Pyrazolone formyl peptide 2 receptor agonists

Abstract

The present invention relates to compounds of Formula I, which are formyl peptide receptor 2 (FPR2) receptor agonists. The invention also provides compositions and methods using the compounds, for example, for treating atherosclerosis, heart failure, chronic obstructive pulmonary disease (COPD), and related diseases.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 049,831, filed July 9, 2020, pursuant to 35 USC §119(e), the entirety of which is incorporated herein by reference. Technical Field

[0003] This invention relates to a novel pyrazolinone compound of formula I, which is a formyl peptide 2 (FPR2) receptor agonist, and also to compositions containing the same, and methods of using the same, for example for treating atherosclerosis, heart failure, chronic obstructive pulmonary disease (COPD) and related diseases. Background Technology

[0004] Formyl peptide receptor 2 (FPR2) belongs to the group of seven-transmembrane domain G protein-coupled receptors, which are expressed in various human tissues (including immune cells) and are known to be important in host defense and inflammation. FPR2 shares a large amount of sequence homology with FPR1 and FPR3 (Chen K et al., Journal of Autoimmunity 85, 2017, 64-77). Commonly, these receptors bind to a number of structurally different agonists, including N-formyl and non-formyl peptides that act as chemoattractants and activate phagocytes. The endogenous peptide Annexin A1 and its N-terminal fragment are examples of ligands that bind to human FPR1 and FPR2. Fatty acids such as eicosanoate lipoxygenase A4 (belonging to the small decay mediator (SPM) class) have also been reported as agonists of FPR2 (Ye RD. et al., Pharmacol. Rev., 2009, 61, 119-61).

[0005] It has been reported that endogenous FPR2-promoting ligands (such as lipoxygen A4 and annexin A1) trigger a wide range of cytoplasmic cascades, such as Gi coupling and Ca2+ coupling. 2+Fixed and β-repressor protein re-recruitment. (Cattaneo, F et al., Int J Mol Sci. 2013 Apr; 14(4):7193-7230). FPR2 regulates both the innate and receptive immune systems, including neutrophils, macrophages, T cells, and B cells. In neutrophils, FPR2 ligands regulate motility, cytotoxicity, and lifespan. In macrophages, FPR2 activation prevents apoptosis and enhances cytotoxicity. (Chandrasekharan JA, Sharma-Walia N, J. Inflamm. Res., 2015, 8, 181-92). Initiating inflammatory resolution through FPR2 activation results in enhanced anti-fibrotic wound healing and restoration of damaged tissue to homeostasis (Romano M. et al., Eur. J. Pharmacol., 2015, 5, 49-63).

[0006] Chronic inflammation is part of the pathogenesis of many human diseases, and the regression pathway can be both protective and reparative when stimulated by FPR2 agonists. Ischemia-reperfusion (I / R) injury is a common feature of several diseases (such as myocardial infarction and stroke) associated with high morbidity and mortality. Nonproductive wound healing associated with cardiomyocyte death and pathological remodeling following ischemia-reperfusion injury leads to scarring, fibrosis, and gradual loss of cardiac function. FPR2 modulation has been proposed to enhance myocardial wound healing after injury and reduce adverse myocardial remodeling (Kain V. et al., J. Mol. Cell. Cardiol., 2015, 84, 24-35). In addition, FPR2-promoting remission agonists may be a viable treatment for various clinical infarction / reperfusion (I / R) conditions in the central nervous system, including stroke (Gavins FN., Trends Pharmacol. Sci., 2010, 31, 266-76) and I / R-induced spinal cord injury (Liu ZQ. et al., Int. J. Clin. Exp. Med., 2015, 8, 12826-33).

[0007] In addition to the beneficial effects of novel remission agonists targeting the FPR2 receptor to treat I / R-induced damage, the efficacy of these ligands can also be applied to other diseases. In the cardiovascular system, the FPR2 receptor and its remission agonists have been found to stabilize and heal atherosclerotic plaques (Petri MH. et al., Cardiovasc. Res., 2015, 105, 65-74; and Fredman G. et al., Sci. Trans. Med., 2015, 7(275); 275ra20). FPR2 agonists have also been shown to be beneficial in preclinical models of chronic inflammatory human diseases, including: infectious diseases, psoriasis, dermatitis, inflammatory bowel syndrome, Crohn's disease, ocular inflammation, sepsis, pain, metabolic / diabetic diseases, cancer, COPD, asthma and allergic diseases, cystic fibrosis, acute lung injury and fibrosis, rheumatoid arthritis and other joint diseases, Alzheimer's disease, renal fibrosis, and organ transplantation (Romano M. et al., Eur. J. Pharmacol., 2015, 5, 49-63; Perrett, M. et al., Trends in Pharm. Sci., 2015, 36, 737-755). Summary of the Invention

[0008] The present invention provides novel pyrazolones and analogues that can be used as FPR2 agonists, including their stereoisomers, tautomers, pharmaceutically acceptable salts or solvates.

[0009] This invention also provides methods and intermediates for preparing the compounds of this invention or their stereoisomers, tautomers, pharmaceutically acceptable salts or solvates.

[0010] The present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention or their stereoisomers, tautomers, pharmaceutically acceptable salts or solvates.

[0011] The compounds of this invention can be used in therapeutic applications.

[0012] The compounds of this invention can be used to treat and / or prevent a variety of diseases or conditions associated with FPR2, such as inflammatory diseases, heart disease, chronic airway diseases, cancer, sepsis, allergic symptoms, HIV retroviral infection, circulatory disorders, neuroinflammation, neurological disorders, pain, prion diseases, amyloidosis, and immune disorders. Heart disease is selected from the group consisting of angina pectoris, unstable angina pectoris, myocardial infarction, acute coronary artery disease, iatrogenic cardiac injury, and heart failure, including (but not limited to) ischemic and non-ischemic acute heart failure, chronic heart failure, systolic heart failure, diastolic heart failure, and low ejection fraction heart failure (HF). R EF), and heart failure with preserved ejection fraction (HF) P EF).

[0013] The compounds of the present invention can be used alone, in combination with other compounds of the present invention, or in combination with one or more other agents.

[0014] Other features and advantages of the present invention will become apparent from the following embodiments and claims. Detailed Implementation

[0015] This invention covers compounds of formula I, which are formyl peptide 2 (FPR2) receptor agonists, compositions containing the same, and methods of using the same, for example, for treating atherosclerosis, heart failure, chronic obstructive pulmonary disease (COPD), and related diseases.

[0016] One aspect of the present invention is a compound of formula I.

[0017]

[0018] Or its pharmaceutically acceptable salt, wherein

[0019] R 1 Alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxycarbonylalkyl, cycloalkyl, (Ar 1 )alkyl, or Ar 1 ;

[0020] Ar 1 It is a cycloalkyl, piperidinyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrazinyl, pyrroleyl, furanyl, thiopheneyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazoleyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiazolyl, quinolinyl, isoquinolinyl, or quinoxalolinyl and is determined by 0 to 2 R... 5a and 0 to 2 R 5b replace;

[0021] R 2 It is an alkyl or haloalkyl group;

[0022] R3 It is phenyl or pyridyl and has one R 3a and 0 to 2 R 3b replace;

[0023] R 3a The alkyl, haloalkyl, alkoxy, deuteroalkoxy, haloalkoxy, or cycloalkyl substituents are located at the para position relative to the pyrazol-3-one moiety.

[0024] R 3b It is a halogenated group, alkyl group, hydroxyl group, or haloalkyl group;

[0025] Or R 3a and adjacent R 3b Together with the two carbon atoms it is attached to, it forms a 3- to 6-membered heterocycle containing a carbon atom and 1 to 3 heteroatoms selected from N, NH, O, and S, and substituted with 0 to 3 halogen groups, hydroxyl groups, alkyl groups, haloalkyl groups, or alkoxycarbonyl groups;

[0026] R 4 It is phenyl or pyridyl and has one R 4a and 0 to 2 R 4b replace;

[0027] R 4a The halogen, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, or pyrazolyl substituent is located at the para position relative to the amide moiety;

[0028] R 4b It is a halogenated or haloalkyl group;

[0029] R 5a and R 5b Independently, cyano, halogen, alkyl, haloalkyl, alkoxyalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkoxy, hydroxyalkoxy, haloalkoxy, hydroxyhaloalkoxy, hydroxyalkoxyalkoxy, alkylsulfonylalkoxy, carboxamide, alkoxycarbonyl, alkylaminoalkyl, alkoxycarbonylalkoxy, hydroxyalkylcycloalkylalkyl, alkylsulfonyl, aminocarbonylalkyl, -NR 7 R 8 ; a cycloalkyl group substituted with 0 to 3 halogen groups, hydroxyl groups, alkyl groups or alkoxy groups; a phenyl group substituted with 0 to 3 halogen groups, hydroxyl groups or alkyl groups; a 4 to 8 membered heterocyclic group comprising a carbon atom and 1 to 3 heteroatoms selected from N, NH, O, S and substituted with 0 to 3 halogen groups, alkyl groups, hydroxyalkyl groups, haloalkyl groups, alkoxycarbonyl groups or alkylsulfonyl groups; a heterocyclic oxy group, a heterocyclic alkyl group or a heterocyclic alkoxy group, wherein the heterocyclic moiety of the heterocyclic oxy group, heterocyclic alkyl group or heterocyclic alkoxy group comprises 4 to 8 carbon atoms and 1 to 3 heteroatoms selected from N, NH, O, S and substituted with 0 to 3 halogen groups, hydroxyl groups, hydroxyalkyl groups, alkyl groups or haloalkyl groups;

[0030] R6 It is hydrogen or a lower alkyl group;

[0031] R 7 and R 8 Independently, it is a hydrogen, alkyl, haloalkyl, hydroxyalkyl, halohydroxyalkyl, alkoxyalkyl, aminocarbonylalkyl, alkylsulfonyl, alkylaminocarbonylalkyl, cycloalkylaminocarbonylalkyl, cycloalkylalkyl, hydroxycycloalkylalkyl, hydroxyalkylcycloalkylalkyl, cycloalkylalkyl, cycloalkylalkyl, cycloalkyl, wherein each cycloalkyl group is substituted with 0 to 3 halogen groups, hydroxyl groups or alkyl groups; or hydroxyalkyl, or a 5 to 8 membered heterocyclic group containing a carbon atom and 1 to 3 heteroatoms selected from N, NH, O, S and substituted with 0 to 3 halogen groups, hydroxyl groups, alkyl groups, haloalkyl or alkoxycarbonyl groups;

[0032] Or R 7 and R 8 Together with the nitrogen to which it is attached, it forms a 5- to 12-membered heterocycle containing a carbon atom and 0 to 3 other heteroatoms selected from N, NH, O, and S, and substituted with 0 to 5 halogen, hydroxyl, alkyl, alkoxy, oxo, haloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, alkylsulfonyl, alkylsulfonylalkyl, aminocarbonyl, or alkoxycarbonyl.

[0033] Another aspect of the invention is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein R 1 For Ar 1 .

[0034] Another aspect of the invention is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein R 2 It is an alkyl or haloalkyl group.

[0035] Another aspect of the invention is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein

[0036] R 3 For 1 R 3a and 0 to 2 R 3b Substituted phenyl;

[0037] R 3a The alkyl, haloalkyl, alkoxy, or deuteroxy substituent is located at the para position relative to the pyrazol-3-one moiety; and

[0038] R 3b It is a halogenated or haloalkyl group.

[0039] Another aspect of the invention is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein R 3 It is a pyridinyl group substituted with one halogen, haloalkylalkoxy or haloalkoxy substituent at the 4-position relative to the pyrazol-3-one moiety and 0 to 2 other halogen or haloalkyl substituents.

[0040] Another aspect of the invention is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein

[0041] R 4 For one R at the para position relative to the amide portion 4a and 0 to 2 R 4b Substituted phenyl or pyridyl groups;

[0042] R 4a It is a halogenated group, alkyl group, cycloalkyl group, haloalkyl group, alkoxy group, or haloalkoxy group; and

[0043] R 4b It is a halogenated or haloalkyl group.

[0044] Another aspect of the invention is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein R 4 It is a pyridyl group substituted with one halogen, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, or pyrazolyl substituent at the 4-position relative to the amide moiety and 0 to 2 other halogen or haloalkyl substituents.

[0045] Another aspect of the invention is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein Ar 1 It is a phenyl group substituted with 0 to 3 substituents selected from cyano, halogen, alkyl, cycloalkyl, haloalkyl, alkoxy, hydroxyalkyl, carboxamide, haloalkoxy and phenyl.

[0046] Another aspect of the invention is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein Ar 1 It is a pyridyl group substituted with 0 to 3 substituents selected from cyano, halogen, alkyl, cycloalkyl, haloalkyl, alkoxy, hydroxyalkyl, carboxamide, haloalkoxy and phenyl.

[0047] Another aspect of the present invention is a compound of formula II.

[0048]

[0049] Or its pharmaceutically acceptable salt, wherein

[0050] Ar 1 for

[0051]

[0052] R 2 It is an alkyl or haloalkyl group;

[0053] R 3a It can be a halogenated group, alkyl group, haloalkyl group, alkoxy group, deuterated alkoxy group, haloalkoxy group, or cycloalkyl group;

[0054] R 3b It is a halogenated group, alkyl group, hydroxyl group, or haloalkyl group;

[0055] Or R 3a and adjacent R 3b Together with the two carbon atoms it is attached to, it forms a 3- to 6-membered heterocycle consisting of a carbon atom and 1 to 3 heteroatoms selected from N, NH, O, and S, and substituted with 0 to 3 halogen groups, hydroxyl groups, alkyl groups, haloalkyl groups, or alkoxycarbonyl groups.

[0056] R 4a It can be a halogenated group, alkyl group, cycloalkyl group, haloalkyl group, alkoxy group, haloalkoxy group, or pyrazolyl group;

[0057] R 5a and R 5b Independently, cyano, halogen, alkyl, haloalkyl, alkoxyalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkoxy, hydroxyalkoxy, haloalkoxy, hydroxyhaloalkoxy, hydroxyalkoxyalkoxy, alkylsulfonylalkoxy, carboxamide, alkoxycarbonyl, alkylaminoalkyl, alkoxycarbonylalkoxy, hydroxyalkylcycloalkylalkyl, alkylsulfonyl, -NR 7 R 8 ; cycloalkyl groups substituted with 0 to 3 halogen groups, hydroxyl groups, alkyl groups, or alkoxy groups; phenyl groups substituted with 0 to 3 halogen groups, hydroxyl groups, or alkyl groups; 4- to 8-membered heterocyclic groups comprising a carbon atom and 1 to 3 heteroatoms selected from N, O, NH, and S, and substituted with 0 to 3 halogen groups, alkyl groups, hydroxyalkyl groups, haloalkyl groups, alkoxycarbonyl groups, or alkylsulfonyl groups; heterocyclic oxy, heterocyclic alkyl, or heterocyclic alkoxy groups, wherein the heterocyclic moiety of the heterocyclic oxy or heterocyclic alkoxy group comprises 4 to 8 carbon atoms and 1 to 3 heteroatoms selected from N, NH, O, and S, and substituted with 0 to 3 halogen groups, hydroxyl groups, hydroxyalkyl groups, alkyl groups, or haloalkyl groups; and

[0058] R 7 and R 8 Independently, it is a hydrogen, alkyl, haloalkyl, hydroxyalkyl, halohydroxyalkyl, alkoxyalkyl, aminocarbonylalkyl, alkylsulfonyl, alkylaminocarbonylalkyl, cycloalkylaminocarbonylalkyl, cycloalkylalkyl, hydroxycycloalkylalkyl, hydroxyalkylcycloalkylalkyl, cycloalkylalkyl, cycloalkylalkyl, cycloalkylalkyl, wherein each cycloalkyl group is substituted with 0 to 3 halogen groups, hydroxyl groups, or alkyl or hydroxyalkyl groups, or contains a carbon atom and 1 to 3 heteroatoms selected from N, NH, O, S and substituted with 0 to 3 halogen groups, hydroxyl groups, alkyl groups, haloalkyl groups or alkoxycarbonyl groups, which are 5 to 8-membered heterocyclic groups;

[0059] Or R 7 and R 8Together with the nitrogen to which it is attached, it forms a 5- to 12-membered heterocycle containing a carbon atom and 0 to 3 other heteroatoms selected from N, NH, O, and S, and substituted with 0 to 5 halogen, hydroxyl, alkyl, alkoxy, oxo, haloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, alkylsulfonyl, alkylsulfonylalkyl, aminocarbonyl, or alkoxycarbonyl.

[0060] Another aspect of the invention is a compound of formula II or a pharmaceutically acceptable salt thereof, wherein

[0061] Ar 1 for

[0062] R 5a Cyanoyl, halogen, alkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, alkoxy, haloalkoxy, carboxamide, alkoxycarbonyl, -NR 7 R 8 ; cycloalkyl groups substituted with 0 to 1 halogen, hydroxyl, alkyl or alkoxy groups; phenyl groups substituted with 0 to 1 halogen, hydroxyl or alkyl groups; or 5 to 8-membered heterocyclic groups containing a carbon atom and 1 to 3 heteroatoms selected from N, NH, O, S and substituted with 0 to 1 halogen, hydroxyl or alkyl groups;

[0063] R 5b It is cyano, halogen, alkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, alkoxy, haloalkoxy, carboxamide, alkoxycarbonyl, or cycloalkyl; and

[0064] R 7 and R 8 It is independently hydrogen, alkyl, haloalkyl, or hydroxyalkyl; or R 7 and R 8 Together with the nitrogen to which it is attached, it forms a heterocycle having 0 to 3 additional heteroatoms selected from N, NH, O, and S and substituted with 0 to 3 halogen groups, hydroxyl groups, alkyl groups, alkoxy groups, or oxo groups;

[0065] Other variables are defined as shown in Equation II above.

[0066] Another aspect of the invention is a compound of formula II or a pharmaceutically acceptable salt thereof, wherein

[0067] Ar 1 for

[0068] R 5a Alkyl, hydroxyalkyl, -NR 7 R 8 Cyclobutyl group substituted with 0 to 1 halogen, hydroxyl, alkyl, alkoxy or phenyl group;

[0069] R 5b It is an alkoxy group; and

[0070] R 7 and R 8 It is independently an alkyl or hydroxyalkyl group; or R 7 and R 8 Together with the nitrogen to which it is attached, it forms a heterocycle having 0 to 2 additional nitrogen atoms and being substituted by 0 to 3 halogen, hydroxyl, alkyl, alkoxy or oxo groups;

[0071] Other variables are defined as shown in Equation II above.

[0072] Another aspect of the invention is a compound of formula II or a pharmaceutically acceptable salt thereof, wherein

[0073] R 5a For -NR 7 R 8 ;and

[0074] R 7 and R 8 It is independently an alkyl or hydroxyalkyl group; or R 7 and R 8 It forms together with the nitrogen it is attached to

[0075]

[0076] Other variables are defined as shown in Equation II above.

[0077] Another aspect of the invention is a compound of formula II or a pharmaceutically acceptable salt thereof, wherein

[0078] Ar 1 for

[0079] R 5a Cyanoyl, halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, -NR 7 R 8 Or cycloalkyl groups substituted with 0 to 1 alkoxy group;

[0080] R 5b It is cyano, halogen, alkyl, dimethylamino, or haloalkyl; and

[0081] R 7 and R 8 It is independently an alkyl or hydroxyalkyl group; or R 7 and R 8 Together with the nitrogen to which it is attached, it forms a heterocycle selected from the following:

[0082]

[0083] Other variables are defined as shown in Equation II above.

[0084] Another aspect of the invention is a compound of formula II or a pharmaceutically acceptable salt thereof, wherein

[0085] Ar 1 for

[0086] R 5a It is cyano, halogen, alkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, alkoxy, or haloalkoxy; and

[0087] R 5b It can be cyano, halogen, alkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, alkoxy, or haloalkoxy;

[0088] Other variables are defined as shown in Equation II above.

[0089] Another aspect of the invention is a compound of formula II or a pharmaceutically acceptable salt thereof, wherein

[0090] Ar 1 for and

[0091] R 5a It is an alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, or cycloalkyl group;

[0092] Other variables are defined as shown in Equation II above.

[0093] Another aspect of the invention is a compound of formula II or a pharmaceutically acceptable salt thereof, wherein

[0094] Ar 1 for

[0095] R 5a It is a halogenated group, alkoxy group, haloalkoxy group, carboxamide group, alkoxycarbonyl group, or cycloalkyl group substituted with 0 to 1 hydroxyl group; and

[0096] R 5b It can be cyano, halogen, alkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, alkoxy, haloalkoxy, carboxamide, alkoxycarbonyl, or cycloalkyl;

[0097] Other variables are defined as shown in Equation II above.

[0098] Another aspect of the invention is a compound of formula II or a pharmaceutically acceptable salt thereof, wherein

[0099] Ar 1 for

[0100] R 5a It is cyano, halogen, alkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, or alkoxy; and

[0101] R 5b It is cyano, halo, alkyl, or haloalkyl;

[0102] Other variables are defined as shown in Equation II above.

[0103] Another aspect of the invention is a compound of formula II or a pharmaceutically acceptable salt thereof, wherein

[0104] Ar 1 for

[0105] R 5a It is a halogenated group; and

[0106] R 5b It is a halogenated group;

[0107] Other variables are defined as shown in Equation II above.

[0108] Another aspect of the invention is a compound of formula II or a pharmaceutically acceptable salt thereof, wherein

[0109] Ar 1 for

[0110] R 5a It is a halogenated group, alkyl group, alkoxy group, or haloalkoxy group; and

[0111] R 5b It can be a halogen group, alkyl group, haloalkyl group, alkoxyalkyl group, hydroxyalkyl group, alkoxy group, or haloalkoxy group;

[0112] Other variables are defined as shown in Equation II above.

[0113] Another aspect of the present invention is a compound of formula III:

[0114]

[0115] Or its pharmaceutically acceptable salt, wherein

[0116] R 2 It is an alkyl or haloalkyl group;

[0117] R 3a It can be a halogenated group, alkyl group, haloalkyl group, alkoxy group, deuterated alkoxy group, haloalkoxy group, or cycloalkyl group;

[0118] R 3b It is a halogenated group, alkyl group, hydroxyl group, or haloalkyl group; or R 3a and adjacent R 3b Together with the two carbon atoms it is attached to, it forms a 3- to 6-membered heterocycle containing a carbon atom and 1 to 3 heteroatoms selected from N, NH, O, and S, and substituted with 0 to 3 halogen groups, hydroxyl groups, alkyl groups, haloalkyl groups, or alkoxycarbonyl groups;

[0119] R 4a It can be a halogenated group, alkyl group, cycloalkyl group, haloalkyl group, alkoxy group, haloalkoxy group, or pyrazolyl group;

[0120] R 5a Halogenated, hydroxyalkyl, alkoxy, alkoxyalkoxy, hydroxyalkoxy, alkylaminoalkyl, alkoxycarbonylalkoxy, hydroxyalkylcycloalkylalkyl, alkylsulfonyl, aminocarbonylalkyl, hydroxyalkylcycloalkylalkyl, -NR 7 R 8 ; a 5- to 8-membered heterocyclic group comprising a carbon atom and 1 to 3 heteroatoms selected from N, NH, O, S and substituted with 0 to 3 halogen groups, hydroxyl groups, alkyl groups, haloalkyl groups, alkoxycarbonyl groups, or alkylsulfonyl groups; or a heterocyclic alkyl group comprising 5 to 8 carbon atoms and 1 to 3 heteroatoms selected from N, NH, O, S and substituted with 0 to 3 halogen groups, hydroxyl groups, alkyl groups, or haloalkyl groups;

[0121] R 5b It is cyano, halogen, allyl, alkoxy, or haloalkyl; and

[0122] R 7 and R 8 Independently, it is a hydrogen, alkyl, haloalkyl, hydroxyalkyl, halohydroxyalkyl, alkoxyalkyl, aminocarbonylalkyl, alkylsulfonyl, alkylaminocarbonylalkyl, cycloalkylaminocarbonylalkyl, cycloalkylalkyl, hydroxycycloalkylalkyl, hydroxyalkylcycloalkylalkyl, cycloalkylalkyl, cycloalkylalkyl, cycloalkyl, wherein each cycloalkyl group is substituted with 0 to 3 halogen groups, hydroxyl groups, or alkyl groups, or hydroxyalkyl groups; or it is a 5 to 8 membered heterocyclic group containing a carbon atom and 1 to 3 heteroatoms selected from N, NH, O, S and substituted with 0 to 3 halogen groups, hydroxyl groups, alkyl groups, haloalkyl groups or alkoxycarbonyl groups;

[0123] or R 7 and R 8 Together with the nitrogen to which it is attached, it forms a 5- to 12-membered heterocycle containing a carbon atom and 0 to 3 other heteroatoms selected from N, NH, O, and S, and substituted with 0 to 5 halogen, hydroxyl, alkyl, alkoxy, oxo, haloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, alkylsulfonyl, alkylsulfonylalkyl, aminocarbonyl, or alkoxycarbonyl.

[0124] Another aspect of the present invention is a compound of formula IV.

[0125]

[0126] Or its pharmaceutically acceptable salt, wherein

[0127] R 5aHalogenated, alkoxy, alkoxyalkoxy, hydroxyalkyl, hydroxyalkoxy, aminocarbonylalkyl, hydroxyalkylcycloalkylalkyl, -NR 7 R 8 ,or

[0128] R 5b It is a halogenated or haloalkyl group;

[0129] R 7 and R 8 Independently, it is hydrogen, alkyl, hydroxyalkyl, halohydroxyalkyl, alkoxyalkyl, aminocarbonylalkyl, hydroxycycloalkylalkyl, hydroxyalkylcycloalkylalkyl, cycloalkylalkyl, cycloalkylalkyl, cycloalkyl

[0130] or R 7 and R 8 Together with the nitrogen to which it is attached, it forms a heterocyclic group selected from the following:

[0131]

[0132] And the other variables are defined as in Equation III above.

[0133] Another aspect of the present invention is a compound of formula V.

[0134]

[0135] Or its pharmaceutically acceptable salt, wherein

[0136] R 5a Halogenated, alkoxyalkoxy, hydroxyalkyl, hydroxyalkoxy, -NR 7 R 8 ,or

[0137] R 5b It is Cl or CF3;

[0138] R 7 It is hydrogen;

[0139] R 8 Alkyl, hydroxyalkyl, halohydroxyalkyl, alkoxyalkyl, aminocarbonylalkyl, hydroxycycloalkylalkyl, hydroxyalkylcycloalkylalkyl, cycloalkylalkyl, cycloalkylalkyl, cycloalkyl

[0140] or R 7 and R 8 Together with the nitrogen to which it is attached, it forms a heterocyclic group selected from the following:

[0141]

[0142] Another aspect of the present invention is a compound of formula VI.

[0143]

[0144] Or its pharmaceutically acceptable salt, wherein

[0145] R 3a It is a halogenated group, alkyl group, alkoxy group, or deuterated alkoxy group;

[0146] R 3b It is a halogenated group;

[0147] R 4a It is a haloalkoxy group;

[0148] R 5a It is a cyano, halo, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkoxy, hydroxyalkoxy, hydroxyhaloalkoxy, hydroxyalkoxyalkoxy, or alkylsulfonylalkoxy group; comprising a carbon atom and 1 to 3 heteroatoms selected from N, O, NH, and S, and substituted with 0 to 3 halo, alkyl, hydroxyalkyl, haloalkyl, or alkylsulfonyl groups, forming a 5 to 8 membered heterocyclic group; or a heterocyclic alkoxy group, wherein the heterocyclic group comprises 5 to 8 carbon atoms and 1 to 3 heteroatoms selected from N, NH, O, and S, and substituted with 0 to 3 halo, hydroxy, hydroxyalkyl, alkyl, or haloalkyl groups; and

[0149] R 5b It is a cyano, alkyl, hydroxyalkyl, alkoxy, or hydroxyalkoxy group; a 5- to 8-membered heterocyclic group comprising a carbon atom and 1 to 3 heteroatoms selected from N, O, NH, and S and substituted with 0 to 3 halogen or alkyl groups; or a heterocyclic group comprising 5 to 8 carbon atoms and 1 to 3 heteroatoms selected from N, NH, O, and S and substituted with alkyl groups; or a heterocyclic group substituted with 0 to 1 alkyl group.

[0150] Another aspect of the invention is a compound of formula VI or a pharmaceutically acceptable salt thereof, wherein

[0151] R 5a for

[0152]

[0153] R 5b -OCH3 or CH3 and

[0154] Other variables are defined as shown in equation VI above.

[0155] Another aspect of the present invention is a compound of formula VII.

[0156]

[0157] Or its pharmaceutically acceptable salt, wherein

[0158] R 3a It can be Cl, CF3, CH3, CH3CH2, CD3, OCH3, OCF3, OCF2, or OCD3;

[0159] R 4a It is either OCF3 or OCF2; and

[0160] R 5a for

[0161] Another aspect of the present invention is a compound of formula VIII.

[0162]

[0163] Or its pharmaceutically acceptable salt, wherein

[0164] R 5a Cyanoyl, alkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, -NR 7 R 8 ,

[0165] R 5b It is cyano, alkyl, or haloalkyl;

[0166] R 7 It is hydrogen or alkyl; and

[0167] R 8 It is an alkyl or hydroxyalkyl group.

[0168] For compounds of formulas I to VIII, the scope of any embodiment with variable substituents can be used independently of the scope of any other embodiment with variable substituents. Therefore, the invention comprises combinations of different aspects.

[0169] In one non-limiting embodiment, for compounds of formula (I), R 1 For Ar 1 or (Ar) 1 alkyl; Ar 1 For 0 to 2 R 5a Or 0 to 2 R 5b Substituted phenyl; R 5a and R 5b Independently, it is a halogenated group, alkyl group, hydroxyalkyl group, haloalkyl group, alkoxy group, or alkoxycarbonyl group; R 2 It is a lower alkyl group; R 3 For 1 R 3a and 0 to 2 R 3b Substituted phenyl; R 3a It is an alkoxy group; R3b It is a halogenated group; R 4 For 1 R 4a Substituted phenyl; R 4a It is a haloalkyl or haloalkoxy; and R 6 It is hydrogen.

[0170] In another non-limiting embodiment, for compounds of formula (I), R 1 For Ar 1 Ar 1 For 0 to 2 R 5a Or 0 to 2 R 5b Substituted cycloalkyl; R 5a and R 5b Independently, it is a halogenated group, alkyl group, hydroxyalkyl group, haloalkyl group, alkoxy group, or alkoxycarbonyl group; R 2 It is a lower alkyl group; R 3 For 1 R 3a and 0 to 2 R 3b Substituted phenyl; R 3a It is an alkoxy group; R 3b It is a halogenated group; R 4 For 1 R 4a Substituted phenyl; R 4a It is a haloalkyl or haloalkoxy; and R 6 It is hydrogen.

[0171] In another non-limiting embodiment, for compounds of formula (I), R 1 For Ar 1 Ar 1 For 0 to 2 R 5a Or 0 to 2 R 5b Substituted quinolinyl group; R 5a and R 5b Independently, it is a halogenated group, alkyl group, hydroxyalkyl group, haloalkyl group, alkoxy group, or alkoxycarbonyl group; R 2 It is a lower alkyl group; R 3 For 1 R 3a and 0 to 2 R 3b Substituted phenyl; R 3a It is an alkoxy group; R 3b It is a halogenated group; R 4 For 1 R 4a Substituted phenyl; R 4a It is a haloalkyl or haloalkoxy; and R 6 It is hydrogen.

[0172] In one non-limiting embodiment, for compounds of formula (I), R 1 For Ar 1 Ar 1 For 1 R 5a Substituted pyridinyl group; R5a It is a halogenated group, alkyl group, hydroxyalkyl group, haloalkyl group, alkoxy group, or alkoxycarbonyl group; R 2 It is a lower alkyl group; R 3 For 1 R 3a and 0 to 2 R 3b Substituted phenyl; R 3a It is an alkoxy group; R 3b It is a halogenated group; R 4 For 1 R 4a Substituted phenyl; R 4a It is a haloalkyl or haloalkoxy; and R 6 It is hydrogen.

[0173] In another non-limiting embodiment, for compounds of formula (I), R 1 For Ar 1 Ar 1 For 1 R 5a Substituted pyridinyl group; R 5a is F, Cl, -CHF2, -CF3, -CH2OH, -C(CH3)2OH, -OCH3, -OCH(CH3)2, -O(CH3)2OH, -OCH2C(CH3)2OH, -C(CH3)2OH; R 2 -CH3; R 3 For 1 R 3a and 0 to 2 R 3b Substituted phenyl; R 3a It is methoxy, ethoxy, deuterated methoxy, or deuterated ethoxy; R 3b It is a halogenated group; R 4 For 1 R 4a Substituted phenyl; R 4a It is -CF3, -OCHF2, or -OCF3; and R 6 It is hydrogen.

[0174] In another non-limiting embodiment, for compounds of formula (I), R 1 For Ar 1 Ar 1 For 1 R 5a Substituted pyridinyl group; R 5a For -NR 7 R 8 ;R 2 -CH3; R 3 For 1 R 3a and 0 to 2 R 3b Substituted phenyl; R 3a It is methoxy, ethoxy, deuterated methoxy, or deuterated ethoxy; R 3b It is a halogenated group; R 4 For 1 R 4aSubstituted phenyl; R 4a For -CF3, -OCHF2, or -OCF3; R 6 It is hydrogen; and R 7 and R 8 Independently hydrogen, -CH3 or -CH2CH3; or R 7 and R 8 It forms together with the nitrogen it is attached to

[0175] In one non-limiting embodiment, for compounds of formula (I), R 1 For Ar 1 Ar 1 For 0 to 2 R 5a Or 0 to 2 R 5b Substituted pyridinyl group; R 5a and R 5b Independently, it is a halogenated group, alkyl group, hydroxyalkyl group, haloalkyl group, alkoxy group, or alkoxycarbonyl group; R 2 It is a lower alkyl group; R 3 For 1 R 3a and 0 to 2 R 3b Substituted phenyl; R 3a It is an alkoxy group; R 3b It is a halogenated group; R 4 For 1 R 4a Substituted phenyl; R 4a It is a haloalkyl or haloalkoxy; and R 6 It is hydrogen.

[0176] In another non-limiting embodiment, for compounds of formula (I), R 1 For Ar 1 Ar 1 For 1 R 5a Or 0 to 1 R 5b Substituted pyridinyl group; R 5a and R 5b Independently, it can be F, Cl, -CHF2, or -CF3, -CH2OH, -C(CH3)2OH, -OCH3, -OCH(CH3)2, -O(CH3)2OH, -OCH2C(CH3)2OH, or -C(CH3)2OH; R 2 -CH3; R 3 For 1 R 3a and 0 to 2 R 3b Substituted phenyl; R 3a It is methoxy, ethoxy, deuterated methoxy, or deuterated ethoxy; R 3b It is a halogenated group; R 4 For 1 R 4a Substituted phenyl; R4a It is CF3, OCHF2, or OCF3; and R 6 It is hydrogen.

[0177] In another non-limiting embodiment, for compounds of formula (I), R 1 For Ar 1 Ar 1 For 1 R 5a Or 1 R 5b Substituted pyridinyl group; R 5a It is a hydroxyl-substituted cycloalkyl group; R 5b It is an alkoxy group; R 2 -CH3; R 3 For 1 R 3a and 0 to 2 R 3b Substituted phenyl; R 3a It is methoxy, ethoxy, deuterated methoxy, or deuterated ethoxy; R 3b It is a halogenated group; R 4 For 1 R 4a Substituted phenyl; and R 4a It is CF3, OCHF2, or OCF3; and R 6 It is hydrogen.

[0178] In another non-limiting embodiment, for compounds of formula (I), R 1 For Ar 1 Ar 1 For 1 R 5a Or 1 R 5b Substituted pyridinyl group; R 5a It can be -OCH(CH3)2, -O(CH3)2OH, -OCH2C(CH3)2OH or -NR 7 R 8 And R 5b For -CF3 or -OCH3; R 2 CH3; R 3 For 1 R 3a and 0 to 2 R 3b Substituted phenyl; R 3a It is methoxy, ethoxy, deuterated methoxy, or deuterated ethoxy; R 3b It is a halogenated group; R 4 For 1 R 4a Substituted phenyl; and R 4a It is CF3, OCHF2, or OCF3; and R 6 It is hydrogen; R 7 and R 8 For hydrogen, CH3, CH2CH3, -CH2CH2OH, -CH2CH(OH)CH3, R 7and R 8 It forms together with the nitrogen it is attached to

[0179] In another non-limiting embodiment, for compounds of formula (I), R 1 For Ar 1 Ar 1 for R 5a For -NR 7 R 8 Or hydroxylated cycloalkyl groups; R 5b -OCH3; R 2 CH3; R 3 For 1 R 3a and 0 to 2 R 3b Substituted phenyl; R 3a It is methoxy, ethoxy, deuterated methoxy, or deuterated ethoxy; R 3b It is a halogenated group; R 4 For 1 R 4a Substituted phenyl; and R 4a For CF3, OCHF2, or OCF3; R 7 and R 8 For hydrogen, CH3, CH2CH3, -CH2CH2OH, -CH2CH(OH)CH3, And R 6 It is hydrogen; R 7 and R 8 It forms together with the nitrogen it is attached to

[0180] In another non-limiting embodiment, for compounds of formula (I), R 1 For Ar 1 Ar 1 for R 5a for R 5b -CH3 or -OCH3; R 2 -CH3; R 3 For 1 R 3a and 0 to 2 R 3b Substituted phenyl; R 3a It is methoxy, ethoxy, deuterated methoxy, or deuterated ethoxy; R 3b It is a halogenated group; R 4 For 1 R 4a Substituted phenyl; and R 4a It is CF3, OCHF2, or OCF3; and R 6 It is hydrogen.

[0181] In another non-limiting embodiment, for compounds of formula (I), R 1 For Ar 1 Ar 1 for R 5a For -CH3, -OCH2CH2OH, -OCH2C(OH)CF3, -OCH(CF3)CH2OH, OCH2CH2S(O)2CH3, or -NR 7 R 8 ;R 5b For CH3 or -OCH3; R 2 CH3; R 3 For 1 R 3a and 0 to 2 R 3b Substituted phenyl; R 3a It is methoxy, ethoxy, deuterated methoxy, or deuterated ethoxy; R 3b It is a halogenated group; R 4 For 1 R 4a Substituted phenyl; and R 4a For CF3, OCHF2, or OCF3; R 6 It is hydrogen; R 7 and R 8 It forms together with the nitrogen it is attached to

[0182] In another non-limiting embodiment, for compounds of formula (I), R 1 For Ar 1 Ar 1 for R 5a For F, Cl, -OCH2C(CH3)2OH or -NR 7 R 8 ;R 5b -CF3; R 2 CH3; R 3 For 1 R 3a and 0 to 2 R 3b Substituted phenyl; R 3a It is methoxy, ethoxy, deuterated methoxy, or deuterated ethoxy; R 3b It is either absent or a halogen group; R 4 For 1 R 4a Substituted phenyl; and R 4a For CF3, OCHF2, or OCF3; R 6 It is hydrogen; R 7 It is hydrogen; R 8For CH3, CH2CH3, -CH2CH2OH, -CH2CH(CH3)OH, -CH2C(CH3)2OH, -CH2CH(OH)CH3, R 7 and R 8 It forms together with the nitrogen it is attached to

[0183] In another embodiment, the compound of the present invention is selected from those having FPR2 EC. 50 Compounds with a value ≥ 0.1 μM.

[0184] In another embodiment, the compound of the present invention is selected from those having FPR2 EC. 50 Compounds with a value ≥ 0.01 μM < 0.1 μM.

[0185] In another embodiment, the compound of the present invention is selected from those having FPR2 EC. 50 Compounds with a value ≥ 0.006 μM < 0.01 μM.

[0186] In another embodiment, the compound of the present invention is selected from those having FPR2 EC. 50 Compounds with a value ≥ 0.001 μM < 0.006 μM.

[0187] In another embodiment, the compound of the present invention is selected from those having FPR2 EC. 50 Compounds with a value < 0.001 μM.

[0188] Unless otherwise specified, these terms have the following meanings.

[0189] The hyphen "-" not between two letters or symbols is used to indicate the connection point of a substituent, for example, -CONH2 is connected by a carbon atom.

[0190] Keys pointing to wavy lines, such as As used in the structural formulas of this paper, the connection points of portions or substituents that connect to the core or main chain structure are described.

[0191] “Cyanogen” refers to -CN.

[0192] "Hydroxy" refers to -OH.

[0193] "Alkyl" refers to a straight-chain or branched alkyl group containing 1 to 6 carbons. "Lower alkyl" refers to a straight-chain or branched alkyl group containing 1 to 3 carbons.

[0194] "Alkenyl" refers to a straight-chain or branched alkyl group containing 2 to 6 carbons and at least one double bond.

[0195] "Alkyne" refers to a straight-chain or branched alkyl group containing 2 to 6 carbons and at least one triple bond.

[0196] "Cycloalkyl" refers to a monocyclic ring system containing 3 to 7 carbons. Terms with a hydrocarbon moiety (e.g., alkoxy) include both straight-chain and branched isomers of that hydrocarbon moiety.

[0197] "Halogen" refers to fluorine, chlorine, bromine, and iodine.

[0198] "Haloalkyl" refers to an alkyl group that has been substituted with a halogen group. Haloalkyl includes all halogenated isomers ranging from monohalogen to all-halogen.

[0199] "Alkoxy" refers to an alkyl group that is linked to the rest of the molecule via an oxygen bond. Representative examples of these groups are -OCH3 and -OC2H5. Unless stated or detailed to the contrary, all alkoxy groups described or claimed herein may be straight-chain or branched. The term "deuterated alkoxy" refers to an alkoxy group in which 1 to 5 hydrogen atoms have been replaced by deuterium. An example of a "deuterated alkoxy" is -OCD3.

[0200] "Alkoxyalkoxy" refers to an alkoxy group in which at least one of the hydrogen atoms of the alkoxy group has been replaced by another alkoxy group.

[0201] "Hydroxyalkoxy" refers to alkoxyalkoxy, in which at least one of the hydrogen atoms has been replaced by a hydroxyl group.

[0202] "Hydroxyhaloalkoxy" refers to an alkoxy group in which at least one of the hydrogen atoms of the alkoxy group has been replaced by a halogen group and at least one of the hydrogen atoms of the alkoxy group has been replaced by a hydroxyl group.

[0203] "alkylsulfonylalkoxy" refers to an alkoxy group in which at least one of the hydrogen atoms of the alkoxy group has been replaced by an alkylsulfonyl group.

[0204] "Heterocyclic alkoxy" refers to an alkoxy group in which at least one of the hydrogen atoms of the alkoxy group has been replaced by a heterocyclic group.

[0205] "alkylsulfonyl" refers to the group -SO2-alkyl, where alkyl is as defined herein.

[0206] "Hydroxyalkyl" refers to an alkyl group having at least one hydrogen atom substituted with a hydroxyl group.

[0207] "Alkoxyalkyl" refers to an alkyl group having at least one hydrogen atom substituted with an alkoxy group.

[0208] "Haloalkoxy" refers to an alkyl group that is substituted with a halogenated group and linked by an oxygen atom. Haloalkoxy groups include monosubstituted alkoxy groups and alkoxy groups substituted with multiple halogenated groups, up to and including all-halogenated alkoxy groups. Examples include trifluoromethoxy, chloromethoxy, and bromomethoxy.

[0209] "Alkoxycarbonyl" refers to a carbonyl radical (such as -C(O)OR) substituted with an alkoxy group, where R represents an optionally substituted alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl or similar moiety.

[0210] "Aminocarbonylalkyl" refers to the group "-alkyl-C(O)NRR", where each R represents hydrogen or an optionally substituted alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl or similar moiety.

[0211] "Aryl" refers to a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 12 carbon atoms, or a bicyclic fused ring system, wherein one or both of the rings are aromatic. A bicyclic fused ring system consists of a phenyl group fused to a four- to seven-membered aromatic or non-aromatic carbon ring. Representative examples of aryl groups include (but are not limited to) phenyl, dihydroindenyl, indenyl, naphthyl, and tetrahydronaphthyl.

[0212] "Heteroaryl" refers to a 5- to 7-membered monocyclic or 8- to 11-membered bicyclic aromatic ring system having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0213] "Heterocyclic group" or "heterocycle" refers to a 5- to 7-membered monocyclic or 8- to 11-membered polycyclic heterocycle that is saturated, partially unsaturated, or fully unsaturated and contains a carbon atom and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O, and S; and includes any polycyclic group, wherein any of the heterocycles defined above is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N→O and S(O)p, where p is 0, 1, or 2). The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or another substituent, if defined). The heterocycle may be attached to its side group at any heteroatom or carbon atom that results in a stable structure. If the resulting compound is stable, the heterocycle described herein may be substituted on a carbon atom or on a nitrogen atom. The nitrogen in the heterocycle may optionally be quadratically ammonized. Preferably, when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heterocycle does not exceed 1. When the term "heterocyclic" is used, it is intended to include heteroaryl groups.

[0214] "Heterocyclic oxy group" refers to the -O-heterocyclic group, which is as defined herein.

[0215] "Heterocyclic alkyl" refers to an alkyl group having at least one hydrogen atom substituted with a heterocyclic group as defined herein.

[0216] Where no bond connection position is specified, the bond may be connected at any suitable location, as understood by those skilled in the art. Combinations of substituents and bonding partners are only those that result in stable compounds, as understood by those skilled in the art. Intercalation and multiple intercalation terms are intended to clarify bonding relationships to those skilled in the art. For example, terms such as ((R)alkyl) refer to alkyl substituents further substituted by substituent R.

[0217] The following describes the compound (where R) 3a Some examples of para-substituted pyrazole-3-one.

[0218]

[0219] The following describes the compound (where R) 4a Some examples (with the amide moiety being para-substituted).

[0220]

[0221] This invention includes all pharmaceutically acceptable salt forms of compounds. Pharmaceutically acceptable salts are those in which the counterions do not significantly promote the physiological activity or toxicity of the compound and thus act as pharmacological equivalences. These salts can be prepared using commercially available reagents according to common organic techniques. Some anionic salt forms include acetate, acetate, benzenesulfonate, bromide, chloride, citrate, fumarate, gluconate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, methanesulfonate, nitrate, pyrate, phosphate, succinate, sulfate, tartrate, toluenesulfonate, and xinofoate. Some cationic salt forms include ammonium, aluminum, benzathine, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium, thiocyanate, and zinc.

[0222] Some compounds of this invention exist in stereoisomeric forms (including structures having specified carbon atoms). This invention encompasses all stereoisomeric forms of the compounds, including enantiomers and diastereomers. Methods for preparing and isolating stereoisomers are known in the art. This invention encompasses all tautomeric forms of the compounds. This invention includes rotationally inhibited isomers and rotational isomers.

[0223] This invention aims to encompass all isotopes of atoms appearing in compounds. Isotopes include atoms having the same number of atoms but different mass numbers. Generally, and without limitation, isotopes of hydrogen include deuterium (D) and tritium (T). Isotopes of carbon include... 11 C 13 C and 14C. The isotopically labeled compounds of the present invention can generally be prepared using conventional techniques known to those skilled in the art or by methods similar to those described herein, using suitable isotopically labeled reagents instead of the unlabeled reagents originally employed. These compounds can have a variety of potential uses, such as as standards and reagents for determining biological activity. With stable isotopes, these compounds can have the potential to advantageously improve biological, pharmacological, or pharmacokinetic properties.

[0224] biological methods

[0225] N-formyl peptide receptors (FPRs) are a family of chemotherapeutic receptors that promote leukocyte responses during inflammation. FPRs belong to the seven-transmembrane G protein-coupled receptor superfamily and are linked to inhibitory G proteins (Gi). Three family members (FPR1, FPR2, and FPR3) have been identified in humans, primarily in bone marrow cells with varying distributions, and have also been reported in multiple organs and tissues. Upon agonist binding, FPRs activate numerous physiological pathways, such as intracellular transduction and calcium channel blockers. 2+ Immobilization and transcription. This family interacts with different groups of ligands, including proteins, peptides, and fatty acid metabolites that activate both pro-inflammatory and pro-remission downstream reactions. The in vitro activity of the compounds disclosed in this application was measured using FPR2 and FPR1 cyclic adenosine monophosphate (cAMP) assays.

[0226] FPR2 and FPR1 cyclic adenosine monophosphate (cAMP) analysis. A mixture of forskolin (5 μM final for FPR2 or 10 μM final for FPR1) and IBMX (200 μM final) was added to 384-well Proxiplate (Perkin-Elmer) pre-coated with the test compound (final 1%) in DMSO at final concentrations ranging from 0.020 nM to 100 μM. Chinese hamster ovary cells (CHO) overexpressing human FPR1 or human FPR2 receptors were cultured in F-12 (Ham's) medium supplemented with 10% qualified FBS, 250 μg / mL zeocin, and 300 μg / mL hygromycin (Life Technologies). The reaction was initiated by adding 2,000 human FPR2 cells / well or 4,000 human FPR1 cells / well to Dulbecco's PBS (with calcium and magnesium) (Life Technologies) supplemented with 0.1% BSA (Perkin-Elmer). The reaction mixture was incubated at room temperature for 30 minutes. Intracellular cAMP levels were determined using the HTRF HiRange cAMP assay kit (Cisbio) according to the manufacturer's instructions. Solutions of crypt-bound anti-cAMP and d2-fluorophore-labeled cAMP were prepared separately in the supplied lysis buffer. After the reaction was complete, cells were lysed with equal volumes of d2-cAMP and anti-cAMP solutions. After 1 hour of incubation at room temperature, time-varying fluorescence intensity was measured using an Envision (Perkin-Elmer) microscope at excitation at 400 nm and dual emission at 590 nm and 665 nm. Calibration curves were constructed using an external cAMP standard at concentrations ranging from 1 μM to 0.1 pM, by plotting the fluorescence intensity ratio from 665 nm to 590 nm against cAMP concentration. The efficacy and activity of the compound in inhibiting cAMP production were then determined by fitting a graph of cAMP content relative to compound concentration to a 4-parameter logistic equation.

[0227] The examples disclosed below are those tested in the above FPR2 and FPR1 cAMP analyses and found to possess FPR2 and / or FPR1 agonist activity. Table 1 below lists the EC50 values ​​from the FPR2 and FPR1 cAMP analyses. 50 value.

[0228] Table 1

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236]

[0237]

[0238]

[0239]

[0240]

[0241]

[0242]

[0243] Pharmaceutical Compositions and Methods of Use

[0244] The compounds of this invention can be administered to mammals (preferably humans) to treat a variety of conditions and illnesses, including atherosclerosis, heart failure, lung diseases (including asthma), COPD, and cystic fibrosis; neuroinflammatory diseases, including multiple sclerosis, Alzheimer's disease, and stroke; and chronic inflammatory diseases, such as inflammatory bowel disease, rheumatoid arthritis, psoriasis, sepsis, and renal fibrosis.

[0245] Unless otherwise specified, the following terms have specific meanings. The term "individual" means any human or other mammalian species who may potentially benefit from treatment with FPR2 and / or FPR1 agonists, as understood by those skilled in the art. Some individuals include humans of any age with risk factors for cardiovascular disease. Common risk factors include age, sex, weight, family history, sleep apnea, alcohol or opioid use, physical inactivity, arrhythmias, or signs of insulin resistance such as acanthosis nigricans, hypertension, dyslipidemia, or polycystic ovary syndrome (PCOS). The term "patient" means a person to whom the therapy is appropriate, as determined by those skilled in the art. "Treating / treatment" encompasses treatment of a patient or individual, as understood by those skilled in the art. "Preventing / prevention" encompasses preventative treatment (i.e., prevention and / or risk reduction) of a patient or individual's subclinical disease state, designed to reduce the probability of the occurrence of a clinical disease state, as understood by those skilled in the art. For preventative therapy, patients are selected based on factors known to increase the risk of suffering a clinical disease state compared to the general population. "Therapeuticly effective amount" means the amount of an effective compound, as understood by those skilled in the art.

[0246] Another aspect of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound of formulas I-VIII combined with a pharmaceutical carrier.

[0247] Another aspect of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I-VIII combined with at least one other therapeutic agent and a drug carrier.

[0248] "Pharmaceutical composition" means a composition comprising the compounds of the present invention combined with at least one other pharmaceutically acceptable carrier. "Pharmaceutically acceptable carrier" means a medium generally accepted in the art for delivering a bioactive agent to an animal, particularly a mammal, including, i.e., adjuvants, excipients, or catalysts, such as diluents, preservatives, fillers, flow conditioners, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, aroma agents, antibacterial agents, antifungal agents, lubricants, and dispensing agents, depending on the nature of the administration method and dosage form.

[0249] Pharmaceutically acceptable carriers are formulated based on a number of factors well known to those skilled in the art. These include (but are not limited to): the type and nature of the active agent being formulated; the individual to whom the drug-containing composition is to be administered; the intended route of administration; and the targeted therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as various solid and semi-solid dosage forms. These carriers may include many different components and additives in addition to the active agent, which are included in the formulation for various reasons, such as stabilizing agents, binders, etc., well known to those skilled in the art. Descriptions of suitable pharmaceutically acceptable carriers and the factors involved in their selection can be found in various readily available sources, such as, for example, Allen, LV, Jr. et al., Remington: The Science and Practice of Pharmacy (Vol. 2), 22nd ed., Pharmaceutical Press (2012).

[0250] In particular, when provided in a single dose unit, there is a potential for chemical interactions between the combined active ingredients. For this reason, when the compound of the present invention and the second therapeutic agent are combined in a single dose unit, they are formulated such that, although the active ingredients are combined in a single dose unit, the physical contact between the active ingredients is minimized (i.e., reduced). For example, an active ingredient may be enterically coated. By enterically coating one of the active ingredients, not only is the contact between the combined active ingredients minimized, but the release of one of these components in the gastrointestinal tract can also be controlled so that one of these components is released in the intestine but not in the stomach. One of the active ingredients may also be coated with a material that affects sustained release through the gastrointestinal tract and also serves to minimize the physical contact between the combined active ingredients. Furthermore, a sustained-release component may be further enterically coated so that the release of this component occurs only in the intestine. Another approach would involve the formulation of a combination product in which one component is coated with a sustained-release and / or enteric polymer, and another component is also coated with a polymer (such as a low-viscosity grade of hydroxypropyl methylcellulose (HPMC)) or other suitable materials as known in the art to further separate the active components. The polymer coating serves to form an additional barrier to interaction with other components.

[0251] Another aspect of the present invention is a method for treating heart disease, comprising administering to a patient a therapeutically effective amount of compounds of formulas I-VII.

[0252] Another aspect of the present invention is a method for treating heart disease, wherein the heart disease is selected from the group consisting of: angina pectoris, unstable angina pectoris, myocardial infarction, heart failure, acute coronary heart disease, acute heart failure, chronic heart failure, and iatrogenic cardiac injury.

[0253] It is understandable that the treatment or prevention of heart failure may also involve the treatment or prevention of cardiovascular events. The treatment or prevention mentioned in this article may refer to the treatment or prevention of certain negative symptoms or conditions associated with or resulting from cardiovascular events. For example, treatment or prevention may involve reducing or preventing negative changes associated with or resulting from cardiovascular events, such as shortened fraction, heart weight, lung weight, myocyte cross-sectional area, cardiac fibrosis due to stress overload, stress-induced cellular senescence and / or cardiac hypertrophic characteristics, or any combination thereof. Treatment may be performed in preparation for or in response to cardiovascular events to mitigate negative effects. Prevention may involve proactive or preventative treatment to prevent cardiovascular events or reduce the occurrence of their negative effects.

[0254] In one embodiment, the present invention provides compounds of formulas I-VIII or pharmaceutically acceptable salts thereof for the preparation of pharmaceutical compositions for treating or preventing heart failure, for example, heart failure caused by hypertension, ischemic heart disease, non-ischemic heart disease, exposure to cardiotoxic compounds, myocarditis, Kawasaki disease, type I and type II diabetes, thyroid disease, viral infection, gingivitis, drug abuse, alcohol abuse, pericarditis, atherosclerosis, vascular disease, hypertrophic cardiomyopathy, dilated cardiomyopathy, myocardial infarction, atrial fibrosis, left ventricular systolic dysfunction, left ventricular diastolic dysfunction, coronary artery bypass grafting, pacemaker implantation, starvation, eating disorders, muscular dystrophy, and genetic defects. Preferably, the heart failure to be treated is diastolic heart failure, heart failure with reduced ejection fraction (HF). R EF), heart failure with preserved ejection fraction (HF) P EF), acute heart failure, and ischemic and non-ischemic chronic heart failure.

[0255] In one embodiment, the present invention provides the use of compounds of formulas I-VIII for treating systolic and / or diastolic dysfunction, wherein the compound is administered in a therapeutically effective amount to increase the ability of myocardial cells to contract and relax, thereby increasing the filling and emptying of the right and left ventricles, preferably the left ventricle.

[0256] In another embodiment, the present invention provides the use of compounds of formula I-VIII for treating heart failure, wherein the compounds are administered in a therapeutically effective amount to increase the ejection fraction of the left ventricle.

[0257] In another embodiment, the present invention provides the use of compounds of formulas I-VIII for treating heart failure, wherein the compounds are administered in a therapeutically effective amount to reduce fibrosis of cardiac tissue.

[0258] Another aspect of the present invention is a method for treating heart disease, wherein the treatment is performed after a myocardial infarction.

[0259] Another aspect of the present invention is a method for treating heart disease, comprising administering to a patient a therapeutically effective amount of a compound of formula I in combination with other therapeutic agents.

[0260] The compounds of this invention can be administered by any suitable method, such as orally, including tablets, capsules (each including sustained-release or timed-release formulations), pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried suspensions), syrups, and emulsions; sublingually; buccally; non-enterically, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection, or by infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, including administration to the nasal membrane, such as by inhalation sprays; topically, such as in the form of creams or ointments; or rectally, such as in the form of suppositories. They can be administered alone, but are generally administered with a drug carrier selected based on the chosen route of administration and the physical form of the standard drug.

[0261] The dosage regimen of the compounds of this invention will, of course, depend on variations in known factors, such as the pharmacodynamic properties of the particular agent and its mode and route of administration; the recipient’s species, age, sex, health, medical condition and weight; the nature and severity of symptoms; the type of concomitant treatment; the frequency of treatment; the route of administration, the patient’s renal and hepatic function, and the desired effect.

[0262] Based on general guidelines, when used for a specified effect, the daily oral dose range for each active ingredient will be from about 0.01 to about 5000 mg / day, preferably from about 0.1 to about 1000 mg / day, and most preferably from about 0.1 to about 250 mg / day. Intravenously, the optimal dose range during constant-rate infusion will be from about 0.01 to about 10 mg / kg / min. The compounds of the present invention can be administered as a single daily dose, or the total daily dose can be administered in two, three, or four separate doses per day.

[0263] Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 mg to about 2000 mg of the active ingredient / dose unit. In these pharmaceutical compositions, the active ingredient is generally present in an amount of about 0.1 to 95% by weight based on the total weight of the composition. Typical capsules for oral administration contain at least one of the compounds of the present invention (250 mg), lactose (75 mg), and magnesium stearate (15 mg). The mixture is passed through a 60-mesh sieve and packaged into No. 1 gelatin capsules. Typical injectable formulations are prepared by aseptically placing at least one of the compounds of the present invention (250 mg) into a vial, aseptically freeze-drying, and sealing. For use, the contents of the vial are mixed with 2 mL of physiological saline to produce an injectable formulation.

[0264] The compounds of this invention can be used in combination with other suitable therapeutic agents that can be used to treat the above-mentioned diseases or conditions, including: anti-atherosclerotic agents, anti-dyslipidemia agents, anti-diabetic agents, anti-hyperglycemic agents, anti-hyperinsulinemia agents, antithrombotic agents, anti-retinopathy agents, anti-neuropathy agents, anti-nephropathy agents, anti-ischemic agents, antihypertensive agents, anti-obesity agents, anti-hyperlipidemia agents, anti-hypertriglyceride agents, anti-hypercholesterol agents, anti-restenosis agents, anti-pancreatic agents, lipid-lowering agents, anorexia agents, memory enhancers, anti-dementia agents, cognitive promoters, appetite suppressants, agents for treating heart failure, agents for treating peripheral artery disease, agents for treating malignant tumors, and anti-inflammatory agents.

[0265] The compounds of this invention can be used in conjunction with at least one of the following heart failure agents selected from: heinz cyclic diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), angiotensin receptor-neprilysin inhibitors (ARNIs), beta blockers, mineral corticosteroid receptor antagonists, nitrohydroxy donors, RXFP1 agonists, APJ agonists, SGLT2 inhibitors, HCN potassium-sodium channel inhibitors, myosin modulators, calcium channel inhibitors, chymase inhibitors, and cardiotonic agents. These medications include (but are not limited to) furosemide, bumetanide, torsemide, sacubitrial-valsartan, thiazide diuretics, captopril, enalapril, lisinopril, carvedilol, metopolol, bisoprolol, serelaxin, spironolactone, eplerenone, ivabradine, candesartan, eprosartan, irbestarain, losartan, olmesartan, telmisartan, and valsartan.

[0266] The compounds of this invention can be used in combination with at least one of the following therapeutic agents for treating atherosclerosis: anti-hyperlipidemic agents, plasma HDL-raising agents, anti-hypercholesterol agents, cholesterol biosynthesis inhibitors (such as HMG-CoA reductase inhibitors), LXR agonists, probucol, raloxifene, nicotinic acid, nicotinamide, cholesterol absorption inhibitors, bile acid blocking agents (such as anion exchange resins, or fourth amines, for example, cholesterolyramine or colestipol), low-density lipoprotein receptor inducers, clofibrate, fenofibrate, benzofibrate, cipofibrate, gemfibrizol, vitamin B6, vitamin B12. 12 Antioxidant vitamins, beta-blockers, antidiabetic agents, angiotensin II antagonists, angiotensin-converting enzyme inhibitors, platelet aggregation inhibitors, fibrinogen receptor antagonists, aspirin, and fibrinolytic derivatives.

[0267] The compounds of this invention can be used in combination with at least one of the following therapeutic agents for treating cholesterol: biosynthesis inhibitors, specifically HMG-CoA reductase inhibitors. Suitable examples of HMG-CoA reductase inhibitors include (but are not limited to) lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, and rosuvastatin.

[0268] The compounds of this invention can be used in combination with at least one of the following antidiabetic agents, depending on the desired targeted therapy. Studies indicate that the regulation of diabetes and hyperlipidemia can be further improved by adding a second agent to the treatment regimen. Examples of antidiabetic agents include (but are not limited to) sulfonylureas (such as chlorpropamide, tolbutamide, acetohexamide, tolazamide, glyburide, gliclazide, glynase, glimepiride, and glipizide), biguanides (such as metformin), thiazolidinediones (such as ciglitazone, pioglitazone, troglitazone, and rosiglitazone), and related insulin stabilizers, such as selective and non-selective activators of PPARα, PPARβ, and PPARγ; dehydroepiandrosterone (dehydroepiandrosterone). Roepiandrosterone (also known as DHEA or its conjugated sulfate, DHEA-SO4); anti-glucocorticoids; TNFα inhibitors; dipeptidyl peptidase IV (DPP4) inhibitors (such as sitagliptin, saxagliptin)); GLP-1 agonists or analogs (such as exenatide); α-glucosidase inhibitors (such as acarbose, miglitol, and voglibose)); pramlintide (a synthetic analog of the human hormone amylin); other insulin secretagogues (such as repaglinide, gliquidone, and nateglinide)); insulin; and the therapeutic agents discussed above for the treatment of atherosclerosis.

[0269] The compounds of this invention can be used in combination with at least one of the following anti-obesity agents selected from: phenylpropanolamine, phentermine, diethylpropion, mazindol, fenfluramine, dexfenfluramine, phentiramine, β3-adrenergic receptor agonists; sibutramine, gastrointestinal lipase inhibitors (such as orlistat), and leptin. Other agents for the treatment of obesity or obesity-related conditions include neuropeptide Y, enterostatin, cholecystokinin, bombesin, amylin, histamine H3 receptor, dopamine D2 receptor modulators, melanocyte-stimulating hormone, corticotrophin-releasing factor, galanin, and gamma-aminobutyric acid (GABA).

[0270] The compounds of this invention can also be used as standard or reference compounds, for example, as quality standards or controls in tests or analyses involving FPR2. These compounds are available in commercial kits, for example, for pharmaceutical studies involving FPR2 activity. For example, the compounds of this invention can be used as references in analyses to compare their known activities with those of compounds with unknown activities. This will assure the experimenter that the analysis is being performed appropriately and provide a basis for comparison, especially if the test compound is a derivative of the reference compound. When developing novel analyses or protocols, the compounds according to this invention can be used to test their effectiveness. The compounds of this invention can also be used in diagnostic analyses involving FPR2.

[0271] This invention also covers articles of manufacture. As used herein, articles of manufacture are intended to include (but are not limited to) kits and packaging. Articles of manufacture of the present invention comprise: (a) a first container; (b) a pharmaceutical composition located within the first container, wherein the composition comprises a first therapeutic agent comprising a compound of the present invention or a pharmaceutically acceptable salt thereof; and (c) a package insert indicating that the pharmaceutical composition may be used to treat dyslipidemia and its sequelae. In another embodiment, the package insert indicates that the pharmaceutical composition may be used in combination with a second therapeutic agent for treating dyslipidemia and its sequelae (as previously defined). Articles of manufacture may further comprise: (d) a second container, wherein components (a) and (b) are located within the second container and component (c) is located within or outside the second container. Located within the first and second containers means that the respective container contains the item within its boundaries. The first container is a container for containing the pharmaceutical composition. This container may be used for manufacture, storage, shipping, and / or individual / bulk sales. The first container is intended to encompass bottles, cans, vials, flasks, syringes, tubes (e.g., for cream formulations) or any other container for manufacturing, containing, storing, or dispensing pharmaceutical products. The second container is for containing the first container and optional instruction manuals. Examples of the second container include (but are not limited to) boxes (e.g., cardboard or plastic), crates, cardboard boxes, bags (e.g., paper or plastic bags), sacks, and jute bags. The instruction manuals may be physically attached to the outside of the first container by tape, glue, staples, or another adhesive method, or may be placed inside the second container without being attached to the first container by any physical method. Alternatively, the instruction manuals may be located outside the second container. When located outside the second container, it is preferred that the instruction manuals be physically attached by tape, glue, staples, or another adhesive method. Alternatively, they may be adjacent to or in contact with the outside of the second container without being physically attached. The instruction manuals are labels, tags, markings, etc., that detail information about the pharmaceutical composition located within the first container. The detailed information will generally be determined by the regulatory agency governing the area where the product is sold (e.g., the United States Food and Drug Administration). Preferably, the instruction manuals specifically detail the indications for which the approved pharmaceutical composition is applicable. The packaging instructions can be made of any material, on which information can be read or contained. Preferably, the packaging instructions are made of a printable material (e.g., paper, plastic, cardboard, foil, adhesive wrapping paper or plastic, etc.) on which the desired information is formed (e.g., printed or coated).

[0272] Chemical methods

[0273] The disclosed compounds can be prepared by various methods known in the art, including those in the following reaction diagrams and specific embodiment sections. The structure and variable numbers shown in the synthesis reaction diagrams are different from and should not be confused with the structure or variable numbers in the rest of the claims or specification. The variables in the reaction diagrams are only intended to illustrate how some of the compounds of the invention can be prepared.

[0274] This invention is not limited to the illustrative embodiments described above, and the embodiments are to be considered illustrative and non-limiting in all respects, and are therefore intended to include all variations that occur within the equivalent meaning and scope of the claims.

[0275] Consideration in planning any synthetic route in this field is the selection of protecting groups for protecting reactive functional groups present in the compounds described in this invention. Many alternatives are described to a trained person in authoritative reporting such as Greene, TW et al., Protecting Groups in Organic Synthesis, 4th ed., Wiley (2007).

[0276] The abbreviations used below are standard organic chemical abbreviations known to those skilled in the art.

[0277] Abbreviations:

[0278] AcOH or HOAc acetic acid

[0279] ACN Acetonitrile

[0280] ADDP 1,1'-(azodicarbonyl)dipiperidine

[0281] CDCl3 Deuterated-chloroform

[0282] CD3OD Deuterated-Methanol

[0283] CDI 1,1-Carbonidimidazolium

[0284] conc (concentrated)

[0285] DCM dichloromethane

[0286] DIEA or DIPEA (diisopropylethylamine)

[0287] DMF (dimethylformamide)

[0288] DMSO (dimethyl sulfoxide)

[0289] DMSO-d6 Deuterated Dimethyl Sulfoxide

[0290] Et3N or TEA triethylamine

[0291] EtOAc (ethyl acetate)

[0292] EtOH (ethanol)

[0293] HATU hexafluorophosphate 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide

[0294] HCl hydrochloric acid

[0295] HPLC (High Performance Liquid Chromatography)

[0296] K2HPO4 Potassium hydrogen phosphate

[0297] LCMS (Liquid Chromatography-Mass Spectrometry)

[0298] MeOH (methanol)

[0299] MgSO4 Magnesium sulfate

[0300] NMP (N-methyl-2-pyrrolidone)

[0301] NaCl (Sodium Chloride)

[0302] Na2CO3 (Sodium carbonate)

[0303] NaHCO3 (Sodium bicarbonate)

[0304] NaOH (sodium hydroxide)

[0305] Na2SO4 Sodium sulfate

[0306] NH4Cl ammonium chloride

[0307] NH4OAc ammonium acetate

[0308] Pd(OAc)₂ Palladium(II) acetate

[0309] Pd(PPh3)4 tetrakis(triphenylphosphine)palladium(0)

[0310] Rt retention time

[0311] SiO2 (silicon dioxide)

[0312] SOCl2 thionyl chloride

[0313] TEA Triethylamine

[0314] TFA (trifluoroacetic acid)

[0315] THF Tetrahydrofuran

[0316] 1-Propane phosphate cyclic anhydride

[0317] Normal-phase chromatography was performed using pre-packed SiO2 filter cartridges. Reverse-phase preparative HPLC of the examples was performed using a Waters XBridge C18 column (19x200 mm, 5-μm particles) with UV and LCMS detection, and a variable gradient of mobile phase A (95% water, 5% ACN) and mobile phase B (5% water, 95% ACN) containing 0.1% TFA or 10 mM NH4OAc. The column was coupled with a Waters XBridge C18 column (19x200 mm, 5-μm particles) for detection. The examples were performed using reverse-phase analytical HPLC / MS on the Waters Acquity system of the ZQ mass spectrometer.

[0318] Method A: A linear gradient from 0 to 100% B over 3 minutes, with a hold time of 0.75 minutes at 100% B;

[0319] UV observation at 220nm

[0320] Column: Waters BEH C18 2.1x50mm

[0321] Flow rate: 1.0 mL / min

[0322] Solvent A: 10 mM NH4OAc, 95% water, 5% ACN

[0323] Solvent B: 10mM NH4OAc, 5% water, 95% ACN

[0324] Method B: A linear gradient from 0 to 100% B over 3 minutes, with a hold time of 0.75 minutes at 100% B;

[0325] UV observation at 220nm

[0326] Column: Waters BEH C18 2.1x50mm

[0327] Flow rate: 1.0 mL / min

[0328] Solvent A: 0.1% TFA, 95% water, 5% ACN

[0329] Solvent B: 0.1% TFA, 5% water, 95% ACN

[0330] Method C: A linear gradient from 2 to 98% B over 1 minute, with a hold time of 0.50 minutes at 100% B;

[0331] UV observation at 220nm

[0332] Column: Waters BEH C18 2.1x50mm

[0333] Flow rate: 0.8 mL / min

[0334] Solvent A: Water containing 0.05% TFA

[0335] Solvent B: ACN containing 0.05% TFA

[0336] Method D: A linear gradient from 0 to 100% B over 10 minutes, held at 100% B for 5 minutes.

[0337] UV observation at 254nm

[0338] Column: SunFire C18; 3.5μm; 4.6x150mm

[0339] Flow rate: 1 mL / min

[0340] Solvent A: 10% acetonitrile, 90% water, 0.05% TFA

[0341] Solvent B: 10% water, 90% acetonitrile, 0.05% TFA

[0342] Method E: A linear gradient from 0 to 100% B over 3 minutes, held at 100% B for 0.5 minutes.

[0343] Detection: MS and UV (220nm)

[0344] Column: Waters XBridge C18, 2.1mm x 50mm, 1.7μm particles

[0345] Flow rate: 1 mL / min (Method A)

[0346] Temperature: 50℃

[0347] Solvent A: 5:95 acetonitrile:water and 10mM ammonium acetate

[0348] Solvent B: 95:5 acetonitrile:water and 10mM ammonium acetate.

[0349] Some compounds of formula I can be prepared as shown in reaction diagram 1.

[0350] Reaction diagram 1.

[0351]

[0352] Step 1 describes the preparation of compound G1b by condensation of an acid of formula G1a (which has been activated with a reagent (e.g., CDI or SOCl2)) with a metal salt (e.g., potassium or sodium) of alkyl malonate. Step 2 describes the preparation of compound G1b by condensation of compound G1b with hydrazine R. 1 The condensation of NHNH2 prepares G1c compounds. Step 3 describes the preparation of G1c compounds using R... 2The alkylation of X (where X represents a leaving group (e.g., a halogen or sulfonate ester)) prepares compounds of formula G1d. Step 4 describes the preparation of compounds of formula G1e via the amination of the G1d compound. The conversion from a G1d compound to a G1e compound generally involves a two-step process: nitrosation, followed by the reduction of the intermediate nitroso compound. Step 5 describes the reaction of the G1e compound with acid R. 4 Compound I is prepared by condensation of CO2H or an activated equivalent.

[0353] Example 1. N-[5-(2,6-difluoro-4-methoxyphenyl)-1-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl]-4-(difluoromethoxy)benzamide

[0354]

[0355] Compound 1a. Ethyl 3-(2,6-difluoro-4-methoxyphenyl)-3-oxopropionate: (i) CDI (1.18 g, 7.28 mmol) was added aliquots to a mixture of 2,6-difluoro-4-methoxybenzoic acid (1.14 g, 6.07 mmol) and anhydrous THF (7.5 mL), and the mixture was stirred for 8 hours. (ii) Magnesium chloride (1.45 g, 15.2 mmol) was added aliquots to a mixture of potassium ethyl malonate (2.07 g, 12.2 mmol), DIEA (3.18 mL, 18.2 mmol), and anhydrous ACN (30 mL), and the temperature was kept below 20 °C. The mixture was stirred at room temperature for 4 hours and then cooled in an ice bath. The solution from step (i) was added gradually, and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure, and then toluene (20 mL) was added. The mixture was cooled in an ice bath, and 4M HCl (8 mL) was slowly added. The mixture was allowed to warm to room temperature, diluted with EtOAc and water, and the layers were separated. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with water and brine, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0–20% EtOAc / hexane to give compound 1a (1.22 g, 4.71 mmol, 78% yield) as a clear, colorless oil. LCMS (Method C) Rt = 0.98 min, m / z = 259.1 (M+H). The compound appears to exist as a ketone / enol tautomer in a 3:1 ratio. Major tautomer:

[0356] 1H NMR (500MHz, CDCl3) δ6.51 (d, J = 10.5Hz, 2H), 4.22 (q, J = 7.2Hz, 2H), 3.90 (s, 2H), 3.87 (s, 2H), 1.27 (t, J = 7.2Hz, 3H).

[0357] Compound 1b, 5-(2,6-difluoro-4-methoxyphenyl)-2-phenyl-2,4-dihydro-3H-pyrazole-3-one. Phenylhydrazine (0.26 mL, 2.6 mmol) was added to a solution of compound 1a (680 mg, 2.63 mmol) in 50% aq AcOH (20 mL), and the mixture was heated at 115 °C for 2 hours. The mixture was allowed to cool to room temperature, then poured into brine and extracted with EtOAc (3x). The combined extracts were dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using elution with 5 to 45% EtOAc / hexane to give compound 1b (510 mg, 1.7 mmol, 65% yield) as a white solid. LCMS (Method C): Rt = 0.87 min, m / z = 303.1 (M+H). 1 H NMR (500MHz, CDCl3) δ7.98 (d, J = 7.7Hz, 2H), 7.45 (t, J = 8.0Hz, 2H), 7.27-7.20 (m, 1H), 6.59 (d, J = 10.7Hz, 2H), 3.94 (s, 2H), 3.88 (s, 3H).

[0358] Compound 1c, 5-(2,6-difluoro-4-methoxyphenyl)-1-methyl-2-phenyl-1,2-dihydro-3H-pyrazole-3-one. Methyl 4-nitrobenzenesulfonate (540 mg, 2.5 mmol) was added to a solution of compound 1b (250 mg, 0.83 mmol) in NMP (2 mL), and the mixture was heated at 160 °C for 1 hour. The mixture was cooled to room temperature, poured into water, and extracted with 50% EtOAc / hexane (3x). The combined extracts were washed with brine, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 5-60% EtOAc / DCM elution to give compound 1c (150 mg, 0.47 mmol, 57% yield). LCMS (Method C): Rt = 0.79 min, m / z = 317.1 (M+H). 1 H NMR (500MHz, CDCl3) δ7.56-7.46 (m, 4H), 7.39-7.31 (m, 1H), 6.63 (d, J = 9.6Hz, 2H), 8.

[0359] Compound 1d, 4-amino-5-(2,6-difluoro-4-methoxyphenyl)-1-methyl-2-phenyl-1,2-dihydro-3H-pyrazole-3-one. A solution of compound 1c (550 mg, 1.7 mmol) in a mixture of acetic acid (6.5 mL) and concentrated HCl (1.3 mL) in an ice bath was added dropwise with sodium nitrite (480 mg, 7.0 mmol) in water (0.80 mL), and the mixture was stirred for 2 hours. The mixture was poured into ice water and extracted with DCM (3x). The combined extracts were washed with brine, dried (Na₂SO₄), filtered, and evaporated under reduced pressure. The residue was dissolved in a 1:1 mixture of EtOAc / MeOH (20 mL) and 10% Pd / C (catalytic amount) was added. The mixture was stirred under a H₂ balloon for 16 hours. The mixture was filtered, evaporated under reduced pressure, and the residue was purified by silica gel chromatography using 0 to 85% EtOAc / hexane elution to give compound 1d as a grayish-white solid (290 mg, 0.88 mmol, 50% yield). LCMS (Method C) Rt = 0.76 min, m / z = 322.2 (M+H). 1 H NMR (500MHz, CDCl3) δ7.70-7.55(m,2H),7.48(t,J=8.0Hz,2H),7.34-7.20(m,1H),6.63(d,J=9.9Hz,2H),3.87(s,3H),3.41(br s,2H),2.73(s,3H).

[0360] Example 1. N-[5-(2,6-difluoro-4-methoxyphenyl)-1-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl]-4-(difluoromethoxy)benzamide. DIEA (6.2 μL, 0.035 mmol) was added to a solution of compound 1d (7.8 mg, 0.024 mmol) contained in ACN (0.25 mL), followed by HATU (10.7 mg, 0.028 mmol), and the mixture was stirred at 80 °C for 4 hours. The mixture was cooled to room temperature and evaporated under reduced pressure. The residue was purified by silica gel chromatography using elution with 10 to 90% EtOAc / hexane to give Example 1 (9.0 mg, 0.018 mmol, 75% yield) as a white solid. LCMS (Method C) Rt = 0.86 min, m / z = 502.1 (M+H). 1H NMR (500MHz, CD3OD) δ7.84(br d,J=8.3Hz,2H),7.56-7.50(m,2H),7.49-7.45(m,2H),7.43-7.37(m,1H),7.13(br d,J=8.5Hz,2H),6.60(t,J=73.5Hz,1H),6.58(d,J=9.9Hz,2H),3.81(s,3H),3.04(s,3H).

[0361] Examples 2 to 33 were prepared as described in Example 1 (Table 2).

[0362] Example 34. N-[2-(2,3-dichlorophenyl)-5-(2,6-difluoro-4-methoxyphenyl)-1-methyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl]-4-(difluoromethoxy)benzamide

[0363]

[0364] Compound 34b. 4-Amino-2-(2,3-dichlorophenyl)-5-(2,6-difluoro-4-methoxyphenyl)-1-methyl-1,2-dihydro-3H-pyrazole-3-one. A solution of sodium nitrite (64 mg, 0.92 mmol) in water (0.12 mL) was added dropwise to a solution of compound 34a (89 mg, 0.23 mmol, prepared as described for compound 1c) in AcOH (0.86 mL) and concentrated HCl (0.17 mL) at ice bath temperature, and the mixture was stirred for 0.5 hours. The mixture was poured into ice water and extracted with DCM (3x). The combined extracts were washed with brine, dried (Na₂SO₄), filtered, and evaporated under reduced pressure. The residue was dissolved in a 4:1 mixture of EtOH and water (3 mL). Ammonium chloride (38 mg, 0.72 mmol) was added, followed by iron (39 mg, 0.69 mmol) and concentrated HCl (19 μl, 0.23 mmol), and the mixture was heated at 90 °C for 15 min. The mixture was cooled to room temperature and then poured into 1.5 N K₂HPO₄ and extracted with DCM (3x). The combined extracts were dried (Na₂SO₄), filtered, and evaporated under reduced pressure. The residue was purified by silica gel chromatography using 0 to 60% EtOAc / DCM to give compound 34b as a grayish-white solid (33 mg, 0.082 mmol, 36% yield). LCMS (Method C) Rt = 0.85 min, m / z = 400.0 (M+H).

[0365] Example 34. N-[2-(2,3-dichlorophenyl)-5-(2,6-difluoro-4-methoxyphenyl)-1-methyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl]-4-(difluoromethoxy)benzamide

[0366] Prepared from compound 34b as described in Example 1. LCMS (Method A) Rt = 1.86 min, m / z = 570.2 (M+H). 1 H NMR(500MHz,DMSO-d6)δ9.58(br s,1H),7.89(br d,J=7.9Hz,2H),7.82(d,J=8.1Hz,1H),7.59(t,J=8.0Hz,1H),7.55-7.50(m,1H),7.42-7.06(m,3H),6.86(br d,J=10.9Hz,2H),3.82(s,3H),2.92(s,3H).

[0367] Examples 35 to 38 (Table 2) were prepared as described with respect to Example 34.

[0368] Example 39. N-[2-(6-chloropyridin-2-yl)-5-(2,6-difluoro-4-methoxyphenyl)-1-methyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl]-4-(difluoromethoxy)benzamide

[0369]

[0370] Compound 39b. 2-(6-chloropyridin-2-yl)-5-(2,6-difluoro-4-methoxyphenyl)-1-methyl-1,2-dihydro-3H-pyrazol-3-one. Iodomethane (0.13 mL, 2.0 mmol) was added to a solution of compound 39a (460 mg, 1.4 mmol, prepared as described for compound 1b) in DMF (3.5 mL), and the mixture was heated at 100 °C for 16 hours. Additional iodomethane (0.065 mL, 1.0 mmol) was added, and the mixture was heated at 100 °C for 4 hours. The mixture was cooled to room temperature, diluted with EtOAc, washed with brine (3x), dried (Na₂SO₄), filtered, and evaporated under reduced pressure. The residue was purified by silica gel chromatography using 0 to 100% EtOAc / DCM elution to give compound 39b as a grayish-white solid (354 mg, 1.01 mmol, 74% yield). LCMS (Method C) Rt = 0.81 min, m / z = 352.0 (M+H).

[0371] Compound 39c, 4-amino-2-(6-chloropyridin-2-yl)-5-(2,6-difluoro-4-methoxyphenyl)-1-methyl-1,2-dihydro-3H-pyrazol-3-one. A solution of compound 39b (300 mg, 0.85 mmol) in water (0.8 mL) was added dropwise to a solution of compound 39b (300 mg, 0.85 mmol) in AcOH (6.5 mL) and concentrated HCl (1.3 mL) at ice bath temperature, and the mixture was stirred for 0.5 hours. The mixture was poured into ice water and extracted with DCM (3x). The combined extracts were washed with brine, dried (Na₂SO₄), filtered, and evaporated under reduced pressure. The residue was suspended in a 4:1 mixture of MeOH and water (10 mL), cooled in an ice bath, and then treated with concentrated HCl (71 μL, 0.85 mmol), ammonium chloride (141 mg, 2.64 mmol), and zinc (167 mg, 2.56 mmol). The mixture was heated to room temperature and stirred for 15 minutes. The mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with saturated NaHCO3, dried (Na2SO4), filtered, and evaporated under reduced pressure. The residue was purified by silica gel chromatography using 0 to 100% EtOAc / DCM elution to give compound 39c as a white solid (150 mg, 0.41 mmol, 48% yield). LCMS (Method C): Rt = 0.76 min, m / z = 367.0 (M+H).

[0372] Example 39. N-[2-(6-chloropyridin-2-yl)-5-(2,6-difluoro-4-methoxyphenyl)-1-methyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl]-4-(difluoromethoxy)benzamide. Prepared from compound 39c as described in Example 1. LCMS (Method A) Rt = 1.84 min, m / z = 537.4 (M+H). 1 H NMR(500MHz,CD3OD)δ8.00-7.94(m,1H),7.92-7.84(m,3H),7.41(d,J=7.7H z, 1H), 7.19 (d, J = 8.6Hz, 2H), 7.05-6.72 (m, 3H), 3.87 (s, 3H), 3.33 (s, 3H).

[0373] Examples 40 and 41 (Table 2) were prepared as described with respect to Example 39.

[0374] Example 42. N-[2-(5-chloropyridin-2-yl)-5-(2,6-difluoro-4-methoxyphenyl)-1-methyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl]-4-(difluoromethoxy)benzamide

[0375]

[0376] Compound 42a, 2-(5-chloropyridin-2-yl)-5-(2,6-difluoro-4-methoxyphenyl)-2,4-dihydro-3H-pyrazol-3-one. A mixture of 5-chloro-2-hydrazinopyridine hydrochloride (450 mg, 2.5 mmol) and potassium tert-butoxide (280 mg, 2.5 mmol) in EtOH (3.2 mL) was stirred for 15 minutes, and then compound 1a was added. The mixture was stirred at 90 °C for 16 hours. The mixture was cooled to room temperature, and the reaction was stopped with saturated NH4Cl, followed by extraction with EtOAc (3x). The combined extracts were dried (Na2SO4), filtered, and evaporated under reduced pressure. The residue was purified by silica gel chromatography using elution with 0 to 100% EtOAc / hexane to give compound 42a (215 mg, 0.64 mmol, 66% yield) as a grayish-white solid. LCMS (Method C) Rt = 1.12 min, m / z = 338.1 (M+H).

[0377] Compound 42b, 2-(5-chloropyridin-2-yl)-5-(2,6-difluoro-4-methoxyphenyl)-1-methyl-1,2-dihydro-3H-pyrazol-3-one. To a solution of compound 39a (210 mg, 0.63 mmol) contained in THF (6.3 mL), MeOH (0.26 mL, 6.3 mmol), tri-n-butylphosphine (0.32 mL, 1.3 mmol), and ADDP (190 mg, 0.76 mmol) were added, and the mixture was stirred for 16 hours. The mixture was diluted with brine and extracted with EtOAc. The extract was washed with brine, dried (Na₂SO₄), filtered, and evaporated under reduced pressure. The residue was treated with DCM and diethyl ether, and the solids were removed by filtration. The filtrate was concentrated, and the residue was purified by silica gel chromatography using elution with 0 to 100% EtOAc / hexane to give compound 42b as a white solid (100 mg, 0.28 mmol, 45% yield). LCMS (Method C) Rt = 0.95 min, m / z = 352.1 (M+H). 1 H NMR(500MHz,DMSO-d6)δ8.62(d,J=2.5Hz,1H),8.12(dd,J=8.8,2.8Hz,1H),7.95 (d,J=8.8Hz,1H),7.03(d,J=10.2Hz,2H),5.74(s,1H),3.89(s,3H),3.19(s,3H).

[0378] Compound 42c. 4-Amino-2-(5-chloropyridin-2-yl)-5-(2,6-difluoro-4-methoxyphenyl)-1-methyl-1,2-dihydro-3H-pyrazol-3-one. Prepared from compound 42b as described with respect to compound 39c. LCMS (Method C) Rt = 0.78 min, m / z = 367.0 (M+H).

[0379] Example 42. N-[2-(5-chloropyridin-2-yl)-5-(2,6-difluoro-4-methoxyphenyl)-1-methyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl]-4-(difluoromethoxy)benzamide. Prepared from compound 42c as described in Example 1. LCMS (Method A) Rt = 1.85 min, m / z = 537.2 (M+H). 1 H NMR(500MHz,CD3OD)δ8.57(d,J=2.4Hz,1H),8.02(dd,J=8.8,2.5Hz,1H),7.96-7.91(m, 1H),7.90-7.84(m,2H),7.27-7.14(m,2H),7.05-6.71(m,3H),3.86(m,3H),3.31(s,3H).

[0380] Example 43 was prepared as described with respect to Example 42 (Table 2).

[0381] Example 44. N-[5-(2,6-difluoro-4-methoxyphenyl)-1-methyl-3-oxo-2-(pyridin-2-yl)-2,3-dihydro-1H-pyrazol-4-yl]-4-(difluoromethoxy)benzamide

[0382]

[0383] Compound 44a, 4-amino-5-(2,6-difluoro-4-methoxyphenyl)-1-methyl-2-(pyridin-2-yl)-1,2-dihydro-3H-pyrazol-3-one. 10% Pd / C (10 mg) was added to a solution of compound 39c (24 mg, 0.065 mmol) in MeOH (3 mL). The mixture was stirred under a hydrogen balloon for 16 hours. The mixture was filtered through diatomaceous earth, and the filtrate was evaporated under reduced pressure to give compound 44a (22 mg, 0.065 mmol, 100% yield). LCMS (Method C): Rt = 0.64 min, m / z = 333.1 (M+H).

[0384] Example 44. N-[5-(2,6-difluoro-4-methoxyphenyl)-1-methyl-3-oxo-2-(pyridin-2-yl)-2,3-dihydro-1H-pyrazol-4-yl]-4-(difluoromethoxy)benzamide. Prepared from compound 44a as described in Example 1. LCMS (Method A) Rt = 1.50 min, m / z = 503.2 (M+H). 1 H NMR (500MHz, CD3OD) δ8.59(br d,J=4.1Hz,1H),8.00(br d,J=1.3Hz,1H),7.88(br d,J=8.2Hz,3H),7.40(dd,J=7.0,5.2Hz,1H),7.19(d,J=8.7Hz,2H),7.06-6.69(m,3H),3.86(s,3H),3.30(s,3H).

[0385] Example 45. N-[2-(6-cyclopropylpyridin-2-yl)-5-(2,6-difluoro-4-methoxyphenyl)-1-methyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl]-4-(difluoromethoxy)benzamide

[0386]

[0387] Example 45. N-[2-(6-cyclopropylpyridin-2-yl)-5-(2,6-difluoro-4-methoxyphenyl)-1-methyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl]-4-(difluoromethoxy)benzamide. Cyclopropyl dihydroxyboronic acid (125 mg, 1.45 mmol), palladium(II) acetate (11 mg, 0.048 mmol), tricyclohexylphosphonium tetrafluoroborate (36 mg, 0.097 mmol), and potassium phosphate (210 mg, 0.97 mmol) were added to a solution of Example 39 (130 mg, 0.24 mmol) contained in toluene (2.5 mL) and water (0.50 mL). The reaction mixture was degassed and heated at 140 °C for 1 hour. The mixture was filtered through diatomaceous earth and evaporated under reduced pressure. The residue was purified by preparative HPLC to give Example 45 (91 mg, 0.17 mmol, 69% yield) as a grayish-white solid. LCMS (Method C) Rt = 0.88 min, m / z = 543.1 (M+H). 1H NMR (500MHz, CD3OD) δ7.92(d,J=8.8Hz,2H),7.84(t,J=7.8Hz,1H),7.63(d,J=7.7Hz,1H),7.30(d,J=7 .4Hz,1H),7.22(d,J=8.8Hz,2H),6.96(t,J=73.5Hz,1H),6.81(d,J=10.2Hz,2H),3.89(s,3H),3.33(s 3H),2.25-2.11(m,1H),1.13-1.00(m,4H).

[0388] Examples 46 to 53 (Table 2) were prepared as described with respect to Example 45.

[0389] Example 54. N-[2-(5-cyanopyridin-2-yl)-5-(2,6-difluoro-4-methoxyphenyl)-1-methyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl]-4-(difluoromethoxy)benzamide

[0390]

[0391] Example 54. N-[2-(5-cyanopyridin-2-yl)-5-(2,6-difluoro-4-methoxyphenyl)-1-methyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl]-4-(difluoromethoxy)benzamide. Zinc dicyanophosphate (6.9 mg, 0.058 mmol) and Pd(PPh3)4 (3.4 mg, 2.9 μmol) were added to a solution of Example 42 (17 mg, 0.029 mmol) contained in degassed NMP (0.3 mL). The solution was placed under nitrogen and stirred at 110 °C for 16 hours. The mixture was cooled to room temperature, filtered, and the residue was purified by preparative HPLC to give Example 54 (7.6 mg, 0.014 mmol, 48% yield). LCMS (Method A) Rt = 1.83 min, m / z = 528.0 (M+H). 1 H NMR (500MHz, CD3OD) δ 8.90 (d, J = 1.4 Hz, 1H), 8.35-8.18 (m, 2H), 7.88 (br d, J = 8.6 Hz, 2H), 7.20 (s, 2H), 7.07-6.69 (m, 3H), 3.87 (s, 3H), 3.35 (s, 3H).

[0392] Examples 55 and 56 (Table 2) were prepared as described with respect to Example 54.

[0393] Example 57. N-[5-(2,6-difluoro-4-methoxyphenyl)-1-methyl-3-oxo-2-{[5-(propyl-2-yl)-1,3,4-oxadiazol-2-yl]methyl}-2,3-dihydro-1H-pyrazol-4-yl]-4-(difluoromethoxy)benzamide

[0394]

[0395] Example 57. N-[5-(2,6-difluoro-4-methoxyphenyl)-1-methyl-3-oxo-2-{[5-(propyl-2-yl)-1,3,4-oxadiazol-2-yl]methyl}-2,3-dihydro-1H-pyrazol-4-yl]-4-(difluoromethoxy)benzamide. Hydrazine (17 μL, 0.53 mmol) was added to a solution of Example 21 (27 mg, 0.053 mmol) contained in 10% EtOH / DCM (0.5 mL), and the mixture was stirred for 16 hours. The mixture was diluted with Et2O and filtered to give a white solid intermediate, acylhydrazide N-(5-(2,6-difluoro-4-methoxyphenyl)-2-(2-hydrazyl-2-oxoethyl)-1-methyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-4-(difluoromethoxy)benzamide (26 mg, 0.052 mmol, 99% yield). LCMS (Method C) Rt = 0.64 min, m / z = 498.0 (M+H). The intermediate acylhydrazide (13 mg, 0.026 mmol) and isobutyric acid (2.7 μL, 0.029 mmol) were dissolved in dioxane (0.2 mL), and a solution containing 50%... ACN (0.062 mL, 0.11 mmol) was added, followed by DIEA (0.018 mL, 0.11 mmol). The mixture was heated at 70 °C for 16 hours. The mixture was cooled to room temperature, filtered, and the residue was purified by preparative HPLC to give Example 57 (1.6 mg, 0.0028 mmol, 11% yield). LCMS (Method A) Rt = 1.62 min, m / z = 550.3 (M+H). 1 H NMR (500MHz, DMSO-d6) δ9.62(br s,1H),7.89(br d,J=8.2Hz,2H),7.33(t,J=73.6Hz,1H),7.23(br d,J=8.2Hz,2H),6.88(br d,J=10.4Hz,2H),5.38(s,2H),3.81(s,3H),3.18(br d,J=4.9Hz,1H),3.14(s,3H),1.30(d,J=6.7Hz,6H).

[0396] Example 58. N-[5-(2,6-difluoro-4-methoxyphenyl)-2-(2-hydroxyethyl)-1-methyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl]-4-(difluoromethoxy)benzamide

[0397]

[0398] Example 58. N-[5-(2,6-difluoro-4-methoxyphenyl)-2-(2-hydroxyethyl)-1-methyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl]-4-(difluoromethoxy)benzamide. Calcium chloride (4.3 mg, 0.039 mmol) was added to a solution of Example 21 (10 mg, 0.020 mmol) containing EtOH (0.25 mL), followed by sodium borohydride (1.5 mg, 0.039 mmol), and the mixture was stirred for 3 hours. The mixture was diluted with water and extracted with DCM (3x). The combined extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give Example 58 (5.9 mg, 0.012 mmol, 62% yield). LCMS (Method A) Rt = 1.40 min, m / z = 469.9 (M+H). 1 H NMR (500MHz, DMSO-d6) δ7.87(br d,J=8.1Hz,2H),7.26(t,J=72.8Hz,1H),7.21(br d,J=8.4Hz,2H),6.83(br d, J=10.4Hz, 2H), 3.95 (t, J=5.9Hz, 2H), 3.82 (s, 3H), 3.63 (br t, J=5.7Hz, 2H), 3.19 (s, 3H).

[0399] Example 59. N-[5-(2,6-difluoro-4-methoxyphenyl)-2-(4-methoxypyridin-2-yl)-1-methyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl]-4-(difluoromethoxy)benzamide

[0400]

[0401] Compound 59a, methyl 3-(2,6-difluoro-4-methoxyphenyl)propynate: Under nitrogen atmosphere, trifluoromethanesulfonic anhydride (0.54 mL, 3.2 mmol) was added to compound 1a (0.71 g, 2.9 mmol) contained in DCE (3.6 mL). The mixture was stirred for 15 minutes, followed by dropwise addition of a solution of DIPEA (1.3 mL, 7.3 mmol) over 15 minutes, resulting in an exothermic reaction. The reaction mixture was stirred for 30 minutes. The reaction was stopped with water, extracted with EtOAc, washed with 1N HCl and brine, dried over Na2SO4, and concentrated. The crude residue was purified by silica gel chromatography using 0 to 100% EtOAc / hexane elution to give compound 59a (430 mg, 1.9 mmol, 65% yield). MS (ESI) m / z 226.9 (M+H).

[0402] Compound 59b. 5-(2,6-difluoro-4-methoxyphenyl)-1-methyl-1,2-dihydro-3H-pyrazole-3-one: H₂O (2 mL) was added to a solution of compound 59a (425 mg, 1.88 mmol) in MeOH (2 mL), followed by the addition of methylhydrazine (0.109 mL, 2.07 mmol), and the mixture was heated overnight at 50 °C. The reaction mixture was cooled to room temperature, concentrated, and then poured into water and extracted with EtOAc. The combined extracts were washed with brine, dried over Na₂SO₄, filtered, and evaporated. The residue was suspended in DCM, and the resulting solid was collected by filtration to give compound 59b as a white solid (155 mg, 0.646 mmol, 34.3% yield). NMR (500MHz, DMSO-d6) δ9.72 (br s, 1H), 6.92 (d, J = 9.6Hz, 2H), 5.59 (s, 1H), 3.85 (s, 3H), 3.44 (s, 3H).

[0403] Compound 59c. 5-(2,6-difluoro-4-methoxyphenyl)-2-(4-methoxypyridin-2-yl)-1-methyl-1,2-dihydro-3H-pyrazol-3-one: A mixture of 2-bromo-4-methoxypyridine (47.0 mg, 0.250 mmol), compound 59b (60 mg, 0.25 mmol), 1,10-phenanthroline (4.1 mg, 0.023 mmol), K3PO4 (74.2 mg, 0.350 mmol), copper iodide (I) (2.38 mg, 0.012 mmol), and iPrOH (0.5 mL) in a pressure vial was purged with nitrogen, then sealed and heated overnight at 110 °C. The reaction mixture was cooled to room temperature, diluted with water, and then extracted with DCM (3x). The combined extracts were dried over Na2SO4, filtered, and evaporated. The residue was purified by silica gel chromatography using 0 to 100% EtOAc / hexane elution to give compound 59c (45 mg, 0.13 mmol, 52%). 1 ¹H NMR (500MHz, CDCl₃) δ 8.34 (d, J = 5.8 Hz, 1H), 7.65 (d, J = 2.2 Hz, 1H), 6.74 (dd, J = 5.8, 2.2 Hz, 1H), 6.68–6.57 (m, 2H), 5.73 (s, 1H), 3.96 (s, 3H), 3.89 (s, 3H), 3.30 (s, 3H) and O-arylation byproduct, 2-((5-(2,6-difluoro-4-methoxyphenyl)-1-methyl-1H-pyrazol-3-yl)oxy)-4-methoxypyridine (24 mg, 0.069 mmol, 27.4%). 1 H NMR (500MHz, CDCl3) δ8.06 (d, J = 6.1 Hz, 1H), 6.67-6.55 (m, 3H), 6.53 (d, J = 2.2 Hz, 1H), 6.18 (s, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 3.72 (s, 3H).

[0404] Compound 59d. 4-Amino-5-(2,6-difluoro-4-methoxyphenyl)-2-(4-methoxypyridin-2-yl)-1-methyl-1,2-dihydro-3H-pyrazol-3-one: Compound 59d was prepared from compound 59c using the procedure described for compound 1d.

[0405] Example 59. N-(5-(2,6-difluoro-4-methoxyphenyl)-2-(4-methoxypyridin-2-yl)-1-methyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-4-(difluoromethoxy)benzamide: Example 59 was prepared from compound 59d using the procedure described for Example 1. LCMS (Method C) Rt = 1.59 min, m / z = 533.2 (M+H). 1 H NMR(500MHz,DMSO-d6)δ9.69(s,1H),8.41(d,J=5.5Hz,1H),7.91(d,J=8.2Hz,2H),7.49-7.41(m,1H),7.37 -7.15(m,3H),7.00(dd,J=5.8,2.4Hz,1H),6.94(d,J=10.4Hz,2H),3.92(s,3H),3.83(s,3H),3.18(s,3H).

[0406] Preparation Examples 60 to 84 (Table 2) were performed as described with respect to Example 59. In the case of the trifluoromethoxyamide examples, trifluoromethoxybenzoic acid was used instead of difluoromethoxybenzoic acid for amide formation.

[0407] Example 85.

[0408]

[0409] Compound 85a. 2-(6-bromopyridin-2-yl)prop-2-ol: A 3M solution of magnesium methyl bromide in Et₂O (570 μL, 1.71 mmol) was added dropwise to a cooled solution of 1-(6-bromopyridin-2-yl)ethyl-1-one (285 mg, 1.42 mmol) in anhydrous THF (2.8 mL) for 1.5 h, followed by overnight at room temperature. The reaction mixture was stopped with aqueous NH₄Cl and extracted twice with EtOAc. The combined extracts were dried over Na₂SO₄, filtered, and evaporated. The crude product was used in the next step without further purification. MS (ESI) 215.9 (M+H).

[0410] Compound 85b. 4-Amino-5-(2,6-difluoro-4-methoxyphenyl)-2-(6-(2-hydroxypropyl-2-yl)pyridin-2-yl)-1-methyl-1,2-dihydro-3H-pyrazol-3-one: Compound 85b was prepared from compounds 59b and 85a using the methods described for compounds 59c and 59d. MS (ESI) m / z 391.3 (M+H).

[0411] Example 85. Under nitrogen atmosphere, a mixture of compound 85b and K₂CO₃ (49.6 mg, 0.359 mmol) was stirred in an ice bath, and 4-(difluoromethoxy)benzoyl chloride (26.0 μL, 0.172 mmol) was added. The reaction mixture was stirred in an ice bath for 10 minutes, and then incubated overnight at room temperature. The reaction mixture was diluted with about 1 mL of DMF and purified by RP-HPLC to give Example 85 (32.4 mg, 0.057 mmol, 40.0% yield). LCMS (Method A) Rt = 1.64 min, m / z 561.4 (M+H). 1 HNMR(500MHz,DMSO-d6)δ9.70(s,1H),7.98(t,J=7.9Hz,1H),7.89(d,J=8.3Hz,2H),7.70(d,J=7.7Hz,1H),7.60(d,J=7.7Hz,1H ),7.25(d,J=8.3Hz,2H),7.50-7.12(m,1H),6.92(d,J=10.6Hz,2H),5.57-5.43(m,1H),3.82(s,3H),3.22(s,3H),1.49(s,6H).

[0412] Example 87. N-(5-(2,6-difluoro-4-methoxyphenyl)-2-(6-(1-hydroxycyclobutyl)pyridin-2-yl)-1-methyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-4-(difluoromethoxy)benzamide.

[0413]

[0414] Compound 87a. 1-(6-bromopyridin-2-yl)cyclobut-1-ol: Under a nitrogen atmosphere, 2,6-dibromopyridine (0.300 g, 1.27 mmol) was dissolved in anhydrous DCM (7.5 mL). The solution was cooled to -78 °C and a solution of 1.6 M nBuLi in hexane (0.863 mL, 1.38 mmol) was added very slowly via syringe. After complete addition, the reaction mixture was stirred at -78 °C for 1 hour. Then, a solution of cyclobutanone (0.089 g, 1.3 mmol) in anhydrous DCM (1.0 mL) was added dropwise via syringe. The reaction mixture was stirred at -78 °C and allowed to slowly warm to room temperature overnight. The reaction was stopped with saturated NaHCO3 solution and extracted twice with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and evaporated. The residue was purified by silica gel chromatography with elution of 0 to 30% MeOH / DCM to give compound 87a (210 mg, 0.922 mmol, 72.8% yield). 1H NMR (500MHz, CDCl3) δ7.67-7.58(m,1H),7.54(d,J=7.7Hz,1H),7.42(d,J=8.0Hz,1H) ,4.33(s,1H),2.57-2.47(m,4H),2.16-2.03(m,1H),1.88(dquin,J=11.7,8.6Hz,1H).

[0415] Example 87 was prepared from compound 87a using the method described for Example 85. LCMS (Method B) Rt = 1.68 min. m / z 573.3 (M+H). 1 ¹H NMR (500MHz, DMSO-d⁶) δ 9.72 (s, ¹H), 7.99–7.88 (m, ³H), 7.74 (d, J = 7.9 Hz, ¹H), 7.53–7.43 (m, ¹H), 7.35–7.14 (m, ³H), 6.95 (d, J = 10.4 Hz, ²H), 3.82 (s, ³H), 3.27 (s, ³H), 2.61–2.56 (m, ²H), 2.37–2.25 (m, ²H), 2.01–1.82 (m, ²H). No OH protons were observed.

[0416] Example 88. N-(2-(6-cyclopropyl-4-methoxypyridin-2-yl)-5-(2,6-difluoro-4-methoxyphenyl)-1-methyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-4-(difluoromethoxy)benzamide

[0417]

[0418] Compound 88a. 2-Bromo-6-cyclopropyl-4-methoxypyridine: A solution of 2,6-dibromo-4-methoxypyridine (152 mg, 0.569 mmol) and (Ph3P)4Pd (32.9 mg, 0.028 mmol) in THF (2.2 mL) was bubbled with N2 for a few minutes, and then 0.5 M (1.34 mL, 0.672 mmol) of cyclopropyl zinc bromide (II) in THF was added.

[0419] The mixture was stirred overnight at room temperature. The reaction mixture was partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The organic phase was dried over Na2SO4, filtered, and evaporated. The residue was purified by silica gel chromatography with elution of 0 to 100% EtOAc / hexane to give compound 88a (37.4 mg, 0.164 mmol, 28.8% yield). 1H NMR (400MHz, CDCl3-d) δ6.78 (d, J = 2.2 Hz, 1H), 6.59 (d, J = 2.0 Hz, 1H), 3.84 (s, 3H), 2.03-1.88 (m, 1H), 1.06-0.95 (m, 4H).

[0420] Example 88 was prepared from compound 88a using the method described in Example 85. LCMS (Method B) Rt = 1.92 min. m / z 573.0 (M+H). 1 H NMR (500MHz, DMSO-d6) δ9.65(s,1H),7.89(d,J=8.5Hz,2H),7.24(d,J=8.5Hz,2H),7.18(d,J=1.8Hz,1H),7.30(t ,J=73.9Hz,1H),6.95-6.85(m,3H),3.88(s,3H),3.82(s,3H),3.16(s,3H),2.16-2.06(m,1H),1.00-0.90(m,4H).

[0421] Example 91. N-(5-(2,6-difluoro-4-methoxyphenyl)-2-(4-methoxy-6-(pyrrolidin-1-yl)pyridin-2-yl)-1-methyl-3-oxo-2,3-dihydro-1H-pyrazole-4-yl)-4-(difluoromethoxy)benzamide

[0422]

[0423] Compound 91a, 2-bromo-4-methoxy-6-(pyrrolidine-1-yl)pyridine: In a sealed tube, a mixture of 2,6-dibromo-4-methoxypyridine (300 mg, 1.12 mmol), pyrrolidine (0.103 mL, 1.24 mmol), and TEA (0.172 mL, 1.24 mmol) in EtOH (1.5 mL) was heated to 150 °C for 1 hour under microwave irradiation. The reaction mixture was partitioned between water and EtOAc, and the organic phase was dried (Na2SO4), filtered, and evaporated. The residue was purified by silica gel chromatography, eluting with 0 to 100% EtOAc / hexane, to give compound 91a (235 mg, 0.914 mmol, 81% yield). MS (ESI) m / z 259.0 (M+H).

[0424] Example 91 was prepared from compound 91a using the method described in Example 85. LCMS (Method B) Rt = 1.73 min. m / z 602.1 (M+H). 1H NMR(500MHz,DMSO-d6)δ9.63(s,1H),7.91(d,J=7.6Hz,2H),7.27-7.21(m,2H),7.52-7.17(m,1H),7.13(s,1H),7 .02(s,1H),6.92(d,J=10.4Hz,2H),3.84(s,3H),3.82(s,3H),3.92-3.78(m,4H),3.25(s,3H),1.98-1.93(m,4H).

[0425] Examples 86, 89, 90, 92, and 107 (Table 2) were prepared using the methods described for Examples 85, 87 to 88, or 91.

[0426] Example 108. N-[3,5-dimethoxyphenyl)-5-(2,6-difluoro-4-methoxyphenyl)-1-methyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl]-4-(difluoromethoxy)benzamide

[0427]

[0428] Compound 108a. 5-(2,6-difluoro-4-methoxyphenyl)-2-(3,5-dimethoxyphenyl)-1-methyl-1,2-dihydro-3H-pyrazole-3-one: A mixture of compound 59c (100 mg, 0.416 mmol), (3,5-dimethoxyphenyl)dihydroxyboronic acid (152 mg, 0.833 mmol), copper(II) acetate (113 mg, 0.624 mmol), and pyridine (0.067 mL, 0.83 mmol) contained in DCM (3 mL) was stirred overnight in air. The reaction mixture was diluted with DCM and water, and the aqueous layer was re-extracted with DCM. The combined extracts were washed with brine, dried over Na2SO4, filtered, and evaporated. The residue was purified by silica gel chromatography by elution with 0 to 100% EtOAc / hexane to give compound 108a (78 mg, 0.21 mmol, 50% yield). LCMS(ESI) m / z: 377.1 (M+H). 1 H NMR (400MHz, CDCl3) δ6.67 (d, J = 2.2 Hz, 2H), 6.63-6.55 (m, 2H), 6.42 (t, J = 2.3 Hz, 1H), 5.76 (s, 1H), 3.86 (s, 3H), 3.83 (s, 6H), 3.00 (s, 3H).

[0429] Example 108 was obtained from compound 108a in two steps using the method described for compound 1d and Example 1. LCMS (Method C) Rt = 1.77 min, m / z = 562.3 (M+H). 1 H NMR (500MHz, DMSO-d6) δ9.72(s,1H),7.89(br d,J=8.2Hz,2H),7.24(br d,J=8.5Hz,2H),7.31(t,J=74.0Hz,1H),6.91(br d,J=10.7Hz,2H),6.63-6.46(m,3H),3.82(s,3H),3.80(s,6H),2.94(s,3H).

[0430] Examples 109 to 134 (Table 2) were prepared using the method described for Example 108.

[0431] Example 135. N-[5-(2,6-difluoro-4-methoxyphenyl)-1-methyl-2-[6-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)pyridin-2-yl]-3-oxo-2,3-dihydro-1H-pyrazol-4-yl]-4-(difluoromethoxy)benzamide

[0432]

[0433] Compound 135a was prepared by heating a mixture of 2,6-dichloro-3-(trifluoromethyl)pyridine (2.49 mL, 23.2 mmol) and hydrazine hydrate (4.49 mL, 93.0 mmol) in iPrOH (42 mL) under reflux at 100 °C with stirring under nitrogen overnight. The reaction mixture was cooled to room temperature and partially concentrated. The concentrate was diluted with water and extracted with EtOAc (5x). The combined extracts were washed with brine, dried over Na2SO4, filtered, and evaporated. The residue was purified by silica gel chromatography with 0 / 100% EtOAc / hexane elution to give compound 135a (a small number of positional isomers; 0.78 g, 0.37 mmol, 16% yield). 1 H NMR (500MHz, DMSO-d6) δ8.17 (br s, 1H), 7.80 (d, J = 7.7Hz, 1H), 6.73 (d, J = 8.0Hz, 1H), 4.41 (br s, 2H).

[0434] Compound 135b. 2-(6-chloro-3-(trifluoromethyl)pyridin-2-yl)-5-(2,6-difluoro-4-methoxyphenyl)-1-methyl-1,2-dihydro-3H-pyrazol-3-one: Compound 135b was prepared from compound 135a and ethyl 3-(2,6-difluoro-4-methoxyphenyl)-3-oxopropionate using the procedure described for compound 1b, followed by the procedure described for compound 39b. MS (ESI) m / z: 419.9 (M+H).

[0435] Compound 135c. 5-(2,6-difluoro-4-methoxyphenyl)-1-methyl-2-(6-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)pyridin-2-yl)-1,2-dihydro-3H-pyrazole-3-one: A mixture of compound 135b (286 mg, 0.681 mmol), 1-methylpiperazine (0.378 mL, 3.41 mmol), and K₂CO₃ (330 mg, 2.38 mmol) contained in NMP (2.2 mL) was heated overnight at 100 °C with stirring. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (3x). The combined extracts were washed with water (2x) and brine, dried over anhydrous Na₂SO₄, filtered, and evaporated. The residue was purified by silica gel chromatography, eluting with 0 to 20% DCM / MeOH, to give compound 135c (215 mg, 0.445 mmol, 65.3% yield) as a white foamy substance. MS (ESI) m / z: 484.1 (M+H).

[0436] Using the steps shown in the reaction diagram, the procedure described above was followed to prepare Example 135 from compound 135c. LCMS (Method A) Rt = 1.79 min, m / z 669.0 (M+H). 1 H NMR(500MHz,CD3CN)δ8.01(br s,1H),7.90(d,J=9.1Hz,1H),7.85-7.75(m,2H),7.17(d,J=8.8Hz,2H),6.88(d ,J=9.1Hz,1H),6.79-6.66(m,2H),6.82(t,J=74.0Hz,1H),3.83(s,3H),3.65(br d, J=3.3Hz, 4H), 3.03 (s, 3H), 2.44 (t, J=5.1Hz, 4H), 2.26 (s, 3H).

[0437] Examples 136 to 141 (Table 2) were prepared using the method described in Example 135 and / or modifications thereof known to those skilled in the art.

[0438] Example 241: N-[5-(2,6-difluoro-4-methoxyphenyl)-1-methyl-2-[6-(N-methylmethanesulfonamido)-3-(trifluoromethyl)pyridin-2-yl]-3-oxo-2,3-dihydro-1H-pyrazol-4-yl]-4-(difluoromethoxy)benzamide

[0439]

[0440] Compound 241a. N-(5-(2,6-difluoro-4-methoxyphenyl)-2-(6-((4-methoxybenzyl)(methyl)amino)-3-(trifluoromethyl)pyridin-2-yl)-1-methyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-4-(difluoromethoxy)benzamide: Example 222 (15.1 mg, 25.0 μmol) and potassium carbonate (5.2 mg, 38 μmol) were placed in a vial equipped with a stir bar and a pressure-relief diaphragm. The vial was purified with nitrogen, and a solution of 1-(4-methoxyphenyl)-N-methylmethylamine (3.8 mg, 25 μmol) in NMP (1.0 mL) was introduced. The mixture was heated to 80°C overnight. The reaction mixture was diluted with water and EtOAc, the phase was separated, and the aqueous solution was extracted twice more with EtOAc. All combined organic compounds were washed with brine, dried (Na2SO4), filtered, and evaporated to give the title compound (17.2 mg, 96% yield), which was ready for use without further purification. MS (ESI) m / z: 720.3 (M+H) + .

[0441] Compound 241b. N-(5-(2,6-difluoro-4-methoxyphenyl)-1-methyl-2-(6-(methylamino)-3-(trifluoromethyl)pyridin-2-yl)-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-4-(difluoromethoxy)benzamide, TFA: Compound 241a (17.2 mg, 0.024 mmol) and DCM (2 mL) were placed in a vial equipped with a stir bar and a pressure-relief diaphragm. TFA (0.4 mL) was added, and the mixture was stirred at ambient temperature for 4 hours. The reaction mixture was evaporated under reduced pressure, EtOAc was added, and evaporation was repeated twice to give the title compound, which was ready for use without further purification. MS (ESI) m / z: 600.3 (M+H) + .

[0442] Example 241. N-(5-(2,6-difluoro-4-methoxyphenyl)-1-methyl-2-(6-(N-methylmethylsulfonamido)-3-(trifluoromethyl)pyridin-2-yl)-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-4-(difluoromethoxy)benzamide: Compound 241b (17.1 mg, 24 μmol) was placed in a vial equipped with a stir bar and a pressure-relief diaphragm. DCM (1 mL) and TEA (0.017 mL, 120 μmol) were added, followed by MsCl (2.8 μl, 36 μmol). The mixture was stirred overnight at ambient temperature. The reaction mixture was stopped with water, the phase was separated, and the aqueous solution was extracted three times with DCM. All combined organic matter was dried (Na₂SO₄), filtered, and evaporated to the residue. The crude substance was purified by preparative LC / MS to give the title compound (0.8 mg, 5% yield). MS(ESI) m / z: 678.1 (M+H) + . 1 H NMR (500MHz, DMSO-d6) δ9.74(s,1H),8.42(d,J=9.0Hz,1H),7.91(br d,J=8.0Hz,2H),7.64(br d,J=8.8Hz,1H),7.23(br d,J=8.8Hz,2H),7.33(br t,J=73.8Hz,1H),6.93(br dd,J=28.2,10.2Hz,2H),3.82(s,3H),3.45(s,3H),3.42(s,3H),3.04(s,3H).

[0443] Example 318: N-(5-(2,6-difluoro-4-methoxyphenyl)-1-methyl-2-(6-(methanesulfonyl)-3-(trifluoromethyl)pyridin-2-yl)-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-4-(difluoromethoxy)benzamide

[0444]

[0445] Compound 318a. N-(5-(2,6-difluoro-4-methoxyphenyl)-1-methyl-2-(6-(methylthio)-3-(trifluoromethyl)pyridin-2-yl)-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-4-(difluoromethoxy)benzamide: A 1-darab vial equipped with a stir bar and pressure-release diaphragm was placed in Example 222 (30 mg, 50 μmol). The vial was purified with nitrogen, then NMP (0.5 mL) was added, followed by sodium methanethiol (3.9 mg, 5 μmol), and the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and EtOAc, the phases were separated, and the aqueous layer was extracted with EtOAc (2x). The organic layers were combined, washed with brine, dried (Na2SO4), filtered, and evaporated to a residue (29 mg).

[0446] Example 318: Compound 318a (29 mg, 47 μmol) was dissolved in a mixture of DCM (0.5 mL) and AcOH (0.005 mL). m-CPBA (23.7 mg, 104 μmol) was added to this solution, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was stopped with a saturated aqueous solution of Na₂SO₃ and diluted with NaHCO₃. The phases were separated, and the aqueous layer was extracted with DCM (2x). The organic layers were combined, dried (Na₂SO₄), filtered, and concentrated. The crude substance was purified by preparative LC / MS to give the title compound (6.1 mg, 19%). MS (ESI) m / z: 649.3 (M+H) + . 1H NMR (500MHz, DMSO-d6) δ9.75(s,1H),8.84(d,J=8.2Hz,1H),8.35(d,J=7.9Hz,1H),7.90(br d,J=8.5Hz,2H),7.23(br d,J=8.2Hz,2H),7.32(br t,J=73.5Hz,1H),7.02-6.86(m,2H),3.82(s,3H),3.37(s,3H),3.05(s,3H).

[0447] Example 319: 6-(3-(2,6-difluoro-4-methoxyphenyl)-4-(4-(difluoromethoxy)benzamido)-2-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-5-(trifluoromethyl)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-tert-butyl formate

[0448]

[0449] Compound 222a. 6-(3-(2,6-difluoro-4-methoxyphenyl)-4-(4-(difluoromethoxy)benzamido)-2-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-5-(trifluoromethyl)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-tert-butyl carboxylate: Example 222 (61 mg, 0.10 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron) were placed in a 2-darabin vial equipped with a stir bar and a pressure-release diaphragm. tert-butyl 1,4-dihydropyridine-1(2H)-carboxylate (47 mg, 0.15 mmol), PdCl2 (dppf) (11 mg, 0.015 mmol), and tripotassium phosphate (64 mg, 0.30 mmol) were added. The vials were purified with nitrogen and a mixture of degassed 1,4-dioxane (0.9 mL) / water (0.1 mL) was added. The vials were covered and heated at 90 °C with stirring overnight. After cooling to room temperature, the reaction mixture was diluted with EtOAc / water, and the phases were separated. The aqueous layer was extracted with EtOAc (3x). The organic compounds were combined, washed with brine, dried (Na2SO4), filtered, and concentrated. The crude product was purified by silica gel chromatography (0 to 100% EtOAc / n-hexane) to give the title compound (36 mg, 48%) as a colorless solid. MS (ESI) m / z: 752.0 (M+H) + . 1H NMR (400MHz, CDCl3) δ8.13(d,J=8.4Hz,1H),7.80(br d,J=7.9Hz,2H),7.74-7.63(m,1H),7.57(br d,J=8.1Hz,1H),7.13(d,J=8.6Hz,2H),6.88(brs,1H),6.64-6.56(m,2H),6.55(br t,J=73.3Hz,1H),4.19(br d,J=1.3Hz,2H),3.84(s,3H),3.74-3.58(m,2H),3.03(s,3H),2.66(br d,J=14.1Hz,2H),1.51(s,9H).

[0450] Compound 222b: N-(5-(2,6-difluoro-4-methoxyphenyl)-1-methyl-3-oxo-2-(5-(trifluoromethyl)-1',2',3',6'-tetrahydro-[2,4'-bipyridin]-6-yl)-2,3-dihydro-1H-pyrazol-4-yl)-4-(difluoromethoxy)benzamide, HCl: into a 1-drench vial equipped with a stir bar and a pressure relief diaphragm. Add tert-butyl 6-(3-(2,6-difluoro-4-methoxyphenyl)-4-(4-(difluoromethoxy)benzamido)-2-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-5-(trifluoromethyl)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate (36.1 mg, 0.048 mmol) and dioxane (1 mL). Add hydrogen chloride (4 M in dioxane, 1.0 mL, 4.0 mmol) to this solution and stir the reaction mixture overnight at room temperature. Dilute the reaction mixture with H2O and evaporate several times from EtOAc under reduced pressure to give a pale yellow solid (32 mg, 98%). The substance is used in the next step without further purification. MS (ESI) m / z: 652.3 (M+H) + ¹H NMR (500MHz, DMSO-d⁶) δ 9.71 (s, ¹H), 8.37 (d, J = 8.2Hz, ¹H), 7.91 (d, J = 8.2Hz, 2H), 7.85 (d, J = 8.2Hz, 1H), 7.23 (d, J = 8.2Hz, 2H), 7.33 (t, J = 73.7Hz, 1H), 7.02 (s, ¹H), 6.99–6.86 (m, 2H), 3.82 (s, 3H), 2.98 (s, 3H), 2.95–2.89 (m, ¹H), 2.47–2.40 (m, 2H), 1.68 (s, 3H). (Peak loss due to water inhibition).

[0451] Compound 222c. N-(5-(2,6-difluoro-4-methoxyphenyl)-1-methyl-2-(1'-(methylsulfonyl)-5-(trifluoromethyl)-1',2',3',6'-tetrahydro-[2,4'-bipyridin]-6-yl)-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-4-(difluoromethoxy)benzamide: Under nitrogen atmosphere, N-(5-(2,6-difluoro-4-methyl)-1-methyl(2,6-difluoro-4-yl)-1-methyl(2,3-dihydro-1H-pyrazol-4-yl)-4-(difluoromethoxy)benzamide is added to THF (2.0 mL). A mixture of 1,1-methyl-3-oxo-2-(5-(trifluoromethyl)-1',2',3',6'-tetrahydro-[2,4'-bipyridin]-6-yl)-2,3-dihydro-1H-pyrazol-4-yl)-4-(difluoromethoxy)benzamide, HCl (11 mg, 0.016 mmol), was reacted with TEA (11 μl, 0.078 mmol), followed by methanesulfonyl chloride (1.3 μl, 0.017 mmol). The reaction mixture was stirred overnight at room temperature under nitrogen. The reaction mixture was diluted with water and EtOAc, and the phases were separated. The aqueous layer was extracted with DCM (3x). The organic compounds were combined, washed with brine, dried (Na2SO4), filtered, and evaporated to give the title compound (11 mg) as a brown solid. The substance was used in the next step without further purification. MS (ESI) m / z: 730.1 (M+H) + .

[0452] Example 319: Under nitrogen atmosphere, carbon-supported 10% Pd (3.2 mg, 3.0 μmol) was added to a solution of N-(5-(2,6-difluoro-4-methoxyphenyl)-1-methyl-2-(1'-(methanesulfonyl)-5-(trifluoromethyl)-1',2',3',6'-tetrahydro-[2,4'-bipyridin]-6-yl)-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-4-(difluoromethoxy)benzamide (11 mg, 0.015 mmol) in EtOH (3 mL). The mixture was purified three times with nitrogen (evacuation / N2 backfill) and the reaction mixture was stirred overnight at room temperature under hydrogen atmosphere. The reaction mixture was filtered through a diatomaceous earth pad, which was washed with MeOH. The combined filtrates were evaporated to the residue. The crude material was purified by preparative LC / MS to give the title compound (5.5 mg, 50%). MS(ESI) m / z: 732.2(M+H) +. 1H NMR (500MHz, DMSO-d6) δ9.69 (s, 1H), 8.41 (d, J = 8.2Hz, 1H), 7.91 (d, J = 8.2Hz, 2H), 7.74 (d, J = 8. 2Hz,1H),7.23(d,J=8.5Hz,2H),7.32(t,J=73.5Hz,1H),6.99-6.86(m,2H),3.82(s,3H),3.68(br d,J=11.9Hz,2H),3.08-3.00(m,1H),2.98(s,3H),2.90(s,3H),2.89-2.83(m,2H),2.09-2.00(m,2H),1.85-1.72(m,2H).

[0453] Examples 142 to 408 (Table 2) use the methods described above and / or their modified preparations known to those skilled in the art.

[0454] Table 2

[0455]

[0456]

[0457]

[0458]

[0459]

[0460]

[0461]

[0462]

[0463]

[0464]

[0465]

[0466]

[0467]

[0468]

[0469]

[0470]

[0471]

[0472]

[0473]

[0474]

[0475]

[0476]

[0477]

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487]

[0488]

[0489]

[0490]

[0491]

[0492]

[0493]

[0494]

[0495]

[0496]

[0497]

[0498]

[0499]

[0500]

[0501]

[0502]

[0503]

[0504]

[0505]

[0506]

[0507]

[0508]

[0509]

[0510]

[0511]

[0512]

[0513]

[0514]

[0515]

[0516]

[0517]

[0518]

[0519]

[0520]

[0521]

[0522]

[0523]

[0524]

[0525]

[0526]

[0527]

[0528]

[0529]

[0530]

[0531]

[0532]

[0533]

[0534]

[0535]

[0536]

[0537]

[0538]

[0539]

[0540]

[0541]

[0542]

[0543]

[0544]

[0545]

[0546]

[0547]

[0548]

[0549]

[0550]

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557]

[0558]

[0559]

[0560]

[0561]

[0562]

[0563]

[0564]

[0565]

[0566]

[0567]

[0568]

[0569]

[0570] Examples in Table 2 1 H NMR data:

[0571] Example 2:

[0572] 1H NMR(500MHz,DMSO-d6)δ9.87(s,1H),7.93(br d,J=7.9Hz,2H),7.69-7.56(m,1H),7.44(br d,J=8.2Hz,2H),7.34-7.16(m,3H),6.90(br d,J=10.4Hz,2H),3.72(br s,3H),2.96(s,3H).

[0573] Example 3:

[0574] 1 H NMR(500MHz,CD3OD)δ7.87(br d,J=6.1Hz,2H),7.39-7.23(m,3H),7.21-7.12(m,2H),7.05-6.68(m,3H),3.85(s,3H),3.07(s,3H),2.39(s,3H),2.16(s,3H).

[0575] Example 4:

[0576] 1 H NMR (500MHz, CD3OD) δ7.92(br d,J=7.0Hz,2H),7.65-7.42(m,5H),7.33(br d,J=7.9Hz,2H),6.76(br d,J=10.8Hz,2H),3.86(s,3H),3.10(s,3H).

[0577] Example 5:

[0578] 1 H NMR (500MHz, CD3OD) δ7.98 (br d, J=7.2Hz, 2H), 7.74 (br d,J=8.2Hz,2H),7.59(t,J=7.8Hz,2H),7.54-7.50(m,2H),7.50-7.43(m,1H),6.77(d,J=10.0Hz,2H),3.86(s,3H),3.11(s,3H).

[0579] Example 6:

[0580] 1 H NMR (500MHz, DMSO-d6) δ7.89 (br d, J = 7.7Hz, 2H), 7.43-7.09 (m, 8H), 6.81 (brd, J = 10.4Hz, 2H), 5.13 (s, 2H), 3.80 (s, 3H), 3.09 (s, 3H).

[0581] Example 7:

[0582] 1 H NMR (500MHz, DMSO-d6) δ9.64 (s, 1H), 7.98 (br d, J = 8.5Hz, 2H), 7.66-7.53 (m, 6H), 7.39-7.19 (m, 4H), 7.11 (br d,J=8.5Hz,2H),3.81(s,3H),2.96(s,3H)

[0583] Example 8:

[0584] 1 H NMR (500MHz, DMSO-d6) δ7.89(br d,J=8.2Hz,2H),7.69-7.55(m,1H),7.46-7.11(m,6H),6.91(br d,J=10.7Hz,2H),2.96(s,3H),2.55(s,3H).

[0585] Example 9:

[0586] 1 H NMR (50MHz, CD3OD) δ7.80 (br d, J = 7.2 Hz, 2H), 7.62-7.54 (m, 2H), 7.53-7.42 (m, 5H), 6.75 (br d, J = 10.9 Hz, 2H), 3.86 (s, 3H), 3.09 (s, 3H).

[0587] Example 10:

[0588] 1 H NMR (500MHz, DMSO-d6) δ9.86 (s, 1H), 7.95 (br d, J = 7.9Hz, 2H), 7.52-7.37 (m, 6H), 6.93 (br d, J = 10.7Hz, 2H), 3.83 (s, 3H), 2.94 (s, 3H).

[0589] Example 11:

[0590] 1 H NMR(500MHz,DMSO-d6)δ7.82(br s,2H),7.71-7.58(m,1H),7.59-7.48(m,2H),7.39-7.17(m,3H),6.91(br d,J=10.4Hz,2H),3.82(s,3H),2.96(s,3H).

[0591] Example 12:

[0592] 1 H NMR(500MHz,DMSO-d6)δ9.75(s,1H),7.91(br d,J=8.2Hz,2H),7.50-7.40(m,4H),7.33(t,J=73.9Hz,1H),7.25(br d,J=8.2Hz,2H),6.93(br d,J=10.7Hz,2H),3.83(s,3H),2.93(s,3H).

[0593] Example 13:

[0594] 1 H NMR(500MHz,CD3OD)δ7.83(br d,J=7.8Hz,2H),7.16(d,J=8.7Hz,2H),6.86(t,J=73.6Hz,1H),6.71(d,J=9.9H z, 2H), 3.84 (s, 3H), 3.45 (s, 3H), 3.00 (quin, J = 5.2Hz, 1H), 1.22-1.16 (m, 4H).

[0595] Example 14:

[0596] 1 H NMR (500MHz, CD3OD) δ7.87 (br d, J=7.2Hz, 2H), 7.45 (br t, J=6.6Hz, 1H), 7.20 (br dd,J=14.5,8.7Hz,4H),7.06-6.66(m,3H),3.85(s,3H),3.07(s,3H),2.27(s,3H).

[0597] Example 15:

[0598] 1 H NMR (500MHz, DMSO-d6) δ9.80 (br s, 1H), 7.84 (br d, J = 7.9Hz, 2H), 7.53 (brd, J = 8.2Hz, 2H), 7.49-7.39 (m, 4H), 6.92 (br d,J=10.4Hz,2H),3.82(s,3H),2.93(s,3H).

[0599] Example 16:

[0600] 1H NMR(500MHz,CD3OD)δ7.70(br d,J=7.3Hz,2H),7.61-7.40(m,5H),7.18-7.08(m,2H),6.88-6.67(m,2H) ,3.85(s,3H),3.08(s,3H),2.01-1.89(m,1H),1.08-0.96(m,2H),0.73(br d,J=3.2Hz,2H).

[0601] Example 17:

[0602] 1 H NMR (500MHz, DMSO-d6) δ8.00(br d,J=7.4Hz,2H),7.82(br d,J=8.2Hz,2H),7.52-7.45(m,2H),7.44-7.37(m,2H),6.89(br d,J=10.4Hz,2H),3.83(s,3H),2.95(s,3H).

[0603] Example 18:

[0604] 1 H NMR(500MHz,CD3OD)δ7.84(br d,J=7.6Hz,2H),7.17(d,J=8.6Hz,2H),7.04-6.63(m,3H),3.84(s,3H),3.79-3.73(m,1H),3.28(s,3H),1.56(d,J=7.0Hz,6H).

[0605] Example 19:

[0606] 1 H NMR (500MHz, CD3OD) δ7.92 (br d, J = 5.9Hz, 2H), 7.66-7.42 (m, 7H), 6.93-6.65 (m, 3H), 3.86 (s, 3H), 3.10 (s, 3H).

[0607] Example 20:

[0608] 1 H NMR (500MHz, CD3OD) δ7.87(br s,2H),7.61-7.54(m,2H),7.51(br d,J=7.3Hz,2H),7.49-7.44(m,1H),7.15(br t,J=8.1Hz,2H),6.75(br d,J=10.8Hz,2H),3.86(s,3H),3.09(s,3H).

[0609] Example 21:

[0610] 1 H NMR (500MHz, CDCl3) δ7.92 (br s, 1H), 7.82 (br d, J = 8.0Hz, 2H), 7.14 (br d,J=8.5Hz,2H),6.74-6.40(m,3H),4.69(s,2H),4.27(q,J=7.0Hz,2H),3.84(s,3H),3.16(s,3H),1.32(t,J=7.2Hz,3H).

[0611] Example 22:

[0612] 1 H NMR (500MHz, CD3OD) δ7.80 (br d, J = 8.1Hz, 2H), 7.64-7.40 (m, 5H), 7.03-6.89 (m, 2H), 6.81-6.70 (m, 2H), 3.87-3.82 (m, 6H), 3.08 (s, 3H).

[0613] Example 23:

[0614] 1 H NMR (500MHz, CD3OD) δ10.42(br s,1H),9.31(br s,1H),8.77(br d,J=7.7Hz,2H),8.74-8.69(m,2H),8.59(s,1H),8.45-8.32(m,2H),8.27(br d,J=7.7Hz,2H),8.24-8.19(m,1H),7.69(br d,J=11.2Hz,2H),7.38(s,1H),4.64(s,3H),3.76(s,3H).

[0615] Example 24:

[0616] 1 H NMR (500MHz, CD3OD) δ 8.67-8.56 (m, 1H), 8.15 (s, 1H), 7.89 (br d, J = 7.7Hz, 1H), 7.53 (s, 5H), 6.75 (d, J = 10.1Hz, 2H), 3.86 (s, 3H), 3.10 (s, 3H).

[0617] Example 25:

[0618] 1H NMR (500MHz, CD3OD) δ 8.81-8.73 (m, 1H), 8.21-8.15 (m, 1H), 7.63-7.42 (m, 6H), 6.77 (d, J = 10.0Hz, 2H), 3.87 (s, 3H), 3.11 (s, 3H).

[0619] Example 26:

[0620] 1 H NMR (500MHz, DMSO-d6) δ9.80 (s, 1H), 7.95 (br d, J = 8.5Hz, 2H), 7.74-7.67 (m, 1H), 7.47-7.37 (m, 4H), 6.90 (br d,J=10.7Hz,2H),3.81(s,3H),2.98(s,3H).

[0621] Example 27:

[0622] 1 H NMR (500MHz, DMSO-d6) δ9.69(br s,1H),7.94-7.87(m,2H),7.74-7.67(m,1H),7.41(br t,J=8.5Hz,2H),7.30(t,J=73.6Hz,1H),7.23(br d,J=8.5Hz,2H),6.90(br d,J=10.7Hz,2H),3.81(s,3H),2.97(s,3H).

[0623] Example 28:

[0624] 1 H NMR(500MHz,DMSO-d6)δ9.81(br s,1H),7.94(br d,J=8.2Hz,2H),7.57(br d,J=6.1Hz,1H),7.51-7.40(m,5H),6.90(br d,J=10.7Hz,2H),3.81(s,3H),2.93(s,3H).

[0625] Example 29:

[0626] 1H NMR(500MHz,DMSO-d6)δ9.59(s,1H),7.91(br d,J=8.3Hz,2H),7.65-7.54(m,1H),7.54-7.40(m,3H),7.29(t,J=73.6Hz,1H),7.24(br d,J=8.5Hz,2H),6.89(br d,J=10.4Hz,2H),3.84(s,3H),2.94(s,3H).

[0627] Example 30:

[0628] 1 H NMR(500MHz,DMSO-d6)δ9.77(br s,1H),7.85(br d,J=7.9Hz,2H),7.60-7.46(m,5H),7.45-7.38(m,1H),6.91(br d,J=10.4Hz,2H),3.82(s,3H),2.93(s,3H).

[0629] Example 31:

[0630] 1 H NMR (500MHz, DMSO-d6) δ9.78(br s,1H),7.86(br d,J=7.9Hz,2H),7.77-7.67(m,1H),7.54(br d,J=8.2Hz,2H),7.42(br t,J=8.5Hz,2H),6.92(br d,J=10.4Hz,2H),3.82(s,3H),2.98(s,3H).

[0631] Example 32:

[0632] 1 H NMR(500MHz,DMSO-d6)δ9.81(s,1H),8.51(br d,J=4.0Hz,1H),8.04(br t,J=8.9Hz,1H),7.95(br d,J=7.9Hz,2H),7.69-7.59(m,1H),7.45(br d,J=7.9Hz,2H),6.92(br d,J=10.7Hz,2H),3.82(s,3H),3.04(s,3H).

[0633] Example 33:

[0634] 11H NMR (500 MHz, DMSO-d6) δ 9.71 (s, 1H), 8.96 (br d, J = 4.6 Hz, 1H), 8.48 (br d, J = 7.9 Hz, 1H), 7.95 - 7.86 (m, 2H), 7.86 - 7.78 (m, 1H), 7.31 (t, J = 73.6 Hz, 1H), 7.22 (br d, J = 8.2 Hz, 2H), 7.00 - 6.80 (m, 2H), 3.81 (s, 3H), 2.95 (s, 3H).

[0635] Example 35:

[0636] 1 1H NMR (500 MHz, DMSO-d6) δ 9.87 (br s, 1H), 7.97 (br d, J = 8.2 Hz, 2H), 7.85 (br d, J = 7.9 Hz, 1H), 7.62 - 7.58 (m, 1H), 7.56 - 7.52 (m, 1H), 7.45 (br d, J = 8.2 Hz, 2H), 6.92 (br s, 2H), 3.82 (s, 3H), 2.91 (s, 3H).

[0637] Example 36: <​​

[0642] 1 H NMR (500 MHz, CD3OD) δ7.92 (br d, J = 8.6 Hz, 2H), 7.59 (d, J = 7.7 Hz, 2H), 7.53 (s, 3H), 7.32 (dd, J = 15.4, 8.0 Hz, 4H), 3.10 (s, 3H).

[0643] Example 40:

[0644] 1 H NMR(500MHz,CD3OD)δ8.67(d,J=2.2Hz,1H),8.15(dd,J=8.7,2.4Hz,1H),7.91–7.83(m,3H),7. 19(d,J=8.7Hz,2H), 6.88(t,J=73.6Hz,1H), 6.76(d,J=10.0Hz,2H), 3.86(s,3H), 3.31(s,3H).

[0645] Example 41:

[0646] 1 H NMR (500MHz, CD3OD) δ8.62(dd,J=4.7,1.5Hz,1H),8.15(dd,J=8.2,1.4Hz,1H),7.91(br d,J=7.1Hz,2H),7.60(dd,J=8.1,4.7Hz,1H),7.32(br d,J=8.3Hz,2H),6.76(d,J=10.3Hz,2H),3.86(s,3H),3.16(s,3H).

[0647] Example 43:

[0648] 1 H NMR (500MHz, CD3OD) δ8.57(d,J=2.4Hz,1H),8.02(dd,J=8.8,2.5Hz,1H),7.92(d,J=8.8Hz,1H),7.80(br d,J=8.2Hz,2H),7.44(d,J=8.5Hz,2H),6.76(d,J=10.0Hz,2H),3.86(s,3H),3.31(s,3H).

[0649] Example 46:

[0650] 1H NMR (500MHz, CD3OD) δ7.90-7.85(m,3H),7.64(d,J=8.1Hz,1H),7.27(d,J=7.6Hz,1H),7.19(d,J =8.7Hz,2H),6.88(t,J=73.6,1H),6.76(d,J=9.9Hz,2H),3.86(s,3H),3.31(s,3H),2.59(s,3H).

[0651] Example 47:

[0652] 1 H NMR(500MHz,CD3OD)δ8.41(d,J=1.9Hz,1H),7.87(br d,J=8.3Hz,2H),7.77-7.62(m,2H),7.18(d,J=8.6Hz,2H),7.04-6.70(m,3H),3. 86(s,3H),3.26(s,3H),2.10-2.00(m,1H),1.15-1.06(m,2H),0.90-0.73(m,2H).

[0653] Example 48:

[0654] 1 H NMR (500MHz, DMSO-d6) δ9.83-9.63(m,1H),8.42(s,1H),7.84(br s,3H),7.75(d,J=8.2Hz,1H),7.54(br d,J=8.2Hz,2H),6.93(br d,J=10.7Hz,2H),3.83(s,3H),3.17(m,3H),2.36(s,3H).

[0655] Example 49:

[0656] 1 H NMR (500MHz, CD3OD) δ8.52-8.37(m,1H),7.87(br d,J=8.4Hz,3H),7.72(br d,J=8.2Hz,1H),7.18(d,J=8.6Hz,2H),7.05-6.69(m,3H),3.85(s,3H),3.26(s,3H),2.41(s,3H).

[0657] Example 50:

[0658] 1H NMR(500MHz,CD3OD)δ8.43(br s,1H),7.95-7.89(m,2H),7.87-7.68(m,2H),7.32(br d,J=8.3Hz,2H),6.76(d,J=10.0Hz,2H),3.86(s,3H),3.27(s,3H),2.42(s,3H).

[0659] Example 51:

[0660] 1 H NMR(500MHz,DMSO-d6)δ9.60(s,1H),8.93-8.88(m,1H),8.31(dd,J=8.6,2.3Hz,1H),8.00(d,J=8.5Hz,1H),7.96-7.88(m,2 H),7.79(d,J=7.5Hz,2H),7.54(t,J=7.6Hz,2H),7.50-7.41(m,1H),7.28(t,J=73.6Hz,1H),7.25(d,J=8.7Hz,2H),6.91(br d,J=10.4Hz,2H),3.85(s,3H),3.24(s,3H).

[0661] Example 52:

[0662] 1 H NMR (500MHz, CD3OD) δ8.41(d,J=1.8Hz,1H),7.92(br d,J=8.2Hz,2H),7.73-7.68(m,1H),7.68-7.64(m,1H),7.32(br d,J=8.2Hz,2H),6.76(d,J=10.0Hz,2H),3.86(s,3H),3.28-3.25(m,3H),2.07-1.98(m,1H),1.15-1.05(m,2H),0.86-0.77(m,2H).

[0663] Example 53:

[0664] 1H NMR (500MHz, DMSO-d6) δ9.51(s,1H),8.42(s,1H),7.72(br d,J=8.2Hz,3H),7.63(br d,J=8.5Hz,1H),7.13(br d,J=7.9Hz,2H),6.91(br d,J=10.4Hz,2H),3.82(s,3H),3.13(s,3H),2.06-1.99(m,1H),1.97-1.92(m,1H),1.07-0.96(m,4H),0.79(br d,J=4.9Hz,2H),0.72(br d,J=4.9Hz,2H).

[0665] Example 55:

[0666] 1 H NMR (500MHz, CD3OD) δ8.87 (dd, J=4.8, 1.6Hz, 1H), 8.39 (dd, J=7.8, 1.7Hz, 1H), 7.86 (br d,J=8.3Hz,2H),7.63(dd,J=7.8,4.9Hz,1H),7.18(d,J=8.7Hz,2H),7.04-6.67(m,3H),3.87(s,3H),3.26(s,3H).

[0667] Example 56:

[0668] 1 H NMR(500MHz, CDCl3)δ8.85(dd,J=4.8,1.8Hz,1H),8.20(dd,J=7.7,1.7Hz,1H),7.92-7.78(m,3H),7 .45(dd,J=7.8,4.8Hz,1H),7.25(d,J=8.3Hz,2H),6.61(d,J=9.9Hz,2H),3.86(s,3H),3.20(s,3H).

[0669] Example 60:

[0670] 1H NMR(500MHz,DMSO-d6)δ9.75(br s,1H),8.55(d,J=8.9Hz,1H),8.14(d,J=8.8Hz,1H),8.04(t,J=6.9Hz,2H),7.92(d,J=8.2Hz,2H),7.82(t, J=7.5Hz,1H),7.63(t,J=7.5Hz,1H),7.54-7.13(m,3H),6.96(d,J=10.4Hz,2H),3.84(s,3H),3.31(s,3H).

[0671] Example 61:

[0672] 1 H NMR (500MHz, DMSO-d6) δ9.75(s,1H),8.99(s,1H),8.49(s,1H),7.91(br d,J=8.2Hz,2H),7.54-7.12(m,3H),6.94(br d,J=10.7Hz,2H),3.83(s,3H),3.20(s,3H),2.58(s,3H).

[0673] Example 62:

[0674] 1 H NMR(500MHz,DMSO-d6)δ9.78(s,1H),8.92-8.81(m,1H),8.25(s,1H),7.90(d,J=6.5Hz,2H),7.75(d,J=2 .7Hz,1H),7.51-7.10(m,3H),6.95(dd,J=10.4,2.9Hz,2H),3.83(d,J=2.4Hz,3H),3.23(d,J=2.1Hz,3H).

[0675] Example 63:

[0676] 1 H NMR(500MHz,DMSO-d6)δ9.88(s,1H),8.87(d,J=5.0Hz,1H),8.24(s,1H),7.95(d,J=8.2Hz,2H), 7.74(d,J=5.0Hz,1H),7.47(d,J=7.9Hz,2H),6.95(d,J=11.8Hz,2H),3.83(s,3H),3.23(s,3H).

[0677] Example 64:

[0678] 1H NMR(500MHz,DMSO-d6)δ9.82(s,1H),9.53(s,1H),8.21-8.06(m,2H),7.99-7.8 1(m,4H),7.49-7.12(m,3H),6.96(d,J=10.4Hz,2H),3.84(s,3H),3.33(s,3H).

[0679] Example 65:

[0680] 1 H NMR (500MHz, DMSO-d6) δ9.66 (s, 1H), 7.90 (d, J = 8.2Hz, 2H), 7.54-7.41 (m, 1H), 7.38-7. 12(m,3H),7.08(s,1H),6.92(d,J=10.1Hz,2H),3.82(s,3H),3.16(s,3H),2.55(s,6H).

[0681] Example 66:

[0682] 1 H NMR (500MHz, DMSO-d6) δ9.78 (s, 1H), 7.95 (d, J = 8.5Hz, 2H), 7.55-7.32 (m, 3H), 7.08 (s,1H),6.93(d,J=10.4Hz,2H),3.83(s,3H),3.17(s,3H),2.49(s,3H),2.38(s,3H).

[0683] Example 67:

[0684] 1 H NMR(500MHz,DMSO-d6)δ9.75(s,1H),8.25-8.15(m,1H),8.10-8.01(m,1H),7.95-7.81(m,2H),7 .66(d,J=7.7Hz,1H),7.49-7.00(m,4H),6.92(d,J=10.0Hz,2H),3.87-3.60(m,3H),3.22(s,3H).

[0685] Example 68:

[0686] 1H NMR (500MHz, DMSO-d6) δ9.86 (s, 1H), 8.21 (t, J = 7.8Hz, 1H), 8.07 (d, J = 8.2Hz, 1H), 7.94 (d, J = 8.1Hz, 2H), 7.66 (d, J = 7.5Hz, 1H), 7.46 (d, J = 8.2Hz, 2H), 7.22-6.87 (m, 3H), 3.91-3.56 (m, 3H), 3.22 (s, 3H).

[0687] Example 69:

[0688] 1 H NMR (500MHz, DMSO-d6) δ9.76 (s, 1H), 8.39 (d, J = 1.7Hz, 1H), 8.15 (t, J = 8.0Hz, 1H), 7.92 (br d,J=8.5Hz,2H),7.81-7.70(m,2H),7.55-7.13(m,3H),7.02-6.88(m,2H),6.47(d,J=2.2Hz,1H),3.84(s,3H),3.26(s,3H),2.32(s,3H).

[0689] Example 70:

[0690] 1 H NMR(500MHz,DMSO-d6)δ9.88(s,1H),8.40(d,J=2.2Hz,1H),8.15(t,J=8.0Hz,1H),7.97(d,J=8.3Hz,2H),7.82-7.69 (m,2H),7.48(d,J=8.2Hz,2H),6.97(d,J=10.5Hz,2H),6.47(d,J=2.4Hz,1H),3.84(s,3H),3.27(s,3H),2.32(s,3H).

[0691] Example 71:

[0692] 1 H NMR(500MHz,DMSO-d6)δ9.77(s,1H),8.77-8.64(m,1H),8.26(s,1H),7.90(d,J=7.9Hz, 2H),7.52-7.14(m,3H),6.94(d,J=10.7Hz,2H),3.99(s,3H),3.83(s,3H),3.26(s,3H).

[0693] Example 72:

[0694] 1H NMR(500MHz,DMSO-d6)δ9.73(s,1H),8.17-8.06(m,3H),8.00-7.83(m,4H),7.61-7.44(m,3H),7.35-7.14(m,3H),6.96(br d,J=10.4Hz,2H),3.84(s,3H),3.30(s,3H).

[0695] Example 73:

[0696] 1 H NMR(500MHz,DMSO-d6)δ9.84(s,1H),8.17-8.08(m,3H),7.96(br d,J=7.3Hz,3H),7.88(d,J=8.2Hz,1H),7.59-7.53(m,2H),7.52-7.43(m,3H),6.97(br d,J=10.1Hz,2H),3.84(s,3H),3.31(s,3H).

[0697] Example 74:

[0698] 1 H NMR(500MHz,DMSO-d6)δ9.80(s,1H),7.98-7.84(m,3H),7.50-7.40(m,3H),6.92(br d,J=10.4Hz,2H),6.79(d,J=8.2Hz,1H),3.91(s,3H),3.82(s,3H),3.24(s,3H).

[0699] Example 75:

[0700] 1 H NMR (500MHz, DMSO-d6) δ9.69 (s, 1H), 7.98-7.82 (m, 3H), 7.44 (d, J = 7.3Hz, 1H), 7.34-7.10 (m ,3H),6.92(d,J=10.7Hz,2H),6.79(d,J=7.9Hz,1H),3.91(s,3H),3.82(s,3H),3.24(s,3H).

[0701] Example 76:

[0702] 1H NMR(500MHz,DMSO-d6)δ9.76(s,1H),8.76(d,J=5.0Hz,1H),8.09(s,1H),7.91(d,J=8.3Hz,2H ),7.55(d,J=4.9Hz,1H),7.49-7.08(m,4H),6.94(d,J=10.2Hz,2H),3.83(s,3H),3.20(s,3H).

[0703] Example 77:

[0704] 1 H NMR(500MHz,DMSO-d6)δ9.66(s,1H),8.21(s,1H),7.88(d,J=8.5Hz,2H),7.47-7.06 (m,4H),6.90(d,J=10.4Hz,2H),3.93(s,3H),3.81(s,3H),3.15(s,3H),2.15(s,3H).

[0705] Example 78:

[0706] 1 H NMR(500MHz,DMSO-d6)δ9.72(s,1H),7.98-7.80(m,3H),7.51-7.16(m,4H),6.95(br d,J=10.4Hz,2H),6.76(d,J=8.1Hz,1H),4.36(q,J=7.0Hz,2H),3.83(s,3H),3.23(s,3H),1.37(t,J=7.0Hz,3H).

[0707] Example 79:

[0708] 1 H NMR (500MHz, DMSO-d6) δ9.66 (s, 1H), 7.91 (br d, J = 8.2Hz, 2H), 7.75 (t, J = 7.9Hz, 1H), 7.51-7.11 (m, 4H), 6.93 (br d,J=10.4Hz,2H),6.77(d,J=8.2Hz,1H),3.82(s,3H),3.77-3.69(m,4H),3.53-3.47(m,2H),3.44-3.33(m,2H),3.19(s,3H).

[0709] Example 80:

[0710] 1H NMR (500MHz, DMSO-d6) δ9.65(s,1H),7.90(d,J=8.2Hz,2H),7.68(t,J=7.9Hz,1H),7.24(d,J=8.5Hz,2H),7.30(t,J=73.9Hz,1H),7. 01(d,J=7.6Hz,1H),6.92(d,J=10.1Hz,2H),6.74(d,J=8.5Hz,1H),3.82(s,3H),3.63-3.39(m,4H),3.19(s,3H),1.67-1.47(m,6H).

[0711] Example 81:

[0712] 1 H NMR(500MHz,DMSO-d6)δ9.68(s,1H),8.01(t,J=7.9Hz,1H),7.89(d,J=8.5Hz,2H),7.72(d,J=7.9Hz, 1H),7.47-7.41(m,1H),7.32-7.12(m,3H),6.91(d,J=10.4Hz,2H),4.61(s,2H),3.82(s,3H),3.56(br s,1H),3.18(s,3H).

[0713] Example 82:

[0714] 1 H NMR (500MHz, DMSO-d6) δ9.66(s,1H),7.89(d,J=8.5Hz,2H),7.67(t,J=8.0Hz,1H),7.24(d,J=8.5Hz,2H),7.23(t,J=73 .5Hz,1H),6.99(d,J=7.7Hz,1H),6.90(d,J=10.3Hz,2H),6.57(d,J=8.4Hz,1H),3.81(s,3H),3.22(s,3H),3.05(s,6H).

[0715] Example 83:

[0716] 1H NMR (500MHz, DMSO-d6) δ9.69(s,1H),7.91(d,J=8.5Hz,2H),7.72(t,J=8.0Hz,1H),7.25(d,J=8.6Hz,2H),7.29(t,J= 75.1Hz,1H),7.10(d,J=7.7Hz,1H),6.94(d,J=10.4Hz,2H),6.78(d,J=8.4Hz,1H),3.83(s,3H),3.19(s,3H),2.45(br s,4H),2.25(s,3H),1.92(s,4H).

[0717] Example 84:

[0718] 1 H NMR(500MHz,DMSO-d6)δ9.91(s,1H),9.72(s,1H),8.04-7.96(m,2H),7.91(d,J=8.3Hz,2H),7.54-7.50(m,1 H),7.25(d,J=8.4Hz,2H),7.50-7.16(m,1H),6.94(d,J=10.7Hz,2H),3.83(s,3H),3.21(s,3H),1.27(s,9H).

[0719] Example 86:

[0720] 1 H NMR (500MHz, DMSO-d6) δ9.69(s,1H),8.00(t,J=7.9Hz,1H),7.91(d,J=8.5Hz,2H),7.74(d,J=7.9Hz,1H),7.47(d,J=7.0Hz,1H),7. 36-7.14(m,3H),6.93(d,J=10.4Hz,2H),5.52(d,J=4.6Hz,1H),4.85-4.72(m,1H),3.83(s,3H),3.21(s,3H),1.43(d,J=6.4Hz,3H).

[0721] Example 89:

[0722] 1 H NMR (500MHz, DMSO-d6) δ9.66 (s, 1H), 7.89 (br d, J = 8.2Hz, 2H), 7.48-7.10 (m, 5H), 6.92 (br d,J=10.4Hz,2H),5.41(s,1H),3.90(s,3H),3.82(s,3H),3.22(s,3H),1.46(s,6H).

[0723] Example 90:

[0724] 1 H NMR (500MHz, DMSO-d6) δ9.69(s,1H),7.91(d,J=8.6Hz,2H),7.30(d,J=1.9Hz,1H),7.25(d,J=8.7Hz,2H),7.34(t,J=73.8Hz,1 H),7.02(s,1H),6.93(d,J=10.2Hz,2H),5.61(t,J=5.8Hz,1H),4.57(d,J=5.8Hz,2H),3.92(s,3H),3.83(s,3H),3.19(s,3H).

[0725] Example 92:

[0726] 1 H NMR(500MHz,DMSO-d6)δ9.63(s,1H),7.89(d,J=8.2Hz,2H),7.47-7.10(m,3H),6.91(d,J=10.7Hz,2H),6.69(s,1H),6.28(s, 1H),4.21-4.07(m,2H),3.85(s,3H),3.81(s,3H),3.65-3.59(m,2H),3.18(s,3H),2.49-2.40(m,2H),1.15(d,J=6.1Hz,6H).

[0727] Example 93:

[0728] 1 H NMR(500MHz,DMSO-d6)δ9.65(s,1H),7.88(d,J=8.4Hz,2H),7.24(d,J=8.6Hz,2H),7.46-7.09(m,1H),6.91(d,J=11.0Hz,2H),6.66(s,1H),6 .28(s,1H),4.13(d,J=13.0Hz,2H),3.84(s,3H),3.80(s,3H),3.18(s,3H),2.62(t,J=11.9Hz,2H),2.23-2.13(m,5H),1.08(d,J=6.1Hz,6H).

[0729] Example 94:

[0730] 1H NMR (500MHz, DMSO-d6) δ9.64(s,1H),7.89(d,J=7.8Hz,2H),7.24(d,J=8.6Hz,2H),7.32(t,J=84.6Hz,1H),6.91(d,J=10.4Hz,2H),6.65(s,1H ), 6.58 (d, J = 1.9Hz, 1H), 6.00 (d, J = 1.3Hz, 1H), 3.81 (s, 3H), 3.78 (s, 3H), 3.62-3.59 (m, 2H), 3.33 (q, J = 5.7Hz, 2H), 3.20 (s, 3H), 1.91 (s, 1H).

[0731] Example 95:

[0732] 1 H NMR (500MHz, DMSO-d6) δ9.64(s,1H),7.88(d,J=8.0Hz,2H),7.46-7.10(m,4H),6.89(d,J=10.4Hz,2H),6.63(d,J=1.9Hz,1H),5.86(s,1H),4.40(br s,1H),3.83(brs,3H),3.79-3.78(m,3H),3.73(br d,J=1.4Hz,1H),3.54-3.42(m,2H),3.35(br d,J=10.4Hz,1H),3.24(s,3H),2.09-1.97(m,1H),1.94-1.86(m,1H).

[0733] Example 96:

[0734] 1 H NMR (500MHz, DMSO-d6) δ9.65 (s, 1H), 7.90 (d, J = 8.6Hz, 2H), 7.24 (d, J = 8.6Hz, 2H), 7.52-7.13 (m, 1H), 6.92 (d, J = 10. 3Hz, 2H), 6.76-6.67 (m, 1H), 5.86 (d, J = 1.4Hz, 1H), 3.93-3.78 (m, 8H), 3.57-3.50 (m, 3H), 3.22 (s, 3H), 1.45 (s, 3H).

[0735] Example 97:

[0736] 1H NMR(500MHz,DMSO-d6)δ9.63(s,1H),7.90(d,J=8.2Hz,2H),7.24(d,J=8.5Hz,2H),7.31(t,J =71.4Hz,1H),6.91(d,J=10.1Hz,2H),6.67(d,J=1.5Hz,1H),5.86(d,J=1.5Hz,1H),4.40(br s,1H),3.84(s,3H),3.81(s,3H),3.81-3.78(m,1H),3.59-3.49(m,1H),3.49-3. 42(m,2H),3.41-3.30(m,1H),3.25(s,3H),2.09-1.97(m,1H),1.94-1.83(m,1H).

[0737] Example 98:

[0738] 1 H NMR (500MHz, DMSO-d6) δ9.63(s,1H),7.89(d,J=8.5Hz,2H),7.24(d,J=8.5Hz,2H),7.30(t,J=72.6Hz,1H),6.91(d,J=10.7Hz,2H) ,6.72(s,1H),5.94(s,1H),5.45(d,J=56.2Hz,1H),3.85(s,3H),3.81(s,3H),3.78-3.38(m,4H),3.24(s,3H),2.33-2.06(m,2H).

[0739] Example 99:

[0740] 1 H NMR(500MHz,DMSO-d6)δ9.67(s,1H),7.91(d,J=8.7Hz,2H),7.25(d,J=8.6Hz,2H),7.53-7.14(m,1H),6.93( d,J=10.4Hz,2H),6.79(s,1H),6.02(d,J=1.5Hz,1H),3.87(s,3H),3.82(s,3H),3.94-3.75(m,2H),3.67(br t,J=7.3Hz,2H),3.24(s,3H),2.63-2.54(m,2H).

[0741] Example 100:

[0742] 1H NMR(500MHz,DMSO-d6)δ9.71(s,1H),7.91(d,J=8.6Hz,2H),7.32-7.28(m,1H),7.26(d,J=8.6Hz,2H),7.32(t,J=75.4Hz,1H),7.06(s,1H),6.9 5(dd,J=10.5,3.8Hz,2H),3.90(s,3H),3.82(s,3H),3.48-3.46(m,1H) ,3.27(s,3H),2.55-2.53(m,2H),2.34-2.24(m,2H),2.05-1.82(m,2H).

[0743] Example 101:

[0744] 1 H NMR (500MHz, DMSO-d6) δ9.69 (s, 1H), 7.94 (d, J = 8.2Hz, 2H), 7.29 (d, J = 8.5Hz, 2H), 7.36 (t, J = 75.4Hz, 1H), 6.96 (d, J = 10. 4Hz,2H),6.80(s,1H),6.33(s,1H),3.90(s,3H),3.86(s,3H),3.68-3.49(m,4H),3.23(s,3H),2.59(s,3H),2.34(s,4H).

[0745] Example 102:

[0746] 1 H NMR (500MHz, DMSO-d6) δ9.65(s,1H),7.91(d,J=8.5Hz,2H),7.66(t,J=7.9Hz,1H),7.25(d,J=8.5Hz,2H),7.33(t,J =73.5Hz,1H),7.02(d,J=7.6Hz,1H),6.93(d,J=10.1Hz,2H),6.38(d,J=8.2Hz,1H),5.04(d,J=3.7Hz,1H),4.42(br d,J=1.8Hz,1H),3.83(s,3H),3.63-3.40(m,4H),3.25(s,3H),2.11-2.00(m,1H),1.97-1.84(m,1H).

[0747] Example 103:

[0748] 1H NMR(500MHz,DMSO-d6)δ9.70(s,1H),7.93(d,J=8.6Hz,2H),7.71(t,J=8.0Hz,1H),7.26(d,J=8.6Hz,2H ),7.36(t,J=72.5Hz,1H),7.06(d,J=7.7Hz,1H),6.96(d,J=10.4Hz,2H),6.80(d,J=8.5Hz,1H),4.17(br d,J=12.5Hz,2H),3.83(s,3H),3.19(s,3H),2.64(br t,J=11.9Hz,2H),2.20(m,5H),1.10(d,J=6.1Hz,6H).

[0749] Example 104:

[0750] 1 H NMR (500MHz, DMSO-d6) δ9.67(s,1H),7.91(d,J=8.9Hz,2H),7.81(t,J=7.9Hz,1H),7.28-7.22(m,3H),7.32(t,J =78.4Hz, 1H), 6.93 (d, J = 10.1Hz, 2H), 6.53 (d, J = 7.9Hz, 1H), 4.45 (t, J = 12.4Hz, 4H), 3.83 (s, 3H), 3.22 (s, 3H).

[0751] Example 105:

[0752] 1 H NMR(500MHz,DMSO-d6)δ9.64(s,1H),7.91(d,J=8.5Hz,2H),7.25(d,J=8.5Hz,2H), 7.32(t,J=73.5Hz,1H),6.92(d,J=10.4Hz,2H),6.71(s,1H),6.21(s,1H),4.52(br s,2H),3.84(s,3H),3.82(s,3H),3.20(s,3H),2.65-2.58(m,2H),2.32-2.23(m,2H),2.13(s,3H),1.97-1.81(m,4H).

[0753] Example 106:

[0754] 1H NMR (500MHz, DMSO-d6) δ9.66 (s, 1H), 7.91 (d, J = 8.7Hz, 2H), 7.25 (d, J = 8.7Hz, 2H),7.34(t,J=73.7Hz,1H),6.93(d,J=10.2Hz,2H),6.74(s,1H),5.87(s,1H) ,4.51(quin,J=5.5Hz,1H),4.25-4.18(m,2H),3.84(s,3H),3.82(s,3H),3.74 (dd,J=8.8,4.5Hz,2H),3.70-3.61(m,1H),3.22(s,3H),1.12(d,J=6.1Hz,6H).

[0755] Example 107:

[0756] 1 H NMR(500MHz,DMSO-d6)δ9.70(s,1H),7.92(d,J=8.8Hz,2H),7.83(t,J=8.1Hz,1H),7.26(d,J=8.5Hz,2H ),7.22(d,J=7.7Hz,1H),7.35(t,J=73.2Hz,1H),6.94(d,J=10.2Hz,2H),6.91(d,J=8.5Hz,1H),4.40(br d,J=13.5Hz,2H),3.84(s,3H),3.81-3.76(m,3H),3.63(br d,J=11.3Hz,2H),3.38-3.29(m,2H),3.26(br s,2H),3.21-3.16(m,5H).

[0757] Example 109:

[0758] 1 H NMR (500MHz, DMSO-d6) δ9.70(s,1H),7.89(br d,J=7.9Hz,2H),7.23(br d,J=8.2Hz,2H),7.30(t,J=74.0Hz,1H),7.03(s,3H),6.89(br s,2H),3.81(s,3H),2.91(s,3H),2.35(s,6H).

[0759] Example 110:

[0760] 1H NMR (500MHz, DMSO-d6) δ9.90-9.69(m,1H),7.93-7.86(m,3H),7.83(br d,J=4.9Hz,1H),7.78(br d,J=4.9Hz,2H),7.24(br d,J=8.5Hz,2H),7.30(t,J=74.0Hz,1H),6.92(br d,J=10.4Hz,2H),3.82(s,3H),2.96(s,3H).

[0761] Example 111:

[0762] 1 H NMR (500MHz, DMSO-d6) δ9.71 (s, 1H), 8.02-7.79 (m, 2H), 7.48-7.39 (m, 1H), 7.24 (br d, J = 8.5Hz, 2H), 7.18 (t, J = 74.0Hz, 1H), 7.15 (br d,J=5.8Hz,2H),7.07(br d,J=7.9Hz,1H),6.91(br d,J=10.4Hz,2H),3.81(s,3H),2.91(s,3H),2.15-1.96(m,1H),1.12-0.94(m,2H),0.78-0.63(m,2H).

[0763] Example 112:

[0764] 1 H NMR(500MHz,DMSO-d6)δ9.76(s,1H),7.91(br d,J=8.5Hz,2H),7.52-7.46(m,1H),7.25(d,J=8.6Hz,2H),7.30(t,J=74.0H z, 1H), 7.05-6.96 (m, 3H), 6.93 (d, J = 10.4Hz, 2H), 3.83 (s, 6H), 2.94 (s, 3H).

[0765] Example 113:

[0766] 1H NMR(500MHz,DMSO-d6)δ9.78(s,1H),8.00(s,1H),7.95(br d,J=6.7Hz,1H),7.91(br d,J=8.5Hz,2H),7.79-7.67(m,2H),7.25(d,J=8.5Hz,2H),7.32(t,J=74.0Hz,1H),6.93(br d,J=10.4Hz,2H),3.91(s,3H),3.83(s,3H),2.94(s,3H).

[0767] Example 114:

[0768] 1 H NMR(500MHz,DMSO-d6)δ9.79(s,1H),7.91(br d,J=8.5Hz,2H),7.68-7.58(m,1H),7.53(d,J=1.8Hz,1H),7.50-7.44(m,1H),7.41(br d,J=7.9Hz,1H),7.36-7.12(m,3H),6.94(br d,J=10.1Hz,2H),3.83(s,3H),2.96(s,3H).

[0769] Example 115:

[0770] 1 H NMR (500MHz, DMSO-d6) δ9.84(s,1H),8.30(d,J=5.6Hz,1H),7.89(br d,J=8.4Hz,2H),7.24(br d,J=8.6Hz,2H),7.50-7.15(m,1H),7.14-7.08(m,1H),6.93(br d,J=10.4Hz,2H),6.86(s,1H),3.90(s,3H),3.82(s,3H),2.96(s,3H).

[0771] Example 116:

[0772] 1¹H NMR (500MHz, DMSO-d⁶) δ 9.87 (s, ¹H), 8.53 (d, J = 5.6 Hz, ¹H), 7.88 (br d, J = 8.7 Hz, 2H), 7.60 (d, J = 1.7 Hz, 1H), 7.50 (dd, J = 5.6, 1.8 Hz, 1H), 7.28 (t, J = 74.0 Hz, 1H), 7.24 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 10.6 Hz, 2H), 3.82 (s, 3H), 2.98 (s, 3H). 16 / 17 protons were observed.

[0773] Example 117:

[0774] 1 H NMR(500MHz,DMSO-d6)δ9.79(s,1H),7.89(d,J=8.5Hz,2H),7.28(d,J=14.6Hz,2H),7.26-7.21(m, 3H), 7.30 (t, J = 74.0Hz, 1H), 6.92 (d, J = 10.4Hz, 2H), 3.91 (s, 3H), 3.82 (s, 3H), 2.98-2.89 (m, 3H).

[0775] Example 118:

[0776] 1 H NMR (500MHz, DMSO-d6) δ9.84-9.67(m,1H),7.90(br d,J=7.2Hz,2H),7.46(t,J=7.9Hz,1H),7.24(br d,J=8.2Hz,2H),7.34-7.13(m,1H),7.01-6.87(m,5H),4.08(q,J=7.1Hz,2H),3.82(s,3H),2.93(s,3H),1.36(br t,J=6.9Hz,3H).

[0777] Example 119:

[0778] 1 H NMR(500MHz,DMSO-d6)δ9.80(s,1H),7.89(br d,J=8.4Hz,2H),7.76(s,1H),7.70(s,1H),7.60(s,1H),7.24(d,J=8.6Hz,2H),7.32(t,J=74.0Hz,1H), 6.93(d,J=10.5Hz,2H),3.82(s,3H),3.07(dt,J=13.7,6.9Hz,1H),2.95(s,3H),1.26(d,J=6.8Hz,6H).

[0779] Example 120:

[0780] 1 H NMR (500MHz, DMSO-d6) δ9.81(s,1H),7.89(br t,J=6.6Hz,4H),7.78(s,1H),7.24(br d,J=8.5Hz,2H),7.29(t,J=74.0Hz,1H),6.92(br d,J=10.7Hz,2H),3.91(s,3H),3.82(s,3H),2.95(s,3H).

[0781] Example 121:

[0782] 1 H NMR(500MHz,DMSO-d6)δ9.73(s,1H),7.89(br d,J=8.3Hz,2H),7.45-7.44(m,1H),7.24(d,J=8.6Hz,1H),7.31(t,J=74.0Hz,1H),6.91(d,J=10.4 Hz, 2H), 6.81 (s, 1H), 6.80 (d, J = 14.0Hz, 2H), 3.81 (s, 3H), 3.79 (s, 3H), 2.92 (s, 3H), 2.36 (s, 3H).

[0783] Example 122:

[0784] 1 H NMR(500MHz,DMSO-d6)δ9.79(s,1H),7.90(br d,J=8.2Hz,2H),7.29(s,1H),7.26-7.23(m,3H),7.22(s,1H),7.31(t,J=74.0Hz,1H),6.93(br d, J=10.7Hz, 2H), 4.19 (q, J=7.0Hz, 2H), 3.82 (s, 3H), 2.96 (s, 3H), 1.38 (t, J=6.9Hz, 3H).

[0785] Example 123:

[0786] 1H NMR(500MHz,DMSO-d6)δ9.81(s,1H),7.88(br d,J=8.5Hz,2H),7.59-7.52(m,J=7.6Hz,2H),7.40(s,1H),7.24(d,J=8.5Hz,2H),7.29(t,J=74.0Hz,1H),6.92(br d,J=10.7Hz,2H),3.82(s,3H),2.96(s,3H).

[0787] Example 124:

[0788] 1 H NMR(500MHz,DMSO-d6)δ9.79(s,1H),7.90(br d,J=8.3Hz,2H),7.24(d,J=8.6Hz,2H),7.31(t,J=74.0Hz,1H),7.10-7.03(m,2H),6.97-6.89(m,3H),3.85(s,3H),3.82(s,3H),2.95(s,3H).

[0789] Example 125:

[0790] 1 H NMR (500MHz, DMSO-d6) δ9.78(s,1H),7.90(br d,J=7.9Hz,2H),7.24(br d,J=8.6Hz,2H),7.32(t,J=74.0Hz,1H),6.92(br d,J=10.6Hz,2H),6.87-6.76(m,3H),4.68(spt,J=5.7Hz,1H),3.82(s,3H),2.95(s,3H),1.30(d,J=5.9Hz,6H).

[0791] Example 126:

[0792] 1 H NMR(500MHz,DMSO-d6)δ9.91-9.76(m,1H),7.88(br d,J=7.5Hz,2H),7.57(s,1H),7.47(d,J=1.3Hz,1H),7.36(s,1H),7.24(d,J=8.3Hz,2H),7.30(t,J=74.0Hz,1H),6.92(br d,J=10.7Hz,2H),3.81(s,3H),3.00(s,3H),2.96(s,3H),2.95-2.92(m,3H).

[0793] Example 127:

[0794] 1 H NMR(500MHz,DMSO-d6)δ9.88-9.76(m,1H),7.88(br d,J=8.2Hz,2H),7.62(d,J=1.5Hz,1H),7.46(d,J=1.8Hz,2H),7.26-7.19(m,1H ), 7.25 (t, J = 74.0Hz, 2H), 6.91 (brd, J = 10.4Hz, 2H), 3.81 (s, 3H), 2.95 (s, 3H).

[0795] Example 128:

[0796] 1 H NMR (500MHz, DMSO-d6) δ9.85 (s, 1H), 9.05 (s, 1H), 8.92 (d, J = 1.7Hz, 1H), 8.25 (s, 1H), 7.89 (br d,J=8.3Hz,2H),7.24(d,J=8.6Hz,2H),7.29(t,J=74.0Hz,1H),6.93(br d,J=10.7Hz,2H),3.93(s,3H),3.82(s,3H),2.98(s,3H).

[0797] Example 129:

[0798] 1 H NMR(500MHz,DMSO-d6)δ9.79(s,1H),8.38-8.17(m,2H),7.89(br d,J=8.6Hz,2H),7.50-7.11(m,4H),6.97-6.84(m,2H),3.91(s,3H),3.81(s,3H),2.97(s,3H).

[0799] Example 130:

[0800] 1 H NMR (500MHz, DMSO-d6) δ9.84(s,1H),8.67-8.58(m,2H),8.01(s,1H),7.89(brd,J=8.1Hz,2H),7.24(d,J=8.6Hz,2H),7.31(t,J=74.0Hz,1H),6.93(br d,J=10.5Hz,2H),3.82(s,3H),2.99(s,3H).

[0801] Example 131:

[0802] 1H NMR (500MHz, DMSO-d6) δ9.84(s,1H),7.88(br d,J=5.2Hz,3H),7.77(s,1H),7.70(s,1H),7.24(br d,J=8.7Hz,2H),7.27(t,J=74.0Hz,1H),6.92(br d,J=10.3Hz,2H),3.81(s,3H),2.96(s,3H).

[0803] Example 132:

[0804] 1 H NMR(500MHz,DMSO-d6)δ9.75(s,1H),7.87(d,J=8.2Hz,2H),7.23(d,J=8.5Hz,2H), 7.26(t,J=74.0Hz,1H),6.99-6.71(m,5H),3.82(s,3H),3.80(s,3H),2.94(s,3H).

[0805] Example 133:

[0806] 1 H NMR (500MHz, DMSO-d6) δ9.83(s,1H),7.89(br d,J=8.2Hz,2H),7.83(s,1H),7.69(br d,J=8.6Hz,1H),7.58(br d,J=9.5Hz,1H),7.24(br d,J=8.7Hz,2H),7.29(t,J=74.0Hz,1H),6.93(br d,J=10.6Hz,2H),4.36(q,J=7.0Hz,2H),3.81(s,3H),2.96(s,3H),1.33(t,J=7.1Hz,3H).

[0807] Example 134:

[0808] 1 H NMR (500MHz, DMSO-d6) δ9.76 (s, 1H), 7.90 (br d, J = 8.5Hz, 2H), 7.32-7.19 (m, 5H), 7.32 (t, J = 74.0Hz, 1H), 6.93 (br d,J=10.4Hz,2H),3.83(s,3H),2.94(s,3H),2.41(s,3H).

[0809] Example 136:

[0810] 11H NMR (500 MHz, DMSO-d6) δ 9.68 (s, 1H), 7.94 (br dd, J = 19.0, 8.9 Hz, 3H), 7.24 (d, J = 8.6 Hz, 2H), 7.33 (t, J = 73.6 Hz, 1H), 6.99 - 6.82 (m, 3H), 3.82 (s, 3H), 3.13 (s, 6H), 2.98 (s, 3H).

[0811] Example 137:

[0812] 1 1H NMR (500 MHz, DMSO-d6) δ 9.67 (s, 1H), 7.99 - 7.87 (m, 3H), 7.24 (br d, J = 8.5 Hz, 2H), 7.33 (t, J = 73.9 Hz, 1H), 7.02 - 6.84 (m, 3H), 4.69 - 4.52 (m, 2H), 3.82 (s, 3H), 2.99 (s, 3H), 2.65 (br d, J = 10.7 Hz, 2H), 2.19 (br t, J = 10.1 Hz, 2H), 2.13 (s, 3H), 1.96 (br d, J = 7.6 Hz, 2H), 1.93 - 1.86 (m, 2H).

[0813] Example 138:

[0814] 1 1H NMR (500 MHz, DMSO-d6) δ 9.66 (s, 1H), 7.96 (d, J = 8.9 Hz, 1H), 7.91 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 8.5 Hz, 2H), 7.32 (t, J = 73.2 Hz, 1H), 6.90 (dd, J = 18.0, 11.9 Hz, 2H), 6.63 (d, J = 8.9 Hz, 1H), 5.79 (s, 1H), 4.01 - 3.88 (m, 4H), 3.82 (s, 3H), 2.96 (s, 3H), 1.46 (s, 3H).

[0815] Example 139:

[0816] 1 1H NMR (500 MHz, DMSO-d6) δ 9.67 (s, 1H), 7.92 (br dd, J = 8.7, 5.6 Hz, 3H), 7.27 - 7.21 (m, 2H), 7.34 (t, J = 76.0 Hz, 1H), 7.00 - 6.84 (m, 3H), 3.83 (s, 3H), 3.78 - 3.52 (m, 8H), 3.08 (s, 2H), 2.97 (s, 3H).

[0817] Example 140:

[0818] 1 H NMR(500MHz,DMSO-d6)δ9.66(s,1H),8.00-7.93(m,1H),7.89(br d,J=8.7Hz,2H),7.25-7.19(m,J=8.6Hz,2H),7.30(t,J=74.0Hz,1H),6.98-6.78(m,2H),6.62(d,J=8.8Hz,1H),4.53(br t,J=4.5Hz,1H),4.37-4.27(m,2H),3.91-3.82(m,2H),3.80(s,3H),3.71-3.60(m,1H),2.94(s,3H),1.11(d,J=6.1Hz,6H).

[0819] Example 141:

[0820] 1 H NMR (500MHz, DMSO-d6) δ9.74(s,1H),7.98(d,J=8.9Hz,1H),7.86(br d,J=8.2Hz,2H),7.53(br d,J=8.2Hz,2H),7.00-6.84(m,2H),6.64(d,J=8.5Hz,1H),4.55(brd,J=4.9Hz,1H),4.33(br s,2H),3.94-3.85(m,2H),3.83(s,3H),3.68(dt,J=12.2,6.1Hz,1H),2.97(s,3H),1.13(d,J=6.1Hz,6H).

[0821] Example 142:

[0822] 1 H NMR (500MHz, CD3CN) δ8.23(d,J=4.1Hz,1H),8.13(br s,1H),7.84(br d,J=7.7Hz,2H),7.66(d,J=8.3Hz,1H),7.48(dd,J=8.3,4.4Hz,1H),7.21(br d,J=8.5Hz,2H),6.77(d,J=10.2Hz,2H),6.87(t,J=79.0Hz,1H),3.87(s,3H),3.18(s,3H),2.93(s,6H).

[0823] Example 143:

[0824] 11H NMR (500 MHz, DMSO-d6) δ 9.68 (br s, 1H), 7.96 - 7.87 (m, 2H), 7.83 (d, J = 9.0 Hz, 1H), 7.32 (br s, 1H), 7.26 - 7.21 (m, J = 8.3 Hz, 2H), 7.02 (br d, J = 9.2 Hz, 1H), 6.91 (br s, 1H), 3.82 (s, 3H), 3.63 - 3.50 (m, 4H), 3.00 (s, 3H), 2.45 - 2.36 (m, 4H), 2.22 (s, 3H).

[0825] Example 144:

[0826] 1 1H NMR (500 MHz, DMSO-d6) δ 9.62 (s, 1H), 7.93 (br d, J = 8.5 Hz, 2H), 7.47 (d, J = 8.5 Hz, 1H), 7.24 (br d, J = 8.5 Hz, 2H), 7.33 (t, J = 73.6 Hz, 1H), 7.20 - 7.15 (m, 1H), 6.93 (brd, J = 12.2 Hz, 2H), 4.67 (s, 4H), 4.13 - 4.08 (m, 2H), 4.04 (br d, J = 8.5 Hz, 2H), 3.82 (s, 3H), 2.98 (s, 3H).

[0827] Example 145:

[0828] 1 1H NMR (500 MHz, DMSO-d6) δ 9.71 (br s, 1H), 8.00 - 7.88 (m, 3H), 7.49 - 7.24 (br d, J = 6.4 Hz, 1H), 7.19 (br s, 1H), 6.92 (br s, 2H), 6.79 (dd, J = 8.8, 3.5 Hz, 2H), 4.48 (br t, J = 11.9 Hz, 4H), 3.83 (s, 3H), 3.01 (s, 3H)

[0829] Example 146:

[0830] 1 1H NMR (500 MHz, CDCl3 + CD3OD) δ 7.77 (br d, J = 8.5 Hz, 2H), 7.64 (t, J = 8.3 Hz, 1H), 7.39 (dd, J = 8.7, 2.9 Hz, 1H), 7.06 (br d, J = 8.5 Hz, 2H), 6.56 - 6.47 (m, 2H), 6.52 (t, J = 73.2 Hz, 1H), 3.76 (s, 3H), 3.14 (s, 3H).

[0831] Example 147:

[0832] 1 H NMR(500MHz,DMSO-d6)δ9.68(s,1H),7.93(br d,J=8.5Hz,2H),7.79(d,J=9.2Hz,2H),7.49-7.19(s,1H),7.24(br d,J=8.5Hz,1H),6.92(br s,1H),6.82(d,J=9.2Hz,2H),3.84(s,3H),3.07(s,6H),3.02(s,3H)

[0833] Example 148:

[0834] 1 H NMR (500MHz, DMSO-d6) δ9.74 (s, 1H), 7.87 (br d, J = 8.2Hz, 2H), 7.44-7.08 (m, 6H), 6.89 (br d,J=10.7Hz,2H),5.47(s,1H),3.80(s,3H),2.95(s,3H),1.45(s,6H).

[0835] Example 150:

[0836] 1 ¹H NMR (500MHz, DMSO-d⁶) δ 9.72 (s, 1H), 8.00 (t, J = 7.9Hz, 1H), 7.93 (d, J = 8.5Hz, 2H), 7.72 (d, J = 8.2Hz, 1H), 7.68 (d, J = 7.9Hz, 1H), 7.26 (d, J = 8.5Hz, 2H), 7.35 (t, J = 74.8Hz, 1H), 6.95 (d, J = 10.4Hz, 2H), 3.92 (br t, J = 5.8Hz, 2H), 3.84 (s, 3H), 3.22 (s, 3H), 1.97–1.80 (m, 4H). The two protons of the piperidinone group were masked by the solvent peak.

[0837] Example 151:

[0838] 1H NMR (500MHz, CD3OD) δ8.47(d,J=5.2Hz,1H),7.97(br d,J=8.8Hz,2H),7.74(s,1H),7.38(br d,J=8.3Hz,2H),7.31(d,J=5.2Hz,1H),6.82(d,J=9.9Hz,2H),3.89(s,3H),3.32(s,3H),2.52(s,3H).

[0839] Example 152:

[0840] 1 H NMR(400MHz, CDCl3)8.46(d,J=5.3Hz,1H),8.11(d,J=1.8Hz,1H),7.81(d,J=8.8Hz,2 H),7.24(m,1H),7.14(d,J=8.8Hz,2H),6.77-6.29(m,3H),3.84(s,3H),3.31(s,3H).

[0841] Example 154:

[0842] 1 H NMR (500MHz, DMSO-d6) δ9.82(s,1H),8.95(br d,J=4.0Hz,1H),8.48(br d,J=7.9Hz,1H),7.94(br d,J=8.2Hz,2H),7.84-7.77(m,1H),7.43(br d,J=7.9Hz,2H),7.00-6.80(m,2H),3.81(s,3H),2.94(s,3H)

[0843] Example 155:

[0844] 1 H NMR (500MHz, DMSO-d6) δ9.86(s,1H),8.35-8.27(m,1H),8.27-8.21(m,1H),7.95(br d,J=8.2Hz,2H),7.86(br d,J=7.3Hz,1H),7.46(br d, J=8.2Hz, 2H), 6.94 (brd, J=10.4Hz, 2H), 3.83 (s, 3H), 3.23 (s, 3H).

[0845] Example 156:

[0846] 11H NMR (500 MHz, DMSO-d6) δ 9.75 (s, 1H), 8.33 - 8.27 (m, 1H), 8.27 - 8.20 (m, 1H), 7.90 (br d, J = 8.2 Hz, 2H), 7.85 (br d, J = 7.3 Hz, 1H), 7.32 (t, J = 73.6 Hz, 1H), 7.24 (br d, J = 8.5 Hz, 2H), 6.93 (br d, J = 10.7 Hz, 2H), 3.82 (s, 3H), 3.22 (s, 3H).

[0847] Example 157:

[0848] 1 1H NMR (500 MHz, DMSO-d6) δ 9.85 (s, 1H), 8.87 (d, J = 7.9 Hz, 1H), 8.15 (d, J = 8.2 Hz, 1H), 7.91 (br d, J = 8.5 Hz, 2H), 7.29 (t, J = 73.6 Hz 1H), 7.24 (br d, J = 8.5 Hz, 2H), 6.94 (br d, J = 10.7 Hz, 2H), 3.82 (s, 3H), 3.19 (s, 3H).

[0849] Example 158:

[0850] 1 1H NMR (500 MHz, DMSO-d6) δ 9.73 (s, 1H), 8.57 (dd, J = 4.6, 1.2 Hz, 1H), 7.97 (d, J = 7.9 Hz, 1H), 7.93 (br d, J = 8.2 Hz, 2H), 7.66 (dd, J = 8.2, 4.9 Hz, 1H), 7.33 (dt, J = 73.6, 14.3 Hz, 1H), 7.25 (d, J = 8.5 Hz, 2H), 6.94 (d, J = 10.7 Hz, 2H), 3.84 (s, 3H), 3.02 (s, 3H).

[0851] Example 159:

[0852] 1 1H NMR (500 MHz, CDCl3) δ 8.31 (d, J = 8.0 Hz, 1H), 7.83 (br d, J = 8.3 Hz, 2H), 7.71 (br s, 1H), 7.67 (d, J = 8.3 Hz, 1H), 7.16 (br d, J = 8.5 Hz, 2H), 6.60 (br d, J = 9.9 Hz, 2H), 6.57 (t, J = 73.2 Hz, 1H), 3.86 (s, 3H), 3.11 (s, 3H).

[0853] Example 160:

[0854] 1 H NMR (400MHz, CD3OD containing CDCl3) δ7.99 (d, J = 8.4Hz, 1H), 7.87 (br d,J=8.6Hz,2H),7.27(d,J=8.1Hz,1H),7.16(d,J=8.8Hz,2H),6.70(t,J=73.3Hz,1H),6.64(br s,2H),3.86(s,3H),3.16(s,3H),2.16-2.07(m,1H),1.15-0.97(m,4H).

[0855] Example 161:

[0856] 1 H NMR (400MHz, DMSO-d6) δ9.79(s,1H),8.35(d,J=8.1Hz,1H),7.92(d,J=8.8Hz,2H),7.59(d,J=8.1Hz,1H),7.34(t,J=7 3.5Hz,1H),7.24(d,J=8.8Hz,2H),6.98-6.93(m,2H),3.84(s,3H),3.11(s,3H),2.38-2.31(m,1H),1.24-1.05(m,4H).

[0857] Example 162:

[0858] 1 H NMR(500MHz, CDCl3)δ7.98(d,J=2.2Hz,1H),7.83(d,J=8.8Hz,2H),7.79-7.68(m,1H),7.19-7 .10(m,3H),6.63-6.58(m,2H),6.58(t,J=73.5Hz,1H),4.01(s,3H),3.86(s,3H),3.40(s,3H).

[0859] Example 163:

[0860] 1 H NMR (400MHz, CD3OD) δ7.93(s,3H),7.70(d,J=8.0Hz,1H),7.31(d,J=7.5Hz,1H),7.24-7.19(m, 2H),7.16-6.75(m,3H),3.88(s,3H),3.37(s,3H),2.91(q,J=7.5Hz,2H),1.37(t,J=7.6Hz,3H).

[0861] Example 164:

[0862] 1 H NMR (500MHz, CD3OD) δ8.62 (dd, J=4.6, 1.4Hz, 1H), 8.15 (dd, J=8.2, 1.4Hz, 1H), 7.79 (br d,J=7.7Hz,2H),7.59(dd,J=8.1,4.7Hz,1H),7.43(d,J=8.5Hz,2H),6.75(d,J=10.3Hz,2H),3.86(s,3H),3.16(s,3H).

[0863] Example 165:

[0864] 1 H NMR (500MHz, CD3OD) δ8.66 (dd, J=4.6, 1.3Hz, 1H), 8.31 (dd, J=8.1, 1.4Hz, 1H), 7.86 (br d,J=8.0Hz,2H),7.51(dd,J=8.1,4.7Hz,1H),7.18(d,J=8.6Hz,2H),7.04-6.67(m,3H),3.86(s,3H),3.15(s,3H).

[0865] Example 166:

[0866] 1 H NMR(500MHz,DMSO-d6)δ9.67(br s,1H),8.51(br d,J=3.7Hz,1H),8.03-7.84(m,3H),7.62-7.14(m,4H),7.01-6.84(m,2H),3.83(s,3H),2.97(s,3H),2.82-2.70(m,2H),1.21(br t,J=7.5Hz,3H).

[0867] Example 167:

[0868] 1 H NMR (500MHz, CD3OD) δ7.92(br d,J=7.9Hz,2H),7.80(t,J=7.8Hz,1H),7.60(d,J=7.9Hz,1H),7.32(br d,J=8.3Hz,2H),7.26(d,J=7.7Hz,2H),6.76(d,J=10.0Hz,2H),3.86(s,3H),3.30(br s,3H),2.20-2.10(m,1H),1.11-0.93(m,4H).

[0869] Example 168:

[0870] 1 H NMR (400MHz, CD3OD) δ8.08(t,J=8.0Hz,1H),7.92(d,J=8.6Hz,2H),7.76(d,J=7.8Hz,1H),7.55(t,J=72.8Hz,1H),7.22(d,J =8.7Hz,2H),7.00(d,J=8.1Hz,1H),7.03-6.98(m,1H),6.86-6.79(m,1H),6.96(t,J=73.5Hz,1H),3.89(s,3H),3.36(s,3H)

[0871] Example 169:

[0872] 1 H NMR (400MHz, CD3OD) δ8.09(t,J=8.0Hz,1H),7.97(d,J=8.7Hz,2H),7.81-7.31( m, 4H), 7.01 (d, J = 8.0Hz, 1H), 6.83 (d, J = 10.0Hz, 2H), 3.89 (s, 3H), 3.37 (s, 3H).

[0873] Example 170:

[0874] 1 H NMR (500MHz, CD3OD) δ8.79(br d,J=4.1Hz,1H),8.08(br d,J=8.2Hz,1H),7.96-7.85(m,3H),7.33(br d,J=8.2Hz,2H),6.77(br d,J=11.3Hz,2H),3.87(s,3H),3.11(s,3H).

[0875] Example 171:

[0876] 1 H NMR(500MHz,CD3OD)δ7.89(d,J=8.7Hz,2H),7.70(dd,J=7.8,1.6Hz,1H),7.66(dd,J=7.4,1.8 Hz,1H),7.63-7.54(m,2H),7.19(d,J=8.6Hz,2H),7.09-6.74(m,3H),3.85(s,3H),3.13(s,3H)

[0877] Example 172:

[0878] 1H NMR (500MHz, CD3OD) δ7.94(d,J=8.7Hz,2H),7.75-7.64(m,2H),7.64-7.55(m,2H),7.35(br d,J=8.3Hz,2H),6.78(br d,J=10.6Hz,2H),3.85(s,3H),3.14(s,3H).

[0879] Example 173:

[0880] 1 H NMR(500MHz,DMSO-d6)δ9.86(s,1H),8.05(d,J=7.6Hz,1H),7.97-7.84(m,3H),7.65(t,J=7.5Hz,1H),7.50(d,J=7.9Hz,1H),7.46-7.14(m,3H),6.92(br d,J=9.2Hz,2H),3.82(s,3H),2.94(s,3H).

[0881] Example 174:

[0882] 1 H NMR (500MHz, CD3OD) 8.01 δ 7.88 (m, 4H), 7.74-7.61 (m, 2H), 7.35 (br d, J = 8.2Hz, 2H), 6.80 (br d, J = 10.5Hz, 2H), 3.86 (s, 3H), 3.12 (s, 3H).

[0883] Example 175:

[0884] 1 H NMR (400MHz, CD3OD) δ7.91(br d,J=8.6Hz,2H),7.54(m,3H),7.21(d,J=8.8Hz,2H),7.14-6.74(m,3H),3.88(s,3H),3.14(s,3H).

[0885] Example 176:

[0886] 1 H NMR (500MHz, CD3OD) δ7.89(br d,J=8.6Hz,2H),7.76(d,J=2.1Hz,1H),7.71-7.66(m,1H),7.65-7.60(m,1H),7.19(br d,J=8.6Hz,2H),7.11-6.72(m,3H),3.85(s,3H),3.13(s,3H).

[0887] Example 177:

[0888] 1 H NMR(400MHz,CD3OD)δ7.92(br d,J=8.6Hz,2H),7.67-7.59(m,1H),7.42-7.36(m,2H),7.30-7.12(m,3H),6.9 6(d,J=9.0Hz,1H),6.84-6.76(m,2H),6.82(s,1H),3.88(s,3H),3.14(s,3H).

[0889] Example 178:

[0890] 1 H NMR (500MHz, CD3OD) δ 8.01-7.86 (m, 3H), 7.56-7.45 (m, 2H), 7.19 (d, J = 8.6Hz, 2H), 7.14-6.68 (m, 3H), 3.86 (s, 3H), 3.12 (s, 3H).

[0891] Example 179:

[0892] 1 H NMR(500MHz,CD3OD)δ8.15(d,J=8.0Hz,1H),8.08-7.99(m,2H),7.89(br d,J=8.6Hz,2H),7.20(d,J=8.7Hz,2H),7.11-6.76(m,3H),3.86(s,3H),3.12(s,3H).

[0893] Example 180:

[0894] 1 H NMR (500MHz, DMSO-d6)9.73(br s,1H),8.53-8.43(m,1H),7.91(br d,J=7.3Hz,2H),7.60(br d,J=4.4Hz,1H),7.51-7.12(m,3H),6.98-6.82(m,2H),3.89-3.76(m,3H),3.65(br s,3H),2.96(s,3H).

[0895] Example 182:

[0896] 1H NMR(500MHz,CD3OD)δ8.00-7.94(m,1H),7.92-7.83(m,2H),7.19(br d,J=8.3Hz,2H),7.11-6.90(m,2H),6.85-6.69(m,2H),3.96(s,3H),3.85(s,3H),3.22(s,3H).

[0897] Example 183:

[0898] 1 H NMR (500MHz, CD3OD) δ7.89 (t, J = 8.5 Hz, 3H), 7.40-7.16 (m, 4H), 7.13-6.72 (m, 3H), 3.96 (s, 3H), 3.86 (s, 3H), 3.13 (s, 3H).

[0899] Example 184:

[0900] 1 H NMR(500MHz,CD3OD)δ7.89(d,J=8.6Hz,2H),7.56-7.47(m,1H),7.38-7.30(m,1H),7.25-7 .22(m,1H),7.21-7.16(m,2H),7.09-6.74(m,3H),3.98(s,3H),3.85(s,3H),3.12(s,3H).

[0901] Example 185:

[0902] 1 H NMR(500MHz,CD3OD)δ7.96(d,J=8.8Hz,1H),7.89(d,J=8.7Hz,2H),7.20(s,2H) ,7.12-6.91(m,2H),6.85-6.68(m,2H),3.96(s,3H),3.85(s,3H),3.22(s,3H).

[0903] Example 186:

[0904] 1 H NMR (500MHz, methanol-d4) δ7.89 (br d,J=8.6Hz,2H),7.72(dd,J=9.0,5.3Hz,1H),7.53(dd,J=8.3,2.7Hz,1H),7.45- 7.36(m,1H),7.19(d,J=8.6Hz,2H),7.09-6.73(m,3H),3.85(s,3H),3.14(s,3H)

[0905] Example 187:

[0906] 1 H NMR(500MHz,CD3OD)δ7.89(br d,J=8.5Hz,2H),7.75-7.67(m,1H),7.57-7.49(m,1H),7.44-7.35(m,1H),7.19(d,J=8.6Hz,2H),7.12-6.75(m,3H),3.85(s,3H),3.14(s,3H).

[0907] Example 188:

[0908] 1 H NMR (500MHz, CD3OD) δ8.04 (dd, J=8.6, 5.6Hz, 1H), 7.89 (br d,J=8.5Hz,2H),7.54-7.42(m,2H),7.25-7.14(m,2H),7.11-6.76(m,3H),3.86(s,3H),3.13-3.12(m,3H).

[0909] Example 189:

[0910] 1 H NMR(500MHz,CD3OD)δ7.99-7.93(m,1H),7.91-7.85(m,3H),7.59(t,J=8.0H z, 1H), 7.20 (d, J = 8.7Hz, 2H), 7.12-6.76 (m, 3H), 3.86 (s, 3H), 3.13 (s, 3H).

[0911] Example 190:

[0912] 1 H NMR (500MHz, CD3OD) δ8.30(d,J=8.2Hz,1H),7.89(br d,J=8.7Hz,2H),7.69(d,J=8.2Hz,1H),7.19(br d,J=8.7Hz,2H),7.09-6.76(m,3H),3.87(s,3H),3.32(s,3H),1.43(s,9H).

[0913] Example 191:

[0914] 1H NMR (500MHz, CD3OD) δ8.81(d,J=5.3Hz,1H),7.92(s,2H),7.68(d,J=5.3Hz,1H),7.21(br d,J=8.8Hz,2H),7.11-6.79(m,3H),4.08-3.96(m,1H),3.89(s,3H),3.28(s,3H),2.65-2.56(m,2H),2.44-2.35(m,2H),2.28-2.17(m,2H).

[0915] Example 192:

[0916] 1 H NMR(500MHz,CD3OD)δ8.36-8.30(m,1H),7.90-7.86(m,2H),7.84-7.80(m,1H),7.19(s,2H),7.10-6.69( m,3H),3.86(s,3H),3.63(q,J=7.0Hz,2H),3.23(s,3H),1.45(brd,J=6.3Hz,4H),1.28(t,J=7.0Hz,3H).

[0917] Example 193:

[0918] 1 H NMR (500MHz, CD3OD) δ8.40(d,J=8.0Hz,1H),7.88(br d,J=8.5Hz,2H),7.72(d,J=8.1Hz,1H),7.18(br d,J=8.5Hz,2H),7.09-6.64(m,3H),4.69(s,2H),3.86(s,3H),3.53(s,3H),3.28(s,3H).

[0919] Example 194:

[0920] 1 H NMR (500MHz, CD3OD) δ8.52-8.39(m,1H),7.88(br d,J=8.6Hz,2H),7.84-7.77(m,1H),7.19(br d,J=8.4Hz,2H),7.09-6.75(m,3H),3.86(s,3H),3.30(s,3H),1.76(s,3H),1.72(s,3H).

[0921] Example 195:

[0922] 1H NMR (500MHz, CD3OD) δ8.43(d,J=8.2Hz,1H),7.93(d,J=8.2Hz,1H),7.87(brd,J=8.5Hz,2H),7.18(br d,J=8.4Hz,2H),7.10-6.72(m,3H),4.82(br d,J=8.4Hz,2H),3.85(s,3H),3.14(s,3H).

[0923] Example 196:

[0924] 1 H NMR(500MHz,CD3OD)δ8.43(d,J=8.2Hz,1H),7.90-7.86(m,3H),7.18(br d,J=8.6Hz,2H),7.10-6.73(m,3H),4.69(s,2H),3.85(s,3H),3.53(s,3H),3.14(s,3H).

[0925] Example 197:

[0926] 1 H NMR (500MHz, CDCl3) δ8.60(d,J=4.7Hz,1H),7.97(d,J=8.0Hz,1H),7.83(brd,J=8.0Hz,3H),7.41(ddd ,J=8.0,4.7,0.8Hz,1H),7.15(d,J=8.5Hz,2H),6.80-6.39(m,3H),3.85(s,3H),3.41(t,J=7.0Hz,3H).

[0927] Example 200:

[0928] 1 H NMR (500MHz, CDCl3) δ7.96 (d, J = 8.3Hz, 1H), 7.84 (br d,J=8.5Hz,2H),7.57(d,J=8.3Hz,1H),7.18-7.14(m,2H),6.47-6.46(m,1 H),6.76-6.40(m,2H),4.64(s,2H),3.85(s,3H),3.53(s,3H),3.07(s,3H).

[0929] Example 201:

[0930] 1H NMR(400MHz,CD3OD)δ8.75-8.68(m,1H),7.90(br d,J=8.8Hz,2H),7.57(dd,J=5.1,0.7Hz,1H),7.21(d,J=8.6Hz,2H),7.15-6.69(m,3H),3.88(s,3H),3.29(s,3H),2.72(s,3H).

[0931] Example 202:

[0932] 1 H NMR (500MHz, DMSO-d) 6, ws)δ9.82(s,1H),8.17(d,J=8.8Hz,1H),7.91(d,J=8.6Hz,2H),7.25(br d,J=8.5Hz,2H),7.26(t,J=73.4Hz,1H),7.10(d,J=9.0Hz,1H),6.94(d,J=10.6Hz,2H),3.83(s,3H),3.14(s,3H),2.54(s,3H).

[0933] Example 203:

[0934] 1 H NMR (500MHz, DMSO-d6) δ9.61(s,1H),7.90(d,J=8.5Hz,2H),7.46(d,J=8.5Hz,1H),7.23(d,J=8.5Hz,2H),7.18(d,J=8.9Hz, 1H), 7.31 (t, J = 73.2Hz, 1H), 6.90 (d, J = 10.4Hz, 2H), 3.80 (s, 3H), 3.90-3.65 (m, 4H), 2.96 (s, 3H), 1.76 (s, 1H), 1.41 (s, 3H).

[0935] Example 204:

[0936] 1 H NMR(500MHz,DMSO-d6)δ9.76(s,1H),8.23-8.08(m,1H),7.92(d,J=8.2Hz,3H),7.53(d,J= 7.6Hz,1H),7.27(d,J=8.5Hz,2H),7.35(t,J=73.5Hz,1H),6.96(d,J=10.4Hz,2H),4.47(br s,2H),3.85(s,3H),3.22(s,3H),2.89(s,6H).

[0937] Example 205:

[0938] 1 H NMR (500MHz, DMSO-d6) δ9.70(s,1H),7.98(t,J=8.0Hz,1H),7.91(d,J=8.5Hz,2H),7.76(d,J=8.0Hz,1H),7.39(d,J=7.6Hz,1H),7.25(d ,J=8.0Hz,2H),7.33(t,J=73.4Hz,1H),6.94(d,J=10.9Hz,2H),3.83(s,3H),3.65(s,2H),3.21(s,3H),2.49-2.32(m,8H),2.18(s,3H).

[0939] Example 206:

[0940] 1 H NMR (500MHz, DMSO-d6) δ9.68 (s, 1H), 7.91 (d, J = 8.6Hz, 2H), 7.73 (m, 1H), 7. 25(d,J=8.7Hz,2H),7.33(t,J=73.6Hz,1H),7.10(d,J=7.7Hz,1H),6.93(d,J =10.4Hz,2H),6.79(d,J=8.4Hz,1H),3.83(s,3H),3.63-3.45(m,4H),3.39-3 .29(m,2H),3.19(s,3H),3.06(s,3H),2.84-2.73(m,2H),2.62-2.57(m,4H).

[0941] Example 207:

[0942] 1 H NMR(500MHz,DMSO-d6)δ9.71(s,1H),7.91(br d,J=8.3Hz,2H),7.82(m,1H),7.26(d,J=8.8Hz,2H),7.53-7.16(m,2H),6.99-6.8 7(m,3H),3.83(s,3H),3.61-3.30(m,4H),3.20(s,3H),3.12-2.90(m,4H),2.57(br s,2H),1.17-1.02(m,1H),0.71-0.61(m,2H),0.43-0.33(m,2H).

[0943] Example 208:

[0944] 1H NMR (500MHz, DMSO-d6) δ9.67(s,1H),7.92(d,J=8.2Hz,2H),7.72(m,1H),7.25(d,J=8.5Hz,2H),7.34(t,J =72.3Hz,1H),7.10(d,J=7.6Hz,1H),6.94(d,J=10.1Hz,2H),6.77(d,J=8.2Hz,1H),3.83(s,3H),3.54(br s,4H),3.47(t,J=6.3Hz,2H),3.20(s,3H),2.50-2.45(m,4H),2.40(br t,J=7.2Hz,2H),1.92(s,1H),1.64(quin,J=6.7Hz,2H).

[0945] Example 209:

[0946] 1 H NMR (500MHz, DMSO-d6) δ9.61(s,1H),7.90(d,J=8.5Hz,2H),7.60(d,J=8.9Hz,1H),7.50(d,J=8.5Hz,1H),7.23(br d,J=8.5Hz,2H),7.32(t,J=74.5Hz,1H),6.90(m,2H),3.81(s,3H),2.99(s,3H),2.81(s,6H).

[0947] Example 210:

[0948] 1 H NMR (500MHz, DMSO-d6) δ9.66(s,1H),7.90(br d,J=8.2Hz,2H),7.74(m,1H),7.23(d,J=8.5Hz,2H),7.34(t,J=73.3Hz,1H),6.92(br d,J=10.7Hz,2H),6.56(m,1H),3.90(s,1H),3.82(s,3H),3.83(dd,J=26.3,8.0Hz,2H),3.79-3.78(m,1H),3.04(s,3H),1.44(s,3H).

[0949] Example 211:

[0950] 1H NMR(500MHz,DMSO-d6,ws)δ9.60(s,1H),7.96(d,J=4.0Hz,1H),7.92(d,J=8.2Hz,2H),7.37(m,1H),7.23(d,J=8.2 Hz,2H),7.32(t,J=73.8Hz,1H),7.09(d,J=8.2Hz,1H),6.90(d,J=10.4Hz,2H),3.89(s,1H),3.81(s,3H),3.76(br d,J=7.3Hz,1H),3.70-3.64(m,1H),2.94(s,3H),1.42(s,3H)

[0951] Example 212:

[0952] 1 H NMR (500MHz, DMSO-d6) δ9.67(s,1H),7.90(d,J=8.4Hz,2H),7.72(m,1H),7.24(d,J=8.4Hz,2H),7.30(t,J=73.5Hz,1H),7.08(d,J=7.6Hz,1H), 6.91(d,J=10.3Hz,2H),6.76(d,J=8.3Hz,1H),3.81(s,3H),3.72-3.61( m,6H),3.59-3.46(m,2H),3.25(s,3H),3.19(s,3H),2.61-2.56(m,4H).

[0953] Example 213:

[0954] 1 H NMR (500MHz, DMSO-d6) δ9.68(s,1H),7.91(d,J=8.5Hz,2H),7.77(m,1H),7.25(d,J=8.7Hz,2H),7.32(t,J=73.7Hz,1H),7.13(d,J=7. 7Hz,1H),6.93(d,J=10.3Hz,2H),6.84(d,J=8.5Hz,1H),3.82(s,3H),3.74-3.62(m,4H),3.27-3.20(m,4H),3.19(s,3H),2.91(s,3H).

[0955] Example 214:

[0956] 1H NMR (500MHz, DMSO-d6) δ9.66(s,1H),8.21(br s,1H),8.03(d,J=9.2Hz,1H),7.90(br d,J=8.2Hz,2H),7.22(br d,J=8.5Hz,2H),7.31(t,J=74.0Hz,1H),7.04(d,J=9.2Hz,1H),6.98-6.75(m,2H),4.13(s,2H),3.81(s,4H),2.97(s,3H).

[0957] Example 215:

[0958] 1 H NMR(500MHz,DMSO-d6)δ9.66(s,1H),7.90(br d,J=8.5Hz,2H),7.24(d,J=8.5Hz,2H),7.63-7.16(m,3H),6.91(d,J=10.7Hz ,2H),5.90(d,J=4.9Hz,1H),3.82(s,3H),2.98(s,3H),2.78(d,J=4.9Hz,3H).

[0959] Example 217:

[0960] 1 H NMR (500MHz, DMSO-d6, ws) δ9.80 (s, 1H), 8.01 (d, J = 8.5Hz, 1H), 7.93 (br d,J=8.5Hz,2H),7.75(d,J=8.5Hz,1H),7.25(d,J=8.9Hz,2H),7.33(t,J=73.8Hz,1H),6.93(m,2H),3.82(s,3H),3.01(s,3H),2.83(s,3H).

[0961] Example 218:

[0962] 1 H NMR(500MHz,DMSO-d6)δ9.65(s,1H),7.92(d,J=8.5Hz,2H),7.68(m,1H),7.25(d,J=8.9Hz,2H),7.34(t,J=74.8Hz,1H),7 .10(d,J=7.6Hz,1H),6.93(d,J=10.1Hz,2H),6.30(d,J=8.2Hz,1H),3.83(s,3H),3.70(s,4H),3.23(s,3H),1.31(s,6H).

[0963] Example 219:

[0964] 1 H NMR(500MHz,CD3OD)δ7.89(d,J=8.8Hz,2H),7.76(m,1H),7.20(d,J=8.5Hz,2H), 7.15(dd,J=9.2,2.3Hz,1H),6.93(t,J=73.5Hz,1H),6.81-6.75(m,2H),4.47(br d,J=12.1Hz,2H),3.86(s,3H),3.61(br d,J=10.5Hz,2H),3.25(s,3H),3.28-3.15(m,4H),2.96(s,3H).

[0965] Example 220:

[0966] 1 H NMR (500MHz, DMSO-d6) δ9.68 (s, 1H), 8.04 (d, J = 9.1Hz, 1H), 7.91 (br d,J=8.2Hz,2H),7.28-7.20(m,1H),7.33(t,J=74.0Hz,1H),7.09(d,J=9.0Hz,1H),7.28-7.02(m,1H),6.99-6.84(m,2H) ,4.27-4.12(m,2H),3.91(d,J=3.3Hz,2H),3.82(s,3H),3.59-3.37(m,1H),3.07-2.98(m,1H),2.97(s,3H),2.91(s,3H).

[0967] Example 221:

[0968] 1 H NMR(500MHz,DMSO-d6)δ9.65(s,1H),8.96(d,J=4.0Hz,1H),8.48(d,J=7.6Hz,1H),7.94(d,J=8.5 Hz,2H),7.81(dd,J=7.9,4.8Hz,1H),7.64(d,J=2.0Hz,1H),7.54(dd,J=8.5,1.9Hz,1H),7.27(br d,J=8.6Hz,2H),7.49-7.18(m,2H),3.90(s,3H),2.99(s,3H)

[0969] Example 222:

[0970] 1H NMR (500MHz, DMSO-d6) δ9.77(s,1H),8.54(d,J=8.4Hz,1H),7.96(d,J=8.2Hz,1H),7.91(d,J=8.4H z, 2H), 7.24 (d, J = 8.6Hz, 2H), 7.33 (t, J = 76.7Hz, 1H), 7.01-6.85 (m, 2H), 3.83 (s, 3H), 3.00 (s, 3H).

[0971] Example 223:

[0972] 1 H NMR (500MHz, DMSO-d6) δ9.68(s,1H),8.99(br d,J=3.7Hz,1H),8.51(br d,J=7.6Hz,1H),8.20(s,1H),8.05(s,1H),7.95(br d,J=8.5Hz,2H),7.87-7.74(m,2H),7.59(br d,J=8.9Hz,1H),7.26(br d,J=8.5Hz,2H),7.33(t,J=73.5Hz,1H),4.08(s,3H),3.02(s,3H)

[0973] Example 224:

[0974] 1 H NMR (500MHz, DMSO-d6, ws) δ9.80 (s, 1H), 8.52 (d, J = 5.0Hz, 1H), 7.90 (br d, J = 8.4Hz, 2H), 7.23 (br d,J=8.6Hz,2H),7.32(t,J=74.0Hz,1H),6.98-6.86(m,3H),3.82(s,3H),2.90(s,3H),2.44(br s,4H),2.22(s,3H).

[0975] Example 225:

[0976] 1H NMR (500MHz, DMSO-d6) δ9.68 (s, 1H), 7.92 (d, J = 8.5Hz, 2H), 7.87-7.78 (m, 1H), 7.74 (br s,1H),7.23(d,J=8.5Hz,2H),7.34(t,J=70.8Hz,1H),6.98-6.83(m,2H),6.76(d,J=8.7Hz, 1H), 4.83-4.68 (m, 1H), 3.82 (s, 3H), 3.57 (q, J = 5.3Hz, 2H), 3.48-3.36 (m, 2H), 2.97 (s, 3H).

[0977] Example 226:

[0978] 1 H NMR (500MHz, DMSO-d) 6, ws)δ9.64(s,1H),7.96-7.79(m,4H),7.46(d,J=6.4Hz,1H),7.31-7.19(m,3H) ,7.19-7.10(m,1H),7.05(m,1H),6.97-6.77(m,2H),3.81(s,3H),2.99(s,3H).

[0979] Example 227:

[0980] 1 H NMR(500MHz,DMSO-d6)δ9.65(s,1H),7.90(d,J=8.2Hz,2H),7.89-7.79(m,1H),7.64(q,J=4.4Hz,1H),7.23(d,J=8.5Hz,2H),7 .30(t,J=73.5Hz,1H),6.89(dd,J=19.1,11.7Hz,2H),6.69(d,J=8.9Hz,1H),3.81(s,3H),2.98(s,3H),2.84(d,J=4.9Hz,3H).

[0981] Example 228:

[0982] 1H NMR (500MHz, DMSO-d6) δ9.73 (s, 1H), 9.34-9.19 (m, 1H), 8.07-7.86 (m, 4H), 7.23 (d, J = 8.5Hz, 2H), 7.31 (t, J = 79.0Hz, 1H), 7.00 (br d,J=11.6Hz,2H),6.89(d,J=11.3Hz,1H),3.83(s,3H),3.77(s,3H),3.01(s,3H),2.18(br s,3H).

[0983] Example 229:

[0984] 1 H NMR(500MHz,DMSO-d6)δ9.63(s,1H),8.12-8.02(m,1H),7.94-7.85(m,3H),7.82(s,1H) ,7.22(d,J=8.5Hz,2H),7.29(t,J=76.9Hz,1H),6.94-6.75(m,3H),3.81(s,3H),3.60(br d, J=7.3Hz, 2H), 2.96 (s, 3H), 2.62 (td, J=7.2, 3.8Hz, 1H), 0.68-0.52 (m, 2H), 0.48-0.32 (m, 2H).

[0985] Example 230:

[0986] 1 H NMR (500MHz, acetonitrile-d3) δ8.17(br s,1H),7.92-7.79(m,3H),7.20(d,J=8.3Hz,2H),6.88(t,J=73.2Hz,1H),6.73-6.69(m,J=5.8,3.3Hz,1H),6.49-6.37(m, 2H),6.37-6.17(m,1H),5.48(s,1H),4.67-4.43(m,1H),3.80(s,3H),3.73-3.64(m,2H),3.55-3.39(m,2H),3.06(s,3H).

[0987] Example 231:

[0988] 1H NMR(500MHz,DMSO-d6,ws)δ9.68(s,1H),8.06(s,1H),7.92(d,J=7.9Hz,2H),7.23(d,J=8.5Hz,2H),7.33(t,J=7 3.9Hz,1H),6.96-6.86(m,3H),3.82(s,3H),2.96(brs,3H),1.92(s,1H),0.91-0.79(m,2H),0.74-0.66(m,2H).

[0989] Example 232:

[0990] 1 H NMR(500MHz,DMSO-d6)δ9.74-9.56(m,1H),8.02-7.78(m,4H),7.26-7.19(m,2H),7.30(t,J=74.2Hz,1 H),7.06-6.75(m,3H),4.53-4.17(m,1H),3.81(s,3H),3.01-2.87(m,3H),2.63-2.56(m,3H),1.34(br d,J=6.4Hz,3H).

[0991] Example 233:

[0992] 1 ¹H NMR (500MHz, acetonitrile-d³) δ 8.19–8.01 (m, 1H), 7.91–7.78 (m, 3H), 7.21 (d, J = 8.5 Hz, 2H), 6.87 (t, J = 74.8 Hz, 1H), 6.67 (d, J = 5.8 Hz, 1H), 6.49–6.38 (m, 2H), 6.01 (br s, 1H), 3.81 (s, 3H), 3.06 (s, 3H), 2.92 (d, J = 4.7 Hz, 3H).

[0993] Example 234:

[0994] 1 H NMR(500MHz, DMSO-d6)9.84(s,1H),δ8.59(d,J=8.9Hz,1H),8.00(d,J=8.8Hz,1H),7.92(d,J=8.5Hz,2H),7.76(s, 1H), 7.69 (s, 2H), 7.25 (d, J = 8.9Hz, 2H), 7.32 (t, J = 73.9Hz, 1H), 6.92 (d, J = 10.7Hz, 2H), 3.84 (s, 3H), 3.03 (s, 3H).

[0995] Example 235:

[0996] 1 H NMR (500MHz, DMSO-d6) δ9.65 (s, 1H), 7.90 (d, J = 8.4Hz, 2H), 7.86-7.79 (m, 1H), 7.79-7.69 (m, 1H), 7.22 (d, J = 8.4Hz, 2H), 7.47-7. 15(m,1H),6.95-6.83(m,2H),6.75(d,J=8.6Hz,1H),3.81(s,3H),3.63-3.57(m,2H),3.52-3.35(m,2H),3.27(s,3H),2.97(s,3H).

[0997] Example 236:

[0998] 1 H NMR(500MHz,DMSO-d6)δ9.68(s,1H),7.91(d,J=8.1Hz,2H),7.86-7.78(m,1H),7.76-7.63(m,1H),7.23(d,J=8.5Hz,2H),7.32(t,J=70.0Hz,1H ),6.99-6.84(m,2H),6.78(dd,J=8.2,4.2Hz,1H),4.87-4.76(m,1H),3. 88-3.76(m,4H),3.51-3.50(m,2H),2.96(s,3H),1.10(d,J=5.4Hz,3H).

[0999] Example 237:

[1000] 1 H NMR (500MHz, DMSO-d6) δ9.66(d,J=4.9Hz,1H),7.91(d,J=8.5Hz,2H),7.86-7.75(m,1H),7.56(m,1H),7.22(d,J=8.5Hz,2H),7.32(t,J=73. 2Hz,1H),6.96-6.84(m,2H),6.73(dd,J=8.9,4.3Hz,1H),3.90(s,4H),3.51-3.36(m,2H),2.96(s,3H),1.79(s,1H),1.14(t,J=7.2Hz,3H).

[1001] Example 238:

[1002] 1H NMR (500MHz, DMSO-d6) δ9.66 (s, 1H), 8.04-7.78 (m, 5H), 7.23 (d, J = 8.7Hz, 2H), 7.34 (t, J = 73.6 Hz,1H),7.01-6.73(m,3H),4.03-3.82(m,2H),3.81(s,3H),2.95(s,3H),2.60(d,J=4.5Hz,3H).

[1003] Example 239:

[1004] 1 H NMR (500MHz, DMSO-d6) δ9.65(s,1H),7.90(d,J=8.2Hz,2H),7.82(d,J=8.9Hz,1H),7.22(d,J=8.2Hz,2H),7.30(t,J=73.2Hz,1H),7.01( d,J=9.2Hz,1H),6.96-6.83(m,2H),3.81(s,3H),3.57-3.51(m,2H),3.49-3.42(m,2H),3.23(q,J=9.9Hz,2H),2.99(s,3H),2.71(s,4H)

[1005] Example 240:

[1006] 1 H NMR (500MHz, DMSO-d6) δ9.67(s,1H),7.91(br d,J=8.9Hz,2H),7.83(d,J=8.9Hz,1H),7.23(br d,J=8.2Hz,2H),7.32(t,J=73.8Hz,1H),7.02(d,J=9.2Hz,1H),6.91(br t,J=12.1Hz,2H),6.18(tt,J=55.8,4.3Hz,1H),3.81(s,3H),3.54(br s, 4H), 2.99 (s, 3H), 2.79 (td, J = 15.6, 4.1Hz, 2H), 2.63 (br t, J = 4.0Hz, 4H).

[1007] Example 242:

[1008] 1H NMR (500MHz, DMSO-d6) δ9.74 (s, 1H), 8.29 (d, J = 8.4Hz, 1H), 7.89 (br d,J=8.6Hz,2H),7.74(d,J=8.4Hz,1H),7.23(d,J=8.5Hz,2H),7.30(t,J=73.6Hz,1H),6.91(br s,2H),3.81(s,3H),2.99(s,3H).

[1009] Example 243:

[1010] 1 H NMR(500MHz,DMSO-d6)δ9.66(s,1H),7.90(d,J=8.2Hz,2H),7.79(d,J=7.9Hz,1H),7. 74-7.62(m,1H),7.22(d,J=8.5Hz,2H),7.31(t,J=77.8Hz,1H),6.93(m,1H),6.86(d, J=11.3Hz,1H),6.68(dd,J=17.4,8.9Hz,1H),3.80(s,3H),2.94(s,3H),1.37-1.24(m ,1H),1.21(d,J=6.4Hz,3H),1.03-0.82(m,1H),0.52-0.30(m,3H),0.26-0.07(m,1H).

[1011] Example 244:

[1012] 1 H NMR (500MHz, DMSO-d6) δ9.63(s,1H),7.92(d,J=8.6Hz,2H),7.67(d,J=8.7Hz,1H),7.24(d,J=8.4Hz,2H),7.34(t,J=72.5Hz,1H),7.00 -6.86(m,3H),3.82(s,3H),3.62-3.32(m,4H),3.00(s,3H),2.68-2.54(m,2H),2.46-2.36(m,4H),2.24(s,3H),1.13(t,J=7.4Hz,3H).

[1013] Example 245:

[1014] 1H NMR(500MHz,DMSO-d6)δ9.63(s,1H),8.68-8.62(m,1H),8.25(d,J=7.9Hz,1H),7.98(d,J=8.9Hz,2H),7.62(m,1H),7 .55(d,J=8.5Hz,2H),7.29(d,J=8.5Hz,2H),7.36(t,J=73.9Hz,1H),7.11(d,J=8.9Hz,2H),3.81(s,3H),2.99(s,3H).

[1015] Example 246:

[1016] 1 H NMR (500MHz, DMSO-d6) δ9.60(s,1H),8.97(d,J=3.7Hz,1H),8.49(d,J=8.2Hz,1H),7.97(d,J=8.5Hz,2H),7.81(t,J=6.1Hz,1H)),7.45(br d,J=8.2Hz,1H),7.40(s,1H),7.30-7.26(d,J=8.9Hz,3H),7.11(d,J=8.5Hz,1H),3.90(s,3H),3.00(s,3H),2.19(s,3H).

[1017] Example 247:

[1018] 1 H NMR(500MHz,DMSO-d6)δ9.66(s,1H),7.90(br d,J=8.5Hz,2H),7.87(d,J=8.9Hz,1H),7.22(d,J=8.5Hz,2H),7.30(t,J=7 2.9Hz,1H),7.07(d,J=9.2Hz,1H),6.96-6.84(m,2H),3.81(s,3H),3.67(br d,J=3.4Hz,4H),3.25-3.19(m,4H),3.00(s,3H),2.89(s,3H).

[1019] Example 248:

[1020] 1H NMR (500MHz, DMSO-d6) δ9.64(s,1H),7.91(d,J=8.5Hz,2H),7.86(d,J=8.9Hz,1H),7.67(d,J=8.9Hz,1H),7.23(d,J=8.5Hz, 2H), 7.33 (t, J = 73.6Hz, 1H), 6.91 (d, J = 10.7Hz, 2H), 4.20 (q, J = 6.8Hz, 2H), 3.81 (s, 3H), 2.95 (s, 3H), 1.31 (t, J = 7.0Hz, 3H).

[1021] Example 249:

[1022] 1 H NMR (500MHz, DMSO-d6) δ9.64(s,1H),8.97-8.83(m,1H),8.44(d,J=7.9Hz,1H),7.89(d,J=8.5Hz,1H),7.78(dd,J= 8.1,4.4Hz,1H),7.69-7.53(m,5H),7.22(d,J=8.5Hz,1H),7.29(t,J=73.5Hz,1H),2.98-2.88(m,3H),2.64(s,3H)

[1023] Example 250:

[1024] 1 H NMR(500MHz,DMSO-d6)δ9.65(s,1H),9.00(d,J=3.7Hz,1H),8.52(d,J=7.3Hz,1H),8.00(d,J=8.9Hz,2H),7.84(m,1H) ,7.58(d,J=8.5Hz,2H),7.31(d,J=8.9Hz,1H),7.53(t,J=73.5Hz,1H),7.15(d,J=8.9Hz,2H),3.02(s,3H),2.59(m,3H)

[1025] Example 251:

[1026] 1H NMR(500MHz,DMSO-d6)δ9.70(s,1H),8.12-7.94(m,2H),7.91(d,J=8.6Hz,2H),7.23(d,J=8.6Hz,2H ),7.33(t,J=73.7Hz,1H),7.00-6.81(m,3H),3.81(s,3H),3.00(s,3H),2.99-2.94(m,1H),0.78(br d,J=5.9Hz,2H),0.58-0.43(m,2H).

[1027] Example 252:

[1028] 1 H NMR (500MHz, DMSO-d6) δ9.67(s,1H),7.98-7.80(m,4H),7.23(d,J=8.5Hz,2H),7.32(t,J=69.9Hz,1H),6.95(d,J=11.6Hz ,1H),6.88(d,J=10.3Hz,2H),4.33-4.21(m,1H),4.11-3.97(m,1H),3.82(s,3H),3.04(s,3H),2.95(s,3H),2.85(s,3H).

[1029] Example 253:

[1030] 1 H NMR (500MHz, DMSO-d6) δ9.69 (s, 1H), 8.43 (d, J = 3.7Hz, 1H), 7.97-7.86 (m, 3H), 7.29-7.21 (m, 2H), 7.54-7.16 (m, 1H), 6.98 (d, J = 1 0.4Hz, 1H), 6.89 (d, J = 10.4Hz, 1H), 6.74 (d, J = 8.2Hz, 1H), 4.91-4.77 (m, 3H), 4.61-4.42 (m, 2H), 3.86-3.80 (m, 3H), 2.96 (s, 3H).

[1031] Example 254:

[1032] 1H NMR (500MHz, DMSO-d6) δ9.71-9.66(m,1H),8.02-7.82(m,4H),7.23(d,J=8.4Hz,2H),7.32(t,J=79.1Hz,1H),7.00-6.83(m,2H),6.74(d,J=8.9Hz,1H ),4.39-4.27(m,1H),3.97-3.84(m,2H),3.82(s,3H),3.78-3.70(m,1H),3 .62-3.53(m,1H),3.02-2.95(m,3H),2.26-2.17(m,1H),1.93-1.78(m,1H).

[1033] Example 255:

[1034] 1 H NMR(500MHz,DMSO-d6)δ9.66(br s,1H),7.99-7.80(m,4H),7.22(d,J=8.5Hz,2H),7.28(t,J=73.5Hz,1H),6.99-6.82(m,2H),6.73(d,J=8.8Hz,1H),4.36- 4.21(m,1H),3.95-3.82(m,2H),3.82-3.78(m,3H),3.69-3.65(m,2H),2.97(s,3H),2.30-2.15(m,1H),1.92-1.77(m,1H).

[1035] Example 256:

[1036] 1 H NMR (500MHz, DMSO-d6) δ9.67(s,1H),7.91(d,J=8.6Hz,2H),7.75(d,J=8.9Hz,1H),7.50-7.04(m,5H),6.99-6.91(m,1H),6.90-6.83(m,1H),6.75(br d,J=8.9Hz,1H),3.81(s,3H),3.00(s,3H),2.96(s,2H),1.31(s,6H).

[1037] Example 257:

[1038] 1H NMR(500MHz,DMSO-d6)δ9.69(s,1H),8.28(d,J=8.8Hz,1H),7.89(d,J=7.9Hz,2H),7.23(d,J=8.4Hz,2H), 7.18(d,J=8.8Hz,1H),7.26(t,J=76.3Hz,1H),6.97-6.82(m,2H),3.95(s,3H),3.81(s,3H),3.01(s,3H).

[1039] Example 260:

[1040] 1 H NMR (500MHz, DMSO-d6) δ9.62(s,1H),7.97(d,J=9.2Hz,1H),7.87(d,J=8.2Hz,3H),7.21(d,J=8.5Hz,2H),7.26(t,J=174.0Hz,1 H), 6.93-6.81 (m, 3H), 4.40-4.26 (m, 1H), 4.04 (d, J = 17.4Hz, 1H), 3.79 (s, 3H), 3.11 (s, 3H), 2.93 (s, 3H), 2.58 (d, J = 4.3Hz, 3H).

[1041] Example 261:

[1042] 1 H NMR(500MHz,DMSO-d6,ws)δ9.64(s,1H),7.89(d,J=8.5Hz,2H),7.21(d,J=8.5Hz,2H),7.2 7(m,2H),6.96-6.81(m,3H),3.80(s,3H),3.16(s,3H),2.92(s,2H),1.12(s,3H),1.08(br s,3H).

[1043] Example 262:

[1044] 1 H NMR(500MHz,DMSO-d6)δ9.60(s,1H),8.62(m,1H),8.21(dd,J=8.1,1.4Hz,1H),7.91(d,J=8.9Hz,2H),7.59(dd ,J=7.9,4.6Hz,1H),7.50-7.41(m,1H),7.30-7.04(m,4H),7.00(m,1H),6.92(m,1H),3.79(s,3H),2.95(s,3H).

[1045] Example 263:

[1046] 1 H NMR(500MHz,DMSO-d6)δ9.61(s,1H),8.94(d,J=3.6Hz,1H),8.46(d,J=7.3Hz,1H),7.90(d,J=8.7Hz,2H),7.79 (m,1H),7.45(m,1H),7.23(d,J=8.5Hz,2H),7.28(m,1H),7.00(m,1H),6.92(m,1H),3.79(s,3H),2.94(s,3H).

[1047] Example 264:

[1048] 1 H NMR(500MHz,DMSO-d6)δ9.65(s,1H),7.90(d,J=8.5Hz,2H),7.81(m,2H),7.22(d,J=8.5Hz,2H),7.31(t,J=78.7Hz,1H ),6.97-6.81(m,2H),6.72(d,J=8.9Hz,1H),3.81(s,3H),3.51-3.02(m,2H),2.95(s,3H),1.14-0.94(m,1H),0.45(br d,J=7.9Hz,2H),0.32-0.11(m,2H).

[1049] Example 265:

[1050] 1 H NMR(500MHz,DMSO-d6)δ9.66(s,1H),7.92(d,J=8.2Hz,2H),7.76(d,J=8.5Hz,1H),7.37(s,1H),7.23(d,J=8.2H z,2H),7.32(t,J=73.9Hz,1H),6.98-6.83(m,2H),6.70(d,J=8.9Hz,1H),3.82(s,3H),2.96(s,3H),1.40(s,9H).

[1051] Example 266:

[1052] 1H NMR (500MHz, DMSO-d6) δ9.70 (s, 1H), 8.22-8.06 (m, 1H), 8.04-7.95 (m, 1H), 7.93 (d, J = 8.5Hz, 2H), 7.24 (d, J = 8.5Hz, 2H),7.34(t,J=74.2Hz,1H),6.98-6.76(m,3H),3.83(s,3H),3.06-2.90(m,3H),1.37(s,3H),0.73(d,J=8.9Hz,4H).

[1053] Example 267:

[1054] 1 H NMR (500MHz, DMSO-d6) δ9.66(s,1H),8.02(d,J=8.8Hz,1H),7.91(d,J=8.2Hz,2H),7.24(d,J=8.5Hz,2H),7.32(t,J=81.8Hz,1H ),7.13(d,J=8.9Hz,1H),7.01-6.80(m,2H),3.82(s,3H),3.03(s,3H),2.76-2.66(m,2H),1.05-0.76(m,6H),0.66-0.48(m,2H).

[1055] Example 268:

[1056] 1 H NMR(500MHz,DMSO-d6)δ9.66(s,1H),8.04(d,J=9.2Hz,1H),7.90(d,J=8.5Hz,2H),7.23(d,J =8.2Hz,2H),7.47-7.08(m,2H),6.97-6.81(m,2H),3.81(s,3H),3.72-3.55(m,4H),3.24(br t,J=4.7Hz,4H),2.99(s,3H),2.90(s,3H).

[1057] Example 269:

[1058] 1H NMR (500MHz, DMSO-d6) δ9.66(s,1H),8.00(d,J=9.2Hz,1H),7.91(d,J=8.5Hz,2H),7.24(d,J=8.5Hz,2H),7.31(t,J=73.5Hz,1H),7.0 9(d,J=9.2Hz,1H),6.98-6.82(m,2H),3.82(s,3H),3.73-3.40(m,4H),3.26(q,J=10.1Hz,2H),2.98(s,3H),2.74(brt,J=4.4Hz,4H).

[1059] Example 270:

[1060] 1 H NMR (500MHz, DMSO-d6) δ9.64(s,1H),7.99(d,J=8.9Hz,1H),7.89(d,J=8.5Hz,2H),7.23(d,J=8.5Hz,2H),7.27(t,J=71.7Hz,1H),7.07(d,J=9.2Hz,1H) ,6.89(dd,J=19.7,11.7Hz,2H),6.16(t,J=56.5Hz,1H),3.81(s,3H),3.76- 3.62(m,4H),2.99(s,3H),2.81(td,J=15.7,4.3Hz,2H),2.68-2.60(m,4H).

[1061] Example 271:

[1062] 1 H NMR (500MHz, DMSO-d6) δ9.66 (s, 1H), 7.91 (d, J = 8.5Hz, 2H), 7.82 (d, J = 7.6Hz, 1H), 7.61-7.52 (m, 1H), 7.23 (d, J = 8.2Hz, 2H), 7. 30(t,J=73.9Hz,1H),6.99-6.77(m,3H),3.82(s,3H),3.64-3.44(m,2H),3.22-3.10(m,1H),2.95(s,3H),1.14(d,J=8.9Hz,6H).

[1063] Example 272:

[1064] 1H NMR(500MHz,DMSO-d6)δ9.67(s,1H),7.92(d,J=8.5Hz,2H),7.83(d,J=2.7Hz,1H),7.75-7.62(m,1H), 7.24(d,J=8.9Hz,2H),7.32(t,J=73.2Hz,1H),6.98-6.83(m,2H),6.78(dd,J=8.7,3.8Hz,1H),4.81(br d,J=4.3Hz,1H),3.82(s,3H),3.53-3.38(m,1H),3.18(d,J=5.2Hz,2H),2.97(s,3H),1.14-1.06(m,3H).

[1065] Example 273:

[1066] 1 H NMR (500MHz, DMSO-d6) δ9.65 (s, 1H), 7.90 (d, J = 8.5Hz, 2H), 7.86-7.77 (m, 1H) ,7.73-7.59(m,1H),7.23(d,J=8.5Hz,2H),7.29(t,J=73.5Hz,1H),6.98-6.81 (m,2H),6.78(dd,J=8.9,3.4Hz,1H),3.81(s,3H),3.65-3.49(m,1H),3.32-3. 15(m,1H),3.15-3.05(m,1H),2.97(s,3H),1.92(s,1H),1.10(t,J=5.0Hz,3H).

[1067] Example 274:

[1068] 1 H NMR (500MHz, DMSO-d6) δ9.63 (s, 1H), 7.94-7.78 (m, 4H), 7.22 (d, J = 8.2Hz, 2H), 7.27 (t, J = 69.6Hz, 1H), 6.93-6.76 (m, 3H), 4.21 (br d,J=2.4Hz,1H),3.81(s,3H),3.74-3.58(m,1H),3.54-3.14(m,1H),2.98(br d,J=7.6Hz,3H),1.92(s,1H).

[1069] Example 275:

[1070] 1H NMR (500MHz, DMSO-d6) δ9.66(br s,1H),8.42(d,J=8.3Hz,1H),7.98(d,J=8.2Hz,1H),7.88(d,J=8.0Hz,2H),7.21(br d,J=8.4Hz,2H),7.26(t,J=73.3Hz,1H),6.96-6.80(m,2H),5.79-5.68(m,1H),3.80(s,3H),2.96(s,3H),1.47(s,6H).

[1071] Example 276:

[1072] 1 H NMR (500MHz, DMSO-d6) δ9.66(s,1H),8.15(d,J=8.5Hz,1H),7.88(d,J=8.2Hz,2H),7.79(d,J=8.5Hz,1H),7.22( d,J=8.5Hz,2H),7.26(t,J=73.6Hz,1H),6.94-6.83(m,2H),5.62(s,1H),3.80(s,3H),2.98(s,3H),1.45(s,6H).

[1073] Example 277:

[1074] 1 H NMR (500MHz, DMSO-d6) δ9.61(s,1H),8.95(d,J=4.6Hz,1H),8.47(d,J=8.0Hz,1H),7.94(br d,J=8.5Hz,2H),7.79(dd,J=7.6,5.1Hz,1H),7.45(br d,J=8.2Hz,2H),7.24(br dd,J=14.1,8.4Hz,5H),2.96(s,3H),2.54(s,3H),2.02-1.89(m,1H),0.99(brdd,J=8.3,2.0Hz,2H),0.78-0.66(m,2H)

[1075] Example 278:

[1076] 1H NMR (500MHz, CD3OD) δ7.95-7.84(m,3H),7.21(d,J=8.5Hz,2H),6.89(d,J=9.9Hz,2H),6.97(t,J=74.0Hz,1H),6. 85-6.79(m,1H),4.37-4.19(m,2H),3.89(s,3H),3.84-3.72(m,1H),3.67-3.60(m,1H),3.37(s,3H),3.27(s,3H).

[1077] Example 279:

[1078] 1 H NMR(500MHz,DMSO-d6)δ9.66(s,1H),7.91(d,J=8.2Hz,2H),7.81(d,J=0.9Hz,1H),7.46(s,1H), 7.34-7.12(m,4H),7.07-6.78(m,4H),3.82(s,3H),3.60-3.41(m,2H),2.95(s,3H),1.13(s,6H).

[1079] Example 280:

[1080] 1 H NMR(500MHz,DMSO-d6)δ9.66(br s,1H),7.99-7.84(m,3H),7.24(d,J=8.2Hz,2H),7.31(t,J=74.2Hz,1H),6.97-6.83(m,2H),6.72(d,J=8.2Hz ,1H),5.32-5.02(m,1H),4.52-4.32(m,1H),3.82(s,3H),3.59-3.41(m,4H),2.99(s,3H),2.19-1.84(m,2H).

[1081] Example 281:

[1082] 1 H NMR(500MHz,DMSO-d6)δ9.68(s,1H),8.98(d,J=4.3Hz,1H),8.50(d,J=8.2Hz,1H),7.9 6(d,J=8.5Hz,2H),7.83(m,1H),7.67(d,J=8.5Hz,2H),7.53-7.14(m,6H),3.00(s,3H)

[1083] Example 282:

[1084] 1H NMR(500MHz,DMSO-d6)δ9.66(br s,1H),8.00-7.85(m,3H),7.23(d,J=8.5Hz,2H),7.32(t,J=74.1Hz,1H),6.98-6.84(m,2H),6.74-6.59( m,1H),5.07-4.82(m,1H),3.82(s,3H),3.62-3.38(m,4H),2.98(s,3H),2.03-1.85(m,2H),1.37(s,3H).

[1085] Example 283:

[1086] 1 H NMR(500MHz,DMSO-d6)δ9.69(s,1H),8.00-7.75(m,3H),7.24(d,J=5.8Hz,2H),7.34(t,J=71.1Hz,1H),7.09(d,J=38.1Hz,1H),6.95(d,J=11.6Hz ,1H),6.89(d,J=11.6Hz,1H),6.83(d,J=9.2Hz,1H),4.34-4.04(m,2H),3 .83(s,3H),2.99-2.86(m,3H),0.98(t,J=7.2Hz,1H),0.68-0.51(m,4H).

[1087] Example 284:

[1088] 1 H NMR(500MHz,DMSO-d6)δ9.66(br s,1H),8.00-7.85(m,3H),7.23(d,J=8.5Hz,2H),7.32(t,J=74.1Hz,1H),6.98-6.84(m,2H),6.74-6.59( m,1H),5.07-4.82(m,1H),3.82(s,3H),3.62-3.38(m,4H),2.98(s,3H),2.03-1.85(m,2H),1.37(s,3H).

[1089] Example 285:

[1090] 1H NMR(500MHz,DMSO-d6)δ9.73(s,1H),8.30(d,J=8.9Hz,1H),7.93(d,J=8.5Hz,2H),7.25(d,J=8.5Hz,2H),7.34(t,J=73.9Hz,1H), 7.19(d,J=7.6Hz,1H),7.03-6.82(m,2H),4.46-4.31(m,2H),3.84(s,3H),3.78(q,J=4.9Hz,2H),3.49-3.39(m,1H),3.01(s,3H).

[1091] Example 286:

[1092] 1 H NMR(500MHz,DMSO-d6)δ9.89-9.76(m,1H),7.92(d,J=8.5Hz,2H),7.87(d,J=9.8Hz,1H),7.24(d,J=8.6Hz,2H),7.3 3(t,J=75.2Hz,1H),6.97-6.90(m,2H),6.82(d,J=9.8Hz,1H),3.82(s,3H),3.81-3.62(m,2H),3.05(s,3H),1.23(br t,J=6.9Hz,3H).

[1093] Example 287:

[1094] 1 H NMR(500MHz,DMSO-d6)δ9.82(s,1H),7.94(d,J=8.9Hz,2H),7.89(d,J=10.1Hz,1H),7.26(d,J=7.9Hz,2H),7.35(t,J=80.0Hz,1H), 6.95(d,J=10.7Hz,2H),6.85(d,J=9.5Hz,1H),3.84(s,3H),4.04-3.69(m,2H),3.08(s,3H),1.33-1.14(m,1H),0.56-0.28(m,4H).

[1095] Example 288:

[1096] 1H NMR(500MHz,DMSO-d6)δ9.72(s,1H),8.30(d,J=8.9Hz,1H),7.92(d,J=8.2Hz,2H),7.25(d,J=8.2Hz,2H), 7.20(d,J=8.5Hz,1H),7.31(t,J=73.9Hz,1H),7.04-6.78(m,2H),4.28-4.02(m,2H),3.83(s,3H),3.53(br s,1H),3.00(s,3H),1.22(s,6H).

[1097] Example 289:

[1098] 1 H NMR (500MHz, CD3OD) δ8.31(d,J=8.8Hz,1H),7.89(d,J=8.8Hz,2H),7.28(d,J=8.8Hz,1H),7.21(d,J=8.5Hz, 2H),7.00(t,J=74.8Hz,1H),6.86-6.76(m,2H),5.17(d,J=16.0Hz,2H),3.88(s,3H),3.79(s,3H),3.13(s,3H

[1099] Example 290:

[1100] 1 H NMR(500MHz,DMSO-d6)δ9.65(s,1H),7.90(d,J=8.4Hz,2H),7.84-7.73(m,1H),7.63-7.55(m,1H),7.22(d,J=8.5Hz,2H),7.31(t,J=50.8Hz,1H),6 .96-6.80(m,2H),6.77(d,J=8.8Hz,1H),4.80-4.53(m,1H),3.80(s,3H), 3.39(d,J=4.0Hz,2H),3.30-3.12(m,2H),2.94(s,3H),1.88-1.67(m,6H).

[1101] Example 291:

[1102] 1H NMR (500MHz, DMSO-d6) δ9.77(s,1H),8.47(d,J=8.2Hz,1H),7.88(d,J=7.9Hz,2H),7.84(d,J=7.9Hz,1H),7.22( d,J=8.2Hz,2H),7.27(t,J=73.2Hz,1H),6.92(d,J=10.7Hz,2H),3.81(s,3H),3.14(s,3H),2.97(s,1H),1.47(br s,6H).

[1103] Example 292:

[1104] 1 H NMR (500MHz, DMSO-d6) δ9.65 (s, 1H), 7.96-7.87 (m, 3H), 7.24 (d, J = 8.5Hz, 2H),7.31(t,J=73.5Hz,1H),6.90(m,2H),6.71(d,J=8.9Hz,1H),4.91-4.83 (m,1H),3.82(s,3H),3.61-3.49(m,2H),3.48-3.39(m,2H),3.29-3.15(m, 2H),2.99(s,3H),2.50-2.38(m,1H),2.14-2.00(m,1H),1.87-1.72(m,1H).

[1105] Example 293:

[1106] 1 H NMR (500MHz, DMSO-d6) δ9.67 (s, 1H), 8.97 (d, J = 4.0Hz, 1H), 8.50 (d, J = 7.6Hz, 1H), 7.96 (d, J = 8.5Hz, 2H),7.83(m,1H),7.50-7.40(m,2H),7.39-7.34(m,1H),7.32-7.14(m,3H),3.90(s,3H),3.02(s,3H).

[1107] Example 294:

[1108] 1 H NMR(500MHz,DMSO-d6)δ9.66(s,1H),8.65(d,J=4.0Hz,1H),8.24(d,J=7.3Hz,1H) ,7.97(d,J=8.9Hz,2H),7.62(m,1H),7.50-7.04(m,6H),3.89(s,3H),3.01(s,3H).

[1109] Example 295:

[1110] 1 H NMR (500MHz, DMSO-d6) δ9.64(s,1H),8.51(d,J=8.4Hz,1H),7.96-7.87(m,3H),7.46(m,1H),7.24(d,J=8.4Hz,2H),7.30(t,J=73.8Hz,1H),7.02(br d,J=12.5Hz,1H),6.93(br d,J=8.5Hz,1H),3.80(s,3H),2.98(s,3H).

[1111] Example 296:

[1112] 1 ¹H NMR (500MHz, DMSO-d⁶) shifts: 8.26 (d, J = 8.5 Hz, 1H), 8.07 (d, J = 8.5 Hz, 1H), 7.90 (d, J = 8.2 Hz, 2H), 7.70 (d, J = 8.2 Hz, 1H), 7.22 (d, J = 8.2 Hz, 2H), 7.30 (t, J = 73.7 Hz, 1H), 6.40–6.14 (m, 2H), 3.70 (s, 3H), 2.95 (s, 3H)

[1113] Example 297:

[1114] 1 H NMR (500MHz, DMSO-d6) δ9.72(s,1H),8.58(d,J=8.5Hz,1H),8.43(d,J=8.9Hz,1H),7.92(d,J=7.3Hz,2H),7.25(d,J=8.5Hz,2H) ,7.34(t,J=72.6Hz,1H),7.01-6.86(m,2H),4.10-3.93(m,2H),3.84(s,3H),3.03(s,3H),2.76-2.60(m,2H),2.17-2.01(m,2H).

[1115] Example 298:

[1116] 1H NMR (500MHz, DMSO-d6) δ9.70(s,1H),8.43(s,1H),8.06(d,J=8.8Hz,1H),7.91(d,J=7.9Hz,2H),7.23(d,J=8.2Hz,1H),7. 32(t,J=73.8Hz,1H),7.06(d,J=8.5Hz,1H),6.99-6.83(m,2H),4.13-3.98(m,2H),3.81(s,3H),3.00(s,3H),1.20(s,6H).

[1117] Example 299:

[1118] 1 H NMR (500MHz, DMSO-d6) δ9.66 (s, 1H), 7.90 (d, J = 8.2Hz, 2H), 7.77 (m, 1H), 7.28-7 .25(m,1H),7.22(d,J=8.5Hz,2H),7.31(t,J=73.8Hz,1H),7.18-7.14(m,1H),7. 05(s,1H),6.95-6.82(m,2H),6.51(d,J=8.8Hz,1H),4.00(t,J=7.1Hz,1H),3.97 (s,1H),3.92(s,1H),3.81(s,3H),2.97(s,3H),2.49-2.43(m,2H),2.02(m,2H).

[1119] Example 300:

[1120] 1 H NMR (500MHz, DMSO-d6) δ9.64 (s, 1H), 8.44-8.19 (m, 1H), 7.89 (d, J = 8.5Hz, 2H), 7.78 (d, J = 8.5Hz, 1H), 7.22 (d, J = 8.2Hz, 2H), 7.28 (t, J = 73. 6Hz,1H),6.88(s,2H),6.56(d,J=8.9Hz,1H),4.59(m,1H),4.20(m,2H),3.80(s,3H),3.76-3.68(m,2H),2.98(s,3H),2.91(d,J=4.9Hz,1H).

[1121] Example 301:

[1122] 1H NMR (500MHz, DMSO-d6) δ9.75 (s, 1H), 9.02-8.92 (m, 1H), 8.50 (d, J = 7.3Hz, 1H), 8.08-7.77 (m, 7H), 7.26 (br d,J=8.5Hz,2H),7.29(t,J=73.2Hz,1H),3.00(br s,3H)

[1123] Example 302:

[1124] 1 H NMR(500MHz,DMSO-d6)δ9.70(br s,1H),8.17-8.07(m,1H),7.92(d,J=8.5Hz,2H),7.25(d,J=8.5Hz,2H),7.32(t,J=61.3Hz,1H),7.05-6.84(m,3 H),5.13-4.96(m,1H),3.83(s,3H),3.77-3.65(m,1H),3.53-3.36(m,1H),3.03-2.94(m,3H),2.29-2.04(m,4H).

[1125] Example 303:

[1126] 1 H NMR(500MHz,DMSO-d6)δ9.67(s,1H),7.96(d,J=9.2Hz,1H),7.93(d,J=8.5Hz,2 H),7.57(s,1H),7.24(d,J=8.2Hz,2H),7.33(t,J=73.5Hz,1H),7.01(s,1H),6. 98-6.84(m,2H),6.73(d,J=8.5Hz,1H),3.91(s,1H),3.83(s,3H),3.57-3.38(m ,2H),3.19(d,J=4.6Hz,1H),3.14-3.05(m,1H),3.00(s,3H),2.28-2.04(m,2H).

[1127] Example 304:

[1128] 1H NMR (500MHz, DMSO-d6) δ9.71(s,1H),8.98(d,J=4.0Hz,1H),8.50(d,J=7.6Hz,1H),7.95(d,J=8.5Hz,2H),7.83(m,1H),7.74(br d,J=8.9Hz,2H),7.57(d,J=8.2Hz,2H),7.27(br d,J=8.2Hz,2H),7.32(t,J=73.2Hz,1H),3.00(s,3H)

[1129] Example 305:

[1130] 1 H NMR(500MHz,DMSO-d6)δ9.67(s,1H),7.96(d,J=9.2Hz,1H),7.93(d,J=8.5Hz,2 H),7.57(s,1H),7.24(d,J=8.2Hz,2H),7.33(t,J=73.5Hz,1H),7.01(s,1H),6. 98-6.84(m,2H),6.73(d,J=8.5Hz,1H),3.91(s,1H),3.83(s,3H),3.57-3.38(m ,2H),3.19(d,J=4.6Hz,1H),3.14-3.05(m,1H),3.00(s,3H),2.28-2.04(m,2H).

[1131] Example 306:

[1132] 1 H NMR (500MHz, DMSO-d6) δ9.65(s,1H),7.97(d,J=9.0Hz,1H),7.90(d,J=8.2Hz,2H),7.22(d,J =8.5Hz,2H),7.29(t,J=77.0Hz,1H),7.09(d,J=9.0Hz,1H),6.99-6.81(m,2H),4.56-4.45(m ,1H),4.40-4.23(m,1H),3.81(s,3H),3.12-2.99(m,2H),2.97(s,3H),2.78-2.60(m,1H),2. 21-2.06(m,2H),2.03-1.94(m,1H),1.89-1.80(m,1H),1.80-1.62(m,2H),1.46-1.33(m,1H)

[1133] Example 307:

[1134] 1H NMR(500MHz,DMSO-d6)δ9.65(s,1H),7.90(d,J=8.2Hz,2H),7.79(d,J=8.9Hz,1H),7.22(d ,J=8.2Hz,2H),7.30(t,J=73.5Hz,1H),6.96-6.83(m,2H),6.57(d,J=8.9Hz,1H),5.72(br s,1H),3.91-3.81(m,4H),3.80(s,3H),2.98(s,3H),1.44(s,3H).

[1135] Example 308:

[1136] 1 H NMR(500MHz,DMSO-d6)δ9.66(s,1H),7.94(d,J=8.9Hz,1H),7.91(d,J=8.2Hz,2H),7.23(d,J=8.5Hz,2H), 7.27(t,J=73.5Hz,1H),6.96-6.82(m,2H),6.57(d,J=8.9Hz,1H),4.09-3.99(m,4H),3.82(s,3H),3.32(br t, J=6.9Hz, 1H), 2.96 (s, 3H), 2.05 (br dd, J=11.4, 7.8Hz, 4H).

[1137] Example 309:

[1138] 1 H NMR (500MHz, DMSO-d6) δ9.66(s,1H),7.93(d,J=7.9Hz,2H),7.86(d,J=8.5Hz,1H),7.25(d,J=8.5Hz,2H),7.33(t,J=77.5Hz,1H ),7.01-6.85(m,3H),4.13-3.94(m,2H),3.83(s,3H),3.53-3.30(m,1H),3.01(s,3H),2.73-2.56(m,2H),1.21(s,6H),1.17(br t,J=7.5Hz,3H).

[1139] Example 310:

[1140] 1H NMR (500MHz, DMSO-d6) δ9.61(s,1H),7.92(d,J=8.0Hz,2H),7.64(d,J=8.5Hz,1H),7.23(d,J=8.4Hz,2H),7.33(t,J=73.2Hz,1H),7. 03-6.83(m,2H),6.54(d,J=8.5Hz,1H),5.71-5.51(m,1H),4.02-3.69(m,7H),3.45-3.42(m,2H),2.99(s,3H),1.45(s,3H),1.11(br t,J=7.3Hz,3H).

[1141] Example 311:

[1142] 1 H NMR(500MHz,DMSO-d6)δ9.63(s,1H),7.88(d,J=8.2Hz,2H),7.67(m,1H),7.23(d,J=8.5Hz,2H),7.29(t,J=73.4Hz,1H),7.0 7(d,J=7.3Hz,1H),6.90(d,J=10.4Hz,2H),6.33(d,J=8.2Hz,1H),3.89-3.81(m,4H),3.81(s,3H),3.20(s,3H),1.44(s,3H).

[1143] Example 312:

[1144] 1 H NMR(500MHz,DMSO-d6)δ9.63(s,1H),7.88(d,J=8.2Hz,2H),7.67(m,1H),7.23(d,J=8.5Hz,2H),7.29(t,J=73.4Hz,1H),7.0 7(d,J=7.3Hz,1H),6.90(d,J=10.4Hz,2H),6.33(d,J=8.2Hz,1H),3.89-3.81(m,4H),3.81(s,3H),3.20(s,3H),1.44(s,3H)

[1145] Example 313:

[1146] 1H NMR(500MHz,DMSO-d6,ws)δ9.56(s,1H),7.95-7.89(m,3H),7.43(m,1H),7.24(d,J=8.2Hz,2H),7.33(t,J=73.8Hz, 1H),7.08-6.99(m,2H),6.93(m,1H),4.05-3.94(m,1H),3.80(s,3H),2.97(s,3H),1.59-1.43(m,4H),1.16(s,3H).

[1147] Example 314:

[1148] 1 H NMR (500MHz, DMSO-d6) δ9.64(s,1H),7.96-7.85(m,3H),7.22(d,J=8.7Hz,2H),7.30(t,J=73.6Hz,1H),7.05(d,J=9.0Hz,1H),6.92(d,J= 10.2Hz,1H),6.87(d,J=11.7Hz,1H),4.03-3.93(m,1H),3.80(s,3H),3.16(d,J=5.1Hz,4H),2.96(s,3H),1.59-1.43(m,4H),1.15(s,3H).

[1149] Example 315:

[1150] 1 H NMR (500MHz, DMSO-d6) δ9.70 (s, 1H), 7.98 (d, J = 8.5Hz, 2H), 7.91 (m, 1H), 7.72 (br d,J=8.5Hz,2H),7.55(d,J=7.6Hz,1H),7.30(d,J=8.5Hz,2H),7.52-7.19(m,4H),6.78(d,J=7.9Hz,1H),3.99(s,3H),3.26(s,3H)

[1151] Example 316:

[1152] 1H NMR (500MHz, DMSO-d6) δ9.69(s,1H),8.15(d,J=8.2Hz,1H),7.90(d,J=8.2Hz,2H),7.54(d,J=8.2Hz,1H),7.23(d,J=8.5Hz,2H),7.31(t,J=73.5Hz, 1H),6.99-6.84(m,2H),3.81(s,3H),3.67(d,J=12.2Hz,2H),2.99(s,3H), 2.89(s,3H),2.99-2.81(m,3H),2.02(d,J=12.2Hz,2H),1.83-1.68(m,2H)

[1153] Example 317:

[1154] 1 H NMR (500MHz, DMSO-d6) δ8.04(s,1H),8.00(d,J=8.9Hz,2H),7.74(d,J=8.2Hz,1H),7.63(d,J=8.9Hz,2H),7.31(d,J=8 .2Hz, 2H), 7.35 (d, J = 8.2Hz, 2H), 7.40 (t, J = 73.5Hz, 1H), 7.30 (t, J = 73.6Hz, 1H), 6.72 (d, J = 7.9Hz, 1H), 3.79 (s, 3H).

[1155] Example 320:

[1156] 1 H NMR(400MHz,DMSO-d6)δ=9.68(br s,1H),7.91(d,J=8.8Hz,2H),7.34(t,J=76.0Hz,1H),7.26-7.23(m,3H),6.93(d,J=10.3Hz,2H),6.85(d,J=1.8Hz,1H),5.26-5.05 (m,1H),3.97-3.89(m,1H),3.89-3.82(m,5H),3.82-3.73(m,1H),3.21(s,3H),2.48(s,3H),2.35-2.19(m,1H),2.07-1.96(m,1H).

[1157] Example 321:

[1158] 1H NMR(400MHz,DMSO-d6)δ=9.68(br s,1H),7.91(d,J=8.8Hz,2H),7.34(t,J=76.0Hz,1H),7.26-7.23(m,3H),6.93(d,J=10.3Hz,2H),6.85(d,J=1.8Hz,1H),5.26-5.05 (m,1H),3.97-3.89(m,1H),3.89-3.82(m,5H),3.82-3.73(m,1H),3.21(s,3H),2.48(s,3H),2.35-2.19(m,1H),2.07-1.96(m,1H).

[1159] Example 322:

[1160] 1 H NMR (400MHz, DMSO-d6) δ=9.86-9.31(m,1H),7.91(d,J=8.4Hz,2H),7.34(t,J=73.6Hz,1H),7.25(d,J=8.4Hz,2H),7.04(d,J=2.0Hz ,1H),6.95(d,J=10.0Hz,2H),6.36(d,J=2.0Hz,1H),4.67(s,1H),4.07(s,2H),3.88(s,3H),3.83(s,3H),3.23(s,3H),1.21(s,6H).

[1161] Example 323:

[1162] 1 H NMR(400MHz,DMSO-d6)δ=9.66(br s,1H),7.91(d,J=8.8Hz,2H),7.56(s,1H),7.34(t,J=72.5Hz,1H),7.28-7.20(m,2H),7.11(s,1H),6.93(d,J=10.0Hz,2H) ,3.83(s,3H),3.18(s,3H),3.11-3.07(m,2H),2.75-2.59(m,3H),1.88-1.83(m,4H),1.83-1.70(m,2H),1.61-1.57(m,2H).

[1163] Example 324:

[1164] 1H NMR (400MHz, DMSO-d6) δ = 9.65 (s, 1H), 7.90 (d, J = 8.8Hz, 2H), 7.57 (s, 1H), 7. 34(t,J=71.3Hz,1H),7.24(d,J=8.8Hz,2H),7.14(s,1H),6.93(d,J=10.0Hz, 2H),3.83(s,3H),3.17(s,3H),2.91-2.87(m,2H),2.61-2.52(m,1H),2.20(s ,3H),2.02-1.97(m,2H),1.89(s,3H),1.85-1.76(m,2H),1.74-1.59(m,2H).

[1165] Example 325:

[1166] 1 H NMR (400MHz, DMSO-d6) δ=9.67(s,1H),7.90(d,J=8.8Hz,2H),7.33(t,J=73.5Hz,1H),7.24(d,J=8.8Hz,2H),7.02(d,J=2.0Hz,1H),6.93(d,J=1 0.0Hz,2H),6.32(d,J=2.0Hz,1H),4.47(t,J=5.3Hz,2H),4.13(s,2H), 3.87(s,3H),3.82(s,3H),3.38-3.35(m,4H),3.22(s,3H),0.90(s,3H).

[1167] Example 326:

[1168] 1 H NMR(400MHz,DMSO-d6)δ=11.12(br s,1H),9.67(s,1H),7.90(d,J=8.5Hz,2H),7.34(t,J=73.5Hz,1H),7.24(d,J=8.8Hz,2H),6. 92(d,J=10.0Hz,2H),6.91-6.74(m,1H),6.13(s,1H),3.88(s,3H),3.83(s,3H),3.16(s,3H).

[1169] Example 327:

[1170] 1H NMR (400MHz, DMSO-d6) δ = 9.65 (s, 1H), 7.91 (d, J = 8.8Hz, 2H), 7.34 (t, J = 72.5Hz, 1H), 7.29 (d, J = 2.0Hz, 1H), 7.24 (d, J = 8.8Hz, 2H), 6.97-6.88(m,3H),4.51(d,J=5.8Hz,2H),4.33(d,J=5.8Hz,2H),4.20(s,2H),3.83(s,3H),3.19(s,3H),2.48(s,3H),1.38(s,3H).

[1171] Example 328:

[1172] 1 H NMR (400MHz, DMSO-d6) δ = 9.75 (s, 1H), 8.11 (s, 1H), 7.91 (d, J = 8.8Hz, 2H), 7.71 (s, 1H), 7.25 (d, J = 8.8Hz, 2H), 7.34 (t, J = 74.6Hz, 1H), 6.94 (d, J = 10.0Hz, 2H), 3.83 (s, 3H), 3.22 (s, 3H), 2.61 (s, 3H).

[1173] Example 329:

[1174] 1 H NMR (400MHz, DMSO-d6) δ = 9.67 (s, 1H), 7.91 (d, J = 8.8Hz, 2H), 7.34 (t, J = 73.8Hz, 1H), 7.25 (d ,J=8.8Hz,2H),7.05(d,J=2.0Hz,1H),6.93(d,J=10.0Hz,2H),6.34(d,J=1.8Hz,1H),4.51(br s,1H),4.35(t,J=6.4Hz,2H),3.87(s,3H),3.82(s,3H),3.56(t,J=6.4Hz,2H),3.23(s,3H),1.92-1.86(m,2H).

[1175] Example 330:

[1176] 1H NMR (400MHz, DMSO-d6) δ=9.56(s,1H),7.94-7.89(m,3H),7.71(dd,J=7.3,2.0Hz,1H),7.32(t,J=73.5Hz,1H ),7.22(d,J=8.8Hz,2H),6.88(d,J=10.5Hz,2H),6.4(t,J=6.9Hz,1H),3.8(s,3H),3.53(s,3H),2.99(s,3H).

[1177] Example 331:

[1178] 1 H NMR (400MHz, DMSO-d6) δ=9.67(s,1H),7.91(d,J=8.8Hz,2H),7.33(t,J=74.0Hz,1H),7.28-7.24(m,3H),6.93(d,J=10.3Hz,2 H), 6.62 (s, 1H), 4.85 (t, J = 5.1Hz, 1H), 4.30 (t, J = 5.1Hz, 2H), 3.82 (s, 3H), 3.74 (q, J = 5.1Hz, 2H), 3.19 (s, 3H), 2.37 (s, 3H).

[1179] Example 332:

[1180] 1 H NMR (400MHz, DMSO-d6) δ = 9.68 (s, 1H), 7.91 (br d,J=8.8Hz,2H),7.33(t,J=73.6Hz,1H),7.24(d,J=8.8Hz,2H),7.07(d,J=1.8Hz,1H),6.94(d,J=10.3Hz,2H),6.35(d,J =1.8Hz,1H),4.84(t,J=5.4Hz,1H),4.31(t,J=5.4Hz,2H),3.88(s,3H),3.83(s,3H),3.74(q,J=5.4Hz,2H),3.23(s,3H).

[1181] Example 333:

[1182] 1H NMR (400MHz, DMSO-d6) δ = 9.69 (s, 1H), 7.94-7.81 (m, 3H), 7.45 (d, J = 7.8Hz, 1H), 7.33 (t, J = 73.8Hz, 1H), 7.24 (d, J = 8.5Hz, 2H), 6.94 (d ,J=10.3Hz,2H),6.77(d,J=8.3Hz,1H),4.87(t,J=5.5Hz,1H),4.32(t,J=5.5Hz,2H),3.83(s,3H),3.76(q,J=5.5Hz,2H),3.22(s,3H).

[1183] Example 334:

[1184] 1 H NMR (400MHz, DMSO-d6) δ = 9.72 (s, 1H), 7.90 (d, J = 8.5Hz, 2H), 7.74 (d, J = 2.0Hz, 1 H),7.47(d,J=2.0Hz,1H),7.34(t,J=74.0Hz,1H),7.25(d,J=8.8Hz,2H),6.95(d, J=10.3Hz,2H),4.27-4.13(m,2H),3.86-3.73(m,5H),3.69-3.65(m,1H),3.60-3. 55(m,1H),3.22(s,3H),2.76-2.71(m,1H),2.11-2.00(m,1H),1.74-1.70(m,1H).

[1185] Example 335:

[1186] 1 H NMR (400MHz, DMSO-d6) δ = 9.70 (s, 1H), 7.91 (d, J = 8.8Hz, 2H), 7.34 (t, J = 72.8Hz, 1H), 7.25 (d, J = 8.8Hz, 2H), 7.11 (d, J = 2.0Hz, 1H), 6.94 (d ,J=10.3Hz,2H),6.42(d,J=2.0Hz,1H),4.68(t,J=5.5Hz,2H),3.89(s,3H),3.83(s,3H),3.67(t,J=5.5Hz,2H),3.23(s,3H),3.08(s,3H).

[1187] Example 336:

[1188] 1H NMR (400MHz, DMSO-d6) δ = 9.68 (s, 1H), 7.91 (d, J = 8.8Hz, 2H), 7.34 (t, J = 73.8Hz, 1H) ,7.27-7.24(m,2H),7.09(d,J=2.0Hz,1H),7.01-6.86(m,2H),6.70(s,1H),5.52(br s,1H),4.86(br s,1H),4.58(s,2H),4.31(t,J=5.0Hz,2H),3.83(s,3H),3.74(brt,J=5.0Hz,2H),3.20(s,3H).

[1189] Example 337:

[1190] 1 H NMR (400MHz, DMSO-d6) δ = 9.68 (s, 1H), 7.94-7.83 (m, 2H), 7.34 (t, J = 74.8Hz, 2H), 7.25 (d, J = 8.8Hz, 2H), 7.05 (d, J = 2.0Hz, 1H), 6.94 (d, J = 10.0Hz, 2H) ,6.37(d,J=2.0Hz,1H),4.21(d,J=6.0Hz,2H),3.87(s,3H),3.83(s,3H),3 .22-3.16(m,5H),3.12-3.06(m,2H),2.15-2.07(m,3H),1.80-1.76(m,2H).

[1191] Example 338:

[1192] 1 H NMR (400MHz, DMSO-d6) δ = 9.66 (s, 1H), 7.91 (d, J = 8.8Hz, 2H), 7.34 (t, J = 75.3Hz, 1H),7.29-7.23(m,3H),6.95(d,J=10.5Hz,2H),6.91(d,J=2.0Hz,1H),4.39(s,1 H),3.90(s,3H),3.84(s,3H),3.55-3.52(m,2H),3.24(s,3H),3.07-3.02(m,1H) ,2.96-2.86(m,2H),2.43(t,J=6.3Hz,2H),2.02-1.86(m,3H),1.69-1.55(m,3H).

[1193] Example 339:

[1194] 1H NMR (400MHz, DMSO-d6) δ = 9.68 (s, 1H), 7.91 (d, J = 8.8Hz, 2H), 7.34 (t, J = 75.3H z,1H),7.25(d,J=8.8Hz,2H),7.05(d,J=2.0Hz,1H),6.94(d,J=10.5Hz,2H),6 .36(d,J=2.0Hz,1H),4.33-4.16(m,3H),3.88(s,3H),3.80(s,3H),3.82-3.81 (m,1H),3.72-3.64(m,1H),3.22(s,3H),2.05-1.80(m,3H),1.71-1.60(m,1H).

[1195] Example 340:

[1196] 1 H NMR (400MHz, DMSO-d6) δ = 9.66 (s, 1H), 7.91 (d, J = 8.8Hz, 2H), 7.34 (t, J = 75.3Hz, 1H),7.29-7.23(m,3H),6.95(d,J=10.5Hz,2H),6.91(d,J=2.0Hz,1H),4.39(s,1 H),3.90(s,3H),3.84(s,3H),3.55-3.52(m,2H),3.24(s,3H),3.07-3.03(m,1H) ,2.96-2.86(m,2H),2.43(t,J=6.3Hz,2H),2.02-1.86(m,3H),1.69-1.55(m,3H).

[1197] Example 341:

[1198] 1 H NMR (400MHz, DMSO-d6) δ = 9.82 (s, 1H), 8.68 (s, 1H), 8.43 (s, 1H), 7.92 (d, J = 8.8Hz, 2H), 7.35 (t, J = 75.1Hz, 1H), 7.26 (d, J = 8.8Hz, 2H), 6.97 (d, J = 10.3Hz, 2H), 3.84 (s, 3H), 3.24 (s, 3H).

[1199] Example 342:

[1200] 11H NMR (400 MHz, DMSO-d6) δ = 9.66 (s, 1H), 7.91 (d, J = 8.5 Hz, 2H), 7.34 (t, J = 74.0 Hz, 1H), 7.30 (d, J = 2.0 Hz, 1H), 7.25 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 10.5 Hz, 2H), 6.90 (d, J = 2.0 Hz, 1H), 3.90 (s, 3H), 3.84 (s, 3H), 3.23 (s, 3H), 3.05 - 2.91 (m, 2H), 2.87 - 2.78 (m, 1H), 2.26 (br s, 3H), 2.26 - 2.23 (m, 1H), 2.03 - 1.85 (m, 2H), 1.80 - 1.71 (m, 1H), 1.69 - 1.49 (m, 2H).

[1201] Example 343:

[1202] 1 1H NMR (400 MHz, DMSO-d6) δ = 9.66 (s, 1H), 7.91 (d, J = 8.5 Hz, 2H), 7.34 (t, J = 72.8 Hz, 1H), 7.30 (d, J = 2.0 Hz, 1H), 7.25 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 10.5 Hz, 2H), 6.90 (d, J = 2.0 Hz, 1H), 3.90 (s, 3H), 3.84 (s, 3H), 3.23 (s, 3H), 3.04 - 2.90 (m, 2H), 2.88 - 2.78 (m, 1H), 2.26 (br s, 3H), 2.26 - 2.23 (m, 1H), 1.91 (br s, 2H), 1.78 - 1.72 (m, 1H), 1.70 - 1.46 (m, 2H).

[1203] Example 344:

[1204] 1 1H NMR (400 MHz, DMSO-d6) δ = 9.69 (s, 1H), 7.91 (d, J = 9.0 Hz, 2H), 7.34 (t, J = 72.8 Hz, 1H), 7.25 (d, J = 8.8 Hz, O2H), 7.06 (d, J = 2.0 Hz, 1H), 6.95 (d, J = 10.5 Hz, 2H), 6.41 (d, J = 2.0 Hz, 1H), 4.51 (d, J = 6.0 Hz, 2H), 4.39 (s, 2H), 4.31 (d, J = 6.0 Hz, 2H), 3.89 (s, 3H), 3.83 (s, 3H), 3.23 (s, 3H), 1.38 (s, 3H).

[1205] Example 345:

[1206] 1 H NMR (400MHz, DMSO-d6) δ = 9.68 (s, 1H), 7.92 (d, J = 8.8Hz, 2H), 7.35 (t, J = 74.3Hz, 1H), 7.33 (d, J = 2.0Hz, 1H), 7.26 (d, J = 8.8Hz, 2H), 6.95 (d, J = 10.3 Hz,2H),6.88(d,J=2.0Hz,1H),4.04-3.93(m,2H),3.90(s,3H),3.84(s,3 H),3.53-3.40(m,2H),3.24(s,3H),3.01-2.90(m,1H),1.90-1.73(m,4H).

[1207] Example 346:

[1208] 1 H NMR (400MHz, DMSO-d6) δ = 9.66 (s, 1H), 7.90 (d, J = 8.5Hz, 2H), 7.35 (t, J = 73.6H z,1H),7.29(d,J=2.0Hz,1H),7.24(d,J=8.5Hz,2H),6.94(d,J=10.5Hz,2H),6 .83(d,J=2.0Hz,1H),3.88(s,3H),3.83(s,3H),3.23(s,3H),3.14-3.08(m,1H ),2.97-2.88(m,2H),2.80-2.72(m,2H),2.68-2.63(m,1H),1.86-1.61(m,4H).

[1209] Example 347:

[1210] 1 H NMR (400MHz, DMSO-d6) δ = 9.68 (s, 1H), 7.91 (d, J = 8.5Hz, 2H), 7.35 (t, J = 73.6H z,1H),7.29(d,J=2.0Hz,1H),7.24(d,J=8.5Hz,2H),6.94(d,J=10.5Hz,2H),6 .83(d,J=2.0Hz,1H),3.88(s,3H),3.83(s,3H),3.23(s,3H),3.14-3.08(m,1H ),2.97-2.88(m,2H),2.80-2.72(m,2H),2.68-2.63(m,1H),1.86-1.61(m,4H).

[1211] Example 348:

[1212] 1 H NMR (400MHz, DMSO-d6) δ=9.73(s,1H),7.91(d,J=8.8Hz,2H),7.74(d,J=2.0Hz,1H),7.45(d,J=2.0Hz,1H),7.34(t,J=73.0Hz,1H),7.2 5(d,J=8.8Hz,2H),6.95(d,J=10.3Hz,2H),5.01(t,J=5.5Hz,1H),4.28(t,J=4.8Hz,2H),3.83(s,3H),3.81-3.75(m,2H),3.23(s,3H).

[1213] Example 349:

[1214] 1 H NMR (400MHz, DMSO-d6) δ=9.72(s,1H),7.91(d,J=8.8Hz,2H),7.78(d,J=2.0Hz,1H),7.52(d,J=4.2Hz,1H),7.33(t,J=74.0Hz,1H) ,7.24(d,J=8.8Hz,2H),6.95(d,J=10.0Hz,2H),4.54(d,J=5.8Hz,2H),4.42-4.28(m,4H),3.83(s,3H),3.23(s,3H),1.40(s,3H).

[1215] Example 350:

[1216] 1 H NMR (400MHz, DMSO-d6) δ = 9.68 (s, 1H), 7.91 (d, J = 8.5Hz, 2H), 7.34 (t, J = 75.3Hz ,1H),7.25(d,J=8.8Hz,2H),7.05(d,J=2.0Hz,1H),6.94(d,J=10.5Hz,2H),6.36 (d,J=2.0Hz,1H),4.33-4.16(m,3H),3.88(s,3H),3.84-3.76(m,3H),3.82-3.8 1(m,1H),3.72-3.64(m,1H),3.22(s,3H),2.05-1.80(m,3H),1.71-1.60(m,1H).

[1217] Example 351:

[1218] 11H NMR (400 MHz, DMSO-d6) δ = 9.67 (s, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.34 (t, J = 73.5 Hz, 1H), 7.25 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 2.0 Hz, 1H), 6.94 (d, J = 10.3 Hz, 2H), 6.36 (d, J = 2.0 Hz, 1H), 4.29 (dd, J = 10.6, 6.6 Hz, 1H), 4.19 (dd, J = 10.6, 7.8 Hz, 1H), 3.87 (s, 3H), 3.85 - 3.74 (m, 5H), 3.71 - 3.62 (m, 1H), 3.56 - 3.52 (m, 1H), 3.31 (s, 3H), 2.77 - 2.63 (m, 1H), 2.08 - 1.97 (m, 1H), 1.72 - 1.57 (m, 1H).

[1219] Example 352:

[1220] 1 1H NMR (400 MHz, DMSO-d6) δ = 9.69 (s, 1H), 7.92 (br d, J = 8.6 Hz, 2H), 7.35 (t, J = 73.4 Hz, 1H), 7.30 - 7.18 (m, 3H), 6.95 (d, J = 11.0 Hz, 2H), 6.64 (s, 1H), 4.34 - 4.25 (m, 1H), 4.19 (dd, J = 10.4, 8.0 Hz, 1H), 3.87 (s, 3H), 3.86 - 3.73 (m, 2H), 3.69 - 3.64 (m, 1H), 3.56 - 3.52 (m, 1H), 3.2 (s, 3H) 2.74 - 2.70 (m, 1H), 2.38 (s, 3H), 2.08 - 1.94 (m, 1H), 1.68 - 1.64 (m, 1H).

[1221] Example 353:

[1222] 1 1H NMR (400 MHz, DMSO-d6) δ = 9.68 (s, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.34 (t, J = 75.8 Hz, 1H), 7.30 (s, 1H), 7.25 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 10.0 Hz, 2H), 6.69 (s, 1H), 4.51 (d, J = 5.9 Hz, 2H), 4.38 (s, 2H), 4.31 (d, J = 5.9 Hz, 2H), 3.83 (s, 3H), 3.21 (s, 3H), 2.39 (s, 3H), 1.37 (s, 3H).

[1223] Example 354:

[1224] 1 H NMR (400MHz, DMSO-d6) δ = 9.64 (s, 1H), 7.91 (br d, J = 8.8Hz, 2H), 7.34 (t, J = 75.8Hz, 1H), 7.24 (br d,J=8.8Hz,2H),6.93(d,J=10.5Hz,2H),6.71(d,J=1.5Hz,1H),5.96(br s,1H),4.64(br s,1H),3.86(s,3H),3.83(s,3H),3.52-3.48(m,2H),3.22(s,3H),2.95-2.84(m,2H),2.61-2.41(m,1H),2.30(s,3H),1.91-1.83(m,2H).

[1225] Example 355:

[1226] 1 H NMR (400MHz, DMSO-d6) δ = 9.71 (s, 1H), 7.92 (d, J = 8.8Hz, 2H), 7.35 (t, J = 73. 6Hz,1H),7.26(d,J=8.8Hz,2H),7.07(d,J=2.0Hz,1H),6.95(d,J=10.5Hz,2H ),6.37(d,J=2.0Hz,1H),5.47-5.42(m,1H),4.01-3.96(m,1H),3.90-3.85(m ,4H),3.84-3.76(m,5H),3.21(s,3H),2.31-2.22(m,1H),2.10-2.02(m,1H).

[1227] Example 356:

[1228] 1 H NMR (400MHz, DMSO-d6) δ = 9.71 (s, 1H), 7.92 (d, J = 8.8Hz, 2H), 7.35 (t, J = 73. 6Hz,1H),7.26(d,J=8.8Hz,2H),7.07(d,J=2.0Hz,1H),6.95(d,J=10.5Hz,2H ),6.37(d,J=2.0Hz,1H),5.47-5.42(m,1H),4.01-3.96(m,1H),3.90-3.85(m ,4H),3.84-3.76(m,5H),3.21(s,3H),2.31-2.22(m,1H),2.10-2.02(m,1H).

[1229] Example 357:

[1230] 1 H NMR (400MHz, DMSO-d6) δ=9.81(s,1H),8.43(d,J=8.1Hz,1H),7.92(d,J=8.6Hz,2H),7.55(d,J=8.1Hz,1H),7 .34(t,J=73.6Hz,1H),7.24(d,J=8.6Hz,2H),6.95(d,J=10.5Hz,2H),3.84(s,3H),3.14(s,3H),2.65(s,3H).

[1231] Example 358

[1232] 1 H NMR (400MHz, DMSO-d6) δ=9.66(s,1H),8.13(d,J=8.8Hz,1H),7.99(d,J=8.8Hz,1H),7.91(d,J=8.8Hz,2H),7.24(d,J=8.6Hz,2H ),7.33(t,J=74.0Hz,1H),6.96-6.84(m,2H),4.48(d,J=6.0Hz,2H),4.36-4.22(m,4H),3.81(s,3H),2.93(s,3H),1.28(s,3H).

[1233] Example 359:

[1234] 1 H NMR (400MHz, DMSO-d6) δ = 9.71 (s, 1H), 7.92 (d, J = 8.6Hz, 2H), 7.35 (t, J = 73.8Hz, 1H), 7.30 (s, 1H), 7.26 (d, J = 8.6Hz, 2H), 6.95 (d, J = 10.5Hz, 2H), 6.64(s,1H),5.45-5.41(m,1H),3.99(dd,J=10.3,4.9Hz,1H),3.90-3.74 (m,6H),3.19(s,3H),2.38(s,3H),2.31-2.21(m,1H),2.10-1.99(m,1H).

[1235] Example 360:

[1236] 1H NMR (400MHz, DMSO-d6) δ = 9.71 (s, 1H), 7.92 (d, J = 8.8Hz, 2H), 7.35 (t, J = 73.4Hz, 1H), 7.30 (s, 1H), 7.26 (d, J = 8.6Hz, 2H), 6.95 (d, J = 10.8Hz, 2H), 6.64(s,1H),5.47-5.37(m,1H),3.99(dd,J=10.1,4.8Hz,1H),3.90-3.73 (m,6H),3.19(s,3H),2.38(s,3H),2.30-2.21(m,1H),2.11-1.99(m,1H).

[1237] Example 361:

[1238] 1 H NMR (400MHz, DMSO-d6) δ = 9.68 (s, 1H), 7.91 (d, J = 8.6Hz, 2H), 7.56 (s, 1H), 7.35 (t, J = 73.4Hz, 1H), 7.25 (d, J = 8.6Hz, 2H), 7 .10(s,1H),6.94(d,J=10.0Hz,2H),3.83(s,3H),3.21(s,3H),2.96-2.90(m,2H),2.66-2.59(m,2H),2.40(s,3H),2.26(br s,3H),2.11-2.06(m,2H),1.86-1.82(m,3H).

[1239] Example 362:

[1240] 1 H NMR (400MHz, DMSO-d6) δ = 9.75 (s, 1H), 8.07 (s, 1H), 7.96-7.83 (m, 3H), 7.35 (t, J = 73.6Hz, 1H), 7.26 (d, J = 8.8Hz, 2H), 6.96 (d, J = 10.0Hz, 2H), 3.84 (s, 3H), 3.18 (s, 3H), 2.5 (s, 3H).

[1241] Example 363:

[1242] 1H NMR (400MHz, DMSO-d6) δ = 9.65 (s, 1H), 7.91 (d, J = 8.5Hz, 2H), 7.34 (t, J = 72.1 Hz,1H),7.31(d,J=2.0Hz,1H),7.25(d,J=8.5Hz,2H),6.94(d,J=10.0Hz,2H) ,6.86(d,J=2.0Hz,1H),3.89(s,3H),3.84(s,3H),3.24(s,3H),2.90-2.86(m ,2H),2.66-2.60(m,1H),2.20(s,3H),2.02-1.93(m,2H),1.86-1.77(m,4H).

[1243] Example 364:

[1244] 1 H NMR (400MHz, DMSO-d6) δ = 9.66 (s, 1H), 7.91 (d, J = 8.8Hz, 2H), 7.35 (t, J = 75.3Hz, 1H), 7.25 (d, J = 8.8Hz, 2H), 6.94 (d, J = 10.0Hz, 2H), 6.81 (d, J = 1.5Hz, 1H), 6.29 (d, J = 1.5Hz, 1H), 3.86 (s, 3H), 3.83 (s, 3H), 3.76-3.66 (m, 4H), 3.56-3.41 (m, 4H), 3.20 (s, 3H).

[1245] Example 365:

[1246] 1 H NMR (400MHz, DMSO-d6) δ = 9.66 (s, 1H), 7.92 (d, J = 8.8Hz, 2H), 7.35 (t, J = 73.6Hz, 1H),7.32(d,J=2.0Hz,1H),7.26(d,J=8.6Hz,2H),6.94(d,J=10.3Hz,2H),6.87(d ,J=2.0Hz,1H),6.18(tt,J=55.5,5.6Hz,1H),3.90(s,3H),3.84(s,3H),3.24(s, 3H),3.05-3.00(m,2H),2.82-2.63(m,3H),2.35-2.16(m,2H),1.90-1.66(m,4H).

[1247] Example 366:

[1248] 1H NMR (400MHz, DMSO-d6) δ = 9.67 (s, 1H), 7.92 (d, J = 8.6Hz, 2H), 7.33 (t, J = 73.6Hz ,1H),7.28-7.24(m,3H),7.00-6.82(m,3H),3.91(s,3H),3.84(s,3H),3.69(br d,J=12.0Hz,2H),3.24(s,3H),2.91(s,3H),2.89-2.80(m,3H),2.00(br d,J=12.2Hz,2H),1.91-1.76(m,2H).

[1249] Example 367:

[1250] 1 H NMR (400MHz, DMSO-d6) δ = 9.67 (s, 1H), 7.99-7.84 (m, 2H), 7.35 (t, J = 75.1Hz, 1H), 7.33 (d, J = 2.0Hz, 1H), 7. 26(d,J=8.8Hz,2H),6.94(d,J=10.0Hz,2H),6.84(d,J=2.2Hz,1H),3.90(s,3H),3.84(s,3H),3.80-3.33(br s,1H),3.24(s,3H),3.19-3.13(m,2H),2.90-2.81(m,1H),2.80-2.70(m,2H),1.94-1.83(m,2H),1.82-1.70(m,2H).

[1251] Example 368:

[1252] 1 H NMR (400MHz, DMSO-d6) δ = 9.66 (s, 1H), 7.91 (d, J = 8.6Hz, 2H), 7.35 (t, J = 75.1Hz, 1H), 7. 32(d,J=2.0Hz,1H),7.25(d,J=8.6Hz,2H),6.94(d,J=10.0Hz,2H),6.87(d,J=2.2Hz,1H ),4.64-4.39(m,1H),3.90(s,3H),3.84(s,3H),3.62-3.54(m,2H),3.24(s,3H),3.17-3 .03(m,2H),2.76-2.72(m,1H),2.63-2.56(m,3H),2.31-2.19(m,1H),1.95-1.80(m,4H).

[1253] Example 369:

[1254] 1 H NMR (400MHz, DMSO-d6) δ = 9.66 (s, 1H), 8.09 (d, J = 8.5Hz, 1H), 7.97 (d, J = 8.5Hz, 1H), 7.9 1(d,J=8.8Hz,2H),7.33(t,J=74.3Hz,1H),7.24(d,J=8.8Hz,2H),6.98-6.86(m,2H),4.2 1-4.16(m,1H),4.13-4.05(m,1H),3.82(s,3H),3.77-3.68(m,2H),3.66-3.58(m,1H),3 .55-3.50(m,1H),2.95(s,3H),2.67-2.60(m,1H),2.05-1.92(m,1H),1.66-1.60(m,1H).

[1255] Example 370:

[1256] 1 H NMR (400MHz, DMSO-d6) δ = 9.66 (s, 1H), 8.09 (d, J = 8.5Hz, 1H), 7.97 (d, J = 8.5Hz, 1H), 7.9 1(d,J=8.8Hz,2H),7.33(t,J=74.3Hz,1H),7.24(d,J=8.8Hz,2H),6.98-6.86(m,2H),4.2 1-4.16(m,1H),4.13-4.05(m,1H),3.82(s,3H),3.77-3.68(m,2H),3.66-3.58(m,1H),3 .55-3.50(m,1H),2.95(s,3H),2.67-2.60(m,1H),2.05-1.92(m,1H),1.66-1.60(m,1H).

[1257] Example 371:

[1258] 1 H NMR (400MHz, DMSO-d6) δ=9.68(s,1H),8.10(d,J=8.8Hz,1H),7.98(d,J=8.6Hz,1H),7.92(d,J=8.6Hz,2H),7 .34(t,J=74.1Hz,1H),7.24(d,J=8.6Hz,2H),6.92(d,J=10.5Hz,2H),4.00(s,3H),3.83(s,3H),2.98(s,3H).

[1259] Example 372:

[1260] 1 H NMR (400MHz, DMSO-d6) δ=9.69(s,1H),8.10-7.98(m,2H),7.92(d,J=8.8Hz,2H),7.34(t,J=73.8Hz,1H),7.25(d,J=8.6H z, 2H), 6.99-6.86 (m, 2H), 4.85 (t, J = 5.8Hz, 1H), 4.34 (t, J = 4.8Hz, 2H), 3.83 (s, 3H), 3.74 (q, J = 5.8Hz, 2H), 3.04 (s, 3H).

[1261] Example 373:

[1262] 1 ¹H NMR (400MHz, DMSO-d⁶) δ=9.68(s, 1H), 8.10–8.00(m, 2H), 7.92(br d, J=8.8Hz, 2H), 7.34(t, J=73.8Hz, 1H), 7.24(d, J=8.6Hz, 2H), 6.99–6.86(m, 2H), 4.93(d, J=3.9Hz, 1H), 4.22–4.15(m, 1H), 4.14–4.04(m, 1H), 4.03–3.94(m, 1H), 3.83(s, 3H), 3.03(s, 3H), 1.33–1.07(2d, J=3.9Hz, 3H). (A mixture of interchangeable transisomers)

[1263] Example 374:

[1264] 1 H NMR (400MHz, DMSO-d6) δ = 9.69 (br s, 1H), 8.11-8.03 (m, 1H), 8.03-7.95 (m, 1H), 7.92 (br d,J=8.8Hz,2H),7.34(t,J=74.1Hz,1H),7.24(d,J=8.8Hz,2H),6.93(d,J=10.5Hz,2H),4.22(t,J=5.3Hz,2H),3.83(s,3H),3.40-3.10(br s, 2H), 3.00 (s, 3H), 2.89 (t, J = 5.3Hz, 2H).

[1265] Example 375:

[1266] 1H NMR (400MHz, DMSO-d6) δ=9.81(s,1H),8.65-8.44(s,1H),8.17-8.13(m,2H),8.01-7.90(m,2H),7.36(t,J=73.4Hz,1H ),7.30(d,J=8.8Hz,2H),7.06-6.93(m,2H),4.72-4.57(m,2H),3.86(s,3H),3.49-3.42(m,2H),3.17(s,3H),2.72(br s,3H).

[1267] Example 376:

[1268] 1 H NMR (400MHz, DMSO-d6) δ = 9.66 (s, 1H), 7.91 (d, J = 8.5Hz, 2H), 7.35 (t, J = 73.3Hz, 1H), 7.29-7.20 (m, 3H ), 6.93 (d, J = 10.0Hz, 2H), 6.88 (d, J = 2.0Hz, 1H), 3.89 (s, 3H), 3.84 (s, 3H), 3.20 (s, 3H), 2.48 (s, 3H).

[1269] Example 377:

[1270] 1 H NMR (400MHz, DMSO-d6) δ = 9.67 (s, 1H), 7.91 (d, J = 8.8Hz, 2H), 7.34 (t, J = 75.6Hz, 1H), 7.24 (d, J = 8.8Hz, 2H), 6.99 (m, 3H), 6.94 (d, J=10.3Hz,1H),4.78(sept,J=6.0Hz,1H),4.63(s,1H),4.06(s,2H),3.82(s,3H),3.22(s,3H),1.33(d,J=6.0Hz,6H),1.20(s,6H).

[1271] Example 378:

[1272] 1H NMR (400MHz, DMSO-d6) δ = 9.68 (s, 1H), 7.91 (d, J = 8.8Hz, 2H), 7.34 (t, J = 73.5Hz, 1H),7.25(d,J=8.8Hz,2H),7.02(d,J=1.8Hz,1H),6.94(d,J=10.3Hz,2H),6.31( d,J=1.8Hz,1H),4.84(t,J=5.4Hz,1H),4.78(sept,J=6.0Hz,1H),4.30(t,J=5.4 Hz, 2H), 3.83 (s, 3H), 3.74 (q, J = 5.4Hz, 2H), 3.23 (s, 3H), 1.33 (d, J = 6.0Hz, 6H).

[1273] Example 379:

[1274] 1 H NMR (400MHz, DMSO-d6) δ=9.68(s,1H),7.91(d,J=8.8Hz,2H),7.34(t,J=72.3Hz,1H),7.24(d,J=8.8Hz,2H),7.04(d,J=1.8Hz,1H),6.93(d,J=10 .0Hz,2H),6.31(d,J=1.8Hz,1H),4.41(t,J=7.4Hz,2H),4.36(s,1H),3. 87(s,3H),3.82(s,3H),3.23(s,3H),1.86(t,J=7.4Hz,2H),1.17(s,6H).

[1275] Example 380:

[1276] 1 H NMR (400MHz, DMSO-d6) δ = 9.70 (s, 1H), 7.91 (d, J = 8.8Hz, 2H), 7.34 (t, J = 74.8Hz, 1 H),7.24(d,J=8.8Hz,2H),7.09(d,J=1.8Hz,1H),6.94(d,J=10.5Hz,2H),6.63(br d,J=6.3Hz,1H),6.39(d,J=1.8Hz,1H),4.58(dd,J=11.4,3.9Hz,1H),4.52-4.4 3(m,1H),4.35(dd,J=11.4,7.0Hz,1H),3.88(s,3H),3.82(s,3H),3.19(s,3H).

[1277] Example 381:

[1278] 1H NMR (400MHz, DMSO-d6) δ = 9.70 (s, 1H), 7.91 (d, J = 8.8Hz, 2H), 7.35 (t, J = 72.3Hz, 1H), 7.25 (d, J = 8.8Hz, 2H), 7.09 (d, J = 2.0Hz, 1H), 6.94 (d, J = 10.5 Hz,2H),6.66-6.56(m,1H),6.39(d,J=2.0Hz,1H),4.61-4.58(m,1H),4.5 3-4.43(m,1H),4.40-4.31(m,1H),3.89(s,3H),3.83(s,3H),3.20(s,3H).

[1279] Example 382:

[1280] 1 H NMR (400MHz, DMSO-d6) δ=9.70(s,1H),7.91(d,J=8.8Hz,2H),7.34(t,J=73.5Hz,1H),7.24(d,J=8.8Hz,2H ),7.04(d,J=1.8Hz,1H),6.93(d,J=10.5Hz,2H),6.33(d,J=1.8Hz,1H),5.25(quin,J=5.1Hz,1H),4.89(br s,1H),3.87(s,3H),3.82(s,3H),3.68-3.55(m,4H),3.28(s,3H),3.20(s,3H).

[1281] Example 383:

[1282] 1 H NMR (400MHz, DMSO-d6) δ = 9.70 (s, 1H), 7.91 (d, J = 8.8Hz, 2H), 7.34 (t, J = 74.8Hz, 1 H),7.24(d,J=8.8Hz,2H),7.09(d,J=1.8Hz,1H),6.94(d,J=10.5Hz,2H),6.63(br d,J=6.3Hz,1H),6.39(d,J=1.8Hz,1H),4.58(dd,J=11.4,3.9Hz,1H),4.52-4.4 3(m,1H),4.35(dd,J=11.4,7.0Hz,1H),3.88(s,3H),3.82(s,3H),3.19(s,3H).

[1283] Example 384:

[1284] 1H NMR (400MHz, DMSO-d6) δ = 9.67 (s, 1H), 7.91 (d, J = 8.8Hz, 2H), 7.34 (t, J = 74.8H) z,1H),7.24(d,J=8.5Hz,2H),7.06(d,J=2.0Hz,1H),6.93(d,J=10.3Hz,2H),6. 39(d,J=2.0Hz,1H),4.99(t,J=5.4Hz,1H),4.47(s,2H),4.45-4.42(m,2H),4. 41-4.37(m,2H),3.88(s,3H),3.82(s,3H),3.71(d,J=5.4Hz,2H),3.23(s,3H).

[1285] Example 385:

[1286] 1 H NMR (400MHz, DMSO-d6) δ=9.69(s,1H),7.91(d,J=8.8Hz,2H),7.35(t,J=73.0Hz,1H),7.25(d,J=8.8Hz,2H),7.06(d,J=2.0Hz,1H),6 .93(d,J=10.3Hz,2H),6.44(d,J=2.0Hz,1H),4.38(d,J=20.0Hz,2H),3.90(s,3H),3.83(s,3H),3.32(s,3H),1.44(d,J=19.0Hz,6H).

[1287] Example 386:

[1288] 1 H NMR (400MHz, DMSO-d6) δ=9.69(s,1H),7.91(d,J=8.8Hz,2H),7.34(t,J=71.5Hz,1H),7.26(d,J=8.8Hz,2H ),7.04(d,J=2.0Hz,1H),6.93(d,J=10.5Hz,2H),6.33(d,J=2.0Hz,1H),5.25(quin,J=5.2Hz,1H),4.89(br s,1H),3.87(s,3H),3.82(s,3H),3.68-3.56(m,4H),3.28(s,3H),3.20(s,3H).

[1289] Example 387:

[1290] 1H NMR (400MHz, DMSO-d6) δ=9.69(s,1H),7.91(d,J=8.8Hz,2H),7.35(t,J=72.3Hz,1H),7.25(d,J=8.5Hz,2H),7.11(d,J=1.8Hz,1H),6 .95(d,J=10.3Hz,2H),6.49(d,J=2.0Hz,1H),4.60(t,J=12.9Hz,2H),3.90(s,3H),3.83(s,3H),3.21(s,3H),1.76(t,J=19.1Hz,3H).

[1291] Example 388:

[1292] 1 H NMR (400MHz, DMSO-d6) δ = 9.67 (s, 1H), 8.31 (d, J = 3.0Hz, 1H), 7.91 (d, J = 8.5Hz, 2H), 7.77-7.71 (m, 1H), 7.69-7.63(m,1H),7.34(t,J=73.0Hz,1H),7.24(d,J=8.8Hz,2H),6.92(d,J=10.3Hz,2H),4.61-4.50(br s, 1H), 4.13 (t, J = 4.9Hz, 2H), 3.82 (s, 3H), 3.76 (t, J = 4.9Hz, 2H), 3.11 (s, 3H).

[1293] Example 389:

[1294] 1 H NMR (400MHz, DMSO-d6) δ=9.69(s,1H),7.91(d,J=8.8Hz,2H),7.34(t,J=73.3Hz,1H),7.25(d,J=8.5Hz,2H),7.14(d,J=1 .8Hz,1H),6.94(d,J=10.3Hz,2H),6.56(d,J=1.8Hz,1H),5.02(q,J=9.0Hz,2H),3.91(s,3H),3.83(s,3H),3.20(s,3H).

[1295] Example 390:

[1296] 1H NMR (400MHz, DMSO-d6) δ = 9.70 (s, 1H), 7.91 (d, J = 8.8Hz, 2H), 7.35 (t, J = 72.3Hz, 1H), 7.25 (d, J = 8.8Hz, 2H), 7.09 (d, J = 2.0Hz, 1H), 6.99-6.88 (m ,2H),6.66-6.56(m,1H),6.39(d,J=2.0Hz,1H),4.61-4.57(m,1H),4.53 -4.43(m,1H),4.40-4.31(m,1H),3.89(s,3H),3.83(s,3H),3.20(s,3H).

[1297] Example 391:

[1298] 1 H NMR (400MHz, DMSO-d6) δ = 9.66 (s, 1H), 7.91 (d, J = 8.8Hz, 2H), 7.34 (t, J = 73.5Hz, 1H), 7.29-7.21(m,3H),6.93(d,J=10.3Hz,2H),6.88(d,J=2.0Hz,1H),4.25-4.17(m,1H),4 .15-4.09(m,1H),4.08-4.01(m,1H),3.88-3.77(m,1H),3.83(s,3H),3.75-3.66(m,1H ),3.20(s,3H),2.47(s,3H),2.07-1.98(m,1H),1.95-1.77(m,2H),1.74-1.63(m,1H).

[1299] Example 392:

[1300] 1 H NMR (400MHz, DMSO-d6) δ = 9.69 (s, 1H), 7.96-7.83 (m, 3H), 7.44 (d, J = 7.5Hz, 1H), 7.34 (t, J = 74.6Hz,1H),7.25(d,J=8.8Hz,2H),6.94(d,J=10.3Hz,2H),6.79(d,J=8.3Hz,1H),4.65(br s,1H),4.09(s,2H),3.83(s,3H),3.22(s,3H),1.21(s,6H).

[1301] Example 393:

[1302] 1H NMR(400MHz,DMSO-d6)δ=9.66(br s,1H),7.91(d,J=8.8Hz,2H),7.34(t,J=72.0Hz,1H),7.29-7.18(m,3H),6.92(d,J=10.0Hz,2H),6.86(d,J= 2.0Hz,1H),5.02(brs,1H),4.05-3.91(m,3H),3.82(s,3H),3.19(s,3H),2.47(s,3H),1.16(d,J=6.0Hz,3H).

[1303] Example 394:

[1304] 1 H NMR(400MHz,DMSO-d6)δ=9.66(br s,1H),7.91(d,J=8.8Hz,2H),7.34(t,J=72.0Hz,1H),7.29-7.18(m,3H),6.92(d,J=10.0Hz,2H),6.86(d,J= 2.0Hz,1H),5.02(brs,1H),4.05-3.91(m,3H),3.82(s,3H),3.19(s,3H),2.47(s,3H),1.16(d,J=6.0Hz,3H).

[1305] Example 395:

[1306] 1 H NMR (400MHz, DMSO-d6) δ = 9.57 (s, 1H), 7.96-7.89 (m, 2H), 7.72 (dd, J = 7.0, 2.0Hz, 1H), 7.33 (t, J = 73.5Hz, 1H), 7.25-7.20 (m, 2H),7.12-7.08(m,1H),6.99-6.95(m,1H),6.93-6.85(m,1H),6.41(t,J=6.9Hz,1H),3.82(s,3H),3.54(s,3H),3.00(s,3H).

[1307] Example 396:

[1308] 1H NMR (400MHz, DMSO-d6) δ = 9.66 (s, 1H), 7.91 (d, J = 8.8Hz, 2H), 7.34 (t, J = 73.5Hz, 1H), 7.29-7.21(m,3H),6.93(d,J=10.3Hz,2H),6.88(d,J=2.0Hz,1H),4.25-4.17(m,1H),4 .15-4.09(m,1H),4.08-4.01(m,1H),3.88-3.77(m,1H),3.83(s,3H),3.75-3.66(m,1H ),3.20(s,3H),2.47(s,3H),2.07-1.98(m,1H),1.95-1.77(m,2H),1.74-1.63(m,1H).

[1309] Example 397:

[1310] 1 H NMR (500MHz, DMSO-d6) δ9.74(s,1H),8.76(d,J=5.0Hz,1H),8.09(s,1H),7.90(br d,J=8.4Hz,2H),7.54(br d,J=4.9Hz,1H),7.31(t,J=73.6Hz,1H),7.25(br d,J=8.2Hz,2H),7.22(t,J=55.0Hz,1H),6.93(br d,J=10.8Hz,2H),3.20(s,2H).

[1311] Example 398:

[1312] 1 H NMR (500MHz, DMSO-d6) δ9.93(s,1H),7.95(br d,J=8.5Hz,2H),7.60(br d,J=7.9Hz,2H),7.47(br d,J=8.2Hz,2H),7.00(d,J=1.2Hz,1H),6.33(d,J=1.5Hz,1H),4.83-4.73(m,1H), 4.29 (t, J = 4.9 Hz, 2H), 3.74 (q, J = 5.1 Hz, 2H), 3.25 (s, 3H), 1.33 (d, J = 5.8 Hz, 6H).

[1313] Example 399:

[1314] 11H NMR (500 MHz, DMSO-d6) δ 9.81 (s, 1H), 7.90 (br d, J = 8.6 Hz, 2H), 7.59 (d, J = 7.9 Hz, 2H), 7.33 (s, 1H), 7.25 (d, J = 8.5 Hz, 2H), 7.00 (d, J = 1.7 Hz, 1H), 6.32 (d, J = 1.6 Hz, 1H), 4.83 - 4.73 (m, 1H), 4.29 (t, J = 5.0 Hz, 2H), 3.77 - 3.70 (m, 2H), 3.24 (s, 3H), 1.33 (d, J = 6.0 Hz, 6H)

[1315] Example 400:

[1316] 1 1H NMR (500 MHz, DMSO-d6) δ 7.91 (br d, J = 8.9 Hz, 2H), 7.42 (t, J = 72.6 Hz, 1H), 7.34 (t, J = 73.9 Hz, 1H), 7.29 - 7.22 (m, 5H), 6.66 (s, 1H), 4. , 07 (s, 2H), 3.21 (s, 3H), 2.39 (s, 3H), 1.21 (s, 6H).

[1317] Example 401:

[1318] 1 1H NMR (500 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.01 (t, J = 8.0 Hz, 1H), 7.90 (br d, J = 8.5 Hz, 2H), 7.87 (br d, J = 7.9 Hz, 2H), 7.74 (br d, J = 8.0 Hz, 1H), 7.63 (d, J = 7.7 Hz, 1H), 7.33 (t, J = 72.3 Hz, 1H), 7.25 (br d, J = 8.5 Hz, 2H), 3.43 (s, 3H), 1.50 (s, 6H).

[1319] Example 402:

[1320] 1 1H NMR (500 MHz, DMSO-d6) δ 9.87 (br s, 1H), 8.87 (br s, 1H), 8.24 (br s, 1H), 7.95 (br d, J = 5.2 Hz, 2H), 7.74 (br s, 1H), 7.46 (br d, J = 6.1 Hz, 2H), 6.93 (br d, J = 12.2 Hz, 2H), 3.62 (br s, 3H), 3.23 (br s, 3H).

[1321] Example {403}:

[1322] 1 H NMR (500 MHz, DMSO-d6) δ 9.82 (s, 1H), 8.06 - 7.93 (m, 3H), 7.73 (d, J = 7.9 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.47 (br d, J = 7.9 Hz, 2H), 7.18 (br d, J = 9.8 Hz, 2H), 3.23 (s, 3H), 2.68 (q, J = 7.4 Hz, 2H), 1.50 (s, 6H), 1.16 - 1.16 (m, 1H), 1.20 (t, J = 7.5 Hz, 2H).

[1323] Example 404:

[1324] 1 H NMR (500 MHz, DMSO-d6) δ 9.69 (s, 1H), 7.99 (br t, J = 7.8 Hz, 1H), 7.92 (br d, J = 8.2 Hz, 2H), 7.74 (br d, J = 7.9 Hz, 1H), 7.61 (br d, J = 7.9 Hz, 1H), 7.34 (t, J = 1.0 Hz, 1H), 7.26 (br d, J = 8.5 Hz, 2H), 6.94 (br t, J = 10.4 Hz, 2H), 3.91 (s, 3H), 3.24 (s, 3H), 1.50 (s, 6H)

[1325] Example 405:

[1326] 1 H NMR (500 MHz, DMSO-d6) δ 9.81 (s, 1H), 8.01 - 7.92 (m, 3H), 7.74 (d, J = 7.9 Hz, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.47 (br d, J = 8.2 Hz, 2H), 6.95 (br d, J = 10.4 Hz, 2H), 3.24 (s, 3H), 1.50 (s, 6H)

[1327] Example 406:

[1328] 1 H NMR (500 MHz, DMSO-d6) δ 9.94 (s, 1H), 8.00 (br t, J = 7.9 Hz, 1H), 7.95 (br d, J = 8.2 Hz, 2H), 7.73 (br d, J = 7.9 Hz, 1H), 7.61 (br dd, J = 15.9, 7.9 Hz, 3H), 7.47 (br d, J = 8.2 Hz, 2H), 3.26 (s, 3H), 1.50 (s, 6H)

[1329] Example 407:

[1330] 1 H NMR(500MHz,CHLOROFORM-d)δ7.96-7.88(m,2H),7.83(d,J=8.7Hz,2H),7.37(br d,J=8.5Hz,1H),7.16(d,J=8.6Hz,2H),7.10(d,J=7.4Hz,2H),6.57(t,J=75.9Hz,1H),3.24(s,3H),1.62(s,6H)

[1331] Example 408:

[1332] 1 H NMR (500MHz, DMSO-d6) δ7.95 (br d, J=8.5Hz, 2H), 7.60 (br d, J=7.9Hz, 2H), 7.47 (br d,J=8.2Hz,2H),6.98(s,1H),6.33(s,1H),4.79(dt,J=12.1,6.0Hz,1H),4.06(s,2H),3.25(s,3H),1.34(d,J=6.1Hz,6H),1.21(s,6H)

[1333] It will be apparent to those skilled in the art that the invention is not limited to the illustrative embodiments described above, and that it may be implemented in other specific forms without departing from its essential properties. Therefore, it is intended that the embodiments be considered illustrative and non-limiting in all respects, and that reference be made to the appended claims, rather than the embodiments described above, and that all variations arising within the equivalent meaning and scope of the claims are intended to be encompassed therein.

Claims

1. A compound of formula I Or its pharmaceutically acceptable salt, wherein R 1 C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxycarbonyl C 1-6 Alkyl, C 3-7 cycloalkyl, (Ar) 1 C 1-6 Alkyl, or Ar 1 ; Ar 1 It is phenyl, pyridinyl, pyridinyl, pyrazinyl, oxadiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, or quinoxalinyl and is determined by 0 to 2 R groups. 5a and 0 to 2 R 5b replace; R 2 C 1-6 alkyl; R 3 It is a phenyl group and has one R 3a and 0 to 2 R 3b replace; R 3a The halogen group at the para position relative to the pyrazol-3-one moiety, C 1-6 Halogenated, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy or C 3-7 Cycloalkyl substituents; R 3b Halogenated, C 1-6 Alkyl or hydroxyl; Or R 3a and adjacent R 3b Together with the two carbon atoms it is attached to, it forms a heteroatom consisting of a carbon atom and 1 to 3 heteroatoms selected from N and NH, and is formed by 0 to 3 carbon atoms. 1-6 Alkyl-substituted 3- to 6-membered heterocycles; R 4 It is phenyl or pyridyl and has one R 4a replace; R 4a For the halogen group located at the para position relative to the amide moiety, C 3-7 cycloalkyl, C 1-6 Halogenated, C 1-6 Haloalkoxy or pyrazolyl substituents; R 5a and R 5b Independently cyano, halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Alkoxy C 1-6 Alkyl, hydroxyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Hydroxyalkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyhaloalkoxy, C 1-6 Hydroxyalkoxy C 1-6 Alkoxy, C 1-6 alkylsulfonyl C 1-6 Alkoxy, C 1-6 Alkoxycarbonyl, C 1-6 Alkoxycarbonyl C 1-6 Alkoxy, C 1-6 alkylsulfonyl, -NR 7 R 8 ; via 0 to 3 hydroxyl groups or C 1-6 alkoxy-substituted C 3-7 Cycloalkyl; phenyl; comprising a carbon atom and 1 to 3 heteroatoms selected from N, NH, O, S and passing through 0 to 3 halogen groups, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated, C 1-6 Alkoxycarbonyl or C 1-6 Alkylsulfonyl-substituted 4- to 8-membered heterocyclic group; heterocyclic oxygen or heterocyclic alkoxy, wherein the heterocyclic moiety of the heterocyclic oxygen or heterocyclic alkoxy comprises 4 to 8 carbon atoms and 1 to 3 heteroatoms selected from N, NH, O, and S; R 6 It is hydrogen; R 7 and R 8 Independently hydrogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 aminocarbonylalkyl, C 1-6 alkylsulfonyl, C 1-6 Alkylaminocarbonyl C 1-6 Alkyl, C 3-7 Cycloalkylaminocarbonyl C 1-6 Alkyl, C 3-7 cycloalkyl C 1-6 Alkyl, C 3-7 Cycloalkyl groups, wherein each cycloalkyl group is derived from 0 to 3 hydroxyl groups, C 1-6 Alkyl or C 1-6 Hydroxyalkyl substitution, or containing a carbon atom and 1 to 3 heteroatoms selected from N, NH, O, and S, and having 0 to 3 C atoms. 1-6 Alkyl-substituted 5- to 8-membered heterocyclic groups; or R 7 and R 8 Together with the nitrogen atom it is attached to, it forms a carbon atom and 0 to 3 other heteroatoms selected from N, NH, O, and S, and is further bounded by 0 to 5 halogen groups, hydroxyl groups, and C groups. 1-6 Alkyl, C 1-6 Alkoxy, oxo, C 1-6 Halogenated, C 3-7 cycloalkyl C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonyl C 1-6 alkyl, aminocarbonyl or C 1-6 Alkoxycarbonyl-substituted 5- to 12-membered heterocycles.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein... R 1 For Ar 1 .

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein... R 3a The halogen group at the para position relative to the pyrazol-3-one moiety, C 1-6 Halogenated, C 1-6 Alkoxy or C 1-6 Deuterated alkoxy substituents; and R 3b It is a halogen group.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein... R 4a Halogenated, C 3-7 cycloalkyl, C 1-6 Halogenated or C 1-6 Haloalkoxy groups.

5. The compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt thereof, wherein the compound has formula II. in Ar 1 for ； R 2 C 1-6 alkyl; R 3a Halogenated, C 1-6 Halogenated, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy or C 3-7 cycloalkyl; R 3b Halogenated, C 1-6 Alkyl or hydroxyl; or R 3a and adjacent R 3b Together with the two carbon atoms it is attached to, it forms a heteroatom consisting of a carbon atom and 1 to 3 heteroatoms selected from N and NH, and is formed by 0 to 3 carbon atoms. 1-6 Alkyl-substituted 3- to 6-membered heterocycles; R 4a Halogenated, C 3-7 cycloalkyl, C 1-6 Halogenated, C 1-6 Haloalkoxy or pyrazolyl; R 5a and R 5b Independently cyano, halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Alkoxy C 1-6 Alkyl, hydroxyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Hydroxyalkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyhaloalkoxy, C 1-6 Hydroxyalkoxy C 1-6 Alkoxy, C 1-6 alkylsulfonyl C 1-6 Alkoxy, C 1-6 Alkoxycarbonyl, C 1-6 Alkoxycarbonyl C 1-6 Alkoxy, C 1-6 alkylsulfonyl, -NR 7 R 8 ; via 0 to 3 hydroxyl groups or C 1-6 alkoxy-substituted C 3-7 Cycloalkyl; phenyl; comprising a carbon atom and 1 to 3 heteroatoms selected from N, O, NH, S and passing through 0 to 3 halogen groups, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated, C 1-6 Alkoxycarbonyl or C 1-6 An alkylsulfonyl-substituted 4- to 8-membered heterocyclic group; a heterocyclic oxygen or heterocyclic alkoxy group, wherein the heterocyclic moiety of the heterocyclic oxygen or heterocyclic alkoxy group comprises 4 to 8 carbon atoms and 1 to 3 heteroatoms selected from N, NH, O, and S; and R 7 and R 8 Independently hydrogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 aminocarbonylalkyl, C 1-6 alkylsulfonyl, C 1-6 Alkylaminocarbonyl C 1-6 Alkyl, C 3-7 Cycloalkylaminocarbonyl C 1-6 Alkyl, C 3-7 cycloalkyl C 1-6 Alkyl, C 3-7 Cycloalkyl groups, wherein each cycloalkyl group is derived from 0 to 3 hydroxyl groups, C 1-6 Alkyl or C 1-6 Hydroxyalkyl substitution, or containing a carbon atom and 1 to 3 heteroatoms selected from N, NH, O, and S, and having 0 to 3 C atoms. 1-6 Alkyl-substituted 5- to 8-membered heterocyclic groups; Or R 7 and R 8 Together with the nitrogen atom it is attached to, it forms a carbon atom and 0 to 3 other heteroatoms selected from N, NH, O, and S, and is further bounded by 0 to 5 halogen groups, hydroxyl groups, and C groups. 1-6 Alkyl, C 1-6 Alkoxy, oxo, C 1-6 Halogenated, C 3-7 cycloalkyl C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonyl C 1-6 alkyl, aminocarbonyl or C 1-6 Alkoxycarbonyl-substituted 5- to 12-membered heterocycles.

6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein... Ar 1 for ; R 5a It is cyano, halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkoxycarbonyl, -NR 7 R 8 ; via 0 to 1 hydroxyl group or C 1-6 alkoxy-substituted C 3-7 Cycloalkyl; phenyl; or comprising a carbon atom and 1 to 3 heteroatoms selected from N, NH, O, S and terminated by 0 to 1 halogen group or C 1-6 Alkyl-substituted 5- to 8-membered heterocyclic groups; R 5b It is cyano, halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 alkoxycarbonyl, or C 3-7 cycloalkyl; and R 7 and R 8 Independently hydrogen, C 1-6 Alkyl, or C 1-6 Hydroxyalkyl; or R 7 and R 8 Together with the nitrogen it is attached to, it forms an additional heteroatom having 0 to 3 selected from N, NH, O, and S, and is further joined by 0 to 3 halogen groups, hydroxyl groups, and C groups. 1-6 Alkyl, C 1-6 Alkoxy or oxo-substituted 5- to 12-membered heterocycles.

7. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein... Ar 1 for ; R 5a C 1-6 Alkyl, C 1-6 Hydroxyalkyl, -NR 7 R 8 ; via 0 to 1 hydroxyl group, C 1-6 Cyclobutyl groups substituted with alkoxy or phenyl groups; R 5b C 1-6 alkoxy groups; and R 7 and R 8 Independently for C 1-6 Alkyl or C 1-6 Hydroxyalkyl; or R 7 and R 8 Together with the nitrogen it is attached to, it forms a group having 0 to 2 additional nitrogen atoms and passing through 0 to 3 halogen groups, hydroxyl groups, and C atoms. 1-6 Alkyl, C 1-6 Alkoxy or oxo-substituted 5- to 12-membered heterocycles.

8. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein... Ar 1 for ; R 5a For -NR 7 R 8 ;and R 7 and R 8 Independently for C 1-6 Alkyl or C 1-6 Hydroxyalkyl; or R 7 and R 8 It forms together with the nitrogen it is attached to 。 9. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein... Ar 1 for ; R 5a It is cyano, halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -NR 7 R 8 Or via 0 to 1 C 1-6 alkoxy-substituted C 3-7 cycloalkyl; R 5b It is cyano, halogen, C 1-6 Alkyl or C 1-6 Halogenated groups; and R 7 and R 8 Independently for C 1-6 Alkyl or C 1-6 Hydroxyalkyl; or R 7 and R 8 It forms together with the nitrogen it is attached to 。 10. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein... Ar 1 for ; R 5a It is cyano, halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; and R 5b It is cyano, halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy groups.

11. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein... Ar 1 for or ;and R 5a C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or C 3-7 Cycloalkyl.

12. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein... Ar 1 for ; R 5a Halogenated, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 alkoxycarbonyl or C-substituted with 0 to 1 hydroxyl group 3-7 cycloalkyl; and R 5b It is cyano, halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkoxycarbonyl or C 3-7 Cycloalkyl.

13. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein... Ar 1 for ; R 5a It is cyano, halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Hydroxyalkyl or C 1-6 alkoxy groups; and R 5b It is cyano, halogen, C 1-6 Alkyl or C 1-6 Halogenated groups.

14. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein... Ar 1 for ; R 5a It is a halogenated group; and R 5b It is a halogen group.

15. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein... Ar 1 for ; R 5a Halogenated, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; and R 5b Halogenated, C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy groups.

16. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound has formula III. in R 2 C 1-6 alkyl; R 3a Halogenated, C 1-6 Halogenated, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Haloalkoxy or C 3-7 cycloalkyl; R 3b Halogenated, C 1-6 Alkyl or hydroxyl; or R 3a and adjacent R 3b Together with the two carbon atoms it is attached to, it forms a heteroatom consisting of a carbon atom and 1 to 3 heteroatoms selected from N and NH, and is formed by 0 to 3 carbon atoms. 1-6 Alkyl-substituted 3- to 6-membered heterocycles; R 4a Halogenated, C 3-7 cycloalkyl, C 1-6 Halogenated, C 1-6 Haloalkoxy or pyrazolyl; R 5a Halogenated, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Hydroxyalkoxy, C 1-6 Alkoxycarbonyl C 1-6 Alkoxy, C 1-6 alkylsulfonyl, -NR 7 R 8 It contains carbon atoms and 1 to 3 heteroatoms selected from N, NH, O, and S, and is connected by 0 to 3 halogen groups and C. 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Alkoxycarbonyl or C 1-6 5- to 8-membered heterocyclic groups substituted with alkyl sulfonyl groups; or heterocyclic oxy or heterocyclic alkoxy groups, wherein the heterocyclic group comprises 5 to 8 carbon atoms and 1 to 3 heteroatoms selected from N, NH, O, and S; R 5b It is cyano, halogen, C 1-6 Alkoxy or C 1-6 Halogenated groups; and R 7 and R 8 Independently hydrogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 aminocarbonylalkyl, C 1-6 alkylsulfonyl, C 1-6 Alkylaminocarbonyl C 1-6 Alkyl, C 3-7 Cycloalkylaminocarbonyl C 1-6 Alkyl, C 3-7 cycloalkyl C 1-6 Alkyl, C 3-7 Cycloalkyl groups, wherein each cycloalkyl group is derived from 0 to 3 hydroxyl groups, C 1-6 Alkyl or C 1-6 Hydroxyalkyl substitution; or containing a carbon atom and 1 to 3 heteroatoms selected from N, NH, O, and S, and having 0 to 3 C atoms. 1-6 Alkyl-substituted 5- to 8-membered heterocyclic groups; or R 7 and R 8 Together with the nitrogen atom it is attached to, it forms a carbon atom and 0 to 3 other heteroatoms selected from N, NH, O, and S, and is further bounded by 0 to 5 halogen groups, hydroxyl groups, and C groups. 1-6 Alkyl, C 1-6 Alkoxy, oxo, C 1-6 Halogenated, C 3-7 cycloalkyl C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonyl C 1-6 alkyl, aminocarbonyl, or C 1-6 Alkoxycarbonyl-substituted 5- to 12-membered heterocycles.

17. The compound of claim 16 or a pharmaceutically acceptable salt thereof, wherein the compound has formula IV. in R 5a Halogenated, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Hydroxyalkoxy, -NR 7 R 8 ,or ; R 5b Halogenated or C 1-6 Halogenated groups; and R 7 and R 8 Independently hydrogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 aminocarbonylalkyl, C 3-7 cycloalkyl, or ; Or R 7 and R 8 It forms together with the nitrogen it is attached to 。 18. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein the compound has formula V in R 5a Halogenated, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Hydroxyalkoxy, -NR 7 R 8 ,or ; R 5b It is Cl or CF3; R 7 It is hydrogen; and R 8 C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 aminocarbonylalkyl, C 3-7 cycloalkyl, or ; or R 7 and R 8 It forms together with the nitrogen it is attached to 。 19. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein the compound has formula VI. Or its pharmaceutically acceptable salt, wherein R 3a Halogenated, C 1-6 Halogenated, C 1-6 Alkoxy, C 1-6 Haloalkoxy, or C 1-6 Deuterated alkoxy groups; R 3b It is a halogenated group; R 4a C 1-6 Haloalkoxy; R 5a It is cyano, halogen, C 1-6 Alkyl, C 1-6 Halogenated, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Hydroxyalkoxy, C 1-6 Hydroxyhaloalkoxy, C 1-6 Hydroxyalkoxy C 1-6 Alkoxy, C 1-6 alkylsulfonyl C 1-6 Alkyl group; comprising a carbon atom and 1 to 3 heteroatoms selected from N, NH, O, and S, and further defined by 0 to 3 halogen groups, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated or C 1-6 An alkylsulfonyl-substituted 5- to 8-membered heterocyclic group; or a heterocyclic alkoxy group, wherein the heterocyclic group comprises 5 to 8 carbon atoms and 1 to 3 heteroatoms selected from N, NH, O, and S; and R 5b It is cyano, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Hydroxylalkoxy group; comprising a carbon atom and 1 to 3 heteroatoms selected from N, NH, O, and S, and further defined by 0 to 3 halogen groups, C 1-6 Alkyl-substituted 5- to 8-membered heterocyclic group; or heterocyclic oxygen group, wherein the heterocyclic moiety comprises 5 to 8 carbon atoms and 1 to 3 heteroatoms selected from N, NH, O, and S.

20. The compound of claim 19 or a pharmaceutically acceptable salt thereof, wherein... R 5a for R 5b It is -OCH3 or CH3.

21. A compound or a pharmaceutically acceptable salt thereof, wherein the compound has formula VII in R 3a It can be Cl, CF3, CD3, OCH3, OCF3, OCHF2, or OCD3; R 4a It is either OCF3 or OCFH2; and R 5a for , or .

22. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein the compound has formula VIII in R 5a It is cyano, C 1-6 Alkyl or C 1-6 Halogenated groups; R 5b It is cyano, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkoxy, -NR 7 R 8 , or ; R 7 It is hydrogen or C 1-6 Alkyl; and R 8 C 1-6 Alkyl or C 1-6 Hydroxyalkyl.

23. A compound or a pharmaceutically acceptable salt thereof, the compound having the following structure: 。 24. A compound or a pharmaceutically acceptable salt thereof, the compound having the following structure: 。 25. A compound or a pharmaceutically acceptable salt thereof, the compound having any of the following structures: 。 26. A pharmaceutical composition comprising a compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

27. Use of the compound of any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 26 in the preparation of a medicament for treating heart disease.

28. The use according to claim 27, wherein the heart disease is selected from the group consisting of angina pectoris, myocardial infarction, heart failure, acute coronary artery disease, and iatrogenic cardiac injury.

29. The use according to claim 28, wherein the heart failure is selected from the group consisting of: congestive heart failure, systolic heart failure, diastolic heart failure, and low ejection fraction heart failure (HF). R EF), heart failure with preserved ejection fraction (HF) P EF), acute heart failure, and chronic heart failure of ischemic and non-ischemic origin.

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