Compounds and compositions for treating conditions associated with APJ receptor activity

Abstract

The present disclosure features chemical entities (e.g., compounds, or pharmaceutically acceptable salts and / or hydrates and / or prodrugs of the compounds) 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 comprising the same, as well as other methods of using and making the same. For example, the chemical entities are useful for treating a subject (e.g., a human) with a disease, disorder, or condition in which decreased 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 pathology and / or symptoms and / or progression of the disease, disorder, or condition. Non-limiting examples of such diseases, disorders, or conditions include (i) cardiovascular disease; (ii) metabolic disorders; (iii) diseases, disorders, and conditions associated with vascular pathology; 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 above or any of those 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.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 62 / 742,218, filed October 5, 2018, which is incorporated herein 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 of the compounds) 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 comprising the same, as well as other methods of using and making the same. For example, the chemical entities are useful for treating a subject (e.g., a human) with a disease, disorder, or condition in which decreased 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 pathology and / or symptoms and / or progression of the disease, disorder, or condition. Non-limiting examples of such diseases, disorders, or conditions include (i) cardiovascular disease; (ii) metabolic disorders; (iii) diseases, disorders, and conditions associated with vascular pathology; 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 above or any of those 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 technology]

[0003] background Pulmonary arterial hypertension (PAH) is a severe cardiopulmonary disorder characterized by vascular remodeling of pulmonary arterioles, including the formation of plexiform and concentric lesions composed of proliferating vascular cells. PAH is thought to be caused by cellular proliferation and fibrosis of small pulmonary arteries. Clinically, PAH leads to elevated pulmonary arterial pressure and subsequent right ventricular failure, one of the leading causes of morbidity and mortality. Mortality remains very high, with mortality rates of 15%, 30%, and 45% at one, two, and three years after diagnosis, respectively. See, for example, Kim, J., Mol. Cells 2014; 37(3): 196-201 (Non-Patent Document 1) and Lau, EMT, Nature Reviews, 2017, 1-12 (Non-Patent Document 2).

[0004] Type 2 diabetes mellitus (T2DM) is characterized by high blood glucose levels and insulin resistance. Tens of millions of people in the United States alone suffer from T2DM and conditions that are comorbid or sequelae of T2DM. T2DM is often associated with obesity.

[0005] The apelin receptor (APJ receptor) is a G protein-coupled receptor containing seven hydrophobic transmembrane domains (see, e.g., Kim, supra). Apelin (also known as APLN), a 36-amino acid peptide encoded by the APLN gene in humans, is the endogenous ligand of the APJ receptor (see, e.g., 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, including the heart, kidney, pancreas, lung, vasculature, central nervous system, liver, adipose, gastrointestinal tract, brain, adrenal glands, endothelium, and human plasma.

[0007] Furthermore, evidence indicates that both apelin and APJ are regulators of central and peripheral responses to multiple homeostatic perturbations, including cardiovascular regulation and function; angiogenesis; fluid homeostasis; water balance; hypothalamic-pituitary-adrenal axis (HPA) regulation; metabolic homeostasis; energy metabolism; and renal function. For example, emerging evidence suggests that APJ-apelin signaling plays a role in maintaining pulmonary vascular homeostasis (see, e.g., Kim, supra). Evidence also indicates a link between the apelinergic system (e.g., apelin receptors and APJ receptors) 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). As another example, apelin, synthesized and secreted by adipocytes, has been described as a beneficial adipokine in obesity, and furthermore, there is evidence for a potential role of apelin receptors and APJ receptors in glucose and energy metabolism (see, e.g., O'Carroll, supra). [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Kim, J., Mol. Cells 2014; 37(3): 196-201 [Non-patent document 2] Lau, EMT, Nature Reviews, 2017, 1-12 [Non-patent document 3] O'Carroll, AM., et al., J Endocrinol 2013, 219, R13-R35 [Non-patent document 4] Coquerel, D., et al., Critical Care 2018, 22: 10 Summary of the Invention

[0009] overview The present disclosure features chemical entities (e.g., compounds, or pharmaceutically acceptable salts and / or hydrates and / or prodrugs of the compounds) 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 comprising the same, as well as other methods of using and making the same. For example, the chemical entities are useful for treating a subject (e.g., a human) with a disease, disorder, or condition in which decreased 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 pathology and / or symptoms and / or progression of the disease, disorder, or condition. Non-limiting examples of such diseases, disorders, or conditions include (i) cardiovascular disease; (ii) metabolic disorders; (iii) diseases, disorders, and conditions associated with vascular pathology; 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 above or any of those 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 compounds that directly bind to or modify the APJ receptor at the protein level such that APJ receptor activity is increased, for example by activation, stabilization, altered distribution, or in other ways.

[0011] Certain chemical entities described herein that stimulate the APJ receptor to a lesser extent than a full APJ receptor agonist may function in assays as both agonists and antagonists. These chemical entities prevent the full effect of APJ receptor interaction and therefore antagonize APJ receptor activation by a full APJ receptor agonist. However, the chemical entities themselves also activate some APJ receptor activity, usually to a lesser extent than the corresponding amount of a full APJ receptor agonist. 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 in a pathway-specific manner. Accordingly, the present disclosure also features chemical entities that exhibit activity as ligand-biased modulators (e.g., ligand-biased agonists). APJ receptor activity can modulate (e.g., alter or bias) the competitive level of downstream G protein signaling (activation) and β-arrestin recruitment. APJ receptor signaling through β-arrestin has been shown to mediate stretch-induced myocardial hypertrophy. See, e.g., Scimia, MC, et al., Nature 2012, 488, 394-398. In certain embodiments, the chemical entities described herein modulate (e.g., decrease, e.g., attenuate, interfere, or inhibit) β-arrestin signaling. In certain embodiments, the chemical entities described herein modulate (e.g., decrease, e.g., attenuate, interfere, or 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 recruitment.

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

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

[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 recruitment, for example, the chemical entities described herein can fully stimulate both β-arrestin and G protein signaling pathways.

[0019] Generally, receptors exist in an active conformation (Ra) and an inactive conformation (Ri). Certain compounds that affect receptors can alter the Ra to Ri ratio (Ra / Ri). For example, a full agonist increases the Ra / Ri ratio and can cause a "maximal" saturation effect. A partial agonist, upon binding to the receptor, produces a response that is lower than that elicited by a full agonist (e.g., an endogenous agonist). Thus, the Ra / Ri of a partial agonist is lower than that of a full agonist. However, the potency of a partial agonist can be greater or less than that of a full agonist.

[0020] In one aspect, the characterized chemical entity has formula I: TIFF0007640458000001.tif30128, or a pharmaceutically acceptable salt thereof; In the formula, R 1 , R 2 , A1 , X 1 , X 2 , X 3 , and X 4 may be as defined anywhere herein.

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

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

[0023] A further aspect features a method for treating a disease, disorder, or condition in which decreased 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 pathology and / or symptoms and / or progression of the disease, disorder, or condition. The method includes administering to a subject in need of such treatment 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 same).

[0024] In another aspect, the disclosure features a method of treating a subject having a disease, disorder, or condition in which decreased 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 pathology and / or symptoms and / or progression of the disease, disorder, or condition. The method includes administering a chemical entity described herein (e.g., a compound described generally or specifically herein, a pharmaceutically acceptable salt thereof, or a composition comprising same) in an amount effective to treat the disease, disorder, or condition.

[0025] A further aspect features a method of treatment that includes 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 same), in an amount effective to treat a disease, disorder, or condition in which decreased 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 pathology 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, the PAH is idiopathic. In other embodiments, the 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 (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.

[0027] Another non-limiting example of the disease, disorder, and condition is cardiovascular disease, such as coronary heart 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 myocardial remodeling after infarction or cardiac surgery, and valvular heart disease.

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

[0029] Other non-limiting examples of such 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 coronary artery disease (CAD), peripheral vascular disease (PVD), non-CAD atherosclerotic conditions including aortic atherosclerosis and cerebral arteriosclerosis, diabetic retinopathy, ischemia-reperfusion injury, pulmonary emphysema, radiation-induced organ and tissue damage, luteal regression, scleroderma, systemic sclerosis, and immune dysregulation disorders.

[0031] In one aspect, the present disclosure features methods for identifying and / or selecting subjects (e.g., humans) likely to benefit from the methods described herein, as well as methods for determining whether a subject (e.g., a human) is responsive to the methods. In certain embodiments, a biological sample, which may be, for example, but not limited to, breath, sputum, tissue, a plasma or serum sample, or urine, is obtained from a subject, and 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 are not afflicted with 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 higher (or elevated) level of a measured parameter compared to a control value determined from a normal, unaffected individual or population indicates that the methods described herein will benefit the subject. Generally, a lower level compared to the control value indicates that the patient is responding to the treatment, or, relative to subjects not receiving the treatment, that the treatment may be less beneficial to the subject.

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

[0033] In certain embodiments, the parameter is LTB4 level.For example, the baseline or reference value of LTB4 can be 100pg / mL or more, 200pg / mL or more, 300pg / mL or more, 400pg / mL or more, 500pg / mL or more, 600pg / mL or more, or 100pg / mL or more.In certain embodiments, the provided treatment is effective if the subject's endpoint LTB4 level decreases below baseline or reference LTB4 level after treatment begins.For example, the subject's endpoint LTB4 level decreases below 600pg / mL, below 500pg / mL, below 400pg / mL, below 300pg / mL, below 200pg / mL, or below 100pg / mL. In certain embodiments, the provided treatment is effective if, after treatment begins, 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. In other embodiments, the provided treatment is effective if, after treatment begins, 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.

[0034] In certain embodiments, the parameter is pulmonary vascular resistance (PVR). A baseline or reference PVR level is 200 dynsec / cm 5 More than 240dynsec / cm 5 More than 300dynsec / cm 5 Over 400 dynsec / cm 5 Over 500 dynsec / cm 5 Over 600 dynsec / cm 5 More than 700dynsec / cm 5 or more, or 800 dynsec / cm 5 In certain embodiments, the treatment provided comprises a treatment in which the subject's endpoint PVR level is 70 dynsec / cm or greater than the baseline or reference PVR level after treatment has begun. 5 Over 100 dynsec / cm 5 Over 130 dynsec / cm 5 or more than 160 dynsec / cm 5If it decreases by more than this, it is valid.

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

[0036] In certain embodiments, the parameter is cardiac index (CI). Baseline or reference CI levels can be 5 L / min / m² or less, 2.5 L / min / m² or less, 2 L / min / m² or less, 1.5 L / min / m² or less, or 1 L / min / m² or less. In certain embodiments, the provided treatment is efficacious if, after treatment begins, 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.

[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 less, or 5 mmHg or less. In certain embodiments, the provided treatment is effective if, after treatment begins, the endpoint PCWP level increases from the baseline or reference PCWP level 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.

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

[0039] In certain embodiments, the parameter is 6-minute walking distance (6 MWD). The baseline or reference 6 MWD 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 treatment begins, the subject's endpoint 6 MWD 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 6 MWD. ​​Alternatively, or in addition, the provided treatment is effective if, after treatment begins, the subject's endpoint 6 MWD 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 brain natriuretic peptide (BNP) level. 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 the subject's endpoint BNP level decreases from the baseline or reference BNP level after treatment begins. 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 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 the subject's endpoint ANP level decreases from the baseline or reference ANP level after treatment begins. For example, the subject's endpoint ANP 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.

[0042] In certain embodiments, the parameter is pulmonary diffusion capacity (DLCO), or CO diffusion capacity, and may be used in the present methods as a parameter for determining efficacy. The baseline or reference DLCO may 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 treatment begins. For example, the endpoint DLCO may increase from the baseline or reference DLCO by 1% or more, 5% or more, 10% or more, 15% or more, 20% or more, or 50% or more.

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

[0044] The methods described herein can further include treating one or more conditions that are concomitant, comorbid, 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 concomitant, comorbid, or sequelae of PAH, such as coronary heart disease or 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 myocardial remodeling after infarction or cardiac surgery, 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 uncontrolled cholesterol 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 (eg, in combination with the chemical entities described herein).

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

[0049] Apelin peptides are unstable, and therefore only acute pharmacodynamic effects of apelin peptides can be observed. In some embodiments, the compounds described herein exhibit relatively high metabolic stability, allowing for the observation of non-acute pharmacodynamic effects.

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

[0051] In some embodiments, the compounds described herein can selectively activate G protein pathways through APJ receptors, thereby reducing the tachyphylaxis often associated with the administration of strong agonists. Thus, in certain embodiments, the compounds described herein can reduce arrestin-associated cardiac hypertrophy.

[0052] In some embodiments, the compounds described herein may exhibit pleiotropic properties (eg, inotropic activity, cardiorenal protection, and fluid homeostasis regulation).

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

[0054] Further definitions In order to facilitate understanding of the disclosure described herein, some additional terms are defined below.Generally, the nomenclature used herein and the experimental methods in organic chemistry, medicinal chemistry and pharmacology described herein are well known and commonly used in the art.Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as those commonly understood by those skilled in the art to which this disclosure belongs.Patents, applications, application publications and other publications mentioned throughout this specification and appendix are each incorporated herein in their entirety by reference.

[0055] The term "APJ receptor" as used herein is intended to include, but is not limited to, nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide strands, complementary sequences, peptides, polypeptides, proteins, homologous and / or orthologous APJ molecules or APJ receptor molecules, isoforms, precursors, mutants, variants, derivatives, splice variants, alleles, different species, and active fragments thereof.

[0056] As used herein, the term "acceptable" in reference to a formulation, composition, or ingredient means that it has no lasting adverse effects on the general health of the subject being treated.

[0057] "API" means active pharmaceutical ingredient.

[0058] The term "IC50" or "EC50" refers to the amount, concentration, or dosage of a compound required for 50% inhibition or activation of a maximal response in an assay that measures this maximal response.

[0059] As used herein, the term "effective amount" or "therapeutically effective amount" refers to the amount of a chemical entity (e.g., a compound described generally or specifically herein, a pharmaceutically acceptable salt thereof, or a composition comprising the same) being administered that is sufficient to alleviate to some extent one or more symptoms of the disease or condition being treated. The result includes a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" in therapeutic applications refers to the amount of a composition comprising a compound disclosed herein that is required to achieve a clinically significant reduction in a disease symptom. An appropriate "effective" amount in any individual case can be 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 of being compatible with the other ingredients of the pharmaceutical formulation, suitable for use in contact with the tissues or organs of humans and animals, without excessive toxicity, irritation, allergic response, immunogenicity, or other problem or complication, commensurate with a reasonable benefit / risk ratio. For example, Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

[0061] The term "pharmaceutically acceptable salt" refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In certain cases, pharmaceutically acceptable salts can be obtained by reacting a compound described herein with an acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, or salicylic acid. In some cases, pharmaceutically acceptable salts can be obtained by reacting a compound having an acidic group described herein with a base to form a salt, such as an alkali metal salt such as an ammonium salt, a sodium salt, or a potassium salt, an alkaline earth metal salt such as a calcium salt or a magnesium salt, a salt of an organic base such as dicyclohexylamine, N-methyl-D-glucamine, or tris(hydroxymethyl)methylamine, or a salt with an amino acid such as arginine or lysine, or by other methods previously established. There is no particular limitation on the pharmacologically acceptable salt, as long as it can be used in pharmaceuticals. Examples of salts that the compounds described herein form with bases include: salts with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts with organic bases such as methylamine, ethylamine, and ethanolamine; salts with basic amino acids such as lysine and ornithine; and ammonium salts. The salts may be acid addition salts, exemplified by 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" refers to a mixture of a compound described herein with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and / or thickening agents (collectively referred to herein as "excipients"). A pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques for administering a compound exist in the art, including, but not limited to, rectal, oral, intravenous, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0063] The term "subject" means an animal, including, but not limited to, a primate (e.g., a human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. As used herein, the terms "subject" and "patient" are used interchangeably in reference to a mammalian subject, such as a human.

[0064] The terms "treat," "treating," and "treatment" in the context of treating a disease, disorder, or condition are intended to include alleviating or arresting the disorder, disease, or condition, or one or more symptoms associated with the disorder, disease, or condition; or slowing the progression, spread, or worsening of the disease, disorder, or condition, or one or more symptoms thereof.

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

[0066] The term "alkyl" means a hydrocarbon chain, which may be straight or branched, containing the indicated number of carbon atoms. For example, C 1~10 indicates that the group may have from 1 to 10 carbon atoms in it. 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 replaced with an independently selected halo.

[0068] The term "alkoxy" refers to an -O-alkyl group (e.g., -OCH3).

[0069] The term "haloalkoxy" means an -O-haloalkyl group (e.g., -OCH3).

[0070] The term "alkylene" means a divalent branched or unbranched alkyl (eg, -CH2-).

[0071] Terms such as "arylene" refer to a divalent ring system form, here a divalent aryl.

[0072] The term "alkenyl" refers to a hydrocarbon chain that may 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 may have at least 2 but no more than 6 carbon atoms in it.

[0073] The term "alkynyl" refers to a hydrocarbon chain that may 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 may have at least 2 but no more than 6 carbon atoms in it.

[0074] The term "aryl" refers to a 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system in which 0, 1, 2, 3, or 4 atoms of each ring may be substituted, and in which the ring comprising the monocyclic group is aromatic and at least one fused ring comprising the bicyclic or tricyclic group is aromatic, e.g., tetrahydronaphthyl. Examples of aryl groups include phenyl, naphthyl, and the like.

[0075] As used herein, the term "cycloalkyl" includes an optionally substituted saturated cyclic hydrocarbon group having 3 to 10 carbons, preferably 3 to 8 carbons, and 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" refers to a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic aromatic ring system having 1-3 heteroatoms in the monocyclic ring, 1-6 heteroatoms in the bicyclic ring, or 1-9 heteroatoms in the tricyclic ring, selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 N, O, or S heteroatoms in the monocyclic, bicyclic, or tricyclic ring, respectively), in which 0, 1, 2, 3, or 4 atoms in each ring are optionally substituted, and in which the ring comprising the monocyclic group is aromatic and at least one fused ring comprising the bicyclic or tricyclic group is aromatic (but need not be a ring containing a heteroatom, e.g., tetrahydroisoquinolinyl). Exemplary heteroaryl systems include, but are 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, pyriazole imidazoles, pyrazines, [1,2,3]triazines, [1,2,4]triazines, [1,3,5]triazines, indoles, isoindoles, benzofurans, benzothiophenes, [1,3]benzoxazoles, [1,3]benzothiazoles, benzimidazoles, indazoles, quinolines, isoquinolines, cinnolines, quinazolines, quinoxalines, phthalazines, different naphthyridines, e.g., [1,8]naphthyridine, different thienopyridines, e.g., thieno[2,3-b]pyridine, and purines.

[0077] The term "heterocyclyl" refers to 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 ring, 1 to 6 heteroatoms in the bicyclic ring, or 1 to 9 heteroatoms in the tricyclic ring, the heteroatoms being 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 ring, respectively), and 0, 1, 2, or 3 atoms in each ring may be optionally substituted. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like.

[0078] Furthermore, atoms constituting the compounds of this embodiment are intended to include all isotopic forms of the atoms. As used herein, isotopes include atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include tetrahydrogen, tetrahydrofuran ... 13 C and 14 C is one example.

[0079] The compounds provided herein may include various stereochemical forms. The compounds also include diastereomers and optical isomers resulting from structural asymmetry in a particular compound, for example, mixtures of enantiomers (including atropisomers), including racemic mixtures, as well as individual enantiomers and diastereomers. Separation of individual isomers or selective synthesis of individual isomers can be achieved by applying various methods well known to those skilled in the art. Unless otherwise indicated, when a disclosed compound is named or depicted by a structure without specifying the stereochemical structure and has one or more chiral centers, it is understood that the disclosed compound represents all possible stereoisomers of the compound. For example, -S(O)(=NH)-R 4 is an enantiomer TIFF0007640458000002.tif10128 and enantiomers TIFF0007640458000003.tif10128, as well as mixtures thereof (e.g., racemic mixtures).

[0080] [The present invention 1001] Formula (I): TIFF0007640458000004.tif30128 or a pharmaceutically acceptable salt thereof, During the ceremony, A 1 is CH or N; X 1 、X 2 、X 3 , and X 4 each independently represents 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 optionally substituted with 1~6 alkylene; and ·Y 2 is: (a) 1 to 4 R b C optionally substituted with 3~10 cycloalkyl; (b) 1 to 4 R c C optionally substituted with 6~10 aryl; (c) 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 the group consisting of 1 to 4 independently selected R c heteroaryl, optionally substituted with (d) Heterocyclyl containing 3 to 10 ring atoms, wherein 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 the group consisting of 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 optionally 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 optionally substituted with 2~7 is alkyl; or (iii) 1 to 6 independently selected R a C optionally 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 optionally substituted with 1~3 is alkylene; ·Z 5 -N(H)-, -N(R d )-, -O-, or -S-; ·Z 6 is 1 to 4 Ra C optionally 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 with 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 the group consisting of 1 to 4 independently selected R c heteroaryl, optionally substituted with (iii) 1 to 4 R b C optionally 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 the group consisting of 1 to 4 independently selected R b heterocyclyl, optionally substituted by (v) 1 to 6 independently selected R a C optionally substituted with 1~10 Alkyl and; R 3 Each occurrence of independently represents -L 4 -R 4 , H, and R c ' selected from the group consisting of; L 4 Each occurrence of is independently: (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)(=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 is independently: (i) -(Y 3 ) p -Y4 , 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 optionally substituted with 3~6 cycloalkyl; (b) 1 to 4 R c C optionally substituted with 6~10 aryl; (c) 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 the group consisting of 1 to 4 independently selected R c heteroaryl, optionally substituted with (d) Heterocyclyl containing 3 to 10 ring atoms, wherein 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 the group consisting of 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 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 is 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; (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 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 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; and However, the compound is represented by formula (I-1): TIFF0007640458000005.tif35128 If R is a compound of 1 is other than unsubstituted phenyl, p-dimethylaminophenyl, p-aminosulfonylphenyl, and unsubstituted 4-pyridinyl; The compound has the formula (I-2): TIFF0007640458000006.tif34128 If R is a compound of 1 is other than unsubstituted phenyl; However, the compound has the formula (I-3): TIFF0007640458000007.tif34128 rather than a compound of; However, the compound is represented by formula (I-4): TIFF0007640458000008.tif34128 If R is a compound of 1 is other than p-fluorophenyl; However, the compound is represented by formula (I-5): TIFF0007640458000009.tif34128 If R is a compound of 3 is other than trifluoromethyl; However, the compound is represented by formula (I-6): TIFF0007640458000010.tif34128 If R is a compound of 2 is the following: (i) unsubstituted phenyl; (ii) TIFF0007640458000011.tif10128 ; (iii) TIFF0007640458000012.tif20128 ; (iv) unsubstituted pyridinyl; (v) TIFF0007640458000013.tif12128 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 the group consisting of 1 to 2 independently selected R c Heteroaryl, optionally substituted with Except, A compound of formula (I), or a pharmaceutically acceptable salt thereof. [The present invention 1002] X 1 、X 2 、X 3 , and X 4 1 or 2 of the X are independently N; and X 1 、X 2 、X 3 , and X 4 Two or three of these are independently selected CR 3 The compound of the present invention 1001, [The present invention 1003] Formula (Ia): TIFF0007640458000014.tif30128 1001. A compound of the present invention, which is a compound of formula (I) or a pharmaceutically acceptable salt thereof. [The present invention 1004] Formula (I-a1): TIFF0007640458000015.tif34128 or a pharmaceutically acceptable salt thereof. [The present invention 1005] Formula (I-a2): TIFF0007640458000016.tif34128 or a pharmaceutically acceptable salt thereof. [The present invention 1006] Formula (Ib): TIFF0007640458000017.tif30128 1001. A compound of the present invention, which is a compound of formula (I) or a pharmaceutically acceptable salt thereof. [The present invention 1007] Formula (I-b1): TIFF0007640458000018.tif34128 or a pharmaceutically acceptable salt thereof. [The present invention 1008] Formula (Ic) or (Id): TIFF0007640458000019.tif30128 1001. A compound of the present invention, which is a compound of formula (I) or a pharmaceutically acceptable salt thereof. [The present invention 1009] Formula (I-c1) or (I-d1): TIFF0007640458000020.tif35128 or a pharmaceutically acceptable salt thereof. [The present invention 1010] R 1 -(Y 1 ) n -Y 2 The compound of any one of 1001 to 1009 of the present invention, [The present invention 1011] The compound of any one of 1001 to 1010 of the present invention, wherein n is 0. [The present invention 1012] The compound of any one of claims 1001 to 1010, wherein n is 1. [The present invention 1013] Y 1 C 1~3 The compound of the present invention 1012, which is alkylene. [The present invention 1014] 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 the group consisting of 1 to 4 independently selected R c Heteroaryl, optionally substituted with The compound of any one of claims 1001 to 1013 of the present invention, [The present invention 1015] Y 2 but, Heteroaryl containing 5 to 6 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 the group consisting of 1 to 4 independently selected R c Heteroaryl, optionally substituted with The compound of any one of claims 1001 to 1014 of the present invention, [The present invention 1016] Y 2 but, Heteroaryl containing 6 ring atoms, wherein 1 to 2 ring atoms are N and one or more of the heteroaryl ring carbon atoms are selected from 1 to 4 independently selected R c Heteroaryl, optionally substituted with The compound of any one of claims 1001 to 1015 of the present invention, [The present invention 1017] 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 The compound of the present invention 1016, [The present invention 1018] Y 2 but, One or more of the ring carbon atoms may be selected from the group consisting of one independently selected R c pyridyl (e.g., 2-pyridyl or 6-pyridyl), optionally substituted with The compound of the present invention 1017, [The present invention 1019] 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 the group consisting of 1 to 3 independently selected R c Heteroaryl, optionally substituted with The compound of any one of claims 1001 to 1015 of the present invention, [The present invention 1020] Y 2 but, One or more of the ring carbon atoms are substituted with 1 to 2 (e.g., 1) independently selected R c furanyl, optionally substituted with The compound of the present invention 1019. [The present invention 1021] 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 Any of the compounds of 1014 to 1020 of the present invention selected from the group consisting of: [The present invention 1022] R c each occurrence independently of the following: (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) Any of the compounds of 1014 to 1020 of the present invention selected from the group consisting of: [The present invention 1023] R c Each occurrence of C is independently selected 1~4 Alkoxy (e.g., -OCH 3 , -OCH 2 CH 3 ) is any one of the compounds of the present invention 1014 to 1020. [The present invention 1024] R c Each occurrence of C is independently selected 1~6 The compound of any one of claims 1014 to 1020, wherein the alkyl group is alkyl (for example, methyl). [The present invention 1025] The compound of any one of 1014 to 1024 of the present invention, wherein n is 0. [The present invention 1026] R 1 but TIFF0007640458000021.tif14128 The compound of any one of 1001 to 1011, 1014 to 1018, and 1021 to 1023 of the present invention, [The present invention 1027] R 1 but TIFF0007640458000022.tif15128 The compound of any one of 1001 to 1011, 1014 to 1018, 1021, and 1024 of the present invention, [The present invention 1028] R 1 but TIFF0007640458000023.tif11128 The compound of any one of 1001 to 1011, 1014 to 1015, 1019 to 1021, and 1024 of the present invention, [The present invention 1029] R 2 However, 1 to 4 R c C optionally substituted with 6~10 The compound of any one of 1001 to 1028 of the present invention, which is aryl. [The present invention 1030] R 2 However, 1 to 4 R c The compound of any one of claims 1001 to 1029 of the present invention, wherein the compound is phenyl which may be substituted with [The present invention 1031] R 2 But 1-2 R c The compound of any one of claims 1001 to 1030, wherein the compound is phenyl optionally substituted with [The present invention 1032] R 2 But two R c The compound of any one of claims 1001 to 1031, wherein the compound is phenyl which may be substituted with [The present invention 1033] R c each occurrence independently 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 Any of the compounds of the present invention 1029 to 1032 selected from the group consisting of: [The present invention 1034] R c Each occurrence of independently halo, C 1~4 Alkoxy, and C 1~4 The compound of any one of claims 1029 to 1033 of the present invention, selected from haloalkyl. [This invention 1035] R c Each occurrence of -OCH independently 3 , CF 3 or F. [The present invention 1036] R 2 but TIFF0007640458000024.tif17128 For example, R 2 but TIFF0007640458000025.tif16128 The compound of any one of claims 1001 to 1035 of the present invention, [This invention 1037] 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 the group consisting of 1 to 4 independently selected R c Heteroaryl, optionally substituted with The compound of any one of 1001 to 1028 of the present invention, [The present invention 1038] 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 the group consisting of 1 to 4 independently selected R c Heteroaryl, optionally substituted with The compound of any one of 1001 to 1028 and 1037 of the present invention, [This invention 1039] R 2 is one to two independently selected R c The compound of any one of claims 1001 to 1028 and 1037 to 1038 of the present invention, wherein the compound is pyridinyl optionally substituted with [The present invention 1040] Each R c but independently 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 The compound of any one of 1001 to 1028 and 1037 to 1039 of the present invention selected from the group consisting of: [The present invention 1041] Each R c independently C 1~4 Compounds of any of claims 1001 to 1028 and 1037 to 1039, which are alkoxy (e.g., methoxy). [The present invention 1042] R 2 but TIFF0007640458000026.tif17128 The compound of any one of the present inventions 1001 to 1028 and 1037 to 1041, [This invention 1043] R 2 but TIFF0007640458000027.tif17128 The compound of any one of the present inventions 1001 to 1028 and 1037 to 1041, [This invention 1044] R 3 One occurrence of -L 4 -R 4 The compound of any one of claims 1001 to 1043 of the present invention, [This invention 1045] 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 may be), any one of compounds 1001 to 1044 of the present invention. [The present invention 1046] R 3 The compound of any one of claims 1001 to 1045, wherein one occurrence of is H. [This invention 1047] R 3 One occurrence of -L 4 -R 4 and R3 each of the remaining occurrences of independently H and R c ' (e.g., R c ' may be halo, e.g., Br or Cl; or R c ' is NH 2 may be), any one of compounds 1001 to 1046 of the present invention. [This invention 1048] R 3 One occurrence of -L 4 -R 4 and R 3 The compound of any of claims 1001 to 1047, wherein each remaining occurrence of is H. [This invention 1049] 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' may be Cl), any one of compounds 1001 to 1047 of the present invention. [The present invention 1050] R 3 One occurrence of -L 4 -R 4 and R 3 The compound of any one of claims 1001 to 1049, wherein one occurrence of is H. [This invention 1051] R 3 Two occurrences of are independently selected -L 4 -R 4 The compound of any one of claims 1001 to 1043 of the present invention, [This invention 1052] R 3 Any remaining occurrences of H and R c' The compound of any one of 1001 to 1043 and 1051 of the present invention selected from the group consisting of: [This invention 1053] R 3 A compound of any of 1001-1043 and 1051-1052, wherein any remaining occurrences of are H. [This invention 1054] L 4 -N(H)S(O) 1~2 -or-N(R d )S(O) 1~2 (e.g., N(C 1~3 alkyl)S(O) 2 ) is any one of the compounds of the present invention 1001 to 1053. [This invention 1055] L 4 -N(H)S(O) 2 Any of compounds 1001 to 1054 of the present invention, wherein [This invention 1056] L 4 is -N(H)C(O)- or -N(R d )C(O). [This invention 1057] L 4 The compound of any one of claims 1001 to 1053 and 1056, wherein is -N(H)C(O)-. [This invention 1058] L 4 is -C(O)NH- or -C(O)N(R d )-. [This invention 1059] L 4 -N(H)-, -N(R d )-, or -N(R 4 )-. [The present invention 1060] L 4 The compound of any one of claims 1001 to 1053, wherein is a single bond. [This invention 1061] L 4 The compound of any one of claims 1001 to 1053, wherein C≡C. [This invention 1062] L 4 The compound of any one of claims 1001 to 1053, wherein is -O-. [The present invention 1063] 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 )-, any one of the compounds of 1001 to 1053 of the present invention selected from the group consisting of [The present invention 1064] L 4 -N(H)S(O) 1~2 N(H)- (e.g., -N(H)S(O) 2 N(H)-). [This invention 1065] 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 The compound of any one of claims 1001 to 1053 and 1063 of the present invention, wherein the compound is alkyl)-). [The present invention 1066] R 4 -(Y 3 ) p -Y 4 The compound of any one of claims 1001 to 1065 of the present invention, [This invention 1067] The compound of any one of 1001 to 1066 of the present invention, wherein p is 1. [The present invention 1068] Y 3 C 1~3 The compound of any one of 1001 to 1067 of the present invention, which is alkylene. [This invention 1069] Y 3 is CH 2 or CH 2 -CH 2 The compound of any one of claims 1001 to 1068 of the present invention, [The present invention 1070] The compound of any one of 1001 to 1066 of the present invention, wherein p is 0. [This invention 1071] Y 4 However, 1 to 4 R c C optionally substituted with 6~10 The compound of any one of 1001 to 1070 of the present invention, which is aryl. [This invention 1072] Y 4 However, there are 1 to 2 (for example, 1) R c The compound of any one of claims 1001 to 1071, wherein the compound is phenyl which may be substituted by. [This invention 1073] 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 The compound of the present invention 1071 or 1072, selected from the group consisting of: [This invention 1074] 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 The compound of the present invention 1071 or 1072, selected from the group consisting of: [This invention 1075] R c each occurrence of independently: (vii) C 1~4 Alkoxy; (viii) C 1~4 haloalkoxy; and (xiv) -C 1~4 Thioalkoxy The compound of the present invention 1071 or 1072, selected from the group consisting of: [This invention 1076] Y 4 is non-substituted C 6~10 The compound of any one of claims 1001 to 1072, which is aryl (for example, phenyl). [This invention 1077] Y 4 However, 1 to 4 R b C optionally substituted with 3~6 (For example, C 3~4 or C 6 ) A compound of any one of 1001 to 1070 of the present invention, wherein R is cycloalkyl. [This invention 1078] Y 4 But 1-2 R b The compound of any one of claims 1001 to 1070 and 1077 of the present invention, wherein the compound is cyclopropyl or cyclobutyl optionally substituted with [This invention 1079] Y 4 But 1-2 R b C optionally substituted with 6 Compounds of any of claims 1001 to 1070 and 1077, which are cycloalkyl (e.g., cyclohexyl). [The present invention 1080] R b Each occurrence of 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 The compound of any one of the present inventions 1001 to 1070 and 1077 to 1079, may be an alkyl, for example, methyl. [This invention 1081] Y 4 is non-substituted C 3~6 (For example, C 3~4 or C 6 ) A compound of any one of 1001 to 1070 and 1077 of the present invention, wherein the compound is cycloalkyl. [This invention 1082] Y 4 1081. A compound of the present invention wherein is unsubstituted cyclopropyl or unsubstituted cyclobutyl (e.g., unsubstituted cyclopropyl). [This invention 1083] 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 the group consisting of 1 to 4 independently selected R c Heteroaryl, optionally substituted with The compound of any one of claims 1001 to 1070 of the present invention, [This invention 1084] 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 the group consisting of 1 to 4 independently selected R c Heteroaryl, optionally substituted with The compound of any one of the present inventions 1001 to 1070 and 1083, [This invention 1085] Y 4 is one to two independently selected R c Any of compounds 1001 to 1070 and 1083 to 1084 of the present invention, 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. [The present invention 1086] R c each occurrence independently 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) 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 Any of the compounds of 1083 to 1085 of the present invention selected from the group consisting of: [This invention 1087] R c each occurrence independently of the following: (i) Halo (e.g., F, Cl); (iii) C 1~6 alkyl (e.g., methyl); and (xii) OH 1086. A compound of the present invention selected from the group consisting of: [This invention 1088] Y 4 is an unsubstituted pyridinyl, pyrimidinyl, or pyrazinyl, respectively. [This invention 1089] Y 4 but, Heterocyclyl containing 3 to 10 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(Rd ), and O, wherein one or more of the heterocyclyl ring carbon atoms are selected from the group consisting of 1 to 4 independently selected R b heterocyclyl optionally substituted with The compound of any one of claims 1001 to 1070 of the present invention, [The present invention 1090] Y 4 but, Heterocyclyl containing 4 to 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 the group consisting of 1 to 4 independently selected R b heterocyclyl optionally substituted with The compound of any one of 1001 to 1070 and 1089 of the present invention, [This invention 1091] Y 4 but, Heterocyclyl containing four ring atoms, one ring atom of which is a heteroatom, and independently N, N(H), N(R d ), and O, wherein one or more of the heterocyclyl ring carbon atoms are selected from the group consisting of 1 to 2 independently selected R b heterocyclyl optionally substituted with The compound of any one of 1001 to 1070 and 1089 to 1090 of the present invention, [This invention 1092] Y 4 is one to two independently selected R b The compound of any one of claims 1001 to 1070 and 1089 to 1091 of the present invention, which is an oxetanyl optionally substituted by (for example, an unsubstituted oxetanyl). [This invention 1093] Y 4 is one to two independently selected R b Azetidinyl optionally substituted with (e.g., one R b The compound of any one of claims 1001 to 1070 and 1089 to 1091 of the present invention, wherein the compound is azetidinyl substituted with [This invention 1094] Y 4 but, Heterocyclyl containing 6 ring atoms, wherein 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 the group consisting of 1 to 4 independently selected R b heterocyclyl optionally substituted with The compound of any one of 1001 to 1070 and 1089 to 1090 of the present invention, [This invention 1095] Y 4 is one to two independently selected R b The compound of any one of claims 1001 to 1070, 1089 to 1090, and 1094 of the present invention, which is selected from the group consisting of tetrahydropyranyl, piperidinyl, piperazinyl, and morpholinyl, each of which may be substituted with [This invention 1096] Y 4 is one to two independently selected R b The compound of any one of claims 1001 to 1070, 1089 to 1090, and 1094 to 1095 of the present invention, which is selected from the group consisting of tetrahydropyranyl, piperidinyl, and morpholinyl, each of which may be substituted with [This invention 1097] R b Each occurrence of independently -F, C 1~6 Alkyl, C 1~4 The compound of any one of claims 1089 to 1096, wherein the compound is selected from the group consisting of haloalkyl, oxo, and -OH. [This invention 1098] R b Each occurrence of independently -F, C 1~6 Alkyl, C 1~4 haloalkyl, and —OH (e.g., R b may be OH), any one of compounds 1089 to 1096 of the present invention. [This invention 1099] R 4 But the following: TIFF0007640458000028.tif50137 The compound of any one of 1001 to 1069 and 1071 to 1076 of the present invention selected from the group consisting of: [The present invention 1100] R 4 But the following: TIFF0007640458000029.tif30128 The compound of any one of 1001 to 1069 and 1071 to 1076 of the present invention selected from the group consisting of: [The present invention 1101] R 4 but TIFF0007640458000030.tif17128 The compound of any one of 1001 to 1066, 1070, and 1071 to 1076 of the present invention, [The present invention 1102] R 4 but TIFF0007640458000031.tif21128 The compound of any one of 1001 to 1066, 1070, and 1071 to 1076 of the present invention, [The present invention 1103] R 4 But the following: TIFF0007640458000032.tif14128 The compound of any one of 1001 to 1069 and 1077 to 1082 of the present invention selected from the group consisting of: [The present invention 1104] R 4 But the following: TIFF0007640458000033.tif14128 The compound of any one of 1001 to 1069 and 1077 to 1082 of the present invention selected from the group consisting of: [This invention 1105] R 4 But the following: TIFF0007640458000034.tif24128 The compound of any one of 1001 to 1066, 1070, and 1077 to 1082 of the present invention, selected from the group consisting of: [The present invention 1106] R 4 But the following: TIFF0007640458000035.tif52156 The compound of any one of 1001 to 1069 and 1083 to 1088 of the present invention selected from the group consisting of: [This invention 1107] R 4 But the following: TIFF0007640458000036.tif15128 The compound of any one of 1001 to 1069 and 1083 to 1088 of the present invention selected from the group consisting of: [This invention 1108] R 4 But the following: TIFF0007640458000037.tif15128 The compound of any one of 1001 to 1066, 1070, and 1083 to 1088 of the present invention, selected from the group consisting of: [This invention 1109] R 4 But the following: TIFF0007640458000038.tif15128 The compound of any one of 1001 to 1066, 1070, and 1083 to 1088 of the present invention, selected from the group consisting of: [The present invention 1110] R 4 But the following: TIFF0007640458000039.tif26128 The compound of any one of 1001 to 1069 and 1089 to 1098 of the present invention selected from the group consisting of: [The present invention 1111] R4 but TIFF0007640458000040.tif24128 The compound of any one of 1001 to 1069 and 1089 to 1098 of the present invention, [The present invention 1112] R 4 But the following: TIFF0007640458000041.tif24138 The compound of any one of 1001 to 1066, 1070, and 1089 to 1098 of the present invention, selected from the group consisting of: [The present invention 1113] R 4 But the following: TIFF0007640458000042.tif24128 The compound of any one of 1001 to 1066, 1070, and 1089 to 1098 of the present invention, selected from the group consisting of: [This invention 1114] R 4 is 1 to 6 independently selected R a C optionally substituted with 1~10 The compound of any one of 1001 to 1065 of the present invention, which is alkyl. [This invention 1115] R 4 is 1 to 6 independently selected R a C optionally substituted with 1~6 The compound of any one of 1001 to 1065 and 1114 of the present invention, wherein the compound is alkyl. [The present invention 1116] R 4 is one to two independently selected R a C optionally substituted with 1~6 The compound of any one of 1001 to 1065 and 1114 to 1115 of the present invention, wherein the compound is alkyl. [This invention 1117] R a Each occurrence of is independently -F; -OH; C 1~4 Alkoxy; and C 1~4 The compound of any one of 1001 to 1065 and 1114 to 1116 of the present invention, selected from the group consisting of haloalkoxy. [This invention 1118] R a A compound of any of claims 1001-1065 and 1114-1117, wherein each occurrence of is independently -OH. [This invention 1119] R4 is methyl, ethyl, TIFF0007640458000043.tif14128 The compound of any one of 1001 to 1065 and 1114 to 1118 of the present invention selected from the group consisting of: [The present invention 1120] R 4 is methyl and TIFF0007640458000044.tif12128 The compound of any one of 1001 to 1065 and 1114 to 1118 of the present invention selected from the group consisting of: [This invention 1121] R 4 is 1 to 6 (e.g., 1 to 3) independently selected R a C optionally substituted with 2~10 (For example, C 2~4 ) alkynyl (e.g. TIFF0007640458000045.tif8128 Non-substituted C such as 2~4 The compound of any one of claims 1001 to 1065, wherein the aryl group is alkynyl. [This invention 1122] R 4 is 1 to 6 (e.g., 1 to 3) independently selected R a C optionally substituted with 2~10 (For example, C 2~4 ) alkenyl (e.g., unsubstituted C such as vinyl 2~4 The compound of any one of claims 1001 to 1065, wherein the aryl group is aryl, ... [This invention 1123] -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 the following: (i) 1 to 2 R a C optionally substituted with 1~6 alkyl; and (ii) -(Y 3 ) p -Y 4 The compound of any one of 1001 to 1053 of the present invention selected from the group consisting of: [This invention 1124] -L 4 -N(H)S(O) 2 -, single bond, -NH-, -N(R 4 )—, and —N(H)C(O)—; and R 4 But the following: (i) 1 to 2 R a C optionally substituted with 1~6 alkyl; and (ii) -(Y 3 ) p -Y 4 The compound of any one of 1001 to 1053 and 1123 of the present invention selected from the group consisting of: [Invention 1125] -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 the following: (i) 1 to 2 R a C optionally 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 1001 to 1053 of the present invention selected from the group consisting of: [The present invention 1126] -L4 -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 the following: (i) 1 to 2 R a C optionally 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 1001 to 1053 and 1125 of the present invention selected from the group consisting of: [This invention 1127] -L 4 -N(H)S(O) 2 Any of compounds 1123 to 1126 of the present invention, wherein [This invention 1128] -L 4 -N(H)S(O) 2 N(H)- or -N(H)S(O) 2 N(R d )-. [This invention 1129] -L 4 The compound of any one of 1123 to 1125 of the present invention, wherein is a single bond. [The present invention 1130] -L 4 is -NH- or -N(R 4 )-. [This invention 1131] -L 4 The compound of any one of claims 1123 to 1125, wherein is -N(H)C(O)-. [This invention 1132] R4 But 1-2 R a C optionally substituted with 1~6 The compound of any one of 1123 to 1131 of the present invention, which is alkyl. [This invention 1133] R 4 is 1 to 3 independently selected R a C, each of which may be substituted with 2~10 Alkenyl or C 2~10 The compound of any one of 1123 to 1131 of the present invention, which is alkynyl. [This invention 1134] R 4 is 1 to 3 independently selected R a C optionally substituted with 2~10 (For example, C 2~5 ) alkynyl (e.g. TIFF0007640458000046.tif8128 Non-substituted C such as 2~5 1133 compounds of the present invention, wherein the aryl group is alkynyl. [This invention 1135] R 4 -(Y 3 ) p -Y 4 Compounds 1123 to 1131 of the present invention, [This invention 1136] Y 4 However, 1 to 4 R c C optionally substituted with 6~10 The compound of the present invention 1135, which is aryl. [This invention 1137] Y 4 However, there are 1 to 2 (for example, 1) R c The compound of the present invention 1136, which is phenyl optionally substituted with [This invention 1138] Y 4 However, 1 to 4 R b C optionally substituted with 3~6 (For example, C 3~4 or C 6 ) cycloalkyl. [This invention 1139] 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), 1138 compounds of the present invention. [This invention 1140] 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 the group consisting of 1 to 2 independently selected R b heterocyclyl optionally substituted with The compound of the present invention 1135, [This invention 1141] 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 the group consisting of 1 to 2 independently selected R b heterocyclyl optionally substituted with (e.g., Y 4 is one to two independently selected R b 1140 compounds of the present invention, which may be tetrahydropyranyl, piperidinyl, or morpholinyl, each of which may be optionally substituted with [This invention 1142] 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 the group consisting of 1 to 2 independently selected R b heterocyclyl optionally substituted with (e.g., Y 4 or Y may be oxetanyl; 4 may be azetidinyl), compound 1140 of the present invention. [This invention 1143] 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 the group consisting of 1 to 4 independently selected R c Heteroaryl, optionally substituted with The compound of the present invention 1135, [This invention 1144] Y 4 is one to two independently selected R c 1143 Compounds of the Invention which are pyridinyl (eg, 2-pyridinyl, 3-pyridinyl, or 4-pyridinyl), pyrimidinyl (eg, 2-pyrimidinyl or 5-pyrimidinyl), or pyrazinyl, each of which may be substituted with: [Invention 1145] The compound of any one of 1135 to 1144 of the present invention, wherein p is 0. [Invention 1146] The compound of any one of 1135 to 1144 of the present invention, wherein p is 1. [This invention 1147] Y 3 C 1~3 Alkylene (e.g., CH 2 , C.H. 2 -CH 2 ) Compound 1146 of the present invention. [This invention 1148] R 3 But the following: TIFF0007640458000047.tif63143 Any of the compounds of the present invention 1001 to 1043 selected from the group consisting of: [This invention 1149] R 3 But the following: TIFF0007640458000048.tif35128 1148 compounds of the present invention selected from the group consisting of: [This invention 1150] R 3 But the following: TIFF0007640458000049.tif31128 Any of the compounds of the present invention 1001 to 1043 selected from the group consisting of: [This invention 1151] R 3 But the following: TIFF0007640458000050.tif27128 Any of the compounds of the present invention 1001 to 1043 selected from the group consisting of: [This invention 1152] R 3 But the following: TIFF0007640458000051.tif24128 Any of the compounds of the present invention 1001 to 1043 selected from the group consisting of: [This invention 1153] R 3 But the following: TIFF0007640458000052.tif22140 Any of the compounds of the present invention 1001 to 1043 selected from the group consisting of: [This invention 1154] R 3 But the following: TIFF0007640458000053.tif20128 Any of the compounds of the present invention 1001 to 1043 selected from the group consisting of: [Invention 1155] R 3 But the following: TIFF0007640458000054.tif19128 Any of the compounds of the present invention 1001 to 1043 selected from the group consisting of: [Invention 1156] R 3 But the following: TIFF0007640458000055.tif34140 Any of the compounds of the present invention 1001 to 1043 selected from the group consisting of: [This invention 1157] R 3 But the following: TIFF0007640458000056.tif42141 Any of the compounds of the present invention 1001 to 1043 selected from the group consisting of: [This invention 1158] R 3 But the following: TIFF0007640458000057.tif18128 Any of the compounds of the present invention 1001 to 1043 selected from the group consisting of: [This invention 1159] R 3 But the following: TIFF0007640458000058.tif19134 Any of the compounds of the present invention 1001 to 1043 selected from the group consisting of: [The present invention 1160] R 3 But the following: TIFF0007640458000059.tif19148 Any of the compounds of the present invention 1001 to 1043 selected from the group consisting of: [This invention 1161] R 3 But the following: TIFF0007640458000060.tif40150 Any of the compounds of the present invention 1001 to 1043 selected from the group consisting of: [This invention 1162] R 3 But the following: TIFF0007640458000061.tif17128 , NHMe, and NMe 2 Any of the compounds of the present invention 1001 to 1043 selected from the group consisting of: [This invention 1163] R 3 But the following: TIFF0007640458000062.tif15128 Any of the compounds of the present invention 1001 to 1043 selected from the group consisting of: [Invention 1164] R 3 But the following: TIFF0007640458000063.tif15128 Any of the compounds of the present invention 1001 to 1043 selected from the group consisting of: [This invention 1165] R 3 One occurrence of TIFF0007640458000064.tif12128 The compound of the present invention 1162 or 1163, [Invention 1166] R 1 -(Y 1 ) n -Y 2 and R 2 However, 1 to 4 R c C optionally substituted with 6~10 is aryl, 1001 compounds of the present invention. [This invention 1167] 1166. The compound of the present invention, wherein n is 0. [Invention 1168] X 1 、X 2 、X 3 , and X 4 1 or 2 of these 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 1166 to 1167 of the present invention, [This invention 1169] 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 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 3 That is, Compound 1168 of the present invention. [This invention 1170] X 2 and X 3 CR 3 For example, X 2 and X 3 Both of these are independently selected CR 3 The compound of any one of claims 1168 to 1169 of the present invention, [This invention 1171] 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 optionally substituted with 1~10 The compound of any one of 1168 to 1170 of the present invention, which is alkyl. [This invention 1172] R 4 (Y 3 ) p -Y 4 and p is 1. [This invention 1173] R 4 (Y 3 ) p -Y 4 and p is 0. [This invention 1174] R 3 each of the remaining occurrences of independently H and R c ' (e.g., R 3 and each remaining occurrence of is H), any of compounds 1171 to 1173 of the present invention. [This invention 1175] R 3 One occurrence of -L 4 -R 4 and R 3 One occurrence of R c' , for example halo. [Invention 1176] R 3 One occurrence of R c' (e.g., Br or Cl, e.g., Cl); and R 3 The compound of any of claims 1166 to 1169, wherein each remaining occurrence of is H. [This invention 1177] Y 2 is as defined in any of claims 1014-1020 and 1026-1028 of the present invention; and each R c The compound of any one of claims 1166 to 1176, wherein, if present, is independently as defined in any one of claims 1021 to 1024. [This invention 1178] Y 2 is as defined in any one of claims 1014 to 1018 of the present invention; and each R c A compound of any one of claims 1166 to 1176, wherein, when present, is as defined in any one of claims 1021 to 1023. [This invention 1179] Y 2 is as defined in any one of claims 1016 to 1018 of the present invention; and each R c A compound of any one of claims 1166 to 1176, wherein, when present, is as defined in any one of claims 1021 to 1023. [This invention 1180] R 1 but TIFF0007640458000065.tif14128 For example, R 1 but TIFF0007640458000066.tif13128 The compound of any one of claims 1166 to 1176 of the present invention, [This invention 1181] R 2 However, 1 to 4 R c C optionally substituted with 6~10 Aryl, e.g., 1 to 4 R c Or 1-2 R c or two R's c phenyl optionally substituted with; and R c When present, the compound of any one of claims 1166 to 1180 is as defined in any one of claims 1033 to 1035. [This invention 1182] R 2 But two R c phenyl, which may be substituted with, for example, R 2 but TIFF0007640458000067.tif17128 and R c When present, the compound of any one of claims 1166 to 1181 is as defined in any one of claims 1033 to 1035. [This invention 1183] 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 the group consisting of 1 to 4 independently selected R c Heteroaryl, optionally substituted with For example, R 2 is one to two independently selected R c or pyridinyl optionally substituted with, for example, R 2 but TIFF0007640458000068.tif17128 and R c When present, the compound of any one of claims 1166 to 1180 is as defined in any one of claims 1040 to 1041. [This invention 1184] R 2 but TIFF0007640458000069.tif17128 The compound of any one of claims 1166 to 1180 of the present invention, [This invention 1185] -L 4 But the following: -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 -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 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)-)) The compound of any one of 1171 to 1184 of the present invention selected from the group consisting of: [Invention 1186] -L 4 But the following: -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., L4 is -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 bonds; and C≡C The compound of any one of 1171 to 1184 of the present invention selected from the group consisting of: [This invention 1187] -L 4 But the following: 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 1171 to 1184 of the present invention selected from the group consisting of: [This invention 1188] -L 4 But the following: -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 -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(Rd )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)-)) The compound of any one of 1171 to 1184 of the present invention selected from the group consisting of: [This invention 1189] -L 4 -N(H)S(O) 2 Any of the compounds of the present invention 1171 to 1188, wherein [This invention 1190] Y 4 However, 1 to 4 R c C optionally 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 When present, the compound of any one of claims 1171 to 1189 is as defined in any one of claims 1073 to 1075. [This invention 1191] Y 4 However, 1 to 4 R c C optionally substituted with 6~10 Aryl, e.g., 1 to 4 R c phenyl optionally substituted with; and R c Each occurrence, if 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 1171 to 1189 of the present invention selected from the group consisting of: [This invention 1192] Y 4 is as defined in any of inventions 1077, 1078, 1079, 1081, and 1082; and R b When present, the compound of any of claims 1171 to 1189 is as defined in claim 1080. [This invention 1193] Y 4 is as defined in any one of inventions 1077 to 1079; and R b When present, the compound of any of claims 1171 to 1189 is as defined in claim 1080. [This invention 1194] Y 4 is as defined in any one of inventions 1083-1085 and 1088; and R c A compound of any one of claims 1171 to 1189, wherein, when present, is as defined in any one of claims 1086 to 1087. [This invention 1195] Y 4 1171-1189, wherein the compound is as defined in any one of claims 1083-1085 and 1088. [Invention 1196] Y 4 is as defined in any one of inventions 1089 to 1096; and R b When present, the compound of any one of claims 1171 to 1189 is as defined in any one of claims 1097 to 1098. [This invention 1197] Y 4 is as defined in any of inventions 1089-1092, 1094, and 1096; and R b When present, the compound of any of claims 1171 to 1189 is as defined in claim 1098. [This invention 1198] R 4 The compound of any one of claims 1171 to 1189 of the present invention, wherein the compound is selected from the group consisting of the structures of claims 1099 to 1113 of the present invention. [This invention 1199] R 4 The compound of any one of claims 1171 to 1189 of the present invention, wherein the compound is selected from the group consisting of structures of claims 1100, 1101, 1104 to 1105, 1107, 1109, 1111, and 1113 of the present invention. [The present invention 1200] ·R 4 is 1 to 6 independently selected R a C optionally substituted with 1~10 is alkyl; or ·R 4 is 1 to 6 independently selected R a C optionally substituted with 1~6 is alkyl; or ·R 4 is one to two independently selected R a C optionally substituted with 1~6 alkyl, e.g., R 4 is methyl, ethyl, TIFF0007640458000070.tif14128 (e.g., methyl and TIFF0007640458000071.tif12128 or ·R 4 is 1 to 6 (e.g., 1 to 3) independently selected R a C optionally substituted with 2~10 Alkynyl (e.g., C 2~4 alkynyl) (e.g. TIFF0007640458000072.tif8128 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 optionally 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, The compound of the present invention is any one of compounds 1171 and 1174 to 1189. [The present invention 1201] ·R 4 is 1 to 6 independently selected R a C optionally substituted with 1~10 is alkyl; or ·R 4 is 1 to 6 independently selected R a C optionally substituted with 1~6 is alkyl; or ·R 4 is one to two independently selected R a C optionally substituted with 1~6 Alkyl, such as methyl and TIFF0007640458000073.tif12128 and; Here, each R a When present, independently, -OH, e.g., -F; -OH; C 1~4 Alkoxy; and C 1~4 haloalkoxy, The compound of the present invention is any one of compounds 1171 and 1174 to 1189. [This invention 1202] -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 the following: (i) 1 to 2 R a C optionally 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 1171 to 1184 of the present invention selected from the group consisting of: [This invention 1203] -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 the following: (i) 1 to 2 R a C optionally 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 1171 to 1184 of the present invention selected from the group consisting of: [The present invention 1204] R 3 is selected from the group consisting of structures 1148 to 1165 of the present invention; or R 3 The compound of any one of claims 1171 to 1189 of the present invention, wherein the compound is selected from the group consisting of structures of claims 1148 to 1149, 1151, 1153, 1155 to 1156, 1158, 1160, 1162, and 1165 of the present invention. [This invention 1205] X 2 and X 3 Each of the 3 and X 1 and X 4 The compound of any one of claims 1166 to 1169, wherein each of the following is N. [This invention 1206] Each R 3 are independently selected -L 4 -R 4 The compound of the present invention 1205, [This invention 1207] -L 4 -R 4 One occurrence of -R 4 (i.e., L 4 wherein one occurrence of is a bond), 1206 compounds of the present invention. [This invention 1208] -L 4 Other occurrences of are: -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 -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 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)-)) Any of the compounds of 1205 to 1207 of the present invention selected from the group consisting of: [This invention 1209] -L 4 Other occurrences of are: -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 -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 bonds; and C≡C Any of the compounds of 1205 to 1207 of the present invention selected from the group consisting of: [The present invention 1210] -L 4 Other occurrences of are: -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 Any of compounds 1205 to 1207 of the present invention, wherein [The present invention 1211] -L 4 Other occurrences of are: -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 -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 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)-)) Any of the compounds of 1205 to 1207 of the present invention selected from the group consisting of: [The present invention 1212] R 3 One occurrence of -L 4 -R 4 (e.g., L 4 N(H)S(O) 2 - and); and R 3 Other occurrences of R c 1205 compounds of the invention, wherein the aryl group is aryl, aryl, or aryl; [This invention 1213] Formula (I-a1-a): TIFF0007640458000074.tif38128 The compound of any one of 1001 to 1004 of the present invention, which is a compound of the formula (I) or a pharmaceutically acceptable salt thereof. [This invention 1214] Formula (I-a1-a1), (I-a1-a2), or (I-a1-a3): TIFF0007640458000075.tif43128 or a pharmaceutically acceptable salt thereof. [This invention 1215] The compound of formula (I-a1-a) may be a compound of formula (I-a1-a5): TIFF0007640458000076.tif38128 or a pharmaceutically acceptable salt thereof. [This invention 1216] R c' 1215 compounds of the invention wherein is halo (eg, -Cl). [This invention 1217] L 4 Ga-NHS(O) 2 Any of compounds 1215 to 1216 of the present invention, wherein [This invention 1218] L 4 -N(H)S(O) 2 N(H)- or -N(H)S(O) 2 N(R d )-. [This invention 1219] The compound of formula (I-a1-a) may be a compound of formula (I-a1-a6): TIFF0007640458000077.tif38128 or a pharmaceutically 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, Compound 1213 of the present invention. [The present invention 1220] L 4B The compound of the present invention 1219, wherein is a bond. [This invention 1221] L 4A Ga-NHS(O) 2 Any of compounds 1219 to 1220 of the present invention, wherein [This invention 1222] L 4A -N(H)S(O) 2 N(H)- or -N(H)S(O) 2 N(R d )-. [This invention 1223] Formula (I-a1-a7), (I-a1-a8), or (I-a1-a9): TIFF0007640458000078.tif47137 or a pharmaceutically acceptable salt thereof, In the formula, R d' is H or R d (e.g., H or C 1~3 alkyl), Compound 1213 of the present invention. [This invention 1224] Formula (I-a1-b): TIFF0007640458000079.tif34128 The compound of any one of 1001 to 1004 of the present invention, which is a compound of the formula (I) or a pharmaceutically acceptable salt thereof. [This invention 1225] Formula (I-a1-b1) or Formula (I-a1-b2): TIFF0007640458000080.tif38128 (For example, L 4 is N(H)SO 2 , -N(H)-, or NHC(O) or a pharmaceutically acceptable salt thereof. [This invention 1226] Formula (I-a2-a): TIFF0007640458000081.tif34128 or a pharmaceutically acceptable salt thereof. [This invention 1227] Formula (I-a2-a1): TIFF0007640458000082.tif43128 1226. The compound of the present invention, which is a compound of formula (I) or a pharmaceutically acceptable salt thereof. [This invention 1228] Formula (I-b1-a): TIFF0007640458000083.tif34128 or a pharmaceutically acceptable salt thereof. [This invention 1229] Formula (I-b1-a1): TIFF0007640458000084.tif43128 or a pharmaceutically acceptable salt thereof. [This invention 1230] Formula (I-b1-a3): TIFF0007640458000085.tif51128 or a pharmaceutically acceptable salt thereof, In the formula, R d' is H or R d (e.g., H or C 1~3 alkyl), Compound 1228 of the present invention. [This invention 1231] Formula (I-c1-a): TIFF0007640458000086.tif34128 or a pharmaceutically acceptable salt thereof. [This invention 1232] Formula (I-c1-a1): TIFF0007640458000087.tif43128 or a pharmaceutically acceptable salt thereof. [This invention 1233] Formula (I-d1-a): TIFF0007640458000088.tif34128 or a pharmaceutically acceptable salt thereof. [This invention 1234] Formula (I-d1-a1): TIFF0007640458000089.tif43128 or a pharmaceutically acceptable salt thereof. [This invention 1235] R 4 But the following: (i) 1 to 6 independently selected R a C optionally 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 1213 to 1234 of the present invention selected from the group consisting of: [This invention 1236] R 4 -(Y 3 ) p -Y 4 The compound of any one of 1213 to 1235 of the present invention, [This invention 1237] Y 4 However, 1 to 4 R c C optionally 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 When present, the compound of any one of claims 1205 to 1236 is as defined in any one of claims 1073 to 1075. [This invention 1238] Y 4 However, 1 to 4 R c C optionally substituted with 6~10 Aryl, e.g., 1 to 4 R c phenyl optionally substituted with; and R c Each occurrence, if 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 1205 to 1236 of the present invention selected from the group consisting of: [This invention 1239] Y 4 is as defined in any of inventions 1077, 1078, 1079, 1081, and 1082; and R b When present, the compound of any one of claims 1205 to 1236 is as defined in claim 1080. [This invention 1240] Y 4 is as defined in any one of inventions 1077 to 1079; and R b When present, the compound of any one of claims 1205 to 1236 is as defined in claim 1080. [This invention 1241] Y 4 is as defined in any one of inventions 1083-1085 and 1088; and R c When present, the compound of any one of claims 1205 to 1236 is as defined in any one of claims 1086 to 1087. [This invention 1242] Y 4 The compound of any one of claims 1205 to 1236, wherein [This invention 1243] Y 4 is as defined in any one of inventions 1089 to 1096; and R b When present, the compound of any one of claims 1205 to 1236 is as defined in any one of claims 1097 to 1098. [This invention 1244] Y 4 is as defined in any of inventions 1089-1092, 1094, and 1096; and R b The compound of any one of claims 1205 to 1236, wherein, when present, is as defined in claim 1098. [Invention 1245] The compound of any one of 1235 to 1244 of the present invention, wherein p is 0. [Invention 1246] The compound of any one of 1235 to 1244 of the present invention, wherein p is 1. [This invention 1247] Y 3 C 1~3 Alkylene, e.g. CH 2 or CH 2 -CH 2 The compound of the present invention 1244, [Invention 1248] R 4 The compound of any one of claims 1205 to 1236 of the present invention, wherein the compound is selected from the group consisting of the structures of claims 1099 to 1113 of the present invention. [Invention 1249] Each R 4 The compound of any one of claims 1205 to 1236, wherein the compound is selected from the group consisting of structures 1100, 1101, 1104 to 1105, 1107, 1109, 1111, and 1113 of the present invention. [This invention 1250] ·R 4 is 1 to 6 independently selected R a C optionally substituted with 1~10 is alkyl; or ·R 4 is 1 to 6 independently selected R a C optionally substituted with1~6 is alkyl; or ·R 4 is one to two independently selected R a C optionally substituted with 1~6 alkyl, e.g., R 4 is methyl, ethyl, TIFF0007640458000090.tif14128 (e.g., methyl and TIFF0007640458000091.tif12128 or ·R 4 is 1 to 6 (e.g., 1 to 3) independently selected R a C optionally substituted with 2~10 Alkynyl (e.g., C 2~4 alkynyl) (e.g. TIFF0007640458000092.tif8128 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 optionally 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, The compound of any one of 1205 to 1235 of the present invention. [This invention 1251] ·R 4 is 1 to 6 independently selected R a C optionally substituted with 1~10 is alkyl; or ·R 4 is 1 to 6 independently selected R a C optionally substituted with1~6 is alkyl; or ·R 4 is one to two independently selected R a C optionally substituted with 1~6 Alkyl, such as methyl and TIFF0007640458000093.tif12128 and; Here, each R a When present, independently, -OH, e.g., -F; -OH; C 1~4 Alkoxy; and C 1~4 haloalkoxy, The compound of any one of 1205 to 1235 of the present invention. [This invention 1252] R 1 -(Y 1 ) n -Y 2 The compound of any one of 1205 to 1251 of the present invention, [This invention 1253] Y 2 is as defined in any one of claims 1014 to 1020 of the present invention; and each R c is, if present, independently as defined in any of inventions 1021 to 1024. [Invention 1254] Y 2 is as defined in any of claims 1014 to 1018 and 1026 of the present invention; and each R c When present, the compound of any one of claims 1205 to 1253 is as defined in any one of claims 1021 to 1023. [Invention 1255] Y 2 is as defined in any one of claims 1016 to 1018 of the present invention; and each R c When present, the compound of any one of claims 1205 to 1252 is as defined in any one of claims 1021 to 1023. [Invention 1256] R 1 but TIFF0007640458000094.tif14128 ,for example TIFF0007640458000095.tif13128 The compound of any one of 1205 to 1252 of the present invention, [Invention 1257] The compound of any one of 1250 to 1256 of the present invention, wherein n is 0. [Invention 1258] R 2 However, 1 to 4 R c C optionally substituted with 6~10 Aryl, e.g., 1 to 4 R c or 1-2 R c or two R c phenyl optionally substituted with; and R c When present, the compound of any one of claims 1205 to 1257 is as defined in any one of claims 1033 to 1035. [Invention 1259] R 2 But two R c phenyl, which may be substituted with, for example, R 2 but TIFF0007640458000096.tif17128 and R c When present, the compound of any one of claims 1205 to 1257 is as defined in any one of claims 1033 to 1035. [This invention 1260] 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), 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 pyridinyl optionally substituted with, for example, R 2 but TIFF0007640458000097.tif17128 and R c When present, the compound of any one of claims 1205 to 1257 is as defined in any one of claims 1040 to 1041. [This invention 1261] R 2 but TIFF0007640458000098.tif17128 The compound of any one of 1205 to 1257 of the present invention, [This invention 1262] R 1 -(Y 1 ) n -Y 2 and R 2 However, 1 to 4 R c C optionally substituted with 6~10 is aryl, Any of the compounds 1213 to 1251 of the present invention. [This invention 1263] The compound of the present invention 1262, wherein n is 0. [Invention 1264] Y 2 but, Heteroaryl containing 6 ring atoms, wherein 1 to 2 ring atoms are N and one or more of the heteroaryl ring carbon atoms are selected from 1 to 4 independently selected R c Heteroaryl, optionally substituted with The compound of any one of claims 1262 to 1263 of the present invention, [Invention 1265] Y 2 but, One or more of the ring carbon atoms are selected from 1 to 4 (e.g., 1) independently selected R c pyridyl (e.g., 2-pyridyl or 6-pyridyl), optionally substituted with The compound of any one of claims 1262 to 1264 of the present invention, [Invention 1266] R c Each occurrence of C is independently selected 1~4 Alkoxy (e.g., -OCH 3 , -OCH 2 CH 3 ) Any of the compounds of the present invention 1262 to 1265. [Invention 1267] R 1 but TIFF0007640458000099.tif13128 The compound of any one of claims 1262 to 1266 of the present invention, [Invention 1268] R 2 However, 1 to 4 R c The compound of any one of claims 1262 to 1267, wherein the compound is phenyl which may be substituted by. [This invention 1269] R 2 But two R c The compound of any one of 1262 to 1268 of the present invention, wherein the phenyl is optionally substituted with [Invention 1270] R 2 but TIFF0007640458000100.tif16128 The compound of the present invention 1269, [This invention 1271] R 1 but TIFF0007640458000101.tif13128 and R 2 but TIFF0007640458000102.tif16128 The compound of any one of 1205 to 1251 of the present invention, [Invention 1272] Formula (I-a1-a4): TIFF0007640458000103.tif50128 The compound of the present invention is any one of compounds 1213, 1235 to 1251, and 1271. [This invention 1273] R 3 The compound of the present invention 1272, wherein is H. [Invention 1274] R 3 R c' , for example halo (eg Cl). [Invention 1275] Formula (I-b1-a2): TIFF0007640458000104.tif52128 The compound of the present invention is any one of compounds 1228, 1235 to 1251, and 1271. [Invention 1276] L 4 NHS(O) 2 The compound of any one of 1272 to 1275 of the present invention, [Invention 1277] The table below: TIFF0007640458000105.tif72153TIFF0007640458000106.tif205153TIFF0007640458000107.tif204153TIFF0007640458000108.tif198153TIFF0007640458000109.tif208153TIFF0007640458000110.tif215153TIFF0007640458000111.tif191153TIFF0007640458000112.tif200153TIFF0007640458000113.tif189153TIFF0007640458000114.tif213153TIFF0007640458000115.tif204153TIFF0007640458000116.tif210153TIFF0007640458000117.tif211153TIFF0007640458000118.tif214153TIFF0007640458000119.tif213153TIFF0007640458000120.tif212153TIFF0007640458000121.tif209153TIFF0007640458000122.tif203153TIFF0007640458000123.tif213153TIFF0007640458000124.tif219153TIFF0007640458000125.tif199153TIFF0007640458000126.tif194153TIFF0007640458000127.tif185153TIFF0007640458000128.tif102153 1001. A compound of the present invention selected from the group consisting of the compounds in formula (I) and pharmaceutically acceptable salts thereof. [Invention 1278] A pharmaceutical composition comprising any one of the compounds or salts of the present invention 1001 to 1277 and one or more pharmaceutically acceptable excipients. [Invention 1279] A method for regulating APJ receptor activity, comprising contacting an APJ receptor with any of the compounds of the present inventions 1001 to 1277. [This invention 1280] 1279. The method of claim 1279, wherein said modulating comprises stimulating an APJ receptor. [This invention 1281] 1279 or 1280. The method of claim 1279 or 1280, which is carried out in vitro. [This invention 1282] 1279 or 1280, a method of the present invention carried out in vivo. [This invention 1283] A method for regulating (e.g., decreasing) pulmonary vascular resistance in a subject in need thereof, the method comprising administering to the subject an effective amount of any of compounds 1001 to 1277 of the present invention. [This invention 1284] A method for regulating (e.g., reducing) right ventricular afterload in a subject in need thereof, the method comprising administering to the subject an effective amount of any of compounds 1001 to 1277 of the present invention. [Invention 1285] A method for regulating (e.g., decreasing) mean pulmonary arterial pressure in a subject in need thereof, the method comprising administering to the subject an effective amount of any of compounds 1001 to 1277 of the present invention. [Invention 1286] The method of claim 1285, wherein the subject exhibits a mean pulmonary artery pressure of greater than 25 mmHg. [This invention 1287] 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 any of the compounds 1001 to 1277 of the present invention. [Invention 1288] 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 any of the compounds of the present inventions 1001 to 1277. [This invention 1289] The method of claim 1288, wherein said disease, disorder, or condition is pulmonary arterial hypertension ("PAH"). [This invention 1290] The method of claim 1289, wherein the PAH is idiopathic. [This invention 1291] PAH is hereditary, toxic or drug-induced, or: Congenital heart disease, connective tissue disorders (e.g., scleroderma, systemic lupus erythematosus, systemic sclerosis, Hashimoto's thyroiditis, Sjögren's syndrome, and antiphospholipid syndrome), portal hypertension, BMPR2 mutations, schistosomiasis, and HIV infection The method of the present invention 1289, wherein the PAH is associated with one or more of the following: [This invention 1292] The method of claim 1288, wherein said disease, disorder, or condition is fibrosis. [This invention 1293] The method of claim 1292, 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. [Invention 1294] The method of claims 1288 and 1292, wherein said disease, disorder, or condition is idiopathic pulmonary fibrosis (IPF). [This invention 1295] The method of claim 1288, wherein said disease, disorder, or condition is a connective tissue disorder. [Invention 1296] 1295. The method of claim 1295, 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. [This invention 1297] The method of any of claims 1288 and 1295 to 1296, wherein the disease, disorder, or condition is systemic sclerosis. [Invention 1298] The method of any one of claims 1279 to 1297, further comprising identifying the subject. [This invention 1299] The 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 pulmonary diffusing capacity 1298. The method of claim 1298, comprising determining the level of [The present invention 1300] The method of any one of claims 1279 to 1299, wherein the subject is a human. [This invention 1301] The method of any of claims 1279 to 1300, further comprising administering one or more additional therapeutic agents. [This invention 1302] The method of any of claims 1279-1301, further comprising treating one or more diseases, disorders, or conditions that are sequelae or comorbidities of PAH. The details of one or more embodiments of the invention are set forth in the following description and in the accompanying appendix, which are expressly incorporated into this disclosure. Other features and advantages will be apparent from the claims. DETAILED DESCRIPTION OF THE INVENTION

[0081] Detailed Description The present disclosure features chemical entities (e.g., compounds, or pharmaceutically acceptable salts and / or hydrates and / or prodrugs of the compounds) 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 comprising the same, as well as other methods of using and making the same. For example, the chemical entities are useful for treating a subject (e.g., a human) with a disease, disorder, or condition in which decreased 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 pathology and / or symptoms and / or progression of the disease, disorder, or condition. Non-limiting examples of such diseases, disorders, or conditions include (i) cardiovascular disease; (ii) metabolic disorders; (iii) diseases, disorders, and conditions associated with vascular pathology; 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 above or any of those 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): TIFF0007640458000129.tif30128, or a pharmaceutically acceptable salt thereof; During the ceremony, A 1 is CH or N; X 1 , X 2 , X 3 , and X 4 are 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 optionally substituted with 1~6 alkylene; and Y 2 is: (a) 1 to 4 R b C optionally substituted with 3~10 cycloalkyl; (b) 1 to 4 R c C optionally substituted with 6~10 aryl; (c) 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 the group consisting of 1 to 4 independently selected R c heteroaryl, optionally substituted with (d) Heterocyclyl containing 3 to 10 ring atoms, wherein 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 the group consisting of 1 to 4 independently selected R bheterocyclyl optionally substituted by; or (ii) -Z 1 -Z 2 -Z 3 , where Z 1 is 1 to 4 R a C optionally 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 optionally substituted with 2~7 is alkyl; or (iii) 1 to 6 independently selected R a C optionally 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 optionally 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 optionally 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 with 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 the group consisting of 1 to 4 independently selected R c heteroaryl, optionally substituted with (iii) 1 to 4 R b C optionally 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 the group consisting of 1 to 4 independently selected R b heterocyclyl, optionally substituted by (v) 1 to 6 independently selected R a C optionally substituted with 1~10 Alkyl and; R 3 Each occurrence of independently represents -L 4 -R 4 , H, and R c ' selected from the group consisting of; L 4 Each occurrence of is independently: (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(Rd ); (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 is independently: (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 optionally substituted with 3~6 cycloalkyl; (b) 1 to 4 Rc C optionally substituted with 6~10 aryl; (c) 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 the group consisting of 1 to 4 independently selected R c heteroaryl, optionally substituted with (d) Heterocyclyl containing 3 to 10 ring atoms, wherein 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 the group consisting of 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 independently 1~6 Alkyl; C 1~4Haloalkyl; -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 is 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; (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) -NO2; (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) -NO2; (v) -C(=O)(C 1~4 alkyl); (vi) -C(=O)O(C 1~4 alkyl); (vii) -C(=O)OH; and (viii) -NH2 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 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.

[0083] In some embodiments, the present disclosure provides a compound of formula (I): TIFF0007640458000130.tif30128, or a pharmaceutically acceptable salt thereof; During the ceremony, A 1 is CH or N; X 1 , X 2 , X 3 , and X 4 are independently 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 3or N), provided that X 1 , X 2 , X 3 , and X 4 1 to 3 of these are N; 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 optionally substituted with 1~6 alkylene; and Y 2 is: (a) 1 to 4 R b C optionally substituted with 3~10 cycloalkyl; (b) 1 to 4 R c C optionally substituted with 6~10 aryl; (c) 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 the group consisting of 1 to 4 independently selected R c heteroaryl, optionally substituted with (d) Heterocyclyl containing 3 to 10 ring atoms, wherein 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 the group consisting of 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 optionally 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 optionally substituted with 2~7 is alkyl; or (iii) 1 to 6 independently selected R a C optionally 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 optionally 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 optionally 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 with 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 the group consisting of 1 to 4 independently selected R c heteroaryl, optionally substituted with (iii) 1 to 4 R b C optionally 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 the group consisting of 1 to 4 independently selected R b heterocyclyl, optionally substituted by (v) 1 to 6 independently selected R a C optionally substituted with 1~10 Alkyl and; R 3 Each occurrence of independently represents -L 4 -R 4 , H, and R c ' selected from the group consisting of; L 4 Each occurrence of is independently: (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 -; and (xii) -S(O)(=NH)- or -S(O)(=NR d ) selected from the group consisting of: R 4 Each occurrence of is independently: (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 optionally substituted with 3~6 cycloalkyl; (b) 1 to 4 R c C which may be further substituted with 6~10 aryl; (c) 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 the group consisting of 1 to 4 independently selected R c heteroaryl, optionally substituted with (d) Heterocyclyl containing 3 to 10 ring atoms, wherein 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 the group consisting of 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 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 is 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; (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) -NO2; (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) -NO2; (v) -C(=O)(C 1~4 alkyl); (vi) -C(=O)O(C 1~4 alkyl); (vii) -C(=O)OH; and (viii) -NH2 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 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 1~4alkyl, 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.

[0084] In some embodiments, the compound has the formula (I-1): If it is a compound of TIFF0007640458000131.tif34128, R 1 is other than unsubstituted phenyl, p-dimethylaminophenyl, p-aminosulfonylphenyl, and unsubstituted 4-pyridinyl.

[0085] In some embodiments, the compound has the formula (I-1): If it is a compound of TIFF0007640458000132.tif34128, R 1 is other than unsubstituted phenyl, p-monosubstituted phenyl, and unsubstituted pyridinyl.

[0086] In some embodiments, the compound has the formula (I-2): If it is a compound of TIFF0007640458000133.tif34128, R 1 is other than unsubstituted phenyl.

[0087] In some embodiments, the compound has formula (I-1) or formula (I-2): It is assumed to be a compound other than TIFF0007640458000134.tif34128.

[0088] In some embodiments, the compound has formula (I-3): It is not a compound of TIFF0007640458000135.tif34128.

[0089] In some embodiments, the compound has formula (I-4): If it is a compound of TIFF0007640458000136.tif34128, R 1 is other than p-monosubstituted phenyl (eg, p-fluorophenyl).

[0090] In some embodiments, the compound has formula (I-5): If the compound is TIFF0007640458000137.tif34128, R 3 is other than trifluoromethyl.

[0091] In some embodiments, the compound has formula (I-6): If the compound is TIFF0007640458000138.tif34128, R 2 is the following: (i) unsubstituted phenyl; (ii) TIFF0007640458000139.tif10128; (iii) TIFF0007640458000140.tif20128; (iv) unsubstituted pyridinyl; (v) TIFF0007640458000141.tif12128Here, 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 the group consisting of 1 to 2 independently selected R c Heteroaryl, optionally substituted with This excludes:

[0092] In some embodiments, the compound excludes one or more of the following: TIFF0007640458000142.tif79128. TIFF0007640458000143.tif30128.

[0093] In some embodiments, the compound excludes one or more of the following: TIFF0007640458000144.tif32141.

[0094] In certain embodiments, the compound is other than a compound disclosed in European Journal of Medicinal Chemistry (2014), 86, 270-278. In certain embodiments, the compound is other than a compound disclosed in Tetrahedron Letters (2012), 53(25), 3126-3130. In certain embodiments, the compound is other than a compound disclosed in Organic Letters (2011), 13(24), 6516-6519. In certain embodiments, the compound is other than a compound 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 a compound disclosed in Angewandte Chemie, International Edition (2018), 57(5), 1399-1403. In certain embodiments, the compound is other than a compound disclosed in Organic Letters (2017), 19(19), 5118-5121. In certain embodiments, the compound is other than a compound disclosed in Tetrahedron (2009), 65(44), 8930-8939. In certain embodiments, the compound is other than a compound disclosed in Organic Letters (2016), 18(13), 3250-3253. In certain embodiments, the compound is other than a compound 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 a compound disclosed in International Patent Application Publication No. 2001 / 030778. In certain embodiments, the compound is other than a compound disclosed in U.S. 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 WO 2017 / 171234. In certain embodiments, the compound is other than the compounds disclosed in International Patent Application Publication WO 2016 / 176460. In certain embodiments, the compound is other than the compounds disclosed in Japanese Patent Publication No. 2013-018771 and / or Japanese Patent No. 5,959,330. In certain embodiments, the compound is other than the compounds disclosed in International Patent Application Publication WO 2011 / 153310. In certain embodiments, the compound is other than a compound disclosed in International Patent Application Publication No. WO 2011 / 082270. In certain embodiments, the compound is other than a compound disclosed in Australian Patent Application Publication No. AU 2010 / 331175 and / or U.S. Patent Application Publication No. US 2012 / 0258951 and / or US 2014 / 0194407. In certain embodiments, the compound is other than a compound 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 a compound disclosed in WO 2010 / 030360. In certain embodiments, the compound is other than a compound 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 a compound disclosed in International Patent Application WO 2007 / 075629. In certain embodiments, the compound is other than a compound disclosed in JP 2000-302754 A and / or U.S. Pat. No. 6,358,634.

[0097] Variable 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, X 1 , X 2 , X 3 , and X 4 One or two of these are independently N.

[0101] In certain embodiments, X 1 , X 2 , X 3 , and X 4 1-2 of which are independently N; X 1 , X 2 , X 3 , and X 4 Two or three of these are independently selected CRs. 3 is.

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

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

[0104] In certain embodiments, the compound of formula (I) has the formula (Ia): TIFF0007640458000145.tif30128, or a pharmaceutically acceptable salt thereof.

[0105] In certain embodiments, the compound of formula (I) has formula (Ib): TIFF0007640458000146.tif30128, or a pharmaceutically acceptable salt thereof.

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

[0107] In certain embodiments, the compound of formula (I) has the formula (I-a1): TIFF0007640458000147.tif34128, or a pharmaceutically acceptable salt thereof.

[0108] In certain embodiments, the compound of formula (I) has the formula (I-a2): TIFF0007640458000148.tif34128, or a pharmaceutically acceptable salt thereof.

[0109] In certain embodiments, the compound of formula (I) has the formula (I-b1): TIFF0007640458000149.tif34128, or a pharmaceutically acceptable salt thereof.

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

[0111] In certain embodiments, the compound of formula (I) has the formula (Ic): TIFF0007640458000150.tif30128, or a pharmaceutically acceptable salt thereof.

[0112] In certain embodiments, the compound of formula (I) has the formula (Id): TIFF0007640458000151.tif30128, or a pharmaceutically acceptable salt thereof.

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

[0114] In certain embodiments, the compound of formula (I) has the formula (I-c1): TIFF0007640458000152.tif34128, or a pharmaceutically acceptable salt thereof.

[0115] In certain embodiments, the compound of formula (I) has the formula (I-d1): TIFF0007640458000153.tif35128, or a pharmaceutically acceptable salt thereof.

[0116] In certain embodiments, the compound of formula (I-d1) has the formula: TIFF0007640458000154.tif32128, During the ceremony, 1 R 3 is independently -L 4 -R 4 and R c'Selected from; Other R 3 are 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 the following: (a) 1 to 4 R b Partially unsaturated C optionally substituted with 3~10 cycloalkyl; (b) 1 to 4 R c C optionally substituted with 6~10 aryl; (c) 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 the group consisting of 1 to 4 independently selected R c heteroaryl, optionally substituted with (d) Partially unsaturated heterocyclyl containing 3 to 10 ring atoms, wherein 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 the group consisting of 1 to 4 independently selected R b partially unsaturated heterocyclyl optionally substituted with and; R 2 is the following: (i) 1 to 4 R c C which may be further substituted with 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 the group consisting of 1 to 4 independently selected R c heteroaryl, optionally substituted with (iii) 1 to 4 R b Partially unsaturated C optionally substituted with 3~10 cycloalkyl; or (iv) Partially unsaturated heterocyclyl containing 3 to 10 ring atoms, wherein 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 the group consisting of 1 to 4 independently selected R b partially unsaturated heterocyclyl optionally substituted with is.

[0117] Variable factor R 1 In some embodiments, R 1 Ha-(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 It is 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 N, N(H), N(R d ), O, and S, and one or more of the heteroaryl ring carbon atoms are selected from the group consisting of 1 to 4 independently selected R c In certain of the above embodiments, n is 0.

[0121] In some embodiments, Y2 is a heteroaryl containing six ring atoms, of which one to four 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 the group consisting of 1 to 4 independently selected R c or heteroaryl containing 5 or 9-10 ring atoms, wherein 1-4 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 the group consisting of 1 to 4 independently selected R c In certain of the above embodiments, n is 0.

[0122] In certain embodiments, Y 2 is a 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 the group consisting of 1 to 4 independently selected R c In certain of these embodiments, n is 0.

[0123] In certain embodiments, 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 selected from 1 to 4 independently selected R c For example, Y 2 is a group in which one or more of the ring carbon atoms are substituted with 1 to 4 (e.g., 1, 2, 3, or 4) independently selected R c It may also be pyridyl (e.g., 2-pyridyl or 6-pyridyl) optionally substituted with (e.g., Y 2 is a group in which one or more of the ring carbon atoms are bonded to one independently selected R cIn certain of these embodiments, n is 0.

[0124] In certain embodiments, Y 2 is a heteroaryl containing 5 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 the group consisting of 1 to 2 independently selected R c For example, Y 2 Any substitutable nitrogen atom is R d and one or more of the ring carbon atoms may be substituted with 1 to 2 independently selected R c In certain of these embodiments, n is 0.

[0125] In certain embodiments, Y 2 is a heteroaryl containing 5 ring atoms, 1 to 3 of which 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 the group consisting of 1 to 3 independently selected R c In certain of these embodiments, n is 0.

[0126] In some of these embodiments, Y 2 is a group in which one or more of the ring carbon atoms are bonded to one or two (e.g., one) independently selected R c In certain of these embodiments, n is 0.

[0127] In some of the above embodiments, Y 2 When is heteroaryl, R c Each occurrence of 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, Y 2 When is heteroaryl, R c Each occurrence of is independently selected from the group consisting of: (vii) C 1~4 Alkoxy; (viii) C 1~4 haloalkoxy (e.g., OCH2CF3 or OCF3); (xiv) -C 1~4 thioalkoxy; and (xx) C 3~6 Cycloalkoxy (eg cyclopropoxy).

[0129] For example, R c Each occurrence of is independently selected C 1~4 Alkoxy (e.g., -OCH3, -OCH2CH3).

[0130] Another example is R c Each occurrence of is independently selected C 1~6 It is alkyl (eg, methyl).

[0131] In some of the above embodiments, Y 2 When is heteroaryl, R d Each occurrence of is independently selected C 1~6 It is alkyl.

[0132] In some of the above embodiments, Y 2 is heteroaryl and n is 0, then R 1 is the following: TIFF0007640458000155.tif26143.

[0133] In some of the above embodiments, Y 2 is heteroaryl and n is 0, then R 1 is the following: TIFF0007640458000156.tif13128.

[0134] As a non-limiting example of the above embodiment, Y 2 is heteroaryl and n is 0, then R 1 teeth It could also be TIFF0007640458000157.tif14128.

[0135] In certain embodiments, Y 2 is heteroaryl and n is 0, then R 1 teeth It could also be TIFF0007640458000158.tif15128.

[0136] In certain embodiments, Y 2 is heteroaryl and n is 0, then R 1 teeth It could also be TIFF0007640458000159.tif11128.

[0137] In some embodiments, Y 2 is 1 to 4 R b C optionally substituted with 3~10In certain of these embodiments, n is 0.

[0138] In some embodiments, Y 2 is 1 to 4 R c C optionally substituted with 6~10 It is aryl.

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

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

[0141] In some embodiments, Z 1 is CH2.

[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 It is alkylene.

[0144] In certain embodiments, Z 1 is CH2 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 It is alkylene.

[0146] In certain embodiments, Z 1 is CH2 and Z 2 is -O- or -S- (e.g., -O-), and Z 3 is C 2~3 It is alkylene.

[0147] In some of the above embodiments, R 1 Ga-Z 1 -Z 2 -Z 3 If R 1 teeth The file is TIFF0007640458000160.tif6128.

[0148] Variable factor R 2 In some embodiments, R 2 is: (i) 1 to 4 R c C which may be further substituted with 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 the group consisting of 1 to 4 independently selected R c heteroaryl, optionally substituted with (iii) 1 to 4 R b Partially unsaturated C optionally substituted with 3~10 cycloalkyl; or (iv) Partially unsaturated heterocyclyl containing 3 to 10 ring atoms, wherein 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 the group consisting of 1 to 4 independently selected R b optionally substituted partially unsaturated heterocyclyl;

[0149] In some embodiments, R2 is 1 to 4 R c C optionally substituted with 6~10 It is aryl.

[0150] In certain embodiments, R 2 is 1 to 4 R c In some of the above embodiments, R 2 is 1 to 2 R c Non-limiting examples include phenyl optionally substituted with R 2 is two R c It may be phenyl optionally substituted with

[0151] In some of the above embodiments, R 2 is aryl (e.g., phenyl), R c Each occurrence of is independently selected from the group consisting of: (i) Halo (e.g., F); (vi) C 1~4 haloalkyl (e.g., CF3); (vii) C 1~4 Alkoxy; (viii) C 1~4 haloalkoxy; and (xiv) -C 1~4 Thioalkoxy.

[0152] As a non-limiting example, R c Each occurrence of is a halo, C 1~4 Alkoxy, and C 1~4 haloalkyl (e.g., R c each occurrence is independently -OCH3, CF3, or F).

[0153] In some of the above embodiments, R 2 is aryl (e.g., phenyl), R 2 is the following formula (A): TIFF0007640458000161.tif25128, In the formula, R 2a , R2b , R 2c , R 2d , and R 2e are each independently H and R c is selected from the group consisting of:

[0154] In certain embodiments, R 2a , R 2b , R 2c , R 2d , and R 2e Four of these are independently selected R c and the others are H.

[0155] In certain embodiments, R 2a , R 2b , R 2c , R 2d , and R 2e Three of these are independently selected R c and the others are H.

[0156] In certain embodiments, R 2a , R 2b , R 2c , R 2d , and R 2e Two of these are independently selected R c and others are H. In some of these embodiments, R 2a and R 2e are each independently selected R c (For example, C 1~4 Alkoxy; C 1~4 Haloalkoxy; -C 1~4 Thioalkoxy; C 1~4 haloalkyl; and halo), such as R c Each occurrence of is independently selected C 1~4 Alkoxy (e.g., -OCH3). For example, R 2a and R 2e are OCH3, respectively.

[0157] In certain embodiments, R 2 teeth The file is TIFF0007640458000162.tif18128.

[0158] In some of the above embodiments, R 2 is aryl (e.g., phenyl), R 2 is the formula (B): I have TIFF0007640458000163.tif18128.

[0159] In some embodiments, R 2 is aryl (e.g., phenyl); R 2 is the following formula (A): If you have TIFF0007640458000164.tif25128, 2a , R 2b , R 2d , and R 2e 1 to 4 of which are independently selected R c is.

[0160] In some of the above embodiments, each R c are independently selected from: (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) 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); (xii) -OH; (xiv) -C 1~4 Thioalkoxy; (xv) -NO2; (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 a 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 the group consisting of 1 to 4 independently selected R c is heteroaryl, optionally substituted with

[0162] In some of the above embodiments, R 2 is a heteroaryl containing six ring atoms, wherein one to three 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 the group consisting of 1 to 4 independently selected R c is heteroaryl, optionally substituted with

[0163] As a non-limiting example, R 2 is one to two independently selected R c It may be pyridinyl optionally substituted with

[0164] In some of the above embodiments, R 2 When R is a heteroaryl as defined above (e.g., 2is a 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 the group consisting of 1 to 4 independently selected R c and when it is heteroaryl, each R c are independently selected from: (i) Halo; (vi) C 1~4 haloalkyl (e.g., CF3); (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 is independently C 1~4 It may also be alkoxy (eg, methoxy).

[0166] In some of the above embodiments, R 2 When is heteroaryl, R 2 teeth The file is TIFF0007640458000165.tif17128.

[0167] In some of the above embodiments, R 2 When is heteroaryl, R 2 teeth The file is TIFF0007640458000166.tif17128.

[0168] In some embodiments (e.g., when the compound has Formula I-d1), R 2 When R is heteroaryl as defined elsewhere herein, 2 is selected from: (a) Heteroaryl containing 5 ring atoms, wherein 1 to 2 ring atoms are heteroatoms, each independently selected from N, N(H), N(Rd ), O, and S, and one or more of the heteroaryl ring carbon atoms are selected from the group consisting of 1 to 4 independently selected R c heteroaryl, optionally substituted with (b) TIFF0007640458000167.tif12128Here, Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 are each independently N, CH, and CR c is selected from, with the proviso that: Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 1 to 4 of them are CR independently c and; Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 one or more of are independently N; and Q 5 is CR c If Q 1 , Q 2 , Q 3 , and Q 4 One or more of the following is CR c and (c) Heteroaryl containing 9 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 the group consisting of 1 to 4 independently selected R c heteroaryl substituted with; where R c Each occurrence of is independently selected from: (i) -F; (ii) cyano; (iii) C 2~6 alkyl; (iv) C2~6 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 ; (xiii) -S(O) 1~2 (NR'R''); (xiv) -C 1~4 Thioalkoxy; (xv) -NO2; (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 factor R 3 In some embodiments, R 3 One or more occurrences of each independently represent R c' and -L 4 -R 4 is selected from.

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

[0171] In some of the above embodiments, R 3 One occurrence of -L 4 -R 4 If R 3 Each of the remaining occurrences of is independently H and R c ' (e.g., R c ' may be halo, e.g., Br or Cl; or R c ' may be -OH or NH2). For example, R 3 Each of the remaining occurrences of may be H.

[0172] In some embodiments, R 3 One occurrence of -L 4 -R 4 and R 3 One occurrence of H or R c ' (e.g., R c ' may be halo, e.g., Br or Cl; or R c ' may be NH2).

[0173] In some embodiments, 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' may be Cl).

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

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

[0176] In some of the above embodiments, R 3 Any remaining occurrences of H and R c' For example, R 3 Any remaining occurrences of may be H.

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

[0178] In some embodiments, R 3 One occurrence of H or R c ' (e.g., R c ' may be halo, e.g., Br or Cl; or R c ' may be -OH or NH2).

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

[0180] In certain embodiments, R 3 One occurrence of R c ', then the remaining R 3 One or more occurrences of -L may be used independently. 4 -R 4 and R c' is selected from.

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

[0182] X 1 ~X4 and R 3 Non-limiting combinations of In some embodiments, the moiety TIFF0007640458000168.tif18128 (To further clarify the connection points, the structure originally shown in U.S. Provisional Application No. 62 / 742,218 TIFF0007640458000169.tif14128 has been redrawn) TIFF0007640458000170.tif23128 (To further clarify the connection points, the structure originally shown in U.S. Provisional Application No. 62 / 742,218 TIFF0007640458000171.tif19128 redrawn), where * is NR 2 indicates the point of attachment to; TIFF0007640458000172.tif3128 is A 1 indicates the attachment point to

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

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

[0185] In certain embodiments, R 3B Ha-L 4 -R 4 and; R 3C are independently selected -L 4 -R 4 In some of the above embodiments, R 3B -L 4 is R3C -L 4 As a non-limiting example, R 3B -L 4 may be NHS(O)2; R 3C -L 4 may be a bond.

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

[0187] In certain embodiments, R 3B is R c' and; R 3C Ha-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' is.

[0189] In some embodiments, the moiety TIFF0007640458000173.tif18128 (To further clarify the connection points, the structure originally shown in U.S. Provisional Application No. 62 / 742,218 TIFF0007640458000174.tif14128 has been redrawn) TIFF0007640458000175.tif23128 (To further clarify the connection points, the structure originally shown in U.S. Provisional Application No. 62 / 742,218 TIFF0007640458000176.tif19128 redrawn), where * is NR 2 indicates the point of attachment to; TIFF0007640458000177.tif3128 is A 1 indicates the attachment point to

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

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

[0192] In some embodiments, the moiety TIFF0007640458000178.tif18128 (To further clarify the connection points, the structure originally shown in U.S. Provisional Application No. 62 / 742,218 TIFF0007640458000179.tif15128 has been redrawn) TIFF0007640458000180.tif23128 (To further clarify the connection points, the structure originally shown in U.S. Provisional Application No. 62 / 742,218 TIFF0007640458000181.tif19128 redrawn), where * indicates NR 2 indicates the point of attachment to; TIFF0007640458000182.tif3128 is A 1 indicates the attachment point to

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

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

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

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

[0197] In some of the above embodiments, R 3B Ha-L 4 -R 4 (e.g., -L 4 may be NHS(O)2); R 3C are independently selected -L 4 -R 4 In some of the above embodiments, R 3B -L 4 is R 3C -L 4 As a non-limiting example, R 3B -L 4 may be NHS(O)2; R 3C -L 4 may be a bond.

[0198] In some embodiments, the moiety TIFF0007640458000183.tif18128 (To further clarify the connection points, the structure originally shown in U.S. Provisional Application No. 62 / 742,218 TIFF0007640458000184.tif15128 has been redrawn) TIFF0007640458000185.tif23128 (To further clarify the connection points, the structure originally shown in U.S. Provisional Application No. 62 / 742,218 TIFF0007640458000186.tif19128 redrawn), where * indicates NR 2 indicates the point of attachment to; TIFF0007640458000187.tif3128 is A 1 indicates the attachment point to

[0199] In certain embodiments, R3D is H.

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

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

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

[0203] In some of the above embodiments, R 3B Ha-L 4 -R 4 (e.g., -L 4 may be NHS(O)2); R 3C are independently selected -L 4 -R 4 In some of the above embodiments, R 3B -L 4 is R 3C -L 4 As a non-limiting example, R 3B -L 4 may be NHS(O)2; R 3C -L 4 may be a bond.

[0204] Variable factor 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 -S(O)(=NH)NH-, -S(O)(=NR d )NH-, -S(O)(=NH)NR d - or -S(O)(=NR d )NR d -It is.

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

[0210] In some embodiments, -L 4 -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)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 -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 )-.

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

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

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

[0225] In some embodiments, -L 1 is selected from: (i) a bond (in certain embodiments, -L 4 is a bond; R 4 -(Y 3 ) p -Y 4 if so, then 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 factor R 4 In some embodiments, R 4 Ha-(Y 3 ) p -Y 4 is.

[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 CH2 or CH2-CH2.

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

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

[0231] In certain embodiments, Y 4 However, 1 to 4 R c C optionally substituted with 6~10If aryl (e.g., Y 4 However, there are 1 to 2 (for example, 1) R c phenyl optionally substituted with R c Each occurrence of 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 optionally substituted with alkyl -(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 However, 1 to 4 R c C optionally substituted with 6~10 If aryl (e.g., Y 4 However, there are 1 to 2 (for example, 1) R c phenyl optionally substituted with R c Each occurrence of 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 C 6~10 When R is aryl, c Each occurrence of 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 a non-substituted C 6~10 It is aryl (eg, phenyl).

[0235] In certain embodiments, p=1 and Y 4 C 6~10 When R is aryl, 4 is the following: TIFF0007640458000188.tif58138.

[0236] In certain embodiments, p=1 and Y 4 C 6~10 When R is aryl, 4 is the following: TIFF0007640458000189.tif30128.

[0237] In certain embodiments, p=0 and Y 4 C 6~10 When R is aryl, 4 teeth The file is TIFF0007640458000190.tif21128.

[0238] In certain embodiments, p=0 and Y 4 C 6~10 When R is aryl, 4 teeth The file is TIFF0007640458000191.tif17128.

[0239] In some embodiments, Y 4 is 1 to 4 R b C optionally substituted with 3~6 (For example, C 3~4 or C6) cycloalkyl.

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

[0241] In some embodiments, Y 4 is 1 to 2 R b and C6 cycloalkyl (e.g., cyclohexyl) optionally substituted with.

[0242] In some of the above embodiments, Y 4 However, 1 to 4 R b When R is cycloalkyl optionally substituted with 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 is C 1~6 It may be alkyl, for example methyl).

[0243] In certain embodiments, p=1 and Y 4 However, 1 to 4 R b C optionally substituted with 3~6 When R is cycloalkyl, 4 is the following: TIFF0007640458000192.tif14128.

[0244] In certain embodiments, p=1 and Y 4 However, 1 to 4 R b C optionally substituted with 3~6When R is cycloalkyl, 4 is the following: TIFF0007640458000193.tif13128.

[0245] In certain embodiments, p=0 and Y 4 However, 1 to 4 R b C optionally substituted with 3~6 When R is cycloalkyl, 4 is the following: TIFF0007640458000194.tif24128.

[0246] In certain embodiments, Y 4 is a non-substituted C 3~6 (For example, C 3~4 or C6) 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 a 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 the group consisting of 1 to 4 independently selected R c is heteroaryl, optionally substituted with

[0249] In some of the above embodiments, Y 4 is a heteroaryl containing six ring atoms, wherein one to four 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 the group consisting of 1 to 4 independently selected R c is heteroaryl, optionally substituted with

[0250] As a non-limiting example of the above embodiment, Y 4 is one to two independently selected R c and may be pyridinyl (eg, 2-pyridinyl, 3-pyridinyl, or 4-pyridinyl), pyrimidinyl (eg, 2-pyrimidinyl or 5-pyrimidinyl), or pyrazinyl, each of which may be optionally substituted with.

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

[0252] In certain embodiments, Y 4 is one or more independently selected R c When R is heteroaryl optionally substituted with c Each occurrence of 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 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.

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

[0254] In certain embodiments, p = 1 and Y 4 When is heteroaryl, R 4 is the following: TIFF0007640458000195.tif52159.

[0255] In certain embodiments, p = 1 and Y 4 When is heteroaryl, R 4 is the following: TIFF0007640458000196.tif14128.

[0256] In certain embodiments, p = 0 and Y 4 When is heteroaryl, R 4 is the following: TIFF0007640458000197.tif15128.

[0257] In certain embodiments, p = 0 and Y 4 When is heteroaryl, R 4 is the following: TIFF0007640458000198.tif15128.

[0258] In some embodiments, Y 4 is a heterocyclyl containing 3 to 10 ring atoms, wherein 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 the group consisting of 1 to 4 independently selected R b is heterocyclyl, optionally substituted by

[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 N, N(H), N(R d ), and O, wherein one or more of the heterocyclyl ring carbon atoms are selected from the group consisting of 1 to 4 independently selected R b is heterocyclyl, optionally substituted by

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

[0261] As a non-limiting example, Y 4 is one to two independently selected R b It may also be an oxetanyl optionally substituted by (for example, unsubstituted oxetanyl).

[0262] Another non-limiting example is Y 4 is one to two independently selected R b Azetidinyl optionally substituted with (e.g., one R b substituted azetidinyl).

[0263] In some embodiments, Y 4 is a heterocyclyl containing 6 ring atoms, in 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 the group consisting of 1 to 4 independently selected R b is heterocyclyl, optionally substituted by

[0264] As a non-limiting example, Y4 is one to two independently selected R b and morpholinyl, each of which may be optionally substituted with .

[0265] As a non-limiting example, Y 4 is one to two independently selected R b and morpholinyl, each of which may be optionally substituted with .

[0266] In some of the above embodiments, Y 4 is 1 to 4 independently selected R b When R is heterocyclyl optionally substituted with b Each occurrence of is independently -F, C 1~6 Alkyl, C 1~4 It is selected from the group consisting of haloalkyl, oxo, and -OH.

[0267] In some of the above embodiments, Y 4 is 1 to 4 independently selected R b When R is heterocyclyl optionally substituted with b Each occurrence of is independently -F, C 1~6 Alkyl, C 1~4 haloalkyl, and —OH (e.g., R b may be OH).

[0268] In certain embodiments, p = 1 and Y 4 is 1 to 4 independently selected R b When R is heterocyclyl optionally substituted with 4 is the following: TIFF0007640458000199.tif26128.

[0269] In certain embodiments, p = 1 and Y 4 is 1 to 4 independently selected R bWhen R is heterocyclyl optionally substituted with 4 teeth The file is TIFF0007640458000200.tif24128.

[0270] In certain embodiments, p = 0 and Y 4 is 1 to 4 independently selected R b When R is heterocyclyl optionally substituted with 4 is the following: TIFF0007640458000201.tif24140.

[0271] In certain embodiments, p = 0 and Y 4 is 1 to 4 independently selected R b When R is heterocyclyl optionally substituted with 4 is the following: TIFF0007640458000202.tif24128.

[0272] In some embodiments, R 4 is 1 to 6 independently selected R a C optionally substituted with 1~10 It is alkyl.

[0273] In certain embodiments, R 4 is 1 to 6 independently selected R a C optionally substituted with 1~6 It is alkyl.

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

[0275] In some of the above embodiments, R 4 C 1~6 If it is alkyl, R aEach occurrence of is independently -F; -OH; C 1~4 Alkoxy; and C 1~4 haloalkoxy.

[0276] In certain embodiments, R a Each occurrence of is independently -OH. For example, R 4 teeth The file is TIFF0007640458000203.tif12128.

[0277] In some embodiments, R 4 is methyl, ethyl, TIFF0007640458000204.tif14128.

[0278] In some embodiments, R 4 is methyl and Selected from TIFF0007640458000205.tif12128.

[0279] In some embodiments, R 4 is 1 to 6 (e.g., 1 to 3) independently selected R a C optionally substituted with 2~10 (For example, C 2~4 ) alkynyl (e.g. Non-substituted C, such as TIFF0007640458000206.tif8128 2~4 alkynyl).

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

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

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

[0283] -L 4 and R 4 Non-limiting combinations of Non-limiting combination [A] In some embodiments, -L 4 -N(H)S(O)2-, -N(H)S(O)2N(H)-, -N(H)S(O)2N(R d )-, C≡C, 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) 1 to 2 R a C optionally 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.

[0284] In certain embodiments, -L 4 are -N(H)S(O)2-, -N(H)S(O)2N(H)-, and -N(H)S(O)2N(R d)-selected from the group consisting of; R 4 is selected from the group consisting of: (i) 1 to 2 R a C optionally 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.

[0285] 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)—; R 4 is selected from the group consisting of: (i) 1 to 2 R a C optionally substituted with 1~6 alkyl; and (ii) -(Y 3 ) p -Y 4 .

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

[0287] In certain embodiments, -L4 is -N(H)S(O)2-; R 4 is selected from the group consisting of: (i) 1 to 2 R a C optionally substituted with 1~6 alkyl; 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) 1 to 2 R a C optionally substituted with 1~6 alkyl; and (ii) -(Y 3 ) p -Y 4 .

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

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

[0292] In certain embodiments, -L 4 is -N(H)S(O)2-; R 4 is selected from the group consisting of: R 4 is selected from the group consisting of: (i) 1 to 2 R a C optionally 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.

[0293] In certain embodiments, -L 4 is a single bond; R 4 is selected from the group consisting of: R 4 is selected from the group consisting of: (i) 1 to 2 R a C optionally 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.

[0294] In certain embodiments, -L 4 is -NH- or -N(R 4 )-and; R 4 is selected from the group consisting of: R 4 is selected from the group consisting of: (i) 1 to 2 R a C optionally 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.

[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) 1 to 2 R a C optionally 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.

[0296] In certain embodiments, -L 4 is -N(H)S(O)2N(H)- or -N(H)S(O)2N(R d )-and; R 4 is selected from the group consisting of: (i) 1 to 2 R a C optionally substituted with1~6 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.

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

[0298] In some embodiments of [A], 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 It is alkynyl.

[0299] In some of these embodiments, R 4 is one to three independently selected R a C optionally substituted with 2~10 (For example, C 2~5 ) alkynyl (e.g. Non-substituted C, such as TIFF0007640458000207.tif8128 2~5 alkynyl).

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

[0301] In some embodiments of [A], R 4 -(Y 3 ) p -Y 4 If Y 4 is 1 to 4 R b C optionally substituted with 3~6 (For example, C 3~4 or C6) cycloalkyl. In certain embodiments, Y 4 is 1 to 2 R b C, each of which may be substituted with 3~4 cycloalkyl or C6 cycloalkyl (e.g., R b may be -OH).

[0302] In some embodiments of [A], R 4 Ha-(Y 3 ) p -Y 4 In certain embodiments, Y 4 is a 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 the group consisting of 1 to 2 independently selected R b In certain embodiments, Y is heterocyclyl, optionally substituted with 4 is a heterocyclyl containing 6 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 the group consisting of 1 to 2 independently selected R b and heterocyclyl, optionally substituted with (e.g., Y 4 is one to two independently selected R b In certain embodiments, Y may be tetrahydropyranyl, piperidinyl, or morpholinyl, each of which may be optionally substituted with 4 is a heterocyclyl containing four ring atoms, in which one to three 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 the group consisting of 1 to 2 independently selected R b and heterocyclyl, optionally substituted with (e.g., Y 4 may be oxetanyl; or Y 4 may be azetidinyl).

[0303] In some embodiments of [A], R 4 Ha-(Y 3 ) p -Y 4 In certain embodiments, Y 4 is a heteroaryl containing six ring atoms, wherein one to four 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 the group consisting of 1 to 4 independently selected R c In certain embodiments, Y is heteroaryl, optionally substituted with 4 is one to two independently selected R c pyridinyl (eg, 2-pyridinyl, 3-pyridinyl, or 4-pyridinyl), pyrimidinyl (eg, 2-pyrimidinyl or 5-pyrimidinyl), or pyrazinyl, each of which may be optionally substituted with

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

[0305] In another embodiment of [A], R 4 -(Y 3 ) p -Y 4 In some of these embodiments, when Y 3 is C 1~3 Alkylene (e.g., CH2, CH2-CH2).

[0306] In some embodiments, R 3 Ga-L4 -R 4 If R 3 is the following: TIFF0007640458000208.tif64132.

[0307] In some embodiments, R 3 Ga-L 4 -R 4 If R 3 is the following: TIFF0007640458000209.tif35128.

[0308] In some embodiments, R 3 Ga-L 4 -R 4 If R 3 is the following: TIFF0007640458000210.tif31128.

[0309] In some embodiments, R 3 Ga-L 4 -R 4 If R 3 is the following: TIFF0007640458000211.tif27128.

[0310] In some embodiments, R 3 Ga-L 4 -R 4 If R 3 is the following: TIFF0007640458000212.tif24128.

[0311] In some embodiments, R 3 Ga-L 4 -R 4 If R 3 is the following: TIFF0007640458000213.tif21147.

[0312] In some embodiments, R 3 Ga-L 4 -R 4 If R 3 is the following: TIFF0007640458000214.tif20128.

[0313] In some embodiments, R 3 Ga-L 4 -R 4 If R 3 is the following: TIFF0007640458000215.tif19128.

[0314] In some embodiments, R 3 Ga-L 4 -R 4 If R 3 is the following: TIFF0007640458000216.tif35140.

[0315] In some embodiments, R 3 Ga-L 4 -R 4 If R 3 is the following: TIFF0007640458000217.tif42147.

[0316] In some embodiments, R 3 Ga-L 4 -R 4 If R 3 is the following: TIFF0007640458000218.tif18128.

[0317] In some embodiments, R 3 Ga-L 4 -R 4 If R 3 is the following: TIFF0007640458000219.tif19140.

[0318] In some embodiments, R 3 Ga-L 4 -R 4 If R 3 is the following: TIFF0007640458000220.tif19148.

[0319] In some embodiments, R 3 Ga-L 4 -R 4 If R 3 is the following: TIFF0007640458000221.tif40150.

[0320] In some embodiments, R 3 Ga-L 4 -R 4 If R 3 is the following: TIFF0007640458000222.tif17128, NHMe, and NMe2 is selected from the group consisting of:

[0321] In some embodiments, R 3 Ga-L 4 -R 4 If R 3 is the following: TIFF0007640458000223.tif15128.

[0322] In some embodiments, R 3 Ga-L 4 -R 4 If R 3 is the following: TIFF0007640458000224.tif15128.

[0323] In some of the above embodiments, R 3 teeth The file is TIFF0007640458000225.tif12128.

[0324] Variable factor 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) -NO2; (v) -C(=O)(C 1~4 alkyl); (vi) -C(=O)O(C 1~4 alkyl); (vii) -C(=O)OH; and (viii) -NH2.

[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) -NO2; (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 (eg, -F, Cl).

[0327] In certain embodiments, R c Each occurrence of ' is independently selected from OH and NH2.

[0328] Non-limiting combinations Non-limiting combinations[1] In some embodiments, R 1 Ha-(Y 1 ) n-Y 2 and; R 2 is 1 to 4 R c C optionally substituted with 6~10 It is aryl.

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

[0330] In some of the above aspects of [1], X 1 , X 2 , X 3 , and X 4 1-2 of them are N; X 1 , X 2 , X 3 , and X 4 Two or three of these are independently selected CRs. 3 is.

[0331] In some of the above aspects of [1], X 1 , X 2 , X 3 , and X 4 One of them is N; the remaining X 1 , X 2 , X 3 , and X 4 are each independently selected CR 3 is; or X 1 , X 2 , X 3 , and X 4 Two of them are N; the remaining X 1 , X 2 , X 3 , and X 4 are each independently selected CR 3 is.

[0332] In certain embodiments, X 2 and X 3 One or two of them are independently CR 3 For example, X 2 and X 3 Both are independently selected CR 3In some of the above embodiments, X 1 and X 4 are each independently CH or N (e.g., X 1 and X 4 are N respectively).

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

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

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

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

[0337] In some of the above aspects of [1], R 3 Each of the remaining occurrences of is independently H and R c For example, R 3 Each remaining occurrence of may independently be H.

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

[0339] In some of the above aspects of [1], R 3 One occurrence of -L4 -R 4 If R 3 One occurrence of R c' (e.g. halo (e.g. Br or Cl, e.g. Cl)).

[0340] In some embodiments of [1], R 3 One occurrence of R c' (e.g., Br or Cl, e.g., Cl); R 3 Each of the remaining occurrences of 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; and each R c and, when present, are 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; and each R c If 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; and each R c If 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; and each R c When present, is as defined in claim 23.

[0345] In certain embodiments of [1], R 1 teeth TIFF0007640458000226.tif15128, for example The file is TIFF0007640458000227.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 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 October 5, 2018. In some embodiments of [1], R 2 is 1 to 4 R c C optionally substituted with 6~10 Aryl, e.g., 1 to 4 R c Or 1-2 R c or two R's c phenyl optionally substituted with R c is, if present, 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 October 5, 2018. In some of the above embodiments, R 2 is two R c phenyl, which may be substituted with, for example, R 2 teeth TIFF0007640458000228.tif16128, TIFF0007640458000229.tif17128; R c is, if present, 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 teeth It could also be TIFF0007640458000230.tif16128.

[0349] In some embodiments of [1], R 2 is a 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 the group consisting of 1 to 4 independently selected R c Heteroaryl, optionally substituted with, for example, R 2 is one to two independently selected R c or pyridinyl optionally substituted with, for example, R 2 teeth TIFF0007640458000231.tif17128; R c If present, is as defined in any one of claims 40-41.

[0350] In certain embodiments of [1], R 2 teeth The file is TIFF0007640458000232.tif17128.

[0351] In some embodiments of [1], R 2 is as defined in any one of claims 32-37 of US 62 / 742,218, filed 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 October 5, 2018.

[0352] In some embodiments of [1], R 3 One occurrence of -L 4 -R4 If -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(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)N(H)-), or L 4 is -N(H)S(O) 1~2 N(R d )-(e.g., -N(H)S(O)N(R d )-(e.g., -N(H)S(O)N(C 1~3 alkyl)-)); And 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], R 3 One occurrence of -L 4 -R 4If -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(R d )-, or -N(R 4 )-; Single bonds; and ·C≡C.

[0354] In some embodiments of [1], R 3 One occurrence of -L 4 -R 4 If -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 October 5, 2018. For example, L 4 may be as defined in claim 49 of US 62 / 742,218, filed October 5, 2018. In some embodiments of [1], R 3 One occurrence of -L 4 -R 4 If -L 4 is -NHS(O)(=NH)-.

[0356] In some embodiments of [1], R 3 One occurrence of -L 4 -R 4 If -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)N(H)-), or L 4 is -N(H)S(O) 1~2 N(R d )-(e.g., -N(H)S(O)N(R d )-(e.g., -N(H)S(O)N(C 1~3 alkyl)-)).

[0357] In some embodiments of [1], R 3 One occurrence of -L 4 -R 4 And; R 4 (Y 3 ) p -Y 4 If Y 4 is 1 to 4 R c C optionally 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; R cis as defined in any one of claims 73 to 75, if present.

[0358] In some embodiments of [1], R 3 One occurrence of -L 4 -R 4 And; R 4 (Y 3 ) p -Y 4 If Y 4 is 1 to 4 R c C optionally substituted with 6~10 Aryl, e.g., 1 to 4 R c phenyl optionally substituted with R c Each occurrence of, 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.

[0359] In some embodiments of [1], R 3 One occurrence of -L 4 -R 4 And; R 4 (Y 3 ) p -Y 4 If 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.

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

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

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

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

[0364] In some embodiments of [1], R 3 One occurrence of -L 4 -R 4 And; R 4 (Y 3 ) p -Y 4 If Y 4is as defined in any one of claims 89 to 92, 94 and 96; 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 described in claims 99 to 113.

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

[0367] In some embodiments of [1], R 3 One occurrence of -L 4 -R 4 If ·R 4 is 1 to 6 independently selected R a C optionally substituted with 1~10 is alkyl; or ·R 4 is 1 to 6 independently selected R a C optionally substituted with 1~6 is alkyl; or ·R 4 is one to two independently selected R a C optionally substituted with 1~6 alkyl, e.g., R 4 is methyl, ethyl, TIFF0007640458000233.tif14128 (e.g., methyl and TIFF0007640458000234.tif12128); or ·R 4 is 1 to 6 (e.g., 1 to 3) independently selected R a C optionally substituted with 2~10 Alkynyl (e.g., C 2~4 alkynyl) (e.g. Non-substituted C, such as TIFF0007640458000235.tif8128 2~4 alkynyl); or ·R 4 is 1 to 6 (e.g., 1 to 3) independently selected R a C optionally 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.

[0368] In some embodiments of [1], R 3 One occurrence of -L 4 -R 4 If ·R 4 is 1 to 6 independently selected R a C optionally substituted with 1~10 is alkyl; or ·R 4 is 1 to 6 independently selected R a C optionally substituted with 1~6 is alkyl; or ·R 4 is one to two independently selected R a C optionally substituted with 1~6 Alkyl, such as methyl and TIFF0007640458000236.tif12128; Here, each R a When present, independently, such as -OH; -F; -OH; C 1~4 Alkoxy; and C 1~4 haloalkoxy.

[0369] In some embodiments of [1], R 3One occurrence of -L 4 -R 4 If 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], R 3 One occurrence of -L 4 -R 4 If 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], R 3 One occurrence of -L 4 -R 4 If 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], R 3 One occurrence of -L 4 -R 4 If 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], R 3 One occurrence of -L 4 -R 4 If 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 -L 4 -R 4 If R 4is 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 -N(H)S(O)2-, -N(H)S(O)2N(H)-, -N(H)S(O)2N(R d )-, C≡C, 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) 1 to 2 R a C optionally 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.

[0376] In certain embodiments of [1], -L 4 are -N(H)S(O)2-, -N(H)S(O)2N(H)-, and -N(H)S(O)2N(R d )-selected from the group consisting of; R 4 is selected from the group consisting of: (i) 1 to 2 R a C optionally 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.

[0377] In some embodiments of [1], R 3 is selected from the group consisting of the structures of 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.

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

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

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

[0381] In some of these embodiments, -L 4 and other occurrences of 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)N(H)-), or L 4 is -N(H)S(O) 1~2 N(R d )-(e.g., -N(H)S(O)N(R d )-(e.g., -N(H)S(O)N(C 1~3 alkyl)-)).

[0382] In certain embodiments, -L 4 and other occurrences of 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 bonds; and ·C≡C.

[0383] In certain embodiments, -L 4 and other occurrences of 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., -L 4 Another occurrence of is N(H)S(O)2-.

[0384] In certain embodiments, -L 4 and other occurrences of 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(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)N(H)-), or L 4 is -N(H)S(O) 1~2 N(R d )-(e.g., -N(H)S(O)N(R d )-(e.g., -N(H)S(O)N(C 1~3 alkyl)-)).

[0385] In some of the above embodiments, -L4 Other occurrences of are as defined in any one of claims 48 to 55 of US 62 / 742,218, filed October 5, 2018. For example, -L 4 Other occurrences of may be as defined in any one of claims 49, 51, and 53 (e.g., claim 49) of US 62 / 742,218, filed October 5, 2018.

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

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

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

[0389] In some embodiments of [1-1], each R 4 are 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 are independently as defined in any one of claims 79 to 86 of US 62 / 742,218, filed October 5, 2018.

[0391] In some embodiments of [1-1], each R 4 are independently as defined in any one of claims 87 to 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 to 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 to 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 to 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 to 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 October 5, 2018.

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

[0399] In some embodiments of [1-2], R 3 One occurrence of -L 4 -R 4 (e.g., -L 4 is as defined in claim 49); R 3 Other occurrences of R c ' (e.g., R c' may be halo, for example -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(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)N(H)-), or L 4 is -N(H)S(O) 1~2 N(Rd )-(e.g., -N(H)S(O)N(R d )-(e.g., -N(H)S(O)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 (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 bonds; 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 )-, e.g., -L 4 Another occurrence of is 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), 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)N(H)-), or L 4 is -N(H)S(O) 1~2 N(R d )-(e.g., -N(H)S(O)N(R d )-(e.g., -N(H)S(O)N(C 1~3 alkyl)-)).

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

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

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

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

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

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

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

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

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

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

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

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

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

[0417] Non-limiting combinations[2] In some embodiments, the compound of Formula (I) has the formula (I-a1-a): TIFF0007640458000237.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), 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)N(H)-), or L 4 is -N(H)S(O) 1~2 N(R d )-(e.g., -N(H)S(O)N(R d )-(e.g., -N(H)S(O)N(C 1~3 alkyl)-)).

[0419] In a particular embodiment of [2], the compound of formula (I-a1-a) has the formula (I-a1-a1): TIFF0007640458000238.tif43128, or a pharmaceutically acceptable salt thereof.

[0420] In a particular embodiment of [2], the compound of formula (I-a1-a) has the formula (I-a1-a2): TIFF0007640458000239.tif43128, or a pharmaceutically acceptable salt thereof.

[0421] In a particular embodiment of [2], the compound of formula (I-a1-a) has the formula (I-a1-a3): TIFF0007640458000240.tif43128 (e.g., R c' is halo, e.g., -Cl) or a pharmaceutically acceptable salt thereof.

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

[0423] In a particular embodiment of [2], the compound of formula (I-a1-a) has the formula (I-a1-a4): TIFF0007640458000241.tif50128 (e.g., R 3 is R c' or R 3 Ha-L 4 -R 4 is) or a pharmaceutically acceptable salt thereof.

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

[0425] In certain embodiments of formula (I-a1-a4), R 3 is H.

[0426] In certain embodiments of formula (I-a1-a4), R 3 is R c' , for example halo (eg, —Cl).

[0427] In certain embodiments of formula (I-a1-a4), R 3 Ha-L 4 -R 4 is.

[0428] In some of the above embodiments of [2] (e.g., when the compound has formula (I-a1-a4)), L 4 is as defined in any one of claims 48 to 55 of US 62 / 742,218, filed October 5, 2018; and / or R 4 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 and 72-78 of US 62 / 742,218 filed on October 5, 2018; or as defined in any one of claims 79-86 of US 62 / 742,218 filed on October 5, 2018; or as defined in any one of claims 87-92 of US 62 / 742,218 filed on October 5, 2018.

[0429] [2-1] In some embodiments of [2], the compound of formula (I-a1-a) has the formula (I-a1-a5): TIFF0007640458000242.tif38128, or a pharmaceutically acceptable salt thereof.

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

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

[0432] In some embodiments of [2-1], R 2 is as defined in any one of claims 24 to 37 (e.g., 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 (e.g., 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)2N(H)- or -N(H)S(O)2N(R d )-.

[0435] [2-2] In some embodiments of [2], the compound of formula (I-a1-a) has the formula (I-a1-a6): TIFF0007640458000243.tif38128, or a pharmaceutically acceptable salt thereof; In the formula, L 4A and L 4BEach of the L 4 and; R 4A and R 4B Each of R is independently selected 4 is.

[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 October 5, 2018.

[0438] In some embodiments of [2-2], R 2 is as defined in any one of claims 24 to 37 (e.g., 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 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)2N(H)- or -N(H)S(O)2N(R d )-.

[0442] In some embodiments of [2-2], R 4B is as defined in any one of claims 56 to 92 (e.g., 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) has formula (I-a1-a7), (I-a1-a8), or (I-a1-a9): TIFF0007640458000244.tif47143, or a pharmaceutically acceptable salt thereof; In the formula, R d' is H or R d (e.g., H or C 1~3 alkyl).

[0444] Non-limiting combinations[3] In some embodiments, the compound of Formula (I) has the formula (I-a1-b): TIFF0007640458000245.tif34128, or a pharmaceutically acceptable salt thereof.

[0445] In a particular embodiment of [3], the compound of formula (I-a1-b) is of formula (I-a1-b1) or formula (I-a1-b2): TIFF0007640458000246.tif39128 (e.g., L 4 is N(H)SO2, -N(H)-, or NHC(O) 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)N(H)-), or L 4 is -N(H)S(O) 1~2 N(R d )-(e.g., -N(H)S(O)N(R d )-(e.g., -N(H)S(O)N(C 1~3 alkyl)-)).

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

[0448] In some of the above aspects of [3], R c ' is selected from halo (e.g., Cl, Br), -OH, and NH2.

[0449] Non-limiting combinations[4] In some embodiments, the compound of Formula (I) has the formula (I-a2-a): TIFF0007640458000247.tif34128, or a pharmaceutically acceptable salt thereof.

[0450] In a particular embodiment of [4], the compound of formula (I-a2-a1) has the formula (I-a2-a1): TIFF0007640458000248.tif43128, or a pharmaceutically acceptable salt thereof.

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

[0452] In a particular embodiment of [4], the compound of formula (I-a2-a) has the formula (I-a1-a2): TIFF0007640458000249.tif50128 (e.g., L 4 is NHS(O)2) 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 October 5, 2018; and / or R 4claims 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 68-71 of US 62 / 742,218 filed on October 5, 2018 No. 62 / 742,218 filed on October 5, 2018; claims 56-60 of US 62 / 742,218 filed on October 5, 2018; 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.

[0454] Non-limiting combinations[5] In some embodiments, the compound of Formula (I) has the formula (I-b1-a): TIFF0007640458000250.tif34128, or a pharmaceutically acceptable salt thereof.

[0455] In a particular embodiment of [5], the compound of formula (I-b1-a) has the formula (I-b1-a1): TIFF0007640458000251.tif43128, or a pharmaceutically acceptable salt thereof.

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

[0457] In a particular embodiment of [5], the compound of formula (I-b1-a) has the formula (I-b1-a3): TIFF0007640458000252.tif51128, or a pharmaceutically acceptable salt thereof; In the formula, R d' is H or R d (e.g., H or C 1~3 alkyl).

[0458] In a particular embodiment of [5], the compound of formula (I-b1-a) has the formula (I-b1-a2): TIFF0007640458000253.tif52128 (e.g., L 4 is NHS(O)2) or a pharmaceutically acceptable salt thereof.

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

[0460] In some of the above embodiments of [5] (e.g., when the compound has formula (I-b1-a2)), L 4 is as defined in any one of claims 48-55 (e.g., 49) of US 62 / 742,218, filed October 5, 2018; and / or R 4claims 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 68-71 of US 62 / 742,218 filed on October 5, 2018 No. 62 / 742,218 filed on October 5, 2018; claims 56-60 of US 62 / 742,218 filed on October 5, 2018; 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 combinations[6] In some embodiments, the compound of Formula (I) has the formula (I-c1-a): TIFF0007640458000254.tif34128, or a pharmaceutically acceptable salt thereof.

[0462] In a particular embodiment of [6], the compound of formula (I-c1-a) has the formula (I-c1-a1): TIFF0007640458000255.tif43128, or a pharmaceutically acceptable salt thereof.

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

[0464] In a particular embodiment of [6], the compound of formula (I-c1-a) has the formula (I-c1-a2): TIFF0007640458000256.tif50128 (e.g., L 4 is NHS(O)2) 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 48-55 (e.g., 49) of US 62 / 742,218, filed October 5, 2018; and / or R 4 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 68-71 of US 62 / 742,218 filed on October 5, 2018 No. 62 / 742,218 filed on October 5, 2018; claims 56-60 of US 62 / 742,218 filed on October 5, 2018; 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.

[0466] Non-limiting combinations[7] In some embodiments, the compound of Formula (I) has the formula (I-d1-a): TIFF0007640458000257.tif34128, or a pharmaceutically acceptable salt thereof.

[0467] In a particular embodiment of [7], the compound of formula (I-d1-a) has the formula (I-d1-a1): TIFF0007640458000258.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 October 5, 2018; and / or R 2 is as defined in any one of claims 24 to 37 of US 62 / 742,218, filed October 5, 2018; and / or R 4 is as defined in any one of claims 56 to 92 of US 62 / 742,218 filed October 5, 2018.

[0469] In a particular embodiment of [7], the compound of formula (I-d1-a) has the formula (I-d1-a2): TIFF0007640458000259.tif50128 (e.g., L 4 is NHS(O)2) or a pharmaceutically acceptable salt thereof.

[0470] In some of the above embodiments of [7] (e.g., when the compound has formula (I-c1-a2)), L 4 is as defined in any one of claims 48-55 (e.g., 49) of US 62 / 742,218, filed October 5, 2018; and / or R 4claims 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 68-71 of US 62 / 742,218 filed on October 5, 2018 No. 62 / 742,218 filed on October 5, 2018; claims 56-60 of US 62 / 742,218 filed on October 5, 2018; 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.

[0471] 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 4 is selected from the group consisting of: (i) 1 to 6 independently selected R a C optionally 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.

[0472] 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 4 Ha-(Y 3 ) p -Y 4 is.

[0473] 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 4 -(Y 3 ) p -Y 4 If Y 4 is 1 to 4 R c C optionally 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; R c If present, is as defined in any one of claims 73 to 75 (eg claim 75).

[0474] 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 4 -(Y 3 ) p -Y 4 If Y 4 is 1 to 4 R c C optionally substituted with 6~10 Aryl, e.g., 1 to 4 R c phenyl optionally substituted with R c Each occurrence of, 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 of any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3], [3], [4], [5], [6], and [7], R4 -(Y 3 ) p -Y 4 If 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.

[0476] 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 4 -(Y 3 ) p -Y 4 If Y 4 is as defined in any one of claims 77 to 79; R b When present, is as defined in claim 80.

[0477] 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 4 -(Y 3 ) p -Y 4 If Y 4 is as defined in any one of claims 83 to 85 and 88; R c If present, is as defined in any one of claims 86-87.

[0478] 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 4 -(Y 3 ) p -Y 4 If Y 4 is as defined in any one of claims 83 to 85 and 88.

[0479] 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 4 -(Y 3 ) p -Y 4 If Y 4 is as defined in any one of claims 89 to 96; R b is as defined in any one of claims 97-98, if present.

[0480] 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 4 -(Y 3 ) p -Y 4 If Y 4 is as defined in any one of claims 89 to 92, 94 and 96; R b When present, is as defined in claim 98.

[0481] 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 4 -(Y 3 ) p -Y 4 If , then p is 0.

[0482] In other embodiments, p is 1. In some of these embodiments, Y 3 is C 1~3 Alkylene, for example CH2 or CH2-CH2.

[0483] 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 4 is selected from the group consisting of the structures described in claims 99 to 113.

[0484] 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], each R 4 is selected from the group consisting of the structures set forth in claims 100, 101, 104-105, 107, 109, 111, and 113.

[0485] 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 optionally substituted with 1~10 is alkyl; or ·R 4 is 1 to 6 independently selected R a C optionally substituted with 1~6 is alkyl; or ·R 4 is one to two independently selected R a C optionally substituted with 1~6 alkyl, e.g., R 4 is methyl, ethyl, TIFF0007640458000260.tif14128 (e.g., methyl and TIFF0007640458000261.tif12128); or ·R 4 is 1 to 6 (e.g., 1 to 3) independently selected R a C optionally substituted with 2~10 Alkynyl (e.g., C 2~4 alkynyl) (e.g. Unsubstituted C, such as TIFF0007640458000262.tif8128 2~4 alkynyl); or ·R 4 is 1 to 6 (e.g., 1 to 3) independently selected R aC optionally 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 optionally substituted with 1~10 is alkyl; or ·R 4 is 1 to 6 independently selected R a C optionally substituted with 1~6 is alkyl; or ·R 4 is one to two independently selected R a C optionally substituted with 1~6 Alkyl, such as methyl and TIFF0007640458000263.tif12128; Here, each R a When present, independently, such as -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 Ha-(Y 1 ) n -Y 2 is.

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

[0489] 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 -(Y 1 ) n -Y 2 If Y 2 is as defined in any one of claims 14 to 18 and 26; and each R c If present, is as defined in any one of claims 21 to 23.

[0490] 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 -(Y 1 ) n -Y 2 If Y 2 is as defined in any one of claims 16 to 18; and each R c If present, is as defined in any one of claims 21 to 23.

[0491] 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 -(Y 1 ) n -Y 2 If n is 0, then

[0492] 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 -(Y 1 ) n -Y 2 If R 1 teeth TIFF0007640458000264.tif15128. As a non-limiting example, R 1 teeth It could also be TIFF0007640458000265.tif13128.

[0493] 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 2 is 1 to 4 R c C optionally substituted with 6~10 Aryl, e.g., 1 to 4 R c Or 1-2 R c or two R's c phenyl optionally substituted with R c is, if present, as defined in any one of claims 33 to 35.

[0494] 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 2 is two R c phenyl, which may be substituted with, for example, R 2 teeth TIFF0007640458000266.tif17128; R c is, if present, as defined in any one of claims 33 to 35.

[0495] 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 2 is a 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), 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 pyridinyl optionally substituted with, for example, R 2 teeth TIFF0007640458000267.tif17128; R c If present, is as defined in any one of claims 40-41.

[0496] 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 2 teeth TIFF0007640458000268.tif17128.

[0497] 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 Ha-(Y 1 ) n -Y 2 and;R 2 is 1 to 4 R c C optionally substituted with 6~10 It is aryl.

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

[0499] 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 -(Y 1 ) n -Y 2 If 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 selected from 1 to 4 independently selected R c is heteroaryl, optionally substituted with

[0500] 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 -(Y 1 ) n -Y 2 If Y 2 is a group in which one or more of the ring carbon atoms are bonded to 1 to 4 (e.g., 1) independently selected R c and optionally substituted pyridyl (for example, 2-pyridyl or 6-pyridyl).

[0501] 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 -(Y 1 ) n -Y 2 Y 2 is 1 to 4 independently selected R c When R is heteroaryl, such as pyridyl, which may be substituted with c Each occurrence of is independently selected C 1~4 Alkoxy (e.g., -OCH3, -OCH2CH3).

[0502] As a non-limiting example, R 1 teeth The file is TIFF0007640458000269.tif13128.

[0503] 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 -(Y 1 ) n -Y 2 ), R 2 is 1 to 4 R c C optionally substituted with 6~10 aryl, e.g., R 2 is 1 to 4 R c and phenyl optionally substituted with .

[0504] In some of these embodiments, R 2 is two R c For example, R 2 teeth It could also be TIFF0007640458000270.tif15128.

[0505] 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 teeth TIFF0007640458000271.tif13128; R 2 teeth The file is TIFF0007640458000272.tif16128.

[0506] This specification concludes with 302 claims. For ease of explanation, certain variable provisions will refer to one or more specific claim numbers, and accordingly, the entire subject matter of each referenced claim will be understood to be incorporated by reference in its entirety into the portion of this disclosure to which it refers. For the avoidance of doubt, and as a non-limiting example, "Y4 The use of phrases such as "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 definitions. Y 4 is 1 to 4 R b C optionally substituted with 3~6 (For example, C 3~4 or C6) cycloalkyl. Y 4 is 1 to 2 R b and cyclopropyl or cyclobutyl optionally substituted by Y 4 is 1 to 2 R b and C6 cycloalkyl (e.g., cyclohexyl) optionally substituted with. Y 4 is a non-substituted C 3~6 (For example, C 3~4 or C6) cycloalkyl. Y 4 is unsubstituted cyclopropyl or unsubstituted cyclobutyl (e.g., unsubstituted cyclopropyl). Y 4 is 1 to 4 R b C optionally substituted with 3~6 (For example, C 3~4 or C6) cycloalkyl; 1 to 2 R b cyclopropyl or cyclobutyl optionally substituted with one or two R b C cycloalkyl (e.g., cyclohexyl) optionally substituted with; unsubstituted C 3~6 (For example, C 3~4 or C6) cycloalkyl; and unsubstituted cyclopropyl or unsubstituted cyclobutyl (e.g., unsubstituted cyclopropyl).

[0507] This also applies to claims referenced from priority document US 62 / 742,218, filed October 5, 2018.

[0508] Pharmaceutical Compositions and Administration general In some embodiments, a chemical entity (e.g., a compound, or a pharmaceutically acceptable salt and / or hydrate and / or prodrug of the compound) that modulates (e.g., 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, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, surfactants used in pharmaceutical dosage forms, such as self-emulsifying drug delivery systems (SEDDS) (e.g., d-α-tocopherol polyethylene glycol 1000 succinate), Tween, poloxamer, or other similar polymer delivery matrices, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphate, Tris), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, protamine sulfate, salts or electrolytes (e.g., disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block copolymers, and wool fat. Additionally, chemically modified derivatives, such as cyclodextrins, including α-, β-, and γ-cyclodextrin, or hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrin, or other solubilizing derivatives, can be used to enhance delivery of the compounds described herein. Dosage forms or compositions can be prepared containing 0.005% to 100% of the chemical entities described herein, with the remainder consisting of non-toxic excipients. Contemplated compositions may contain 0.001% to 100%, in one embodiment 0.1 to 95%, in another embodiment 75 to 85%, and in a further embodiment 20 to 80%, of the chemical entities provided herein. Actual methods for preparing these dosage forms are known or will be apparent to those skilled in the art. See, for example, Remington: The Science and Practice of Pharmacy, 22 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, can be administered to a subject in need thereof by any acceptable route of administration, including buccal, cutaneous, intracervical, intrasinusial, intratracheal, intraintestinal, epidural, intrainterstitial, intraperitoneal, intra-arterial, intrabronchial, intravesical, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intraantral, intravenous ... asinal, intraspinal, intrasynovial, intratesticular, intrathecal, intraductal, 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] Composition can be formulated for parenteral administration, for example, can be formulated for injection by intravenous, intramuscular, subcutaneous or even intraperitoneal route.Usually, these compositions can be prepared as injections as solution or suspension, and can also be prepared as solid forms suitable for preparing solution or suspension by adding liquid before injection, or preparation can be emulsified.In light of the present disclosure, the preparation method of these preparations will be clear to those skilled in the art.

[0512] The pharmaceutical forms suitable for injection include sterile aqueous solution or aqueous dispersion; formulations containing sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solution or dispersion.Generally, the form must be sterile and fluid enough to be easily syringable.In addition, the form must 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] The carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerin, propylene glycol, and liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. Prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it is preferable to include an isotonic agent, for example, sugar or sodium chloride. Prolonged absorption of injectable compositions can be brought about by the use in the composition of absorption delaying agents, for example, aluminum monostearate and gelatin.

[0514] Sterile injectable solution is prepared by incorporating required amount of active compound into suitable solvent with various other components as listed above as necessary, then sterilizing by filtration.Generally, dispersion is prepared by incorporating various sterilized active ingredients into the sterile medium that contains basic dispersion medium and other components that are required among the components listed above.For the sterile powder that is used to prepare sterile injectable solution, the preferred preparation method is vacuum drying and freeze-drying technology, which makes the powder of active ingredient and any other desired components from the solution that has already been sterilized and filtered.

[0515] Pharmaceutically 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 (as in PEG ointment), glycerin, glycerinated gelatin, hydrogenated vegetable oils, poloxamer, mixtures of polyethylene glycols of various molecular weights and polyethylene glycol fatty acid esters, petrolatum, anhydrous lanolin, shark liver oil, sodium saccharinate, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxide. SBN, vanilla essential oil, aerosol, parabens in phenoxyethanol, sodium methyl p-hydroxybenzoate, sodium propyl p-hydroxybenzoate, diethylamine, carbomer, Carbopol, methyl hydroxybenzoate, macrogol cetostearyl ether, cocoyl caprylocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metabisulfite, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methylsulfonylmethane (MSM), lactic acid, glycine, vitamins such as vitamins A and E, and potassium acetate.

[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 a suppository wax, which is solid at ambient temperature but liquid at body temperature and will therefore melt in the rectum to release the active compound. In other embodiments, the composition for rectal administration is in the form of an enema.

[0517] In other embodiments, the compounds described herein, or pharmaceutical compositions thereof, are suitable for local delivery to the digestive or gastrointestinal tract by oral administration (eg, in solid or liquid dosage form).

[0518] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the chemical entity is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and gum arabic; c) humectants, such as glycerin; d) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarding agents, such as paraffin; f) absorption accelerators, such as quaternary ammonium compounds; g) humectants, such as, for example, 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 glycols, sodium lauryl sulfate, and combinations thereof. In the case of capsules, tablets, and pills, the dosage forms may also contain buffering agents.Solid compositions of a similar type may also be employed as fillers in soft- and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0519] In one embodiment, the composition is in the form of a unit dosage form such as a pill or tablet, and thus the composition may contain, together with the chemical entities provided herein, diluents such as lactose, sucrose, dicalcium phosphate, etc.; lubricants such as magnesium stearate; and binders such as starch, gum arabic, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives, etc. In another solid dosage form, a powder, marume, solution, or suspension (e.g., in propylene carbonate, vegetable oil, PEG, poloxamer 124, or triglycerides) is encapsulated in a capsule (gelatin or cellulose-based capsule). Unit dosage forms in which one or more chemical entities provided herein or additional active agents are physically separated are also contemplated, such as capsules with granules (or tablets within capsules) of each drug; two-layer tablets; two-compartment gel capsules, etc. Enteric-coated oral dosage forms or delayed-release oral dosage forms are also contemplated.

[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 and include, for example, phenol and ascorbic acid.

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

[0522] The ophthalmic composition may include, but is not limited to, any one or more of the following: viscogens (e.g., carboxymethylcellulose, glycerin, polyvinylpyrrolidone, polyethylene glycol); stabilizers (e.g., Pluronic (triblock copolymer), cyclodextrin); preservatives (e.g., benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloro complex; Allergan, Inc.)).

[0523] Topical compositions can include ointments and creams. Ointments are semi-solid preparations typically based on petrolatum or other petroleum derivatives. Creams, typically containing the selected active agent, are often liquid or semi-solid emulsions, often oil-in-water or water-in-oil. Cream bases are typically water-washable and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase, sometimes referred to as the "internal" phase, is typically composed of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol, while the aqueous phase usually, but not necessarily, exceeds the oil phase in volume and typically contains a humectant. Generally, emulsifiers in cream formulations are nonionic, anionic, cationic, or amphoteric surfactants. Like other carriers or vehicles, ointment bases should be inert, stable, non-irritating, and non-sensitizing.

[0524] In any of the above embodiments, the pharmaceutical compositions described herein can include one or more of the following: lipids, interbilayer 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 Dosage can vary depending on the patient's requirement, the severity of the condition to be treated and the specific compound used.The appropriate dosage for specific circumstances can be determined by those skilled in the medical field.In some cases, the total daily dose can be divided and administered in several doses throughout the day, or administered by means of continuous delivery.

[0526] In some embodiments, the compounds described herein are administered at a dose of from about 0.001 mg / Kg to about 500 mg / Kg (e.g., from about 0.001 mg / Kg to about 200 mg / Kg; from about 0.01 mg / Kg to about 200 mg / Kg; from about 0.01 mg / Kg to about 150 mg / Kg; from about 0.01 mg / Kg to about 100 mg / Kg; from about 0.01 mg / Kg to about 50 mg / Kg; from about 0.01 mg / Kg to about 10 mg / Kg; from about 0.01 mg / Kg to about 5 mg / Kg; from about 0.01 mg / Kg to about 1 mg / Kg; from about 0.01 mg / Kg to about 0.5 mg / Kg; from about 0.01 mg / Kg to about 0.1 mg / Kg; from about 0.1 mg / Kg to about 200 mg / Kg; It is administered at a dosage of 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 one or more divided doses), or non-daily (e.g., every other day, every two days, every three days, weekly, twice every few weeks, biweekly, monthly).

[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 further embodiments, the period of time during which administration is suspended 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, a therapeutic compound is administered to an individual for one period, followed by another period. In another embodiment, a therapeutic compound is administered for a first period and a second period following the first period, administration is suspended during the second period, followed by administration of the therapeutic compound for a third period, after which administration is suspended for a fourth period following the third period. In one aspect of this embodiment, a period of administration of a therapeutic compound followed by a period of withdrawal is repeated for a predetermined or indefinite period. In a further embodiment, the administration period is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In further embodiments, the period of time for 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 decreased 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 pathology and / or symptoms and / or progression of the disease, disorder, or condition. In certain embodiments, the methods described herein can include, or can further include, treating one or more conditions that are concomitant, comorbid, or sequelae of any one or more of the conditions described herein.

[0530] In some embodiments, the method further includes identifying the subject. In some embodiments, identifying includes determining levels 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, 6-minute walk distance, brain natriuretic peptide level, atrial natriuretic peptide, and pulmonary 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 reduce the risk of right ventricular failure.

[0532] In certain aspects, the chemical entities described herein regulate vascular tone, regulate fluid homeostasis, regulate renal function, regulate energy metabolism, regulate the inflammatory response, and regulate 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-induced or toxic PAH, and PAH associated with conditions including, but not limited to, connective tissue diseases (CTDs) (e.g., scleroderma, systemic lupus erythematosus, systemic sclerosis, Hashimoto's thyroiditis, Sjogren's syndrome, and antiphospholipid 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, toxic or drug-induced PAH, or PAH 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 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 the condition include, but are not limited to, pulmonary hypertension due to left heart disease (e.g., left ventricular systolic dysfunction, left ventricular diastolic dysfunction, valvular heart disease, and congenital / acquired left ventricular inflow / outflow tract obstruction and congenital cardiomyopathy), pulmonary hypertension due to lung disease and / or hypoxia (e.g., chronic obstructive pulmonary disease, interstitial lung disease, other lung diseases with mixed restrictive and obstructive patterns, sleep-disordered breathing, alveolar hypoventilation disorder, chronic exposure to high altitude, developmental lung disease), chronic thromboembolic pulmonary hypertension and other pulmonary obstructive diseases (e.g., chronic thromboembolic pulmonary hypertension, other pulmonary obstructive diseases), and pulmonary hypertension due to unknown multifactorial mechanisms (e.g., blood disorders, systemic disorders, metabolic disorders, etc.).

[0537] cardiovascular conditions, cardiovascular disease, or cardiovascular disorders 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 cardiac 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, pre-eclampsia, ventricular tachycardia, and cardiac fibrosis.

[0538] In some embodiments, the cardiovascular condition, disease, or disorder is heart failure, non-limiting examples of which 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 that involves vascular pathology (e.g., increased vascular permeability and vascular dysfunction).Non-limiting examples of such conditions, diseases, or disorders include vascular hypertrophy, vascular remodeling (e.g., vascular sclerosis), atherosclerosis, peripheral arterial occlusive disease (PAOD), restenosis (e.g., angioplastic restenosis), thrombosis, and vascular permeability disorders, and ischemia and / or reperfusion injury (e.g., ischemia and / or reperfusion injury of the heart, kidney, and retina).In some embodiments, the condition, disease, or disorder is venous-related.Non-limiting examples of such conditions, diseases, or disorders include hemangioma, venous insufficiency, congestion, or thrombosis.

[0540] In some embodiments, the chemical entities described herein can improve cardiac contractility (e.g., diastolic function), ventricular-arterial 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 dysfunction and associated conditions, diseases, or disorders In some embodiments, the condition, disease, or disorder is associated with metabolic dysfunction, including, but not limited to, 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., macroangiopathy and microangiopathy, diabetic neuropathy, diabetic retinopathy, cardiac autonomic neuropathy), renal disease (e.g., chronic kidney disease), edema, dyslipidemia, anorexia, bulimia, polyphagia, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, growth hormone disorders (e.g., gigantism, acromegaly), galactorrhea, and cardiac wasting.

[0542] In some embodiments, the condition, disease, or disorder is associated with the syndrome of inappropriate vasopressin secretion (SIADH), non-limiting examples of which include neurogenic diabetes (e.g., diabetic complications such as diabetic nephropathy, diabetic neuropathy, and diabetic retinopathy), lung cancer, septic shock, and dry mouth problems.

[0543] In some embodiments, the condition, disease, or disorder is associated with systemic inflammation. Non-limiting examples of such conditions, diseases, or disorders include systemic inflammatory response syndromes (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 sepsis-associated conditions, diseases, or disorders include septic myocardial dysfunction, sepsis-associated inflammatory responses (e.g., systemic inflammation), sepsis-associated hemodynamic changes, hypovolemia, sepsis-associated organ failure (e.g., multiple organ failure, renal failure), acute kidney injury, vasoplegia, lung injury, syndrome of inappropriate vasopressin secretion, persistent hypertension associated with systemic vasodilation, refractory muscle contractile responsiveness, giant plasma cell capillary leak syndrome, coagulation / fibrinolysis imbalance, and metabolic disorders characterized by elevated bloodstream 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 impaired fluid homeostasis due to CNS-dependent and -independent effects, non-limiting examples of which include renal failure (e.g., acute and chronic renal failure), renal perfusion, renal dysfunction (e.g., polycystic kidney disease), aquaresis, and polyuria.

[0546] Dementia and related conditions, diseases, or disorders In some embodiments, the condition, disease, or disorder is dementia, non-limiting examples of which include senile dementia, vascular dementia, dementia due to system degeneration, dementia due to degenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, Pick's disease, Huntington's disease, etc.), dementia due to infectious diseases (e.g., slow-onset viral infections such as Creutzfeldt-Jakob disease), dementia associated with endocrine diseases, metabolic diseases, or toxicities (e.g., hypothyroidism, vitamin B12 deficiency, alcoholism, toxicities caused by various drugs, metals, or organic compounds), dementia caused by tumors (e.g., brain tumors), and dementia due to traumatic diseases (e.g., chronic subdural hematoma), depression, hyperactive child syndrome (microencephaly), disorders of consciousness, anxiety disorders, schizophrenia, and phobias.

[0547] connective tissue disorders In some embodiments, the condition, disease, or disorder is a connective tissue disorder. In particular 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 syndrome. In particular 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 lung, liver, heart, mediastinum, bone marrow, retroperitoneum, skin, intestine, joint, reproductive organs, and combinations thereof. In certain embodiments, the fibrosis is idiopathic pulmonary fibrosis (IPF). In certain embodiments, the fibrosis is hepatic 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 liver disease, non-limiting examples of which 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 retinopathy (for example, 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), brain trauma, pancreatitis, Turner syndrome, neuropathy, rheumatoid arthritis, spinal cord injury, immune function, inflammation, spinocerebellar degeneration, fractures, wounds, atopic dermatitis, osteoporosis, asthma, epilepsy, and infertility.

[0552] Activating stem cells The chemical entities described herein can also 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 can be used to regrow tissue, assist in functional recovery after transplantation of cells (e.g., cells with bone marrow-derived mesenchymal stem cells), enhance cardiac stem cell proliferation (e.g., in patients who have suffered a myocardial infarction), reduce infarct size, promote cardiac repair, activate stem and progenitor cells in subjects after a myocardial infarction, or reduce reperfusion injury (e.g., during surgery, such as cardiac bypass surgery or heart transplant surgery).

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

[0554] In some embodiments, the methods described herein may further include administering one or more additional therapies (e.g., one or more additional therapeutic agents and / or one or more therapeutic 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] Exemplary 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, arrhythmias, asthma, atherosclerosis, atrial fibrillation, Brugada syndrome, burns (e.g., sunburn), cancer, cardiac fibrosis, cardiomyopathy, cerebrovascular accidents, 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, pre-eclampsia, restenosis, transient ischemic attack, cerebral trauma, ventricular tachycardia, edema, or immune function.

[0557] In some embodiments, the one or more additional therapeutic agents include, for example, therapeutic agents useful as PAH treatments. Non-limiting examples include: Prostacyclin analogues (e.g. epoprostenol, treprostinil, iloprost); · Prostacyclin IP receptor (e.g., selexipag); · Endothelin receptor antagonists (e.g. bosentan, ambrisentan, macitentan); PDE 5 inhibitors (e.g. sildenafil, tadalafil); Soluble guanylate cyclase stimulators (e.g., riociguat); · Mitochondrial dysfunction treatments (e.g., bardoxolone methyl); Anti-inflammatory drugs (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 therapeutic agents useful, for example, as therapeutic agents for heart failure or hypertension. Non-limiting examples include: 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 dihydropyridines (DHPs) (e.g., amlodipine, felodipine, isradipine, lacidipine, nicardipine, nifedipine, nigulpidine, nilutipine, nimodiphine, nisoldipine, nitrendipine, nivaldipine, ryosidine) and non-DHPs (e.g., anipamil, diltiazem, fendiline, flunarizine, gallpamil, mibefradil, prenylamine, tiapamil, verapamil); Diuretics (e.g., thiazide derivatives such as, but not limited to, amiloride, chlorothalidon, chlorothiazide, hydrochlorothiazide, and methylchlorothiazide) Central hypertensive drugs (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., 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, sitaxsentan, tezosentan); Paradoxical current inhibitors (e.g. ivabradine); Myosin activators (e.g. cardiac myosin activators); · Natriuretics; · Salt diuretics; Vasodilators / vasorelaxants (e.g., nitrates) Mineralocorticoid receptor antagonists; Renin inhibitors; Digitalis compounds; ·Inotropics and beta-receptor agonists; Antihyperlipidemic agents, ·Plasma HDL raising agents; Antihypercholesterolemic 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 B6, vitamin B 12 , antioxidant vitamins); Platelet aggregation inhibitors; Fibrinogen receptor antagonists; Aspirin; and Fibric acid derivatives.

[0559] In some embodiments, the one or more additional therapeutic agents include, for example, a therapeutic agent useful for treating diabetes. Non-limiting examples include: sulfonylureas (e.g. chlorpropamide, tolbutamide, acetohexamide, tolazamide, glyburide, gliclazide, glinase, glimepiride, glipizide); 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 (also known as DHEA or its conjugated sulfate ester DHEA-SO4); Antiglucocorticoids; TNF-α inhibitors, Dipeptidyl peptidase IV (DPP4) inhibitors (e.g., sitagliptin, saxagliptin); GLP-1 agonists or analogues (e.g. exenatide); · α-glucosidase inhibitors (e.g., acarbose, miglitol, and voglibose); Pramlintide (a synthetic analogue of the human hormone amylin); Other insulin secretagogues (e.g., repaglinide, gliquidone, and nateglinide); and Insulin.

[0560] In some embodiments, the one or more additional therapeutic agents comprise a therapeutic agent useful for treating obesity, for example, non-limiting examples include phenylpropanolamine, phentermine, diethylpropion, mazindol, fenfluramine, dexfenfluramine, pheniramine, β3-adrenergic receptor agonists, sibutramine, gastrointestinal lipase inhibitors (e.g., orlistat), leptin, neuropeptide Y, enterostatin, cholecystokinin, bombesin, amylin, histamine H3 receptor, dopamine D2 receptor modulators, melanocyte-stimulating hormone, corticotropin-releasing factor, galanin, and gamma-aminobutyric acid (GABA).

[0561] Other additional therapeutic agents include: Antiatherosclerotic agents; ·Anti-dyslipidemic agents; ·Antihyperinsulinemia agents; ·Antithrombotic agents; Antiretinopathy drugs; ·Antineuropathic agents; Antinephrotic drugs; Anti-ischemic agents; Antihyperlipidemic agents, Antihypertriglyceridemic agents; Antihypercholesterolemic agents; Antirestenotic agents; ·Antipancreatic agents; · Appetite suppressants; ·Memory enhancers; · Nootropics; · Cognitive enhancers; · Appetite suppressants; Agents for treating peripheral arterial disease; Agents for treating malignant tumors; Anti-inflammatory agents; Aquaretics; Digoxin; · Nitric oxide donors; Hydralazine; ·Inotropic agents; · Vasopressin receptor antagonists; Statins; Antiarrhythmic drugs; Phosphodiesterase inhibitors (e.g., PDE5 inhibitors); and Renal protector.

[0562] Non-limiting examples of additional therapeutic agents may include those described in US9156796B2, which is incorporated herein by reference.

[0563] In certain embodiments, the second therapeutic agent or treatment regimen is administered to the subject prior to contacting with or administering the chemical entity (e.g., 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).

[0564] In other embodiments, the second therapeutic agent or therapeutic regimen is administered to the subject at approximately the same time as the chemical entity is contacted or administered.For example, the second therapeutic agent or therapeutic regimen and the chemical entity are administered to the subject at the same time in the same dosage form.In another example, the second therapeutic agent or therapeutic regimen and the chemical entity are administered to the subject at the same time in separate dosage forms.

[0565] In still other embodiments, a second therapeutic agent or treatment regimen is administered to the subject after contacting with or administering the chemical entity (e.g., 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 those skilled in the art will recognize, methods for synthesizing compounds of the formulae herein will be readily 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 R.G.M. 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), and subsequent editions thereof.

[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 1-4 show, for illustrative purposes, general methods for preparing the compounds and intermediates provided herein. See the Synthetic Examples section below for a more detailed description of the individual reaction steps. Those skilled in the art will recognize that other synthetic routes can be used to synthesize the compounds of the present invention. While specific starting materials and reagents are shown in the schemes and described below, other starting materials and reagents can be readily substituted 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 this disclosure using conventional chemistry well known to those skilled in the art.

[0569] Scheme 1 TIFF0007640458000273.tif62150 Referring to Scheme 1, compounds of formula (I) (designated as I-6 and I-7) are reacted with R 1 and R 2 The amide I-3 (where X is halo, e.g., bromo or chloro) can be prepared from compounds I-1, I-2, and I-4, where X is as defined herein. Aminopyrazine I-1 can be reacted 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) to provide amide I-3. Next, the S reaction between I-3 and amine I-4 is carried out. N Reaction under Ar or metal-catalyzed cross-coupling conditions (e.g., Buchwald-Hartwig coupling using Xantphos and Pd(OAc)) can provide compound I-5. Condensation of the carbonyl moiety in I-5 with an amino group can provide compound I-6 of formula (I).

[0570] Alternatively, I-3 can be obtained through coupling between I-1 and an ester of I-2 (eg, an alkyl ester, such as a methyl or ethyl ester) under appropriate conditions (eg, in the presence of AlMe3).

[0571] In some cases, the X part in I-6 can be replaced with other R 3The conversion of I-6 to the aryl group can provide I-7, another compound of formula (I). As a non-limiting example of the conversion between I-6 and I-7, I-6 can be reacted with a sulfonamide under Ullmann coupling conditions to provide compound I-8 (see Scheme 1 above).

[0572] The following starting materials can be used in place of I-1 and subjected to the sequence shown in Scheme 1: TIFF0007640458000274.tif14128

[0573] Scheme 2 TIFF0007640458000275.tif92151 Regarding Scheme 2, the compounds of formula (I) in Scheme 2 (shown as compounds II-7 to II-9) are reacted with R 1 Compound II-1, in which X is as defined elsewhere herein and X is a halo (e.g., Br) or pseudohalo (e.g., OTf) group, can be prepared from compound II-1. II-1 can be subjected to a Sonogashira coupling or equivalent reaction with a protected acetylene (e.g., TMS-acetylene) to give compound II-2. Subsequent removal of the alkyne protecting group can give II-3, which can be coupled with pyrazine derivative II-4 to give compound II-5. Compound II-6 can be obtained by cyclization of the amino group in II-5 to an alkynyl moiety, which can then be reacted with R 2 is as defined elsewhere herein; 2 Cross-coupling of -B(OH) with a boronic acid or its boronic ester (e.g., under Chan-Lam coupling conditions) can provide compound II-7, a compound of formula (I). Compound II-7 can be further functionalized to provide compound II-8, also a compound of formula (I).

[0574] A non-limiting example of the conversion of II-7 to II-8 is the reaction of II-7 with R 4 is as defined elsewhere herein, 4(eg, under Ullmann coupling conditions) to give compound II-9, a non-limiting example of compound II-8.

[0575] Scheme 3 TIFF0007640458000276.tif72151 With reference to Scheme 3, compounds of formula (I) (shown as compounds III-5 to III-7 in Scheme 3) are reacted with R 1 can be prepared from compound III-1, where R is as defined elsewhere herein. Coupling between III-1 and III-2 (e.g., in the presence of a Lewis acid such as AlMe) can provide compound III-3, which can be prepared by reacting R 2 is as defined elsewhere herein; 2 Cross-coupling with a compound of NH2 can give compound III-4. Cyclization of the amino group in III-4 to an amide moiety (e.g., with heat and in the presence of P(O)Cl3) can give compound III-5, a compound of formula (I). Functionalization of III-5 can give compound III-6, also of formula (I).

[0576] A non-limiting example of the conversion of III-5 to III-6 is the reaction of II-5 with R 4 is as defined elsewhere herein, 4 (eg, under Ullmann coupling conditions) to give compound III-7, a non-limiting example of compound III-6.

[0577] Scheme 4 With reference to Scheme 4, compounds of formula (I) (shown as compounds IV-6 to IV-8 in Scheme 4) can be prepared from pyridazine derivative IV-1. IV-1 can be treated sequentially with ammonium hydroxide and bromine to give IV-3, which can then be reacted with R 1 CO2H (in the formula, R 1is as defined elsewhere herein) to give IV-4. 2 R is as defined elsewhere herein 2 Coupling with NH (e.g., under Buchwald-Hartwig coupling conditions) can provide IV-5, which can be cyclized (e.g., under heat and / or microwave irradiation) to provide IV-6, a compound of formula (I). Compound IV-6 can be functionalized to provide IV-7, also a compound of formula (I).

[0578] A non-limiting example of the conversion of IV-6 to IV-7 is the reaction of IV-6 with R 4 is as defined elsewhere herein, 4 (eg, under Ullmann coupling conditions) to give compound IV-8, a non-limiting example of compound IV-7.

[0579] Scheme 5 TIFF0007640458000278.tif62150 Referring to Scheme 5, compounds of formula (I) (designated as V-6 and V-7) are reacted with R 1 and R 2 The aminopyrazine V-1 can be prepared from compounds V-1, V-2, and V-4, where V is as defined herein. Aminopyrazine V-1 can be reacted with carboxylic acid V-2 under standard conditions to give amide V-3, where X is halo, e.g., bromo or chloro. S reaction between V-3 and amine V-4 can then be carried out. N Reaction under Ar or metal-catalyzed cross-coupling conditions (e.g., Buchwald-Hartwig coupling using Xantphos and Pd(OAc)) can provide compound V-5. Condensation of the carbonyl moiety in V-5 with an amino group can provide compound V-6 of formula (I).

[0580] Alternatively, V-3 can be obtained through coupling between V-1 and an ester of V-2 (eg, an alkyl ester, such as a methyl or ethyl ester) under appropriate conditions (eg, in the presence of AlMe3).

[0581] In some cases, the X part in V-6 can be replaced with other R 3 group to afford I-7, another compound of formula (I). As a non-limiting example of the conversion between V-6 and V-7, V-6 can be reacted with a sulfonamide under Ullmann coupling conditions to afford compound V-8 (see Scheme 5 above).

[0582] General Procedure Moisture- or air-sensitive reactions were carried out under nitrogen or argon using anhydrous solvents and reagents. Reaction progress was monitored by analytical thin-layer chromatography (TLC), routinely performed using Sanpont precoated TLC plates, silica gel GF-254, 0.25 mm layer thickness, or by liquid chromatography-mass spectrometry (LC-MS).

[0583] The analytical LC-MS system used typically consisted 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 typically an Agilent Poroshell C18, 3.0 x 50 mm, 2.7 μm column. The flow rate was 0.6 mL / min, and the injection volume was 5 μL. UV detection was in the 190-400 nm range. The mobile phase consisted of solvent A (water + 0.1% TFA) and solvent B (acetonitrile + 0.05% TFA), with a gradient of 90% solvent A over 1.7 min, changing to 95% solvent B over 1.8 min, and then back to 90% solvent A over 0.1 min and holding for 1.4 min.

[0584] Preparative HPLC purification was typically performed on a Waters 2555-2767 system equipped with a 2489 UV detector. The column was a 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 UV detector channels were used: 254 nm and 280 nm. The mobile phase gradient was optimized for each compound.

[0585] Reactions carried out using microwave irradiation were typically carried out using a Biotage Initiator. Solutions were concentrated under reduced pressure on a rotary evaporator. Flash chromatography was typically carried out using a Biotage flash chromatography system (Dyax Corp.) on silica gel (40-63 mm, 60 Å pore size) in pre-packed cartridges of the size indicated. Unless otherwise noted, 1H NMR spectra were acquired on a 400 MHz spectrometer in CDCl3 solution. Chemical shifts are reported in parts per million (ppm). Tetramethylsilane (TMS) was used as the internal standard in CD3Cl solution, and the residual CH3OH peak or TMS was used as the internal standard in CD3OD solution. Coupling constants (J) are reported in hertz (Hz). Chiral analytical chromatography was performed on one of Chiralpak AS, Chiralpak AD, Chiralcel OD, Chiralcel IA, or Chiralcel OJ columns (250 x 4.6 mm) (Daicel Chemical Industries, Ltd.) using the indicated proportions of ethanol in hexane (%Et / Hex) or isopropanol in heptane (%IPA / Hep) as the isocratic solvent system. Chiral preparative chromatography was performed on one of the following columns (20 × 250 mm): Chiralpak AS, Chiralpak AD, Chiralcel OD, Ciralcel IA, or Chiralcel OJ (Daicel Chemical Industries, Ltd.). The desired isocratic solvent system was identified under chiral analytical chromatography or supercritical fluid (SFC) conditions.

[0586] Abbreviation -C(O)CH3(Ac); acetic acid (AcOH); -OC(O)CH3(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 Et2O); petroleum ether (PE); gram (g); time (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); t-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-bromosuccinamide (NBS); thin layer chromatography (TLC). [Example]

[0587] Synthesis Example Below are representative procedures for the preparation of compounds used in the examples below, or compounds that may replace the compounds used in the examples below, which may not be commercially available.

[0588] Method A TIFF0007640458000279.tif87151

[0589] Example 1 6-Bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine TIFF0007640458000280.tif34128 and Example 2 N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide TIFF0007640458000281.tif33128

[0590] Process A 6-Ethoxypicolinic acid ethyl ester To a suspension of 6-hydroxy-pyridine-2-carboxylic acid (25.0 g, 180 mmol, 1 equiv.) and silver(I) carbonate (100 g, 360 mmol, 2 equiv.) in CHCl3 (400 mL) was added ethyl iodide (112.2 g, 720 mmol, 4 equiv.). The mixture was stirred at 30 °C for 1 day. The insoluble material was removed by filtration, and the solid was washed with CHCl3. The filtrate was concentrated under reduced pressure to give the title compound, ethyl 6-ethoxypicolinate, as a light yellow oil, which was used in the next step without further purification. LC-MS: m / z 196.0 (M+H) +

[0591] Process B 6-ethoxypicolinic acid To a solution of ethyl 6-ethoxypicolinate (25 g, 128 mmol, 1 equiv.) in EtOH (30 mL) was added sodium hydroxide solution (1 mol / L, 384 mL, 384 mmol, 3 equiv.). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was neutralized with 1N HCl (aqueous) solution and extracted with ethyl acetate. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure to give the title compound 6-ethoxypicolinic acid. LC-MS: m / z 168.0 (M+H) +

[0592] Process C N-(3,5-dibromopyrazin-2-yl)-6-ethoxypicolinamide To a solution of 6-ethoxypicolinic acid (10 g, 59.9 mmol, 1 equiv.) in DCM (100 mL) was added oxalyl chloride (11.4 g, 89.8 mmol, 1.5 equiv.) and DMF (1 mL) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to give the crude product, 6-ethoxypicolinic acid chloride, as a light yellow solid. A suspension of 3,5-dibromopyrazin-2-amine (14.4 g, 56.9 mmol, 0.95 equiv.) and NaH (6.8 g, 170.7 mmol, 2.85 equiv.) in DMF (100 mL) was stirred at room temperature for 1 hour. Next, a solution of the crude product, 6-ethoxypicolinic acid chloride, in DMF (100 mL) was added dropwise over 30 minutes. After the addition, the mixture was stirred at room temperature overnight. The mixture was quenched with saturated NH4Cl(aq) (100 mL) and extracted with DCM (3*150 mL). The extract was washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was recrystallized in DCM to give compound N-(3,5-dibromopyrazin-2-yl)-6-ethoxypicolinamide. LC-MS: m / z 400.9, 402.9, 404.9 (M+H) +

[0593] Process D N-(5-bromo-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide A suspension of N-(3,5-dibromopyrazin-2-yl)-6-ethoxypicolinamide (1.0 g, 2.5 mmol, 1 equiv.), 2,6-dimethoxyaniline (380 mg, 2.5 mmol, 1 equiv.), Pd(OAc) (112 mg, 0.5 mmol, 0.2 equiv.), Xantphos (576 mg, 1.0 mmol, 0.4 equiv.), and KCO (680 mg, 3.0 mmol, 2 equiv.) in 1,4-dioxane (10 mL) was stirred at 120 °C for 2 h under N2 atmosphere with microwave irradiation. The mixture was diluted with DCM (20 mL) and filtered through Celite. The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography (PE / EtOAc = 4 / 1) to give the title compound N-(5-bromo-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide. LC-MS: m / z 474.0, 476.0 (M+H) +

[0594] Process E 6-Bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine (Example 1) A solution of N-(5-bromo-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide (1.0 g, 2.1 mmol, 1 equiv.) in AcOH (10 mL) was stirred at 120° C. for 2 h by microwave irradiation. The mixture was cooled to room temperature. The precipitate was filtered off and washed with EtOAc / PE = 1 / 2 mixture (3*1 mL) to give the title compound as a white solid. TIFF0007640458000282.tif30153

[0595] Process F N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide (Example 2) A suspension of 6-bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine (150 mg, 0.33 mmol), methanesulfonamide (62 mg, 0.66 mmol, 2 equiv.), CuI (125 mg, 0.66 mmol, 2 equiv.), trans-N,N'-dimethylcyclohexane-1,2-diamine (94 mg, 0.66 mmol, 2 equiv.), and KCO (137 mg, 0.99 mmol, 3 equiv.) in DMF (5 mL) was stirred at 115 °C for 1.5 h under N2 atmosphere with microwave irradiation. The reaction mixture was washed with water (150 mL) and then extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with PE / EtOAc = 20 / 1 to 5 / 1) to give the title compound as a yellow solid. TIFF0007640458000283.tif19153

[0596] Example 3 N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-phenylmethanesulfonamide TIFF0007640458000284.tif33128 The title compound was prepared according to General Procedure A, Step F, starting from Example 1 using benzylsulfonamide. TIFF0007640458000285.tif27153

[0597] Example 4 1-Cyclopropyl-N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide TIFF0007640458000286.tif34128 The title compound was prepared according to General Procedure A, Step F, starting from Example 1 using 1-cyclopropylmethanesulfonamide. TIFF0007640458000287.tif27153

[0598] Example 5 N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)benzenesulfonamide TIFF0007640458000288.tif31128 The title compound was prepared according to General Procedure A, Step F, starting from Example 1 using benzenesulfonamide. TIFF0007640458000289.tif27153

[0599] Example 6 1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-6-(phenylethynyl)-1H-imidazo[4,5-b]pyrazine TIFF0007640458000290.tif33128 and Example 7 1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-6-phenethyl-1H-imidazo[4,5-b]pyrazine TIFF0007640458000291.tif33128

[0600] Process A 1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-6-(phenylethynyl)-1H-imidazo[4,5-b]pyrazine (Example 6) A suspension of 6-bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine (Example 1, 100 mg, 0.22 mmol, 1 equiv.), ethynylbenzene (...

Claims

1. Formula (I-a1-a1), (I-a1-a2), or (I-a1-a3): or a pharma- ceutically acceptable salt thereof, or Formula (I-a1-a7), (I-a1-a8), or (I-a1-a9): (In the formula, R d' is H or C 1-6 alkyl, or a pharma- ceutically acceptable salt thereof; or Formula (I-b1-a1): or a pharma- ceutically acceptable salt thereof: During the ceremony, R 1 teeth and; R 2 teeth and; R 4 Each occurrence of may independently be: (i) -(Y 3 ) p -Y 4 , where p is 0 or 1; ・Y 3 is C 1～6 alkylene; 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) C 1～10 C 1-10 alkyl, C 2-10 alkenyl, or C 2-10 alkynyl, each of which is optionally substituted with 1 to 6 independently selected R a ; and; R a Each occurrence of is independently -OH; and C 1～4 haloalkoxy; R b Each occurrence of is independently 1～6 Selected from the group consisting of alkyl; -OH; and oxo; R c Each occurrence of may independently be: (i) Halo; (iii) C 1～6 Alkyl; (vi) C 1～4 haloalkyl; and (vii) C 1～4 Alkoxy; selected from the group consisting of; R c Each occurrence of ' is independently: (i) Halo; (iii) -OH; and (viii) -NH 2 selected from the group consisting of; R d is C 1～6 It is an alkyl.

2. R c 2. The compound of claim 1, wherein each occurrence of is independently selected from halo.

3. R 4 -(Y 3 ) p -Y 4 The compound according to any one of claims 1 to 2,

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

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

6. Y 4 But 1 to 4 R b C which may be substituted with 3～6 cycloalkyl, or 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 or 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 The compound according to any one of claims 1 to 4,

7. 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 1 to 2, which is alkyl.

8. 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 1-2 and 7, which is alkyl.

9. R 4 is 1 to 6 independently selected R a C which may be substituted with 2～10 alkynyl or R 4 is 1 to 6 independently selected R a C which may be substituted with 2～10 The compound of any one of claims 1 to 2, which is alkenyl.

10. R 4 But non-substituted C 2～4 alkynyl or R 4 But non-substituted C 2～4 10. The compound of claim 9, which is alkenyl.

11. R 4 But the following: (i) 1 to 2 R a C which may be substituted with 1～6 Alkyl; and (ii) -(Y 3 ) p -Y 4 The compound according to any one of claims 1 to 2, selected from the group consisting of:

12. R 4 But the following: (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 each of which may be substituted with 2～10 Alkenyl or C 2～10 Alkynyl The compound according to any one of claims 1 to 2, selected from the group consisting of:

13. Formula (I-a1-a1):

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

14. Formula (I-b1-a1):

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

15. R 4 But the following: (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 each of which may be substituted with 2～10 Alkenyl or C 2～10 Alkynyl 15. The compound of claim 13 or 14, selected from the group consisting of:

16. ・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 is alkyl; or ・R 4 is 1 to 6 independently selected R a C which may be substituted with 2～10 is alkynyl; or ・R 4 is 1 to 6 independently selected R a C which may be substituted with 2～10 alkenyl, Each R a is -OH, if present; and C 1～4 Independently selected from the group consisting of haloalkoxy, 16. The compound according to any one of claims 13 to 15.

17. R 4 However, methyl, ethyl, 17. The compound of claim 16, selected from the group consisting of:

18. R 4 But non-substituted C 2～4 17. The compound of claim 16, which is alkynyl.

19. R d ' is H or C 1-3 Is it alkyl; R c is F or CF 3 Is it; Y 4 C 3～4 is cycloalkyl; or Y 4 C 6 is cycloalkyl, 2. The compound of claim 1.

20. The table below:

2. A compound selected from the group consisting of the compounds in the formula:

21. The compound of claim 1, which is: or a pharma- ceutically acceptable salt thereof.

22. The compound of claim 1, which is: or a pharma- ceutically acceptable salt thereof.

23. The compound of claim 1, which is: or a pharma- ceutically acceptable salt thereof.

24. The compound of claim 1, which is: or a pharma- ceutically acceptable salt thereof.

25. The compound of claim 1, which is: or a pharma- ceutically acceptable salt thereof.

26. The compound of claim 1, which is: or a pharma- ceutically acceptable salt thereof.

27. 27. A pharmaceutical composition comprising a compound or salt according to any one of claims 1 to 26 and one or more pharma- ceutically acceptable excipients.

28. 27. A pharmaceutical composition 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 an effective amount of a compound according to any one of claims 1 to 26.

29. 29. The pharmaceutical composition of claim 28, wherein the disease, disorder, or condition is pulmonary arterial hypertension ("PAH"), optionally wherein the PAH is idiopathic, or optionally wherein the PAH is hereditary, toxic or drug-induced PAH; or wherein the PAH is PAH associated with one or more of congenital heart disease, connective tissue disorder, portal hypertension, BMPR2 mutations, schistosomiasis, and HIV infection, or wherein the disease, disorder, or condition is fibrosis, or wherein the disease, disorder, or condition is idiopathic pulmonary fibrosis (IPF), or wherein the disease, disorder, or condition is a connective tissue disorder.

30. 30. The pharmaceutical composition of claim 29, wherein the connective tissue disorder is scleroderma, systemic lupus erythematosus, systemic sclerosis, Hashimoto's thyroiditis, Sjogren's syndrome, or antiphospholipid syndrome.

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