Naphthyridinone derivatives for the treatment of a disease or disorder

Abstract

This invention relates to compounds having formula (I): or pharmaceutically acceptable salts thereof, wherein A, R1 and R3 are as described herein, as well as compositions and methods of using such compounds.

Description

Technical Field

[0001] This invention relates to pyridone compounds, their use in inhibiting GIRK1 / 4 channels, and methods of using them to treat diseases or disorders. Prior Technology

[0002] A normal cardiac cycle begins in the sinoatrial node, which generates an excitatory electrical stimulus. This stimulus propagates in an orderly fashion throughout the atrial and ventricular myocardium to induce contraction (systole). At the cellular level, the excitatory electrical impulse triggers the cardiac action potential. The cardiac action potential is characterized by an initial rapid membrane depolarization, followed by a plateau phase, and then repolarization to return to the resting membrane potential. The cardiac action potential controls signal propagation throughout the heart. For example, the rate of initial cellular depolarization determines the speed at which the excitatory stimulus propagates. The duration of the repolarization phase determines the action potential duration (APD) and refractory period, or the time during which cardiomyocytes are unable to respond to another electrical stimulus.

[0003] Abnormalities in cardiac action potentials are associated with arrhythmias. For example, excessive reduction in action potential duration and associated effective refractory period can provide a basis for so-called reentrant tachyarrhythmia. In this condition, cardiac impulses do not propagate normally but instead feed back to themselves via excitable tissue to form a reentrant circuit (Waldo et al., Lancet 341, 1189-1193). Existing class III antiarrhythmic drugs are thought to work by prolonging the effective refractory period (APD) and associated effective refractory period (ERP), thereby minimizing the risk of re-excitation and subsequent formation of fibrillary reentrant circuits (Singh et al., British Journal of Pharmacology 39, 675-687).

[0004] Certain class III antiarrhythmic drugs (such as sotalol) are used to treat atrial fibrillation (AF). AF is the most common form of persistent arrhythmia in humans and is characterized by fibrillating contractions that affect atrial function. AF is associated with adverse cardiovascular events. In particular, the presence of AF is an independent risk factor for thromboembolic stroke, heart failure, and all-cause mortality (Estes et al., (2008). Journal of the American College of Cardiology 51, 865-884)(Fang et al., 2008. Journal of the American College of Cardiology 51, 810-815). AF can also reduce the quality of life for some patients by inducing palpitations and reducing exercise tolerance (Thrall et al., 2006. The American journal of medicine 119, 448.e441-419). The goal of antiarrhythmic therapy for AF is to avoid these adverse effects and outcomes.

[0005] A drawback of existing Class III antiarrhythmic drugs is that they prolong the effective refractory period of both the atria and ventricles. Excessive prolongation of ventricular tissue can prolong the QTc interval and may lead to arrhythmias. Some drugs with this mechanism of action (e.g., dofetilide) are known to induce potentially life-threatening ventricular arrhythmias, such as torsades de pointes (Redfern et al., 2003. Cardiovascular Research 58, 32-45). Therefore, there is a need for novel antiarrhythmic therapies for arrhythmia that selectively target atrial tissue rather than ventricular tissue.

[0006] The configuration and duration of cardiac action potentials are controlled at the cellular level through the action of multiple different transmembrane ion channels. For example, the initial depolarization phase is mediated by sodium influx via cardiac-specific Nav1.5 channels. Potassium channels are responsible for the later stages of repolarization and thus contribute to regulating the total duration of the action potential. In fact, class III antiarrhythmic drugs targeting potassium channels (e.g., dofetilide) prolong both the duration of the action potential and the effective refractory period. Several different types of transmembrane potassium channels exist (Schmitt et al., 2014. Physiological reviews 94, 609-653; Tamargo et al., 2004. Cardiovascular research 62, 9-33), including: • Voltage-gated channels (Kv1-9) • Calcium-activated channels (KCa1-2) • Dual-channel design (e.g., TASK) • Inward rectifier channels (Kir1-6)

[0007] While most cardiac potassium channels contribute to the repolarization of both atrial and ventricular tissues in humans, Kv1.5 and GIRK1 / 4 (i.e., G protein-regulated inward rectifier potassium channels 1 / 4) are thought to be present only in the atria (Gaborit et al., 2007. The Journal of Physiology 582, 675-693). This atrial-specific pattern of expression makes these particularly attractive targets for novel antiarrhythmic therapies for AF, as they do not have the adverse ventricular effects of existing class III drugs such as dofetilide.

[0008] Mammalians exhibit four distinct GIRK channels (GIRK 1, 2, 3, and 4; encoded by KCNJ3, KCNJ6, KCNJ9, and KCNJ5, respectively). These transmembrane proteins arrange themselves into tetramers (homoterams or heterotetramers) to form functional potassium channels (Krapivinsky et al., 1995. Nature 374, 135-141). These channels are ligand-gated (i.e., regulated by the binding of ligands to Gi protein-coupled receptors present in the same cell membrane). For example, the GIRK1 / 4 channel is a heterotetramer (two subunits of GIRK1 and GIRK4), strongly expressed in the sinoatrial and atrioventricular nodes, as well as in the atrial myocardium (Wickman et al., 1999. Annals of the New York Academy of Sciences 868, 386-398). One function of this channel is to regulate the autonomic regulation of heart rate. Acetylcholine released upon parasympathetic stimulation of the cardiac vagal efferent neurons binds to Gi-coupled M2 muscarinic receptors in the heart. This releases the Gβγ subunit, which in turn opens GIRK1 / 4 channels to allow potassium outflow from cardiomyocytes, thereby promoting membrane repolarization. In the spontaneously depolarizing pacemaker cells of the sinoatrial node, the intensity of this repolarization determines the time interval between depolarizations, thus determining the heart rate. Because the current mediated by GIRK1 / 4 channels is regulated by acetylcholine, it is called IKAch (Wickman et al., 1999).

[0009] Several pieces of evidence point to the GIRK1 / 4 lineage as a desired antiarrhythmic target for arrhythmias. In animals, vagal stimulation promotes the release of acetylcholine from the vagus nerve and an increase in IKAch. This, in turn, shortens the duration of atrial (but not ventricular) action potentials and the effective refractory period, and can induce arrhythmias via reentry mechanisms (Hashimoto et al., 2006. Pharmacological research: the official journal of the Italian Pharmacological Society] 54, 136-141). IKAch lineage dysregulation has been shown in atrial tissue of individuals with persistent arrhythmias and in animals subjected to rapid atrial pacing (an accepted model for promoting electrical remodeling and arrhythmia susceptibility). Specifically, even in the absence of acetylcholine, the pathway tends to be open (Cha et al., 2006. Circulation 113, 1730-1737; Voigt et al., 2014. Advances in pharmacology (San Diego, CA) 70, 393-409). In these studies, short atrial APD / ERP ratios were observed in both patients and animals.

[0010] Therefore, the development of GIRK1 / 4 blockers will be beneficial for the treatment of a range of heart-related diseases. For these reasons, small molecule inhibitors of GIRK1 / 4 remain needed. Summary of the Invention

[0011] In a first aspect, the present invention relates to compounds having formula (I): (I) Or its pharmaceutically acceptable salt, wherein R1 is a (C1-C6) alkyl group substituted with one or more substituents independently selected from -OH, -C(O)NHRa, and, as desired, one or more -OH groups of 4 to 6-membered heterocyclic rings; A-series -OR 2 or (C 1-C 6) alkyl groups substituted as needed by one or more independent substituents selected from -SO 2 (C 1-C 4) alkyl, -NHC(O)R b and -C(O)NHR c; R2 is a (C1-C6) alkyl group substituted with one or more substituents independently selected from -NHC(O)Rd and -C(O)NHRe, wherein the (C1-C6) alkyl group is further substituted with one or more substituents independently selected from halogen, -OH and -CN as needed; Ra, Rb, Rc, Rd, and Re are each independently selected from H and (C1-C6) alkyl groups that are substituted with one or more -OH groups as needed; and R3 series (C1-C4) alkyl.

[0012] On the other hand, the present invention relates to the crystalline form of a compound having formula (I) as defined herein or a pharmaceutically acceptable salt thereof.

[0013] On the other hand, the present invention relates to pharmaceutical compositions comprising a compound having formula (I) as defined herein or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.

[0014] On the other hand, the present invention relates to a combination comprising a compound having formula (I) as defined herein or a pharmaceutically acceptable salt thereof and one or more pharmaceutical agents.

[0015] On the other hand, the present invention relates to a method for treating a disease or disorder, the method comprising administering to a patient in need a therapeutically effective amount of a compound having formula (I) as defined herein or a pharmaceutically acceptable salt thereof.

[0016] In some embodiments, the disease or disorder is selected from arrhythmias, atrial fibrillation, bradycardia, bradycardia, heart block, atrial cavity disorder syndrome, parasympathetic hyperactivation, primary hyperaldosteronism, hypotension, and vasovagal syncope. In some embodiments, the disease or disorder responds to inhibition of GIRK1 / 4 receptors.

[0017] On the other hand, the present invention relates to a method for treating a disease or disorder, the method comprising administering to a patient in need a therapeutically effective amount of a compound having formula (I) as defined herein or a pharmaceutically acceptable salt thereof.

[0018] In another aspect, the present invention relates to a method for maintaining sinus rhythm or preventing recurrence in patients with paroxysmal atrial fibrillation after cardiac remission in patients with persistent or recently occurring atrial fibrillation, the method comprising administering to a patient in need a compound having formula (I) as defined herein or a pharmaceutically acceptable salt thereof.

[0019] On the other hand, the present invention relates to compounds having formula (I) as defined herein, or pharmaceutically acceptable salts thereof, used as medicines.

[0020] On the other hand, the present invention relates to compounds having formula (I) as defined herein, or pharmaceutically acceptable salts thereof, for the treatment of diseases or disorders.

[0021] In another aspect, the present invention relates to compounds having formula (I) as defined herein, for the preparation of medicaments for treating diseases or disorders.

[0022] In another aspect, the present invention relates to the use of a compound having formula (I) as defined herein or a pharmaceutically acceptable salt thereof in the treatment of a disease or disorder.

[0023] Other features and advantages of the present invention will become apparent from the following detailed description and as requested. Simple Explanation of the Diagram

[0024] [Figure 1A] shows the X-ray powder diffraction pattern of variant A-1 of Example 1. [Figure 2A] shows the differential scanning calorimetry thermogram of variant A-1 of Example 1. [Figure 3A] shows the thermogravimetric analysis of variant A-1 of Example 1. [Figure 1B] shows the X-ray powder diffraction pattern of variant A-2 of Example 1. [Figure 2B] shows the differential scanning calorimetry (DSC) thermogram of variant A-2 of Example 1. [Figure 3B] shows the thermogravimetric analysis of variant A-2 of Example 1. [Figure 1C] shows the X-ray powder diffraction pattern of variant A-3 of Example 1. [Figure 2C] shows the differential scanning calorimetry thermogram of variant A-3 of Example 1. [Figure 3C] shows the thermogravimetric analysis of variant A-3 of Example 1. [Figure 1D] shows the X-ray powder diffraction pattern of variant A-4 of Example 1. [Figure 2D] shows the differential scanning calorimetry (DSC) thermogram of variant A-4 of Example 1. [Figure 3D] shows the thermogravimetric analysis of variant A-4 of Example 1. [Figure 1E] shows the X-ray powder diffraction pattern of variant A-5 of Example 1. [Figure 2E] shows the differential scanning calorimetry thermogram of variant A-5 of Example 1. [Figure 3E] shows the thermogravimetric analysis of variant A-5 of Example 1. [Figure 1F] shows the X-ray powder diffraction pattern of variant A-6 of Example 1. [Figure 1G] shows the X-ray powder diffraction pattern of variant A-7 of Example 1. [Figure 1H] shows the X-ray powder diffraction pattern of variant A-8 of Example 1. [Figure 1I] shows the X-ray powder diffraction pattern of variant A-9 of Example 1. [Figure 2I] shows the differential scanning calorimetry thermogram of variant A-9 of Example 1. [Figure 3I] shows the thermogravimetric analysis of variant A-9 of Example 1. [Figure 1J] shows the X-ray powder diffraction pattern of variant A-10 of Example 1. [Figure 2J] shows the differential scanning calorimetry thermogram of variant A-10 of Example 1. [Figure 3J] shows the thermogravimetric analysis of variant A-10 of Example 1. [Figure 1K] shows the X-ray powder diffraction pattern of variant A-11 of Example 1. [Figure 2K] shows the differential scanning calorimetry (DSC) thermogram of variant A-11 of Example 1. [Figure 3K] shows the thermogravimetric analysis of variant A-11 of Example 1. [Figure 1L] shows the X-ray powder diffraction pattern of variant A-12 of Example 1. [Figure 2L] shows the differential scanning calorimetry (DSC) thermogram of variant A-12 of Example 1. [Figure 3L] shows the thermogravimetric analysis of variant A-12 of Example 1. [Figure 1M] shows the X-ray powder diffraction pattern of variant A-13 of Example 1. [Figure 2M] shows the differential scanning calorimetry (DSC) thermogram of variant A-13 of Example 1. [Figure 3M] shows the thermogravimetric analysis of variant A-13 of Example 1. Implementation

[0025] In some aspects, the present invention provides substituted pyridone compounds and pharmaceutical compositions thereof. In particular, such substituted compounds can be used as inhibitors of GIRK1 / 4 receptors and have good oral bioavailability, and are therefore suitable for the treatment or prevention of diseases or conditions.

[0026] The details of this invention are set forth in the appended specification. While methods and materials similar to or equivalent to those described herein may be used in the practice or testing of this invention, illustrative methods and materials are described hereafter. Other features, objects, and advantages of this invention will be apparent from the specification and from the claims. In this specification and the appended claims, the singular form also includes the plural, unless the context clearly indicates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. All patents and disclosures cited in this specification are incorporated herein by reference in their entirety. [, compound , ] [, , ]

[0027] In one aspect, the present invention therefore provides compounds having formula (I): (I) Or its pharmaceutically acceptable salt, wherein R1 is a (C1-C6) alkyl group substituted with one or more substituents independently selected from -OH, -C(O)NHRa, and, as desired, one or more -OH groups of 4 to 6-membered heterocyclic rings; A-series -OR 2 or (C 1-C 6) alkyl groups substituted as needed by one or more independent substituents selected from -SO 2 (C 1-C 4) alkyl, -NHC(O)R b and -C(O)NHR c; R2 is a (C1-C6) alkyl group substituted with one or more substituents independently selected from -NHC(O)Rd and -C(O)NHRe, wherein the (C1-C6) alkyl group is further substituted with one or more substituents independently selected from halogen, -OH and -CN as needed; Ra, Rb, Rc, Rd, and Re are each independently selected from H and (C1-C6) alkyl groups substituted with one or more -OH groups as desired; and R3 series (C1-C4) alkyl.

[0028] Unless otherwise specified, the term "compound of the present invention" means a compound having formula (I), an example compound, or a pharmaceutically acceptable salt thereof, and all stereoisomers (including non-mirror image isomers and mirror image isomers), rotational isomers, tautomers, hydrates, solvates, homomorphs, co- and isotopically labeled compounds (including deuterated derivatives), and the inherently formed portion.

[0029] This document describes various embodiments of the invention. It will be appreciated that the features specified in each embodiment can be combined with other specified features of other embodiments to provide additional embodiments.

[0030] In some embodiments, R1 is a (C1-C6) alkyl group independently selected from -OH, -C(O)NHR a, and a 4- to 6-membered heterocyclic ring containing at least one O, which may be substituted with one or more -OH groups as desired. In some embodiments, R1 is a (C1-C6) alkyl group independently selected from -OH, -C(O)NHR a, and a 4- to 6-membered heterocyclic ring containing at least one O, which may be substituted with one -OH group as desired. In some embodiments, R1 is a (C1-C6) alkyl group independently selected from -OH, -C(O)NHR a, and a 4-membered heterocyclic ring containing at least one O, which may be substituted with one or more -OH groups as desired. In some embodiments, R1 is a (C1-C6) alkyl group independently selected from -OH, -C(O)NHR a, and a 4-membered heterocyclic ring containing at least one O, which may be substituted with one -OH group as desired.

[0031] In some embodiments, R1 is independently selected from -OH, -C(O)NHCH3 and The (C1-C6) alkyl group is substituted with a substituent. In some embodiments, R1 is replaced by one or more groups independently selected from -OH, -C(O)NHCH3, and The substituents are substituted (C1-C4) alkyl groups.

[0032] In some implementations, R1 is selected from... , , , and In some instances, R1 is selected from... , and In some instances, R1 is selected from... and In some instances, the R1 series... .

[0033] In some instances, Ra is selected from H and (C1-C6) alkyl groups.

[0034] In some instances, A-OR 2.

[0035] In some embodiments, R2 is a (C1-C6) alkyl group substituted with one or more substituents independently selected from -NHC(O)CH3, -C(O)NHCH3, -C(O)NHCH2CH2OH, and -C(O)NH2, wherein the (C1-C6) alkyl group is further substituted with one or more substituents independently selected from halogens, -OH, and -CN as desired. In some embodiments, R2 is a (C1-C4) alkyl group substituted with one or more substituents independently selected from -NHC(O)CH3, -C(O)NHCH3, -C(O)NHCH2CH2OH, and -C(O)NH2, wherein the (C1-C4) alkyl group is further substituted with one or more substituents independently selected from halogens, -OH, and -CN as desired. In some embodiments, R2 is a (C1-C4) alkyl group substituted with one or more substituents independently selected from -NHC(O)CH3, -C(O)NHCH3, -C(O)NHCH2CH2OH, and -C(O)NH2, wherein the (C1-C4) alkyl group is further substituted with one or more substituents independently selected from halogens and -OH, as desired. In some embodiments, R2 is a (C1-C4) alkyl group substituted with one or more substituents independently selected from -NHC(O)CH3, -C(O)NHCH3, -C(O)NHCH2CH2OH, and -C(O)NH2, wherein the (C1-C4) alkyl group is further substituted with one or more substituents independently selected from fluorines and -OH, as desired.

[0036] In some implementations, R2 is selected from... , , , , , , , , and In some instances, R2 is selected from... , , , , , and In some instances, R2 is selected from... , , , , ,and In some implementations, R2 is selected from... and In some implementations, R2 is selected from... and .

[0037] In some embodiments, the A-series may be substituted with one or more (C1-C6) alkyl groups independently selected from -SO2CH3 and -NHC(O)CH3. In some embodiments, the A-series may be substituted with one or more (C1-C4) alkyl groups independently selected from -SO2CH3 and -NHC(O)CH3.

[0038] In some instances, A is selected from , , and In some instances, A is selected from... , and In some implementations, the A series .

[0039] In some embodiments, R3 is selected from -CH3 and -CH2CH3. In some embodiments, R3 is -CH3.

[0040] In some instances, Ra is selected from H and (C1-C6) alkyl. In some embodiments, Rb is selected from H and (C1-C6) alkyl. In some embodiments, Rc is selected from H and (C1-C6) alkyl. In some embodiments, Rd is selected from H and (C1-C6) alkyl. In some embodiments, R3 is selected from H and (C1-C6) alkyl. In some instances, Ra is selected from H and (C1-C4) alkyl. In some embodiments, Rb is selected from H and (C1-C4) alkyl. In some embodiments, Rc is selected from H and (C1-C4) alkyl. In some embodiments, Rd is selected from H and (C1-C4) alkyl. In some embodiments, R3 is selected from H and (C1-C4) alkyl. In some embodiments, Re is selected from H and (C1-C4) alkyl that is substituted with one or more -OH groups as needed.

[0041] In some embodiments, the compounds of formula (I) according to the present invention are selected from compounds of the group consisting of: compound structure Chemical name C-1 3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-N-methylpropionic acid C-2 2-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-dipyridin-5-yl)oxy)-N-(2-hydroxyethyl)acetamide C-3 3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxy-2-methylpropoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-N-methylpropionic acid C-4 2-((8-chloro-1-(2,6-dichloro-4-(2-hydroxy-2-methylpropoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-N-methylacetamide C-5 2-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-N-methylacetamide C-6 (R)-3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxypropoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-N-methylpropionic acid C-7 (R)-3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-dipyridin-5-yl)oxy)-N,2-dimethylpropionic acid C-8 (S)-3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-dipyridin-5-yl)oxy)-N,2-dimethylpropionic acid C-9 N-(2-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)ethyl)acetamide C-10 (S)-3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxypropoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-N-methylpropionic acid C-11 3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-N,2,2-trimethylpropionic acid C-12 (R)-3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-2-hydroxy-N-methylpropionic acid C-13 (S)-3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-2-hydroxy-N-methylpropionic acid C-14 (S)-3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxy-2-methylpropoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-2-hydroxy-N-methylpropionic acid C-15 3-((8-chloro-1-(2,6-dichloro-4-((3-hydroxyoxetane-3-yl)methoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-N-methylpropionic acid C-16 3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-2,2-difluoro-N-methylpropionic acid C-17 2-(4-(5-(2-amino-2-sideoxyethoxy)-8-chloro-2-methyl-4-sideoxy-1,6-diphenyl-1(4H)-yl)-3,5-dichlorophenoxy)-N-methylacetamide C-18 3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)propionic acid C-19 N-(3-(8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)propyl)acetamide C-20 8-Chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-5-(2-(methylsulfonylurea)ethyl)-1,6-diphenyl-4(1H)-one C-21 8-Chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-5-(2-(methylsulfonylurea)propyl)-1,6-diphenyl-4(1H)-one C-22 8-Chloro-1-(2,6-dichloro-4-(2-hydroxy-2-methylpropoxy)phenyl)-2-methyl-5-(3-(methylsulfonylurea)propyl)-1,6-diphenyl-4(1H)-one

[0042] As used herein, the term "salt" refers to an acid addition salt or a base addition salt of the compounds of the present invention. "Salt" specifically includes "pharmaceutically acceptable salts." The term "pharmaceutically acceptable salt" means a salt that retains the bioavailability and properties of the compounds of the present invention and is typically not biologically or otherwise undesirable. In many cases, the compounds of the present invention can form acid salts and / or base salts due to the presence of amino and / or carboxyl groups or similar groups. The compounds of the present invention can also form internal salts, such as zwitterionic molecules, when both basic and acidic groups are present in the same molecule.

[0043] Pharmaceutically acceptable acid addition salts can be formed from inorganic and organic acids.

[0044] Inorganic acids that can form salts include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid.

[0045] Organic acids that can be used to derive salts include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, etc.

[0046] Pharmaceutically acceptable base addition salts can be formed using inorganic and organic bases.

[0047] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I through XII of the periodic table. In some embodiments, the salt is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts.

[0048] Organic bases that can derive salts include, for example, primary, secondary, and tertiary amines; substituted amines (including naturally occurring substituted amines); cyclic amines; and basic ion exchange resins. Some organic amines include isopropylamine, benzylamine, choline salts, diethanolamine, diethylamine, lysine, meglumine, piperazine, and aminobutanetriol.

[0049] In another aspect, the present invention provides compounds of the invention in the following forms: acetate, ascorbate, adipic acid salt, aspartate, benzoate, benzenesulfonate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, decanoate, chloride / hydrochloride, chlortheophyllonate, citrate, ethanedisulfonate, fumarate, gluconate, gluconate, glucuronate, glutamate, glycolate, hippurate, hydroiodate / iodide, hydroxyethylsulfonate. Lactates, lacturonates, dodecyl sulfates, malates, maleates, malonates, amygdalinates, methanesulfonates, methyl sulfates, mucilages, naphthates, naphthalenesulfonates, nicotinates, nitrates, octadecanoates, oleates, oxalates, palmitates, dihydroxynaphthalates, phosphates / hydrogen phosphates / dihydrogen phosphates, polygalacturonates, propionates, sebacic acid salts, stearates, succinates, sulfosalicylates, sulfates, tartrates, toluenesulfonates, trifenatates, trifluoroacetates, or sinetates.

[0050] Any formulas given herein are also intended to represent the unlabeled form of the compound as well as the isotopically labeled form. Isotopically labeled compounds have the structures represented by the formulas given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Isotopes that may be incorporated into the compounds of this invention include, for example, isotopes of hydrogen.

[0051] Furthermore, the incorporation of certain isotopes, particularly deuterium (i.e., 2H or D), can provide certain therapeutic advantages due to increased metabolic stability, such as increased in vivo half-life, reduced dose requirements, therapeutic index, or improved tolerability. It should be understood that deuterium in this context is considered a substituent in the compounds of this invention. The concentration of deuterium can be defined by an isotope enrichment factor. As used herein, the term "isotope enrichment factor" refers to the ratio between the isotope abundance and the native abundance of the specified isotope. If the substituent in the compound of the present invention indicates deuterium, then such a compound has an isotopic enrichment factor for each specified deuterium atom of at least 3500 (52.5% deuterium doping on each specified deuterium atom), at least 4000 (60% deuterium doping), at least 4500 (67.5% deuterium doping), at least 5000 (75% deuterium doping), at least 5500 (82.5% deuterium doping), at least 6000 (90% deuterium doping), at least 6333.3 (95% deuterium doping), at least 6466.7 (97% deuterium doping), at least 6600 (99% deuterium doping), or at least 6633.3 (99.5% deuterium doping). It should be understood that the term "isotopic enrichment factor" can be applied to any isotope in the same manner as described for deuterium.

[0052] Other examples of isotopes that can be incorporated into the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 3H, 11C, 13C, 14C, 15N, 18F, 31P, 32P, 35S, 36Cl, 123I, 124I, and 125I, respectively. Therefore, it should be understood that this invention includes compounds incorporated with one or more of the aforementioned isotopes (including, for example, radioactive isotopes such as 3H and 14C), or compounds containing non-radioactive isotopes such as 2H and 13C. Such isotopically labeled compounds can be used for metabolic studies (with 14C), reaction kinetic studies (e.g., with 2H or 3H), detection or imaging techniques including drug or substrate tissue distribution determination (e.g., positron emission tomography (PET) or single-photon emission computed tomography (SPECT)), or for use in the radiotherapy of patients. In particular, 18F or labeled compounds may be especially desirable for PET or SPECT studies. Isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the appended examples and general synthetic schemes, using appropriate isotopically labeled reagents instead of previously used unlabeled reagents.

[0053] Any asymmetric atom (e.g., carbon, etc.) in one or more compounds of the present invention may be present in a racemic or mirror-isomer enriched form (e.g., (R)-, (S)-, or (R,S)- configuration). In some embodiments, each asymmetric atom has at least 50% mirror-isomer excess, at least 60% mirror-isomer excess, at least 70% mirror-isomer excess, at least 80% mirror-isomer excess, at least 90% mirror-isomer excess, at least 95% mirror-isomer excess, or at least 99% mirror-isomer excess in the (R)- or (S)- configuration. If possible, substitutions on atoms having unsaturated double bonds may be present in cis-(Z)- or trans-(E)- form.

[0054] Therefore, as used herein, the compounds of the present invention may be in the form of one of the following: stereoisomers, rotational isomers, tautomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) stereoisomers, non-mirror image isomers, optical isomers (enantiomers), racemates or mixtures thereof.

[0055] Based on the physicochemical differences of the components, such as by chromatography and / or fractional crystallization, any resulting mixture of stereoisomers can be separated into pure or substantially pure geometric or optical isomers, non-mirror isomers, and racemates.

[0056] Any racemic derivative of the compounds or intermediates of the present invention can be resolved into optically active enantiomers by known methods, for example, by separating their non-mirror image isomer salts obtained with optically active acids or bases, releasing optically active acidic or basic compounds. In particular, the basic moiety can therefore be used to resolve the compounds of the present invention into their optically active enantiomers, for example, by fractional crystallization with salts formed from optically active acids such as tartaric acid, dibenzoyltartaric acid, diacetylated tartaric acid, di-O,O'-p-toluenetartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid. The racemic compounds or racemic intermediates of the present invention can also be resolved by chiral chromatography (e.g., high-performance liquid chromatography (HPLC) using chiral adsorbents).

[0057] The compounds of formula (I) of the present invention, including their free form, pharmaceutically acceptable salts, hydrates and solvates, can be isolated in one or more crystalline forms under suitable conditions.

[0058] As used herein, the term "crystalline form" includes references to anhydrous crystalline forms, hydrated crystalline forms, solvate crystalline forms, and mixtures of crystalline forms.

[0059] In one embodiment, the crystalline form of a compound of formula (I) according to the invention or a pharmaceutically acceptable salt thereof is selected from its free form, hydrate, solvate, homomorph, and eutectic.

[0060] As used herein, the term "free form" refers to a compound of formula (I) that does not itself form a salt or bind with a solvent (e.g., a solvate).

[0061] As used herein, the term "hydrate" refers to a crystalline form containing one or more water molecules arranged in a three-dimensional periodic pattern. It can include non-stoichiometric or stoichiometric hydrates, such as hemihydrates, monohydrates, dihydrates, and trihydrates.

[0062] As used herein, the term "solvent" refers to a crystalline form containing one or more solvent molecules other than water arranged in a three-dimensional periodic pattern. Solvents may contain stoichiometric or non-stoichiometric amounts of solvent molecules.

[0063] In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof according to the invention may inherently or by design form a hydrate or solvate with a pharmaceutically acceptable solvent.

[0064] As used herein, the term "homogeneous heteromorphic material" refers to a crystalline form that has the same chemical composition but differs in the spatial arrangement of the molecules, atoms and / or ions that form the crystal.

[0065] In one embodiment, a compound of formula (I) according to the invention, or a pharmaceutically acceptable salt thereof, containing groups capable of acting as hydrogen bond donors and / or acceptors, may be able to form a eutectic form with a suitable eutectic forming agent.

[0066] The terms “cocrystal” and “cocrystal” are used interchangeably herein and refer to a cocrystal comprising a compound having formula (I) as defined herein or a pharmaceutically acceptable salt thereof and a suitable cocrystal forming agent.

[0067] Such eutectic crystals can be prepared from compounds having formula (I) or pharmaceutically acceptable salts thereof by known eutectic formation methods, such as grinding, heating, co-sublimating, co-melting, or contacting a eutectic forming agent with a compound having formula (I) or a pharmaceutically acceptable salt thereof under crystallization conditions, and then separating the eutectic crystals formed therefrom. Suitable eutectic forming agents include, for example, those described in WO 2004 / 078163.

[0068] In one embodiment, the invention relates to the free crystalline form of a compound having formula (I) as defined herein.

[0069] In another embodiment, the invention relates to a hydrated crystalline form of a compound having formula (I) as defined herein or a pharmaceutically acceptable salt thereof. In one aspect of this embodiment, the hydrated crystalline form of a compound having formula (I) as defined herein or a pharmaceutically acceptable salt thereof is a hemihydrate, monohydrate, dihydrate, or trihydrate crystalline form.

[0070] In one embodiment, the invention relates to the hydrate crystalline form of a compound having formula (I) as defined herein. In one aspect of this embodiment, the hydrate crystalline form of a compound having formula (I) as defined herein is a hemihydrate, monohydrate, dihydrate, or trihydrate crystalline form.

[0071] In another embodiment, the invention relates to the crystalline form of a solvate of a compound having formula (I) as defined herein or a pharmaceutically acceptable salt thereof.

[0072] In one embodiment, the invention relates to the crystalline form of a solvate of a compound having formula (I) as defined herein with cyclopentanone.

[0073] In another embodiment, the invention relates to the solvate crystallization of a compound having formula (I) as defined herein with methanol.

[0074] In another embodiment, the invention relates to the crystalline form of a solvate of a compound having formula (I) as defined herein.

[0075] In another embodiment, the invention relates to a eutectic of a compound having formula (I) as defined herein or a pharmaceutically acceptable salt thereof.

[0076] In one embodiment, the invention relates to a cocrystal comprising a compound having formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, and a cocrystal forming agent. Preferably, the cocrystal forming agent is selected from the group consisting of: phosphoric acid, benzoic acid, succinic acid, saccharin, and salts thereof.

[0077] In one embodiment of the invention, a eutectic comprising a compound having formula (I) as defined herein or a pharmaceutically acceptable salt thereof and phosphoric acid is provided.

[0078] In another embodiment of the invention, a eutectic comprising a compound having formula (I) as defined herein or a pharmaceutically acceptable salt thereof and benzoic acid is provided.

[0079] In another embodiment of the invention, a cocrystal comprising a compound having formula (I) as defined herein or a pharmaceutically acceptable salt thereof and succinic acid is provided.

[0080] In another embodiment of the invention, a cocrystal comprising a compound having formula (I) as defined herein or a pharmaceutically acceptable salt thereof and saccharin is provided.

[0081] In the cocrystal according to the invention, the molar ratio of the compound having formula (I) or its pharmaceutically acceptable salt to the cocrystal forming agent may be stoichiometric or non-stoichiometric. For example, in the cocrystal according to the invention, a suitable molar ratio of the compound having formula (I) or its pharmaceutically acceptable salt to the cocrystal forming agent is 1:2 to 2:1, preferably 1.5:1 to 1:1.5, and more preferably 1:1.1 to 1.1:1.

[0082] In one embodiment, the crystalline form of the compound having formula (I) according to the invention, or a pharmaceutically acceptable salt thereof, is provided in substantially pure form. As used herein, "substantially pure," when referring to crystalline form, means a compound having a purity of more than 90% by weight (including more than 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% by weight), and also includes approximately 100% by weight of the compound having formula (I) or a pharmaceutically acceptable salt thereof. The remaining material comprises one or more other forms of the compound having formula (I), and / or reaction impurities and / or processing impurities arising from its preparation. For example, a crystalline form of a compound having formula (I) according to the invention or a pharmaceutically acceptable salt thereof may be considered substantially pure because it has a purity of more than 90% by weight (as measured by methods currently known and generally accepted in the art), wherein the remaining less than 10% by weight of the material comprises one or more other forms of the compound having formula (I) and / or reaction impurities and / or processing impurities.

[0083] A specific crystalline form of a compound having formula (I) according to the invention, or a pharmaceutically acceptable salt thereof, may be referred to as "crystalline form X", "crystalline form X", "eutectic form", "polymorphic form X", "variant X" or "HX", wherein "X" is a letter assigned to that specific crystalline form. The names used herein to characterize a specific crystalline form (e.g., "A-1", etc.) should not be considered as limitations on any other substance having similar or identical physical and chemical characteristics, but should be understood as merely identifiers to be interpreted in light of the characteristic information also presented herein.

[0084] In one embodiment, the invention relates to crystalline forms of compounds having formula (I) as defined herein or pharmaceutically acceptable salts thereof, wherein the crystalline forms are selected from various variants detailed herein, preferably variants A-1, A-2, A-3, A-4, A-5, A-6, A-7, A-8, A-9, A-10, A-11, A-12 and A-13.

[0085] Each variant is characterized by having an X-ray powder diffraction pattern with peaks substantially as shown in the accompanying figures. Therefore, crystalline forms selected from the various variants detailed herein are provided, characterized in that the X-ray powder diffraction patterns of said crystalline forms are substantially consistent with those shown in the corresponding figures.

[0086] In a further embodiment, the present invention provides any crystalline form of a compound having formula (I) or a pharmaceutically acceptable salt thereof as described in the examples, in a specific variant form, characterized in that the crystalline form has at least one of the following features: (a) An X-ray powder diffraction pattern substantially consistent with that shown in the accompanying figures related to that particular variant; and / or (b) The melting point as listed for each variant in the Examples section; and / or (c) Differential scanning calorimetry thermograms as listed for each variant in the Examples section.

[0087] In one embodiment of the invention, a free crystalline form of 3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-N-methylpropionic acid (compound C-1) is provided, designated variant A-1, characterized in that, when measured using CuKα radiation at a wavelength of 1.5418 Å at a temperature of approximately 22°C, the crystalline form has an X-ray powder diffraction pattern substantially consistent with that shown in FIG. 1A, or comprises four or more 2θ values ​​(± 0.1 degrees) selected from the 2θ values ​​listed in the table below: serial number angle 2θ d value Å relative strength % 1 7.7 11.47 99 2 11.3 7.86 5 3 15.4 5.74 10 4 16.4 5.40 32 5 17.7 5.00 9 6 21.2 4.19 19 7 22.7 3.91 9 8 23.3 3.81 43 9 24.0 3.70 100 10 26.4 3.37 12 11 27.2 3.28 twenty three

[0088] In another embodiment of the invention, a hydrated crystalline form of 3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-N-methylpropionic acid (compound C-1) is provided, designated variant A-2, characterized in that, when measured using CuKα radiation at a wavelength of 1.5418 Å at a temperature of approximately 22°C, the crystalline form has an X-ray powder diffraction pattern substantially consistent with that shown in Figure 1B, or comprises four or more 2θ values ​​(± 0.1 degrees) selected from the 2θ values ​​listed in the table below: serial number angle 2θ d value Å relative strength % 1 7.6 11.62 17 2 10.7 8.30 3 3 15.2 5.81 4 4 16.9 5.24 27 5 21.4 4.15 17 6 24.0 3.70 100 7 25.8 3.45 3 8 27.4 3.26 17 9 30.7 2.91 2

[0089] In another embodiment of the invention, a hydrated crystalline form of 3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-N-methylpropionic acid (compound C-1) is provided, designated variant A-3, characterized in that, when measured at approximately 22°C using CuKα radiation at a wavelength of 1.5418 Å, the crystalline form has an X-ray powder diffraction pattern substantially consistent with that shown in FIG. 1C, or comprises four or more 2θ values ​​(± 0.1 degrees) selected from the 2θ values ​​listed in the table below: serial number angle 2θ d value Å relative strength % 1 7.6 11.55 twenty three 2 15.3 5.78 9 3 17.0 5.22 18 4 20.7 4.29 5 5 21.4 4.14 8 6 22.2 3.99 33 7 25.9 3.44 20 8 29.1 3.07 10 9 32.3 2.77 12

[0090] In another embodiment of the invention, a hydrated crystalline form of 3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-N-methylpropionic acid (compound C-1) is provided, designated variant A-4, characterized in that, when measured using CuKα radiation at a wavelength of 1.5418 Å at a temperature of approximately 22°C, the crystalline form has an X-ray powder diffraction pattern substantially consistent with that shown in Figure 1D, or comprises four or more 2θ values ​​(± 0.1 degrees) selected from the 2θ values ​​listed in the table below: serial number angle 2θ d value Å relative strength % 1 7.3 12.11 29 2 10.3 8.59 3 3 15.5 5.73 10 4 22.1 4.02 3 5 23.1 3.84 100 6 23.9 3.73 19 7 25.5 3.49 7 8 25.9 3.44 6 9 26.4 3.37 50 10 31.2 2.86 8

[0091] In another embodiment of the invention, a hydrated crystalline form of 3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-N-methylpropionic acid (compound C-1) is provided, designated variant A-5, characterized in that, when measured using CuKα radiation at a wavelength of 1.5418 Å at a temperature of approximately 22°C, the crystalline form has an X-ray powder diffraction pattern substantially consistent with that shown in FIG. 1E, or comprises four or more 2θ values ​​(± 0.1 degrees) selected from the 2θ values ​​listed in the table below: serial number angle 2θ d value Å relative strength % 1 5.0 17.84 47 2 9.9 8.93 14 3 14.9 5.96 twenty one 4 15.9 5.58 39 5 17.7 5.01 14 6 19.8 4.47 87 7 24.0 3.71 84 8 25.5 3.49 68 9 27.2 3.28 twenty three [, Drug composition , ] [, , ]

[0092] On the other hand, the present invention provides a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers. In another embodiment, the composition comprises at least two pharmaceutically acceptable carriers (e.g., those described herein).

[0093] In some embodiments, the pharmaceutical composition further comprises at least one additional pharmaceutically active agent. In some embodiments, the additional pharmaceutically active agent is selected from Class I antiarrhythmic agents, Class II antiarrhythmic agents, Class III antiarrhythmic agents, Class IV antiarrhythmic agents, Class V antiarrhythmic agents, cardiac glycosides, and other drugs affecting atrial refractory; hemostatic modifiers, antithrombotic agents; thrombin inhibitors; factor VI1a inhibitors; anticoagulants, factor Xa inhibitors, and direct thrombin inhibitors; antiplatelet agents, cyclooxygenase inhibitors, adenosine diphosphate (ADP) receptor inhibitors, phosphodiesterase inhibitors, glycoprotein IIB / IIA; adenosine reuptake inhibitors; anti-dyslipidemia agents, HMG-CoA reductase inhibitors, other cholesterol-lowering agents; bile acid sequestrants; cholesterol absorption inhibitors; cholesterol ester transfer protein (CETP) inhibitors; ileal bile acid transport system inhibitors (IBAT inhibitors); bile acid conjugating resins; nicotinic acid and its analogues; antioxidants; ω-3 fatty acids; antihypertensive agents, including adrenergic receptor antagonists, β-blockers, α-blockers, and mixed α / β-blockers; adrenergic receptor agonists and α-2 agonists; angiotensinogens. ACE inhibitors, calcium channel blockers; angiotensin II receptor antagonists; aldosterone receptor antagonists; centrally acting adrenergic drugs, centrally acting alpha agonists; and diuretics; anti-obesity agents, pancreatic lipase inhibitors, microsomal transfer protein (MTP) modulators, diacylglycerol acetylglucosamine (DGAT) inhibitors, cannabinoid (CBI) receptor antagonists; insulin and insulin analogs; insulin secretagogues; agents that improve the action of intestinal hypoglycemic agents, dipeptidyl peptidase IV (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) inhibitors. -1) Agonists; insulin sensitizers, peroxisome proliferator-activated receptor γ (PPARγ) agonists, agents that regulate hepatic glucose homeostasis, fructose-1,6-bisphosphatase inhibitors, glycogen phosphorylase inhibitors, glycogen synthase kinase inhibitors, glucosamine activators; agents designed to reduce / slow down intestinal glucose absorption, α-glucosidase inhibitors; agents that antagonize the effects of glucagon or reduce glucagon secretion, islet amyloid analogs; agents that prevent renal reabsorption of glucose and sodium-dependent glucose transporter 2 (SGLT-2) inhibitors and combinations thereof.

[0094] Pharmaceutical compositions can be formulated for specific routes of administration, such as oral administration, parenteral administration (e.g., by injection, infusion, transdermal or topical administration), and rectal administration. Topical administration may also involve inhalation or intranasal application. The pharmaceutical compositions of the present invention can be formulated in solid form (including but not limited to capsules, tablets, pills, granules, powders, or suppositories) or in liquid form (including but not limited to solutions, suspensions, or emulsions). Tablets may be coated with a film or enteric coating according to methods known in the art. Typically, pharmaceutical compositions are tablets or gelatin capsules containing an active ingredient and one or more of the following: a) Diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and / or glycine; b) Lubricants, such as silica, talc, stearic acid, its magnesium or calcium salts, and / or polyethylene glycol; also included in tablets. c) Adhesives, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth gum, methylcellulose, sodium carboxymethyl cellulose, and / or polyvinylpyrrolidone; if desired. d) Disintegrants, such as starch, agar, alginate, or their sodium salts or effervescent mixtures; and e) Adsorbents, colorants, flavoring agents and sweeteners.

[0095] Liquid (especially injectable) compositions can be prepared, for example, by dissolution, dispersion, etc. For example, the disclosed compound is dissolved in or mixed with pharmaceutically acceptable solvents (such as, for example, water, saline, aqueous dextran, glycerol, ethanol, etc.), thereby forming an injectable isotonic solution or suspension. Proteins (e.g., albumin, chylous microdroplets, or serum proteins) can be used to dissolve the disclosed compound.

[0096] The disclosed compounds can also be formulated into suppositories, which can be prepared as fat emulsions or suspensions, using polyalkylene glycols such as propylene glycol as carriers.

[0097] Injectable formulations are typically administered subcutaneously, intramuscularly, or intravenously. Injectable formulations can be prepared in conventional forms (as a liquid solution or suspension, or in a solid form suitable for dissolving in a liquid prior to injection).

[0098] The compositions can be prepared according to conventional mixing, granulation or coating methods, and the pharmaceutical compositions of the present invention may contain from about 0.1% to about 99%, from about 5% to about 90%, or from about 1% to about 20% by weight or volume of the disclosed compounds.

[0099] Dosing regimens using the disclosed compounds are selected based on a variety of factors, including the patient's type, species, age, weight, sex, and medical condition; the severity of the condition to be treated; the route of administration; the patient's renal or hepatic function; and the specific disclosed compound used. A physician or veterinarian with general skills can easily determine and prescribe the effective amount of the drug needed to prevent, counteract, or halt the progression of the condition.

[0100] The pharmaceutical composition or combination of the present invention may, for example, be in a unit dose form having one or more active ingredients of about 1-1000 mg for a subject weighing about 50-70 kg. In one embodiment, the composition is in the form of a scoreable tablet. The therapeutically effective dose of the compound, pharmaceutical composition, or combination thereof depends on the species, weight, age, and individual condition, disorder, or disease being treated, or its severity. [, How to use , ] [, , ]

[0101] In another aspect, the present invention relates to a method for treating or preventing a disease or disorder, the method comprising administering to a patient in need an effective amount of a compound having formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound having formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0102] On the other hand, the present invention relates to a method for treating a disease or disorder, the method comprising administering to a patient in need an effective amount of a compound having formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound having formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein the disease or disorder is selected from arrhythmias, atrial fibrillation, bradycardia, bradycardia, cardiac conduction block, atrial cavity disorder syndrome, parasympathetic hyperactivation, primary hyperaldosteronism, hypotension, and vasovagal syncope.

[0103] On the other hand, the present invention relates to a method for maintaining sinus rhythm or preventing recurrence in patients with paroxysmal atrial fibrillation after cardiac remission in patients with persistent or recently recurrent atrial fibrillation, the method comprising administering to a patient in need a therapeutically effective amount of a compound having formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound having formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0104] On the other hand, the present invention relates to compounds having formula (I) or pharmaceutically acceptable salts thereof used as medicines.

[0105] Another aspect of the present invention relates to a compound having formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound having formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, for use in the treatment of a disease or disorder that responds to inhibition of GIRK1 / 4 receptors.

[0106] In another aspect, the present invention relates to a compound having formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound having formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, for the treatment, prevention, inhibition or elimination of a disease or disorder, wherein the disease or disorder is selected from arrhythmias, atrial fibrillation, bradycardia, bradycardia, cardiac conduction block, atrial cavity disorder syndrome, parasympathetic hyperactivation, primary hyperaldosteronism, hypotension and vasovagal syncope.

[0107] In another aspect, the present invention relates to a compound having formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound having formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, for maintaining sinus rhythm after cardiac remission in a patient with persistent or recently occurring atrial fibrillation, or for preventing recurrence in a patient with paroxysmal atrial fibrillation.

[0108] Another aspect of the present invention relates to the use of a compound having formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound having formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, in the preparation of a medicament for treating a disease or disorder that responds to inhibition of GIRK1 / 4 receptors.

[0109] In another aspect, the present invention relates to the use of a compound having formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound having formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, in the treatment of a disease or disorder selected from arrhythmias, atrial fibrillation, bradycardia, bradycardia, heart block, atrial cavity disorder syndrome, parasympathetic hyperactivation, primary hyperaldosteronism, hypotension, and vasovagal syncope.

[0110] In another aspect, the present invention relates to the use of a compound having formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound having formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, in maintaining sinus rhythm or preventing recurrence in patients with persistent or recently occurring atrial fibrillation after cardiac remission.

[0111] In some embodiments, the disease or disorder is one that responds to inhibition of GIRK1 / 4 receptors. In some embodiments, the disease or disorder that responds to inhibition of GIRK1 / 4 receptors is selected from arrhythmias, atrial fibrillation, bradycardia, bradycardia, heart block, atrial cavity disorder syndrome, parasympathetic hyperactivation, primary hyperaldosteronism, hypotension, and vasovagal syncope.

[0112] In some implementations, the disease or disorder is selected from arrhythmia, atrial fibrillation, bradycardia, bradycardia, cardiac conduction block, atrial cavity disorder syndrome, parasympathetic hyperactivation, primary hyperaldosteronism, hypotension, and vasovagal syncope.

[0113] The compounds disclosed in this invention can be administered in effective amounts to treat or prevent disorders and / or prevent their development in subjects.

[0114] In some embodiments, the compound is administered orally. [, Combination therapy , ]

[0115] The compounds of this invention can be administered in therapeutically effective amounts in combination therapy with one or more pharmaceutical activities (drug combinations) or methods (e.g., non-pharmacological therapies). For example, synergistic effects may occur with other cardiovascular agents, antihypertensive agents, coronary vasodilators, and diuretics. When the compounds of this application are administered in combination with other therapies, the dosage of the co-administered compounds will naturally vary depending on the type of combined drugs used, the specific drugs used, the condition being treated, etc.

[0116] The compounds of this invention can be administered simultaneously with, before, or after one or more other pharmaceutically active agents. The compounds of this invention can be administered separately via the same or different routes of administration as other pharmaceutical agents, or administered together in the same pharmaceutical composition. Pharmaceutically active agents are, for example, chemical compounds, peptides, antibodies, antibody fragments, or nucleic acids that have therapeutic activity or enhance therapeutic activity when administered to a patient in combination with the compounds of this invention.

[0117] In one embodiment, the present invention provides a product comprising the compound of the present invention and at least one other pharmaceutically active agent, as a combination formulation for simultaneous, separate, or sequential use in a therapy. In one embodiment, the therapy is for treating a disease or disorder that responds to inhibition of GIRK1 / 4 receptors. The product provided as a combination formulation comprises a composition that collectively comprises the compound of the present invention and one or more other pharmaceutically active agents in the same pharmaceutical composition as described herein, or comprises the compound of the present invention and one or more other pharmaceutically active agents in a separate form (e.g., in a kit).

[0118] In another aspect, the present invention includes compounds having formula (I) or pharmaceutically acceptable salts thereof, used in combination therapies.

[0119] Another aspect of the present invention relates to pharmaceutical compositions comprising a compound having formula (I) or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, and one or more pharmaceutically active agents. The pharmaceutically acceptable carrier may further comprise excipients, diluents, or surfactants.

[0120] Combination therapy involves further combining the subject compound with other bioactive ingredients. For example, the compound of this application can be used in combination with other pharmaceutically active agents (preferably compounds that enhance the effect of the compound of this application). The compound of this application can be administered simultaneously (as a single formulation or alone) or sequentially to other drug therapies or modes of treatment. Typically, combination therapy envisions administering two or more drugs during a single cycle or course of treatment.

[0121] Exemplary additional pharmaceutically active agents that can be used in combination with the compounds of the present invention include, but are not limited to, any other antiarrhythmic agents, such as Class I antiarrhythmic agents (e.g., quinidine, lidocaine, and propafenone), Class II antiarrhythmic agents (e.g., propranolol), Class III antiarrhythmic agents (e.g., sotalol, dofetilide, amiodarone, dronedarone, buiodarone, azlilide, and ibutilide), Class IV antiarrhythmic agents (e.g., diltiazem and verapamil), Class V antiarrhythmic agents (e.g., adenosine), cardiac glycosides (e.g., digitalis and urobilinogen), and other drugs that affect atrial refractoryness (e.g., INa, a late blocker as described in WO 2013 / 112932). Hemostatic modifiers, including antithrombotic agents such as fibrinolytic activators; thrombin inhibitors; factor V1a inhibitors; anticoagulants such as vitamin K antagonists (e.g., warfarin), heparin and its low molecular weight analogs (e.g., dalteparin sodium), factor Xa inhibitors (e.g., rivaroxaban and apixaban), and direct thrombin inhibitors (e.g., argatroban); antiplatelet agents such as cyclooxygenase inhibitors (e.g., aspirin and NSAIDs), adenosine diphosphate (ADP) receptor inhibitors (e.g., clopidogrel), phosphodiesterase inhibitors (e.g., cilostazol), glycoprotein IIB / IIA inhibitors (e.g., tirofiban hydrochloride), and adenosine reuptake inhibitors (e.g., dipyridamole); antilipidemic agents such as HMG-CoA reductase inhibitors (statins) and other cholesterol-lowering agents; PPARα agonists (fibrates, e.g., gemfibrozil and fenofibrate); bile acid sequestrants (e.g., cholestyramine); cholesterol absorption inhibitors (e.g., phytosterols, i.e., plant... Steroids; synthesis inhibitors; cholesterol ester transfer protein (CETP) inhibitors; ileal bile acid transport system inhibitors (IBAT inhibitors); bile acid conjugating resins; nicotinic acid (Nicotinic acid) and its analogues; antioxidants; and ω-3 fatty acids; antihypertensive agents, including adrenergic receptor antagonists such as beta blockers (e.g., atenolol), alpha blockers (e.g., doxazosin), and mixed alpha / beta blockers (e.g., labetalol); adrenergic receptor agonists, including Alpha-2 agonists (e.g., clonidine); angiotensin-converting enzyme (ACE) inhibitors (e.g., lisinopril); calcium channel blockers such as dihydropyridine (e.g., nifedipine), phenylalkylamines (e.g., verapamil), and benzothiazazepines (e.g., diltiazem); angiotensin II receptor antagonists (e.g., losartan); aldosterone receptor antagonists (e.g., eplerenone); centrally acting adrenergic drugs, such as centrally acting alpha agonists (e.g., clonidine); and diuretics (e.g., furosemide).Anti-obesity drugs, such as appetite suppressants (e.g., ephedrine), include norepinephrine-like drugs (e.g., phenbutazone) and serotonin-activating drugs (e.g., sibutramine), pancreatic lipase inhibitors (e.g., orlistat), microsomal transfer protein (MTP) modulators, diacylglycerol amide (DGAT) inhibitors, and cannabinoid (CBI) receptor antagonists (e.g., rimonaban); insulin and insulin analogs; insulin secretagogues, including sulfonylureas (e.g., glipizide) and prandial glucose regulators (sometimes called... Short-acting secretagogues such as chloroquine (e.g., repaglinide and nateglinide); agents that improve the action of intestinal glucagons, such as dipeptidyl peptidase IV (DPP-4) inhibitors (e.g., vildagliptin, sitagliptin, LAF237, MK-431) and glucagon-like peptide-1 (GLP-1) agonists (e.g., exenatide); insulin sensitizers, including peroxisome proliferator-activated receptor gamma (PPARγ) agonists, such as thiazolidinediones (e.g., pioglitazone and rosiglitazone), and those with PPARγ... Medications with any combination of α, γ, and δ activities; medications that regulate hepatic glucose homeostasis, such as biguanides (e.g., metformin), fructose-1,6-bisphosphatase inhibitors, glycogen phosphorylase inhibitors, glycogen synthase kinase inhibitors, and glucokine activators; medications designed to reduce / slow down intestinal glucose absorption, such as α-glucosidase inhibitors (e.g., miglitol and acarbose); medications that antagonize the effects of glucagon or reduce its secretion, such as islet amyloid analogs (e.g., pramlintide); and medications that prevent renal reabsorption of glucose, such as sodium-dependent glucose transporter 2 (SGLT-2) inhibitors.

[0122] The term "HMG-Co-A reductase inhibitor" (also known as β-hydroxy-β-methylpentanediol-coenzyme-A reductase inhibitor) includes active agents that can be used to lower lipid levels such as cholesterol in the blood. Examples include atorvastatin, cerivastatin, compattin, davastatin, dihydrocompattin, fludostatin, fluvastatin, lovastatin, pitavastatin, mevastatin, pravastatin, rivastatin, simvastatin, and velotasone, or pharmaceutically acceptable salts thereof.

[0123] The term "ACE inhibitor" (also known as angiotensin-converting enzyme inhibitor) includes molecules that interrupt the enzymatic degradation of angiotensin I into angiotensin II. These compounds are used to regulate blood pressure and treat congestive heart failure. Examples include alapril, benazepril, benazeprilat, captopril, siropril, cilazapril, delapril, enalapril, fosinopril, imidapril, lisinopril, mopeltopril, perindopril, quinapril, ramipril, spiropril, temopril, and trandopril, or pharmaceutically acceptable salts thereof.

[0124] Angiotensin II receptor antagonists or pharmaceutically acceptable salts thereof should be understood as active ingredients that bind to the AT1-receptor subtype of the angiotensin II receptor but do not cause receptor activation. As a result of inhibiting the AT1 receptor, such antagonists can be used, for example, as antihypertensive drugs or for the treatment of congestive heart failure.

[0125] The term "diuretic" includes thiazolidinediones (such as chlorophenoxy ...

[0126] DPP-IV is responsible for inactivating GLP-1. More specifically, DPP-IV produces GLP-1 receptor antagonists and thereby shortens the physiological response to GLP-1. GLP-1 is the main stimulator of pancreatic insulin secretion and has a direct beneficial effect on glucose processing. DPP-IV inhibitors may be peptides or, preferably, non-peptides. DPP-IV inhibitors include, but are not limited to, sitagliptin, linagliptin, saxagliptin, and alogliptin. DPP-IV inhibitors are also generally and specifically disclosed in, for example, WO 98 / 19998, DE 196 16 486 A1, WO 00 / 34241, and WO 95 / 15309, in each case, particularly in the final product, pharmaceutical formulation, and claims of the compound claims and working examples, which are incorporated herein by reference to these publications. Preferably, those compounds specifically disclosed in Example 3 of WO 98 / 19998 and Example 1 of WO 00 / 34241 are preferred.

[0127] GLP-1 is an insulin-stimulating protein, described by WESchmidt et al. in Diabetologia, 28, 1985, 704-707 and in US 5,705,483. The term "GLP-1 agonist" includes variants and analogs of GLP-1(7-36)NH2, specifically disclosed in the following literature: US 5,120,712, US 5,118666, US 5,512,549, WO 91 / 11457 and C. Orskov et al. J. Biol. Chem. 264 (1989) 12826. Other examples include: GLP-1(7-37), compounds in which the carboxyl-terminal amide functional group of Arg 36 is replaced by Gly at position 37 of the GLP-1(7-36)NH 2 molecule, and their variants and analogs, including GLN 9-GLP-1(7-37), D-GLN 9-GLP-1(7-37), acetylated LYS 9-GLP-1(7-37), LYS 18-GLP-1(7-37), and particularly, GLP-1(7-37)OH, VAL 8-GLP-1(7-37), GLY 8-GLP-1(7-37), THR 8-GLP-1(7-37), MET 8-GLP-1(7-37) and 4-imidazopropionic-GLP-1. GLP-1 receptor agonists include, but are not limited to, semaglutide, exenatide, and liraglutide.

[0128] Aldosterone synthase inhibitors or pharmaceutically acceptable salts thereof should be understood as active ingredients with properties that inhibit aldosterone production. Aldosterone synthase (CYP11B2) is a mitochondrial cytochrome P450 enzyme that catalyzes the final step in aldosterone production in the adrenal cortex: the conversion of 11-deoxycorticosterone to aldosterone. Inhibition of aldosterone production with so-called aldosterone synthase inhibitors is known to be a successful variant for treating hypokalemia, hypertension, congestive heart failure, atrial fibrillation, or renal failure. Such aldosterone synthase inhibitory activity can be readily determined by those skilled in the art using standard assays (e.g., US 2007 / 0049616).

[0129] Aldosterone synthase inhibitors include steroidal and nonsteroidal aldosterone synthase inhibitors, with the latter being the best.

[0130] The class of aldosterone synthase inhibitors includes compounds with different structural features. For example, reference may be made to compounds selected from the group consisting of: nonsteroidal aromatase inhibitors anastrozole, fazodazole (including its (+)-mirror isomers), and steroidal aromatase inhibitor isomestan, or, in each applicable case, its pharmaceutically acceptable salts.

[0131] The best nonsteroidal aldosterone synthase inhibitor is the (+)-mirror isomer of fazolidinium hydrochloride.

[0132] Preferred steroidal aldosterone antagonists are eplerenone or spironolactone; or (in each case, if appropriate) their pharmaceutically acceptable salts.

[0133] Aldosterone synthase inhibitors that can be used in the aforementioned combinations are compounds and analogues generally and specifically disclosed, for example, in US 2007 / 0049616, specifically in the final product, subject matter, pharmaceutical formulation, and claims of the compound claims and working examples, which are incorporated herein by reference to the aforementioned publications.

[0134] The term aldosterone synthase inhibitor also includes compounds and analogues disclosed in WO 2008 / 076860, WO 2008 / 076336, WO 2008 / 076862, WO 2008 / 027284, WO 2004 / 046145, WO 2004 / 014914, and WO 2001 / 076574.

[0135] In addition, aldosterone synthase inhibitors also include compounds and analogues disclosed in U.S. patent applications US 2007 / 0225232, US 2007 / 0208035, US 2008 / 0318978, US 2008 / 0076794, US 2009 / 0012068, US 2009 / 0048241 and PCT applications WO 2006 / 005726, WO 2006 / 128853, WO 2006128851, WO 2006 / 128852, WO 2007 / 065942, WO 2007 / 116099, WO 2007 / 116908, WO 2008 / 119744 and European patent application EP 1886695.

[0136] The term "CETP inhibitor" refers to a compound that inhibits the CETP-mediated transport of various cholesterol esters and triglycerides from HDL to LDL and VLDL. Such CETP inhibitory activity can be readily determined by those skilled in the art using standard assays (e.g., U.S. Patent No. 6,140,343). Examples include compounds disclosed in U.S. Patent Nos. 6,140,343 and 6,197,786 (e.g., ethyl [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylate (torcetrapib)); compounds disclosed in U.S. Patent No. 6,723,752 (e.g., (2R)-3-{[3-(4-chloro-3-ethyl-phenoxy)-phenyl]-[[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-methyl]-amino}-1,1,1-trifluoro-2-propanol); compounds disclosed in U.S. Patent Application Serial No. 10 / 807,838; polypeptide derivatives disclosed in U.S. Patent No. 5,512,548; and those disclosed in J. Antibiot., 49(8): 815-816 (1996), and Bioorg. Med. Chem. Lett.; 6:1951-1954 (1996) as rosemary derivatives and phosphate-containing analogs of cholesterol esters. In addition, CETP inhibitors also include those disclosed in WO 2000 / 017165, WO 2005 / 095409, and WO 2005 / 097806.

[0137] In another embodiment, the other therapeutic agents are selected from any other antiarrhythmic agents, such as Class I antiarrhythmic agents (e.g., quinidine, lidocaine, and propafenone), Class II antiarrhythmic agents (e.g., propranolol), Class III antiarrhythmic agents (e.g., sotalol, dofetilide, amiodarone, dronedarone, buiodarone, azlilide, and ibutilide), Class IV antiarrhythmic agents (e.g., diltiazem and verapamil), Class V antiarrhythmic agents (e.g., adenosine), cardiac glycosides (e.g., digitalis and urobilinogen), and other drugs that affect atrial refractoryness (e.g., INa, a late blocker as described in WO 2013 / 112932).

[0138] "Combination therapy" is intended to include the sequential administration of such therapeutic agents, wherein each therapeutic agent is administered at different times and in any order, or in an alternating manner and in any order, and in a substantially simultaneous manner, or at least two therapeutic agents. Substantially simultaneous administration can be achieved, for example, by administering to the subject a single capsule or multiple single capsules for each therapeutic agent in a fixed proportion. The sequential or substantially simultaneous administration of each therapeutic agent can be carried out by any suitable route, including but not limited to oral, intravenous, intramuscular, and direct absorption through mucosal tissue. Therapeutic agents can be administered via the same or different routes. For example, the first therapeutic agent of a selected combination can be administered intravenously, while the other therapeutic agents in the combination can be administered orally. Alternatively, for example, all therapeutic agents can be administered orally or all therapeutic agents can be administered intravenously. The order of administration of the therapeutic agents is not strictly defined. [, Having a style , ] [, (I) , ] [, Preparation method of the compound , ] [, , ]

[0139] The compounds of formula (I) of this invention can be prepared by various methods (including standard chemistry). Suitable synthetic routes are described in the schemes given below.

[0140] Compounds having formula (I) can be prepared by methods known in the field of organic synthesis, as illustrated in part by the following synthetic schemes. In the schemes described below, it is readily understood that, according to general principles or chemistry, protecting groups of sensitive or reactive groups are used where necessary. Protecting groups are manipulated according to standard methods of organic synthesis (TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", 3rd ed., Wiley, NY 1999). These groups are removed at a convenient stage of compound synthesis using methods readily apparent to those skilled in the art. The selection of procedures, reaction conditions, and their sequence of execution should be consistent with the preparation of compounds having formula (I).

[0141] Those skilled in the art will recognize the presence of a stereocenter in compounds having formula (I). Therefore, the present invention includes two possible stereoisomers (unless otherwise indicated in the synthesis) and includes not only racemic compounds but also individual mirror-image and / or non-mirror-image isomers. When a compound is required as a single mirror-image or non-mirror-image isomer, it can be obtained by stereo-oriented synthesis or by resolving the final product or any convenient intermediate. The resolving of the final product, intermediate, or starting material can be influenced by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E.L. Eliel, S.H. Wilen, and L.N. Mander (Wiley-Interscience, 1994).

[0142] The compounds described herein can be prepared from commercially available starting materials or synthesized using known organic, inorganic, and / or enzymatic methods. [, definition , ] [, , ]

[0143] Terms not explicitly defined herein shall be understood to have the meaning that a person skilled in the art would derive from the invention and the context. For the purposes of interpreting this specification, unless otherwise stated, the following definitions shall apply, and where appropriate, terms used in the singular form shall also include the plural form, and vice versa.

[0144] It is important to note that, as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural indicators unless the context clearly specifies otherwise. Thus, for example, reference to “medicinal formulation” includes reference to one or more pharmaceutical formulations; etc.

[0145] As used herein, the term "acetylated" refers to a group represented by the general formula hydrocarbon C(O)- (preferably alkyl C(O)-).

[0146] As used herein, the term "aceoxy group" refers to a group represented by the general formula hydrocarbon C(O)O- (preferably alkyl C(O)O-).

[0147] As used herein, the term "alkenyl" refers to an aliphatic group containing at least one double bond and is intended to include both "unsubstituted alkenyl" and "substituted alkenyl," the latter referring to an alkenyl moiety having a substituent replacing a hydrogen atom on one or more carbons of the alkenyl group. Such substituents may occur on one or more carbons, including or not included in one or more double bonds. Furthermore, such substituents include all those considered in relation to alkyl groups, as discussed below, unless stability is prohibited. For example, consider substituting an alkenyl group with one or more alkyl, carbocyclic, aryl, heterocyclic, or heteroaryl groups. Examples of alkenyl groups include vinyl, propenyl, n-butenyl, isobutenyl, pentenyl, or hexenyl.

[0148] As used herein, the term "alkoxy" refers to an alkyl group having an oxygen atom attached to it, preferably a lower alkyl group, such as -O (alkyl). Representative alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, and tertiary butoxy. Representative substituted alkoxy groups include, but are not limited to, -OCF3.

[0149] "Alkyl" groups or "alkane" refer to fully saturated straight-chain or branched non-aromatic hydrocarbons. Typically, straight-chain or branched alkyl groups have 1 to about 20 carbon atoms, preferably 1 to about 10, unless otherwise defined. Examples of straight-chain and branched alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, tertiary butyl, pentyl, hexyl, pentyl, and octyl. C1-C6 straight-chain or branched alkyl groups are also called "lower alkyl" groups.

[0150] As used herein, the term "alkynyl" refers to an aliphatic group containing at least one triple bond. Examples of alkynyl groups include ethynyl, propynyl, n-butynyl, isobutynyl, pentyynyl, or hexynyl.

[0151] As used herein, the term "aryl" includes substituted or unsubstituted monocyclic aromatic groups, wherein each atom of the ring is a carbon. Preferably, the ring system is a 5- to 7-membered ring, and more preferably a 6-membered ring. The term "aryl" also includes polycyclic systems having two or more rings, wherein two or more carbons are shared by two adjacent rings, wherein at least one ring is aromatic, for example, the other rings may be cycloalkyl, cycloalkenyl, cycloynyl, aryl, heteroaryl, and / or heterocyclic. Aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthraceneyl, ferroyl, phenanthryl, dihydroindenyl, indenyl, tetrahydronaphthyl, tetrahydrobenzoxanthyl, etc.

[0152] The term "Cxy" when used in conjunction with a chemical moiety (e.g., acetyl, aceoxy, alkyl, alkenyl, alkynyl, or alkoxy) is intended to include groups containing x to y carbon atoms in the chain. For example, the term "Cxyalkyl" refers to a substituted or unsubstituted saturated hydrocarbon group, including straight-chain alkyl and branched-chain alkyl groups containing x to y carbons in the chain, including haloalkyl groups such as trifluoromethyl, 2,2,2-trifluoroethyl, etc. C0alkyl indicates hydrogen when the group is terminal, and a bond if it is internal. The terms "C2-yalkenyl" and "C2-yalkynyl" refer to substituted or unsubstituted unsaturated aliphatic groups that are similar in length and possible substitutions to the alkyl groups described herein, but respectively contain at least one double or triple bond.

[0153] As used herein, the terms "carbocyclic" and "of a carbocyclic ring" refer to a saturated or unsaturated ring in which every atom of the ring is carbon. The term carbocyclic includes aromatic and non-aromatic carbocyclic rings. Non-aromatic carbocyclic rings include cycloalkanes in which all carbon atoms are saturated and cycloalkenes containing at least one double bond. "Carbocyclic" includes 5-7 member monocyclic rings and 8-12 member bicyclic rings. Each ring of a bicyclic carbocyclic ring can be selected from saturated, unsaturated, and aromatic rings. A carbocyclic ring includes a bicyclic molecule in which two rings share one, two, three, or more atoms. The term "fused carbocyclic" refers to a bicyclic carbocyclic ring in which each ring shares two adjacent atoms with another ring. Each ring of a fused carbocyclic ring can be selected from saturated, unsaturated, and aromatic rings. In one exemplary embodiment, an aromatic ring, such as a phenyl group, can be fused to a saturated or unsaturated ring, such as cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated bicyclic, unsaturated bicyclic, and aromatic bicyclic rings, provided that the valence allows, is included in the definition of a carbocyclic ring. Exemplary "carbocyclic rings" include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene, and adamantane. Exemplary fused carbocyclic rings include naphthane, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-1H-indene, and bicyclo[4.1.0]hept-3-ene. The "carbocyclic ring" can be substituted at any one or more positions capable of carrying hydrogen atoms.

[0154] A "cycloalkyl" group is a fully saturated cyclic hydrocarbon. "Cycloalkyl" includes monocyclic and bicyclic rings. Typically, monocyclic cycloalkyl groups have 3 to about 10 carbon atoms, more typically 3 to 8 carbon atoms, unless otherwise defined. The second ring of a bicyclic cycloalkyl group can be selected from saturated, unsaturated, and aromatic rings. Cycloalkyl includes bicyclic molecules in which two rings share one, two, or three or more atoms. The term "fused cycloalkyl" refers to a bicyclic cycloalkyl in which each ring shares two adjacent atoms with the other ring. The second ring of a fused bicyclic cycloalkyl group can be selected from saturated, unsaturated, and aromatic rings.

[0155] As used herein, the terms "halogenated" and "halogen" refer to halogens and include chlorine, fluorine, bromine, and iodine.

[0156] As used herein, the terms "heteroalkyl" and "heteroaryl" refer to alkyl groups substituted with heteroaryl groups.

[0157] As used herein, the term "heteroalkyl" refers to a saturated or unsaturated chain having a carbon atom and at least one heteroatom, wherein no two heteroatoms are adjacent to each other.

[0158] The terms "heteroaryl" and "hetaryl" include substituted or unsubstituted aromatic monocyclic structures, preferably 5 to 7-membered rings, more preferably 5 to 6-membered rings, whose ring structure includes at least one heteroatom, preferably 1 to 4 heteroatoms, and more preferably one or two heteroatoms. The terms "heteroaryl" and "hetaryl" also include polycyclic systems having two or more rings, wherein two or more carbons are shared by two adjacent rings, wherein at least one ring is heteroaromatic; for example, the other rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclic. Heteroaryl groups include, but are not limited to: furanyl, thiophene, pyrrolyl, pyridyl, pyridyl N-oxide, pyrazolyl, pyrimidinyl, imidazoleyl, isozolyl, azolyl, azidiazoleyl, pyrrolyl, indolyl, thiophene-2-yl, quinolinyl, benzopiperanyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazolyl, imidozolo[1,2-b]pyrazolyl, fluoro[2,3-c]pyridyl, imidozolo[1,2-a]pyridyl, indazoleyl, pyrrolo[2,3-c]pyridyl, Pyrrolo[3,2-c]pyridyl, pyrazolo[3,4-c]pyridyl, thieno[3,2-c]pyridyl, thieno[2,3-c]pyridyl, thieno[2,3-b]pyridyl, benzothiazolyl, indole, dihydroindole, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, thiobenzoyl, tetrahydroquinolinyl, dihydrobenzothiazolyl, dihydrobenzoalkyl, quinolinyl, isoquinolinyl, 1,6-quinolinyl, benzo[de]isoquinolinyl, pyrido[4, 3-b][1,6]pyridyl, thieno[2,3-b]pyridyl, quinazolinyl, tetrazo[1,5-a]pyridyl, [1,2,4]triazol[4,3-a]pyridyl, isoindolyl, pyrrolo[2,3-b]pyridyl, pyrrolo[3,4-b]pyridyl, pyrrolo[3,2-b]pyridyl, imidazo[5,4-b]pyridyl, pyrrolo[1,2-a]pyrimidinyl, tetrahydropyrrolo[1,2-a]pyrimidinyl, 3,4-dihydro-2H-1Δ2-pyrrolo[2,1-b]pyrimidinyl, dibenzo[ [b,d]thiophene, pyridin-2-one, fluoro[3,2-c]pyridyl, fluoro[2,3-c]pyridyl, 1H-pyrido[3,4-b][1,4]thiazolyl, benzo[3,2-b]pyridyl, fluoro[2,3-b]pyridyl, benzo[3,4-b]thiazolyl, 1H-pyrido[3,4-b][1,4]thiazolyl, 1,5-pyridyl, fluoro[3,2-b]pyridine, [1,2,4]triazolo[1,5-a]pyridyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[4,3-b]pyridyl, benzo[c][1,2,5] Thiadiazolyl, benzo[c][1,2,5] acediazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo[1,5-b][1,2] acediyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridyl, thiazo[5,4] [d] Thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrroleyl, 3H-indolyl, indololinyl, indoloneyl, dihydrobenzothiophenyl, dihydrobenzofuran, oxoquinolinyl, thioquinolinyl, tetrahydroquinolinyl, dihydrobenzothiazolyl, 3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuran, indololinyl, indolyl, and dihydrobenzoalkyl.

[0159] As used in this article, the term "heteroatom" refers to an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0160] The terms "heterocyclic", "heterocyclic", and "heterocyclic" refer to substituted or unsubstituted non-aromatic ring structures, preferably 3 to 10-membered rings, more preferably 3 to 7-membered rings, whose ring structure includes at least one heteroatom, more preferably 1 to 4 heteroatoms, and even more preferably one or two heteroatoms. The terms "heterocyclic" and "heterocyclic" also include polycyclic systems having two or more rings, wherein two or more carbons are shared by two adjacent rings, wherein at least one ring is heterocyclic, for example, the other rings may be cycloalkyl, cycloalkenyl, cycloynyl, aryl, heteroaryl, and / or heterocyclic. Heterocyclic groups include, for example, piperidine, piperazine, pyrrolidine, succinyl, lactone, and lactamine. Heterocyclic groups can also be substituted with lateral oxygen groups. For example, "heterocyclic groups" include pyrrolidine and pyrrolidone.

[0161] As used herein, "halogenated alkyl" refers to an alkyl group that is substituted with one or more halogens. Examples of halogenated alkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc.

[0162] As used herein, the term "sidekole" refers to a carbonyl group. When a sidekole substituent appears on a group that is not saturated, such as in the case of sidekole-substituted cycloalkyl groups (e.g., 3-sidekole-cyclobutyl), the substituted group is still intended to be a saturated group. When a group is referred to as being substituted by a "sidekole" group, this may mean that the carbonyl moiety (i.e., -C(=O)-) replaces the methylene unit (i.e., -CH2-).

[0163] The term "substitutable as desired" means that a given chemical moiety (e.g., an alkyl group) may (but is not required to) be bonded to other substituents (e.g., heteroatoms). For example, a substitutable alkyl group may be a fully saturated alkyl chain (e.g., a pure hydrocarbon). Alternatively, the same substituent alkyl group may have substituents other than hydrogen, wherein the substituents are as defined herein. As used herein, "substitutable as desired" also refers to substituted or unsubstituted, the meaning of which is described below.

[0164] The term "substituted" means that a specified group or portion carries one or more suitable substituents, wherein such substituents may be attached to the specified group or portion at one or more positions. For example, an aryl group substituted with a cycloalkyl group may indicate that the cycloalkyl group is attached to one atom of the aryl group by a bond or by fusion with the aryl group and sharing two or more common atoms.

[0165] The term "unsubstituted" means that a particular group does not have substituents.

[0166] "Patient" or "subject" refers to a mammal, such as a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or a non-human primate, such as a monkey, chimpanzee, baboon, or rhesus monkey. In some embodiments, the subject is a primate. In other embodiments, the subject is a human.

[0167] The terms "effective amount of medicine," "therapeutic effective amount," or "effective amount" mean an amount of a compound according to the invention that, when administered to a patient in need, is sufficient to treat a disease state, symptom, or disorder in which the compound is effective. This amount is sufficient to elicit a biological or medical response in the tissue, system, or patient sought by the researcher or clinician. The amount of the compound according to the invention constituting a therapeutically effective amount will vary depending on factors such as the compound and its biological activity, the composition used for administration, the time of administration, the route of administration, the rate of excretion of the compound, the duration of treatment, the type and severity of the disease state or disorder being treated, the drugs used in combination with or in combination with the compound of the invention, and the patient's age, weight, general health, sex, and diet. This therapeutically effective amount can be determined by those skilled in the art based on their own knowledge, prior art, and the conventional practice of the invention.

[0168] As used herein, the term "pharmaceutical composition" refers to the compound of the present invention or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer, and at least one pharmaceutically acceptable carrier, in a form suitable for oral or parenteral administration.

[0169] "Carrier" encompasses carriers, excipients, and diluents, and refers to materials, components, or media that involve carrying or transporting a pharmaceutical agent from one organ or part of a subject's body to another organ or part of a subject's body, such as liquid or solid fillers, diluents, excipients, solvents, or encapsulation materials.

[0170] "Combination" refers to a fixed combination in the form of a single dose unit, or a combination administration (whereby the compounds of the present invention and at least one combination partner (e.g., another drug explained below, also referred to as a "therapeutic agent" or "co-agent")) can be administered independently at the same time or separately at time intervals, particularly where such time intervals allow the combination partner to exhibit the beneficial effects of the combined effects of the therapeutic agents). The beneficial effects of a combination include, but are not limited to, synergistic effects resulting from the combination of therapeutic agents, such as synergistic effects and / or pharmacokinetic or pharmacodynamic synergistic effects, or any combination thereof. In one embodiment, the combined administration of the therapeutic agents is performed over a defined time period (e.g., minutes, hours, days, or weeks, depending on the chosen combination).

[0171] Individual components may be packaged in a kit or separately. One or both components (e.g., powder or liquid) may be reconstituted or diluted to the desired dose prior to administration. As used herein, the terms “co-administration” or “combination administration” are intended to cover the administration of a selected combination of agents to a single subject (e.g., a patient) in need, and are intended to include treatment regimens in which the agents are not necessarily administered via the same route of administration or administered simultaneously.

[0172] As used herein, the term "drug combination" means a product resulting from a mixture or combination of more than one therapeutic agent, and includes both fixed and non-fixed combinations of therapeutic agents. The term "fixed combination" means that therapeutic agents (e.g., the compounds and combination partners of the present invention) are administered to a patient simultaneously as a single entity or dose. The term "non-fixed combination" means that therapeutic agents (e.g., the compounds and combination partners of the present invention) are administered to a patient simultaneously, in parallel, or sequentially as separate entities (without a specific time limit), wherein such administration provides a therapeutically effective level of two compounds in the patient's body. The latter also applies to cocktail therapies, such as the administration of three or more therapeutic agents.

[0173] Such subjects are considered to "need" the treatment (preferably, human beings) if they would benefit from it biologically, medically, or in terms of quality of life.

[0174] As used herein, the term "inhibit (inhibition or inhibiting)" means a reduction or inhibition of a given condition, symptom or disorder, or disease, or a significant reduction in baseline activity of a biological activity or process.

[0175] As used herein, the term “treatment” for any disease or disorder means relief or reduction of the disease or disorder (i.e., slowing or halting the development of the disease or at least one of its clinical symptoms); or relief or reduction of at least one physical parameter or biomarker associated with the disease or disorder, including those physical parameters or biomarkers that the patient may not be able to identify.

[0176] As used herein, the term "prevent, preventing, or prevention" for any disease or disorder refers to preventive treatment of the disease or disorder; or delaying the onset or progression of the disease or disorder.

[0177] "Pharmaceutical acceptable" means that a substance or composition must be chemically and / or toxicologically compatible with other components of the formulation and / or the mammals to which it is being treated.

[0178] Unless otherwise indicated, “obstacle” means the terms disease, ailment, or ailment, and is used interchangeably with those terms.

[0179] "Administering" means administering the disclosed compound, or a pharmaceutically acceptable salt or composition thereof, directly to a subject, or administering the compound, or a pharmaceutically acceptable salt or composition thereof, as a precursor or analogue to the subject, which may result in the formation of an equivalent amount of the active compound in the subject's body.

[0180] "Compounds of the present invention", "compounds having formula (I)", "compounds of the invention" and equivalent expressions (unless otherwise specifically stated) refer to compounds having formulas (I) and (Ia) as described herein, including salts, especially pharmaceutically acceptable salts thereof, where the context permits, and all stereoisomers (including non-mirror image isomers and mirror image isomers), rotational isomers, tautomers and isotopically labeled compounds (including deuterium ("D") substitution).

[0181] In one particular implementation, the terms "about" or "approximately" mean within 20%, more preferably within 10%, and even more preferably within 5% of a given value or range.

[0182] As used herein, "disorders or diseases that respond to inhibition of GIRK1 / 4 receptors" and "disorders that respond to inhibition of GIRK1 / 4 receptors" and similar terms include, but are not limited to, arrhythmia, atrial fibrillation, bradycardia, bradycardia, heart block, atrial cavity disorder syndrome, parasympathetic hyperactivation, primary hyperaldosteronism, hypotension, and vasovagal syncope. [] [Example] []

[0183] The invention is further illustrated by the following examples and synthetic embodiments, which should not be construed as limiting the scope or spirit of the invention to the specific procedures described herein. It should be understood that these examples are provided to illustrate certain implementations, and the scope of the invention is not intended to be limited thereto. It should be further understood that various other embodiments, modifications, and equivalents thereof may be adopted by those skilled in the art without departing from the spirit of the invention and / or the scope of the appended claims.

[0184] The compounds of this invention can be prepared by methods known in the field of organic synthesis. In all methods, it should be understood that protecting groups against sensitive or reactive groups can be used, as necessary, according to general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (TW Green and PGM Wuts (1999) Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons). These groups are removed at a convenient stage of compound synthesis using methods readily apparent to those skilled in the art.

[0185] Unless otherwise specified, use reagents and solvents received from commercial suppliers. Unless otherwise specified, obtain proton nuclear magnetic resonance (NMR) spectra on a Bruker Avance spectrometer or a Varian Oxford 400 MHz spectrometer. NMR spectra are given in ppm (δ), and the coupling constant J is reported in Hertz. Tetramethylsilane (TMS) is used as an internal standard. Chemical shifts are reported in ppm relative to dimethyl sulfoxide (δ 2.50), methanol (δ 3.31), chloroform (δ 7.26), or other solvents shown in the NMR spectral data. Dissolve a small amount of dried sample (2 mg–5 mg) in a suitable deuterated solvent (1 mL). Mass spectra (ESI-MS) are collected using a Waters system (Acquity UPLC and Micromass ZQ mass spectrometers) or an Agilent-1260 Infinity (6120 quadrupole); unless otherwise specified, all reported masses are m / z of the protonated parent ion. Chemical names were generated using ChemBioDraw Ultra v14 from CambridgeSoft.

[0186] Temperatures are given in degrees Celsius. As used herein, unless otherwise stated, the terms "room temperature" or "ambient temperature" refer to temperatures between 15 and 30 degrees Celsius, e.g., 20 to 30 degrees Celsius, e.g., 20 to 25 degrees Celsius. Unless otherwise mentioned, all evaporation is carried out under reduced pressure, typically between about 15 mm Hg and 100 mm Hg (= 20–133 mbar). The structures of the final products, intermediates, and starting materials are confirmed by standard analytical methods (e.g., trace analysis and spectroscopic characterization (e.g., MS, IR, NMR)). Abbreviations used are those commonly used in the art.

[0187] All starting materials, structural units, reagents, acids, bases, dehydrating agents, solvents and catalysts used to synthesize the compounds of this invention are commercially available or can be prepared by organic synthesis methods known to those skilled in the art. [ [surface] [1] [.] [The following examples and abbreviations used elsewhere in this article:] [] ACN Acetonitrile aq. water-based 9-BBN 9-Boronbicyclo[3.3.1]nonane BOC tert-butyloxycarbonyl br wide peak bs broad single peak °C Celsius conc. concentrated δ NMR chemical shift from tetramethylsilane to lower field (in ppm) d Double peak DCE 1,2-Dichloroethane DCM dichloromethane DEA diethylamine DIPEA N,N-Diisopropylethylamine DMA dimethylacetamide DMAP 4-(dimethylamino)pyridine DME dimethoxyethane DMF N,N-dimethylformamide DMSO (dimethyl sulfoxide) DPPF 1,1'-bis(diphenylphosphino)ferrocene Et Ethyl EtOAc (ethyl acetate) g gram h(r) hours HEPES (4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid) HATU O-(7-azabenzotriazol-1-yl)-N,N,Nˊ,Nˊ-tetramethylurea hexafluorophosphate HRMS (High Resolution Mass Spectrometry) i-Pr isopropyl L rise LDA Diethylamine Lithium LC / MS (Liquid Chromatography-Mass Spectrometry) M molar concentration m multiplet Me methyl mg MHz min minutes mL μL mmol N equivalent concentration NBS N-bromosuccinimide NCS N-chlorosuccinimide n-Bu n-butyl n-BuLi n-Butyllithium NMM N-methylphospholine NMR (Nuclear Magnetic Resonance) NMP (N-methyl-2-pyrrolidone) NMO N-methylphospholine-N-oxide o / n overnight Ph phenyl pH - log 10H+ concentration ppm (parts per million) q Quadruple Peak Rt Detention Time RP-HPLC (Reversed-Phase High-Performance Liquid Chromatography) s single peak SFC Supercritical Liquid Chromatography sat. saturated t triple peak t-Bu Tertiary Butyl TBAF Tertiary Butyl Ammonium Fluoride Tf trifluoromethanesulfonyl TFA (trifluoroacetic acid) TFAA (trifluoroacetic anhydride) TBS Tertiary Butyldimethylsilyl TEA Triethylamine temp. temperature THF Tetrahydrofuran TLC (Thin Layer Chromatography) [General Synthesis Scheme] []

[0188] Examples of compounds of formula (I) can be prepared as described in schemes B, C, and D below. The intermediates required for schemes B, C, and D are... [F] Prepared as described in Scheme A below.

[0189] As shown in Scheme A, pyridine [A] Chlorination and methylation are carried out in a one-pot reaction with POCl3 in a suitable solvent (e.g., DMF) at a suitable temperature (typically 0°C to 90°C (e.g., room temperature)) to produce aromatic aldehydes. [B]. Aldehydes [B] It can be reacted with deprotonated alkynes (e.g., gerinia reagents) (where R3 is as defined herein) in a suitable solvent (e.g., THF) at a suitable temperature (e.g., -70°C) to provide benzyl alcohol. [C]. Benzyl alcohol [C] [(where R 3, as defined herein)] is oxidized to the corresponding ketone under suitable oxidation conditions (e.g., Desmond-Martin periodoyl alkyl reagent), in a suitable solvent (e.g., DCM), and at a suitable temperature (generally 0°C to room temperature). Aniline [AX] (where X is F, Br, or I) provides an intermediate in the reaction of Lewis acid (e.g., AlCl3) in a suitable solvent (e.g., DCM) at a suitable temperature (typically 0°C to room temperature). [E], where X is F, Br, or I and R 3 is as defined herein. Intermediate [E] can be used under alkaline conditions (e.g., for intermediates of the X series F or I and R3 as defined herein). [E], triethylamine used in DMF; or for intermediates in which X-based Br and R 3 as defined herein. [E], NaOH used in DCM) is cyclized into a cyclic 4-pyridone at a suitable temperature (generally from room temperature to 60°C). [F] (where X-series F, Br or I, R 3 as defined in this paper). Option A:

[0190] Having a general formula ( Examples of compounds of [Ia) can be prepared as described in Scheme B below. Option B:

[0191] As shown in Scheme B, intermediate [F] (where X is F or Br and R3 is as defined herein) can be converted into an intermediate by nucleophilic aromatic conversion of R2-OH (where R2 is as defined herein). [G]. Intermediates can be used. [G] (where X is F or Br and R2 and R3 are as defined herein) by introducing a substituent -OR1 with a second nucleophilic aromatic substitution of R1-OH (where R1 is as defined herein), produces a product having the formula ( [Ia)] compounds, wherein R1, R2, and R3 are as defined herein. The desired R1-OH and R2-OH alcohols are commercially available or can be prepared according to literature or in a similar manner. Other transformations, such as protecting group operations or the formation of amides at any position in the synthetic sequence, can be performed to produce compounds having the general formula [Ia]. Other compounds of [(Ia)], wherein R1 and R3 are as defined herein and R'2 is a (C1-C6) alkyl group substituted with one or more substituents independently selected from -NHC(O)Rd and -C(O)NHRe, wherein the (C1-C6) alkyl group is further substituted with one or more substituents independently selected from halogen, -OH and -CN as desired, and wherein R2 is different from R'2.

[0192] Alternatively, as shown in Scheme C, the intermediate [G] (where X is Br or I and R2 and R3 are as defined herein) can be converted to borate esters in the presence of a suitable catalyst (e.g., PdCl2(dppf)). [H]. Boronate [H] can be oxidized to phenol by hydrogen peroxide in the presence of a suitable catalyst. [J], where R2 and R3 are as defined in this paper. Intermediate [J] can be transformed by nucleophilic substitution of bromide or trifluoromethanesulfonate in the presence of a suitable base to obtain the product with the general formula [J]. Compounds of [(Ia)], wherein R1, R2 and R3 are as defined herein. [。] As shown in Scheme B, other transformations can be performed, such as protecting group operations or the formation of amides at any position in the synthetic sequence, to produce a product having the general formula Other compounds of [(Ia)], wherein R1 and R3 are as defined herein and R'2 is a (C1-C6) alkyl group substituted with one or more substituents independently selected from -NHC(O)Rd and -C(O)NHRe, wherein the (C1-C6) alkyl group is further substituted with one or more substituents independently selected from halogen, -OH and -CN as desired, and wherein R2 is different from R'2. Option C:

[0193] According to scheme D, intermediate [F] (wherein the X-series F) can also react with tinanes (e.g., vinyl- or allyl-tributyltinane) via Stille coupling in the presence of a suitable Pd catalyst (e.g., Pd 2(dba) 3) and a suitable base (e.g., trifuranylphosphine) to generate compounds. [K], where RA is vinyl or allyl and R3 is as defined herein. Nucleophilic aromatic substitution with R1-OH (where R1 is as defined herein) yields an intermediate. [L], which can undergo addition of sodium alkyl sulfonate RA'SO2Na (where RA' is a (C1-C6) alkyl group substituted with -SO2(C1-C4)alkyl) in a suitable solvent (e.g., EtOH or AcOH) to provide a product having the general formula ( [Ib)] compounds, wherein R A' is a (C1-C6) alkyl group substituted with -SO2 (C1-C4) alkyl and R1 and R3 are as defined herein. Alternatively, olefins can be used to form terminal boranes in situ with 9-BBN, which undergo Pd-catalyzed reaction with intermediates in the presence of a suitable Pd catalyst (e.g., Pd(PPh3)4). The coupling of [F] (where X is F) forms an intermediate. [M], wherein RB is a (C1-C6) alkyl group substituted with -S(C1-C4)alkyl or -C(O)NHRc, and R3 and Rc are as defined herein. In the case of sulfide side chains, oxidation (e.g., with H2O2) provides alkyl in a subsequent step. Further nucleophilic aromatic substitution with R1-OH (where R1 is as defined herein) provides alkyl with the general formula [(Ic)] compounds, wherein R B' is a (C1-C6) alkyl group substituted with -SO2 (C1-C4) alkyl or -C(O)NHR c and R1, R3 and Rc are as defined herein. Option D:

[0194] The following LC-MS methods are used to characterize instances and intermediates:

[0195] [LCMS] [method] [1] System: Shimadzu LCMS 2020 Column: Synergi 2.5 µ MAX-RP100 A Mercury Column temperature: 40°C Gradient (time / %B): 0.1 / 5, 0.5 / 5, 1.0 / 95, 1.5 / 95, 2.0 / 5, 3.0 / 5 Eluent A: 0.1% HCO₂ + 2H₂O in water Eluent B: CH 3CN Flow rate: 2.0 mL / min Ion source: DUIS-ESI & APCI Atomizing airflow: 1.5 L / min; DL temperature: 250°C Hot block temperature: 400°C

[0196] [LCMS] [method] [2] System: Shimadzu LCMS 2020 Column: Kinetex 2.6 µm, C18 100 A, 30 x 3 mm. Column temperature: 40°C Gradient (time / %B): 0.1 / 20, 0.25 / 20, 0.75 / 95, 1.75 / 95, 2 / 20, 2.5 / 20 Eluent A: 0.1% HCO₂ + 2H₂O in water Eluent B: CH 3CN Flow rate: 1.0 mL / min Ion source: DUIS-ESI & APCI Atomizing airflow: 1.5 L / min DL temperature: 250°C Hot block temperature: 400°C

[0197] [LCMS] [method] [3] System: Shimadzu LCMS 2020 Column: Synergi 2.5 µ MAX-RP100 A Mercury Column temperature: 40°C Gradient (time / %B): 0.1 / 5, 0.5 / 5, 1.0 / 95, 1.5 / 95, 2.0 / 5, 3.0 / 5 Eluent A: 0.1% HCO₂ + 2H₂O in water Eluent B: CH 3CN Flow rate: 1.0 mL / min Ion source: DUIS-ESI & APCI Atomizing airflow: 1.5 L / min; DL temperature: 250°C Hot block temperature: 400°C

[0198] [LCMS] [method] [4] System: SCI EX API 3200 Column: Kinetex EVO C18 100 A, 2.6 µm, 50 x 4.6 mm, Column temperature: 30°C Gradient: (time / %B): 0 / 30, 0.2 / 30, 0.7 / 95, 2.0 / 95, 2.5 / 30, 3.5 / 30 Eluent A: 0.1% HCO₂ + 2H₂O in water Eluent B: 0.1% HCO₂ in CH₃CN Flow rate: 1.5 mL / min Ion source: Turbo Spray Hot block temperature: 450°C

[0199] [LCMS] [method] [5] System: SCI EX API 2000 Column: Synergi 2.5 µ MAX-RP100 A Mercury Column temperature: 30°C Gradient: (time / %B): 0 / 30, 0.5 / 30, 1.0 / 95, 1.5 / 95, 2.5 / 30, 3.0 / 30 Eluent A: 0.1% HCO₂ + 2H₂O in water Eluent B: 0.1% HCO₂ in CH₃CN Flow rate: 2 mL / min Ion source: Turbo Spray Hot block temperature: 450°C

[0200] [LCMS] [method] [6] System: Shimadzu LCMS 2020 Column: Synergi 2.5 µ MAX-RP100 A Mercury Column temperature: 40°C Gradient (time / %B): 0.1 / 5, 0.5 / 5, 1.0 / 95, 1.5 / 95, 2.0 / 5, 3.0 / 5 Eluent A: 0.1% HCO₂ + 2H₂O in water Eluent B: CH 3CN Flow rate: 2.0 mL / min Ion source: DUIS-ESI & APCI Atomizing airflow: 1.5 L / min; DL temperature: 250°C Hot block temperature: 400°C

[0201] [LCMS] [method] [7] System: Agilent 1100 Column: Acquity UPLC BEH C18 column, 2.1 x 30 mm, 1.7 µm column Column oven temperature: 50°C Gradient: (Time / %B): 0 min / 2 for 0.1 min, 0.1 min / 2 to 1.5 min / 98, 1.8 min / 98, 1.8 min / 98 to 1.9 min / 2, 2.0 min / 2 Eluent A: 0.1% formic acid in water Eluent B: 0.1% formic acid in CH3CN Flow rate: 1 mL / min

[0202] [Chirality] [HPLC] [method] [1] Column: Chiral PAL-IH (150 x 4.6 mm x 5 µM) Mobile phase: A: n-hexane, B: 0.1% HCOOH in ethanol:methanol (80:20) Isometrics: 70 : 30 (A : B) Flow rate: 1 mL / min Diluent: Ethanol Column temperature 25°C

[0203] [Chirality] [HPLC] [method] [2] Column: Lux cellulose (150 x 4.6 mm x 5 µM) Mobile phase: A: n-hexane, B: 0.1% HCOOH in ethanol:methanol (80:20) Isometrics: 70 : 30 (A : B) Flow rate: 1 mL / min Diluent: Ethanol Column temperature 25°C

[0204] [Intermediate] [F] [(] [F1] [、] [F2] [and] [F3] [) Synthesis []

[0205] [5,8-] [Dichloro] [-1-(2,6-] [Dichloro] [-4-] [Fluorophenyl] [)-2-] [methyl] [-1,6-] [Ding] [-4(1H)-] [Ketone (intermediate)] [F1] [) Synthesis []

[0206] Step 1: 2,4,5-Trichloronicotinaldehyde

[0207] Phosphorus trichloride (475 mL) was added dropwise to DMF (750 mL) at 0°C under nitrogen. The resulting mixture was stirred at 0°C for 1 hour. Then, 5-chloropyridine-2,4-diol (150 g, 1.03 mol) was added. The mixture was stirred at 90°C for 12 hours. LCMS showed that the reaction was complete. The reaction mixture was cooled to 0°C, poured into 2000 mL of ice water, and extracted with 3 x 1000 mL DCM. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:9). This yielded 131 g (48%) of 2,4,5-trichloropyridinecarboxaldehyde as a yellow solid. ESI-MS m / z: 210.0 [M+H] +; 1H NMR (400 MHz, DCM- d 2) δ ppm = 10.43 (s, 1H), 8.61 (s, 1H).

[0208] Step 2: 1-(2,4,5-trichloropyridin-3-yl)but-2-yn-1-ol

[0209] At -60°C, prop-1-yn-1-ylmagnesium bromide (1.2 L, 0.62 mol) was added dropwise to a solution of 2,4,5-trichloropyridinaldehyde (117 g, 0.56 mol) in THF (1000 mL), and stirring was continued at -60°C for 1 hour. LCMS showed the reaction was complete. The reaction mixture was quenched at -20°C with ammonium chloride solution (1000 mL). The resulting solution was extracted with ethyl acetate. The mixture was washed with H₂O and brine, dried over anhydrous sodium sulfate, and concentrated. This yielded 120 g (86%) of 1-(2,4,5-trichloropyridin-3-yl)but-2-yn-1-ol as a yellow solid. ESI-MS m / z: 250.0 [M+H] +; 1H NMR (400 MHz, DCM- d 2) δ ppm = 8.42 (s, 1H), 6.13 (s, 1H), 3.11 (bs, 1H), 1.90 (s, 3H).

[0210] Step 3: 1-(2,4,5-trichloropyridin-3-yl)but-2-yn-1-one

[0211] Dysmart reagent (280 g, 0.66 mol) was added to a solution of 1-(2,4,5-trichloropyridin-3-yl)but-2-yn-1-one (150 g, 0.60 mol) in 1000 mL DCM at 0°C. The mixture was stirred at room temperature for 2 hours. LCMS showed the reaction was complete. The solid was filtered off. The filtrate was washed with sodium sulfite and sodium carbonate solutions. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. This yielded 1-(2,4,5-trichloropyridin-3-yl)but-2-yn-1-one (160 g crude) as a brown solid. ESI-MS m / z: 248.0 [M+H]+; 1H NMR (400 MHz, DCM-d2) δ ppm = 8.51 (s, 1H), 2.16 (s, 3H).

[0212] Step 4: (E)-3-((2,6-dichloro-4-fluorophenyl)amino)-1-(2,4,5-trichloropyridin-3-yl)but-2-en-1-one

[0213] AlCl₃ (102 g, 0.76 mol) was added to a solution of 1-(2,4,5-trichloropyridin-3-yl)but-2-yn-1-one (160 g, 0.64 mol) and 4-fluoro-2,6-dichloroaniline (115 g, 0.64 mol) in DCM (1200 mL) at 5°C. The mixture was stirred for 2 hours at room temperature. LC-MS showed the reaction was complete. The solution was quenched with water at 5°C. The resulting solution was extracted with ethyl acetate (2 x 1000 mL) and the organic layers were combined. The organic layers were dried over anhydrous sodium sulfate and concentrated. This yielded 340 g (crude) of (E)-3-((2,6-dichloro-4-fluorophenyl)amino)-1-(2,4,5-trichloropyridin-3-yl)but-2-en-1-one as a brown solid. The crude product was used directly in the next step. ESI-MS m / z: 427 [M+H]+.

[0214] Step 5: 5,8-Dichloro-1-(2,6-dichloro-4-fluorophenyl)-2-methyl-1,6-dichloro-4(1H)-one

[0215] TEA (252 g, 2.5 mol) was added to a solution of (E)-3-((2,6-dichloro-4-fluorophenyl)amino)-1-(2,4,5-trichloropyridin-3-yl)but-2-en-1-one (340 g crude) in DMF (1000 mL) at room temperature. The mixture was stirred at 60°C for 1 hour. LCMS showed that the reaction was complete. The solution was quenched with 2 L of water and extracted with ethyl acetate (3 x 1000 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The residue was applied to a silicone column using ethyl acetate / petroleum ether (3:7) as eluent. This yielded 162.6 g (64% after two steps) of 5,8-dichloro-1-(2,6-dichloro-4-fluorophenyl)-2-methyl-1,6-diphenyl-4(1H)-one as a light brown solid. ESI-MS m / z: 391.0 [M+H]+; 1H NMR (300 MHz, chloroform-d3) δ ppm = 8..31 (s, 1H), 7.26 (d, J = 12.3 Hz, 2H), 6.47 (s, 1H), 1.99 (m, 3H).

[0216] [1-(4-)] [bromine] [-2,6-] [Dichlorophenyl] [)-5,8-] [Dichloro] [-2-] [methyl] [-1,6-] [Ding] [-4(1H)-] [Ketone (intermediate)] [F2] [) Synthesis

[0217] Steps 1 to 3: See intermediates [F1] Synthesis

[0218] Step 4: (E)-3-((4-bromo-2,6-dichlorophenyl)amino)-1-(2,4,5-trichloropyridin-3-yl)but-2-en-1-one

[0219] AlCl₃ (78 g, 0.58 mol) was added to a solution of 1-(2,4,5-trichloropyridin-3-yl)but-2-yn-1-one (120 g, 0.49 mol) and 4-bromo-2,6-dichloroaniline (118 g, 0.49 mol) in DCM (800 mL) at 5°C. The mixture was stirred for 2 hours at room temperature. LC-MS showed the reaction was complete. The solution was quenched with water at 5°C. The resulting solution was extracted with ethyl acetate (2 x 1000 mL) and the organic layers were combined. The organic layers were dried over anhydrous sodium sulfate and concentrated. This yielded 240 g (crude) of (E)-3-((4-bromo-2,6-dichlorophenyl)amino)-1-(2,4,5-trichloropyridin-3-yl)but-2-en-1-one as a brown solid. The crude product was used directly in the next step. ESI-MS m / z: 487 [M+H]+.

[0220] Step 5: 1-(4-bromo-2,6-dichlorophenyl)-5,8-dichloro-2-methyl-1,6-diphenyl-4(1H)-one

[0221] Add 2.83 g (1.2 equivalents) of NaOH to a solution of (E)-3-((4-bromo-2,6-dichlorophenyl)amino)-1-(2,4,5-trichloropyridin-3-yl)but-2-en-1-one (240 g crude) in DCM (270 mL). Stir the reaction mixture at 15°C to 25°C for 8 to 12 hours. After the reaction is complete, concentrate the mixture to 50-60 g. Add toluene (143 mL). Concentrate the mixture to 50 to 60 g. Add toluene (289 mL). Wash the organic layer with water (3 x 289 mL). Combine the aqueous layers and extract with toluene (289 mL). Stir the combined toluene layers with activated carbon (1.45 g, 50 to 60°C, 2 to 3 hours), filter, and concentrate. Crystallization in toluene / heptane (v / v = 1 / 1) yielded 1-(4-bromo-2,6-dichlorophenyl)-5,8-dichloro-2-methyl-1,6-diphenyl-4(1H)-one as a light brown solid in 69% yield. ESI-MS m / z: 452 [M+H]+; 1H NMR (300 MHz, chloroform-d3) δ ppm = 8..33 (s, 1H), 7.67 (s, 2H), 6.49 (d, J = 0.6 Hz, 1H), 1.99 (m, 3H).

[0222] [5,8-] [Dichloro] [-1-(2,6-] [Dichloro] [-4-] [Iodophenyl] [)-2-] [methyl] [-1,6-] [Ding] [-4(1H)-] [Ketone (intermediate)] [F3] [) Synthesis

[0223] intermediate [F3] with intermediate [F1] and [F2] was prepared in a similar manner, but using 2,6-dichloro-4-iodoaniline. ESI-MS m / z: 498.8 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm = 8..52 (s, 1H), 8.22 (s, 2H), 6.61 (s, 1H), 1.94 (s, 3H).

[0224] [with style] [(I)] [Synthesis of compounds]

[0225] Having a style [(Ia)] or formula [(Ib)] or formula The following examples of compounds of [(Ic)] have been derived from intermediates [F1] and [F2] is prepared as described below.

[0226] [Example] [1] [:] [3-((8-] [chlorine] [-1-(2,6-] [Dichloro] [-4-(2-)] [Hydroxyethoxy] [)] [Phenyl] [)-2-] [methyl] [-4-] [Side group] [-1,4-] [Dihydrogen] [-1,6-] [Ding] [-5-] [base] [)] [Oxygen group] [)-N-] [Methylpropionamide (compound)] [C-1] [)]

[0227] Step 1: 3-((8-chloro-1-(2,6-dichloro-4-fluorophenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-N-methylpropionic acid

[0228] 5,8-dichloro-1-(2,6-dichloro-4-fluorophenyl)-2-methyl-1,6-diphenyl-4(1H)-one (intermediate) in acetonitrile (40 mL) [F1] (3.5 g, 8.927 mmol) and 3-hydroxy-N-methylpropionic acid (1.38 g, 13.39 mmol) were reacted with potassium carbonate (3.08 g, 22.31 mmol) and DMAP (327.1 mg, 2.678 mmol) and the mixture was heated to 80°C for 16 hours. The reaction progress was monitored by TLC until the starting material was completely consumed. The color of the reaction mixture changed from light brown to dark brown. The mixture was quenched with cold water and extracted with ethyl acetate (3 x 25 mL), dried and concentrated. The crude material was purified by rapid chromatography (using 1% MeOH in dichloromethane as eluent) to give the desired product (2.8 g, 69%) as a grayish-white solid.

[0229] Step 2: 3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-N-methylpropionic acid

[0230] Cesium carbonate (4.99 g, 15.315 mmol) was added to 3-((8-chloro-1-(2,6-dichloro-4-fluorophenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-N-methylpropionic acid (2.8 g; 6.126 mmol) and anhydrous ethylene glycol (1.521 g; 24.506 mmol) in DMF (30 mL), and the mixture was stirred at room temperature for 4 hours. The reaction progress was monitored by TLC. The color of the reaction mixture changed from light brown to dark brown. The reaction mixture was quenched with ice-cold water and extracted with ethyl acetate (3 x 25 mL). The organic layer was dried and concentrated to give the crude product. The crude material was purified by rapid chromatography (using 3% MeOH in dichloromethane as eluent) to obtain the desired product (1.4 g, 46%) as a grayish-white solid, and the remaining 20% ​​of the starting material was recovered. A second chromatographic step using the same eluent was required to obtain a white powder with a purity of 99%. [C-1]:HRMS m / z: Calculated value 500.05413 [M+H]+, found value 500.05482. 1H NMR (600 MHz, DMSO-d6) δ ppm = 8.24 (s, 1H), 8.23 ​​(q, 1H), 7.36 (s, 2H), 6.48 (s, 1H), 4.96 (s, 1H), 4.53 (t, 2H), 4.15 (t, 2H), 3.72 (t, 2H), 2.78 (s, 3H), 2.62 (d, 3H), 2.60 (t, 2H), 1.91 (m, 3H). 13C NMR (150 MHz, DMSO-d6) δ ppm =175.0, 170.1161.8, 150.9, 149.8, 145.0, 135.8, 126.8, 117.0, 115.0110.4, 109.8, 71.1, 63.3, 59.2, 35.2, 25.6, 20.0.

[0231] The crystalline forms of compound C-1 have been isolated as shown in the following variants A-1, A-2, A-3, A-4, A-5, A-6, A-7, A-8, A-9, A-10, A-11, A-12, and A-13. The crystalline forms were characterized using the analytical methods shown in Table 2 below, including X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), ultra-high performance liquid chromatography (UPLC), and NMR.

[0232] XRPD spectra for each crystal form are shown in the figures. A list of characteristic XRPD peaks is provided in the table below and described in the figures. Peaks listed here are given in degrees 2θ (±0.1 degrees). As those skilled in the art will understand, the relative intensities of the individual peaks in the table below may vary due to many factors, such as the orientation effect of the crystals in the X-ray beam or the purity or crystallinity of the analyzed material. Peak positions may also shift with variations in sample height, but the peak positions will remain substantially as defined in the given table. Those skilled in the art will also understand that measurements using different wavelengths will result in different shifts according to the Bragg equation nλ = 2d sin θ. However, such alternative XRPD patterns generated by using alternative wavelengths represent the same material. [ [surface] [2] [.] [Analysis Methods] [] [Analysis Methods] [detail] [TGA] [method] instrument: TA Discovery Temperature range Room temperature to 300°C Scan speed 10 K / min Nitrogen flow 20 mL / min Sample quality Approximately 2-10 mg [DSC] [method] instrument: TA Discovery Temperature range 0°C to 250°C or 300°C Scan speed 10 K / min Nitrogen flow 50 mL / min Sample quality Approximately 2 mg [XRPD] [method] [1] [and] [2] instrument: Bruker D8 Advance detector LynxEye (1D mode), opening angle: 2.948° radiation CuKα (wavelength = 0.15418 nm) Monochromator Ni filter X-ray generator power 40 kV, 40 mA Step length 0.0164° or 0.0410°(2θ) Time / Step 0.3 s Scan range 2°-40° 2θ Scan time 768 s or 279 s Slit Main immobilized luminescent sample size: 10 mm; Secondary: Opening angle: 2.2°; Axial Soler: 2.5° [NMR] instrument: Bruker Ascend 400 MHZ probe 5 mm PABBO BB-1H / D Z-GRD Z108618 / 0226 temperature 295.7 K Relaxation delay 1 second [UPLC] [method] instrument: Waters Acquity UPLC column ACQUITY BEH C18 Particle size (µm) 1.7 Dimensions (mm) 2.1 x 100 Temperature (°C) 45 Flow rate (mL / min) 0.5 Injection volume (µl) 1 Sample solvent Acetonitrile / water (80:20) Sample concentration (µg / mL) 100 Detection wavelength (nm) 210 Mobile phase A 95% 10 mM ammonium acetate buffer / 5% ACN Mobile phase B 95% acetonitrile / 5% water Running time (min) 14 gradient [minute] [% B] 0 initial 0 2.0 50 8.0 95 11.0 95 12.0 0 12.1 0 14.0

[0233] [Variation] [A-1] [:] [3-((8-] [chlorine] [-1-(2,6-] [Dichloro] [-4-(2-)] [Hydroxyethoxy] [)] [Phenyl] [)-2-] [methyl] [-4-] [Side group] [-1,4-] [Dihydrogen] [-1,6-] [Ding] [-5-] [base] [)] [Oxygen group] [)-N-] [Free crystalline form of methylpropionylamine (compound)] [C-1] [)] []

[0234] Compound C-1 (2.0 g) of Example 1 was dissolved in an aqueous / ethanol solution at a temperature below 35°C. The resulting solution was filtered to remove undissolved impurities. Seed crystals were obtained by adding the first portion of water to the reactor at 25°C with stirring. The second portion of water was added, and the resulting solid was filtered, washed, and dried at 50°C under a vacuum of 0–100 mbar. The solid residue (1.77 g) was recovered with a purity of 99.52% (UPLC) and analyzed by XRPD, DSC, TGA, and NMR. The physicochemical properties are shown in Table 3. [ [surface] [3] [.] [Variation] [A-1] [、] [A-2] [、] [A-3] [、] [A-4] [and] [A-5] [Physical and chemical properties] [] [parameter] [A-1] [A-2] [A-3] [A-4] [A-5] T Initial melting point (DSC, °C) 159.0 157.5 156.6 121.5 157.4 110.8 157.4 LOD (TGA, % at °C) 0.17% (120°C) 3.4% (80°C) 3.0% (70°C) 3.6% (110°C) 1.4% (110°C) Water content (Karl Fischer) % m / m) 0.4 4.0 3.6 4.1 2.0

[0235] The DSC thermogram of variant A-1 of Example 1 is shown in Figure 2A. The TGA of variant A-1 of Example 1 is shown in Figure 3A. Table 3 presents the DSC data (showing the melting transition of variant A-1) and the total water loss (loss on drying - LOD) measured by TGA.

[0236] The XRPD plot of variant A-1 of Example 1 is shown in Figure 1A. When measured using CuKα radiation at a wavelength of 1.5418 Å at a temperature of approximately 22°C, the XRPD peaks are shown in the table below: serial number angle 2θ d value Å relative strength % 1 7.7 11.47 99 2 11.3 7.86 5 3 15.4 5.74 10 4 16.4 5.40 32 5 17.7 5.00 9 6 21.2 4.19 19 7 22.7 3.91 9 8 23.3 3.81 43 9 24.0 3.70 100 10 26.4 3.37 12 11 27.2 3.28 twenty three

[0237] [Variation] [A-2] [:] [3-((8-] [chlorine] [-1-(2,6-] [Dichloro] [-4-(2-)] [Hydroethoxy] [)] [Phenyl] [)-2-] [methyl] [-4-] [Sidekyl group] [-1,4-] [Dihydrogen] [-1,6-] [Ding] [-5-] [base] [)] [Oxygen group] [)-N-] [Crystal form of hydrated methylpropionic acid (compound)] [C-1] [)]

[0238] Compound C-1 (2.0 g) of Example 1 was dissolved in an aqueous / ethanol solution at a temperature below 35°C. The resulting solution was filtered to remove undissolved impurities. Seed crystals were obtained by adding the first portion of water to the reactor at 25°C with stirring. The second portion of water was added dropwise to the suspension at 16°C over 10 hours, and the resulting suspension was maintained at 16°C for 13 hours. The solid thus obtained was then filtered, washed, and dried at 45°C under a vacuum of 40 mbar. The solid residue (1.94 g) was recovered with a purity of 99.59% (UPLC) and analyzed by XRPD, DSC, TGA, and NMR. The physicochemical properties are shown in Table 3.

[0239] The DSC thermogram of variant A-2 of Example 1 is shown in Figure 2B. The TGA of variant A-2 of Example 1 is shown in Figure 3B. Table 3 presents the DSC data (showing the melting transition of variant A-2) and the total water loss (loss on drying - LOD) measured by TGA. []

[0240] The XRPD plot of variant A-2 of Example 1 is shown in Figure 1B. When measured using CuKα radiation at a wavelength of 1.5418 Å at a temperature of approximately 22°C, the XRPD peaks are shown in the table below: [] serial number angle 2θ d value Å relative strength % 1 7.6 11.62 17 2 10.7 8.30 3 3 15.2 5.81 4 4 16.9 5.24 27 5 21.4 4.15 17 6 24.0 3.70 100 7 25.8 3.45 3 8 27.4 3.26 17 9 30.7 2.91 2

[0241] [Variation] [A-3] [:] [3-((8-] [chlorine] [-1-(2,6-] [Dichloro] [-4-(2-)] [Hydroxyethoxy] [)] [Phenyl] [)-2-] [methyl] [-4-] [Side group] [-1,4-] [Dihydrogen] [-1,6-] [Ding] [-5-] [base] [)] [Oxygen group] [)-N-] [Crystal form of hydrated methylpropionic acid (compound)] [C-1] [)] []

[0242] Compound C-1 from Example 1 was transferred to a chamber at 75% relative humidity and maintained for approximately 24 hours, yielding a solid residue (5.1 g). It was recovered with a purity of 99.09% (UPLC) and analyzed by XRPD, DSC, TGA, and NMR. The physicochemical properties are shown in Table 3.

[0243] The DSC thermogram of variant A-3 of Example 1 is shown in Figure 2C. The TGA of variant A-3 of Example 1 is shown in Figure 3C. Table 3 presents the DSC data (showing the melting transition of variant A-3) and the total water loss (loss on drying - LOD) measured by TGA.

[0244] The XRPD plot of variant A-3 of Example 1 is shown in Figure 1C. When measured using CuKα radiation at a wavelength of 1.5418 Å at approximately 22°C, the XRPD peaks are shown in the table below: serial number angle 2θ d value Å relative strength % 1 7.6 11.55 twenty three 2 15.3 5.78 9 3 17.0 5.22 18 4 20.7 4.29 5 5 21.4 4.14 8 6 22.2 3.99 33 7 25.9 3.44 20 8 29.1 3.07 10 9 32.3 2.77 12

[0245] [Variation] [A-4] [:] [3-((8-] [chlorine] [-1-(2,6-] [Dichloro] [-4-(2-)] [Hydroxyethoxy] [)] [Phenyl] [)-2-] [methyl] [-4-] [Side group] [-1,4-] [Dihydrogen] [-1,6-] [Ding] [-5-] [base] [)] [Oxygen group] [)-N-] [Crystal form of hydrated methylpropionic acid (compound)] [C-1] [)]

[0246] Compound C-1 (10.0 g) of Example 1 was suspended in 60 mL of a methanol / water mixture at 40°C. The resulting suspension was stirred at 60°C to obtain a clear solution. The solution was cooled to 50°C and stirred for 1 hour. The solution was then cooled to 40°C and held for 10 hours. The solid thus obtained was filtered, washed, and dried under vacuum at room temperature. The solid residue was recovered with a purity of 99.57% (UPLC) and analyzed by XRPD, DSC, TGA, and NMR. The physicochemical properties are shown in Table 3. []

[0247] The DSC thermogram of variant A-4 of Example 1 is shown in Figure 2D. The TGA of variant A-4 of Example 1 is shown in Figure 3D. Table 3 presents the DSC data (showing the melting transition of variant A-4) and the total water loss (loss on drying - LOD) according to the TGA. []

[0248] The XRPD plot of variant A-4 in Example 1 is shown in Figure 1D. When measured using CuKα radiation at a wavelength of 1.5418 Å at approximately 22°C, the XRPD peaks are shown in the table below: [] serial number angle 2θ d value Å relative strength % 1 7.3 12.11 29 2 10.3 8.59 3 3 15.5 5.73 10 4 22.1 4.02 3 5 23.1 3.84 100 6 23.9 3.73 19 7 25.5 3.49 7 8 25.9 3.44 6 9 26.4 3.37 50 10 31.2 2.86 8

[0249] [Variation] [A-5] [:] [3-((8-] [chlorine] [-1-(2,6-] [Dichloro] [-4-(2-)] [Hydroxyethoxy] [)] [Phenyl] [)-2-] [methyl] [-4-] [Side group] [-1,4-] [Dihydrogen] [-1,6-] [Ding] [-5-] [base] [)] [Oxygen group] [)-N-] [Crystal form of hydrated methylpropionic acid (compound)] [C-1] [)]

[0250] The hydrate crystal form of variant A-4 from Example 1 was kept at 80°C and 11% relative humidity for one week. The solid residue was analyzed by XRPD, DSC, TGA, and NMR. The physicochemical properties are shown in Table 3.

[0251] The DSC thermogram of variant A-5 of Example 1 is shown in Figure 2E. The TGA of variant A-5 of Example 1 is shown in Figure 3E. Table 3 presents the DSC data (showing the melting transition of variant A-5) and the total water loss (loss on drying - LOD) according to the TGA.

[0252] The XRPD plot of variant A-5 of Example 1 is shown in Figure 1E. When measured using CuKα radiation at a wavelength of 1.5418 Å at a temperature of approximately 22°C, the XRPD peaks are shown in the table below: serial number angle 2θ d value Å relative strength % 1 5.0 17.84 47 2 9.9 8.93 14 3 14.9 5.96 twenty one 4 15.9 5.58 39 5 17.7 5.01 14 6 19.8 4.47 87 7 24.0 3.71 84 8 25.5 3.49 68 9 27.2 3.28 twenty three

[0253] [Variation] [A-6] [:] [3-((8-] [chlorine] [-1-(2,6-] [Dichloro] [-4-(2-)] [Hydroxyethoxy] [)] [Phenyl] [)-2-] [methyl] [-4-] [Side group] [-1,4-] [Dihydrogen] [-1,6-] [Ding] [-5-] [base] [)] [Oxygen group] [)-N-] [Methylpropionamide (compound)] [C-1] [) and the solvate of cyclopentanone] []

[0254] Compound C-1 of Example 1 was equilibrated with cyclopentanone at 4°C for 14 days. The solid residue was recovered and analyzed by XRPD, DSC, TGA, UPLC, and NMR.

[0255] Variant A-6 is a highly crystalline form with a melting point of approximately 157°C. The desolvation temperature is approximately 102°C. It shows a weight loss of 4.6% at 150°C via TGA. The XRPD plot is shown in Figure 1F, measured at approximately 22°C using CuKα radiation at a wavelength of 1.5418 Å.

[0256] [Variation] [A-7] [:] [3-((8-] [chlorine] [-1-(2,6-] [Dichloro] [-4-(2-)] [Hydroxyethoxy] [)] [Phenyl] [)-2-] [methyl] [-4-] [Side group] [-1,4-] [Dihydrogen] [-1,6-] [Ding] [-5-] [base] [)] [Oxygen group] [)-N-] [Methylpropionamide (compound)] [C-1] [) and its solvate with methanol]

[0257] Compound C-1 of Example 1 was equilibrated at 4°C for 14 days with methanol or methanol / water (97:3 v / v). The solid residue was recovered and analyzed by XRPD, DSC, TGA, UPLC and NMR.

[0258] Variant A-7 is a highly crystalline form with a melting point of approximately 157°C. The desolvation temperature is approximately 79°C. It shows a weight loss of 3.7% at 105°C via TGA. The XRPD plot is shown in Figure 1G, measured at approximately 22°C using CuKα radiation at a wavelength of 1.5418 Å.

[0259] [Variation] [A-8] [:] [3-((8-] [chlorine] [-1-(2,6-] [Dichloro] [-4-(2-)] [Hydroxyethoxy] [)] [Phenyl] [)-2-] [methyl] [-4-] [Side group] [-1,4-] [Dihydrogen] [-1,6-] [Ding] [-5-] [base] [)] [Oxygen group] [)-N-] [Methylpropionamide (compound)] [C-1] [) and solvates of pyridine]

[0260] Compound C-1 of Example 1 was equilibrated with pyridine at 4°C for 7 days. The solid residue was recovered and analyzed by XRPD, DSC, TGA, UPLC, and NMR. The XRPD plot is shown in Figure 1H, which was measured at approximately 22°C using CuKα radiation at a wavelength of 1.5418 Å.

[0261] [Compound] [C-1] [The eutectic (variant)] [A-9] [、] [A-10] [、] [A-11] [、] [A-12] [and] [A-13] [)]

[0262] Compound C-1 from Example 1 was mixed with an appropriate amount of eutectic forming agent. The resulting mixture was dissolved / slurried in a separate solvent at 50°C and cooled to room temperature until precipitation occurred. The resulting solution was evaporated to dryness to obtain a solid. The solid residue was recovered and analyzed by XRPD, DSC, TGA, UPLC, and NMR. The physicochemical properties of the eutectic of compound C-1 are shown in Table 4. [] [ [surface] [4] [.] [Variation] [A-9] [、] [A-10] [、] [A-11] [、] [A-12] [and] [A-13] [Physical and chemical properties] [] [parameter] [A-9] [A-10] [A-11] [A-12] [A-13] purity (UPLC,%) 99.83 99.73 99.86 99.39 99.44 C-1 / eutectic forming agent (NMR, Molecular weight) 1 / 0.76 1 / 0.97 1 / 1.01 1 / 1.02 1 / 0.50 T Initial melting point (DSC, °C) 161.8 167.2 98.4 130.0 134.9 147.9 LOD (TGA, % at °C) 1.5% (105°C) 0.3% (120°C) 0.2% (110°C) < 0.1% (120°C) 0.1% (120°C) Residual solvent (NMR) 0.24% Acetonitrile 0.12% acetone 0.20% Isopropanol 0.11% Isopropanol < 0.1% isopropanol

[0263] [Variation] [A-9] [:] [3-((8-] [chlorine] [-1-(2,6-] [Dichloro] [-4-(2-)] [Hydroxyethoxy] [)] [Phenyl] [)-2-] [methyl] [-4-] [Side group] [-1,4-] [Dihydrogen] [-1,6-] [Ding] [-5-] [base] [)] [Oxygen group] [)-N-] [Methylpropionamide (compound)] [C-1] [) and phosphate (] [1 : 0.76] [Morby] eutectic []

[0264] Compound C-1 (0.2 g) from Example 1 and 1.0 equivalent of phosphoric acid were dissolved in 4.0 mL of acetonitrile: H₂O (95:5 v / v). The resulting mixture was dissolved at 50°C and cooled to room temperature to give a 1:0.76 molar eutectic of compound C-1 and phosphoric acid.

[0265] The DSC thermogram of variant A-9 of Example 1 is shown in Figure 2I. The TGA of variant A-9 of Example 1 is shown in Figure 3I. Table 4 presents the DSC data (showing the melting transition of variant A-9) and the total water loss (loss on drying - LOD) measured by TGA.

[0266] The XRPD plot of variant A-9 in Example 1 is shown in Figure 1I. When measured using CuKα radiation at a wavelength of 1.5418 Å at approximately 22°C, the XRPD peaks are shown in the table below: serial number angle 2θ d value Å relative strength % 1 7.5 11.85 11 2 9.5 9.27 17 3 11.1 7.94 18 4 17.9 4.95 twenty one 5 18.4 4.82 28 6 23.6 3.77 35 7 30.7 2.91 11 8 32.4 2.76 8

[0267] [Variation] [A-10] [:] [3-((8-] [chlorine] [-1-(2,6-] [Dichloro] [-4-(2-)] [Hydroxyethoxy] [)] [Phenyl] [)-2-] [methyl] [-4-] [Side group] [-1,4-] [Dihydrogen] [-1,6-] [Ding] [-5-] [base] [)] [Oxygen group] [)-N-] [Methylpropionamide (compound)] [C-1] [) and phosphate (] [1 : 0.97] [Morby] eutectic

[0268] Compound C-1 (30 mg) from Example 1 and 1.5 equivalents of phosphoric acid were dissolved in 0.6 mL of acetone. The resulting mixture was dissolved at 50°C and cooled to room temperature to give a 1:0.97 molar eutectic of compound C-1 and phosphoric acid.

[0269] The DSC thermogram of variant A-10 of Example 1 is shown in Figure 2J. The TGA of variant A-10 of Example 1 is shown in Figure 3J. Table 4 presents the DSC data (showing the melting transition of variant A-10) and the total water loss (loss on drying - LOD) measured by TGA.

[0270] The XRPD plot of variant A-10 in Example 1 is shown in Figure 1J. When measured using CuKα radiation at a wavelength of 1.5418 Å at approximately 22°C, the XRPD peaks are shown in the table below: serial number angle 2θ d value Å relative strength % 1 7.5 11.82 5 2 9.5 9.35 27 3 11.1 7.97 17 4 13.2 6.69 6 5 13.6 6.48 5 6 15.0 5.91 11 7 18.1 4.90 25 8 18.4 4.82 28 9 19.0 4.67 6 10 23.8 3.73 36 11 25.9 3.44 11 12 27.5 3.24 10

[0271] [Variation] [A-11] [:] [3-((8-] [chlorine] [-1-(2,6-] [Dichloro] [-4-(2-)] [Hydroxyethoxy] [)] [Phenyl] [)-2-] [methyl] [-4-] [Side group] [-1,4-] [Dihydrogen] [-1,6-] [Ding] [-5-] [base] [)] [Oxygen group] [)-N-] [Methylpropionamide (compound)] [C-1] [) and benzoic acid (] [1 : 1.01] [Morby] eutectic

[0272] Compound C-1 (60 mg) and 28 mg (2 equivalents) of benzoic acid were dissolved in 0.30 mL of isopropanol. The resulting mixture was dissolved at 50°C and cooled to room temperature to give a 1:1.01 molar eutectic of compound C-1 and benzoic acid.

[0273] The DSC thermogram of variant A-11 of Example 1 is shown in Figure 2K. The TGA of variant A-11 of Example 1 is shown in Figure 3K. Table 4 presents the DSC data (showing the melting transition of variant A-11) and the total water loss (loss on drying - LOD) measured by TGA.

[0274] The XRPD plot of variant A-11 in Example 1 is shown in Figure 1K. When measured using CuKα radiation at a wavelength of 1.5418 Å at approximately 22°C, the XRPD peaks are shown in the table below: serial number angle 2θ d value Å relative strength % 1 6.1 14.42 15 2 9.1 9.72 9 3 10.3 8.54 25 4 11.3 7.82 14 5 12.3 7.21 58 6 12.7 6.95 12 7 14.9 5.92 8 8 15.3 5.79 7 9 16.8 5.29 19 10 17.1 5.17 9 11 20.8 4.26 11 12 24.7 3.60 40

[0275] [Variation] [A-12] [:] [3-((8-] [chlorine] [-1-(2,6-] [Dichloro] [-4-(2-)] [Hydroxyethoxy] [)] [Phenyl] [)-2-] [methyl] [-4-] [Side group] [-1,4-] [Dihydrogen] [-1,6-] [Ding] [-5-] [base] [)] [Oxygen group] [)-N-] [Methylpropionamide (compound)] [C-1] [) and succinic acid () [1 : 1.02] [Morby] eutectic

[0276] Compound C-1 (1.0 g) and 2 equivalents of succinic acid were dissolved in 5.2 mL of isopropanol. The resulting mixture was dissolved at 50°C and cooled to room temperature to give a 1:1.02 molar eutectic of compound C-1 and succinic acid.

[0277] The DSC thermogram of variant A-12 of Example 1 is shown in Figure 2L. The TGA of variant A-12 of Example 1 is shown in Figure 3L. Table 4 presents the DSC data (showing the melting transition of variant A-12) and the total water loss (loss on drying - LOD) measured by TGA.

[0278] The XRPD plot of variant A-12 in Example 1 is shown in Figure 1L. When measured using CuKα radiation at a wavelength of 1.5418 Å at approximately 22°C, the XRPD peaks are shown in the table below: serial number angle 2θ d value Å relative strength % 1 6.8 12.96 58 2 8.7 10.16 32 3 10.5 8.40 6 4 15.6 5.68 11 5 16.4 5.40 45 6 17.4 5.08 5 7 19.2 4.61 10 8 21.1 4.20 48 9 24.1 3.69 18 10 24.6 3.61 7 11 27.5 3.24 twenty three 12 28.4 3.14 4

[0279] [Variation] [A-13] [:] [3-((8-] [chlorine] [-1-(2,6-] [Dichloro] [-4-(2-)] [Hydroxyethoxy] [)] [Phenyl] [)-2-] [methyl] [-4-] [Side group] [-1,4-] [Dihydrogen] [-1,6-] [Ding] [-5-] [base] [)] [Oxygen group] [)-N-] [Methylpropionamide (compound)] [C-1] [) and saccharin () [1 : 0.50] [Morby] eutectic

[0280] Compound C-1 (1.0 g) and 1.5 equivalents of saccharin were dissolved in 20.0 mL of isopropanol. The resulting mixture was dissolved at 50°C and cooled to room temperature to give a 1:0.50 molar eutectic of compound C-1 and saccharin.

[0281] The DSC thermogram of variant A-13 of Example 1 is shown in Figure 2M. The TGA of variant A-13 of Example 1 is shown in Figure 3M. Table 4 presents the DSC data (showing the melting transition of variant A-13) and the total water loss (loss on drying - LOD) measured by TGA.

[0282] The XRPD plot of variant A-13 of Example 1 is shown in Figure 1M. When measured using CuKα radiation at a wavelength of 1.5418 Å at approximately 22°C, the XRPD peaks are shown in the table below: serial number angle 2θ d value Å relative strength % 1 6.0 14.61 26 2 8.6 10.27 46 3 12.2 7.24 4 4 13.0 6.78 2 5 15.5 5.70 14 6 16.2 5.47 28 7 21.7 4.09 16 8 23.5 3.79 15 9 30.1 2.96 5 10 31.4 2.85 12

[0283] [Implementation Method] [2] [:] [2-((8-] [chlorine] [-1-(2,6-] [Dichloro] [-4-(2-)] [Hydroxyethoxy] [)] [Phenyl] [)-2-] [methyl] [-4-] [Side group] [-1,4-] [Dihydrogen] [-1,6-] [Ding] [-5-] [base] [)] [Oxygen group] [)-N-(2-] [Hydroxyethyl] [)] Acetamide (compound) [C-2] [)] []

[0284] Step 1: Methyl 2-((1-(4-bromo-2,6-dichlorophenyl)-8-chloro-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)acetate

[0285] To 1-(4-bromo-2,6-dichlorophenyl)-5,8-dichloro-2-methyl-1,6-diphenyl-4(1H)-one (intermediate) [F2], 2.5 g, 2.21 mmol) was added to a stirred solution in CH3CN (25 mL) with methyl glycolate (0.24 g, 2.65 mmol), potassium carbonate (0.92 g, 6.62 mmol), and DMAP (0.09 g, 0.66 mmol). The resulting reaction mixture was stirred at 80°C for 12 hours. The reaction mixture was filtered off and washed with CH3CN. The organic layer was concentrated under vacuum. The residue was purified by MPLC (using a 40 g silica gel column and 10-65% EtOAc in hexane) to give the title product (2.4 g, 82% yield) as a grayish-white solid. ESI-MS m / z: 504.8 [M+H]+ (Rt = 1.55 min, LC-method 6).

[0286] Step 2: (3,5-Dichloro-4-(8-chloro-5-(2-methoxy-2-ethoxy)-2-methyl-4-ethoxy-1,6-diphenyl-1(4H)-yl)phenyl)boronic acid

[0287] Methyl 2-((1-(4-bromo-2,6-dichlorophenyl)-8-chloro-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)acetate (2.3 g, 4.55 mmol) was added to a degassed (argon-filled) solution of 1,4-dioxane (25 mL) in a screw-capped tube to a solution containing bis(dioxane)boron (1.73 g, 6.82 mmol), potassium acetate (0.67 g, 6.82 mmol), PdCl₂ (dppf), and DCM (0.37 g, 0.45 mmol). The reaction mixture was stirred at 90°C for 8 hours. The reaction mixture was filtered through a diatomaceous earth mat and washed with 1,4-dioxane. The filtrate was concentrated under vacuum to give the crude title product (2.14 g, crude). ESI-MS m / z: 470.80 [M+H] + (Rt = 1.41 min, LC-method 1).

[0288] Step 3: Methyl 2-((8-chloro-1-(2,6-dichloro-4-hydroxyphenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)acetate

[0289] Montmorillonite K10 (1.69 g, 6.17 mmol) was added to a solution of (3,5-dichloro-4-(8-chloro-5-(2-methoxy-2-tefoxyethoxy)-2-methyl-4-tefoxy-1,6-diphenyl-1(4H)-yl)phenyl)boronic acid (1.94 g, 4.11 mmol) in MeOH : H 2O (10 mL : 10 mL) at 0°C, and 30% hydrogen peroxide (10 mL) was added dropwise at the same temperature. The solution was stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum to give a crude product. The crude product was purified by MPLC (using a 24.0 g silica column and 1-5% MeOH in dichloromethane) to give the title product (1.3 g, yield: 71%) as a brown solid. ESI-MS m / z: 442.90 [MH] + (Rt = 1.43 min, LC method 6).

[0290] Step 4: 2-((8-chloro-1-(2,6-dichloro-4-hydroxyphenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)acetic acid

[0291] Trimethyltin hydroxide (2.05 g, 11.29 mmol) was added to a solution of methyl 2-((8-chloro-1-(2,6-dichloro-4-hydroxyphenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)acetate (0.5 g, 1.13 mmol) in 1,2-dichloroethane (6 mL). The resulting solution was stirred at room temperature for 5 minutes, and then stirred at 80°C for 12 hours. The evaporation was evaporated under reduced pressure to give a residue. The residue was acidified with 10% KHSO4 and extracted with 10% MeOH in dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the desired product (0.23 g, yield: 42%) as a pale brown solid. ESI-MS m / z: 429.00 [M+H] + (Rt = 1.38 min, LC-method 6).

[0292] Step 5: N-(2-((tributyldimethylsilyl)oxy)ethyl)-2-((8-chloro-1-(2,6-dichloro-4-hydroxyphenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)acetamide

[0293] HATU (0.36 g, 0.95 mmol) was added to a solution of 2-((8-chloro-1-(2,6-dichloro-4-hydroxyphenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)acetic acid (0.2 g, 0.48 mmol) in DMF (3 mL). The resulting solution was stirred at room temperature for 5 min. 2-((tributyldimethylsilyl)oxy)ethyl-1-amine (0.1 g, 0.57 mmol) and DIPEA (0.15 g, 1.19 mmol) were added to this solution, and the resulting solution was stirred at room temperature for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title product (0.22 g, yield: 79%) as a pale brown solid. ESI-MS m / z: 586.15 [M+H] + (Rt = 1.63 min, LC-method 6).

[0294] Step 6: N-(2-((tributyldimethylsilyl)oxy)ethyl)-2-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)acetamide

[0295] Silver carbonate (0.31 g, 1.12 mmol) and 2-bromoethanol (0.07 g, 0.56 mmol) were added to a solution of N-(2-((tributyldimethylsilyl)oxy)ethyl)-2-((8-chloro-1-(2,6-dichloro-4-hydroxyphenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)acetamide (0.22 g, 0.38 mmol) in DMF (3 mL). The resulting reaction mixture was stirred at 80°C for 12 hours. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by MPLC (using a 12.0 g silica column and 20–60% EtOAc in hexane) to give the title product (0.13 g, yield: 56%) as a light brown solid. ESI-MS m / z: 630.15 [M+H]+ (Rt = 1.59 min, LC-method 6).

[0296] Step 7: 2-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-dipyridin-5-yl)oxy)-N-(2-hydroxyethyl)acetamide

[0297] At 0°C, 4.0 mL of HCl in 1,4-dimethylsilyl)oxy)ethyl)-2-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-dipyridin-5-yl)oxy)acetamide (0.13 g, 0.21 mmol) in anhydrous dimethyl ether (2 mL) was added. The resulting solution was stirred at ambient temperature for 1 hour. The evaporation was evaporated under reduced pressure to give a residue. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. The crude product was purified by preparative HPLC (column: X SELECT (250 mm x 19.0 mm), 5.0 μm); mobile phase: 0.02% NH₄OH in water and acetonitrile; gradient elution). The fractions were lyophilized to give the title product (0.046 g, yield: 30%) as a grayish-white powder. [C-2]: ESI-MS m / z: 516.05 [M+H]+(Rt = 1.35 min, LC-method 6); 1H NMR (300 MHz, chloroform-d3) δ ppm = 8.21 (s, 1H), 7.27 (s, 2H), 6.55 (s, 1H), 4.92 (s, 2H), 4.18 (t, J=4.2 Hz, 2H), 3.92 (t, J=4.5 Hz, 2H), 3.71 (t, J= 6.0 Hz, 2H), 3.49 (t, J=6.0 Hz, 2H), 2.04 (s, 3H).

[0298] [Example] [3] [:] [3-((8-] [chlorine] [-1-(2,6-] [Dichloro] [-4-(2-)] [Hydroxy] [-2-] [Methylpropoxy] [)] [Phenyl] [)-2-] [methyl] [-4-] [Side group] [-1,4-] [Dihydrogen] [-1,6-] [Ding] [-5-] [base] [)] [Oxygen group] [)-N-] [Methylpropionamide (compound)] [C-3] [)]

[0299] Step 1: 3-((8-chloro-1-(2,6-dichloro-4-fluorophenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-N-methylpropionic acid

[0300] To 5,8-dichloro-1-(2,6-dichloro-4-fluorophenyl)-2-methyl-1,6-diphenyl-4(1H)-one (intermediate) [F1] (1.0 g, 2.55 mmol) was added to a solution of acetonitrile (10 mL) with 3-hydroxy-N-methylpropionic acid (0.32 g, 3.06 mmol), K₂CO₃ (0.88 g, 6.38 mmol), and DMAP (0.09 g, 0.77 mmol). The reaction mixture was stirred at 80°C for 16 hours. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by MPLC (using a 40 g Silicycle column and 0–2% MeOH in dichloromethane as eluent) to give the title product (0.78 g, yield: 67%) as a grayish-white solid. ESI-MS m / z: 458.1 [M+1]⁺ (Rt = 1.40 min, LC method 5).

[0301] Step 2: 3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxy-2-methylpropoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-N-methylpropionic acid

[0302] To a stirred solution of 3-((8-chloro-1-(2,6-dichloro-4-fluorophenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-dipyridin-5-yl)oxy)-N-methylpropionic acid (0.78 g, 1.71 mmol) in DMF (8 mL), 2-methylpropane-1,2-diol (0.46 g, 5.12 mmol) and Cs₂CO₃ (1.67 g, 5.12 mmol) were added. The resulting reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by MPLC (using a 40 g Silicycle column and 0-2% MeOH in dichloromethane as eluent) to give the title product (0.22 g, yield: 24%) as a grayish-white solid. [C-3]: ESI-MS m / z: 527.90 [M+H]+(Rt = 1.42 min, LC-method-6). 1H NMR (400 MHz, methanol-d4) δ ppm = 8.19 (s, 1H), 7.27 (s, 2H), 6.51 (s, 1H), 4.66 (t, J = 5.6 Hz, 2H), 3.91 (s, 2H), 2.78 (s, 3H), 2.76 (t, J = 6.0 Hz, 2H), 2.03 (s, 3H), 1.33 (s, 6H).

[0303] [Example] [4] [:] [2-((8-] [chlorine] [-1-(2,6-] [Dichloro] [-4-(2-)] [Hydroxy] [-2-] [Methylpropoxy] [)] [Phenyl] [)-2-] [methyl] [-4-] [Side group] [-1,4-] [Dihydrogen] [-1,6-] [Ding] [-5-] [base] [)] [Oxygen group] [)-N-] [Methylacetamide (compound)] [C-4] [)] []

[0304] Step 1: 2-((8-chloro-1-(2,6-dichloro-4-fluorophenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-N-methylacetamide []

[0305] To 5,8-dichloro-1-(2,6-dichloro-4-fluorophenyl)-2-methyl-1,6-diphenyl-4(1H)-one (intermediate) [F1] (0.3 g, 0.76 mmol) was added to a stirred solution of acetonitrile (8 mL) containing K₂CO₃ (0.31 g, 2.29 mmol), DMAP (0.03 g, 0.22 mmol), and 2-hydroxy-N-methylacetamide (0.1 g, 1.14 mmol). The reaction mixture was heated at 80°C for 16 hours. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by MPLC (using a 12 g Silicycle column and 0–2% MeOH in dichloromethane as eluent) to give the title product as a white solid (0.2 g, yield: 59%). ESI-MS m / z: 444.0 [M+H]⁺ (Rt = 1.48 min, LC-method 6).

[0306] Step 2: 2-((8-chloro-1-(2,6-dichloro-4-(2-hydroxy-2-methylpropoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-N-methylacetamide

[0307] Cs₂CO₃ (0.28 g, 0.87 mmol) and 2-methylpropane-1,2-diol (0.04 g, 0.43 mmol) were added to a stirred solution of 2-((8-chloro-1-(2,6-dichloro-4-fluorophenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-dipyridin-5-yl)oxy)-N-methylacetamide (0.13 g, 0.29 mmol) in DMF (5 mL). The reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by MPLC (using a 12 g Silicycle column and 0-5% MeOH in dichloromethane as eluent) and preparative HPLC (column: X SELECT C-18 (250 mm x 19 mm, 5.0 µm); mobile phase: 0.1% formic acid and acetonitrile in water; gradient elution) to give the title product (0.023 g, yield: 15%) as a grayish-white solid. [C-4]: ESI-MS m / z: 514.05 [M+H]+(Rt = 1.42 min, LC-method 6); 1H NMR (300 MHz, methanol-d4) δ ppm = 8.21 (s, 1H), 7.28 (s, 2H), 6.55 (s, 1H), 4.91 (s, 2H), 3.91 (s, 2H), 2.89 (s, 3H), 2.05 (s, 3H), 1.33 (s, 6H).

[0308] [Example] [5] [:] [2-((8-] [chlorine] [-1-(2,6-] [Dichloro] [-4-(2-)] [Hydroxyethoxy] [)] [Phenyl] [)-2-] [methyl] [-4-] [Side group] [-1,4-] [Dihydrogen] [-1,6-] [Ding] [-5-] [base] [)] [Oxygen group] [)-N-] [Methylacetamide (compound)] [C-5] [)]

[0309] Using the intermediate from step 1 of Example 4 and ethylene glycol, 0.027 g (yield: 22%) of the off-white powder of Example 5 was prepared in a manner similar to that of Example 4. [C-5]: ESI-MS m / z: 486.05 [M+H] + (Rt = 1.38 min, LC-method 6); 1H NMR (400 MHz, chloroform-d3) δ ppm = 8.8 (brs, 1H), 8.10 (s, 1H), 7.03 (s, 2H), 6.44 (s, 1H), 4.91 (s, 2H), 4.17 (t, J= 4.4 Hz, 2H), 4.05 (t, J= 5.2 Hz, 2H), 2.98 (d, J=4.8 Hz, 3H), 2.08 (t, 1H), 1.97 (s, 3H).

[0310] [Example] [6] [:] [(R)-3-((8-] [chlorine] [-1-(2,6-] [Dichloro] [-4-(2-)] [Hydroxypropoxy] [)] [Phenyl] [)-2-] [methyl] [-4-] [Side group] [-1,4-] [Dihydrogen] [-1,6-] [Ding] [-5-] [base] [)] [Oxygen group] [)-N-] [Methylpropionamide (compound)] [C-6] [)]

[0311] To a stirred solution of 3-((8-chloro-1-(2,6-dichloro-4-fluorophenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-N-methylpropaneamine (0.4 g, 0.87 mmol) [Step 1 of Example 3] in DMF (10 mL), (R)-propane-1,2-diol (0.17 g, 1.31 mmol) and Cs₂CO₃ (0.09 g, 2.62 mmol) were added. The reaction mixture was stirred at 50°C for 3 hours. The reaction mixture was partitioned between water and EtOAc. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give the crude product. The crude compound was purified by MPLC (using a 24 g Silicycle column and 0-10% methanol in dichloromethane) to obtain a mixture of regioisomers as a pale yellow solid (0.23 g, yield: 51%). The regioisomers were separated by chiral preparative HPLC [LUX CELLULOSE-4, C-18 (250 mm x 21.2 mm, 5.0 µm) column; hexane (A) and 0.1% HCOOH (B) in IPA:MeOH (1:1); isocratic elution] to give the title product as a grayish-white powder (0.15 g, yield: 68%). [C-6]: ESI-MS m / z: 514.0 [M+H] +(Rt = 0.71 min, LC-method 2); 1H NMR (300 MHz, CD 3OD) δ ppm = 8.19 (s, 1H), 7.26 (s, 2H), 6.51 (s, 1H), 4.67 (t, J= 5.7 Hz, 2H), 4.14-3.94 (m, 3H), 2.78-2.72 (m, 5H), 2.02 (s, 3H), 1.29 (d, J= 6.3 Hz, 3H).

[0312] [Example] [7] [:] [(R)-3-((8-] [chlorine] [-1-(2,6-] [Dichloro] [-4-(2-)] [Hydroxyethoxy] [)] [Phenyl] [)-2-] [methyl] [-4-] [Side group] [-1,4-] [Dihydrogen] [-1,6-] [Ding] [-5-] [base] [)] [Oxygen group] [)-N,2-] [Dimethylpropionamide (compound)] [C-7] [)]

[0313] Step 1: (R)-3-hydroxy-N,2-dimethylpropionic acid

[0314] 40% methylamine (20.5 mL, 114.34 mmol) in methanol was added to a stirred solution of methyl(R)-3-hydroxy-2-methylpropionate (0.5 g, 4.24 mmol) in MeOH (5 mL) in a screw-capped tube. The contents of the tube were stirred at 85°C for 20 hours. The reaction mixture was evaporated under reduced pressure to give the title product (0.45 g, 95%) as a yellow solid. ¹H NMR (400 MHz, chloroform-d3) δ ppm = 5.98 (bs, 1H), 3.72 (m, 2H), 2.82 (d, 3H), 2.47 (m, 1H), 1.172 (d, 3H).

[0315] Step 2: (R)-3-((8-chloro-1-(2,6-dichloro-4-fluorophenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-N,2-dimethylpropionic acid

[0316] To 5,8-dichloro-1-(2,6-dichloro-4-fluorophenyl)-2-methyl-1,6-diphenyl-4(1H)-one (intermediate) [F1], 0.3 g, 0.77 mmol) was added to a solution of acetonitrile (4.00 mL) with (R)-3-hydroxy-N,2-dimethylpropionic acid (0.11 g, 0.92 mmol), K₂CO₃ (0.26 g, 1.91 mmol), and DMAP (0.03 g, 0.23 mmol). The resulting reaction mixture was stirred at 80°C for 16 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give the crude product. The crude compound was purified by MPLC (using a 12 g Silicycle column and 0–3% MeOH in dichloromethane) to give the title product (0.25 g, yield: 69%) as a grayish-white solid. ESI-MS m / z: 471.8 [M+H]⁺ (Rt = 1.49 min, LC-method-6).

[0317] Step 3: (R)-3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-dipyridin-5-yl)oxy)-N,2-dimethylpropionic acid

[0318] Ethylene glycol (0.09 g, 1.53 mmol) and Cs₂CO₃ (0.49 g, 1.53 mmol) were added to a stirred solution of (R)-3-((8-chloro-1-(2,6-dichloro-4-fluorophenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-dipyridin-5-yl)oxy)-N,2-dimethylpropionic acid (0.24 g, 0.51 mmol) in DMF (3 mL). The reaction mixture was stirred at ambient temperature for 4 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give the crude product. The crude compound was purified by MPLC (using a 12 g Silicycle column and 0–3% MeOH in dichloromethane) to give the title product (0.071 g, yield: 27%) as a grayish-white solid. [C-7]: ESI-MS m / z: 513.9 [M+H] + (Rt = 1.39 min, LC-Method-6). ESI-MS m / z: 515.90 [M+3H] + (Rt = 1.39 min, LC-Method-6). 1H NMR (400 MHz, CD 3OD) δ ppm = 8.18 (s, 1H), 7.26 (s, 2H), 6.51 (s, 1H), 4.49-4.45 (m, 2H), 4.17 (t, J=4.8 Hz, 2H), 3.91 (t, J= 5.2 Hz, 2H), 2.83-279 (m, 1H), 2.77 (s, 3H), 2.026 (s, 3H), 1.27 (d, J=7.2 Hz, 3H).

[0319] [Example] [8] [:] [(S)-3-((8-] [chlorine] [-1-(2,6-] [Dichloro] [-4-(2-)] [Hydroxyethoxy] [)] [Phenyl] [)-2-] [methyl] [-4-] [Side group] [-1,4-] [Dihydrogen] [-1,6-] [Ding] [-5-] [base] [)] [Oxygen group] [)-N,2-] [Dimethylpropionamide (compound)] [C-8] [)]

[0320] Example 8 was prepared in a manner similar to Example 7, using (S)-3-hydroxy-2-methylpropionate instead of (R)-3-hydroxy-2-methylpropionate to produce 0.038 g (a light-colored solid, yield: 18%). The crude product was purified by preparative HPLC (column: X-select C-18 (19 mm x 250 mm, µm); mobile phase: 0.1% HCOOH in water and acetonitrile; gradient elution). [C-8]: ESI-MS m / z: 514.2 [M+H]+(Rt = 0.78 min, LC-method-5). 1H NMR (400 MHz, methanol-d4) δ ppm = 8.18 (s, 1H), 7.26 (s, 2H), 6.51 (s, 1H), 4.49–4.45 (m, 2H), 4.18 (t, J = 4.4 Hz, 2H), 3.91 (t, J = 5.2 Hz, 2H), 2.90 (m, 1H), 2.77 (s, 3H), 2.03 (s, 3H), 1.27 (d, J = 7.2 Hz, 3H).

[0321] [Example] [9] [:] [N-(2-((8-] [chlorine] [-1-(2,6-] [Dichloro] [-4-(2-)] [Hydroxyethoxy] [)] [Phenyl] [)-2-] [methyl] [-4-] [Side group] [-1,4-] [Dihydrogen] [-1,6-] [Ding] [-5-] [base] [)] [Oxygen group] [)] [Ethyl] [)] Acetamide (compound) [C-9] [)]

[0322] Step 1: Tributyl(2-((8-chloro-1-(2,6-dichloro-4-fluorophenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)ethyl)aminocarbamate

[0323] To a stirred solution of 5,8-dichloro-1-(2,6-dichloro-4-fluorophenyl)-2-methyl-1,6-diphenyl-4(1H)-one (intermediate F1, 0.7 g, 1.79 mmol) in acetonitrile (20 mL), tributyl(2-aminoethyl)carbamate (0.35 g, 2.14 mmol), K₂CO₃ (0.74 g, 5.36 mmol), and DMAP (0.07 g, 0.54 mmol) were added. The reaction mixture was stirred at 80°C for 6 hours. The reaction mixture was partitioned between water and EtOAc, and the aqueous layer was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give the crude product. The crude compound was purified by MPLC (using a 12 g Silicycle column and 20–100% ethyl acetate in hexane) to give the title product (0.62 g, yield: 67%) as a grayish-white solid. ESI-MS m / z: 516.6 (M+H)+ (Rt = 1.79 min, LC-method 4).

[0324] Step 2: 5-(2-aminoethoxy)-8-chloro-1-(2,6-dichloro-4-fluorophenyl)-2-methyl-1,6-diphenyl-4(1H)-one hydrochloride

[0325] To a stirred solution of tributyl(2-((8-chloro-1-(2,6-dichloro-4-fluorophenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)ethyl)carbamate (0.6 g, 1.16 mmol) in dimethyl ether (5 mL), 4.0 M HCl (10 mL) in 1,4-dimethyl ether was added. The reaction mixture was stirred at 30°C for 6 hours. The evaporation was evaporated under reduced pressure to give the title product (0.55 g, yield: 100%) as a grayish-white solid. The resulting product was used directly in the next step.

[0326] Step 3: N-(2-((8-chloro-1-(2,6-dichloro-4-fluorophenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)ethyl)acetamide

[0327] Triethylamine (0.49 mL, 3.64 mmol) and acetyl chloride (0.12 mL, 1.82 mmol) were added to a suspension of 5-(2-aminoethoxy)-8-chloro-1-(2,6-dichloro-4-fluorophenyl)-2-methyl-1,6-diphenyl-4(1H)-one hydrochloride (0.54 g, 1.213 mmol) in dichloromethane (10 mL) at 0°C. The reaction mixture was stirred at 30°C for 5 hours. The reaction mixture was partitioned between water and EtOAc, and the aqueous layer was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give the crude product. The crude product was purified by MPLC (using a 24 g Silicycle column and 20–70% ethyl acetate in hexane) to give the title product (0.45 g, yield: 81%) as a yellow semi-solid. ESI-MS m / z: 458.0 (M+H) + (Rt = 1.29 min, LC-method 5).

[0328] Step 4: N-(2-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)ethyl)acetamide

[0329] Ethylene glycol (0.04 g, 0.65 mmol) and Cs₂CO₃ (0.43 g, 1.31 mmol) were added to a stirred solution of N-(2-((8-chloro-1-(2,6-dichloro-4-fluorophenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)ethyl)acetamide (0.2 g, 0.44 mmol) in DMF (5 mL). The reaction mixture was stirred at 30°C for 6 hours. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give the crude product. The crude product was purified by MPLC (using a 24 g Silicycle column and 0-5% methanol in dichloromethane) to give the title product (0.058 g, yield: 32%) as a grayish-white powder. [C-9]: ESI-MS m / z: 499.85 [M+H]+(Rt = 1.35 min, LC-method 6); 1H NMR (300 MHz, methanol-d4) δ ppm = 8.18 (s, 1H), 7.26 (s, 2H), 6.53 (s, 1H), 4.55 (t, J= 5.1 Hz, 2H), 4.18 (t J= 4.2 Hz, 2H), 3.92 (t J=4.5 Hz, 2H), 3.65 (t, J=5.4 Hz, 2H), 2.03 (s, 3H), 1.97 (s, 3H).

[0330] [Example]

[10] [:] [(S)-3-((8-] [chlorine] [-1-(2,6-] [Dichloro] [-4-(2-)] [Hydroxypropoxy] [)] [Phenyl] [)-2-] [methyl] [-4-] [Side group] [-1,4-] [Dihydrogen] [-1,6-] [Ding] [-5-] [base] [)] [Oxygen group] [)-N-] [Methylpropionamide (compound)] [C-10] [)]

[0331] To a stirred solution of 3-((8-chloro-1-(2,6-dichloro-4-fluorophenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-N-methylpropaneamine [Step 1 of Example 1] (0.450 g, 0.98 mmol) in DMF (5 mL), (S)-propane-1,2-diol (0.11 g, 1.47 mmol) and potassium carbonate (0.19 g, 1.39 mmol) were added. The reaction mixture was stirred at 80°C for 24 hours. The reaction mixture was partitioned between water and EtOAc. The combined organic phases were washed with water and brine, dried over Na₂SO₄, and evaporated under reduced pressure to give the crude product. The crude product was purified by MPLC (Combi-Flash, 12 g Redisep column, and 0-15% MeOH in dichloromethane) and preparative HPLC (column: Kinetex C18 (150 mm x 21.2 mm, 5.0 µm) column; mobile phase: water and acetonitrile; gradient elution) to give the title product (0.024 g, yield: 10%) as a grayish-white solid. [C-10]: ESI-MS m / z: 514.4 [M+H]+(Rt = 0.78 min, LC-method 5); 1H NMR (300 MHz, chloroform-d3) δ ppm = 8.73 (s, 1H), 8.09 (s, 1H), 7.02 (s, 2H), 6.43 (s, 1H), 5.29 (s, 1H), 4.57-4.59 (m, 2H), 4.26-4.36 (m, 1H), 4.01-3.88 (m, 2H), 2.88 (d, J = 3.2 Hz, 3H), 2.77-2.72 (m, 2H), 2.29-2.27 (m, 1H), 1.96 (s, 3H). 1.34 (d, J = 4.5 Hz, 3H).

[0332] [Example]

[11] [:] [3-((8-] [chlorine] [-1-(2,6-] [Dichloro] [-4-(2-)] [Hydroxyethoxy] [)] [Phenyl] [)-2-] [methyl] [-4-] [Side group] [-1,4-] [Dihydrogen] [-1,6-] [Ding] [-5-] [base] [)] [Oxygen group] [)-N,2,2-] [Trimethylpropionamide (compound)] [C-11] [)] []

[0333] Step 1: 3-Hydroxy-N,2,2-Trimethylpropionamide []

[0334] 40% methylamine (12 mL, 114.28 mmol) in methanol was added to a stirred solution of methyl 3-hydroxy-2,2-dimethylpropionate (0.5 g; 4.23 mmol) in 12 mL of MeOH in a screw-capped tube. The resulting solution was stirred at 85°C for 12 h. The evaporation was evaporated under high vacuum to give the title product (0.5 g, yield: 100%). ¹H NMR (400 MHz, chloroform-d³) δ ppm = 3.70 (s, 2H), 2.80 (t, J = 4.8 Hz, 3H), 1.19 (s, 3H), 1.17 (s, 3H).

[0335] Step 2: 3-((8-chloro-1-(2,6-dichloro-4-fluorophenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-N,2,2-trimethylpropionic acid

[0336] To 5,8-dichloro-1-(2,6-dichloro-4-fluorophenyl)-2-methyl-1,6-diphenyl-4(1H)-one (intermediate) [F1] (0.25 g; 0.64 mmol) and 3-hydroxy-N,2,2-trimethylpropionic acid (0.13 g, 0.96 mmol) were added to a stirred solution of acetonitrile (2.5 mL) with potassium carbonate (0.22 g, 1.59 mmol) and DMAP (0.02 g, 0.19 mmol). The resulting reaction mixture was stirred at 80°C for 16 hours. The reaction mixture was partitioned between water and EtOAc. The combined organic phases were washed with water and brine, dried over Na₂SO₄ and evaporated under reduced pressure to give a crude product. The crude product was purified by MPLC (Combi-Flash, 12 g Redisep column, 20-100% ethyl acetate in hexane) to give the title product (0.2 g, yield: 64%) as a grayish-white solid. ESI-MS m / z: 486.3 [M+H]⁺ (Rt = 1.68 min, LC-method 5).

[0337] Step 3: 3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-N,2,2-trimethylpropionic acid

[0338] Cesium carbonate (0.47 g, 1.44 mmol) was added to a solution of 3-((8-chloro-1-(2,6-dichloro-4-fluorophenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-N,2,2-trimethylpropionic acid (0.2 g, 0.41 mmol) and ethylene glycol (0.1 g, 1.64 mmol) in DMF (3 mL). The resulting reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was partitioned between water and EtOAc. The combined organic phases were washed with water and brine, dried over Na₂SO₄, and evaporated under reduced pressure to give the crude product. The crude product was purified by MPLC (Combi-Flash, 12 g Rediff column, and 0-3% methanol in dichloromethane) and preparative HPLC (column: YMC-C18 (20 mm x 150 mm, 5.0 µm); mobile phase: 0.02% amine water and acetonitrile in water, gradient elution) to give the title product (0.065 g, yield: 34%) as a grayish-white solid. [C-11]: ESI-MS m / z: 528.2 [M+H]+(Rt = 1.37min, LC-method 5); 1H NMR (300 MHz, methanol-d4) δ ppm = 8.19 (s, 1H), 7.27 (s, 2H), 6.53 (s, 1H), 4.33 (s, 2H), 4.17 (s, 2H), 3.91 (s, 2H), 2.79 (s, 3H), 2.04 (s, 3H), 1.29 (s, 6H).

[0339] [Example]

[12] [:] [(R)-3-((8-] [chlorine] [-1-(2,6-] [Dichloro] [-4-(2-)] [Hydroxyethoxy] [)] [Phenyl] [)-2-] [methyl] [-4-] [Side group] [-1,4-] [Dihydrogen] [-1,6-] [Ding] [-5-] [base] [)] [Oxygen group] [)-2-] [Hydroxy] [-N-] [Methylpropionamide (compound)] [C-12] [)]

[0340] Example 12, which prepared 0.01 g (a light-colored powder, yield: 10%) in a manner similar to Example 13, used O-benzyl-D-serine instead of O-benzyl-L-serine. [C-12]: ESI-MS m / z: 515.9 [M+H]+(Rt = 1.36 min, LC-method-6). 1H NMR (300 MHz, methanol-d4) δ ppm = 8.51 (bs, 1H), 8.19 (s, 1H), 7.25 (s, 2H), 6.53 (s, 1H), 4.64–4.57 (m, 2H), 4.49 (t, J=4.8 Hz, 1H), 4.17–4.14 (t, J=4.4 Hz, 2H), 3.90 (t, J=4.8 Hz, 2H), 2.79 (s, 3H), 2.02 (s, 3H). Chiral HPLC (Rt = 6.50 min, chiral HPLC method 1): 99.0%.

[0341] [Example]

[13] [:] [(S)-3-((8-] [chlorine] [-1-(2,6-] [Dichloro] [-4-(2-)] [Hydroxyethoxy] [)] [Phenyl] [)-2-] [methyl] [-4-] [Side group] [-1,4-] [Dihydrogen] [-1,6-] [Ding] [-5-] [base] [)] [Oxygen group] [)-2-] [Hydroxy] [-N-] [Methylpropionamide (compound)] [C-13] [)]

[0342] Step 1: (S)-3-(benzyloxy)-2-hydroxypropionic acid

[0343] At 0°C, 0.5 M NaNO₂ (300 mL; 290.98 mmol) in water was added dropwise to a solution of O-benzyl-L-serine (10.0 g, 51.23 mmol) in 1.0 M H₂SO₄ (123 mL), and the mixture was kept at 0°C for 1 hour. The resulting solution was then slowly heated to ambient temperature and kept there for 20 hours. The reaction mixture was basified to pH 6–7 using 1.0 M NaOH in water and washed with EtOAc. The aqueous layer was acidified to pH 2 with 1.0 M H₂SO₄ and extracted with EtOAc. The combined organic phases were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to give a product as a pale yellow oil (9.71 g, yield: 97%). ¹H NMR (400 MHz, chloroform-d³) δ ppm = 7.36–7.26 (m, 5H), 4.59 (dd, 2H, J = 2.8 Hz, 14.8 Hz), 4.38 (t, J = 3.6 Hz, 1H), 3.83–3.76 (m, 2H).

[0344] Step 2: Methyl(S)-3-(benzyloxy)-2-hydroxypropionate

[0345] SOCl₂ (0.72 mL, 9.88 mmol) was added dropwise to (S)-3-(benzyloxy)-2-hydroxypropionic acid (9.7 g, 49.43 mmol) in methanol (50 mL) at 0°C and maintained at 0°C for 5 minutes. The resulting reaction mixture was stirred at ambient temperature for 1 hour. Trimethyl orthoformate (10.81 mL, 98.86 mmol) was added to the reaction mixture. The resulting reaction mixture was stirred at ambient temperature for 20 hours. The evaporation under reduced pressure gave the crude product. The crude product was purified by Combi-Flash column chromatography (using an 80 g Silicycle column and 0–20% EtOAc in hexane) to give the desired product as a colorless oil (8.58 g, yield: 83%). ESI-MS m / z: 211.10 [M+H]⁺, (Rt = 1.09 min, LC-method 3). ¹H NMR (400 MHz, chloroform-d³) δ ppm = 7.36–7.26 (m, 5H), 4.61 (d, 1H, J = 12.0 Hz), 4.53 (d, J = 12.4 Hz, 1H), 4.34–4.31 (m, 1H), 3.78 (s, 3H), 3.75 (d, J = 3.6 Hz, 2H), 3.15 (d, J = 6.8 Hz, 1H).

[0346] Step 3: Methyl(S)-3-(benzyloxy)-2-((tert-butyldimethylsilyl)oxy)propionate

[0347] DMAP (0.99 g; 8.08 mmol) and imidazole (3.05 g, 44.85 mmol) were added to a stirred solution of methyl (S)-3-(benzyloxy)-2-hydroxypropionate (8.5 g, 40.41 mmol) in dichloromethane (120 mL) at 0°C. The resulting solution was stirred at 0°C for 15 min. TBSCl (6.76 g, 44.86 mmol) was added to the solution and the mixture was stirred at ambient temperature for 44 h. The reaction mixture was diluted with dichloromethane and washed with brine. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude product. The crude product was purified by Combi-Flash column chromatography (using an 80 g Silicycle column and 0–20% EtOAc in hexane) to give the desired product as a colorless oil (12.4 g, yield: 95%). ¹H NMR (300 MHz, chloroform-d³) δ ppm = 7.31–7.26 (m, 5H), 4.58 (d, J = 2.1 Hz, 2H), 4.41 (t, J = 6.0 Hz, 1H), 3.73 (s, 3H), 3.66 (t, J = 3.9 Hz, 2H), 0.91 (s, 9H), 0.10 (s, 3H), 0.08 (s, 3H).

[0348] Step 4: Methyl(S)-2-((tributyldimethylsilyl)oxy)-3-hydroxypropionate

[0349] 10% carbon-supported palladium (0.65 g) was added to a stirred solution of methyl(S)-3-(benzyloxy)-2-((tributyldimethylsilyl)oxy)-propionate (6.0 g, 18.490 mmol) in dichloromethane (20 mL). The resulting reaction mixture was stirred for 16 hours under a hydrogen atmosphere (1 atm). The reaction mixture was filtered through a diatomaceous earth pad and washed with dichloromethane. The filtrate was evaporated under reduced pressure to give the crude product. The crude material was purified by Combi-Flash (using a 40 g Silicycle column and 0–30% EtOAc in hexane) to give the title product (2.57 g, yield: 59%) as a colorless oil. ¹H NMR (300 MHz, chloroform-d³) δ ppm = 4.29 (t, J = 4.5 Hz, 1H), 3.79 (d, J = 4.5 Hz, 2H), 3.74 (s, 3H), 2.22 (t, J = 6.6 Hz, 1H), 0.90 (s, 9H), 0.13 (s, 3H), 0.08 (s, 3H).

[0350] Step 5: (S)-3-((tributyldimethylsilyl)oxy)-2-hydroxy-N-methylpropionic acid

[0351] A solution of methyl(S)-2-((tributyldimethylsilyl)oxy)-3-hydroxypropionate (2.5 g, 10.66 mmol) in MeOH (5 mL) was mixed with 40% methylamine in methanol (61.5 mL, 160.00 mmol). The resulting reaction mixture was stirred at 85°C for 12 hours. The evaporation was evaporated under high vacuum to obtain the title product (2.2 g, crude). Note: During amide formation, the silyl group migrates, resulting in the product shown in the title. ESI-MS m / z: 233.75 (M+H)+, (Rt = 1.454 min, LC-method 6). ¹H NMR (300 MHz, chloroform-d3) δ ppm = 4.15 (d, 1H), 4.07 (t, 1H), 3.81–3.65 (m, 1H), 2.94–2.82 (m, 3H), 0.88 (s, 9H), 0.07 (s, 6H).

[0352] Step 6: (S)-3-((tributyldimethylsilyl)oxy)-2-((8-chloro-1-(2,6-dichloro-4-fluorophenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-N-methylpropionic acid

[0353] To 5,8-dichloro-1-(2,6-dichloro-4-fluorophenyl)-2-methyl-1,6-diphenyl-4(1H)-one (intermediate) [F1] (1.0 g, 2.55 mmol) and (S)-3-((tributyldimethylsilyl)oxy)-2-hydroxy-N-methylpropionic acid (0.72 g, 3.06 mmol) in acetonitrile (10 mL) were reacted with potassium carbonate (0.88 g, 6.38 mmol) and DMAP (0.06 g, 0.51 mmol). The resulting reaction mixture was stirred at 80°C for 16 hours. The reaction mixture was diluted with water and extracted with EtOAC. The combined organic phases were washed with water and brine, dried over Na₂SO₄ and evaporated under reduced pressure to give the crude product. The crude product was purified by MPLC (Combi-Flash, 40 g Rediff column, 20-100% ethyl acetate in hexane) to give the title product (0.52 g, yield: 35%) as a pale brown semi-solid. ESI-MS m / z: 588.05 (M+H)+, (Rt = 1.74 min, LC-method 5). 1H NMR (300 MHz, chloroform-d3) δ ppm = 9.13 (s, 1H), 8.06 (s, 1H), 7.28 (s, 2H), 6.43 (s, 1H), 5.65 (t, J= 2.7 Hz, 1H), 4.25 (d, J=2.7 Hz, 2H), 2.93 (d, J=4.5 Hz, 3H), 2.04 (s, 3H), 0.81 (s, 9H), -0.05 (d, J=5.7 Hz, 6H).

[0354] Step 7: (S)-3-((tributyldimethylsilyl)oxy)-2-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-N-methylpropionic acid

[0355] Cesium carbonate (0.44 g, 1.36 mmol) was added to a solution of (S)-3-((tributyldimethylsilyl)oxy)-2-((8-chloro-1-(2,6-dichloro-4-fluorophenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-N-methylpropionic acid (0.4 g, 0.68 mmol) and ethylene glycol (0.06 g, 1.02 mmol) in acetonitrile (6 mL) in a screw-cap microwave-safe vial. The resulting reaction mixture was stirred at 80°C for 30 min in an Anton Parr microwave reactor. (Note: This reaction was carried out in batches of 4 x 0.1 g). The combined reaction mixture was diluted with water and extracted with EtOAC. The combined organic phases were washed with water and brine, dried over Na₂SO₄, and evaporated under reduced pressure to give the crude product. The crude product was purified by MPLC (using a 24 g Redisep column and 20–100% ethyl acetate in hexane) to give the title product (0.15 g, yield: 20%) as a pale yellow semi-solid. ESI-MS m / z: 630.2 (M+H)+, (Rt = 1.591 min, LC-method 5). 1H NMR (400 MHz, chloroform-d3) δ ppm = 9.21 (d, 1H), 8.06 (s, 1H), 7.03(s, 2H), 6.43(s,1H), 5.65 (t, 1H, J=2.1 Hz), 4.17 (t, 2H, J=4 Hz), 4.05-4.02 (m, 2H), 3.74 (s, 2H), 2.93 (d, 3H, J=4.84 Hz), 2.10 (d, 1H, J= 6 Hz), 1.97 (s, 3H), 0.81 (s, 9H), -0.04 (m, 6H).

[0356] Step 8: (S)-3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-2-hydroxy-N-methylpropionic acid

[0357] At 0°C, 1.0 M TBAF (0.36 mL, 0.36 mmol) in THF was added to a solution of ((S)-3-((tributyldimethylsilyl)oxy)-2-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-N-methylpropionic acid (0.15 g, 0.24 mmol) in THF (4 mL). The resulting reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was quenched with ice-cold water and extracted with EtOAC. The combined organic phases were washed with water and brine, dried over Na₂SO₄, and evaporated under reduced pressure to give the crude product. The crude product was subjected to Combi-Flash chromatography (using a 12 g Redisep silica gel column and 0-1.5% TBAF in dichloromethane). The product was purified by MeOH and further purified by Combi-Flash (using a 12 g Redisep silica column and 0-2% MeOH in dichloromethane) to give a pure, off-white solid of the desired product (0.038 g, yield: 31%). Note: During the deprotection of the silica junction, the ether rearranged to form the title compound. [C-13]: HRMS m / z: calculated value 516.0496 [M+H]+, found value 516.0592. ESI-MS m / z: 515.9 [M+H]+ (Rt = 1.35 min, LC-method 6); 1H NMR (300 MHz, methanol-d4) δ ppm = 8.19 (s, 1H), 7.26 (s, 2H), 6.52 (s, 1H), 4.63-4.55 (m, 2H), 4.49-4.47 (m, 1H), 4.18 (t, J=4.2 Hz, 2H), 3.91 (t, J=4.5 Hz, 2H), 2.81 (s, 3H), 2.03 (s, 3H). Chiral HPLC (Rt = 4.80 min, chiral HPLC method 1): 97.9%.

[0358] [Example]

[14] [:] [(S)-3-((8-] [chlorine] [-1-(2,6-] [Dichloro] [-4-(2-)] [Hydroxy] [-2-] [Methylpropoxy] [)] [Phenyl] [)-2-] [methyl] [-4-] [Side group] [-1,4-] [Dihydrogen] [-1,6-] [Ding] [-5-] [base] [)] [Oxygen group] [)-2-] [Hydroxy] [-N-] [Methylpropionamide (compound)] [C-14] [)]

[0359] Cesium carbonate (0.83 g, 2.55 mmol) was added to a solution of (S)-3-((tributyldimethylsilyl)oxy)-2-((8-chloro-1-(2,6-dichloro-4-fluorophenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-N-methylpropane [Step 6 of Example 13] (0.5 g, 0.85 mmol) and 2-methylpropane-1,2-diol (0.15 g, 1.7 mmol) in DMF (5 mL). The resulting reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was diluted with water and extracted with EtOAC. The combined organic phases were washed with water and brine, dried over Na₂SO₄, and evaporated under reduced pressure to give the crude product. The crude product was purified by Combi-Flash (using a 12 g Redisep silicone column and 0-2% MeOH in dichloromethane) and preparative HPLC (column: ATLANTIS-T3 (250 mm x 19 mm, 5.0 µm); mobile phase: 0.1% HCOOH and acetonitrile in water; gradient elution) to give the desired product (0.003 g, yield: 3%) as a grayish-white solid. [C-14]: ESI-MS m / z: 544.10 [M+H]+ (Rt = 1.10 min, LC-method 3); 1H NMR (300 MHz, methanol-d4) δ ppm = 8.19 (s, 1H), 7.27 (s, 2H), 6.52 (s, 1H), 4.63–4.59 (m, 2H), 4.49–4.47 (m, 1H), 3.91 (s, 2H), 2.81 (s, 3H), 2.03 (s, 3H), 1.33 (s, 6H). Chiral HPLC (Rt = 8.04 min, chiral HPLC method 2): 98.6%.

[0360] [Example]

[15] [:] [3-((8-] [chlorine] [-1-(2,6-] [Dichloro] [-4-((3-] [Hydroxyhexacyclic butane] [-3-] [base] [)] [Methoxy] [)] [Phenyl] [)-2-] [methyl] [-4-] [Side group] [-1,4-] [Dihydrogen] [-1,6-] [Ding] [-5-] [base] [)] [Oxygen group] [)-N-] [Methylpropionamide (compound)] [C-15] [)] []

[0361] Step 1: 3-(hydroxymethyl)oxetane-3-ol []

[0362] At 0°C, osmium tetroxide (4%) (0.1 mL, 7.13 mmol) and H₂O₂ (50%) (1.0 mL, 16.32 mmol) were added sequentially to a solution of 3-methyleneoxetane (500 mg, 7.13 mmol) in THF (1.0 mL) and H₂O (1.0 mL). The mixture was allowed to reach room temperature and stirred for 1 hour. It was then diluted with 3 mL of water and filtered through a diatomaceous earth mat. The filtrate was concentrated in a rotary evaporator at 42°C and 50 mbar for 30 min to give the title compound. ¹H NMR (400 MHz, methanol-d⁴) δ ppm = 4.63–4.48 (m, 4H), 3.70 (s, 2H).

[0363] Step 2: 3-((8-chloro-1-(2,6-dichloro-4-fluorophenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-N-methylpropionic acid

[0364] To 5,8-dichloro-1-(2,6-dichloro-4-fluorophenyl)-2-methyl-1,6-diphenyl-4(1H)-one (intermediate) [F1] (1500 mg, 3.826 mmol) and 3-hydroxy-N-methylpropionic acid (512.9 mg, 4.974 mmol) were added to a solution in CH3CN (50 mL) along with DMAP (233.7 mg, 1.913 mmol) and K2CO3 (1586 mg, 11.48 mmol). The mixture was stirred at 80°C for 16 hours. It was then cooled to room temperature and filtered, washing with MeOH. The filtrate was concentrated to dryness. The residue was purified by rapid column chromatography (0-10% MeOH / DCM) to provide the title compound. ESI-MS m / z: 458.1 [M+H]+ (Rt = 0.93 min, LC-Method 7).

[0365] Step 3: 3-((8-chloro-1-(2,6-dichloro-4-((3-hydroxyoxetane-3-yl)methoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-N-methylpropionic acid

[0366] Cs₂CO₃ (1.07 g, 3.27 mmol) was added to a solution of 3-((8-chloro-1-(2,6-dichloro-4-fluorophenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-dipyridin-5-yl)oxy)-N-methylpropionic acid (300 mg, 0.654 mmol) and 3-(hydroxymethyl)oxetane-3-ol (204 mg, 1.96 mmol) in DMF (6 mL). The mixture was stirred at 40°C for 24 hours. It was then cooled to room temperature, diluted in MeOH, and filtered. The filtrate was purified by HPLC to give the title compound. [C-15]: ESI-MS m / z: 541.9 [M+H]+(Rt = 0.93 min, LC-Method 7), 1H NMR (400 MHz, methanol-d4) δ ppm = 8.20 (s, 1H), 7.33 (s, 2H), 6.52 (s, 1H), 4.71-4.59 (m, 6H), 4.33 (s, 2H), 2.79 (s, 3H), 2.75 (t, J = 5.9 Hz, 2H), 2.04 (s, 3H).

[0367] [Example]

[16] [:] [3-((8-] [chlorine] [-1-(2,6-] [Dichloro] [-4-(2-)] [Hydroxyethoxy] [)] [Phenyl] [)-2-] [methyl] [-4-] [Side group] [-1,4-] [Dihydrogen] [-1,6-] [Ding] [-5-] [base] [)] [Oxygen group] [)-2,2-] [Difluoride] [-N-] [Methylpropionamide (compound)] [C-16] [)]

[0368] Step 1: 2,2-Difluoro-3-hydroxy-N-methylpropionic acid

[0369] To a solution of ethyl 2,2-difluoro-3-hydroxypropionate (0.2 g, 0.65 mmol) in MeOH (1.0 mL) in a screw-capped tube, 40% methylamine (2.0 mL) in methanol was added. The reaction mixture was stirred at 80°C for 16 hours. The evaporation was carried out under reduced pressure to give the crude product (0.12 g, yield: 40%). ¹H NMR (300 MHz, methanol-d4D) δ ppm = 6.49 (bs, 1H), 4.06–3.97 (m, 2H), 2.93 (s, 3H).

[0370] Step 2: 3-((8-chloro-1-(2,6-dichloro-4-fluorophenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-2,2-difluoro-N-methylpropionic acid

[0371] To a solution of 5,8-dichloro-1-(2,6-dichloro-4-fluorophenyl)-2-methyl-1,6-diphenyl-4(1H)-one (intermediate F1, 0.35 g, 0.88 mmol) and 2,2-difluoro-3-hydroxy-N-methylpropionic acid (0.11 g, 0.79 mmol) in acetonitrile (5 mL), K₂CO₃ (0.3 g, 2.19 mmol) and DMAP (0.03 g, 0.26 mmol) were added. The resulting reaction mixture was stirred at 80°C for 16 hours. The reaction mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by MPLC (using a 24 g Silicycle column and 40-70% EtOAc in hexane) to give the title product (0.2 g, yield: 37%) as a grayish-white solid. ESI-MS m / z: 493.8 [M+H]+ (Rt = 1.08 min, LC-method 6).

[0372] Step 3: 3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-2,2-difluoro-N-methylpropionic acid

[0373] To a solution of 3-((8-chloro-1-(2,6-dichloro-4-fluorophenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-2,2-difluoro-N-methylpropionic acid (0.06 g, 0.12 mmol) in DMF (3 mL) in a microwave-safe vial, K₂CO₃ (0.04 g, 0.30 mmol) and ethylene glycol (0.01 g, 0.18 mmol) were added. The resulting reaction mixture was stirred in an Anton Parr microwave reactor at 80°C for 3 hours. The reaction mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to obtain the crude product. The crude product was purified twice by MPLC (using a 24 g Redisep column and 5-10% methanol in dichloromethane) to give the title product (0.008 g, yield: 15%) as a grayish-white solid. [C-16]: ESI-MS m / z: 536.05 [M+H]+(Rt = 0.83 min, LC-method-3). 1H NMR (400 MHz, methanol-d4) δ ppm = 8.22 (s, 1H), 7.27 (s, 2H), 6.52 (s, 1H), 4.87–4.81 (m, 2H), 4.18 (t, J=4.4 Hz, 2H), 3.92 (t, J=4.8 Hz, 2H), 2.88 (s, 3H), 2.04 (s, 3H).

[0374] [Example]

[17] [:] [2-(4-(5-(2-] [Amine] [-2-] [Side-oxygenated ethoxylated] [)-8-] [chlorine] [-2-] [methyl] [-4-] [Side group] [-1,6-] [Ding] [-1(4H)-] [base] [)-3,5-] [Dichlorophenoxy] [)-N-] [Methylacetamide (compound)] [C-17] [)]

[0375] Step 1: 2-((1-(4-bromo-2,6-dichlorophenyl)-8-chloro-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)acetamide

[0376] To 1-(4-bromo-2,6-dichlorophenyl)-5,8-dichloro-2-methyl-1,6-diphenyl-4(1H)-one (intermediate) [F2] (5.0 g, 11.06 mmol), K2CO3 (4.57 g, 33.18 mmol) were added to a solution of acetonitrile (50 mL) in a screw-capped tube, along with 2-hydroxyacetamide (0.83 g, 11.06 mmol) and DMAP (0.67 g, 5.53 mmol). The contents of the sealed tube were stirred at 75°C for 24 hours. The reaction mixture was filtered and washed with CH3CN. The organic layer was concentrated under vacuum. The residue was purified by MPLC (using a 40 g Redisep column and 20–100% EtOAc in hexane) to give the title product (4.5 g, yield: 83%) as a grayish-white solid. ESI-MS m / z: 489.85 [M+H]+ (Rt = 1.48 min, LC-method 6).

[0377] Step 2: (4-(5-(2-amino-2-sideoxyethoxy)-8-chloro-2-methyl-4-sideoxy-1,6-dichlorophenyl-1(4H)-yl)-3,5-dichlorophenyl)boronic acid

[0378] PdCl₂ dppf.DCM (0.66 g, 0.81 mmol) was added to a degassed (argon-treated) solution of 1,4-dioxane (40 mL) in a screw-capped tube containing 2-((1-(4-bromo-2,6-dichlorophenyl)-8-chloro-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)acetamide (4.0 g, 8.14 mmol), bis(dioxane)diboron (3.09 g, 12.21 mmol), and potassium acetate (1.19 g, 12.21 mmol). The contents of the tube were stirred at 90°C for 4 hours. The reaction mixture was filtered through a diatomaceous earth mat and washed with 1,4-dioxane. The filtrate was evaporated under reduced pressure to give a crude product (4.2 g, crude product) as a pale brown solid. Therefore, the crude product obtained can be used in the next step without further purification. ESI-MS m / z: 456.0 [M+H]+ (Rt = 1.38 min, LC-method 1).

[0379] Step 3: 2-((8-chloro-1-(2,6-dichloro-4-hydroxyphenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)acetamide

[0380] Montmorillonite K-10 (2.25 g, 8.22 mmol) and 30% hydrogen peroxide (100 mL) were added to a solution of 4-(5-(2-amino-2-sideoxyethoxy)-8-chloro-2-methyl-4-sideoxy-1,6-dichlorophenyl)boronic acid (2.5 g, 5.48 mmol) in MeOH : water (20 mL, 1:1). The resulting reaction mixture was stirred at ambient temperature for 4 hours. The reaction mixture was quenched with excess ice water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by Combi-Flash column chromatography (using a 24 g Silicycle column and 20–100 ethyl acetate in hexane) to give the title product (1.3 g, yield: 55%) as a grayish-white solid. ESI-MS m / z: 429.9 [M+H] + (Rt = 1.41 min, LC-method 1).

[0381] Step 4: 2-(4-(5-(2-amino-2-sideoxyethoxy)-8-chloro-2-methyl-4-sideoxy-1,6-diphenyl-1(4H)-yl)-3,5-dichlorophenoxy)-N-methylacetamide

[0382] Potassium carbonate (0.96 g, 0.7 mmol) and 2-bromo-N-methylacetamide (0.05 g, 0.35 mmol) were added to a solution of 2-((8-chloro-1-(2,6-dichloro-4-hydroxyphenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)acetamide (0.1 g, 0.23 mmol) in DMF (4 mL). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by Combi-Flash column chromatography (using a 12 g Redisep column and 70-100% EtOAc in hexane) to give the title product (0.035 g, yield: 38%) as a grayish-white solid. [C-17]: ESI-MS m / z: 499.0 [M+H] + (Rt = 1.37 min, LC-method-1). 1H NMR (300 MHz, DMSO-d 6) δ ppm = 8.27 (s, 1H), 8.13 (m, 2H), 7.60 (s, 1H), 7.41 (s, 2H), 6.55 (s, 1H), 4.74 (s, 2H), 4.66 (s, 2H), 2.68 (d, J=4.8 Hz, 3H), 1.94 (s, 3H).

[0383] [Implementation Method]

[18] [:] [3-((8-] [chlorine] [-1-(2,6-] [Dichloro] [-4-(2-)] [Hydroxyethoxy] [)] [Phenyl] [)-2-] [methyl] [-4-] [Side group] [-1,4-] [Dihydrogen] [-1,6-] [Ding] [-5-] [base] [)] [Oxygen group] [)] [Acetylated amino acid (compound)] [C-18] [)]

[0384] Silver carbonate (0.46 g, 1.69 mmol) and 2-bromoethanol (0.14 g, 1.13 mmol) were added to a solution of 250 mg (0.565 mmol) of 3-((8-chloro-1-(2,6-dichloro-4-hydroxyphenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)propionic acid [prepared in a manner similar to steps 1 to 3 of Example 17 using 3-hydroxypropionic acid instead of 2-hydroxyacetamide]. The reaction mixture was stirred at 80°C for 16 hours. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by Combi-Flash column chromatography (using a 12 g Redisep column and 20–100% EtOAc in hexane) followed by preparative HPLC (column: GEMINI 250 mm x 21.2 mm, 5.0 µm; mobile phase: 0.02% NH4OH and acetonitrile in water, gradient elution) to give the title product (0.022 g, yield: 8%) as a grayish-white solid. [C-18] [:]ESI-MS m / z: 487.35 [M+1] + (Rt = 1.38 min, LC-method-1). 1H NMR (300 MHz, DMSO-d 6) δ ppm = 8.23 ​​(s, 1H), 7.70 (s, 1H), 7.34 (s, 2H), 6.94 (s, 1H), 6.43 (s, 1H), 4.52 (t, J=6.0 Hz, 2H), 4.14 (t, J= 3.9 Hz, 2H), 3.74 (t, J=4.8 Hz, 2H), 2.58 (t, J=6.0 Hz, 3H), 1.89 (s, 3H).

[0385] [Example]

[19] [:] [N-(3-(8-)] [chlorine] [-1-(2,6-] [Dichloro] [-4-(2-)] [Hydroxyethoxy] [)] [Phenyl] [)-2-] [methyl] [-4-] [Side group] [-1,4-] [Dihydrogen] [-1,6-] [Ding] [-5-] [base] [)] [Propyl] [)] Acetamide (compound) [C-19] [)] []

[0386] Step 1: Tributyl(3-(8-chloro-1-(2,6-dichloro-4-fluorophenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)propyl)carbamate []

[0387] Under N2, (1s, 5s)-9-boronbicyclo[3.3.1]nonane (0.5 M in THF) (3.32 mL, 1.66 mmol) was added dropwise to a sealed vial containing a solution of tributylallylaminocarbamate (241 mg, 1.53 mmol) in 3 mL of THF. The mixture was stirred at room temperature for 16 hours. Under N2, 5,8-dichloro-1-(2,6-dichloro-4-fluorophenyl)-2-methyl-1,6-diphenyl-4(1H)-one (intermediate) in DMF (10.0 mL) was added. [F1] (500 mg, 1.28 mmol), Pd(Ph3P)4 (147 mg, 128 µmol), and potassium phosphate (2.0 M solution) (1.28 mL, 2.55 mmol) were added via syringe. The reaction mixture was heated at 80°C for 2 hours under N2. It was then cooled to room temperature, diluted with EtOAc, and washed with water. The aqueous layer was extracted with EtOAc. The combined organic layers were concentrated under reduced pressure. The residue was purified by rapid column chromatography (EtOAc / heptane 0-100%) to provide the title compound. ESI-MS m / z: 514.3 [M+H]+ (Rt = 1.20 min, LC-Method 7).

[0388] Step 2: 5-(3-aminopropyl)-8-chloro-1-(2,6-dichloro-4-fluorophenyl)-2-methyl-1,6-diphenyl-4(1H)-one hydrochloride

[0389] To a solution of tributyl(3-(8-chloro-1-(2,6-dichloro-4-fluorophenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)propyl)carbamate (582 mg, 1.13 mmol) in dimethicone (3 mL), HCl (4 M in dimethicone) (2.83 mL, 11.3 mmol) was added. The mixture was stirred at 23°C for 2 hours. The mixture was concentrated under reduced pressure and the residue was dried under high vacuum to provide the title compound. ESI-MS m / z: 414.2 [M+H]+ (Rt = 0.77 min, LC-Method 7).

[0390] Step 3: N-(3-(8-chloro-1-(2,6-dichloro-4-fluorophenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)propyl)acetamide

[0391] TEA (712 mg, 7.03 mmol) and HATU (497 mg, 1.31 mmol) were added to a solution of 5-(3-aminopropyl)-8-chloro-1-(2,6-dichloro-4-fluorophenyl)-2-methyl-1,6-diphenyl-4(1H)-one hydrochloride (490 mg, 1.00 mmol) and acetic acid (302 mg, 5.02 mmol) in DMF (10 mL). The mixture was stirred at 23°C for 1 hour. The solution was diluted in MeOH and filtered. The filtrate was purified by HPLC to give the title compound. ESI-MS m / z: 456.2 [M+H]+ (Rt = 0.91 min, LC-Method 7).

[0392] Step 4: N-(3-(8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)propyl)acetamide

[0393] Cs₂CO₃ (428 mg, 1.31 mmol) was added to a solution of N-(3-(8-chloro-1-(2,6-dichloro-4-fluorophenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)propyl)acetamide (200 mg, 0.44 mmol) and ethane-1,2-diol (81.5 mg, 1.31 mmol) in DMF (6 mL). The mixture was stirred at 23°C for 16 hours. It was then diluted in MeOH and filtered. The filtrate was purified by HPLC to give the title compound. [C-19]: ESI-MS m / z: 498.1 [M+H]+(Rt = 0.79 min, LC-Method 7), 1H NMR (400 MHz, methanol-d4) δ ppm = 8.49 (s, 1H), 7.29 (s, 2H), 6.54 (s, 1H), 4.26 - 4.15 (m, 2H), 3.99 - 3.87 (m, 2H), 3.57 - 3.44 (m, 2H), 2.07 (s, 3H), 1.98 (s, 3H), 1.97 - 1.90 (m, 2H), 2H overlaps with solvent.

[0394] [Implementation Method]

[20] [:] [8-] [chlorine] [-1-(2,6-] [Dichloro] [-4-(2-)] [Hydroxyethoxy] [)] [Phenyl] [)-2-] [methyl] [-5-(2-(] [Methylsulfonyl] [)] [Ethyl] [)-1,6-] [Ding] [-4(1H)-] [Ketone (compound)] [C-20] [)]

[0395] Step 1: 8-Chloro-1-(2,6-dichloro-4-fluorophenyl)-2-methyl-5-vinyl-1,6-diphenyl-4(1H)-one

[0396] To 5,8-dichloro-1-(2,6-dichloro-4-fluorophenyl)-2-methyl-1,6-diphenyl-4(1H)-one (intermediate) [F1], 0.4 g, 1.02 mmol) was added to a stirred solution of THF (10 mL), followed by purging with N2 gas. Tri-2-furanylphosphine (0.02 g, 0.1 mmol) and Pd2(dba)3 (0.09 g, 0.1 mmol) were then added to the solution. [。] The reaction mixture was stirred at 70°C for 16 hours. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na₂SO₄, and the solvent was removed under reduced pressure to give the crude product. The crude product was purified by MPLC (Combi-Flash, 24 g column, gradient elution, 0-40% EtOAc in hexane) to give the title product (0.21 g, yield: 54%) as a pale yellow solid. ESI-MS m / z: 384.40 [M+3H]⁺ (Rt = 1.54 min, LC-Method 1).

[0397] Step 2: 8-Chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-5-vinyl-1,6-diphenyl-4(1H)-one

[0398] Ethylene glycol (0.04 g, 0.63 mmol) and K₂CO₃ (0.2 g, 1.56 mmol) were added to a solution of 8-chloro-1-(2,6-dichloro-4-fluorophenyl)-2-methyl-5-vinyl-1,6-diphenyl-4(1H)-one (0.2 g, 0.521 mmol) in DMF (3 mL). The reaction mixture was stirred at 80°C for 16 hours. The reaction mixture was diluted with water and EtOAc and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na₂SO₄, and the solvent was removed under reduced pressure to give a crude product. The crude product was purified by MPLC (Combi-Flash, 12 g column, gradient elution, 0-10% MeOH in dichloromethane) to give the desired product (0.1 g, yield: 48%) as a pale yellow solid. ESI-MS m / z: 424.90 [M+1H] + (Rt = 1.45 min, LC-method 6).

[0399] Step 3: 8-Chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-5-(2-(methylsulfonylurea)ethyl)-1,6-diphenyl-4(1H)-one

[0400] Sodium methanesulfinate (0.19 g, 1.89 mmol) and acetic acid (0.01 g, 0.19 mmol) were added to a solution of 8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-5-vinyl-1,6-diphenyl-4(1H)-one (0.08 g, 0.19 mmol) in ethanol (3 mL). The reaction mixture was stirred at 60°C for 16 hours. The reaction mixture was concentrated under reduced pressure to give a crude product. The crude product was purified by preparative HPLC (column: X SELECT, 250 mm x 19 mm, 5.0 µm, mobile phase: 0.02% NH4OH in water and acetonitrile; gradient elution) to give the title product (0.04 g, yield: 56%) as a grayish-white solid. [C-20]: ESI-MS m / z: 504.95 [M+1H] + (Rt = 1.38 min, LC-Method 6). 1H NMR (300 MHz, DMSO-d 6) δ ppm = 8.59 (s, 1H), 7.38 (s, 2H), 6.59 (s, 1H), 4.99 (t, J=5.4 Hz, 1H), 4.17 (t, J= 4.8 Hz, 2H), 3.86-3.82 (m, 2H), 3.76 (m, 2H), 3.56-3.51 (m, 2H), 3.06 (s, 3H), 1.96 (s, 3H).

[0401] [Implementation Method] [twenty one] [:] [8-] [chlorine] [-1-(2,6-] [Dichloro] [-4-(2-)] [Hydroxyethoxy] [)] [Phenyl] [)-2-] [methyl] [-5-(2-(] [Methylsulfonyl] [)] [Propyl] [)-1,6-] [Ding] [-4(1H)-] [Ketone (compound)] [C-21] [)]

[0402] Step 1: 5-Allyl-8-chloro-1-(2,6-dichloro-4-fluorophenyl)-2-methyl-1,6-diphenyl-4(1H)-one

[0403] To 5,8-dichloro-1-(2,6-dichloro-4-fluorophenyl)-2-methyl-1,6-diphenyl-4(1H)-one (intermediate) [F1], 0.05 g, 1.28 mmol) was added to a stirred solution of tributyl(allyl)stanane (0.51 g, 1.53 mmol) in THF (5 mL), and then purged with N2 gas. Tri-2-furanylphosphine (0.03 g, 0.13 mmol) and Pd2(dba)3 (0.12 g, 0.13 mmol) were added to the solution. The reaction mixture was stirred at 70°C for 4 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, and the solvent was removed under reduced pressure to give the crude product. The crude product was purified by MPLC (Combi-Flash, 12 g column, gradient elution, 20-100% EtOAc in hexane) to give the desired product (0.27 g, yield: 53.25%) as a pale yellow solid. ESI-MS m / z: 397.0 [M+1H] + (Rt = 1.77 min, LC-method 5).

[0404] Step 2: 5-Allyl-8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-1,6-diphenyl-4(1H)-one

[0405] Ethylene glycol (0.05 g, 0.75 mmol) and K₂CO₃ (0.26 g, 1.88 mmol) were added to a solution of 5-allyl-8-chloro-1-(2,6-dichloro-4-fluorophenyl)-2-methyl-1,6-diphenyl-4(1H)-one (0.25 g, 0.63 mmol) in DMF (3 mL). The reaction mixture was stirred at 80°C for 16 hours. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic phases were washed once with cold water, dried over Na₂SO₄, and the solvent was removed under reduced pressure to give a crude product. The crude product was purified by MPLC (Combi-Flash, 12 g column, gradient elution, 0-10% MeOH in dichloromethane) to give the desired product (0.24 g, yield: 87%) as a grayish-white solid. ESI-MS m / z: 441.2 [M+3H] + (Rt = 0.48 min, LC-method 4).

[0406] Step 3: 8-Chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-5-(2-(methylsulfonylurea)propyl)-1,6-diphenyl-4(1H)-one

[0407] Sodium methanesulfinate (0.53 g, 5.23 mmol) and acetic acid (0.03 g, 0.52 mmol) were added to a solution of 5-allyl-8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-1,6-diphenyl-4(1H)-one (0.23 g, 0.52 mmol) in ethanol (8 mL). The reaction mixture was stirred at 60°C for 16 hours. The reaction mixture was concentrated under reduced pressure to give a crude product. The crude product was purified by preparative HPLC (column: Waters xbridge C18, 20 mm x 150 mm, 5.0 µm; mobile phase: 0.02% NH4OH and acetonitrile in water; gradient elution) to give a mixture of mirror-image isomers (0.1 g, yield: 45%) as a grayish-white solid. The mirror-image isomer was rapidly eluted as a grayish-white solid (0.03 g, yield: 22%, based on a single mirror-image isomer) by preparative chiral HPLC [column: LUX AMYLOSE-2, 250 mm X 21.2 mm, 5.0 µm, in EtOH : MeOH (1 : 1) with 0.1% formic acid; isocratic elution]. [C-21]: ESI-MS m / z: 519.1 [M+H]+(Rt = 0.44 min, LC-method-4). 1H NMR (300 MHz, methanol-d4) δ ppm = 8.54 (s, 1H), 7.28 (s, 2H), 6.55 (s, 1H), 4.31–4.25 (m, 1H), 4.19 (t, J=4.5 Hz, 2H), 3.92 (t, J=5.1 Hz, 2H), 3.86–3.82 (m, 1H), 3.56–3.48 (m, 1H), 3.08 (s, 3H), 2.06 (s, 3H), 1.34 (d, J=7.2 Hz, 3H).

[0408] [Example] [twenty two] [:] [8-] [chlorine] [-1-(2,6-] [Dichloro] [-4-(2-)] [Hydroxy] [-2-] [Methylpropoxy] [)] [Phenyl] [)-2-] [methyl] [-5-(3-(] [Methylsulfonyl] [)] [Propyl] [)-1,6-] [Ding] [-4(1H)-] [Ketone (compound)] [C-22] [)]

[0409] Step 1: 8-Chloro-1-(2,6-dichloro-4-fluorophenyl)-2-methyl-5-(3-(methylthio)propyl)-1,6-diphenyl-4(1H)-one

[0410] Under N2, 9-BBN (0.5 M in THF) (3.98 mL, 1.990 mmol) was added dropwise to a sealed vial containing allyl(methyl)thion (0.202 mL, 1.837 mmol) in 3 mL of THF. The mixture was stirred at room temperature for 16 hours. Under N2, 5,8-dichloro-1-(2,6-dichloro-4-fluorophenyl)-2-methyl-1,6-diphenyl-4(1H)-one (intermediate) in DMF (15 mL) was added. [F1] (600 mg, 1.530 mmol), K₃PO₄ (2.0 M) (1.530 mL, 3.06 mmol), and Pd(PPh₃)₄ (177 mg, 0.153 mmol) were added to the above solution via syringe in flasks. The reaction mixture was heated to 80°C under N₂ and maintained for 2 hours. It was then cooled to room temperature, diluted with EtOAc, and washed with water. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to provide the crude title compound. This was used for the next step without purification. ESI-MS m / z: 445.0 [M+H]⁺ (Rt = 1.17 min, LC-Method 7).

[0411] Step 2: 8-Chloro-1-(2,6-dichloro-4-fluorophenyl)-2-methyl-5-(3-(methylsulfonylurea)propyl)-1,6-diphenyl-4(1H)-one

[0412] To a solution of Oxone (1881 mg, 3.06 mmol) in H₂O (50 mL) and MeOH (25 mL), 8-chloro-1-(2,6-dichloro-4-fluorophenyl)-2-methyl-5-(3-(methylthio)propyl)-1,6-diphenyl-4(1H)-one (682 mg, 1.53 mmol) in MeOH (25 mL) was added dropwise. The mixture was stirred at 23°C for 4 hours. It was then concentrated to about 50 mL under reduced pressure and extracted three times with EtOAc. The combined organic layers were concentrated and purified by rapid column chromatography (0-100% EtOAc / heptane) to provide the title compound. ESI-MS m / z: 476.9 [M+H]⁺ (Rt = 0.94 min, LC-Method 7).

[0413] Step 3: 8-Chloro-1-(2,6-dichloro-4-(2-hydroxy-2-methylpropoxy)phenyl)-2-methyl-5-(3-(methylsulfonylurea)propyl)-1,6-diphenyl-4(1H)-one

[0414] Cs₂CO₃ (409 mg, 1.256 mmol) was added to a solution of 2-methylpropane-1,2-diol (113 mg, 1.256 mmol) and 8-chloro-1-(2,6-dichloro-4-fluorophenyl)-2-methyl-5-(3-(methylsulfonylurea)propyl)-1,6-diphenyl-4(1H)-one (200 mg, 0.419 mmol) in DMF (4 mL). The reaction mixture was stirred at 50°C for 16 hours. It was then cooled to room temperature, diluted with MeOH, and filtered. The filtrate was purified by HPLC to provide the title compound. [C-22]: ESI-MS m / z: 547.3 [M+H]+(Rt = 0.91 min, LC-Method 7), 1H NMR (400 MHz, methanol-d4) δ ppm = 8.54 (s, 1H), 7.30 (s, 2H), 6.56 (s, 1H), 3.94 (s, 2H), 3.65 - 3.58 (m, 2H), 3.32 - 3.24 (m, 2H), 3.01 (s, 3H), 2.35 - 2.22 (m, 2H), 2.07 (s, 3H), 1.36 (s, 6H).

[0415] [Example] [twenty three] [:] [GIRK1 / 4] [Activity Assay]

[0416] The GIRK1 / 4 activity of the compounds according to the present invention was evaluated by the following in vitro methods.

[0417] [Buffer solution:] [] a. External buffer: 10 mM NaCl, 50 mM sodium gluconate, 80 mM potassium gluconate, 1.8 mM CaCl2, 1 mM MgCl2, 10 mM HEPES, 10 mM glucose, pH 7.4; osmolarity 300-310 Osm / L. b. Internal buffer: 30 mM KCl, 100 mM potassium gluconate, 1 mM MgCl2, 10 mM HEPES, 1 mM EGTA, 10 mM NaCl, pH 7.2; osmolarity 284-292 Osm / L.

[0418] [Compound]: c. Prepare a series of 7-fold compound dilutions (10 mM to 20 uM) in 100% DMSO in 384-well polypropylene plates. d. Propafenone (Sigma Aldrich, catalog number P4670) was used as a positive control, and DMSO was used as a neutral control. e. Suspend 1 µl of the compound in DMSO in 66.7 µl of external buffer in a 384-well polypropylene plate and load it into section 1 of a Molecular Devices Quattro® plate.

[0419] [Quattro] [set up]: f. Load the 384-well Population Patch Plate (Molecular Instruments, catalog number 9000-0902) into Quattro. g. Fill the Quattro F soaking tank with 20% DMSO and 50% EtOH. h. Fill the Quattro buffer tank with external buffer solution. i. Attach the internal buffer bottle to the Quattro internal buffer tube. j. Attach the PBS (phosphate-buffered saline, minus Ca++ and Mg++, pH 7.4) bottle to the F and E heads of the Quattro wash applicator.

[0420] [antibiotic]: k. Suspend 5.1–5.8 mg of amphotericin B (Sigma-Aldrich, catalog number A2411) in 175 µl DMSO. 1. Add the resulting solution to 50 mL of internal buffer and attach it to the antibiotic tubing port on the Quattro.

[0421] [cell]: m. Stable GIRK1 / 4 HEK293 cells grown to approximately 80% confluence in the following cell culture medium (obtained from ChanTest, 14656 Neo Parkway, Cleveland, Ohio 44128): containing 10% (v / v) fetal bovine serum, penicillin / streptomycin ("1X" concentration from 100X stock solution), 0.5 mg / mL G418, and 0.1 mg / mL zeocin. n. Cells were detached using Detachin (Genlantis, 11011 Torreyana, San Diego, CA 92121), washed with PBS (minus Ca++ and Mg++), and resuspended in external buffer (5 mL final volume, 2.0–2.1 x 10⁶ cells / mL). o. Loaded into Quattro's cell slots

[0422] [Testing Protocol]: To control Quattro using IonWorks v2 software, follow these steps: p. Add 3.5 µl of cells and 3.5 µl of external buffer to the wells of the Quattro Patch Plate®. q. Circulate amphotericin B and internal buffer to the cells. r. Apply the following voltage scheme: Pulse 1: 15 mV, lasting 300 milliseconds (ms), followed by Pulse 2: -120 mV, lasting 400 ms, then Pulse 3: -15 mV, lasting 400 ms, and finally Pulse 4: -120 mV to 40 mV in 500 ms (this is a voltage ramp). s. The intensity of the inward potassium current was measured at time points between 1200 and 1220 ms, starting from pulse 1 (i.e., during the voltage ramp-up phase). t. Add 3.5 µl of diluted compound (or DMSO) to the well and repeat step cd (the final compound concentration is from 50 uM to 0.1 uM, and each concentration is tested in quadruplicate - i.e. in 4 separate wells). u. The difference between the compounds before and after the current intensity provides a measure of GIRK1 / 4 inhibition.

[0423] [Data Analysis]:

[0424] The IC50 value was calculated by plotting the percentage of current suppression as a function of compound concentration using standard data analysis software (normalized to DMSO control only).

[0425] Using the tests described above, the compounds of the present invention exhibited inhibitory activity as shown in Table 5 provided below.

[0426] [Example] [twenty four] [Pharmacokinetic properties]

[0427] The pharmacokinetic properties of the compound in rats were evaluated using the following in vivo studies.

[0428] [animal] Species, strain, sex Rats, Spargue Dawley / CD, male Age / Weight 8-10 weeks / 240-320 grams animal models Double jugular vein cannulation Animal numbers Three rats per dose per route were used in discrete (non-crossover) studies. In crossover studies, n = 3 for both the IV and PO groups. captive breeding Before the surgery, three animals were kept in each cage in a polypropylene cage (864 square centimeters floor, 18 cm high), which contained irradiated corn cob bedding material and paper cutouts. During the study, the temperature was maintained between 22 ± 3°C, and the relative humidity was maintained between 30% and 70%. Automatic timers were used to maintain a 12-hour light and 12-hour dark cycle in all rooms. Feeding / Water Throughout the experiment, the animals were allowed to eat and drink freely.

[0429] [Animal Model] []

[0430] At least four days prior to the first drug administration, rats (250–350 g) were anesthetized, and under sterile conditions, catheters were surgically inserted into the left and right jugular veins (one for blood collection and the other for intravenous injection). The catheters were externally positioned and secured to the neck. For analgesia, animals received analgesics preoperatively, followed by two additional analgesics at appropriate postoperative times. Freely mobile animals equipped with catheters were housed individually in macrolon cages with free access to food and water throughout the experiment. After a recovery period of at least four days, a single test compound was administered intravenously or orally, depending on individual weight.

[0431] Experimental conditions

[0432] [weight]

[0433] Rats were weighed before administration, and the weight was recorded in the original data file.

[0434] [Preparation]

[0435] intravenous administration

[0436] Test articles were administered as a solution in NMP:PEG 200 (10:90 v / v). Test articles for which a solution could not be obtained were rejected and not used for discrete or cassette administration.

[0437] Oral administration

[0438] The test product was administered as a suspension in MC : Tween 80 : water (0.5 : 0.1 : 99.4 w / v / v).

[0439] [Dosage Regimen]

[0440] intravenous administration

[0441] Test items were administered as a solution and by bolus or short IV infusion to conscious rats via a left jugular vein catheter (over 30 seconds). The dose volume was 0.5 mL / kg body weight. The exact start and end times of administration and the exact dose volume were recorded. Plastic syringes and / or plastic infusion tubing were used.

[0442] Oral administration

[0443] The test item, as a solution or suspension, was administered via tube feeding into the esophagus of conscious rats. The dose volume was 5 mL / kg body weight. The exact start time and exact dose volume of administration were recorded. Grouping, route of administration and target dose Research Design Group Animal numbers Animal identification Investment channels Dosage (mg / kg) Discrete (non-crossing) I 3 1-3 Intravenous 0.3-1 II 3 4-6 oral 3 cross I 3 1-3 Intravenous and oral 0.3-1(IV) 3(PO) Dosage in discrete and cassette studies Species For discrete research For box-type research Investment channels IV Dosage / Compound (mg / kg) PO dosage / compound (mg / kg) rats yes yes IV 0.3 NA rats yes no IV 1 NA rats yes yes PO NA 3 rats yes yes IV / PO 0.3 3 rats yes no IV / PO 1 3

[0444] [Clinical signs] []

[0445] Examine the animals before and after administration and record any clinical signs observed.

[0446] Sampling and Collection

[0447] Blood samples (20 µL) were collected from the right jugular vein catheter of the cannulated animals at different time intervals (exceptions may be made if the JV catheter becomes non-open during the PK experiment (i.e., after administration), blood may be collected by tail vein puncture, but must be clearly specified in the live observation and data study report in tubes containing 10% blood and 2% w / v K2 EDTA (2.0 mg / mL)). Blood was collected after intravenous administration at 0.083, 0.25, 0.5, 1, 2, 4, 7, and 24 hours post-administration. Blood was also collected after PO administration at 0.25, 0.5, 1, 2, 4, 7, and 24 hours post-administration.

[0448] It is important to record the exact time of drug administration and sampling. Time points may be changed as needed and for appropriate reasons. The rats were euthanized by CO2 after the last sampling time.

[0449] Blood samples should be immediately placed on ice, frozen to -20°C or lower, and stored until analysis. Test tubes should be stored in plastic bags / shelves pre-labeled with the compound name, sample number, study number, route of administration, time, and date.

[0450] [Bioanalysis]

[0451] Bioanalysis of the formulation

[0452] Aliquots of each dosing formulation were taken, appropriately diluted, and the drug concentration was analyzed. The observed concentrations were scaled using a dilution factor to determine the final concentration.

[0453] Bioanalysis of blood samples

[0454] The concentrations of compounds in whole blood were determined using liquid chromatography-mass spectrometry (LC-MS / MS). 20 μL of each blood sample was precipitated with 100 μL of acetonitrile containing a universal internal standard (cabamapin / telmisartan / verapamil; c = 50 ng / mL). The sample was thoroughly vortexed and then centrifuged (5 min, 4°C). The supernatant (80 μL) was transferred to a clean 96-well plate and mixed with 80 μL of water.

[0455] Samples are injected (1 to 20 μL) onto a suitable analytical column using various isocratic methods and flow rates. The mobile phase typically consists of 0.1% formic acid in water (solvent A) and 0.1% formic acid in acetonitrile (solvent B), and other modifiers may be added if necessary. The compound and internal standard elute at different retention times. The HPLC system is connected to a mass spectrometer. MS / MS analysis is performed using electrospray ionization (ESI), typically in positive ionization mode. Multiple reaction monitoring (MRM) is used to monitor the compound and internal standard.

[0456] The standard curve used for sample quantification spans several log units. The lower limit of quantification (LLOQ) in blood is determined and used as a cutoff value for analytical sensitivity. Known amounts of the compound are incorporated into blood to create quality control samples with six known concentrations exhibiting a unimodal peak. The accuracy of in vivo blood concentration determination is considered acceptable when the intra-assay accuracy of the quality control samples is within 70% to 130% of the expected concentration. Subsequently, pharmacokinetic parameters are calculated using non-compartmental regression analysis with an internal fitting program based on time-concentration data.

[0457] [Pharmacokinetic Analysis]

[0458] Based on time-concentration data, pharmacokinetic parameters were calculated using an internal fitting program via non-compartmental regression analysis. AUC (nM*h) The AUC ultimately refers to the area under the concentration-time curve from t = 0 to the final t. This data is calculated using the linear trapezoidal rule, the log-linear trapezoidal rule (when the decay between time points is exponential), or a combination of both from t = 0 to the final T. Therefore, the choice of method depends on the judgment of the PK analyst (e.g., MAP PTM). CL (mL / min / kg) The clearance rate CL is calculated as dose after IV administration / AUCinf. F(%) The optimal exovascular availability F is calculated as the dose-normalized ratio of extravascular AUCinf to intravenous AUCinf. For example, for orally administered substances: F = [AUCinfPO / PO dose] / [IV AUCinfIV / IV dose] x 100% For crossover design studies, F is calculated for each animal. For studies with continuous sampling but no crossover design, the mean intravenous AUCinf was used to calculate the bioavailability per animal administered via extravascular route. If AUCinf is unavailable (because λz is undefined or because AUC is extrapolated infinitely beyond 25% of AUCinf), then AUC is used to replace AUCinf in the final calculation. [ [surface] [5] [.] [Inhibitory activity and pharmacokinetic properties in rats] [] [Example] [GIRK1 / 4 IC, 50 , ] [(] [µM] [)] [Rat] [Cl] [(] [mL / min / kg] [)] [Rat] [AUC, 0-24h , ] [3 mg / kg] [(] [nMh] [)] [Rat] [F] [(] [%] [)] [1] 0.09 20.2 3270 71 [2] 0.22 23.0 1288 29 [3] 0.22 5.7 7738 47 [4] 0.16 5.5 3674 22 [5] 0.06 14.6 2336 33 [6] 0.13 21.6 3570 82 [7] 0.07 13.6 4410 61 [8] 0.07 n / a n / a n / a [9] 0.08 24.2 1460 40

[10] 0.33 n / a n / a n / a

[11] 0.16 n / a n / a n / a

[12] 0.20 n / a n / a n / a

[13] 0.06 18.4 2410 55

[14] 0.17 n / a n / a n / a

[15] 0.32 32.8 1290 46

[16] 0.03 n / a n / a n / a

[17] 0.25 31.7 2310 73

[18] 0.03 38.9 1702 65

[19] 0.05 27.9 1290 46

[20] 0.05 19.8 2407 44

[21] 0.17 10.4 3200 34

[22] 0.19 23.6 1360 37

[0459] The pharmacokinetic studies of the compound in Example 1 in male beagle dogs administered 0.3 mg / kg IV (as a solution) and 1 mg / kg PO (as a suspension) yielded the following PK parameters: Scavenging rate (Cl): 5.5 mL / min / kg; AUC 0-24h: 5270 nMh; and Oral bioavailability (F): 87%.

[0460] The compounds of formula (I) according to the present invention, especially the compounds of Example 1, exhibited low to moderate clearance and good oral bioavailability in rats and dogs, consistent with human oral administration regimens. [Equivalent] []

[0461] Those skilled in the art will recognize or be able to identify many equivalents of the particular embodiments described herein using only conventional experimentation. Such equivalents are intended to be covered within the scope of the following claims.

[0462] none

[0463] none

Claims

1. A compound having formula (I) or its hydrate or stereoisomer, rotational isomer, tautomer, or any of the foregoing, a pharmaceutically acceptable salt thereof, (I) wherein R1 is a (C1-C6) alkyl group substituted with one or more substituents independently selected from -OH, -C(O)NHRa, and optionally substituted with one or more -OH groups; A is a -OR2 or a (C1-C6) alkyl group substituted with one or more substituents independently selected from -SO2 (C1-C4) alkyl, -NHC(O)Rb, and -C(O)NHRc; R2 is a (C1-C6) alkyl group substituted with one or more substituents independently selected from -NHC(O)Rd and -C(O)NHRe, wherein the (C1-C6) alkyl group is further substituted with one or more substituents independently selected from halogen, -OH, and -CN groups as desired; Ra, Rb, Rc, Rd, and Re are each independently selected from H and (C1-C6) alkyl groups that are substituted with one or more -OH groups as needed; and R3 is a (C1-C4) alkyl group.

2. The compound of claim 1 or its hydrate or stereoisomer, rotational isomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R1 is selected from , , , and .

3. The hydrate or stereoisomer, rotational isomer, tautomer, or pharmaceutically acceptable salt of the compound of claim 1 or claim 2, wherein A is a-OR2.

4. A compound of claim 1 or claim 2, or its hydrate or stereoisomer, rotational isomer, tautomer, or pharmaceutically acceptable salt thereof, wherein Re is selected from H and (C1-C4) alkyl groups substituted with one or more -OH groups as desired.

5. A compound of claim 1 or claim 2, or its hydrate or stereoisomer, rotational isomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R2 is a (C1-C4) alkyl group independently substituted with one or more substituents selected from -NHC(O)CH3, -C(O)NHCH3, -C(O)NHCH2CH2OH, and -C(O)NH2, wherein the (C1-C4) alkyl group is further substituted with one or more substituents independently selected from halogenated, -OH, and -CN as desired.

6. A compound of claim 1 or claim 2, or a hydrate or stereoisomer, rotational isomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R2 is selected from , , , , , , , , and .

7. The compound of claim 1 or claim 2, or its hydrate or stereoisomer, rotational isomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R3 is -CH3.

8. A compound of claim 1 or its hydrate or stereoisomer, rotational isomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: 3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-dipyridin-5-yl)oxy)-N-methylpropionic acid; 2-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-dipyridin-5-yl)oxy)-N-(2-hydroxyethyl)acetamide; 3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxy-2-methylpropoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-nitin-5-yl)oxy)-N-methylpropionic acid; 2-((8-chloro-1-(2,6-dichloro-4-(2-hydroxy-2-methylpropoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-nitin-5-yl)oxy)-N-methylacetamide; 2-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-nitin-5-yl)oxy)-N-methylacetamide; (R)-3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxypropoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-N-methylpropionic acid; (R)-3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-N,2-dimethylpropionic acid; (S)-3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-N,2-dimethylpropionic acid; N-(2-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)ethyl)acetamide; (S)-3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxypropoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-N-methylpropionic acid; 3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-N,2,2-trimethylpropionic acid;(R)-3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-2-hydroxy-N-methylpropionic acid; (S)-3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-2-hydroxy-N-methylpropionic acid; (S)-3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxy-2-methylpropoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-2-hydroxy-N-methylpropionic acid; 3-((8-chloro-1-(2,6-dichloro-4-((3-hydroxyoxetane-3-yl)methoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-N-methylpropionic acid; 3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-2,2-difluoro-N-methylpropionic acid; 2-(4-(5-(2-amino-2-sideoxyethoxy)-8-chloro-2-methyl-4-sideoxy-1,6-diphenyl-1(4H)-yl)-3,5-dichlorophenoxy)-N-methylacetamide; 3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)propionic acid; N-(3-(8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)propyl)acetamide; 8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-5-(2-(methylsulfonylurea)ethyl)-1,6-diphenyl-4(1H)-one; 8-Chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-5-(2-(methylsulfonylurea)propyl)-1,6-diphenyl-4(1H)-one; and 8-chloro-1-(2,6-dichloro-4-(2-hydroxy-2-methylpropoxy)phenyl)-2-methyl-5-(3-(methylsulfonylurea)propyl)-1,6-diphenyl-4(1H)-one.

9. The compound of claim 8 or its hydrate or stereoisomer, rotational isomer, tautomer, or any of the foregoing, wherein the compound is 3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-N,2,2-trimethylpropionic acid.

10. The compound of claim 8 or its hydrate or stereoisomer, rotational isomer, tautomer or any of the foregoing, wherein the compound is 3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-N-methylpropionic acid.

11. The compound of claim 8 or its hydrate or stereoisomer, rotational isomer, tautomer or any of the foregoing, wherein the compound is 2-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-N-methylacetamide.

12. The compound of claim 8 or its hydrate or stereoisomer, rotational isomer, tautomer or any of the foregoing, wherein the compound is N-(3-(8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)propyl)acetamide.

13. The compound of claim 8 or its hydrate or stereoisomer, rotational isomer, tautomer, or any of the foregoing, wherein the compound is (S)-3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-diphenyl-5-yl)oxy)-2-hydroxy-N-methylpropionic acid.

14. A compound of any one of claims 1, 2 or 8, or a hydrate or stereoisomer, rotational isomer, tautomer or pharmaceutically acceptable salt thereof, wherein the compound is in a crystalline form selected from its free form, hydrate, solvate, isomorph, and eutectic.

15. The compound of claim 14 or its hydrate or stereoisomer, rotational isomer, tautomer, or pharmaceutically acceptable salt of any of the foregoing, wherein the compound is 3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-4-sideoxy-1,4-dihydro-1,6-dipyridin-5-yl)oxy)-N-methylpropionic acid in any of the following crystalline forms: (i) the free crystalline form designated as variant A-1, characterized in that, when measured with CuKα radiation at a temperature of about 22°C using wavelength 1.5418 Å, the crystalline form has an X-ray powder diffraction pattern comprising four or more 2θ values ​​(± 0.1 degrees) selected from the 2θ values ​​listed in the table below: (ii) the hydrated crystalline form designated as variant A-2, characterized in that, when measured with CuKα radiation at a temperature of about 22°C using wavelength 1.5418 Å, the crystalline form has an X-ray powder diffraction pattern comprising four or more 2θ values ​​(± 0.1 degrees) selected from the 2θ values ​​listed in the table below: When measured with CuKα radiation at a wavelength of 1.5418 Å at a temperature of about 22°C, the crystalline form has an X-ray powder diffraction pattern comprising four or more 2θ values ​​(± 0.1 degrees) selected from the 2θ values ​​listed in the table below: (iii) A hydrate crystalline form designated as variant A-3, characterized in that when measured with CuKα radiation at a wavelength of 1.5418 Å at a temperature of about 22°C, the crystalline form has an X-ray powder diffraction pattern comprising four or more 2θ values ​​(± 0.1 degrees) selected from the 2θ values ​​listed in the table below: (iv) A hydrate crystalline form designated as variant A-4, characterized in that when measured with CuKα radiation at a wavelength of 1.5418 Å at a temperature of about 22°C, the crystalline form has an X-ray powder diffraction pattern comprising four or more 2θ values ​​(± 0.1 degrees) selected from the 2θ values ​​listed in the table below: (v) A hydrate crystalline form designated as variant A-5, characterized in that when measured with CuKα radiation at a wavelength of 1.5418 Å at a temperature of about 22°C, the crystalline form has an X-ray powder diffraction pattern comprising four or more 2θ values ​​(± 0.1 degrees) selected from the 2θ values ​​listed in the table below: When CuKα radiation in Å is measured at a temperature of approximately 22°C, the crystalline form has an X-ray powder diffraction pattern containing four or more 2θ values ​​(± 0.1 degrees) selected from those listed in the table below: .

16. A pharmaceutical composition comprising a compound of any one of claims 1 to 15, or a hydrate or stereoisomer, rotational isomer, tautomer, or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

17. The pharmaceutical composition of claim 16 further comprises at least one additional pharmaceutically active agent selected from: Class I antiarrhythmic agents, Class II antiarrhythmic agents, Class III antiarrhythmic agents, Class IV antiarrhythmic agents, Class V antiarrhythmic agents, cardiac glycosides and other drugs affecting atrial refractoryness; hemostatic modifiers, antithrombotic agents; thrombin inhibitors; factor VI1a inhibitors; anticoagulants, factor Xa inhibitors, and direct thrombin inhibitors; antiplatelet agents, cyclooxygenase inhibitors, adenosine diphosphate (ADP) receptor inhibitors, phosphodiesterase inhibitors, glycoproteins IIB / IIA, and adenosine reuptake inhibitors; HMG-CoA reductase inhibitors, other cholesterol-lowering agents; bile acid sequestrants; cholesterol absorption inhibitors; cholesterol ester transfer protein (CETP) inhibitors; ileal bile acid transport system inhibitors (IBAT inhibitors); bile acid conjugating resins; nicotinic acid and its analogues; antioxidants; ω-3 fatty acids; β-blockers, α-blockers, mixed α / β-blockers; α-2 agonists; angiotensin-converting enzyme (ACE) inhibitors, calcium channel blockers; angiotensin II receptor antagonists; aldosterone receptor antagonists; central α-agonists; and diuretics; pancreatic lipase inhibitors, microsomal transfer protein (M... TP) regulators, diacylglycerol acetylated transferase (DGAT) inhibitors, cannabinoid (CBI) receptor antagonists; insulin and insulin analogs; insulin secretagogues; dipeptidyl peptidase IV (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) agonists; insulin sensitizers, peroxisome proliferator-activated receptor gamma (PPARγ) agonists, fructose-1,6-bisphosphatase inhibitors, glycogen phosphorylase inhibitors, glycogen synthase kinase inhibitors, glucokine kinase activators; α-glucosidase inhibitors; islet amyloid analogs; sodium-dependent glucose transporter 2 (SGLT-2) inhibitors.

18. Use of a compound as claimed in any one of claims 1 to 15, or a hydrate or stereoisomer, rotatimer, tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as claimed in claims 16 or 17, in the preparation of a medicament for treating a disease or disorder responsive to inhibition of GIRK1 / 4 receptors, wherein the disease or disorder responsive to inhibition of GIRK1 / 4 receptors is selected from arrhythmias, atrial fibrillation, bradycardia, bradycardia, heart block, atrial cavity disorder syndrome, parasympathetic hyperactivation, primary hyperaldosteronism, hypotension, and vasovagal syncope.

19. As claimed in claim 18, wherein the compound or its hydrate or stereoisomer, rotatory isomer, tautomer or any of the foregoing pharmaceutically acceptable salt, or the pharmaceutical composition thereof is formulated into an oral preparation.

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