Carbocyclic phenyl pyrrolidone urea FPR2 agonists

Abstract

The present disclosure relates to compounds of formula (I) as formyl peptide 2 (FPR2) receptor agonists and / or formyl peptide 1 (FPR1) receptor agonists. The present disclosure also provides compositions and methods of using the compounds, for example, for the treatment of atherosclerosis, heart failure, and related diseases.

Description

[0001] Cross-references to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 496747, filed April 18, 2023, the disclosure of which is incorporated herein by reference in its entirety. Background Technology

[0003] This invention relates to novel carbocyclic phenylpyrrolidone compounds as formyl peptide 2 (FPR2) receptor agonists, compositions containing these compounds, and methods of using these compounds, for example, for treating atherosclerosis, heart failure, chronic obstructive pulmonary disease (COPD), and related diseases.

[0004] Formyl peptide receptor 2 (FPR2) belongs to the group of seven-span membrane domain G protein-coupled receptors, which are primarily expressed by mammalian phagocytic leukocytes and are known to be important in host defense and inflammation. FPR2 shares significant sequence homology with FPR1 and FPR3. These receptors collectively bind a large and structurally diverse group of agonists, including N-formyl peptides and nonformyl peptides that act as chemoretin and activate phagocytic cells. The endogenous anti-inflammatory peptide annexin A1 and its N-terminal fragment also bind human FPR1 and FPR2. Importantly, the anti-inflammatory arachidonic acid arachidonic acid A4, belonging to a newly discovered class of small pro-resolution mediators (SPMs), has been identified as a specific agonist of FPR2 (Ye RD., et al., Pharmacol. Rev., 2009, 61, 119-61).

[0005] Endogenous FPR2 decay ligands (such as lipoxygenin A4 and annexin A1) bind to receptors, triggering a series of cytoplasmic cascade reactions, such as Gi coupling and Ca2+ coupling. 2+Lipoxobin A4 activates FPR2, altering the action of peptide agonists such as serum amyloid A (SAA) and acting as a substitute for phosphorylation pathways depending on cell type. Lipoxobin regulates components of the innate and adaptive immune systems, including neutrophils, macrophages, T cells, and B cells. In neutrophils, lipoxobin regulates motility, cytotoxicity, and lifespan. In macrophages, lipoxobin inhibits apoptosis and enhances cytotoxicity. In most inflammatory cells, lipoxobin also downregulates the expression of several pro-inflammatory cytokines, such as IL-6, IL-1β, and IL-8, and upregulates the expression of the anti-inflammatory cytokine IL-10 (Chandrasekharan JA, Sharma-Walia N, J. Inflamm. Res., 2015, 8, 181-92). The primary role of lipoxobin in neutrophils and macrophages is to terminate inflammation and induce inflammatory resolution. The latter is primarily responsible for enhancing the healing of antifibrotic wounds and restoring injured tissues to homeostasis (Romano M. et al., Eur. J. Pharmacol., 2015, 5, 49-63).

[0006] Chronic inflammation is part of the pathogenesis of many diseases, and stimulation of the resolution pathway with FPR2 agonists can have protective and reparative effects. Ischemia-reperfusion (I / R) injury is a common feature of several diseases associated with high morbidity and mortality, such as myocardial infarction and stroke. Healing of non-productive wounds associated with cardiomyocyte death and pathological remodeling induced by I / R injury leads to scarring, fibrosis, and progressive loss of cardiac function. It has been proposed that FPR2 modulation can enhance myocardial wound healing after injury and reduce adverse myocardial remodeling (Kain V. et al., J. Mol. Cell. Cardiol., 2015, 84, 24-35). Furthermore, in the central nervous system, FPR2 extinction agonists may be useful therapeutic agents for treating a variety of clinical I / R conditions, including stroke (Gavins FN., Trends Pharmacol. Sci., 2010, 31, 266-76) and I / R-induced spinal cord injury (Liu ZQ. et al., Int. J. Clin. Exp. Med., 2015, 8, 12826-33).

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

[0008] The present invention includes compounds of formula I as formyl peptide 2 (FPR2) receptor agonists and / or formyl peptide 1 (FPR1) receptor agonists, compositions comprising these compounds, and methods of using these compounds for example to treat atherosclerosis, heart failure, chronic obstructive pulmonary disease (COPD), and related diseases.

[0009] One aspect of the present invention is a compound of formula I.

[0010]

[0011] I

[0012] in:

[0013] * It consists of asymmetric carbon atoms;

[0014] Ring A is a C6 aryl or a 6-membered heteroaryl group;

[0015] Ring B is a C6 aryl or a 6-membered heteroaryl;

[0016] R 1 It is a halogenated group, alkyl group, or haloalkyl group;

[0017] R 2 It is a halogenated or haloalkyl group;

[0018] R3 It is by 1-3 Rs 4 Replacement C 3-5 Alkyl or (R) 5 (R) 6 )NCO-substituted cycloalkyl groups or those with 1-3 R groups 4 Replacement C 1-4 alkyl;

[0019] R 4 It is a halogenated group, hydroxyl group, cyano group, alkyl group, alkoxy group, (R 5 (R) 6 )N, (alkyl)2(O)P, (alkoxy)2(O)P, (alkoxy)(alkyl)(O)P, alkylSO2 or cycloalkylSO2;

[0020] R 5 It is hydrogen, alkyl, alkyl CO or alkyl SO2;

[0021] R 6 It is hydrogen or alkyl;

[0022] Or NR 5 R 6 Together they are selected from aziridine, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, and are substituted by 0 to 3 substituents selected from the following: oxo, hydroxy, fluorine, alkyl, haloalkyl, alkoxy and haloalkoxy;

[0023] R 7 It is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl;

[0024] Or its pharmaceutically acceptable salt.

[0025] Another aspect of the present invention is a compound of formula II.

[0026]

[0027] II

[0028] in:

[0029] R 1 It is a halogenated or haloalkyl group;

[0030] R 2 It is a halogenated group;

[0031] R 4 It is a halogenated group, hydroxyl group, cyano group, alkyl group, alkoxy group, (R 5 (R) 6 )N, (alkyl)2(O)P, alkyl SO2 or cycloalkyl SO2;

[0032] R 5 It is hydrogen, alkyl, alkyl CO or alkyl SO2;

[0033] R 6 It is hydrogen or alkyl;

[0034] Or NR 5 R 6 They are selected from nitrogen-containing heterocyclic butyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl groups, and are substituted with 0-1 oxo groups;

[0035] Or its pharmaceutically acceptable salt.

[0036] Another aspect of the present invention is a compound of formula III.

[0037]

[0038] III

[0039] in:

[0040] R 1 It is Cl or CF3;

[0041] R 2 It is F;

[0042] R 4 It is hydroxyl, alkyl, (Me)2(O)P or (Et)2(O)P;

[0043] Or its pharmaceutically acceptable salt.

[0044] Another aspect of the present invention is a compound of formula IV.

[0045]

[0046] IV

[0047] in:

[0048] R 1 It is Cl or CF3;

[0049] R 2 It is F;

[0050] R 4 It is hydroxyl, cyano, alkyl, alkoxy, (R 5 (R) 6 (N), (Me)2(O)P, (Et)2(O)P, alkyl SO2 or cycloalkyl SO2;

[0051] R 5 It is hydrogen, alkyl, alkyl CO or alkyl SO2;

[0052] R 6 It is hydrogen or alkyl;

[0053] Or NR5 R 6 Together they are selected from aziridine, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, and are substituted by 0 to 3 substituents selected from the following: oxo, hydroxy, fluorine, alkyl, haloalkyl, alkoxy and fluoroalkoxy;

[0054] Or its pharmaceutically acceptable salt.

[0055] Another aspect of the present invention is a compound of formula V.

[0056]

[0057] V

[0058] in:

[0059] R 1 It is Cl or CF3;

[0060] R 2 It is F;

[0061] R 4 It is a hydroxyl group, (Me)2(O)P, or (Et)2(O)P;

[0062] Or its pharmaceutically acceptable salt.

[0063] Another aspect of the present invention is a compound of formula VI.

[0064]

[0065] VI

[0066] in:

[0067] R 1 It is Cl or CF3;

[0068] R 2 It is F;

[0069] R 4 It is a hydroxyl group, (Me)2(O)P, or (Et)2(O)P;

[0070] Or its pharmaceutically acceptable salt.

[0071] Another aspect of the present invention is a compound of formula VII.

[0072]

[0073] VII

[0074] in:

[0075] R 1 It is Cl or CF3;

[0076] R 2 It is F;

[0077] R 4 It is a hydroxyl group, (Me)2(O)P, or (Et)2(O)P;

[0078] Or its pharmaceutically acceptable salt.

[0079] For compounds of formulas I-VII, variable substituents (including R) 1 R 2 R 3 R 4 R 5 R 6 and R 7 The scope of any example of ) can be used independently of the scope of any other example of variable substituents. Therefore, the invention includes combinations of different aspects.

[0080] Unless otherwise stated, these terms have the following meanings: "alkyl" means a straight-chain or branched alkyl group consisting of 1 to 6 carbon atoms. "alkenyl" means a straight-chain or branched alkyl group consisting of 2 to 6 carbon atoms having at least one double bond. "alkynyl" means a straight-chain or branched alkyl group consisting of 2 to 6 carbon atoms having at least one triple bond. "cycloalkyl" means a monocyclic ring system consisting of 3 to 7 carbon atoms. Terms with a hydrocarbon moiety (e.g., alkoxy) include straight-chain and branched isomers of the hydrocarbon moiety. "Halogenated" includes fluorine, chlorine, bromine, and iodine. "Halogenated alkyl" and "halogenated alkoxy" include all halogenated isomers from monohalogenated to perhalogenated. "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 carbon ring. Representative examples of aryl groups include, but are not limited to, phenyl, indenyl, indanyl, naphthyl, and tetrahydronaphthyl. "Heteroaryl" refers to a 5- to 7-membered monocyclic aromatic ring system or an 8- to 11-membered bicyclic aromatic ring system having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. If the bonding attachment site is not specified, the bonding can be attached at any suitable location as understood by those skilled in the art. Combinations of substituents and bonding patterns are only those combinations that produce stable compounds as understood by those skilled in the art. Terms enclosed in parentheses and multiple parentheses are intended to clarify the bonding relationship to those skilled in the art. For example, terms such as ((R)alkyl) indicate that the alkyl substituent is further substituted by the substituent R.

[0081] This invention includes all pharmaceutically acceptable salt forms of the compounds. Pharmaceutically acceptable salts are those in which the counterions do not significantly promote the physiological activity or toxicity of the compounds and thus act as pharmacologically equivalents. These salts can be prepared using commercially available reagents according to commonly used organic techniques. Some anionic salt forms include acetates, stearates, benzenesulfonates, bromides, chlorides, citrates, fumarates, glucurons, hydrobroms, hydrochlorides, hydroiodates, iodides, lactates, maleates, methanesulfonates, nitrates, dihydroxynaphthyl salts, phosphates, succinates, sulfates, tartrates, toluenesulfonates, and xinofoate. Some cationic salt forms include ammonium, aluminum, benzathine, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium, tromethamine, and zinc.

[0082] Some of the compounds of this invention exist in stereoisomeric forms. This invention includes all stereoisomers of the said compounds, including enantiomers and diastereomers. Methods for preparing and isolating stereoisomers are known in the art. This invention includes all tautomers of the said compounds. This invention includes both rotational and isomers.

[0083] This invention aims to include all isotopes of atoms appearing in the said compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and not limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include... 13 C and 14 C. The isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described herein, using a suitable isotopically labeled reagent instead of the originally employed unlabeled reagent. Such compounds can have many potential uses, such as serving as standards and reagents in determining biological activity. In the case of stable isotopes, such compounds can have the potential to advantageously alter biological, pharmacological, or pharmacokinetic properties.

[0084] Biological methods

[0085] N-formyl peptide receptors (FPRs) belong to the chemotactic receptor family and promote leukocyte responses in inflammatory processes. FPRs belong to the seven-transmembrane G protein-coupled receptor superfamily and are associated with inhibitory G proteins (Gi). Three family members (FPR1, FPR2, and FPR3) have been identified in humans, primarily distributed in bone marrow cells, and have also been reported in multiple organs and tissues. Upon agonist binding, FPRs activate various physiological pathways, such as intracellular signal transduction and calcium channel blockers. 2+Mobilization and transcription. The family interacts with a diverse set of ligands, including proteins, peptides, and fatty acid metabolites that activate pro-inflammatory and pro-remission downstream responses.

[0086] The FPR2 receptor binds to multiple ligands to elicit both inflammatory and anti-inflammatory responses. Inflammatory mediators released by FPR2 are promoted by endogenous protein ligands such as serum amyloid A (SAA) and amyloid β (1-42), while resolution of inflammation is induced by ligands including the arachidonic acid metabolites lipoxygenin A4 (LXA4) and Epi-lipoxygenin (ATL), and the docosahexaenoic acid metabolite regressor D1 (RvD1). Regressor fatty acid metabolites mediate the suppression and resolution of inflammation via the FPR2 receptor by stimulating macrophage phagocytosis of apoptotic neutrophils. Removal of apoptotic neutrophils induces the release of cytokines that activate the regressor pathway.

[0087] The FPR1 receptor was initially isolated as a high-affinity receptor for peptides containing N-formylmethionine, such as N-formylmethionine-leucyl-phenylalanine (FMLP). This protein guides mammalian phagocytes and blood leukocytes to sites of invading pathogens or inflamed tissue and activates these cells to kill pathogens or clear cellular debris.

[0088] FPR2 and FPR1 cyclic adenosine monophosphate (cAMP) assays were performed. A mixture of tuftin (final 5 µM for FPR2 or final 10 µM for FPR1) and IBMX (final 200 µM) was added to the test compound (final 1%) pre-treated in DMSO to spot at final concentrations ranging from 1.7 nM to 100 μM in 384-well Proxiplate (Perkin-Elmer). Chinese hamster ovary cells (CHO) overexpressing the human FPR1 or human FPR2 receptor were cultured in F-12 (Ham's) medium supplemented with 10% qualified FBS, 250 μg / ml bleomycin, and 300 μg / ml hygromycin (Life Technologies). The reaction was initiated by adding 2,000 human FPR2 cells / well or 4,000 human FPR1 cells / well to Durbeco PBS (with calcium and magnesium) (Life Technologies) supplemented with 0.1% BSA (Perkin-Elmer). The reaction mixture was incubated at room temperature for 30 min. Intracellular cAMP levels were determined using the HTRF HiRange cAMP assay kit (Cisbio) according to the manufacturer's instructions. Solutions of anti-cAMP conjugated with the cryptoid and d2-fluorophore-labeled cAMP were prepared separately in the provided lysis buffer. After the reaction, cells were lysed with equal volumes of d2-cAMP and anti-cAMP solutions. After incubation at room temperature for 1 h, time-resolved fluorescence intensity was measured using an Envision (Perkin-Elmer) microscope at 400 nm excitation and dual emission at 590 nm and 665 nm. Calibration curves were constructed using external cAMP standards with concentrations ranging from 1 μM to 0.1 pM, plotting the ratio of fluorescence intensity emitted from 665 nm to that emitted from 590 nm against cAMP concentration. The potency and activity of the compound in inhibiting cAMP production were then determined by fitting a four-parameter logistic equation to the cAMP level versus compound concentration graph.

[0089] The examples disclosed below were tested in the above-described FPR2 and FPR1 cAMP assays and were found to have FPR2 and / or FPR1 agonist activity. Table 1 below lists the EC values ​​in the FPR2 and FPR1 cAMP assays measured for the following examples. 50 value.

[0090] Table 1

[0091]

[0092]

[0093] Pharmaceutical Compositions and Methods of Use

[0094] The compounds of the present invention can be administered to patients to treat a variety of conditions and disorders, including atherosclerosis, heart failure, lung diseases including asthma, COPD, and cystic fibrosis, neuroinflammatory diseases including multiple sclerosis, Alzheimer's disease, stroke, and chronic inflammatory diseases such as inflammatory bowel disease, rheumatoid arthritis, psoriasis, sepsis, lupus, and renal fibrosis.

[0095] Another aspect of the present invention is a pharmaceutical composition comprising a combination of a therapeutically effective amount of a compound of formula I and a drug carrier.

[0096] Another aspect of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I combined with at least one other therapeutic agent and a pharmaceutical carrier.

[0097] Unless otherwise stated, the following terms have the meanings described. The term "patient" means a subject deemed suitable for therapy as determined by a practitioner of the art, and includes all suitable mammalian species, including humans, that can benefit from treatment with FPR2 and / or FPR1 agonists as understood by a practitioner of the art. Common risk factors include, but are not limited to, age, sex, weight, family history, sleep apnea, alcohol or smoking, lack of exercise-induced arrhythmias, or signs of insulin resistance such as acanthosis nigricans, hypertension, dyslipidemia, or polycystic ovary syndrome (PCOS). "Treatment" includes treatment of a patient as understood by a practitioner of the art, and includes suppressing a disease-state, i.e., preventing its development; alleviating a disease-state, i.e., causing the remission of a disease-state; and / or preventing the occurrence of a disease-state in the patient. "Therapeutic effective amount" is intended to include an amount of an effective or beneficial compound as understood by a practitioner of the art.

[0098] "Pharmaceutical composition" means a composition comprising a combination of the compounds of the present invention with at least one other pharmaceutically acceptable carrier. "Pharmaceutically acceptable carrier" refers to a medium for delivering a bioactive agent as understood by those skilled in the art, such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, aromatics, antibacterial agents, antifungal agents, lubricants, and dispensing agents. Pharmaceutically acceptable carriers are formulated based on a number of factors known to those skilled in the art. These include, but are not limited to, the type and nature of the formulated active agent; the subject to be administered the composition containing the pharmaceutical agent; the intended route of administration of the composition; and the target therapeutic indication. Descriptions of suitable pharmaceutically acceptable carriers and the factors involved in their selection are known in the art, for example, in Allen, LV, Jr. et al., Remington: The Science and Practice of Pharmacy (Vol. 2), 22nd ed., Pharmaceutical Press (2012).

[0099] Solid compositions are typically formulated in dosage units, and compositions providing an active ingredient / dosage from about 1 to 1000 mg are preferred. Some examples of dosages are 1 mg, 10 mg, 100 mg, 250 mg, 500 mg, and 1000 mg.

[0100] Liquid compositions are typically sold in dose units ranging from 1 to 100 mg / mL. Some examples of doses are 1 mg / mL, 10 mg / mL, 25 mg / mL, 50 mg / mL, and 100 mg / mL.

[0101] Another aspect of the present invention is a method for treating heart disease, the method comprising administering a therapeutically effective amount of a compound of formula I to a patient.

[0102] Another aspect of the present invention is a method for treating heart disease, wherein the heart disease is selected from angina pectoris, unstable angina pectoris, myocardial infarction, heart failure, acute coronary artery disease, acute heart failure, chronic heart failure, and iatrogenic cardiac damage.

[0103] Another aspect of the present invention is a method for treating heart disease, wherein the treatment is performed after a myocardial infarction.

[0104] Another aspect of the present invention is the method relating the aforementioned heart disease to chronic heart failure.

[0105] Another aspect of the invention is a method for improving myocardial wound healing, wherein the treatment is described.

[0106] Another aspect of the invention is a method for reducing myocardial fibrosis, wherein the treatment is described.

[0107] This invention covers all conventional methods of administration; oral and parenteral administration are preferred. Generally, the dosing regimen will be similar to that of other cardiovascular agents used clinically. The dosage regimen and administration mode of the compounds used in this invention will depend on factors known to those skilled in the art, including the recipient's age, sex, health, medical condition, and weight; the nature and severity of symptoms; the type of concurrent treatment; the frequency of treatment; the route of administration; and the desired effect. Typically, the daily dose will be 0.1–100 mg / kg body weight daily. Generally, oral administration requires a larger amount of the compound, while parenteral administration requires a smaller amount. However, the specific dosing regimen will be determined by the physician using reasonable medical judgment.

[0108] Another aspect of the present invention is a method for treating heart disease, the method comprising administering a therapeutically effective amount of a compound of formula I in combination with at least one other therapeutic agent to a patient.

[0109] The compounds of the present invention can be used in combination with other suitable therapeutic agents for treating the aforementioned diseases or disorders, including: anti-atherosclerotic agents, anti-dyslipidemia agents, anti-diabetic agents, anti-hyperglycemic agents, anti-hyperinsulinemia agents, antithrombotic agents, anti-retinopathy agents, anti-neuropathy agents, anti-nephropathy agents, anti-ischemic agents, antihypertensive agents, anti-obesity agents, anti-hyperlipidemia agents, anti-hypertriglyceridemia agents, anti-hypercholesterol agents, anti-restenosis agents, anti-pancreatic agents, lipid-lowering agents, anorexia agents, memory-enhancing agents, anti-dementia agents, cognitive-promoting agents, appetite suppressants, agents for treating heart failure, agents for treating peripheral artery disease, agents for treating malignant tumors, and anti-inflammatory agents.

[0110] The compounds of the present invention can be used with one or more, preferably one to three, heart failure agents selected from loop diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), angiotensin receptor-neprilysin inhibitors (ARNIs), beta-blockers, mineralocorticoid receptor antagonists, nitroglycerin donors, RXFP1 agonists, APJ agonists, and cardiotonic agents. These agents include, but are not limited to, furosemide, bumetanide, torasemide, sacubitrial-valsartan, thiazide diuretics, captopril, enalapril, lisinopril, carvedilol, metoprolol, bisoprolol, serelaxin, spironolactone, eplerenone, ivabradine, candesartan, eprosartan, irbestarain, losartan, olmesartan, telmisartan, and valsartan.

[0111] The compounds of the present invention can also be used as standard or reference compounds in tests or assays involving FPR2, for example, as quality standards or controls. Such compounds can be provided in commercial kits, for example, for use in pharmaceutical studies involving FPR2 activity. For example, the compounds of the present invention can be used as references in assays to compare their known activities with those of compounds having unknown activities. This ensures that the experimenter performs the assay correctly and provides a basis for comparison, especially if the test compound is a derivative of the reference compound. When developing new assays or protocols, the compounds according to the present invention can be used to test their effectiveness. The compounds of the present invention can also be used in diagnostic assays involving FPR2.

[0112] Chemical methods

[0113] The abbreviations used in this document are defined as follows: "1x" means once, "2x" means twice, "3x" means three times, "ºC" means degrees Celsius, "aq" means aqueous, "Col" means column, "eq" means one or more equivalents, "g" means gram, "mg" means milligram, "L" means liter, "mL" means milliliter, "μL" means microliter, "N" means equivalent concentration, "M" means mole, "nM" means nanomolar, "mol" means mole, "mmol" means millimole, "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 concentrated, "aq" means "aqueous", "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" means... "Spec" indicates mass spectrometry, "ESI" indicates electrospray ionization mass spectrometry, "HR" indicates high resolution, "HRMS" indicates high resolution mass spectrometry, "LCMS" indicates liquid chromatography-mass spectrometry, "HPLC" indicates high performance liquid chromatography, "RP HPLC" indicates reversed-phase HPLC, "TLC" or "tlc" indicates thin-layer chromatography, "NMR" indicates nuclear magnetic resonance spectroscopy, and "nOe" indicates nuclear overhausener effect spectroscopy. 1 "H" represents proton, "δ" represents delta, "s" represents singlet, "d" represents doublet, "t" represents triplet, "q" represents quartet, "m" represents multiplet, "br" represents broad peak, "Hz" represents Hertz, and "α", "β", "R", "S", "E" and "Z" are stereochemical names familiar to those skilled in the art.

[0114]

[0115] The compounds of this invention can be prepared by a variety of methods known in the art, including those described in the following embodiments and the detailed embodiments section. The structure and variable numbers shown in the synthetic embodiments differ from and should not be confused with those in the claims or the remainder of the specification. The variables in the embodiments are intended only to illustrate how some compounds of this invention can be prepared.

[0116] It will also be recognized that another major consideration in the planning of any synthetic route in this field is the prudent selection of protecting groups for protecting the reactive functional groups present in the compounds described in this invention. An authoritative report describing the many alternatives to trained practitioners is Greene, TW et al., Protecting Groups in Organic Synthesis, 4th ed., Wiley (2007).

[0117] Compounds having general formula I, wherein ring A and ring B are substituted phenyl and heteroaryl groups, respectively, and can be prepared by one or more of the following synthetic schemes.

[0118]

[0119] (I)

[0120] The 1-arylpyrrolidone compounds of the present invention, wherein ring A is a substituted phenyl and ring B is a substituted phenyl or heteroaryl group, can be prepared by the general route shown in Scheme 1, starting from a suitably substituted aryl halide such as compound 1a. Palladium or copper-catalyzed coupling of 1a with a suitably protected substituted 3-aminopyrrolidone-2-one, wherein PG is a protecting group such as Boc or Cbz. Methods for this conversion include variations of ketone-catalyzed amidation by Ullmann, Goldberg, and Buchwald or Pd-catalyzed amidation (depending on the nature of ring B, using methods known in the art for these types of coupling) (see, for example, Yin and Buchwald Organic Lett. 2000, 2 , 1101; Klapers et al. JACS, 2001, 123 , 7727; Klapars et al. JACS, 2002, 124, 7421; Yin and Buchwald JACS. 2002, 124, 6043; Kiyomor, Madoux and Buchwald, Tet. Lett., 1999, 40 , 2657; Surry and Buchwald Angew. Chem. Int. ed., 2008, 47, 6338; Surry and Buchwald ChemSci. 2011; 2(1): 27–50; Shaughnessy, Ciganek and DeVasher, Organic Reactions.2014, 85:1:1–668). Urea 1d can be obtained by removing the protecting group from 1b and then condensing the resulting free amine with a suitably substituted aryl isocyanate 1e or phenyl carbamate 1f. Suitable isocyanates or phenyl carbamates are commercially available or readily obtained from the corresponding arylamines by methods known to those skilled in the art. Alternatively, urea 1d can be obtained by treating the deprotected 3-aminopyrrolidone-2-one intermediate with 4-nitrophenyl chloroformate to form a carbamate, followed by condensation with a suitably substituted arylamine 1g. Those skilled in the art will also recognize that further compounds of the present invention, wherein rings A and B are heteroaryl rings (such as pyridine, pyrimidine, thiazole, etc.), can be prepared by substituting 1a and the heteroaryl amine with a suitable heteroaryl iodide or heteroaryl bromide using the methods outlined in Scheme 1. Those skilled in the art can synthesize other aryl bromides substituted with heteroatom-containing rings and use them in Scheme 1 to obtain other compounds of the present invention. Substitution on R at intermediates 1a, 1b, 1c, or 1d can be manipulated using synthetic methods known to those skilled in the art. Racemic compounds can be prepared using chiral HPLC or SFC to provide a single enantiomer.

[0121] Option 1

[0122]

[0123] Other features of the invention will become clear in the following description of exemplary embodiments given for the purpose of illustrating the invention and not intended to limit it.

[0124] Unless otherwise specified, the following methods are used in the exemplary embodiments. Purification of intermediates and final products is performed by normal-phase or reversed-phase chromatography. Unless otherwise instructed, normal-phase chromatography is performed using a pre-packed SiO2 column with gradient elution of hexane and ethyl acetate or DCM and MeOH. Reversed-phase preparative HPLC was performed using a C18 column with UV 220 nm or preparative LCMS detection. Elution was performed using a gradient of solvent A (90% water, 10% MeOH, 0.1% TFA) and solvent B (10% water, 90% MeOH, 0.1% TFA), or a gradient of solvent A (95% water, 5% Acn, 0.1% TFA) and solvent B (5% water, 95% Acn, 0.1% TFA), or a gradient of solvent A (95% water, 2% Acn, 0.1% HCOOH) and solvent B (98% Acn, 2% water, 0.1% HCOOH), or a gradient of solvent A (95% water, 5% Acn, 10 mM NH4OAc) and solvent B (98% Acn, 2% water, 10 mM NH4OAc), or a gradient of solvent A (98% water, 2% Acn, 10 mM NH4OAc). Elution was performed using a gradient of Acn (0.1% NH4OH) and solvent B (98% Acn, 2% water, 0.1% NH4OH).

[0125] The LC / MS method used in the characterization of the examples was performed on a Waters Acquity system coupled to a Waters MICROMASS® ZQ mass spectrometer. The analysis was conducted using reversed-phase HPLC / MS.

[0126] Method A: A linear gradient from 0 to 100% B over 3 minutes, with a hold time of 0.75 minutes at 100% B;

[0127] UV visualization at 220 nm

[0128] Column: Waters BEH C18 2.1 x 50 mm

[0129] Flow rate: 1.0 mL / min

[0130] Solvent A: 0.1% TFA, 95% water, 5% Acn

[0131] Solvent B: 0.1% TFA, 5% water, 95% Acn

[0132] Method B: A linear gradient from 0 to 100% B over 3 minutes, with a hold time of 0.75 minutes at 100% B;

[0133] UV visualization at 220 nm

[0134] Column: Waters BEH C18 2.1 x 50 mm

[0135] Flow rate: 1.0 mL / min

[0136] Solvent A: 10 mM ammonium acetate, 95% water, 5% Acn

[0137] Solvent B: 10 mM ammonium acetate, 5% water, 95% Acn

[0138] Analytical HPLC: The method used in the characterization of the examples

[0139] Product analysis was performed using reversed-phase analytical HPLC on a Shimadzu analytical HPLC system running Discovery VP software. RT = retention time.

[0140] Method C: Ascentis Express C18, 2.1 x 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: 50ºC; Gradient: 0-100% B for 3 min, then hold at 100% B for 1 min; Flow rate: 1.1 mL / min.

[0141] Method D: Ascentis Express C18, 2.1 x 50 mm, 2.7 μm particles; Solvent A: 95% water, 5% acetonitrile (containing 10 mM ammonium acetate); Solvent B: 95% acetonitrile, 5% water (containing 10 mM ammonium acetate); Temperature: 50ºC; Gradient: 0-100% B for 3 min, then hold at 100% B for 1 min; Flow rate: 1.1 mL / min.

[0142] Method E: Kinetex BIPHENYL (4.6 x 100) mm, 2.6 μm particles; Solvent A: 95% buffer (0.05% TFA in water), 5% acetonitrile; Solvent B: 95% acetonitrile, 5% buffer (0.05% TFA in water); Temperature: 50ºC; Gradient: 0-100% B for 3 min, then hold at 100% B for 1 min; Flow rate: 1.1 mL / min.

[0143] Method F: Ascentis Express C18, 2.1 x 50 mm, 2.7 μm particles; Solvent A: 95% water, 5% acetonitrile (containing 10 mM ammonium formate); Solvent B: 95% acetonitrile, 5% water (containing 10 mM ammonium formate); Temperature: 50ºC; Gradient: 0-100% B for 3 min, then hold at 100% B for 1 min; Flow rate: 1.1 mL / min.

[0144] SFC and chiral purity methods

[0145] Method A: DAD-1: CHIRALPAK IA (250*4.6) mm, 5 μm; DAD-2: CHIRALPAK IB (250*4.6) mm, 5 μm. Co-solvent: 0.2% ammonia in Acn:MeOH (1:1).

[0146] Method B: DAD-1: CHIRALPAK IC (250*4.6) mm, 5 μm; DAD-2: CHIRALPAK ID (250*4.6) mm, 5 μm. Co-solvent: 0.2% ammonia in Acn:MeOH (1:1).

[0147] Method C: DAD-1: CHIRALPAK IE (250*4.6) mm, 5 μm; DAD-2: CHIRALPAK IF (250*4.6) mm, 5 μm. Co-solvent: 0.2% ammonia in Acn:MeOH (1:1).

[0148] The NMR used in the characterization of the examples was obtained using a Bruker or JEOL® Fourier transform spectrometer operating at the following frequencies. 1 H NMR spectrum: 1 H NMR: 300 MHz (Bruker or JEOL®) or 400 MHz (Bruker or JEOL®) or 500 MHz (Bruker or JEOL®). 13 C NMR: 100 MHz (Bruker or JEOL®). Spectral data are reported in the following format: chemical shifts (multiplicity, coupling constant, and hydrogen number). Chemical shifts at the low field of the tetramethylsilane internal standard are specified in ppm (δ units, tetramethylsilane = 0 ppm) and / or reference solvent peaks, where the solvent peaks are located at... 1 In H NMR spectra, it appears at 2.49 ppm for CD2HSOCD3, 3.30 ppm for CD2HOD, 1.94 ppm for CD3CN, and 7.24 ppm for CHCl3, and... 13In the C NMR spectrum, it appears at 39.7 ppm for CD3SOCD3, 49.0 ppm for CD3OD, and 77.0 ppm for CDCl3. All 13 C NMR spectra are all proton decoupled.

[0149] Intermediate 1: 1-(4-bromo-2,3-difluorophenyl)cyclopropane-1-carboxynitrile

[0150]

[0151] NaH (1.29 g, 32.3 mmol) was added to a stirred solution of 2-(4-bromo-2,3-difluorophenyl)acetonitrile (3.00 g, 12.9 mmol) in THF (30 mL) at 0°C under an argon atmosphere, and the mixture was stirred for 30 min. A mixture of 1,2-dibromoethane (2.67 g, 14.2 mmol) in THF (5 mL) was added to the reaction mixture. The mixture was gradually warmed to room temperature and stirred for 15 h. The reaction mixture was quenched with a saturated ammonium chloride solution (10 mL) and extracted with ethyl acetate (100 mL x 2). The combined organics were washed with brine (50 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give 1-(4-bromo-2,3-difluorophenyl)cyclopropane-1-carboxynitrile (2.9 g, 11 mmol, 87% yield) 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).

[0152] Intermediate 2: 1-(4-bromo-2,3-difluorophenyl)cyclopropane-1-carboxaldehyde

[0153]

[0154] 1.2 M DIBAL-H (8.90 mL, 10.7 mmol) in toluene was added to a stirred solution of 1-(4-bromo-2,3-difluorophenyl)cyclopropane-1-carboxynitrile (2.50 g, 9.69 mmol) in diethyl ether (40 mL) at -10ºC under an argon atmosphere. The reaction mixture was gradually heated to 5ºC over a period of 2 h and quenched with 1 N aqueous HCl solution (50 mL). The biphase layers were extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over MgSO4, and concentrated under reduced pressure to give 1-(4-bromo-2,3-difluorophenyl)cyclopropane-1-carboxaldehyde (2.10 g, 8.04 mmol, 83% yield) as a brown solid. 1 H NMR (400 MHz, CDCl3) δ = 9.00 (d, J = 1.51 Hz, 1H), 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).

[0155] Intermediate 3: (R)-(1-(2,3-difluoro-4-(1-formylcyclopropyl)phenyl)-2-oxopyrrolidone-3-yl)tert-butyl carbamate

[0156]

[0157] At room temperature, 1-(4-bromo-2,3-difluorophenyl)cyclopropane-1-carboxaldehyde (978 mg, 3.75 mmol) and K3PO4 (1.06 g, 4.99 mmol) were added to a stirred solution of (R)-(2-oxopyrrolidone-3-yl)carbamate (500 mg, 2.50 mmol) in 1,4-dioxane (10 mL). The reaction mixture was purged with nitrogen for 5 min, and then N,N'-dimethylethylenediamine (44 mg, 0.50 mmol) and cuprous iodide (I) (48 mg, 0.25 mmol) were added. The reaction mixture was again purged with nitrogen for 3 min and heated at 90ºC for 6 h. The brown reaction mixture was cooled, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether / ethyl acetate) to give (R)-(1-(2,3-difluoro-4-(1-formylcyclopropyl)phenyl)-2-oxopyrrolidine-3-yl)carbamate tert-butyl ester (700 mg, 1.84 mmol, 73.7% yield) 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, 1H), 1.65 - 1.75 (m, 2 H), 1.47 - 1.54 (m, 2 H), 1.34 - 1.44 (m, 9 H).

[0158] Intermediate 4: (R)-(1-(2,3-difluoro-4-(1-(hydroxymethyl)cyclopropyl)phenyl)-2-oxopyrrolidone-3-yl)tert-butyl carbamate

[0159]

[0160] Sodium borohydride (43.8 mg, 1.16 mmol) was added to a stirred solution of (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) under an argon atmosphere at 0°C, and the mixture was stirred for 30 min. The reaction mixture was quenched by adding 1 N HCl aqueous solution (12 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na₂SO₄, and concentrated under reduced pressure to give (R)-(1-(2,3-difluoro-4-(1-(hydroxymethyl)cyclopropyl)phenyl)-2-oxopyrrolidine-3-yl)carbamate tert-butyl ester (350 mg, 0.92 mmol, 87% yield) as a brown solid, which was used for the next step without further purification. MS (ESI) m / z: 327.1 [M+H-isobutylene] + .

[0161] Intermediate 5: (R)-(1-(2,3-difluoro-4-(1-(iodomethyl)cyclopropyl)phenyl)-2-oxopyrrolidone-3-yl)tert-butyl carbamate

[0162]

[0163] Triphenylphosphine (247 mg, 0.941 mmol), imidazole (64 mg, 0.94 mmol), and iodine (240 mg, 0.94 mmol) were added to a stirred solution of (R)-(1-(2,3-difluoro-4-(1-(iodomethyl)cyclopropyl)phenyl)-2-oxopyrrolidine-3-yl)carbamate (300 mg, 0.785 mmol) in DCM (10 mL) at room temperature under an argon atmosphere. The resulting reaction mixture was stirred for 3 h and then concentrated under reduced pressure to give a crude product, which was purified by column chromatography (petroleum ether / ethyl acetate) to give (R)-(1-(2,3-difluoro-4-(1-(iodomethyl)cyclopropyl)phenyl)-2-oxopyrrolidine-3-yl)carbamate (220 mg, 0.45 mmol, 49% yield) as a grayish-white solid. MS (ESI) m / z: 437.1 [M+H-isobutene] + .

[0164] Intermediate 6: (R)-(1-(2,3-difluoro-4-(1-(((methanesulfonyl)methyl)cyclopropyl)phenyl)-2-oxopyrrolidone-3-yl)tert-butyl carbamate

[0165]

[0166] Sodium methanesulfonate (197 mg, 1.93 mmol) was added to a stirred solution of (R)-(1-(2,3-difluoro-4-(1-(iodomethyl)cyclopropyl)phenyl)-2-oxopyrrolidine-3-yl)carbamate (190 mg, 0.39 mmol) in ethanol (8 mL) under an argon atmosphere at room temperature, and the resulting reaction mixture was heated at 90ºC for 15 h. The reaction mixture was cooled and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate) to give (R)-(1-(2,3-difluoro-4-(1-((methanesulfonyl)methyl)cyclopropyl)phenyl)-2-oxopyrrolidine-3-yl)carbamate (125 mg, 0.281 mmol, 72.9% yield) as a brown solid. MS (ESI) m / z: 389.3 [M+H-isobutylene] + .

[0167] Intermediate 7: (R)-3-amino-1-(2,3-difluoro-4-(1-((methanesulfonyl)methyl)cyclopropyl)phenyl)pyrrolidine-2-one hydrochloride

[0168]

[0169] 4 M HCl (4.50 mL, 18.0 mmol) in 1,4-dioxane was added to a stirred solution of (R)-1-(2,3-difluoro-4-(1-((methanesulfonyl)methyl)cyclopropyl)phenyl)-2-oxopyrrolidine-3-yl)carbamate (400 mg, 0.90 mmol) in 1,4-dioxane (2 mL) under an argon atmosphere at room temperature, and the mixture was stirred for 2 h. The solvent was evaporated under reduced pressure to obtain a gel-like solid. This solid was further ground with diethyl ether (10 mL x 2) and dried to give (R)-3-amino-1-(2,3-difluoro-4-(1-((methanesulfonyl)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] + .

[0170] Example 1: (R)-1-(4-chloro-2-fluorophenyl)-3-(1-(2,3-difluoro-4-(1-((methanesulfonyl)methyl)cyclopropyl)phenyl)-2-oxopyrrolidone-3-yl)urea

[0171]

[0172] DIPEA (0.28 mL, 1.6 mmol) and (4-chloro-2-fluorophenyl)carbamate (170 mg, 0.63 mmol) were added to a stirred solution of ((R)-3-amino-1-(2,3-difluoro-4-(1-(((methanesulfonyl)methyl)cyclopropyl)phenyl)pyrrolidine-2-one hydrochloride (200 mg, 0.53 mmol) in DCE (10 mL) at room temperature, and the mixture was heated at 50ºC for 3 h. The reaction mixture was concentrated under reduced pressure to give a crude product, which was purified by reversed-phase chromatography followed by chiral HPLC to give (R)-1-(4-chloro-2-fluorophenyl)-3-(1-(2,3-difluoro-4-(1-(((methanesulfonyl)methyl)cyclopropyl)phenyl)-2-oxopyrrolidine-3-yl)urea (100 mg, 0.19 mmol) as a grayish-white solid. (mmol, 37% yield). MS (ESI) m / z: 516.2 [M+H] + . 1H 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).

[0173] Example 2: (R)-1-(1-(2,3-difluoro-4-(1-((methanesulfonyl)methyl)cyclopropyl)phenyl)-2-oxopyrrolidone-3-yl)-3-(2-fluoro-4-(trifluoromethyl)phenyl)urea

[0174]

[0175] DIPEA (0.35 mL, 2.0 mmol) and (2-fluoro-4-(1-((methanesulfonyl)methyl)cyclopropyl)phenyl)pyrrolidine-2-one hydrochloride (250 mg, 0.66 mmol) were added to a stirred suspension of (R)-3-amino-1-(2,3-difluoro-4-(1-((methanesulfonyl)methyl)cyclopropyl)phenyl)carbamate (200 mg, 0.66 mmol) in a DCE (2 mL) at room temperature and heated at 50ºC for 3 h. The reaction mixture was concentrated under reduced pressure to give a crude product, which was purified by reversed-phase chromatography followed by chiral HPLC to give (R)-1-(1-(2,3-difluoro-4-(1-((methanesulfonyl)methyl)cyclopropyl)phenyl)-2-oxopyrrolidine-3-yl)-3-(2-fluoro-4-(trifluoromethyl)phenyl)urea (67 mg, 0.12 mmol, 19% yield) as a grayish-white solid. MS (ESI) m / z: 550.1 [M+H] + . 1H 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).

[0176] The following embodiments in Table 2 are manufactured using the same procedures as those shown in Embodiments 1 and 2 above.

[0177] Table 2

[0178]

[0179]

[0180]

[0181]

[0182]

[0183]

[0184]

[0185]

[0186]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192] It will be apparent to those skilled in the art that this disclosure is not limited to the foregoing illustrative embodiments, and that it may be embodied in other specific forms without departing from its essential nature. Therefore, it is intended that the embodiments be considered illustrative rather than restrictive in all respects, with reference to the appended claims rather than the foregoing embodiments, and all variations falling within the meaning and scope of the equivalents of the claims are intended to be included therein.

Claims

1. A compound of formula I I in: * It consists of asymmetric carbon atoms; Ring A is a C6 aryl or a 6-membered heteroaryl group; Ring B is a C6 aryl or a 6-membered heteroaryl; R 1 It is a halogenated group, alkyl group, or haloalkyl group; R 2 It is a halogenated or haloalkyl group; R 3 It is by 1-3 Rs 4 Substituted alkyl or (R 5 (R) 6 )NCO-substituted cycloalkyl groups or those with 1-3 R groups 4 Replacement C 1-4 alkyl; R 4 It is a halogenated group, hydroxyl group, cyano group, alkyl group, alkoxy group, (R 5 (R) 6 )N, (alkyl)2(O)P, (alkoxy)2(O)P, (alkoxy)(alkyl)(O)P, alkylSO2 or cycloalkylSO2; R 5 It is hydrogen, alkyl, alkyl CO or alkyl SO2; R 6 It is hydrogen or alkyl; Or NR 5 R 6 Together they are selected from aziridine, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, and are substituted by 0 to 3 substituents selected from the following: oxo, hydroxy, fluorine, alkyl, haloalkyl, alkoxy and fluoroalkoxy; R 7 It is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl; Or its pharmaceutically acceptable salt.

2. The compound according to claim 1, wherein the compound has formula II. II in: R 1 It is a halogenated or haloalkyl group; R 2 It is a halogenated group; R 4 It is a halogenated group, hydroxyl group, cyano group, alkyl group, alkoxy group, (R 5 (R) 6 )N, (alkyl)2(O)P, alkyl SO2 or cycloalkyl SO2; R 5 It is hydrogen, alkyl, alkyl CO or alkyl SO2; R 6 It is hydrogen or alkyl; Or NR 5 R 6 They are selected from nitrogen-containing heterocyclic butyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl groups, and are substituted with 0-1 oxo groups; Or its pharmaceutically acceptable salt.

3. The compound according to claim 2, wherein the compound has formula III III in: R 1 It is Cl or CF3; R 2 It is F; R 4 It is hydroxyl, alkyl, (Me)2(O)P or (Et)2(O)P; Or its pharmaceutically acceptable salt.

4. The compound according to claim 2, wherein the compound has formula IV. IV in: R 1 It is Cl or CF3; R 2 It is F; R 4 It is hydroxyl, cyano, alkyl, alkoxy, (R 5 (R) 6 (N), (Me)2(O)P, (Et)2(O)P, alkyl SO2 or cycloalkyl SO2; R 5 It is hydrogen, alkyl, alkyl CO or alkyl SO2; R 6 It is hydrogen or alkyl; Or NR 5 R 6 Together they are selected from aziridine, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, and are substituted by 0 to 3 substituents selected from the following: oxo, hydroxy, fluorine, alkyl, haloalkyl, alkoxy and haloalkoxy; Or its pharmaceutically acceptable salt.

5. The compound according to claim 2, wherein the compound has formula V V in: R 1 It is Cl or CF3; R 2 It is F; R 4 It is a hydroxyl group, (Me)2(O)P, or (Et)2(O)P; Or its pharmaceutically acceptable salt.

6. The compound according to claim 2, wherein the compound has formula VI VI in: R 1 It is Cl or CF3; R 2 It is F; R 4 It is a hydroxyl group, (Me)2(O)P, or (Et)2(O)P; Or its pharmaceutically acceptable salt.

7. The compound according to claim 1, wherein the compound has formula VII. VII in: R 1 It is Cl or CF3; R 2 It is F; R 4 It is a hydroxyl group, (Me)2(O)P, or (Et)2(O)P; Or its pharmaceutically acceptable salt.

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

9. The compound according to any one of claims 1-7 or the composition according to claim 8, for use in a therapeutic manner.

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

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

12. The method of claim 11, wherein the heart failure is selected from congestive heart failure, systolic heart failure, diastolic heart failure, and heart failure with reduced ejection fraction (HF). R EF), heart failure with preserved ejection fraction (HF) P EF), acute heart failure, and chronic heart failure of ischemic and non-ischemic origin.

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