Pyrazolone formyl peptide 2 receptor agonist

Abstract

The present disclosure relates to compounds of Formula I, which are formylpeptide 2 (FPR2) receptor agonists. The disclosure also provides compositions and methods using the compounds to treat, for example, atherosclerosis, heart failure, chronic obstructive pulmonary disease (COPD), and related diseases. TIFF2023533039000208.tif37142

Description

Technical Field

[0001] Cross - reference to related applications This application claims priority under 35 U.S.C.§119(e) to U.S. Provisional Patent Application No. 63 / 049,831, filed July 9, 2020, the entire content of which is incorporated herein by reference.

Background Art

[0002] The present invention relates to novel pyrazolone compounds of formula I which are formyl peptide 2 (FPR2) receptor agonists, and also to compositions containing such compounds for treating, for example, atherosclerosis, heart failure, chronic obstructive pulmonary disease (COPD) and related diseases, and to methods of using them therefor.

[0003] Formyl peptide receptor 2 (FPR2) belongs to a small group of seven - transmembrane domain G - protein - coupled receptors that are expressed in multiple human tissues (including immune cells) and are known to be important in host defense and inflammation. FPR2 shares significant sequence homology with FPR1 and FPR3 (Chen K. et al., Journal of Autoimmunity 85, 2017, 64 - 77). Collectively, these receptors bind to many structurally different agonists that act as chemoattractants, including N - formyl and non - formyl peptides, and activate phagocytes. Endogenous peptide Annexin A1 and its N - terminal fragment are examples of ligands that bind to human FPR1 and FPR2. Fatty acids such as eicosanoids, lipoxin A4, which belong to the group of small pro - resolution mediators (SPM), have also been reported as agonists of FPR2 (Ye RD. et al., Pharmacol. Rev., 2009, 61, 119 - 61).

[0004] Endogenous FPR2 pro - resolution ligands such as lipoxin A4 and Annexin A1 are Gi - coupled, Ca 2+It has been reported to trigger diverse cytoplasmic cascades such as mobilization and β-arrestin replenishment (Cattaneo, F. et al., Int J Mol Sci. 2013 April;14(4):7193-7230). FPR2 controls both innate and adaptive immune systems, including neutrophils, macrophages, T cells, and B cells. In neutrophils, FPR2 ligands control activity, cytotoxicity, and lifespan. In macrophages, activation of FPR2 prevents apoptosis and enhances efferocytosis (Chandrasekharan JA, Sharma-Walia N, J. Inflamm. Res., 2015, 8, 181-92). The onset of inflammation resolution by activation of FPR2 has been associated with enhanced anti-fibrotic wound healing and return to homeostasis of damaged tissues (Romano M. et al., Eur. J. Pharmacol., 2015, 5, 49-63).

[0005] Chronic inflammation is part of the pathway that causes many human diseases, and stimulating the inflammation resolution pathway with FPR2 agonists may have both protective and reparative effects. Ischemia-reperfusion (I / R) injury is a common feature of several diseases associated with high morbidity and mortality, such as myocardial infarction and stroke. The non-productive wound healing associated with cardiomyocyte death and pathological remodeling resulting from I / R injury leads to scar formation, fibrosis, and progressive loss of cardiac function. FPR2 modulation has been proposed to enhance myocardial wound healing and reduce harmful myocardial remodeling after injury (Kain V. et al., J. Mol. Cell. Cardiol., 2015, 84, 24-35). In addition, FPR2 inflammation resolution agonists in the central nervous system may be useful therapeutic agents for treating various clinical I / R conditions, 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).

[0006] In addition to the beneficial effects of targeting the FPR2 receptor with novel anti-inflammatory agonists for treating I / R-induced injury, the utility of these ligands may also be applicable to other diseases. In the cardiovascular system, it has been found that both the FPR2 receptor and its anti-inflammatory agonists are involved in the stabilization and healing of 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, eye inflammation, sepsis, pain, metabolism / diabetes, 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

[0007] The present invention provides novel oxopyrrolidines and analogs thereof (including their stereoisomers, tautomers, pharmaceutically acceptable salts or solvates) that are useful as FPR2 agonists. The present invention also provides methods and intermediates for preparing the compounds of the present invention, or their stereoisomers, tautomers, pharmaceutically acceptable salts or solvates.

[0008] The present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound of the compound of the present invention, or its stereoisomers, tautomers, pharmaceutically acceptable salts or solvates. The compounds of the present invention may be used in therapy.

[0009] The compounds of the present invention can be used in the treatment and / or prevention of a plurality of diseases or disorders associated with FPR2, such as inflammatory diseases, heart diseases, chronic airway diseases, cancer, sepsis, allergic symptoms, HIV retroviral infection, circulatory disorders, neuroinflammation, neuropathy, pain, prion diseases, amyloidosis, and immune disorders. Heart diseases include, but are not limited to, angina pectoris, unstable angina, myocardial infarction, acute coronary disease, cardiac iatrogenic injury, and heart failure (acute heart failure, chronic heart failure of ischemic and non-ischemic origin, systolic heart failure, diastolic heart failure, heart failure with reduced left ventricular systolic function (HF R EF), and heart failure with preserved left ventricular systolic function (HF P EF)), and are selected from the group consisting of.

[0010] 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. Other features and advantages of the present invention will be apparent from the following detailed description and claims.

Mode for Carrying Out the Invention

[0011] The present invention encompasses compounds of formula I that are formyl peptide 2 (FPR2) receptor agonists, compositions containing such compounds, and methods of using them, for example, in the treatment of atherosclerosis, heart failure, chronic obstructive pulmonary disease (COPD) and related diseases.

[0012] One aspect of the present invention is formula I:

Chemical formula

[0013] Another aspect of the present invention is that R 1 is Ar 1 and is a compound of formula I or a pharmaceutically acceptable salt thereof. Another aspect of the present invention is that R 2 is alkyl or haloalkyl and is a compound of formula I or a pharmaceutically acceptable salt thereof.

[0014] Another aspect of the present invention is a compound represented by formula I or a pharmaceutically acceptable salt thereof, wherein R 3 is phenyl substituted with one R 3a and 0-2 R 3b ; R 3a is a halo, alkyl, haloalkyl, alkoxy, or deuterated alkoxy substituent para to the pyrazol-3-one moiety; R 3b is halo or haloalkyl, a compound or a pharmaceutically acceptable salt thereof.

[0015] Another aspect of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein R 3 is pyridinyl substituted at the 4-position relative to the pyrazol-3-one moiety with one halo, haloalkylalkoxy, or haloalkoxy substituent and substituted with 0-2 additional halo or haloalkyl substituents, a compound or a pharmaceutically acceptable salt thereof.

[0016] Another aspect of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein R 4 is phenyl or pyridinyl substituted at the para position relative to the amide moiety with one R 4a and substituted with 0-2 R 4b ; R 4a is halo, alkyl, cycloalkyl, haloalkyl, alkoxy, or haloalkoxy; R 4b is halo or haloalkyl, a compound or a pharmaceutically acceptable salt thereof.

[0017] Another aspect of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein R 4 is pyridinyl (substituted at the 4-position relative to the amide moiety with one halo, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, or pyrazolyl substituent and substituted with 0-2 additional halo or haloalkyl substituents), a compound or a pharmaceutically acceptable salt thereof. Another aspect of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein Ar 1 is phenyl (substituted with 0 to 3 substituents selected from cyano, halo, alkyl, cycloalkyl, haloalkyl, alkoxy, hydroxyalkyl, carboxamide, haloalkoxy, and phenyl), a compound or a pharmaceutically acceptable salt thereof.

[0018] Another aspect of the present invention is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein Ar 1 is pyridinyl (substituted with 0 to 3 substituents selected from cyano, halo, alkyl, cycloalkyl, haloalkyl, alkoxy, hydroxyalkyl, carboxamide, haloalkoxy, and phenyl), a compound or a pharmaceutically acceptable salt thereof.

[0019] Another aspect of the present invention is formula II:

Chemical formula

Chemical formula

[0020] Another aspect of the present invention is a compound of formula II or a pharmaceutically acceptable salt thereof, wherein Ar 1 is

Chemical formula

[0021] Another aspect of the present invention is a compound represented by formula II or a pharmaceutically acceptable salt thereof, wherein Ar 1 is

Chemical formula

[0022] Another aspect of the present invention is a compound of formula II or a pharmaceutically acceptable salt thereof, wherein R 5a is -NR 7 R 8 and; R 7 and R 8 are independently alkyl or hydroxyalkyl; or R 7 and R 8 together with the nitrogen to which they are attached form

Chemical formula

[0023] Another aspect of the present invention is a compound of formula II or a pharmaceutically acceptable salt thereof, wherein Ar 1 is

Chemical formula

Chemical formula

[0024] Another aspect of the present invention is a compound represented by formula II or a pharmaceutically acceptable salt thereof, wherein Ar 1 is

Chemical formula

[0025] Another aspect of the present invention is a compound represented by formula II or a pharmaceutically acceptable salt thereof, wherein Ar 1 is

Chemical formula

[0026] Another aspect of the present invention is a compound represented by Formula II or a pharmaceutically acceptable salt thereof, wherein Ar 1 is

Chem.

[0027] Another aspect of the present invention is a compound represented by Formula II or a pharmaceutically acceptable salt thereof, wherein Ar 1 is

Chem.

[0028] Another aspect of the present invention is a compound represented by formula II or a pharmaceutically acceptable salt thereof, wherein Ar 1 is

Chemical formula

[0029] Another aspect of the present invention is a compound represented by formula II or a pharmaceutically acceptable salt thereof, wherein Ar 1 is

Chemical formula

[0030] Another aspect of the present invention is formula III:

Chemical formula

[0031] Another aspect of the present invention is Formula IV:

Chemical formula

Chemical formula

Chem.

Chem.

[0032] Another aspect of the present invention is formula V:

Chem.

Chem.

[0033] Another aspect of the present invention is formula VI: [Chemistry] [wherein: R 3a is halo, alkyl, alkoxy, or deuterated alkoxy; R 3b is halo; R 4a is haloalkoxy; R 5a is cyano, halo, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkoxy, hydroxyalkoxy, hydroxyhaloalkoxy, hydroxyalkoxyalkoxy, alkylsulfonylalkoxy, a 5- to 8-membered heterocyclyl (containing a carbon atom and 1 to 3 heteroatoms selected from N, NH, O, S, and substituted with 0 to 3 halo, alkyl, hydroxyalkyl, haloalkyl, or alkylsulfonyl), or heterocyclylalkoxy (wherein the heterocyclyl contains 5 to 8 carbon atoms and 1 to 3 heteroatoms selected from N, NH, O, S, and is substituted with 0 to 3 halo, hydroxy, hydroxyalkyl, alkyl, or haloalkyl); and R 5bis cyano, alkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, a 5- to 8-membered heterocyclyl (including a carbon atom and 1 to 3 heteroatoms selected from N, NH, O, S, and substituted with 0 to 3 halo, alkyl, or heterocyclyloxy), where the heterocyclyl moiety contains 5 to 8 carbon atoms and 1 to 3 heteroatoms selected from N, NH, O, S, and is substituted with alkyl, heterocyclyl (substituted with 0 to 1 alkyl)] is a compound represented by the formula or a pharmaceutically acceptable salt thereof.

[0034] Another aspect of the present invention is a compound of formula VI or a pharmaceutically acceptable salt thereof, wherein R 5a is

Chemical formula

[0035] Another aspect of the present invention is formula VII:

Chemical formula

Chemical formula

[0036] ​Another aspect of the present invention is formula VIII: [Chemical formula] [Wherein: R 5a is cyano, alkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, -NR 7 R 8 , [Chemical formula] ; R 5b is cyano, alkyl, or haloalkyl; R 7 is hydrogen or alkyl; R 8 is alkyl or hydroxyalkyl] is a compound represented by or a pharmaceutically acceptable salt thereof.

[0037] In the compounds of formulas I - VIII, the scope of any example of a variable substituent can be used independently of the scope of any other example of a variable substituent. Thus, the present invention encompasses combinations of different aspects.

[0038] In a non - limiting embodiment of 1, in the compound of formula (I), R 1 is Ar 1 or (Ar 1 ) alkyl; Ar 1 is phenyl (substituted with 0 - 2 R 5a or 0 - 2 R 5b ); R 5a and R 5b are, independently, halo, alkyl, hydroxyalkyl, haloalkyl, alkoxy, alkoxycarbonyl; R 2 is lower alkyl; R 3 is phenyl (substituted with 1 R 3a and substituted with 0 - 2 R 3b ); R 3a is alkoxy; R 3b is halo; R 4is phenyl (substituted with one R 4a ); R 4a is haloalkyl or haloalkoxy; and R 6 is hydrogen.

[0039] In another non-limiting embodiment, in the compound of formula (I), R 1 is Ar 1 ; Ar 1 is cycloalkyl (substituted with 0 - 2 R 5a or 0 - 2 R 5b ); R 5a and R 5b are, independently, halo, alkyl, hydroxyalkyl, haloalkyl, alkoxy, alkoxycarbonyl; R 2 is lower alkyl; R 3 is phenyl (substituted with one R 3a and 0 - 2 R 3b ); R 3a is alkoxy; R 3b is halo; R 4 is phenyl (substituted with one R 4a ); R 4a is haloalkyl or haloalkoxy; and R 6 is hydrogen.

[0040] In another non-limiting embodiment, in the compound of formula (I), R 1 is Ar 1 ; Ar 1 is quinolinyl (substituted with 0 - 2 R 5a or 0 - 2 R 5b ); R 5a and R 5b are, independently, halo, alkyl, hydroxyalkyl, haloalkyl, alkoxy, alkoxycarbonyl; R 2 is lower alkyl; R 3 is phenyl (substituted with one R 3a and 0 - 2 R 3b ); R 3a is alkoxy; R 3b is halo; R4 is phenyl (substituted by one R 4a ); R 4a is haloalkyl or haloalkoxy; and R 6 is hydrogen.

[0041] In one non-limiting embodiment of formula (I), for the compound of formula (I), R 1 is Ar 1 ; Ar 1 is pyridinyl (substituted by one R 5a ); R 5a is halo, alkyl, hydroxyalkyl, haloalkyl, alkoxy, alkoxycarbonyl; R 2 is lower alkyl; R 3 is phenyl (substituted by one R 3a and 0 - 2 R 3b ); R 3a is alkoxy; R 3b is halo; R 4 is phenyl (substituted by one R 4a ); R 4a is haloalkyl or haloalkoxy; R 6 is hydrogen.

[0042] In another non-limiting embodiment of formula (I), for the compound of formula (I), R 1 is Ar 1 ; Ar 1 is pyridinyl (substituted by one R 5a ); R 5a is F, Cl, -CHF2, -CF3, -CH2OH, -C(CH3)2OH, -OCH3, -OCH(CH3)2, -O(CH3)2OH, -OCH2C(CH3)2OH, or -C(CH3)2OH; R 2 is -CH3; R 3 is phenyl (substituted by one R 3a and 0 - 2 R 3b ); R 3a is methoxy, ethoxy, deuteromethoxy or deuteroethoxy; R 3b is halo; R 4is phenyl (substituted by one R 4a ); R 4a is -CF3, -OCHF2, or -OCF3; R 6 is hydrogen.

[0043] In another non-limiting embodiment, in the compound of formula (I), R 1 is Ar 1 ; Ar 1 is pyridinyl (substituted by one R 5a ); R 5a is -NR 7 R 8 ; R 2 is -CH3; R 3 is phenyl (substituted by one R 3a and 0 to 2 R 3b ); R 3a is methoxy, ethoxy, deuterated methoxy, or deuterated ethoxy; R 3b is halo; R 4 is phenyl (substituted by one R 4a ); R 4a is -CF3, -OCHF2, or -OCF3; R 6 is hydrogen; R 7 and R 8 are, independently, hydrogen, -CH3, or -CH2CH3; or R 7 and R 8 together with the nitrogen to which they are attached form

Chemical formula

[0044] In one non-limiting embodiment, in the compound of formula (I), R 1 is Ar 1 ; Ar 1 is pyridinyl (substituted by 0 to 2 R 5a or 0 to 2 R 5b ); R 5a and R 5bis, independently, halo, alkyl, hydroxyalkyl, haloalkyl, alkoxy, alkoxycarbonyl; R 2 is lower alkyl; R 3 is phenyl (substituted by one R 3a and 0 to 2 R 3b ); R 3a is alkoxy; R 3b is halo; R 4 is phenyl (substituted by one R 4a ); R 4a is haloalkyl or haloalkoxy; and R 6 is hydrogen.

[0045] In yet another non-limiting embodiment, in the compound of formula (I), R 1 is Ar 1 ; Ar 1 is pyridinyl (substituted by one R 5a or 0 to 1 R 5b ); R 5a and R 5b are, independently, F, Cl, -CHF2, or -CF3, -CH2OH, -C(CH3)2OH, -CF3, -OCH3, -OCH(CH3)2, -O(CH3)2OH, -OCH2C(CH3)2OH, -C(CH3)2OH; R 2 is CH3; R 3 is phenyl (substituted by one R 3a and 0 to 2 R 3b ); R 3a is methoxy, ethoxy, deuteromethoxy, or deuteroethoxy; R 3b is halo; R 4 is phenyl (substituted by one R 4a ); R 4a is CF3, OCHF2, or OCF3; and R 6 is hydrogen.

[0046] In yet another non-limiting embodiment, in the compound of formula (I), R 1 is Ar 1 ; Ar 1is pyridinyl (substituted with one R 5a or one R 5b ); R 5a is cycloalkyl (substituted with hydroxy); R 5b is alkoxy; R 2 is CH3; R 3 is phenyl (substituted with one R 3a and zero to two R 3b ); R 3a is methoxy, ethoxy, deuteromethoxy, or deuteroethoxy; R 3b is halo; R 4 is phenyl (substituted with one R 4a ); R 4a is CF3, OCHF2, or OCF3; and R 6 is hydrogen.

[0047] In yet another non-limiting embodiment, in the compounds of formula (I), R 1 is Ar 1 ; Ar 1 is pyridinyl (substituted with one R 5a or one R 5b ); R 5a is -OCH(CH3)2, -O(CH3)2OH, -OCH2C(CH3)2OH, or -NR 7 R 8 ; R 5b is -CF3 or -OCH3; R 2 is CH3; R 3 is phenyl (substituted with one R 3a and zero to two R 3b ); R 3a is methoxy, ethoxy, deuteromethoxy, or deuteroethoxy; R 3b is halo; R 4 is phenyl (substituted with one R 4a ); R 4a is CF3, OCHF2, or OCF3; R 6 is hydrogen; R 7 and R 8is hydrogen, CH3, CH2CH3, -CH2CH2OH, -CH2CH(OH)CH3,

Chem.

Chem.

[0048] In another non-limiting embodiment, in the compound of formula (I), R 1 is Ar 1 ; Ar 1 is

Chem.

Chem.

[0049] In another non - limiting embodiment, for the compound of formula (I), R 1 is Ar 1 ; Ar 1 is [Chemical formula] ; R 5a is [Chemical formula] ; R 5b is -CH3 or -OCH3; R 2 is -CH3; R 3 is phenyl (substituted with one R 3a and 0 - 2 R 3b ); R 3a is methoxy, ethoxy, deuterated methoxy, or deuterated ethoxy; R 3b is halo; R 4 is phenyl (substituted with one R 4a ); R 4a is CF3, OCHF2, or OCF3; and R 6 is hydrogen.

[0050] In another non - limiting embodiment, for the compound of formula (I), R 1 is Ar 1 ; Ar 1 is [Chemical formula] ; R 5a is -CH3, -OCH2CH2OH, -OCH2C(OH)CF3, -OCH(CF3)CH2OH, OCH2CH2S(O)2CH3, [Chemical formula] or -NR 7 R 8and; R 5b is CH3 or -OCH3; R 2 is CH3; R 3 is phenyl (substituted by 1 R 3a and 0 - 2 R 3b ); R 3a is methoxy, ethoxy, deuteromethoxy, or deuteroethoxy; R 3b is halo; R 4 is phenyl (substituted by 1 R 4a ); R 4a is CF3, OCHF2, or OCF3; R 6 is hydrogen; R 7 and R 8 , together with the nitrogen to which they are attached,

Chemical formula

[0051] In another non - limiting embodiment, for the compound of formula (I), R 1 is Ar 1 ; Ar 1 is

Chemical formula

Chem.

Chem.

[0052] In another embodiment, the compound of the present invention is selected from compounds having an FPR2 EC 50 value of > 0.1 μM. In another embodiment, the compound of the present invention is selected from compounds having an FPR2 EC 50 value of > 0.01 μM and < 0.1 μM. In another embodiment, the compound of the present invention is selected from compounds having an FPR2 EC 50 value of > 0.006 μM and < 0.01 μM. In another embodiment, the compound of the present invention is selected from compounds having an FPR2 EC 50 value of > 0.001 μM and < 0.006 μM. In another embodiment, the compound of the present invention is selected from compounds having an FPR2 EC 50 value < 0.001 μM.

[0053] Unless otherwise specified, these terms have the following meanings. A dash "-" not between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -CONH2 is attached via a carbon atom.

[0054] As used in the structural formulas herein, [Chem.] Bonds directed toward wavy lines such as etc. represent that the moiety or substituent is attached at the point where it is attached to the core or skeletal structure. "Cyano" means -CN. "Hydroxy" means -OH.

[0055] "Alkyl" means a straight-chain or branched alkyl group consisting of 1 to 6 carbons. "Lower alkyl" means a straight-chain or branched alkyl group consisting of 1 to 3 carbons. "Alkenyl" means a straight-chain or branched alkyl group consisting of 2 to 6 carbons and at least 1 double bond. "Alkynyl" means a straight-chain or branched alkyl group consisting of 2 to 6 carbons and at least 1 triple bond. Terms having a hydrocarbon moiety (e.g., alkoxy) include straight-chain or branched isomers in the hydrocarbon moiety.

[0056] "Cycloalkyl" means a monocyclic ring system consisting of 3 to 7 carbons. Terms having a hydrocarbon moiety (e.g., alkoxy) include straight-chain or branched isomers in the hydrocarbon moiety. "Halo" refers to fluoro, chloro, bromo, and iodo. "Haloalkyl" refers to a halo-substituted alkyl group. Haloalkyl includes all halogenated isomers from monohalo to perhalo.

[0057] "Alkoxy" means an alkyl group attached to the residue of the molecule via an oxygen linkage. Representative examples of such groups are -OCH3 and -OC2H5. Unless otherwise stated or indicated, all alkoxy groups described or claimed in this specification may be either straight-chain or branched-chain. 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" group is -OCD3.

[0058] "Alkoxyalkoxy" refers to an alkoxy group in which at least one hydrogen atom of the alkoxy group is substituted with another alkoxy group. "Hydroxyalkoxyalkoxy" refers to an alkoxyalkoxy group in which at least one hydrogen atom of the alkoxyalkoxy group is substituted with a hydroxy group. "Hydroxyhaloalkoxy" refers to an alkoxy group in which at least one hydrogen atom of the alkoxy group is substituted with a halo group and at least one hydrogen atom of the alkoxy group is substituted with a hydroxy group.

[0059] "Alkylsulfonylalkoxy" refers to an alkoxy group in which at least one hydrogen atom of the alkoxy group is substituted with an alkylsulfonyl group. "Heterocyclylalkoxy" refers to an alkoxy group in which at least one hydrogen atom of the alkoxy group is substituted with a heterocyclyl group. "Alkylsulfonyl" refers to the group -SO2-alkyl, where alkyl is as defined herein. "Hydroxyalkyl" refers to an alkyl group in which at least one hydrogen atom is substituted with a hydroxy group. "Alkoxyalkyl" refers to an alkyl group in which at least one hydrogen atom is substituted with an alkoxy group.

[0060] "Haloalkoxy" refers to a halo-substituted alkyl group linked via an oxygen atom. Haloalkoxy encompasses mono-substituted as well as poly-halo-substituted alkoxy groups up to perhalo-substituted alkoxy. For example, trifluoromethoxy, chloromethoxy, and bromomethoxy are included. "Alkoxycarbonyl" refers to an alkoxy-substituted carbonyl group (such as -C(O)OR), where R represents an alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl or similar group which may optionally be substituted. "Aminocarbonylalkyl" refers to the group "-alkyl-C(O)NRR", where each R represents hydrogen or an alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl or similar group which may optionally be substituted.

[0061] "Aryl" refers to a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 12 carbon atoms or a bicyclic condensed ring system in which one or both of the rings are aromatic. The bicyclic condensed ring system consists of phenyl groups condensed to a 4- to 7-membered aromatic or non-aromatic carbocyclic ring. Representative examples of aryl groups include, but are not limited to, phenyl, indanyl, indenyl, naphthyl, and tetrahydronaphthyl. "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.

[0062] "Heterocyclyl" or "heterocycle" refers to a saturated, partially unsaturated or fully unsaturated 5- to 7-membered monocyclic or 8- to 11-membered bicyclic heterocyclic ring containing carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O and S, including any polycyclic group in which any of the above heterocyclic rings is fused to a benzene ring. The heteroatoms of nitrogen and sulfur may optionally be oxidized (i.e., N→O and S(O) pwhere p is 0, 1 or 2). The nitrogen atom may or may not be substituted (i.e., it is N or NR, where R, if defined, is H or another substituent). The heterocyclic ring may be attached to its pendant group by any heteroatom or carbon atom, and a stable structure may be provided. The heterocyclic rings described herein may be substituted on a carbon atom or on a nitrogen atom provided that the resulting compound is stable. The nitrogen of the heterocycle may optionally be quaternized. When the total number of S and O atoms in the heterocycle exceeds 1, then preferably these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heterocycle is 1 or less. When the term "heterocycle" is used, it is intended to include heteroaryl.

[0063] "Heterocyclyloxy" refers to the group -O-heterocyclyl, where the heterocyclyl is as defined herein. "Heterocyclylalkyl" refers to an alkyl group in which at least one hydrogen atom is substituted with a heterocyclyl as described herein. When the bonding position is not specified, the bond may be made at any appropriate position, as will be understood by those skilled in the art. The combinations of substituents and bonding patterns are only those combinations that result in stable compounds, as will be understood by those skilled in the art. The terms in parentheses and multiple parentheses are intended to clarify the bonding relationship to those skilled in the art. For example, the term ((R)alkyl) means an alkyl substituent further substituted with the substituent R.

[0064] R 3a Some examples of compounds where R is a substituent in the para position to the pyrazol-3-one are shown below.

Chemical formula

[0065] R 4aSome examples of the compounds are shown below, which are substituents para to the amide moiety. [Chemical formula]

[0066] The present invention encompasses all forms of pharmaceutically acceptable salts of the compound. Pharmaceutically acceptable salts are those in which the counterion does not significantly contribute to the physiological activity or toxicity of the compound and which itself functions as a pharmacological equivalent. These salts can be prepared using commercially available reagents according to common organic techniques. Some forms of anionic salts include acetate, ascorbate, besylate, bromide, chloride, citrate, fumarate, glucuronate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, and quinoate. Some forms of cationic salts include ammonium, aluminum, benzathine, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium, tromethamine, and zinc.

[0067] Some compounds of the present invention exist in the form of stereoisomers, including those below the carbon whose structure is specified. The present invention encompasses compounds in all forms of stereoisomers, including enantiomers and diastereomers. Methods for the production and separation of stereoisomers are known in the art. The present invention encompasses compounds in all forms of tautomers. The present invention encompasses atropisomers and rotational isomers.

[0068] The present invention is intended to encompass all isotopes of the atoms present in the compound. Isotopes include those atoms that have the same atomic number but different mass numbers. By way of general example, without limitation, isotopes of hydrogen include deuterium (D) and tritium (T). Isotopes of carbon are 11 C,13 C and 14 C. The isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or, in other cases, by using appropriately isotopically labeled reagents in place of the unlabeled reagents utilized, by methods similar to those described herein. Such compounds have various potential uses, for example, potential use as reagents in measuring standards and biological activities. When the isotope is stable, such compounds may preferably modify biological, pharmacological, or pharmacokinetic properties.

[0069] Biological methods The N-formyl peptide receptor (FPR) is a family of chemotactic receptors that promote the leukocyte response during inflammation. FPR belongs to the seven-transmembrane G-protein-coupled receptor superfamily and binds to the inhibitory G protein (Gi). Three family members (FPR1, FPR2, and FPR3) have been identified in humans, are mainly found in a diverse distribution in bone marrow cells, and have also been reported in multiple organs and tissues. After binding to an agonist, FPR activates a number of physiological pathways such as intracellular signaling, Ca 2+ mobilization, and transcription. The family interacts with a diverse series of ligands, including proteins, polypeptides, and fatty acid metabolites, that activate downstream responses in both inflammation induction and inflammation resolution. The in vitro activity of the compounds disclosed in the present application was measured using the cyclic adenosine monophosphate (cAMP) assays for FPR2 and FPR1.

[0070] FPR2 and FPR1 cyclic adenosine monophosphate (cAMP) assays A mixture of forskolin (final 5 μM for FPR2 or final 10 μM for FPR1) and IBMX (final 200 μM) was added to a 384-well Proxiplate (Perkin-Elmer) pre-dotted with test compound / DMSO (final 1%) at final concentrations in the range of 0.020 nM to 100 μM. Chinese Hamster Ovary (CHO) cells overexpressing human FPR1 or human FPR2 receptor were cultured in F-12 (Ham) medium supplemented with 10% modified 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 PBS (containing calcium and magnesium) (Life Technologies) supplemented with 0.1% BSA (Perkin-Elmer). The reaction mixture was incubated at room temperature for 30 minutes. The level of intracellular cAMP was measured using the HTRF HiRange cAMP assay reagent kit (Cisbio) according to the manufacturer's instructions. Solutions of cryptate conjugate anti-cAMP and d2 fluorophore-labeled cAMP were prepared separately in the supplied lysis buffer. After the reaction was completed, the cells were lysed with an equal volume of d2cAMP solution and anti-cAMP solution. After incubation at room temperature for 1 hour, the time-resolved fluorescence intensity was measured using Envision (Perkin-Elmer) with excitation at 400 nm and dual emission at 590 nm and 665 nm. An external cAMP standard was used at concentrations in the range of 1 μM to 0.1 pM, and a calibration curve was created by plotting the fluorescence ratio of the emission intensity at 665 nm to the emission intensity at 590 nm against the cAMP concentration. Next, the potency and activity of the compound to inhibit cAMP production were determined by fitting to a four-parameter logistic equation with the cAMP level plotted against the concentration of the compound.

[0071] The examples disclosed below were tested in the above FPR2 and FPR1 cAMP assays and were found to have FPR2 and / or FPR1 agonist activity. Table 1 below lists the EC 50 values.

[0072] Table 1 [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6]

[0073] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11] [Table 12] [Table 13]

[0074] Pharmaceutical Composition and Method of Use The compounds of the present invention can be administered to mammals, preferably humans, for the treatment of various conditions and disorders including atherosclerotic diseases, heart failure, asthma, COPD, and pulmonary diseases including 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.

[0075] Unless otherwise specified, the following terms have their defined meanings. The term "subject" refers to either a human or other mammalian species that can benefit from treatment with an FPR2 and / or FPR1 agonist, as understood by those skilled in the art. A subject includes humans of an age with risk factors for cardiovascular disease. Common risk factors include age, gender, weight, family history, sleep apnea, alcohol or tobacco use, lack of exercise, arrhythmia, or signs of insulin resistance such as acanthosis nigricans, hypertension, dyslipidemia, or polycystic ovary syndrome (PCOS). The term "patient" means a human suitable for treatment, as defined by those skilled in the art. "Treat" or "treatment" extends to the treatment of a patient or subject, as understood by those skilled in the art. "Prevent" or "prevention" extends to the prophylactic treatment (i.e., prevention and / or risk reduction) of asymptomatic conditions in a patient or subject, aimed at reducing the likelihood of the occurrence of a clinical condition, as understood by those skilled in the art. Patients are selected for prophylactic treatment based on factors known to increase the risk of developing a clinical condition compared to the general population. "Therapeutically effective amount" means an amount of a compound that is effective, as understood by those skilled in the art.

[0076] Another aspect of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formulas I - VIII in combination with a pharmaceutical carrier. Another aspect of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formulas I - VIII in combination with at least one other therapeutic agent and a pharmaceutical carrier.

[0077] "Pharmaceutical composition" means a composition comprising a compound of the present invention in combination with at least one further pharmaceutically acceptable carrier. "Pharmaceutically acceptable carrier" refers to a medium generally acceptable in the art for delivering a biologically active agent to an animal, particularly a mammal, i.e., a diluent, preservative, bulking agent, flow regulator, disintegrant, wetting agent, emulsifying agent, anti-precipitant, sweetening agent, flavoring and masking agent, fragrance, antibacterial agent, antifungal agent, lubricant, and dispersing agent, etc., according to the characteristics of the administration method and dosage form, including adjuvants, excipients or vehicles.

[0078] Pharmaceutically acceptable carriers are formulated according to a number of well-known factors within the purview of those skilled in the art. These include, but are not limited to, the type and properties of the active agent being formulated; the subject to which the composition containing the agent is to be administered; the intended route of administration of the composition; 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. Such carriers can contain, in addition to the active agent, many different components and additives, and for various reasons, such as to stabilize the active agent, such further components are incorporated into the composition and are well-known to those skilled in the art, such as binders. Descriptions of suitable pharmaceutically acceptable carriers and the factors involved in their selection can be found in various readily available sources of information, such as Allen, L.V., Jr. et al., Remington: The Science and Practice of Pharmacy (2 volumes), 22nd edition, Pharmaceutical Press (2012).

[0079] Particularly when provided as a single dosage unit, there may be a chemical interaction between the combined active ingredients. For this reason, when the compounds of the present invention and a second therapeutic agent are combined in a single dosage unit, the active ingredients are combined in a single dosage unit, but the active ingredients are formulated such that physical contact between them is minimized (i.e., reduced). For example, one of the active ingredients may be enterically coated. By enterically coating one of the active ingredients, it is possible not only to minimize contact between the combined active ingredients, but also to adjust the release of one of these ingredients in the gastrointestinal tract such that one of these ingredients is not released in the stomach but rather in the intestine. One of the active ingredients may be coated with a material that affects sustained release throughout the gastrointestinal tract and serves to minimize physical contact between the combined active ingredients. Furthermore, the sustained release component may additionally be enterically coated such that release of this component occurs only in the intestine. Yet another method is a formulation of the combination product, which also encompasses a formulation in which one component is coated with a sustained and / or enteric release polymer to further separate the active ingredients, and the other component is also coated with a polymer such as a low viscosity grade of hydroxypropyl methylcellulose (HPMC) or other suitable material known in the art. The polymer coating serves to form an additional partition against interaction with other components.

[0080] 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 Formulas I - VIII. 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, myocardial infarction, heart failure, acute coronary disease, acute heart failure, chronic heart failure, and cardiac iatrogenic injury.

[0081] It will be understood that the treatment or prevention of heart failure may also encompass the treatment or prevention of cardiovascular events thereon. As used herein, the treatment or prevention refers to the treatment or prevention of specific negative signs or symptoms that accompany or result from the consequences of cardiovascular events. By way of example, the treatment or prevention includes reducing or preventing negative changes in the fractional shortening of the left ventricular internal diameter, heart weight, lung weight, cross-sectional area of muscle cells, pressure overload-induced cardiac fibrosis, stress-induced cellular senescence, and / or cardiac hypertrophy characteristics, or any combination thereof, that accompany or result from the consequences of cardiovascular events. Treatment may be administered with or in response to an agent for cardiovascular events and may mitigate negative effects. Prevention includes proactive or prophylactic treatment and can prevent cardiovascular events or reduce the onset of the negative effects of cardiovascular events.

[0082] In one embodiment, the present invention provides the use of a compound of formulae I-VIII or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the treatment or prevention of heart failure, such as heart failure resulting from 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, periodontitis, drug intoxication, alcoholism, pericarditis, atherosclerosis, vascular disease, hypertrophic cardiomyopathy, dilated cardiomyopathy, myocardial infarction, atrial fibrillation, left ventricular systolic dysfunction, left ventricular diastolic dysfunction, coronary artery bypass surgery, 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 left ventricular systolic function (HF R EF), heart failure with preserved left ventricular systolic function (HF P EF), acute heart failure, and chronic heart failure of ischemic and non-ischemic origin.

[0083] In one embodiment, the present invention is for the use of the compounds of Formulas I - VIII for treating systolic and / or diastolic dysfunction, wherein the compounds are administered in a therapeutically effective amount to increase the ability to contract and relax cardiomyocytes, thereby increasing the ability to fill and empty, preferably of the left ventricle, of both the right and left ventricles. In another embodiment, the present invention is for the use of the compounds of Formulas I - VIII for treating heart failure, wherein the compounds are administered in a therapeutically effective amount to increase the contractility in the left ventricle.

[0084] In yet another embodiment, the present invention is for the use of the compounds of Formulas I - VIII for treating heart failure, wherein the compounds are administered in a therapeutically effective amount to reduce fibrosis in heart tissue. Another aspect of the present invention is a method for treating heart disease, wherein the treatment of heart disease is after myocardial infarction. Another aspect of the present invention is a method for treating heart disease, which comprises administering to a patient a therapeutically effective amount of a compound of Formula I in combination with other therapeutic agents.

[0085] The compounds of the present invention can be administered by any suitable means, for example, orally in the form of tablets, capsules (each containing sustained release or controlled release formulations), pills, powders, granules, elixirs, tinctures, suspensions (including nano - suspensions, micro - suspensions, spray - dried dispersions), syrups, and emulsions; sublingually; via the buccal side; parenterally by subcutaneous, intravenous, intramuscular, or intracardiac injection, or infusion (for example, as a sterile injectable aqueous or non - aqueous solution or suspension); intranasally by administration to the nasal mucosa, such as by inhalation spray; topically in the form of creams or ointments; or rectally in the form of suppositories. The compounds can be administered alone, but will generally be administered in combination with a pharmaceutical carrier selected based on the chosen route of administration and standard pharmaceutical practice.

[0086] The dosage regimen of the compounds of the present invention will, of course, vary according to known factors such as the pharmacokinetic properties of the particular drug and its method and route of administration; the species, age, sex, health status, disease state, and body weight of the recipient; the nature and degree of the symptoms; the type of current treatment; the treatment frequency; the route of administration, the renal and hepatic functions of the patient, and the desired effect.

[0087] As a general indication, the oral dosage per day of each active ingredient, when used for the indicated effect, will be in the range of about 0.01 to about 5000 mg per day, preferably about 0.1 to about 1000 mg, and most preferably about 0.1 to about 250 mg. In the case of intravenous administration, the most preferred dosage will be in the range of about 0.001 to about 10 mg / kg / min during continuous quantitative infusion. The compounds of the present invention may be administered once a day or the total daily dose may be administered in divided doses 2, 3, or 4 times a day.

[0088] Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 milligram to about 2000 milligrams of the active ingredient per dosage unit. In these pharmaceutical compositions, the active ingredient will usually be formulated in an amount of about 0.1 to 95% by weight, based on the total weight of the composition. A typical capsule for oral administration contains at least one compound (250 mg) of the present invention, lactose (75 mg), and magnesium stearate (15 mg). The mixture is passed through a 60-mesh sieve and filled into No. 1 gelatin capsules. A typical injection preparation is produced by aseptically placing at least one compound (250 mg) of the present invention in a vial, aseptically freeze-drying, and sealing it. For use, the contents of the vial are mixed with 2 mL of physiological saline to produce an injection preparation.

[0089] The compounds of the present invention may be used in combination with other suitable therapeutic agents useful for the treatment of the above-mentioned diseases or disorders, such as anti-atherosclerotic agents, anti-dyslipidemic agents, anti-diabetic agents, anti-hyperglycemic agents, anti-hyperinsulinemic agents, antithrombotic agents, anti-retinal agents, anti-neuropathic agents, anti-renal agents, anti-ischemic agents, anti-hypertensive agents, anti-obesity agents, anti-hyperlipidemic agents, anti-hypertriglyceridemic agents, anti-hypercholesterolemic agents, anti-restenosis agents, anti-pancreatic agents, lipid-lowering agents, anorectic agents, memory enhancers, anti-dementia agents, cognitive enhancers, appetite suppressants, therapeutic agents for heart failure, therapeutic agents for peripheral arterial diseases, therapeutic agents for malignant tumors, and anti-inflammatory agents.

[0090] The compounds of the present invention may be used together with at least one heart failure agent selected from the following: loop diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), angiotensin receptor-neprilysin inhibitors (ARNIs), beta blockers, mineralocorticoid receptor antagonists, nitroxyl donors, RXFP1 agonists, APJ agonists, SGLT2 inhibitors, HCN potassium-sodium channel inhibitors, myosin regulators, calcium channel inhibitors, kinase inhibitors, and cardiotonic agents. These agents include, but are not limited to, furosemide, bumetanide, torsemide, sacubitril-valsartan, thiazide diuretics, captopril, enalapril, lisinopril, carvedilol, metoprolol, bisoprolol, serelaxin, spironolactone, eplerenone, ivabradine, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, and valsartan.

[0091] The compounds of the present invention may be used in combination with at least one of the following therapeutic agents for treating atherosclerosis: hyperlipidemic agents, agents for increasing HDL in plasma, antihypercholesterolemic agents, cholesterol biosynthesis inhibitors (such as HMG-CoA reductase inhibitors), LXR agonists, probucol, raloxifene, nicotinic acid, niacinamide, cholesterol absorption inhibitors, bile acid sequestrants (such as anion exchange resins or quaternary amines (e.g., cholestyramine or colestipol)), low density lipoprotein receptor inducers, clofibrate, fenofibrate, bezafibrate, ciprofibrate, gemfibrozil, vitamin B6, vitamin B12, antioxidant vitamins, β-blockers, antidiabetic agents, angiotensin II antagonists, angiotensin converting enzyme inhibitors, platelet aggregation inhibitors, fibrinogen receptor antagonists, aspirin and fibrin acid derivatives.

[0092] The compounds of the present invention may be used in combination with at least one of the following therapeutic agents when treating with a cholesterol biosynthesis inhibitor, particularly an HMG CoA reductase inhibitor. Examples of suitable HMG CoA reductase inhibitors include, but are not limited to, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, and rosuvastatin.

[0093] The compounds of the present invention may be used in combination with at least one of the following anti-diabetic agents, depending on the desired target therapy. Studies have shown that the regulation of diabetes and hyperlipidemia can be further improved by adding a second agent to the treatment regimen. Examples of anti-diabetic agents include sulfonylureas (such as chlorpropamide, tolbutamide, acetohexamide, tracazamide, glibenclamide, glipizide, glyclazide, glimepiride, and glibendamide), biguanides (such as metformin), thiazolidinediones (such as ciglitazone, pioglitazone, troglitazone, and rosiglitazone), and related insulin sensitizers such as selective and non-selective activators of PPARα, PPARβ, and PPARγ; dehydroepiandrosterone (DHEA or its conjugated sulfate ester, also referred to as DHEA·SO4); antiglucocorticoids; TNFα inhibitors; dipeptidyl peptidase IV (DPP4) inhibitors (such as sitagliptin, saxagliptin, etc.), GLP-1 agonists or analogs (such as exenatide, etc.), α-glucosidase inhibitors (such as acarbose, miglitol, and voglibose, etc.), pramlintide (a synthetic analog of human hormone amylin), other insulin secretagogues (such as repaglinide, gliclazide, and nateglinide, etc.), insulin, and the above-mentioned therapeutic agents for treating atherosclerosis, but are not limited thereto.

[0094] The compounds of the present invention may be used in combination with at least one anti-obesity agent selected from the following phenylpropanolamine, phentermine, diethylpropion, mazindol, fenfluramine, dexfenfluramine, phenteramine, β3-adrenergic receptor agonist; sibutramine, gastrointestinal lipase inhibitor (such as orlistat, etc.), and leptin. Other agents used in the treatment of obesity or obesity-related disorders include neuropeptide Y, enterostatin, cholecystokinin, bombesin, amylin, histamine H3 receptor, dopamine D2 receptor modulator, melanocyte-stimulating hormone, corticotropin-releasing factor, galanin, and gamma-aminobutyric acid (GABA).

[0095] The compounds of the present invention are also useful as test substances or reference compounds, for example, as quality standards or controls, in tests or assays involving FPR2. Such compounds can be provided in commercially available kits for use, for example, in pharmaceutical research involving FPR2 activity. For example, the compounds of the present invention can be used as references in assays to compare the known activity of a compound of unknown activity. This assures the experimenter that the assay has been properly conducted and provides a basis for comparison, particularly when the test compound is a derivative of the reference compound. When a new assay or protocol is developed, the compounds of the present invention can be used to test its effectiveness. The compounds of the present invention may also be used in diagnostic assays involving FPR2.

[0096] The present invention also encompasses a manufactured article. As used herein, a manufactured article shall include, but not be limited to, kits and packages. A manufactured article of the present invention comprises: (a) a first container; (b) a pharmaceutical composition within the first container, wherein the composition comprises a first therapeutic agent in the form of a compound of the present invention or a pharmaceutically acceptable salt thereof; and (c) a package insert stating that the pharmaceutical composition can be used for the treatment of dyslipidemia and its sequelae. In another alternative embodiment, the package insert states that the pharmaceutical composition can be used for the treatment of dyslipidemia and its sequelae in combination with a second therapeutic agent (as defined above). The manufactured article may further comprise (d) a second container, wherein components (a) and (b) are placed within the second container and component (c) is placed inside or outside the second container. Placing within the first and second containers means that each container holds the component within its area. The first container is a container used to hold the pharmaceutical composition. This container can be for manufacturing, storage, transportation, and / or individual / bulk sales. The first container shall include, but not be limited to, bottles, jars, vials, flasks, syringes, tubes (e.g., for cream formulations), or any other container used in the manufacture, holding, storage, or distribution of pharmaceutical formulations. The second container is used to hold the first container and optionally the package insert. Examples of the second container include, but are not limited to, boxes (e.g., cardboard or plastic), wooden boxes, cartons, bags (e.g., paper or plastic bags), pouches, and sacks. The package insert can be physically attached to the outside of the first container by tape, adhesive, staples, or other attachment methods, or can be placed within the second container without using any physical means to attach it to the first container. Alternatively, the package insert can be placed outside the second container. When placed outside the second container, the package insert is preferably physically attached by tape, adhesive, staples, or other attachment methods. Alternatively, it can also be brought into proximity to or in contact with the outside of the second container without physical attachment.The accompanying document is a label, tag, marker, etc. that describes information related to the pharmaceutical composition contained within the first container. Such information will typically be determined by the regulatory authority (e.g., the U.S. Food and Drug Administration) that governs the region in which the product is sold. Preferably, the accompanying document specifically describes the indications for which the pharmaceutical composition is approved. The accompanying document may be made of any material that allows a person to read the information contained therein or thereon. Preferably, the accompanying document is a printable material (e.g., paper, plastic, cardboard, wheel, or a seal made of paper or plastic) on which the desired information is formed (e.g., printed or affixed).

[0097] Chemical method The disclosed compounds can be prepared by various methods known in the art, including the methods of the following schemes and the methods described in the specific embodiments section. The numbering of the structures and the numbering of the variable groups shown in the synthetic schemes are different from the numbering of the structures or variable groups in the claims or the rest of the specification and should not be confused. The variable groups in the schemes are only intended to illustrate a method for preparing some of the compounds of the present invention. One consideration in planning any synthetic route in the art is the choice of protecting groups used to protect the functional groups present in the compounds described in the present invention. A formal account that describes many alternative choices for those skilled in the art is Greene, T.W. et al., Protecting Groups in Organic Synthesis, 4th Edition, Wiley (2007).

[0098] The abbreviations used hereinafter are standard organic chemistry abbreviations known to those skilled in the art. Abbreviations: [Table 14] [Table 15]

[0099] Normal-phase chromatography was performed using a prepacked SiO2 cartridge. The reverse-phase preparative HPLC of the examples was performed using a Waters XBridge C18 column (19 x 200 mm, 5 μm particles), with variable gradients of mobile phase A (95% water, 5% ACN) and mobile phase B (5% water, 95% ACN) containing 0.1% TFA or 10 mM NH4OAc, and detected by UV and LCMS. The reverse-phase analytical HPLC / MS of the examples was performed by combining a Waters Acquity system with a Waters MICROMASS (registered trademark) ZQ mass spectrometer.

[0100] Method A: Subjected to a linear gradient from 0 to 100% B over 3 minutes and held at 100% B for 0.75 minutes; UV visualization (220 nm) Column: Waters BEH C18 2.1 x 50 mm Flow rate: 1.0 mL / min Solvent A: 10 mM NH4OAc, 95% water, 5% ACN Solvent B: 10 mM NH4OAc, 5% water, 95% ACN Method B: Subjected to a linear gradient from 0 to 100% B over 3 minutes and held at 100% B for 0.75 minutes; UV visualization (220 nm) Column: Waters BEH C18 2.1 x 50 mm Flow rate: 1.0 mL / min Solvent A: 0.1% TFA, 95% water, 5% ACN Solvent B: 0.1% TFA, 5% water, 95% ACN

[0101] Method C: Subjected to a linear gradient from 2 to 98% B over 1 minute and held at 100% B for 0.50 minutes; UV visualization (220 nm) Column: Waters BEH C18 2.1 x 50 mm Flow rate: 0.8 mL / min Solvent A: Water containing 0.05% TFA Solvent B: ACN containing 0.05% TFA Method D: Subjected to a linear gradient from 0 to 100% B over 10 minutes and held at 100% B for 5 minutes UV visualization (254 nm) Column: SunFire C18; 3.5 μm; 4.6 x 150 mm Flow rate: 1 mL / min Solvent A: 10% acetonitrile, 90% water, 0.05% TFA Solvent B: 10% water, 90% acetonitrile, 0.05% TFA

[0102] Method E: Subjected to a linear gradient from 0 to 100% B over 3 minutes and held at 100% B for 0.5 minutes; Detection: MS and UV (220 nm) Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 μm particles Flow rate: 1 mL / min (Method A) Temperature: 50 °C Solvent A: 5:95 acetonitrile:water + 10 mM ammonium acetate Solvent B: 95:5 acetonitrile:water + 10 mM ammonium acetate

[0103] Some of the compounds represented by Formula I can be prepared as described in Scheme 1. Scheme 1

Chemical formula

[0104] Step 1 describes the preparation of a compound of formula G1b by condensing an acid of formula G1a, which has been activated using a reagent (e.g., CDI or SOCl2), with a metal salt of alkylmalonic acid (e.g., potassium or sodium). Step 2 describes the preparation of a compound of formula G1c by condensing the compound of formula G1b with hydrazine R 1 NHNH2. Step 3 is R 2The production of a compound of formula G1d from a compound of formula G1c by alkylation using X (where X represents a leaving group such as a halogen or a sulfonate) is described. Step 4 describes the production of a compound of formula G1e by amination of a compound of formula G1d. The conversion of a compound of formula G1d to a compound of formula G1e generally involves two processes: nitrosation and subsequent reduction of the intermediate nitroso compound. Step 5 describes the production of a compound of formula I by condensing a compound of formula G1e with an acid R 4 CO2H or an activated equivalent.

[0105] 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 [Chemical formula]

[0106] Compound 1a. Ethyl 3-(2,6-difluoro-4-methoxyphenyl)-3-oxopropanoate: (i) CDI (1.18 g, 7.28 mmol) was added portionwise 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 portionwise 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) while maintaining the temperature below 20 °C. The mixture was stirred at room temperature for 4 h and then cooled in an ice bath. The solution from step (i) was added dropwise, and the mixture was stirred at room temperature for 16 h. 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 warmed to room temperature, diluted with EtOAc and water, and the layers were separated. The aqueous layer was extracted with EtOAc, and then the organic layers were combined, washed with water and brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography and eluted with 0 - 20% EtOAc / hexane for purification to obtain 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 tautomer with a keto / enol ratio of 3:1. Major tautomer: 1 H NMR (500 MHz, CDCl3) δ 6.51 (d, J = 10.5 Hz, 2H), 4.22 (q, J = 7.2 Hz, 2H), 3.90 (s, 2H), 3.87 (s, 2H), 1.27 (t, J = 7.2 Hz, 3H)

[0107] Compound 1b. 5-(2,6-Difluoro-4-methoxyphenyl)-2-phenyl-2,4-dihydro-3H-pyrazol-3-one To a solution of compound 1a (680 mg, 2.63 mmol) in 50% aqueous AcOH (20 mL) was added phenylhydrazine (0.26 mL, 2.6 mmol), and the mixture was heated at 115 °C for 2 h. The mixture was cooled to room temperature and then poured into brine and extracted with EtOAc (3x). The combined extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography and eluted with 5 - 45% EtOAc / hexane for purification 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 (500 MHz, CDCl3) δ 7.98 (d, J = 7.7 Hz, 2H), 7.45 (t, J = 8.0 Hz, 2H), 7.27 - 7.20 (m, 1H), 6.59 (d, J = 10.7 Hz, 2H), 3.94 (s, 2H), 3.88 (s, 3H)

[0108] Compound 1c. 5-(2,6-Difluoro-4-methoxyphenyl)-1-methyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one To a solution of compound 1b (250 mg, 0.83 mmol) in NMP (2 mL) was added methyl 4-nitrobenzenesulfonate (540 mg, 2.5 mmol), and the mixture was heated at 160 °C for 1 h. 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 subjected to silica gel chromatography and eluted with 5 - 60% EtOAc / DCM for purification 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 (500 MHz, CDCl3) δ 7.56 - 7.46 (m, 4H), 7.39 - 7.31 (m, 1H), 6.63 (d, J = 9.6 Hz, 2H)

[0109] Compound 1d. 4-Amino-5-(2,6-difluoro-4-methoxyphenyl)-1-methyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one To 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, a solution of sodium nitrite (480 mg, 7.0 mmol) in water (0.80 mL) was added dropwise, and the mixture was stirred for 2 hours. The mixture was poured into ice water and extracted with DCM (3x). The extracts were combined, 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 balloon of H2 for 16 hours. The mixture was filtered and evaporated under reduced pressure, and the residue was subjected to silica gel chromatography and eluted with 0 - 85% EtOAc / hexane for purification to obtain compound 1d (290 mg, 0.88 mmol, 50% yield) as an off-white solid. LCMS (method C) Rt = 0.76 minutes, m / z = 322.2 (M + H); 1 H NMR (500 MHz, CDCl3) δ 7.70 - 7.55 (m, 2H), 7.48 (t, J = 8.0 Hz, 2H), 7.34 - 7.20 (m, 1H), 6.63 (d, J = 9.9 Hz, 2H), 3.87 (s, 3H), 3.41 (brs, 2H), 2.73 (s, 3H)

[0110] 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 To a solution of Compound 1d (7.8 mg, 0.024 mmol) and 4-(difluoromethoxy)benzoic acid (5.8 mg, 0.031 mmol) in ACN (0.25 mL) was added DIEA (6.2 μL, 0.035 mmol), followed by HATU (10.7 mg, 0.028 mmol), and the mixture was stirred at 80 °C for 4 h. The mixture was cooled to room temperature and evaporated under reduced pressure. The residue was subjected to silica gel chromatography and purified by elution with 10 - 90% EtOAc / hexane to obtain 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); 1 H NMR (500 MHz, CD3OD) δ 7.84 (brd, J = 8.3 Hz, 2H), 7.56 - 7.50 (m, 2H), 7.49 - 7.45 (m, 2H), 7.43 - 7.37 (m, 1H), 7.13 (brd, J = 8.5 Hz, 2H), 6.60 (t, J = 73.5 Hz, 1H), 6.58 (d, J = 9.9 Hz, 2H), 3.81 (s, 3H), 3.04 (s, 3H)

[0111] Examples 2 - 33 (Table 2) were prepared as described for Example 1.

[0112] 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 [Chemical Structure]

[0113] Compound 34b. 4-Amino-2-(2,3-dichlorophenyl)-5-(2,6-difluoro-4-methoxyphenyl)-1-methyl-1,2-dihydro-3H-pyrazol-3-one 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, a solution of sodium nitrite (64 mg, 0.92 mmol) in water (0.12 mL) was added dropwise, and the mixture was stirred for 0.5 h. The mixture was poured into ice water and extracted with DCM (3x). The extracts were combined, washed with brine, dried (Na2SO4), filtered, and evaporated under reduced pressure. The residue was dissolved in a 4:1 mixture of EtOH / 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 stirred at 90 °C for 15 min. The mixture was cooled to room temperature, then poured into 1.5 N K2HPO4 and extracted with DCM (3x). The extracts were combined, dried (Na2SO4), filtered, and evaporated under reduced pressure. The residue was subjected to silica gel chromatography and eluted with 0 - 60% EtOAc / DCM for purification to obtain compound 34b (33 mg, 0.082 mmol, 36% yield) as an off - white solid. LCMS (method C) Rt = 0.85 min, m / z = 400.0 (M + H)

[0114] 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 The title compound was prepared from compound 34b as described for Example 1. LCMS (method A) Rt = 1.86 min, m / z = 570.2 (M + H); 1 H NMR (500 MHz, DMSO - d6) δ 9.58 (brs,1H), 7.89 (brd,J = 7.9 Hz,2H), 7.82 (d,J = 8.1 Hz,1H), 7.59 (t,J = 8.0 Hz,1H), 7.55 - 7.50 (m,1H), 7.42 - 7.06 (m,3H), 6.86 (brd,J = 10.9 Hz,2H), 3.82 (s,3H), 2.92 (s,3H)

[0115] Examples 35 to 38 (Table 2) were produced as described for Example 34.

[0116] 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

Chemical formula

[0117] Compound 39b. 2-(6-Chloropyridin-2-yl)-5-(2,6-difluoro-4-methoxyphenyl)-1-methyl-1,2-dihydro-3H-pyrazol-3-one To a solution of compound 39a (460 mg, 1.4 mmol, prepared as described for compound 1b) in DMF (3.5 mL) was added methyl iodide (0.13 mL, 2.0 mmol), and the mixture was heated at 100 °C for 16 h. Additional methyl iodide (0.065 mL, 1.0 mmol) was added, and the mixture was heated at 100 °C for 4 h. 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 subjected to silica gel chromatography and eluted with 0 - 100% EtOAc / DCM for purification to obtain compound 39b (354 mg, 1.01 mmol, 74% yield) as an off-white solid. LCMS (method C) Rt = 0.81 min, m / z = 352.0 (M + H)

[0118] Compound 39c. 4-Amino-2-(6-chloropyridin-2-yl)-5-(2,6-difluoro-4-methoxyphenyl)-1-methyl-1,2-dihydro-3H-pyrazol-3-one 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, a solution of sodium nitrite (160 mg, 2.3 mmol) in water (0.8 mL) was added dropwise, and the mixture was stirred for 0.5 h. The mixture was poured into ice water and extracted with DCM (3x). The extracts were combined, washed with brine, dried (Na2SO4), filtered, and evaporated under reduced pressure. The residue was suspended in a 4:1 mixture of MeOH / 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 warmed to room temperature and stirred for 15 min. 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 subjected to silica gel chromatography and eluted with 0 - 100% EtOAc / DCM for purification to obtain compound 39c (150 mg, 0.41 mmol, 48% yield) as a white solid. LCMS (method C) Rt = 0.76 min, m / z = 367.0 (M+H)

[0119] 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 The title compound was prepared from compound 39c as described for Example 1. LCMS (method A) Rt = 1.84 min, m / z = 537.4 (M+H); 1 H NMR (500 MHz, CD3OD) δ 8.00 - 7.94 (m, 1H), 7.92 - 7.84 (m, 3H), 7.41 (d, J = 7.7 Hz, 1H), 7.19 (d, J = 8.6 Hz, 2H), 7.05 - 6.72 (m, 3H), 3.87 (s, 3H), 3.33 (s, 3H)

[0120] Examples 40 - 41 (Table 2) were prepared as described for Example 39.

[0121] 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 [Chemical formula]

[0122] 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-hydrazinylpyridine 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, then quenched with saturated NH4Cl, and the mixture was extracted with EtOAc (3x). The extracts were combined, dried (Na2SO4), filtered, and evaporated under reduced pressure. The residue was subjected to silica gel chromatography and eluted with 0 - 100% EtOAc / hexane for purification to obtain Compound 42a (215 mg, 0.64 mmol, 66% yield) as an off-white solid. LCMS (Method C) Rt = 1.12 minutes, m / z = 338.1 (M + H)

[0123] 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) in THF (6.3 mL) were added MeOH (0.26 mL, 6.3 mmol), tri-n-butylphosphine (0.32 mL, 1.3 mmol), and ADDP (190 mg, 0.76 mmol), and the mixture was stirred for 16 h. 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 solid was removed by filtration. The filtrate was concentrated, and the residue was subjected to silica gel chromatography and eluted with 0 - 100% EtOAc / hexane for purification to obtain compound 42b (100 mg, 0.28 mmol, 45% yield) as a white solid. LCMS (method C) Rt = 0.95 min, m / z = 352.1 (M + H); 1 H NMR (500 MHz, DMSO-d6) δ 8.62 (d, J = 2.5 Hz, 1H), 8.12 (dd, J = 8.8, 2.8 Hz, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.03 (d, J = 10.2 Hz, 2H), 5.74 (s, 1H), 3.89 (s, 3H), 3.19 (s, 3H)

[0124] Compound 42c. 4-Amino-2-(5-chloropyridin-2-yl)-5-(2,6-difluoro-4-methoxyphenyl)-1-methyl-1,2-dihydro-3H-pyrazol-3-one The title compound was prepared from compound 42b as described for compound 39c. LCMS (method C) Rt = 0.78 min, m / z = 367.0 (M + H)

[0125] 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 The title compound was prepared from compound 42c as described for compound 1. LCMS (method A) Rt = 1.85 min, m / z = 537.2 (M + H); 11H NMR (500 MHz, CD3OD) δ 8.57 (d, J = 2.4 Hz, 1H), 8.02 (dd, J = 8.8, 2.5 Hz, 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) Example 43 (Table 2) was prepared as described for Example 42.

[0126] 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

Chemical formula

[0127] 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 The title compound was prepared from compound 44a as described for Example 1. LCMS (Method A) Rt = 1.50 min, m / z = 503.2 (M + H); 11H NMR (500 MHz, CD3OD) δ 8.59 (brd, J = 4.1 Hz, 1H), 8.00 (brd, J = 1.3 Hz, 1H), 7.88 (brd, J = 8.2 Hz, 3H), 7.40 (dd, J = 7.0, 5.2 Hz, 1H), 7.19 (d, J = 8.7 Hz, 2H), 7.06 - 6.69 (m, 3H), 3.86 (s, 3H), 3.30 (s, 3H)

[0128] 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

Chemical Structure

[0129] 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 To a solution of Example 39 (130 mg, 0.24 mmol) in toluene (2.5 mL) and water (0.50 mL) were added cyclopropylboronic 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). The reaction mixture was degassed and heated at 140 °C for 1 hour. The mixture was filtered through Celite and evaporated under reduced pressure. The residue was purified by preparative HPLC to give Example 45 (91 mg, 0.17 mmol, 69% yield) as an off-white solid. LCMS (Method C) Rt = 0.88 min, m / z = 543.1 (M + H); 11H NMR (500 MHz, CD3OD) δ 7.92 (d, J = 8.8 Hz, 2H), 7.84 (t, J = 7.8 Hz, 1H), 7.63 (d, J = 7.7 Hz, 1H), 7.30 (d, J = 7.4 Hz, 1H), 7.22 (d, J = 8.8 Hz, 2H), 6.96 (t, J = 73.5 Hz, 1H), 6.81 (d, J = 10.2 Hz, 2H), 3.89 (s, 3H), 3.33 (s, 3H), 2.25 - 2.11 (m, 1H), 1.13 - 1.00 (m, 4H)

[0130] Examples 46 - 53 (Table 2) were prepared as described for Example 45.

[0131] 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 [Chemical formula]

[0132] 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 To a solution of Example 42 (17 mg, 0.029 mmol) in degassed NMP (0.3 mL) were added zinc dicyanide (6.9 mg, 0.058 mmol) and Pd(PPh3)4 (3.4 mg, 2.9 μmol). 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 minutes, m / z = 528.0 (M + H); 11H NMR (500 MHz, CD3OD) δ 8.90 (d, J = 1.4 Hz, 1H), 8.35 - 8.18 (m, 2H), 7.88 (brd, J = 8.6 Hz, 2H), 7.20 (s, 2H), 7.07 - 6.69 (m, 3H), 3.87 (s, 3H), 3.35 (s, 3H)

[0133] Examples 55 - 56 (Table 2) were produced as described for Example 54.

[0134] Example 57. N-[5-(2,6-Difluoro-4-methoxyphenyl)-1-methyl-3-oxo-2-{[5-(propan-2-yl)-1,3,4-oxadiazol-2-yl]methyl}-2,3-dihydro-1H-pyrazol-4-yl]-4-(difluoromethoxy)benzamide [Chemical formula]

[0135] Example 57. N-[5-(2,6-Difluoro-4-methoxyphenyl)-1-methyl-3-oxo-2-{[5-(propan-2-yl)-1,3,4-oxadiazol-2-yl]methyl}-2,3-dihydro-1H-pyrazol-4-yl]-4-(difluoromethoxy)benzamide To a solution of Example 21 (27 mg, 0.053 mmol) in 10% EtOH / DCM (0.5 mL), hydrazine (17 μL, 0.53 mmol) was added and the mixture was stirred for 16 h. The mixture was diluted with Et2O and filtered to give the intermediate hydrazide, N-(5-(2,6-difluoro-4-methoxyphenyl)-2-(2-hydrazinyl-2-oxoethyl)-1-methyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-4-(difluoromethoxy)benzamide (26 mg, 0.052 mmol, 99% yield) as a white solid. LCMS (Method C) Rt = 0.64 min, m / z = 498.0 (M+H). The intermediate hydrazide (13 mg, 0.026 mmol) and isobutyric acid (2.7 μL, 0.029 mmol) were dissolved in dioxane (0.2 mL), 50% T3P® in 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 h. 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 (500 MHz, DMSO-d6) δ 9.62 (brs,1H), 7.89 (brd, J = 8.2 Hz,2H), 7.33 (t, J = 73.6 Hz,1H), 7.23 (brd, J = 8.2 Hz,2H), 6.88 (brd, J = 10.4 Hz,2H), 5.38 (s,2H), 3.81 (s,3H), 3.18 (brd, J = 4.9 Hz,1H), 3.14 (s,3H), 1.30 (d, J = 6.7 Hz,6H)

[0136] 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

Chemical formula

[0137] 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 To a solution of Example 21 (10 mg, 0.020 mmol) in EtOH (0.25 mL) was added calcium chloride (4.3 mg, 0.039 mmol), followed by the addition of 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 extracts were combined, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain Example 58 (5.9 mg, 0.012 mmol, 62% yield). LCMS (Method A) Rt = 1.40 minutes, m / z = 469.9 (M+H); 1 H NMR (500 MHz, DMSO-d6) δ 7.87 (brd, J = 8.1 Hz, 2H), 7.26 (t, J = 72.8 Hz, 1H), 7.21 (brd, J = 8.4 Hz, 2H), 6.83 (brd, J = 10.4 Hz, 2H), 3.95 (t, J = 5.9 Hz, 2H), 3.82 (s, 3H), 3.63 (brt, J = 5.7 Hz, 2H), 3.19 (s, 3H)

[0138] 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

Chemical formula

[0139] Compound 59a. Methyl 3-(2,6-difluoro-4-methoxyphenyl)propionate: To a solution of Compound 1a (0.71 g, 2.9 mmol) in DCE (3.6 mL) under nitrogen was added trifluoromethanesulfonic anhydride (0.54 mL, 3.2 mmol). The mixture was stirred for 15 minutes, and then a DIPEA solution (1.3 mL, 7.3 mmol) was added dropwise over 15 minutes, resulting in an exothermic reaction. The reaction mixture was stirred for 30 minutes. The reaction was quenched with water, extracted with EtOAc, washed with 1N HCl and brine, dried over Na2SO4 and concentrated. The crude residue was subjected to silica gel chromatography and eluted with 0 - 100% EtOAc / hexane for purification to obtain Compound 59a (430 mg, 1.9 mmol, 65% yield). MS(ESI) m / z 226.9(M+H)

[0140] Compound 59b. 5-(2,6-Difluoro-4-methoxyphenyl)-1-methyl-1,2-dihydro-3H-pyrazol-3-one: To a solution of Compound 59a (425 mg, 1.88 mmol) in MeOH (2 mL) was added H2O (2 mL), followed by methylhydrazine (0.109 mL, 2.07 mmol), and the mixture was heated at 50 °C overnight. The reaction mixture was cooled to room temperature, concentrated, 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 obtain Compound 59b as a white solid (155 mg, 0.646 mmol, 34.3% yield). NMR(500 MHz, DMSO-d6) δ 9.72(brs,1H), 6.92(d,J = 9.6Hz,2H), 5.59(s,1H), 3.85(s,3H), 3.44(s,3H)

[0141] 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) and copper(I) iodide (2.38 mg, 0.012 mmol) in iPrOH (0.5 mL) was flushed with nitrogen in a pressure vial, then sealed and heated at 110 °C overnight. The reaction mixture was cooled to room temperature, diluted with water and then extracted with DCM (3x). The extracts were combined, dried over Na2SO4, filtered and evaporated. The residue was subjected to silica gel chromatography and eluted with 0 - 100% EtOAc / hexane for purification to give compound 59c (45 mg, 0.13 mmol, 52%); 1 H NMR (500 MHz, 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 the O-arylated by-product, 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 (500 MHz, CDCl3) δ 8.06 (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) were obtained.

[0142] 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.

[0143] 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 procedures described for compound 1. LCMS (Method C) Rt = 1.59 minutes, m / z = 533.2 (M+H); 1 H NMR (500 MHz, DMSO-d6) δ 9.69 (s, 1H), 8.41 (d, J = 5.5 Hz, 1H), 7.91 (d, J = 8.2 Hz, 2H), 7.49 - 7.41 (m, 1H), 7.37 - 7.15 (m, 3H), 7.00 (dd, J = 5.8, 2.4 Hz, 1H), 6.94 (d, J = 10.4 Hz, 2H), 3.92 (s, 3H), 3.83 (s, 3H), 3.18 (s, 3H)

[0144] Examples 60 - 84 (Table 2) were prepared as described for Example 59. In the case of examples of trifluoromethoxyamides, trifluoromethoxybenzoic acid was used instead of difluoromethoxybenzoic acid for amide formation.

[0145] Example 85.

Chemical formula

[0146] Compound 85a. 2-(6-Bromopyridin-2-yl)propan-2-ol: A 3M solution of bromomagnesium methyl in Et2O (570 μL, 1.71 mmol) was added dropwise over 1.5 hours at 0 °C to a cooled solution of 1-(6-bromopyridin-2-yl)ethan-1-one (285 mg, 1.42 mmol) in anhydrous THF (2.8 mL), and then stirred overnight at room temperature. The reaction mixture was quenched with an aqueous NH4Cl solution and extracted twice with EtOAc. The extracts were combined, dried over Na2SO4, filtered, and evaporated. The crude product was used without further purification in the next step. MS (ESI) 215.9 (M+H)

[0147] Compound 85b. 4-Amino-5-(2,6-difluoro-4-methoxyphenyl)-2-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-1-methyl-1,2-dihydro-3H-pyrazol-3-one: Compound 85b was prepared from Compound 59b and Compound 85a using the method described for Compound 59c and Compound 59d. MS(ESI) m / z 391.3(M+H)

[0148] Example 85. A mixture of Compound 85b and K2CO3 (49.6 mg, 0.359 mmol) under nitrogen 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 the ice bath for 10 minutes and then stirred at room temperature overnight. 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 minutes, m / z 561.4(M+H); 1 H NMR (500 MHz, DMSO-d6) δ 9.70(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)

[0149] 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

Chemical Structure

[0150] Compound 87a. 1-(6-Bromopyridin-2-yl)cyclobutan-1-ol: 2,6-Dibromopyridine (0.300 g, 1.27 mmol) was dissolved in anhydrous DCM (7.5 mL) under a nitrogen atmosphere. The solution was cooled to -78 °C, and a 1.6 M solution of nBuLi in hexane (0.863 mL, 1.38 mmol) was added very slowly via syringe. After the addition was complete, the reaction mixture was stirred at -78 °C for 1 hour. Next, 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 slowly warmed to room temperature overnight. The reaction was quenched with saturated NaHCO3 solution and extracted twice with DCM. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4 and evaporated. The residue was subjected to silica gel chromatography and eluted with 0 - 30% MeOH / DCM for purification to obtain compound 87a (210 mg, 0.922 mmol, yield 72.8%). 1 H NMR (500 MHz, CDCl3) δ 7.67 - 7.58 (m, 1H), 7.54 (d, J = 7.7 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 4.33 (s, 1H), 2.57 - 2.47 (m, 4H), 2.16 - 2.03 (m, 1H), 1.88 (dquin, J = 11.7, 8.6 Hz, 1H)

[0151] Example 87 was prepared from compound 87a using the method described for Example 85. LCMS (Method B) Rt = 1.68 minutes; m / z 573.3 (M + H); 1 H NMR (500 MHz, 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); OH proton not observed

[0152] 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

Chem.

[0153] Compound 88a. 2-Bromo-6-cyclopropyl-4-methoxypyridine: A stirred 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 sparged with N2 for several minutes, and then a 0.5 M solution of cyclopropylzinc(II) bromide in THF (1.34 mL, 0.672 mmol) was added. The mixture was stirred at room temperature overnight. The reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO3. The organic phase was dried over Na2SO4, filtered, and evaporated. The residue was purified by silica gel chromatography, eluting with 0 - 100% EtOAc / hexane to give compound 88a (37.4 mg, 0.164 mmol, 28.8% yield). 1 H NMR (400 MHz, CDCl3-d) δ 6.78 (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)

[0154] Example 88 was prepared from compound 88a using the method described for Example 85. LCMS (Method B) Rt = 1.92 minutes; m / z 573.0 (M + H); 11H NMR (500 MHz, DMSO-d6) δ 9.65 (s, 1H), 7.89 (d, J = 8.5 Hz, 2H), 7.24 (d, J = 8.5 Hz, 2H), 7.18 (d, J = 1.8 Hz, 1H), 7.30 (t, J = 73.9 Hz, 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)

[0155] 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-pyrazol-4-yl)-4-(difluoromethoxy)benzamide

Chemical Structure

[0156] Compound 91a. 2-Bromo-4-methoxy-6-(pyrrolidin-1-yl)pyridine: 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 at 150 °C for 1 h under microwave irradiation in a sealed test tube. The reaction mixture was partitioned between water and EtOAc, the organic phase was dried (Na2SO4), filtered and evaporated. The residue was subjected to silica gel chromatography and eluted with 0 - 100% EtOAc / hexane for purification to give Compound 91a (235 mg, 0.914 mmol, 81% yield). MS (ESI) m / z 259.0 (M + H)

[0157] Example 91 was prepared from Compound 91a using the method described for Example 85. LCMS (Method B) Rt = 1.73 min; m / z 602.1 (M + H); 11H NMR (500 MHz, DMSO-d6) δ 9.63 (s, 1H), 7.91 (d, J = 7.6 Hz, 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 = 10.4 Hz, 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)

[0158] Examples 86, 89 - 90, 92 - 107 (Table 2) were prepared using the method described for Example 85, 87 - 88 or 91.

[0159] 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

Chemical Structure

[0160] Compound 108a. 5-(2,6-Difluoro-4-methoxyphenyl)-2-(3,5-dimethoxyphenyl)-1-methyl-1,2-dihydro-3H-pyrazol-3-one: A mixture of compound 59c (100 mg, 0.416 mmol), (3,5-dimethoxyphenyl)boronic acid (152 mg, 0.833 mmol), copper(II) acetate (113 mg, 0.624 mmol) and pyridine (0.067 mL, 0.83 mmol) in DCM (3 mL) was stirred overnight under an air atmosphere. The reaction mixture was diluted with DCM and water, and the aqueous layer was extracted again with DCM. The extracts were combined, washed with brine, dried over Na2SO4, filtered and evaporated. The residue was subjected to silica gel chromatography and eluted with 0 - 100% EtOAc / hexane for purification to obtain compound 108a (78 mg, 0.21 mmol, 50% yield). LCMS (ESI) m / z: 377.1 (M + H); 11H NMR (400 MHz, CDCl3) δ 6.67 (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)

[0161] Example 108 was obtained in two steps from Compound 1d using the method described for Example 1. LCMS (Method C) Rt = 1.77 minutes, m / z = 562.3 (M + H); 1 1H NMR (500 MHz, DMSO-d6) δ 9.72 (s, 1H), 7.89 (brd, J = 8.2 Hz, 2H), 7.24 (brd, J = 8.5 Hz, 2H), 7.31 (t, J = 74.0 Hz, 1H), 6.91 (brd, J = 10.7 Hz, 2H), 6.63 - 6.46 (m, 3H), 3.82 (s, 3H), 3.80 (s, 6H), 2.94 (s, 3H)

[0162] Examples 109 - 134 (Table 2) were prepared using the method described for Example 108.

[0163] 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

Chemical Structure

[0164] Compound 135a. 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) was heated at 100 °C under reflux overnight with stirring under nitrogen. The reaction mixture was cooled to room temperature and concentrated somewhat. The concentrate was diluted with water and extracted with EtOAc (5x). The extracts were combined, washed with brine, dried over Na2SO4, filtered and evaporated. The residue was subjected to silica gel chromatography and purified by elution with 0 / 100% EtOAc / hexane to give compound 135a (minor positional isomer; 0.78 g, 0.3.7 mmol, 16% yield). 1 H NMR (500 MHz, DMSO-d6) δ 8.17 (brs, 1H), 7.80 (d, J = 7.7 Hz, 1H), 6.73 (d, J = 8.0 Hz, 1H), 4.41 (brs, 2H)

[0165] 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-oxopropanoate using the procedure described for compound 1b, followed by the procedure described for compound 39b. MS (ESI) m / z: 419.9 (M+H)

[0166] 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-pyrazol-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) in NMP (2.2 mL) was heated at 100 °C overnight with stirring in a pressure vial. 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 subjected to silica gel chromatography and eluted with 0 - 20% DCM / MeOH for purification to obtain compound 135c (215 mg, 0.445 mmol, 65.3% yield) as a white foam. MS (ESI) m / z: 484.1 (M+H)

[0167] Example 135 was prepared from compound 135c using the steps shown in the scheme and the operations described above. LCMS (Method A) Rt = 1.79 minutes, m / z 669.0 (M+H); 1 H NMR (500 MHz, CD3CN) δ 8.01 (brs, 1H), 7.90 (d, J = 9.1 Hz, 1H), 7.85 - 7.75 (m, 2H), 7.17 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 9.1 Hz, 1H), 6.79 - 6.66 (m, 2H), 6.82 (t, J = 74.0 Hz, 1H), 3.83 (s, 3H), 3.65 (brd, J = 3.3 Hz, 4H), 3.03 (s, 3H), 2.44 (t, J = 5.1 Hz, 4H), 2.26 (s, 3H)

[0168] Examples 136 - 141 (Table 2) were prepared using the method described for Example 135 and / or its modifications known to those skilled in the art.

[0169] 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

Chemical Structure

[0170] 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: A vial equipped with a stir bar and a pressure release septum was charged with Example 222 (15.1 mg, 25.0 micromoles) and potassium carbonate (5.2 mg, 38 micromoles). The vial was purged with nitrogen, and a solution of 1-(4-methoxyphenyl)-N-methylmethanamine (3.8 mg, 25 micromoles) in NMP (1.0 mL) was introduced, and the mixture was heated at 80 °C overnight. The reaction mixture was diluted with water and EtOAc, the phases were separated, the aqueous phase was extracted with EtOAc two or more times, all the organic phases were combined, washed with brine, dried (Na2SO4), filtered and evaporated to give the title compound (17.2 mg, 96% yield), which was used without further purification. MS (ESI) m / z: 720.3 (M+H) +

[0171] 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: A vial equipped with a stir bar and a pressure release septum was charged with Example 241a (17.2 mg, 0.024 mmol) and DCM (2 mL), to which 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 evaporated, and this operation was repeated two or more times to give the title compound, which was used without further purification. MS (ESI) m / z: 600.3 (M+H) +

[0172] Example 241. N-(5-(2,6-Difluoro-4-methoxyphenyl)-1-methyl-2-(6-(N-methylmethylsulfonamide)-3-(trifluoromethyl)pyridin-2-yl)-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-4-(difluoromethoxy)benzamide: A vial equipped with a stir bar and a pressure release septum was charged with Example 241b (17.1 mg, 24 μmol), to which DCM (1 mL) and TEA (0.017 mL, 120 μmol) were added, followed by MsCl (2.8 μl, 36 μmol), and the mixture was stirred at ambient temperature overnight. The reaction mixture was quenched with water, the phases were separated, the aqueous phase was extracted 3 times with DCM, all the organic phases were combined, dried (Na2SO4), filtered and evaporated to give a residue. The crude material was purified via preparative LC / MS to give the title compound (0.8 mg, 5% yield). MS (ESI) m / z: 678.1 (M+H) + ; 1 H NMR (500 MHz, DMSO-d6) δ 9.74 (s, 1H), 8.42 (d, J = 9.0 Hz, 1H), 7.91 (brd, J = 8.0 Hz, 2H), 7.64 (brd, J = 8.8 Hz, 1H), 7.23 (brd, J = 8.8 Hz, 2H), 7.33 (brt, J = 73.8 Hz, 1H), 6.93 (brdd, J = 28.2, 10.2 Hz, 2H), 3.82 (s, 3H), 3.45 (s, 3H), 3.42 (s, 3H), 3.04 (s, 3H)

[0173] Example 318: N-(5-(2,6-Difluoro-4-methoxyphenyl)-1-methyl-2-(6-(methylsulfonyl)-3-(trifluoromethyl)pyridin-2-yl)-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-4-(difluoromethoxy)benzamide

Chemical formula

[0174] 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-drum vial equipped with a stir bar and a pressure release septum was charged with Example 222 (30 mg, 50 micromoles). The vial was purged with nitrogen, then NMP (0.5 mL) was added, followed by sodium methanethiolate (3.9 mg, 5 micromoles), and the reaction mixture was stirred at room temperature overnight. 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 give a residue (29 mg).

[0175] Example 318: Compound 318a (29 mg, 47 micromoles) was dissolved in a mixture of DCM (0.5 mL) and AcOH (0.005 mL). To this solution, m-CPBA (23.7 mg, 104 micromoles) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched 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 material was purified by preparative LC / MS to give the title compound (6.1 mg, 19%). MS (ESI) m / z: 649.3 (M+H) + ; 1 H NMR (500 MHz, DMSO-d6) δ 9.75 (s, 1H), 8.84 (d, J = 8.2 Hz, 1H), 8.35 (d, J = 7.9 Hz, 1H), 7.90 (brd, J = 8.5 Hz, 2H), 7.23 (brd, J = 8.2 Hz, 2H), 7.32 (brt, J = 73.5 Hz, 1H), 7.02 - 6.86 (m, 2H), 3.82 (s, 3H), 3.37 (s, 3H), 3.05 (s, 3H)

[0176] Example 319: tert-Butyl 6-(3-(2,6-difluoro-4-methoxyphenyl)-4-(4-(difluoromethoxy)benzamide)-2-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-5-(trifluoromethyl)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate

Chemical formula

[0177] Compound 222a. tert-Butyl 6-(3-(2,6-difluoro-4-methoxyphenyl)-4-(4-(difluoromethoxy)benzamide)-2-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-5-(trifluoromethyl)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate: A 2-drum vial equipped with a stir bar and a pressure-release septum was charged with Example 222 (61 mg, 0.10 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (47 mg, 0.15 mmol), PdCl2(dppf) (11 mg, 0.015 mmol) and tripotassium phosphate (64 mg, 0.30 mmol). The vial was purged with nitrogen and a degassed mixture of 1,4-dioxane (0.9 mL) / water (0.1 mL) was added. The vial was stoppered and heated at 90 °C overnight with stirring. 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 layers were combined, washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by silica gel chromatography (0 - 100% EtOAc in n-hexane) to give the title compound (36 mg, 48%) as a colorless solid. MS (ESI) m / z: 752.0 (M+H) + ; 11H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 8.4 Hz, 1H), 7.80 (brd, J = 7.9 Hz, 2H), 7.74 - 7.63 (m, 1H), 7.57 (brd, J = 8.1 Hz, 1H), 7.13 (d, J = 8.6 Hz, 2H), 6.88 (brs, 1H), 6.64 - 6.56 (m, 2H), 6.55 (brt, J = 73.3 Hz, 1H), 4.19 (brd, J = 1.3 Hz, 2H), 3.84 (s, 3H), 3.74 - 3.58 (m, 2H), 3.03 (s, 3H), 2.66 (brd, J = 14.1 Hz, 2H), 1.51 (s, 9H)

[0178] 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 A 1-drum vial equipped with a stir bar and a pressure-release septum was charged with tert-butyl 6-(3-(2,6-difluoro-4-methoxyphenyl)-4-(4-(difluoromethoxy)benzamide)-2-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-5-(trifluoromethyl)-3',6'-dihydro-[2,4'-bipyridin]-1'(2'H)-carboxylate (36.1 mg, 0.048 mmol) and dioxane (1 mL). To this solution was added hydrogen chloride (4 M in dioxane, 1.0 mL, 4.0 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with H2O and evaporated several times from EtOAc under reduced pressure to afford a pale yellow solid (32 mg, 98%). The material was used in the next step without further purification. MS (ESI) m / z: 652.3 (M + H) + ; 11H NMR (500 MHz, DMSO-d6) δ 9.71 (s, 1H), 8.37 (d, J = 8.2 Hz, 1H), 7.91 (d, J = 8.2 Hz, 2H), 7.85 (d, J = 8.2 Hz, 1H), 7.23 (d, J = 8.2 Hz, 2H), 7.33 (t, J = 73.7 Hz, 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 suppression)

[0179] 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: To a mixture of 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 (11 mg, 0.016 mmol) in THF (2.0 mL) under nitrogen, TEA (11 μl, 0.078 mmol) was added, 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 layers were combined, washed with brine, dried (Na2SO4), filtered, and evaporated to give the title compound (11 mg) as a light brown solid. The material was used in the next step without further purification. MS (ESI) m / z: 730.1 (M+H) +

[0180] Example 319: A solution of 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 (11 mg, 0.015 mmol) in EtOH (3 mL) under nitrogen was charged with 10% Pd on carbon (3.2 mg, 3.0 micromol). The mixture was purged three times with nitrogen (evacuate / N2 backfill), and the reaction mixture was stirred overnight at room temperature under hydrogen. The reaction mixture was filtered through a pad of celite, and the pad was washed with MeOH. The filtrates were combined and evaporated to give a 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) + ; 1 H NMR (500 MHz, DMSO-d6) δ 9.69 (s, 1H), 8.41 (d, J = 8.2 Hz, 1H), 7.91 (d, J = 8.2 Hz, 2H), 7.74 (d, J = 8.2 Hz, 1H), 7.23 (d, J = 8.5 Hz, 2H), 7.32 (t, J = 73.5 Hz, 1H), 6.99 - 6.86 (m, 2H), 3.82 (s, 3H), 3.68 (brd, J = 11.9 Hz, 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)

[0181] Examples 142 - 408 (Table 2) were prepared using the methods described above and / or modifications thereof known to those skilled in the art.

[0182] Table 2

Table 16

Table 17

Table 18

Table 19

Table 20

Table 21

Table 22

Table 23

Table 24

Table 25

Table 26

[0183]

Table 27

Table 28

Table 29

Table 30

Table 31

Table 32

Table 33

Table 34

Table 35

Table 36

[0184]

Table 37

Table 38

Table 39

Table 40

Table 41

Table 42

Table 43

Table 44

Table 45

Table 46

[0185]

Table 47

Table 48

Table 49

Table 50

Table 51

Table 52

Table 53

Table 54

Table 55

Table 56

[0186]

Table 57

Table 58

Table 59

Table 60

Table 61

Table 62

Table 63

Table 64

Table 65

Table 66

[0187]

Table 67

Table 68

Table 69

Table 70

Table 71

Table 72

Table 73

Table 74

Table 75

Table 76

[0188]

Table 77

Table 78

Table 79

Table 80

Table 81

Table 82

Table 83

Table 84

Table 85

Table 86

[0189]

Table 87

Table 88

Table 89

Table 90

Table 91

Table 92

Table 93

Table 94

Table 95

Table 96

[0190]

Table 97

Table 98

Table 99

Table 100

Table 101

Table 102

Table 103

Table 104

Table 105

Table 106

[0191]

Table 107

Table 108

Table 109

Table 110

Table 111

[0192] The 1 H NMR data of the examples in Table 2: Example 2: 1 H NMR (500 MHz, DMSO-d6) δ 9.87 (s, 1H), 7.93 (brd, J = 7.9 Hz, 2H), 7.69 - 7.56 (m, 1H), 7.44 (brd, J = 8.2 Hz, 2H), 7.34 - 7.16 (m, 3H), 6.90 (brd, J = 10.4 Hz, 2H), 3.72 (brs, 3H), 2.96 (s, 3H) Example 3: 11H NMR (500 MHz, CD3OD) δ 7.87 (brd, J = 6.1 Hz, 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) Example 4: 1 1H NMR (500 MHz, CD3OD) δ 7.92 (brd, J = 7.0 Hz, 2H), 7.65 - 7.42 (m, 5H), 7.33 (brd, J = 7.9 Hz, 2H), 6.76 (brd, J = 10.8 Hz, 2H), 3.86 (s, 3H), 3.10 (s, 3H) Example 5: 1 1H NMR (500 MHz, CD3OD) δ 7.98 (brd, J = 7.2 Hz, 2H), 7.74 (brd, J = 8.2 Hz, 2H), 7.59 (t, J = 7.8 Hz, 2H), 7.54 - 7.50 (m, 2H), 7.50 - 7.43 (m, 1H), 6.77 (d, J = 10.0 Hz, 2H), 3.86 (s, 3H), 3.11 (s, 3H) Example 6: 1 1H NMR (500 MHz, DMSO - d6) δ 7.89 (brd, J = 7.7 Hz, 2H), 7.43 - 7.09 (m, 8H), 6.81 (brd, J = 10.4 Hz, 2H), 5.13 (s, 2H), 3.80 (s, 3H), 3.09 (s, 3H) Example 7: 1 1H NMR (500 MHz, DMSO - d6) δ 9.64 (s, 1H), 7.98 (brd, J = 8.5 Hz, 2H), 7.66 - 7.53 (m, 6H), 7.39 - 7.19 (m, 4H), 7.11 (brd, J = 8.5 Hz, 2H), 3.81 (s, 3H), 2.96 (s, 3H) Example 8: 1 1H NMR (500 MHz, DMSO - d6) δ 7.89 (brd, J = 8.2 Hz, 2H), 7.69 - 7.55 (m, 1H), 7.46 - 7.11 (m, 6H), 6.91 (brd, J = 10.7 Hz, 2H), 2.96 (s, 3H), 2.55 (s, 3H) Example 9: 1 H NMR (500 MHz, CD3OD) δ 7.80 (brd, J = 7.2 Hz, 2H), 7.62 - 7.54 (m, 2H), 7.53 - 7.42 (m, 5H), 6.75 (brd, J = 10.9 Hz, 2H), 3.86 (s, 3H), 3.09 (s, 3H) Example 10: 1 H NMR (500 MHz, DMSO-d6) δ 9.86 (s, 1H), 7.95 (brd, J = 7.9 Hz, 2H), 7.52 - 7.37 (m, 6H), 6.93 (brd, J = 10.7 Hz, 2H), 3.83 (s, 3H), 2.94 (s, 3H)

[0193] Example 11: 1 H NMR (500 MHz, DMSO-d6) δ 7.82 (brs, 2H), 7.71 - 7.58 (m, 1H), 7.59 - 7.48 (m, 2H), 7.39 - 7.17 (m, 3H), 6.91 (brd, J = 10.4 Hz, 2H), 3.82 (s, 3H), 2.96 (s, 3H) Example 12: 1 H NMR (500 MHz, DMSO-d6) δ 9.75 (s, 1H), 7.91 (brd, J = 8.2 Hz, 2H), 7.50 - 7.40 (m, 4H), 7.33 (t, J = 73.9 Hz, 1H), 7.25 (brd, J = 8.2 Hz, 2H), 6.93 (brd, J = 10.7 Hz, 2H), 3.83 (s, 3H), 2.93 (s, 3H) Example 13: 1 H NMR (500 MHz, CD3OD) δ 7.83 (brd, J = 7.8 Hz, 2H), 7.16 (d, J = 8.7 Hz, 2H), 6.86 (t, J = 73.6 Hz, 1H), 6.71 (d, J = 9.9 Hz, 2H), 3.84 (s, 3H), 3.45 (s, 3H), 3.00 (quin, J = 5.2 Hz, 1H), 1.22 - 1.16 (m, 4H) Example 14: 11H NMR (500 MHz, CD3OD) δ 7.87 (brd, J = 7.2 Hz, 2H), 7.45 (brt, J = 6.6 Hz, 1H), 7.20 (brdd, J = 14.5, 8.7 Hz, 4H), 7.06 - 6.66 (m, 3H), 3.85 (s, 3H), 3.07 (s, 3H), 2.27 (s, 3H) Example 15: 1 1H NMR (500 MHz, DMSO-d6) δ 9.80 (brs, 1H), 7.84 (brd, J = 7.9 Hz, 2H), 7.53 (brd, J = 8.2 Hz, 2H), 7.49 - 7.39 (m, 4H), 6.92 (brd, J = 10.4 Hz, 2H), 3.82 (s, 3H), 2.93 (s, 3H) Example 16: 1 1H NMR (500 MHz, CD3OD) δ 7.70 (brd, J = 7.3 Hz, 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 (brd, J = 3.2 Hz, 2H) Example 17: 1 1H NMR (500 MHz, DMSO-d6) δ 8.00 (brd, J = 7.4 Hz, 2H), 7.82 (brd, J = 8.2 Hz, 2H), 7.52 - 7.45 (m, 2H), 7.44 - 7.37 (m, 2H), 6.89 (brd, J = 10.4 Hz, 2H), 3.83 (s, 3H), 2.95 (s, 3H) Example 18: 1 1H NMR (500 MHz, CD3OD) δ 7.84 (brd, J = 7.6 Hz, 2H), 7.17 (d, J = 8.6 Hz, 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 = 7.0 Hz, 6H) Example 19: 11H NMR (500 MHz, CD3OD) δ 7.92 (brd, J = 5.9 Hz, 2H), 7.66 - 7.42 (m, 7H), 6.93 - 6.65 (m, 3H), 3.86 (s, 3H), 3.10 (s, 3H) Example 20: 1 1H NMR (500 MHz, CD3OD) δ 7.87 (brs, 2H), 7.61 - 7.54 (m, 2H), 7.51 (brd, J = 7.3 Hz, 2H), 7.49 - 7.44 (m, 1H), 7.15 (brt, J = 8.1 Hz, 2H), 6.75 (brd, J = 10.8 Hz, 2H), 3.86 (s, 3H), 3.09 (s, 3H)

[0194] Example 21: 1 1H NMR (500 MHz, CDCl3) δ 7.92 (brs, 1H), 7.82 (brd, J = 8.0 Hz, 2H), 7.14 (brd, J = 8.5 Hz, 2H), 6.74 - 6.40 (m, 3H), 4.69 (s, 2H), 4.27 (q, J = 7.0 Hz, 2H), 3.84 (s, 3H), 3.16 (s, 3H), 1.32 (t, J = 7.2 Hz, 3H) Example 22: 1 1H NMR (500 MHz, CD3OD) δ 7.80 (brd, J = 8.1 Hz, 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) Example 23: 1 1H NMR (500 MHz, CD3OD) δ 10.42 (brs, 1H), 9.31 (brs, 1H), 8.77 (brd, J = 7.7 Hz, 2H), 8.74 - 8.69 (m, 2H), 8.59 (s, 1H), 8.45 - 8.32 (m, 2H), 8.27 (brd, J = 7.7 Hz, 2H), 8.24 - 8.19 (m, 1H), 7.69 (brd, J = 11.2 Hz, 2H), 7.38 (s, 1H), 4.64 (s, 3H), 3.76 (s, 3H) Example 24: 11H NMR (500 MHz, CD3OD) δ 8.67 - 8.56 (m, 1H), 8.15 (s, 1H), 7.89 (brd, J = 7.7 Hz, 1H), 7.53 (s, 5H), 6.75 (d, J = 10.1 Hz, 2H), 3.86 (s, 3H), 3.10 (s, 3H) Example 25: 1 1H NMR (500 MHz, CD3OD) δ 8.81 - 8.73 (m, 1H), 8.21 - 8.15 (m, 1H), 7.63 - 7.42 (m, 6H), 6.77 (d, J = 10.0 Hz, 2H), 3.87 (s, 3H), 3.11 (s, 3H) Example 26: 1 1H NMR (500 MHz, DMSO-d6) δ 9.80 (s, 1H), 7.95 (brd, J = 8.5 Hz, 2H), 7.74 - 7.67 (m, 1H), 7.47 - 7.37 (m, 4H), 6.90 (brd, J = 10.7 Hz, 2H), 3.81 (s, 3H), 2.98 (s, 3H) Example 27: 1 1H NMR (500 MHz, DMSO-d6) δ 9.69 (brs, 1H), 7.94 - 7.87 (m, 2H), 7.74 - 7.67 (m, 1H), 7.41 (brt, J = 8.5 Hz, 2H), 7.30 (t, J = 73.6 Hz, 1H), 7.23 (brd, J = 8.5 Hz, 2H), 6.90 (brd, J = 10.7 Hz, 2H), 3.81 (s, 3H), 2.97 (s, 3H) Example 28: 1 1H NMR (500 MHz, DMSO-d6) δ 9.81 (brs, 1H), 7.94 (brd, J = 8.2 Hz, 2H), 7.57 (brd, J = 6.1 Hz, 1H), 7.51 - 7.40 (m, 5H), 6.90 (brd, J = 10.7 Hz, 2H), 3.81 (s, 3H), 2.93 (s, 3H) Example 29: 11H NMR (500 MHz, DMSO-d6) δ 9.59 (s, 1H), 7.91 (brd, J = 8.3 Hz, 2H), 7.65 - 7.54 (m, 1H), 7.54 - 7.40 (m, 3H), 7.29 (t, J = 73.6 Hz, 1H), 7.24 (brd, J = 8.5 Hz, 2H), 6.89 (brd, J = 10.4 Hz, 2H), 3.84 (s, 3H), 2.94 (s, 3H) Example 30: 1 1H NMR (500 MHz, DMSO-d6) δ 9.77 (brs, 1H), 7.85 (brd, J = 7.9 Hz, 2H), 7.60 - 7.46 (m, 5H), 7.45 - 7.38 (m, 1H), 6.91 (brd, J = 10.4 Hz, 2H), 3.82 (s, 3H), 2.93 (s, 3H)

[0195] Example 31: 1 1H NMR (500 MHz, DMSO-d6) δ 9.78 (brs, 1H), 7.86 (brd, J = 7.9 Hz, 2H), 7.77 - 7.67 (m, 1H), 7.54 (brd, J = 8.2 Hz, 2H), 7.42 (brt, J = 8.5 Hz, 2H), 6.92 (brd, J = 10.4 Hz, 2H), 3.82 (s, 3H), 2.98 (s, 3H) Example 32: 1 1H NMR (500 MHz, DMSO-d6) δ 9.81 (s, 1H), 8.51 (brd, J = 4.0 Hz, 1H), 8.04 (brt, J = 8.9 Hz, 1H), 7.95 (brd, J = 7.9 Hz, 2H), 7.69 - 7.59 (m, 1H), 7.45 (brd, J = 7.9 Hz, 2H), 6.92 (brd, J = 10.7 Hz, 2H), 3.82 (s, 3H), 3.04 (s, 3H) Example 33: 11H NMR (500 MHz, DMSO-d6) δ 9.71 (s, 1H), 8.96 (brd, J = 4.6 Hz, 1H), 8.48 (brd, 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 (brd, J = 8.2 Hz, 2H), 7.00 - 6.80 (m, 2H), 3.81 (s, 3H), 2.95 (s, 3H) Example 35: 1 1H NMR (500 MHz, DMSO-d6) δ 9.87 (brs, 1H), 7.97 (brd, J = 8.2 Hz, 2H), 7.85 (brd, J = 7.9 Hz, 1H), 7.62 - 7.58 (m, 1H), 7.56 - 7.52 (m, 1H), 7.45 (brd, J = 8.2 Hz, 2H), 6.92 (brs, 2H), 3.82 (s, 3H), 2.91 (s, 3H) Example 36: 1 1H NMR (500 MHz, DMSO-d6) δ 9.84 (s, 1H), 7.85 (brd, J = 7.9 Hz, 2H), 7.64 (brd, J = 8.9 Hz, 2H), 7.54 (brd, J = 8.2 Hz, 2H), 7.47 (brd, J = 8.5 Hz, 2H), 6.93 (brd, J = 10.4 Hz, 2H), 3.83 (s, 3H), 2.94 (s, 3H) Example 37: 1 1H NMR (500 MHz, DMSO-d6) δ 9.67 (brs, 1H), 7.87 (brd, J = 7.9 Hz, 2H), 7.61 (brd, J = 8.2 Hz, 1H), 7.43 (brt, J = 7.9 Hz, 1H), 7.30 (brd, J = 7.6 Hz, 1H), 7.23 (t, J = 73.6 Hz, 1H), 7.22 (brd, J = 7.9 Hz, 2H), 6.87 (brt, J = 10.7 Hz, 2H), 3.86 (brs, 3H), 2.90 (s, 3H), 2.23 (brs, 3H) Example 38: 11H NMR (500 MHz, CD3OD) δ 7.92 (brd, 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) Example 40: 1 1H NMR (500 MHz, CD3OD) δ 8.67 (d, J = 2.2 Hz, 1H), 8.15 (dd, J = 8.7, 2.4 Hz, 1H), 7.91 - 7.83 (m, 3H), 7.19 (d, J = 8.7 Hz, 2H), 6.88 (t, J = 73.6 Hz, 1H), 6.76 (d, J = 10.0 Hz, 2H), 3.86 (s, 3H), 3.31 (s, 3H)

[0196] Example 41: 1 1H NMR (500 MHz, CD3OD) δ 8.62 (dd, J = 4.7, 1.5 Hz, 1H), 8.15 (dd, J = 8.2, 1.4 Hz, 1H), 7.91 (brd, J = 7.1 Hz, 2H), 7.60 (dd, J = 8.1, 4.7 Hz, 1H), 7.32 (brd, J = 8.3 Hz, 2H), 6.76 (d, J = 10.3 Hz, 2H), 3.86 (s, 3H), 3.16 (s, 3H) Example 43: 1 1H NMR (500 MHz, CD3OD) δ 8.57 (d, J = 2.4 Hz, 1H), 8.02 (dd, J = 8.8, 2.5 Hz, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.80 (brd, J = 8.2 Hz, 2H), 7.44 (d, J = 8.5 Hz, 2H), 6.76 (d, J = 10.0 Hz, 2H), 3.86 (s, 3H), 3.31 (s, 3H) Example 46: 1 1H NMR (500 MHz, CD3OD) δ 7.90 - 7.85 (m, 3H), 7.64 (d, J = 8.1 Hz, 1H), 7.27 (d, J = 7.6 Hz, 1H), 7.19 (d, J = 8.7 Hz, 2H), 6.88 (t, J = 73.6, 1H), 6.76 (d, J = 9.9 Hz, 2H), 3.86 (s, 3H), 3.31 (s, 3H), 2.59 (s, 3H) Example 47: 1 1H NMR (500 MHz, CD3OD) δ 8.41 (d, J = 1.9 Hz, 1H), 7.87 (brd, J = 8.3 Hz, 2H), 7.77 - 7.62 (m, 2H), 7.18 (d, J = 8.6 Hz, 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) Example 48: 1 1H NMR (500 MHz, DMSO-d6) δ 9.83 - 9.63 (m, 1H), 8.42 (s, 1H), 7.84 (brs, 3H), 7.75 (d, J = 8.2 Hz, 1H), 7.54 (brd, J = 8.2 Hz, 2H), 6.93 (brd, J = 10.7 Hz, 2H), 3.83 (s, 3H), 3.17 (m, 3H), 2.36 (s, 3H) Example 49: 1 1H NMR (500 MHz, CD3OD) δ 8.52 - 8.37 (m, 1H), 7.87 (brd, J = 8.4 Hz, 3H), 7.72 (brd, J = 8.2 Hz, 1H), 7.18 (d, J = 8.6 Hz, 2H), 7.05 - 6.69 (m, 3H), 3.85 (s, 3H), 3.26 (s, 3H), 2.41 (s, 3H) Example 50: 1 1H NMR (500 MHz, CD3OD) δ 8.43 (brs, 1H), 7.95 - 7.89 (m, 2H), 7.87 - 7.68 (m, 2H), 7.32 (brd, J = 8.3 Hz, 2H), 6.76 (d, J = 10.0 Hz, 2H), 3.86 (s, 3H), 3.27 (s, 3H), 2.42 (s, 3H)

[0197] Example 51: 11H NMR (500 MHz, DMSO-d6) δ 9.60 (s, 1H), 8.93 - 8.88 (m, 1H), 8.31 (dd, J = 8.6, 2.3 Hz, 1H), 8.00 (d, J = 8.5 Hz, 1H), 7.96 - 7.88 (m, 2H), 7.79 (d, J = 7.5 Hz, 2H), 7.54 (t, J = 7.6 Hz, 2H), 7.50 - 7.41 (m, 1H), 7.28 (t, J = 73.6 Hz, 1H), 7.25 (d, J = 8.7 Hz, 2H), 6.91 (brd, J = 10.4 Hz, 2H), 3.85 (s, 3H), 3.24 (s, 3H) Example 52: 1 1H NMR (500 MHz, CD3OD) δ 8.41 (d, J = 1.8 Hz, 1H), 7.92 (brd, J = 8.2 Hz, 2H), 7.73 - 7.68 (m, 1H), 7.68 - 7.64 (m, 1H), 7.32 (brd, J = 8.2 Hz, 2H), 6.76 (d, J = 10.0 Hz, 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) Example 53: 1 1H NMR (500 MHz, DMSO-d6) δ 9.51 (s, 1H), 8.42 (s, 1H), 7.72 (brd, J = 8.2 Hz, 3H), 7.63 (brd, J = 8.5 Hz, 1H), 7.13 (brd, J = 7.9 Hz, 2H), 6.91 (brd, J = 10.4 Hz, 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 (brd, J = 4.9 Hz, 2H), 0.72 (brd, J = 4.9 Hz, 2H) Example 55: 11H NMR (500 MHz, CD3OD) δ 8.87 (dd, J = 4.8, 1.6 Hz, 1H), 8.39 (dd, J = 7.8, 1.7 Hz, 1H), 7.86 (brd, J = 8.3 Hz, 2H), 7.63 (dd, J = 7.8, 4.9 Hz, 1H), 7.18 (d, J = 8.7 Hz, 2H), 7.04 - 6.67 (m, 3H), 3.87 (s, 3H), 3.26 (s, 3H) Example 56: 1 1H NMR (500 MHz, CDCl3) δ 8.85 (dd, J = 4.8, 1.8 Hz, 1H), 8.20 (dd, J = 7.7, 1.7 Hz, 1H), 7.92 - 7.78 (m, 3H), 7.45 (dd, J = 7.8, 4.8 Hz, 1H), 7.25 (d, J = 8.3 Hz, 2H), 6.61 (d, J = 9.9 Hz, 2H), 3.86 (s, 3H), 3.20 (s, 3H) Example 60: 1 1H NMR (500 MHz, DMSO-d6) δ 9.75 (brs, 1H), 8.55 (d, J = 8.9 Hz, 1H), 8.14 (d, J = 8.8 Hz, 1H), 8.04 (t, J = 6.9 Hz, 2H), 7.92 (d, J = 8.2 Hz, 2H), 7.82 (t, J = 7.5 Hz, 1H), 7.63 (t, J = 7.5 Hz, 1H), 7.54 - 7.13 (m, 3H), 6.96 (d, J = 10.4 Hz, 2H), 3.84 (s, 3H), 3.31 (s, 3H)

[0198] Example 61: 1 1H NMR (500 MHz, DMSO-d6) δ 9.75 (s, 1H), 8.99 (s, 1H), 8.49 (s, 1H), 7.91 (brd, J = 8.2 Hz, 2H), 7.54 - 7.12 (m, 3H), 6.94 (brd, J = 10.7 Hz, 2H), 3.83 (s, 3H), 3.20 (s, 3H), 2.58 (s, 3H) Example 62: 11H NMR (500 MHz, DMSO-d6) δ 9.78 (s, 1H), 8.92 - 8.81 (m, 1H), 8.25 (s, 1H), 7.90 (d, J = 6.5 Hz, 2H), 7.75 (d, J = 2.7 Hz, 1H), 7.51 - 7.10 (m, 3H), 6.95 (dd, J = 10.4, 2.9 Hz, 2H), 3.83 (d, J = 2.4 Hz, 3H), 3.23 (d, J = 2.1 Hz, 3H) Example 63: 1 1H NMR (500 MHz, DMSO-d6) δ 9.88 (s, 1H), 8.87 (d, J = 5.0 Hz, 1H), 8.24 (s, 1H), 7.95 (d, J = 8.2 Hz, 2H), 7.74 (d, J = 5.0 Hz, 1H), 7.47 (d, J = 7.9 Hz, 2H), 6.95 (d, J = 11.8 Hz, 2H), 3.83 (s, 3H), 3.23 (s, 3H) Example 64: 1 1H NMR (500 MHz, DMSO-d6) δ 9.82 (s, 1H), 9.53 (s, 1H), 8.21 - 8.06 (m, 2H), 7.99 - 7.81 (m, 4H), 7.49 - 7.12 (m, 3H), 6.96 (d, J = 10.4 Hz, 2H), 3.84 (s, 3H), 3.33 (s, 3H) Example 65: 1 1H NMR (500 MHz, DMSO-d6) δ 9.66 (s, 1H), 7.90 (d, J = 8.2 Hz, 2H), 7.54 - 7.41 (m, 1H), 7.38 - 7.12 (m, 3H), 7.08 (s, 1H), 6.92 (d, J = 10.1 Hz, 2H), 3.82 (s, 3H), 3.16 (s, 3H), 2.55 (s, 6H) Example 66: 1 1H NMR (500 MHz, DMSO-d6) δ 9.78 (s, 1H), 7.95 (d, J = 8.5 Hz, 2H), 7.55 - 7.32 (m, 3H), 7.08 (s, 1H), 6.93 (d, J = 10.4 Hz, 2H), 3.83 (s, 3H), 3.17 (s, 3H), 2.49 (s, 3H), 2.38 (s, 3H) Example 67: 11H NMR (500 MHz, DMSO-d6) δ 9.75 (s, 1H), 8.25 - 8.15 (m, 1H), 8.10 - 8.01 (m, 1H), 7.95 - 7.81 (m, 2H), 7.66 (d, J = 7.7 Hz, 1H), 7.49 - 7.00 (m, 4H), 6.92 (d, J = 10.0 Hz, 2H), 3.87 - 3.60 (m, 3H), 3.22 (s, 3H) Example 68: 1 1H NMR (500 MHz, DMSO-d6) δ 9.86 (s, 1H), 8.21 (t, J = 7.8 Hz, 1H), 8.07 (d, J = 8.2 Hz, 1H), 7.94 (d, J = 8.1 Hz, 2H), 7.66 (d, J = 7.5 Hz, 1H), 7.46 (d, J = 8.2 Hz, 2H), 7.22 - 6.87 (m, 3H), 3.91 - 3.56 (m, 3H), 3.22 (s, 3H) Example 69: 1 1H NMR (500 MHz, DMSO-d6) δ 9.76 (s, 1H), 8.39 (d, J = 1.7 Hz, 1H), 8.15 (t, J = 8.0 Hz, 1H), 7.92 (brd, J = 8.5 Hz, 2H), 7.81 - 7.70 (m, 2H), 7.55 - 7.13 (m, 3H), 7.02 - 6.88 (m, 2H), 6.47 (d, J = 2.2 Hz, 1H), 3.84 (s, 3H), 3.26 (s, 3H), 2.32 (s, 3H) Example 70: 1 1H NMR (500 MHz, DMSO-d6) δ 9.88 (s, 1H), 8.40 (d, J = 2.2 Hz, 1H), 8.15 (t, J = 8.0 Hz, 1H), 7.97 (d, J = 8.3 Hz, 2H), 7.82 - 7.69 (m, 2H), 7.48 (d, J = 8.2 Hz, 2H), 6.97 (d, J = 10.5 Hz, 2H), 6.47 (d, J = 2.4 Hz, 1H), 3.84 (s, 3H), 3.27 (s, 3H), 2.32 (s, 3H)

[0199] Example 71: 11H NMR (500 MHz, DMSO-d6) δ 9.77 (s, 1H), 8.77 - 8.64 (m, 1H), 8.26 (s, 1H), 7.90 (d, J = 7.9 Hz, 2H), 7.52 - 7.14 (m, 3H), 6.94 (d, J = 10.7 Hz, 2H), 3.99 (s, 3H), 3.83 (s, 3H), 3.26 (s, 3H) Example 72: 1 1H NMR (500 MHz, DMSO-d6) δ 9.73 (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 (brd, J = 10.4 Hz, 2H), 3.84 (s, 3H), 3.30 (s, 3H) Example 73: 1 1H NMR (500 MHz, DMSO-d6) δ 9.84 (s, 1H), 8.17 - 8.08 (m, 3H), 7.96 (brd, J = 7.3 Hz, 3H), 7.88 (d, J = 8.2 Hz, 1H), 7.59 - 7.53 (m, 2H), 7.52 - 7.43 (m, 3H), 6.97 (brd, J = 10.1 Hz, 2H), 3.84 (s, 3H), 3.31 (s, 3H) Example 74: 1 1H NMR (500 MHz, DMSO-d6) δ 9.80 (s, 1H), 7.98 - 7.84 (m, 3H), 7.50 - 7.40 (m, 3H), 6.92 (brd, J = 10.4 Hz, 2H), 6.79 (d, J = 8.2 Hz, 1H), 3.91 (s, 3H), 3.82 (s, 3H), 3.24 (s, 3H) Example 75: 1 1H NMR (500 MHz, DMSO-d6) δ 9.69 (s, 1H), 7.98 - 7.82 (m, 3H), 7.44 (d, J = 7.3 Hz, 1H), 7.34 - 7.10 (m, 3H), 6.92 (d, J = 10.7 Hz, 2H), 6.79 (d, J = 7.9 Hz, 1H), 3.91 (s, 3H), 3.82 (s, 3H), 3.24 (s, 3H) Example 76: 11H NMR (500 MHz, DMSO-d6) δ 9.76 (s, 1H), 8.76 (d, J = 5.0 Hz, 1H), 8.09 (s, 1H), 7.91 (d, J = 8.3 Hz, 2H), 7.55 (d, J = 4.9 Hz, 1H), 7.49 - 7.08 (m, 4H), 6.94 (d, J = 10.2 Hz, 2H), 3.83 (s, 3H), 3.20 (s, 3H) Example 77: 1 1H NMR (500 MHz, DMSO-d6) δ 9.66 (s, 1H), 8.21 (s, 1H), 7.88 (d, J = 8.5 Hz, 2H), 7.47 - 7.06 (m, 4H), 6.90 (d, J = 10.4 Hz, 2H), 3.93 (s, 3H), 3.81 (s, 3H), 3.15 (s, 3H), 2.15 (s, 3H) Example 78: 1 1H NMR (500 MHz, DMSO-d6) δ 9.72 (s, 1H), 7.98 - 7.80 (m, 3H), 7.51 - 7.16 (m, 4H), 6.95 (brd, J = 10.4 Hz, 2H), 6.76 (d, J = 8.1 Hz, 1H), 4.36 (q, J = 7.0 Hz, 2H), 3.83 (s, 3H), 3.23 (s, 3H), 1.37 (t, J = 7.0 Hz, 3H) Example 79: 1 1H NMR (500 MHz, DMSO-d6) δ 9.66 (s, 1H), 7.91 (brd, J = 8.2 Hz, 2H), 7.75 (t, J = 7.9 Hz, 1H), 7.51 - 7.11 (m, 4H), 6.93 (brd, J = 10.4 Hz, 2H), 6.77 (d, J = 8.2 Hz, 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) Example 80: 11H NMR (500 MHz, DMSO-d6) δ 9.65 (s, 1H), 7.90 (d, J = 8.2 Hz, 2H), 7.68 (t, J = 7.9 Hz, 1H), 7.24 (d, J = 8.5 Hz, 2H), 7.30 (t, J = 73.9 Hz, 1H), 7.01 (d, J = 7.6 Hz, 1H), 6.92 (d, J = 10.1 Hz, 2H), 6.74 (d, J = 8.5 Hz, 1H), 3.82 (s, 3H), 3.63 - 3.39 (m, 4H), 3.19 (s, 3H), 1.67 - 1.47 (m, 6H)

[0200] Example 81: 1 1H NMR (500 MHz, DMSO-d6) δ 9.68 (s, 1H), 8.01 (t, J = 7.9 Hz, 1H), 7.89 (d, J = 8.5 Hz, 2H), 7.72 (d, J = 7.9 Hz, 1H), 7.47 - 7.41 (m, 1H), 7.32 - 7.12 (m, 3H), 6.91 (d, J = 10.4 Hz, 2H), 4.61 (s, 2H), 3.82 (s, 3H), 3.56 (brs, 1H), 3.18 (s, 3H) Example 82: 1 1H NMR (500 MHz, DMSO-d6) δ 9.66 (s, 1H), 7.89 (d, J = 8.5 Hz, 2H), 7.67 (t, J = 8.0 Hz, 1H), 7.24 (d, J = 8.5 Hz, 2H), 7.23 (t, J = 73.5 Hz, 1H), 6.99 (d, J = 7.7 Hz, 1H), 6.90 (d, J = 10.3 Hz, 2H), 6.57 (d, J = 8.4 Hz, 1H), 3.81 (s, 3H), 3.22 (s, 3H), 3.05 (s, 6H) Example 83: 1 1H NMR (500 MHz, DMSO-d6) δ 9.69 (s, 1H), 7.91 (d, J = 8.5 Hz, 2H), 7.72 (t, J = 8.0 Hz, 1H), 7.25 (d, J = 8.6 Hz, 2H), 7.29 (t, J = 75.1 Hz, 1H), 7.10 (d, J = 7.7 Hz, 1H), 6.94 (d, J = 10.4 Hz, 2H), 6.78 (d, J = 8.4 Hz, 1H), 3.83 (s, 3H), 3.19 (s, 3H), 2.45 (brs, 4H), 2.25 (s, 3H), 1.92 (s, 4H) Example 84: 1 H NMR (500 MHz, DMSO-d6) δ 9.91 (s, 1H), 9.72 (s, 1H), 8.04 - 7.96 (m, 2H), 7.91 (d, J = 8.3 Hz, 2H), 7.54 - 7.50 (m, 1H), 7.25 (d, J = 8.4 Hz, 2H), 7.50 - 7.16 (m, 1H), 6.94 (d, J = 10.7 Hz, 2H), 3.83 (s, 3H), 3.21 (s, 3H), 1.27 (s, 9H) Example 86: 1 H NMR (500 MHz, DMSO-d6) δ 9.69 (s, 1H), 8.00 (t, J = 7.9 Hz, 1H), 7.91 (d, J = 8.5 Hz, 2H), 7.74 (d, J = 7.9 Hz, 1H), 7.47 (d, J = 7.0 Hz, 1H), 7.36 - 7.14 (m, 3H), 6.93 (d, J = 10.4 Hz, 2H), 5.52 (d, J = 4.6 Hz, 1H), 4.85 - 4.72 (m, 1H), 3.83 (s, 3H), 3.21 (s, 3H), 1.43 (d, J = 6.4 Hz, 3H) Example 89: 1 H NMR (500 MHz, DMSO-d6) δ 9.66 (s, 1H), 7.89 (brd, J = 8.2 Hz, 2H), 7.48 - 7.10 (m, 5H), 6.92 (brd, J = 10.4 Hz, 2H), 5.41 (s, 1H), 3.90 (s, 3H), 3.82 (s, 3H), 3.22 (s, 3H), 1.46 (s, 6H) Example 90: 1 H NMR (500 MHz, DMSO-d6) δ 9.69 (s, 1H), 7.91 (d, J = 8.6 Hz, 2H), 7.30 (d, J = 1.9 Hz, 1H), 7.25 (d, J = 8.7 Hz, 2H), 7.34 (t, J = 73.8 Hz, 1H), 7.02 (s, 1H), 6.93 (d, J = 10.2 Hz, 2H), 5.61 (t, J = 5.8 Hz, 1H), 4.57 (d, J = 5.8 Hz, 2H), 3.92 (s, 3H), 3.83 (s, 3H), 3.19 (s, 3H)

[0201] Example 92: 1 1H NMR (500 MHz, DMSO-d6) δ 9.63 (s, 1H), 7.89 (d, J = 8.2 Hz, 2H), 7.47 - 7.10 (m, 3H), 6.91 (d, J = 10.7 Hz, 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 = 6.1 Hz, 6H) Example 93: 1 1H NMR (500 MHz, DMSO-d6) δ 9.65 (s, 1H), 7.88 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.6 Hz, 2H), 7.46 - 7.09 (m, 1H), 6.91 (d, J = 11.0 Hz, 2H), 6.66 (s, 1H), 6.28 (s, 1H), 4.13 (d, J = 13.0 Hz, 2H), 3.84 (s, 3H), 3.80 (s, 3H), 3.18 (s, 3H), 2.62 (t, J = 11.9 Hz, 2H), 2.23 - 2.13 (m, 5H), 1.08 (d, J = 6.1 Hz, 6H) Example 94: 1 1H NMR (500 MHz, DMSO-d6) δ 9.64 (s, 1H), 7.89 (d, J = 7.8 Hz, 2H), 7.24 (d, J = 8.6 Hz, 2H), 7.32 (t, J = 84.6 Hz, 1H), 6.91 (d, J = 10.4 Hz, 2H), 6.65 (s, 1H), 6.58 (d, J = 1.9 Hz, 1H), 6.00 (d, J = 1.3 Hz, 1H), 3.81 (s, 3H), 3.78 (s, 3H), 3.62 - 3.59 (m, 2H), 3.33 (q, J = 5.7 Hz, 2H), 3.20 (s, 3H), 1.91 (s, 1H) Example 95: 11H NMR (500 MHz, DMSO-d6) δ 9.64 (s, 1H), 7.88 (d, J = 8.0 Hz, 2H), 7.46 - 7.10 (m, 4H), 6.89 (d, J = 10.4 Hz, 2H), 6.63 (d, J = 1.9 Hz, 1H), 5.86 (s, 1H), 4.40 (brs, 1H), 3.83 (brs, 3H), 3.79 - 3.78 (m, 3H), 3.73 (brd, J = 1.4 Hz, 1H), 3.54 - 3.42 (m, 2H), 3.35 (brd, J = 10.4 Hz, 1H), 3.24 (s, 3H), 2.09 - 1.97 (m, 1H), 1.94 - 1.86 (m, 1H) Example 96: 1 1H NMR (500 MHz, DMSO-d6) δ 9.65 (s, 1H), 7.90 (d, J = 8.6 Hz, 2H), 7.24 (d, J = 8.6 Hz, 2H), 7.52 - 7.13 (m, 1H), 6.92 (d, J = 10.3 Hz, 2H), 6.76 - 6.67 (m, 1H), 5.86 (d, J = 1.4 Hz, 1H), 3.93 - 3.78 (m, 8H), 3.57 - 3.50 (m, 3H), 3.22 (s, 3H), 1.45 (s, 3H) Example 97: 1 1H NMR (500 MHz, DMSO-d6) δ 9.63 (s, 1H), 7.90 (d, J = 8.2 Hz, 2H), 7.24 (d, J = 8.5 Hz, 2H), 7.31 (t, J = 71.4 Hz, 1H), 6.91 (d, J = 10.1 Hz, 2H), 6.67 (d, J = 1.5 Hz, 1H), 5.86 (d, J = 1.5 Hz, 1H), 4.40 (brs, 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) Example 98: 11H NMR (500 MHz, DMSO-d6) δ 9.63 (s, 1H), 7.89 (d, J = 8.5 Hz, 2H), 7.24 (d, J = 8.5 Hz, 2H), 7.30 (t, J = 72.6 Hz, 1H), 6.91 (d, J = 10.7 Hz, 2H), 6.72 (s, 1H), 5.94 (s, 1H), 5.45 (d, J = 56.2 Hz, 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) Example 99: 1 1H NMR (500 MHz, DMSO-d6) δ 9.67 (s, 1H), 7.91 (d, J = 8.7 Hz, 2H), 7.25 (d, J = 8.6 Hz, 2H), 7.53 - 7.14 (m, 1H), 6.93 (d, J = 10.4 Hz, 2H), 6.79 (s, 1H), 6.02 (d, J = 1.5 Hz, 1H), 3.87 (s, 3H), 3.82 (s, 3H), 3.94 - 3.75 (m, 2H), 3.67 (brt, J = 7.3 Hz, 2H), 3.24 (s, 3H), 2.63 - 2.54 (m, 2H) Example 100: 1 1H NMR (500 MHz, DMSO-d6) δ 9.71 (s, 1H), 7.91 (d, J = 8.6 Hz, 2H), 7.32 - 7.28 (m, 1H), 7.26 (d, J = 8.6 Hz, 2H), 7.32 (t, J = 75.4 Hz, 1H), 7.06 (s, 1H), 6.95 (dd, J = 10.5, 3.8 Hz, 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)

[0202] Example 101: 11H NMR (500 MHz, DMSO-d6) δ 9.69 (s, 1H), 7.94 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.5 Hz, 2H), 7.36 (t, J = 75.4 Hz, 1H), 6.96 (d, J = 10.4 Hz, 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) Example 102: 1 1H NMR (500 MHz, DMSO-d6) δ 9.65 (s, 1H), 7.91 (d, J = 8.5 Hz, 2H), 7.66 (t, J = 7.9 Hz, 1H), 7.25 (d, J = 8.5 Hz, 2H), 7.33 (t, J = 73.5 Hz, 1H), 7.02 (d, J = 7.6 Hz, 1H), 6.93 (d, J = 10.1 Hz, 2H), 6.38 (d, J = 8.2 Hz, 1H), 5.04 (d, J = 3.7 Hz, 1H), 4.42 (brd, J = 1.8 Hz, 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) Example 103: 1 1H NMR (500 MHz, DMSO-d6) δ 9.70 (s, 1H), 7.93 (d, J = 8.6 Hz, 2H), 7.71 (t, J = 8.0 Hz, 1H), 7.26 (d, J = 8.6 Hz, 2H), 7.36 (t, J = 72.5 Hz, 1H), 7.06 (d, J = 7.7 Hz, 1H), 6.96 (d, J = 10.4 Hz, 2H), 6.80 (d, J = 8.5 Hz, 1H), 4.17 (brd, J = 12.5 Hz, 2H), 3.83 (s, 3H), 3.19 (s, 3H), 2.64 (brt, J = 11.9 Hz, 2H), 2.20 (m, 5H), 1.10 (d, J = 6.1 Hz, 6H) Example 104: 11H NMR (500 MHz, DMSO-d6) δ 9.67 (s, 1H), 7.91 (d, J = 8.9 Hz, 2H), 7.81 (t, J = 7.9 Hz, 1H), 7.28 - 7.22 (m, 3H), 7.32 (t, J = 78.4 Hz, 1H), 6.93 (d, J = 10.1 Hz, 2H), 6.53 (d, J = 7.9 Hz, 1H), 4.45 (t, J = 12.4 Hz, 4H), 3.83 (s, 3H), 3.22 (s, 3H) Example 105: 1 1H NMR (500 MHz, DMSO-d6) δ 9.64 (s, 1H), 7.91 (d, J = 8.5 Hz, 2H), 7.25 (d, J = 8.5 Hz, 2H), 7.32 (t, J = 73.5 Hz, 1H), 6.92 (d, J = 10.4 Hz, 2H), 6.71 (s, 1H), 6.21 (s, 1H), 4.52 (brs, 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) Example 106: 1 1H NMR (500 MHz, DMSO-d6) δ 9.66 (s, 1H), 7.91 (d, J = 8.7 Hz, 2H), 7.25 (d, J = 8.7 Hz, 2H), 7.34 (t, J = 73.7 Hz, 1H), 6.93 (d, J = 10.2 Hz, 2H), 6.74 (s, 1H), 5.87 (s, 1H), 4.51 (quin, J = 5.5 Hz, 1H), 4.25 - 4.18 (m, 2H), 3.84 (s, 3H), 3.82 (s, 3H), 3.74 (dd, J = 8.8, 4.5 Hz, 2H), 3.70 - 3.61 (m, 1H), 3.22 (s, 3H), 1.12 (d, J = 6.1 Hz, 6H) Example 107: 11H NMR (500 MHz, DMSO-d6) δ 9.70 (s, 1H), 7.92 (d, J = 8.8 Hz, 2H), 7.83 (t, J = 8.1 Hz, 1H), 7.26 (d, J = 8.5 Hz, 2H), 7.22 (d, J = 7.7 Hz, 1H), 7.35 (t, J = 73.2 Hz, 1H), 6.94 (d, J = 10.2 Hz, 2H), 6.91 (d, J = 8.5 Hz, 1H), 4.40 (brd, J = 13.5 Hz, 2H), 3.84 (s, 3H), 3.81 - 3.76 (m, 3H), 3.63 (brd, J = 11.3 Hz, 2H), 3.38 - 3.29 (m, 2H), 3.26 (brs, 2H), 3.21 - 3.16 (m, 5H) Example 109: 1 1H NMR (500 MHz, DMSO-d6) δ 9.70 (s, 1H), 7.89 (brd, J = 7.9 Hz, 2H), 7.23 (brd, J = 8.2 Hz, 2H), 7.30 (t, J = 74.0 Hz, 1H), 7.03 (s, 3H), 6.89 (brs, 2H), 3.81 (s, 3H), 2.91 (s, 3H), 2.35 (s, 6H) Example 110: 1 1H NMR (500 MHz, DMSO-d6) δ 9.90 - 9.69 (m, 1H), 7.93 - 7.86 (m, 3H), 7.83 (brd, J = 4.9 Hz, 1H), 7.78 (brd, J = 4.9 Hz, 2H), 7.24 (brd, J = 8.5 Hz, 2H), 7.30 (t, J = 74.0 Hz, 1H), 6.92 (brd, J = 10.4 Hz, 2H), 3.82 (s, 3H), 2.96 (s, 3H)

[0203] Example 111: 11H NMR (500 MHz, DMSO-d6) δ 9.71 (s, 1H), 8.02 - 7.79 (m, 2H), 7.48 - 7.39 (m, 1H), 7.24 (brd, J = 8.5 Hz, 2H), 7.18 (t, J = 74.0 Hz, 1H), 7.15 (brd, J = 5.8 Hz, 2H), 7.07 (brd, J = 7.9 Hz, 1H), 6.91 (brd, J = 10.4 Hz, 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) Example 112: 1 1H NMR (500 MHz, DMSO-d6) δ 9.76 (s, 1H), 7.91 (brd, J = 8.5 Hz, 2H), 7.52 - 7.46 (m, 1H), 7.25 (d, J = 8.6 Hz, 2H), 7.30 (t, J = 74.0 Hz, 1H), 7.05 - 6.96 (m, 3H), 6.93 (d, J = 10.4 Hz, 2H), 3.83 (s, 6H), 2.94 (s, 3H) Example 113: 1 1H NMR (500 MHz, DMSO-d6) δ 9.78 (s, 1H), 8.00 (s, 1H), 7.95 (brd, J = 6.7 Hz, 1H), 7.91 (brd, J = 8.5 Hz, 2H), 7.79 - 7.67 (m, 2H), 7.25 (d, J = 8.5 Hz, 2H), 7.32 (t, J = 74.0 Hz, 1H), 6.93 (brd, J = 10.4 Hz, 2H), 3.91 (s, 3H), 3.83 (s, 3H), 2.94 (s, 3H) Example 114: 1 1H NMR (500 MHz, DMSO-d6) δ 9.79 (s, 1H), 7.91 (brd, J = 8.5 Hz, 2H), 7.68 - 7.58 (m, 1H), 7.53 (d, J = 1.8 Hz, 1H), 7.50 - 7.44 (m, 1H), 7.41 (brd, J = 7.9 Hz, 1H), 7.36 - 7.12 (m, 3H), 6.94 (brd, J = 10.1 Hz, 2H), 3.83 (s, 3H), 2.96 (s, 3H) Example 115: 11H NMR (500 MHz, DMSO-d6) δ 9.84 (s, 1H), 8.30 (d, J = 5.6 Hz, 1H), 7.89 (brd, J = 8.4 Hz, 2H), 7.24 (brd, J = 8.6 Hz, 2H), 7.50 - 7.15 (m, 1H), 7.14 - 7.08 (m, 1H), 6.93 (brd, J = 10.4 Hz, 2H), 6.86 (s, 1H), 3.90 (s, 3H), 3.82 (s, 3H), 2.96 (s, 3H) Example 116: 1 1H NMR (500 MHz, DMSO-d6) δ 9.87 (s, 1H), 8.53 (d, J = 5.6 Hz, 1H), 7.88 (brd, 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 out of 17 protons were observed. Example 117: 1 1H NMR (500 MHz, DMSO-d6) δ 9.79 (s, 1H), 7.89 (d, J = 8.5 Hz, 2H), 7.28 (d, J = 14.6 Hz, 2H), 7.26 - 7.21 (m, 3H), 7.30 (t, J = 74.0 Hz, 1H), 6.92 (d, J = 10.4 Hz, 2H), 3.91 (s, 3H), 3.82 (s, 3H), 2.98 - 2.89 (m, 3H) Example 118: 1 1H NMR (500 MHz, DMSO-d6) δ 9.84 - 9.67 (m, 1H), 7.90 (brd, J = 7.2 Hz, 2H), 7.46 (t, J = 7.9 Hz, 1H), 7.24 (brd, J = 8.2 Hz, 2H), 7.34 - 7.13 (m, 1H), 7.01 - 6.87 (m, 5H), 4.08 (q, J = 7.1 Hz, 2H), 3.82 (s, 3H), 2.93 (s, 3H), 1.36 (brt, J = 6.9 Hz, 3H) Example 119: 11H NMR (500 MHz, DMSO-d6) δ 9.80 (s, 1H), 7.89 (brd, J = 8.4 Hz, 2H), 7.76 (s, 1H), 7.70 (s, 1H), 7.60 (s, 1H), 7.24 (d, J = 8.6 Hz, 2H), 7.32 (t, J = 74.0 Hz, 1H), 6.93 (d, J = 10.5 Hz, 2H), 3.82 (s, 3H), 3.07 (dt, J = 13.7, 6.9 Hz, 1H), 2.95 (s, 3H), 1.26 (d, J = 6.8 Hz, 6H) Example 120: 1 1H NMR (500 MHz, DMSO-d6) δ 9.81 (s, 1H), 7.89 (brt, J = 6.6 Hz, 4H), 7.78 (s, 1H), 7.24 (brd, J = 8.5 Hz, 2H), 7.29 (t, J = 74.0 Hz, 1H), 6.92 (brd, J = 10.7 Hz, 2H), 3.91 (s, 3H), 3.82 (s, 3H), 2.95 (s, 3H)

[0204] Example 121: 1 1H NMR (500 MHz, DMSO-d6) δ 9.73 (s, 1H), 7.89 (brd, J = 8.3 Hz, 2H), 7.45 - 7.44 (m, 1H), 7.24 (d, J = 8.6 Hz, 1H), 7.31 (t, J = 74.0 Hz, 1H), 6.91 (d, J = 10.4 Hz, 2H), 6.81 (s, 1H), 6.80 (d, J = 14.0 Hz, 2H), 3.81 (s, 3H), 3.79 (s, 3H), 2.92 (s, 3H), 2.36 (s, 3H) Example 122: 1 1H NMR (500 MHz, DMSO-d6) δ 9.79 (s, 1H), 7.90 (brd, J = 8.2 Hz, 2H), 7.29 (s, 1H), 7.26 - 7.23 (m, 3H), 7.22 (s, 1H), 7.31 (t, J = 74.0 Hz, 1H), 6.93 (brd, J = 10.7 Hz, 2H), 4.19 (q, J = 7.0 Hz, 2H), 3.82 (s, 3H), 2.96 (s, 3H), 1.38 (t, J = 6.9 Hz, 3H) Example 123: 11H NMR (500 MHz, DMSO-d6) δ 9.81 (s, 1H), 7.88 (brd, J = 8.5 Hz, 2H), 7.59 - 7.52 (m, J = 7.6 Hz, 2H), 7.40 (s, 1H), 7.24 (d, J = 8.5 Hz, 2H), 7.29 (t, J = 74.0 Hz, 1H), 6.92 (brd, J = 10.7 Hz, 2H), 3.82 (s, 3H), 2.96 (s, 3H) Example 124: 1 1H NMR (500 MHz, DMSO-d6) δ 9.79 (s, 1H), 7.90 (brd, J = 8.3 Hz, 2H), 7.24 (d, J = 8.6 Hz, 2H), 7.31 (t, J = 74.0 Hz, 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) Example 125: 1 1H NMR (500 MHz, DMSO-d6) δ 9.78 (s, 1H), 7.90 (brd, J = 7.9 Hz, 2H), 7.24 (brd, J = 8.6 Hz, 2H), 7.32 (t, J = 74.0 Hz, 1H), 6.92 (brd, J = 10.6 Hz, 2H), 6.87 - 6.76 (m, 3H), 4.68 (spt, J = 5.7 Hz, 1H), 3.82 (s, 3H), 2.95 (s, 3H), 1.30 (d, J = 5.9 Hz, 6H) Example 126: 1 1H NMR (500 MHz, DMSO-d6) δ 9.91 - 9.76 (m, 1H), 7.88 (brd, J = 7.5 Hz, 2H), 7.57 (s, 1H), 7.47 (d, J = 1.3 Hz, 1H), 7.36 (s, 1H), 7.24 (d, J = 8.3 Hz, 2H), 7.30 (t, J = 74.0 Hz, 1H), 6.92 (brd, J = 10.7 Hz, 2H), 3.81 (s, 3H), 3.00 (s, 3H), 2.96 (s, 3H), 2.95 - 2.92 (m, 3H) Example 127: 11H NMR (500 MHz, DMSO-d6) δ 9.88 - 9.76 (m, 1H), 7.88 (brd, J = 8.2 Hz, 2H), 7.62 (d, J = 1.5 Hz, 1H), 7.46 (d, J = 1.8 Hz, 2H), 7.26 - 7.19 (m, 1H), 7.25 (t, J = 74.0 Hz, 2H), 6.91 (brd, J = 10.4 Hz, 2H), 3.81 (s, 3H), 2.95 (s, 3H) Example 128: 1 1H NMR (500 MHz, DMSO-d6) δ 9.85 (s, 1H), 9.05 (s, 1H), 8.92 (d, J = 1.7 Hz, 1H), 8.25 (s, 1H), 7.89 (brd, J = 8.3 Hz, 2H), 7.24 (d, J = 8.6 Hz, 2H), 7.29 (t, J = 74.0 Hz, 1H), 6.93 (brd, J = 10.7 Hz, 2H), 3.93 (s, 3H), 3.82 (s, 3H), 2.98 (s, 3H) Example 129: 1 1H NMR (500 MHz, DMSO-d6) δ 9.79 (s, 1H), 8.38 - 8.17 (m, 2H), 7.89 (brd, J = 8.6 Hz, 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) Example 130: 1 1H NMR (500 MHz, DMSO-d6) δ 9.84 (s, 1H), 8.67 - 8.58 (m, 2H), 8.01 (s, 1H), 7.89 (brd, J = 8.1 Hz, 2H), 7.24 (d, J = 8.6 Hz, 2H), 7.31 (t, J = 74.0 Hz, 1H), 6.93 (brd, J = 10.5 Hz, 2H), 3.82 (s, 3H), 2.99 (s, 3H)

[0205] Example 131: 11H NMR (500 MHz, DMSO-d6) δ 9.84 (s, 1H), 7.88 (brd, J = 5.2 Hz, 3H), 7.77 (s, 1H), 7.70 (s, 1H), 7.24 (brd, J = 8.7 Hz, 2H), 7.27 (t, J = 74.0 Hz, 1H), 6.92 (brd, J = 10.3 Hz, 2H), 3.81 (s, 3H), 2.96 (s, 3H) Example 132: 1 1H NMR (500 MHz, DMSO-d6) δ 9.75 (s, 1H), 7.87 (d, J = 8.2 Hz, 2H), 7.23 (d, J = 8.5 Hz, 2H), 7.26 (t, J = 74.0 Hz, 1H), 6.99 - 6.71 (m, 5H), 3.82 (s, 3H), 3.80 (s, 3H), 2.94 (s, 3H) Example 133: 1 1H NMR (500 MHz, DMSO-d6) δ 9.83 (s, 1H), 7.89 (brd, J = 8.2 Hz, 2H), 7.83 (s, 1H), 7.69 (brd, J = 8.6 Hz, 1H), 7.58 (brd, J = 9.5 Hz, 1H), 7.24 (brd, J = 8.7 Hz, 2H), 7.29 (t, J = 74.0 Hz, 1H), 6.93 (brd, J = 10.6 Hz, 2H), 4.36 (q, J = 7.0 Hz, 2H), 3.81 (s, 3H), 2.96 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H) Example 134: 1 1H NMR (500 MHz, DMSO-d6) δ 9.76 (s, 1H), 7.90 (brd, J = 8.5 Hz, 2H), 7.32 - 7.19 (m, 5H), 7.32 (t, J = 74.0 Hz, 1H), 6.93 (brd, J = 10.4 Hz, 2H), 3.83 (s, 3H), 2.94 (s, 3H), 2.41 (s, 3H) Example 136: 11H NMR (500 MHz, DMSO-d6) δ 9.68 (s, 1H), 7.94 (brdd, 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) Example 137: 1 1H NMR (500 MHz, DMSO-d6) δ 9.67 (s, 1H), 7.99 - 7.87 (m, 3H), 7.24 (brd, 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 (brd, J = 10.7 Hz, 2H), 2.19 (brt, J = 10.1 Hz, 2H), 2.13 (s, 3H), 1.96 (brd, J = 7.6 Hz, 2H), 1.93 - 1.86 (m, 2H) Example 138: 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) Example 139: 1 1H NMR (500 MHz, DMSO-d6) δ 9.67 (s, 1H), 7.92 (brdd, 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) Example 140: 11H NMR (500 MHz, DMSO-d6) δ 9.66 (s, 1H), 8.00 - 7.93 (m, 1H), 7.89 (brd, J = 8.7 Hz, 2H), 7.25 - 7.19 (m, J = 8.6 Hz, 2H), 7.30 (t, J = 74.0 Hz, 1H), 6.98 - 6.78 (m, 2H), 6.62 (d, J = 8.8 Hz, 1H), 4.53 (brt, J = 4.5 Hz, 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 = 6.1 Hz, 6H)

[0206] Example 141: 1 1H NMR (500 MHz, DMSO-d6) δ 9.74 (s, 1H), 7.98 (d, J = 8.9 Hz, 1H), 7.86 (brd, J = 8.2 Hz, 2H), 7.53 (brd, J = 8.2 Hz, 2H), 7.00 - 6.84 (m, 2H), 6.64 (d, J = 8.5 Hz, 1H), 4.55 (brd, J = 4.9 Hz, 1H), 4.33 (brs, 2H), 3.94 - 3.85 (m, 2H), 3.83 (s, 3H), 3.68 (dt, J = 12.2, 6.1 Hz, 1H), 2.97 (s, 3H), 1.13 (d, J = 6.1 Hz, 6H) Example 142: 1 1H NMR (500 MHz, CD3CN) δ 8.23 (d, J = 4.1 Hz, 1H), 8.13 (brs, 1H), 7.84 (brd, J = 7.7 Hz, 2H), 7.66 (d, J = 8.3 Hz, 1H), 7.48 (dd, J = 8.3, 4.4 Hz, 1H), 7.21 (brd, J = 8.5 Hz, 2H), 6.77 (d, J = 10.2 Hz, 2H), 6.87 (t, J = 79.0 Hz, 1H), 3.87 (s, 3H), 3.18 (s, 3H), 2.93 (s, 6H) Example 143: 11H NMR (500 MHz, DMSO-d6) δ 9.68 (brs, 1H), 7.96 - 7.87 (m, 2H), 7.83 (d, J = 9.0 Hz, 1H), 7.32 (brs, 1H), 7.26 - 7.21 (m, J = 8.3 Hz, 2H), 7.02 (brd, J = 9.2 Hz, 1H), 6.91 (brs, 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) Example 144: 1 1H NMR (500 MHz, DMSO-d6) δ 9.62 (s, 1H), 7.93 (brd, J = 8.5 Hz, 2H), 7.47 (d, J = 8.5 Hz, 1H), 7.24 (brd, 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 (brd, J = 8.5 Hz, 2H), 3.82 (s, 3H), 2.98 (s, 3H) Example 145: 1 1H NMR (500 MHz, DMSO-d6) δ 9.71 (brs, 1H), 8.00 - 7.88 (m, 3H), 7.49 - 7.24 (brd, J = 6.4 Hz, 1H), 7.19 (brs, 1H), 6.92 (brs, 2H), 6.79 (dd, J = 8.8, 3.5 Hz, 2H), 4.48 (brt, J = 11.9 Hz, 4H), 3.83 (s, 3H), 3.01 (s, 3H) Example 146: 1 1H NMR (500 MHz, CDCl3 + CD3OD) δ 7.77 (brd, 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 (brd, 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) Example 147: 11H NMR (500 MHz, DMSO-d6) δ 9.68 (s, 1H), 7.93 (brd, J = 8.5 Hz, 2H), 7.79 (d, J = 9.2 Hz, 2H), 7.49 - 7.19 (s, 1H), 7.24 (brd, J = 8.5 Hz, 1H), 6.92 (brs, 1H), 6.82 (d, J = 9.2 Hz, 2H), 3.84 (s, 3H), 3.07 (s, 6H), 3.02 (s, 3H) Example 148: 1 1H NMR (500 MHz, DMSO-d6) δ 9.74 (s, 1H), 7.87 (brd, J = 8.2 Hz, 2H), 7.44 - 7.08 (m, 6H), 6.89 (brd, J = 10.7 Hz, 2H), 5.47 (s, 1H), 3.80 (s, 3H), 2.95 (s, 3H), 1.45 (s, 6H) Example 150: 1 1H NMR (500 MHz, DMSO-d6) δ 9.72 (s, 1H), 8.00 (t, J = 7.9 Hz, 1H), 7.93 (d, J = 8.5 Hz, 2H), 7.72 (d, J = 8.2 Hz, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.26 (d, J = 8.5 Hz, 2H), 7.35 (t, J = 74.8 Hz, 1H), 6.95 (d, J = 10.4 Hz, 2H), 3.92 (brt, J = 5.8 Hz, 2H), 3.84 (s, 3H), 3.22 (s, 3H), 1.97 - 1.80 (m, 4H); Two protons of the piperidinone group were obscured by the solvent peak.

[0207] Example 151: 1 1H NMR (500 MHz, CD3OD) δ 8.47 (d, J = 5.2 Hz, 1H), 7.97 (brd, J = 8.8 Hz, 2H), 7.74 (s, 1H), 7.38 (brd, J = 8.3 Hz, 2H), 7.31 (d, J = 5.2 Hz, 1H), 6.82 (d, J = 9.9 Hz, 2H), 3.89 (s, 3H), 3.32 (s, 3H), 2.52 (s, 3H) Example 152: 11H NMR (400 MHz, CDCl3) δ 8.46 (d, J = 5.3 Hz, 1H), 8.11 (d, J = 1.8 Hz, 1H), 7.81 (d, J = 8.8 Hz, 2H), 7.24 (m, 1H), 7.14 (d, J = 8.8 Hz, 2H), 6.77 - 6.29 (m, 3H), 3.84 (s, 3H), 3.31 (s, 3H) Example 154 1 1H NMR (500 MHz, DMSO-d6) δ 9.82 (s, 1H), 8.95 (brd, J = 4.0 Hz, 1H), 8.48 (brd, J = 7.9 Hz, 1H), 7.94 (brd, J = 8.2 Hz, 2H), 7.84 - 7.77 (m, 1H), 7.43 (brd, J = 7.9 Hz, 2H), 7.00 - 6.80 (m, 2H), 3.81 (s, 3H), 2.94 (s, 3H) Example 155 1 1H NMR (500 MHz, DMSO-d6) δ 9.86 (s, 1H), 8.35 - 8.27 (m, 1H), 8.27 - 8.21 (m, 1H), 7.95 (brd, J = 8.2 Hz, 2H), 7.86 (brd, J = 7.3 Hz, 1H), 7.46 (brd, J = 8.2 Hz, 2H), 6.94 (brd, J = 10.4 Hz, 2H), 3.83 (s, 3H), 3.23 (s, 3H) Example 156 1 1H NMR (500 MHz, DMSO-d6) δ 9.75 (s, 1H), 8.33 - 8.27 (m, 1H), 8.27 - 8.20 (m, 1H), 7.90 (brd, J = 8.2 Hz, 2H), 7.85 (brd, J = 7.3 Hz, 1H), 7.32 (t, J = 73.6 Hz, 1H), 7.24 (brd, J = 8.5 Hz, 2H), 6.93 (brd, J = 10.7 Hz, 2H), 3.82 (s, 3H), 3.22 (s, 3H) Example 157 11H 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 (brd, J = 8.5 Hz, 2H), 7.29 (t, J = 73.6 Hz 1H), 7.24 (brd, J = 8.5 Hz, 2H), 6.94 (brd, J = 10.7 Hz, 2H), 3.82 (s, 3H), 3.19 (s, 3H) Example 158: 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 (brd, 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) Example 159: 1 1H NMR (500 MHz, CDCl3) δ 8.31 (d, J = 8.0 Hz, 1H), 7.83 (brd, J = 8.3 Hz, 2H), 7.71 (brs, 1H), 7.67 (d, J = 8.3 Hz, 1H), 7.16 (brd, J = 8.5 Hz, 2H), 6.60 (brd, J = 9.9 Hz, 2H), 6.57 (t, J = 73.2 Hz, 1H), 3.86 (s, 3H), 3.11 (s, 3H) Example 160: 1 1H NMR (400 MHz, CD3OD containing CDCl3) δ 7.99 (d, J = 8.4 Hz, 1H), 7.87 (brd, J = 8.6 Hz, 2H), 7.27 (d, J = 8.1 Hz, 1H), 7.16 (d, J = 8.8 Hz, 2H), 6.70 (t, J = 73.3 Hz, 1H), 6.64 (brs, 2H), 3.86 (s, 3H), 3.16 (s, 3H), 2.16 - 2.07 (m, 1H), 1.15 - 0.97 (m, 4H)

[0208] Example 161: 11H NMR (400 MHz, DMSO-d6) δ 9.79 (s, 1H), 8.35 (d, J = 8.1 Hz, 1H), 7.92 (d, J = 8.8 Hz, 2H), 7.59 (d, J = 8.1 Hz, 1H), 7.34 (t, J = 73.5 Hz, 1H), 7.24 (d, J = 8.8 Hz, 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) Example 162: 1 1H NMR (500 MHz, CDCl3) δ 7.98 (d, J = 2.2 Hz, 1H), 7.83 (d, J = 8.8 Hz, 2H), 7.79 - 7.68 (m, 1H), 7.19 - 7.10 (m, 3H), 6.63 - 6.58 (m, 2H), 6.58 (t, J = 73.5 Hz, 1H), 4.01 (s, 3H), 3.86 (s, 3H), 3.40 (s, 3H) Example 163: 1 1H NMR (400 MHz, CD3OD) δ 7.93 (s, 3H), 7.70 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 7.5 Hz, 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 = 7.5 Hz, 2H), 1.37 (t, J = 7.6 Hz, 3H) Example 164: 1 1H NMR (500 MHz, CD3OD) δ 8.62 (dd, J = 4.6, 1.4 Hz, 1H), 8.15 (dd, J = 8.2, 1.4 Hz, 1H), 7.79 (brd, J = 7.7 Hz, 2H), 7.59 (dd, J = 8.1, 4.7 Hz, 1H), 7.43 (d, J = 8.5 Hz, 2H), 6.75 (d, J = 10.3 Hz, 2H), 3.86 (s, 3H), 3.16 (s, 3H) Example 165: 11H NMR (500 MHz, CD3OD) δ 8.66 (dd, J = 4.6, 1.3 Hz, 1H), 8.31 (dd, J = 8.1, 1.4 Hz, 1H), 7.86 (brd, J = 8.0 Hz, 2H), 7.51 (dd, J = 8.1, 4.7 Hz, 1H), 7.18 (d, J = 8.6 Hz, 2H), 7.04 - 6.67 (m, 3H), 3.86 (s, 3H), 3.15 (s, 3H) Example 166: 1 1H NMR (500 MHz, DMSO-d6) δ 9.67 (brs, 1H), 8.51 (brd, J = 3.7 Hz, 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 (brt, J = 7.5 Hz, 3H) Example 167: 1 1H NMR (500 MHz, CD3OD) δ 7.92 (brd, J = 7.9 Hz, 2H), 7.80 (t, J = 7.8 Hz, 1H), 7.60 (d, J = 7.9 Hz, 1H), 7.32 (brd, J = 8.3 Hz, 2H), 7.26 (d, J = 7.7 Hz, 2H), 6.76 (d, J = 10.0 Hz, 2H), 3.86 (s, 3H), 3.30 (brs, 3H), 2.20 - 2.10 (m, 1H), 1.11 - 0.93 (m, 4H) Example 168: 1 1H NMR (400 MHz, CD3OD) δ 8.08 (t, J = 8.0 Hz, 1H), 7.92 (d, J = 8.6 Hz, 2H), 7.76 (d, J = 7.8 Hz, 1H), 7.55 (t, J = 72.8 Hz, 1H), 7.22 (d, J = 8.7 Hz, 2H), 7.00 (d, J = 8.1 Hz, 1H), 7.03 - 6.98 (m, 1H), 6.86 - 6.79 (m, 1H), 6.96 (t, J = 73.5 Hz, 1H), 3.89 (s, 3H), 3.36 (s, 3H) Example 169: 11H NMR (400 MHz, CD3OD) δ 8.09 (t, J = 8.0 Hz, 1H), 7.97 (d, J = 8.7 Hz, 2H), 7.81 - 7.31 (m, 4H), 7.01 (d, J = 8.0 Hz, 1H), 6.83 (d, J = 10.0 Hz, 2H), 3.89 (s, 3H), 3.37 (s, 3H) Example 170: 1 1H NMR (500 MHz, CD3OD) δ 8.79 (brd, J = 4.1 Hz, 1H), 8.08 (brd, J = 8.2 Hz, 1H), 7.96 - 7.85 (m, 3H), 7.33 (brd, J = 8.2 Hz, 2H), 6.77 (brd, J = 11.3 Hz, 2H), 3.87 (s, 3H), 3.11 (s, 3H)

[0209] Example 171: 1 1H NMR (500 MHz, CD3OD) δ 7.89 (d, J = 8.7 Hz, 2H), 7.70 (dd, J = 7.8, 1.6 Hz, 1H), 7.66 (dd, J = 7.4, 1.8 Hz, 1H), 7.63 - 7.54 (m, 2H), 7.19 (d, J = 8.6 Hz, 2H), 7.09 - 6.74 (m, 3H), 3.85 (s, 3H), 3.13 (s, 3H) Example 172: 1 1H NMR (500 MHz, CD3OD) δ 7.94 (d, J = 8.7 Hz, 2H), 7.75 - 7.64 (m, 2H), 7.64 - 7.55 (m, 2H), 7.35 (brd, J = 8.3 Hz, 2H), 6.78 (brd, J = 10.6 Hz, 2H), 3.85 (s, 3H), 3.14 (s, 3H) Example 173: 1 1H NMR (500 MHz, DMSO - d6) δ 9.86 (s, 1H), 8.05 (d, J = 7.6 Hz, 1H), 7.97 - 7.84 (m, 3H), 7.65 (t, J = 7.5 Hz, 1H), 7.50 (d, J = 7.9 Hz, 1H), 7.46 - 7.14 (m, 3H), 6.92 (brd, J = 9.2 Hz, 2H), 3.82 (s, 3H), 2.94 (s, 3H) Example 174: 11H NMR (500 MHz, CD3OD) δ 8.01, 7.88 (m, 4H), 7.74 - 7.61 (m, 2H), 7.35 (brd, J = 8.2 Hz, 2H), 6.80 (brd, J = 10.5 Hz, 2H), 3.86 (s, 3H), 3.12 (s, 3H) Example 175: 1 1H NMR (400 MHz, CD3OD) δ 7.91 (brd, J = 8.6 Hz, 2H), 7.54 (m, 3H), 7.21 (d, J = 8.8 Hz, 2H), 7.14 - 6.74 (m, 3H), 3.88 (s, 3H), 3.14 (s, 3H) Example 176: 1 1H NMR (500 MHz, CD3OD) δ 7.89 (brd, J = 8.6 Hz, 2H), 7.76 (d, J = 2.1 Hz, 1H), 7.71 - 7.66 (m, 1H), 7.65 - 7.60 (m, 1H), 7.19 (brd, J = 8.6 Hz, 2H), 7.11 - 6.72 (m, 3H), 3.85 (s, 3H), 3.13 (s, 3H) Example 177: 1 1H NMR (400 MHz, CD3OD) δ 7.92 (brd, J = 8.6 Hz, 2H), 7.67 - 7.59 (m, 1H), 7.42 - 7.36 (m, 2H), 7.30 - 7.12 (m, 3H), 6.96 (d, J = 9.0 Hz, 1H), 6.84 - 6.76 (m, 2H), 6.82 (s, 1H), 3.88 (s, 3H), 3.14 (s, 3H) Example 178: 1 1H NMR (500 MHz, CD3OD) δ 8.01 - 7.86 (m, 3H), 7.56 - 7.45 (m, 2H), 7.19 (d, J = 8.6 Hz, 2H), 7.14 - 6.68 (m, 3H), 3.86 (s, 3H), 3.12 (s, 3H) Example 179: 11H NMR (500 MHz, CD3OD) δ 8.15 (d, J = 8.0 Hz, 1H), 8.08 - 7.99 (m, 2H), 7.89 (brd, J = 8.6 Hz, 2H), 7.20 (d, J = 8.7 Hz, 2H), 7.11 - 6.76 (m, 3H), 3.86 (s, 3H), 3.12 (s, 3H) Example 180: 1 1H NMR (500 MHz, DMSO-d6) 9.73 (brs, 1H), 8.53 - 8.43 (m, 1H), 7.91 (brd, J = 7.3 Hz, 2H), 7.60 (brd, J = 4.4 Hz, 1H), 7.51 - 7.12 (m, 3H), 6.98 - 6.82 (m, 2H), 3.89 - 3.76 (m, 3H), 3.65 (brs, 3H), 2.96 (s, 3H)

[0210] Example 182: 1 1H NMR (500 MHz, CD3OD) δ 8.00 - 7.94 (m, 1H), 7.92 - 7.83 (m, 2H), 7.19 (brd, J = 8.3 Hz, 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) Example 183: 1 1H NMR (500 MHz, CD3OD) δ 7.89 (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) Example 184: 1 1H NMR (500 MHz, CD3OD) δ 7.89 (d, J = 8.6 Hz, 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) Example 185: 11H NMR (500 MHz, CD3OD) δ 7.96 (d, J = 8.8 Hz, 1H), 7.89 (d, J = 8.7 Hz, 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) Example 186: 1 1H NMR (500 MHz, methanol-d4) δ 7.89 (brd, J = 8.6 Hz, 2H), 7.72 (dd, J = 9.0, 5.3 Hz, 1H), 7.53 (dd, J = 8.3, 2.7 Hz, 1H), 7.45 - 7.36 (m, 1H), 7.19 (d, J = 8.6 Hz, 2H), 7.09 - 6.73 (m, 3H), 3.85 (s, 3H), 3.14 (s, 3H) Example 187: 1 1H NMR (500 MHz, CD3OD) δ 7.89 (brd, J = 8.5 Hz, 2H), 7.75 - 7.67 (m, 1H), 7.57 - 7.49 (m, 1H), 7.44 - 7.35 (m, 1H), 7.19 (d, J = 8.6 Hz, 2H), 7.12 - 6.75 (m, 3H), 3.85 (s, 3H), 3.14 (s, 3H) Example 188: 1 1H NMR (500 MHz, CD3OD) δ 8.04 (dd, J = 8.6, 5.6 Hz, 1H), 7.89 (brd, J = 8.5 Hz, 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) Example 189: 1 1H NMR (500 MHz, CD3OD) δ 7.99 - 7.93 (m, 1H), 7.91 - 7.85 (m, 3H), 7.59 (t, J = 8.0 Hz, 1H), 7.20 (d, J = 8.7 Hz, 2H), 7.12 - 6.76 (m, 3H), 3.86 (s, 3H), 3.13 (s, 3H) Example 190: 11H NMR (500 MHz, CD3OD) δ 8.30 (d, J = 8.2 Hz, 1H), 7.89 (brd, J = 8.7 Hz, 2H), 7.69 (d, J = 8.2 Hz, 1H), 7.19 (brd, J = 8.7 Hz, 2H), 7.09 - 6.76 (m, 3H), 3.87 (s, 3H), 3.32 (s, 3H), 1.43 (s, 9H)

[0211] Example 191: 1 1H NMR (500 MHz, CD3OD) δ 8.81 (d, J = 5.3 Hz, 1H), 7.92 (s, 2H), 7.68 (d, J = 5.3 Hz, 1H), 7.21 (brd, J = 8.8 Hz, 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) Example 192: 1 1H NMR (500 MHz, CD3OD) δ 8.36 - 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 = 7.0 Hz, 2H), 3.23 (s, 3H), 1.45 (brd, J = 6.3 Hz, 4H), 1.28 (t, J = 7.0 Hz, 3H) Example 193: 1 1H NMR (500 MHz, CD3OD) δ 8.40 (d, J = 8.0 Hz, 1H), 7.88 (brd, J = 8.5 Hz, 2H), 7.72 (d, J = 8.1 Hz, 1H), 7.18 (brd, J = 8.5 Hz, 2H), 7.09 - 6.64 (m, 3H), 4.69 (s, 2H), 3.86 (s, 3H), 3.53 (s, 3H), 3.28 (s, 3H) Example 194: 11H NMR (500 MHz, CD3OD) δ 8.52 - 8.39 (m, 1H), 7.88 (brd, J = 8.6 Hz, 2H), 7.84 - 7.77 (m, 1H), 7.19 (brd, J = 8.4 Hz, 2H), 7.09 - 6.75 (m, 3H), 3.86 (s, 3H), 3.30 (s, 3H), 1.76 (s, 3H), 1.72 (s, 3H) Example 195: 1 1H NMR (500 MHz, CD3OD) δ 8.43 (d, J = 8.2 Hz, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.87 (brd, J = 8.5 Hz, 2H), 7.18 (brd, J = 8.4 Hz, 2H), 7.10 - 6.72 (m, 3H), 4.82 (brd, J = 8.4 Hz, 2H), 3.85 (s, 3H), 3.14 (s, 3H) Example 196: 1 1H NMR (500 MHz, CD3OD) δ 8.43 (d, J = 8.2 Hz, 1H), 7.90 - 7.86 (m, 3H), 7.18 (brd, J = 8.6 Hz, 2H), 7.10 - 6.73 (m, 3H), 4.69 (s, 2H), 3.85 (s, 3H), 3.53 (s, 3H), 3.14 (s, 3H) Example 197: 1 1H NMR (500 MHz, CDCl3) δ 8.60 (d, J = 4.7 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.83 (brd, J = 8.0 Hz, 3H), 7.41 (ddd, J = 8.0, 4.7, 0.8 Hz, 1H), 7.15 (d, J = 8.5 Hz, 2H), 6.80 - 6.39 (m, 3H), 3.85 (s, 3H), 3.41 (t, J = 7.0 Hz, 3H) Example 200: 1 1H NMR (500 MHz, CDCl3) δ 7.96 (d, J = 8.3 Hz, 1H), 7.84 (brd, J = 8.5 Hz, 2H), 7.57 (d, J = 8.3 Hz, 1H), 7.18 - 7.14 (m, 2H), 6.47 - 6.46 (m, 1H), 6.76 - 6.40 (m, 2H), 4.64 (s, 2H), 3.85 (s, 3H), 3.53 (s, 3H), 3.07 (s, 3H)

[0212] Example 201: 1 H NMR (400 MHz, CD3OD) δ 8.75 - 8.68 (m, 1H), 7.90 (brd, J = 8.8 Hz, 2H), 7.57 (dd, J = 5.1, 0.7 Hz, 1H), 7.21 (d, J = 8.6 Hz, 2H), 7.15 - 6.69 (m, 3H), 3.88 (s, 3H), 3.29 (s, 3H), 2.72 (s, 3H) Example 202: 1 H NMR (500 MHz, DMSO-d6, ws) δ 9.82 (s, 1H), 8.17 (d, J = 8.8 Hz, 1H), 7.91 (d, J = 8.6 Hz, 2H), 7.25 (brd, J = 8.5 Hz, 2H), 7.26 (t, J = 73.4 Hz, 1H), 7.10 (d, J = 9.0 Hz, 1H), 6.94 (d, J = 10.6 Hz, 2H), 3.83 (s, 3H), 3.14 (s, 3H), 2.54 (s, 3H) Example 203: 1 H NMR (500 MHz, DMSO-d6) δ 9.61 (s, 1H), 7.90 (d, J = 8.5 Hz, 2H), 7.46 (d, J = 8.5 Hz, 1H), 7.23 (d, J = 8.5 Hz, 2H), 7.18 (d, J = 8.9 Hz, 1H), 7.31 (t, J = 73.2 Hz, 1H), 6.90 (d, J = 10.4 Hz, 2H), 3.80 (s, 3H), 3.90 - 3.65 (m, 4H), 2.96 (s, 3H), 1.76 (s, 1H), 1.41 (s, 3H) Example 204: 1 H NMR (500 MHz, DMSO-d6) δ 9.76 (s, 1H), 8.23 - 8.08 (m, 1H), 7.92 (d, J = 8.2 Hz, 3H), 7.53 (d, J = 7.6 Hz, 1H), 7.27 (d, J = 8.5 Hz, 2H), 7.35 (t, J = 73.5 Hz, 1H), 6.96 (d, J = 10.4 Hz, 2H), 4.47 (brs, 2H), 3.85 (s, 3H), 3.22 (s, 3H), 2.89 (s, 6H) Example 205: 11H NMR (500 MHz, DMSO-d6) δ 9.70 (s, 1H), 7.98 (t, J = 8.0 Hz, 1H), 7.91 (d, J = 8.5 Hz, 2H), 7.76 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.25 (d, J = 8.0 Hz, 2H), 7.33 (t, J = 73.4 Hz, 1H), 6.94 (d, J = 10.9 Hz, 2H), 3.83 (s, 3H), 3.65 (s, 2H), 3.21 (s, 3H), 2.49 - 2.32 (m, 8H), 2.18 (s, 3H) Example 206: 1 1H NMR (500 MHz, DMSO-d6) δ 9.68 (s, 1H), 7.91 (d, J = 8.6 Hz, 2H), 7.73 (m, 1H), 7.25 (d, J = 8.7 Hz, 2H), 7.33 (t, J = 73.6 Hz, 1H), 7.10 (d, J = 7.7 Hz, 1H), 6.93 (d, J = 10.4 Hz, 2H), 6.79 (d, J = 8.4 Hz, 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) Example 207: 1 1H NMR (500 MHz, DMSO-d6) δ 9.71 (s, 1H), 7.91 (brd, J = 8.3 Hz, 2H), 7.82 (m, 1H), 7.26 (d, J = 8.8 Hz, 2H), 7.53 - 7.16 (m, 2H), 6.99 - 6.87 (m, 3H), 3.83 (s, 3H), 3.61 - 3.30 (m, 4H), 3.20 (s, 3H), 3.12 - 2.90 (m, 4H), 2.57 (brs, 2H), 1.17 - 1.02 (m, 1H), 0.71 - 0.61 (m, 2H), 0.43 - 0.33 (m, 2H) Example 208: 11H NMR (500 MHz, DMSO-d6) δ 9.67 (s, 1H), 7.92 (d, J = 8.2 Hz, 2H), 7.72 (m, 1H), 7.25 (d, J = 8.5 Hz, 2H), 7.34 (t, J = 72.3 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 6.94 (d, J = 10.1 Hz, 2H), 6.77 (d, J = 8.2 Hz, 1H), 3.83 (s, 3H), 3.54 (brs, 4H), 3.47 (t, J = 6.3 Hz, 2H), 3.20 (s, 3H), 2.50 - 2.45 (m, 4H), 2.40 (brt, J = 7.2 Hz, 2H), 1.92 (s, 1H), 1.64 (quin, J = 6.7 Hz, 2H) Example 209: 1 1H NMR (500 MHz, DMSO-d6) δ 9.61 (s, 1H), 7.90 (d, J = 8.5 Hz, 2H), 7.60 (d, J = 8.9 Hz, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.23 (brd, J = 8.5 Hz, 2H), 7.32 (t, J = 74.5 Hz, 1H), 6.90 (m, 2H), 3.81 (s, 3H), 2.99 (s, 3H), 2.81 (s, 6H) Example 210: 1 1H NMR (500 MHz, DMSO-d6) δ 9.66 (s, 1H), 7.90 (brd, J = 8.2 Hz, 2H), 7.74 (m, 1H), 7.23 (d, J = 8.5 Hz, 2H), 7.34 (t, J = 73.3 Hz, 1H), 6.92 (brd, J = 10.7 Hz, 2H), 6.56 (m, 1H), 3.90 (s, 1H), 3.82 (s, 3H), 3.83 (dd, J = 26.3, 8.0 Hz, 2H), 3.79 - 3.78 (m, 1H), 3.04 (s, 3H), 1.44 (s, 3H)

[0213] Example 211: 11H NMR (500 MHz, DMSO-d6, ws) δ 9.60 (s, 1H), 7.96 (d, J = 4.0 Hz, 1H), 7.92 (d, J = 8.2 Hz, 2H), 7.37 (m, 1H), 7.23 (d, J = 8.2 Hz, 2H), 7.32 (t, J = 73.8 Hz, 1H), 7.09 (d, J = 8.2 Hz, 1H), 6.90 (d, J = 10.4 Hz, 2H), 3.89 (s, 1H), 3.81 (s, 3H), 3.76 (brd, J = 7.3 Hz, 1H), 3.70 - 3.64 (m, 1H), 2.94 (s, 3H), 1.42 (s, 3H) Example 212: 1 1H NMR (500 MHz, DMSO-d6) δ 9.67 (s, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.72 (m, 1H), 7.24 (d, J = 8.4 Hz, 2H), 7.30 (t, J = 73.5 Hz, 1H), 7.08 (d, J = 7.6 Hz, 1H), 6.91 (d, J = 10.3 Hz, 2H), 6.76 (d, J = 8.3 Hz, 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) Example 213: 1 1H NMR (500 MHz, DMSO-d6) δ 9.68 (s, 1H), 7.91 (d, J = 8.5 Hz, 2H), 7.77 (m, 1H), 7.25 (d, J = 8.7 Hz, 2H), 7.32 (t, J = 73.7 Hz, 1H), 7.13 (d, J = 7.7 Hz, 1H), 6.93 (d, J = 10.3 Hz, 2H), 6.84 (d, J = 8.5 Hz, 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) Example 214: 11H NMR (500 MHz, DMSO-d6) δ 9.66 (s, 1H), 8.21 (brs, 1H), 8.03 (d, J = 9.2 Hz, 1H), 7.90 (brd, J = 8.2 Hz, 2H), 7.22 (brd, J = 8.5 Hz, 2H), 7.31 (t, J = 74.0 Hz, 1H), 7.04 (d, J = 9.2 Hz, 1H), 6.98 - 6.75 (m, 2H), 4.13 (s, 2H), 3.81 (s, 4H), 2.97 (s, 3H) Example 215: 1 1H NMR (500 MHz, DMSO-d6) δ 9.66 (s, 1H), 7.90 (brd, J = 8.5 Hz, 2H), 7.24 (d, J = 8.5 Hz, 2H), 7.63 - 7.16 (m, 3H), 6.91 (d, J = 10.7 Hz, 2H), 5.90 (d, J = 4.9 Hz, 1H), 3.82 (s, 3H), 2.98 (s, 3H), 2.78 (d, J = 4.9 Hz, 3H) Example 217: 1 1H NMR (500 MHz, DMSO-d6, ws) δ 9.80 (s, 1H), 8.01 (d, J = 8.5 Hz, 1H), 7.93 (brd, J = 8.5 Hz, 2H), 7.75 (d, J = 8.5 Hz, 1H), 7.25 (d, J = 8.9 Hz, 2H), 7.33 (t, J = 73.8 Hz, 1H), 6.93 (m, 2H), 3.82 (s, 3H), 3.01 (s, 3H), 2.83 (s, 3H) Example 218: 1 1H NMR (500 MHz, DMSO-d6) δ 9.65 (s, 1H), 7.92 (d, J = 8.5 Hz, 2H), 7.68 (m, 1H), 7.25 (d, J = 8.9 Hz, 2H), 7.34 (t, J = 74.8 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 6.93 (d, J = 10.1 Hz, 2H), 6.30 (d, J = 8.2 Hz, 1H), 3.83 (s, 3H), 3.70 (s, 4H), 3.23 (s, 3H), 1.31 (s, 6H) Example 219: 11H NMR (500 MHz, CD3OD) δ 7.89 (d, J = 8.8 Hz, 2H), 7.76 (m, 1H), 7.20 (d, J = 8.5 Hz, 2H), 7.15 (dd, J = 9.2, 2.3 Hz, 1H), 6.93 (t, J = 73.5 Hz, 1H), 6.81 - 6.75 (m, 2H), 4.47 (brd, J = 12.1 Hz, 2H), 3.86 (s, 3H), 3.61 (brd, J = 10.5 Hz, 2H), 3.25 (s, 3H), 3.28 - 3.15 (m, 4H), 2.96 (s, 3H) Example 220: 1 1H NMR (500 MHz, DMSO-d6) δ 9.68 (s, 1H), 8.04 (d, J = 9.1 Hz, 1H), 7.91 (brd, J = 8.2 Hz, 2H), 7.28 - 7.20 (m, 1H), 7.33 (t, J = 74.0 Hz, 1H), 7.09 (d, J = 9.0 Hz, 1H), 7.28 - 7.02 (m, 1H), 6.99 - 6.84 (m, 2H), 4.27 - 4.12 (m, 2H), 3.91 (d, J = 3.3 Hz, 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)

[0214] Example 221: 1 1H NMR (500 MHz, DMSO-d6) δ 9.65 (s, 1H), 8.96 (d, J = 4.0 Hz, 1H), 8.48 (d, J = 7.6 Hz, 1H), 7.94 (d, J = 8.5 Hz, 2H), 7.81 (dd, J = 7.9, 4.8 Hz, 1H), 7.64 (d, J = 2.0 Hz, 1H), 7.54 (dd, J = 8.5, 1.9 Hz, 1H), 7.27 (brd, J = 8.6 Hz, 2H), 7.49 - 7.18 (m, 2H), 3.90 (s, 3H), 2.99 (s, 3H) Example 222: 11H NMR (500 MHz, DMSO-d6) δ 9.77 (s, 1H), 8.54 (d, J = 8.4 Hz, 1H), 7.96 (d, J = 8.2 Hz, 1H), 7.91 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.6 Hz, 2H), 7.33 (t, J = 76.7 Hz, 1H), 7.01 - 6.85 (m, 2H), 3.83 (s, 3H), 3.00 (s, 3H) Example 223: 1 1H NMR (500 MHz, DMSO-d6) δ 9.68 (s, 1H), 8.99 (brd, J = 3.7 Hz, 1H), 8.51 (brd, J = 7.6 Hz, 1H), 8.20 (s, 1H), 8.05 (s, 1H), 7.95 (brd, J = 8.5 Hz, 2H), 7.87 - 7.74 (m, 2H), 7.59 (brd, J = 8.9 Hz, 1H), 7.26 (brd, J = 8.5 Hz, 2H), 7.33 (t, J = 73.5 Hz, 1H), 4.08 (s, 3H), 3.02 (s, 3H) Example 224: 1 1H NMR (500 MHz, DMSO-d6, ws) δ 9.80 (s, 1H), 8.52 (d, J = 5.0 Hz, 1H), 7.90 (brd, J = 8.4 Hz, 2H), 7.23 (brd, J = 8.6 Hz, 2H), 7.32 (t, J = 74.0 Hz, 1H), 6.98 - 6.86 (m, 3H), 3.82 (s, 3H), 2.90 (s, 3H), 2.44 (brs, 4H), 2.22 (s, 3H) Example 225: 1 1H NMR (500 MHz, DMSO-d6) δ 9.68 (s, 1H), 7.92 (d, J = 8.5 Hz, 2H), 7.87 - 7.78 (m, 1H), 7.74 (brs, 1H), 7.23 (d, J = 8.5 Hz, 2H), 7.34 (t, J = 70.8 Hz, 1H), 6.98 - 6.83 (m, 2H), 6.76 (d, J = 8.7 Hz, 1H), 4.83 - 4.68 (m, 1H), 3.82 (s, 3H), 3.57 (q, J = 5.3 Hz, 2H), 3.48 - 3.36 (m, 2H), 2.97 (s, 3H) Example 226: 11H NMR (500 MHz, DMSO-d6, ws) δ 9.64 (s, 1H), 7.96 - 7.79 (m, 4H), 7.46 (d, J = 6.4 Hz, 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) Example 227: 1 1H NMR (500 MHz, DMSO-d6) δ 9.65 (s, 1H), 7.90 (d, J = 8.2 Hz, 2H), 7.89 - 7.79 (m, 1H), 7.64 (q, J = 4.4 Hz, 1H), 7.23 (d, J = 8.5 Hz, 2H), 7.30 (t, J = 73.5 Hz, 1H), 6.89 (dd, J = 19.1, 11.7 Hz, 2H), 6.69 (d, J = 8.9 Hz, 1H), 3.81 (s, 3H), 2.98 (s, 3H), 2.84 (d, J = 4.9 Hz, 3H) Example 228: 1 1H NMR (500 MHz, DMSO-d6) δ 9.73 (s, 1H), 9.34 - 9.19 (m, 1H), 8.07 - 7.86 (m, 4H), 7.23 (d, J = 8.5 Hz, 2H), 7.31 (t, J = 79.0 Hz, 1H), 7.00 (brd, J = 11.6 Hz, 2H), 6.89 (d, J = 11.3 Hz, 1H), 3.83 (s, 3H), 3.77 (s, 3H), 3.01 (s, 3H), 2.18 (brs, 3H) Example 229: 1 1H NMR (500 MHz, DMSO-d6) δ 9.63 (s, 1H), 8.12 - 8.02 (m, 1H), 7.94 - 7.85 (m, 3H), 7.82 (s, 1H), 7.22 (d, J = 8.5 Hz, 2H), 7.29 (t, J = 76.9 Hz, 1H), 6.94 - 6.75 (m, 3H), 3.81 (s, 3H), 3.60 (brd, J = 7.3 Hz, 2H), 2.96 (s, 3H), 2.62 (td, J = 7.2, 3.8 Hz, 1H), 0.68 - 0.52 (m, 2H), 0.48 - 0.32 (m, 2H) Example 230: 11H NMR (500 MHz, acetonitrile-d3) δ 8.17 (brs, 1H), 7.92 - 7.79 (m, 3H), 7.20 (d, J = 8.3 Hz, 2H), 6.88 (t, J = 73.2 Hz, 1H), 6.73 - 6.69 (m, J = 5.8, 3.3 Hz, 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)

[0215] Example 231: 1 1H NMR (500 MHz, DMSO-d6, ws) δ 9.68 (s, 1H), 8.06 (s, 1H), 7.92 (d, J = 7.9 Hz, 2H), 7.23 (d, J = 8.5 Hz, 2H), 7.33 (t, J = 73.9 Hz, 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) Example 232: 1 1H NMR (500 MHz, DMSO-d6) δ 9.74 - 9.56 (m, 1H), 8.02 - 7.78 (m, 4H), 7.26 - 7.19 (m, 2H), 7.30 (t, J = 74.2 Hz, 1H), 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 (brd, J = 6.4 Hz, 3H) Example 233: 1 1H NMR (500 MHz, 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 (brs, 1H), 3.81 (s, 3H), 3.06 (s, 3H), 2.92 (d, J = 4.7 Hz, 3H) Example 234: 1 1H NMR (500 MHz, DMSO-d6) δ 9.84 (s, 1H), 8.59 (d, J = 8.9 Hz, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.92 (d, J = 8.5 Hz, 2H), 7.76 (s, 1H), 7.69 (s, 2H), 7.25 (d, J = 8.9 Hz, 2H), 7.32 (t, J = 73.9 Hz, 1H), 6.92 (d, J = 10.7 Hz, 2H), 3.84 (s, 3H), 3.03 (s, 3H) Example 235: 1 1H NMR (500 MHz, DMSO-d6) δ 9.65 (s, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.86 - 7.79 (m, 1H), 7.79 - 7.69 (m, 1H), 7.22 (d, J = 8.4 Hz, 2H), 7.47 - 7.15 (m, 1H), 6.95 - 6.83 (m, 2H), 6.75 (d, J = 8.6 Hz, 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) Example 236: 1 1H NMR (500 MHz, DMSO-d6) δ 9.68 (s, 1H), 7.91 (d, J = 8.1 Hz, 2H), 7.86 - 7.78 (m, 1H), 7.76 - 7.63 (m, 1H), 7.23 (d, J = 8.5 Hz, 2H), 7.32 (t, J = 70.0 Hz, 1H), 6.99 - 6.84 (m, 2H), 6.78 (dd, J = 8.2, 4.2 Hz, 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 = 5.4 Hz, 3H) Example 237: 11H NMR (500 MHz, DMSO-d6) δ 9.66 (d, J = 4.9 Hz, 1H), 7.91 (d, J = 8.5 Hz, 2H), 7.86 - 7.75 (m, 1H), 7.56 (m, 1H), 7.22 (d, J = 8.5 Hz, 2H), 7.32 (t, J = 73.2 Hz, 1H), 6.96 - 6.84 (m, 2H), 6.73 (dd, J = 8.9, 4.3 Hz, 1H), 3.90 (s, 4H), 3.51 - 3.36 (m, 2H), 2.96 (s, 3H), 1.79 (s, 1H), 1.14 (t, J = 7.2 Hz, 3H) Example 238: 1 1H NMR (500 MHz, DMSO-d6) δ 9.66 (s, 1H), 8.04 - 7.78 (m, 5H), 7.23 (d, J = 8.7 Hz, 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 = 4.5 Hz, 3H) Example 239: 1 1H NMR (500 MHz, DMSO-d6) δ 9.65 (s, 1H), 7.90 (d, J = 8.2 Hz, 2H), 7.82 (d, J = 8.9 Hz, 1H), 7.22 (d, J = 8.2 Hz, 2H), 7.30 (t, J = 73.2 Hz, 1H), 7.01 (d, J = 9.2 Hz, 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 = 9.9 Hz, 2H), 2.99 (s, 3H), 2.71 (s, 4H) Example 240: 11H NMR (500 MHz, DMSO-d6) δ 9.67 (s, 1H), 7.91 (brd, J = 8.9 Hz, 2H), 7.83 (d, J = 8.9 Hz, 1H), 7.23 (brd, J = 8.2 Hz, 2H), 7.32 (t, J = 73.8 Hz, 1H), 7.02 (d, J = 9.2 Hz, 1H), 6.91 (brt, J = 12.1 Hz, 2H), 6.18 (tt, J = 55.8, 4.3 Hz, 1H), 3.81 (s, 3H), 3.54 (brs, 4H), 2.99 (s, 3H), 2.79 (td, J = 15.6, 4.1 Hz, 2H), 2.63 (brt, J = 4.0 Hz, 4H)

[0216] Example 242: 1 1H NMR (500 MHz, DMSO-d6) δ 9.74 (s, 1H), 8.29 (d, J = 8.4 Hz, 1H), 7.89 (brd, J = 8.6 Hz, 2H), 7.74 (d, J = 8.4 Hz, 1H), 7.23 (d, J = 8.5 Hz, 2H), 7.30 (t, J = 73.6 Hz, 1H), 6.91 (brs, 2H), 3.81 (s, 3H), 2.99 (s, 3H) Example 243: 1 1H NMR (500 MHz, DMSO-d6) δ 9.66 (s, 1H), 7.90 (d, J = 8.2 Hz, 2H), 7.79 (d, J = 7.9 Hz, 1H), 7.74 - 7.62 (m, 1H), 7.22 (d, J = 8.5 Hz, 2H), 7.31 (t, J = 77.8 Hz, 1H), 6.93 (m, 1H), 6.86 (d, J = 11.3 Hz, 1H), 6.68 (dd, J = 17.4, 8.9 Hz, 1H), 3.80 (s, 3H), 2.94 (s, 3H), 1.37 - 1.24 (m, 1H), 1.21 (d, J = 6.4 Hz, 3H), 1.03 - 0.82 (m, 1H), 0.52 - 0.30 (m, 3H), 0.26 - 0.07 (m, 1H) Example 244: 11H NMR (500 MHz, DMSO-d6) δ 9.63 (s, 1H), 7.92 (d, J = 8.6 Hz, 2H), 7.67 (d, J = 8.7 Hz, 1H), 7.24 (d, J = 8.4 Hz, 2H), 7.34 (t, J = 72.5 Hz, 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 = 7.4 Hz, 3H) Example 245 1 1H NMR (500 MHz, DMSO-d6) δ 9.63 (s, 1H), 8.68 - 8.62 (m, 1H), 8.25 (d, J = 7.9 Hz, 1H), 7.98 (d, J = 8.9 Hz, 2H), 7.62 (m, 1H), 7.55 (d, J = 8.5 Hz, 2H), 7.29 (d, J = 8.5 Hz, 2H), 7.36 (t, J = 73.9 Hz, 1H), 7.11 (d, J = 8.9 Hz, 2H), 3.81 (s, 3H), 2.99 (s, 3H) Example 246 1 1H NMR (500 MHz, DMSO-d6) δ 9.60 (s, 1H), 8.97 (d, J = 3.7 Hz, 1H), 8.49 (d, J = 8.2 Hz, 1H), 7.97 (d, J = 8.5 Hz, 2H), 7.81 (t, J = 6.1 Hz, 1H)), 7.45 (brd, J = 8.2 Hz, 1H), 7.40 (s, 1H), 7.30 - 7.26 (d, J = 8.9 Hz, 3H), 7.11 (d, J = 8.5 Hz, 1H), 3.90 (s, 3H), 3.00 (s, 3H), 2.19 (s, 3H) Example 247 1 1H NMR (500 MHz, DMSO-d6) δ 9.66 (s, 1H), 7.90 (brd, J = 8.5 Hz, 2H), 7.87 (d, J = 8.9 Hz, 1H), 7.22 (d, J = 8.5 Hz, 2H), 7.30 (t, J = 72.9 Hz, 1H), 7.07 (d, J = 9.2 Hz, 1H), 6.96 - 6.84 (m, 2H), 3.81 (s, 3H), 3.67 (brd, J = 3.4 Hz, 4H), 3.25 - 3.19 (m, 4H), 3.00 (s, 3H), 2.89 (s, 3H) Example 248: 1 H NMR (500 MHz, DMSO-d6) δ 9.64 (s, 1H), 7.91 (d, J = 8.5 Hz, 2H), 7.86 (d, J = 8.9 Hz, 1H), 7.67 (d, J = 8.9 Hz, 1H), 7.23 (d, J = 8.5 Hz, 2H), 7.33 (t, J = 73.6 Hz, 1H), 6.91 (d, J = 10.7 Hz, 2H), 4.20 (q, J = 6.8 Hz, 2H), 3.81 (s, 3H), 2.95 (s, 3H), 1.31 (t, J = 7.0 Hz, 3H) Example 249: 1 H NMR (500 MHz, DMSO-d6) δ 9.64 (s, 1H), 8.97 - 8.83 (m, 1H), 8.44 (d, J = 7.9 Hz, 1H), 7.89 (d, J = 8.5 Hz, 1H), 7.78 (dd, J = 8.1, 4.4 Hz, 1H), 7.69 - 7.53 (m, 5H), 7.22 (d, J = 8.5 Hz, 1H), 7.29 (t, J = 73.5 Hz, 1H), 2.98 - 2.88 (m, 3H), 2.64 (s, 3H) Example 250: 1 H NMR (500 MHz, DMSO-d6) δ 9.65 (s, 1H), 9.00 (d, J = 3.7 Hz, 1H), 8.52 (d, J = 7.3 Hz, 1H), 8.00 (d, J = 8.9 Hz, 2H), 7.84 (m, 1H), 7.58 (d, J = 8.5 Hz, 2H), 7.31 (d, J = 8.9 Hz, 1H), 7.53 (t, J = 73.5 Hz, 1H), 7.15 (d, J = 8.9 Hz, 2H), 3.02 (s, 3H), 2.59 (m, 3H)

[0217] Example 251: 11H NMR (500 MHz, DMSO-d6) δ 9.70 (s, 1H), 8.12 - 7.94 (m, 2H), 7.91 (d, J = 8.6 Hz, 2H), 7.23 (d, J = 8.6 Hz, 2H), 7.33 (t, J = 73.7 Hz, 1H), 7.00 - 6.81 (m, 3H), 3.81 (s, 3H), 3.00 (s, 3H), 2.99 - 2.94 (m, 1H), 0.78 (brd, J = 5.9 Hz, 2H), 0.58 - 0.43 (m, 2H) Example 252: 1 1H NMR (500 MHz, DMSO-d6) δ 9.67 (s, 1H), 7.98 - 7.80 (m, 4H), 7.23 (d, J = 8.5 Hz, 2H), 7.32 (t, J = 69.9 Hz, 1H), 6.95 (d, J = 11.6 Hz, 1H), 6.88 (d, J = 10.3 Hz, 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) Example 253: 1 1H NMR (500 MHz, DMSO-d6) δ 9.69 (s, 1H), 8.43 (d, J = 3.7 Hz, 1H), 7.97 - 7.86 (m, 3H), 7.29 - 7.21 (m, 2H), 7.54 - 7.16 (m, 1H), 6.98 (d, J = 10.4 Hz, 1H), 6.89 (d, J = 10.4 Hz, 1H), 6.74 (d, J = 8.2 Hz, 1H), 4.91 - 4.77 (m, 3H), 4.61 - 4.42 (m, 2H), 3.86 - 3.80 (m, 3H), 2.96 (s, 3H) Example 254: 11H NMR (500 MHz, DMSO-d6) δ 9.71 - 9.66 (m, 1H), 8.02 - 7.82 (m, 4H), 7.23 (d, J = 8.4 Hz, 2H), 7.32 (t, J = 79.1 Hz, 1H), 7.00 - 6.83 (m, 2H), 6.74 (d, J = 8.9 Hz, 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) Example 255: 1 1H NMR (500 MHz, DMSO-d6) δ 9.66 (brs, 1H), 7.99 - 7.80 (m, 4H), 7.22 (d, J = 8.5 Hz, 2H), 7.28 (t, J = 73.5 Hz, 1H), 6.99 - 6.82 (m, 2H), 6.73 (d, J = 8.8 Hz, 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) Example 256: 1 1H NMR (500 MHz, DMSO-d6) δ 9.67 (s, 1H), 7.91 (d, J = 8.6 Hz, 2H), 7.75 (d, J = 8.9 Hz, 1H), 7.50 - 7.04 (m, 5H), 6.99 - 6.91 (m, 1H), 6.90 - 6.83 (m, 1H), 6.75 (brd, J = 8.9 Hz, 1H), 3.81 (s, 3H), 3.00 (s, 3H), 2.96 (s, 2H), 1.31 (s, 6H) Example 257: 1 1H NMR (500 MHz, DMSO-d6) δ 9.69 (s, 1H), 8.28 (d, J = 8.8 Hz, 1H), 7.89 (d, J = 7.9 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.8 Hz, 1H), 7.26 (t, J = 76.3 Hz, 1H), 6.97 - 6.82 (m, 2H), 3.95 (s, 3H), 3.81 (s, 3H), 3.01 (s, 3H) Example 260: 1 H NMR (500 MHz, DMSO-d6) δ 9.62 (s, 1H), 7.97 (d, J = 9.2 Hz, 1H), 7.87 (d, J = 8.2 Hz, 3H), 7.21 (d, J = 8.5 Hz, 2H), 7.26 (t, J = 174.0 Hz, 1H), 6.93 - 6.81 (m, 3H), 4.40 - 4.26 (m, 1H), 4.04 (d, J = 17.4 Hz, 1H), 3.79 (s, 3H), 3.11 (s, 3H), 2.93 (s, 3H), 2.58 (d, J = 4.3 Hz, 3H)

[0218] Example 261: 1 H NMR (500 MHz, DMSO-d6, ws) δ 9.64 (s, 1H), 7.89 (d, J = 8.5 Hz, 2H), 7.21 (d, J = 8.5 Hz, 2H), 7.27 (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 (brs, 3H) Example 262: 1 H NMR (500 MHz, DMSO-d6) δ 9.60 (s, 1H), 8.62 (m, 1H), 8.21 (dd, J = 8.1, 1.4 Hz, 1H), 7.91 (d, J = 8.9 Hz, 2H), 7.59 (dd, J = 7.9, 4.6 Hz, 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) Example 263: 1 H NMR (500 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.94 (d, J = 3.6 Hz, 1H), 8.46 (d, J = 7.3 Hz, 1H), 7.90 (d, J = 8.7 Hz, 2H), 7.79 (m, 1H), 7.45 (m, 1H), 7.23 (d, J = 8.5 Hz, 2H), 7.28 (m, 1H), 7.00 (m, 1H), 6.92 (m, 1H), 3.79 (s, 3H), 2.94 (s, 3H) Example 264: 11H NMR (500 MHz, DMSO-d6) δ 9.65 (s, 1H), 7.90 (d, J = 8.5 Hz, 2H), 7.81 (m, 2H), 7.22 (d, J = 8.5 Hz, 2H), 7.31 (t, J = 78.7 Hz, 1H), 6.97 - 6.81 (m, 2H), 6.72 (d, J = 8.9 Hz, 1H), 3.81 (s, 3H), 3.51 - 3.02 (m, 2H), 2.95 (s, 3H), 1.14 - 0.94 (m, 1H), 0.45 (brd, J = 7.9 Hz, 2H), 0.32 - 0.11 (m, 2H) Example 265: 1 1H NMR (500 MHz, DMSO-d6) δ 9.66 (s, 1H), 7.92 (d, J = 8.2 Hz, 2H), 7.76 (d, J = 8.5 Hz, 1H), 7.37 (s, 1H), 7.23 (d, J = 8.2 Hz, 2H), 7.32 (t, J = 73.9 Hz, 1H), 6.98 - 6.83 (m, 2H), 6.70 (d, J = 8.9 Hz, 1H), 3.82 (s, 3H), 2.96 (s, 3H), 1.40 (s, 9H) Example 266: 1 1H NMR (500 MHz, DMSO-d6) δ 9.70 (s, 1H), 8.22 - 8.06 (m, 1H), 8.04 - 7.95 (m, 1H), 7.93 (d, J = 8.5 Hz, 2H), 7.24 (d, J = 8.5 Hz, 2H), 7.34 (t, J = 74.2 Hz, 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 = 8.9 Hz, 4H) Example 267: 1 1H NMR (500 MHz, DMSO-d6) δ 9.66 (s, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.91 (d, J = 8.2 Hz, 2H), 7.24 (d, J = 8.5 Hz, 2H), 7.32 (t, J = 81.8 Hz, 1H), 7.13 (d, J = 8.9 Hz, 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) Example 268: 1 1H NMR (500 MHz, DMSO-d6) δ 9.66 (s, 1H), 8.04 (d, J = 9.2 Hz, 1H), 7.90 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 8.2 Hz, 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 (brt, J = 4.7 Hz, 4H), 2.99 (s, 3H), 2.90 (s, 3H) Example 269: 1 1H NMR (500 MHz, DMSO-d6) δ 9.66 (s, 1H), 8.00 (d, J = 9.2 Hz, 1H), 7.91 (d, J = 8.5 Hz, 2H), 7.24 (d, J = 8.5 Hz, 2H), 7.31 (t, J = 73.5 Hz, 1H), 7.09 (d, J = 9.2 Hz, 1H), 6.98 - 6.82 (m, 2H), 3.82 (s, 3H), 3.73 - 3.40 (m, 4H), 3.26 (q, J = 10.1 Hz, 2H), 2.98 (s, 3H), 2.74 (brt, J = 4.4 Hz, 4H) Example 270: 1 1H NMR (500 MHz, DMSO-d6) δ 9.64 (s, 1H), 7.99 (d, J = 8.9 Hz, 1H), 7.89 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 8.5 Hz, 2H), 7.27 (t, J = 71.7 Hz, 1H), 7.07 (d, J = 9.2 Hz, 1H), 6.89 (dd, J = 19.7, 11.7 Hz, 2H), 6.16 (t, J = 56.5 Hz, 1H), 3.81 (s, 3H), 3.76 - 3.62 (m, 4H), 2.99 (s, 3H), 2.81 (td, J = 15.7, 4.3 Hz, 2H), 2.68 - 2.60 (m, 4H)

[0219] Example 271: 11H NMR (500 MHz, DMSO-d6) δ 9.66 (s, 1H), 7.91 (d, J = 8.5 Hz, 2H), 7.82 (d, J = 7.6 Hz, 1H), 7.61 - 7.52 (m, 1H), 7.23 (d, J = 8.2 Hz, 2H), 7.30 (t, J = 73.9 Hz, 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 = 8.9 Hz, 6H) Example 272: 1 1H NMR (500 MHz, DMSO-d6) δ 9.67 (s, 1H), 7.92 (d, J = 8.5 Hz, 2H), 7.83 (d, J = 2.7 Hz, 1H), 7.75 - 7.62 (m, 1H), 7.24 (d, J = 8.9 Hz, 2H), 7.32 (t, J = 73.2 Hz, 1H), 6.98 - 6.83 (m, 2H), 6.78 (dd, J = 8.7, 3.8 Hz, 1H), 4.81 (brd, J = 4.3 Hz, 1H), 3.82 (s, 3H), 3.53 - 3.38 (m, 1H), 3.18 (d, J = 5.2 Hz, 2H), 2.97 (s, 3H), 1.14 - 1.06 (m, 3H) Example 273: 1 1H NMR (500 MHz, DMSO-d6) δ 9.65 (s, 1H), 7.90 (d, J = 8.5 Hz, 2H), 7.86 - 7.77 (m, 1H), 7.73 - 7.59 (m, 1H), 7.23 (d, J = 8.5 Hz, 2H), 7.29 (t, J = 73.5 Hz, 1H), 6.98 - 6.81 (m, 2H), 6.78 (dd, J = 8.9, 3.4 Hz, 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 = 5.0 Hz, 3H) Example 274: 11H NMR (500 MHz, DMSO-d6) δ 9.63 (s, 1H), 7.94 - 7.78 (m, 4H), 7.22 (d, J = 8.2 Hz, 2H), 7.27 (t, J = 69.6 Hz, 1H), 6.93 - 6.76 (m, 3H), 4.21 (brd, J = 2.4 Hz, 1H), 3.81 (s, 3H), 3.74 - 3.58 (m, 1H), 3.54 - 3.14 (m, 1H), 2.98 (brd, J = 7.6 Hz, 3H), 1.92 (s, 1H) Example 275: 1 1H NMR (500 MHz, DMSO-d6) δ 9.66 (brs, 1H), 8.42 (d, J = 8.3 Hz, 1H), 7.98 (d, J = 8.2 Hz, 1H), 7.88 (d, J = 8.0 Hz, 2H), 7.21 (brd, J = 8.4 Hz, 2H), 7.26 (t, J = 73.3 Hz, 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) Example 276: 1 1H NMR (500 MHz, DMSO-d6) δ 9.66 (s, 1H), 8.15 (d, J = 8.5 Hz, 1H), 7.88 (d, J = 8.2 Hz, 2H), 7.79 (d, J = 8.5 Hz, 1H), 7.22 (d, J = 8.5 Hz, 2H), 7.26 (t, J = 73.6 Hz, 1H), 6.94 - 6.83 (m, 2H), 5.62 (s, 1H), 3.80 (s, 3H), 2.98 (s, 3H), 1.45 (s, 6H) Example 277: 1 1H NMR (500 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.95 (d, J = 4.6 Hz, 1H), 8.47 (d, J = 8.0 Hz, 1H), 7.94 (brd, J = 8.5 Hz, 2H), 7.79 (dd, J = 7.6, 5.1 Hz, 1H), 7.45 (brd, J = 8.2 Hz, 2H), 7.24 (brdd, J = 14.1, 8.4 Hz, 5H), 2.96 (s, 3H), 2.54 (s, 3H), 2.02 - 1.89 (m, 1H), 0.99 (brdd, J = 8.3, 2.0 Hz, 2H), 0.78 - 0.66 (m, 2H) Example 278: 1 1H NMR (500 MHz, CD3OD) δ 7.95 - 7.84 (m, 3H), 7.21 (d, J = 8.5 Hz, 2H), 6.89 (d, J = 9.9 Hz, 2H), 6.97 (t, J = 74.0 Hz, 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) Example 279: 1 1H NMR (500 MHz, DMSO-d6) δ 9.66 (s, 1H), 7.91 (d, J = 8.2 Hz, 2H), 7.81 (d, J = 0.9 Hz, 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) Example 280: 1 1H NMR (500 MHz, DMSO-d6) δ 9.66 (brs, 1H), 7.99 - 7.84 (m, 3H), 7.24 (d, J = 8.2 Hz, 2H), 7.31 (t, J = 74.2 Hz, 1H), 6.97 - 6.83 (m, 2H), 6.72 (d, J = 8.2 Hz, 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)

[0220] Example 281: 1 1H NMR (500 MHz, DMSO-d6) δ 9.68 (s, 1H), 8.98 (d, J = 4.3 Hz, 1H), 8.50 (d, J = 8.2 Hz, 1H), 7.96 (d, J = 8.5 Hz, 2H), 7.83 (m, 1H), 7.67 (d, J = 8.5 Hz, 2H), 7.53 - 7.14 (m, 6H), 3.00 (s, 3H) Example 282: 11H NMR (500 MHz, DMSO-d6) δ 9.66 (brs, 1H), 8.00 - 7.85 (m, 3H), 7.23 (d, J = 8.5 Hz, 2H), 7.32 (t, J = 74.1 Hz, 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) Example 283: 1 1H NMR (500 MHz, DMSO-d6) δ 9.69 (s, 1H), 8.00 - 7.75 (m, 3H), 7.24 (d, J = 5.8 Hz, 2H), 7.34 (t, J = 71.1 Hz, 1H), 7.09 (d, J = 38.1 Hz, 1H), 6.95 (d, J = 11.6 Hz, 1H), 6.89 (d, J = 11.6 Hz, 1H), 6.83 (d, J = 9.2 Hz, 1H), 4.34 - 4.04 (m, 2H), 3.83 (s, 3H), 2.99 - 2.86 (m, 3H), 0.98 (t, J = 7.2 Hz, 1H), 0.68 - 0.51 (m, 4H) Example 284: 1 1H NMR (500 MHz, DMSO-d6) δ 9.66 (brs, 1H), 8.00 - 7.85 (m, 3H), 7.23 (d, J = 8.5 Hz, 2H), 7.32 (t, J = 74.1 Hz, 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) Example 285: 11H NMR (500 MHz, DMSO-d6) δ 9.73 (s, 1H), 8.30 (d, J = 8.9 Hz, 1H), 7.93 (d, J = 8.5 Hz, 2H), 7.25 (d, J = 8.5 Hz, 2H), 7.34 (t, J = 73.9 Hz, 1H), 7.19 (d, J = 7.6 Hz, 1H), 7.03 - 6.82 (m, 2H), 4.46 - 4.31 (m, 2H), 3.84 (s, 3H), 3.78 (q, J = 4.9 Hz, 2H), 3.49 - 3.39 (m, 1H), 3.01 (s, 3H) Example 286: 1 1H NMR (500 MHz, DMSO-d6) δ 9.89 - 9.76 (m, 1H), 7.92 (d, J = 8.5 Hz, 2H), 7.87 (d, J = 9.8 Hz, 1H), 7.24 (d, J = 8.6 Hz, 2H), 7.33 (t, J = 75.2 Hz, 1H), 6.97 - 6.90 (m, 2H), 6.82 (d, J = 9.8 Hz, 1H), 3.82 (s, 3H), 3.81 - 3.62 (m, 2H), 3.05 (s, 3H), 1.23 (brt, J = 6.9 Hz, 3H) Example 287: 1 1H NMR (500 MHz, DMSO-d6) δ 9.82 (s, 1H), 7.94 (d, J = 8.9 Hz, 2H), 7.89 (d, J = 10.1 Hz, 1H), 7.26 (d, J = 7.9 Hz, 2H), 7.35 (t, J = 80.0 Hz, 1H), 6.95 (d, J = 10.7 Hz, 2H), 6.85 (d, J = 9.5 Hz, 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) Example 288: 1 1H NMR (500 MHz, DMSO-d6) δ 9.72 (s, 1H), 8.30 (d, J = 8.9 Hz, 1H), 7.92 (d, J = 8.2 Hz, 2H), 7.25 (d, J = 8.2 Hz, 2H), 7.20 (d, J = 8.5 Hz, 1H), 7.31 (t, J = 73.9 Hz, 1H), 7.04 - 6.78 (m, 2H), 4.28 - 4.02 (m, 2H), 3.83 (s, 3H), 3.53 (brs, 1H), 3.00 (s, 3H), 1.22 (s, 6H) Example 289: 1 1H NMR (500 MHz, CD3OD) δ 8.31 (d, J = 8.8 Hz, 1H), 7.89 (d, J = 8.8 Hz, 2H), 7.28 (d, J = 8.8 Hz, 1H), 7.21 (d, J = 8.5 Hz, 2H), 7.00 (t, J = 74.8 Hz, 1H), 6.86 - 6.76 (m, 2H), 5.17 (d, J = 16.0 Hz, 2H), 3.88 (s, 3H), 3.79 (s, 3H), 3.13 (s, 3H) Example 290: 1 1H NMR (500 MHz, DMSO-d6) δ 9.65 (s, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.84 - 7.73 (m, 1H), 7.63 - 7.55 (m, 1H), 7.22 (d, J = 8.5 Hz, 2H), 7.31 (t, J = 50.8 Hz, 1H), 6.96 - 6.80 (m, 2H), 6.77 (d, J = 8.8 Hz, 1H), 4.80 - 4.53 (m, 1H), 3.80 (s, 3H), 3.39 (d, J = 4.0 Hz, 2H), 3.30 - 3.12 (m, 2H), 2.94 (s, 3H), 1.88 - 1.67 (m, 6H)

[0221] Example 291: 1 1H NMR (500 MHz, DMSO-d6) δ 9.77 (s, 1H), 8.47 (d, J = 8.2 Hz, 1H), 7.88 (d, J = 7.9 Hz, 2H), 7.84 (d, J = 7.9 Hz, 1H), 7.22 (d, J = 8.2 Hz, 2H), 7.27 (t, J = 73.2 Hz, 1H), 6.92 (d, J = 10.7 Hz, 2H), 3.81 (s, 3H), 3.14 (s, 3H), 2.97 (s, 1H), 1.47 (brs, 6H) Example 292: 11H NMR (500 MHz, DMSO-d6) δ 9.65 (s, 1H), 7.96 - 7.87 (m, 3H), 7.24 (d, J = 8.5 Hz, 2H), 7.31 (t, J = 73.5 Hz, 1H), 6.90 (m, 2H), 6.71 (d, J = 8.9 Hz, 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) Example 293: 1 1H NMR (500 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.97 (d, J = 4.0 Hz, 1H), 8.50 (d, J = 7.6 Hz, 1H), 7.96 (d, J = 8.5 Hz, 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) Example 294: 1 1H NMR (500 MHz, DMSO-d6) δ 9.66 (s, 1H), 8.65 (d, J = 4.0 Hz, 1H), 8.24 (d, J = 7.3 Hz, 1H), 7.97 (d, J = 8.9 Hz, 2H), 7.62 (m, 1H), 7.50 - 7.04 (m, 6H), 3.89 (s, 3H), 3.01 (s, 3H) Example 295: 1 1H NMR (500 MHz, DMSO-d6) δ 9.64 (s, 1H), 8.51 (d, J = 8.4 Hz, 1H), 7.96 - 7.87 (m, 3H), 7.46 (m, 1H), 7.24 (d, J = 8.4 Hz, 2H), 7.30 (t, J = 73.8 Hz, 1H), 7.02 (brd, J = 12.5 Hz, 1H), 6.93 (brd, J = 8.5 Hz, 1H), 3.80 (s, 3H), 2.98 (s, 3H) Example 296: 11H NMR (500 MHz, DMSO-d6) shift 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) Example 297: 1 1H NMR (500 MHz, DMSO-d6) δ 9.72 (s, 1H), 8.58 (d, J = 8.5 Hz, 1H), 8.43 (d, J = 8.9 Hz, 1H), 7.92 (d, J = 7.3 Hz, 2H), 7.25 (d, J = 8.5 Hz, 2H), 7.34 (t, J = 72.6 Hz, 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) Example 298: 1 1H NMR (500 MHz, DMSO-d6) δ 9.70 (s, 1H), 8.43 (s, 1H), 8.06 (d, J = 8.8 Hz, 1H), 7.91 (d, J = 7.9 Hz, 2H), 7.23 (d, J = 8.2 Hz, 1H), 7.32 (t, J = 73.8 Hz, 1H), 7.06 (d, J = 8.5 Hz, 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) Example 299: 11H NMR (500 MHz, DMSO-d6) δ 9.66 (s, 1H), 7.90 (d, J = 8.2 Hz, 2H), 7.77 (m, 1H), 7.28 - 7.25 (m, 1H), 7.22 (d, J = 8.5 Hz, 2H), 7.31 (t, J = 73.8 Hz, 1H), 7.18 - 7.14 (m, 1H), 7.05 (s, 1H), 6.95 - 6.82 (m, 2H), 6.51 (d, J = 8.8 Hz, 1H), 4.00 (t, J = 7.1 Hz, 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) Example 300: 1 1H NMR (500 MHz, DMSO-d6) δ 9.64 (s, 1H), 8.44 - 8.19 (m, 1H), 7.89 (d, J = 8.5 Hz, 2H), 7.78 (d, J = 8.5 Hz, 1H), 7.22 (d, J = 8.2 Hz, 2H), 7.28 (t, J = 73.6 Hz, 1H), 6.88 (s, 2H), 6.56 (d, J = 8.9 Hz, 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 = 4.9 Hz, 1H)

[0222] Example 301: 1 1H NMR (500 MHz, DMSO-d6) δ 9.75 (s, 1H), 9.02 - 8.92 (m, 1H), 8.50 (d, J = 7.3 Hz, 1H), 8.08 - 7.77 (m, 7H), 7.26 (brd, J = 8.5 Hz, 2H), 7.29 (t, J = 73.2 Hz, 1H), 3.00 (brs, 3H) Example 302: 11H NMR (500 MHz, DMSO-d6) δ 9.70 (brs, 1H), 8.17 - 8.07 (m, 1H), 7.92 (d, J = 8.5 Hz, 2H), 7.25 (d, J = 8.5 Hz, 2H), 7.32 (t, J = 61.3 Hz, 1H), 7.05 - 6.84 (m, 3H), 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) Example 303: 1 1H NMR (500 MHz, DMSO-d6) δ 9.67 (s, 1H), 7.96 (d, J = 9.2 Hz, 1H), 7.93 (d, J = 8.5 Hz, 2H), 7.57 (s, 1H), 7.24 (d, J = 8.2 Hz, 2H), 7.33 (t, J = 73.5 Hz, 1H), 7.01 (s, 1H), 6.98 - 6.84 (m, 2H), 6.73 (d, J = 8.5 Hz, 1H), 3.91 (s, 1H), 3.83 (s, 3H), 3.57 - 3.38 (m, 2H), 3.19 (d, J = 4.6 Hz, 1H), 3.14 - 3.05 (m, 1H), 3.00 (s, 3H), 2.28 - 2.04 (m, 2H) Example 304: 1 1H NMR (500 MHz, DMSO-d6) δ 9.71 (s, 1H), 8.98 (d, J = 4.0 Hz, 1H), 8.50 (d, J = 7.6 Hz, 1H), 7.95 (d, J = 8.5 Hz, 2H), 7.83 (m, 1H), 7.74 (brd, J = 8.9 Hz, 2H), 7.57 (d, J = 8.2 Hz, 2H), 7.27 (brd, J = 8.2 Hz, 2H), 7.32 (t, J = 73.2 Hz, 1H), 3.00 (s, 3H) Example 305: 11H NMR (500 MHz, DMSO-d6) δ 9.67 (s, 1H), 7.96 (d, J = 9.2 Hz, 1H), 7.93 (d, J = 8.5 Hz, 2H), 7.57 (s, 1H), 7.24 (d, J = 8.2 Hz, 2H), 7.33 (t, J = 73.5 Hz, 1H), 7.01 (s, 1H), 6.98 - 6.84 (m, 2H), 6.73 (d, J = 8.5 Hz, 1H), 3.91 (s, 1H), 3.83 (s, 3H), 3.57 - 3.38 (m, 2H), 3.19 (d, J = 4.6 Hz, 1H), 3.14 - 3.05 (m, 1H), 3.00 (s, 3H), 2.28 - 2.04 (m, 2H) Example 306: 1 1H NMR (500 MHz, DMSO-d6) δ 9.65 (s, 1H), 7.97 (d, J = 9.0 Hz, 1H), 7.90 (d, J = 8.2 Hz, 2H), 7.22 (d, J = 8.5 Hz, 2H), 7.29 (t, J = 77.0 Hz, 1H), 7.09 (d, J = 9.0 Hz, 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) Example 307: 1 1H NMR (500 MHz, DMSO-d6) δ 9.65 (s, 1H), 7.90 (d, J = 8.2 Hz, 2H), 7.79 (d, J = 8.9 Hz, 1H), 7.22 (d, J = 8.2 Hz, 2H), 7.30 (t, J = 73.5 Hz, 1H), 6.96 - 6.83 (m, 2H), 6.57 (d, J = 8.9 Hz, 1H), 5.72 (brs, 1H), 3.91 - 3.81 (m, 4H), 3.80 (s, 3H), 2.98 (s, 3H), 1.44 (s, 3H) Example 308: 11H NMR (500 MHz, DMSO-d6) δ 9.66 (s, 1H), 7.94 (d, J = 8.9 Hz, 1H), 7.91 (d, J = 8.2 Hz, 2H), 7.23 (d, J = 8.5 Hz, 2H), 7.27 (t, J = 73.5 Hz, 1H), 6.96 - 6.82 (m, 2H), 6.57 (d, J = 8.9 Hz, 1H), 4.09 - 3.99 (m, 4H), 3.82 (s, 3H), 3.32 (brt, J = 6.9 Hz, 1H), 2.96 (s, 3H), 2.05 (brdd, J = 11.4, 7.8 Hz, 4H) Example 309: 1 1H NMR (500 MHz, DMSO-d6) δ 9.66 (s, 1H), 7.93 (d, J = 7.9 Hz, 2H), 7.86 (d, J = 8.5 Hz, 1H), 7.25 (d, J = 8.5 Hz, 2H), 7.33 (t, J = 77.5 Hz, 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 (brt, J = 7.5 Hz, 3H) Example 310: 1 1H NMR (500 MHz, DMSO-d6) δ 9.61 (s, 1H), 7.92 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 8.5 Hz, 1H), 7.23 (d, J = 8.4 Hz, 2H), 7.33 (t, J = 73.2 Hz, 1H), 7.03 - 6.83 (m, 2H), 6.54 (d, J = 8.5 Hz, 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 (brt, J = 7.3 Hz, 3H)

[0223] Example 311: 11H NMR (500 MHz, DMSO-d6) δ 9.63 (s, 1H), 7.88 (d, J = 8.2 Hz, 2H), 7.67 (m, 1H), 7.23 (d, J = 8.5 Hz, 2H), 7.29 (t, J = 73.4 Hz, 1H), 7.07 (d, J = 7.3 Hz, 1H), 6.90 (d, J = 10.4 Hz, 2H), 6.33 (d, J = 8.2 Hz, 1H), 3.89 - 3.81 (m, 4H), 3.81 (s, 3H), 3.20 (s, 3H), 1.44 (s, 3H) Example 312: 1 1H NMR (500 MHz, DMSO-d6) δ 9.63 (s, 1H), 7.88 (d, J = 8.2 Hz, 2H), 7.67 (m, 1H), 7.23 (d, J = 8.5 Hz, 2H), 7.29 (t, J = 73.4 Hz, 1H), 7.07 (d, J = 7.3 Hz, 1H), 6.90 (d, J = 10.4 Hz, 2H), 6.33 (d, J = 8.2 Hz, 1H), 3.89 - 3.81 (m, 4H), 3.81 (s, 3H), 3.20 (s, 3H), 1.44 (s, 3H) Example 313: 1 1H NMR (500 MHz, DMSO-d6, ws) δ 9.56 (s, 1H), 7.95 - 7.89 (m, 3H), 7.43 (m, 1H), 7.24 (d, J = 8.2 Hz, 2H), 7.33 (t, J = 73.8 Hz, 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) Example 314: 1 1H NMR (500 MHz, DMSO-d6) δ 9.64 (s, 1H), 7.96 - 7.85 (m, 3H), 7.22 (d, J = 8.7 Hz, 2H), 7.30 (t, J = 73.6 Hz, 1H), 7.05 (d, J = 9.0 Hz, 1H), 6.92 (d, J = 10.2 Hz, 1H), 6.87 (d, J = 11.7 Hz, 1H), 4.03 - 3.93 (m, 1H), 3.80 (s, 3H), 3.16 (d, J = 5.1 Hz, 4H), 2.96 (s, 3H), 1.59 - 1.43 (m, 4H), 1.15 (s, 3H) Example 315: 1 H NMR (500 MHz, DMSO-d6) δ 9.70 (s, 1H), 7.98 (d, J = 8.5 Hz, 2H), 7.91 (m, 1H), 7.72 (brd, J = 8.5 Hz, 2H), 7.55 (d, J = 7.6 Hz, 1H), 7.30 (d, J = 8.5 Hz, 2H), 7.52 - 7.19 (m, 4H), 6.78 (d, J = 7.9 Hz, 1H), 3.99 (s, 3H), 3.26 (s, 3H) Example 316: 1 H NMR (500 MHz, DMSO-d6) δ 9.69 (s, 1H), 8.15 (d, J = 8.2 Hz, 1H), 7.90 (d, J = 8.2 Hz, 2H), 7.54 (d, J = 8.2 Hz, 1H), 7.23 (d, J = 8.5 Hz, 2H), 7.31 (t, J = 73.5 Hz, 1H), 6.99 - 6.84 (m, 2H), 3.81 (s, 3H), 3.67 (d, J = 12.2 Hz, 2H), 2.99 (s, 3H), 2.89 (s, 3H), 2.99 - 2.81 (m, 3H), 2.02 (d, J = 12.2 Hz, 2H), 1.83 - 1.68 (m, 2H) Example 317: 1 H NMR (500 MHz, DMSO-d6) δ 8.04 (s, 1H), 8.00 (d, J = 8.9 Hz, 2H), 7.74 (d, J = 8.2 Hz, 1H), 7.63 (d, J = 8.9 Hz, 2H), 7.31 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 8.2 Hz, 2H), 7.40 (t, J = 73.5 Hz, 1H), 7.30 (t, J = 73.6 Hz, 1H), 6.72 (d, J = 7.9 Hz, 1H), 3.79 (s, 3H) Example 320: 11H NMR (400 MHz, DMSO-d6) δ = 9.68 (brs, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.34 (t, J = 76.0 Hz, 1H), 7.26 - 7.23 (m, 3H), 6.93 (d, J = 10.3 Hz, 2H), 6.85 (d, J = 1.8 Hz, 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)

[0224] Example 321: 1 1H NMR (400 MHz, DMSO-d6) δ = 9.68 (brs, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.34 (t, J = 76.0 Hz, 1H), 7.26 - 7.23 (m, 3H), 6.93 (d, J = 10.3 Hz, 2H), 6.85 (d, J = 1.8 Hz, 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) Example 322: 1 1H NMR (400 MHz, DMSO-d6) δ = 9.86 - 9.31 (m, 1H), 7.91 (d, J = 8.4 Hz, 2H), 7.34 (t, J = 73.6 Hz, 1H), 7.25 (d, J = 8.4 Hz, 2H), 7.04 (d, J = 2.0 Hz, 1H), 6.95 (d, J = 10.0 Hz, 2H), 6.36 (d, J = 2.0 Hz, 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) Example 323: 11H NMR (400 MHz, DMSO-d6) δ = 9.66 (brs, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.56 (s, 1H), 7.34 (t, J = 72.5 Hz, 1H), 7.28 - 7.20 (m, 2H), 7.11 (s, 1H), 6.93 (d, J = 10.0 Hz, 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) Example 324: 1 1H NMR (400 MHz, DMSO-d6) δ = 9.65 (s, 1H), 7.90 (d, J = 8.8 Hz, 2H), 7.57 (s, 1H), 7.34 (t, J = 71.3 Hz, 1H), 7.24 (d, J = 8.8 Hz, 2H), 7.14 (s, 1H), 6.93 (d, J = 10.0 Hz, 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) Example 325: 1 1H NMR (400 MHz, DMSO-d6) δ = 9.67 (s, 1H), 7.90 (d, J = 8.8 Hz, 2H), 7.33 (t, J = 73.5 Hz, 1H), 7.24 (d, J = 8.8 Hz, 2H), 7.02 (d, J = 2.0 Hz, 1H), 6.93 (d, J = 10.0 Hz, 2H), 6.32 (d, J = 2.0 Hz, 1H), 4.47 (t, J = 5.3 Hz, 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) Example 326: 11H NMR (400 MHz, DMSO-d6) δ = 11.12 (brs, 1H), 9.67 (s, 1H), 7.90 (d, J = 8.5 Hz, 2H), 7.34 (t, J = 73.5 Hz, 1H), 7.24 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 10.0 Hz, 2H), 6.91 - 6.74 (m, 1H), 6.13 (s, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.16 (s, 3H) Example 327: 1 1H NMR (400 MHz, DMSO-d6) δ = 9.65 (s, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.34 (t, J = 72.5 Hz, 1H), 7.29 (d, J = 2.0 Hz, 1H), 7.24 (d, J = 8.8 Hz, 2H), 6.97 - 6.88 (m, 3H), 4.51 (d, J = 5.8 Hz, 2H), 4.33 (d, J = 5.8 Hz, 2H), 4.20 (s, 2H), 3.83 (s, 3H), 3.19 (s, 3H), 2.48 (s, 3H), 1.38 (s, 3H) Example 328: 1 1H NMR (400 MHz, DMSO-d6) δ = 9.75 (s, 1H), 8.11 (s, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.71 (s, 1H), 7.25 (d, J = 8.8 Hz, 2H), 7.34 (t, J = 74.6 Hz, 1H), 6.94 (d, J = 10.0 Hz, 2H), 3.83 (s, 3H), 3.22 (s, 3H), 2.61 (s, 3H) Example 329: 1 1H NMR (400 MHz, DMSO-d6) δ = 9.67 (s, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.34 (t, J = 73.8 Hz, 1H), 7.25 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 2.0 Hz, 1H), 6.93 (d, J = 10.0 Hz, 2H), 6.34 (d, J = 1.8 Hz, 1H), 4.51 (brs, 1H), 4.35 (t, J = 6.4 Hz, 2H), 3.87 (s, 3H), 3.82 (s, 3H), 3.56 (t, J = 6.4 Hz, 2H), 3.23 (s, 3H), 1.92 - 1.86 (m, 2H) Example 330: 1 1H NMR (400 MHz, DMSO-d6) δ = 9.56 (s, 1H), 7.94 - 7.89 (m, 3H), 7.71 (dd, J = 7.3, 2.0 Hz, 1H), 7.32 (t, J = 73.5 Hz, 1H), 7.22 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 10.5 Hz, 2H), 6.4 (t, J = 6.9 Hz, 1H), 3.8 (s, 3H), 3.53 (s, 3H), 2.99 (s, 3H)

[0225] Example 331: 1 1H NMR (400 MHz, DMSO-d6) δ = 9.67 (s, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.33 (t, J = 74.0 Hz, 1H), 7.28 - 7.24 (m, 3H), 6.93 (d, J = 10.3 Hz, 2H), 6.62 (s, 1H), 4.85 (t, J = 5.1 Hz, 1H), 4.30 (t, J = 5.1 Hz, 2H), 3.82 (s, 3H), 3.74 (q, J = 5.1 Hz, 2H), 3.19 (s, 3H), 2.37 (s, 3H) Example 332: 1 1H NMR (400 MHz, DMSO-d6) δ = 9.68 (s, 1H), 7.91 (brd, J = 8.8 Hz, 2H), 7.33 (t, J = 73.6 Hz, 1H), 7.24 (d, J = 8.8 Hz, 2H), 7.07 (d, J = 1.8 Hz, 1H), 6.94 (d, J = 10.3 Hz, 2H), 6.35 (d, J = 1.8 Hz, 1H), 4.84 (t, J = 5.4 Hz, 1H), 4.31 (t, J = 5.4 Hz, 2H), 3.88 (s, 3H), 3.83 (s, 3H), 3.74 (q, J = 5.4 Hz, 2H), 3.23 (s, 3H) Example 333: 11H NMR (400 MHz, DMSO-d6) δ = 9.69 (s, 1H), 7.94 - 7.81 (m, 3H), 7.45 (d, J = 7.8 Hz, 1H), 7.33 (t, J = 73.8 Hz, 1H), 7.24 (d, J = 8.5 Hz, 2H), 6.94 (d, J = 10.3 Hz, 2H), 6.77 (d, J = 8.3 Hz, 1H), 4.87 (t, J = 5.5 Hz, 1H), 4.32 (t, J = 5.5 Hz, 2H), 3.83 (s, 3H), 3.76 (q, J = 5.5 Hz, 2H), 3.22 (s, 3H) Example 334: 1 1H NMR (400 MHz, DMSO-d6) δ = 9.72 (s, 1H), 7.90 (d, J = 8.5 Hz, 2H), 7.74 (d, J = 2.0 Hz, 1H), 7.47 (d, J = 2.0 Hz, 1H), 7.34 (t, J = 74.0 Hz, 1H), 7.25 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 10.3 Hz, 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) Example 335: 1 1H NMR (400 MHz, DMSO-d6) δ = 9.70 (s, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.34 (t, J = 72.8 Hz, 1H), 7.25 (d, J = 8.8 Hz, 2H), 7.11 (d, J = 2.0 Hz, 1H), 6.94 (d, J = 10.3 Hz, 2H), 6.42 (d, J = 2.0 Hz, 1H), 4.68 (t, J = 5.5 Hz, 2H), 3.89 (s, 3H), 3.83 (s, 3H), 3.67 (t, J = 5.5 Hz, 2H), 3.23 (s, 3H), 3.08 (s, 3H) Example 336: 11H NMR (400 MHz, DMSO-d6) δ = 9.68 (s, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.34 (t, J = 73.8 Hz, 1H), 7.27 - 7.24 (m, 2H), 7.09 (d, J = 2.0 Hz, 1H), 7.01 - 6.86 (m, 2H), 6.70 (s, 1H), 5.52 (brs, 1H), 4.86 (brs, 1H), 4.58 (s, 2H), 4.31 (t, J = 5.0 Hz, 2H), 3.83 (s, 3H), 3.74 (brt, J = 5.0 Hz, 2H), 3.20 (s, 3H) Example 337: 1 1H NMR (400 MHz, DMSO-d6) δ = 9.68 (s, 1H), 7.94 - 7.83 (m, 2H), 7.34 (t, J = 74.8 Hz, 2H), 7.25 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 2.0 Hz, 1H), 6.94 (d, J = 10.0 Hz, 2H), 6.37 (d, J = 2.0 Hz, 1H), 4.21 (d, J = 6.0 Hz, 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) Example 338: 1 1H NMR (400 MHz, DMSO-d6) δ = 9.66 (s, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.34 (t, J = 75.3 Hz, 1H), 7.29 - 7.23 (m, 3H), 6.95 (d, J = 10.5 Hz, 2H), 6.91 (d, J = 2.0 Hz, 1H), 4.39 (s, 1H), 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 = 6.3 Hz, 2H), 2.02 - 1.86 (m, 3H), 1.69 - 1.55 (m, 3H) Example 339: 11H NMR (400 MHz, DMSO-d6) δ = 9.68 (s, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.34 (t, J = 75.3 Hz, 1H), 7.25 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 2.0 Hz, 1H), 6.94 (d, J = 10.5 Hz, 2H), 6.36 (d, J = 2.0 Hz, 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) Example 340: 1 1H NMR (400 MHz, DMSO-d6) δ = 9.66 (s, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.34 (t, J = 75.3 Hz, 1H), 7.29 - 7.23 (m, 3H), 6.95 (d, J = 10.5 Hz, 2H), 6.91 (d, J = 2.0 Hz, 1H), 4.39 (s, 1H), 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 = 6.3 Hz, 2H), 2.02 - 1.86 (m, 3H), 1.69 - 1.55 (m, 3H)

[0226] Example 341: 1 1H NMR (400 MHz, DMSO-d6) δ = 9.82 (s, 1H), 8.68 (s, 1H), 8.43 (s, 1H), 7.92 (d, J = 8.8 Hz, 2H), 7.35 (t, J = 75.1 Hz, 1H), 7.26 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 10.3 Hz, 2H), 3.84 (s, 3H), 3.24 (s, 3H) Example 342: 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 (brs, 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) Example 343 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 (brs, 3H), 2.26 - 2.23 (m, 1H), 1.91 (brs, 2H), 1.78 - 1.72 (m, 1H), 1.70 - 1.46 (m, 2H) Example 344 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, 2H), 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) Example 345 11H NMR (400 MHz, DMSO-d6) δ = 9.68 (s, 1H), 7.92 (d, J = 8.8 Hz, 2H), 7.35 (t, J = 74.3 Hz, 1H), 7.33 (d, J = 2.0 Hz, 1H), 7.26 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 10.3 Hz, 2H), 6.88 (d, J = 2.0 Hz, 1H), 4.04 - 3.93 (m, 2H), 3.90 (s, 3H), 3.84 (s, 3H), 3.53 - 3.40 (m, 2H), 3.24 (s, 3H), 3.01 - 2.90 (m, 1H), 1.90 - 1.73 (m, 4H) Example 346: 1 1H NMR (400 MHz, DMSO-d6) δ = 9.66 (s, 1H), 7.90 (d, J = 8.5 Hz, 2H), 7.35 (t, J = 73.6 Hz, 1H), 7.29 (d, J = 2.0 Hz, 1H), 7.24 (d, J = 8.5 Hz, 2H), 6.94 (d, J = 10.5 Hz, 2H), 6.83 (d, J = 2.0 Hz, 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) Example 347: 1 1H NMR (400 MHz, DMSO-d6) δ = 9.68 (s, 1H), 7.91 (d, J = 8.5 Hz, 2H), 7.35 (t, J = 73.6 Hz, 1H), 7.29 (d, J = 2.0 Hz, 1H), 7.24 (d, J = 8.5 Hz, 2H), 6.94 (d, J = 10.5 Hz, 2H), 6.83 (d, J = 2.0 Hz, 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) Example 348: 11H NMR (400 MHz, DMSO-d6) δ = 9.73 (s, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.74 (d, J = 2.0 Hz, 1H), 7.45 (d, J = 2.0 Hz, 1H), 7.34 (t, J = 73.0 Hz, 1H), 7.25 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 10.3 Hz, 2H), 5.01 (t, J = 5.5 Hz, 1H), 4.28 (t, J = 4.8 Hz, 2H), 3.83 (s, 3H), 3.81 - 3.75 (m, 2H), 3.23 (s, 3H) Example 349: 1 1H NMR (400 MHz, DMSO-d6) δ = 9.72 (s, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.78 (d, J = 2.0 Hz, 1H), 7.52 (d, J = 4.2 Hz, 1H), 7.33 (t, J = 74.0 Hz, 1H), 7.24 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 10.0 Hz, 2H), 4.54 (d, J = 5.8 Hz, 2H), 4.42 - 4.28 (m, 4H), 3.83 (s, 3H), 3.23 (s, 3H), 1.40 (s, 3H) Example 350: 1 1H NMR (400 MHz, DMSO-d6) δ = 9.68 (s, 1H), 7.91 (d, J = 8.5 Hz, 2H), 7.34 (t, J = 75.3 Hz, 1H), 7.25 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 2.0 Hz, 1H), 6.94 (d, J = 10.5 Hz, 2H), 6.36 (d, J = 2.0 Hz, 1H), 4.33 - 4.16 (m, 3H), 3.88 (s, 3H), 3.84 - 3.76 (m, 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)

[0227] Example 351: 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) Example 352: 1 1H NMR (400 MHz, DMSO-d6) δ = 9.69 (s, 1H), 7.92 (brd, 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) Example 353: 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) Example 354: 11H NMR (400 MHz, DMSO-d6) δ = 9.64 (s, 1H), 7.91 (brd, J = 8.8 Hz, 2H), 7.34 (t, J = 75.8 Hz, 1H), 7.24 (brd, J = 8.8 Hz, 2H), 6.93 (d, J = 10.5 Hz, 2H), 6.71 (d, J = 1.5 Hz, 1H), 5.96 (brs, 1H), 4.64 (brs, 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) Example 355: 1 1H NMR (400 MHz, DMSO-d6) δ = 9.71 (s, 1H), 7.92 (d, J = 8.8 Hz, 2H), 7.35 (t, J = 73.6 Hz, 1H), 7.26 (d, J = 8.8 Hz, 2H), 7.07 (d, J = 2.0 Hz, 1H), 6.95 (d, J = 10.5 Hz, 2H), 6.37 (d, J = 2.0 Hz, 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) Example 356: 1 1H NMR (400 MHz, DMSO-d6) δ = 9.71 (s, 1H), 7.92 (d, J = 8.8 Hz, 2H), 7.35 (t, J = 73.6 Hz, 1H), 7.26 (d, J = 8.8 Hz, 2H), 7.07 (d, J = 2.0 Hz, 1H), 6.95 (d, J = 10.5 Hz, 2H), 6.37 (d, J = 2.0 Hz, 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) Example 357: 11H NMR (400 MHz, DMSO-d6) δ = 9.81 (s, 1H), 8.43 (d, J = 8.1 Hz, 1H), 7.92 (d, J = 8.6 Hz, 2H), 7.55 (d, J = 8.1 Hz, 1H), 7.34 (t, J = 73.6 Hz, 1H), 7.24 (d, J = 8.6 Hz, 2H), 6.95 (d, J = 10.5 Hz, 2H), 3.84 (s, 3H), 3.14 (s, 3H), 2.65 (s, 3H) Example 358 1 1H NMR (400 MHz, DMSO-d6) δ = 9.66 (s, 1H), 8.13 (d, J = 8.8 Hz, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.24 (d, J = 8.6 Hz, 2H), 7.33 (t, J = 74.0 Hz, 1H), 6.96 - 6.84 (m, 2H), 4.48 (d, J = 6.0 Hz, 2H), 4.36 - 4.22 (m, 4H), 3.81 (s, 3H), 2.93 (s, 3H), 1.28 (s, 3H) Example 359: 1 1H NMR (400 MHz, DMSO-d6) δ = 9.71 (s, 1H), 7.92 (d, J = 8.6 Hz, 2H), 7.35 (t, J = 73.8 Hz, 1H), 7.30 (s, 1H), 7.26 (d, J = 8.6 Hz, 2H), 6.95 (d, J = 10.5 Hz, 2H), 6.64 (s, 1H), 5.45 - 5.41 (m, 1H), 3.99 (dd, J = 10.3, 4.9 Hz, 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) Example 360: 11H NMR (400 MHz, DMSO-d6) δ = 9.71 (s, 1H), 7.92 (d, J = 8.8 Hz, 2H), 7.35 (t, J = 73.4 Hz, 1H), 7.30 (s, 1H), 7.26 (d, J = 8.6 Hz, 2H), 6.95 (d, J = 10.8 Hz, 2H), 6.64 (s, 1H), 5.47 - 5.37 (m, 1H), 3.99 (dd, J = 10.1, 4.8 Hz, 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)

[0228] Example 361: 1 1H NMR (400 MHz, DMSO-d6) δ = 9.68 (s, 1H), 7.91 (d, J = 8.6 Hz, 2H), 7.56 (s, 1H), 7.35 (t, J = 73.4 Hz, 1H), 7.25 (d, J = 8.6 Hz, 2H), 7.10 (s, 1H), 6.94 (d, J = 10.0 Hz, 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 (brs, 3H), 2.11 - 2.06 (m, 2H), 1.86 - 1.82 (m, 3H) Example 362: 1 1H NMR (400 MHz, DMSO-d6) δ = 9.75 (s, 1H), 8.07 (s, 1H), 7.96 - 7.83 (m, 3H), 7.35 (t, J = 73.6 Hz, 1H), 7.26 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 10.0 Hz, 2H), 3.84 (s, 3H), 3.18 (s, 3H), 2.5 (s, 3H) Example 363: 11H NMR (400 MHz, DMSO-d6) δ = 9.65 (s, 1H), 7.91 (d, J = 8.5 Hz, 2H), 7.34 (t, J = 72.1 Hz, 1H), 7.31 (d, J = 2.0 Hz, 1H), 7.25 (d, J = 8.5 Hz, 2H), 6.94 (d, J = 10.0 Hz, 2H), 6.86 (d, J = 2.0 Hz, 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) Example 364: 1 1H NMR (400 MHz, DMSO-d6) δ = 9.66 (s, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.35 (t, J = 75.3 Hz, 1H), 7.25 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 10.0 Hz, 2H), 6.81 (d, J = 1.5 Hz, 1H), 6.29 (d, J = 1.5 Hz, 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) Example 365: 1 1H NMR (400 MHz, DMSO-d6) δ = 9.66 (s, 1H), 7.92 (d, J = 8.8 Hz, 2H), 7.35 (t, J = 73.6 Hz, 1H), 7.32 (d, J = 2.0 Hz, 1H), 7.26 (d, J = 8.6 Hz, 2H), 6.94 (d, J = 10.3 Hz, 2H), 6.87 (d, J = 2.0 Hz, 1H), 6.18 (tt, J = 55.5, 5.6 Hz, 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) Example 366: 11H NMR (400 MHz, DMSO-d6) δ = 9.67 (s, 1H), 7.92 (d, J = 8.6 Hz, 2H), 7.33 (t, J = 73.6 Hz, 1H), 7.28 - 7.24 (m, 3H), 7.00 - 6.82 (m, 3H), 3.91 (s, 3H), 3.84 (s, 3H), 3.69 (brd, J = 12.0 Hz, 2H), 3.24 (s, 3H), 2.91 (s, 3H), 2.89 - 2.80 (m, 3H), 2.00 (brd, J = 12.2 Hz, 2H), 1.91 - 1.76 (m, 2H) Example 367: 1 1H NMR (400 MHz, DMSO-d6) δ = 9.67 (s, 1H), 7.99 - 7.84 (m, 2H), 7.35 (t, J = 75.1 Hz, 1H), 7.33 (d, J = 2.0 Hz, 1H), 7.26 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 10.0 Hz, 2H), 6.84 (d, J = 2.2 Hz, 1H), 3.90 (s, 3H), 3.84 (s, 3H), 3.80 - 3.33 (brs, 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) Example 368: 1 1H NMR (400 MHz, DMSO-d6) δ = 9.66 (s, 1H), 7.91 (d, J = 8.6 Hz, 2H), 7.35 (t, J = 75.1 Hz, 1H), 7.32 (d, J = 2.0 Hz, 1H), 7.25 (d, J = 8.6 Hz, 2H), 6.94 (d, J = 10.0 Hz, 2H), 6.87 (d, J = 2.2 Hz, 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) Example 369: 11H NMR (400 MHz, DMSO-d6) δ = 9.66 (s, 1H), 8.09 (d, J = 8.5 Hz, 1H), 7.97 (d, J = 8.5 Hz, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.33 (t, J = 74.3 Hz, 1H), 7.24 (d, J = 8.8 Hz, 2H), 6.98 - 6.86 (m, 2H), 4.21 - 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) Example 370: 1 1H NMR (400 MHz, DMSO-d6) δ = 9.66 (s, 1H), 8.09 (d, J = 8.5 Hz, 1H), 7.97 (d, J = 8.5 Hz, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.33 (t, J = 74.3 Hz, 1H), 7.24 (d, J = 8.8 Hz, 2H), 6.98 - 6.86 (m, 2H), 4.21 - 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)

[0229] Example 371: 1 1H NMR (400 MHz, DMSO-d6) δ = 9.68 (s, 1H), 8.10 (d, J = 8.8 Hz, 1H), 7.98 (d, J = 8.6 Hz, 1H), 7.92 (d, J = 8.6 Hz, 2H), 7.34 (t, J = 74.1 Hz, 1H), 7.24 (d, J = 8.6 Hz, 2H), 6.92 (d, J = 10.5 Hz, 2H), 4.00 (s, 3H), 3.83 (s, 3H), 2.98 (s, 3H) Example 372: 11H NMR (400 MHz, DMSO-d6) δ = 9.69 (s, 1H), 8.10 - 7.98 (m, 2H), 7.92 (d, J = 8.8 Hz, 2H), 7.34 (t, J = 73.8 Hz, 1H), 7.25 (d, J = 8.6 Hz, 2H), 6.99 - 6.86 (m, 2H), 4.85 (t, J = 5.8 Hz, 1H), 4.34 (t, J = 4.8 Hz, 2H), 3.83 (s, 3H), 3.74 (q, J = 5.8 Hz, 2H), 3.04 (s, 3H) Example 373: 1 1H NMR (400 MHz, DMSO-d6) δ = 9.68 (s, 1H), 8.10 - 8.00 (m, 2H), 7.92 (brd, J = 8.8 Hz, 2H), 7.34 (t, J = 73.8 Hz, 1H), 7.24 (d, J = 8.6 Hz, 2H), 6.99 - 6.86 (m, 2H), 4.93 (d, J = 3.9 Hz, 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 = 3.9 Hz, 3H) (mixture of atropisomers convertible to each other) Example 374: 1 1H NMR (400 MHz, DMSO-d6) δ = 9.69 (brs, 1H), 8.11 - 8.03 (m, 1H), 8.03 - 7.95 (m, 1H), 7.92 (brd, J = 8.8 Hz, 2H), 7.34 (t, J = 74.1 Hz, 1H), 7.24 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 10.5 Hz, 2H), 4.22 (t, J = 5.3 Hz, 2H), 3.83 (s, 3H), 3.40 - 3.10 (brs, 2H), 3.00 (s, 3H), 2.89 (t, J = 5.3 Hz, 2H) Example 375: 11H NMR (400 MHz, 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 = 73.4 Hz, 1H), 7.30 (d, J = 8.8 Hz, 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 (brs, 3H) Example 376: 1 1H NMR (400 MHz, DMSO-d6) δ = 9.66 (s, 1H), 7.91 (d, J = 8.5 Hz, 2H), 7.35 (t, J = 73.3 Hz, 1H), 7.29 - 7.20 (m, 3H), 6.93 (d, J = 10.0 Hz, 2H), 6.88 (d, J = 2.0 Hz, 1H), 3.89 (s, 3H), 3.84 (s, 3H), 3.20 (s, 3H), 2.48 (s, 3H) Example 377: 1 1H NMR (400 MHz, DMSO-d6) δ = 9.67 (s, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.34 (t, J = 75.6 Hz, 1H), 7.24 (d, J = 8.8 Hz, 2H), 6.99 (m, 3H), 6.94 (d, J = 10.3 Hz, 1H), 4.78 (sept, J = 6.0 Hz, 1H), 4.63 (s, 1H), 4.06 (s, 2H), 3.82 (s, 3H), 3.22 (s, 3H), 1.33 (d, J = 6.0 Hz, 6H), 1.20 (s, 6H) Example 378: 11H NMR (400 MHz, DMSO-d6) δ = 9.68 (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), 7.02 (d, J = 1.8 Hz, 1H), 6.94 (d, J = 10.3 Hz, 2H), 6.31 (d, J = 1.8 Hz, 1H), 4.84 (t, J = 5.4 Hz, 1H), 4.78 (sept, J = 6.0 Hz, 1H), 4.30 (t, J = 5.4 Hz, 2H), 3.83 (s, 3H), 3.74 (q, J = 5.4 Hz, 2H), 3.23 (s, 3H), 1.33 (d, J = 6.0 Hz, 6H) Example 379: 1 1H NMR (400 MHz, DMSO-d6) δ = 9.68 (s, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.34 (t, J = 72.3 Hz, 1H), 7.24 (d, J = 8.8 Hz, 2H), 7.04 (d, J = 1.8 Hz, 1H), 6.93 (d, J = 10.0 Hz, 2H), 6.31 (d, J = 1.8 Hz, 1H), 4.41 (t, J = 7.4 Hz, 2H), 4.36 (s, 1H), 3.87 (s, 3H), 3.82 (s, 3H), 3.23 (s, 3H), 1.86 (t, J = 7.4 Hz, 2H), 1.17 (s, 6H) Example 380: 1 1H NMR (400 MHz, DMSO-d6) δ = 9.70 (s, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.34 (t, J = 74.8 Hz, 1H), 7.24 (d, J = 8.8 Hz, 2H), 7.09 (d, J = 1.8 Hz, 1H), 6.94 (d, J = 10.5 Hz, 2H), 6.63 (brd, J = 6.3 Hz, 1H), 6.39 (d, J = 1.8 Hz, 1H), 4.58 (dd, J = 11.4, 3.9 Hz, 1H), 4.52 - 4.43 (m, 1H), 4.35 (dd, J = 11.4, 7.0 Hz, 1H), 3.88 (s, 3H), 3.82 (s, 3H), 3.19 (s, 3H)

[0230] Example 381: 11H NMR (400 MHz, DMSO-d6) δ = 9.70 (s, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.35 (t, J = 72.3 Hz, 1H), 7.25 (d, J = 8.8 Hz, 2H), 7.09 (d, J = 2.0 Hz, 1H), 6.94 (d, J = 10.5 Hz, 2H), 6.66 - 6.56 (m, 1H), 6.39 (d, J = 2.0 Hz, 1H), 4.61 - 4.58 (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) Example 382: 1 1H NMR (400 MHz, DMSO-d6) δ = 9.70 (s, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.34 (t, J = 73.5 Hz, 1H), 7.24 (d, J = 8.8 Hz, 2H), 7.04 (d, J = 1.8 Hz, 1H), 6.93 (d, J = 10.5 Hz, 2H), 6.33 (d, J = 1.8 Hz, 1H), 5.25 (quin, J = 5.1 Hz, 1H), 4.89 (brs, 1H), 3.87 (s, 3H), 3.82 (s, 3H), 3.68 - 3.55 (m, 4H), 3.28 (s, 3H), 3.20 (s, 3H) Example 383: 1 1H NMR (400 MHz, DMSO-d6) δ = 9.70 (s, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.34 (t, J = 74.8 Hz, 1H), 7.24 (d, J = 8.8 Hz, 2H), 7.09 (d, J = 1.8 Hz, 1H), 6.94 (d, J = 10.5 Hz, 2H), 6.63 (brd, J = 6.3 Hz, 1H), 6.39 (d, J = 1.8 Hz, 1H), 4.58 (dd, J = 11.4, 3.9 Hz, 1H), 4.52 - 4.43 (m, 1H), 4.35 (dd, J = 11.4, 7.0 Hz, 1H), 3.88 (s, 3H), 3.82 (s, 3H), 3.19 (s, 3H) Example 384: 11H NMR (400 MHz, DMSO-d6) δ = 9.67 (s, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.34 (t, J = 74.8 Hz, 1H), 7.24 (d, J = 8.5 Hz, 2H), 7.06 (d, J = 2.0 Hz, 1H), 6.93 (d, J = 10.3 Hz, 2H), 6.39 (d, J = 2.0 Hz, 1H), 4.99 (t, J = 5.4 Hz, 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 = 5.4 Hz, 2H), 3.23 (s, 3H) Example 385: 1 1H NMR (400 MHz, DMSO-d6) δ = 9.69 (s, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.35 (t, J = 73.0 Hz, 1H), 7.25 (d, J = 8.8 Hz, 2H), 7.06 (d, J = 2.0 Hz, 1H), 6.93 (d, J = 10.3 Hz, 2H), 6.44 (d, J = 2.0 Hz, 1H), 4.38 (d, J = 20.0 Hz, 2H), 3.90 (s, 3H), 3.83 (s, 3H), 3.32 (s, 3H), 1.44 (d, J = 19.0 Hz, 6H) Example 386: 1 1H NMR (400 MHz, DMSO-d6) δ = 9.69 (s, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.34 (t, J = 71.5 Hz, 1H), 7.26 (d, J = 8.8 Hz, 2H), 7.04 (d, J = 2.0 Hz, 1H), 6.93 (d, J = 10.5 Hz, 2H), 6.33 (d, J = 2.0 Hz, 1H), 5.25 (quin, J = 5.2 Hz, 1H), 4.89 (brs, 1H), 3.87 (s, 3H), 3.82 (s, 3H), 3.68 - 3.56 (m, 4H), 3.28 (s, 3H), 3.20 (s, 3H) Example 387: 11H NMR (400 MHz, DMSO-d6) δ = 9.69 (s, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.35 (t, J = 72.3 Hz, 1H), 7.25 (d, J = 8.5 Hz, 2H), 7.11 (d, J = 1.8 Hz, 1H), 6.95 (d, J = 10.3 Hz, 2H), 6.49 (d, J = 2.0 Hz, 1H), 4.60 (t, J = 12.9 Hz, 2H), 3.90 (s, 3H), 3.83 (s, 3H), 3.21 (s, 3H), 1.76 (t, J = 19.1 Hz, 3H) Example 388: 1 1H NMR (400 MHz, DMSO-d6) δ = 9.67 (s, 1H), 8.31 (d, J = 3.0 Hz, 1H), 7.91 (d, J = 8.5 Hz, 2H), 7.77 - 7.71 (m, 1H), 7.69 - 7.63 (m, 1H), 7.34 (t, J = 73.0 Hz, 1H), 7.24 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 10.3 Hz, 2H), 4.61 - 4.50 (brs, 1H), 4.13 (t, J = 4.9 Hz, 2H), 3.82 (s, 3H), 3.76 (t, J = 4.9 Hz, 2H), 3.11 (s, 3H) Example 389: 1 1H NMR (400 MHz, DMSO-d6) δ = 9.69 (s, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.34 (t, J = 73.3 Hz, 1H), 7.25 (d, J = 8.5 Hz, 2H), 7.14 (d, J = 1.8 Hz, 1H), 6.94 (d, J = 10.3 Hz, 2H), 6.56 (d, J = 1.8 Hz, 1H), 5.02 (q, J = 9.0 Hz, 2H), 3.91 (s, 3H), 3.83 (s, 3H), 3.20 (s, 3H) Example 390: 11H NMR (400 MHz, DMSO-d6) δ = 9.70 (s, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.35 (t, J = 72.3 Hz, 1H), 7.25 (d, J = 8.8 Hz, 2H), 7.09 (d, J = 2.0 Hz, 1H), 6.99 - 6.88 (m, 2H), 6.66 - 6.56 (m, 1H), 6.39 (d, J = 2.0 Hz, 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)

[0231] Example 391: 1 1H NMR (400 MHz, DMSO-d6) δ = 9.66 (s, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.34 (t, J = 73.5 Hz, 1H), 7.29 - 7.21 (m, 3H), 6.93 (d, J = 10.3 Hz, 2H), 6.88 (d, J = 2.0 Hz, 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) Example 392: 1 1H NMR (400 MHz, DMSO-d6) δ = 9.69 (s, 1H), 7.96 - 7.83 (m, 3H), 7.44 (d, J = 7.5 Hz, 1H), 7.34 (t, J = 74.6 Hz, 1H), 7.25 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 10.3 Hz, 2H), 6.79 (d, J = 8.3 Hz, 1H), 4.65 (brs, 1H), 4.09 (s, 2H), 3.83 (s, 3H), 3.22 (s, 3H), 1.21 (s, 6H) Example 393: 11H NMR (400 MHz, DMSO-d6) δ = 9.66 (brs, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.34 (t, J = 72.0 Hz, 1H), 7.29 - 7.18 (m, 3H), 6.92 (d, J = 10.0 Hz, 2H), 6.86 (d, J = 2.0 Hz, 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 = 6.0 Hz, 3H) Example 394: 1 1H NMR (400 MHz, DMSO-d6) δ = 9.66 (brs, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.34 (t, J = 72.0 Hz, 1H), 7.29 - 7.18 (m, 3H), 6.92 (d, J = 10.0 Hz, 2H), 6.86 (d, J = 2.0 Hz, 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 = 6.0 Hz, 3H) Example 395: 1 1H NMR (400 MHz, DMSO-d6) δ = 9.57 (s, 1H), 7.96 - 7.89 (m, 2H), 7.72 (dd, J = 7.0, 2.0 Hz, 1H), 7.33 (t, J = 73.5 Hz, 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 = 6.9 Hz, 1H), 3.82 (s, 3H), 3.54 (s, 3H), 3.00 (s, 3H) Example 396: 11H NMR (400 MHz, DMSO-d6) δ = 9.66 (s, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.34 (t, J = 73.5 Hz, 1H), 7.29 - 7.21 (m, 3H), 6.93 (d, J = 10.3 Hz, 2H), 6.88 (d, J = 2.0 Hz, 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) Example 397: 1 1H NMR (500 MHz, DMSO-d6) δ 9.74 (s, 1H), 8.76 (d, J = 5.0 Hz, 1H), 8.09 (s, 1H), 7.90 (brd, J = 8.4 Hz, 2H), 7.54 (brd, J = 4.9 Hz, 1H), 7.31 (t, J = 73.6 Hz, 1H), 7.25 (brd, J = 8.2 Hz, 2H), 7.22 (t, J = 55.0 Hz, 1H), 6.93 (brd, J = 10.8 Hz, 2H), 3.20 (s, 2H) Example 398: 1 1H NMR (500 MHz, DMSO-d6) δ 9.93 (s, 1H), 7.95 (brd, J = 8.5 Hz, 2H), 7.60 (brd, J = 7.9 Hz, 2H), 7.47 (brd, J = 8.2 Hz, 2H), 7.00 (d, J = 1.2 Hz, 1H), 6.33 (d, J = 1.5 Hz, 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) Example 399: 11H NMR (500 MHz, DMSO-d6) δ 9.81 (s, 1H), 7.90 (brd, 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) Example 400: 1 1H NMR (500 MHz, DMSO-d6) δ 7.91 (brd, 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)

[0232] Example 401: 1 1H NMR (500 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.01 (t, J = 8.0 Hz, 1H), 7.90 (brd, J = 8.5 Hz, 2H), 7.87 (brd, J = 7.9 Hz, 2H), 7.74 (brd, J = 8.0 Hz, 1H), 7.63 (d, J = 7.7 Hz, 1H), 7.33 (t, J = 72.3 Hz, 1H), 7.25 (brd, J = 8.5 Hz, 2H), 3.43 (s, 3H), 1.50 (s, 6H) Example 402: 1 1H NMR (500 MHz, DMSO-d6) δ 9.87 (brs, 1H), 8.87 (brs, 1H), 8.24 (brs, 1H), 7.95 (brd, J = 5.2 Hz, 2H), 7.74 (brs, 1H), 7.46 (brd, J = 6.1 Hz, 2H), 6.93 (brd, J = 12.2 Hz, 2H), 3.62 (brs, 3H), 3.23 (brs, 3H) Example 403: 11H 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 (brd, J = 7.9 Hz, 2H), 7.18 (brd, 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) Example 404: 1 1H NMR (500 MHz, DMSO-d6) δ 9.69 (s, 1H), 7.99 (brt, J = 7.8 Hz, 1H), 7.92 (brd, J = 8.2 Hz, 2H), 7.74 (brd, J = 7.9 Hz, 1H), 7.61 (brd, J = 7.9 Hz, 1H), 7.34 (t, J = 1.0 Hz, 1H), 7.26 (brd, J = 8.5 Hz, 2H), 6.94 (brt, J = 10.4 Hz, 2H), 3.91 (s, 3H), 3.24 (s, 3H), 1.50 (s, 6H) Example 405: 1 1H 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 (brd, J = 8.2 Hz, 2H), 6.95 (brd, J = 10.4 Hz, 2H), 3.24 (s, 3H), 1.50 (s, 6H) Example 406: 1 1H NMR (500 MHz, DMSO-d6) δ 9.94 (s, 1H), 8.00 (brt, J = 7.9 Hz, 1H), 7.95 (brd, J = 8.2 Hz, 2H), 7.73 (brd, J = 7.9 Hz, 1H), 7.61 (brdd, J = 15.9, 7.9 Hz, 3H), 7.47 (brd, J = 8.2 Hz, 2H), 3.26 (s, 3H), 1.50 (s, 6H) Example 407: 11H NMR (500 MHz, chloroform-d) δ 7.96 - 7.88 (m, 2H), 7.83 (d, J = 8.7 Hz, 2H), 7.37 (brd, J = 8.5 Hz, 1H), 7.16 (d, J = 8.6 Hz, 2H), 7.10 (d, J = 7.4 Hz, 2H), 6.57 (t, J = 75.9 Hz, 1H), 3.24 (s, 3H), 1.62 (s, 6H) Example 408: 1 1H NMR (500 MHz, DMSO-d6) δ 7.95 (brd, J = 8.5 Hz, 2H), 7.60 (brd, J = 7.9 Hz, 2H), 7.47 (brd, J = 8.2 Hz, 2H), 6.98 (s, 1H), 6.33 (s, 1H), 4.79 (dt, J = 12.1, 6.0 Hz, 1H), 4.06 (s, 2H), 3.25 (s, 3H), 1.34 (d, J = 6.1 Hz, 6H), 1.21 (s, 6H)

[0233] It will be apparent to those skilled in the art that the disclosure of the present invention is not limited to the embodiments described above as illustrative, and that it can be embodied in other specific forms without departing from its essential characteristics. Therefore, the embodiments are to be considered in all respects as illustrative and not restrictive, and reference is rather made to the appended claims than to the above-described embodiments. Thus, all modifications that fall within the meaning and scope equivalent to the claims are intended to be included therein.

Claims

1. Formula I: 【Chemical 1】 [Wherein: R １ is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxycarbonylalkyl, cycloalkyl, (Ar １ )alkyl, or Ar １ ; Ar １ is cycloalkyl, piperidinyl, phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furanyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, or quinoxalinyl, substituted with 0 to 2 R ５ａ and 0 to 2 R ５ｂ ; R ２ is alkyl or haloalkyl; R ３ is phenyl or pyridinyl, and one R ３ａ and zero to two R ３ｂ are substituted; R ３ａ is a halo, alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy, or cycloalkyl substituent that is para to the pyrazole-3-one moiety; R ３ｂ is a halo, alkyl, hydroxy, or haloalkyl; Alternatively, R ３ａ and the adjacent R ３ｂ together with the two carbon atoms to which they are attached form a 3- to 6-membered heterocyclyl (containing a carbon atom and 1 to 3 heteroatoms selected from N, NH, O, S, and substituted with 0 to 3 halo, hydroxy, alkyl, haloalkyl, or alkoxycarbonyl); R ４ is phenyl or pyridinyl, and one R ４ａ and zero to two R ４ｂ are substituted; R ４ａ is a halo, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, or pyrazolyl substituent that is para to the amide moiety; R ４ｂ is a halo or haloalkyl; R ５ａ and R ５ｂ are each, independently, cyano, halo, alkyl, haloalkyl, alkoxyalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkoxy, hydroxyalkoxy, haloalkoxy, hydroxyhaloalkoxy, hydroxyalkoxyalkoxy, alkylsulfonylalkoxy, carboxamide, alkoxycarbonyl, alkylaminoalkyl, alkoxycarbonylalkoxy, hydroxyalkylcycloalkylalkyl, alkylsulfonyl, aminocarbonylalkyl, -NR ７ R ８ , cycloalkyl (substituted with 0 to 3 halo, hydroxy, alkyl, or alkoxy), phenyl (substituted with 0 to 3 halo, hydroxy, or alkyl), 4- to 8-membered heterocyclyl (containing a carbon atom and 1 to 3 heteroatoms selected from N, NH, O, S, and substituted with 0 to 3 halo, alkyl, hydroxyalkyl, haloalkyl, alkoxycarbonyl, or alkylsulfonyl), heterocyclyloxy, heterocyclylalkyl, or heterocyclylalkoxy, wherein the heterocyclyl moiety of the heterocyclyloxy, heterocyclylalkyl, and heterocyclylalkoxy contains 4 to 8 carbon atoms and 1 to 3 heteroatoms selected from N, NH, O, S, and is substituted with 0 to 3 halo, hydroxy, hydroxyalkyl, alkyl, or haloalkyl; R ６ is hydrogen or lower alkyl; R ７ and R ８ are each, independently, hydrogen, alkyl, haloalkyl, hydroxyalkyl, halohydroxyalkyl, alkoxyalkyl, aminocarbonylalkyl, alkylsulfonyl; alkylaminocarbonylalkyl, cycloalkylaminocarbonylalkyl, cycloalkylalkyl, hydroxycycloalkylalkyl, hydroxyalkylcycloalkylalkyl, cycloalkylalkyl, cycloalkyl (wherein each cycloalkyl is substituted with 0 to 3 halo, hydroxy, or alkyl, or hydroxyalkyl), or a 5- to 8-membered heterocyclyl (containing a carbon atom and 1 to 3 heteroatoms selected from N, NH, O, S, and substituted with 0 to 3 halo, hydroxy, alkyl, haloalkyl, or alkoxycarbonyl); Alternatively, R ７ and R ８ together with the nitrogen to which they are attached form a 5- to 12-membered heterocycle (containing a carbon atom and 0 to 3 additional heteroatoms selected from N, NH, O, S and substituted with 0 to 5 halo, hydroxy, alkyl, alkoxy, oxo, haloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, alkylsulfonyl, alkylsulfonylalkyl, aminocarbonyl, or alkoxycarbonyl). The compound represented by or a pharmaceutically acceptable salt thereof.

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

3. R ２ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R is alkyl or haloalkyl.

4. R ３ is phenyl (one R ３ａ and 0 to 2 R ３ｂ substituted); R ３ａ is a halo, alkyl, haloalkyl, alkoxy, or deuterated alkoxy substituent that is para to the pyrazole-3-one moiety; and R ３ｂ is a halo or haloalkyl, The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

5. R ４ is one R para to the amide moiety ４ａ substituted with, and 0 to 2 R ４ｂ substituted phenyl or pyridinyl; R ４ａ is halo, alkyl, cycloalkyl, haloalkyl, alkoxy, or haloalkoxy; R ４ｂ is a halo or haloalkyl, The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

6. Formula II: [Chemical 2] [Wherein: Ar １ is [Chemical 3] is; R ２ is alkyl or haloalkyl; R ３ａ is halo, alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy or cycloalkyl; R ３ｂ is a halo, alkyl, hydroxy, or haloalkyl; Or R ３ａ and the adjacent R ３ｂ together with the two carbon atoms to which they are attached form a 3- to 6-membered heterocyclyl (containing a carbon atom and 1 to 3 heteroatoms selected from N, NH, O, S, and substituted with 0 to 3 halo, hydroxy, alkyl, haloalkyl, or alkoxycarbonyl); R ４ａ is halo, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, or pyrazolyl; R ５ａ and R ５ｂ are each independently cyano, halo, alkyl, haloalkyl, alkoxyalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkoxy, hydroxyalkoxy, haloalkoxy, hydroxyhaloalkoxy, hydroxyalkoxyalkoxy, alkylsulfonylalkoxy, carboxamide, alkoxycarbonyl, alkylaminoalkyl, alkoxycarbonylalkoxy, hydroxyalkylcycloalkylalkyl, alkylsulfonyl, -NR ７ R ８ , cycloalkyl (substituted with 0 to 3 halo, hydroxy, alkyl, or alkoxy), phenyl (substituted with 0 to 3 halo, hydroxy, or alkyl), 4- to 8-membered heterocyclyl (containing 1 to 3 heteroatoms selected from carbon atoms and N, O, NH, S, and substituted with 0 to 3 halo, alkyl, hydroxyalkyl, haloalkyl, alkoxycarbonyl, or alkylsulfonyl), heterocyclyloxy, heterocyclylalkyl or heterocyclylalkoxy, wherein the heterocyclyl moiety of the heterocyclyloxy and heterocyclylalkoxy contains 4 to 8 carbon atoms and 1 to 3 heteroatoms selected from N, NH, O, S, and is substituted with 0 to 3 halo, hydroxy, hydroxyalkyl, alkyl, or haloalkyl; and R ７ and R ８ are, independently, hydrogen, alkyl, haloalkyl, hydroxyalkyl, halohydroxyalkyl, alkoxyalkyl, aminocarbonylalkyl, alkylsulfonyl; alkylaminocarbonylalkyl, cycloalkylaminocarbonylalkyl, cycloalkylalkyl, hydroxycycloalkylalkyl, hydroxyalkylcycloalkylalkyl, cycloalkylalkyl, cycloalkyl (where each cycloalkyl is substituted with 0 to 3 halo, hydroxy, or alkyl, or hydroxyalkyl), or a 5- to 8-membered heterocyclyl (containing a carbon atom and 1 to 3 heteroatoms selected from N, NH, O, S, and substituted with 0 to 3 halo, hydroxy, alkyl, haloalkyl, or alkoxycarbonyl); Or R ７ and R ８ together with the nitrogen to which they are attached form a 5- to 12-membered heterocycle (containing carbon atoms and 0 to 3 additional heteroatoms selected from N, NH, O, S, and substituted with 0 to 5 halo, hydroxy, alkyl, alkoxy, oxo, haloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, alkylsulfonyl, alkylsulfonylalkyl, aminocarbonyl, or alkoxycarbonyl). The compound according to any one of claims 1 to 5 represented by or a pharmaceutically acceptable salt thereof.

7. Ar １ is 【Chemical Formula 4】 is; R ５ａ is cyano, halo, alkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, alkoxy, haloalkoxy, carboxamide, alkoxycarbonyl, -NR ７ R ８ , cycloalkyl (substituted with 0 to 1 halo, hydroxy, alkyl, or alkoxy), phenyl (substituted with 0 to 1 halo, hydroxy, or alkyl), or 5- to 8-membered heterocyclyl (containing a carbon atom and 1 to 3 heteroatoms selected from N, NH, O, S, and substituted with 0 to 1 halo, hydroxy, or alkyl); R ５ｂ is cyano, halo, alkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, alkoxy, haloalkoxy, carboxamide, alkoxycarbonyl, or cycloalkyl; R ７ and R ８ are each independently hydrogen, alkyl, haloalkyl, or hydroxyalkyl; or R ７ and R ８ together with the nitrogen to which they are attached form a heterocycle (having 0 to 3 additional heteroatoms selected from N, NH, O, S and substituted with 0 to 3 halo, hydroxy, alkyl, alkoxy, or oxo). The compound according to claim 6 or a pharmaceutically acceptable salt thereof.

8. Ar １ is 【Chemical Formula 5】 is; R ５ａ is alkyl, hydroxyalkyl, -NR ７ R ８ , cyclobutyl (substituted with 0 to 1 halo, hydroxy, alkyl, alkoxy), or phenyl; R ５ｂ is an alkoxy; R ７ and R ８ are each independently alkyl or hydroxyalkyl; or R ７ and R ８ together with the nitrogen to which they are attached form a heterocycle (having 0 to 2 additional nitrogen atoms and substituted with 0 to 3 halo, hydroxy, alkyl, alkoxy, or oxo). The compound according to claim 7 or a pharmaceutically acceptable salt thereof.

9. R ５ａ is -NR ７ R ８ and; R ７ and R ８ is independently alkyl or hydroalkyl; or R ７ and R ８ together with the nitrogen to which they are attached form 【Chemical Formula 6】 forming The compound according to claim 8 or a pharmaceutically acceptable salt thereof.

10. Ar １ is 【Chemical Formula 7】 is; R ５ａ is cyano, halo, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, -NR ７ R ８ , or cycloalkyl (substituted with 0 to 1 alkoxy); R ５ｂ is cyano, halo, alkyl, or haloalkyl; R ７ and R ８ are each independently alkyl or hydroxyalkyl; or R ７ and R ８ together with the nitrogen to which they are attached, 【Chemical Formula 8】 forming The compound according to claim 6 or a pharmaceutically acceptable salt thereof.

11. Ar １ is 【Chemical Formula 9】 is; R ５ａ is cyano, halo, alkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, alkoxy, or haloalkoxy; R ５ｂ is cyano, halo, alkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, alkoxy, or haloalkoxy, The compound according to claim 6 or a pharmaceutically acceptable salt thereof.

12. Ar １ is 【Chemical 10】 being; R ５ａ is alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, or cycloalkyl, The compound according to claim 6 or a pharmaceutically acceptable salt thereof.

13. Ar １ is 【Chemical 11】 is; R ５ａ is halo, alkoxy, haloalkoxy, carboxamide, alkoxycarbonyl, or cycloalkyl (substituted with 0 to 1 hydroxy); R ５ｂ is cyano, halo, alkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, alkoxy, haloalkoxy, carboxamide, alkoxycarbonyl, or cycloalkyl, The compound according to claim 6 or a pharmaceutically acceptable salt thereof.

14. Ar １ is 【Chemical 12】 is; R ５ａ is cyano, halo, alkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, or alkoxy; R ５ｂ is cyano, halo, alkyl, or haloalkyl, The compound according to claim 6 or a pharmaceutically acceptable salt thereof.

15. Ar １ is 【Chemical 13】 is; R ５ａ is a halo; R ５ｂ is a halo, The compound according to claim 6 or a pharmaceutically acceptable salt thereof.

16. Ar １ is 【Chemical Formula 14】 is; R ５ａ is halo, alkyl, alkoxy, or haloalkoxy; R ５ｂ is halo, alkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, alkoxy, or haloalkoxy, The compound according to claim 6 or a pharmaceutically acceptable salt thereof.

17. Formula III: 【Chemical Formula 15】 [Wherein: R ２ is alkyl or haloalkyl; R ３ａ is halo, alkyl, haloalkyl, alkoxy, deuterated alkoxy, haloalkoxy or cycloalkyl; R ３ｂ is a halo, alkyl, hydroxy, or haloalkyl; Alternatively, R ３ａ and the adjacent R ３ｂ together with the two carbon atoms to which they are attached, contain a carbon atom and 1 to 3 heteroatoms selected from N, NH, O, S, and form a 3- to 6-membered heterocyclyl substituted with 0 to 3 halo, hydroxy, alkyl, haloalkyl, or alkoxycarbonyl; R ４ａ is halo, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, or pyrazolyl; R ５ａ is halo, hydroxyalkyl, alkoxy, alkoxyalkoxy, hydroxyalkoxy, alkylaminoalkyl, alkoxycarbonylalkoxy, hydroxyalkylcycloalkylalkyl, alkylsulfonyl, aminocarbonylalkyl, hydroxyalkylcycloalkylalkyl, -NR ７ R ８ , a 5- to 8-membered heterocyclyl (containing a carbon atom and 1 to 3 heteroatoms selected from N, NH, O, S, and substituted with 0 to 3 halo, hydroxy, alkyl, haloalkyl, alkoxycarbonyl, or alkylsulfonyl), or heterocyclylalkyl (wherein heterocyclyl contains 5 to 8 carbon atoms and 1 to 3 heteroatoms selected from N, NH, O, S, and is substituted with 0 to 3 halo, hydroxy, alkyl, or haloalkyl); R ５ｂ is cyano, halo, allyl, alkoxy, or haloalkyl; R ７ and R ８ are, independently, hydrogen, alkyl, haloalkyl, hydroxyalkyl, halohydroxyalkyl, alkoxyalkyl, aminocarbonylalkyl, alkylsulfonyl; alkylaminocarbonylalkyl, cycloalkylaminocarbonylalkyl, cycloalkylalkyl, hydroxycycloalkylalkyl, hydroxyalkylcycloalkylalkyl, cycloalkylalkyl, cycloalkyl (wherein each cycloalkyl is substituted with 0 to 3 halo, hydroxy, or alkyl, or hydroxyalkyl), or a 5- to 8-membered heterocyclyl (containing a carbon atom and 1 to 3 heteroatoms selected from N, NH, O, S, and substituted with 0 to 3 halo, hydroxy, alkyl, haloalkyl, or alkoxycarbonyl); Or R ７ and R ８ together with the nitrogen to which they are attached form a 5- to 12-membered heterocycle (containing a carbon atom and 0 to 3 additional heteroatoms selected from N, NH, O, S, and substituted with 0 to 5 halo, hydroxy, alkyl, alkoxy, oxo, haloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, alkylsulfonyl, alkylsulfonylalkyl, aminocarbonyl, or alkoxycarbonyl)] The compound according to claim 6 represented by or a pharmaceutically acceptable salt thereof.

18. Formula IV: 【Chemical 16】 [Wherein: R ５ａ is halo, hydroxyalkyl, alkoxy, alkoxyalkoxy, hydroxyalkoxy, hydroxyalkylcycloalkylalkyl, aminocarbonylalkyl, -NR ７ R ８ or 【Chemical 17】 is; R ５ｂ is a halo or haloalkyl; R ７ and R ８ each independently is hydrogen, alkyl, hydroxyalkyl, halohydroxyalkyl, alkoxyalkyl, aminocarbonylalkyl, hydroxycycloalkylalkyl, hydroxyalkylcycloalkylalkyl, cycloalkylalkyl, cycloalkyl, 【Chemical Formula 18】 or is; Or R ７ and R ８ together with the nitrogen to which they are attached, 【Chemical Formula 19】 forming The compound according to claim 17 represented by or a pharmaceutically acceptable salt thereof.

19. Formula V: 【Chemical formula 20】 [Wherein: R ５ａ is halo, hydroxyalkyl, alkoxyalkoxy, hydroxyalkoxy, -NR ７ R ８ or 【Chemical 21】 is; R ５ｂ is Cl or CF ３ ; R ７ is hydrogen; R ８ is alkyl, hydroxyalkyl, halohydroxyalkyl, alkoxyalkyl, aminocarbonylalkyl, hydroxycycloalkylalkyl, hydroxyalkylcycloalkylalkyl, cycloalkylalkyl, cycloalkyl, 【Chemical 22】 or is; Alternatively, R ７ and R ８ together with the nitrogen to which they are attached, 【Chemical 23】 forming The compound according to claim 18 represented by or a pharmaceutically acceptable salt thereof.

20. Formula VI: 【Chemical 24】 [Wherein: R ３ａ is halo, alkyl, haloalkyl, alkoxy, haloalkoxy, or deuterated alkoxy; R ３ｂ is a halo; R ４ａ is a haloalkoxy; R ５ａ is cyano, halo, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkoxy, hydroxyalkoxy, hydroxyhaloalkoxy, hydroxyalkoxyalkoxy, alkylsulfonylalkoxy, a 5- to 8-membered heterocyclyl (including a carbon atom and 1 to 3 heteroatoms selected from N, NH, O, S, and substituted with 0 to 3 halo, alkyl, hydroxyalkyl, haloalkyl, or alkylsulfonyl), or heterocyclylalkoxy (wherein the heterocyclyl includes 5 to 8 carbon atoms and 1 to 3 heteroatoms selected from N, NH, O, S, and is substituted with 0 to 3 halo, hydroxy, hydroxyalkyl, alkyl, or haloalkyl); R ５ｂ is cyano, alkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, a 5- to 8-membered heterocyclyl (including a carbon atom and 1 to 3 heteroatoms selected from N, NH, O, S, substituted with 0 to 3 halo, alkyl, or heterocyclyloxy, where the heterocyclyl moiety includes 5 to 8 carbon atoms and 1 to 3 heteroatoms selected from N, NH, O, S, and is substituted with 0 to 1 alkyl)] The compound according to claim 6 represented by or a pharmaceutically acceptable salt thereof.

21. R ５ａ is 【Chemical 25】 being; R ５ｂ is - OCH ３ or CH ３ is, The compound according to claim 20 or a pharmaceutically acceptable salt thereof.

22. Formula VII: 【Chemical 26】 [Wherein: R ３ａ is Cl, CF ３ , CH ３ , CH ３ CH ２ , CD ３ , OCH ３ , OCF ３ , OCF ２ , or OCD ３ ; R ４ａ is OCF ３ or OCF ２ and; R ５ａ is 【Chemical 27】 is] The compound according to claim 20 represented by or a pharmaceutically acceptable salt thereof.

23. Formula VIII: 【Chemical 28】 [Wherein: R ５ａ is cyano, alkyl, or haloalkyl; R ５ｂ is cyano, alkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, -NR ７ R ８ , 【Chemical Formula 29】 is; R ７ is hydrogen or alkyl; R ８ is alkyl or hydroxyalkyl] The compound according to claim 6 represented by or a pharmaceutically acceptable salt thereof.

24. A pharmaceutical composition comprising the compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

25. A pharmaceutical composition for the treatment of heart disease, comprising the compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof.

26. The pharmaceutical composition according to claim 25, wherein the heart disease is selected from the group consisting of angina pectoris, unstable angina pectoris, myocardial infarction, heart failure, acute coronary disease, acute heart failure, chronic heart failure, and cardiac iatrogenic injury.

27. Heart failure is selected from the group consisting of congestive heart failure, systolic heart failure, diastolic heart failure, heart failure with reduced left ventricular systolic function (HF Ｒ EF), and heart failure with preserved left ventricular systolic function (HF Ｐ EF), acute heart failure, and chronic heart failure of ischemic and non-ischemic origin, the pharmaceutical composition according to claim 26.

28. A pharmaceutical composition for use in therapy, comprising the compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof.

29. FPR2 EC ５０ A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the value is < 0.005 μM.

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