EP4698275A1 - Pyrrolidinone urea fpr2 agonists - Google Patents

Abstract

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

Description

PYRROLIDINONE UREA FPR2 AGONISTS CROSS-REFERENCE TO RELATED APPLICATIONS 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 OF THE INVENTION The present invention relates to novel pyrrolidinone urea compounds, which are formyl peptide 2 (FPR2) receptor agonists, compositions containing them, and methods of using them, for example, for the treatment of atherosclerosis, heart failure, chronic obstructive pulmonary disease (COPD), and related diseases. Formyl peptide receptor 2 (FPR2) belongs to a small group of seven- transmembrane domain, G protein-coupled receptors that are expressed mainly by mammalian phagocytic leukocytes and are known to be important in host defense and inflammation. FPR2 shares significant sequence homology with FPR1 and FPR3. Collectively, these receptors bind large number of structurally diverse group of agonists, including N-formyl and nonformyl peptides which act as chemo attractants and activate phagocytes. The endogenous anti-inflammatory peptide Annexin A1 and its N-terminal fragments also bind human FPR1 and FPR2. Importantly, anti-inflammatory eicosanoid lipoxin A4, which belongs to newly discovered class of small pro-resolution mediators (SPMs), has been identified as a specific agonist for FPR2 (Ye RD., et al., Pharmacol. Rev., 2009, 61, 119-61). Endogenous FPR2 pro-resolution ligands, such as lipoxin A₄ and Annexin A1 bind to the receptor triggering a wide array of cytoplasmatic cascades such as Gi coupling, Ca²⁺ mobilization and E-arrestin recruitment. Activation of FPR2 by lipoxin A4 modifies the effects of peptidic agonists, such as serum amyloid A (SAA), and has alternative effects on phosphorylation pathways depending on the cell type. Lipoxins regulate components of both innate and adaptive immune systems including neutrophils, macrophages, T-, and B-cells. In neutrophils, lipoxins modulate their movement, cytotoxicity and life span. In macrophages, lipoxins prevent their apoptosis and enhance efferocytosis. In most inflammatory cells, lipoxins also down-regulate expression of several pro-inflammatory cytokines, such as IL-6, IL-1E and IL-8 as well as up-regulate expression of anti-inflammatory cytokine IL-10 (Chandrasekharan JA, Sharma-Walia N,. J. Inflamm. Res., 2015, 8, 181-92). The primary effects of lipoxin on neutrophils and macrophages are termination of inflammation and initiation of resolution of inflammation. The latter is primarily responsible for enhancing anti-fibrotic wound healing and returning of the injured tissue to homeostasis (Romano M., et al., Eur. J. Pharmacol., 2015, 5, 49-63). Chronic inflammation is part of the pathway of pathogenesis of many human diseases and stimulation of resolution pathways with FPR2 agonists may have both protective and reparative effects. Ischaemia-reperfusion (I/R) injury is a common feature of several diseases associated with high morbidity and mortality, such as myocardial infarction and stroke. Non-productive wound healing associated with cardiomyocyte death and pathological remodeling resulting from ischemia-reperfusion injury leads to scar formation, fibrosis, and progressive loss of heart function. FPR2 modulation is proposed to enhance myocardial wound healing post injury and diminish adverse myocardial remodeling (Kain V., et al., J. Mol. Cell. Cardiol., 2015, 84, 24-35). In addition, FPR2 pro-resolution agonists, in the central nervous system, may be useful therapeutics for the treatment of a variety of clinical I/R conditions, including stroke in brain (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). In addition to beneficial effects of targeting the FPR2 with novel pro-resolution agonists for treatment of I/R induced injury therapeutic, utility of these ligands can also be applied to other diseases. In the cardiovascular system both the FPR2 receptor and its pro-resolution agonists were found to be responsible for atherogenic-plaque stabilization and healing (Petri MH., et al., Cardiovasc. Res., 2015, 105, 65-74; and Fredman G., et al., Sci. Trans. Med., 2015, 7(275);275ra20). FPR2 agonists also have been shown to be beneficial in preclinical models of chronic inflammatory human diseases, including: infectious diseases, psoriasis, dermatitis, occular inflammation, sepsis, pain, metabolic/diabetes diseases, cancer, COPD, asthma and allergic diseases, cystic fibrosis, acute lung injury and fibrosis, rheumatoid arthritis and other joint diseases, Alzheimer's disease, kidney 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 The present invention provides novel pyrrolidinone ureas, and their analogues thereof, which are useful as FPR2 agonists, including stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof. The compounds of the present invention either show high selectivity for FPR2 compared to FPR1 or have superior oral bioavailability. The present invention also provides processes and intermediates for making the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof. The present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof. The compounds of the invention may be used in therapy. The compounds of the invention may be used in the treatment and/or prophylaxis of multiple diseases or disorders associated with FPR2, such as inflammatory diseases, heart diseases, chronic airway diseases, cancers, septicemia, allergic symptoms, HIV retrovirus infection, circulatory disorders, neuroinflammation, nervous disorders, pains, prion diseases, amyloidosis, and immune disorders. The heart diseases are selected from the group consisting of angina pectoris, unstable angina, myocardial infarction, acute coronary disease, cardiac iatrogenic damage, and heart failure including, but not limited to, acute heart failure, chronic heart failure of ischemic and non-ischemic origin, systolic heart failure, diastolic heart failure, heart failure with reduced ejection fraction (HF_REF), and heart failure with preserved ejection fraction (HF_PEF). The compounds of the invention can be used alone, in combination with other compounds of the present invention, or in combination with one or more other agent(s). Other features and advantages of the invention will be apparent from the following detailed description and claims. DESCRIPTION OF THE INVENTION The invention encompasses compounds of formula I, which are formyl peptide 2 (FPR2) receptor agonists, compositions containing them, and methods of using them, for example, in the treatment of atherosclerosis, heart failure, chronic obstructive pulmonary disease (COPD), and related diseases. One aspect of the invention is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein R¹ is halo or haloalkyl; R² is halo; R⁵ is lower alkyl or hydroxyalkyl; and R⁶ is hydrogen or lower alkyl. Another aspect of the invention is a compound of formula II

or a pharmaceutically acceptable salt thereof, wherein R¹ is Cl; R² is F; R⁵ is C1-2 alkyl; and R⁶ is C1-2 alkyl. Another aspect of the invention is a compound of formula III or a pharmaceutically acceptable salt thereof, wherein R¹ is Cl or CF₃; R² is F; R⁵ is C1-2 alkyl or C1-2 hydroxyalkyl; and R⁶ is hydrogen or C1-2 alkyl. Another aspect of the invention is a compound of formula IV or a pharmaceutically acceptable salt thereof, wherein * is an asymmetric carbon atom; R¹ is halo or haloalkyl; and R² is halo. Another aspect of the invention is a compound of formula V or a pharmaceutically acceptable salt thereof, wherein R¹ is Cl or CF3; and R² is F. Another aspect of the invention is a compound of formula VI or a pharmaceutically acceptable salt thereof, wherein R¹ is halo or haloalkyl; R² is halo; R⁵ is lower alkyl or hydroxyalkyl; and R⁶ is hydrogen or lower alkyl. In one embodiment, the compounds of the present invention are selected from the compounds having at least 2000-fold selectivity for FPR2 for FPR1, wherein the selectivity is based on the ratio of the EC50 values of FPR2 to the EC50 values of FPR1. In another embodiment, the compounds of the present invention are selected from the compounds having at least 4000-fold selectivity for FPR2 for FPR1, wherein the selectivity is based on the ratio of the EC50 values of FPR2 to the EC50 values of FPR1. In another embodiment, the compounds of the present invention are selected from the compounds having at least 8000-fold selectivity for FPR2 for FPR1, wherein the selectivity is based on the ratio of the EC50 values of FPR2 to the EC50 values of FPR1. A dash that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CONH2 is attached through the carbon atom. A bond pointing to a wave line, such as , as used in structural formulas herein, depicts the bond that is the point of attachment of the moiety or substituent to the core or backbone structure. “Hydroxy” means -OH. “Alkyl” refers to a straight or branched alkyl group composed of 1 to 6 carbons. “Lower alkyl” refers to a straight or branched alkyl group composed of 1 to 3 carbons. “Halo” refers to fluoro, chloro, bromo, and iodo. “Haloalkyl” refers to halo substituted alkyl groups. Haloalkyl includes all halogenated isomers from monohalo to perhalo. “Hydroxyalkyl” refers to an alkyl group that has at least one hydrogen atom substituted with a hydroxy group. The invention includes all pharmaceutically acceptable salt forms of the compounds. Pharmaceutically acceptable salts are those in which the counter ions do not contribute significantly to the physiological activity or toxicity of the compounds and as such function as pharmacological equivalents. These salts can be made according to common organic techniques employing commercially available reagents. Some anionic salt forms include acetate, acistrate, besylate, bromide, chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, 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. Some of the compounds of the invention exist in stereoisomeric forms. The invention includes all stereoisomeric forms of the compounds including enantiomers and diastereomers. Methods of making and separating stereoisomers are known in the art. The invention includes all tautomeric forms of the compounds. The invention includes atropisomers and rotational isomers. The invention is intended to include all isotopes of atoms occurring in the compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include ¹³C and ¹⁴C. Isotopically- labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed. Such compounds may have a variety of potential uses, for example as standards and reagents in determining biological activity. In the case of stable isotopes, such compounds may have the potential to favorably modify biological, pharmacological, or pharmacokinetic properties. BIOLOGICAL METHODS N-formyl peptide receptors (FPRs) are a family of chemo attractant receptors that facilitate leukocyte response during inflammation. FPRs belong to the seven- transmembrane G protein-coupled receptor superfamily and are linked to inhibitory G- proteins (Gi). Three family members (FPR1, FPR2 and FPR3) have been identified in humans and are predominantly found in myeloid cells with varied distribution and have also been reported in multiple organs and tissues. After agonist binding, the FPRs activate a multitude of physiological pathways, such as intra cellular signaling transduction, Ca2+ mobilization and transcription. The family interacts with a diverse set of ligands that includes proteins, polypeptides and fatty acid metabolites which activate both pro-inflammatory and pro-resolution downstream responses. The FPR2 receptor binds multiple ligands to invoke both inflammatory and anti- inflammatory responses. Inflammation mediator release by FPR2 is promoted by endogenous protein ligands such as Serum amyloid A (SAA) and Amyloid E (1-42), whereas resolution of inflammation is induced by ligands that include arachidonic acid metabolites, lipoxin A4 (LXA4) and Epi-lipoxin (ATL), and a docosahexenoic acid metabolite, resolvin D1 (RvD1). The pro-resolving fatty acid metabolites mediate inhibition and resolution of inflammation through the FPR2 receptor by stimulating phagocytosis of apototic neutrophils by macrophages. Removal of the apototic neutrophils induce the release of cytokines that activate pro-resolution pathways. The FPR1 receptor was originally isolated as a high affinity receptor for N- Formylmethionine containing peptides, such as N-Formylmethionine-leucyl- phenylalanine (FMLP). The protein directs mammalian phagocytic and blood leukocyte cells to sites of invading pathogens or inflamed tissues and activates these cells to kill pathogens or to remove cellular debris. FPR2 and FPR1 Cyclic Adenosine Monophosphate (cAMP) Assays. A mixture of forskolin (5 μM final for FPR2 or 10 μM final for FPR1) and IBMX (200 μM final) were added to 384-well Proxiplates (Perkin-Elmer) pre-dotted with test compounds in DMSO (1% final) at final concentrations in the range of 1.7 nM to 100 PM. 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 Pg/ml zeocin and 300 Pg/ml hygromycin (Life Technologies). Reactions were initiated by adding 2,000 human FPR2 cells per well or 4,000 human FPR1 cells per well in Dulbecco’s PBS (with calcium and magnesium) (Life Technologies) supplemented with 0.1% BSA (Perkin- Elmer). The reaction mixtures were incubated for 30 min at room temperature. The level of intracellular cAMP was determined using the HTRF HiRange cAMP assay reagent kit (Cisbio) according to manufacturer’s instruction. Solutions of cryptate conjugated anti- cAMP and d2 flurorophore-labelled cAMP were made in a supplied lysis buffer separately. Upon completion of the reaction, the cells were lysed with equal volume of the d2-cAMP solution and anti-cAMP solution. After a 1-h room temperature incubation, time-resolved fluorescence intensity was measured using the Envision (Perkin-Elmer) at 400 nm excitation and dual emission at 590 nm and 665 nm. A calibration curve was constructed with an external cAMP standard at concentrations ranging from 1 PM to 0.1 pM by plotting the fluorescent intensity ratio from 665 nm emission to the intensity from the 590 nm emission against cAMP concentrations. The potency and activity of a compound to inhibit cAMP production was then determined by fitting to a 4-parametric logistic equation from a plot of cAMP level versus compound concentrations. The examples disclosed below were tested in the FPR2 and FPR1 cAMP assay described above and found having FPR2 and/or FPR1 agonist activity. Table 1 below ^{lists EC} ₅₀ ^{values in the FPR2 and FPR1 cAMP assays measured for the following} examples. The selectivity of the cmpounds for FPR2 is based on the ratio of the EC₅₀ for agonizing FPR2 to the EC₅₀ for agonizing FPR1 as measured in the assay described above. Table 1 ANIMAL MODELS To assess myocardial fibrosis in the setting of non-ischemic heart disease with hypertension, mice were challenged with angiotensin II to stimulate cardiac hypertrophy and left ventricular fibrosis. Mice were administered angiotensin II using subcutaneously implanted osmotic mini-pumps. A separate group of mice were implanted with subcutaneous pumps containing saline (surgical “sham” group); these mice served as control for pump implantation surgery. Mice were treated with compounds (QD) or dosing solution without compound (QD, referred to as vehicle) starting following pump implantation. In this model, cardiac fibrosis development reaches its peak and without treatment, will remain fibrotic at this high level until the angII is depleted (~ 4 weeks post implantation). Interventional treatment with compounds to regress cardiac fibrosis was given to mice for 2-4 weeks. At the end of treatment phase, hearts were removed from animals and evaluated for collagen levels/fibrosis by cross-sectional histology of the hearts. PHARMACEUTICAL COMPOSITIONS AND METHODS OF USE The compounds of the present invention may be administered to patients for the treatment of a variety of conditions and disorders, including atherosclerosis, heart failure, lung diseases including asthma, COPD, 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 kidney fibrosis. Another aspect of the invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I in combination with a pharmaceutical carrier. Another aspect of the invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I in combination with at least one other therapeutic agent and a pharmaceutical carrier. Unless otherwise specified, the following terms have the stated meanings. The term "patient" means a subject suitable for therapy as determined by practitioners in the field and encompasses all suitable mammalian species including humans that could potentially benefit from treatment with a FPR2 and/or FPR1 agonist as understood by practioners in this field. Common risk factors include, but are not limited to, age, sex, weight, family history, sleep apnea, alcohol or tobacco use, physical inactivity arrhythmia or signs of insulin resistance such as acanthosis nigricans, hypertension, dyslipidemia, or polycystic ovary syndrome (PCOS). "Treating" or "treatment" encompass the treatment of a patient as understood by practitioners in the art and include inhibiting the disease-state, i.e., arresting it development; relieving the disease-state, i.e., causing regression of the disease state; and/or preventing the disease-state from occurring in a patient. "Therapeutically effective amount" is intended to include an amount of a compound that is effective or beneficial as understood by practitioners in this field. "Pharmaceutical composition" means a composition comprising a compound of the invention in combination with at least one additional pharmaceutically acceptable carrier. A "pharmaceutically acceptable carrier" refers to media for the delivery of biologically active agents as understood by practitioners in the art, such as diluents, preserving agents, fillers, flow regulating agents, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, anti-bacterial agents, anti-fungal agents, lubricating agents, and dispensing agents. Pharmaceutically acceptable carriers are formulated according to a number of factors known to those of ordinary skill in the art. These include, without limitation, the type and nature of the active agent being formulated; the subject to which the agent-containing composition is to be administered; the intended route of administration of the composition; and the therapeutic indication being targeted. Descriptions of suitable pharmaceutically acceptable carriers and factors involved in their selection are known in the art in such references as Allen, L.V., Jr. et al., Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition, Pharmaceutical Press (2012). Solid compositions are normally formulated in dosage units and compositions providing form about 1 to 1000 mg of the active ingredient per dose are preferred. Some examples of dosages are 1 mg, 10 mg, 100 mg, 250 mg, 500 mg, and 1000 mg. Liquid compositions are usually in dosage unit ranges. Generally, the liquid composition will be in a unit dosage range of 1-100 mg/mL. Some examples of dosages are 1 mg/mL, 10 mg/mL, 25 mg/mL, 50 mg/mL, and 100 mg/mL. Another aspect of the invention is a method for treating heart disease comprising administering a therapeutically effective amount of a compound of formula I to a patient. Another aspect of the invention is a method for treating heart disease wherein the heart disease is selected from the group consisting of angina pectoris, unstable angina, myocardial infarction, heart failure, acute coronary disease, acute heart failure, chronic heart failure, and cardiac iatrogenic damage. Another aspect of the invention is a method for treating heart disease wherein the treatment is post myocardial infarction. Another aspect of the invention is the method wherein the heart disease is associated with chronic heart failure. Another aspect of the invention is the method wherein the treatment is to improve myocardial wound healing. Another aspect of the invention is the method wherein the treatment is to diminish myocardial fibrosis. The invention encompasses all conventional modes of administration; oral and parenteral methods are preferred. Generally, the dosing regimen will be similar to other cardiovascular agents used clinically. The dosage regimen and mode for administration for the compounds of the present invention will depend on known factors known by practitioners in the art and include age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, and the effect desired. Typically, the daily dose will be 0.1-100 mg/kg body weight daily. Generally, more compound is required orally and less parenterally. The specific dosing regimen, however, will be determined by a physician using sound medical judgment. Another aspect of the invention is a method for treating heart diseases comprising administering a therapeutically effective amount of a compound of formula I to a patient in need thereof with at least one other therapeutic agent. The compounds of the present invention may be employed in combination with other suitable therapeutic agents useful in the treatment of the aforementioned diseases or disorders including: anti-atherosclerotic agents, anti-dyslipidemic agents, anti-diabetic agents, anti-hyperglycemic agents, anti-hyperinsulinemic agents, anti-thrombotic agents, anti-retinopathic agents, anti-neuropathic agents, anti-nephropathic agents, anti-ischemic agents, anti-hypertensive agents, anti-obesity agents, anti-hyperlipidemic agents, anti-hypertriglyceridemic agents, anti-hypercholesterolemic agents, anti-restenotic agents, anti-pancreatic agents, lipid lowering agents, anorectic agents, memory enhancing agents, anti-dementia agents, cognition promoting agents, appetite suppressants, agents for treating heart failure, agents for treating peripheral arterial disease, agents for treating malignant tumors, and anti-inflammatory agents. The compounds of the invention may be used with one or more, preferable one to three, of the following heart failure agents selected from loop diuretics, Angiotensin converting enzyme (ACE) inhibitors, Angiotensin II receptor blockers (ARBs), angiotensin receptor-neprilysin inhibitors (ARNI), beta blockers, mineralocorticoid receptor antagonists, nitroxyl donors, RXFP1 agonists, APJ agonists and cardiotonic agents. These agents include, but are not limited to furosemide, bumetanide, torsemide, sacubitrial-valsartan, thiazide diruetics, captopril, enalapril, lisinopril, carvedilol, metopolol, bisoprolol, serelaxin, spironolactone, eplerenone, ivabradine, candesartan, eprosartan, irbestarain, losartan, olmesartan, telmisartan, and valsartan. The compounds of the present invention are also useful as standard or reference compounds, for example as a quality standard or control, in tests or assays involving the FPR2. Such compounds may be provided in a commercial kit, for example, for use in pharmaceutical research involving FPR2 activity. For example, a compound of the present invention could be used as a reference in an assay to compare its known activity to a compound with an unknown activity. This would ensure the experimenter that the assay was being performed properly and provide a basis for comparison, especially if the test compound was a derivative of the reference compound. When developing new assays or protocols, compounds according to the present invention could be used to test their effectiveness. The compounds of the present invention may also be used in diagnostic assays involving FPR2. CHEMISTRY METHODS Abbreviations as used herein, are defined as follows: "1x" for once, "2x" for twice, "3x" for thrice, " ºC" for degrees Celsius, "aq" for aqueous, "Col" for column, "eq" for equivalent or equivalents, "g" for gram or grams, "mg" for milligram or milligrams, "L" for liter or liters, "mL" for milliliter or milliliters, "^L" for microliter or microliters, "N" for normal, "M" for molar, "nM" for nanomolar, "mol" for mole or moles, "mmol" for millimole or millimoles, "min" for minute or minutes, "h" for hour or hours, "rt" for room temperature, "RT" for retention time, "ON" for overnight, "atm" for atmosphere, "psi" for pounds per square inch, "conc." for concentrate, "aq" for "aqueous", "sat" or "sat'd " for saturated, "MW" for molecular weight, "mw" or "^wave" for microwave, "mp" for melting point, "Wt" for weight, "MS" or "Mass Spec" for mass spectrometry, "ESI" for electrospray ionization mass spectroscopy, "HR" for high resolution, "HRMS" for high resolution mass spectrometry, "LCMS" for liquid chromatography mass spectrometry, "HPLC" for high pressure liquid chromatography, "RP HPLC" for reverse phase HPLC, "TLC" or "tlc" for thin layer chromatography, "NMR" for nuclear magnetic resonance spectroscopy, "nOe" for nuclear Overhauser effect spectroscopy, "¹H" for proton, "į " for delta, "s" for singlet, "d" for doublet, "t" for triplet, "q" for quartet, "m" for multiplet, "br" for broad, "Hz" for hertz, and "Į", "ȕ", "R", "S", "E", and "Z" are stereochemical designations familiar to one skilled in the art. The compounds of this invention can be made by various methods known in the art including those of the following schemes and in the specific embodiments section. The structure numbering and variable numbering shown in the synthetic schemes are distinct from, and should not be confused with, the structure or variable numbering in the claims or the rest of the specification. The variables in the schemes are meant only to illustrate how to make some of the compounds of this invention. It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group used for protection of the reactive functional groups present in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Greene, T.W. et al., Protecting Groups in Organic Synthesis, 4^th Edition, Wiley (2007)). Compounds having the general formula I wherein rings A, B, and C are as defined above can be prepared by the following one or more of the synthetic Schemes. 1-Arylpyrrolidinone compounds of this 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- aminopyrrolidin-2-one 1a, where PG is a protecting group such as Boc or Cbz. Copper- catalyzed coupling of 1a to a substituted iodobenzene 1b or other suitable halo aryl or heteroaryl compound in a suitable solvent such as butanol or dioxane, in the presence of a base such as potassium carbonate and a suitable ligand such as N,N’- dimethylethylenediamine, can afford 1-arylpyrrolidinones 1c. Additional methods for 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, using methods known to one skilled in the art for these types of couplings (see for example Yin & Buchwald Organic Lett. 2000, 2, 1101; Klapers et al.JACS, 2001, 123, 7727; Klapars et al. JACS, 2002,124, 7421; Yin & Buchwald JACS. 2002,124, 6043; Kiyomor, Madoux & Buchwald, Tet. Lett., 1999, 40, 2657, Surry and Buchwald Angew. Chem. Int. Ed., 2008, 47, 6338). Subsequent palladium-catalyzed amination of 1c to a suitably substituted amine 1d can provide compound 1e. Other methods for forming this bond can be found in the literature and can used by those skilled in the art. (Surry & Buchwald Chem Sci. 2011; 2(1): 27–50; Shaughnessy, Ciganek & 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 can provide ureas 1f. Suitable isocyanates or 4-nitrophenylcarbamates are either commercially available or can be readily obtained from the corresponding aniline by methods known to one skilled in the art. Alternately, the ureas 1f can be obtained by treatment of the deprotected 3- aminopyrrolidinone intermediate with 4-nitrophenylchloroformate to form the carbamate, followed by condensation with an appropriately substituted aniline 1j. It will also be recognized by one skilled in the art that additional compounds of this 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 the appropriate heteroaryl iodide or bromide for 1b and heteroaryl amine, isocyanate or p-nitrophenylcarbamate for 1g, 1h or 1i. The chemistry for introducing Ring C can also be used with other saturated amine containing heterocycles. Racemic compounds were separated using either chiral HPLC or SFC to provide single enantiomers.

Scheme 1 Alternatively as described in Scheme 2, compounds of this invention can be prepared from intermediate 1c by first deprotecting the amine and forming the urea linkage to ring A using the conditions described above for the conversion of 1e to 1f to provide compounds 2a. Compound 2a can then be coupled with amine under Pd-catalysis or Cu- catalysis conditions as shown in Scheme 1 for the transformation of 1c to 1e. Racemic compounds can be separated using either chiral HPLC or SFC to provide single enantiomers.

Scheme 2 Additionally, compounds of this invention can be prepared from intermediate 2a by conversion to boronate 3b using palladium-catalyzed borylation according to the method of Suzuki and Miyaura followed by coupling of the resulting pinacolatoboron species with an amine copper catalyzed Chan-Lam coupling to provide compounds 1f (J. Org. Chem., 2016, 81 (9), pp 3942–3950). Racemic compounds can be separated using either chiral HPLC or SFC to provide single enantiomers. Scheme 3 Alternatively, compounds of this invention can be prepared from intermediate 4b by nucleophilic displacement of the aryl fluoride with cyclic amines 1d to form intermediate 4c. Deprotection and installation of the urea, as shown in the above schemes, results in the synthesis of some compounds described by this invention. Racemic compounds can be separated using either chiral HPLC or SFC to provide single enantiomers. Scheme 4 Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments that are given for illustration of the invention and are not intended to be limiting thereof. The following methods were used in the exemplified Examples, except where noted otherwise. Purification of intermediates and final products was carried out via either normal or reverse phase chromatography. Normal phase chromatography was carried out using prepacked SiO2 cartridges eluting with either gradient of hexane and ethyl acetate or DCM and MeOH unless otherwise indicated. Reverse phase preparative HPLC was carried out using C18 columns with UV 220 nm or prep LCMS detection eluting with gradients of Solvent A (90% water, 10% MeOH, 0.1% TFA) and Solvent B (10% water, 90% MeOH, 0.1% TFA) or with gradients of Solvent A (95% water, 5% Acn, 0.1% TFA) and Solvent B (5% water, 95% Acn, 0.1% TFA) or with gradients of Solvent A (95% water, 2% Acn, 0.1% HCOOH) and Solvent B (98% Acn, 2% water, ^{0.1% HCOOH) or with gradients of Solvent A (95% water, 5% Acn, 10 mM NH} ₄ ^{Oac) and Solvent B (98% Acn, 2% water, 10 mM NH} ₄ ^{Oac) or with gradients of Solvent A} (98% water, 2% Acn, 0.1% NH₄OH) and Solvent B (98% Acn, 2% water, 0.1% ^NH ₄ ^OH). LC/MS Methods Employed in Characterization of Examples. Reverse phase analytical HPLC/MS was performed on a Waters Acquity system coupled with a Waters _MICROMASS ^® _{ZQ Mass Spectrometer.} Method A: Linear gradient of 0 to 100% B over 3 min, with 0.75 min hold time at 100% B; UV visualization at 220 nm Column: Waters BEH C182.1 x 50 mm Flow rate: 1.0 mL/min Solvent A: 0.1% TFA, 95% water, 5% Acn Solvent B: 0.1% TFA, 5% water, 95% Acn Method B: Linear gradient of 0 to 100% B over 3 min, with 0.75 min hold time at 100% B; UV visualization at 220 nm Column: Waters BEH C182.1 x 50 mm Flow rate: 1.0 mL/min Solvent A: 10 mM ammonium acetate, 95% water, 5% Acn Solvent B: 10 mM ammonium acetate, 5% water, 95% Acn Analytical HPLC: Methods Employed in Characterization of Examples Products were analyzed by reverse phase analytical HPLC: carried out on a Shimadzu Analytical HPLC: system running Discovery VP software. RT = retention time. Method C: Ascentis Express C18, 2.1 x 50 mm, 2.7-^m particles; Solvent A: 95% water, 5% Acn, 0.05% TFA; Solvent B: 95% Acn, 5% water, 0.1% TFA; Temperature: 50 ºC; Gradient: 0-100% B over 3 minutes, then a 1-minute hold at 100% B; Flow: 1.1 mL/min. Method D: Ascentis Express C18, 2.1 x 50 mm, 2.7-^m particles; Solvent A: 95% water, 5% acetonitrile with 10 mM ammonium acetate; Solvent B: 95% Acn, 5% water with 10 mM ammonium acetate; Temperature: 50 ºC; Gradient: 0-100% B over 3 min, then a 1-minute hold at 100% B; Flow: 1.1 mL/min. Method E: Kinetex BIPHENYL (4.6X100) mm, 2.6-^m particles; Solvent A: 95% buffer (0.05% TFA in water), 5% Acn; Solvent B: 95% Acn, 5% buffer (0.05% TFA in water); Temperature: 50 ºC; Gradient: 0-100% B over 3 min, then a 1-min hold at 100% B; Flow: 1.1 mL/min. Method F: Ascentis Express C18, 2.1 x 50 mm, 2.7-^m particles; Solvent A: 95% water, 5% Acn with 10 mM ammonium formate; Solvent B: 95% Acn, 5% water with 10 mM ammonium formate; Temperature: 50 ºC; Gradient: 0-100% B over 3 min, then a 1- minute hold at 100% B; Flow: 1.1 mL/min. SFC and chiral purity methods Method A: DAD-1: CHIRALPAK IA (250*4.6) mm, 5^m; DAD-2: CHIRALPAK IB (250*4.6) mm, 5^m. Solvent system: 0.2% ammonia in Acn: MeOH (1:1) Method B: DAD-1: CHIRALPAK IC (250*4.6) mm, 5^m; DAD-2: CHIRALPAK ID (250*4.6) mm, 5^m. Solvent system: 0.2% ammonia in Acn: MeOH (1:1) Method C: DAD-1: CHIRALPAK IE (250*4.6) mm, 5^m; DAD-2: CHIRALPAK IF (250*4.6) mm, 5^m. Solvent system: 0.2% ammonia in Acn: MeOH (1:1) N_{MR Employed in Characterization of Examples.} ¹ _{H NMR spectra were obtained with Bruker or JEOL} ^® _{Fourier transform spectrometers operating at frequencies as follows:} 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} ^® _{). Spectra data are} reported in the format: chemical shift (multiplicity, coupling constants, and number of hydrogens). Chemical shifts are specified in ppm downfield of a tetramethylsilane internal standard (G units, tetramethylsilane = 0 ppm) and/or referenced to solvent peaks, which in ^{1H NMR spectra appear at 2.49 ppm for CD} ₂ ^HSOCD ₃ ^{, 3.30 ppm for CD} ₂ ^{HOD, 1.94 for} CD₃CN, and 7.24 ppm for CHCl₃, and which in ¹³C NMR spectra appear at 39.7 ppm for ^CD ₃ ^SOCD ₃ ^{, 49.0 ppm for CD} ₃ ^{OD, and 77.0 ppm for CDCl} ₃ ^{. All 13C NMR spectra were} proton decoupled. Intermediate 1: 3-Aminopyrrolidin-2-one To a stirred solution of hexamethyldisilazane (11 mL, 52 mmol) in CH3CN (100 mL) at rt was added a solution of DL-2,4-diaminobutyric acid dihydrochloride (10 g, 52 mmol) in Acn (100 mL). The resulting reaction mixture was heated to reflux for 40 h. The crude reaction mixture was poured into ice cold MeOH (400 mL), stirred at rt for 30 min and evaporated under reduced pressure. The resulting solid was dissolved in CH₂Cl₂ (700 mL), and the insoluble residue was removed by filtration under vacuum. The filtrate was concentrated under reduced pressure to give 3-aminopyrrolidin-2-one (4.1 g, 41 mmol, 78% yield) as a yellow solid.¹H NMR (400MHz, DMSO-d6): į 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). Intermediate 2: tert-Butyl (2-oxopyrrolidin-3-yl)carbamate To a stirred solution of 3-aminopyrrolidin-2-one (4.0 g, 40 mmol) in methanol- triethylamine (130 mL, 9:1) under argon atmosphere at rt, was added Boc-anhydride (9.6 mL, 41 mmol). The reaction mixture was stirred at rt overnight followed by heating to reflux for 2 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. Ether (50 mL) was added to the crude residue and the solid was filtered through Buchner funnel to yield Intermediate 2 (4.0 g, 20 mmol, 50% yield) as brown solid. ¹H NMR (400MHz, DMSO-d6): į 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). Intermediate 3: tert-Butyl (1-(4-bromo-2,3-difluorophenyl)-2-oxopyrrolidin-3- yl)carbamate To a stirred solution of Intermediate 2 (1.0 g, 5.0 mmol) in 1,4-dioxane (10 mL), were added 1,4-dibromo-2,3-difluorobenzene (1.6 g, 6.0 mmol), and Cs2CO3 (3.3 g, 10 mmol). The reaction mixture was purged with nitrogen for 5 min and charged 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 120°C for 16 h. The reaction mixture was cooled, filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. The crude product was purified using column chromatography (pet. ether-EtOAc) to yield Intermediate 3 (1.1 g, 2.8 mmol, 47% yield) as brown solid. MS(ESI) m/z: 391.2 (M+H)⁺. ¹H NMR (400MHz, DMSO-d₆) į 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). Intermediate 4: tert-butyl (1-(2,3-difluoro-4-iodophenyl)-2-oxopyrrolidin-3-yl)carbamate A 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 110 °C for 15 h. The reaction mixture was diluted with EtOAc, filtered through Celite, and concentrated under reduced pressure. The crude product was purified by column chromatography (EtOAc-hexanes) to obtain Intermediate 4 (1.4 g, 3.2 mmol, 32% yield) as a brown solid. MS(ESI) m/z: 439.2 (M+H)⁺.¹H NMR (300 MHz, CDCl₃į = 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), 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) at 0 °C. The reaction mixture was stirred at rt overnight under nitrogen. The reaction mixture was concentrated in vacuo, and the crude product was purified by column chromatography (MeOH/DCM). The product was recrystallized with EtOAc/pet. ether to obtain Intermediate 5 (32 g, 70 mmol, 70% yield) as a white solid. MS(ESI) m/z: 201.2 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d6) į = 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). Intermediate 6: tert-butyl (R)-(1-(2,3-difluoro-4-bromophenyl)-2-oxopyrrolidin-3- yl)carbamate A reaction mixture of Intermediate 5 (20 g, 100 mmol), 2,3-difluoro-1,4- dibromobenzene (14 g, 110 mmol), potassium phosphate tribasic (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 65 °C for 12 h. The reaction mixture was diluted with EtOAc, filtered through Celite, and concentrated under reduced pressure. The crude product was purified by column chromatography (35% EtOAc in pet ether) and recrystallized (EtOAc/pet ether) to obtain 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) į = 7.54 (ddd, J = 8.5, 6.3, 2.3 Hz, 1H), 7.09 (ddd, J = 8.5, 6.3, 2.3 Hz, 1H), 5.16 (br. s., 1H), 4.41 - 4.30 (m, 1H), 1.48 (m, To a stirred solution of 4-bromo-2,6-difluoroaniline (5.0 g, 24 mmol) in acetonitrile (20 mL) at 0°C under argon atmosphere, were added potassium phosphate tribasic (2.55 g, 12.0 mmol) and 2,4-dibromobutanoyl chloride (3.18 mL, 24.0 mmol). The resulting reaction mixture was gradually warmed up to rt over 30 min and stirred for additional 1 hour. A solution of 6N aqueous NaOH (1 mL, 6.00 mmol) was added to the reaction mixture and the mixture was stirred for an additional 16 hours. After completion, the reaction mixture was filtered through Celite pad and washed with acetonitrile (10 mL). The filtrate was concentrated under reduced pressure to afford crude 3-bromo-1-(4-bromo-2,6- difluorophenyl)pyrrolidin-2-one (8.0 g, 23 mmol, 94% yield) as a pale yellow liquid, which was taken to the next step without further purification. MS(ESI) m/z: 354.0 [M+H]⁺. Intermediate 8: 3-amino-1-(4-bromo-2,6-difluorophenyl)pyrrolidin-2-one To a stirred solution of 3-bromo-1-(4-bromo-2,6-difluorophenyl)pyrrolidin-2-one (8.0 g, 23 mmol) in acetonitrile (50 mL) at rt under argon atmosphere, was added ammonium hydroxide (29.3 mL, 225 mmol). The resulting reaction mixture was gradually heated to 40 °C and stirred for 16 h. The reaction mixture was cooled to rt 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 afford crude 3-amino-1-(4-bromo-2,6-difluorophenyl)pyrrolidin-2-one (5.0 g, 17 mmol, 76% yield) as a pale yellow liquid, which was taken to next step without any purification. Intermediate 9: tert-butyl (1-(4-bromo-2,6-difluorophenyl)-2-oxopyrrolidin-3- yl)carbamate To a stirred solution of 3-amino-1-(4-bromo-2,6-difluorophenyl)pyrrolidin-2-one (6.0 g, 21 mmol) in THF (100 mL) at rt under argon atmosphere, were added 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 Celite pad and the filtrate was concentrated under reduced pressure and purified through silica gel column chromatography (60% EtOAc-pet. ether) to afford tert-butyl (1-(4-bromo-2,6-difluorophenyl)-2-oxopyrrolidin-3- yl)carbamate (5.0 g, 12 mmol, 62 % yield) as an off-white solid. MS(ESI) m/z: 391.1 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) į = 7.64 (br d, J = 9.0 Hz, 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). To a stirred solution of tert-butyl (R)-(1-(4-bromo-2,3-difluorophenyl)-2- oxopyrrolidin-3-yl)carbamate (Intermediate 6) (2.0 g, 5.1 mmol) in toluene (20 mL) at rt, were added (3R)-(+)-3-(dimethylamino)pyrrolidine (0.58 g, 5.1 mmol) and cesium carbonate (3.33 g, 10.2 mmol). The reaction mixture was purged with nitrogen for 5 min and 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 100 °C for 16 h. The reaction mixture was cooled and filtered through a Celite pad. The filtrate was concentrated under reduced pressure to give the crude compound which was purified by column chromatography (pet. ether-ethyl acetate as eluent with 1% TEA) to afford tert- butyl ((R)-1-(4-((R)-3-(dimethylamino)pyrrolidin-1-yl)-2,3-difluorophenyl)-2- oxopyrrolidin-3-yl)carbamate (850 mg, 2.00 mmol, 39.2 % yield) as a brown solid. MS(ESI) m/z: 425.3 [M+H]⁺. Intermediate 11: (R)-3-Amino-1-(4-((R)-3-(dimethylamino)pyrrolidin-1-yl)-2,3- difluorophenyl)pyrrolidin-2-one hydrochloride To a stirred solution of tert- (dimethylamino)pyrrolidin-1-yl)- 2,3-difluorophenyl)-2-oxopyrrolidin-3-yl)carbamate (Intermediate 10) (0.85 g, 2.0 mmol) in 1,4-dioxane (10 mL) under argon atmosphere at rt, was added 4M HCl (10.0 mL, 40.0 mmol) in 1,4-dioxane and stirred for two h. The solvent was evaporated under reduced pressure to obtain a gummy solid, which was further triturated with diethyl ether (10 ml x 2) and dried to afford (R)-3-amino-1-(4-((R)-3-(dimethylamino)pyrrolidin-1-yl)-2,3- difluorophenyl)pyrrolidin-2-one hydrochloride (0.65 g, 1.8 mmol, 90% yield) as a brown solid. MS(ESI) m/z: 325.3 Example 1: 1-(4-chlorophenyl)-3-((R)-1-(4-((R)-3-(dimethylamino)pyrrolidin-1-yl)-2,3- To a stirred suspension of (R)-3-amino-1-(4-((R)-3-(dimethylamino)pyrrolidin-1- yl)-2,3-difluorophenyl)pyrrolidin-2-one hydrochloride (Intermediate 11) (350 mg, 0.97 mmol) in DCM (10 mL) under argon atmosphere at rt, were added DIPEA (0.51 mL, 2.9 mmol) and 1-chloro-4-isocyanatobenzene (150 mg, 0.97 mmol). The resulting solution was stirred at rt for 3 h. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by reverse phase chromatography followed by chiral HPLC to afford 1-(4-chlorophenyl)-3-((R)-1-(4-((R)-3-(dimethylamino)pyrrolidin-1-yl)- 2,3-difluorophenyl)-2-oxopyrrolidin-3-yl)urea (300 mg, 64 % yield) as off white solid. The following Examples in Table 2 were made by using analogous procedures as shown above in Intermediates 1-11 and Example 1. Table 2 It will be evident to one skilled in the art that the present disclosure is not limited to the foregoing illustrative examples, and that it can be embodied in other specific forms without departing from the essential attributes thereof. It is therefore desired that the examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing examples, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

Claims

WHAT IS CLAIMED IS 1. A compound of formula I or a pharmaceutically acceptable salt thereof, wherein R¹ is halo or haloalkyl; R² is halo; R³ is hydrogen; R⁵ is lower alkyl or hydroxyalkyl; and R⁶ is hydrogen or lower alkyl. The compound of claim 1 of formula II or a pharmaceutically acceptable salt thereof, wherein

R¹ is Cl; R² is F; R⁵ is C1-2 alkyl and R⁶ is C1-2 alkyl. The compound of claim 1 of formula III III or a pharmaceutically acceptable salt thereof, wherein R¹ is Cl or CF₃; R² is F; R⁵ is C1-2 alkyl or C1-2 hydroxyalkyl; and R⁶ is hydrogen or C1-2 alkyl.

4. A compound of formula IV

IV or a pharmaceutically acceptable salt thereof, wherein * is an asymmetric carbon atom; R¹ is halo or haloalkyl; and R² is halo.

5. The compound of formula V V or a pharmaceutically acceptable salt thereof, wherein R¹ is Cl or CF₃; and R² is F.

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

7. A compound according to any one of claims 1-5 or a pharmaceutical composition according to claim 6 for use in therapy.

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

9. The method of claim 8 wherein the heart disease is selected from the group consisting of angina pectoris, unstable angina, myocardial infarction, heart failure, acute coronary disease, acute heart failure, chronic heart failure, and cardiac iatrogenic damage.

10. The method of claim 9 wherein the heart failure is selected from the group consisting of congestive heart failure, systolic heart failure, diastolic heart failure, heart failure with reduced ejection fraction (HF_REF), heart failure with preserved ejection fraction (HFPEF), acute heart failure, chronic heart failure of ischemic and non-ischemic origin.