WO2010136474A2 - Substituted aminobutyric derivatives as neprilysin inhibitors - Google Patents

Substituted aminobutyric derivatives as neprilysin inhibitors Download PDF

Info

Publication number
WO2010136474A2
WO2010136474A2 PCT/EP2010/057213 EP2010057213W WO2010136474A2 WO 2010136474 A2 WO2010136474 A2 WO 2010136474A2 EP 2010057213 W EP2010057213 W EP 2010057213W WO 2010136474 A2 WO2010136474 A2 WO 2010136474A2
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
halo
heteroaryl
nmr
pharmaceutically acceptable
Prior art date
Application number
PCT/EP2010/057213
Other languages
French (fr)
Other versions
WO2010136474A3 (en
Inventor
Gary Mark Coppola
Yuki Iwaki
Rajeshri Ganesh Karki
Toshio Kawanami
Gary Michael Ksander
Muneto Mogi
Robert Sun
Original Assignee
Novartis Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to CN201080023253.0A priority Critical patent/CN102448928B/en
Priority to MX2011012627A priority patent/MX2011012627A/en
Priority to ES10726924.3T priority patent/ES2582395T3/en
Priority to EP10726924.3A priority patent/EP2435402B1/en
Application filed by Novartis Ag filed Critical Novartis Ag
Priority to BRPI1015069A priority patent/BRPI1015069A2/en
Priority to SG2011083102A priority patent/SG176010A1/en
Priority to AU2010251948A priority patent/AU2010251948A1/en
Priority to JP2012512347A priority patent/JP5466759B2/en
Priority to MA34456A priority patent/MA33364B1/en
Priority to EA201101672A priority patent/EA201101672A1/en
Priority to CA2763565A priority patent/CA2763565A1/en
Publication of WO2010136474A2 publication Critical patent/WO2010136474A2/en
Publication of WO2010136474A3 publication Critical patent/WO2010136474A3/en
Priority to IL216284A priority patent/IL216284A0/en
Priority to TNP2011000593A priority patent/TN2011000593A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/04—Drugs for genital or sexual disorders; Contraceptives for inducing labour or abortion; Uterotonics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/06—Antiabortive agents; Labour repressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/02—Local antiseptics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • 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
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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
    • A61P9/06—Antiarrhythmics
    • 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
    • A61P9/08—Vasodilators for multiple indications
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C233/63—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/81—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/82—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/87—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/52—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
    • C07C235/74—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of a saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/82—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/02—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups
    • C07C251/04—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C251/10—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton
    • C07C251/12—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton being acyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
    • C07C257/04—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines without replacement of the other oxygen atom of the carboxyl group, e.g. imino-ethers
    • C07C257/06—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines without replacement of the other oxygen atom of the carboxyl group, e.g. imino-ethers having carbon atoms of imino-carboxyl groups bound to hydrogen atoms, to acyclic carbon atoms, or to carbon atoms of rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/12—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
    • C07C275/06—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an acyclic and saturated carbon skeleton
    • C07C275/16—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an acyclic and saturated carbon skeleton being further substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/19—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • 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
    • C07D207/30—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 two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—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 two 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more 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
    • C07D261/18—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/48—Compounds containing oxirane rings 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, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three 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
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/34—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D309/36—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
    • C07D309/40—Oxygen atoms attached in positions 3 and 4, e.g. maltol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D333/40—Thiophene-2-carboxylic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • Atrial natriuretic peptides also called atrial natriuretic factors (ANF) have diuretic, natriuretic and vasorelaxant functions in mammals.
  • ANF peptides is metabolically inactivated, in particular by a degrading enzyme which has been recognized to correspond to the enzyme neutral endopeptidase (NEP) EC 3.4.24.1 1 , also responsible for e.g. the metabolic inactivation of enkephalins.
  • NEP neutral endopeptidase
  • Neutral endopeptidase (EC 3.4.24.1 1 ; enkephalinase; atriopeptidase; NEP) is a zinc- containing metalloprotease that cleaves a variety of peptide substrates on the amino side of hydrophobic residues [see Pharmacol Rev, Vol. 45, p. 87 (1993)].
  • Substrates for this enzyme include, but are not limited to, atrial natriuretic peptide (ANP, also known as ANF), brain natriuretic peptide (BNP), met- and leu-enkephalin, bradykinin, neurokinin A, endothelin-1 and substance P.
  • ANP is a potent vasorelaxant and natriuretic agent [see J Hypertens, Vol. 19, p. 1923 (2001 )]. Infusion of ANP in normal subjects resulted in a reproducible, marked enhancement of natriuresis and diuresis, including increases in fractional excretion of sodium, urinary flow rate and glomerular filtration rate [see J CHn Pharmacol, Vol. 27, p. 927 (1987)]. However, ANP has a short half-life in circulation, and NEP in kidney cortex membranes has been shown to be the major enzyme responsible for degrading this peptide [see Peptides, Vol. 9, p. 173 (1988)]. Thus, inhibitors of NEP (neutral endopeptidase inhibitors, NEPi) should increase plasma levels of ANP and, hence, are expected to induce natriuretic and diuretic effects.
  • NEPi neutral endopeptidase inhibitors
  • This enzyme is involved in the breakdown of several bioactive oligopeptides, cleaving peptide bonds on the amino side of hydrophobic amino acid residues.
  • the peptides metabolised include atrial natriuretic peptides (ANP), bombesin, bradykinin, calcitonin gene- related peptide, endothelins, enkephalins, neurotensin, substance P and vasoactive intestinal peptide.
  • the aim of the present invention is to provide novel compounds which are useful as neutral endopeptidase inhibitors, e.g. as inhibitors of the ANF-degrading enzyme in mammals, so as to prolong and potentiate the diuretic, natriuretic and vasodilator properties of ANF in mammals, by inhibiting the degradation thereof to less active metabolites.
  • the compounds of this invention are thus particularly useful for the treatment of conditions and disorders responsive to the inhibition of neutral endopeptidase (NEP) EC 3.4.24.1 1 .
  • the compounds of the invention by inhibiting the neutral endopeptidase EC.3.4.24.1 1 , can potentiate the biological effects of bioactive peptides.
  • the compounds have utility in the treatment of a number of disorders, including hypertension, pulmonary hypertension, isolated systolic hypertension, resistant hypertension, peripheral vascular disease, heart failure, congestive heart failure, left ventricular hypertrophy, angina, renal insufficiency (diabetic or non-diabetic), renal failure (including edema and salt retension), diabetic nephropathy, non-diabetic nephropathy, nephroic syndrome, glomerulonephritis, scleroderma, glomerular sclerosis, proteinurea of primary renal disease, renal vascular hypertention, diabetic retinopathy and end-stage renal disease (ESRD), endothelial dysfunction, diastolic dysfunction, hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and
  • the compounds of the invention may have activity in other therapeutic areas including for example the treatment of menstrual disorders, preterm labour, pre-eclampsia, endometriosis, and reproductive disorders (especially male and female infertility, polycystic ovarian syndrome, implantation failure).
  • the compounds of the invention should treat asthma, obstructive sleep apnea, inflammation, leukemia, pain, epilepsy, affective disorders such as depression and psychotic condition such as dementia and geriatric confusion, obesity and gastrointestinal disorders (especially diarrhea and irritable bowel syndrome), wound healing (especially diabetic and venous ulcers and pressure sores), septic shock, the modulation of gastric acid secretion, the treatment of hyperreninaemia, cystic fibrosis, restenosis, type-2 diabetes, metabolic syndrome, diabetic complications and athereosclerosis, male and female sexual dysfunction.
  • the compounds of the invention are useful in the treatment of cardiovascular disorders.
  • the invention pertains to the compounds, methods for using them, and uses thereof as described herein.
  • Examples of compounds of the invention include the compounds according to anyone of Formulae I' and I to VIC, or a pharmaceutically acceptable salt thereof, and the compounds of the examples.
  • the invention therefore provides a compound of the formula (T):
  • R 1 is Ci- 7 alkyl
  • R 2 is independently Ci- 7 alkyl, NO 2 , CN, halo, C 3 - 7 cycloalkyl, hydroxy, Ci- 7 alkoxy, halo-Ci- 7 alkyl, NR b R c , C 6 -i 0 aryl, heteroaryl or heterocyclyl; wherein R b and R c for each occurrence, are independently H or Ci_ 7 alkyl
  • R 3 is A 1 C(O)X 1 or A 2 -R 4 ;
  • R 4 is C 6 -ioaryl or a heteroaryl, which can be monocyclic or bicyclic and which can be optionally substituted with one or more substituents independently selected from hydroxy, hydroxy-Ci- 7 alkyl, NR b R c , nitro, Ci- 7 alkoxy, halo, Ci- 7 alkyl, halo-Ci- 7 alkyl, C 2 - 7 alkenyl, C 6 - i O aryl, heteroaryl, -C(O)Ci- 7 alkyl , -NHS(O) 2 -Ci- 7 alkyl, -SO 2 Ci- 7 alkyl and benzyl;
  • R 5 is H, halo, hydroxy, Ci- 7 alkoxy, halo, Ci_ 7 alkyl or halo-Ci- 7 akyl; and X and X 1 are independently OH, -O-Ci- 7 alkyl, -NR b R c
  • a 1 is a bond or a linear d- 4 alkylene substituted with one or more substituents independently selected from the group consisting of halo, O-acetate, Ci -7 alkyl and C 3 - 7 cycloalkyl; in which two geminal alkyl can optionally combine to form a C 3 - 7 cycloalkyl; or
  • a 1 is a linear or branched C 2 - 6 alkenylene
  • a 1 is a linear Ci -4 alkylene wherein one or more carbon atom(s) is/are replaced with an heteroatom selected from O, NR a ; and A 1 is optionally substituted with one or more substituents independently selected from the group consisting of halo and d- 7 alkyl; in which
  • R a for each occurrence is independently H, d- 7 alkyl or CH 2 C(O)OH; or
  • a 1 is a C 3 . 7 cycloalkyl, a heterocyclyl, a phenyl or a heteroaryl in which phenyl and heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Ci_ 7 alkyl, C 3 . 7 cycloalkyl, halo-Ci_ 7 alkyl, hydroxy, Ci_ 7 alkoxy, halo, NR b R c ,
  • a 1 is -Ci- 4 alkylene-heteroaryl- or wherein
  • a 1 may be in either direction
  • a 2 is a bond or a linear or branched Ci- 7 alkylene which is optionally substituted with one or more substituents independently selected from the group consisting of halo, Ci_ 7 alkoxy, hydroxy, O-Acetate and C 3 .
  • n is O, 1 , 2, 3, 4 or 5; wherein each heteroaryl is a monocyclic or bicyclic aromatic ring comprising 5-10 ring atoms selected from carbon atoms and 1 to 5 heteroatoms, and each heterocyclyl is a monocyclic saturated or partially saturated but non-aromatic moiety comprising 4-7 ring atoms selected from carbon atoms and 1 -5 heteroatoms, wherein each heteroatom of a heteroaryl or a heterocyclyl is independently selected from O, N and S.
  • the invention therefore provides a compound of the formula (I):
  • R 1 is Ci- 7 alkyl; for each occurrence, R 2 is independently d- 7 alkyl, NO 2 , CN, halo, C 3 - 7 cycloalkyl, hydroxy, Ci- 7 alkoxy, halo-Ci_ 7 alkyl, NR b R c , C 6 -ioaryl, heteroaryl or heterocyclyl; wherein R b and R c for each occurrence, are independently H or Ci_ 7 alkyl; R 3 is A 1 C(O)X 1 or A 2 -R 4 ;
  • R 4 is C 6 -i 0 aryl or a heteroaryl, which can be monocyclic or bicyclic and which can be optionally substituted with hydroxy, hydroxy-Ci- 7 alkyl, nitro, Ci_ 7 alkoxy, halo, Ci_ 7 alkyl, halo- Ci- 7 alkyl, C 6 -i 0 aryl, heteroaryl, -NHS(O) 2 -Ci- 7 alkyl, -SO 2 Ci- 7 alkyl or benzyl;
  • R 5 is H, halo, hydroxy, Ci- 7 alkoxy, halo, Ci_ 7 alkyl or halo-Ci- 7 akyl; and
  • X and X 1 are independently OH, -O-Ci- 7 alkyl or NR b R c , -O- C 6 -i 0 aryl; wherein alkyl is optionally substituted with one or more substituents independently selected from the group consisting of
  • a 1 is a bond, or a linear d- 4 alkylene substituted with one or more substituents independently selected from the group consisting of halo, O-acetate, Ci- 7 alkyl and C 3 - 7 cycloalkyl; in which two geminal alkyl can optionally combine to form a C 3 - 7 cycloalkyl; or A 1 is a linear C 1 - 4 alkylene wherein one or more carbon atom(s) is/are replaced with an heteroatom selected from O, NR a ; and A 1 is optionally substituted with one or more substituents independently selected from the group consisting of halo and Ci_ 7 alkyl; in which R a for each occurrence, is independently H, Ci_ 7 alkyl or CH 2 C(O)OH; or A 1 is a C 3 - 7 cycloalkyl, a heterocyclyl, a phenyl or a heteroaryl in which phenyl and heteroaryl are optionally substituted with one or more
  • a 1 is wherein A 1 may be in either direction;
  • a 2 is a bond or a linear or branched Ci_ 7 alkylene which is optionally substituted with one or more substituents independently selected from the group consisting of halo, Ci- 7 alkoxy, hydroxy, O-Acetate and C 3 .
  • n is O, 1 , 2, 3, 4 or 5; wherein each heteroaryl is a monocyclic or bicyclic aromatic ring comprising 5-10 ring atoms selected from carbon atoms and 1 to 5 heteroatoms, and each heterocyclyl is a monocyclic saturated or partially saturated but non-aromatic moiety comprising 4-7 ring atoms selected from carbon atoms and 1 -5 heteroatoms, wherein each heteroatom of a heteroaryl or a heterocyclyl is independently selected from O, N and S.
  • the invention pertains to a method for treating a disorders or diseases responsive to the inhibition of neutral endopeptidase EC 3.4. 24.1 1 (NEP), in a subject in need of such treatment, comprising: administering to the subject an effective amount of a compound according to anyone of Formulae I-VIC, or a pharmaceutically acceptable salt thereof, such that the disorder or disease responsive to the inhibition of neutral endopeptidase EC 3.4. 24.1 1 (NEP) in the subject is treated.
  • the invention pertains to a method for treating hypertension, pulmonary hypertension, isolated systolic hypertension, resistant hypertension, peripheral vascular disease, heart failure, congestive heart failure, left ventricular hypertrophy, angina, renal insufficiency (diabetic or non-diabetic), renal failure (including edema and salt retension), diabetic nephropathy, non-diabetic nephropathy, nephroic syndrome, glomerulonephritis, scleroderma, glomerular sclerosis, proteinurea of primary renal disease, renal vascular hypertention, diabetic retinopathy and end-stage renal disease (ESRD), endothelial dysfunction, diastolic dysfunction, hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation (AF), cardiac fibrosis, atrial flutter, detrimental vascular remodeling, plaque stabilization, myocardial infarction (Ml),
  • AF
  • the invention pertains to pharmaceutical compositions, comprising a compound according to anyone of Formulae I-VIC, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.
  • the invention pertains to combinations including, a compound according to anyone of Formulae I-VIC, or a pharmaceutically acceptable salt thereof, and pharmaceutical combinations of one or more therapeutically active agents.
  • the invention pertains to a method for inhibiting neutral endopeptidase EC 3.4. 24.1 1 in a subject in need thereof, comprising: administering to the subject a therapeutically effective amount of a compound according to anyone of Formulae I-VIC, or a pharmaceutically acceptable salt thereof, such that neutral endopeptidase EC 3.4. 24.1 1 is inhibited.
  • the invention provides a compound of the Formula I or I', or a pharmaceutically acceptable salt thereof wherein: R 1 is Ci- 7 alkyl; for each occurrence R 2 is independently d- 7 alkyl, halo, C 3 - 7 cycloalkyl, hydroxy, d- 7 alkoxy, halo-Ci- 7 alkyl, NR b R c , C 6 -ioaryl, heteroaryl or heterocyclyl; wherein R b and R c for each occurrence, are independently H or Ci_ 7 alkyl; R 3 is A 1 C(O)X 1 or A 2 -R 4 ; R 4 is aryl or a heteroaryl, which can be monocyclic or bicyclic and which can be optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, d- 7 alkoxy, halo, d- 7 alkyl, halo-Ci- 7 alkyl, C 6 -i 0 ary
  • R 5 is H
  • X and X 1 are independently OH, -O-Ci- 7 alkyl or NR b R c ;
  • a 1 is a linear C 1 - 4 alkylene substituted with one or more substituents independently selected from the group consisting of halo, O-acetate, Ci- 7 alkyl and C 3 - 7 cycloalkyl; in which two geminal alkyl can optionally combine to form a C 3 . 7 cycloalkyl; or
  • a 1 is a linear C 1 - 4 alkylene wherein one or more carbon atom(s) is/are replaced with an heteroatom selected from O, NR a ; wherein A 1 is optionally substituted with one or more substituents independently selected from the group consisting of halo and Ci_ 7 alkyl; in which
  • R a for each occurence is independently H, Ci_ 7 alkyl or CH 2 C(O)OH; or
  • a 1 is a C 3 - 7 cycloalkyl, a heterocyclyl, a phenyl or a heteroaryl in which phenyl and heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Ci- 7 alkyl, C 3 - 7 cycloalkyl, halo-Ci- 7 alkyl, hydroxy, Ci- 7 alkoxy, halo, NR b R c ,
  • a 2 is a bond or a linear or branched Ci_ 7 alkylene which is optionally substituted with one or more substituents independently selected from the group consisting of halo, Ci- 7 alkoxy, hydroxy, O-Acetate and C 3 .
  • n is O, 1 , 2, 3, 4 or 5; wherein each heteroaryl is a monocyclic or bicyclic aromatic ring comprising 5-10 ring atoms selected from carbon atoms and 1 to 5 heteroatoms, and each heterocyclyl is a monocyclic saturated or partially saturated but non-aromatic moiety comprising 4-7 ring atoms selected from carbon atoms and 1 -5 heteroatoms, wherein each heteroatom of a heteroaryl or heterocyclyl is independently selected from O, N and S.
  • Certain compounds of Formula I or I' include compounds of Formula IA:
  • Formula IA or a pharmaceutically acceptable salt thereof, wherein X, R 1 , R 2 , R 3 and n have the definitions of Formula I, supra.
  • R 2 is halo and is attached to the meta position and the other optional R 2 groups are independently Ci- 7 alkyl, NO 2 , CN, halo, C 3 - 7 cycloalkyl, hydroxy, d- 7 alkoxy, halo-Ci- 7 alkyl, NR b R c , C 6 -i 0 aryl, heteroaryl or heterocyclyl.
  • This embodiment is illustrated by compounds of Formulae IB and IC:
  • Certain compounds of Formula I or I' include compounds of Formula II:
  • Certain compounds of Formulae I, I' or Il include compounds of Formula NA:
  • Formula NA or a pharmaceutically acceptable salt thereof, wherein X, X 1 , A 1 , R 1 , R 2 and n have the definitions of Formula I or I', supra.
  • Certain compounds of Formula I or I' include compounds of Formula NB and NC:
  • Formula NB Formula NC or a pharmaceutically acceptable salt thereof, wherein X, X 1 , A 1 , R 1 , R 2 have the definitions
  • the invention provides a compound according to anyone of of the formulae I', I to IC and Il to NC, or of any classes and subclasses described herein, or a pharmaceutically acceptable salt or solvate thereof, wherein A 1 is a linear Ci -4 alkylene substituted with one or more substituents independently selected from the group consisting of halo, O-acetate, d- 7 alkyl and C 3 - 7 cycloalkyl; in which two geminal alkyl can optionally combine to form a C 3 - 7 cycloalkyl.
  • a further embodiment includes compounds according to any one of Formulae I', I to IC and Il to NC, or of any classes and subclasses described herein, or a pharmaceutically acceptable salt thereof, wherein A 1 has the following formulae:
  • R and R are independently H, halo, C 3 - 7 cycloalkyl, or d- 7 alkyl and at least one of R d1 and R d2 is other than H; and alternatively R d1 and R d2 can form together with the atoms to which they are attached a C 3 - 7 cycloalkyl; and
  • R e1 and R e2 are independently H, halo, C 3 - 7 cycloalkyl, or Ci_ 7 alkyl and at least one of R e1 and
  • R e2 is other than H; and alternatively R e1 and R e2 can form together with the atoms to which they are attached a C 3 - 7 cycloalkyl.
  • a 1 is one of the following:
  • Yet another further embodiment include compounds according to any one of Formulae I', I to IC and Il to NC, or of any classes and subclasses described herein, or a pharmaceutically acceptable salt thereof, wherein A 1 has the following formulae:
  • R d3 , R d4 , R d5 and R d6 are independently H, halo, O-acetate or Ci -7 alkyl and at least one of R d3 , R d4 , R d5 and R d6 is other than H.
  • a 1 is one of the following:
  • the invention provides a compound according to any one of the formulae I', I to IC and Il to NC, or of any classes and subclasses described herein, or a pharmaceutically acceptable salt or solvate thereof, wherein A 1 is a linear Ci -4 alkylene wherein one or more carbon atom(s) is/are replaced with an heteroatom selected from O, NR a ; and A 1 is optionally substituted with one or more substituents independently selected from the group consisting of halo and d- 7 alkyl; in which R a for each occurrence is independenently H, d- 7 alkyl or CH 2 C(O)OH.
  • a 1 is one of the following:
  • the invention provides a compound according to any one of Formulae I', I to IC and Il to NC or of any classes and subclasses described herein, or a pharmaceutically acceptable salt or solvate thereof, wherein A 1 is a C 3 - 7 cycloalkyl, a heterocyclyl, a phenyl or a heteroaryl in which phenyl and heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Ci- 7 alkyl, C 3 - 7 cycloalkyl, halo-Ci- 7 alkyl, hydroxy, Ci- 7 alkoxy, halo, NR b R c , OCH 2 CO 2 H, and OCH 2 C(O)NH 2 .
  • the invention provides compounds according to any one of Formulae I', I to IC and Il to NC, or a pharmaceutically acceptable salt thereof, wherein A 1 is a optionally substituted C 3 . 7 cycloalkyl or a optionally substituted heterocyclyl.
  • One further embodiment includes compounds according to any one of Formulae I', I to IC and Il to NC, or a pharmaceutically acceptable salt thereof, wherein A 1 is one of the following:
  • Certain compounds of the a.bove embodime.nt include compounds according to any one of Formulae I', I to IC and Il to NC, or a pharmaceutically acceptable salt thereof, wherein A 1 is a 5-membered ring heteroaryl. This embodiment is illustrated by compounds of Formula III:
  • Formula or a pharmaceutically acceptable salt thereof wherein X, X 1 , R 1 , R 2 and n have the definitions of Formula I or I', supra and Y 1 , Y 2 and Y 3 are independently N, NH, S, O or CH and form together with the ring atoms to which they are attached a 5-membered heteroaryl ring.
  • the invention pertains to compounds of Formula INA:
  • Formula INA or a pharmaceutically acceptable salt thereof, wherein X, X 1 , R 1 , R 2 and n have the definitions of Formula I or I', supra and Y 1 , Y 2 and Y 3 are independently N, NH, S, O or CH and form together with the ring atoms to which they are attached a 5-membered heteroaryl ring.
  • the invention pertains to compounds of Formula NIB or NIC:
  • Formula NIB Formula NIC or a pharmaceutically acceptable salt thereof, wherein X, X 1 , R 1 , R 2 have the definitions of Formula I, supra and Y 1 , Y 2 and Y 3 are independently N, NH, S, O or CH and form together with the ring atoms to which they are attached a 5-membered heteroaryl ring, p is O, 1 , 2, 3
  • the invention pertains to compounds of Formula III to NIC or a pharmaceutically acceptable salt thereof, wherein Y 1 , Y 2 and Y 3 form together with the ring atoms to which they are attached a 5-membered heteroaryl ring selected from furan, thiophene, pyrrole, pyrazole, oxazole, thiazole, oxadiazole, thiadiazole, and triazole.
  • a 5-membered heteroaryl selected from furan, thiophene, pyrrole, pyrazole, oxazole, thiazole, oxadiazole, thiadiazole, and triazole.
  • the invention pertains to compounds according to any one of Formulae I', I to IC and Il to NC or a pharmaceutically acceptable salt thereof, wherein A 1 is a 5-membered heteroaryl attached at a nitrogen atom.
  • a 1 is a 5-membered heteroaryl attached at a nitrogen atom.
  • Formula IV Formula IVA or a pharmaceutically acceptable salt thereof, wherein X, X 1 , R 1 , R 2 and n have the definitions of Formula I or I', supra and each Y 4 is independently N, S, O or CH.
  • the invention pertains to compounds of Formula IV or IVA wherein n is 1 , 2, 3, 4 or 5; R 2 is halo in the meta position and the other optional R 2 groups are independently Ci- 7 alkyl, NO 2 , CN, halo, C 3 - 7 cycloalkyl, hydroxy, Ci- 7 alkoxy, halo-C
  • the invention provides a compound according to any one of Formulae I', I to IC and Il to NC or of any classes and subclasses described herein, or a pharmaceutically acceptable salt or solvate thereof, wherein A 1 is a phenyl or a 6-membered heteroaryl in which phenyl and heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Ci- 7 alkyl, C 3-7 cycloalkyl, halo-Ci -7 alkyl, hydroxy, Ci- 7 alkoxy, halo, NR b R c , OCH 2 CO 2 H, and OCH 2 C(O)NH 2 .
  • One aspect of this embodiment include compounds according to anyone of Formulae I to IC and Il to NC, or a pharmaceutically salt thereof, wherein A 1 is connected to the amide C(O)NH moiety and to the C(O)X 1 moieties in a para arrangement.
  • Another aspect of this embodiment include compounds according to any one of Formulae I', to IC, and Il to NC, or a pharmaceutically acceptable salt thereof, wherein A 1 is connected to the amide C(O)NH moiety and to the C(O)X 1 moieties in a meta arrangement.
  • Compounds of this embodiment include compounds of Formula V:
  • Formula V or a pharmaceutically acceptable salt thereof, wherein X, X 1 , R 1 , R 2 and n have the definitions of Formula I or I', supra and W 1 , W 2 , W 3 and W 4 are independently N or CR e , in which each R e is independently selected from H, Ci_ 7 alkyl, C 3 . 7 cycloalkyl, halo-Ci_ 7 alkyl, hydroxy, Ci- 7 alkoxy, halo, NR b R c , OCH 2 CO 2 H and OCH 2 C(O)NH 2
  • the invention pertains to compounds of Formula VA:
  • Formula VA or a pharmaceutically acceptable salt thereof, wherein X, X 1 , R 1 , R 2 , W 1 , W 2 , W 3 and W 4 and n have the definitions of Formulae I, I' or V, supra.
  • the invention pertains to compounds of Formula V or VA, or a pharmaceutically acceptable salt thereof, wherein A 1 is phenyl, pyridine or pyrimidine.
  • a 1 is one of the following:
  • the invention pertains to compounds of Formula V or VA, or a pharmaceutically acceptable salt thereof, wherein n is 1 , 2, 3, 4 or 5; R 2 is halo in the meta position and the other optional R 2 groups are independently d- 7 alkyl, NO 2 , CN, halo, C 3 - 7 cycloalkyl, hydroxy, Ci- 7 alkoxy, halo-Ci -7 alkyl, NR b R c , C 6 -ioaryl, heteroaryl or heterocyclyl.
  • Certain compounds of the above embodiment include compounds according to any one of Formulae I', I to IC and Il to NC, or a pharmaceutically acceptable salt thereof, wherein A 1 is -heteroaryl-Ci. 4 alkylene or In one aspect of this embodiment, A 1 is or -Ci- 4 alkylene-heterocyclyl-, wherein the alkylene portion is attached to C(O)NH group and the aryl, heteroaryl or heterocyclyl moities are attached to C(O)X 1 . In another aspect of this embodiment, A 1 is -CH 2 -phenyl- or -phenyl-CH 2 -.
  • a 1 is -CH 2 -heteroaryl or -heteroaryl-CH 2 -. In a further embodiment, A 1 is -CH 2 -heterocyclyl or -heterocyclyl-CH 2 -. Representative examples of A 1 are the following:
  • Certain compounds of Formula I or I' include compounds of Formula Vl:
  • Formula Vl or a pharmaceutically acceptable salt thereof, wherein X, A 2 , R 1 , R 2 , R 4 and n have the definitions of Formula I or I', supra.
  • Formula VIA or a pharmaceutically acceptable salt thereof, wherein X, A 2 , R 1 , R 2 , R 4 and n have the definitions of Formula I or I', supra.
  • Certain compounds of Formula Vl or VIA include compounds of Formua VIB and VIC:
  • Formula VIB Formula VIC or a pharmaceutically acceptable salt thereof, wherein X, A 2 , R 1 , R 2 , R 4 have the definitions
  • a further aspect of this embodiment includes compounds according to anyone of Formulae Vl to VIC, or a pharmaceutically acceptable salt thereof, wherein A 2 is (CH 2 ) P and p is 0, 1 , 2 or 3. In one aspect of this embodiment, p is 0, therefore A 2 is a bond. In another aspect of this embodiment, A 2 is CH 2 or CH 2 -CH 2 .
  • the invention provide compounds according to anyone of Formulae Vl to VIC or a pharmaceutically acceptable salt thereof, wherein R 4 is an optionally substituted C 6 -i 0 aryl.
  • aryl are benzoimidazolone, benzoisothiazolone or phenyl.
  • R 4 is phenyl.
  • Substituents on the phenyl ring include for example, halo ⁇ e.g. F, Cl), hydroxy, halo-Ci. 7 alkyl (e.g. CF 3 ), Ci- 7 alkoxy or d- 7 alkyl.
  • the invention provides compounds according to anyone of Formulae Vl to VIC or a pharmaceutically acceptable salt thereof, wherein R 4 is an optionally substituted bicyclic heteroaryl.
  • the invention provide compounds according to anyone of Formulae Vl to VIC, or a pharmaceutically acceptable salt thereof, wherein R 4 is an optionally substituted 5- or 6-membered heteroaryl.
  • R 4 is a 6-membered ring heteroaryl selected from the group consisting of pyrazinyl, pyridinyl, pyrimidinyl, oxo-pyranyl (e.g. pyranone, optionally substituted pyran-4-one, pyran- 2-one such as 3-hydroxy-pyran-4-one, 3-hydroxy-pyran-2-one), and oxo-pyridinyl (e.g.
  • R 4 is a 5-membered ring heteroaryl selected from the group consisting of oxazole, pyrrole, pyrazole, isooxazole, triazole, tetrazole, oxadiazole (e.g.
  • R 4 oxazolone, thiazolone, oxadiazolone triazolone, oxazolone, imidazolone, pyrazolone.
  • the optional substituents on C 6 -i 0 aryl and heteroaryl are selected from hydroxy, d- 7 alkyl, Ci- 7 alkoxy, halo, halo-Ci- 7 alkyl or benzyl.
  • the invention provide compounds according to anyone of Formulae Vl to VIC or a pharmaceutically acceptable salt thereof, wherein R 4 is a bicyclic heteroaryl.
  • a further embodiment includes compounds of Formula Vl wherein R 4 is indolyl, benzothiazolyl or benzimidazolyl.
  • Representative examples of R 4 are the following:
  • the invention provide compounds according to any one of Formulae I', I to IC, Il to NC, III to NIC, IV, IVA, V, VA and Vl to VIC or a pharmaceutically acceptable salt thereof, wherein R 1 is methyl.
  • the invention provide compounds according to any one of Formulae I', I, IA II, NA, III, INA, IV, IVA, V, VA and Vl to VIC or a pharmaceutically acceptable salt thereof, wherein each R 2 is independently halo, alkyl, alkoxy, hydroxy, haloalkyl and n is O, 1 or 2.
  • n is 1 , 2, 3, 4 or 5
  • R 2 is halo in the meta position and the other optional R 2 groups are independently halo, Ci- 7 alkyl, d- 7 alkoxy, hydroxy, haloalkyl.
  • the invention provide compounds according to any one of Formulae I', I, IA II, NA, III, INA, IV, IVA, V, VA and Vl to VIC, or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2, R 2 is meta- chloro and the other optional R 2 group is halo, Ci. 7 alkyl, d- 7 alkoxy, hydroxy, haloalkyl.
  • the invention provide compounds according to any one of Formulae I', I to IC, Il to NC, III to NIC, IV, IVA, V, VA and Vl to VIC or a pharmaceutically acceptable salt thereof, wherein X and X 1 are independently OH or -O-Ci- 7 alkyl (e.g. O-ethyl or O-methyl). In one particular aspect of this embodiment X and X 1 are OH.
  • X and X 1 are independently -O-Ci- 7 alkyl in which alkyl is substituted with C 6 -i 0 aryl, heteroaryl, heterocyclyl, C(O)NH 2 , C(O)NH-Ci- 6 alkyl, or C(O)N(Ci- 6 alkyl) 2 .
  • Representative examples of X or X 1 are -0-CH 2 -C(O)N(CHa) 2 , -0-CH 2 -CH 2 - morpholine, -O-CH 2 -dioxolone or -O-benzyl.
  • X and X 1 are -O-C 6 -i 0 aryl.
  • a representative examples of -O-C 6 -i 0 aryl is -O-(2,3-dihydro-1 H- indene).
  • X, X 1 , A 1 , A 2 , R 2 , R 1 and R 4 groups are those defined by the X, X 1 , A 1 , A 2 , R 2 , R 1 and R 4 groups in the Examples section below.
  • alkyl refers to a fully saturated branched or unbranched (or straight chain or linear) hydrocarbon moiety, comprising 1 to 20 carbon atoms.
  • the alkyl comprises 1 to 7 carbon atoms, and more preferably 1 to 4 carbon atoms.
  • alkyl examples include methyl, ethyl, n-propyl, /so-propyl, n-butyl, sec-butyl, /so-butyl, te/t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2- dimethylpentyl, 2,3-dimethylpentyl, n-heptyl.
  • the term "Ci. 7 alkyl” refers to a hydrocarbon having one to seven carbon atoms.
  • alkylene refers to a divalent alkyl radical, wherein alkyl is as previously defined.
  • alkenyl refers to a branched or unbranched hydrocarbon having at least one carbon-carbon double bond.
  • C ⁇ alkenyl refers to a hydrocarbon having two to seven carbon atoms and comprising at least one carbon-carbon double bond.
  • Representative examples of alkenyl are vinyl, prop-1 -enyl, allyl, butenyl, isopropenyl or isobutenyl.
  • alkeylene refers to a divalent alkenyl radical, wherein alkenyl is as previously defined.
  • haloalkyl refers to an alkyl as defined herein, that is substituted by one or more halo groups as defined herein.
  • the haloalkyl can be monohaloalkyl, dihaloalkyl or polyhaloalkyl including perhaloalkyl.
  • a monohaloalkyl can have one iodo, bromo, chloro or fluoro within the alkyl group.
  • Dihaloalky and polyhaloalkyl groups can have two or more of the same halo atoms or a combination of different halo groups within the alkyl.
  • the polyhaloalkyl contains up to 12, or 10, or 8, or 6, or 4, or 3, or 2 halo groups.
  • haloalkyl are fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
  • a perhaloalkyl refers to an alkyl having all hydrogen atoms replaced with halo atoms.
  • halo-Ci_ 7 alkyl refers to a hydrocarbon having one to seven carbon atoms and being substituted by one or more halo groups.
  • alkoxy refers to alkyl-O-, wherein alkyl is defined herein above.
  • Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, te/t-butoxy, pentyloxy, hexyloxy, cyclopropyloxy-, cyclohexyloxy- and the like.
  • alkoxy groups have about 1 -7, more preferably about 1 -4 carbons.
  • cycloalkyl refers to saturated or unsaturated but non- aromatic monocyclic, bicyclic or tricyclic hydrocarbon groups of 3-12 carbon atoms, preferably 3-8, or 3-7 carbon atoms.
  • monocyclic hydrocarbon groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl.
  • Exemplary bicyclic hydrocarbon groups include bornyl, decahydronaphthyl, bicyclo[2.1 .1 ]hexyl, bicyclo[2.2.1 ]heptyl, bicyclo[2.2.1 ]heptenyl, bicyclo[2.2.2]octyl.
  • Exemplary tricyclic hydrocarbon groups include adamantyl.
  • the term "C 3 - 7 cycloakyl" refers to a cyclic hydrocarbon groups having 3 to 7 carbon atoms.
  • aryl refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6-10 carbon atoms in the ring portion.
  • aryl also refer to a group in which the aromatic ring is fused to a cycloalkyl ring, where the radical of attachment is on the aromatic ring or on the fused cycloalkyl ring. Resentative examples of aryl are phenyl, naphthyl, hexahydroindyl, indanyl or tetrahydronaphthyl.
  • C 6 -ioaryl refers to an aromatic hydrocarbon groups having 6 to 10 carbon atoms in the ring portion.
  • Heteroaryl includes monocyclic or bicyclic heteroaryl, containing from 5- 10 ring members selected from carbon atoms and 1 to 5 heteroatoms, and each heteroatoms is independently selected from O, N or S, wherein S and N may be oxidized to various oxidation states.
  • the system is fully aromatic (i.e. all rings are aromatic).
  • Typical monocyclic heteroaryl groups include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxa-2,3-diazolyl, oxa-2,4-diazolyl, oxa-2,5-diazolyl, oxa-3,4- diazolyl, thia-2,3-diazolyl, thia-2,4-diazolyl, thia-2,5-diazolyl, thia-3,4-diazolyl, 3-, 4-, or 5- isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or 5-1 ,2,4-triazolyl, 4- or 5-1 ,2, 3- triazolyl, tetrazolyl, 2-, 3-, or 4-pyridyl, 3- or 4-pyridazinyl, 3-
  • heteroaryl also refers to a group in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring or on the fused aryl ring.
  • bicyclic heteroaryl are indolyl, isoindolyl, indazolyl, indolizinyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, quinazolinyl, quinaxalinyl, thieno[2,3-b]furanyl, furo[3,2-b]-pyranyl, 5H-pyrido[2,3-d]-o-oxazinyl, 1 H- pyrazolo[4,3-d]-oxazolyl, 4H-imidazo[4,5-d] thiazolyl, pyrazino[2,3-d]pyridazinyl, imidazo[2,1 - b] thiazolyl, imidazo[1 ,2-b][1 ,2,4]triazinyl, 7-benzo[
  • an oxadiazole substituted with hydroxy also includes oxo- oxadiazole or also known as oxadiazolone.
  • the tautomerisation is represented as follow:
  • heterocyclyl refers to an optionally substituted, saturated or unsaturated non-aromatic (partially unsaturated) ring or ring system, e.g., which is a 3-, 4-, 5-, 6-, or 7-membered monocyclic, 7-, 8-, 9-, 10-, 1 1 -, or 12-membered bicyclic or 10-, 1 1 -, 12-, 13-, 14- or 15-membered tricyclic ring system and contains at least one heteroatom selected from O, S and N, where the N and S can also optionally be oxidized to various oxidation states.
  • bicyclic and tricyclic heterocyclyl ring system a non-aromatic ring system is defined as being a non-fully or partially unsaturated ring system. Therefore bicyclic and tricyclic heterocyclyl ring systems includes heterocyclyl ring systems wherein one of the fused rings is aromatic but the other(s) is (are) non-aromatic.
  • heterocyclyl moiety represents a saturated monocyclic ring containing from 5- 7 ring atoms and optionally containing a further heteroatom, selected from O, S or N.
  • the heterocyclic group can be attached at a heteroatom or a carbon atom.
  • the heterocyclyl can include fused or bridged rings as well as spirocyclic rings.
  • heterocycles include dihydrofuranyl, dioxolanyl, dioxanyl, dithianyl, piperazinyl, pyrrolidine, dihydropyranyl, oxathiolanyl, dithiolanyl, oxathianyl, thiomorpholino, oxiranyl, aziridinyl, oxetanyl, oxepanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholino, piperazinyl, azepinyl, oxapinyl, oxaazepanyl, oxathianyl, thiepanyl, azepanyl, dioxepanyl, and diazepanyl.
  • hydroxyalkyl refers to alkyl groups, as decribed above, in which the alkyl group is substituted with one or more hydroxy.
  • hydroxy includes groups with an -OH.
  • halogen includes fluorine, bromine, chlorine and iodine.
  • perhalogenated generally refers to a moiety wherein all hydrogens are replaced by halogen atoms.
  • heteroatom includes atoms of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur and phosphorus. In another embodiment, the heteroatom is nitrogen, oxygen or sulfur.
  • the structure of some of the compounds of this invention includes asymmetric carbon atoms. It is to be understood accordingly that the isomers arising from such asymmetry ⁇ e.g., all enantiomers and diastereomers) are included within the scope of this invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemical ⁇ controlled synthesis. Furthermore, the structures and other compounds and moieties discussed in this application also include all tautomers thereof.
  • the term “isomers” refers to different compounds that have the same molecular formula but differ in arrangement and configuration of the atoms.
  • an optical isomer or “a stereoisomer” refers to any of the various stereo isomeric configurations which may exist for a given compound of the present invention and includes geometric isomers. It is understood that a substituent may be attached at a chiral center of a carbon atom. Therefore, the invention includes enantiomers, diastereomers or racemates of the compound. "Enantiomers” are a pair of stereoisomers that are non- superimposable mirror images of each other.
  • a 1 :1 mixture of a pair of enantiomers is a "racemic" mixture.
  • the term is used to designate a racemic mixture where appropriate.
  • "Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.
  • the absolute stereochemistry is specified according to the Cahn- Ingold- Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S.
  • Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line.
  • Certain of the compounds described herein contain one or more asymmetric centers or axes and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-.
  • the present invention is meant to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures.
  • Optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration. All tautomeric forms are also intended to be included.
  • any asymmetric atom (e.g., carbon or the like) of the compound(s) of the present invention can be present in racemic or enantiomerically enriched, for example the (R)-, (S)- or (R,S)- configuration.
  • each asymmetric atom has at least 50 % enantiomeric excess, at least 60 % enantiomeric excess, at least 70 % enantiomeric excess, at least 80 % enantiomeric excess, at least 90 % enantiomeric excess, at least 95 % enantiomeric excess, or at least 99 % enantiomeric excess in the (R)- or (S)- configuration.
  • Substituents at atoms with unsaturated bonds may, if possible, be present in cis- (Z)- or trans- (E)- form.
  • a compound of the present invention can be in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof.
  • Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.
  • any resulting racemates of final products or intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound.
  • a basic moiety may thus be employed to resolve the compounds of the present invention into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-0,0'-p-toluoyl tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid.
  • an optically active acid e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-0,0'-p-toluoyl tartaric acid, mandelic acid, malic acid
  • Racemic products can also be resolved by chiral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent.
  • pharmaceutically acceptable salts refers to salts that retain the biological effectiveness and properties of the compounds of this invention and, which are not biologically or otherwise undesirable.
  • the compounds of the present invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid, and the like.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound, a basic or acidic moiety, by conventional chemical methods.
  • such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid.
  • a stoichiometric amount of the appropriate base such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like
  • Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two.
  • non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred, where practicable.
  • any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds.
  • any hydrogen represented by “H” in any of the formulae herein is intended to represent all isotopic forms of hydrogen (e.g. 1 H, 2 H or D, 3 H);
  • any carbon represented by “C” in any of the formulae herein is intended to represent all isotopic forms of carbon (e.g. 11 C, 13 C, 14 C);
  • any nitrogen represented by "N” is intended to represent all isotopic forms of nitrogen (e.g. 14 N, 15 N).
  • isotopes that are included in the invention include isotopes of oxygen, sulfur, phosphorous, fluorine, iodine and chlorine, such as 18 F 31 P, 32 P, 35 S, 36 CI, 125 I.
  • the invention includes various isotopically labeled compounds as defined herein, for example those into which radioactive isotopes, such as 3 H, 13 C, and 14 C are present.
  • the atoms in the formulae herein occur in their natural abundance.
  • one or more hydrogen atom may be enriched in 2 H; or/and one or more carbon atom may be enriched in 11 C, 13 C or 14 C; or/and one or more nitrogen may be enriched in 14 N.
  • Such isotopically labelled compounds are useful in metabolic studies (with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • an 18 F or labeled compound may be particularly desirable for PET or SPECT studies.
  • Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • isotopic enrichment factor means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
  • a substituent in a compound of this invention is denoted deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
  • Isotopically-enriched compounds according to anyone of formulae I', I to VIC can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-enriched reagent in place of the non-enriched reagent previously employed.
  • solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 O, d 6 -acetone, de-DMSO.
  • Compounds of the invention i.e. compounds according to anyone of formulae I', I to VIC that contain groups capable of acting as donors and/or acceptors for hydrogen bonds may be capable of forming co-crystals with suitable co-crystal formers.
  • These co-crystals may be prepared from compounds according to anyone of formulae I', I to VIC by known co- crystal forming procedures. Such procedures include grinding, heating, co-subliming, co- melting, or contacting in solution compounds according to anyone of formulae I', I to VIC with the co-crystal former under crystallization conditions and isolating co-crystals thereby formed.
  • Suitable co-crystal formers include those described in WO 2004/078163.
  • the invention further provides co-crystals comprising a compound according to anyone of formulae I' and I to VIC.
  • the term "pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, such like materials and combinations thereof, as would be known to one of ordinary skill in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289- 1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.
  • a therapeutically effective amount of a compound of the present invention refers to an amount of the compound of the present invention that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or amelioration of a symptom, alleviation of a condition, slow or delay disease progression, or prevention of a disease, etc.
  • the term "a therapeutically effective amount” refers to the amount of the compound of the present invention that, when administered to a subject, is effective to (1 ) at least partially alleviate, inhibit, prevent and/or ameliorate a condition, a disorder or a disease, or a symptom thereof (i) ameliorated by the inhibition of neutral endopeptidase EC 3.4.
  • a therapeutically effective amount refers to the amount of the compound of the present invention that, when administered to a cell, or a tissue, or a non-cellular biological material, or a medium, is effective to at least partially reduce or inhibit the activity of neutral endopeptidase EC 3.4. 24.1 1 ; or at least partially reduce or inhibit the expression of neutral endopeptidase EC 3.4. 24.1 1
  • the term "subject" refers to an animal.
  • the animal is a mammal.
  • a subject also refers to for example, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like.
  • the subject is a human.
  • the term “inhibition” or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.
  • treating refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof).
  • treating refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
  • treating or “treatment” refers to modulating the disease or disorder, either physically, ⁇ e.g., stabilization of a discernible symptom), physiologically, ⁇ e.g., stabilization of a physical parameter), or both.
  • “treating” or “treatment” refers to preventing or delaying the onset or development or progression of the disease or disorder.
  • hypertension refers to a condition where the pressure of blood within the blood vessels is higher than normal as it circulates through the body.
  • the systolic pressure exceeds 150 mmHg or the diastolic pressure exceeds 90 mmHg for a sustained period of time, damage is done to the body.
  • excessive systolic pressure can rupture blood vessels anywhere, and when it occurs within the brain, a stroke results. Hypertension may also cause thickening and narrowing of the blood vessels which ultimately could lead to atherosclerosis.
  • type 2 diabetes including type 2 diabetes associated with hypertension refers to a disease in which the pancreas does not secrete sufficient insulin due to an impairment of pancreatic beta-cell function and/or in which there is to insensitivity to produced insulin (insulin resistance).
  • the fasting plasma glucose is less than 126 mg/dL
  • pre-diabetes is, e.g., a condition which is characterized by one of following conditions: impaired fasting glucose (1 10-125 mg/dL) and impaired glucose tolerance (fasting glucose levels less than 126 mg/dL and post-prandial glucose level between 140 mg/dL and 199 mg/dL).
  • Type 2 diabetes mellitus can be associated with or without hypertension.
  • Diabetes mellitus occurs frequently, e.g., in African American, Latino/Hispanic American, Native American, Native American, Asian American and Pacific Islanders. Markers of insulin resistance include HbAI C, HOMA IR, measuring collagen fragments, TGF- ⁇ in urine, PAI-1 and prorenin.
  • Compounds of the present invention are either obtained in the free form, as a salt thereof, or as prodrug derivatives thereof.
  • the compounds of the present invention may also form internal salts, e.g., zwitterionic molecules.
  • the present invention also provides pro-drugs of the compounds of the present invention that converts in vivo to the compounds of the present invention.
  • a pro-drug is an active or inactive compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of this invention following administration of the prodrug to a subject.
  • the suitability and techniques involved in making and using pro-drugs are well known by those skilled in the art.
  • Prodrugs can be conceptually divided into two non-exclusive categories, bioprecursor prodrugs and carrier prodrugs. See The Practice of Medicinal Chemistry, Ch. 31 -32 (Ed. Wermuth, Academic Press, San Diego, Calif., 2001 ).
  • bioprecursor prodrugs are compounds, which are inactive or have low activity compared to the corresponding active drug compound that contain one or more protective groups and are converted to an active form by metabolism or solvolysis. Both the active drug form and any released metabolic products should have acceptably low toxicity.
  • Carrier prodrugs are drug compounds that contain a transport moiety, e.g., that improve uptake and/or localized delivery to a site(s) of action. Desirably for such a carrier prodrug, the linkage between the drug moiety and the transport moiety is a covalent bond, the prodrug is inactive or less active than the drug compound, and any released transport moiety is acceptably non-toxic.
  • Carrier prodrugs can, for example, be used to improve one or more of the following properties: increased lipophilicity, increased duration of pharmacological effects, increased site-specificity, decreased toxicity and adverse reactions, and/or improvement in drug formulation (e.g., stability, water solubility, suppression of an undesirable organoleptic or physiochemical property).
  • lipophilicity can be increased by esterification of (a) hydroxyl groups with lipophilic carboxylic acids (e.g., a carboxylic acid having at least one lipophilic moiety), or (b) carboxylic acid groups with lipophilic alcohols (e.g., an alcohol having at least one lipophilic moiety, for example aliphatic alcohols).
  • lipophilic carboxylic acids e.g., a carboxylic acid having at least one lipophilic moiety
  • lipophilic alcohols e.g., an alcohol having at least one lipophilic moiety, for example aliphatic alcohols
  • Exemplary prodrugs are, e.g., esters of free carboxylic acids and S-acyl derivatives of thiols and O-acyl derivatives of alcohols or phenols, wherein acyl has a meaning as defined herein.
  • Preferred are pharmaceutically acceptable ester derivatives convertible by solvolysis under physiological conditions to the parent carboxylic acid, e.g., lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, mono- or di-substituted lower alkyl esters, such as the ⁇ -(amino, mono- or di-lower alkylamino, carboxy, lower alkoxycarbonyl)-lower alkyl esters, the ⁇ -(lower alkanoyloxy, lower alkoxycarbonyl or di- lower alkylaminocarbonyl)-lower alkyl esters, such as the pivaloyloxymethyl ester and the like conventionally used in the art
  • amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bundgaard, J. Med. Chem. 2503 (1989)).
  • drugs containing an acidic NH group such as imidazole, imide, indole and the like, have been masked with N-acyloxymethyl groups (Bundgaard, Design of Prodrugs, Elsevier (1985)). Hydroxy groups have been masked as esters and ethers.
  • EP 039,051 (Sloan and Little) discloses Mannich-base hydroxamic acid prodrugs, their preparation and use.
  • the compounds of the present invention can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.
  • the compounds of the invention can be synthesized using the methods described in the following schemes, examples, and by using art recognized techniques. All compounds described herein are included in the invention as compounds. Compounds of the invention may be synthesized according to at least one of the methods described in schemes 1 -3.
  • protecting group a readily removable group that is not a constituent of the particular desired end product of the compounds of the present invention.
  • the protection of functional groups by such protecting groups, the protecting groups themselves, and their cleavage reactions are described for example in standard reference works, such as J. F. W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, in T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999.
  • Salts of compounds of the present invention having at least one salt-forming group may be prepared in a manner known per se.
  • salts of compounds of the present invention having acid groups may be formed, for example, by treating the compounds with metal compounds, such as alkali metal salts of suitable organic carboxylic acids, e.g. the sodium salt of 2-ethylhexanoic acid, with organic alkali metal or alkaline earth metal compounds, such as the corresponding hydroxides, carbonates or hydrogen carbonates, such as sodium or potassium hydroxide, carbonate or hydrogen carbonate, with corresponding calcium compounds or with ammonia or a suitable organic amine, stoichiometric amounts or only a small excess of the salt-forming agent preferably being used.
  • metal compounds such as alkali metal salts of suitable organic carboxylic acids, e.g. the sodium salt of 2-ethylhexanoic acid
  • organic alkali metal or alkaline earth metal compounds such as the corresponding hydroxides, carbonates or hydrogen carbonates, such as sodium
  • Acid addition salts of compounds of the present invention are obtained in customary manner, e.g. by treating the compounds with an acid or a suitable anion exchange reagent.
  • Internal salts of compounds of the present invention containing acid and basic salt-forming groups, e.g. a free carboxy group and a free amino group, may be formed, e.g. by the neutralisation of salts, such as acid addition salts, to the isoelectric point, e.g. with weak bases, or by treatment with ion exchangers.
  • Salts can be converted in customary manner into the free compounds; metal and ammonium salts can be converted, for example, by treatment with suitable acids, and acid addition salts, for example, by treatment with a suitable basic agent.
  • diastereoisomers can be separated in a manner known per se into the individual isomers; diastereoisomers can be separated, for example, by partitioning between polyphasic solvent mixtures, recrystallisation and/or chromatographic separation, for example over silica gel or by e.g. medium pressure liquid chromatography over a reversed phase column, and racemates can be separated, for example, by the formation of salts with optically pure salt-forming reagents and separation of the mixture of diastereoisomers so obtainable, for example by means of fractional crystallisation, or by chromatography over optically active column materials.
  • Intermediates and final products can be worked up and/or purified according to standard methods, e.g. using chromatographic methods, distribution methods, (re-) crystallization, and the like.
  • All the above-mentioned process steps can be carried out under reaction conditions that are known per se, including those mentioned specifically, in the absence or, customarily, in the presence of solvents or diluents, including, for example, solvents or diluents that are inert towards the reagents used and dissolve them, in the absence or presence of catalysts, condensation or neutralizing agents, for example ion exchangers, such as cation exchangers, e.g.
  • mixtures of isomers that are formed can be separated into the individual isomers, for example diastereoisomers or enantiomers, or into any desired mixtures of isomers, for example racemates or mixtures of diastereoisomers, for example analogously to the methods described under "Additional process steps”.
  • solvents from which those solvents that are suitable for any particular reaction may be selected include those mentioned specifically or, for example, water, esters, such as lower alkyl-lower alkanoates, for example ethyl acetate, ethers, such as aliphatic ethers, for example diethyl ether, or cyclic ethers, for example tetrahydrofuran or dioxane, liquid aromatic hydrocarbons, such as benzene or toluene, alcohols, such as methanol, ethanol or 1 - or 2-propanol, nitriles, such as acetonitrile, halogenated hydrocarbons, such as methylene chloride or chloroform, acid amides, such as dimethylformamide or dimethyl acetamide, bases, such as heterocyclic nitrogen bases, for example pyridine or N- methylpyrrolidin-2-one, carboxylic acid anhydrides, such as lower alkanoic acid anhydrides, for example acetic anhydr
  • the compounds, including their salts, may also be obtained in the form of hydrates, or their crystals may, for example, include the solvent used for crystallization. Different crystalline forms may be present.
  • the invention relates also to those forms of the process in which a compound obtainable as an intermediate at any stage of the process is used as starting material and the remaining process steps are carried out, or in which a starting material is formed under the reaction conditions or is used in the form of a derivative, for example in a protected form or in the form of a salt, or a compound obtainable by the process according to the invention is produced under the process conditions and processed further in situ.
  • the compounds according to anyone of formulae I' and I to VIC can be prepared according to the Schemes 1 to 3 provided infra.
  • Intermediate A was prepared according to the route described in the US patent US 5,217,996 or in WO2008083967 wherein P is alkyl or benzyl and R 1 is defined as in Formula I or I' supra.
  • Amide B wherein R 3 is defined above, is prepared by the condensation of intermediate A with an alkyl or aryl acid chloride in the presence of a base such as, but not limited to, pyridine, triethylamine and diisopropylethylamine.
  • Intermediate A can also be converted to compounds of Formula B by amidation reactions with a variety of alkyl or aryl carboxylic acids using coupling reagents such as, but not limited to, EDCI or HATU.
  • Scheme 2 illustrates the synthesis of compounds according to anyone of Formula I;, to IC and Il to NC wherein A 1 is a linear d- 4 alkylene wherein one carbon is replaced by a nitrigen atom or A 1 is a heterocyclyl or heteroaryl.
  • Substituted analogs represented by compounds G are prepared by reacting compound F with an appropriate protected amino acid in the presence of a base such as, but not limited to NaHCO 3 .
  • compounds according to anyone of Formulae Il to NC wherein A 1 is a heterocyclyl or a heteroaryl containing a Nitrogen atom which is linked to C(O)NH amide bond, and represented by compounds H are prepared from the reaction of compound F with protected cyclic amino acids wherein B is heterocyclyl or heteroaryl and the carboxylate group can be attached at any position not occupied by a heteroatom.
  • Scheme 3 illustrates the synthesis of compounds of Formula V wherein R 4 is a tetrazole.
  • Intermediate A is reacted with an appropriate carboxylic acid as described in step 1 a, using standard coupling reagents selected from, but not limited to, DCC, EDCI, PyBOP or BOP in presence or absence of a reagent such as 1 -hydroxybenazotriazole, 1 -hydroxy-7- azabenzotriazole or pentafluorophenol to generate intermediate I, in which protecting group P1 can be removed using a base selected from, but not limited to, NaOH, KOH or LiOH, or an acid selected from, but not limited to, TFA or HCI, or hydrogenation with a catalyst such as, but not limited to, palladium-on-carbon under hydrogen to generate intermediate J; alternatively, intermediate A is reacted with an appropriate anhydride as described in step 1 b, in the presence of a base selected from, but not limited to, pyridine, triethylamine or diisopropylethylamine to generate intermediate J.
  • a base selected from, but not limited to, pyr
  • Intermediate J is then coupled with P 2 protected amine wherein P 2 is selected from, but not limited to, methyl, ethyl, benzyl or propionitrile using standard coupling reagents selected from, but not limited to, DCC, EDCI, PyBOP or BOP in presence or absence of a reagent such as 1 -hydroxybenazotriazole, 1 - hydroxy-7-azabenzotriazole or pentafluorophenol to generate intermediate K.
  • standard coupling reagents selected from, but not limited to, DCC, EDCI, PyBOP or BOP in presence or absence of a reagent such as 1 -hydroxybenazotriazole, 1 - hydroxy-7-azabenzotriazole or pentafluorophenol to generate intermediate K.
  • K is converted into a compound of Formula V wherein R 4 is a tetrazole using reagents such as, but not limited to, trimethylsilyl azide, triphenylphosphine and diisopropyl azodicarboxylate, to generate intermediate L, in which protecting group P2 can be removed using, for example if P2 protected amine used in step 3 is 3-aminopropionitrile, base such as 1 ,8- diazabicyclo[5.4.0]undec-7-ene.
  • reagents such as, but not limited to, trimethylsilyl azide, triphenylphosphine and diisopropyl azodicarboxylate
  • Scheme 4 illustrates the synthesis of intermediate A which is useful for the preparation of compounds of Formula I' or I.
  • Aldehyde M is prepared by reduction of a protected amino acid ester with a reducing agent such as, but not limited to, diisobutyl aluminum hydride.
  • the protecting group P 3 can be chosen from, but not limited to, Boc or Cbz and group Y can be chosen from, but not limited to, halogen or triflate.
  • Intermediate N is prepared from intermediate M by methodology such as, but not limited to, a Wittig reaction employing an appropriate phosphorus reagent such as, but not limited to, a triphenyl phosphonium ylide.
  • the substituted biphenyl intermediate O is prepared from Intermediate N by methodology such as, but not limited to, a Suzuki reaction employing reactants such as, but not limited to, arylboronic acids or arylboronic esters catalyzed by a palladium(O) complex such as, but not limited to, tetrakis(triphenylphosphine)palladium or dichloro[1 ,1 '- bis(diphenylphosphino)ferrocene]palladium(ll) dichloromethane adduct.
  • a catalyst such as, but not limited to, platinum-on-carbon or platinum oxide at atmospheric or elevated pressure.
  • the reduction can be performed using chiral catalysts and ligands such as, but not limited to, those described in patent application WO2008031567.
  • the protecting group P 3 can be removed with an acid selected from, but not limited to, TFA or HCI, or hydrogenation with a catalyst such as, but not limited to, palladium-on-carbon under hydrogen to generate intermediate A.
  • the invention further includes any variant of the present processes, in which an intermediate product obtainable at any stage thereof is used as starting material and the remaining steps are carried out, or in which the starting materials are formed in situ under the reaction conditions, or in which the reaction components are used in the form of their salts or optically pure antipodes.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.
  • the pharmaceutical composition can be formulated for particular routes of administration such as oral administration, parenteral administration, and rectal administration, etc.
  • the pharmaceutical compositions of the present invention can be made up in a solid form including capsules, tablets, pills, granules, powders or suppositories, or in a liquid form including solutions, suspensions or emulsions.
  • compositions can be subjected to conventional pharmaceutical operations such as sterilization and/or can contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifers and buffers etc.
  • the pharmaceutical compositions are tablets and gelatin capsules comprising the active ingredient together with a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if desired d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, colorants, flavors and sweeteners.
  • diluents e.g., lactose, dextrose, sucrose
  • Tablets may be either film coated or enteric coated according to methods known in the art.
  • compositions for oral administration include an effective amount of a compound of the invention in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.
  • Formulations for oral use can be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example, peanut oil, liquid paraffin or olive oil.
  • compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions.
  • Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances.
  • Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1 -75%, or contain about 1 -50%, of the active ingredient.
  • compositions for transdermal application include an effective amount of a compound of the invention with carrier.
  • Carriers include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host.
  • transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound of the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
  • compositions for topical application include aqueous solutions, suspensions, ointments, creams, gels or sprayable formulations, e.g., for delivery by aerosol or the like.
  • topical delivery systems will in particular be appropriate for dermal application. They are thus particularly suited for use in topical, including cosmetic, formulations well-known in the art.
  • Such may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
  • a topical application may also pertain to an inhalation or to an intranasal application. They are conveniently delivered in the form of a dry powder (either alone, as a mixture, for example a dry blend with lactose, or a mixed component particle, for example with phospholipids) from a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray, atomizer or nebuliser, with or without the use of a suitable propellant.
  • a dry powder either alone, as a mixture, for example a dry blend with lactose, or a mixed component particle, for example with phospholipids
  • the present invention further provides anhydrous pharmaceutical compositions and dosage forms comprising the compounds of the present invention as active ingredients, since water may facilitate the degradation of certain compounds.
  • Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.
  • An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained.
  • anhydrous compositions are preferably packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e. g., vials), blister packs, and strip packs.
  • suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e. g., vials), blister packs, and strip packs.
  • the invention further provides pharmaceutical compositions and dosage forms that comprise one or more agents that reduce the rate by which the compound of the present invention as an active ingredient will decompose. Such agents, which are referred to herein as "stabilizers,” include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers
  • pharmacological properties e.g. neutral endopeptidase EC 3.4. 24.1 1 modulating properties, e.g. as indicated in in vitro and in vivo tests as provided in the next sections and are therefore indicated for therapy.
  • Compounds of the invention may be useful in the treatment of an indication selected from hypertension, pulmonary hypertension, isolated systolic hypertension, resistant hypertension, peripheral vascular disease, heart failure, congestive heart failure, left ventricular hypertrophy, angina, renal insufficiency (diabetic or non-diabetic), renal failure (including edema and salt retension), diabetic nephropathy, non-diabetic nephropathy, nephroic syndrome, glomerulonephritis, scleroderma, glomerular sclerosis, proteinurea of primary renal disease, renal vascular hypertention, diabetic retinopathy and end-stage renal disease (ESRD), endothelial dysfunction, diastolic dysfunction, hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation (AF), cardiac fibrosis, atrial flutter, detrimental vascular remodeling, plaque stabilization, myocardial infarction (
  • the present invention provides the use of a compound according to anyone of formulae I', I to VIC, Il to NC, III to NIC, IV, IVA, V, VA and Vl to VIC, or a pharmaceutically acceptable salt thereof.
  • the therapy is selected from a disease which is associated with neutral endopeptidase EC 3.4. 24.1 1 activity.
  • the disease is selected from the afore-mentioned list, suitably hypertension, pulmonary hypertension, isolated systolic hypertension, resistant hypertension, peripheral vascular disease, heart failure, congestive heart failure, left ventricular hypertrophy, angina, renal insufficiency, renal failure (including edema and salt retension), diabetic nephropathy, non-diabetic nephropathy, type-2 diabetis, and diabetic complications and most suitably cardiovascular disorders, such as hypertension, renal insufficiency including edema and congestive heart failure.
  • the invention provides a method of treating a disease which is associated with neutral endopeptidase EC 3.4. 24.1 1 activity comprising administration of a therapeutically acceptable amount of a compound according to anyone of formulae I', I to VIC, Il to NC, III to NIC, IV, IVA, V, VA and Vl to VIC, or a pharmaceutically acceptable salt thereof.
  • the disease is selected from the afore-mentioned list, suitably hypertension, pulmonary hypertension, isolated systolic hypertension, resistant hypertension, peripheral vascular disease, heart failure, congestive heart failure, left ventricular hypertrophy, angina, renal insufficiency, renal failure (including edema and salt retension), diabetic nephropathy, non-diabetic nephropathy, type-2 diabetis, and diabetic complications and most suitably cardiovascular disorders, such as hypertension, renal insufficiency including edema and congestive heart failure.
  • the pharmaceutical composition or combination of the present invention can be in unit dosage of about 1 -1000 mg of active ingredient(s) for a subject of about 50-70 kg, or about 1 -500 mg or about 1 -250 mg or about 1 -150 mg or about 0.5-100 mg, or about 1 -50 mg of active ingredients.
  • the therapeutically effective dosage of a compound, the pharmaceutical composition, or the combinations thereof is dependent on the species of the subject, the body weight, age and individual condition, the disorder or disease or the severity thereof being treated. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progress of the disorder or disease.
  • the above-cited dosage properties are demonstrable in vitro and in vivo tests using advantageously mammals, e.g., mice, rats, dogs, monkeys or isolated organs, tissues and preparations thereof.
  • the compounds of the present invention can be applied in vitro in the form of solutions, e.g., preferably aqueous solutions, and in vivo either enterally, parenterally, advantageously intravenously, e.g., as a suspension or in aqueous solution.
  • the dosage in vitro may range between about 10 "3 molar and 10 9 molar concentrations.
  • a therapeutically effective amount in vivo may range depending on the route of administration, between about 0.1 -500 mg/kg, or between about 1 -100 mg/kg.
  • the activity of a compound according to the present invention can be assessed by the following in vitro & in vivo methods and/or by the following in vitro & in vivo methods well- described in the art. See A fluorescence lifetime-based assay for protease inhibitor profiling on human kallikrein 7 Doering K, Meder G, Hinnenberger M, Woelcke J, Mayr LM, Hassiepen U Biomol Screen. 2009 Jan; 14(1 ):1 -9.
  • Recombinant human neutral endopeptidase (expressed in insect cells and purified using standard methods, final concentration 7 pM) is pre-incubated with test compounds at various concentrations for 1 hour at room temperature in 10 mM sodium phosphate buffer at pH 7.4, containing 150 mM NaCI and 0.05 % (w/v) CHAPS.
  • the enzymatic reaction is started by the addition of a synthetic peptide substrate Cys(PT14)-Arg-Arg-Leu-Trp-OH to a final concentration of 0.7 ⁇ M.
  • Substrate hydrolysis leads to an increase fluorescence lifetime (FLT) of PT14 measured by the means of a FLT reader as described by Doering et al. (2009).
  • the IC50 values corresponding to the inhibitor concentration showing 50% reduction of the FLT values measured in absence of inhibitor, are calculated from the plot of percentage of inhibition vs. inhibitor concentration using non-linear regression analysis software.
  • the compound of the present invention may be administered either simultaneously with, or before or after, at least one other therapeutic agent.
  • the compound of the present invention may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition.
  • the invention provides a product comprising a compound according to anyone of formulae I', I to VIC, Il to NC, III to NIC, IV, IVA, V, VA and Vl to VIC and at least one other therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy.
  • the therapy is the treatment of a disease or condition associated with neutral endopeptidase EC 3.4. 24.1 1 activity.
  • Products provided as a combined preparation include a composition comprising the compound according to anyone of formulae I', I to VIC, Il to NC, III to NIC, IV, IVA, V, VA and Vl to VIC, or a pharmaceutically acceptable salt thereof, and the other therapeutic agent(s) together in the same pharmaceutical composition, or the compound according to anyone of formulae I' and I to VIC, or a pharmaceutically acceptable salt thereof, and the other therapeutic agent(s) in separate form, e.g. in the form of a kit.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to anyone of formulae I' and I to VIC, or a pharmaceutically acceptable salt thereof, and another therapeutic agent(s).
  • the pharmaceutical composition may comprise a pharmaceutically acceptable excipient, as described above.
  • the invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound according to anyone of formulae I' and I to VIC, or a pharmaceutically acceptable salt thereof.
  • the kit comprises means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet.
  • An example of such a kit is a blister pack, as typically used for the packaging of tablets, capsules and the like.
  • the kit of the invention may be used for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another.
  • the kit of the invention typically comprises directions for administration.
  • the compound of the invention and the other therapeutic agent may be manufactured and/or formulated by the same or different manufacturers. Moreover, the compound of the invention and the other therapeutic may be brought together into a combination therapy: (i) prior to release of the combination product to physicians ⁇ e.g. in the case of a kit comprising the compound of the invention and the other therapeutic agent); (ii) by the physician themselves (or under the guidance of the physician) shortly before administration; (iii) in the patient themselves, e.g. during sequential administration of the compound of the invention and the other therapeutic agent.
  • the invention provides the use of a compound according to anyone of formulae i to VIC, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or condition associated with neutral endopeptidase EC 3.4. 24.1 1 activity, wherein the medicament is prepared for administration with another therapeutic agent.
  • the invention also provides the use of another therapeutic agent in the manufacture of medicament for treating a disease or condition associated with neutral endopeptidase EC 3.4. 24.1 1 activity, wherein the medicament is prepared for administration with a compound according to anyone of formulae I' and I to VIC, or a pharmaceutically acceptable salt thereof.
  • the invention also provides a compound according to anyone of Formulae I' and I to VIC, or a pharmaceutically acceptable salt thereof, for use in a method of treating a disease or condition associated with neutral endopeptidase EC 3.4. 24.1 1 activity, wherein the compound according to anyone of formulae I' and I to VIC, or a pharmaceutically acceptable salt thereof, is prepared for administration with another therapeutic agent.
  • the invention also provides another therapeutic agent for use in a method of treating a disease or condition associated with neutral endopeptidase EC 3.4. 24.1 1 , wherein the other therapeutic agent is prepared for administration with a compound according to anyone of formulae I' and I to VIC, or a pharmaceutically acceptable salt thereof.
  • the invention also provides a compound according to anyone of formulae I' and I toVIC, or a pharmaceutically acceptable salt thereof, for use in a method of treating a disease or condition associated with neutral endopeptidase EC 3.4. 24.1 1 , wherein the compound according to anyone of formulae I' and I to VIC, or a pharmaceutically acceptable salt thereof, is administered with another therapeutic agent.
  • the invention also provides another therapeutic agent for use in a method of treating a disease or condition associated with neutral endopeptidase EC 3.4. 24.1 1 activity, wherein the other therapeutic agent is administered with a compound according to anyone of formulae I' and I to VIC, or a pharmaceutically acceptable salt thereof.
  • the invention also provides the use of a compound according to anyone of formulae I' and I to VIC, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or condition associated with neutral endopeptidase EC 3.4. 24.1 1 activity, wherein the patient has previously ⁇ e.g. within 24 hours) been treated with another therapeutic agent.
  • the invention also provides the use of another therapeutic agent in the manufacture of a medicament for treating a disease or condition associated with neutral endopeptidase EC 3.4. 24.1 1 activity, wherein the patient has previously (e.g. within 24 hours) been treated with a compound according to anyone of formulae I' and I to VIC, or a pharmaceutically acceptable salt thereof.
  • the other therapeutic agent is selected from: HMG-Co-A reductase inhibitor, an anigiotensin receptor blocker (ARBs, angiotensin Il receptor antagonist), angiotensin converting enzyme (ACE) Inhibitor, a calcium channel blocker (CCB), an endothelin antagonist, a renin inhibitor, a diuretic, an ApoA-l mimic, an antidiabetic agent, an obesity-reducing agent, an aldosterone receptor blocker, an endothelin receptor blocker, an aldosterone synthase inhibitors (ASI), a CETP inhibitor or a phophodiesterase type 5 (PDE5) inhibitor.
  • HMG-Co-A reductase inhibitor an anigiotensin receptor blocker (ARBs, angiotensin Il receptor antagonist), angiotensin converting enzyme (ACE) Inhibitor
  • a calcium channel blocker (CCB) an endothelin antagonist
  • a renin inhibitor a ren
  • combination with a second agent or treatment includes co-administration of the compound of the invention ⁇ e.g., a compound according to anyone of Formulae I' and I to VIC or a compound otherwise described herein) with the second agent or treatment, administration of the compound of the invention first, followed by the second agent or treatment and administration of the second agent or treatment first, followed by the compound of the invention.
  • the compound of the invention e.g., a compound according to anyone of Formulae I' and I to VIC or a compound otherwise described herein
  • second agent includes any agent which is known in the art to treat, prevent, or reduce the symptoms of a disease or disorder described herein, e.g .a disorder or disease responsive to the inhibition of neutral endopeptidase, such as for example, hypertension, pulmonary hypertension, isolated systolic hypertension, resistant hypertension, peripheral vascular disease, heart failure, congestive heart failure, left ventricular hypertrophy, angina, renal insufficiency (diabetic or non-diabetic), renal failure (including edema and salt retension), diabetic nephropathy, non-diabetic nephropathy, nephroic syndrome, glomerulonephritis, scleroderma, glomerular sclerosis, proteinurea of primary renal disease, renal vascular hypertention, diabetic retinopathy and end-stage renal disease (ESRD), endothelial dysfunction, diastolic dysfunction, hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and
  • second agents examples include HMG-Co-A reductase inhibitors, angiotensin Il receptor antagonists, angiotensin converting enzyme (ACE) Inhibitors, calcium channel blockers (CCB), endothelin antagonists, renin inhibitors, diuretics, ApoA-l mimics, antidiabetic agents, obesity-reducing agents, aldosterone receptor blockers, endothelin receptor blockers, aldosterone synthase inhibitors (ASI) and CETP inhibitors.
  • HMG-Co-A reductase inhibitors examples include HMG-Co-A reductase inhibitors, angiotensin Il receptor antagonists, angiotensin converting enzyme (ACE) Inhibitors, calcium channel blockers (CCB), endothelin antagonists, renin inhibitors, diuretics, ApoA-l mimics, antidiabetic agents, obesity-reducing agents, aldosterone receptor blockers, endothelin receptor blockers, aldosterone synth
  • HMG-Co-A reductase inhibitor also called beta-hydroxy-beta- methylglutaryl-co-enzyme-A reductase inhibitors
  • active agents that may be used to lower the lipid levels including cholesterol in blood. Examples include atorvastatin, cerivastatin, compactin, dalvastatin, dihydrocompactin, fluindostatin, fluvastatin, lovastatin, pitavastatin, mevastatin, pravastatin, rivastatin, simvastatin, and velostatin, or, pharmaceutically acceptable salts thereof.
  • ACE-inhibitor also called angiotensin converting enzyme inhibitors
  • ACE-inhibitor includes molecules that interrupt the enzymatic degradation of angiotensin I to angiotensin II. Such compounds may be used for the regulation of blood pressure and for the treatment of congestive heart failure.
  • Examples include alacepril, benazepril, benazeprilat, captopril, ceronapril, cilazapril, delapril, enalapril, enaprilat, fosinopril, imidapril, lisinopril, moveltopril, perindopril, quinapril, ramipril, spirapril, temocapril, and trandolapril, or, pharmaceutically acceptables salt thereof.
  • endothelin antagonist includes bosentan (cf. EP 526708 A), tezosentan (cf. WO 96/19459), or, pharmaceutically acceptable salts thereof.
  • renin inhibitor includes ditekiren (chemical name: [1 S- [1 fl * ,2fl * ,4fl * (1 fl * ,2fl * )]]-1 -[(1 ,1 -dimethylethoxy)carbonyl]-L-proly l-L-phenylalanyl-N-[2- hydroxy-5-methyl-1 -(2-methylpropyl)-4-[[[2-methyl-1 -[[(2- pyridinylmrthyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]- ⁇ /-alfa-methyl-L-histidinamide); terlakiren (chemical name: [R-(Ft, S * )]-N-(4-morpholinylcarbonyl)-L-phenylalanyl-N-[1 - (cyclohexylmethyl)-2-hydroxy-3-(1 -methylethoxy)-3
  • aliskiren if not defined specifically, is to be understood both as the free base and as a salt thereof, especially a pharmaceutically acceptable salt thereof, most preferably a hemi-fumarate salt thereof.
  • angiotensin Il receptor antagonist or a pharmaceutically acceptable salt thereof is understood to be an active ingredient which bind to the ATi -receptor subtype of angiotensin Il receptor but do not result in activation of the receptor.
  • these antagonists can, for example, be employed as antihypertensives or for treating congestive heart failure.
  • the class of AT 1 receptor antagonists comprises compounds having differing structural features, essentially preferred are the non-peptidic ones.
  • Preferred ATVreceptor antagonist are those agents which have been marketed, most preferred is valsartan or a pharmaceutically acceptable salt thereof.
  • CCB calcium channel blocker
  • DHPs dihydropyridines
  • non-DHPs e.g., diltiazem-type and verapamil-type CCBs
  • Examples include amlodipine, felodipine, ryosidine, isradipine, lacidipine, nicardipine, nifedipine, niguldipine, niludipine, nimodipine, nisoldipine, nitrendipine, and nivaldipine, and is preferably a non-DHP representative selected from the group consisting of flunarizine, prenylamine, diltiazem, fendiline, gallopamil, mibefradil, anipamil, tiapamil and verapamil, or, pharmaceutically acceptable salts thereof.
  • CCBs may be used as anti-hypertensive, anti-angina pectoris, or anti-
  • diuretic includes thiazide derivatives ⁇ e.g., chlorothiazide, hydrochlorothiazide, methylclothiazide, and chlorothalidon).
  • ApoA-l mimic includes D4F peptides ⁇ e.g., formula D-W-F-K-A-F-Y-D-K- V-A-E-K-F-K-E-A-F)
  • anti-diabetic agent includes insulin secretion enhancers that promote the secretion of insulin from pancreatic ⁇ -cells.
  • examples include biguanide derivatives ⁇ e.g., metformin), sulfonylureas (SU) ⁇ e.g., tolbutamide, chlorpropamide, tolazamide, acetohexamide, 4-chloro- ⁇ /-[(1 -pyrolidinylamino)carbonyl]-benzensulfonamide (glycopyramide), glibenclamide (glyburide), gliclazide, 1 -butyl-3-metanilylurea, carbutamide, glibonuride, glipizide, gliquidone, glisoxepid, glybuthiazole, glibuzole, glyhexamide, glymidine, glypinamide, phenbutamide, and tolylcyclamide), or pharmaceutically acceptable salts thereof.
  • phenylalanine derivatives ⁇ e.g., nateglinide [N- (frans ⁇ -isopropylcyclohexylcarbony ⁇ -D-phenylalanine] (cf. EP 196222 and EP 526171 ) of the formula
  • DPP-IV is responsible for inactivating GLP-1 . More particularly, DPP-IV generates a GLP-1 receptor antagonist and thereby shortens the physiological response to GLP-1 .
  • GLP- 1 is a major stimulator of pancreatic insulin secretion and has direct beneficial effects on glucose disposal.
  • the DPP-IV inhibitor can be peptidic or, preferably, non-peptidic.
  • DPP-IV inhibitors are in each case generically and specifically disclosed e.g. in WO 98/19998, DE 196 16 486 A1 , WO 00/34241 and WO 95/15309, in each case in particular in the compound claims and the final products of the working examples, the subject-matter of the final products, the pharmaceutical preparations and the claims are hereby incorporated into the present application by reference to these publications.
  • Preferred are those compounds that are specifically disclosed in Example 3 of WO 98/19998 and Example 1 of WO 00/34241 , respectively.
  • GLP-1 is an insulinotropic protein which is described, e.g., by W. E. Schmidt et al. in Diabetologia, 28, 1985, 704-707 and in US 5,705,483.
  • GLP-1 agonists includes variants and analogs of GLP-1 (7-36)NH 2 which are disclosed in particular in US 5,120,712, US 5,1 18666, US 5,512,549, WO 91/1 1457 and by C. Orskov et al in J. Biol. Chem. 264 (1989) 12826.
  • GLP-1 (7- 37) in which compound the carboxy-terminal amide functionality of Arg 36 is displaced with GIy at the 37 th position of the GLP-1 (7-36)NH 2 molecule and variants and analogs thereof including GLN 9 -GLP-1 (7-37), D-GLN 9 -GLP-1 (7-37), acetyl LYS 9 -GLP-1 (7-37), LYS 18 -GLP- 1 (7-37) and, in particular, GLP-1 (7-37)OH, VAL 8 -GLP-1 (7-37), GLY 8 -GLP-1 (7-37), THR 8 - GLP-1 (7-37), MET 8 -GLP-1 (7-37) and 4-imidazopropionyl-GLP-1 .
  • Special preference is also given to the GLP agonist analog exendin-4, described by Greig et al. in Diabetologia 1999, 42, 45-50.
  • insulin sensitivity enhancers which restore impaired insulin receptor function to reduce insulin resistance and consequently enhance the insulin sensitivity.
  • examples include hypoglycemic thiazolidinedione derivatives ⁇ e.g., glitazone, (S)-((3,4-dihydro-2-(phenyl-methyl)-2H-1 - benzopyran-6-yl)methyl-thiazolidine-2,4-dione (englitazone), 5- ⁇ [4-(3-(5-methyl-2-phenyl-4- oxazolyl)-1 -oxopropyl)-phenyl]-methyl ⁇ -thiazolidine-2,4-dione (darglitazone), 5- ⁇ [4-(1 -methyl- cyclohexyl)methoxy)-phenyl]methyl ⁇ -thiazolidine-2,4-dione (ciglitazone), 5- ⁇ [4-(2-(1 - indolyl
  • insulin signalling pathway modulators like inhibitors of protein tyrosine phosphatases (PTPases), antidiabetic non-small molecule mimetic compounds and inhibitors of glutamine-fructose-6-phosphate amidotransferase (GFAT); compounds influencing a dysregulated hepatic glucose production, like inhibitors of glucose-6-phosphatase (G6Pase), inhibitors of fructose-1 ,6-bisphosphatase (F- 1 ,6-Bpase), inhibitors of glycogen phosphorylase (GP), glucagon receptor antagonists and inhibitors of phosphoenolpyruvate carboxykinase (PEPCK); pyruvate dehydrogenase kinase (PDHK) inhibitors; inhibitors of gastric emptying; insulin; inhibitors of GSK-3; retinoid X receptor (RXR) agonists; agonists of Beta-3 AR; agonists of uncoupling
  • PTPases protein tyros
  • oil-reducing agent includes lipase inhibitors (e.g., orlistat) and appetite suppressants ⁇ e.g., sibutramine and phentermine).
  • lipase inhibitors e.g., orlistat
  • appetite suppressants e.g., sibutramine and phentermine
  • aldosterone synthase inhibitor or a pharmaceutically acceptable salt thereof is understood to be an active ingredient that has the property to inhibit the production of aldosterone.
  • Aldosterone synthase (CYP1 1 B2) is a mitochondrial cytochrome P450 enzyme catalyzing the last step of aldosterone production in the adrenal cortex, i.e., the conversion of 1 1 -deoxycorticosterone to aldosterone.
  • the inhibition of the aldosterone production with so-called aldosterone synthase inhibitors is known to be a successful variant to treatment of hypokalemia, hypertension, congestive heart failure, atrial fibrillation or renal failure.
  • Such aldosterone synthase inhibition activity is readily determined by those skilled in the art according to standard assays (e.g., US 2007/0049616).
  • the class of aldosterone synthase inhibitors comprises both steroidal and nonsteroidal aldosterone synthase inhibitors, the later being most preferred.
  • the class of aldosterone synthase inhibitors comprises compounds having differing structural features.
  • the most preferred non-steroidal aldosterone synthase inhibitor is the (+)-enantiomer of the hydrochloride of fadrozole (US patents 4617307 and 4889861 ) of formula
  • a preferred steroidal aldosterone antagonist is eplerenone (cf. EP 122232 A) of the formula
  • Aldosterone synthase inhibitors useful in said combination are compounds and analogs generically and specifically disclosed e.g. in US2007/0049616, in particular in the compound claims and the final products of the working examples, the subject-matter of the final products, the pharmaceutical preparations and the claims are hereby incorporated into the present application by reference to this publication.
  • Preferred aldosterone synthase inhibitors suitable for use in the present invention include, without limitation 4-(6,7-dihydro- 5H-pyrrolo[1 ,2-c]imidazol-5-yl)-3-methylbenzonitrile; 5-(2-chloro-4-cyanophenyl)-6,7-dihydro- 5H-pyrrolo[1 ,2-c]imidazole-5-carboxylic acid (4-methoxybenzyl)methylamide; 4'-fluoro-6- (6,7,8,9-tetrahydro-5H-imidazo[1 ,5-a]azepin-5-yl)biphenyl-3-carbonitrile; 5-(4-Cyano-2- methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1 ,2-c]imidazole-5-carboxylic acid butyl ester; 4-(6,7- Dihydro-5H-pyrrolo[1 ,2-c]imid
  • aldosterone synthase inhibitors also include compounds and analogs disclosed in WO2008/076860, WO2008/076336, WO2008/076862, WO2008/027284, WO2004/046145, WO2004/014914, WO2001 /076574.
  • Aldosterone synthase inhibitors also include compounds and analogs disclosed in U.S. patent applications US2007/0225232, US2007/0208035, US2008/0318978, US2008/0076794, US2009/0012068, US20090048241 and in PCT applications WO2006/005726, WO2006/128853, WO2006128851 , WO2006/128852, WO2007065942, WO2007/1 16099, WO2007/1 16908, WO2008/1 19744 and in European patent application EP 1886695.
  • Preferred aldosterone synthase inhibitors suitable for use in the present invention include, without limitation 8-(4-Fluorophenyl)-5,6-dihydro-8H- imidazo[5,1 -c1 [1 ,41 oxazine; 4-(5,6-Dihydro-8H-imidazo[5,1 -c][1 ,4]oxazin-8-yl)-2- fluorobenzonitrile; 4-(5,6-Dihydro-8H-imidazo[5,1 -c][1 ,4]oxazin-8-yl)-2,6- difluorobenzonitrile; 4-(5,6-Dihydro-8H-imidazo[5,1 -c][1 ,4]oxazin-8-yl)-2- methoxybenzonitrile; 3-(5,6-Dihydro-8H-imidazo[5,1 -c][1 ,4]oxazin-8-yl)benzon
  • endothelin receptor blocker includes bosentan.
  • CETP inhibitor refers to a compound that inhibits the cholesteryl ester transfer protein (CETP) mediated transport of various cholesteryl esters and triglycerides from HDL to LDL and VLDL.
  • CETP inhibition activity is readily determined by those skilled in the art according to standard assays (e.g., U.S. Pat. No. 6,140,343). Examples include compounds disclosed in U.S. Pat. No. 6,140,343 and U. S. Pat. No.
  • 6,723,752 e.g., (2R)-3- ⁇ [3-(4-Chloro-3-ethyl-phenoxy)-phenyl]-[[3-(1 , 1 ,2,2- tetrafluoro-ethoxy)-phenyl]-methyl]-amino ⁇ -1 ,1 ,1 -trifluoro-2-propanol
  • compounds disclosed in U.S. patent application Ser. No. 10/807,838 polypeptide derivatives disclosed in U.S. Pat. No. 5,512,548; rosenonolactone derivatives and phosphate-containing analogs of cholesteryl ester disclosed in J. Antibiot, 49(8): 815- 816 (1996), and Bioorg. Med. Chem. Lett.; 6:1951 -1954 (1996), respectively.
  • the CETP inhibitors also include those disclosed in WO2000/017165, WO2005/095409 and WO2005/097806.
  • Second agent of particular interest include Endothelin antagonists, renin inhibitors, angiotensin Il receptor antagonists, calcium channel blockers, diuretics, antidiabetic agents such as DPPIV inhibitors, and aldosterone synthase inhibitors.
  • the compounds in the examples 1 -1 to 59-1 have been found to have IC 50 values in the range of about 0.01 nM to about 10,000 nM for NEP.
  • HPLC condition A HPLC condition A
  • the relative stereochemistry was determined using two dimensional NMR. Under the reaction condition, it would be unexpected that the stereocenter bearing the bisphenyl- methyl group racemize. Therefore, the absolute stereochemistry was determined based on the relative stereochemistry and the absolute stereochemistry of the stereocenter bearing the bisphenyl-methyl group.
  • Example 1-1 Synthesis of N-((1 S,3R)-1-biphenyl-4-ylmethyl-3-carboxy-butyl)- isophthalamic acid
  • the solution is acidified with 1 M HCI and the mixture is extracted with ethyl acetate.
  • the organic phase is dried over sodium sulfate and the solvent is removed under reduced pressure.
  • the residue is purified by preparative HPLC using a gradient of MeCN/water (0.1 % TFA). The proper fractions are lyophilized to furnish N-((1 S,3R)-1 -biphenyl-4-ylmethyl-3-carboxy-butyl)-isophthalamic acid.
  • Example 2-15 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .02 (m, 9H), 1 .31 (m, 1 H), 1 .72 (m,
  • Example 3-33: 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .06 (d, J 7.07 Hz, 3H), 1 .71 (m, 1 H),
  • Example 3-60 1 H NMR (400 MHz, DMSO-d6): 1 H NMR (400 MHz, DMSO-d6): • ppm 1 .06-
  • Example 3-70 1 H NMR (400 MHz, DMSO-d6) ⁇ ppm 1 .08 (d, 3 H) 1 .42 - 1 .61 (m, 1 H) 1 .86
  • Example 3-72 1 H NMR (400 MHz, DMSO-d6): 1 H NMR (400 MHz, DMSO-d6): ⁇ ppm 1 .06-
  • Example 3-74 1 H NMR (400 MHz, DMSO-d6): 1 H NMR (400 MHz, DMSO-d6): • ppm 1 .07-
  • Example 3-75 1 H NMR (400 MHz, DMSO-d6) ⁇ ppm 1 .07 (d, 4 H) 1 .51 - 1 .69 (m, 1 H) 1 .87
  • Example 5-1 Synthesis of 6-((1 S,3R)-1-biphenyl-4-ylmethyl-3-carboxy- butylcarbamoyl)-4-oxo-4H-pyran-2-carboxylic acid
  • the mixture is washed with aqueous 1 M HCI and the organic phase is dried over sodium sulfate and the solvent is removed under reduced pressure.
  • the residue is purified by column chromatography using hexane/methylene chloride to elute the product.
  • Example 9-1 Synthesis of 1-((1 S,3R)-1-biphenyl-4-ylmethyl-3-carboxy- butylcarbamoyl)-1 H-pyrazole-3-carboxylic acid
  • the residue is purified by preparative HPLC using a gradient of 10% MeCN to 100% MeCN (0.1 % TFA). Lyophilization of the appropriate fractions furnishes 1 -((1 S,3R)-1 -biphenyW-ylmethyl-S-carboxy-butylcarbamoyO-i H- pyrazole-3-carboxylic acid.
  • Example 10-1 (2R,4S)-5-biphenyl-4-yl-4-[(5-carbamoyl-thiophene-2-carbonyl)-amino]- 2-methyl-pentanoic acid
  • Example 12-1 Synthesis of (2S,4S)-5-biphenyl-4-yl-4-((S)-3-carboxy-3-cyclohexyl- propionylamino)-2-methyl-pentanoic acid
  • Example 13-1 Synthesis of (2ff,4S)-5-biphenyl-4-yl-2-methyl-4-[(1 W-tetrazole-5- carbonyl)-amino]-pentanoic acid
  • reaction mixture is concentrated and purified by reverse phase HPLC to give (2/ : ?,4S)-5-biphenyl-4-yl-2-methyl-4-[(1 /-/-tetrazole-5-carbonyl)- amino]-pentanoic acid.
  • Example 14-1 Synthesis of (2R,4S)-5-biphenyl-4-yl-2-methyl-4-[(5-trifluoromethyl- [1 ,3,4]oxadiazole-2-carbonyl)-amino]-pentanoic acid
  • the combined organic layer is concentrated and purified by reverse phase HPLC [70% to 85% acetonitrile-H 2 O (containing 0.1 % TFA)] to give the benzyl ester of the title compound.
  • the obtained benzyl ester intermediate is dissolved in MeOH (4 mL) and is hydrogenated with 10% Pd/C at room temperature for 20 minutes.
  • the reaction mixture is purified by reverse phase HPLC [45% to70% acetonitrile-H 2 O
  • Example 26-1 Synthesis of 1-((1S,3R)-1-Biphenyl-4-ylmethyl-3-ethoxycarbonyl- butylcarbamoyl)-1 H-pyrazole-3-carboxylic acid
  • Example 33-1 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .09 (q, 6 H) 1 .65 (br. s., 1 H) 1 .83 (d,
  • Example 34-1 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .03 - 1 .14 (m, 6 H) 1 .60 - 1 .72 (m, 1
  • Example 37-1 Synthesis of (2R,4S)-5-Biphenyl-4-yl-4-(3-carboxymethyl- benzoylamino)-2-methyl-pentanoic acid and
  • Example 38-1 Synthesis of 3-[((1 S,3R)-1-Biphenyl-4-ylmethyl-3-carboxy- butylcarbamoyl)-methyl]-benzoic acid
  • Example 38-2 Synthesis of 5-[((1 S,3R)-1-Biphenyl-4-ylmethyl-3-carboxy- butylcarbamoyl)-methyl]-furan-2-carboxylic acid
  • Example 39-1 Synthesis of 6-Amino-2-((1 S,3R)-1-biphenyl-4-ylmethyl-3-carboxy- butylcarbamoyl)-pyrimidine-4-carboxylic acid and
  • Example 40-1 Synthesis of 4-Amino-6-((1 S,3R)-1-biphenyl-4-ylmethyl-3-carboxy- butylcarbamoyl)-pyrimidine-2-carboxylic acid
  • Example 41-1 Synthesis of 6-((1S,3R)-1-Biphenyl-4-ylmethyl-3-ethoxycarbonyl- butylcarbamoyl)-2-hydroxy-pyrimidine-4-carboxylic acid
  • Example 42-1 Synthesis of 6-((1 S,3R)-1-Biphenyl-4-ylmethyl-3-carboxy- butylcarbamoyl)-2-ethoxy-pyrimidine-4-carboxylic acid
  • Example 43-1 Synthesis of 6-((1 S,3R)-1-Biphenyl-4-ylmethyl-3-carboxy- butylcarbamoyl)-2-methoxy-pyrimidine-4-carboxylic acid
  • Example 47-3 1 H NMR (400 MHz, CHLOROFORM-cQ ⁇ ppm 1 .14 - 1 .30 (m, 6 H) 1 .55 - 1 .76 (m, 1 H) 1 .99 - 2.17 (m, 1 H) 2.55 - 2.75 (m, 1 H) 2.88 - 3.07 (m, 2 H) 4.02 - 4.22 (m, 2 H) 4.45 - 4.66 (m, 1 H) 6.49 - 6.69 (m, 1 H) 6.77 - 6.94 (m, 1 H) 7.24 - 7.36 (m, 3 H) 7.36 - 7.47 (m, 2 H) 7.48 - 7.65 (m, 5 H) 8.88 (br.
  • Example 49-1 Synthesis of (2R,4S)-5-(3'-Chloro-biphenyl-4-yl)-4-[(3-hydroxy-isoxazole- 5-carbonyl)-amino]-2-methyl-pentanoic acid and
  • Example 50-1 Synthesis of (2S,4S)-5-(3'-Chloro-biphenyl-4-yl)-4-[(3-hydroxy-isoxazole- 5-carbonyl)-amino]-2-methyl-pentanoic acid
  • any insoluble material is filtered and the filtrate purified by preparative HPLC using a gradient of 10% MeCN/water to 100% MeCN (0.1 % TFA).
  • the diastereomeric mixture is further purified by chiral HPLC on a Chirapak IA column using heptane/ethanol (80:20) (0.1 % TFA) to elute each diastereomer, (2R,4S)-5-(3'-chloro- biphenyl-4-yl)-4-[(3-hydroxy-isoxazole-5-carbonyl)-amino]-2-methyl-pentanoic acid ethyl ester and (2S,4S)-5-(3'-chloro-biphenyl-4-yl)-4-[(3-hydroxy-isoxazole-5-carbonyl)-amino]-2- methyl-pentanoic acid ethyl ester.
  • Example 49-6 1 H NMR (400 MHz, DMSO- cfe): ⁇ ppm 1 .07-1 .10 (m, 6H), 1 .49-1 .56 (m, 1 H),
  • Example 49-7 1 H NMR (400 MHz, DMSO-Cf 6 ) ⁇ ppm 1 .07 (d, 3 H) 1 .64 - 1 .74 (m, 1 H) 1 .84 -
  • Example 50-6 1 H NMR (400 MHz, DMSO-d 6 ) ⁇ ppm 1 .08 (d, 3 H) 1 .51 - 1 .62 (m, 1 H) 2.01 - 2.1 1 (m, 1 H) 2.28 - 2.36 (m, 1 H) 2.86 - 2.95 (m, 1 H) 2.95 - 3.04 (m, 1 H) 4.38 (br.
  • Example 51-1 Synthesis of (2R,4S)-4-(3-Carboxymethyl-ureido)-5-(3'-chloro-biphenyl- 4-yl)-2-methyl-pentanoic acid ethyl ester
  • (S)-5-(3'-Chloro-biphenyl-4-yl)-4-isocyanato-2-methyl-pentanoic acid ethyl ester is prepared from (S)-4-amino-5-(3'-chloro-biphenyl-4-yl)-2-methyl-pentanoic acid ethyl ester hydrochloride (Intermediate 31 ) and triphosgene analogous to the procedure described for Example 6-1 .
  • Example 54-1 Synthesis of (2R,4S)-5-(3'-chlorobiphenyl-4-yl)-2-methyl-4-(5-oxo-4,5- dihydro-1 ,2,4-oxadiazole-3-carboxamido)pentanoic acid
  • Example 58-1 Syntheis of (2R,4S)-ethyl 5-(biphenyl-4-yl)-2-methyl-4-(2-oxo-2,3- dihydrooxazole-5-carboxamido)pentanoate
  • Example 60-1 Synthesis of (2S,4S)-5-(3'-chlorobiphenyl-4-yl)-4-(2-ethyloxazole-5- carboxamido)-2-methylpentanoic acid

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Cardiology (AREA)
  • Diabetes (AREA)
  • Neurosurgery (AREA)
  • Hematology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Reproductive Health (AREA)
  • Endocrinology (AREA)
  • Epidemiology (AREA)
  • Pain & Pain Management (AREA)
  • Obesity (AREA)
  • Urology & Nephrology (AREA)
  • Psychiatry (AREA)
  • Ophthalmology & Optometry (AREA)
  • Pregnancy & Childbirth (AREA)
  • Gynecology & Obstetrics (AREA)
  • Pulmonology (AREA)
  • Hospice & Palliative Care (AREA)
  • Dermatology (AREA)
  • Oncology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Anesthesiology (AREA)
  • Rheumatology (AREA)
  • Communicable Diseases (AREA)

Abstract

The present invention provides a compound of formula (I') or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, X and n are defined herein. The invention also relates to a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.

Description

SUBSTITUTED AMINOBUTYRIC DERIVATIVES AS NEPRILYSIN INHIBITORS
BACKGROUND OF THE INVENTION:
Endogenous atrial natriuretic peptides (ANP), also called atrial natriuretic factors (ANF) have diuretic, natriuretic and vasorelaxant functions in mammals. The natural ANF peptides is metabolically inactivated, in particular by a degrading enzyme which has been recognized to correspond to the enzyme neutral endopeptidase (NEP) EC 3.4.24.1 1 , also responsible for e.g. the metabolic inactivation of enkephalins.
Neutral endopeptidase (EC 3.4.24.1 1 ; enkephalinase; atriopeptidase; NEP) is a zinc- containing metalloprotease that cleaves a variety of peptide substrates on the amino side of hydrophobic residues [see Pharmacol Rev, Vol. 45, p. 87 (1993)]. Substrates for this enzyme include, but are not limited to, atrial natriuretic peptide (ANP, also known as ANF), brain natriuretic peptide (BNP), met- and leu-enkephalin, bradykinin, neurokinin A, endothelin-1 and substance P. ANP is a potent vasorelaxant and natriuretic agent [see J Hypertens, Vol. 19, p. 1923 (2001 )]. Infusion of ANP in normal subjects resulted in a reproducible, marked enhancement of natriuresis and diuresis, including increases in fractional excretion of sodium, urinary flow rate and glomerular filtration rate [see J CHn Pharmacol, Vol. 27, p. 927 (1987)]. However, ANP has a short half-life in circulation, and NEP in kidney cortex membranes has been shown to be the major enzyme responsible for degrading this peptide [see Peptides, Vol. 9, p. 173 (1988)]. Thus, inhibitors of NEP (neutral endopeptidase inhibitors, NEPi) should increase plasma levels of ANP and, hence, are expected to induce natriuretic and diuretic effects.
This enzyme is involved in the breakdown of several bioactive oligopeptides, cleaving peptide bonds on the amino side of hydrophobic amino acid residues. The peptides metabolised include atrial natriuretic peptides (ANP), bombesin, bradykinin, calcitonin gene- related peptide, endothelins, enkephalins, neurotensin, substance P and vasoactive intestinal peptide. Some of these peptides have potent vasodilatory and neurohormone functions, diuretic and natriuretic activity or mediate behaviour effects.
SUMMARY OF THE INVENTION:
The aim of the present invention is to provide novel compounds which are useful as neutral endopeptidase inhibitors, e.g. as inhibitors of the ANF-degrading enzyme in mammals, so as to prolong and potentiate the diuretic, natriuretic and vasodilator properties of ANF in mammals, by inhibiting the degradation thereof to less active metabolites.
The compounds of this invention are thus particularly useful for the treatment of conditions and disorders responsive to the inhibition of neutral endopeptidase (NEP) EC 3.4.24.1 1 .
Thus, the compounds of the invention, by inhibiting the neutral endopeptidase EC.3.4.24.1 1 , can potentiate the biological effects of bioactive peptides. Thus, in particular the compounds have utility in the treatment of a number of disorders, including hypertension, pulmonary hypertension, isolated systolic hypertension, resistant hypertension, peripheral vascular disease, heart failure, congestive heart failure, left ventricular hypertrophy, angina, renal insufficiency (diabetic or non-diabetic), renal failure (including edema and salt retension), diabetic nephropathy, non-diabetic nephropathy, nephroic syndrome, glomerulonephritis, scleroderma, glomerular sclerosis, proteinurea of primary renal disease, renal vascular hypertention, diabetic retinopathy and end-stage renal disease (ESRD), endothelial dysfunction, diastolic dysfunction, hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation (AF), cardiac fibrosis, atrial flutter, detrimental vascular remodeling, plaque stabilization, myocardial infarction (Ml), renal fibrosis, polycystic kidney disease (PKD), Pulmonary Arterial hypertension, renal failure (including edema and salt retension), cyclical oedema, Menieres disease, hyperaldosteroneism (primary and secondary) and hypercalciuria, ascites. In addition, because of their ability to potentiate the effects of ANF the compounds have utility in the treatment of glaucoma. As a further result of their ability to inhibit the neutral endopeptidase E. C.3.4.24.1 1 the compounds of the invention may have activity in other therapeutic areas including for example the treatment of menstrual disorders, preterm labour, pre-eclampsia, endometriosis, and reproductive disorders (especially male and female infertility, polycystic ovarian syndrome, implantation failure). Also the compounds of the invention should treat asthma, obstructive sleep apnea, inflammation, leukemia, pain, epilepsy, affective disorders such as depression and psychotic condition such as dementia and geriatric confusion, obesity and gastrointestinal disorders (especially diarrhea and irritable bowel syndrome), wound healing (especially diabetic and venous ulcers and pressure sores), septic shock, the modulation of gastric acid secretion, the treatment of hyperreninaemia, cystic fibrosis, restenosis, type-2 diabetes, metabolic syndrome, diabetic complications and athereosclerosis, male and female sexual dysfunction. In a preferred embodiment the compounds of the invention are useful in the treatment of cardiovascular disorders.
The invention pertains to the compounds, methods for using them, and uses thereof as described herein. Examples of compounds of the invention include the compounds according to anyone of Formulae I' and I to VIC, or a pharmaceutically acceptable salt thereof, and the compounds of the examples.
The invention therefore provides a compound of the formula (T):
Figure imgf000005_0001
Formula I' or a pharmaceutically acceptable salt thereof, wherein: R1 is Ci-7alkyl; for each occurrence, R2 is independently Ci-7alkyl, NO2, CN, halo, C3-7cycloalkyl, hydroxy, Ci-7alkoxy, halo-Ci-7alkyl, NRbRc, C6-i0aryl, heteroaryl or heterocyclyl; wherein Rb and Rc for each occurrence, are independently H or Ci_7alkyl; R3 is A1C(O)X1 or A2-R4;
R4 is C6-ioaryl or a heteroaryl, which can be monocyclic or bicyclic and which can be optionally substituted with one or more substituents independently selected from hydroxy, hydroxy-Ci-7alkyl, NRbRc, nitro, Ci-7alkoxy, halo, Ci-7alkyl, halo-Ci-7alkyl, C2-7alkenyl, C6- iOaryl, heteroaryl, -C(O)Ci-7alkyl , -NHS(O)2-Ci-7alkyl, -SO2Ci-7alkyl and benzyl; R5 is H, halo, hydroxy, Ci-7alkoxy, halo, Ci_7alkyl or halo-Ci-7akyl; and X and X1 are independently OH, -O-Ci-7alkyl, -NRbRc, -NHS(O)2-Ci-7alkyl, -NHS(O)2-benzyl or -0-C6-ioaryl; wherein alkyl is optionally substituted with one or more substituents independently selected from the group consisting of aryl, heteroaryl, heterocyclyl, -C(O)NH2, -C(O)NH- Ci-6alkyl, and -C(O)N(d-6alkyl)2; - A -
A1 is a bond or a linear d-4alkylene substituted with one or more substituents independently selected from the group consisting of halo, O-acetate, Ci-7 alkyl and C3-7cycloalkyl; in which two geminal alkyl can optionally combine to form a C3-7cycloalkyl; or
A1 is a linear or branched C2-6alkenylene; or
A1 is a linear Ci-4 alkylene wherein one or more carbon atom(s) is/are replaced with an heteroatom selected from O, NRa; and A1 is optionally substituted with one or more substituents independently selected from the group consisting of halo and d-7alkyl; in which
Ra for each occurrence, is independently H, d-7alkyl or CH2C(O)OH; or
A1 is a C3.7cycloalkyl, a heterocyclyl, a phenyl or a heteroaryl in which phenyl and heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Ci_7alkyl, C3.7cycloalkyl, halo-Ci_7alkyl, hydroxy, Ci_7alkoxy, halo, NRbRc,
OCH2CO2H, and OCH2C(O)NH2; or
A1 is
Figure imgf000006_0001
-Ci-4alkylene-heteroaryl- or
Figure imgf000006_0002
wherein
A1 may be in either direction; and
A2 is a bond or a linear or branched Ci-7alkylene which is optionally substituted with one or more substituents independently selected from the group consisting of halo, Ci_7alkoxy, hydroxy, O-Acetate and C3.7cycloalkyl; n is O, 1 , 2, 3, 4 or 5; wherein each heteroaryl is a monocyclic or bicyclic aromatic ring comprising 5-10 ring atoms selected from carbon atoms and 1 to 5 heteroatoms, and each heterocyclyl is a monocyclic saturated or partially saturated but non-aromatic moiety comprising 4-7 ring atoms selected from carbon atoms and 1 -5 heteroatoms, wherein each heteroatom of a heteroaryl or a heterocyclyl is independently selected from O, N and S.
The invention therefore provides a compound of the formula (I):
(R2)n
Figure imgf000006_0003
Formula I or a pharmaceutically acceptable salt thereof, wherein: R1 is Ci-7alkyl; for each occurrence, R2 is independently d-7alkyl, NO2, CN, halo, C3-7cycloalkyl, hydroxy, Ci-7alkoxy, halo-Ci_7alkyl, NRbRc, C6-ioaryl, heteroaryl or heterocyclyl; wherein Rb and Rc for each occurrence, are independently H or Ci_7alkyl; R3 is A1C(O)X1 or A2-R4;
R4 is C6-i0aryl or a heteroaryl, which can be monocyclic or bicyclic and which can be optionally substituted with hydroxy, hydroxy-Ci-7alkyl, nitro, Ci_7alkoxy, halo, Ci_7alkyl, halo- Ci-7alkyl, C6-i0aryl, heteroaryl, -NHS(O)2-Ci-7alkyl, -SO2 Ci-7alkyl or benzyl; R5 is H, halo, hydroxy, Ci-7alkoxy, halo, Ci_7alkyl or halo-Ci-7akyl; and X and X1 are independently OH, -O-Ci-7alkyl or NRbRc, -O- C6-i0aryl; wherein alkyl is optionally substituted with one or more substituents independently selected from the group consisting of aryl, heteroaryl, heterocyclyl, C(O)NH2, C(O)NH- d-6alkyl, and C(O)N(Ci- 6alkyl)2;
A1 is a bond, or a linear d-4alkylene substituted with one or more substituents independently selected from the group consisting of halo, O-acetate, Ci-7 alkyl and C3- 7cycloalkyl; in which two geminal alkyl can optionally combine to form a C3-7cycloalkyl; or A1 is a linear C1-4 alkylene wherein one or more carbon atom(s) is/are replaced with an heteroatom selected from O, NRa; and A1 is optionally substituted with one or more substituents independently selected from the group consisting of halo and Ci_7alkyl; in which Ra for each occurrence, is independently H, Ci_7alkyl or CH2C(O)OH; or A1 is a C3-7cycloalkyl, a heterocyclyl, a phenyl or a heteroaryl in which phenyl and heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Ci-7alkyl, C3.7cycloalkyl, halo-Ci-7alkyl, hydroxy, Ci-7alkoxy, halo, NRbRc, OCH2CO2H, and OCH2C(O)NH2; or
A1 is
Figure imgf000007_0001
wherein A1 may be in either direction; and
A2 is a bond or a linear or branched Ci_7alkylene which is optionally substituted with one or more substituents independently selected from the group consisting of halo, Ci-7alkoxy, hydroxy, O-Acetate and C3.7cycloalkyl; n is O, 1 , 2, 3, 4 or 5; wherein each heteroaryl is a monocyclic or bicyclic aromatic ring comprising 5-10 ring atoms selected from carbon atoms and 1 to 5 heteroatoms, and each heterocyclyl is a monocyclic saturated or partially saturated but non-aromatic moiety comprising 4-7 ring atoms selected from carbon atoms and 1 -5 heteroatoms, wherein each heteroatom of a heteroaryl or a heterocyclyl is independently selected from O, N and S.
In another embodiment, the invention pertains to a method for treating a disorders or diseases responsive to the inhibition of neutral endopeptidase EC 3.4. 24.1 1 (NEP), in a subject in need of such treatment, comprising: administering to the subject an effective amount of a compound according to anyone of Formulae I-VIC, or a pharmaceutically acceptable salt thereof, such that the disorder or disease responsive to the inhibition of neutral endopeptidase EC 3.4. 24.1 1 (NEP) in the subject is treated.
In yet another embodiment, the invention pertains to a method for treating hypertension, pulmonary hypertension, isolated systolic hypertension, resistant hypertension, peripheral vascular disease, heart failure, congestive heart failure, left ventricular hypertrophy, angina, renal insufficiency (diabetic or non-diabetic), renal failure (including edema and salt retension), diabetic nephropathy, non-diabetic nephropathy, nephroic syndrome, glomerulonephritis, scleroderma, glomerular sclerosis, proteinurea of primary renal disease, renal vascular hypertention, diabetic retinopathy and end-stage renal disease (ESRD), endothelial dysfunction, diastolic dysfunction, hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation (AF), cardiac fibrosis, atrial flutter, detrimental vascular remodeling, plaque stabilization, myocardial infarction (Ml), renal fibrosis, polycystic kidney disease (PKD), Pulmonary Arterial hypertension, renal failure (including edema and salt retension), cyclical oedema, Menieres disease, hyperaldosteroneism (primary and secondary) and hypercalciuria, ascites, glaucoma, menstrual disorders, preterm labour, pre-eclampsia, endometriosis, and reproductive disorders (especially male and female infertility, polycystic ovarian syndrome, implantation failure), asthma, obstructive sleep apnea, inflammation, leukemia, pain, epilepsy, affective disorders such as depression and psychotic condition such as dementia and geriatric confusion, obesity and gastrointestinal disorders (especially diarrhea and irritable bowel syndrome), wound healing (especially diabetic and venous ulcers and pressure sores), septic shock, gastric acid secretion dysfunction, hyperreninaemia, cystic fibrosis, restenosis, type-2 diabetes, metabolic syndrome, diabetic complications and atherosclerosis, male and female sexual dysfunction; comprising administering to the subject a therapeutically effective amount of a compound according to anyone of Formulae I-VIC, or a pharmaceutically acceptable salt thereof such that the subject is treated.
In yet another embodiment, the invention pertains to pharmaceutical compositions, comprising a compound according to anyone of Formulae I-VIC, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.
In still another embodiment, the invention pertains to combinations including, a compound according to anyone of Formulae I-VIC, or a pharmaceutically acceptable salt thereof, and pharmaceutical combinations of one or more therapeutically active agents.
In another embodiment, the invention pertains to a method for inhibiting neutral endopeptidase EC 3.4. 24.1 1 in a subject in need thereof, comprising: administering to the subject a therapeutically effective amount of a compound according to anyone of Formulae I-VIC, or a pharmaceutically acceptable salt thereof, such that neutral endopeptidase EC 3.4. 24.1 1 is inhibited.
DETAILED DESCRIPTION OF THE INVENTION
Compounds of the Invention
References hereinafter to compounds of Formula I or I' apply equally to compounds according to anyone of Formulae IB to VIC.
References hereinafter to embodiments of the invention apply equally to compounds of Formula I or I' and compounds according to anyone of Formulae IB to VIC, insofar as the embodiments are present.
Various embodiments of the invention are described herein. It will be recognized that features specified in each embodiment may be combined with other specified features to provide further embodiments.
In one embodiment the invention provides a compound of the Formula I or I', or a pharmaceutically acceptable salt thereof wherein: R1 is Ci-7alkyl; for each occurrence R2 is independently d-7alkyl, halo, C3-7cycloalkyl, hydroxy, d-7alkoxy, halo-Ci-7alkyl, NRbRc, C6-ioaryl, heteroaryl or heterocyclyl; wherein Rb and Rc for each occurrence, are independently H or Ci_7alkyl; R3 is A1C(O)X1 or A2-R4; R4 is aryl or a heteroaryl, which can be monocyclic or bicyclic and which can be optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, d-7alkoxy, halo, d-7alkyl, halo-Ci-7alkyl, C6-i0aryl, heteroaryl, -NHS(O)2-Ci-7alkyl,
-SO2 Ci_7alkyl and benzyl;
R5 is H; and
X and X1 are independently OH, -O-Ci-7alkyl or NRbRc;
A1 is a linear C1-4 alkylene substituted with one or more substituents independently selected from the group consisting of halo, O-acetate, Ci-7 alkyl and C3-7cycloalkyl; in which two geminal alkyl can optionally combine to form a C3.7cycloalkyl; or
A1 is a linear C1-4 alkylene wherein one or more carbon atom(s) is/are replaced with an heteroatom selected from O, NRa; wherein A1 is optionally substituted with one or more substituents independently selected from the group consisting of halo and Ci_7alkyl; in which
Ra for each occurence, is independently H, Ci_7alkyl or CH2C(O)OH; or
A1 is a C3-7cycloalkyl, a heterocyclyl, a phenyl or a heteroaryl in which phenyl and heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Ci-7alkyl, C3-7cycloalkyl, halo-Ci-7alkyl, hydroxy, Ci-7alkoxy, halo, NRbRc,
OCH2CO2H, and OCH2C(O)NH2; and
A2 is a bond or a linear or branched Ci_7alkylene which is optionally substituted with one or more substituents independently selected from the group consisting of halo, Ci-7alkoxy, hydroxy, O-Acetate and C3.7cycloalkyl; n is O, 1 , 2, 3, 4 or 5; wherein each heteroaryl is a monocyclic or bicyclic aromatic ring comprising 5-10 ring atoms selected from carbon atoms and 1 to 5 heteroatoms, and each heterocyclyl is a monocyclic saturated or partially saturated but non-aromatic moiety comprising 4-7 ring atoms selected from carbon atoms and 1 -5 heteroatoms, wherein each heteroatom of a heteroaryl or heterocyclyl is independently selected from O, N and S.
Certain compounds of Formula I or I' include compounds of Formula IA:
Figure imgf000011_0001
Formula IA or a pharmaceutically acceptable salt thereof, wherein X, R1, R2, R3 and n have the definitions of Formula I, supra.
Certain compounds of Formulae I or I' wherein n is 1 , 2, 3, 4 or 5; R2 is halo and is attached to the meta position and the other optional R2 groups are independently Ci-7alkyl, NO2, CN, halo, C3-7cycloalkyl, hydroxy, d-7alkoxy, halo-Ci-7alkyl, NRbRc, C6-i0aryl, heteroaryl or heterocyclyl. This embodiment is illustrated by compounds of Formulae IB and IC:
Figure imgf000011_0002
or a pharmaceutically acceptable salt thereof, wherein X, R1, R2, R3 have the definitions of
Formula I or I', supra; p is O, 1 , 2, 3 or 4 and R a is halo.
Certain compounds of Formula I or I' include compounds of Formula II:
Figure imgf000011_0003
Formula or a pharmaceutically acceptable salt thereof, wherein X, X1, A1, R1, R2 and n have the definitions of Formula I or I', supra.
Certain compounds of Formulae I, I' or Il include compounds of Formula NA:
Figure imgf000012_0001
Formula NA or a pharmaceutically acceptable salt thereof, wherein X, X1, A1, R1, R2 and n have the definitions of Formula I or I', supra.
Certain compounds of Formula I or I' include compounds of Formula NB and NC:
Figure imgf000012_0002
Formula NB Formula NC or a pharmaceutically acceptable salt thereof, wherein X, X1, A1, R1, R2 have the definitions
2a of Formula I or I', supra; p is 0, 1 , 2, 3 or 4 and R is halo.
In another embodiment the invention provides a compound according to anyone of of the formulae I', I to IC and Il to NC, or of any classes and subclasses described herein, or a pharmaceutically acceptable salt or solvate thereof, wherein A1 is a linear Ci-4 alkylene substituted with one or more substituents independently selected from the group consisting of halo, O-acetate, d-7alkyl and C3-7cycloalkyl; in which two geminal alkyl can optionally combine to form a C3-7cycloalkyl. A further embodiment includes compounds according to any one of Formulae I', I to IC and Il to NC, or of any classes and subclasses described herein, or a pharmaceutically acceptable salt thereof, wherein A1 has the following formulae:
Figure imgf000013_0001
->d1 in which R and R are independently H, halo, C3-7cycloalkyl, or d-7alkyl and at least one of Rd1 and Rd2 is other than H; and alternatively Rd1 and Rd2 can form together with the atoms to which they are attached a C3-7cycloalkyl; and
Re1 and Re2 are independently H, halo, C3-7cycloalkyl, or Ci_7alkyl and at least one of Re1 and
Re2 is other than H; and alternatively Re1 and Re2can form together with the atoms to which they are attached a C3-7cycloalkyl. In one aspect of this embodiment, A1 is one of the following:
Figure imgf000013_0002
Yet another further embodiment include compounds according to any one of Formulae I', I to IC and Il to NC, or of any classes and subclasses described herein, or a pharmaceutically acceptable salt thereof, wherein A1 has the following formulae:
Figure imgf000013_0003
in which Rd3, Rd4, Rd5 and Rd6 are independently H, halo, O-acetate or Ci-7alkyl and at least one of Rd3, Rd4, Rd5 and Rd6 is other than H. In a further aspect of this embodiment, A1 is one of the following:
Figure imgf000014_0001
In another embodiment the invention provides a compound according to any one of the formulae I', I to IC and Il to NC, or of any classes and subclasses described herein, or a pharmaceutically acceptable salt or solvate thereof, wherein A1 is a linear Ci-4 alkylene wherein one or more carbon atom(s) is/are replaced with an heteroatom selected from O, NRa; and A1 is optionally substituted with one or more substituents independently selected from the group consisting of halo and d-7alkyl; in which Ra for each occurrence is independenently H, d-7alkyl or CH2C(O)OH. One further embodiment includes compounds according to anyone of Formulae I', I to IC and Il to NC wherein A1 is one of the following:
Figure imgf000014_0002
In yet another embodiment the invention provides a compound according to any one of Formulae I', I to IC and Il to NC or of any classes and subclasses described herein, or a pharmaceutically acceptable salt or solvate thereof, wherein A1 is a C3-7cycloalkyl, a heterocyclyl, a phenyl or a heteroaryl in which phenyl and heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Ci-7alkyl, C3-7cycloalkyl, halo-Ci-7 alkyl, hydroxy, Ci-7alkoxy, halo, NRbRc, OCH2CO2H, and OCH2C(O)NH2. In one aspect of this embodiment the invention provides compounds according to any one of Formulae I', I to IC and Il to NC, or a pharmaceutically acceptable salt thereof, wherein A1 is a optionally substituted C3.7 cycloalkyl or a optionally substituted heterocyclyl. One further embodiment includes compounds according to any one of Formulae I', I to IC and Il to NC, or a pharmaceutically acceptable salt thereof, wherein A1 is one of the following:
Figure imgf000015_0001
Figure imgf000015_0002
Figure imgf000015_0003
Certain compounds of the a.bove embodime.nt include compounds according to any one of Formulae I', I to IC and Il to NC, or a pharmaceutically acceptable salt thereof, wherein A1 is a 5-membered ring heteroaryl. This embodiment is illustrated by compounds of Formula III:
Figure imgf000015_0004
Formula or a pharmaceutically acceptable salt thereof, wherein X, X1, R1, R2 and n have the definitions of Formula I or I', supra and Y1, Y2 and Y3 are independently N, NH, S, O or CH and form together with the ring atoms to which they are attached a 5-membered heteroaryl ring. In one aspect of this embodiment, the invention pertains to compounds of Formula INA:
Figure imgf000016_0001
Formula INA or a pharmaceutically acceptable salt thereof, wherein X, X1, R1, R2 and n have the definitions of Formula I or I', supra and Y1, Y2 and Y3 are independently N, NH, S, O or CH and form together with the ring atoms to which they are attached a 5-membered heteroaryl ring.
In another aspect of this embodiment, the invention pertains to compounds of Formula NIB or NIC:
Figure imgf000016_0002
Formula NIB Formula NIC or a pharmaceutically acceptable salt thereof, wherein X, X1, R1, R2 have the definitions of Formula I, supra and Y1, Y2 and Y3 are independently N, NH, S, O or CH and form together with the ring atoms to which they are attached a 5-membered heteroaryl ring, p is O, 1 , 2, 3
,2a or 4 and R is halo. In a further embodiment, the invention pertains to compounds of Formula III to NIC or a pharmaceutically acceptable salt thereof, wherein Y1, Y2 and Y3 form together with the ring atoms to which they are attached a 5-membered heteroaryl ring selected from furan, thiophene, pyrrole, pyrazole, oxazole, thiazole, oxadiazole, thiadiazole, and triazole. One further embodiment includes compounds of Formula III wherein the 5-membered heteroaryl is one of the following:
Figure imgf000017_0001
Figure imgf000017_0002
Figure imgf000017_0003
In yet another aspect of the above embodiment, the invention pertains to compounds according to any one of Formulae I', I to IC and Il to NC or a pharmaceutically acceptable salt thereof, wherein A1 is a 5-membered heteroaryl attached at a nitrogen atom. This embodiment is illustrated by compounds of Formula IV or IVA:
Figure imgf000017_0004
Formula IV Formula IVA or a pharmaceutically acceptable salt thereof, wherein X, X1, R1, R2 and n have the definitions of Formula I or I', supra and each Y4 is independently N, S, O or CH. In a further embodiment, the invention pertains to compounds of Formula IV or IVA wherein n is 1 , 2, 3, 4 or 5; R2 is halo in the meta position and the other optional R2 groups are independently Ci-7alkyl, NO2, CN, halo, C3-7cycloalkyl, hydroxy, Ci-7alkoxy, halo-C
7alkyl, NRbRc, C6-i0aryl, heteroaryl or heterocyclyl.
In yet another aspect of the above embodiment the invention provides a compound according to any one of Formulae I', I to IC and Il to NC or of any classes and subclasses described herein, or a pharmaceutically acceptable salt or solvate thereof, wherein A1 is a phenyl or a 6-membered heteroaryl in which phenyl and heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Ci-7alkyl, C3-7cycloalkyl, halo-Ci-7alkyl, hydroxy, Ci-7alkoxy, halo, NRbRc, OCH2CO2H, and OCH2C(O)NH2. One aspect of this embodiment include compounds according to anyone of Formulae I to IC and Il to NC, or a pharmaceutically salt thereof, wherein A1 is connected to the amide C(O)NH moiety and to the C(O)X1 moieties in a para arrangement. Another aspect of this embodiment include compounds according to any one of Formulae I', to IC, and Il to NC, or a pharmaceutically acceptable salt thereof, wherein A1 is connected to the amide C(O)NH moiety and to the C(O)X1 moieties in a meta arrangement. Compounds of this embodiment include compounds of Formula V:
Figure imgf000018_0001
Formula V or a pharmaceutically acceptable salt thereof, wherein X, X1, R1, R2 and n have the definitions of Formula I or I', supra and W1, W2, W3 and W4 are independently N or CRe, in which each Re is independently selected from H, Ci_7alkyl, C3.7cycloalkyl, halo-Ci_7alkyl, hydroxy, Ci-7alkoxy, halo, NRbRc, OCH2CO2H and OCH2C(O)NH2
In a further embodiment, the invention pertains to compounds of Formula VA:
Figure imgf000019_0001
Formula VA or a pharmaceutically acceptable salt thereof, wherein X, X1, R1, R2, W1, W2, W3 and W4 and n have the definitions of Formulae I, I' or V, supra.
In one aspect of this embodiment, the invention pertains to compounds of Formula V or VA, or a pharmaceutically acceptable salt thereof, wherein A1 is phenyl, pyridine or pyrimidine. One further embodiment includes compounds of Formula V or VA, or a pharmaceutically acceptable salt thereof, wherein A1 is one of the following:
Figure imgf000019_0002
In a further aspect of the above embodiment, the invention pertains to compounds of Formula V or VA, or a pharmaceutically acceptable salt thereof, wherein n is 1 , 2, 3, 4 or 5; R2 is halo in the meta position and the other optional R2 groups are independently d-7alkyl, NO2, CN, halo, C3-7cycloalkyl, hydroxy, Ci-7alkoxy, halo-Ci-7alkyl, NRbRc, C6-ioaryl, heteroaryl or heterocyclyl. Certain compounds of the above embodiment include compounds according to any one of Formulae I', I to IC and Il to NC, or a pharmaceutically acceptable salt thereof, wherein A1 is
Figure imgf000020_0001
Figure imgf000020_0002
-heteroaryl-Ci.4alkylene or
Figure imgf000020_0003
In one aspect of this embodiment, A1 is
Figure imgf000020_0004
or -Ci- 4alkylene-heterocyclyl-, wherein the alkylene portion is attached to C(O)NH group and the aryl, heteroaryl or heterocyclyl moities are attached to C(O)X1. In another aspect of this embodiment, A1 is -CH2-phenyl- or -phenyl-CH2-. In another aspect of this embodiment, A1 is -CH2-heteroaryl or -heteroaryl-CH2-. In a further embodiment, A1 is -CH2-heterocyclyl or -heterocyclyl-CH2-. Representative examples of A1 are the following:
Figure imgf000020_0005
Certain compounds of Formula I or I' include compounds of Formula Vl:
Figure imgf000020_0006
Formula Vl or a pharmaceutically acceptable salt thereof, wherein X, A2, R1, R2, R4 and n have the definitions of Formula I or I', supra.
A further embodiment includes compounds of Formula VIA:
Figure imgf000021_0001
Formula VIA or a pharmaceutically acceptable salt thereof, wherein X, A2, R1, R2, R4 and n have the definitions of Formula I or I', supra.
Certain compounds of Formula Vl or VIA include compounds of Formua VIB and VIC:
Figure imgf000021_0002
Formula VIB Formula VIC or a pharmaceutically acceptable salt thereof, wherein X, A2, R1, R2, R4 have the definitions
,2a of Formula I or I', supra; p is 0, 1 , 2, 3 or 4 and R is halo.
A further aspect of this embodiment includes compounds according to anyone of Formulae Vl to VIC, or a pharmaceutically acceptable salt thereof, wherein A2 is (CH2)P and p is 0, 1 , 2 or 3. In one aspect of this embodiment, p is 0, therefore A2 is a bond. In another aspect of this embodiment, A2 is CH2 or CH2-CH2.
In another aspect of this embodiment the invention provide compounds according to anyone of Formulae Vl to VIC or a pharmaceutically acceptable salt thereof, wherein R4 is an optionally substituted C6-i0aryl. Representative examples of aryl are benzoimidazolone, benzoisothiazolone or phenyl. In one further aspect of this embodiment, R4 is phenyl. Substituents on the phenyl ring include for example, halo {e.g. F, Cl), hydroxy, halo-Ci.7alkyl (e.g. CF3), Ci-7alkoxy or d-7alkyl.
In yet another aspect of this embodiment the invention provides compounds according to anyone of Formulae Vl to VIC or a pharmaceutically acceptable salt thereof, wherein R4 is an optionally substituted bicyclic heteroaryl.
In yet another aspect of this embodiment the invention provide compounds according to anyone of Formulae Vl to VIC, or a pharmaceutically acceptable salt thereof, wherein R4 is an optionally substituted 5- or 6-membered heteroaryl. In one aspect of this embodiment, R4 is a 6-membered ring heteroaryl selected from the group consisting of pyrazinyl, pyridinyl, pyrimidinyl, oxo-pyranyl (e.g. pyranone, optionally substituted pyran-4-one, pyran- 2-one such as 3-hydroxy-pyran-4-one, 3-hydroxy-pyran-2-one), and oxo-pyridinyl (e.g. pyridinone, optionally substituted pyridin-4-one or pyridin-2-one such as for example 3- hydroxy-1 -methyl-pyridin-4-one or 1 -benzyl-pyridin-2-one); or pyrimidinone (i.e. oxo- pyrimidinyl). In another aspect of this embodiment R4 is a 5-membered ring heteroaryl selected from the group consisting of oxazole, pyrrole, pyrazole, isooxazole, triazole, tetrazole, oxadiazole (e.g. 1 -oxa-3,4-diazole, 1 -oxa-2,4-diazole), oxadiazolone (e.g. oxadiazol-2-one), thiazole, isothiazole, thiophene, imidazole and thiadiazole. Other representative examples of R4 are oxazolone, thiazolone, oxadiazolone triazolone, oxazolone, imidazolone, pyrazolone. In a further embodiment, the optional substituents on C6-i0aryl and heteroaryl are selected from hydroxy, d-7alkyl, Ci-7alkoxy, halo, halo-Ci-7alkyl or benzyl.
In yet another aspect of the above embodiment the invention provide compounds according to anyone of Formulae Vl to VIC or a pharmaceutically acceptable salt thereof, wherein R4 is a bicyclic heteroaryl. A further embodiment includes compounds of Formula Vl wherein R4 is indolyl, benzothiazolyl or benzimidazolyl. Representative examples of R4 are the following:
Figure imgf000023_0001
In one embodiment the invention provide compounds according to any one of Formulae I', I to IC, Il to NC, III to NIC, IV, IVA, V, VA and Vl to VIC or a pharmaceutically acceptable salt thereof, wherein R1 is methyl.
In another embodiment the invention provide compounds according to any one of Formulae I', I, IA II, NA, III, INA, IV, IVA, V, VA and Vl to VIC or a pharmaceutically acceptable salt thereof, wherein each R2 is independently halo, alkyl, alkoxy, hydroxy, haloalkyl and n is O, 1 or 2. In a further embodiment of anyone of Formulae I', I, IA, II, NA, III, INA, IV, IVA, V, VA and Vl to VIC, or a pharmaceutically acceptable salt thereof, n is 1 , 2, 3, 4 or 5, R2 is halo in the meta position and the other optional R2 groups are independently halo, Ci-7alkyl, d-7alkoxy, hydroxy, haloalkyl. In yet a further embodiment, the invention provide compounds according to any one of Formulae I', I, IA II, NA, III, INA, IV, IVA, V, VA and Vl to VIC, or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2, R2 is meta- chloro and the other optional R2 group is halo, Ci.7alkyl, d-7alkoxy, hydroxy, haloalkyl.
In yet another embodiment the invention provide compounds according to any one of Formulae I', I to IC, Il to NC, III to NIC, IV, IVA, V, VA and Vl to VIC or a pharmaceutically acceptable salt thereof, wherein X and X1 are independently OH or -O-Ci-7alkyl (e.g. O-ethyl or O-methyl). In one particular aspect of this embodiment X and X1 are OH. In another aspect of this embodiment, X and X1 are independently -O-Ci-7alkyl in which alkyl is substituted with C6-i0aryl, heteroaryl, heterocyclyl, C(O)NH2, C(O)NH-Ci-6alkyl, or C(O)N(Ci- 6alkyl)2. Representative examples of X or X1 are -0-CH2-C(O)N(CHa)2, -0-CH2-CH2- morpholine, -O-CH2-dioxolone or -O-benzyl. In yet another aspect of this embodiment, X and X1 are -O-C6-i0aryl. A representative examples of -O-C6-i0aryl is -O-(2,3-dihydro-1 H- indene).
In another embodiment X, X1, A1, A2, R2, R1 and R4 groups are those defined by the X, X1, A1, A2, R2, R1 and R4 groups in the Examples section below.
In another embodiment individual compounds according to the invention are those listed in the Examples section below or a pharmaceutically acceptable salt thereof.
For purposes of interpreting this specification, the following definitions will apply unless specified otherwise and whenever appropriate, terms used in the singular will also include the plural and vice versa.
As used herein, the term "alkyl" refers to a fully saturated branched or unbranched (or straight chain or linear) hydrocarbon moiety, comprising 1 to 20 carbon atoms. Preferably the alkyl comprises 1 to 7 carbon atoms, and more preferably 1 to 4 carbon atoms. Representative examples of alkyl include methyl, ethyl, n-propyl, /so-propyl, n-butyl, sec-butyl, /so-butyl, te/t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2- dimethylpentyl, 2,3-dimethylpentyl, n-heptyl. The term "Ci.7alkyl" refers to a hydrocarbon having one to seven carbon atoms. The term "alkylene" refers to a divalent alkyl radical, wherein alkyl is as previously defined.
The term "alkenyl" refers to a branched or unbranched hydrocarbon having at least one carbon-carbon double bond. The term "C^alkenyl" refers to a hydrocarbon having two to seven carbon atoms and comprising at least one carbon-carbon double bond. Representative examples of alkenyl are vinyl, prop-1 -enyl, allyl, butenyl, isopropenyl or isobutenyl. The term "alkeylene" refers to a divalent alkenyl radical, wherein alkenyl is as previously defined.
As used herein, the term "haloalkyl" refers to an alkyl as defined herein, that is substituted by one or more halo groups as defined herein. Preferably the haloalkyl can be monohaloalkyl, dihaloalkyl or polyhaloalkyl including perhaloalkyl. A monohaloalkyl can have one iodo, bromo, chloro or fluoro within the alkyl group. Dihaloalky and polyhaloalkyl groups can have two or more of the same halo atoms or a combination of different halo groups within the alkyl. Preferably, the polyhaloalkyl contains up to 12, or 10, or 8, or 6, or 4, or 3, or 2 halo groups. Representative examples of haloalkyl are fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. A perhaloalkyl refers to an alkyl having all hydrogen atoms replaced with halo atoms. The term "halo-Ci_7alkyl" refers to a hydrocarbon having one to seven carbon atoms and being substituted by one or more halo groups.
As used herein, the term "alkoxy" refers to alkyl-O-, wherein alkyl is defined herein above. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, te/t-butoxy, pentyloxy, hexyloxy, cyclopropyloxy-, cyclohexyloxy- and the like. Preferably, alkoxy groups have about 1 -7, more preferably about 1 -4 carbons.
As used herein, the term "cycloalkyl" refers to saturated or unsaturated but non- aromatic monocyclic, bicyclic or tricyclic hydrocarbon groups of 3-12 carbon atoms, preferably 3-8, or 3-7 carbon atoms. For bicyclic, and tricyclic cycloalkyl system, all rings are non-aromatic. Exemplary monocyclic hydrocarbon groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl. Exemplary bicyclic hydrocarbon groups include bornyl, decahydronaphthyl, bicyclo[2.1 .1 ]hexyl, bicyclo[2.2.1 ]heptyl, bicyclo[2.2.1 ]heptenyl, bicyclo[2.2.2]octyl. Exemplary tricyclic hydrocarbon groups include adamantyl. The term "C3-7cycloakyl" refers to a cyclic hydrocarbon groups having 3 to 7 carbon atoms.
The term "aryl" refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6-10 carbon atoms in the ring portion. The term "aryl" also refer to a group in which the aromatic ring is fused to a cycloalkyl ring, where the radical of attachment is on the aromatic ring or on the fused cycloalkyl ring. Resentative examples of aryl are phenyl, naphthyl, hexahydroindyl, indanyl or tetrahydronaphthyl. The term "C6-ioaryl" refers to an aromatic hydrocarbon groups having 6 to 10 carbon atoms in the ring portion.
The term "Heteroaryl" includes monocyclic or bicyclic heteroaryl, containing from 5- 10 ring members selected from carbon atoms and 1 to 5 heteroatoms, and each heteroatoms is independently selected from O, N or S, wherein S and N may be oxidized to various oxidation states. For bicyclic heteroaryl system, the system is fully aromatic (i.e. all rings are aromatic).
Typical monocyclic heteroaryl groups include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxa-2,3-diazolyl, oxa-2,4-diazolyl, oxa-2,5-diazolyl, oxa-3,4- diazolyl, thia-2,3-diazolyl, thia-2,4-diazolyl, thia-2,5-diazolyl, thia-3,4-diazolyl, 3-, 4-, or 5- isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or 5-1 ,2,4-triazolyl, 4- or 5-1 ,2, 3- triazolyl, tetrazolyl, 2-, 3-, or 4-pyridyl, 3- or 4-pyridazinyl, 3-, 4-, or 5-pyrazinyl, 2-pyrazinyl, 2-, 4-, or 5-pyrimidinyl.
The term "heteroaryl" also refers to a group in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring or on the fused aryl ring. Representative examples of bicyclic heteroaryl are indolyl, isoindolyl, indazolyl, indolizinyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, quinazolinyl, quinaxalinyl, thieno[2,3-b]furanyl, furo[3,2-b]-pyranyl, 5H-pyrido[2,3-d]-o-oxazinyl, 1 H- pyrazolo[4,3-d]-oxazolyl, 4H-imidazo[4,5-d] thiazolyl, pyrazino[2,3-d]pyridazinyl, imidazo[2,1 - b] thiazolyl, imidazo[1 ,2-b][1 ,2,4]triazinyl, 7-benzo[b]thienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzoxapinyl, benzoxazinyl, 1 H-pyrrolo[1 ,2-b][2]benzazapinyl, benzofuryl, benzothiophenyl, benzotriazolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[3,2- c]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl, pyrazolo[4,3-d]pyridinyl, pyrazolo[4,3-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[3,4- d]pyridinyl, pyrazolo[3,4-b]pyridinyl, imidazo[1 ,2-a]pyridinyl, pyrazolo[1 ,5-a]pyridinyl, pyrrolo[1 ,2-b]pyridazinyl, imidazo[1 ,2-c]pyrimidinyl, pyrido[3,2-d]pyrimidinyl, pyrido[4,3- d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, pyrido[2,3-b]pyrazinyl, pyrido[3,4-b]pyrazinyl, pyrimido[5,4-d]pyrimidinyl, pyrazino[2,3-b]pyrazinyl, or pyrimido[4,5- d]pyrimidinyl.
When a heteroaryl moiety is substituted with hydroxy, the invention also pertains to its oxo tautomeric. For example, an oxadiazole substituted with hydroxy also includes oxo- oxadiazole or also known as oxadiazolone. The tautomerisation is represented as follow:
Figure imgf000027_0001
As used herein, the term "heterocyclyl" refers to an optionally substituted, saturated or unsaturated non-aromatic (partially unsaturated) ring or ring system, e.g., which is a 3-, 4-, 5-, 6-, or 7-membered monocyclic, 7-, 8-, 9-, 10-, 1 1 -, or 12-membered bicyclic or 10-, 1 1 -, 12-, 13-, 14- or 15-membered tricyclic ring system and contains at least one heteroatom selected from O, S and N, where the N and S can also optionally be oxidized to various oxidation states. For bicyclic and tricyclic heterocyclyl ring system, a non-aromatic ring system is defined as being a non-fully or partially unsaturated ring system. Therefore bicyclic and tricyclic heterocyclyl ring systems includes heterocyclyl ring systems wherein one of the fused rings is aromatic but the other(s) is (are) non-aromatic. In one embodiment, heterocyclyl moiety represents a saturated monocyclic ring containing from 5- 7 ring atoms and optionally containing a further heteroatom, selected from O, S or N. The heterocyclic group can be attached at a heteroatom or a carbon atom. The heterocyclyl can include fused or bridged rings as well as spirocyclic rings. Examples of heterocycles include dihydrofuranyl, dioxolanyl, dioxanyl, dithianyl, piperazinyl, pyrrolidine, dihydropyranyl, oxathiolanyl, dithiolanyl, oxathianyl, thiomorpholino, oxiranyl, aziridinyl, oxetanyl, oxepanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholino, piperazinyl, azepinyl, oxapinyl, oxaazepanyl, oxathianyl, thiepanyl, azepanyl, dioxepanyl, and diazepanyl.
The term "hydroxyalkyl" refers to alkyl groups, as decribed above, in which the alkyl group is substituted with one or more hydroxy.
The term "hydroxy" includes groups with an -OH. The term "halogen" includes fluorine, bromine, chlorine and iodine. The term "perhalogenated" generally refers to a moiety wherein all hydrogens are replaced by halogen atoms.
The term "heteroatom" includes atoms of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur and phosphorus. In another embodiment, the heteroatom is nitrogen, oxygen or sulfur.
It will be noted that the structure of some of the compounds of this invention includes asymmetric carbon atoms. It is to be understood accordingly that the isomers arising from such asymmetry {e.g., all enantiomers and diastereomers) are included within the scope of this invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemical^ controlled synthesis. Furthermore, the structures and other compounds and moieties discussed in this application also include all tautomers thereof.
As used herein, the term "isomers" refers to different compounds that have the same molecular formula but differ in arrangement and configuration of the atoms. Also as used herein, the term "an optical isomer" or "a stereoisomer" refers to any of the various stereo isomeric configurations which may exist for a given compound of the present invention and includes geometric isomers. It is understood that a substituent may be attached at a chiral center of a carbon atom. Therefore, the invention includes enantiomers, diastereomers or racemates of the compound. "Enantiomers" are a pair of stereoisomers that are non- superimposable mirror images of each other. A 1 :1 mixture of a pair of enantiomers is a "racemic" mixture. The term is used to designate a racemic mixture where appropriate. "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry is specified according to the Cahn- Ingold- Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line. Certain of the compounds described herein contain one or more asymmetric centers or axes and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present invention is meant to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures. Optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration. All tautomeric forms are also intended to be included.
Any asymmetric atom (e.g., carbon or the like) of the compound(s) of the present invention can be present in racemic or enantiomerically enriched, for example the (R)-, (S)- or (R,S)- configuration. In certain embodiments, each asymmetric atom has at least 50 % enantiomeric excess, at least 60 % enantiomeric excess, at least 70 % enantiomeric excess, at least 80 % enantiomeric excess, at least 90 % enantiomeric excess, at least 95 % enantiomeric excess, or at least 99 % enantiomeric excess in the (R)- or (S)- configuration. Substituents at atoms with unsaturated bonds may, if possible, be present in cis- (Z)- or trans- (E)- form.
Accordingly, as used herein a compound of the present invention can be in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof.
Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.
Any resulting racemates of final products or intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound. In particular, a basic moiety may thus be employed to resolve the compounds of the present invention into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-0,0'-p-toluoyl tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid. Racemic products can also be resolved by chiral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent. As used herein, the term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds of this invention and, which are not biologically or otherwise undesirable. In many cases, the compounds of the present invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate salts. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. The pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound, a basic or acidic moiety, by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred, where practicable. Lists of additional suitable salts can be found, e.g., in "Remington's Pharmaceutical Sciences", 20th ed., Mack Publishing Company, Easton, Pa., (1985); and in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. For example, any hydrogen represented by "H" in any of the formulae herein is intended to represent all isotopic forms of hydrogen (e.g. 1H, 2H or D, 3H); any carbon represented by "C" in any of the formulae herein is intended to represent all isotopic forms of carbon (e.g. 11C, 13C, 14C); any nitrogen represented by "N" is intended to represent all isotopic forms of nitrogen (e.g. 14N, 15N). Other examples of isotopes that are included in the invention include isotopes of oxygen, sulfur, phosphorous, fluorine, iodine and chlorine, such as 18F 31P, 32P, 35S, 36CI, 125I. The invention includes various isotopically labeled compounds as defined herein, for example those into which radioactive isotopes, such as 3H, 13C, and 14C are present. In one embodiment, the atoms in the formulae herein occur in their natural abundance. In another embodiment, one or more hydrogen atom may be enriched in 2H; or/and one or more carbon atom may be enriched in 11C, 13C or 14C; or/and one or more nitrogen may be enriched in 14N. Such isotopically labelled compounds are useful in metabolic studies (with 14C), reaction kinetic studies (with, for example 2H or 3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an 18F or labeled compound may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
Further, enrichment with heavier isotopes, particularly deuterium (i.e., 2H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index. It is understood that deuterium in this context is regarded as a substituent of a compound according to anyone of the formulae I', I to VIC. The concentration of such a heavier isotope, specifically deuterium, may be defined by the isotopic enrichment factor. The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent in a compound of this invention is denoted deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
Isotopically-enriched compounds according to anyone of formulae I', I to VIC can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-enriched reagent in place of the non-enriched reagent previously employed.
Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D2O, d6-acetone, de-DMSO.
Compounds of the invention, i.e. compounds according to anyone of formulae I', I to VIC that contain groups capable of acting as donors and/or acceptors for hydrogen bonds may be capable of forming co-crystals with suitable co-crystal formers. These co-crystals may be prepared from compounds according to anyone of formulae I', I to VIC by known co- crystal forming procedures. Such procedures include grinding, heating, co-subliming, co- melting, or contacting in solution compounds according to anyone of formulae I', I to VIC with the co-crystal former under crystallization conditions and isolating co-crystals thereby formed. Suitable co-crystal formers include those described in WO 2004/078163. Hence the invention further provides co-crystals comprising a compound according to anyone of formulae I' and I to VIC.
As used herein, the term "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, such like materials and combinations thereof, as would be known to one of ordinary skill in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289- 1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.
The term "a therapeutically effective amount" of a compound of the present invention refers to an amount of the compound of the present invention that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or amelioration of a symptom, alleviation of a condition, slow or delay disease progression, or prevention of a disease, etc. In one non-limiting embodiment, the term "a therapeutically effective amount" refers to the amount of the compound of the present invention that, when administered to a subject, is effective to (1 ) at least partially alleviate, inhibit, prevent and/or ameliorate a condition, a disorder or a disease, or a symptom thereof (i) ameliorated by the inhibition of neutral endopeptidase EC 3.4. 24.1 1 or (ii) associated with neutral endopeptidase EC 3.4. 24.1 1 activity, or (iii) characterized by abnormal activity of neutral endopeptidase EC 3.4. 24.1 1 ; or (2) reduce or inhibit the activity of neutral endopeptidase EC 3.4. 24.1 1 ; or (3) reduce or inhibit the expression of neutral endopeptidase EC 3.4. 24.1 1. In another non-limiting embodiment, the term "a therapeutically effective amount" refers to the amount of the compound of the present invention that, when administered to a cell, or a tissue, or a non-cellular biological material, or a medium, is effective to at least partially reduce or inhibit the activity of neutral endopeptidase EC 3.4. 24.1 1 ; or at least partially reduce or inhibit the expression of neutral endopeptidase EC 3.4. 24.1 1
As used herein, the term "subject" refers to an animal. Preferably, the animal is a mammal. A subject also refers to for example, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In a preferred embodiment, the subject is a human.
As used herein, the term "inhibition" or "inhibiting" refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.
As used herein, the term "treating" or "treatment" of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment "treating" or "treatment" refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient. In yet another embodiment, "treating" or "treatment" refers to modulating the disease or disorder, either physically, {e.g., stabilization of a discernible symptom), physiologically, {e.g., stabilization of a physical parameter), or both. In yet another embodiment, "treating" or "treatment" refers to preventing or delaying the onset or development or progression of the disease or disorder.
As used herein, the term "a," "an," "the" and similar terms used in the context of the present invention (especially in the context of the claims) are to be construed to cover both the singular and plural unless otherwise indicated herein or clearly contradicted by the context.
The term "hypertension" refers to a condition where the pressure of blood within the blood vessels is higher than normal as it circulates through the body. When the systolic pressure exceeds 150 mmHg or the diastolic pressure exceeds 90 mmHg for a sustained period of time, damage is done to the body. For example, excessive systolic pressure can rupture blood vessels anywhere, and when it occurs within the brain, a stroke results. Hypertension may also cause thickening and narrowing of the blood vessels which ultimately could lead to atherosclerosis.
The term "type 2 diabetes" including type 2 diabetes associated with hypertension refers to a disease in which the pancreas does not secrete sufficient insulin due to an impairment of pancreatic beta-cell function and/or in which there is to insensitivity to produced insulin (insulin resistance). Typically, the fasting plasma glucose is less than 126 mg/dL, while pre-diabetes is, e.g., a condition which is characterized by one of following conditions: impaired fasting glucose (1 10-125 mg/dL) and impaired glucose tolerance (fasting glucose levels less than 126 mg/dL and post-prandial glucose level between 140 mg/dL and 199 mg/dL). Type 2 diabetes mellitus can be associated with or without hypertension. Diabetes mellitus occurs frequently, e.g., in African American, Latino/Hispanic American, Native American, Native American, Asian American and Pacific Islanders. Markers of insulin resistance include HbAI C, HOMA IR, measuring collagen fragments, TGF-β in urine, PAI-1 and prorenin.
All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language {e.g. "such as") provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed.
Compounds of the present invention are either obtained in the free form, as a salt thereof, or as prodrug derivatives thereof. When both a basic group and an acid group are present in the same molecule, the compounds of the present invention may also form internal salts, e.g., zwitterionic molecules.
The present invention also provides pro-drugs of the compounds of the present invention that converts in vivo to the compounds of the present invention. A pro-drug is an active or inactive compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of this invention following administration of the prodrug to a subject. The suitability and techniques involved in making and using pro-drugs are well known by those skilled in the art. Prodrugs can be conceptually divided into two non-exclusive categories, bioprecursor prodrugs and carrier prodrugs. See The Practice of Medicinal Chemistry, Ch. 31 -32 (Ed. Wermuth, Academic Press, San Diego, Calif., 2001 ). Generally, bioprecursor prodrugs are compounds, which are inactive or have low activity compared to the corresponding active drug compound that contain one or more protective groups and are converted to an active form by metabolism or solvolysis. Both the active drug form and any released metabolic products should have acceptably low toxicity. Carrier prodrugs are drug compounds that contain a transport moiety, e.g., that improve uptake and/or localized delivery to a site(s) of action. Desirably for such a carrier prodrug, the linkage between the drug moiety and the transport moiety is a covalent bond, the prodrug is inactive or less active than the drug compound, and any released transport moiety is acceptably non-toxic. For prodrugs where the transport moiety is intended to enhance uptake, typically the release of the transport moiety should be rapid. In other cases, it is desirable to utilize a moiety that provides slow release, e.g., certain polymers or other moieties, such as cyclodextrins. Carrier prodrugs can, for example, be used to improve one or more of the following properties: increased lipophilicity, increased duration of pharmacological effects, increased site-specificity, decreased toxicity and adverse reactions, and/or improvement in drug formulation (e.g., stability, water solubility, suppression of an undesirable organoleptic or physiochemical property). For example, lipophilicity can be increased by esterification of (a) hydroxyl groups with lipophilic carboxylic acids (e.g., a carboxylic acid having at least one lipophilic moiety), or (b) carboxylic acid groups with lipophilic alcohols (e.g., an alcohol having at least one lipophilic moiety, for example aliphatic alcohols).
Exemplary prodrugs are, e.g., esters of free carboxylic acids and S-acyl derivatives of thiols and O-acyl derivatives of alcohols or phenols, wherein acyl has a meaning as defined herein. Preferred are pharmaceutically acceptable ester derivatives convertible by solvolysis under physiological conditions to the parent carboxylic acid, e.g., lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, mono- or di-substituted lower alkyl esters, such as the ω-(amino, mono- or di-lower alkylamino, carboxy, lower alkoxycarbonyl)-lower alkyl esters, the α-(lower alkanoyloxy, lower alkoxycarbonyl or di- lower alkylaminocarbonyl)-lower alkyl esters, such as the pivaloyloxymethyl ester and the like conventionally used in the art. In addition, amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bundgaard, J. Med. Chem. 2503 (1989)). Moreover, drugs containing an acidic NH group, such as imidazole, imide, indole and the like, have been masked with N-acyloxymethyl groups (Bundgaard, Design of Prodrugs, Elsevier (1985)). Hydroxy groups have been masked as esters and ethers. EP 039,051 (Sloan and Little) discloses Mannich-base hydroxamic acid prodrugs, their preparation and use.
Furthermore, the compounds of the present invention, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.
GENERAL SYNTHETIC ASPECTS
The compounds of the invention can be synthesized using the methods described in the following schemes, examples, and by using art recognized techniques. All compounds described herein are included in the invention as compounds. Compounds of the invention may be synthesized according to at least one of the methods described in schemes 1 -3.
Within the scope of this text, only a readily removable group that is not a constituent of the particular desired end product of the compounds of the present invention is designated a "protecting group", unless the context indicates otherwise. The protection of functional groups by such protecting groups, the protecting groups themselves, and their cleavage reactions are described for example in standard reference works, such as J. F. W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, in T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999.
Salts of compounds of the present invention having at least one salt-forming group may be prepared in a manner known per se. For example, salts of compounds of the present invention having acid groups may be formed, for example, by treating the compounds with metal compounds, such as alkali metal salts of suitable organic carboxylic acids, e.g. the sodium salt of 2-ethylhexanoic acid, with organic alkali metal or alkaline earth metal compounds, such as the corresponding hydroxides, carbonates or hydrogen carbonates, such as sodium or potassium hydroxide, carbonate or hydrogen carbonate, with corresponding calcium compounds or with ammonia or a suitable organic amine, stoichiometric amounts or only a small excess of the salt-forming agent preferably being used. Acid addition salts of compounds of the present invention are obtained in customary manner, e.g. by treating the compounds with an acid or a suitable anion exchange reagent. Internal salts of compounds of the present invention containing acid and basic salt-forming groups, e.g. a free carboxy group and a free amino group, may be formed, e.g. by the neutralisation of salts, such as acid addition salts, to the isoelectric point, e.g. with weak bases, or by treatment with ion exchangers.
Salts can be converted in customary manner into the free compounds; metal and ammonium salts can be converted, for example, by treatment with suitable acids, and acid addition salts, for example, by treatment with a suitable basic agent.
Mixtures of isomers obtainable according to the invention can be separated in a manner known per se into the individual isomers; diastereoisomers can be separated, for example, by partitioning between polyphasic solvent mixtures, recrystallisation and/or chromatographic separation, for example over silica gel or by e.g. medium pressure liquid chromatography over a reversed phase column, and racemates can be separated, for example, by the formation of salts with optically pure salt-forming reagents and separation of the mixture of diastereoisomers so obtainable, for example by means of fractional crystallisation, or by chromatography over optically active column materials.
Intermediates and final products can be worked up and/or purified according to standard methods, e.g. using chromatographic methods, distribution methods, (re-) crystallization, and the like.
The following applies in general to all processes mentioned herein before and hereinafter.
All the above-mentioned process steps can be carried out under reaction conditions that are known per se, including those mentioned specifically, in the absence or, customarily, in the presence of solvents or diluents, including, for example, solvents or diluents that are inert towards the reagents used and dissolve them, in the absence or presence of catalysts, condensation or neutralizing agents, for example ion exchangers, such as cation exchangers, e.g. in the H+ form, depending on the nature of the reaction and/or of the reactants at reduced, normal or elevated temperature, for example in a temperature range of from about -100 QC to about 190 QC, including, for example, from approximately -80 QC to approximately 150 QC, for example at from -80 to -60 QC, at room temperature, at from -20 to 40 QC or at reflux temperature, under atmospheric pressure or in a closed vessel, where appropriate under pressure, and/or in an inert atmosphere, for example under an argon or nitrogen atmosphere.
At all stages of the reactions, mixtures of isomers that are formed can be separated into the individual isomers, for example diastereoisomers or enantiomers, or into any desired mixtures of isomers, for example racemates or mixtures of diastereoisomers, for example analogously to the methods described under "Additional process steps".
The solvents from which those solvents that are suitable for any particular reaction may be selected include those mentioned specifically or, for example, water, esters, such as lower alkyl-lower alkanoates, for example ethyl acetate, ethers, such as aliphatic ethers, for example diethyl ether, or cyclic ethers, for example tetrahydrofuran or dioxane, liquid aromatic hydrocarbons, such as benzene or toluene, alcohols, such as methanol, ethanol or 1 - or 2-propanol, nitriles, such as acetonitrile, halogenated hydrocarbons, such as methylene chloride or chloroform, acid amides, such as dimethylformamide or dimethyl acetamide, bases, such as heterocyclic nitrogen bases, for example pyridine or N- methylpyrrolidin-2-one, carboxylic acid anhydrides, such as lower alkanoic acid anhydrides, for example acetic anhydride, cyclic, linear or branched hydrocarbons, such as cyclohexane, hexane or isopentane, methycyclohexane, or mixtures of those solvents, for example aqueous solutions, unless otherwise indicated in the description of the processes. Such solvent mixtures may also be used in working up, for example by chromatography or partitioning.
The compounds, including their salts, may also be obtained in the form of hydrates, or their crystals may, for example, include the solvent used for crystallization. Different crystalline forms may be present.
The invention relates also to those forms of the process in which a compound obtainable as an intermediate at any stage of the process is used as starting material and the remaining process steps are carried out, or in which a starting material is formed under the reaction conditions or is used in the form of a derivative, for example in a protected form or in the form of a salt, or a compound obtainable by the process according to the invention is produced under the process conditions and processed further in situ.
All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents and catalysts utilized to synthesize the compounds of the present invention are either commercially available or can be produced by organic synthesis methods known to one of ordinary skill in the art (Houben-Weyl 4th Ed. 1952, Methods of Organic Synthesis, Thieme, Volume 21 ).
Typically, the compounds according to anyone of formulae I' and I to VIC can be prepared according to the Schemes 1 to 3 provided infra.
The general methods of preparation and synthesis of the described compounds herein are illustrated in Schemes 1 , 2, 3 and 4.
Figure imgf000039_0001
Figure imgf000039_0002
Figure imgf000039_0003
Figure imgf000039_0004
Scheme 1
Intermediate A, or salts thereof, was prepared according to the route described in the US patent US 5,217,996 or in WO2008083967 wherein P is alkyl or benzyl and R1 is defined as in Formula I or I' supra. Amide B, wherein R3 is defined above, is prepared by the condensation of intermediate A with an alkyl or aryl acid chloride in the presence of a base such as, but not limited to, pyridine, triethylamine and diisopropylethylamine. Intermediate A can also be converted to compounds of Formula B by amidation reactions with a variety of alkyl or aryl carboxylic acids using coupling reagents such as, but not limited to, EDCI or HATU. Compounds of formula C are obtained from intermediate A by reaction with an appropriate anhydride, wherein A1 is defined above, in the presence of a base such as, but not limited to, pyridine, triethylamine and diisopropylethylamine. Similarly, compounds or Formula D wherein A1 is a cycloalkyl, can be obtained using a bicyclic anhydride wherein n = 1 -4.
Scheme 2 illustrates the synthesis of compounds according to anyone of Formula I;, to IC and Il to NC wherein A1 is a linear d-4alkylene wherein one carbon is replaced by a nitrigen atom or A1 is a heterocyclyl or heteroaryl.
Figure imgf000040_0001
Figure imgf000040_0003
Figure imgf000040_0002
Figure imgf000040_0004
Scheme 2
Compounds according to anyone o 3ff FFoorrmmuullaaee Il to NC wherein A1 is a linear Ci- 4alkylene wherein one carbon is replaced by a nitrogen atom, represented by compounds E, are prepared from intermediate A by reaction with an alkyl isocyanate, wherein P1 is alkyl or benzyl and AK is an alkyl, in the presence of a base such as, but not limited to, pyridine, triethylamine and diisopropylethylamine. Alternatively, intermediate A is converted to isocyanate F with reagents such as, but not limited to, triphosgene in the presence of a base such as, but not limited to NaHCO3. Substituted analogs, represented by compounds G, are prepared by reacting compound F with an appropriate protected amino acid in the presence of a base such as, but not limited to NaHCO3. Similarly, compounds according to anyone of Formulae Il to NC wherein A1 is a heterocyclyl or a heteroaryl containing a Nitrogen atom which is linked to C(O)NH amide bond, and represented by compounds H, are prepared from the reaction of compound F with protected cyclic amino acids wherein B is heterocyclyl or heteroaryl and the carboxylate group can be attached at any position not occupied by a heteroatom. Compounds B to H are converted to their corresponding carboxylic acids (P, P1 = H) by standard hydrolytic methods using a base such as, but not limited to, NaOH or LiOH. The hydrolysis reactions are performed at either ambient or elevated temperatures. When P or P1 is benzyl, the preferable method of deprotection is hydrogenation in the presence of a catalyst such as, but not limited to, palladium-on-carbon at atmospheric or elevated pressure.
Scheme 3 illustrates the synthesis of compounds of Formula V wherein R4 is a tetrazole.
Figure imgf000042_0001
Scheme 3
Intermediate A is reacted with an appropriate carboxylic acid as described in step 1 a, using standard coupling reagents selected from, but not limited to, DCC, EDCI, PyBOP or BOP in presence or absence of a reagent such as 1 -hydroxybenazotriazole, 1 -hydroxy-7- azabenzotriazole or pentafluorophenol to generate intermediate I, in which protecting group P1 can be removed using a base selected from, but not limited to, NaOH, KOH or LiOH, or an acid selected from, but not limited to, TFA or HCI, or hydrogenation with a catalyst such as, but not limited to, palladium-on-carbon under hydrogen to generate intermediate J; alternatively, intermediate A is reacted with an appropriate anhydride as described in step 1 b, in the presence of a base selected from, but not limited to, pyridine, triethylamine or diisopropylethylamine to generate intermediate J. Intermediate J is then coupled with P2 protected amine wherein P2 is selected from, but not limited to, methyl, ethyl, benzyl or propionitrile using standard coupling reagents selected from, but not limited to, DCC, EDCI, PyBOP or BOP in presence or absence of a reagent such as 1 -hydroxybenazotriazole, 1 - hydroxy-7-azabenzotriazole or pentafluorophenol to generate intermediate K. Finally K is converted into a compound of Formula V wherein R4 is a tetrazole using reagents such as, but not limited to, trimethylsilyl azide, triphenylphosphine and diisopropyl azodicarboxylate, to generate intermediate L, in which protecting group P2 can be removed using, for example if P2 protected amine used in step 3 is 3-aminopropionitrile, base such as 1 ,8- diazabicyclo[5.4.0]undec-7-ene.
Scheme 4 illustrates the synthesis of intermediate A which is useful for the preparation of compounds of Formula I' or I.
alkyl
Figure imgf000043_0001
M
Figure imgf000043_0002
reduce
Figure imgf000043_0003
Figure imgf000043_0004
Aldehyde M is prepared by reduction of a protected amino acid ester with a reducing agent such as, but not limited to, diisobutyl aluminum hydride. The protecting group P3 can be chosen from, but not limited to, Boc or Cbz and group Y can be chosen from, but not limited to, halogen or triflate. Intermediate N is prepared from intermediate M by methodology such as, but not limited to, a Wittig reaction employing an appropriate phosphorus reagent such as, but not limited to, a triphenyl phosphonium ylide. The substituted biphenyl intermediate O is prepared from Intermediate N by methodology such as, but not limited to, a Suzuki reaction employing reactants such as, but not limited to, arylboronic acids or arylboronic esters catalyzed by a palladium(O) complex such as, but not limited to, tetrakis(triphenylphosphine)palladium or dichloro[1 ,1 '- bis(diphenylphosphino)ferrocene]palladium(ll) dichloromethane adduct. The olefin of Intermediate O is reduced to furnish Intermediate P by hydrogenation in the presence of a catalyst such as, but not limited to, platinum-on-carbon or platinum oxide at atmospheric or elevated pressure. Alternatively, the reduction can be performed using chiral catalysts and ligands such as, but not limited to, those described in patent application WO2008031567. The protecting group P3 can be removed with an acid selected from, but not limited to, TFA or HCI, or hydrogenation with a catalyst such as, but not limited to, palladium-on-carbon under hydrogen to generate intermediate A.
The invention further includes any variant of the present processes, in which an intermediate product obtainable at any stage thereof is used as starting material and the remaining steps are carried out, or in which the starting materials are formed in situ under the reaction conditions, or in which the reaction components are used in the form of their salts or optically pure antipodes.
Compounds of the invention and intermediates can also be converted into each other according to methods generally known per se. US patent application of attorney docket number PAT053601 -US-USP3 filed on April 16, 2010, also describes the synthesis of various intermediates for incorporation of the R3 moiety as described in Formula I or I; and is therefore incorporated by reference.
In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers. The pharmaceutical composition can be formulated for particular routes of administration such as oral administration, parenteral administration, and rectal administration, etc. In addition, the pharmaceutical compositions of the present invention can be made up in a solid form including capsules, tablets, pills, granules, powders or suppositories, or in a liquid form including solutions, suspensions or emulsions. The pharmaceutical compositions can be subjected to conventional pharmaceutical operations such as sterilization and/or can contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifers and buffers etc.
Typically, the pharmaceutical compositions are tablets and gelatin capsules comprising the active ingredient together with a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if desired d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, colorants, flavors and sweeteners.
Tablets may be either film coated or enteric coated according to methods known in the art.
Suitable compositions for oral administration include an effective amount of a compound of the invention in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed. Formulations for oral use can be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
Certain injectable compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances. Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1 -75%, or contain about 1 -50%, of the active ingredient.
Suitable compositions for transdermal application include an effective amount of a compound of the invention with carrier. Carriers include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host. For example, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound of the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
Suitable compositions for topical application, e.g., to the skin and eyes, include aqueous solutions, suspensions, ointments, creams, gels or sprayable formulations, e.g., for delivery by aerosol or the like. Such topical delivery systems will in particular be appropriate for dermal application. They are thus particularly suited for use in topical, including cosmetic, formulations well-known in the art. Such may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
As used herein a topical application may also pertain to an inhalation or to an intranasal application. They are conveniently delivered in the form of a dry powder (either alone, as a mixture, for example a dry blend with lactose, or a mixed component particle, for example with phospholipids) from a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray, atomizer or nebuliser, with or without the use of a suitable propellant.
The present invention further provides anhydrous pharmaceutical compositions and dosage forms comprising the compounds of the present invention as active ingredients, since water may facilitate the degradation of certain compounds.
Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions are preferably packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e. g., vials), blister packs, and strip packs. The invention further provides pharmaceutical compositions and dosage forms that comprise one or more agents that reduce the rate by which the compound of the present invention as an active ingredient will decompose. Such agents, which are referred to herein as "stabilizers," include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers, etc.
The compounds according to anyone of formulae I', I to VIC, Il to NC, III to NIC, IV, IVA, V, VA and Vl to VIC in free form or in pharmaceutically acceptable salt form, exhibit valuable pharmacological properties, e.g. neutral endopeptidase EC 3.4. 24.1 1 modulating properties, e.g. as indicated in in vitro and in vivo tests as provided in the next sections and are therefore indicated for therapy.
Compounds of the invention may be useful in the treatment of an indication selected from hypertension, pulmonary hypertension, isolated systolic hypertension, resistant hypertension, peripheral vascular disease, heart failure, congestive heart failure, left ventricular hypertrophy, angina, renal insufficiency (diabetic or non-diabetic), renal failure (including edema and salt retension), diabetic nephropathy, non-diabetic nephropathy, nephroic syndrome, glomerulonephritis, scleroderma, glomerular sclerosis, proteinurea of primary renal disease, renal vascular hypertention, diabetic retinopathy and end-stage renal disease (ESRD), endothelial dysfunction, diastolic dysfunction, hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation (AF), cardiac fibrosis, atrial flutter, detrimental vascular remodeling, plaque stabilization, myocardial infarction (Ml), renal fibrosis, polycystic kidney disease (PKD), Pulmonary Arterial hypertension, renal failure (including edema and salt retension), cyclical oedema, Menieres disease, hyperaldosteroneism (primary and secondary) and hypercalciuria, ascites, glaucoma, menstrual disorders, preterm labour, pre-eclampsia, endometriosis, and reproductive disorders (especially male and female infertility, polycystic ovarian syndrome, implantation failure), asthma,obstructive sleep apnea, inflammation, leukemia, pain, epilepsy, affective disorders such as depression and psychotic condition such as dementia and geriatric confusion, obesity and gastrointestinal disorders (especially diarrhea and irritable bowel syndrome), wound healing (especially diabetic and venous ulcers and pressure sores), septic shock, the modulation of gastric acid secretion, the treatment of hyperreninaemia, cystic fibrosis, restenosis, type-2 diabetes, metabolic syndrome, diabetic complications and atherosclerosis, male and female sexual dysfunction. Thus, as a further embodiment, the present invention provides the use of a compound according to anyone of formulae I', I to VIC, Il to NC, III to NIC, IV, IVA, V, VA and Vl to VIC, or a pharmaceutically acceptable salt thereof. In a further embodiment, the therapy is selected from a disease which is associated with neutral endopeptidase EC 3.4. 24.1 1 activity. In another embodiment, the disease is selected from the afore-mentioned list, suitably hypertension, pulmonary hypertension, isolated systolic hypertension, resistant hypertension, peripheral vascular disease, heart failure, congestive heart failure, left ventricular hypertrophy, angina, renal insufficiency, renal failure (including edema and salt retension), diabetic nephropathy, non-diabetic nephropathy, type-2 diabetis, and diabetic complications and most suitably cardiovascular disorders, such as hypertension, renal insufficiency including edema and congestive heart failure.
In another embodiment, the invention provides a method of treating a disease which is associated with neutral endopeptidase EC 3.4. 24.1 1 activity comprising administration of a therapeutically acceptable amount of a compound according to anyone of formulae I', I to VIC, Il to NC, III to NIC, IV, IVA, V, VA and Vl to VIC, or a pharmaceutically acceptable salt thereof. In a further embodiment, the disease is selected from the afore-mentioned list, suitably hypertension, pulmonary hypertension, isolated systolic hypertension, resistant hypertension, peripheral vascular disease, heart failure, congestive heart failure, left ventricular hypertrophy, angina, renal insufficiency, renal failure (including edema and salt retension), diabetic nephropathy, non-diabetic nephropathy, type-2 diabetis, and diabetic complications and most suitably cardiovascular disorders, such as hypertension, renal insufficiency including edema and congestive heart failure.
The pharmaceutical composition or combination of the present invention can be in unit dosage of about 1 -1000 mg of active ingredient(s) for a subject of about 50-70 kg, or about 1 -500 mg or about 1 -250 mg or about 1 -150 mg or about 0.5-100 mg, or about 1 -50 mg of active ingredients. The therapeutically effective dosage of a compound, the pharmaceutical composition, or the combinations thereof, is dependent on the species of the subject, the body weight, age and individual condition, the disorder or disease or the severity thereof being treated. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progress of the disorder or disease.
The above-cited dosage properties are demonstrable in vitro and in vivo tests using advantageously mammals, e.g., mice, rats, dogs, monkeys or isolated organs, tissues and preparations thereof. The compounds of the present invention can be applied in vitro in the form of solutions, e.g., preferably aqueous solutions, and in vivo either enterally, parenterally, advantageously intravenously, e.g., as a suspension or in aqueous solution. The dosage in vitro may range between about 10 "3 molar and 10 9 molar concentrations. A therapeutically effective amount in vivo may range depending on the route of administration, between about 0.1 -500 mg/kg, or between about 1 -100 mg/kg.
The activity of a compound according to the present invention can be assessed by the following in vitro & in vivo methods and/or by the following in vitro & in vivo methods well- described in the art. See A fluorescence lifetime-based assay for protease inhibitor profiling on human kallikrein 7 Doering K, Meder G, Hinnenberger M, Woelcke J, Mayr LM, Hassiepen U Biomol Screen. 2009 Jan; 14(1 ):1 -9.
In particular, the in vitro inhibition of recombinant human neutral endopeptidase (NEP, EC 3.4.24.1 1 ) can be determined as follows:
Recombinant human neutral endopeptidase (expressed in insect cells and purified using standard methods, final concentration 7 pM) is pre-incubated with test compounds at various concentrations for 1 hour at room temperature in 10 mM sodium phosphate buffer at pH 7.4, containing 150 mM NaCI and 0.05 % (w/v) CHAPS. The enzymatic reaction is started by the addition of a synthetic peptide substrate Cys(PT14)-Arg-Arg-Leu-Trp-OH to a final concentration of 0.7 μM. Substrate hydrolysis leads to an increase fluorescence lifetime (FLT) of PT14 measured by the means of a FLT reader as described by Doering et al. (2009). The effect of the compound on the enzymatic activity was determined after 1 hour (t = 60 min) incubation at room temperature. The IC50 values, corresponding to the inhibitor concentration showing 50% reduction of the FLT values measured in absence of inhibitor, are calculated from the plot of percentage of inhibition vs. inhibitor concentration using non-linear regression analysis software.
Using the test assay (as described above) compounds of the invention exhibited inhibitory efficacy in accordance to Table 1 , provided infra.
Table 1 Inhibitory Activity of Compounds
Figure imgf000049_0001
Figure imgf000050_0001
The compound of the present invention may be administered either simultaneously with, or before or after, at least one other therapeutic agent. The compound of the present invention may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition.
In one embodiment, the invention provides a product comprising a compound according to anyone of formulae I', I to VIC, Il to NC, III to NIC, IV, IVA, V, VA and Vl to VIC and at least one other therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy. In one embodiment, the therapy is the treatment of a disease or condition associated with neutral endopeptidase EC 3.4. 24.1 1 activity.
Products provided as a combined preparation include a composition comprising the compound according to anyone of formulae I', I to VIC, Il to NC, III to NIC, IV, IVA, V, VA and Vl to VIC, or a pharmaceutically acceptable salt thereof, and the other therapeutic agent(s) together in the same pharmaceutical composition, or the compound according to anyone of formulae I' and I to VIC, or a pharmaceutically acceptable salt thereof, and the other therapeutic agent(s) in separate form, e.g. in the form of a kit.
In one embodiment, the invention provides a pharmaceutical composition comprising a compound according to anyone of formulae I' and I to VIC, or a pharmaceutically acceptable salt thereof, and another therapeutic agent(s). Optionally, the pharmaceutical composition may comprise a pharmaceutically acceptable excipient, as described above.
In one embodiment, the invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound according to anyone of formulae I' and I to VIC, or a pharmaceutically acceptable salt thereof. In one embodiment, the kit comprises means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is a blister pack, as typically used for the packaging of tablets, capsules and the like.
The kit of the invention may be used for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit of the invention typically comprises directions for administration.
In the combination therapies of the invention, the compound of the invention and the other therapeutic agent may be manufactured and/or formulated by the same or different manufacturers. Moreover, the compound of the invention and the other therapeutic may be brought together into a combination therapy: (i) prior to release of the combination product to physicians {e.g. in the case of a kit comprising the compound of the invention and the other therapeutic agent); (ii) by the physician themselves (or under the guidance of the physician) shortly before administration; (iii) in the patient themselves, e.g. during sequential administration of the compound of the invention and the other therapeutic agent. Accordingly, the invention provides the use of a compound according to anyone of formulae i to VIC, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or condition associated with neutral endopeptidase EC 3.4. 24.1 1 activity, wherein the medicament is prepared for administration with another therapeutic agent. The invention also provides the use of another therapeutic agent in the manufacture of medicament for treating a disease or condition associated with neutral endopeptidase EC 3.4. 24.1 1 activity, wherein the medicament is prepared for administration with a compound according to anyone of formulae I' and I to VIC, or a pharmaceutically acceptable salt thereof.
The invention also provides a compound according to anyone of Formulae I' and I to VIC, or a pharmaceutically acceptable salt thereof, for use in a method of treating a disease or condition associated with neutral endopeptidase EC 3.4. 24.1 1 activity, wherein the compound according to anyone of formulae I' and I to VIC, or a pharmaceutically acceptable salt thereof, is prepared for administration with another therapeutic agent. The invention also provides another therapeutic agent for use in a method of treating a disease or condition associated with neutral endopeptidase EC 3.4. 24.1 1 , wherein the other therapeutic agent is prepared for administration with a compound according to anyone of formulae I' and I to VIC, or a pharmaceutically acceptable salt thereof. The invention also provides a compound according to anyone of formulae I' and I toVIC, or a pharmaceutically acceptable salt thereof, for use in a method of treating a disease or condition associated with neutral endopeptidase EC 3.4. 24.1 1 , wherein the compound according to anyone of formulae I' and I to VIC, or a pharmaceutically acceptable salt thereof, is administered with another therapeutic agent. The invention also provides another therapeutic agent for use in a method of treating a disease or condition associated with neutral endopeptidase EC 3.4. 24.1 1 activity, wherein the other therapeutic agent is administered with a compound according to anyone of formulae I' and I to VIC, or a pharmaceutically acceptable salt thereof.
The invention also provides the use of a compound according to anyone of formulae I' and I to VIC, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or condition associated with neutral endopeptidase EC 3.4. 24.1 1 activity, wherein the patient has previously {e.g. within 24 hours) been treated with another therapeutic agent. The invention also provides the use of another therapeutic agent in the manufacture of a medicament for treating a disease or condition associated with neutral endopeptidase EC 3.4. 24.1 1 activity, wherein the patient has previously (e.g. within 24 hours) been treated with a compound according to anyone of formulae I' and I to VIC, or a pharmaceutically acceptable salt thereof.
In one embodiment, the other therapeutic agent is selected from: HMG-Co-A reductase inhibitor, an anigiotensin receptor blocker (ARBs, angiotensin Il receptor antagonist), angiotensin converting enzyme (ACE) Inhibitor, a calcium channel blocker (CCB), an endothelin antagonist, a renin inhibitor, a diuretic, an ApoA-l mimic, an antidiabetic agent, an obesity-reducing agent, an aldosterone receptor blocker, an endothelin receptor blocker, an aldosterone synthase inhibitors (ASI), a CETP inhibitor or a phophodiesterase type 5 (PDE5) inhibitor.
The term "in combination with" a second agent or treatment includes co-administration of the compound of the invention {e.g., a compound according to anyone of Formulae I' and I to VIC or a compound otherwise described herein) with the second agent or treatment, administration of the compound of the invention first, followed by the second agent or treatment and administration of the second agent or treatment first, followed by the compound of the invention.
The term "second agent" includes any agent which is known in the art to treat, prevent, or reduce the symptoms of a disease or disorder described herein, e.g .a disorder or disease responsive to the inhibition of neutral endopeptidase, such as for example, hypertension, pulmonary hypertension, isolated systolic hypertension, resistant hypertension, peripheral vascular disease, heart failure, congestive heart failure, left ventricular hypertrophy, angina, renal insufficiency (diabetic or non-diabetic), renal failure (including edema and salt retension), diabetic nephropathy, non-diabetic nephropathy, nephroic syndrome, glomerulonephritis, scleroderma, glomerular sclerosis, proteinurea of primary renal disease, renal vascular hypertention, diabetic retinopathy and end-stage renal disease (ESRD), endothelial dysfunction, diastolic dysfunction, hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation (AF), cardiac fibrosis, atrial flutter, detrimental vascular remodeling, plaque stabilization, myocardial infarction (Ml), renal fibrosis, polycystic kidney disease (PKD), Pulmonary Arterial hypertension, renal failure (including edema and salt retension), cyclical oedema, Menieres disease, hyperaldosteroneism (primary and secondary) and hypercalciuria, ascites, glaucoma, menstrual disorders, preterm labour, pre-eclampsia, endometriosis, and reproductive disorders (especially male and female infertility, polycystic ovarian syndrome, implantation failure), obstructive sleep apnea, asthma, inflammation, leukemia, pain, epilepsy, affective disorders such as depression and psychotic condition such as dementia and geriatric confusion, obesity and gastrointestinal disorders (especially diarrhea and irritable bowel syndrome), wound healing (especially diabetic and venous ulcers and pressure sores), septic shock, the modulation of gastric acid secretion, the treatment of hyperreninaemia, cystic fibrosis, restenosis, type-2 diabetes, metabolic syndrome, diabetic complications and atherosclerosis, male and female sexual dysfunction.
Examples of second agents include HMG-Co-A reductase inhibitors, angiotensin Il receptor antagonists, angiotensin converting enzyme (ACE) Inhibitors, calcium channel blockers (CCB), endothelin antagonists, renin inhibitors, diuretics, ApoA-l mimics, antidiabetic agents, obesity-reducing agents, aldosterone receptor blockers, endothelin receptor blockers, aldosterone synthase inhibitors (ASI) and CETP inhibitors.
The term "HMG-Co-A reductase inhibitor" (also called beta-hydroxy-beta- methylglutaryl-co-enzyme-A reductase inhibitors) includes active agents that may be used to lower the lipid levels including cholesterol in blood. Examples include atorvastatin, cerivastatin, compactin, dalvastatin, dihydrocompactin, fluindostatin, fluvastatin, lovastatin, pitavastatin, mevastatin, pravastatin, rivastatin, simvastatin, and velostatin, or, pharmaceutically acceptable salts thereof.
The term "ACE-inhibitor" (also called angiotensin converting enzyme inhibitors) includes molecules that interrupt the enzymatic degradation of angiotensin I to angiotensin II. Such compounds may be used for the regulation of blood pressure and for the treatment of congestive heart failure. Examples include alacepril, benazepril, benazeprilat, captopril, ceronapril, cilazapril, delapril, enalapril, enaprilat, fosinopril, imidapril, lisinopril, moveltopril, perindopril, quinapril, ramipril, spirapril, temocapril, and trandolapril, or, pharmaceutically acceptables salt thereof. The term "endothelin antagonist" includes bosentan (cf. EP 526708 A), tezosentan (cf. WO 96/19459), or, pharmaceutically acceptable salts thereof.
The term "renin inhibitor" includes ditekiren (chemical name: [1 S- [1 fl*,2fl*,4fl*(1 fl*,2fl*)]]-1 -[(1 ,1 -dimethylethoxy)carbonyl]-L-proly l-L-phenylalanyl-N-[2- hydroxy-5-methyl-1 -(2-methylpropyl)-4-[[[2-methyl-1 -[[(2- pyridinylmrthyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-Λ/-alfa-methyl-L-histidinamide); terlakiren (chemical name: [R-(Ft, S*)]-N-(4-morpholinylcarbonyl)-L-phenylalanyl-N-[1 - (cyclohexylmethyl)-2-hydroxy-3-(1 -methylethoxy)-3-oxopropyl]-S-methyl-L-cysteineamide); Aliskiren (chemical name: (2S,4S,5S,7S)-5-amino-Λ/-(2-carbamoyl-2,2-dimethylethyl)-4- hydroxy-7-{[4-methoxy-3-(3-methoxypropoxy) phenyl]methyl}-8-methyl-2-(propan-2-yl)nonanamide) and zankiren (chemical name: [1 S- [1 Rk[Rk(Rk)],2Sk,3Rk]]-N-^ -(cyclohexylmethyl)-2,3-dihydroxy-5-m ethylhexyl]-alfa-[[2-[[(4- methyl-1 -piperazinyl)sulfonyl]methyl]-1 -oxo-3-phenylpropyl]-amino]-4-thiazolepropanamide), or, hydrochloride salts thereof, or, SPP630, SPP635 and SPP800 as developed by Speedel, or RO 66-1 132 and RO 66-1 168 of Formula (A) and (B):
Figure imgf000054_0001
(A) and <B) , or, pharmaceutically acceptable salts thereof.
The term "aliskiren", if not defined specifically, is to be understood both as the free base and as a salt thereof, especially a pharmaceutically acceptable salt thereof, most preferably a hemi-fumarate salt thereof.
An angiotensin Il receptor antagonist or a pharmaceutically acceptable salt thereof is understood to be an active ingredient which bind to the ATi -receptor subtype of angiotensin Il receptor but do not result in activation of the receptor. As a consequence of the inhibition of the AT1 receptor, these antagonists can, for example, be employed as antihypertensives or for treating congestive heart failure.
The class of AT1 receptor antagonists comprises compounds having differing structural features, essentially preferred are the non-peptidic ones. For example, mention may be made of the compounds which are selected from the group consisting of valsartan, losartan, candesartan, eprosartan, irbesartan, saprisartan, tasosartan, telmisartan, the compound with the designation E-1477 of the following formula
Figure imgf000055_0001
the compound with the designation SC-52458 of the following formula
Figure imgf000055_0002
and the compound with the designation ZD-8731 of the following formula
Figure imgf000055_0003
or, in each case, a pharmaceutically acceptable salt thereof.
Preferred ATVreceptor antagonist are those agents which have been marketed, most preferred is valsartan or a pharmaceutically acceptable salt thereof.
The term "calcium channel blocker (CCB)" includes dihydropyridines (DHPs) and non-DHPs (e.g., diltiazem-type and verapamil-type CCBs). Examples include amlodipine, felodipine, ryosidine, isradipine, lacidipine, nicardipine, nifedipine, niguldipine, niludipine, nimodipine, nisoldipine, nitrendipine, and nivaldipine, and is preferably a non-DHP representative selected from the group consisting of flunarizine, prenylamine, diltiazem, fendiline, gallopamil, mibefradil, anipamil, tiapamil and verapamil, or, pharmaceutically acceptable salts thereof. CCBs may be used as anti-hypertensive, anti-angina pectoris, or anti-arrhythmic drugs.
The term "diuretic" includes thiazide derivatives {e.g., chlorothiazide, hydrochlorothiazide, methylclothiazide, and chlorothalidon).
The term "ApoA-l mimic" includes D4F peptides {e.g., formula D-W-F-K-A-F-Y-D-K- V-A-E-K-F-K-E-A-F)
The term "anti-diabetic agent" includes insulin secretion enhancers that promote the secretion of insulin from pancreatic β-cells. Examples include biguanide derivatives {e.g., metformin), sulfonylureas (SU) {e.g., tolbutamide, chlorpropamide, tolazamide, acetohexamide, 4-chloro-Λ/-[(1 -pyrolidinylamino)carbonyl]-benzensulfonamide (glycopyramide), glibenclamide (glyburide), gliclazide, 1 -butyl-3-metanilylurea, carbutamide, glibonuride, glipizide, gliquidone, glisoxepid, glybuthiazole, glibuzole, glyhexamide, glymidine, glypinamide, phenbutamide, and tolylcyclamide), or pharmaceutically acceptable salts thereof. Further examples include phenylalanine derivatives {e.g., nateglinide [N- (frans^-isopropylcyclohexylcarbony^-D-phenylalanine] (cf. EP 196222 and EP 526171 ) of the formula
Figure imgf000056_0001
repaglinide [(S)-2-ethoxy-4-{2-[[3-methyl-1 -[2-(1 -piperidinyl)phenyl]butyl]amino]-2- oxoethyljbenzoic acid] (cf. EP 589874, EP 147850 A2, in particular Example 1 1 on page 61 , and EP 207331 A1 ); calcium (2S)-2-benzyl-3-(c/s-hexahydro-2-isoindolinlycarbonyl)- propionate dihydrate {e.g., mitiglinide (cf. EP 507534)); and glimepiride (cf. EP 31058). Further examples include DPP-IV inhibitors, GLP-1 and GLP-1 agonists.
DPP-IV is responsible for inactivating GLP-1 . More particularly, DPP-IV generates a GLP-1 receptor antagonist and thereby shortens the physiological response to GLP-1 . GLP- 1 is a major stimulator of pancreatic insulin secretion and has direct beneficial effects on glucose disposal.
The DPP-IV inhibitor can be peptidic or, preferably, non-peptidic. DPP-IV inhibitors are in each case generically and specifically disclosed e.g. in WO 98/19998, DE 196 16 486 A1 , WO 00/34241 and WO 95/15309, in each case in particular in the compound claims and the final products of the working examples, the subject-matter of the final products, the pharmaceutical preparations and the claims are hereby incorporated into the present application by reference to these publications. Preferred are those compounds that are specifically disclosed in Example 3 of WO 98/19998 and Example 1 of WO 00/34241 , respectively.
GLP-1 is an insulinotropic protein which is described, e.g., by W. E. Schmidt et al. in Diabetologia, 28, 1985, 704-707 and in US 5,705,483.
The term "GLP-1 agonists" includes variants and analogs of GLP-1 (7-36)NH2 which are disclosed in particular in US 5,120,712, US 5,1 18666, US 5,512,549, WO 91/1 1457 and by C. Orskov et al in J. Biol. Chem. 264 (1989) 12826. Further examples include GLP-1 (7- 37), in which compound the carboxy-terminal amide functionality of Arg36 is displaced with GIy at the 37th position of the GLP-1 (7-36)NH2 molecule and variants and analogs thereof including GLN9-GLP-1 (7-37), D-GLN9-GLP-1 (7-37), acetyl LYS9-GLP-1 (7-37), LYS18-GLP- 1 (7-37) and, in particular, GLP-1 (7-37)OH, VAL8-GLP-1 (7-37), GLY8-GLP-1 (7-37), THR8- GLP-1 (7-37), MET8-GLP-1 (7-37) and 4-imidazopropionyl-GLP-1 . Special preference is also given to the GLP agonist analog exendin-4, described by Greig et al. in Diabetologia 1999, 42, 45-50.
Also included in the definition "anti-diabetic agent" are insulin sensitivity enhancers which restore impaired insulin receptor function to reduce insulin resistance and consequently enhance the insulin sensitivity. Examples include hypoglycemic thiazolidinedione derivatives {e.g., glitazone, (S)-((3,4-dihydro-2-(phenyl-methyl)-2H-1 - benzopyran-6-yl)methyl-thiazolidine-2,4-dione (englitazone), 5-{[4-(3-(5-methyl-2-phenyl-4- oxazolyl)-1 -oxopropyl)-phenyl]-methyl}-thiazolidine-2,4-dione (darglitazone), 5-{[4-(1 -methyl- cyclohexyl)methoxy)-phenyl]methyl}-thiazolidine-2,4-dione (ciglitazone), 5-{[4-(2-(1 - indolyl)ethoxy)phenyl]methyl}-thiazolidine-2,4-dione (DRF2189), 5-{4-[2-(5-methyl-2-phenyl- 4-oxazolyl)-ethoxy)]benzyl}-thiazolidine-2,4-dione (BM-13.1246), 5-(2-naphthylsulfonyl)- thiazolidine-2,4-dione (AY-31637), bis{4-[(2,4-dioxo-5-thiazolidinyl)methyl]phenyl}methane (YM268), 5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)-2-hydroxyethoxy]benzyl}-thiazolidine-2,4- dione (AD-5075), 5-[4-(1 -phenyl-1 -cyclopropanecarbonylamino)-benzyl]-thiazolidine-2,4- dione (DN-108) 5-{[4-(2-(2,3-dihydroindol-1 -yl)ethoxy)phenyl]methyl}-thiazolidine-2,4-dione, 5-[3-(4-chloro-phenyl])-2-propynyl]-5-phenylsulfonyl)thiazolidine-2,4-dione, 5-[3-(4- chlorophenyl])-2-propynyl]-5-(4-fluorophenyl-sulfonyl)thiazolidine-2,4-dione, 5-{[4-(2-(methyl- 2-pyridinyl-amino)-ethoxy)phenyl]methyl}-thiazolidine-2,4-dione (rosiglitazone), 5-{[4-(2-(5- ethyl-2-pyridyl)ethoxy)phenyl]-methyl}thiazolidine-2,4-dione (pioglitazone), 5-{[4-((3,4- dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1 -benzopyran-2-yl)methoxy)-phenyl]-methyl}- thiazolidine-2,4-dione (troglitazone), 5-[6-(2-fluoro-benzyloxy)naphthalen-2-ylmethyl]- thiazolidine-2,4-dione (MCC555), 5-{[2-(2-naphthyl)-benzoxazol-5-yl]-methyl}thiazolidine- 2,4-dione (T- 174) and 5-(2,4-dioxothiazolidin-5-ylmethyl)-2-methoxy-N-(4-trifluoromethyl- benzyl)benzamide (KRP297)).
Further anti-diabetic agents include, insulin signalling pathway modulators, like inhibitors of protein tyrosine phosphatases (PTPases), antidiabetic non-small molecule mimetic compounds and inhibitors of glutamine-fructose-6-phosphate amidotransferase (GFAT); compounds influencing a dysregulated hepatic glucose production, like inhibitors of glucose-6-phosphatase (G6Pase), inhibitors of fructose-1 ,6-bisphosphatase (F- 1 ,6-Bpase), inhibitors of glycogen phosphorylase (GP), glucagon receptor antagonists and inhibitors of phosphoenolpyruvate carboxykinase (PEPCK); pyruvate dehydrogenase kinase (PDHK) inhibitors; inhibitors of gastric emptying; insulin; inhibitors of GSK-3; retinoid X receptor (RXR) agonists; agonists of Beta-3 AR; agonists of uncoupling proteins (UCPs); non- glitazone type PPARγ agonists; dual PPAR* / PPAR* agonists; antidiabetic vanadium containing compounds; incretin hormones, like glucagon-like peptide-1 (GLP-1 ) and GLP-1 agonists; beta-cell imidazoline receptor antagonists; miglitol; • 2-adrenergic antagonists; and pharmaceutically acceptable salts thereof.
The term "obesity-reducing agent" includes lipase inhibitors (e.g., orlistat) and appetite suppressants {e.g., sibutramine and phentermine).
An aldosterone synthase inhibitor or a pharmaceutically acceptable salt thereof is understood to be an active ingredient that has the property to inhibit the production of aldosterone. Aldosterone synthase (CYP1 1 B2) is a mitochondrial cytochrome P450 enzyme catalyzing the last step of aldosterone production in the adrenal cortex, i.e., the conversion of 1 1 -deoxycorticosterone to aldosterone. The inhibition of the aldosterone production with so-called aldosterone synthase inhibitors is known to be a successful variant to treatment of hypokalemia, hypertension, congestive heart failure, atrial fibrillation or renal failure. Such aldosterone synthase inhibition activity is readily determined by those skilled in the art according to standard assays (e.g., US 2007/0049616).
The class of aldosterone synthase inhibitors comprises both steroidal and nonsteroidal aldosterone synthase inhibitors, the later being most preferred.
Preference is given to commercially available aldosterone synthase inhibitors or those aldosterone synthase inhibitors that have been approved by the health authorities.
The class of aldosterone synthase inhibitors comprises compounds having differing structural features. For example, mention may be made of the compounds which are selected from the group consisting of the non-steroidal aromatase inhibitors anastrozole, fadrozole (including the (+)-enantiomer thereof), as well as the steroidal aromatase inhibitor exemestane, or, in each case where applicable, a pharmaceutically acceptable salt thereof. The most preferred non-steroidal aldosterone synthase inhibitor is the (+)-enantiomer of the hydrochloride of fadrozole (US patents 4617307 and 4889861 ) of formula
Figure imgf000059_0001
or, if appropriable, a pharmaceutically acceptable salt thereof.
A preferred steroidal aldosterone antagonist is eplerenone (cf. EP 122232 A) of the formula
Figure imgf000059_0002
or Spironolactone; or, in each case, if appropriable, a pharmaceutically acceptable salt thereof.
Aldosterone synthase inhibitors useful in said combination are compounds and analogs generically and specifically disclosed e.g. in US2007/0049616, in particular in the compound claims and the final products of the working examples, the subject-matter of the final products, the pharmaceutical preparations and the claims are hereby incorporated into the present application by reference to this publication. Preferred aldosterone synthase inhibitors suitable for use in the present invention include, without limitation 4-(6,7-dihydro- 5H-pyrrolo[1 ,2-c]imidazol-5-yl)-3-methylbenzonitrile; 5-(2-chloro-4-cyanophenyl)-6,7-dihydro- 5H-pyrrolo[1 ,2-c]imidazole-5-carboxylic acid (4-methoxybenzyl)methylamide; 4'-fluoro-6- (6,7,8,9-tetrahydro-5H-imidazo[1 ,5-a]azepin-5-yl)biphenyl-3-carbonitrile; 5-(4-Cyano-2- methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1 ,2-c]imidazole-5-carboxylic acid butyl ester; 4-(6,7- Dihydro-5H-pyrrolo[1 ,2-c]imidazol-5-yl)-2-methoxybenzonitrile; 5-(2-Chloro-4-cyanophenyl)- 6,7-dihydro-5H-pyrrolo[1 ,2-c]imidazole-5-carboxylic acid 4-fluorobenzyl ester; 5-(4-Cyano-2- trifluoromethoxyphenyl)-6,7-dihydro-5H-pyrrolo[1 ,2-c]imidazole-5-carboxylic acid methyl ester; 5-(4-Cyano-2-methoxyphenyl)-6,7-dihydro-5/-/-pyrrolo[1 ,2-c]imidazole-5-carboxylic acid 2-isopropoxyethyl ester; 4-(6,7-Dihydro-5H-pyrrolo[1 ,2-c]imidazol-5-yl)-2- methylbenzonitrile; 4-(6,7-dihydro-5H-pyrrolo[1 ,2-c]imidazol-5-yl)-3-fluorobenzonitrile ; A- (6,7-Dihydro-5H-pyrrolo[1 ,2-c]imidazol-5-yl)-2-methoxybenzonitrile; 3-Fluoro-4-(7- methylene-6,7-dihydro-5/-/-pyrrolo[1 ,2-c]imidazol-5-yl)benzonitrile; c/s-3-Fluoro-4-[7-(4- fluoro-benzyl)-5,6,7,8-tetrahydro-imidazo[1 ,5-a]pyridin-5-yl]benzonitrile; 4'-Fluoro-6-(9- methyl-6,7,8,9-tetrahydro-5/-/-imidazo[1 ,5-a]azepin-5-yl)biphenyl-3-carbonitrile; 4'-Fluoro-6- (9-methyl-6,7,8,9-tetrahydro-5/-/-imidazo[1 ,5-a]azepin-5-yl)biphenyl-3-carbonitrile or in each case, the (R) or (S) enantiomer thereof; or if appropriable, a pharmaceutically acceptable salt thereof.
The term aldosterone synthase inhibitors also include compounds and analogs disclosed in WO2008/076860, WO2008/076336, WO2008/076862, WO2008/027284, WO2004/046145, WO2004/014914, WO2001 /076574.
Furthermore Aldosterone synthase inhibitors also include compounds and analogs disclosed in U.S. patent applications US2007/0225232, US2007/0208035, US2008/0318978, US2008/0076794, US2009/0012068, US20090048241 and in PCT applications WO2006/005726, WO2006/128853, WO2006128851 , WO2006/128852, WO2007065942, WO2007/1 16099, WO2007/1 16908, WO2008/1 19744 and in European patent application EP 1886695. Preferred aldosterone synthase inhibitors suitable for use in the present invention include, without limitation 8-(4-Fluorophenyl)-5,6-dihydro-8H- imidazo[5,1 -c1 [1 ,41 oxazine; 4-(5,6-Dihydro-8H-imidazo[5,1 -c][1 ,4]oxazin-8-yl)-2- fluorobenzonitrile; 4-(5,6-Dihydro-8H-imidazo[5,1 -c][1 ,4]oxazin-8-yl)-2,6- difluorobenzonitrile; 4-(5,6-Dihydro-8H-imidazo[5,1 -c][1 ,4]oxazin-8-yl)-2- methoxybenzonitrile; 3-(5,6-Dihydro-8H-imidazo[5,1 -c][1 ,4]oxazin-8-yl)benzonitrile; 4-(5,6- Dihvdro-8H-imidazo[5,1 -c][1 ,4]oxazin-8-yl)phthalonitrile; 4-(8-(4-Cyanophenyl)-5,6-dihydro- 8H-imidazo[5,1 -c][1 ,4]oxazin-8-yl)benzonitrile; 4-(5,6-Dihydro-8H-imidazo[5,1 -c][1 ,4]oxazin-8-yl)benzonitrile; 4-(5,6-Dihydro-8H-imidazo[5,1 -c][1 ,4]oxazin-8-yl)naphthalene-1 - carbonitrile; 8-[4-(1 H-Tetrazol-5-yl)phenyl1 -5,6-dihvdro-8H-imidazo[5,1 -c][1 ,4]oxazine as developed by Speedel or in each case, the (R) or (S) enantiomer thereof; or if appropriable, a pharmaceutically acceptable salt thereof.
The term "endothelin receptor blocker" includes bosentan.
The term "CETP inhibitor" refers to a compound that inhibits the cholesteryl ester transfer protein (CETP) mediated transport of various cholesteryl esters and triglycerides from HDL to LDL and VLDL. Such CETP inhibition activity is readily determined by those skilled in the art according to standard assays (e.g., U.S. Pat. No. 6,140,343). Examples include compounds disclosed in U.S. Pat. No. 6,140,343 and U. S. Pat. No. 6,197,786 (e.g., [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl- amino]-2-ethyl-6-trifluoromethyl- 3,4-dihydro-2H-quinoline-1 -carboxylic acid ethyl ester (torcetrapib); compounds disclosed in U.S. Pat. No. 6,723,752 (e.g., (2R)-3-{[3-(4-Chloro-3-ethyl-phenoxy)-phenyl]-[[3-(1 , 1 ,2,2- tetrafluoro-ethoxy)-phenyl]-methyl]-amino}-1 ,1 ,1 -trifluoro-2-propanol); compounds disclosed in U.S. patent application Ser. No. 10/807,838; polypeptide derivatives disclosed in U.S. Pat. No. 5,512,548; rosenonolactone derivatives and phosphate-containing analogs of cholesteryl ester disclosed in J. Antibiot, 49(8): 815- 816 (1996), and Bioorg. Med. Chem. Lett.; 6:1951 -1954 (1996), respectively. Furthermore, the CETP inhibitors also include those disclosed in WO2000/017165, WO2005/095409 and WO2005/097806.
Second agent of particular interest include Endothelin antagonists, renin inhibitors, angiotensin Il receptor antagonists, calcium channel blockers, diuretics, antidiabetic agents such as DPPIV inhibitors, and aldosterone synthase inhibitors.
Exemplification of the invention: Abbreviations:
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees centrigrade. If not mentioned otherwise, all evaporations are performed under reduced pressure, preferably between about 15 mm Hg and 100 mm Hg (= 20-133 mbar). The structure of final products, intermediates and starting materials is confirmed by standard analytical methods, e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR, NMR. Abbreviations used are those conventional in the art.
All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts utilized to synthesis the compounds of the present invention are either commercially available or can be produced by organic synthesis methods known to one of ordinary skill in the art (Houben-Weyl 4th Ed. 1952, Methods of Organic Synthesis, Thieme, Volume 21 ). Further, the compounds of the present invention can be produced by organic synthesis methods known to one of ordinary skill in the art as shown in the following examples.
The compounds in the examples 1 -1 to 59-1 have been found to have IC50 values in the range of about 0.01 nM to about 10,000 nM for NEP.
The conditions for measuring the retention times are as follows: HPLC condition A:
Column: INERTSIL C8-3, 3 μm x 33 mm x 3.0 mm at 40 0C. Flow rate: 2 mL / min Mobile phase: H2O (5 mM NH4+HCOO-) Gradient: linear gradient from 5% to 95% MeCN in 2 min Detection: DAD-UV at 200-400 nm
HPLC condition B:
Column: INERTSIL C8-3, 3 μm x 33 mm x 3.0 mm at 40 0C.
Flow rate: 2mL/min Mobile phase: 0.1 % Formic acid
Gradient: linear gradient from 5% to 95% MeCN/MeOH in 2 min
Detection: UV at 215 nm
HPLC condition C:
Column: INERTSIL C8-3, 3 μm x 33 mm x 3.0 mm at 40 0C.
Flow rate: 2 ml / min
Mobile phase: A) H2O (5 mM NH4+HCOO-), B) 50% MeOH/50% MeCN
Gradient: linear gradient from 5% B to 95% B in 2 min
Detection: DAD-UV at 200-400 nm
HPLC condition D:
Column: lnertsil C8-3, 3 μm x 33 mm x 3.0 mm at 40 0C.
Flow rate: 2 ml / min
Mobile phase: A) H2O (5 mM NH4+HCOO-), B) 50% MeOH/50%MeCN
Gradient: linear gradient from 40% B to 95% B in 2 min
Detection: UV at 214 nm
HPLC condition E
Column: lnertsil C8-3, 3 μm x 33 mm x 3.0 mm at 40 0C.
Flow rate: 2 ml / min
Mobile phase: A) H2O (5 mM NH4+HCOO-), B) 50% MeOH/50%MeCN
Gradient: linear gradient from 60% B to 95% B in 2 min
Detection: UV at 214 nm
The relative stereochemistry was determined using two dimensional NMR. Under the reaction condition, it would be unexpected that the stereocenter bearing the bisphenyl- methyl group racemize. Therefore, the absolute stereochemistry was determined based on the relative stereochemistry and the absolute stereochemistry of the stereocenter bearing the bisphenyl-methyl group.
Example 1-1 : Synthesis of N-((1 S,3R)-1-biphenyl-4-ylmethyl-3-carboxy-butyl)- isophthalamic acid
Figure imgf000065_0001
To a mixture of (2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid ethyl ester hydrochloride (70 mg, 0.201 mmol) and S-chlorocarbonylbenzoic acid methyl ester (0.302 mmol) in methylene chloride (0.5 ml_) is added pyridine (0.5 ml_) and the mixture is stirred at room temperature for 24 hours. The solvents are removed under reduced pressure and ethyl acetate is added. The solution is washed with aqueous 1 M HCI and brine and the organic phase is dried over sodium sulfate. The solvent is removed under reduced pressure and the residue is purified by column chromatography using methylene chloride to furnish N-((1 S,3R)-1 -biphenyW-ylmethyl-S-ethoxycarbonyl-butyO-isophthalamic acid. Next, to a solution of N-((1 S,3R)-1 -biphenyl-4-ylmethyl-3-ethoxycarbonyl-butyl)- isophthalamic acid (0.287 mmol) in ethanol (10 ml_) is added aqueous 1 M NaOH (1.2 ml_, 1 .12 mmol) and the mixture is stirred at 50-60 0C for 5 hours. The ethanol is removed under reduced pressure and water is added. The solution is acidified with 1 M HCI and the mixture is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC using a gradient of MeCN/water (0.1 % TFA). The proper fractions are lyophilized to furnish N-((1 S,3R)-1 -biphenyl-4-ylmethyl-3-carboxy-butyl)-isophthalamic acid. HPLC Retention time 1 .05 minutes (condition A); MS 432.3 (M+1 ); 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .09 (d, J=7.07 Hz, 3H), 1 .60 (m, 1 H), 1 .89 (m, 1 H), 2.47 (m, 1 H), 2.86 (m, 2H), 4.27 (m, 1 H), 7.27- 7.35 (m, 3H), 7.34 (t, 1 H), 7.43 (t, 2H), 7.55-7.66 (m, 5H), 8.01 -8.07 (m, 2H), 8.39 (s, 1 H), 8.47 (d, J=8.46 Hz, 1 H).
Following compounds are prepared using similar procedure as example 1 -1 with appropriate reagents and conditions:
Figure imgf000065_0002
Figure imgf000066_0002
Example 1 -2: 1 H NMR (400 MHz, MeOD-d4) • ppm 1 .15 (d, J=7.07 Hz, 3H), 1 .50 (m, 1 H), 1 .95 (m, 1 H), 2.50 (m, 1 H), 2.71 (dd, J=7.83 Hz, 7.71 Hz, 1 H), 2.83 (dd, J=5.56 Hz, 5.70 Hz, 1 H), 3.40 (s, 2H), 3.70 (s, 3H), 4.18 (m, 1 H), 6.75 (m, 3H), 7.14 (t, J=8.34 Hz, 3H), 7.31 (t, J=7.33 Hz, 1 H), 7.42 (m, 4H), 7.56 (d, J=7.33 Hz, 2H), 7.85 (d, J=8.97 Hz, 1 H). Example 1 -3: 1 H NMR (400 MHz, DMSO-d6) • ppm 0.96 (d, J=7.20 Hz, 3H), 1 .49 (m, 1 H), 1 .68 (m, 1 H), 2.33 (m, 1 H), 2.77 (m, 1 H), 3.06 (dd, 1 H), 4.1 1 (m, 1 H), 7.30-7.35 (m, 3H), 7.44 (t, 1 H), 7.59 (td, J=8.21 Hz, 2H), 7.65 (d, J=7.20, 2H), 7.85 (q, 4H), 10.46 (m, 1 H).
Example 2-1 : Synthesis of (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-3-methyl- butyrylamino)-2-methyl-pentanoic acid
Figure imgf000066_0001
A solution of (2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid ethyl ester hydrochloride (100 mg, 0.287 mmol) and 3,3-dimethyl-dihydro-furan-2,5-dione (0.431 mmol) in 1 :1 methylene chloride/pyridine (1 .4 ml_) is stirred at room temperature for 24 hours. The solvents are removed under reduced pressure and obtained residue is used directly in the subsequent hydrolysis reaction.
Next, to a solution of the obtained residue (0.287 mmol) in ethanol (10 ml_) is added aqueous 1 M NaOH (2 ml_, 6.97 mmol) and the mixture is stirred at room temperature for 18 hours. The mixture is poured into ethyl acetate and is washed with aqueous 1 M HCI, the organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC using a gradient of MeCN/water (0.1 % TFA). The proper fractions are lyophilized to furnish (2R,4S)-5-biphenyl-4-yl-4-(3- carboxy-3-methyl-butyrylamino)-2-methyl-pentanoic acid. HPLC Retention time 1 .03 minutes (condition A); MS 412.4 (M+1 ); 1 H NMR (400 MHz, DMSO-d6) • ppm 0.97-1 .07 (m, 9H), 1 .32 (m, 1 H), 1 .72 (m, 1 H), 2.25 (q, 2H), 2.45 (m, 1 H), 2.64-2.74 (m, 2H), 3.91 (s, 1 H), 7.25 (d, J=8.08 Hz, 2H), 7.34 (t, 1 H), 7.45 (t, 2H), 7.56 (d, J=8.08 Hz, 2H), 7.64 (d, J=7.58 Hz, 2H), 7.88 (s, broad, 1 H).
Following compounds are prepared using similar procedure as example 2-1 with appropriate reagents and conditions:
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Example 2-2: 1 H NMR (400 MHz, MeCN-d3) • ppm 1 .1 1 (d, J=6.95 Hz, 3H), 1 .56 (m, 1 H),
1 .88 (m, 1 H), 2.51 (m, 1 H), 2.78-2.90 (m, 2H), 4.20 (m, 1 H), 7.09 (d, J=8.97 Hz, 1 H), 7.29
(d, J=8.08 Hz, 2H), 7.35 (t, 1 H), 7.45 (t, 2H), 7.57 (d, J=8.08 Hz, 2H), 7.6 (d, J=7.58 Hz,
2H).
Example 2-3: 1 H NMR (400 MHz, MeOD-d4) • ppm 1 .16 (d, J=7.20 Hz, 3H), 1 .62 (m, 1 H),
1 .97 (m, 1 H), 2.52 (m, 1 H), 2.87 (m, 2H), 4.25 (m, 1 H), 7.32 (m, 3H), 7.43 (t, 2H), 7.54 (d,
J=8.21 Hz, 2H), 7.59 (d, J=7.83 Hz, 1 H), 7.60 (d, J=8.34Hz, 1 H), 8.99 (d, J=8.58 Hz, 1 H).
Example 2-4: 1 H NMR (400 MHz, MeCN-d3) • ppm 1 .07 (d, J=6.82 Hz, 3H), 1 .47 (m, 1 H),
1 .61 (m, 2H), 1 .73-1 .95 (m, 4H), 2.45 (m, 1 H), 2.73-2.96 (m, 5H), 4.0.6 (m, 1 H), 6.64 (d,
J=8.72 Hz, 1 H), 7.29 (d, J=8.08 Hz, 2H), 7.35 (t, 1 H), 7.45 (t, 2H), 7.57 (d, J=8.21 Hz, 2H),
7.64 (d, J=7.33 Hz, 2H).
Example 2-5: 1 H NMR (400 MHz, MeCN-d3) • ppm 1 .09 (d, J=6.69 Hz, 3H), 1 .37 (m, 1 H),
1 .46 (m, 2H), 1 .61 (m, 2H), 1 .73-1 .86 (m, 4H), 2.51 (m, 1 H), 2.72 (m, 1 H), 2.84-2.96 (m,
3H), 4.0.6 (m, 1 H), 6.77 (d, J=8.72 Hz, 1 H), 7.30 (d, J=8.08 Hz, 2H), 7.35 (t, 1 H), 7.45 (t,
2H), 7.56 (d, J=7.96 Hz, 2H), 7.62 (d, J=7.71 Hz, 2H).
Example 2-6: 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .05 (d, J=6.95 Hz, 3H), 1 .10 (m, 1 H),
1 .27 (m, 1 H), 1 .38 (m, 1 H), 1 .77 (m, 1 H), 1 .85-1 .96 (m, 2H), 2.43 (m, 1 H), 2.67-2.77 (m,
2H), 3.94 (m, 1 H), 7.27 (d, J=8.21 Hz, 2H), 7.34 (t, 1 H), 7.45 (t, 2H), 7.58 (d, J=8.21 Hz,
2H), 7.65 (d, J=7.20 Hz, 2H), 8.18 (d, J=8.34 Hz, 1 H). Example 2-7: 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .01 (d, J=7.20 Hz, 3H), 1 .30 (m, 1 H),
1 .70 (m, 1 H), 2.38-2.44 (m, 2H), 1 .93-2.05 (m, 3H), 2.31 -2.42 (m,2H), 2.59 (m, 1 H), 2.84 (m,
1 H), 3.18-3.30 (m, 2H), 3.92 (m, 1 H), 7.28 (d, J=8.21 Hz, 2H), 7.34 (t, 1 H), 7.45 (t, 2H), 7.58
(d, J=8.21 Hz, 2H), 7.66 (d, J=7.20 Hz, 3H).
Example 2-8: 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .06 (d, J=6.95 Hz, 3H), 1 .36 (m, 1 H),
1 .76 (m, 2H), 1 .94 (m, 2H), 2.25 (m, 1 H), 2.45 (m, 1 H), 2.71 (m, 2H), 3.18 (m, 2H), 3.95 (m,
1 H), 7.25 (d, J=8.34 Hz, 2H), 7.34 (t, 1 H), 7.44 (t, 2H), 7.56 (d, J=8.21 Hz, 2H), 7.64 (d,
J=7.07 Hz, 3H).
Example 2-9: 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .02 (d, J=7.20 Hz, 3H), 1 .45 (m, 1 H),
1 .70 (m, 1 H), 2.40 (m, 1 H), 2.59 (m, 1 H), 2.76 (m, 1 H), 3.69 (d, J=5.05 Hz, 1 H), 3.75 (d,
J=5.05 Hz, 1 H), 3.98 (m, 1 H), 7.27 (d, J=8.08 Hz, 2H), 7.34 (t, 1 H), 7.45 (t, 2H), 7.59 (d,
J=8.21 Hz, 2H), 7.66 (d, J=7.20 Hz, 2H), 7.95 (d, J=8.59 Hz, 1 H).
Example 2-10: 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .04 (d, J=7.07 Hz, 3H), 1 .37 (m, 1 H),
1 .76 (m, 1 H), 2.43 (m, 1 H), 2.66-2.81 (m, 2H), 3.59 (d, J=5.18 Hz, 1 H), 3.72 (d, J=4.93 Hz,
1 H), 4.02 (m, 1 H), 7.26 (d, J=8.21 Hz, 2H), 7.34 (t, 1 H), 7.45 (t, 2H), 7.58 (d, J=8.21 Hz,
2H), 7.66 (d, J=7.20 Hz, 2H), 7.83 (d, J=8.84 Hz, 1 H).
Example 2-1 1 : 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .06 (d, J=7.07 Hz, 3H), 1 .15 (m, 1 H),
1 .30-2.08 (m, 1 1 H), 2.40 (m, 1 H), 2.66 (m, 2H), 2.76 (m,1 H), 3.99 (m, 1 H), 7.26 (t, 2H), 7.34
(t, 1 H), 7.45 (t, 2H), 7.53-7.66 (m, 4H).
Example 2-12: 1 H NMR (400 MHz, MeOD-d4) • ppm 0.88 (t, J=7.07 Hz, 3H), 1 .15 (d,
J=7.07 Hz, 3H), 1 .43 (m, 7H), 1 .90 (m, 1 H), 2.24 (dd, J=6.69 Hz, 6.57 Hz, 1 H), 2.39 (dd,
J=7.58 Hz, 7.58 Hz, 1 H), 2.57 (m, 2H), 2.81 (m, 2H), 4.15 (m, 1 H), 7.30 (d, J=8.21 Hz, 2H),
7.41 (m, 2H), 7.51 (m, 2H), 7.57 (m, 2H).
Example 2-13: 1 H NMR (400 MHz, MeOD-d4) • ppm 0.85 (t, J=7.07 Hz, 3H), 1 .16 (d,
J=7.07 Hz, 3H), 1 .43 (m, 7H), 1 .92 (m, 1 H), 2.21 (dd, J=7.71 Hz, 7.71 Hz, 1 H), 2.47 (m,
2H), 2.59 (m, 1 H), 2.81 (m, 2H), 4.13 (m, 1 H), 7.30 (m, 3H), 7.41 (m, 2H), 7.52 (m, 2H), 7.59
(m, 2H).
Example 2-14: 1 H NMR (400 MHz, MeOD-d4) • ppm 0.73 (t, J=7.33 Hz, 3H), 0.97 (m, 2H),
1 .13 (m, 2H), 1 .16 (d, J=7.07 Hz, 3H), 1 .29 (m, 1 H), 1 .39 (m, 1 H), 1 .50 (m, 1 H), 1 .94 (m,
1 H), 2.24 (m, 1 H), 2.51 (m, 2H), 2.61 (m, 1 H), 2.74 (dd, J=9.09 Hz, 8.97 Hz, 1 H), 2.88 (dd,
J=5.18 Hz, 4.67 Hz, 1 H), 4.25 (m, 1 H), 7.30 (m, 3H), 7.41 (m, 2H), 7.52 (d, J=8.34 Hz, 2H),
7.57 (dd, J=0.63 Hz, 1 .26 hz, 2H).
Example 2-15: 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .02 (m, 9H), 1 .31 (m, 1 H), 1 .72 (m,
1 H), 2.20 (m, 2H), 2.45 (m, 1 H), 2.68 (m, 2H), 3.91 (m, 1 H), 7.23 (d, J=8.08 Hz, 2H), 7.33 (d, J=7.20 Hz, 1 H), 7.44 (d, J=7.83 Hz, 2H), 7.55 (d, J=8.08 Hz, 2H), 7.63 (dd, J=0.76 Hz,
1 .14 Hz, 2H), 7.88 (s, 1 H).
Example 2-16: 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .05 (d, J=7.06 Hz, 3H), 1 .10 (m, 1 H),
1 .27 (m, 1 H), 1 .39 (m, 1 H), 1 .78 (m, 1 H), 1 .86-1 .95 (m, 2H), 2.44 (m, 1 H), 2.69-2.77 (m,
2H), 3.95 (m, 1 H), 7.28 (d, J=8.25 Hz, 2H), 7.35 (t, 1 H), 7.46 (t, 2H), 7.59 (d, J=8.25 Hz,
2H), 7.66 (d, J=7.15 Hz, 2H), 8.19 (d, J=8.25 Hz, 1 H).
Example 3-1 : Synthesis of (2R,4S)-5-biphenyl-4-yl-2-methyl-4-(2-thiophen-2-yl- acetylamino)-pentanoic acid
Figure imgf000072_0001
To a solution of thiophen-2-yl-acetic acid (0.144 mmol) in DMF (5 ml_) is added HATU (0.216 mmol). After stirring the mixture at room temperature for 10 minutes, (2R,4S)-4- amino-5-biphenyl-4-yl-2-methyl-pentanoic acid ethyl ester hydrochloride (0.144 mmol) and triethylamine (0.359 mmol) is added and the mixture is stirred at room temperature for 18 hours. The mixture is poured into ethyl acetate and the mixture is washed with aqueous 1 M HCI and brine. The organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure to give (2R,4S)-5-biphenyl-4-yl-2-methyl-4-(2-thiophen-2- yl-acetylamino)-pentanoic acid ethyl ester which is used directly in the subsequent hydrolysis reaction.
Next, to a solution of (2R,4S)-5-biphenyl-4-yl-2-methyl-4-(2-thiophen-2-yl-acetylamino)- pentanoic acid ethyl ester (0.287 mmol) in ethanol (10 ml_) is added aqueous 1 M NaOH (2 ml_, 6.97 mmol) and the mixture is stirred at room temperature for 18 hours. The mixture is poured into ethyl acetate and is washed with aqueous 1 M HCI, the organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC using a gradient of MeCN/water (0.1% TFA). The proper fractions are lyophilized to furnish (2R,4S)-5-biphenyl-4-yl-2-methyl-4-(2-thiophen-2-yl- acetylamino)-pentanoic acid. HPLC Retention time 1 .23 minutes (condition A); MS 408.3 (M+1 ); 1 H NMR (400 MHz, MeOD-d4) • ppm 1 .16 (d, J=7.07 Hz, 3H), 1 .50 (m, 1 H), 1 .96 (m, 1 H), 2.52 (m, 1 H), 2.72 (dd, J=7.71 Hz,7.58 Hz, 1 H), 2.84 (dd, J=5.81 Hz, 5.66 Hz, 1 H), 3.64 (d, J=1 .26 Hz, 2H), 4.20 (m, 1 H), 6.82 (m, 1 H), 6.89 (m, 1 H), 7.21 (m, 3H), 7.32 (m, 1 H), 7.42 (m, 2H), 7.46 (m, 2H), 7.57 (m, 2H), 7.95 (d, J=8.59 Hz, 1 H). Following compounds are prepared using similar procedure as example 3-1 with appropriate reagents and conditions:
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Example 3-2: 1 H NMR (400 MHz, Acetone-d6) • ppm 1 .28 (d, J=6.95 Hz, 3H), 1 .54-1 .70 (m, 2H), 2.09 (m, 1 H), 2.67 (m, 1 H), 2.81 (m, 1 H), 3.06 (m, 2H), 3.26 (m, 2H), 4.47 (M, 1 H), 7.25 (t, 1 H), 7.34 (t, 1 H), 7.36 (s, 1 H), 7.49 (d, J=8.08 Hz, 2H), 7.60 (t, 2H), 7.69 (t, 2H), 7.7 (d, J=8.08 Hz, 2H), 7.80 (d, J=7.83 Hz, 1 H), 7.88 (d, J=7.33 Hz, 2H).
Example 3-3: 1 H NMR (400 MHz, Acetone-d6) • ppm 1 .36 (d, J=6.95 Hz, 3H), 1 .79 (m, 1 H), 2.07-2.19 (m, 5H), 2.26-2.33 (m, 2H), 2.80 (m, 1 H), 2.98-3.06 (m, 2H), 3.1 1 (t, 1 H), 4.48 (M, 1 H), 7.53-7.57 (m, 3H), 7.67 (t, 2H), 7.80 (d, J=8.21 Hz, 2H), 7.87 (d, J=7.33 Hz, 2H). Example 3-4: 1 H NMR (400 MHz, MeOD-d4) • ppm 1 .19 (d, J=7.07 Hz, 3H), 1 .58 (m, 1 H), 2.01 (m, 1 H), 2.55 (m, 1 H), 2.71 (dd, J=8.84 Hz, 8.72 Hz, 1 H), 2.91 (dd, J=5.43 Hz, 5.32 Hz, 1 H), 3.72(d, J=5.81 Hz, 2H), 4.28 (m, 1 H), 7.24 (d, J=8.08 Hz, 2H), 7.33 (m, 1 H), 7.44
(t, J=7.83 Hz, 2H), 7.48 (d, J=8.08 Hz, 2H), 7.58 (d, J=7.96 Hz, 2H), 7.65 (d, J=6.32 Hz,
2H), 8.22 (d, J=9.09 Hz, 1 H), 8.53 (d, J=6.32 Hz, 2H).
Example 3-5: 1 H NMR (400 MHz, MeOD-d4) • ppm 1 .01 (d, J=7.07 Hz, 3H), 1 .32 (m, 1 H),
1 .84 (m, 1 H), 2.27 (m, 1 H), 2.50 (m, 2H), 2.66 (dd, J=7.33 Hz, 7.20 Hz, 1 H), 2.73(dd,
J=5.81 Hz, 5.61 Hz, 1 H), 2.99 (t, J=7.20 Hz, 2H), 4.13 (m, 1 H), 7.09 (d, J=8.21 Hz, 2H),
7.32 (m, 2H), 7.41 (m, 4H), 7.53 (m, 2H), 7.72 (d, J=1 .26 Hz, 1 H), 7.78 (d, J=8.34 Hz, 1 H).
Example 3-6: 1 H NMR (400 MHz, MeOD-d4) • ppm 1 .18 (d, J=7.07 Hz, 3H), 1 .50 (m, 1 H),
1 .80 (m, 1 H), 1 .97 (m, 1 H), 2.14 (m, 2H), 2.54 (m, 3H), 2.70 (m, 1 H), 2.79 (s, 3H), 2.87 (dd,
J=5.43 Hz, 1 H), 4.28 (m, 1 H), 7.21 (m, 2H), 7.29 (m, 4H), 7.41 (m, 2H), 7.46 (d, J=8.21 Hz,
2H), 7.57 (d, J=1 .01 Hz, 1 H), 7.67 (d, J=8.34 Hz, 1 H), 7.81 (d, J=9.22 Hz, 1 H).
Example 3-9: 1 H NMR (400 MHz, CDCI3) • ppm 1 .09 (d, J=6.95 Hz, 3H), 1 .45 (m, 1 H), 1 .81
(m, 1 H), 2.19-2.33 (m, 2H), 2.47 (m, 1 H), 2.69-2.80 (m, 2H), 2.99 (t, 2H), 3.82 (m, 2H), 4.08
(m, 1 H), 6.61 (d, J=8.97 Hz, 1 H), 7.26 (d, J=8.21 Hz, 2H), 7.35 (t, 1 H), 7.45 (t, 2H), 7.55 (d,
J=8.21 Hz, 2H), 7.62 d, J=7.45 Hz, 2H), 7.79 (d, J=7.58 Hz, 1 H).
Example 3-10: 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .06 (d, J=7.07 Hz, 3H), 1 .38 (m, 1 H),
1 .82 (m, 1 H), 2.41 (m, 1 H), 2.63-2.77 (m, 2H), 3.41 (s, 2H), 3.97 (m, 1 H), 6.88 (d, J=6.32
Hz, 2H), 7.05 (m, 1 H), 7.19 (d, J=8.21 Hz, 2H), 7.34 (t, 1 H), 7.45 (t, 2H), 7.51 (d, J=8.21 Hz,
2H), 7.62 (d, J=8.08 Hz, 2H), 7.99 (d, J=8.46 Hz, 1 H).
Example 3-1 1 : 1 H NMR (400 MHz, MeOD-d4) • ppm 1 .15 (d, J=7.07 Hz, 3H), 1 .51 (m, 1 H),
1 .95 (m, 1 H), 2.51 (m, 1 H), 2.74 (dd, J=7.83 Hz, 7.71 Hz, 1 H), 2.85 (dd, J=5.68 Hz, 5.81
Hz, 1 H), 3.38 (s, 2H), 3.56 (s, 3H), 4.22 (m, 1 H), 6.72 (s, 1 H), 7.23 (d, J=8.08 Hz, 2H), 7.31
(t, J=7.33 Hz, 1 H), 7.42 (t, J=7.83 Hz, 2H), 7.52 (t, J=8.08 Hz, 3H), 7.59 (d, J=7.33 Hz, 2H).
Example 3-12: 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .07 (d, J=7.07 Hz, 3H), 1 .22 (t, 3H),
1 .39 (m, 1 H), 1 .83 (m, 1 H), 2.43 (m, 1 H), 2.65-2.79 (m, 2H), 2.95 (q, 2H), 3.92 (s, 2H), 3.99
(m, 1 H), 7.22 (d, J=8.21 Hz, 2H), 7.34 (t, 1 H), 7.45 (t, 2H), 7.52 (d, J=8.21 Hz, 2H), 7.63 (d,
J=7.20 Hz, 2H), 8.26 (d, J=8.59 Hz, 1 H).
Example 3-13: 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .07 (d, J=7.07 Hz, 3H), 1 .60 (m, 1 H),
1 .88 (m, 1 H), 2.42 (m, 1 H), 2.84 (m, 2H), 4.23 (m, 1 H), 7.19 (d, J=3.66 Hz, 1 H), 7.28 (m,
3H), 7.33 (t, 1 H), 7.44 (t, 1 H), 7.57 (d, J=8.34 Hz, 2H), 7.63 (d, J=8.08, 2H), 8.43 (d, J=8.84
Hz, 1 H).
Example 3-14: 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .08 (d, J=7.07 Hz, 3H), 1 .57 (m, 1 H),
1 .88 (m, 1 H), 2.42 (m, 1 H), 2.84 (m, 2H), 4.18 (m, 1 H), 7.28 (d, J=8.21 Hz, 2H), 7.33 (t, 1 H), 7.44 (t, 1 H), 7.57 (d, J=8.21 Hz, 2H), 7.63 (d, J=8.08 Hz, 2H), 7.71 (d, J=3.92 Hz, 1 H), 7.76 (d, J=3.92 Hz, 1 H).
Example 3-15: 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .06 (d, J=7.07 Hz, 3H), 1 .35 (m, 1 H), 1 .66 (m, 2H), 1 .79 (m, 1 H), 2.00 (m, 2H), 2.39 (m, 3H), 2.69 (m, 2H), 3.69 (s, 3H), 4.01 (m, 1 H), 6.78 (d, J=8.59 Hz, 2H), 7.02 (d, J=8.46 Hz, 2H), 7.25 (d, J=8.08 Hz, 2H), 7.33 (t, 1 H), 7.43 (t, 1 H), 7.55 (d, J=8.08 Hz, 2H), 7.60 (d, J=7.83 Hz, 2H), 7.67 (d, J=8.59 Hz, 1 H). Example 3-16: 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .07 (d, J=7.07 Hz, 3H), 1 .52 (m, 1 H),
1 .86 (m, 1 H), 2.44 (m, 1 H), 2.80 (d,J=6.57 Hz, 2H), 4.18 (m, 1 H), 5.15 (q, 2H), 6.47 (d, J=9.47 Hz, 1 H), 7.23-7.38 (m, 8H), 7.44 (t, 2H), 7.53 (d, J=8.21 Hz, 2H), 7.61 (d, J=7.20 Hz, 2H), 7.87 (m, 1 H), 8.01 (d, J=8.46 Hz, 1 H).
Example 3-17: 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .08 (d, J=7.07 Hz, 3H), 1 .57 (m, 1 H),
1 .87 (m, 1 H), 2.45 (m, 1 H), 2.84 (m, 2H), 3.86 (s, 3H), 4.24 (m, 1 H), 7.18 (d, J=8.97 Hz, 1 H), 7.28 (d, J=8.21 Hz, 2H), 7.33 (t, 1 H), 7.43 (t, 2H), 7.56 (d, J=8.21 Hz, 2H), 7.63 (d, J=7.96 Hz, 2H), 7.96 (m, 1 H), 8.14 (m, 1 H), 8.26 (d, J=8.46 Hz, 1 H), 12.04 (s, broad, 1 H), 12.84 (s, broad, 1 H).
Example 3-18: 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .10 (d, J=7.07 Hz, 3H), 1 .51 (m, 1 H),
1 .88 (m, 1 H), 2.54 (m, 1 H), 2.84 (d, J=6.57 Hz, 2H), 3.90 (s, 3H), 4.24 (m, 1 H), 7.20 (d, J=8.72 Hz, 1 H), 7.32 (d, J=8.21 Hz, 2H), 7.34 (t, 1 H), 7.45 (t, 2H), 7.60 (d, J=8.21 Hz, 2H), 7.66 (d, J=7.20 Hz, 2H), 7.98-8.07 (m, 3H).
Example 3-19: 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .10 (d, J=7.07 Hz, 3H), 1 .64 (m, 1 H), 1 .97 (m, 1 H), 2.45 (m, 1 H), 2.92 (m, 2H), 4.34 (m, 1 H), 7.31 (d, J=8.08 Hz, 2H), 7.33 (t, 1 H), 7.43 (t, 2H), 7.56 (d, J=8.21 Hz, 2H), 7.63 (d, J=7.20 Hz, 2H), 8.18-8.26 (m, 3H), 9.02 (d, J=9.22 Hz, 1 H). Example 3-20: 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .09 (d, J=7.07 Hz, 3H), 1 .60 (m, 1 H),
1 .89 (m, 1 H), 2.45 (m, 1 H), 2.87 (d, J=6.82 Hz, 2H), 4.26 (m, 1 H), 7.29 (d, J=8.21 Hz, 2H), 7.33 (t, 1 H), 7.44 (t, 2H), 7.57 (d, J=8.34 Hz, 2H), 7.63 (d, J=7.83 Hz, 2H), 8.02 (m, 1 H), 8.06 (m, 1 H), 8.32 (m,1 H), 8.57 (d, J=8.46 Hz, 1 H).
Example 3-21 : 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .04 (t, 3H), 1 .34 (m, 1 H), 1 .77 (m, 1 H), 1 .88-2.01 (m, 4H), 2.37 (m, 1 H), 2.64-2.77 (m, 2H), 3.13 (m, 2H), 3.94 (m, 1 H), 7.23 (d, J=7.71 Hz, 2H), 7.34 (t, 1 H), 7.45 (t, 2H), 7.55 (m, 2H), 7.64 (m, 3H). Example 3-22: 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .06 (d, J=7.07 Hz, 3H), 1 .1 1 (m, 1 H), 1 .16 (m, 1 H), 1 .36 (m, 1 H), 1 .65 (m, 1 H), 1 .80 (m, 1 H), 2.04 (m, 1 H), 2.40 (m, 1 H), 2.72 (m, 2H), 3.95 (m, 1 H), 7.24 (d, J=8.21 Hz, 2H), 7.34 (t, 1 H), 7.45 (t, 2H), 7.57 (d, J=8.21 Hz, 2H), 7.65 (d, J=7.20 Hz, 2H), 8.15 (d, J=8.34 Hz, 1 H). Example 3-23: 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .06 (d, J=7.20 Hz, 3H), 1 .09 (m, 2H),
1 .37 (m, 1 H), 1 .73-1 .83 (m, 2H), 2.03 (m, 1 H), 2.41 (m, 1 H), 2.71 (d, J=6.57 Hz, 2H), 3.96 (m, 1 H), 7.24 (d, J=8.21 Hz, 2H), 7.35 (t, 1 H), 7.45 (t, 2H), 7.58 (d, J=8.21 Hz, 2H), 7.65 (d, J=7.20 Hz, 2H), 8.16 (d, J=8.34 Hz, 1 H).
Example 3-24: 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .09 (d, J=7.07 Hz, 3H), 1 .62 (m, 1 H),
1 .91 (m, 1 H), 2.45 (m, 1 H), 2.88 (d, J=6.57 Hz, 2H), 4.29 (m, 1 H), 7.31 (d, J=8.08 Hz, 2H),
7.34 (t, 1 H), 7.45 (t, 2H), 7.58 (d, J=8.08 Hz, 2H), 7.64 (d, J=7.58 Hz, 2H), 8.63 (s, 1 H), 8.67
(d, J=8.46 Hz, 1 H), 9.14 (dd, J=14.02 Hz, 2H).
Example 3-25: 1 H NMR (400 MHz, MeOD-d4) • ppm 1 .20 (d, J=7.07 Hz, 3H), 1 .75 (m, 1 H),
2.05 (m, 1 H), 2.61 (m, 1 H), 2.93 (m, 2H), 4.46 (m, 1 H), 7.31 (m, 3H), 7.40 (t, J=7.83 Hz,
2H), 7.54 (dd, J=8.21 Hz, 8.34 Hz, 2H), 8.60 (d, J=8.46 Hz, 1 H), 9.02 (m, 2H), 9.24 (m,
1 H).
Example 3-26: 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .09 (d, J=7.07 Hz, 3H), 1 .61 (m, 1 H),
1 .90 (m, 1 H), 2.45 (m, 1 H), 2.86 (d, J=6.69 Hz, 2H), 4.27 (m, 1 H), 7.29 (d, J=8.21 Hz, 2H), 7.33 (t, 1 H), 7.43 (t, 2H), 7.57 (d, J=8.21 Hz, 2H), 7.63 (d, J=7.20 Hz, 2H), (7.90 m, 1 H),
8.38 (s, 1 H), 8.74 (d, J=8.59 Hz, 1 H), 8.83 (d, J=4.42 Hz, 1 H).
Example 3-27: 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .08 (d, J=7.07 Hz, 3H), 1 .71 (m, 1 H),
1 .91 (m, 1 H), 2.43 (m, 1 H), 2.83-2.99 (m, 2H), 4.33 (m, 1 H), 7.29 (d, J=8.21 Hz, 2H), 7.33 (t, 1 H), 7.43 (t, 2H), 7.55 (d, J=8.21 Hz, 2H), 7.62 (d, J=7.20 Hz, 2H), 8.00 (m, 1 H), 8.35 (s,
1 H), 8.78 (d, J=9.35 Hz, 1 H), 8.86 (d, J=4.93 Hz, 1 H).
Example 3-28: 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .09 (d, J=7.07 Hz, 3H), 1 .60 (m, 1 H), 1 .89 (m, 1 H), 2.45 (m, 1 H), 2.86 (m, 2H), 4.25 (m, 1 H), 7.29 (d, J=8.21 Hz, 2H), 7.33 (t, 1 H), 7.43 (t, 2H), 7.56 (m, 4H), 7.64 (d, J=7.20 Hz, 2H), 7.99 (s, 1 H), 8.43 (d, J=8.46 Hz, 1 H). Example 3-29: 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .09 (d, J=7.07 Hz, 3H), 1 .59 (m, 1 H), 1 .89 (m, 1 H), 2.45 (m, 1 H), 2.85 (m, 2H), 4.26 (m, 1 H), 4.55 (s, 2H), 7.29 (d, J=8.21 Hz, 2H), 7.33 (t, 1 H), 7.45 (m, 3H), 7.56-7.64 (m, 7H), 8.03 (s, 1 H), 8.46 (d, J=8.59 Hz, 1 H). Example 3-30: 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .09 (d, J=7.07 Hz, 3H), 1 .59 (m, 1 H), 1 .88 (m, 1 H), 2.45 (m, 1 H), 2.85 (m, 2H), 4.25 (m, 1 H), 4.82 (s, 2H), 7.29 (d, J=8.21 Hz, 2H), 7.33 (t, 1 H), 7.43 (m, 3H), 7.51 (m, 1 H), 7.57 (d, J=8.08 Hz, 2H), 7.58 (s, 1 H), 7.63 (d, J=7.20 Hz, 2H), 8.01 (s, 1 H), 8.45 (d, J=8.46 Hz, 1 H).
Example 3-31 : 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .07 (d, J=7.07 Hz, 3H), 1 .60 (m, 1 H), 1.86 (m, 1 H), 2.41 (m, 1 H), 2.77-2.88 (m, 2H), 4.19 (m, 1 H), 6.82 (s, 1 H), 7.27 (d, J=7.96 Hz, 2H), 7.33 (t, 1 H), 7.44 (t, 2H), 7.57 (d, J=8.08 Hz, 2H), 7.65 (d, J=7.20, 2H), 8.12 (s, 1 H), 8.75 (d, J=8.72,1 H). Example 3-32: 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .07 (d, J=7.20 Hz, 3H), 1 .72 (m, 1 H), 1 .91 (m, 1 H), 2.42 (m, 1 H), 2.85 (dd, J=7.45 Hz, 6.19 Hz, 1 H), 2.96 (dd, J=7.96 Hz, 8.08 Hz, 1 H), 4.32 (m, 1 H), 7.30 (m, 3H), 7.43 (m, 2H), 7.54 (m, 2H), 7.62 (m, 2H), 8.33 (s, 1 H), 9.03 (d, J=9.22 Hz, 1 H), 9.51 (s, 1 H), 12.04 (s, 1 H), 14.16 (s, 1 H). Example 3-33: 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .06 (d, J=7.07 Hz, 3H), 1 .71 (m, 1 H),
1 .90 (m, 1 H), 2.42 (m, 1 H), 2.83 (dd, J=6.06 Hz, 6.06 Hz, 1 H), 2.94 (dd, J=7.83 Hz, 7.96 Hz, 1 H), 4.30 (m, 1 H), 7.29 (m, 3H), 7.43 (t, J=7.83 Hz, 2H), 7.54 (d, J=8.08 Hz, 2H), 7.61 (d, J=7.58 Hz, 2H), 7.94 (d, J=1 .26 Hz, 1 .26 Hz, 1 H), 8.91 (d, J=9.35 Hz, 1 H), 9.03 (d, J=5.05 Hz, 1 H), 9.34 (d, J=1 .14 Hz, 1 H), 12.03 (s, 1 H).
Example 3-34: 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .07 (d, J=7.07 Hz, 3H), 1 .69 (m, 1 H), 1 .89 (m, 1 H), 2.42 (m, 1 H), 2.81 -2.98 (m, 2H), 4.31 (m, 1 H), 7.28 (d, J=8.21 Hz, 2H), 7.32 (t, 1 H), 7.43 (t, 2H), 7.55 (d, J=8.34 Hz, 2H), 7.62 (d, J=7.83 Hz, 2H), 8.07 (d, J=7.45 Hz, 1 H), 8.42 (m, 1 H), 8.83 (d, J=9.22 Hz, 1 H), 9.10 (m, 1 H). Example 3-36: 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .10 (d, J=7.07 Hz, 3H), 1 .43 (m, 1 H),
1 .91 (m, 1 H), 2.47 (m, 1 H), 2.76-2.90 (m, 2H), 4.19 (m, 1 H), 7.30 (d, J=8.08 Hz, 2H), 7.35 (t, 1 H), 7.46 (t, 2H), 7.60 (d, J=8.21 Hz, 2H), 7.66 (d, J=7.20 Hz, 2H), 8.87 (d, J=8.49 Hz, 1 H). Example 3-37: 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .07 (d, J=7.07 Hz, 3H), 1 .55 (m, 1 H), 1 .85 (m, 1 H), 2.45 (m, 1 H), 2.76-2.89 (m, 2H), 4.21 (m, 1 H), 6.77 (d, J=8.72 Hz, 2H), 7.28 (d, J=8.21 Hz, 2H), 7.33 (t, 1 H), 7.43 (t, 2H), 7.56 (d, J=8.34 Hz, 2H), 7.65 (d, J=7.83 Hz, 2H), 7.68 (d, J=8.84 Hz, 2H), 7.99 (d, J=8.46 Hz, 1 H), 9.92 (s, broad, 1 H).
Example 3-38: 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .08 (d, J=7.07 Hz, 3H), 1 .56 (m, 1 H),
1 .87 (m, 1 H), 2.45 (m, 1 H), 2.79-2.88 (m, 2H), 4.23 (m, 1 H), 7.05 (d, J = 8.59 Hz, 1 H), 7.28
(d, J=8.21 Hz, 2H), 7.33 (t, 1 H), 7.43 (t, 2H), 7.56 (d, J=8.21 Hz, 2H), 7.63 (d, J=7.20 Hz,
2H), 7.92 (dd, 1 H), 7.99 (s, 1 H), 8.24 (d, J=8.46 Hz, 1 H).
Example 3-39: 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .10 (d, J=7.07 Hz, 3H), 1 .61 (m, 1 H),
1 .91 (m, 1 H), 2.48 (m, 1 H), 2.87 (d, J=6.82 Hz, 2H), 4.28 (m, 1 H), 7.30 (d, J=8.21 Hz, 2H),
7.33 (t, 1 H), 7.44 (t, 2H), 7.57 (d, J=8.21 Hz, 2H), 7.63 (d, J=7.20 Hz, 2H), 7.71 (t, 1 H), 7.89
(d, J=8.08 Hz, 1 H), 8.09 (s, 1 H), 8.1 1 (s, 1 H), 8.52 (d, J=8.46 Hz, 1 H).
Example 3-40: 1 H NMR (400 MHz, MeOD-d4) • ppm 1 .14 (d, J=7.07 Hz, 3H), 1 .54 (m, 7H),
1 .93 (m, 3H), 2.57 (m, 3H), 2.82 (d, J=7.83 Hz, 2H), 4.23 (m, 1 H), 7.30 (m, 3H), 7.41 (t,
J=7.83 Hz, 2H), 7.49 (m, 2H), 7.56 (m, 2H).
Example 3-41 : 1 H NMR (400 MHz, MeOD-d4) • ppm 1 .16 (d, J=7.07 Hz, 3H), 1 .53 (m, 7H),
1 .96 (m, 3H), 2.55 (m, 3H), 2.74 (dd, J=7.83 Hz, 7.71 Hz, 1 H), 2.84 (dd, J=6.95 Hz, 6.06 Hz, 1 H), 4.17 (m, 1 H), 7.30 (m, 3H), 7.42 (t, J=7.83 Hz, 2H), 7.51 (d, J=8.21 Hz, 2H), 7.56
(m, 2H).
Example 3-42: 1 H NMR (400 MHz, MeOD-d4) • ppm 1 .08 (d, J=7.07 Hz, 3H), 1 .15 (d,
J=7.07 Hz, 3H), 1 .19 (t, J=7.07, 1 H), 1 .47 (m, 1 H), 1 .92 (m, 1 H), 2.16 (dd, J=8.21 Hz, 8.21
Hz, 1 H), 2.52 (dd, J=6.19 Hz, 6.32 Hz, 1 H), 2.69 (dd, J=6.95 Hz, 7.83 Hz, 1 H), 2.81 (m, 2H),
4.16 (m, 1 H), 7.30 (m, 3H), 7.41 (m, 2H), 7.52 (m, 2H), 7.58 (m, 2H).
Example 3-43: 1 H NMR (400 MHz, MeOD-d4) • ppm 1 .09 (d, J=6.95 Hz, 3H), 1 .14 (d,
J=7.07 Hz, 3H), 1 .50 (m, 1 H), 1 .93 (m, 1 H), 2.15 (dd, J=7.96 Hz, 7.96 Hz, 1 H), 2.38 (dd,
J=6.44 Hz, 6.32 Hz, 1 H), 2.49 (m, 1 H), 2.69 (m, 1 H), 2.82 (m, 2H), 4.12 (m, 1 H), 7.30 (m,
3H), 7.41 (m, 2H), 7.51 (m, 2H), 7.58 (m, 2H).
Example 3-44: 1 H NMR (400 MHz, CHLOROFORM-d) • ppm 1 .19 (d, J=6.82 Hz, 3 H) 1 .62
(ddd, J=14.27, 1 1 .12, 3.16 Hz, 1 H) 2.05 (ddd, J=14.27, 1 1 .12, 3.16 Hz, 1 H) 2.51 - 2.63 (m,
1 H) 2.96 (dd, J=14.20, 5.90 Hz, 2 H) 4.49 - 4.61 (m, 1 H) 6.63 (dd, J=8.10, 4.50 Hz, 1 H)
6.88 (dd, J=8.20, 1 .80 Hz, 1 H) 7.28 (d, J=8.08 Hz, 2 H) 7.43 (t, J=7.58 Hz, 2 H) 7.56 (t,
J=8.10 Hz, 4 H) 7.75 (dt, J=8.53, 2.15 Hz, 1 H).
Example 3-45: 1 H NMR (400 MHz, CHLOROFORM-d) • ppm 1 .17 (d, J=6.82 Hz, 3 H) 1 .61
- 1 .79 (m, 1 H) 1 .88 - 2.04 (m, 1 H) 2.46 - 2.64 (m, 1 H) 2.80 - 2.96 (m, 2 H) 4.27 - 4.40 (m, 1 H) 6.53 - 6.60 (m, 1 H) 6.73 (br. s., 1 H) 7.19 - 7.38 (m, 6 H) 7.43 - 7.55 (m, 4 H). Example 3-46: 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .09 (d, J=7.07 Hz, 3H), 1 .60 (m, 1 H), 1 .91 (m, 1 H), 2.47 (m, 1 H), 2.87 (d, J=6.69 Hz, 2H), 4.28 (m, 1 H), 7.30 (d, J=8.08 Hz, 2H), 7.33 (t, 1 H), 7.43 (t, 2H), 7.57 (d, J=8.08 Hz, 2H), 7.63 (d, J=7.83 Hz, 2H), 7.75 (t, 1 H), 8.07 (d, J=8.08 Hz, 1 H), 8.13 (d, J=7.83 Hz, 1 H), 8.31 (s, 1 H), 8.56 (d, J=8.59 Hz, 1 H). Example 3-47: 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .0.8 (d, J=7.07 Hz, 3H), 1 .58 (m, 1 H), 1 .88 (m, 1 H), 2.43 (m, 1 H), 2.83 (m, 2H), 4.23 (m, 1 H), 7.28(d, J=8.34, 2H), 7.33 (t, 1 H), 7.43 (t, 2H), 7.56 (d, J=8.08 Hz, 2H), 7.63 (d, J=8.34 Hz, 2H), 8.05-8.45 (m, broad, 1 H). Example 3-48: 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .08 (d, J=7.07 Hz, 3H), 1 .58 (m, 1 H), 1 .86 (m, 1 H), 2.42 (m, 1 H), 2.79 (m, 1 H), 2.88 (m, 1 H), 4.23 (m, 1 H), 6.63 (s, 1 H), 7.28 (d, J=8.08 Hz, 2H), 7.33 (t, 1 H), 7.43 (t, 2H), 7.56 (d, J=8.34 Hz, 2H), 7.63 (d, J=8.08 Hz, 2H), 7.73 (s, 1 H), 8.01 (d, J=8.84 Hz, 1 H).
Example 3-49: 1 H NMR (400 MHz, MeOD) • ppm 1 .19 (d, J=7.3 Hz, 3 H), 1 .67 - 1 .77 (m, 1 H), 1 .98 - 2.09 (m, 1 H), 2.51 - 2.63 (m, 4 H), 2.85 - 2.99 (m, 2 H), 4.35 - 4.49 (m, 1 H), 7.26
- 7.34 (m, 3 H), 7.36 - 7.43 (m, 2 H), 7.49 - 7.54 (m, 2 H), 7.54 - 7.59 (m, 2 H), 8.94 (d, J=9.1 Hz, 1 H). Example 3-50: 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .07 (d, J=7.07 Hz, 3H), 1 .49 (m, 1 H),
1 .86 (m, 1 H), 2.45 (m, 1 H), 2.80 (m, 2H), 4.18 (m, 1 H), 7.27 (d, J=8.34 Hz, 2H), 7.33 (t,
1 H), 7.43 (t, 2H), 7.56 (d, J=8.34 Hz, 2H), 7.63 (d, J=8.08 Hz, 2H), 7.81 (d, J=8.59 Hz, 1 H), 8.00 (s, broad, 2H).
Example 3-51 : 1 H NMR (400 MHz, MeOD-d4): • ppm 1 .17-1 .19 (d, J=7.07 Hz, 3H), 1 .59 -
1 .66 (m, 1 H), 1 .96-2.03 (m, 1 H), 2.54-2.60 (m, 1 H), 2.86-2.95 (m, 2H), 4.32-4.37 (m, 1 H),
6.14-6.16 (m, 1 H), 6.79-6.81 (dd, J=1 .26 Hz, 1 .52 Hz, 1 H), 6.88-6.89 (m, 1 H), 7.25-7.32 (m,
3 H), 7.38-7.42 (m, 2H), 7.50-7.52 (m, 2H), 7.55-7.58 (m, 2H).
Example 3-52: 1 H NMR (400 MHz, MeOD-d4): • ppm 1 .17-1 .19 (d, J=7.07 Hz, 3H), 1 .61 -
1 .68 (m, 1 H), 1 .97-2.04 (m, 1 H), 2.51 -2.60 (m, 1 H), 2.91 -2.93 (d, J=6.82 Hz, 2H), 4.32-4.39
(m, 1 H), 6.68-6.69 (d, J=3.79 Hz, 1 H), 6.77-6.78 (d, J=3.79 Hz, 1 H), 7.27-7.32 (m, 3 H),
7.38-7.42 (m, 2H), 7.51 -7.53 (m, 2H), 7.57-7.59 (m, 2H).
Example 3-53: 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .07 (d, J=7.07 Hz, 3H), 1 .49 - 1 .56
(m, 1 H), 1 .83 - 1 .90 (m, 1 H), 2.41 - 2.51 (m, 1 H), 2.80 (A of AB, J = 14.5 Hz, 1 H), 2.81 (B of AB, J = 14.5 Hz, 1 H) 4.14 - 4.23 (m, 1 H), 7.27 (d, J = 8.3 Hz, 2H), 7.31 - 7.35 (m, 1 H)
7.42 - 7.46 (m, 2H), 7.57 (d, J=8.3 Hz, 2H), 7.63 - 7.65 (m, 2 H) 8.08 (d, J=8.59 Hz, 1 H)
8.65 (br s, 2 H) 12.04 (br s, 1 H).
Example 3-54: 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .08 (d, J=7.07 Hz, 3H), 1 .65 (m, 1 H),
1 .87 (m, 1 H), 2.41 (m, 1 H), 2.78-2.94 (m, 2H), 4.26 (m, 1 H), 7.28 (d, J=8.34 Hz, 2H), 7.33 (t, 1 H), 7.43 (t, 2H), 7.56 (d, J=8.34 Hz, 2H), 7.63 (d, J=7.07 Hz, 2H), 8.09 (s, broad, 0.35H), 8.33 (s, broad, 0.5H), 8.61 -8.81 (m, 2H), 12.04 (s, broad, 1 h), 14.42 (s, broad, 0.45 H), 14.88 (s, broad, 0.35 H).
Example 3-55: 1 H NMR (400 MHz, MeOD) • ppm 1 .19 (d, J=6.32 Hz, 3 H) 1 .63 - 1 .76 (m, 1
H) 1 .95 - 2.08 (m, 1 H) 2.50 - 2.65 (m, 1 H) 2.83 - 2.97 (m, 2 H) 4.31 - 4.46 (m, 1 H) 6.51 (d,
J=9.09 Hz, 1 H) 7.27 - 7.33 (m, 3 H) 7.40 (t, J=7.71 Hz, 2 H) 7.52 (d, J=7.58 Hz, 2 H) 7.57
(d, J=7.58 Hz, 2 H) 7.88 - 7.96 (m, 2 H).
Example 3-56: 1 H NMR (400 MHz, ACETONITRILE-d3) • ppm 1 .17 (d, J=6.95 Hz, 3 H)
1 .74 (ddd, J=14.24, 10.77, 3.66 Hz, 1 H) 2.13 - 2.23 (m, 1 H) 2.58 - 2.69 (m, 1 H) 2.97 -
3.02 (m, 2 H) 4.40 - 4.51 (m, 1 H) 7.22 (d, J=9.09 Hz, 1 H) 7.33 - 7.48 (m, 5 H) 7.56 - 7.64
(m, 4 H) 7.85 (br. s., 1 H).
Example 3-57: 1 H NMR (400 MHz, ACETONITRILE-d3) • ppm 1 .09 (d, J=7.07 Hz, 3 H)
1 .64 - 1 .69 (m, 2 H) 2.43 - 2.50 (m, 1 H) 2.86 - 2.93 (m, 2 H) 4.20 - 4.35 (m, 1 H) 6.88 (d,
J=1 .01 Hz, 1 H) 7.25 - 7.34 (m, 4 H) 7.38 - 7.44 (m, 2 H) 7.50 - 7.54 (m, 2 H) 7.56 - 7.61 (m,
2 H) 8.04 (d, J=1 .01 Hz, 1 H). Example 3-58: 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .08 (d, J=7.07 Hz, 3H), 1 .61 (m, 1 H),
1 .89 (m, 1 H), 2.44 (m, 1 H), 2.79-2.93 (m, 2H), 4.24 (m, 1 H), 7.27 (d, J=8.34 Hz, 2H), 7.30
(s, 2H), 7.33 (t, 1 H), 7.44 (t, 2H), 7.55 (d, J=8.08 Hz, 2H), 7.63 (d, J=7.33 Hz, 2H), 8.37 (d,
J=9.35 Hz, 1 H).
Example 3-59: 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .09 (d, J=7.07 Hz, 3H), 1 .56 (m, 1 H),
1 .92 (m, 1 H), 2.08 (s, 1 H), 2.45 (m, 1 H), 2.84 (d, J=6.82 Hz, 2H), 4.24 (m, 1 H), 7.29 (d,
J=8.34 Hz, 2H), 7.34 (t, 1 H), 7.44 (t, 2H), 7.56 (d, J=8.34 Hz, 2H), 7.63 (d, J=8.34 Hz, 2H),
8.01 (s, 1 H), 8.42 (d, J=8.59 Hz, 1 H), 8.79 (s, broad, 1 H).
Example 3-60: 1 H NMR (400 MHz, DMSO-d6): 1 H NMR (400 MHz, DMSO-d6): • ppm 1 .06-
1 .08 (d, J=7.07 Hz, 3H), 1 .58-1 .65 (m, 1 H), 1 .82-1 .89 (m, 1 H), 2.38-2.45 (m, 1 H), 2.77-2.82
(m, 1 H), 2.89-2.94 (m, 1 H), 4.21 -4.30 (m, 1 H), 7.26-7.28 (m, 2H), 7.30-7.35 (m, 1 H), 7.41 -
7.45 (m, 2H), 7.54-7.56 (m, 2H), 7.62-7.64 (m, 2H), 7.67 (s, 1 H), 7.89-7.91 (d, J=9.09 Hz,
1 H), 12.01 (s, 1 H).
Example 3-61 : 1 H NMR (400 MHz, DMSO-d6): • ppm 1 .06-1 .07 (d, J=7.07 Hz, 3H), 1 .45-
1 .52 (m, 1 H), 1 .79-1 .86 (m, 1 H), 2.41 -2.47 (m, 1 H), 2.73-2.86 (m, 2H), 4.12-4.21 (m, 1 H),
6.45-6.46 (q, J=2.53 Hz, 4.29 Hz, 1 H), 6.71 -6.73 (q, J=2.27 Hz, 4.45 Hz, 1 H), 7.27-7.34 (m,
4H), 7.41 -7.45 (m, 2H), 7.52-7.57 (m, 3H), 7.62-7.64 (m, 2H), 1 1 .09 (s, 1 H), 12.07 (s, 1 H).
Example 3-62: 1 H NMR (400 MHz, DMSO-d6) δ ppm 1 .07 (d, 3 H) 1 .62 (ddd, J=13.89, 9.85,
4.55 Hz, 1 H) 1 .86 (ddd, J=13.77, 9.47, 4.04 Hz, 1 H) 2.41 (ddd, J=9.35, 7.07, 4.55 Hz, 1 H)
2.73 - 2.96 (m, 2 H) 4.16 - 4.31 (m, 1 H) 7.27 (d, J=8.08 Hz, 2 H) 7.30 - 7.37 (m, 1 H) 7.44
(t, J=7.71 Hz, 2 H) 7.56 (d, J=8.34 Hz, 2 H) 7.60 - 7.69 (m, 2 H) 8.15 (d, J=9.09 Hz, 1 H)
8.51 (d, J=1 .01 Hz, 1 H) 8.54 (d, J=1 .01 Hz, 1 H).
Example 3-63: 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .08 (d, J=7.07 Hz, 3H), 1 .57 (m, 1 H),
1 .87 (m, 1 H), 2.43 (m, 1 H), 2.76-2.87 (m, 2H), 4.21 (m, 1 H), 7.27 (d, J=8.34 Hz, 2H), 7.33
(t, 1 H), 7.44 (t, 2H), 7.57 (d, J=8.34 Hz, 2H), 7.65 (d, J=7.07 Hz, 2H), 7.72 (s, 1 H), 8.45 (d,
J=8.59 Hz, 1 H), 8.54 (s, 1 H).
Example 3-64: 1 H NMR (400 MHz, DMSO-d6) δ ppm 1 .05 (d, J=7.33 Hz, 3 H) 1 .58 (ddd,
J=13.89, 9.73, 4.17 Hz, 1 H) 1 .84 (ddd, J=13.71 , 9.66, 3.92 Hz, 1 H) 2.29 - 2.47 (m, 1 H)
2.67 (dt, J=3.73, 1 .80 Hz, 0 H) 2.77 - 2.94 (m, 2 H) 4.19 (d, J=6.06 Hz, 1 H) 7.02 (d, J=1 .77
Hz, 1 H) 7.28 (d, J=8.08 Hz, 2 H) 7.30 - 7.37 (m, 1 H) 7.40 - 7.47 (m, 2 H) 7.57 (d, J=8.08
Hz, 2 H) 7.61 - 7.67 (m, 1 H) 8.71 (d, J=2.02 Hz, 1 H).
Example 3-65: 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .07 (d, J=7.07 Hz, 3H), 1 .58 (m, 1 H),
1 .87 (m, 1 H), 2.41 (m, 1 H), 2.77-2.87 (m, 2H), 4.17 (m, 1 H), 6.50 (s, 1 H), 7.27 (d, J=8.34 Hz, 2H), 7.33 (s, 2H), 7.33 (t, 1 H), 7.44 (t, 2H), 7.57 (d, J=8.34 Hz, 2H), 7.64 (d, J=8.08 Hz,
2H), 8.66 (d, J=8.84 Hz, 1 H), 1 1 .66 (s, broad, 1 H).
Example 3-66: 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .06 (d, J=7.07 Hz, 3 H) 1 .59 (ddd,
J=14.02, 9.98, 4.55 Hz, 1 H) 1 .84 (ddd, J=13.64, 9.60, 4.04 Hz, 1 H) 2.30 - 2.47 (m, 1 H)
2.67 - 2.82 (m, 1 H) 2.89 (dd, J=13.64, 7.58 Hz, 1 H) 3.89 (s, 3 H) 4.23 (dd, J=9.60, 7.07
Hz, 1 H) 6.55 (d, J=2.27 Hz, 1 H) 7.21 - 7.39 (m, 3 H) 7.37 - 7.48 (m, 2 H) 7.56 (d, J=8.34
Hz, 2 H) 7.60 - 7.68 (m, 2 H) 7.74 (d, J=2.27 Hz, 1 H) 7.92 (d, J=8.84 Hz, 1 H).
Example 3-67: 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .09 (d, J=7.07 Hz, 3H), 1 .57 (m, 1 H),
1 .87 (m, 1 H), 2.46 (m, 1 H), 2.81 (d, J=6.82 Hz, 2H), 4.00 (s, 3H), 4.20 (m, 1 H), 7.29 (d,
J=8.34 Hz, 2H), 7.30 (s, 1 H), 7.34 (t, 1 H), 7.44 (t, 2H), 7.58 (d, J=8.08 Hz, 2H), 7.64 (d,
J=7.07 Hz, 2H), 8.38 (d, J=8.59 Hz, 1 H).
Example 3-68: 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .07 (d, J=7.07 Hz, 3H), 1 .60 (m, 1 H),
1 .85 (m, 1 H), 2.41 (m, 1 H), 2.75-2.91 (m, 2H), 4.13 (s, 3H), 4.24 (m, 1 H), 7.10 (s, 1 H), 7.27
(d, J=8.08 Hz, 2H), 7.33 (t, 1 H), 7.44 (t, 2H), 7.56 (d, J=8.34 Hz, 2H), 7.64 (d, J=7.07 Hz,
2H), 8.14 (d, J=9.09 Hz, 1 H).
Example 3-69: 1 H NMR (400 MHz, DMSO-d6): • ppm 1 .08-1 .10 (d, J=7.07 Hz, 3H), 1 .53-
1 .60 (m, 1 H), 1 .83-1 .90 (m, 1 H), 2.43-2.47 (m, 1 H), 2.80-2.81 (d, J=7.07 Hz, 2H), 3.94 (s,
3H), 4.16-4.24 (m, 1 H), 6.59-6.60 (d, J=4.04 Hz, 1 H), 6.77-6.78 (d, J=4.04 Hz, 1 H), 7.28-
7.30 (d, J=8.08 Hz, 2H), 7.31 -7.35 (m, 1 H), 7.42-7.46 (m, 2H), 7.56-7.58 (d, J=8.34 Hz, 2H),
7.61 -7.64 (m, 4H), 8.12-8.14 (d, J=8.84 Hz, 1 H), 12.05 (s, 1 H), 12.52 (s, 1 H)
Example 3-70: 1 H NMR (400 MHz, DMSO-d6) δ ppm 1 .08 (d, 3 H) 1 .42 - 1 .61 (m, 1 H) 1 .86
(ddd, J=13.64, 9.47, 4.17 Hz, 1 H) 2.35 - 2.46 (m, 2 H) 2.75 - 2.86 (m, 2 H) 4.18 (d, J=9.09
Hz, 1 H) 5.95 (br. s., 1 H) 7.27 (d, J=8.34 Hz, 2 H) 7.30 - 7.37 (m, 1 H) 7.40 - 7.48 (m, 2 H)
7.56 (d, J=8.08 Hz, 2 H) 7.60 - 7.67 (m, 2 H) 7.97 (d, J=8.59 Hz, 1 H).
Example 3-71 : 1 H NMR (400 MHz, DMSO-d6) δ ppm 1 .07 (d, J=7.07 Hz, 3 H) 1 .56 - 1 .70
(m, 1 H) 1 .79 - 1 .92 (m, 1 H) 2.36 - 2.45 (m, 1 H) 2.74 - 2.96 (m, 2 H) 4.15 - 4.29 (m, 1 H)
6.90 - 6.97 (m, 1 H) 7.27 (d, J=8.34 Hz, 2 H) 7.30 - 7.37 (m, 1 H) 7.44 (s, 2 H) 7.56 (d,
J=8.34 Hz, 2 H) 7.63 (s, 2 H) 7.75 (d, J=9.85 Hz, 1 H) 8.24 - 8.34 (m, 1 H) 12.03 (br. s., 1
H).
Example 3-72: 1 H NMR (400 MHz, DMSO-d6): 1 H NMR (400 MHz, DMSO-d6): δ ppm 1 .06-
1 .08 (d, J=7.07 Hz, 3H), 1 .53-1 .60 (m, 1 H), 1 .83-1 .89 (m, 1 H), 2.41 -2.46 (m, 1 H), 2.78-2.88
(m, 2H), 4.20-4.27 (m, 1 H), 6.99-7.01 (d, J=8.84 Hz, 1 H), 7.27-7.29 (d, J=8.08 Hz, 2H),
7.30-7.34 (m, 1 H), 7.41 -7.46 (m, 2H), 7.54-7.56 (m, 2H), 7.61 -7.63 (m, 2H), 7.94-7.97 (dd, J=2.27 Hz, 1 H), 8.25-8.27 (d, J=8.34 Hz, 1 H), 8.31 -8.32 (d, J=2.27 Hz, 1 H), 1 1 .66 (s, 1 H),
12.02 (s, 1 H).
Example 3-73: 1 H NMR (400 MHz, MeOD-d4) • ppm 1 .19-1 .21 (d, J=7.33 Hz, 3H), 1 .73 -
1 .81 (m, 1 H), 2.04-2.13 (m, 1 H), 2.59-2.63 (m, 1 H), 2.98-3.00 (d, J=6.82 Hz, 2H), 4.49-4.53
(m, 1 H), 7.27-7.41 (m, 6 H), 7.49-7.51 (m, 2H), 7.55-7.57 (m, 2H), 8.18-8.19 (d, J=4.80 Hz,
1 H), 9.17-9.18 (d, J=4.80, 1 H).
Example 3-74: 1 H NMR (400 MHz, DMSO-d6): 1 H NMR (400 MHz, DMSO-d6): • ppm 1 .07-
1 .09 (d, J=7.07 Hz, 3H), 1 .65-1 .72 (m, 1 H), 1 .90-1 .97 (m, 1 H), 2.41 -2.47 (m, 1 H), 2.86-2.95
(m, 2H), 4.28-4.37 (m, 1 H), 7.29-7.34 (m, 3H), 7.41 -7.45 (t, J=7.83 Hz, 2H), 7.55-7.57 (m,
2H), 7.61 -7.64 (m, 2H), 8.07-8.08 (d, J=5.05 Hz, 1 H), 8.94-8.96 (d, J=9.09 Hz, 1 H), 9.18-
9.19 (d, J=5.05 Hz, 1 H), 12.06 (s, 1 H), 13.58 (s, 1 H).
Example 3-75: 1 H NMR (400 MHz, DMSO-d6) δ ppm 1 .07 (d, 4 H) 1 .51 - 1 .69 (m, 1 H) 1 .87
(ddd, J=13.83, 9.66, 4.04 Hz, 1 H) 2.43 (ddd, J=9.54, 7.14, 4.55 Hz, 2 H) 2.74 - 2.92 (m, 2
H) 4.12 - 4.29 (m, 1 H) 6.42 (dd, J=5.81 , 2.53 Hz, 1 H) 6.73 (d, J=2.78 Hz, 1 H) 7.27 (d,
J=8.34 Hz, 2 H) 7.30 - 7.39 (m, 1 H) 7.39 - 7.49 (m, 2 H) 7.58 (d, J=8.34 Hz, 2 H) 7.61 -
7.70 (m, 2 H) 8.22 (d, J=5.81 Hz, 1 H) 8.78 (d, J=8.84 Hz, 1 H) 12.07 (br. s., 1 H).
Example 3-76: 1 H NMR (600 MHz, DMSO-Cf6) δ ppm 1 .07 (d, J=7.06 Hz, 3 H) 1 .62 (s, 1 H)
1 .84 (s, 1 H) 2.74 - 2.81 (m, 1 H) 2.89 (s, 1 H) 4.20 (br. s., 1 H) 6.71 (d, J=7.43 Hz, 1 H)
6.91 (d, J=7.52 Hz, 1 H) 7.26 (d, J=8.16 Hz, 2 H) 7.30 - 7.36 (m, 1 H) 7.44 (s, 2 H) 7.57 (d,
J=7.98 Hz, 2 H) 7.64 (s, 2 H) 8.38 (s, 1 H) 10.77 (s, 1 H).
Example 3-77: 1 H NMR (400 MHz, DMSO-d6): δ ppm 1 .06-1 .07 (d, J=7.07 Hz, 3H), 1 .63-
1 .70 (m, 1 H), 1 .82-1 .89 (m, 1 H), 2.32-2.40 (m, 1 H), 2.77-2.82 (m, 1 H), 2.88-2.94 (m, 1 H),
4.16-4.25 (m, 1 H), 6.76 (s, 1 H), 7.25-7.27(d, J=8.08 Hz, 2H), 7.31 -7.35 (m, 1 H), 7.41 -7.45
(t, J = 7.83 Hz, 2H), 7.55-7.57 (d, J= 8.34 Hz, 2H), 7.62-7.65 (m, 2H), 8.10 (s, 1 H), 8.63-
8.65 (d, J=9.35 Hz, 1 H), 12.03 (s, 1 H), 12.34 (s, 1 H).
Example 3-78: 1 H NMR (400 MHz, DMSO-d6) δ ppm 1 .09 (d, J=7.07 Hz, 3 H) 1 .61 (ddd,
J=14.02, 10.1 1 , 4.42 Hz, 1 H) 1 .90 (ddd, J=13.71 , 9.66, 3.92 Hz, 1 H) 2.86 (d, J=6.32 Hz, 2
H) 4.23 - 4.32 (m, 2 H) 7.30 (d, J=8.34 Hz, 2 H) 7.32 - 7.36 (m, 1 H) 7.40 - 7.47 (m, 2 H)
7.57 (d, J=8.08 Hz, 2 H) 7.60 - 7.67 (m, 2 H) 7.96 (d, J=8.08 Hz, 1 H) 8.18 (dd, J=7.96, 1 .39
Hz, 1 H) 8.33 (s, 1 H) 8.64 (d, J=8.59 Hz, 1 H).
Example 3-79: 1 H NMR (400 MHz, MeOD-d4): δ ppm 1 .16-1 .18 (d, J=7.07 Hz, 3H), 1 .71 -
1 .78 (m, 1 H), 2.00-2.07 (m, 1 H), 2.52-2.59 (m, 1 H), 2.92-2.94 (m, 2H), 4.36-4.44 (m, 1 H),
7.27-7.32 (m, 3 H), 7.37-7.41 (m, 2H), 7.50-7.58 (m, 5H), 8.61 -8.63 (d, J=9.53, 1 H). Example 3-80: 1 H NMR (400 MHz, DMSO-d6): δ ppm 1 .05-1 .07 (d, J=7.07 Hz, 3H), 1 .51 - 1 .59 (m, 1 H), 1 .81 -1 .89 (m, 1 H), 2.38-2.45 (m, 1 H), 2.77-2.89 (m, 2H), 4.16-4.22 (m, 1 H), 4.53 (s, 2H), 5.77 (s, 1 H), 7.26-7.28 (m, 2H), 7.31 -7.35 (m, 1 H), 7.42-7.46 (m, 2H), 7.56- 7.58 (m, 2H), 7.63-7.66 (m, 3H).
Example 3-81 : 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .08 (d, J=7.07 Hz, 3H), 1 .57 (m, 1 H), 1 .88 (m, 1 H), 2.45 (m, 1 H), 2.79-2.89 (m, 2H), 4.23 (m, 1 H), 7.17 (d, J=8.59 Hz, 1 H), 7.28 (d, J=8.08 Hz, 2H), 7.33 (t, 1 H), 7.44 (t, 2H), 7.57 (d, J=8.34 Hz, 2H), 7.63 (d, J=7.33 Hz, 2H), 7.98 (dd, J=8.59 and 2.27, 1 H), 8.34 (d, J=8.59 Hz, 1 H), 8.38 (d, J=2.27 Hz, 1 H), 1 1 .57 (s, broad, 1 H).
Example 3-83: 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .08 (d, J=7.07 Hz, 3 H) 1 .34 - 1 .46 (m, 1 H) 1 .86 (ddd, J=13.64, 9.60, 4.04 Hz, 2 H) 1 .91 - 2.06 (m, 2 H) 2.26 - 2.36 (m, 1 H) 2.43 (td, J=4.74, 2.65 Hz, 1 H) 2.70 (dd, J=13.39, 7.33 Hz, 1 H) 2.75 - 2.85 (m, 1 H) 3.04 (d, J=10.36 Hz, 1 H) 3.82 (d, J=15.41 Hz, 1 H) 3.96 - 4.10 (m, 2 H) 4.23 (br. s., 1 H) 7.27 (d, J=8.34 Hz, 2 H) 7.35 (t, J=7.33 Hz, 1 H) 7.46 (t, J=7.58 Hz, 2 H) 7.58 (d, J=8.08 Hz, 2 H) 7.61 - 7.67 (m, 2 H) 8.36 (d, J=8.59 Hz, 1 H).
Example 3-84: 1 H NMR (400 MHz, DMSOd6) • ppm 1 .07 (d, J=7.1 Hz, 3 H), 1 .33 - 1 .44 (m, 1 H), 1 .78 - 1 .87 (m, 1 H), 2.39 - 2.47 (m, 1 H), 2.73 (d, J=7.3 Hz, 2 H), 3.84 (s, 2 H), 3.91 - 4.01 (m, 1 H), 7.23 (d, J=8.3 Hz, 2 H), 7.30 - 7.38 (m, 1 H), 7.45 (t, J=7.7 Hz, 2 H), 7.54 (d, J=8.1 Hz, 2 H), 7.64 (dd, J=8.2, 1 .1 Hz, 2 H), 8.24 (d, J=8.3 Hz, 1 H), 12.02 (br. s., 1 H). Example 3-85: 1 H NMR (400 MHz, DMSOd6) • ppm 1 .08 (d, J=7.1 Hz, 3 H), 1 .67 - 1 .80 (m, 1 H), 1 .86 - 1 .97 (m, 1 H), 2.37 - 2.47 (m, 1 H), 2.86 (dd, J=13.6, 6.1 Hz, 1 H), 2.97 (dd, J=13.6, 7.8 Hz, 1 H), 4.26 - 4.39 (m, 1 H), 7.26 - 7.36 (m, 3 H), 7.42 (t, J=7.6 Hz, 2 H), 7.54 (d, J=8.1 Hz, 2 H), 7.61 (d, J=7.3 Hz, 2 H), 8.26 (s, 1 H), 9.1 1 (d, J=9.3 Hz, 1 H), 9.60 (s, 1 H), 12.01 (br. s., 1 H).
Example 3-86: 1 H NMR (400 MHz, ACETONITRILE-Cf3) δ ppm 1 .04 (d, J=6.8 Hz, 3 H), 1 .56 (ddd, J=14.1 , 10.7, 3.7 Hz, 1 H), 2.38 - 2.54 (m, 1 H), 2.68 - 2.87 (m, 3 H), 4.18 - 4.35 (m, 1 H), 6.88 (d, J=8.8 Hz, 1 H), 7.23 (d, J=8.3 Hz, 2 H), 7.26 (dt, J=IA, 1 .6 Hz, 1 H), 7.30 - 7.39 (m, 2 H), 7.46 (d, J=8.1 Hz, 2 H), 7.49 - 7.55 (m, 2 H), 7.97 (d, J=2.3 Hz, 1 H), 8.08 (d, J=1 .5 Hz, 1 H).
Example 3-87: 1 H NMR (400 MHz, DMSO-Cf6) δ ppm 1 .07 (d, J=7.3 Hz, 3 H), 1 .44 (ddd, J=13.9, 9.9, 4.6 Hz, 1 H), 1 .85 (ddd, J=13.6, 9.4, 4.0 Hz, 1 H), 2.42 (ddd, J=9.3, 7.1 , 4.6 Hz, 1 H), 2.78 (d, J=6.6 Hz, 2 H), 4.02 - 4.19 (m, 1 H), 7.00 (t, J=2.2 Hz, 1 H), 7.26 (s, 1 H), 7.33 (t, J=I.3 Hz, 1 H), 7.44 (t, J=IJ Hz, 2 H), 7.50 - 7.61 (m, 3 H), 7.61 - 7.71 (m, 2 H), 10.1 1
(s, 1 H), 10.22 (br. s., 1 H), 12.03 (br. s., 1 H).
Example 3-89: 1 H NMR (400 MHz, DMSO-Cf6) δ ppm 1 .08 (d, J=I Λ Hz, 3 H), 1 .48 (ddd,
J=14.0, 10.0, 4.6 Hz, 1 H), 1 .87 (ddd, J=13.8, 9.6, 4.2 Hz, 1 H), 2.43 (ddd, J=9.4, 7.0, 4.6
Hz, 1 H), 2.72 - 2.87 (m, 2 H), 3.98 - 4.22 (m, 1 H), 7.27 (m, J=8.1 Hz, 2 H), 7.34 (t, J=7.3
Hz, 1 H), 7.39 - 7.50 (m, 2 H), 7.58 (m, J=8.3 Hz, 2 H), 7.61 - 7.71 (m, 3 H), 8.06 (d, J=8.6
Hz, 1 H), 1 1 .12 (s, 1 H), 12.04 (br. s., 1 H).
Example 3-90: 1 H NMR (400 MHz, CD3OD) δ ppm 1 .17 (d, J=7.3 Hz, 3 H), 1 .63 (ddd,
J=14.2, 10.3, 4.0 Hz, 1 H), 1 .98 (ddd, J=13.9, 9.9, 3.8 Hz, 1 H), 2.54 (ddd, J=9.7, 7.1 , 4.2 Hz,
1 H), 2.86 (d, J=6.8 Hz, 2H), 4.22-4.39 (m, 1 H), 7.23-7.34 (m, 3H), 7.34-7.44 (m, 3H), 7.47-
7.54 (m, 2H), 7.54-7.61 (m, 2H), 7.90 (d, J=8.6 Hz, 1 H).
Example 3-91 : 1 H NMR (400 MHz, CD3OD) δ ppm 1 .18 (d, J=7.1 Hz, 3H), 1 .68 (ddd,
J=14.2, 10.4, 4.2 Hz, 1 H), 1 .99 (ddd, J=14.0, 10.0, 3.8 Hz, 1 H), 2.46-2.61 (m, 1 H), 2.88 (dd,
2H), 4.28-4.42 (m, 1 H), 7.24-7.33 (m, 3H), 7.40 (t, J=7.7 Hz, 2H), 7.52 (d, J=8.3 Hz, 2H),
7.57 (dd, J=8.3, 1 .3 Hz, 2H).
Example 3-92: 1 H NMR (400 MHz, ACETONITRILE-Cf3) δ ppm 1 .06 (d, J=7.1 Hz, 3 H) 1 .55
(ddd, J=14.2, 10.5, 3.9 Hz, 1 H) 1 .86 - 1 .92 (m, 1 H) 2.57 (m, 1 H) 2.73 - 2.90 (m, 2 H) 4.21
- 4.37 (m, 1 H) 6.84 (dd, J=8.5, 5.4 Hz, 1 H) 6.91 (ddd, J=10.7, 8.5, 6.1 Hz, 1 H) 7.21 - 7.26
(m, 2 H) 7.31 - 7.38 (m, 2 H) 7.47 (d, J=8.1 Hz, 2 H) 7.52 (d, J=7.1 Hz, 2 H)
Example 3-93: 1 H NMR (400 MHz, CD3OD) δ ppm 1 .12 (d, J=7.1 Hz, 3 H) 1 .49 (ddd,
J=14.0, 10.0, 4.0 Hz, 1 H) 1 .99 (ddd, J=13.9, 10.2, 3.7 Hz, 1 H) 2.43 (ddd, J=10.6, 6.9, 4.0
Hz, 1 H) 2.86 (dd, J=13.6, 5.8 Hz, 1 H) 2.94 (dd, J=13.6, 5.8 Hz, 1 H) 4.24 - 4.50 (m, 1 H)
7.25 - 7.34 (m, 3 H) 7.35 - 7.41 (m, 2 H) 7.47 (d, J=8.3 Hz, 2 H) 7.52 - 7.57 (m, 2 H)
Example 3-94: 1 H NMR (400 MHz, DMSO-Cf6) δ ppm 1 .08 (d, J=7.3 Hz, 3 H) 1 .53 (ddd,
J=13.9, 9.9, 4.6 Hz, 1 H) 1 .87 (ddd, J=13.7, 9.3, 4.0 Hz, 1 H) 2.42 (ddd, J=9.2, 7.1 , 4.7 Hz,
1 H) 2.75 - 2.90 (m, 2 H) 4.13 - 4.23 (m, 1 H) 5.95 (s, 1 H) 7.27 (d, J=8.3 Hz, 2 H) 7.29 -
7.36 (m, 1 H) 7.38 - 7.47 (m, 2 H) 7.56 (d, J=8.3 Hz, 2 H) 7.61 - 7.69 (m, 2 H) 7.94 (d, J=8.6
Hz, 1 H).
Example 3-95: 1 H NMR (400 MHz, CD3OD) δ ppm 1 .18 (d, J=7.1 Hz, 3 H) 1 .64 - 1 .75 (m, 1
H) 2.00 (ddd, J=14.0, 10.0, 3.8 Hz, 1 H) 2.48 - 2.63 (m, 1 H) 2.86 - 2.91 (m, 2 H) 4.30 - 4.40
(m, 1 H) 7.25 - 7.33 (m, 4 H) 7.37 - 7.43 (m, 3 H) 7.52 (d, J=8.3 Hz, 2 H) 7.55 - 7.60 (m, 2
H) Example 3-96: 1 H NMR (400 MHz, DMSO-d6) δ ppm 1 .07 (d, J=I Λ Hz, 3 H) 1 .47 - 1 .61 (m, 1 H) 1 .75 - 1 .88 (m, 1 H) 2.31 - 2.45 (m, 1 H) 2.75 (dd, J=I 3 A, 7.6 Hz, 1 H) 2.83 (dd, J=13.4, 7.6 Hz, 1 H) 4.06 - 4.24 (m, 1 H) 7.26 (d, J=8.1 Hz, 2 H) 7.30 - 7.37 (m, 1 H) 7.44 (t, J=7.7 Hz, 2 H) 7.51 (d, J=2.5 Hz, 1 H) 7.57 (d, J=8.3 Hz, 2 H) 7.61 - 7.71 (m, 2 H) 8.09 (d, J=8.8 Hz, 1 H) 1 1 .24 (s, 1 H) 12.03 (br. s., 1 H).
Example 4-1 : Synthesis of (2R,4S)-5-biphenyl-4-yl-4-((2S,3S)-2,3-diacetoxy-3-carboxy- propionylamino)-2-methyl-pentanoic acid
Figure imgf000107_0001
A solution of (2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid benzyl ester hydrochloride (100 mg, 0.287 mmol) and acetic acid (3S,4S)-4-acetoxy-2,5-dioxo- tetrahydro-furan-3-yl ester (0.431 mmol) in 1 :1 methylene chloride/pyridine (1 .4 ml_) is stirred at room temperature for 24 hours. The solvents are removed under reduced pressure and obtained residue is used directly in the subsequent hydrolysis reaction. Next, a solution of the benzyl ester in ethyl acetate is hydrogenated at 1 atm over 10% Pd/C for 18 hours. Methanol is added and the catalyst is filtered through Celite. The Solvent is removed under reduced pressure and the residue is purified by preparative HPLC using a gradient of 10-100% MeCN/water (0.1 % TFA). The proper fractions are lyophilized to furnish (2R,4S)-5-biphenyl-4-yl-4-((2S,3S)-2,3-diacetoxy-3-carboxy-propionylamino)-2- methyl-pentanoic acid. HPLC Retention time 0.95 minutes (condition A); MS 500.3 (M+1 ); 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .09 (d, J=7.20 Hz, 3H), 1 .45 (m, 1 H), 1 .82 (m, 1 H), 2.39 (m, 1 H), 2.70 (d, J=6.82 Hz, 2H), 4.01 (m, 1 H), 5.38 (m, 2H), 7.19 (d, J=8.21 Hz, 2H), 7.34 (t, 1 H), 7.45 (t, 2H), 7.53 (d, J=8.21 Hz, 2H), 7.64 (d, J=7.20 Hz, 2H), 8.00 (d, J=8.72 Hz, 1 H).
Example 5-1 : Synthesis of 6-((1 S,3R)-1-biphenyl-4-ylmethyl-3-carboxy- butylcarbamoyl)-4-oxo-4H-pyran-2-carboxylic acid
Figure imgf000108_0001
To a solution of 4-oxo-4H-pyran-2,6-dicarboxylic acid (99 mg. 0.535 mmol) in DMF (10 ml_) is added HOBt (98 mg. 0.643 mmol) and EDCI (123 mg, 0.643 mmol) and the mixture is stirred at room temperature for 10 minutes. To this is then added (2R,4S)-4-amino-5- biphenyl-4-yl-2-methyl-pentanoic acid benzyl ester hydrochloride (200 mg, 0.535 mmol) and triethylamine (0.224 ml_, 1 .61 mmol) and the mixture is stirred at room temperature for 48 hours. Water is added and the mixture is extracted with ethyl acetate. The organic phase is washed with water and brine and is dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue is purified by preparative HPLC using a gradient of 10-100% MeCN/water (0.1 % TFA) to elute the product, 6-((1 S,3R)-3-benzyloxycarbonyl-1 - biphenyl-4-ylmethyl-butylcarbamoyl)-4-oxo-4H-pyran-2-carboxylic acid. MS 540.2 (M+1 ). Next, to a solution of 6-((1 S,3R)-3-benzyloxycarbonyl-1 -biphenyl-4-ylmethyl- butylcarbamoyl)-4-oxo-4H-pyran-2-carboxylic acid (100 mg, 0.185 mmol) in methylene chloride (5 ml_) is added BCI3 (65.1 mg, 0.556 mmol) and the mixture is stirred at room temperature for 10 minutes. The mixture is acidified to pH 2-3 with aqueous 1 M HCI and is extracted with ethyl acetate. The organic phase is washed with water and brine and is dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue is purified by preparative HPLC using a gradient of 10-100% MeCN/water (0.1 % TFA) to elute the product. The proper fractions are lyophilized to furnish 6-((1 S,3R)-1 -biphenyl-4-ylmethyl- 3-carboxy-butylcarbamoyl)-4-oxo-4H-pyran-2-carboxylic acid. MS 450.1 (M+1 ); 1H-NMR (400 Hz, DMSO-d6); • ppm 1 .07 (d, J=7.07 Hz, 3H), 1 .59 (m, 1 H), 1 .88 (m, 1 H), 2.45 (m, 1 H), 2.84 (d, J=6.69 Hz, 2H), 4.19 (m, 1 H), 6.84 (s, 1 H), 6.93 (s, 1 H), 7.32 (dd, J=8.08 Hz, 6.57 Hz, 3H), 7.45 (t, J=7.83 Hz, 2H), 7.58 (d, J=8.21 Hz, 2H), 7.64 (d, J=7.33 Hz, 2H), 8.61 (d, J=8.72 Hz, 1 H).
Example 6-1 : Synthesis of (S)-1-((1 S,3R)-1-biphenyl-4-ylmethyl-3-carboxy- butylcarbamoyl)-pyrrolidine-2-carboxylic acid
Figure imgf000109_0001
To a vigorously stirred 1 :1 mixture of methylene chloride/8 % aqueous NaHCO3 (30 ml_) at O 0C is added triphosgene (1 14 mg , 0.384 mmol). After stirring the mixture at O 0C for 5 minutes, (2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid ethyl ester hydrochloride (400 mg, 1 .15 mmol) is added and stirring is continued for 15 minutes. The organic phase is separated and dried over sodium sulfate. The solvent is removed under reduced pressure to furnish (2R,4S)-5-biphenyl-4-yl-4-isocyanato-2-methyl-pentanoic acid ethyl ester. Next, to a solution of (2R,4S)-5-biphenyl-4-yl-4-isocyanato-2-methyl-pentanoic acid ethyl ester (1.15 mmol) in methylene chloride (10 ml_) is added (S)-pyrrolidine-2-carboxylic acid methyl ester (1.15 mmol) and diisopropylethylamine (2.3 mmol). The mixture is stirred at room temperature for 18 hours. The mixture is washed with aqueous 1 M HCI and the organic phase is dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is purified by column chromatography using hexane/methylene chloride to elute the product.
Next, to a solution of the obtained residue (0.287 mmol) in ethanol (10 ml_) is added aqueous 1 M NaOH (2 ml_, 6.97 mmol) and the mixture is stirred at room temperature for 18 hours. The mixture is poured into ethyl acetate and is washed with aqueous 1 M HCI, the organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC using a gradient of MeCN/water (0.1 % TFA). The proper fractions are lyophilized to furnish (S)-1 -((1 S,3R)-1 -biphenyl-4- ylmethyl-3-carboxy-butylcarbamoyl)-pyrrolidine-2-carboxylic acid. HPLC Retention time 0.97 minutes (condition A); MS 425.3 (M+1 ); 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .03 (d, J=7.07 Hz, 3H), 1 .43 (m, 1 H), 1 .71 (m, 1 H), 1 .86 (m, 3H), 2.09 (m, 1 H), 2.45 (m, 1 H), 2.66- 2.83 (m, 2H), 3.84 (m,1 H), 6.00 (d, J=8.21 Hz, 1 H), 7.27 (d, J=8.08 Hz, 2H), 7.34 (t, 1 H), 7.45 (t, 2H), 7.57 (d, J=8.21 Hz, 2H), 7.65 (d, J=7.20, 2H). Following compounds are prepared using similar procedure as example 6-1 with appropriate reagents and conditions:
Figure imgf000109_0002
Figure imgf000110_0001
Figure imgf000111_0001
Example 6-2: 1 H NMR (400 MHz, DMS0-d6) • ppm 1 .02 (d, J=6.95 Hz, 3H), 1 .43 (m, 1 H),
1 .70 (m, 1 H), 2.45 (m, 1 H), 2.66 (m, 1 H), 2.78 (m, 2H), 2.79 (s, 2H), 3.81 (m, 3H), 7.26 (d, J=8.08 Hz, 2H), 7.34 (t, 1 H), 7.45 (t, 2H), 7.56 (d, J=8.21 Hz, 2H), 7.65 (d, J=7.20 Hz, 2H). Example 6-3: 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .06 (d, J=7.07 Hz, 3H), 1 .20 (d, J=7.20, 3H), 1 .27 (m, 1 H), 1 .76 (m, 1 H), 2.45 (m, 1 H), 2.71 (m, 2H), 3.77 (m,1 H), 4.06 (m,
1 H), 5.99 (d, J=8.46 Hz, 1 H), 6.07 (d, J=7.83 Hz, 1 H), 7.25 (d, J=8.21 Hz, 2H), 7.34 (t, 1 H),
7.45 (t, 2H), 7.57 (d, J=8.21 Hz, 2H), 7.65 (d, J=7.20, 2H).
Example 6-4: 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .05 (d, J=7.07 Hz, 3H), 1 .22 (m, 1 H),
1 .39-1 .58 (m, 3H), 1 .74 (m, 1 H), 1 .89 (m, 1 H), 2.18 (m, 1 H), 2.43 (m, 1 H), 2.62-2.77 (m,
4H), 3.79 (t, 1 H), 3.89 (m, 1 H), 4.01 (m, 1 H), 6.28 (d, J=8.34 Hz, 1 H), 7.25 (d, J=7.83 Hz,
2H), 7.34 (t, 1 H), 7.44 (t, 2H), 7.56 (d, J=8.34 Hz, 2H), 7.64 (d, J=7.20 Hz, 2H).
Example 6-5: 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .03 (d, J=7.07 Hz, 3H), 1 .36 (m, 1 H),
1 .71 (m, 1 H), 2.41 (m, 1 H), 2.63-2.78 (m, 2H), 3.83 (m,1 H), 3.96 (m, 4H), 6.33 (d, J=7.96 Hz, 1 H), 7.25 (d, J=8.21 Hz, 2H), 7.34 (t, 1 H), 7.45 (t, 2H), 7.55 (d, J=8.21 Hz, 2H), 7.65 (d, J=7.20, 2H).
Example 6-6: 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .04 (d, J=7.07 Hz, 3H), 1 .44 (m, 1 H), 1 .73 (m, 1 H), 1 .91 -2.08 (m, 2H), 2.45 (m, 1 H), 2.64-2.81 (m, 2H), 3.03 (m,1 H), 3.20 (m, 1 H), 3.26-3.46 (m,3H), 3.84 (m, 1 H), 5.94 (d, J=8.46 Hz, 1 H), 7.25 (d, J=8.21 Hz, 2H), 7.34 (t,
1 H), 7.45 (t, 2H), 7.57 (d, J=7.96 Hz, 2H), 7.65 (d, J=7.20, 2H).
Example 6-7: 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .04 (d, J=6.95 Hz, 3H), 1 .44 (m, 1 H),
1 .73 (m, 1 H), 1 .91 -2.08 (m, 2H), 2.45 (m, 1 H), 2.64-2.81 (m, 2H), 3.02 (m,1 H), 3.20 (m, 1 H),
3.26-3.44 (m, 4H), 3.84 (m, 1 H), 5.94 (d, J=8.46 Hz, 1 H), 7.25 (d, J=8.08 Hz, 2H), 7.34 (t,
1 H), 7.45 (t, 2H), 7.57 (d, J=8.21 Hz, 2H), 7.65 (d, J=7.20, 2H).
Example 6-8: 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .04 (d, J=7.07 Hz, 3H), 1 .45 (m, 1 H),
1 .73 (m, 1 H), 1 .91 -2.06 (m, 2H), 2.45 (m, 1 H), 2.64-2.81 (m, 2H), 3.02 (m,1 H), 3.20 (m, 1 H),
3.27-3.46 (m, 4H), 3.84 (m, 1 H), 5.94 (d, J=8.46 Hz, 1 H), 7.25 (d, J=8.21 Hz, 2H), 7.34 (t,
1 H), 7.45 (t, 2H), 7.57 (d, J=8.21 Hz, 2H), 7.65 (d, J=7.20, 2H).
Example 7-1 : Synthesis of (2R,4S)-5-biphenyl-4-yl-4-(3-carboxymethyl-ureido)-2- methyl-pentanoic acid
Figure imgf000112_0001
To a mixture of (2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid ethyl ester hydrochloride (50 mg, 0.161 mmol) and Isocyanato-acetic acid ethyl ester (0.161 mmol) in DMF (8 ml_) is added pyridine (0.161 mmol) and the mixture is stirred at room temperature for 18 hours. Water is added and the mixture is extracted with ethyl acetate (3x). The combined organic layers are washed with water and brine then is dried over magnesium sulfate. The solvent is removed under reduced pressure to afford the ester product. This is used in the subsequent hydrolysis reaction.
Next, to a solution of the obtained residue (0.287 mmol) in ethanol (10 ml_) is added aqueous 1 M NaOH (2 ml_, 6.97 mmol) and the mixture is stirred at room temperature for 18 hours. The mixture is poured into ethyl acetate and is washed with aqueous 1 M HCI, the organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC using a gradient of MeCN/water (0.1 % TFA). The proper fractions are lyophilized to furnish (S)-1 -((1 S,3R)-1 -biphenyl-4- ylmethyl-3-carboxy-butylcarbamoyl)-pyrrolidine-2-carboxylic acid. HPLC Retention time 0.91 minutes (condition A); MS 385.4 (M+1 ); 1 H NMR (400 MHz, MeOD-d4) • ppm 1 .15 (d, J=7.20 Hz, 3H), 1 .40 (m, 1 H), 1 .91 (m, 1 H), 2.60 (m, 1 H), 2.81 (d, J=6.32 Hz, 2H), 3.85 (d, J=1 .89Hz, 2H), 4.00 (m, 1 H), 7.32 (m, 3H), 7.42 (m, 2H), 7.53 (m, 2H), 7.59 (m, 2H). Following compounds are prepared using similar procedure as example 7-1 with appropriate reagents and conditions:
Figure imgf000113_0002
Example 7-2: 1 H NMR (400 MHz, MeOD-d4) • ppm 1 .14 (d, J=7.07 Hz, 3H), 1 .40 (m, 1 H), 1 .88 (m, 1 H), 2.39 (t, J=6.44 Hz, 2H), 2.55 (m, 1 H), 2.79 (m, 2H), 3.34 (m, 2H), 3.96 (m, 1 H), 7.28 (m, 3H), 7.41 (m, 2H), 7.51 (m, 2H), 7.58 (m, 2H).
Example 8-1 : Synthesis of (2R,4S)-5-biphenyl-4-yl-4-[3-((R)-1-carboxy-ethyl)-ureido]-2- methyl-pentanoic acid
Figure imgf000113_0001
To a vigorously stirred 1 :1 mixture of methylene chloride/8 % aqueous NaHCO3 (30 ml_) at 0 0C is added triphosgene. After stirring the mixture at 0 0C for 5 minutes, (2R,4S)-4-amino-5- biphenyl-4-yl-2-methyl-pentanoic acid ethyl ester hydrochloride (400 mg, 1 .15 mmol) is added and stirring is continued for 15 minutes. The organic phase is separated and dried over sodium sulfate. The solvent is removed under reduced pressure to furnish (2R,4S)-5- biphenyl-4-yl-4-isocyanato-2-methyl-pentanoic acid ethyl ester.
Next, to a solution of (2R,4S)-5-biphenyl-4-yl-4-isocyanato-2-methyl-pentanoic acid ethyl ester (1.15 mmol) in methylene chloride (10 ml_) is added (R)-2-amino-propionic acid benzyl ester (1.15 mmol) and diisopropylethylamine (2.3 mmol). The mixture is stirred at room temperature for 18 hours. The mixture is washed with aqueous 1 M HCI and the organic phase is dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is purified by column chromatography using hexane/methylene chloride to elute the product.
Next, a solution of the benzyl ester in ethyl acetate is hydrogenated at 1 atm over 10% Pd/C for 18 hours. Methanol is added and the catalyst is filtered through Celite. The Solvent is removed under reduced pressure and the residue is purified by preparative HPLC using a gradient of 10-100% MeCN/water (0.1 % TFA). The proper fractions are lyophilized to furnish (2R,4S)-5-biphenyl-4-yl-4-[3-((R)-1 -carboxy-ethyl)-ureido]-2-methyl-pentanoic acid. HPLC Retention time 0.94 minutes (condition A); MS 399.3 (M+1 ); 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .03 (d, J=7.20 Hz, 3H), 1 .23 (d, J=7.20, 3H), 1 .26 (m, 1 H), 1 .74 (m, 1 H), 2.43 (m, 1 H), 2.71 (d, J=6.19 Hz, 2H), 3.78 (m,1 H), 4.08 (m, 1 H), 5.98 (d, J=8.34 Hz, 1 H), 6.07 (d, broad, J=6.44 Hz, 1 H), 7.26 (d, J=8.21 Hz, 2H), 7.34 (t, 1 H), 7.45 (t, 2H), 7.57 (d, J=8.21 Hz, 2H), 7.65 (d, J=7.20, 2H).
Example 9-1 : Synthesis of 1-((1 S,3R)-1-biphenyl-4-ylmethyl-3-carboxy- butylcarbamoyl)-1 H-pyrazole-3-carboxylic acid
Figure imgf000114_0001
To a vigorously stirred 1 :1 mixture of methylene chloride/8% aqueous NaHCO3 (6 mL) at 0 0C is added triphosgene (18 mg, 0.061 mmol). After stirring the mixture at 0 0C for 5 minutes, (2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid benzyl ester hydrochloride (75 mg, 0.183 mmol) is added and stirring is continued for 15 minutes. The organic phase is separated and dried over sodium sulfate. The solvent is removed under reduced pressure to furnish (2R,4S)-5-biphenyl-4-yl-4-isocyanato-2-methyl-pentanoic acid benzyl ester.
Next, to a solution of 1 H-pyrazole-3-carboxylic acid (20.5 mg, 0.183 mmol) in DMF (1 mL) is added diisopropylethylamine (0.032 mL, 0.183 mmol). After 15 min a solution of the above (2R,4S)-5-biphenyl-4-yl-4-isocyanato-2-methyl-pentanoic acid benzyl ester in DMF (1 mL) is added dropwise and the mixture is stirred at room temperature for 18 hours. The mixture is purified by preparative HPLC using a gradient of 10% MeCN to 100% MeCN (0.1 % TFA). Lyophilization of the appropriate fractions furnishes 1 -((1 S,3R)-3-benzyloxycarbonyl-1 - biphenyl-4-ylmethyl-butylcarbamoyl)-1 H-pyrazole-3-carboxylic acid. Next, a solution of 1 -((1 S,3R)-3-benzyloxycarbonyl-1 -biphenyl-4-ylmethyl-butylcarbamoyl)- 1 H-pyrazole-3-carboxylic acid (60 mg, 0.1 17 mmol) in EtOAc (10 ml_) is hydrogenated over 10% Pd/C (40 mg) at 1 atm for 5 hours. The catalyst is filtered through Celite and the filtrate evaporated under reduced pressure. The residue is purified by preparative HPLC using a gradient of 10% MeCN to 100% MeCN (0.1 % TFA). Lyophilization of the appropriate fractions furnishes 1 -((1 S,3R)-1 -biphenyW-ylmethyl-S-carboxy-butylcarbamoyO-i H- pyrazole-3-carboxylic acid. HPLC Retention time 0.96 minutes (condition A); MS 422.0 (M+1 ); 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .09 (d, J=7.07 Hz, 3H), 1 .78 (m, 1 H), 1 .88 (m, 1 H), 2.45 (m, 1 H), 2.86 (m, 1 H), 2.98 (m, 1 H), 4.14 (m, 1 H), 6.84 (d, J=2.65 Hz, 1 H), 7.28 (d, J=8.34 Hz, 2H), 7.33 (t, 1 H), 7.43 (t, 2H), 7.56 (d, J=8.34 Hz, 2H), 7.63 (d, J=7.07 Hz, 2H), 8.29 (d, J=2.78 Hz, 1 H), 8.58 (d, J=9.09 Hz, 1 H). Following compounds are prepared using similar procedure as example 9-1 with appropriate reagents and conditions:
Figure imgf000115_0001
Example 9-2: 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .08 (d, J=7.07 Hz, 3H), 1 .73 (m, 1 H), 1 .89 (m, 1 H), 2.44 (m, 1 H), 2.84 (m, 1 H), 2.96 (m, 1 H), 4.1 1 (m, 1 H), 7.28 (d, J=8.34 Hz, 2H), 7.33 (t, 1 H), 7.43 (t, 2H), 7.56 (d, J=8.08 Hz, 2H), 7.63 (d, J=7.07 Hz, 2H), 8.10 (s, 1 H), 8.52 (s, 1 H), 8.68 (d, J=9.09 Hz, 1 H).
Example 10-1 : (2R,4S)-5-biphenyl-4-yl-4-[(5-carbamoyl-thiophene-2-carbonyl)-amino]- 2-methyl-pentanoic acid
Figure imgf000116_0001
To a solution of 5-((1 S,3R)-1 -biphenyl-4-ylmethyl-3-ethoxycarbonyl-butylcarbamoyl)- thiophene-2-carboxylic acid (1 15 mg, 0.247 mmol) in THF (1 ml_) at 0 0C is added diisopropylethylamine (63.8 mg, 0.494 mmol) followed by dropwise addition of a solution of isobutyl chloroformate (33.7 mg, 0.247 mmol) in THF (0.1 ml_). The mixture is stirred at 0 0C for 30 minutes then ammonium hydroxide (0.3 ml_ of 14.8 M solution) is added. The mixture is allowed to warm to room temperature then aqueous 1 M HCI (3 ml_) is added. Most of the THF is removed under reduced pressure and the mixture is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is removed under reduced pressure to give (2R,4S)-5-biphenyl-4-yl-4-[(5-carbamoyl-thiophene-2-carbonyl)-amino]-2- methyl-pentanoic acid ethyl ester. MS 465.3 (M+1 ).
Next, to a solution of (2R,4S)-5-biphenyl-4-yl-4-[(5-carbamoyl-thiophene-2-carbonyl)-amino]- 2-methyl-pentanoic acid ethyl ester (1 15 mg, 0.248 mmol) in ethanol (8 ml_) is added aqueous 1 M NaOH (0.866 ml_, 0.866 mmol) and the mixture is stirred at 50 0C for 3.5 hours. The ethanol is removed under reduced pressure and water is added to the residue. The resulting solution is acidified with aqueous 1 M HCI and the resulting precipitate is filtered and washed with water. The solid is purified by preparative HPLC using 50% MeCN/water to elute the product. The appropriate fractions are lyophilized to give (2R,4S)-5-biphenyl-4- yl-4-[(5-carbamoyl-thiophene-2-carbonyl)-amino]-2-methyl-pentanoic acid. MS 437.2 (M+1 ); 1H-NMR (400 MHz, DMSO-d6); δ ppm 1 .09 (d, J=7.20 Hz, 3H), 1 .57 (m, 1 H), 1 .88 (m, 1 H), 2.46 (m, 1 H), 2.84 (m, 2H), 4.18 (m, 1 H), 7.28 (d, J=8.21 Hz, 1 H), 7.33 (t, 1 H), 7.44 (t, 1 H), 7.57 (d, J=8.21 Hz, 2H), 7.64 (d, J=7.33, 2H), 7.69 (m, 2H), 8.06 (s, 1 H), 8.38 (d, J=8.59 Hz, 1 H), 12.07 (s, broad, 1 H).
Example 11-1 : Synthesis of (2R,4S)-5-biphenyl-4-yl-2-methyl-4-(3-1 H-tetrazol-5-yl- propionylamino)-pentanoic acid
Figure imgf000117_0001
To a solution of (2R,4S)-5-Biphenyl-4-yl-4-{3-[1 -(2-cyano-ethyl)-1 H-tetrazol-5-yl]- propionylamino}-2-methyl-pentanoic acid ethyl ester (32 mg, 0.065 mmol) in dichloromethane (1 ml_) is added DBU (24 mg, 0.164 mmol). After stirring for 3 hours, additional DBU (24mg, 0.146mmol) is added. After stirring for 2 hours, the reaction mixture is diluted with dichloromethane and washed with saturated aqueous NH4CI . The organic layer is dried over Na2SO4 and concentrated. The residue is dissolved in MeOH and treated with aqueous 2M NaOH. After stirring for 1 hours, the reaction mixture is diluted with ethyl acetate and acidified with aqueous 1 M HCI. The mixture is extracted with ethyl acetate and washed with brine. The organic layer is dried over Na2SO4 and concentrated. The residue is purified by reverse phase HPLC (0.1 %TFA-H2O / MeCN) to give (2R,4S)-5-biphenyl-4-yl-2- methyl-4-(3-1 H-tetrazol-5-yl-propionylamino)-pentanoic acid (14mg). HPLC Retention time 1 .17 minutes (condition C); MS 408.0 (M+1 ); 1 H NMR (400 MHz, DMSO-d6) δ ppm 1 .03 (d, J=7.07Hz, 3H), 1 .34 (ddd, J=4.80, 10.1 1 , 14.91 Hz, 1 H), 1 .78 (ddd, J=4.04, 9.60, 13.64Hz, 1 H), 2.31 -2.42 (m, 1 H), 2.52-2.59 (m, 2H), 2.68 (d, J=7.07Hz, 2H), 3.03 (dd, J=7.58, 7.58Hz, 2H), 3.90-4.01 (m, 1 H), 7.20 (d, J=8.08Hz, 2H), 7.34 (t, J=9.09Hz, 1 H), 7.45 (d, J=7.83Hz, 2H), 7.55 (d, J=8.34Hz, 2H), 7.64 (d, J=7.33Hz, 2H), 7.84 (d, J=8.34Hz, 1 H), 1 1 .99 (bs, 1 H).
Example 12-1 : Synthesis of (2S,4S)-5-biphenyl-4-yl-4-((S)-3-carboxy-3-cyclohexyl- propionylamino)-2-methyl-pentanoic acid
Figure imgf000117_0002
To a solution of (S)-2-cyclohexyl-succinic acid 1 -methyl ester (0.144 mmol) in DMF (5 mL) is added HATU (0.216 mmol). After stirring the mixture at room temperature for 10 minutes, (2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid ethyl ester hydrochloride (0.144 mmol) and triethylamine (0.359 mmol) is added and the mixture is stirred at room temperature for 18 hours. The mixture is poured into ethyl acetate and the mixture is washed with aqueous 1 M HCI and brine. The organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure to give the ester product which is used directly in the subsequent hydrolysis reaction.
Next, to a solution of the obtained ester product (0.287 mmol) in ethanol (10 ml_) is added aqueous 1 M NaOH (2 ml_, 6.97 mmol) and the mixture is stirred at room temperature for 18 hours. The mixture is poured into ethyl acetate and is washed with aqueous 1 M HCI, the organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure. The residue is purified, and the diastereomers are separated, by preparative HPLC using a gradient of MeCN/water (0.1 % TFA). The proper fractions are lyophilized to furnish (2S,4S)-5-biphenyl-4-yl-4-((S)-3-carboxy-3-cyclohexyl-propionylamino)-2-methyl- pentanoic acid. HPLC Retention time 1 .21 minutes (condition A); MS 466.4 (M+1 ).
Example 13-1 : Synthesis of (2ff,4S)-5-biphenyl-4-yl-2-methyl-4-[(1 W-tetrazole-5- carbonyl)-amino]-pentanoic acid
Figure imgf000118_0001
A mixture of (2R,4S)-4-[(1 -benzyl-1 H-tetrazole-5-carbonyl)-amino]-5-biphenyl-4-yl-2-methyl- pentanoic acid benzyl ester and (2R,4S)-4-[(2-benzyl-2H-tetrazole-5-carbonyl)-amino]-5- biphenyl-4-yl-2-methyl-pentanoic acid benzyl ester (126 mg, 0.225 mmol) in MeOH is hydrogenated with 10% Pd/C for 6h. The reaction mixture is concentrated and purified by reverse phase HPLC to give (2/:?,4S)-5-biphenyl-4-yl-2-methyl-4-[(1 /-/-tetrazole-5-carbonyl)- amino]-pentanoic acid. HPLC Retention time 1 .16 minutes (condition D); MS 380.0 (M+1 ); 1H NMR (400 MHz, DMSO-d6) δ ppm 1 .09 (d, J=7.20Hz, 3H), 1 .63-1 .73 (m, 1 H), 1 .86-1 .95 (m, 1 H), 2.40-2.50 (m, 1 H), 2.80-2.95 (m, 2H), 4.22-4.34 (m, 1 H), 7.29-7.35 (m, 1 H), 7.43 (dd, J=7.83, 7.83Hz, 2H), 7.55 (d, J=10.23Hz, 2H), 7.61 -7.64 (2H, m), 9.16 (d, J=9.09Hz, 1 H), 12.03, (s, 1 H).
Example 14-1 : Synthesis of (2R,4S)-5-biphenyl-4-yl-2-methyl-4-[(5-trifluoromethyl- [1 ,3,4]oxadiazole-2-carbonyl)-amino]-pentanoic acid
Figure imgf000119_0001
To a solution of (2R,4S)-5-biphenyl-4-yl-2-methyl-4-{2-oxo-2-[N'-(2,2,2-trifluoro-acetyl)- hydrazino]-acetylamino}-pentanoic acid benzyl ester (177 mg, 0.319 mmol) in THF (10 mL) at room temperature is added Burgess reagent (304 mg, 1 .274 mmol). The reaction is carried out in a microwave at 130 0C for 30 minutes. The reaction is quenched by brine and is extracted with ethyl acetate. The combined organic layer is concentrated and purified by reverse phase HPLC [70% to 85% acetonitrile-H2O (containing 0.1 % TFA)] to give the benzyl ester of the title compound. The obtained benzyl ester intermediate is dissolved in MeOH (4 mL) and is hydrogenated with 10% Pd/C at room temperature for 20 minutes. The reaction mixture is purified by reverse phase HPLC [45% to70% acetonitrile-H2O
(containing 0.1 % TFA)] to give (2R,4S)-5-biphenyl-4-yl-2-methyl-4-[(5-trifluoromethyl- [1 ,3,4]oxadiazole-2-carbonyl)-amino]-pentanoic acid. HPLC Retention time 1 .38 minutes (condition D); MS 448 (M+1 ); 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .09 (d, J=7.3 Hz, 3 H), 1 .60 - 1 .71 (m, 1 H), 1 .84 - 1 .95 (m, 1 H), 2.41 - 2.49 (m, 1 H), 2.80 - 2.88 (m, J=13.9, 6.1 Hz, 1 H), 2.92 (dd, J=13.6, 7.8 Hz, 1 H), 4.21 - 4.34 (m, 1 H), 7.27 - 7.37 (m, 3 H), 7.44 (t, J=7.7 Hz, 2 H), 7.58 (d, J=8.3 Hz, 2 H), 7.61 - 7.66 (m, 2 H), 9.50 (d, J=8.8 Hz, 1 H), 12.05 (br. s., 1 H). Example 15-1 : Synthesis of (2R,4S)-5-biphenyl-4-yl-4-(3,5-difluoro-4-hydroxy- benzoylamino)-2-methyl-pentanoic acid
Figure imgf000120_0001
To a solution of (2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid ethyl ester hydrochloride salt (200 mg, 0.58 mmol) in CH2CI2 (2 ml_) and DMF (2 ml_) at rt is added 3,5 difluoro-4-methoxy benzoic acid (108 mg, 0.58 mmol) followed by an addition of TEA (0.32 ml_, 2.3 mmol) and HATU (262 mg, 0.69 mmol). The mixture is stirred at rt for 4 hours and quenched with saturated NaHCO3 and diluted in ethyl acetate. The organic layer is washed with water, brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained material is purified by preparative silica gel thin-layer chromatography plates (eluent: EtOAc/hepane = 3/2) to give 265 mg of (2R,4S)-5-biphenyl-4-yl-4-(3,5-difluoro-4- methoxy-benzoylamino)-2-methyl-pentanoic acid ethyl ester.
Next, to a solution of (2R,4S)-5-biphenyl-4-yl-4-(3,5-difluoro-4-methoxy-benzoylamino)-2- methyl-pentanoic acid ethyl ester (125 mg, 0.260 mmol) in DCM (2.6 ml_) is slowly added BBr3 (2.60 ml_, 2.60 mmol) under nitrogen. The reaction is stirred for 18 hours at rt. The reaction is quenched with MeOH, diluted with EtOAc, washed with H2O and brine, dried over MgSO4, and concentrated under reduced pressure. The obtained material is purified by preparative silica gel thin-layer chromatography (7% MeOH in DCM) to give 100 mg (2R,4S)-5-biphenyl-4-yl-4-(3,5-difluoro-4-hydroxy-benzoylamino)-2-methyl-pentanoic acid ethyl ester.
Next, to a solution of (2R,4S)-5-biphenyl-4-yl-4-(3,5-difluoro-4-hydroxy-benzoylamino)-2- methyl-pentanoic acid ethyl ester (30mg, 0.064mmol) in MeOH (2 ml_) at room temperature is added aqueous 1 M NaOH (4 ml_, 4.0 mmol). After stirring for 1 hour the reaction is quenched with aqueous 1 M HCI (4 ml_, 4.0 mmol). The mixture is concentrated under reduced pressure and filtered to remove NaCI salt. The obtained residue is purified by preparative silica gel thin-layer chromatography (7% MeOH in DCM) to give 17.1 mg of (2R,4S)-5-biphenyl-4-yl-4-(3,5-difluoro-4-hydroxy-benzoylamino)-2-methyl-pentanoic acid. HPLC Retention time 1 .56 minutes (condition B); MS 440 (M+1 ); 1 H NMR (400 MHz, ACETONITRILE-d3) • ppm 1 .19 (d, J=7.07 Hz, 3 H) 1 .55 (ddd, J=14.27, 10.74, 3.79 Hz, 1 H) 1 .90 - 1 .96 (m, 1 H) 2.54 - 2.71 (m, 1 H) 2.91 (dd, J=6.69, 3.16 Hz, 2 H) 4.25 - 4.43 (m, 1 H) 6.49 (d, J=9.60 Hz, 2 H) 6.93 (d, J=8.84 Hz, 1 H) 7.33 - 7.42 (m, 3 H) 7.49 (t, J=7.71 Hz, 2 H) 7.61 (d, J=8.34 Hz, 2 H) 7.67 (dd, J=8.34, 1 .26 Hz, 2 H).
Following compounds are prepared and isolated after the coupling reaction and prior to the hydrolysis reaction described in the above example:
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Example 16-1 : 1 H NMR (400 MHz, MeOD-d4) • ppm 1 .12 (d, J=7.07 Hz, 3H), 1 .19 (t, J=7.20 Hz, 3H), 1 .59 (m, 1 H), 1 .92 (m, 1 H), 2.58 (m, 1 H), 2.78 (dd, J=7.20 Hz, 7.20 Hz, 1 H), 2.90 (dd, J=6.57 Hz, 6.69 Hz, 1 H), 4.06 (d, J-7.20 Hz, 2H), 4.19 (m, 1 H), 7.30 (m, 3H), 7.41 (t, J=6.69 Hz, 2H), 7.52 (d, J=8.21 Hz, 2H), 7.58 (dd, J=1 .01 Hz, 1 .26 Hz, 2H), 8.93 (d, J=8.72 Hz, 1 H).
Example 18-1 : 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .09 (m, 6H), 1 .66 (m, 1 H), 1 .86 (m, 1 H), 2.77-2.90 (m, 2H), 3.98 (q, 2H), 4.19 (m, 1 H), 7.19 (d, J=3.54 Hz, 1 H), 7.28 (m, 3H), 7.33 (t, 1 H), 7.44 (t, 1 H), 7.58 (d, J=8.34 Hz, 2H), 7.64 (d, J=7.07, 2H), 8.43 (d, J=8.84 Hz, 1 H).
Example 19-1 : 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .09 (m, 6H), 1 .65 (m, 1 H), 1 .87 (m, 1 H), 2.78-2.91 (m, 2H), 3.99 (q, 2H), 4.22 (m, 1 H), 4.55 (s, 2H), 7.29 (d, J=8.08 Hz, 2H), 7.33 (t, 1 H), 7.43 (m, 3H), 7.57-7.65 (m, 7H), 8.03 (s, 1 H), 8.47 (d, J=8.46 Hz, 1 H). Example 20-1 : 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .09 (m, 6H), 1 .78 (m, 1 H), 1 .88 (m, 1 H), 2.48 (m, 1 H), 2.80-2.98 (m, 2H), 3.97 (q, 2H), 4.30 (m, 1 H), 7.29 (d, J=8.21 Hz, 2H), 7.33 (t, 1 H), 7.43 (t, 2H), 7.56 (d, J=8.21 Hz, 2H), 7.63 (d, J=7.20 Hz, 2H), 8.00 (m, 1 H), 8.35 (s, 1 H), 8.77 (d, J=9.35 Hz, 1 H), 8.85 (d, J=4.29 Hz, 1 H). Example 21 -1 : 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .1 10 (t, 6H), 1 .66 (m, 1 H), 1 .89 (m, 1 H), 2.55 (m, 1 H), 2.80-2.91 (m, 2H), 3.99 (q, 2H), 4.23 (m, 1 H), 7.29 (d, J=8.21 Hz, 2H), 7.33 (t, 1 H), 7.44 (t, 2H), 7.57 (d, J=8.21 Hz, 2H), 7.63 (d, J=7.20 Hz, 2H), 7.92 (m, 1 H), 8.39 (s, 1 H), 8.76 (d, J=8.46 Hz, 1 H), 8.84 (d, J=4.93 Hz, 1 H).
Example 22-1 : 1 H NMR (400 MHz, MeOD-d4) • ppm 1 .18 (m, 6H), 1 .79 (m, 1 H), 2.04 (m, 1 H), 2.59 (m, 1 H), 2.95 (m, 2H), 4.07 (q, J=7.07 Hz, 2H), 4.44 (m, 1 H), 7.30 (m, 3H), 7.40 (m, 2H), 7.50 (m, 2H), 7.55 (m, 2H), 8.54 (s, 1 H), 8.98 (d, J=9.47 Hz, 1 H), 9.42 (s, 1 H). Example 23-1 : 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .07 (d, J=7.07 Hz, 3H), 1 .10 (t, 3H), 1 .66 (m, 1 H), 1 .84 (m, 1 H), 2.75-2.89 (m, 2H), 4.14 (m, 1 H), 6.83 (s, 1 H), 7.27 (d, J=8.21 Hz, 2H), 7.34 (t, 1 H), 7.44 (t, 2H), 7.58 (d, J=8.21 Hz, 2H), 7.64 (d, J=7.20 Hz, 2H), 8.13 (s, 1 H), 8.77 (d, J=8.84,1 H).
Example 24-1 : 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .0.8 (d, J=7.07 Hz, 3H), 1 .09 (t, 3H), 1 .62 (m, 1 H), 1 .86 (m, 1 H), 2.52 (m, 1 H), 2.76-2.89 (m, 2H), 3.97 (q, 2H), 4.20 (m, 1 H), 7.05 (d, J=8.59, 1 H), 7.29(d, J=8.21 , 2H), 7.33 (t, 1 H), 7.44 (t, 2H), 7.57 (d, J=8.21 Hz, 2H), 7.63 (d, J=7.33 Hz, 2H), 7.93 (m, 1 H), 8.00 (s, 1 H), 8.25 (d, J=8.46 Hz, 1 H), 1 1 .16 (s, 1 H). Example 25-1 : 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .0.8 (d, J=7.07 Hz, 3H), 1 .10 (t, 3H), 1 .64 (m, 1 H), 1 .86 (m, 1 H), 2.53 (m, 1 H), 2.75-2.90 (m, 2H), 3.98 (q, 2H), 4.19 (m, 1 H), 7.18 (s, broad, 1 H), 7.28 (d, J=8.34, 2H), 7.33 (t, 1 H), 7.44 (t, 2H), 7.57 (d, J=8.34 Hz, 2H), 7.63 (d, J=7.33 Hz, 2H), 8.25 (d, broad, J=8.34 Hz, 1 H).
Example 26-1 : Synthesis of 1-((1S,3R)-1-Biphenyl-4-ylmethyl-3-ethoxycarbonyl- butylcarbamoyl)-1 H-pyrazole-3-carboxylic acid
Figure imgf000124_0001
To a vigorously stirred 1 :1 mixture of methylene chloride/8% aqueous NaHCO3 (8 ml_) at 0 0C is added triphosgene (28.4 mg, 0.096 mmol). After stirring the mixture at 0 0C for 5 minutes, (2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid ethyl ester hydrochloride (100 mg, 0.287 mmol) is added and stirring is continued for 15 minutes. The organic phase is separated and dried over sodium sulfate. The solvent is removed under reduced pressure to furnish (2R,4S)-5-biphenyl-4-yl-4-isocyanato-2-methyl-pentanoic acid ethyl ester. Next, to a solution of 1 H-pyrazole-3-carboxylic acid (32.2 mg, 0.287 mmol) in DMF (1 ml_) is added diisopropylethylamine (0.05 mL, 0.287 mmol). After 15 min a solution of the above (2R,4S)-5-biphenyl-4-yl-4-isocyanato-2-methyl-pentanoic acid ethyl ester in DMF (1 mL) is added dropwise and the mixture is stirred at room temperature for 18 hours. The mixture is purified by preparative HPLC using a gradient of 10% MeCN to 100% MeCN (0.1% TFA). Lyophilization of the appropriate fractions furnishes the title compound. HPLC Retention time 1 .5 minutes (condition A); MS 450.3 (M+1 ); 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .08 (d, J=7.07 Hz, 3H), 1 .10 (t, 3H), 1 .86 (t, 2H), 2.52 (m, 1 H), 2.85 (m, 1 H), 2.98 (m, 1 H), 3.98 (q, 2H), 4.1 1 (m, 1 H), 6.85 (d, J=2.65 Hz, 1 H), 7.28 (d, J-8.08 Hz, 2H), 7.33 (t, 1 H), 7.44 (t, 2H), 7.57 (d, J=8.21 Hz, 2H), 7.63 (d, J=7.33 Hz, 2H), 8.29 (d, J=2.65 Hz, 1 H), 8.58 (d, J=9.22 Hz, 1 H), 13.33 (s, broad, 1 H).
Following compounds are prepared and isolated after the coupling reaction and prior to the hydrolysis reaction described in example 15-1 :
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Example 27-1 : 1 H NMR (400 MHz, DMSO-d6): • ppm 1 .05-1 .10 (m, 6H), 1 .49-1 .56 (m, 1 H), 1 .84-1 .91 (m, 1 H), 2.52-2.56 (m, 1 H), 2.77-2.86 (m, 2H), 3.91 -3.99 (q, J=7.07 Hz, 2H), 4.1 1 - 4.20 (m, 1 H), 6.73-6.74 (d, J=2.27 Hz, 2H), 7.27-7.29 (d, J=8.08 Hz, 2H), 7.31 -7.35 (J=7.33 Hz, 1 H), 7.42-7.45 (m, 2H), 7.57-7.59 (d, J=8.08 Hz, 2H), 7.63-7.65 (m, 2H), 8.08-8.10 (d, J=8.34 Hz, 1 H), 1 1 .90 (s, 1 H), 12.75 (s, 1 H).
Example 28-1 : 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .08-1 .12 (m, 6H), 1 .60 (m, 1 H), 1 .90 (m, 1 H), 2.52 (m, 1 H), 2.79-2.88 (m, 2H), 3.95-4.03 (m, 3H), 4.20 (m, 1 H), 7.29 (d, J=8.34 Hz, 2H), 7.34 (t, 1 H), 7.44 (t, 2H), 7.57 (d, J=8.34 Hz, 2H), 7.63 (d, J=7.07 Hz, 2H), 7.99 (s, 1 H), 8.39 (d, broad, J=8.34 Hz, 1 H), 8.73 (s, broad, 1 H).
Example 29-1 : 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .07 (d, J=7.07 Hz, 3H), 1 .1 1 (t, 3H), 1 .64 (m, 1 H), 1 .85 (m, 1 H), 2.75-2.87 (m, 2H), 3.98 (q, 2H), 4.14 (m, 1 H), 6.51 (s, 1 H), 7.27 (d, J=8.08 Hz, 2H), 7.34 (t, 1 H), 7.44 (t, 2H), 7.58 (d, J=8.34 Hz, 2H), 7.64 (d, J=7.07 Hz, 2H), 8.67 (d, J=8.59 Hz, 1 H), 1 1 .67 (s, 1 H).
Example 30-1 : 1 H NMR (400 MHz, DMSO-d6): 1 H NMR (400 MHz, DMSO-d6): • ppm 1 .07- 1 .12 (m, 6H), 1 .69-1 .77 (m, 1 H), 1 .84-1 .92 (m, 1 H), 2.45-2.55 (m, 1 H), 2.80-2.85 (m, 1 H), 2.93-2.99 (m, 1 H), 3.96-4.01 (q, J=7.33 Hz, 2H), 4.23-4.31 (m, 1 H), 7.26 (s, br, 1 H), 7.30- 7.35 (m, 2H), 7.40-7.46 (m, 2H), 7.56-7.58 (m, 2H), 7.62-7.65 (m, 2H), 7.94-7.95 (d, J=4.80 Hz, 1 H), 8.85-8.88 (d, J=9.09 Hz, 1 H), 9.02-9.03 (d, J=4.80 Hz, 1 H). Example 31 -1 : 1 H NMR (400 MHz, DMSO-d6): 1 H NMR (400 MHz, DMSO-d6): • ppm 1 .06-
1 .1 1 (m, 6H), 1 .73-1 .81 (m, 1 H), 1 .85-1 .92 (m, 1 H), 2.43-2.54 (m, 1 H), 2.82-2.87 (m, 1 H), 2.92-2.97 (m, 1 H), 3.95-4.00 (q, J=7.07 Hz, 2H), 4.24-4.32 (m, 1 H), 7.28-7.35 (m, 3H), 7.42- 7.45 (t, J= 8.08 Hz, 2H), 7.56-7.58 (d, J = 8.34 Hz, 2H), 7.62-7.64 (m, 2H), 7.84-7.88 (s, 1 H), 8.77-8.79 (d, J=8.08 Hz, 1 H), 9.00(s, 1 H).
Example 32-1 : 1 H NMR (600 MHz, DMSO-d6) • ppm 1 .07 (d, J=7.06 Hz, 3 H) 1 .1 1 (t,
J=7.1 1 Hz, 3 H) 1 .59 - 1 .70 (m, 1 H) 1 .79 - 1 .90 (m, 1 H) 2.73 - 2.90 (m, 2 H) 3.98 (d,
J=6.79 Hz, 2 H) 4.06 - 4.19 (m, 1 H) 6.50 (s, 1 H) 7.28 (d, J=8.07 Hz, 2 H) 7.41 (s, 1 H) 7.47
(s, 1 H) 7.62 (d, J=8.07 Hz, 3 H) 7.70 (s, 1 H) 8.68 (d, J=8.80 Hz, 1 H) 1 1 .63 - 1 1 .73 (m, 1
H).
Example 33-1 : 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .09 (q, 6 H) 1 .65 (br. s., 1 H) 1 .83 (d,
J=9.60 Hz, 1 H) 2.71 - 2.95 (m, 2 H) 3.98 (q, J=7.07 Hz, 2 H) 4.19 (dd, J=8.97, 6.19 Hz, 1
H) 7.29 (d, J=8.34 Hz, 2 H) 7.36 - 7.42 (m, 1 H) 7.46 (t, J=7.96 Hz, 1 H) 7.55 - 7.65 (m, 3 H)
7.69 (t, J=1 .89 Hz, 1 H) 7.97 - 8.27 (m, 1 H).
Example 34-1 : 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .03 - 1 .14 (m, 6 H) 1 .60 - 1 .72 (m, 1
H) 1 .85 (ddd, J=13.77, 9.85, 3.92 Hz, 1 H) 2.75 - 2.94 (m, 2 H) 3.98 (q, J=7.07 Hz, 2 H)
4.12 - 4.26 (m, 1 H) 7.10 - 7.21 (m, 2 H) 7.29 (d, J=8.08 Hz, 2 H) 7.37 - 7.42 (m, 1 H) 7.46 (t, J=7.83 Hz, 1 H) 7.62 (d, J=8.08 Hz, 3 H) 7.69 (t, J=1 .89 Hz, 1 H) 8.37 (d, J=8.59 Hz, 1 H).
Example 35-1 : 1 H NMR (400 MHz, DMSO-d6): • ppm 1 .07-1 .10 (m, 6H), 1 .49-1 .56 (m, 1 H), 1 .84-1 .91 (m, 1 H), 2.47-2.56 (m, 1 H), 2.77-2.87 (m, 2H), 3.94-3.99 (q, J=7.07 Hz, 14.05 Hz, 2H), 4.1 1 --4.20 (m, 1 H), 6.72-6.73 (d, J=2.27 Hz, 2H), 7.28-7.30 (m, 2H), 7.38-7.41 (m, 1 H), 7.44-7.48 (t, J=7.83 Hz, 1 H), 7.61 -7.64 (m, 3H), 7.69-7.70 (t, J=1 .77 Hz, 1 H), 8.07-8.10 (d, J=8.34 Hz, 1 H), 1 1 .89 (s, 1 H), 12.74 (s, 1 H).
Example 36-1 : 1 H NMR (400 MHz, DMSO-d6): • ppm 1 .05-1 .13 (m, 6H), 1 .53-1 .60 (m, 1 H), 1 .75-1 .83 (m, 1 H), 2.43-2.50 (m, 1 H), 2.71 -2.83 (m, 2H), 3.96-4.00 (m, 3H), 7.26-7.28 (m, 2H), 7.39-7.42 (m, 1 H), 7.46-7.50 (t, J=7.83 Hz, 1 H), 7.61 -7.65 (m, 3H), 7.70-7.71 (t, J=1 .77 Hz, 1 H), 9.60 (s, 1 H).
Example 37-1 : Synthesis of (2R,4S)-5-Biphenyl-4-yl-4-(3-carboxymethyl- benzoylamino)-2-methyl-pentanoic acid and
Example 38-1 : Synthesis of 3-[((1 S,3R)-1-Biphenyl-4-ylmethyl-3-carboxy- butylcarbamoyl)-methyl]-benzoic acid
Figure imgf000130_0001
To a solution of Intermediate 1 (100 mg, 0.287 mmol), Intermediate 21 (57 mg, 0.316 mmol), EDCI (71 .6 mg, 0.374 mmol) and HOBt (50.5 mg, 0.374 mmol) in DMF (3 ml_) is added triethylamine (1 16 mg, 0.159 ml_) and the mixture is stirred at room temperature for 18 hrs. Any insoluble material is removed by filtration and the solvent is removed under reduced pressure.
Next, the above residue is dissolved in EtOH (8 ml_) and 1 N NaOH (1 .27 ml_, 1 .27 mmol) is added. The mixture is stirred at 50 0C for 5 hrs then the solvent is removed under reduced pressure. Water (5 ml_) is added and the mixture is acidified with 1 N HCI. The mixture is extracted with EtOAc and the organic phase is dried over sodium sulfate. The solvent is removed under reduced pressure and the residue is purified by preparative HPLC using a gradient of 10% MeCN/water to 100% MeCN (0.1 % TFA) to elute the products (2R,4S)-5- biphenyl-4-yl-4-(3-carboxymethyl-benzoylamino)-2-methyl-pentanoic acid, HPLC Retention time 1 .02 minutes (condition C); MS 446.3 (M+1 ); 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .08 (d, J=7.07 Hz, 3H), 1 .58 (m, 1 H), 1 .88 (m, 1 H), 2.46 (m, 1 H), 2.79-2.90 (m, 2H), 3.62 (s, 2H), 4.25 (m, 1 H), 7.29 (d, J=8.08 Hz, 2H), 7.34 (d, J=7.33 Hz, 1 H), 7.40 (m, 2H), 7.43 (t, 2H), 7.57 (d, J=8.08 Hz, 2H), 7.63 (d, J=8.08 Hz, 2H), 7.68 (m, 2H), 8.22 (d, J=8.34 Hz, 1 H) and 3-[((1 S,3R)-1 -biphenyW-ylmethyl-S-carboxy-butylcarbamoyO-methylJ-benzoic acid, HPLC Retention time 1 .03 minutes (condition C); MS 446.3 (M+1 ); 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .05 (d, J=7.07 Hz, 3H), 1 .36 (m, 1 H), 1 .81 (m, 1 H), 2.41 (m, 1 H), 2.63- 2.75 (m, 2H), 3.37-3.46 (m, 2H), 3.94 (m, 1 H), 7.15 (d, J=8.08 Hz, 2H), 7.32-7.50 (m, 7H), 7.61 (d, J=7.33 Hz, 2H), 7.80 (m, 1 H), 7.88 (s, 1 H), 8.00 (d, J=8.59 Hz, 1 H). Example 37-2: Synthesis of (2R,4S)-5-Biphenyl-4-yl-4-[(5-carboxymethyl-furan-2- carbonyl)-amino]-2-methyl-pentanoic acid and
Example 38-2: Synthesis of 5-[((1 S,3R)-1-Biphenyl-4-ylmethyl-3-carboxy- butylcarbamoyl)-methyl]-furan-2-carboxylic acid
Figure imgf000131_0001
The title compounds are prepared analogous to Example 37-1 and Example 38-1 using Intermediates 1 and 22.
(2R,4S)-5-biphenyl-4-yl-4-[(5-carboxymethyl-furan-2-carbonyl)-amino]-2-methyl-pentanoic acid, HPLC Retention time 1 .13 minutes (condition C); MS 436.3 (M+1 ); 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .07 (d, J=7.07 Hz, 3H), 1 .55 (m, 1 H), 1 .85 (m, 1 H), 2.41 (m, 1 H), 2.75- 2.88 (m, 2H), 3.74 (s, 2H), 4.19 (m, 1 H), 6.39 (d, J=3.28 Hz, 1 H), 7.01 (d, J=3.28 Hz, 1 H), 7.27 (d, J=8.08 Hz, 2H), 7.33 (t, 1 H), 7.44 (t, 2H), 7.56 (d, J=8.34 Hz, 2H), 7.64 (d, J=7.33 Hz, 2H), 8.08 (d, J=8.59 Hz, 1 H).
5-[((1 S,3R)-1 -biphenyl-4-ylmethyl-3-carboxy-butylcarbamoyl)-methyl]-furan-2-carboxylic acid, HPLC Retention time 1 .03 minutes (condition C); MS 436.3 (M+1 ); 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .06 (d, J=7.07 Hz, 3H), 1 .36 (m, 1 H), 1 .81 (m, 1 H), 2.42 (m, 1 H), 2.67- 2.78 (m, 2H), 3.54 (s, 2H), 3.97 (m, 1 H), 6.30 (d, J=3.28 Hz, 1 H), 7.12 (d, J=3.28 Hz, 1 H), 7.23 (d, J=8.08 Hz, 2H), 7.34 (t, 1 H), 7.45 (t, 2H), 7.56 (d, J=8.34 Hz, 2H), 7.64 (d, J=7.33 Hz, 2H), 8.05 (d, J=8.34 Hz, 1 H).
Example 38-3: (2R,4S)-4-[(5-Carboxymethyl-furan-2-carbonyl)-amino]-5-(3'-chloro- biphenyl-4-yl)-2-methyl-pentanoic acid
The title compound is prepared analogous to Example 37-1 and Example 38-1 using Intermediates 22 and 31 .
Figure imgf000132_0001
HPLC Retention time 1 .37 minutes (condition C); MS (m+1 ) = 470.0; 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .07 (d, J=7.07 Hz, 3H), 1 .55 (m, 1 H), 1 .85 (m, 1 H), 2.41 (m, 1 H), 2.76- 2.88 (m, 2H), 3.74 (s, 2H), 4.19 (m, 1 H), 6.39 (d, J=3.28 Hz, 1 H), 7.01 (d, J=3.28 Hz, 1 H), 7.28 (d, J=8.08 Hz, 2H), 7.39 (m, 1 H), 7.46 (t, 2H), 7.59-7.63 (m, 3H), 7.69 (m,1 H), 8.09 (d, J=8.84 Hz, 1 H)
Example 39-1 : Synthesis of 6-Amino-2-((1 S,3R)-1-biphenyl-4-ylmethyl-3-carboxy- butylcarbamoyl)-pyrimidine-4-carboxylic acid and
Example 40-1 : Synthesis of 4-Amino-6-((1 S,3R)-1-biphenyl-4-ylmethyl-3-carboxy- butylcarbamoyl)-pyrimidine-2-carboxylic acid
Figure imgf000132_0002
To a stirred solution of triethyl 1 ,3,5-triazine-2,4,6-tricarboxylate (J. Org. Chem. 59, 4950, 1994) (2.02 g, 6.80 mmol.) in DMF (15 ml_) is added 1 -aminoethaniminium chloride (1.29 g, 13.60 mmol). After the addition, the mixture is heated at 100 0C for 18 hours then the mixture is extracted three times with ethyl acetate. The combined organic layers are washed with water and brine then is dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue is purified by flash chromatography (heptane/ethyl acetate =3:1 ) to give diethyl 6-aminopyrimidine-2,4-dicarboxylate; HPLC Retention time 0.89 minutes (condition C); MS 240.3 (M+1 ). Next, to a stirred solution of diethyl 6-aminopyrimidine-2,4-dicarboxylate (120 mg, 0.50 mmol) in EtOH (3 ml_) is added 1 N NaOH (0.5 ml_) and the mixture is stirred at room temperature for 18 hours. The solution is carefully acidified with 1 N HCI and the solvent is removed under reduced pressure to give a mixture of 4-amino-6-
(ethoxycarbonyl)pyrimidine-2-carboxylic acid and 6-amino-pyrimidine-2,4-dicarboxylic acid 2-ethyl ester.
Next, to a solution of Intermediate 1 (100 mg, 0.321 mmol) and the above monoester mixture in DMF (8 ml_) is added HATU (122 mg, 0.321 mmol) and triethylamine (0.134 ml_, 0.963 mmol) and the mixture is stirred at room temperature for 2 hours. The solvent is removed under reduced pressure and the residue is used directly in the next reaction. Next, to a solution of the above residue in EtOH (5 ml_) is added 1 N NaOH (3 ml_) and the mixture is stirred at room temperature for 2 hours. The mixture is acidified withi N HCI and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC using a gradient of 10% MeCN/water to 100% MeCN (0.1 % TF) to elute the products 6-Amino-2-((1 S,3R)-1 -biphenyl-4-ylmethyl-3-carboxy-butylcarbamoyl)-pyrimidine-4- carboxylic acid; HPLC Retention time 1.03 minutes (condition C); MS 449.3 (M+1 ); 1 H NMR (400 MHz, DMSO-d6) • ppm 0.97-0.99 (d, J=6.82 Hz, 3H), 1 .75 - 1 .79 (m, 2H), 2.45-2.55 (m, 1 H), 2.82-2.87 (m, 1 H), 2.92-2.97 (m, 1 H), 4.16-4.22 (m, 1 H), 6.95 (s, 1 H), 7.29-7.35 (m, 3 H), 7.41 -7.45 (m, 2H), 7.57-7.59 (m, 2H), 7.63-7.65 (m, 2H), 8.85-8.88 (d, J=8.84 Hz, 1 H) and 4-Amino-6-((1 S,3R)-1 -biphenyl-4-ylmethyl-3-carboxy-butylcarbamoyl)-pyrimidine-2- carboxylic acid; HPLC Retention time 1 .13 minutes (condition C); MS 449.3 (M+1 ); 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .07-1 .09 (d, J=7.07Hz, 3H), 1 .57 - 1 .65 (m, 1 H), 1 .89-1 .96 (m, 1 H), 2.38-2.44 (m, 1 H), 2.86-2.89 (m, 2H), 4.21 -4.30 (m, 1 H), 7.06 (s, 1 H), 7.27-7.35 (m, 3 H), 7.41 -7.45 (m, 2H), 7.55-7.57 (m, 2H), 7.62-7.64 (m, 2H), 8.78-8.80 (d, J=9.35 Hz, 1 H), 12.05 (s, 1 H), 12.89 (s, 1 H).
Example 41-1 : Synthesis of 6-((1S,3R)-1-Biphenyl-4-ylmethyl-3-ethoxycarbonyl- butylcarbamoyl)-2-hydroxy-pyrimidine-4-carboxylic acid
Figure imgf000134_0001
To a stirred solution of 2-hydroxypyrimidine-4,6-dicarboxylic acid (71 mg, 0.39 mmol) in DMF (10 ml_) is added HOBT (59 mg, 0.39 mmol) and EDCI (74 mg, 0.39 mmol) and the mixture is stirred at room temperature for 10 minutes then (2R,4S)-4-amino-5-biphenyl-4-yl- 2-methyl-pentanoic acid ethyl ester hydrochloride (Intermediate 1 ) (120 mg, 0.35 mmol) and triethylamine (0.15 ml, 1 .16 mmol) are added. After stirring the mixture at room temperature for five hours, water is added and the mixture is extracted with ethyl acetate (3x). The combined organic layers are washed with water and brine then is dried over magnesium sulfate. The solvent is removed under reduced pressure and residue is purified by preparative HPLC using a gradient of 10% MeCN/water to 100% MeCN (0.1 % TFA) to elute the title compound. HPLC retention time 1 .32 minutes (condition C); MS 478.3 (M+H); 1 H NMR (400 MHz, DMSO-d6): • ppm 1 .05-1 .07 (d, J=7.07 Hz, 3H), 1 .09-1 .12 (t, J=7.07 Hz, 3H), 1 .72-1 .79 (m, 1 H), 1 .81 -1 .89 (m, 1 H), 2.44-2.49 (m, 1 H), 2.77-2.82 (m, 1 H), 2.89-2.95 (m, 1 H), 3.95-4.01 (q, J=7.07 Hz, 2H), 4.16-4.26 (m, 1 H), 7.26-7.28 (m, 2H), 7.31 -7.35 (m, 1 H), 7.41 -7.45 (m, 2H), 7.55-7.57 (m, 2H), 7.62-7.64 (m, 2H), 8.73-8.76 (d, J=9.35 Hz, 1 H).
Example 42-1 : Synthesis of 6-((1 S,3R)-1-Biphenyl-4-ylmethyl-3-carboxy- butylcarbamoyl)-2-ethoxy-pyrimidine-4-carboxylic acid
Figure imgf000134_0002
To a solution of Intermediate 1 (31 1 mg, 1 mmol) and Intermediate 24 (260 mg, 1 .2 mmol) in DMF (10 ml_) is added HATU (380 mg, 1 mmol) and triethylamine (0.418 ml_, 3 mmol) and the mixture is stirred at room temperature for 1 hour. Water is added and the mixture is extracted with EtOAc. The organic phase is washed wit brine and is dried over magnesium sulfate. The solvent is removed under reduced pressure to give 6-((1 S,3R)-1 -biphenyl-4- ylmethyl-3-ethoxycarbonyl-butylcarbamoyl)-2-chloro-pyrimidine-4-carboxylic acid methyl ester which is used directly in the next reaction.
Next, to a solution of the above product in EtOH (7 ml_) is added 1 N NaOH (10 ml_) and the mixture is stirred at room temperature for 18 hours. The mixture is acidified withi N HCI and extracted with EtOAc. The organic phase is washed with brine and dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue is purified by preparative HPLC using a gradient of 10% MeCN/water to 100% MeCN to elute the title compound; HPLC retention time 1 .15 minutes (condition C); MS 478.3 (M+H); 1 H NMR (400 MHz, MeOD-d4): • ppm 1 .18-1 .20 (d, J=7.07 Hz, 3H), 1 .43-1 .46 (t, J=7.07 Hz, 3H), 1 .76 - 1 .83 (m, 1 H), 2.02-2.09 (m, 1 H), 2.55-2.61 (m, 1 H), 2.96-2.98 (d, J=6.82 Hz, 2H), 4.42-4.49 (m, 1 H), 4.55-4.61 (q, J=7.07 Hz, 2H), 7.27-7.33 (m, 3 H), 7.37-7.41 (t, J=7.83 Hz, 2H), 7.50-7.52 (d, J=8.34 Hz, 2H), 7.55-7.57 (d, J=7.33 Hz, 2H), 8.1 1 (s, 1 H), 8.58-8.61 (d, J=9.35, 1 H).
Example 43-1 : Synthesis of 6-((1 S,3R)-1-Biphenyl-4-ylmethyl-3-carboxy- butylcarbamoyl)-2-methoxy-pyrimidine-4-carboxylic acid
Figure imgf000135_0001
To a solution of 6-((1 S,3R)-1 -biphenyl-4-ylmethyl-3-ethoxycarbonyl-butylcarbamoyl)-2- chloro-pyrimidine-4-carboxylic acid methyl ester (74 mg, 0.145 mmol, from Example 42-1 ) in THF (5 mL) is added sodium methoxide (47 mg, 0.218 mmol) and the mixture is stirred at room temperature for 18 hours. Water is added and the mixture is extracted with EtOAc. The organic phase is washed with brine and dried over magnesium sulfate. The solvent is removed under reduced pressure to give 6-((1 S,3R)-1 -biphenyl-4-ylmethyl-3- ethoxycarbonyl-butylcarbamoyl)-2-methoxy-pyrimidine-4-carboxylic acid methyl ester. Next, to a solution of the above diester in EtOH (3 ml_) is added 1 N NaOH (3 ml_) and the mixture is stirred at room temperature for 18 hours. The mixture is acidified to pH3 and is extracted with EtOAc. The organic phase is washed with brine and dried over magnesium sulfate. The solvent is removed under reduced pressure to give the title compound; HPLC retention time 1 .31 minutes (condition C); MS 464.3 (M+H); 1 H NMR (400 MHz, MeOD- d4): • ppm 1 .18-1 .20 (d, J=7.07 Hz, 3H), 1 .77 - 1 .84 (m, 1 H), 2.02-2.09 (m, 1 H), 2.55-2.61 (m, 1 H), 2.96-2.98 (d, J=7.07 Hz, 2H), 4.15 (s, 3H), 4.43-4.49 (m, 1 H), 7.27-7.34 (m, 3 H), 7.38-7.41 (m, 2H), 7.50-7.52 (m, 2H), 7.55-7.57 (m, 2H), 8.12 (s, 1 H), 8.63-8.66 (d, J=9.35, 1 H).
Example 44-1 : Synthesis of (2R,4S)-5-Biphenyl-4-yl-4-[(6-carbamoyl-2-hydroxy- pyrimidine-4-carbonyl)-amino]-2-methyl-pentanoic acid
Figure imgf000136_0001
To a 7N solution of ammonia in MeOH (5 ml_) is added 6-((1 S,3R)-1 -biphenyl-4-ylmethyl-3- ethoxycarbonyl-butylcarbamoyl)-2-chloro-pyrimidine-4-carboxylic acid methyl ester (120 mg, 0.235 mmol, from Example 42-1 ) and the mixture is stirred at room temperature for 20 minutes. The solvent is removed under reduced pressure to give (2R,4S)-5-biphenyl-4-yl-4- [(6-carbamoyl-2-chloro-pyrimidine-4-carbonyl)-amino]-2-methyl-pentanoic acid ethyl ester; HPLC retention time 1 .50 minutes (condition C); MS 495.3 (M+H); Next, to a solution of the above compound in EtOH (5 mL) is added 1 N NaOH (5 mL) and the mixture is stirred at room temperature for 18 hours. The mixture is acidified to pH3 and is extracted with EtOAc. The organic phase is washed with brine and dried over magnesium sulfate. The solvent is removed under reduced pressure to give the title compound; HPLC retention time 1 .08 minutes (condition C); MS 449.3 (M+H); 1 H NMR (400 MHz, DMSO- d6): 1 H NMR (400 MHz, DMSO-d6): • ppm 1 .06-1 .07 (d, J=7.07 Hz, 3H), 1 .57-1 .64 (m, 1 H), 1.85-1 .92 (m, 1 H), 2.39-2.45 (m, 1 H), 2.81 -2.92 (m, 2H), 4.21 -4.30 (m, 1 H), 7.27-7.29 (m, 2H), 7.31 -7.35 (m, 1 H), 7.42-7.45 (m, 3H), 7.56-7.59 (m, 2H), 7.63-7.65 (m, 2H), 8.29- 8.31 (d, J=9.35 Hz, 1 H), 12.09 (s, 1 H), 13.60 (s, 1 H).
Example 45-1 : Synthesis of (2R,4S)-5-Biphenyl-4-yl-4-[(5-methoxy-4-oxo-4H-pyran-2- carbonyl)-amino]-2-methyl-pentanoic acid
Figure imgf000137_0001
(2R,4S)-5-Biphenyl-4-yl-4-[(5-hydroxy-4-oxo-4H-pyran-2-carbonyl)-amino]-2-methyl- pentanoic acid benzyl ester is prepared from Intermediate 2 and 5-hydroxy-4-oxo-4H-pyran- 2-carboxylic acid analogous to Example 41 -1 ; HPLC Retention time 1 .32 minutes (condition C): MS 510.3 (M -1 ).
Next, to a solution of (2R,4S)-5-biphenyl-4-yl-4-[(5-hydroxy-4-oxo-4H-pyran-2-carbonyl)- amino]-2-methyl-pentanoic acid benzyl ester (54 mg, 0.106mmol) in DMF (1 ml_) is added K2CO3 (29.2 mg, 0.21 1 mmol) and MeI (16.5 mg, 0.1 16mmol), and the resulting mixture is stirred at room temperature overnight. Then ice/water is added and the mixture is extracted with EtOAc. The combined organic phases are washed with brine, dried over MgSO4, filtered and concentrated to give (2R,4S)-5-biphenyl-4-yl-4-[(5-methoxy-4-oxo-4H-pyran-2- carbonyl)-amino]-2-methyl-pentanoic acid benzyl ester which is used without further purification. HPLC Retention time 1 .55 minutes (condition C): MS 526.3 (M+1 ). Next, To a solution of (2R,4S)-5-biphenyl-4-yl-4-[(5-methoxy-4-oxo-4H-pyran-2-carbonyl)- amino]-2-methyl-pentanoic acid benzyl ester in methylene chloride (1 mL) is added BCI3 (0.12 mL of a 1 M solution in methylene chloride) and the mixture is stirred at room temperature for 18 hours. An additional 0.12 mL of the BCI3 solution is added and stirring is continued for 5 hours. An additional 0.12 mL of the BCI3 solution is added and stirring is continued for 18 hours. The mixture is quenched with water (2 drops) and DMF (1 mL) is added. The solution is purified by preparative HPLC using a gradient of 10% MeCN/water to 100% MeCN (0.1 % TFA) to elute the title compound; HPLC Retention time 1 .28 minutes (condition C): MS 436.1 (M+1 )
1 H NMR (400 MHz, DMSO-Cf6) • ppm 0.87 - 1 .30 (m, 3 H) 1 .43 - 1 .74 (m, 1 H) 1 .74 - 1 .99 (m, 1 H) 2.71 - 3.01 (m, 2 H) 3.17 (s, 1 H) 3.71 (s, 3 H) 3.97 - 4.42 (m, 1 H) 6.52 - 6.94 (m, 1 H) 7.15 - 7.37 (m, 2 H) 7.44 (t, J=7.71 Hz, 2 H) 7.59 - 7.71 (m, 2 H) 8.13 (s, 1 H) 8.77 (d, J=8.84 Hz, 1 H).
Example 46-1 : Synthesis of (2R,4S)-5-Biphenyl-4-yl-4-[(5-hydroxy-1-methyl-4-oxo-1 ,4- dihydro-pyridine-2-carbonyl)-amino]-2-methyl-pentanoic acid
Figure imgf000138_0001
To a suspension of (2R,4S)-5-biphenyl-4-yl-4-[(5-hydroxy-4-oxo-4H-pyran-2-carbonyl)- amino]-2-methyl-pentanoic acid ethyl ester (Example 23-1 ) (50mg) in water (1 ml_) is added methylamine (1 ml_ of a 40% solution in water) and the resulting mixture is heated to reflux for 6 hours. The mixture is under reduced pressure and is purified by preparative HPLC using a gradient of 10% MeCN/water to 100% MeCN (0.1 % TFA) to elute the title compound; HPLC Retention time 1 .21 minutes (condition C): MS 435.1 (M+1 ); 1 H NMR (400 MHz, DMSO-Cf6) • ppm 1 .12 (d, J=7.07 Hz, 3 H) 1.45 - 1 .65 (m, 1 H) 1 .82 - 1 .98 (m, 1 H) 2.25 - 2.38 (m, 1 H) 2.63 - 2.78 (m, 1 H) 2.79 - 2.97 (m, 1 H) 4.14 - 4.32 (m, 1 H) 6.45 (br. s., 1 H) 7.26 - 7.39 (m, 2 H) 7.45 (t, J=7.58 Hz, 2 H) 7.55 - 7.68 (m, 4 H) 8.79 (d, J=9.09 Hz, 1 H).
Example 47-1 : Synthesis of (2R,4S)-5-Biphenyl-4-yl-2-methyl-4-[(pyridazine-4- carbonyl)-amino]-pentanoic acid
Figure imgf000139_0001
To a stirred solution of pyridazine-4-carboxylic acid (21 mg, 0.17 mmol) in DMF (6 ml_) is added HOBT (26 mg, 0.17 mmol) and HBTU (65 mg, 0.17 mmol) and the mixture is stirred at room temperature for 10 minutes. (2R,4S)-4-Amino-5-biphenyl-4-yl-2-methyl-pentanoic acid ethyl ester hydrochloride (50 mg, 0.14 mmol) and DIEA (42 mg, 0.56 mmol) are added. After stirring the mixture at room temperature for 18 hours, water is added and the mixture is extracted three times with ethyl acetate. The combined organic layers are washed with water and brine then is dried over magnesium sulfate. The solvent is removed under reduced pressure to give the title compound; HPLC retention time 1.19 minutes (condition C); MS 390.3 (M+H); 1 H NMR (400 MHz, DMSO-d6): • ppm 1 .08-1 .10 (d, J=7.07 Hz, 3H), 1 .59-1 .66 (m, 1 H), 1 .88-1 .95 (m, 1 H), 2.46-2.53 (m, 1 H), 2.85-2.87 (d, J=6.82 Hz, 2H), 4.22- 4.30 (m, 1 H), 7.29-7.32 (m, 2H), 7.33-7.36 (m, 1 H), 7.42-7.46 (m, 2H), 7.57-7.59 (m, 2H), 7.62-7.65 (m, 2H), 7.91 -7.93 (q, J=2.27 Hz, 1 H), 8.76-8.78 (d, J=8.59 Hz, 1 H), 9.41 -9.43 (m, 1 H), 9.45-9.46 (m, 1 H), 12.09 (s, 1 H).
Following compounds are prepared and isolated after the coupling reaction and prior to the hydrolysis reaction described in the above example:
Figure imgf000139_0002
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Example 47-2: 1 H NMR (400 MHz, CHLOROFORM-cQ δ ppm 1 .1 1 (d, J=7.3 Hz, 3 H) 1 .14 (t, J=7.2 Hz, 3 H) 1 .64 (ddd, J=14.2, 9.9, 4.2 Hz, 1 H) 1 .93 (ddd, J=14.0, 9.5, 4.0 Hz, 1 H) 2.57 (m, 1 H) 2.83 (dd, J=13.7, 6.3 Hz, 1 H) 2.92 (dd, J=13.7, 6.3 Hz, 1 H) 4.04 (q, J=7.2 Hz, 2 H) 4.22 - 4.42 (m, 1 H) 6.45 (d, J=6.6 Hz, 1 H) 6.68 (d, J=8.6 Hz, 1 H) 6.74 (s, 1 H) 7.19 (d, J=8.1 Hz, 2 H) 7.21 - 7.28 (m, 2 H) 7.33 (t, J=7.6 Hz, 2 H) 7.46 (dd, J=14.5, 7.7 Hz, 4 H) 12.79 (br. s., 1 H)
Example 47-3: 1 H NMR (400 MHz, CHLOROFORM-cQ δ ppm 1 .14 - 1 .30 (m, 6 H) 1 .55 - 1 .76 (m, 1 H) 1 .99 - 2.17 (m, 1 H) 2.55 - 2.75 (m, 1 H) 2.88 - 3.07 (m, 2 H) 4.02 - 4.22 (m, 2 H) 4.45 - 4.66 (m, 1 H) 6.49 - 6.69 (m, 1 H) 6.77 - 6.94 (m, 1 H) 7.24 - 7.36 (m, 3 H) 7.36 - 7.47 (m, 2 H) 7.48 - 7.65 (m, 5 H) 8.88 (br. s., 1 H) Example 47-4: 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1 .07 - 1 .22 (m, 6 H) 1 .80 - 2.16 (m, 2 H) 2.33 - 2.55 (m, 1 H) 2.70 (dd, J=I 3 A, 7.4 Hz, 1 H) 2.80 (dd, J=I 3 A, 7.4 Hz, 1 H) 3.69 - 3.87 (m, 1 H) 3.87 - 4.53 (m, 2 H) 5.46 - 5.70 (m, 1 H) 7.16 (s, 1 H) 7.25 - 7.31 (m, 2 H) 7.34 - 7.40 (m, 3 H) 7.42 - 7.48 (m, 2 H) 7.48 - 7.53 (m, 3 H)
Example 47-5: 1 H NMR (400 MHz, CD3OD) δ ppm 1 .15 (d, J=7.1 Hz, 3 H) 1 .19 (t, J=7.1 Hz, 3 H) 1 .62 - 1 .75 (m, 1 H) 1 .89 - 2.03 (m, 1 H) 2.50 - 2.64 (m, 1 H) 2.75 - 2.95 (m, 2 H) 3.98 - 4.14 (m, 2 H) 4.20 - 4.36 (m, 1 H) 7.29 (d, J=8.1 Hz, 3 H) 7.36 - 7.44 (m, 2 H) 7.52 (d, J=8.3 Hz, 2 H) 7.54 - 7.59 (m, 2 H)
Example 47-6: 1 H NMR (400 MHz, DMSO-d6) δ ppm 1 .08 (d, J=7.1 Hz, 3 H) 1 .13 (t, J=7.1 Hz, 3 H) 1 .67 (ddd, J=14.1 , 10.2, 4.3 Hz, 1 H) 1 .86 (ddd, J=13.8, 9.9, 3.8 Hz, 1 H) 2.78 (dd, J=13.4, 7.5 Hz, 1 H) 2.85 (dd, J=13.4, 7.5 Hz, 1 H) 3.23 - 3.46 (m, 1 H) 3.92 - 4.08 (m, 2 H) 4.08 - 4.22 (m, 1 H) 7.27 (d, J=8.1 Hz, 2 H) 7.31 - 7.38 (m, 1 H) 7.45 (t, J=7.7 Hz, 2 H) 7.58 (d, J=8.3 Hz, 2 H) 7.64 (d, J=7.3 Hz, 2 H) 9.03 (d, J=8.8 Hz, 1 H) 13.10 (br. s., 1 H) Example 47-7: 1 H NMR (400 MHz, DMSO-Cf6) δ ppm 0.97 (d, J=7.1 Hz, 3 H) 1 .1 1 (t, J=7.1 Hz, 3 H) 1 .85 (ddd, J=13.7, 9.7, 3.9 Hz, 1 H) 1 .99 (ddd, J=12.4, 8.8, 3.0 Hz, 1 H) 2.09 - 2.25 (m, 1 H) 2.74 - 2.86 (m, 2 H) 3.91 - 4.05 (m, 2 H) 4.08 - 4.24 (m, 1 H) 5.95 (br s, 1 H) 7.27 (d, J=8.1 Hz, 2 H) 7.33 (t, J=7.6 Hz, 2 H) 7.45 (q, J=7.4 Hz, 2 H) 7.55 - 7.67 (m, 3 H) 7.74 (s, 1 H) 7.95 (d, J=8.6 Hz, 1 H)
Example 47-8: 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1 .12 (d, J=7.1 Hz, 3 H), 1 .16 (t, J=7.1 Hz, 3 H), 1 .54 (ddd, J=14.3, 10.0, 4.3 Hz, 1 H), 1 .93 (ddd, J=14.1 , 9.6, 4.0 Hz, 1 H), 2.47 - 2.64 (m, 1 H), 2.76 - 2.99 (m, 2 H), 3.65 - 3.76 (m, 3 H), 4.04 (q, J=7.1 Hz, 2 H), 4.24 - 4.44 (m, 1 H), 5.81 (d, J=8.3 Hz, 1 H), 6.30 - 6.43 (m, 2 H), 7.20 - 7.28 (m, 3 H), 7.34 (t, J=7.6 Hz, 2 H), 7.45 (d, J=8.1 Hz, 2 H), 7.47 - 7.54 (m, 2 H).
Example 47-9: 1 H NMR (400 MHz, CHLOROFORM-cQ δ ppm 1 .23 (d, J=7.3 Hz, 3 H), 1 .28 (t, J=7.2 Hz, 3 H), 1 .68 - 1 .86 (m, 1 H), 1 .91 - 2.04 (m, 1 H), 2.73 (ddd, J=9.1 , 7.2, 3.4 Hz, 1 H), 2.90 (dd, J=13.6, 7.3 Hz, 1 H), 3.1 1 (dd, J=13.6, 5.6 Hz, 1 H), 4.18 (q, 2 H), 4.35 - 4.51 (m, 1 H), 6.77 (d, J=7.8 Hz, 1 H), 7.31 (d, J=8.1 Hz, 2 H), 7.33 - 7.40 (m, 1 H), 7.42 - 7.50 (m, 2 H), 7.53 - 7.65 (m, 4 H), 8.20 (d, J=2.3 Hz, 1 H), 8.28 (s, 1 H). Example 47-10: 1 H NMR (400 MHz, CD3OD) δ ppm 1 .15 (d, J=7.1 Hz, 3 H), 1 .18 (t, J=7.2 Hz, 3 H), 1 .58 (ddd, J=14.2, 10.6, 4.0 Hz, 1 H), 1 .97 (ddd, J=13.9, 10.2, 3.7 Hz, 1 H), 2.56 (ddd, J=10.5, 7.0, 4.0 Hz, 1 H), 2.84 (dd, J=6.7, 4.2 Hz, 2 H), 3.96 - 4.15 (m, 2 H), 4.19 - 4.37 (m, 1 H), 7.03 (s, 1 H), 7.20 - 7.34 (m, 3 H), 7.40 (t, J=7.6 Hz, 2 H), 7.52 (d, J=8.1 Hz, 2 H), 7.57 (d, J=7.3 Hz, 2 H), 7.72 (d, J=8.8 Hz, 1 H). Example 47-1 1 : 1 H NMR (400 MHz, DMSO-d6) δ ppm 1 .07 (d, J=7.1 Hz, 3 H) 1 .12 (t, J=7.1 Hz, 3 H) 1 .66 (ddd, J=14.1 , 10.3, 4.4 Hz, 1 H) 1 .83 (ddd, J=13.7, 9.9, 3.7 Hz, 1 H) 2.43 - 2.49 (m, 1 H) 2.77 (dd, J=13.7, 7.9 Hz, 1 H) 2.85 (dd, J=13.7, 7.9 Hz, 1 H) 3.94 - 4.05 (m, 2 H) 4.07 - 4.20 (m, 1 H) 7.28 (d, J=8.3 Hz, 2 H) 7.37 - 7.43 (m, 1 H) 7.47 (t, J=7.8 Hz, 1 H) 7.59 - 7.66 (m, 3 H) 7.70 (t, J=1 .9 Hz, 1 H) 8.83 (br. s., 1 H) 13.12 (br. s., 1 H).
Example 49-1 : Synthesis of (2R,4S)-5-(3'-Chloro-biphenyl-4-yl)-4-[(3-hydroxy-isoxazole- 5-carbonyl)-amino]-2-methyl-pentanoic acid and
Example 50-1 : Synthesis of (2S,4S)-5-(3'-Chloro-biphenyl-4-yl)-4-[(3-hydroxy-isoxazole- 5-carbonyl)-amino]-2-methyl-pentanoic acid
Figure imgf000144_0001
To a solution of S-hydroxy-isoxazole-δ-carboxylic acid (Intermediate 20) (74.6 mg, 0.578 mmol), HATU (264 mg, 0.694 mmol) in DMF (3 ml_) is added pyridine (0.14 ml_, 1.735 mmol) and the resulting mixture is stirred at room temperature for 15 minutes. Then (S)-4- amino-5-(3'-chloro-biphenyl-4-yl)-2-methyl-pentanoic acid ethyl ester hydrochloride (Intermediate 31 ) (200 mg, 0.578 mmol) is added and the mixture is stirred at room temperature for 2 hours. Any insoluble material is filtered and the filtrate purified by preparative HPLC using a gradient of 10% MeCN/water to 100% MeCN (0.1 % TFA). The diastereomeric mixture is further purified by chiral HPLC on a Chirapak IA column using heptane/ethanol (80:20) (0.1 % TFA) to elute each diastereomer, (2R,4S)-5-(3'-chloro- biphenyl-4-yl)-4-[(3-hydroxy-isoxazole-5-carbonyl)-amino]-2-methyl-pentanoic acid ethyl ester and (2S,4S)-5-(3'-chloro-biphenyl-4-yl)-4-[(3-hydroxy-isoxazole-5-carbonyl)-amino]-2- methyl-pentanoic acid ethyl ester.
Next, to a solution of (2R,4S)-5-(3'-chloro-biphenyl-4-yl)-4-[(3-hydroxy-isoxazole-5- carbonyl)-amino]-2-methyl-pentanoic acid ethyl ester (73 mg, 0.16 mmol) in ethanol (4m L) is added 1 N NaOH (2mL) and the resulting mixture is stirred at room temperature for 2 hours. The mixture is acidified with 1 N HCI and the solvent is removed under reduced pressure. The resulting residue is purified by preparative HPLC using a gradient of 10% MeCN/water to 100% MeCN (0.1 % TFA) to give (2R,4S)-5-(3'-chloro-biphenyl-4-yl)-4-[(3-hydroxy- isoxazole-5-carbonyl)-amino]-2-methyl-pentanoic acid; HPLC Retention time 1 .05 minutes (condition C): MS 429.1 (M+1 ); 1 H NMR (400 MHz, DMSO-Cf6) • ppm 1 .07 (d, 3 H) 1 .58 (ddd, J=13.89, 9.98, 4.42 Hz, 1 H) 1 .87 (ddd, J=13.71 , 9.66, 3.92 Hz, 1 H) 2.41 (ddd, J=9.54, 7.14, 4.55 Hz, 1 H) 2.82 (dd, J=6.69, 3.41 Hz, 2 H) 4.10 - 4.24 (m, 1 H) 6.50 (s, 1 H) 7.28 (d, J=8.34 Hz, 2 H) 7.36 - 7.42 (m, 1 H) 7.47 (t, J=7.83 Hz, 1 H) 7.58 - 7.65 (m, 3 H) 7.70 (t, J=1 .89 Hz, 1 H) 8.66 (d, J=8.59 Hz, 1 H).
The second diastereomer, (2S,4S)-5-(3'-chloro-biphenyl-4-yl)-4-[(3-hydroxy-isoxazole-5- carbonyl)-amino]-2-methyl-pentanoic acid is prepared from the hydrolysis of (2R,4S)-5-(3'- chloro-biphenyl-4-yl)-4-[(3-hydroxy-isoxazole-5-carbonyl)-amino]-2-methyl-pentanoic acid ethyl ester analogous to the above example; HPLC Retention time 1 .17 minutes (condition C): MS 429.3 (M+1 ); 1 H NMR (400 MHz, DMSO-d6) • ppm 1 .06 (d, J=7.07 Hz, 3 H) 1.55 (ddd, J=13.64, 9.47, 3.92 Hz, 1 H) 1 .96 (ddd, J=13.83, 10.67, 4.80 Hz, 1 H) 2.32 (ddd, J=9.09, 7.07, 5.05 Hz, 1 H) 2.86 (d, J=7.07 Hz, 2 H) 4.17 - 4.31 (m, 1 H) 6.50 (s, 1 H) 7.30 (d, J=8.34 Hz, 2 H) 7.36 - 7.43 (m, 1 H) 7.46 (t, J=7.83 Hz, 1 H) 7.56 - 7.65 (m, 3 H) 7.70 (t, J=1 .89 Hz, 1 H) 8.68 (d, J=9.09 Hz, 1 H) 1 1 .67 (s, 1 H).
The following compounds are prepared using similar procedure as example 49-1 with appropriate reagents and conditions:
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Example 49-2: 1 H NMR (400 MHz, DMS0-d6) • ppm 1 .08 (d, J=7.07 Hz, 3 H) 1 .50 - 1 .66
(m, 1 H) 1 .78 - 1 .94 (m, 1 H) 2.70 - 2.93 (m, 2 H) 4.22 (br. s., 1 H) 7.29 (d, J=8.34 Hz, 2 H)
7.35 - 7.41 (m, 1 H) 7.46 (t, J=7.83 Hz, 1 H) 7.53 - 7.64 (m, 3 H) 7.69 (t, J=1 .89 Hz, 1 H)
8.25 (br. s., 1 H).
Example 49-3: 1 H NMR (400 MHz, DMS0-d6) • ppm 1 .08 (d, J=7.07 Hz, 3H, 1 .54 - 1 .65
(m, 1 H) 1 .81 - 1 .93 (m, 1 H) 2.37 - 2.46 (m, 2 H) 2.85 (dd, J=10.23, 6.95 Hz, 2 H) 4.23 (br. s., 1 H) 7.16 (d, J=3.54 Hz, 1 H) 7.22 (br. s., 1 H) 7.29 (d, J=8.34 Hz, 2 H) 7.34 - 7.42 (m, 1
H) 7.46 (t, J=7.83 Hz, 1 H) 7.57 - 7.65 (m, 3 H) 7.69 (t, J=1 .89 Hz, 1 H) 8.40 (d, J=8.84 Hz,
1 H).
Example 49-4: 1 H NMR (400 MHz, DMS0-d6) • ppm 1 .08 (d, J=7.07 Hz, 3H), 1 .46 (m, 1 H),
1 .88 (m, 1 H), 2.45 (m, 1 H), 2.83 (d, J=6.57 Hz, 2H), 4.19 (m, 1 H), 6.72 (d, J=2.53 Hz, 1 H),
7.29 (d, J=8.34 Hz, 2H), 7.38-7.41 (m, 1 H), 7.46 (t, 2H), 7.62 (d, J=8.08 Hz, 3H), 7.70 (m,
1 H), 8.09 (d, J=8.34, 1 H), 1 1 .89 (s, broad, 1 H).
Example 49-5: 1 H NMR (400 MHz, DMSO-d6): δ ppm 1 .03-1 .05 (d, J=7.07 Hz, 3H), 1 .21 -
1 .35 (m, 2H), 1 .69-1 .77 (m, 1 H), 2.62-2.67 (m, 1 H), 2.70-2.71 (m, 2H), 3.67-3.68 (d, J=5.81
Hz, 2H), 3.73-3.80 (m, 1 H), 5.97-6.01 (t, J=8.08 Hz, 1 H), 6.12-6.14 (d, J=8.34 Hz, 1 H), 7.26-
7.28 (m, 2H), 7.38-7.41 (m, 1 H), 7.45-7.49 (t, J=7.83 Hz, 1 H), 7.59-7.64 (m, 3H), 7.69-7.70
(t, J=2.02 Hz, 1 H), 12.09 (s, 1 H), 12.43 (s, 1 H). Example 49-6: 1 H NMR (400 MHz, DMSO- cfe): δ ppm 1 .07-1 .10 (m, 6H), 1 .49-1 .56 (m, 1 H),
1 .84-1 .91 (m, 1 H), 2.47-2.56 (m, 1 H), 2.77-2.87 (m, 2H), 3.94-3.99 (q, J=7.07 Hz, 14.05 Hz,
2H), 4.1 1 --4.20 (m, 1 H), 6.72-6.73 (d, J=2.27 Hz, 2H), 7.28-7.30 (m, 2H), 7.38-7.41 (m, 1 H),
7.44-7.48 (t, J=7.83 Hz, 1 H), 7.61 -7.64 (m, 3H), 7.69-7.70 (t, J=1 .77 Hz, 1 H), 8.07-8.10 (d,
J=8.34 Hz, 1 H), 1 1 .89 (s, 1 H), 12.74 (s, 1 H).
Example 49-7: 1 H NMR (400 MHz, DMSO-Cf6) δ ppm 1 .07 (d, 3 H) 1 .64 - 1 .74 (m, 1 H) 1 .84 -
1 .94 (m, 1 H) 2.41 (ddd, J=9.35, 7.07, 4.55 Hz, 1 H) 2.80 - 2.89 (m, 1 H) 2.92 - 3.01 (m, 1
H) 4.26 - 4.40 (m, 1 H) 7.30 (d, J=8.08 Hz, 2 H) 7.35 - 7.40 (m, 1 H) 7.45 (t, J=7.83 Hz, 1 H)
7.52 - 7.63 (m, 3 H) 7.68 (t, J= 1 .77 Hz, 1 H) 8.00 (dd, J=4.93, 1 .64 Hz, 1 H) 8.33 (s, 1 H)
8.78 (d, J=9.35 Hz, 1 H) 8.85 (d, J=4.80 Hz, 1 H).
Example 49-8: 1 H NMR (400 MHz, DMSO- cfe): δ ppm 1 .08-1 .10 (d, J=7.07 Hz, 3H), 1 .62-
1 .69 (m, 1 H), 1 .89-1 .96 (m, 1 H), 2.41 -2.50 (m, 1 H), 2.85-2.98 (m, 2H), 4.26-36 (m, 1 H), 7.33-7.35 (m, 2H), 7.38-7.41 (m, 1 H), 7.45-7.49 (t, J=7.83 Hz, 1 H), 7.60-7.63 (m, 3H), 7.69-
7.70 (t, J=2.02 Hz, 1 H), 8.12-8.13 (d, J=5.05 Hz, 1 H), 8.87-8.89 (d, J=9.09 Hz, 1 H), 9.19- 9.21 (d, J=5.05 Hz, 1 H), 12.06 (s, 1 H), 13.99 (s, 1 H).
Example 49-9: 1 H NMR (400 MHz, DMSO-Cf6) δ ppm 1 .09 (d, J=7.07 Hz, 3 H) 1 .68 (ddd, J= 13.96, 10.04, 4.29 Hz, 1 H) 1 .90 (ddd, J= 13.71 , 9.79, 4.04 Hz, 1 H) 2.79 - 2.96 (m, 2 H) 4.27 (br. s., 1 H) 7.30 (d, J=8.34 Hz, 2 H) 7.37 - 7.42 (m, 1 H) 7.46 (t, J=7.83 Hz, 1 H) 7.56 - 7.64 (m, 3 H) 7.68 (t, J= 1 .77 Hz, 1 H) 9.24 (br. s., 1 H) 1 1 .59 - 12.34 (m, 1 H) Example 49-10: 1 H NMR (400 MHz, DMSO-Cf6) δ ppm 1 .02 - 1 .13 (m, 3 H) 1 .59 (ddd, J=13.89, 9.85, 4.55 Hz, 1 H) 1 .88 (ddd, J= 13.71 , 9.54, 4.04 Hz, 1 H) 2.42 (ddd, J=9.35, 7.07, 4.55 Hz, 1 H) 2.78 - 2.92 (m, 2 H) 4.13 - 4.29 (m, 1 H) 6.50 (s, 1 H) 7.24 - 7.32 (m, 2 H) 7.33 - 7.39 (m, 2 H) 7.41 - 7.49 (m, 2 H) 7.55 - 7.62 (m, 1 H) 8.68 (d, J=8.84 Hz, 1 H) 1 1 .66 (br. s., 1 H)
The following (2S,4S)-compounds are prepared using similar procedure as example 50-1 with appropriate reagents and conditions:
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Example 50-2: 1 H NMR (400 MHz, DMSO-d6) • ppm 0.99 - 1 .13 (m, J=7.07, Hz 3 H) 1 .42 - 1 .65 (m, 1 H) 1 .86 - 2.10 (m, 1 H) 2.73 - 2.96 (m, 2 H) 4.17 - 4.37 (m, 1 H) 7.28 - 7.34 (m, 2 H) 7.35 - 7.42 (m, 1 H) 7.45 (t, J=7.96 Hz, 1 H) 7.55 - 7.64 (m, 3 H) 7.66 - 7.72 (m, 1 H) 8.10 - 8.49 (m, 1 H) 12.12 (br. s., 1 H) 13.98 - 14.30 (m, 1 H).
Example 50-3: 1 H NMR (400 MHz, DMSO-d6): • ppm 1 .04-1 .05 (d, J=6.82 Hz, 3H), 1 .50- 1 .58 (m, 1 H), 1 .83-1 .90 (m, 1 H), 2.32-2.39 (m, 1 H), 2.80-2.89 (m, 2H), 4.22-4.31 (m, 1 H), 6.72 (d, J=1 .77 Hz, 2H), 7.28-7.32 (m, 2H), 7.38-7.40 (m, 1 H), 7.44-7.48 (t, J=7.83 Hz, 1 H), 7.61 -7.63 (m, 3H), 7.70 (s, 1 H), 8.10-8.12 (d, J=8.84 Hz, 1 H), 1 1 .91 (s, 1 H). Example 50-4: 1 H NMR (400 MHz, DMSO-d6): • ppm 1 .10-1 .12 (d, J=6.82 Hz, 3H), 1 .48- 1 .55 (m, 1 H), 1 .90-1 .97 (m, 1 H), 2.32-2.39 (m, 1 H), 2.82-2.89 (m, 2H), 4.06-4.13 (m, 1 H), 7.27-7.29 (d, J=8.34 Hz, 2H), 7.39-7.42 (m, 1 H), 7.46-7.50 (t, J=7.83 Hz, 1 H), 7.61 -7.65 (m, 3H), 7.70-7.71 (t, J=1 .77 Hz, 1 H), 9.25-9.28 (d, J=9.09 Hz, 1 H).
Example 50-5: 1 H NMR (400 MHz, DMSO-d6): • ppm 0.99-1 .01 (d, J=6.82 Hz, 3H), 1 .35- 1 .42 (m, 1 H), 1 .62-1 .69 (m, 1 H), 2.35-2.41 (m, 1 H), 2.71 -2.74 (m, 2H), 3.68-3.69 (d, J=7.33 Hz, 2H), 3.84-3.91 (m, 1 H), 5.98-6.01 (m, 1 H), 6.07-6.13 (m, 1 H), 7.27-7.29 (m, 2H), 7.38- 7.41 (m, 1 H), 7.45-7.49 (t, J=7.71 Hz, 1 H), 7.60-7.65 (m, 3H), 7.69-7.71 (m, 1 H). Example 50-6: 1 H NMR (400 MHz, DMSO-d6) δ ppm 1 .08 (d, 3 H) 1 .51 - 1 .62 (m, 1 H) 2.01 - 2.1 1 (m, 1 H) 2.28 - 2.36 (m, 1 H) 2.86 - 2.95 (m, 1 H) 2.95 - 3.04 (m, 1 H) 4.38 (br. s., 1 H) 7.31 (d, J=8.34 Hz, 2 H) 7.35 - 7.41 (m, 1 H) 7.45 (t, J=7.96 Hz, 1 H) 7.55 - 7.62 (m, 3 H) 7.68 (t, J= 1 .77 Hz, 1 H) 8.00 (dd, J=4.93, 1 .64 Hz, 1 H) 8.33 (s, 1 H) 8.78 (d, J=9.60 Hz, 1 H) 8.85 (d, J=5.05 Hz, 1 H).
Example 50-7: 1 H NMR (400 MHz, DMSO- cfe): δ ppm 1 .06-1 .08 (d, J=6.82 Hz, 3H), 1 .54- 1 .61 (m, 1 H), 1 .98-2.06 (m, 1 H), 2.31 -2.37 (m, 1 H), 2.91 -2.99 (m, 2H), 4.31 -40 (m, 1 H), 7.32-7.34 (m, 2H), 7.36-7.39 (m, 1 H), 7.42-7.46 (t, J=7.58 Hz, 1 H), 7.58-7.61 (m, 3H), 7.67- 7.68 (t, J=1 .77 Hz, 1 H), 8.10-8.1 1 (d, J=4.80 Hz, 1 H), 8.88-8.90 (d, J=9.85 Hz, 1 H), 9.17- 9.18 (d, J=5.05 Hz, 1 H), 12.1 1 (s, 1 H)
Example 50-8: 1 H NMR (400 MHz, DMSO-Cf6) δ ppm 1 .08 (d, 3 H) 1 .59 (ddd, J= 13.64, 9.60, 3.79 Hz, 1 H) 1 .93 - 2.15 (m, 1 H) 2.28 - 2.44 (m, 1 H) 2.77 - 3.00 (m, 2 H) 4.32 (br. s., 1 H) 7.32 (d, J=8.08 Hz, 2 H) 7.36 - 7.41 (m, 1 H) 7.46 (t, J=7.83 Hz, 1 H) 7.55 - 7.63 (m, 3 H) 7.68 (t, J=1 .77 Hz, 1 H) 9.19 (d, J=9.09 Hz, 1 H) 12.13 (br. s., 1 H)
Example 51-1 : Synthesis of (2R,4S)-4-(3-Carboxymethyl-ureido)-5-(3'-chloro-biphenyl- 4-yl)-2-methyl-pentanoic acid ethyl ester
Figure imgf000153_0001
(S)-5-(3'-Chloro-biphenyl-4-yl)-4-isocyanato-2-methyl-pentanoic acid ethyl ester is prepared from (S)-4-amino-5-(3'-chloro-biphenyl-4-yl)-2-methyl-pentanoic acid ethyl ester hydrochloride (Intermediate 31 ) and triphosgene analogous to the procedure described for Example 6-1 .
Next, to a solution of tert-butyl 2-aminoacetate (140 mg, 1 .065 mmol) in DMF (5 ml_) is added DIEA (344 mg, 2.66 mmol). The solution is stirred at room temperature for 5 minutes then (S)-5-(3'-chloro-biphenyl-4-yl)-4-isocyanato-2-methyl-pentanoic acid ethyl ester (330 mg, 0.887 mmol) is added. The mixture is stirred at room temperature for 2 hours then the solvent is removed under reduced pressure to give (S)-4-(3-tert-butoxycarbonylmethyl- ureido)-5-(3'-chloro-biphenyl-4-yl)-2-methyl-pentanoic acid ethyl ester which is used directly in the following reaction.
Next, a solution of (S)-4-(3-tert-butoxycarbonylmethyl-ureido)-5-(3'-chloro-biphenyl-4-yl)-2- methyl-pentanoic acid ethyl ester (261 mg, 59.1 mmol) in 8 ml_ of methylene chloride/TFA (1 :1 ) is stirred at room temperature for 1 hour. The solvent is removed under reduced pressure and the residue is purified by preparative HPLC using a gradient of 10% MeCN/water to 100% MeCN (0.1 % TFA) and the product is further purified by chiral HPLC on a Chirapak OD-H column using heptane/ethanol (90:10) (0.1 % TFA) to elute the title compound; HPLC Retention time 1 .48 minutes (condition C): MS 447.3 (M+1 ); 1 H NMR (400 MHz, DMSO-d6): • ppm 1 .03-1 .05 (d, J=7.07 Hz, 3H), 1 .08-1 .12 (t, J=7.33 Hz, 3H), 1 .27-1 .34 (m, 1 H), 1 .70-1 .76 (m, 1 H), 2.62-2.67 (m, 1 H), 2.71 -2.76 (m, 2H), 3.66-3.68 (d, J=5.81 Hz, 2H), 3.71 -3.78 (m, 1 H), 3.95-4.00 (q, J=7.07 Hz, 14.40 Hz, 2H), 5.94-5.97 (t, J=5.56 Hz, 1 H), 6.07-6.09 (d, J=8.34 Hz, 1 H), 7.25-7.28 (m, 2H), 7.38-7.41 (m, 1 H), 7.45- 7.49 (t, J=7.83 Hz, 1 H), 7.60-7.63 (m, 3H), 7.69-7.70 (t, J=1 .77 Hz, 1 H), 12.42 (s, 1 H). Example 52-1 : Synthesis of (2R,4S)-5-(3'-Chloro-biphenyl-4-yl)-2-methyl-4-[(2H- tetrazole-5-carbonyl)-amino]-pentanoic acid ethyl ester
Figure imgf000154_0001
To a solution of 2-(4-methoxy-benzyl)-2H-tetrazole-5-carboxylic acid (Intermediate 32) (149 mg, 0.636 mmol) in DMF (2 ml_) is added HATU. The mixture is stirred at room temperature for 15 minutes then (S)-4-amino-5-(3'-chloro-biphenyl-4-yl)-2-methyl-pentanoic acid ethyl ester hydrochloride (Intermediate 31 ) (200 mg, 0.578 mmol) is added and the mixture is stirred at room temperature for 2 hours. Any insoluble material is filtered and the filtrate is purified by preparative HPLC using a gradient of 10% MeCN/water to 100% MeCN (0.1 % TFA) to give (S)-5-(3'-chloro-biphenyl-4-yl)-4-{[2-(4-methoxy-benzyl)-2H-tetrazole-5- carbonyl]-amino}-2-methyl-pentanoic acid ethyl ester; HPLC Retention time 1 .79 minutes (condition C): MS 562.4 (M+1 ).
Next, a solution of (S)-5-(3'-chloro-biphenyl-4-yl)-4-{[2-(4-methoxy-benzyl)-2H-tetrazole-5- carbonyl]-amino}-2-methyl-pentanoic acid ethyl ester (212 mg, 0.377 mmol) in TFA (5 mL) is stirred at room temperature for 18 hours. The solvent is removed under reduced pressure and the residue is purified by chiral HPLC on a Chirapak IA column using heptane/ethanol (80:20) (0.1 % TFA) to elute the title compound; HPLC Retention time 1 .59 minutes (condition C): MS 442.2 (M+1 ); 1 H NMR (400 MHz, DMSO-d6) δ ppm 1 .05 - 1 .10 (m, 3 H) 1 .10 - 1 .16 (m, 3 H) 1 .69 - 1 .79 (m, 1 H) 1 .88 (ddd, J=13.89, 9.98, 3.92 Hz, 1 H) 2.77 - 2.87 (m, 1 H) 2.87 - 2.96 (m, 1 H) 3.91 - 4.05 (m, J=10.72, 7.14, 7.14, 3.66, 3.66 Hz, 2 H) 4.24 (br. s., 1 H) 6.85 - 6.85 (m, 0 H) 7.30 (d, J=8.34 Hz, 2 H) 7.37 - 7.42 (m, 1 H) 7.46 (t, J=7.83 Hz, 1 H) 7.56 - 7.64 (m, 3 H) 7.68 (t, J=1 .77 Hz, 1 H) 9.18 (br. s., 1 H).
Example 53-1 : Synthesis of (2R,4S)-5-Biphenyl-4-yl-2-methyl-4-(1 H-tetrazol-5- ylcarbamoyl)-pentanoic acid ethyl ester
Figure imgf000155_0001
Prepared using similar procedure described in Example 52-1 with appropriate intermediates and conditions. Intermediate 1 and benzyl-H-tetrazole-5-carbonyl chloride (prepared according to J.Med.Chem. 1986, 29, 538-549) are used instead of intermediates 31 and 32. For coupling reaction, Et3N and DCM are used instead of HATU and DMF. For deprotection, hydrogeneation with Pd on carbon is used instead of TFA. HPLC Retention time 1 .36 minutes (condition C): MS 408 (M+1 ); 1H NMR (400MHz, DMSO- dβ) δ 1 .08 (d, 3H, J = 7.1 Hz), 1 .10 (t, 3H, J = 7.3 Hz), 1 .75 (ddd, 1 H, J = 4.2, 10.4, 13.9 Hz), 1 .89 (ddd, 1 H, J = 4.1 , 9.9, 13.9 Hz), 2.50-2.56 (m, 2H), 2.82 (dd, 1 H1 J = 6.1 , 13.6 Hz), 2.91 (dd, 1 H, J = 8.1 , 13.6 Hz), 3.93-4.03 (m, 2H), 4.19-4.31 (m, 1 H), 7.28 (d, 2H, J = 8.3 Hz), 7.30-7.36 (m, 1 H), 7.43 (dd, 2H, J = 7.8, 7.8 Hz), 7.56 (d, 2H, J = 8.1 Hz), 7.62 (d, 2H, J = 7.1 Hz).
Example 54-1 : Synthesis of (2R,4S)-5-(3'-chlorobiphenyl-4-yl)-2-methyl-4-(5-oxo-4,5- dihydro-1 ,2,4-oxadiazole-3-carboxamido)pentanoic acid
Figure imgf000155_0002
To a solution of (2R,4S)-ethyl 5-(3'-chlorobiphenyl-4-yl)-2-methyl-4-(5-oxo-4,5-dihydro-1 ,2,4- oxadiazole-3-carboxamido)pentanoate (25 mg, 0.055 mmol) in MeOH (2 ml_) is added aqueous 1 N NaOH (4 ml_). After stirring at room temperature for 2 hours, the crude is quenched with 1 N HCI and concentrated under reduced pressure to remove MeOH. The crude is diluted with EtOAc. The organic layer is washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The obtained residue is purified by RP- HPLC (SunFire C18, H2O(0.1 % TFA)/CH3CN), and then lyophilized to give (2R,4S)-5-(3'- chlorobiphenyl-4-yl)-2-methyl-4-(5-oxo-4,5-dihydro-1 ,2,4-oxadiazole-3- carboxamido)pentanoic acid (22 mg). HPLC retention time = 1 .64 minutes (condition B); MS (m+1 ) = 430.2; 1 H NMR (400 MHz, CD3OD) δ ppm 1 .18 (d, J=7.1 Hz, 3 H) 1 .68 (ddd, J=14.3, 10.5, 4.0 Hz, 1 H) 1 .99 - 2.05 (m, 1 H) 2.55 (ddd, J=10.2, 6.8, 3.9 Hz, 1 H) 2.80 - 2.97 (m, 2 H) 4.27 - 4.44 (m, 1 H) 7.28 - 7.35 (m, 3 H) 7.39 (t, J=7.8 Hz, 1 H) 7.49 - 7.55 (m, 3 H) 7.58 (t, J=1 .9 Hz, 1 H)
Example 55-1 : Synthesis of (2R,4S)-5-(3'-chlorobiphenyl-4-yl)-2-methyl-4-(5-oxo-4,5- dihydro-1 ,3,4-oxadiazole-2-carboxamido)pentanoic acid
Figure imgf000156_0001
To a solution of (2R,4S)-ethyl 5-(3'-chlorobiphenyl-4-yl)-2-methyl-4-(5-oxo-4,5-dihydro-1 ,3,4- oxadiazole-2-carboxamido)pentanoate (91 mg, 0.198 mmol) in MeOH (2 mL) is added aqueous 1 N NaOH (4 mL, 4 mmol). After stirring at room temperature for 2 hours, the crude is quenched with 1 N HCI and concentrated under reduced pressure to remove MeOH and is diluted with EtOAc, the organic layer is washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The obtained residue is purified by RP-HPLC (SunFire C18, H2O(0.1 % TFA)/CH3CN), and then lyophilized to give (2R,4S)-5-(3'- chlorobiphenyl-4-yl)-2-methyl-4-(5-oxo-4,5-dihydro-1 ,3,4-oxadiazole-2- carboxamido)pentanoic acid (62 mg). HPLC retention time = 1 .60 minutes (condition B); MS (m+1 ) = 430.1 ; 1 H NMR (400 MHz, DMSO-d6) δ ppm 1 .01 - 1 .12 (d, J=7.1 Hz, 3 H) 1 .60 (ddd, J=13.8, 9.9, 4.3 Hz, 1 H) 1 .85 (ddd, J=13.6, 9.6, 4.0 Hz, 1 H) 2.35 - 2.47 (m, 1 H) 2.79 (dd, J=13.7, 7.8 Hz, 1 H) 2.86 (dd, J=13.7, 7.8 Hz, 1 H) 4.1 1 - 4.28 (m, 1 H) 7.28 (d, J=8.3 Hz, 2 H) 7.35 - 7.43 (m, 1 H) 7.47 (t, J=7.8 Hz, 1 H) 7.57 - 7.65 (m, 3 H) 7.70 (t, J=1 .8 Hz, 1 H) 8.84 (d, J=8.8 Hz, 1 H) 12.05 (br. s., 1 H) 12.92 (s, 1 H). Example 56-1 : Synthesis of (2R,4S)-ethyl 5-(biphenyl-4-yl)-2-methyl-4-(2-oxo-2,3- dihydrothiazole-5-carboxamido)pentanoate
Figure imgf000157_0001
To a solution of (2R,4S)-ethyl 5-(biphenyl-4-yl)-4-(2-methoxythiazole-5-carboxamido)-2- methylpentanoate, intermediate 19, (171 mg, 0.38 mmol) in dioxane (6 ml_) is added 4 M HCI in dioxane (0.25 ml_, 1 .00 mmol). The crude is stirred at room temperature for 5 hrs. The residue is purified by preparative HPLC using a gradient of MeCN/water (0.1 % TFA). The proper fractions are lyophilized to furnish (2R,4S)-ethyl 5-(biphenyl-4-yl)-2-methyl-4-(2- oxo-2,3-dihydrothiazole-5-carboxamido)pentanoate (57 mg). HPLC retention time = 1 .80 minutes (condition A), MS 439.3 (M+1 ). 1 H NMR (400 MHz, CHLOROFORM-cQ δ ppm 1 .17 (d, J=7.1 Hz, 3 H), 1 .23 (t, J=7.2 Hz, 3 H), 1 .67 (ddd, J=14.0, 10.0, 3.5 Hz, 1 H), 1 .85 - 2.03 (m, 1 H), 2.51 - 2.69 (m, 1 H), 2.77 - 2.91 (m, 1 H), 2.93 - 3.05 (m, 1 H), 4.13 (q, J=7.1 Hz, 2 H), 4.26 - 4.42 (m, 1 H), 5.97 (d, J=8.1 Hz, 1 H), 7.17 - 7.29 (m, 2 H) 7.29 - 7.37 (m, 1 H) 7.42 (t, J=7.6 Hz, 2 H) 7.53 (d, J=7.8 Hz, 2 H) 7.57 (d, J=8.1 Hz, 2 H) 9.46 (br. s., 1 H).
Example 57-1 (2R,4S)-ethyl 5-(biphenyl-4-yl)-2-methyl-4-(5-oxo-4,5-dihydro-1 ,3,4- oxadiazole-2-carboxamido)pentanoate
Figure imgf000157_0002
To a solution of (2R,4S)-ethyl 5-(biphenyl-4-yl)-4-(2-hydrazinyl-2-oxoacetamido)-2- methylpentanoate, intermediate 24, (200 mg, 0.50 mmol) in THF (10 mL) is added CDI (86 mg, 0.53 mmol). The crude is stirred at room temperature for 4 hrs. The crude is heated to 60 deg C for 30 mins. This reaction is quenched with water and diluted in EtOAc. The organic layer is washed with brine, dried over MgSO4, filtered and concentrated. The crude residue is purified via HPLC MeCN/water (0.1 % TFA) to give (2R,4S)-ethyl 5-(biphenyl-4-yl)- 2-methyl-4-(5-oxo-4,5-dihydro-1 ,3,4-oxadiazole-2-carboxamido)pentanoate (69 mg). HPLC retention time = 1 .79 minutes (condition A), MS 424.2 (M+1 ).1 H NMR (400 MHz, CHLOROFORM-cQ δ ppm 1 .17 (d, J=7.1 Hz, 3H), 1 .22 (t, J=7.1 Hz, 3H), 1 .66 (ddd, J=14.3, 10.2, 3.8 Hz, 1 H), 2.02 (ddd, J=14.2, 10.0, 3.8 Hz, 1 H), 2.59 (m, 1 H), 2.89 (dd, 1 H), 2.96 (dd, 1 H), 4.03-4.19 (q, 2H), 4.37-4.47 (m, 1 H), 6.91 (d, J=8.8 Hz, 1 H), 7.25 (d, 1 H), 7.28- 7.35 (m, 1 H), 7.40 (t, J=7.6 Hz, 2H), 7.49-7.60 (m, 4H), 10.51 (br. s., 1 H).
Example 58-1 : Syntheis of (2R,4S)-ethyl 5-(biphenyl-4-yl)-2-methyl-4-(2-oxo-2,3- dihydrooxazole-5-carboxamido)pentanoate
Figure imgf000158_0001
To a solution of (2R,4S)-ethyl 5-(biphenyl-4-yl)-4-(2-methoxyoxazole-5-carboxamido)-2- methylpentanoate, intermediate 20, (175 mg, 0.40 mmol) in dioxane (5 mL) is added a solution of 4M HCI in dioxane (501 μL, 2.01 mmol) at room temperature. After stirring at room temperature for 1 hour, the reaction mixture is concentrated under reduced pressure. The obtained residue is purified by RP-HPLC (SunFire C18, H2O(0.1 % TFA)/CH3CN), and then lyophilized to give (2R,4S)-ethyl 5-(biphenyl-4-yl)-2-methyl-4-(2-oxo-2,3- dihydrooxazole-5-carboxamido)pentanoate (154 mg). HPLC retention time = 1 .89 minutes (condition B); MS 423.3 (M+1 ). 1 HNMR (400 MHz, DMSO-d6) δ ppm 1 .07 (d, J=7.1 Hz, 3 H) 1 .1 1 (t, J=7.1 Hz, 3 H) 1 .61 (ddd, J=14.0, 10.2, 4.3 Hz, 1 H) 1 .81 (ddd, J=13.8, 9.9, 3.9 Hz, 1 H) 2.41 - 2.50 (m, 1 H) 2.73 (dd, J=13.3, 7.3 Hz, 1 H) 2.83 (dd, J=13.3, 7.3 Hz, 1 H) 3.99 (q, J=7.1 , 2 H) 4.05 - 4.22 (m, 1 H) 7.26 (d, J=8.1 Hz, 2 H) 7.30 - 7.39 (m, 1 H) 7.44 (t, J=7.7 Hz, 2 H) 7.53 (s, 1 H) 7.58 (d, J=8.3 Hz, 2 H) 7.64 (d, J=7.1 Hz, 2 H) 8.10 (d, J=8.8 Hz, 1 H) 1 1 .25 (s, 1 H) Example 59-1 : Syntheis of (2R,4S)-ethyl 5-(3'-chlorobiphenyl-4-yl)-2-methyl-4-(5-oxo- 4,5-dihydro-1 ,3,4-oxadiazole-2-carboxamido)pentanoate
Figure imgf000159_0001
To a solution of (4S)-ethyl 5-(3'-chlorobiphenyl-4-yl)-4-(2-hydrazinyl-2-oxoacetamido)-2- methylpentanoate, intermediate 26, (542 mg, 1 .25 mmol) in THF (16 mL) is added CDI (244 mg, 1 .50 mmol) at room temperature. After stirring for 18 hour at room temperature, the reaction is quenched with H2O and 1 M HCI and diluted in EtOAc. The organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by RP-HPLC (SunFire C18, H2O(0.1 % TFA)/CH3CN) and by Chiral-HPLC (OJ-H 21 x250mm, EtOH(0.1 % TFA)/Heptane = 30/70) to give (2R,4S)-ethyl 5- (3'-chlorobiphenyl-4-yl)-2-methyl-4-(5-oxo-4,5-dihydro-1 ,3,4-oxadiazole-2- carboxamido)pentanoate (333 mg). HPLC retention time = 1 .74 minutes (condition A); MS 458.2 (M+1 ); 1 H NMR (400 MHz, DMSO-d6) δ ppm 1 .07 (d, J=7.1 Hz, 3 H) 1 .12 (t, J=7.1 Hz, 3 H) 1 .58 - 1 .74 (m, 1 H) 1 .76 - 1 .91 (m, 1 H) 2.45 - 2.50 (m, 1 H) 2.77 (dd, J=13.7, 7.9 Hz, 1 H) 2.86 (dd, J=13.7, 7.9 Hz, 1 H) 4.00 (q, J=7.1 Hz, 2 H) 4.06 - 4.22 (m, 1 H) 7.28 (d, J=8.1 Hz, 2 H) 7.37 - 7.42 (m, 1 H) 7.47 (t, J=7.8 Hz, 1 H) 7.58 - 7.66 (m, 3 H) 7.67 - 7.73 (m, 1 H) 8.86 (d, J=8.8 Hz, 1 H) 12.95 (s, 1 H).
Example 60-1 : Synthesis of (2S,4S)-5-(3'-chlorobiphenyl-4-yl)-4-(2-ethyloxazole-5- carboxamido)-2-methylpentanoic acid
Example 61-1 : (2R,4S)-5-(3'-chlorobiphenyl-4-yl)-4-(2-ethyloxazole-5-carboxamido)-2- methylpentanoic acid
Figure imgf000160_0001
To a solution of 2-ethyloxazole-5-carboxylic acid (95 mg, 0.68 mmol) in DMF (2 ml_) and DCM (2 ml_) is added (4S)-ethyl 4-amino-5-(3'-chlorobiphenyl-4-yl)-2-methylpentanoate hydrochloride (215 mg, 0.56 mmol), HATU (321 mg, 0.84 mmol), and TEA (392 μl_, 2.81 mmol). After stirring for 2 hours, the reaction is quenched with H2O, and the crude is diluted with EtOAc, the organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by RP-HPLC (SunFire C18, H2O(0.1 % TFA)/CH3CN) to give (4S)-ethyl 5-(3'-chlorobiphenyl-4-yl)-4-(2- ethyloxazole-5-carboxamido)-2-methylpentanoate (264 mg), HPLC retention time = 0.71 minutes (condition B); MS (m+1 ) = 469.3.
Next, to a solution of (4S)-ethyl 5-(3'-chlorobiphenyl-4-yl)-4-(2-ethyloxazole-5-carboxamido)- 2-methylpentanoate (264 mg, 0.56 mmol) in MeOH (2 mL) is added aqueous 1 N NaOH (4 mL) After stirring at room temperature for 2 hours, the crude is concentrated under reduced pressure to remove MeOH and is diluted with EtOAc, the organic layer is washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The obtained residue is purified by RP-HPLC (SunFire C18, H2O(0.1 % TFA)/CH3CN) and then is purified by chiral-HPLC (OJ-H, 15% EtOH(0.1 % TFA)/Heptane), and then lyophilized to give (2S,4S)-5-(3'-chlorobiphenyl-4-yl)-4-(2-ethyloxazole-5-carboxamido)-2- methylpentanoic acid (43 mg), HPLC retention time = 1 .63 minutes (condition B); MS (m+1 ) = 441 .2; 1 H NMR (400 MHz, CD3OD) δ ppm 1 H NMR (400 MHz, CD3OD) δ ppm 1 .17 (d, J=7.1 Hz, 3 H) 1 .35 (t, J=7.7 Hz, 3 H) 1 .69 (ddd, J=14.0, 8.3, 3.9 Hz, 1 H) 2.06 (ddd, J=14.1 , 10.8, 5.9 Hz, 1 H) 2.39 - 2.55 (m, 1 H) 2.85 (q, J=7.6 Hz, 2 H) 2.90 (dd, J=13.4, 7.6 Hz, 1 H) 2.95 (dd, J=13.1 , 5.8 Hz, 1 H) 4.31 - 4.52 (m, 1 H) 7.26 - 7.35 (m, 3 H) 7.38 (t, J=7.8 Hz, 1 H) 7.46 - 7.55 (m, 4 H) 7.57 (t, J=1 .9 Hz, 1 H) and (2R,4S)-5-(3'-chlorobiphenyl- 4-yl)-4-(2-ethyloxazole-5-carboxamido)-2-methylpentanoic acid (60 mg). HPLC retention time = 1 .62 minutes (condition B); MS (m+1 ) = 441 .2; 1 H NMR (400 MHz, CD3OD) δ ppm 1 .18 (d, J=7.1 Hz, 3 H) 1 .35 (t, J=7.6 Hz, 3 H) 1 .69 (ddd, J=14.1 , 10.4, 4.3 Hz, 1 H) 2.01 (ddd, J=14.0, 10.0, 3.8 Hz, 1 H) 2.46 - 2.63 (m, 1 H) 2.85 (q, J=7.6 Hz, 2 H) 2.91 (d, J=7.1 Hz, 2 H) 4.30 - 4.49 (m, 1 H) 7.26 - 7.34 (m, 3 H) 7.38 (t, J=7.8 Hz, 1 H) 7.46 - 7.52 (m, 3 H) 7.52 (s, 1 H) 7.56 (t, J=1 .9 Hz, 1 H) 8.31 (d, J=9.1 Hz, 1 H).
The following examples are prepared using a similar procedure described examples 60- 1 and examples 61 -1 via amide bond coupling reactions of various amine hydrochloride intermediates with various carboxylic acids with HATU. The ethyl ester hydrolysis proceeds under aq. NaOH conditions in methanol at rt.
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0001
Example 62-1 : 1 H NMR (400 MHz, CD3OD) δ ppm 1 .18 (d, J=6.8 Hz, 3 H) 1 .34 (t, J=7.6 Hz, 3 H) 1 .71 (ddd, J=14.0, 8.4, 3.9 Hz, 1 H) 2.07 (ddd, J=14.0, 10.7, 5.8 Hz, 1 H) 2.41 - 2.56 (m, 1 H) 2.85 (q, J=7.6 Hz, 2 H) 2.92 (dd, J=13.6, 8.3 Hz, 1 H) 2.97 (dd, J=13.6, 6.3 Hz, 1 H) 4.37 - 4.52 (m, 1 H) 7.26 - 7.35 (m, 6 H) 7.44 (d, J=8.8 Hz, 1 H) 7.52 (s, 1 H) 8.30 (d, J=9.3 Hz, 1 H).
Example 63-1 : 1 H NMR (400 MHz, DMSO-Cf6) δ ppm 1 .08 (d, J=7.1 Hz, 3 H) 1 .26 (t, J=7.6 Hz, 3 H) 1 .57 (ddd, J=13.9, 9.7, 4.2 Hz, 1 H) 1 .89 (ddd, J=13.9, 9.5, 4.2 Hz, 1 H) 2.35 - 2.47 (m, 1 H) 2.80 (q, J=7.6 Hz, 2 H) 2.84 (d, J=4.0 Hz, 1 H) 2.87 (dd, J=13.9, 7.8 Hz, 1 H) 4.15 - 4.30 (m, 1 H) 7.29 (d, J=8.3 Hz, 2 H) 7.36 (d, J=8.3 Hz, 2 H) 7.42 - 7.48 (m, 2 H) 7.55 - 7.61 (m, 2 H) 8.30 (d, J=8.6 Hz, 1 H) 12.00 (br. s., 1 H).
Example 64-1 : 1 H NMR (400 MHz, CD3OD) δ ppm 1 .17 (d, J=7.1 Hz, 3 H) 1 .35 (t, J=7.6 Hz, 3 H) 1 .70 (ddd, J=14.1 , 8.4, 4.0 Hz, 1 H) 2.05 (ddd, J=14.1 , 10.8, 5.7 Hz, 1 H) 2.41 - 2.52 (m, 1 H) 2.86 (q, J=7.6 Hz, 2 H) 2.90 (dd, J=5.8, 2.8 Hz, 1 H) 2.93 (dd, J=13.9, 6.6 Hz, 1 H)
3.72 (s, 3 H) 4.33 - 4.49 (m, 1 H) 6.94 - 7.06 (m, 3 H) 7.26 (d, J=8.1 Hz, 2 H) 7.39 (d, J=8.1
Hz, 2 H) 7.53 (s, 1 H) 8.29 (d, J=9.1 Hz, 1 H).
Example 65-1 : 1 H NMR (400 MHz, CD3OD) δ ppm 1 .19 (d, J=7.1 Hz, 3 H) 1 .35 (t, J=7.7 Hz,
3 H) 1 .69 (ddd, J=14.2, 10.3, 4.0 Hz, 1 H) 2.02 (ddd, J=14.0, 10.0, 3.8 Hz, 1 H) 2.49 - 2.61
(m, 1 H) 2.86 (q, J=7.7 Hz, 2 H) 2.90 (d, J=7.1 Hz, 2 H) 3.72 (s, 3 H) 4.34 - 4.46 (m, 1 H)
6.95 - 7.04 (m, 3 H) 7.25 (d, J=8.3 Hz, 2 H) 7.38 (d, J=8.1 Hz, 2 H) 7.52 (s, 1 H) 8.29 (d,
J=8.8 Hz, 1 H).
Example 66-1 : 1 H NMR (400 MHz, CD3OD) δ ppm 1 .19 (d, J=7.1 Hz, 3 H) 1 .70 (ddd,
J=14.2, 10.3, 4.0 Hz, 1 H) 2.04 (ddd, J=13.9, 9.9, 3.8 Hz, 1 H) 2.47 - 2.64 (m, 1 H) 2.87 -
2.93 (m, J=13.6, 7.8 Hz, 1 H) 2.97 (dd, J=13.6, 6.3 Hz, 1 H) 4.29 - 4.56 (m, 1 H) 7.28 - 7.34
(m, 6 H) 7.44 (d, J=8.6 Hz, 1 H) 7.64 (s, 1 H) 8.28 (s, 1 H).
Example 67-1 : 1 H NMR (400 MHz, CD3OD) δ ppm 1 .18 (d, J=6.8 Hz, 3 H) 1 .68 - 1 .74 (m, 1
H) 2.07 (ddd, J=14.0, 10.7, 5.9 Hz, 1 H) 2.42 - 2.55 (m, 1 H) 2.91 (dd, J=13.6, 8.1 Hz, 1 H)
2.98 (dd, J=13.6, 6.1 Hz, 1 H) 4.37 - 4.51 (m, 1 H) 7.29 - 7.35 (m, 6 H) 7.45 (d, J=8.8 Hz, 1
H) 7.64 (s, 1 H) 8.28 (s, 1 H).
Example 68-1 : 1 H NMR (400 MHz, CD3OD) δ ppm 1 .19 (d, J=7.3 Hz, 3 H) 1 .70 (ddd,
J=14.1 , 10.4, 4.0 Hz, 1 H) 2.03 (ddd, J=14.0, 10.0, 3.8 Hz, 1 H) 2.47 - 2.66 (m, 1 H) 2.89
(dd, J=13.6, 7.6 Hz, 1 H) 2.95 (dd, J=13.9, 6.6 Hz, 1 H) 4.33 - 4.51 (m, 1 H) 7.10 - 7.20 (m,
1 H) 7.27 - 7.36 (m, 3 H) 7.38 - 7.47 (m, 3 H) 7.65 (s, 1 H) 8.28 (s, 1 H).
Example 69-1 : 1 H NMR (400 MHz, CD3OD) δ ppm 1 .18 (d, J=7.1 Hz, 3 H) 1 .71 (ddd,
J=14.0, 8.2, 4.0 Hz, 1 H) 2.07 (ddd, J=14.0, 10.7, 6.1 Hz, 1 H) 2.40 - 2.59 (m, 1 H) 2.91 (dd,
J=13.4, 8.1 Hz, 1 H) 2.97 (dd, J=13.6, 6.3 Hz, 1 H) 4.36 - 4.53 (m, 1 H) 7.09 - 7.20 (m, 1 H)
7.27 - 7.36 (m, 3 H) 7.39 - 7.47 (m, 3 H) 7.65 (s, 1 H) 8.28 (s, 1 H).
Example 70-1 : 1 H NMR (400 MHz, CD3OD) δ ppm 1 .17 (d, J=6.8 Hz, 3 H) 1 .35 (t, J=7.7 Hz,
3 H) 1 .70 (ddd, J=14.1 , 8.3, 3.9 Hz, 1 H) 2.06 (ddd, J=14.0, 10.7, 5.8 Hz, 1 H) 2.40 - 2.55
(m, 1 H) 2.85 (q, J=7.6 Hz, 2 H) 2.91 (dd, J=13.9, 8.1 Hz, 1 H) 2.96 (dd, J=13.6, 6.3 Hz, 1
H) 4.35 - 4.55 (m, 1 H) 7.16 (dd, J=10.1 , 8.8 Hz, 1 H) 7.27 - 7.37 (m, 3 H) 7.39 - 7.47 (m, 3
H) 7.53 (s, 1 H).
Example 71 -1 : 1 H NMR (400 MHz, CD3OD) δ ppm 1 .19 (d, J=7.3 Hz, 3 H) 1 .34 (t, J=7.7 Hz,
3 H) 1 .70 (ddd, J=14.1 , 10.4, 4.0 Hz, 1 H) 2.02 (ddd, J=14.0, 10.0, 3.8 Hz, 1 H) 2.46 - 2.65
(m, 1 H) 2.85 (q, J=7.6 Hz, 2 H) 2.90 (dd, J=8.3, 2.0 Hz, 1 H) 2.95 (dd, J=14.1 , 6.6 Hz, 1 H) 4.27 - 4.52 (m, 1 H) 7.15 (dd, J= 10.1 , 8.8 Hz, 1 H) 7.26 - 7.37 (m, 3 H) 7.42 (d, J=9.3 Hz, 3 H) 7.53 (s, 1 H).
Example 72-1 : 1 H NMR (400 MHz, DMSO-Cf6) δ ppm 1 .06 (d, 3 H) 1 .56 (ddd, J= 13.64, 9.47, 3.92 Hz, 1 H) 1 .88 - 2.03 (m, 1 H) 2.33 (ddd, J=9.16, 6.76, 5.05 Hz, 1 H) 2.88 (d, J=6.82 Hz, 2 H) 4.25 (dd, J=9.09, 6.57 Hz, 1 H) 6.50 (s, 1 H) 7.26 - 7.33 (m, 2 H) 7.33 - 7.39 (m, 2 H) 7.42 - 7.49 (m, 2 H) 7.52 - 7.63 (m, 1 H) 8.62 - 8.77 (m, 1 H) 1 1 .66 (br. s., 1 H) 1 1 .97 - 12.31 (m, 1 H)
Example 73-1 : Synthesis of (2R,4S)-ethyl 5-(5'-fluoro-2'-methoxybiphenyl-4-yl)-4-(3- hydroxyisoxazole-5-carboxamido)-2-methylpentanoate
Example 74-1 : Synthesis of (2S,4S)-ethyl 5-(5'-fluoro-2'-methoxybiphenyl-4-yl)-4-(3- hydroxyisoxazole-5-carboxamido)-2-methylpentanoate
Figure imgf000167_0001
To a solution of S-hydroxyisoxazole-δ-carboxylic acid (137 mg, 1 .06 mmol) in DMF (3 ml_) and DCM (3 ml_) is added (4S)-ethyl 4-amino-5-(5'-fluoro-2'-methoxybiphenyl-4-yl)-2- methylpentanoate hydrochloride (350 mg, 0.88 mmol), HATU (504 mg, 1 .33 mmol), and TEA (616 μl_, 4.42 mmol). After stirring for 2 hours, the reaction is quenched with H2O, and the crude is diluted with EtOAc, the organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure.
The obtained residue is purified by RP-HPLC (SunFire C18, H2O(0.1 % TFA)/CH3CN) and then is purified by chiral-HPLC (OJ-H, 15% EtOH(0.1 % TFA)/Heptane), and then lyophilized to give (2R,4S)-ethyl 5-(5'-fluoro-2'-methoxybiphenyl-4-yl)-4-(3-hydroxyisoxazole-5- carboxamido)-2-methylpentanoate (1 10 mg), HPLC retention time = 1 .46 minutes (condition A); MS (m+1 ) = 471 .2; 1 H NMR (400 MHz, CD3OD) δ ppm 1 .16 (d, J=7.1 Hz, 3 H) 1 .19 (t, J=7.1 Hz, 3 H) 1 .70 (ddd, J=14.2, 10.7, 3.9 Hz, 1 H) 1 .98 (ddd, J=14.0, 10.4, 3.7 Hz, 1 H) 2.49 - 2.63 (m, 1 H) 2.85 (dd, J=13.6, 6.8 Hz, 1 H) 2.89 (dd, J=13.6, 7.3 Hz, 1 H) 3.72 (s, 3 H) 4.02 - 4.12 (m, 2 H) 4.23 - 4.42 (m, 1 H) 6.42 (s, 1 H) 7.00 (d, J=7.8 Hz, 3 H) 7.24 (d, J=8.1 Hz, 2 H) 7.39 (d, J=8.3 Hz, 2 H) 8.58 (d, J=8.8 Hz, 1 H), and (2S,4S)-ethyl 5-(5'- fluoro-2'-methoxybiphenyl-4-yl)-4-(3-hydroxyisoxazole-5-carboxamido)-2-methylpentanoate (66 mg). HPLC retention time = 1 .60 minutes (condition A); MS (m+1 ) = 471 .2; 1 H NMR (400 MHz, CD3OD) δ ppm 1 .15 (d, J=7.1 Hz, 3 H) 1 .19 (t, J=7.1 Hz, 3 H) 1 .70 (ddd, J=14.1 , 7.5, 3.9 Hz, 1 H) 2.05 (ddd, J=14.0, 10.6, 6.7 Hz, 1 H) 2.43 - 2.55 (m, 1 H) 2.86 (dd, J=13.6, 7.8 Hz, 1 H) 2.92 (dd, J=13.6, 6.6 Hz, 1 H) 3.72 (s, 3 H) 3.97 - 4.10 (m, 2 H) 4.32 - 4.43 (m, 1 H) 6.41 (s, 1 H) 6.97 - 7.04 (m, 3 H) 7.25 (d, J=8.3 Hz, 2 H) 7.39 (d, J=8.1 Hz, 2 H).
The title compound is prepared analogous to Example 73-1 and Exaple 74-1 using Intermediate 31 or 31 -3.
Figure imgf000168_0001
Figure imgf000169_0001
Example 75-1 : 1 H NMR (400 MHz, DMSO-Cf6) δ ppm 1 .08-1 .15 (m, 6H), 1 .69-1 .77 (m, 1 H), 1 .87-1 .95 (m, 1 H), 2.83-2.88 (m, 1 H), 2.94-2.99 (m, 2H), 3.97-4.02 (q, J=6.95 Hz,14.02 Hz, 2H), 4.24-4.33 (m, 1 H), 7.33-7.35 (m, 2H), 7.38-7.41 (m, 1 H), 7.45-7.49 (t, J=7.83 Hz, 1 H), 7.61 -7.63 (m, 3H), 7.68-7.69 (t, J=1 .77 Hz, 1 H), 8.08-8.10 (d, J=5.18 Hz, 1 H), 8.83-8.85 (d, J=7.33 Hz, 1 H), 9.17-9.18 (d, J=4.80 Hz, 1 H).
Example 76-1 : 1 H NMR (400 MHz, DMSO-d6) δ ppm 1 .03 - 1 .20 (m, 6 H) 1 .70 - 1 .82 (m, 1 H) 1 .82 - 1 .91 (m, 1 H) 2.79 - 2.87 (m, 1 H) 2.90 - 2.98 (m, 1 H) 3.92 - 4.01 (m, 2 H) 4.19 - 4.33 (m, 1 H) 7.30 (d, J=8.34 Hz, 2 H) 7.36 - 7.42 (m, 1 H) 7.46 (t, J=7.83 Hz, 1 H) 7.56 - 7.63 (m, 3 H) 7.68 (t, J=1 .77 Hz, 1 H) 7.96 (dd, J=4.80, 1 .52 Hz, 1 H) 8.32 (s, 1 H) 8.73 (d, J=9.35 Hz, 1 H) 8.78 (d, J=5.05 Hz, 1 H)
Example 77-1 : 1 H NMR (400 MHz, DMSO-Cf6) δ ppm 1 .03 - 1 .16 (m, 6 H) 1 .65 (ddd, J=14.02, 10.1 1 , 4.42 Hz, 1 H) 1 .86 (ddd, J=13.77, 9.85, 3.92 Hz, 1 H) 2.75 - 2.93 (m, 2 H) 3.93 - 4.03 (m, 2 H) 4.09 - 4.23 (m, 1 H) 6.50 (s, 1 H) 7.25 - 7.32 (m, 2 H) 7.33 - 7.40 (m, 2 H) 7.41 - 7.49 (m, 2 H) 7.54 - 7.63 (m, 1 H) 8.69 (d, J=8.84 Hz, 1 H) 1 1 .71 (br. s., 1 H) Example 79-1 : Synthesis of 2H-Tetrazole-5-carboxylic acid ((1S, 3R)-1-biphenyl-4- ylmethyl-4-methanesulfonylamino-3-methyl-4-oxo-butyl)-amide
Figure imgf000170_0001
To a solution of ((1 S, 3R)-1 -biphenyl-4-ylmethyl-4-methanesulfonylamino-3-methyl-4-oxo- butyl)-carbamic acid tert-butyl ester (90 mg, 0.195 mmol) in DCM (3 ml) at room temperature is added TFA (1 ml, 12.98 mmol). The reaction is stirred at room temperature. The mixture is concentrated to give N-((2R,4S)-4-Amino-5-biphenyl-4-yl-2-methyl-pentanoyl)- methanesulfonamide. Next, this crude is added a half solution of 2-benzyl-2H-tetrazole-5- carbonyl chloride (131 mg, 0.588 mmol) in DCM at O 0C and is followed by half of TEA (0.109 ml_, 0.782 mmol). And then after half hour, the other half reagents are added into the reaction. The reaction is warmed up slowly to room temperature. The reaction is quenched by brine and is extracted with DCM. The combined organic layer i washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated. Reverse phase HPLC [15 to 50% ACN-H2O (0.1 % NH4OH) over 10 min by X-bridge phenyl column] provides 2-Benzyl-2H-tetrazole-5-carboxylic acid ((1 S,3R)-1 -biphenyl-4-ylmethyl-4- methanesulfonylamino-3-methyl-4-oxo-butyl)-amide. HPLC retention time = 1 .50 minutes (condition C), MS (M-I ) = 545.3.
Next, A solution of 2-benyl-2H-tetrazole-5-carboxylic acid ((1 S, 3R)-1 -biphenyl-4-ylmethyl-4- methanesulfonylamino-3-methyl-4-oxo-butyl)-amide in MeOH/EtOAc is hydrogenated under H2 baloon by catalyst 10% Pd/C wet for 2 hours. The reaction is filtered off the catalyst and is concentrated. Reverse phase HPLC [35 to 80% ACN-H2O (0.1 % TFA) over 10 min by Sunfire C18 column] provides 2H-Tetrazole-5-carboxylic acid ((1 S, 3R)-1 -biphenyl-4- ylmethyl-4-methanesulfonylamino-3-methyl-4-oxo-butyl)-amide. 1 H NMR (400 MHz, DMSO- Cf6) δ ppm 1 .06 (d, J=7.1 Hz, 2 H), 1 .66 (ddd, J=13.8, 10.9, 3.5 Hz, 1 H), 1 .91 (ddd, J=13.7, 10.7, 3.4 Hz, 1 H), 2.54 - 2.63 (m, 1 H), 2.79 - 2.86 (m, 1 H), 2.86 - 2.93 (m, 1 H), 3.24 (s, 3 H), 4.15 - 4.28 (m, 1 H), 7.27 (d, J=8.3 Hz, 2 H), 7.30 - 7.36 (m, 1 H), 7.43 (t, J=7.6 Hz, 2 H), 7.55 (d, J=8.3 Hz, 2 H), 7.59 - 7.65 (m, 2 H), 9.19 (br. s., 1 H), 1 1 .54 (br. s., 1 H). HPLC retention time = 1 .24 min (method C): MS (m+1 ) = 457.1 .
Starting materials or intermediates are prepared in following manner:
Intermediate 1 : (2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid ethyl ester
Figure imgf000171_0001
Using the same procedure described in WO2008083967 or US005217996.
Intermediate 2: (2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid benzyl ester hydrochloride
Figure imgf000171_0002
To a solution of (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methyl-pentanoic acid (prepared using the procedure described in WO 2008083967)(1 .0 g, 2.61 mmol) and benzyl bromide (468 mg, 2.74 mmol) in DMF (15 ml_) is added potassium carbonate (541 mg, 3.91 mmol) and the mixture is stirred at room temperature for 2 hours. Water is added and the mixture is extracted with ethyl acetate. The combined organic layers are washed with water and dried over magnesium sulfate. The solvent is removed under reduced pressure and the residual oil is purified by column chromatography using heptane/EtOAc (4:1 ) to furnish (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methyl-pentanoic acid benzyl ester.
Next, to a solution of (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methyl- pentanoic acid benzyl ester in THF (5 ml_) is added 4M HCI in dioxane (3 ml_) and the solution is stirred at room temperature for 1 hour. The solvent is removed under reduced pressure to give the title compound. MS 374.4 (M+1 ). Intermediate 3: (2R,4S)-4-[(1-Benzyl-1 H-tetrazole-5-carbonyl)-amino]-5-biphenyl-4-yl-2- methyl-pentanoic acid benzyl ester and (2R,4S)-4-[(2-benzyl-2H-tetrazole-5-carbonyl)- amino]-5-biphenyl-4-yl-2-methyl-pentanoic acid benzyl ester
Figure imgf000172_0001
To a solution of (2/3,4S)-DeHZyI 4-amino-5-(biphenyl-4-yl)-2-methylpentanoate (92mg, 0.224mmol) and Et3N (0.078 ml_, 0.561 mmol)) in DCM (2 mL) are added benzyl-H- tetrazole-5-carbonyl chloride (mixture of 1 and 2-benzyl isomers, 60 mg, 0.269 mmol, prepared according to J.Med.Chem. 1986, 29, 538-549). After stirring for 0.5 hour, Et3N (0.078ml_, 0.561 mmol) and the acid chloride (60mg, 0.269mmol) are added. After stirring for 0.5 hour, the reaction mixture is diluted with ethyl acetate, washed with H2O and brine, dried over Na2SO4, and concentrated. The residue is purified by silica gel column chromatography to give a mixture of (2R,4S)-4-[(1 -benzyl-1 H-tetrazole-5-carbonyl)-amino]- 5-biphenyl-4-yl-2-methyl-pentanoic acid benzyl ester and (2R,4S)-4-[(2-benzyl-2H-tetrazole- 5-carbonyl)-amino]-5-biphenyl-4-yl-2-methyl-pentanoic acid benzyl ester. HPLC Retention time 1 .71 minutes (condition D); MS 560.0 (M+1 ); 1H NMR (400 MHz, CDCI3) δ ppm 1 .19 (d, J=7.07Hz, 3H), 1 .62-1 .71 (m, 1 H), 2.03-2.1 1 (m, 1 H), 2.62-2.71 (m, 1 H), 2.89-3.00 (m, 2H), 4.45-4.56 (m, 1 H), 5.05 (d, J=12.38Hz, 1 H), 5.13 (d, J=12.38Hz, 1 H), 5.79 (s, 2H), 6.97 (d, J=9.09Hz, 1 H), 7.21 (d, J=8.08Hz, 2H), 7.27-7.50 (m, 15H), 7.55 (d, J=7.07Hz, 2H).
Intermediate 4: (2R,4S)-5-Biphenyl-4-yl-2-methyl-4-{2-oxo-2-[N'-(2,2,2-trifluoro-acetyl)- hydrazino]-acetylamino}-pentanoic acid benzyl ester
Figure imgf000172_0002
To a suspension of (2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid benzyl ester HCI salt (800 mg, 2.142 mmol) in dichloromethane (30 ml_) at ice bath is added ethyl oxalyl chloride (0.288 ml_, 2.57 mmol) and followed by triethylamine (0.657 ml_, 4.71 mmol). The mixture is stirred at ice bath for 5 minutes, and the reaction is quenched by brine and added dichloromethane. The combined organic layer is washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue is purified by flash chromatography (silica gel, 20% to 40% ethyl acetate/heptane) to give (2R,4S)-5-biphenyl-4-yl-4-(ethoxyoxalyl-amino)-2-methyl-pentanoic acid benzyl ester (830 mg, 82% yield). HPLC Retention time 1 .61 minutes (condition D); MS 474.0 (M+1 ). Next, to a solution of (2R,4S)-5-biphenyl-4-yl-4-(ethoxyoxalyl-amino)-2-methyl-pentanoic acid benzyl ester (645 mg, 1 .362 mmol) in EtOH (25 ml_) at -20 0C is added a solution of hydrazine hydrate (0.066 ml_, 1 .362 mmol) in EtOH (10 ml_) and the mixture is stirred at -20 0C to -5 0C. After 3 hours, more hydrazine hydrate is added and the reaction is continued to stir at -20 0C to -5 0C. The suspension mixture is filtered to collect (2R,4S)-5-bipheyl-4-yl-4- (hydrazinooxalyl-amino)-2-methyl-pentanoic acid benzyl ester (555 mg, 89% yield). HPLC Retention time 1 .44 minutes (condition D); MS 460.0 (M+1 ).
Next, to a solution of (2R,4S)-5-bipheyl-4-yl-4-(hydrazinooxalyl-amino)-2-methyl-pentanoic acid benzyl ester (200 mg, 0.435 mmol) in THF (6 mL) cooled in ice bath is added DIPEA (0.099 mL, 0.566 mmol) followed by trifluoroacetic anhydride (0.080 mL, 0.566 mmol). The reaction is stirred at room temperature. The reaction is quenched by brine and is extracted with ethyl acetate. The combined organic layer is washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue is purified by flash chromatography (silica gel, 1 % to 5% MeOH/DCM) to give (2R,4S)-5-biphenyl-4-yl-2-methyl-4-{2-oxo-2-[N'-(2,2,2-trifluoro-acetyl)-hydrazino]- acetylaminoj-pentanoic acid benzyl ester (177 mg). HPLC Retention time 1 .01 minutes (condition E); MS 554.0 (M-1 ).
Intermediate 5: trans-1 ,2-cyclopropanedicarboxylic acid monoethyl ester
Figure imgf000173_0001
To a solution of diethyl trans-1 ,2-cyclopropanedicarboxylate (1 10 mg, 0.59 mmol) in ethanol (3 mL) is added aqueous 1 M NaOH (0.65 mL, 0.65 mmol) and the mixture is stirred at room temperature for 48 hours. To this mixture is added 0.65 ml_ of aqueous 1 M HCI and the solvent is removed under reduced pressure to afford the title compound.
Intermediate 6: 5-chloroisophthalic acid monomethyl ester
Figure imgf000174_0001
To a solution of 5-chloroisophthalic acid dimethyl ester (457 mg, 2 mmol) in methanol (10 ml_) is added aqueous 1 M NaOH (1 .0 ml_, 0.65 mmol) and the mixture is stirred at room temperature for 18 hours. The solvent is removed under reduced pressure and water is added to the residue. The solution is washed with ethyl acetate and the aqueous phase is acidified with aqueous 1 M HCI. The mixture is extracted with ethyl acetate and the organic phase is washed with brine and dried over sodium sulfate. The solvent is removed under reduced pressure to give the title compound. MS 213.2 (M-1 ); 1H-NMR (400 MHz, DMSO- d6); δ ppm 3.91 (s, 3H), 8.15 (s, 2H), 8.38 (s, 1 H), 13.71 (s, 1 H).
Intermediate 7: 5-carbamoylmethoxyisophthalic acid monomethyl ester
Figure imgf000174_0002
To a mixture of 5-hydroxyisophthalic acid dimethyl ester (500 mg, 2.38 mmol) and chloroacetamide (245 mg, 2.62 mmol) in DMF (7 ml_) is added potassium carbonate (986 mg, 7.14 mmol) and the mixture is stirred at room temperature for 2 days. Water is added to the mixture and then it is extracted with ethyl acetate. The organic phase is washed with water and brine and is dried over sodium sulfate. The organic solution is concentrated to one fourth volume to give a precipitate. The solid is filtered, washed with ethyl acetate and dried under reduced pressure to give 5-carbamoylmethoxyisophthalic acid dimethyl ester. MS 268.2 (M+1 ); ); 1H-NMR (400 MHz, CDCI3); δ ppm 3.96 (s, 6H), 4.59 (s, 2H), 5.87 (s, broad, 1 H), 6.55 (s, broad, 1 H), 7.79 (s, 2H), 8.37 (s, 1 H).
Next, to a solution of 5-carbamoylmethoxyisophthalic acid dimethyl ester (371 mg, 1 .39 mmol) in MeOH (10 ml_) is added aqueous 1 M NaOH (1 .39 ml_, 1 .39 mmol) and the mixture is stirred at 50 0C for 18 hours. The solvent is removed under reduced pressure and water is added to the residue. The aqueous solution is acidified with aqueous 1 M HCI and the resulting precipitate is filtered, washed with water and dried under reduced pressure to give 5-carbamoylmethoxyisophthalic acid monomethyl ester. MS 254.3 (M+1 ); 1H-NMR (400 MHz, DMSO-d6); δ ppm 3.89 (s, 3H), 4.59 (s, 2H), 7.43 (s, 1 H), 7.70 (m 3H), 8.10 (s, 1 ), 13.38 (s, 1 H).
Intermediate 8: pyrimidine-4,6-dicarboxylic acid
Figure imgf000175_0001
Prepared by the KMnO4 oxidation of 2,6-dimethylpyrimidine according to the procedure described in J. Chem. Soc. 525 (1959).
Intermediate 9: (5-ethyl-[1 ,3,4]thiadiazol-2-yl)-acetic acid
Figure imgf000175_0002
To a mixture of hydrazinocarbonylacetic acid ethyl ester (1 .0 g, 6.84 mmol) and diisopropypethylamine (1.77 g, 13.69 mmol) in THF (7 ml_) is added a solution of propionyl chloride (633 mg, 6.84 mmol) in THF (2 ml_) dropwise and the mixture is stirred at room temperature for 18 hours. The mixture is poured into ethyl acetate and is washed with aqueous 1 M HCI and brine. The organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure to furnish 3-oxo-3-(N'-propionylhydrazino)- propionic acid ethyl ester. 1H-NMR (400 MHz, CDCI3); δ ppm 1 .21 (t, 3H), 1 .30 (t, 3H), 2.31 (q, 2H), 3.43 (s, 2H), 4.23 (q, 2H), 8.27 (s, 1 H), 9.63 (s, 1 H).
Next, a mixture of 3-oxo-3-(N'-propionylhydrazino)-propionic acid ethyl ester (600 mg, 2.97 mmol) and Lawesson's reagent (3.6 g, 8.90 mmol) in THF (30 ml_) is stirred at 50 0C for 18 hours. The solvent is removed under reduced pressure and the residue is purified by column chromatography using a gradient of 20-50% heptane/EtOAc to elute the product, (5- ethyl-[1 ,3,4]thiadiazol-2-yl)-acetic acid ethyl ester. MS 201 .2 (M+1 ); 1H-NMR (400 MHz, CDCI3); δ ppm 1 .31 (t, 3H), 1 .43 (t, 3H), 3.14 (q, 2H), 4.17 (s, 2H), 4.24 (q, 2H). Next, to a solution of (5-ethyl-[1 ,3,4]thiadiazol-2-yl)-acetic acid ethyl ester (230 mg, 1 .15 mmol) in ethanol (5 ml_) is added aqueous 1 M NaOH (2 ml_, 2.0 mmol) and the mixture is stirred at room temperature for 18 hours. The mixture is acidified with aqueous 1 M HCI and the ethanol is removed under reduced pressure. The remaining aqueous solution is lyophilized to give (5-ethyl-[1 ,3,4]thiadiazol-2-yl)-acetic acid.
Intermediate 10: 3-benzenesulfonylaminopropionic acid
Figure imgf000176_0001
To a solution of benzenesulfonyl chloride (500 mg, 2.83 mmol) in pyridine (10 ml_) is added 3-amino-propionic acid ethyl ester (672 mg, 8.49 mmol) and the mixture is stirred at room temperature for 18 hours. The mixture is poured into ethyl acetate and is washed with aqueous 1 M HCI and brine. The organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure. The residue is purified by column chromatography using a gradient of 10-50% heptane/EtOAc to afford 3- benzenesulfonylaminopropionic acid ethyl ester. MS 258.3 (M+1 ); 1H-NMR (400 MHz, CDCI3); δ ppm 1 .24 (t, 3H), 2.53 (t, 2H), 3.21 (q, 2H), 5.22 (m, 1 H), 7.51 -7.61 (m, 3H), 7.87 (d, J=7.20 Hz, 2H).
Next, to a solution of 3-benzenesulfonylaminopropionic acid ethyl ester (340 mg, 1 .32 mmol) in ethanol (15 ml_) is added aqueous 1 M NaOH (4 ml_, 4.0 mmol) and the mixture is stirred at room temperature for 4 hours. The mixture is poured into water and is extracted with ether. The aqueous phase is acidified with aqueous 1 M HCI and the solution is lyophilized to give 3-benzenesulfonylaminopropionic acid.
Intermediate 11 : 3-(2-methyl-benzothiazol-6-yl)-propionic acid
Figure imgf000176_0002
A mixture of 6-iodo-2-methylbenzo[d]thiazole (275 mg, 1 mmol), methyl acrylate (103 mg, 1 .2 mmol), diacetoxypalladium (22 mg, 0.1 mmol) and triethylamine (304 mg, 3 mmol) MeCN (8 ml_) is heated in a microwave apparatus at 100 0C for 10 min. The solvent is removed under reduce pressure and the residue is purified by flash chromatography (heptane:EtOAc, 2:1 ) to give (E)-3-(2-methyl-benzothiazol-6-yl)-acrylic acid methyl ester. MS 234.3 (M+1 ).
Next, a solution of (E)-3-(2-methyl-benzothiazol-6-yl)-acrylic acid methyl ester in ethyl acetate (10 ml_) is hydrogenated over 10% Pd/C (22 mg, 10%w) at 1 atm for 18 hours. The catalyst is filtered through Celite and the solvent is removed under reduced pressure. The residue is purified by flash chromatography (heptane:EtOAc, 2:1 ) to give 3-(2-methyl- benzothiazol-6-yl)-propionic acid methyl ester. MS 236.3 (M+1 ).
Next, to a solution of 3-(2-methyl-benzothiazol-6-yl)-propionic acid methyl ester (150 mg, 1 .67 mmol) in EtOH (5 ml_) is added aqueous 1 M NaOH (5 ml_) and the mixture is stirred at room temperature for 2 hours. The solution is acidified to pH 3 with aqueous 1 M HCI and is extracted with ethyl acetate. The organic layer is washed with water, brine, dried over magnesium sulfate and filtered. The solvent is removed under reduced pressure and the residue is purified by preparative HPLC using a gradient of 10-100% MeCN/water (0.1 % TFA) to give 3-(2-methyl-benzothiazol-6-yl)-propionic acid.
Intermediate 12: 4-(2-methyl-benzothiazol-6-yl)-butyric acid
Figure imgf000177_0001
A mixture of 6-iodo-2-methylbenzo[d]thiazole (275 mg, 1 mmol), but-3-enoic acid methyl ester (100 mg, 1 .2 mmol), diacetoxypalladium (22 mg, 0.1 mmol) and triethylamine (304 mg, 3 mmol) MeCN (8 ml_) is heated in a microwave apparatus at 130 0C for 30 minutes. The solvent is removed under reduce pressure and the residue is purified by flash chromatography (heptane:EtOAc, 2:1 ) to give (E)-4-(2-methyl-benzothiazol-6-yl)-but-3-enoic acid methyl ester. MS 248.3 (M+1 ).
Next, a solution of (E)-4-(2-methyl-benzothiazol-6-yl)-but-3-enoic acid methyl ester in THF (10 ml_) is hydrogenated over 10% Pd/C (22 mg, 10% wet) at 1 atm for 48 hours. The catalyst is filtered through Celite and the solvent is removed under reduced pressure. The residue is purified by flash chromatography (heptane:EtOAc, 2:1 ) to give 4-(2-methyl- benzothiazol-6-yl)-butyric acid methyl ester. MS 250.4 (M+1 ).
Next, to a solution of 4-(2-methyl-benzothiazol-6-yl)-butyric acid methyl ester in EtOH (4 ml_) is added aqueous 1 M NaOH (4 ml_) and the mixture is stirred at room temperature for 2 hours. The solution is acidified to pH 2 with aqueous 1 M HCI and is extracted with ethyl acetate. The organic layer is washed with water, brine, dried over magnesium sulfate and filtered. The solvent is removed under reduced pressure to give 4-(2-methyl-benzothiazol-6- yl)-butyric acid. MS 236.3 (M+1 ).
Intermediate 13: 2-methyl-succinic acid 1-tert-butyl ester
Figure imgf000178_0001
Succinic acid mono-tert-butyl ester is prepared according to the procedure described in J. Org. Chem. 59, 4862 (1994).
To a stirred solution of LDA (6.3 mmol, 2M in hexane) in THF (5 ml_) at -78 0C is added a solution of succinic acid mono-tert-butyl ester (523 mg, 3 mmol) in THF (2 ml_) dropwise. After the addition, the mixture is warmed to -20 0C slowly and stirred at -20 0C for 30 minutes. The solution is re-cooled to -78 0C and MeI (51 1 mg, 3.6 mmol) is added dropwise. The mixture is warmed to room temperature and stirred for 18 hours. The mixture is quenched with water and extracted with ethyl acetate. The organic layer is washed with water, brine, dried over MgSO4 and filtered. The solvent is removed under reduced pressure to give 2-methyl-succinic acid 1 -tert-butyl ester.
Intermediate 14: 1-carboxymethyl-cyclopentanecarboxylic acid benzyl ester
Figure imgf000178_0002
To a stirred solution of cyclopentanecarboxylic acid (1 .14g, 10 mmol) in DMF (15 ml_) is added K2CO3 (2.07 g, 15 mmol) and benzyl bromide (1.71 g, 10 mmol). The suspension is stirred at room temperature for 18 hours. The mixture is quenched with water and extracted with ethyl acetate. The organic layer is washed with water, brine, dried over MgSO4 and filtered. The solvent is removed under reduced pressure and the residue is purified by flash chromatography (heptane:EtOAc, 10:1 ) to give cyclopentanecarboxylic acid benzyl ester.
Next, to a stirred solution of LDA (4 mmol, 2M in Hexane) in THF (8 mL) at -78 0C is added a solution of cyclopentanecarboxylic acid benzyl ester (817 mg, 4 mmol) in THF (3 mL) dropwise. After the addition, the mixture is stirred at -78 0C for 5 hours then allyl bromide (726 mg, 6 mmol) is added dropwise. The mixture is warmed to room temperature during 4 hours then the reaction mixture is quenched with saturated NaHCO3. Magnesium sulfate (2 g) is added and stirred until all the MgSO4 is dissolved. The mixture is extracted with ethyl acetate and the organic layer is washed with water, brine, dried over MgSO4 and filtered. The solvent is removed under reduced pressure and the residue is purified by flash chromatography (hep:EtOAc, 10:1 ) to give 1 -allyl-cyclopentanecarboxylic acid benzyl ester. Next, Ozone is bubbled through a solution of 1 -allyl-cyclopentanecarboxylic acid benzyl ester in methylene chloride (15 ml_) for 30 min then PS-triphenolphosphine (300 mg) is added and the mixture is stirred at room temperature for 5 hours. The resin is filtered and solvent is removed under reduced pressure. The residue is purified by flash chromatography (heptane:EtOAc, 10:1 ) to give 1 -(2-oxo-ethyl)-cyclopentanecarboxylic acid benzyl ester MS 247.3 (M+1 ).
Next, to a solution of 1 -(2-oxo-ethyl)-cyclopentanecarboxylic acid benzyl ester (200 mg, 0.81 mmol) in THF (5 ml_) is added silver(ll) oxide (201 mg, 1 .62 mmol) and aqueous 1 M NaOH (0.81 ml_ of 1 .0 N, 0.81 mmol) and the suspension is stirred at room temperature for 18 hours. The mixture is acidified to pH 3 with aqueous 1 M HCI and is extracted with ethyl acetate. The organic layer is washed with water, brine, dried over MgSO4 and filtered. The solvent is removed under reduced pressure to furnish 1 -carboxymethyl- cyclopentanecarboxylic acid benzyl ester MS 263.3 (M+1 ).
Intermediate 15: (2R,4S)-5-biphenyl-4-yl-4-[3-(2-cyano-ethylcarbamoyl)- propionylamino]-2-methyl pentanoic acid ethyl ester
Figure imgf000179_0001
To a solution of (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester (prepared by using the procedure described in US005217996) (200 mg, 0.486 mmol) in DMF (3 ml_) are added EDC-HCI (1 12 mg, 0.583 mmol) and HOAt (79 mg, 0.583 mmol) at room temperature. After stirring for 10 minutes, 3-aminopropionitrile (41 mg, 0.583 mmol) and triethylamine (0.081 ml_, 0.583 mmol) is added and stirred overnight. Additional EDC-HCI (66 mg, 0.292 mmol), HOAt (40 mg, 0.292 mmol), aminopropionitrile (21 mg, 0.292mmol), and triethylamine (0.081 ml_, 0.583 mmol) are added. After stirring for 1 hour, the reaction mixture is heated to 5O0C and stirred for 5 hours. The reaction mixture is diluted with ethyl acetate and washed with H2O and brine. The organic layer is dried over Na2SO4 and concentrated. The residue is purified by silica gel column chromatography to give (2R,4S)-5-biphenyl-4-yl-4-[3-(2-cyano-ethylcarbamoyl)-propionylamino]-2-methyl pentanoic acid ethyl ester. HPLC Retention time 1 .37 minutes (condition B); MS 464 (M+1 ); 1 H NMR (400 MHz, CDCI3) δ ppm 1 .17 (d, J=7.33Hz, 3H), 1 .25 (t, J=7.07Hz, 3H), 1 .51 (ddd, J=4.29, 0.85, 14.14Hz, 1 H), 1 .95 (ddd, J=4.29, 9.60, 13.89Hz, 1 H), 2.41 -2.59 (m, 5H), 2.58 (t, J=6.57Hz, 2H), 2.83 (d, J=6.57Hz, 2H), 3.45 (ddd, J=2.53, 8.00, 12.0Hz, 2H), 4.14 (ddd, J=2.53, 8.00, 14.01 Hz, 2H), 4.21 -4.31 (m, 1 H), 5.64 (d, J=9.09Hz, 1 H), 6.60-6.67 (m, 1 H), 7.24 (d, J=8.34Hz, 2H), 7.34 (t, J=7.33Hz, 1 H), 7.43 (t, J=7.83Hz, 2H), 7.53 (d, J=8.34Hz, 2H), 7.58 (d, J=7.07Hz, 2H).
Intermediate 16: (2R,4S)-5-biphenyl-4-yl-4-{3-[1-(2-cyano-ethyl)-1 H-tetrazol-5-yl]- propionylamino}-2-methyl-pentanoic acid ethyl ester
Figure imgf000180_0001
To a solution of (2R,4S)-5-biphenyl-4-yl-4-[3-(2-cyano-ethylcarbamoyl)-propionylamino]-2- methyl pentanoic acid ethyl ester (150 mg, 0.324 mmol) in THF(2 ml_) is added triphenylphosphine (85 mg, 0.324 mmol). After stirring for 10 minutes, diisopropyl azodicarboxylate (0.063 ml_, 0.324 mmol) and trimethylsilyl azide (0.043 ml_, 0.324 mmol) are added. The mixture is stirred for 8 hours and additional triphenylphosphine, diisopropyl azocarboxylate, and trimethylsilyl azide (each 0.324 mmol) are added. After stirring overnight, the mixture is concentrated and purified by silica gel column chromatography to give (2R,4S)-5-biphenyl-4-yl-4-{3-[1 -(2-cyano-ethyl)-1 H-tetrazol-5-yl]-propionylamino}-2- methyl-pentanoic acid ethyl ester. HPLC Retention time 1 .42 minutes (condition B); MS 489 (M+1 ); 1 H NMR (400 MHz, CDCI3) δ ppm 1 .1 1 (d, J=7.07Hz, 3H), 1 .23 (t, J=7.07Hz, 3H), 1 .47 (ddd, J=4.29, 10.10, 14.39Hz, 1 H), 1 .91 (ddd, J=4.04, 9.60, 13.64Hz, 1 H), 2.31 -2.41 (m, 1 H), 2.67-2.81 (m, 4H), 3.00 (t, J=6.82Hz, 2H), 3.05-3.17 (m, 2H), 4.03-4.22 (m, 3H), 4.50-4.68 (m, 2H), 5.69 (d, J=9.09Hz, 1 H), 7.14 (d, J=8.08Hz, 2H), 7.34 (t, J=7.33Hz, 1 H), 7.44 (t, J=7.83Hz, 2H), 7.50 (d, J=8.34Hz, 2H), 7.59 (d, J=7.07Hz, 2H).
Intermediate 17: 1 H-Pyrrole-2,5-dicarboxylic acid monomethyl ester
Figure imgf000180_0002
Prepared from methyl 2-pyrrolecarboxylate according to the procedure described in Eur. J. Org. Chem. 2397 (1999).
Intermediate 18: 1 H-Pyrrole-2,5-dicarboxylic acid monobenzyl ester
Figure imgf000181_0001
To a stirred solution of 1 H-pyrrole-2-carboxylic acid (1 .1 1 g, 10 mmol) in DMF (15 ml_) is added potassium carbonate (2.07 g, 15 mmol) and (bromomethyl)benzene (1 .80 g, 10.50 mmol). After stirring the mixture at room temperature for 18 hours, water is added and the mixture is extracted three times with ethyl acetate. The combined organic layers are washed with water and brine then is dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue is purified by flash chromatography (heptane/ethyl acetate =5:1 ) to give 1 H-pyrrole-2-carboxylic acid benzylester.
Next, To a stirred solution of 1 H-pyrrole-2-carboxylic acid benzylester (2.0 g, 9.94 mmol) in 1 ,2-dichloroethane (15 ml_) at 5 0C is sequentially added DMF (1 .12 g, 15.31 mmol) and phosphoryl trichloride (2.35 g, 15.31 mmol). After the addition, the mixture is heated to 50 0C and stirred for an hour. Water is added and the mixture is extracted with ethyl acetate (3x). The combined organic layers are washed with water and brine then is dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue is purified by flash chromatography (heptane/ethyl acetate =3:1 ) to give 5-formyl-1 H-pyrrole-2- carboxylic acid benzyl ester; HPLC Retention time 1 .64 minutes (condition C): MS 230.3 (M+1 ).
Next, to a stirred solution of 5-formyl-1 H-pyrrole-2-carboxylic acid benzyl ester (1.10 g, 4.80 mmol) in acetone (10OmL) is added a solution of potassium permanganate (1.52 g, 9.60 mmol) in 150 mL acetone/water (1 :1 ) dropwise and the mixture is stirred for three hours. The mixture is poured into a solution of 200 mL of 10% NaHSOβ in 1 N HCI and the mixture is extracted three times with ethyl acetate. The combined organic layers are washed with water and brine then is dried over magnesium sulfate. The solvent is removed under reduced pressure to give the title compound; HPLC Retention time 0.88 minutes (condition C): MS 244.3 (M -1 ).
Intermediate 19: 1-Methyl-1 H-pyrrole-2,5-dicarboxylic acid monobenzyl ester
Figure imgf000182_0001
To a stirred solution of 5-formyl-1 H-pyrrole-2-carboxylic acid benzyl ester (from the preparation of Intermediate 18) (400 mg, 1 .75 mmol) in DMF (10 ml_) is added cesium carbonate (853 mg, 2.62 mmol) and MeI (297 mg, 2.09 mmol). The mixture is stirred at room temperature for 2 hours then water is added and the mixture is extracted with ethyl acetate (3x). The combined organic layers are washed with water and brine then is dried over magnesium sulfate. The solvent is removed under reduced pressure to give benzyl 5- formyl-1 -methyl-1 H-pyrrole-2-carboxylate; HPLC Retention time 1 .26 minutes (condition C): MS 244.3 (M+1 ).
Next, to a stirred solution of benzyl 5-formyl-1 -methyl-1 H-pyrrole-2-carboxylate (400 mg, 1 .64 mmol) in acetone (25 ml_) is added a solution of potassium permanganate (520 mg, 3.29 mmol) in 40 ml_ acetone/water (1 :1 ) dropwise and the mixture is stirred for 3 hours. The mixture is poured into a solution of 60 ml_ 10% NaHSOβ in 1 N HCI and the mixture is extracted with ethyl acetate (3x). The combined organic layers are washed with water and brine then is dried over magnesium sulfate. The solvent is removed under reduced pressure to give the title compound. HPLC retention time 1 .10 minutes (condition C); MS 260.3 (M+H).
Intermediate 20: S-Hydroxy-isoxazole-δ-carboxylic acid
Figure imgf000182_0002
To a solution of S-hydroxy-isoxazole-δ-carboxylic acid methyl ester (286 mg, 2.0 mmol) in methanol (7 mL) is added 1 N NaOH (4.0 mL, 4.0 mmol) and the mixture is stirred at room temperature for 18 hrs. The solvent is removed under reduced pressure and 4.0 mL of 1 N HCI is added to the residue. The resulting solution is lyophilized to give the product which is used as is in subsequent reactions.
Intermediate 21 : 3-Carboxymethylbenzoic acid
Figure imgf000182_0003
To a solution of 3-bromomethylbenzoic acid (2.29 g, 10 mmol) in methanol (30 ml_) is added sodium cyanide (0.49 g, 10 mmol) and the mixture is stirred at 70 0C for 2 hrs. The solvent is removed under reduced pressure and water is added to the residue. The mixture is extracted with ether and the organic phase is dried over sodium sulfate. The solvent is removed under reduced pressure and the residue purified by column chromatography using CH2CI2 as eluent to give 3-cyanomethylbenzoic acid.
Next, a mixture of the 3-cyanomethylbenzoic acid (950 mg, 5.42 mmol) in water (2.5 ml_) and sulfuric acid (2.5 ml_, d 1 .84) is heated at 1 15 0C for 18 hrs. The mixture is cooled to room temperature and the resulting precipitate is filtered, washed with water and dried under reduced pressure to give 3-carboxymethylbenzoic acid.
Intermediate 22: δ-Carboxymethyl-furan^-carboxylic acid
Figure imgf000183_0001
To a solution of 5-methoxycarbonylmethyl-furan-2-carboxylic acid methyl ester (250 mg, 1 .26 mmol) in methanol (5 ml_) is added 1 N NaOH (2.78 ml_, 2.78 mmol) and the mixture is stirred at room temperature for 18 hrs. The solvent is removed under reduced pressure and 2.78 ml_ of 1 N HCI is added to the residue. The resulting solution is lyophilized to give the product which is used as is in subsequent reactions.
Intermediate 23: δ-Methoxycarbonylmethyl-furan^-carboxylic acid
Figure imgf000183_0002
To a solution of Intermediate 22 (220 mg, 1.29 mmol) in methanol (8 ml_) is added Amberlyst-15 resin (50 mg) and the mixture is stirred at room temperature for 18 hrs. The resin is filtered and the solvent is removed under reduced pressure to give the product which is used as is in subsequent reactions. 1 H NMR (400 MHz, CHLOROFORM-d) • ppm 3.75 (s, 3H), 3.82 (s, 2H), 6.45 (d, J=3.54 Hz, 1 H), 7.29 (d, J=3.54 Hz, 1 H), 10.17 (s, broad, 1 H).
Intermediate 24: 2-chloro-pyrimidine-4,6-dicarboxylic acid monomethyl ester
Figure imgf000184_0001
To a stirred solution of methyl 2-chloro-6-methylpyrimidine-4-carboxylate (3.73 g, 20 mmol.) in dioxane (20 ml_) is added selenium dioxide (3.55 g, 32 mmol) and the mixture is heated at 10 50C for 12 hours. The suspension is filtered through Celite and washed well with dioxane. The solvent is removed under reduced pressure to give 2-chloro-pyrimidine-4,6- dicarboxylic acid monomethyl ester; HPLC Retention time 0.65 minutes (condition C); MS 217.2 (M+1 ).
Intermediate 25: 2-Hydroxy-pyrimidine-4,6-dicarboxylic acid
Figure imgf000184_0002
Next, to a stirred solution of 2-chloro-pyrimidine-4,6-dicarboxylic acid monomethyl ester (120 mg, 0.55 mmol) in THF (3 ml_) is added 1 N NaOH (1 .10 ml_) and the mixture is stirred at room temperature for 18 hours. The solution is carefully acidified with 1 N HCI and the solvent is removed under reduced pressure to give 2-hydroxypyrimidine-4,6-dicarboxylic acid. This is used as is in subsequent reactions.
Intermediate 26: Pyrimidine-2,4-dicarboxylic acid
Figure imgf000184_0003
To a stirred solution of triethyl 1 ,3,5-triazine-2,4,6-tricarboxylate (J. Org. Chem. 59, 4950, 1994) (2.02 g, 6.80 mmol.) in DMF (15 ml_) is added 1 -aminoethaniminium chloride (1.29 g, 13.60 mmol). After the addition, the mixture is heated at 100 0C for 18 hours then the mixture is extracted three times with ethyl acetate. The combined organic layers are washed with water and brine then is dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue is purified by flash chromatography (heptane/ethyl acetate =3:1 ) to give diethyl 6-aminopyrimidine-2,4-dicarboxylate; HPLC Retention time 0.89 minutes (condition C); MS 240.3 (M+1 ).
Next, To a stirred solution of tert-butyl nitrite (268 mg, 2.34 mmol.) in DMF (5 mL) at 60 0C is added a solution of diethyl 6-aminopyrimidine-2,4-dicarboxylate (280 mg, 1 .17 mmol) in DMF (0.5 mL) dropwise and mixture is heated at 60 0C for 18 hours. The mixture is cooled to room temperature and poured into 1 N HCI (10 ml_). The mixture is extracted three times with ethyl acetate and the combined organic layers are washed with water and brine then is dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue is purified by flash chromatography (heptane/ethyl acetate =4:1 ) to give diethyl pyrimidine-2,4-dicarboxylate.
Next, to a stirred solution of diethyl pyrimidine-2,4-dicarboxylate (130 mg, 0.58 mmol) in MeOH (3 ml_) is added 1 N NaOH (2 ml_) and the mixture is stirred at room temperature for 3 hours. The solution is carefully acidified with 1 N HCI and the solvent is removed under reduced pressure to give pyrimidine-2,4-dicarboxylic acid. This is used as is in subsequent reactions.
Intermediate 27: 1 H-lmidazole-2,4-dicarboxylic acid 2-methyl ester
Figure imgf000185_0001
This intermediate is prepared according to the procedure described in patent application WO2005/040345.
Intermediate 28: 2-Chloromethyl-oxazole-5-carboxylic acid
Figure imgf000185_0002
A mixture of 2-chloromethyl-oxazole-5-carboxylic acid ethyl ester (J. Chromatography B, 674, 167, 1995) (190 mg, 1 mmol) and 1 N NaOH (2 ml_, 2 mmol) is stirred at room temperature for 3 hours then 1 N HCI (2 ml_, 2 mmol) is added and the solvent is removed under reduced pressure to give the title compound which is used as is in subsequent reactions.
Intermediate 29: 5-Hydroxy-6-oxo-6H-pyran-2-carboxylic acid
Figure imgf000185_0003
This intermediate is prepared according to the procedure described in Nippon Kagaku Zasshi, 82, 932 (1961 ). lntermediate 30: (E)-(R)-5-(4-Bromo-phenyl)-4-tert-butoxycarbonylamino-2-methyl-pent- 2-enoic acid ethyl ester
Figure imgf000186_0001
To a solution of (R)-3-(4-Bromo-phenyl)-2-tert-butoxycarbonylamino-propionic acid (1 .0 g, 2.91 mmol) in DMF (5 ml_) is added Cs2CO3 (1.041 g, 3.2 mmol) and the mixture is stirred at room temperature for 30 minutes. Then iodomethane (1.031 g, 7.26 mmol) is added and the mixture is stirred at room temperature about 72 hours. The pH is adjusted to 5-6 by adding 1 N HCI then the mixture is extracted with EtOAc. The combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated to give (R)-3-(4- bromo-phenyl)-2-tert-butoxycarbonylamino-propionic acid methyl ester. HPLC Retention time 1 .49 minutes (condition C): MS 358.3 (M-1 ).
Next, to a solution of (R)-3-(4-bromo-phenyl)-2-tert-butoxycarbonylamino-propionic acid methyl ester (1 .0 g, 2.79 mmol) in DCM (20 ml_ ) is added DIBAL-H (4.85 mL, 1 .OM in DCM) slowly by using syringe pump at -78 0C. After the addition is complete the reaction is quenched by adding EtOAc and the mixture is warmed to room temperature. Then a saturated sodium potassium tartaric acid is added and the mixture is and stirred at room temperature for 1 hour. The organic phase is separated and the aqueous layer is extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to give [(R)-I -(4-bromo-benzyl)-2-oxo-ethyl]-carbamic acid tert- butyl ester which is used directly in the next reaction.
Next, to a solution of [(R)-I -(4-bromo-benzyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester (800 mg, 2.438 mmol) in DCM (20 mL) is added (carbethoxylidene)triphenylphosphorane (1 .767 g, 4.88 mmol) and the mixture is stirred at room temperature overnight. The solvent is removed under reduced pressure and the residue is purified by column chromatography to afford the title compound.
Intermediate 31 : (S)-4-Amino-5-(3'-chloro-biphenyl-4-yl)-2-methyl-pentanoic acid ethyl ester hydrochloride
Figure imgf000187_0001
To a mixture of (R)-5-(4-bromo-phenyl)-4-tert-butoxycarbonylamino-2-methyl-pent-2-enoic acid ethyl ester (Intermediate 30) (2.6 g, 6.31 mmol), 3-chlorophenyl boronic acid (1 .085 g, 6.94 mmol), PdCI2(dppf)-CH2CI2 (0.257 g, 0.315 mmol) in DMF (30 ml_) is bubbled nitrogen for 10 minutes then Na2CO3 (6.3ml_ of a 2N aqueous solution) is added. The resulting mixture is heated to 100 0C for 2 hours then is cooled to room temperature. A mixture of ice and water is added and the mixture is extracted with EtOAc. The combined organic phases were washed with water and brine, dried over MgSO4, filtered and concentrated to give (E)- (R)-4-tert-butoxycarbonylamino-5-(3'-chloro-biphenyl-4-yl)-2-methyl-pent-2-enoic acid ethyl ester.
Next, to a solution of (E)-(R)-4-tert-butoxycarbonylamino-5-(3'-chloro-biphenyl-4-yl)-2- methyl-pent-2-enoic acid ethyl ester (2.5 g, 5.63 mmol) in ethanol (20 ml_) is added Pt/C (250mg) and the mixture is stirred overnight under an atmosphere of hydrogen (H2 balloon). The catalyst is filtered through a Celite pad and,the filtrate is concentrated to give (S)-4-tert- butoxycarbonylamino-5-(3'-chloro-biphenyl-4-yl)-2-methyl-pentanoic acid ethyl ester. Next, to a solution of (S)-4-tert-butoxycarbonylamino-5-(3'-chloro-biphenyl-4-yl)-2-methyl- pentanoic acid ethyl ester (2.47 g, 5.54 mmol) in DCM (15 ml_) is added 5 ml_ of HCI (4N in dioxane) and the mixture is stirred at room temperature for 2 hours. The solvent is removed under reduced pressure to afford the title compound; HPLC Retention time 1 .48 minutes (condition C): MS 346.2 (M+1 ).
The following intermediates are synthesized according to the procedures described above using a suzuki reaction of (E)-(R)-5-(4-Bromo-phenyl)-4-tert-butoxycarbonylamino-2-methyl- pent-2-enoic acid ethyl ester with the relavant boronic acids, hydrogenation reaction, and HCI mediated deprotection of the Boc group to give the corresponding amine hydrochloride salt.
Figure imgf000187_0002
Figure imgf000188_0001
Intermediate 32: 2-(4-Methoxy-benzyl)-2H-tetrazole-5-carboxylic acid
Figure imgf000188_0002
To a solution of sodium tetrazole-5-carboxylic acid ethyl ester (2 g, 12.19 mmol) in DMF (8 ml_) is added 4-methoxybenzyl bromide (3.68 g, 18.28 mmol) followed by the addition of triethylamine (5.10 ml_). The resulting mixture is stirred at room temperature overnight then ice/water is added. The mixture is extracted with EtOAc and the combined organic phases were washed with water and brine, dried over MgSO4, filtered and concentrated. The residue is purified by column chromatography to afford 2-(4-methoxy-benzyl)-2H-tetrazole- 5-carboxylic acid ethyl ester; HPLC Retention time 1 .37 minutes (condition C): MS 263.2 (M+1 ).
Next, to a solution of 2-(4-methoxy-benzyl)-2H-tetrazole-5-carboxylic acid ethyl ester (1 .5 g, 5.72 mmol) in ethanol (10 ml_) is added 1 N NaOH (10 ml_, 10 mmol) and the mixture is stirred at room temperature for 2 hours. The solvent is removed under reduced pressure and the mixture acidified with 1 N HCI. The mixture is extracted with EtOAc and the organic phase is washed with brine and dried over MgSO4. The solvent is removed under reduced pressure to give the title compound; HPLC Retention time 0.73 minutes (condition C): MS 233.2 (M -1 ).
Intermediate 33: (SJ-i-Carboxymethyl-pyrrolidine^-carboxylic acid methyl ester
Figure imgf000189_0001
To a solution of chloroacetic benzyl ester(1 .8 g, 9.75 mmol) in DCM (5OmL) is added (S)- pyrrolidine-2-carboxylic acid methyl ester hydrochloride (1 .51 g, 1 1 .70 mmol), diisopropylethylamine (4.09 mL, 23.40 mmol) and tetrabutylammonium iodide (3.60 g, 9.75 mmol) and the resulting mixture is stirred at room temperature overnight. The solvent is removed under reduced pressure and the residue purified by column chromatography using a gradient of 2-45% EtOAc/heptane to give (S)-1 -benzyloxycarbonylmethyl-pyrrolidine-2- carboxylic acid methyl ester; 1 H NMR (400 MHz, CHLOROFORM-cQ • ppm 1 .81 -2.05 (m, 3H), 2.13-2.24 (m, 1 H), 2.78-2.84 (m, 1 H), 3.15-3.20 (m, 1 H), 3.57-3.69 (m, 3H), 3.70 (s, 3H), 5.15 (s, 2H), 7.36 (m, 5H).
Next, to the solution of (S)-1 -benzyloxycarbonylmethyl-pyrrolidine-2-carboxylic acid methyl ester (2.50 g, 9.01 mmol) in methanol (30 mL)/ethyl acetate (30 mL) is added Pd/C (300 mg) and the mixture is stirred under an atmosphere of hydrogen (H2 balloon) for 18 hours. The catalyst is filtered through a Celite pad and the filtrate is evaporated under reduced pressure to give the title compound; HPLC Retention time 0.94 minutes (condition C): MS 188.4 (M+1 ).
Intermediate 34: ethyl 5-oxo-4,5-dihydro-1 ,2,4-oxadiazole-3-carboxylate
Figure imgf000190_0001
To a solution of ethyl 2-(hydroxyamino)-2-iminoacetate (2 g, 15.14 mmol) in dioxane (15.00 ml_) is added CDI (2.7 g, 16.65 mmol) and DBU (2.5 ml, 16.65 mmol) at room temperature. After stirring for 1 hour at 8O0C, the reaction is quenched with 1 N HCI, and the crude is diluted with EtOAc. The organic layer is washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give ethyl 5-oxo-4,5-dihydro-1 ,2,4-oxadiazole-3- carboxylate (2.4 g). HPLC retention time = 0.72 minutes (condition B); MS 159.1 (M+1 ).
Intermediate 35: 5-oxo-4,5-dihydro-1 ,2,4-oxadiazole-3-carboxylic acid
Figure imgf000190_0002
To a solution of crude ethyl 5-oxo-4,5-dihydro-1 ,2,4-oxadiazole-3-carboxylate (2.4 g, 15.14 mmol) in MeOH (2 ml_) is added aqueous 1 M NaOH (4ml_, 4 mmol) at room temperature. After stirring for 5 hours at room temperature the reaction was quenched with 1 N HCI (5 ml_, 5 mmol), the crude is concentrated under reduced pressure to remove MeOH. The crude is diluted with EtOAc, the organic layer is washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give 5-oxo-4,5-dihydro-1 ,2,4-oxadiazole-3- carboxylic acid (1 .9 g).
Intermediate 36: 6-methoxy-5-(trifluoromethyl)nicotinic acid
Figure imgf000190_0003
To a solution of 6-methoxy-5-(trifluoromethyl)nicotinonitrile (2g, 9.89 mmol) in EtOH (12 ml_) at room temperature is added 5 M NaOH (1 1 .9 ml_, 59.4 mmol). The crude is refluxed for 1 .5 hrs. The crude is concentrated to remove EtOH. The crude is diluted in ether and water. The aq. layer is extracted with ether. The aq. layer is acidified with 1 N HCI at which time white precipitate forms. This crude is redissolved in ether. The ether layer is washed with brine, dried over MgSO4, filtered and concentrated to give 6-methoxy-5- (trifluoromethyl)nicotinic acid (1 .7 g).
Intermediate 37: Synthesis of 6-hydroxy-5-(trifluoromethyl)nicotinic acid
Figure imgf000191_0001
To a solution of TMSCI (0.75 ml_, 5.88 mmol) in dry MeCN is added potassium iodide (0.98 g, 5.88 mmol). The crude is stirred at room temperature for 10 mins. To this crude is added a solution of 6-methoxy-5-(trifluoromethyl)nicotinic acid (1 .3 g, 5.88 mmol) in MeCN (2 ml_). The crude is stirred at 80 deg C for 4 hrs and room temperature for overnight. The crude is concentrated and diluted in ether and 1 N HCI. The organic layer is washed with water, brine, dried over MgSO4, filtered and concentrated. The crude is purified via RP-HPLC (SunFire C18, H2O(O. I 0ZoTFA)ZCH3CN) to give 6-hydroxy-5-(trifluoromethyl)nicotinic acid (377 mg). HPLC retention time = 0.85 minutes (condition B); MS 208.0 (M+1 ). 1 H NMR (400 MHz, CD3OD) δ ppm 8.34 (s, 2 H).
Intermediate 38: (2R,4S)-ethyl 5-(biphenyl-4-yl)-4-(2-methoxythiazole-5-carboxamido)- 2-methylpentanoate
Figure imgf000191_0002
To a solution of 2-methoxythiazole-5-carboxylic acid (101 mg, 0.64 mmol) in DMF (6 ml_) is added HOAt (107 mg, 0.58 mmol), EDCI (133 mg, 0.69 mmol), and TEA (0.48 ml_, 3.47 mmol). The crude is stirred at room temperature for 15 mins. To this crude is added (2R,4S)-ethyl 4-amino-5-(biphenyl-4-yl)-2-methylpentanoate hydrochloride salt. The crude is stirred at room temperature for overnight. The crude is quenched with 1 N HCI and water, diluted in EtOAc. The organic layer is washed with brine, dried over MgSO4, filtered, and concentrated. The residue is purified via flash column chromatography using 30% EtOAc/heptane to 70% EtOAc/heptane to give (2R,4S)-ethyl 5-(biphenyl-4-yl)-4-(2- methoxythiazole-5-carboxamido)-2-methylpentanoate (170 mg). HPLC retention time 1 .94 minutes (condition A); MS 453.3 (M+1 ); 1 H NMR (400 MHz, CHLOROFORM-cQ δ ppm 1 .18 (d, J=7.1 Hz, 3 H), 1 .23 (t, J=7.1 Hz, 3 H), 1 .71 (ddd, J=14.0, 9.9, 3.9 Hz, 1 H), 1 .88 - 2.04 (m, 1 H), 2.56 - 2.73 (m, 1 H), 2.78 - 2.96 (m, 1 H), 2.96 - 3.09 (m, 1 H), 4.09 (s, 3 H), 4.09 - 4.18 (m, 2 H), 4.30 - 4.47 (m, 1 H), 6.15 (d, J=8.1 Hz, 1 H), 7.27 (d, J=6.8 Hz, 2 H), 7.29 - 7.36 (m, 1 H), 7.42 (t, J=7.6 Hz, 2 H), 7.49 (s, 1 H), 7.53 (d, J=8.1 Hz, 2 H), 7.57 (d, J=7.3 Hz, 2 H).
Intermediate 39: (2R,4S)-ethyl 5-(biphenyl-4-yl)-4-(2-methoxyoxazole-5-carboxamido)- 2-methylpentanoate
Figure imgf000192_0001
To a solution of 2-methoxyoxazole-5-carboxylic acid, intermediate 22, (68 mg, 0.47 mmol) in DMF (2 ml_) and DCM (2 ml_) is added (2R,4S)-ethyl 4-amino-5-(biphenyl-4-yl)-2- methylpentanoate hydrochloride (150 mg, 0.43 mmol), HATU (246 mg, 0.65 mmol), and triethylamine (180 μl_, 1 .29 mmol). After stirring the reaction for 2 hours at room temperature, the reaction is quenched with H2O, and the crude is diluted in EtOAc. The organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by RP-HPLC (SunFire C18, H2O(0.1 % TFA)/CH3CN), and then lyophilized to give (2R,4S)-ethyl 5-(biphenyl-4-yl)-4-(2- methoxyoxazole-5-carboxamido)-2-methylpentanoate (175 mg). HPLC retention time = 1 .71 minutes (condition A); MS 437.5 (M+1 ); 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1 .20 (d, J=7.1 Hz, 3 H) 1 .25 (t, J=7.1 Hz, 3 H) 1 .65 (ddd, J=14.3, 10.0, 4.3 Hz, 1 H) 1 .96 - 2.10 (m, 1 H) 2.63 (ddd, J=9.4, 7.1 , 4.2 Hz, 1 H) 2.92 (dd, J=13.9, 6.3 Hz, 1 H) 2.99 (dd, J=13.9, 6.3 Hz, 1 H) 4.1 1 (s, 3 H) 4.12 - 4.18 (m, 2 H) 4.34 - 4.54 (m, 1 H) 6.15 (d, J=8.8 Hz, 1 H) 7.28 (d, J=8.3 Hz, 2 H) 7.31 - 7.37 (m, 1 H) 7.40 - 7.47 (m, 3 H) 7.54 (d, J=8.3 Hz, 2 H) 7.59 (dd, J=8.3, 1 .26 Hz, 2 H)
Intermediate 40: 2-oxo-2,3-dihydrooxazole-4-carboxylic acid
Figure imgf000193_0001
This intermediate is prepared according to: Okonya, J. F.; Hoffman, R. V.; Johnson, M. C; J. Org. Chem. 2002, 67, 1 102-1 108.
Intermediate 41 : 2-methoxyoxazole-5-carboxylic acid
Figure imgf000193_0002
To a solution of ethyl 2-chlorooxazole-5-carboxylate (510 mg, 2.90 mmol) in anhdryous MeCN (10 ml_) and anhydrous MeOH (10 ml_) is added NaOMe (628 mg, 1 1.62 mmol). The crude is stirred at reflux for 2 hrs. To this crude is added additional MeOH. The crude is refluxed for another 4 hrs. The crude is cooled and then concentrated and is redissolved in MeOH (10 ml_). To this crude is added 1 N NaOH (10 ml, 10 mmol). The crude is stirred at room temperature for 3 hrs. The crude is quenched with concentrated HCI, PH adjusted to 7 via pH paper indicator. The crude is concentrated to remove MeOH. The crude is diluted in water. The aq. layer is acidified with concentrated HCI and diluted in EtOAc. The organic layer is washed with water, brine, dried over MgSO4, filtered, and concentrated to give 2- methoxyoxazole-5-carboxylic acid (290 mg). This acid is used without further purification. HPLC retention time = 0.58 minutes (condition B); MS 144.0 (M+1 ).
Intermediate 42: (2R,4S)-ethyl 5-(biphenyl-4-yl)-4-(2-ethoxy-2-oxoacetamido)-2- methylpentanoate
Figure imgf000194_0001
To a solution of (2R,4S)-ethyl 4-amino-5-(biphenyl-4-yl)-2-methylpentanoate hydrochloride salt (1 g, 2.87 mmol) in DMF (10 ml_) is added TEA (0.42 ml_, 3.02 mmol) followed by ethyl 2-chloro-2-oxoacetate (392 mg, 2.87 mmol). The crude is stirred at rt for 1 hr. To the crude is added an additional 0.2 ml of ethyl 2-chloro-2-oxoacetate followed by triethylamine (1.26 ml_, 9.06 mmol). The crude is quenched with water and diluted in EtOAc. The organic layer is washed with brine, dried over MgSO4, filtered, and concentrated. The crude is purified via flash chromatography using 30% EtOAc/heptane to 50% EtOAc/heptane to give (2R,4S)-ethyl 5-(biphenyl-4-yl)-4-(2-ethoxy-2-oxoacetamido)-2-methylpentanoate (970 mg).
Intermediate 43: (2R,4S)-ethyl 5-(biphenyl-4-yl)-4-(2-hydrazinyl-2-oxoacetamido)-2- methylpentanoate
Figure imgf000194_0002
To a stirred solution of (2R,4S)-ethyl 5-(biphenyl-4-yl)-4-(2-ethoxy-2-oxoacetamido)-2- methylpentanoate (970 mg, 2.34 mmol) in anhydrous MeOH (20 ml_) cooled to -20 deg C is added a solution of 50% wt hydrazine hydrate (0.15 ml_, 2.36 mmol) in MeOH (10 ml_) dropwise. The crude is allowed to warm to rt in 2 hrs and is stirred overnight. The crude white precipitate is filtered to give (2R,4S)-ethyl 5-(biphenyl-4-yl)-4-(2-hydrazinyl-2- oxoacetamido)-2-methylpentanoate (870 mg). HPLC retention time = 1 .70 minutes (condition A); MS 398.2 (M+1 ). lntermediate 44: (4S)-ethyl 5-(3'-chlorobiphenyl-4-yl)-4-(2-ethoxy-2-oxoacetamido)-2- methylpentanoate
Figure imgf000195_0001
To a solution of (4S)-ethyl 4-amino-5-(3'-chlorobiphenyl-4-yl)-2-methylpentanoate hydrochloride salt (600 mg, 1 .74 mmol) in DMF (13.1 ml_) is added TEA (0.25 ml_, 1 .82 mmol) and ethyl 2-chloro-2-oxoacetate (0.19 ml_, 1 .74 mmol) at room temperature. After stirring this reaction for 1 hour at room temperature, the reaction is quenched with H2O, and diluted in EtOAc. The organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by flash column chromatography (eluent: heptane/EtOAc = 70:30 to 50:50) to give (4S)-ethyl 5-(3'- chlorobiphenyl-4-yl)-4-(2-ethoxy-2-oxoacetamido)-2-methylpentanoate (637 mg). HPLC retention time = 1 .66 minutes (condition A); MS 446.5 (M+1 ).
Intermediate 45: (4S)-ethyl 5-(3'-chlorobiphenyl-4-yl)-4-(2-hydrazinyl-2-oxoacetamido)- 2-methylpentanoate
Figure imgf000195_0002
To a solution of (4S)-ethyl 5-(3'-chlorobiphenyl-4-yl)-4-(2-ethoxy-2-oxoacetamido)-2- methylpentanoate (637 mg, 1 .43 mmol) in MeOH (40 ml_) is added a solution of 50% wt hydrazine (0.09 ml_, 1 .43 mmol) in MeOH (10 ml_) at -2O0C. After stirring for 18 hour at room temperature, the reaction mixture is concentrated under reduced pressure to give (4S)-ethyl 5-(3'-chlorobiphenyl-4-yl)-4-(2-hydrazinyl-2-oxoacetamido)-2-methylpentanoate (542 mg). HPLC retention time = 1 .54 minutes (condition A); MS 432.3 (M+1 ). lntermediate 46: ethyl 2-vinyloxazole-5-carboxylate
Figure imgf000196_0001
To a solution of tributyl(vinyl)stannane (1 .1 mL, 3.83 mmol) and ethyl 2-chlorooxazole-5- carboxylate (546 mg, 3.1 1 mmol) in dioxane (37 mL) is added Pd(PPh3)2CI2 (222 mg, 0.32 mmol) at room temperature. After stirring at 100 0C under nitrogen for 4 hours, the solution is cooled to ambient temperature and then quenched with H2O. The crude is diluted with EtOAc, the organic layer is washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The obtained residue is purified by flash column chromatography (eluent: heptane/EtOAc = 90:10 to 80:20) to give ethyl 2-vinyloxazole-5-carboxylate (470 mg). HPLC retention time = 0.39 minutes (condition B); MS (m+1 ) = 168.2; 1 H NMR (400 MHz, CD3OD) δ ppm 1 .38 (t, J=7.1 Hz, 3 H) 4.38 (q, J=7.2 Hz, 2 H) 5.88 (d, J= 1 1 .4 Hz, 1 H) 6.39 (d, J= 17.7 Hz, 1 H) 6.69 (dd, J= 17.6, 1 1 .2 Hz, 1 H) 7.83 (s, 1 H)
Intermediate 47: 2-ethyloxazole-5-carboxylic acid
O O O
^-V ^-W N ^°\ ^-V N \ Ho-V ^-W N
To a solution of ethyl 2-vinyloxazole-5-carboxylate (470 mg, 2.81 mmol) in MeOH (7 mL) is added 10% wt. Pd/C (100 mg, 0.094 mmol) at room temperature. After stirring at room temperature under a balloon of hydrogen for 1 hour, the crude is filtered to remove Pd/C. The filtrate is collected and concentrated to give ethyl 2-ethyloxazole-5-carboxylate (470 mg). HPLC retention time = 1 .09 minutes (condition A); MS (m+1 ) = 170.3; 1 H NMR (400 MHz, CD3OD) δ ppm 1 .35 (t, J=7.6 Hz, 3 H) 1 .36 (t, J=7.2 Hz, 3 H) 2.87 (q, J=7.7 Hz, 2 H) 4.35 (q, J=7.2 Hz, 2 H) 7.71 (s, 1 H)
Next, to a solution of 2-ethyloxazole-5-carboxylate (470 mg, 2.81 mmol) in MeOH (10 mL) is added 1 N NaOH (6 mL, 6 mmol). After stirring at room temperature for 18 hours, the crude is concentrated under reduced pressure to remove MeOH and is diluted with EtOAc. The organic layer is washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give 2-ethyloxazole-5-carboxylic acid (244 mg). 1 H NMR (400 MHz, CD3OD) δ ppm 1 .36 (t, J=7.7 Hz, 3 H) 2.89 (q, J=7.6 Hz, 2 H) 5.15 (br. s., 1 H) 7.69 (s, 1 H) lntermediate 48: ((2R,4S)-5-(biphenyl-4-yl)-4-(tert-butoxycarbonylamino)-2- methylpentanoic acid
Figure imgf000197_0001
Using the same procedure described in WO2008083967.
Intermediate 49: ((1 S, 3R)-1-Biphenyl-4-ylmethyl-4-methanesulfonylamino-3-methyl-4- oxo-butyl)-carbamic acid tert-butyl ester
Figure imgf000197_0002
To a solution of (2R, 4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methyl-pentanoic acid (500 mg, 1 .304 mmol) in DMF (10 ml) at room temperature is added methyl sulfonamide (223 mg, 2.347 mmol), EDCHCI (450 mg, 2.347 mmol), 1 -hydroxy-7- azabenzotriazole (284 mg, 2.086 mmol) and DIPEA (0.501 ml, 2.87 mmol). The reaction mixture is stirred at room temperature over night. The reaction is quenched by brine and is extracted with EtOAc. The combined organic layer is washed with brine and is dried over anhydrous sodium sulfate, filtered and concentrated. Reverse phase HPLC [15 to 60% ACN-H2O (0.1 % NH4OH) over 10 min by X-bridge phenyl column] provides ((1 S, 3R)-1 - Biphenyl-4-ylmethyl-4-methanesulfonylamino-3-methyl-4-oxo-butyl)-carbamic acid tert-butyl ester (333mg, 55%). HPLC retention time = 1 .03 minutes (condition D), MS (m-1 ) = 495.5, MS (m-55) = 405.3, MS (m-99) = 361 .3.
It can be seen that the compounds of the invention are useful as inhibitors of Neutral endopeptidase (EC 3.4.24.1 1 ) activity and therefore useful in the treatment of diseases and conditions associated with Neutral endopeptidase (EC 3.4.24.1 1 ) activity such as the diseases disclosed herein.
It will be understood that the invention has been described by way of example only and modifications may be made whilst remaining within the scope and spirit of the invention.

Claims

CLAIMSWhat is claimed is:
1 . A compound of the formula (T):
Figure imgf000199_0001
Formula I' or a pharmaceutically acceptable salt thereof, wherein: R1 is Ci-7alkyl; for each occurrence, R2 is independently Ci-7alkyl, NO2, CN, halo, C3-7cycloalkyl, hydroxy, Ci-7alkoxy, halo-Ci-7alkyl, NRbRc, C6-i0aryl, heteroaryl or heterocyclyl; wherein Rb and Rc for each occurrence, are independently H or Ci_7alkyl; R3 is A1C(O)X1 or A2-R4;
R4 is C6-ioaryl or a heteroaryl, which can be monocyclic or bicyclic and which can be optionally substituted with one or more substituents independently selected from hydroxy, hydroxy-Ci-7alkyl, NRbRc, nitro, Ci-7alkoxy, halo, Ci-7alkyl, halo-Ci-7alkyl, C2-7alkenyl, C6- iOaryl, heteroaryl, -C(O)Ci-7alkyl , -NHS(O)2-Ci-7alkyl, -SO2Ci-7alkyl and benzyl; R5 is H, halo, hydroxy, Ci-7alkoxy, halo, Ci-7alkyl or halo-Ci-7akyl; and X and X1 are independently OH, -O-Ci-7alkyl, -NRbRc, -NHS(O)2-Ci-7alkyl, -NHS(O)2-benzyl or -0-C6-ioaryl; wherein alkyl is optionally substituted with one or more substituents independently selected from the group consisting of aryl, heteroaryl, heterocyclyl, -C(O)NH2, -C(O)NH- Ci-6alkyl, and -C(O)N(d-6alkyl)2;
A1 is a bond or a linear d-4alkylene substituted with one or more substituents independently selected from the group consisting of halo, O-acetate, Ci-7 alkyl and C3-7cycloalkyl; in which two geminal alkyl can optionally combine to form a C3-7cycloalkyl; or A1 is a linear or branched C2.6alkenylene; or
A1 is a linear Ci-4 alkylene wherein one or more carbon atom(s) is/are replaced with an heteroatom selected from O, NRa; and A1 is optionally substituted with one or more substituents independently selected from the group consisting of halo and Ci-7alkyl; in which
Ra for each occurrence, is independently H, d-7alkyl or CH2C(O)OH; or
A1 is a C3-7cycloalkyl, a heterocyclyl, a phenyl or a heteroaryl in which phenyl and heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of d-7alkyl, C3-7cycloalkyl, halo-Ci-7alkyl, hydroxy, Ci-7alkoxy, halo, NRbRc,
OCH2CO2H, and OCH2C(O)NH2; or
A1 is
Figure imgf000200_0001
-Ci.4alkylene-heteroaryl- or
Figure imgf000200_0002
wherein
A1 may be in either direction; and
A2 is a bond or a linear or branched Ci_7alkylene which is optionally substituted with one or more substituents independently selected from the group consisting of halo, Ci-7alkoxy, hydroxy, O-Acetate and C3.7cycloalkyl; n is O, 1 , 2, 3, 4 or 5; wherein each heteroaryl is a monocyclic or bicyclic aromatic ring comprising 5-10 ring atoms selected from carbon atoms and 1 to 5 heteroatoms, and each heterocyclyl is a monocyclic saturated or partially saturated but non-aromatic moiety comprising 4-7 ring atoms selected from carbon atoms and 1 -5 heteroatoms, wherein each heteroatom of a heteroaryl or a heterocyclyl is independently selected from O, N and S.
2. A compound of formula (I) according to claim 1 :
Figure imgf000200_0003
or a pharmaceutically acceptable salt thereof, wherein:
R1 is Ci-7alkyl; for each occurrence, R2 is independently Ci-7alkyl, NO2, CN, halo, C3-7cycloalkyl, hydroxy,
Ci_7alkoxy, halo-Ci_7alkyl, NRbRc, C6-ioaryl, heteroaryl or heterocyclyl; wherein Rb and Rc for each occurrence are independently H or Ci_7alkyl;
R3 is A1C(O)X1 or A2-R4; R4 is C6-i0aryl or a heteroaryl, which can be monocyclic or bicyclic and which can be optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, hydroxy-Ci-7alkyl, nitro d-7alkoxy, halo, d-7alkyl, halo-Ci-7alkyl, C6- iOaryl, heteroaryl, -NHS(O)2-Ci-7alkyl, -SO2 Ci_7alkyl and benzyl;
R5 is H, halo, hydroxy, Ci_7alkoxy, halo, Ci_7alkyl or halo-Ci_7akyl; and
X and X1 are independently OH, -O-Ci-7alkyl or NRbRc, -O- C6-i0aryl; wherein alkyl is optionally substituted with one or more substituents independently selected from the group consisting of aryl, heteroaryl, heterocyclyl, C(O)NH2, C(O)NH- d-6alkyl, and C(O)N(Ci-
6alkyl)2;
A1 is a bond or a linear d-4alkylene substituted with one or more substituents independently selected from the group consisting of halo, O-acetate, Ci-7 alkyl and C3.7cycloalkyl; in which two geminal alkyl can optionally combine to form a C3-7cycloalkyl; or
A1 is a linear Ci-4 alkylene wherein one or more carbon atom(s) is/are replaced with an heteroatom selected from O, NRa; wherein A1 is optionally substituted with one or more substituents independently selected from the group consisting of halo and Ci_7alkyl; in which
Ra for each occurrence is independently H, Ci-7alkyl or CH2C(O)OH; or
A1 is a C3.7cycloalkyl, a heterocyclyl, a phenyl or a heteroaryl in which phenyl and heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Ci-7alkyl, C3.7cycloalkyl, halo-Ci-7alkyl, hydroxy, Ci-7alkoxy, halo, NRbRc,
OCH2CO2H, and OCH2C(O)NH2; or
A1 is
Figure imgf000201_0001
-d.4alkylene-heteroaryl- or
Figure imgf000201_0002
wherein
A1 may be in either direction; and
A2 is a bond or a linear or branched Ci-7alkylene; optionally substituted with one or more substituents independently selected from the group consisting of halo, Ci-7alkoxy, hydroxy,
O-Acetate and C3.7cycloalkyl; n is O, 1 , 2, 3, 4 or 5; wherein each heteroaryl is a monocyclic or bicyclic aromatic ring comprising 5-10 ring atoms selected from carbon atoms and 1 to 5 heteroatoms, and each heterocyclyl is a monocyclic saturated or partially saturated but non-aromatic moiety comprising 4-7 ring atoms selected from carbon atoms and 1 -5 heteroatoms, wherein each heteroatom of a heteroaryl or a heterocyclyl is independently selected from O, N and S.
3. The compound of claim 1 or 2 wherein:
R1 is Ci-7alkyl; for each occurrence, R2 is independently Ci-7alkyl, halo, C3-7cycloalkyl, hydroxy, Ci.7alkoxy, halo-Ci-7alkyl, NRbRc, C6-i0aryl, heteroaryl or heterocyclyl; wherein Rb and Rc, for each occurrence, are independently H or Ci_7alkyl;
R3 is A1C(O)X1 or A2-R4;
R4 is aryl or a heteroaryl, which can be monocyclic or bicyclic and which can be optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, Ci_7alkoxy, halo, Ci_7alkyl, halo-Ci_7alkyl, C6-ioaryl, heteroaryl, -NHS(O)2-Ci-7alkyl,
-SO2 Ci-7alkyl and benzyl;
R5 is H; and
X and X1 are independently OH, -O-Ci-7alkyl or NRbRc;
A1 is a linear C1-4 alkylene substituted with one or more substituents independently selected from the group consisting of halo, O-acetate, Ci_7 alkyl and C3.7cycloalkyl; in which two geminal alkyl can optionally combine to form a C3-7cycloalkyl; or
A1 is a linear C1-4 alkylene wherein one or more carbon atom(s) is/are replaced with an heteroatom selected from O, NRa; wherein A1 is optionally substituted with one or more substituents independently selected from the group consisting of halo and Ci_7alkyl; in which
Ra for each occurrence, is independently H, Ci_7alkyl or CH2C(O)OH; or
A1 is a C3.7cycloalkyl, a heterocyclyl, a phenyl or a heteroaryl in which phenyl and heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of Ci_7alkyl, C3.7cycloalkyl, halo-Ci_7alkyl, hydroxy, Ci_7alkoxy, halo, NRbRc,
OCH2CO2H, and OCH2C(O)NH2; and
A2 is a bond or a linear or branched Ci-7alkylene; optionally substituted with one or more substituents independently selected from the group consisting of halo, Ci_7alkoxy, hydroxy,
O-Acetate and C3.7cycloalkyl; n is O, 1 , 2, 3, 4 or 5; wherein each heteroaryl is a monocyclic or bicyclic aromatic ring comprising 5-10 ring atoms selected from carbon atoms and 1 to 5 heteroatoms, and each heterocyclyl is a monocyclic saturated or partially saturated but non-aromatic moiety comprising 4-7 ring atoms selected from carbon atoms and 1 -5 heteroatoms, wherein each heteroatom of a heteroaryl or heterocyclyl is independently selected from O, N and S; or a pharmaceutically acceptable salt thereof.
4. The compound according to claim 1 , 2 or 3, having Formulae Il or NA:
Figure imgf000203_0001
or a pharmaceutically acceptable salt thereof.
5. The compound according to any of claims 1 to 4 having Formulae III or INA:
Figure imgf000203_0002
wherein Y1, Y2 and Y3 are independently N, NH, S, O or CH; or a pharmaceutically acceptable salt thereof.
6. The compound according to any of claims 1 to 4 having Formulae IV or IVA:
Figure imgf000203_0003
wherein each Y4 is independently N, S, O or CH; or a pharmaceutically acceptable salt thereof.
7. The compound according to any of claims 1 to 4 having Formulae V or VA:
Figure imgf000204_0001
wherein W1, W2, W3 and W4 are independently N, or CRe, in which each Re is independently selected from H, d-7alkyl, C3-7cycloalkyl, halo-Ci.7alkyl, hydroxy, Ci.7alkoxy, halo, NRbRc, OCH2CO2H and OCH2C(O)NH2, or a pharmaceutically acceptable salt thereof.
8. The compound according to claim 1 , 2 or 3 having Formulae Vl or VIA:
Figure imgf000204_0002
wherein A2 is (CH2)p and p is O, 1 , 2 or 3, or a pharmaceutically acceptable salt thereof.
9. The compound according to claim 8 wherein A2 is a bond, R4 is a 5-membered ring heteroaryl selected from the group consisting of oxazole, pyrrole, pyrazole, isooxazole, triazole, tetrazole, oxadiazole, oxadiazolone, thiazole, isothiazole, thiophene, imidazole and thiadiazole, wherein the heteroaryl is optionally substituted with one or more substituents independently selected from hydroxy, Ci-7alkyl, Ci-7alkoxy, halo, halo-Ci-7alkyl and benzyl; or a pharmaceutically acceptable salt thereof.
10. The compound of any of claims 1 to 9 wherein R1 is methyl, R2 is independently halo, Ci-7alkyl, halo-Ci-7alkyl, hydroxy and d-7alkoxy , n is 0, 1 or 2 and X and X1 are independently OH or -O- Ci.7alkyl; or a pharmaceutically acceptable salt thereof.
1 1 . The compound of any of claims 1 to 10 wherein n is 1 or 2; R2 is meta-chloro and the other optional R2 group is halo, Ci-7alkyl, halo-Ci-7alkyl, hydroxy and Ci-7alkoxy; or a pharmaceutically acceptable salt thereof.
12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 1 1 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.
13. A combination comprising: a compound according to any one of claims 1 to 1 1 or a pharmaceutically acceptable salt thereof, and one or more therapeutically active agents selected from HMG-Co-A reductase inhibitor, an anigiotensin receptor blocker, angiotensin converting enzyme Inhibitor, a calcium channel blocker, an endothelin antagonist, a renin inhibitor, a diuretic, an ApoA-l mimic, an anti-diabetic agent, an obesity-reducing agent, an aldosterone receptor blocker, an endothelin receptor blocker, an aldosterone synthase inhibitors, a CETP inhibitor and a phosphodiesterase of type 5 (PDE5) inhibitor.
14. A method of inhibiting neutral endopeptidase EC. 3.4. 24.1 1 . activity in a subject in need thereof, comprising: administering to the subject a therapeutically effective amount of the compound according to any one of claims 1 to 1 1 or a pharmaceutically acceptable salt thereof.
15. A method of treating a disorder or a disease associated with neutral endopeptidase EC. 3.4. 24.1 1 . activity in a subject in need thereof, comprising: administering to the subject a therapeutically effective amount of the compound according to any one of claims 1 to 1 1 or a pharmaceutically acceptable salt thereof.
16. The method according to claim 15, wherein the disorder or the disease is selected from hypertension, pulmonary hypertension, isolated systolic hypertension, resistant hypertension, peripheral vascular disease, heart failure, congestive heart failure, left ventricular hypertrophy, angina, renal insufficiency, renal failure, diabetic nephropathy, non- diabetic nephropathy, nephroic syndrome, glomerulonephritis, scleroderma, glomerular sclerosis, proteinurea of primary renal disease, renal vascular hypertention, diabetic retinopathy and end-stage renal disease (ESRD), endothelial dysfunction, diastolic dysfunction, hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation (AF), cardiac fibrosis, atrial flutter, detrimental vascular remodeling, plaque stabilization, myocardial infarction (Ml), renal fibrosis, polycystic kidney disease (PKD), Pulmonary Arterial hypertension, renal failure, cyclical oedema, Menieres disease, hyperaldosteroneism hypercalciuria, ascites, glaucoma, menstrual disorders, preterm labour, pre-eclampsia, endometriosis, reproductive disorders, asthma, obstructive sleep apnea, inflammation, leukemia, pain, epilepsy, affective disorders, depression and psychotic condition, dementia, geriatric confusion, obesity and gastrointestinal disorders, wound healing, septic shock, gastric acid secretion dysfunction, hyperreninaemia, cystic fibrosis, restenosis, type-2 diabetes, metabolic syndrome, diabetic complications, atherosclerosis, male and female sexual dysfunction.
17. The compound according to any one of claims 1 to 1 1 , or a pharmaceutically acceptable salt thereof, for use as a medicament.
18. Use of the compound according to any one of claims 1 to 1 1 , or a pharmaceutically acceptable salt thereof, for the treatment of a disorder or disease associated with neutral endopeptidase EC. 3.4. 24.1 1 . activity in a subject in need of such treatment.
19. The use of claim 18, wherein the disorder or disease is selected from from hypertension, pulmonary hypertension, isolated systolic hypertension, resistant hypertension, peripheral vascular disease, heart failure, congestive heart failure, left ventricular hypertrophy, angina, renal insufficiency, renal failure, diabetic nephropathy, non- diabetic nephropathy, nephroic syndrome, glomerulonephritis, scleroderma, glomerular sclerosis, proteinurea of primary renal disease, renal vascular hypertention, diabetic retinopathy and end-stage renal disease (ESRD), endothelial dysfunction, diastolic dysfunction, hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation (AF), cardiac fibrosis, atrial flutter, detrimental vascular remodeling, plaque stabilization, myocardial infarction (Ml), renal fibrosis, polycystic kidney disease (PKD), Pulmonary Arterial hypertension, renal failure, cyclical oedema, Menieres disease, hyperaldosteroneism hypercalciuria, ascites, glaucoma, menstrual disorders, preterm labour, pre-eclampsia, endometriosis, reproductive disorders, asthma, obstructive sleep apnea, inflammation, leukemia, pain, epilepsy, affective disorders, depression and psychotic condition, dementia, geriatric confusion, obesity and gastrointestinal disorders, wound healing, septic shock, gastric acid secretion dysfunction, hyperreninaemia, cystic fibrosis, restenosis, type-2 diabetes, metabolic syndrome, diabetic complications, atherosclerosis, male and female sexual dysfunction.
PCT/EP2010/057213 2009-05-28 2010-05-26 Substituted aminobutyric derivatives as neprilysin inhibitors WO2010136474A2 (en)

Priority Applications (13)

Application Number Priority Date Filing Date Title
SG2011083102A SG176010A1 (en) 2009-05-28 2010-05-26 Substituted aminobutyric derivatives as neprilysin inhibitors
ES10726924.3T ES2582395T3 (en) 2009-05-28 2010-05-26 Substituted aminobutyric derivatives as neprilysin inhibitors
EP10726924.3A EP2435402B1 (en) 2009-05-28 2010-05-26 Substituted aminobutyric derivatives as neprilysin inhibitors
JP2012512347A JP5466759B2 (en) 2009-05-28 2010-05-26 Substituted aminobutyric acid derivatives as neprilysin inhibitors
BRPI1015069A BRPI1015069A2 (en) 2009-05-28 2010-05-26 Substituted aminobutyric derivatives as neprilysin inhibitors, their use, pharmaceutical composition, combination and method for inhibiting neutral endopeptidase activity.
MX2011012627A MX2011012627A (en) 2009-05-28 2010-05-26 Substituted aminobutyric derivatives as neprilysin inhibitors.
AU2010251948A AU2010251948A1 (en) 2009-05-28 2010-05-26 Substituted aminobutyric derivatives as neprilysin inhibitors
CN201080023253.0A CN102448928B (en) 2009-05-28 2010-05-26 Substituted Aminobutyric Derivatives as Neprilysin Inhibitors
MA34456A MA33364B1 (en) 2009-05-28 2010-05-26 SUBSTITUTED AMINOBUTYRIC DERIVATIVES AS NEPRILYSIN INHIBITORS
EA201101672A EA201101672A1 (en) 2009-05-28 2010-05-26 SUBSTITUTED DERIVATIVES OF AMINOISAL ACID AS NEPRILISIN INHIBITORS
CA2763565A CA2763565A1 (en) 2009-05-28 2010-05-26 Substituted aminobutyric derivatives as neprilysin inhibitors
IL216284A IL216284A0 (en) 2009-05-28 2011-11-10 Substituted aminobutyric derivatives as neprilysin inhibitors
TNP2011000593A TN2011000593A1 (en) 2009-05-28 2011-11-21 Substituted aminobutyric derivatives as neprilysin inhibitors

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US18175309P 2009-05-28 2009-05-28
US61/181,753 2009-05-28
US26314109P 2009-11-20 2009-11-20
US61/263,141 2009-11-20
US32493810P 2010-04-16 2010-04-16
US61/324,938 2010-04-16

Publications (2)

Publication Number Publication Date
WO2010136474A2 true WO2010136474A2 (en) 2010-12-02
WO2010136474A3 WO2010136474A3 (en) 2011-01-20

Family

ID=42790758

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2010/057213 WO2010136474A2 (en) 2009-05-28 2010-05-26 Substituted aminobutyric derivatives as neprilysin inhibitors

Country Status (24)

Country Link
US (3) US8263629B2 (en)
EP (2) EP3048100A1 (en)
JP (1) JP5466759B2 (en)
KR (1) KR20120041702A (en)
CN (1) CN102448928B (en)
AR (1) AR076706A1 (en)
AU (1) AU2010251948A1 (en)
BR (1) BRPI1015069A2 (en)
CA (1) CA2763565A1 (en)
CL (1) CL2011002989A1 (en)
CO (1) CO6470846A2 (en)
CR (1) CR20110617A (en)
CU (1) CU20110216A7 (en)
EA (1) EA201101672A1 (en)
EC (1) ECSP11011561A (en)
ES (1) ES2582395T3 (en)
IL (1) IL216284A0 (en)
MA (1) MA33364B1 (en)
MX (1) MX2011012627A (en)
SG (1) SG176010A1 (en)
SV (1) SV2011004077A (en)
TW (1) TW201100393A (en)
UY (1) UY32660A (en)
WO (1) WO2010136474A2 (en)

Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012065956A1 (en) * 2010-11-16 2012-05-24 Novartis Ag Substituted amino bisphenyl pentanoic acid derivatives as nep inhibitors
WO2012082853A1 (en) * 2010-12-15 2012-06-21 Theravance, Inc. Neprilysin inhibitors
WO2012082857A1 (en) * 2010-12-15 2012-06-21 Theravance, Inc. Neprilysin inhibitors
US20120213807A1 (en) * 2011-02-17 2012-08-23 Theravance, Inc. Neprilysin inhibitors
WO2012112742A1 (en) * 2011-02-17 2012-08-23 Theravance, Inc. Substituted aminobutyric derivatives as neprilysin inhibitors
WO2013148768A1 (en) * 2012-03-28 2013-10-03 Theravance, Inc. Crystalline forms of (r)-3-[n-(3'-chlorobiphenyl-4-ylmethyl)-n'-(3-hydroxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic acid isopropyl ester
WO2013184898A1 (en) * 2012-06-08 2013-12-12 Theravance, Inc. Neprilysin inhibitors
CN103748070A (en) * 2011-05-31 2014-04-23 施万制药 Neprilysin inhibitors
WO2014081702A2 (en) 2012-11-20 2014-05-30 Novartis Ag Synthetic linear apelin mimetics for the treatment of heart failure
CN103906509A (en) * 2011-11-02 2014-07-02 施万制药 Neprilysin inhibitors
US8877815B2 (en) 2010-11-16 2014-11-04 Novartis Ag Substituted carbamoylcycloalkyl acetic acid derivatives as NEP
WO2015013168A1 (en) 2013-07-25 2015-01-29 Novartis Ag Cyclic polypeptides for the treatment of heart failure
WO2015013169A2 (en) 2013-07-25 2015-01-29 Novartis Ag Bioconjugates of synthetic apelin polypeptides
CN104350042A (en) * 2012-06-08 2015-02-11 施万生物制药研发Ip有限责任公司 Neprilysin inhibitors
US8993631B2 (en) 2010-11-16 2015-03-31 Novartis Ag Method of treating contrast-induced nephropathy
JP2015523980A (en) * 2012-05-31 2015-08-20 セラヴァンス バイオファーマ アール＆ディー アイピー， エルエルシー Neprilysin inhibitor, a nitric oxide donor
WO2015154673A1 (en) * 2014-04-10 2015-10-15 Zhaoyin Wang Novel prodrugs and combinations for treatment of hypertension and cardiovascular diseases
WO2016116842A1 (en) 2015-01-23 2016-07-28 Novartis Ag Synthetic apelin fatty acid conjugates with improved half-life
CN106083807A (en) * 2012-02-15 2016-11-09 施万生物制药研发Ip有限责任公司 4 amino 5 biphenyl 4 base 2 methylol 2 methylvaleric acid compounds and preparation method thereof
CN107250119A (en) * 2015-02-19 2017-10-13 施万生物制药研发Ip有限责任公司 [(carbonyl of the 5 methyl oxazole 2) amino] valeric acid of (2R, 4R) 5 (base of 5 ' chlorine, 2 ' fluorine biphenyl 4) 2 hydroxyl 4
KR20170117091A (en) * 2015-01-26 2017-10-20 쑤저우 미라크파르마 테크놀로지 컴퍼니 리미티드 Preparation method of sacylitol
CN108586386A (en) * 2018-05-18 2018-09-28 河南福萌商贸有限公司 A kind of synthetic method of thiazole carboxylic acid's class chemical intermediate
EP3544966A4 (en) * 2018-02-07 2019-10-16 Novartis Ag Substituted bisphenyl butanoic ester derivatives as nep inhibitors
WO2020110008A1 (en) 2018-11-27 2020-06-04 Novartis Ag Cyclic pentamer compounds as proprotein convertase subtilisin/kexin type 9 (pcsk9) inhibitors for the treatment of metabolic disorder
WO2020110009A1 (en) 2018-11-27 2020-06-04 Novartis Ag Cyclic tetramer compounds as proprotein convertase subtilisin/kexin type 9 (pcsk9) inhibitors for the treatment of metabolic disorders
WO2020110011A1 (en) 2018-11-27 2020-06-04 Novartis Ag Cyclic peptides as proprotein convertase subtilisin/kexin type 9 (pcsk9) inhibitors for the treatment of metabolic disorders
US11261186B2 (en) 2014-12-24 2022-03-01 Lg Chem. Ltd. Biaryl derivative as GPR120 agonist
RU2784522C2 (en) * 2018-02-07 2022-11-28 Новартис Аг Substituted derivatives of bisphenyl ester of butyric acid as nep inhibitors
WO2023084449A1 (en) 2021-11-12 2023-05-19 Novartis Ag Diaminocyclopentylpyridine derivatives for the treatment of a disease or disorder

Families Citing this family (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10022352B2 (en) 2006-04-07 2018-07-17 Vertex Pharmaceuticals Incorporated Modulators of ATP-binding cassette transporters
EA201101672A1 (en) 2009-05-28 2012-06-29 Новартис Аг SUBSTITUTED DERIVATIVES OF AMINOISAL ACID AS NEPRILISIN INHIBITORS
BRPI1011657A2 (en) 2009-05-28 2019-04-16 Novartis Ag substituted aminopropionic derivatives as neprilysin inhibitors
JO2967B1 (en) 2009-11-20 2016-03-15 نوفارتس ايه جي Substituted carbamoylmethylamino acetic acid derivatives as novel NEP inhibitors
WO2012166390A1 (en) 2011-05-31 2012-12-06 Theravance, Inc. Neprilysin inhibitors
CA2835216A1 (en) 2011-05-31 2012-12-06 Theravance, Inc. Neprilysin inhibitors
AR089954A1 (en) * 2012-02-15 2014-10-01 Theravance Inc CRYSTALLINE FORM OF THE ESTER 5-METHYL-2-OXO- [1,3] DIOXOL-4-ILMETILIC ACID (2S, 4R) -5-BIFENIL-4-IL-2-HYDROXIMETHYL-2-METHYL-4 - [( 1H- [1,2,3] TRIAZOL-4-CARBONIL) AMINO] PENTANOIC
DK2882716T3 (en) 2012-08-08 2017-03-06 Theravance Biopharma R&D Ip Llc Neprilysin inhibitors
CN105008337B (en) 2013-02-14 2017-08-04 诺华股份有限公司 The substituted biphenyl butyric acid derivative as nep inhibitor with improved in vivo efficacy
LT2956464T (en) 2013-02-14 2018-07-10 Novartis Ag Substituted bisphenyl butanoic phosphonic acid derivatives as nep (neutral endopeptidase) inhibitors
PT2964616T (en) 2013-03-05 2017-08-08 Theravance Biopharma R&D Ip Llc Neprilysin inhibitors
CN104230865B (en) * 2013-06-13 2018-01-09 上海翰森生物医药科技有限公司 4 amino butyric acid derivatives of biaryl substituted and its production and use
EP3099668B1 (en) 2014-01-30 2022-05-04 Theravance Biopharma R&D IP, LLC 5-biphenyl-4-heteroarylcarbonylamino-pentanoic acid derivatives as neprilysin inhibitors
AU2015210983B2 (en) 2014-01-30 2018-10-04 Theravance Biopharma R&D Ip, Llc Neprilysin inhibitors
WO2016086798A1 (en) * 2014-12-03 2016-06-09 上海翰森生物医药科技有限公司 Nep inhibitor crystalline free acid, calcium salt polymorph of same, preparation method for same, and applications thereof
WO2016130650A1 (en) 2015-02-11 2016-08-18 Theravance Biopharma R&D Ip, Llc (2s, 4r)-5-(5'-chloro-2'-fluorobiphenyl-4-yl)-2-ethoxyoxalylamino)-2-hydroxymethyl-2-methylpentanoic acid as neprilysin inhibitor
CN105523964B (en) * 2015-12-09 2017-05-24 苏州楚凯药业有限公司 Preparation method of anti-heart-failure drug intermediate
JP7306828B2 (en) * 2016-03-08 2023-07-11 セラヴァンス バイオファーマ アール＆ディー アイピー， エルエルシー Crystalline (2S,4R)-5-(5′-chloro-2′-fluoro-[1,1′-biphenyl]-4-yl)-2-(ethoxymethyl)-4-(3-hydroxyisoxazole -5-carboxamido)-2-methylpentanoic acid and uses thereof
CN107602399B (en) * 2016-07-11 2020-09-25 江西东邦药业有限公司 Preparation method of enkephalinase inhibitor intermediate
CN108892624B (en) * 2018-06-20 2020-12-15 重庆威鹏药业有限公司 Sacubitril nitroxide derivative and preparation method and application thereof
US20220288070A1 (en) * 2019-07-31 2022-09-15 Aclaris Therapeutics, Inc. Deuterated mk2 pathway inhibitors and methods of using the same
CN115484952A (en) 2020-03-27 2022-12-16 阿克拉瑞斯治疗股份有限公司 Methods, compositions, and crystalline forms of substituted pyridone-pyridyl compounds
CN115806501A (en) * 2022-12-13 2023-03-17 中国药科大学 N-oxalyl-D-phenylalanine compounds and ester prodrugs thereof, preparation method, pharmaceutical composition and application

Family Cites Families (139)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES486572A1 (en) 1978-11-25 1980-09-16 Nippon Kayaku Kk Process for producing threo-3-amino-2-hydroxybutanoyl-aminoacetic acids, as well as novel intermediated therefor and process for producing them
DE2951135A1 (en) 1979-12-19 1981-06-25 Hoechst Ag, 6230 Frankfurt SULFONYL UREAS, METHOD FOR THE PRODUCTION THEREOF, PHARMACEUTICAL PREPARATIONS BASED ON THESE COMPOUNDS AND THEIR USE
EP0038046B1 (en) 1980-04-11 1984-02-29 The Wellcome Foundation Limited Pharmaceutical amides, and preparation, formulations and use thereof
PT72878B (en) 1980-04-24 1983-03-29 Merck & Co Inc Process for preparing mannich-base hydroxamic acid pro-drugs for the improved delivery of non-steroidal anti-inflammatory agents
US4721726A (en) 1980-12-18 1988-01-26 Schering Corporation Substituted dipeptides as inhibitors of enkephalinases
US4610816A (en) 1980-12-18 1986-09-09 Schering Corporation Substituted dipeptides as inhibitors of enkephalinases
JPS5865260A (en) 1981-10-13 1983-04-18 Microbial Chem Res Found 3-amino-2-hydroxy-4-phenylbutyric acid derivative and pharmaceutical composition
FR2518088B1 (en) 1981-12-16 1987-11-27 Roques Bernard NOVEL AMINO ACID DERIVATIVES AND THEIR THERAPEUTIC APPLICATION
DE3376649D1 (en) 1982-06-17 1988-06-23 Schering Corp Substituted dipeptides, methods for their production, pharmaceutical compositions containing them, method for making such pharmaceutical compositions
US4617307A (en) 1984-06-20 1986-10-14 Ciba-Geigy Corporation Substituted imidazo[1,5-A]pyridine derivatives as aromatase inhibitors
US4889861A (en) 1982-12-21 1989-12-26 Ciba-Geigy Corp. Substituted imidazo[1,5-a]pyridine derivatives and other substituted bicyclic derivatives and their use as aromatase inhibitors
GR81744B (en) 1983-01-28 1984-12-12 Schering Corp
FI77669C (en) 1983-04-13 1989-04-10 Ciba Geigy Ag 20-SPIROXANER OCH ANALOGER, SOM INNEHAOLLER EN OEPPEN RING E, FOERFARANDE FOER DERAS FRAMSTAELLNING SAMT DESSA INNEHAOLLANDE PHARMACEUTICAL PREPARATION.
EP0136883B1 (en) 1983-10-03 1987-11-25 E.R. Squibb &amp; Sons, Inc. Enkephalinase inhibitors
DE3347565A1 (en) 1983-12-30 1985-07-11 Thomae Gmbh Dr K NEW PHENYL ACETIC DERIVATIVES, MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF
JPS60248659A (en) 1984-05-25 1985-12-09 Microbial Chem Res Found 3(n-(mercaptoacyl))amino-4-arylbutyric acid derivative and analgesic containing said derivative as active component
JPS6354321A (en) 1985-03-27 1988-03-08 Ajinomoto Co Inc Blood sugar lowering agent
US4743587A (en) 1985-09-10 1988-05-10 G. D. Searle & Co. Hydroxamic acid based collagenase inhibitors
FR2597865B1 (en) 1986-04-29 1990-11-09 Roussel Uclaf NOVEL DERIVATIVES OF A BENZYL ALKYL CARBOXYLIC ACID SUBSTITUTED BY A RADICAL 4-PYRIDINYL AMINOCARBONYL, THEIR PREPARATION PROCESS, THE NEW INTERMEDIATES OBTAINED, THEIR APPLICATION AS MEDICAMENTS AND THE PHARMACEUTICAL COMPOSITIONS
US5120712A (en) 1986-05-05 1992-06-09 The General Hospital Corporation Insulinotropic hormone
US5118666A (en) 1986-05-05 1992-06-02 The General Hospital Corporation Insulinotropic hormone
FR2605004B1 (en) 1986-09-25 1989-01-13 Centre Nat Rech Scient NOVEL AMINO ACID DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITION CONTAINING THEM
FR2609289B1 (en) 1987-01-06 1991-03-29 Bellon Labor Sa Roger NOVEL COMPOUNDS HAVING ACTIVITY OF COLLAGENASE INHIBITORS, PROCESS FOR PREPARING SAME AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME
CA1337400C (en) 1987-06-08 1995-10-24 Norma G. Delaney Inhibitors of neutral endopeptidase
WO1990001940A1 (en) 1988-08-18 1990-03-08 California Biotechnology Inc. Atrial natriuretic peptide clearance inhibitors
FR2651229B1 (en) 1989-08-24 1991-12-13 Inst Nat Sante Rech Med NOVEL AMINO ACID DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR THERAPEUTIC APPLICATION.
AU7168091A (en) 1989-12-22 1991-07-24 Schering Corporation Mercaptocycloacyl aminoacid endopeptidase inhibitors
ATE164852T1 (en) 1990-01-24 1998-04-15 Douglas I Buckley GLP-1 ANALOGUE USABLE IN DIABETES TREATMENT
US5223516A (en) 1990-03-22 1993-06-29 E. R. Squibb & Sons, Inc. 3,3,3-trifluoro-2-mercaptomethyl-N-tetrazolyl substituted propanamides and method of using same
US5200426A (en) 1990-08-14 1993-04-06 Board Of Regents, The University Of Texas Inhibitors of neutral endopeptidase/CALLA as chemotherapeutic agents
JPH04149166A (en) 1990-10-12 1992-05-22 Nippon Kayaku Co Ltd Novel keto acid amide derivative
CA2058797A1 (en) 1991-02-01 1992-08-02 Michael John Broadhurst Amino acid derivatives
AU654331B2 (en) 1991-03-30 1994-11-03 Kissei Pharmaceutical Co. Ltd. Succinic acid compounds
US5294632A (en) 1991-05-01 1994-03-15 Ciba-Geigy Corporation Phosphono/biaryl substituted dipetide derivatives
RU2086544C1 (en) 1991-06-13 1997-08-10 Хоффманн-Ля Рош АГ Benzenesulfonamide derivatives of pyrimidine or their salts, pharmaceutical composition for treatment of diseases associated with endothelin activity
AU660930B2 (en) 1991-06-21 1995-07-13 Novo Nordisk A/S (S)(+)-2-ethoxy-4-(N-(1-(2-piperidinophenyl)-3-methyl-1- butyl)aminocarbonylmethyl)benzoic acid
GB9114006D0 (en) 1991-06-28 1991-08-14 Fujisawa Pharmaceutical Co New propionamide derivatives,processes for the preparation thereof and pharmaceutical composition comprising the same
JP2508949B2 (en) 1991-07-30 1996-06-19 味の素株式会社 Crystal of N- (trans-4-isopropylcyclohexylcarbonyl) -D-phenylalanine and process for producing the same
EP0533130A1 (en) 1991-09-19 1993-03-24 Hoechst Aktiengesellschaft 2-Hydroxymethylpyridines, the corresponding pyridine-N-oxides and derivatives thereof, process for their preparation and their use
ZA927211B (en) 1991-09-27 1993-03-24 Merrell Dow Pharma Novel carboxyalkyl derivatives useful as inhibitors of enkephalinase and ACE.
US5250522A (en) 1992-10-09 1993-10-05 Ciba-Geigy Corporation Phosphono/biaryl substituted amino acid derivatives
US5273990A (en) 1992-09-03 1993-12-28 Ciba-Geigy Corporation Phosphono substituted tetrazole derivatives
EP0618803A4 (en) 1991-12-19 1995-03-22 Southwest Found Biomed Res Cetp inhibitor polypeptide, antibodies against the synthetic polypeptide and prophylactic and therapeutic anti-atherosclerosis treatments.
US5217996A (en) 1992-01-22 1993-06-08 Ciba-Geigy Corporation Biaryl substituted 4-amino-butyric acid amides
JPH06234630A (en) 1992-12-17 1994-08-23 Tanabe Seiyaku Co Ltd Neutral metalloendopeptidase inhibitor
WO1994020457A1 (en) 1993-03-02 1994-09-15 G.D. Searle & Co. N-acyl beta amino acid derivatives useful as platelet aggregation inhibitors
JP3576193B2 (en) 1993-12-03 2004-10-13 第一製薬株式会社 Biphenylmethyl-substituted valerylamide derivatives
IL111785A0 (en) 1993-12-03 1995-01-24 Ferring Bv Dp-iv inhibitors and pharmaceutical compositions containing them
US5705483A (en) 1993-12-09 1998-01-06 Eli Lilly And Company Glucagon-like insulinotropic peptides, compositions and methods
US5517996A (en) 1994-04-21 1996-05-21 Hitachi Medical Corporation Ultrasonic diagnostic apparatus
IT1270261B (en) 1994-06-21 1997-04-29 Zambon Spa PEPTIDAL DERIVATIVES WITH INHIBITIVE ACTIVITY OF METALLOPEPTIDASES
US5512549A (en) 1994-10-18 1996-04-30 Eli Lilly And Company Glucagon-like insulinotropic peptide analogs, compositions, and methods of use
US5891912A (en) 1994-11-04 1999-04-06 Santen Pharmaceutical Co., Ltd. 1,3-dialkylurea derivatives having a hydroxyl group
WO1996018606A1 (en) 1994-12-14 1996-06-20 Santen Pharmaceutical Co., Ltd. Novel 1,3-dialkylurea derivatives
TW313568B (en) 1994-12-20 1997-08-21 Hoffmann La Roche
US5550119A (en) 1995-03-02 1996-08-27 Ciba-Geigy Corporation Phosphono substituted tetrazole derivatives as ECE inhibitors
US5710171A (en) 1995-05-24 1998-01-20 Merck & Co., Inc. Bisphenyl inhibitors of farnesyl-protein transferase
DE19616486C5 (en) 1996-04-25 2016-06-30 Royalty Pharma Collection Trust Method for lowering the blood glucose level in mammals
GB9609794D0 (en) 1996-05-10 1996-07-17 Smithkline Beecham Plc Novel compounds
IL118657A0 (en) 1996-06-14 1996-10-16 Arad Dorit Inhibitors for picornavirus proteases
EP0927156A1 (en) 1996-09-04 1999-07-07 Warner-Lambert Company Biphenyl butyric acids and their derivatives as inhibitors of matrix metalloproteinases
FR2755135B1 (en) 1996-10-25 2002-12-27 Inst Nat Sante Rech Med NOVEL (ALPHA-AMINOPHOSPHINO) PEPTIDES DERIVATIVES, PROCESS FOR THEIR PREPARATION AND COMPOSITIONS CONTAINING THEM
TW492957B (en) 1996-11-07 2002-07-01 Novartis Ag N-substituted 2-cyanopyrrolidnes
DE69833654T2 (en) 1997-05-29 2006-12-14 Merck & Co., Inc. (A New Jersey Corp.) BIARYL ALKANIC ACIDS IN USE AS CELL ADHESION INHIBITORS
WO1999026923A1 (en) 1997-11-20 1999-06-03 Merck & Co., Inc. Para-aminomethylaryl carboxamide derivatives
AU1463499A (en) 1997-11-21 1999-06-15 Merck & Co., Inc. Substituted pyrrole derivatives as cell adhesion inhibitors
ES2221227T3 (en) 1997-11-24 2004-12-16 MERCK &amp; CO., INC. SUBSTITUTED DERIVATIVES OF BETA-ALANINA AS INHIBITORS OF CELLULAR ADHESION.
MY153569A (en) 1998-01-20 2015-02-27 Mitsubishi Tanabe Pharma Corp Inhibitors of ?4 mediated cell adhesion
US6169103B1 (en) 1998-03-03 2001-01-02 Warner-Lambert Fluorine-substituted biphenyl butyric acids and their derivatives as inhibitors of matrix metalloproteinases
US6197786B1 (en) 1998-09-17 2001-03-06 Pfizer Inc 4-Carboxyamino-2-substituted-1,2,3,4-tetrahydroquinolines
GT199900147A (en) 1998-09-17 1999-09-06 1, 2, 3, 4- TETRAHIDROQUINOLINAS 2-SUBSTITUTED 4-AMINO SUBSTITUTED.
CO5150173A1 (en) 1998-12-10 2002-04-29 Novartis Ag COMPOUNDS N- (REPLACED GLYCLE) -2-DIPEPTIDYL-IV PEPTIDASE INHIBITING CYANOPIRROLIDINS (DPP-IV) WHICH ARE EFFECTIVE IN THE TREATMENT OF CONDITIONS MEDIATED BY DPP-IV INHIBITION
JP4070357B2 (en) 1999-06-03 2008-04-02 花王株式会社 Skin preparation
GB2354440A (en) 1999-07-20 2001-03-28 Merck & Co Inc Aryl amides as cell adhesion inhibitors
US6544974B2 (en) 1999-09-23 2003-04-08 G.D. Searle & Co. (R)-chiral halogenated substituted fused heterocyclic amino compounds useful for inhibiting cholesteryl ester transfer protein activity
US6509330B2 (en) 2000-02-17 2003-01-21 Bristol-Myers Squibb Company Hydroxamic acid containing compounds useful as ACE inhibitors and/or NEP inhibotors
AU2001273938B2 (en) 2000-04-12 2005-03-03 Novartis Ag Novel medical use of aldosterone synthase inhibitors alone or in combination with ati-receptor antagonists
JP2004509941A (en) 2000-09-29 2004-04-02 プロリフィクス　リミテッド Carbamic acid compounds containing amide bonds as HDAC inhibitors
JP4149166B2 (en) 2002-01-08 2008-09-10 東京エレクトロン株式会社 Processing system and processing method
ATE370732T1 (en) 2002-01-17 2007-09-15 Novartis Pharma Gmbh PHARMACEUTICAL COMPOSITION CONTAINING VALSARTAN AND NEP INHIBITORS
JP4233353B2 (en) 2002-02-27 2009-03-04 田辺三菱製薬株式会社 Pharmaceutical composition
US20040063761A1 (en) 2002-08-06 2004-04-01 Kuduk Scott D. 2-(biarylalkyl)amino-3-(fluoroalkanoylamino)pyridine derivatives
DE60307483T2 (en) 2002-08-07 2007-07-05 Novartis Ag ORGANIC COMPOUNDS AS A MEANS FOR THE TREATMENT OF ALTEROSTERONE-CONDITIONING STATES
ATE398124T1 (en) 2002-11-18 2008-07-15 Novartis Pharma Gmbh IMIDAZOÄ1,5ÜA PYRIDINE DERIVATIVES AND METHODS FOR TREATING ALDOSTERONE-ASSOCIATED DISEASES
US20040142379A1 (en) 2003-01-16 2004-07-22 Carlsberg Research Laboratory Affinity fishing for ligands and proteins receptors
JP2007524596A (en) 2003-02-28 2007-08-30 トランスフォーム・ファーマシューティカルズ・インコーポレイテッド Co-crystal pharmaceutical composition
WO2004099171A2 (en) 2003-04-30 2004-11-18 The Institutes For Pharmaceutical Discovery, Llc Substituted amino carboxylic acids as inhibitors of protein tyrosine phosphatase-1b
WO2005012270A2 (en) 2003-07-29 2005-02-10 Rib-X Pharmaceuticals, Inc. Biaryl heterocyclic amines, amides, and sulfur-containing compounds and methods of making and using the same
WO2005014534A1 (en) 2003-08-08 2005-02-17 Transtech Pharma, Inc. Aryl and heteroaryl compounds, compositions, and methods of use
US7169800B2 (en) 2003-09-24 2007-01-30 Vertex Pharmaceuticals Incorporated Imidazole compositions useful as inhibitors of protein kinases
ES2308477T3 (en) 2004-03-26 2008-12-01 Eli Lilly And Company COMPOUNDS FOR THE TREATMENT OF DYSLIPIDEMIA.
UA90269C2 (en) 2004-04-02 2010-04-26 Мицубиси Танабе Фарма Корпорейшн Tetrahydroquinoline derivatives and a process for preparing the same
TW200616623A (en) 2004-05-28 2006-06-01 Speedel Experimenta Ag Organic compounds
TW200608978A (en) 2004-05-28 2006-03-16 Speedel Experimenta Ag Organic compounds
TW200611898A (en) 2004-05-28 2006-04-16 Speedel Experimenta Ag Organic compounds
WO2006005726A2 (en) 2004-07-09 2006-01-19 Speedel Experimenta Ag Heterocyclic compounds
WO2006020358A2 (en) 2004-07-27 2006-02-23 Smithkline Beecham Corporation Novel biphenyl compounds and their use
JP2008520693A (en) 2004-11-18 2008-06-19 ジ インスチチュート フォー ファーマシューティカル ディスカバリー、エルエルシー Substituted amino acids as protein tyrosine phosphatase inhibitors
WO2006069096A1 (en) 2004-12-20 2006-06-29 Pharmacyclics, Inc. Silanol derivatives as inhibitors of histone deacetylase
MY146830A (en) 2005-02-11 2012-09-28 Novartis Ag Combination of organic compounds
TW200716634A (en) 2005-05-31 2007-05-01 Speedel Experimenta Ag Heterocyclic spiro-compounds
TW200716636A (en) 2005-05-31 2007-05-01 Speedel Experimenta Ag Heterocyclic spiro-compounds
TW200716105A (en) 2005-05-31 2007-05-01 Speedel Experimenta Ag Imidazole compounds
GT200600381A (en) 2005-08-25 2007-03-28 ORGANIC COMPOUNDS
WO2007045663A2 (en) * 2005-10-19 2007-04-26 Novartis Ag Combination of an ati receptor antagonist and a np inhibitor fro treating ia hypertension and heartfailure
RU2008122712A (en) 2005-11-08 2009-12-20 Новартис АГ (CH) COMBINATION OF ORGANIC COMPOUNDS
AR057882A1 (en) 2005-11-09 2007-12-26 Novartis Ag DOUBLE ACTION COMPOUNDS OF ANGIOTENSIN RECEPTOR BLOCKERS AND NEUTRAL ENDOPEPTIDASE INHIBITORS
TW200804378A (en) 2005-12-09 2008-01-16 Speedel Experimenta Ag Organic compounds
JP5262709B2 (en) 2006-03-15 2013-08-14 日本電気株式会社 Molecular structure prediction system, method and program
WO2007116908A1 (en) 2006-04-04 2007-10-18 Taiyo Nippon Sanso Corporation Method for separation of methane, methane separator, and methane utilization system
TW200808813A (en) 2006-04-12 2008-02-16 Speedel Experimenta Ag Imidazo compounds
TW200808812A (en) 2006-04-12 2008-02-16 Speedel Experimenta Ag Imidazo compounds
MX2008014616A (en) 2006-05-15 2008-11-28 Irm Llc Terephthalamate compounds and compositions, and their use as hiv integrase inhibitors.
EP1886695A1 (en) 2006-06-27 2008-02-13 Speedel Experimenta AG Pharmaceutical combination of an aldosterone synthase inhibitor and a glucocorticoid receptor antagonist or a cortisol synthesis inhibitor or a corticotropin releasing factor antagonist
US20080058535A1 (en) 2006-07-25 2008-03-06 Zhengming Chen Methods and compositions for production, formulation and use of 1 aryl-3-azabicyclo[3.1.0]hexanes
WO2008027284A1 (en) 2006-08-25 2008-03-06 Novartis Ag Fused imidazole derivatives for the treatment of disorders mediated by aldosterone synthase and/or 11-beta-hydroxylase and/or aromatase
EP1903027A1 (en) 2006-09-13 2008-03-26 Novartis AG Process for preparing biaryl substituted 4-amino-butyric acid or derivatives thereof and their use in the production of NEP inhibitors
KR20090091817A (en) 2006-12-18 2009-08-28 노파르티스 아게 Imidazoles as aldosterone synthase inhibitors
JP2010513560A (en) 2006-12-18 2010-04-30 ノバルティス アーゲー 1-Substituted imidazole derivatives and their use as aldosterone synthesis inhibitors
EP2121652A1 (en) 2006-12-18 2009-11-25 Novartis AG 4-imidazolyl-1,2,3,4-tetrahydroquinoline derivatives and their use as aldosterone/11-beta-hydroxylase inhibitors
NZ577910A (en) 2007-01-12 2012-04-27 Novartis Ag Process for preparing 5-biphenyl-4-amino-2-methyl pentanoic acid
TW200838501A (en) 2007-02-02 2008-10-01 Theravance Inc Dual-acting antihypertensive agents
AR066691A1 (en) 2007-03-29 2009-09-09 Speedel Experimenta Ag HIDEROCICLIC ESPIRO COMPOUNDS DERIVED FROM IMIDAZOL. PHARMACEUTICAL COMPOSITIONS.
TWI448284B (en) 2007-04-24 2014-08-11 Theravance Inc Dual-acting antihypertensive agents
CA2723671C (en) 2007-05-10 2018-06-19 R & D Biopharmaceuticals Gmbh Tubulysine derivatives
TWI406850B (en) 2007-06-05 2013-09-01 Theravance Inc Dual-acting benzoimidazole antihypertensive agents
PT3067043T (en) 2007-11-06 2023-03-01 Novartis Ag Pharmaceutical compositions based on superstructures of angiotensin receptor antagonist/blocker (arb) and neutral endopeptidase (nep) inhibitor
US8212052B2 (en) 2007-12-11 2012-07-03 Theravance, Inc. Dual-acting benzoimidazole antihypertensive agents
EP2070928A1 (en) 2007-12-12 2009-06-17 NERVIANO MEDICAL SCIENCES S.r.l. 7-azaindol-3-ylacrylamides active as kinase inhibitors
AR070176A1 (en) 2008-01-17 2010-03-17 Novartis Ag SYNTHESIS PROCESSES OF NEP INHIBITORS, INTERMEDIATE COMPOUNDS AND USE OF THE SAME IN SYNTHESIS
EP2334651A2 (en) 2008-07-24 2011-06-22 Theravance, Inc. Dual-acting antihypertensive agents
EA201101672A1 (en) 2009-05-28 2012-06-29 Новартис Аг SUBSTITUTED DERIVATIVES OF AMINOISAL ACID AS NEPRILISIN INHIBITORS
BRPI1011657A2 (en) 2009-05-28 2019-04-16 Novartis Ag substituted aminopropionic derivatives as neprilysin inhibitors
CN102639486B (en) 2009-09-23 2014-12-31 浙江九洲药业股份有限公司 Process for manufacture of N-acylbphenyl alanine
JO2967B1 (en) 2009-11-20 2016-03-15 نوفارتس ايه جي Substituted carbamoylmethylamino acetic acid derivatives as novel NEP inhibitors
US8877815B2 (en) 2010-11-16 2014-11-04 Novartis Ag Substituted carbamoylcycloalkyl acetic acid derivatives as NEP
ES2550324T3 (en) 2010-12-15 2015-11-06 Theravance Biopharma R&D Ip, Llc Neprilysin inhibitors
US8449890B2 (en) 2011-02-17 2013-05-28 Theravance, Inc. Neprilysin inhibitors
US8481044B2 (en) 2011-02-17 2013-07-09 Theravance, Inc. Neprilysin inhibitors

Non-Patent Citations (20)

* Cited by examiner, † Cited by third party
Title
BIOORG. MED. CHEM. LETT., vol. 6, 1996, pages 1951 - 1954
BUNDGAARD, J. MED. CHEM, 1989, pages 2503
C. ORSKOV ET AL., J. BIOL. CHEM, vol. 264, 1989, pages 12826
DOERING K; MEDER G; HINNENBERGER M; WOELCKE J. MAYR LM, HASSIEPEN U BIOMOL SCREEN, vol. 14, no. 1, January 2009 (2009-01-01), pages 1 - 9
EUR. J. ORG. CHEM, 1999, pages 2397
J CLIN PHARMACOL, vol. 27, 1987, pages 927
J HYPERTENS, vol. 19, 2001, pages 1923
J, ORG. CHEM., vol. 59, 1994, pages 4862
J, ORG. CHEM., vol. 59, 1994, pages 4950
J. ANTIBIOT., vol. 49, no. 8, 1996, pages 815 - 816
J. CHEM. SOC., vol. 525, 1959
J. CHROMATOGRAPHY B, vol. 674, 1995, pages 167
J. MED.CHEM., vol. 29, 1986, pages 538 - 549
J. ORG. CHEM., vol. 59, 1994, pages 4950
J.MED. CHEM., vol. 29, 1986, pages 538 - 549
NIPPON KAGAKU ZASSHI, vol. 82, 1961, pages 932
OKONYA, J, F.; HOFFMAN, R. V.; JOHNSON, M. C., J. ORG. CHEM., vol. 67, 2002, pages 1102 - 1108
PEPTIDES, vol. 9, 1988, pages 173
PHARMACOL REV, vol. 45, 1983, pages 87
W.E. SCHMIDT, DIABETOLOGIA, vol. 28, 1985, pages 704 - 707

Cited By (71)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012065956A1 (en) * 2010-11-16 2012-05-24 Novartis Ag Substituted amino bisphenyl pentanoic acid derivatives as nep inhibitors
US8673974B2 (en) 2010-11-16 2014-03-18 Novartis Ag Substituted amino bisphenyl pentanoic acid derivatives as NEP inhibitors
US8993631B2 (en) 2010-11-16 2015-03-31 Novartis Ag Method of treating contrast-induced nephropathy
EA021537B1 (en) * 2010-11-16 2015-07-30 Новартис Аг Substituted amino bisphenyl pentanoic acid derivatives as nep inhibitors
US8877815B2 (en) 2010-11-16 2014-11-04 Novartis Ag Substituted carbamoylcycloalkyl acetic acid derivatives as NEP
CN103261168A (en) * 2010-12-15 2013-08-21 施万制药 Neprilysin inhibitors
JP2013545811A (en) * 2010-12-15 2013-12-26 セラヴァンス， インコーポレーテッド Neprilysin inhibitor
AU2011343899A1 (en) * 2010-12-15 2013-06-06 Theravance Biopharma R&D Ip, Llc Neprilysin inhibitors
AU2011343903A1 (en) * 2010-12-15 2013-07-18 Theravance Biopharma R&D Ip, Llc Neprilysin inhibitors
CN103261164A (en) * 2010-12-15 2013-08-21 施万制药 Neprilysin inhibitors
CN105061314A (en) * 2010-12-15 2015-11-18 施万生物制药研发Ip有限责任公司 Neprilysin inhibitors
KR20140036134A (en) * 2010-12-15 2014-03-25 세라밴스 인코포레이티드 Neprilysin inhibitors
AU2011343903B2 (en) * 2010-12-15 2016-06-30 Theravance Biopharma R&D Ip, Llc Neprilysin inhibitors
US11851443B2 (en) 2010-12-15 2023-12-26 Theravance Biopharma R&D Ip, Llc Neprilysin inhibitors
RU2622288C2 (en) * 2010-12-15 2017-06-14 ТЕРЕВАНС БАЙОФАРМА Ар энд Ди АйПи,ЭлЭлСи Inhibitors of nonprilyzine
JP2014503534A (en) * 2010-12-15 2014-02-13 セラヴァンス， インコーポレーテッド Neprilysin inhibitor
WO2012082857A1 (en) * 2010-12-15 2012-06-21 Theravance, Inc. Neprilysin inhibitors
KR20140027918A (en) * 2010-12-15 2014-03-07 세라밴스 인코포레이티드 Neprilysin inhibitors
AU2011343899B2 (en) * 2010-12-15 2016-06-30 Theravance Biopharma R&D Ip, Llc Neprilysin inhibitors
KR101892500B1 (en) 2010-12-15 2018-08-28 세라밴스 바이오파마 알앤디 아이피, 엘엘씨 Neprilysin inhibitors
RU2605557C2 (en) * 2010-12-15 2016-12-20 ТЕРЕВАНС БАЙОФАРМА Ар энд Ди АйПи,ЭлЭлСи Neprilysin inhibitors
WO2012082853A1 (en) * 2010-12-15 2012-06-21 Theravance, Inc. Neprilysin inhibitors
KR101892611B1 (en) 2010-12-15 2018-08-28 세라밴스 바이오파마 알앤디 아이피, 엘엘씨 Neprilysin inhibitors
US8449890B2 (en) * 2011-02-17 2013-05-28 Theravance, Inc. Neprilysin inhibitors
JP2014508755A (en) * 2011-02-17 2014-04-10 セラヴァンス， インコーポレーテッド Substituted aminobutyric acid derivatives as neprilysin inhibitors
US20120213807A1 (en) * 2011-02-17 2012-08-23 Theravance, Inc. Neprilysin inhibitors
TWI548622B (en) * 2011-02-17 2016-09-11 施萬生物製藥研發Ｉｐ有限責任公司 Neprilysin inhibitors
CN103380119B (en) * 2011-02-17 2016-02-17 施万生物制药研发Ip有限责任公司 As the amino butyric acid derivative be substituted of enkephalinase inhibitor
KR101854874B1 (en) 2011-02-17 2018-05-04 세라밴스 바이오파마 알앤디 아이피, 엘엘씨 Substituted aminobutyric derivatives as neprilysin inhibitors
JP2014505734A (en) * 2011-02-17 2014-03-06 セラヴァンス， インコーポレーテッド Substituted aminobutyric acid derivatives as neprilysin inhibitors
WO2012112742A1 (en) * 2011-02-17 2012-08-23 Theravance, Inc. Substituted aminobutyric derivatives as neprilysin inhibitors
CN103380119A (en) * 2011-02-17 2013-10-30 施万制药 Substituted aminobutyric derivatives as neprilysin inhibitors
WO2012154249A1 (en) * 2011-02-17 2012-11-15 Theravance, Inc. Substituted aminobutyric derivatives as neprilysin inhibitors
AU2012217615B2 (en) * 2011-02-17 2016-09-29 Theravance Biopharma R&D Ip, Llc Substituted aminobutyric derivatives as neprilysin inhibitors
JP2014528903A (en) * 2011-05-31 2014-10-30 セラヴァンス バイオファーマ アール＆ディー アイピー， エルエルシー Neprilysin inhibitor
CN103748070B (en) * 2011-05-31 2015-06-24 施万生物制药研发Ip有限责任公司 Neprilysin inhibitors
CN103748070A (en) * 2011-05-31 2014-04-23 施万制药 Neprilysin inhibitors
CN103906509A (en) * 2011-11-02 2014-07-02 施万制药 Neprilysin inhibitors
TWI562986B (en) * 2012-02-15 2016-12-21 Theravance Biopharma R&D Ip Llc Process for preparing 4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid compounds
CN106083807A (en) * 2012-02-15 2016-11-09 施万生物制药研发Ip有限责任公司 4 amino 5 biphenyl 4 base 2 methylol 2 methylvaleric acid compounds and preparation method thereof
CN106083807B (en) * 2012-02-15 2018-09-11 施万生物制药研发Ip有限责任公司 4- amino -5- biphenyl -4- base -2- methylol -2- methvl-pentanoic acid compounds and preparation method thereof
WO2013148768A1 (en) * 2012-03-28 2013-10-03 Theravance, Inc. Crystalline forms of (r)-3-[n-(3'-chlorobiphenyl-4-ylmethyl)-n'-(3-hydroxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic acid isopropyl ester
US9271965B2 (en) 2012-03-28 2016-03-01 Theravance Biopharma R&D Ip, Llc Crystalline forms of (R)-3-[N-(3'-chlorobiphenyl-4-ylmethyl)-N'-(3-hydroxyisoxazole-5-carbonyl)hydrazino]-2-hydroxyproprionic acid isopropyl ester
JP2015523980A (en) * 2012-05-31 2015-08-20 セラヴァンス バイオファーマ アール＆ディー アイピー， エルエルシー Neprilysin inhibitor, a nitric oxide donor
JP2015525215A (en) * 2012-06-08 2015-09-03 セラヴァンス バイオファーマ アール＆ディー アイピー， エルエルシー Neprilysin inhibitor
TWI583671B (en) * 2012-06-08 2017-05-21 施萬生物製藥研發Ｉｐ有限責任公司 Neprilysin inhibitors
CN104350042B (en) * 2012-06-08 2017-05-24 施万生物制药研发Ip有限责任公司 Neprilysin inhibitors
JP2015523988A (en) * 2012-06-08 2015-08-20 セラヴァンス バイオファーマ アール＆ディー アイピー， エルエルシー Neprilysin inhibitor
WO2013184898A1 (en) * 2012-06-08 2013-12-12 Theravance, Inc. Neprilysin inhibitors
CN104350042A (en) * 2012-06-08 2015-02-11 施万生物制药研发Ip有限责任公司 Neprilysin inhibitors
WO2014081702A2 (en) 2012-11-20 2014-05-30 Novartis Ag Synthetic linear apelin mimetics for the treatment of heart failure
WO2015013169A2 (en) 2013-07-25 2015-01-29 Novartis Ag Bioconjugates of synthetic apelin polypeptides
WO2015013168A1 (en) 2013-07-25 2015-01-29 Novartis Ag Cyclic polypeptides for the treatment of heart failure
WO2015154673A1 (en) * 2014-04-10 2015-10-15 Zhaoyin Wang Novel prodrugs and combinations for treatment of hypertension and cardiovascular diseases
US11261186B2 (en) 2014-12-24 2022-03-01 Lg Chem. Ltd. Biaryl derivative as GPR120 agonist
WO2016116842A1 (en) 2015-01-23 2016-07-28 Novartis Ag Synthetic apelin fatty acid conjugates with improved half-life
KR101961897B1 (en) 2015-01-26 2019-03-25 쑤저우 미라크파르마 테크놀로지 컴퍼니 리미티드 Preparation method of sacylitol
KR20170117091A (en) * 2015-01-26 2017-10-20 쑤저우 미라크파르마 테크놀로지 컴퍼니 리미티드 Preparation method of sacylitol
CN107250119B (en) * 2015-02-19 2020-09-22 施万生物制药研发Ip有限责任公司 (2R,4R) -5- (5 '-chloro-2' -fluorobiphenyl-4-yl) -2-hydroxy-4- [ (5-methyloxazole-2-carbonyl) amino ] pentanoic acid
CN107250119A (en) * 2015-02-19 2017-10-13 施万生物制药研发Ip有限责任公司 [(carbonyl of the 5 methyl oxazole 2) amino] valeric acid of (2R, 4R) 5 (base of 5 ' chlorine, 2 ' fluorine biphenyl 4) 2 hydroxyl 4
US10668035B2 (en) 2018-02-07 2020-06-02 Novartis Ag Substituted bisphenyl butanoic ester derivatives as NEP inhibitors
EP3778557A1 (en) * 2018-02-07 2021-02-17 Novartis AG Combinations comprising a substituted biphenylbutanoic ester derivative as nep inhibitor and valsartan
AU2019218517B2 (en) * 2018-02-07 2021-03-04 Novartis Ag Substituted bisphenyl butanoic ester derivatives as NEP inhibitors
EP3544966A4 (en) * 2018-02-07 2019-10-16 Novartis Ag Substituted bisphenyl butanoic ester derivatives as nep inhibitors
US11426375B2 (en) 2018-02-07 2022-08-30 Novartis Ag Substituted bisphenyl butanoic ester derivatives as NEP inhibitors
RU2784522C2 (en) * 2018-02-07 2022-11-28 Новартис Аг Substituted derivatives of bisphenyl ester of butyric acid as nep inhibitors
CN108586386A (en) * 2018-05-18 2018-09-28 河南福萌商贸有限公司 A kind of synthetic method of thiazole carboxylic acid's class chemical intermediate
WO2020110008A1 (en) 2018-11-27 2020-06-04 Novartis Ag Cyclic pentamer compounds as proprotein convertase subtilisin/kexin type 9 (pcsk9) inhibitors for the treatment of metabolic disorder
WO2020110009A1 (en) 2018-11-27 2020-06-04 Novartis Ag Cyclic tetramer compounds as proprotein convertase subtilisin/kexin type 9 (pcsk9) inhibitors for the treatment of metabolic disorders
WO2020110011A1 (en) 2018-11-27 2020-06-04 Novartis Ag Cyclic peptides as proprotein convertase subtilisin/kexin type 9 (pcsk9) inhibitors for the treatment of metabolic disorders
WO2023084449A1 (en) 2021-11-12 2023-05-19 Novartis Ag Diaminocyclopentylpyridine derivatives for the treatment of a disease or disorder

Also Published As

Publication number Publication date
CN102448928B (en) 2014-10-01
US20150174089A1 (en) 2015-06-25
MX2011012627A (en) 2011-12-14
EP3048100A1 (en) 2016-07-27
CR20110617A (en) 2012-01-09
JP2012528107A (en) 2012-11-12
US9006249B2 (en) 2015-04-14
KR20120041702A (en) 2012-05-02
CL2011002989A1 (en) 2012-08-31
ECSP11011561A (en) 2012-01-31
WO2010136474A3 (en) 2011-01-20
BRPI1015069A2 (en) 2019-09-24
US8263629B2 (en) 2012-09-11
EA201101672A1 (en) 2012-06-29
AU2010251948A1 (en) 2011-12-01
TW201100393A (en) 2011-01-01
US9603819B2 (en) 2017-03-28
US20120252830A1 (en) 2012-10-04
US20100305145A1 (en) 2010-12-02
UY32660A (en) 2010-12-31
AR076706A1 (en) 2011-06-29
CA2763565A1 (en) 2010-12-02
SV2011004077A (en) 2012-01-04
CN102448928A (en) 2012-05-09
CU20110216A7 (en) 2012-03-15
ES2582395T3 (en) 2016-09-12
IL216284A0 (en) 2012-01-31
CO6470846A2 (en) 2012-06-29
JP5466759B2 (en) 2014-04-09
SG176010A1 (en) 2011-12-29
EP2435402B1 (en) 2016-04-13
MA33364B1 (en) 2012-06-01
EP2435402A2 (en) 2012-04-04

Similar Documents

Publication Publication Date Title
US9603819B2 (en) Substituted aminobutyric derivatives as neprilysin inhibitors
EP2594556B1 (en) Substituted aminopropionic derivatives as neprilysin inhibitors
EP2735561B1 (en) Substituted carbamoylmethoxyacetic acid derivatives as novel NEP inhibitors
AU2011331294B2 (en) Substituted amino bisphenyl pentanoic acid derivatives as NEP inhibitors
US8877815B2 (en) Substituted carbamoylcycloalkyl acetic acid derivatives as NEP

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 201080023253.0

Country of ref document: CN

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10726924

Country of ref document: EP

Kind code of ref document: A2

WWE Wipo information: entry into national phase

Ref document number: 596303

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: 2010251948

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: CR2011-000617

Country of ref document: CR

WWE Wipo information: entry into national phase

Ref document number: 9186/DELNP/2011

Country of ref document: IN

Ref document number: 002011-2011

Country of ref document: PE

WWE Wipo information: entry into national phase

Ref document number: 2011002989

Country of ref document: CL

Ref document number: 2763565

Country of ref document: CA

Ref document number: 2012512347

Country of ref document: JP

Ref document number: MX/A/2011/012627

Country of ref document: MX

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 11165097

Country of ref document: CO

Ref document number: 2010726924

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2010251948

Country of ref document: AU

Date of ref document: 20100526

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 201101672

Country of ref document: EA

WWE Wipo information: entry into national phase

Ref document number: A201114060

Country of ref document: UA

ENP Entry into the national phase

Ref document number: 20117031123

Country of ref document: KR

Kind code of ref document: A

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: PI1015069

Country of ref document: BR

ENP Entry into the national phase

Ref document number: PI1015069

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20111125