Pyrrolidinone 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. I

Description

Cross-reference to related applications

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 496,750, filed April 18, 2023, the disclosure of which is incorporated herein by reference in its entirety. Background Technology

[0002] This invention relates to novel pyrrolidone urea compounds as formyl peptide 2 (FPR2) receptor agonists, compositions comprising them, and methods of using them, for example, for treating atherosclerosis, heart failure, chronic obstructive pulmonary disease (COPD), and related diseases.

[0003] Formyl peptide receptor 2 (FPR2) belongs to the group of seven-transmembrane 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 (YeRD., et al., Pharmacol. Rev., 2009, 61, 119-61).

[0004] 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+Lipoxoxin 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. Lipoxoxin regulates components of the innate and adaptive immune systems, including neutrophils, macrophages, T cells, and B cells. In neutrophils, lipoxoxin regulates motility, cytotoxicity, and lifespan. In macrophages, lipoxoxin inhibits apoptosis and enhances cytotoxicity. In most inflammatory cells, lipoxoxin 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 lipoxoxin 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).

[0005] 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, FPR2 extinction agonists in the central nervous system can 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).

[0006] In addition to the beneficial effects of targeting FPR2 with novel remission agonists to treat I / R-induced damage, the therapeutic efficacy of these ligands can also be applied to other diseases. In the cardiovascular system, the FPR2 receptor and its remission agonists have been found to be 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). Summary of the Invention

[0007] This invention provides novel pyrrolidone ureas and analogues thereof that can be used as FPR2 agonists, including their stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates. The compounds of this invention exhibit high selectivity for FPR2 compared to FPR1 or excellent oral bioavailability.

[0008] The present invention also provides methods and intermediates for manufacturing the compounds of the present invention or their stereoisomers, tautomers, pharmaceutically acceptable salts or solvates.

[0009] The present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof.

[0010] The compounds of this invention can be used in therapeutic applications.

[0011] The compounds of this invention can be used to treat and / or prevent a variety of diseases or disorders associated with FPR2, such as inflammatory diseases, heart disease, chronic airway disease, cancer, sepsis, allergic symptoms, HIV retroviral infection, circulatory disorders, neuroinflammation, neurological disorders, pain, prion diseases, amyloidosis, and immune disorders. The heart disease is selected from angina pectoris, unstable angina pectoris, myocardial infarction, acute coronary artery disease, iatrogenic cardiac damage, and heart failure. The heart failure includes, but is not limited to, acute heart failure, ischemic and non-ischemic chronic heart failure, systolic heart failure, diastolic heart failure, and heart failure with reduced ejection fraction (HF). R EF) and heart failure with preserved ejection fraction (HF) P EF).

[0012] The compounds of the present invention can be used alone, in combination with other compounds of the present invention, or in combination with one or more other pharmaceutical agents.

[0013] Other features and advantages of the present invention will become clear from the following detailed description and claims. Detailed Implementation

[0014] The present invention covers compounds of formula I that are formyl peptide 2 (FPR2) receptor agonists, compositions comprising them, and methods of using them, for example, to treat atherosclerosis, heart failure, chronic obstructive pulmonary disease (COPD), and related diseases.

[0015] One aspect of the present invention is a compound of formula I.

[0016]

[0017] I

[0018] Or its pharmaceutically acceptable salt, wherein

[0019] R 1 It is a halogenated or haloalkyl group;

[0020] R 2 It is a halogenated group;

[0021] R 5 It is a lower alkyl or hydroxyalkyl; and

[0022] R 6 It is hydrogen or a lower alkyl group.

[0023] Another aspect of the present invention is a compound of formula II.

[0024]

[0025] II

[0026] Or its pharmaceutically acceptable salt, wherein

[0027] R 1 It is Cl;

[0028] R 2 It is F;

[0029] R 5 It is C 1-2 Alkyl; and

[0030] R 6 It is C 1-2 alkyl.

[0031] Another aspect of the present invention is a compound of formula III.

[0032]

[0033] III

[0034] Or its pharmaceutically acceptable salt, wherein

[0035] R 1 It is Cl or CF3;

[0036] R 2 It is F;

[0037] R 5 It is C 1-2 Alkyl or C 1-2 Hydroxyalkyl; and

[0038] R 6 Is it hydrogen or C? 1-2 alkyl.

[0039] Another aspect of the present invention is a compound of formula IV.

[0040]

[0041] IV

[0042] Or its pharmaceutically acceptable salt, wherein

[0043] * It is an asymmetric carbon atom;

[0044] R 1 It is a halogroup or haloalkyl group; and

[0045] R 2 It is a halogen group.

[0046] Another aspect of the present invention is a compound of formula V.

[0047]

[0048] V

[0049] Or its pharmaceutically acceptable salt, wherein

[0050] R 1 It is Cl or CF3; and

[0051] R 2 It is F.

[0052] Another aspect of the present invention is a compound of formula VI.

[0053]

[0054] VI

[0055] Or its pharmaceutically acceptable salt, wherein

[0056] R 1 It is a halogenated or haloalkyl group;

[0057] R 2 It is a halogenated group;

[0058] R 5 It is a lower alkyl or hydroxyalkyl; and

[0059] R 6 It is hydrogen or a lower alkyl group.

[0060] In one embodiment, the compounds of the present invention are selected from compounds that have at least 2000-fold selectivity for FPR2 compared to FPR1, wherein the selectivity is based on the EC of FPR2. 50 EC value of FPR1 50 The ratio of values.

[0061] In another embodiment, the compounds of the present invention are selected from compounds that have at least 4000 times selectivity for FPR2 compared to FPR1, wherein the selectivity is based on the EC of FPR2. 50 EC value of FPR1 50 The ratio of values.

[0062] In another embodiment, the compounds of the present invention are selected from compounds that have at least 8000 times selectivity for FPR2 compared to FPR1, wherein the selectivity is based on the EC of FPR2. 50 EC value of FPR1 50 The ratio of values.

[0063] The hyphen "-" not located between two letters or symbols is used to indicate the attachment point of a substituent. For example, -CONH2 is attached via a carbon atom.

[0064] For example, the key pointing to the wavy line used in the structural formula of this article is as follows: It describes the bond that serves as a connection point between a part or substituent and the core or skeletal structure.

[0065] "Hydroxy" refers to -OH.

[0066] "Alkyl" refers to a straight-chain or branched alkyl group consisting of 1 to 6 carbon atoms.

[0067] "Lower alkyl" refers to straight-chain or branched alkyl groups consisting of 1 to 3 carbon atoms.

[0068] "Halogen" refers to fluorine, chlorine, bromine, and iodine.

[0069] "Haloalkyl" refers to alkyl groups that are substituted with halogen groups. Haloalkyl includes all halogen isomers from monohalogen to fully halogenated.

[0070] "Hydroxyalkyl" refers to an alkyl group in which at least one hydrogen atom is replaced by a hydroxyl group.

[0071] 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.

[0072] Some of the compounds of this invention exist in stereoisomeric forms. This invention includes all stereoisomeric forms of the compounds, including enantiomers and diastereomers. Methods for preparing and isolating stereoisomers are known in the art. This invention includes all tautomeric forms of the compounds. This invention includes both rotational and rotational isomers.

[0073] This invention aims to include all isotopes of atoms appearing in the said compounds. Isotopes include atoms that have 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 14C. The isotopically labeled compounds of the present invention can generally be prepared using conventional techniques known to those skilled in the art or by methods similar to those described herein, using a suitable isotopically labeled reagent instead of the originally used unlabeled reagent. Such compounds can have many potential uses, such as as standards and reagents in the determination of biological activity. In the case of stable isotopes, such compounds can have the potential to advantageously alter biological, pharmacological, or pharmacokinetic properties.

[0074] Biological methods

[0075] N-formylpeptide receptors (FPRs) are a family of chemically induced receptors that 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 a variety of physiological pathways, such as intracellular signal transduction, Ca2+ mobilization, and transcription. This family interacts with a diverse set of ligands, including proteins, peptides, and fatty acid metabolites that activate pro-inflammatory and pro-remission downstream responses.

[0076] 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 arachidonic acid metabolites lipoxygenin A4 (LXA4) and Epi-lipoxygenin (ATL), and docosahexaenoic acid metabolite regressor D1 (RvD1). Regressor fatty acid metabolites induce inflammation suppression and resolution 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.

[0077] 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.

[0078] 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 human FPR1 or human FPR2 receptors 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 personal FPR2 cells / well or 4,000 personal FPR1 cells / well to Dulbecco's PBS (with calcium and magnesium) (Life Technologies) supplemented with 0.1% BSA (Perkin-Elmer). The reaction mixture was incubated at room temperature for 30 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 to cavitary structures and d2-fluorophore-labeled cAMP were prepared separately in the provided lysis buffer. After the reaction was complete, 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) 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, by plotting the ratio of fluorescence intensity emitted from 665 nm to fluorescence intensity emitted from 590 nm against cAMP concentration. The efficacy and activity of the compounds in inhibiting cAMP production were then determined by fitting a 4-parameter logistic equation to the cAMP level versus compound concentration graph.

[0079] 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. The selectivity of the compound for FPR2 is based on the EC value of FPR2 activation. 50 With the exciting FPR1 EC 50 The ratio, as measured in the determinations described above.

[0080] Table 1

[0081]

[0082] animal models

[0083] To evaluate myocardial fibrosis in non-ischemic heart disease with hypertension, mice were challenged with angiotensin II to stimulate cardiac hypertrophy and left ventricular fibrosis. Angiotensin II was administered to mice using a subcutaneously implanted osmotic micropump. A separate group of mice was implanted with a subcutaneous pump containing saline (“sham” surgery group); these mice served as controls for the pump implantation surgery. Following pump implantation, mice were treated with either a compound (QD) or a drug solution without the compound (QD, referred to as the mediator). In this model, cardiac fibrosis development reached its peak and would remain at this high level without treatment until angII depletion (approximately 4 weeks post-implantation). Interventional treatment with the compound was administered to mice for 2–4 weeks to allow cardiac fibrosis to regress. At the end of the treatment period, the heart was removed from the animals, and collagen levels / fibrosis were evaluated histologically by cross-sectional heart tissue.

[0084] Pharmaceutical Compositions and Methods of Use

[0085] 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.

[0086] 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.

[0087] 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.

[0088] 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" ("Treating" or "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.

[0089] "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).

[0090] 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.

[0091] 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.

[0092] 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.

[0093] 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.

[0094] Another aspect of the present invention is a method for treating heart disease, wherein the treatment is performed after a myocardial infarction.

[0095] Another aspect of the present invention is the method relating the aforementioned heart disease to chronic heart failure.

[0096] Another aspect of the invention is a method for improving myocardial wound healing, wherein the treatment is described.

[0097] Another aspect of the invention is a method for reducing myocardial fibrosis, wherein the treatment is described.

[0098] 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 method 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; and 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 more compounds, while parenteral administration requires less. However, the specific dosing regimen will be determined by the physician using reasonable medical judgment.

[0099] Another aspect of the invention is a method for treating heart disease, the method comprising administering a therapeutically effective amount of a compound of formula I together with at least one other therapeutic agent to a patient in need.

[0100] 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.

[0101] 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.

[0102] 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.

[0103] Chemical methods

[0104] 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.

[0105]

[0106] 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.

[0107] 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 account of the many alternatives described to trained practitioners is Greene, TW et al., Protecting Groups in Organic Synthesis, 4th ed., Wiley (2007).

[0108] Compounds having general formula I, where rings A, B, and C are as defined above, can be prepared by one or more of the following synthetic methods.

[0109]

[0110] (I)

[0111] The 1-arylpyrrolidone compounds of the present invention, wherein rings A and B are substituted phenyl or heteroaryl rings and ring C is a substituted saturated heterocycle, can be prepared by the general route shown in Scheme 1, starting from a suitably protected 3-aminopyrrolidone-2-one 1a (where PG is a protecting group, such as Boc or Cbz). In the presence of a base such as potassium carbonate and a suitable ligand such as N,N'-dimethylethylenediamine, in a suitable solvent such as butanol or dioxane, copper-catalyzed coupling of 1a with a substituted iodobenzene 1b or other suitable haloaryl or heteroaryl compound yields 1-arylpyrrolidone 1c. Other methods of this transformation include other variations of Ullmann, Goldberg, and Buchwald copper-catalyzed amidation or Buchwald Pd-catalyzed amidation, depending on the nature of ring B; the above are carried out using methods known to those skilled 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). Subsequent palladium-catalyzed amination of 1c to a suitably substituted amine 1d provides compound 1e. Other methods for forming this bond can be found in the literature and are available to those skilled in the art. (Surry and Buchwald Chem Sci. 2011; 2(1): 27-50; Shaughnessy, Ciganek and DeVasher, Organic Reactions. 2014, 85:1:1-668). Removal of the Boc or Cbz protecting group from 1e, followed by condensation of the resulting free amine with a suitably substituted phenyl isocyanate 1g or 4-nitrophenyl phenylcarbamate 1h, provides urea 1f. Suitable isocyanates or 4-nitrophenyl carbamates are commercially available or readily obtained from the corresponding aniline by methods known to those skilled in the art. Alternatively, urea 1f can be obtained by treating the deprotected 3-aminopyrrolidone intermediate with 4-nitrobenzene chloroformate to form a carbamate, followed by condensation with a suitably substituted aniline 1j. Those skilled in the art will also recognize that other compounds of the invention, wherein rings A and B are heteroaryl rings (such as pyridine, pyrimidine, thiazole, etc.), can also be prepared using the methods outlined in Scheme 1 by substituting 1b with a suitable heteroaryl iodine or heteroaryl bromide and 1g, 1h, or 1i with a heteroaryl amine, isocyanate, or p-nitrobenzene carbamate. The chemical used to introduce ring C can also be used with other heterocyclic saturated amines. Racemic compounds are separated using chiral HPLC or SFC to provide a single enantiomer.

[0112] Option 1

[0113]

[0114] Alternatively, as described in Scheme 2, the compounds of the present invention can be prepared from intermediate 1c by first deprotecting the amine using the conditions described above for converting 1e to 1f and forming a urea bond linked to ring A to provide compound 2a. Compound 2a can then be coupled to the amine under Pd-catalyzed or Cu-catalyzed conditions as shown in Scheme 1 for converting 1c to 1e. Racemic compounds can be separated using chiral HPLC or SFC to provide a single enantiomer.

[0115] Option 2

[0116]

[0117] Alternatively, the compounds of the present invention can be prepared from intermediate 2a by converting it to borate ester 3b using palladium-catalyzed borylation according to the method of Suzuki and Miyaura, followed by coupling the resulting pinacol boron compound to an amine via copper-catalyzed Chan-Lam coupling to provide compound 1f (J. Org. Chem., 2016, 81 (9), pp. 3942-3950). Racemic compounds can be separated using chiral HPLC or SFC to provide a single enantiomer.

[0118] Option 3

[0119]

[0120] Alternatively, the compounds of the present invention can be prepared from intermediate 4b by nucleophilic substitution of an aryl fluoride with a cyclic amine 1d to form intermediate 4c. As shown in the above schemes, deprotection and mounting of urea leads to the synthesis of some of the compounds described in the present invention. Racemic compounds can be separated using chiral HPLC or SFC to provide a single enantiomer.

[0121] Option 4

[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] LC / MS methods used to characterize the examples. Reversed-phase analytical HPLC / MS was performed on a WatersAcquity system coupled to a Waters MICROMASS® ZQ mass spectrometer.

[0126] Method A: After a linear gradient from 0 to 100% B over 3 min, the hold time at 100% B is 0.75 min;

[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: After a linear gradient from 0 to 100% B over 3 min, the hold time at 100% B is 0.75 min;

[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: A method for characterizing 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% Acn, 0.05% TFA; Solvent B: 95% Acn, 5% water, 0.1% TFA; Temperature: 50ºC; Gradient: 0-100% B for 3 minutes, then held at 100% B for 1 minute; 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% Acn, 5% water (containing 10 mM ammonium acetate); Temperature: 50ºC; Gradient: 3 min at 0-100% B, then 1 min at 100% B; 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% Acn; Solvent B: 95% Acn, 5% buffer (0.05% TFA in water); Temperature: 50ºC; Gradient: 0-100% B for 3 min, then held 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% Acn (containing 10 mM ammonium formate); Solvent B: 95% Acn, 5% water (containing 10 mM ammonium formate); Temperature: 50ºC; Gradient: 3 min at 0-100% B, then 1 min at 100% B; 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. Solvent system: 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. Solvent system: 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. Solvent system: 0.2% ammonia in Acn: MeOH (1:1).

[0148] NMR spectrometry was used to characterize the examples. Results were 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... 1In the ¹H NMR spectrum, 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... 13 In 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: 3-Aminopyrrolidone-2-one

[0150]

[0151] A solution of DL-2,4-diaminobutyric acid dihydrochloride (10 g, 52 mmol) in Acn (100 mL) was added to a stirred solution of hexamethyldisilazane (11 mL, 52 mmol) in CH3CN (100 mL) at room temperature. The resulting reaction mixture was heated to reflux for 40 h. The crude reaction mixture was poured into ice-cold MeOH (400 mL), stirred for 30 min at room temperature, and evaporated under reduced pressure. The resulting solid was dissolved in CH2Cl2 (700 mL), and insoluble residues were removed by filtration under vacuum. The filtrate was concentrated under reduced pressure to give 3-aminopyrrolidone-2-one (4.1 g, 41 mmol, 78% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6): δ 7.59 (br. s., 2H), 3.23-3.10 (m,1H), 3.09 - 3.03 (m, 2H), 2.23-2.22 (m, 1H), 1.70 - 1.57 (m, 1H).

[0152] Intermediate 2: (2-oxopyrrolidone-3-yl)tert-butyl carbamate

[0153]

[0154] At room temperature, under an argon atmosphere, a stirred solution of 3-aminopyrrolidone-2-one (4.0 g, 40 mmol) in methanol-triethylamine (130 mL, 9:1) was added to Boc anhydride (9.6 mL, 41 mmol). The reaction mixture was stirred overnight at room temperature, then heated to reflux for 2 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Diethyl ether (50 mL) was added to the crude residue, and the solid was filtered through a Buchner funnel to give intermediate 2 (4.0 g, 20 mmol, 50% yield) as a brown solid. 1 H NMR (400MHz, DMSO-d6): δ 7.69 (br. s., 1H), 6.99 (d, J=8.0 Hz, 1H), 4.06 - 3.96 (m, 1H), 3.19 - 3.10 (m, 2H), 2.29 - 2.19 (m, 1H), 1.89 - 1.76 (m, 1H), 1.35 (s, 9H).

[0155] Intermediate 3: (1-(4-bromo-2,3-difluorophenyl)-2-oxopyrrolidone-3-yl)tert-butyl carbamate

[0156]

[0157] To a stirred solution of intermediate 2 (1.0 g, 5.0 mmol) in 1,4-dioxane (10 mL), 1,4-dibromo-2,3-difluorobenzene (1.6 g, 6.0 mmol) and Cs₂CO₃ (3.3 g, 10 mmol) were added. The reaction mixture was purged with nitrogen for 5 min and then loaded with Xantphos (0.29 g, 0.50 mmol) and Pd₂(dba)₃ (0.23 g, 0.25 mmol). The reaction mixture was again purged with nitrogen for 3 min and heated at 120ºC for 16 h. The reaction mixture was cooled, filtered through a diatomaceous earth pad, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether-EtOAc) to give intermediate 3 (1.1 g, 2.8 mmol, 47% yield) as a brown solid. MS (ESI) m / z: 391.2 (M+H) + . 1H NMR (400MHz, DMSO-d6) δ 7.61-7.59 (m, 1H), 7.35 - 7.28 (m, 2H), 4.39 - 4.28 (m, 1H), 3.82- 3.64 (m, 2H), 2.42 - 2.31 (m, 1H), 2.10 - 1.97 (m, 1H), 1.40 (s, 9H).

[0158] Intermediate 4: (1-(2,3-difluoro-4-iodophenyl)-2-oxopyrrolidone-3-yl)tert-butyl carbamate

[0159]

[0160] The reaction mixture of intermediate 2 (2.0 g, 10 mmol), 2,3-difluoro-1,4-diiodobenzene (3.7 g, 10 mmol), cesium carbonate (6.5 g, 20 mmol), and Xantphos (0.58 g, 1.0 mmol) in dioxane (30 mL) was purged with nitrogen for 10 min. Pd2(dba)3 (0.46 g, 0.50 mmol) was added, and the reaction mixture was heated in a pressure tube at 110ºC for 15 h. The reaction mixture was diluted with EtOAc, filtered through diatomaceous earth, and concentrated under reduced pressure. The crude product was purified by column chromatography (EtOAc-hexane) to give intermediate 4 (1.4 g, 3.2 mmol, 32% yield) as a brown solid. MS (ESI) m / z: 439.2 (M+H) + . 1 H NMR (300 MHz, CDCl3δ = 7.49 - 7.42 (m, 1H), 7.05 - 6.98(m, 1H), 5.13 (br. s., 1H), 4.36 - 4.18 (m, 1H), 3.85 - 3.62 (m, 2H), 2.78 -2.62 (m, 1H), 2.12 - 1.95 (m, 1H), 1.47 - 1.33 (s, 9H).

[0161] Intermediate 5: (R)-(2-oxopyrrolidone-3-yl)tert-butyl carbamate

[0162]

[0163] At 0ºC, 1-propanephosphonic anhydride (50% in EtOAc, 210 mL, 340 mmol) was added to a solution of Boc-D-2,4-diaminobutyric acid (50 g, 230 mmol) and TEA (96 mL, 690 mmol) in DCM (1500 mL). The reaction mixture was stirred overnight under nitrogen at room temperature. The reaction mixture was concentrated under vacuum, and the crude product was purified by column chromatography (MeOH / DCM). The product was recrystallized from EtOAc / petroleum ether to give intermediate 5 (32 g, 70 mmol, 70% yield) as a white solid. MS (ESI) m / z: 201.2 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ = 7.69 (s,1H), 6.99 (br. d., J = 9.0 Hz, 1H), 4.01 (q, J = 9.0 Hz, 1H), 3.17 - 3.09 (m,2H), 2.28 - 2.19 (m, 1H), 1.90 - 1.75 (m, 1H), 1.39 (s, 9H).

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

[0165]

[0166] The reaction mixture of intermediate 5 (20 g, 100 mmol), 2,3-difluoro-1,4-dibromobenzene (14 g, 110 mmol), tripotassium phosphate (32 g, 150 mmol), and cuprous iodide (7.6 g, 40 mmol) in 1,4-dioxane (250 mL) was purged with nitrogen for 5 min. N,N'-dimethylethylenediamine (5.5 mL, 50 mmol) was added, and the reaction mixture was heated in a pressure tube at 65ºC for 12 h. The reaction mixture was diluted with EtOAc, filtered through diatomaceous earth, and concentrated under reduced pressure. The crude product was purified by column chromatography (35% EtOAc in petroleum ether) and recrystallized (EtOAc / petroleum ether) to give intermediate 6 (18 g, 39 mmol, 39% yield) as a white solid. MS (ESI) m / z: 439.0 (M+H) + . 1H NMR (400 MHz, CDCl3) δ = 7.54 (ddd, J = 8.5, 6.3, 2.3 Hz, 1H), 7.09 (ddd, J = 8.5, 6.3, 2.3Hz, 1H), 5.16 (br. s., 1H), 4.41 - 4.30 (m, 1H), 3.87 (m, 1H), 3.79 - 3.69 (m, 1H), 2.85 - 2.73 (m, 1H), 2.17 - 2.05 (m, 1H), 1.48 (m, 9H).

[0167] Intermediate 7: 3-bromo-1-(4-bromo-2,6-difluorophenyl)pyrrolidone-2-one

[0168]

[0169] At 0ºC, under an argon atmosphere, tripotassium phosphate (2.55 g, 12.0 mmol) and 2,4-dibromobutyryl chloride (3.18 mL, 24.0 mmol) were added to a stirred solution of 4-bromo-2,6-difluoroaniline (5.0 g, 24 mmol) in acetonitrile (20 mL). The reaction mixture was gradually warmed to room temperature over 30 min and stirred for another 1 h. A 6 N NaOH aqueous solution (1 mL, 6.00 mmol) was added to the reaction mixture, and the mixture was stirred for another 16 h. After completion, the reaction mixture was filtered through a diatomaceous earth mat and washed with acetonitrile (10 mL). The filtrate was concentrated under reduced pressure to give crude 3-bromo-1-(4-bromo-2,6-difluorophenyl)pyrrolidone-2-one (8.0 g, 23 mmol, 94% yield) as a pale yellow liquid, which proceeded to the next step without further purification. MS (ESI) m / z: 354.0 [M+H] + .

[0170] Intermediate 8: 3-amino-1-(4-bromo-2,6-difluorophenyl)pyrrolidone-2-one

[0171]

[0172] Ammonium hydroxide (29.3 mL, 225 mmol) was added to a stirred solution of 3-bromo-1-(4-bromo-2,6-difluorophenyl)pyrrolidone-2-one (8.0 g, 23 mmol) in acetonitrile (50 mL) at room temperature under an argon atmosphere. The resulting reaction mixture was gradually heated to 40ºC and stirred for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with DCM, washed with water (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give crude 3-amino-1-(4-bromo-2,6-difluorophenyl)pyrrolidone-2-one (5.0 g, 17 mmol, 76% yield) as a pale yellow liquid, which proceeded to the next step without any purification. MS (ESI) m / z: 291.2 [M+H] + .

[0173] Intermediate 9: (1-(4-bromo-2,6-difluorophenyl)-2-oxopyrrolidone-3-yl)tert-butyl carbamate

[0174]

[0175] At room temperature, under an argon atmosphere, a stirred solution of 3-amino-1-(4-bromo-2,6-difluorophenyl)pyrrolidone-2-one (6.0 g, 21 mmol) in THF (100 mL) was added with DIPEA (10.8 mL, 61.8 mmol) and Boc anhydride (5.74 mL, 24.7 mmol), and the mixture was stirred for 16 h. The reaction mixture was filtered through a diatomaceous earth mat, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (60% EtOAc-petroleum ether) to give tert-butyl (1-(4-bromo-2,6-difluorophenyl)-2-oxopyrrolidone-3-yl)carbamate (5.0 g, 12 mmol, 62% yield) as a grayish-white solid. MS (ESI) m / z: 391.1 [M+H] + . 1 H NMR (300 MHz, DMSO-d6) δ = 7.64 (br d, J = 9.0Hz, 2H), 7.32 (br d, J = 9.0 Hz, 1H), 4.43 - 4.25 (m, 1H), 3.69 - 3.52 (m,2H), 2.42 - 2.31 (m, 1H), 2.18 - 1.98 (m, 1H), 1.40 (s, 9H).

[0176] Intermediate 10: ((R)-1-(4-((R)-3-(dimethylamino)pyrrolidone-1-yl)-2,3-difluorophenyl)-2-oxopyrrolidone-3-yl)tert-butyl carbamate

[0177]

[0178] At room temperature, (3R)-(+)-3-(dimethylamino)pyrrolidine (0.58 g, 5.1 mmol) and cesium carbonate (3.33 g, 10.2 mmol) were added to a stirred solution of (R)-(1-(4-bromo-2,3-difluorophenyl)-2-oxopyrrolidine-3-yl)carbamate (intermediate 6) (2.0 g, 5.1 mmol) in toluene (20 mL). The reaction mixture was purged with nitrogen for 5 min and then charged with xantphos (0.59 g, 1.0 mmol) and Pd2(dba)3 (0.47 g, 0.51 mmol). The reaction mixture was again purged with nitrogen for 3 min and then heated at 100ºC for 16 h. The reaction mixture was cooled and filtered through a diatomaceous earth mat. The filtrate was concentrated under reduced pressure to obtain the crude compound, which was purified by column chromatography (petroleum ether-ethyl acetate as eluent, containing 1% TEA) to give tert-butyl ((R)-1-(4-((R)-3-(dimethylamino)pyrrolidone-1-yl)-2,3-difluorophenyl)-2-oxopyrrolidone-3-yl)carbamate as a brown solid (850 mg, 2.00 mmol, 39.2% yield). MS (ESI) m / z: 425.3 [M+H] + .

[0179] Intermediate 11: (R)-3-amino-1-(4-((R)-3-(dimethylamino)pyrrolidone-1-yl)-2,3-difluorophenyl)pyrrolidone-2-one hydrochloride

[0180]

[0181] At room temperature, under an argon atmosphere, 4 M HCl (10.0 mL, 40.0 mmol) in 1,4-dioxane was added to a stirred solution of ((R)-1-(4-((R)-3-(dimethylamino)pyrrolidine-1-yl)-2,3-difluorophenyl)-2-oxopyrrolidine-3-yl)carbamate (intermediate 10) (0.85 g, 2.0 mmol) in 1,4-dioxane (10 mL) and stirred for 2 h. The solvent was evaporated under reduced pressure to give a gel-like solid, which was further ground with diethyl ether (10 mL x 2) and dried to give (R)-3-amino-1-(4-((R)-3-(dimethylamino)pyrrolidine-1-yl)-2,3-difluorophenyl)pyrrolidine-2-one hydrochloride (0.65 g, 1.8 mmol, 90% yield) as a brown solid. MS(ESI) m / z: 325.3 [M+H] + .

[0182] Example 1: 1-(4-chlorophenyl)-3-((R)-1-(4-((R)-3-(dimethylamino)pyrrolidine-1-yl)-2,3-difluorophenyl)-2-oxopyrrolidine-3-yl)urea

[0183]

[0184] At room temperature, under an argon atmosphere, DIPEA (0.51 mL, 2.9 mmol) and phenyl 1-chloro-4-isocyanate (150 mg, 0.97 mmol) were added to a stirred solution of (R)-3-amino-1-(4-((R)-3-(dimethylamino)pyrrolidone-1-yl)-2,3-difluorophenyl)pyrrolidone-2-one hydrochloride (intermediate 11) (350 mg, 0.97 mmol) in DCM (10 mL). The resulting solution was stirred at room temperature 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 1-(4-chlorophenyl)-3-((R)-1-(4-((R)-3-(dimethylamino)pyrrolidone-1-yl)-2,3-difluorophenyl)-2-oxopyrrolidone-3-yl)urea (300 mg, 64% yield) as a grayish-white solid.

[0185] The examples in Table 2 below were prepared using a similar procedure as shown in Intermediates 1-11 above and Example 1.

[0186] Table 2

[0187]

[0188]

[0189] 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 Or its pharmaceutically acceptable salt, wherein R 1 It is a halogenated or haloalkyl group; R 2 It is a halogenated group; R 3 It is hydrogen; R 5 It is a lower alkyl or hydroxyalkyl; and R 6 It is hydrogen or a lower alkyl group.

2. The compound according to claim 1, wherein the compound has formula II. II Or its pharmaceutically acceptable salt, wherein R 1 It is Cl; R 2 It is F; R 5 It is C 1-2 alkyl and R 6 It is C 1-2 alkyl.

3. The compound according to claim 1, wherein the compound has formula III III Or its pharmaceutically acceptable salt, wherein R 1 It is Cl or CF3; R 2 It is F; R 5 It is C 1-2 Alkyl or C 1-2 Hydroxyalkyl; and R 6 Is it hydrogen or C? 1-2 alkyl.

4. A compound of formula IV IV Or its pharmaceutically acceptable salt, wherein * It is an asymmetric carbon atom; R 1 It is a halogroup or haloalkyl group; and R 2 It is a halogen group.

5. A compound of formula V V Or its pharmaceutically acceptable salt, wherein R 1 It is Cl or CF3; and R 2 It is F.

6. A pharmaceutical composition comprising a compound according to claim 1 or 4 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

7. The compound according to any one of claims 1-5 or the pharmaceutical composition according to claim 6, wherein the compound or the pharmaceutical composition is used in a therapeutic manner.

8. A method for treating heart disease, the method comprising administering a therapeutically effective amount of the pharmaceutical composition according to claim 6 to a patient in need.

9. The method of claim 8, 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.

10. The method of claim 9, 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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