Compounds and compositions for treating diseases associated with APJ receptor activity

Abstract

The present disclosure features modulating (e.g., agonizing) an apelin receptor (also referred to herein as an APJ receptor; in particular, the present invention relates to chemical entities (e.g., compounds or pharmaceutically acceptable salts and / or hydrates of compounds and / or prodrugs of compounds) that have a molecular marker APLNR (e.g., a gene symbol APLNR). The disclosure also features compositions comprising the chemical entities, as well as other methods of use and preparation. The chemical entities are useful, for example, in the treatment of a subject (e.g., a human) having a disease, disorder or condition in which APJ receptor activity is reduced (e.g., APJ receptor signaling is hindered or impaired; e.g., apelin-APJ receptor signaling is hindered or impaired) or down-regulation of endogenous apelin contributes to the pathology and / or symptom and / or progression of the disease, disorder or condition. Non-limiting examples of these diseases, disorders or conditions include: (i) cardiovascular disease; (ii) a metabolic disorder; (iii) diseases, conditions and conditions associated with vasopathology; (iv) organ failure; (v) diseases, disorders, and conditions associated with infection (e.g., microbial infection); (vi) a disease, disorder or condition of a sequelae or complication of any of the foregoing or disclosed herein. More specific non-limiting examples of these diseases, disorders or conditions include pulmonary arterial hypertension (e.g., PAH); heart failure; type II diabetes; renal failure; , sepsis and systemic hypertension.

Description

[0001] Cross - reference to related applications

[0002] This application claims priority to U.S. Provisional Application No. 62 / 742,218, filed on October 5, 2018, the entire content of which is incorporated herein by reference. Technical field

[0003] The present disclosure features chemical entities (e.g., compounds or pharmaceutically acceptable salts and / or hydrates and / or prodrugs of the compounds) that modulate (e.g., agonize) the apelin receptor (also referred to herein as the APJ receptor; gene symbol APLNR). The present disclosure also features compositions containing such chemical entities and other methods of use and preparation. The chemical entity can be used, for example, to treat a subject (e.g., a human) having a disease, disorder, or condition in which APJ receptor activity is reduced (e.g., APJ receptor signaling is blocked or impaired; e.g., apelin - APJ receptor signaling is blocked or impaired) or down - regulation 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 diseases; (ii) metabolic disorders; (iii) diseases, disorders, and conditions related to vascular pathologies; (iv) organ failure; (v) diseases, disorders, and conditions associated with infections (e.g., microbial infections); (vi) diseases, disorders, or conditions that are sequelae or comorbidities of any of the foregoing or as disclosed herein. More specific non - limiting examples of such diseases, disorders, or conditions include pulmonary arterial hypertension (e.g., PAH); heart failure; type II diabetes; renal failure; sepsis; and systemic hypertension. Background art

[0004] Pulmonary arterial hypertension (PAH) is a severe cardio - pulmonary disease characterized by vascular remodeling of the small pulmonary arteries, including the formation of plexiform and concentric lesions composed of proliferative vascular cells. It is thought that PAH is caused by cell proliferation and fibrosis of the small pulmonary arteries. Clinically, PAH leads to elevated pulmonary arterial pressure and subsequent right ventricular failure, which is one of the major causes of morbidity and mortality. Mortality remains high at 1 year, 2 years, and 3 years after diagnosis, with mortality rates of 15%, 30%, and 45% respectively. See, e.g., Kim, J., Mol. Cells 2014; 37(3):196 - 201 and Lau, E.M.T., Nature Reviews, 2017, 1 - 12.

[0005] Type 2 diabetes (type 2 diabetes) is characterized by hyperglycemia and insulin resistance. Type 2 diabetes, as well as its comorbidities or sequelae, affects tens of millions of people in the United States alone. Type 2 diabetes is commonly associated with obesity.

[0006] Apelin or the APJ receptor is a G protein-coupled receptor that contains seven hydrophobic transmembrane domains (see, e.g., Kim, supra). Apelin (also known as APLN) is a 36-amino acid peptide encoded by the APLN gene in humans and is the endogenous ligand of the APJ receptor (see, e.g., O’Carroll, A-M. et al., J Endocrinol 2013, 219, R13-R35).

[0007] The apelin / APJ system is present in many tissues such as the heart, kidney, pancreas, lung, vasculature, central nervous system, liver, adipose, gastrointestinal tract, brain, adrenal glands, endothelium, and human plasma.

[0008] In addition, there is evidence that both apelin and APJ are regulators of central and peripheral responses to a variety of homeostatic disturbances such as cardiovascular control and function; angiogenesis; fluid homeostasis; water balance; hypothalamic-pituitary-adrenal (HPA) axis regulation; metabolic homeostasis; energy metabolism, and renal function. For example, emerging evidence suggests that APJ-apelin signaling plays a role in maintaining pulmonary vascular homeostasis (see, e.g., Kim, supra). Evidence also suggests a link between the apelinergic system (e.g., apelin and the 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 associated with obesity, and there is additional evidence suggesting a potential role for apelin and the APJ receptor in glucose and energy metabolism (see, e.g., O'Carroll, supra). SUMMARY OF THE INVENTION

[0009] The present disclosure features chemical entities (e.g., compounds or pharmaceutically acceptable salts and / or hydrates and / or prodrugs of the compounds) that modulate (e.g., agonize) the apelin receptor (also referred to herein as the APJ receptor; gene symbol APLNR). The present disclosure also features compositions comprising such chemical entities and other methods of use and preparation. The chemical entity can be used, for example, to treat a subject (e.g., a human) having a disease, disorder, or condition in which APJ receptor activity is reduced (e.g., APJ receptor signaling is blocked or impaired; e.g., apelin-APJ receptor signaling is blocked or impaired) 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 diseases; (ii) metabolic disorders; (iii) diseases, disorders, and conditions associated with vascular pathologies; (iv) organ failure; (v) diseases, disorders, and conditions associated with infection (e.g., microbial infection); (vi) diseases, disorders, or conditions that are sequelae or comorbidities of any of the foregoing or as disclosed herein. More specific non-limiting examples of such diseases, disorders, or conditions include pulmonary arterial hypertension (e.g., PAH); heart failure; type II diabetes; renal failure; sepsis and systemic hypertension; idiopathic pulmonary fibrosis (IPF); and systemic sclerosis.

[0010] An “agonist” of the APJ receptor includes a compound that directly binds to or modifies the APJ receptor at the protein level, thereby increasing the activity of the APJ receptor, for example, by activation, stabilization, altering distribution, or otherwise.

[0011] Compared to a full agonist of the APJ receptor, certain chemical entities that agonize the APJ receptor described herein have a lesser degree of agonism and can act as antagonists and agonists. These chemical entities antagonize the activation of the APJ receptor by a full agonist of the APJ receptor because they prevent the full effect of APJ receptor interaction. However, these chemical entities can also activate some APJ receptor activity on their own, typically to a lesser extent than a corresponding amount of a full agonist of the APJ receptor. Such chemical entities are sometimes referred to herein as “partial agonists of the APJ receptor”.

[0012] In some embodiments, the chemical entity described herein is an agonist (e.g., a full agonist) of the APJ receptor. In other embodiments, the chemical entity described herein is a partial agonist of the APJ receptor.

[0013] In other embodiments, the chemical entities described herein modulate (e.g., agonize) the APJ receptor in a pathway-specific manner. Accordingly, the invention also features chemical entities that exhibit activity as ligand-biased modulators (e.g., ligand-biased agonists). The activity of the APJ receptor can modulate (e.g., alter or bias) the competing levels of downstream G protein signaling (activation) and β-arrestin recruitment. APJ receptor signaling through β-arrestin has been shown to mediate stretch-induced cardiac 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, such as attenuate, disrupt, inhibit) β-arrestin signaling. In certain embodiments, the chemical entities described herein modulate (e.g., reduce, such as attenuate, disrupt, inhibit) the recruitment of β-arrestin.

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

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

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

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

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

[0019] Generally, receptors exist in active (Ra) and inactive (Ri) conformations. Certain compounds that affect the receptor can alter the ratio of Ra to Ri (Ra / Ri). For example, full agonists increase the Ra / Ri ratio and can cause "maximal" saturation. When bound to the receptor, partial agonists produce a response lower than that caused by a full agonist (e.g., an endogenous agonist). Thus, the Ra / Ri of a partial agonist is less than that of a full agonist. However, the potency of a partial agonist can be greater than or less than that of a full agonist.

[0020] In one aspect, the chemical entities of the invention include compounds of formula I or pharmaceutically acceptable salts thereof:

[0021]

[0022] wherein R 1 and R 2 and A 1 and X 1 and X 2 and X 3 and X 4 may be defined anywhere herein.

[0023] In one aspect, the present invention provides a pharmaceutical composition comprising a chemical entity as described herein (e.g., a compound as generally or specifically described herein or a pharmaceutically acceptable salt thereof or a composition comprising the compound) and one or more pharmaceutically acceptable excipients.

[0024] In one aspect, a method of modulating (e.g., agonizing, partially agonizing) APJ receptor activity is provided, which comprises contacting an APJ receptor with a chemical entity as described herein (e.g., a compound as generally or specifically described herein or a pharmaceutically acceptable salt thereof or a composition comprising the compound). The method includes in vitro methods, e.g., contacting a sample comprising one or more cells, each cell independently comprising one or more APJ receptors, with the chemical entity. The method may also include in vivo methods. These methods may include, for example, administering the chemical entity to a subject (e.g., a human) suffering from a disease, disorder or condition, wherein APJ receptor activity is reduced (e.g., APJ receptor signal transduction is blocked or impaired; e.g., apelin-APJ receptor signal transduction is blocked or impaired) 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., reducing) right ventricular afterload; modulating (e.g., reducing) mean pulmonary artery pressure; modulating (e.g., increasing) insulin levels; and modulating (e.g., reducing) glucose levels in a subject (e.g., a human).

[0025] In another aspect, a method of treating a disease, disorder or condition is provided, which is characterized in that reduction of APJ receptor activity (e.g., APJ receptor signal transduction is blocked or impaired; e.g., apelin-APJ receptor signal transduction is blocked or impaired) or downregulation of endogenous apelin contributes to the pathology and / or symptoms and / or progression of the disease, disorder or condition. The method comprises administering to a subject in need of such treatment an effective amount of a chemical entity as described herein (e.g., a compound as generally or specifically described herein, a pharmaceutically acceptable salt thereof or a composition comprising the same).

[0026] In another aspect, the present disclosure features methods of treating a subject having a disease, disorder, or condition, wherein reduced APJ receptor activity (e.g., blocked or impaired APJ receptor signaling; e.g., apelin-APJ receptor signaling is blocked or impaired) 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 generally or specifically herein, a pharmaceutically acceptable salt thereof, or a composition comprising the same) in an amount effective to treat the disease, disorder, or condition.

[0027] In another aspect, the features are methods of treatment that include administering a chemical entity described herein (e.g., a compound described generally or specifically herein, a pharmaceutically acceptable salt thereof, or a composition comprising the same). The methods include administering the chemical entity in an amount effective to treat a disease, disorder, or condition, wherein reduced APJ receptor activity (e.g., blocked or impaired APJ receptor signaling; e.g., apelin-APJ receptor signaling is blocked or impaired) 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.

[0028] Non-limiting examples of such diseases, disorders, and conditions are PAH. In some embodiments, the PAH is idiopathic. In other embodiments, the PAH is hereditary PAH, toxin- or drug-induced PAH; or PAH associated with one or more of the following: congenital heart disease, connective tissue disease (e.g., scleroderma, systemic lupus erythematosus, systemic sclerosis, Hashimoto's thyroiditis, Sjogren's syndrome, and antiphospholipid antibody syndrome), portal hypertension, BMPR2 mutation, schistosomiasis, and HIV infection.

[0029] Another non-limiting example of such diseases, disorders, and conditions is cardiovascular disease, such as 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 post-myocardial infarction), right ventricular dysfunction, right ventricular failure, cardiac hypertrophy, myocardial remodeling (including post-infarct or post-cardiac surgery myocardial remodeling), and valvular heart disease.

[0030] Another non-limiting example of such diseases, disorders, and conditions is metabolic disorders, such as metabolic syndrome; diabetes (e.g., type 2 diabetes); obesity; obesity-related diseases; impaired glucose tolerance; and insulin resistance.

[0031] Other non-limiting examples of these diseases, disorders, and conditions include sepsis, septic shock, renal failure, systemic hypertension, idiopathic pulmonary fibrosis (IPF), and systemic sclerosis.

[0032] Other non-limiting examples include coronary artery disease (CAD), non-CAD atherosclerotic diseases, including peripheral vascular disease (PVD), aortic atherosclerosis, and cerebral atherosclerosis, diabetic retinopathy, ischemia-reperfusion injury, emphysema, radiation-induced organ and tissue damage, luteal regression, scleroderma, systemic sclerosis, and immune dysregulation diseases.

[0033] In one aspect, the present disclosure features methods for identifying and / or selecting subjects (e.g., humans) who may benefit from the methods described herein, and methods for determining whether a subject (e.g., a human) responds to the methods. In certain embodiments, a biological sample is obtained from the subject, which can be, for example but not limited to, a breath, sputum, tissue, plasma or serum sample, urine, the level of a specific parameter in the sample is determined, and compared to a control value. In some cases, the control value can be determined from one or more normal individuals who do not have the disease, disorder, or condition being treated. In other cases, the control value can also be determined from a sample previously obtained from the subject. Generally, a higher (or elevated) measured parameter level, relative to the control value determined from normal, non-diseased individuals or populations, indicates that the subject will benefit from the methods described herein. A lower level generally indicates that the patient responds to the treatment, or that the treatment method may not be beneficial to the subject who has not received the treatment.

[0034] In certain of the foregoing embodiments, the subject has PAH or is at risk of developing PAH. Non-limiting exemplary parameters related to PAH are described below.

[0035] In certain embodiments, the parameter is the LTB4 level. For example, the baseline or reference value of LTB4 can be 100 pg / mL or higher, 200 pg / mL or higher, 300 pg / mL or higher, 400 pg / mL or higher, 500 pg / mL or higher, 600 pg / mL or higher, or 100 pg / mL or higher. In certain embodiments, if the endpoint LTB4 level of the subject decreases from the baseline or reference LTB4 level after the start of treatment, the provided treatment is effective. For example, the endpoint LTB4 level of the subject decreases to 600 pg / mL or lower, 500 pg / mL or lower, 400 pg / mL or lower, 300 pg / mL or lower, 200 pg / mL or lower, or 100 pg / mL or lower. In certain embodiments, if the endpoint LTB4 level is 30 pg / mg tissue or lower, 20 pg / mg tissue or lower, 10 pg / mg tissue or lower, 7.5 pg / mg tissue or lower, or 5 pg / mg tissue or lower after the start of treatment, the provided treatment is effective. In other embodiments, if the endpoint LTB4 level is 2-fold or more, 3-fold or more, 4-fold or more, or 5-fold or more lower than the baseline LTB4 level after the start of treatment, the provided treatment is effective.

[0036] In certain embodiments, the parameter is pulmonary vascular resistance (PVR). The baseline or reference PVR level can be 200 dynsec / cm 5 or higher, 240 dynsec / cm 5 or higher, 300 dynsec / cm 5 or higher, 400 dynsec / cm 5 or higher, 500 dynsec / cm 5 or higher, 600 dynsec / cm 5 or higher, 700 dynsec / cm 5 or higher, or 800 dynsec / cm 5 or higher. In certain embodiments, if the endpoint PVR level of the subject decreases by 70 dynsec / cm 5 or more, 100 dynsec / cm 5 or more, 130 dynsec / cm 5 or more, or 160 dynsec / cm 5 or more from the baseline or reference PVR level after the start of treatment, the provided treatment is effective.

[0037] In certain embodiments, the parameter is pulmonary artery pressure (PAP). The baseline or reference PAP level can be 20 mmHg or higher, 25 mmHg or higher, 30 mmHg or higher, 35 mmHg or higher, 40 mmHg or higher, 45 mmHg or higher, 50 mmHg or higher, 60 mmHg or higher, or 70 mmHg or higher. In certain embodiments, if the endpoint PAP level in the subject after the start of treatment is reduced by 0.5 mmHg or more, 1 mmHg or more, 1.5 mmHg or more, 5 mmHg or more, 10 mmHg or more, 20 mmHg or more, 30 mmHg or more, 40 mmHg or more, or 50 mmHg from the baseline or reference PAP level, the treatment provided is effective. In certain embodiments, the subject exhibits a mean pulmonary artery pressure greater than 25 mmHg.

[0038] In certain embodiments, the parameter is cardiac index (CI). The baseline or reference CI level can be 5 L / min / m 2 or lower, 2.5 L / min / m 2 or lower, 2 L / min / m 2 or lower, 1.5 L / min / m 2 or lower, or 1 L / min / m 2 or lower. In certain embodiments, if the endpoint CI level after the start of treatment is increased 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 compared to the baseline or reference CI level, the treatment provided is effective.

[0039] In certain embodiments, the parameter is pulmonary capillary wedge pressure (PCWP). The baseline or reference PCWP level can be 36 mmHg or lower, 24 mmHg or lower, 18 mmHg or lower, 10 mmHg, or 5 mmHg or lower. In certain embodiments, if the endpoint PCWP level after the start of treatment is increased by 0.2 mmHg or higher, 0.3 mmHg or higher, 0.4 mmHg or higher, 0.5 mmHg or higher, 0.6 mmHg or greater, 1 mmHg or greater, or 5 mmHg or greater from the baseline or reference PCWP level, the treatment provided is effective.

[0040] In certain embodiments, the parameter is right atrial pressure (RAP). The baseline or reference RAP level can be 4 mmHg or higher, 6 mmHg or higher, 8 mmHg or higher, 10 mmHg or higher, 12 mmHg or higher, 16 mmHg or higher, 20 mmHg or higher, or 25 mmHg or higher. In certain embodiments, if the endpoint RAP level of the subject decreases by 5 mmHg or more, 2.5 mmHg or more, 1 mmHg or more, 0.5 mmHg or more, or 0.2 mmHg or more from the baseline or reference RAP level after the start of treatment, the treatment provided is effective.

[0041] In certain embodiments, the parameter is six-minute walk distance (6MWD). The baseline or reference 6MWD can be 50 m or less, 100 m or less, 200 m or less, 300 m or less, 400 m or less, or 500 m or less. In certain embodiments, if the endpoint 6MWD of the subject increases by 10 m or more, 15 m or more, 20 m or more, 25 m or more, 30 m or more, or 50 m or more from the baseline or reference 6MWD after the start of treatment, the treatment provided is effective. Alternatively or additionally, if after the start of treatment, the endpoint 6MWD of the subject increases by 3% or more, 4% or more, 5% or more, 10% or more, or 20% or more relative to the baseline level, the treatment provided by the present invention is effective.

[0042] In certain embodiments, the parameter is the brain natriuretic peptide (BNP) level. The 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, if the endpoint BNP level of the subject decreases from the baseline or reference BNP level after the start of treatment, the treatment provided is effective. 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.

[0043] In certain embodiments, the parameter is the atrial natriuretic peptide (ANP) level. The 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, if the endpoint ANP level of the subject decreases from the baseline or reference ANP level after the start of treatment, the treatment provided is effective. 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.

[0044] In certain embodiments, the parameter is the diffusing capacity of the lung for carbon monoxide (DLCO) or the diffusing capacity of the CO, which can also be used as a parameter for determining efficacy in the method. The baseline or reference DLCO can be 90% or less, 80% or less, 70% or less, 50% or less, 45% or less, or 40% or less. In certain embodiments, if the endpoint DLCO increases from the baseline level after the start of treatment, the treatment provided is effective. For example, the endpoint DLCO can increase by 1% or more, 5% or more, 10% or more, 15% or more, 20% or more, or 50% or more relative to the baseline or reference DLCO.

[0045] In another aspect, the present disclosure features a method for reducing the risk of right ventricular failure in a subject in need thereof, the method comprising administering to the subject an effective amount of a chemical entity described herein.

[0046] The methods described herein can further comprise treating one or more conditions associated with, complicating, or resulting from any one or more of the conditions described herein.

[0047] For example, the method can further comprise treating one or more conditions associated with, complicating, or resulting from PAH, such as coronary heart disease or heart failure. In certain embodiments, the cardiovascular disease is heart failure; for example, 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 heart failure, cardiac hypertrophy, myocardial remodeling, including post-infarct or post-cardiac surgery myocardial remodeling, and valvular heart disease.

[0048] As another example, the method may further comprise treating one or more diseases associated with or subsequent to diabetes (e.g., type 2 diabetes), such as obesity, diseases associated with obesity, metabolic syndrome, impaired glucose tolerance; insulin resistance; cardiovascular risk factors. (e.g., coronary artery disease, peripheral artery disease, cerebrovascular disease, hypertension, risk factors associated with uncontrolled cholesterol and / or lipid levels, and / or inflammation), retinopathy, nephropathy, neuropathy, NASH, fractures, and cognitive impairment.

[0049] The method may further comprise administering one or more other therapeutic agents (e.g., in combination with the chemical entities described herein).

[0050] Embodiments may include one or more of the following advantageous features.

[0051] Apelin peptide is unstable; thus, only acute pharmacodynamic effects of apelin are observed. In some embodiments, the compounds described herein exhibit relatively high metabolic stability to allow for the observation of non-acute pharmacodynamic effects.

[0052] In some embodiments, the compounds described herein may result in decreased atrial pressure in addition to enhancing cardiac output.

[0053] In some embodiments, the compounds described herein can selectively activate the G protein pathway via the APJ receptor, thereby reducing the tachyphylaxis typically associated with the administration of an effective agonist. Thus, in certain embodiments, the compounds described herein can reduce arrestin-related cardiac hypertrophy.

[0054] In some embodiments, the compounds described herein may exhibit pleiotropic properties (e.g., vasodilator activity, cardiorenal protection, and control of fluid homeostasis).

[0055] Other embodiments include those described in the specific embodiments and / or claims.

[0056] Additional Definitions

[0057] To facilitate understanding of the disclosure set forth herein, several other terms are defined below. Generally, the nomenclature used herein and the laboratory procedures of organic chemistry, medicinal chemistry, and pharmacology described herein are well known and commonly employed in the art. Unless otherwise defined, all technical and scientific terms used herein have the meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. Every patent, application, published application, and other publication and the appendix attached hereto mentioned throughout this specification are hereby incorporated by reference in their entirety.

[0058] As used herein, the term "APJ receptor" is intended 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, isotypes, precursors, mutants, variants, derivatives, splice variants, alleles, different species, and active fragments thereof.

[0059] As used herein, with respect to a formulation, composition, or ingredient, the term "acceptable" means that there is no continuing adverse effect on the overall health of the subject being treated.

[0060] "API" means active pharmaceutical ingredient.

[0061] The term "IC50" or "EC50" means the amount, concentration, or dose of a compound required to inhibit or activate 50% of the maximal response in an assay measuring such response.

[0062] As used herein, the term "effective amount" or "therapeutically effective amount" means an amount of a chemical entity (e.g., a compound generally or specifically described herein, a pharmaceutically acceptable salt thereof, or a composition comprising the same) sufficient to alleviate to some extent one or more symptoms of a disease or disorder being treated. The results include 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 use is an amount that comprises a compound disclosed herein to provide a clinically significant alleviation of symptoms of a disease. In any case, any suitable technique (e.g., dose escalation studies) can be used to determine an appropriate "effective" amount.

[0063] The term "excipient" or "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable material, composition, or carrier, such as a liquid or solid filler, diluent, vehicle, solvent, or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical formulation and suitable for contact with the tissues or organs of humans and animals without undue 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 et al., eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash, eds., Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed., Gibson, ed., CRC Press LLC: Boca Raton, FL, 2009).

[0064] The term "pharmaceutically acceptable salt" refers to a preparation of a compound that does not cause significant irritation to the organism to which it is administered and does not eliminate the biological activity and properties of the compound. In certain cases, a pharmaceutically acceptable salt is obtained by reacting a compound described herein with an acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. In certain cases, a salt is formed by reacting a compound having an acidic group described herein with a base, such as an ammonium salt, an alkali metal salt, such as a sodium or potassium salt, an alkaline earth metal salt, such as a calcium or magnesium salt, a salt of an organic base, such as dicyclohexylamine, N-methyl-D-glucosamine, tris(hydroxymethyl)methylamine , and salts formed with amino acids, such as arginine, lysine and the like, or by other previously determined methods. There is no particular limitation on the pharmaceutically acceptable salt as long as it can be used in medicine. Examples of salts formed by the compounds described herein with bases include the following: salts with inorganic bases such as sodium , potassium, magnesium, calcium and aluminum; salts with organic bases such as methylamine, ethylamine and ethanolamine; salts with basic amino acids such as lysine and ornithine; and ammonium salts. The salts may be acid addition salts, specific examples of which are addition salts formed with the following acids: inorganic 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.

[0065] The term "pharmaceutical composition" refers to a mixture of a compound described herein with other chemical components (collectively referred to herein as "excipients"), such chemical components being, for example, carriers, stabilizers , diluents, dispersants, suspending agents and / or thickening agents. Pharmaceutical compositions facilitate the administration of compounds to organisms. There are a variety of techniques for administering compounds in the art, including but not limited to rectal, oral, intravenous , aerosol, parenteral, ocular, pulmonary and topical administration.

[0066] The term "subject" can refer to an animal, including but not limited to primates (such as humans), monkeys, cows, pigs, sheep, goats, horses, dogs, cats, rabbits, rats or mice. The terms "subject" and "patient" are used interchangeably herein, for example to refer to a mammalian subject, such as a human subject.

[0067] In the context of treating a disease, disorder or condition, the term "treatment" is intended to include alleviating or eliminating the disease, disorder or condition or one or more symptoms associated with the disease, disorder or condition; or slowing the progression, spread or worsening of the disease, disorder or condition or one or more of its symptoms.

[0068] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0069] The term "alkyl" refers to a hydrocarbon chain that can be straight-chain or branched-chain and contains the indicated number of carbon atoms. For example, C 1-10 indicates that the group can have from 1 to 10 (inclusive) carbon atoms. Non-limiting examples include methyl, ethyl, isopropyl, tert-butyl, n-hexyl.

[0070] The term "haloalkyl" refers to an alkyl in which one or more hydrogen atoms are replaced by independently selected halogen.

[0071] The term "alkoxy" refers to -O-alkyl (e.g., -OCH3).

[0072] The term "haloalkoxy" refers to -O-haloalkyl (e.g., -OCH3).

[0073] The term "alkylene" refers to a branched or unbranched divalent alkyl (e.g., CH2-).

[0074] The term "arylene" etc. refers to the divalent form of a ring system, here a divalent aryl.

[0075] The term "alkenyl" refers to a straight-chain or branched-chain hydrocarbon chain that can have one or more carbon-carbon double bonds. The alkenyl moiety contains the specified number of carbon atoms. For example, C 2-6 indicates that the group can have from 2 to 6 (inclusive) carbon atoms.

[0076] The term "alkynyl" refers to a straight-chain or branched-chain hydrocarbon chain that can have one or more carbon-carbon triple bonds. The alkynyl moiety contains the specified number of carbon atoms. For example, C 2-6 indicates that the group can have from 2 to 6 (inclusive) carbon atoms.

[0077] The term "aryl" refers to a 6-carbon monocyclic, 10-carbon bicyclic or 14-carbon tricyclic aromatic ring system, where 0, 1, 2, 3 or 4 atoms of each ring can be substituted, and where the ring containing the monocyclic group is aromatic, and where at least one of the fused rings containing the bicyclic or tricyclic group is aromatic, such as tetrahydronaphthyl. Examples of aryl also include phenyl, naphthyl, etc.

[0078] As used herein, the term "cycloalkyl" includes saturated cyclic hydrocarbon groups having 3 to 10 carbons, preferably 3 to 8 carbons, more preferably 3 to 6 carbons, where the cycloalkyl can be optionally substituted. Preferred cycloalkyls include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl and cyclooctyl.

[0079] The term "heteroaryl" refers to an aromatic 5- to 8-membered monocyclic, 8- to 12-membered bicyclic or 11- to 14-membered tricyclic system which, if monocyclic, has 1 to 3 heteroatoms, if bicyclic, has 1 to 6 heteroatoms, and if tricyclic, has 1 to 9 heteroatoms, said heteroatoms being selected from O, N or S (e.g., carbon atoms and 1 to 3, 1 to 6 or 1 to 9 N, O or S heteroatoms respectively for the monocyclic, bicyclic or tricyclic rings), where 0, 1, 2, 3 or 4 atoms of each ring may be substituted by substituents, and where the ring containing the monocyclic group is aromatic, and where at least one of the fused rings containing the bicyclic or tricyclic group is aromatic (but not necessarily the ring containing the heteroatom, e.g., tetrahydroisoquinolinyl).

[0080] Exemplary heteroaryl systems are derived from, but not limited to, the following ring systems: pyrrole, furan, thiophene, imidazole, pyrazole, oxazole (= [1,3]oxazole), isoxazole (= [1,2]oxazole), thiazole (= [1,3]thiazole), isothiazole (= [1,2]thiazole), [1,2,3]triazole, [1,2,4]triazole, [1,2,4]oxadiazole, [1,3,4]oxadiazole, [1,2,4]thiadiazole, [1,3,4]thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, [1,2,3]triazine, [1,2,4]triazine, [1,3,5]triazine, indole, isoindole, benzofuran, benzothiophene [1,3]benzoxazole, [1,3]benzothiazole, benzimidazole, indazole, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, various naphthyridines, e.g., [1,8]naphthyridine, various thiophenopyridines, e.g., thiophen[2,3-b]pyridine, and purine.

[0081] The term "heterocyclyl" refers to a non-aromatic 5- to 8-membered monocyclic, 8- to 12-membered bicyclic or 11- to 14-membered tricyclic system which, if monocyclic, has 1 to 3 heteroatoms, if bicyclic, has 1 to 6 heteroatoms, and if tricyclic, has 1 to 9 heteroatoms, said heteroatoms being selected from O, N or S (e.g., carbon atoms and 1 to 3, 1 to 6 or 1 to 9 N, O or S heteroatoms respectively for the monocyclic, bicyclic or tricyclic rings), where 0, 1, 2 or 3 atoms of each ring may be substituted by substituents. Examples of heterocyclyl include piperazinyl, pyrrolidinyl, dioxolanyl, morpholinyl, tetrahydrofuranyl, etc.

[0082] In addition, the atoms constituting the compounds of this embodiment 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 not limitation, isotopes of hydrogen include tritium and deuterium, while isotopes of carbon include 13 C and 14 C.

[0083] The compounds provided herein can include various stereochemical forms. The compounds also include diastereoisomers and optical isomers, such as mixtures (including racemic mixtures) of enantiomers (including atropisomers), as well as individual enantiomers and diastereoisomers, which arise due to structural asymmetry in a particular compound. The various isomers can be separated or selectively synthesized using methods well known to those skilled in the art. Unless otherwise specified, when a structure with one or more chiral centers but without specified stereochemistry is used to name or describe the disclosed compounds, it is to be understood as representing all possible stereoisomers of the compound. For example, -S(O)(=NH)-R 4 is intended to include enantiomers: and enantiomers: and mixtures thereof (such as racemic mixtures).

[0084] Details of one or more embodiments of the invention are set forth in the following description and the appended appendix, which is specifically incorporated herein by reference. Other features and advantages will be apparent from the claims. DETAILED DESCRIPTION

[0085] The present disclosure features chemical entities (e.g., compounds or pharmaceutically acceptable salts and / or hydrates and / or prodrugs of the compounds) that modulate (e.g., agonize) the apelin receptor (also referred to herein as the APJ receptor; gene symbol APLNR). The present disclosure also features compositions comprising such chemical entities and other methods of use and preparation. The chemical entity can be used, for example, to treat a subject (e.g., a human) suffering from a disease, disorder, or condition in which APJ receptor activity is reduced (e.g., APJ receptor signaling is blocked or impaired; e.g., apelin-APJ receptor signaling is blocked or impaired) 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 diseases; (ii) metabolic disorders; (iii) diseases, disorders, and conditions related to vascular pathologies; (iv) organ failure; (v) diseases, disorders, and conditions associated with infection (e.g., microbial infection); (vi) diseases, disorders, or conditions that are sequelae or comorbidities of any of the foregoing or disclosed herein. More specific non-limiting examples of such diseases, disorders, or conditions include pulmonary arterial hypertension (e.g., PAH); heart failure; type II diabetes; renal failure; sepsis; and systemic hypertension.

[0086] Compounds of formula (I)

[0087] In one aspect, the present invention features a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0088]

[0089] (I) or a pharmaceutically acceptable salt thereof;

[0090] Wherein:

[0091] A 1 is CH or N;

[0092] X 1 、X 2 、X 3 、and X 4 each independently is selected from N and CR 3 ;

[0093] R 1 is:

[0094] (i)-(Y 1 ) n -Y 2 wherein:

[0095] ·n is 0 or 1;

[0096] ·Y 1 is C 1-6 alkylene, which is optionally substituted by 1-6 R a ; and

[0097] ·Y 2 is:

[0098] (a)C 3-10 cycloalkyl, which is optionally substituted by 1-4 R b ;

[0099] (b)C 6-10 aryl, which is optionally substituted by 1-4 R c ;

[0100] (c) heteroaryl containing 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S, and wherein one or more heteroaryl ring carbon atoms are optionally substituted by 1-4 independently selected R c ; or

[0101] (d) heterocyclic group containing 3-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ) and O, and wherein one or more heterocyclic group ring carbon atoms are optionally substituted by 1-4 independently selected R b ; or

[0102] (ii)-Z1 -Z 2 -Z 3 , wherein:

[0103] ·Z 1 is C 1-3 alkylene, which is optionally substituted by 1-4 R a substituents;

[0104] ·Z 2 is -N(H)-, -N(R d )-, -O- or -S-; and

[0105] ·Z 3 is C 2-7 alkyl, which is optionally substituted by 1-4 R a substituents;

[0106] or

[0107] (iii) C 3-10 alkyl, optionally substituted by 1-6 independently selected R a substituents;

[0108] or

[0109] (iv) -Z 4 -Z 5 -Z 6 -Y 2 wherein:

[0110] ·Z 4 is C 1-3 alkylene, which is optionally substituted by 1-4 R a substituents;

[0111] ·Z 5 is -N(H)-, -N(R d )-, -O- or -S-;

[0112] ·Z 6 is C 1-4 alkylene, which is optionally substituted by 1-4 R a substituents; and

[0113] ·Y 2 is as defined above;

[0114] R 2 is:

[0115] (i) C 6-10 aryl, which is optionally further substituted by 1-4 R c substituents;

[0116] (ii) heteroaryl containing 5 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O, and S, and wherein one or more heteroaryl ring carbon atoms are optionally substituted with 1 to 4 independently selected R c ;

[0117] (iii) C 3-10 cycloalkyl, which is optionally substituted with 1 to 4 R b ;

[0118] (iv) heterocyclic group containing 3 to 10 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), and O, and wherein one or more heterocyclic group ring carbon atoms are optionally substituted with 1 to 4 independently selected R b ; or

[0119] (v) C 1-10 alkyl, which is optionally substituted with 1 to 6 independently selected R a ;

[0120] Each occurrence of R 3 is independently selected from -L 4 -R 4 , H, and R c ';

[0121] Each occurrence of L 4 is independently selected from:

[0122] (i) a single bond;

[0123] (ii) N(H), N(R d ), or N(R 4 );

[0124] (iii) -N(H)S(O) 1-2 - or -N(R d )S(O) 1-2 -;

[0125] (iv) -S(O) 1-2 N(H)- or -S(O) 1-2 N(R d );

[0126] (v) -O-;

[0127] (vi) -S(O) 0-2 -;

[0128] (vii) -C(O)NH- or -C(O)N(R d );

[0129] (viii) -N(H)C(O)- or -N(R d )C(O)-;

[0130] (ix) -C≡C;

[0131] (x)-N(H)S(O)(=NH)-, -N(R d )S(O)(=NH), -N(H)S(O)(=NR d )-,or

[0132] -N(R d )S(O)(=NR d )-

[0133] (xi)-S(O)(=NH)NH-, -S(O)(=NR d )NH-, -S(O)(=NH)NR d -, or -S(O)(=NR d )NR d -;

[0134] (xii) -S(O)(=NH)- or -S(O)(=NR d );as well as

[0135] (xiii)-N(H)S(O) 1-2 N(H)-、-N(R d )S(O) 1-2 N(H)-、-N(H)S(O) 1-2 N(R d )-, or-N(R d )S(O) 1-2 N(R d )-;

[0136] Each occurrence of R 4 Independently are:

[0137] (i)-(Y 3 ) p -Y 4 ,in:

[0138] p is 0 or 1;

[0139] ·Y 3 It is C 1-6 Alkylene or C 1-6 alkenylene, each of which is optionally substituted by 1 to 6 R a replace;

[0140] as well as

[0141] ·Y 4is:

[0142] (a) C 3-6 cycloalkyl, optionally substituted by 1 - 4 R b substituents;

[0143] (b) C 6-10 aryl, optionally substituted by 1 - 4 R c substituents;

[0144] (c) heteroaryl containing 5 - 10 ring atoms, where 1 - 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O, and S, and where one or more heteroaryl ring carbon atoms are optionally substituted by 1 - 4 independently selected R c substituents, or

[0145] (d) heterocyclic group containing 3 - 10 ring atoms, where 1 - 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), and O, and where one or more heterocyclic group ring carbon atoms are optionally substituted by 1 - 4 independently selected R b substituents, or

[0146] (ii) C 1-10 alkyl, C 1-10 alkenyl, or C 1-10 alkynyl, each optionally substituted by 1 - 6 independently selected R a substituents;

[0147] Each occurrence of R a is independently selected from: -OH; -F; -Cl; -Br; -NR e R f ; C 1-4 alkoxy; C 1-4 haloalkoxy; -C(=O)O(C 1-4 alkyl); -C(=O)(C 1-4 alkyl); -C(=O)OH; -CON(R’)(R”); -S(O) 1-2 (NR’R”); -S(O) 1-2 (C 1-4 alkyl); cyano; and cycloalkyl optionally substituted by 1 - 4 independently selected C 1-4 alkyl; 3-6

[0148] Each occurrence of R b is independently selected from: C 1-6 alkyl; C 1-4 haloalkyl; -OH; oxo; -F; -Cl; -Br; -NR e R f ​; C 1-4 alkoxy; C 1-4 haloalkoxy; -C(=O)(C 1-4 alkyl); -C(=O)O(C 1-4 alkyl); -C(=O)OH; -C(=O)N(R’)(R”); -S(O) 1-2 (NR’R”); -S(O) 1-2 (C 1-4 alkyl); cyano; and C 3-6 cycloalkyl, which is optionally substituted by 1 - 4 independently selected C 1-4 alkyl;

[0149] Each occurrence of R c is independently selected from:

[0150] (i) halogen;

[0151] (ii) cyano;

[0152] (iii) C 1-6 alkyl;

[0153] (iv) C 2-6 alkenyl;

[0154] (v) C 2-6 alkynyl;

[0155] (vi) C 1-4 haloalkyl;

[0156] (vii) C 1-4 alkoxy;

[0157] (viii) C 1-4 haloalkoxy;

[0158] (ix) -(C 1-4 substituted by 1 - 4 independently selected C 0-3 alkylene)-C 3-6 cycloalkyl;

[0159] (x) -S(O) 1-2 (C 1-4 alkyl);

[0160] (xi) -NR e R f ;

[0161] (xii) -OH;

[0162] (xiii) -S(O) 1-2 (NR’R”);

[0163] (xiv) -C1-4 Thioalkoxy;

[0164] (xv)-NO2;

[0165] (xvi)-C(=O)(C 1-4 alkyl);

[0166] (xvii)-C(=O)O(C 1-4 alkyl);

[0167] (xviii)-C(=O)OH,

[0168] (xix)-C(=O)N(R’)(R”), and

[0169] (xx)C 3-6 Cycloalkoxy;

[0170] Each occurrence of R c ’ is independently selected from:

[0171] (i) Halogen;

[0172] (ii) Cyano;

[0173] (iii)-OH;

[0174] (iv)-NO2;

[0175] (v)-C(=O)(C 1-4 alkyl);

[0176] (vi)-C(=O)O(C 1-4 alkyl);

[0177] (vii)-C(=O)OH; and

[0178] (viii)-NH2;

[0179] R d is selected from: C 1-6 alkyl; C 3-6 cycloalkyl; -C(O)(C 1-4 alkyl); -C(O)O(C 1-4 alkyl); -CON(R’)(R”); -S(O) 1-2 (NR’R”); -S(O) 1-2 (C 1-4 alkyl); -OH; and C 1-4 alkoxy;

[0180] Each occurrence of R e and R f are independently selected from: H; C 1-6 alkyl; C3-6 Cycloalkyl; -C(O)(C 1-4 alkyl); -C(O)O(C 1-4 alkyl); -CON(R’)(R”); -S(O) 1-2 (NR’R”); -S(O) 1-2 (C 1-4 alkyl); -OH; and C 1-4 alkoxy; or R e and R f together with the nitrogen atom to which they are attached form a ring containing 3 - 8 ring atoms, wherein the ring contains: (a) 1 - 7 ring carbon atoms, each carbon atom being substituted with 1 - 2 substituents independently selected from H and C 1-3 alkyl; (b) 0 - 3 ring heteroatoms (other than the nitrogen atoms attached to R’ and R”), each independently selected from N(R d ), O, and S; and

[0181] each occurrence of R’ and R” is independently selected from: H and C 1-4 alkyl; or R’ and R” together with the nitrogen atom to which they are attached form a ring containing 3 - 8 ring atoms, wherein the ring contains: (a) 1 - 7 ring carbon atoms, each carbon atom being substituted with 1 - 2 substituents independently selected from H and C 1-3 alkyl; (b) 0 - 3 ring heteroatoms (other than the nitrogen atoms attached to R’ and R”), each independently selected from N(R d ), O, and S.

[0182] In some embodiments, the invention is directed to a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0183]

[0184] Wherein:

[0185] A 1 is CH or N;

[0186] X 1 , X 2 , X 3 , and X 4 each independently is selected from N and CR 3 (e.g., each of X 1 and X 4 is independently CH or N; and each of X 2 and X 3 is independently CR 3 or N), provided that X 1 , X 2 , X 3 , and X4 1 to 3 of which are N;

[0187] R1 is:

[0188] (i)-(Y 1 ) n -Y 2 , where:

[0189] ·n is 0 or 1;

[0190] ·Y 1 is C 1-6 alkylene, which is optionally substituted by 1 to 6 Rs a ; and

[0191] ·Y 2 is:

[0192] (a)C 3-10 cycloalkyl, which is optionally substituted by 1 to 4 Rs b ;

[0193] (b)C 6-10 aryl, which is optionally substituted by 1 to 4 Rs c ;

[0194] (c)heteroaryl containing 5 to 10 ring atoms, where 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S, and where one or more heteroaryl ring carbon atoms are optionally substituted by 1 to 4 independently selected Rs c ; or

[0195] (d)heterocyclic group containing 3 to 10 ring atoms, where 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ) and O, and where one or more heterocyclic group ring carbon atoms are optionally substituted by 1 to 4 independently selected Rs b ; or

[0196] (ii)-Z 1 -Z 2 -Z 3 , where:

[0197] ·Z 1 is C 1-3 alkylene, which is optionally substituted by 1 to 4 Rs a ;

[0198] ·Z 2 is -N(H)-, -N(R d )-, -O- or -S-; and

[0199] ·Z 3is C 2-7 alkyl, optionally substituted by 1 - 4 Rs a substituted;

[0200] or

[0201] (iii) C 3-10 alkyl, optionally substituted by 1 - 6 independently selected Rs a substituted;

[0202] or

[0203] (iv) -Z 4 -Z 5 -Z 6 -Y 2 wherein:

[0204] ·Z 4 is C 1-3 alkylene, optionally substituted by 1 - 4 Rs a substituted;

[0205] ·Z 5 is -N(H)-, -N(R d )-, -O- or -S-;

[0206] ·Z 6 is C 1-4 alkylene, optionally substituted by 1 - 4 Rs a substituted; and

[0207] ·Y 2 is as defined above;

[0208] R 2 is:

[0209] (i) C 6-10 aryl, optionally further substituted by 1 - 4 Rs c substituted;

[0210] (ii) heteroaryl containing 5 - 10 ring atoms, wherein 1 - 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S, and wherein one or more heteroaryl ring carbon atoms are optionally substituted by 1 - 4 independently selected Rs c substituted;

[0211] (iii) C 3-10 cycloalkyl, optionally substituted by 1 - 4 Rs b substituted;

[0212] (iv) heterocyclic group containing 3 - 10 ring atoms, wherein 1 - 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d) and O, and one or more of the carbon atoms of the heterocyclic group ring are optionally substituted by 1-4 independently selected R b or

[0213] (v) C 1-10 alkyl, which is optionally substituted by 1-6 independently selected R a substituted

[0214] Each occurrence of R 3 is independently selected from -L 4 -R 4 、H and, R c ';

[0215] Each occurrence of L 4 is independently selected from:

[0216] (i) a single bond;

[0217] (ii) N(H), N(R d ), or N(R 4 );

[0218] (iii) -N(H)S(O) 1-2 - or -N(R d )S(O) 1-2 -;

[0219] (iv) -S(O) 1-2 N(H)- or -S(O) 1-2 N(R d );

[0220] (v) -O-;

[0221] (vi) -S(O) 0-2 -;

[0222] (vii) -C(O)NH- or -C(O)N(R d );

[0223] (viii) -N(H)C(O)- or -N(R d )C(O)-;

[0224] (ix) -C≡C;

[0225] (x) -N(H)S(O)(=NH)-, -N(R d )S(O)(=NH), -N(H)S(O)(=NR d ), or -N(R d )S(O)(=NR d )-

[0226] (xi)-S(O)(=NH)NH-, -S(O)(=NR d )NH-, -S(O)(=NH)NR d -, or

[0227] -S(O)(=NR d )NR d -; and

[0228] (xii)-S(O)(=NH)- or -S(O)(=NR d );

[0229] Each occurrence of R 4 is independently:

[0230] (i)-(Y 3 ) p -Y 4 wherein:

[0231] · p is 0 or 1;

[0232] · Y 3 is C 1-6 alkylene or C 1-6 alkenylene, each of which is optionally substituted with 1 - 6 R a substituents;

[0233] and

[0234] · Y 4 is:

[0235] (a)C 3-6 cycloalkyl, which is optionally substituted with 1 - 4 R b substituents,

[0236] (b)C 6-10 aryl, which is optionally further substituted with 1 - 4 R c substituents;

[0237] (c)heteroaryl containing 5 - 10 ring atoms, wherein 1 - 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O, and S, and wherein one or more heteroaryl ring carbon atoms are optionally substituted with 1 - 4 independently selected R c substituents, or

[0238] (d)heterocyclic group containing 3 - 10 ring atoms, wherein 1 - 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), and O, and wherein one or more heterocyclic group ring carbon atoms are optionally substituted with 1 - 4 independently selected R b substituents, or

[0239] (ii) C 1-10 alkyl, C 1-10 alkenyl, or C 1-10 alkynyl, each of which is optionally substituted by 1 - 6 independently selected R a substituents;

[0240] Each occurrence of R a is independently selected from: -OH; -F; -Cl; -Br; -NR e R f ; C 1-4 alkoxy; C 1-4 haloalkoxy; -C(=O)O(C 1-4 alkyl); -C(=O)(C 1-4 alkyl); -C(=O)OH; -CON(R’)(R”); -S(O) 1-2 (NR’R”); -S(O) 1-2 (C 1-4 alkyl); cyano; and optionally C 1-4 alkyl-substituted C 3-6 cycloalkyl;

[0241] Each occurrence of R b is independently selected from: C 1-6 alkyl; C 1-4 haloalkyl; -OH; oxo; -F; -Cl; -Br; -NR e R f ; C 1-4 alkoxy; C 1-4 haloalkoxy; -C(=O)(C 1-4 alkyl); -C(=O)O(C 1-4 alkyl); -C(=O)OH; -C(=O)N(R’)(R”); -S(O) 1-2 (NR’R”); -S(O) 1-2 (C 1-4 alkyl); cyano; and C 3-6 cycloalkyl, which is optionally substituted by 1 - 4 independently selected C 1-4 alkyl;

[0242] Each occurrence of R c is independently selected from:

[0243] (i) halogen;

[0244] (ii) cyano;

[0245] (iii) C 1-6 alkyl;

[0246] (iv) C 2-6 alkenyl;

[0247] (v)C 2-6 alkynyl;

[0248] (vi)C 1-4 haloalkyl;

[0249] (vii)C 1-4 alkoxy;

[0250] (viii)C 1-4 haloalkoxy;

[0251] (ix) -(C 1-4 alkylene)-C 0-3 optionally substituted by 1-4 independently selected C 3-6 cycloalkyl;

[0252] (x) -S(O) 1-2 (C 1-4 alkyl);

[0253] (xi) -NR e R f ;

[0254] (xii) -OH;

[0255] (xiii) -S(O) 1-2 (NR’R”);

[0256] (xiv) -C 1-4 thioalkoxy;

[0257] (xv) -NO2;

[0258] (xvi) -C(=O)(C 1-4 alkyl);

[0259] (xvii) -C(=O)O(C 1-4 alkyl);

[0260] (xviii) -C(=O)OH;

[0261] (xix) -C(=O)N(R’)(R”); and

[0262] (xx)C 3-6 cycloalkoxy;

[0263] Each occurrence of R c ’ is independently selected from:

[0264] (i) halogen;

[0265] (ii) cyano;

[0266] (iii) -OH;

[0267] (iv) -NO2;

[0268] (v) -C(=O)(C 1-4 alkyl);

[0269] (vi) -C(=O)O(C 1-4 alkyl);

[0270] (vii) -C(=O)OH; and

[0271] (viii) -NH2;

[0272] R d is selected from the group consisting of: C 1-6 alkyl; C 3-6 cycloalkyl; -C(O)(C 1-4 alkyl); -C(O)O(C 1-4 alkyl); -CON(R')(R"); -S(O) 1-2 (NR'R"); -S(O) 1-2 (C 1-4 alkyl); -OH; and C 1-4 alkoxy;

[0273] Each occurrence of R e and R f is independently selected from: H; C 1-6 alkyl; C 3-6 cycloalkyl; -C(O)(C 1-4 alkyl); -C(O)O(C 1-4 alkyl); -CON(R')(R"); -S(O) 1-2 (NR'R"); -S(O) 1-2 (C 1-4 alkyl); -OH; and C 1-4 alkoxy; or R e and R f together with the nitrogen atom to which they are each attached form a ring containing 3 - 8 ring atoms, wherein said ring contains: (a) 1 - 7 ring carbon atoms, each carbon atom being substituted with 1 - 2 substituents independently selected from H and C 1-3 alkyl; (b) 0 - 3 ring heteroatoms (other than the nitrogen atom to which R' and R" are attached), each independently selected from N(R d ); O and S; and

[0274] Each occurrence of R' and R" is independently selected from: H and C 1-4alkyl; or R' and R" together with the nitrogen atom to which they are attached form a ring containing 3 - 8 ring atoms, wherein said ring contains: (a) 1 - 7 ring carbon atoms, each carbon atom being substituted by 1 - 2 substituents independently selected from H and C 1-3 alkyl; (b) 0 - 3 ring heteroatoms (other than the nitrogen atoms attached to R' and R"), each independently selected from N(R d ), O, and S.

[0275] In some embodiments, when the compound is of formula (I - 1):

[0276]

[0277] R 1 is not unsubstituted phenyl, p - dimethylaminophenyl, p - aminosulfonylphenyl, and unsubstituted 4 - pyridyl.

[0278] In some embodiments, when the compound is of formula (I - 1):

[0279]

[0280] R 1 is not unsubstituted phenyl, p - monosubstituted phenyl, and unsubstituted pyridyl.

[0281] In some embodiments, when the compound is of formula (I - 2):

[0282]

[0283] R 1 is not unsubstituted phenyl.

[0284] In some embodiments, the compound is not a compound of formula (I - 1) or formula (I - 2):

[0285]

[0286] In some embodiments, the compound is not of formula (I - 3):

[0287]

[0288] In some embodiments, when the compound is of formula (I - 4):

[0289]

[0290] R 1 is not p - monosubstituted phenyl (e.g., p - fluorophenyl).

[0291] In some embodiments, when the compound is of formula (I - 5):

[0292]

[0293] R 3 is not trifluoromethyl.

[0294] In some embodiments, when the compound is of formula (I-6):

[0295]

[0296] R 2 is not:

[0297] (i) unsubstituted phenyl;

[0298] (ii)

[0299] (iii)

[0300] (iv) unsubstituted pyridyl;

[0301] (v) wherein each of Q 1 、Q 2 、Q 3 、and Q 4 is independently selected from N and CH; or

[0302] (vi) a heteroaryl containing 9 - 10 ring atoms, wherein 1 - 2 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O, and S, and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with 1 - 2 independently selected R c .

[0303] In some embodiments, the compound is not one or more of the following:

[0304]

[0305] In some embodiments, the compound is not one or more of the following:

[0306]

[0307] In certain embodiments, the compounds are not those disclosed in European Journal of Medicinal Chemistry (2014), 86, 270-278. In certain embodiments, the compounds are not those disclosed in Tetrahedron Letters (2012), 53(25), 3126-3130. In certain embodiments, the compounds are not those disclosed in Organic Letters (2011), 13(24), 6516-6519. In certain embodiments, the compounds are not those disclosed in U.S. Patent Application Publication No. 2012 / 0095037 and / or U.S. Patent 8,362,019.

[0308] In certain embodiments, the compounds are not those disclosed in Angewandte Chemie, International Edition (2018), 57(5), 1399-1403. In certain embodiments, the compounds are not those disclosed in Organic Letters (2017), 19(19), 5118-5121. In certain embodiments, the compounds are not those disclosed in Tetrahedron (2009), 65(44), 8930-8939. In certain embodiments, the compounds are not those disclosed in Organic Letters (2016), 18(13), 3250-3253. In certain embodiments, the compounds are not those disclosed in Organic & Biomolecular Chemistry (2015), 13(21), 6047-6058. In certain embodiments, the compounds are not those disclosed in Chemistry - A European Journal (2013), 19(49), 16760-16771. In certain embodiments, the compounds are not those disclosed in Organic & Biomolecular Chemistry (2013), 11(18), 3064-3072. In certain embodiments, the compounds are not those disclosed in Organic Letters (2011), 13(24), 6516-6519. In certain embodiments, the compounds are not those disclosed in Bioorganic & Medicinal Chemistry Letters (2004), 14(13), 3595-3599. In certain embodiments, the compounds are not those disclosed in International Patent Application Publication No. 2015 / 073528. In certain embodiments, the compounds are not those disclosed in International Patent Application Publication No. 2012 / 146667. In certain embodiments, the compounds are not those disclosed in International Patent Application Publication No. 2001 / 030778. In certain embodiments, the compounds are not those disclosed in US Patent Application Publication No. 2012 / 0095037.

[0309] In certain embodiments, the compounds are not those disclosed in Journal of Medicinal Chemistry (2012), 55(11), 5291-5310. In certain embodiments, the compounds are not those disclosed in Tetrahedron Letters (2000), 41(28), 5383-5386. In certain embodiments, the compounds are not those disclosed in International Patent Application Publication WO 2017 / 171234. In certain embodiments, the compounds are not those disclosed in International Patent Application Publication WO 2016 / 176460. In certain embodiments, the compounds are not those disclosed in Japanese Patent Application Publication JP 2013 / 018771 and / or JP 5,959,330. In certain embodiments, the compounds are not those disclosed in International Patent Application Publication WO 2011 / 153310. In certain embodiments, the compounds are not those disclosed in International Patent Application Publication WO 2011 / 082270. In certain embodiments, the compounds are not those disclosed in Australian Patent Application Publication AU 2010 / 331175 and / or U.S. Patent Application Publication.US2012 / 0258951 and / or U.S. 2014 / 0194407. In certain embodiments, the compounds are not those disclosed in International Patent Application Publication WO 2010 / 051245 and / or U.S. Patent Application Publication No. US2011 / 0207750. In certain embodiments, the compounds are not those disclosed in WO 2010 / 030360. In certain embodiments, the compounds are not those disclosed in European Patent Application Publication EP 1878724 and / or U.S. Patent 8,188,282. In certain embodiments, the compounds are not those disclosed in International Patent Application Publication WO 2007 / 075629. In certain embodiments, the compounds are not those disclosed in Japanese Patent Application Publication JP 2000 / 302754 and / or U.S. Patent No. 6,358,634.

[0310] Variable A 1 and X 1 -X 4

[0311] In some embodiments, A 1 is N.

[0312] In other embodiments, A 1 is CH.

[0313] In some embodiments, X 1 and X 4 each independently selected from CH and N.

[0314] In some embodiments, X 1 、X 2 、X 3 、and X 4 1-2 of them are independently N.

[0315] In certain embodiments, X 1 、X 2 、X 3 、and X 4 的 1-2 of them are independently N; and each of X 1 、X 2 、X 3 、and X 4 2-3 is independently selected CR 3 .

[0316] In certain embodiments, X 1 、X 2 、X 3 、and X 4 1-2 of them are independently N; and each of X 1 and X 4 is independently N or CH.

[0317] In some embodiments, two of X 1 、X 2 、X 3 、and X 4 are independently N; and the other two of X 1 、X 2 、X 3 、and X 4 are independently selected from N and CR 3 .

[0318] In certain embodiments, the compound of formula (I) is formula (I-a):

[0319]

[0320] or a pharmaceutically acceptable salt thereof.

[0321] In certain embodiments, the compound of formula (I) is formula (I-b):

[0322]

[0323] or a pharmaceutically acceptable salt thereof.

[0324] In certain of the foregoing embodiments, when two of X 1 、X 2 、X 3 、and X 4 are independently N, X1 , X 2 , X 3 , and X 4 's other two are independently selected CR 3 .

[0325] In certain embodiments, the compound of formula (I) is of formula (I-a1):

[0326]

[0327] or a pharmaceutically acceptable salt thereof.

[0328] In certain embodiments, the compound of formula (I) is of formula (I-a2):

[0329]

[0330] or a pharmaceutically acceptable salt thereof.

[0331] In certain embodiments, the compound of formula (I) is of formula (I-b1):

[0332] (e.g., );

[0333] or a pharmaceutically acceptable salt thereof.

[0334] In some embodiments, X 1 , X 2 , X 3 , and X 4 is independently N; and X 1 , X 2 , X 3 , and X 4 's other three are independently selected from N and CR 3 .

[0335] In certain embodiments, the compound of formula (I) is of formula (I-c):

[0336]

[0337] or a pharmaceutically acceptable salt thereof.

[0338] In certain embodiments, the compound of formula (I) is of formula (I-d):

[0339]

[0340] or a pharmaceutically acceptable salt thereof.

[0341] In certain of the foregoing embodiments, when X 1 , X 2 , X3 , and X 4 One of which is independently N, X 1 , X 2 , X 3 , and X 4 The other three are independently selected CR 3 .

[0342] In certain embodiments, the compound of formula (I) is of formula (I-c1):

[0343] (for example, );

[0344] or a pharmaceutically acceptable salt thereof.

[0345] In certain embodiments, the compound of formula (I) is of formula (I-d1):

[0346] (for example, );

[0347] or a pharmaceutically acceptable salt thereof.

[0348] In certain embodiments, the compound of formula (I-d1) has the following formula:

[0349]

[0350] Wherein: one R 3 is independently selected from -L 4 -R 4 and R c ';

[0351] The other R 3 are independently selected from H, -L 4 -R 4 , and R c ';

[0352] R 1 is (i)-(Y 1 ) n -Y 2 , wherein:

[0353] ·n is 0;

[0354] ·Y 2 is:

[0355] (a) Partially unsaturated C 3-10 cycloalkyl, which is optionally substituted with 1-4 R b substituents,

[0356] (b) C 6-10An aryl group, optionally substituted with 1 to 4 Rs c substituted;

[0357] (c) A heteroaryl group containing 5 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O, and S, and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with 1 to 4 independently selected Rs c substituted, or

[0358] (d) A partially unsaturated heterocyclic group containing 3 to 10 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), and O, and wherein one or more of the heterocyclic group ring carbon atoms are optionally substituted with 1 to 4 independently selected Rs b substituted; and

[0359] R 2 is:

[0360] (i) C 6-10 An aryl group, optionally further substituted with 1 to 4 Rs c substituted;

[0361] (ii) A heteroaryl group containing 5 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O, and S, and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted with 1 to 4 independently selected Rs c substituted;

[0362] (iii) A partially unsaturated C 3-10 cycloalkyl group, optionally substituted with 1 to 4 Rs b substituted; or

[0363] (iv) A partially unsaturated heterocyclic group containing 3 to 10 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), and O, and wherein one or more of the heterocyclic group ring carbon atoms are optionally substituted with 1 to 4 independently selected Rs b substituted.

[0364] Variable R 1

[0365] In some embodiments, R 1 is -(Y 1 ) n -Y 2 .

[0366] In some embodiments, n is 0.

[0367] In other embodiments, n is 1. In some of these embodiments, Y 1 is C 1-3 alkylene.

[0368] In some embodiments, Y 2 is a heteroaryl containing 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O, and S, and wherein one or more heteroaryl ring carbon atoms are optionally substituted with 1-4 independently selected R c . In some of the foregoing embodiments, n is 0.

[0369] In some embodiments, Y 2 is a heteroaryl containing 6 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O, and S, and wherein one or more heteroaryl ring carbon atoms are substituted with 1-4 independently selected R c ; or a heteroaryl containing 5 or 9-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O, and S, and wherein one or more heteroaryl ring carbon atoms are optionally substituted with 1-4 independently selected R c . In some of the foregoing embodiments, n is 0.

[0370] In some embodiments, Y 2 is a heteroaryl containing 5-6 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O, and S, and wherein one or more heteroaryl ring carbon atoms are optionally substituted with 1-4 independently selected R c . In some of these embodiments, n is 0.

[0371] In some embodiments, Y 2 is a heteroaryl containing 6 ring atoms, wherein 1-2 ring atoms are N, and wherein one or more heteroaryl ring carbon atoms are optionally substituted with 1-4 independently selected R c . For example, Y 2 can be pyridyl (e.g., 2-pyridyl or 6-pyridyl), wherein one or more ring carbon atoms are optionally substituted with 1-4 (e.g., 1, 2, 3, or 4) independently selected R c (e.g., Y 2 is pyridyl (e.g., 2-pyridyl or 6-pyridyl), wherein one or more ring carbon atoms are optionally substituted with one independently selected R c(substituted). In some of these embodiments, n is 0.

[0372] In certain embodiments, Y 2 is a heteroaryl containing 5 ring atoms, wherein 1 - 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O, and S, and wherein one or more heteroaryl ring carbon atoms are optionally substituted with 1 - 2 independently selected R c . For example, Y 2 can be pyrazolyl, oxazolyl, or thiazolyl, wherein any substitutable nitrogen atom is optionally substituted with R d , and wherein one or more ring carbon atoms are optionally substituted with 1 - 2 independently selected R c . In some of these embodiments, n is 0.

[0373] In certain embodiments, Y 2 is a heteroaryl containing 5 ring atoms, wherein 1 - 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O, and S, and wherein one or more heteroaryl ring carbon atoms are optionally substituted with 1 - 3 independently selected R c . In some of these embodiments, n is 0.

[0374] In some of these embodiments, Y 2 is furanyl, wherein one or more ring carbon atoms are optionally substituted with 1 - 2 (e.g., 1) independently selected R c . In some of these embodiments, n is 0.

[0375] In some of the foregoing embodiments, when Y 2 is heteroaryl, each occurrence of R c is independently selected from:

[0376] (iii) C 1-6 alkyl;

[0377] (iv) C 2-6 alkenyl;

[0378] (v) C 2-6 alkynyl;

[0379] (vi) C 1-4 haloalkyl;

[0380] (vii) C 1-4 alkoxy;

[0381] (viii) C 1-4 haloalkoxy;

[0382] (ix) Optionally substituted by 1 - 4 independently selected C 1-4 alkyl-substituted -(C 0-3 alkylene)-C 3-6 cycloalkyl;

[0383] (xiv)-C 1-4 thioalkoxy;

[0384] and

[0385] (xx)C 3-6 cycloalkoxy.

[0386] In certain of the foregoing embodiments, when Y 2 is a heteroaryl, each occurrence of R c is independently selected from:

[0387] (vii)C 1-4 alkoxy;

[0388] (viii)C 1-4 haloalkoxy (e.g., OCH2CF3 or OCF3);

[0389] (xiv)-C 1-4 thioalkoxy; and

[0390] (xx)C 3-6 cycloalkoxy (e.g., cyclopropoxy).

[0391] For example, each occurrence of R c is independently selected C 1-4 alkoxy (e.g., -OCH3, -OCH2CH3).

[0392] As another example, each occurrence of R c is independently selected C 1-6 alkyl (e.g., methyl).

[0393] In certain of the foregoing embodiments, when Y 2 is a heteroaryl, each occurrence of R d is independently selected C 1-6 alkyl.

[0394] In certain of the foregoing embodiments, when Y 2 is a heteroaryl and n is 0, R 1 may be selected from:

[0395]

[0396] In certain of the foregoing embodiments, when Y 2 is a heteroaryl and n is 0, R 1 may be selected from:

[0397] As a non-limiting example of the foregoing embodiments, when Y 2 is a heteroaryl and n is 0, R 1 can be:

[0398]

[0399] In certain embodiments, when Y 2 is a heteroaryl and n is 0, R 1 can be:

[0400] In certain embodiments, when Y 2 is a heteroaryl and n is 0, R 1 can be:

[0401] In some embodiments, Y 2 is a C 3-10 cycloalkyl which is optionally substituted with 1 - 4 R b . In some of these embodiments, n is 0.

[0402] In some embodiments, Y 2 is a C 6-10 aryl which is optionally substituted with 1 - 4 R c .

[0403] In certain embodiments, Y 2 is a phenyl which is substituted with 1 - 4 R c . In certain embodiments, when Y 2 is a phenyl; and the ring carbon atom para to the point of attachment of Y 1 is substituted with R c , then one or more other ring carbon atoms are optionally substituted with 1 - 3 R c .

[0404] In some embodiments, R 1 is -Z 1 -Z 2 -Z 3 .

[0405] In some embodiments, Z 1 is CH2.

[0406] In some embodiments, Z 2 is -O-, or -S-. For example, Z 2 can be -O-.

[0407] In some embodiments, Z 3 is a C 2-3Alkylene

[0408] In certain embodiments, Z 1 is CH2, and Z 2 is -O-, or -S- (e.g., -O-).

[0409] In certain embodiments, Z 2 is -O- or -S- (e.g., -O-), and Z 3 is C 2-3 Alkylene

[0410] In certain embodiments, Z 1 is CH2, and Z 2 is -O- or -S- (e.g., -O-), and Z 3 is C 2-3 Alkylene

[0411] In certain of the foregoing embodiments, when R 1 is -Z 1 -Z 2 -Z 3 then R 1 is

[0412] Variable R 2

[0413] In some embodiments, R 2 is:

[0414] (i) C 6-10 Aryl, which is optionally further substituted with 1 - 4 R c substituents;

[0415] (ii) Heteroaryl containing 5 - 10 ring atoms, wherein 1 - 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O, and S, and wherein one or more heteroaryl ring carbon atoms are optionally substituted with 1 - 4 independently selected R c substituents;

[0416] (iii) Partially unsaturated C 3-10 Cycloalkyl, which is optionally substituted with 1 - 4 R b substituents; or

[0417] (iv) Partially unsaturated heterocyclic group containing 3 - 10 ring atoms, wherein 1 - 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ) and O, and wherein one or more heterocyclic group ring carbon atoms are optionally substituted with 1 - 4 independently selected R b substituents.

[0418] In some embodiments, R 2 is C 6-10 aryl, which is optionally substituted with 1 - 4 R c .

[0419] In certain embodiments, R 2 is phenyl, which is optionally substituted with 1 - 4 R c . In certain of the foregoing embodiments, R 2 can be phenyl, which is optionally substituted with 1 - 2 R c . As a non - limiting example, R 2 can be phenyl, which is optionally substituted with 2 R c .

[0420] In certain of the foregoing embodiments, when R 2 is aryl (e.g., phenyl), each occurrence of R c is independently selected from:

[0421] (i) halogen (e.g., F);

[0422] (vi) C 1-4 haloalkyl (e.g., CF3);

[0423] (vii) C 1-4 alkoxy;

[0424] (viii) C 1-4 haloalkoxy; and

[0425] (xiv) - C 1-4 thioalkoxy.

[0426] As a non - limiting example, each occurrence of R c can be independently selected from halogen, C 1-4 alkoxy, and C 1-4 haloalkyl (e.g., each occurrence of R c is independently - OCH3, CF3, or F).

[0427] In certain of the foregoing embodiments, when R 2 is aryl (e.g., phenyl), R 2 has the formula (A):

[0428]

[0429] wherein R 2a , R 2b , R 2c , R 2d and R 2e are each independently selected from H and R c .

[0430] In certain embodiments, R 2a , R 2b , R 2c , R 2d and R 2e four of which are each independently selected R c , and the other is H.

[0431] In certain embodiments, R 2a , R 2b , R 2c , R 2d and R 2e three of which are each independently selected R c , and the other two are H.

[0432] In certain embodiments, two of R 2a , R 2b , R 2c , R 2d and R 2e are each independently selected R c , and the other two are H. In some of these embodiments, R 2a and R 2e are each independently selected R c (e.g., C 1-4 alkoxy; C 1-4 haloalkoxy; -C 1-4 thioalkoxy; C 1-4 haloalkyl and halogen, e.g., each occurrence of R c is independently selected C 1-4 alkoxy (e.g., -OCH3). For example, R 2a and R 2e are each OCH3.

[0433] In certain embodiments, R 2 is:

[0434] In certain of the foregoing embodiments, when R 2 is aryl (e.g., phenyl), R 2 has the formula (B):

[0435]

[0436] In some embodiments, when R 2 is aryl (e.g., phenyl); and R 2 has the formula (A):

[0437]

[0438] R2a , R 2b , R 2d 1 to 4 of R 2e and R are independently selected c .

[0439] In certain of the foregoing embodiments, each of the R c is independently selected from:

[0440] (i) -F;

[0441] (ii) cyano;

[0442] (iii) C 1-3 alkyl, C 5-6 alkyl, n-butyl, sec-butyl, isobutyl;

[0443] (iv) C 2-6 alkenyl;

[0444] (v) C 2-6 alkynyl;

[0445] (vi) C 1-4 haloalkyl;

[0446] (vii) C 1-4 alkoxy;

[0447] (viii) C 1-4 haloalkoxy;

[0448] (ix) -(C 1-4 alkylene)-C 0-3 cycloalkyl optionally substituted with 1 to 4 independently selected C 3-6 alkyl;

[0449] (x) -S(O) 1-2 (C 1-4 alkyl);

[0450] (xii) -OH;

[0451] (xiv) -C 1-4 thioalkoxy;

[0452] (xv) -NO2;

[0453] (xvi) -C(=O)(C 1-4 alkyl);

[0454] (xvii) -C(=O)O(C 1-4 alkyl);

[0455] (xviii) -C(=O)OH;

[0456] (xix)-C(=O)N(R’)(R”); and

[0457] (xx)C 3-6 cycloalkoxy.

[0458] In some embodiments, R 2 is a heteroaryl containing 5 - 10 ring atoms, where 1 - 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O, and S, and where one or more of the heteroaryl ring carbon atoms are optionally substituted with 1 - 4 independently selected R c .

[0459] In certain of the foregoing embodiments, R 2 is a heteroaryl containing 6 ring atoms, where 1 - 3 ring atoms are heteroatoms, each independently selected from N, N(H), and N(R d ), and where one or more of the heteroaryl ring carbon atoms are optionally substituted with 1 - 4 independently selected R c .

[0460] As a non - limiting example, R 2 can be a pyridyl optionally substituted with 1 - 2 independently selected R c .

[0461] In certain of the foregoing embodiments, when R 2 is a heteroaryl as defined above (e.g., R 2 is a heteroaryl containing 5 - 10 ring atoms, where 1 - 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O, and S, and where one or more of the heteroaryl ring carbon atoms are optionally substituted with 1 - 4 independently selected R c ), each R c is independently selected from:

[0462] (i) halogen

[0463] (vi)C 1-4 haloalkyl (e.g., CF3);

[0464] (vii)C 1-4 alkoxy;

[0465] (viii)C 1-4 haloalkoxy; and

[0466] (xiv)-C 1-4 thioalkoxy.

[0467] As a non - limiting example, each R c can independently be C 1-4Alkoxy (e.g., methoxy).

[0468] In certain of the foregoing embodiments, when R 2 is heteroaryl, R 2 is:

[0469] In certain of the foregoing embodiments, when R 2 is heteroaryl, R 2 is:

[0470] In some embodiments (e.g., when the compound has Formula I-d1), when R 2 is heteroaryl as defined elsewhere herein, R 2 is selected from:

[0471] (a) Heteroaryl containing 5 ring atoms, where 1 - 2 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O, and S, and where one or more of the heteroaryl ring carbon atoms are optionally substituted with 1 - 4 independently selected R c ;

[0472] (b) where each of Q 1 , Q 2 , Q 3 , Q 4 , Q 5 is independently selected from N, CH, and CR c , provided that:

[0473] · One to four of Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 are independently CR c ;

[0474] · One or more of Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 are independently N; and

[0475] · When Q 5 is CR c , one or more of Q 1 , Q 2 , Q 3 , and Q 4 are CR c ; and

[0476] (c) Heteroaryl containing 9-10 ring atoms, where 1-4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O, and S, and where one or more of the heteroaryl ring carbon atoms are substituted with 1-4 independently selected R c substituents,

[0477] where each occurrence of R c is independently selected from:

[0478] (i) -F;

[0479] (ii) Cyano;

[0480] (iii) C2 -6 alkyl;

[0481] (iv) C 2-6 alkenyl;

[0482] (v) C 2-6 alkynyl;

[0483] (vi) C 1-4 haloalkyl;

[0484] (vii) C 1-4 alkoxy;

[0485] (viii) C 1-4 haloalkoxy;

[0486] (ix) -(C 1-4 alkylene)-C 0-3 cycloalkyl, optionally substituted with 1-4 independently selected C 3-6 alkyl;

[0487] (x) -S(O) 1-2 (C 1-4 alkyl);

[0488] (xi) -NR e R f ;

[0489] (xiii) -S(O) 1-2 (NR’R”);

[0490] (xiv) C 1-4 thioalkoxy;

[0491] (xv) -NO2;

[0492] (xvi) -C(=O)(C 1-4 alkyl);

[0493] (xvii) -C(=O)O(C1-4 alkyl);

[0494] (xviii) - C(=O)OH;

[0495] (xix) - C(=O)N(R’)(R”); and

[0496] (xx) C 3-6 cycloalkyloxy.

[0497] Variable R 3

[0498] In some embodiments, each occurrence of R 3 is independently selected from R c’ and - L 4 - R 4 .

[0499] In some embodiments, one occurrence of R 3 is - L 4 - R 4 .

[0500] In certain of the foregoing embodiments, when one occurrence of R 3 is - L 4 - R 4 , each of the remaining occurrences of R 3 is independently selected from H and R c ’ (e.g., R c ’ can be a halogen, e.g., Br or Cl; or R c ’ can be - OH or NH2). For example, each of the remaining occurrences of R 3 can be H.

[0501] In some embodiments, one occurrence of R 3 is - L 4 - R 4 , and one occurrence of R 3 is H or R c ’ (e.g., R c ’ can be a halogen, e.g., Br or Cl; or R c ’ can be NH2).

[0502] In some embodiments, one occurrence of R 3 is - L 4 - R 4 , and one occurrence of R 3 is R c ’ (e.g., R c ’ can be a halogen, e.g., Br or Cl (e.g., R c’ can be Cl)).

[0503] In some embodiments, R 3 has one occurrence of -L 4 -R 4 , and R 3 has one occurrence of H.

[0504] In some embodiments, R 3 has two occurrences that are independently selected from -L 4 -R 4 .

[0505] In certain of the foregoing embodiments, any remaining occurrences of R 3 are selected from H and R c’ . For example, any remaining occurrences of R 3 can be H.

[0506] As a non-limiting example of the foregoing embodiments, each of X 2 and X 3 can be CR 3 , where each R 3 is independently selected from -L 4 -R 4 (in certain embodiments, each of X 1 and X 4 is independently CH or N).

[0507] In some embodiments, R 3 has one occurrence of H or R c '(for example, R c ' can be a halogen, for example, Br or Cl; or R c ' can be -OH or NH2).

[0508] In certain embodiments, when R 3 has one occurrence of R c ', each of the remaining occurrences of R 3 is independently H or R c '. For example, each of the remaining occurrences of R 3 can be H.

[0509] In certain embodiments, when R 3 has one occurrence of R c’ ; and one or more of the remaining occurrences of R 3 are independently selected from -L 4 -R 4 and R c’ .

[0510] In some embodiments, R 3 has one occurrence of H.

[0511] X1 -X 4 and R 3 a non-limiting combination of

[0512] In some embodiments, part (the structure originally provided in U.S. Provisional Application Serial No. 62 / 742,218 has been redrawn to further clarify the connection points) is (the structure originally provided in U.S. Provisional Application Serial No. 62 / 742,218 has been redrawn to further clarify the connection points), where * represents the connection point with NR 2 ; and represents the connection point with A 1 .

[0513] In certain embodiments, R 3B is -L 4 -R 4 ; and R 3C is H (e.g., -L 4 can be NHS(O)2).

[0514] In certain embodiments, R 3B is -L 4 -R 4 ; and R 3C is R c’ (e.g., R c’ can be a halogen such as -Cl; and / or -L 4 can be NHS(O)2).

[0515] In certain embodiments, R 3B is -L 4 -R 4 ; and R 3C is independently selected -L 4 -R 4 . In certain of the foregoing embodiments, the -L 3B of R 4 is different from the -L 3C of R 4 . As a non-limiting example, the -L 3B of R 4 can be NHS(O)2; and the -L 3C of R 4 can be a bond.

[0516] In certain embodiments, R 3B is H; and R 3C is -L 4 -R 4( For example, -L 4It can be NHS(O)2).

[0517] In certain embodiments, R 3B is R c’ ; and R 3C is -L 4 -R 4( For example, -L 4 can be NHS(O)2).

[0518] In certain embodiments, R 3B is H; and R 3C is R c’ .

[0519] In some embodiments, the moiety (the structure originally provided in U.S. Provisional Application Serial No. 62 / 742,218 has been redrawn to further clarify the point of attachment) is (the structure originally provided in U.S. Provisional Application Serial No. 62 / 742,218 has been redrawn to further clarify the point of attachment), where * represents the point of attachment to NR 2 ; and represents the point of attachment to A 1 .

[0520] In certain embodiments, R 3A is H.

[0521] In certain of the foregoing embodiments, R 3B is -L 4 -R 4( For example, -L 4 can be NHS(O)2).

[0522] In some embodiments, the moiety (the structure originally provided in U.S. Provisional Application Serial No. 62 / 742,218 has been redrawn to further clarify the point of attachment) is (the structure originally provided in U.S. Provisional Application Serial No. 62 / 742,218 has been redrawn to further clarify the point of attachment), where * represents the point of attachment to NR 2 ; and represents the point of attachment to A 1 .

[0523] In certain embodiments, R 3A is H.

[0524] In certain of the foregoing embodiments, R 3B is -L 4 -R4( For example, -L 4 can be NHS(O)2).

[0525] In certain of the foregoing embodiments, R 3B is -L 4 -R 4( For example, -L 4 can be NHS(O)2); and R 3C is H.

[0526] In certain of the foregoing embodiments, R 3B is -L 4 -R 4( For example, -L 4 can be NHS(O)2); and R 3C is R c’ .

[0527] In certain of the foregoing embodiments, R 3B is -L 4 -R 4( For example, -L 4 can be NHS(O)2); and R 3C is independently selected -L 4 -R 4 . In certain of the foregoing embodiments, the -L of R 3B is different from the -L of R 4 . As a non-limiting example, the -L of R 3C can be NHS(O)2; and the -L of R 4 can be a bond. 3B 4 3C 4 2 1 3D 3B

[0528] In some embodiments, the moiety (the structure originally provided in U.S. Provisional Application Serial No. 62 / 742,218 has been redrawn to further illustrate the point of attachment) is (the structure originally provided in U.S. Provisional Application Serial No. 62 / 742,218 has been redrawn to further illustrate the point of attachment), where * represents the point of attachment to NR 2 ; and represents the point of attachment to A 1 .

[0529] In certain embodiments, R 3D is H.

[0530] In certain of the foregoing embodiments, R 3B is -L 4-R 4( For example, -L 4 can be NHS(O)2).

[0531] In certain of the foregoing embodiments, R 3B is -L 4 -R 4( For example, -L 4 can be NHS(O)2); and R 3C is H.

[0532] In certain of the foregoing embodiments, R 3B is -L 4 -R 4( For example, -L 4 can be NHS(O)2); and R 3C is R c’ .

[0533] In certain of the foregoing embodiments, R 3B is -L 4 -R 4( For example, -L 4 can be NHS(O)2); and R 3C is independently selected -L 4 -R 4 . In certain of the foregoing embodiments, the -L of R 3B is different from the -L of R 4 . As a non-limiting example, the -L of R 3C can be NHS(O)2; and the -L of R 4 can be a bond. 3B 4 3C 4 4 4 1-2 d

[0534] The variable L 4

[0535] In some embodiments, -L 4 is -N(H)S(O) 1-2 - or -N(R d )S(O) 1-2 . (For example, N(C 1-3 alkyl)S(O)2).

[0536] In certain of the foregoing embodiments, -L 4 is -N(H)S(O)2-.

[0537] In some embodiments, -L 4 is -N(H)S(O)(=NH)-, -N(R d)S(O)(=NH), N(H)S(O)(=NR d )-, or -N(R d )S(O)(=NR d )-.

[0538] In certain of the foregoing embodiments, -L 4 is -N(H)S(O)(=NH)-.

[0539] In some embodiments, -L 4 is -S(O)(=NH)NH-, -S(O)(=NR d )NH-, -S(O)(=NH)NR d -, or -S(O)(=NR d )NR d )-.

[0540] In certain of the foregoing embodiments, -L 4 is -S(O)(=NH)NH-.

[0541] In some embodiments, -L 4 is -S(O) 1-2 N(H)- or -S(O) 1-2 N(R d )-.

[0542] In certain of the foregoing embodiments, -L 4 is -S(O)2N(H)-.

[0543] In some embodiments, -L 4 is -N(H)C(O)- or -N(R d )C(O).

[0544] In certain of the foregoing embodiments, -L 4 is -N(H)C(O)-.

[0545] In some embodiments, L 4 is -C(O)NH- or -C(O)N(R d )-.

[0546] In some embodiments, -L 4 is -N(H)-, -N(R d )-, or -N(R 4 )-.

[0547] In certain embodiments, -L 4 is -N(H)- or -N(R 4 )-.

[0548] In some embodiments, -L 4 is a single bond.

[0549] In some embodiments, -L 4 is C≡C.

[0550] In some embodiments, -L 4 is -O-.

[0551] In some embodiments, L 4 is selected from: -N(H)S(O) 1-2 N(H)-, -N(R d )S(O) 1-2 N(H)-, -N(H)S(O) 1- 2N(R d )-, and -N(R d )S(O) 1-2 N(R d )-.

[0552] In some embodiments, L 4 is -N(H)S(O) 1-2 N(H)-(e.g., -N(H)S(O)2N(H)-).

[0553] In some embodiments, L 4 is -N(H)S(O) 1-2 N(R d )-(e.g., -N(H)S(O)2N(R d )-, e.g., -N(H)S(O)2N(C 1-3 alkyl)-).

[0554] In some embodiments, -L 4 is selected from -N(H)S(O)2-, C≡C, single bond, -C(O)N(H)-, -N(H)-, -N(R 4 )-, -N(R d )-, and -N(H)C(O)-.

[0555] In certain of the foregoing embodiments, -L 4 is selected from --N(H)S(O)2-, single bond, -NH-, -N(R 4 )-, and -N(H)C(O)-.

[0556] In some embodiments, -L 4 is selected from:

[0557] (i) a bond (in certain embodiments, when -L 4 is a bond; and R 4 is -(Y3 ) p -Y 4 , then p is 1).

[0558] (ii) N(R 4 )

[0559] (iii) -N(H)S(O) 1-2 - or -N(R d )S(O) 1-2 -

[0560] (iv) -S(O) 1-2 N(H)- or -S(O) 1-2 N(R d )-

[0561] (vi) -S(O) 1-2 -

[0562] (viii) -N(H)C(O)- or -N(R d )C(O)-

[0563] (ix) -C≡C

[0564] (x) -N(H)S(O)(=NH)-, -N(R d )S(O)(=NH), -N(H)S(O)(=NR d )-, or -N(R d )S(O)(=NR d )-

[0565] (xi) -S(O)(=NH)NH-, -S(O)(=NR d )NH-, -S(O)(=NH)NR d -, or

[0566] -S(O)(=NR d )NR d -; and

[0567] (xii) -S(O)(=NH)- or -S(O)(=NR d )

[0568] The variable R 4

[0569] In some embodiments, R 4 is -(Y 3 ) p -Y 4 .

[0570] In some embodiments, p is 0.

[0571] In other embodiments, p is 1. In some of these embodiments, Y 3 is C 1-3 alkylene. For example, Y 3 can be CH2 or CH2-CH2.

[0572] In some embodiments, Y 2 is C 6-10 aryl, which is optionally substituted with 1-4 R c groups.

[0573] In some embodiments, Y 2 is phenyl, which is optionally substituted with 1-2 (e.g., 1) R c groups.

[0574] In certain embodiments, when Y 4 is C 6-10 aryl, which is optionally substituted with 1-4 R c (e.g., when Y 4 is phenyl, which is optionally substituted with 1-2 (e.g., 1) R c ), each occurrence of R c is independently selected from:

[0575] (i) halogen;

[0576] (ii) cyano;

[0577] (iii) C 1-6 alkyl;

[0578] (iv) C 2-6 alkenyl;

[0579] (v) C 2-6 alkynyl;

[0580] (vi) C 1-4 haloalkyl;

[0581] (vii) C 1-4 alkoxy;

[0582] (viii) C 1-4 haloalkoxy;

[0583] (ix) -(C 1-4 alkylene)-C 0-3 cycloalkyl optionally substituted with 1-4 independently selected C 3-6 alkyl;

[0584] (xiv) -C 1-4 thioalkoxy, and

[0585] (xx) C3-6 Cyclanoxy

[0586] In certain embodiments, when Y 4 is C 6-10 aryl, which is optionally substituted with 1 - 4 R c (e.g., when Y 4 is phenyl, which is optionally substituted with 1 - 2 (e.g., 1) R c ), each occurrence of R c is independently selected from:

[0587] (i) halogen;

[0588] (iii) C 1-6 alkyl;

[0589] (vi) C 1-4 haloalkyl;

[0590] (vii) C 1-4 alkoxy; and

[0591] (viii) C 1-4 haloalkoxy.

[0592] In certain embodiments, when Y 4 is C 6-10 aryl, each occurrence of R c is independently selected from:

[0593] (vii) C 1-4 alkoxy;

[0594] (viii) C 1-4 haloalkoxy; and

[0595] (xiv) - C 1-4 thioalkoxy.

[0596] In certain embodiments, Y 4 is C 6-10 aryl (e.g., phenyl), which is unsubstituted.

[0597] In certain embodiments, when p = 1 and Y 4 is C 6-10 aryl, R 4 is selected from:

[0598]

[0599] In certain embodiments, when p = 1 and Y 4 is C 6-10 aryl, R 4 is selected from:

[0600]

[0601] In certain embodiments, when p = 0 and Y 4 is C 6-10 aryl, R 4 is:

[0602]

[0603] In certain embodiments, when p = 0 and Y 4 is C 6-10 aryl, R 4 is:

[0604]

[0605] In some embodiments, Y 4 is C 3-6 (e.g., C 3-4 or C6) cycloalkyl, which is optionally substituted with 1 - 4 R b substituents.

[0606] In certain of the foregoing embodiments, Y 4 is cyclopropyl, which is optionally substituted with 1 - 2 R b substituents. For example, Y 4 is unsubstituted cyclopropyl.

[0607] In some embodiments, Y 4 is C6 cycloalkyl (e.g., cyclohexyl), which is optionally substituted with 1 - 2 R b substituents.

[0608] In certain of the foregoing embodiments when Y 4 is cycloalkyl, which is optionally substituted with 1 - 4 R b substituents, each occurrence of R b is independently selected from: -F, C 1-6 alkyl, C 1-4 haloalkyl, and -OH (e.g., R b can be OH; and / or R b can be C 1-6 alkyl such as methyl).

[0609] In certain embodiments, when p = 1 and Y 4 is C b cycloalkyl optionally substituted with 1 - 4 R 3-6 substituents, R 4 is selected from:

[0610]

[0611] In certain embodiments, when p = 1 and Y4 is optionally C-cycloalkyl substituted by 1-4 R b -cycloalkyl, where R 3-6 is selected from: 4 Selected from:

[0612]

[0613] In certain embodiments, when p = 0 and Y 4 is optionally C-cycloalkyl substituted by 1-4 R b -cycloalkyl, where R 3-6 is selected from: 4 Selected from:

[0614]

[0615] In certain embodiments, Y 4 is C 3-6 (e.g., C 3-4 or C6) cycloalkyl, which is unsubstituted.

[0616] In some of these embodiments, Y 4 is unsubstituted cyclopropyl or unsubstituted cyclobutyl (e.g., unsubstituted cyclopropyl).

[0617] In some embodiments, Y 4 is a heteroaryl containing 5-10 ring atoms, where 1-4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O, and S, and where one or more heteroaryl ring carbon atoms are optionally substituted by 1-4 independently selected R c .

[0618] In certain of the foregoing embodiments, Y 4 is a heteroaryl containing 6 ring atoms, where 1-4 ring atoms are heteroatoms, each independently selected from N, N(H), and N(R d ), and where one or more heteroaryl ring carbon atoms are optionally substituted by 1-4 independently selected R c .

[0619] As a non-limiting example of the foregoing, Y 4 can be pyridyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), pyrimidinyl (e.g., 2-pyrimidinyl or 5-pyrimidinyl), or pyrazinyl, each of which is optionally substituted by 1-2 independently selected R c .

[0620] For example, Y 4 can be pyridyl, pyrimidinyl, or pyrazinyl, each of which is unsubstituted.

[0621] In certain embodiments, when Y 4 is an optionally substituted heteroaryl group with one or more independently selected R as defined above c each occurrence of R c is independently selected from

[0622] (i) halogen;

[0623] (ii) cyano;

[0624] (iii) C 1-6 alkyl;

[0625] (iv) C 2-6 alkenyl;

[0626] (v) C 2-6 alkynyl;

[0627] (vi) C 1-4 haloalkyl;

[0628] (vii) C 1-4 alkoxy;

[0629] (viii) C 1-4 haloalkoxy;

[0630] (ix) -(C 1-4 alkylene)-C 0-3 cycloalkyl, optionally substituted with 1 - 4 independently selected C 3-6 alkyl;

[0631] (xii) OH;

[0632] (xiv) -C 1-4 thioalkoxy, and

[0633] (xx) C 3-6 cycloalkoxy.

[0634] In some of these embodiments, each occurrence of R c is independently selected from

[0635] (i) halogen (e.g., F, Cl);

[0636] (iii) C 1-6 alkyl (e.g., methyl); and

[0637] (xii) OH.

[0638] In certain embodiments, when p = 1; and Y 4 is a heteroaryl group, R 4 is selected from

[0639]

[0640]

[0641] In certain embodiments, when p = 1; and Y 4 is a heteroaryl, R 4 is selected from:

[0642]

[0643] In certain embodiments, when p = 0; and Y 4 is a heteroaryl, R 4 is selected from:

[0644]

[0645] In certain embodiments, when p = 0; and Y 4 is a heteroaryl, R 4 is selected from:

[0646]

[0647] In some embodiments, Y 4 is a heterocyclic group containing 3 to 10 ring atoms, wherein 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), and O, and wherein one or more of the heterocyclic group ring carbon atoms are optionally substituted by 1 to 4 independently selected R b .

[0648] In certain of the foregoing embodiments, Y 4 is a heterocyclic group containing 4 to 6 ring atoms, wherein 1 to 2 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), and O, and wherein one or more of the heterocyclic group ring carbon atoms are optionally substituted by 1 to 4 independently selected R b .

[0649] In certain embodiments, Y 4 is a heterocyclic group containing 4 ring atoms, wherein 1 ring atom is a heteroatom, independently selected from N, N(H), N(R d ), and O, and wherein one or more of the heterocyclic group ring carbon atoms are optionally substituted by 1 to 2 independently selected R b .

[0650] As a non-limiting example, Y 4 can be an oxetanyl optionally substituted by 1 to 2 independently selected R b (e.g., unsubstituted oxetanyl).

[0651] As another non-limiting example, Y4 can be an azetidinyl optionally substituted with 1-2 independently selected R b (e.g., an azetidinyl substituted with one R b ).

[0652] In some embodiments, Y 4 is a heterocyclic group containing 6 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), and O, and wherein one or more of the heterocyclic group ring carbon atoms are optionally substituted with 1-4 independently selected R b .

[0653] As a non-limiting example, Y 4 can be selected from tetrahydropyranyl, piperidinyl, piperazinyl, and morpholinyl, each of which is optionally substituted with 1-2 independently selected R b .

[0654] As a non-limiting example, Y 4 can be selected from tetrahydropyranyl, piperidinyl, and morpholinyl, each of which is optionally substituted with 1-2 independently selected R b .

[0655] In certain of the foregoing embodiments, when Y 4 is a heterocyclic group optionally substituted with 1-4 independently selected R b , each occurrence of R b is independently selected from: -F, C 1-6 alkyl, C 1-4 haloalkyl, oxo, and -OH.

[0656] In certain of the foregoing embodiments, when Y 4 is a heterocyclic group optionally substituted with 1-4 independently selected R b , each occurrence of R b is independently selected from: -F, C 1-6 alkyl, C 1-4 haloalkyl, and -OH (e.g., R b can be OH).

[0657] In some embodiments, when p = 1; and Y 4 is a heterocyclic group optionally substituted with 1-4 independently selected R b , R 4 is selected from:

[0658] In some embodiments, when p = 1; and Y 4 is a heterocyclic group optionally substituted with 1-4 independently selected R b , R4 is

[0659] In certain embodiments, when p = 0; and Y 4 is a heterocyclic group optionally substituted by 1 - 4 independently selected R b groups, R 4 is selected from:

[0660]

[0661] In certain embodiments, when p = 0; and Y 4 is a heterocyclic group optionally substituted by 1 - 4 independently selected R b groups, R 4 is selected from:

[0662]

[0663] In some embodiments, R 4 is C 1-10 alkyl, optionally substituted by 1 - 6 independently selected R a groups.

[0664] In certain embodiments, R 4 is C 1-6 alkyl, optionally substituted by 1 - 6 independently selected R a groups.

[0665] In certain embodiments, R 4 is C 1-6 alkyl, optionally substituted by 1 - 2 independently selected R a groups. For example, R 4 can be methyl.

[0666] In certain of the foregoing embodiments, when R 4 is C 1-6 alkyl, each occurrence of R a is independently selected from: -F, -OH; C 1-4 alkoxy; and C 1-4 haloalkoxy.

[0667] In certain embodiments, each occurrence of R a is independently -OH. For example, R 4 is

[0668] In some embodiments, R 4 is selected from methyl, ethyl,

[0669] In some embodiments, R 4Selected from methyl and

[0670] In some embodiments, R 4 is C 2-10( For example, C 2-4 ) alkynyl, which is optionally substituted with 1-6 (e.g., 1-3) independently selected R a (e.g., unsubstituted C 2-4 alkynyl such as ).

[0671] In some embodiments, R 4 is C 2-10( For example, C 2-4 ) alkenyl, which is optionally substituted with 1-6 (e.g., 1-3) independently selected R a (e.g., unsubstituted C 2-4烯基 , such as vinyl).

[0672] In some embodiments (e.g., when -L 4 is a bond or -O-), R 4 is C 2-10 alkyl, optionally substituted with 1-6 independently selected R a ; or methyl, optionally substituted with 1-2 independently selected R a .

[0673] In certain embodiments (e.g., when -L 4 is a bond or -O-), R 4 is C 2-10 alkyl, optionally substituted with 1-6 independently selected R a ; or methyl, substituted with 1-2 independently selected R a .

[0674] –L 4 and R 4 Non-limiting combinations

[0675] Non-limiting combination [A]

[0676] In some embodiments, -L 4 is selected from -N(H)S(O)2-, -N(H)S(O)2N(H)-, -N(H)S(O)2N(R d ), C≡C, a single bond, -C(O)N(H)-, -N(H)-, -N(R 4 ), -N(R d ), and -N(H)C(O)-; and

[0677] R 4 is selected from:

[0678] (i) C 1-6 alkyl, optionally substituted with 1 - 2 R a substituents;

[0679] (ii) -(Y 3 ) p -Y 4 ; and

[0680] (iii) C 2-10 alkenyl or C 2-10 alkynyl, each optionally substituted with 1 - 3 independently selected R a substituents.

[0681] In certain embodiments, -L 4 is selected from -N(H)S(O)2-, -N(H)S(O)2N(H)-, and -N(H)S(O)2N(R d )-; and

[0682] R 4 is selected from:

[0683] (i) C 1-6 alkyl, optionally substituted with 1 - 2 R a substituents;

[0684] (ii) -(Y 3 ) p -Y 4 ; and

[0685] (iii) C 2-10 alkenyl or C 2-10 alkynyl, each optionally substituted with 1 - 3 independently selected R a substituents.

[0686] In some embodiments, -L 4 is selected from -N(H)S(O)2-, C≡C, single bond, -C(O)N(H)-, -N(H)-, -N(R 4 )-, -N(R d )-, and -N(H)C(O)-; and

[0687] R 4 is selected from:

[0688] (i) C 1-6 alkyl, optionally substituted with 1 - 2 R a substituents; and

[0689] (ii) -(Y 3 ) p -Y 4 .

[0690] In certain embodiments, -L 4Selected from --N(H)S(O)2-, single bond, -NH-, -N(R 4 )-, and -N(H)C(O)-; and

[0691] R 4 is selected from:

[0692] (i) C 1-6 alkyl, optionally substituted by 1-2 R a substituents; and

[0693] (ii) -(Y 3 ) p -Y 4 .

[0694] In certain embodiments, -L 4 is -N(H)S(O)2-; and R 4 is selected from:

[0695] (i) C 1-6 alkyl, optionally substituted by 1-2 R a substituents; and

[0696] (ii) -(Y 3 ) p -Y 4 .

[0697] In certain embodiments, -L 4 is a single bond; and R 4 is selected from:

[0698] (i) C 1-6 alkyl, optionally substituted by 1-2 R a substituents; and

[0699] (ii) -(Y 3 ) p -Y 4 .

[0700] In certain embodiments, -L 4 is -NH- or -N(R 4 )-; and R 4 is selected from:

[0701] (i) C 1-6 alkyl, optionally substituted by 1-2 R a substituents; and

[0702] (ii) -(Y 3 ) p -Y 4 .

[0703] In certain embodiments, -L 4is -N(H)C(O)-; and R 4 is selected from:

[0704] (i) C 1-6 alkyl, optionally substituted with 1 - 2 R a substituents; and

[0705] (ii) -(Y 3 ) p -Y 4 .

[0706] In certain of these embodiments, -L 4 is -N(H)S(O)2N(H)- or -N(H)S(O)2N(R d ); and

[0707] R 4 is selected from:

[0708] (i) C 1-6 alkyl, optionally substituted with 1 - 2 R a substituents; and

[0709] (ii) -(Y 3 ) p -Y 4 .

[0710] In certain embodiments, -L 4 is -N(H)S(O)2-; and R 4 is selected from:

[0711] R 4 is selected from:

[0712] (i) C 1-6 alkyl, optionally substituted with 1 - 2 R a substituents;

[0713] (ii) -(Y 3 ) p -Y 4 ; and

[0714] (iii) C 2-10 alkenyl or C 2-10 alkynyl, each of which is optionally substituted with 1 - 3 independently selected R a substituents.

[0715] In certain embodiments, -L 4 is a single bond; and R 4 is selected from:

[0716] R 4 is selected from:

[0717] (i) C 1-6Alkyl, optionally substituted by 1-2 R a substituents;

[0718] (ii)-(Y 3 ) p -Y 4 ; and

[0719] (iii)C 2-10 alkenyl or C 2-10 alkynyl, each of which is optionally substituted by 1-3 independently selected R a substituents.

[0720] In certain embodiments, -L 4 is -NH- or -N(R 4 )-; and R 4 is selected from:

[0721] R 4 is selected from:

[0722] (i)C 1-6 alkyl, optionally substituted by 1-2 R a substituents;

[0723] (ii)-(Y 3 ) p -Y 4 ; and

[0724] (iii)C 2-10 alkenyl or C 2-10 alkynyl, each of which is optionally substituted by 1-3 independently selected R a substituents.

[0725] In certain embodiments, -L 4 is -N(H)C(O)-; and R 4 is selected from:

[0726] R 4 is selected from:

[0727] (i)C 1-6 alkyl, optionally substituted by 1-2 R a substituents;

[0728] (ii)-(Y 3 ) p -Y 4 ; and

[0729] (iii)C 2-10 alkenyl or C 2-10 alkynyl, each of which is optionally substituted by 1-3 independently selected R a substituents.

[0730] In certain embodiments, -L4 is -N(H)S(O)2N(H)- or -N(H)S(O)2N(R d )-; and

[0731] R 4 is selected from:

[0732] (i) C 1-6 alkyl, optionally substituted with 1 - 2 R a substituents;

[0733] (ii) -(Y 3 ) p -Y 4 ; and

[0734] (iii) C 2-10 alkenyl or C 2-10 alkynyl, each of which is optionally substituted with 1 - 3 independently selected R a substituents.

[0735] In some embodiments of [A], R 4 is C a alkyl optionally substituted with 1 - 2 R 1-6 substituents.

[0736] In some embodiments of [A], R 4 is C 2-10 alkenyl or C 2-10 alkynyl, each of which is optionally substituted with 1 - 3 independently selected R a substituents.

[0737] In certain of these embodiments, R 4 is C 2-10( For example, C 2-5 ) alkynyl, which is optionally substituted with 1 - 3 independently selected R a substituents (for example, unsubstituted C 2-5 alkynyl such as ).

[0738] In some embodiments of [A], R 4 is -(Y 3 ) p -Y 4 . In certain embodiments, Y 2 is C 6-10 aryl, which is optionally substituted with 1 - 4 R c substituents. For example, Y 4 can be phenyl, which is optionally substituted with 1 - 2 (for example, 1) R c substituents.

[0739] In some embodiments of [A], when R 4is -(Y 3 ) p -Y 4 When Y 4 is C 3-6 (e.g., C 3-4 or C6) cycloalkyl, which is optionally substituted by 1 - 4 R b . In certain embodiments, Y 4 is C 3-4 cycloalkyl or C6 cycloalkyl, each of which is optionally substituted by 1 - 2 R b (e.g., R b can be -OH).

[0740] In some embodiments of [A], R 4 is -(Y 3 ) p -Y 4 . In certain embodiments, Y 4 is a heterocyclic group containing 4 - 6 ring atoms, wherein 1 - 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ) and O, and one or more of the heterocyclic group ring carbon atoms are optionally substituted by 1 - 2 independently selected R b . In certain embodiments, Y 4 is a heterocyclic group containing 6 ring atoms, wherein 1 - 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ) and O, and one or more of the heterocyclic group ring carbon atoms are optionally substituted by 1 - 2 independently selected R b (e.g., Y 4 can be tetrahydropyranyl, piperidinyl, or morpholinyl, each of which is optionally substituted by 1 - 2 independently selected R b ). In certain embodiments, Y 4 is a heterocyclic group containing 4 ring atoms, wherein 1 - 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ) and O, and one or more of the heterocyclic group ring carbon atoms are optionally substituted by 1 - 2 independently selected R b (e.g., Y 4 can be oxetanyl; or Y 4 can be azetidinyl).

[0741] In some embodiments of [A], R 4 is -(Y 3 ) p -Y 4 . In certain embodiments, Y 4is a heteroaryl containing 6 ring atoms, where 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), and N(R d ), and where one or more of the heteroaryl ring carbon atoms are optionally substituted with 1 to 4 independently selected R c . In certain embodiments, Y 4 is pyridyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), pyrimidinyl (e.g., 2-pyrimidinyl or 5-pyrimidinyl), or pyrazinyl, each of which is optionally substituted with 1 to 2 independently selected R c .

[0742] In certain of the foregoing embodiments of [A], when R 4 is -(Y 3 ) p -Y 4 , p = 0.

[0743] In other embodiments of [A], when R 4 is -(Y 3 ) p -Y 4 , p = 1. In certain of these embodiments, Y 3 is C 1-3 alkylene (e.g., CH2, CH2-CH2).

[0744] In some embodiments, when R 3 is -L 4 -R 4 , R 3 is selected from:[[]]

[0745]

[0746] In some embodiments, when R 3 is -L 4 -R 4 , R 3 is selected from:[[]]

[0747]

[0748] In some embodiments, when R 3 is -L 4 -R 4 , R 3 is selected from:[[]]

[0749]

[0750] In some embodiments, when R 3 is -L 4 -R 4 , R3 Selected from:

[0751]

[0752] In some embodiments, when R 3 is -L 4 -R 4 then R 3 is selected from:

[0753]

[0754] In some embodiments, when R 3 is -L 4 -R 4 then R 3 is selected from:

[0755]

[0756] In some embodiments, when R 3 is -L 4 -R 4 then R 3 is selected from:

[0757]

[0758] In some embodiments, when R 3 is -L 4 -R 4 then R 3 is selected from:

[0759]

[0760] In some embodiments, when R 3 is -L 4 -R 4 then R 3 is selected from:

[0761]

[0762] In some embodiments, when R 3 is -L 4 -R 4 then R 3 is selected from:

[0763]

[0764] In some embodiments, when R 3 is -L 4 -R 4 then R 3 is selected from:

[0765]

[0766] In some embodiments, when R 3 is -L 4 -R 4 then R 3 is selected from:

[0767]

[0768] In some embodiments, when R 3 is -L 4 -R 4 then R 3 is selected from:

[0769]

[0770] In some embodiments, when R 3 is -L 4 -R 4 then R 3 is selected from:

[0771]

[0772]

[0773] In some embodiments, when R 3 is -L 4 -R 4 then R 3 is selected from: NHMe, and NMe2.

[0774] In some embodiments, when R 3 is -L 4 -R 4 then R 3 is selected from:

[0775]

[0776] In some embodiments, when R 3 is -L 4 -R 4 then R 3 is selected from:

[0777]

[0778] In certain of the foregoing embodiments, R 3 is

[0779] the variable R c’

[0780] In some embodiments, each occurrence of R c ’ is independently selected from:

[0781] (i) a halogen (e.g., -F, Cl);

[0782] (ii) a cyano group;

[0783] (iii) -OH;

[0784] (iv) -NO2;

[0785] (v) -C(=O)(C 1-4 alkyl);

[0786] (vi) -C(=O)O(C 1-4 alkyl);

[0787] (vii) -C(=O)OH; and

[0788] (viii) -NH2.

[0789] In certain embodiments, each occurrence of R c ’ is independently selected from:

[0790] (i) a halogen (e.g., -F, Cl);

[0791] (iii) -OH;

[0792] (iv) -NO2;

[0793] (v) -C(=O)(C 1-4 alkyl); and

[0794] (vi) -C(=O)O(C 1-4 alkyl).

[0795] In certain embodiments, each occurrence of R c ’ is independently selected from a halogen (e.g., -F, Cl).

[0796] In certain embodiments, each occurrence of R c ’ is independently selected from OH and NH2.

[0797] Non-limiting combinations

[0798] Non-limiting combination [1]

[0799] In some embodiments:

[0800] R 1 is -(Y 1 ) n -Y2 ; and

[0801] R 2 is C 6-10 aryl, which is optionally substituted with 1 - 4 R c .

[0802] In some of these embodiments, n is 0.

[0803] In certain of the foregoing embodiments of [1], X 1 , X 2 , X 3 , and X 4 of 1 - 2 are N; X 1 , X 2 , X 3 , and X 4 of 2 - 3 are each independently selected CR 3 .

[0804] In certain of the foregoing embodiments of [1], one of X 1 , X 2 , X 3 , and X 4 is N; each of the remaining X 1 , X 2 , X 3 , and X 4 is independently selected CR 3 ; or

[0805] Two of X 1 , X 2 , X 3 , and X 4 are N; each of the remaining X 1 , X 2 , X 3 , and X 4 is independently selected CR 3 .

[0806] In certain embodiments, 1 - 2 of X 2 and X 3 are independently CR 3 , such as where each of X 2 and X 3 is independently selected CR 3 . In certain of the foregoing embodiments, each of X 1 and X 4 is independently CH or N (for example, each of X 1 and X 4 is N).

[0807] In certain of the foregoing embodiments of [1], R3 One occurrence of is -L 4 -R 4 .

[0808] In certain of the foregoing embodiments of [1], R 4 is -(Y 3 ) p -Y 4 .

[0809] In certain of the foregoing embodiments, when R 4 is (Y 3 ) p -Y 4 , p = 1. In other embodiments, p = 0.

[0810] In certain of the foregoing embodiments of [1], R 4 is C 1-10 alkyl, optionally substituted by 1 - 6 independently selected R a substituents.

[0811] In certain of the foregoing embodiments of [1], each of the remaining occurrences of R 3 is independently selected from H and R c '. For example, each of the remaining occurrences of R 3 can independently be H.

[0812] In certain of the foregoing embodiments of [1], when one occurrence of R 3 is -L 4 -R 4 , one occurrence of R 3 is H.

[0813] In certain of the foregoing embodiments of [1], when one occurrence of R 3 is -L 4 -R 4 , one occurrence of R 3 is R c’ (for example, a halogen (for example, Br or Cl, for example, Cl)).

[0814] In some embodiments of [1], one occurrence of R 3 is R c’ (for example, Br or Cl, for example, Cl); and each of the remaining occurrences of R 3 is H.

[0815] In some embodiments of [1], Y 2 is defined as in any one of claims 14 - 20 and 26 - 28; and each R c , when present, is independently defined as in any one of claims 21 - 24.

[0816] In some embodiments of [1], Y 2 as defined in any one of claims 14 - 18; and each R c , when present, as defined in any one of claims 21 - 23.

[0817] In some embodiments of [1], Y 2 as defined in any one of claims 16 - 18; and each R c , when present, as defined in any one of claims 21 - 23.

[0818] In some embodiments of [1], Y 2 as defined in claim 18; and each R c , when present, as defined in claim 23.

[0819] In certain embodiments of [1], R 1 is R 1 is as

[0820] In some embodiments of [1], R 1 is as defined in any one of claims 10 - 23 of US 62 / 742,218 filed on October 5, 2018. In certain of the foregoing embodiments, R 1 is as defined in any one of claims 16 - 23 of US 62 / 742,218 filed on October 5, 2018. For example, R 1 may be as defined in claim 23 of US 62 / 742,218 filed on October 5, 2018. In some embodiments of [1], R 2 is C 6-10 aryl, which is optionally substituted with 1 - 4 R c substituents, such as phenyl, which is optionally substituted with 1 - 4 R c or 1 - 2 R c or 2 R c substituents; and R c , when present, is as described in any one of claims 33 - 35.

[0821] In some embodiments of [1], R 2 is as defined in any one of claims 24 - 31 of US 62 / 742,218 filed on October 5, 2018. In certain of the foregoing embodiments, R 2 is phenyl, which is optionally substituted with 2 R c substituents, such as where R 2 is and R c , when present, is defined as in any one of claims 33 - 35.

[0822] In certain embodiments of [1], R 2 is defined as in any one of claims 27 - 31 of US 62 / 742,218 filed on October 5, 2018. For example, R 2 can be

[0823] In some embodiments of [1], R 2 is a heteroaryl containing 5 - 10 (such as 6) ring atoms, wherein 1 - 4 (such as 1 - 3) ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O, and S (such as N, N(H), and N(R d )), and wherein one or more heteroaryl ring carbon atoms are optionally substituted with 1 - 4 independently selected R c substituents, such as wherein R 2 is a pyridyl group optionally substituted with 1 - 2 independently selected R c substituents, or such as wherein R 2 is and R c , when present, is defined as in any one of claims 40 - 41.

[0824] In certain embodiments of [1], R 2 is

[0825] In some embodiments of [1], R2 is defined as in any one of claims 32 - 37 of US 62 / 742,218 filed on October 5, 2018. In certain of the foregoing embodiments, R 2 is defined as in any one of claims 34 - 37 of US 62 / 742,218 filed on October 5, 2018. For example, R2 can be defined as in claim 37 of US 62 / 742,218 filed on October 5, 2018.

[0826] In some embodiments of [1], when one occurrence of R 3 is -L 4 -R 4 , -L 4 is selected from:

[0827] · -N(H)S(O) 1-2 - or -N(R d )S(O) 1-2 (e.g., N(C 1-3(alkyl)S(O)2), such as where L 4 is -N(H)S(O)2-;

[0828] · -N(H)C(O)- or -N(R d )C(O), such as where L 4 is -N(H)C(O)-;

[0829] · -C(O)NH- or -C(O)N(R d )-;

[0830] · -N(H)-, -N(R d )-, or -N(R 4 )-;

[0831] · single bond;

[0832] · C≡C;

[0833] · -O-; and

[0834] · -N(H)S(O) 1-2 N(H)-, -N(R d )S(O) 1-2 N(H)-, -N(H)S(O) 1-2 N(R d )-, and

[0835] -N(R d )S(O) 1-2 N(R d )-, such as where L 4 is -N(H)S(O) 1-2 N(H)-(e.g.,

[0836] -N(H)S(O)2N(H)-) or where L 4 is -N(H)S(O) 1-2 N(R d )-(e.g.,

[0837] -N(H)S(O)2N(R d )-(e.g., -N(H)S(O)2N(C 1-3烷基 )-));

[0838] and as defined in any one of claims 48 - 55 of US 62 / 742,218, filed October 5, 2018.

[0839] In some embodiments of [1], when one occurrence of R 3 is -L 4 -R 4 then -L 4Selected from:

[0840] · -N(H)S(O) 1-2 - or -N(R d )S(O) 1-2 (e.g., N(C 1-3 alkyl)S(O)2), such that L 4 is -N(H)S(O)2-;

[0841] · -N(H)C(O)- or -N(R d )C(O), such that L 4 is -N(H)C(O)-;

[0842] · -C(O)NH- or -C(O)N(R d )-;

[0843] · -N(H)-, -N(R d )-, or -N(R 4 )-;

[0844] · A single bond; and

[0845] · C≡C.

[0846] In some embodiments of [1], when one occurrence of R 3 is -L 4 -R 4 then -L 4 is selected from:

[0847] · N(H)S(O)2-;

[0848] · -N(H)C(O)-; and

[0849] · -N(H)-, -N(R d )-, or -N(R 4 )-.

[0850] In certain embodiments of [1], -L 4 is defined as in any one of claims 49, 51, and 53 of US 62 / 742,218, filed Oct. 5, 2018. For example, L 4 may be defined as in claim 49 of US 62 / 742,218, filed Oct. 5, 2018. In some embodiments of [1], when one occurrence of R 3 is -L 4 -R 4 then -L 4 is -NHS(O)(=NH)-.

[0851] In some embodiments of [1], when R3 One occurrence of is -L 4 -R 4 When, -L 4 Selected from:

[0852] -N(H)S(O) 1-2 - or -N(R d )S(O) 1-2 (e.g., N(C 1-3 alkyl)S(O)2), such as where L 4 is -N(H)S(O)2-; and

[0853] -N(H)S(O) 1-2 N(H)-, -N(R d )S(O) 1-2 N(H)-, -N(H)S(O) 1-2 N(R d )-, and -N(R d )S(O) 1-2 N(R d )-, such as where L 4 is -N(H)S(O) 1-2 N(H)-(e.g., -N(H)S(O)2N(H)-) or where L 4 is -N(H)S(O) 1-2 N(R d )-(e.g., -N(H)S(O)2N(R d )-(e.g., -N(H)S(O)2N(C 1-3烷基 ))).

[0854] In some embodiments of [1], when one occurrence of R 3 is -L 4 -R 4 ; and R 4 is (Y 3 ) p -Y 4 where Y 4 is C 6-10 aryl, which is optionally substituted with 1 - 4 R c such as phenyl, which is optionally substituted with 1 - 2 (e.g., 1) R c or where Y 4 is unsubstituted C 6-10 aryl such as unsubstituted phenyl; and R c , when present, is as defined in any one of claims 73 - 75.

[0855] In some embodiments of [1], when one occurrence of R 3 is -L 4-R 4 ; and R 4 is (Y 3 ) p -Y 4 , where Y 4 is C 6-10 aryl, which is optionally substituted by 1 - 4 R c substituents, such as phenyl, optionally substituted by 1 - 4 R c substituents; and where each occurrence of R c , when present, is independently selected from:

[0856] (vii) C 1-4 alkoxy;

[0857] (viii) C 1-4 haloalkoxy; and

[0858] (xiv) -C 1-4 thioalkoxy.

[0859] In some embodiments of [1], when one occurrence of R 3 is -L 4 -R 4 ; and R 4 is (Y 3 ) p -Y 4 , Y 4 is as defined in any one of claims 77, 78, 79, 81, and 82, and where R b , when present, is as defined in claim 80.

[0860] In some embodiments of [1], when one occurrence of R 3 is -L 4 -R 4 ; and R 4 is (Y 3 ) p -Y 4 , Y 4 is as defined in any one of claims 77 - 79; and R b , when present, is as defined in claim 80.

[0861] In some embodiments of [1], when one occurrence of R 3 is -L 4 -R 4 ; and R 4 is (Y 3 ) p -Y 4 , Y 4 is as defined in any one of claims 83 - 85 and 88; and R c, when present, as defined in any one of claims 86 - 87.

[0862] In some embodiments of [1], when R 3 has one occurrence of -L 4 -R 4 ; and R 4 is (Y 3 ) p -Y 4 , Y 4 as defined in any one of claims 83 - 85 and 88.

[0863] In some embodiments of [1], when R 3 has one occurrence of -L 4 -R 4 ; and R 4 is (Y 3 ) p -Y 4 , Y 4 as defined in any one of claims 89 - 96; and R b , when present, as defined in any one of claims 97 - 98.

[0864] In some embodiments of [1], when R 3 has one occurrence of -L 4 -R 4 ; and R 4 is (Y 3 ) p -Y 4 , Y 4 as defined in any one of claims 89 - 92, 94, 96; and R b , when present, as defined in claim 98.

[0865] In some embodiments of [1], R 4 is selected from the structures defined in claims 99 - 113.

[0866] In some embodiments of [1], R 4 is selected from the structures defined in claims 100, 101, 104 - 105, 107, 109, 111, and 113.

[0867] In some embodiments of [1], when R 3 has one occurrence of -L 4 -R 4 ;

[0868] ·R 4 is C 1-10 alkyl, which is optionally substituted with 1 - 6 independently selected R ais replaced by, or

[0869] ·R 4 is C 1-6 alkyl, which is optionally substituted by 1 to 6 independently selected R a is replaced by, or

[0870] ·R 4 is C 1-6 alkyl, optionally substituted by 1 to 2 independently selected R a wherein R 4 is selected from: methyl, ethyl, (such as methyl and ); or

[0871] ·R 4 is C 2-10 alkynyl (e.g., C 2-4 alkynyl), which is optionally substituted by 1 to 6 (e.g., 1 to 3) independently selected R a substituted (e.g., unsubstituted C 2-4 alkynyl, such as ); or

[0872] ·R 4 is C 2-10 alkenyl (e.g., C 2-4 alkenyl), which is optionally substituted by 1 to 6 (e.g., 1 to 3) independently selected R a substituted (e.g., unsubstituted C 2-4烯基 , such as vinyl); and

[0873] wherein each R a , when present, is independently selected from: -F; -OH; C 1-4 alkoxy; and C 1-4 haloalkoxy, such as wherein each occurrence of R a is independently -OH.

[0874] In some embodiments of [1], when one occurrence of R 3 is -L 4 -R 4 ,

[0875] ·R 4 is C 1-10 alkyl, which is optionally substituted by 1 to 6 independently selected R a substituted by, or

[0876] ·R 4 is C 1-6 alkyl, which is optionally substituted by 1 to 6 independently selected R a substituted by, or

[0877] ·R 4is C 1-6 alkyl, optionally substituted with 1-2 independently selected R a substituents, such as methyl and and

[0878] where each R a , when present, is independently selected from: -F; -OH; C 1-4 alkoxy; and C 1-4 haloalkoxy, such as -OH.

[0879] In some embodiments of [1], when one occurrence of R 3 is -L 4 -R 4 , R 4 is defined by any one of claims 56-60 and 61-63 of US 62 / 742,218 filed on October 5, 2018.

[0880] In some embodiments of [1], when one occurrence of R 3 is -L 4 -R 4 , R 4 is defined by any one of claims 56-60 and 64-67 of US 62 / 742,218 filed on October 5, 2018.

[0881] In some embodiments of [1], when one occurrence of R 3 is -L 4 -R 4 , R 4 is defined by any one of claims 56-60 and 68-71 of US 62 / 742,218 filed on October 5, 2018.

[0882] In some embodiments of [1], when one occurrence of R 3 is -L 4 -R 4 , R 4 is defined by any one of claims 56-60 and 72-78 of US 62 / 742,218 filed on October 5, 2018.

[0883] In some embodiments of [1], when one occurrence of R 3 is -L 4 -R 4 , R 4 is defined by any one of claims 56-60 and 79-86 of US 62 / 742,218 filed on October 5, 2018.

[0884] In some embodiments of [1], when R3 One occurrence of is -L 4 -R 4 When, R 4 As defined in any one of claims 56 - 60 and 87 - 92 of US 62 / 742,218 filed on October 5, 2018.

[0885] In certain embodiments of [1], -L 4 Selected from -N(H)S(O)2-, -N(H)S(O)2N(H)-, -N(H)S(O)2N(R d )-, C≡C, single bond, -C(O)N(H)-, -N(H)-, -N(R 4 )-, -N(R d )-, and -N(H)C(O)-; and

[0886] R 4 Selected from:

[0887] (i) C 1-6 alkyl, optionally substituted by 1 - 2 R a substituents;

[0888] (ii) -(Y 3 ) p -Y 4 ; and

[0889] (iii) C 2-10 alkenyl or C 2-10 alkynyl, each of which is optionally substituted by 1 - 3 independently selected R a substituents.

[0890] In certain embodiments of [1], -L 4 Selected from -N(H)S(O)2-, -N(H)S(O)2N(H)-, and -N(H)S(O)2N(R d )-; and

[0891] R 4 Selected from:

[0892] (i) C 1-6 alkyl, optionally substituted by 1 - 2 R a substituents;

[0893] (ii) -(Y 3 ) p -Y 4 ; and

[0894] (iii) C 2-10 alkenyl or C 2-10 alkynyl, each of which is optionally substituted by 1 - 3 independently selected R a substituents.

[0895] In some embodiments of [1], R 3 is selected from the structures defined in claims 148 - 165; or wherein R 3 is selected from the structures defined in claims 148 - 149, 151, 153, 155 - 156, 158, 160, 162, and 165.

[0896] In some embodiments of [1], R3 is defined as any one of claims 113 - 122 of US 62 / 742,218 filed on October 5, 2018.

[0897] [1 - 1]

[0898] In some embodiments of [1], X 2 and X 3 each is independently selected CR 3 ; and X 1 and X 4 的 each is independently N, or CH. In certain of these embodiments, X 1 and X 4 each is N. In certain of the foregoing embodiments, each R 3 is independently selected -L 4 -R 4 .

[0899] In some embodiments of [1 - 1], one occurrence of -L 4 -R 4 is -R 4 (i.e., one occurrence of L 4 is a bond).

[0900] In certain of these embodiments, other occurrences of -L 4 are selected from:

[0901] · -N(H)S(O) 1-2 - or -N(R d )S(O) 1-2 (e.g., N(C 1-3 alkyl)S(O)2), such as where L 4 is -N(H)S(O)2-;

[0902] · -N(H)C(O)- or -N(R d )C(O), such as where L 4 is -N(H)C(O)-;

[0903] · -C(O)NH- or -C(O)N(R d )-;

[0904] · -N(H)-, -N(R d )-, or -N(R 4 )-;

[0905] · A single bond;

[0906] · C≡C;

[0907] · -O-; and

[0908] · -N(H)S(O) 1-2 N(H)-, -N(R d )S(O) 1-2 N(H)-, -N(H)S(O) 1-2 N(R d )-, and -N(R d )S(O) 1-2 N(R d )-, such as where L 4 is -N(H)S(O) 1-2 N(H)-(e.g., -N(H)S(O)2N(H)-) or where L 4 is -N(H)S(O) 1-2 N(R d )-(e.g., -N(H)S(O)2N(R d )-(e.g., -N(H)S(O)2N(C 1-3烷基 )-)).

[0909] In certain embodiments, the other occurrences of -L 4 are selected from:

[0910] · -N(H)S(O) 1-2 - or -N(R d )S(O) 1-2 (e.g., N(C 1-3 alkyl)S(O)2), such as where L 4 is -N(H)S(O)2-;

[0911] · -N(H)C(O)- or -N(R d )C(O), such as where L 4 is -N(H)C(O)-;

[0912] · -C(O)NH- or -C(O)N(R d )-;

[0913] · -N(H)-, -N(R d )-, or -N(R 4 )-;

[0914] · a single bond; and

[0915] · C≡C.

[0916] In certain embodiments, -L 4 's other occurrences are selected from:

[0917] · -N(H)S(O)2-;

[0918] · -N(H)C(O)-; and

[0919] · -N(H)-, -N(R d )-, or -N(R 4 )-, where the other occurrences of -L 4 are N(H)S(O)2-.

[0920] In certain embodiments, -L 4 's other occurrences are selected from:

[0921] -N(H)S(O) 1-2 - or -N(R d )S(O) 1-2 (e.g., N(C 1-3 alkyl)S(O)2), where L 4 is -N(H)S(O)2-; and

[0922] -N(H)S(O) 1-2 N(H)-, -N(R d )S(O) 1-2 N(H)-, -N(H)S(O) 1-2 N(R d )-, and -N(R d )S(O) 1-2 N(R d )-, where L 4 is -N(H)S(O) 1-2 N(H)-(e.g., -N(H)S(O)2N(H)-) or where L 4 is -N(H)S(O) 1-2 N(R d )-(e.g., -N(H)S(O)2N(R d )-(e.g., -N(H)S(O)2N(C 1-3烷基 )-)).

[0923] In certain of the foregoing embodiments, -L 4 's other occurrences are defined as in any one of claims 48 - 55 of US 62 / 742,218 filed on October 5, 2018. For example, -L 4Other occurrences may be defined as any one of claims 49, 51, and 53 (e.g., claim 49) filed on October 5, 2018.

[0924] In some embodiments of [1-1], each R 4 is independently defined as any one of claims 56-60 and 61-63 of US 62 / 742,218 filed on October 5, 2018.

[0925] In some embodiments of [1-1], each R 4 is independently defined as any one of claims 56-60 and 64-67 of US 62 / 742,218 filed on October 5, 2018.

[0926] In some embodiments of [1-1], each R 4 is independently defined as any one of claims 56-60 and 68-71 of US 62 / 742,218 filed on October 5, 2018.

[0927] In some embodiments of [1-1], each R 4 is independently defined as any one of claims 56-60 and 72-78 of US 62 / 742,218 filed on October 5, 2018.

[0928] In some embodiments of [1-1], each R 4 is independently defined as any one of claims 79-86 of US 62 / 742,218 filed on October 5, 2018.

[0929] In some embodiments of [1-1], each R 4 is independently defined as any one of claims 87-92 of US 62 / 742,218 filed on October 5, 2018.

[0930] In some embodiments of [1-1], R 1 is defined as any one of claims 10-23 of US 62 / 742,218 filed on October 5, 2018.

[0931] In some embodiments of [1-1], R 1 is defined as any one of claims 16-23 of US 62 / 742,218 filed on October 5, 2018.

[0932] In some embodiments of [1-1], R 1 is defined as defined in claim 23 of US 62 / 742,218 filed on October 5, 2018.

[0933] In some embodiments of [1-1], R2 is defined as in any one of claims 24-31 of US 62 / 742,218 filed on October 5, 2018.

[0934] In some embodiments of [1-1], R2 is defined as in any one of claims 27-31 of US 62 / 742,218 filed on October 5, 2018.

[0935] In some embodiments of [1-1], R 2 is defined as in any one of claims 32-37 (e.g., 34-37) of US 62 / 742,218 filed on October 5, 2018.

[0936] [1-2]

[0937] In some embodiments of [1], each of X 2 and X 3 is independently selected from CR 3 ; and each of X 1 and X 4 的 is independently N or CH. In certain of these embodiments, each of X 1 and X 4 is N.

[0938] In some embodiments of [1-2], one occurrence of R 3 is -L 4 -R 4 (e.g., -L 4 as defined in claim 49); and the other occurrences of R 3 are R c’ (e.g., R c’ can be a halogen such as -Cl).

[0939] In certain of these embodiments, -L 4 is selected from:

[0940] · -N(H)S(O) 1-2 - or -N(R d )S(O) 1-2 (e.g., N(C 1-3 alkyl)S(O)2), such as where L 4 is -N(H)S(O)2-;

[0941] · -N(H)C(O)- or -N(R d )C(O), such as where L 4 is -N(H)C(O)-;

[0942] · -C(O)NH- or -C(O)N(R d )-;

[0943] · -N(H)-, -N(R d )-, or -N(R 4 )-;

[0944] · Single bond;

[0945] · C≡C;

[0946] · -O-; and

[0947] · -N(H)S(O) 1-2 N(H)-, -N(R d )S(O) 1-2 N(H)-, -N(H)S(O) 1-2 N(R d )-, and -N(R d )S(O) 1-2 N(R d )-, such that L 4 is -N(H)S(O) 1-2 N(H)-(e.g., -N(H)S(O)2N(H)-) or where L 4 is -N(H)S(O) 1-2 N(R d )-(e.g., -N(H)S(O)2N(R d )-(e.g., -N(H)S(O)2N(C 1-3烷基 )-)).

[0948] In certain embodiments, -L 4 is selected from:

[0949] · -N(H)S(O) 1-2 - or -N(R d )S(O) 1-2 (e.g., N(C 1-3 alkyl)S(O)2), such that L 4 is -N(H)S(O)2-;

[0950] · -N(H)C(O)- or -N(R d )C(O), such that L 4 is -N(H)C(O)-;

[0951] · -C(O)NH- or -C(O)N(R d )-;

[0952] · -N(H)-, -N(R d)-, or -N(R 4 )-;

[0953] · A single bond; and

[0954] · C≡C.

[0955] In certain embodiments, -L 4 is selected from:

[0956] · -N(H)S(O)2-;

[0957] · -N(H)C(O)-; and

[0958] · -N(H)-, -N(R d )-, or -N(R 4 )-, such that where -L 4 is otherwise N(H)S(O)2-.

[0959] In certain embodiments, -L 4 is selected from:

[0960] -N(H)S(O) 1-2 - or -N(R d )S(O) 1-2 (e.g., N(C 1-3 alkyl)S(O)2), such that where L 4 is -N(H)S(O)2-; and

[0961] -N(H)S(O) 1-2 N(H)-, -N(R d )S(O) 1-2 N(H)-, -N(H)S(O) 1-2 N(R d )-, and -N(R d )S(O) 1-2 N(R d )-, such that where L 4 is -N(H)S(O) 1-2 N(H)-(e.g., -N(H)S(O)2N(H)-) or where L 4 is -N(H)S(O) 1-2 N(R d )-(e.g., -N(H)S(O)2N(R d )-(e.g., -N(H)S(O)2N(C 1-3烷基 ))).

[0962] In certain of the foregoing embodiments, -L 4Other occurrences of are defined as any one of claims 48 - 55 of US 62 / 742,218 filed on October 5, 2018. For example, -L 4 Other occurrences of can be defined as any one of claims 49, 51, and 53 (e.g., claim 49) of the application filed on October 5, 2018.

[0963] In some embodiments of [1 - 2], each R 4 is independently defined as any one of claims 56 - 60 and 61 - 63 of US 62 / 742,218 filed on October 5, 2018.

[0964] In some embodiments of [1 - 2], each R 4 is independently defined as any one of claims 56 - 60 and 64 - 67 of US 62 / 742,218 filed on October 5, 2018.

[0965] In some embodiments of [1 - 2], each R 4 is independently defined as any one of claims 56 - 60 and 68 - 71 of US 62 / 742,218 filed on October 5, 2018.

[0966] In some embodiments of [1 - 2], each R 4 is independently defined as any one of claims 56 - 60 and 72 - 78 of US 62 / 742,218 filed on October 5, 2018.

[0967] In some embodiments of [1 - 2], each R 4 is independently defined as any one of claims 79 - 86 of US 62 / 742,218 filed on October 5, 2018.

[0968] In some embodiments of [1 - 2], each R 4 is independently defined as any one of claims 87 - 92 of US 62 / 742,218 filed on October 5, 2018.

[0969] In some embodiments of [1 - 2], R 1 is defined as any one of claims 10 - 23 of US 62 / 742,218 filed on October 5, 2018.

[0970] In some embodiments of [1 - 2], R 1 is defined as any one of claims 16 - 23 of US 62 / 742,218 filed on October 5, 2018.

[0971] In some embodiments of [1-2], R 1 As defined in claim 23 of US 62 / 742,218, filed October 5, 2018.

[0972] In some embodiments of [1-2], R2 is as defined in any one of claims 24-31 of US 62 / 742,218, filed October 5, 2018.

[0973] In some embodiments of [1-2], R2 is as defined in any one of claims 27-31 of US 62 / 742,218, filed October 5, 2018.

[0974] In some embodiments of [1-2], R 2 As defined in any one of claims 32-37 (e.g., 34-37) of US 62 / 742,218, filed October 5, 2018.

[0975] Non-limiting combination [2]

[0976] In some embodiments, the compound of formula (I) is of formula (I-a1-a):

[0977]

[0978] Or a pharmaceutically acceptable salt thereof.

[0979] In some embodiments of [2], -L 4 Is selected from:

[0980] -N(H)S(O) 1-2 - Or -N(R d )S(O) 1-2 (e.g., N(C 1-3 alkyl)S(O)2), such as where L 4 Is -N(H)S(O)2-; and

[0981] -N(H)S(O) 1-2 N(H)-, -N(R d )S(O) 1-2 N(H)-, -N(H)S(O) 1-2 N(R d )-, and -N(R d )S(O) 1-2 N(R d )-, such as where L 4 Is -N(H)S(O) 1-2 N(H)-(e.g., -N(H)S(O)2N(H)-) or where L 4is -N(H)S(O) 1-2 N(R d )-(e.g., -N(H)S(O)2N(R d )-(e.g., -N(H)S(O)2N(C 1-3烷基 )-)).

[0982] In certain embodiments of [2], the compound of formula (I-a1-a) is of formula (I-a1-a1):

[0983]

[0984] or a pharmaceutically acceptable salt thereof.

[0985] In certain embodiments of [2], the compound of formula (I-a1-a) is of formula (I-a1-a2):

[0986]

[0987] or a pharmaceutically acceptable salt thereof.

[0988] In certain embodiments of [2], the compound of formula (I-a1-a) is of formula (I-a1-a3):

[0989] (e.g., R c’ is a halogen, e.g., -Cl);

[0990] or a pharmaceutically acceptable salt thereof.

[0991] In certain of the foregoing embodiments of [2], R 1 is defined as in any one of claims 10-23 of US 62 / 742,218 filed on October 5, 2018; and / or R 2 is defined as in any one of claims 24-37 of US 62 / 742,218 filed on October 5, 2018; and / or R 4 is defined as in any one of claims 56-92 of US 62 / 742,218 filed on October 5, 2018.

[0992] In certain embodiments of [2], the compound of formula (I-a1-a) is of formula (I-a1-a4):

[0993] (e.g., R 3 is R c’ ; or R 3 is -L 4 -R 4 );

[0994] or a pharmaceutically acceptable salt thereof. In certain embodiments of formula (I-a1-a4), L 3 is NHS(O)2.

[0995] In certain embodiments of formula (I-a1-a4), R 3 is H.

[0996] In certain embodiments of formula (I-a1-a4), R 3 is R c’ , such as a halogen (e.g., -Cl).

[0997] In certain embodiments of formula (I-a1-a4), R 3 is -L 4 -R 4 .

[0998] In certain of the foregoing embodiments of [2] (e.g., when the compound has formula (I-a1-a4)), L 4 is defined as in any one of claims 48-55 of US 62 / 742,218 filed on October 5, 2018; and / or R 4 is defined as in any one of the following: claims 56-60 of US 62 / 742,218 filed on October 5, 2018 and claims 61-63 of US 62 / 742,218 filed on October 5, 2018; or claims 56-60 of US 62 / 742,218 filed on October 5, 2018 and claims 64-67 of US 62 / 742,218 filed on October 5, 2018; or claims 56-60 of US 62 / 742,218 filed on October 5, 2018 and claims 68-71 of US 62 / 742,218 filed on October 5, 2018; or claims 56-60 of US 62 / 742,218 filed on October 5, 2018 and 72-78; or claims 79-86 of US 62 / 742,218 filed on October 5, 2018; or claims 87-92 of US 62 / 742,218 filed on October 5, 2018.

[0999] [2-1]

[1000] In some embodiments of [2], the compound of formula (I-a1-a) is of formula (I-a1-a5):

[1001] or a pharmaceutically acceptable salt thereof.

[1002] In some embodiments of [2-1], R c’is a halogen (e.g., -Cl).

[1003] In some embodiments of [2-1], R 1 is defined as any one of claims 10-23 of US 62 / 742,218 filed on October 5, 2018.

[1004] In some embodiments of [2-1], R 2 is defined as any one of claims 24-37 (e.g., claims 24-31) of US 62 / 742,218 filed on October 5, 2018.

[1005] In some embodiments of [2-1], R4 is defined as any one of claims 56-92 (e.g., claims 87-92) of US 62 / 742,218 filed on October 5, 2018. In some embodiments of [2-1], L 4 is -NHS(O)2-.

[1006] In some embodiments of [2-1], L 4 is -N(H)S(O)2N(H)- or -N(H)S(O)2N(R d )-.

[1007] [2-2]

[1008] In some embodiments of [2], the compound of formula (I-a1-a) is of formula (I-a1-a6):

[1009]

[1010] wherein each of L 4A and L 4B is independently selected L 4 ; and

[1011] each of R 4A and R 4B is independently selected R 4 ;

[1012] or a pharmaceutically acceptable salt thereof.

[1013] In some embodiments of [2-2], L 4B is a bond.

[1014] In some embodiments of [2-2], R 1 is defined as any one of claims 10-23 of US 62 / 742,218 filed on October 5, 2018.

[1015] In some embodiments of [2-2], R2 As defined in any one of claims 24 - 37 (e.g., claims 24 - 31) of US 62 / 742,218 filed on October 5, 2018.

[1016] In some embodiments of [2 - 2], R 4A As defined in any one of claims 56 - 92 of US 62 / 742,218 filed on October 5, 2018.

[1017] In some embodiments of [2 - 2], L 4A is - NHS(O)2 -.

[1018] In some embodiments of [2 - 2], L 4 is - N(H)S(O)2N(H)- or - N(H)S(O)2N(R d )-.

[1019] In some embodiments of [2 - 2], R 4B As defined in any one of claims 56 - 92 (e.g., claims 56 - 60 and 64 - 67) of US 62 / 742,218 filed on October 5, 2018.

[1020] [2 - 3]

[1021] In some embodiments of [2], the compound of formula (I - a1 - a) is of formula (I - a1 - a7), (I - a1 - a8) or (I - a1 - a9):

[1022]

[1023] wherein R d’ is H or R d (e.g., H or C 1-3 alkyl); or a pharmaceutically acceptable salt thereof.

[1024] Non-limiting combination [3]

[1025] In some embodiments, the compound of formula (I) is of formula (I - a1 - b):

[1026]

[1027] or a pharmaceutically acceptable salt thereof.

[1028] In certain embodiments of [3], the compound of formula (I - a1 - b) is of formula (I - a1 - b1) or formula (I - a1 - b2):

[1029] (e.g., L4 is N(H)SO2, -N(H)-, or NHC(O));

[1030] or a pharmaceutically acceptable salt thereof.

[1031] In some embodiments of [3], -L 4 is selected from:

[1032] -N(H)S(O) 1-2 - or -N(R d )S(O) 1-2 (e.g., N(C 1-3 alkyl)S(O)2), such as where L 4 is -N(H)S(O)2-; and

[1033] -N(H)S(O) 1-2 N(H)-, -N(R d )S(O) 1-2 N(H)-, -N(H)S(O) 1-2 N(R d )-, and -N(R d )S(O) 1-2 N(R d )-, such as where L 4 is -N(H)S(O) 1-2 N(H)-(e.g., -N(H)S(O)2N(H)-) or where L 4 is -N(H)S(O) 1-2 N(R d )-(e.g., -N(H)S(O)2N(R d )-(e.g., -N(H)S(O)2N(C 1-3烷基 ))).

[1034] In certain of the foregoing embodiments of [3], R 1 is defined as in any one of claims 10 - 23 of US 62 / 742,218 filed on October 5, 2018; and / or R 2 is defined as in any one of claims 24 - 37 of US 62 / 742,218 filed on October 5, 2018; and / or R 4 is defined as in any one of claims 56 - 92 of US 62 / 742,218 filed on October 5, 2018.

[1035] In certain of the foregoing embodiments of [3], R c ' is selected from halogen (e.g., Cl, Br), -OH, and NH2.

[1036] Non-limiting combination [4]

[1037] In some embodiments, the compound of formula (I) is of formula (I-a2-a):

[1038]

[1039] or a pharmaceutically acceptable salt thereof.

[1040] In certain embodiments of [4], the compound of formula (I-a2-a1) is the compound of formula (I-a2-a1):

[1041]

[1042] or a pharmaceutically acceptable salt thereof.

[1043] In certain of the foregoing embodiments of [4], R 1 is defined as in any one of claims 10-23 of US 62 / 742,218 filed on October 5, 2018; and / or R 2 is defined as in any one of claims 24-37 of US 62 / 742,218 filed on October 5, 2018; and / or R 4 is defined as in any one of claims 56-92 of US 62 / 742,218 filed on October 5, 2018.

[1044] In certain embodiments of [4], the compound of formula (I-a2-a) is of formula (I-a1-a2):

[1045] (e.g., L 4 is NHS(O)2);

[1046] or a pharmaceutically acceptable salt thereof.

[1047] In certain of the foregoing embodiments of [4] (e.g., when the compound has the formula (I-a2-a2)), L 4 is defined as in any one of claims 48-55 (e.g., 49) of US 62 / 742,218 filed on October 5, 2018; and / or R 4As defined in any of the following: claims 56 - 60 of US 62 / 742,218 filed on October 5, 2018 and claims 61 - 63 of US 62 / 742,218 filed on October 5, 2018; or claims 56 - 60 of US 62 / 742,218 filed on October 5, 2018 and claims 64 - 67 of US 62 / 742,218 filed on October 5, 2018; or claims 56 - 60 of US 62 / 742,218 filed on October 5, 2018 and claims 68 - 71 of US 62 / 742,218 filed on October 5, 2018; or claims 56 - 60 of US 62 / 742,218 filed on October 5, 2018 and claims 72 - 78 of US 62 / 742,218 filed on October 5, 2018; or claims 79 - 86 of US 62 / 742,218 filed on October 5, 2018; or claims 87 - 92 of US 62 / 742,218 filed on October 5, 2018.

[1048] Non-limiting combination [5]

[1049] In some embodiments, the compound of formula (I) is of formula (I - b1 - a):

[1050]

[1051] or a pharmaceutically acceptable salt thereof.

[1052] In certain embodiments of [5], the compound of formula (I - b1 - a) is of formula (I - b1 - a1):

[1053]

[1054] or a pharmaceutically acceptable salt thereof.

[1055] In certain of the foregoing embodiments of [5], R 1 as defined in any one of claims 10 - 23 of US 62 / 742,218 filed on October 5, 2018; and / or R 2 as defined in any one of claims 24 - 37 of US 62 / 742,218 filed on October 5, 2018; and / or R 4 as defined in any one of claims 56 - 92 of US 62 / 742,218 filed on October 5, 2018.

[1056] In certain embodiments of [5], the compound of formula (I - b1 - a) is of formula (I - b1 - a3):

[1057]

[1058] wherein R d’ is H or R d (e.g., H or C 1-3 alkyl); or a pharmaceutically acceptable salt thereof.

[1059] In certain embodiments of [5], the compound of formula (I-b1-a) is of formula (I-b1-a2):

[1060] (e.g., L 4 is NHS(O)2);

[1061] or a pharmaceutically acceptable salt thereof.

[1062] In certain embodiments of formula (I-b1-a2), L 4 is NHS(O)2.

[1063] In certain of the foregoing embodiments of [5] (e.g., when the compound has formula (I-b1-a2)), L 4 is defined as in any one of claims 48 - 55 (e.g., 49) of US 62 / 742,218 filed on October 5, 2018; and / or R 4 is defined as in any one of the following: claims 56 - 60 of US 62 / 742,218 filed on October 5, 2018 and claims 61 - 63 of US 62 / 742,218 filed on October 5, 2018; or claims 56 - 60 of US 62 / 742,218 filed on October 5, 2018 and claims 64 - 67 of US 62 / 742,218 filed on October 5, 2018; or claims 56 - 60 of US 62 / 742,218 filed on October 5, 2018 and claims 68 - 71 of US 62 / 742,218 filed on October 5, 2018; or claims 56 - 60 of US 62 / 742,218 filed on October 5, 2018 and claims 72 - 78 of US 62 / 742,218 filed on October 5, 2018; or claims 79 - 86 of US 62 / 742,218 filed on October 5, 2018; or claims 87 - 92 of US 62 / 742,218 filed on October 5, 2018.

[1064] Non-limiting combination [6]

[1065] In some embodiments, the compound of formula (I) is of formula (I-c1-a):

[1066]

[1067] or a pharmaceutically acceptable salt thereof.

[1068] In certain embodiments of [6], the compound of formula (I-c1-a) is of formula (I-c1-a1):

[1069]

[1070] or a pharmaceutically acceptable salt thereof.

[1071] In certain foregoing embodiments of [6], R 1 is defined as in any one of claims 10-23 of US 62 / 742,218 filed on October 5, 2018; and / or R 2 is defined as in any one of claims 24-37 of US 62 / 742,218 filed on October 5, 2018; and / or R 4 is defined as in any one of claims 56-92 of US 62 / 742,218 filed on October 5, 2018.

[1072] In certain embodiments of [6], the compound of formula (I-c1-a) is of formula (I-c1-a2):

[1073] (e.g., L 4 is NHS(O)2);

[1074] or a pharmaceutically acceptable salt thereof.

[1075] In certain foregoing embodiments of [6] (e.g., when the compound has formula (I-c1-a2)), L 4 is defined as in any one of claims 48-55 (e.g., 49) of US 62 / 742,218 filed on October 5, 2018; and / or R 4As defined in any of the following: Claims 56 - 60 of US 62 / 742,218 filed on October 5, 2018 and Claims 61 - 63 of US 62 / 742,218 filed on October 5, 2018; or Claims 56 - 60 of US 62 / 742,218 filed on October 5, 2018 and Claims 64 - 67 of US 62 / 742,218 filed on October 5, 2018; or Claims 56 - 60 of US 62 / 742,218 filed on October 5, 2018 and Claims 68 - 71 of US 62 / 742,218 filed on October 5, 2018; or Claims 56 - 60 of US 62 / 742,218 filed on October 5, 2018 and Claims 72 - 78 of US 62 / 742,218 filed on October 5, 2018; or Claims 79 - 86 of US 62 / 742,218 filed on October 5, 2018; or Claims 87 - 92 of US 62 / 742,218 filed on October 5, 2018.

[1076] Non-limiting combination [7]

[1077] In some embodiments, the compound of formula (I) is of formula (I-d1-a):

[1078]

[1079] or a pharmaceutically acceptable salt thereof.

[1080] In certain embodiments of [7], the compound of formula (I-d1-a) is of formula (I-d1-a1):

[1081]

[1082] or a pharmaceutically acceptable salt thereof.

[1083] In certain embodiments of [7], R 1 is defined as in any of Claims 10 - 23 of US 62 / 742,218 filed on October 5, 2018; and / or R 2 is defined as in any of Claims 24 - 37 of US 62 / 742,218 filed on October 5, 2018; and / or R 4 is defined as in any of Claims 56 - 92 of US 62 / 742,218 filed on October 5, 2018.

[1084] In certain embodiments of [7], the compound of formula (I-d1-a) is of formula (I-d1-a2):

[1085] (e.g., L 4 is NHS(O)2);

[1086] or a pharmaceutically acceptable salt thereof.

[1087] In certain of the foregoing embodiments of [7] (e.g., when the compound has the formula (I-c1-a2)), L 4 is defined as in any one of claims 48-55 (e.g., 49) of US 62 / 742,218 filed on October 5, 2018; and / or R 4 is defined as in any one of: claims 56-60 of US 62 / 742,218 filed on October 5, 2018 and claims 61-63 of US 62 / 742,218 filed on October 5, 2018; or claims 56-60 of US 62 / 742,218 filed on October 5, 2018 and claims 64-67 of US 62 / 742,218 filed on October 5, 2018; or claims 56-60 of US 62 / 742,218 filed on October 5, 2018 and claims 68-71 of US 62 / 742,218 filed on October 5, 2018; or claims 56-60 of US 62 / 742,218 filed on October 5, 2018 and claims 72-78 of US 62 / 742,218 filed on October 5, 2018; or claims 79-86 of US 62 / 742,218 filed on October 5, 2018; or claims 87-92 of US 62 / 742,218 filed on October 5, 2018.

[1088] In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3], [3], [4], [5], [6], and [7], R 4 is selected from:

[1089] (i) C 1-10 alkyl, optionally substituted with 1-6 independently selected R a substituents;

[1090] (ii) -(Y 3 ) p -Y 4 ; and

[1091] (iii) C 2-10 alkenyl or C 2-10 alkynyl, each of which is optionally substituted with 1-3 independently selected R a substituents.

[1092] In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3], [3], [4], [5], [6], and [7], R 4 is -(Y 3 ) p -Y 4 .

[1093] In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3], [3], [4], [5], [6], and [7], when R 4 is -(Y 3 ) p -Y 4 , Y 4 is C 6-10 aryl, which is optionally substituted with 1-4 R c , such as phenyl, which is optionally substituted with 1-2 (e.g., 1) R c , or wherein Y 4 is unsubstituted C 6-10 aryl such as unsubstituted phenyl; and R c , when present, is as defined in any one of claims 73-75 (e.g., claim 75).

[1094] In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3], [3], [4], [5], [6], and [7], when R 4 is -(Y 3 ) p -Y 4 , Y 4 is C 6-10 aryl, which is optionally substituted with 1-4 R c , such as phenyl, optionally substituted with 1-4 R c ; and wherein each occurrence of R c , when present, is independently selected from:

[1095] (vii) C 1-4 alkoxy;

[1096] (viii) C 1-4 haloalkoxy; and

[1097] (xiv) -C 1-4 thioalkoxy.

[1098] In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3], [3], [4], [5], [6], and [7], when R 4 is -(Y 3 ) p -Y 4 then Y 4 is as defined in any one of claims 77, 78, 79, 81, and 82, and wherein R b , when present, is as defined in claim 80.

[1099] In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3], [3], [4], [5], [6], and [7], when R 4 is -(Y 3 ) p -Y 4 then Y 4 is as defined in any one of claims 77-79; and R b , when present, is as defined in claim 80.

[1100] In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3], [3], [4], [5], [6], and [7], when R 4 is -(Y 3 ) p -Y 4 then Y 4 is as defined in any one of claims 83-85 and 88; and R c , when present, is as defined in any one of claims 86-87.

[1101] In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3], [3], [4], [5], [6], and [7], when R 4 is -(Y 3 ) p -Y 4 then Y 4 is as defined in any one of claims 83-85 and 88.

[1102] In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3], [3], [4], [5], [6], and [7], when R 4 is -(Y 3 )p -Y 4 when, Y 4 as defined in any one of claims 89 - 96; and R b , when present, as defined in any one of claims 97 - 98.

[1103] In certain embodiments of any one or more of [1 - 1], [1 - 2], [2], [2 - 1], [2 - 2], [2 - 3], [3], [4], [5], [6], and [7], when R 4 is -(Y 3 ) p -Y 4 when, Y 4 as defined in any one of claims 89 - 92, 94, and 96; and R b , when present, as defined in claim 98.

[1104] In certain embodiments of any one or more of [1 - 1], [1 - 2], [2], [2 - 1], [2 - 2], [2 - 3], [3], [4], [5], [6], and [7], when R 4 is -(Y 3 ) p -Y 4 when, p is 0.

[1105] In other embodiments, p is 1. In certain of these embodiments, Y 3 is C 1-3 alkylene, such as CH2 or CH2 - CH2.

[1106] In certain embodiments of any one or more of [1 - 1], [1 - 2], [2], [2 - 1], [2 - 2], [2 - 3], [3], [4], [5], [6], and [7], R 4 is selected from the structures defined in claims 99 - 113.

[1107] In certain embodiments of any one or more of [1 - 1], [1 - 2], [2], [2 - 1], [2 - 2], [2 - 3], [3], [4], [5], [6], and [7], each R 4 is selected from the structures defined in claims 100, 101, 104 - 105, 107, 109, 111, and 113.

[1108] In certain embodiments of any one or more of [1 - 1], [1 - 2], [2], [2 - 1], [2 - 2], [2 - 3], [3], [4], [5], [6], and [7]],

[1109] ·R 4 is C 1-10 alkyl, which is optionally substituted by 1-6 independently selected Ra, or

[1110] ·R 4 is C 1-6 alkyl, which is optionally substituted by 1-6 independently selected Ra, or

[1111] ·R 4 is C 1-6 alkyl, optionally substituted by 1-2 independently selected Ra, such as where R 4 is selected from: methyl, ethyl, (such as methyl and ); or

[1112] ·R 4 is C 2-10 (for example, C 2-4 alkynyl) alkynyl, which is optionally substituted by 1-6 (for example, 1-3) independently selected Ra (for example, unsubstituted C 2-4 alkynyl, such as ); or

[1113] ·R 4 is C 2-10 (for example, C 2-4 alkenyl) alkenyl, which is optionally substituted by 1-6 (for example, 1-3) independently selected R a substituted (for example, unsubstituted C 2-4烯基 , such as vinyl); and

[1114] where each R a , when present, is independently selected from: -F; -OH; C 1-4 alkoxy; and C 1-4 haloalkoxy, such as where each occurrence of R a is independently -OH.

[1115] In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3], [3], [4], [5], [6], and [7],

[1116] ·R 4 is C 1-10 alkyl, which is optionally substituted by 1-6 independently selected R a substituted, or

[1117] ·R 4 is C 1-6 alkyl, which is optionally substituted by 1-6 independently selected R a substituted, or

[1118] ·R 4 is C 1-6 alkyl, optionally substituted by 1 - 2 independently selected R a substituents, such as methyl and

[1119] and

[1120] wherein each R a , when present, is independently selected from: -F; -OH; C 1-4 alkoxy; and C 1-4 haloalkoxy, such as -OH.

[1121] In certain embodiments of any one or more of [1 - 1], [1 - 2], [2], [2 - 1], [2 - 2], [2 - 3], [3], [4], [5], [6], and [7], R 1 is -(Y 1 ) n -Y 2 .

[1122] In certain of these embodiments, Y 2 is as defined in any one of claims 14 - 20; and each R c , when present, is independently as defined in any one of claims 21 - 24.

[1123] In certain embodiments of any one or more of [1 - 1], [1 - 2], [2], [2 - 1], [2 - 2], [2 - 3], [3], [4], [5], [6], and [7], when R 1 is -(Y 1 ) n -Y 2 , Y 2 is as defined in any one of claims 14 - 18 and 26; and each R c , when present, is as defined in any one of claims 21 - 23.

[1124] In certain embodiments of any one or more of [1 - 1], [1 - 2], [2], [2 - 1], [2 - 2], [2 - 3], [3], [4], [5], [6], and [7], when R 1 is -(Y 1 ) n -Y 2 , Y 2 is as defined in any one of claims 16 - 18; and each R c , when present, is as defined in any one of claims 21 - 23.

[1125] In certain embodiments of any one or more of [1 - 1], [1 - 2], [2], [2 - 1], [2 - 2], [2 - 3], [3], [4], [5], [6], and [7], when R 1 is -(Y 1 ) n -Y 2 then n is 0.

[1126] In certain embodiments of any one or more of [1 - 1], [1 - 2], [2], [2 - 1], [2 - 2], [2 - 3], [3], [4], [5], [6], and [7], when R 1 is -(Y 1 ) n -Y 2 then R 1 is As a non - limiting example, R 1 can be

[1127] In certain embodiments of any one or more of [1 - 1], [1 - 2], [2], [2 - 1], [2 - 2], [2 - 3], [3], [4], [5], [6], and [7], R 2 is C 6-10 aryl, which is optionally substituted with 1 - 4 R c , such as phenyl, which is optionally substituted with 1 - 4 R c or 1 - 2 R c or 2 R c ; and R c , when present, is as defined in any one of claims 33 - 35.

[1128] In certain embodiments of any one or more of [1 - 1], [1 - 2], [2], [2 - 1], [2 - 2], [2 - 3], [3], [4], [5], [6], and [7], R 2 is phenyl, which is optionally substituted with 2 R c , such as where R 2 is and R c , when present, is as defined in any one of claims 33 - 35.

[1129] In certain embodiments of any one or more of [1 - 1], [1 - 2], [2], [2 - 1], [2 - 2], [2 - 3], [3], [4], [5], [6], and [7], R 2is a heteroaryl containing 5 to 10 (such as 6) ring atoms, where 1 to 4 (such as 1 to 3) ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O, and S (such as N, N(H), N(R d ), and O), and where one or more heteroaryl ring carbon atoms are optionally substituted with 1 to 4 independently selected R c , such as where R 2 is a pyridyl optionally substituted with 1 to 2 independently selected R c , or such as where R 2 is and R c , when present, is as defined in any one of claims 40 - 41.

[1130] In certain embodiments of any one or more of [1 - 1], [1 - 2], [2], [2 - 1], [2 - 2], [2 - 3], [3], [4], [5], [6], and [7], R 2 is

[1131] In certain embodiments of any one or more of [1 - 1], [1 - 2], [2], [2 - 1], [2 - 2], [2 - 3], [3], [4], [5], [6], and [7], R 1 is -(Y 1 ) n -Y 2 ; and R 2 is C 6-10 aryl, which is optionally substituted with 1 to 4 R c .

[1132] In certain of these embodiments, n is 0.

[1133] In certain embodiments of any one or more of [1 - 1], [1 - 2], [2], [2 - 1], [2 - 2], [2 - 3], [3], [4], [5], [6], and [7], when R 1 is -(Y 1 ) n -Y 2 , Y 2 is a heteroaryl containing 6 ring atoms, where 1 to 2 ring atoms are N, and where one or more heteroaryl ring carbon atoms are optionally substituted with 1 to 4 independently selected R c .

[1134] In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3], [3], [4], [5], [6], and [7], when R 1 is -(Y 1 ) n -Y 2 where Y 2 is pyridyl (e.g., 2-pyridyl or 6-pyridyl), and one or more of the ring carbon atoms are optionally substituted with 1-4 (e.g., 1) independently selected R c .

[1135] In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3], [3], [4], [5], [6], and [7], when R 1 is -(Y 1 ) n -Y 2 ; and Y 2 is a heteroaryl (such as pyridyl) optionally substituted with 1-4 independently selected R c as defined above, each occurrence of R c is independently selected C 1-4 alkoxy (e.g., -OCH3, -OCH2CH3).

[1136] As a non-limiting example, R 1 is:.

[1137] In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3], [3], [4], [5], [6], and [7] (when R 1 is -(Y 1 ) n -Y 2 ; and R 2 is C 6-10 aryl, which is optionally substituted with 1-4 R c ), such as R 2 is phenyl, which is optionally substituted with 1-4 R c .

[1138] In certain of these embodiments, R 2 is phenyl, which is optionally substituted with 2 R c . For example, R 2 can be:.

[1139] In certain embodiments of any one or more of [1-1], [1-2], [2], [2-1], [2-2], [2-3], [3], [4], [5], [6], and [7], R 1 is and R 2 is

[1140] The specification ends with 302 claims. For ease of exposition, the definitions of certain variables refer to one or more specific claim numbers. Accordingly, it should be understood that the entire subject matter of each claim so referenced is incorporated by reference in its entirety into the portion of the present disclosure in which it is cited. To avoid doubt and by way of non-limiting example, use of the phrase (e.g., “Y 4 as defined in any one of claims 77, 78, 79, 81, and 82”) is intended to represent a shorthand for the following set of definitions:

[1141] Y 4 is C 3-6 (e.g., C 3-4 or C6) cycloalkyl, which is optionally substituted with 1-4 R b substituents.

[1142] Y 4 is cyclopropyl or cyclobutyl, which is optionally substituted with 1-2 R b substituents.

[1143] Y 4 is C6 cycloalkyl (e.g., cyclohexyl), which is optionally substituted with 1-2 R b substituents.

[1144] Y 4 is C 3-6 (e.g., C 3-4 or C6) cycloalkyl, which is unsubstituted.

[1145] Y 4 is unsubstituted cyclopropyl or unsubstituted cyclobutyl (e.g., unsubstituted cyclopropyl).

[1146] Y 4 is selected from C 3-6 (e.g., C 3-4 or C6) cycloalkyl, which is optionally substituted with 1-4 R b substituents; cyclopropyl or cyclobutyl, which is optionally substituted with 1-2 R b substituents; C6 cycloalkyl (e.g., cyclohexyl), which is optionally substituted with 1-2 R b substituents; C 3-6 (e.g., C 3-4a (C6) cycloalkyl group, which is unsubstituted; and an unsubstituted cyclopropyl or an unsubstituted cyclobutyl (e.g., unsubstituted cyclopropyl).

[1147] This also applies to the claims recited in the priority document US 62 / 742,218 filed on October 5, 2018.

[1148] Pharmaceutical compositions and administration

[1149] Overview

[1150] 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 comprising the chemical entity and one or more pharmaceutically acceptable excipients, and optionally one or more other therapeutic agents described herein.

[1151] In some embodiments, the chemical entity can be administered in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include, but are not limited to: ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS), such as d-α-tocopheryl 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, buffering substances, such as phosphates, tris(hydroxymethyl)aminomethane (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 silicon dioxide, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polypropylene-block polymers, and lanolin. Cyclodextrins such as α-, β- and γ-cyclodextrins, or chemically modified derivatives such as hydroxyalkyl cyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrin, or other solubilized derivatives can also be used to enhance the delivery of the compounds described herein. Dosage forms or compositions can be prepared that contain the chemical entities described herein in the range of 0.005%-100%, the balance being made up of non-toxic excipients. The compositions contemplated can contain 0.001%-100% of the chemical entities provided herein, 0.1-95% in one embodiment, 75-85% in another embodiment, and 20-80% in yet another embodiment. The actual methods of preparing such dosage forms are known or will be apparent to those skilled in the art; see, for example, Remington: The Science and Practice of Pharmacy, 22nd Edition (Pharmaceutical Press, London, UK, 2012).

[1152] Routes of administration and composition components

[1153] In some embodiments, the chemical entities described herein or their pharmaceutical compositions can be administered to a subject in need thereof by any acceptable route of administration. Acceptable routes of administration include, but are not limited to: buccal, transdermal, intra-cervical, intra-nasal, intra-tracheal, enteral, epidural, interstitial, intraperitoneal, intra-arterial, intra-bronchial, intrabursal, intracerebral, intracisternal, intra-coronary, intradermal, intra-catheter, intra-duodenal, intradural, intra-epidermal, intra-esophageal, intra-gastric, intra-gingival, intra-ileal, intra-lymphatic, intramedullary, intrameningeal, intramuscular, intra-ovarian, intraperitoneal, intra-prostatic, intra-pulmonary, intra-sinus, intraspinal, intra-synovial, intra-testicular, intrathecal, intra-tubular, intra-tumoral, intra-uterine, intra-vascular, intravenous, nasal, naso-gastric, oral, parenteral, transdermal, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral, and vaginal.

[1154] The composition can be formulated for parenteral administration, for example, formulated for injection by intravenous, intramuscular, subcutaneous or even intraperitoneal routes. Generally, such compositions can be made into injections, in the form of a liquid solution or a suspension; solid forms suitable for adding to a liquid to prepare a solution or a suspension before injection can also be prepared; and, the preparation can also be emulsified. According to the present disclosure, the preparation of such formulations is known to those skilled in the art.

[1155] Drug forms suitable for injection include sterile aqueous solutions or dispersions; formulations including aqueous solutions of sesame oil, peanut oil or propylene glycol; and sterile powders for the temporary preparation of sterile injectable solutions or dispersions. Generally, the form must be sterile and must be fluid to the extent that it is easy to inject. It should also be stable under the conditions of manufacture and storage and must be able to resist the contaminating action of microorganisms such as bacteria and fungi during storage.

[1156] The carrier can also be a solvent or dispersion medium comprising, for example, water, ethanol, polyols (such as glycerol, propylene glycol and liquid polyethylene glycol, etc.) and suitable mixtures thereof, as well as vegetable oils. Suitable fluidity can be maintained, for example, by using coatings such as lecithin, by maintaining the required particle size in the case of a dispersion system, and by using surfactants. The action of microorganisms can be prevented by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc. In many cases, it is preferred to include isotonic agents, such as sugars or sodium chloride. The absorption of the injectable composition can be prolonged by using agents that delay absorption, such as aluminum monostearate and gelatin, in the composition.

[1157] Sterile injectable solutions are prepared by incorporating the required amount of the active compound in a suitable solvent into the other aforesaid ingredients in different amounts and filtering sterilizing as required. Ordinarily, the various sterile active components are incorporated into a sterile vehicle containing a basic dispersion medium and the aforesaid other required ingredients to prepare a dispersion. When preparing sterile powders required for sterile injectable preparations, the preferred methods of preparation are vacuum drying and freeze drying techniques to obtain powders of the active component and any other required components from previously sterile filtered solutions.

[1158] Pharmaceutically acceptable excipients useful in rectal compositions as gels, creams, enemas or rectal suppositories include, but are not limited to, one or more of the following: cocoa butter glycerides, synthetic polymers (such as polyvinylpyrrolidone, PEG (such as PEG ointment)), glycerol, glycerogelatin, hydrogenated vegetable oils, poloxamers, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol, petrolatum, anhydrous lanolin, shark liver oil, sodium saccharin, menthol, sweet almond oil, sorbitol, sodium benzoate, Anoxid SBN, vanilla essential oil, aerosols, parabens in phenoxyethanol, sodium methylparaben, sodium propylparaben, diethylamine, carbomer, carbopol, methylparaben, cetostearyl ether of polyethylene glycol, caprylic / capric / capric triglyceride, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-pyrosulfite, sodium ethylenediaminetetraacetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methylsulfonylmethane (MSM), lactic acid, glycine, vitamins (such as vitamins A and E) and potassium acetate.

[1159] In certain embodiments, suppositories can be prepared by mixing the chemical entities described herein with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or suppository wax, which is solid at ambient temperature but liquid at body temperature and thus melts in the rectum and releases the active compound. In other embodiments, the compositions for rectal administration are in the form of enemas.

[1160] In other embodiments, the compounds or their pharmaceutical compositions described herein are adapted for topical delivery to the digestive tract or gastrointestinal tract by oral administration (e.g., solid or liquid dosage forms).

[1161] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the chemical entity is admixed with one or more pharmaceutically acceptable excipients such as sodium citrate or calcium phosphate dibasic and / or: a) fillers or diluents such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerin, d) disintegrants such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solubilizers such as paraffin wax, f) absorption promoters such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) adsorbents such as kaolin and bentonite, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, buffering agents may also be present in the dosage form. Similar types of solid compositions may also be used as fillers in soft and hard gelatin capsules, using excipients such as lactose or lactose fractions and high molecular weight polyethylene glycols.

[1162] In one embodiment, the composition may take the form of unit dosage forms such as pills or tablets and thus may contain in addition to the chemical entity provided herein: diluents such as lactose, sucrose, calcium phosphate dibasic, etc.; lubricants such as magnesium stearate, etc.; binders such as starch, acacia, polyvinylpyrrolidone, gelatin, cellulose, cellulose derivatives, etc. In another solid dosage form, powders, pills, solutions, or suspensions (e.g., in propylene carbonate, vegetable oils, PEG’s, poloxamer 124, or triglycerides) are encapsulated in a capsule (gelatin or cellulose-based capsule). Unit dosage forms in which one or more of the chemical entities provided herein or other active agents are physically separated are also contemplated, such as capsules containing the individual drug particles (or tablets in capsules); bilayer tablets; two-chamber gelatin capsules, etc. Enteric-coated or delayed-release oral dosage forms are also contemplated.

[1163] Other physiologically acceptable compounds include wetting agents, emulsifying agents, dispersing agents, or preservatives, and preservatives are particularly useful for preventing microbial growth or action. A variety of preservatives are well known, including for example phenol and ascorbic acid.

[1164] In certain embodiments, the excipients are sterile and generally free of undesirable substances. The composition may be sterilized by conventional, well-known sterilization techniques. For various oral dosage form excipients, such as tablets and capsules, sterility is not required. USP / NF standards are generally sufficient.

[1165] Ophthalmic compositions can include, but are not limited to, any one or more of the following: viscogens (e.g., carboxymethylcellulose, glycerin, polyvinylpyrrolidone, polyethylene glycol); stabilizers (e.g., Pluronic (a triblock copolymer), cyclodextrin); preservatives (e.g., benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories Inc.), Purite (a stabilized chlorine dioxide complex; Allergan, Inc.)).

[1166] Topical compositions can include ointments and creams. Ointments are semi-solid preparations, usually based on petrolatum or other petroleum derivatives. Creams containing the selected active agent are usually viscous liquids or semi-solid emulsions, usually water-in-oil or oil-in-water. Cream bases are usually washable and contain an oil phase, an emulsifier, and a water phase. The oil phase is sometimes also referred to as the "internal phase" and is usually composed of petrolatum and fatty alcohols (such as cetyl alcohol or stearyl alcohol); although not necessarily, the water phase usually exceeds the volume of the oil phase and usually contains a humectant. Emulsifiers in cream formulations are usually nonionic, anionic, cationic, or amphoteric surfactants. Like other carriers or vehicles, ointment bases should be inert, stable, non-irritating, and insensitive.

[1167] In any of the foregoing embodiments, the pharmaceutical compositions described herein can include one or more of the following: lipids, bilayer-interlinked multilamellar vesicles, biodegradable poly(D,L-lactic-co-glycolic acid) [PLGA]-based or polyanhydride-based nanoparticles or microparticles, and lipid bilayer-loaded nanoporous particles.

[1168] Dosage

[1169] The dosage can vary depending on the needs of the patient, the severity of the disease being treated, and the particular compound being used. The appropriate dosage for a particular situation can be determined by a person skilled in the medical art. In some cases, the total daily dose can be divided and administered in fractions throughout the day or by means of continuous delivery.

[1170] In some embodiments, the dosage of the compounds described herein is 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).

[1171] Mode of administration

[1172] The foregoing dosages may be administered daily (e.g., as a single dose or as two or more divided doses) or non-daily (e.g., every other day, every two days, every three days, once a week, twice a week, once every two weeks, once a month).

[1173] In some embodiments, the administration time of the compounds described herein is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or longer. In another embodiment, the administration stop time is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or longer. In one embodiment, an individual is administered a therapeutic compound for a period of time, followed by a separate period of time. In another embodiment, the therapeutic compound is administered during a first period of time, administration of the therapeutic compound is stopped during a second period of time after the first period of time, then administration of the therapeutic compound is restarted during a third period of time, and then administration of the therapeutic compound is stopped during a fourth period of time after the third period of time. In one aspect of this embodiment, the periods of administration of the therapeutic compound and subsequent cessation of administration are repeated over a defined or undefined period of time. In another embodiment, the administration time is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or longer. In another embodiment, the time of cessation of administration is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or longer.

[1174] Methods of treatment

[1175] The present disclosure features methods for treating a subject (e.g., a human) having a disease, disorder, or condition, wherein reduced APJ receptor activity (e.g., blocked or impaired APJ receptor signaling; e.g., apelin-APJ receptor signaling is blocked or impaired) 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 may include or further include treating one or more associated, concurrent, or sequelae conditions related to any of the one or more conditions described herein.

[1176] In some embodiments, the method further comprises identifying an object. In some embodiments, the identifying comprises determining the level of one or more of the following parameters in the object: leukotriene B4 level, pulmonary vascular resistance, pulmonary artery pressure, cardiac index, pulmonary capillary wedge pressure, right atrial pressure, six-minute walk distance, brain natriuretic peptide level, atrial natriuretic peptide, and pulmonary diffusing capacity.

[1177] In certain embodiments, the chemical entity described herein modulates (e.g., reduces) pulmonary vascular resistance, modulates (e.g., reduces) right ventricular afterload, and modulates (e.g., reduces) mean pulmonary artery pressure. In certain embodiments, the chemical entity described herein reduces the risk of right ventricular failure.

[1178] In certain embodiments, the chemical entity described herein modulates vascular tone, modulates fluid homeostasis, modulates renal function, modulates energy metabolism, modulates inflammatory responses, and modulates thrombosis.

[1179] Indications

[1180] Pulmonary arterial hypertension

[1181] In some embodiments, the condition, disease, or disorder is pulmonary arterial hypertension (PAH). Non-limiting examples of PAH and related diseases include: idiopathic PAH, hereditary PAH (e.g., BMPR2 mutations and other mutations), drug-induced or toxin-induced PAH, and PAH associated with a condition, including but not limited to connective tissue diseases (CTD) (e.g., scleroderma, systemic lupus erythematosus, systemic sclerosis, Hashimoto's thyroiditis, Sjogren's syndrome, antiphospholipid antibody syndrome), HIV infection, portal hypertension, congenital heart disease, and schistosomiasis.

[1182] In some embodiments, the PAH is idiopathic.

[1183] In other embodiments, the PAH is hereditary PAH, toxin- or drug-induced PAH; or PAH associated with one or more of the following: congenital heart disease, connective tissue diseases (e.g., scleroderma, systemic lupus erythematosus, systemic sclerosis, Hashimoto's thyroiditis, Sjogren's syndrome, and antiphospholipid antibody syndrome), portal hypertension, BMPR2 mutations, schistosomiasis, and HIV infection.

[1184] In some embodiments, the condition, disease, or disorder is pulmonary hypertension other than PAH. Examples of such diseases include, but are not limited to: pulmonary hypertension due to left heart diseases (e.g., left ventricular systolic dysfunction, left ventricular diastolic dysfunction, valvular heart disease, and congenital / acquired left heart inflow / outflow obstruction and congenital cardiomyopathy), pulmonary hypertension due to lung diseases and / or hypoxia (e.g., chronic obstructive pulmonary disease, interstitial lung disease, other restrictive and obstructive mixed lung diseases, sleep disordered breathing, alveolar hypoventilation, long-term exposure to high altitude, developmental lung disease), chronic thromboembolic pulmonary hypertension and other pulmonary artery obstruction (e.g., chronic thromboembolic pulmonary hypertension, other pulmonary artery obstruction), and pulmonary hypertension with unclear multifactorial mechanisms (e.g., hematologic diseases, systemic diseases, metabolic disorders, etc.).

[1185] Cardiovascular disease, condition, or disorder

[1186] In some embodiments, the condition, disease, or disorder is a cardiovascular condition, disease, or disorder. Non-limiting examples of cardiovascular conditions, diseases, or disorders include: coronary heart disease, acute coronary syndrome, peripheral vascular disease, angina, stroke, cerebrovascular accident, transient ischemic attack, heart failure, cardiomyopathy, myocardial infarction, myocardial remodeling after cardiac surgery, valvular heart disease, hypertension (e.g., systemic hypertension, essential hypertension, pulmonary hypertension, portal hypertension, systolic hypertension), aortic aneurysm (e.g., abdominal aortic aneurysm), atrial fibrillation, arrhythmia, atherosclerosis, Brugada syndrome, ischemic cardiovascular disease, peripheral artery disease, preeclampsia, ventricular tachycardia, and cardiac fibrosis.

[1187] 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).

[1188] In some embodiments, the cardiovascular condition, disease or disorder is a condition, disease or disorder having a vascular pathology (e.g., having increased vascular permeability and non-functional blood vessels). Non-limiting examples of such a condition, disease or disorder include: vascular hypertrophy, vascular remodeling (e.g., vascular stiffness), atherosclerosis, peripheral arterial occlusive disease (PAOD), restenosis (e.g., vascular proliferative restenosis), thrombosis and vascular permeability disorders, and ischemia and / or reperfusion injury (e.g., ischemia and / or reperfusion injury of the heart, kidney and retina). In some embodiments, the condition, disease or disorder is related to veins. Non-limiting examples of such a condition, disease or disorder include hemangioma, venous insufficiency, stasis or thrombosis.

[1189] In some embodiments, the chemical entities described herein can improve the contractility (e.g., cardiac relaxation), ventricular-arterial coupling, inotropic, or lusitropic function of a subject having a cardiovascular disease. In some embodiments, the chemical entities described herein can increase the ejection fraction of a subject having a cardiovascular disease.

[1190] Metabolic and homeostatic dysfunction and related conditions, diseases or disorders

[1191] In some embodiments, the condition, disease or disorder is related to metabolic dysfunction. Non-limiting examples of such a condition, disease or disorder include: metabolic dysfunction, obesity, diabetes (e.g., type II diabetes, gestational diabetes), diabetic complications (e.g., metabolic syndrome, insulin resistance, organ damage of microvascular or macrovascular origin, e.g., large and small vacuolar lesions, diabetic neuropathy, diabetic retinopathy, cardiac autonomic neuropathy), kidney disease (e.g., chronic kidney disease), edema, dyslipidemia, anorexia, hyperphagia, polyphagia, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, growth hormone disorders (e.g., gigantism, obesity, galactorrhea and cardiac atrophy.

[1192] In some embodiments, the condition, disease or disorder is related to inappropriate vasopressin secretion (SIADH). Non-limiting examples of such a condition, disease or disorder include neurogenic diabetes (e.g., diabetic complications, e.g., diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, etc.), lung cancer, septic shock and thirst.

[1193] In some embodiments, the condition, disease or disorder is associated with systemic inflammation. Non-limiting examples of such conditions, diseases or disorders include systemic inflammatory response syndrome (SIR), sepsis (e.g., severe sepsis) and septic shock. In some embodiments, the condition, disease or disorder is associated with sepsis (e.g., a complication, comorbidity or sequela of sepsis). Non-limiting examples of conditions, diseases or disorders associated with sepsis include: sepsis-induced myocardial dysfunction, sepsis-associated inflammatory response (e.g., systemic inflammation), sepsis-associated hemodynamic alterations, hypovolemia, sepsis-associated organ failure (e.g., multiple organ failure, renal failure), acute kidney injury, vasoplegia, lung injury, inappropriate vasopressin secretion, persistent hypertension associated with generalized vasodilation, refractory contractile response, massive plasma capillary leak syndrome, coagulation / fibrinolysis imbalance, and metabolic disorders characterized by elevated lactate levels in the bloodstream. See, e.g., Coquerel et al., Critical Care (2018) 22:10.

[1194] In some embodiments, the chemical entities described herein can modulate arginine vasopressin (AVP) or angiotensin receptors.

[1195] In some embodiments, the condition, disease or disorder is associated with disrupted fluid homeostasis through CNS-dependent and independent actions. Non-limiting examples of such conditions, diseases or disorders include renal failure (e.g., acute and chronic renal failure), renal perfusion, renal dysfunction (e.g., polycystic kidney disease), aquaresis and diuresis.

[1196] Dementia and related conditions, diseases or disorders

[1197] In some embodiments, the condition, disease or disorder is dementia. Non-limiting examples of such a condition, disease or disorder include: senile dementia, cerebrovascular dementia, dementia caused by familial degenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, Pick's disease, Huntington's disease, etc.), dementia caused by infectious diseases (e.g., delayed viral 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 tumors) and dementia caused by traumatic diseases (e.g., chronic subdural hematoma), depression, attention deficit hyperactivity disorder in children (minencephalopathy), disturbance of consciousness, anxiety disorder, schizophrenia and phobia.

[1198] Connective tissue diseases

[1199] In some embodiments, the condition, disease or disorder is a connective tissue disease. In certain embodiments, the connective tissue disease is selected from: scleroderma, systemic lupus erythematosus, systemic sclerosis, Hashimoto's thyroiditis, Sjogren's syndrome, and antiphospholipid antibody syndrome. In certain embodiments, the condition, disease or disorder is systemic sclerosis.

[1200] Fibrosis

[1201] In some embodiments, the condition, disease or disorder is fibrosis. In certain embodiments, the fibrosis is associated with an organ or tissue selected from: lung, liver, heart, mediastinum, bone marrow, retroperitoneum, skin, intestine, joint, reproductive organ, and combinations thereof. In certain embodiments, the fibrosis is idiopathic pulmonary fibrosis (IPF). In certain embodiments, the fibrosis is liver fibrosis. In certain embodiments, the fibrosis is associated with non-alcoholic fatty liver disease (NAFLD).

[1202] Other conditions, diseases or disorders

[1203] In some embodiments, the condition, disease or disorder is a liver disease. Non-limiting examples of such a condition, disease or disorder include alcoholic liver disease, toxin-induced liver disease, virus-induced liver disease, and cirrhosis.

[1204] In some embodiments, the condition, disease or disorder is a lung disease. Non-limiting examples of such a condition, disease or disorder include chronic obstructive pulmonary disease (COPD), asthma, acute respiratory distress syndrome (ARDS), and amyotrophic lateral sclerosis. In some embodiments, the condition, disease or disorder is a retinal disease (e.g., macular degeneration).

[1205] In some embodiments, the condition, disease or disorder is HIV infection, HIV neurodegenerative disease, neurodegenerative disease, cancer (e.g., breast cancer, lymphocytic leukemia, bladder cancer, ovarian cancer, prostate cancer, etc.), asthma, burns (e.g., sunburn), traumatic brain injury, pancreatitis, Turner's syndrome, neurosis, rheumatoid arthritis, spinal cord injury, immune function, inflammation, spinocerebellar degeneration, fracture, wound, atopic dermatitis, osteoporosis, asthma, epilepsy, and infertility.

[1206] Activating stem cells

[1207] 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 for tissue regrowth, to aid in functional recovery following transplantation of cells (e.g., cells having mesenchymal stem cells of bone marrow origin), to increase the proliferation of cardiac stem cells (e.g., in patients with myocardial infarction), to reduce infarct size, to promote cardiac repair, to activate stem cells and progenitor cells in a subject following myocardial infarction, or to reduce reperfusion injury (e.g., during procedures such as coronary artery bypass surgery or heart transplantation surgery).

[1208] Combination therapy

[1209] The present disclosure encompasses single therapy regimens as well as combination therapy regimens.

[1210] In some embodiments, the methods described herein can further comprise administering one or more additional therapies (e.g., one or more additional therapeutic agents and / or one or more treatment regimens) in combination with the compounds described herein.

[1211] In some embodiments, the compounds described herein can be administered in combination with one or more other therapeutic agents.

[1212] Representative additional therapeutic agents include, but are not limited to, therapeutic agents for the following diseases: PAH, pulmonary arterial hypertension, heart failure (e.g., ADHF, chronic heart failure), hypertension (e.g., systemic hypertension), amyotrophic lateral sclerosis, arrhythmia, asthma, atherosclerosis, atrial fibrillation, Brugada syndrome, burns (e.g., sunburn), cancer, cardiac fibrosis, cardiomyopathy, cerebrovascular accident, diabetes (e.g., gestational diabetes), septic shock, sepsis, renal failure, dyslipidemia, HIV neurodegenerative disease, inflammation, ischemic cardiovascular disease, liver disease, metabolic disorder, neurodegenerative disease, obesity, peripheral arterial disease, preeclampsia, restenosis, transient ischemic attack, traumatic brain injury, ventricular tachycardia, edema or immune function.

[1213] In some embodiments, one or more additional therapeutic agents include, for example, those used as therapeutic agents for PAH. Non-limiting examples include:

[1214] · Prostaglandin analogs (e.g., Epoprostenol, Treprostinil, Iloprost);

[1215] · Prostaglandin IP receptor (e.g., Selexipag);

[1216] ​

[1217] · Endothelin receptor antagonists (e.g., bosentan, Ambrisentan, Macitentan);

[1218] · PDE5 inhibitors (e.g., Sildenafil, Tadalafil);

[1219] · Soluble guanylate cyclase stimulators (e.g., Riociguat);

[1220] · Therapeutic agents for mitochondrial dysfunction (e.g., Bardoxolone methyl);

[1221] · Anti-inflammatory agents (e.g., Rituximab, Tocilizumab, Ubenimex); and

[1222] · Agents for regulating oxidative stress (e.g., dimethyl fumarate, intravenous iron agents).

[1223] In some embodiments, one or more additional therapeutic agents include, for example, those used as therapeutic agents for heart failure or hypertension. Non-limiting examples include:

[1224] · α-blockers (e.g., doxazosin, prazosin, tamsulosin, terazosin);

[1225] · β-blockers (e.g., acebutolol, acetutolol, atenolol, bisoprol, bupranolol, carteolol, carvedilol, celiprolol, esmolol, mepindolol, metoprolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol, taliprolol);

[1226] · Calcium channel blockers, including but not limited to dihydropyridines (DHP) (e.g., amlodipine, felodipine, isradipine, lacidipine, nicardipine, nifedipine, nigulpidine, nilutipine, nimodiphine, nisoldipine, nitrendipine, nivaldipine, ryosidine) and non-DHP (e.g., anipamil, diltiazem, fendiline, flunarizine, gallpamil, mibefradil, prenylamine, tiapamil, verapamil);

[1227] · Diuretics (e.g., thiazide derivatives, such as but not limited to amiloride, chlorothalidon, chlorothiazide, hydrochlorchlorthiazide, and methylchlorothiazide)

[1228] · Centrally acting antihypertensive agents (e.g., clonidine, guanabenz, guanfacine, methyldopa);

[1229] · 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);

[1230] · Angiotensin receptor blockers (ARBs) (e.g., candesartan, eprosartan, irbesartan, losartan, olmesartan, tasosartan, telmisartan, valsartan) and dual ARB / NEP inhibitors (e.g., the combination of valsartan and sacubitril);

[1231] · Neutral endopeptidase (NEP) inhibitors (e.g., sacubitril);

[1232] · Aldosterone synthase inhibitors (e.g., anastrozole, fadrozole, exemestane);

[1233] · Endothelin antagonists (e.g., bosentan, enrasentan, atrasentan, darusentan, macitentan, sitaxentan, tezosentan);

[1234] · Inhibitors of the pacing current (e.g., ivabradine);

[1235] · Myosin activators (e.g., cardiac myosin activators);

[1236] · Natriuretics;

[1237] · Uricosuric agents;

[1238] · Vasodilators (e.g., nitrates)

[1239] · Mineralocorticoid receptor antagonists;

[1240] · Renin inhibitors;

[1241] · Digitalis compounds;

[1242] · Inotropic agents and β - agonists;

[1243] · Anti - hyperlipidemics;

[1244] · Plasma HDL - elevating agents;

[1245] · Anti - hypercholesterolemics;

[1246] · Cholesterol biosynthesis inhibitors (e.g., HMG CoA reductase inhibitors)

[1247] · LXR agonists;

[1248] · Probucol;

[1249] · Raloxifene;

[1250] · Niacin;

[1251] · Nicotinamide;

[1252] · Cholesterol absorption inhibitors;

[1253] · Bile acid sequestrants (e.g., anion exchange resins or quaternary amines, e.g., cholestyramine or colestipol);

[1254] · Low - density lipoprotein receptor inducers;

[1255] · Clofibrate;

[1256] · Fenofibrate;

[1257] · Bezafibrate;

[1258] · ciprofibrate;

[1259] · gemfibrizol;

[1260] · vitamins (such as vitamin B6, vitamin B 12 , antioxidant vitamins);

[1261] · platelet aggregation inhibitors;

[1262] · fibrinogen receptor antagonists;

[1263] · aspirin; and

[1264] · fibric acid derivatives.

[1265] In some embodiments, one or more additional therapeutic agents include, for example, those for treating diabetes. Non-limiting examples include:

[1266] · sulfonylureas (such as chlorpropamide, tolbutamide, acetohexamide, tolazamide, glyburide

[1267] (glyburide), gliclazide, glynase, glimepiride

[1268] (glimepiride), glipizide));

[1269] · biguanides (such as metformin);

[1270] · thiazolidinediones (such as ciglitazone, pioglitazone, troglitazone, rosiglitazone));

[1271] · insulin sensitizers related to the above (such as selective and non-selective activators of ppar-α, ppar-β and ppar-γ);

[1272] · dehydroepiandrosterone (also known as DHEA or its conjugated sulfate DHEA-SO4);

[1273] · antiglucocorticoids;

[1274] · TNF-α inhibitors;

[1275] · Dipeptidyl peptidase-IV (DPP4) inhibitors (e.g., sitagliptin, saxagliptin);

[1276] (saxagliptin));

[1277] · GLP-1 agonists or analogs (e.g., exenatide);

[1278] · Alpha-glucosidase inhibitors (e.g., acarbose, miglitol, and voglibose);

[1279] · Pramlintide (a synthetic analog of the human hormone amylin);

[1280] · Other insulin secretagogues (e.g., repaglinide, gliquidone, and nateglinide); and

[1281] · Insulin.

[1282] In some embodiments, one or more additional therapeutic agents include, for example, those used to treat obesity. Non-limiting examples include phenylpropanolamine, phentermine, diethylpropion, mazindol, fenfluramine, dexfenfluramine, phentermine, beta3-adrenergic receptor agonists, sibutramine, gastrointestinal lipase inhibitors (e.g., orlistat), leptin, neuropeptide Y, enterostatin, cholecytokinin, bombesin, amylin, histamine H3 receptor, dopamine D2 receptor modulators, melanocyte-stimulating hormone, corticotropin-releasing factor, galanin, and gamma-aminobutyric acid (GABA).

[1283] Other additional therapeutic agents include:

[1284] · Anti-atherosclerotic agents;

[1285] · Anti-dyslipidemic agents;

[1286] · Anti-hyperinsulinemic agents;

[1287] · Anti-thrombotic agents;

[1288] · Anti-retinopathy agents;

[1289] · Anti-neuropathic agents;

[1290] · Anti-nephropathy agents;

[1291] · Anti-ischemic agents;

[1292] · Anti - hyperlipidemic agents;

[1293] · Anti - triglyceride agents;

[1294] · Anti - cholesterol agents;

[1295] · Anti - restenosis agents;

[1296] · Anti - pancreatic agents;

[1297] · Anorectic agents;

[1298] · Memory enhancing agents;

[1299] · Anti - dementia agents;

[1300] · Cognition - promoting agents;

[1301] · Appetite - suppressing agents;

[1302] · Agents for treating peripheral arterial diseases;

[1303] · Agents for treating malignant tumors;

[1304] · Anti - inflammatory agents;

[1305] · Diuretics;

[1306] · Digoxin;

[1307] · Nitric oxide donors;

[1308] · Hydralazine;

[1309] · Inotropes;

[1310] · Vasopressin receptor antagonists;

[1311] · Statins;

[1312] · Anti - arrhythmic drugs;

[1313] · Phosphodiesterase inhibitors (e.g., PDE5 inhibitors); and

[1314] · Nephro - protectives.

[1315] Non - limiting examples of other therapeutic agents may also include those described in US9156796B2, which is incorporated herein by reference.

[1316] In certain embodiments, a second therapeutic agent or regimen is administered to the subject before contact with or administration of the chemical entity (e.g., about one hour before, or about 6 hours before, or about 12 hours before or about 24 hours before, or about 48 hours before, about 1 week before or about 1 month before).

[1317] In other embodiments, a second therapeutic agent or regimen is administered to the subject at about the same time as contact with or administration of 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 simultaneously in separate dosage forms.

[1318] In other embodiments, a second therapeutic agent or regimen is administered to the subject after contact with or administration of 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, about 1 week after or about 1 month after).

[1319] Preparation of compounds and biological tests

[1320] As will be appreciated by those skilled in the art, methods for synthesizing the compounds of the formulas described herein will be apparent to those of ordinary skill in the art. Synthetic chemical transformations and protecting group methods (protection and deprotection) useful in synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof.

[1321] In some embodiments, intermediates useful in preparing the compounds described herein can be prepared using the chemical methods described in any one or more of the following schemes and non-limiting examples.

[1322] Compound preparation

[1323] For illustrative purposes, Schemes 1-4 show general methods for preparing the compounds and intermediates provided herein. For a more detailed description of each reaction step, see the Synthetic Examples section below. Those skilled in the art will understand that other synthetic routes can be used to synthesize the compounds of the present invention. Although specific starting materials and reagents are described in the schemes and discussed below, other starting materials and reagents can be readily substituted to provide various derivatives and / or reaction conditions. In addition, many compounds prepared by the methods described below can be further modified / functionalized using conventional chemical methods well known to those skilled in the art, in accordance with the present disclosure.

[1324] Scheme 1

[1325]

[1326] Referring to Scheme 1, compounds of formula (I) (shown as I-6 and I-7) can be prepared from compounds I-1, I-2, and I-4, where R 1 and R 2 are as defined herein. Under standard conditions (e.g., in the presence of oxalyl chloride to convert I-2 to an acyl chloride or in the presence of a peptide coupling agent), the aminopyrazine I-1 can react with the carboxylic acid I-2 to form the amide I-3 (where X is a halogen, e.g., bromine or chlorine). Then, a reaction under cross-coupling conditions between I-3 and the amine I-4 in S N Ar or metal-catalyzed (e.g., Buchwald-Hartwig coupling using Xantphos and Pd(OAc)2) can provide compound I-5. Condensation of the carbonyl moiety in I-5 onto the amino group can provide I-6, a compound of formula (I).

[1327] Alternatively, I-3 can be obtained by coupling an ester of I-2 (e.g., an alkyl ester, e.g., methyl ester or ethyl ester) with I-1 under suitable conditions (e.g., in the presence of AlMe3).

[1328] Optionally, the X moiety in I-6 can be converted to other R 3 groups to provide I-7, another compound of formula (I). As a non-limiting example of the transformation between I-6 and I-7, I-6 can react with a sulfonamide under Ullmann coupling conditions to provide compound I-8 (see above, Scheme 1).

[1329] The following starting materials can be used in place of I-1 and processed in the order described in Scheme 1.

[1330]

[1331] Scheme 2

[1332]

[1333] Referring to Scheme 2, the compounds of formula (I) in Scheme 2 (shown as Compounds II-7 to II-9) can be prepared from Compound II-1, where R 1 is as defined elsewhere herein, and X is a halogen (e.g., Br) or a pseudohalogen (e.g., OTf) group. II-1 can undergo Sonogashira coupling or its equivalent with a protected acetylene (e.g., TMS-acetylene) to provide Compound II-2. Subsequent removal of the alkyne protecting group gives II-3, which can be coupled with the pyrazine derivative II-4 to provide Compound II-5. Cyclization of the amino group in II-5 onto the alkyne moiety can produce Compound II-6, which can be cross-coupled (e.g., under Chan-Lam coupling conditions) with a boronic acid of the formula R 2 -B(OH)2, where R 2 is as defined elsewhere herein, or its boronate ester to provide Compound II-7, which is a compound of formula (I). Compound II-7 can be further functionalized to provide Compound II-8, also a compound of formula (I).

[1334] As a non-limiting example of converting II-7 to II-8, II-7 can be coupled (e.g., under Ullmann coupling conditions) with a compound of the formula H2NS(O)2R 4 , where R 4 is as defined elsewhere herein, to provide Compound II-9, which is a non-limiting example of Compound II-8.

[1335] Scheme 3

[1336]

[1337] Referring to Scheme 3, the compounds of formula (I) (shown as Compounds III-5 to III-7 in Scheme 3) can be prepared from Compound III-1, where R 1 is as defined elsewhere herein. Coupling between III-1 and III-2 (e.g., in the presence of a Lewis acid such as AlMe3) can provide Compound III-3, which can be cross-coupled with a compound of the formula R 2 NH2, where R 2 is as defined elsewhere herein, to provide Compound III-4. Cyclization of the amino group in III-4 onto the amide moiety (e.g., by heating in the presence of P(O)Cl3) can provide III-5, which is a compound of formula (I). III-5 can be functionalized to provide III-6, also a compound of formula (I).

[1338] As a non-limiting example of converting III-5 to III-6, III-5 can be coupled with a compound of the formula H2NS(O)2R 4coupled (e.g., under Ullmann coupling conditions) of the compound, wherein R 4 as defined elsewhere herein to provide compound III-7, which is a non-limiting example of compound III-6.

[1339] Scheme 4

[1340]

[1341] Referring to Scheme 4, the compound of formula (I) (shown as compounds IV-6 to IV-8 in Scheme 4) can be prepared from the pyridazine derivative IV-1. Treatment of IV-1 with ammonium hydroxide and bromine in sequence can provide IV-3, and thus the coupling of IV-3 with R 1 CO2H (wherein R 1 as defined elsewhere herein) can provide IV-4. IV-4 can be coupled with R 2 NH2, wherein R 2 as defined elsewhere herein (e.g., under Buchwald-Hartwig coupling conditions) to provide IV-5, which can be cyclized (e.g., under heating and / or microwave irradiation) to provide IV-6, which is a compound of formula (I). Compound IV-6 can be functionalized to provide IV-7, also a compound of formula (I).

[1342] As a non-limiting example of converting IV-6 to IV-7, IV-6 can be coupled with a compound of the formula H2NS(O)2R 4 wherein R 4 as defined elsewhere herein to provide compound IV-8, which is a non-limiting example of compound IV-7.

[1343] Scheme 5

[1344]

[1345] Referring to Scheme 5, the compound of formula (I) (shown as V-6 and V-7) can be prepared from compounds V-1, V-2 and V-4, wherein R 1 and R 2 as defined herein. Under standard conditions, the aminopyrazine V-1 can react with the carboxylic acid V-2 to give the amide V-3 (wherein X is a halogen, such as bromine or chlorine). Then the reaction under cross-coupling conditions between S N Ar or metal-catalyzed V-3 and the amine V-4 (e.g., Buchwald Hartwig coupling using Xantphos and Pd(OAc)2) can provide compound V-5. The condensation of the carbonyl moiety in V-5 onto the amino group can provide V-6, which is a compound of formula (I).

[1346] Alternatively, V-3 can be obtained by coupling an ester of V-2 (e.g., an alkyl ester such as methyl or ethyl ester) with V-1 under suitable conditions (e.g., in the presence of AlMe3).

[1347] Optionally, the X moiety in V-6 can be converted to another R 3 group to provide V-7, another compound of formula (I). As a non-limiting example of the conversion between V-6 and V-7, V-6 can be reacted with a sulfonamide under Ullmann coupling conditions to provide compound V-8 (see above, Scheme 5).

[1348] General methods

[1349] Reactions sensitive to moisture or air were carried out under nitrogen or argon using anhydrous solvents and reagents. The progress of the reaction was determined by analytical thin-layer chromatography (TLC) using commonly used Sanpont pre-coated TLC plates, silica gel GF-254, layer thickness 0.25 mm or liquid chromatography-mass spectrometry (LC-MS).

[1350] Generally, the analytical LC-MS system used consists of an Agilent 6120 platform with electrospray ionization in positive ion detection mode and an Agilent 1260 series HPLC with an autosampler. The chromatographic column is typically an Agilent poroshell C18 of 3.0×50 mm, 2.7 μm. The flow rate is 0.6 mL / minute and the injection volume is 5 μL. The UV detection range is 190 - 400 nm. The mobile phase consists of solvent A (water plus 0.1% TFA) and solvent B (acetonitrile plus 0.05% TFA), with a gradient where 90% of solvent A changes to 95% of solvent B in 1.7 minutes, held for 1.8 minutes, then returns to 90% of solvent A in 0.1 minute and is held for 1.4 minutes.

[1351] Preparative HPLC purification is generally carried out on a Waters 2555 - 2767 system with a 2489 UV detector. The column is a Welch C-18, 21.2×150 mm, 5 μm. The mobile phase consists of a mixture of acetonitrile (5 - 95%) in water containing 0.05% TFA. The flow rate is maintained at 20 mL / minute, the injection volume is 1800 μL, and the UV detector uses two channels at 254 nm and 280 nm. The mobile phase gradient was optimized for each compound.

[1352] Reactions under microwave irradiation are generally carried out using an Initiator manufactured by Biotage. Solution concentration is carried out on a rotary evaporator under reduced pressure. Flash chromatography is generally carried out using a Biotage flash chromatograph (Dyax Corporation), on silica gel (40 - 63 mM, pore size ) on a pre-packed cartridge of a specified size. Unless otherwise stated, the 1H NMR spectra were obtained in CDCl3 solution on a 400 MHz spectrometer. Chemical shifts are reported in parts per million (ppm). Tetramethylsilane (TMS) was used as an internal reference in CD3Cl solution, and the residual CH3OH peak or TMS was used as an internal reference in CD3OD solution. Coupling constants (J) are expressed in Hertz (Hz). Chiral analytical chromatography was performed on one of the Chiralpak AS, Chiralpak AD, Chiralcel OD, Chiralcel IA or Chiralcel OJ columns (250x4.6 mm) (Daicel Chemical Industries, Ltd.), with the specified percentage of ethanol in hexane (%Et / Hex) or the specified percentage of isopropanol in heptane (%IPA / Hep) as an isocratic solvent system. Chiral preparative chromatography was performed on one of the Chiralpak AS, Chiralpak AD, Chiralcel OD, Chiralcel IA or Chiralcel OJ columns (20x250 mm) (Daicel Chemical Industries, Ltd.), and the isocratic solvent system required was identified on chiral analytical chromatography or by supercritical fluid (SFC) conditions. 1 1H NMR spectra. Chemical shifts are reported in parts per million (ppm). Tetramethylsilane (TMS) was used as an internal reference in CD3Cl solution, and the residual CH3OH peak or TMS was used as an internal reference in CD3OD solution. Coupling constants (J) are expressed in Hertz (Hz). Chiral analytical chromatography was performed on one of the Chiralpak AS, Chiralpak AD, Chiralcel OD, Chiralcel IA or Chiralcel OJ columns (250x4.6 mm) (Daicel Chemical Industries, Ltd.), with the specified percentage of ethanol in hexane (%Et / Hex) or the specified percentage of isopropanol in heptane (%IPA / Hep) as an isocratic solvent system. Chiral preparative chromatography was performed on one of the Chiralpak AS, Chiralpak AD, Chiralcel OD, Chiralcel IA or Chiralcel OJ columns (20x250 mm) (Daicel Chemical Industries, Ltd.), and the isocratic solvent system required was identified on chiral analytical chromatography or by supercritical fluid (SFC) conditions.

[1353] Abbreviations

[1354] -C(O)CH3 (Ac); acetic acid (AcOH); -OC(O)CH3 (OAc); aqueous solution (aq); Cbz (benzyloxycarbonyl); N,N-diisopropylethylamine (DIEA); N,N-dimethylformamide (DMF); 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI); ethyl acetate (EtOAc); diethyl ether (Et2O); petroleum ether (PE); gram (g); hour (h or hr); 2-propanol (IPA); mass spectrometry (ms or MS); microliter (μL); milligram (mg); milliliter (mL); millimole (mmol); minute (min); methyl tert-butyl ether (MTBE); (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP); retention time (R t); room temperature (rt or RT); saturated aqueous sodium chloride solution (brine); trifluoroacetic acid (TFA); tetrahydrofuran (THF); flash chromatography (FC); liquid chromatography (LC); liquid chromatography - mass spectrometry (LCMS or LC - MS); supercritical fluid chromatography (SFC); tert - butyloxycarbonyl (Boc or BOC); diethylaminosulfur trifluoride (DAST); dichloromethane (DCM); dimethylacetamide (DMA or DMAC); dimethyl sulfoxide (DMSO); 1,3 - bis(diphenylphosphino)propane (DPPP); acetic acid (HOAc); 3 - chloroperoxybenzoic acid (m - CPBA); methyl (Me); methanol (MeOH); N - bromosuccinimide (NBS); thin - layer chromatography (TLC).

[1355] Synthesis example:

[1356] The following are representative methods for preparing the compounds used in the following examples or for preparing alternative compounds that may not be commercially available and are used in the following examples.

[1357] Method A:

[1358]

[1359] Example 1: 6 - Bromo - 1-(2,6 - dimethoxyphenyl)-2-(6 - ethoxypyridin - 2 - yl)-1H - imidazo[4,5 - b]pyrazine

[1360]

[1361] and

[1362] Example 2: N-(1-(2,6 - dimethoxyphenyl)-2-(6 - ethoxypyridin - 2 - yl)-1H - imidazo[4,5 - b]pyrazin - 6 - yl)methanesulfonamide

[1363]

[1364] Step A: Ethyl 6-ethoxypicolinate

[1365] Ethyl iodide (112.2 g, 720 mmol, 4 equiv) was added to a suspension of 6 - hydroxypyridine - 2 - carboxylic acid (25.0 g, 180 mmol, 1 equiv) and silver(I) carbonate (100 g, 360 mmol, 2 equiv) in CHCl3 (400 mL). The mixture was stirred at 30 °C for 1 day. The insoluble material was filtered off and the solid was washed with CHCl3. The filtrate was concentrated in vacuo to give the title compound ethyl 6 - ethoxypicolinate as a pale yellow oil, which was used in the next step without further purification.

[1366] LC-MS: m / z 196.0 (M+H) +

[1367] Step B: 6-Ethoxypicolinic acid To a solution of ethyl 6-ethoxypicolinate (25 g, 128 mmol, 1 equiv) in EtOH (30 mL) was added sodium hydroxide solution (1 mol / L, 384 mL, 384 mmol, 3 equiv). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was neutralized with 1N HCl (aqueous) solution and extracted with ethyl acetate. The extract was washed with brine, dried over MgSO4 and concentrated in vacuo to give the title compound 6-ethoxypicolinic acid.

[1368] LC-MS: m / z 168.0 (M+H) +

[1369] Step C: N-(3,5-Dibromopyrazin-2-yl)-6-ethoxypicolinamide To a solution of 6-ethoxypicolinic acid (10 g, 59.9 mmol, 1 equiv) in DCM (100 mL) at 0 °C was added dropwise oxalyl chloride (11.4 g, 89.8 mmol, 1.5 equiv) and DMF (1 mL). The resulting mixture was stirred at room temperature for 1 h. The reaction solution was concentrated to give crude 6-ethoxypicolinoyl chloride as a pale 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 h. Then the crude 6-ethoxypicolinoyl chloride in DMF (100 mL) was added dropwise over 30 min. After the addition, the mixture was stirred at room temperature overnight. The mixture was quenched with saturated NH4Cl (aqueous) (100 mL) and extracted with DCM (3 × 150 mL). The extract was washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was recrystallized from DCM to afford the compound N-(3,5-dibromopyrazin-2-yl)-6-ethoxypicolinamide.

[1370] LC-MS: m / z 400.9, 402.9, 404.9 (M+H) +

[1371] Step D: N-(5-Bromo-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide

[1372] 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 under N₂ atmosphere by microwave irradiation at 120 °C for 2 h. 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.

[1373] LC-MS: m / z 474.0, 476.0 (M+H) +

[1374] Step E: 6-Bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5- b]pyrazine (Example 1)

[1375] A solution of N-(5-bromo-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide (1.0 g, 2.1 mmol, 1 equiv) in AcOH (10 mL) was stirred at 120 °C for 2 h by microwave irradiation. The mixture was cooled to room temperature. The precipitate was filtered off and washed with a mixture of EtOAc / PE = 1 / 2 (3×1 mL) to give the title compound as a white solid.

[1376] 1 ¹H NMR (400 MHz, DMSO-d₆) δ: 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).

[1377] LC-MS: m / z 456.1, 458.1 (M+H) +

[1378] Step F: N-(1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b] pyrazin-6-yl)methanesulfonamide (Example 2)

[1379] 6-Bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine (150 mg, 0.33 mmol), methanesulfonamide (62 mg, 0.66 mmol, 2 equiv), CuI (125 mg, 0.66 mmol, 2 equiv), trans-N,N'-dimethylcyclohexane-1,2-diamine (94 mg, 0.66 mmol, 2 equiv) and K2CO3 (137 mg, 0.99 mmol, 3 equiv) in DMF (5 mL) were stirred under microwave irradiation at 115 °C for 1.5 h under a N2 atmosphere. The reaction was washed with water (150 mL) and then extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (eluting with PE / EtOAc = 20 / 1 to 5 / 1) to afford the title compound as a yellow solid.

[1380] 1 1H NMR (400 MHz, DMSO-d6) δ: 11.05 (s, 1H), 8.27 (s, 1H), 7.95 (dd, J = 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, 3H). LC-MS: m / z 471.0 (M+H) +

[1381] Example 3: N-(1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-phenylmethanesulfonamide

[1382]

[1383] According to general method A step F, starting from Example 1, the title compound was prepared using benzylsulfonamide.

[1384] 11H NMR (400 MHz, DMSO-d6) δ: 11.04 (s, 1H), 8.14 (s, 1H), 7.97 (dd, J = 7.4 Hz, 0.8 Hz, 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) +

[1385] Example 4: 1-Cyclopropyl-N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide

[1386]

[1387] According to Step F of General Method A, starting from Example 1, the title compound was prepared using 1-cyclopropylmethanesulfonamide.

[1388] 1 1H NMR (400 MHz, DMSO-d6) δ: 11.03 (s, 1H), 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, 1H), 6.81 - 6.87 (m, 3H), 3.57 (s, 6H), 3.39 (q, J = 7.0 Hz, 2H), 3.27 (d, J = 3.4 Hz, 2H), 1.02 (t, J = 7.0 Hz, 3H), 0.47 (d, J = 4.0 Hz, 3H), 0.13 (d, J = 2.2 Hz, 2H). LC-MS: m / z 511.0 (M + H) +

[1389] Example 5: N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)benzenesulfonamide

[1390]

[1391] According to Step F of General Method A, starting from Example 1, the title compound was prepared using benzenesulfonamide. 11H NMR (400 MHz, DMSO-d6) δ: 11.53 (s, 1H), 8.24 (s, 1H), 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, 0.8 Hz, 2H), 7.55 (t, J = 8.4 Hz, 2H), 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+H) +

[1392] Example 6: 1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-6-(phenylethynyl)-1H-imidazo[4,5-b]pyrazine

[1393]

[1394] and

[1395] Example 7: 1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-6-phenethyl-1H-imidazo[4,5-b]pyrazine

[1396]

[1397] Step A: 1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-6-(phenylethynyl)-1H-imidazo [4,5-b]pyrazine (Example 6)

[1398] A suspension of 6-bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine (Example 1, 100 mg, 0.22 mmol, 1 equiv), phenylacetylene (44.5 mg, 0.44 mmol, 2 equiv), Pd(PPh3)2Cl2 (15.3 mg, 0.022 mmol, 0.1 equiv), CuI (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 minute and then stirred at 80 °C for 4 h. The reaction mixture was diluted with water (50 mL) and extracted with ether (3 × 100 mL). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 1) to afford the title compound.

[1399] 11H NMR (400 MHz, DMSO-d6) δ: 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 (M + H) +

[1400] Step B: 1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-6-phenethyl-1H-imidazo [4,5-b]pyrazine (Example 7)

[1401] A mixture of 1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-6-(phenylethynyl)-1H-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.

[1402] 1 1H NMR (400 MHz, DMSO-d6) δ: 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). LC-MS: m / z 482.2 (M + H) +

[1403] Example 8: N-Benzyl-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine-6-carboxamide

[1404]

[1405] Step A: Methyl 1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]py razine-6-carboxylate6-Bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-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. The reaction mixture was then stirred overnight at 90 °C and 3 MPa. The reaction mixture was filtered, concentrated and purified by column chromatography (silica gel, eluting with 25% EtOAc in PE) to give the title compound methyl 1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine-6-carboxylate.

[1406] LC-MS: m / z 436.1 (M+H) +

[1407] Step B: N-Benzyl-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4, 5-b]pyrazine-6-carboxamide (Example 8)

[1408] Methyl 1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine-6-carboxylate (32.4 mg, 0.074 mmol, 1 equiv) and benzylamine (15 mg, 0.148 mmol, 2 equiv) were loaded into a sealed tube and the mixture was heated at 90 °C for 2 h. The reaction mixture was then purified by column chromatography (silica gel, eluting with 25% EtOAc in PE) to afford the title compound.

[1409] 1 1H NMR (400 MHz, DMSO-d6) δ: 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) +

[1410] Example 9: 1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-N-methyl-1H-imidazo[4,5-b]pyrazin-6-amine

[1411]

[1412] A mixture of 6-bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine (Example 1, 60 mg, 0.1 mmol, equimolar), and CH3NH2 (aqueous, 40 wt%, 5 mL) was stirred by microwave irradiation at 120 °C for 2 hours. The reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel (PE / EtOAc = 1 / 2) to afford the title compound.

[1413] 1 H NMR (400 MHz, DMSO-d6) δ: 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) +

[1414] Method B:

[1415]

[1416] Step A: tert-Butyl (1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]py razin-6-yl)carbamate

[1417] A suspension of 6-bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine (500 mg, 1.09 mmol, 1 equiv), BocNH2 (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 1,4-dioxane (10 mL) was stirred by microwave irradiation at 120 °C 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 give the title compound, tert-butyl (1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)carbamate.

[1418] LC-MS: m / z 493.2 (M+H) +

[1419] Step B: 1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]py razin-6-amine (Example 10)

[1420]

[1421] (1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)carbamic acid tert-butyl ester (350 mg, 0.71 mmol, 1 equiv) and a mixture of HCl in dioxane (4 mol / L, 20 mL), at 0 °C. The mixture was then stirred at room temperature for 4 h. The reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel (100% EtOAc) to afford Example 10. 1 1H NMR (400 MHz, DMSO-d6) δ: 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) +

[1422] Example 11: N,N-Dibenzyl-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-amine

[1423]

[1424] A mixture of the compound of 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 min. Benzyl bromide (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 ether (3 × 500 mL). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (PE / EtOAc = 1 / 1) to afford the title compound.

[1425] 11H NMR (400 MHz, DMSO-d6) δ: 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) +

[1426] Example 12: 1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-N,N-dimethyl-1H-imidazo[4,5-b]pyrazin-6-amine

[1427]

[1428] A mixture of the compound of 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 ether (3 × 500 mL). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 3 / 7) to afford the desired product.

[1429] 1 1H NMR (400 MHz, DMSO-d6) δ: 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 (M + H) +

[1430] Example 13: N-Benzyl-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-amine

[1431]

[1432] To a well-stirred red suspension of 1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-amine (Example 10, 60 mg, 0.15 mmol, 1 equiv) in 1,2-dichloroethane (20 mL) was added benzaldehyde (65 mg, 0.61 mmol, 4 equiv), 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 15 minutes. The resulting suspension was slowly warmed to 50 °C and stirred overnight. The reaction was quenched by the slow addition of saturated NaHCO3 (20 mL) while stirring at 0 °C. The two-phase mixture was stirred for 30 minutes and extracted with DCM (3 × 25 mL). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 1 / 1) to afford the desired product.

[1433] 1 H NMR (400 MHz, DMSO-d6) δ: 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) +

[1434] Example 14: N-(1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-2-phenylacetamide

[1435]

[1436] A mixture of 1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-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 ether (3 × 500 mL). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 3 / 7) to afford the desired product.

[1437] 1 H NMR (400 MHz, DMSO-d6) δ: 11.11 (s, 1H), 9.33 (s, 1H), 7.99 (d, J = 7.4 Hz, 1H), 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) +

[1438] Example 15: 5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine

[1439]

[1440] and

[1441] Example 16: 1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-5-amine

[1442]

[1443] Step A: N-(3-Bromo-6-chloropyrazin-2-yl)-6-ethoxypicolinamideA 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 AlMe3 was added dropwise. The mixture was then stirred at 100 °C for 16 h. The mixture was quenched with NH4Cl solution and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over anhydrous Na2SO4 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-(3-bromo-6-chloropyrazin-2-yl)-6-ethoxypicolinamide.

[1444] 1 1H NMR (400 MHz, DMSO-d6) δ: 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) +

[1445] Step B: N-(6-Chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide A mixture of N-(3-bromo-6-chloropyrazin-2-yl)-6-ethoxypicolinamide (500 mg, 1.4 mmol, 1 equiv), 2,6-dimethoxyaniline (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-methylprop-2-olate ( 297 mg, 2.8 mmol, 2 equiv) in toluene (10 mL) was stirred at 110 °C for 16 h under a 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.

[1446] 11H NMR (400 MHz, CDCl3) δ: 10.11 (s, 1H), 8.40 (s, 1H), 8.02 (s, 1H), 7.92 (d, J = 7.2 Hz, 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) +

[1447] Step C: 5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5- b]pyrazine (Example 15)

[1448] N-(6-Chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxynicotinamide (280 mg, 0.56 mmol, 1 equiv) in AcOH (20 mL) was stirred at 120 °C under MW for 1 h. The reaction mixture was concentrated in vacuo. The residue was washed with ether, filtered and dried to give the desired product. 1 1H NMR (400 MHz, CDCl3) δ: 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) +

[1449] Step D: tert-Butyl (1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]py razin-5-yl)carbamate

[1450] 5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-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-methylprop-2-olate (A mixture of (43 mg, 0.38 mmol, 2 equiv) in toluene (5 mL) was stirred at 110 °C for 16 h under a N2 atmosphere. The mixture was filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 3 / 1) to afford the title compound, tert-butyl (1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)carbamate.

[1451] 1 1H NMR (400 MHz, CD3OD) δ: 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 (m, 2H), 1.55 (s, 9H), 1.11 - 1.09 (t, J = 7.2 Hz, 3H). LC-MS: m / z 492.7 (M+H) +

[1452] Step E: 1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine-5-amine (Example 16) Step A: Ethyl 6-ethoxynicotinate

[1453] A solution of tert-butyl (1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)carbamate (30 mg, 0.06 mmol, 1 equiv) in HCl / MeOH (4 mol / L, 10 mL) was stirred at room temperature for 6 h. The mixture was concentrated in vacuo and the residue was washed with diethyl ether to afford the desired product.

[1454] 1 1H NMR (400 MHz, CD3OD) δ: 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) +

[1455] Example 17: N-(1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)-2-phenylacetamide

[1456]

[1457] 5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine (Example 15, 60 mg, 0.15 mmol, 1 equiv), 2-phenylacetamide (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), Cs2CO 3( 95 mg, 0.3 mmol, 2 equiv) in a mixture of dioxane (5 mL) was stirred at 110 °C for 16 h under a 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.

[1458] 1 1H NMR (400 MHz, CDCl3) δ: 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 = 7.2 Hz, 2H), 1.08 (t, J = 7.2 Hz, 3H). LC-MS: m / z 511.3 (M + H) +

[1459] Example 18: 1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine

[1460]

[1461] Step B: (6-Ethoxypyridin-2-yl)methanol

[1462] To a solution of 6-hydroxynicotinic acid (12 g, 86.33 mmol) in DCM (250 ml) was added Ag2CO3 (48 g, 174 mmol), and then EtI (27.6 ml, 345.32 mmol) was added dropwise. The mixture was stirred at 25 °C for 12 h and filtered. The filtrate was concentrated in vacuo to give ethyl 6-ethoxynicotinate as a grey oil, which was used in the next step without further purification.

[1463] LC-MS: m / z 196.3 (M + H) +

[1464] Step C: 6-Ethoxypyridinecarbaldehyde

[1465] At 0 °C, LiAlH4 (15 ml, 1 M THF solution) was added dropwise to a solution of ethyl 6-ethoxypicolinate (5.8 g, 29.7 mmol) in THF (60 ml). The reaction mixture was stirred at 25 °C for 3 hours and quenched with H2O / EA. The collected organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography to give (6-ethoxypyridin-2-yl)methanol.

[1466] LC-MS: m / z 154.3 (M+H) +

[1467] Step D: 3-Chloro-N-(2,6-dimethoxyphenyl)pyrazin-2-amine

[1468] MnO2 (12 g, 137.25 mmol) was added to a solution of (6-ethoxypyridin-2-yl)methanol (3 g, 19.61 mmol) in 1,4-dioxane (30 mL), and the reaction mixture was refluxed for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give 6-ethoxypyridinecarbaldehyde.

[1469] LC-MS: m / z 152.3 (M+H) +

[1470] Step E: N-(2,6-Dimethoxyphenyl)tetrazolo[1,5-a]pyrazin-8-amine

[1471] At 0 °C, KHMDS (1 N TMF, 6 mL, 6 mmol) was slowly added to a solution of 2,3-dichloropyrazine (0.918 g, 6 mmol) in THF (15 mL). The mixture was stirred at 0 °C for 15 minutes, and then a solution of 3-5 (0.74 g, 5 mmol) in THF (5 mL) was added dropwise at 0 °C. The dark green mixture was stirred at room temperature for 3 hours, poured into ice water (40 mL), and extracted with EA (10 mL × 3). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give a residue, which was purified by column chromatography (PE:EA = 97:3 to 66:34) to give 3-chloro-N-(2,6-dimethoxyphenyl)pyrazin-2-amine.

[1472] Step F: N-(2,6-Dimethoxyphenyl)tetrazolo[1,5-a]pyrazin-8-amine

[1473] 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 hours. The solution was poured into 10 mL of ice water and extracted with EA. The organic layer was dried and evaporated to give a dark red oil, which was used in the next step without any purification.

[1474] LC-MS: m / z 273.1 (M+H)+

[1475] Step G: 1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine To a concentrated aqueous HCl solution (3 mL) of crude N-(2,6-dimethoxyphenyl)tetrazolo[1,5-a]pyrazin-8-amine (143.7 mg, 0.53 mmol) was added SnCl2·H2O (1.19 g, 5.3 mmol) and the mixture was stirred at 115 °C for 2 h. After cooling to room temperature, K2CO3 was added to adjust the mixture to pH = 8 - 9 and filtered. The filtrate was extracted with EA, the organic layer was dried over Na2SO4 and concentrated in vacuo to give a residue, which was purified by column chromatography (PE:EA = 97:3 - 66:34) to give N-(2,6-dimethoxyphenyl)tetrazolo[1,5-a]pyrazin-8-amine.

[1476] LC-MS: m / z 247.1 (M+H) +

[1477] Step A: 2-Bromo-6-ethoxypyridine A mixture of N-(2,6-dimethoxyphenyl)tetrazolo[1,5-a]pyrazin-8-amine (70 mg, 0.285 mmol) and 6-ethoxypyridinecarboxaldehyde (43 mg, 0.285 mmol) in AcOH (1 mL) was stirred at 110 °C under MW for 10 min. The mixture was concentrated and the residue was purified by preparative HPLC to give 1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine. LC-MS: m / z 378.2 (M+H) +

[1478] Example 19: N-(5-(2,6-dimethoxyphenyl)-6-(6-ethoxypyridin-2-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl)methanesulfonamide

[1479]

[1480] Step B: 2-Ethoxy-6-((trimethylsilyl)ethynyl)pyridine To a solution of 2,6-dibromopyridine (20 g, 84 mmol, 1 equiv) in EtOH (200 mL) was added sodium ethoxide (22.9 g, 336 mmol, 4 equiv). The mixture was stirred at reflux temperature for 3 days. The reaction mixture was concentrated in vacuo. Water (300 mL) was added to the residue and the mixture was extracted with DCM (2 × 300 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (100% PE) to afford the title compound.

[1481] LC-MS: m / z 202.0, 204.0 (M+H) +

[1482] Step C: 2-Ethoxy-6-ethynylpyridine

[1483] 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)2Cl 2( 1.13 g, 1.6 mmol, 0.025 equiv) and CuI (610 mg, 3.2 mmol, 0.05 equiv) in Et3N (230 mL) was stirred at 85 °C for 2.5 h under a 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 give the title compound 6-chloro-3-((6-ethoxypyridin-2-yl)ethynyl)pyrazin-2-amine.

[1484] LC-MS: m / z 220.3 (M+H) +

[1485] Step D: 6-Chloro-3-((6-ethoxypyridin-2-yl)ethynyl)pyrazin-2-amine

[1486] 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 resulting mixture was stirred at room temperature for 16 h. The reaction solution was concentrated in vacuo and the residue was purified by flash chromatography (PE / EtOAc = 100 / 1) to give the title compound 2-ethoxy-6-ethynylpyridine.

[1487] LC-MS: m / z 148.1 (M+H) +

[1488] Step E: 3-Chloro-6-(6-ethoxypyridin-2-yl)-5H-pyrrolo[2,3-b]pyrazine 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)2Cl 2( 238 mg, 0.34 mmol, 0.03 equiv) and CuI (129 mg, 0.68 mmol, 0.06 equiv) in Et3N (80 mL) was stirred at 85 °C for 2 h under a 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 give the title compound 6-chloro-3-((6-ethoxypyridin-2-yl)ethynyl)pyrazin-2-amine.

[1489] LC-MS: m / z 275.1 (M+H) +

[1490] Step F: 3-Chloro-5-(2,6-dimethoxyphenyl)-6-(6-ethoxypyridin-2-yl)-5H-pyrrolo[2,3-b]pyrazine 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) at 0 °C was added NaH (0.5 g, 12.6 mmol, 1.5 equiv). The mixture was stirred at room temperature for 1 h and then heated to 60 °C overnight. The mixture was quenched with 0.5 mL of H2O and then concentrated in vacuo to dryness 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.

[1491] LC-MS: m / z 275.1 (M+H) +

[1492] Step G: N-(5-(2,6-Dimethoxyphenyl)-6-(6-ethoxypyridin-2-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl)methanesulfonamide Step A: N-(5-Bromo-3-iodopyridin-2-yl)-6-ethoxynicotinamide 3-Chloro-6-(6-ethoxypyridin-2-yl)-5H-pyrrolo[2,3-b]pyrazine (1 g, 3.65 mmol, 1.0 equiv), (2,6-dimethoxyphenyl)boronic acid (1.3 g, 7.3 mmol, 2 equiv), Cu(OAc)2 (1.3 g, 7.3 mmol, 2 equiv), dry pyridine (865 mg, 11 mmol, 3 equiv) and a suspension of molecular sieves in anhydrous DCE (10 mL) was stirred at 25 °C for 30 h under an O2 atmosphere. The reaction was diluted with DCM (50 mL) and filtered through celite. 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.

[1493] LC-MS: m / z 411.1 (M+H) +

[1494] Step B: N-(5-Bromo-3-((2,6-dimethoxyphenyl)amino)pyridin-2-yl)-6-ethoxynicotinamide Step C: 6-Bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyridine

[1495] Stir 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'-dimethylcyclohexane-1,2-diamine (22 mg, 0.14 mmol, 2 equiv), CuI (29 mg, 0.14 mmol, 2 equiv) and K2CO3 (30 mg, 0.22 mmol, 3 equiv) in DMF (2 mL) for 2 h by microwave irradiation at 115 °C under N2 atmosphere. Pour the reaction mixture into H2O (20 mL) and extract with EtOAc (3 × 20 mL). Wash the extracts with water (10 mL) and brine (10 mL), dry over MgSO4 and concentrate in vacuo. Purify the residue by flash chromatography (PE / EtOAc = 1 / 1) to give the title compound N-(5-(2,6-dimethoxyphenyl)-6-(6-ethoxypyridin-2-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl)methanesulfonamide.

[1496] 1 1H NMR (DMSO-d6) δ: 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), 3.12 (s, 3H), 1.08 (t, J = 7.2 Hz, 3H).

[1497] LC-MS: m / z 470.0 (M + H) +

[1498] Example 20: N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyridin-6-yl)methanesulfonamide

[1499]

[1500] Step D: N-(1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyridin-6-yl)methanesulfonamide

[1501] To a solution of 5-bromo-3-iodopyridin-2-amine compound (2 g, 6.7 mmol, 1.1 eq) in toluene (50 mL) at room temperature was added dropwise Al(Me)3 (a toluene solution of 1.6 mol / L, 7.6 mL, 12.2 mmol, 2 eq). After the mixture was stirred at 50 °C for 30 minutes, ethyl 6-ethoxypicolinate (1.19 g, 6.1 mmol, 1 eq) was added and the mixture was stirred at 110 °C for 2 hours. The reaction mixture was quenched with water (50 mL), and then extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography, eluting with PE / EtOAc (20 / 1 to 5 / 1), to give the title compound N-(5-bromo-3-iodopyridin-2-yl)-6-ethoxypicolinamide.

[1502] LC-MS: m / z 447.9, 449.9 (M+H) +

[1503] Step A: 6-Chloropyridazin-3-amine

[1504] A suspension of N-(5-bromo-3-iodopyridin-2-yl)-6-ethoxypicolinamide (200 mg, 0.45 mmol, 1 eq), 2,6-dimethoxyaniline (68 mg, 0.45 mmol, 1 eq), Pd2(dba)3 (82 mg, 0.09 mmol, 0.1 eq), Xantphos (208 mg, 0.36 mmol, 0.8 eq) and Cs2CO3 (292 mg, 0.87 mmol, 2 eq) in 1,4-dioxane (50 mL) was stirred under N2 atmosphere by microwave irradiation at 120 °C for 2 hours. The mixture was diluted with water (30 mL), and then extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by preparative TLC (PE / EtOAc = 5 / 1) to give the title compound N-(5-bromo-3-((2,6-dimethoxyphenyl)amino)pyridin-2-yl)-6-ethoxypicolinamide.

[1505] LC-MS: m / z 473.0, 475.0 (M+H) +

[1506] Step B: 4-Bromo-6-chloropyridazin-3-amine Step C: N-(4-Bromo-6-chloropyridazin-3-yl)-6-ethoxynicotinamideTo a solution of N-(5-bromo-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxynicotinamide (100 mg, 0.21 mmol, 1 equiv) in AcOH (10 mL) was added 1 drop of POCl3. The mixture was stirred by microwave irradiation at 120 °C for 2 h. The mixture was cooled to room temperature, evaporated and the residue was purified by preparative TLC (PE / EtOAc = 1 / 1) to afford the title compound 6-bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyridine.

[1507] LC-MS: m / z 455.0, 457.0 (M+H) +

[1508] Step D: N-(6-Chloro-4-((2,6-dimethoxyphenyl)amino)pyridazin-3-yl)-6-ethoxynicotinamide Step E: 7-(2,6-Dimethoxyphenyl)-8-(6-ethoxypyridin-2-yl)-7H-imidazo[4,5-c]pyridazine

[1509] A suspension of 6-bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine (40 mg, 0.09 mmol, 1 equiv), methanesulfonamide (17 mg, 0.18 mmol, 2 equiv), CuI (34 mg, 0.18 mmol, 2 equiv), trans-N,N'-dimethylcyclohexane-1,2-diamine (25 mg, 0.18 mmol, 2 equiv) and K2CO3 (37 mg, 0.27 mmol, 3 equiv) in DMF (5 mL) was stirred by microwave irradiation at 115 °C under N2 atmosphere for 1.5 h. The reaction was diluted with water (15 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by preparative TLC (PE / EtOAc = 1 / 2) to give the title compound N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyridin-6-yl)methanesulfonamide.

[1510] 1 1H NMR (DMSO-d6) δ: 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), 7.19 (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).

[1511] LC-MS: m / z 470.1 (M+H) +

[1512] Example 21: N-(5-(2,6-Dimethoxyphenyl)-6-(6-ethoxypyridin-2-yl)-5H-imidazo[4,5-c]pyridazin-3-yl)methanesulfonamide

[1513]

[1514] Step F: N-(7-(2,6-Dimethoxyphenyl)-8-(6-ethoxypyridin-2-yl)-7H-imidazo[4,5-c]pyridazinyl)methanesulfonamide

[1515] A suspension of 3,6-dichloropyridazine (10 g, 67 mmol, 1 equiv) in 25% aqueous ammonia (50 mL) was heated in a PTFE-lined pressure reactor at 120 °C for about 12 h. After cooling to room temperature, the resulting crystalline solid was collected by filtration, washed with water and dried to give the title compound 6-chloropyridazin-3-amine. LC-MS: m / z 130.0 (M+H) +

[1516] A suspension of 3,6-dichloropyridazine (10 g, 67 mmol, 1 equiv) in 25% aqueous ammonia (50 mL) was heated in a PTFE-lined pressure reactor at 120 °C for about 12 h. After cooling to room temperature, the resulting crystalline solid was collected by filtration, washed with water and dried to give the title compound 6-chloropyridazin-3-amine. LC-MS: m / z 130.0 (M+H) +

[1517] Step A: N-(3-Bromo-5-chloropyrazin-2-yl)-6-ethoxynicotinamide

[1518] To a solution of 6-chloropyridazin-3-amine (6.2 g, 48 mmol, 1 equiv) in methanol (200 mL) was added NaHCO3 (8.1 g, 96 mmol, 2 equiv). After stirring the mixture at room temperature for 30 min, bromine (11.5 g, 72 mmol, 1.5 equiv) was added dropwise. The reaction mixture was then stirred for an additional 16 h and concentrated in vacuo to afford a residue. The residue was purified by silica gel column chromatography (eluting with 40% EtOAc / hexane) to give the title compound 4-bromo-6-chloropyridazin-3-amine.

[1519] LC-MS: m / z 207.9, 209.9 (M+H) +

[1520] Step B: N-(5-Chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxynicotinamide

[1521] To a solution of 6-ethoxypicolinic acid (2.3 g, 13.9 mmol, 1.2 equiv) and oxalyl chloride (2.2 g, 17.4 mmol, 1.5 equiv) in DCM (50 mL) at 0 °C was added DMF (0.1 mL). The resulting mixture was stirred at room temperature for 1 h. The reaction solution was concentrated in vacuo to give 6-ethoxypicolinoyl chloride for direct use. To a solution of 4-bromo-6-chloropyridazin-3-amine (2.4 g, 11.6 mmol, 1 equiv) in DMF (50 mL) at room temperature was added NaH (1.4 g, 34.8 mmol, 3 equiv). The mixture was stirred at room temperature for 1 h and then a solution of 6-ethoxypicolinoyl chloride in DMF (50 mL) was added. The mixture was stirred at room temperature overnight. The reaction mixture was quenched with ammonium chloride solution (aqueous, 100 mL) and extracted with DCM (3 × 150 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was recrystallized from DCM to give the title compound N-(4-bromo-6-chloropyridazin-3-yl)-6-ethoxypicolinamide.

[1522] LC-MS: m / z 356.9, 358.9 (M+H) +

[1523] ​

[1524] A suspension of N-(4-bromo-6-chloropyridazin-3-yl)-6-ethoxypicolinamide (500 mg, 1.4 mmol, 1 equiv), 2,6-dimethoxyaniline (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 under N2 atmosphere by microwave irradiation at 120 °C for 2 h. 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 give the desired product N-(6-chloro-4-((2,6-dimethoxyphenyl)amino)pyridazin-3-yl)-6-ethoxypicolinamide.

[1525] LC-MS: m / z 430.1 (M+H) +

[1526] ​ ​

[1527] 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 for 2 h by microwave irradiation. After the reaction solution was cooled to room temperature, the pale yellow precipitate was filtered off and rinsed with EtOAc / PE = 1 / 2 (2 * 0.5 mL) to obtain the title compound chloro-7-(2,6-dimethoxyphenyl)-8-(6-ethoxypyridin-2-yl)-7H-imidazo[4,5-c]pyridazine.

[1528] 1 H NMR (400 MHz, DMSO-d6) δ 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 Hz, 2H), 3.60 (s, 6H), 3.40 (q, J = 7.2 Hz, 2H), 1.04 (t, J = 7.2 Hz, 3H).

[1529] LC-MS: m / z 412.1 (M + H) +

[1530] ​ ​

[1531] 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), CuI (44 mg, 0.23 mmol, 2 equiv), trans-N,N'-dimethylcyclohexane-1,2-diamine (33 mg, 0.23 mmol, 2 equiv) and K2CO3 (48 mg, 0.23 mmol, 3 equiv) in DMF (2 mL) were stirred under N2 atmosphere at 130 °C for 1.5 h by microwave irradiation. The reaction solution was diluted with water (150 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (eluting with DCM / MeOH = 100 / 1) to afford the title compound as a yellow solid (30 mg, 55% yield).

[1532] 11H NMR (400 MHz, DMSO-d6) δ 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), 3.39 (q, J = 7.2 Hz, 2H), 3.22 (s, 3H), 1.03 (t, J = 7.2 Hz, 3H). LC-MS: m / z 471.1 (M+H) +

[1533] Method C:

[1534]

[1535] ​

[1536]

[1537] 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 AlMe3 (2 mol / L, 51 mL, 102 mmol, 1.5 equiv) and the resulting mixture was stirred at 55 °C for 30 min. Ethyl 6-ethoxynicotinate (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 1N HCl (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-pulped in DCM to afford the title compound N-(3-bromo-5-chloropyrazin-2-yl)-6-ethoxynicotinamide as a pale yellow solid (12 g, 50% yield).

[1538] LC-MS: m / z 356.9, 358.9 (M+H) +

[1539] ​

[1540]

[1541] A suspension of N-(3-bromo-5-chloropyrazin-2-yl)-6-ethoxynicotinamide (1 g, 2.8 mmol, 1.0 equiv), 2,6-dimethoxyaniline (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 1,4-dioxane (15 mL) was stirred under N2 atmosphere by microwave irradiation at 120 °C 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 give the desired product N-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxynicotinamide as a yellow solid (6.3 g, 52% yield). LC-MS: m / z 430.1 (M+H) +

[1542] Step C: 6-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5- b]pyrazine

[1543]

[1544] A solution of N-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxynicotinamide (2.0 g, 4.66 mmol) in AcOH (10 mL) was stirred at 130 °C for 2 h by microwave irradiation. The mixture was cooled to room temperature and the precipitate was filtered off and washed with EtOAc / PE = 1 / 2 to give the title compound 6-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine as a light yellow solid (1.6 g, 83% yield).

[1545] LC-MS: m / z 412.1 (M+H) +

[1546] Step D: N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b] pyrazin-6-yl)methanesulfonamide (Example 2)

[1547]

[1548] 6-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine (1 g, 2.43 mmol), methanesulfonamide (462 mg, 4.87 mmol, 3.0 equiv), CuI (924 mg, 4.87 mmol, 3.0 equiv), trans-N,N'-dimethylcyclohexane-1,2-diamine (691 mg, 4.87 mmol, 3.0 equiv) and K2CO3 (1006 mg, 7.29 mmol, 3 equiv) in DMF (10 mL) were stirred under N2 atmosphere by microwave irradiation at 130 °C for 1.5 h. The mixture was diluted with EtOAc (30 mL) and filtered through celite. The filtrate was poured into aqueous K2CO3 solution (2 mol / L, 50 mL) and stirred for 15 min. Then the aqueous layer was separated and washed with EtOAc (2 × 30 mL). The aqueous layer was adjusted to pH = 4 with formic acid and extracted with DCM (3 × 100 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography, eluting with DCM / MeOH = 20 / 1 to 10 / 1 to give the title compound N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide (Example 2) as a yellow solid (800 mg, 70% yield).

[1549] 1 H NMR (400 MHz, DMSO-d6) δ: 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, 3H), 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) +

[1550] Example 22: N-(1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)cyclopropanesulfonamide

[1551]

[1552] According to Method C, Step D, starting from N-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxynicotinamide, the title compound was prepared using cyclopropanesulfonamide (22 mg, 37% yield).

[1553] 1 1H NMR (400 MHz, DMSO-d6) δ: 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 - 0.83 (m, 2H), 0.64 - 0.69 (m, 2H). LCMS: m / z 497.1 (M + H) +

[1554] Example 23: N-(1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)pyridine-2-sulfonamide

[1555]

[1556] According to Method C, Step D, starting from N-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxynicotinamide, the title compound was prepared using pyridine-2-sulfonamide (30 mg, 23% yield).

[1557] 1 1H NMR (400 MHz, DMSO-d6) δ: 11.77 (s, 1H), 8.55 (d, J = 4.0 Hz, 1H), 8.21 (s, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.80 (t, J = 7.6 Hz, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.49 (t, J = 8.4 Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H), 6.77 (d, J = 8.0 Hz, 1H), 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) +

[1558] Example 24: N-(1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)pyridine-3-sulfonamide

[1559]

[1560] According to Method C, Step D, starting from N-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxynicotinamide, the title compound (58 mg, 54% yield) was prepared using pyridine-3-sulfonamide.

[1561] 1 1H NMR (400 MHz, DMSO-d6) δ: 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) +

[1562] Example 25: N-(1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)pyridine-4-sulfonamide

[1563]

[1564] According to Method C, Step D, starting from N-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxynicotinamide, the title compound (45 mg, 57% yield) was prepared using pyridine-4-sulfonamide.

[1565] 1 1H NMR (400 MHz, DMSO-d6) δ: 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) +

[1566] Example 26: N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(pyridin-3-yl)methanesulfonamide

[1567]

[1568] According to Method C, Step D, starting from N-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxynicotinamide, the title compound was prepared using pyridin-3-ylmethanesulfonamide (24 mg, 25% yield).

[1569] 1 H NMR (400 MHz, DMSO-d6) δ: 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 = 4.0 Hz, 2H), 6.84 (dd, J = 4.0, 8.0 Hz, 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) +

[1570] Example 27: N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(pyridin-2-yl)methanesulfonamide

[1571]

[1572] According to Method C, Step D, starting from N-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxynicotinamide, the title compound was prepared using pyridin-2-ylmethanesulfonamide (30 mg, 37% yield).

[1573] 11H NMR (400M, DMSO-d6) δ: 11.12 (br, 1H), 8.45 - 8.47 (m, 1H), 8.14 (s, 1H), 7.94 (dd, J = 7.6 Hz, J = 0.8 Hz, 1H), 7.86 (t, J = 7.6 Hz, 1H), 7.75 (td, J = 7.6 Hz, J = 1.6 Hz, 1H), 7.47 (t, J = 8.4 Hz, 1H), 7.31 - 7.34 (m, 1H), 7.2 (d, J = 7.6 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 6.82 (dd, J = 8.0 Hz, J = 0.8 Hz, 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) +

[1574]

[1575] To a solution of methyl pyrimidine-2-carboxylate (25 g, 181 mmol, 1.0 equiv) in MeOH (500 mL) at 0 °C was added NaBH4 (8.2 g, 217 mmol, 1.2 equiv). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with H2O (10 mL) and concentrated in vacuo. The residue was purified by flash column chromatography (PE / EtOAc = 1 / 1) to give the title compound pyrimidin-2-ylmethanol as a yellow oil (16 g, 80% yield).

[1576] LC-MS: m / z 111.0 (M + H) +

[1577] Step B: 2-((pyrimidin-2-ylmethyl)thio)benzo[d]thiazole

[1578]

[1579] To a solution of pyrimidin-2-ylmethanol (16.6 g, 151 mmol, 1.0 equiv), benzothiazole-2-thiol (30 g, 181 mmol, 1.2 equiv) and PPh3 (47.4 g, 181 mmol, 1.2 equiv) in THF (500 mL) at 0 °C was added DEAD (36.6 g, 181 mmol, 1.2 equiv). The mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with HCl-dioxane and the white precipitate was filtered off. The solid was then dissolved in 1N aqueous Na2CO3 (100 mL) and extracted with EtOAc (3×200 mL). The combined organic phases were concentrated in vacuo to give the title compound 2-((pyrimidin-2-ylmethyl)thio)benzothiazole as a crude yellow solid (27 g, 77% yield).

[1580] LC-MS: m / z 260.0 (M+H) +

[1581] Step C: 2-((pyrimidin-2-ylmethyl)sulfonyl)benzo[d]thiazole

[1582]

[1583] To a solution of 2-((pyrimidin-2-ylmethyl)thio)benzothiazole (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 h and quenched with 1N aqueous Na2SO3. The organic phase was separated, washed with saturated Na2CO3 and concentrated in vacuo. The residue was purified by flash column chromatography (PE / EtOAc = 5 / 1) to give the title compound 2-((pyrimidin-2-ylmethyl)sulfonyl)benzothiazole as a white solid (17 g, 80% yield).

[1584] LC-MS: m / z 292.0 (M+H) +

[1585] Step D: pyrimidin-2-ylmethanesulfonamide

[1586]

[1587] 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 minutes, a solution of NH2OSO3H (250 mg, 2.0 mmol, 1.2 equiv) in H2O (1 mL) was added. The mixture was stirred at room temperature for 15 minutes and another portion 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).

[1588] 1 H NMR (400 MHz, DMSO) δ 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) +

[1589] Example 28: N-(1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(pyrimidin-2-yl)methanesulfonamide

[1590]

[1591] According to Method C, Step D, starting from N-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxynicotinamide, the title compound was prepared using pyrimidin-2-ylmethanesulfonamide (27 mg, 34% yield).

[1592] 1 H NMR (400 MHz, DMSO-d6) δ: 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+H) +

[1593] 2-Cyclopropylethanesulfonamide

[1594]

[1595] The title compound was prepared from 2-cyclopropylethanol following the preparation of pyrimidin-2-ylmethanesulfonamide in Step A.

[1596] LC-MS: m / z 150.2 (M+H) +

[1597] Example 29: 2-Cyclopropyl-N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)ethanesulfonamide

[1598]

[1599] According to Method C, Step D, starting from 6-bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine (Example 1), the title compound was prepared using 2-cyclopropylethanesulfonamide (50 mg, 47% yield).

[1600] 1 1H NMR (400M, DMSO-d6) δ: 10.98 (br, 1H), 8.27 (s, 1H), 7.95 (d, J = 7.2 Hz, 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), 1.03 (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) +

[1601] Oxetan-3-sulfonamide

[1602]

[1603] The title compound was prepared from oxetan-3-ol following the preparation of pyrimidin-2-ylmethanesulfonamide in Step A.

[1604] 11H NMR (400 MHz, DMSO) δ: 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).

[1605] Example 30: N-(1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)oxetane-3-sulfonamide

[1606]

[1607] According to Method C, Step D, starting from N-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxynicotinamide, the title compound was prepared using oxetane-3-sulfonamide (36.3 mg, 35% yield).

[1608] 1 1H NMR (400 MHz, DMSO-d6) δ: 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) +

[1609]

[1610] Step A: 2-(cyclobutylthio)pyrimidine

[1611]

[1612] Under N2 atmosphere, DIAD (3.37 g, 16.7 mmol, 1.2 equiv) was added dropwise to a solution of PPh3 (4.37 g, 16.7 mmol, 1.2 equiv) in THF (30 mL) at 0 °C. After stirring the mixture at 0 °C for 10 minutes, 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 minutes and then at room temperature for 1 hour. 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).

[1613] LC-MS: m / z 167.0 (M+H) +

[1614] Step B: 2-(cyclobutylsulfonyl)pyrimidine

[1615]

[1616] 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 hours. Saturated aqueous Na2S2O3 solution (20 mL) was added and the mixture was stirred at room temperature for 30 minutes. The organic phase was separated, washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (PE / EtOAc = 1 / 1) to give the title compound 2-(cyclobutylsulfonyl)pyrimidine as a yellow solid (1.7 g, 78% yield).

[1617] LC-MS: m / z 199.0 (M+H) +

[1618] Step C: cyclobutanesulfonamide

[1619]

[1620] To a solution of 2-(cyclobutanesulfonyl)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 stirring the reaction mixture at 0 °C for 30 min, 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 give the title compound cyclobutanesulfonamide as a white solid (300 mg, 25% yield). LC-MS: m / z 136.0 (M+H) +

[1621] Example 31: N-(1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)cyclobutanesulfonamide

[1622]

[1623] According to Method C, Step D, starting from N-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxynicotinamide, the title compound was prepared using cyclobutanesulfonamide (85 mg, 64% yield).

[1624] 1 1H NMR (400 MHz, DMSO-d6) δ: 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) +

[1625] Example 32: N-(1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-N-methylmethanesulfonamide

[1626]

[1627] According to Method C, Step D, starting from 6-bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine (Example 1), the title compound was prepared using N-methylmethanesulfonamide (40 mg, 75% yield).

[1628] 1 H NMR (400 MHz, DMSO-d6) δ: 8.63 (s, 1H), 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) +

[1629] trans-3-(Benzyloxy)cyclobutane-1-sulfonamide

[1630]

[1631] The title compound was prepared using cis-3-(benzyloxy)cyclobutanol according to the preparation of cyclobutanesulfonamide in Step A.

[1632] 1 H NMR (400 MHz, DMSO-d6) δ: 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).

[1633]

[1634] trans-3-(Benzyloxy)-N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)cyclobutane-1-sulfonamide

[1635]

[1636] According to Method C, Step D, starting from N-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxynicotinamide, the title compound was prepared using trans-3-(benzyloxy)cyclobutane-1-sulfonamide (460 mg, 48% yield).

[1637] 1 H NMR (400 MHz, DMSO-d6) δ: 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 - 2.26 (m, 2H), 1.02 (t, J = 8.0 Hz, 3H). LC-MS: m / z 617.0 (M+H) +

[1638] Example 33: cis-N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-3-hydroxycyclobutane-1-sulfonamide

[1639]

[1640] At 0 °C and under a N2 atmosphere, trifluoromethanesulfonic acid (1 mL) and trifluoromethanesulfonic anhydride (0.5 mL) were added to a mixture of trans-3-(benzyloxy)-N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)cyclobutane-1-sulfonamide (200 mg, 0.324 mmol, 1.0 equiv) in DCM (16 mL). The resulting mixture was stirred at 0 °C for 15 minutes under a N2 atmosphere. Then the mixture was adjusted to pH = 6 by adding aqueous NaHCO3 solution (3 mol / L), and DCM (60 mL) was added to the mixture. The combined organic layers were washed with brine (20 mL), dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with DCM / MeOH = 20 / 1 to 10 / 1) to give the title compound as a brown solid (50 mg, 29% yield).

[1641] 11H NMR (400 MHz, DMSO-d6) δ: 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) +

[1642] Step B: N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b] pyrazin-6-yl)-3-oxocyclobutane-1-sulfonamide

[1643]

[1644] A solution of cis-N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-3-hydroxycyclobutane-1-sulfonamide (Example 33, 60 mg, 0.114 mmol, 1.0 eq) in DCM (2 mL) was cooled to 0 °C and Dess-Martin periodinane (193 mg, 0.456 mmol, 4 eq) was added. The mixture was stirred overnight at room temperature. The mixture was washed with Na2SO3 (aqueous) brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by preparative TLC to afford N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-3-oxocyclobutane-1-sulfonamide as a pale yellow solid (50 mg, 83% yield).

[1645] LC-MS: m / z 525.2 (M+H) +

[1646] Example 34: trans-N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-3-hydroxycyclobutane-1-sulfonamide

[1647]

[1648] A solution of N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-3-oxocyclobutane-1-sulfonamide (50 mg, 0.095 mmol, 1.0 equiv) in MeOH (1 mL) was cooled to 0 °C and NaBH4 (7.2 mg, 0.191 mmol, 3.0 equiv) was added. The mixture was warmed to room temperature and stirred for 2 h. Thereafter, H2O (1 mL) was added and the mixture was extracted 3 times with DCM. The combined organic layers were washed with brine, concentrated and purified by preparative TLC to give the title compound as a white solid (22 mg, 44% yield).

[1649] 1 1H NMR (400 MHz, CDCl3) δ: 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) +

[1650] Pyrimidin-5-ylmethanesulfonamide

[1651]

[1652] The title compound was prepared using pyrimidin-5-ylmethanol according to the preparation of cyclobutanesulfonamide in Step A.

[1653] 1 1H NMR (400 MHz, DMSO-d6) δ: 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) +

[1654] Example 35: N-(1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(pyrimidin-5-yl)methanesulfonamide

[1655]

[1656] According to Method C, Step D, starting from N-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide, the title compound was prepared using pyrimidin-5-ylmethanesulfonamide.

[1657] 1 H NMR (400 MHz, DMSO-d6) δ: 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) +

[1658]

[1659] Step A: tetrahydro-2H-pyran-4-sulfonamide

[1660]

[1661] To a solution of tetrahydro-2H-pyran-4-sulfonyl chloride (300 mg, 1.6 mmol, 1.6 eq) in acetone (5 mL) was added aqueous NH4OH (34% wt., 10 mL, 140 mmol, 88 eq). The mixture was stirred overnight at room temperature and then concentrated to dryness. The residue was purified by silica gel column chromatography (DCM / EtOAc = 2 / 1) to give the title compound tetrahydro-2H-pyran-4-sulfonamide as a white solid (150 mg, 56% yield).

[1662] LC-MS: m / z 166.2 (M+H) +

[1663] Example 36: N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)tetrahydro-2H-pyran-4-sulfonamide

[1664]

[1665] According to Method C, Step D, starting from N-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxynicotinamide, the title compound was prepared (25 mg, 32% yield) using tetrahydro-2H-pyran-4-sulfonamide.

[1666] 1 H NMR (DMSO-d6) δ: 10.93 - 11.20 (m, 1H), 8.28 (s, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.85 (t, 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) +

[1667] Morpholine-4-sulfonamide

[1668]

[1669] The title compound was prepared using morpholine-4-sulfonyl chloride according to the preparation of tetrahydro-2H-pyran-4-sulfonamide.

[1670] 1 H NMR (400 MHz, d6-DMSO) δ: 6.82 (s, 2H), 3.61 - 3.68 (m, 4H), 2.89 - 2.94 (m, 4H).

[1671] Example 37: N-(1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)morpholine-4-sulfonamide

[1672]

[1673] According to Method C, Step D, starting from 6-bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine (Example 1), the title compound was prepared (39 mg, 65% yield) using morpholine-4-sulfonamide.

[1674] 11H NMR (400 MHz, DMSO-d6) δ: 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) +

[1675] Benzyl 4-(aminosulfonylmethyl)piperidine-1-carboxylate

[1676]

[1677] The title compound was prepared from benzyl 4-((chlorosulfonyl)methyl)piperidine-1-carboxylate according to the preparation of tetrahydro-2H-pyran-4-sulfonamide (350 mg, 56% yield).

[1678] LC-MS: m / z 313.1 (M + H) + .

[1679] Benzyl 4-((N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)aminosulfonyl)methyl)piperidine-1-carboxylate

[1680]

[1681] According to Method C, Step D, starting from N-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxynicotinamide, the title compound was prepared using benzyl 4-(aminosulfonylmethyl)piperidine-1-carboxylate (210 mg, 45% yield).

[1682] LC-MS: m / z 688.2 (M + H) +

[1683] Example 38: N-(1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-(piperidin-4-yl)methanesulfonamide

[1684]

[1685] Benzyl 4-((N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)sulfamoyl)methyl)piperidine-1-carboxylate (55 g, 0.08 mmol, 1.0 equiv) and a solution of concentrated HCl (1 mL) in EtOH (4 mL) were refluxed at 90 °C for 8 h. The reaction mixture was concentrated and the residue was purified by flash column chromatography on silica gel (DCM / MeOH = 10 / 1) to afford the title compound as a yellow solid (40 mg, 90% yield).

[1686] 1 H NMR (400 MHz, DMSO-d6) δ: 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, 1H), 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) + .

[1687] 4-oxocyclohexane-1-sulfonamide

[1688]

[1689] The title compound was prepared from 4-oxocyclohexane-1-sulfonyl chloride according to the preparation of tetrahydro-2H-pyran-4-sulfonamide (150 mg, 56% yield).

[1690] LC-MS: m / z 178.0 (M+H) +

[1691] N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-4-oxocyclohexane-1-sulfonamide

[1692]

[1693] According to Method C, Step D, starting from N-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxynicotinamide, the title compound (140 mg, 69% yield) was prepared using 4-oxocyclohexane-1-sulfonamide.

[1694] LC-MS: m / z 553.2 (M+H) +

[1695] Example 39: trans-N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-4-hydroxycyclohexane-1-sulfonamide

[1696] Example 40: cis-N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-4-hydroxycyclohexane-1-sulfonamide

[1697]

[1698] To a solution of N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-4-oxocyclohexane-1-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 minutes and at room temperature for 3 hours. The reaction solution was quenched with 1N HCl (25 mL) and extracted with DCM (3 × 25 mL). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (DCM / MeOH = 10 / 1) to give Example 39 (50 mg, 37% yield) and Example 40 (12 mg, 9% yield) as white solids.

[1699] Example 39: 11H NMR (400 MHz, DMSO-d6) δ 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) +

[1700] Example 40: 1 1H NMR (400 MHz, DMSO-d6) δ 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) +

[1701]

[1702] Step A: pyrimidine-2-sulfonyl chloride

[1703]

[1704] Under rapid stirring, sodium hypochlorite (30.9 mL, 60.0 mmol) was added dropwise to a solution of 2-mercaptopyrimidine (1.1 g, 10 mmol) in CH2Cl2 (60 mL) and 1N HCl (55.0 mL, 55.0 mmol) at -20 °C. After the addition was complete, the mixture was stirred at -20 °C for 15 minutes. The organic layer was separated and used directly in the next step.

[1705] Step B: pyrimidine-2-sulfonamide

[1706]

[1707] A solution of pyrimidine-2-sulfonyl chloride in CH2Cl2 (60 mL) was added to NH4OH (aqueous, 34%, 60 mL) at 0 °C and the mixture was slowly warmed to room temperature and stirred for 1 h. The mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (CH2Cl2 / MeOH = 20 / 1) to afford the title compound pyrimidine-2-sulfonamide as a pale yellow solid (350 mg, 1.98 mmol, 20% yield in two steps).

[1708] LC-MS: m / z 160.0 (M+H) +

[1709] Example 41: N-(1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)pyrimidine-2-sulfonamide

[1710]

[1711] According to Method C, Step D, starting from 6-bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine (Example 1), the title compound was prepared using pyrimidine-2-sulfonamide (55 mg, 70% yield).

[1712] 1 1H NMR (400 MHz, DMSO-d6) δ: 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) +

[1713]

[1714] Step A: 4-hydroxypiperidine-1-sulfonamide

[1715]

[1716] A mixture of piperidin-4-ol (1.0 g, 10 mmol, 1.0 equiv) and thioamide (960 mg, 10 mmol, 1.0 equiv) in dioxane (20 mL) was stirred at 120 °C for 16 h. After evaporation, the residue was purified by flash column chromatography (eluting with DCM / MeOH = 10 / 1) to give the title compound 4-hydroxypiperidine-1-sulfonamide as a white solid, (1.09 g, 61% yield).

[1717] 1 1H NMR (400 MHz, DMSO-d6) δ: 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).

[1718] Example 42: N-(1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-4-hydroxypiperidine-1-sulfonamide

[1719]

[1720] According to Method C, Step D, starting from N-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxynicotinamide, the title compound was prepared using 4-hydroxypiperidine-1-sulfonamide (34.5 mg, 31% yield).

[1721] 1 1H NMR (400 MHz, CDCl3) δ 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) +

[1722] Method D:

[1723]

[1724] Example 43: N-(1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)methanesulfonamide

[1725]

[1726] According to Method C, Step D, starting from 5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine (Example 15), the title compound was prepared using methanesulfonamide (26 mg, 23% yield).

[1727] 1 H NMR (400 MHz, DMSO-d6) δ: 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) +

[1728] Example 44: N-(1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)methanesulfonamide

[1729]

[1730] According to Method C, Step D, starting from 5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine (Example 15), the title compound was prepared using 2-cyclopropylethanesulfonamide (30 mg, 16% yield).

[1731] 11H NMR (400 MHz, DMSO-d6) δ: 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) +

[1732] Example 45: 1 - Cyclopropyl - N-(1-(2,6 - dimethoxyphenyl) - 2-(6 - ethoxypyridin - 2 - yl)-1H - imidazo[4,5 - b]pyrazin - 5 - yl)methanesulfonamide

[1733]

[1734] According to Method C, Step D, starting from 5 - chloro - 1-(2,6 - dimethoxyphenyl)-2-(6 - ethoxypyridin - 2 - yl)-1H - imidazo[4,5 - b]pyrazine (Example 15), the title compound (20 mg, 32% yield) was prepared using cyclopropylmethanesulfonamide. 1 1H NMR (400 MHz, DMSO-d6) δ: 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) + .

[1735]

[1736] Example 46: 1-(2,6 - dimethoxyphenyl)-2-(6 - ethoxypyridin - 2 - yl)-N-(4 - methoxybenzyl)-1H - imidazo[4,5 - b]pyrazin - 5 - amine

[1737]

[1738] 5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine (Example 15, 100 mg, 0.24 mmol, 1.0 equiv), PMBNH2 (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), t A mixture of BuOK (55 mg, 0.48 mmol, 2.0 equiv) in toluene (5 mL) was stirred at 110 °C for 16 h under a N2 atmosphere. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (PE / EtOAc = 10 / 1 to 1 / 1) to afford the title compound as a yellow solid (30 mg, 24% yield).

[1739] 1 1H NMR (400 MHz, DMSO) δ: 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 513.2 (M+H) +

[1740] Method E:

[1741]

[1742] Step A: N-(5-chloro-3-((2-methoxy-6-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)-6-ethoxy pyridinecarboxamide

[1743]

[1744] A suspension of N-(3-bromo-5-chloropyrazin-2-yl)-6-ethoxynicotinamide (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 1,4-dioxane (2 mL) was stirred under a N2 atmosphere by microwave irradiation at 130 °C for 2 h. The mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (eluting with EtOAc / PE = 1 / 6) to afford the title compound N-(5-chloro-3-((2-methoxy-6-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)-6-ethoxynicotinamide as a yellow solid (2 mg, 2% yield), along with the byproduct 2-(6-ethoxypyridin-2-yl)-1-(2-methoxy-6-(trifluoromethyl)phenyl)-1H-imidazo[4,5-b]pyrazin-6-ol (Example 47, 22 mg, 18% yield).

[1745] LC-MS: m / z 468.1 (M+H) +

[1746] Example 47: 2-(6-ethoxypyridin-2-yl)-1-(2-methoxy-6-(trifluoromethyl)phenyl)-1H-imidazo[4,5-b]pyrazin-6-ol

[1747]

[1748] 1 1H NMR (400 MHz, DMSO-d6) δ: 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 (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) +

[1749] Step B: 6-chloro-2-(6-ethoxypyridin-2-yl)-1-(2-methoxy-6-(trifluoromethyl)phenyl)-1H-imi dazo[4,5-b]pyrazine

[1750]

[1751] A solution of N-(5-chloro-3-((2-methoxy-6-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)-6-ethoxynicotinamide (35 mg, 0.075 mmol) in AcOH (2 mL) was stirred at 130 °C for 2 h. The mixture was concentrated and the residue was purified by preparative TLC to give the title compound 6-chloro-2-(6-ethoxypyridin-2-yl)-1-(2-methoxy-6-(trifluoromethyl)phenyl)-1H-imidazo[4,5-b]pyrazine as a yellow solid (25 mg, 74% yield).

[1752] LC-MS: m / z 450.0 (M+H) +

[1753] Example 48: N-(2-(6-Ethoxypyridin-2-yl)-1-(2-methoxy-6-(trifluoromethyl)phenyl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide

[1754]

[1755] A suspension of 6-chloro-2-(6-ethoxypyridin-2-yl)-1-(2-methoxy-6-(trifluoromethyl)phenyl)-1H-imidazo[4,5-b]pyrazine (25 mg, 0.056 mmol), methanesulfonamide (11 mg, 0.112 mmol, 2 equiv), CuI (21 mg, 0.112 mmol, 2 equiv), trans-N,N'-dimethylcyclohexane-1,2-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 for 2 h under N2 atmosphere by microwave irradiation. The mixture was diluted with EtOAc (30 mL) and filtered through celite. The filtrate was poured into an aqueous solution of K2CO3 (2 mol / L, 50 mL) and stirred for 15 min. Then the aqueous phase was separated and washed with EtOAc (2 × 30 mL). The aqueous phase was adjusted to pH = 3 with 1N HCl and extracted with DCM (3 × 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (eluting with DCM / MeOH = 20 / 1 to 10 / 1) to afford the title compound as a white solid. (10 mg, 35% yield).

[1756] 11H NMR (400 MHz, DMSO-d6) δ: 11.13 (s, 1H), 8.32 (s, 1H), 8.06 (dd, J = 7.4, 0.8 Hz, 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) +

[1757] Example 49: N-(2-(6-Ethoxypyridin-2-yl)-1-(3-methoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide

[1758]

[1759] The title compound was prepared according to Method E using 3-methoxypyridin-2-amine in Step A.

[1760] 1 1H NMR (400 MHz, CDCl3) δ: 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) + .

[1761] Example 50: N-(Benzylsulfonyl)-4-(2-fluoro-6-methoxyphenyl)-5-(6-methoxypyridin-2-yl)-4H-1,2,4-triazole-3-carboxamide

[1762]

[1763] The title compound was prepared according to Method E using 2-fluoro-6-methoxyaniline in Step A.

[1764] 11H NMR (400 MHz, DMSO-d6) δ: 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) +

[1765] Method F:

[1766]

[1767] Step A: N-(3,5-dibromopyrazin-2-yl)-6-methoxypyridinecarboxamide

[1768]

[1769] At room temperature under an argon atmosphere, a solution of AlMe3 (1.6 mol / L, 34 mL, 54 mmol, 1.3 equiv) was added dropwise to a THF solution of 3,5-dibromopyrazin-2-amine (13.6 g, 54 mmol, 1.3 equiv). The mixture was stirred at room temperature for 0.5 h. Then 3,5-dibromopyrazin-2-amine (6.8 g, 41 mmol, 1.0 equiv) was added in one portion. The mixture was stirred at 60 °C for 1.5 h, quenched with 1 N HCl (aqueous) and extracted three times with ethyl acetate. The extract was washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound N-(3,5-dibromopyrazin-2-yl)-6-methoxypicolinamide as a yellow solid (14 g, 88.1% yield).

[1770] LC-MS: m / z 386.8, 388.8, 390.8 (M+H) +

[1771] Step B: N-(5-bromo-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-methoxypyridinecarboxamide

[1772]

[1773] N-(3,5-dibromopyrazin-2-yl)-6-methoxypicolinamide (600 mg, 1.54 mmol, 1.0 equiv), 2,6-dimethoxyaniline (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 a suspension of 1,4-dioxane (10 mL) was stirred for 2 h by microwave irradiation under N2 atmosphere at 120 °C. 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 give the desired product N-(5-bromo-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-methoxypicolinamide (70 mg, 10% yield).

[1774] LC-MS: m / z 459.9, 461.9 (M+H) +

[1775] Step C: 6-bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5- b]pyrazine

[1776]

[1777] 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 120 °C for 2 h by microwave irradiation. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography to give the desired product 6-bromo-1-(2,6-dimethoxyphenyl)-2-(6-methoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine as a light yellow solid (475 mg, 70%).

[1778] LC-MS: m / z 442.3, 444.3 (M+H) +

[1779] Example 51: N-(1-(2,6-dimethoxyphenyl)-2-(6-methoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide

[1780]

[1781] The title compound was prepared according to Method F using methanesulfonamide in Step D (72 mg, 78% yield).

[1782] 11H NMR (400 MHz, DMSO-d6) δ: 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) +

[1783] Example 52: N-(1-(2,6-Dimethoxyphenyl)-2-(6-methoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)pyridine-2-sulfonamide

[1784]

[1785] The title compound (34 mg, 33% yield) was prepared according to Method F by using pyridine-2-sulfonamide in Step D.

[1786] 1 1H NMR (400 MHz, DMSO-d6) δ: 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) +

[1787] Example 53: N-(1-(2,6-Dimethoxyphenyl)-2-(6-methoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)pyrimidine-2-sulfonamide

[1788]

[1789] The title compound (15 mg, 29% yield) was prepared according to Method F by using pyridine-2-sulfonamide in Step D.

[1790] 11H NMR (400 MHz, DMSO-d6) δ: 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) +

[1791] Method G:

[1792]

[1793] Step A: methyl 6-fluoropicolinate

[1794]

[1795] 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 CHCl3 (100 mL). The suspension was stirred at 30 °C for 1 day. The insoluble material was filtered off and the filter cake was washed with CHCl3. The filtrate was concentrated in vacuo to give the title compound as a pale yellow solid (9.0 g, 82% yield). The material was used in the next step without further purification.

[1796] LC-MS: m / z 156.0 (M+H) +

[1797] Step B: 6-cyclopropoxypicolinic acid

[1798]

[1799] To a mixture of cyclopropanol (1.5 g, 25.8 mmol, 3.0 eq) in dioxane (20 mL) at 0 °C was added NaH (1032 mg, 25.8 mmol, 3.0 eq) and the mixture was stirred at 0 °C for 30 minutes. Then methyl 6-fluoropicolinate (2.0 g, 12.9 mmol, 1.0 eq) was added and the mixture was stirred at 25 °C for 2 hours. The reaction mixture was quenched with saturated aqueous NH4Cl. The mixture was washed 3 times with EtOAc. 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).

[1800] LC-MS: m / z 180.0 (M+H) +

[1801] Step C: methyl 6-cyclopropoxypicolinate

[1802]

[1803] Methyl iodide (0.41 mL, 6.59 mmol, 3.0 eq) was added to a suspension of 6-cyclopropoxypicolinic acid (590 mg, 3.29 mmol, 1.0 eq) and silver(I) carbonate (1091 mg, 3.95 mmol, 1.2 eq) in CHCl3 (10 mL). The suspension was stirred at 30 °C for 4 hours. The insoluble material was removed by filtration and the cake was washed with CHCl3. The filtrate was concentrated in vacuo to give the title compound methyl 6-cyclopropoxypicolinate as a pale yellow oil (600 mg, 94% yield). This material was used in the next step without further purification.

[1804] LC-MS: m / z 194.0 (M+H) +

[1805] Step D: N-(3-bromo-5-chloropyrazin-2-yl)-6-cyclopropoxypyridinecarboxamide

[1806]

[1807] 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 solution in toluene, 4 mL, 6.2 mmol, 2.0 equiv). After the mixture was stirred at 50 °C for 30 minutes, methyl 6-cyclopropoxypicolinate (600 mg, 3.1 mmol, 1.0 equiv) was added. The mixture was stirred at 110 °C for 1 hour and quenched with 1N aqueous HCl. The mixture was extracted 3 times with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrate...

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt thereof; wherein: A 1 is CH or N; X 1 , X 2 , X 3 , and X 4 each independently selected from N and CR 3 ; R1 is: (i)-(Y 1 ) n -Y 2 , wherein: · n is 0 or 1; ·Y 1 is C 1-6 an alkylene group, optionally substituted by 1-6 R a substituents; and ·Y 2 is: (a) C 3-10 cycloalkyl, optionally substituted with 1 to 4 R b substituents; (b)C 6-10 aryl, optionally substituted with 1-4 R c substituents; (c) heteroaryl containing 5-10 ring atoms, wherein 1-4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S, and one or more of the heteroaryl ring carbon atoms are optionally substituted by 1-4 independently selected R c substituents, or (d) Heterocyclic groups containing 3 to 10 ring atoms, where 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), and O, and where one or more of the heterocyclic group ring carbon atoms are optionally substituted with 1 to 4 independently selected R b substituents, or (ii)-Z 1 -Z 2 -Z 3 , wherein: ·Z 1 is C 1-3 alkylene, optionally substituted by 1 to 4 R a substituents; ·Z 2 is -N(H)-, -N(R d )-, -O- or -S-; and ·Z 3 is C 2-7 alkyl, which is optionally substituted by 1 to 4 R a substituents; or (iii)C 3-10 alkyl, optionally substituted by 1 to 6 independently selected R a substituents; or (iv)-Z 4 -Z 5 -Z 6 -Y 2 Wherein: ·Z 4 is C 1-3 alkylene, which is optionally substituted with 1-4 R a substituents; ·Z 5 is -N(H)-, -N(R d )-, -O- or -S-; ·Z 6 is C 1-4 alkylene, which is optionally substituted by 1-4 R a substituents; and ·Y 2 As defined above; R 2 is: (i) C 6-10 aryl, optionally further substituted by 1-4 R c substituents; (ii) Heteroaryl containing 5 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S, and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted by 1 to 4 independently selected R c substituents; (iii)C 3-10 cycloalkyl, optionally substituted by 1 to 4 R b substituents; (iv) Heterocyclic groups containing 3 to 10 ring atoms, where 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), and O, and where one or more of the ring carbon atoms of the heterocyclic group are optionally substituted with 1 to 4 independently selected R b ; or (v)C 1-10 alkyl, optionally substituted by 1 to 6 independently selected R a substituents; Each occurrence of R 3 is independently selected from -L 4 -R 4 , H and, R c '; Each occurrence of L 4 Independently selected from: (i) a single bond; (ii) N(H), N(R d ), or N(R 4 ); (iii)-N(H)S(O) 1-2 - or -N(R d )S(O) 1-2 -; (iv)-S(O) 1-2 N(H)- or -S(O) 1-2 N(R d )-; (v) -O-; (vi)-S(O) 0-2 -; (vii) -C(O)NH- or -C(O)N(R d ); (viii) -N(H)C(O)- or -N(R d )C(O)-; (ix) -C≡C; (x)-N(H)S(O)(=NH)-, -N(R d )S(O)(=NH), -N(H)S(O)(=NR d )-, or -N(R d )S(O)(=NR d )- (xi)-S(O)(=NH)NH-, -S(O)(=NR d )NH-, -S(O)(=NH)NR d -, or -S(O)(=NR d )NR d -; (xii) -S(O)(=NH)- or -S(O)(=NR d );and (xiii)-N(H)S(O) 1-2 N(H)-, -N(R d )S(O) 1-2 N(H)-, -N(H)S(O) 1-2 N(R d )-, or -N(R d )S(O) 1-2 N(R d )-; Each occurrence of R 4 independently is: (i)-(Y 3 ) p -Y 4 , wherein: · p is 0 or 1; ·Y 3 is C 1-6 alkylene or C 1-6 alkenylene, each of which is optionally substituted with 1-6 R a substituents; and ·Y 4 is: (a)C 3-6 cycloalkyl, optionally substituted by 1 to 4 R b substituents (b)C 6-10 aryl, optionally substituted with 1 to 4 R c substituents; (c) Heteroaryl containing 5 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S, and wherein one or more of the heteroaryl ring carbon atoms are optionally substituted by 1 to 4 independently selected R c substituents, or (d) Heterocyclic groups containing 3 - 10 ring atoms, wherein 1 - 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), and O, and wherein one or more of the heterocyclic group ring carbon atoms are optionally substituted by 1 - 4 independently selected R b substituents, or (ii) C 1-10 alkyl, C 1-10 alkenyl, or C 1-10 alkynyl, each of which is optionally substituted by 1 - 6 independently selected R a substituents; Each occurrence of R a is independently selected from: -OH; -F; -Cl; -Br; -NR e R f ; C 1-4 alkoxy; C 1-4 haloalkoxy; -C(=O)O(C 1-4 alkyl); -C(=O)(C 1-4 alkyl); -C(=O)OH; -CON(R’)(R”); -S(O) 1-2 (NR’R”); -S(O) 1-2 (C 1-4 alkyl); cyano; and optionally C 1-4 cycloalkyl substituted with 1-4 independently selected C 3-6 alkyl; Each occurrence of R b is independently selected from: C 1-6 alkyl; C 1-4 haloalkyl; -OH; oxo; -F; -Cl; -Br; -NR e R f ; C 1-4 alkoxy; C 1-4 haloalkoxy; -C(=O)(C 1-4 alkyl); -C(=O)O(C 1-4 alkyl); -C(=O)OH; -C(=O)N(R’)(R”); -S(O) 1-2 (NR’R”); -S(O) 1-2 (C 1-4 alkyl); cyano; and C 3-6 cycloalkyl, which is optionally substituted by 1-4 independently selected C 1-4 alkyl; Each occurrence of R c is independently selected from: (i) a halogen; (ii) a cyano group; (iii)C 1-6 alkyl; (iv) C 2-6 Alkenyl; (v)C 2-6 alkynyl; (vi) C 1-4 Halogenated alkyl; (vii) C 1-4 alkoxy group; (viii)C 1-4 haloalkoxy group; (ix) Optionally substituted by 1 to 4 independently selected C 1-4 alkyl-substituted -(C 0-3 alkylene)-C 3-6 cycloalkyl; (x)-S(O) 1-2 (C 1-4 (alkyl); (xi)-NR e R f ; (xii) -OH; (xiii)-S(O) 1-2 (NR’R”); (xiv)-C 1-4 Thioalkoxy; (xv) -NO2; (xvi)-C(=O)(C 1-4 alkyl); (xvii)-C(=O)O(C 1-4 alkyl); (xviii) -C(=O)OH, (xix) -C(=O)N(R’)(R”), and (xx)C 3-6 Cyclanoxy; Each occurrence of R c is independently selected from: (i) a halogen; (ii) a cyano group; (iii) -OH; (iv) -NO2; (v)-C(=O)(C 1-4 alkyl); (vi)-C(=O)O(C 1-4 alkyl); (vii) -C(=O)OH; and (viii) -NH2; R d selected from the group consisting of: C 1-6 alkyl; C 3-6 cycloalkyl; -C(O)(C 1-4 alkyl); -C(O)O(C 1-4 alkyl); -CON(R’)(R”); -S(O) 1-2 (NR’R”); -S(O) 1-2 (C 1-4 alkyl); -OH; and C 1-4 alkoxy; Each occurrence of R e and R f are independently selected from: H; C 1-6 alkyl; C 3-6 cycloalkyl; -C(O)(C 1-4 alkyl); -C(O)O(C 1-4 alkyl); -CON(R’)(R”); -S(O) 1-2 (NR’R”); -S(O) 1-2 (C 1-4 alkyl); -OH; and C 1-4 alkoxy; or R e and R f together with the nitrogen atom to which they are each attached form a ring containing 3 - 8 ring atoms, wherein the ring contains: (a) 1 - 7 ring carbon atoms, each carbon atom being substituted with 1 - 2 substituents independently selected from H and C 1-3 alkyl; (b) 0 - 3 ring heteroatoms (other than the nitrogen atoms attached to R’ and R”), each independently selected from N(R d ), O, and S; and Each occurrence of R’ and R” is independently selected from: H and C 1-4 alkyl; or R’ and R” together with the nitrogen atom to which they are attached form a ring containing 3 - 8 ring atoms, wherein the ring contains: (a) 1 - 7 ring carbon atoms, each carbon atom being substituted by 1 - 2 substituents independently selected from H and C 1-3 alkyl; (b) 0 - 3 ring heteroatoms (in addition to the nitrogen atom to which R’ and R” are attached), each independently selected from N(R d ), O, and S; provided that when the compound is of formula (I-1): R 1 is not an unsubstituted phenyl, p-dimethylaminophenyl, p-aminosulfonylphenyl, and unsubstituted 4-pyridyl; when the compound is of formula (I-2): R 1 is not an unsubstituted phenyl group; provided that the compound is not of formula (I-3): provided that when the compound is of formula (I-4): R 1 is not p-fluorophenyl; and provided that when the compound is of formula (I-5): R 3 is not trifluoromethyl; and provided that when the compound is of formula (I-6): R 2 Not: (i) an unsubstituted phenyl group; (ii) (iii) (iv) unsubstituted pyridyl; (v) where Q 1 、Q 2 、Q 3 、and Q 4 is each independently selected from N and CH; or (vi) Heteroaryl containing 9-10 ring atoms, wherein 1-2 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ), O and S, and one or more of the heteroaryl ring carbon atoms are optionally substituted with 1-2 independently selected R c .

2. The compound according to claim 1, wherein X 1 、 X 2 、 X 3 、 and X 4 的 1 - 2 are independently N; and X 1 、 X 2 、 X 3 、 and X 4 each of 2 - 3 of which is independently selected CR 3 。 3. The compound according to claim 1, wherein the compound is of formula (I-a): or a pharmaceutically acceptable salt thereof.

4. The compound according to any one of claims 1-3, wherein The compound is of formula (I-a1): or a pharmaceutically acceptable salt thereof.

5. The compound according to any one of claims 1-3, wherein, The compound is of formula (I-a2): or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1, wherein the compound is of formula (I-b): or a pharmaceutically acceptable salt thereof.

7. The compound according to any one of claims 1 and 6, wherein The compound is of formula (I-b1): or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 1, wherein the compound is of formula (I-c) or (I-d): or a pharmaceutically acceptable salt thereof.

9. The compound according to any one of claims 1 and 8, wherein, The compound is of formula (I-c1) or (I-d1): or a pharmaceutically acceptable salt thereof.

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

Images