EP4698515A1 - Carbocyclic phenylpyrrolidinone 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

CARBOCYCLIC PHENYLPYRROLIDINONE UREA FPR2 AGONISTS CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63/496,747, 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 carbocyclic phenylpyrrolidinone 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 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 lost 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). DESCRIPTION OF THE INVENTION The invention encompasses compounds of formula I, which are formyl peptide 2 (FPR2) receptor agonists and/or formyl peptide 1 (FPR1) 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 where: * is an asymmetric carbon atom; Ring A is C₆ aryl or 6-membered heteroaryl; Ring B is C₆ aryl or 6-membered heteroaryl; R¹ is halo, alkyl, or haloalkyl; R² halo or haloalkyl; R³ is C_3-5 alkyl substituted with 1-3 R⁴ or cycloalkyl substituted with (R⁵)(R⁶)NCO or C_1-4 alkyl substituted with 1-3 R⁴; R⁴ is halo, hydroxy, cyano, alkyl, alkoxy, (R⁵)(R⁶)N, (alkyl)₂(O)P, (alkoxy)₂(O)P, (alkoxy)(alkyl)(O)P, alkylSO2, or cycloalkylSO2; R⁵ is hydrogen, alkyl, alkylCO, or alkylSO2; R⁶ is hydrogen or alkyl; or NR⁵R⁶ taken together is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, and is substituted with 0-3 substituents selected from oxo, hydroxy, fluoro, alkyl, haloalkyl, alkoxy, and haloalkoxy; R⁷ is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl; or a pharmaceutically acceptable salt thereof. Another aspect of the invention is a compound of formula II where: R¹ is halo or haloalkyl; R² is halo; R⁴ is halo, hydroxy, cyano, alkyl, alkoxy, (R⁵)(R⁶)N, (alkyl)₂(O)P, alkylSO₂, or cycloalkylSO₂; R⁵ is hydrogen, alkyl, alkylCO, or alkylSO₂; R⁶ is hydrogen or alkyl; or NR⁵R⁶ taken together is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, and is substituted with 0-1 oxo; or a pharmaceutically acceptable salt thereof. Another aspect of the invention is a compound of formula III

where: R¹ is Cl or CF₃; R² is F; R⁴ is hydroxy, alkyl, (Me)2(O)P, or (Et)2(O)P; or a pharmaceutically acceptable salt thereof. Another aspect of the invention is a compound of formula IV where: R¹ is Cl or CF₃; R² is F; R⁴ is hydroxy, cyano, alkyl, alkoxy, (R⁵)(R⁶)N, (Me)2(O)P, (Et)2(O)P, alkylSO2, or cycloalkylSO2; R⁵ is hydrogen, alkyl, alkylCO, or alkylSO2; R⁶ is hydrogen or alkyl; or NR⁵R⁶ taken together is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, and is substituted with 0-3 substituents selected from oxo, hydroxy, fluoro, alkyl, haloalkyl, alkoxy, and fluoroalkoxy; or a pharmaceutically acceptable salt thereof. Another aspect of the invention is a compound of formula V where: R¹ is Cl or CF3; R² is F; R⁴ is hydroxy, (Me)2(O)P, or (Et)2(O)P; or a pharmaceutically acceptable salt thereof. Another aspect of the invention is a compound of formula VI

R² is F; R⁴ is hydroxy, (Me)₂(O)P, or (Et)₂(O)P; or a pharmaceutically acceptable salt thereof. Another aspect of the invention is a compound of formula VII R² is F; R⁴ is hydroxy, (Me)₂(O)P, or (Et)₂(O)P; or a pharmaceutically acceptable salt thereof. For a compound of Formulae I-VII, the scope of any instance of a variable substituent, including R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ can be used independently with the scope of any other instance of a variable substituent. As such, the invention includes combinations of the different aspects. Unless specified otherwise, these terms have the following meanings. “Alkyl” means a straight or branched alkyl group composed of 1 to 6 carbons. “Alkenyl” means a straight or branched alkyl group composed of 2 to 6 carbons with at least one double bond. “Alkynyl” means a straight or branched alkyl group composed of 2 to 6 carbons with at least one triple bond. “Cycloalkyl” means a monocyclic ring system composed of 3 to 7 carbons. Terms with a hydrocarbon moiety (e.g. alkoxy) include straight and branched isomers for the hydrocarbon portion. “Halo” includes fluoro, chloro, bromo, and iodo. “Haloalkyl” and “haloalkoxy” include all halogenated isomers from monohalo to perhalo. “Aryl” means a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 12 carbon atoms. Bicyclic ring systems can consist of a phenyl group fused to an aromatic or non-aromatic carbocyclic ring. Representative examples of aryl groups include but are not limited to phenyl, indanyl, indenyl, naphthyl, and tetrahydronaphthyl. “Heteroaryl” means a 5 to 7 membered monocyclic or 8 to 11 membered bicyclic aromatic ring system with 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Where a bonding attachment location is not specified, the bonding may be attached at any appropriate location as understood by practitioners in the art. Combinations of substituents and bonding patterns are only those that result in stable compounds as understood by practitioners in the art. Parenthetic and multiparenthetic terms are intended to clarify bonding relationships to those skilled in the art. For example, a term such as ((R)alkyl) means an alkyl substituent further substituted with the substituent R. 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. Table 1 Example hFPR2 cAMP2 EC₅₀ hFPR1 cAMP EC₅₀ (PM) (PM) 1 0.0022 0.83 2 0.0017 0.98 3 0.0062 1.1 4 0.0017 0.78 5 0.0013 1.5 6 0.0014 0.87 7 0.035 >10 8 0.00059 1.0 9 0.00067 0.57 10 0.0053 0.59 11 0.0049 0.50 12 0.0015 0.14 13 0.0011 0.29 14 0.0018 0.017 15 0.00041 0.022 16 0.069 1.5 17 0.055 0.12 Example hFPR2 cAMP2 EC₅₀ hFPR1 cAMP EC₅₀ (PM) (PM) 18 0.00023 0.029 19 0.00032 0.004 20 0.00010 0.028 21 0.0027 1.7 22 0.00098 0.26 23 0.010 2.0 24 0.0025 0.54 25 0.019 0.53 26 0.011 1.1 27 0.0092 0.29 28 0.0060 0.26 29 0.00077 2.7 30 0.0014 2.5 31 0.00065 1.0 32 0.0017 1.9 33 0.026 2.6 34 0.0011 0.20 35 0.00049 0.054 36 0.0022 0.20 37 0.0033 0.77 38 0.0032 0.63 39 0.0027 1.0 40 0.00048 1.6 41 0.0043 1.7 42 0.0048 >10 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, 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 disease comprising administering a therapeutically effective amount of a compound of formula I to a patient in conjunction 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. CHEMICAL 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, "} ¹ _{H" 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. Ac Acetic AcOH acetic acid Acn (or acetonitrile MeCN) Bn benzyl Boc tert-butyl carbonyl ^Boc ₂ ^{O Di-tert-butyl dicarbonate} Bu butyl dba dibenzylideneacetone DCE dichloroethane DCM dichloromethane DIEA or diisopropylethylamine DIPEA DME Dimethoxyethane DMF dimethylformamide DMEDA N,N'-dimethylethylenediamine DMSO dimethyl sulfoxide dppf 1,1ƍ-bis(diphenylphosphino)ferrocene Et ethyl EtOH ethanol EtOAc ethyl acetate i-Bu isobutyl i-Pr isopropyl Me methyl MeOH methanol NMP N-Methylpyrrolidone OAc Acetate Ph phenyl Pr propyl RuPhos 2-dicyclohexylphosphino-2',6'-diipropoxy-1,1'-biphenyl t-Bu tert-butyl TEA Triethylamine TFA Trifluoroacetic acid THF tetrahydrofuran 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 and B are substituted phenyl and heteroaryl groups, respectively, and can be prepared by the following one or more of the synthetic schemes. 1-Arylpyrrolidinone compounds of this invention wherein ring A is substituted phenyl and ring B is substituted phenyl or heteroaryl can be prepared by the general route shown in Scheme 1, starting from a suitably substituted aryl halide such as compound 1a. Palladium or copper-catalyzed coupling of 1a to a substituted suitably protected 3- aminopyrrolidin-2-one, where PG is a protecting group such as Boc or Cbz. Methods for this transformation include 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, Surry & Buchwald Chem Sci.2011; 2(1): 27–50; Shaughnessy, Ciganek & DeVasher, Organic Reactions.2014, 85:1:1–668). Removal of the protecting group from 1b, followed by condensation of the resulting free amine with a suitably substituted aryl isocyanate, 1e or phenylcarbamate 1f can provide ureas 1d. Suitable isocyanates or phenylcarbamates are either commercially available or can be readily obtained from the corresponding aylamine by methods known to one skilled in the art. Alternately, the ureas 1d can be obtained by treatment of the deprotected 3- aminopyrrolidin-2-one intermediate with 4-nitrophenylchloroformate to form the carbamate, followed by condensation with an appropriately substituted arylamine 1g. 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 1a and heteroaryl amine. Other aryl bromides that are substituted with heteroatom containing rings can be synthesized by those skilled in the art and be used in Scheme 1 to access other compounds of the invention. Substitution at R can be manipulated at intermediates 1a, 1b, 1c or 1d using synthetic methods known to those skilled in the art. Racemic compounds can be separated using either chiral HPLC or SFC to provide single enantiomers.

Scheme 1 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% NH} ₄ ^{OH) 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% acetonitrile, 0.05% TFA; Solvent B: 95% acetonitrile, 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% acetonitrile, 5% water with 10 mM ammonium acetate; Temperature: 50 ºC; Gradient: 0-100% B over 3 minutes, 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% acetonitrile; Solvent B: 95% acetonitrile, 5% buffer (0.05% TFA in water); Temperature: 50 ºC; Gradient: 0-100% B over 3 minutes, then a 1- minute 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% acetonitrile with 10 mM ammonium formate; Solvent B: 95% acetonitrile, 5% water with 10 mM ammonium formate; Temperature: 50 ºC; Gradient: 0-100% B over 3 minutes, 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. co-solvent: 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. co-solvent: 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. co-solvent: 0.2% ammonia in Acn: MeOH (1:1) NMR Employed in Characterization of Examples.¹H 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} CD₂HOD, 1.94 for CD₃CN, and 7.24 ppm for CHCl₃, and which in 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} s_{pectra were proton decoupled.} Intermediate 1: 1-(4-Bromo-2,3-difluorophenyl)cyclopropane-1-carbonitrile To a stirred solution of 2-(4-bromo-2,3-difluorophenyl)acetonitrile (3.00 g, 12.9 mmol) in THF (30 mL) under argon atmosphere at 0 ^ was added NaH (1.29 g, 32.3 mmol) and the mixture was stirred for 30 min. A solution of 1,2-dibromoethane (2.67 g, 14.2 mmol) in THF (5 mL) was added to the reaction mixture. The mixture was gradually warmed to rt and stirred for 15 h. The reaction mixture was quenched with saturated ammonium chloride solution (10 mL) and extracted with ethyl acetate (100 mL x 2). The combined organics were washed with brine (50 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 1-(4-bromo-2,3- difluorophenyl)cyclopropane-1-carbonitrile (2.9 g, 11 mmol, 87% yield) as brown liquid. 1H NMR (400 MHz, CDCl₃) į = 7.28 - 7.39 (m, 1 H), 7.01 - 7.11 (m, 1 H), 1.40 - 1.48 (m, 2 H), 1.21 - 1.31 (m, 2 H). Intermediate 2: 1-(4-Bromo-2,3-difluorophenyl)cyclopropane-1-carbaldehyde To a stirred solution of 1-(4-bromo-2,3-difluorophenyl)cyclopropane-1- carbonitrile (2.50 g, 9.69 mmol) in diethyl ether (40 mL) at -10 ^ under argon atmosphere was added 1.2M DIBAL-H (8.90 mL, 10.7 mmol) in toluene. The reaction mixture was gradually warmed to 5 ^ over a period of 2 h and quenched with a 1N aqueous HCl (50 mL) solution. The biphasic layer was extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over MgSO₄ and concentrated under reduced pressure to give 1-(4-bromo-2,3- difluorophenyl)cyclopropane-1-carbaldehyde (2.10 g, 8.04 mmol, 83% yield) as brown liquid.¹H NMR (400 MHz, CDCl3) į = 9.00 (d, J = 1.51 Hz, 1 H), 7.29 - 7.35 (m, 1 H), 6.88 - 6.94 (m, 1 H), 1.66 - 1.71 (m, 2 H), 1.42 - 1.47 (m, 2 H). Intermediate 3: tert-Butyl (R)-(1-(2,3-difluoro-4-(1-formylcyclopropyl)phenyl)-2- To a stirred solution of tert-butyl (R)-(2-oxopyrrolidin-3-yl)carbamate (500 mg, 2.50 mmol) in 1,4-dioxane (10 mL) at rt, were added 1-(4-bromo-2,3- difluorophenyl)cyclopropane-1-carbaldehyde (978 mg, 3.75 mmol), and K3PO4 (1.06 g, 4.99 mmol). The reaction mixture was purged with nitrogen for 5 min and then charged with dimethylethylenediamine (44 mg, 0.50 mmol) and copper (I) iodide (48 mg, 0.25 mmol). The reaction mixture was again purged with nitrogen for 3 min and heated at 90 °C for 6 h. The brown color reaction mixture was cooled, filtered through Celite and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (pet. ether/ ethyl acetate) to afford the tert-butyl (R)-(1-(2,3- difluoro-4-(1-formylcyclopropyl)phenyl)-2-oxopyrrolidin-3-yl)carbamate (700 mg, 1.84 mmol, 73.7 % yield) as brown solid. MS(ESI) m/z: 381.2 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) į = 8.72 - 8.78 (m, 1 H), 7.22 - 7.36 (m, 2 H), 7.09 - 7.21 (m, 1 H), 4.28 - 4.41 (m, 1 H), 3.64 - 3.81 (m, 2 H), 2.30 - 2.44 (m, 1 H), 1.97 - 2.11 (m, 1 H), 1.65 - 1.75 (m, 2 H), 1.47 - 1.54 (m, 2 H), 1.34 - 1.44 (m, 9 H). Intermediate 4: tert-Butyl (R)-(1-(2,3-difluoro-4-(1-(hydroxymethyl)cyclopropyl)phenyl)- 2-oxopyrrolidin-3-yl)carbamate To a stirred solution of tert-butyl (R)-(1-(2,3-difluoro-4-(1- formylcyclopropyl)phenyl)-2-oxopyrrolidin-3-yl)carbamate (400 mg, 1.05 mmol) in THF (10 mL)-methanol (2 mL) under argon atmosphere at 0 °C, was added sodium borohydride (43.8 mg, 1.16 mmol) and the mixture was stirred for 30 min. The reaction mixture was quenched by addition of 1N aqueous HCl (12 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na₂SO₄ and concentrated under reduced pressure to afford tert- butyl (R)-(1-(2,3-difluoro-4-(1-(hydroxymethyl)cyclopropyl)phenyl)-2-oxopyrrolidin-3- yl)carbamate (350 mg, 0.92 mmol, 87% yield) as brown solid, which was taken to next step without further purification.. MS(ESI) m/z: 327.1 [M+H-isobutylene]⁺. Intermediate 5: tert-Butyl (R)-(1-(2,3-difluoro-4-(1-(iodomethyl)cyclopropyl)phenyl)-2- To a stirred solution of tert-butyl (R)-(1-(2,3-difluoro-4-(1- (hydroxymethyl)cyclopropyl)phenyl)-2-oxopyrrolidin-3-yl)carbamate (300 mg, 0.785 mmol) in DCM (10 mL) under argon atmosphere at rt, were added triphenylphosphine (247 mg, 0.941 mmol), imidazole (64 mg, 0.94 mmol) and iodine (240 mg, 0.94 mmol). The resulting reaction mixture was stirred for 3 h and then concentrated under reduced pressure to give the crude product, which was purified by column chromatography (pet. ether/ethyl acetate) to afford the tert-butyl (R)-(1-(2,3-difluoro-4-(1- (iodomethyl)cyclopropyl)phenyl)-2-oxopyrrolidin-3-yl)carbamate (220 mg, 0.45 mmol, 49% yield) as off white solid. MS(ESI) m/z: 437.1 [M+H-isobutylene]⁺. Intermediate 6: tert-Butyl (R)-(1-(2,3-difluoro-4-(1- ((methylsulfonyl)methyl)cyclopropyl)phenyl)-2-oxopyrrolidin-3-yl)carbamate To a stirred solution of tert-butyl (R)-(1-(2,3-difluoro-4-(1- (iodomethyl)cyclopropyl)phenyl)-2-oxopyrrolidin-3-yl)carbamate (190 mg, 0.39 mmol) in ethanol (8 mL) under argon atmosphere at rt, was added sodium methanesulfinate (197 mg, 1.93 mmol) and the resulting reaction mixture was heated at 90 °C for 15 h. The reaction mixture was cooled, and concentrated under reduced pressure. The residue was purified by column chromatography (pet. ether/ethyl acetate) to afford the tert-butyl (R)- (1-(2,3-difluoro-4-(1-((methylsulfonyl)methyl)cyclopropyl)phenyl)-2-oxopyrrolidin-3- yl)carbamate (125 mg, 0.281 mmol, 72.9 % yield) as a brown solid. MS(ESI) m/z: 389.3 [M+H-isobutylene]⁺. Intermediate 7: (R)-3-Amino-1-(2,3-difluoro-4-(1- 2-one hydrochloride To a stirred solution of tert-butyl (R)-(1-(2,3-difluoro-4-(1- ((methylsulfonyl)methyl)cyclopropyl)phenyl)-2-oxopyrrolidin-3-yl)carbamate (400 mg, 0.90 mmol) in 1,4-dioxane (2 mL) under argon atmosphere at rt, was added 4M HCl (4.50 mL, 18.0 mmol) in 1,4-dioxane and stirred for two h. The solvent was evaporated under reduced pressure to obtain a gummy solid. It was further triturated with diethyl ether (10 mL x 2) and dried to afford (R)-3-amino-1-(2,3-difluoro-4-(1- ((methylsulfonyl)methyl)cyclopropyl)phenyl)pyrrolidin-2-one hydrochloride (325 mg, 0.853 mmol, 95 % yield) as brown solid. MS(ESI) m/z: 345.3 [M+H]⁺. Example 1: (R)-1-(4-Chloro-2-fluorophenyl)-3-(1-(2,3-difluoro-4-(1- ((methylsulfonyl)methyl)cyclopropyl)phenyl)-2-oxopyrrolidin-3-yl)urea To a stirred solution of ((R)-3-amino-1-(2,3-difluoro-4-(1- ((methylsulfonyl)methyl)cyclopropyl)phenyl)pyrrolidin-2-one hydrochloride (200 mg, 0.53 mmol) in DCE (10 mL) at rt, were added DIPEA (0.28 mL, 1.6 mmol) and phenyl (4-chloro-2-fluorophenyl)carbamate (170 mg, 0.63 mmol) and the mixture was heated at 50 °C 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 (R)-1-(4-chloro-2-fluorophenyl)-3-(1-(2,3-difluoro-4-(1- ((methylsulfonyl)methyl)cyclopropyl)phenyl)-2-oxopyrrolidin-3-yl)urea (100 mg, 0.19 mmol, 37% yield) as off white solid. MS(ESI) m/z: 516.2 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) į = 8.62 (s, 1H), 8.14 (t, J = 9.0 Hz, 1H), 7.42 (dd, J = 11.0, 2.3 Hz, 1H), 7.33 - 7.10 (m, 4H), 4.57 - 4.47 (m, 1H), 3.86 - 3.77 (m, 1H), 3.73 - 3.62 (m, 1H), 3.46 (s, 2H), 2.87 (s, 3H), 2.59 - 2.53 (m, 1H), 2.09 - 1.97 (m, 1H), 1.18 - 1.12 (m, 2H), 1.05 - 1.01 (m, 2H). Example 2: (R)-1-(1-(2,3-Difluoro-4-(1-((methylsulfonyl)methyl)cyclopropyl)phenyl)-2- oxopyrrolidin-3-yl)-3-(2-fluoro-4-(trifluoromethyl)phenyl)urea To a stirred suspension of (R)-3-amino-1-(2,3-difluoro-4-(1- ((methylsulfonyl)methyl)cyclopropyl)phenyl)pyrrolidin-2-one hydrochloride (250 mg, 0.66 mmol) in DCE (2 mL) at rt, were added DIPEA (0.35 mL, 2.0 mmol) and phenyl (2- fluoro-4-(trifluoromethyl)phenyl)carbamate (200 mg, 0.66 mmol) and heated at 50 °C over a period of 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 (R)-1-(1-(2,3-difluoro-4-(1- ((methylsulfonyl)methyl)cyclopropyl)phenyl)-2-oxopyrrolidin-3-yl)-3-(2-fluoro-4- (trifluoromethyl)phenyl)urea (67 mg, 0.12 mmol, 19 % yield) as off white solid. MS(ESI) m/z: 550.1 [M+H]⁺.¹H NMR (400 MHz, DMSO-d6) į = 8.99 (s, 1H), 8.39 (t, J = 8.4 Hz, 1H), 7.64 (dd, J = 11.4, 2.0 Hz, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.41 (d, J = 7.3 Hz, 1H), 7.33 - 7.18 (m, 2H), 4.61 - 4.48 (m, 1H), 3.84 - 3.81 (m, 1H), 3.73 - 3.64 (m, 1H), 3.47 (s, 2H), 2.87 (s, 3H), 2.61 - 2.54 (m, 1H), 2.14 - 1.98 (m, 1H), 1.20 - 1.13 (m, 2H), 1.07 - 0.97 (m, 2H).^ The following Examples in Table 2 were made by using the same procedure as shown above in Examples 1 and 2. Table 2 HPLC ^{# Structure IUPAC LCMS} Method, (_M+H)+ RT (min.) 1H NMR & Purity ¹H NMR (400 MHz, DMSO- d₆) į = 8.64 (d, J = 1.8 Hz, 1-(4-Chloro-2- 1H), 8.14 (t, J = 8.9 Hz, 1H), fluorophenyl)-3- 7.42 (dd, J = 11.0, 2.3 Hz, ((3R)-1-(4-(1- 1H), 7.32 - 7.14 (m, 4H), 6.06 ((dimethylphosphor Method C, (br s, 1H), 4.56 - 4.47 (m, yl)(hydroxy)methyl 559.2 RT = 1.552 1H), 3.98 - 3.93 (m, 1H), 3.85 )cyclopentyl)-2,3- min, 100% - 3.77 (m, 1H), 3.73 - 3.67 (m, difluorophenyl)-2- 1H), 2.64 - 2.56 (m, 1H), 2.47 oxopyrrolidin-3- - 2.44 (m, 1H), 2.07 - 1.90 (m, yl)urea 3H), 1.80 - 1.66 (m, 3H), 1.62 - 1.47 (m, 2H), 1.18 (d, J = 12.8 Hz, 3H), 0.91 (d, J = 12.8 Hz, 3H). 1H NMR (400 MHz, DMSO- d₆) į = 8.67 (br s, 1H), 8.13 (t, 1-(4-Chloro-2- J = 8.9 Hz, 1H), 7.41 (dd, J = fluorophenyl)-3- 11.1, 2.1 Hz, 1H), 7.34 - 7.11 ((3R)-1-(4-(1- (m, 4H), 6.20 - 6.02 (m, 1H), ((dimethylphosphor Method C, 4.59 - 4.44 (m, 1H), 3.96 (br yl)(hydroxy)methyl 559.2 RT = 1.554 d, J = 3.5 Hz, 1H), 3.89 - 3.78 )cyclopentyl)-2,3- min, 100% (m, 1H), 3.69 (br t, J = 8.9 difluorophenyl)-2- Hz, 1H), 2.55 (br s, 1H), 2.47 oxopyrrolidin-3- - 2.39 (m, 1H), 2.12 - 1.86 (m, yl)urea 3H), 1.80 - 1.47 (m, 5H), 1.17 (br d, J = 12.5 Hz, 3H), 0.92 (br d, J = 12.5 Hz, 3H). 1H NMR (400 MHz, DMSO- d₆) į = 9.04 (br s, 1H), 8.38 (t, 1-((3R)-1-(4-(1- J = 8.1 Hz, 1H), 7.68 - 7.58 ((Dimethylphospho (m, 1H), 7.54 - 7.42 (m, 2H), ryl)(hydroxy)methy 7.35 - 7.16 (m, 2H), 6.10 (s, l)cyclopentyl)-2,3- Method D, 1H), 4.59 - 4.46 (m, 1H), 3.95 difluorophenyl)-2- 592.1 RT = 1.392 (d, J = 4.3 Hz, 1H), 3.86 - oxopyrrolidin-3- min, 100% 3.77 (m, 1H), 3.75 - 3.67 (m, yl)-3-(2-fluoro-4- 1H), 2.65 - 2.54 (m, 2H), 2.46 (trifluoromethyl)ph - 2.39 (m, 1H), 2.12 - 2.01 (m, enyl)urea 1H), 2.00 - 1.84 (m, 2H), 1.77 - 1.44 (m, 4H), 1.17 (d, J = 12.8 Hz, 3H), 0.90 (d, J = 12.8 Hz, 3H). 1H NMR (400 MHz, DMSO- d6) į = 8.90 (br s, 1H), 8.39 1-((3R)-1-(4-(1- (br t, J = 8.3 Hz, 1H), 7.65 (br ((Dimethylphospho d, J = 11.5 Hz, 1H), 7.50 (br ryl)(hydroxy)methy d, J = 8.5 Hz, 1H), 7.38 - 7.13 l)cyclopentyl)-2,3- Method D, (m, 3H), 6.07 - 6.03 (m, 1H), difluorophenyl)-2- 592.1 RT = 1.697 4.60 - 4.49 (m, 1H), 3.96 (br t, oxopyrrolidin-3- min, 100% J = 5.4 Hz, 1H), 3.89 - 3.79 yl)-3-(2-fluoro-4- (m, 1H), 3.75 - 3.64 (m, 1H), (trifluoromethyl)ph 2.65 - 2.55 (m, 2H), 2.46 - enyl)urea 2.40 (m, 1H), 2.11 - 1.84 (m, 3H), 1.78 - 1.38 (m, 4H), 1.17 (br d, J = 12.8 Hz, 3H), 0.91 (br d, J = 12.8 Hz, 3H). ¹H NMR (400 MHz, DMSO- d₆) į = 8.90 (d, J = 2.8 Hz, 1-((3R)-1-(4-(1- 1H), 8.45 - 8.34 (m, 1H), 7.65 (Dimethylphosphor (dd, J = 11.5, 1.5 Hz, 1H), yl)-1-hydroxy-2- 7.50 (d, J = 9.3 Hz, 1H), 7.30 methylpropan-2- Method D, (d, J = 7.0 Hz, 1H), 7.29 - yl)-2,3- RT 7.17 (m, 2H), 5.88 - 5.76 (m, difluorophenyl)-2- 566.1 = 1.584 min, 1H), 4.59 - 4.47 (m, 1H), 4.05 oxopyrrolidin-3- 94.65% (dd, J = 7.8, 3.3 Hz, 1H), 3.86 yl)-3-(2-fluoro-4- - 3.78 (m, 1H), 3.74 - 3.65 (m, (trifluoromethyl)ph 1H), 2.53 (br s, 1H), 2.12 - enyl)urea 2.00 (m, 1H), 1.54 (s, 3H), 1.49 (s, 3H), 1.31 (d, J = 12.5 Hz, 3H), 1.23 (d, J = 12.5 Hz, 3H). 1H NMR (400 MHz, DMSO- d₆) į = 8.90 (br s, 1H), 8.40 (t, J = 8.0 Hz, 1H), 7.65 (dd, J = 1-((3R)-1-(4-(1- 11.5, 1.8 Hz, 1H), 7.51 -7.49 ((Dimethylphospho (m, 1H), 7.31 (d, J = 7.3 Hz, ryl)(hydroxy)methy 1H), 7.26 - 7.24 (m, 2H), 6.17 l)cyclobutyl)-2,3- Method D, - 6.12 (m, 1H), 4.56 - 4.53 (m, difluorophenyl)-2- 578.1 RT = 1.638 1H), 4.7 - 4.14 (m, 1H), 3.82 oxopyrrolidin-3- min, (dt, J = 9.5, 6.3 Hz, 1H), 3.73 yl)-3-(2-fluoro-4- 97.92% - 3.71 (m, 1H), 2.84 - 2.75 (m, (trifluoromethyl)ph 1H), 2.68 - 2.67 (m, 1H), 2.58 enyl)urea - 2.50 (m, 1H), 2.35 - 2.32 (m, 2H), 2.10 - 2.03 (m, 2H), 1.82 - 1.70 (m, 1H), 1.22 (d, J = 12.8 Hz, 3H), 0.86 (d, J = 12.8 Hz, 3H). 1H NMR (400 MHz, DMSO- d₆) į = 8.90 (br s, 1H), 8.39 (t, J = 8.0 Hz, 1H), 7.65 (dd, J = 1-((3R)-1-(4-(1- 11.5, 1.8 Hz, 1H), 7.53 - 7.44 ((Dimethylphospho (m, 1H), 7.31 (d, J = 7.3 Hz, ryl)(hydroxy)methy 1H), 7.28 - 7.14 (m, 2H), 6.19 l)cyclobutyl)-2,3- Method D, - 6.06 (m, 1H), 4.62 - 4.48 (m, difluorophenyl)-2- 578.1 RT = 1.638 1H), 4.20 - 4.10 (m, 1H), 3.84 oxopyrrolidin-3- min, 100% (dt, J = 9.5, 6.3 Hz, 1H), 3.73 yl)-3-(2-fluoro-4- - 3.62 (m, 1H), 2.84 - 2.75 (m, (trifluoromethyl)ph 1H), 2.73 - 2.68 (m, 1H), 2.61 enyl)urea - 2.53 (m, 1H), 2.41 - 2.25 (m, 2H), 2.13 - 1.99 (m, 2H), 1.82 - 1.70 (m, 1H), 1.22 (d, J = 12.8 Hz, 3H), 0.86 (d, J = 12.8 Hz, 3H)

¹H NMR (400 MHz, DMSO- d₆) į = 8.93 (d, J = 2.9 Hz, 1-((3R)-1-(4-(1- 1H), 8.40 (t, J = 8.3 Hz, 1H), ((Diethylphosphory 7.70 - 7.61 (m, 1H), 7.51 (d, J l)(hydroxy)methyl) = 7.8 Hz, 1H), 7.38 - 7.27 (m, cyclopropyl)-2,3- Method D, 2H), 7.21-7.17 (m, 1H), 5.93 - difluorophenyl)-2- 592.2 RT = 1.64 5.89 (m, 1H), 4.59 - 4.50 (m, oxopyrrolidin-3- min, 98% 1H), 3.86 - 3.74 (m, 2H), 3.74 yl)-3-(2-fluoro-4- - 3.66 (m, 1H), 2.62 - 2.54 (m, (trifluoromethyl)ph 1H), 2.11 - 2.00 (m, 1H), 1.66 enyl)urea - 1.40 (m, 4H), 1.18 - 1.11 (m, 1H), 1.08 - 0.87 (m, 8H), 0.72 - 0.66 (m, 1H). 1H NMR (400 MHz, DMSO- d₆) į = 8.94 (d, J = 2.9 Hz, 1-((3R)-1-(4-(1- 1H), 8.40 (t, J = 8.3 Hz, 1H), ((Diethylphosphory 7.66 - 7.63 (m, 1H), 7.49 (d, J l)(hydroxy)methyl) = 7.8 Hz, 1H), 7.38 - 7.33 (m, cyclopropyl)-2,3- Method D, 2H), 7.21 - 7.17 (m, 1H), 5.91 difluorophenyl)-2- 592.2 RT = 1.65 - 5.87 (m, 1H), 4.59 - 4.50 (m, oxopyrrolidin-3- min, 97% 1H), 3.86 - 3.74 (m, 2H), 3.74 yl)-3-(2-fluoro-4- - 3.66 (m, 1H), 2.62 - 2.54 (m, (trifluoromethyl)ph 1H), 2.11 - 2.00 (m, 1H), 1.66 enyl)urea - 1.45 (m, 4H), 1.19 - 1.11 (m, 1H), 1.08 - 0.87 (m, 8H), 0.72 - 0.66 (m, 1H). 1H NMR (400 MHz, DMSO- 1-(4-Chloro-2- d₆) į = 8.66 (br s, 1H), 8.14 (t, fluorophenyl)-3- J = 8.9 Hz, 1H), 7.42 (dd, J = ((3R)-1-(4-(1- 11.1, 2.3 Hz, 1H), 7.38 - 7.27 ((diethylphosphoryl Method C, (m, 1H), 7.23 - 7.07 (m, 3H), )(hydroxy)methyl)c 558.2 RT = 1.44 5.91 (br s, 1H), 4.58 - 4.42 yclopropyl)-2,3- min, 100% (m, 1H), 3.87 - 3.73 (m, 2H), difluorophenyl)-2- 3.73 - 3.56 (m, 1H), 2.55 - oxopyrrolidin-3- 2.51 (m, 1H), 2.10 - 1.96 (m, yl)urea 1H), 1.67 - 1.35 (m, 4H), 1.15 - 1.10 (m, 1H), 1.07 - 0.82 (m, 8H), 0.73 - 0.63 (m, 1H). 1H NMR (400 MHz, DMSO- d₆) į = 8.67 (br s, 1H), 8.14 (t, 1-(4-Chloro-2- J = 8.9 Hz, 1H), 7.42 (dd, J = fluorophenyl)-3- 11.1, 2.3 Hz, 1H), 7.38 - 7.31 ((3R)-1-(4-(1- (m, 1H), 7.27 - 7.15 (m, 3H), ((diethylphosphoryl Method D, 5.89 (br s, 1H), 4.56 - 4.47 )(hydroxy)methyl)c 558.1 RT = 1.50 (m, 1H), 3.87 - 3.78 (m, 1H), yclopropyl)-2,3- min, 97% 3.75 (d, J = 4.6 Hz, 1H), 3.73 difluorophenyl)-2- - 3.65 (m, 1H), 2.59 - 2.53 (m, oxopyrrolidin-3- 1H), 2.09 - 1.97 (m, 1H), 1.67 yl)urea - 1.34 (m, 4H), 1.19 - 1.09 (m, 1H), 1.08 - 0.85 (m, 8H), 0.74 - 0.65 (m, 1H). ¹H NMR (400 MHz, DMSO- d₆) į = 8.92 (d, J = 2.9 Hz, (R)-N-((1-(2,3- 1H), 8.40 (t, J = 8.2 Hz, 1H), Difluoro-4-(3-(3- 7.98 - 7.84 (m, 1H), 7.66 (dd, (2-fluoro-4- J = 11.5, 2.0 Hz, 1H), 7.51 (br (trifluoromethyl)ph Method D, d, J = 8.6 Hz, 1H), 7.32 (d, J enyl)ureido)-2- 529.1 RT = 1.72 = 7.1 Hz, 1H), 7.27 - 7.10 (m, oxopyrrolidin-1- min,100% 2H), 4.61 - 4.47 (m, 1H), 3.87 yl)phenyl)cyclopro - 3.77 (m, 1H), 3.74 - 3.63 (m, pyl)methyl)acetami 1H), 3.25 (d, J = 6.1 Hz, 2H), de 2.63 - 2.54 (m, 1H), 2.14 - 2.00 (m, 1H), 1.74 (s, 3H), 0.97 - 0.88 (m, 2H), 0.80 - 0.68 (m, 2H). 1H NMR (400 MHz, DMSO- d₆) į = 8.62 (d, J = 2.2 Hz, (R)-N-((1-(4-(3-(3- 1H), 8.14 (t, J = 8.9 Hz, 1H), (4-chloro-2- 7.90 (t, J = 6.1 Hz, 1H), 7.42 fluorophenyl)ureid (dd, J = 11.1, 2.3 Hz, 1H 2-oxopyrrolidin- Meth ), o)- od D, 495 7.30 - 7.08 (m, 4H), 4.59 - 1-yl)-2,3- .1 RT = 1.58 4.44 (m, 1 uorophenyl)cycl min, 1 H), 3.87 - 3.76 (m, difl 00% 1H), 3.72 - 3.63 (m, 1H), 3.25 opropyl)methyl)ace (d, J = 6.1 Hz, 2H), 2.60 - tamide 2.53 (m, 1H), 2.11 - 1.97 (m, 1H), 1.74 (s, 3H), 0.96 - 0.87 (m, 2H), 0.79 - 0.71 (m, 2H). 1H NMR (400 MHz, DMSO- 1-(1-(2,3-Difluoro- d₆) į = 8.98 (s, 1H), 8.38 (t, J 4-(1-(pyrrolidin-1- = 8.4 Hz, 1H), 7.68 - 7.59 (m, ylmethyl)cycloprop 1H), 7.53 - 7.47 (m, 1H), 7.41 yl)phenyl)-2- Method C, (d, J = 7.0 Hz, 1H), 7.23 - oxopyrrolidin-3- 541.2 RT = 1.45 7.14 (m, 2H), 4.57 - 4.48 (m, yl)-3-(2-fluoro-4- min, 100% 1H), 3.84 - 3.77 (m, 1H), 3.73 (trifluoromethyl)ph - 3.67 (m, 1H), 2.54 - 2.50 (m, enyl)urea 3H), 2.46 - 2.39 (m, 4H), 2.10 - 2.01 (m, 1H), 1.62 - 1.57 (m, 4H), 0.90 - 0.73 (m, 4H). 1H NMR (400 MHz, DMSO- d6) į = 8.62 (br s, 1H), 8.14 (t, (R)-N-((1-(4-(3-(3- J = 8.9 Hz, 1H), 7.44 - 7.40 (4-Chloro-2- (m, 1H), 7.31 - 7.09 (m, 4H), fluorophenyl)ureid 4.55 - 4.48 (m, 1H), 3.86 - o)-2-oxopyrrolidin- Method C, 3.78 (m, 1H), 3.73 - 3.64 (m, 1-yl)-2,3- 509.2 RT = 1.59 1H), 3.53 - 3.49 (2s, 2H), 2.89 difluorophenyl)cycl min, 100% - 2.85 (2s, 3H), 2.54 (br s, opropyl)methyl)-N- 1H), 2.13 - 1.98 (m, 1H), 1.86 methylacetamide - 1.54 (2s, 3H), 1.01 - 0.71 (m, 4H). (Mixture of interconvertible atrop isomers) ¹H NMR (400 MHz, DMSO- (R)-1-(1-(2,3- d₆) į = 9.00 (br s, 1H), 8.43 - Difluoro-4-(1-((2- 8.32 (m, 1H), 7.66 (br d, J = oxopyrrolidin-1- 11.0 Hz, 1H), 7.51 (br d, J = yl)methyl)cyclopro Method C, 8.6 Hz, 1H), 7.38 (br d, J = pyl)phenyl)-2- 555.2 RT = 1.77 6.8 Hz, 1H), 7.27 - 7.11 (m, oxopyrrolidin-3- min, 96% 2H), 4.58 - 4.48 (m, 1H), 3.89 yl)-3-(2-fluoro-4- - 3.78 (m, 1H), 3.74 - 3.67 (m, (trifluoromethyl)ph 1H), 3.38 - 3.34 (m, 4H), 2.62 enyl)urea - 2.54 (m, 1H), 2.13 - 2.00 (m, 3H), 1.91 - 1.80 (m, 2H), 1.04 - 0.78 (m, 4H). 1 (R)-1-(4-Chloro-2- H NMR (400 MHz, DMSO- fluorophenyl)-3-(1- d₆) į = 8.80 (s, 1H), 8.12 (t, J (2,3-difluoro-4-(1- = 8.8 Hz, 1H), 7.46 - 7.31 (m, ((2-oxopyrrolidin- Method C, 2H), 7.26 - 7.06 (m, 3H), 4.57 1- 521.2 RT = 1.63 - 4.41 (m, 1H), 3.87 - 3.76 (m, yl)methyl)cyclopro min, 100% 1H), 3.74 - 3.61 (m, 1H), 3.35 pyl)phenyl)-2- - 3.31 (m, 4H), 2.50 - 2.49 (m, oxopyrrolidin-3- 1H), 2.12 - 1.97 (m, 3H), 1.85 yl)urea - 1.82 (m, 2H), 0.99 - 0.75 (m, 4H). 1H NMR (400 MHz, DMSO- d₆) į = 8.92 (br s, 1H), 8.41 - (R)-N-((1-(2,3- 8.37 (m, 1H), 7.67 -7.63 (m, Difluoro-4-(3-(3- 1H), 7.50 (d, J = 8.8 Hz, 1H), (2-fluoro-4- 7.33 (d, J = 7.3 Hz, 1H), 7.30 (trifluoromethyl)ph Method C, - 7.14 (m, 2H), 4.59 - 4.46 (m, enyl)ureido)-2- 543.2 RT = 1.73 1H), 3.88 - 3.77 (m, 1H), 3.72 oxopyrrolidin-1- min, 100% - 3.66 (m, 1H), 3.52 - 3.49 yl)phenyl)cyclopro (2s, 2H), 2.92 - 2.79 (2s, 3H), pyl)methyl)-N- 2.60 - 2.54 (m, 1H), 2.11 - methylacetamide 1.99 (m, 1H), 1.86 - 1.53 (2s, 3H), 0.96 - 0.73 (m, 4H). (Mixture of interconvertible atrop isomers) 1H NMR (400 MHz, DMSO- d₆) į = 8.91 (d, J = 2.4 Hz, 1H), 8.40 (t, J = 8.1 Hz, 1H), 1-(1-(2,3-Difluoro- 7.69 - 7.61 (m, 1H), 7.51 (d, J 4-(1-(1-hydroxy-2- = 9.3 Hz, 1H), 7.34 - 7.19 (m, methylpropyl)cyclo 3H), 4.73 (d, J = 5.1 Hz, 1H), propyl)phenyl)-2- Method C, 4.58 - 4.48 (m, 1H), 3.86 - oxopyrrolidin-3- 530.2 RT = 2.01 3.78 (m, 1H), 3.75 - 3.68 (m, yl)-3-(2-fluoro-4- min, 100% 1H), 3.19 - 3.14 (m, 1H), 2.63 (trifluoromethyl)ph - 2.55 (m, 1H), 2.11 - 1.99 (m, enyl)urea 1H), 1.43 - 1.32 (m, 1H), 0.99 - 0.95 (m, 2H), 0.91 (d, J = 6.6 Hz, 3H), 0.82 (d, J = 6.6 Hz, 3H), 0.78 - 0.71 (m, 1H), 0.67 - 0.58 (m, 1H). ¹H NMR (400 MHz, DMSO- d₆) į = 8.93 (s, 1H), 8.39 (t, J = 8.2 Hz, 1H), 7.69 - 7.60 (m, 1-(1-(2,3-Difluoro- 1H), 7.50 (br d, J = 8.6 Hz, 4-(1-(1-hydroxy-2- 1H), 7.34 (d, J = 7.1 Hz, 1H), methylpropyl)cyclo 7.32 - 7.15 (m, 2H), 4.74 (d, J propyl)phenyl)-2- Method D, = 5.4 Hz, 1H), 4.58 - 4.48 (m, oxopyrrolidin-3- 530.1 RT = 2.01 1H), 3.86 - 3.78 (m, 1H), 3.74 yl)-3-(2-fluoro-4- min, 98% - 3.68 (m, 1H), 3.19 - 3.14 (m, (trifluoromethyl)ph 1H), 2.61 - 2.55 (m, 1H), 2.11 enyl)urea - 1.99 (m, 1H), 1.42 - 1.34 (m, 1H), 0.99 - 0.95 (m, 2H), 0.91 (d, J = 6.6 Hz, 3H), 0.82 (d, J = 6.6 Hz, 3H), 0.78 - 0.72 (m, 1H), 0.66 - 0.58 (m, 1H). 1H NMR (400 MHz, DMSO- d₆) į = 8.61 (s, 1H), 8.16 (t, J = 8.1 Hz, 1H), 7.43-7.40 (m, 1-(4-Chloro-2- 1H), 7.27-7.14 (m, 4H), 4.73 fluorophenyl)-3-(1- (d, J = 5.1 Hz, 1H), 4.51- 4.49 (2,3-difluoro-4-(1- (m, 1H), 3.81 - 3.79 (m 1-hydroxy-2- Me , 1H), ( thod D, 496.2 RT = 1. 3.72 - 3.69 (m, 1H), 3.17 - methylpropyl)cyclo 94 phenyl)-2- min, 96 3.15 (m, 1H), 2.68 - 2.66 (m, propyl) % 1H), 2.06 - 2.00 (m, 1H), 1.43 oxopyrrolidin-3- - 1.35 (m, 1H), 0.96 - 0.94 (m, yl)urea 2H), 0.91 (d, J = 6.6 Hz, 3H), 0.82 (d, J = 6.6 Hz, 3H), 0.76 - 0.74 (m, 1H), 0.63 - 0.61 (m, 1H). 1H NMR (400 MHz, DMSO- d₆) į = 8.63 (s, 1H), 8.13 (t, J = 8.1 Hz, 1H), 7.43-7.40 (m, 1-(4-Chloro-2- 1H), 7.29-7.16 (m, 4H), 4.73 fluorophenyl)-3-(1- (d, J = 5.1 Hz, 1H), 4.52- 4.50 (2,3-difluoro-4-(1- M (m, 1H), 3.81 - 3.79 (m, 1H), (1-hydroxy-2- ethod D, ylpropyl)cyclo 4 3.72 - 3.69 (m, 1H), 3.17 - meth 96.2 RT = 1.88 )-2- min, 9 3.15 (m, 1H), 2.68 - 2.66 (m, propyl)phenyl 7% 1H), 2.06 - 2.00 (m, 1H), oxopyrrolidin-3- 1.438 - 1.35 (m, 1H), 0.96 - yl)urea 0.94 (m, 2H), 0.91 (d, J = 6.6 Hz, 3H), 0.82 (d, J = 6.6 Hz, 3H), 0.76 - 0.74 (m, 1H), 0.63 - 0.61 (m, 1H). 1H NMR (400 MHz, DMSO- d₆) į = 8.72 (s, 1H), 8.12 (t, J (R)-1-(4-Chloro-2- = 8.9 Hz, 1H), 7.42 (dd, J = fluorophenyl)-3-(1- 11.2, 2.2 Hz, 1H), 7.32 - 7.23 (2,3-difluoro-4-(1- (m, 3H), 7.21 - 7.16 (m, 1H) olidine-1- Method , (pyrr D, 521.1 RT = 1.61 4.54 - 4.47 (m, 1H), 3.85 - carbonyl)cycloprop 3.79 (m, 1H), l)-2- mi 3.73 - 3.71 (m, yl)pheny n, 100% 1H), 3.30 - 3.27 (m, 2H), 3.10 oxopyrrolidin-3- - 3.01 (m, 2H), 2.57 - 2.54 (m, yl)urea 1H), 2.07 - 2.01 (m, 1H), 1.77 - 1.64 (m, 4H), 1.42 - 1.35 (m, 2H), 1.20 - 1.14 (m, 2H). ¹H NMR (400 MHz, DMSO- d₆) į = 8.92 (d, J = 2.9 Hz, 1H), 8.40 (t, J = 7.9 Hz, 1H), 1-((R)-1-(2,3- 7.66 (dd, J = 11.5, 2.2 Hz, Difluoro-4-(1-(((S)- 1H), 7.51 (d, J = 10.0 Hz, 3- 1H), 7.33 (d, J = 7.1 Hz, 1H), hydroxypyrrolidin- 7.23 - 7.18 (m, 2H), 4.63 (br 1- Method D, d, J = 4.6 Hz, 1H), 4.58 - 4.48 yl)methyl)cyclopro 557.2 RT = 1.56 (m, 1H), 4.15 - 4.08 (m, 1H), pyl)phenyl)-2- min, 100% 3.82 - 3.80 (m, 1H), 3.72 - oxopyrrolidin-3- 3.70 (m, 1H), 3.17 - 3.16 yl)-3-(2-fluoro-4- (m,1H), 2.80 - 2.78 (m, 1H), (trifluoromethyl)ph 2.54 - 2.52 (m, 3H), 2.29 - enyl)urea 2.21 (m, 1H), 2.10 - 2.00 (m, 1H), 1.94 - 1.80 (m, 2H), 1.48 - 1.41 (m, 1H), 0.87 - 0.76 (m, 4H). 1H NMR (400 MHz, DMSO- d₆) į = 9.10 (br s, 1H), 8.39 (t, (R)-1-(1-(2,3- J = 8.3 Hz, 1H), 7.69 - 7.60 Difluoro-4-(1- (m, 1H), 7.56 (br d, J = 7.1 (hydroxymethyl)cy pyl)phenyl)- Method Hz, 1H), 7.50 (br d, J = 9.3 clopro C, idin-3- 488.1 RT = Hz, 1H), 7.29 - 7.15 (m, 2H),2-oxopyrrol 1.70 4.77 (br s, 1H), 4.57 - 4.50 yl)-3-(2-fluoro-4- min, 100% (m, 1H), 3.82 - 3.80 (m, 1H), (trifluoromethyl)ph 3.71 - 3.67 (m, 1H), 3.46 (s, enyl)urea 2H), 2.62 - 2.53 (m, 1H), 2.14 - 2.00 (m, 1H), 0.92 - 0.83 (m, 2H), 0.80 - 0.68 (m, 2H). 1H NMR (400 MHz, DMSO- d₆) į = 8.71 (s, 1H), 8.13 (t, J (R)-1-(4-chloro-2- = 8.8 Hz, 1H), 7.41 (dd, J = fluorophenyl)-3-(1- 11.0, 2.2 Hz, 1H), 7.28 (d, J = (2,3-difluoro-4-(1- Method D, 6.8 Hz, 1H), 7.24 - 7.13 (m, (hydroxymethyl)cy 454.1 RT = 1.55 3H), 4.77 (br s, 1H), 4.57 - clopropyl)phenyl)- min, 93% 4.44 (m, 1H), 3.85 - 3.75 (m,2-oxopyrrolidin-3- 1H), 3.72 - 3.63 (m, 1H), 3.46 yl)urea (s, 2H), 2.60 - 2.54 (m, 1H), 2.10 - 1.97 (m, 1H), 0.92 - 0.82 (m, 2H), 0.79 - 0.70 (m, 2H). 1H NMR (400 MHz, DMSO- d6) į = 8.91 (d, J = 2.4 Hz, 1H), 8.40 (t, J = 8.3 Hz, 1H), 1-((3R)-1-(4-(1- 7.69 - 7.64 (m, 1H), 7.51 (d, J ((Dimethylphospho = 8.6 Hz, 1H), 7.41 - 7.28 (m, ryl)(hydroxy)methy 2H), 7.21 (t, J = 7.6 Hz, 1H), l)cyclopropyl)-2,3- Method D, 5.94 (dd, J = 15.0, 6.7 Hz, difluorophenyl)-2- 564.2 RT = 1.56 1H), 4.55 - 4.50 (m, 1H), 3.88 oxopyrrolidin-3- min, 100% - 3.78 (m, 1H), 3.73 - 3.67 (m, yl)-3-(2-fluoro-4- 1H), 3.63 (t, J = 5.7 Hz, 1H), (trifluoromethyl)ph 2.61 - 2.54 (m, 1H), 2.11 - enyl)urea 1.99 (m, 1H), 1.29 (d, J = 13.0 Hz, 3H), 1.19 - 1.12 (m, 4H), 1.04 - 1.02 (m, 1H), 0.92 - 0.84 (m, 1H), 0.77 - 0.69 (m, 1H). ¹H NMR (400 MHz, DMSO- (R)-1-(1-(4-(1- d₆) į = 8.92 (d, J = 2.4 Hz, ((Dimethylphospho 1H), 8.40 (t, J = 8.4 Hz, 1H), ryl)methyl)cyclopr 7.66 (dd, J = 11.5, 2.3 Hz, opyl)-2,3- Method D, 1H), 7.51 (d, J = 8.3 Hz, 1H), difluorophenyl)-2- 548.1 RT = 1.63 7.39 - 7.26 (m, 2H), 7.26 - oxopyrrolidin-3- min, 100% 7.17 (m, 1H), 4.61 - 4.48 (m, yl)-3-(2-fluoro-4- 1H), 3.88 - 3.77 (m, 1H), 3.75 (trifluoromethyl)ph - 3.65 (m, 1H), 2.61 - 2.54 (m, enyl)urea 1H), 2.17 - 1.98 (m, 3H), 1.23 (d, J = 13.0 Hz, 6H), 1.04 - 0.81 (m, 4H). 1H NMR (400 MHz, DMSO- (R)-1-(4-Chloro-2- d₆) į = 8.62 (d, J = 2.4 Hz, fluorophenyl)-3-(1- 1H), 8.14 (t, J = 8.8 Hz, 1H), (4-(1- 7.42 (dd, J = 11.1 ,2.3 Hz, ((dimethylphosphor Method D, 1H), 7.32 - 7.26 (m, 1H), 7.26 yl)methyl)cyclopro 514.1 RT = 1.49 - 7.04 (m, 3H), 4.57 - 4.44 (m, pyl)-2,3- min, 100% 1H), 3.89 - 3.75 (m, 1H), 3.71 difluorophenyl)-2- - 3.58 (m, 1H), 2.58 - 2.53 (m, oxopyrrolidin-3- 1H), 2.15 - 1.95 (m, 3H), 1.22 yl)urea (d, J = 13.0 Hz, 6H), 1.03 - 0.81 (m, 4H). 1H NMR (400 MHz, DMSO- d₆) į = 8.91 (d, J = 2.4 Hz, 1H), 8.40 (t, J = 8.3 Hz, 1H), 7.69 - 7.64 (m, 1H), 7.51 (d, J 1-(1-(4-(1- = 8.6 Hz, 1H), 7.41 - 7.28 (m, ((Dimethylphospho 2H), 7.21 (t, J = 7.6 Hz, 1H), ryl)(hydroxy)methy 5.94 (dd, J = 15.0, 6.7 Hz, l)cyclopropyl)-2,3- Method D, 1H), 4.55 - 4.50 (m, 1H), 3.88 difluorophenyl)-2- 564.2 RT = 1.56 - 3.78 (m, 1H), 3.73 - 3.67 (m, oxopyrrolidin-3- min, 100% 1H), 3.63 (t, J = 5.7 Hz, 1H), yl)-3-(2-fluoro-4- 2.61 - 2.54 (m, 1H), 2.11 - (trifluoromethyl)ph 1.99 (m, 1H), 1.29 (d, J = enyl)urea 13.0 Hz, 3H), 1.19 - 1.12 (m, 1H), 1.10 (d, J = 13.0 Hz, 3H), 1.04 - 1.02 (m, 1H), 0.92 - 0.84 (m, 1H), 0.77 - 0.69 (m, 1H). 1H NMR (400 MHz, DMSO- d₆) į = 8.91 (d, J = 2.7 Hz, 1H), 8.40 (t, J = 8.4 Hz, 1H), 1-(1-(4-(1- 7.69 - 7.62 (m, 1H), 7.51 (d, J ((Dimethylphospho = 9.0 Hz, 1H), 7.39 - 7.29 (m, ryl)(hydroxy)methy 2H), 7.24 - 7.17 (m, 1H), 5.95 l)cyclopropyl)-2,3- Method D, (dd, J = 15.3, 6.5 Hz, 1H), difluorophenyl)-2- 564.2 RT = 1.56 4.55 - 4.53 (m, 1H), 3.87 - oxopyrrolidin-3- min, 100% 3.77 (m, 1H), 3.68 - 3.62 (m, yl)-3-(2-fluoro-4- 1H), 3.61 - 3.59 (m, 1H), 2.62 (trifluoromethyl)ph - 2.54 (m, 1H), 2.11 - 2.00 (m, enyl)urea 1H), 1.29 (d, J = 13.0 Hz, 3H), 1.20 - 1.14 (m, 1H), 1.11 (d, J = 13.0 Hz, 3H), 1.04 - 1.02 (m, 1H), 0.90 - 0.82 (m, 1H), 0.78 - 0.71 (m, 1H). ¹H NMR (400 MHz, DMSO- d₆) į = 8.90 (s, 1H), 8.39 (t, J (R)-1-(1-(2,3- = 8.3 Hz, 1H), 7.65 (dd, J Difluoro-4-(1- =11.4, 1.9 Hz, 1H), 7.50 (d, J ((isopropylsulfonyl Method E, = 8.8 Hz, 1H), 7.31 - 7.27 (m, )methyl)cyclopropy 578.2 RT = 2.73 3H), 4.57 - 4.51 (m, 1H), 3.82 l)phenyl)-2- min, 100% - 3.80 (m, 1H), 3.74 - 3.63 (m, oxopyrrolidin-3- 1H), 3.50 (s, 2H), 3.13 - 3.06 yl)-3-(2-fluoro-4- (m, 1H), 2.60 - 2.52 (m, 1H), (trifluoromethyl)ph 2.12 - 1.97 (m, 1H), 1.64 - 1.47 enyl)urea (m, 8H), 1.02 - 0.98 (m, 2H). 1H NMR (400 MHz, DMSO- d₆) į = 8.61 (s, 1H), 8.13 (t, J = 9.0 Hz, 1H), 7.41 (dd, J = (R)-1-(4-Chloro-2- 11.3, 2.5 Hz, 1H), 7.28 - fluorophenyl)-3-(1- Method E, 7.17(m, 4H), 4.54 - 4.48 (m, (2,3-difluoro-4-(1- 544.2 RT = 2.56 mi 1H), 3.81 -3.79 (m, 1H), 3.73 - ((isopropylsulfonyl n, 100% 3.62 (m, 1H), 3.50 (s, 2H), )methyl)cyclopropy 3.12 - 3.07 (m, 1H), 2.59 - 2.52 l)phenyl)-2- (m, 1H), 2.09 - 1.95 (m, 1H), oxopyrrolidin-3- 1.15 - 1.14 (m, 8H), 1.05-1.00 yl)urea (m, 2H). 1H NMR (400 MHz, DMSO- d₆) į = 8.61 (s, 1H), 8.13 (t, J (R)-1-(4-Chloro-2- = 9.0 Hz, 1H), 7.41 (dd, J = fluorophenyl)-3-(1- 11.3, 2.5 Hz, 1H), 7.33 - 7.03 (4-(1- Method D, (m, 4H), 4.59 - 4.45 (m, 1H), ((cyclopropylsulfon 542.1 RT = 1.63 3.81 - 3.79 (m, 1H), 3.73 - 3.62 yl)methyl)cyclopro min, 100% (m, 1H), 3.50 (s, 2H), 2.59 - pyl)-2,3- 2.52 (m, 2H), 2.09 - 1.95 (m, difluorophenyl)-2- 1H), 1.22 - 1.12 (m, 2H), 1.09 oxopyrrolidin-3- - 0.99 (m, 2H), 0.98 - 0.85 (m, yl)urea 4H). 1H NMR (400 MHz, DMSO- d₆) į = 8.90 (s, 1H), 8.39 (t, J F (R)-1-(1-(4-(1- = 8.3 Hz, 1H), 7.65 (dd, J HN ((Cyclopropylsulfo =11.4, 1.9 Hz, 1H), 7.50 (d, J HN CF nyl)methyl)cyclopr Method D, = 8.8 Hz, 1H), 7.35 - 7.13 (m, O opyl)-2,3- 576.1 RT = 1.78 3H), 4.60 - 4.43 (m, 1H), 3.82 N ^O difluorophenyl)-2- min, 100% - 3.80 (m, 1H), 3.74 - 3.63 (m, F oxopyrrolidin-3- 1H), 3.50 (s, 2H), 2.60 - 2.52 F O yl)-3-(2-fluoro-4- (m, 2H), 2.12 - 1.97 (m, 1H), S (trifluoromethyl)ph 1.22 - 1.13 (m, 2H), 1.09 - 1.00 O enyl)urea (m, 2H), 0.97 - 0.82 (m, 4H). 1H NMR (400 MHz, DMSO- d₆) į = 9.11 - 9.32 (m, 1H), 8.09 (t, J = 8.8 Hz, 1H), 7.92 (br d, J = 7.25 Hz, 1H), 7.38 1-(4-Chloro-2- (dd, J = 11.1, 2.4 Hz, 1H), 7.12 fluorophenyl)-3- Method C, - 7.28 (m, 3H), 6.03 (s, 1H), ((3R)-1-(4-(1- 53 RT = 1.373 4.51 (dt, J = 10.1, 8.2 Hz, 1H), (dimethylphosphor 2.1 min, 4.07 (d, J = 3.0 Hz, 1H), 3.76 - yl)-1-hydroxy-2- 95.13% 3.86 (m, 1H), 3.64 - 3.74 (m, methylpropan-2- 1H), 2.55 (m, 1H), 2.07 (td, J yl)-2,3- = 10.1, 2.4 Hz, 1H), 1.55 (s, difluorophenyl)-2- 3H), 1.49 (s, 3H), 1.32 (d, J = oxopyrrolidin-3- 12.3 Hz, 3H), 1.23 (d, J = 12.3 #NAME? yl)urea Hz, 3 H). ¹H NMR (400 MHz, DMSO- d₆) į = 8.81 (br s, 1H), 8.13 (t, 1-(4-Chloro-2- J = 8.8 Hz, 1H), 7.34 - 7.45 (m, fluorophenyl)-3- 2H), 7.13 - 7.30 (m, 3H), 5.86 ((3R)-1-(4-(1- Method C, (br s, 1H), 4.43 - 4.60 (m, 1H), (dimethylphosphor RT = 1.3 )-1-hydroxy-2- 532 70 4.06 (d, J = 3.0 Hz, 1H), 3.81 yl .1 min, (td, J = 9.2, 6.7 Hz, 1H), 3.66 - methylpropan-2- 98.84% 3.73 (m, 1H), 2.52 - 2.56 (m, yl)-2,3- 1H), 1.99 - 2.09 (m, 1H), 1.55 difluorophenyl)-2- (s, 3H), 1.49 (s, 3H), 1.32 (d, J oxopyrrolidin-3- = 12.5 Hz, 3H), 1.23 (d, J = #NAME? yl)urea 12.5 Hz, 3H). 1H NMR (400 MHz, DMSO- d₆) į = 8.91 (d, J = 2.3 Hz, 1H), 8.40 (t, J = 8.3 Hz, 1H), 7.66 (d, J = 11.5 Hz, 1H), 7.51 (d, J (R)-1-(1-(4-(1- = 8.5 Hz, 1H), 7.36 - 7.17 (m, ((Dimethylphospho Method C, 3H), 4.60 - 4.46 (m, 1H), 3.88 ryl)methyl)cyclope 576.2 RT = 1.786 - 3.80 (m, 1H), 3.76 - 3.66 (m, ntyl)-2,3- min, 100% 1H), 2.62 - 2.53 (m, 1H), 2.31 difluorophenyl)-2- - 2.14 (m, 4H), 2.11 - 1.92 (m, oxopyrrolidin-3- 3H), 1.83 - 1.70 (m, 2H), 1.67 yl)-3-(2-fluoro-4- - 1.52 (m, 2H), 1.04 (d, J = (trifluoromethyl)ph 12.5 Hz, 3H), 1.00 (d, J = 12.5 #NAME? enyl)urea Hz, 3H). 1H NMR (400 MHz, DMSO- d₆) į = 8.91 (br s, 1H), 8.39 (t, J = 8.3 Hz, 1H), 7.65 (dd, J = 11.6, 1.6 Hz, 1H), 7.50 (d, J = 1-((3R)-1-(4-(1- 8.5 Hz, 1H), 7.33 (d, J = 7.3 (Dimethylphosphor Method C, Hz, 1H), 7.29 - 7.12 (m, 2H), yl)-1-hydroxy-2- 566. RT = 1.562 5.94 - 5.75 (br s, 1H), 4.64 - methylpropan-2- 2 min, 4.46 (m, 1H), 4.08 - 4.03 (m, yl)-2,3- 97.34% 1H), 3.85 - 3.80 (m, 1H), 3.74 difluorophenyl)-2- - 3.62 (m, 1H), 2.63 - 2.53 (m, oxopyrrolidin-3- 1H), 2.12 - 1.96 (m, 1H), 1.54 yl)-3-(2-fluoro-4- (s, 3H), 1.49 (s, 3H), 1.32 (d, J (trifluoromethyl)ph = 12.5 Hz, 3H), 1.23 (d, J = #NAME? enyl)urea 12.5 Hz, 3H). 1H NMR (400 MHz, DMSO- d6) į = 8.91 (br d, J = 1.3 Hz, 1H), 8.39 (t, J = 8.5 Hz, 1H), #NAME? 7.65 (d, J = 11.0 Hz, 1H), 7.50 1-((3R)-1-(4-(1- (d, J = 8.5 Hz, 1H), 7.31 (d, J (Dimethylphosphor Method C, = 7.0 Hz, 1H), 7.28 - 7.16 (m, yl)-1-hydroxy-2- RT = 1.559 2H), 5.87 - 5.77 (br s, ropan-2- 566. 1H), methylp 2 min, 4.59 - 4.50 (m, 1H), 4.08 - 4.03 yl)-2,3- 98.40% (m, 1H), 3.86 - 3.79 (m, 1H), difluorophenyl)-2- 3.74 - 3.67 (m, 1H), 2.58 - 2.53 oxopyrrolidin-3- (m, 1H), 2.13 - 2.00 (m, 1H), yl)-3-(2-fluoro-4- 1.54 (s, 3H), 1.49 (s, 3H), 1.31 (trifluoromethyl)ph (d, J = 12.5 Hz, 3H), 1.23 (d, J enyl)urea = 12.5 Hz, 3H). ill be evident to one skilled in the art that the present disclosure is not limitedgoing 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

CLAIMS 1. A compound of formula I I where: * is an asymmetric carbon atom; Ring A is C₆ aryl or 6-membered heteroaryl; Ring B is C₆ aryl or 6-membered heteroaryl; R¹ is halo, alkyl, or haloalkyl; R² halo or haloalkyl; R³ is alkyl substituted with 1-3 R⁴ or cycloalkyl substituted with (R⁵)(R⁶)NCO or C1-4 alkyl substituted with 1-3 R⁴; R⁴ is halo, hydroxy, cyano, alkyl, alkoxy, (R⁵)(R⁶)N, (alkyl)2(O)P, (alkoxy)2(O)P, (alkoxy)(alkyl)(O)P, alkylSO2, or cycloalkylSO2; R⁵ is hydrogen, alkyl, alkylCO, or alkylSO2; R⁶ is hydrogen or alkyl; or NR⁵R⁶ taken together is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, and is substituted with 0-3 substituents selected from oxo, hydroxy, fluoro, alkyl, haloalkyl, alkoxy, and fluoroalkoxy; R⁷ is hydrogen, alkyl, hydroxyalkyl, or alkoxyalkyl; or a pharmaceutically acceptable salt thereof. A compound of claim 1 of formula II

II where: R¹ is halo or haloalkyl; R² is halo; R⁴ is halo, hydroxy, cyano, alkyl, alkoxy, (R⁵)(R⁶)N, (alkyl)2(O)P, alkylSO2, or cycloalkylSO2; R⁵ is hydrogen, alkyl, alkylCO, or alkylSO2; R⁶ is hydrogen or alkyl; or NR⁵R⁶ taken together is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, and is substituted with 0-1 oxo; or a pharmaceutically acceptable salt thereof. A compound of claim 2 of formula III R¹ is Cl or CF₃; R² is F; R⁴ is hydroxy, alkyl, (Me)2(O)P, or (Et)2(O)P; or a pharmaceutically acceptable salt thereof. 4. A compound of claim 2 of formula IV where: R¹ is Cl or CF₃; R² is F; R⁴ is hydroxy, cyano, alkyl, alkoxy, (R⁵)(R⁶)N, (Me)₂(O)P, (Et)₂(O)P, alkylSO₂, or cycloalkylSO₂; R⁵ is hydrogen, alkyl, alkylCO, or alkylSO2; R⁶ is hydrogen or alkyl; or NR⁵R⁶ taken together is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, and is substituted with 0-3 substituents selected from oxo, hydroxy, fluoro, alkyl, haloalkyl, alkoxy, and haloalkoxy; or a pharmaceutically acceptable salt thereof. 5. A compound of claim 2 of formula V

where: R¹ is Cl or CF₃; R² is F; R⁴ is hydroxy, (Me)2(O)P, or (Et)2(O)P; or a pharmaceutically acceptable salt thereof. 6. A compound of claim 2 of formula VI where: R¹ is Cl or CF₃; R² is F; R⁴ is hydroxy, (Me)₂(O)P, or (Et)₂(O)P; or a pharmaceutically acceptable salt thereof. A compound of claim 1 of formula VII where: R¹ is Cl or CF₃; R² is F; R⁴ is hydroxy, (Me)₂(O)P, or (Et)₂(O)P; or a pharmaceutically acceptable salt thereof. 8. A pharmaceutical composition comprising a compound of any one of claims 1-7 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. 9. A compound according to any one of claims 1-7 or composition according to claim 8 for use in therapy. 10. A method for treating a heart disease comprising administering a therapeutically effective amount of a pharmaceutical composition of claim 8 to a patient in need thereof. 11. The method of claim 10 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. 12. The method of claim 11 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.