Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• • 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
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
  • C07D211/56—Nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
  • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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, directly attached to ring carbon atoms
  • C07D211/74—Oxygen atoms
  • C07D211/76—Oxygen atoms attached in position 2 or 6
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• the present invention relates to novel piperidinone compounds, 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, for the treatment of atherosclerosis, heart failure, chronic obstructive pulmonary disease (COPD), and related diseases.
• FPR2 formyl peptide 2
• FPR1 formyl peptide 1
• Formyl peptide receptor 2 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 antiinflammatory peptide Annexin Al 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 A4 and Annexin Al bind to the receptor triggering a wide array of cytoplasmatic cascades such as Gi coupling, Ca 2+ mobilization and D-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.
• 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-1 ⁇ 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
• 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).
• 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).
• 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,
• the invention encompasses compounds of formula I, which are formyl peptide 2 (FPR2) receptor agonists and/or formyl peptide 1 (FPRl) 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
• FPRl formyl peptide 1 receptor agonists
• COPD chronic obstructive pulmonary disease
• One aspect of the invention is a compound of formula I
• Ar 1 is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, or benzodioxyl, and is substituted with 1-3 substituents selected from cyano, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, and alkylsulfonyl;
• Ar 2 is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl, and is substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy;
• Ar 3 is 5- or 6-membered monocyclic heteroaromatic ring system with 1 -5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• R 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahyrofuranyl, or
• tetrahydropyranyl and is substituted with 0-2 substituents selected from cyano, alkyl, fluoroalkyl, hydroxyalkyl, alkoxyalkyl, ((R 2 )(R )N)alkyl, hydroxy, alkoxy, (R 2 )(R )N, (R 2 )(R )NCO, and Ar 3 ;
• R 2 is hydrogen, alkyl, alkylcarbonyl, or alkylsulfonyl;
• R 3 is hydrogen or alkyl; or NR 2 R 3 taken together is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, and is substituted with 0-3 substituents selected from fluoro, alkyl, haloalkyl, alkoxy, and fluoroalkoxy; and
• X is hydrogen, fluoro, hydroxy, or alkoxy; or a pharmaceutically acceptable salt thereof.
• Another aspect of the invention is a compound of formula I where Ar 1 is phenyl, pyrazinyl or pyridinyl and is substituted with 1-3 substituents selected from cyano, halo, alkyl, haloalkyl, alkoxy, fluoroalkoxy, alkylthio, and alkylsulfonyl;
• Ar 2 is phenyl or pyridinyl and is substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy;
• Ar 3 is 5- or 6-membered monocyclic heteroaromatic ring system with 1 -5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
• R 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahyrofuranyl, or
• R 2 is hydrogen, alkyl, alkylcarbonyl, or alkylsulfonyl;
• R 3 is hydrogen or alkyl; or NR 2 R 3 taken together is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, and is substituted with 0-3 substituents selected from halo, alkyl, haloalkyl, alkoxy, and haloalkoxy; and
• X is hydrogen, fluoro, hydroxy, or alkoxy; or a pharmaceutically acceptable salt thereof.
• Another aspect of the invention is a compound of formula I where Ar 1 is phenyl or pyridinyl and is substituted with 1-3 substituents selected from cyano, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, and alkylsulfonyl.
• Another aspect of the invention is a compound of formula I where Ar 2 is phenyl or pyridinyl and is substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy.
• Another aspect of the invention is a compound of formula I where Ar 3 is 5-membered monocyclic heteroaromatic ring system with 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
• Another aspect of the invention is a compound of formula I where Ar 3 is 6-membered monocyclic heteroaromatic ring system with 1-3 nitrogen atoms.
• R 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahyrofuranyl, or tetrahydropyranyl, and is substituted with 0-2 substituents selected from cyano, ((R 2 )(R )N)alkyl, and hydroxy.
• any instance of a variable substituent including Ar 1 , Ar 2 , Ar 3 , R 1 , R 2 , R 3 , and X can be used independently with the scope of any other instance of a variable substituent.
• the invention includes combinations of the different aspects.
• 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.
• Hydrocarbon moiety e.g. alkoxy
• 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 a 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 1 1 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.
• Heteroaryl includes N-substituted pyridinonyl:
• 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,
• 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 1 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.
• FPRs 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).
• 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. 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 antiinflammatory responses.
• Inflammation mediator release by FPR2 is promoted by endogenous protein ligands such as Serum amyloid A (SAA) and Amyloid ⁇ (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 Dl (RvDl).
• SAA Serum amyloid A
• LXA4 lipoxin A4
• ATL Epi-lipoxin
• RvDl 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
• the FPRl 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.
• FPR2 and FPRl Cyclic Adenosine Monophosphate (cAMP) Assays A mixture of forskolin (5 ⁇ final for FPR2 or 10 ⁇ final for FPRl) and IBMX (200 ⁇ 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 ⁇ .
• Chinese Hamster Ovary cells (CHO) overexpressing human FPRl or human FPR2 receptors were cultured in F-12 (Ham's) medium supplemented with 10% qualified FBS, 250 ⁇ g/ml zeocin and 300 ⁇ g/ml hygromycin (Life Technologies).
• Reactions were initiated by adding 2,000 human FPR2 cells per well or 4,000 human FPRl 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 ⁇ 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 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.
• 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 arrthymia or signs of insulin resistance such as acanthosis nigricans, hypertension, dyslipidemia, or polycystic ovary syndrome (PCOS).
• PCOS polycystic ovary syndrome
• Treating encompass the treatment of a patient as understood by practitioners in the art and include inhibiting the disease-state, i. e. , arresting it development; relieving the disease-state, i. e. , causing regression of the disease state; and/or preventing the disease-state from occurring in a patient.
• “Therapeutically effective amount” is intended to include an amount of a compound that is effective or beneficial as understood by practitioners in this field.
• “Pharmaceutical composition” means a composition comprising a compound of the invention in combination with at least one additional pharmaceutically acceptable carrier.
• a “pharmaceutically acceptable carrier” refers to media for the delivery of biologically active agents as understood by practitioners in the art, such as diluents, preserving agents, fillers, flow regulating agents, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, anti-bacterial agents, anti-fungal agents, lubricating agents, and dispensing agents.
• Pharmaceutically acceptable carriers are formulated according to a number of factors known to those of ordinary skill in the art. These include, without limitation, the type and nature of the active agent being formulated; the subject to which the agent-containing composition is to be administered; the intended route of administration of the
• 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.
• 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.
• 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 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 conjuction 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
• 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, captopnl, enalapril, lisinoprii, 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.
• 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.
• 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.
• the ureas Id can be obtained by treatment of the deprotected 3- aminopiperidinone intermediate with 4-nitrophenylchloroformate to form the carbamate, followed by condensation with an appropriately substituted arylamine lg.
• rings A and B are heteroaryl rings, such as pyridine, pyrimidine, thiazole, etc.
• Scheme 1 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 bromine for la 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 la, lb, lc or Id using synthetic methods known to those skilled in the art.
• Reverse phase preparative HPLC was carried out using CI 8 columns eluting with gradients of Solvent A (10 mM ammonium acetate in water) and Solvent B (ACN, UV 220 nm) or with gradients of Solvent A (10 mM ammonium acetate in water) and Solvent B (MeOH, UV 220 nm) or with gradients of Solvent A (0.1% TFA in water) and Solvent B (ACN, UV 220 nm) (or) SunFire Prep C18 OBD 5 ⁇ 19x150mm, 25 min gradient from 0-100% B.
• A 10 mM ammonium acetate in water.
• Method B XBridge Phenyl column (3.5 ⁇ C 18, 3.0 ⁇ 150 mm). Gradient elution (1.0 mL/min) from 10-100% Solvent B over 12 min and then 100% Solvent B for 3 min was used.
• Solvent A is 95% water, 5% acetonitrile, 0.05% TFA and Solvent B is 5% water, 95% acetonitrile, 0.05% TFA, UV 220 nm.
• Method C Ascentis Express CI 8, 2.1 x 50 mm, 2.7- ⁇ particles; Solvent A: 95% water, 5% acetonitrile, 0.05% TFA; Solvent B: 95% acetonitrile, 5% water, 0.1% TFA; Temperature: 50 °C; Gradient: 0-100% B over 4 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- ⁇ 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 °C; Gradient: 0-100% B over 4 minutes, then a 1 -minute hold at 100% B; Flow: 1.1 mL/min.
• Method E Ascentis Express C18, 2.1 x 50 mm, 2.7- ⁇ particles; Solvent A: 95% water, 5% acetonitrile, 0.05% TFA; Solvent B: 95% acetonitrile, 5% water, 0.1% TFA; Temperature: 50 °C; Gradient: 0-100% B over 3 minutes, then a 1-minute hold at 100% B; Flow: 1.1 mL/min.
• Method F Ascentis Express CI 8, 2.1 x 50 mm, 2.7- ⁇ 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 °C; Gradient: 0-100% B over 3 minutes, then a 1 -minute hold at 100% B; Flow: 1.1 mL/min.
• Method G SunFire C18 column (3.5 ⁇ C18, 3.0 ⁇ 150 mm). Gradient elution (1.0 mL/min) from 10-100% Solvent B over 25 min and then 100% Solvent B for 5 min was used. Solvent A is 95% water, 5% acetonitrile, 0.05% TFA and Solvent B is 5% water, 95% acetonitrile, 0.05% TFA, UV 220 nm.
• Method H XBridge Phenyl column (3.5 ⁇ CI 8, 3.0 ⁇ 150 mm). Gradient elution (1.0 mL/min) from 10-100% Solvent B over 25 min and then 100% Solvent B for 5 min was used.
• Solvent A is 95% water, 5% acetonitrile, 0.05% TFA and Solvent B is 5% water, 95% acetonitrile, 0.05% TFA, UV 220 nm.
• Method I SunFire C18 column (3.5 ⁇ , 4.6 ⁇ 150 mm). Gradient elution (1.0 mL/min) from 10-100% Solvent B over 12 min and then 100% Solvent B for 3 min was used. Solvent A is 95% water, 5% acetonitrile, 0.05% TFA and Solvent B is 5% water, 95% acetonitrile, 0.05% TFA, UV 220 nm.
• Method J XBridge Phenyl column (3.5 ⁇ , 4.6 150 mm). Gradient elution (1.0 mL/min) from 10-100% Solvent B over 12 min and then 100% Solvent B for 3 min was used.
• Solvent A is 95% water, 5% acetonitrile, 0.05% TFA and Solvent B is 5% water, 95% acetonitrile, 0.05% TFA, UV 220 nm.
• Method K SunFire C18 column (3.5 ⁇ , 4.6 ⁇ 150 mm). Gradient elution (1.0 mL/min) from 10-100% Solvent B over 25 min and then 100% Solvent B for 5 min was used. Solvent A is 95% water, 5% acetonitrile, 0.05% TFA and Solvent B is 5% water, 95% acetonitrile, 0.05% TFA, UV 220 nm.
• Method M SunFire C18 column (3.5 ⁇ , 4.6 ⁇ 150 mm). Gradient elution (1.0 mL/min) from 10-100% Solvent B over 18 min and then 100% Solvent B for 5 min was used. Solvent A is 95% water, 5% acetonitrile, 0.05% TFA and Solvent B is 5% water, 95% acetonitrile, 0.05% TFA, UV 220 nm.
• Method N XBridge Phenyl column (3.5 ⁇ , 4.6 ⁇ 150 mm). Gradient elution (1.0 mL/min) from 10-100% Solvent B over 18 min and then 100% Solvent B for 5 min was used. Solvent A is 95% water, 5% acetonitrile, 0.05% TFA and Solvent B is 5% water, 95% acetonitrile, 0.05% TFA, UV 220 nm.
• Method I Chiralpak AD-H, 250 x 4.6 mm, 5.0- ⁇ particles; % CC : 60%, % Co solvent: 40% ⁇ 0.2%DEA IN IPA:A CN(1 : 1) ⁇ , Total Flow: 4.0g/min, Back Pressure: lOObars, Temperature : 25°C, UV: 218 nm.
• Method III Chiralpak OJ-H, 250 x 4.6 mm, 5.0- ⁇ particles; % CCh: 60%, % Co- solvent: 30%(0.3% DEA in Methanol), Total Flow: 4.0g/min, Back Pressure: 101 bars, Temperature : 23.6°C, UV: 272 nm.
• Method IV Chiralpak AS-H, 250 x 4.6 mm, 5.0- ⁇ particles; % CCh: 60%, % Co- solvent: 40%(0.3% DEA in Methanol), Total Flow: 4.0g/min, Back Pressure: 102 bars, Temperature : 25.4°C, UV: 272 nm.
• Method V Chiralcel OJ-H, 250 x 4.6 mm, 5.0- ⁇ particles; % CCh: 60%, % Co- solvent: 40%(0.2% DEA in Methanol), Total Flow: 4.0g/min, Back Pressure: 102 bars, Temperature : 24.6°C, UV: 272 nm.
• Method VII Chiralcel AS-H, 250 x 4.6 mm, 5.0- ⁇ particles; % CCh: 60%, %
• Co- solvent 40%(0.2% DEA in Methanol), Total Flow: 4.0 g/min, Back Pressure: 101 bars, Temperature : 24.4°C, UV: 270 nm.
• Method VIII Chiralpak IC, 250 x 4.6 mm, 5.0- ⁇ particles; % CCh: 60%, % Co- solvent: 40%(0.2% DEA in Methanol), Total Flow: 4.0 g/min, Back Pressure: 101 bars, Temperature : 24.4°C, UV: 270 nm.
• Method IX COLUMN: chiralpaklF (250 X 4.6mm), 5 micron, MOBILE PHASE: -0.2% DEA in ETHANOL, FLOW: 1.0ml/min.
• Example 1 (i?)-N-((l -(4-(2-Oxo-3-(3-(6-(trifluoromethyl)pyridin-3-yl)ureido)piperidin-l- yl)phenyl)cyclobutyl)methyl)methanesulfonamide
• Example 1A l -(4-Bromophenyl)cyclobutane-l-carbonitrile
• Example 1A was purified by silica gel column chromatography (5% EtO Ac-Pet ether) to afford Example 1A as a colorless liquid.
• Example 1A (1.1 g, 4.7 mmol) and CS2CO3 (2.3 g, 7.0 mmol) were added to a stirred solution of fert-butyl (2-oxopiperidin-3-yl)carbamate (1 g, 4.7 mmol) in 1,4-dioxane (10 mL). The reaction mixture was purged with nitrogen for 5 min and then charged with Xantphos (0.27 g, 0.47 mmol) and Pd2(dba)3 (0.21 g, 0.23 mmol). The reaction mixture was again purged with nitrogen for 3 min and heated at 110°C for 16 hours. The reaction mixture was cooled, filtered through a Celite pad and the filtrate was concentrated under reduced pressure.
• Example IB 1.0 g, 2.7 mmol, 58 % yield
• Example 1C fert-Butyl (l-(4-(l-(aminomethyl)cyclobutyl)phenyl)-2-oxopiperidin-3- yl)carbamate
• Example 1B To a stirred solution of Example IB (300 mg, 0.812 mmol) in MeOH (10 mL), was added Raney nickel (70 mg, 0.81 mmol). The resulting mixture was stirred for overnight under H2, filtered through syringe filter and concentrated under reduced pressure. The crude residue was triturated with hexane (2 x 10 mL) to afford Example 1C (150 mg, 0.40 mmol, 50 % yield) as a brown solid. MS(ESI) m/z: 374.3 (M+H) + .
• Example ID fert-Butyl (l-(4-(l-(methylsulfonamidomethyl)cyclobutyl)phenyl)-2- oxopiperidin-3-yl)carbamate
• DCM dimethyl methyl
• TEA tetramethylethyl
• mesylchloride tethylchloride
• Example IE N-((l -(4-(3-Amino-2-oxopiperidin-l- yl)phenyl)cyclobutyl)methyl)methanesulfonamide hydrochloride
• Example ID 200 mg, 0.44 mmol
• 1,4-dioxane 2 mL
• 4 ⁇ HC1 in 1 ,4-dioxane 2.2 ml, 8.9 mmol
• the solvent was evaporated and dried under reduced pressure to obtain a gummy solid.
• the solid was triturated with diethyl ether (2 x 20 mL) and dried to afford Example IE (150 mg, 0.43 mmol, 96% yield) as a brown solid.
• MS(ESI) m/z: 352.2 (M+H) + .
• Example 1 (i?)-N-((l -(4-(2-Oxo-3-(3-(6-(trifluoromethyl)pyridin-3-yl)ureido)piperidin-l- yl)phenyl)cyclobutyl)methyl)methanesulfonamide
• Example IE 75 mg, 0.19 mmol
• 1,2-dichloroethane (2 mL) 1,2-dichloroethane (2 mL) were added DIPEA (0.068 mL, 0.39 mmol) and phenyl (6-(trifluoromethyl)pyridin- 3-yl)carbamate (55 mg, 0.19 mmol).
• DIPEA 0.068 mL, 0.39 mmol
• phenyl (6-(trifluoromethyl)pyridin- 3-yl)carbamate 55 mg, 0.19 mmol.
• the resulting solution was heated at 50 °C for 15 hours.
• the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography followed by chiral HPLC to afford Example 1 (24 mg, 0.044 mmol, 23 % yield) as a white solid.
• Example 52A 400 mg, 1.7 mmol, 79% yield
• 3 ⁇ 4 NMR 400 MHz, CDCh: ⁇ 9.52 (s, 1H), 7.55 - 7.23 (m, 2H), 7.05 - 7.00 (m, 2H), 2.75 - 2.68 (m, 2H), 2.44 - 2.39 (m, 2H), 2.06 - 1. 88 (m, 2H).
• Example 52A (450 mg, 1.9 mmol), and CS2CO3 (910 mg, 2.8 mmol) were added to a stirred solution of fert-butyl (2-oxopiperidin-3-yl)carbamate (400 mg, 1.9 mmol) in 1,4- dioxane (4 mL).
• the reaction mixture was purged with nitrogen for 5 min and charged with Xantphos (1 10 mg, 0.19 mmol) and Pd2(dba)3 (85 mg, 0.093 mmol).
• the reaction mixture was again purged with nitrogen for 3 min and heated at 1 10°C for 16 h.
• the reaction mixture was cooled, filtered through a Celite pad and the filtrate was
• Example 52B (240 mg, 0.63 mmol, 34% yield) as a brown solid.
• 3 ⁇ 4 NMR 400 MHz, CDCh: ⁇ 9.55 (s, 1H), 7.27 - 7.20 (m, 2H), 7.18 - 7.13 (m, 2H), 5.52 (br.
• Example 52C fert-Butyl (l -(4-(l-(morpholinomethyl)cyclobutyl)phenyl)-2-oxopiperidin- 3-yl)carbamate
• Example 52B Morpholine (0.058 mL, 0.67 mmol) and sodium triacetoxyborohydride (210 mg, 1.0 mmol) were added to a stirred solution of Example 52B (250 mg, 0.67 mmol) in 1 ,2- dichloroethane (2 mL) under argon atmosphere. The resulting reaction mixture was stirred for 48 h at rt. The reaction mixture was quenched with an aqueous saturated NaHCCb (20 mL) solution and extracted with DCM (2 x 30 mL). The combined organic layers were washed with brine (20 mL), dried over Na2S04 and concentrated under reduced pressure to afford crude Example 52C (260 mg, 0.59 mmol, 87% yield) as a brown solid. The crude residue was carried forward to the next step without further purification. MS(ESI) m/z: 444.6 (M+H) + .
• Example 52D 3-Amino-l-(4-(l -(morpholinomethyl)cyclobutyl)phenyl)piperidin-2-one hydrochloride
• Example 52C 260 mg, 0.586 mmol
• 1,4-dioxane (2 mL) 1,4-dioxane
• 4 N HC1 4 N HC1 in 1 ,4-dioxane
• the solvent was evaporated and dried under reduced pressure to obtain a gummy solid.
• Example 52D (200 mg, 0.53 mmol, 90% yield) as a brown solid.
• Example 52 (i?)-l -(l-(4-(l-(Morpholinomethyl)cyclobutyl)phenyl)-2-oxopiperidin-3- yl)-3-(6-(trifluoromethyl)pyridin-3-yl)urea
• Example 68A fra « , -5-((tert-butoxycarbonyl)amino)-6-oxopiperidin-3-yl acetate fert-Butyl trans-5-hydroxy-2-oxopiperidin-3-yl)carbamate was synthesized using the procedures found in Gordon, Sandra et al, Farmaco, 52(10), 603-608; 1997.
• Example 68B fra « , -5-((teri-Butoxycarbonyl)amino)-l-(4-(l-cyanocyclopropyl)phenyl)- 6-oxopiperidin-3-yl acetate
• Example 68 A 500 mg, 1.8 mmol
• 1,4-dioxane 4 mL
• l-(4-bromophenyl)cyclopropane-l-carbonitrile 410 mg, 1.8 mmol
• CS2CO3 1200 mg, 3.7 mmol
• the reaction mixture was purged with nitrogen for 5 min and charged with Xantphos (110 mg, 0.18 mmol) and Pd 2 (dba) 3 (84 mg, 0.092 mmol).
• the reaction mixture was again purged with nitrogen for 3 min and heated at 110 °C for 16 h.
• the reaction mixture was cooled, filtered through a Celite pad, and the filtrate was concentrated under reduced pressure.
• Example 68B 250 mg, 0.61 mmol, 33 % yield
• MS (ES) m/z 414.6 [M+H] + ; 3 ⁇ 4 NMR (400 MHz, CDCh): ⁇ 7.36 - 7.30 (m, 2H), 7.30 - 7.23 (m, 2H), 5.61 (br.
• Example 68C trans-tert-butyl (l-(4-(l-(aminomethyl)cyclopropyl)phenyl)-5-hydroxy-2- oxopiperidin-3-yl)carbamate
• Example 68B To a stirred solution of Example 68B (250 mg, 0.605 mmol) in MeOH (5 mL), was added Raney nickel (160 mg, 1.8 mmol). The reaction mixture was stirred under hydrogen atmosphere (70 psi) at rt for an hour. The resulting mixture was filtered through a syringe filter and concentrated under reduced pressure. The crude residue was triturated with hexane (2 x 10 mL) to afford Example 68C (200 mg, 0.53 mmol, 88% yield).
• Example 68D trans-tert-butyl (l-(4-(l-(aminomethyl)cyclopropyl)phenyl)-5-((tert- butyldimethylsilyl)oxy)-2-oxopiperidin-3-yl)carbamate
• Example 68C Imidazole (45 mg, 0.67 mmol) and TBDMS-C1 (100 mg, 0.67 mmol) were added to a stirred solution of Example 68C (250 mg, 0.67 mmol) in DCM (2 mL). The reaction mixture was stirred at rt for additional 12 hours. The reaction mixture was evaporated, and the residue was washed with EtOAc (3 x 5 mL). The combined organic layer was evaporated to give Example 68D (250 mg, 0.510 mmol, 77% yield). MS (ES) m/z: 490.7 [M+H] + .
• Example 68E trans-tert-butyl (5-((tert-butyldimethylsilyl)oxy)-l-(4-(l- (methylsulfonamidomethyl)cyclopropyl)phenyl)-2-oxopiperidin-3-yl)carbamate
• Example 68D (230 mg, 0.47 mmol) in DCM (2 mL) at 0 °C, were added TEA (0.20 mL, 1.4 mmol) and mesylchloride (0.044 mL, 0.56 mmol). The reaction mixture was gradually warmed to room temperature and stirred for an additional 1 hour. The reaction mixture was quenched with water (10 mL), and extracted with DCM (2 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2S04 and concentrated under reduced pressure. The crude residue was triturated with pet ether (20 mL) to afford Example 68E (230 mg, 0.405 mmol, 86% yield).
• Example 68F fra «s-N-((l-(4-(3-aimno-5-hydroxy-2-oxopiperidin-l- yl)phenyl)cyclopropyl)methyl)methanesulfonamide hydrochloride
• Example 68F (140 mg, 0.396 mmol, 98 % yield).
• Example 68F To an ice cooled solution of Example 68F (80 mg, 0.23 mmol) in DMSO (2 mL) under nitrogen, were added K2CO3 (63 mg, 0.45 mmol) and phenyl (3-fluoro-5- (trifluoromethyl)pyridin-2-yl)carbamate (82 mg, 0.27 mmol). The reaction mixture was gradually warmed up to rt and stirred for 15 hours. The reaction mixture was filtered through a syringe filter and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography followed by chiral HPLC to afford Example 68 (6.0 mg, 11 ⁇ , 4.7 % yield).
• Racemization can occur during the synthesis that can be separated at the final stage with chiral chromatography to give all possible stereoisomers.

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