Carbocyclic phenylpyrrolidinenon urea FPR2 agonist

Abstract

This disclosure relates to compounds of formula I that are formylpeptide 2 (FPR2) receptor agonists and / or formylpeptide 1 (FPR1) receptor agonists. This disclosure also provides compositions and methods using the compounds for, for example, the treatment of atherosclerosis, heart failure, and related diseases. JPEG2026514861000047.jpg5158I

Description

Technical Field

[0001] Cross-references to related applications This application claims the benefit of U.S. Provisional Application No. 63 / 496,747, filed Apr. 18, 2023, the disclosure of which is incorporated herein by reference in its entirety.

Background Art

[0002] The present invention relates to novel carbocyclic phenylpyrrolidinone compounds that are formyl peptide 2 (FPR2) receptor agonists, compositions containing them, and methods of using them for the treatment of, for example, atherosclerosis, heart failure, chronic obstructive pulmonary disease (COPD), and related diseases.

[0003] Formyl peptide receptor 2 (FPR2) belongs to a small group of G protein-coupled receptors having seven transmembrane domains, which are mainly expressed in mammalian phagocytic leukocytes and are known to play important roles in host defense and inflammation. FPR2 has high sequence homology with FPR1 and FPR3. These receptors act as chemoattractants and bind a large number of structurally diverse agonists, including N-formyl peptides and non-formyl peptides that activate phagocytic cells. The endogenous anti-inflammatory peptide annexin A1 and its N-terminal fragment also bind to human FPR1 and FPR2. Importantly, lipoxin A4, an anti-inflammatory eicosanoid belonging to a newly discovered class of low molecular weight inflammation-resolving mediators (SPMs), has been identified as a specific agonist of FPR2 (Ye RD., et al., Pharmacol. Rev., 2009, 61, 119-61).

[0004] Endogenous FPR2 inflammation-resolving ligands such as lipoxin A4 and annexin A1 bind to the receptor, Gi coupling, Ca 2+Lipoxins induce diverse cytoplasmic cascades, including mobilization and β-arrestin recruitment. Activation of FPR2 by lipoxin A4 alters the action of peptide agonists such as serum amyloid A (SAA), affecting phosphorylation pathways differently depending on the cell type. Lipoxins regulate components of both the innate and adaptive immune systems, including neutrophils, macrophages, T cells, and B cells. In neutrophils, lipoxins regulate their motility, cytotoxicity, and lifespan. In macrophages, lipoxins inhibit macrophage apoptosis and promote efferocytosis. In most inflammatory cells, lipoxins suppress the expression of pro-inflammatory cytokines such as IL-6, IL-1β, and IL-8, and enhance the expression of the anti-inflammatory cytokine IL-10 (Chandrasekharan JA, Sharma-Walia N,. J. Inflamm. Res., 2015, 8, 181-92). The primary effects of lipoxins on neutrophils and macrophages are the termination of inflammation and the initiation of inflammatory healing. The latter is mainly involved in promoting anti-fibrotic wound healing and restoring homeostasis to damaged tissue (Romano M., et al., Eur. J. Pharmacol., 2015, 5, 49-63).

[0005] Chronic inflammation is part of the pathogenesis of many human diseases, and stimulation of the inflammation resolution pathway by FPR2 agonists may have both protective and reparative effects. Ischemia-reperfusion (I / R) injury is a common feature of several diseases with high morbidity and mortality, such as myocardial infarction and stroke. Non-productive wound healing associated with cardiomyocyte death and pathological remodeling due to I / R injury leads to scar formation, fibrosis, and progressive loss of cardiac function. Modulation of FPR2 has been proposed to promote myocardial wound healing after injury and reduce harmful myocardial remodeling (Kain V., et al., J. Mol. Cell. Cardiol., 2015, 84, 24-35). Furthermore, FPR2 anti-inflammatory agents in the central nervous system may be useful therapeutic agents for the treatment of various clinical I / R conditions, such as stroke (Gavins FN., Trends Pharmacol. Sci., 2010, 31, 266-76) and I / R-induced spinal cord injury (Liu ZQ., et al., Int. J. Clin. Exp. Med., 2015, 8, 12826-33).

[0006] Novel anti-inflammatory agonists targeting FPR2 have shown beneficial effects in treating I / R-induced injury, and the usefulness of these ligands can be applied to other diseases. In the cardiovascular system, both the FPR2 receptor and its anti-inflammatory agonist have been found to be involved in the stabilization and healing of atherosclerotic plaques (Petri MH., et al., Cardiovasc. Res., 2015, 105, 65-74; and Fredman G., et al., Sci. Trans. Med., 2015, 7(275);275ra20). FPR2 agonists have also been shown to be beneficial in preclinical models of chronic inflammatory human diseases such as infections, psoriasis, dermatitis, ocular inflammation, sepsis, pain, metabolic / diabetic diseases, cancer, COPD, asthma and allergic diseases, cystic fibrosis, acute lung injury and fibrosis, rheumatoid arthritis and other joint diseases, Alzheimer's disease, renal fibrosis, and organ transplantation (Romano M., et al., Eur. J. Pharmacol., 2015, 5, 49-63, Perrett, M., et al., Trends in Pharm. Sci., 2015, 36, 737-755). [Modes for carrying out the invention]

[0007] Description of the Invention The present invention encompasses compounds represented by formula I, which are formylpeptide 2 (FPR2) receptor agonists and / or formylpeptide 1 (FPR1) receptor agonists, compositions comprising the same, and methods of using them in the treatment of, for example, atherosclerosis, heart failure, chronic obstructive pulmonary disease (COPD), and related diseases.

[0008] One aspect of the present invention is formula I: [ka] I [In the formula, * is an asymmetric carbon atom; Ring A is a C6 aryl or a 6-membered heteroaryl; Ring B is C6 aryl or 6-member heteroaryl; R 1 is halo, alkyl, or haloalkyl; R 2 is halo or haloalkyl; R 3 is C 4 alkyl substituted with 1 to 3 R 3-5 s, or cycloalkyl substituted with (R 5 )(R 6 )NCO, or C 4 alkyl substituted with 1 to 3 R 1-4 s; R 4 is halo, hydroxy, cyano, alkyl, alkoxy, (R 5 )(R 6 )N, (alkyl)2(O)P, (alkoxy)2(O)P, (alkoxy)(alkyl)(O)P, alkylSO2, or cycloalkylSO2; R 5 is hydrogen, alkyl, alkylCO, or alkylSO2; R 6 is hydrogen or alkyl; or NR 5 R 6 together are selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, and are substituted with 0 to 3 substituents selected from oxo, hydroxy, fluoro, alkyl, haloalkyl, alkoxy, and haloalkoxy; R 7 is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl] is a compound represented by the formula, or a pharmaceutically acceptable salt thereof.

[0009] Another aspect of the present invention is Formula II:

Chemical formula

[0010] Another aspect of the present invention is Formula III: [ka] III [In the formula, R 1 is Cl or CF3; R 2 is F; R 4 [These are hydroxy, alkyl, (Me)2(O)P, or (Et)2(O)P] The compound represented by [formula], or a pharmaceutically acceptable salt thereof.

[0011] Another aspect of the present invention is formula IV: [ka] IV [In the formula, R 1 is Cl or CF3; R 2 is F; R 4(R) 5 )(R 6 )N, (Me)2(O)P, (Et)2(O)P, alkylSO2, or cycloalkylSO2; R 5 is hydrogen, alkyl, alkylCO, or alkylSO2; R 6 is hydrogen or alkyl; or NR 5 R 6 [These are combined and substituted with 0-3 substituents selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, and selected from oxo, hydroxy, fluoro, alkyl, haloalkyl, alkoxy, and fluoroalkoxy.] The compound represented by [formula], or a pharmaceutically acceptable salt thereof.

[0012] Another aspect of the present invention is formula V: [ka] V [In the formula, R 1 is Cl or CF3; R 2 is F; R 4 [These are hydroxyl, (Me)2(O)P, or (Et)2(O)P] The compound represented by [formula], or a pharmaceutically acceptable salt thereof.

[0013] Another aspect of the present invention is formula VI: [ka] VI [In the formula, R 1 is Cl or CF3; R 2 is F; R 4 [These are hydroxyl, (Me)2(O)P, or (Et)2(O)P] The compound represented by [formula], or a pharmaceutically acceptable salt thereof.

[0014] Another aspect of the present invention is formula VII: [ka] VII [In the formula, R 1 is Cl or CF3; R 2 is F; R 4 [These are hydroxyl, (Me)2(O)P, or (Et)2(O)P] The compound represented by [formula], or a pharmaceutically acceptable salt thereof.

[0015] For compounds of formulas I to VII, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 The range of any example of variable substituents including can be applied independently of the range of any other example of variable substituents. Therefore, the present invention includes combinations of different embodiments.

[0016] Unless otherwise specified, these terms have the following meanings: "Alkyl" means a linear or branched alkyl group having 1 to 6 carbon atoms. "Alkenyl" means a linear or branched alkyl group consisting of 2 to 6 carbon atoms and having at least one double bond. "Alkynyl" means a linear or branched alkyl group consisting of 2 to 6 carbon atoms and having at least one triple bond. "Cycloalkyl" means a monocyclic ring system consisting of 3 to 7 carbon atoms. Terms containing a hydrocarbon moiety (e.g., alkoxy) include linear and branched isomers of the hydrocarbon moiety. "Halo" includes fluoro, chloro, bromo, and iodine. "Haloalkyl" and "haloalkoxy" include all halide isomers from monohalo to perhalo. "Aryl" means a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 12 carbon atoms. Bicyclic ring systems may consist of a phenyl group fused to an aromatic or non-aromatic carbocyclic ring. Typical examples of aryl groups include, but are not limited to, phenyl, indanyl, indenyl, naphthyl, and tetrahydronaphthyl. “Heteroaryl” means a 5-7 member monocyclic or 8-11 member bicyclic aromatic ring system having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. If no bond position is specified, the bond may be at any suitable position as understood by those skilled in the art. Combinations of substituents and bond patterns are limited to those that result in stable compounds, as understood by those skilled in the art. Terms in parentheses and multiple parentheses are intended to clarify the bond relationships for those skilled in the art. For example, a term such as “((R)alkyl)” means an alkyl substituent further substituted with substituent R.

[0017] This invention encompasses all pharmaceutically acceptable salt forms of the compound. A pharmaceutically acceptable salt is one in which the counterion does not significantly contribute to the physiological activity or toxicity of the compound and functions as a pharmacological equivalent in itself. These salts can be prepared using commercially available reagents according to general organic synthesis techniques. Examples of anionic salts include acetates, acistrates, besilates, bromides, chlorides, citrates, fumarates, glucuronides, hydrobroms, hydrochlorides, hydroiodides, iodides, lactates, maleates, mesilates, nitrates, pamoates, phosphates, succinates, sulfates, tartrates, tosylates, and xinofoates. Examples of cationic salts include ammonium, aluminum, benzathine, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium, tromethamine, and zinc.

[0018] Some of the compounds of the present invention have stereoisomers. The present invention includes all stereoisomers of the compounds, including enantiomers and diastereomers. Methods for producing and separating stereoisomers are known in the art. The present invention includes all tautomers of the compounds. The present invention includes atropisomers and rotational isomers.

[0019] This invention is intended to encompass all isotopes of atoms present in a compound. Isotopes include atoms with the same atomic number but different mass numbers. As a general example, but not limited to, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include, 13 C and 14It contains C. The isotope-labeled compounds of the present invention can usually be prepared by means of the prior art known to those skilled in the art, or by methods similar to those described herein, using a suitable isotope-labeled reagent instead of an unlabeled reagent. Such compounds can be used in a variety of applications, such as standards and reagents in the measurement of biological activity. In the case of stable isotopes, such compounds may modify their biological, pharmacological, or pharmacokinetic properties in a desirable manner.

[0020] biological methods N-formyl peptide receptors (FPRs) are a family of chemoattractant receptors that promote leukocyte responses during inflammation. FPRs belong to the seven-transmembrane G protein-coupled receptor superfamily and bind to inhibitory G proteins (Gi). Three family members (FPR1, FPR2, and FPR3) have been identified in humans, primarily present in bone marrow cells, with diverse distributions and reported expression in multiple organs and tissues. Following agonist binding, FPRs activate numerous physiological pathways, including intracellular signaling, Ca2+ recruitment, and transcription. This family interacts with a variety of ligands, including proteins, polypeptides, and fatty acid metabolites, activating both pro-inflammatory and pro-inflammatory downstream responses.

[0021] The FPR2 receptor binds to multiple ligands and triggers both inflammatory and anti-inflammatory responses. The release of inflammatory mediators by FPR2 is promoted by endogenous protein ligands such as serum amyloid A (SAA) and amyloid β (1-42), while the resolution of inflammation is induced by ligands such as the arachidonic acid metabolites lipoxin A4 (LXA4) and epilipoxin (ATL), and the docosahexenoic acid metabolite resolvin D1 (RvD1). Fatty acid metabolites that promote inflammation resolution mediate the suppression and resolution of inflammation via the FPR2 receptor by stimulating phagocytosis of apoptotic neutrophils by macrophages. The removal of apoptotic neutrophils induces the release of cytokines that activate the inflammation resolution pathway.

[0022] The FPR1 receptor was isolated as a high-affinity receptor for N-formylmethionine-containing peptides (e.g., N-formylmethionine-leucyl-phenylalanine (FMLP)). This protein guides mammalian phagocytic and leukocytes to invading pathogens or inflammatory tissue, activating these cells to kill pathogens or remove cellular debris.

[0023] Cyclic adenosine monophosphate (cAMP) assays for FPR2 and FPR1 384-well Proxiplates (Perkin-Elmer) pre-added with the test compound in DMSO (1% final concentration) were mixed with a mixture of forskolin (5 μM final concentration for FPR2, 10 μM final concentration for FPR1) and IBMX (200 μM final concentration) at a final concentration of 1.7 nM to 100 μM. Chinese hamster ovary cells (CHO cells) overexpressing human FPR1 or human FPR2 receptors were cultured in F-12 (Ham's) medium supplemented with 10% qualified FBS, 250 μg / ml zeosin, and 300 μg / ml hygromycin (Life Technologies). The reaction was initiated by adding 2,000 human FPR1 cells or 4,000 human FPR2 cells per well to Dulbecco's PBS (containing calcium and magnesium) (Life Technologies) supplemented with 0.1% BSA (Perkin-Elmer). The reaction mixture was incubated at room temperature for 30 minutes. Intracellular cAMP concentration was measured using the HTRF HiRange cAMP assay reagent kit (Cisbio) according to the manufacturer's instructions. Solutions of cryptotate-labeled anti-cAMP antibody and d2-fluorescent-labeled cAMP antibody were prepared separately in the provided lysis buffer. After the reaction was complete, cells were lysed with equal volumes of d2-cAMP solution and anti-cAMP solution. After incubation at room temperature for 1 hour, time-resolved fluorescence intensity was measured using Envision (Perkin-Elmer) at excitation wavelengths of 400 nm and emission wavelengths of 590 nm and 665 nm. Calibration curves were created by plotting the ratio of emission intensity at 665 nm to 590 nm against cAMP concentration using external cAMP standards in the concentration range of 1 μM to 0.1 pM. Next, the potency of the compounds and their inhibitory effect on active cAMP production were determined by fitting a four-parameter logistic equation from the cAMP level versus compound concentration plots.

[0024] The examples disclosed below were tested in the FPR2 and FPR1 cAMP assays described above and were confirmed to possess FPR2 and / or FPR1 agonist activity. Table 1 below shows the EC2 values ​​measured in the FPR2 and FPR1 cAMP assays for the following examples.50 Show the value.

[0025] Table 1 [Table 1] [Table 2]

[0026] Pharmaceutical composition and method of use The compounds of the present invention can be administered to patients for the treatment of various conditions and disorders, including atherosclerosis, heart failure, asthma, COPD, lung diseases including cystic fibrosis, neuroinflammatory diseases including multiple sclerosis, Alzheimer's disease, and stroke, as well as chronic inflammatory diseases such as inflammatory bowel disease, rheumatoid arthritis, psoriasis, sepsis, lupus, and renal fibrosis.

[0027] Another aspect of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I in combination with a pharmaceutical carrier.

[0028] Another aspect of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I in combination with at least one other therapeutic agent and a pharmaceutical carrier.

[0029] Unless otherwise specified, the following terms have the meanings set forth below. "Patient" means a person deemed suitable for treatment by a practitioner in the field, and to the best of the practitioner's understanding, includes all appropriate mammalian species, including humans, that may potentially benefit from treatment with FPR2 and / or FPR1 agonists. Common risk factors include, but are not limited to, age, sex, weight, family history, sleep apnea, alcohol or smoking, arrhythmias due to physical inactivity, or signs of insulin resistance such as acanthosis nigricans, hypertension, dyslipidemia, or polycystic ovary syndrome (PCOS). "To treat" or "treatment" includes treatment of a patient as understood by a practitioner in the field, and includes suppression of the disease (i.e., halting disease progression), alleviation of the disease (i.e., causing disease regression), and / or prevention of disease onset in the patient. "Therapeutic dose" is intended to include the amount of an effective or beneficial compound as understood by a practitioner in the field.

[0030] "Pharmaceutical composition" means a composition comprising the compound of the present invention in combination with at least one additional pharmaceutically acceptable carrier. "Pharmaceutically acceptable carrier" refers to a medium for delivering a biologically active agent as understood by those skilled in the art, such as diluents, preservatives, fillers, flow modifiers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants, and compounding agents. Pharmaceutically acceptable carriers are formulated according to several factors known to those skilled in the art. These include, but are not limited to, the type and nature of the active agent being formulated, the target recipient of the drug-containing composition, the intended route of administration of the composition, and the target therapeutic indication. A description of a suitable pharmaceutically acceptable carrier and the factors involved in its selection is publicly known in the art in reference to Allen, LV, Jr. et al., Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition, Pharmaceutical Press (2012).

[0031] The solid composition is usually formulated in dose units, and compositions that provide approximately 1 to 1000 mg of the active ingredient per single dose are preferred. Examples of doses include 1 mg, 10 mg, 100 mg, 250 mg, 500 mg, and 1000 mg.

[0032] Liquid compositions are typically specified in terms of dosage unit ranges. Generally, the dosage unit range for liquid compositions is 1 to 100 mg / mL. Examples of dosages include 1 mg / mL, 10 mg / mL, 25 mg / mL, 50 mg / mL, and 100 mg / mL.

[0033] Another aspect of the present invention is a method for treating a heart disease, comprising administering a therapeutically effective amount of a compound of formula I to a patient.

[0034] Another aspect of the present invention is a method for treating a heart disease, wherein the heart disease is selected from the group consisting of angina pectoris, unstable angina, myocardial infarction, heart failure, acute coronary artery disease, acute heart failure, chronic heart failure, and iatrogenic injury of the heart.

[0035] Another aspect of the present invention is a method for treating cardiac disease following myocardial infarction.

[0036] Another aspect of the present invention is a method by which heart disease is associated with chronic heart failure.

[0037] Another aspect of the present invention is a method in which the treatment improves the healing of myocardial wounds.

[0038] Another aspect of the present invention is a method that is a treatment for alleviating myocardial fibrosis.

[0039] The present invention encompasses all conventional methods of administration, but oral and parenteral administration are preferred. Generally, the administration regimen is similar to that of other clinically used cardiovascular drugs. The administration regimen and method of administration of the compounds of the present invention depend on factors known to practitioners of the art, including the age, sex, health status, medical condition, and weight of the recipient; the nature and severity of symptoms; the type of concomitant therapy; the frequency of treatment; the route of administration; and the desired effect. Typically, the daily dose is 0.1 to 100 mg per kg of body weight. Generally, more of the compound is required for oral administration, and less for parenteral administration. However, the specific administration regimen is determined by the physician based on appropriate medical judgment.

[0040] Another aspect of the present invention is a method for treating a heart disease, comprising administering to a patient a therapeutically effective amount of a compound of formula I together with at least one other therapeutic agent.

[0041] The compounds of the present invention can be used in combination with other suitable therapeutic agents useful for treating the aforementioned diseases or disorders, such as anti-atherosclerotic agents, anti-dyslipidemia agents, antidiabetic agents, antihyperglycemic agents, anti-hyperinsulinic agents, antithrombotic agents, anti-retinopathy agents, antineuropathy agents, antinephropathy agents, anti-ischemic agents, antihypertensive agents, anti-obesity agents, anti-hyperlipidemia agents, anti-hypertriglyceridemia agents, anti-hypercholesterolemia agents, anti-restenosis agents, anti-pancreatic cancer agents, lipid-lowering inhibitors, appetite suppressants, memory enhancers, anti-dementia agents, cognitive function enhancers, appetite suppressants, heart failure agents, peripheral artery disease treatment agents, malignant tumor treatment agents, and anti-inflammatory agents.

[0042] The compounds of the present invention can be used in combination with one or more, preferably one to three, of the following heart failure treatments selected from loop diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), angiotensin receptor neprilysin inhibitors (ARNIs), beta-blockers, mineralocorticoid receptor antagonists, nitroxyl donors, RXFP1 agonists, APJ agonists, and inotropic agents. These drugs include, but are not limited to, furosemide, bumetanide, torsemide, sacubitril, valsartan, thiazide diuretics, captopril, enalapril, lisinopril, carvedilol, metopolol, bisoprolol, celeracin, spironolactone, eplerenone, ivabradine, candesartan, eprosartan, irvestaline, losartan, olmesartan, telmisartan, and valsartan.

[0043] The compounds of the present invention are useful as standard or reference compounds, for example, as quality standards or controls, in tests or assays targeting FPR2. Such compounds can be provided, for example, as commercially available kits for use in pharmaceutical research targeting FPR2 activity. For example, the compounds of the present invention can be used as reference compounds in assays to compare their known activity with that of compounds having unknown activity. This allows the experimenter to be confident that the assay is being performed correctly and to have a basis for comparison, especially when the test compound is a derivative of the reference compound. When developing new assays or protocols, their effectiveness can be tested using the compounds of the present invention. The compounds of the present invention can also be used in diagnostic assays that include FPR2.

[0044] Methods of Chemistry The abbreviations used in this book are defined as follows: "1x" means once, "2x" means twice, "3x" means three times, "℃" means Celsius, "aq" means aqueous solution, "Col" means column, "eq" means equivalent, "g" means gram, "mg" means milligram, "L" means liter, "mL" means milliliter, "μL" means microliter, "N" means standard, "M" means mole, "nM" means nanomoles, "mol" means mole, "mmol" means millimoles, "min" means minute, "h" means hour, "rt" means room temperature, "RT" means retention time, "ON" means overnight, "atm" means atmospheric pressure, "psi" means pounds per square inch, "conc." means concentrate, "aq" means aqueous solution, "sat" or "sat'd" means saturated, "MW" means molecular weight, "mw" or "μwave" means microwave, "mp" means melting point, "Wt" means weight, "MS" or "Mass" "Spec" is mass spectrometry, "ESI" is electrospray ionization mass spectrometry, "HR" is high resolution, "HRMS" is high resolution mass spectrometry, "LCMS" is liquid chromatography-mass spectrometry, "HPLC" is high-pressure liquid chromatography, "RP HPLC" is reversed-phase HPLC, "TLC" or "tlc" is thin-layer chromatography, "NMR" is nuclear magnetic resonance spectroscopy, "nOe" is nuclear Overhauser effect spectroscopy, "1H" is proton, "δ" is delta, "s" is singlet, "d" is doublet, "t" is triplet, "q" is quadrant, "m" is multiplet, "br" is broadband, "Hz" is Hertz, and "α", "β", "R", "S", "E", and "Z" are stereochemical names well known to those skilled in the art.

[0045] [Table 3] [Table 4]

[0046] The compounds of the present invention can be produced by various methods known in the art, including the methods described in the following schemes and sections on specific embodiments. The structural and variable numbers shown in the synthesis schemes should not be confused with the structural or variable numbers described in the claims or other parts of this specification. The variables in the schemes are for illustrative purposes only to illustrate some methods of producing the compounds of the present invention.

[0047] When planning any synthetic route in this field, it will be recognized that another important consideration is the careful selection of protecting groups to be used to protect the reactive functional groups present in the compounds described in this invention. For experienced professionals, a well-established and authoritative publication describing many alternatives is Greene, TW et al., Protecting Groups in Organic Synthesis, 4th Edition, Wiley (2007).

[0048] Compounds having general formula I (wherein rings A and B are a substituted phenyl group and a heteroaryl group, respectively) can be prepared by one or more of the following synthetic schemes. [ka] (I) The 1-arylpyrrolidinene compounds of the present invention (ring A being a substituted phenyl and ring B being a substituted phenyl or heteroaryl) can be prepared by the general route shown in Scheme 1, starting from a well-substituted aryl halide such as compound 1a. This involves a palladium-catalyzed or copper-catalyzed coupling reaction of 1a with a well-protected substituted 3-aminopyrrolidine-2-one (PG being a protecting group such as Boc or Cbz). Depending on the properties of ring B, this conversion method may involve variations of Ullmann, Goldberg, Buchwald copper-catalyzed amidation or Buchwald palladium-catalyzed amidation, using methods known to those skilled in the art for these types of coupling (e.g., Yin & Buchwald Organic Lett. 2000). 2 , 1101; Klapers et al. JACS, 2001, 123 , 7727;Klapars et al. JACS, 2002, 124, 7421;Yin & Buchwald JACS. 2002, 124, 6043;Kiyomor, Madoux & Buchwald, Tet. Lett., 1999, 40 , 2657, Surry and Buchwald Angew. Chem. Int. Ed., 2008, 47See 6338, Surry & Buchwald Chem Sci. 2011;2(1):27-50; Shaughnessy, Ciganek & DeVasher, Organic Reactions. 2014, 85:1:1-668). Urea 1d can be obtained by removing the protecting group from 1b and condensing the resulting free amine with a appropriately substituted aryl isocyanate 1e or phenylcarbamate 1f. Suitable isocyanates or phenylcarbamates are commercially available or can be readily obtained from the corresponding arylamine by methods known to those skilled in the art. Alternatively, urea 1d can be obtained by treating a deprotected 3-aminopyrrolidine-2-one intermediate with 4-nitrophenyl chloroformate to form a carbamate, followed by condensation with a appropriately substituted arylamine 1g. Those skilled in the art will also understand that additional compounds of the present invention, in which rings A and B are heteroaryl rings such as pyridine, pyrimidine, and thiazole, can also be prepared using the method outlined in Scheme 1 by using appropriate heteroaryl iodides or bromides instead of 1a and heteroarylamines. Other aryl bromides substituted with heteroatom-containing rings can be synthesized by those skilled in the art and used in Scheme 1 to obtain other compounds of the present invention. The substitution of R in intermediates 1a, 1b, 1c, or 1d can be carried out using synthetic methods known to those skilled in the art. The racemic compounds can be separated using either chiral HPLC or SFC to obtain a single enantiomer.

[0049] Scheme 1 [ka]

[0050] Other features of the present invention will become apparent from the following description of exemplary embodiments for illustrating the invention, but these embodiments are not intended to limit the invention.

[0051] In the exemplary examples, unless otherwise specified, the following methods were used. The intermediates and final products were purified by normal-phase chromatography or reverse-phase chromatography. Unless otherwise specified, normal-phase chromatography was performed using a pre-packed SiO2 cartridge with gradient elution of hexane and ethyl acetate, or DCM and MeOH. Reverse-phase preparative HPLC is performed using a C18 column (UV 220 nm) or a preparative LC-MS detector to obtain gradients between solvent A (90% water, 10% MeOH, 0.1% TFA) and solvent B (10% water, 90% MeOH, 0.1% TFA), or between solvent A (95% water, 5% Acn, 0.1% TFA) and solvent B (5% water, 95% Acn, 0.1% TFA), or between solvent A (95% water, 2% Acn, 0.1% HCOOH) and solvent B (98% Acn, 2% water, 0.1% HCOOH), or between solvent A (95% water, 5% Acn, 10 mM NH4OAc) and solvent B (98% Acn, 2% water, 10 mM NH4OAc), or between solvent A (98% water, 2% Acn, 0.1% NH4OH) and solvent B (98% Elution was performed using a gradient of Acn, 2% water, and 0.1% NH4OH.

[0052] LC / MS method used for characterization of the examples Reverse-phase HPLC / MS analysis was performed using a Waters Acquity system and a Waters MICROMASS® ZQ mass spectrometer.

[0053] Method A: A straight gradient from 0 to 100% B over 3 minutes, with a holding time of 0.75 minutes at 100% B. Ultraviolet visualization at 220 nm Column: Waters BEH C18 2.1×50 mm Flow rate: 1.0 mL / min Solvent A: 0.1% TFA, 95% water, 5% Acn Solvent B: 0.1% TFA, 5% water, 95% Acn Method B: A straight gradient from 0 to 100% B over 3 minutes, with a holding time of 0.75 minutes at 100% B. Ultraviolet visualization at 220 nm Column: Waters BEH C18 2.1×50 mm Flow rate: 1.0 mL / min Solvent A: 10 mM ammonium acetate, 95% water, 5% Acn Solvent B: 10 mM ammonium acetate, 5% water, 95% Acn

[0054] Analytical HPLC: Method used for characterizing the examples. The products were analyzed using reversed-phase HPLC (analytical HPLC system with Shimadzu Discovery VP software). RT = retention time. Method C: Ascentis Express C18, 2.1 × 50 mm, 2.7 μm particles; Solvent A: 95% water, 5% acetonitrile, 0.05% TFA; Solvent B: 95% acetonitrile, 5% water, 0.1% TFA; Temperature: 50°C; Gradient: 0-100% B over 3 minutes, then held at 100% B for 1 minute; Flow rate: 1.1 mL / min. Method D: Ascentis Express C18, 2.1 × 50 mm, 2.7 μm particles; Solvent A: 95% water, 5% acetonitrile and 10 mM ammonium acetate; Solvent B: 95% acetonitrile, 5% water and 10 mM ammonium acetate; Temperature: 50°C; Gradient: 0-100% B over 3 minutes, then held at 100% B for 1 minute; Flow rate: 1.1 mL / min. Method E: Kinetex BIPHENYL (4.6 x 100 mm), 2.6 μm particles; Solvent A: 95% buffer (0.05% TFA aqueous solution), 5% acetonitrile; Solvent B: 95% acetonitrile, 5% buffer (0.05% TFA aqueous solution); Temperature: 50°C; Gradient: 0-100% B over 3 minutes, then held at 100% B for 1 minute; Flow rate: 1.1 mL / min. Method F: Ascentis Express C18, 2.1 × 50 mm, 2.7 μm particles; Solvent A: 95% water, 5% acetonitrile and 10 mM ammonium formate; Solvent B: 95% acetonitrile, 5% water and 10 mM ammonium formate; Temperature: 50°C; Gradient: 0-100% B over 3 minutes, then held at 100% B for 1 minute; Flow rate: 1.1 mL / min.

[0055] SFC and Chiral Purification Method Method A: DAD-1: CHIRALPAK IA (250*4.6)mm, 5μm; DAD-2: CHIRALPAK IB (250*4.6)mm, 5μm. Co-solvent: 0.2% ammonia / Acn:MeOH (1:1) Method B: DAD-1: CHIRALPAK IC (250*4.6)mm, 5μm; DAD-2: CHIRALPAK ID (250*4.6)mm, 5μm. Co-solvent: 0.2% ammonia / Acn:MeOH (1:1) Method C:DAD-1:CHIRALPAK IE (250*4.6)mm, 5μm;DAD-2:CHIRALPAK IF (250*4.6)mm, 5μm. Co-solvent: 0.2% ammonia / Acn:MeOH (1:1)

[0056] NMR used for characterization of the examples 1 ¹H NMR spectra were acquired using a Bruker or JEOL® Fourier transform spectrometer operating at the following frequencies: ¹H NMR: 300 MHz (Bruker or JEOL®), 400 MHz (Bruker or JEOL®), or 500 MHz (Bruker or JEOL®). 13 ¹³C NMR: 100 MHz (Bruker or JEOL®). Spectral data are reported in the form of chemical shifts (multiplicity, bond constants, number of hydrogen atoms). Chemical shifts are identified in ppm on the low-field side of the tetramethylsilane internal standard (δ units, tetramethylsilane = 0 ppm) and / or relative to the solvent peak. The solvent peak is,1 In the 1H NMR spectrum, CD2HSOCD3 was observed at 2.49 ppm, CD2HOD at 3.30 ppm, CD3CN at 1.94 ppm, and CHCl3 at 7.24 ppm. 13 In the 13C NMR spectrum, it appears at 39.7 ppm for CD3SOCD3, 49.0 ppm for CD3OD, and 77.0 ppm for CDCl3. 13 The 13C NMR spectrum was proton-separated.

[0057] Intermediate 1: 1-(4-bromo-2,3-difluorophenyl)cyclopropane-1-carbonitrile [ka] Under an argon atmosphere, a solution of 2-(4-bromo-2,3-difluorophenyl)acetonitrile (3.00 g, 12.9 mmol) in THF (30 mL), stirred at 0°C, was mixed with NaH (1.29 g, 32.3 mmol) and stirred for 30 minutes. A solution of 1,2-dibromoethane (2.67 g, 14.2 mmol) in THF (5 mL) was added to the reaction mixture. The mixture was gradually heated to room temperature and stirred for 15 hours. The reaction mixture was stopped with saturated ammonium chloride solution (10 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic matter was washed with saline solution (50 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain 1-(4-bromo-2,3-difluorophenyl)cyclopropane-1-carbonitrile (2.9 g, 11 mmol, yield 87%) as a brown liquid. 1 H NMR (400 MHz, CDCl3) δ = 7.28 - 7.39 (m, 1 H), 7.01 - 7.11 (m, 1 H), 1.40 - 1.48 (m, 2 H), 1.21 - 1.31 (m, 2 H).

[0058] Intermediate 2: 1-(4-bromo-2,3-difluorophenyl)cyclopropane-1-carbaldehyde [ka] Under an argon atmosphere, a solution of 1-(4-bromo-2,3-difluorophenyl)cyclopropane-1-carbonitrile (2.50 g, 9.69 mmol) in diethyl ether (40 mL) was stirred at -10°C, and a solution of 1.2 M DIBAL-H (8.90 mL, 10.7 mmol) in toluene was added. The reaction mixture was gradually heated to 5°C over 2 hours, and the reaction was stopped with 1N HCl (50 mL) aqueous solution. The two phases were extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with water (30 mL) and saline solution (30 mL), dried over MgSO4, and concentrated under reduced pressure to obtain 1-(4-bromo-2,3-difluorophenyl)cyclopropane-1-carbaldehyde (2.10 g, 8.04 mmol, yield 83%) as a brown liquid. 1 H NMR (400 MHz, CDCl3) δ = 9.00 (d, J = 1.51 Hz, 1 H), 7.29 - 7.35 (m, 1 H), 6.88 - 6.94 (m, 1 H), 1.66 - 1.71 (m, 2 H), 1.42 - 1.47 (m, 2 H).

[0059] Intermediate 3: tert-butyl (R)-(1-(2,3-difluoro-4-(1-formylcyclopropyl)phenyl)-2-oxopyrrolidine-3-yl)carbamate [ka] To a solution of tert-butyl(R)-(2-oxopyrrolidine-3-yl)carbamate (500 mg, 2.50 mmol) in 1,4-dioxane (10 mL), 1-(4-bromo-2,3-difluorophenyl)cyclopropane-1-carbaldehyde (978 mg, 3.75 mmol) and K3PO4 (1.06 g, 4.99 mmol) were added while stirring at room temperature. After purging the reaction mixture with nitrogen for 5 minutes, N,N'-dimethylethylenediamine (44 mg, 0.50 mmol) and copper(I) iodide (48 mg, 0.25 mmol) were added. After purging the reaction mixture with nitrogen again for 3 minutes, the mixture was heated at 90°C for 6 hours. The brown reaction mixture was cooled, filtered through Celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate) to obtain tert-butyl (R)-(1-(2,3-difluoro-4-(1-formylcyclopropyl)phenyl)-2-oxopyrrolidine-3-yl)carbamate (700 mg, 1.84 mmol, yield 73.7%) as a brown solid. MS(ESI) m / z:381.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ = 8.72 - 8.78 (m, 1 H), 7.22 - 7.36 (m, 2 H), 7.09 - 7.21 (m, 1 H), 4.28 - 4.41 (m, 1 H), 3.64 - 3.81 (m, 2 H), 2.30 - 2.44 (m, 1 H), 1.97 - 2.11 (m, 1 H), 1.65 - 1.75 (m, 2 H), 1.47 - 1.54 (m, 2 H), 1.34 - 1.44 (m, 9 H).

[0060] Intermediate 4: tert-butyl (R)-(1-(2,3-difluoro-4-(1-(hydroxymethyl)cyclopropyl)phenyl)-2-oxopyrrolidine-3-yl)carbamate [ka] Under an argon atmosphere, at 0°C, a solution of tert-butyl (R)-(1-(2,3-difluoro-4-(1-formylcyclopropyl)phenyl)-2-oxopyrrolidine-3-yl)carbamate (400 mg, 1.05 mmol) in THF (10 mL)-methanol (2 mL) was mixed with sodium borohydride (43.8 mg, 1.16 mmol) and stirred for 30 minutes. The reaction mixture was stopped by adding 12 mL of 1N HCl aqueous solution, and the mixture was extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with water (20 mL) and saline solution (20 mL), dried over Na2SO4, and then concentrated under reduced pressure to obtain tert-butyl (R)-(1-(2,3-difluoro-4-(1-(hydroxymethyl)cyclopropyl)phenyl)-2-oxopyrrolidine-3-yl)carbamate (350 mg, 0.92 mmol, yield 87%) as a brown solid, which was used in the next step without further purification. MS(ESI) m / z:327.1 [M+H-isobutylene] + .

[0061] Intermediate 5: tert-butyl (R)-(1-(2,3-difluoro-4-(1-(iodomethyl)cyclopropyl)phenyl)-2-oxopyrrolidine-3-yl)carbamate [ka] Under an argon atmosphere, at room temperature, a solution of tert-butyl (R)-(1-(2,3-difluoro-4-(1-(hydroxymethyl)cyclopropyl)phenyl)-2-oxopyrrolidine-3-yl)carbamate (300 mg, 0.785 mmol) in DCM (10 mL) was mixed with triphenylphosphine (247 mg, 0.941 mmol), imidazole (64 mg, 0.94 mmol), and iodine (240 mg, 0.94 mmol). The resulting reaction mixture was stirred for 3 hours and concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (petroleum ether / ethyl acetate) to obtain tert-butyl (R)-(1-(2,3-difluoro-4-(1-(iodomethyl)cyclopropyl)phenyl)-2-oxopyrrolidine-3-yl)carbamate (220 mg, 0.45 mmol, yield 49%) as an off-white solid. MS(ESI) m / z:437.1 [M+H-isobutylene] + .

[0062] Intermediate 6: tert-butyl (R)-(1-(2,3-difluoro-4-(1-((methylsulfonyl)methyl)cyclopropyl)phenyl)-2-oxopyrrolidine-3-yl)carbamate [ka] Under an argon atmosphere, at room temperature, a solution of tert-butyl (R)-(1-(2,3-difluoro-4-(1-(iodomethyl)cyclopropyl)phenyl)-2-oxopyrrolidine-3-yl)carbamate (190 mg, 0.39 mmol) in ethanol (8 mL) was added, to which sodium methanesulfinate (197 mg, 1.93 mmol) was added. The resulting reaction mixture was heated at 90°C for 15 hours. The reaction mixture was cooled and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate) to obtain tert-butyl (R)-(1-(2,3-difluoro-4-(1-((methylsulfonylmethyl)cyclopropyl)phenyl)-2-oxopyrrolidine-3-yl)carbamate (125 mg, 0.281 mmol, yield 72.9%) as a brown solid. MS(ESI) m / z:389.3 [M+H-isobutylene] + .

[0063] Intermediate 7: (R)-3-amino-1-(2,3-difluoro-4-(1-((methylsulfonyl)methyl)cyclopropyl)phenyl)pyrrolidine-2-one hydrochloride [ka] To a solution of tert-butyl (R)-(1-(2,3-difluoro-4-(1-((methylsulfonyl)methyl)cyclopropyl)phenyl)-2-oxopyrrolidine-3-yl)carbamate (400 mg, 0.90 mmol) in 1,4-dioxane (2 mL), 4M HCl (4.50 mL, 18.0 mmol) in the 1,4-dioxane was added under an argon atmosphere at room temperature while stirring, and the mixture was stirred for 2 hours. The solvent was evaporated under reduced pressure to obtain a rubbery solid. Furthermore, the solid was pulverized with diethyl ether (10 mL x 2) and dried to obtain (R)-3-amino-1-(2,3-difluoro-4-(1-((methylsulfonyl)methyl)cyclopropyl)phenyl)pyrrolidine-2-one hydrochloride (325 mg, 0.853 mmol, 95% yield) as a brown solid. MS(ESI) m / z: 345.3 [M+H] + . [Examples]

[0064] (R)-1-(4-chloro-2-fluorophenyl)-3-(1-(2,3-difluoro-4-(1-((methylsulfonyl)methyl)cyclopropyl)phenyl)-2-oxopyrrolidine-3-yl)urea [ka] To a solution of (R)-3-amino-1-(2,3-difluoro-4-(1-((methylsulfonyl)methyl)cyclopropyl)phenyl)pyrrolidine-2-one hydrochloride (200 mg, 0.53 mmol) in DCE (10 mL), DIPEA (0.28 mL, 1.6 mmol) and phenyl (4-chloro-2-fluorophenyl) carbamate (170 mg, 0.63 mmol) were added while stirring at room temperature, and the mixture was heated at 50 °C for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was purified by reverse-phase chromatography followed by chiral HPLC to obtain (R)-1-(4-chloro-2-fluorophenyl)-3-(1-(2,3-difluoro-4-(1-((methylsulfonyl)methyl)cyclopropyl)phenyl)-2-oxopyrrolidine-3-yl)urea (100 mg, 0.19 mmol, yield 37%) as an off-white solid. MS(ESI) m / z:516.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ = 8.62 (s, 1H), 8.14 (t, J = 9.0 Hz, 1H), 7.42 (dd, J = 11.0, 2.3 Hz, 1H), 7.33 - 7.10 (m, 4H), 4.57 - 4.47 (m, 1H), 3.86 - 3.77 (m, 1H), 3.73 - 3.62 (m, 1H), 3.46 (s, 2H), 2.87 (s, 3H), 2.59 - 2.53 (m, 1H), 2.09 - 1.97 (m, 1H), 1.18 - 1.12 (m, 2H), 1.05 - 1.01 (m, 2H). [Examples]

[0065] (R)-1-(1-(2,3-difluoro-4-(1-((methylsulfonyl)methyl)cyclopropyl)phenyl)-2-oxopyrrolidine-3-yl)-3-(2-fluoro-4-(trifluoromethyl)phenyl)urea [ka] To a suspension of (R)-3-amino-1-(2,3-difluoro-4-(1-((methylsulfonylmethyl)cyclopropyl)phenyl)pyrrolidine-2-one hydrochloride (250 mg, 0.66 mmol) in DCE (2 mL), DIPEA (0.35 mL, 2.0 mmol) and phenyl (2-fluoro-4-(trifluoromethyl)phenyl) carbamate (200 mg, 0.66 mmol) were added while stirring at room temperature, and the mixture was heated at 50°C for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by reverse-phase chromatography followed by chiral HPLC to obtain (R)-1-(1-(2,3-difluoro-4-(1-((methylsulfonylmethyl)cyclopropyl)phenyl)-2-oxopyrrolidine-3-yl)-3-(2-fluoro-4-(trifluoromethyl)phenyl)urea (67 mg, 0.12 mmol, yield 19%) as an off-white solid. MS(ESI) m / z: 550.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ = 8.99 (s, 1H), 8.39 (t, J = 8.4 Hz, 1H), 7.64 (dd, J = 11.4, 2.0 Hz, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.41 (d, J = 7.3 Hz, 1H), 7.33 - 7.18 (m, 2H), 4.61 - 4.48 (m, 1H), 3.84 - 3.81 (m, 1H), 3.73 - 3.64 (m, 1H), 3.47 (s, 2H), 2.87 (s, 3H), 2.61 - 2.54 (m, 1H), 2.14 - 1.98 (m, 1H), 1.20 - 1.13 (m, 2H), 1.07 - 0.97 (m, 2H).

[0066] The following examples listed in Table 2 were manufactured using the same procedure as those shown in Examples 1 and 2 above. Table 2 [Table 5] Table 6 Table 7 Table 8 Table 9 Table 10 Table 11 Table 12 Table 13 Table 14 Table 15 Table 16 Table 17 Table 18 Table 19 Table 20

[0067] Those skilled in the art will see that this disclosure is not limited to the exemplary embodiments described above and can be implemented in other specific forms without departing from its essential features. Therefore, these embodiments should be considered in all respects to be exemplary and not restrictive, and refer to the appended claims rather than the embodiments described above. Accordingly, all modifications within the meaning and equivalents of the claims are intended to be incorporated within the claims.

Claims

1. Formula I: 【Chemistry 1】 I [In the formula, * is an asymmetric carbon atom; Ring A is C 6 It is an aryl or six-membered heteroaryl; Ring B is C 6 It is an aryl or six-membered heteroaryl; R 1 is a halo, alkyl, or haloalkyl; R 2 is a halo or haloalkyl; R 3 is alkyl substituted with 1 to 3 R 4 groups, or cycloalkyl substituted with (R 5 )(R 6 )NCO groups, or C 4 alkyl substituted with 1 to 3 R 1-4 groups; R 4 (R) 5 )(R 6 )N, (alkyl) 2 (O)P, (alkoxy) 2 (O)P, (alkoxy)(alkyl)(O)P, alkylSO 2 , or cycloalkyl SO 2 And; R 5 These are hydrogen, alkyl, alkyl CO, or alkyl SO 2 And; R 6 is hydrogen or alkyl; or NR 5 R 6 These are combined and substituted with 0 to 3 substituents selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, and selected from oxo, hydroxy, fluoro, alkyl, haloalkyl, alkoxy, and fluoroalkoxy; R 7 [These are hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl.] The compound indicated by, or a pharmaceutically acceptable salt thereof.

2. Formula II: 【Chemistry 2】 II [In the formula, R 1 is a halo or haloalkyl; R 2 It is a halo; R 4 (R) 5 )(R 6 )N, (alkyl) 2 (O)P, alkylSO 2 , or cycloalkyl SO 2 And; R 5 These are hydrogen, alkyl, alkyl CO, or alkyl SO 2 And; R 6 is hydrogen or alkyl; or NR 5 R 6 [These are combined and selected from azetidinil, pyrrolidinil, piperidinil, piperazinil, and morpholinil, and substituted with 0 to 1 oxo.] The compound according to claim 1, as shown in [the provided text], or a pharmaceutically acceptable salt thereof.

3. Formula III: 【Transformation 3】 III [In the formula, R 1 is Cl or CF 3 And; R 2 is F; R 4 is hydroxy, alkyl, (Me) 2 (O)P, or (Et) 2 (O)P] The compound according to claim 2, as shown in [the provided text], or a pharmaceutically acceptable salt thereof.

4. Formula IV: 【Chemistry 4】 IV [In the formula, R 1 is Cl or CF 3 And; R 2 is F; R 4 (R) 5 )(R 6 )N, (Me) 2 (O)P, (Et) 2 (O)P, alkylSO 2 , or cycloalkyl SO 2 And; R 5 These are hydrogen, alkyl, alkyl CO, or alkyl SO 2 And; R 6 is hydrogen or alkyl; or NR 5 R 6 [These molecules are combined and substituted with 0 to 3 substituents selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, and selected from oxo, hydroxy, fluoro, alkyl, haloalkyl, alkoxy, and haloalkoxy.] The compound according to claim 2, as shown in [the provided text], or a pharmaceutically acceptable salt thereof.

5. Formula V: 【Transformation 5】 V [In the formula, R 1 is Cl or CF 3 And; R 2 is F; R 4 is hydroxy, (Me) 2 (O)P, or (Et) 2 (O)P] The compound according to claim 2, as shown in [the provided text], or a pharmaceutically acceptable salt thereof.

6. Formula VI: 【Transformation 6】 VI [In the formula, R 1 is Cl or CF 3 And; R 2 is F; R 4 is hydroxy, (Me) 2 (O)P, or (Et) 2 (O)P] The compound according to claim 2, as shown in [the provided text], or a pharmaceutically acceptable salt thereof.

7. Formula VII: 【Transformation 7】 VII [In the formula, R 1 is Cl or CF 3 And; R 2 is F; R 4 is hydroxy, (Me) 2 (O)P, or (Et) 2 (O)P] The compound according to claim 1, as shown in [the provided text], or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

9. A compound according to any one of claims 1 to 7 or a pharmaceutical composition according to claim 8, for use in treatment.

10. A method for treating heart disease, comprising administering a therapeutically effective amount of the pharmaceutical composition according to claim 8 to a patient in need thereof.

11. The method according to claim 10, wherein the cardiac disease is selected from the group consisting of angina pectoris, unstable angina pectoris, myocardial infarction, heart failure, acute coronary artery disease, acute heart failure, chronic heart failure, and iatrogenic injury of the heart.

12. Heart failure can be classified into congestive heart failure, systolic heart failure, diastolic heart failure, and heart failure with reduced ejection fraction (HF). R EF), preserved ejection fraction heart failure (HF) P The method according to claim 11, selected from the group consisting of EF, acute heart failure, ischemic and non-ischemic chronic heart failure.

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