Compounds and compositions for treating conditions associated with apj receptor activity

Abstract

This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt and / or hydrate and / or prodrug of the compound) that modulate (e.g., agonize) the apelin receptor (also referred to herein as the APJ receptor; gene symbol APLNR). This disclosure also features compositions containing the same as well as other methods of using and making the same. The chemical entities are useful, e.g., for treating a subject (e.g., a human) having a disease, disorder, or condition in which a decrease in APJ receptor activity (e.g., repressed or impaired APJ receptor signaling; e.g., repressed or impaired apelin-APJ receptor signaling) or downregulation of endogenous apelin contributes to the pathology and / or symptoms and / or progression of the disease, disorder, or condition. 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 infections (e.g., microbial infections); and (vi) diseases, disorders, or conditions that are sequela or comorbid with any of the foregoing or any disclosed herein. More particular 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

[0001] Compounds and Compositions for Treating Conditions Associated with APJ Receptor Activity

[0002] CROSS REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of United States Provisional Application No. 62 / 742,218, filed on Oct 5th, 2018, which is incorporated herein by reference in its entirety.

[0004] TECHNICAL FIELD

[0005] This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt and / or hydrate and / or prodrug of the compound) that modulate (e.g., agonize) the apelin receptor (also referred to herein as the APJ receptor; gene symbol “APLNR”). This disclosure also features compositions containing the same as well as other methods of using and making the same. The chemical entities are useful, e.g., for treating a subject (e.g., a human) having a disease, disorder, or condition in which a decrease in APJ receptor activity (e.g., repressed or impaired APJ receptor signaling; e.g., repressed or impaired apelin-APJ receptor signaling) or downregulation of endogenous apelin contributes to the pathology and / or symptoms and / or progression of the disease, disorder, or condition. 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 infections (e.g., microbial infections); and (vi) diseases, disorders, or conditions that are sequela or comorbid with any of the foregoing or any disclosed herein. More particular 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.

[0006] BACKGROUND

[0007] Pulmonary arterial hypertension (PAH) is a severe cardiopulmonary disorder characterized by the vascular remodeling of the pulmonary arterioles, including formation of plexiform and concentric lesions comprised of proliferative vascular cells. PAH is believed to be caused by cellular proliferation and fibrosis of the small pulmonary arteries. Clinically, PAH leads to increased pulmonary arterial pressure and subsequent right ventricular failure, which is one of the major causes of morbidity and mortality. Mortality rates remain exceedingly high with 15%, 30%, and 45% mortality at 1, 2, and 3 years after diagnosis, respectively. See, e.g., Kim, J., Mol. Cells 2014; 37(3): 196-201 and Lau, E.M.T., Nature Reviews , 2017, 1-12.

[0008] Diabetes mellitus type 2 (type-2 diabetes) is characterized by high blood glucose and insulin resistance. Type 2 diabetes as well as conditions that are co-morbid or sequela with type-2 diabetes affect tens of millions of people in the United States alone. Type-2 diabetes is frequently associated with obesity.

[0009] The apelin or APJ receptor is a G protein-coupled receptor containing seven hydrophobic transmembrane domains (see, e.g., Kim, supra). Apelin (also known as APLN) is a 36 amino acid peptide that in humans is encoded by the APLN gene and is the endogenous ligand for the APJ receptor (see, e.g., O’ Carroll, A-M., el al ., J Endocrinol 2013, 219, R13-R35).

[0010] The apelin / APJ system is present in many tissues such as heart, kidney, pancreas, lung, vasculature, central nervous system, liver, adipose, gastrointestinal tract, brain, adrenal glands, endothelium, and human plasma.

[0011] Additionally, there is evidence showing that both apelin and APJ are regulators of central and peripheral responses to multiple homeostatic perturbations such as cardiovascular control and function; angiogenesis; fluid homeostasis; water balance; hypothalamic-pituitary-adrenal (HPA) axis regulation; metabolic homeostasis; energy metabolism; and kidney function. For example, there is emerging evidence that APJ-apelin signaling plays a role in the maintenance of pulmonary vascular homeostasis (see, e.g., Kim supra). Evidence also points to a nexus between apelinergic system (e.g., apelin and APJ receptor) and the treatment of conditions such as sepsis, septic shock, and renal failure (see, e.g., Coquerel, D., et al., Critical Care 2018, 22: 10). As another example, apelin, synthesized and secreted by adipocytes, has been described as a beneficial adipokine related to obesity, and there is additional evidence of a potential role for apelin and APJ receptor in glucose and energy metabolism (see e.g., O’ Carroll supra). SUMMARY

[0012] This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt and / or hydrate and / or prodrug of the compound) that modulate (e.g., agonize) the apelin receptor (also referred to herein as the APJ receptor; gene symbol “APLNR”). This disclosure also features compositions containing the same as well as other methods of using and making the same. The chemical entities are useful, e.g., for treating a subject (e.g., a human) having a disease, disorder, or condition in which a decrease in APJ receptor activity (e.g., repressed or impaired APJ receptor signaling; e.g., repressed or impaired apelin-APJ receptor signaling) or downregulation of endogenous apelin contributes to the pathology and / or symptoms and / or progression of the disease, disorder, or condition. 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 infections (e.g., microbial infections); and (vi) diseases, disorders, or conditions that are sequela or comorbid with any of the foregoing or any disclosed herein. More particular 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.

[0013] An "agonist" of the APJ receptor includes compounds that, at the protein level, directly bind or modify the APJ receptor such that an activity of the APJ receptor is increased, e.g., by activation, stabilization, altered distribution, or otherwise.

[0014] Certain chemical entities described herein that agonize the APJ receptor to a lesser extent than an APJ receptor full agonist can function in assays as antagonists as well as agonists. These chemical entities antagonize activation of the APJ receptor by an APJ receptor full agonist because they prevent the full effect of APJ receptor interaction. However, the chemical entities also, on their own, activate some APJ receptor activity, typically less than a corresponding amount of the APJ receptor full agonist. Such chemical entities are sometimes referred to herein as "partial agonists of the APJ receptor ". 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. In other embodiments, the chemical entities described herein modulate (e.g., agonize) the APJ receptor in a pathway-specific manner. Accordingly, this 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) competing levels of downstream G-protein signaling (activation) and b-arrestin recruitment. APJ receptor signaling through b-arrestin has been shown to mediate stretch-induced myocardial hypertrophy. See, e.g., Scimia, M.C., et al., Nature 2012, 488 , 394-398. In certain embodiments, the chemical entities described herein modulate (e.g., reduce, e.g., attenuate, disrupt, inhibit) b-arrestin signaling. In certain embodiments, the chemical entities described herein modulate (e.g., reduce, e.g., attenuate, disrupt, inhibit) recruitment of b- arrestin.

[0015] In certain embodiments, the chemical entities described herein activate or increase the levels of downstream G-protein signaling.

[0016] In certain embodiments, the chemical entities described herein inhibit or decrease the levels of b-arrestin recruitment.

[0017] In certain embodiments, the chemical entities described herein activate or increase the levels of b-arrestin recruitment.

[0018] In certain embodiments, the chemical entities described herein selectively modulate (e.g., increase) one of the pathways over the other. For example, the chemical entities described herein can activate or increase the levels of downstream G-protein signaling, and inhibit or decrease the levels of b-arrestin recruitment.

[0019] In other embodiments, the chemical entities described herein can activate or increase the levels of downstream G-protein signaling, and activate or increase the levels of b-arrestin recruitment. For example, the chemical entities described herein can fully agonize both b-arrestin and G protein signaling pathways. Generally, a receptor exists in an active (Ra) and an inactive (Ri) conformation. Certain compounds that affect the receptor can alter the ratio of Ra to Ri (Ra / Ri). For example, a full agonist increases the ratio of Ra / Ri and can cause a "maximal", saturating effect. A partial agonist, when bound to the receptor, gives a response that is lower than that elicited by a full agonist (e.g., an endogenous agonist). Thus, the Ra / Ri for a partial agonist is less than for a full agonist. However, the potency of a partial agonist may be greater or less than that of the full agonist.

[0020] In one aspect, the featured chemical entities include compounds of Formula I, or a pharmaceutically acceptable salt thereof:

[0021]

[0022] in which R1, R2, A1, X1, X2, X3, and X4can be as defined anywhere herein.

[0023] In one aspect, pharmaceutical compositions are featured that include a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same) and one or more pharmaceutically acceptable excipients.

[0024] In one aspect, methods for modulating (e.g., agonizing, partially agonizing,) APJ receptor activity are featured that include contacting the APJ receptor with a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same). Methods include in vitro methods, e.g., contacting a sample that includes one or more cells, each independently comprising one or more APJ receptors with the chemical entity. Methods can also include in vivo methods. Such methods can include, e.g., administering the chemical entity to a subject (e.g., a human) having a disease, disorder, or condition in which a decrease in APJ receptor activity (e.g., repressed or impaired APJ receptor signaling; e.g., repressed or impaired apelin-APJ receptor signaling) or downregulation of endogenous apelin contributes to the pathology and / or symptoms and / or progression of the disease, disorder, or condition (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; modulating (e.g., decreasing) mean pulmonary artery pressure; modulating (e.g., increasing) insulin levels; and modulating (e.g., decreasing) glucose levels in a subject (e.g., a human).

[0025] In a further aspect, methods of treatment of a disease, disorder, or condition are featured, in a decrease in APJ receptor activity (e.g., repressed or impaired APJ receptor signaling; e.g., repressed or impaired apelin-APJ receptor signaling) or downregulation of endogenous apelin contributes to the pathology and / or symptoms and / or progression of the disease, disorder, or condition. The methods include administering to a subject in need of such treatment an effective amount of a chemical entity described herein (e.g., a compound described generically or specifically herein, a pharmaceutically acceptable salt thereof, or compositions containing the same).

[0026] In another aspect, this disclosure features methods of treating a subject having a disease, disorder, or condition in which a decrease in APJ receptor activity (e.g., repressed or impaired APJ receptor signaling; e.g., repressed or impaired apelin-APJ receptor signaling) or downregulation of endogenous apelin contributes to the pathology and / or symptoms and / or progression of the disease, disorder, or condition. The methods include administering a chemical entity described herein (e.g., a compound described generically or specifically herein, a pharmaceutically acceptable salt thereof or compositions containing the same) in an amount effective to treat the disease, disorder, or condition.

[0027] In a further aspect, methods of treatment are featured that include administering to a subject chemical entity described herein (e.g., a compound described generically or specifically herein, a pharmaceutically acceptable salt thereof, or compositions containing the same). The methods include administering the chemical entity in an amount effective to treat a disease, disorder, or condition, wherein a decrease in APJ receptor activity (e.g., repressed or impaired APJ receptor signaling; e.g., repressed or impaired apelin-APJ receptor signaling) or downregulation of endogenous apelin contributes to the pathology and / or symptoms and / or progression of the disease, disorder, or condition, thereby treating the disease, disorder, or condition. A non-limiting example of such diseases, disorders, and conditions is PAH. In some embodiments, the PAH is idiopathic. In other embodiments, the PAH is heritable PAH, toxin or drug-induced PAH; or a 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 the antiphospholipid antibody syndrome), portal hypertension, BMPR2 mutations, Schistosomiasis, and HIV infection.

[0028] Another non-limiting example of such diseases, disorders, and conditions is cardiovascular disease, e.g., coronary heart disease and heart failure. In certain embodiments, the cardiovascular disease is heart failure; e.g., 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 after cardiac surgery, and valvular heart diseases.

[0029] Still another non-limiting example of such diseases, disorders, and conditions is a metabolic disorder, such as metabolic syndrome; diabetes (e.g., type 2 diabetes); obesity; obesity-related disorders; impaired glucose tolerance; and insulin resistance.

[0030] Other non-limiting examples of such diseases, disorders, and conditions include sepsis, septic shock, renal failure, systemic hypertension, idiopathic pulmonary fibrosis (IFF), and systemtic sclerosis.

[0031] Further non-limiting examples include coronary artery disease (CAD), non-CAD atherosclerotic conditions, including peripheral vascular disease (PVD), aortic atherosclerosis, and cerebral arteriosclerosis, diabetic retinopathy, ischemia-reperfusion injury, emphysema, radiation-induced organ and tissue injury, corpus luteum regression, scleroderma, systemic sclerosis, and diseases of immune dysregulation. In one aspect, this disclosure features methods for identifying and / or selecting a subject (e.g., a human) likely to benefit from the methods described herein, as well as methods for determining whether a subject (e.g., a human) is responding to such methods. In certain embodiments, a biological sample, which may be, for example and without limitation, a breath, sputum, tissue, plasma or serum sample, urine, is obtained from the subject, and the level of a particular parameter in the sample is determined and compared to a control value. In some instances, the control value may be determined from one or more normal individuals not suffering from the disease, disorder, or conditions being treated. In other instances, the control value can also be determined from a sample previously obtained from the subj ect. Generally, higher (or elevated) levels of the measured parameter relative to a control value determined from a normal, non-diseased individual or population indicate that a subject will benefit from methods described herein. Lower levels generally indicate that a patient is responding to therapy or, for a subject not on such therapy, that the therapeutic methods may not be as beneficial for that subject.

[0032] In certain of the foregoing embodiments, the subject is suffering from, or at risk of suffering from PAH. Non-limiting, exemplary parameters related to PAH are delineated below.

[0033] In certain embodiments, the parameter is LTB4 level. For example, a baseline or reference value of LTB4 can be 100 pg / mL or greater, 200 pg / mL or greater, 300 pg / mL or greater, 400 pg / mL or greater, 500 pg / mL or greater, 600 pg / mL or greater, or 100 pg / mL or greater. In certain embodiments, the treatment provided is efficacious if, after treatment has started, the endpoint LTB4 level of the subject decreases from the baseline or reference LTB4 level. For example, the endpoint LTB4 level of the subject decreases to 600 pg / mL or less, 500 pg / mL or less, 400 pg / mL or less, 300 pg / mL or less, 200 pg / mL or less, or 100 pg / mL or less. In certain embodiments, the treatment provided is efficacious if, after treatment has started, the endpoint LTB4 level is 30 pg / mg of tissue or lower, 20 pg / mg of tissue of lower, 10 pg / mg of tissue or lower, 7.5 pg / mg of tissue or lower, or 5 pg / mg of tissue or lower. In other embodiments, the treatment provided is efficacious if, after treatment has started, the endpoint LTB4 level is lower than the baseline LTB4 level by 2- fold or more, 3-fold or more, 4-fold or more, or 5-fold or more. In certain embodiments, the parameter is pulmonary vascular resistance (PVR). The baseline or reference PVR level can be 200 dynsec / cm5or greater, 240 dynsec / cm5or greater, 300 dynsec / cm5or greater, 400 dynsec / cm5or greater, 500 dynsec / cm5or greater, 600 dynsec / cm5or greater, 700 dynsec / cm5or greater, or 800 dynsec / cm5or greater. In certain embodiments, the treatment provided is efficacious if, after treatment has started, the endpoint PVR level of the subject decreases from the baseline or reference PVR level by 70 dynsec / cm5or more, 100 dynsec / cm5or more, 130 dynsec / cm5or more, or 160 dynsec / cm5or more.

[0034] In certain embodiments, the parameter is pulmonary arterial pressure (PAP). The baseline or reference PAP level can be 20 mmHg or greater, 25 mmHg or greater, 30 mmHg or greater, 35 mmHg or greater, 40 mmHg or greater, 45 mmHg or greater, 50 mmHg or greater, 60 mmHg or greater, or 70 mmHg or greater. In certain embodiments, the treatment provided is efficacious if, after treatment has started, the endpoint PAP level of the subject decreases from the baseline or reference PAP level by 0.5 mmHg or more, 1 mmHg or more, 1.5 mmHg or more, 5 mmHg or more, 10 mmHg or more, 20 mmHg or more, 30 mmHg or more, 40 mmHg or more, or 50 mmHg. In certain embodiments, the subject exhibits a mean pulmonary artery pressure of greater than 25 mmHg.

[0035] In certain embodiments, the parameter is cardiac index (Cl). A baseline or reference Cl level can be 5 L / min / m.sup.2 or lower, 2.5 L / min / m.sup.2 or lower, 2 L / min / m.sup.2 or lower, 1.5 L / min / m.sup.2 or lower, or 1 L / min / m.sup.2 or lower. In certain embodiments, the treatment provided is efficacious if, after treatment has started, the endpoint Cl level increases from the baseline or reference Cl level 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.

[0036] In certain embodiments, the parameter is pulmonary capillary wedge pressure (PCWP). A baseline or reference PCWP level can be 36 mmHg or less, 24 mmHg or less, 18 mmHg or less, 10 mmHg, or 5 mmHg or less. In certain embodiments, the treatment provided is efficacious if, after treatment has started, 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. In certain embodiments, the parameter is right atrial pressure (RAP). A baseline or reference RAP level can be 4 mmHg or more, 6 mmHg or more, 8 mmHg or more, 10 mmHg or more, 12 mmHg or more, 16 mmHg or more, 20 mmHg or more, or 25 mmHg or more. In certain embodiments, the treatment provided is efficacious if, after treatment has started, the endpoint RAP level of the subject decreases from the baseline or reference RAP level by 5 mmHg or more 2.5 mmHg or more, 1 mmHg or more, 0.5 mmHg or more, or 0.2 mmHg or more.

[0037] In certain embodiments, the parameter is the six-minute walk distance (6 MWD). A 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 treatment provided is efficacious it after treatment has started, the endpoint 6 MWD of the subject increases from the baseline or reference 6 MWD 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. Alternatively or in addition, treatment provided in the invention is efficacious if, after treatment has started, the endpoint 6 MWD of the subject increases by 3% or more, 4% or more, 5% or more, 10% or more, or 20% or more of the baseline level.

[0038] In certain embodiments, the parameter is brain natriuretic peptide (BNP) level. A baseline or reference BNP level can be 60 pg / mL or higher, 80 pg / mL or higher, 100 pg / mL or higher, 120 pg / mL or higher, 140 pg / mL or higher, 200 pg / mL or higher, 500 pg / mL or higher, or 1000 pg / mL or higher. In certain embodiments, the treatment provided is efficacious if, after treatment has started, the endpoint BNP level of the subject decreases from the baseline or reference BNP level. For example, the endpoint BNP level of the subject 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.

[0039] In certain embodiments, the parameter is atrial natriuretic peptide (ANP) level. A baseline or reference ANP level can be 60 pg / mL or higher, 80 pg / mL or higher, 100 pg / mL or higher, 120 pg / mL or higher, 140 pg / mL or higher, 200 pg / mL or higher, 500 pg / mL or higher, or 1000 pg / mL or higher. In certain embodiments, the treatment provided is efficacious if, after treatment has started, the endpoint ANP level of the subject decreases from the baseline or reference ANP level. For example, the endpoint ANP level of the subject 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.

[0040] In certain embodiments, the parameter is Diffusion of lung capacity (DLCO), or diffusion capacity of CO, can also be used in the methods as a parameter to determine efficacy. A baseline or reference DLCO can be 90% or less, 80% or less, 70% or less, 50% or less, 45% or less, or 40% or less. In certain embodiments, the treatment provided is efficacious if, after treatment has started, the endpoint DLCO is increased from the baseline level. For example, the endpoint DLCO can be increased 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.

[0041] In another aspect, this disclosure features methods for reducing the risk of right ventricular failure in a subject in need of such reducing, the method comprising administering to the subject an effective amount of a chemical entity described herein.

[0042] The methods described herein can further include treating one or more conditions that are associated, co-morbid or sequela with any one or more of the conditions described herein.

[0043] For example, the methods can further include treating one or more conditions that are associated, co-morbid or sequela with PAH, e.g., coronary heart disease or heart failure. In certain embodiments, the cardiovascular disease is heart failure, e.g., 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 after cardiac surgery, and valvular heart diseases.

[0044] As another example, the methods can further include treating one or more conditions that are co-morbid or sequela with 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 related to unmanaged cholesterol and / or lipid levels, and / or inflammation), retinopathy, nephropathy, neuropathy, NASH, bone fracture and cognitive dysfunction.

[0045] The methods can further include administering one or more other therapeutic agents (e.g., in combination with a chemical entity described herein). Embodiments can include one of more of the following advantageous properties.

[0046] Apelin peptide is labile; as such, only acute pharmacodynamics effect of apelin peptide is observable. In some embodiments, the compounds described herein exhibit relatively high metabolic stability to allow observations of non-acute pharmacodynamics effect.

[0047] In some embodiments, the compounds described herein can lead to reduced atrial pressure in addition to enhancing cardiac output.

[0048] In some embodiments, the compounds described herein can selectively activate the G-protein pathway through APJ receptor, thereby reducing tachyphylaxis often associated with dosing potent agonists. As such, in certain embodiments, compounds described herein can reduce arrestin-associated cardiac hyperthrophy.

[0049] In some embodiments, the compounds described herein can exhibit pleiotropic properties (e.g., inodilator activity, cardio-renal protection, and control of fluid homeostasis). Other embodiments include those described in the Detailed Description and / or in the claims. Additional Definitions

[0050] To facilitate understanding of the disclosure set forth herein, a number of additional terms are defined below. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Each of the patents, applications, published applications, and other publications that are mentioned throughout the specification and the attached appendices are incorporated herein by reference in their entireties.

[0051] As used herein, the term“APJ receptor” is meant to include, without limitation, nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide strands, complementary sequences, peptides, polypeptides, proteins, homologous and / or orthologous APJ or APJ receptor molecules, isoforms, precursors, mutants, variants, derivatives, splice variants, alleles, different species, and active fragments thereof.

[0052] The term“acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

[0053] “API” refers to an active pharmaceutical ingredient.

[0054] The term "IC50" or "EC50" refers an amount, concentration, or dosage of a compound that is required for 50% inhibition or activation of a maximal response in an assay that measures such response.

[0055] The terms“effective amount” or“therapeutically effective amount,” as used herein, refer to a sufficient amount of a chemical entity (e.g., a compound described generically or specifically herein, a pharmaceutically acceptable salt thereof, or compositions containing the same) being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes 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” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate“effective” amount in any individual case is determined using any suitable technique, such as a dose escalation study.

[0056] 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 embodiment, each component is“ pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit / risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed:, Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed !; Rowe el 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

[0057] Preformulation and Formulation, 2nd ed !; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

[0058] 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 instances, pharmaceutically acceptable salts are obtained by reacting a compound described herein, with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. In some instances, pharmaceutically acceptable salts are obtained by reacting a compound having acidic group described herein with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, / V-m ethyl -D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined. The pharmacologically acceptable salt s not specifically limited as far as it can be used in medicaments. Examples of a salt that the compounds described hereinform with a base include the following: salts thereof with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts thereof with organic bases such as methylamine, ethylamine and ethanolamine; salts thereof with basic amino acids such as lysine and ornithine; and ammonium salt. The salts may be acid addition salts, which are specifically exemplified by acid addition salts with the following: 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; acidic amino acids such as aspartic acid and glutamic acid.

[0059] The term “pharmaceutical composition” refers to a mixture of a compound described herein with other chemical components (referred to collectively herein as “excipients”), such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and / or thickening agents. The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to rectal, oral, intravenous, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.

[0060] The term“subject” refers to an animal, including, but not limited to, a primate ( e.g ., human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms “subject” and“patient” are used interchangeably herein in reference, for example, to a mammalian subject, such as a human.

[0061] The terms“treat,”“treating,” and“treatment,” in the context of treating a disease, disorder, or condition, are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or to slowing the progression, spread or worsening of a disease, disorder or condition or of one or more symptoms thereof.

[0062] The term "halo" refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

[0063] The term "alkyl" refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, Ci-io indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it. Non-limiting examples include methyl, ethyl, No-propyl, fer / -butyl, «-hexyl.

[0064] The term "haloalkyl" refers to an alkyl, in which one or more hydrogen atoms is / are replaced with an independently selected halo.

[0065] The term "alkoxy" refers to an -O-alkyl radical (e.g., -OCH3).

[0066] The term "haloalkoxy" refers to an -O-haloalkyl radical (e.g., -OCH3).

[0067] The term "alkylene" refers to a branched or unbranched divalent alkyl (e.g., -CH2-

[0068] )·

[0069] The term "arylene" and the like refer to divalent forms of the ring system, here divalent aryl.

[0070] The term "alkenyl" refers to a hydrocarbon chain that may be a straight chain or branched chain having one or more carbon-carbon double bonds. The alkenyl moiety contains the indicated number of carbon atoms. For example, C2-6 indicates that the group may have from 2 to 6 (inclusive) carbon atoms in it.

[0071] The term "alkynyl" refers to a hydrocarbon chain that may be a straight chain or branched chain having one or more carbon-carbon triple bonds. The alkynyl moiety contains the indicated number of carbon atoms. For example, C2-6 indicates that the group may have from 2 to 6 (inclusive) carbon atoms in it.

[0072] The term "aryl" refers to a 6-carbon monocyclic, lO-carbon bicyclic, or l4-carbon tricyclic aromatic ring system wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted by a substituent, and wherein the ring comprising a monocyclic radical is aromatic and wherein at least one of the fused rings comprising a bicyclic or tricyclic radical is aromatic e.g. tetrahydronaphthyl. Examples of aryl groups also include phenyl, naphthyl and the like.

[0073] The term "cycloalkyl" as used herein includes saturated cyclic hydrocarbon groups having 3 to 10 carbons, preferably 3 to 8 carbons, and more preferably 3 to 6 carbons, wherein the cycloalkyl group may be optionally substituted. Preferred cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. The term "heteroaryl" refers to an aromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted by a substituent, and wherein the ring comprising a monocyclic radical is aromatic and wherein at least one of the fused rings comprising a bicyclic or tricyclic radical is aromatic (but does not have to be a ring which contains a heteroatom, e.g. tetrahydroisoquinolinyl. Exemplary heteroaryl systems are derived from, but not limited to, the following ring systems: pyrrole, furan, thiophene, imidazole, pyrazole, oxazole (=[l,3]oxazole), isoxazole (=[l,2]oxazole), thiazole (=[l,3]thiazole), isothiazole (=[l,2]thiazole), [l,2,3]triazole, [l,2,4]triazole, [l,2,4]oxadiazole, [l,3,4]oxadiazole, [l,2,4]thiadiazole, [l,3,4]thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, [l,2,3]triazine, [l,2,4]triazine, [l,3,5]triazine, indole, isoindole, benzofuran, benzothiophene [l,3]benzoxazole, [l,3]benzothiazole, benzoimidazole, indazole, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, different naphthyridines, e.g. [l,8]naphthyridine, different thienopyridines, e.g. thieno[2,3- bjpyridine and purine.

[0074] The term "heterocyclyl" refers to a nonaromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like.

[0075] In addition, atoms making up the compounds of the present embodiments are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include those 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 include13C and14C. The compounds provided herein may encompass various stereochemical forms. The compounds also encompass diastereomers as well as optical isomers, e.g., mixtures of enantiomers (including atropisomers) including racemic mixtures, as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in certain compounds. Separation of the individual isomers or selective synthesis of the individual isomers is accomplished by application of various methods which are well known to practitioners in the art. Unless otherwise indicated, when a disclosed compound is named or depicted by a structure without specifying the stereochemistry and has one or more chiral centers, it is understood to represent all possible stereoisomers of the

[0076] O NH

[0077] 's' compound. For example, -S(0)(=NH)-R4is intended to encompass enantiomer: V "R4

[0078] O. NH

[0079] 's'

[0080] and enantiomer: ¾r4as well as a mixture thereof (e.g., racemic mixture).

[0081] The details of one or more embodiments of the invention are set forth in the description below and in the accompanying Appendix, which is expressly considered part of this disclosure. Other features and advantages will also be apparent from the claims.

[0082] DETAILED DESCRIPTION

[0083] This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt and / or hydrate and / or prodrug of the compound) that modulate (e.g., agonize) the apelin receptor (also referred to herein as the APJ receptor; gene symbol “APLNR”). This disclosure also features compositions containing the same as well as other methods of using and making the same. The chemical entities are useful, e.g., for treating a subject (e.g., a human) having a disease, disorder, or condition in which a decrease in APJ receptor activity (e.g., repressed or impaired APJ receptor signaling; e.g., repressed or impaired apelin-APJ receptor signaling) or downregulation of endogenous apelin contributes to the pathology and / or symptoms and / or progression of the disease, disorder, or condition. 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 infections (e.g., microbial infections); and (vi) diseases, disorders, or conditions that are sequela or comorbid with any of the foregoing or any disclosed herein. More particular 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.

[0084] Formula fD Compounds

[0085] In one aspect, this disclosure features compounds of Formula (I), or a pharmaceutically acceptable salt thereof:

[0086]

[0087] or a pharmaceutically acceptable salt thereof;

[0088] wherein:

[0089] A1is CH or N; each of X1, X2, X3, and X4is independently selected from the group consisting of N and CR3;

[0090] R1is:

[0091] (i) -(Y^n-Y2, wherein:

[0092] • n is 0 or 1;

[0093] • Y1is Ci-6 alkylene, which is optionally substituted with from 1-6 Ra; and

[0094] • Y2is:

[0095] (a) C3-10 cycloalkyl, which is optionally substituted with from 1-4 Rb;

[0096] (b) C6-10 aryl, which is optionally substituted with from 1-4 Rc; (c) heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-4 independently selected Rc, or

[0097] (d) heterocyclyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), and O, and wherein one or more of the heterocyclyl ring carbon atoms are optionally substituted with from 1-4 independently selected Rb,

[0098] OR

[0099] (ii) -Z1-Z2-Z3, wherein:

[0100] • Z1is Ci-3 alkylene, which is optionally substituted with from 1-4 Ra;

[0101] • Z2is -N(H)-, -N(Rd)-, -0-, or -S-; and

[0102] • Z3is C2-7 alkyl, which is optionally substituted with from 1-4 Ra;

[0103] OR

[0104] (iii) C3-10 alkyl, optionally substituted with from 1-6 independently selected Ra;

[0105] OR

[0106] (iv) -Z4-Z5-Z6-Y2wherein:

[0107] • Z4is Ci-3 alkylene, which is optionally substituted with from 1-4 Ra;

[0108] • Z5is -N(H)-, -N(Rd)-, -0-, or -S-;

[0109] • Z6is Ci-4 alkylene, which is optionally substituted with from 1-4 Ra; and

[0110] • Y2is as defined above;

[0111] R2is:

[0112] (i) C6-10 aryl, which is optionally further substituted with from 1-4 Rc;

[0113] (ii) heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-4 independently selected Rc;

[0114] (iii) C3-10cycloalkyl, which is optionally substituted with from 1-4 Rb;

[0115] (iv) heterocyclyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), and O, and wherein one or more of the heterocyclyl ring carbon atoms are optionally substituted with from 1-4 independently selected Rb; or

[0116] (v) Ci-10 alkyl, which is optionally substituted with from 1-6 independently selected Ra; each occurrence of R3is independently selected from the group consisiting of -L4- R4, H and, Rc’; each occurrence of L4is independently selected from the group consisting of:

[0117] (i) a single bond;

[0118] (ii) N(H), N(Rd), or N(R4);

[0119] (iii) -N(H)S(0)I-2- or -N(Rd)S(0)i-2-;

[0120] (iv) -S(0)I-2N(H)- or -S(0)i-2N(Rd)-;

[0121] (v) -O- ;

[0122] (vi) -S(0)o-2-;

[0123] (vii) -C(0)NH- or -C(0)N(Rd);

[0124] (viii) -N(H)C(0)- or -N(Rd)C(0)-;

[0125] (ix) -CºC;

[0126] (x) -N(H)S(0)(=NH)-, -N(Rd)S(0)(=NH), -N(H)S(0)(=NRd)-, or - N(Rd)S(0)(=NRd)-

[0127] (xi) -S(0)(=NH)NH-, -S(0)(=NRd)NH-, -S(0)(=NH)NRd-, or -S(0)(=NRd)NRd-;

[0128] (xii) -S(0)(=NH)- or -S(0)(=NRd); and

[0129] (xiii) -N(H)S(0)I-2N(H)-, -N(Rd)S(0)i-2N(H)-, -N(H)S(0)i-2N(Rd)-, or -

[0130] N (Rd) S (O) i -2N (Rd)- ; each occurrence of R4is, independently:

[0131] (i) -(Y3)p-Y4, wherein:

[0132] • p is O or l;

[0133] • Y3is Ci-6alkylene or C1-6 alkenylene, each of which is optionally substituted with from 1-6 Ra; and

[0134] • Y4is:

[0135] (a) C3-6 cycloalkyl, which is optionally substituted with from 1-4 Rb,

[0136] (b) C6-10 aryl, which is optionally substituted with from 1-4 Rc;

[0137] (c) heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-4 independently selected Rc, or

[0138] (d) heterocyclyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), and O, and wherein one or more of the heterocyclyl ring carbon atoms are optionally substituted with from 1-4 independently selected Rb,

[0139] OR

[0140] (ii) Ci-io alkyl, Ci-io alkenyl, or Ci-io alkynyl, each of which is optionally substituted with from 1-6 independently selected Ra;

[0141] each occurrence of Rais independently selected from the group consisting of: -OH; -F; - Cl; -Br; -NReRf; CM alkoxy; CM haloalkoxy; -C(=0)0(CM alkyl); -C(=0)(CM alkyl); - C(=0)OH; -CON(R’)(R”); -S(0)I-2(NR’R”); -S(0)I-2(CM alkyl); cyano, and C3-6 cycloalkyl optionally substituted with from 1-4 independently selected C M alkyl; each occurrence of Rbis independently selected from the group consisting of: Ci-6 alkyl; Ci-4 haloalkyl; -OH; oxo; -F; -Cl; -Br; -NReRf; Ci-4 alkoxy; Ci-4 haloalkoxy; -C(=0)(Ci-4 alkyl); -C(=0)0(Ci-4alkyl); -C(=0)0H; -C (=0)N(R’ )(R” ) ; -S(0)I-2(NR’R”); -S(0)i- 2(Ci-4 alkyl); cyano; and C3-6 cycloalkyl optionally substituted with from 1-4 independently selected Ci-4 alkyl; each occurrence of Rcis independently selected from the group consisting of:

[0142] (i) halo;

[0143] (ii) cyano;

[0144] (iii) C1-6 alkyl;

[0145] (iv) C2-6 alkenyl;

[0146] (v) C2-6 alkynyl;

[0147] (vi) Ci-4 haloalkyl;

[0148] (vii) Ci-4 alkoxy;

[0149] (viii) Ci-4 haloalkoxy;

[0150] (ix) -(C0-3 alkylene)-C3-6cycloalkyl optionally substituted with from 1-4 independently selected Ci-4 alkyl;

[0151] (x) -S(0)i-2(Ci-4 alkyl);

[0152] (xi) -NReRf;

[0153] (xii) -OH;

[0154] (xiii) -S(0)I-2(NR’R”);

[0155] (xiv) -Ci-4 thioalkoxy;

[0156] (xv) -NO2;

[0157] (xvi) -C(=0)(Ci-4 alkyl);

[0158] (xvii) -C(=0)0(Ci-4 alkyl);

[0159] (xviii) -C(=0)OH,

[0160] (xix) -C(=0)N(R’)(R”), and

[0161] (xx) C3-6 cycloalkoxy; each occurrence of Rc’ is independently selected from the group consisting of: (i) halo;

[0162] (ii) cyano;

[0163] (iii) -OH;

[0164] (iv) -NO2;

[0165] (v) -C(=0)(Ci-4 alkyl);

[0166] (vi) -C(=0)0(Ci-4 alkyl);

[0167] (vii) -C(=0)OH; and

[0168] (viii) -NH2; Rdis selected from the group consisting of: Ci-6alkyl; C3-6cycloalkyl; -C(0)(Ci-4 alkyl); -C(0)0(Ci-4 alkyl); -CON(R’)(R”); -S(0)I-2(NR’R”); - S(0)I.2(CM alkyl); -OH; and Ci- 4 alkoxy; each occurrence of Reand Rfis independently selected from the group consisting of: H; Ci-6 alkyl; C3-6 cycloalkyl; -C(0)(Ci-4alkyl); -C(0)0(Ci-4alkyl); -CON(R’)(R”); -S(0)i- 2(NR’R”); - S(0)i-2(Ci-4 alkyl); -OH; and C1-4 alkoxy; or Reand Rftogether with the nitrogen atom to which each is attached forms a ring including from 3-8 ring atoms, wherein the ring includes: (a) from 1-7 ring carbon atoms, each of which is substituted with from 1-2 substituents independently selected from H and C1-3 alkyl; and (b) from 0-3 ring heteroatoms (in addition to the nitrogen atom attached to R’ and R”), which are each independently selected from the group consisting of N(Rd), O, and S; and each occurrence of R’ and R” is independently selected from the group consisting of: H and Ci-4 alkyl; or R’ and R” together with the nitrogen atom to which each is attached forms a ring including from 3-8 ring atoms, wherein the ring includes: (a) from 1-7 ring carbon atoms, each of which is substituted with from 1-2 substituents independently selected from H and C1-3alkyl; and (b) from 0-3 ring heteroatoms (in addition to the nitrogen atom attached to R’ and R”), which are each independently selected from the group consisting of N(Rd), O, and S. In some embodiments, this disclosure features compounds of Formula (I), or a pharmaceutically acceptable salt thereof:

[0169]

[0170] wherein:

[0171] A1is CH or N; each of X1, X2, X3, and X4is independently selected from the group consisting of N and CR3(e.g., each of X1and X4is independently CH or N; and each of X2and X3is independently CR3or N), provided that from 1-3 of X1, X2, X3, and X4is N;

[0172] R1is:

[0173] (i) -(Y^n-Y2, wherein:

[0174] • n is 0 or 1;

[0175] • Y1is Ci-6 alkylene, which is optionally substituted with from 1-6 Ra; and

[0176] Y2is:

[0177] (a) C3-10cycloalkyl, which is optionally substituted with from

[0178] 1-4 Rb,

[0179] (b) C6-10 aryl, which is optionally substituted with from 1-4 Rc;

[0180] (c) heteroaryl including from 5-10 ring atoms, wherein from 1- 4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-4 independently selected Rc, or

[0181] (d) heterocyclyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), and O, and wherein one or more of the heterocyclyl ring carbon atoms are optionally substituted with from 1-4 independently selected Rb,

[0182] OR

[0183] (ii) -Z1-Z2-Z3, wherein:

[0184] • Z1is Ci-3 alkylene, which is optionally substituted with from 1-4 Ra;

[0185] • Z2is -N(H)-, -N(Rd)-, -0-, or -S-; and

[0186] • Z3is C2-7 alkyl, which is optionally substituted with from 1-4 Ra;

[0187] OR

[0188] (iii) C3-10 alkyl, optionally substituted with from 1-6 independently selected Ra; OR

[0189] (iv) -Z4-Z5-Z6-Y2wherein:

[0190] • Z4is Ci-3alkylene, which is optionally substituted with from 1-4 Ra;

[0191] • Z5is -N(H)-, -N(Rd)-, -0-, or -S-;

[0192] • Z6is Ci-4 alkylene, which is optionally substituted with from 1-4 Ra; and

[0193] • Y2is as defined above;

[0194] R2is:

[0195] (i) C6-10 aryl, which is optionally further substituted with from 1-4 Rc;

[0196] (ii) heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd),

[0197] O, and S, and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-4 independently selected Rc;

[0198] (iii) C3-10 cycloalkyl, which is optionally substituted with from 1-4 Rb;

[0199] (iv) heterocyclyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), and O, and wherein one or more of the heterocyclyl ring carbon atoms are optionally substituted with from 1-4 independently selected Rb; or

[0200] (v) Ci-io alkyl, which is optionally substituted with from 1-6 independently selected Raeach occurrence of R3is independently selected from the group consisiting of -L4- R4, H and, Rc’; each occurrence of L4is independently selected from the group consisting of:

[0201] (i) a single bond;

[0202] (ii) N(H), N(Rd), or N(R4);

[0203] (iii) -N(H)S(0)I-2- or -N(Rd)S(0)i-2-;

[0204] (iv) -S(0)I-2N(H)- or -S(0)i-2N(Rd)-;

[0205] (v) -O- ;

[0206] (vi) -S(0)o-2-;

[0207] (vii) -C(0)NH- or -C(0)N(Rd);

[0208] (viii) -N(H)C(0)- or -N(Rd)C(0)-;

[0209] (ix) -CºC;

[0210] (x) -N(H)S(0)(=NH)-, -N(Rd)S(0)(=NH), -N(H)S(0)(=NRd)-, or - N (Rd) S (0)(=NRd)-

[0211] (xi) -S(0)(=NH)NH-, - S (0)(=NRd)NH-, -S(0)(=NH)NRd-, or -

[0212] S (0)(=NRd)NRd- ; and

[0213] (xii) -S(0)(=NH)- or -S(0)(=NRd); each occurrence of R4is, independently:

[0214] (i) -(Y3)p-Y4, wherein:

[0215] • p is O or l;

[0216] • Y3is Ci-6alkylene or Ci-6alkenylene, each of which is optionally substituted with from 1-6 Ra; and

[0217] • Y4is: (a) C3-6cycloalkyl, which is optionally substituted with from

[0218] 1-4 Rb,

[0219] (b) C6-10 aryl, which is optionally further substituted with from

[0220] 1-4 Rc;

[0221] (c) heteroaryl including from 5-10 ring atoms, wherein from 1- 4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-4 independently selected Rc, or

[0222] (d) heterocyclyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), and O, and wherein one or more of the heterocyclyl ring carbon atoms are optionally substituted with from 1-4 independently selected Rb,

[0223] OR

[0224] (ii) Ci-io alkyl, Ci-io alkenyl, or Ci-io alkynyl, each of which is optionally substituted with from 1-6 independently selected Ra;

[0225] each occurrence of Rais independently selected from the group consisting of: - OH; -F; -Cl; -Br; -NReRf; CM alkoxy; CM haloalkoxy; -C(=0)0(CM alkyl); -C(=0)(Ci 4 alkyl); -C(=0)OH; -CON(R’)(R”); -S(0)I-2(NR’R”); -S(0)I-2(CM alkyl); cyano, and C3-6 cycloalkyl optionally substituted with from 1-4 independently selected CM alkyl;

[0226] each occurrence of Rbis independently selected from the group consisting of: Ci- 6 alkyl; Ci-4 haloalkyl; -OH; oxo; -F; -Cl; -Br; -NReRf; Ci-4 alkoxy; Ci-4 haloalkoxy; - C(=0)(Ci-4 alkyl); -C(=0)0(Ci-4alkyl); -C(=0)0H; -C(=0)N(R’)(R”); -S(0)i- 2(NR’R”); -S(0)I-2(CI-4 alkyl); cyano; and C3-6 cycloalkyl optionally substituted with from 1-4 independently selected C1-4 alkyl; each occurrence of Rcis independently selected from the group consisting of: (i) halo;

[0227] (ii) cyano;

[0228] (iii) Ci-6alkyl;

[0229] (iv) C2-6 alkenyl;

[0230] (v) C2-6 alkynyl;

[0231] (vi) C1-4 haloalkyl;

[0232] (vii) Ci-4 alkoxy;

[0233] (viii) Ci-4 haloalkoxy;

[0234] (ix) -(C0-3 alkylene)-C3-6cycloalkyl optionally substituted with from 1-4 independently selected Ci-4 alkyl;

[0235] (x) -S(0)i-2(Ci-4 alkyl);

[0236] (xi) -NReRf;

[0237] (xii) -OH;

[0238] (xiii) -S(0)I-2(NR’R”);

[0239] (xiv) -Ci-4 thioalkoxy;

[0240] (xv) -NO2;

[0241] (xvi) -C(=0)(Ci-4 alkyl);

[0242] (xvii) -C(=0)0(Ci-4 alkyl);

[0243] (xviii) -C(=0)OH;

[0244] (xix) -C(=0)N(R’)(R”); and

[0245] (xx) C3-6 cycloalkoxy;

[0246] each occurrence of Rc’ is independently selected from the group consisting of:

[0247] (i) halo;

[0248] (ii) cyano; (iii) -OH;

[0249] (iv) -NO2;

[0250] (v) -C(=0)(Ci-4 alkyl);

[0251] (vi) -C(=0)0(Ci-4 alkyl);

[0252] (vii) -C(=0)0H; and

[0253] (viii) -NH2;

[0254] Rdis selected from the group consisting of: C1-6alkyl; C3-6cycloalkyl; -C(0)(Ci- 4 alkyl); -C(0)0(Ci-4alkyl); -CON(R’)(R”); -S(0)I-2(NR’R”); - S(0)I-2(CM alkyl); - OH; and C1-4 alkoxy; each occurrence of Reand Rfis independently selected from the group consisting of: H; Ci-6 alkyl; C3-6 cycloalkyl; -C(0)(Ci-4alkyl); -C(0)0(Ci-4alkyl); -CON(R’)(R”); -S(0)I-2(NR’R”); - S(0)i-2(Ci-4 alkyl); -OH; and C1-4 alkoxy; or Reand Rftogether with the nitrogen atom to which each is attached forms a ring including from 3-8 ring atoms, wherein the ring includes: (a) from 1-7 ring carbon atoms, each of which is substituted with from 1-2 substituents independently selected from H and C1-3 alkyl; and (b) from 0- 3 ring heteroatoms (in addition to the nitrogen atom attached to R’ and R”), which are each independently selected from the group consisting of N(Rd), O, and S; and each occurrence of R’ and R” is independently selected from the group consisting of: H and C1-4 alkyl; or R’ and R” together with the nitrogen atom to which each is attached forms a ring including from 3-8 ring atoms, wherein the ring includes: (a) from 1-7 ring carbon atoms, each of which is substituted with from 1-2 substituents independently selected from H and C1-3 alkyl; and (b) from 0-3 ring heteroatoms (in addition to the nitrogen atom attached to R’ and R”), which are each independently selected from the group consisting of N(Rd), O, and S.

[0255] In some embodiments, it is provided that when the compound is of Formula (1-1):

[0256] R1is other than unsubstituted phenyl, >ara-dimethylaminophenyl, para- aminosulfonylphenyl, and unsubstituted 4-pyridinyl. In some embodiments, it is provided that when the compound of of Formula (1-1):

[0257]

[0258] R1is other than unsubstituted phenyl, para-mono- substituted phenyl, and unsubstituted pyridinyl. In some embodiments, it is provided that when the compound of Formula (1-2):

[0259]

[0260] R1is other than unsubstituted phenyl.

[0261] In some embodiments, it is provided that the compound is other than a compound of Formula (1-1) or Formula (1-2):

[0262] In some embodiments, it is provided that the compound is not of Formula (1-3):

[0263] In some embodiments, it is provided that when the compound is of Formula (1-4):

[0264] R1is other than para-m on osub sti tuted phenyl (e.g., / ¾ / ra-fluorophenyl )

[0265] In some embodiments, it is provided that when the compound is of Formula (1-5):

[0266] R3is other than trifluoromethyl. In some embodiments, it is provided that when the compound is of Formula (1-6):

[0267]

[0268] R2is other than:

[0269] (i) unsubstituted phenyl;

[0270]

[0271] (iv) unsubstituted pyridinyl;

[0272] Q1=Q2

[0273] (v) K QQ3^,-Q i4*~R‘ wherein each of Q1, Q2, Q3, and Q4is independently selected from N and CH; or

[0274] (vi) heteroaryl including from 9-10 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-2 independently selected Rc. In some embodiments, the compound is other than one or more of the following:

[0275]

[0276] In some embodiments, the compound is other than one or more of the following:

[0277]

[0278] In certain embodiments, the compound is other than those disclosed in European

[0279] Journal of Medicinal Chemistry (2014), 86, 270-278. In certain embodiments, the compound is other than those disclosed in Tetrahedron Letters (2012), 53(25), 3126- 3130. In certain embodiments, the compound is other than those disclosed in Organic Letters (2011), 13(24), 6516-6519. In certain embodiments, the compound is other than those disclosed in U.S. Patent Application Publication No. 2012 / 0095037 and / or U.S. Patent 8,362,019.

[0280] In certain embodiments, the compound is other than those disclosed in Angewandte Chemie, International Edition (2018), 57(5), 1399-1403. In certain embodiments, the compound is other than those disclosed in Organic Letters (2017), 79(19), 5118-5121. In certain embodiments, the compound is other than those disclosed in Tetrahedron (2009), 65(44), 8930-8939. In certain embodiments, the compound is other than those disclosed in Organic Letters (2016), 75(13), 3250-3253. In certain embodiments, the compound is other than those disclosed in Organic & Biomolecular Chemistry (2015), 73(21), 6047-6058. In certain embodiments, the compound is other than those disclosed in Chemistry - A European Journal (2013), 79(49), 16760-16771. In certain embodiments, the compound is other than those disclosed in Organic & Biomolecular Chemistry (2013), 77(18), 3064- 3072. In certain embodiments, the compound is other than those disclosed in Organic Letters (2011), 13(24), 6516-6519. In certain embodiments, the compound is other than those disclosed in Bioorganic & Medicinal Chemistry Letters (2004), 74(13), 3595-3599. In certain embodiments, the compound is other than those disclosed in International Patent Application Publication No. 2015 / 073528. In certain embodiments, the compound is other than those disclosed in International Patent Application Publication No. 2012 / 146667. In certain embodiments, the compound is other than those disclosed in International Patent Application Publication No. 2001 / 030778. In certain embodiments, the compound is other than those disclosed in U.S. Patent Application Publication No. 2012 / 0095037.

[0281] In certain embodiments, the compound is other than those disclosed in Journal of Medicinal Chemistry (2012), 55(11), 5291-5310. In certain embodiments, the compound is other than those disclosed in Tetrahedron Letters (2000), 41(28), 5383-5386. In certain embodiments, the compound is other than those disclosed in International Patent Application Publication No. WO 2017 / 171234. In certain embodiments, the compound is other than those disclosed in International Patent Application Publication No. WO 2016 / 176460. In certain embodiments, the compound is other than those disclosed in Japanese Patent Application Publication No. JP 2013 / 018771 and / or JP 5,959,330. In certain embodiments, the compound is other than those disclosed in International Patent Application Publication No. WO 2011 / 153310. In certain embodiments, the compound is other than those disclosed in International Patent Application Publication No. WO 2011 / 082270. In certain embodiments, the compound is other than those disclosed in Australia Patent Application Publication No. AU 2010 / 331175 and / or U.S. Patent Application Publication No. US 2012 / 0258951 and / or U.S. 2014 / 0194407. In certain embodiments, the compound is other than those 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 those disclosed in WO 2010 / 030360. In certain embodiments, the compound is other than those disclosed in European Patent Application No. EP 1878724 and / or U.S. Patent 8,188,282. In certain embodiments, the compound is other than those disclosed in International Patent Application No. WO 2007 / 075629. In certain embodiments, the compound is other than those disclosed in Japan Patent Application Publication No. JP 2000 / 302754 and / or U.S. Patent No. 6,358,634.

[0282] Variable A1and X4-X4

[0283] In some embodiments, A1is N.

[0284] In other embodiments, A1is CH.

[0285] In some embodiments, each of X1and X4is independently selected from CH and N.

[0286] In some embodiments, from 1-2 of X1, X2, X3, and X4are independently N.

[0287] In certain embodiments from 1-2 of X1, X2, X3, and X4are independently N; and from 2-3 of X1, X2, X3, and X4are each an independently selected CR3.

[0288] In certain embodiments, from 1-2 of X1, X2, X3, and X4are independently N; and each of X1and X4is independently N or CH. In some embodiments, two of X1, X2, X3, and X4are independently N; and the other two of X1, X2, X3, and X4are independently selected from N and CR3.

[0289] In certain embodiments, a compound of Formula (I) is of Formula (I-a):

[0290]

[0291] or a pharmaceutically acceptable salt thereof.

[0292] In certain embodiments, a compound of Formula (I) is of Formula (I-b):

[0293]

[0294] or a pharmaceutically acceptable salt thereof.

[0295] In certain of the foregoing embodiments when two of X1, X2, X3, and X4are independently N, the other two of X1, X2, X3, and X4are independently selected CR3.

[0296] In certain embodiments, a compound of Formula (I) is of Formula (I-al):

[0297] al);

[0298] or a pharmaceutically acceptable salt thereof.

[0299] In certain embodiments, a compound of Formula (I) is of Formula (I-a2):

[0300] or a pharmaceutically acceptable salt thereof.

[0301] In certain embodiments, a compound of Formula (I) is of Formula (I-bl):

[0302]

[0303] or a pharmaceutically acceptable salt thereof.

[0304] In some embodiments, one of X1, X2, X3, and X4is independently N; and the other three of X1, X2, X3, and X4are independently selected from N and CR3.

[0305] In certain embodiments, a compound of Formula (I) is of Formula (I-c):

[0306]

[0307] or a pharmaceutically acceptable salt thereof.

[0308] In certain embodiments, a compound of Formula (I) is of Formula (I-d):

[0309]

[0310] or a pharmaceutically acceptable salt thereof. In certain of the foregoing embodiments when one of X1, X2, X3, and X4is independently N, the other three of X1, X2, X3, and X4are independently selected CR3.

[0311] In certain embodiments, a compound of Formula (I) is of Formula (I-cl):

[0312]

[0313] or a pharmaceutically acceptable salt thereof.

[0314] In certain embodiments, a compound of Formula (I) is of Formula (I-dl):

[0315]

[0316] or a pharmaceutically acceptable salt thereof.

[0317] In certain embodiments, the compound of Formula (I-dl) has the following formula:

[0318] wherein: one R3is independently selected from -L4-R4and Rc’;

[0319] the other R3is independently selected from H, -L4-R4, and Rc’;

[0320] R1is (i) -(Y^n-Y2, wherein: • n is 0;

[0321] • Y2is:

[0322] (a) partially unsaturated C3-10cycloalkyl, which is optionally substituted with from 1-4 Rb,

[0323] (b) C6-10 aryl, which is optionally substituted with from 1-4 Rc;

[0324] (c) heteroaryl including from 5-10 ring atoms, wherein from 1- 4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-4 independently selected Rc, or

[0325] (d) partially unsaturated heterocyclyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), and O, and wherein one or more of the heterocyclyl ring carbon atoms are optionally substituted with from 1-4 independently selected Rb; and

[0326] R2is:

[0327] (i) C6-10 aryl, which is optionally further substituted with from 1-4 Rc;

[0328] (ii) heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd),

[0329] O, and S, and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-4 independently selected Rc;

[0330] (iii) partially unsaturated C3-10cycloalkyl, which is optionally substituted with from 1-4 Rb; or

[0331] (iv) partially unsaturated heterocyclyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), and O, and wherein one or more of the heterocyclyl ring carbon atoms are optionally substituted with from 1-4 independently selected Rb. Variable R1

[0332] In some embodiments, R1is -(Y' )n-Y2.

[0333] In some embodiments, n is 0.

[0334] In other embodiments, n is 1. In certain of these embodiments, Y1is C1-3 alkylene.

[0335] In some embodiments, Y2is heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-4 independently selected Rc. In certain of the foregoing embodiments, n is 0.

[0336] In some embodiments, Y2is heteroaryl including from 6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein one or more of the heteroaryl ring carbon atoms are substituted with from 1-4 independently selected Rc; or heteroaryl including 5 or from 9-10 ring atoms, wherein from 1 -4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-4 independently selected Rc; In certain of the foregoing embodiments, n is 0.

[0337] In certain embodiments, Y2is heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-4 independently selected Rc. In certain of these embodiments, n is 0.

[0338] In certain embodiments, Y2is heteroaryl including 6 ring atoms, wherein from 1-2 ring atoms are N, and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-4 independently selected Rc. For example, Y2can be pyridyl (e.g., 2-pyridyl or 6-pyridyl), wherein one or more of the ring carbon atoms are optionally substituted with from 1-4 (e.g., 1, 2, 3, or 4) independently selected Rc(e.g., Y2is pyridyl (e.g., 2-pyridyl or 6-pyridyl), wherein one or more of the ring carbon atoms are optionally substituted with one independently selected Rc). In certain of these embodiments, n is 0.

[0339] In certain embodiments, Y2is heteroaryl including 5 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-2 independently selected Rc. For example, Y2can be pyrazolyl, oxazolyl, or thiazolyl, wherein any substitutable nitrogen atom is optionally substituted with Rd, and wherein one or more of the ring carbon atoms are optionally substituted with from 1-2 independently selected Rc. In certain of these embodiments, n is 0.

[0340] In certain embodiments, Y2is heteroaryl including 5 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-3 independently selected Rc. In certain of these embodiments, n is 0.

[0341] In certain of these embodiments, Y2is furanyl, wherein one or more of the ring carbon atoms are optionally substituted with from 1-2 (e.g., 1) independently selected Rc. In certain of these embodiments, n is 0. In certain of the foregoing embodiments when Y2is heteroaryl, each occurrence of

[0342] Rcis independently selected from the group consisting of:

[0343] (iii) Ci-6alkyl;

[0344] (iv) C2-6 alkenyl;

[0345] (v) C2-6 alkynyl;

[0346] (vi) Ci-4 haloalkyl;

[0347] (vii) Ci-4 alkoxy;

[0348] (viii) Ci-4 haloalkoxy;

[0349] (ix) -(C0-3 alkylene)-C3-6cycloalkyl optionally substituted with from 1-4 independently selected Ci-4 alkyl;

[0350] (xiv) -Ci-4 thioalkoxy; and

[0351] (xx) C3-6 cycloalkoxy.

[0352] In certain of the foregoing embodiments when Y2is heteroaryl, each occurrence of

[0353] Rcis independently selected from the group consisting of:

[0354] (vii) Ci-4 alkoxy;

[0355] (viii) Ci-4 haloalkoxy (e.g., OCH2CF3 or OCF3);

[0356] (xiv) -Ci-4 thioalkoxy; and

[0357] (xx) C3-6 cycloalkoxy (e.g., cyclopropoxy).

[0358] For example, each occurrence of Rcis an independently selected Ci-4 alkoxy (e.g., -OCH3, -OCH2CH3). As another example, each occurrence of Rcis an independently selected C1-6 alkyl

[0359] (e.g., methyl).

[0360] In certain of the foregoing embodiments when Y2is heteroaryl, each occurrence of Rdis an independently selected C1-6 alkyl.

[0361] In certain of the foregoing embodiments when Y2is heteroaryl and n is 0, R1can be selected from the group consisting of:

[0362] In certain of the foregoing embodiments when Y2is heteroaryl and n is 0, R1can be selected from the group consisting of:

[0363] As a non-limiting example of the foregoing embodiments, when Y2is heteroaryl and n is 0, R1can be:

[0364] In certain embodiments, when Y2is heteroaryl and n is 0, R1can be:

[0365] In certain embodiments, when Y2is heteroaryl and n is 0, R1can be:

[0366] In some embodiments, Y2is C3-10 cycloalkyl, which is optionally substituted with from 1-4 Rb. In certain of these embodiments, n is 0.

[0367] In some embodiments, Y2is C6-10 aryl, which is optionally substituted with from 1-

[0368] 4 Rc.

[0369] In certain embodiments, Y2is phenyl, which is substituted with from 1-4 Rc.

[0370] In certain embodiments when Y2is phenyl; and the ring carbon atom para to the point of attachment to Y1is substituted with Rc, then one or more of the other ring carbon atoms is optionally substituted with from 1-3 Rc. In some embodiments, R1is -Z1-Z2-Z3.

[0371] In some embodiments, Z1is CH2.

[0372] In some embodiments, Z2is -0-, or -S-. For example, Z2can be -0-.

[0373] In some embodiments, Z3is C2-3 alkylene.

[0374] In certain embodiments, Z1is CH2, and Z2is -0-, or -S- (e.g., -0-). In certain embodiments, Z2is -0-, or -S- (e.g., -0-), and Z3is C2-3 alkylene.

[0375] In certain embodiments, Z1is CH2, and Z2is -0-, or -S- (e.g., -0-), and Z3is C2-3 alkylene.

[0376] In certain of the foregoing embodiments when R1is -Z'-Z2-Z3, R1is

[0377] Variable R2

[0378] In some embodiments, R2is:

[0379] (i) C6-10 aryl, which is optionally further substituted with from 1-4 Rc;

[0380] (ii) heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd),

[0381] O, and S, and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-4 independently selected Rc;

[0382] (iii) partially unsaturated C3-10cycloalkyl, which is optionally substituted with from 1-4 Rb; or

[0383] (iv) partially unsaturated heterocyclyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), and O, and wherein one or more of the heterocyclyl ring carbon atoms are optionally substituted with from 1-4 independently selected Rb.

[0384] In some embodiments, R2is C6-10 aryl, which is optionally substituted with from

[0385] 1-4 Rc.

[0386] In certain embodiments, R2is phenyl, which is optionally substituted with from 1- 4 Rc. In certain of the foregoing embodiments, R2can be phenyl, which is optionally substituted with from 1-2 Rc. As a non-limiting example, R2can be phenyl, which is optionally substituted with 2 Rc.

[0387] In certain of the foregoing embodiments when R2is aryl (e.g., phenyl), each occurrence of Rcis independently selected from the group consisting of: (i) halo (e.g., F);

[0388] (vi) Ci-4 haloalkyl (e.g., CF3);

[0389] (vii) Ci-4 alkoxy;

[0390] (viii) Ci-4 haloalkoxy; and

[0391] (xiv) -Ci-4 thioalkoxy.

[0392] As a non-limiting example, each occurrence of Rccan be independently selected from halo, Ci-4 alkoxy, and Ci-4 haloalkyl (e.g., each occurrence of Rcis independently - OCH3, CF3, or F). In certain of the foregoing embodiments when R2is aryl (e.g., phenyl), R2has the following formula (A):

[0393]

[0394] in which each of R2a, R2b, R2c, R2d, and R2eare each independently selected from the group consisting of H and Rc.

[0395] In certain embodiments, four of R2a, R2b, R2c, R2 l, and R2eare each an independently selected Rc, and the other is H.

[0396] In certain embodiments, three of R2a, R2b, R2c, R2tl, and R2eare each an independently selected Rc, and the others are H.

[0397] In certain embodiments, two of R2a, R2b, R2c, R2 l, and R2eare each an independently selected Rc, and the others are H. In certain of these embodiments, R2aand R2eare each an independently selected Rc(e.g., Ci-4 alkoxy; Ci-4 haloalkoxy; -Ci-4 thioalkoxy; Ci-4 haloalkyl and halo e.g., each occurrence of Rcis an independently selected Ci-4 alkoxy (e.g., -OCH3). For example, R2aand R2eare each OCFb.

[0398] In certain embodiments. R2is: In certain of the foregoing embodiments when R2is aryl (e.g., phenyl), R2has formula (B)

[0399] In some embodiments, when R2is aryl (e.g., phenyl); and R2has the following formula (A):

[0400]

[0401] from 1-4 of R2a, R2b, R2 l, and R2eis an independently selected Rc.

[0402] In certain of the foregoing embodiments, each Rcis independently selected from:

[0403] (i) -F;

[0404] (ii) cyano;

[0405] (iii) Ci-3 alkyl, C5-6 alkyl, n-butyl, sec-butyl, iso-butyl;

[0406] (iv) C2-6 alkenyl;

[0407] (v) C2-6 alkynyl;

[0408] (vi) Ci-4 haloalkyl;

[0409] (vii) Ci-4 alkoxy;

[0410] (viii) Ci-4 haloalkoxy;

[0411] (ix) -(C0-3 alkylene)-C3-6cycloalkyl optionally substituted with from 1-4 independently selected Ci-4 alkyl;

[0412] (x) -S(0)i-2(Ci-4 alkyl);

[0413] (xii) -OH;

[0414] (xiv) -Ci-4 thioalkoxy;

[0415] (xv) -NO2;

[0416] (xvi) -C(=0)(Ci-4 alkyl); (xvii) -C(=0)0(Ci-4 alkyl);

[0417] (xviii) -C(=0)OH;

[0418] (xix) -C(=0)N(R’)(R”); and

[0419] (xx) C3-6 cycloalkoxy.

[0420] In some embodiments, R2is heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-4 independently selected Rc.

[0421] In certain of the foregoing embodiments, R2is heteroaryl including from 6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), and N(Rd), and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-4 independently selected Rc.

[0422] As a non-limiting example, R2can be pyridinyl optionally substituted with from 1-2 independently selected Rc.

[0423] In certain of the foregoing embodiments when R2is heteroaryl as defined above (e.g·, R2is heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-4 independently selected Rc), each Rcis independently selected from:

[0424] (i) halo

[0425] (vi) Ci-4 haloalkyl (e.g., CF3);

[0426] (vii) Ci-4 alkoxy;

[0427] (viii) Ci-4 haloalkoxy; and

[0428] (xiv) -Ci-4 thioalkoxy. As a non-limiting example, each Rccan be independently Ci-4 alkoxy (e.g., methoxy).

[0429] In certain of the foregoing embodiments when R2is heteroaryl, R2is:

[0430] In certain of the foregoing embodiments when R2is heteroaryl, R2is:

[0431] In some embodiments (e.g., when the compound has Formula I-dl), when R2is heteroaryl as defined elsewhere herein, R2is selected from:

[0432] (a) heteroaryl including 5 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-4 independently selected Rc;

[0433] (b) wherein each of Q1, Q2, Q3, Q4, and Q5is independently selected from N, CH, and CRC, provided that:

[0434] • from 1-4 of Q1, Q2, Q3, Q4, and Q5is independently CRC;

[0435] • one or more of Q1, Q2, Q3, Q4, and Q5is independently N; and

[0436] • when Q5is CRC, one or more of Q1, Q2, Q3, and Q4is CRC; and (c) heteroaryl including from 9-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein one or more of the heteroaryl ring carbon atoms are substituted with from 1-4 independently selected Rc, wherein each occurrence of Rcis independently selected from:

[0437] (i) -F;

[0438] (ii) cyano;

[0439] (iii) C2-6alkyl;

[0440] (iv) C2-6alkenyl;

[0441] (v) C2-6alkynyl;

[0442] (vi) Ci-4 haloalkyl;

[0443] (vii) Ci-4 alkoxy;

[0444] (viii) Ci-4 haloalkoxy;

[0445] (ix) -(C0-3 alkylene)-C3-6cycloalkyl optionally substituted with from 1-4 independently selected Ci-4 alkyl;

[0446] (x) -S(0)i-2(Ci-4 alkyl);

[0447] (xi) -NReRf;

[0448] (xiii) -S(0)I-2(NR’R”);

[0449] (xiv) -Ci-4 thioalkoxy;

[0450] (xv) -NO2;

[0451] (xvi) -C(=0)(Ci-4 alkyl);

[0452] (xvii) -C(=0)0(Ci-4 alkyl);

[0453] (xviii) -C(=0)OH;

[0454] (xix) -C(=0)N(R’)(R”); and

[0455] (xx) C3-6 cycloalkoxy.

[0456] Variable R3

[0457] In some embodiments, one or more occurrences of R3is each independently selected from Rc’ and -L4-R4. In some embodiments, one occurrence of R3is -L4-R4.

[0458] In certain of the foregoing embodiments when one occurrence R3is -L4-R4, each of the remaining occurrences of R3is independently selected from the group consisting of H and Rc’ (e.g., Rc’ can be halo, e.g., Br or Cl; or Rc’ can be -OH or ML·). For example, each of the remaining occurrences of R3can be H.

[0459] In some embodiments, one occurrence of R3is -L4-R4, and one occurrence of R3is H or Rc’ (e.g., Rc’ can be halo, e.g., Br or Cl; or Rc’ can be ML·).

[0460] In some embodiments, one occurrence of R3is -L4-R4, and one occurrence of R3is Rc’ (e.g., Rc’ can be halo, e.g., Br or Cl (e.g., Rc’ can be Cl)).

[0461] In some embodiments, one occurrence of R3is -L4-R4, and one occurrence of R3is H.

[0462] In some embodiments, two occurrences of R3are independently selected -L4-R4.

[0463] In certain of the foregoing embodiments, any remaining occurrence of R3is selected from the group consisting of H and Rc’. For example, any remaining occurrence of R3can be H.

[0464] As a non-limiting example of the foregoing embodiments, each of X2and X3can be CR3, wherein each R3is an independently selected -L4-R4(in certain embodiments, each of X1and X4is independently CH or N).

[0465] In some embodiments, one occurrence of R3is H or Rc’ (e.g., Rc’ can be halo, e.g., Br or Cl; or Rc’ can be -OH or ML·).

[0466] In certain embodiments, when one occurrence of R3is Rc’, each of the remaining occurrences of R3is independently H or Rc’. For example, each of the remaining occurrences of R3can be H.

[0467] In certain embodiments, when one occurrence of R3is Rc’; and one or more occurrences of the remaining R3is independently selected from -L4-R4and Rc’.

[0468] In some embodiments, one occurrence of R3is H. Non-Limiting Combinations ofX'-X4and R3

[0469] x2— x3

[0470] In some embodiments, the moiety (the originally provided structure in

[0471] x2— x3

[0472] x'1Q X4

[0473] U.S. Provisional Application Serial No. 62 / 742,218 V-V ^ has been redrawn to further

[0474] clarify points of connection) i (the originally provided structure in U.S. Provisional Application Serial No. 62 / 742,218 has been redrawn to further clarify points of connection), wherein * denotes point of attachment to NR2; and denotes point of attachment to A1.

[0475] In certain embodiments, R3Bis -L4-R4; and R3Cis H (e.g., -L4can be NHS(0)2). In certain embodiments, R3Bis -L4-R4; and R3Cis Rc’ (e.g., Rc’ can be halo such as -Cl; and / or -L4can be NHS(0)2).

[0476] In certain embodiments, R3Bis -L4-R4; and R3Cis an independently selected -L4- R4. In certain of the foregoing embodiments, the -L4of R3Bis different from the -L4of R3C. As a non-limiting example, the -L4of R3Bcan be NHS(0)2; and the -L4of R3Ccan be a bond.

[0477] In certain embodiments, R3Bis H; and R3Cis -L4-R4(e.g., -L4can be NHS(0)2).

[0478] In certain embodiments, R3Bis Rc’; and R3Cis -L4-R4(e.g., -L4can be NHS(0)2). In certain embodiments, R3Bis H; and R3Cis Rc’.

[0479] x2-x3

[0480] cίG)c4

[0481] In some embodiments, the moiety (the originally provided structure x2-x3

[0482] <iQ x4

[0483] \ /

[0484] in U.S. Provisional Application Serial No. 62 / 742,218 has been redrawn to

[0485] further clarify points of connection) (the originally provided structure Provisional Application Serial No. 62 / 742,218 has been redrawn to further clarify points of connection), wherein * denotes point of attachment to NR2; and ^ denotes point of attachment to A1.

[0486] In certain embodiments, R3Ais H.

[0487] In certain of the foregoing embodiments, R3Bis -L4-R4(e.g., -L4can be NHS(0)2). x2-x3

[0488] In some embodiments, the moiety (the originally provided structure x2-x3

[0489] <iQ x4

[0490] v ' / '· in U.S. Provisional Application Serial No. 62 / 742,218 has been redrawn to

[0491] further clarify points of connection) (the originally provided structure}3B}3C \0N

[0492] in U.S. Provisional Application Serial No. 62 / 742,218 has been redrawn to further clarify points of connection) , wherein * denotes point of attachment to NR2; and denotes point of attachment to A1.

[0493] In certain embodiments, R3Ais H.

[0494] In certain of the foregoing embodiments, R3Bis -L4-R4(e.g., -L4can be NHS(0)2). In certain of the foregoing embodiments, R3Bis -L4-R4(e.g., -L4can be NHS(0)2); and R3Cis H.

[0495] In certain of the foregoing embodiments, R3Bis -L4-R4(e.g., -L4can be NHS(0)2); and R3Cis Rc’.

[0496] In certain of the foregoing embodiments, R3Bis -L4-R4(e.g., -L4can be NHS(0)2); and R3Cis an independently selected -L4-R4. In certain of the foregoing embodiments, the -L4of R3Bis different from the -L4of R3C. As a non-limiting example, the -L4of R3Bcan be NHS(0)2; and the -L4of R3Ccan be a bond.

[0497] x2— x3

[0498] x’O'x4

[0499] In some embodiments, the moiety (the originally provided structure x2-x3

[0500] <iQ x4

[0501] in U.S. Provisional Application Serial No. 62 / 742,218 has been redrawn to

[0502] further clarify points of connection) (the originally provided structure Provisional Application Serial No. 62 / 742,218 has been redrawn to further clarify points of connection) , wherein * denotes point of attachment to NR2; and ^ denotes point of attachment to A1.

[0503] In certain embodiments, R3Dis H.

[0504] In certain of the foregoing embodiments, R3Bis -L4-R4(e.g., -L4can be

[0505] NHS(0)2).

[0506] In certain of the foregoing embodiments, R3Bis -L4-R4(e.g., -L4can be

[0507] NHS(0)2); and R3Cis H.

[0508] In certain of the foregoing embodiments, R3Bis -L4-R4(e.g., -L4can be

[0509] NHS(0)2); and R3Cis Rc’.

[0510] In certain of the foregoing embodiments, R3Bis -L4-R4(e.g., -L4can be NHS(0)2); and R3Cis an independently selected -L4-R4. In certain of the foregoing embodiments, the -L4of R3Bis different from the -L4of R3C. As a non-limiting example, the -L4of R3Bcan be NHS(0)2; and the -L4of R3Ccan be a bond.

[0511] Variable L4

[0512] In some embodiments, -L4is -N(H)S(0)I-2- or -N(Rd)S(0)i-2. (e.g., N(CI-3 alkyl)S(0)2).

[0513] In certain of the foregoing embodiments, -L4is -N(H)S(0)2-.

[0514] In some embodiments, -L4is -N(H)S(0)(=NH)-, -N(Rd)S(0)(=NH),

[0515] N(H)S(0)(=NRd)-, or -N(Rd)S(0)(=NRd)-.

[0516] In certain of the foregoing embodiments, -L4is -N(H)S(0)(=NH)-.

[0517] In some embodiments, -L4is -S(0)(=NH)NH-, -S(0)(=NRd)NH-, - s(O)0 =NH)NRd-, or -S(0)(=NRd)NRd-. In certain of the foregoing embodiments, -L4is -S(0)(=NH)NH-.

[0518] In some embodiments, -L4is -S(0)I-2N(H)- or -S(0)i-2N(Rd)-.

[0519] In certain of the foregoing embodiments, -L4is -S(0)2N(H)-.

[0520] In some embodiments, -L4is -N(H)C(0)- or -N(Rd)C(0).

[0521] In certain of the foregoing embodiments, -L4is -N(H)C(0)-.

[0522] In some embodiments, L4is -C(0)NH- or -C(0)N(Rd)-.

[0523] In some embodiments, -L4is -N(H)-, -N(Rd)-, or -N(R4)-.

[0524] In certain embodiments, -L4is -N(H)- or -N(R4)-.

[0525] In some embodiments, -L4is a single bond.

[0526] In some embodiments, -L4is CºC.

[0527] In some embodiments, -L4is -0-.

[0528] In some embodiments, L4is selected from the group consisting of: -N(H)S(0)i-2N(H)-, -N(Rd)S(0)i-2N(H)-, -N(H)S(0)i-2N(Rd)-, and -N(Rd)S(0)i-2N(Rd)-.

[0529] In some embodiments, L4is -N(H)S(0)I-2N(H)- (e.g., -N(H)S(0)2N(H)-).

[0530] In some embodiments, L4is -N(H)S(0)i-2N(Rd)- (e.g., -N(H)S(0)2N(Rd)-, e.g., - N(H)S(0)2N(CI-3alkyl)-).

[0531] In some embodiments, -L4is selected from the group consisting of-N(H)S(0)2-, CºC, a single bond, -C(0)N(H)-, -N(H)-, -N(R4)-, -N(Rd)-, and -N(H)C(0)-.

[0532] In certain of the foregoing embodiments, -L4is selected from the group consisting of— N(H)S(0)2-, a single bond, -NH-, -N(R4)-, and -N(H)C(0)-.

[0533] In some embodiments, -L4is selected from: (i) a bond (in certain embodiments, when -L4is a bond; and R4is (Y3)P- Y4, then p is 1).

[0534] (ii) N(R4);

[0535] (iii) -N(H)S(0)I-2- or -N(Rd)S(0)i-2-;

[0536] (iv) -S(0)I-2N(H)- or -S(0)i-2N(Rd)-;

[0537] (vi) -S(0)i-2-;

[0538] (viii) -N(H)C(0)- or -N(Rd)C(0)-;

[0539] (ix) -CºC;

[0540] (x) -N(H)S(0)(=NH)-, -N(Rd)S(0)(=NH), -N(H)S(0)(=NRd)-, or

[0541] N(Rd)S(0)(=NRd)-

[0542] (xi) -S(0)(=NH)NH-, - S (0)(=NRd)NH-, -S(0)(=NH)NRd-, or -

[0543] S (0)(=NRd)NRd- ; and

[0544] (xii) -S(0)(=NH)- or -S(0)(=NRd).

[0545] Variable R4

[0546] In some embodiments, R4is -(Y3)p-Y4.

[0547] In some embodiments, p is 0.

[0548] In other embodiments, p is 1. In certain of these embodiments, Y3is C1-3 alkylene. For example, Y3can be CH2 or CH2-CH2.

[0549] In some embodiments, Y4is C6-10 aryl, which is optionally substituted with from

[0550] 1-4 Rc.

[0551] In some embodiments, Y4is phenyl, which is optionally substituted with from 1-2 (e.g., 1) Rc.

[0552] In certain embodiments when Y4is C6-10 aryl, which is optionally substituted with from 1-4 Rc(e.g., when Y4is phenyl, which is optionally substituted with from 1-2 (e.g., 1) Rc), each occurrence of Rcis independently selected from the group consisting of:

[0553] (i) halo; (ii) cyano;

[0554] (iii) Ci-6alkyl;

[0555] (iv) C2-6 alkenyl;

[0556] (v) C2-6 alkynyl;

[0557] (vi) Ci-4 haloalkyl;

[0558] (vii) Ci-4 alkoxy;

[0559] (viii) Ci-4 haloalkoxy;

[0560] (ix) -(C0-3 alkylene)-C3-6cycloalkyl optionally substituted with from 1-4 independently selected Ci-4 alkyl;

[0561] (xiv) -Ci-4 thioalkoxy, and

[0562] (xx) C3-6 cycloalkoxy.

[0563] In certain embodiments when Y4is C6-10 aryl, which is optionally substituted with from 1-4 Rc(e.g., when Y4is phenyl, which is optionally substituted with from 1-2 (e.g., 1) Rc), each occurrence of Rcis independently selected from the group consisting of:

[0564] (i) halo;

[0565] (iii) Ci-6alkyl;

[0566] (vi) Ci-4 haloalkyl;

[0567] (vii) Ci-4 alkoxy; and

[0568] (viii) Ci-4 haloalkoxy.

[0569] In certain embodiments when Y4is C6-10 aryl, each occurrence of Rcis independently selected from the group consisting of:

[0570] (vii) Ci-4 alkoxy;

[0571] (viii) Ci-4 haloalkoxy; and

[0572] (xiv) -Ci-4 thioalkoxy.

[0573] In certain embodiments, Y4is C6-10 aryl (e.g., phenyl), which is unsubstituted. In certain embodiments when p=l and Y4is C6-10 aryl, R4is selected from the group consisting of:

[0574]

[0575] In certain embodiments when p=l and Y4is C6-10 aryl, R4is selected from the group consisting of:

[0576]

[0577] In certain embodiments when p=0 and Y4is C6-10aryl, R4is:

[0578]

[0579] In certain embodiments when p=0 and Y4is C6-10 aryl, R4is

[0580] In some embodiments, Y4is C3-6 (e.g., C3-4 or C6) cycloalkyl, which is optionally substituted with from 1-4 Rb.

[0581] In certain of the foregoing embodiments, Y4is cyclopropyl, which is optionally substituted with from 1-2 Rb. For example, Y4is unsubstituted cyclopropyl.

[0582] In some embodiments, Y4is C6 cycloalkyl (e.g., cyclohexyl), which is optionally substituted with from 1-2 Rb.

[0583] In certain of the foregoing embodiments when Y4is cycloalkyl which is optionally substituted with from 1-4 Rb, each occurrence of Rbis independently selected from the group consisting of: -F, C 1-6 alkyl, C1-4 haloalkyl, and -OH (e.g., Rbcan be OH; and / or Rbcan be C1-6 alkyl such as methyl).

[0584] In certain embodiments when p=l and Y4is C3-6 cycloalkyl optionally substituted with from 1-4 Rb, R4is selected from the group consisting of:

[0585] In certain embodiments when p=l and Y4is C3-6 cycloalkyl optionally substituted with from 1-4 Rb, R4is selected from the group consisting of:

[0586] In certain embodiments when p=0 and Y4is C3-6 cycloalkyl optionally substituted with from 1-4 Rb, R4is selected from the group consisting of:

[0587]

[0588] In certain embodiments, Y4is C3-6 (e.g., C3-4 or C6) cycloalkyl, which is unsubstituted. In certain of these embodiments, Y4is unsubstituted cyclopropyl or unsubstituted cyclobutyl (e.g., unsubstituted cyclopropyl).

[0589] In some embodiments, Y4is heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-4 independently selected Rc.

[0590] In certain of the foregoing embodiments, Y4is heteroaryl including 6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), and N(Rd), and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-4 independently selected Rc.

[0591] As non-limiting examples of the foregoing, Y4can be pyridinyl (e.g., 2-pyridinyl, 3-pyridinyl, or 4-pyridinyl), pyrimidinyl (e.g., 2-pyrimidinyl or 5-pyrimidinyl), or pyrazinyl, each of which is optionally substituted with from 1-2 independently selected Rc.

[0592] For example Y4can be pyridinyl, pyrimidinyl, or pyrazinyl, each of which is unsubstituted.

[0593] In certain embodiments when Y4is heteroaryl optionally substituted with one or more independently selected Rcas defined supra , each occurrence of Rcis independently selected from the group consisting of:

[0594] (i) halo;

[0595] (ii) cyano;

[0596] (iii) Ci-6alkyl;

[0597] (iv) C2-6 alkenyl;

[0598] (v) C2-6 alkynyl;

[0599] (vi) Ci-4 haloalkyl;

[0600] (vii) Ci-4 alkoxy;

[0601] (viii) Ci-4 haloalkoxy;

[0602] (ix) -(C0-3 alkylene)-C3-6cycloalkyl optionally substituted with from 1-4 independently selected Ci-4 alkyl; (xii) OH;

[0603] (xiv) -Ci-4 thioalkoxy, and

[0604] (xx) C3-6 cycloalkoxy.

[0605] In certain of these embodiments, each occurrence of Rcis independently selected from the group consisting of:

[0606] (i) halo (e.g., F, Cl);

[0607] (iii) Ci-6 alkyl (e.g., methyl); and

[0608] (xii) OH.

[0609] In certain embodiments when p 1; and Y4is heteroaryl, R4is selected from the group consisting of:

[0610]

[0611] In certain embodiments when p 1; and Y4is heteroaryl, R4is selected from the group consisting of:

[0612] In certain embodiments when p = 0; and Y4is heteroaryl, R4is selected from the group consisting of:

[0613] In certain embodiments when p = 0; and Y4is heteroaryl, R4is selected from the group consisting of:

[0614] In some embodiments, Y4is heterocyclyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), and O, and wherein one or more of the heterocyclyl ring carbon atoms are optionally substituted with from 1-4 independently selected Rb.

[0615] In certain of the foregoing embodiments, Y4is heterocyclyl including from 4-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), and O, and wherein one or more of the heterocyclyl ring carbon atoms are optionally substituted with from 1-4 independently selected Rb.

[0616] In certain embodiments, Y4heterocyclyl including from 4 ring atoms, wherein 1 ring atom is a heteroatom, independently selected from the group consisting of N, N(H), N(Rd), and O, and wherein one or more of the heterocyclyl ring carbon atoms are optionally substituted with from 1-2 independently selected Rb.

[0617] As a non-limiting example, Y4can be oxetanyl optionally substituted with from 1- 2 independently selected Rb(e.g., unsubstituted oxetanyl).

[0618] As another non-limiting example, Y4can be azetidinyl optionally substituted with from 1-2 independently selected Rb(e.g., azetidinyl substituted with one Rb).

[0619] In some embodiments, Y4is heterocyclyl including from 6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), and O, and wherein one or more of the heterocyclyl ring carbon atoms are optionally substituted with from 1-4 independently selected Rb. As non-limiting examples, Y4can be selected from the group consisting of tetrahydropyranyl, piperidinyl, piperazinyl, and morpholinyl, each of which is optionally substituted with from 1-2 independently selected Rb.

[0620] As non-limiting examples, Y4can be selected from tetrahydropyranyl, piperidinyl, and morpholinyl, each of which is optionally substituted with from 1-2 independently selected Rb.

[0621] In certain of the foregoing embodiments when Y4is heterocyclyl optionally substituted with from 1-4 independently selected Rb, each occurrence of Rbis independently selected from the group consisting of: -F, Ci-6alkyl, Ci-4 haloalkyl, oxo, and -OH.

[0622] In certain of the foregoing embodiments when Y4is heterocyclyl optionally substituted with from 1-4 independently selected Rb, each occurrence of Rbis independently selected from the group consisting of: -F, Ci-6alkyl, Ci-4 haloalkyl, and - OH (e g., Rbcan be OH).

[0623] In certain embodiments when p = 1; and Y4is heterocyclyl optionally substituted with from 1-4 independently selected Rb, R4is selected from the group consisting of:

[0624]

[0625] In certain embodiments when p = 1; and Y4is heterocyclyl optionally substituted

[0626]

[0627] with from 1-4 independently selected Rb, R4isH In certain embodiments when p = 0; and Y4is heterocyclyl optionally substituted with from 1-4 independently selected Rb, R4is selected from the group consisting of:

[0628] In certain embodiments when p = 0; and Y4is heterocyclyl optionally substituted with from 1-4 independently selected Rb, R4is selected from the group consisting of:

[0629]

[0630] In some embodiments, R4is Ci-io alkyl, optionally substituted with from 1-6 independently selected Ra.

[0631] In certain embodiments, R4is Ci-6alkyl, optionally substituted with from 1-6 independently selected Ra.

[0632] In certain embodiments, R4is Ci-6alkyl, optionally substituted with from 1-2 independently selected Ra. For example, R4can be methyl.

[0633] In certain of the foregoing embodiments when R4is Ci-6alkyl, each occurrence of Rais independently selected from the group consisting of: -F, -OH; Ci-4 alkoxy; and Ci-4 haloalkoxy.

[0634] In certain embodiments, each occurrence of Rais independently -OH. For example, In some embodiments, R4is selected from the group consisting of methyl, ethyl,

[0635]

[0636] In some embodiments, R4is selected from methyl and CH3

[0637] In some embodiments, R4is C2-10 (e.g., C2-4) alkynyl, which is optionally substituted with from 1-6 (e.g., from 1-3) independently selected Ra(e.g., unsubstituted

[0638] C2-4 alkynyl such

[0639] In some embodiments, R4is C2-10 (e.g., C2-4) alkenyl, which is optionally substituted with from 1-6 (e.g., from 1-3) independently selected Ra(e.g., unsubstituted C2-4 alkenyl such as vinyl).

[0640] In some embodiments (e.g., when -L4is a bond or -0-), R4is C2-10 alkyl, optionally substituted with from 1-6 independently selected Ra; or methyl optionally substituted with from 1-2 independently selected Ra.

[0641] In certain embodiments (e.g., when -L4is a bond or -0-), R4is C2-10 alkyl, optionally substituted with from 1-6 independently selected Ra; or methyl substituted with from 1-2 independently selected Ra.

[0642] Non-limiting Combinations of L4and R4

[0643] Non-Limiting Combination [A]

[0644] In some embodiments, -L4is selected from the group consisting of-N(H)S(0)2-, - N(H)S(0)2N(H)-, -N (H) S (0)2N (Rd)-, CºC, a single bond, -C(0)N(H)-, -N(H)-, -N(R4)-, -N(Rd)-, and -N(H)C(0)-; and

[0645] R4is selected from the group consisting of: (i) Ci-6alkyl optionally substituted with 1-2 Ra;

[0646] (ii) -(Y3)p-Y4; and

[0647] (iii) C2-10 alkenyl or C2-10 alkynyl, each of which is optionally substituted with from 1-3 independently selected Ra.

[0648] In certain embodiments, -L4is selected from the group consisting of -N(H)S(0)2- , -N(H)S(0)2N(H)-, and -N(H)S(0)2N(Rd)-; and

[0649] R4is selected from the group consisting of:

[0650] (i) Ci-6alkyl optionally substituted with 1-2 Ra;

[0651] (ii) -(Y3)p-Y4; and

[0652] (iii) C2-10 alkenyl or C2-10 alkynyl, each of which is optionally substituted with from 1-3 independently selected Ra.

[0653] In some embodiments, -L4is selected from the group consisting of-N(H)S(0)2-, CºC, a single bond, -C(0)N(H)-, -N(H)-, -N(R4)-, -N(Rd)-, and -N(H)C(0)-; and

[0654] R4is selected from the group consisting of:

[0655] (i) Ci-6alkyl optionally substituted with 1-2 Ra; and

[0656] (ii) -(YVY4In certain embodiments, -L4is selected from the group consisting of—

[0657] N(H)S(0)2-, a single bond, -NH-, -N(R4)-, and -N(H)C(0)-; and

[0658] R4is selected from the group consisting of :

[0659] (i) Ci-6alkyl optionally substituted with 1-2 Ra; and

[0660] (ii) -(Y3)p-Y4.

[0661] In certain embodiments, -L4is -N(H)S(0)2-; and R4is selected from the group consisting of :

[0662] (i) Ci-6alkyl optionally substituted with 1-2 Ra; and

[0663] (ii) -(YVY4 In certain embodiments, -L4is a single bond; and R4is selected from the group consisting of :

[0664] (i) Ci-6alkyl optionally substituted with 1-2 Ra; and

[0665] (ii) -(Y3)p-Y4.

[0666] In certain embodiments, -L4is -NH- or -N(R4)-; and R4is selected from the group consisting of :

[0667] (i) Ci-6alkyl optionally substituted with 1-2 Ra; and

[0668] (ii) -(Y3)p-Y4.

[0669] In certain embodiments, -L4is -N(H)C(0)-; and R4is selected from the group consisting of :

[0670] (i) Ci-6alkyl optionally substituted with 1-2 Ra; and

[0671] (ii) -(Y3)p-Y4.

[0672] In certain of these embodiments, -L4is -N(H)S(0)2N(H)- or -N(H)S(0)2N(Rd)-; and

[0673] R4is selected from the group consisting of:

[0674] (i) Ci-6alkyl optionally substituted with 1-2 Ra; and

[0675] (ii) -(Y3)p-Y4.

[0676] In certain embodiments, -L4is -N(H)S(0)2-; and R4is selected from the group consisting of :

[0677] R4is selected from the group consisting of:

[0678] (i) Ci-6alkyl optionally substituted with 1-2 Ra;

[0679] (ii) -(Y3)p-Y4; and

[0680] (iii) C2-10 alkenyl or C2-10 alkynyl, each of which is optionally substituted with from 1-3 independently selected Ra. In certain embodiments, -L4is a single bond; and R4is selected from the group consisting of :

[0681] R4is selected from the group consisting of:

[0682] (i) Ci-6alkyl optionally substituted with 1-2 Ra;

[0683] (ii) -(Y3)p-Y4; and

[0684] (iii) C2-10 alkenyl or C2-10 alkynyl, each of which is optionally substituted with from 1-3 independently selected Ra.

[0685] In certain embodiments, -L4is -NH- or -N(R4)-; and R4is selected from the group consisting of :

[0686] R4is selected from the group consisting of:

[0687] (i) Ci-6alkyl optionally substituted with 1-2 Ra;

[0688] (ii) -(Y3)p-Y4; and

[0689] (iii) C2-10 alkenyl or C2-10 alkynyl, each of which is optionally substituted with from 1-3 independently selected Ra.

[0690] In certain embodiments, -L4is -N(H)C(0)-; and R4is selected from the group consisting of :

[0691] R4is selected from the group consisting of:

[0692] (i) Ci-6alkyl optionally substituted with 1-2 Ra;

[0693] (ii) -(Y3)p-Y4; and

[0694] (iii) C2-10 alkenyl or C2-10 alkynyl, each of which is optionally substituted with from 1-3 independently selected Ra. In certain embodiments, -L4is -N(H)S(0)2N(H)- or -N(H)S(0)2N(Rd)-; and

[0695] R4is selected from the group consisting of:

[0696] (i) Ci-6alkyl optionally substituted with 1-2 Ra;

[0697] (ii) -(Y3)p-Y4; and

[0698] (iii) C2-10 alkenyl or C2-10 alkynyl, each of which is optionally substituted with from 1-3 independently selected Ra. In some embodiments of [A], R4is Ci-6 alkyl optionally substituted with 1-2 Ra.

[0699] In some embodiments of [A], R4is C2-10 alkenyl or C2-10 alkynyl, each of which is optionally substituted with from 1-3 independently selected Ra.

[0700] In certain of these embodiments, R4is C2-10 (e.g., C2-5) alkynyl, which is optionally substituted with from 1-3 independently selected Ra(e.g., unsubstituted C2-5 alkynyl such

[0701] In some embodiments of [A], R4is -(Y3)p-Y4. In certain embodiments, Y4is C6-10 aryl, which is optionally substituted with from 1-4 Rc. For example, Y4can be phenyl which is optionally substituted with from 1-2 (e.g., 1) Rc.

[0702] In some embodiments of [A] when R4is -(Y3)p-Y4, Y4is is C3-6 (e.g., C3-4 or C6) cycloalkyl, which is optionally substituted with from 1-4 Rb. In certain embodiments, Y4is C3-4 cycloalkyl or C6 cycloalkyl, each of which is optionally substituted with from 1-2 Rb(e.g., Rbcan be -OH).

[0703] In some embodiments of [A], R4is -(Y3)p-Y4. In certain embodiments, Y4is heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), and O, and wherein one or more of the heterocyclyl ring carbon atoms are optionally substituted with from 1-2 independently selected Rb. In certain embodiments, Y4is heterocyclyl including 6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), and O, and wherein one or more of the heterocyclyl ring carbon atoms are optionally substituted with from 1-2 independently selected Rb(e.g., Y4can be tetrahydropyranyl, piperidinyl, or morpholinyl, each of which is optionally substituted with from 1-2 independently selected Rb). In certain embodiments, Y4is heterocyclyl including 4 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), and O, and wherein one or more of the heterocyclyl ring carbon atoms are optionally substituted with from 1-2 independently selected Rb(e.g., Y4can be oxetanyl; or Y4can be azetidinyl).

[0704] In some embodiments of [A], R4is -(Y3)p-Y4. In certain embodiments, Y4is heteroaryl including 6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), and N(Rd), and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-4 independently selected Rc. In certain embodiments, Y4is pyridinyl (e.g., 2-pyridinyl, 3- pyridinyl, or 4-pyridinyl), pyrimidinyl (e.g., 2-pyrimidinyl or 5-pyrimidinyl), or pyrazinyl, each of which is optionally substituted with from 1-2 independently selected Rc.

[0705] In certain of the foregoing embodiments of [A] when R4is -(Y3)p-Y4, p=0.

[0706] In other embodiments of [A] when R4is -(Y3)p-Y4, p=l. In certain of these embodiments, Y3is C1-3 alkylene (e.g., CH2, CH2-CH2).

[0707] In some embodiments when R3is -L4-R4, R3is selected from the group consisting of:

[0708] In some embodiments when R3is -L4-R4, R3is selected from the group consisting of:

[0709] In some embodiments when R3is -L4-R4, R3is selected from the group consisting of:

[0710]

[0711] In some embodiments when R3is -L4-R4, R3is selected from the group consisting of:

[0712]

[0713] In some embodiments when R3is -L4-R4, R3is selected from the group consisting of:

[0714] In some embodiments when R3is -L4-R4, R3is selected from the group consisting of:

[0715]

[0716] In some embodiments when R3is -L4-R4, R3is selected from the group consisting of:

[0717] In some embodiments when R3is -L4-R4, R3is selected from the group consisting of:

[0718] O O ° °

[0719] V A ° V-0A ^N8n A3*

[0720] a',IT 'D,H^ 0H ,andH

[0721] In some embodiments when R3is -L4-R4, R3is selected from the group consisting of:

[0722]

[0723] In some embodiments when R3is -L4-R4, R3is selected from the group consisting of:

[0724] In some embodiments when R3is -L4-R4, R3is selected from the group consisting of:

[0725] In some embodiments when R3is -L4-R4, R3is selected from the group consisting of:

[0726] In some embodiments when R3is -L4-R4, R3is selected from the group consisting of:

[0727] In some embodiments when R3is -L4-R4, R3is selected from the group consisting of:

[0728] In some embodiments when R3is -L4-R4, R3is selected from the group consisting of:

[0729] In some embodiments when R3is -L4-R4, R3is selected from the group consisting of:

[0730] In some embodiments when R3is -L4-R4, R3is selected from the group consisting of:

[0731]

[0732] In certain of the foregoing embodiments, R3isH

[0733] Variable Rc’

[0734] In some embodiments, each occurrence of Rc’ is independently selected from the group consisting of: (i) halo (e.g., -F, Cl);

[0735] (ii) cyano;

[0736] (iii) -OH;

[0737] (iv) -NO2;

[0738] (v) -C(=0)(Ci-4 alkyl);

[0739] (vi) -C(=0)0(Ci-4 alkyl);

[0740] (vii) -C(=0)0H; and

[0741] (viii) -NH2. In certain embodiments, each occurrence of Rc’ is independently selected from the group consisting of:

[0742] (i) halo (e.g., -F, Cl);

[0743] (iii) -OH;

[0744] (iv) -NO2;

[0745] (v) -C(=0)(Ci-4 alkyl); and

[0746] (vi) -C(=0)0(Ci-4 alkyl).

[0747] In certain embodiments, each occurrence of Rc’ is independently selected from halo (e.g., -F, Cl).

[0748] In certain embodiments, each occurrence of Rc’ is independently selected from

[0749] OH and NH2.

[0750] Non-Limiting Combinations

[0751] Non-Limiting Combinations [11

[0752] In some embodiments:

[0753] R1is -(Y^n-Y2; and

[0754] R2is C6-io aryl, which is optionally substituted with from 1-4 Rc. In certain of these embodiments, n is 0.

[0755] In certain of the foregoing embodiments of [1], from 1-2 of X1, X2, X3, and X4are N; and from 2-3 of X1, X2, X3, and X4are each an independently selected CR3.

[0756] In certain of the foregoing embodiments of [1], one of X1, X2, X3, and X4is N; and each of the remaining X1, X2, X3, and X4is an independently selected CR3; or

[0757] two of X1, X2, X3, and X4are N; and each of the remaining X1, X2, X3, and X4is an independently selected CR3.

[0758] In certain embodiments, from 1-2 of X2and X3is independently CR3, such as wherein both of X2and X3are each an independently selected CR3. In certain of the foregoing embodiments, each of X1and X4is independently CH or N (e.g., each of X1and X4is N).

[0759] In certain of the foregoing embodiments of [1], one occurrence of R3is -L4-R4.

[0760] In certain of the foregoing embodiments of [1], R4is -(Y3)p-Y4.

[0761] In certain of the foregoing embodiments when R4is (Y3)p-Y4, p=l. In other embodiments, p=0.

[0762] In certain of the foregoing embodiments of [1], R4is Ci-io alkyl optionally substituted with from 1-6 independently selected Ra.

[0763] In certain of the foregoing embodiments of [1], each of the remaining occurrences of R3is independently selected from the group consisting of H and Rc’. For example, each of the remaining occurrences of R3can be independently H.

[0764] In certain of the foregoing embodiments of [1], when one occurrence of R3is -L4- R4, one occurrence of R3is H.

[0765] In certain of the foregoing embodiments of [1], when one occurrence of R3is -L4- R4, one occurrence of R3is Rc’ (e.g., halo (e.g., Br or Cl, e.g., Cl)). In some embodiments of [1], one occurrence of R3is Rc’ (e.g., Br or Cl, e.g., Cl); and each of the remaining occurrences of R3is H.

[0766] In some embodiments of [1], Y2is as defined in any one of claims 14-20 and 26- 28; and each Rc, when present, is independently as defined in any one of claims 21-24.

[0767] In some embodiments of [1], Y2is as defined in any one of claims 14-18; and each Rc, when present, is as defined in any one of claims 21-23.

[0768] In some embodiments of [1], Y2is as defined in any one of claims 16-18; and each Rc, when present, is as defined in any one of claims 21-23.

[0769] In some embodiments of [1], Y2is as defined in claim 18; and each Rc, when present, is as defined in claim 23.

[0770] In certain embodiments such In some embodiments of is as defined in any one of claims 10-23 of US

[0771] 62 / 742,218, filed October 5, 2018. In certain of the foregoing embodiments, R1is as defined in any one of claims 16-23 US 62 / 742,218, filed October 5, 2018. For example, R1can be as defined in claim 23 US 62 / 742,218, filed October 5, 2018. In some embodiments of [i], R2is C6-10 aryl, which is optionally substituted with from 1-4 Rc, such as phenyl, which is optionally substituted with from 1-4 Rcor 1-2 Rcor 2 Rc; and Rc, when present, is as defined in any one of claims 33-35.

[0772] In some embodiments of [1], R2is as defined in any one of claims 24-31 of US 62 / 742,218, filed October 5, 2018. In certain of the foregoing embodiments, R2is phenyl,

[0773] which is optionally substituted with 2 Rc, such as wherein R2is and Rc, when present, is as defined in any one of claims

[0774] 33-35.

[0775] In certain embodiments of [1], R2is as defined in any one of claims 27-31 of US

[0776] 62 / 742,218, filed October 5, 2018. For example, R2can be

[0777] In some embodiments of [1], R2is heteroaryl including from 5-10 (such as 6) ring atoms, wherein from 1-4 (such as 1-3) ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S (such as the group consisting of N, N(H), and N(Rd)), and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-4 independently selected Rc, such as wherein R2is pyridinyl which is optionally substituted with from 1-2 independently selected Rc, or

[0778] such as wherein when present, is as defined in any one of claims 40-41.

[0779] In certain embodiments

[0780] In some embodiments of [1], R2is as defined in any one of claims 32-37 of US 62 / 742,218, filed October 5, 2018. In certain of the foregoing embodiments, R2is as defined in any one of claims 34-37 of US 62 / 742,218, filed October 5, 2018. For example, R2can be as defined in claim 37 of US 62 / 742,218, filed October 5, 2018.

[0781] In some embodiments of [1] when one occurrence of R3is -L4-R4, -L4is selected from the group consisting of:

[0782] • -N(H)S(0)I-2- or -N(Rd)S(0)i-2 (e.g., N(CI-3 alkyl)S(0)2), such as wherein L4is -N(H)S(0)2-;

[0783] • -N(H)C(0)- or -N(Rd)C(0), such as wherein L4is -N(H)C(0)-; • -C(0)NH- or -C(0)N(Rd)-;

[0784] • -N(H)-, -N(Rd)-, or -N(R4)-;

[0785] • a single bond;

[0786] • CºC;

[0787] • -0-; and

[0788] • -N(H)S(0)I-2N(H)-, -N(Rd)S(0)i-2N(H)-, -N(H)S(0)i-2N(Rd)-, and - N(Rd)S(0)i-2N(Rd)-, such as wherein L4is -N(H)S(0)i-2N(H)- (e.g., - N(H)S(0)2N(H)-) or wherein L4is -N(H)S(0)i-2N(Rd)- (e.g., - N(H)S(0)2N(Rd)- (e.g., -N(H)S(0)2N(Ci-3alkyl)-));

[0789] as well as defined in any one of claims 48-55 of US 62 / 742,218, filed October 5,

[0790] 2018.

[0791] In some embodiments of [1] when one occurrence of R3is -L4-R4, -L4is selected from the group consisting of:

[0792] • -N(H)S(0)I-2- or -N(Rd)S(0)i-2(e.g., N(CI-3alkyl)S(0)2), such as wherein L4is -N(H)S(0)2-;

[0793] • -N(H)C(0)- or -N(Rd)C(0), such as wherein L4is -N(H)C(0)-;

[0794] • -C(0)NH- or -C(0)N(Rd)-;

[0795] • -N(H)-, -N(Rd)-, or -N(R4)-;

[0796] • a single bond; and

[0797] • CºC.

[0798] In some embodiments of [1] when one occurrence of R3is -L4-R4, -L4is selected from the group consisting of:

[0799] • N(H)S(0)2-;

[0800] • -N(H)C(0)-; and

[0801] • -N(H)-, -N(Rd)-, or -N(R4)-.

[0802] In certain embodiments of [1], -L4is as defined in any one of claims 49, 51, and 53 of US 62 / 742,218, filed October 5, 2018. For example, L4can be as defined in claim 49 ofUS 62 / 742,218, filed October 5, 2018. In some embodiments of [1] when one occurrence of R3is -L4-R4, -L4is -NHS(0)(=NH)-.

[0803] In some embodiments of [1] when one occurrence of R3is -L4-R4, -L4is selected from the group consisting of:

[0804] -N(H)S(0)I-2- or -N(Rd)S(0)i-2 (e.g., N(CI-3 alkyl)S(0)2), such as wherein L4is -N(H)S(0)2-; and

[0805] -N(H)S(0)I.2N(H)-, -N(Rd)S(0)i-2N(H)-, -N(H)S(0)i-2N(Rd)-, and -N(Rd)S(0)i- 2N(Rd)-, such as wherein L4is -N(H)S(0)I-2N(H)- (e.g., -N(H)S(0)2N(H)-) or wherein L4is -N(H) S (O) l -2N (Rd) - (e.g., -N(H)S(0)2N(Rd)- (e.g., -N(H)S(0)2N(CI-3 alkyl)-)).

[0806] In some embodiments of [1] when one occurrence of R3is -L4-R4; and R4is (Y3)p- Y4, Y4is C6-10 aryl, which is optionally substituted with from 1-4 Rc, such as phenyl, which is optionally substituted with from 1-2 (e.g., 1) Rc, or wherein Y4is unsubstituted C6-10 aryl such as unsubstituted phenyl; and Rc, when present, is as defined in any one of claims 73- 75

[0807] In some embodiments of [1] when one occurrence of R3is -L4-R4; and R4is (Y3)p- Y4, Y4is C6-10 aryl, which is optionally substituted with from 1-4 Rc, such as phenyl optionally substituted with from 1-4 Rc; and wherein each occurrence of Rc, when present, is independently selected from the group consisting of:

[0808] (vii) Ci-4 alkoxy;

[0809] (viii) Ci-4 haloalkoxy; and

[0810] (xiv) -Ci-4 thioalkoxy.

[0811] In some embodiments of [1] when one occurrence of R3is -L4-R4; and R4is (Y3)p- Y4, Y4is as defined in any one of claims 77, 78, 79, 81, and 82, and wherein Rb, when present, is as defined in claim 80.

[0812] In some embodiments of [1] when one occurrence of R3is -L4-R4; and R4is (Y3)p- Y4, Y4is as defined in any one of claims 77-79; and Rb, when present, is as defined in claim 80. In some embodiments of [1] when one occurrence of R3is -L4-R4; and R4is (Y3)p- Y4, Y4is as defined in any one of claims 83-85 and 88; and Rc, when present, is as defined in any one of claims 86-87.

[0813] In some embodiments of [1] when one occurrence of R3is -L4-R4; and R4is (Y3)p- Y4, Y4is as defined in any one of claims 83-85, and 88.

[0814] In some embodiments of [1] when one occurrence of R3is -L4-R4; and R4is (Y3)p-Y4, Y4is as defined in any one of claims 89-96; and Rb, when present, is as defined in any one of claims 97-98.

[0815] In some embodiments of [1] when one occurrence of R3is -L4-R4; and R4is (Y3)p- Y4, Y4is as defined in any one of claims 89-92, 94, and 96; and Rb, when present, is as defined in claim 98.

[0816] In some embodiments of [1], R4is selected from the group consisting of the structures delineated in claims 99-113.

[0817] In some embodiments of [1], R4is selected from the group consisting of the structures delineated in claims 100, 101, 104-105, 107, 109, 111, and 113.

[0818] In some embodiments of [1] when one occurrence of R3is -L4-R4,

[0819] • R4is Ci-io alkyl, optionally substituted with from 1-6 independently selected Ra; or · R4is Ci-6alkyl, optionally substituted with from 1-6 independently selected Ra; or

[0820] • R4is Ci-6alkyl, optionally substituted with from 1-2 independently selected Ra, such as wherein R4is selected from the group consisting of: methyl, ethyl,

[0821] • R4is C2-10 alkynyl (e.g., C2-4 alkynyl), which is optionally substituted with from 1- 6 (e.g., from 1-3) independently selected Ra(e.g., unsubstituted C2-4 alkynyl such

[0822] • R4is C2-10 alkenyl (e.g., C2-4 alkenyl), which is optionally substituted with from 1- 6 (e.g., from 1-3) independently selected Ra(e.g., unsubstituted C2-4 alkenyl such as vinyl); and

[0823] wherein each Ra, when present, is independently selected from the group consisting of: -F; -OH; C1-4 alkoxy; and C1-4 haloalkoxy, such as wherein each occurrence of Rais independently -OH.

[0824] In some embodiments of [1] when one occurrence of R3is -L4-R4,

[0825] • R4is Ci-10 alkyl, optionally substituted with from 1-6 independently selected Ra; or

[0826] • R4is Ci-6alkyl, optionally substituted with from 1-6 independently selected Ra; or

[0827] • R4is Ci-6alkyl, optionally substituted with from 1-2 independently selected Ra, such as methyl

[0828] wherein each Ra, when present, is independently selected from the group consisting of: -F; -OH; C1-4 alkoxy; and C1-4 haloalkoxy, such as -OH.

[0829] In some embodiments of [1] when one occurrence of R3is -L4-R4, R4is as defined in any one of claims 56-60 and 61-63 of US 62 / 742,218, filed October 5, 2018.

[0830] In some embodiments of [1] when one occurrence of R3is -L4-R4, R4is as defined in any one of claims 56-60 and 64-67 of US 62 / 742,218, filed October 5, 2018.

[0831] In some embodiments of [1] when one occurrence of R3is -L4-R4, R4is as defined in any one of claims 56-60 and 68-71 of US 62 / 742,218, filed October 5, 2018.

[0832] In some embodiments of [1] when one occurrence of R3is -L4-R4, R4is as defined in any one of claims 56-60 and 72-78 of US 62 / 742,218, filed October 5, 2018.

[0833] In some embodiments of [1] when one occurrence of R3is -L4-R4, R4is as defined in any one of claims 56-60 and 79-86 of US 62 / 742,218, filed October 5, 2018. In some embodiments of [1] when one occurrence of R3is -L4-R4, R4is as defined in any one of claims 56-60 and 87-92 of US 62 / 742,218, filed October 5, 2018.

[0834] In certain embodiments of [1], -L4is selected from the group consisting of- N(H)S(0)2-, -N(H)S(0)2N(H)-, -N(H)S(0)2N(Rd)-, CºC, a single bond, -C(0)N(H)-, -

[0835] N(H)-, -N(R4)-, -N(Rd)-, and -N(H)C(0)-; and

[0836] R4is selected from the group consisting of:

[0837] (i) Ci-6alkyl optionally substituted with 1-2 Ra;

[0838] (ii) -(Y3)p-Y4; and

[0839] (iii) C2-io alkenyl or C2-io alkynyl, each of which is optionally substituted with from 1-3 independently selected Ra.

[0840] In certain embodiments of [1], -L4is selected from the group consisting of- N(H)S(0)2-, -N(H)S(0)2N(H)-, and -N(H)S(0)2N(Rd)-; and

[0841] R4is selected from the group consisting of:

[0842] (i) Ci-6alkyl optionally substituted with 1-2 Ra;

[0843] (ii) -(Y3)p-Y4; and

[0844] (iii) C2-io alkenyl or C2-io alkynyl, each of which is optionally substituted with from 1-3 independently selected Ra.

[0845] In some embodiments of [1], R3is selected from the group consisting of structures delineated in claims 148-165; or wherein R3is selected from the group consisting of structures delineated in claims 148-149, 151, 153, 155-156, 158, 160, 162, and 165. In some embodiments of [1], R3is as defined in any one of claims 113-122 of US

[0846] 62 / 742,218, filed October 5, 2018.

[0847] [1-1]

[0848] In some embodiments of [1], each of X2and X3is an independently selected CR3; and each of X1and X4is independently N, or CH. In certain of these embodiments, each of X1and X4is N. In certain of the foregoing embodiments, each R3is an independently selected -L4-R4.

[0849] In some embodiments of [1-1], one occurrence of -L4-R4is -R4(i.e., one occurrence of L4is a bond).

[0850] In certain of these embodiments, the other occurrence of -L4is selected from the group consisting of:

[0851] • -N(H)S(0)I-2- or -N(Rd)S(0)i-2 (e.g., N(CI-3 alkyl)S(0)2), such as wherein L4is -N(H)S(0)2-;

[0852] • -N(H)C(0)- or -N(Rd)C(0), such as wherein L4is -N(H)C(0)-;

[0853] • -C(0)NH- or -C(0)N(Rd)-;

[0854] • -N(H)-, -N(Rd)-, or -N(R4)-;

[0855] • a single bond;

[0856] • CºC;

[0857] • -0-; and

[0858] • -N(H)S(0)I-2N(H)-, -N(Rd)S(0)i-2N(H)-, -N(H)S(0)i-2N(Rd)-, and - N(Rd)S(0)i-2N(Rd)-, such as wherein L4is -N(H)S(0)I-2N(H)- (e.g., - N(H)S(0)2N(H)-) or wherein L4is -N(H)S(0)i-2N(Rd)- (e.g., - N(H)S(0)2N(Rd)- (e.g., -N(H)S(0)2N(CI-3 alkyl)-)).

[0859] In certain embodiments, the other occurrence of -L4is selected from the group consisting of:

[0860] • -N(H)S(0)I-2- or -N(Rd)S(0)i-2 (e.g., N(CI-3alkyl)S(0)2), such as wherein L4is -N(H)S(0)2-;

[0861] • -N(H)C(0)- or -N(Rd)C(0), such as wherein L4is -N(H)C(0)-;

[0862] • -C(0)NH- or -C(0)N(Rd)-;

[0863] • -N(H)-, -N(Rd)-, or -N(R4)-;

[0864] • a single bond; and

[0865] • CºC. In certain embodiments, the other occurrence of -L4is selected from the group consisting of:

[0866] • -N(H)S(0)2-;

[0867] • -N(H)C(0)-; and

[0868] · -N(H)-, -N(Rd)-, or -N(R4)-, such as wherein the other occurrence of -L4is

[0869] N(H)S(0)2-.

[0870] In certain embodiments, the other occurrence of -L4is selected from the group consisting of:

[0871] -N(H)S(0)I-2- or -N(Rd)S(0)i-2 (e.g., N(CI-3 alkyl)S(0)2), such as wherein L4is

[0872] -N(H)S(0)2-; and

[0873] -N(H)S(0)I-2N(H)-, -N(Rd)S(0)i-2N(H)-, -N(H)S(0)i-2N(Rd)-, and -N(Rd)S(0)i- 2N(Rd)-, such as wherein L4is -N(H)S(0)I-2N(H)- (e.g., -N(H)S(0)2N(H)-) or wherein L4is -N(H) S (O)l-2N (Rd) - (e.g., -N(H)S(0)2N(Rd)- (e.g., -N(H)S(0)2N(CI-3alkyl)-)).

[0874] In certain of the foregoing embodiments, the other occurrence of -L4is as defined in any one of claims defined in claims 48-55 of US 62 / 742,218, filed October 5, 2018.

[0875] For example, the other occurrence of -L4can 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.

[0876] In some embodiments of [1-1], each R4is independently as defined in any one of claims 56-60 and 61-63 of US 62 / 742,218, filed October 5, 2018.

[0877] In some embodiments of [1-1], each R4is independently as defined in any one of claims 56-60 and 64-67 of US 62 / 742,218, filed October 5, 2018.

[0878] In some embodiments of [1-1], each R4is independently as defined in any one of claims 56-60 and 68-71 of US 62 / 742,218, filed October 5, 2018.

[0879] In some embodiments of [1-1], each R4is independently as defined in any one of claims 56-60 and 72-78 of US 62 / 742,218, filed October 5, 2018.

[0880] In some embodiments of [1-1], each R4is independently as defined in any one of claims 79-86 of US 62 / 742,218, filed October 5, 2018. In some embodiments of [1-1], each R4is independently as defined in any one of claims 87-92 of US 62 / 742,218, filed October 5, 2018.

[0881] In some embodiments of [1-1], R1is as defined in any one of claims 10-23 of US 62 / 742,218, filed October 5, 2018.

[0882] In some embodiments of [1-1], R1is as defined in any one of claims 16-23 of US 62 / 742,218, filed October 5, 2018.

[0883] In some embodiments of [1-1], R1is as defined in claim 23 of US 62 / 742,218, filed October 5, 2018.

[0884] In some embodiments of [1-1], R2is as defined in any one of claims 24-31 of US 62 / 742,218, filed October 5, 2018.

[0885] In some embodiments of [1-1], R2is as defined in any one of claims 27-31 of US 62 / 742,218, filed October 5, 2018.

[0886] In some embodiments of [1-1], R2is as defined in any one of claims 32-37 (e.g., 34-37) of US 62 / 742,218, filed October 5, 2018.

[0887] [1-2]

[0888] In some embodiments of [1], each of X2and X3is an independently selected CR3; and each of X1and X4is independently N, or CH. In certain of these embodiments, each of X1and X4is N.

[0889] In some embodiments of [1-2], one occurrence of R3is -L4-R4(e.g., -L4is as defined in claim 49); and the other occurrence of R3is Rc’ (e.g., Rc’ can be halo such as - Cl).

[0890] In certain of these embodiments, -L4is selected from the group consisting of:

[0891] • -N(H)S(0)I-2- or -N(Rd)S(0)i-2 (e.g., N(CI-3 alkyl)S(0)2), such as wherein L4is -N(H)S(0)2-;

[0892] • -N(H)C(0)- or -N(Rd)C(0), such as wherein L4is -N(H)C(0)-;

[0893] • -C(0)NH- or -C(0)N(Rd)-;

[0894] • -N(H)-, -N(Rd)-, or -N(R4)-;

[0895] • a single bond; • CºC;

[0896] • -0-; and

[0897] • -N(H)S(0)I-2N(H)-, -N(Rd)S(0)i-2N(H)-, -N(H)S(0)i-2N(Rd)-, and - N(Rd)S(0)i-2N(Rd)-, such as wherein L4is -N(H)S(0)I-2N(H)- (e.g., - N(H)S(0)2N(H)-) or wherein L4is -N(H)S(0)i-2N(Rd)- (e.g., - N(H)S(0)2N(Rd)- (e.g., -N(H)S(0)2N(CI-3 alkyl)-)).

[0898] In certain embodiments, -L4is selected from the group consisting of:

[0899] • -N(H)S(0)I-2- or -N(Rd)S(0)i-2 (e.g., N(CI-3alkyl)S(0)2), such as wherein L4is -N(H)S(0)2-;

[0900] • -N(H)C(0)- or -N(Rd)C(0), such as wherein L4is -N(H)C(0)-;

[0901] • -C(0)NH- or -C(0)N(Rd)-;

[0902] • -N(H)-, -N(Rd)-, or -N(R4)-;

[0903] • a single bond; and

[0904] • CºC.

[0905] In certain embodiments, -L4is selected from the group consisting of:

[0906] • -N(H)S(0)2-;

[0907] • -N(H)C(0)-; and

[0908] • -N(H)-, -N(Rd)-, or -N(R4)-, such as wherein the other occurrence of -L4is

[0909] N(H)S(0)2-.

[0910] In certain embodiments, -L4is selected from the group consisting of:

[0911] -N(H)S(0)I-2- or -N(Rd)S(0)i-2 (e.g., N(CI-3alkyl)S(0)2), such as wherein L4is -N(H)S(0)2-; and

[0912] -N(H)S(0)I-2N(H)-, -N(Rd)S(0)i-2N(H)-, -N(H)S(0)i-2N(Rd)-, and -N(Rd)S(0)i- 2N(Rd)-, such as wherein L4is -N(H)S(0)I-2N(H)- (e.g., -N(H)S(0)2N(H)-) or wherein L4is -N(H) S (O)l-2N (Rd) - (e.g., -N(H)S(0)2N(Rd)- (e.g., -N(H)S(0)2N(CI-3 alkyl)-)). In certain of the foregoing embodiments, the other occurrence of -L4is as defined in any one of claims defined in claims 48-55 of US 62 / 742,218, filed October 5, 2018.

[0913] For example, the other occurrence of -L4can 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.

[0914] In some embodiments of [1-2], each R4is independently as defined in any one of claims 56-60 and 61-63 of US 62 / 742,218, filed October 5, 2018.

[0915] In some embodiments of [1-2], each R4is independently as defined in any one of claims 56-60 and 64-67 of US 62 / 742,218, filed October 5, 2018.

[0916] In some embodiments of [1-2], each R4is independently as defined in any one of claims 56-60 and 68-71 of US 62 / 742,218, filed October 5, 2018.

[0917] In some embodiments of [1-2], each R4is independently as defined in any one of claims 56-60 and 72-78 of US 62 / 742,218, filed October 5, 2018.

[0918] In some embodiments of [1-2], each R4is independently as defined in any one of claims 79-86 of US 62 / 742,218, filed October 5, 2018.

[0919] In some embodiments of [1-2], each R4is independently as defined in any one of claims 87-92 of US 62 / 742,218, filed October 5, 2018.

[0920] In some embodiments of [1-2], R1is as defined in any one of claims 10-23 of US 62 / 742,218, filed October 5, 2018.

[0921] In some embodiments of [1-2], R1is as defined in any one of claims 16-23 of US

[0922] 62 / 742,218, filed October 5, 2018.

[0923] In some embodiments of [1-2], R1is as defined in claim 23 of US 62 / 742,218, filed October 5, 2018.

[0924] In some embodiments of [1-2], R2is as defined in any one of claims 24-31 of US 62 / 742,218, filed October 5, 2018.

[0925] In some embodiments of [1-2], R2is as defined in any one of claims 27-31 of US 62 / 742,218, filed October 5, 2018.

[0926] In some embodiments of [1-2], R2is as defined in any one of claims 32-37 (e.g., 34-37) of US 62 / 742,218, filed October 5, 2018. Non-Limiting Combinations [21

[0927] In some embodiments, a compound of Formula (I) is of Formula (I-al-a):

[0928] al-a);

[0929] or a pharmaceutically acceptable salt thereof.

[0930] In some embodiments of [2], -L4is selected from the group consisting of:

[0931] -N(H)S(0)I-2- or -N(Rd)S(0)i-2 (e.g., N(CI-3 alkyl)S(0)2), such as wherein L4is -N(H)S(0)2-; and

[0932] -N(H)S(0)I.2N(H)-, -N(Rd)S(0)i-2N(H)-, -N(H)S(0)i-2N(Rd)-, and -N(Rd)S(0)i- 2N(Rd)-, such as wherein L4is -N(H)S(0)I-2N(H)- (e.g., -N(H)S(0)2N(H)-) or wherein L4is -N(H) S (O) l -2N (Rd) - (e.g., -N(H)S(0)2N(Rd)- (e.g., -N(H)S(0)2N(CI-3 alkyl)-)).

[0933] In certain embodiments of [2], a compound of Formula (I-al-a) is of Formula (I- al-al):

[0934] al-al);

[0935] or a pharmaceutically acceptable salt thereof.

[0936] In certain embodiments of [2], a compound of Formula (I-al-a) is of Formula (I- al-a2): al-a2);

[0937] or a pharmaceutically acceptable salt thereof.

[0938] In certain embodiments of [2], a compound of Formula (I-al-a) is of Formula (I- al-a3):

[0939] al-a3) (e.g., Rc’ is halo, e.g., -Cl);

[0940] or a pharmaceutically acceptable salt thereof.

[0941] In certain of the foregoing embodiments of [2], R1is as defined in any one of claims 10-23 of US 62 / 742,218, filed October 5, 2018; and / or R2is as defined in any one of claims 24-37 of US 62 / 742,218, filed October 5, 2018; and / or R4is as defined in any one of claims 56-92 of US 62 / 742,218, filed October 5, 2018.

[0942] In certain embodiments of [2], a compound of Formula (I-al-a) is of Formula (I- al-a4):

[0943] -al-a4) (e.g., R3is Rc’; or R3is -L4-R4);

[0944] or a pharmaceutically acceptable salt thereof.

[0945] In certain embodiments of Formula (I-al-a4), L3is NHS(0)2.

[0946] In certain embodiments of Formula (I-al-a4), R3is H.

[0947] In certain embodiments of Formula (I-al-a4), R3is Rc’, such as halo (e.g., -Cl).

[0948] In certain embodiments of Formula (I-al-a4), R3is -L4-R4.

[0949] In certain of the foregoing embodiments of [2] (e.g., when the compound has Formula (I-al-a4)), L4is as defined in any one of claims 48-55 of US 62 / 742,218, filed October 5, 2018; and / or R4is as defined in any one of claims 56-60 of US 62 / 742,218, filed October 5, 2018 and 61-63 of US 62 / 742,218, filed October 5, 2018; or 56-60 of US 62 / 742,218, filed October 5, 2018 and 64-67 of US 62 / 742,218, filed October 5, 2018; or 56-60 of US 62 / 742,218, filed October 5, 2018 and 68-71 of US 62 / 742,218, filed October 5, 2018; or 56-60 and 72-78 of US 62 / 742,218, filed October 5, 2018; or 79-86 of US 62 / 742,218, filed October 5, 2018; or 87-92 of US 62 / 742,218, filed October 5, 2018.

[0950] [2-1]

[0951] In some embodiments of [2], the compound of Formula (I-al-a) is of Formula (I- al-a5): al-a5); or a pharmaceutically acceptable salt thereof.

[0952] In some embodiments of [2-1], W is halo (e.g., -Cl).

[0953] In some embodiments of [2-1], R1is as defined in any one of claims 10-23 of US 62 / 742,218, filed October 5, 2018.

[0954] In some embodiments of [2-1], R2is as defined in any one of claims 24-37 (e.g., claims 24-31) of US 62 / 742,218, filed October 5, 2018.

[0955] In some embodiments of [2-1], R4is as defined in any one of claims 56-92 (e.g., claims 87-92) of US 62 / 742,218, filed October 5, 2018. In some embodiments of [2-1], L4is -NHS(0)2-

[0956] In some embodiments of [2-1], L4is -N(H)S(0)2N(H)- or -N(H)S(0)2N(Rd)-.

[0957] [2-2]

[0958] In some embodiments of [2], compound of Formula (I-al-a) is of Formula (I-al- a6):

[0959] -al-a6);

[0960] wherein each of L4Aand L4Bis an independently selected L4; and

[0961] each of R4Aand R4Bis an independently selected R4;

[0962] or a pharmaceutically acceptable salt thereof. In some embodiments of [2-2], L4Bis a bond.

[0963] In some embodiments of [2-2], R1is as defined in any one of claims 10-23 of US 62 / 742,218, filed October 5, 2018.

[0964] In some embodiments of [2-2], R2is as defined in any one of claims 24-37 (e.g., claims 24-31) of US 62 / 742,218, filed October 5, 2018.

[0965] In some embodiments of [2-2], R4Ais as defined in any one of claims 56-92 of US 62 / 742,218, filed October 5, 2018.

[0966] In some embodiments of [2-2], L4Ais -NHS(0)2-.

[0967] In some embodiments of [2-2], L4is -N(H)S(0)2N(H)- or -N(H)S(0)2N(Rd)-.

[0968] In some embodiments of [2-2], R4Bis as defined in any one of claims 56-92 (e.g., claims 56-60 and 64-67) of US 62 / 742,218, filed October 5, 2018.

[0969] [2-3]

[0970] In some embodiments of [2], compound of Formula (I-al-a) is of Formula (I-al- a7), (I-al-a8) or (I-al-a9):

[0971]

[0972] r1(I-al-a7),r1(I-al-a8), orr1(I-al-a9);

[0973] wherein Rd’ is H or Rd(e.g., H or C1-3 alkyl); or a pharmaceutically acceptable salt thereof.

[0974] Non-Limiting Combinations [31

[0975] In some embodiments, a compound of Formula (I) is of Formula (I-al-b): al-b);

[0976] or a pharmaceutically acceptable salt thereof.

[0977] In certain embodiments of [3], a compound of Formula (I-al-b) is of Formula (I- al-bl) or Formula (I-al-b2):

[0978] -al-b2) (e.g, L4is N(H)S02, -N(H)-, or

[0979] NHC(O));

[0980] or a pharmaceutically acceptable salt thereof.

[0981] In some embodiments of [3], -L4is selected from the group consisting of:

[0982] -N(H)S(0)I-2- or -N(Rd)S(0)i-2 (e.g., N(CI-3 alkyl)S(0)2), such as wherein L4is -N(H)S(0)2-; and

[0983] -N(H)S(0)I.2N(H)-, -N(Rd)S(0)i-2N(H)-, -N(H)S(0)i-2N(Rd)-, and -N(Rd)S(0)i- 2N(Rd)-, such as wherein L4is -N(H)S(0)I-2N(H)- (e.g., -N(H)S(0)2N(H)-) or wherein L4is -N(H) S (O) i -2N (Rd) - (e.g., -N(H)S(0)2N(Rd)- (e.g., -N(H)S(0)2N(CI-3alkyl)-)).

[0984] In certain of the foregoing embodiments of [3], R1is as defined in any one of claims 10-23 of US 62 / 742,218, filed October 5, 2018; and / or R2is as defined in any one of claims 24-37 of US 62 / 742,218, filed October 5, 2018; and / or R4is as defined in any one of claims 56-92 of US 62 / 742,218, filed October 5, 2018. In certain of the foregoing embodiments of [3], Rc’ is selected from halo (e.g., Cl, Br), -OH, and NH2.

[0985] Non-Limiting Combinations [41

[0986] In some embodiments, a compound of Formula (I) is of Formula (I-a2-a):

[0987]

[0988] or a pharmaceutically acceptable salt thereof.

[0989] In certain embodiments of [4], a compound of Formula (I-a2-al) is a compound of Formula (I-a2-al):

[0990] al);

[0991] or a pharmaceutically acceptable salt thereof.

[0992] In certain of the foregoing embodiments of [4], R1is as defined in any one of claims 10-23 of US 62 / 742,218, filed October 5, 2018; and / or R2is as defined in any one of claims 24-37 of US 62 / 742,218, filed October 5, 2018; and / or R4is as defined in any one of claims 56-92 of US 62 / 742,218, filed October 5, 2018.

[0993] In certain embodiments of [4], a compound of Formula (I-a2-a) is of Formula (I- al-a2):

[0994] or a pharmaceutically acceptable salt thereof.

[0995] In certain of the foregoing embodiments of [4] (e.g., when the compound has Formula (I-a2-a2)), L4is as defined in any one of claims 48-55 (e.g., 49) of US 62 / 742,218, filed October 5, 2018; and / or R4is as defined in any one of claims 56-60 of US 62 / 742,218, filed October 5, 2018 and 61-63 of US 62 / 742,218, filed October 5, 2018; or 56-60 of US 62 / 742,218, filed October 5, 2018 and 64-67 of US 62 / 742,218, filed October 5, 2018; or 56-60 of US 62 / 742,218, filed October 5, 20l8and 68-71 of US 62 / 742,218, filed October 5, 2018; or 56-60 of US 62 / 742,218, filed October 5, 20l8and 72-78 of US 62 / 742,218, filed October 5, 2018; or 79-86 of US 62 / 742,218, filed October 5, 2018; or 87-92 of US 62 / 742,218, filed October 5, 2018.

[0996] Non-Limiting Combinations [51

[0997] In some embodiments, a compound of Formula (I) is of Formula (I-bl-a):

[0998]

[0999] or a pharmaceutically acceptable salt thereof. In certain embodiments of [5], a compound of Formula (I-bl-a) is of Formula (I- bl-al):

[1000] -bl-al);

[1001] or a pharmaceutically acceptable salt thereof.

[1002] In certain of the foregoing embodiments of [5], R1is as defined in any one of claims 10-23 of US 62 / 742,218, filed October 5, 2018; and / or R2is as defined in any one of claims 24-37 of US 62 / 742,218, filed October 5, 2018; and / or R4is as defined in any one of claims 56-92 of US 62 / 742,218, filed October 5, 2018.

[1003] In certain embodiments of [5], a compound of Formula (I-bl-a) is of Formula (I- bl-a3):

[1004] -bl-a3);

[1005] wherein Rd’ is H or Rd(e.g., H or C1-3 alkyl); or a pharmaceutically acceptable salt thereof.

[1006] In certain embodiments of [5], a compound of Formula (I-bl-a) of Formula (I- bl-a2): -bl-a2) (e g., L4is NHS(0)2);

[1007] or a pharmaceutically acceptable salt thereof.

[1008] In certain embodiments of Formula (I-bl-a2), L4is NHS(0)2.

[1009] In certain of the foregoing embodiments of [5] (e.g., when the compound has Formula (I-bl-a2)), L4is as defined in any one of claims 48-55 (e.g., 49) of US 62 / 742,218, filed October 5, 2018; and / or R4is as defined in any one of claims 56-60 of US 62 / 742,218, filed October 5, 20l8and 61-63 of US 62 / 742,218, filed October 5, 2018; or 56-60 of US 62 / 742,218, filed October 5, 2018 and 64-67 of US 62 / 742,218, filed October 5, 2018; or 56-60 of US 62 / 742,218, filed October 5, 20l8and 68-71 of US 62 / 742,218, filed October 5, 2018; or 56-60 of US 62 / 742,218, filed October 5, 20l8and 72-78 of US 62 / 742,218, filed October 5, 2018; or 79-86 of US 62 / 742,218, filed October 5, 2018; or 87-92 of US 62 / 742,218, filed October 5, 2018.

[1010] Non-Limiting Combinations [61

[1011] In some embodiments, a compound of Formula (I) is of Formula (I-cl-a):

[1012] cl-a);

[1013] or a pharmaceutically acceptable salt thereof. In certain embodiments of [6], a compound of Formula (I-cl-a) is of Formula (I- cl-al):

[1014] cl-al);

[1015] or a pharmaceutically acceptable salt thereof.

[1016] In certain of the foregoing embodiments of [6], R1is as defined in any one of claims 10-23 of US 62 / 742,218, filed October 5, 2018; and / or R2is as defined in any one of claims 24-37 of US 62 / 742,218, filed October 5, 2018; and / or R4is as defined in any one of claims 56-92 of US 62 / 742,218, filed October 5, 2018. In certain embodiments of [6], a compound of Formula (I-cl-a) of Formula (I-cl- al):

[1017] cl-a2) (e g., L4is NHS(0)2);

[1018] or a pharmaceutically acceptable salt thereof.

[1019] In certain of the foregoing embodiments of [6] (e.g., when the compound has Formula (I-cl-a2)), L4is as defined in any one of claims 48-55 (e.g., 49) of US 62 / 742,218, filed October 5, 2018; and / or R4is as defined in any one of claims 56-60 of US 62 / 742,218, filed October 5, 2018 and 61-63 of US 62 / 742,218, filed October 5, 2018; or 56-60 of US 62 / 742,218, filed October 5, 20l8and 64-67 of US 62 / 742,218, filed October 5, 2018; or 56-60 of US 62 / 742,218, filed October 5, 2018 and 68-71 of US 62 / 742,218, filed October 5, 2018; or 56-60 of US 62 / 742,218, filed October 5, 2018 and 72-78 of US 62 / 742,218, filed October 5, 2018; or 79-86 of US 62 / 742,218, filed October 5, 2018; or 87-92 of US 62 / 742,218, filed October 5, 2018.

[1020] Non-Limiting Combinations [71

[1021] In some embodiments, the compound of Formula (I) is of Formula (I-dl-a):

[1022] dl-a);

[1023] or a pharmaceutically acceptable salt thereof.

[1024] In certain embodiments of [7], the compound of Formula (I-dl-a) is of Formula

[1025] (I-dl-al):

[1026] -dl-al);

[1027] or a pharmaceutically acceptable salt thereof.

[1028] In certain embodiments of [7], R1is as defined in any one of claims 10-23 of US 62 / 742,218, filed October 5, 2018; and / or R2is as defined in any one of claims 24-37 of US 62 / 742,218, filed October 5, 2018; and / or R4is as defined in any one of claims 56-92 of US 62 / 742,218, filed October 5, 2018. In certain embodiments of [7], a compound of Formula (I-dl-a) of Formula (I- dl-a2):

[1029] dl-a2) (e g., L4is NHS(0)2);

[1030] or a pharmaceutically acceptable salt thereof.

[1031] In certain of the foregoing embodiments of [7] (e.g., when the compound has Formula (I-cl-a2)), L4is as defined in any one of claims 48-55 (e.g., 49) of US

[1032] 62 / 742,218, filed October 5, 2018; and / or R4is as defined in any one of claims 56-60 of

[1033] US 62 / 742,218, filed October 5, 20l8and 61-63 of US 62 / 742,218, filed October 5, 2018; or 56-60 of US 62 / 742,218, filed October 5, 2018 and 64-67 of US 62 / 742,218, filed October 5, 2018; or 56-60 of US 62 / 742,218, filed October 5, 2018 and 68-71 of US 62 / 742,218, filed October 5, 2018; or 56-60 of US 62 / 742,218, filed October 5, 2018 and 72-78 of US 62 / 742,218, filed October 5, 2018; or 79-86 of US 62 / 742,218, filed October

[1034] 5, 2018; or 87-92 of US 62 / 742,218, filed October 5, 2018.

[1035] In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3],

[1036] [3], [4], [5], [6], and [7], R4is selected from the group consisting of:

[1037] (i) Ci-io alkyl, optionally substituted with from 1-6 independently selected Ra;

[1038] (ii) -(Y3)p-Y4; and

[1039] (iii) C2-10 alkenyl or C2-10 alkynyl, each of which is optionally substituted with from 1-3 independently selected Ra. In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3],

[1040] [3], [4], [5], [6], and [7], R4is -(Y3)P-Y4.

[1041] In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3],

[1042] [3], [4], [5], [6], and [7] when R4is -(Y3)p-Y4, Y4is C6-10 aryl, which is optionally substituted with from 1-4 Rc, such as phenyl, which is optionally substituted with from 1- 2 (e.g., 1) Rc, or wherein Y4is unsubstituted C6-10 aryl such as unsubstituted phenyl; and Rc, when present, is as defined in any one of claims 73-75 (e.g., claim 75).

[1043] In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3],

[1044] [3], [4], [5], [6], and [7] when R4is -(Y3)p-Y4, Y4is C6-10 aryl, which is optionally substituted with from 1-4 Rc, such as phenyl optionally substituted with from 1-4 Rc; and wherein each occurrence of Rc, when present, is independently selected from the group consisting of:

[1045] (vii) Ci-4 alkoxy;

[1046] (viii) Ci-4 haloalkoxy; and

[1047] (xiv) -Ci-4 thioalkoxy.

[1048] In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3],

[1049] [3], [4], [5], [6], and [7] when R4is -(Y3)p-Y4, Y4is as defined in any one of claims 77, 78, 79, 81, and 82, and wherein Rb, when present, is as defined in claim 80.

[1050] In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3],

[1051] [3], [4], [5], [6], and [7] when R4is -(Y3)p-Y4, Y4is as defined in any one of claims 77- 79; and Rb, when present, is as defined in claim 80.

[1052] In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3],

[1053] [3], [4], [5], [6], and [7] when R4is -(Y3)p-Y4, Y4is as defined in any one of claims 83-85 and 88; and Rc, when present, is as defined in any one of claims 86-87.

[1054] In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3],

[1055] [3], [4], [5], [6], and [7] when R4is -(Y3)p-Y4, Y4is as defined in any one of claims 83- 85, and 88. In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3],

[1056] [3], [4], [5], [6], and [7] when R4is -(Y3)p-Y4, Y4is as defined in any one of claims 89- 96; and Rb, when present, is as defined in any one of claims 97-98.

[1057] In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3],

[1058] [3], [4], [5], [6], and [7] when R4is -(Y3)p-Y4, Y4is as defined in any one of claims 89- 92, 94, and 96; and Rb, when present, is as defined in claim 98.

[1059] In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3],

[1060] [3], [4], [5], [6], and [7] when R4is -(Y3)„-Y4, p is 0.

[1061] In other embodiments, p is 1. In certain of these embodiments, Y3is C1-3 alkylene, such as CH2 or CH2-CH2.

[1062] In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3],

[1063] [3], [4], [5], [6], and [7], R4is selected from the group consisting of the structures delineated in claims 99-113.

[1064] In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3],

[1065] [3], [4], [5], [6], and [7], each R4is selected from the group consisting of the structures delineated in claims 100, 101, 104-105, 107, 109, 111, and 113.

[1066] In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3],

[1067] [3], [4], [5], [6], and [7],

[1068] • R4is Ci-10 alkyl, optionally substituted with from 1-6 independently selected Ra;

[1069] or

[1070] • R4is Ci-6alkyl, optionally substituted with from 1-6 independently selected Ra;

[1071] or

[1072] • R4is Ci-6alkyl, optionally substituted with from 1-2 independently selected Ra, such as wherein R4is selected from the group consisting of: methyl, ethyl,

[1073] R4is C2-10 (e.g., C2-4 alkynyl) alkynyl, which is optionally substituted with from 1- 6 (e.g., from 1-3) independently selected Ra(e.g., unsubstituted C2-4 alkynyl such

[1074] • R4is C2-10 (e.g., C2-4 alkenyl) alkenyl, which is optionally substituted with from 1- 6 (e.g., from 1-3) independently selected Ra(e.g., unsubstituted C2-4 alkenyl such as vinyl); and

[1075] wherein each Ra, when present, is independently selected from the group consisting of: -F; -OH; Ci-4 alkoxy; and Ci-4 haloalkoxy, such as wherein each occurrence of Rais independently -OH.

[1076] In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3],

[1077] [3], [4], [5], [6], and [7],

[1078] R4is Ci-10 alkyl, optionally substituted with from 1-6 independently selected Ra; or

[1079] • R4is Ci-6 alkyl, optionally substituted with from 1-6 independently selected Ra; or

[1080] • R4is Ci-6 alkyl, optionally substituted with from 1-2 independently selected Ra, such as methyl

[1081] wherein each Ra, when present, is independently selected from the group consisting of: -F; -OH; Ci-4 alkoxy; and Ci-4 haloalkoxy, such as -OH.

[1082] In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3],

[1083] [3], [4], [5], [6], and [7], R1is -(YVY2. In certain of these embodiments, Y2is as defined in any one of claims 14-20; and each Rc, when present, is independently as defined in any one of claims 21-24.

[1084] In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3],

[1085] [3], [4], [5], [6], and [7] when R1is -(Y^n-Y2, Y2is as defined in any one of claims 14-18 and 26; and each Rc, when present, is as defined in any one of claims 21-23.

[1086] In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3],

[1087] [3], [4], [5], [6], and [7] when R1is -(Y1)n-Y2, Y2is as defined in any one of claims 16- 18; and each Rc, when present, is as defined in any one of claims 21-23.

[1088] In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3],

[1089] [3], [4], [5], [6], and [7] when R1is -(YVY2, n is 0.

[1090] In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3],

[1091] [3], [4], [5], [6], and [7] when

[1092] As a non-limiting example, R1can be

[1093] In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3],

[1094] [3], [4], [5], [6], and [7], R2is C6-10 aryl, which is optionally substituted with from 1-4 Rc, such as phenyl, which is optionally substituted with from 1-4 Rcor 1-2 Rcor 2 Rc; and Rc, when present, is as defined in any one of claims 33-35.

[1095] In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3],

[1096] [3], [4], [5], [6], and [7], R2is phenyl, which is optionally substituted with 2 Rc, such as

[1097] wherein when present, is as defined in any one of claims 33-35.

[1098] In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3],

[1099] [3], [4], [5], [6], and [7], R2is heteroaryl including from 5-10 (such as 6) ring atoms, wherein from 1-4 (such as 1-3) ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S (such as the group consisting of N, N(H), N(Rd), and O), and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-4 independently selected Rc, such as wherein R2is pyridinyl which is optionally substituted with from 1-2 independently selected Rc, or

[1100] such as wherein R2is and Rc, when present, is as defined in any one of claims 40-41.

[1101] In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3],

[1102] In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3],

[1103] [3], [4], [5], [6], and [7], R1is -(Y^n-Y2; and R2is C6-10 aryl, which is optionally substituted with from 1-4 Rc.

[1104] In certain of these embodiments, n is 0.

[1105] In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3],

[1106] [3], [4], [5], [6], and [7] when R1is -(Y')n-Y2, Y2is heteroaryl including 6 ring atoms, wherein from 1-2 ring atoms are N, and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-4 independently selected Rc.

[1107] In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3],

[1108] [3], [4], [5], [6], and [7] when R1is -(Y^n-Y2, Y2is pyridyl (e.g., 2-pyridyl or 6-pyridyl), wherein one or more of the ring carbon atoms are optionally substituted with from 1-4 (e.g., 1) independently selected Rc.

[1109] In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3],

[1110] [3], [4], [5], [6], and m when R1is -(Y1)n-Y2; and Y2is heteroaryl such as pyridyl optionally substituted with 1-4 independnetly selected Rcas defined supra , each occurrence of Rcis an independently selected Ci-4alkoxy (e.g., -OCH3, -OCH2CH3). As a non-limiting example, R1is:

[1111] In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3],

[1112] [3], [4], [5], [6], and [7] (when R1is -(Y^n-Y2; and R2is C6-10 aryl, which is optionally substituted with from 1-4 Rc), such as R2is phenyl, which is optionally substituted with from 1-4 Rc.

[1113] In certain of these embodiments, R2is phenyl, which is optionally substituted

[1114] with 2 Rc. For example, R2can be:

[1115] In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3],

[1116] This specification concludes with 302 claims. For ease of exposition, certain variable definitions refer to one or more specific claim numbers, and as such, it is understood that the entire subject matter of each claim referenced is incorporated by reference in its entirety into the portion of the disclosure, in which it is referenced. For the avoidance of doubt and as a non-limiting example, use of a phrase, such as“Y4is as defined in any one of claims 77, 78, 79, 81, and 82” is intended to represent a short-hand recitation for the following set of defmtions:

[1117] Y4is C3-6 (e.g., C3-4 or C6) cycloalkyl, which is optionally substituted with from 1- 4 Rb.

[1118] Y4is cyclopropyl or cyclobutyl which is optionally substituted with from 1-2 Rb. Y4is C6 cycloalkyl (e.g., cyclohexyl), which is optionally substituted with from 1-

[1119] 2 Rb.

[1120] Y4is C3-6 (e.g., C3-4 or C6) cycloalkyl, which is unsubstituted. Y4is unsubstituted cyclopropyl or unsubstituted cyclobutyl (e.g., unsubstituted cyclopropyl).

[1121] Y4is selected from the group consisting of C3-6 (e.g., C3-4 or C6) cycloalkyl, which is optionally substituted with from 1-4 Rb; cyclopropyl or cyclobutyl which is optionally substituted with from 1-2 Rb; C6 cycloalkyl (e.g., cyclohexyl), which is optionally substituted with from 1-2 Rb; is C3-6 (e.g., C3-4 or C6) cycloalkyl, which is unsubstituted; and unsubstituted cyclopropyl or unsubstituted cyclobutyl (e.g., unsubstituted cyclopropyl).

[1122] The same also applies to claims referenced from the priority document US 62 / 742,218, filed on October 5, 2018.

[1123] Pharmaceutical Compositions and Administration

[1124] General

[1125] 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., agonizes) the APJ receptor is administered as a pharmaceutical composition that includes the chemical entity and one or more pharmaceutically acceptable excipients, and optionally one or more additional therapeutic agents as described herein.

[1126] In some embodiments, the chemical entities 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, self-emulsifying drug delivery systems (SEDDS) such as d-a-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, poloxamers or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium-chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, and wool fat. Cyclodextrins such as a-, b, and g-cyclodextrin, or chemically modified derivatives such as hydroxyalkyl cyclodextrins, including 2- and 3- hydroxypropyl-P-cyclodextrins, or other solubilized derivatives can also be used to enhance delivery of compounds described herein. Dosage forms or compositions containing a chemical entity as described herein in the range of 0.005% to 100% with the balance made up from non-toxic excipient may be prepared. The contemplated compositions may contain 0.001%-100% of a chemical entity provided herein, in one embodiment 0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington: The Science and Practice of Pharmacy, 22ndEdition (Pharmaceutical Press, London, UK. 2012).

[1127] Routes of Administration and Composition Components

[1128] In some embodiments, the chemical entities described herein or a pharmaceutical composition thereof can be administered to subject in need thereof by any accepted route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, endocervical, endosinusial, endotracheal, enteral, epidural, interstitial, intra-abdominal, intra-arterial, intrabronchial, intrabursal, intracerebral, intraci sternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral and vaginal.

[1129] Compositions can be formulated for parenteral administration, e.g., formulated for injection via the intravenous, intramuscular, sub-cutaneous, or even intraperitoneal routes. Typically, such compositions can be prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for use to prepare solutions or suspensions upon the addition of a liquid prior to injection can also be prepared; and the preparations can also be emulsified. The preparation of such formulations will be known to those of skill in the art in light of the present disclosure.

[1130] The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil, or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In general, the form must be sterile and must be fluid to the extent that it may be easily injected. It also should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.

[1131] The carrier also can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants. The 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 will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[1132] Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques, which yield a powder of the active ingredient, plus any additional desired ingredient from a previously sterile-filtered solution thereof. Pharmacologically acceptable excipients usable in the rectal composition as a gel, cream, enema, or rectal suppository, include, without limitation, any one or more of cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (like PEG ointments), glycerine, glycerinated gelatin, hydrogenated vegetable oils, poloxamers, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol Vaseline, anhydrous lanolin, shark liver oil, sodium saccharinate, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxid SBN, vanilla essential oil, aerosol, parabens in phenoxyethanol, sodium methyl p-oxybenzoate, sodium propyl p- oxybenzoate, diethylamine, carbomers, carbopol, methyl oxybenzoate, macrogol cetostearyl ether, cocoyl caprylocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metabisulfite, sodium edetate, sodium benzoate, potassium metabi sulfite, grapefruit seed extract, methyl sulfonyl methane (MSM) , lactic acid, glycine, vitamins, such as vitamin A and E and potassium acetate.

[1133] In certain embodiments, suppositories can be prepared by mixing the chemical entities described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum and release the active compound. In other embodiments, compositions for rectal administration are in the form of an enema.

[1134] In other embodiments, the compounds described herein or a pharmaceutical composition thereof are suitable for local delivery to the digestive or GI tract by way of oral administration (e.g., solid or liquid dosage forms.).

[1135] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such 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 starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, 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) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise 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.

[1136] In one embodiment, the compositions will take the form of a unit dosage form such as a pill or tablet and thus the composition may contain, along with a chemical entity provided herein, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like. In another solid dosage form, a powder, marume, solution or suspension (e.g, in propylene carbonate, vegetable oils, PEG’s, poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin or cellulose base capsule). Unit dosage forms in which one or more chemical entities provided herein or additional active agents are physically separated are also contemplated; e.g. , capsules with granules (or tablets in a capsule) of each drug; two-layer tablets; two- compartment gel caps, etc. Enteric coated or delayed release oral dosage forms are also contemplated.

[1137] 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.

[1138] In certain embodiments the excipients are sterile and generally free of undesirable matter. These compositions can be sterilized by conventional, well-known sterilization techniques. For various oral dosage form excipients such as tablets and capsules, sterility is not required. The USP / NF standard is usually sufficient. Ocular compositions can include, without limitation, one or more of any of the following: viscogens (e.g., Carboxymethylcellulose, Glycerin, Polyvinylpyrrolidone, Polyethylene glycol); Stabilizers (e.g., Pluronic (triblock copolymers), Cyclodextrins); Preservatives (e.g., Benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloro complex; Allergan, Inc.)).

[1139] Topical compositions can include ointments and creams. Ointments are semisolid preparations that are typically based on petrolatum or other petroleum derivatives. Creams containing the selected active agent are typically viscous liquid or semisolid emulsions, often either 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, also sometimes called the“internal” phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. The emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant. As with other carriers or vehicles, an ointment base should be inert, stable, nonirritating and non sensitizing.

[1140] In any of the foregoing embodiments, pharmaceutical compositions described herein can include one or more one or more of the following: lipids, interbilayer crosslinked multilamellar vesicles, biodegradeable poly(D,L-lactic-co-glycolic acid) [PLGA]-based or poly anhydride-based nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers. Dosages

[1141] The dosages may be varied depending on the requirement of the patient, the severity of the condition being treating and the particular compound being employed. Proper dosage for a particular situation can be determined by one skilled in the medical arts. In some cases, the total daily dosage may be divided and administered in portions throughout the day or by means providing continuous delivery. In some embodiments, the compounds described herein are administered at a dosage 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; from about 0. 1 mg / Kg to about 150 mg / Kg; from about 0. 1 mg / Kg to about 100 mg / Kg; from about 0.1 mg / Kg to about 50 mg / Kg; from about 0. 1 mg / Kg to about 10 mg / Kg; from about 0. 1 mg / Kg to about 5 mg / Kg; from about 0. 1 mg / Kg to about 1 mg / Kg; from about 0. 1 mg / Kg to about 0.5 mg / Kg).

[1142] Regimens

[1143] The foregoing dosages can be administered on a daily basis (e.g., as a single dose or as two or more divided doses) or non-daily basis (e.g., every other day, every two days, every three days, once weekly, twice weeks, once every two weeks, once a month).

[1144] In some embodiments, the period of administration of a compound described herein is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 1 1 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, 1 1 months, 12 months, or more. In a further embodiment, a period of during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 1 1 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 1 1 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 1 1 months, 12 months, or more. In an embodiment, a therapeutic compound is administered to an individual for a period of time followed by a separate period of time. In another embodiment, a therapeutic compound is administered for a first period and a second period following the first period, with administration stopped during the second period, followed by a third period where administration of the therapeutic compound is started and then a fourth period following the third period where administration is stopped. In an aspect of this embodiment, the period of administration of a therapeutic compound followed by a period where administration is stopped is repeated for a determined or undetermined period of time. In a further embodiment, a period of administration is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In a further embodiment, a period of during which administration is stopped is for 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,

[1145] 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.

[1146] Methods of Treatment

[1147] This disclosure features methods for treating a subject (e.g., a human) having a disease, disorder, or condition in which a decrease in APJ receptor activity (e.g., repressed or impaired APJ receptor signaling; e.g., repressed or impaired apelin-APJ receptor signaling) or downregulation of endogenous apelin contributes to the pathology and / or symptoms and / or progression of the disease, disorder, or condition. In certain embodiments, the methods described herein can include or further include treating one or more conditions associated, co-morbid or sequela with any one or more of the conditions described herein.

[1148] In some embodiments, the method further comprises identifying the subject. In some embodiments, identifying comprises determining the level of one or more of the following parameters in the subject: leukotriene B4 level, pulmonary vascular resistance, pulmonary arterial pressure, cardiac index, pulmonary capillary wedge pressure, right atrial pressure, six-minute walk distance, brain natriuretic peptide level, atrial natriuretic peptide, and diffusion of lung capacity.

[1149] 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.

[1150] In certain embodiments, the chemical entities described herein modulate vascular tone, modulate fluid homeostasis, modulate kidney function, modulate energy metabolism, modulate inflammatory response, and modulate thrombosis.

[1151] Indications

[1152] Pulmonary Hypertension

[1153] In some embodiments, the condition, disease or disorder is pulmonary arterial hypertension (PAH). Non-limiting examples of PAH and related conditions include idiopathic PAH, heritable PAH (e.g., BMPR2 mutations and other mutations), drug- induced or toxin-induced PAH, and PAH associated with conditions including but not limited to connective tissue diseases (CTD) (e.g., scleroderma, systemic lupus erythematosus, systemic sclerosis, Hashimoto's thyroiditis, Sjogren's Syndrome, and the antiphospholipid antibody syndrome), HIV infection, portal hypertension, congenital heart disease, and schistosomiasis.

[1154] In some embodiments, the PAH is idiopathic.

[1155] In other embodiments, the PAH is heritable PAH, toxin or drug-induced PAH; or a 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 the antiphospholipid antibody syndrome), portal hypertension, BMPR2 mutations, Schistosomiasis, and HIV infection.

[1156] In some embodiments, the condition, disease or disorder is pulmonary hypertension other than PAH. Examples of such conditions include, without limitation, pulmonary hypertension due to left heart disease (e.g., left ventricular systolic dysfunction, left ventricular diastolic dysfunction, valvular heart disease, and congenital / acquired left heart inflow / outflow obstruction and congenital cardiomyopathies), pulmonary hypertension due to lung disease and / or hypoxia (e.g., choronic obstructive pulmonary disease, interstitial lung disease, other pulmonary disease with mixed restrictive and obstructive pattern, sleep-disordered breathing, alveolar hypoventilation disorders, chronic exposure to high altitude, developmental lung disease), chronic thromboembolic pulmonary hypertension and other pulmonary artery obstructions (e.g., chronic thromboembolic pulmonary hypertension, other pulmonary artery obstructions), and pulmonary hypertension with unclear multifactorial mechanisms (e.g., haematologic disorders, systemic disorders, metabolic disorders, and others).

[1157] Cardiovascular Conditions, Diseases or Disorders

[1158] In some embodiments, the condition, disease or disorder is a cardiovascular condition, disease or disorder. Non-limiting examples of cardiovascular condition, disease or disorder include coronary heart disease, acute coronary syndrome, peripheral vascular disease, angina, stroke, cerebrovascular accidents, transient ischemic attacks, 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 diseases, peripheral arterial disease, preeclampsia, ventricular tachycardia, and cardiac fibrosis.

[1159] In some embodiments, the cardiovascular condition, disease or disorder is heart failure. Non-limiting examples of heart failure include chronic heart failure, systolic heart failure, diastolic heart failure, diabetic heart failure, congestive heart failure, heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, left ventricular dysfunction (e.g., left ventricular dysfunction after myocardial infarction), right ventricular dysfunction, cardiac hypertrophy, myocardial remodeling, and acute decompensated heart failure (ADHF).

[1160] In some embodiments, the cardiovascular condition, disease or disorder is a condition, disease or disorder with vascular pathology (e.g., with increased vascular permeability and nonfunctional blood vessels). Non-limiting examples of such condition, disease or disorder include vascular hypertrophy, vascular remodeling (e.g., vascular stiffness), atherosclerosis, peripheral arterial occlusive disease (PAOD), restenosis (e.g., angioplastic restenosis), thrombosis and vascular permeability disorders, and ischemia and / or reperfusion damage (e.g., ischemia and / or reperfusion damage of the heart, kidney and retina). In some embodiments, the conditions, disease or disorder is vein related. Non limiting examples of such condition, disease or disorder include angioma, veinous insufficiency, stasis, or thrombosis.

[1161] In some embodiments, the chemical entities described herein can improve cardiac contractility (e.g., cardiac relaxation), ventricular arterial coupling, inotropic function, or luistropic function in a subject suffering from a cardiovascular condition. In some embodiments, the chemical entities described herein can increase ejection fraction in a subject suffering from a cardiovascular condition.

[1162] Metabolic and Homeostatic Dysfunction and Related Conditions, Diseases or Disorders

[1163] In some embodiments, the condition, disease or disorder is associated with metabolic dysfunction. Non-limiting examples of such condition, disease or disorder include metabolic dysfunction, obesity, diabetes (e.g., type II diabetes mellitus, gestational diabetes), complications of diabetes (e.g., metabolic syndrome, insulin resistance, organ damages of micro- or macrovascular origins such as macro- and microvaculopathies, diabetic neuropathy, diabetic retinopathy, cardiac autonomic neuropathy), kidney disease (e.g., chronic kidney disease), edema, dyslipidemia, anorexia, hyperphagia, polyphagia, hypercholesterolemia, hyperglyceridemia, hyperlipemia, growth hormone disorder (e.g., gigantism, aromegaly), galactorrhea, and cardiac wasting.

[1164] In some embodiments, the condition, disease or disorder is associated with inappropriate vasopressin secretions (SIADH). Non-limiting examples of such condition, disease or disorder include neurogenic diabetes mellitus (e.g. diabetic complications such as diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, etc.), lung cancer, septic shock, and thirst troubles.

[1165] In some embodiments, the condition, disease or disorder is associated with systemic inflammation. Non-limiting examples of such condition, disease or disorder include systemic inflammatory response syndrome (SIRs), sepsis (e.g., severe sepsis), and septic shock. In some embodiments, the condition, disease or disorder is associated with sepsis (e.g., a complication, co-morbidity, or sequela of sepsis). Non-limiting examples of conditions, diseases or disorders associated with sepsis include sepsis-induced myocardial dysfunction, sepsis-related inflammatory response (e.g., systemic inflammation), sepsis- related hemodynamic alterations, hypovolemia, sepsis-related organ failures (e.g., multi- organ failure, renal failure), acute kidney injury, vasoplegia, lung injury, inappropriate vasopressin secretions, persistent hypertension related to generalized vasodilation, refractory constrictive responsiveness, huge plasma capillary leak syndrome, coagulation / fibrinolysis imbalance, and metabolic disturbance highlighted by elevated blood-stream lactates. See. e.g., Coquerel et al. Critical Care (2018) 22: 10.

[1166] In some embodiments, the chemical entities described herein can regulate arginine vasopressin (A VP) or angiotensin receptor.

[1167] In some embodiments, the condition, disease or disorder is associated with disturbed body’s fluid homeostasis by CNS-dependent and -independent effects. Non- limiting examples of such condition, disease or disorder include renal failure (e.g., acute and chronic renal failure), renal perfusion, renal dysfunction (e.g., polycystic kidney disease), aquaresis, and diuresis.

[1168] Dementia and Related Conditions, Diseases or Disorders

[1169] In some embodiments, the condition, disease or disorder is dementia. Non-limiting examples of such condition, disease or disorder include senile dementia, cerebrovascular dementia, dementia due to genealogical denaturation degenerative diseases (e.g. Alzheimer’s disease, Parkinson’s disease, Pick’s disease, Huntington’s disease, etc.), dementia resulting from infectious diseases (e.g. delayed virus infections such as Creutzfeldt-Jakob disease), dementia associated with endocrine diseases, metabolic diseases, or poisoning (e.g. hypothyroidism, vitamin B12 deficiency, alcoholism, poisoning caused by various drugs, metals, or organic compounds), dementia caused by tumors (e.g. brain tumor), and dementia due to traumatic diseases (e.g. chronic subdural hematoma), depression, hyperactive child syndrome (microencephalopathy), disturbance of consciousness, anxiety disorder, schizophrenia, and phobia. Connective Tissue Disorder

[1170] In some embodiments, the condition, disease or disorder is a connective tissue disorder. In certain embodiments, the connective tissue disorder is selected from the group consisting of: scleroderma, systemic lupus erythematosus, systemic sclerosis, Hashimoto's thyroiditis, Sjogren's Syndrome, and the antiphospholipid antibody syndrome. In certain embodiments, the condition, disease or disorder is systemic sclerosis.

[1171] Fibrosis

[1172] 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, retroperitoneaum, skin, intestine, joint, a reproductive organ, and a combination thereof. In certain embodiments, the fibrosis is idiopathic pulmonary fibrosis (IPF). In certain embodiments, the fibrosis is liver fibrosis. In certain embodiments, the fibrosis is associated with non-alcoholic fatty liver disease (NAFLD)

[1173] Other Conditions, Diseases or Disorders

[1174] In some embodiments, the condition, disease or disorder is a liver disease. Non- limiting examples of such condition, disease or disorder include alcoholic liver disease, toxicant-induced liver disease, viral induced liver disease, and liver cirrhosis.

[1175] In some embodiments, the condition, disease or disorder is a pulmonary disease. Non-limiting examples of such condition, disease or disorder include chronic obstructive pulmonary disease (COPD), asthma, acute respiratory dystress syndrome (ARDS), and amyotrophiclateral sclerosis. In some embodiments, the condition, disease or disorder is a retinal disease (e.g., macular degeneration).

[1176] In some embodiments, the condition, disease or disorder is HIV infection, HIV neurodegeneration, neurodegenerative disease, cancer (e.g., mammary cancer, lymphocytic leukemia, bladder cancer, ovary cancer, carcinoma of prostate, etc.), asthma, burn injuries (e.g., sun burn), traumatic brain injuries, pancreatitis, Turner’s syndrome, neurosis, rheumatoid arthritis, spinal cord injury, immune function, inflammation, spinocerebellar degeneration, bone fracture, wounds, atopic dermatitis, osteoporosis, asthma, epilepsy, and sterility.

[1177] Activating Stem Cells

[1178] 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 in regrowing tissue, assisting functional recovery after transplanting cells (e.g., cells with bone marrow-derived mesenchymal stem cells), increasing cardiac stem cell proliferation (e.g., in patents that have suffered a myocardial infarction), reducing infarct size, promoting cardiac repair, activating stem cells and progenitors in postmyocardial infarction subjects, or reducing reperfusion injury (e.g., during surgeries such as heart bypass surgery or heart transplant procedures).

[1179] Combination Therapy

[1180] This disclosure contemplates both monotherapy regimens as well as combination therapy regimens.

[1181] In some embodiments, the methods described herein can 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 administration of the compounds described herein.

[1182] In some embodiments, the compound described herein can be administered in combination with one or more of additional therapeutic agents.

[1183] Representative additional therapeutic agents include, but are not limited to, therapeutic agents for PAH, pulmonary hypertension, heart failure (e.g., ADHF, chronic heart failure), hypertension (e.g., systemic hypertension), amyotrophic lateral sclerosis, arrhythmia, asthma, atherosclerosis, atrial fibrillation, Brugada syndrome, bum injuries (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 disorder, neurodegenerative disease, obesity, peripheral arterial disease, preeclampsia, restenosis, transient ischemic attacks, traumatic brain injuries, ventricular tachycardia, edema, or immune function.

[1184] In some embodiments, the one or more additional therapeutic agents include those useful, e.g., as therapeutics for PAH. Non-limiting examples include:

[1185] • prostacyclin analogues (e.g., Epoprostenol, Treprostinil, Iloprost);

[1186] • prostacyclin IP receptor (e.g., Selexipag);

[1187] • endothelin receptor antagonists (e.g., Bosentan, Ambrisentan,

[1188] Macitentan);

[1189] • PDE 5 inhibitors (e.g., Sildenafil, Tadalafil);

[1190] • soluble guanylate cyclase stimulator (e.g., Riociguat);

[1191] • therapeutics for mitochondria dysfunction (e.g., Bardoxolone methyl);

[1192] • anti-inflammation agents (e.g., Rituximab, Tocilizumab, Ubenimex); and

[1193] • agents that modulate oxidative stress (e.g., dimethyl fumarate, intravenous iron).

[1194] In some embodments, the one or more additional therapeutic agents include those useful, e.g., as therapeutics for heart failure or hypertension. Non-limiting examples include:

[1195] • a-blockers (e.g., doxazosin, prazosin, tamsulosin, terazosin);

[1196] • b-blockers (e.g., acebutolol, acetutolol, atenolol, bisoprol, bupranolol, carteolol, carvedilol, celiprolol, esmolol, mepindolol, metoprolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol, taliprolol);

[1197] • calcium channel blockers including but not limited to dihydropyridines (DHPs) (e.g., amlodipine, felodipine, isradipine, lacidipine, nicardipine, nifedipine, nigulpidine, nilutipine, nimodiphine, nisoldipine, nitrendipine, nival dipine, ryosidine) and non -DHPs (e.g., anipamil, diltiazem, fendiline, flunarizine, gallpamil, mibefradil, prenylamine, tiapamil, verapamil); • diurectics (e.g., thiazide derivatives such as, but not limited to, amiloride, chlorothalidon, chlorothiazide, hydrochlorthiazide, and methyl chl orothi azi de)

[1198] • centrally acting hypertensive agents (e.g., clonidine, guanabenz, guanfacine, methyldopa);

[1199] • angiotensin converting enzyme (ACE) inhibitors (alaceptril, benazepril, benazaprilat, captopril, ceronapril, cilazapril, delapril, enalapril, analaprilat, fosinopril, Lisinopril, moexipiril, moveltopril, perindopril, quinapril, quinaprilat, ramipril, ramiprilat, spriapril, temocapril, trendolapril, and zofenopril) and dual ACE / NEP inhibitors (e.g., omapatrilat, fasidotril, and fasidotrilat);

[1200] • angiotensin receptor blockers (ARBs) (e.g., candesartan, eprosartan, irbesartan, losartan, olmesartan, tasosartan, telmisartan, valsartan) and dual ARB / NEP inhibitors (e.g., combinations of valsartan and sacubitril);

[1201] • neutral endopeptidase (NEP) inhibitor (e.g., sacubitril);

[1202] • aldosterone synthase inhibitors (e.g., anastrozole, fadrozole, exemestane);

[1203] • endothelin antagonists (e.g., bosentan, enrasentan, atrasentan, darusentan, macitentan, sitaxentan, tezosentan);

[1204] • inhibitors of funny current (e.g., ivabradine);

[1205] • myosin activators (e.g., cardiac myosin activators);

[1206] • natriuretic;

[1207] • saluretic;

[1208] • vasodilator / vasorelaxation agents (e.g., nitrates)

[1209] • mineralocorticoid receptor antagonists;

[1210] • renin inhibitors;

[1211] • digitalis compounds;

[1212] • inotropic agents and b-receptor agonists;

[1213] • anti-hyperlipidemic agents;

[1214] • plasma HDL-raising agents; • anti-hypercholesterolemic agents;

[1215] • cholesterol biosynthesis inhibitors (e.g., HMG CoA reductase inhibitors)

[1216] • LXR agonist;

[1217] • probucol;

[1218] • raloxifene;

[1219] • nicotinic acid;

[1220] • niacinamide;

[1221] • cholesterol absorption inhibitors;

[1222] • bile acid sequestrants (e.g., anion exchange resins, or quaternary amines such as cholestyramine or colestipol);

[1223] • low density lipoprotein receptor inducers;

[1224] • clofibrate;

[1225] • fenofibrate;

[1226] • bezafibrate;

[1227] • ciprofibrate;

[1228] • gemfibrizol;

[1229] • vitamins (e.g., vitamin B6, vitamin B12, anti-oxidant vitamins);

[1230] • platelet aggregation inhibitors;

[1231] • fibrinogen receptor antagonists;

[1232] • aspirin; and

[1233] • fibric acid derivatives.

[1234] In some embodments, the one or more additional therapeutic agents include those useful, e.g., for treating diabetes. Non-limiting examples include:

[1235] • sulfonylureas (e.g., chlorpropamide, tolbutamide, acetohexamide, tolazamide, glyburide, gliclazide, glynase, glimepiride, glipizide);

[1236] • biguanides (e.g., metformin);

[1237] • thiazolidinediones (e.g., ciglitazone, pioglitazone, troglitazone, rosiglitazone) • insulin sensitizers related to the above (e.g., selective and non-selective activators of PPAR-alpha, PPAR-beta and PPAR-gamma);

[1238] • dehydroepiandrosterone (also referred to as DHEA or its conjugated sulfate ester, DHEA-S04);

[1239] • anti-glucocorticoids;

[1240] • TNF-alpha inhibitors;

[1241] • dipeptidyl peptidase IV (DPP4) inhibitors (e.g.; sitagliptin, saxagliptin);

[1242] • GLP-l agonists or analogs (such as exenatide);

[1243] • alpha-glucosidase inhibitors (such as acarbose, miglitol, and voglibose);

[1244] • pramlintide (a synthetic analog of the human hormone amylin);

[1245] • other insulin secretagogues (such as repaglinide, gliquidone, and nateglinide); and

[1246] • insulin.

[1247] In some embodiments, the one or more additional therapeutic agents include those useful, e.g., for treating obesity. Non-limiting examples include phenylpropanolamine, phentermine, diethylpropion, mazindol, fenfluramine, dexfenfluramine, phentiramine, beta3 -adrenergic receptor agonist agents, sibutramine, gastrointestinal lipase inhibitors (e.g., orlistat), leptins, neuropeptide Y, enterostatin, cholecytokinin, bombesin, amylin, histamine H3 receptors, dopamine D2 receptor modulators, melanocyte stimulating hormone, corticotrophin releasing factor, galanin, and gamma amino butyric acid (GABA).

[1248] Other additional therapeutic agents include:

[1249] • anti-atherosclerotic agents;

[1250] • anti-dyslipidemic agents;

[1251] • antihyperinsulinemic agents;

[1252] • anti -thrombotic agents;

[1253] • anti-retinopathic agents;

[1254] • anti-neuropathic agents; • anti-nephropathic agents;

[1255] • anti -ischemic agents;

[1256] • anti-hyperlipidemic agents;

[1257] • anti-hypertriglyceridemic agents;

[1258] • anti-hypercholesterolemic agents;

[1259] • anti-restenotic-agents;

[1260] • anti-pancreatic agents;

[1261] • anorectic agents;

[1262] • memory enhancing agents;

[1263] • antidementia agents;

[1264] • cognition promoting agents;

[1265] • appetite suppressants;

[1266] • agents for treating peripheral arterial disease;

[1267] • agents for treating malignant tumors;

[1268] • anti-innammatory agents;

[1269] • aquaretics;

[1270] • digoxin;

[1271] • nitric oxide donors;

[1272] • hydralazines;

[1273] • ionotropes;

[1274] • vasopressin receptor antagonists;

[1275] • statins;

[1276] • anti-arrhythmics;

[1277] • phosphodiesterase inhibitors (e.g., PDE5 inhibitors); and

[1278] • nephro-protectives.

[1279] Non-limiting examples of additional therapeutic agents can also include those described in US9156796B2, which is incorporated herein by reference. In certain embodiments, the second therapeutic agent or regimen is administered to the subject prior to contacting with or administering the chemical entity (e.g., about one hour prior, or about 6 hours prior, or about 12 hours prior, or about 24 hours prior, or about 48 hours prior, or about 1 week prior, or about 1 month prior).

[1280] In other embodiments, the second therapeutic agent or regimen is administered to the subject at about the same time as contacting with or administering the chemical entity. By way of example, the second therapeutic agent or regimen and the chemical entity are provided to the subject simultaneously in the same dosage form. As another example, the second therapeutic agent or regimen and the chemical entity are provided to the subject concurrently in separate dosage forms.

[1281] In still other embodiments, the second therapeutic agent or regimen is administered to the subject after contacting with or administering the chemical entity (e.g., about one hour after, or about 6 hours after, or about 12 hours after, or about 24 hours after, or about 48 hours after, or about 1 week after, or about 1 month after).

[1282] Compound Preparation and Biological Assays

[1283] As can be appreciated by the skilled artisan, methods of synthesizing the compounds of the formulae herein will be evident to those of ordinary skill in the art. Synthetic chemistry 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 such as described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and RGM. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof.

[1284] In some embodiments, intermediates useful for preparing the compounds described herein can be prepared using the chemistries delineated in any one or more of the following schemes and non-limiting examples. Compound Preparation

[1285] For illustrative purposes, Schemes 1-4 show general methods for preparing the compounds provided herein as well as intermediates. For a more detailed description of the individual reaction steps, see the Synthetic Examples section below. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the inventive compounds. Although specific starting materials and reagents are depicted in the Scheme and discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives and / or reaction conditions. In addition, 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.

[1286] Scheme 1

[1287]

[1288] 1-8 |-7 1-6 Referring to Scheme 1, a compound of Formula (I) (shown as 1-6 and 1-7) may be prepared from compound 1-1, 1-2, and 1-4 wherein R1and R2are as defined herein. Aminopyrazine 1-1 can be reacted with carboxylic acid 1-2 to afford amide 1-3 (wherein X is a halo such as bromo or chloro) under standard conditions (e.g., in the presence of oxalyl chloride which converts 1-2 into an acyl chloride or in the presence of peptide coupling reagents). Then a reaction under SNAr or metal catalyzed cross-coupling conditions (e.g., Buchwald Hartwig coupling using Xantphos and Pd(OAc)2) between 1-3 and amine 1-4 can provide compound 1-5. Condensation of the carbonyl moiety in 1-5 onto the amino group can provide 1-6, a compound of Formula (I). Alternatively, 1-3 may be obtained through the coupling between 1-1 and an ester of 1-2 (e.g., alkyl ester, e.g., methyl or ethyl ester) under appropriate conditions (e.g., in the presence of AliVfe).

[1289] Optionally, the X moiety in 1-6 can be converted into other R3groups to provide 1-7, another compound of Formula (I). As non-limiting examples for the transformation between 1-6 and 1-7, 1-6 can be reacted with a sulfonamide under Ullmann coupling conditions to provide compound 1-8 ( vide supra , Scheme 1).

[1290] The following starting materials can be used in place of 1-1 and subjected to the sequence depicted in Scheme 1.

[1291] Scheme 2

[1292]

[1293] Referring to Scheme 2, a compound of Formula (I) (shown as compounds II-7 to II-9) in Scheme 2 may be prepared from compound II-l wherein R1is as defined elsewhere herein, and X is a halo (e.g., Br) or pseudohalo (e.g., OTf) group. II-l can be subjected to a Sonogashira coupling or equivalent thereof with a protected acetylene (e.g., TMS-acetylene) to provide compound II-2. Subsequent removal of the alkyne protecting group can afford II-3 which can be coupled with pyrazine derivative II-4 to furnish compound II-5. Cyclization of the amino group in II-5 onto the alkynyl moiety can result in compound II-6, which can be subjected to cross-coupling with a boronic acid of the formula R2-B(OH)2wherein R2is as defined elsewhere herein or a boronate ester thereof (e.g., under Chan-Lam coupling conditions) to afford compound II-7, which is a compound of Formula (I). Compound II-7 can be further functionalized provide compound II-8, also a compound of Formula (I).

[1294] As an non-limiting example for the transformation of II-7 to II-8, II-7 can be coupled with a compound of formula H2NS(0)2R4wherein R4is as defined elsewhere herein (e.g., under Ullmann coupling conditions) to afford compound II-9, a non-limiting example of compound II-8. Scheme 3

[1295]

[1296] MI-7 111-6 MI-5

[1297] Referring to Scheme 3, a compound of Formula (I) (shown as compounds III-5 to III-7 in Scheme 3) may be prepared from compound III-l wherein R1is as defined elsewhere herein. Coupling between III-l and III-2 (e.g., in the presence of a Lewis acid such as AliVfe) can provide compound III-3, which can be subjected to cross-coupling with a compound of formula R2NH2 wherein R2is as defined elsewhere herein to afford compound III-4. Cyclization of the amino group in III-4 onto the amide moiety (e.g., in the presence of P(0)Cb under heat) can provide III-5, which is a compound of Formula (I) III- 5 can functionalized to provide III-6, also a compound of Formula (I).

[1298] As an non-limiting example for the transformation of III-5 to III-6, II-5 can be coupled with a compound of formula H2NS(0)2R4wherein R4is as defined elsewhere herein (e.g., under Ullmann coupling conditions) to afford compound III-7, a non-limiting example of compound III-6.

[1299] Scheme 4

[1300] Referring to Scheme 4, a compound of Formula (I) (shown as compounds IV-6 to IV-8 in Scheme 4) may be prepared from pyridazine derivative IV- 1. Sequential treatment of IV-1 with ammonium hydroxide and bromine can provide IV-3, whereupon the coupling of IV-3 and R'CCbH (wherein R1is as defined elsewhere herein) can provide IV-4. IV-4 can be subjected to coupling with R2NH2 wherein R2is as defined elsewhere herein (e.g., under Buchwald-Hartwig coupling conditions) to provide IV-5 which can undergo cyclization (e.g., under heat and / or microwave irradiation) to afford IV-6, a compound of Formula (I). Compound IV-6 may be functionalized to provide IV-7, also a compound of Formula (I).

[1301] As an non-limiting example for the transformation of IV-6 to IV-7, IV-6 can be coupled with a compound of formula H2NS(0)2R4wherein R4is as defined elsewhere herein (e.g., under Ullmann coupling conditions) to afford compound IV-8, a non-limiting example of compound IV-7.

[1302] Scheme 5

[1303] V-8 V-7 V-6

[1304] Referring to Scheme 5, a compound of Formula (I) (shown as V-6 and V-7) may be prepared from compound V-l, V-2, and V-4 wherein R1and R2are as defined herein. Aminopyrazine V-l can be reacted with carboxylic acid V-2 to afford amide V-3 (wherein X is a halo such as bromo or chloro) under standard conditions. Then a reaction under SNAr or metal catalyzed cross-coupling conditions (e.g., Buchwald Hartwig coupling using Xantphos and Pd(OAc)2) between V-3 and amine V-4 can provide compound V-5. Condensation of the carbonyl moiety in V-5 onto the amino group can provide V-6, a compound of Formula (I).

[1305] Alternatively, V-3 may be obtained through the coupling between V-l and an ester of V-2 (e.g., alkyl ester, e.g., methyl or ethyl ester) under appropriate conditions (e.g., in the presence of AhVfe).

[1306] Optionally, the X moiety in V-6 can be converted into other R3groups to provide 1-7, another compound of Formula (I). As non-limiting examples for the transformation between V-6 and V-7, V-6 can be reacted with a sulfonamide under Ullmann coupling conditions to provide compound V-8 ( vide supra , Scheme 5).

[1307] General Procedures Reactions sensitive to moisture or air were performed under nitrogen or argon using anhydrous solvents and reagents. The progress of reactions was determined by either analytical thin layer chromatography (TLC) usually performed with Sanpont precoated TLC plates, silica gel GF-254, layer thickness 0.25 mm or liquid chromatography-mass spectrometry (LC-MS).

[1308] Typically the analytical LC-MS system used consisted of an Agilent 6120 platform with electrospray ionization in positive ion detection mode with an Agilent 1260 series HPLC with autosampler. The column was usually an Agilent poroshell C 18, 3.0 x 50 mm, 2.7 mnh. The flow rate was 0.6 mL / min, and the injection volume was 5 / L UV detection was in the range 190-400 nm. The mobile phase consisted of solvent A (water plus 0.1% TFA) and solvent B (acetonitrile plus 0.05% TFA) with a gradient of 90% solvent A changing to 95% solvent B over 1.7 min, maintained for 1.8 min, then reverting to 90% solvent A over 0.1 min and maintained for l.4mins.

[1309] Preparative HPLC purifications were usually performed Waters 2555-2767 system with a 2489 UV detector. The column was Welch C-18, 21.2 xl50 mm, 5 mh\. The mobile phases consisted of mixtures of acetonitrile (5-95%) in water containing 0.05%TFA. Flow rates were maintained at 20 mL / min, the injection volume was 1800 / L, and the UV detector used two channels 254 nm and 280 nm. Mobile phase gradients were optimized for the individual compounds. Reactions performed using microwave irradiation were normally carried out using an Initiator manufactured by Biotage. Concentration of solutions was carried out on a rotary evaporator under reduced pressure. Flash chromatography was usually performed using a Biotage Flash Chromatography apparatus (Dyax Corp.) on silica gel (40-63 mM, 60 A pore size) in pre-packed cartridges of the size noted. ¾ NMR spectra were acquired at 400 MHz spectrometers in CDCl3solutions unless otherwise noted. Chemical shifts were reported in parts per million (ppm). Tetramethylsilane (TMS) was used as internal reference in CD3CI solutions, and residual CH3OH peak or TMS was used as internal reference in CD3OD solutions. Coupling constants (J) were reported in hertz (Hz). Chiral analytical chromatography was performed on one of Chiralpak AS, Chiralpak AD, Chiralcel OD, Chiralcel IA, or Chiralcel OJ columns (250x4.6 mm) (Daicel Chemical Industries, Ltd.) with noted percentage of either ethanol in hexane (%Et / Hex) or isopropanol in heptane (%IP A / Hep) as isocratic solvent systems. Chiral preparative chromatography was conducted on one of Chiralpak AS, Chiralpak AD, Chiralcel OD, Ciralcel IA, or Chiralcel OJ columns (20x250 mm) (Daicel Chemical Industries, Ltd.) with desired isocratic solvent systems identified on chiral analytical chromatography or by supercritical fluid (SFC) conditions.

[1310] Abbreviations

[1311] -C(0)CH3(AC); acetic acid (AcOH); -0C(0)CH3(OAc); aqueous (aq); Cbz (benzyloxycarbonyl); N,N-d\ i sopropy 1 ethyl am i ne (DIEA); Af;A-di methyl form am i de (DMF); l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI); ethyl acetate (EtOAc); diethyl ether (ether or Et20); petroleum ether (PE); gram(s) (g); hour(s) (h or hr); 2- propanol (IP A); mass spectrum (ms or MS); microliter(s) (pL); milligram(s) (mg); milliliter(s) (mL); millimole (mmol); minute(s) (min); methyl t-butylether (MTBE); (benzotriazol- 1 -yloxy)tripyrrolidino-phosphonium hexafluorophosphate (PyBOP); retention time (Rt); room temperature (rt or RT); saturated aq 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); / -butyloxycarbonyl (Boc or BOC); Diethylaminosulfur trifluoride (DAST); dichloromethane (DCM); dimethylacetamide (DMA; DMAC); dimethylsulfoxide (DMSO); l,3-Bis(diphenylphosphino)propane (DPPP); acetic acid (HO Ac); 3-chloroperoxybenzoic acid (m-CPBA); methyl (Me); methanol (MeOH); N-bromosuccinamide (NBS); thin layer chromatography (TLC).

[1312] Synthetic Examples

[1313] The following are representative procedures for the preparation of the compounds used in the following Examples, or which can be substituted for the compounds used in the following Examples which may not be commercially available.

[1314] Method A:

[1315]

[1316] Example 1 : 6-bromo-l-(2, 6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH- imidazo[4, 5-b]pyrazine

[1317] And Example 2: N-(l-(2, 6-dimethoxyphenyl)-2- ( 6-ethoxypyridin-2-yl)-lH-imidazo[4, 5- b]pyrazin-6-yl)methanesulfonamide

[1318]

[1319] Step A: ethyl 6-ethoxypicolinate Ethyl iodide (112.2 g, 720 mmol, 4 equiv) was added to a suspension of 6-hydroxy - pyridme-2-carboxylic acid (25.0 g, 180 mmol, 1 equiv) and silver(I) carbonate (100 g, 360 mmol, 2 equiv) in CHCb (400 mL). The mixture was stirred at 30°C for 1 day. Insoluble material was removed by filtration and the solid was washed with CHCb. The filtrate was concentrated in vacuo to afford the title compound ethyl 6-ethoxypicolinate as light yellow oil which was used in the next step without further purification.

[1320] LC-MS: m / z 196.0 (M+H)+

[1321] Step B: 6-ethoxypicolinic acid

[1322] To a solution of ethyl 6-ethoxypicolinate (25 g, 128 mmol, 1 equiv) in EtOH (30 mL) was added sodium hydroxide solution (lmol / L, 384 mL, 384 mmol, 3 equiv). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was neutralized with 1 N HC1 (aq.) solution and extracted with ethyl acetate. The extract was washed with brine, dried over MgSCri and concentrated in vacuo to afford the title compound 6- ethoxypicolinic acid.

[1323] LC-MS: m / z 168.0 (M+H)+Step C: N- dibromopyrazin-2-yl )-6-ethoxypi col inamide

[1324] 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 resulted mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to afford the crude 6-ethoxypicolinic 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. Then the crude 6-ethoxypicolinic chloride in DMF (100 mL) was added dropwise over a period of 30 min. After the addition, the mixture was stirred at room temperature overnight. The mixture was quenched with saturated NH4CI (aq.) (100 mL) and extracted with DCM (3 * 150 mL). The extract was washed with brine (100 mL), dried over anhydrous Na2S04and concentrated in vacuo. The residue was recrystalized in DCM to afford the compound N-(3,5-dibromopyrazin-2-yl)-6-ethoxypicolinamide.

[1325] LC-MS: m / z 400.9, 402.9, 404.9(M+H)+

[1326] Step D: N-(5-bromo-3-((2.6-dimethoxyphenv0amino)pyrazin-2-v0-6-ethoxypicolinamide

[1327] 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)2 (112 mg, 0.5 mmol, 0.2 equiv), Xantphos (576 mg, 1.0 mmol, 0.4 equiv) and K2CO3 (680 mg, 3.0 mmol, 2 equiv) in 1.4-dioxane (10 mL) was stirred at 120°C via microwave irradiation for 2 hours under N2 atmosphere. The mixture was diluted with DCM (20 mL) and filtered through celite. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (PE / EtOAc = 4 / 1) to afford the title compound N-(5-bromo-3-((2,6- dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide.

[1328] LC-MS: m / z 474.0, 476.0 (M+H)+

[1329] Step E: 6-bromo-l-(2.6-dimethoxyphenvO-2-(6-ethoxypyridin-2-vO-lH-imidazor4.5- blpyrazine (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 via microwave irradiation for 2 hours. The mixture was cooled to room temperature. The precipitate was filtered off and washed with a mixture of EtO Ac / PE = 1 / 2 (3 * 1 mL) to afford the title compound as a white solid.

[1330] ¾ NMR (400 MHz, DMSO-de) d: 8.75 (s, 1H), 8.04 (dd, J = 7.4, 0.8 Hz, 1H), 7.89 (dd, J = 8.4, 7.4 Hz, 1H), 7.50 (t, J = 8.4 Hz, 1H), 6.89 (d, J = 8.4 Hz, 3H), 3.60 (s, 6H), 3.40 (q, J = 7.0 Hz, 2H), 1.05 (t, J = 7.0 Hz, 3H).

[1331] LC-MS: m / z 456.1, 458.1 (M+H)+

[1332] Step F: N- dimethoxyphenvD-2-(6-ethoxypyridin-2-vD-lH-imidazor4.5-b1pyrazin-

[1333] 6-vDmethanesulfonamide (Example 2)

[1334] A suspension of 6-bromo-l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH- imidazo[4,5-b]pyrazine (150 mg, 0.33 mmol), methanesulfonamide (62 mg, 0.66 mmol, 2 equiv), Cul (125 mg, 0.66 mmol, 2 equiv), trans-N,N'-Dimethylcy cl ohexane- 1,2-diamine (94 mg, 0.66 mmol, 2 equiv) and K2CO3 (137 mg, 0.99 mmol, 3 equiv) in DMF (5 mL) was stirred at 115°C via microwave irradiation for 1.5 hour under N2 atmosphere. The reaction was washed with water (150 mL), followed by extraction with EtO Ac (3 * 100 mL). The combined organic layer was dried over anhydrous Na2S04and concentrated in vacuo. The residue was purified by flash chromatography (eluting with PE / EtOAc = 20 / 1-5 / 1 ) to obtain the title compound as a yellow solid.

[1335] ¾NMR (400 MHz, DMSO-de) d: 11.05 (s, 1H), 8.27 (s, 1 H), 7.95 (dd, .1 = 7.4 Hz, J = 0.8 Hz, 1H), 7.86 (t, J = 7.8 Hz, 1H), 7.45 (t, J = 8.4 Hz, 1H), 6.81-6.87 (m, 3H), 3.57 (s, 6H), 3.39 (q, J = 7.0 Hz, 2H), 3 20 (s, 3H), 1.03 (t, J = 7.0 Hz, 31 ! ) LC-MS: / z 471.0 (M I ! )

[1336] Example 3: N~(l-(2,6-dimethoxyphenyi)-2-(6~ethoxypyridin-2-yl)-lH-imidazo[4,5- b / pyrazin-6-yl)-l-phenylmethanesulfonamide

[1337]

[1338] The title compound was prepared according to general procedure A, step F, starting from Example 1 by using benzyl sulfonamide

[1339] ¾ NMR (400 MHz, DMSO-de) d: 1 1.04 (s, 1 H), 8.14 (s, 1 H), 7.97 (dd, J = 7.4 Hz, 0.8 Hz,

[1340] 1H), 7.87 (t, J = 7.8 Hz, 1H), 7.49 (t, J = 8.4 Hz, 1H), 7.31-7.33 (m, 3H), 7.12-7.14 (m, 2H), 6.83-6.90 (m, 3H), 4 68 (s, 2H), 3.58 (s, 6H), 3.41 (q, J = 7.0 Hz, 2H), 1 .03 (t, J = 7 0 Hz, 3H). LC-MS: m / z 547.0 (M+H)+

[1341]

[1342] The title compound was prepared according to general procedure A, step F, starting from Example 1 by using 1-cyclopropylmethanesulfonamide.

[1343] ' I I NMR (400 MHz, DMSO-de) 0: 11.03 (s, 1 1 1 ), 8.30 (s, 1H), 7 94 (dd, J = 7.4 Hz, 0.8 Hz, 1H), 7.85 (t, J = 7.8 Hz, 1H), 7.45 (t, J = 8 4 Hz, 1 H), 6.81-6.87 (m, 3H), 3.57 (s, 6H), 3 39 (q, J = 7.0Hz, 2H), 3.27 (d, J = 3.4 Hz, 2H), 1.02 (t, J = 7.0 Hz, 3H), 0.47 (d, J = 4.0 Hz,

[1344] 3H), 0.13 (d, J = 2.2 Hz, 2H). LC-MS: m / z 511.0 (M+Hf

[1345] b]pyrazin-6-yl)benzenesulfonamide

[1346] The title compound was prepared according to general procedure A, step F, starting from Example 1 by using benzenesulfonamide.

[1347] ¾ NMR (400 MHz, DMSO-de) d: 11 53 (s, 1H), 8.24 (s, 1 H), 7 93 (dd, J = 7.4 Hz, 0.8 Hz, 1H), 7.83 (t, J = 7.8 Hz, 1H), 7.66 (dd, J = 8.4 Hz, 0.8Hz, 2H), 7.55 (t, J = 8.4 Hz, 2H),

[1348] 7.38 (t, J = 7 8 Hz, 2H), 6.93 (d, J = 4.4 Hz, 2H), 6.81 (d, J = 4 Hz 1H), 3.54 (s, 6H), 3.38 (q, J = 7.0 Hz, 2H), 1.03 (t, J = 7.0 Hz, 3H). LC-MS: m / z 533.0 (M i l)

[1349] Example 6: l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-6-(phenylethynyl)-lH- imidazo[4,5-b]pyrazine

[1350]

[1351] And

[1352] Example 7 : l-(2, 6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-6-phenethyl-lH- imidazo[4, 5-b]pyrazine

[1353]

[1354] Step A: l- dimethoxyphenvD-2-(6-ethoxypyridin-2-vD-6-(phenylethynvD-lH-

[1355] imidazor4.5-b1pyrazine (Example 6)

[1356] A suspension of 6-bromo-l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH- imidazo[4,5-b]pyrazine (Example 1, 100 mg, 0.22 mmol, 1 equiv), ethynylbenzene (44.5 mg, 0.44 mmol, 2 equiv), Pd(PPh3)2Cl2 (15.3 mg, 0.022 mmol, 0.1 equiv), Cul (8.3 mg, 0.044 mmol, 0.2 equiv) and Et3N (66 mg, 0.66 mmol, 3.0 equiv) in DMF (5 mL) was bubbled with N2 for 1 min followed by stirred at 80 °C for 4 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl ether (3 * 100 mL). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by flash chromatography on silica gel (PE / EtOAc = 1 / 1) to afford the title compound.

[1357] ¾ NMR (400 MHz, DMSO-de) d: 8.85 (s, 1H), 8.07 (d, J = 7.0 Hz, 1H), 7.87 -7.93 (m, 1H), 7.64 - 7.68 (m, 2H), 7.49 -7.53 (m, 1H), 7.43 - 7.49 (m, 3H), 6.90 (dd, J = 8.4, 1.6 Hz, 3H), 3.61 (s, 6H), 3.41 (q, J = 7.0 Hz, 2H), 1.06 (t, J = 7.0 Hz, 3H). LC-MS: m / z 478.2

[1358] (M+H)+

[1359] Step B: l- dimethoxyphenvD-2-(6-ethoxypyridin-2-vD-6-phenethyl-lH-imidazor4.5- blpyrazine (Example 7)

[1360] A mixture of l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-6-(phenylethynyl)-lH- imidazo[4,5-b]pyrazine (70 mg, 0.157 mmol) and 10% Pd / C (7 mg) in EtOAc (10 mL) was stirred under H2 at room temperature overnight. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (PE / EtOAc = 1 / 1) to afford the title compound. ¾ NMR (400 MHz, DMSO-de) d: 8.40 (s, 1H), 7.98 (d, J = 7.4 Hz, 1H), 7.86 (t, J = 7.8 Hz, 1H), 7.47 (t, J = 8.4 Hz, 1H), 7.19 - 7.26 (m, 2H), 7.09 - 7.18 (m, 3H), 6.86 (dd, J = 17.4, 8.4 Hz, 3H), 3.59 (s, 6H), 3.41 (q, J = 7.0 Hz, 2H), 3.13 (dd, J = 8.4, 6.8 Hz, 2H), 2.96 (t, J = 7.6 Hz, 2H), 1.05 (t, J = 7.0 Hz, 3H).

[1361] LC-MS: m / z 482.2 (M+H)+

[1362] Example 8: N-Benzyl-l-(2, 6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH- imidazo[4,5-b]pyrazine-6-carboxamide

[1363]

[1364] Step A: Methyl l- dimethoxyphenvD-2-(6-ethoxypyridin-2-vD-lH-imidazor4.5-

[1365] blpyrazine-6-carboxylate

[1366] 6-Bromo-l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH-imidazo[4,5-b]pyrazine (105 mg, 0.23 mmol, 1 equiv) was dissolved in MeOH. Then Pd(dppf)Cl2 (33 mg, 0.046 mmol, 0.2 equiv) and triethylamine (70 mg, 0.69 mmol, 3 equiv) were added. The suspension was degassed and purged with CO three times. Then the reaction mixture was stirred at 90°C under 3MPa overnight. The reaction mixture was filtered, concentrated and purified via column chromatography (silica gel, eluting with 25% EtOAc in PE) to afford the title compound methyl l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH- imidazo[4,5-b]pyrazine-6-carboxylate. LC-MS: m / z 436.1 (M+H)+

[1367] Step B: N-Benzyl- 1 -(2.6-dimethoxyphenyl )-2-(6-ethoxypyridin-2-yl )- 1 H-imidazc>r4.5- blpyrazine-6-carboxamide (Example 8)

[1368] Methyl l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH-imidazo[4,5-b]pyrazine-6- carboxylate (32.4 mg, 0.074 mmol, 1 equiv) and benzylamine (15 mg, 0. l48mmol, 2 equiv) were charged into sealed tube and the mixture was heated at 90°C for 2h. Then the reaction mixture was purified via column chromatography (silica gel, eluting with 25% EtOAc in PE) to afford the title compound.

[1369] ¾ NMR (400 MHz, DMSO-de) d: 9.21 (s, 1H), 8.85 (t, J = 6.4 Hz, 1H), 8.04 (d, J = 6.8 Hz, 1H), 7.90 (t, J = 7.2 Hz, 1H), 7.46 (t, J = 8.4 Hz, 1H), 7.23-7.30 (m, 5H), 6.88 (t, J = 8.4 Hz, 3H), 4.50 (d, J = 6.4 Hz , 2H), 3.59 (s, 6H), 3.41 (q, J = 7.0 Hz, 2H), 1.05 (t, J = 7.0 Hz, 3H). LC-MS: m / z 511.2 (M+H)+

[1370] Example 9: l-(2, 6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-N-methyl-lH- imidazo[4,5-b]pyrazin-6-amine

[1371]

[1372] A mixture of 6-bromo- 1 -(2,6-dimethoxyphenyi)-2-(6-ethoxypyridin-2-yl)- 1H- imidazo[4,5-b]pyrazine (Example 1, 60 mg, 0.1 mmol, equiv), and CH3NH2 (aq., 40wt%, 5 mL) was stirred at 120 °C via microwave irradiation for 2 hours. The reaction mixture was concentrated and residue was purified by flash chromatography on silica gel (PE / EtOAc = 1 / 2) to afford the title compound.

[1373] ¾ NMR (400 MHz, DMSO-de) d: 7.84 (s, 1H), 7.82 (dd, J = 7.4, 1.0 Hz, 1H), 7.73 - 7.79 (m, 1H), 7.40 (t, J = 8.4 Hz, 1H), 7.19 (q, J = 4.8 Hz, 1H), 6.83 (d, J = 8.4 Hz, 2H), 6.69 (dd, J = 8.0, 1.0 Hz, 1H), 3.58 (s, 6H), 3.37 (q, J = 7.0 Hz, 2H), 2.70 (d, J = 4.8 Hz, 3H), 1.02 (t, J = 7.0 Hz, 3H). LC-MS: m / z 407.2 (M+H)+

[1374] Method B:

[1375] step A

[1376]

[1377] Step A: tert-butyl (T-f2,6-dimethQxyphenv¾)-2-f6-ethoxypyridin-2-v¾)-lH-imidaza[4,5- blpyrazin-6-yl carbamate

[1378] A suspension of 6-bromo-l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH- imidazo[4,5-b]pyrazine (500mg, 1.09 mmol, 1 equiv), BocNTh (255 mg, 2.18 mmol, 2 equiv), Pd(OAc)2 (49 mg, 0.22 mmol, 0.2 equiv), Xantphos(252 mg, 0.44 mmol, 0.4 equiv) and CS2CO3 (711 mg, 2.18 mmol, 2 equiv) in l.4-dioxane (10 mL) was stirred at l20°C via microwave irradiation for 2 hours under N2 atmosphere. The mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (PE / EtOAc = 2 / 1) to afford the title compound tert-butyl (l-(2,6- dimethoxyphenyl)-2-(6-ethoxypyri din-2 -yl)-lH-imidazo[4,5-b]pyrazin-6-yl)carbamate.

[1379] LC-MS: m / z 493.2 (M+H)+

[1380] Step B: l-f2.6-dimethoxyphenvD-2-f6-ethoxypyridin-2-yl)-lH-imidazof4 5-b]pyrazin-6- amine (Example 10)

[1381]

[1382] A mixture of tert-butyl (l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH- imidazo[4,5-b]pyrazin-6-yl)carbamate (350 mg, 0.71 mmol, 1 equiv) and HC1 in dioxane (4 mo! / L, 20 mL) at 0°C. The mixture was then stirred at roo temperature for 4 hours. The reaction mixture was concentrated and residue was purified by flash chromatography on silica gel (100% EtOAc) to afford Example 10.

[1383] ¾ NMR (400 MHz, DMSO-de) d: 7.83 - 7.89 (m, 2H), 7.79 (t, J = 7.8 Hz, 1H), 7.41 (t, J = 8.4 Hz, 1H), 6.83 (d, J = 8.4 Hz, 2H), 6.72 (d, J = 8.0 Hz, 1H), 6.64 (s, 2H), 3.60 (s, 6H), 3.42 (q, J = 7.0 Hz, 2H), 1.04 (t, J = 7.0 Hz, 3H). LC-MS: m / z 393.2 (M+H)+

[1384] Example 11 : N ,N-dibenzyl-l-(2, 6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH- imidazo[4,5-b]pyrazin-6-amine

[1385] A mixture of compound Example 10 (50 mg, 0.13 mmol, 1 equiv) and NaH (10.2 mg, 0.26 mmol, 2 equiv) in DMF (5 mL) was stirred at 0°C for 30 minutes. Bromomethylbenzene (24 mg, 0.14 mmol, 1.1 equiv) was added and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (30 mL) and extracted with ethyl ether (3 * 50 mL). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (PE / EtOAc = 1 / 1) to afford the title compound.

[1386] ¾ NMR (400 MHz, DMSO-de) d: 7.90 (s, 1H), 7.85 (dd, J = 7.4, 0.8 Hz, 1H), 7.78 (t, J = 7.8 Hz, 1H), 7.43 (t, J = 8.4 Hz, 1H), 7.18 - 7.32 (m, 10H), 6.85 (d, J = 8.4 Hz, 2H), 6.73 (dd, J = 8.0, 0.8 Hz, 1H), 4.77 (s, 4H), 3.55 (s, 6H), 3.37 (q, J = 7.0 Hz, 2H), 1.01 (t, J = 7.0 Hz, 3H). LC-MS: m / z 573.2 (M+H)+

[1387]

[1388] A mixture of compound Example 10 (50 mg, 0.13 mmol, 1 equiv), and NaH (15.3 mg, 0.38 mmol, 3 equiv) in DMF (5 mL) was stirred at 0°C. for 30 min. iodomethane (54.3 mg, 0.38 mmol, 3 equiv) was added and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (30 mL) and extracted with ethyl ether (3 * 50 mL). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (PE / EtOAc = 3 / 7) to afford the desired product.

[1389] ¾ NMR (400 MHz, DMSO-de) d: 8.08 (s, 1H), 7.84 (dd, J = 7.4, 1.0 Hz, 1H), 7.75 - 7.82 (m, 1H), 7.40 (t, J = 8.4 Hz, 1H), 6.83 (d, J = 8.4 Hz, 2H), 6.71 (dd, J = 8.0, 1.0 Hz, 1H), 3.57 (s, 6H), 3.40 - 3.34 (m, 2H), 3.02 (s, 6H), 1.02 (t, J = 7.0 Hz, 3H). LC-MS: m / z 421.2

[1390] (M+H)+ Example 13: N-henzyl-l-{2,6-dimethexyphenyl)-2-{6-ethexypyridm-2-yl)-lH-

[1391]

[1392] To a well-stirred red suspension of l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH- imidazo[4,5-b]pyrazin-6-amine (Example 10, 60 mg, 0.15 mmol, 1 equiv) in 1, 2- dichloroethane (20 mL), benzylaldehyde (65 mg, 0.61 mmol, 4 equiv) was added, and the reaction flask was immersed in an ice bath. Then AcOH (37 mg, 0.61 mmol, 4 equiv) was added followed by the addition of sodium triacetoxyborohydride (130 mg, 0.61 mmol, 4 equiv) in small portions over a 15 min period. The resulting suspension was slowly allowed to warm to 50°C and stirred overnight. The reaction was quenched by a slow addition of saturated NaHCCb (20 mL) while stirring at 0°C. The biphasic mixture was stirred for 30 min and extracted with DCM(3 * 25 mL). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (PE / EtOAc = 1 / 1) to afford the desired product.

[1393] ¾ NMR (400 MHz, DMSO-de) d: 7.88 (s, 1H), 7.74 - 7.84 (m, 3H), 7.42 (t, J = 8.4 Hz, 1H), 7.28 - 7.17 (m, 5H), 6.83 (d, J = 8.4 Hz, 2H), 6.70 (dd, J = 8.0, 1.0 Hz, 1H), 4.30 (d, J = 6.0 Hz, 2H), 3.54 (s, 6H), 3.34 - 3.40 (m, 2H), 1.01 (t, J = 7.0 Hz, 3H). LC-MS: m / z 483.2 (M+H)+

[1394] Example 14: N-(l-(2, 6-dimethoxyphenyl)-2- ( 6-ethoxypyridin-2-yl)-lH-imidazo[4, 5- b]pyrazin-6-yl)-2-phenylacetamide

[1395]

[1396] A mixture of 1 -(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)- 1 H-imidazo[4,5- b]pyrazin-6-amine (Example 10, 50 mg, 0.13 mmol, 1 equiv), and NaH (15.3 mg, 0.38 mmol, 3 equiv) in DMF (5 mL) was stirred at 0 °C for 30 min. 2-Phenylacetyl chloride (21 mg, 0.13 mmol, 1 equiv) was added and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (30 mL) and extracted with ethyl ether (3 * 50 mL). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (PE / EtOAc = 3 / 7) to afford the desired product. ¾ NMR (400 MHz, DMSO-de) d: 11.11 (s, 1H), 9.33 (s, 1H), 7.99 (d, J = 7.4 Hz, 1H),

[1397] 7.85 (t, J = 7.8 Hz, 1H), 7.46 (t, J = 8.4 Hz, 1H), 7.18 - 7.37 (m, 6H), 6.86 (d, J = 8.4 Hz, 2H), 3.74 (s, 2H), 3.60 (s, 6H), 3.39 (q, J = 7.0 Hz, 2H), 1.05 (t, J = 7.0 Hz, 3H). LC-MS: m / z 511.2 (M+H)+

[1398] Example 15: 5-chloro-l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH- imidazo[4, 5-b]pyrazine

[1399]

[1400] And Example 16: l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH-imidazo[4,5- b]pyrazin-5-amine

[1401]

[1402] Step A: N-(3-bromo-6-chloropyrazin-2-vO-6-ethoxypicolinamide The mixture of ethyl 6-ethoxypicolinate (500 mg, 2.56 mmol, 1 equiv) and 3-bromo-6- chloropyrazin-2-amine (530 mg, 2.56 mmol, 1 equiv) in toluene was cooled to 0°C and AhVfe was added dropwise. Then the mixture was stirred at l00°C for 16 hours. The mixture was quenched with NH4CI solution and extracted with EtOAc (3 * 20 mL). The combined organic layer was dried over anhydrous Na2S04and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (PE / EtOAc = 10 / 1) to afford the title compound N-(3-bromo-6-chloropyrazin-2-yl)-6-ethoxypicolinamide.

[1403] ¾ NMR (400 MHz, DMSO-de) d: 10.94 (s, 1H), 8.50 (s, 1H), 7.99 (d, J = 7.6 Hz, 1H), 7.68 - 7.82 (m, 1H), 7.07 - 7.27 (m, 1H), 4.52 (d, J = 7.0 Hz, 2H), 1.40 (t, J = 7.0 Hz, 3H). LC-MS: m / z 357.7 (M+H)+Step B : N-(6-chloro-3- dimethoxyphenvDamino)pyrazin-2-vD-6-ethoxypicolinamide

[1404]

[1405] The mixture of N-(3-bromo-6-chloropyrazin-2-yl)-6-ethoxypicolinamide (500 mg, 1.4 mmol, 1 equiv), 2, 6-dimethoxy aniline (430 mg, 2.8 mmol, 2 equiv), Xantphos (162 mg, 0.28 mmol, 2 equiv), Pd2(dba)3 (128 mg, 0.14 mmol, 0.1 equiv), potassium 2- methylpropan-2-olate (297 mg, 2.8 mmol, 2 equiv) in toluene (10 mL) was stirred at 1 l0°C for 16 hours under N2 atmosphere. The mixture was filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 10 / 1) to afford the title compound N-(6-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6- ethoxypicolinamide. ¾ NMR (400 MHz, CDCh) d: 10.11 (s, 1H), 8.40 (s, 1H), 8.02 (s, 1H), 7.92 (d, J = 7.2Hz, 1H), 7.77 (t, J = 8.8 Hz, 1H), 7.13 (t, J = 8.4 Hz, 1H), 6.97 (d, J = 8.0 Hz, 1H), 6.65 (d, J = 8.4 Hz, 2H), 4.48 (q, J = 7.2 Hz, 2H), 3.82 (s, 6H), 1.46 - 1.52 (m, 3H). LC-MS: m / z 429.7 (M+H)+Step C: 5-chloro- 1 - dimethoxyphenyl )-2-(6-ethoxypyridin-2-yl )- 1 H-imidazc>r4.5-

[1406] blpyrazine (Example 15)

[1407] N-(6-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide (280 mg, 0.56 mmol, 1 equiv) in AcOH (20 mL) was stirred at l20°C for 1 hour under MW. The mixture was concentrated in vacuo. The residue was washed with ether, filtered and dried to afford the desired product.

[1408] ¾ NMR (400 MHz, CDCh) d: 8.27 (s, 1H), 8.13 - 8.20 (m, 1H), 7.69 (t, J = 8.4 Hz, 1H), 7.39 (t, J = 8.4 Hz, 1H), 6.65 - 6.77 (m, 3H), 3.62 (s, 6H), 3.43 (q, J = 7.2 Hz, 2H), 1.09 (t, J = 7.2 Hz, 3H). LC-MS: m / z 411.7 (M+H)+

[1409] Step D: tert-butyl (T- dimethoxyphenvD-2-(6-ethoxypyridin-2-vD-lH-imidazor4.5-

[1410] blpyrazin-5-vDcarbamate

[1411] The mixture of 5-chloro-l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH- imidazo[4,5-b]pyrazine (80 mg, 0.19 mmol, 1 equiv), tert-butyl carbamate (46 mg, 0.38 mmol, 2 equiv), Xantphos (22 mg, 0.038 mmol, 0.2 equiv), Pd2(dba)3 (17 mg, 0.019 mmol, 0.1 equiv), potassium 2-methylpropan-2-olate (43 mg, 0.38 mmol, 2 equiv) in toluene (5 mL) was stirred at H0°C for 16 hours under N2 atmosphere. The mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (PE / EtOAc = 3 / 1) to afford the title compound tert-butyl (l-(2,6-dimethoxyphenyl)-2-(6- ethoxypyridin-2-yl)-lH-imidazo[4,5-b]pyrazin-5-yl)carbamate.

[1412] ¾ NMR (400 MHz, CD3OD) d: 8.91 (s, 1H), 7.89-7.87 (d, J = 7.2 Hz, 1H), 7.79-7.77 (t, J = 7.2 Hz, 1H), 7.46-7.44 (t, J = 8.4 Hz, 1H), 6.84-6.75 (m, 3H), 3.64 (s, 6H), 3.51 - 3.46

[1413] (m, 2H), 1.55 (s, 9H), 1.11-1.09 (t, J = 7.2 Hz, 3H). LC-MS: m / z 492.7 (M+H)+ Step E: 1 -(2.6-dimethoxyphenyl )-2-(6-ethoxypyridin-2-yl )- 1 H-imidazc>r4.5-b1pyrazin-5- amine (Example 16) tert-butyl (l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH-imidazo[4,5-b]pyrazin- 5-yl) carbamate (30 mg, 0.06mmol, 1 equiv) in HC1 / MeOH (4 mol / L, lOmL) was stirred at room temperature for 6 hours. The mixture was concentrated in vacuo and residue was washed with ether to afford the desired product.

[1414] ¾NMR (400 MHz, CD3OD) d: 7.96 (s, 1H), 7.80 (t, J = 8.0 Hz, 1H), 7.52 - 7.63 (m, 2H), 6.85 - 6.97 (m, 3H), 3.80 (q, J = 7.2 Hz, 2H), 3.70 (s, 6H), 1.19 (t, J = 7.2 Hz, 3H). LC- MS: m / z 393.3 (M+H)+

[1415] Example 17: N-(l-(2, 6-dimethoxyphenyl)-2- ( 6-ethoxypyridin-2-yl)-lH-imidazo[4, 5- b]pyrazin-5-yl)-2-phenylacetamide

[1416]

[1417] The mixture of 5-chloro-l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH- imidazo[4,5-b]pyrazine (Example 15, 60 mg, 0.15 mmol, 1 equiv), 2 -phenyl acetamide (19.7 mg, 0.15 mmol, 1 equiv), Xantphos (17 mg, 0.03 mmol, 0.2 equiv), Pd2(dba)3 (13 mg, 0.015 mmol, 0.1 equiv), CS2CO3 (95 mg, 0.3 mmol, 2 equiv) in dioxane (5 mL) was stirred at H0°C for 16 hours under N2 atmosphere. The mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (PE / EtOAc = 3 / 1) to afford the title compound.

[1418] ¾ NMR (400 MHz, CDCh) d: 9.34 (s, 1H), 8.12 (d, J = 7.2 Hz, 2H), 7.66 (t, J = 7.2 Hz, 1H), 7.33 - 7.41 (m, 5H), 6.63 - 6.73 (m, 3H), 3.85 (s, 2H), 3.55 - 3.66 (m, 6H), 3.43 (q, J

[1419] = 7.2 Hz, 2H), 1.08 (t, J = 7.2 Hz, 3H). LC-MS: m / z 511.3 (M+H)+ Example 18: l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH-imidazo[4,5- bjpyrazine

[1420]

[1421] Step A: ethyl 6-ethoxypicolinate

[1422] To a solution of 6-hydroxypicolinic acid (12 g, 86.33 mmol) in DCM (250 ml) was added Ag2CCb (48 g, 174 mmol), followed by adding Etl (27.6 ml, 345.32 mmol) dropwise. The mixture was stirred at 25 °C for 12 hr. and filtered. The filtrate was concentrated in vacuum to give ethyl 6-ethoxypicolinate as a gray oil, which was used in the next step without further purification.

[1423] LC-MS: m / z 196.3 (M+H)+

[1424] Step B: (6-ethoxypyridin-2-v0methanol

[1425] To a solution of ethyl 6-ethoxypicolinate (5.8 g, 29.7 mmol) in THF (60 ml) was added LiAlEE (15 ml, 1M THF sol.) dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 3 hr and quenched with H2O / EA. The collected organic layers were dried over Na2S04and concentrated in vacuum. The residue was purified by silica gel chromatograph to give (6-ethoxypyridin-2-yl)methanol.

[1426] LC-MS: m / z 154.3 (M+H)+

[1427] Step C: 6-ethoxypicolinaldehyde

[1428] To a solution of (6-ethoxypyridin-2-yl)methanol (3 g, 19.61 mmol) in l,4-dioxane (30 ml) was added MnCh (12 g, 137.25 mmol) and the reaction mixture was refluxed for 3 hr. The reaction mixture was filtered and the filtrate was concentrated in vacuum to give 6- ethoxypicolinaldehyde.

[1429] LC-MS: m / z 152.3 (M+H)+

[1430] Step D: 3-chloro-N-('2.6-dimethoxyphenyl)pyrazin-2-amine

[1431] To a solution of 2,3-dichloropyrazine (0.918 g, 6 mmol) in THF (15 mL) was added KHMDS (1 N in TMF, 6 mL, 6 mmol) slowly at 0 °C and the mixture was stirred at 0 °C for l5min, followed by adding a solution of 3-5 (0.74 g, 5 mmol) in THF (5 mL) dropwise at 0 °C. The dark-green mixture was stirred at room temperature for 3 h, poured into ice- water (40 mL) and extracted with EA (10 mL*3). The combined organic layer was dried over Na2S04and concentrated in vacuum to get the residue, which was purified by column chromatography (PE:EA=97:3~66:34) to give 3-chloro-N-(2,6-dimethoxyphenyl)pyrazin- 2-amine.

[1432] Step E: N- dimethoxyphenyl )tetrazolorL5-a1pyrazin-8-amine

[1433] A mixture of 3-chloro-N-(2,6-dimethoxyphenyl)pyrazin-2-amine (0.14 g, 0.53 mmol) and NaN3 (86 mg, 1.32 mmol) in DMSO (3 mL) was stirred at 130 °C for 18 hr. The solution was poured into 10 mL of ice-water and extracted with EA. The organic layer was dried and evaporated to afford dark-red oil which was used to the next step without any purification.

[1434] LC-MS: m / z 273.1 (M+H)+

[1435] Step F: N-(2.6-dimethoxyphenyl )tetrazolorL5-a1pyrazin-8-amine

[1436] To a solution of crude N-(2,6-dimethoxyphenyl)tetrazolo[l,5-a]pyrazin-8-amine (143.7 mg, 0.53 mmol) in con.HCl aq.(3 mL) was added SnCl2.H20 (1.19 g, 5.3 mmol) and the mixture was stirred at 115 °C for 2 h. After cooled to room temperature, the mixture was added K2CO3 to adjust pH=8-9 and filtered. The filtrate was extracted by EA and the organic layer was dried over Na2S04and concentrated in vacuum to get the residue, which was purified by column chromatography (PE:EA=97:3~66:34) to afford N-(2,6- dimethoxyphenyl)tetrazolo[l,5-a]pyrazin-8-amine.

[1437] LC-MS: m / z 247.1 (M+H)+

[1438] Step G: 1 -(2.6-di ethoxyphenyl)-2-(6-ethoxypyridin-2-yl )- 1 H-imidazor4.5-b1pyrazine

[1439] A mixture of N-(2,6-dimethoxyphenyl)tetrazolo[l,5-a]pyrazin-8-amine (70 mg, 0.285 mmol) and 6-ethoxypicolinaldehyde (43 mg, 0.285 mmol) in AcOH (1 mL) and stirred at 110 °C for 10 min under MW. The mixture was concentrated and the residue was purified by prep-HPLC to give l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH-imidazo[4,5- b]pyrazine.

[1440] LC-MS: m / z 378.2 (M+H)+

[1441] Example 19: N-(5-(2, 6-dimethoxyphenyl)-6- ( 6-ethoxypyridin-2-yl)-5H-pyrrolo[2, 3- b]pyrazin-3-yl)methanesulfonamide

[1442]

[1443]

[1444] To a solution of 2,6-dibromopyridine (20 g, 84 mmol, 1 equiv) in EtOH (200 mL) was added sodium ethanolate (22.9 g, 336 mmol, 4 equiv). The mixture was stirred at reflux temperature for 3 days. The reaction mixture was concentrated in vacuo. To the residue was added water (300 mL) and the mixture was extracted with DCM (2*300 mL). The combined organic layers was dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (100% PE) to afford the title compound.

[1445] LC-MS: m / z 202.0, 204.0 (M+H)+

[1446] Step B: 2-ethoxy-6-(Ytrimethylsilv0ethvnv0pyridine

[1447] A suspension of 2-bromo-6-ethoxypyridine (13.0 g, 64 mmol, 1 equiv), ethynyltrimethylsilane (10.11 g, 103 mmol, 1.6 equiv), Pd(PPh3)2Cl2 (1.13g, 1.6 mmol, 0.025 equiv) and Cul (610 mg, 3.2 mmol, 0.05 equiv) in Et3N (230 mL) was stirred at 85°C for 2.5 hours under N2 atmosphere. The mixture was filtered through celite. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (100% PE) to afford the title compound 6-chloro-3 -((6-ethoxypyri din-2 -yl)ethynyl)pyrazin-2- amine.

[1448] LC-MS: m / z 220.3 (M+H)+

[1449] Step C: 2-ethoxy-6-ethvnylpyridine

[1450] To a solution of 2-ethoxy-6-((trimethylsilyl)ethynyl)pyridine (11 g, 50.2 mmol, 1 equiv) in THF (100 mL) was added TBAF (50 mL, 50.2 mmol, 1 equiv). The resulted mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated in vacuo and the residue was purified by flash chromatography (PE / EtOAc = 100 / 1) to afford the title compound 2-ethoxy-6-ethynylpyridine.

[1451] LC-MS: m / z 148.1 (M+H)+

[1452] Step D: 6-chloro-3-(Y6-ethoxypyridin-2-vDethvnvDpyrazin-2-amine

[1453] A suspension of 2-ethoxy-6-ethynylpyridine (2.0 g, 13.6 mmol, 1 equiv), 3-bromo-6- chloropyrazin-2-amine (2.8 g, 13.6 mmol, 1 equiv), Pd(PPh3)2Cl2 (238 mg, 0.34 mmol, 0.03 equiv) and Cul (129 mg, 0.68 mmol, 0.06 equiv) in Et3N (80 mL) was stirred at 85°C for 2 hours under N2 atmosphere. The mixture was diluted with EtOAc (120 mL) and filtered through celite. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (PE / EtOAc = 6 / 1) to afford the title compound 6-chloro-3-((6- ethoxypyri din-2 -yl)ethynyl)pyrazin-2-amine.

[1454] LC-MS: m / z 275.1 (M+H)+

[1455] Step E: 3-chloro-6-(6-ethoxypyridin-2-yl)-5H-pyrrolor2.3-b1pyrazine

[1456] To a solution of 6-chloro-3-((6-ethoxypyridin-2-yl)ethynyl)pyrazin-2-amine (2.3 g, 8.4 mmol, 1 equiv) in THF (50 mL) was added NaH (0.5 g, 12.6 mmol, 1.5 equiv) at 0°C. The mixture was stirred at room temperature for 1 hour then heated to 60°C for overnight. The mixture was quenched with 0.5 mL H2O, then concentrated under vacuo to dry to give a residue, which was purified by flash chromatography (PE / EtOAc = 5 / 1) to afford the title compound 3-chloro-6-(6-ethoxypyridin-2-yl)-5H-pyrrolo[2,3-b]pyrazine.

[1457] LC-MS: m / z 275.1 (M+H)+

[1458] Step F : 3-chloro-5- dimethoxyphenyl)-6-(6-ethoxypyridin-2-yl)-5H-pyrrolor2.3-

[1459] bfpyrazine

[1460] A suspension of 3-chloro-6-(6-ethoxypyridin-2-yl)-5H-pyrrolo[2,3-b]pyrazine (Ig, 3.65 mmol, 1.0 equiv), (2,6-dimethoxyphenyl)boronic acid (1.3 g, 7.3 mmol, 2 equiv), Cu(OAc)2 (1.3g, 7.3 mmol, 2 equiv), diy pyridine (865 mg, 11 mmol, 3 equiv) and 4 A molecular sieve in dry DCE (10 mL) was stirred at 25 °C for 30 hours under O2 atmosphere. The reaction was diluted with DCM (50 mL) and filtered through ceiite. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (PE / EtOAc = 5 / 1) to afford the title compound 3-chloro-5-(2,6-dimethoxyphenyl)-6-(6-ethoxypyridin-2- yl)-5H-pyrrolo[2,3-b]pyrazine.

[1461] LC-MS : m / z 411.1 (M+H)+

[1462] Step G: N-(5-(2.6-dimethoxyphenyl)-6-(6-ethoxypyridin-2-ylV5H-pyrrolor2.3-blpyrazin- 3 -yl )methanesuf fonamide

[1463] A suspension of 3-chloro-5-(2,6-dimethoxyphenyl)-6-(6-ethoxypyridin-2-yl)-5H- pyrrolo[2,3-b]pyrazine (30 mg, 0.07 mmol, 1.0 equiv), methanesulfonamide (28 mg, 0.28 mmol, 4 equiv), trans-N,N'-Dimethylcy cl ohexane-l, 2-diamine (22 mg, 0.14 mmol, 2 equiv), Cul (29 mg, 0.14 mmol, 2 equiv) and K2CO3 (30 mg, 0.22 mmol, 3 equiv) in DMF (2 mL) was stirred at 115 °C via microwave irradiation for 2 hours under N2 atmosphere. The reaction mixture was poured into H2O (20 mL) and extracted with EtOAc (3*20 mL). The extracts were washed with water (10 mL) and brine (10 mL), dried over MgSCri and concentrated in vacuo. The residue was purified by flash chromatography (PE / EtOAc = 1 / 1) to afford the title compound N-(5-(2,6-dimethoxyphenyl)-6-(6-ethoxypyridin-2-yl)- 5H-pyrrolo[2,3-b]pyrazin-3-yl)methanesulfonamide.

[1464] ¾ NMR (DMSO-de) d: 8.17 (s, 1H), 7.69 (t, J = 7.6 Hz, 1H), 7.36-7.40 (m, 2H), 7.31 (s, 1H), 6.78 (d, J = 8.4 Hz, 2H), 6.61 (d, J = 8.0 Hz, 1H), 3.53-3.55 (m, 2H), 3.52 (s, 6H), 3. l2(s, 3H), 1.08 (t, J = 7.2 Hz, 3H).

[1465] LC-MS: m / z 470.0 (M+H)+

[1466] Example 20: N-(l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH-imidazo[4,5- b]pyridin-6-yl)methanesulfonamide

[1467]

[1468] Cs2C03, 120°C

[1469] 1 step A 2 step B

[1470] Step A: N-(5-bromo-3-iodopyridin-2-vO-6-ethoxypicolinamide

[1471] To a solution of 5-bromo-3-iodopyridin~2-aminecompound (2 g, 6.7 mmol, 1.1 equiv) in toluene (50 mL) was added Al(Me)3 (1.6 mol / L in toluene, 7.6 mL, 12.2 mmol, 2 equiv) drop wise at room temperature. After the mixture was stirred at 50°C for 30 min, ethyl 6- ethoxypico!inate (1.19 g, 6.1 mmol, 1 equiv) was added and the mixture was stirred at 110°C for 2 hours. The reaction mixture was quenched with water (50 mL), followed by extraction with EtOAc (3*50 mL). The combined organic layers was washed with brine (50 mL), dried over anhydrous Na2S04and concentrated in vacuo. The residue was purified by flash chromatography eluting with PE / EtOAc (20 / 1-5 / 1) to afford the title compound N-(5-bromo-3-iodopyridin-2-yl)-6-ethoxypicolinamide.

[1472] LC-MS: m / z 447.9, 449.9 (M+H)+

[1473] Step B : N-(5-bromo-3- dimethoxyphenvDamino)pyridin-2-vD-6-ethoxypicolinamide

[1474]

[1475] A suspension of N-(5-bromo-3-iodopyridin-2-yl)-6-ethoxypicolinamide (200 mg, 0.45 mmol, 1 equiv), 2,6-dimethoxyaniline (68 mg, 0.45 mmol, 1 equiv), Pd2(dba)3 (82 mg, 0.09 mmol, 0.1 equiv), Xantphos (208 mg, 0.36 mmol, 0.8 equiv) and CS2CO3 ( 292 mg, 0.87 mmol, 2 equiv) in l.4-dioxane (50 mL) was stirred at l20°C via microwave irradiation for 2 hours under N2 atmosphere. The mixture was diluted with water (30 mL), followed by extraction with EtOAc (3*20 mL). The combined organic layers was dried over anhydrous Nf SOi and concentrated in vacuo. The residue was purified by prep-TLC (PE / EtOAc = 5 / 1) to afford the title compound N-(5-bromo-3-((2,6-dimethoxyphenyl)amino)pyridin-2- yl)-6-ethoxypicolinamide.

[1476] LC-MS: m / z 473.0, 475.0 (M+H)+

[1477] Step C: 6-bromo-l- dimethoxyphenvD-2-(6-ethoxypyridin-2-vD-lEl-imidazor4.5-

[1478] blpyridine

[1479] To a solution of N-(5-bromo-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6- ethoxypicolinamide (100 mg, 0.21 mmol, 1 equiv) in AcOH (10 mL) was added 1 drop of POCh. The mixture was stirred at l20°C via microwave irradiation for 2 hours. The mixture was cooled to room temperature, evaporated and the residue was purified by prep TLC (PE / EtOAc = 1 / 1) to afford the title compound 6-bromo-l-(2,6-dimethoxyphenyl)-2- (6-ethoxypyridin-2-yl)-lH-imidazo[4,5-b]pyridine.

[1480] LC-MS: m / z 455.0, 457.0 (M+H)+

[1481] Step D: N-(l-(2.6-dimethoxyphenvO-2-(6-ethoxypyridin-2-vO-lH-imidazor4.5-blpyridin- 6-vDmethanesulfonamide

[1482] A suspension of 6-bromo-l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH- imidazo[4,5-b]pyrazine (40 mg, 0.09 mmol, 1 equiv), methanesulfonamide (17 mg, 0.18 mmol, 2 equiv), Cul (34 mg, 0.18 mmol, 2 equiv), trans-N,N'-Dimethylcyclohexane-l,2- diamine (25 mg, 0.18 mmol, 2 equiv) and K2CO3 (37 mg, 0.27 mmol, 3 equiv) in DMF (5 mL) was stirred at 115°C via microwave irradiation for 1.5 hour under N2 atmosphere. The reaction was diluted with water (15 mL) and extracted with EtOAc (3*50 mL). The combined organic layers was dried over anhydrous Na2S04and concentrated in vacuo. The residue was purified by prep TLC (PE / EtOAc = 1 / 2) to obtain the title compound N-(l- (2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH-imidazo[4,5-b]pyri din-6- yl)methanesulfonamide.

[1483] ¾NMR (DMSO-de) d: 9.88 (br. s., 1H), 8.38 (d, J = 2.4 Hz, 1H), 7.91 (dd, J = 7.4 Hz, 0.8 Hz, 1H), 7.84 (t, J = 7.8 Hz, 1H), 7.47 (t, J = 8.4 Hz, 1H), 7. l9(d, J = 2.4 Hz, 1H), 6.89 (d, J = 8.5 Hz, 2H), 6.79 (dd, J = 8.1, 0.9 Hz, 1H), 3.58 (s, 6H), 3.39 (q, J = 7.2 Hz, 2H), 2.96 (s, 3H), 1.02 (t, J = 7.2 Hz, 3H). LC-MS: m / z 470.1 (M+H)+

[1484] Example 21: N-(5-(2, 6-dimethoxyphenyl)-6- ( 6-ethoxypyridin-2-yl)-5H-imidazo[4, 5- c]pyridazin-3-yl)methanesulfonamide

[1485]

[1486] in sealed tube 2) NaH, DMF step A step B step C

[1487]

[1488] Step A: 6-chioiOpyridazin-3-amine

[1489] Asuspension of 3,6-dichloropyridazine (10 g, 67 mmol, 1 equiv) in 25% aqueous ammonia (50 nxL) was heated at 120°C for about 12 h in a PTFE-lined pressure reactor. Upon cooling to room temperature, the resulting crystalline solids were collected by filtration, washed with water and dried to afford the title compound 6-chloropyridazin-3 -amine.

[1490] LC-MS: m / z 130.0 (M+H)+

[1491] Step B: 4-bromo-6-chloropyridazin-3-amine

[1492] To a solution of 6-chloropyridazin-3-amine (6.2 g, 48 mmol, 1 equiv) in methanol (200 mL) was added NaHCCb (8.1 g, 96 mmol, 2 equiv). After the mixture was stirred at room temperature for 30 min, bromine (11.5 g, 72 mmol, 1.5 equiv) was added drop wise. Then reaction mixture was stirred for another 16 h and concentrated under vacuum to obtain a residue. The residue was purified by silica gel column chromatography (eluting with 40 percent EtOAc in hexane) to afford the title compound 4-bromo-6-chloropyridazin-3- amine.

[1493] LC-MS: m / z 207.9, 209.9 (M+H)+

[1494] Step C: N-(4-bromo-6-chloropyridazin-3-yl)-6-ethoxypicolinamide

[1495] To a solution of 6-ethoxypicolinic acid (2.3 g, 13.9 mmol, 1.2 equiv) and Oxa!yl chloride (2.2 g, 17.4 mmol, 1.5 equiv) in DCM (50 mL) was added DMF (0.1 mL) at 0°C. The resulted mixture was stirred at room temperature for lh. The reaction solution was concentrated in vacuo to afford 6-ethoxypicolinoyl chloride which was used directly. To a solution of 4-bromo-6-chloropyridazin-3-amine (2.4 g, ll.6mmol, 1 equiv) in DMF (50 mL) was added NaH (1.4 g, 34.8 mmol, 3 equiv) at RT. The mixture was stirred at room temperature for 1 h, then a solution of 6-ethoxypicolinoyl chloride in DMF (50 mL) was added. The mixture was stirred at room temperature for overnight. The reaction mixture was quenched with ammonium chloride solution (aq., 100 mL) and extracted with DCM (3 * 150 mL). The combined organic layers was washed with brine (100 mL), dried over anhydrous Na2S04, and concentrated in vacuo. The residue was recrystalized in DCM to afford the title compound N-(4-bromo-6-chloropyridazin-3-yl)-6-ethoxypicolinamide.

[1496] LC-MS: m / z 356.9, 358.9 (M+H)+

[1497] Step _ D; _ N-(6-chloro-4-((2.6-dimethoxyphenyl)amino)pyridazin-3-yl)-6- ethoxypicolinamide

[1498] A suspension of N-(4-bromo-6-chloropyridazin-3-yl)-6-ethoxypicolinamide (500 mg, 1.4 mmol, 1 equiv), 2, 6-dimethoxy aniline (214 mg, 1.4 mmol, 1 equiv), Pd(OAc)2 (63 mg, 0.28 mmol, 0.2 equiv), Xantphos (324 mg, 0.56 mmol, 0.4 equiv) and K2CO3 (386 mg, 2.8 mmol, 2.0 equiv) in 1.4-dioxane (10 mL) was stirred at 120°C via microwave irradiation for 2 hours under N2 atmosphere. The mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (DCM / MeOH = 100 / 1) to afford the desired product N-(6-chloro-4-((2,6- dimethoxyphenyl)amino)pyridazin-3-yl)-6-ethoxypicolinamide.

[1499] LC-MS: m / z 430.1 (M+H)+ Step E: chloro-7-(2.6-dimethoxyphenyl)-8-(6-ethoxypyridin-2-yl)-7H-imidazor4.5- clpyridazine

[1500] A solution of N-(6-chloro-4-((2,6-dimethoxyphenyl)amino)pyridazin-3-yl)-6- ethoxypicolinamide (110 mg, 0.25 mmol) in AcOH (10 mL) was stirred at 120 °C via microwave irradiation for 2 hours. After the reaction solution was cooled to room temperature, the light yellow precipitate was filtered off and rinsed with EtO Ac / PE = 1 / 2 (2*0.5 mL) to afford the title compound chloro-7-(2,6-dimethoxyphenyl)-8-(6- ethoxypyridin-2-yl)-7H-imidazo[4,5-c]pyridazine.

[1501] ¾ NMR (400 MHz, DMSO-de) d 8.05 (dd, J = 7.4, 0.8 Hz, 1H), 7.93 (dd, J = 8.4, 7.4 Hz, 1H), 7.67 (s, 1H), 7.50 (t, J = 8.4 Hz, 1H), 6.93 (dd, J = 8.4, 0.8 Hz, 1H), 6.89 (d, J = 8.4

[1502] Hz, 2H), 3.60 (s, 6H), 3.40 (q, J = 7.2 Hz, 2H), 1.04 (t, J = 7.2 Hz, 3H).

[1503] LC-MS: m / z 412.1 (M+H)+

[1504] Step _ E; _ N-(7-(2.6-dimethoxyphenyl)-8-(6-ethoxypyridin-2-yl)-7H-imidazor4.5- clpyridazinvDmethanesulfonamide A suspension of chloro-7-(2,6-dimethoxyphenyl)-8-(6-ethoxypyridin-2-yl)-7H- imidazo[4,5-c]pyridazine (48 mg, 0.12 mmol, 1 equiv), methanesulfonamide (22 mg, 0.23 mmol, 2 equiv), Cul (44 mg, 0.23 mmol, 2 equiv), trans-N,N'-Dimethylcyclohexane-l,2- diamine (33 mg, 0.23 mmol, 2 equiv) and K2CO3 (48 mg, 0.23mmol, 3 equiv) in DMF (2 mL) was stirred at l30°C via microwave irradiation for 1.5 hour under N2 atmosphere. The reaction solution was diluted with water (150 mL) and extracted with EtO Ac (3* 100 mL). The combined organic layers was dried over anhydrous Na2S04and concentrated in vacuo. The residue was purified by flash chromatography (eluting with DCM / MeOH =100 / 1) to afford the title compound as yellow solid (30 mg, 55% yield).

[1505] ¾ NMR (400 MHz, DMSO-de) d 10.78 (s, 1H), 8.01 (dd, J = 7.4, 0.8 Hz, 1H), 7.91 (dd, J = 8.4, 7.4 Hz, 1H), 7.50 (t, J = 8.4 Hz, 1H), 6.91 (dd, J = 8.4, 1.2 Hz, 4H), 3.61 (s, 6H),

[1506] 3.39 (q, J = 7.2 Hz, 2H), 3.22 (s, 3H), 1.03 (t, J = 7.2 Hz, 3H).

[1507] LC-MS: m / z 471.1 (M+H)+ Method C:

[1508]

[1509] Step A: N-(3-bromo-5-chloropyrazin-2-yl)-6-ethoxypicolinamide

[1510] To a mixture of 3-bromo-5-chloropyrazin-2-amine (14 1 g, 67.6 mmol, 1 .0 equiv) and toluene (60 mL) was added AlMe (2 mol / L, 51 mL, 102 mmol, 1.5 equiv) and the resulted mixture was stirred at 55°C for 30 mins. Ethyl 6-ethoxypicolinate (14.5 g, 74.4 mmol, 1.1 equiv) was added, and the mixture was stirred at 110°C for 1.5 h. The mixture was quenched with IN HC1 (102 mL, 102 mmol, 1.5 equiv) and extracted with DCM (3*500 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was re-slurried in DCM to afford the title compound N-(3-bromo-5-chloropyrazin-2-yl)-6-ethoxypicolinamide as a light yellow solid (12 g, 50%yield).

[1511] LC-MS: m / z 356.9, 358.9 (M+H)+

[1512] Step B : N-(5-chloro-3- dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide

[1513]

[1514] A suspension of N-(3-bromo-5-chloropyrazin-2-yl)-6-ethoxypicolinamide (1 g, 2.8 mmol, 1.0 equiv), 2, 6-dimethoxy aniline (475 mg, 3.4 mmol, 1.1 equiv), Pd(OAc)2 (126 mg, 0.56 mmol, 0.2 equiv), Xantphos (650 mg, 1.12 mmol, 0.4 equiv) and K2CO3 (772 mg, 5.6 mmol, 2.0 equiv) in l.4-dioxane (15 mL) was stirred at 120 C via microwave irradiation under N2 atmosphere for 2 h. The mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (100% DCM) to afford the desired product N-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin- 2-yl)-6-ethoxypicolinamide as a yellow solid (6.3 g, 52% yield).

[1515] LC-MS: m / z 430.1 (M+H)+

[1516] Step C: 6-chloro-l- dimethoxyphenvD-2-(6-ethoxypyridin-2-vD-lH-imidazor4.5-

[1517] bfpyrazine

[1518]

[1519] A solution of N-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6- ethoxypicolinamide (2.0 g, 4.66 mmol) in AcOH (10 mL) was stirred at 130 C via microwave irradiation for 2 hours. The mixture was cooled to room temperature, the precipitate was filtered off and washed with EtO Ac / PE = 1 / 2 to afford the title compound 6-chloro-l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH-imidazo[4,5-b]pyrazine as a light yellow solid (1.6 g, 83% yield).

[1520] LC-MS: m / z 412.1 (M+H)+

[1521] Step D: N-(T-(2.6-dimethoxyphenvO-2-(6-ethoxypyridin-2-vO-lE[-imidazor4.5- blpyrazin-6-vDmethanesulfonamide (Example 2)

[1522] A suspension of 6-chloro-l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH- imidazo[4,5-b]pyrazine (1 g, 2.43 mmol), methanesulfonamide (462 mg, 4.87 mmol, 3.0 equiv), Cul (924 mg, 4.87 mmol, 3.0 equiv), trans-N,N'-Dimethylcy cl ohexane-l, 2-diamine (691 mg, 4.87 mmol, 3.0 equiv) and K2CO3 (1006 mg, 7.29 mmol, 3 equiv) in DMF (10 mL) was stirred at 130 C via microwave irradiation for 1.5 hour under N2 atmosphere. The mixture was diluted with EtOAc (30 mL) and filtered through celite. The filtrate was poured onto aqueous K2CO3 (2 mol / L, 50 mL), stirred for 15 mins. Then the aqueous phase was separated and washed by EtOAc (2*30 mL). The aqueous phase was adjusted to pH = 4 with formic acid and extracted with DCM (3* 100 mL). The combined organic layers were dried over anhydrous Na2S04and concentrated in vacuo. The residue was purified by flash column chromatography eluting with DCM / MeOH = 20 / 1-10 / 1 to afford the title compound N-(l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH- imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide (Example 2) as a yellow solid (800 mg, 70% yield).

[1523] ¾ NMR (400 MHz, DMSO-de) 5: 11.05 (s, 1H), 8.27 (s, 1H), 7.95 (dd, J = 7.6 Hz, J = 0.8 Hz, 1H), 7 86 (t, J = 7.6 Hz, 1H), 7 45 (t, J = 8.4 Hz, 1H), 6.81-6.87 (m, 31 1), 3.57 (s, 6H), 3.39 (q, J = 7.2 Hz, 2H), 3.20 (s, 3H), 1.03 (t, J = 7.2 Hz, 3H). LC-MS: m / z 471.0 (M+H)+

[1524] Example 22: N-(l-(2,6-dimethoxyphenyl)-2-(6-ethox pyridin-2-yl)-lH-imidazo[4,5-

[1525]

[1526] The title compound was prepared according to Method C, step D, starting from N-(5- chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide by using cyclopropanesulfonamide (22 mg, 37% yield).

[1527] ¾NMR (400 MHz, DMSO-de) d : 8.25 (s, 1H), 8.02 (s, 1H), 7.86 (d, J = 7.2 Hz, 1H), 7.78 (t, J = 7.6 Hz, 1H), 7.41 (t, J = 8.4 Hz, 1H), 6.82 (d, J = 8.4 Hz, 2H), 6.72 (d, J = 8.0 Hz, 1H), 3.55 (s, 6H), 3.37 (q, J = 7.2 Hz 2H), 2.52-2.54 (m, 1H), 1.01 (t, J = 7.2 Hz, 3H), 0.79-

[1528] 0.83 (m, 2H), 0.64-0.69 (m, 2H). LCMS: m / z 497.1 (M l !)

[1529] Examp!e 23: N~(l-{2,6-dimethoxyphenyi)-2-(6~ethoxypyridin-2-yl)-lH-imidazo[4,5-

[1530]

[1531] The title compound was prepared according to Method C, step D, starting from N-(5- chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide by using pyridine-2-sulfonamide (30 mg, 23% yield).

[1532] 1HNMR (400 MHz, DMSO-de) d: 11.77 (s, 1H), 8.55 (d, J = 4.0 Hz, 1H), 8.21 (s,lH),

[1533] 7.89 (d, J = 7.6 Hz,IH), 7.80 (t, J = 7.6 Hz,IH), 7.71 (d, J = 7.6 Hz,IH), 7.60 (d, J = 7.6 Hz, 1 H), 7.49 (t, J = 8.4 Hz,2H), 6.86 (d, J = 8.4 Hz,2H), 6.77 (d, J = 8.0 Hz,IH), 3.51 (s,6H), 3.37 (q, J = 7.2 Hz,2H), 1.01 (t, J = 7.2 Hz,3H). LC-MS: m / z 534 (M+H)+

[1534] Example 24: N-(l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH-imidazo[4,5- b]pyrazin-6-yl)pyridine-3-sulfonamide

[1535]

[1536] The title compound was prepared according to Method C, step D, starting from N-(5- chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide by using pyridine-3 -sulfonamide (58 mg, 54% yield).

[1537] ¾ NMR (400 MHz, DMSO-de) d: 11.81 (s, 1H), 8.79-8.90 (m, 1H), 8.65-8.78 (m, 1H), 8.23 (s, 1H), 7.93 (t, J = 8.4 Hz, 2H), 7.84 (t, J = 8.0 Hz, 1H), 7.55 (t, J = 8.0 Hz, 1H), 7.37 (dd, J = 8.0, 4.8 Hz, 1H), 6.93 (d, J = 8.0 Hz, 2H), 6.80 - 6.83 (m, 1H), 3.55 (s, 6H), 3.39 (q, J = 7.1 Hz, 2H), 1.03 (t, J = 7.1 Hz, 3H). LC-MS: m / z 534.0 (M+H)+

[1538] Example 25: N-(l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH-imidazo[4,5-

[1539]

[1540] The title compound was prepared according to Method C, step D, starting from N-(5- chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide by using pyridine-4-sulfonamide (45 mg, 57% yield).

[1541] ¾ NMR (400 MHz, DMSO-de) d: 8.40 (s, 2H), 7.79 - 7.86 (m, 2H), 7.75 ((t, J = 8.0 Hz, 1H), 7.53 (t, J = 8.4 Hz, 1H), 7.43 (d, J = 4.8 Hz, 2H), 6.93 (d, J = 8.4 Hz, 2H), 6.69 (d, J = 8.0 Hz, 1H), 3.53 (s, 6H), 3.38 (d, J = 7.2 Hz, 2H), 1.01 (t, J = 7.2 Hz, 3H). LC-MS: m / z 534.0 (M+H)+

[1542] Example 26: N-(l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH-imidazo[4,5- b]pyrazin-6-yl)-l-(pyridin-3-yl)methanesulfonamide

[1543]

[1544] The title compound was prepared according to Method C, step D, starting from N-(5- chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide by using pyri din-3 -ylmethanesulfonamide (24 mg, 25% yield).

[1545] ¾ NMR (400 MHz, DMSO-de) d: 11.13 (s, 1H), 8.32-8.54 (m,8.8 Hz, 2H), 8.17 (s, 1H), 7.97 (dd, J = 7.4, 0.9 Hz, 1H), 7.87 (dd, J = 8.2, 7.6 Hz, 1H), 7.44 - 7.5 (m, 2H), 7.38 (s, 1H), 6.89 (d, J = 4.0Hz, 2H), 6.84 (dd, J = 4.0,8.0Hz,3H), 4.72 (s, 2H), 3.58 (s, 6H), 3.40 (q, J = 6.6 Hz, 2H), 1.03 (t, J = 7.2 Hz, 3H). LC-MS: m / z 548.0 (M+H)+

[1546] Example 27: N-(l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH-imidazo[4,5- b]pyrazin-6-yl)-l-(pyridin-2-yl)methanesulfonamide

[1547]

[1548] The title compound was prepared according to Method C, step D, starting from N-(5- chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide by using pyri din-2 -ylmethanesulfonamide (30 mg, 37% yield). ¾ NMR (400M, DMSO-de) d: 11.12 (br, 1H), 8.45-8.47 (m, 1H), 8.14 (s, 1H), 7.94 (dd, J

[1549] = 7.6Hz, J = 0.8Hz, lH), 7.86 (t, J = 7.6 Hz, 1H), 7.75 (td, J = 7.6 Hz, J = l .6Hz, lH),7.47 (t, J = 8.4 Hz, 1H), 7.31-7.34 (m, 1H), 7.2 (d, J = 7.6Hz,lH), 6.87 (d, J = 8.4Hz, lH),6.82 (dd, J = 8.0Hz, J = 0.8Hz, 1H), 4.79 (s, 2H), 3.56 (s, 6H), 3.40 (q, J = 7.2 Hz, 2H), 1.03 (t, J = 7.2 Hz, 3H). LC-MS: m / z 548.6 (M+H)+

[1550]

[1551] step A step B

[1552] mCPBA 1 ) K2C03, MeOH

[1553] DCM 0°C~r.t. 2) NH20S03H, H20

[1554]

[1555] tep C step D 6

[1556] s Step A: pyrimidin-2-ylmethanol

[1557] To a solution of methyl pyrimidine-2-carboxylate (25 g, 181 mmol, 1.0 equiv) in MeOH (500 mL) was added NaBH4(8.2 g, 217 mmol, 1.2 equiv) at 0°C. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with EbO (10 mL), concentrated in vacuo and the residue was purified by flash column chromatography (PE / EtOAc = 1 / 1) to afford the title compound pyrimidin-2-ylmethanol as a yellow oil (16 g, 80% yield).

[1558] LC-MS: m / z 111.0 (M+H)+Step B: 2-(Ypyrimidin-2-ylmethvDthio)benzord1thiazole

[1559]

[1560] To a solution of pyrimidin-2-ylmethanol (16.6 g, 151 mmol, 1.0 equiv), benzo[d]thiazole- 2-thiol (30 g, 181 mmol, 1.2 equiv) and PPh3(47.4 g, 181 mmol, 1.2 equiv) in THF (500 mL) was added DEAD (36.6 g, 181 mmol, 1.2 equiv) at 0°C. The mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with HCl-dioxane and the white precipitate was filtered off. The solid was then dissolved in 1N NaiCCh aqueous solution (100 mL) and extracted with EtOAc (3*200 mL). The combined organic phase was concentrated in vacuo to afford the title compound 2-((pyrimidin-2- ylmethyl)thio)benzo[d]thiazole as a crude yellow solid (27 g, 77% yield). LC-MS: m / z 260.0 (M+H)+

[1561] Step C: 2-(Ypyrimidin-2-ylmethvDsulfonvDbenzord1thiazole

[1562] To a solution of 2-((pyrimidin-2-ylmethyl)thio)benzo[d]thiazole (27 g, 104 mmol, 1.0 equiv) in DCM (500 mL) was added m-CPBA (51 g, 249 mmol, 2.4 equiv). The mixture was stirred at room temperature for 16 hours and quenched with 1N Na2SCb aqueous solution. The organic phase was separated, washed with saturated Na2CCb and concentrated in vacuo. The residue was purified by flash column chromatography (PE / EtOAc = 5 / 1) to afford the title compound 2-((pyrimidin-2- ylmethyl)sulfonyl)benzo[d]thiazole as a white solid (17 g, 80% yield).

[1563] LC-MS: m / z 292.0 (M+H)+Step D: pyrimidin-2-ylmethanesulfonamide

[1564] To a solution of 2-((pyrimidin-2-ylmethyl)sulfonyl)benzo[d]thiazole (500 mg, 1.7 mmol, 1.0 equiv) in MeOH (10 mL) was added K2CO3 (1.2 g, 8.5 mmol, 5.0 equiv). After the mixture was stirred at room temperature for 10 mins, NH2OSO3H (250 mg, 2.0 mmol, 1.2 equiv) in H2O (1 mL) was added. The mixture was stirred at room temperature for 15 mins and another batch of NH2OSO3H (250 mg, 2.0 mmol, 1.2 equiv) in H2O (1 mL) was added. The resulting mixture was stirred at room temperature for 60 hours. The mixture was evaporated and the residue was purified by flash column chromatography (DCM / MeOH = 50 / 1) to afford the title compound pyrimidin-2-ylmethanesulfonamide as a white solid (100 mg, 34% yield).

[1565] ¾ NMR (400 MHz, DMSO) d 8.83 (d, J = 4.8 Hz, 2H), 7.49 (t, J = 4.8 Hz, 1H), 7.01 (s, 2H), 4.55 (s, 2H). LC-MS: m / z 174.0 (M+H)+

[1566] -2-(6~eihoxypyridin-2-yl)-lH-imidazo[4,S- b]pyrazhi-6-yl)-l-(pyriinidin-2-yl)methanemlfonamide

[1567]

[1568] The title compound was prepared according to Method C, step D, starting from N-(5- chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide by using pyrimidin-2-yimethanesulfonamide (27 mg, 34% yield).

[1569] ¾ NMR (400 MHz, DMSO-de) d: 11.19 (s, 1H), 8.74 (d, J = 4.8 Hz, 2H), 8.21 (s, 1H), 7.94 (d, J = 7.2 Hz, 1H), 7.86 (t, J = 8.0 Hz, 1H), 7.40 - 7.49 (m, 2H), 6.85 (d, J = 8.4 Hz, 2H), 6.82 (dd, J = 8.2, 0.8 Hz, 1H), 3.55 (s, 6H), 3.39 (q, J = 7.2 Hz, 2H), 1.02 (t, J = 7.2 Hz, 3H). LCMS: m / z 548.9 (M i l) 2-cyclopropylethanesulfonamide

[1570] The title compound was prepared according to the preparation of pyrimidin-2- ylmethanesulfonamide by using 2-cyclopropylethanol in step A.

[1571] LC-MS: m / z 150.2 (M+H)+Example 29: 2-cyclopropyl-N-(l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH- imidazo[4,5-b]pyrazin-6-yl)ethanesulfonamide

[1572] The title compound was prepared according to Method C, step D, starting from 6-bromo- l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH-imidazo[4,5-b]pyrazine (Example 1) by using 2-cyclopropylethanesulfonamide (50mg, 47% yield).

[1573] ¾NMR (400M, DMSO-de) 5: 10.98 (br, lH),8.27 (s, 1H), 7.95 (d, J = 7.2Hz, 1H), 7.85 (t, J = 8.4 Hz, 1H), 7.45 (t, J = 8.4 Hz, 1H), 6.86 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 8.4 Hz, 1H), 3.58 (s, 6H), 3.36-3.42 (m, 4H), 1.47-1.52 (m, 2H),l .03 (t, J = 7.2 Hz, 3H), 0.63-0.68 (m, 1H), 0.29-0.33 (m, 2H), 0.06-0.1 (m, 2H). LC-MS: m / z 525.4 (M+H)+oxetane-3-sulfonamide

[1574] The title compound was prepared according to the preparation of pyrimidin-2- ylmethanesulfonamide by using oxetan-3-ol in step A.

[1575] ¾ NMR (400 MHz, DMSO) 5: 7.17 (s, 2H), 4.79 (dd, J = 8.0, 7.2 Hz, 2H), 4.68 - 4.65 (m, 2H), 4.47-4.40 (m, 1H).

[1576] Example 30: N-(l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH-imidazo[4,5- b]pyrazin-6-yl)oxetane-3-sulfonamide

[1577]

[1578] The title compound was prepared according to Method C, step D, starting from N-(5- chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide by using oxetane-3 -sulfonamide (36.3 mg, 35% yield).

[1579] ¾ NMR (400 MHz, DMSO-de) d: 8.05 (s, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.81 (t, J = 7.6 Hz, 1H), 7.43 (t, J = 8.4 Hz, 1H), 6.86 (d, J = 8.4 Hz, 2H), 6.76 (d, J = 8.0 Hz, 1H), 4.49- 4.67 (m, 3H), 4.34 (t, J = 6.6 Hz, 2H), 3.60 (s, 6H), 3.38 (q, J = 7.2 Hz, 2H), 1.02 (t, J = 7.2 Hz, 3H). LC-MS: m / z 513.1 (M+H)+

[1580]

[1581] step C 4 step D 5

[1582] Step A: 2-(cvclobutylthio)pyrimidine

[1583] To a solution of PPh3 (4.37 g, 16.7 mmol, 1.2 equiv) in THF (30 mL) at 0°C was added DIAD (3.37 g, 16.7 mmol, 1.2 equiv) dropwise under N2 atmosphere. After the mixture was stirred at 0°C for 10 mins, a mixture of pyrimidine-2-thiol (1.867 g, 16.7 mmol, 1.2 equiv) and cyclobutanol (1.0 g, 13.9 mmol, 1.0 equiv) in THF (10 mL) was added. The resulting mixture was stirred at 0°C for 10 mins and at room temperature for 1 h. The reaction solution was concentrated and the residue was purified by flash column chromatography (PE / EtOAc = 6 / 1) to afford the desired 2-(cyclobutylthio)pyrimidine as a yellow oil (2.0 g, 87% yield).

[1584] LC-MS: m / z 167.0 (M+H)+

[1585] Step B: 2-(cvclobutylsulfonvDpyrimidine

[1586] To a solution of m-CPBA (5.7 g, 33.1 mmol, 3 equiv) in DCM (80 mL) was added 2- (cyclobutylthio)pyrimidine (1.83 g, 11.0 mmol, 1.0 equiv). The reaction mixture was stirred at room temperature for 16 h. Saturated Na2S2Ch aqueous solution (20 mL) was added and the mixture was stirred at room temperature for 30 mins. The organic phase was separated and washed with brine, dried over anhydrous Na2S04and concentrated in vacuo. The residue was purified by flash column chromatography (PE / EtOAc = 1 / 1) to afford the title compound 2-(cyclobutylsulfonyl)pyrimidine as a yellow solid (1.7 g, 78% yield).

[1587] LC-MS: m / z 199.0 (M+H)+

[1588] Step C: cyclobutanesulfonamide

[1589] To a solution of 2-(cyclobutylsulfonyl)pyrimidine (1.75 g, 8.84 mmol, 1.0 equiv) in MeOH (40 mL) was added NaOMe (5.4 mol / L, 1.64 mL, 1.0 equiv). After the reaction mixture was stirred at 0°C for 30 mins, a solution of NaOAc (906 mg, 11.05 mmol, 1.25 equiv) and HOSO3NH2 (1.25 g, 11.05 mmol, 1.25 equiv) in water (5 mL) was added. The resulting mixture was stirred at room temperature for 16 h. The reaction suspension was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (PE / EtOAc = 1 / 1) to afford the title compound cyclobutanesulfonamide as a white solid (300 mg, 25% yield). LC-MS: m / z 136.0 (M+H)+

[1590] Example 31: N-(l-(2, 6-dimethoxyphenyl)-2- ( 6-ethoxypyridin-2-yl)-lH-imidazo[4, 5- b]pyrazin-6-yl)cyclobutanesulfonamide

[1591] The title compound was prepared according to Method C, step D, starting from N-(5- chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide by using cyclobutanesulfonamide (85 mg, 64 % yield).

[1592] ¾ NMR (400 MHz, DMSO-de) d: 10.87 (s, 1H), 8.31 (s, 1H), 7.95 (dd, J = 7.4, 0.8 Hz, 1H), 7.86 (dd, J = 8.4, 7.6 Hz, 1H), 7.46 (t, J = 8.4 Hz, 1H), 6.87 (d, J = 8.4 Hz, 2H), 6.83 (dd, J = 8.4, 0.8 Hz, 1H), 4.09 - 4.22 (m, 1H), 3.59 (s, 6H), 3.39 (q, J = 7.2 Hz, 2H), 2.28 (ddt, J = 13.0, 10.6, 8.6 Hz, 2H), 2.02 - 2.13 (m, 2H), 1.75 - 1.92 (m, 2H), 1.03 (t, J = 7.2 Hz, 3H). LC-MS: m / z 511.2 (M+H)+

[1593] Example 32: N-(l-(2, 6-dimethoxyphenyl)-2- ( 6-ethoxypyridin-2-yl)-lH-imidazo[4, 5- b]pyrazin-6-yl)-N-methylmethanesulfonamide

[1594]

[1595] The title compound was prepared according to Method C, step D, starting from 6-bromo- l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH-imidazo[4,5-b]pyrazine (Example 1) by using N-methylmethanesulfonamide (40 mg, 75% yield).

[1596] ¾NMR (400 MHz, DMSO-de) d: 8.63 (s, lH),7.98 (t, J = 7.2 Hz, 1H), 7.89 (t, J = 8.4 Hz, 1H), 7.47 (t, J = 8.4 Hz, 1H), 6.87 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H), 3.57 (s, 6H), 3.41 (q, J = 7.2 Hz, 2H), 3.26 (s, 3H), 3.12 (s, 3H), 1.03 (t, J = 7.2 Hz, 3H). LC-MS: m / z 485.2 (M+H)+

[1597] Trans-3-(benzyloxy)cyclobutane-l-sulfonamide

[1598] The title compound was prepared according to the preparation of cyclobutanesulfonamide by using cis-3-(benzyloxy)cyclobutanol in step A.

[1599] ¾ NMR (400 MHz, DMSO-de) d: 7.27 - 7.37 (m, 5H), 6.83 (s, 2H), 4.38 (s, 2H), 4.18 - 4.24 (m, 1H), 3.57 - 3.64 (m, 1H), 2.49 - 2.58 (m, 2H), 2.28 - 2.36 (m, 2H).

[1600]

[1601] trans-3-(benzyloxy)-N-(l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH- imidazo[4,5-b]pyrazin-6-yl)cyclobutane-l-sulfonamide

[1602]

[1603] The title compound was prepared according to Method C, step D, starting from N-(5- chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide by using trans-3-(benzyloxy)cyclobutane-l -sulfonamide (460 mg, 48% yield).

[1604] ¾ NMR (400 MHz, DMSO-de) d: 11.00 (s, 1H), 8.23 (s, 1H), 7.94 - 7.96 (m, 1H), 7.85 (t, J = 8.0 Hz, 1H), 7.43 (t, J = 8.0 Hz, 1H), 7.27 - 7.28 (m, 5H), 6.81 - 6.84 (m, 3H), 4.35 (s, 2H), 4.07 - 4.19 (m, 2H), 3.57 (s, 6H), 3.36 3.41 (m, 2H), 2.54 - 2.60 (m, 2H), 2.19

[1605] 2.26 (m, 2H), 1.02 (t, J = 8.0 Hz, 3H). LC-MS: m / z 617.0 (M+H)+

[1606] Example 33: cis-N-(l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH-imidazo[4,5-

[1607]

[1608] To a mixture of trans-3-(benzyloxy)-N-(l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2- yl)-lH-imidazo[4,5-b]pyrazin-6-yl)cyclobutane-l-sulfonamide (200 mg, 0.324 mmol, 1.0 equiv) in DCM (16 mL) were added trifluoromethanesulfonic acid (1 mL) and trifluoromethanesulfonic anhydride (0.5 mL) at 0°C under N2 atmosphere. The resulting mixture was stirred at 0°C for 15 minutes under N2 atmosphere. Then the mixture was adjusted to pH = 6 by adding aqueous NaHCCh (3 mol / L) and DCM (60 mL) was added into the mixture. The combined organic layers were washed with brine (20 mL), dried over Na2S04, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with DCM / MeOH = 20 / 1-10 / 1) to afford the title compound as a brown solid (50 mg, 29% yield).

[1609] ¾ NMR (400 MHz, DMSO-de) d: 8.19 (s, 1H), 7.90 (d, J = 7.2 Hz, 1H), 7.82 (t, J = 7.6 Hz, 1H), 7.43 (t, J = 8.4 Hz, 1H), 6.84 (d, J = 8.8 Hz, 2H), 6.77 (d, J = 8.4 Hz, 1H), 5.22 (s, 1H), 4.20-4.33 (m, 1H), 3.93-3.98 (m, 1H), 3.59 (s, 6H), 3.39 (q, J = 7.2 Hz, 2H), 2.42 - 2.50 (m, 2H), 1.97-2.12 (m, 2H), 1.02 (t, J = 7.2 Hz, 3H). LC-MS: m / z 527.2 (M+H)+Step B: N-(T- dimethoxyphenvD-2-(6-ethoxypyridin-2-vD-lH-imidazor4.5-b1pyrazin-

[1610] 6-vD-3 -oxocvclobutane- 1 -sulfonamide

[1611] The solution of cis-N-(l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH- imidazo[4,5-b]pyrazin-6-yl)-3-hydroxycyclobutane-l-sulfonamide (Example 33, 60 mg, 0.114 mmol, 1.0 equiv) in DCM (2 mL) was cooled to 0°C and Dess-Matin periodinane (193 mg, 0.456 mmol, 4 equiv) was added. The mixture was stirred at room temperature overnight. The mixture was washed with Na2SCb (aq.) brine, dried over Na2S04, and concentrated in vacuo. The residue was purified by prep-TLC to give N-(l-(2,6- dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH-imidazo[4,5-b]pyrazin-6-yl)-3- oxocyclobutane-l -sulfonamide as a light yellow solid (50mg, 83% yield).

[1612] LC-MS: m / z 525.2 (M+H)+

[1613] Example 34: trans-N-(l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH- imidazo[4,5-b]pyrazin-6-yl)-3-hydroxycyclobutane-l-sulfonamide

[1614]

[1615] The solution of N-(l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH-imidazo[4,5- b]pyrazin-6-yl)-3-oxocyclobutane-l -sulfonamide (50 mg, 0.095mmol, 1.0 equiv) in MeOH (1 mL) was cooled to 0°C and NaBLL (7.2 mg, 0.191 mmol, 3.0 equiv) was added. The mixture was allowed to be warmed to room temperature and stirred for 2 h. After that, H2O (1 mL) was added and the mixture was extracted with DCM three times. The combined organic layers were washed with brine, concentrated and purified via prep-TLC to give the title compound as a white solid (22mg, 44% yield). ¾ NMR (400 MHz, CDCh) d: 8.48 (s, 1H), 8.04 (d, J = 7.6 Hz, 1H), 7.60 (t, J = 7.6 Hz, 1H), 7.30 (t, J = 8.4 Hz, 1H), 6.76 (s, 1H), 6.61-6.65 (m, 3H), 4.01-4.06 (m, 1H), 3.55 (s, 6H), 3.44-3.50 (m, 1H), 3.32-3.38 (m, 2H), 2.50-2.54 (m, 2H), 2.26-2.32 (m, 2H), 1.02 (t, J = 7.2 Hz, 3H). LC-MS: m / z 527.2 (M+H)+

[1616] pyrimidin-5-ylmethanesulfonamide

[1617] The title compound was prepared according to the preparation of cyclobutanesulfonamide by using pyrimidin-5-ylmethanol in step A.

[1618] ¾NMR (400 MHz, DMSO-de) d: 9.17 (s, 1H), 8.77 (s, 2H), 7.03 (br. s, 2H), 4.38 (s, 2H). LC-MS: m / z 174.0 (M+H)+

[1619] Example 35: N-(l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH-imidazo[4,5- b]pyrazin-6-yl)-l-(pyrimidin-5-yl)methanesulfonamide

[1620]

[1621] The title compound was prepared according to Method C, step D, starting from N-(5- chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide by using pyrimidin-5-ylmethanesulfonamide.

[1622] ¾ NMR (400 MHz, DMSO-de) d: 11.20 (s, 1H), 9.15 (s, 1H), 8.54 (s, 2H), 8.27 (s, 1H), 7.98 (d, J = 7.6 Hz, 1H), 7.87 (t, J = 7.6 Hz, 1H), 7.48 (t, J = 8.4 Hz, 1H), 6.89 (d, J = 8.4 Hz, 2H), 6.84 (d, J = 8.0 Hz, 1H), 4.74 (s, 2H), 3.60 (s, 6H), 3.41 (q, J = 7.2 Hz, 2H), 1.03 (t, J = 7.2 Hz, 3H). LC-MS: m / z 549.2 (M+H)+

[1623] 1 step A 2

[1624] Step A: tetrahydro-2H-pyran-4-sulfonamide

[1625] To a solution of tetrahydro-2H-pyran-4-sulfonyl chloride (300 mg, 1.6 mmol, 1.6 equiv) in acetone (5 mL) was added aqueous NH4OH (34%wt., 10 mL, 140 mmol, 88 equiv). The mixture was stirred at room temperature overnight and then concentrated to dryness. The residue was purified by silica gel column chromatography (DCM / EtOAc = 2 / 1) to afford the title compound tetrahydro-2H-pyran-4-sulfonamide as a white solid (150 mg, 56% yield). LC-MS: m / z 166.2 (M+H)+

[1626] Example 36: N-(l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH-imidazo[4,5- b]pyrazin-6-yl)tetrahydro-2H-pyran-4-sulfonamide

[1627]

[1628] The title compound was prepared according to Method C, step D, starting from N-(5- chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide by using tetrahydro-2H-pyran-4-sulfonamide (25 mg, 32% yield).

[1629] ¾ NMR (DMSO-de) 5: 10.93-11.20 (m, lH), 8.28 (s, lH),7.96 (d, J = 8.0 Hz,IH), 7.85 (t,

[1630] J = 8.0 Hz, 1H), 7.46 (t, J = 7.6 Hz, 1H), 6.88 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 8.0 Hz, 1H), 3.87-3.91 (m, 2H), 3.58 (s, 7H), 3.39 (q, J = 7.2 Hz, 2H), 3.07 (t, J = 11.2 Hz, 2H), 1.75- 1.78 (m, 2H), 1.55-1.66 (m, 2H), 1.02 (t, J = 7.2 Hz, 3H). LC-MS: m / z 541.6 (M+H)+morpholine-4-sulfonamide

[1631] The title compound was prepared according to the preparation of tetrahydro-2H-pyran- 4-sulfonamide by using morpholine-4-sulfonyl chloride.

[1632] ¾ NMR (400 MHz, de-DMSO ) d: 6.82 (s, 2H), 3.61-3.68 (m, 4H), 2.89-2.94 (m, 4H).

[1633] Example 37: N-(l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH-imidazo[4,5- b]pyrazin-6-yl)morpholine-4-sulfonamide

[1634]

[1635] The title compound was prepared according to Method C, step D, starting from 6-bromo- l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH-imidazo[4,5-b]pyrazine (Example 1) by using morpholine-4-sulfonamide (39 mg, 65% yield).

[1636] ¾ NMR (400 MHz, DMSO-de) d: 11.03 (s, 1H), 8.24 (s, 1H), 7.97 (dd, J = 7.4, 0.8 Hz, 1H), 7.85 (dd, J = 8.2, 7.6 Hz, 1H), 7.45 (t, J = 8.4 Hz, 1H), 6.86 (d, J = 8.4 Hz, 2H), 6.82 (dd, J = 8.2, 0.8 Hz, 1H), 3.60 (s, 6H), 3.42 - 3.46 (m, 4H), 3.38 (q, J = 7.2 Hz, 2H), 2.90- 2.95 (m, 4H), 1.02 (t, J = 7.2 Hz, 3H). LC-MS: m / z 543.1 (M+H)+

[1637] benzyl 4-(sulfamoylmethyl)piperidine-l-carboxylate

[1638] The title compound was prepared according to the preparation of tetrahydro-2H-pyran- 4-sulfonamide by using benzyl 4-((chlorosulfonyl)methyl)piperidine-l-carboxylate (350 mg, 56% yield).

[1639] LC-MS: m / z 313.1 (M+H)+.

[1640] benzyl-4-((N-(l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH-imidazo[4,5- b]pyrazin-6-yl)sulfamoyl)methyl)piperidine-l-carboxylate

[1641]

[1642] The title compound was prepared according to Method C, step D, starting from N-(5- chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide by using benzyl 4-(sulfamoylmethyl)piperidine-l-carboxylate (210 mg, 45% yield).

[1643] LC-MS: m / z 688.2 (M+H)+

[1644] Example 38: N-(l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH-imidazo[4,5- b]pyrazin-6-yl)-l-(piperidin-4-yl)methanesulfonamide

[1645]

[1646] A solution of benzyl-4-((N-(l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH- imidazo[4,5-b]pyrazin-6-yl)sulfamoyl)methyl)piperidine-l-carboxylate (55 g, 0.08 mmol, 1.0 equiv) and con. HC1 (1 mL) in EtOH (4 mL) was refluxed at 90°C for 8 h. The reaction mixture was concentrated and residue was purified by flash column chromatography on silica gel (DCM / MeOH = 10 / 1) to give the title compound as a yellow solid (40 mg, 90% yield). ¾ NMR (400 MHz, DMSO-de) d : 8.23 (s, 1H), 7.81 - 7.83 (m, 2H), 7.74 - 7.77 (m, 1H), 7.38 (t, J = 8.0 Hz, 1H), 6.81 (d, J = 8.0 Hz, 2H), 6.68 (d, J = 8.0 Hz, lH),3.57 (s, 6H), 3.36 (q, J = 7.2 Hz, 2H), 3.11 - 3.14 (m, 2H), 2.95 - 2.96 (m, 2H), 2.76 - 2.82 (m, 2H), 1.94 (s, 1H), 1.81 - 1.84 (m, 2H), 1.18 - 1.27 (m, 2H), 1.01 (t, J = 7.2 Hz, 3H). LC-MS: m / z 554.2 (M+H)+.

[1647] 4-oxocyclohexane-l-sulfonamide

[1648]

[1649] The title compound was prepared according to the preparation of tetrahydro-2H-pyran- 4-sulfonamide by using 4-oxocyclohexane-l-sulfonyl chloride (150 mg, 56% yield). LC-MS: m / z 178.0 (M+H)+

[1650] N-(l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH-imidazo[4,5-b]pyrazin-6- yl)-4-oxocyclohexane-l-sulfonamide

[1651]

[1652] The title compound was prepared according to Method C, step D, starting from N-(5- chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide by using 4-oxocyclohexane-l-sulfonamide (140 mg, 69% yield).

[1653] LC-MS: m / z 553.2 (M+H)+

[1654] Example 39 : trans-N-(l-(2, 6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH- imidazo[4, 5-b]pyrazin-6-yl)-4-hydroxycyclohexane-l -sulfonamide

[1655] Example 40: cis-N-(l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH-imidazo[4,5- b]pyrazin-6-yl)-4-hydroxycyclohexane-l-sulfonamide

[1656]

[1657] To a solution of N-(l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH-imidazo[4,5- b]pyrazin-6-yl)-4-oxocyclohexane-l -sulfonamide (135 mg, 0.244 mmol, 1.0 equiv) in MeOH (10 mL) was added NaBH4(18.6 mg, 0.49 mmol, 3.0 equiv). The mixture was stirred at 0°C for 30 mins and at room temperature for 3 h. The reaction solution was quenched with 1N HC1 (25 mL), extracted with DCM (3*25 mL). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by prep-TLC (DCM / MeOH = 10 / 1) to give Example 39 (50 mg, 37% yield) and Example 40 (12 mg, 9% yield) as white solid.

[1658] Example 39: ¾ NMR (400 MHz, DMSO-de) d 10.88 (s, 1H), 8.31 (s, 1H), 7.97 (dd, J = 7.4, 0.8 Hz, 1H), 7.86 (dd, J = 8.2, 7.5 Hz, 1H), 7.46 (t, J = 8.4 Hz, 1H), 6.77 - 6.98 (m, 3H), 4.66 (d, J = 4.2 Hz, 1H), 3.59 (s, 6H), 3.40 (q, J = 7.2 Hz, 2H), 3.30 (q, J = 3.4, 2.8 Hz, 1H), 2.44 -2.50 (m, 1H), 1.88 (dd, J = 24.0, 12.8 Hz, 4H), 1.39 - 1.50 (m, 2H), 1.03 (t, J = 7.2 Hz, 3H), 0.96 (dd, J = 13.2, 10.0 Hz, 2H). LC-MS: m / z 555.2 (M+H)+

[1659] Example 40: ¾ NMR (400 MHz, DMSO-de) d 10.86 (s, 1H), 8.31 (s, 1H), 7.97 (dd, J = 7.4, 0.8 Hz, 1H), 7.86 (dd, J = 8.4, 7.6 Hz, 1H), 7.45 (t, J = 8.4 Hz, 1H), 6.87 (d, J = 8.4 Hz, 2H), 6.83 (dd, J = 8.2, 0.8 Hz, 1H), 4.43 (d, J = 2.8 Hz, 1H), 3.76 (d, J = 5.6 Hz, 1H), 3.58 (s, 6H), 3.39 (q, J = 7.2 Hz, 3H), 1.81 (q, J = 14.0, 12.6 Hz, 2H), 1.59 - 1.74 (m, 4H), 1.19 (d, J = 12.0 Hz, 2H), 1.02 (t, J = 7.2 Hz, 3H). LC-MS: m / z 555.2 (M+H)+

[1660]

[1661] step A step B

[1662] Step A: pyrimidine-2-sulfonyl chloride

[1663] Sodium hypochlorite (30.9 mL, 60.0 mmol) was added dropwise with rapid stirring to a solution of 2-mercaptopyrimidine (1.1 g, 10 mmol) in CH2CI2 (60 mL) and 1N HC1 (55.0 mL, 55.0 mmol) at -20°C. After the addition was completed, the mixture was stirred at-20° C for 15 mins. The organic layer was separated and used directly for next step.

[1664] Step B: pyrimidine-2-sulfonamide

[1665] The solution of pyrimidine-2-sulfonyl chloride in CH2CI2 (60 mL) was added to NLLOH (aq., 34%, 60 mL) at 0°C and the mixture was slowly allowed to warm to room temperature and stirred for 1 h. The mixture was concentrated under vacuum, residue was purified by silica gel chromatography (CLLCh / MeOH = 20 / 1) to afford the title compound pyrimidine- 2-sulfonamide as a light yellow solid (350 mg, 1.98 mmol, 20% yield in two steps).

[1666] LC-MS: m / z 160.0 (M+H)+Example 41: N-(l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH-imidazo[4,5-

[1667]

[1668] The title compound was prepared according to Method C, step D, starting from 6-bromo- l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH-imidazo[4,5-b]pyrazine (Example 1) by using pyrimidine-2-sulfonamide (55 mg, 70%yield). ¾ NMR (400 MHz, DMSO-de) d: 11.91 (s, 1H), 8.82 (d, J = 4.8 Hz, 2H), 8.35 (s, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.83 (t, J = 7.6 Hz, 1H), 7.67 (t, J = 4.8 Hz, 1H), 7.41 (t, J = 8.4 Hz, 1H), 6.78 (dd, J = 11.4, 8.4 Hz, 3H), 3.50 (s, 6H), 3.35 (d, J = 7.2 Hz, 2H), 1.00 (t, J = 7.2 Hz, 3H). LC-MS: m / z 534.1 (M+H)+

[1669] O

[1670] OH H2N— s— NH,

[1671] Step A: 4-hydroxypiperidine-l -sulfonamide

[1672] A mixture of piperidin-4-ol (1.0 g, 10 mmol, 1.0 equiv) and sulfuric diamide (960 mg, 10 mmol, 1.0 equiv) in dioxane (20 mL) was stirred at l20°C for 16 h. After evaporation, the residue was purified by flash column chromatography (eluting with DCM / MeOH = 10 / 1) to afford the title compound 4-hydroxypiperidine-l -sulfonamide as a white solid, (1.09 g, 61% yield).

[1673] ¾ NMR (400 MHz, DMSO-de) d: 6.67 (s, 2H), 4.70 (d, J = 3.6 Hz, 1H), 3.54 - 3.61 (m, 1H), 3.18 - 3.24 (m, 2H), 2.70 - 2.76 (m, 2H), 1.73 - 1.78 (m, 2H), 1.41 - 1.49 (m, 2H).

[1674] Example 42: N-(l-(2, 6-dimethoxyphenyl)-2- ( 6-ethoxypyridin-2-yl)-lH-imidazo[4, 5- b]pyrazin-6-yl)-4-hydroxypiperidine-l-sulfonamide

[1675]

[1676] The title compound was prepared according to Method C, step D, starting from N-(5- chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide by using 4-hydroxypiperidine-l -sulfonamide (34.5 mg, 31% yield).

[1677] ¾ NMR (400 MHz, CDCb) d 8.38 (s, 1H), 8.11 (d, J = 7.2 Hz, 1H), 7.65-7.69 (m, 1H), 7.35-7.40 (m, 1H), 7.18 (s, 1H), 6.67-6.70 (m, 3H), 3.67-3.73 (m, 1H), 3.63 (s, 6H), 3.39- 3.49 (m, 4H), 2.96-3.03 (m, 2H), 1.74-1.81 (m, 2H), 1.44-1.53 (m, 2H), 1.08 (t, J = 7.2 Hz, 3H). LC-MS: m / z 555.9 (M+H)+

[1678] Method D:

[1679]

[1680] Example 43: N-(l-(2, 6-dimethoxyphenyl)-2- ( 6-ethoxypyridin-2-yl)-lH-imidazo[4, 5- b]pyrazin-5-yl)methanesulfonamide

[1681]

[1682] The title compound was prepared according to Method C, step D, starting from 5-chloro- l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH-imidazo[4,5-b]pyrazine (Example 15) by using methanesulfonamide (26 mg, 23% yield).

[1683] ¾ MR (400 MHz, DMSO-de) d: 11.11 (s, 1H), 7.98 (d, J = 6.8 Hz, 1H), 7.95 (s, 1H), 7.86 (t, J = 7.6 Hz, 1H), 7.45 (t, J = 8.4 Hz, 1H), 6.85 (d, J = 8.4 Hz, 2H), 6.82 (dd, J = 8.2, 0.4 Hz, 1H), 3.58 (s, 6H), 3.39 (q, J = 7.2 Hz, 2H), 3.36 (s, 3H), 1.03 (t, J = 7.2 Hz, 3H). LCMS: m / z 471.0 (M+H)+

[1684] Example 44: N-(l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH-imidazo[4,5- b]pyrazin-5-yl)methanesulfonamide

[1685]

[1686] The title compound was prepared according to Method C, step D, starting from 5-chloro- l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH-imidazo[4,5-b]pyrazine (Example 15) by using 2-cyclopropylethanesulfonamide (30 mg, 16% yield). ¾ NMR (400 MHz, DMSO-de) d: 7.98-8.00 (m, 2H), 7.86 (t, J = 8.0 Hz, 1H), 7.45 (t, J = 8.4 Hz, 1H), 6.82 - 6.88 (m, 3H), 3.61 - 3.66 (m, 2H), 3.56 (s, 6H), 3.39 (q, J = 7.2 Hz, 2H), 1.57 - 1.67 (m, 2H), 1.03 (t, J = 7.2 Hz, 3H), 0.92-0.82 (m, 1H), 0.46 - 0.38 (m, 2H), 0.09 (q, J = 4.8 Hz, 2H). LCMS: m / z 525.35 (M+H)+

[1687] Example 45: 1— cyclopropyl— N-(l-(2,6-dimethoxyphenyl)— 2-(6— ethoxypyridin— 2-yl)- lH—imidazo[4,5-b]pyrazin—5-yl)methanesulfonamide

[1688]

[1689] The title compound was prepared according to Method C, step D, starting from 5-chloro- l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH-imidazo[4,5-b]pyrazine (Example 15) by using cyclopropylmethanesulfonamide (20 mg, 32% yield). ¾ NMR (400 MHz, DMSO-de) d : 10.95 (s, 1H), 8.06 (s, 1H), 7.98 - 8.00 (m, 1H), 7.87 (t, J = 8.0 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H), 6.83 - 6.88 (m, 3H), 3.58 (s, 6H), 3.55 (d, J = 8.0 Hz, 2H), 3.39 (q, J = 7.2 Hz, 2H). 1.09 - 1.14 (m, 1H), 1.03 (t, J = 7.2 Hz, 3H), 0.59 - 0.61 (m, 2H), 0.36 - 0.37 (m, 2H). LC-MS: m / z 511.0 (M+H)+.

[1690] Example 46: l-(2, 6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-N-(4-methoxybenzyl)- lH-imidazo[4,5-b]pyrazin-5-amine

[1691] The mixture of 5-chloro-l-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH- imidazo[4,5-b]pyrazine (Example 15, 100 mg, 0.24 mmol, 1.0 equiv), PMBNTh (67 mg, 0.48 mmol, 2.0 equiv), Xantphos (29 mg, 0.048 mmol, 0.2 equiv), Pd2(dba)3 (23 mg, 0.024 mmol, 0.1 equiv), *BuOK (55 mg, 0.48 mmol, 2.0 equiv) in toluene (5 mL) was stirred at H0°C for 16 hours under N2 atmosphere. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (PE / EtOAc = 10 / 1-1 / 1) to afford the title compound as a yellow solid (30 mg, 24% yield).

[1692] ¾ NMR (400 MHz, DMSO) d: 7.87 (d, J = 7.2 Hz, 1H), 7.79 (t, J = 7.6 Hz, 1H), 7.72 (s, 1H), 7.49 (t, J = 5.6 Hz, 1H), 7.41 (t, J = 8.4 Hz, 1H), 7.33 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 8.4 Hz, 2H), 6.74 (d, J = 7.6 Hz, 1H), 4.48 (d, J = 5.6 Hz, 2H), 3.73 (s, 3H), 3.57 (s, 6H), 3.36 (q, J = 7.2 Hz, 2H), 1.01 (t, J = 7.2 Hz, 3H). LCMS: m / z

[1693] 513.2 (M+H)+

[1694] Method E:

[1695] Step C

[1696] Step A: N-(5-chloro-3-((2-methoxy-6-(trifluoromethyl)vhenyl)amino)vyrazin-2-yl)-6- ethoxypicolinamide

[1697] A suspension of N-(3-bromo-5-chloropyrazin-2-yl)-6-ethoxypicolinamide (100 mg, 0.28 mmol, 1.0 equiv), 2-methoxy-6-(trifluoromethyl)aniline (53.5 mg, 0.28 mmol, 1.0 equiv), Pd2(dba)3 (102 mg, 0.11 mmol, 0.4 equiv), Xantphos (130 mg, 0.22 mmol, 0.8 equiv) and K2CO3 (77 mg, 0.56 mmol, 2.0 equiv) in l.4-dioxane (2 mL) was stirred at l30°C via microwave irradiation for 2 hours under N2 atmosphere. The mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (eluting with EtO Ac / PE = 1 / 6) to afford the title compound N-(5-chloro- 3-((2-methoxy-6-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide as a yellow solid (2 mg, 2% yield) and byproduct 2-(6-ethoxypyridin-2-yl)-l-(2-methoxy-6- (trifluoromethyl)phenyl)-lH-imidazo[4,5-b]pyrazin-6-ol (Example 47, 22 mg, 18% yield).

[1698] LC-MS: m / z 468.1 (M+H)+ Example 47 : 2-(6-ethoxypyridin-2-yl)-l-(2-methoxy-6-(trifluoromethyl)phenyl)-lH- imidazo[4, 5-b]pyrazin-6-ol

[1699]

[1700] ¾ NMR (400 MHz, DMSO-de) d: 9.28 (s, 1H), 8.17 (s, 1H), 7.91 (dd, J = 8.2, 7.6 Hz, 1H), 7.84 (dd, J = 7.6, 0.8 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.49 (dd, J = 8.4, 1.6 Hz, 1H), 7.40

[1701] (dd, J = 8.0, 1.6 Hz, 1H), 7.00 (dd, J = 8.4, 0.8 Hz, 1H), 4.41 (q, J = 7.2 Hz, 2H), 3.76 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H). LC-MS: m / z 432.1 (M+H)+

[1702] Step B: 6-chloiO-2-(6-ethoxypyridin-2-vD-l-(2-methoxy-6-('trifluoromethvDphenvD-lH- imidazor4.5-b1pyrazine

[1703]

[1704] A solution of N-(5-chloro-3-((2-methoxy-6-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)- 6-ethoxypicolinamide (35 mg, 0.075 mmol) in AcOH (2 mL) was stirred at l30°C via microwave irradiation for 2 hours. The mixture was concentrated and the residue was purified by prep-TLC to afford the title compound 6-chloro-2-(6-ethoxypyridin-2-yl)-l-(2- methoxy-6-(trifluoromethyl)phenyl)-lH-imidazo[4,5-b]pyrazine as a yellow solid (25 mg, 74% yield).

[1705] LC-MS: m / z 450.0 (M+H)+

[1706] Example 48: N-(2-(6-ethoxypyridin-2-yl)-l-(2-methoxy-6-(trifluoromethyl)phenyl)-lH- imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide

[1707] A suspension of 6-chloro-2-(6-ethoxypyridin-2-yl)-l-(2-methoxy-6-

[1708] (trifluoromethyl)phenyl)-lH-imidazo[4,5-b]pyrazine (25 mg, 0.056 mmol), Methanesulfonamide (11 mg, 0.112 mmol, 2 equiv), Cul (21 mg, 0.112 mmol, 2 equiv), trans-N,N'-Dimethylcy cl ohexane-l, 2-diamine (16 mg, 0.112 mmol, 2 equiv) and K2CO3 (23 mg, 0.167 mmol, 3 equiv) in DMF (2 mL) was stirred at 130 °C via microwave irradiation for 2 hours under N2 atmosphere. The mixture was diluted with EtOAc (30 mL) and filtered through celite. The filtrate was poured into aqueous K2CO3 (2 mol / L, 50 mL), stirred for 15 mins. Then the aqueous phase was separated and washed by EtOAc (2*30 mL). The aqueous phase was adjusted to pH = 3 with 1N HC1 and extracted with DCM (3* 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2S04and concentrated in vacuo. The residue was purified by flash chromatography (eluting with DCM / MeOH = 20 / 1-10 / 1) to afford the title compound as a white solid. (10 mg, 35%yield). ¾ NMR (400 MHz, DMSO-de) d: 11.13 (s, 1H), 8.32 (s, 1H), 8.06 (dd, J = 7.4, 0.8 Hz,

[1709] 1H), 7.88 (dd, J = 8.4, 7.6 Hz, 1H), 7.74 - 7.83 (m, 1H), 7.61 - 7.70 (m, 1H), 7.56 (dd, J = 8.0, 1.2 Hz, 1H), 6.85 (dd, J = 8.4, 0.8 Hz, 1H), 3.65 (s, 3H), 3.22 (q, J = 7.2 Hz, 2H), 3.12 (s, 3H), 1.00 (t, J = 7.2 Hz, 3H). LC-MS: m / z 509.1 (M+H)+

[1710] Example 49: N-(2-(6-ethoxypyridin-2-yl)-l-(3-methoxypyridin-2-yl)-lH-imidazo[4,5- b]pyrazin-6-yl)methanesulfonamide

[1711] The title compound was prepared according to Method E by using 3-methoxypyridin-2- amine in step A.

[1712] ¾ NMR (400 MHz, CDCb) d : 8.55 (s, 1H), 8.25 (dd, J = 4.8, 1.2 Hz, 1H), 8.15 (d, J = 4.0 Hz, 1H), 7.71 (t, J = 8.0 Hz, 1H), 7.45 - 7.48 (m, 1H), 7.39 - 7.41 (m, 1H), 7.15 (s, 1H), 6.72 (d, J = 8.0 Hz, 1H), 3.66 (s, 3H), 3.35 - 3.40 (m, 2H), 3.17 (s, 3H), 1.08 (t, J = 8.0 Hz, 3H). LC-MS: m / z 442.0 (M+H)+.

[1713] Example 50: N-(benzylsulfonyl)-4-(2-fluoro-6-methoxyphenyl)-5-(6-methoxypyridin-2- yl)-4H-l,2,4-triazole-3-carboxamide

[1714]

[1715] The title compound was prepared according to Method E by using 2-fluoro-6- methoxyaniline in step A.

[1716] ¾ MR (400 MHz, DMSO-de) d: 11.17 (s, 1H), 8.31 (s, 1H), 7.99 (d, J = 7.6 Hz, 1H), 7.89 (t, J = 7.6 Hz, 1H), 7.56 (dd, J = 15.2, 8.4 Hz, 1H), 7.05 - 7.18 (m, 2H), 6.87 (d, J = 8.4 Hz, 1H), 3.61 (s, 3H), 3.41 (q, J = 7.2 Hz, 2H), 3.19 (s, 3H), 1.04 (t, J = 7.2 Hz, 3H). LC-MS: m / z 459.1 (M+H)+

[1717] Method F:

[1718] Step C Common Intermediate

[1719] Step D

[1720] Step A: N- dibromopyrazin-2-yl )-6-methoxypi col inamide

[1721]

[1722] To a solution of 3,5-dibromopyrazin-2-amine (13.6g, 54mmol, 1.3 equiv) in THF was added AlMe3 (1.6 mol / L, 34 mL, 54 mmol, 1.3 equiv) dropwise at room temperature under argon atmosphere. The mixture was stirred at room temperature for 0.5 h. Then 3,5- dibromopyrazin-2-amine (6.8 g, 4lmmol, 1.0 equiv) was added in one portion. The mixture was stirred at 60°C for 1.5 h, quenched with 1N HC1 (aq.) and extracted with ethyl acetate for three times. The extracts were washed with brine, dried over anhydrous Na2S04and concentrated in vacuo. The residue was purified by column chromatography on silica gel to afford the title compound N-(3,5-dibromopyrazin-2-yl)-6-methoxypicolinamide as a yellow solid (l4g, 88.1% yield). LC-MS: m / z 386.8, 388.8, 390.8 (M+H)+

[1723] Step _ B _ N-(5-bromo-3- dimethoxyphenyl )amino)pyrazin-2-yl )-6-

[1724] methoxypicolinamide

[1725]

[1726] A suspension of N-(3,5-dibromopyrazin-2-yl)-6-methoxypicolinamide (600 mg, 1.54 mmol, 1.0 equiv), 2, 6-dimethoxy aniline (236 mg, 1.54 mmol, 1.0 equiv), Pd(OAc)2 (70 mg, 0.31 mmol, 0.2 equiv), Xantphos (358 mg, 0.62 mmol, 0.4 equiv) and K2CO3 (440 mg, 3.1 mmol, 2.0 equiv) in l.4-dioxane (10 mL) was stirred at 120 °C via microwave irradiation for 2 hour under N2 atmosphere. The mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (PE / EtOAc = 4 / 1) to afford the desired product N-(5-bromo-3-((2,6- dimethoxyphenyl)amino)pyrazin-2-yl)-6-methoxypicolinamide (70 mg, 10% yield). LC-MS: m / z 459.9, 461.9 (M+H)+

[1727] Step C: 6-bromo-l- dimethoxyphenvD-2-(6-ethoxypyridin-2-vD-lH-imidazor4.5-

[1728] blpyrazine

[1729]

[1730] A solution of N-(5-bromo-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6- methoxypicolinamide (700 mg, 1.53 mmol) in AcOH (10 mL) was stirred at l20°C via microwave irradiation for 2 hour. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography to give the desired product 6-bromo-l- (2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-lH-imidazo[4,5-b]pyrazine as a light yellow solid (475 mg, 70%). LC-MS: m / z 442.3, 444.3 (M+H)+

[1731] Example 51: N-(l-(2, 6-dimethoxyphenyl)-2- ( 6-methoxypyridin-2-yl)-lH-imidazo[4, 5- b]pyrazin-6-yl)methanesulfonamide

[1732]

[1733] The title compound was prepared according to Method F by using methanesulfonamide in step D (72 mg, 78% yield).

[1734] ¾ NMR (400 MHz, DMSO-de) d: 11.05 (s, 1H), 8.30 (s, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 6.85 (d, J = 8.0 Hz, 3H), 3.57 (s, 6H), 3.20 (s, 3H), 3.11 (s, 3H). LC-MS: m / z 457.0 (M+H)+

[1735] Example 52: N-(l-(2, 6-dimethoxyphenyl)-2- ( 6-methoxypyridin-2-yl)-lH-imidazo[4, 5- b]pyrazin-6-yl)pyridine-2-sulfonamide

[1736]

[1737] The title compound was prepared according to Method F by using pyridine-2-sulfonamide in step D (34 mg, 33% yield).

[1738] ¾ NMR (400 MHz, DMSO-de) d: 11.77 (s, 1H), 8.59 (d, J = 4.0 Hz, 1H), 8.29 (s, 1H), 7.91 - 7.96 (m, 1H), 7.81 - 7.86 (m, 1H), 7.77 (td, J = 7.8, 1.6 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.57 (dd, J = 4.0, 3.2 Hz, 1H), 7.49 (t, J = 8.4 Hz, 1H), 6.86 (d, J = 8.4 Hz, 2H), 6.83 (dd, J = 8.4, 0.8 Hz, 1H), 3.51 (s, 6H), 3.08 (s, 3H). LC-MS: m / z 520.0 (M+H)+

[1739] Example 53: N-(l-(2, 6-dimethoxyphenyl)-2- ( 6-methoxypyridin-2-yl)-lH-imidazo[4, 5- b]pyrazin-6-yl)pyrimidine-2-sulfonamide

[1740] The title compound was prepared according to Method F by using pyridine-2-sulfonamide in step D (15 mg, 29% yield).

[1741] ¾ NMR (400 MHz, DMSO-de) d: 11.91 (s, 1H), 8.80 (d, J = 4.8 Hz, 2H), 8.32 (s, 1H), 7.91 (dd, J = 7.6, 0.8 Hz, 1H), 7.83 (dd, J = 8.4, 7.6 Hz, 1H), 7.63 (t, J = 4.8 Hz, 1H), 7.39 (t, J = 8.4 Hz, 1H), 6.79 - 6.85 (m, 1H), 6.76 (d, J = 8.4 Hz, 2H), 3.50 (s, 6H), 3.06 (s, 3H). LC-MS: m / z 521.1 (M+H)+

[1742] Method G:

[1743] step A step B

[1744] Step A: methyl 6-fluoropicolinate

[1745]

[1746] Methyl iodide (20 g, 142 mmol, 3.0 equiv) was added to a suspension of 6-fluoropicolinic acid (10.0 g, 71 mmol, 1.0 equiv) and silver(I) carbonate (19.5 g, 71 mmol, 1.0 equiv) in CHCb (100 mL). The suspension was stirred at 30°C for 1 day. Insoluble material was removed by filtration and the filter cake was washed with CHCb. The filtrate was concentrated in vacuo to give the title compound as a light yellow solid (9.0 g, 82% yield). This material was used in the next step without further purification.

[1747] LC-MS: m / z 156.0 (M+H)+Step B: 6-cvclopropoxypicolinic acid

[1748]

[1749] To a mixture of cyclopropanol (1.5 g, 25.8 mmol, 3.0 equiv) in dioxane (20 mL) was added NaH (1032 mg, 25.8 mmol, 3.0 equiv) at 0°C and the mixture was stirred at 0°C for 30 mins. Then methyl 6-fluoropicolinate (2.0 g, 12.9 mmol, 1.0 equiv) was added and the mixture was stirred at 25°C for 2 h. The reaction mixture was quenched with saturated aqueous MLCl solution. The mixture was washed with EtOAc three times. The aqueous phase was acidified with concentrated hydrochloric acid and extracted with DCM (3*30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography to afford 6-cyclopropoxypicolinic acid as a white solid (600 mg, 13% yield).

[1750] LC-MS: m / z 180.0 (M+H)+ Step C: methyl 6-cvclopropoxypicolinate

[1751]

[1752] Methyl iodide (0.41 ml, 6.59 mmol, 3.0 equiv) was added to a suspension of 6- cyclopropoxypicolinic acid (590 mg, 3.29 mmol, 1.0 equiv) and silver(I) carbonate (1091 mg, 3.95 mmol, 1.2 equiv) in CHCb (10 ml). The suspension was stirred at 30°C for 4 h. Insoluble material was removed by filtration and the filter cake was washed with CHCb. The filtrate was concentrated to give the title compound methyl 6-cyclopropoxypicolinate as a light yellow oil (600 mg, 94% yield). This material was used in the next step without further purification. LC-MS: m / z 194.0 (M+H)+

[1753] Step D: N-(3-bromo-5-chloropyrazin-2-vD-6-cvclopropoxypicolinamide

[1754]

[1755] To a mixture of 3-bromo-5-chloropyrazin-2-amine (644 mg, 3.1 mmol, 1.0 equiv) and toluene (10 mL) was added AlMe3 (1.6 mol / L in toluene, 4 mL, 6.2 mmol, 2.0 equiv). After the mixture was stirred at 50°C for 30 mins, methyl 6-cyclopropoxypicolinate (600 mg, 3.1 mmol, 1.0 equiv) was added. The mixture was stirred at H0°C for 1 h and was quenched with 1N aqueous HC1 solution. The mixture was extracted with DCM three times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography

[1756] (100% DCM) to afford the title compound N-(3-bromo-5-chloropyrazin-2-yl)-6- cyclopropoxypicolinamide (500 mg, 44% yield).

[1757] LC-MS: m / z 369.0, 371.0 (M+H)+ Step _ E: _ N-(5-chloro-3-((2.6-dimethoxyphenyl )amino)pyrazin-2-yl )-6- cvclopropoxypicolinamide

[1758]

[1759] A suspension ofN-(3-bromo-5-chloropyrazin-2-yl)-6-cyclopropoxypicolinamide (500 mg, 1.36 mmol, 1.0 equiv), 2, 6-dimethoxy aniline (229 mg, 1.49 mmol, 1.1 equiv), Pd(OAc)2

[1760] (61 mg, 0.27 mmol, 0.2 equiv), Xantphos (315 mg, 0.54 mmol, 0.4 equiv) and K2C03 (375 mg, 2.72 mmol, 2.0 equiv) in l .4-dioxane (3 mL) was stirred at 125 °C via microwave irradiation for 2 hours under N2 atmosphere. The mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (100% DCM) to afford the title compound N-(5-chloro-3-((2,6- dimethoxyphenyl)amino)pyrazin-2-yl)-6-cyclopropoxypicolinamide as a yellow solid (247 mg, 41% yield).

[1761] LC-MS: m / z 442.1 (M+H)+

[1762] Step F : _ 6-chloro-2-(6-cvclopropoxypyridin-2-yl )- 1 - dimethoxyphenyl )- 1 H-

[1763] imidazo A-blpyrazine

[1764]

[1765] A solution of N-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6- cyclopropoxypicolinamide (247 mg, 0.56 mmol, 1.0 equiv) in AcOH (2 mL) was stirred at l30°C via microwave irradiation for 2 hours. The reaction mixture was cooled to room temperature and the precipitate was filtered off and washed with a solvent mixture of EA / PE = 1 / 2 to afford the title compound 6-chloro-2-(6-cyclopropoxypyridin-2-yl)-l-(2,6- dimethoxyphenyl)-lH-imidazo[4,5-b]pyrazine as a light yellow solid (170 mg, 72% yield).

[1766] LC-MS: m / z 424.1 (M+H)+Example 54: N-(2-(6-cyclopropoxypyridin-2-yl)-l-(2,6-dimethoxyphenyl)-lH- imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide

[1767]

[1768] A suspension of 6-chloro-2-(6-cyclopropoxypyridin-2-yl)-l-(2,6-dimethoxyphenyl)-lH- imidazo[4,5-b]pyrazine (80 mg, 0.19 mmol 1.0 equiv), methanesulfonamide (36.1 mg, 0.38 mmol, 2.0 equiv), Cul (72 mg, 0.38 mmol, 2.0 equiv), trans-N,N' -Dimethyl cy cl ohexane- 1, 2-diamine (54 mg, 0.38 mmol, 2.0 equiv) and K2CO3 (78 mg, 0.57 mmol, 3.0 equiv) in DMF (3 mL) was stirred at l20°C via microwave irradiation for 2 hours under N2 atmosphere. The mixture was diluted with EtOAc (30 mL) and filtered through celite. The filtrate was poured into water (50 mL). The mixture was adjusted to pH = 4 with 1N HC1 and extracted with EA (3*100 mL). The organic layers were dried over anhydrous Na2S04and concentrated in vacuo. The residue was purified by flash column chromatography (eluting with DCM / MeOH = 20 / 1) to afford the title compound as write solid (55 mg, 60% yield).

[1769] ¾ NMR (400 MHz, DMSO-de) d: 11.06 (s, 1H), 8.27 (s, 1H), 7.97 (dd, J = 7.6, 0.8 Hz, 1H), 7.87 (t, J = 8.4 Hz, 1H), 7.40 (t, J = 8.4 Hz, 1H), 6.77 - 6.87 (m, 3H), 3.56 (s, 6H),

[1770] 3.15 - 3.22 (m, 4H), 0.42 - 0.50 (m, 2H), 0.27 - 0.41 (m, 2H). LC-MS: m / z 483.1 (M+H)+

[1771] Step A Step B

[1772] Step A: 6- trif1uoroethoxy)picolinic acid

[1773]

[1774] The mixture of methyl 6-bromopicolinate (4.3 g, 20 mmol, 1.0 equiv), ethyl 2- oxocyclohexane-l-carboxylate (680 mg, 4 mmol, 0.2 equiv), Cul (380 mg, 2 mmol, 0.1 equiv) and CS2CO3 (9.1 g, 28 mmol, 1.4 equiv) in 2,2,2-trifluoroethan-l-ol (14.0 g, 280 mmol, 14 equiv) was heated under nitrogen atmosphere at 78 °C for 20 hours. The reaction mixture was cooled to 20°C and poured into water (200 mL). The mixture was adjusted to pH = 5 with 1N HC1 (aq.) and extracted with DCM (3*20 mL). The combined organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to afford the title compound 6-(2,2,2-trifluoroethoxy)picolinic acid as yellow solid (3.3 g, 74% yield).

[1775] LC-MS: m / z 222.0 (M+H)+

[1776] Step B: methyl 6-(2.2.2-trif1uoroethoxy)picolinate

[1777]

[1778] To a solution of 6-(2,2,2-trifluoroethoxy)picolinic acid (2.2 g, 10 mmol, 1.0 equiv) in methanol (20 mL) were added 2 drops of H2SO4 (con.). The mixture was stirred at 20°C for 20 hours, diluted with H2O (100 mL) and extracted with DCM (3*20 mL). The combined organic phase was dried over anhydrous sodium sulfite and concentrated in vacuo. The residue was purified by silica gel chromatography (PE / EA = 20 / 1) to afford the title compound methyl 6-(2,2,2-trifluoroethoxy)picolinate as a colorless oil (2.1 g, 88% yield).

[1779] LC-MS: m / z 236.1 (M+H)+

[1780] Example 55: N-(l-(2, 6-dimethoxyphenyl)-2-(6-(trifluoroethoxy)pyridin-2-yl)-lH- imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide

[1781]

[1782] The title compound was prepared according to Method G by using methyl 6-(2,2,2- trifluoroethoxy)picolinate in step D. (15 mg, 10% yield).

[1783] ¾ NMR (400MHz, CDCb) d: 8.55 (s, 1H), 8.27 (d, J = 4.0 Hz, 1H), 7.79 (t, J = 8.8 Hz, 1H), 7.43 (t, J = 8.4 Hz, 1H), 7.07 (s, 1H), 6.86 (d, J = 4.0 Hz, 1H), 6.73 (d, J = 4.4 Hz, 2H), 3.74 (q, J = 8.8 Hz, 2H), 3.63 (s, 6H), 3.18 (s, 3H). LC-MS: m / z 525.1 (M+H)+

[1784]

[1785] Step A: methyl 6-(trifluoromethoxy)picolinate

[1786]

[1787] To a solution of 2-chloro-6-(trifluoromethoxy)pyridine (5.0 g, 25.3 mmol, 1.0 equiv) in MeOH (120 mL) was added Pd(dppf)Cl2 (930 mg, 1.27 mmol, 0.05 equiv). The mixture was stirred at l00°C under hydrogen atmosphere (50 Psi) for 48 hours. The reaction mixture was cooled to 20°C and concentrated in vacuo. The residue was purified by silica gel chromatography (PE / EA = 10 / 1) to afford the title compound methyl 6- (trifluoromethoxy)picolinate as yellow oil (3.85 g, 68% yield).

[1788] LC-MS: m / z 222.0 (M+H)+

[1789] Example 56: N-(l-(2, 6-dimethoxyphenyl)-2-(6-(trifluoromethoxy)pyridin-2-yl)-lH-

[1790]

[1791] The title compound was prepared according to Method G by using methyl 6- (trifluoromethoxy)picolinate in step D (30 mg, 15% yield).

[1792] ¾NMR (400MHz, DMSO-de) d: 8.26 (t, J = 4.0 Hz, 1H), 8.19 (s, 1H), 8.17 (t, J = 7.6 Hz, 1H), 7.43 (t, J = 8.8 Hz, 1H), 7.29 (d, J = 4.0 Hz, 1H), 6.79 (d, J = 4.4 Hz, 2H), 3.54 (s, 6H), 3.l0(s, 3H). LC-MS: m / z 511.1 (M+H)+

[1793] Example 57: N-(l-(2,6-dimethoxyphenyl)-2-(ethoxymethyl)-lH-imidazo[4,5-bJpyrazin- 6-yl)benzenesulfonamide

[1794]

[1795] The title compound was prepared according to Method G by using ethyl 2-ethoxyacetate in step D and benzenesulfonamide in step G (39 mg, 29 % yield).

[1796] ¾ NMR (400 MHz, DMSO-de) d: 11.52 (s, 1 H), 8.16 (s, 1H), 7.69 (d, J = 7.6 Hz, 2H), 7.54-7.70 (m, 2H), 7.36 (t, J = 7.6 Hz, 2H), 6.94 (d, J = 8.4 Hz, 2H), 4.42 (s, 2H), 3.65 (s, 6H), 3.28 (q, J = 7.2 Hz, 2H), 0.92 (t, J = 7.2 Hz, 3H). LC-MS: m / z 470.1 (M+H)+

[1797] Method H:

[1798] A suspension of 3,5-dibromopyrazin-2-amine (1.0 g, 3.98 mmol, 1.0 equiv) in pentan-3- amine (10 mL) was stirred at l50°C via microwave irradiation for 1 hour . The mixture was diluted with water (15 mL) and extracted with EtOAc (3*50 mL). The combined organic layers were dried over anhydrous Na2S04and concentrated in vacuo. The residue was purified by flash column chromatography (eluting with PE / EtOAc = 20 / 1 to 5 / 1) to afford the title compound 6-bromo-N2-(pentan-3-yl)pyrazine-2, 3-diamine as light yellow solid (0.9 g, 88 % yield). LC-MS: m / z 259.1, 261.1 (M+H)+

[1799] Step B: N-(5-bromo-3-(pentan-3-ylamino)pyrazin-2-vO-6-ethoxypicolinamide

[1800] To a solution of 6-bromo-N2-(pentan-3-yl)pyrazine-2, 3 -diamine (900 mg, 3.5 mmol, 1.1 equiv) in toluene (20 mL) was added Al(Me)3 (1.6 mol / L in toluene, 10 mL, 15.9 mmol, 5 equiv) dropwise at room temperature. After the mixture was stirred at 50°C for 30 mins, ethyl 6-ethoxypicolinate (686 mg, 3.2 mmol, 1.0 equiv) was added and the mixture was stirred at H0°C for 2 hours. The reaction mixture was quenched with water (50 mL), followed by extraction with EtOAc (3*50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2S04and concentrated in vacuo. The residue was purified by flash column chromatography (eluting with PE / EtOAc = 20 / 1 to 5 / 1) to afford the title compound N-(5-bromo-3-(pentan-3-ylamino)pyrazin-2-yl)-6- ethoxypicolinamide as light yellow solid (0.65 g, 46 % yield). LC-MS: m / z 408.1, 410.1 (M+H)+

[1801] Step C: 6-bromo-2-(6-ethoxypyridin-2-vD-l-(pentan-3-vD-lEl-imidazor4.5-b1pyrazine

[1802]

[1803] To a solution of N-(5-bromo-3-(pentan-3-ylamino)pyrazin-2-yl)-6-ethoxypicolinamide (650 mg, 1.6 mmol, 1.0 equiv) in AcOH (10 mL) was added 1 drop of POCb. The mixture was stirred at l20°C via microwave irradiation for 2 hours. The mixture was cooled to room temperature, evaporated and the residue was purified by flash column chromatography (eluting with PE / EtOAc = 20 / 1 to 5 / 1) to afford the title compound 6- bromo-2-(6-ethoxypyridin-2-yl)-l-(pentan-3-yl)-lH-imidazo[4,5-b]pyrazine as a light yellow solid (450 mg, 72% yield).

[1804] LC-MS: m / z 390.1, 392.1 (M+H)+

[1805] Example 58: N-(2-(6-ethoxypyridin-2-yl)-l-(pentan-3-yl)-lH-imidazo[4,5-b]pyrazin-6- yl)methanesulfonamide

[1806]

[1807] A suspension of 6-bromo-2-(6-ethoxypyridin-2-yl)-l-(pentan-3-yl)-lH-imidazo[4,5- bjpyrazine (50 mg, 0.13 mmol, 1.0 equiv), methanesulfonamide (24 mg, 0.26 mmol, 3.0 equiv), Cul (49 mg, 0.26 mmol, 3.0 equiv), trans-N,N'-Dimethylcy cl ohexane-l, 2-diamine (37 mg, 0.26 mmol, 3.0 equiv) and K2CO3 (53 mg, 0.39 mmol, 3 equiv) in DMF (5 mL) was stirred at 115°C via microwave irradiation for 1.5 h under N2 atmosphere. The mixture was diluted with water (15 mL) and extracted with EtOAc (3*50 mL). The combined organic layers were dried over anhydrous Na2S04and concentrated in vacuo. The residue was purified by prep-TLC (PE / EtOAc = 1 / 2) to afford the title compound N-(2-(6- ethoxypyridin-2-yl)-l-(pentan-3-yl)-lH-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide as a light yellow solid (40 mg, 76% yield).

[1808] ¾ NMR (400 MHz, DMSO-de) d: 11.18 (s, lH),8. l9 (s, lH),7.94 (t, J = 7.6 Hz, lH),7.89 (dd, J = 7.6 Hz, 0.8 Hz, lH),7.0l (dd, J = 8.4 Hz, 0.8 Hz, 1H), 5.74-5.79 (m, 1H), 4.40 (q, J = 7.2 Hz, 2H),3.42 (s, 3H), 2.34-2.42 (m, 2H), 2.01-1.99 (m, 2H), 1.39 (t, J = 7.2 Hz, 3H), 0.70 (t, J = 7.6 Hz, 6H). LC-MS: m / z 405.2 (M+H)+

[1809] Example 59: N-(2-(6-ethoxypyridin-2-yl)-l-isopropyl-lH-imidazo[4,5-b]pyrazin-6- yl) methanesulfonamide

[1810]

[1811] The title compound was prepared according to Method H by using propan-2-amine in step

[1812] A.

[1813] 1HNMR (400 MHz, DMSO-de) d: 11.17 (s, 1H), 8.18 (s, lH),7.95 (t, J = 7.6 Hz, 1H), 7.85 (dd, J = 7.6 Hz, 0.8 Hz, 1H), 7.0 (dd, J = 8.4 Hz, 0.8 Hz, 1H), 5.93-6.0 (m, 1H), 4.41 (q, J = 7.2 Hz, 2H), 3.45 (s, 3H), 1.73 (d, J = 6.8 Hz, 6H), 1.38 (t, J = 7.2 Hz, 3H). LC-MS: m / z 377.1 (M+H)+

[1814]

[1815] Step A: 3 -hydroxy-3 -methylbutyl 4-methylbenzenesulfonate

[1816] To a solution of 3-methylbutane-l,3-diol (20.8 g, 200 mmol, 1.0 equiv) in Pyridine (40 mL) was added TsCl (39.6 g, 208 mmol, 1.0 equiv) at 0°C. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was neutralized with saturated NH4CI and extracted with DCM (3*100 mL). The extract was concentrated in vacuo and the residue was purified by flash chromatography (PE / EA = 1 / 1) to afford the title compound 3 -hydroxy-3 -methylbutyl 4-methylbenzenesulfonate as a yellow oil (45 g, 90% yield).

[1817] LC-MS: m / z 259.0 (M+H)+

[1818] Step B: 4-iodo-2-methylbutan-2-ol To a solution of 3 -hydroxy-3 -methylbutyl 4-methylbenzenesulfonate (6 g, 23.2 mmol, 1.0 equiv) in acetone (100 mL) was added Nal (8.7 g, 58 mmo...

Claims

WHAT IS CLAIMED IS:

1. A compound of F ormul a (I) :or a pharmaceutically acceptable salt thereof;wherein:A1is CH or N; each of X1, X2, X3, and X4is independently selected from the group consisting of N and CR3;R1is:(i) -(Y^n-Y2, wherein:• n is 0 or 1;• Y1is Ci-6 alkylene, which is optionally substituted with from 1-6 Ra; and• Y2is:(a) C3-10 cycloalkyl, which is optionally substituted with from 1-4 Rb;(b) C6-10 aryl, which is optionally substituted with from 1-4 Rc;(c) heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-4 independently selected Rc, or(d) heterocyclyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), and O, and wherein one or more of theheterocyclyl ring carbon atoms are optionally substituted with from 1-4 independently selected Rb,(ii) -Z1-Z2-Z3, wherein:• Z1is Ci-3 alkylene, which is optionally substituted with from 1-4 Ra;• Z2is -N(H)-, -N(Rd)-, -0-, or -S-; and• Z3is C2-7 alkyl, which is optionally substituted with from 1-4 Ra;OR(iii) C3-10 alkyl, optionally substituted with from 1-6 independently selected Ra;OR(iv) -Z4-Z5-Z6-Y2wherein:• Z4is Ci-3 alkylene, which is optionally substituted with from 1-4 Ra;• Z5is -N(H)-, -N(Rd)-, -0-, or -S-;• Z6is Ci-4 alkylene, which is optionally substituted with from 1-4 Ra; and• Y2is as defined above;R2is:(i) C6-10 aryl, which is optionally further substituted with from 1-4 Rc;(ii) heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-4 independently selected Rc;(iii) C3-10 cycloalkyl, which is optionally substituted with from 1-4 Rb;(iv) heterocyclyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), and O, and wherein one or more of the heterocyclyl ring carbon atoms are optionally substituted with from 1-4 independently selected Rb; or(v) Ci-io alkyl, which is optionally substituted with from 1-6 independently selectedRaeach occurrence of R3is independently selected from the group consisiting of -L4- R4, H and, Rc’; each occurrence of L4is independently selected from the group consisting of:(i) a single bond;(ii) N(H), N(Rd), or N(R4);(iii) -N(H)S(0)I-2- or -N(Rd)S(0)i-2-;(iv) -S(0)I-2N(H)- or -S(0)i-2N(Rd)-;(v) -O- ;(vi) -S(0)o-2-;(vii) -C(0)NH- or -C(0)N(Rd);(viii) -N(H)C(0)- or -N(Rd)C(0)-;(ix) -CºC;(x) -N(H)S(0)(=NH)-, -N(Rd)S(0)(=NH), -N(H)S(0)(=NRd)-, or - N(Rd)S(0)(=NRd)-(xi) -S(0)(=NH)NH-, -S(0)(=NRd)NH-, -S(0)(=NH)NRd-, or -S(0)(=NRd)NRd-;(xii) -S(0)(=NH)- or -S(0)(=NRd); and(xiii) -N(H)S(0)I-2N(H)-, -N(Rd)S(0)i-2N(H)-, -N(H)S(0)i-2N(Rd)-, or -N (Rd) S (O) i -2N (Rd)- ; each occurrence of R4is, independently:(i) -(Y3)p-Y4, wherein:• p is O or l;• Y3is Ci-6 alkylene or Ci-6 alkenylene, each of which is optionally substituted with from 1-6 Ra; and• Y4is:(a) C3-6 cycloalkyl, which is optionally substituted with from 1-4 Rb,(b) C6-10 aryl, which is optionally substituted with from 1-4 Rc;(c) heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-4 independently selected Rc, or(d) heterocyclyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), and O, and wherein one or more of the heterocyclyl ring carbon atoms are optionally substituted with from 1-4 independently selected Rb,OR(ii) Ci-io alkyl, Ci-io alkenyl, or Ci-io alkynyl, each of which is optionally substituted with from 1-6 independently selected Ra;each occurrence of Rais independently selected from the group consisting of: -OH; -F; - Cl; -Br; -NReRf; CM alkoxy; CM haloalkoxy; -C(=0)0(CM alkyl); -C(=0)(CM alkyl); - C(=0)OH; -CON(R’)(R”); -S(0)i-2(NR’R”); -S(0)I-2(CM alkyl); cyano, and C3-6 cycloalkyl optionally substituted with from 1-4 independently selected CM alkyl;each occurrence of Rbis independently selected from the group consisting of: Ci-6 alkyl; Ci-4 haloalkyl; -OH; oxo; -F; -Cl; -Br; -NReRf; Ci-4 alkoxy; Ci-4 haloalkoxy; -C(=0)(Ci-4 alkyl); -C(=0)0(Ci-4alkyl); -C(=0)0H; -C (=0)N(R’ )(R” ) ; -S(0)i-2(NR’R”); -S(0)i- 2(Ci-4 alkyl); cyano; and C3-6 cycloalkyl optionally substituted with from 1-4 independently selected Ci-4 alkyl; each occurrence of Rcis independently selected from the group consisting of:(i) halo;(ii) cyano;(iii) Ci-6 alkyl;(iv) C2-6 alkenyl;(v) C2-6 alkynyl;(vi) Ci-4 haloalkyl;(vii) Ci-4 alkoxy;(viii) Ci-4 haloalkoxy;(ix) -(C0-3 alkylene)-C3-6 cycloalkyl optionally substituted with from 1-4 independently selected Ci-4 alkyl;(x) -S(0)i-2(Ci-4 alkyl);(xi) -NReRf;(xii) -OH;(xiii) -S(0)I-2(NR’R”);(xiv) -Ci-4 thioalkoxy;(xv) -NO2;(xvi) -C(=0)(Ci-4 alkyl);(xvii) -C(=0)0(Ci-4 alkyl);(xviii) -C(=0)0H,(xix) -C(=0)N(R’)(R”), and(xx) C3-6 cycloalkoxy; each occurrence of Rc’ is independently selected from the group consisting of:(i) halo;(ii) cyano;(iii) -OH;(iv) -NO2;(v) -C(=0)(Ci-4 alkyl);(vi) -C(=0)0(Ci-4 alkyl);(vii) -C(=0)0H; and(viii) -ML·;Rdis selected from the group consisting of: Ci-6alkyl; C3-6 cycloalkyl; -C(0)(Ci-4 alkyl);-C(0)0(Ci-4 alkyl); -CON(R’)(R”); -S(0)I-2(MCR”); - S(0)I.2(CM alkyl); -OH; and Ci 4 alkoxy; each occurrence of Reand Rfis independently selected from the group consisting of: H; Ci-6 alkyl; C3-6 cycloalkyl; -C(0)(Ci-4alkyl); -C(0)0(Ci-4alkyl); -CON(R’)(R”); -S(0)i- 2(NR’R”); - S(0)i-2(Ci-4 alkyl); -OH; and Ci-4 alkoxy; or Reand Rftogether with the nitrogen atom to which each is attached forms a ring including from 3-8 ring atoms, wherein the ring includes: (a) from 1-7 ring carbon atoms, each of which is substituted with from 1-2 substituents independently selected from H and C1-3 alkyl; and (b) from 0-3 ring heteroatoms (in addition to the nitrogen atom attached to R’ and R”), which are each independently selected from the group consisting of N(Rd), O, and S; and each occurrence of R’ and R” is independently selected from the group consisting of: H and Ci-4 alkyl; or R’ and R” together with the nitrogen atom to which each is attached forms a ring including from 3-8 ring atoms, wherein the ring includes: (a) from 1-7 ring carbon atoms, each of which is substituted with from 1-2 substituents independently selected from H and C 1-3 alkyl; and (b) from 0-3 ring heteroatoms (in addition to the nitrogen atom attached to R’ and R”), which are each independently selected from the group consisting of N(Rd), O, and S; provided that when the compound is of Formula (1-1):R1is other than unsubstituted phenyl, / ¾ / ra-dimethylami nophenyl, para- aminosulfonylphenyl, and unsubstituted 4-pyridinyl;when the compound is of Formula (1-2):R1is other than unsubstituted phenyl;provided that the compound is not of Formula (1-3):provided that when the compound is of Formula (1-4):R1is other than para-f] uorophenyl ; andprovided that when the compound is of Formula (1-5):R3is other than trifluoromethyl; andprovided that when the compound is of Formula (1-6):R2is other than:(i) unsubstituted phenyl;(iv) unsubstituted pyridinyl;Q1:Q2(v) K Q3,-Q J4-R‘ wherein each of Q\ Q2, Q3, and Q4is independently selected from N and CH; or(vi) heteroaryl including from 9-10 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-2 independently selected Rc.

2. The compound of claim 1, wherein from 1-2 of X1, X2, X3, and X4are independently N; and from 2-3 of X1, X2, X3, and X4are each an independently selected CR33. The compound of claim 1, wherein the compound is of Formula (I-a):or a pharmaceutically acceptable salt thereof.

4. The compound of any one of claims 1-3, wherein the compound is of Formula (I- al):al);or a pharmaceutically acceptable salt thereof.

5. The compound of any one of claims 1-3, wherein the compound is of Formula (I- a2):or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1, wherein the compound is of Formula (I-b):or a pharmaceutically acceptable salt thereof.

7. The compound of any one of claims 1 and 6, wherein the compound is of Formula(I-bl):bl);or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1, wherein the compound is of Formula (I-c) or (I-d):or a pharmaceutically acceptable salt thereof.

9. The compound of any one of claims 1 and 8, wherein the compound is of Formula(I-cl) or (I-dl):r1(I-cl) orr1(I-dl)or a pharmaceutically acceptable salt thereof.

10. The compound of any one of claims 1-9, wherein R1is -(Y1)n-Y2.

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

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

13. The compound of claim 12, wherein Y1is C1-3 alkylene.

14. The compound of any one of claims 1-13, wherein Y2is heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-4 independently selected Rc.

15. The compound of any one of claims 1-14, wherein Y2is heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-4 independently selected Rc.

16. The compound of any one of claims 1-15, wherein Y2is heteroaryl including 6 ring atoms, wherein from 1-2 ring atoms are N, and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-4 independently selected Rc.

17. The compound of claim 16, wherein Y2is pyridyl (e.g., 2-pyridyl or 6-pyridyl), wherein one or more of the ring carbon atoms are optionally substituted with from 1-4 independently selected Rc.

18. The compound of claim 17, wherein Y2is pyridyl (e.g., 2-pyridyl or 6-pyridyl), wherein one or more of the ring carbon atoms are optionally substituted with one independently selected Rc.

19. The compound of any one of claims 1-15, wherein Y2is heteroaryl including 5 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-3 independently selected Rc.

20. The compound of claim 19, wherein Y2is furanyl, wherein one or more of the ring carbon atoms are optionally substituted with from 1-2 (e.g., 1) independently selected Rc.

21. The compound of any one of claims 14-20, wherein each occurrence of Rcis independently selected from the group consisting of:(iii) Ci-6 alkyl;(iv) C2-6 alkenyl;(v) C2-6 alkynyl;(vi) Ci-4 haloalkyl;(vii) Ci-4 alkoxy;(viii) Ci-4 haloalkoxy;(ix) -(C0-3 alkylene)-C3-6 cycloalkyl optionally substituted with from 1-4 independently selected Ci-4 alkyl;(xiv) -Ci-4 thioalkoxy; and(xx) C3-6 cycloalkoxy.

22. The compound of any one of claims 14-20, wherein each occurrence of Rcis independently selected from the group consisting of:(vii) Ci-4 alkoxy;(viii) Ci-4 haloalkoxy (e.g., OCH2CF3 or OCF3);(xiv) -Ci-4 thioalkoxy; and(xx) C3-6 cycloalkoxy (e.g., cyclopropoxy).

23. The compound of any one of claims 14-20, wherein each occurrence of Rcis an independently selected Ci-4 alkoxy (e.g., -OCH3, -OCH2CH3).

24. The compound of any one of claims 14-20, wherein each occurrence of Rcis an independently selected C1-6 alkyl (e.g., methyl).

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

26. The compound of any one of claims 1-11, 14-18, and 21-23, wherein R1is:

27. The compound of any one of claims 1-11, 14-18, 21, and 24, wherein R1is28. The compound of any one of claims 1-11, 14-15, 19-21, and 24, wherein R1is29. The compound of any one of claims 1-28, wherein R2is C6-10 aryl, which is optionally substituted with from 1-4 Rc.

30. The compound of any one of claims 1-29, wherein R2is phenyl, which is optionally substituted with from 1-4 Rc.

31. The compound of any one of claims 1-30, wherein R2is phenyl, which is optionally substituted with from 1-2 Rc.

32. The compound of any one of claims 1-31, wherein R2is phenyl, which is optionally substituted with 2 Rc.

33. The compound of any one of claims 29-32, wherein each occurrence of Rcis independently selected from the group consisting of:(i) halo (e.g., F);(vi) Ci-4 haloalkyl (e.g., CF3);(vii) Ci-4 alkoxy;(viii) Ci-4 haloalkoxy; and(xiv) -Ci-4 thioalkoxy.

34. The compound of any one of claims 29-33, wherein each occurrence of Rcis independently selected from halo, Ci-4 alkoxy, and Ci-4 haloalkyl.

35. The compound of any one of claims 29-34, wherein each occurrence of Rcis independently -OCFb, CF3, or F.

36. The compound of any one of claims 1-35, wherein37. The compound of any one of claims 1-28, wherein R2is heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S, and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-4 independently selected Rc.

38. The compound of any one of claims 1-28 and 37, wherein R2is heteroaryl including from 6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), and N(Rd), and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-4 independently selected Rc.

39. The compound of any one of claims 1-28 and 37-38, wherein R2is pyridinyl optionally substituted with from 1-2 independently selected Rc.

40. The compound of any one of claims 1-28 and 37-39, wherein each Rcis independently selected from:(i) halo(vi) Ci-4 haloalkyl (e.g., CF3);(vii) Ci-4 alkoxy;(viii) Ci-4 haloalkoxy; and(xiv) -Ci-4 thioalkoxy.

41. The compound of any one of claims 1-28 and 37-39, wherein each Rcis independently Ci-4 alkoxy (e.g., methoxy).

42. The compound of any one of claims 1-28 and 37-41, wherein R2is:

43. The compound of any one of claims 1-28 and 37-41, wherein R2is44. The compound of any one of claims 1-43, wherein one occurrence of R3is -L4-R445. The compound of any one of claims 1-44, wherein one occurrence of R3is H or Rc’ (e.g., Rc’ can be halo, e.g., Br or Cl; or Rc’ can be -OH or ML·).

46. The compound of any one of claims 1-45, wherein one occurrence of R3is H.

47. The compound of any one of claims 1-46, wherein one occurrence of R3is -L4- R4; and each of the remaining occurrences of R3is independently selected from the group consisting of H and Rc’ (e.g., Rc’ can be halo, e.g., Br or Cl; or Rc’ can be ML·).

48. The compound of any one of claims 1-47, wherein one occurrence of R3is -L4- R4, and each of the remaining occurrences of R3is H.

49. The compound of any one of claims 1-47, wherein one occurrence of R3is -L4- R4, and one occurrence of R3is Rc’ (e.g., Rc’ can be halo, e.g., Br or Cl (e.g., Rc’ can be Cl)).

50. The compound of any one of claims 1-49, wherein one occurrence of R3is -L4- R4, and one occurrence of R3is H.

51. The compound of any one of claims 1-43, wherein two occurrences of R3are independently selected -L4-R4.

52. The compound of any one of claims 1-43 and 51, wherein any remaining occurrence of R3is selected from the group consisting of H and Rc’.

53. The compound of any one of claims 1-43 and 51-52, wherein any remaining occurrence of R3is H.54 The compound of any one of claims 1-53, wherein L4is -N(H)S(0)I-2- or - N(Rd)S(0)i-2(e.g., N(CI-3 alkyl)S(0)2).

55. The compound of any one of claims 1-54, wherein L4is -N(H)S(0)2-.

56. The compound of any one of claims 1-53, wherein L4is -N(H)C(0)- or -N(Rd)C(0).

57. The compound of any one of claims 1-53 and 56, wherein L4is -N(H)C(0)-.

58. The compound of any one of claims 1-53, wherein L4is -C(0)NH- orC(0)N(Rd)-.

59. The compound of any one of claims 1-53, wherein L4is -N(H)-, -N(Rd)-, or - N(R4)-.

60. The compound of any one of claims 1-53, wherein L4is a single bond.

61. The compound of any one of claims 1-53, wherein L4is CºC.

62. The compound of any one of claims 1-53, wherein L4is -0-.

63. The compound of any one of claims 1-53, wherein L4is selected from the group consisting of: -N(H)S(0)i-2N(H)-, -N(Rd)S(0)i-2N(H)-, -N(H)S(0)i-2N(Rd)-, and -N (Rd) S (O) l -2N (Rd)- .

64. The compound of any one of claims 1-53 and 63, wherein L4is -N(H)S(0)i-2N(H)- (e g., -N(H)S(0)2N(H)-).

65. The compound of any one of claims 1-53 and 63, wherein L4is -N(H)S(0)i-2N(Rd)- (e.g., -N(H)S(0)2N(Rd)-, e.g., -N(H)S(0)2N(CI-3 alkyl)-).

66. The compound of any one of claims 1-65, wherein R4is -(Y3)p-Y4.

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

68. The compound of any one of claims 1-67, wherein Y3is C1-3 alkylene.

69. The compound of any one of claims 1-68, wherein Y3is CH2or CH2-CH2.

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

71. The compound of any one of claims 1-70, wherein Y4is C6-10 aryl, which is optionally substituted with from 1-4 Rc.

72. The compound of any one of claims 1-71, wherein Y4is phenyl, which is optionally substituted with from 1-2 (e.g., 1) Rc.

73. The compound of claim 71 or 72, wherein each occurrence of Rcis independently selected from the group consisting of:(i) halo;(ii) cyano;(iii) Ci-6alkyl;(iv) C2-6 alkenyl;(v) C2-6 alkynyl;(vi) Ci-4 haloalkyl;(vii) Ci-4 alkoxy;(viii) Ci-4 haloalkoxy;(ix) -(C0-3 alkylene)-C3-6cycloalkyl optionally substituted with from 1-4 independently selected C i-4 alkyl;(xiv) -Ci-4 thioalkoxy, and(xx) C3-6 cycloalkoxy.

74. The compound of claim 71 or 72, wherein each occurrence of Rcis independently selected from the group consisting of:(i) halo;(iii) Ci-6alkyl;(vi) Ci-4 haloalkyl;(vii) Ci-4 alkoxy; and(viii) Ci-4 haloalkoxy.

75. The compound of claim 71 or 72, wherein each occurrence of Rcis independently selected from the group consisting of:(vii) Ci-4 alkoxy;(viii) Ci-4 haloalkoxy; and(xiv) -Ci-4 thioalkoxy.

76. The compound of any one of claims 1-72, wherein Y4is C6-10 aryl (e.g., phenyl), which is unsubstituted.

77. The compound of any one of claims 1-70, wherein Y4is C3-6 (e.g., C3-4 or C6) cycloalkyl, which is optionally substituted with from 1-4 Rb.

78. The compound of any one of claims 1-70 and 77, wherein Y4is cyclopropyl or cyclobutyl which is optionally substituted with from 1-2 Rb.

79. The compound of any one of claims 1-70 and 77, wherein Y4is C6 cycloalkyl (e.g., cyclohexyl), which is optionally substituted with from 1-2 Rb.

80. The compound of any one of claims 1-70 and 77-79, wherein each occurrence of Rbis independently selected from the group consisting of: -F, C 1-6 alkyl, Ci-4 haloalkyl, and -OH (e.g., Rbcan be OH; and / or Rbcan be C 1-6 alkyl such as methyl).

81. The compound of any one of claims 1-70 and 77, wherein Y4is C3-6 (e.g., C3-4 or C6) cycloalkyl, which is unsubstituted.

82. The compound of claim 81, wherein Y4is unsubstituted cyclopropyl or unsubstituted cyclobutyl (e.g., unsubstituted cyclopropyl).

83. The compound of any one of claims 1-70, wherein Y4is heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selectedfrom the group consisting of N, N(H), N(Rd), O, and S, and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-4 independently selected Rc.

84. The compound of any one of claims 1-70 and 83, wherein Y4is heteroaryl including 6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), and N(Rd), and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-4 independently selected Rc.

85. The compound of any one of claims 1-70 and 83-84, wherein Y4is pyridinyl (e.g., 2-pyridinyl, 3-pyridinyl, or 4-pyridinyl), pyrimidinyl (e.g., 2-pyrimidinyl or 5- pyrimidinyl), or pyrazinyl, each of which is optionally substituted with from 1-2 independently selected Rc.

86. The compound of any one of claims 83-85, wherein each occurrence of Rcis independently selected from the group consisting of:(i) halo;(ii) cyano;(iii) Ci-6 alkyl;(iv) C2-6 alkenyl;(v) C2-6 alkynyl;(vi) Ci-4 haloalkyl;(vii) Ci-4 alkoxy;(viii) Ci-4 haloalkoxy;(ix) -(C0-3 alkylene)-C3-6 cycloalkyl optionally substituted with from 1-4 independently selected Ci-4 alkyl;(xii) OH;(xiv) -Ci-4 thioalkoxy, and(xx) C3-6 cycloalkoxy.

87. The compound of claim 86, wherein each occurrence of Rcis independently selected from the group consisting of:(i) halo (e.g., F, Cl);(iii) Ci-6alkyl (e.g., methyl); and(xii) OH.

88. The compound of any one of claims 1-70 and 83-85, wherein Y4is pyridinyl, pyrimidinyl, or pyrazinyl, each of which is unsubstituted.

89. The compound of any one of claims 1-70, wherein Y4is heterocyclyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), and O, and wherein one or more of the heterocyclyl ring carbon atoms are optionally substituted with from 1-4 independently selected Rb.

90. The compound of any one of claims 1-70 and 89, wherein Y4is heterocyclyl including from 4-6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), and O, and wherein one or more of the heterocyclyl ring carbon atoms are optionally substituted with from 1- 4 independently selected Rb.

91. The compound of any one of claims 1-70 and 89-90, wherein Y4heterocyclyl including from 4 ring atoms, wherein 1 ring atom is a heteroatom, independently selected from the group consisting of N, N(H), N(Rd), and O, and wherein one or more of the heterocyclyl ring carbon atoms are optionally substituted with from 1-2 independently selected Rb.

92. The compound of any one of claims 1-70 and 89-91, wherein Y4is oxetanyl optionally substituted with from 1-2 independently selected Rb(e.g., unsubstituted oxetanyl).

93. The compound of any one of claims 1-70 and 89-91, wherein Y4is azetidinyl optionally substituted with from 1-2 independently selected Rb(e.g., azetidinyl substituted with one Rb).

94. The compound of any one of claims 1-70 and 89-90, wherein Y4is heterocyclyl including from 6 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), and O, and wherein one or more of the heterocyclyl ring carbon atoms are optionally substituted with from 1- 4 independently selected Rb.

95. The compound of any one of claims 1-70, 89-90, and 94, wherein Y4is selected from the group consisting of tetrahydropyranyl, piperidinyl, piperazinyl, and morpholinyl, each of which is optionally substituted with from 1-2 independently selected Rb.

96. The compound of any one of claims 1-70, 89-90, and 94-95, wherein Y4is selected from the group consisting of tetrahydropyranyl, piperidinyl, and morpholinyl, each of which is optionally substituted with from 1-2 independently selected Rb.

97. The compound of any one of claims 89-96, wherein each occurrence of Rbis independently selected from the group consisting of: -F, Ci-6 alkyl, Ci-4 haloalkyl, oxo, and -OH.

98. The compound of any one of claims 89-96, wherein each occurrence of Rbis independently selected from the group consisting of: -F, Ci-6 alkyl, Ci-4 haloalkyl, and - OH (e g., Rbcan be OH).

99. The compound of any one of claims 1-69 and 71-76, wherein R4is selected from the group consisting of:

100. The compound of any one of claims 1-69 and 71-76, wherein R4is selected from the group consisting of:

102. The compound of any one of claims 1-66, 70, and 71-76, wherein R4is:

103. The compound of any one of claims 1-69 and 77-82, wherein R4is selected from the group consisting of:

104. The compound of any one of claims 1-69 and 77-82, wherein R4is selected from the group consisting of:

105. The compound of any one of claims 1-66, 70, and 77-82, wherein R4is selected from the group consisting of:

106. The compound of any one of claims 1-69 and 83-88, wherein R4is selected from the group consisting of:

107. The compound of any one of claims 1-69 and 83-88, wherein R4is selected from the group consisting of:

108. The compound of any one of claims 1-66, 70, and 83-88, wherein R4is selected from the group consisting of:

109. The compound of any one of claims 1-66, 70, and 83-88, wherein R4is selected from the group consisting of:

110. The compound of any one of claims 1-69 and 89-98, wherein R4is selected fromthe group consisting of:

111. The compound of any one of claims 1-69 and 89-98, wherein R4isH.

112. The compound of any one of claims 1-66, 70, and 89-98, wherein R4is selected from the group consisting of:

113. The compound of any one of claims 1-66, 70, and 89-98, wherein R4is selected from the group consisting of:

114. The compound of any one of claims 1-65, wherein R4is Ci-io alkyl, optionally substituted with from 1-6 independently selected Ra.

115. The compound of any one of claims 1-65 and 114, wherein R4is Ci-6alkyl, optionally substituted with from 1-6 independently selected Ra.

116. The compound of any one of claims 1-65 and 114-115, wherein R4is Ci-6alkyl, optionally substituted with from 1-2 independently selected Ra.

117. The compound of any one of claims 1-65 and 114-116, wherein each occurrence of Rais independently selected from the group consisting of: -F; -OH; Ci-4 alkoxy; and Ci-4 haloalkoxy.

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

119. The compound of any one of claims 1-65 and 114-118, wherein R4is selected from methyl, ethyl,120. The compound of any one of claims 1-65 and 114-118, wherein R4is selected from methyl121. The compound of any one of claims 1-65, wherein R4is C2-10 (e.g., C2-4) alkynyl, which is optionally substituted with from 1-6 (e.g., from 1-3) independently selected Ra(e.g., unsubstituted C2-4alkynyl such122. The compound of any one of claims 1-65, wherein R4is C2-10 (e.g., C2-4 ) alkenyl, which is optionally substituted with from 1-6 (e.g., from 1-3) independently selected Ra(e.g., unsubstituted C2-4 alkenyl such as vinyl).

123. The compound of any one of claims 1-53, wherein:-L4is selected from the group consisting of -N(H)S(0)2-, CºC, a single bond, - C(0)N(H)-, -N(H)-, -N(R4)-, -N(Rd)-, and -N(H)C(0)-; andR4is selected from the group consisting of:(i) Ci-6alkyl optionally substituted with 1-2 Ra; and(ii) -(YVY4124. The compound of any one of claims 1-53 and 123, wherein:-L4is selected from the group consisting of-N(H)S(0)2-, a single bond, -NH-, - N(R4)-, and -N(H)C(0)-; andR4is selected from the group consisting of:(i) Ci-6alkyl optionally substituted with 1-2 Ra; and(ii) -(YVY4125. The compound of any one of claims 1-53, wherein:-L4is selected from the group consisting of -N(H)S(0)2-, -N(H)S(0)2N(H)-, - N (H) S (0)2N (Rd)-, CºC, a single bond, -C(0)N(H)-, -N(H)-, -N(R4)-, -N(Rd)-, and - N(H)C(0)-; andR4is selected from the group consisting of:(i) Ci-6alkyl optionally substituted with 1-2 Ra;(ii) -(Y3)p-Y4; and(iii) C2-10 alkenyl or C2-10 alkynyl, each of which is optionally substituted with from 1-3 independently selected Ra.

126. The compound of any one of claims 1-53 and 125, wherein:-L4is selected from the group consisting of -N(H)S(0)2-, -N(H)S(0)2N(H)-, and -N (H) S (0)2N (Rd)- ; andR4is selected from the group consisting of:(i) Ci-6alkyl optionally substituted with 1-2 Ra;(ii) -(Y3)p-Y4; and(iii) C2-10 alkenyl or C2-10 alkynyl, each of which is optionally substituted with from 1-3 independently selected Ra.

127. The compound of any one of claims 123-126, wherein -L4is -N(H)S(0)2-.

128. The compound of any one of claims 125-126, wherein -L4is -N(H)S(0)2N(H)- or-N (H) S (0)2N (Rd)- .

129. The compound of any one of claims 123-125, wherein -L4is a single bond.

130. The compound of any one of claims 123-125, wherein -L4is -NH- or -N(R4)-.

131. The compound of any one of claims 123-125, wherein -L4is -N(H)C(0)-.

132. The compound of any one of claims 123-131, wherein R4is Ci-6alkyl optionally substituted with 1-2 Ra.

133. The compound of any one of claims 123-131, wherein R4is C2-10 alkenyl or C2-10 alkynyl, each of which is optionally substituted with from 1-3 independently selected Ra.

134. The compound of claim 133, wherein R4is C2-10 (e.g., C2-5) alkynyl, which is optionally substituted with from 1-3 independently selected Ra(e.g., unsubstituted C2-5 alkynyl such135. The compound of claim 123-131, wherein R4is -(Y3)p-Y4.

136. The compound of claim 135, wherein Y4is C6-10 aryl, which is optionally substituted with from 1-4 Rc.

137. The compound of claim 136, wherein Y4is phenyl, which is optionally substituted with from 1-2 (e.g., 1) Rc.

138. The compound of claim 135, wherein Y4is C3-6 (e.g., C3-4 or C6) cycloalkyl, which is optionally substituted with from 1-4 Rb.

139. The compound of claim 138, wherein Y4is C3-4 cycloalkyl or C6 cycloalkyl, each of which is optionally substituted with from 1-2 Rb(e.g., Rbcan be -OH).

140. The compound of claim 135, wherein Y4is heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), and O, and wherein one or more of theheterocyclyl ring carbon atoms are optionally substituted with from 1-2 independently selected Rb.

141. The compound of claim 140, wherein Y4is heterocyclyl including 6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), and O, and wherein one or more of the heterocyclyl ring carbon atoms are optionally substituted with from 1-2 independently selected Rb(e.g., Y4can be tetrahydropyranyl, piperidinyl, or morpholinyl, each of which is optionally substituted with from 1-2 independently selected Rb).

142. The compound of claim 140, wherein Y4is heterocyclyl including 4 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), and O, and wherein one or more of the heterocyclyl ring carbon atoms are optionally substituted with from 1-2 independently selected Rb(e.g., Y4can be oxetanyl; or Y4can be azetidinyl).

143. The compound of claim 135, wherein Y4is heteroaryl including 6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), and N(Rd), and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-4 independently selected Rc144. The compound of claim 143, wherein Y4is pyridinyl (e.g., 2-pyridinyl, 3-pyridinyl, or 4-pyridinyl), pyrimidinyl (e.g., 2-pyrimidinyl or 5-pyrimidinyl), or pyrazinyl, each of which is optionally substituted with from 1-2 independently selected Rc.

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

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

147. The compound of claim 146, wherein Y3is C1-3 alkylene (e.g., CH2, CH2-CH2).

148. The compound of any one of claims 1-43, wherein R3is selected from the group consisting of:

149. The compound of claim 148, wherein R3is selected from the group consisting of:

150. The compound of any one of claims 1-43, wherein R3is selected from the groupconsisting of:

151. The compound of any one of claims 1-43, wherein R3is selected from the group consisting of:

152. The compound of any one of claims 1-43, wherein R3is selected from the groupconsisting of:

153. The compound of any one of claims 1-43, wherein R3is selected from the group consisting of:

154. The compound of any one of claims 1-43, wherein R3is selected from the groupconsisting of:

155. The compound of any one of claims 1-43, wherein R3is selected from the group consisting of:

156. The compound of any one of claims 1-43, wherein R3is selected from the group consisting of:

157. The compound of any one of claims 1-43, wherein R3is selected from the group consisting of:

158. The compound of any one of claims 1-43, wherein R3is selected from the group consisting of:

159. The compound of any one of claims 1-43, wherein R3is selected from the group consisting of:

160. The compound of any one of claims 1-43, wherein R3is selected from the group consisting of:

161. The compound of any one of claims 1-43, wherein R3is selected from the group consisting of:

162. The compound of any one of claims 1-43, wherein R3is selected from the group consisting of:

163. The compound of any one of claims 1-43, wherein R3is selected from the groupconsisting of:

164. The compound of any one of claims 1-43, wherein R3is selected from the groupconsisting of:o oA165. The compound of claim 162 or 163, wherein one occurrence of R3is166. The compound of claim 1, wherein:R1is -(Y1)n-Y2; andR2is C6-10 aryl, which is optionally substituted with from 1-4 Rc.

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

168. The compound of any one of claims 166-167, wherein from 1-2 of X1, X2, X3, and X4are N; and from 2-3 of X1, X2, X3, and X4are each independently selected CR3.

169. The compound of claim 168, wherein:one of X1, X2, X3, and X4is N; and each of the remaining X1, X2, X3, and X4is an independently selected CR3; ortwo of X1, X2, X3, and X4are N; and each of the remaining X1, X2, X3, and X4is an independently selected CR3.

170. The compound of any one of claims 168-169, wherein from 1-2 of X2and X3are each an independently selected CR3, such as wherein both of X2and X3are each an independently selected CR3.

171. The compound of any one of claims 168-170, wherein one occurrence of R3is - L4-R4, wherein R4is -(Y3)p-Y4; or wherein R4is Ci-io alkyl optionally substituted with from 1-6 independently selected Ra.

172. The compound of claim 171, wherein R4is (Y3)p-Y4; and p is 1.

173. The compound of claim 171, wherein R4is (Y3)p-Y4; and p is 0.

174. The compound of any one of claims 171-173, wherein each of the remaining occurrences of R3is independently selected from the group consisting of H and Rc’ (e.g., each of the remaining occurrences of R3is H).

175. The compound of any one of claims 171-174, wherein one occurrence of R3is - L4-R4; and one occurrence of R3is Rc’, such as halo.

176. The compound of any one of claims 166-169, wherein one occurrence of R3is Rc’ (e.g., Br or Cl, e.g., Cl); and each of the remaining occurrences of R3is H.

177. The compound of any one of claims 166-176, wherein Y2is as defined in any one of claims 14-20 and 26-28; and each Rc, when present, is independently as defined in any one of claims 21-24.

178. The compound of any one of claims 166-176, wherein Y2is as defined in any one of claims 14-18; and each Rc, when present, is as defined in any one of claims 21-23.

179. The compound of any one of claims 166-176, wherein Y2is as defined in any one of claims 16-18; and each Rc, when present, is as defined in any one of claims 21-23.

180. The compound of any one of claims 166-176, wherein R1isor181. The compound of any one of claims 166-180, wherein R2is C6-10 aryl, which is optionally substituted with from 1-4 Rc, such as phenyl, which is optionally substituted with from 1-4 Rcor 1-2 Rcor 2 Rc; and Rc, when present, is as defined in any one of claims 33-35.

182. The compound of any one of claims 166-181, wherein R2is phenyl, which isoptionally substituted with 2 Rc, such as wherein R2is, or; and Rc, when present, is as defined in any one of claims 33-35.

183. The compound of any one of claims 166-180, wherein R2is heteroaryl including from 5-10 (such as 6) ring atoms, wherein from 1-4 (such as 1-3) ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S (such as the group consisting of N, N(H), and N(Rd)), and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-4 independently selected Rc, such as wherein R2is pyridinyl which is optionally substituted with from 1-2independently selected Rc, or such as whereinRc, when present, is as defined in any one of claims 40-41.

184. The compound of any one of claims 166-180, wherein185. The compound of any one of claims 171-184, wherein -L4is selected from the group consisting of:• -N(H)S(0)I-2- or -N(Rd)S(0)i-2 (e.g., N(CI-3 alkyl)S(0)2), such as wherein L4is -N(H)S(0)2-;• -N(H)C(0)- or -N(Rd)C(0), such as wherein L4is -N(H)C(0)-;• -C(0)NH- or -C(0)N(Rd)-;• -N(H)-, -N(Rd)-, or -N(R4)-;• a single bond;• CºC;• -0-; and• -N(H)S(0)I.2N(H)-, -N(Rd)S(0)i-2N(H)-, -N(H)S(0)i-2N(Rd)-, and - N(Rd)S(0)i-2N(Rd)-, such as wherein L4is -N(H)S(0)I-2N(H)- (e.g., - N(H)S(0)2N(H)-) or wherein L4is -N(H)S(0)i-2N(Rd)- (e.g., - N(H)S(0)2N(Rd)- (e.g., -N(H)S(0)2N(CI-3 alkyl)-)).

186. The compound of any one of claims 171-184, wherein -L4is selected from the group consisting of:• -N(H)S(0)I-2- or -N(Rd)S(0)i-2 (e.g., N(CI-3alkyl)S(0)2), such as wherein L4is -N(H)S(0)2-;• -N(H)C(0)- or -N(Rd)C(0), such as wherein L4is -N(H)C(0)-;• -C(0)NH- or -C(0)N(Rd)-;• -N(H)-, -N(Rd)-, or -N(R4)-;• a single bond; and• CºC.

187. The compound of any one of claims 171-184, wherein -L4is selected from the group consisting of:• N(H)S(0)2-;• -N(H)C(0)-; and• -N(H)-, -N(Rd)-, or -N(R4)-.

188. The compound of any one of claims 171-184, wherein -L4is selected from the group consisting of:-N(H)S(0)I-2- or -N(Rd)S(0)i-2 (e.g., N(CI-3 alkyl)S(0)2), such as wherein L4is -N(H)S(0)2-; and-N(H)S(0)I-2N(H)-, -N(Rd)S(0)i-2N(H)-, -N(H)S(0)i-2N(Rd)-, and -N(Rd)S(0)i- 2N(Rd)-, such as wherein L4is -N(H)S(0)I-2N(H)- (e.g., -N(H)S(0)2N(H)-) or wherein L4is -N(H) S (O) l -2N (Rd) - (e.g., -N(H)S(0)2N(Rd)- (e.g., -N(H)S(0)2N(CI-3 alkyl)-)).

189. The compound of any one of claims 171-188, wherein -L4is -N(H)S(0)2-.

190. The compound of any one of claims 171-189, wherein Y4is C6-10 aryl, which is optionally substituted with from 1-4 Rc, such as phenyl, which is optionally substituted with from 1-2 (e.g., 1) Rc, or wherein Y4is unsubstituted C6-10 aryl such as unsubstituted phenyl; and Rc, when present, is as defined in any one of claims 73-75.

191. The compound of any one of claims 171-189, wherein Y4is C6-10 aryl, which is optionally substituted with from 1-4 Rc, such as phenyl optionally substituted with from 1-4 Rc; and wherein each occurrence of Rc, when present, is independently selected from the group consisting of:(vii) Ci-4 alkoxy;(viii) Ci-4 haloalkoxy; and(xiv) -Ci-4 thioalkoxy.

192. The compound of any one of claims 171-189, wherein Y4is as defined in any one of claims 77, 78, 79, 81, and 82, and wherein Rb, when present, is as defined in claim 80.

193. The compound of any one of claims 171-189, wherein Y4is as defined in any one of claims 77-79; and Rb, when present, is as defined in claim 80.

194. The compound of any one of claims 171-189, wherein Y4is as defined in any one of claims 83-85 and 88; and Rc, when present, is as defined in any one of claims 86-87.

195. The compound of any one of claims 171-189, wherein Y4is as defined in any one of claims 83-85, and 88.

196. The compound of any one of claims 171-189, wherein Y4is as defined in any one of claims 89-96; and Rb, when present, is as defined in any one of claims 97-98.

197. The compound of any one of claims 171-189, wherein Y4is as defined in any one of claims 89-92, 94, and 96; and Rb, when present, is as defined in claim 98.

198. The compound of any one of claims 171-189, wherein R4is selected from the group consisting of the structures delineated in claims 99-113.

199. The compound of any one of claims 171-189, wherein R4is selected from the group consisting of the structures delineated in claims 100, 101, 104-105, 107, 109, 111, and 113.

200. The compound of any one of claims 171 and 174-189, wherein:• R4is Ci-io alkyl, optionally substituted with from 1-6 independently selected Ra; or• R4is Ci-6alkyl, optionally substituted with from 1-6 independently selected Ra; or• R4is Ci-6alkyl, optionally substituted with from 1-2 independently selected Ra, such as wherein R4is selected from the group consisting of: methyl, ethyl,R4is C2-10 alkynyl (e.g., C2-4 alkynyl), which is optionally substituted with from 1-6 (e.g., from 1-3) independently selected Ra(e.g., unsubstituted C2-4 alkynyl such• R4is C2-10 alkenyl (e.g., C2-4 alkenyl), which is optionally substituted with from 1-6 (e.g., from 1-3) independently selected Ra(e.g., unsubstituted C2-4 alkenyl such as vinyl); andwherein each Ra, when present, is independently selected from the group consisting of: -F; -OH; C 1-4 alkoxy; and C1-4 haloalkoxy, such as wherein each occurrence of Rais independently -OH.

201. The compound of any one of claims 171 and 174-189, wherein:• R4is Ci-10 alkyl, optionally substituted with from 1-6 independently selected Ra; or• R4is Ci-6alkyl, optionally substituted with from 1-6 independently selected Ra; or• R4is Ci-6alkyl, optionally substituted with from 1-2 independently selected Ra, such as methylwherein each Ra, when present, is independently selected from the group consisting of: -F; -OH; C1-4 alkoxy; and C1-4 haloalkoxy, such as -OH.

202. The compound of any one of claims 171-184, wherein:-L4is selected from the group consisting of -N(H)S(0)2-, -N(H)S(0)2N(H)-, - N (H) S (0)2N (Rd)-, CºC, a single bond, -C(0)N(H)-, -N(H)-, -N(R4)-, -N(Rd)-, and - N(H)C(0)-; andR4is selected from the group consisting of:(i) Ci-6alkyl optionally substituted with 1-2 Ra;(ii) -(Y3)p-Y4; and(iii) C2-10 alkenyl or C2-10 alkynyl, each of which is optionally substituted with from 1-3 independently selected Ra.

203. The compound of any one of claims 171-184, wherein:-L4is selected from the group consisting of -N(H)S(0)2-, -N(H)S(0)2N(H)-, and -N (H) S (0)2N (Rd)- ; andR4is selected from the group consisting of:(i) Ci-6alkyl optionally substituted with 1-2 Ra;(ii) -(Y3)p-Y4; and(iii) C2-10 alkenyl or C2-10 alkynyl, each of which is optionally substituted with from 1-3 independently selected Ra.

204. The compound of any one of claims 171-189, wherein R3is selected from the group consisting of structures delineated in claims 148-165; or wherein R3is selected from the group consisting of structures delineated in claims 148-149, 151, 153, 155-156, 158, 160, 162, and 165.

205. The compound of any one of claims 166-169, wherein each of X2and X3is an independently selected CR3; and each of X1and X4is N.

206. The compound of claim 205, wherein each R3is an independently selected -L4-R4.

207. The compound of claim 206, wherein one occurrence of -L4-R4is -R4(i.e., one occurrence of L4is a bond).

208. The compound of any one of claims 205-207, wherein the other occurrence of -L4is selected from the group consisting of:• -N(H)S(0)I-2- or -N(Rd)S(0)i-2 (e.g., N(CI-3 alkyl)S(0)2), such as wherein L4is -N(H)S(0)2-;• -N(H)C(0)- or -N(Rd)C(0), such as wherein L4is -N(H)C(0)-;• -C(0)NH- or -C(0)N(Rd)-;• -N(H)-, -N(Rd)-, or -N(R4)-;• a single bond;• CºC;• -0-; and• -N(H)S(0)I-2N(H)-, -N(Rd)S(0)i-2N(H)-, -N(H)S(0)i-2N(Rd)-, and - N(Rd)S(0)i-2N(Rd)-, such as wherein L4is -N(H)S(0)I-2N(H)- (e.g., - N(H)S(0)2N(H)-) or wherein L4is -N(H)S(0)i-2N(Rd)- (e.g., - N(H)S(0)2N(Rd)- (e.g., -N(H)S(0)2N(CI-3 alkyl)-)).

209. The compound of any one of claims 205-207, wherein the other occurrence of -L4is selected from the group consisting of:• -N(H)S(0)I-2- or -N(Rd)S(0)i-2 (e.g., N(CI-3alkyl)S(0)2), such as wherein L4is -N(H)S(0)2-;• -N(H)C(0)- or -N(Rd)C(0), such as wherein L4is -N(H)C(0)-;• -C(0)NH- or -C(0)N(Rd)-;• -N(H)-, -N(Rd)-, or -N(R4)-;• a single bond; and• CºC.

210. The compound of any one of claims 205-207, wherein the other occurrence of -L4is selected from the group consisting of:• -N(H)S(0)2-;• -N(H)C(0)-; and• -N(H)-, -N(Rd)-, or -N(R4)-, such as wherein the other occurrence of -L4isN(H)S(0)2-.

211. The compound of any one of claims 205-207, wherein the other occurrence of -L4is selected from the group consisting of:-N(H)S(0)I-2- or -N(Rd)S(0)i-2 (e.g., N(CI-3 alkyl)S(0)2), such as wherein L4is -N(H)S(0)2-; and-N(H)S(0)I-2N(H)-, -N(Rd)S(0)i-2N(H)-, -N(H)S(0)i-2N(Rd)-, and -N(Rd)S(0)i- 2N(Rd)-, such as wherein L4is -N(H)S(0)I-2N(H)- (e.g., -N(H)S(0)2N(H)-) or wherein L4is -N(H) S (O) l -2N (Rd) - (e.g., -N(H)S(0)2N(Rd)- (e.g., -N(H)S(0)2N(CI-3 alkyl)-)).

212. The compound of claim 205, wherein one occurrence of R3is -L4-R4(e.g., L4is N(H)S(0)2-); and the other occurrence of R3is Rc’ (e.g., halo, e.g., -Cl).

213. The compound of any one of claims 1-4, wherein the compound is of Formula (I- al-a):al-a) ; or a pharmaceutically acceptable salt thereof.

214. The compound of claim 213, wherein the compound is of Formula (I-al-al), (I- al-a2), or (I-al-a3):-al-a3); or apharmaceutically acceptable salt thereof.

215. The compound of claim 213, wherein the compound of Formula (I-al-a) is ofFormula (I-al-a5):al-a5); or a pharmaceutically acceptable salt thereof.

216. The compound of claim 215, wherein Rc’ is halo (e.g., -Cl).

217. The compound of any one of claims 215-216, wherein L4is -NHS(0)2-218. The compound of any one of claims 215-216, wherein L4is -N(H)S(0)2N(H)- or -N (H) S (0)2N (Rd)- .

219. The compound of claim 213, wherein the compound of Formula (I-al-a) is of Formula (I-al-a6):-al-a6);wherein each of L4Aand L4Bis an independently selected L4; andeach of R4Aand R4Bis an independently selected R4; or a pharmaceutically acceptable salt thereof.

220. The compound of claim 219, wherein L4Bis a bond.

221. The compound of any one of claims 219-220, wherein L4Ais -NHS(0)2-222. The compound of any one of claims 219-220, wherein L4Ais -N(H)S(0)2N(H)- or -N (H) S (0)2N (Rd)- .

223. The compound of claim 213, wherein the compound is of Formula (I-al-a7), (I- al-a8), or (I-al-a9):R1(I-al-a7), R1(I-al-a8), or R1(I-al-a9);wherein Rd’ is H or Rd(e.g., H or C1-3 alkyl); or a pharmaceutically acceptable salt thereof.

224. The compound of any one of claims 1-4, wherein the compound is of Formula (I- al-b):al-b); or a pharmaceutically acceptable salt thereof.

225. The compound of claim 224, wherein the compound is of Formula (I-al-bl) orFormula (I-al-b2):al-b2) (e g., L4is N(H)S02, -N(H)-, orNHC(O)); or a pharmaceutically acceptable salt thereof.

226. The compound of any one of claims 1-3 and 5, wherein the compound is of Formula (I-a2-a):pharmaceutically acceptable salt thereof.

227. The compound of claim 226, wherein the compound is of Formula (I-a2-al):al); or a pharmaceutically acceptable salt thereof.

228. The compound of any one of claims 1 and 6-7, wherein the compound is of Formula (I-bl-a):bl-a) ; or a pharmaceutically acceptable salt thereof.

229. The compound of claim 228, wherein the compound is of Formula (I-bl-al):-bl-al); or a pharmaceutically acceptable salt thereof.

230. The compound of claim 228, wherein the compound is of Formula (I-bl-a3):-bl-a3);wherein Rd’ is H or Rd(e.g., H or C1-3 alkyl); or a pharmaceutically acceptable salt thereof.

231. The compound of any one of claims 1 and 8-9, wherein the compound is of Formula (I-cl-a):cl-a) ; or a pharmaceutically acceptable salt thereof.

232. The compound of claim 231, wherein the compound is of Formula (I-cl-al):-cl-al); or a pharmaceutically acceptable salt thereof.

233. The compound of any one of claims 1 and 8-9, wherein the compound is of Formula (I-dl-a):dl-a) ; or a pharmaceutically acceptable salt thereof.

234. The compound of claim 233, wherein the compound is of Formula (I-dl-al):-dl-al); or a pharmaceutically acceptable salt thereof.

235. The compound of any one of claims 213-234, wherein R4is selected from the group consisting of:(i) Ci-io alkyl, optionally substituted with from 1-6 independently selected Ra;(ii) -(Y3)p-Y4; and(iii) C2-10 alkenyl or C2-10 alkynyl, each of which is optionally substituted with from 1-3 independently selected Ra.

236. The compound of any one of claims 213-235, wherein R4is -(Y3)p-Y4.

237. The compound of any one of claims 205-236, wherein Y4is C6-10 aryl, which is optionally substituted with from 1-4 Rc, such as phenyl, which is optionally substituted with from 1-2 (e.g., 1) Rc, or wherein Y4is unsubstituted C6-10 aryl such as unsubstituted phenyl; and Rc, when present, is as defined in any one of claims 73-75.

238. The compound of any one of claims 205-236, wherein Y4is C6-10 aryl, which is optionally substituted with from 1-4 Rc, such as phenyl optionally substituted with from 1-4 Rc; and wherein each occurrence of Rc, when present, is independently selected from the group consisting of:(vii) Ci-4 alkoxy;(viii) Ci-4 haloalkoxy; and(xiv) -Ci-4 thioalkoxy.

239. The compound of any one of claims 205-236, wherein Y4is as defined in any one of claims 77, 78, 79, 81, and 82, and wherein Rb, when present, is as defined in claim 80.

240. The compound of any one of claims 205-236, wherein Y4is as defined in any one of claims 77-79; and Rb, when present, is as defined in claim 80.

241. The compound of any one of claims 205-236, wherein Y4is as defined in any one of claims 83-85 and 88; and Rc, when present, is as defined in any one of claims 86-87.

242. The compound of any one of claims 205-236, wherein Y4is as defined in any one of claims 83-85, and 88.

243. The compound of any one of claims 205-236, wherein Y4is as defined in any one of claims 89-96; and Rb, when present, is as defined in any one of claims 97-98.

244. The compound of any one of claims 205-236, wherein wherein Y4is as defined in any one of claims 89-92, 94, and 96; and Rb, when present, is as defined in claim 98.

245. The compound of any one of claims 235-244, wherein p is 0.

246. The compound of any one of claims 235-244, wherein p is 1.

247. The compound of claim 244, wherein Y3is C 1-3 alkylene, such as CH2 or CH2-CH2.

248. The compound of any one of claims 205-236, wherein R4is selected from the group consisting of the structures delineated in claims 99-113.

249. The compound of any one of claims 205-236, wherein each R4is selected from the group consisting of the structures delineated in claims 100, 101, 104-105, 107, 109, 111, and 113.

250. The compound of any one of claims 205-235, wherein:• R4is Ci-io alkyl, optionally substituted with from 1-6 independently selected Ra; or• R4is Ci-6alkyl, optionally substituted with from 1-6 independently selected Ra; or• R4is Ci-6alkyl, optionally substituted with from 1-2 independently selected Ra, such as wherein R4is selected from the group consisting of: methyl, ethyl,R4is C2-10 (e.g., C2-4 alkynyl) alkynyl, which is optionally substituted with from 1- 6 (e.g., from 1-3) independently selected Ra(e.g., unsubstituted C2-4 alkynyl suchR4is C2-10 (e.g., C2-4 alkenyl) alkenyl, which is optionally substituted with from 1- 6 (e.g., from 1-3) independently selected Ra(e.g., unsubstituted C2-4 alkenyl such as vinyl); andwherein each Ra, when present, is independently selected from the group consisting of: -F; -OH; Ci-4 alkoxy; and Ci-4 haloalkoxy, such as wherein each occurrence of Rais independently -OH.

251. The compound of any one of claims 205-235, wherein:• R4is Ci-io alkyl, optionally substituted with from 1-6 independently selected Ra; or• R4is Ci-6 alkyl, optionally substituted with from 1-6 independently selected Ra; or• R4is Ci-6 alkyl, optionally substituted with from 1-2 independently selected Ra, such as methylwherein each Ra, when present, is independently selected from the group consisting of: -F; -OH; Ci-4 alkoxy; and Ci-4 haloalkoxy, such as -OH.

252. The compound of any one of claims 205-251, wherein R1is -(Y1)n-Y2.

253. The compound of any one of claims 205-252, wherein Y2is as defined in any one of claims 14-20; and each Rc, when present, is independently as defined in any one of claims 21-24.

254. The compound of any one of claims 205-253, wherein Y2is as defined in any one of claims 14-18 and 26; and each Rc, when present, is as defined in any one of claims 21-23255. The compound of any one of claims 205-252, Y2is as defined in any one of claims 16-18; and each Rc, when present, is as defined in any one of claims 21-23.

256. The compound of any one of claims 205-252, wherein R1is as257. The compound of any one of claims 250-256, wherein n is 0.

258. The compound of any one of claims 205-257, wherein R2is C6-10 aryl, which is optionally substituted with from 1-4 Rc, such as phenyl, which is optionally substituted with from 1-4 Rcor 1-2 Rcor 2 Rc; and Rc, when present, is as defined in any one of claims 33-35.

259. The compound of any one of claims 205-257, wherein R2is phenyl, which isoptionally substituted with 2 Rc, such as wherein R2isor; and Rc, when present, is as defined in any one of claims 33-35.

260. The compound of any one of claims 205-257, wherein R2is heteroaryl including from 5-10 (such as 6) ring atoms, wherein from 1-4 (such as 1-3) ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(Rd), O, and S (such as the group consisting of N, N(H), N(Rd), and O), and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-4 independentlyselected Rc, such as wherein R2is pyridinyl which is optionally substituted with from 1-2independently selected Rc, or such as whereinRc, when present, is as defined in any one of claims 40-41.

261. The compound of any one of claims 205-257, wherein262. The compound of any one of claims 213-251, wherein:R1is -(Y1)n-Y2; andR2is C6-10 aryl, which is optionally substituted with from 1-4 Rc.

263. The compound of claim 262, wherein n is 0.

264. The compound of any one of claims 262-263, wherein Y2is heteroaryl including 6 ring atoms, wherein from 1-2 ring atoms are N, and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with from 1-4 independently selected Rc.

265. The compound of any one of claims 262-264, wherein Y2is pyridyl (e.g., 2-pyridyl or 6-pyridyl), wherein one or more of the ring carbon atoms are optionally substituted with from 1-4 (e.g., 1) independently selected Rc.

266. The compound of any one of claims 262-265, wherein each occurrence of Rcis an independently selected Ci-4alkoxy (e.g., -OCH3, -OCH2CH3).

267. The compound of any one of claims 262-266, wherein R1is:

268. The compound of any one of claims 262-267, wherein R2is phenyl, which is optionally substituted with from 1-4 Rc.

269. The compound of any one of claims 262-268, wherein R2is phenyl, which is optionally substituted with 2 Rc.

270. The compound of claim 269, wherein R2is271. The compound of any one of claims 205-251, wherein R1is272. The compound of any one of claims 213, 235-251, and 271, wherein the compound is of Formula (I-al-a4):-al-a4).

273. The compound of claim 272, wherein R3is H.

274. The compound of claim 272, wherein R3is Rc’, such as halo (such as Cl).

275. The compound of any one of claims 228, 235-251, and 271, wherein the compound is of Formula (I-bl-a2):-bl-a2).

276. The compound of any one of claims 272-275, wherein L4is NHS(0)2.

277. The compound of claim 1, wherein the compound is selected from the group consisting of those in the table below:and a pharmaceutically acceptable salt thereof.

278. A pharmaceutical composition comprising a compound or salt as claimed in any one of claims 1-277 and one or more pharmaceutically acceptable excipients.

279. A method for modulating APJ receptor activity, the method comprising contacting the APJ receptor with a compound as claimed in any one of claims 1-277.

280. The method of claim 279, wherein the modulating comprises agonizing the APJ receptor.

281. The method of claim 279 or 280, which is carried out in vitro.

282. The method of claim 279 or 280, which is carried out in vivo.

283. A method for modulating (e.g., decreasing) pulmonary vascular resistance in a subject in need of such modulating, the method comprising administering to the subject an effective amount of a compound as claimed in any one of claims 1-277.

284. A method for modulating (e.g., decreasing) right ventricular afterload in a subject in need of such modulating, the method comprising administering to the subject an effective amount of a compound as claimed in any one of claims 1-277.

285. A method for modulating (e.g., decreasing) mean pulmonary artery pressure in a subject in need of such modulating, the method comprising administering to the subject an effective amount of a compound as claimed in any one of claims 1-277.

286. The method of claim 285, wherein the subject exhibits a mean pulmonary artery pressure of greater than 25 mmHg.

287. A method for reducing the risk of right ventricular failure in a subject in need of such reducing, the method comprising administering to the subject an effective amount of a compound as claimed in any one of claims 1-277.

288. A method for treating a disease, disorder, or condition, in which repressed or impaired 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 comprising administering to the subject in need thereof an effective amount of a compound as claimed in any one of claims 1-277.

289. The method of claim 288, wherein the disease, disorder, or condition is pulmonary arterial hypertension (“PAH”).

290. The method of claim 289, wherein the PAH is idiopathic.

291. The method of claim 289, wherein the PAH is heritable PAH, toxin or drug- induced PAH; or a 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 the antiphospholipid antibody syndrome), portal hypertension, BMPR2 mutations, Schistosomiasis, and HIV infection.

292. The method of claim 288, wherein the disease, disorder, or condition is fibrosis.

293. The method of claim 292, wherein the fibrosis is associated with an organ or tissue selected from the group consisting of: lung, liver, heart, mediastinum, bone marrow, retroperitoneaum, skin, intestine, joint, a reproductive organ, and a combination thereof.

294. The method of claim 288 and 292, wherein the the disease, disorder, or condition is idiopathic pulmonary fibrosis (IPF).

295. The method of claim 288, wherein the disease, disorder, or condition is a connective tissue disorder.

296. The method of claim 295, wherein the connective tissue disorder is selected from the group consisting of: scleroderma, systemic lupus erythematosus, systemic sclerosis, Hashimoto's thyroiditis, Sjogren's Syndrome, and the antiphospholipid antibody syndrome.

297. The method of any one of claims 288 and 295-296, wherein the disease, disorder, or condition is systemic sclerosis.

298. The method of any one of claims 279-297 , wherein the method further comprises identifying the subject.

299. The method of claim 298, wherein identifying comprises determining the level of one or more of the following parameters in the subject: leukotriene B4 level, pulmonary vascular resistance, pulmonary arterial pressure, cardiac index, pulmonary capillary wedge pressure, right atrial pressure, six-minute walk distance, brain natriuretic peptide level, atrial natriuretic peptide level, and diffusion of lung capacity.

300. The method of any one of claims 279-299, wherein the subject is a human.

301. The method of any one of claims 279-300, which further comprises administering one or more additional therapeutic agents.

302. The method of any one of claims 279-301, which further comprises treating one or more diseases, disorders, or conditions that are sequela or comorbid with the PAH.