Compounds and compositions for treating diseases associated with APJ receptor activity

Abstract

The present disclosure features chemical entities (e.g., compounds or pharmaceutically acceptable salts and / or hydrates of compounds and / or prodrugs of compounds) that modulate (e.g., agonize) apelin receptors (also referred to herein as APJ receptors; gene symbol APLNR). The present disclosure also features compositions comprising the chemical entities and other methods of use and preparation. The chemical entities can be used, for example, to treat subjects (e.g., humans) suffering from a disease, disorder, or condition in which reduced APJ receptor activity (e.g., blocked or impaired APJ receptor signaling; e.g., blocked or impaired apelin-APJ receptor signaling) or downregulation of endogenous apelin contributes to the pathology and / or symptoms and / or progression of the disease, disorder, or condition. Non-limiting examples of these diseases, disorders or conditions include: (i) cardiovascular disease; (ii) metabolic disorders; (iii) diseases, disorders and conditions related to vascular pathology; (iv) organ failure; (v) diseases, disorders and conditions associated with infection (e.g., microbial infection); (vi) diseases, disorders or conditions that are sequelae or complications of any of the foregoing or disclosed herein. More specific non-limiting examples of these diseases, disorders or conditions include pulmonary 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 contents of which are incorporated herein by reference. Technical Field

[0003] The present disclosure features chemical entities (e.g., compounds or pharmaceutically acceptable salts and / or hydrates of compounds and / or prodrugs of compounds) that modulate (e.g., agonize) apelin receptors (also referred to herein as APJ receptors; gene symbol APLNR). The present disclosure also features compositions comprising the chemical entities and other methods of use and preparation. The chemical entities can be used, for example, to treat subjects (e.g., humans) suffering from a disease, disorder, or condition in which reduced APJ receptor activity (e.g., blocked or impaired APJ receptor signaling; e.g., blocked or impaired apelin-APJ receptor signaling) or downregulation of endogenous apelin contributes to the pathology and / or symptoms and / or progression of the disease, disorder, or condition. Non-limiting examples of these diseases, disorders or conditions include: (i) cardiovascular disease; (ii) metabolic disorders; (iii) diseases, disorders and conditions related to vascular pathology; (iv) organ failure; (v) diseases, disorders and conditions associated with infection (e.g., microbial infection); (vi) diseases, disorders or conditions that are sequelae or complications of any of the foregoing or disclosed herein. More specific non-limiting examples of these diseases, disorders or conditions include pulmonary hypertension (e.g., PAH); heart failure; type II diabetes; renal failure; sepsis and systemic hypertension. Background Art

[0004] Pulmonary arterial hypertension (PAH) is a serious cardiopulmonary disease characterized by vascular remodeling of pulmonary arterioles, including the formation of plexiform and concentric lesions composed of proliferative vascular cells. PAH is believed to be caused by cell proliferation and fibrosis of small pulmonary arteries. Clinically, PAH leads to increased pulmonary artery pressure and subsequent right ventricular failure, which is one of the main causes of morbidity and mortality. Mortality remains high at 1, 2, 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, EMT, Nature Reviews, 2017, 1-12.

[0005] Type 2 diabetes (type 2 diabetes) is characterized by hyperglycemia and insulin resistance. Type 2 diabetes and the complications or sequelae of type 2 diabetes affect tens of millions of people in the United States alone. Type 2 diabetes is often associated with obesity.

[0006] Apelin or APJ receptor is a G protein-coupled receptor containing seven hydrophobic transmembrane domains (see, e.g., Kim, supra). Apelin (also known as APLN) is a 36 amino acid peptide that is encoded by the APLN gene in humans and is an endogenous ligand for the APJ receptor (see, e.g., O'Carroll, AM. 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 that there is a link between apelin systems (e.g., apelin and APJ receptors) and the treatment of conditions such as sepsis, septic shock and renal failure (see, e.g., Coquerel, D. et al., Critical Care 2018, 22: 10). As another example, apelin, which is synthesized and secreted by adipocytes, has been described as a beneficial adipokine associated with obesity, and there is other evidence that apelin and APJ receptors have potential roles 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 of compounds and / or prodrugs of compounds) that modulate (e.g., agonize) apelin receptors (also referred to herein as APJ receptors; gene symbol APLNR). The present disclosure also features compositions comprising the chemical entities and other methods of use and preparation. The chemical entities can be used, for example, to treat subjects (e.g., humans) suffering from a disease, disorder, or condition in which reduced APJ receptor activity (e.g., blocked or impaired APJ receptor signaling; e.g., blocked or impaired apelin-APJ receptor signaling) or downregulation of endogenous apelin contributes to the pathology and / or symptoms and / or progression of the disease, disorder, or condition. Non-limiting examples of these diseases, disorders or conditions include: (i) cardiovascular disease; (ii) metabolic disorders; (iii) diseases, disorders and conditions related to vascular pathology; (iv) organ failure; (v) diseases, disorders and conditions associated with infection (e.g., microbial infection); (vi) diseases, disorders or conditions that are sequelae or complications of any of the foregoing or disclosed herein. More specific non-limiting examples of these diseases, disorders or conditions include pulmonary hypertension (e.g., PAH); heart failure; type II diabetes; renal failure; sepsis and systemic hypertension; idiopathic pulmonary fibrosis (IPF); and systemic sclerosis.

[0010] "Agonists" of the APJ receptor include compounds that directly bind to or modify the APJ receptor at the protein level, thereby increasing the activity of the APJ receptor, for example, by activation, stabilization, alteration of distribution, or other means.

[0011] Compared to APJ receptor full agonists, some chemical entities described herein that agonize APJ receptors are less agonistic and can act as antagonists and agonists. These chemical entities antagonize the activation of APJ receptors by APJ receptor full agonists because they prevent the full effect of APJ receptor interaction. However, these chemical entities can also activate some APJ receptor activity alone, and the degree of activation is generally lower than the corresponding amount of APJ receptor full agonists. Such chemical entities are sometimes referred to as "partial agonists of APJ receptors" in this article.

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

[0013] In other embodiments, the chemical entities described herein modulate (e.g., agonize) APJ receptors in a pathway-specific manner. Therefore, the present invention is also characterized by chemical entities that exhibit activity as ligand-biased modulators (e.g., ligand-biased agonists). The activity of the APJ receptor can modulate (e.g., change or bias) the competitive level of downstream G protein signaling (activation) and beta-arrestin recruitment. APJ receptor signaling through beta-arrestin has been shown to mediate stretch-induced cardiac hypertrophy. See, e.g., Scimia, MC et al., Nature 2012, 488, 394-398. In certain embodiments, the chemical entities described herein modulate (e.g., reduce, such as attenuate, destroy, inhibit) beta-arrestin signaling. In certain embodiments, the chemical entities described herein modulate (e.g., reduce, such as attenuate, destroy, inhibit) the recruitment of beta-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 beta-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 β-arrestin and G protein signaling pathways.

[0019] Typically, receptors exist in active (Ra) and inactive (Ri) conformations. Certain compounds that affect receptors can change the ratio of Ra to Ri (Ra / Ri). For example, a full agonist increases the ratio of Ra / Ri and can cause a "maximal" saturation effect. When bound to a receptor, a partial agonist produces a response that is lower than the response caused by a full agonist (e.g., an endogenous agonist). Therefore, the Ra / Ri of a partial agonist is less than the Ra / Ri of a full agonist. However, the potency of a partial agonist may be greater 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] Where R 1 , R 2 , A 1 , X 1 , X 2 , X 3 , and X 4 May be as defined anywhere herein.

[0023] In one aspect, the invention provides pharmaceutical compositions comprising a chemical entity described herein (eg, a compound 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 characterized, comprising contacting the APJ receptor with a chemical entity as described herein (e.g., a compound generally or specifically described herein, or a pharmaceutically acceptable salt thereof, or a composition comprising the compound). The method includes in vitro methods, for example, contacting a sample comprising one or more cells, each cell independently comprising one or more APJ receptors, with a chemical entity. The method may also include in vivo methods. These methods may include, for example, administering a chemical entity to a subject (e.g., a human) having a disease, disorder, or condition, wherein decreased APJ receptor activity (e.g., blocked or impaired APJ receptor signaling; e.g., blocked or impaired apelin-APJ receptor signaling) or downregulation of endogenous apelin contributes to the pathology and / or symptoms and / or progression of the disease, disorder, or condition (e.g., PAH; heart failure; type II diabetes; sepsis; renal failure; and systemic hypertension). In vivo methods include, but are not limited to, modulating (eg, reducing) right ventricular afterload; modulating (eg, reducing) mean pulmonary artery pressure; modulating (eg, increasing) insulin levels; and modulating (eg, reducing) glucose levels in a subject (eg, a human).

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

[0026] In another aspect, the disclosure features methods of treating a subject having a disease, disorder, or condition in which decreased APJ receptor activity (e.g., blocked or impaired APJ receptor signaling; e.g., blocked or impaired apelin-APJ receptor signaling) or downregulation of endogenous apelin contributes to the pathology and / or symptoms and / or progression of the disease, disorder, or condition. The method comprises administering a chemical entity described herein (e.g., a compound generally or specifically described 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, a method of treatment is characterized, comprising administering a chemical entity as described herein (e.g., a compound generally or specifically described herein, a pharmaceutically acceptable salt thereof, or a composition comprising the same). The method comprises administering the chemical entity in an amount effective to treat a disease, disorder, or condition, wherein decreased APJ receptor activity (e.g., blocked or impaired APJ receptor signaling; e.g., blocked or impaired apelin-APJ receptor signaling) or downregulation of endogenous apelin contributes to the pathology and / or symptoms and / or progression of the disease, disorder, or condition, thereby treating the disease, disorder, or condition.

[0028] A non-limiting example of such diseases, disorders and conditions is PAH. In some embodiments, PAH is idiopathic. In other embodiments, 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, Sjögren's syndrome, and antiphospholipid antibody syndrome), portal hypertension, BMPR2 mutations, schistosomiasis, and HIV infection.

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

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

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

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

[0033] On the one hand, the present disclosure features methods for identifying and / or selecting objects (e.g., humans) that may benefit from the methods described herein, and methods for determining whether an object (e.g., a human) responds to the methods. In certain embodiments, a biological sample is obtained from an object, which may be, for example, but not limited to, a breath, sputum, tissue, plasma or serum sample, urine, and the level of a specific parameter in the sample is determined and compared with a control value. In some cases, a control value can be determined from one or more normal individuals who do not suffer from the disease, disorder, or condition being treated. In other cases, a control value can also be determined from a sample previously obtained from an object. Typically, a higher (or elevated) level of a measured parameter relative to a control value determined by a normal, non-ill individual or population indicates that the object will benefit from the methods described herein. Lower levels typically indicate that the patient responds to treatment, or that, for an object that has not received the treatment, the treatment method may not be beneficial to the object.

[0034] In certain of the foregoing embodiments, the subject suffers from or is at risk for PAH.Non-limiting exemplary parameters associated with PAH are described below.

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

[0036] In certain embodiments, the parameter is pulmonary vascular resistance (PVR). A baseline or reference PVR level may be 200 dynsec / cm 5 or higher, 240dynsec / cm 5 or higher, 300dynsec / cm 5 or higher, 400dynsec / cm 5 or higher, 500dynsec / cm 5 or higher, 600dynsec / cm 5 or higher, 700dynsec / cm 5 or higher, or 800dynsec / cm 5 In certain embodiments, if the subject's endpoint PVR level decreases by 70 dynsec / cm from the baseline or reference PVR level after initiation of treatment, 5 or more, 100dynsec / cm 5 or more, 130dynsec / cm 5 or more, or 160dynsec / cm 5 or more, then the treatment provided 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, the treatment provided is effective if the endpoint PAP level of the subject decreases by 0.5 mmHg or more, 1 mmHg or more, 1.5 mmHg or more, 5 mmHg or more, 10 mmHg or more, 20 mmHg or more, 30 mmHg or more, 40 mmHg or more, or 50 mmHg from the baseline or reference PAP level after the start of treatment. 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 may be 5 L / min / m 2 or lower, 2.5L / min / m 2 or lower, 2L / min / m 2 or lower, 1.5L / min / m 2 or lower, or 1L / min / m 2 In certain embodiments, if the endpoint CI level increases by 0.1 or more, 0.2 or more, 0.3 or more, 0.4 or more, 0.5 or more, 1 or more, or 2 or more compared to the baseline or reference CI level after the start of treatment, 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 less, 24 mmHg or less, 18 mmHg or less, 10 mmHg, or 5 mmHg or less. In certain embodiments, the treatment provided is effective if the endpoint PCWP level increases by 0.2 mmHg or more, 0.3 mmHg or more, 0.4 mmHg or more, 0.5 mmHg or more, 0.6 mmHg or more, 1 mmHg or more, or 5 mmHg or more from the baseline or reference PCWP level after the start of treatment.

[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, the treatment provided is effective if the subject's endpoint RAP level decreases by 5 mmHg or more, 2.5 mmHg or more, 1 mmHg or more, 0.5 mmHg or more, or 0.2 mmHg or more from the baseline or reference RAP level after the start of treatment.

[0041] In certain embodiments, the parameter is six-minute walk distance (6MWD). Baseline or reference 6MWD can be 50m or less, 100m or less, 200m or less, 300m or less, 400m or less, or 500m or less. In certain embodiments, if the endpoint 6MWD of the object increases by 10m or more, 15m or more, 20m or more, 25m or more, 30m or more, or 50m 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 object 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 some embodiments, the parameter is brain natriuretic peptide (BNP) level. Baseline or reference BNP level can be 60pg / mL or higher, 80pg / mL or higher, 100pg / mL or higher, 120pg / mL or higher, 140pg / mL or higher, 200pg / mL or higher, 500pg / mL or higher, or 1000pg / mL or higher. In some embodiments, if the endpoint BNP level of object after treatment starts is reduced from baseline or reference BNP level, the treatment provided is effective. For example, the endpoint BNP level of object can reduce 1pg / mL or more, 2pg / mL or more, 5pg / mL or more, 10pg / mL or more, 20pg / mL or more, 100pg / mL or more, 500pg / mL or more or 1000pg / mL or more.

[0043] In some embodiments, parameter is atrial natriuretic peptide (ANP) level.Baseline or with reference to ANP level can be 60pg / mL or higher, 80pg / mL or higher, 100pg / mL or higher, 120pg / mL or higher, 140pg / mL or higher, 200pg / mL or higher, 500pg / mL or higher or 1000pg / mL or higher.In some embodiments, if the terminal ANP level of object after treatment starts reduces from baseline or with reference to ANP level, then provided treatment is effective.For example, the terminal ANP level of object can reduce 1pg / mL or more, 2pg / mL or more, 5pg / mL or more, 10pg / mL or more, 20pg / mL or more, 100pg / mL or more, 500pg / mL or more or 1000pg / mL or more.

[0044] In certain embodiments, the parameter is lung diffusion capacity (DLCO) or CO diffusion capacity, 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 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 may further comprise treating one or more conditions related to, associated with, or sequelae of any one or more of the conditions described herein.

[0047] For example, the method may further include treating one or more conditions associated with, associated with, or sequelae of 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 myocardial remodeling after infarction or after cardiac surgery, and valvular heart disease.

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

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

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

[0051] Apelin peptides are unstable; therefore, only acute pharmacodynamic effects of apelin are observed. In some embodiments, the compounds described herein exhibit relatively high metabolic stability to allow for 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 through the APJ receptor, thereby reducing the tachyphylaxis typically associated with administration of potent agonists. Thus, in certain embodiments, the compounds described herein can reduce cardiac hypertrophy associated with arrestin.

[0054] In some embodiments, the compounds described herein may exhibit pleiotropic properties (eg, dilator activity, cardio-renal protection, and control of fluid homeostasis).

[0055] Other implementations include what is described in the detailed description and / or claims.

[0056] Additional Definitions

[0057] In order to promote the understanding of the disclosure set forth herein, a plurality of 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 used in the art. Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by those of ordinary skill in the art to which this paper belongs. Each patent, application, disclosed application and other publications mentioned in the entire specification and the appendix attached are incorporated herein by reference in their entirety.

[0058] As used herein, the term "APJ receptor" is intended to include, but is not limited to, nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide chains, complementary sequences, peptides, polypeptides, proteins, homologous and / or orthologous APJ or APJ receptor molecules, isoforms, precursors, mutants, variants, derivatives, splice variants, alleles, different species and active fragments thereof.

[0059] As used herein, the term "acceptable" with respect to a formulation, composition or ingredient means having no persistent detrimental effect on the general health of the subject being treated.

[0060] “API” means active pharmaceutical ingredient.

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

[0062] As used herein, the term "effective amount" or "therapeutically effective amount" refers to a sufficient 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) to alleviate to some extent one or more symptoms of the disease or condition being treated. Results include reduction and / or alleviation of signs, symptoms, or causes of disease, or any other desired changes in a biological system. For example, an "effective amount" for therapeutic use is an amount comprising a compound disclosed herein to provide a clinically significant alleviation of disease symptoms. In any case, any appropriate technique (e.g., a dose escalation study) may be used to determine an appropriate "effective" amount.

[0063] The term "excipient" or "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, carrier, solvent or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical formulation and suitable for contact with the tissues or organs of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity or other problems or complications, commensurate with a reasonable benefit / risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe 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 an organism to which it is administered and does not eliminate the biological activity and properties of the compound. In some 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, and the like. In some 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 salt or a magnesium salt, a salt of an organic base, such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and a salt formed with an amino acid, such as arginine, lysine, and the like, or by other methods previously determined. There is no particular limitation on the pharmaceutically acceptable salt, as long as it can be used in medicine. Examples of salts formed with bases of the compounds described herein 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, specifically exemplified by 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 as carriers, stabilizers, diluents, dispersants, suspending agents and / or thickening agents. Pharmaceutical compositions facilitate administration of compounds to an organism. 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" may refer to an animal, including but not limited to a primate (e.g., human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein, e.g., to refer to a mammalian subject, e.g., a human subject.

[0067] In the context of treating a disease, disorder or condition, the term "treat," ...

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

[0069] The term "alkyl" refers to a hydrocarbon chain which may be straight or branched and contains the indicated number of carbon atoms. 1-10 Indicates that the group may have 1 to 10 (inclusive) carbon atoms. Non-limiting examples include methyl, ethyl, iso-propyl, tert-butyl, n-hexyl.

[0070] The term "haloalkyl" refers to an alkyl group wherein one or more hydrogen atoms are replaced by independently selected halogens.

[0071] The term "alkoxy" refers to an -O-alkyl group (e.g., -OCH 3 ).

[0072] The term "haloalkoxy" refers to an -O-haloalkyl group (e.g., -OCH 3 ).

[0073] The term "alkylene" refers to a branched or unbranched divalent alkyl group (e.g., CH 2 -).

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

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

[0076] The term "alkynyl" refers to a hydrocarbon chain that may be straight or branched and has one or more carbon-carbon triple bonds. The alkynyl moiety contains the specified number of carbon atoms. For example, C 2-6 It means that the group may have 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, wherein 0, 1, 2, 3 or 4 atoms of each ring may be substituted with a substituent, and the ring containing the monocyclic group is aromatic, and 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] The term "cycloalkyl" as used herein includes saturated cyclic hydrocarbon groups having 3 to 10 carbons, preferably 3 to 8 carbons, more preferably 3 to 6 carbons, wherein the cycloalkyl group may be optionally substituted. Preferred cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

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

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

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

[0082] In addition, the atoms constituting the compounds of the present embodiments are intended to include all isotopic forms of such atoms. As used herein, isotopes include those atoms having the same atomic number but different mass numbers. As a 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 may include various stereochemical forms. The compounds also include diastereomers and optical isomers, such as mixtures (including racemic mixtures) of enantiomers (including atropisomers), as well as independent enantiomers and diastereomers, which are produced due to structural asymmetry in a particular compound. Various methods well known to those skilled in the art can be used to separate each isomer or selectively synthesize each isomer. Unless otherwise stated, when a disclosed compound is named or described with a structure having one or more chiral centers but without specifying stereochemistry, it should be understood to represent all possible stereoisomers of the compound. For example, -S(O)(=NH)-R 4 Intended to include enantiomers: And the enantiomers: and mixtures thereof (eg racemic mixtures).

[0084] The details of one or more embodiments of the invention are set forth in the following description and in the appended appendix, which is expressly considered a part of this disclosure. Other features and advantages will also be apparent from the claims. DETAILED DESCRIPTION

[0085] The present disclosure features chemical entities (e.g., compounds or pharmaceutically acceptable salts and / or hydrates of compounds and / or prodrugs of compounds) that modulate (e.g., agonize) apelin receptors (also referred to herein as APJ receptors; gene symbol APLNR). The present disclosure also features compositions comprising the chemical entities and other methods of use and preparation. The chemical entities can be used, for example, to treat subjects (e.g., humans) suffering from a disease, disorder, or condition in which reduced APJ receptor activity (e.g., blocked or impaired APJ receptor signaling; e.g., blocked or impaired apelin-APJ receptor signaling) or downregulation of endogenous apelin contributes to the pathology and / or symptoms and / or progression of the disease, disorder, or condition. Non-limiting examples of these diseases, disorders or conditions include: (i) cardiovascular disease; (ii) metabolic disorders; (iii) diseases, disorders and conditions related to vascular pathology; (iv) organ failure; (v) diseases, disorders and conditions associated with infection (e.g., microbial infection); (vi) diseases, disorders or conditions that are sequelae or complications of any of the foregoing or disclosed herein. More specific non-limiting examples of these diseases, disorders or conditions include pulmonary 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 discloses a compound characterized by formula (I) or a pharmaceutically acceptable salt thereof:

[0088]

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

[0090] in:

[0091] A 1 is CH or N;

[0092] X 1 , X 2 , X 3 , and X 4 Each of which is independently selected from N and CR 3 ;

[0093] R 1 yes:

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

[0095] n is 0 or 1;

[0096] ·Y 1 It is C 1-6 Alkylene, which is optionally substituted by 1 to 6 R a Replacement; and

[0097] ·Y 2 yes:

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

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

[0100] (c) a heteroaryl group containing 5 to 10 ring atoms, wherein 1 to 4 of the 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 replaced by 1-4 independently selected R c Replace, or

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

[0102] or

[0103] (ii) -Z 1 -Z 2 -Z 3 ,in:

[0104] ·Z 1 It is C 1-3 Alkylene, which is optionally substituted by 1 to 4 R a replace;

[0105] ·Z 2 It is -N(H)-, -N(R d )-, -O- or -S-; and

[0106] ·Z 3 It is C 2-7 Alkyl, which is optionally substituted by 1-4 R a replace;

[0107] or

[0108] (iii)C 3-10 Alkyl, optionally with 1-6 independently selected R a replace;

[0109] or

[0110] (iv) -Z 4 -Z 5 -Z 6 -Y 2 in:

[0111] ·Z 4 It is C 1-3 Alkylene, which is optionally substituted by 1 to 4 R a replace;

[0112] ·Z 5 It is -N(H)-, -N(R d )-, -O-, or -S-;

[0113] ·Z 6 It is C 1-4 Alkylene, which is optionally substituted by 1 to 4 R a Replacement; and

[0114] ·Y 2 As defined above;

[0115] R 2 yes:

[0116] (i)C 6-10 Aryl, which is optionally further substituted by 1 to 4 R c replace;

[0117] (ii) a heteroaryl group containing 5 to 10 ring atoms, wherein 1 to 4 of the 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 replaced by 1-4 independently selected R c replace;

[0118] (iii)C 3-10 Cycloalkyl, which is optionally substituted by 1 to 4 R b replace;

[0119] (iv) a heterocyclic group containing 3 to 10 ring atoms, wherein 1 to 3 of the ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ) and O, and wherein one or more heterocyclyl ring carbon atoms are optionally replaced by 1-4 independently selected R b replace; or

[0120] (v)C 1-10 Alkyl, which is optionally substituted by 1-6 independently selected R a replace;

[0121] Each occurrence of R 3 Independently selected from -L 4 -R 4 ,H and ,R c ';

[0122] Each time L appears 4 Independently selected from:

[0123] (i) Single bond;

[0124] (ii) N(H), N(R d ), or N(R 4 );

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

[0126] (iv)-S(O) 1-2 N(H)- or -S(O) 1-2 N(R d )-;

[0127] (v) -O-;

[0128] (vi)-S(O) 0-2 -;

[0129] (vii) -C(O)NH- or -C(O)N(R d );

[0130] (viii) -N(H)C(O)- or -N(R d )C(O)-;

[0131] (ix) -C≡C;

[0132] (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 )-

[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 4 yes:

[0142] (a)C 3-6 Cycloalkyl, which is optionally substituted by 1 to 4 R b replace,

[0143] (b)C 6-10 Aryl, which is optionally substituted by 1 to 4 R c replace;

[0144] (c) a heteroaryl group containing 5 to 10 ring atoms, wherein 1 to 4 of the 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 replaced by 1-4 independently selected R c Replace, or

[0145] (d) a heterocyclic group containing 3 to 10 ring atoms, wherein 1 to 3 of the ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ) and O, and wherein one or more heterocyclyl ring carbon atoms are optionally replaced by 1-4 independently selected R b replace,

[0146] or

[0147] (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 replace;

[0148] Each occurrence of R a 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 1-4 independently selected C 1-4 Alkyl substituted C 3-6 Cycloalkyl;

[0149] Each occurrence of R b 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 substitution;

[0150] Each occurrence of R c Independently selected from:

[0151] (i) halogen;

[0152] (ii) cyano;

[0153] (iii)C 1-6 alkyl;

[0154] (iv)C 2-6 alkenyl;

[0155] (v)C 2-6 Alkynyl;

[0156] (vi)C 1-4 Haloalkyl;

[0157] (vii)C 1-4 Alkoxy;

[0158] (viii)C 1-4 Haloalkoxy;

[0159] (ix) optionally 1 to 4 independently selected C 1-4 Alkyl-substituted-(C 0-3 Alkylene)-C 3-6 Cycloalkyl;

[0160] (x)-S(O) 1-2 (C 1-4 alkyl);

[0161] (xi)-NR e R f ;

[0162] (xii) -OH;

[0163] (xiii)-S(O) 1-2 (NR'R");

[0164] (xiv)-C1-4 Thioalkoxy;

[0165] (xv)-NO 2 ;

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

[0167] (xvii) -C(=O)O(C 1-4 alkyl);

[0168] (xviii) -C(=O)OH,

[0169] (xix)-C(=O)N(R')(R"), and

[0170] (xx)C 3-6 Cycloalkoxy;

[0171] Each occurrence of R c 'Independently selected from:

[0172] (i) halogen;

[0173] (ii) cyano;

[0174] (iii) -OH;

[0175] (iv)-NO 2 ;

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

[0177] (vi) -C(=O)O(C 1-4 alkyl);

[0178] (vii) -C(=O)OH; and

[0179] (viii)-NH 2 ;

[0180] R d 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;

[0181] Each occurrence of R e and R fIndependently 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 attached, they form a ring containing 3-8 ring atoms, wherein the ring contains: (a) 1-7 ring carbon atoms, each carbon atom being replaced by 1-2 independently selected from H and C 1-3 (b) 0-3 ring heteroatoms (except the nitrogen atom connected to R' and R "), each of which is independently selected from N (R d ), O and S; and

[0182] Each occurrence of R' and R" is independently selected from: H and C 1-4 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 replaced by 1-2 independently selected from H and C 1-3 (b) 0-3 ring heteroatoms (except the nitrogen atom connected to R' and R "), each of which is independently selected from N (R d ), O and S.

[0183] In some embodiments, the present invention discloses a compound characterized by formula (I) or a pharmaceutically acceptable salt thereof:

[0184]

[0185] in:

[0186] A 1 is CH or N;

[0187] X 1 , X 2 , X 3 , and X 4 Each of which is independently selected from N and CR 3 (For example, X 1 and X 4 Each of X is independently CH or N; and X 2 and X 3 Each of the CR 3 or N), provided that X 1 , X2 , X 3 , and X 4 1-3 of them are N;

[0188] R1 is:

[0189] (i)-(Y 1 ) n -Y 2 ,in:

[0190] n is 0 or 1;

[0191] ·Y 1 It is C 1-6 Alkylene, which is optionally substituted by 1 to 6 R a Replacement; and

[0192] ·Y 2 yes:

[0193] (a)C 3-10 Cycloalkyl, which is optionally substituted by 1 to 4 R b replace,

[0194] (b)C 6-10 Aryl, which is optionally substituted by 1 to 4 R c replace;

[0195] (c) a heteroaryl group containing 5 to 10 ring atoms, wherein 1 to 4 of the 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 replaced by 1-4 independently selected R c Replace, or

[0196] (d) a heterocyclic group containing 3 to 10 ring atoms, wherein 1 to 3 of the ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ) and O, and wherein one or more heterocyclyl ring carbon atoms are optionally replaced by 1-4 independently selected R b replace,

[0197] or

[0198] (ii) -Z 1 -Z 2 -Z 3 ,in:

[0199] ·Z 1 It is C 1-3 Alkylene, which is optionally substituted by 1 to 4 R a replace;

[0200] ·Z 2 It is -N(H)-, -N(Rd )-, -O- or -S-; and

[0201] ·Z 3 It is C 2-7 Alkyl, which is optionally substituted by 1-4 R a replace;

[0202] or

[0203] (iii)C 3-10 Alkyl, optionally with 1-6 independently selected R a replace;

[0204] or

[0205] (iv) -Z 4 -Z 5 -Z 6 -Y 2 in:

[0206] ·Z 4 It is C 1-3 Alkylene, which is optionally substituted by 1 to 4 R a replace;

[0207] ·Z 5 It is -N(H)-, -N(R d )-, -O-, or -S-;

[0208] ·Z 6 It is C 1-4 Alkylene, which is optionally substituted by 1 to 4 R a Replacement; and

[0209] ·Y 2 As defined above;

[0210] R 2 yes:

[0211] (i)C 6-10 Aryl, which is optionally further substituted by 1 to 4 R c replace;

[0212] (ii) a heteroaryl group containing 5 to 10 ring atoms, wherein 1 to 4 of the 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 replaced by 1-4 independently selected R c replace;

[0213] (iii)C 3-10 Cycloalkyl, which is optionally substituted by 1 to 4 R b replace;

[0214] (iv) a heterocyclic group containing 3 to 10 ring atoms, wherein 1 to 3 of the ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ) and O, and wherein one or more heterocyclyl ring carbon atoms are optionally replaced by 1-4 independently selected R b replace; or

[0215] (v)C 1-10 Alkyl, which is optionally substituted by 1-6 independently selected R a replace

[0216] Each occurrence of R 3 Independently selected from -L 4 -R 4 ,H and ,R c ';

[0217] Each time L appears 4 Independently selected from:

[0218] (i) Single bond;

[0219] (ii) N(H), N(R d ), or N(R 4 );

[0220] (iii)-N(H)S(O) 1-2 -or-N(R d )S(O) 1-2 -;

[0221] (iv)-S(O) 1-2 N(H)- or -S(O) 1-2 N(R d )-;

[0222] (v) -O-;

[0223] (vi)-S(O) 0-2 -;

[0224] (vii) -C(O)NH- or -C(O)N(R d );

[0225] (viii) -N(H)C(O)- or -N(R d )C(O)-;

[0226] (ix) -C≡C;

[0227] (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 )-

[0228] (xi)-S(O)(=NH)NH-, -S(O)(=NR d )NH-, -S(O)(=NH)NR d -, or -S(O)(=NR d )NR d -;as well as

[0229] (xii) -S(O)(=NH)- or -S(O)(=NR d );

[0230] Each occurrence of R 4 Independently are:

[0231] (i)-(Y 3 ) p -Y 4 ,in:

[0232] p is 0 or 1;

[0233] ·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;

[0234] as well as

[0235] ·Y 4 yes:

[0236] (a)C 3-6 Cycloalkyl, which is optionally substituted by 1 to 4 R b replace,

[0237] (b)C 6-10 Aryl, which is optionally further substituted by 1 to 4 R c replace;

[0238] (c) a heteroaryl group containing 5 to 10 ring atoms, wherein 1 to 4 of the 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 replaced by 1-4 independently selected R c Replace, or

[0239] (d) a heterocyclic group containing 3 to 10 ring atoms, wherein 1 to 3 of the ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ) and O, and wherein one or more heterocyclyl ring carbon atoms are optionally replaced by 1-4 independently selected R b replace,

[0240] or

[0241] (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 replace;

[0242] Each occurrence of R a 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 1-4 independently selected C 1-4 Alkyl substituted C 3-6 Cycloalkyl;

[0243] Each occurrence of R b 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 substitution;

[0244] Each occurrence of R c Independently selected from:

[0245] (i) halogen;

[0246] (ii) cyano;

[0247] (iii)C 1-6 alkyl;

[0248] (iv)C 2-6 alkenyl;

[0249] (v)C 2-6 Alkynyl;

[0250] (vi)C 1-4 Haloalkyl;

[0251] (vii)C 1-4 Alkoxy;

[0252] (viii)C 1-4 Haloalkoxy;

[0253] (ix) optionally 1 to 4 independently selected C 1-4 Alkyl-substituted-(C 0-3 Alkylene)-C 3-6 Cycloalkyl;

[0254] (x)-S(O) 1-2 (C 1-4 alkyl);

[0255] (xi)-NR e R f ;

[0256] (xii) -OH;

[0257] (xiii)-S(O) 1-2 (NR'R");

[0258] (xiv)-C 1-4 Thioalkoxy;

[0259] (xv)-NO 2 ;

[0260] (xvi)-C(=O)(C 1-4 alkyl);

[0261] (xvii) -C(=O)O(C 1-4 alkyl);

[0262] (xviii) -C(=O)OH;

[0263] (xix) -C(=O)N(R')(R"); and

[0264] (xx)C 3-6 Cycloalkoxy;

[0265] Each occurrence of R c 'Independently selected from:

[0266] (i) halogen;

[0267] (ii) cyano;

[0268] (iii) -OH;

[0269] (iv)-NO 2 ;

[0270] (v) -C(=O)(C 1-4 alkyl);

[0271] (vi) -C(=O)O(C 1-4 alkyl);

[0272] (vii) -C(=O)OH; and

[0273] (viii)-NH 2 ;

[0274] R d Select from the following group: 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;

[0275] Each occurrence of R e and R f 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 attached, they form a ring containing 3-8 ring atoms, wherein the ring contains: (a) 1-7 ring carbon atoms, each carbon atom being replaced by 1-2 independently selected from H and C 1-3 (b) 0-3 ring heteroatoms (except the nitrogen atom connected to R' and R "), each of which is independently selected from N (R d ), O and S; and

[0276] Each occurrence of R' and R" is independently selected from: H and C 1-4 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 replaced by 1-2 independently selected from H and C 1-3 (b) 0-3 ring heteroatoms (except the nitrogen atom connected to R' and R "), each of which is independently selected from N (R d ), O and S.

[0277] In some embodiments, when the compound is of formula (I-1):

[0278]

[0279] R 1 It is not unsubstituted phenyl, p-dimethylaminophenyl, p-aminosulfonylphenyl, and unsubstituted 4-pyridyl.

[0280] In some embodiments, when the compound is of formula (I-1):

[0281]

[0282] R 1 Except unsubstituted phenyl, p-monosubstituted phenyl, and unsubstituted pyridyl.

[0283] In some embodiments, when the compound is of formula (I-2):

[0284]

[0285] R 1 Not unsubstituted phenyl.

[0286] In some embodiments, the compound is not a compound of formula (I-1) or formula (I-2):

[0287]

[0288] In some embodiments, the compound is not of formula (I-3):

[0289]

[0290] In some embodiments, when the compound is of formula (I-4):

[0291]

[0292] R 1 It is not a p-monosubstituted phenyl group (eg, p-fluorophenyl).

[0293] In some embodiments, when the compound is of formula (I-5):

[0294]

[0295] R 3 Not trifluoromethyl.

[0296] In some embodiments, when the compound is of formula (I-6):

[0297]

[0298] R 2 no:

[0299] (i) unsubstituted phenyl;

[0300] (ii)

[0301] (iii)

[0302] (iv) unsubstituted pyridyl;

[0303] (v) Where Q 1 , Q 2 , Q 3 , and Q 4 Each of is independently selected from N and CH;

[0304] or

[0305] (vi) a heteroaryl group containing 9-10 ring atoms, wherein 1-2 of the 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 replaced by 1-2 independently selected R c replace.

[0306] In some embodiments, the compound is not one or more of the following:

[0307]

[0308] In some embodiments, the compound is not one or more of the following:

[0309]

[0310] In certain embodiments, the compound is not disclosed in European Journal of Medicinal Chemistry (2014), 86, 270-278. In certain embodiments, the compound is not disclosed in Tetrahedron Letters (2012), 53 (25), 3126-3130. In certain embodiments, the compound is not disclosed in Organic Letters (2011), 13 (24), 6516-6519. In certain embodiments, the compound is not disclosed in U.S. Patent Application Publication No. 2012 / 0095037 and / or U.S. Patent No. 8,362,019.

[0311] In certain embodiments, the compound is not those disclosed in Angewandte Chemie, International Edition (2018), 57 (5), 1399-1403. In certain embodiments, the compound is not those disclosed in Organic Letters (2017), 19 (19), 5118-5121. In certain embodiments, the compound is not those disclosed in Tetrahedron (2009), 65 (44), 8930-8939. In certain embodiments, the compound is not those disclosed in Organic Letters (2016), 18 (13), 3250-3253. In certain embodiments, the compound is not those disclosed in Organic & Biomolecular Chemistry (2015), 13 (21), 6047-6058. In certain embodiments, the compound is not those disclosed in Chemistry-A European Journal (2013), 19 (49), 16760-16771. In certain embodiments, the compound is not those disclosed in Organic & Biomolecular Chemistry (2013), 11 (18), 3064-3072. In certain embodiments, the compound is not those disclosed in Organic Letters (2011), 13 (24), 6516-6519. In certain embodiments, the compound is not those disclosed in Bioorganic & Medicinal Chemistry Letters (2004), 14 (13), 3595-3599. In certain embodiments, the compound is not those disclosed in International Patent Application Publication No. 2015 / 073528. In certain embodiments, the compound is not those disclosed in International Patent Application Publication No. 2012 / 146667. In certain embodiments, the compound is not those disclosed in International Patent Application Publication No. 2001 / 030778. In certain embodiments, the compound is not those disclosed in U.S. Patent Application Publication No. 2012 / 0095037.

[0312] In certain embodiments, the compound is not those disclosed in Journal of Medicinal Chemistry (2012), 55 (11), 5291-5310. In certain embodiments, the compound is not those disclosed in Tetrahedron Letters (2000), 41 (28), 5383-5386. In certain embodiments, the compound is not those disclosed in International Patent Application Publication WO 2017 / 171234. In certain embodiments, the compound is not those disclosed in International Patent Application Publication WO 2016 / 176460. In certain embodiments, the compound is not those disclosed in Japanese Patent Application Publication JP 2013 / 018771 and / or JP 5,959,330. In certain embodiments, the compound is not those disclosed in International Patent Application Publication WO 2011 / 153310. In certain embodiments, the compound is not those disclosed in International Patent Application Publication WO 2011 / 082270. In certain embodiments, the compound is not disclosed in Australian Patent Application Publication AU 2010 / 331175 and / or U.S. Patent Application Publication .US 2012 / 0258951 and / or US2014 / 0194407. In certain embodiments, the compound is not disclosed in International Patent Application Publication WO 2010 / 051245 and / or U.S. Patent Application Publication No. US2011 / 0207750. In certain embodiments, the compound is not disclosed in WO 2010 / 030360. In certain embodiments, the compound is not disclosed in European Patent Application Publication EP 1878724 and / or U.S. Patent No. 8,188,282. In certain embodiments, the compound is not disclosed in International Patent Application Publication WO 2007 / 075629. In certain embodiments, the compound is not those disclosed in Japanese Patent Application Publication No. JP2000 / 302754 and / or US Pat. No. 6,358,634.

[0313] VariableA 1 and X 1 -X 4

[0314] In some embodiments, A 1 It is N.

[0315] In other embodiments, A 1 It is CH.

[0316] In some embodiments, X 1 and X 4 Each of R is independently selected from CH and N.

[0317] In some embodiments, X 1 , X 2 , X 3 , and X 4 1-2 of which are independently N.

[0318] In certain embodiments, 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 the 2-3 is an independently selected CR 3 .

[0319] In certain embodiments, X 1 , X 2 , X 3 , and X 4 1-2 of are independently N; and X 1 and X 4 Each of is independently N or CH.

[0320] In some embodiments, X 1 , X 2 , X 3 , and X 4 two of which are independently N; and X 1 , X 2 , X 3 , and X 4 The other two are independently selected from N and CR 3 .

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

[0322]

[0323] or a pharmaceutically acceptable salt thereof.

[0324] In certain embodiments, the compound of formula (I) is of formula (Ib):

[0325]

[0326] or a pharmaceutically acceptable salt thereof.

[0327] In some of the foregoing embodiments, when X 1 , X 2 , X 3 , and X 4 The two independent ones are N, X1 , X 2 , X 3 , and X 4 The other two are independently selected CR 3 .

[0328] In certain embodiments, the compound of formula (I) is of formula (I-a1):

[0329]

[0330] or a pharmaceutically acceptable salt thereof.

[0331] In certain embodiments, the compound of formula (I) is of formula (I-a2):

[0332]

[0333] or a pharmaceutically acceptable salt thereof.

[0334] In certain embodiments, the compound of formula (I) is of formula (I-b1):

[0335] (For example, ):

[0336] or a pharmaceutically acceptable salt thereof.

[0337] In some embodiments, X 1 , X 2 , X 3 , and X 4 one of which is independently N; and X 1 , X 2 , X 3 , and X 4 The other three are independently selected from N and CR 3 .

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

[0339]

[0340] or a pharmaceutically acceptable salt thereof.

[0341] In certain embodiments, the compound of formula (I) is of formula (Id):

[0342]

[0343] or a pharmaceutically acceptable salt thereof.

[0344] In some of the foregoing embodiments, when X 1 , X 2 , X3 , and X 4 An independent one is N, X 1 , X 2 , X 3 , and X 4 The other three are independently selected CR 3 .

[0345] In certain embodiments, the compound of formula (I) is of formula (I-c1):

[0346] (For example, );

[0347] or a pharmaceutically acceptable salt thereof.

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

[0349] (For example, );

[0350] or a pharmaceutically acceptable salt thereof.

[0351] In certain embodiments, the compound of formula (I-d1) has the following formula:

[0352]

[0353] Among them: one R 3 Independently selected from -L 4 -R 4 and R c ';

[0354] Other R 3 Independently selected from H, -L 4 -R 4 , and R c ';

[0355] R 1 is (i)-(Y 1 ) n -Y 2 ,in:

[0356] n is 0;

[0357] ·Y 2 yes:

[0358] (a) Partially unsaturated C 3-10 Cycloalkyl, which is optionally substituted by 1 to 4 R b replace,

[0359] (b)C 6-10Aryl, which is optionally substituted by 1 to 4 R c replace;

[0360] (c) a heteroaryl group containing 5 to 10 ring atoms, wherein 1 to 4 of the 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 replaced by 1-4 independently selected R c Replace, or

[0361] (d) a partially unsaturated heterocyclic group containing 3 to 10 ring atoms, wherein 1 to 3 of the ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ) and O, and wherein one or more heterocyclyl ring carbon atoms are optionally replaced by 1-4 independently selected R b Replacement; and

[0362] R 2 yes:

[0363] (i)C 6-10 Aryl, which is optionally further substituted by 1 to 4 R c replace;

[0364] (ii) a heteroaryl group containing 5 to 10 ring atoms, wherein 1 to 4 of the 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 replaced by 1-4 independently selected R c replace;

[0365] (iii) Partially unsaturated C 3-10 Cycloalkyl, which is optionally substituted by 1 to 4 R b replace; or

[0366] (iv) a partially unsaturated heterocyclic group containing 3 to 10 ring atoms, wherein 1 to 3 of the ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ) and O, and wherein one or more heterocyclyl ring carbon atoms are optionally replaced by 1-4 independently selected R b replace.

[0367] Variable R 1

[0368] In some embodiments, R 1 Yes-(Y 1 ) n -Y 2 .

[0369] In some embodiments, n is 0.

[0370] In other embodiments, n is 1. In certain of these embodiments, Y 1 It is C 1-3 Alkylene.

[0371] In some embodiments, Y 2 is a heteroaryl group containing 5 to 10 ring atoms, wherein 1 to 4 of the 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 replaced by 1-4 independently selected R c In certain of the foregoing embodiments, n is 0.

[0372] In some embodiments, Y 2 is a heteroaryl group containing 6 ring atoms, wherein 1 to 4 of the 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 replaced by 1-4 independently selected R c or a heteroaryl group 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 replaced by 1-4 independently selected R c Substitution; in certain of the foregoing embodiments, n is 0.

[0373] In certain embodiments, Y 2 is a heteroaryl group containing 5-6 ring atoms, wherein 1-4 of the 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 replaced by 1-4 independently selected R c In certain of these embodiments, n is 0.

[0374] In certain embodiments, Y 2 is a heteroaryl group containing 6 ring atoms, wherein 1-2 ring atoms are N, and wherein one or more heteroaryl ring carbon atoms are optionally replaced by 1-4 independently selected R c Replace. For example, Y 2 It can be pyridyl (e.g., 2-pyridyl or 6-pyridyl), wherein one or more ring carbon atoms are optionally replaced by 1-4 (e.g., 1, 2, 3, or 4) independently selected R c Replace (for example, Y 2 is pyridinyl (eg, 2-pyridinyl or 6-pyridinyl), wherein one or more ring carbon atoms are optionally replaced by an independently selected R cIn certain of these embodiments, n is 0.

[0375] In certain embodiments, Y 2 is a heteroaryl group containing 5 ring atoms, wherein 1 to 4 of the 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 replaced by 1-2 independently selected R c Replace. For example, Y 2 may be pyrazolyl, oxazolyl or thiazolyl, wherein any substitutable nitrogen atom is optionally replaced by R d substituted, and wherein one or more ring carbon atoms are optionally replaced by 1-2 independently selected R c In certain of these embodiments, n is 0.

[0376] In certain embodiments, Y 2 is a heteroaryl group containing 5 ring atoms, wherein 1 to 3 of the 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 replaced by 1-3 independently selected R c In certain of these embodiments, n is 0.

[0377] In certain of these embodiments, Y 2 is furanyl, wherein one or more ring carbon atoms are optionally replaced by 1-2 (eg, 1) independently selected R c In certain of these embodiments, n is 0.

[0378] In certain of the foregoing embodiments, when Y 2 When it is a heteroaryl group, each occurrence of R c Independently selected from:

[0379] (iii)C 1-6 alkyl;

[0380] (iv)C 2-6 alkenyl;

[0381] (v)C 2-6 Alkynyl;

[0382] (vi)C 1-4 Haloalkyl;

[0383] (vii)C 1-4 Alkoxy;

[0384] (viii)C 1-4 Haloalkoxy;

[0385] (ix) optionally 1 to 4 independently selected C 1-4 Alkyl-substituted-(C 0-3 Alkylene)-C 3-6 Cycloalkyl;

[0386] (xiv)-C 1-4 Thioalkoxy;

[0387] as well as

[0388] (xx)C 3-6 Cycloalkoxy.

[0389] In certain of the foregoing embodiments, when Y 2 When it is a heteroaryl group, each occurrence of R c Independently selected from:

[0390] (vii)C 1-4 Alkoxy;

[0391] (viii)C 1-4 Haloalkoxy (e.g., OCH 2 CF 3 or OCF 3 );

[0392] (xiv)-C 1-4 Thioalkoxy; and

[0393] (xx)C 3-6 Cycloalkoxy (eg, cyclopropyloxy).

[0394] For example, each occurrence of R c C is an independent choice 1-4 Alkoxy (e.g., -OCH 3 、-OCH 2 CH 3 ).

[0395] As another example, each occurrence of R c C is an independent choice 1-6 Alkyl (eg, methyl).

[0396] In certain of the foregoing embodiments, when Y 2 When it is a heteroaryl group, each occurrence of R d C is an independent choice 1-6 alkyl.

[0397] In certain of the foregoing embodiments, when Y 2 When it is a heteroaryl group and n is 0, R 1 Can be selected from:

[0398]

[0399] In certain of the foregoing embodiments, when Y 2 When it is a heteroaryl group and n is 0, R 1 Can be selected from:

[0400]

[0401] As a non-limiting example of the foregoing embodiment, when Y 2 When it is a heteroaryl group and n is 0, R 1 It can be:

[0402]

[0403] In certain embodiments, when Y 2 When it is a heteroaryl group and n is 0, R 1 It can be:

[0404] In certain embodiments, when Y 2 When it is a heteroaryl group and n is 0, R 1 It can be:

[0405] In some embodiments, Y 2 It is C 3-10 Cycloalkyl, which is optionally substituted by 1 to 4 R b In certain of these embodiments, n is 0.

[0406] In some embodiments, Y 2 It is C 6-10 Aryl, which is optionally substituted by 1 to 4 R c replace.

[0407] In certain embodiments, Y 2 is a phenyl group, which is replaced by 1 to 4 R c In certain embodiments, when Y 2 is phenyl; and Y 1 The ring carbon atom opposite to the point of attachment is R c substituted, then one or more other ring carbon atoms are optionally replaced by 1-3 R c replace.

[0408] In some embodiments, R 1 Yes-Z 1 -Z 2 -Z 3 .

[0409] In some embodiments, Z 1 Yes CH 2 .

[0410] In some embodiments, Z2 It is -O-, or -S-. For example, Z 2 It can be -O-.

[0411] In some embodiments, Z 3 It is C 2-3 Alkylene.

[0412] In certain embodiments, Z 1 Yes CH 2 , and Z 2 is -O-, or -S- (eg, -O-).

[0413] In certain embodiments, Z 2 is -O-, or -S- (e.g., -O-), and Z 3 It is C 2-3 Alkylene.

[0414] In certain embodiments, Z 1 Yes CH 2 , and Z 2 is -O-, or -S- (e.g., -O-), and Z 3 It is C 2-3 Alkylene.

[0415] In certain of the foregoing embodiments, when R 1 Yes-Z 1 -Z 2 -Z 3 When R 1 yes

[0416] Variable R 2

[0417] In some embodiments, R 2 yes:

[0418] (i)C 6-10 Aryl, which is optionally further substituted by 1 to 4 R c replace;

[0419] (ii) a heteroaryl group containing 5 to 10 ring atoms, wherein 1 to 4 of the 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 replaced by 1-4 independently selected R c replace;

[0420] (iii) Partially unsaturated C 3-10 Cycloalkyl, which is optionally substituted by 1 to 4 R b replace; or

[0421] (iv) a partially unsaturated heterocyclic group containing 3 to 10 ring atoms, wherein 1 to 3 of the ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ) and O, and wherein one or more heterocyclyl ring carbon atoms are optionally replaced by 1-4 independently selected R b replace.

[0422] In some embodiments, R 2 It is C 6-10 Aryl, which is optionally substituted by 1 to 4 R c replace.

[0423] In certain embodiments, R 2 is phenyl, which is optionally replaced by 1 to 4 R c In some of the foregoing embodiments, R 2 It may be a phenyl group, which may be optionally substituted by 1-2 R c As a non-limiting example, R 2 It may be a phenyl group, which may be optionally substituted by 2 R c replace.

[0424] In certain of the foregoing embodiments, when R 2 When it is an aromatic group (such as a phenyl group), each occurrence of R c Independently selected from:

[0425] (i) halogen (e.g., F);

[0426] (vi)C 1-4 Haloalkyl (e.g., CF 3 );

[0427] (vii)C 1-4 Alkoxy;

[0428] (viii)C 1-4 haloalkoxy; and

[0429] (xiv)-C 1-4 Thioalkoxy.

[0430] 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 Independently -OCH 3 CF 3 , or F).

[0431] In certain of the foregoing embodiments, when R 2 When it is an aryl group (such as a phenyl group), R 2Has the following formula (A):

[0432]

[0433] Among them, R 2a , R 2b , R 2c , R 2d and R 2e Each independently selected from H and R c .

[0434] In certain embodiments, R 2a , R 2b , R 2c , R 2d and R 2e The four are independently selected R c , and the other is H.

[0435] In certain embodiments, R 2a , R 2b , R 2c , R 2d and R 2e The three are independently selected R c , and the other two are H.

[0436] In certain embodiments, R 2a , R 2b , R 2c , R 2d The two and R 2e R is independently selected c , and the other two are H. In certain of these embodiments, R 2a and R 2e R is independently selected c (For example, C 1-4 Alkoxy; C 1-4 Haloalkoxy; -C 1-4 Thioalkoxy; C 1-4 Haloalkyl and halogen, for example, each occurrence of R c C is an independent choice 1-4 Alkoxy (e.g., -OCH 3 ). For example, R 2a and R 2e Each is OCH 3 .

[0437] In certain embodiments, R 2 yes:

[0438] In certain of the foregoing embodiments, when R 2 When it is an aryl group (such as a phenyl group), R2 Has the following formula (B):

[0439]

[0440] In some embodiments, when R 2 is aryl (eg, phenyl); and R 2 Has the following formula (A):

[0441]

[0442] R 2a , R 2b , R 2d 1-4 and R 2e R is independently selected c .

[0443] In certain of the foregoing embodiments, R c Each of is independently selected from:

[0444] (i)-F;

[0445] (ii) cyano;

[0446] (iii)C 1-3 Alkyl, C 5-6 Alkyl, n-butyl, sec-butyl, isobutyl;

[0447] (iv)C 2-6 alkenyl;

[0448] (v)C 2-6 Alkynyl;

[0449] (vi)C 1-4 Haloalkyl;

[0450] (vii)C 1-4 Alkoxy;

[0451] (viii)C 1-4 Haloalkoxy;

[0452] (ix) optionally 1 to 4 independently selected C 1-4 Alkyl-substituted-(C 0-3 Alkylene)-C 3-6 Cycloalkyl;

[0453] (x)-S(O) 1-2 (C 1-4 alkyl);

[0454] (xii) -OH;

[0455] (xiv)-C 1-4 Thioalkoxy;

[0456] (xv)-NO 2 ;

[0457] (xvi)-C(=O)(C 1-4 alkyl);

[0458] (xvii) -C(=O)O(C 1-4 alkyl);

[0459] (xviii) -C(=O)OH;

[0460] (xix) -C(=O)N(R')(R"); and

[0461] (xx)C 3-6 Cycloalkoxy.

[0462] In some embodiments, R 2 is a heteroaryl group containing 5 to 10 ring atoms, wherein 1 to 4 of the 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 replaced by 1-4 independently selected R c replace.

[0463] In certain of the foregoing embodiments, R 2 is a heteroaryl group containing 6 ring atoms, wherein 1 to 3 of the ring atoms are heteroatoms, each independently selected from N, N(H) and N(R d ), and wherein one or more heteroaryl ring carbon atoms are optionally replaced by 1-4 independently selected R c replace.

[0464] As a non-limiting example, R 2 can be optionally 1-2 independently selected R c Substituted pyridinyl.

[0465] In certain of the foregoing embodiments, when R 2 is a heteroaryl group as defined above (e.g., R 2 is a heteroaryl group containing 5 to 10 ring atoms, wherein 1 to 4 of the 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 replaced by 1-4 independently selected R c Replace), each R c Independently selected from:

[0466] (i) Halogen

[0467] (vi)C 1-4Haloalkyl (e.g., CF 3 );

[0468] (vii)C 1-4 Alkoxy;

[0469] (viii)C 1-4 haloalkoxy; and

[0470] (xiv)-C 1-4 Thioalkoxy.

[0471] As a non-limiting example, each R c Can be independently C 1-4 Alkoxy (eg, methoxy).

[0472] In certain of the foregoing embodiments, when R 2 When it is a heteroaryl group, R 2 yes:

[0473] In certain of the foregoing embodiments, when R 2 When it is a heteroaryl group, R 2 yes:

[0474] In some embodiments (eg, when the compound has Formula I-d1), when R 2 When R is heteroaryl as defined elsewhere herein, 2 Selected from:

[0475] (a) a heteroaryl group containing 5 ring atoms, wherein 1-2 of the 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 replaced by 1-4 independently selected R c replace;

[0476] (b) Where Q 1 , Q 2 , Q 3 , Q 4 , Q 5 Each of which is independently selected from N, CH, and CR c , the condition is:

[0477] Q 1 , Q 2 , Q 3 , Q 4 and Q 5 1-4 of them are independently CR c ;

[0478] Q1 , Q 2 , Q 3 , Q 4 , and Q 5 One and more of are independently N; and

[0479] When Q 5 Yes CR c When 1 , Q 2 , Q 3 , and Q 4 One or more of the CR c ;and

[0480] (c) a heteroaryl group containing 9-10 ring atoms, wherein 1-4 of the 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 replaced by 1-4 independently selected R c replace,

[0481] Each occurrence of R c Independently selected from:

[0482] (i)-F;

[0483] (ii) cyano;

[0484] (iii)C2 -6 alkyl;

[0485] (iv)C 2-6 alkenyl;

[0486] (v)C 2-6 Alkynyl;

[0487] (vi)C 1-4 Haloalkyl;

[0488] (vii)C 1-4 Alkoxy;

[0489] (viii)C 1-4 Haloalkoxy;

[0490] (ix) optionally 1 to 4 independently selected C 1-4 Alkyl-substituted-(C 0-3 Alkylene)-C 3-6 Cycloalkyl;

[0491] (x)-S(O) 1-2 (C 1-4 alkyl);

[0492] (xi)-NR e R f;

[0493] (xiii)-S(O) 1-2 (NR'R");

[0494] (xiv)-C 1-4 Thioalkoxy;

[0495] (xv)-NO 2 ;

[0496] (xvi)-C(=O)(C 1-4 alkyl);

[0497] (xvii) -C(=O)O(C 1-4 alkyl);

[0498] (xviii) -C(=O)OH;

[0499] (xix) -C(=O)N(R')(R"); and

[0500] (xx)C 3-6 Cycloalkoxy.

[0501] Variable R 3

[0502] In some embodiments, R 3 One or more occurrences of are independently selected from R c’ and -L 4 -R 4 .

[0503] In some embodiments, R 3 One occurrence is -L 4 -R 4 .

[0504] In certain of the foregoing embodiments, when R 3 One occurrence is -L 4 -R 4 When the remaining R 3 Each independently selected from H and R c '(For example, R c ' may be a halogen, for example, Br or Cl; or R c ' can be -OH or NH 2 ). For example, the remaining occurrences of R 3 Each of can be H.

[0505] In some embodiments, R 3 One occurrence is -L 4 -R 4 , and R 3 One occurrence of H or Rc '(For example, R c ' may be a halogen, for example, Br or Cl; or R c 'It can be NH 2 ).

[0506] In some embodiments, R 3 One occurrence is -L 4 -R 4 , and R 3 The first occurrence of R c '(For example, R c ' can be a halogen, for example, Br or Cl (for example, R c’ It can be Cl)).

[0507] In some embodiments, R 3 One occurrence is -L 4 -R 4 , and R 3 One occurrence of is H.

[0508] In some embodiments, R 3 The two occurrences of are independently selected -L 4 -R 4 .

[0509] In certain of the foregoing embodiments, any remaining occurrences of R 3 Selected from H and R c’ For example, any remaining occurrences of R 3 It can be H.

[0510] As a non-limiting example of the foregoing embodiment, X 2 and X 3 Each of the CR 3 , where each R 3 Is independently selected -L 4 -R 4 (In certain embodiments, X 1 and X 4 each of which is independently CH or N).

[0511] In some embodiments, R 3 One occurrence of H or R c '(For example, R c ' may be a halogen, for example, Br or Cl; or R c ' can be -OH or NH 2 ).

[0512] In certain embodiments, when R 3 The first occurrence is R c ', the remaining R3 Each of is independently H or R c '. For example, the remaining occurrences of R 3 Each of can be H.

[0513] In certain embodiments, when R 3 The first occurrence is R c’ ; and one or more remaining occurrences of R 3 Independently selected from -L 4 -R 4 and R c’ .

[0514] In some embodiments, R 3 One occurrence of is H.

[0515] X 1 -X 4 and R 3 Non-limiting combinations of

[0516] In some embodiments, part (The structure originally provided in U.S. Provisional Application Serial No. 62 / 742,218 Redrawn to further clarify connection points) is (The structure originally provided in U.S. Provisional Application Serial No. 62 / 742,218 Redrawn to further clarify connection points) where * indicates connection with NR 2 the connection point; and Indicates that 1 connection point.

[0517] In certain embodiments, R 3B Yes-L 4 -R 4 ; and R 3C is H (for example, -L 4 Can be NHS(O) 2 ).

[0518] In certain embodiments, R 3B Yes-L 4 -R 4 ; and R 3C YesR c’ (For example, R c’ It can be a halogen such as -Cl; and / or -L 4 Can be NHS(O) 2 ).

[0519] In certain embodiments, R 3B Yes-L 4 -R 4 ; and R 3CIs independently selected -L 4 -R 4 In certain of the foregoing embodiments, R 3B -L 4 With R 3C -L 4 As a non-limiting example, R 3B -L 4 Can be NHS(O) 2 ; and R 3C -L 4 Can be a key.

[0520] In certain embodiments, R 3B is H; and R 3C Yes-L 4 -R 4( For example, -L 4 Can be NHS(O) 2 ).

[0521] In certain embodiments, R 3B YesR c’ ; and R 3C Yes-L 4 -R 4( For example, -L 4 Can be NHS(O) 2 ).

[0522] In certain embodiments, R 3B is H; and R 3C YesR c’ .

[0523] In some embodiments, part (The structure originally provided in U.S. Provisional Application Serial No. 62 / 742,218 Redrawn to further clarify connection points) is (The structure originally provided in U.S. Provisional Application Serial No. 62 / 742,218 Redrawn to further clarify connection points) where * indicates connection with NR 2 the connection point; and Indicates that 1 connection point.

[0524] In certain embodiments, R 3A It's H.

[0525] In certain of the foregoing embodiments, R 3B Yes-L 4 -R 4( For example, -L 4 Can be NHS(O) 2).

[0526] In some embodiments, part (The structure originally provided in U.S. Provisional Application Serial No. 62 / 742,218 Redrawn to further clarify connection points) is (The structure originally provided in U.S. Provisional Application Serial No. 62 / 742,218 Redrawn to further clarify connection points) where * indicates connection with NR 2 the connection point; and Indicates that 1 connection point.

[0527] In certain embodiments, R 3A It's H.

[0528] In certain of the foregoing embodiments, R 3B Yes-L 4 -R 4( For example, -L 4 Can be NHS(O) 2 ).

[0529] In certain of the foregoing embodiments, R 3B Yes-L 4 -R 4( For example, -L 4 Can be NHS(O) 2 ); and R 3C It's H.

[0530] In certain of the foregoing embodiments, R 3B Yes-L 4 -R 4( For example, -L 4 Can be NHS(O) 2 ); and R 3C YesR c’ .

[0531] In certain of the foregoing embodiments, R 3B Yes-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, R 3B -L 4 With R 3C -L 4 As a non-limiting example, R 3B -L4 Can be NHS(O) 2 ; and R 3C -L 4 Can be a key.

[0532] In some embodiments, part (The structure originally provided in U.S. Provisional Application Serial No. 62 / 742,218 Redrawn to further clarify connection points) is (The structure originally provided in U.S. Provisional Application Serial No. 62 / 742,218 Redrawn to further clarify connection points) where * indicates connection with NR 2 the connection point; and Indicates that 1 connection point.

[0533] In certain embodiments, R 3D It's H.

[0534] In certain of the foregoing embodiments, R 3B Yes-L 4 -R 4( For example, -L 4 Can be NHS(O) 2 ).

[0535] In certain of the foregoing embodiments, R 3B Yes-L 4 -R 4( For example, -L 4 Can be NHS(O) 2 ); and R 3C It's H.

[0536] In certain of the foregoing embodiments, R 3B Yes-L 4 -R 4( For example, -L 4 Can be NHS(O) 2 ); and R 3C YesR c’ .

[0537] In certain of the foregoing embodiments, R 3B Yes-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, R 3B -L4 With R 3C -L 4 As a non-limiting example, R 3B -L 4 Can be NHS(O) 2 ; and R 3C -L 4 Can be a key.

[0538] Variable L 4

[0539] In some embodiments, -L 4 Yes-N(H)S(O) 1-2 -or-N(R d )S(O) 1-2 (For example, N(C 1-3 Alkyl)S(O) 2 ).

[0540] In certain of the foregoing embodiments, -L 4 Yes-N(H)S(O) 2 -.

[0541] 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 )-.

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

[0543] 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 -.

[0544] In certain of the foregoing embodiments, -L 4 It is -S(O)(=NH)NH-.

[0545] In some embodiments, -L 4 Yes-S(O) 1-2 N(H)- or -S(O) 1-2 N(R d )-.

[0546] In certain of the foregoing embodiments, -L 4 Yes-S(O) 2 N(H)-.

[0547] In some embodiments, -L 4 is -N(H)C(O)- or -N(R d )C(O).

[0548] In certain of the foregoing embodiments, -L 4 It is -N(H)C(O)-.

[0549] In some embodiments, L 4 is -C(O)NH- or -C(O)N(R d )-.

[0550] In some embodiments, -L 4 It is -N(H)-, -N(R d )-, or-N(R 4 )-.

[0551] In certain embodiments, -L 4 is -N(H)- or -N(R 4 )-.

[0552] In some embodiments, -L 4 It is a single bond.

[0553] In some embodiments, -L 4 It is C≡C.

[0554] In some embodiments, -L 4 Yes -O-.

[0555] In some embodiments, L 4 Selected from: -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 )-.

[0556] In some embodiments, L 4 Yes-N(H)S(O) 1-2 N(H)-(e.g., -N(H)S(O) 2 N(H)-).

[0557] In some embodiments, L 4 Yes-N(H)S(O) 1-2 N(R d )-(e.g., -N(H)S(O) 2 N(R d )-, for example, -N(H)S(O) 2 N(C 1-3 alkyl)-).

[0558] In some embodiments, -L 4 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)-.

[0559] In certain of the foregoing embodiments, -L 4 Selected from --N(H)S(O) 2 -, single bond, -NH-, -N(R 4 )-, and -N(H)C(O)-.

[0560] In some embodiments, -L 4 Selected from:

[0561] (i) bond (in certain embodiments, when -L 4 is a bond; and R 4 Yes-(Y 3 ) p -Y 4 , then p is 1).

[0562] (ii)N(R 4 );

[0563] (iii)-N(H)S(O) 1-2 -or-N(R d )S(O) 1-2 -;

[0564] (iv)-S(O) 1-2 N(H)- or -S(O) 1-2 N(R d )-;

[0565] (vi)-S(O) 1-2 -;

[0566] (viii) -N(H)C(O)- or -N(R d )C(O)-;

[0567] (ix) -C≡C;

[0568] (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 )-

[0569] (xi)-S(O)(=NH)NH-, -S(O)(=NR d )NH-, -S(O)(=NH)NR d -, or -S(O)(=NR d )NR d -;as well as

[0570] (xii) -S(O)(=NH)- or -S(O)(=NR d ).

[0571] Variable R 4

[0572] In some embodiments, R 4 Yes-(Y 3 ) p -Y 4 .

[0573] In some embodiments, p is 0.

[0574] In other embodiments, p is 1. In certain of these embodiments, Y 3 It is C 1-3 For example, Y 3 It can be CH 2 or CH 2 -CH 2 .

[0575] In some embodiments, Y 2 It is C 6-10 Aryl, which is optionally substituted by 1 to 4 R c replace.

[0576] In some embodiments, Y 2 is phenyl, which is optionally substituted by 1-2 (e.g. 1) R c replace.

[0577] In certain embodiments, when Y 4 It is C 6-10 Aryl, which is optionally substituted by 1 to 4 R c (For example, when Y 4 is phenyl, which is optionally substituted by 1-2 (e.g., 1) Rc ) when replaced by R c Each occurrence of is independently selected from:

[0578] (i) halogen;

[0579] (ii) cyano;

[0580] (iii)C 1-6 alkyl;

[0581] (iv)C 2-6 alkenyl;

[0582] (v)C 2-6 Alkynyl;

[0583] (vi)C 1-4 Haloalkyl;

[0584] (vii)C 1-4 Alkoxy;

[0585] (viii)C 1-4 Haloalkoxy;

[0586] (ix) optionally 1 to 4 independently selected C 1-4 Alkyl-substituted-(C 0-3 Alkylene)-C 3-6 Cycloalkyl;

[0587] (xiv)-C 1-4 Thioalkoxy, and

[0588] (xx)C 3-6 Cycloalkoxy.

[0589] In certain embodiments, when Y 4 It is C 6-10 Aryl, which is optionally substituted by 1 to 4 R c (For example, when Y 4 is phenyl, which is optionally substituted by 1-2 (e.g., 1) R c ) when replaced by R c Each occurrence of is independently selected from:

[0590] (i) halogen;

[0591] (iii)C 1-6 alkyl;

[0592] (vi)C 1-4 Haloalkyl;

[0593] (vii)C 1-4 Alkoxy; and

[0594] (viii)C 1-4Halogenated alkoxy.

[0595] In certain embodiments, when Y 4 It is C 6-10 When the group is aromatic, each occurrence of R c Independently selected from:

[0596] (vii)C 1-4 Alkoxy;

[0597] (viii)C 1-4 haloalkoxy; and

[0598] (xiv)-C 1-4 Thioalkoxy.

[0599] In certain embodiments, Y 4 It is C 6-10 Aryl (eg, phenyl), which is unsubstituted.

[0600] In certain embodiments, when p=1 and Y 4 It is C 6-10 When the group is aromatic, R 4 Selected from:

[0601]

[0602] In certain embodiments, when p=1 and Y 4 It is C 6-10 When the group is aromatic, R 4 Selected from:

[0603]

[0604] In certain embodiments, when p=0 and Y 4 It is C 6-10 When the group is aromatic, R 4 yes:

[0605]

[0606] In certain embodiments, when p=0 and Y 4 It is C 6-10 When the group is aromatic, R 4 yes:

[0607]

[0608] In some embodiments, Y 4 It is C 3-6 (For example, C 3-4 or C 6 ) cycloalkyl, which is optionally substituted by 1 to 4 R b replace.

[0609] In some of the foregoing embodiments, Y 4 is cyclopropyl, which is optionally substituted with 1-2 R b Replace. For example, Y 4 is an unsubstituted cyclopropyl group.

[0610] In some embodiments, Y 4 It is C 6 Cycloalkyl (e.g., cyclohexyl), which is optionally substituted with 1-2 R b replace.

[0611] In some of the foregoing embodiments, when Y 4 is a cycloalkyl group, which is optionally substituted by 1 to 4 R b When replacing, each occurrence of R b 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).

[0612] In certain embodiments, when p=1 and Y 4 is optionally replaced by 1-4 R b Substituted C 3-6 When cycloalkyl, R 4 Selected from:

[0613]

[0614] In certain embodiments, when p=1 and Y 4 is optionally replaced by 1-4 R b Substituted C 3-6 When cycloalkyl, R 4 Selected from:

[0615]

[0616] In certain embodiments, when p=0 and Y 4 is optionally replaced by 1-4 R b Substituted C 3-6 When cycloalkyl, R 4 Selected from:

[0617]

[0618] In certain embodiments, Y 4 It is C 3-6 (For example, C 3-4 or C 6 )cycloalkyl, which is unsubstituted.

[0619] In certain of these embodiments, Y 4 is unsubstituted cyclopropyl or unsubstituted cyclobutyl (eg, unsubstituted cyclopropyl).

[0620] In some embodiments, Y 4 is a heteroaryl group containing 5 to 10 ring atoms, wherein 1 to 4 of the 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 replaced by 1-4 independently selected R c replace.

[0621] In some of the foregoing embodiments, Y 4 is a heteroaryl group containing 6 ring atoms, wherein 1 to 4 of the ring atoms are heteroatoms, each independently selected from N, N(H) and N(R d ), and wherein one or more heteroaryl ring carbon atoms are optionally replaced by 1-4 independently selected R c replace.

[0622] As a non-limiting example of the foregoing, Y 4 It 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 replace.

[0623] For example, Y 4 It may be pyridinyl, pyrimidinyl, or pyrazinyl, each of which is unsubstituted.

[0624] In certain embodiments, when Y 4 is optionally one or more independently selected R defined above c In the case of a substituted heteroaryl group, each occurrence of R c Independently selected from:

[0625] (i) halogen;

[0626] (ii) cyano;

[0627] (iii)C 1-6 alkyl;

[0628] (iv)C 2-6 alkenyl;

[0629] (v)C 2-6 Alkynyl;

[0630] (vi)C 1-4 Haloalkyl;

[0631] (vii)C 1-4 Alkoxy;

[0632] (viii)C 1-4 Haloalkoxy;

[0633] (ix) optionally 1 to 4 independently selected C 1-4 Alkyl-substituted-(C 0-3 Alkylene)-C 3-6 Cycloalkyl;

[0634] (xii) OH;

[0635] (xiv)-C 1-4 Thioalkoxy, and

[0636] (xx)C 3-6 Cycloalkoxy.

[0637] In some of these embodiments, each occurrence of R c Independently selected from:

[0638] (i) halogen (e.g., F, Cl);

[0639] (iii)C 1-6 Alkyl (eg, methyl); and

[0640] (xii) OH.

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

[0642]

[0643]

[0644] In certain embodiments, when p=1; and Y 4 When it is a heteroaryl group, R 4 Selected from:

[0645]

[0646] In certain embodiments, when p=0; and Y 4 When it is a heteroaryl group, R 4 Selected from:

[0647]

[0648] In certain embodiments, when p=0; and Y 4 When it is a heteroaryl group, R 4 Selected from:

[0649]

[0650] 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 heterocyclyl ring carbon atoms are optionally replaced by 1-4 independently selected R b replace.

[0651] In some of the foregoing embodiments, Y 4 is a heterocyclic group containing 4-6 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 heterocyclyl ring carbon atoms are optionally replaced by 1-4 independently selected R b generation.

[0652] In certain embodiments, Y 4 is a heterocyclic group containing 4 ring atoms, one of which is a heteroatom independently selected from N, N(H), N(R d ), and O, and wherein one or more heterocyclyl ring carbon atoms are optionally replaced by 1-2 independently selected R b replace.

[0653] As a non-limiting example, Y 4 can be optionally 1-2 independently selected R b A substituted oxetanyl group (eg, an unsubstituted oxetanyl group).

[0654] As another non-limiting example, Y 4 can be optionally 1-2 independently selected R b Substituted azetidinyl (e.g., with one R b substituted azetidinyl).

[0655] 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 heterocyclyl ring carbon atoms are optionally replaced by 1-4 independently selected R b replace.

[0656] As a non-limiting example, Y 4 can be selected from tetrahydropyranyl, piperidinyl, piperazinyl, and morpholinyl, each of which is optionally substituted by 1-2 independently selected R b replace.

[0657] As a non-limiting example, Y 4can be selected from tetrahydropyranyl, piperidinyl, and morpholinyl, each of which is optionally substituted by 1-2 independently selected R b replace.

[0658] In some of the foregoing embodiments, when Y 4 is optionally 1-4 independently selected R b In the case of a substituted heterocyclic group, each occurrence of R b Independently selected from: -F, C 1-6 Alkyl, C 1-4 haloalkyl, oxo, and -OH.

[0659] In some of the foregoing embodiments, when Y 4 is optionally 1-4 independently selected R b In the case of a substituted heterocyclic group, each occurrence of R b Independently selected from: -F, C 1-6 Alkyl, C 1-4 Haloalkyl, and -OH (e.g., R b It can be OH).

[0660] In certain embodiments, when p=1; and Y 4 is optionally 1-4 independently selected R b When the heterocyclic group is substituted, R 4 Selected from:

[0661] In certain embodiments, when p=1; and Y 4 is optionally 1-4 independently selected R b When the heterocyclic group is substituted, R 4 yes

[0662] In certain embodiments, when p=0; and Y 4 is optionally 1-4 independently selected R b When the heterocyclic group is substituted, R 4 Selected from:

[0663]

[0664] In certain embodiments, when p=0; and Y 4 is optionally 1-4 independently selected R b When the heterocyclic group is substituted, R 4 Selected from:

[0665]

[0666] In some embodiments, R 4 It is C 1-10Alkyl, optionally with 1-6 independently selected R a replace.

[0667] In certain embodiments, R 4 It is C 1-6 Alkyl, optionally with 1-6 independently selected R a replace.

[0668] In certain embodiments, R 4 It is C 1-6 Alkyl, optionally with 1-2 independently selected R a For example, R 4 It may be methyl.

[0669] In certain of the foregoing embodiments, when R 4 It is C 1-6 When the alkyl group is present, each occurrence of R a Independently selected from: -F, -OH; C 1-4 Alkoxy; and C 1-4 Halogenated alkoxy.

[0670] In certain embodiments, each occurrence of R a is independently -OH. For example, R 4 yes

[0671] In some embodiments, R 4 Selected from methyl, ethyl,

[0672] In some embodiments, R 4 Selected from methyl and

[0673] In some embodiments, R 4 It 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 (For example, unsubstituted C 2-4 Alkynyl )replace.

[0674] In some embodiments, R 4 It is C 2-10( For example, C 2-4 ) alkenyl, which is optionally substituted by 1-6 (eg, 1-3) independently selected R a (For example, unsubstituted C 2-4烯基 , such as vinyl) instead.

[0675] In some embodiments (e.g., when -L4 is a bond or -O-), R 4 It is C 2-10 Alkyl, optionally with 1-6 independently selected R a or methyl, optionally substituted with 1-2 independently selected R a replace.

[0676] In certain embodiments (e.g., when -L 4 is a bond or -O-), R 4 It is C 2-10 Alkyl, optionally with 1-6 independently selected R a substituted; or methyl, by 1-2 independently selected R a replace.

[0677] -L 4 and R 4 Non-limiting combinations of

[0678] Unrestricted combination [A]

[0679] In some embodiments, -L 4 Selected from -N(H)S(O) 2 -、-N(H)S(O) 2 N(H)-、-N(H)S(O) 2 N(R d )-、C≡C、single bond、-C(O)N(H)-、-N(H)-、-N(R 4 )-、-N(R d )-, and -N(H)C(O)-; and

[0680] R 4 Selected from:

[0681] (i)C 1-6 Alkyl, optionally with 1-2 R a replace;

[0682] (ii)-(Y 3 ) p -Y 4 ;and

[0683] (iii)C 2-10 Alkenyl or C 2-10 Alkynyl, each of which is optionally substituted by 1-3 independently selected R a replace.

[0684] In certain embodiments, -L 4 Selected from -N(H)S(O) 2 -、-N(H)S(O) 2 N(H)-, and -N(H)S(O)2 N(R d )-;and

[0685] R 4 Selected from:

[0686] (i)C 1-6 Alkyl, optionally with 1-2 R a replace;

[0687] (ii)-(Y 3 ) p -Y 4 ;and

[0688] (iii)C 2-10 Alkenyl or C 2-10 Alkynyl, each of which is optionally substituted by 1-3 independently selected R a replace.

[0689] In some embodiments, -L 4 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

[0690] R 4 Selected from:

[0691] (i)C 1-6 Alkyl, optionally with 1-2 R a replace; and

[0692] (ii)-(Y 3 ) p -Y 4 .

[0693] In certain embodiments, -L 4 Selected from --N(H)S(O) 2 -, single bond, -NH-, -N(R 4 )-, and -N(H)C(O)-; and

[0694] R 4 Selected from:

[0695] (i)C 1-6 Alkyl, optionally with 1-2 R a replace; and

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

[0697] In certain embodiments, -L 4 Yes-N(H)S(O) 2 -; and R 4 Selected from:

[0698] (i)C 1-6 Alkyl, optionally with 1-2 R a replace; and

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

[0700] In certain embodiments, -L 4 is a single bond; and R 4 Selected from:

[0701] (i)C 1-6 Alkyl, optionally with 1-2 R a replace; and

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

[0703] In certain embodiments, -L 4 is -NH- or -N(R 4 )-; and R 4 Selected from:

[0704] (i)C 1-6 Alkyl, optionally with 1-2 R a replace; and

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

[0706] In certain embodiments, -L 4 is -N(H)C(O)-; and R 4 Selected from:

[0707] (i)C 1-6 Alkyl, optionally with 1-2 R a replace; and

[0708] (ii)-(Y 3 ) p -Y 4 .

[0709] In certain of these embodiments, -L 4 Yes-N(H)S(O) 2 N(H)- or -N(H)S(O)2 N(R d )-;and

[0710] R 4 Selected from:

[0711] (i)C 1-6 Alkyl, optionally with 1-2 R a replace; and

[0712] (ii)-(Y 3 ) p -Y 4 .

[0713] In certain embodiments, -L 4 Yes-N(H)S(O) 2 -; and R 4 Selected from:

[0714] R 4 Selected from:

[0715] (i)C 1-6 Alkyl, optionally with 1-2 R a replace;

[0716] (ii)-(Y 3 ) p -Y 4 ;and

[0717] (iii)C 2-10 Alkenyl or C 2-10 Alkynyl, each of which is optionally substituted by 1-3 independently selected R a replace.

[0718] In certain embodiments, -L 4 is a single bond; and R 4 Selected from:

[0719] R 4 Selected from:

[0720] (i)C 1-6 Alkyl, optionally with 1-2 R a replace;

[0721] (ii)-(Y 3 ) p -Y 4 ;and

[0722] (iii)C 2-10 Alkenyl or C 2-10 Alkynyl, each of which is optionally substituted by 1-3 independently selected R a replace.

[0723] In certain embodiments, -L 4 is -NH- or -N(R 4 )-; and R 4 Selected from:

[0724] R 4 Selected from:

[0725] (i)C 1-6 Alkyl, optionally with 1-2 R a replace;

[0726] (ii)-(Y 3 ) p -Y 4 ;and

[0727] (iii)C 2-10 Alkenyl or C 2-10 Alkynyl, each of which is optionally substituted by 1-3 independently selected R a replace.

[0728] In certain embodiments, -L 4 is -N(H)C(O)-; and R 4 Selected from:

[0729] R 4 Selected from:

[0730] (i)C 1-6 Alkyl, optionally with 1-2 R a replace;

[0731] (ii)-(Y 3 ) p -Y 4 ;and

[0732] (iii)C 2-10 Alkenyl or C 2-10 Alkynyl, each of which is optionally substituted by 1-3 independently selected R a replace.

[0733] In certain embodiments, -L 4 Yes-N(H)S(O) 2 N(H)- or -N(H)S(O) 2 N(R d )-;and

[0734] R 4 Selected from:

[0735] (i)C 1-6 Alkyl, optionally with 1-2 R a replace;

[0736] (ii)-(Y3 ) p -Y 4 ;and

[0737] (iii)C 2-10 Alkenyl or C 2-10 Alkynyl, each of which is optionally substituted by 1-3 independently selected R a replace.

[0738] In some embodiments of [A], R 4 is optionally replaced by 1-2 R a Substituted C 1-6 alkyl.

[0739] In some embodiments of [A], R 4 It is C 2-10 Alkenyl or C 2-10 Alkynyl, each of which is optionally substituted by 1-3 independently selected R a replace.

[0740] In certain of these embodiments, R 4 It is C 2-10( For example, C 2-5 ) alkynyl, which is optionally substituted by 1-3 independently selected R a Substitution (e.g., unsubstituted C 2-5 Alkynyl ).

[0741] In some embodiments of [A], R 4 Yes-(Y 3 ) p -Y 4 In certain embodiments, Y 2 It is C 6-10 Aryl, which is optionally substituted by 1 to 4 R c Replace. For example, Y 4 It may be a phenyl group, which is optionally substituted by 1-2 (eg, 1) R c replace.

[0742] In some embodiments of [A], when R 4 Yes-(Y 3 ) p -Y 4 When Y 4 It is C 3-6 (For example, C 3-4 or C 6 ) cycloalkyl, which is optionally substituted by 1 to 4 R b In certain embodiments, Y 4 It is C 3-4 Cycloalkyl or C 6Cycloalkyl, each of which is optionally substituted by 1-2 R b Substitution (e.g., R b can be -OH).

[0743] In some embodiments of [A], R 4 Yes-(Y 3 ) p -Y 4 In certain embodiments, Y 4 is a heterocyclic group containing 4 to 6 ring atoms, of which 1 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ) and O, and wherein one or more heterocyclyl ring carbon atoms are optionally replaced by 1-2 independently selected R b In certain embodiments, Y 4 is a heterocyclic group containing 6 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 heterocyclyl ring carbon atoms are optionally replaced by 1-2 independently selected R b Replace (for example, 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 to 3 ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ) and O, and wherein one or more heterocyclyl ring carbon atoms are optionally replaced by 1-2 independently selected R b Replace (for example, Y 4 It may be oxetane; or Y 4 may be azetidinyl).

[0744] In some embodiments of [A], R 4 Yes-(Y 3 ) p -Y 4 In certain embodiments, Y 4 is a heteroaryl group containing 6 ring atoms, wherein 1 to 4 of the ring atoms are heteroatoms, each independently selected from N, N(H), and N(R d ), and wherein one or more heteroaryl ring carbon atoms are optionally replaced by 1-4 independently selected R c In certain embodiments, Y 4 is pyridinyl (e.g., 2-pyridinyl, 3-pyridinyl, or 4-pyridinyl), pyrimidinyl (e.g., 2-pyrimidinyl or 5-pyrimidinyl), or pyrazinyl, each of which is optionally substituted by 1-2 independently selected Rc replace.

[0745] In certain of the foregoing embodiments of [A], when R 4 Yes-(Y 3 ) p -Y 4 , p=0.

[0746] In other embodiments of [A], when R 4 Yes-(Y 3 ) p -Y 4 When p=1. In some of these embodiments, Y 3 It is C 1-3 Alkylene (e.g., CH 2 , CH 2 -CH 2 ).

[0747] In some embodiments, when R 3 Yes-L 4 -R 4 When R 3 Selected from:

[0748]

[0749] In some embodiments, when R 3 Yes-L 4 -R 4 When R 3 Selected from:

[0750]

[0751] In some embodiments, when R 3 Yes-L 4 -R 4 When R 3 Selected from:

[0752]

[0753] In some embodiments, when R 3 Yes-L 4 -R 4 When R 3 Selected from:

[0754]

[0755] In some embodiments, when R 3 Yes-L 4 -R 4 When R 3 Selected from:

[0756]

[0757] In some embodiments, when R 3 Yes-L 4 -R 4 When R 3 Selected from:

[0758]

[0759] In some embodiments, when R 3 Yes-L 4 -R 4 When R 3 Selected from:

[0760]

[0761] In some embodiments, when R 3 Yes-L 4 -R 4 When R 3 Selected from:

[0762]

[0763] In some embodiments, when R 3 Yes-L 4 -R 4 When R 3 Selected from:

[0764]

[0765] In some embodiments, when R 3 Yes-L 4 -R 4 When R 3 Selected from:

[0766]

[0767] In some embodiments, when R 3 Yes-L 4 -R 4 When R 3 Selected from:

[0768]

[0769] In some embodiments, when R 3 Yes-L 4 -R 4 When R 3 Selected from:

[0770]

[0771] In some embodiments, when R 3 Yes-L 4 -R 4 When R 3 Selected from:

[0772]

[0773] In some embodiments, when R 3 Yes-L 4 -R 4 When R 3 Selected from:

[0774]

[0775]

[0776] In some embodiments, when R 3 Yes-L 4 -R 4 When R 3 Selected from:

[0777] NHMe, and NMe 2 .

[0778] In some embodiments, when R 3 Yes-L 4 -R 4 When R 3 Selected from:

[0779]

[0780] In some embodiments, when R 3 Yes-L 4 -R 4 When R 3 Selected from:

[0781]

[0782] In certain of the foregoing embodiments, R 3 yes

[0783] Variable R c’

[0784] In some embodiments, each occurrence of R c 'Independently selected from:

[0785] (i) halogen (e.g., -F, Cl);

[0786] (ii) cyano;

[0787] (iii) -OH;

[0788] (iv)-NO 2 ;

[0789] (v) -C(=O)(C 1-4 alkyl);

[0790] (vi) -C(=O)O(C 1-4 alkyl);

[0791] (vii) -C(=O)OH; and

[0792] (viii)-NH 2 .

[0793] In certain embodiments, each occurrence of R c 'Independently selected from:

[0794] (i) halogen (e.g., -F, Cl);

[0795] (iii) -OH;

[0796] (iv)-NO 2 ;

[0797] (v) -C(=O)(C 1-4 alkyl); and

[0798] (vi) -C(=O)O(C 1-4 alkyl).

[0799] In certain embodiments, each occurrence of R c ' is independently selected from halogen (eg, -F, Cl).

[0800] In certain embodiments, each occurrence of R c 'Independently selected from OH and NH 2 .

[0801] Non-restricted combinations

[0802] Unrestricted combination[1]

[0803] In some embodiments:

[0804] R 1 Yes-(Y 1 ) n -Y 2 ;and

[0805] R 2 It is C 6-10 Aryl, which is optionally substituted by 1 to 4 Rc replace.

[0806] In certain of these embodiments, n is zero.

[0807] In certain of the foregoing embodiments of [1], X 1 , X 2 , X 3 , and X 4 1-2 of them are N; X 1 , X 2 , X 3 , and X 4 2-3 of them are independently selected CR 3 .

[0808] In certain of the foregoing embodiments of [1], X 1 , X 2 , X 3 , and X 4 of one N; each of the remaining X 1 , X 2 , X 3 , and X 4 Is an independently selected CR 3 ;or

[0809] X 1 , X 2 , X 3 , and X 4 Two of them are N; each of the remaining X 1 , X 2 , X 3 , and X 4 Is an independently selected CR 3 .

[0810] In certain embodiments, X 2 and X 3 1-2 of them are CR independently 3 , such as where X 2 and X 3 Each of the CRs is independently selected 3 In some of the foregoing embodiments, X 1 and X 4 Each of is independently CH or N (e.g., X 1 and X 4 Each of them is N).

[0811] In certain of the aforementioned embodiments of [1], R 3 One occurrence is -L 4 -R 4 .

[0812] In certain of the aforementioned embodiments of [1], R 4 Yes-(Y 3 ) p -Y 4 .

[0813] In certain of the foregoing embodiments, when R 4 Yes 3 ) p -Y 4 When p=1, p=1. In other embodiments, p=0.

[0814] In certain of the aforementioned embodiments of [1], R 4 It is C 1-10 Alkyl, optionally with 1-6 independently selected R a replace.

[0815] In certain of the foregoing embodiments of [1], the remaining occurrences of R 3 Each independently selected from H and R c '. For example, the remaining occurrences of R 3 Each of can independently be H.

[0816] In certain of the aforementioned embodiments of [1], when R 3 One occurrence is -L 4 -R 4 When R 3 One occurrence of is H.

[0817] In certain of the aforementioned embodiments of [1], when R 3 One occurrence is -L 4 -R 4 When R 3 The first occurrence is R c’ (eg, halogen (eg, Br or Cl, eg, Cl)).

[0818] In some embodiments of [1], R 3 The first occurrence is R c’ (e.g., Br or Cl, e.g., Cl); and the remaining occurrences of R 3 Each of is H.

[0819] In some embodiments of [1], Y 2 As defined in any one of claims 14-20 and 26-28; and each R c , when present, is independently as defined in any one of claims 21-24.

[0820] In some embodiments of [1], Y 2 As defined in any one of claims 14 to 18; and each Rc , when present, as defined in any one of claims 21 to 23.

[0821] In some embodiments of [1], Y 2 As defined in any one of claims 16 to 18; and each R c , when present, as defined in any one of claims 21 to 23.

[0822] In some embodiments of [1], Y 2 As defined in claim 18; and each R c , when present, as defined in claim 23.

[0823] In certain embodiments of [1], R 1 YesR 1 yes like

[0824] In some embodiments of [1], R 1 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 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 defined as in claim 23 of US 62 / 742,218 filed on October 5, 2018. In some embodiments of [1], R 2 It is C 6-10 Aryl, which is optionally substituted by 1 to 4 R c Substituted, such as phenyl, which is optionally substituted with 1-4 R c or 1-2 R c or 2 R c Replace; and R c , when present, as described in any one of claims 33-35.

[0825] In some embodiments of [1], R 2 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 Substitution, such as where R 2 yes And R c , when present, as defined in any one of claims 33 to 35.

[0826] In certain embodiments of [1], R 2 As defined in any one of claims 27-31 of US 62 / 742,218 filed on October 5, 2018. For example, R 2 Can be

[0827] In some embodiments of [1], R 2 is a heteroaryl group containing 5-10 (e.g. 6) ring atoms, wherein 1-4 (e.g. 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 replaced by 1-4 independently selected R c Substitution, such as where R 2 is optionally 1-2 independently selected R c Substituted pyridyl, or where R 2 yes And R c , when present, as defined in any one of claims 40-41.

[0828] In certain embodiments of [1], R 2 yes

[0829] In some embodiments of [1], R2 is as defined 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 As defined 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.

[0830] In some embodiments of [1], when R 3 One occurrence is -L 4 -R 4 When -L 4 Selected from:

[0831] -N(H)S(O) 1-2 -or-N(R d )S(O) 1-2 (For example, N(C 1-3 Alkyl)S(O) 2 ), such as where L 4 Yes-N(H)S(O) 2 -;

[0832] -N(H)C(O)- or -N(R d )C(O), such as where L 4 is -N(H)C(O)-;

[0833] -C(O)NH- or -C(O)N(R d )-;

[0834] -N(H)-, -N(R d )-, or -N(R 4 )-;

[0835] ·single bond;

[0836] C≡C;

[0837] -O-; and

[0838] -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 Yes-N(H)S(O) 1-2 N(H)-(e.g., -N(H)S(O) 2 N(H)-) or L 4 Yes-N(H)S(O) 1-2 N(R d )-(e.g., -N(H)S(O) 2 N(R d )-(e.g., -N(H)S(O) 2 N(C 1-3烷基 )-));

[0839] and as defined in any of claims 48-55 of US 62 / 742,218 filed on October 5, 2018.

[0840] In some embodiments of [1], when R 3 One occurrence is -L 4 -R 4 When -L 4 Selected from:

[0841] -N(H)S(O) 1-2 -or-N(R d )S(O) 1-2 (For example, N(C1-3 Alkyl)S(O) 2 ), such as where L 4 Yes-N(H)S(O) 2 -;

[0842] -N(H)C(O)- or -N(R d )C(O), such as where L 4 is -N(H)C(O)-;

[0843] -C(O)NH- or -C(O)N(R d )-;

[0844] -N(H)-, -N(R d )-, or -N(R 4 )-;

[0845] Single key; and

[0846] ·C≡C.

[0847] In some embodiments of [1], when R 3 One occurrence is -L 4 -R 4 When -L 4 Selected from:

[0848] ·N(H)S(O) 2 -;

[0849] -N(H)C(O)-; and

[0850] -N(H)-, -N(R d )-, or-N(R 4 )-.

[0851] In certain embodiments of [1], -L 4 As defined in any of claims 49, 51, and 53 of US 62 / 742,218 filed on October 5, 2018. For example, L 4 May be defined as in claim 49 of US 62 / 742,218 filed on October 5, 2018. In some embodiments of [1], when R 3 One occurrence is -L 4 -R 4 When -L 4 It is -NHS(O)(=NH)-.

[0852] In some embodiments of [1], when R 3 One occurrence is -L 4 -R 4 When -L 4Selected from:

[0853] -N(H)S(O) 1-2 -or-N(R d )S(O) 1-2 (For example, N(C 1-3 Alkyl)S(O) 2 ), such as where L 4 Yes-N(H)S(O) 2 -;as well as

[0854] -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 Yes-N(H)S(O) 1-2 N(H)-(e.g., -N(H)S(O) 2 N(H)-) or L 4 Yes-N(H)S(O) 1-2 N(R d )-(e.g., -N(H)S(O) 2 N(R d )-(e.g., -N(H)S(O) 2 N(C 1-3烷基 )-)).

[0855] In some embodiments of [1], when R 3 One occurrence is -L 4 -R 4 ; and R 4 Yes 3 ) p -Y 4 , Y 4 It is C 6-10 Aryl, which is optionally substituted by 1 to 4 R c Substituted, such as phenyl, which is optionally substituted with 1-2 (e.g., 1) R c Replace, or where Y 4 is unsubstituted C 6-10 Aryl such as unsubstituted phenyl; and R c , when present, as defined in any one of claims 73-75.

[0856] In some embodiments of [1], when R 3 One occurrence is -L 4 -R4 ; and R 4 Yes 3 ) p -Y 4 , Y 4 It is C 6-10 Aryl, which is optionally substituted by 1 to 4 R c Substituted, such as phenyl, optionally with 1-4 R c Replace; and each occurrence of R c , when present, is independently selected from:

[0857] (vii)C 1-4 Alkoxy;

[0858] (viii)C 1-4 haloalkoxy; and

[0859] (xiv)-C 1-4 Thioalkoxy.

[0860] In some embodiments of [1], when R 3 One occurrence is -L 4 -R 4 ; and R 4 Yes 3 ) p -Y 4 , Y 4 As defined in any one of claims 77, 78, 79, 81, and 82, and wherein R b , when present, as defined in claim 80.

[0861] In some embodiments of [1], when R 3 One occurrence is -L 4 -R 4 ; and R 4 Yes 3 ) p -Y 4 , Y 4 As defined in any one of claims 77 to 79; and R b , when present, as defined in claim 80.

[0862] In some embodiments of [1], when R 3 One occurrence is -L 4 -R 4 ; and R 4 Yes 3 ) p -Y 4 , Y 4 As defined in any one of claims 83 to 85 and 88; and R c, when present, as defined in any one of claims 86-87.

[0863] In some embodiments of [1], when R 3 One occurrence is -L 4 -R 4 ; and R 4 Yes 3 ) p -Y 4 , Y 4 As defined in any one of claims 83-85 and 88.

[0864] In some embodiments of [1], when R 3 One occurrence is -L 4 -R 4 ; and R 4 Yes 3 ) p -Y 4 , Y 4 As defined in any one of claims 89 to 96; and R b , when present, as defined in any one of claims 97-98.

[0865] In some embodiments of [1], when R 3 One occurrence is -L 4 -R 4 ; and R 4 Yes 3 ) p -Y 4 , Y 4 As defined in any one of claims 89 to 92, 94 or 96; and R b , when present, as defined in claim 98.

[0866] In some embodiments of [1], R 4 Selected from the structures defined in claims 99-113.

[0867] In some embodiments of [1], R 4 Selected from the structures defined in claims 100, 101, 104-105, 107, 109, 111, and 113.

[0868] In some embodiments of [1], when R 3 One occurrence is -L 4 -R 4 hour,

[0869] ·R 4 It is C 1-10 Alkyl, which is optionally substituted by 1-6 independently selected R aReplace, or

[0870] ·R 4 It is C 1-6 Alkyl, which is optionally substituted by 1-6 independently selected R a Replace, or

[0871] ·R 4 It is C 1-6 Alkyl, optionally with 1-2 independently selected R a Substitution, such as where R 4 Selected from: methyl, ethyl, (such as methyl and );or

[0872] ·R 4 It is C 2-10 Alkynyl (e.g., C 2-4 alkynyl), which is optionally substituted with 1-6 (e.g., 1-3) independently selected R a Substitution (e.g., unsubstituted C 2-4 Alkynyl, such as );or

[0873] ·R 4 It is C 2-10 Alkenyl (e.g., C 2-4 alkenyl), which is optionally substituted by 1-6 (e.g., 1-3) independently selected R a Substitution (e.g., unsubstituted C 2-4烯基 , such as vinyl); and

[0874] 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.

[0875] In some embodiments of [1], when R 3 One occurrence is -L 4 -R 4 hour,

[0876] ·R 4 It is C 1-10 Alkyl, which is optionally substituted by 1-6 independently selected R a Replace, or

[0877] ·R 4 It is C 1-6 Alkyl, which is optionally substituted by 1-6 independently selected R a Replace, or

[0878] ·R 4It is C 1-6 Alkyl, optionally with 1-2 independently selected R a Substitution, such as methyl and as well as

[0879] Each R a , when present, is independently selected from: -F; -OH; C 1-4 Alkoxy; and C 1-4 Haloalkoxy, such as -OH.

[0880] In some embodiments of [1], when R 3 One occurrence is -L 4 -R 4 When R 4 As defined in any of claims 56-60 and 61-63 of US 62 / 742,218 filed on October 5, 2018.

[0881] In some embodiments of [1], when R 3 One occurrence is -L 4 -R 4 When R 4 As defined in any of claims 56-60 and 64-67 of US 62 / 742,218 filed on October 5, 2018.

[0882] In some embodiments of [1], when R 3 One occurrence is -L 4 -R 4 When R 4 As defined in any of claims 56-60 and 68-71 of US 62 / 742,218 filed on October 5, 2018.

[0883] In some embodiments of [1], when R 3 One occurrence is -L 4 -R 4 When R 4 As defined in any of claims 56-60 and 72-78 of US 62 / 742,218 filed on October 5, 2018.

[0884] In some embodiments of [1], when R 3 One occurrence is -L 4 -R 4 When R 4 As defined in any of claims 56-60 and 79-86 of US 62 / 742,218 filed on October 5, 2018.

[0885] In some embodiments of [1], when R3 One occurrence is -L 4 -R 4 When R 4 As defined in any of claims 56-60 and 87-92 of US 62 / 742,218 filed on October 5, 2018.

[0886] In certain embodiments of [1], -L 4 Selected from -N(H)S(O) 2 -、-N(H)S(O) 2 N(H)-、-N(H)S(O) 2 N(R d )-、C≡C、single bond、-C(O)N(H)-、-N(H)-、-N(R 4 )-、-N(R d )-, and -N(H)C(O)-; and

[0887] R 4 Selected from:

[0888] (i)C 1-6 Alkyl, optionally with 1-2 R a replace;

[0889] (ii)-(Y 3 ) p -Y 4 ;and

[0890] (iii)C 2-10 Alkenyl or C 2-10 Alkynyl, each of which is optionally substituted by 1-3 independently selected R a replace.

[0891] In certain embodiments of [1], -L 4 Selected from -N(H)S(O) 2 -、-N(H)S(O) 2 N(H)-, and -N(H)S(O) 2 N(R d )-;and

[0892] R 4 Selected from:

[0893] (i)C 1-6 Alkyl, optionally with 1-2 R a replace;

[0894] (ii)-(Y 3 ) p -Y 4 ;and

[0895] (iii)C 2-10 Alkenyl or C 2-10 Alkynyl, each of which is optionally substituted by 1-3 independently selected R a replace.

[0896] In some embodiments of [1], R 3 Selected from the structures defined in claims 148-165; or wherein R 3 Selected from the structures defined in claims 148-149, 151, 153, 155-156, 158, 160, 162, and 165.

[0897] 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.

[0898] [1-1]

[0899] In some embodiments of [1], X 2 and X 3 Each is an 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 of is N. In certain of the foregoing embodiments, each R 3 Is independently selected -L 4 -R 4 .

[0900] In some embodiments of [1-1], -L 4 -R 4 One occurrence is -R 4 (i.e., L 4 One occurrence of is the key).

[0901] In certain of these embodiments, -L 4 Other occurrences of are selected from:

[0902] -N(H)S(O) 1-2 -or-N(R d )S(O) 1-2 (For example, N(C 1-3 Alkyl)S(O) 2 ), such as where L 4 Yes-N(H)S(O) 2 -;

[0903] -N(H)C(O)- or -N(R d)C(O), such as where L 4 is -N(H)C(O)-;

[0904] -C(O)NH- or -C(O)N(R d )-;

[0905] -N(H)-, -N(R d )-, or -N(R 4 )-;

[0906] ·single bond;

[0907] C≡C;

[0908] -O-; and

[0909] -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 Yes-N(H)S(O) 1-2 N(H)-(e.g., -N(H)S(O) 2 N(H)-) or L 4 Yes-N(H)S(O) 1-2 N(R d )-(e.g., -N(H)S(O) 2 N(R d )-(e.g., -N(H)S(O) 2 N(C 1-3烷基 )-)).

[0910] In certain embodiments, -L 4 Other occurrences of are selected from:

[0911] -N(H)S(O) 1-2 -or-N(R d )S(O) 1-2 (For example, N(C 1-3 Alkyl)S(O) 2 ), such as where L 4 Yes-N(H)S(O) 2 -;

[0912] -N(H)C(O)- or -N(R d )C(O), such as where L 4 is -N(H)C(O)-;

[0913] -C(O)NH- or -C(O)N(R d )-;

[0914] -N(H)-, -N(R d )-, or -N(R 4 )-;

[0915] Single key; and

[0916] ·C≡C.

[0917] In certain embodiments, -L 4 Other occurrences of are selected from:

[0918] -N(H)S(O) 2 -;

[0919] -N(H)C(O)-; and

[0920] -N(H)-, -N(R d )-, or-N(R 4 )-, such as where -L 4 Other occurrences are N(H)S(O) 2 -.

[0921] In certain embodiments, -L 4 Other occurrences of are selected from:

[0922] -N(H)S(O) 1-2 -or-N(R d )S(O) 1-2 (For example, N(C 1-3 Alkyl)S(O) 2 ), such as where L 4 Yes-N(H)S(O) 2 -;as well as

[0923] -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 Yes-N(H)S(O) 1-2 N(H)-(e.g., -N(H)S(O) 2 N(H)-) or L 4 Yes-N(H)S(O)1-2 N(R d )-(e.g., -N(H)S(O) 2 N(R d )-(e.g., -N(H)S(O) 2 N(C 1-3烷基 )-)).

[0924] In certain of the foregoing embodiments, -L 4 Other occurrences of are as defined in any of claims 48-55 of US 62 / 742,218 filed on October 5, 2018. For example, -L 4 Other occurrences of may be as defined in any of claims 49, 51, and 53 filed on October 5, 2018 (e.g., claim 49).

[0925] In some embodiments of [1-1], each R 4 Independently as defined in any one of claims 56-60 and 61-63 of US 62 / 742,218 filed on October 5, 2018.

[0926] In some embodiments of [1-1], each R 4 Independently as defined in any one of claims 56-60 and 64-67 of US 62 / 742,218 filed on October 5, 2018.

[0927] In some embodiments of [1-1], each R 4 Independently as defined in any one of claims 56-60 and 68-71 of US 62 / 742,218 filed on October 5, 2018.

[0928] In some embodiments of [1-1], each R 4 Independently as defined in any one of claims 56-60 and 72-78 of US 62 / 742,218 filed on October 5, 2018.

[0929] In some embodiments of [1-1], each R 4 Independently as defined in any one of claims 79-86 of US 62 / 742,218 filed on October 5, 2018.

[0930] In some embodiments of [1-1], each R 4 Independently as defined in any one of claims 87-92 of US 62 / 742,218 filed on October 5, 2018.

[0931] In some embodiments of [1-1], R1 As defined in any of claims 10-23 of US 62 / 742,218 filed on October 5, 2018.

[0932] In some embodiments of [1-1], R 1 As defined in any of claims 16-23 of US 62 / 742,218 filed on October 5, 2018.

[0933] In some embodiments of [1-1], R 1 As defined in claim 23 of US 62 / 742,218 filed on October 5, 2018.

[0934] In some embodiments of [1-1], R2 is defined as any one of claims 24-31 of US 62 / 742,218 filed on October 5, 2018.

[0935] In some embodiments of [1-1], R2 is defined as any one of claims 27-31 of US 62 / 742,218 filed on October 5, 2018.

[0936] In some embodiments of [1-1], R 2 As defined in any of claims 32-37 (e.g., 34-37) of US 62 / 742,218 filed on October 5, 2018.

[0937] [1-2]

[0938] In some embodiments of [1], X 2 and X 3 Each is an 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 of is N.

[0939] In some embodiments of [1-2], R 3 One occurrence is -L 4 -R 4 (For example, -L 4 as defined in claim 49); and R 3 Other occurrences of R c’ (For example, R c’ It can be a halogen such as -Cl).

[0940] In certain of these embodiments, -L 4Selected from:

[0941] -N(H)S(O) 1-2 -or-N(R d )S(O) 1-2 (For example, N(C 1-3 Alkyl)S(O) 2 ), such as where L 4 Yes-N(H)S(O) 2 -;

[0942] -N(H)C(O)- or -N(R d )C(O), such as where L 4 is -N(H)C(O)-;

[0943] -C(O)NH- or -C(O)N(R d )-;

[0944] -N(H)-, -N(R d )-, or -N(R 4 )-;

[0945] ·single bond;

[0946] C≡C;

[0947] -O-; and

[0948] -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 Yes-N(H)S(O) 1-2 N(H)-(e.g., -N(H)S(O) 2 N(H)-) or L 4 Yes-N(H)S(O) 1-2 N(R d )-(e.g., -N(H)S(O) 2 N(R d )-(e.g., -N(H)S(O) 2 N(C 1-3烷基 )-)).

[0949] In certain embodiments, -L 4 Selected from:

[0950] -N(H)S(O)1-2 -or-N(R d )S(O) 1-2 (For example, N(C 1-3 Alkyl)S(O) 2 ), such as where L 4 Yes-N(H)S(O) 2 -;

[0951] -N(H)C(O)- or -N(R d )C(O), such as where L 4 is -N(H)C(O)-;

[0952] -C(O)NH- or -C(O)N(R d )-;

[0953] -N(H)-, -N(R d )-, or -N(R 4 )-;

[0954] Single key; and

[0955] ·C≡C.

[0956] In certain embodiments, -L 4 Selected from:

[0957] -N(H)S(O) 2 -;

[0958] -N(H)C(O)-; and

[0959] -N(H)-, -N(R d )-, or-N(R 4 )-, such as where -L 4 Other occurrences are N(H)S(O) 2 -.

[0960] In certain embodiments, -L 4 Selected from:

[0961] -N(H)S(O) 1-2 -or-N(R d )S(O) 1-2 (For example, N(C 1-3 Alkyl)S(O) 2 ), such as where L 4 Yes-N(H)S(O) 2 -;as well as

[0962] -N(H)S(O) 1-2 N(H)-、-N(R d )S(O) 1-2N(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 Yes-N(H)S(O) 1-2 N(H)-(e.g., -N(H)S(O) 2 N(H)-) or L 4 Yes-N(H)S(O) 1-2 N(R d )-(e.g., -N(H)S(O) 2 N(R d )-(e.g., -N(H)S(O) 2 N(C 1-3烷基 )-)).

[0963] In certain of the foregoing embodiments, -L 4 Other occurrences of are as defined in any of claims 48-55 of US 62 / 742,218 filed on October 5, 2018. For example, -L 4 Other occurrences of may be as defined in any of claims 49, 51, and 53 filed on October 5, 2018 (e.g., claim 49).

[0964] In some embodiments of [1-2], each R 4 Independently as defined in any one of claims 56-60 and 61-63 of US 62 / 742,218 filed on October 5, 2018.

[0965] In some embodiments of [1-2], each R 4 Independently as defined in any one of claims 56-60 and 64-67 of US 62 / 742,218 filed on October 5, 2018.

[0966] In some embodiments of [1-2], each R 4 Independently as defined in any one of claims 56-60 and 68-71 of US 62 / 742,218 filed on October 5, 2018.

[0967] In some embodiments of [1-2], each R 4 Independently as defined in any one of claims 56-60 and 72-78 of US 62 / 742,218 filed on October 5, 2018.

[0968] In some embodiments of [1-2], each R4 Independently as defined in any one of claims 79-86 of US 62 / 742,218 filed on October 5, 2018.

[0969] In some embodiments of [1-2], each R 4 Independently as defined in any one of claims 87-92 of US 62 / 742,218 filed on October 5, 2018.

[0970] In some embodiments of [1-2], R 1 As defined in any of claims 10-23 of US 62 / 742,218 filed on October 5, 2018.

[0971] In some embodiments of [1-2], R 1 As defined in any of claims 16-23 of US 62 / 742,218 filed on October 5, 2018.

[0972] In some embodiments of [1-2], R 1 As defined in claim 23 of US 62 / 742,218 filed on October 5, 2018.

[0973] In some embodiments of [1-2], R2 is defined as any one of claims 24-31 of US 62 / 742,218 filed on October 5, 2018.

[0974] In some embodiments of [1-2], R2 is defined as any one of claims 27-31 of US 62 / 742,218 filed on October 5, 2018.

[0975] In some embodiments of [1-2], R 2 As defined in any of claims 32-37 (e.g., 34-37) of US 62 / 742,218 filed on October 5, 2018.

[0976] Unrestricted combination[2]

[0977] In some embodiments, the compound of formula (I) is of formula (I-a1-a):

[0978]

[0979] or a pharmaceutically acceptable salt thereof.

[0980] In some embodiments of [2], -L 4 Selected from:

[0981] -N(H)S(O) 1-2 -or-N(R d )S(O) 1-2 (For example, N(C 1-3 Alkyl)S(O) 2 ), such as where L 4 Yes-N(H)S(O) 2 -;as well as

[0982] -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 Yes-N(H)S(O) 1-2 N(H)-(e.g., -N(H)S(O) 2 N(H)-) or L 4 Yes-N(H)S(O) 1-2 N(R d )-(e.g., -N(H)S(O) 2 N(R d )-(e.g., -N(H)S(O) 2 N(C 1-3烷基 )-)).

[0983] In certain embodiments of [2], the compound of formula (I-a1-a) is formula (I-a1-a1):

[0984]

[0985] or a pharmaceutically acceptable salt thereof.

[0986] In certain embodiments of [2], the compound of formula (I-a1-a) is formula (I-a1-a2):

[0987]

[0988] or a pharmaceutically acceptable salt thereof.

[0989] In certain embodiments of [2], the compound of formula (I-a1-a) is formula (I-a1-a3):

[0990] (For example, R c’ is a halogen, e.g., -Cl);

[0991] or a pharmaceutically acceptable salt thereof.

[0992] In certain of the foregoing embodiments of [2], R 1 As defined in any one of claims 10-23 of US62 / 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 of claims 56-92 of US 62 / 742,218 filed on October 5, 2018.

[0993] In certain embodiments of [2], the compound of formula (I-a1-a) is formula (I-a1-a4):

[0994] (For example, R 3 YesR c’ ; or R 3 Yes-L 4 -R 4 );

[0995] or a pharmaceutically acceptable salt thereof. In certain embodiments of formula (I-a1-a4), L 3 Yes NHS(O) 2 .

[0996] In certain embodiments of Formula (I-a1-a4), R 3 It's H.

[0997] In certain embodiments of Formula (I-a1-a4), R 3 YesR c’ , such as halogen (e.g., -Cl).

[0998] In certain embodiments of Formula (I-a1-a4), R 3 Yes-L 4 -R 4 .

[0999] In certain of the foregoing embodiments of [2] (eg, when the compound has formula (I-a1-a4)), L 4 As defined in any one of claims 48-55 of US 62 / 742,218 filed on October 5, 2018; and / or R 4As defined in any 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 US Claims 56-60 and 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.

[1000] [2-1]

[1001] In some embodiments of [2], the compound of formula (I-a1-a) is formula (I-a1-a5):

[1002] or a pharmaceutically acceptable salt thereof.

[1003] In some embodiments of [2-1], R c’ is a halogen (eg, -Cl).

[1004] In some embodiments of [2-1], R 1 As defined in any of claims 10-23 of US 62 / 742,218 filed on October 5, 2018.

[1005] In some embodiments of [2-1], R 2 As defined in any of claims 24-37 (e.g., claims 24-31) of US 62 / 742,218 filed on October 5, 2018.

[1006] In some embodiments of [2-1], R4 is as defined in 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 Yes - NHS(O) 2 -.

[1007] In some embodiments of [2-1], L 4 Yes-N(H)S(O)2 N(H)- or -N(H)S(O) 2 N(R d )-.

[1008] [2-2]

[1009] In some embodiments of [2], the compound of formula (I-a1-a) is formula (I-a1-a6):

[1010]

[1011] Where L 4A and L 4B Each of the L is independently selected 4 ;and

[1012] R 4A and R 4B Each of the R 4 ;

[1013] or a pharmaceutically acceptable salt thereof.

[1014] In some embodiments of [2-2], L 4B is the key.

[1015] In some embodiments of [2-2], R 1 As defined in any of claims 10-23 of US 62 / 742,218 filed on October 5, 2018.

[1016] In some embodiments of [2-2], R 2 As defined in any of claims 24-37 (e.g., claims 24-31) of US 62 / 742,218 filed on October 5, 2018.

[1017] In some embodiments of [2-2], R 4A As defined in any of claims 56-92 of US 62 / 742,218 filed on October 5, 2018.

[1018] In some embodiments of [2-2], L 4A Yes - NHS(O) 2 -.

[1019] In some embodiments of [2-2], L 4 Yes-N(H)S(O) 2 N(H)- or -N(H)S(O) 2 N(R d )-.

[1020] In some embodiments of [2-2], R 4B As defined in any of claims 56-92 (e.g., claims 56-60 and 64-67) of US 62 / 742,218 filed on October 5, 2018.

[1021] [2-3]

[1022] In some embodiments of [2], the compound of formula (I-a1-a) is formula (I-a1-a7), (I-a1-a8) or (I-a1-a9):

[1023]

[1024] Where R d’ Is H or R d (For example, H or C 1-3 alkyl); or a pharmaceutically acceptable salt thereof.

[1025] Unrestricted combination[3]

[1026] In some embodiments, the compound of formula (I) is of formula (I-a1-b):

[1027]

[1028] or a pharmaceutically acceptable salt thereof.

[1029] In certain embodiments of [3], the compound of formula (I-a1-b) is formula (I-a1-b1) or formula (I-a1-b2):

[1030] (For example, L 4 is N(H)SO 2 , -N(H)-, or NHC(O));

[1031] or a pharmaceutically acceptable salt thereof.

[1032] In some embodiments of [3], -L 4 Selected from:

[1033] -N(H)S(O) 1-2 -or-N(R d )S(O) 1-2 (For example, N(C 1-3 Alkyl)S(O) 2 ), such as where L 4 Yes-N(H)S(O) 2 -;as well as

[1034] -N(H)S(O) 1-2N(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 Yes-N(H)S(O) 1-2 N(H)-(e.g., -N(H)S(O) 2 N(H)-) or L 4 Yes-N(H)S(O) 1-2 N(R d )-(e.g., -N(H)S(O) 2 N(R d )-(e.g., -N(H)S(O) 2 N(C 1-3烷基 )-)).

[1035] In certain of the aforementioned embodiments of [3], R 1 As defined in any one of claims 10-23 of US62 / 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 of claims 56-92 of US 62 / 742,218 filed on October 5, 2018.

[1036] In certain of the aforementioned embodiments of [3], R c 'Selected from halogen (e.g., Cl, Br), -OH, and NH 2 .

[1037] Unrestricted combination[4]

[1038] In some embodiments, the compound of formula (I) is of formula (I-a2-a):

[1039]

[1040] or a pharmaceutically acceptable salt thereof.

[1041] In certain embodiments of [4], the compound of formula (I-a2-a1) is a compound of formula (I-a2-a1):

[1042]

[1043] or a pharmaceutically acceptable salt thereof.

[1044] In certain of the aforementioned embodiments of [4], R 1 As defined in any one of claims 10-23 of US62 / 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 of claims 56-92 of US 62 / 742,218 filed on October 5, 2018.

[1045] In certain embodiments of [4], the compound of formula (I-a2-a) is formula (I-a1-a2):

[1046] (For example, L 4 Yes NHS(O) 2 );

[1047] or a pharmaceutically acceptable salt thereof.

[1048] In certain of the foregoing embodiments of [4] (eg, when the compound has formula (I-a2-a2)), L 4 As defined in any one of claims 48-55 (e.g., 49) of US 62 / 742,218 filed on October 5, 2018; and / or R 4 As defined in any 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 US 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.

[1049] Unrestricted combination[5]

[1050] In some embodiments, the compound of formula (I) is formula (I-b1-a):

[1051]

[1052] or a pharmaceutically acceptable salt thereof.

[1053] In certain embodiments of [5], the compound of formula (I-b1-a) is formula (I-b1-a1):

[1054]

[1055] or a pharmaceutically acceptable salt thereof.

[1056] In certain of the aforementioned embodiments of [5], R 1 As defined in any one of claims 10-23 of US62 / 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 of claims 56-92 of US 62 / 742,218 filed on October 5, 2018.

[1057] In certain embodiments of [5], the compound of formula (I-b1-a) is formula (I-b1-a3):

[1058]

[1059] Where R d’ Is H or R d (For example, H or C 1-3 alkyl); or a pharmaceutically acceptable salt thereof.

[1060] In certain embodiments of [5], the compound of formula (I-b1-a) is formula (I-b1-a2):

[1061] (For example, L 4 Yes NHS(O) 2 );

[1062] or a pharmaceutically acceptable salt thereof.

[1063] In certain embodiments of Formula (I-b1-a2), L 4 Yes NHS(O) 2 .

[1064] In certain of the foregoing embodiments of [5] (eg, when the compound has formula (I-b1-a2)), L4 As defined in any one of claims 48-55 (e.g., 49) of US 62 / 742,218 filed on October 5, 2018; and / or R 4 As defined in any 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 US 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.

[1065] Unrestricted combination[6]

[1066] In some embodiments, the compound of formula (I) is of formula (I-c1-a):

[1067]

[1068] or a pharmaceutically acceptable salt thereof.

[1069] In certain embodiments of [6], the compound of formula (I-c1-a) is formula (I-c1-a1):

[1070]

[1071] or a pharmaceutically acceptable salt thereof.

[1072] In certain of the aforementioned embodiments of [6], R 1 As defined in any one of claims 10-23 of US62 / 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 of claims 56-92 of US 62 / 742,218 filed on October 5, 2018.

[1073] In certain embodiments of [6], the compound of formula (I-c1-a) is formula (I-c1-a2):

[1074] (For example, L 4 Yes NHS(O) 2 );

[1075] or a pharmaceutically acceptable salt thereof.

[1076] In certain of the foregoing embodiments of [6] (eg, when the compound has formula (I-c1-a2)), L 4 As defined in any one of claims 48-55 (e.g., 49) of US 62 / 742,218 filed on October 5, 2018; and / or R 4 As defined in any 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 US 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.

[1077] Unrestricted combination[7]

[1078] In some embodiments, the compound of formula (I) is of formula (I-d1-a):

[1079]

[1080] or a pharmaceutically acceptable salt thereof.

[1081] In certain embodiments of [7], the compound of formula (I-d1-a) is formula (I-d1-a1):

[1082]

[1083] or a pharmaceutically acceptable salt thereof.

[1084] In certain embodiments of [7], 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 of claims 56-92 of US 62 / 742,218 filed on October 5, 2018.

[1085] In certain embodiments of [7], the compound of formula (I-d1-a) is formula (I-d1-a2):

[1086] (For example, L 4 Yes NHS(O) 2 );

[1087] or a pharmaceutically acceptable salt thereof.

[1088] In certain of the foregoing embodiments of [7] (eg, when the compound has formula (I-c1-a2)), L 4 As defined in any one of claims 48-55 (e.g., 49) of US 62 / 742,218 filed on October 5, 2018; and / or R 4 As 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 65-66 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.

[1089] 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 Selected from:

[1090] (i)C 1-10 Alkyl, optionally with 1-6 independently selected R a replace;

[1091] (ii)-(Y 3 ) p -Y 4 ;and

[1092] (iii)C 2-10 Alkenyl or C 2-10 Alkynyl, each of which is optionally substituted by 1-3 independently selected R a replace.

[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], R 4 Yes-(Y 3 ) p -Y 4 .

[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 Yes-(Y 3 ) p -Y 4 When Y 4 It is C 6-10 Aryl, which is optionally substituted by 1 to 4 R c Substituted, such as phenyl, which is optionally substituted with 1-2 (e.g., 1) R c Replace, or where Y 4 is unsubstituted C 6-10 Aryl such as unsubstituted phenyl; and R c , when present, as defined in any of claims 73-75 (e.g., claim 75).

[1095] 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 Yes-(Y 3 ) p -Y4 When Y 4 It is C 6-10 Aryl, which is optionally substituted by 1 to 4 R c Substituted, such as phenyl, optionally with 1-4 R c Replace; and each occurrence of R c , when present, is independently selected from:

[1096] (vii)C 1-4 Alkoxy;

[1097] (viii)C 1-4 haloalkoxy; and

[1098] (xiv)-C 1-4 Thioalkoxy.

[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 Yes-(Y 3 ) p -Y 4 When Y 4 As defined in any one of claims 77, 78, 79, 81, and 82, and wherein R b , when present, 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 Yes-(Y 3 ) p -Y 4 When Y 4 As defined in any one of claims 77 to 79; and R b , when present, as defined in claim 80.

[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 Yes-(Y 3 ) p -Y 4 When Y 4 As defined in any one of claims 83 to 85 and 88; and R c , when present, as defined in any one of claims 86-87.

[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 Yes-(Y 3 ) p -Y 4 When Y 4 As defined in any one of claims 83-85 and 88.

[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 Yes-(Y 3 ) p -Y 4 When Y 4 As defined in any one of claims 89 to 96; and R b , when present, as defined in any one of claims 97-98.

[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 Yes-(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.

[1105] 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 Yes-(Y 3 ) p -Y 4 When , p is 0.

[1106] In other embodiments, p is 1. In certain of these embodiments, Y 3 It is C 1-3 Alkylene, such as CH 2 or CH 2 -CH 2 .

[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], R 4 Selected from the structures defined in claims 99-113.

[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], each R 4 Selected from the structures defined in claims 100, 101, 104-105, 107, 109, 111, and 113.

[1109] 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],

[1110] ·R 4 It is C 1-10 Alkyl, which is optionally substituted by 1-6 independently selected R a Replace, or

[1111] ·R 4 It is C 1-6 Alkyl, which is optionally substituted by 1-6 independently selected R a Replace, or

[1112] ·R 4 It is C 1-6 Alkyl, optionally with 1-2 independently selected R a Substitution, such as where R 4 Selected from:

[1113] Methyl, ethyl, (such as methyl and );or

[1114] ·R 4 It is C 2-10 (For example, C 2-4 alkynyl) alkynyl, which is optionally substituted with 1-6 (e.g., 1-3) independently selected R a Substitution (e.g., unsubstituted C 2-4 Alkynyl, such as );or

[1115] ·R 4 It is C 2-10 (For example, C 2-4 alkenyl)alkenyl, which is optionally substituted by 1-6 (e.g., 1-3) independently selected R aSubstitution (e.g., unsubstituted C 2-4烯基 , such as vinyl); and

[1116] 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.

[1117] 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],

[1118] ·R 4 It is C 1-10 Alkyl, which is optionally substituted by 1-6 independently selected R a Replace, or

[1119] ·R 4 It is C 1-6 Alkyl, which is optionally substituted by 1-6 independently selected R a Replace, or

[1120] ·R 4 It is C 1-6 Alkyl, optionally with 1-2 independently selected R a Substitution, such as methyl and as well as

[1121] Each R a , when present, is independently selected from: -F; -OH; C 1-4 Alkoxy; and C 1-4 Haloalkoxy, such as -OH.

[1122] 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 Yes-(Y 1 ) n -Y 2 .

[1123] In certain of these embodiments, Y 2 As defined in any one of claims 14 to 20; and each R c , when present, is independently as defined in any one of claims 21-24.

[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 Yes-(Y 1 ) n -Y 2 When Y 2 As defined in any one of claims 14 to 18 and 26; and each R c , when present, as defined in any one of claims 21 to 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 Yes-(Y 1 ) n -Y 2 When Y 2 As defined in any one of claims 16 to 18; and each R c , when present, as defined in any one of claims 21 to 23.

[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 Yes-(Y 1 ) n -Y 2 When , n is 0.

[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], when R 1 Yes-(Y 1 ) n -Y 2 When R 1 yes As a non-limiting example, R 1 Can be

[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 It is C 6-10 Aryl, which is optionally substituted by 1 to 4 Rc Substituted, such as phenyl, which is optionally substituted with 1-4 R c or 1-2 R c or 2 R c Replace; and R c , when present, as defined in any one of claims 33 to 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 2 is phenyl, which is optionally substituted with 2 R c Substitution, such as where R 2 yes And R c , when present, as defined in any one of claims 33 to 35.

[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 a heteroaryl group containing 5-10 (e.g. 6) ring atoms, wherein 1-4 (e.g. 1-3) 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 wherein one or more heteroaryl ring carbon atoms are optionally replaced by 1-4 independently selected R c Substitution, such as where R 2 is optionally 1-2 independently selected R c Substituted pyridyl, or where R 2 yes And R c , when present, as defined in any one of claims 40-41.

[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 2 yes

[1132] 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 Yes-(Y 1 ) n -Y 2; and R 2 It is C 6-10 Aryl, which is optionally substituted by 1 to 4 R c replace.

[1133] In certain of these embodiments, n is zero.

[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 Yes-(Y 1 ) n -Y 2 When Y 2 is a heteroaryl group containing 6 ring atoms, wherein 1-2 ring atoms are N, and wherein one or more heteroaryl ring carbon atoms are optionally replaced by 1-4 independently selected R c replace.

[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 Yes-(Y 1 ) n -Y 2 When Y 2 is pyridyl (eg, 2-pyridyl or 6-pyridyl), wherein one or more ring carbon atoms are optionally replaced by 1-4 (eg, 1) independently selected R c replace.

[1136] 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 Yes-(Y 1 ) n -Y 2 ; and Y 2 is optionally 1-4 independently selected R as defined above c When the heteroaryl group is substituted (such as pyridyl), R c Each occurrence of is independently selected C 1-4 Alkoxy (e.g., -OCH 3 , -OCH 2 CH 3 ).

[1137] As a non-limiting example, R 1 yes:.

[1138] 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 Yes-(Y 1 ) n -Y 2 ; and R 2 It is C 6-10 Aryl, which is optionally substituted by 1 to 4 R c Replacement), such as R 2 is phenyl, which is optionally replaced by 1 to 4 R c replace.

[1139] In certain of these embodiments, R 2 is phenyl, which is optionally substituted with 2 R c For example, R 2 It can be:.

[1140] 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 yes And R 2 yes

[1141] The specification ends with 302 claims. For ease of exposition, the definitions of certain variables refer to one or more specific claim numbers, and therefore, it should be understood that the entire subject matter of each claim referenced is incorporated by reference in its entirety into the section of this disclosure in which it is referenced. For the avoidance of doubt and as a non-limiting example, the use of phrases (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:

[1142] Y 4 It is C 3-6 (For example, C 3-4 or C 6 ) cycloalkyl, which is optionally substituted by 1 to 4 R b replace.

[1143] Y 4 is cyclopropyl or cyclobutyl, which is optionally substituted by 1-2 R b replace.

[1144] Y 4 It is C 6 Cycloalkyl (e.g., cyclohexyl), which is optionally substituted with 1-2 R b replace.

[1145] Y 4 It is C 3-6 (For example, C 3-4 or C 6 )cycloalkyl, which is unsubstituted.

[1146] Y 4 is unsubstituted cyclopropyl or unsubstituted cyclobutyl (eg, unsubstituted cyclopropyl).

[1147] Y 4 Selected from C 3-6 (For example, C 3-4 or C 6 ) cycloalkyl, which is optionally substituted by 1 to 4 R b Substituted; cyclopropyl or cyclobutyl, which is optionally substituted by 1-2 R b Replace; C 6 Cycloalkyl (e.g., cyclohexyl), which is optionally substituted with 1-2 R b Replace; C 3-6 (For example, C 3-4 or C 6 )cycloalkyl, which is unsubstituted; and unsubstituted cyclopropyl or unsubstituted cyclobutyl (eg, unsubstituted cyclopropyl).

[1148] The same applies to the claims cited in priority document US 62 / 742,218 filed on October 5, 2018.

[1149] Pharmaceutical compositions and administration

[1150] Overview

[1151] In some embodiments, a chemical entity (e.g., a compound or a pharmaceutically acceptable salt and / or hydrate and / or prodrug of a compound) that modulates (e.g., agonizes) an APJ receptor is administered as a pharmaceutical composition comprising the chemical entity and one or more pharmaceutically acceptable excipients, and optionally one or more additional therapeutic agents described herein.

[1152] 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-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms, such as Tweens, poloxamers or other similar polymer delivery matrices, serum proteins, such as human serum albumin, buffer substances, such as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or dielectrics, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-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-cyclodextrins, or other solubilized derivatives can also be used to improve the delivery of the compounds described herein. Dosage forms or compositions containing the chemical entities described herein in the range of 0.005%-100% can be prepared, with the remainder being made up by non-toxic excipients. The contemplated composition may contain 0.001%-100% of the chemical entities provided herein, in one embodiment 0.1-95%, in another embodiment 75-85%, and in yet another embodiment 20-80%. The actual method of preparing such a dosage form is known or understood by those skilled in the art; for example, see Remington: The Science and Practice of Pharmacy, 22nd Edition (Pharmaceutical Press, London, England, 2012).

[1153] Routes of administration and composition components

[1154] In some embodiments, the chemical entities described herein or pharmaceutical compositions thereof can be administered to a subject in need thereof by any acceptable route of administration. Acceptable routes of administration include, but are not limited to, buccal, transdermal, intracervical, intrasinus, intratracheal, enteral, epidural, interstitial, intraperitoneal, intraarterial, intrabronchial, intrabursal, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinus, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumor, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, transdermal, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral, ​​and vaginal.

[1155] The composition can be formulated for parenteral administration, for example, for injection by intravenous, intramuscular, subcutaneous or even intraperitoneal routes. Generally, such compositions can be prepared as injections, in the form of liquid solutions or suspensions; solid forms suitable for adding liquids to prepare solutions or suspensions before injection can also be prepared; and the preparations can also be emulsified. In light of the present disclosure, the preparation of such preparations is known to those skilled in the art.

[1156] Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; including sesame oil, peanut oil or propylene glycol aqueous solution preparations; and sterile powders for the extemporaneous 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 effects of microorganisms such as bacteria and fungi during storage.

[1157] The carrier can also be a solvent or dispersion medium comprising, for example, water, ethanol, a polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, etc.), and suitable mixtures thereof, and vegetable oils. Suitable fluidity can be maintained, for example, by using a coating such as lecithin, by maintaining the desired particle size in the case of a dispersion system, and by using a surfactant. 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, isotonic agents such as sugars or sodium chloride are preferably included. The absorption of the injectable composition can be prolonged by using agents that delay absorption, such as aluminum monostearate and gelatin in the composition.

[1158] Sterile injections are prepared by mixing the required amount of active compound in a suitable solvent with the various other components mentioned above and then filtering and sterilizing as needed. Typically, the various sterile active components are incorporated into a sterile carrier containing an alkaline dispersion medium and the other required ingredients mentioned above to prepare a dispersion. When preparing sterile powders required for sterile injections, the preferred preparation method is vacuum drying and freeze drying techniques to obtain a powder of the active component and any other required components from a previously sterile filtered solution.

[1159] Pharmaceutically acceptable excipients that can be used as gels, creams, enemas or rectal suppositories in rectal compositions include, but are not limited to, one or more of the following: cocoa butter glycerides, synthetic polymers such as polyvinyl pyrrolidone, PEG (such as PEG ointment), glycerin, glycerinated gelatin, 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, parabens in aerosol, phenoxyethanol, sodium methylparaben, sodium propylparaben, diethylamine, carbomer, carbopol, methyl methoxybenzoate, polyethylene glycol cetearyl ether, decyl cocoate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-disulfite, sodium EDTA, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methylsulfonylmethane (MSM), lactic acid, glycine, vitamins (such as vitamin A and E), and potassium acetate.

[1160] In certain embodiments, suppositories can be prepared by mixing the chemical entities described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or suppository wax, which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum and release the active compound. In other embodiments, compositions for rectal administration are in the form of enemas.

[1161] In other embodiments, the compounds described herein, or pharmaceutical compositions thereof, are suitable for local delivery to the digestive or gastrointestinal tract via oral administration (eg, solid or liquid dosage forms).

[1162] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the chemical entity is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate and / or: a) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol and silicic acid, b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia, c) humectants, such as glycerol, d) disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) solubilizers, such as paraffin, f) absorption promoters, such as quaternary ammonium compounds, g) wetting agents, such as cetyl alcohol and glyceryl monostearate, h) absorbents, such as kaolin and bentonite, and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also contain buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or lactose fractions as well as high molecular weight polyethylene glycols.

[1163] In one embodiment, the composition can take the form of a unit dosage form such as a pill or tablet, so the composition can also contain, in addition to the chemical entity provided herein: a diluent such as lactose, sucrose, dicalcium phosphate, etc.; a lubricant such as magnesium stearate, etc.; a binder such as starch, gum arabic, polyvinyl pyrrolidone, gelatin, cellulose, cellulose derivatives, etc. In another solid dosage form, a powder, a pill, a solution or a suspension (e.g., in propylene carbonate, vegetable oil, PEG's, poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin or cellulose-based capsule). It is also possible to consider a unit dosage form in which one or more chemical entities or other active agents provided herein are physically separated, such as a capsule containing each drug particle (or a tablet in a capsule); a double-layer tablet; a double-chamber gel capsule, etc. Enteric-coated or delayed-release oral dosage forms are also considered.

[1164] Other physiologically acceptable compounds include wetting agents, emulsifiers, dispersants or preservatives, which are especially useful for preventing the growth or action of microorganisms. Various preservatives are well known and include, for example, phenol and ascorbic acid.

[1165] In certain embodiments, the excipient is sterile and generally free of undesirable substances. The composition can 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.

[1166] Ophthalmic compositions may include, but are not limited to, any one or more of the following: viscogens (e.g., carboxymethylcellulose, glycerol, polyvinylpyrrolidone, polyethylene glycol); stabilizers (e.g., Pluronic (triblock copolymer), cyclodextrin); preservatives (e.g., benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol and zinc chloride; Alcon Laboratories Inc.), Purite (stabilized chlorine oxide complex; Allergan, Inc.).

[1167] Topical compositions may include ointments and creams. Ointments are semisolid preparations, typically based on petrolatum or other petroleum derivatives. Creams containing the selected active agent are typically viscous liquids or semisolid emulsions, typically oil-in-water or water-in-oil. The cream base is typically washable and comprises an oil phase, an emulsifier, and an aqueous phase. The oil phase, sometimes referred to as the "internal phase," is typically composed of petrolatum and a fatty alcohol (such as cetyl alcohol or stearyl alcohol); although not necessarily, the aqueous phase typically exceeds the volume of the oil phase and typically comprises a wetting agent. The emulsifier in the cream formulation is typically a nonionic, anionic, cationic, or amphoteric surfactant. Like other carriers or vehicles, the ointment base should be inert, stable, non-irritating, and insensitive.

[1168] In any of the foregoing embodiments, the pharmaceutical compositions described herein may comprise one or more of the following: lipids, multilamellar vesicles with crosslinks between bilayers, biodegradable poly (D, L-lactic-co-glycolic acid) [PLGA]-based or polyanhydride-based nanoparticles or microparticles, and nanoporous particle-loaded lipid bilayers.

[1169] dose

[1170] The dosage may vary depending on the needs of the patient, the severity of the disease being treated and the specific compound being used. The appropriate dosage for a particular situation can be determined by a person skilled in the art of medicine. In some cases, the total daily dosage may be divided and administered in portions throughout the day or by providing continuous delivery.

[1171] In some embodiments, the compound described herein is administered at a dose of about 0.001 mg / Kg to about 500 mg / Kg (e.g., about 0.001 mg / Kg to about 200 mg / Kg; about 0.01 mg / Kg to about 200 mg / Kg; about 0.01 mg / Kg to about 150 mg / Kg; about 0.01 mg / Kg to about 100 mg / Kg; about 0.01 mg / Kg to about 50 mg / Kg; about 0.01 mg / Kg to about 10 mg / Kg; about 0.01 mg / Kg to about 5 mg / Kg; about 0.01 mg / Kg to about 1mg / Kg; about 0.01mg / Kg to about 0.5mg / Kg; about 0.01mg / Kg to about 0.1mg / Kg; about 0.1mg / Kg to about 200mg / Kg; about 0.1mg / Kg to about 150mg / Kg; about 0.1mg / Kg to about 100mg / Kg; about 0.1mg / Kg to about 50mg / Kg; about 0.1mg / Kg to about 10mg / Kg; about 0.1mg / Kg to about 5mg / Kg; about 0.1mg / Kg to about 1mg / Kg; about 0.1mg / Kg to about 0.5mg / Kg).

[1172] Dosage

[1173] The foregoing doses can 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).

[1174] 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 is stopped for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or longer. In one embodiment, individual treatment compound is given for a period of time, followed by a separate time period. In another embodiment, treatment compound is given in the first period of time, administration is stopped in the second period of time after the first period of time, then treatment compound is restarted in the third period of time, and then administration is stopped in the fourth period of time after the third period of time. In one aspect of this embodiment, the administration period of treatment compound and the subsequent time period of stopping administration are repeated in a determined or undetermined time period. In another embodiment, administration period is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months or longer. In another embodiment, the time of stopping 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.

[1175] Treatment

[1176] The present disclosure features methods for treating a subject (e.g., a human) having a disease, disorder, or condition in which reduced APJ receptor activity (e.g., blocked or impaired APJ receptor signaling; e.g., blocked or impaired apelin-APJ receptor signaling) or downregulation of endogenous apelin contributes to the pathology and / or symptoms and / or progression of the disease, disorder, or condition. In certain embodiments, the methods described herein may include or further include treating one or more disorders associated with, combined with, or sequelae to any one or more disorders described herein.

[1177] In some embodiments, the method further comprises identifying the subject. In some embodiments, identifying comprises determining the level of one or more of the following parameters in the subject: leukotriene B4 level, pulmonary vascular resistance, pulmonary artery pressure, cardiac index, pulmonary capillary wedge pressure, right atrial pressure, six minute walk distance, brain natriuretic peptide level, cardiac natriuretic peptide, and lung diffusing capacity.

[1178] In certain embodiments, the chemical entities described herein modulate (e.g., reduce) pulmonary vascular resistance, modulate (e.g., reduce) right ventricular afterload, and modulate (e.g., reduce) mean pulmonary artery pressure. In certain embodiments, the chemical entities described herein reduce the risk of right ventricular failure.

[1179] In certain embodiments, the chemical entities described herein modulate vascular tone, modulate fluid homeostasis, modulate renal function, modulate energy metabolism, modulate inflammatory responses, and modulate thrombosis.

[1180] Indications

[1181] Pulmonary hypertension

[1182] 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 disorders, including but not limited to connective tissue diseases (CTDs) (e.g., scleroderma, systemic lupus erythematosus, systemic sclerosis, Hashimoto's thyroiditis, Sjögren's syndrome, antiphospholipid antibody syndrome), HIV infection, portal hypertension, congenital heart disease, and schistosomiasis.

[1183] In some embodiments, the PAH is idiopathic.

[1184] In other embodiments, the PAH is hereditary PAH, toxin- or drug-induced PAH; or PAH associated with one or more of: congenital heart disease, connective tissue disease (e.g., scleroderma, systemic lupus erythematosus, systemic sclerosis, Hashimoto's thyroiditis, Sjögren's syndrome, and antiphospholipid antibody syndrome), portal hypertension, BMPR2 mutations, schistosomiasis, and HIV infection.

[1185] 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 disease (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 disease and / or hypoxia (e.g., chronic obstructive pulmonary disease, interstitial lung disease, other restrictive and obstructive mixed lung diseases, sleep apnea, alveolar ventilation disorders, long-term exposure to high altitude, developmental lung disease), chronic thromboembolic pulmonary hypertension and other pulmonary artery obstructions (e.g., chronic thromboembolic pulmonary hypertension, other pulmonary artery obstructions), and pulmonary hypertension with unclear multifactorial mechanisms (e.g., hematologic diseases, systemic diseases, metabolic disorders, etc.).

[1186] Cardiovascular disease, illness or condition

[1187] 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 pectoris, stroke, cerebrovascular accident, transient ischemic attack, heart failure, cardiomyopathy, myocardial infarction, myocardial remodeling after cardiac surgery, valvular heart disease, hypertension (e.g., systemic hypertension, essential hypertension, pulmonary hypertension, portal hypertension, systolic hypertension), aortic aneurysm (e.g., abdominal aortic aneurysm), atrial fibrillation, arrhythmia, atherosclerosis, Brugada syndrome, ischemic cardiovascular disease, peripheral arterial disease, preeclampsia, ventricular tachycardia and cardiac fibrosis.

[1188] 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).

[1189] In some embodiments, the cardiovascular condition, disease or disorder is a condition, disease or disorder with vascular pathology (e.g., with increased vascular permeability and non-functional blood vessels). Non-limiting examples of such conditions, diseases or disorders include: vascular hypertrophy, vascular remodeling (e.g., vascular stiffness), atherosclerosis, peripheral arterial occlusive disease (PAOD), restenosis (e.g., angioproliferative 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 associated with a vein. Non-limiting examples of such disorders, diseases or disorders include hemangiomas, venous insufficiency, stasis or thrombosis.

[1190] In some embodiments, the chemical entities described herein can improve cardiac contractility (e.g., diastole), ventriculoarterial coupling, positive inotropy, or luistropic function in subjects with cardiovascular disease. In some embodiments, the chemical entities described herein can increase the ejection fraction of subjects with cardiovascular disease.

[1191] Metabolic and homeostatic dysfunction and related conditions, diseases or disorders

[1192] In some embodiments, the condition, disease or disorder is associated with metabolic dysfunction. Non-limiting examples of such condition, disease or disorder include: metabolic dysfunction, obesity, diabetes (e.g., type II diabetes, gestational diabetes), diabetic complications (e.g., metabolic syndrome, insulin resistance, organ damage of microvascular or macrovascular origin, such as macro- and micro-vacuole lesions, diabetic neuropathy, diabetic retinopathy, cardiac autonomic neuropathy), kidney disease (e.g., chronic kidney disease), edema, dyslipidemia, anorexia, hyperphagia, polyphagia, hypercholesterolemia, hyperglyceridemia, hyperlipidemia, growth hormone disorders (e.g., gigantism, obesity, galactorrhea, and cardiac atrophy.

[1193] In some embodiments, the condition, disease or disorder is associated with inappropriate vasopressin secretion (SIADH). Non-limiting examples of such conditions, diseases or disorders include neurological diabetes (e.g., complications of diabetes, such as diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, etc.), lung cancer, septic shock and thirst.

[1194] In some embodiments, the condition, disease or disorder is associated with systemic inflammation. Non-limiting examples of such condition, disease or disorder include systemic inflammatory response syndrome (SIR), sepsis (e.g., severe sepsis) and septic shock. In some embodiments, the condition, disease or disorder is associated with sepsis (e.g., complications, comorbidities or sequelae of sepsis). Non-limiting examples of conditions, diseases or disorders associated with sepsis include: sepsis-induced myocardial dysfunction, sepsis-related inflammatory response (e.g., systemic inflammation), sepsis-related hemodynamic changes, hypovolemia, sepsis-related organ failure (e.g., multiple organ failure, renal failure), acute renal injury, vasoplegia, lung injury, inappropriate vasopressin secretion, persistent hypertension associated with generalized vasodilation, refractory contractile response, huge plasma capillary leak syndrome, coagulation / fibrinolysis imbalance, and metabolic disorders characterized by increased lactate levels in the bloodstream. See, e.g., Coquerel et al., Critical Care (2018) 22:10.

[1195] In some embodiments, the chemical entities described herein can modulate arginine vasopressin (AVP) or angiotensin receptors.

[1196] In some embodiments, the condition, disease or disorder is associated with disturbed fluid homeostasis through CNS-dependent and -independent effects. 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), water diuresis (aquaresis) and diuresis.

[1197] Dementia and related conditions, diseases or disorders

[1198] In some embodiments, the condition, disease or disorder is dementia. Non-limiting examples of such conditions, diseases or disorders 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.), infectious diseases (e.g., delayed viral infection, 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, childhood hyperactivity disorder (microencephalopathy), consciousness disorders, anxiety disorders, schizophrenia and phobias.

[1199] Connective tissue disorders

[1200] In some embodiments, the condition, disease or disorder is a connective tissue disease. In certain embodiments, the connective tissue disease is selected from the group consisting of scleroderma, systemic lupus erythematosus, systemic sclerosis, Hashimoto's thyroiditis, Sjögren's syndrome, and antiphospholipid antibody syndrome. In certain embodiments, the condition, disease or disorder is systemic sclerosis.

[1201] Fibrosis

[1202] In some embodiments, the condition, disease or illness is fibrosis. In certain embodiments, the fibrosis is associated with an organ or tissue selected from the group consisting of lung, liver, heart, mediastinum, bone marrow, retroperitoneum, skin, intestine, joints, reproductive organs and combinations thereof. In certain embodiments, the fibrosis is idiopathic pulmonary fibrosis (IPF). In certain embodiments, the fibrosis is hepatic fibrosis. In certain embodiments, the fibrosis is associated with non-alcoholic fatty liver disease (NAFLD).

[1203] Other conditions, diseases or illnesses

[1204] In some embodiments, the condition, disease or disorder is liver disease. Non-limiting examples of such conditions, diseases or disorders include alcoholic liver disease, toxic liver disease, viral liver disease and cirrhosis.

[1205] In some embodiments, the condition, disease or disorder is a pulmonary disease. Non-limiting examples of such conditions, diseases or disorders 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).

[1206] 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), craniocerebral trauma, pancreatitis, Turner's syndrome, neurosis, rheumatoid arthritis, spinal cord injury, immune function, inflammation, spinocerebellar degeneration, fracture, wound, atopic dermatitis, osteoporosis, asthma, epilepsy and infertility.

[1207] Activate stem cells

[1208] 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, chemical entities described herein can be used for the re-growth of tissues, to help restore function after transplantation of cells (e.g., cells with bone marrow-derived mesenchymal stem cells), 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 subjects after myocardial infarction, or to reduce reperfusion injury (e.g., during surgeries such as heart bypass surgery or heart transplantation).

[1209] Combination therapy

[1210] The present disclosure encompasses monotherapy regimens as well as combination therapy regimens.

[1211] In some embodiments, the methods described herein can further comprise administering one or more additional therapies (eg, one or more additional therapeutic agents and / or one or more treatment regimens) in combination with the compounds described herein.

[1212] In some embodiments, the compounds described herein may be administered in combination with one or more additional therapeutic agents.

[1213] Representative additional therapeutic agents include, but are not limited to, therapeutic agents for PAH, pulmonary hypertension, heart failure (e.g., ADHF, chronic heart failure), hypertension (e.g., systemic hypertension), amyotrophic lateral sclerosis, arrhythmia, asthma, atherosclerosis, atrial fibrillation, Brugada syndrome, 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 disorders, neurodegenerative disease, obesity, peripheral arterial disease, preeclampsia, restenosis, transient ischemic attack, head trauma, ventricular tachycardia, edema, or immune function.

[1214] In some embodiments, the one or more additional therapeutic agents include, for example, those used as therapeutic agents for PAH. Non-limiting examples include:

[1215] Prostacyclin analogs (e.g., epoprostenol, treprostinil, iloprost);

[1216] Prostacyclin IP receptor (eg, Selexipag);

[1217] Endothelin receptor antagonists (e.g., bosentan, ambrisentan, macitentan);

[1218] PDE 5 inhibitors (eg, sildenafil, tadalafil);

[1219] Soluble guanylate cyclase stimulators (e.g., Riociguat);

[1220] Mitochondrial dysfunction treatments (e.g., Bardoxolone methyl);

[1221] Anti-inflammatory agents (e.g., Rituximab, Tocilizumab, Ubenimex); and

[1222] Modulation of oxidative stress agents (eg, dimethyl fumarate, IV iron).

[1223] In some embodiments, the one or more additional therapeutic agents include, for example, those used as therapeutic agents for heart failure or hypertension. Non-limiting examples include:

[1224] alpha-blockers (eg, doxazosin, prazosin, tamsulosin, terazosin);

[1225] beta-blockers (e.g., acebutolol, acetutolol, atenolol, bisoprolol, bupranolol, carteolol, carvedilol, celiprolol, esmolol, mepindolol, metoprolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol, taliprolol);

[1226] Calcium channel blockers, including but not limited to dihydropyridines (DHPs) (e.g., amlodipine, felodipine, isradipine, lacidipine, nicardipine, nifedipine, nigulpidine, nilutipine, nimodiphine, nisoldipine, nitrendipine, nitrendipine, nivaldipine, ryosidine, and non-DHPs (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, hydrochlorthiazide, and methylchlorothiazide)

[1228] Centrally acting antihypertensive drugs (e.g., clonidine, guanabenz, guanfacine, methyldopa);

[1229] Angiotensin-converting enzyme (ACE) inhibitors (alaceptril, benazepril, benazeprilat, captopril, ceronapril, cilazapril, delapril, enalapril, analaprilat, fosinopril, lisinopril, moexipiril, movelt opril, 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 (such as 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 pacemaker current (e.g. ivabradine);

[1235] Myosin activators (e.g., cardiac myosin activators);

[1236] · Natriuretics;

[1237] · Urinary salt excretion agents;

[1238] Vasodilators / vasodilators (eg, nitrates)

[1239] Mineralocorticoid receptor antagonists;

[1240] Renin inhibitors;

[1241] Digitalis compounds;

[1242] Inotropic agents and beta-agonists;

[1243] Antihyperlipidemic agents;

[1244] Plasma HDL-raising agents;

[1245] Anti-hypercholesterol agents;

[1246] Cholesterol biosynthesis inhibitors (eg, HMG CoA reductase inhibitors)

[1247] LXR agonists;

[1248] Probucol;

[1249] raloxifene;

[1250] ·niacin;

[1251] Niacinamide;

[1252] Cholesterol absorption inhibitors;

[1253] Bile acid sequestrants (eg, anion exchange resins or quaternary amines such as cholesterylamine or colestipol);

[1254] Low-density lipoprotein receptor inducers;

[1255] · clofibrate;

[1256] · fenofibrate;

[1257] bezafibrate;

[1258] Ciprofibrate;

[1259] Gemfibrizol;

[1260] Vitamins (such as vitamin B 6 , Vitamin B 12 , antioxidant vitamins);

[1261] Platelet aggregation inhibitors;

[1262] Fibrinogen receptor antagonists;

[1263] aspirin; and

[1264] Fibric acid derivatives.

[1265] In some embodiments, the one or more additional therapeutic agents include, for example, those used to treat diabetes. Non-limiting examples include:

[1266] Sulfonylureas (e.g. chlorpropamide, tolbutamide, acetohexamide, tolazamide, glyburide, gliclazide, glynase, glimepiride, glipizide);

[1267] Biguanides (such as metformin);

[1268] Thiazolidinediones (e.g. ciglitazone, pioglitazone, troglitazone, rosiglitazone);

[1269] Insulin sensitizers related to the above (e.g., selective and non-selective activators of PPAR-α, PPAR-β and PPAR-γ);

[1270] Dehydroepiandrosterone (also known as DHEA or its conjugated sulfate DHEA-SO 4 );

[1271] Anti-glucocorticoids;

[1272] TNF-α inhibitors;

[1273] Dipeptidyl peptidase IV (DPP4) inhibitors (e.g., sitagliptin, saxagliptin);

[1274] GLP-1 agonists or analogs (e.g. exenatide);

[1275] alpha-glucosidase inhibitors (such as acarbose, miglitol, and voglibose);

[1276] Pramlintide (a synthetic analog of the human hormone amylin);

[1277] other insulin secretagogues (such as repaglinide, gliquidone, and nateglinide); and

[1278] ·insulin.

[1279] In some embodiments, the one or more additional therapeutic agents include, for example, those used to treat obesity. Non-limiting examples include phenylpropanolamine, phentermine, diethylpropion, mazindol, fenfluramine, dexfenfluramine, phenethylamine, β3-adrenergic receptor agonists, sibutramine, gastrointestinal lipase inhibitors (e.g., orlistat), leptin, neuropeptide Y, enterostatin, cholecytokinin, bombesin, amylin, histamine H 3 Receptor, dopamine D 2 Receptor modulators, melanocyte stimulating hormone, corticotropin-releasing factor, galanin and gamma-aminobutyric acid (GABA).

[1280] Other additional therapeutic agents include:

[1281] Anti-atherosclerotic agents;

[1282] Anti-dyslipidemic agents;

[1283] Anti-hyperinsulin agents;

[1284] Antithrombotic agents;

[1285] Anti-retinal agents;

[1286] Antineuropathic agents;

[1287] Antinephrotic agents;

[1288] Anti-ischemic agents;

[1289] Antihyperlipidemic agents;

[1290] Anti-hypertriglyceride agents;

[1291] Anti-hypercholesterol agents;

[1292] Anti-restenotic agents;

[1293] Antipancreatic agents;

[1294] Anorexic agents;

[1295] Memory enhancers;

[1296] Anti-dementia drugs;

[1297] Cognitive enhancers;

[1298] Appetite suppressants;

[1299] ·Medications used to treat peripheral arterial disease;

[1300] ·Medications used to treat malignant tumors;

[1301] Anti-innammatory agents;

[1302] Diuretics;

[1303] Digoxin;

[1304] Nitric oxide donor;

[1305] Hydralazine;

[1306] Ionotropes

[1307] Vasopressin receptor antagonists;

[1308] Statins;

[1309] Antiarrhythmic drugs;

[1310] Phosphodiesterase inhibitors (such as PDE5 inhibitors); and

[1311] Nephro-protectives.

[1312] Non-limiting examples of other therapeutic agents may also include those described in US9156796B2, which is incorporated herein by reference.

[1313] In certain embodiments, the subject is administered a second therapeutic agent or regimen prior to contact with or administration of the chemical entity (e.g., about an hour before, or about 6 hours before, or about 12 hours before, or about 24 hours before, or about 48 hours before, about a week before, or about a month before).

[1314] In other embodiments, the second therapeutic agent or regimen is administered to the subject at about the same time as the contact or administration of the chemical entity. For 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.

[1315] In other embodiments, the subject is administered a second therapeutic agent or regimen after contact with or administration of the chemical entity (e.g., after about one hour, or about 6 hours, or about 12 hours, or about 24 hours, or about 48 hours, about 1 week, or about 1 month).

[1316] Preparation and biological experiments of compounds

[1317] As will be appreciated by those skilled in the art, methods for synthesizing compounds of the formula described herein will be readily apparent to those of ordinary skill in the art. Synthetic chemical transformations and protecting group methods (protection and deprotection) useful in synthesizing compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Press (1989); T. W. Greene and R. G. M. Wuts, Protecting Groups in Organic Synthesis, 2nd ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Organic Synthesis Reagents, John Wiley and Sons (1994); L. Paquette, ed., Encyclopedia of Organic Synthesis Reagents, John Wiley and Sons (1995), and subsequent editions thereof.

[1318] In some embodiments, intermediates useful for preparing compounds described herein may be prepared using the chemistry described in any one or more of the following Schemes and non-limiting Examples.

[1319] Compound preparation

[1320] For the purpose of illustration, schemes 1-4 show a general method for preparing the compounds and intermediates provided herein. For a more detailed description of each reaction step, please refer to the synthesis example section below. It will be appreciated by those skilled in the art 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 scheme and discussed below, other starting materials and reagents can be easily replaced to provide various derivatives and / or reaction conditions. In addition, according to the present disclosure, many compounds prepared by the following methods can be further modified / modified using conventional chemical methods well known to those skilled in the art.

[1321] Solution 1

[1322]

[1323] 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, wherein R 1 and R 2 As defined herein. Aminopyrazine I-1 can be reacted with carboxylic acid I-2 to form amide I-3 (wherein X is a halogen, such as bromine or chlorine) under standard conditions (e.g., in the presence of oxalyl chloride to convert I-2 into an acid chloride or in the presence of a peptide coupling agent). Then, in S N Ar or metal catalyzed cross-coupling conditions between I-3 and amine I-4 (e.g., using Xantphos and Pd(OAc) 2 Reaction under Buchwald Hartwig coupling (Buchwald Hartwig coupling) can provide compound 1-5. Condensation of the carbonyl moiety in 1-5 to the amino group can provide 1-6, a compound of formula (I).

[1324] Alternatively, I-3 can be prepared by reacting an ester of I-2 (e.g., an alkyl ester, such as a methyl or ethyl ester) with I-1 under appropriate conditions (e.g., in the presence of AlMe 3 The coupling was carried out in the presence of .

[1325] Optionally, the X moiety in I-6 can be converted to other R 3 to provide 1-7, another compound of formula (I). As a non-limiting example of the transformation between 1-6 and 1-7, 1-6 can be reacted with a sulfonamide under Ullmann coupling conditions to provide compound 1-8 (see above, Scheme 1).

[1326] The following starting materials can be used in place of 1-1 and processed in the order described in Scheme 1.

[1327]

[1328] Solution 2

[1329]

[1330] 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, wherein R 1 As defined elsewhere herein, and X is a halogen (e.g., Br) or pseudohalogen (e.g., OTf) group. II-1 can be Sonogashira coupled with a protected acetylene (e.g., TMS-acetylene) or its equivalent to provide compound II-2. Subsequent removal of the alkyne protecting group can provide II-3, which can be coupled with a pyrazine derivative II-4 to provide compound II-5. Cyclization of the amino group in II-5 to the alkynyl moiety can produce compound II-6, which can be coupled with formula R 2 -B(OH) 2 Boric acid (where R 2 As defined elsewhere herein) or its boronate ester is cross-coupled (e.g., under Chan-Lam coupling conditions) 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).

[1331] As a non-limiting example of converting II-7 to II-8, II-7 can be reacted with a compound of formula H 2 NS(O) 2 R 4 Compounds of 4 As defined elsewhere herein, to provide Compound II-9, which is a non-limiting example of Compound II-8.

[1332] Solution 3

[1333]

[1334] Referring to Scheme 3, compounds of formula (I) (shown as compounds III-5 to III-7 in Scheme 3) can be prepared from compound III-1, wherein R 1 As defined elsewhere herein. III-1 and III-2 (e.g., in the presence of a Lewis acid such as AlMe 3 Coupling between ) can provide compound III-3, which can be combined with formula R 2 NH 2 The cross-coupling of compounds wherein R 2 As defined elsewhere herein, to provide compound III-4. The amino group in III-4 is cyclized to the amide moiety (e.g., in P(O)Cl 3Heating in the presence of ) 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).

[1335] As a non-limiting example of converting III-5 to III-6, III-5 can be reacted with a compound of formula H 2 NS(O) 2 R 4 Compounds of 4 As defined elsewhere herein, to provide Compound III-7, which is a non-limiting example of Compound III-6.

[1336] Solution 4

[1337]

[1338] Referring to Scheme 4, compounds of formula (I) (shown as compounds IV-6 to IV-8 in Scheme 4) can be prepared from pyridazine derivative IV-1. Treatment of IV-1 with ammonium hydroxide and bromine sequentially provides IV-3, and thus IV-3 is reacted with R 1 CO 2 H (where R 1 As defined elsewhere herein) can provide IV-4. IV-4 can be coupled to R 2 NH 2 Coupling, where 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).

[1339] As a non-limiting example of converting IV-6 to IV-7, IV-6 can be reacted with a compound of formula H 2 NS(O) 2 R 4 Compounds of 4 As defined elsewhere herein, to provide compound IV-8, which is a non-limiting example of compound IV-7.

[1340] Solution 5

[1341]

[1342] Referring to Scheme 5, compounds of formula (I) (shown as V-6 and V-7) can be prepared from compounds V-1, V-2 and V-4, wherein R 1 and R2 As defined herein. Aminopyrazine V-1 can be reacted with carboxylic acid V-2 under standard conditions to give amide V-3 (wherein X is a halogen, such as bromine or chlorine). Then in S N Ar or metal-catalyzed cross-coupling conditions between V-3 and amine V-4 (e.g., using Xantphos and Pd(OAc) 2 Reaction under Buchwald Hartwig coupling (Buchwald Hartwig coupling) can provide compound V-5. Condensation of the carbonyl moiety in V-5 to the amino group can provide V-6, a compound of formula (I).

[1343] Alternatively, V-3 may be prepared by reacting an ester (e.g., an alkyl ester, such as a methyl or ethyl ester) of V-2 with V-1 under appropriate conditions (e.g., in the presence of AlMe 3 The coupling was carried out in the presence of .

[1344] Optionally, the X portion of V-6 can be converted to other R 3 to provide V-7, another compound of formula (I). As a non-limiting example of the transformation between V-6 and V-7, V-6 can be reacted with a sulfonamide under Ullmann coupling conditions to provide compound V-8 (see above, Scheme 5).

[1345] General approach

[1346] Reactions sensitive to moisture or air were carried out under nitrogen or argon using anhydrous solvents and reagents. The progress of the reactions was determined by analytical thin layer chromatography (TLC) typically performed using Sanpont pre-coated TLC plates, silica gel GF-254, layer thickness 0.25 mm or liquid chromatography-mass spectrometry (LC-MS).

[1347] Typically, 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 / min 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 of 90% solvent A to 95% solvent B in 1.7 minutes, held for 1.8 minutes, then restored to 90% solvent A in 0.1 minutes, and held for 1.4 minutes.

[1348] Preparative HPLC purifications were usually performed on a Waters 2555-2767 system with a 2489 UV detector. The column was Welch C-18, 21.2×150 mm, 5 μm. The mobile phase consisted of a mixture of acetonitrile (5-95%) in water containing 0.05% TFA. The flow rate was maintained at 20 mL / min, the injection volume was 1800 μL, and the UV detector used two 254 nm and 280 nm channels. The mobile phase gradient was optimized for each compound.

[1349] Microwave irradiation reactions are usually performed using an Initiator manufactured by Biotage. The solution is concentrated on a rotary evaporator under reduced pressure. Flash chromatography is usually performed using a Biotage flash chromatograph (Dyax) on silica gel (40-63 mM, pore size ) in prepacked cartridges of specified size. Unless otherwise stated, the spectrometer was used at 400 MHz in CDCl 3 Obtained in solution 1 H NMR spectra. Chemical shifts are reported in parts per million (ppm). 3 Tetramethylsilane (TMS) was used as an internal reference in the Cl solution. 3 The remaining CH 3 The OH peak or TMS was used as an internal reference. 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 (250 x 4.6 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 the isocratic solvent system. Chiral preparative chromatography was performed on one of the Chiralpak AS, Chiralpak AD, Chiralcel OD, Chiralcel IA or Chiralcel OJ columns (20 x 250 mm) (Daicel Chemical Industries, Ltd.), and the desired isocratic solvent system was identified on the chiral analytical chromatography or by supercritical fluid (SFC) conditions.

[1350] abbreviation

[1351] -C(O)CH 3 (Ac); Acetic acid (AcOH); -OC(O)CH 3(OAc); aqueous solution (aq); Cbz (benzyloxycarbonyl); N,N-diisopropylethylamine (DIEA); N,N-dimethylformamide (DMF); 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI); ethyl acetate (EtOAc); diethyl ether (Et 2 O); 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)tripyrrolidinium 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-bromosuccinamide (NBS); thin layer chromatography (TLC).

[1352] Synthesis example:

[1353] The following are representative methods for preparing compounds used in the following examples or compounds that may be substituted for those used in the following examples and that may not be commercially available.

[1354] Method A:

[1355]

[1356] Example 1: 6-Bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine

[1357]

[1358] and

[1359] Example 2: N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide

[1360]

[1361] Step A: Ethyl 6-ethoxypicolinate

[1362] Ethyl iodide (112.2 g, 720 mmol, 4 eq) was added to 6-hydroxy-pyridine-2-carboxylic acid (25.0 g, 180 mmol, 1 eq) and silver (I) carbonate (100 g, 360 mmol, 2 eq) in CHCl 3 The mixture was stirred at 30°C for 1 day. The insoluble matter was removed by filtration and the mixture was washed with CHCl 3 The solid was washed. The filtrate was concentrated in vacuo to give the title compound, ethyl 6-ethoxypicolinate, as a light yellow oil which was used in the next step without further purification.

[1363] LC-MS: m / z 196.0 (M+H) +

[1364] Step B: 6-Ethoxypicolinic acid To a solution of ethyl 6-ethoxypicolinate (25 g, 128 mmol, 1 eq.) in EtOH (30 mL) was added sodium hydroxide solution (1 mol / L, 384 mL, 384 mmol, 3 eq.). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was neutralized with 1N HCl (aq.) solution and extracted with ethyl acetate. The extract was washed with brine and MgSO 4 Drying and concentration in vacuo afforded the title compound, 6-ethoxypicolinic acid.

[1365] LC-MS: m / z 168.0 (M+H) +

[1366] Step C: N-(3,5-dibromopyrazin-2-yl)-6-ethoxypicolinamide Oxalyl chloride (11.4 g, 89.8 mmol, 1.5 equiv) and DMF (1 mL) were added dropwise to a solution of 6-ethoxypicolinic acid (10 g, 59.9 mmol, 1 equiv) in DCM (100 mL) at 0 ° C. The resulting mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to give crude 6-ethoxypicolinoyl chloride as a light yellow solid. A suspension of 3,5-dibromopyrazine-2-amine (14.4 g, 56.9 mmol, 0.95 equiv) and NaH (6.8 g, 170.7 mmol, 2.85 equiv) in DMF (100 mL) was stirred at room temperature for 1 hour. Then the crude 6-ethoxypicolinoyl chloride in DMF (100 mL) was added dropwise over 30 minutes. After addition, the mixture was stirred at room temperature overnight. The mixture was washed with saturated NH 4 The solution was quenched with Cl(aqueous) (100 mL) and extracted with DCM (3×150 mL). The extract was washed with brine (100 mL) and washed with anhydrous Na 2 SO 4Dry and concentrate in vacuo.The residue is recrystallized in DCM to provide compound N-(3,5-dibromopyrazin-2-yl)-6-ethoxypicolinamide.

[1367] LC-MS:m / z 400.9,402.9,404.9(M+H) +

[1368] Step D: N-(5-bromo-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide

[1369] N-(3,5-dibromopyrazin-2-yl)-6-ethoxypicolinamide (1.0 g, 2.5 mmol, 1 eq), 2,6-dimethoxyaniline (380 mg, 2.5 mmol, 1 eq), Pd(OAc) 2 (112 mg, 0.5 mmol, 0.2 eq), Xantphos (576 mg, 1.0 mmol, 0.4 eq) and K 2 CO 3 A suspension of (680 mg, 3.0 mmol, 2 eq.) in 1,4-dioxane (10 mL) was irradiated by microwaves at 120 °C under N 2 The mixture was stirred for 2 hours under atmosphere. The mixture was diluted with DCM (20 mL) and filtered through celite. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (PE / EtOAc=4 / 1) to provide the title compound N-(5-bromo-3-((2,6-dimethoxyphenyl)amino)pyrazine-2-yl)-6-ethoxypicolinamide.

[1370] LC-MS: m / z 474.0,476.0 (M+H) +

[1371] Step E: 6-Bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5- b] Pyrazine (Example 1)

[1372] A solution of N-(5-bromo-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide (1.0 g, 2.1 mmol, 1 eq.) 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.

[1373] 1 H NMR (400 MHz, DMSO-d 6)δ:8.75(s,1H),8.04(dd,J=7.4,0.8Hz,1H),7.89(dd,J=8.4,7.4Hz,1H),7.50(t,J=8.4 Hz, 1H), 6.89 (d, J = 8.4Hz, 3H), 3.60 (s, 6H), 3.40 (q, J = 7.0Hz, 2H), 1.05 (t, J = 7.0Hz, 3H).

[1374] LC-MS: m / z 456.1,458.1 (M+H) +

[1375] Step F: N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b] Pyrazin-6-yl)methanesulfonamide (Example 2)

[1376] The samples were irradiated with microwave at 115 °C in N 2 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 equivalents), CuI (125 mg, 0.66 mmol, 2 equivalents), trans-N,N'-dimethylcyclohexane-1,2-diamine (94 mg, 0.66 mmol, 2 equivalents) and K were stirred under atmosphere. 2 CO 3 (137 mg, 0.99 mmol, 3 eq) in DMF (5 mL) for 1.5 h. The reaction was washed with water (150 mL) and then extracted with EtOAc (3×100 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 Dry and concentrate in vacuo.The residue was purified by flash chromatography (eluted with PE / EtOAc = 20 / 1 to 5 / 1) to afford the title compound as a yellow solid.

[1377] 1 H NMR (400 MHz, DMSO-d 6 )δ:11.05(s,1H),8.27(s,1H),7.95(dd,J=7.4Hz,J=0.8Hz,1H),7.86(t,J=7.8Hz,1H),7.45(t,J=8.4Hz, 1H),6.81-6.87(m,3H),3.57(s,6H),3.39(q,J=7.0Hz,2H),3.20(s,3H),1.03(t,J=7.0Hz,3H).LC-MS:m / z 471.0(M+H) +

[1378] Example 3: N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-1-phenylmethanesulfonamide

[1379]

[1380] The title compound was prepared according to General Procedure A, Step F, starting from Example 1 using benzylsulfonamide.

[1381] 1 H NMR (400 MHz, DMSO-d 6 )δ:11.04(s,1H),8.14(s,1H),7.97(dd,J=7.4Hz,0.8Hz,1H),7.87(t,J=7.8Hz,1H),7.49(t,J=8.4Hz,1H),7.31-7.33(m,3 H),7.12-7.14(m,2H),6.83-6.90(m,3H),4.68(s,2H),3.58(s,6H),3.41(q,J=7.0Hz,2H),1.03(t,J=7.0Hz,3H).LC-MS:m / z 547.0(M+H) +

[1382] Example 4: 1-cyclopropyl-N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide

[1383]

[1384] The title compound was prepared according to General Procedure A, Step F, starting from Example 1 using 1-cyclopropylmethanesulfonamide.

[1385] 1 H NMR (400 MHz, DMSO-d 6 )δ:11.03(s,1H),8.30(s,1H),7.94(dd,J=7.4Hz,0.8Hz,1H),7.85(t,J=7.8Hz,1H),7.45(t,J=8.4Hz,1H),6.81-6.87(m,3H),3.57(s,6H ), 3.39 (q, J = 7.0Hz, 2H), 3.27 (d, J = 3.4Hz, 2H), 1.02 (t, J = 7.0Hz, 3H), 0.47 (d, J = 4.0Hz, 3H), 0.13 (d, J = 2.2Hz, 2H). LC-MS: m / z511.0 (M+H) +

[1386] Example 5: N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)benzenesulfonamide

[1387]

[1388] The title compound was prepared according to General Procedure A, Step F, starting from Example 1 using benzenesulfonamide. 1 H NMR (400 MHz, DMSO-d 6 )δ:11.53(s,1H),8.24(s,1H),7.93(dd,J=7.4Hz,0.8Hz,1H),7.83(t,J=7.8Hz,1H),7.66(dd,J=8.4Hz,0.8Hz,2H),7.55(t,J=8.4Hz,2H),7.3 8(t,J=7.8Hz,2H),6.93(d,J=4.4Hz,2H),6.81(d,J=4Hz1H),3.54(s,6H),3.38(q,J=7.0Hz,2H),1.03(t,J=7.0Hz,3H).LC-MS:m / z533.0(M+H) +

[1389] Example 6: 1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-6-(phenylethynyl)-1H-imidazo[4,5-b]pyrazine

[1390]

[1391] and

[1392] Example 7: 1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-6-phenethyl-1H-imidazo[4,5-b]pyrazine

[1393]

[1394] Step A: 1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-6-(phenylethynyl)-1H-imidazole [4,5-b]pyrazine (Example 6)

[1395] 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 equivalent), ethynylbenzene (44.5 mg, 0.44 mmol, 2 equivalents), Pd(PPh 3 ) 2 Cl 2(15.3 mg, 0.022 mmol, 0.1 eq), CuI (8.3 mg, 0.044 mmol, 0.2 eq) and Et 3 A suspension of N (66 mg, 0.66 mmol, 3.0 equiv) in DMF (5 mL) was treated with N 2 Bubble for 1 minute and then stir at 80°C for 4 hours. 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) and washed with anhydrous Na 2 SO 4 Dry, filter and concentrate.The residue was purified by flash chromatography on silica gel (PE / EtOAc=1 / 1) to provide the title compound.

[1396] 1 H NMR (400 MHz, DMSO-d 6 )δ:8.85(s,1H),8.07(d,J=7.0Hz,1H),7.87-7.93(m,1H),7.64-7.68(m,2H),7.49-7.53(m,1H),7.43-7.4 9(m,3H),6.90(dd,J=8.4,1.6Hz,3H),3.61(s,6H),3.41(q,J=7.0Hz,2H),1.06(t,J=7.0Hz,3H).LC-MS:m / z 478.2(M+H) +

[1397] Step B: 1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-6-phenylethyl-1H-imidazolyl [4,5-b]pyrazine (Example 7)

[1398] 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 at 4 °C for 1 h. 2 The mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography (PE / EtOAc=1 / 1) to provide the title compound.

[1399] 1 H NMR (400 MHz, DMSO-d 6)δ:8.40(s,1H),7.98(d,J=7.4Hz,1H),7.86(t,J=7.8Hz,1H),7.47(t,J=8.4Hz,1H),7.19-7.26(m,2H),7.09-7.18(m,3H),6.86(dd ,J=17.4,8.4Hz,3H),3.59(s,6H),3.41(q,J=7.0Hz,2H),3.13(dd,J=8.4,6.8Hz,2H),2.96(t,J=7.6Hz,2H),1.05(t,J=7.0Hz,3H).

[1400] LC-MS: m / z 482.2 (M+H) +

[1401] Example 8: N-Benzyl-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine-6-carboxamide

[1402]

[1403] Step A: 1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrrolidone Methyl oxazine-6-carboxylate 6-Bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine (105 mg, 0.23 mmol, 1 eq) was dissolved in MeOH. Pd(dppf)Cl was then added. 2 To the mixture of 4-(2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine-6-carboxylic acid methyl esters was added 4-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine-6-carboxylic acid methyl esters (33mg, 0.046mmol, 0.2 equivalent) and triethylamine (70mg, 0.69mmol, 3 equivalent). The suspension was degassed and purged with CO 3 times. The reaction mixture was then stirred overnight at 90 ° C and 3MPa. The reaction mixture was filtered, concentrated and purified by column chromatography (silica gel, eluted with 25% EtOAc in PE) to obtain the title compound 1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine-6-carboxylic acid methyl esters.

[1404] LC-MS: m / z 436.1 (M+H) +

[1405] Step B: N-benzyl-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4, 5-b] Pyrazine-6-carboxamide (Example 8)

[1406] 1-(2,6-Dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine-6-carboxylic acid methyl ester (32.4 mg, 0.074 mmol, 1 eq) and benzylamine (15 mg, 0.148 mmol, 2 eq) were charged into a sealed tube and the mixture was heated at 90° C. for 2 hours. The reaction mixture was then purified by column chromatography (silica gel, eluted with 25% EtOAc in PE) to provide the title compound.

[1407] 1 H NMR (400 MHz, DMSO-d 6 )δ:9.21(s,1H),8.85(t,J=6.4Hz,1H),8.04(d,J=6.8Hz,1H),7.90(t,J=7.2Hz,1H),7.46(t,J=8.4Hz,1H),7.23-7.30(m ,5H),6.88(t,J=8.4Hz,3H),4.50(d,J=6.4Hz,2H),3.59(s,6H),3.41(q,J=7.0Hz,2H),1.05(t,J=7.0Hz,3H).LC-MS:m / z 511.2(M+H) +

[1408] Example 9: 1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-N-methyl-1H-imidazo[4,5-b]pyrazin-6-amine

[1409]

[1410] 6-bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine (Example 1, 60 mg, 0.1 mmol, equivalent), and CH 3 NH 2 A mixture of (aqueous, 40 wt %, 5 mL) was stirred by microwave irradiation at 120° C. for 2 h. The reaction mixture was concentrated and the residue was purified by silica gel flash chromatography (PE / EtOAc=1 / 2) to provide the title compound.

[1411] 1 H NMR (400 MHz, DMSO-d 6)δ:7.84(s,1H),7.82(dd,J=7.4,1.0Hz,1H),7.73-7.79(m,1H),7.40(t,J=8.4Hz,1H),7.19(q,J=4.8Hz,1H),6.83(d,J=8.4Hz ,2H),6.69(dd,J=8.0,1.0Hz,1H),3.58(s,6H),3.37(q,J=7.0Hz,2H),2.70(d,J=4.8Hz,3H),1.02(t,J=7.0Hz,3H).LC-MS:m / z 407.2(M+H) +

[1412] Method B:

[1413]

[1414] Step A: (1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrrolidone tert-Butyl oxazine-6-yl)carbamate

[1415] 6-Bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine (500 mg, 1.09 mmol, 1 equivalent), BocNH 2 (255 mg, 2.18 mmol, 2 equiv), Pd(OAc) 2 (49 mg, 0.22 mmol, 0.2 eq), Xantphos (252 mg, 0.44 mmol, 0.4 eq) and Cs 2 CO 3 A suspension of (711 mg, 2.18 mmol, 2 eq.) in 1,4-dioxane (10 mL) was stirred at N 2 The mixture was stirred at 120 °C for 2 hours under microwave irradiation. 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 (1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine-6-yl)carbamic acid tert-butyl ester.

[1416] LC-MS: m / z 493.2 (M+H) +

[1417] Step B: 1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrrolidone Oxazine-6-amine (Example 10)

[1418]

[1419] A mixture of tert-butyl (1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine-6-yl)carbamate (350 mg, 0.71 mmol, 1 eq) and HCl in dioxane (4 mol / L, 20 mL) was added at 0°C. The mixture was then stirred at room temperature for 4 hours. The reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel (100% EtOAc) to provide Example 10. 1 H NMR (400 MHz, DMSO-d 6 )δ:7.83-7.89(m,2H),7.79(t,J=7.8Hz,1H),7.41(t,J=8.4Hz,1H),6.83(d,J=8.4Hz,2H),6 .72(d,J=8.0Hz,1H),6.64(s,2H),3.60(s,6H),3.42(q,J=7.0Hz,2H),1.04(t,J=7.0Hz,3H).

[1420] LC-MS: m / z 393.2 (M+H) +

[1421] Example 11: N,N-dibenzyl-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-amine

[1422]

[1423] A mixture of the compound of Example 10 (50 mg, 0.13 mmol, 1 eq.) and NaH (10.2 mg, 0.26 mmol, 2 eq.) in DMF (5 mL) was stirred at 0 °C for 30 minutes. Bromomethylbenzene (24 mg, 0.14 mmol, 1.1 eq.) 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 x 500 mL). The combined organic phases were washed with brine (30 mL) and washed with anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo.The residue was purified by flash chromatography on silica gel (PE / EtOAc=1 / 1) to provide the title compound.

[1424] 1 H NMR (400 MHz, DMSO-d 6)δ:7.90(s,1H),7.85(dd,J=7.4,0.8Hz,1H),7.78(t,J=7.8Hz,1H),7.43(t,J=8.4Hz,1H),7.18-7.32(m,10H),6.85(d,J= 8.4Hz, 2H), 6.73 (dd, J=8.0, 0.8Hz, 1H), 4.77 (s, 4H), 3.55 (s, 6H), 3.37 (q, J=7.0Hz, 2H), 1.01 (t, J=7.0Hz, 3H). LC-MS: m / z 573.2(M+H) +

[1425] Example 12: 1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-N,N-dimethyl-1H-imidazo[4,5-b]pyrazin-6-amine

[1426]

[1427] A mixture of the compound of Example 10 (50 mg, 0.13 mmol, 1 eq.) and NaH (15.3 mg, 0.38 mmol, 3 eq.) in DMF (5 mL) was stirred at 0 °C for 30 minutes. Iodomethane (54.3 mg, 0.38 mmol, 3 eq.) 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 x 500 mL). The combined organic phases were washed with brine (30 mL) and washed with anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo.The residue is purified by flash chromatography on silica gel (PE / EtOAc=3 / 7) to afford the desired product.

[1428] 1 H NMR (400 MHz, DMSO-d 6 )δ:8.08(s,1H),7.84(dd,J=7.4,1.0Hz,1H),7.75-7.82(m,1H),7.40(t,J=8.4Hz,1H),6.83(d,J=8.4Hz,2H) ,6.71(dd,J=8.0,1.0Hz,1H),3.57(s,6H),3.40-3.34(m,2H),3.02(s,6H),1.02(t,J=7.0Hz,3H).LC-MS:m / z 421.2(M+H) +

[1429] Example 13: N-Benzyl-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-amine

[1430]

[1431] 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 eq) in 1,2-dichloroethane (20 mL) was added benzaldehyde (65 mg, 0.61 mmol, 4 eq) and the reaction flask was immersed in an ice bath. AcOH (37 mg, 0.61 mmol, 4 eq) was then added, followed by sodium triacetoxyborohydride (130 mg, 0.61 mmol, 4 eq) in small portions over 15 min. The resulting suspension was slowly warmed to 50 °C and stirred overnight. The mixture was stirred for 1 h by slowly adding saturated NaHCO 3 The reaction was quenched by adding 20 mL of 4% paraformaldehyde (20 mL) while stirring at 0 °C. The biphasic mixture was stirred for 30 min and extracted with DCM (3 x 25 mL). The combined organic phases were washed with brine (30 mL) and washed with anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo.The residue is purified by flash chromatography on silica gel (PE / EtOAc=1 / 1) to afford the desired product.

[1432] 1 H NMR (400 MHz, DMSO-d 6 )δ:7.88(s,1H),7.74-7.84(m,3H),7.42(t,J=8.4Hz,1H),7.28-7.17(m,5H),6.83(d,J=8.4Hz,2H),6.70(dd ,J=8.0,1.0Hz,1H),4.30(d,J=6.0Hz,2H),3.54(s,6H),3.34-3.40(m,2H),1.01(t,J=7.0Hz,3H).LC-MS:m / z 483.2(M+H) +

[1433] Example 14: N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-2-phenylacetamide

[1434]

[1435] 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 eq.), and NaH (15.3 mg, 0.38 mmol, 3 eq.) in DMF (5 mL) was stirred at 0 °C for 30 minutes. 2-Phenylacetyl chloride (21 mg, 0.13 mmol, 1 eq.) 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) and washed with anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo.The residue is purified by flash chromatography on silica gel (PE / EtOAc=3 / 7) to afford the desired product.

[1436] 1 H NMR (400 MHz, DMSO-d 6 )δ:11.11(s,1H),9.33(s,1H),7.99(d,J=7.4Hz,1H),7.85(t,J=7.8Hz,1H),7.46(t,J=8.4Hz,1H),7.18-7.37( m,6H),6.86(d,J=8.4Hz,2H),3.74(s,2H),3.60(s,6H),3.39(q,J=7.0Hz,2H),1.05(t,J=7.0Hz,3H).LC-MS:m / z 511.2(M+H) +

[1437] Example 15: 5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine

[1438]

[1439] and

[1440] Example 16: 1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-5-amine

[1441]

[1442] Step A: N-(3-bromo-6-chloropyrazin-2-yl)-6-ethoxypicolinamide

[1443] A mixture of ethyl 6-ethoxypicolinate (500 mg, 2.56 mmol, 1 eq.) and 3-bromo-6-chloropyrazin-2-amine (530 mg, 2.56 mmol, 1 eq.) in toluene was cooled to 0 °C and AlMe3 The mixture was then stirred at 100°C for 16 hours. 4 The precipitate was quenched with Cl solution and extracted with EtOAc (3×20 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 Dry and concentrate in vacuo.The residue was purified by flash chromatography on silica gel (PE / EtOAc=10 / 1) to provide the title compound N-(3-bromo-6-chloropyrazin-2-yl)-6-ethoxypicolinamide.

[1444] 1 H NMR (400 MHz, DMSO-d 6 )δ:10.94(s,1H),8.50(s,1H),7.99(d,J=7.6Hz,1H),7.68-7.82(m,1H),7 .07-7.27(m,1H),4.52(d,J=7.0Hz,2H),1.40(t,J=7.0Hz,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

[1446] N-(3-bromo-6-chloropyrazin-2-yl)-6-ethoxypicolinamide (500 mg, 1.4 mmol, 1 equivalent), 2,6-dimethoxyaniline (430 mg, 2.8 mmol, 2 equivalents), Xantphos (162 mg, 0.28 mmol, 2 equivalents), Pd 2 (dba) 3 A mixture of (128 mg, 0.14 mmol, 0.1 eq.), potassium 2-methylpropane-2-oleate (297 mg, 2.8 mmol, 2 eq.) in toluene (10 mL) was stirred at N 2 Stir at 110° C. for 16 hours under atmosphere. Filter the mixture and concentrate in vacuo. Purify the residue by silica gel flash column chromatography (PE / EtOAc=10 / 1) to provide the title compound N-(6-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide.

[1447] 1 H NMR (400 MHz, CDCl 3)δ:10.11(s,1H),8.40(s,1H),8.02(s,1H),7.92(d,J=7.2Hz,1H),7.77(t,J=8.8Hz,1H),7.13(t,J=8.4Hz,1H) ,6.97(d,J=8.0Hz,1H),6.65(d,J=8.4Hz,2H),4.48(q,J=7.2Hz,2H),3.82(s,6H),1.46-1.52(m,3H).LC-MS:m / z 429.7(M+H) +

[1448] Step C: 5-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5- b] Pyrazine (Example 15)

[1449] N-(6-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide (280 mg, 0.56 mmol, 1 eq) in AcOH (20 mL) was stirred at 120 °C for 1 hour under MW. The reaction mixture was concentrated in vacuo. The residue was washed with ether, filtered and dried to give the desired product. 1 H NMR (400 MHz, CDCl 3 )δ:8.27(s,1H),8.13-8.20(m,1H),7.69(t,J=8.4Hz,1H),7.39(t,J=8.4Hz,1H),6.6 5-6.77(m,3H),3.62(s,6H),3.43(q,J=7.2Hz,2H),1.09(t,J=7.2Hz,3H).LC-MS:m / z 411.7(M+H) +

[1450] Step D: (1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrrolidone tert-Butyl (2-(2-oxazine-5-yl)carbamate

[1451] 5-Chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine (80 mg, 0.19 mmol, 1 equivalent), tert-butyl carbamate (46 mg, 0.38 mmol, 2 equivalents), Xantphos (22 mg, 0.038 mmol, 0.2 equivalents), Pd 2 (dba) 3 A mixture of (17 mg, 0.019 mmol, 0.1 eq.) and potassium 2-methylpropane-2-oleate (43 mg, 0.38 mmol, 2 eq.) in toluene (5 mL) was stirred at N 2The mixture was stirred at 110° C. for 16 hours under an atmosphere of 4-(2-nitropropene)-2-nitropropene. The mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (PE / EtOAc=3 / 1) to give the title compound tert-butyl (1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)carbamate.

[1452] 1 H NMR (400MHz, CD 3 OD)δ:8.91(s,1H),7.89-7.87(d,J=7.2Hz,1H),7.79-7.77(t,J=7.2Hz,1H),7.46-7.44(t,J=8.4Hz,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=7.2Hz,3H).LC-MS:m / z 492.7(M+H) +

[1453] Step E: 1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrrolidone Oxazine-5-amine (Example 16)

[1454] 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 eq) in HCl / MeOH (4 mol / L, 10 mL) was stirred at room temperature for 6 hours. The mixture was concentrated in vacuo and the residue was washed with ether to give the desired product.

[1455] 1 H NMR (400MHz, CD 3 OD)δ:7.96(s,1H),7.80(t,J=8.0Hz,1H),7.52-7.63(m,2H),6.85-6.97(m,3H), 3.80(q,J=7.2Hz,2H),3.70(s,6H),1.19(t,J=7.2Hz,3H).LC-MS:m / z393.3(M+H) +

[1456] Example 17: N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)-2-phenylacetamide

[1457]

[1458] 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 equivalent), 2-phenylacetamide (19.7 mg, 0.15 mmol, 1 equivalent), Xantphos (17 mg, 0.03 mmol, 0.2 equivalent), Pd 2 (dba) 3 (13 mg, 0.015 mmol, 0.1 eq), Cs 2 CO 3( 95 mg, 0.3 mmol, 2 eq.) in dioxane (5 mL) under N 2 Stir at 110°C under atmosphere for 16 hours. Filter the mixture and concentrate in vacuo. Purify the residue by flash chromatography on silica gel (PE / EtOAc=3 / 1) to provide the title compound.

[1459] 1 H NMR (400 MHz, CDCl 3 )δ:9.34(s,1H),8.12(d,J=7.2Hz,2H),7.66(t,J=7.2Hz,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=7.2Hz,2H),1.08(t,J=7.2Hz,3H).LC-MS:m / z511.3(M+H) +

[1460] Example 18: 1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine

[1461]

[1462] Step A: Ethyl 6-ethoxypicolinate

[1463] To a solution of 6-hydroxypicolinic acid (12 g, 86.33 mmol) in DCM (250 ml) was added Ag 2 CO 3 (48 g, 174 mmol) was then added dropwise EtI (27.6 ml, 345.32 mmol). The mixture was stirred at 25°C for 12 hours and filtered. The filtrate was concentrated in vacuo to give ethyl 6-ethoxypicolinate as a grey oil which was used in the next step without further purification.

[1464] LC-MS: m / z 196.3 (M+H) +

[1465] Step B: (6-ethoxypyridin-2-yl)methanol

[1466] To a solution of ethyl 6-ethoxypicolinate (5.8 g, 29.7 mmol) in THF (60 ml) was added dropwise LiAlH 4 (15 ml, 1 M THF sol). The reaction mixture was stirred at 25 °C for 3 h and heated with H 2 O / EA quenching. The collected organic layer was washed with Na 2 SO 4 Dry and concentrate in vacuo.The residue is purified by silica gel chromatography to give (6-ethoxypyridin-2-yl)methanol.

[1467] LC-MS: m / z 154.3 (M+H) +

[1468] Step C: 6-Ethoxypyridinecarboxaldehyde

[1469] To a solution of (6-ethoxypyridin-2-yl)methanol (3 g, 19.61 mmol) in 1,4-dioxane (30 mL) was added MnO 2 (12 g, 137.25 mmol) and reflux the reaction mixture for 3 hours. Filter the reaction mixture and concentrate the filtrate in vacuo to obtain 6-ethoxypicolinaldehyde.

[1470] LC-MS: m / z 152.3 (M+H) +

[1471] Step D: 3-Chloro-N-(2,6-dimethoxyphenyl)pyrazin-2-amine

[1472] To a solution of 2,3-dichloropyrazine (0.918 g, 6 mmol) in THF (15 mL) was slowly added KHMDS (1NTMF, 6 mL, 6 mmol) at 0°C, 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 washed with Na 2 SO 4 Drying and concentration in vacuo gave a residue, which was purified by column chromatography (PE:EA=97:3-66:34) to give 3-chloro-N-(2,6-dimethoxyphenyl)pyrazin-2-amine.

[1473] Step E: N-(2,6-dimethoxyphenyl)tetrazo[1,5-a]pyrazin-8-amine

[1474] 3-Chloro-N-(2,6-dimethoxyphenyl)pyrazin-2-amine (0.14 g, 0.53 mmol) and NaN 3 A mixture of (86 mg, 1.32 mmol) in DMSO (3 mL) was stirred at 130°C for 18 h. 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.

[1475] LC-MS: m / z 273.1 (M+H) +

[1476] Step F: N-(2,6-dimethoxyphenyl)tetrazo[1,5-a]pyrazin-8-amine

[1477] To a solution of crude N-(2,6-dimethoxyphenyl)tetrazo[1,5-a]pyrazin-8-amine (143.7 mg, 0.53 mmol) in concentrated aqueous HCl (3 mL) was added SnCl 2 ·H 2 O (1.19 g, 5.3 mmol) was added and the mixture was stirred at 115 °C for 2 hours. After cooling to room temperature, K 2 CO 3 The mixture was adjusted to pH = 8-9 and filtered. The filtrate was extracted with EA and the organic layer was washed with Na 2 SO 4 Drying and concentration in vacuo gave a residue, which was purified by column chromatography (PE:EA=97:3-66:34) to give N-(2,6-dimethoxyphenyl)tetrazo[1,5-a]pyrazin-8-amine.

[1478] LC-MS: m / z 247.1 (M+H) +

[1479] Step G: 1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine

[1480] A mixture of N-(2,6-dimethoxyphenyl)tetrazo[1,5-a]pyrazin-8-amine (70 mg, 0.285 mmol) and 6-ethoxypicolinaldehyde (43 mg, 0.285 mmol) in AcOH (1 mL) was stirred at 110° C. for 10 min at MW. 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) +

[1481] Example 19: N-(5-(2,6-dimethoxyphenyl)-6-(6-ethoxypyridin-2-yl)-5H-pyrrolo[2,3-b]pyrazin-3-yl)methanesulfonamide

[1482]

[1483] Step A: 2-Bromo-6-ethoxypyridine

[1484] To a solution of 2,6-dibromopyridine (20 g, 84 mmol, 1 eq.) in EtOH (200 mL) was added sodium ethoxide (22.9 g, 336 mmol, 4 eq.). 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 purified by Na 2 SO 4 Dry, filter and concentrate in vacuo.The residue was purified by silica gel chromatography (100% PE) to provide the title compound.

[1485] LC-MS: m / z 202.0, 204.0 (M+H) +

[1486] Step B: 2-Ethoxy-6-((trimethylsilyl)ethynyl)pyridine

[1487] 2-Bromo-6-ethoxypyridine (13.0 g, 64 mmol, 1 equivalent), ethynyltrimethylsilane (10.11 g, 103 mmol, 1.6 equivalent), Pd(PPh 3 ) 2 Cl 2( 1.13 g, 1.6 mmol, 0.025 equiv) and CuI (610 mg, 3.2 mmol, 0.05 equiv) in Et 3 The suspension in N (230 mL) was stirred for 2 h. 2 Stir at 85°C under atmosphere for 2.5 hours. Filter the mixture through celite. Concentrate the filtrate in vacuo and purify the residue by flash chromatography (100% PE) to give the title compound 6-chloro-3-((6-ethoxypyridin-2-yl)ethynyl)pyrazin-2-amine.

[1488] LC-MS: m / z 220.3 (M+H) +

[1489] Step C: 2-ethoxy-6-ethynylpyridine

[1490] To a solution of 2-ethoxy-6-((trimethylsilyl)ethynyl)pyridine (11 g, 50.2 mmol, 1 eq) in THF (100 mL) was added TBAF (50 mL, 50.2 mmol, 1 eq). The resulting mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated in vacuo and the residue was purified by flash chromatography (PE / EtOAc=100 / 1) to give the title compound 2-ethoxy-6-ethynylpyridine.

[1491] LC-MS: m / z 148.1 (M+H) +

[1492] Step D: 6-Chloro-3-((6-ethoxypyridin-2-yl)ethynyl)pyrazin-2-amine

[1493] 2-Ethoxy-6-ethynylpyridine (2.0 g, 13.6 mmol, 1 eq.), 3-bromo-6-chloropyrazin-2-amine (2.8 g, 13.6 mmol, 1 eq.), Pd(PPh 3 ) 2 Cl 2( 238 mg, 0.34 mmol, 0.03 equiv) and CuI (129 mg, 0.68 mmol, 0.06 equiv) in Et 3 The suspension in N (80 mL) was stirred for 2 h. 2 The mixture was stirred at 85°C for 2 hours under 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.

[1494] LC-MS: m / z 275.1 (M+H) +

[1495] Step E: 3-Chloro-6-(6-ethoxypyridin-2-yl)-5H-pyrrolo[2,3-b]pyrazine

[1496] To a solution of 6-chloro-3-((6-ethoxypyridin-2-yl)ethynyl)pyrazin-2-amine (2.3 g, 8.4 mmol, 1 eq) in THF (50 mL) was added NaH (0.5 g, 12.6 mmol, 1.5 eq) at 0°C. The mixture was stirred at room temperature for 1 hour and then heated to 60°C overnight. The mixture was washed with 0.5 mL of H 2 O, then concentrated to dryness in vacuo to give a residue, which was purified by flash chromatography (PE / EtOAc=5 / 1) to give the title compound, 3-chloro-6-(6-ethoxypyridin-2-yl)-5H-pyrrolo[2,3-b]pyrazine.

[1497] LC-MS: m / z 275.1 (M+H) +

[1498] Step F: 3-Chloro-5-(2,6-dimethoxyphenyl)-6-(6-ethoxypyridin-2-yl)-5H-pyrrolo[2,3- b]pyrazine

[1499] 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 eq.), dry pyridine (865 mg, 11 mmol, 3 eq.) and A suspension of molecular sieves in anhydrous DCE (10 mL) was stirred at 4 °C for 2 h. 2 The mixture was stirred at 25°C for 30 hours under 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 give the title compound 3-chloro-5-(2,6-dimethoxyphenyl)-6-(6-ethoxypyridin-2-yl)-5H-pyrrolo[2,3-b]pyrazine.

[1500] LC-MS: m / z 411.1 (M+H) +

[1501] Step G: N-(5-(2,6-dimethoxyphenyl)-6-(6-ethoxypyridin-2-yl)-5H-pyrrolo[2,3-b] Pyrazin-3-yl)methanesulfonamide

[1502] The samples were irradiated with microwave at 115 °C in N 2 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 K were stirred under atmosphere. 2 CO 3 (30 mg, 0.22 mmol, 3 eq.) in DMF (2 mL) for 2 h. The reaction mixture was poured into H 2 O (20 mL) and extracted with EtOAc (3 × 20 mL). The extract was washed with water (10 mL) and brine (10 mL), and MgSO 4Dry and concentrate in vacuo.The residue is purified 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.

[1503] 1 H NMR (DMSO-d 6 )δ:8.17(s,1H),7.69(t,J=7.6Hz,1H),7.36-7.40(m,2H),7.31(s,1H),6.78(d,J=8.4Hz,2H ),6.61(d,J=8.0Hz,1H),3.53-3.55(m,2H),3.52(s,6H),3.12(s,3H),1.08(t,J=7.2Hz,3H).

[1504] LC-MS: m / z 470.0 (M+H) +

[1505] Example 20: N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyridin-6-yl)methanesulfonamide

[1506]

[1507] Step A: N-(5-bromo-3-iodopyridin-2-yl)-6-ethoxypicolinamide

[1508] To a toluene (50 mL) solution of 5-bromo-3-iodopyridin-2-amine (2 g, 6.7 mmol, 1.1 eq.) was added Al(Me) dropwise at room temperature. 3 (1.6 mol / L toluene solution, 7.6 mL, 12.2 mmol, 2 eq.). After the mixture was stirred at 50 °C for 30 min, ethyl 6-ethoxypicolinate (1.19 g, 6.1 mmol, 1 eq.) was added and the mixture was stirred at 110 °C for 2 h. 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) and washed with anhydrous Na 2 SO 4 Dry and concentrate in vacuo. The residue is 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.

[1509] LC-MS: m / z 447.9,449.9 (M+H) +

[1510] Step B: N-(5-bromo-3-((2,6-dimethoxyphenyl)amino)pyridin-2-yl)-6-ethoxypicolinamide

[1511] N-(5-bromo-3-iodopyridin-2-yl)-6-ethoxypicolinamide (200 mg, 0.45 mmol, 1 equivalent), 2,6-dimethoxyaniline (68 mg, 0.45 mmol, 1 equivalent), Pd 2 (dba) 3 (82 mg, 0.09 mmol, 0.1 eq), Xantphos (208 mg, 0.36 mmol, 0.8 eq) and Cs 2 CO 3 A suspension of (292 mg, 0.87 mmol, 2 eq.) in 1,4-dioxane (50 mL) was irradiated by microwaves at 120 °C under N 2 The mixture was diluted with water (30 mL) and then extracted with EtOAc (3×20 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 Dry and concentrate 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.

[1512] LC-MS: m / z 473.0,475.0 (M+H) +

[1513] Step C: 6-bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5- b]pyridine

[1514] To a solution of N-(5-bromo-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide (100 mg, 0.21 mmol, 1 eq) in AcOH (10 mL) was added 1 drop of POCl 3 The mixture was stirred at 120°C for 2 hours by microwave irradiation. The mixture was cooled to room temperature, evaporated and the residue was purified by preparative TLC (PE / EtOAc=1 / 1) to provide the title compound 6-bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyridine.

[1515] LC-MS: m / z 455.0,457.0 (M+H) +

[1516] Step D: N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b] Pyridin-6-yl)methanesulfonamide

[1517] The samples were irradiated with microwave at 115 °C in N 26-Bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine (40 mg, 0.09 mmol, 1 eq.), methanesulfonamide (17 mg, 0.18 mmol, 2 eq.), CuI (34 mg, 0.18 mmol, 2 eq.), trans-N,N'-dimethylcyclohexane-1,2-diamine (25 mg, 0.18 mmol, 2 eq.) and K were stirred under atmosphere. 2 CO 3 (37 mg, 0.27 mmol, 3 eq.) in DMF (5 mL) for 1.5 h. The reaction was diluted with water (15 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 Dry and concentrate 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.

[1518] 1 H NMR (DMSO-d 6 )δ:9.88(br.s.,1H),8.38(d,J=2.4Hz,1H),7.91(dd,J=7.4Hz,0.8Hz,1H),7.84(t,J=7.8Hz,1H),7.47(t,J=8.4Hz,1H),7.19(d,J=2 .4Hz,1H),6.89(d,J=8.5Hz,2H),6.79(dd,J=8.1,0.9Hz,1H),3.58(s,6H),3.39(q,J=7.2Hz,2H),2.96(s,3H),1.02(t,J=7.2Hz,3H).

[1519] LC-MS: m / z 470.1 (M+H) +

[1520] Example 21: N-(5-(2,6-dimethoxyphenyl)-6-(6-ethoxypyridin-2-yl)-5H-imidazo[4,5-c]pyridazin-3-yl)methanesulfonamide

[1521]

[1522] Step A: 6-Chloropyridazin-3-amine

[1523] A suspension of 3,6-dichloropyridazine (10 g, 67 mmol, 1 eq) in 25% aqueous ammonia (50 mL) was heated at 120° C. for about 12 hours in a PTFE-lined pressure reactor. 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.

[1524] LC-MS: m / z 130.0 (M+H) +

[1525] A suspension of 3,6-dichloropyridazine (10 g, 67 mmol, 1 eq) in 25% aqueous ammonia (50 mL) was heated at 120° C. for about 12 hours in a PTFE-lined pressure reactor. 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.

[1526] LC-MS: m / z 130.0 (M+H) +

[1527] Step B: 4-Bromo-6-chloropyridazin-3-amine

[1528] To a solution of 6-chloropyridazin-3-amine (6.2 g, 48 mmol, 1 eq.) in methanol (200 mL) was added NaHCO 3 (8.1 g, 96 mmol, 2 equivalents). After the mixture was stirred at room temperature for 30 minutes, bromine (11.5 g, 72 mmol, 1.5 equivalents) was added dropwise. The reaction mixture was then stirred for another 16 hours and concentrated in vacuo to obtain a residue. The residue was purified by silica gel column chromatography (eluted with 40% EtOAc / hexane) to give the title compound 4-bromo-6-chloropyridazine-3-amine.

[1529] LC-MS: m / z 207.9, 209.9 (M+H) +

[1530] Step C: N-(4-bromo-6-chloropyridazin-3-yl)-6-ethoxypicolinamide

[1531] DMF (0.1 mL) was added to a solution of 6-ethoxypicolinic acid (2.3 g, 13.9 mmol, 1.2 eq) and oxalyl chloride (2.2 g, 17.4 mmol, 1.5 eq) in DCM (50 mL) at 0 ° C. The resulting mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated in vacuo to give 6-ethoxypicolinoyl chloride, which was used directly. NaH (1.4 g, 34.8 mmol, 3 eq) was added to a solution of 4-bromo-6-chloropyridazine-3-amine (2.4 g, 11.6 mmol, 1 eq) in DMF (50 mL) at room temperature. The mixture was stirred at room temperature for 1 hour, 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) and washed with anhydrous Na 2 SO 4 Dry and concentrate in vacuo. The residue is recrystallized from DCM to give the title compound N-(4-bromo-6-chloropyridazin-3-yl)-6-ethoxypicolinamide.

[1532] LC-MS: m / z 356.9, 358.9 (M+H) +

[1533] Step D: N-(6-chloro-4-((2,6-dimethoxyphenyl)amino)pyridazin-3-yl)-6-ethoxypicolinamide

[1534] N-(4-bromo-6-chloropyridazin-3-yl)-6-ethoxypicolinamide (500 mg, 1.4 mmol, 1 eq), 2,6-dimethoxyaniline (214 mg, 1.4 mmol, 1 eq), Pd(OAc) 2 (63 mg, 0.28 mmol, 0.2 eq), Xantphos (324 mg, 0.56 mmol, 0.4 eq) and K 2 CO 3 A suspension of (386 mg, 2.8 mmol, 2.0 equiv) in 1,4-dioxane (10 mL) was irradiated by microwaves at 120 °C under N 2 Stir for 2 hours under atmosphere. Filter the mixture through celite and concentrate the filtrate in vacuo. Purify the residue 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.

[1535] LC-MS: m / z 430.1 (M+H) +

[1536] Step E: Chloro-7-(2,6-dimethoxyphenyl)-8-(6-ethoxypyridin-2-yl)-7H-imidazo[4,5-c] Pyridazine

[1537] 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 hours by microwave irradiation. After the reaction solution was cooled to room temperature, the light yellow precipitate was filtered out and washed with EtOAc / PE=1 / 2 (2*0.5 mL) to give the title compound chloro-7-(2,6-dimethoxyphenyl)-8-(6-ethoxypyridin-2-yl)-7H-imidazo[4,5-c]pyridazine.

[1538] 1 H NMR (400 MHz, DMSO-d 6 )δ8.05(dd,J=7.4,0.8Hz,1H),7.93(dd,J=8.4,7.4Hz,1H),7.67(s,1H),7.50(t,J=8.4Hz,1H),6.93(d d,J=8.4,0.8Hz,1H),6.89(d,J=8.4Hz,2H),3.60(s,6H),3.40(q,J=7.2Hz,2H),1.04(t,J=7.2Hz,3H).

[1539] LC-MS: m / z 412.1 (M+H) +

[1540] Step E: N-(7-(2,6-dimethoxyphenyl)-8-(6-ethoxypyridin-2-yl)-7H-imidazo[4,5-c] Pyridazinyl)methanesulfonamide

[1541] The samples were irradiated with microwave at 130 °C in N 2 Chloro-7-(2,6-dimethoxyphenyl)-8-(6-ethoxypyridin-2-yl)-7H-imidazo[4,5-c]pyridazine (48 mg, 0.12 mmol, 1 eq.), methanesulfonamide (22 mg, 0.23 mmol, 2 eq.), CuI (44 mg, 0.23 mmol, 2 eq.), trans-N,N'-dimethylcyclohexane-1,2-diamine (33 mg, 0.23 mmol, 2 eq.) and K were stirred under atmosphere. 2 CO 3 (48 mg, 0.23 mmol, 3 eq.) in DMF (2 mL) for 1.5 h. The reaction solution was diluted with water (150 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 Dried and concentrated in vacuo.The residue was purified by flash chromatography (eluted with DCM / MeOH = 100 / 1) to afford the title compound (30 mg, 55% yield) as a yellow solid.

[1542] 1 H NMR (400 MHz, DMSO-d 6 )δ10.78(s,1H),8.01(dd,J=7.4,0.8Hz,1H),7.91(dd,J=8.4,7.4Hz,1H),7.50(t,J=8.4Hz,1H),6.91(d d,J=8.4,1.2Hz,4H),3.61(s,6H),3.39(q,J=7.2Hz,2H),3.22(s,3H),1.03(t,J=7.2Hz,3H).LC-MS:m / z 471.1(M+H) +

[1543] Method C:

[1544]

[1545] Step A: N-(3-bromo-5-chloropyrazin-2-yl)-6-ethoxypicolinamide

[1546]

[1547] To a mixture of 3-bromo-5-chloropyrazin-2-amine (14.1 g, 67.6 mmol, 1.0 eq.) and toluene (60 mL) was added AlMe 3 (2mol / L, 51mL, 102mmol, 1.5 equivalents) and the resulting mixture was stirred at 55°C for 30 minutes. Ethyl 6-ethoxypicolinate (14.5g, 74.4mmol, 1.1 equivalents) was added and the mixture was stirred at 110°C for 1.5 hours. The mixture was quenched with 1N HCl (102mL, 102mmol, 1.5 equivalents) and extracted with DCM (3×500mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was re-slurried in DCM to give the title compound N-(3-bromo-5-chloropyrazine-2-yl)-6-ethoxypicolinamide as a light yellow solid (12g, 50% yield).

[1548] LC-MS: m / z 356.9, 358.9 (M+H) +

[1549] Step B: N-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide

[1550]

[1551] N-(3-bromo-5-chloropyrazin-2-yl)-6-ethoxypicolinamide (1 g, 2.8 mmol, 1.0 eq), 2,6-dimethoxyaniline (475 mg, 3.4 mmol, 1.1 eq), Pd(OAc) 2 (126 mg, 0.56 mmol, 0.2 eq), Xantphos (650 mg, 1.12 mmol, 0.4 eq) and K 2 CO 3 A suspension of (772 mg, 5.6 mmol, 2.0 equiv) in 1,4-dioxane (15 mL) was irradiated by microwaves at 120 °C under N 2 Stir for 2 hours under atmosphere. The mixture is filtered through celite and the filtrate is concentrated in vacuo. The residue is purified by flash column chromatography (100% DCM) to give the desired product, N-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide, as a yellow solid (6.3 g, 52% yield).

[1552] LC-MS: m / z 430.1 (M+H) +

[1553] Step C: 6-chloro-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5- b]pyrazine

[1554]

[1555] A solution of N-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide (2.0 g, 4.66 mmol) in AcOH (10 mL) was stirred at 130° C. for 2 hours by microwave irradiation. The mixture was cooled to room temperature, 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).

[1556] LC-MS: m / z 412.1 (M+H) +

[1557] Step D: N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b] Pyrazin-6-yl)methanesulfonamide (Example 2)

[1558]

[1559] The samples were irradiated with microwave at 130 °C in N 26-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 equivalents), CuI (924 mg, 4.87 mmol, 3.0 equivalents), trans-N,N'-dimethylcyclohexane-1,2-diamine (691 mg, 4.87 mmol, 3.0 equivalents) and K were stirred under atmosphere. 2 CO 3 (1006 mg, 7.29 mmol, 3 eq) in DMF (10 mL) for 1.5 h. The mixture was diluted with EtOAc (30 mL) and filtered through celite. The filtrate was poured into K 2 CO 3 The mixture was added to an aqueous solution (2 mol / L, 50 mL) and stirred for 15 minutes. The aqueous phase was then separated and washed with EtOAc (2×30 mL). The aqueous phase was adjusted to pH=4 with formic acid and extracted with DCM (3×100 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 The residue was purified by flash column chromatography using DCM / MeOH = 20 / 1 to 10 / 1 as eluent 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).

[1560] 1 H NMR (400 MHz, DMSO-d 6 )δ:11.05(s,1H),8.27(s,1H),7.95(dd,J=7.6Hz,J=0.8Hz,1H),7.86(t,J=7.6Hz,1H),7.45(t,J=8.4Hz, 1H),6.81-6.87(m,3H),3.57(s,6H),3.39(q,J=7.2Hz,2H),3.20(s,3H),1.03(t,J=7.2Hz,3H).LC-MS:m / z 471.0(M+H) +

[1561] Example 22: N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)cyclopropanesulfonamide

[1562]

[1563] The title compound was prepared according to Method C, Step D starting from N-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide using cyclopropanesulfonamide (22 mg, 37% yield).

[1564] 1 H NMR (400 MHz, DMSO-d 6 )δ:8.25(s,1H),8.02(s,1H),7.86(d,J=7.2Hz,1H),7.78(t,J=7.6Hz,1H),7.41(t,J= 8.4Hz,1H),6.82(d,J=8.4Hz,2H),6.72(d,J=8.0Hz,1H),3.55(s,6H),3.37(q,J=7.2Hz 2H),2.52-2.54(m,1H),1.01(t,J=7.2Hz,3H),0.79-0.83(m,2H),0.64-0.69(m,2H).LCMS:m / z497.1(M+H) +

[1565] Example 23: N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)pyridine-2-sulfonamide

[1566]

[1567] The title compound was prepared according to Method C, Step D starting from N-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide using pyridine-2-sulfonamide (30 mg, 23% yield).

[1568] 1 HNMR (400 MHz, DMSO-d 6 )δ:11.77(s,1H),8.55(d,J=4.0Hz,1H),8.21(s,1H),7.89(d,J=7.6Hz,1H),7.80(t,J=7.6Hz,1H),7.71(d,J=7.6Hz,1H),7.60(d,J=7.6Hz,1 H),7.49(t,J=8.4Hz,2H),6.86(d,J=8.4Hz,2H),6.77(d,J=8.0Hz,1H),3.51(s,6H),3.37(q,J=7.2Hz,2H),1.01(t,J=7.2Hz,3H).LC-MS:m / z 534(M+H) +

[1569] Example 24: N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)pyridine-3-sulfonamide

[1570]

[1571] The title compound was prepared according to Method C, Step D starting from N-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide using pyridine-3-sulfonamide (58 mg, 54% yield).

[1572] 1 H NMR (400 MHz, DMSO-d 6 )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=8.4Hz,2H),7.84(t,J=8.0Hz,1H),7.55(t,J=8.0Hz,1H),7.37(d d,J=8.0,4.8Hz,1H),6.93(d,J=8.0Hz,2H),6.80-6.83(m,1H),3.55(s,6H),3.39(q,J=7.1Hz,2H),1.03(t,J=7.1Hz,3H).LC-MS:m / z534.0(M+H) +

[1573] Example 25: N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)pyridine-4-sulfonamide

[1574]

[1575] The title compound was prepared according to Method C, Step D starting from N-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide using pyridine-4-sulfonamide (45 mg, 57% yield).

[1576] 1 H NMR (400 MHz, DMSO-d 6)δ:8.40(s,2H),7.79-7.86(m,2H),7.75((t,J=8.0Hz,1H),7.53(t,J=8.4Hz,1H),7.43(d,J=4.8Hz,2H),6.93 (d,J=8.4Hz,2H),6.69(d,J=8.0Hz,1H),3.53(s,6H),3.38(d,J=7.2Hz,2H),1.01(t,J=7.2Hz,3H).LC-MS:m / z 534.0(M+H) +

[1577] 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

[1578]

[1579] The title compound was prepared according to Method C, Step D starting from N-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide using pyridin-3-ylmethanesulfonamide (24 mg, 25% yield).

[1580] 1 H NMR (400 MHz, DMSO-d 6 )δ:11.13(s,1H),8.32-8.54(m,8.8Hz,2H),8.17(s,1H),7.97(dd,J=7.4 ,0.9Hz,1H),7.87(dd,J=8.2,7.6Hz,1H),7.44-7.5(m,2H),7.38(s,1H), 6.89(d,J=4.0Hz,2H),6.84(dd,J=4.0,8.0Hz,3H),4.72(s,2H),3.58(s,6H),3.40(q,J=6.6Hz,2H),1.03(t,J=7.2Hz,3H).LC-MS:m / z548.0(M+H) +

[1581] 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

[1582]

[1583] The title compound was prepared according to Method C, Step D starting from N-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide using pyridin-2-ylmethanesulfonamide (30 mg, 37% yield).

[1584] 1 H NMR (400M, DMSO-d 6 )δ:11.12(br,1H),8.45-8.47(m,1H),8.14(s,1H),7.94(dd,J=7.6Hz,J=0.8Hz,1H),7.8 6(t,J=7.6Hz,1H),7.75(td,J=7.6Hz,J=1.6Hz,1H),7.47(t,J=8.4Hz,1H),7.31-7.34(m ,1H),7.2(d,J=7.6Hz,1H),6.87(d,J=8.4Hz,1H),6.82(dd,J=8.0Hz,J=0.8Hz,1H),4.79 (s,2H),3.56(s,6H),3.40(q,J=7.2Hz,2H),1.03(t,J=7.2Hz,3H).LC-MS:m / z548.6(M+H) +

[1585]

[1586] Step A: Pyrimidin-2-ylmethanol

[1587]

[1588] To a solution of methyl pyrimidine-2-carboxylate (25 g, 181 mmol, 1.0 eq.) in MeOH (500 mL) was added NaBH 4 (8.2 g, 217 mmol, 1.2 eq.). The reaction mixture was stirred at room temperature for 3 h. 2 O (10 mL), concentrated in vacuo, and 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).

[1589] LC-MS: m / z 111.0 (M+H) +

[1590] Step B: 2-((Pyrimidin-2-ylmethyl)thio)benzo[d]thiazole

[1591]

[1592] Pyrimidin-2-ylmethanol (16.6 g, 151 mmol, 1.0 eq), benzo[d]thiazole-2-thiol (30 g, 181 mmol, 1.2 eq) and PPh 3 DEAD (36.6 g, 181 mmol, 1.2 eq.) was added to a solution of (47.4 g, 181 mmol, 1.2 eq.) in THF (500 mL). The mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with HCl-dioxane and the white precipitate was filtered out. The solid was then dissolved in 1N Na 2 CO 3 The reaction mixture was added to an aqueous solution (100 mL) and extracted with EtOAc (3 x 200 mL). The combined organic phases were concentrated in vacuo to afford the title compound 2-((pyrimidin-2-ylmethyl)thio)benzo[d]thiazole as a crude yellow solid (27 g, 77% yield).

[1593] LC-MS: m / z 260.0 (M+H) +

[1594] Step C: 2-((Pyrimidin-2-ylmethyl)sulfonyl)benzo[d]thiazole

[1595]

[1596] To a solution of 2-((pyrimidin-2-ylmethyl)thio)benzo[d]thiazole (27 g, 104 mmol, 1.0 eq) in DCM (500 mL) was added m-CPBA (51 g, 249 mmol, 2.4 eq). The mixture was stirred at room temperature for 16 h and heated to 1 N Na 2 SO 3 The organic phase was separated and quenched with saturated Na 2 CO 3 Washed 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)benzo[d]thiazole as a white solid (17 g, 80% yield).

[1597] LC-MS: m / z 292.0 (M+H) +

[1598] Step D: Pyrimidin-2-ylmethanesulfonamide

[1599]

[1600] 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 K 2 CO 3(1.2 g, 8.5 mmol, 5.0 equiv.). After the mixture was stirred at room temperature for 10 minutes, NH 2 OSO 3 H (250 mg, 2.0 mmol, 1.2 eq.) 2 The mixture was stirred at room temperature for 15 minutes and another portion of H 2 NH in O (1 mL) 2 OSO 3 H (250 mg, 2.0 mmol, 1.2 eq). The resulting mixture was stirred at room temperature for 60 h. 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).

[1601] 1 H NMR (400MHz, DMSO) δ8.83 (d, J=4.8Hz, 2H), 7.49 (t, J=4.8Hz, 1H), 7.01 (s, 2H), 4.55 (s, 2H). LC-MS: m / z 174.0 (M+H) +

[1602] 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

[1603]

[1604] The title compound was prepared according to Method C, Step D starting from N-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide using pyrimidin-2-ylmethanesulfonamide (27 mg, 34% yield).

[1605] 1 H NMR (400 MHz, DMSO-d 6 )δ:11.19(s,1H),8.74(d,J=4.8Hz,2H),8.21(s,1H),7.94(d,J=7.2Hz,1H),7.86(t,J=8.0Hz,1H),7.40-7.49(m,2H), 6.85(d,J=8.4Hz,2H),6.82(dd,J=8.2,0.8Hz,1H),3.55(s,6H),3.39(q,J=7.2Hz,2H),1.02(t,J=7.2Hz,3H).LCMS:m / z 548.9(M+H) +

[1606] 2-Cyclopropylethanesulfonamide

[1607]

[1608] The title compound was prepared according to the preparation of pyrimidin-2-ylmethanesulfonamide in step A using 2-cyclopropylethanol.

[1609] LC-MS: m / z 150.2 (M+H) +

[1610] Example 29: 2-Cyclopropyl-N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)ethanesulfonamide

[1611]

[1612] The title compound (50 mg, 47% yield) was prepared 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) using 2-cyclopropylethanesulfonamide.

[1613] 1 H NMR (400M, DMSO-d 6 )δ:10.98(br,1H),8.27(s,1H),7.95(d,J=7.2Hz,1H),7.85(t,J=8.4Hz,1H),7.45(t,J=8.4Hz,1H),6.86(d,J=8.4Hz,2H),6.82(d,J=8.4Hz,1H ),3.58(s,6H),3.36-3.42(m,4H),1.47-1.52(m,2H),1.03(t,J=7.2Hz, 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) +

[1614] Oxetane-3-sulfonamide

[1615]

[1616] The title compound was prepared according to the preparation of pyrimidin-2-ylmethanesulfonamide in Step A using oxetan-3-ol.

[1617] 1H NMR (400MHz, DMSO) δ: 7.17 (s, 2H), 4.79 (dd, J = 8.0, 7.2Hz, 2H), 4.68-4.65 (m, 2H), 4.47-4.40 (m, 1H).

[1618] Example 30: N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)oxetane-3-sulfonamide

[1619]

[1620] The title compound was prepared according to Method C, Step D starting from N-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide using oxetane-3-sulfonamide (36.3 mg, 35% yield).

[1621] 1 H NMR (400 MHz, DMSO-d 6 )δ:8.05(s,1H),7.91(d,J=7.6Hz,1H),7.81(t,J=7.6Hz,1H),7.43(t,J=8.4Hz,1H),6.86(d,J=8.4Hz,2H),6.76(d,J=8. 0Hz,1H),4.49-4.67(m,3H),4.34(t,J=6.6Hz,2H),3.60(s,6H),3.38(q,J=7.2Hz,2H),1.02(t,J=7.2Hz,3H).LC-MS:m / z 513.1(M+H) +

[1622]

[1623] Step A: 2-(Cyclobutylthio)pyrimidine

[1624]

[1625] In N 2 atmosphere at 0°C to PPh 3To a solution of 2-(4.37 g, 16.7 mmol, 1.2 equiv) in THF (30 mL) was added DIAD (3.37 g, 16.7 mmol, 1.2 equiv) dropwise. After the mixture was stirred 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 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 provide the desired 2-(cyclobutylthio)pyrimidine as a yellow oil (2.0 g, 87% yield).

[1626] LC-MS: m / z 167.0 (M+H) +

[1627] Step B: 2-(Cyclobutylsulfonyl)pyrimidine

[1628]

[1629] To a solution of m-CPBA (5.7 g, 33.1 mmol, 3 eq.) in DCM (80 mL) was added 2-(cyclobutylthio)pyrimidine (1.83 g, 11.0 mmol, 1.0 eq.). The reaction mixture was stirred at room temperature for 16 h. Saturated Na 2 S 2 O 3 Aqueous solution (20 mL) was added and the mixture was stirred at room temperature for 30 minutes. The organic phase was separated and washed with brine and then with anhydrous Na 2 SO 4 Dry and concentrate 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).

[1630] LC-MS: m / z 199.0 (M+H) +

[1631] Step C: Cyclobutanesulfonamide

[1632]

[1633] To a solution of 2-(cyclobutylsulfonyl)pyrimidine (1.75 g, 8.84 mmol, 1.0 eq.) in MeOH (40 mL) was added NaOMe (5.4 mol / L, 1.64 mL, 1.0 eq.). After the reaction mixture was stirred at 0 °C for 30 min, NaOAc (906 mg, 11.05 mmol, 1.25 eq.) and HOSO3 NH 2 (1.25 g, 11.05 mmol, 1.25 equiv) in water (5 mL). The resulting mixture was stirred at room temperature for 16 hours. 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).

[1634] LC-MS: m / z 136.0 (M+H) +

[1635] Example 31: N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)cyclobutanesulfonamide

[1636]

[1637] The title compound was prepared according to Method C, Step D starting from N-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide using cyclobutanesulfonamide (85 mg, 64% yield).

[1638] 1 H NMR (400 MHz, DMSO-d 6 )δ:10.87(s,1H),8.31(s,1H),7.95(dd,J=7.4,0.8Hz,1H),7.86(dd,J=8.4,7.6H z,1H),7.46(t,J=8.4Hz,1H),6.87(d,J=8.4Hz,2H),6.83(dd,J=8.4,0.8Hz,1H), 4.09-4.22(m,1H),3.59(s,6H),3.39(q,J=7.2Hz,2H),2.28(ddt,J=13.0,10.6,8 .6Hz,2H),2.02-2.13(m,2H),1.75-1.92(m,2H),1.03(t,J=7.2Hz,3H).LC-MS:m / z 511.2(M+H) +

[1639] Example 32: N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-N-methylmethanesulfonamide

[1640]

[1641] The title compound (40 mg, 75% yield) was prepared 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) using N-methylmethanesulfonamide.

[1642] 1 H NMR (400 MHz, DMSO-d 6 )δ:8.63(s,1H),7.98(t,J=7.2Hz,1H),7.89(t,J=8.4Hz,1H),7.47(t,J=8.4Hz,1H),6.87(d,J=8.4Hz,2H),6.86(d,J= 8.4Hz,2H),3.57(s,6H),3.41(q,J=7.2Hz,2H),3.26(s,3H),3.12(s,3H),1.03(t,J=7.2Hz,3H).LC-MS:m / z485.2(M+H) +

[1643] trans-3-(Benzyloxy)cyclobutane-1-sulfonamide

[1644]

[1645] The title compound was prepared according to the preparation of cyclobutanesulfonamide in Step A using cis-3-(benzyloxy)cyclobutanol.

[1646] 1 H NMR (400 MHz, DMSO-d 6 )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).

[1647]

[1648] trans-3-(Benzyloxy)-N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)cyclobutane-1-sulfonamide

[1649]

[1650] The title compound was prepared according to Method C, Step D starting from N-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide using trans-3-(benzyloxy)cyclobutane-1-sulfonamide (460 mg, 48% yield).

[1651] 1 H NMR (400 MHz, DMSO-d 6 )δ:11.00(s,1H),8.23(s,1H),7.94-7.96(m,1H),7.85(t,J=8.0Hz,1H),7.43(t,J=8.0Hz,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=8.0Hz,3H).LC-MS:m / z617.0(M+H) +

[1652] 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

[1653]

[1654] At 0°C and N 2 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) was added trifluoromethanesulfonic acid (1 mL) and trifluoromethanesulfonic anhydride (0.5 mL) under N atmosphere. 2 Stir at 0°C for 15 minutes under atmosphere. Then, NaHCO 3 The mixture was adjusted to pH = 6 with aqueous solution (3 mol / L), and DCM (60 mL) was added to the mixture. The combined organic layers were washed with brine (20 mL) and purified by Na 2 SO 4 Dry and evaporate under reduced pressure.The residue was purified by silica gel column chromatography (eluted with DCM / MeOH=20 / 1 to 10 / 1) to give the title compound as a brown solid (50 mg, 29% yield).

[1655] 1 H NMR (400 MHz, DMSO-d 6 )δ:8.19(s,1H),7.90(d,J=7.2Hz,1H),7.82(t,J=7.6Hz,1H),7.43(t,J=8.4Hz,1H),6.84(d,J=8.8Hz,2H),6.77(d,J=8.4Hz,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=7.2Hz,2H) ,2.42-2.50(m,2H),1.97-2.12(m,2H),1.02(t,J=7.2Hz,3H).LC-MS:m / z 527.2(M+H) +

[1656] Step B: N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b] Pyrazin-6-yl)-3-oxocyclobutane-1-sulfonamide

[1657]

[1658] 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 at room temperature overnight. The mixture was treated with Na 2 SO 3 (aqueous) brine, washed with anhydrous Na 2 SO 4 Dry and concentrate in vacuo.The residue was purified by preparative TLC to give N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-3-oxocyclobutane-1-sulfonamide as a light yellow solid (50 mg, 83% yield).

[1659] LC-MS: m / z 525.2 (M+H) +

[1660] 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

[1661]

[1662] 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 NaBH 4 (7.2 mg, 0.191 mmol, 3.0 equiv.). The mixture was allowed to warm to room temperature and stirred for 2 h. Afterwards, H 2 O (1 mL) 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).

[1663] 1 H NMR (400 MHz, CDCl 3 )δ:8.48(s,1H),8.04(d,J=7.6Hz,1H),7.60(t,J=7.6Hz,1H),7.30(t,J=8.4Hz,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=7.2Hz,3H).LC-MS:m / z527.2(M+H) +

[1664] Pyrimidin-5-ylmethanesulfonamide

[1665]

[1666] The title compound was prepared according to the preparation of cyclobutanesulfonamide in Step A using pyrimidin-5-ylmethanol.

[1667] 1 H NMR (400 MHz, DMSO-d 6 )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) +

[1668] 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

[1669]

[1670] The title compound was prepared according to Method C, Step D starting from N-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide using pyrimidin-5-ylmethanesulfonamide.

[1671] 1 H NMR (400 MHz, DMSO-d 6 )δ:11.20(s,1H),9.15(s,1H),8.54(s,2H),8.27(s,1H),7.98(d,J=7.6Hz,1H),7.87(t,J=7.6Hz,1H),7.48(t,J=8.4Hz,1H),6 .89(d,J=8.4Hz,2H),6.84(d,J=8.0Hz,1H),4.74(s,2H),3.60(s,6H),3.41(q,J=7.2Hz,2H),1.03(t,J=7.2Hz,3H).LC-MS:m / z 549.2(M+H) +

[1672]

[1673] Step A: Tetrahydro-2H-pyran-4-sulfonamide

[1674]

[1675] To a solution of tetrahydro-2H-pyran-4-sulfonyl chloride (300 mg, 1.6 mmol, 1.6 eq.) in acetone (5 mL) was added NH 4 OH aqueous solution (34% wt., 10 mL, 140 mmol, 88 equiv.). The mixture was stirred at room temperature overnight and then concentrated to dryness. The residue was purified by silica gel column chromatography (DCM / EtOAc=2 / 1) to give the title compound tetrahydro-2H-pyran-4-sulfonamide as a white solid (150 mg, 56% yield).

[1676] LC-MS: m / z 166.2 (M+H) +

[1677] 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

[1678]

[1679] The title compound was prepared according to Method C, Step D starting from N-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide using tetrahydro-2H-pyran-4-sulfonamide (25 mg, 32% yield).

[1680] 1 H NMR (DMSO-d 6 )δ:10.93-11.20(m,1H),8.28(s,1H),7.96(d,J=8.0Hz,1H),7.85(t,J=8.0 Hz,1H),7.46(t,J=7.6Hz,1H),6.88(d,J=8.8Hz,2H),6.82(d,J=8.0Hz,1H) ,3.87-3.91(m,2H),3.58(s,7H),3.39(q,J=7.2Hz,2H),3.07(t,J=11.2Hz, 2H),1.75-1.78(m,2H),1.55-1.66(m,2H),1.02(t,J=7.2Hz,3H).LC-MS:m / z 541.6(M+H) +

[1681] Morpholine-4-sulfonamide

[1682]

[1683] The title compound was prepared according to the preparation of tetrahydro-2H-pyran-4-sulfonamide using morpholine-4-sulfonyl chloride.

[1684] 1 H NMR (400MHz, d 6 -DMSO)δ:6.82(s,2H),3.61-3.68(m,4H),2.89-2.94(m,4H).

[1685] Example 37: N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)morpholine-4-sulfonamide

[1686]

[1687] The title compound (39 mg, 65% yield) was prepared 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) using morpholine-4-sulfonamide.

[1688] 1H NMR (400 MHz, DMSO-d 6 )δ:11.03(s,1H),8.24(s,1H),7.97(dd,J=7.4,0.8Hz,1H),7.85(dd,J=8.2,7.6Hz,1H),7.45(t,J=8.4Hz,1H),6.86(d,J=8.4Hz,2H),6 .82(dd,J=8.2,0.8Hz,1H),3.60(s,6H),3.42-3.46(m,4H),3.38(q,J=7.2Hz,2H),2.90-2.95(m,4H),1.02(t,J=7.2Hz,3H).LC-MS:m / z 543.1(M+H) +

[1689] Benzyl 4-(sulfamoylmethyl)piperidine-1-carboxylate

[1690]

[1691] The title compound was prepared according to the preparation of tetrahydro-2H-pyran-4-sulfonamide using benzyl 4-((chlorosulfonyl)methyl)piperidine-1-carboxylate (350 mg, 56% yield).

[1692] LC-MS: m / z 313.1 (M+H) + .

[1693] 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

[1694]

[1695] The title compound was prepared according to Method C, Step D starting from N-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide using benzyl 4-(sulfamoylmethyl)piperidine-1-carboxylate (210 mg, 45% yield).

[1696] LC-MS: m / z 688.2 (M+H) +

[1697] 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

[1698]

[1699] A solution of 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 concentrated HCl (1 mL) in EtOH (4 mL) was 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 give the title compound as a yellow solid (40 mg, 90% yield).

[1700] 1 H NMR (400 MHz, DMSO-d 6 )δ:8.23(s,1H),7.81-7.83(m,2H),7.74-7.77(m,1H),7.38(t,J=8.0Hz,1H ),6.81(d,J=8.0Hz,2H),6.68(d,J=8.0Hz,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,1 H),1.81-1.84(m,2H),1.18-1.27(m,2H),1.01(t,J=7.2Hz,3H).LC-MS:m / z 554.2(M+H) + .

[1701] 4-Oxocyclohexane-1-sulfonamide

[1702]

[1703] The title compound was prepared according to the preparation of tetrahydro-2H-pyran-4-sulfonamide using 4-oxocyclohexane-1-sulfonyl chloride (150 mg, 56% yield).

[1704] LC-MS: m / z 178.0 (M+H) +

[1705] N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-4-oxocyclohexane-1-sulfonamide

[1706]

[1707] The title compound was prepared according to Method C, Step D starting from N-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide using 4-oxocyclohexane-1-sulfonamide (140 mg, 69% yield).

[1708] LC-MS: m / z 553.2 (M+H) +

[1709] 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

[1710] 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

[1711]

[1712] 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 NaBH 4 (18.6 mg, 0.49 mmol, 3.0 equiv.). The mixture was stirred at 0 °C for 30 min and at room temperature for 3 h. 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) and washed with anhydrous Na 2 SO 4 Dried, 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.

[1713] Embodiment 39: 1 H NMR (400 MHz, DMSO-d 6)δ10.88(s,1H),8.31(s,1H),7.97(dd,J=7.4,0.8Hz,1H),7.86(dd,J=8.2,7.5Hz,1H), 7.46(t,J=8.4Hz,1H),6.77-6.98(m,3H),4.66(d,J=4.2Hz,1H),3.59(s,6H),3.40(q,J =7.2Hz,2H),3.30(q,J=3.4,2.8Hz,1H),2.44-2.50(m,1H),1.88(dd,J=24.0,12.8Hz,4 H),1.39-1.50(m,2H),1.03(t,J=7.2Hz,3H),0.96(dd,J=13.2,10.0Hz,2H).LC-MS:m / z 555.2(M+H) +

[1714] Embodiment 40: 1 H NMR (400 MHz, DMSO-d 6 )δ10.86(s,1H),8.31(s,1H),7.97(dd,J=7.4,0.8Hz,1H),7.86(dd,J=8.4,7.6Hz,1H), 7.45(t,J=8.4Hz,1H),6.87(d,J=8.4Hz,2H),6.83(dd,J=8.2,0.8Hz,1H),4.43(d,J=2. 8Hz,1H),3.76(d,J=5.6Hz,1H),3.58(s,6H),3.39(q,J=7.2Hz,3H),1.81(q,J=14.0,12 .6Hz,2H),1.59-1.74(m,4H),1.19(d,J=12.0Hz,2H),1.02(t,J=7.2Hz,3H).LC-MS:m / z 555.2(M+H) +

[1715]

[1716] Step A: Pyrimidine-2-sulfonyl chloride

[1717]

[1718] Sodium hypochlorite (30.9 mL, 60.0 mmol) was added dropwise to a solution of 2-mercaptopyrimidine (1.1 g, 10 mmol) in CH 2 Cl 2(60 mL) and 1 N HCl (55.0 mL, 55.0 mmol). 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.

[1719] Step B: Pyrimidine-2-sulfonamide

[1720]

[1721] At 0 °C, CH 2 Cl 2 (60 mL) solution was added with NH 4 OH (aqueous, 34%, 60 mL) and the mixture was slowly warmed to room temperature and stirred for 1 hour. The mixture was concentrated under vacuum and purified by silica gel chromatography (CH 2 Cl 2 The residue was purified by 4% paraformaldehyde (5% HCl / MeOH=20 / 1) to afford the title compound pyrimidine-2-sulfonamide as a light yellow solid (350 mg, 1.98 mmol, 20% yield in two steps).

[1722] LC-MS: m / z 160.0 (M+H) +

[1723] Example 41: N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)pyrimidine-2-sulfonamide

[1724]

[1725] The title compound (55 mg, 70% yield) was prepared 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) using pyrimidine-2-sulfonamide.

[1726] 1 H NMR (400 MHz, DMSO-d 6 )δ:11.91(s,1H),8.82(d,J=4.8Hz,2H),8.35(s,1H),7.92(d,J=7.6Hz,1H),7.83(t,J=7.6Hz,1H),7.67(t,J=4.8Hz,1H), 7.41(t,J=8.4Hz,1H),6.78(dd,J=11.4,8.4Hz,3H),3.50(s,6H),3.35(d,J=7.2Hz,2H),1.00(t,J=7.2Hz,3H).LC-MS:m / z 534.1(M+H)+

[1727]

[1728] Step A: 4-Hydroxypiperidine-1-sulfonamide

[1729]

[1730] A mixture of piperidin-4-ol (1.0 g, 10 mmol, 1.0 equiv) and sulfamide (960 mg, 10 mmol, 1.0 equiv) in dioxane (20 mL) was stirred at 120° C. for 16 hours. After evaporation, the residue was purified by flash column chromatography (eluted with DCM / MeOH=10 / 1) to give the title compound 4-hydroxypiperidine-1-sulfonamide as a white solid, (1.09 g, 61% yield).

[1731] 1 H NMR (400 MHz, DMSO-d 6 )δ:6.67(s,2H),4.70(d,J=3.6Hz,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).

[1732] Example 42: N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)-4-hydroxypiperidine-1-sulfonamide

[1733]

[1734] The title compound was prepared according to Method C, Step D starting from N-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide using 4-hydroxypiperidine-1-sulfonamide (34.5 mg, 31% yield).

[1735] 1 H NMR (400 MHz, CDCl 3)δ8.38(s,1H),8.11(d,J=7.2Hz,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=7.2Hz,3H).LC-MS:m / z 555.9(M+H) +

[1736] Method D:

[1737]

[1738] Example 43: N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)methanesulfonamide

[1739]

[1740] The title compound (26 mg, 23% yield) was prepared 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) using methanesulfonamide.

[1741] 1 H NMR (400 MHz, DMSO-d 6 )δ:11.11(s,1H),7.98(d,J=6.8Hz,1H),7.95(s,1H),7.86(t,J=7.6Hz,1H),7.45(t,J=8.4Hz,1H),6.85(d,J=8.4Hz ,2H),6.82(dd,J=8.2,0.4Hz,1H),3.58(s,6H),3.39(q,J=7.2Hz,2H),3.36(s,3H),1.03(t,J=7.2Hz,3H).LCMS:m / z 471.0(M+H) +

[1742] Example 44: N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-5-yl)methanesulfonamide

[1743]

[1744] The title compound was prepared 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) using 2-cyclopropylethanesulfonamide (30 mg, 16% yield).

[1745] 1 H NMR (400 MHz, DMSO-d 6 )δ:7.98-8.00(m,2H),7.86(t,J=8.0Hz,1H),7.45(t,J=8.4Hz,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=7.2Hz,3H),0.92-0.82(m,1H),0.46-0.38(m,2H),0.09(q,J=4.8Hz,2H).LCMS:m / z525.35(M+H) +

[1746] Example 45: 1-cyclopropyl-N-(1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazole[4,5-b]pyrazin-5-yl)methanesulfonamide

[1747]

[1748] The title compound (20 mg, 32% yield) was prepared 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) using cyclopropylmethanesulfonamide. 1 H NMR (400 MHz, DMSO-d 6 )δ:10.95(s,1H),8.06(s,1H),7.98-8.00(m,1H),7.87(t,J=8.0Hz,1H),7.46(t,J=8.0Hz,1H),6.83-6.88(m,3H),3.58(s,6H),3.5 5(d,J=8.0Hz,2H),3.39(q,J=7.2Hz,2H).1.09-1.14(m,1H),1.03(t,J=7.2Hz,3H),0.59-0.61(m,2H),0.36-0.37(m,2H).LC-MS:m / z 511.0(M+H) + .

[1749]

[1750] Example 46: 1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-N-(4-methoxybenzyl)-1H-imidazo[4,5-b]pyrazin-5-amine

[1751]

[1752] 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 equivalent), PMBNH 2 (67 mg, 0.48 mmol, 2.0 equiv), Xantphos (29 mg, 0.048 mmol, 0.2 equiv), Pd 2 (dba) 3 (23 mg, 0.024 mmol, 0.1 eq.), t A mixture of BuOK (55 mg, 0.48 mmol, 2.0 equiv) in toluene (5 mL) was stirred under N 2 Stir at 110°C under atmosphere for 16 hours. Filter the mixture and concentrate the filtrate in vacuo. Purify the residue by silica gel flash chromatography (PE / EtOAc=10 / 1 to 1 / 1) to provide the title compound as a yellow solid (30 mg, 24% yield).

[1753] 1 H NMR(400MHz,DMSO)δ:7.87(d,J=7.2Hz,1H),7.79(t,J=7.6Hz,1H),7.72(s,1H), 7.49(t,J=5.6Hz,1H),7.41(t,J=8.4Hz,1H),7.33(d,J=8.4Hz,2H),6.90(d,J=8 .4Hz,2H),6.82(d,J=8.4Hz,2H),6.74(d,J=7.6Hz,1H),4.48(d,J=5.6Hz,2H),3 .73(s,3H),3.57(s,6H),3.36(q,J=7.2Hz,2H),1.01(t,J=7.2Hz,3H).LCMS:m / z 513.2(M+H) +

[1754] Method E:

[1755]

[1756] Step A: N-(5-chloro-3-((2-methoxy-6-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)-6-ethoxy Pyridinecarboxamide

[1757]

[1758] N-(3-bromo-5-chloropyrazin-2-yl)-6-ethoxypicolinamide (100 mg, 0.28 mmol, 1.0 equiv), 2-methoxy-6-(trifluoromethyl)aniline (53.5 mg, 0.28 mmol, 1.0 equiv), Pd 2 (dba) 3 (102 mg, 0.11 mmol, 0.4 eq), Xantphos (130 mg, 0.22 mmol, 0.8 eq) and K 2 CO 3 A suspension of (77 mg, 0.56 mmol, 2.0 equiv) in 1,4-dioxane (2 mL) was irradiated by microwaves at 130 °C under N 2 Atmosphere stirred for 2 hours.The mixture was filtered through diatomaceous earth and the filtrate was concentrated in vacuo.The residue was purified by flash chromatography (eluted with EtOAc / PE=1 / 6) to give the title compound N-(5-chloro-3-((2-methoxy-6-(trifluoromethyl)phenyl)amino)pyrazine-2-yl)-6-ethoxypicolinamide as a yellow solid (2 mg, 2% yield), and by-product 2-(6-ethoxypyridine-2-yl)-1-(2-methoxy-6-(trifluoromethyl)phenyl)-1H-imidazo[4,5-b]pyrazine-6-ol (Example 47, 22 mg, 18% yield).

[1759] LC-MS: m / z 468.1 (M+H) +

[1760] Example 47: 2-(6-ethoxypyridin-2-yl)-1-(2-methoxy-6-(trifluoromethyl)phenyl)-1H-imidazo[4,5-b]pyrazin-6-ol

[1761]

[1762] 1 H NMR (400 MHz, DMSO-d 6)δ:9.28(s,1H),8.17(s,1H),7.91(dd,J=8.2,7.6Hz,1H),7.84(dd,J=7.6,0.8Hz,1H),7.57(t,J=8.0Hz,1H),7.49(dd,J=8.4,1.6Hz,1H), 7.40 (dd, J=8.0, 1.6Hz, 1H), 7.00 (dd, J=8.4, 0.8Hz, 1H), 4.41 (q, J=7.2Hz, 2H), 3.76 (s, 3H), 1.35 (t, J=7.2Hz, 3H). LC-MS: m / z432.1 (M+H) +

[1763] Step B: 6-chloro-2-(6-ethoxypyridin-2-yl)-1-(2-methoxy-6-(trifluoromethyl)phenyl)-1H-imidazole Oxalo[4,5-b]pyrazine

[1764]

[1765] A solution of N-(5-chloro-3-((2-methoxy-6-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)-6-ethoxypicolinamide (35 mg, 0.075 mmol) in AcOH (2 mL) was stirred at 130° C. for 2 h by microwave irradiation. 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).

[1766] LC-MS: m / z 450.0 (M+H) +

[1767] Example 48: N-(2-(6-ethoxypyridin-2-yl)-1-(2-methoxy-6-(trifluoromethyl)phenyl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide

[1768]

[1769] The samples were irradiated with microwave at 130 °C in N 2 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 equivalents), CuI (21 mg, 0.112 mmol, 2 equivalents), trans-N,N'-dimethylcyclohexane-1,2-diamine (16 mg, 0.112 mmol, 2 equivalents) and K were stirred under atmosphere. 2 CO3 (23 mg, 0.167 mmol, 3 eq.) in DMF (2 mL) for 2 h. The mixture was diluted with EtOAc (30 mL) and filtered through celite. The filtrate was poured into K 2 CO 3 The mixture was added to an aqueous solution (2 mol / L, 50 mL) and stirred for 15 minutes. The aqueous phase was then 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 and purified by anhydrous Na 2 SO 4 Dry and concentrate 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).

[1770] 1 H NMR (400 MHz, DMSO-d 6 )δ:11.13(s,1H),8.32(s,1H),8.06(dd,J=7.4,0.8Hz,1H),7.88(dd,J=8.4,7.6Hz,1H),7.74-7.83(m,1H),7.61-7.70(m,1H),7.56(dd,J= 8.0,1.2Hz,1H),6.85(dd,J=8.4,0.8Hz,1H),3.65(s,3H),3.22(q,J=7.2Hz,2H),3.12(s,3H),1.00(t,J=7.2Hz,3H).LC-MS:m / z509.1(M+H) +

[1771] Example 49: N-(2-(6-ethoxypyridin-2-yl)-1-(3-methoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide

[1772]

[1773] The title compound was prepared according to Method E using 3-methoxypyridin-2-amine in step A.

[1774] 1 H NMR (400 MHz, CDCl 3)δ:8.55(s,1H),8.25(dd,J=4.8,1.2Hz,1H),8.15(d,J=4.0Hz,1H),7.71(t,J=8.0Hz,1H),7.45-7.48(m,1H),7.39-7.41( m,1H),7.15(s,1H),6.72(d,J=8.0Hz,1H),3.66(s,3H),3.35-3.40(m,2H),3.17(s,3H),1.08(t,J=8.0Hz,3H).LC-MS:m / z 442.0(M+H) + .

[1775] Example 50: N-(Benzylsulfonyl)-4-(2-fluoro-6-methoxyphenyl)-5-(6-methoxypyridin-2-yl)-4H-1,2,4-triazole-3-carboxamide

[1776]

[1777] The title compound was prepared according to Method E using 2-fluoro-6-methoxyaniline in step A.

[1778] 1 H NMR (400 MHz, DMSO-d 6 )δ:11.17(s,1H),8.31(s,1H),7.99(d,J=7.6Hz,1H),7.89(t,J=7.6Hz,1H),7.56(dd,J=15.2,8.4Hz,1H),7.05-7. 18(m,2H),6.87(d,J=8.4Hz,1H),3.61(s,3H),3.41(q,J=7.2Hz,2H),3.19(s,3H),1.04(t,J=7.2Hz,3H).LC-MS:m / z 459.1(M+H) +

[1779] Method F:

[1780]

[1781] Step A: N-(3,5-dibromopyrazin-2-yl)-6-methoxypicolinamide

[1782]

[1783] To a THF solution of 3,5-dibromopyrazin-2-amine (13.6 g, 54 mmol, 1.3 eq.) was added dropwise AlMe 3(1.6 mol / L, 34 mL, 54 mmol, 1.3 equiv). The mixture was stirred at room temperature for 0.5 h. 3,5-dibromopyrazine-2-amine (6.8 g, 41 mmol, 1.0 equiv) was then added in one portion. The mixture was stirred at 60 °C for 1.5 h, quenched with 1N HCl (aqueous) and extracted 3 times with ethyl acetate. The extract was washed with brine and purified by anhydrous Na 2 SO 4 Dry and concentrate 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).

[1784] LC-MS:m / z 386.8,388.8,390.8(M+H) +

[1785] Step B: N-(5-bromo-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-methoxypicolinamide

[1786]

[1787] 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 eq), Xantphos (358 mg, 0.62 mmol, 0.4 eq) and K 2 CO 3 A suspension of (440 mg, 3.1 mmol, 2.0 equiv) in 1,4-dioxane (10 mL) was irradiated by microwaves at 120 °C under N 2 Stir for 2 hours under atmosphere. Filter the mixture through celite and concentrate the filtrate in vacuo. The residue is 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).

[1788] LC-MS: m / z 459.9,461.9 (M+H) +

[1789] Step C: 6-bromo-1-(2,6-dimethoxyphenyl)-2-(6-ethoxypyridin-2-yl)-1H-imidazo[4,5- b]pyrazine

[1790]

[1791] 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-ethoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazine, as a light yellow solid (475 mg, 70%).

[1792] LC-MS: m / z 442.3,444.3 (M+H) +

[1793] Example 51: N-(1-(2,6-dimethoxyphenyl)-2-(6-methoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide

[1794]

[1795] The title compound was prepared according to Method F using methanesulfonamide in step D (72 mg, 78% yield).

[1796] 1 H NMR (400 MHz, DMSO-d 6 )δ:11.05(s,1H),8.30(s,1H),7.95(d,J=8.0Hz,1H),7.87(d,J=8.0Hz,1H),7.44(t,J =8.0Hz,1H),6.85(d,J=8.0Hz,3H),3.57(s,6H),3.20(s,3H),3.11(s,3H).LC-MS:m / z 457.0(M+H) +

[1797] Example 52: N-(1-(2,6-dimethoxyphenyl)-2-(6-methoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)pyridine-2-sulfonamide

[1798]

[1799] The title compound was prepared according to Method F using pyridine-2-sulfonamide in Step D (34 mg, 33% yield).

[1800] 1 H NMR (400 MHz, DMSO-d 6)δ:11.77(s,1H),8.59(d,J=4.0Hz,1H),8.29(s,1H),7.91-7.96(m,1H),7.81-7.86(m,1H),7.77(td,J=7.8,1.6Hz,1H),7.61(d,J=7.6Hz,1H ),7.57(dd,J=4.0,3.2Hz,1H),7.49(t,J=8.4Hz,1H),6.86(d,J=8.4Hz,2H),6.83(dd,J=8.4,0.8Hz,1H),3.51(s,6H),3.08(s,3H).LC-MS:m / z 520.0(M+H) +

[1801] Example 53: N-(1-(2,6-dimethoxyphenyl)-2-(6-methoxypyridin-2-yl)-1H-imidazo[4,5-b]pyrazin-6-yl)pyrimidine-2-sulfonamide

[1802]

[1803] The title compound was prepared according to Method F using pyridine-2-sulfonamide in Step D (15 mg, 29% yield).

[1804] 1 H NMR (400 MHz, DMSO-d 6 )δ:11.91(s,1H),8.80(d,J=4.8Hz,2H),8.32(s,1H),7.91(dd,J=7.6,0.8Hz,1H),7.83(dd,J=8.4,7.6Hz,1H),7.63( t,J=4.8Hz,1H),7.39(t,J=8.4Hz,1H),6.79-6.85(m,1H),6.76(d,J=8.4Hz,2H),3.50(s,6H),3.06(s,3H).LC-MS:m / z 521.1(M+H) +

[1805] Method G:

[1806]

[1807] Step A: Methyl 6-fluoropicolinate

[1808]

[1809] Iodomethane (20 g, 142 mmol, 3.0 eq.) was added to 6-fluoropicolinic acid (10.0 g, 71 mmol, 1.0 eq.) and silver (I) carbonate (19.5 g, 71 mmol, 1.0 eq.) in CHCl 3 The suspension was stirred at 30°C for 1 day. The insoluble matter was removed by filtration and the mixture was washed with CHCl 3 The filter cake was washed. The filtrate was concentrated in vacuo to afford the title compound as a light yellow solid (9.0 g, 82% yield). This material was used in the next step without further purification.

[1810] LC-MS: m / z 156.0 (M+H) +

[1811] Step B: 6-Cyclopropyloxypicolinic acid

[1812]

[1813] To a mixture of cyclopropanol (1.5 g, 25.8 mmol, 3.0 eq.) in dioxane (20 mL) was added NaH (1032 mg, 25.8 mmol, 3.0 eq.) at 0°C 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 washed with saturated NH 4 The product was quenched with Cl aqueous solution. 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 provide 6-cyclopropyloxypicolinic acid as a white solid (600 mg, 13% yield).

[1814] LC-MS: m / z 180.0 (M+H) +

[1815] Step C: Methyl 6-cyclopropyloxypicolinate

[1816]

[1817] Iodomethane (0.41 mL, 6.59 mmol, 3.0 equiv) was added to 6-cyclopropyloxypicolinic acid (590 mg, 3.29 mmol, 1.0 equiv) and silver (I) carbonate (1091 mg, 3.95 mmol, 1.2 equiv) in CHCl 3 The suspension was stirred at 30°C for 4 hours. The insoluble matter was removed by filtration and the filter cake was washed with CHCl 3The filtrate was concentrated in vacuo to give the title compound, methyl 6-cyclopropyloxypicolinate, as a light yellow oil (600 mg, 94% yield). This material was used in the next step without further purification.

[1818] LC-MS: m / z 194.0 (M+H) +

[1819] Step D: N-(3-bromo-5-chloropyrazin-2-yl)-6-cyclopropyloxypicolinamide

[1820]

[1821] To a mixture of 3-bromo-5-chloropyrazin-2-amine (644 mg, 3.1 mmol, 1.0 eq.) and toluene (10 mL) was added AlMe 3 (1.6mol / L toluene solution, 4mL, 6.2mmol, 2.0 equivalents). After the mixture was stirred at 50°C for 30 minutes, 6-cyclopropyloxypicolinic acid methyl ester (600mg, 3.1mmol, 1.0 equivalents) was added. The mixture was stirred at 110°C for 1 hour and quenched with 1N HCl aqueous solution. The mixture was extracted 3 times with DCM. 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 (100% DCM) to give the title compound N-(3-bromo-5-chloropyrazine-2-yl)-6-cyclopropyloxypicolinamide (500mg, 44% yield).

[1822] LC-MS: m / z 369.0,371.0 (M+H) +

[1823] Step E: N-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-cyclopropyloxypicolinoyl amine

[1824]

[1825] N-(3-bromo-5-chloropyrazin-2-yl)-6-cyclopropyloxypicolinamide (500 mg, 1.36 mmol, 1.0 equiv), 2,6-dimethoxyaniline (229 mg, 1.49 mmol, 1.1 equiv), Pd(OAc) 2 (61 mg, 0.27 mmol, 0.2 eq), Xantphos (315 mg, 0.54 mmol, 0.4 eq) and K 2 CO 3 A suspension of (375 mg, 2.72 mmol, 2.0 equiv) in 1,4-dioxane (3 mL) was irradiated by microwaves at 125 °C under N 2Stir for 2 hours under atmosphere. Filter the mixture through celite and concentrate the filtrate in vacuo. The residue is purified by flash chromatography (100% DCM) to give the title compound N-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazine-2-yl)-6-cyclopropyloxypicolinamide as a yellow solid (247 mg, 41% yield).

[1826] LC-MS: m / z 442.1 (M+H) +

[1827] Step F: 6-chloro-2-(6-cyclopropyloxypyridin-2-yl)-1-(2,6-dimethoxyphenyl)-1H-imidazo[4, 5-b]pyrazine

[1828]

[1829] A solution of N-(5-chloro-3-((2,6-dimethoxyphenyl)amino)pyrazin-2-yl)-6-cyclopropyloxypicolinamide (247 mg, 0.56 mmol, 1.0 equiv) in AcOH (2 mL) was stirred at 130° C. for 2 h by microwave irradiation. The reaction mixture was cooled to room temperature, the precipitate was filtered off and washed with a solvent mixture of EA / PE=1 / 2 to give the title compound 6-chloro-2-(6-cyclopropyloxypyridin-2-yl)-1-(2,6-dimethoxyphenyl)-1H-imidazo[4,5-b]pyrazine as a light yellow solid (170 mg, 72% yield). LC-MS: m / z 424.1 (M+H) +

[1830] Example 54: N-(2-(6-cyclopropyloxypyridin-2-yl)-1-(2,6-dimethoxyphenyl)-1H-imidazo[4,5-b]pyrazin-6-yl)methanesulfonamide

[1831]

[1832] at 120 °C in N 2 6-Chloro-2-(6-cyclopropyloxypyridin-2-yl)-1-(2,6-dimethoxyphenyl)-1H-imidazo[4,5-b]pyrazine (80 mg, 0.19 mmol 1.0 equivalent), methanesulfonamide (36.1 mg, 0.38 mmol, 2.0 equivalent), CuI (72 mg, 0.38 mmol, 2.0 equivalent), trans-N,N'-dimethylcyclohexane-1,2-diamine (54 mg, 0.38 mmol, 2.0 equivalent) and K were stirred under atmosphere. 2 CO 3(78 mg, 0.57 mmol, 3.0 equiv) in DMF (3 mL) for 2 h. The mixture was diluted with EtOAc (30 mL) and filtered through celite. The filtrate was poured into water (50 mL). The mixture was adjusted to pH = 4 with 1N HCl and extracted with EA (3×100 mL). The organic layer was washed with anhydrous Na 2 SO 4 Dry and concentrate in vacuo.The residue was purified by flash column chromatography (eluting with DCM / MeOH = 20 / 1) to afford the title compound as a white solid (55 mg, 60% yield).

[1833] 1 H NMR (400 MHz, DMSO-d 6 )δ:11.06(s,1H),8.27(s,1H),7.97(dd,J=7.6,0.8Hz,1H),7.87(t,J=8.4Hz,1H),7.40(t,J=8.4Hz,1H ),6.77-6.87(m,3H),3.56(s,6H),3.15-3.22(m,4H),0.42-0.50(m,2H),0.27-0.41(m,2H).LC-MS:m / z 483.1(M+H) +

[1834] Step A: 6-(2,2,2-trifluoroethoxy)picolinic acid

[1835]

[1836] Methyl 6-bromopicolinate (4.3 g, 20 mmol, 1.0 eq.), ethyl 2-oxocyclohexane-1-carboxylate (680 mg, 4 mmol, 0.2 eq.), CuI (380 mg, 2 mmol, 0.1 eq.) and Cs 2 CO 3 A mixture of (9.1 g, 28 mmol, 1.4 equiv) in 2,2,2-trifluoroeth...

Claims

1. A compound of formula (I-a1-a1), (I-a1-a2) or (I-a1-a3): or a pharmaceutically acceptable salt thereof; or a compound of formula (I-a1-a7), (I-a1-a8) or (I-a1-a9), Where R d’ Is H or R d ; or a pharmaceutically acceptable salt thereof; or a compound of formula (I-b1-a1), or a pharmaceutically acceptable salt thereof; in: R 1 yes: (i)-(Y 1 ) n -Y 2 , in which: n is 0 or 1; ·Y 1 It is C 1-6 Alkylene, which is optionally substituted by 1 to 6 R a Replacement; and ·Y 2 yes: (a)C 3-10 Cycloalkyl, which is optionally substituted by 1 to 4 R b replace; (b)C 6-10 Aryl, which is optionally substituted by 1 to 4 R c replace; (c) a heteroaryl group containing 5 to 10 ring atoms, wherein 1 to 4 of the 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 replaced by 1-4 independently selected R c Replace, or (d) a heterocyclic group containing 3 to 10 ring atoms, wherein 1 to 3 of the ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ) and O, and wherein one or more heterocyclyl ring carbon atoms are optionally replaced by 1-4 independently selected R b Replace, or (ii) -Z 1 -Z 2 -Z 3 ,in: ·Z 1 It is C 1-3 Alkylene, which is optionally substituted by 1 to 4 R a replace; ·Z 2 It is -N(H)-, -N(R d )-, -O- or -S-; and ·Z 3 It is C 2-7 Alkyl, which is optionally substituted by 1-4 R a replace; or (iii)C 3-10 Alkyl, optionally with 1-6 independently selected R a replace; or (iv)–Z 4 –Z 5 -Z 6 -Y 2 Wherein: ·Z 4 It is C 1-3 Alkylene, which is optionally substituted by 1 to 4 R a replace; ·Z 5 It is –N(H)-, -N(R d )-, -O-, or –S-; ·Z 6 It is C 1-4 Alkylene, which is optionally substituted by 1 to 4 R a Replacement; and ·Y 2 As defined above; R 2 yes: (i)C 6-10 Aryl, which is optionally further substituted by 1 to 4 R c replace; (ii) a heteroaryl group containing 5 to 10 ring atoms, wherein 1 to 4 of the 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 replaced by 1-4 independently selected R c replace; (iii)C 3-10 Cycloalkyl, which is optionally substituted by 1 to 4 R b replace; (iv) a heterocyclic group containing 3 to 10 ring atoms, wherein 1 to 3 of the ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ) and O, and wherein one or more heterocyclyl ring carbon atoms are optionally replaced by 1-4 independently selected R b replace; or (v)C 1-10 Alkyl, which is optionally substituted by 1-6 independently selected R a replace; Each occurrence of R 4 Independently are: (i)-(Y 3 ) p -Y 4 , in which: p is 0 or 1; ·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 Replacement; and ·Y 4 yes: (a)C 3-6 Cycloalkyl, which is optionally substituted by 1 to 4 R b replace, (b)C 6-10 Aryl, which is optionally substituted by 1 to 4 R c replace; (c) a heteroaryl group containing 5 to 10 ring atoms, wherein 1 to 4 of the 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 replaced by 1-4 independently selected R c Replace, or (d) a heterocyclic group containing 3 to 10 ring atoms, wherein 1 to 3 of the ring atoms are heteroatoms, each independently selected from N, N(H), N(R d ) and O, and wherein one or more heterocyclyl ring carbon atoms are optionally replaced by 1-4 independently selected R b Replace, 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 replace; Each occurrence of R a 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 1-4 independently selected C 1-4 Alkyl substituted C 3-6 Cycloalkyl; Each occurrence of R b 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 substitution; Each occurrence of R c Independently selected from: (i) halogen; (ii) cyano; (iii)C 1-6 alkyl; (iv)C 2-6 alkenyl; (v)C 2-6 Alkynyl; (vi)C 1-4 Haloalkyl; (vii)C 1-4 Alkoxy; (viii)C 1-4 Haloalkoxy; (ix) optionally 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 Cycloalkoxy; Each occurrence of R c 'Independently selected from: (i) halogen; (ii) cyano; (iii) –OH; (iv) -NO2; (v) -C(=O)(C 1-4 alkyl); (vi) -C(=O)O(C 1-4 alkyl); (vii) -C(=O)OH; and (viii) –NH2; R d Select from the following group: C 1-6 Alkyl; C 3-6 Cycloalkyl; -C(O)(C 1-4 alkyl); -C(O)O(C 1-4 Alkyl); -S(O) 1-2 (C 1-4 alkyl); -OH; and C 1-4 Alkoxy; Each occurrence of R e and R f 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 atoms to which they are attached, they form a ring containing 3-8 ring atoms, wherein the ring contains: (a) 1-7 ring carbon atoms, each carbon atom being replaced by 1-2 independently selected from H and C 1-3 (b) 0-3 ring heteroatoms, each of which is independently selected from N(R d ), O and S, wherein the ring heteroatom is a ring heteroatom other than the nitrogen atom to which R' and R" are attached; and Each occurrence of R' and R" is independently selected from: H and C 1-4 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 replaced by 1-2 independently selected from H and C 1-3 (b) 0-3 ring heteroatoms, each of which is independently selected from N(R d ), O and S, and the ring heteroatom is a ring heteroatom other than the nitrogen atom to which R' and R" are attached.

2. The compound of claim 1, wherein R 1 Yes-(Y 1 ) n -Y 2 .

3. The compound according to claim 1 or 2, wherein n is 0.

4. The compound according to claim 1 or 2, wherein n is 1.

5. The compound according to claim 4, wherein Y 1 It is C 1-3 Alkylene.

6. The compound according to any one of claims 1 to 5, wherein Y 2 is a heteroaryl group containing 5 to 10 ring atoms, wherein 1 to 4 of the 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 replaced by 1-4 independently selected R c replace.

7. The compound according to any one of claims 1 to 6, wherein Y 2 is a heteroaryl group containing 5-6 ring atoms, wherein 1-4 of the 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 replaced by 1-4 independently selected R c replace.

8. The compound according to any one of claims 1 to 7, wherein Y 2 is a heteroaryl group containing 6 ring atoms, wherein 1-2 ring atoms are N, and wherein one or more heteroaryl ring carbon atoms are optionally replaced by 1-4 independently selected R c replace.

9. The compound according to claim 8, wherein Y 2 is pyridinyl, wherein one or more ring carbon atoms are optionally replaced by 1-4 independently selected R c replace.

10. The compound according to any one of claims 1 to 7, wherein Y 2 is a heteroaryl group containing 5 ring atoms, wherein 1 to 3 of the 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 replaced by 1-3 independently selected R c replace.

11. The compound of claim 10, wherein Y 2 is furanyl, wherein one or more ring carbon atoms are optionally replaced by 1-2 independently selected R c replace.

12. The compound according to any one of claims 6 to 11, wherein Each occurrence of R c Independently selected from: (iii)C 1-6 alkyl; (iv)C 2-6 alkenyl; (v)C 2-6 Alkynyl; (vi)C 1-4 Haloalkyl; (vii)C 1-4 Alkoxy; (viii)C 1-4 Haloalkoxy; (ix) optionally 1 to 4 independently selected C 1-4 Alkyl-substituted-(C 0-3 Alkylene)-C 3-6 Cycloalkyl; (xiv)-C 1-4 Thioalkoxy; and (xx)C 3-6 Cycloalkoxy.

13. The compound according to any one of claims 6 to 11, wherein Each occurrence of R c Independently selected from: (vii)C 1-4 Alkoxy; (viii)C 1-4 Haloalkoxy; (xiv)-C 1-4 Thioalkoxy; and (xx)C 3-6 Cycloalkoxy.

14. The compound according to any one of claims 6 to 11, wherein Each occurrence of R c C is an independent choice 1-4 Alkoxy.

15. The compound according to any one of claims 6 to 11, wherein Each occurrence of R c C is an independent choice 1-6 alkyl.

16. The compound according to any one of claims 6 to 15, wherein n is 0.

17. A compound as described in any one of claims 1-3, 6-9 and 12-14, wherein R 1 yes:

18. A compound as described in any one of claims 1-3, 6-9, 12 and 15, wherein R 1 yes 19. A compound as described in any one of claims 1-3, 6-7, 10-12 and 15, wherein R 1 yes 20. The compound of any one of claims 1 to 19, wherein R 2 It is C 6-10 Aryl, which is optionally substituted by 1 to 4 R c replace.

21. A compound as described in any one of claims 1 to 20, wherein R 2 is phenyl, which is optionally substituted by 1 to 4 R c replace.

22. A compound as described in any one of claims 1 to 21, wherein R 2 is phenyl, which is optionally substituted with 2 R c replace.

23. A compound as described in any one of claims 20 to 22, wherein Each occurrence of R c Independently selected from: (i) halogen; (vi)C 1-4 Haloalkyl; (vii)C 1-4 Alkoxy; (viii)C 1-4 haloalkoxy; and (xiv)-C 1-4 Thioalkoxy.

24. The compound according to any one of claims 20 to 23, wherein Each occurrence of R c Independently selected from halogen, C 1-4 Alkoxy and C 1-4 Halogenated alkyl.

25. The compound according to any one of claims 20 to 24, wherein Each occurrence of R c is independently -OCH3, CF3, or F.

26. A compound as described in any one of claims 1 to 25, wherein R 2 yes:

27. A compound as described in any one of claims 1-19 and 26, wherein each R c Independently C 1-4 Alkoxy.

28. A compound as described in any one of claims 1 to 19, wherein R 2 yes:

29. A compound as described in any one of claims 1 to 19, wherein R 2 yes 30. The compound of any one of claims 1 to 29, R c One occurrence of ' is halogen.

31. A compound as described in any one of claims 1 to 30, wherein R 4 Yes-(Y 3 ) p -Y 4 .

32. The compound of any one of claims 1-31, wherein p is 1.

33. A compound as described in any one of claims 1-32, wherein Y 3 It is C 1-3 Alkylene.

34. A compound as described in any one of claims 1-33, wherein Y 3 It is CH2 or CH2-CH2.

35. The compound of any one of claims 1-31, wherein p is 0.

36. A compound as described in any one of claims 1-35, wherein Y 4 It is C 6-10 Aryl, which is optionally substituted by 1 to 4 R c replace.

37. A compound as described in any one of claims 1-36, wherein Y 4 is phenyl, which is optionally replaced by 1-2 R c replace.

38. The compound of claim 36 or 37, wherein Each occurrence of R c Independently selected from: (i) halogen; (ii) cyano; (iii)C 1-6 alkyl; (iv)C 2-6 alkenyl; (v)C 2-6 Alkynyl; (vi)C 1-4 Haloalkyl; (vii)C 1-4 Alkoxy; (viii)C 1-4 Haloalkoxy; (ix) optionally 1 to 4 independently selected C 1-4 Alkyl-substituted-(C 0-3 Alkylene)-C 3-6 Cycloalkyl; (xiv)-C 1-4 Thioalkoxy, and (xx)C 3-6 Cycloalkoxy.

39. The compound of claim 36 or 37, wherein Each occurrence of R c Independently selected from: (i) halogen; (iii)C 1-6 alkyl; (vi)C 1-4 Haloalkyl; (vii)C 1-4 Alkoxy; and (viii)C 1-4 Halogenated alkoxy.

40. The compound of claim 36 or 37, wherein Each occurrence of R c Independently selected from: (vii)C 1-4 Alkoxy; (viii)C 1-4 haloalkoxy; and (xiv)-C 1-4 Thioalkoxy.

41. A compound as described in any one of claims 1-36, wherein Y 4 It is C 6-10 Aryl, which is unsubstituted.

42. A compound as described in any one of claims 1 to 35, wherein Y 4 It is C 3-6 Cycloalkyl, which is optionally substituted by 1 to 4 R b replace.

43. A compound as described in any one of claims 1-35 and 42, wherein Y 4 is cyclopropyl or cyclobutyl, which is optionally substituted by 1-2 R b replace.

44. A compound as described in any one of claims 1-35 and 42, wherein Y 4 is a C6 cycloalkyl group, which is optionally substituted by 1-2 R b replace.

45. A compound as described in any one of claims 1-35 and 42-44, wherein Each occurrence of R b Independently selected from: -F, C 1-6 Alkyl, C 1-4 Alkyl halide and –OH.

46. ​​A compound as described in any one of claims 1-35 and 42, wherein Y 4 It is C 3-6 Cycloalkyl, which is unsubstituted.

47. The compound of claim 46, Y 4 is unsubstituted cyclopropyl or unsubstituted cyclobutyl.

48. A compound as described in any one of claims 1 to 35, wherein Y 4 is a heteroaryl group containing 5 to 10 ring atoms, wherein 1 to 4 of the 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 replaced by 1-4 independently selected R c replace.

49. A compound as described in any one of claims 1-35 and 48, wherein Y 4 is a heteroaryl group containing 6 ring atoms, wherein 1 to 4 of the ring atoms are heteroatoms, each independently selected from N, N(H) and N(R d ), and wherein one or more heteroaryl ring carbon atoms are optionally replaced by 1-4 independently selected R c replace.

50. The compound of any one of claims 1-35 and 48-49, wherein Y 4 is pyridinyl, pyrimidinyl, or pyrazinyl, each of which is optionally substituted by 1-2 independently selected R c replace.

51. A compound as described in any one of claims 48 to 50, wherein Each occurrence of R c Independently selected from: (i) halogen; (ii) cyano; (iii)C 1-6 alkyl; (iv)C 2-6 alkenyl; (v)C 2-6 Alkynyl; (vi)C 1-4 Haloalkyl; (vii)C 1-4 Alkoxy; (viii)C 1-4 Haloalkoxy; (ix) optionally 1 to 4 independently selected C 1-4 Alkyl-substituted-(C 0-3 Alkylene)-C 3-6 Cycloalkyl; (xii) OH; (xiv)-C 1-4 Thioalkoxy, and (xx)C 3-6 Cycloalkoxy.

52. The compound of claim 51, wherein Each occurrence of R c Independently selected from: (i) halogen; (iii)C 1-6 Alkyl; and (xii) OH.

53. A compound as described in any one of claims 1-35 and 48-50, wherein Y 4 is pyridinyl, pyrimidinyl, or pyrazinyl, each of which is unsubstituted.

54. A compound as described in any one of claims 1 to 35, wherein 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 heterocyclyl ring carbon atoms are optionally replaced by 1-4 independently selected R b replace.

55. A compound as described in any one of claims 1-35 and 54, wherein Y 4 is a heterocyclic group containing 4-6 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 heterocyclyl ring carbon atoms are optionally replaced by 1-4 independently selected R b replace.

56. A compound as described in any one of claims 1-35 and 54-55, wherein 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 heterocyclyl ring carbon atoms are optionally replaced by 1-2 independently selected R b replace.

57. A compound as described in any one of claims 1-35 and 54-56, wherein Y 4 is optionally 1-2 independently selected R b Substituted oxetane.

58. A compound as described in any one of claims 1-35 and 54-56, wherein Y 4 is optionally 1-2 independently selected R b Substituted azetidinyl groups.

59. A compound as described in any one of claims 1-35 and 54-55, wherein Y 4 is a heterocyclic group containing 6 ring atoms, wherein 1-2 ring atoms are heteroatoms independently selected from N, N(H), N(R d ) and O, and wherein one or more heterocyclyl ring carbon atoms are optionally replaced by 1-4 independently selected R b replace.

60. The compound of any one of claims 1-35, 54-55 and 59, wherein Y 4 is selected from tetrahydropyranyl, piperidinyl, piperazinyl and morpholinyl, each of which is optionally substituted by 1-2 independently selected R b replace.

61. A compound as described in any one of claims 1-35, 54-55 and 59-60, wherein Y 4 is selected from tetrahydropyranyl, piperidinyl and morpholinyl, each of which is optionally substituted by 1-2 independently selected R b replace.

62. A compound as described in any one of claims 54-61, wherein Each occurrence of R b Independently selected from: -F, C 1-6 Alkyl, C 1-4 Alkyl halide, oxo, and –OH.

63. A compound as described in any one of claims 54-61, wherein Each occurrence of R b Independently selected from: -F, C 1-6 Alkyl, C 1-4 Alkyl halide and –OH.

64. A compound as described in any one of claims 1-34 and 36-41, wherein R 4 Selected from:

65. A compound as described in any one of claims 1-31, 35 and 36-41, wherein R 4 yes:

66. A compound as described in any one of claims 1-34 and 42-47, wherein R 4 Selected from:

67. A compound as described in any one of claims 1-31, 35 and 42-47, wherein R 4 Selected from:

68. A compound as described in any one of claims 1-34 and 48-53, wherein R 4 Selected from:

69. A compound as described in any one of claims 1-31, 35 and 48-53, wherein R 4 Selected from:

70. The compound of any one of claims 1-34 and 54-63, wherein R 4 Selected from:

71. A compound as described in any one of claims 1-31, 35 and 54-63, wherein R 4 Selected from:

72. The compound of any one of claims 1 to 30, wherein R 4 It is C 1-6 Alkyl, optionally with 1-2 independently selected R a replace.

73. A compound as described in any one of claims 1-30 and 72, wherein Each occurrence of R a Independently selected from: -F; -OH; C 1-4 Alkoxy; and C 1-4 Halogenated alkoxy.

74. A compound as described in any one of claims 1-30 and 72-73, wherein Each occurrence of R a independently is –OH.

75. A compound as described in any one of claims 1-30 and 72-73, wherein R 4 Selected from methyl, ethyl, 76. A compound as described in any one of claims 1-30, wherein R 4 It is C 2-10 Alkynyl, optionally substituted with 1-6 independently selected R a replace.

77. A compound as described in any one of claims 1-30, wherein R 4 It is C 2-10 alkenyl, which is optionally substituted by 1-6 independently selected R a replace.

78. The compound of claim 1, wherein the compound is of formula (I-a1-a1), (I-a1-a2), or (I-a1-a3): or a pharmaceutically acceptable salt thereof.

79. The compound of claim 1, wherein The compound is of formula (I-b1-a1): or a pharmaceutically acceptable salt thereof.

80. A compound as described in any one of claims 78-79, wherein R 4 Selected from: (i)C 1-10 Alkyl, optionally with 1-6 independently selected R a replace; (ii)-(Y 3 ) p -Y 4 ; and (iii)C 2-10 Alkenyl or C 2-10 Alkynyl, each of which is optionally substituted by 1-3 independently selected R a replace.

81. A compound as described in any one of claims 78-80, wherein R 4 Yes-(Y 3 ) p -Y 4 .

82. The compound of claim 1 or 81, wherein Y 4 It is C 6-10 Aryl, which is optionally substituted by 1 to 4 R c Replace; and R c , when present, as defined in any one of claims 73-75.

83. The compound of claim 1 or 81, wherein Y 4 It is C 6-10 Aryl, which is optionally substituted by 1 to 4 R c Replace; and each occurrence of R c , when present, are independently selected from: (vii)C 1-4 Alkoxy; (viii)C 1-4 haloalkoxy; and (xiv)-C 1-4 Thioalkoxy.

84. The compound of any one of claims 80-83, wherein p is 0.

85. The compound of any one of claims 80-83, wherein p is 1.

86. The compound of claim 1 or 80, wherein: ·R 4 It is C 1-10 Alkyl, which is optionally substituted by 1-6 independently selected R a Replace, or ·R 4 It is C 2-10 Alkynyl, optionally substituted with 1-6 independently selected R a replace; or ·R 4 It is C 2-10 alkenyl, which is optionally substituted by 1-6 independently selected R a Replacement; and Each R a , when present, is independently selected from: -F; -OH; C 1-4 Alkoxy; and C 1-4 Halogenated alkoxy.

87. The compound of claim 1 or 80, wherein: ·R 4 It is C 1-10 Alkyl, which is optionally substituted by 1-6 independently selected R a Replace, and Each R a , when present, is independently selected from: -F; -OH; C 1-4 Alkoxy; and C 1-4 Halogenated alkoxy.

88. A compound as described in any one of claims 78-87, wherein R 1 Yes-(Y 1 ) n -Y 2 .

89. The compound of any one of claims 1 or 78-88, wherein Y 2 As defined in any one of claims 6 to 11; and each R c , when present, is independently as defined in any one of claims 12-15.

90. The compound of any one of claims 78-89, wherein Y 2 As defined in any one of claims 6 to 9; and each R c , when present, as defined in any one of claims 12 to 14.

91. The compound of any one of claims 78-88, Y 2 As defined in any one of claims 8 to 9; and each R c , when present, as defined in any one of claims 12 to 14.

92. The compound of any one of claims 78-88, wherein R 1 like 93. A compound as described in any one of claims 88 to 92, wherein n is 0.

94. A compound as described in any one of claims 78 to 93, wherein R 2 It is C 6-10 Aryl, which is optionally substituted by 1 to 4 R c Replace; and R c , when present, as defined in any one of claims 23 to 25.

95. A compound as described in any one of claims 78-93, wherein R 2 is phenyl, which is optionally substituted with 2 R c Replace; and R c , when present, as defined in any one of claims 23 to 25.

96. A compound as described in any one of claims 78-93, wherein R 2 is a heteroaryl group containing 5 to 10 ring atoms, wherein 1 to 4 of the 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 replaced by 1-4 independently selected R c Replace; and R c , when present, as defined in claim 27.

97. A compound as described in any one of claims 78-93, wherein R 2 yes 98. The compound of any one of claims 78-87, wherein: R 1 Yes-(Y 1 ) n -Y 2 ;and R 2 It is C 6-10 Aryl, which is optionally substituted by 1 to 4 R c replace.

99. The compound of claim 98, wherein n is 0.

100. The compound of any one of claims 98-99, wherein Y 2 is a heteroaryl group containing 6 ring atoms, wherein 1-2 ring atoms are N, and wherein one or more heteroaryl ring carbon atoms are optionally replaced by 1-4 independently selected R c replace.

101. A compound as described in any one of claims 98-100, wherein Y 2 is pyridinyl, wherein one or more ring carbon atoms are optionally replaced by 1-4 independently selected R c replace.

102. A compound as described in any one of claims 98-101, wherein Each occurrence of R c C is an independent choice 1-4 Alkoxy.

103. A compound as described in any one of claims 98-102, wherein R 1 yes:

104. A compound as described in any one of claims 98-103, wherein R 2 is phenyl, which is optionally substituted by 1 to 4 R c replace.

105. A compound as described in any one of claims 98-104, wherein R 2 is phenyl, which is optionally substituted with 2 R c replace.

106. The compound of any one of claims 105, wherein R 2 yes 107. A compound as described in any one of claims 78-87, wherein R 1 yes And R 2 yes 108. A compound selected from the following table: and pharmaceutically acceptable salts thereof.

109. Compounds: or a pharmaceutically acceptable salt thereof.

110. Compounds:

111. Compounds: or a pharmaceutically acceptable salt thereof.

112. Compounds:

113. Compounds: or a pharmaceutically acceptable salt thereof.

114. Compounds:

115. Compounds: or a pharmaceutically acceptable salt thereof.

116. Compounds:

117. Compounds: or a pharmaceutically acceptable salt thereof.

118. Compounds:

119. Compounds: or a pharmaceutically acceptable salt thereof.

120. Compounds:

121. A pharmaceutical composition comprising a compound or salt as described in any one of claims 1-120 and one or more pharmaceutically acceptable excipients.

122. Use of a compound as described in any one of claims 1-120 in the preparation of a medicament for treating a disease, disorder or condition, wherein blocked or impaired APJ receptor signaling or downregulation of endogenous apelin contributes to the pathology and / or symptoms and / or progression of the disease, disorder or condition, wherein an effective amount of a compound as described in any one of claims 1-120 is administered to a subject in need thereof.

123. The use according to claim 122, wherein The disease, disorder or condition is pulmonary arterial hypertension ("PAH").

124. The use according to claim 123, wherein The PAH was idiopathic.

125. The use of claim 123, wherein PAH was hereditary PAH, toxin- or drug-induced PAH; or PAH associated with one or more of the following: congenital heart disease, connective tissue disease, portal hypertension, BMPR2 mutation, schistosomiasis, and HIV infection.

126. The use of claim 122, wherein The disease, disorder or condition is fibrosis.

127. The use according to claim 126, wherein The fibrosis is associated with an organ or tissue selected from the group consisting of lung, liver, heart, mediastinum, bone marrow, retroperitoneum, skin, intestine, joints, reproductive organs, and combinations thereof.

128. The use according to claims 122 and 126, wherein The disease, disorder or condition is idiopathic pulmonary fibrosis (IPF).

129. The use of claim 122, wherein The disease, disorder or condition is a connective tissue disease.

130. The use according to claim 129, wherein The connective tissue disease is selected from the group consisting of scleroderma, systemic lupus erythematosus, systemic sclerosis, Hashimoto's thyroiditis, Sjögren's syndrome and antiphospholipid antibody syndrome.

131. The use of any one of claims 122 and 129-130, wherein the disease, disorder or condition is systemic sclerosis.

132. The use according to any one of claims 122 to 131, wherein The subject is a human being.

133. The use of any one of claims 122-132, further comprising administering one or more additional therapeutic agents.

134. The use of any one of claims 122-133, further comprising treating one or more diseases, disorders or conditions that are sequelae or complications of PAH, wherein the one or more diseases, disorders or conditions are selected from coronary heart disease and heart failure.

135. The use of claim 134, wherein the heart failure is selected from systolic heart failure, diastolic heart failure, diabetic heart failure and heart failure with preserved ejection fraction, cardiomyopathy, myocardial infarction, left ventricular dysfunction, right ventricular dysfunction, right heart failure, cardiac hypertrophy, myocardial remodeling, and valvular heart disease.

136. The use of claim 135, wherein the left ventricular dysfunction comprises left ventricular dysfunction after myocardial infarction.

137. The use of claim 135, wherein the myocardial remodeling comprises myocardial remodeling after infarction or after cardiac surgery.

138. The compound of claim 82, wherein Y 4 is unsubstituted C 6-10 Aryl.

139. The compound of claim 86, wherein R 4 It is C 1-6 Alkyl, which is optionally substituted by 1-6 independently selected R a replace.

140. The compound of claim 139, wherein R 4 It is C 1-6 Alkyl, optionally with 1-2 independently selected R a replace.

141. The compound of claim 87, wherein R 4 It is C 1-6 Alkyl, which is optionally substituted by 1-6 independently selected R a replace.

142. The compound of claim 141, wherein R 4 It is C 1-6 Alkyl, optionally with 1-2 independently selected R a replace.

Images