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WO2024220482A1 - Agonistes de pyrrolidinone urée fpr2 - Google Patents

Agonistes de pyrrolidinone urée fpr2 Download PDF

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Publication number
WO2024220482A1
WO2024220482A1 PCT/US2024/024904 US2024024904W WO2024220482A1 WO 2024220482 A1 WO2024220482 A1 WO 2024220482A1 US 2024024904 W US2024024904 W US 2024024904W WO 2024220482 A1 WO2024220482 A1 WO 2024220482A1
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Prior art keywords
heart failure
compound
pharmaceutically acceptable
compounds
mmol
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Inventor
Pravin Sudhakar Shirude
Vishweshwaraiah BALIGAR
Amit Kumar Chattopadhyay
Nagarjuna AKUTHOTA
Nicholas R. Wurtz
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Bristol Myers Squibb Co
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Bristol Myers Squibb Co
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Priority to CN202480025580.1A priority Critical patent/CN121013837A/zh
Priority to KR1020257038073A priority patent/KR20250172674A/ko
Publication of WO2024220482A1 publication Critical patent/WO2024220482A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • 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.
  • FPR2 formyl peptide 2
  • Formyl peptide receptor 2 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.
  • 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 A 4 and Annexin A1 bind to the receptor triggering a wide array of cytoplasmatic cascades such as Gi coupling, Ca 2+ 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.
  • SAA serum amyloid A
  • 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.
  • lipoxins 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).
  • 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).
  • 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).
  • 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).
  • I/R induced spinal cord injury Liu ZQ ., et al., Int. J. Clin. Exp. Med., 2015, 8, 12826-33
  • utility of these ligands can also be applied to other diseases.
  • 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).
  • 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.
  • 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 R EF), and heart failure with preserved ejection fraction (HF P EF).
  • 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.
  • 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.
  • FPR2 formyl peptide 2
  • One aspect of the invention is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein R 1 is halo or haloalkyl; R 2 is halo; R 5 is lower alkyl or hydroxyalkyl; and R 6 is hydrogen or lower alkyl.
  • Another aspect of the invention is a compound of formula II
  • R 1 is Cl; R 2 is F; R 5 is C1-2 alkyl; and R 6 is C1-2 alkyl.
  • Another aspect of the invention is a compound of formula III or a pharmaceutically acceptable salt thereof, wherein R 1 is Cl or CF 3 ; R 2 is F; R 5 is C1-2 alkyl or C1-2 hydroxyalkyl; and R 6 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; R 1 is halo or haloalkyl; and R 2 is halo.
  • Another aspect of the invention is a compound of formula V or a pharmaceutically acceptable salt thereof, wherein R 1 is Cl or CF3; and R 2 is F.
  • Another aspect of the invention is a compound of formula VI or a pharmaceutically acceptable salt thereof, wherein R 1 is halo or haloalkyl; R 2 is halo; R 5 is lower alkyl or hydroxyalkyl; and R 6 is hydrogen or lower alkyl.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • isotopes of hydrogen include deuterium and tritium.
  • Isotopes of carbon include 13 C and 14 C.
  • 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 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).
  • Gi inhibitory G- proteins
  • 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.
  • 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).
  • SAA Serum amyloid A
  • LXA4 lipoxin A4
  • ATL Epi-lipoxin
  • RvD1 docosahexenoic acid metabolite
  • 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).
  • FMLP N-Formylmethionine-leucyl- phenylalanine
  • 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.
  • a mixture of forskolin (5 ⁇ M final for FPR2 or 10 ⁇ M final for FPR1) and IBMX (200 ⁇ M 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.
  • 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.
  • Table 1 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 EC 50 for agonizing FPR2 to the EC 50 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.
  • QD compounds
  • QD dosing solution without compound
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • suitable therapeutic agents useful in the treatment of the aforementioned diseases
  • 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.
  • ACE Angiotensin converting enzyme
  • ARBs Angiotensin II receptor blockers
  • ARNI angiotensin receptor-neprilysin inhibitors
  • beta blockers beta blockers
  • mineralocorticoid receptor antagonists nitroxyl donors
  • RXFP1 agonists APJ agonists
  • cardiotonic agents selected from loop diuretics, Angiotensin converting enzyme (ACE) inhibitors, Angiotensin II receptor blockers (ARBs), angiotensin receptor-
  • 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.
  • 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.
  • 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”
  • 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)).
  • 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.
  • 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.
  • rings A and B are heteroaryl rings, such as pyridine, pyrimidine, thiazole, etc.
  • 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.
  • 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).
  • 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).
  • reaction mixture was purged with nitrogen for 5 min and charged with xantphos (0.59 g, 1.0 mmol) and Pd 2 (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.

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Abstract

L'invention concerne des composés de formule I, qui sont des agonistes du récepteur 2 du peptide formyle (FPR2) et/ou des agonistes du récepteur 1 du peptide formyle (FPR1). L'invention concerne également des compositions et des procédés d'utilisation des composés, par exemple, pour le traitement de l'athérosclérose, de l'insuffisance cardiaque et de maladies associées.
PCT/US2024/024904 2023-04-18 2024-04-17 Agonistes de pyrrolidinone urée fpr2 Pending WO2024220482A1 (fr)

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US20190270704A1 (en) * 2018-03-05 2019-09-05 Bristol-Myers Squibb Company Phenylpyrrolidinone formyl peptide 2 receptor agonists

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US20190270704A1 (en) * 2018-03-05 2019-09-05 Bristol-Myers Squibb Company Phenylpyrrolidinone formyl peptide 2 receptor agonists

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