisting of:

161. R 3 But below:

44. The compound of any one of claims 1 to 43, selected from the group consisting of:

162. R 3 But below: , NHMe, and NMe 2 44. The compound of any one of claims 1 to 43, selected from the group consisting of:

163. R 3 But below:

44. The compound of any one of claims 1 to 43, selected from the group consisting of:

164. R 3 But below:

44. The compound of any one of claims 1 to 43, selected from the group consisting of:

165. R 3 One occurrence of 164. The compound of claim 162 or 163,

166. R 1 -(Y 1 ) n -Y 2 and R 2 But 1 to 4 R c C which may be substituted with 6～10 is aryl, 2. The compound of claim 1.

167. The compound of claim 166, wherein n is 0.

168. X 1 , X 2 , X 3 , and X 4 1-2 of are N; and X 1 , X 2 , X 3 , and X 4 Two or three of these are independently selected CR 3 The compound of any one of claims 166-167,

169. X 1 , X 2 , X 3 , and X 4 One of them is N; and the remaining X 1 , X 2 , X 3 , and X 4 Each of the independently selected CR 3 is; or X 1 , X 2 , X 3 , and X 4 Two of them are N; and the remaining X 1 , X 2 , X 3 , and X 4 Each of the independently selected CR 3 That is, The compound of claim 168.

170. X 2 and X 3 CR 3 For example, X 2 and X 3 Both of these are independently selected CR 3 170. The compound of any one of claims 168-169, wherein

171. R 3 One occurrence of -L 4 -R 4 and R 4 -(Y 3 ) p -Y 4 or R 4 is 1 to 6 independently selected R a C which may be substituted with 1～10 The compound of any one of claims 168-170, which is alkyl.

172. R 4 (Y 3 ) p -Y 4 and p is 1. The compound of claim 171,

173. R 4 (Y 3 ) p -Y 4 and p is 0.

174. R 3 each of the remaining occurrences of independently selects H and R c ' (e.g., R 3 and each remaining occurrence of is H.

175. R 3 One occurrence of -L 4 -R 4 and R 3 One occurrence of R c' 175. The compound of any one of claims 171-174, wherein R is 0, R is 1, R is 2, R is 3, R is 4, R is 5, R is 6, R is 7, R is 8, R is 9, R is 10, R is11, R is12, R is13, R is14, R is15, R is16, R is17,

176. R 3 One occurrence of R c' (e.g. Br or Cl, e.g. Cl); and R 3 and each remaining occurrence of is H.

177. Y 2 is as defined in any one of claims 14 to 20 and 26 to 28; and each R c The compound of any one of claims 166-176, wherein, if present, is independently as defined in any one of claims 21-24.

178. Y 2 is as defined in any one of claims 14 to 18; and each R c The compound of any one of claims 166-176, wherein, when present, is as defined in any one of claims 21-23.

179. Y 2 is as defined in any one of claims 16 to 18; and each R c The compound of any one of claims 166-176, wherein, when present, is as defined in any one of claims 21-23.

180. R 1 but For example, R 1 but The compound of any one of claims 166-176,

181. R 2 But 1 to 4 R c C which may be substituted with 6～10 Aryl, e.g., 1 to 4 R c or 1-2 R c or 2 R's c phenyl optionally substituted with; and R c The compound of any one of claims 166-180, wherein, when present, is as defined in any one of claims 33-35.

182. R 2 But two R c phenyl, which may be substituted with, for example, R 2 but and R c The compound of any one of claims 166-181, wherein, when present, is as defined in any one of claims 33-35.

183. R 2 but, Heteroaryl containing 5 to 10 (e.g., 6) ring atoms, of which 1 to 4 (e.g., 1 to 3) ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O, and S (e.g., N, N(H), and N(R d ) wherein one or more of the heteroaryl ring carbon atoms are selected from 1 to 4 independently selected R c Heteroaryl, optionally substituted with For example, R 2 is one to two independently selected R c or, for example, R 2 but and R c The compound of any one of claims 166-180, wherein, when present, is as defined in any one of claims 40-41.

184. R 2 but The compound of any one of claims 166-180,

185. -L 4 But below: -N(H)S(O) 1～2 -or-N(R d )S(O) 1～2 (For example, N(C 1～3 Alkyl)S(O) 2 ), e.g., L 4 -N(H)S(O) 2 - is; -N(H)C(O)- or -N(R d )C(O), e.g., L 4 is -N(H)C(O)-; -C(O)NH- or -C(O)N(R d )-; -N(H)-, -N(R d )- or -N(R 4 )-; - single bond; · C≡C; -O-; and -N(H)S(O) 1～2 N(H)-, -N(R d )S(O) 1～2 N(H)-, -N(H)S(O) 1～2 N(R d )- and -N(R d )S(O) 1～2 N(R d )-, e.g., L 4 -N(H)S(O) 1～2 N(H)- (e.g. -N(H)S(O) 2 N(H)-) or L 4 -N(H)S(O) 1～2 N(R d )-(e.g. -N(H)S(O) 2 N(R d )-(e.g. -N(H)S(O) 2 N(C 1～3 alkyl)-) The compound of any one of claims 171-184, selected from the group consisting of:

186. -L 4 But below: -N(H)S(O) 1～2 -or-N(R d )S(O) 1～2 (For example, N(C 1～3 Alkyl)S(O) 2 ), e.g., L 4 -N(H)S(O) 2 - is; -N(H)C(O)- or -N(R d )C(O), e.g., L 4 is -N(H)C(O)-; -C(O)NH- or -C(O)N(R d )-; -N(H)-, -N(R d )- or -N(R 4 )-; a single bond; and ・C≡C The compound of any one of claims 171-184, selected from the group consisting of:

187. -L 4 But below: ・N(H)S(O) 2 -; -N(H)C(O)-; and -N(H)-, -N(R d )- or -N(R 4 )- The compound of any one of claims 171-184, selected from the group consisting of:

188. -L 4 But below: -N(H)S(O) 1～2 -or-N(R d )S(O) 1～2 (For example, N(C 1～3 Alkyl)S(O) 2 ), e.g., L 4 -N(H)S(O) 2 - is; and -N(H)S(O) 1～2 N(H)-, -N(R d )S(O) 1～2 N(H)-, -N(H)S(O) 1～2 N(R d )- and -N(R d )S(O) 1～2 N(R d )-, e.g., L 4 -N(H)S(O) 1～2 N(H)- (e.g. -N(H)S(O) 2 N(H)-) or L 4 -N(H)S(O) 1～2 N(R d )-(e.g. -N(H)S(O) 2 N(R d )-(e.g. -N(H)S(O) 2 N(C 1～3 alkyl)-) The compound of any one of claims 171-184, selected from the group consisting of:

189. -L 4 -N(H)S(O) 2 The compound of any one of claims 171 to 188, wherein

190. Y 4 But 1 to 4 R c C which may be substituted with 6～10 Aryl, e.g., 1 to 2 (e.g., 1) R c or Y 4 is unsubstituted C 6～10 aryl, e.g., unsubstituted phenyl; and R c The compound of any one of claims 171-189, wherein, when present, is as defined in any one of claims 73-75.

191. Y 4 But 1 to 4 R c C which may be substituted with 6～10 Aryl, e.g., 1 to 4 R c phenyl optionally substituted with; and R c Each occurrence, when present, is independently: (vii) C 1～4 Alkoxy; (viii) C 1～4 haloalkoxy; and (xiv) -C 1～4 Thioalkoxy The compound of any one of claims 171-189, selected from the group consisting of:

192. Y 4 is as defined in any one of claims 77, 78, 79, 81, and 82; and R b The compound of any one of claims 171-189, wherein, when present, is as defined in claim 80.

193. Y 4 is as defined in any one of claims 77 to 79; and R b The compound of any one of claims 171-189, wherein, when present, is as defined in claim 80.

194. Y 4 is as defined in any one of claims 83 to 85 and 88; and R c The compound of any one of claims 171-189, wherein, when present, is as defined in any one of claims 86-87.

195. Y 4 189. The compound of any one of claims 171-189, wherein:

196. Y 4 is as defined in any one of claims 89 to 96; and R b The compound of any one of claims 171-189, wherein, when present, is as defined in any one of claims 97-98.

197. Y 4 is as defined in any one of claims 89 to 92, 94, and 96; and R b The compound of any one of claims 171-189, wherein, when present, is as defined in claim 98.

198. R 4 is selected from the group consisting of the structures of claims 99-113.

199. R 4 is selected from the group consisting of the structures set forth in claims 100, 101, 104-105, 107, 109, 111, and 113.

200. ・R 4 is 1 to 6 independently selected R a C which may be substituted with 1～10 is alkyl; or ・R 4 is 1 to 6 independently selected R a C which may be substituted with 1～6 is alkyl; or ・R 4 is one to two independently selected R a C which may be substituted with 1～6 alkyl, e.g., R 4 Methyl, ethyl, (e.g. methyl and or ・R 4 is 1 to 6 (e.g., 1 to 3) independently selected R a C which may be substituted with 2～10 Alkynyl (e.g., C 2～4 alkynyl) (e.g. Non-substituted C such as 2～4 alkynyl); or ・R 4 is 1 to 6 (e.g., 1 to 3) independently selected R a C which may be substituted with 2～10 Alkenyl (e.g., C 2～4 alkenyl) (e.g. unsubstituted C 2～4 alkenyl); Here, each R a are, if present, independently: -F; -OH; C 1～4 Alkoxy; and C 1～4 haloalkoxy, for example, R a each occurrence is independently -OH; A compound according to any one of claims 171 and 174-189.

201. ・R 4 is 1 to 6 independently selected R a C which may be substituted with 1～10 is alkyl; or ・R 4 is 1 to 6 independently selected R a C which may be substituted with 1～6 is alkyl; or ・R 4 is one to two independently selected R a C which may be substituted with 1～6 Alkyl, such as methyl and and; Here, each R a When present, they are independently -OH, e.g. -F; -OH; C 1～4 Alkoxy; and C 1～4 haloalkoxy, A compound according to any one of claims 171 and 174-189.

202. -L 4 -N(H)S(O) 2 -, -N(H)S(O) 2 N(H)-, -N(H)S(O) 2 N(R d )-, C≡C, single bond, -C(O)N(H)-, -N(H)-, -N(R 4 )-, -N(R d )-, and -N(H)C(O)-; and R 4 But below: (i) 1 to 2 R a C which may be substituted with 1～6 Alkyl; (ii) -(Y 3 ) p -Y 4 and (iii) 1 to 3 independently selected R a C, each of which may be substituted with 2～10 Alkenyl or C 2～10 Alkynyl The compound of any one of claims 171-184, selected from the group consisting of:

203. -L 4 -N(H)S(O) 2 -, -N(H)S(O) 2 N(H)- and -N(H)S(O) 2 N(R d )-; and R 4 But below: (i) 1 to 2 R a C which may be substituted with 1～6 Alkyl; (ii) -(Y 3 ) p -Y 4 and (iii) 1 to 3 independently selected R a C, each of which may be substituted with 2～10 Alkenyl or C 2～10 Alkynyl The compound of any one of claims 171-184, selected from the group consisting of:

204. R 3 is selected from the group consisting of structures according to claims 148 to 165; or R 3 is selected from the group consisting of the structures set forth in claims 148-149, 151, 153, 155-156, 158, 160, 162, and 165.

205. X 2 and X 3 Each of the independently selected CR 3 and X 1 and X 4 The compound of any one of claims 166-169, wherein each of is N.

206. Each R 3 are selected independently -L 4 -R 4 The compound of claim 205,

207. -L 4 -R 4 One occurrence of -R 4 (i.e., L 4 The compound of claim 206, wherein one occurrence of is a bond.

208. -L 4 Other occurrences of: -N(H)S(O) 1～2 -or-N(R d )S(O) 1～2 (For example, N(C 1～3 Alkyl)S(O) 2 ), e.g., L 4 -N(H)S(O) 2 - is; -N(H)C(O)- or -N(R d )C(O), e.g., L 4 is -N(H)C(O)-; -C(O)NH- or -C(O)N(R d )-; -N(H)-, -N(R d )-, or -N(R 4 )-; - single bond; · C≡C; -O-; and -N(H)S(O) 1～2 N(H)-, -N(R d )S(O) 1～2 N(H)-, -N(H)S(O) 1～2 N(R d )- and -N(R d )S(O) 1～2 N(R d )-, e.g., L 4 -N(H)S(O) 1～2 N(H)- (e.g. -N(H)S(O) 2 N(H)-) or L 4 -N(H)S(O) 1～2 N(R d )-(e.g. -N(H)S(O) 2 N(R d )-(e.g. -N(H)S(O) 2 N(C 1～3 alkyl)-)) The compound of any one of claims 205-207, selected from the group consisting of:

209. -L 4 Other occurrences of: -N(H)S(O) 1～2 -or-N(R d )S(O) 1～2 (For example, N(C 1～3 Alkyl)S(O) 2 ), e.g., L 4 -N(H)S(O) 2 - is; -N(H)C(O)- or -N(R d )C(O), e.g., L 4 is -N(H)C(O)-; -C(O)NH- or -C(O)N(R d )-; -N(H)-, -N(R d )- or -N(R 4 )-; a single bond; and ・C≡C The compound of any one of claims 205-207, selected from the group consisting of:

210. -L 4 Other occurrences of: ・-N(H)S(O) 2 -; -N(H)C(O)-; and -N(H)-, -N(R d )- or -N(R 4 )- For example, -L 4 Other occurrences of N(H)S(O) 2 The compound of any one of claims 205 to 207, wherein

211. -L 4 Other occurrences of: -N(H)S(O) 1～2 -or-N(R d )S(O) 1～2 (For example, N(C 1～3 Alkyl)S(O) 2 ), e.g., L 4 -N(H)S(O) 2 - is; and -N(H)S(O) 1～2 N(H)-, -N(R d )S(O) 1～2 N(H)-, -N(H)S(O) 1～2 N(R d )- and -N(R d )S(O) 1～2 N(R d )-, e.g., L 4 -N(H)S(O) 1～2 N(H)- (e.g. -N(H)S(O) 2 N(H)-) or L 4 -N(H)S(O) 1～2 N(R d )-(e.g. -N(H)S(O) 2 N(R d )-(e.g. -N(H)S(O) 2 N(C 1～3 alkyl)-) The compound of any one of claims 205-207, selected from the group consisting of:

212. R 3 One occurrence of -L 4 -R 4 (For example, L 4 N(H)S(O) 2 - and R 3 Other occurrences of R c '(e.g. halo, e.g. -Cl).

213. Formula (I-a1-a): or a pharma- ceutically acceptable salt thereof.

214. Formula (I-a1-a1), (I-a1-a2), or (I-a1-a3): or a pharma- ceutically acceptable salt thereof.

215. The compound of formula (I-a1-a) may be represented by the formula (I-a1-a5): or a pharma- ceutically acceptable salt thereof.

216. R c' The compound of claim 215, wherein is halo (e.g., -Cl).

217. L 4 -NHS(O) 2 The compound of any one of claims 215 to 216, wherein

218. L 4 -N(H)S(O) 2 N(H)- or -N(H)S(O) 2 N(R d 217. The compound of any one of claims 215-216, wherein

219. The compound of formula (I-a1-a) may be represented by the formula (I-a1-a6): or a pharma- ceutically acceptable salt thereof, In the formula, L 4A and L 4B Each of the L 4 and R 4A and R 4B Each of R is independently selected 4 That is, The compound of claim 213.

220. L 4B The compound of claim 219, wherein is a bond.

221. L 4A -NHS(O) 2 The compound of any one of claims 219 to 220, wherein

222. L 4A -N(H)S(O) 2 N(H)- or -N(H)S(O) 2 N(R d 221. The compound of any one of claims 219-220, wherein

223. Formula (I-a1-a7), (I-a1-a8), or (I-a1-a9): or a pharma- ceutically acceptable salt thereof, In the formula, R d' is H or R d (e.g. H or C 1～3 alkyl), The compound of claim 213.

224. Formula (I-a1-b): or a pharma- ceutically acceptable salt thereof.

225. Formula (I-a1-b1) or Formula (I-a1-b2): (For example, L 4 is N(H)SO 2 , -N(H)-, or NHC(O) or a pharma- ceutically acceptable salt thereof.

226. Formula (I-a2-a):

6. The compound of any one of claims 1 to 3 and 5, which is a compound of the formula:

227. Formula (I-a2-a1): or a pharma- ceutically acceptable salt thereof.

228. Formula (I-b1-a): or a pharma- ceutically acceptable salt thereof.

229. Formula (I-b1-a1): or a pharma- ceutically acceptable salt thereof.

230. Formula (I-b1-a3): or a pharma- ceutically acceptable salt thereof, In the formula, R d' is H or R d (e.g. H or C 1～3 alkyl), The compound of claim 228.

231. Formula (I-c1-a):

10. The compound of any one of claims 1 and 8 to 9, which is a compound of the formula:

232. Formula (I-c1-a1): or a pharma- ceutically acceptable salt thereof.

233. Formula (I-d1-a):

10. The compound of any one of claims 1 and 8 to 9, which is a compound of the formula:

234. Formula (I-d1-a1): or a pharma- ceutically acceptable salt thereof.

235. R 4 But below: (i) 1 to 6 independently selected R a C which may be substituted with 1～10 Alkyl; (ii) -(Y 3 ) p -Y 4 and (iii) 1 to 3 independently selected R a C, each of which may be substituted with 2～10 Alkenyl or C 2～10 Alkynyl The compound of any one of claims 213-234, selected from the group consisting of:

236. R 4 -(Y 3 ) p -Y 4 The compound of any one of claims 213-235,

237. Y 4 But 1 to 4 R c C which may be substituted with 6～10 Aryl, e.g., 1 to 2 (e.g., 1) R c or Y 4 is unsubstituted C 6～10 aryl, e.g., unsubstituted phenyl; and R c The compound of any one of claims 205-236, wherein, when present, is as defined in any one of claims 73-75.

238. Y 4 But 1 to 4 R c C which may be substituted with 6～10 Aryl, e.g., 1 to 4 R c phenyl optionally substituted with; and R c Each occurrence, when present, is independently: (vii) C 1～4 Alkoxy; (viii) C 1～4 haloalkoxy; and (xiv) -C 1～4 Thioalkoxy The compound of any one of claims 205-236, selected from the group consisting of:

239. Y 4 is as defined in any one of claims 77, 78, 79, 81, and 82; and R b The compound of any one of claims 205-236, wherein, when present, is as defined in claim 80.

240. Y 4 is as defined in any one of claims 77 to 79; and R b The compound of any one of claims 205-236, wherein, when present, is as defined in claim 80.

241. Y 4 is as defined in any one of claims 83 to 85 and 88; and R c The compound of any one of claims 205-236, wherein, when present, is as defined in any one of claims 86-87.

242. Y 4 The compound of any one of claims 205-236, wherein

243. Y 4 is as defined in any one of claims 89 to 96; and R b The compound of any one of claims 205-236, wherein, when present, is as defined in any one of claims 97-98.

244. Y 4 is as defined in any one of claims 89 to 92, 94, and 96; and R b The compound of any one of claims 205-236, wherein, when present, is as defined in claim 98.

245. The compound of any one of claims 235-244, wherein p is 0.

246. The compound of any one of claims 235-244, wherein p is 1.

247. Y 3 C 1～3 Alkylene, e.g. CH 2 or CH 2 -CH 2 The compound of claim 244,

248. R 4 The compound of any one of claims 205-236, wherein:

249. Each R 4 is selected from the group consisting of the structures of claims 100, 101, 104-105, 107, 109, 111, and 113.

250. ・R 4 is 1 to 6 independently selected R a C which may be substituted with 1～10 is alkyl; or ・R 4 is 1 to 6 independently selected R a C which may be substituted with 1～6 is alkyl; or ・R 4 is one to two independently selected R a C which may be substituted with 1～6 alkyl, e.g., R 4 Methyl, ethyl, (e.g. methyl and or ・R 4 is 1 to 6 (e.g., 1 to 3) independently selected R a C which may be substituted with 2～10 Alkynyl (e.g., C 2～4 alkynyl) (e.g. Non-substituted C such as 2～4 alkynyl); or ・R 4 is 1 to 6 (e.g., 1 to 3) independently selected R a C which may be substituted with 2～10 Alkenyl (e.g., C 2～4 alkenyl) (e.g. unsubstituted C 2～4 alkenyl); Here, each R a are, if present, independently: -F; -OH; C 1～4 Alkoxy; and C 1～4 haloalkoxy, for example, R a each occurrence is independently -OH; The compound of any one of claims 205-235.

251. ・R 4 is 1 to 6 independently selected R a C which may be substituted with 1～10 is alkyl; or ・R 4 is 1 to 6 independently selected R a C which may be substituted with 1～6 is alkyl; or ・R 4 is one to two independently selected R a C which may be substituted with 1～6 Alkyl, such as methyl and and; Here, each R a When present, they are independently -OH, e.g. -F; -OH; C 1～4 Alkoxy; and C 1～4 haloalkoxy, The compound of any one of claims 205-235.

252. R 1 -(Y 1 ) n -Y 2 The compound of any one of claims 205-251,

253. Y 2 is as defined in any one of claims 14 to 20; and each R c The compound of any one of claims 205-252, wherein, if present, is independently as defined in any one of claims 21-24.

254. Y 2 is as defined in any one of claims 14 to 18 and 26; and each R c The compound of any one of claims 205-253, wherein, when present, is as defined in any one of claims 21-23.

255. Y 2 is as defined in any one of claims 16 to 18; and each R c The compound of any one of claims 205-252, wherein, when present, is as defined in any one of claims 21-23.

256. R 1 but ,for example The compound of any one of claims 205-252,

257. The compound of any one of claims 250-256, wherein n is 0.

258. R 2 But 1 to 4 R c C which may be substituted with 6～10 Aryl, e.g., 1 to 4 R c or 1-2 R c or 2 R's c phenyl optionally substituted with; and R c The compound of any one of claims 205-257, wherein, if present, is as defined in any one of claims 33-35.

259. R 2 But two R c phenyl, which may be substituted with, for example, R 2 but and R c The compound of any one of claims 205-257, wherein, if present, is as defined in any one of claims 33-35.

260. R 2 but, Heteroaryl containing 5 to 10 (e.g., 6) ring atoms, of which 1 to 4 (e.g., 1 to 3) ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O, and S (e.g., N, N(H), N(R d ), and O), where one or more of the heteroaryl ring carbon atoms are selected from 1 to 4 independently selected R c Heteroaryl, optionally substituted with For example, R 2 is one to two independently selected R c or, for example, R 2 but and R c The compound of any one of claims 205-257, wherein, when present, is as defined in any one of claims 40-41.

261. R 2 but The compound of any one of claims 205-257,

262. R 1 -(Y 1 ) n -Y 2 and R 2 But 1 to 4 R c C which may be substituted with 6～10 is aryl, A compound according to any one of claims 213-251.

263. The compound of claim 262, wherein n is 0.

264. Y 2 but, Heteroaryl containing 6 ring atoms, wherein 1-2 ring atoms are N and one or more of the heteroaryl ring carbon atoms are selected from 1-4 independently selected R c Heteroaryl, optionally substituted with The compound of any one of claims 262-263,

265. Y 2 but, One or more of the ring carbon atoms are each independently selected from 1 to 4 (e.g., 1) R c pyridyl (e.g. 2-pyridyl or 6-pyridyl), optionally substituted with The compound of any one of claims 262-264,

266. R c Each occurrence of is selected independently 1～4 Alkoxy (e.g. -OCH 3 , -OCH 2 CH 3 266. The compound of any one of claims 262-265, wherein

267. R 1 but The compound of any one of claims 262-266,

268. R 2 But 1 to 4 R c The compound of any one of claims 262-267, which is phenyl optionally substituted with.

269. R 2 But two R c The compound of any one of claims 262-268, which is phenyl optionally substituted with.

270. R 2 but The compound of claim 269,

271. R 1 but and R 2 but The compound of any one of claims 205-251,

272. Formula (I-a1-a4): The compound of any one of claims 213, 235-251, and 271,

273. R 3 The compound of claim 272, wherein

274. R 3 R c' , for example halo (e.g. Cl).

275. Formula (I-b1-a2): The compound of any one of claims 228, 235-251, and 271,

276. L 4 NHS(O) 2 The compound of any one of claims 272-275,

277. The table below:

2. The compound of claim 1, selected from the group consisting of compounds in the formula:

278. 278. A pharmaceutical composition comprising a compound or salt of any one of claims 1-277 and one or more pharma- ceutically acceptable excipients.

279. 278. A method for modulating APJ receptor activity, comprising contacting an APJ receptor with a compound according to any one of claims 1-277.

280. The method of claim 279, wherein said modulating comprises stimulating an APJ receptor.

281. The method of claim 279 or 280, which is performed in vitro.

282. The method of claim 279 or 280, which is performed in vivo.

283. A method for modulating (e.g., decreasing) pulmonary vascular resistance in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of claims 1-277.

284. A method for modulating (e.g., decreasing) right ventricular afterload in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of claims 1-277.

285. A method for modulating (e.g., decreasing) mean pulmonary arterial pressure in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of claims 1-277.

286. The method of claim 285, wherein the subject exhibits a mean pulmonary artery pressure of greater than 25 mmHg.

287. A method for reducing the risk of right ventricular failure in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of claims 1-277.

288. A method for treating a disease, disorder, or condition in which inhibition or deficiency of APJ receptor signaling or downregulation of endogenous apelin contributes to the pathology and / or symptoms and / or progression of the disease, disorder, or condition, comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1-277.

289. The method of claim 288, wherein said disease, disorder, or condition is pulmonary arterial hypertension ("PAH").

290. The method of claim 289, wherein the PAH is idiopathic.

291. PAH is hereditary PAH, toxic or drug-induced PAH, or: Congenital heart disease, connective tissue disorders (e.g., scleroderma, systemic lupus erythematosus, systemic sclerosis, Hashimoto's thyroiditis, Sjogren's syndrome, and antiphospholipid syndrome), portal hypertension, BMPR2 mutations, schistosomiasis, and HIV infection The method of claim 289, wherein the PAH is associated with one or more of the following:

292. The method of claim 288, wherein the disease, disorder, or condition is fibrosis.

293. 293. The method of claim 292, wherein the fibrosis is associated with an organ or tissue selected from the group consisting of lung, liver, heart, mediastinum, bone marrow, retroperitoneum, skin, intestine, joints, reproductive organs, and combinations thereof.

294. The method of claims 288 and 292, wherein the disease, disorder, or condition is idiopathic pulmonary fibrosis (IPF).

295. The method of claim 288, wherein the disease, disorder, or condition is a connective tissue disorder.

296. The method of claim 295, wherein the connective tissue disorder is selected from the group consisting of scleroderma, systemic lupus erythematosus, systemic sclerosis, Hashimoto's thyroiditis, Sjogren's syndrome, and antiphospholipid syndrome.

297. The method of any one of claims 288 and 295-296, wherein said disease, disorder, or condition is systemic sclerosis.

298. The method of any one of claims 279-297, further comprising identifying the subject.

299. The identifying determines in the subject one or more of the following parameters: Leukotriene B4 level, pulmonary vascular resistance, pulmonary artery pressure, cardiac index, pulmonary capillary wedge pressure, right atrial pressure, 6-minute walk distance, brain natriuretic peptide level, atrial natriuretic peptide level, and pulmonary diffusing capacity The method of claim 298, comprising determining a level of.

300. The method of any one of claims 279-299, wherein the subject is a human.

301. The method of any one of claims 279-300, further comprising administering one or more additional therapeutic agents.

302. The method of any one of claims 279-301, further comprising treating one or more diseases, disorders, or conditions that are sequelae or comorbidities of PAH.

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