EP2035372A1 - Modulators of the histamine h3-receptor useful for the treatment of disorders related thereto - Google Patents

Modulators of the histamine h3-receptor useful for the treatment of disorders related thereto

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Publication number
EP2035372A1
EP2035372A1 EP07796576A EP07796576A EP2035372A1 EP 2035372 A1 EP2035372 A1 EP 2035372A1 EP 07796576 A EP07796576 A EP 07796576A EP 07796576 A EP07796576 A EP 07796576A EP 2035372 A1 EP2035372 A1 EP 2035372A1
Authority
EP
European Patent Office
Prior art keywords
ethyl
methyl
pyrrolidin
biphenyl
sulfonic acid
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP07796576A
Other languages
German (de)
French (fr)
Inventor
Vincent J. Santora
Jonathan A. Covel
Jason B. Ibarra
Graeme Semple
Brian Smith
Jeffrey Smith
Michael I. Weinhouse
Jeffrey A. Schultz
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Park Douglas M
Arena Pharmaceuticals Inc
Original Assignee
Park Douglas M
Arena Pharmaceuticals Inc
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Filing date
Publication date
Application filed by Park Douglas M, Arena Pharmaceuticals Inc filed Critical Park Douglas M
Publication of EP2035372A1 publication Critical patent/EP2035372A1/en
Withdrawn legal-status Critical Current

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • 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
    • A61P11/02—Nasal agents, e.g. decongestants
    • 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
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    • A61P25/00—Drugs for disorders of the nervous system
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    • 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
    • A61P25/26—Psychostimulants, e.g. nicotine, ***e
    • 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
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • 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
    • C07D207/04—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 no double bonds between ring members or between ring members and non-ring members
    • C07D207/06—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 no double bonds between ring members or between ring members and non-ring members with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • 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
    • C07D207/04—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 no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—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 no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms
    • 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
    • C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
    • C07D207/48—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D419/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms
    • C07D419/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D419/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the present invention relates to certain compounds of Formula (Ia) and pharmaceutical compositions thereof that modulate the activity of the histamine H3-receptor.
  • Compounds of the present invention and pharmaceutical compositions thereof are directed to methods useful in the treatment of histamine H3-receptor associated disorders, such as, cognitive disorders, epilepsy, brain trauma, depression, obesity, disorders of sleep and wakefulness such as narcolepsy, hypersomnia, somnolence syndrome, jet lag, sleep apnea and the like, attention deficit hyperactivity disorder (ADHD), schizophrenia, allergies, allergic responses in the upper airway, allergic rhinitis, nasal congestion, dementia, Alzheimer's disease and the like.
  • ADHD attention deficit hyperactivity disorder
  • R 1 andR 2 are each selected independently from the group consisting of H, C]-C 6 acyl,
  • each R 1 andR 2 is optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting OfCi-C 6 acyl, Cj-C 6 acyloxy, C 2 -C 8 alkenyl, Cj-C 6 alkoxy, Ci-C 8 alkyl, Ci-C 8 alkylcarboxamide, C 2 -C 8 alkynyl, Cj-C 8 alkylsulfonamide, C]-C 8 alkyls
  • R 2 is selected independently from the group consisting of H, Ci-C 6 acyl, C]-C 8 alkyl, C 2 - C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 7 cycloalkyl, aryl, heterocyclyl, heteroaryl, aryl-Q-C 4 -alkylenyl, aryloxy-Q-C 4 -alkylenyl, heteroaryl-Ci-C 4 -alkylenyl and heteroaryloxy-Q-Q-alkylenyl, and each R 2 is optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting OfCi-C 6 acyl, Ci-C 6 acyloxy, C 2 -C 8 alkenyl, C]-C 6 alkoxy, Ci-C 8 alkyl, C r C 8 alkylcarboxamide, C 2 -C 8 alkynyl, Cj-C 8 alkyls
  • J is -CH 2 CH 2 - or a l,2-C ⁇ -C7-cycloalkylenyl group, each optionally substituted with 1, 2, 3 or 4 substituents selected independently from the group consisting OfCi-C 3 alkyl, Q-C 4 alkoxy, carboxy, cyano, C]-C 3 haloalkyl, halogen, hydroxyl and oxo;
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , R 11 and R 12 are each selected independently from the group consisting of H, Ci-C 6 acyl, Ci-C 6 acyloxy, C 2 -C 8 alkenyl, Ci-C 6 alkoxy, Ci-C 8 alkyl, C 1 -C 8 alkylcarboxamide, C 2 -C 8 alkynyl, Ci-C 8 alkylsulfonamide, C r C 8 alkylsulfinyl, Ci-C 8 alkylsulf
  • R 8 and R 9 together with the nitrogen atom to which they are both bonded form a C 3 -C 7 heterocyclyl or a Cj-Ci 0 heterobicyclyl group each optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected independently from the group consisting OfCj-C 6 acyl, Cj-C 6 acyloxy, C 2 - C 8 alkenyl, Ci-C 6 alkoxy, C 1 -C 8 alkyl, Cj-C 8 alkylcarboxamide, C 2 -C 8 alkynyl, Cj-C 8 alkylsulfonamide, Cj-C 8 alkylsulfinyl, Cj-C 8 alkylsulfonyl, Cj-C 8 alkylthio, Cj-C 8 alkylureyl, amino, Cj-C 8 alkylamino, C 2 -C 8 dialkylamino, carbo-Cj-C 6 -alkoxy, carboxamide,
  • One aspect of the present invention pertains to methods for treating histamine H3- receptor associated disorders in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.
  • One aspect of the present invention pertains to methods for treating histamine H3- receptor associated disorders selected from the group consisting of cognitive disorders, epilepsy, brain trauma, depression, obesity, disorders of sleep and wakefulness such as narcolepsy, hypersomnia, somnolence syndrome, jet lag, sleep apnea and the like, attention deficit hyperactivity disorder (ADHD), schizophrenia, allergies, allergic responses in the upper airway, allergic rhinitis, nasal congestion, dementia and Alzheimer's disease.
  • One aspect of the present invention pertains to methods for treating disorders of sleep and wakefulness in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.
  • One aspect of the present invention pertains to methods for treating cognitive disorders in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.
  • One aspect of the present invention pertains to methods for inducing wakefulness in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.
  • One aspect of the present invention pertains to methods for treating pain in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.
  • One aspect of the present invention pertains to the use of compounds of the present invention for production of a medicament for use in the treatment of a histamine H3-receptor associated disorder.
  • One aspect of the present invention pertains to the use of compounds of the present invention for production of a medicament for use in the treatment of a histamine H3-receptor associated disorder selected from the group consisting of cognitive disorders, epilepsy, brain trauma, depression, obesity, disorders of sleep and wakefulness such as narcolepsy, hypersomnia, somnolence syndrome, jet lag, sleep apnea and the like, attention deficit hyperactivity disorder (ADHD), schizophrenia, allergies, allergic responses in the upper airway, allergic rhinitis, nasal congestion, dementia and Alzheimer's disease.
  • a histamine H3-receptor associated disorder selected from the group consisting of cognitive disorders, epilepsy, brain trauma, depression, obesity, disorders of sleep and wakefulness such as narcolepsy, hypersomnia, somnolence syndrome, jet lag, sleep apnea and the like, attention deficit hyperactivity disorder (ADHD), schizophrenia, allergies, allergic responses in the upper airway, allergic rhinitis, nasal congestion, dementia and Alzheimer'
  • One aspect of the present invention pertains to the use of compounds of the present invention for production of a medicament for use in the treatment of disorders of sleep and wakefulness.
  • One aspect of the present invention pertains to the use of compounds of the present invention for production of a medicament for use in the treatment of cognitive disorders.
  • One aspect of the present invention pertains to the use of compounds of the present invention for production of a medicament for use in inducing wakefulness.
  • One aspect of the present invention pertains to the use of compounds of the present invention for production of a medicament for use in treating pain.
  • One aspect of the present invention pertains to compounds of the present invention for use in a method of treatment of the human or animal body by therapy.
  • One aspect of the present invention pertains to compounds of the present invention for use in a method for the treatment of a histamine H3-receptor associated disorder in the human or animal body by therapy.
  • One aspect of the present invention pertains to compounds of the present invention for use in a method for the treatment of a histamine H3-receptor associated disorder selected from the group consisting of cognitive disorders, epilepsy, brain trauma, depression, obesity, disorders of sleep and wakefulness such as narcolepsy, hypersomnia, somnolence syndrome, jet lag, sleep apnea and the like, attention deficit hyperactivity disorder (ADHD), schizophrenia, allergies, allergic responses in the upper airway, allergic rhinitis, nasal congestion, dementia and Alzheimer's disease in the human or animal body by therapy.
  • a histamine H3-receptor associated disorder selected from the group consisting of cognitive disorders, epilepsy, brain trauma, depression, obesity, disorders of sleep and wakefulness such as narcolepsy, hypersomnia, somnolence syndrome, jet lag, sleep apnea and the like, attention deficit hyperactivity disorder (ADHD), schizophrenia, allergies, allergic responses in the upper airway, allergic rhinitis, nasal congestion, dementia
  • One aspect of the present invention pertains to compounds of the present invention for use in a method for the treatment of a disorder of sleep or wakefulness in the human or animal body by therapy.
  • One aspect of the present invention pertains to compounds of the present invention for use in a method for the treatment of a cognitive disorder in the human or animal body by therapy.
  • One aspect of the present invention pertains to compounds of the present invention for use in a method of inducing wakefulness in the human or animal body by therapy.
  • One aspect of the present invention pertains to compounds of the present invention for use in a method for the treatment of pain in the human or animal body by therapy.
  • One aspect of the present invention pertains to processes for preparing a composition comprising admixing a compound of the present invention and a pharmaceutically acceptable carrier.
  • Figure 1 shows, a general synthetic scheme for the synthesis of (i?)-2-methylpyrrolidine via reduction of L-prolinol and for its subsequent conversion into ( ⁇ )-l-(4-bromophenethyl)-2- methylpyrrolidine and (i?)-4-(2-(2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid.
  • Figure 2 shows a general synthetic scheme for preparation of compounds of the present invention by microwave mediated, palladium catalyzed Suzuki reaction between a phenylboronic acid, and a phenyl sulfonamide substituted with a leaving group such as halogen or triflate.
  • the sulfonamide is prepared by reaction of a precursor containing a suitable leaving group with an amine.
  • the boronic acid is prepared in two steps from a precursor containing two leaving groups. The first step involves reaction with an amine. The second step involves reaction with a trialkyl borate.
  • Figure 3 shows a general synthetic scheme for preparation of compounds of the present invention by microwave mediated, palladium catalyzed Suzuki reaction between a phenyl halide or triflate or the like and a phenylboronic acid substituted with a sulfonamide.
  • Figure 4 shows a general synthetic scheme for preparation of compounds of the present invention.
  • carboxylic acid function is reduced and the resulting alcohol is converted to a leaving group.
  • This is then alkylated with an amine in the presence of a base and the biaryl group is sulfonylated using a halosulfonic acid.
  • the final step is reaction of the sulfonyl halide with an amine in the presence of a base.
  • Figure 5 shows two general methods for preparing compounds of the present invention.
  • the first method involves the alkylation of a secondary amine.
  • a sulfonyl halide is first alkylated with a secondary amine in which one of the substituents bears a protecting group. Subsequent deprotection provides compounds of the present invention.
  • agonists is intended to mean moieties that interact and activate the receptor, such as the histamine H3-receptor, and initiate a physiological or pharmacological response characteristic of that receptor. For example, when moieties activate the intracellular response upon binding to the receptor, or enhance GTP binding to membranes.
  • antagonists is intended to mean moieties that competitively bind to the receptor at the same site as agonists (for example, the endogenous ligand), but which do not activate the intracellular response initiated by the active form of the receptor, and can thereby inhibit the intracellular responses by agonists or partial agonists. Antagonists do not diminish the baseline intracellular response in the absence of an agonist or partial agonist.
  • contacting is intended to mean bringing the indicated moieties together, whether in an in vitro system or an in vivo system.
  • "contacting" a histamine H3- receptor with a compound of the invention includes the administration of a compound of the present invention to an individual, preferably a human, having a histamine H3 -receptor, as well as, for example, introducing a compound of the invention into a sample containing a cellular or more purified preparation containing a histamine H3 -receptor.
  • in need of treatment and the term “in need thereof when referring to treatment are used interchangeably to mean a judgment made by a caregiver (e.g. physician, nurse, nurse practitioner, etc. in the case of humans; veterinarian in the case of animals, including non-human mammals) that an individual or animal requires or will benefit from treatment. This judgment is made based on a variety of factors that are in the realm of a caregiver's expertise, but that includes the knowledge that the individual or animal is ill, or will become ill, as the result of a disease, condition or disorder that is treatable by the compounds of the invention. Accordingly, the compounds of the invention can be used in a protective or preventive manner; or compounds of the invention can be used to alleviate, inhibit or ameliorate the disease, condition or disorder.
  • a caregiver e.g. physician, nurse, nurse practitioner, etc. in the case of humans; veterinarian in the case of animals, including non-human mammals
  • mice rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • inverse agonists is intended to mean moieties that bind to the endogenous form of the receptor or to the constitutively activated form of the receptor, and which inhibit the baseline intracellular response initiated by the active form of the receptor below the normal base level of activity which is observed in the absence of agonists or partial agonists, or decrease GTP binding to membranes.
  • the baseline intracellular response is inhibited in the presence of the inverse agonist by at least 30%, more preferably by at least 50%, and most preferably by at least 75%, as compared with the baseline response in the absence of the inverse agonist.
  • modulate or modulating is intended to mean an increase or decrease in the amount, quality, response or effect of a particular activity, function or molecule.
  • pharmaceutical composition is intended to mean a composition comprising at least one active ingredient; including but not limited to, salts, solvates and hydrates of compounds of the present invention; whereby the composition is amenable to investigation for a specified, efficacious outcome in a mammal (for example, without limitation, a human).
  • a mammal for example, without limitation, a human.
  • terapéuticaally effective amount is intended to mean the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following: (1) Preventing the disease, for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease; (2) Inhibiting the disease, for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology); and (3) Ameliorating the disease, for example, ameliorating a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology).
  • Ci-Ce acyl is intended to mean a Ci-Ce alkyl radical attached to the carbon of a carbonyl group wherein the definition of alkyl has the same definition as described herein; some examples include, but are not limited to, acetyl, propionyl, n-butanoyl, sec-butanoyl, pivaloyl, pentanoyl and the like.
  • Cj-Ce acyloxy is intended to mean an acyl radical attached to an oxygen atom wherein acyl has the same definition has described herein; some embodiments are when acyloxy is Ci-C 5 acyloxy, some embodiments are when acyloxy is C]-C 4 acyloxy. Some examples include, but are not limited to, acetyloxy, propionyloxy, butanoyloxy, iso- butanoyloxy, pentanoyloxy, hexanoyloxy and the like.
  • C 2 -C 8 alkenyl is intended to mean a radical containing 2 to 8 carbons wherein at least one carbon-carbon double bond is present, some embodiments are 2 to 7 carbons, some embodiments are 2 to 6 carbons, some embodiments are 2 to 5 carbons, some embodiments are 2 to 4 carbons, some embodiments are 2 to 3 carbons, and some embodiments have 2 carbons.
  • E and Z isomers are embraced by the term “alkenyl.”
  • alkenyl includes di- and tri-alkenyls. Accordingly, if more than one double bond is present then the bonds may be all E or all Z or a mixture thereof.
  • alkenyl examples include vinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3- ⁇ entenyl, 4-pentenyl, 2-hexenyl, 3- hexenyl, 4-hexenyl, 5-hexanyl, 2,4-hexadienyl and the like.
  • Ci-C 6 alkoxy is intended to mean a C]-C 6 alkyl radical, as defined herein, attached directly to an oxygen atom, some embodiments are 1 to 5 carbons, some embodiments are 1 to 4 carbons, some embodiments are 1 to 3 carbons, and some embodiments are 1 or 2 carbons. Examples include methoxy, ethoxy, /z-propoxy, iso-propoxy, «-butoxy, f-butoxy, iso- butoxy, sec-butoxy and the like.
  • Ci-C 8 alkyl is intended to mean a straight or branched carbon radical containing 1 to 8 carbons, some embodiments are 1 to 7 carbons, some embodiments are 1 to 6 carbons, some embodiments are 1 to 5 carbons, some embodiments are 1 to 4 carbons, some embodiments are 1 to 3 carbons, and some embodiments are 1 or 2 carbons.
  • alkyl examples include, but not limited to, methyl, ethyl, M-propyl, iso-propyl, n-butyl, sec-butyl, iso- butyl, f-butyl, pentyl, is ⁇ -pentyl, f-pentyl, neo-pentyl, 1-methylbutyl [i.e.,
  • C 1 -C 8 alkylcarboxamido or "C 1 -C 8 alkylcarboxamide” is intended to mean a single Cj-C 8 alkyl group attached to either the carbon or the nitrogen of an amide group, wherein alkyl has the same definition as found herein.
  • the C 1 -Cs alkylcarboxamido may be represented by the following:
  • Examples include, but are not limited to, N-methylcarboxamide, N-ethylcarboxamide, N-n-propylcarboxamide, N- £s ⁇ -propylcarboxamide, N-H-butylcarboxamide, N-sec- butylcarboxamide, N- /so-butylcarboxamide, N-f-butylcarboxamide and the like.
  • Ci-C 4 -alkyIenyl is intended to mean a C]-C 4 divalent straight carbon group containing 1 to 4 carbons, some embodiments are 1 to 3 carbons, and some embodiments are 1 to 2 carbons.
  • alkylenyl refers to, for example, -CH 2 -, -CH 2 CH 2 -, - CH 2 CH 2 CH 2 -, and/or -CH 2 CH 2 CH 2 CH 2 -.
  • aryloxy is intended to mean an aromatic ring radical as defined herein, attached directly to an oxygen atom. Examples include phenoxy, naphthyloxy and the like.
  • heteroaryloxy is intended to mean a heteroaryl radical as defined herein, attached directly to an oxygen atom.
  • examples include pyridyloxy, benzofuranyloxy, pyrazinyloxy, pyridazinyloxy, pyrimidinyloxy, triazinyloxy, quinolinyloxy, benzoxazolyloxy, benzothiazolyloxy, lH-benzimidazolyloxy, isoquinolinyloxy, quinazolinyloxy, quinoxalinyloxy and the like.
  • aryl-Ci-Gra ⁇ kylenyl is intended to mean a Cj-C 4 alkylene group bonded to an aryl group, each as defined herein.
  • aryl-Ci-C 4 alkylenyl refers to, for example, benzyl (-C ⁇ 2 -phenyl), phenylethyl (-CH 2 CH 2 -phenyl), and the like.
  • heteroaryl-Ci-C 4 -alkylenyl is intended to mean a C 1 -C 4 alkylene group bonded to a heteroaryl group, each as defined herein.
  • heteroaryl-Cj-C 4 ⁇ alkyleneyl refers to, for example, pyridinylmethyl (-CH 2 -pyridinyl) and the like.
  • aryloxy-Ci-C 4 -alkylenyl is intended to mean a Cj-C 4 alkylene group bonded to an aryloxy group, each as defined herein. Ih some embodiments, aryloxy-Cj-C 4 - alkylenyl refers to, for example, 2-phenoxy-ethyl, phenoxy-methyl and the like.
  • heteroaryloxy-Ci-Q-alkylenyl is intended to mean a Cj-C 4 alkylene group bonded to a heteroaryloxy group, each as defined herein.
  • heteroaryloxy- Cj-Cj-alkylenyl refers to, for example 2-(pyridin-2-yloxy)ethyl, (pyridin-2-yloxy)methyl and the like.
  • Cj-C 8 alkylsulfinyl is intended to mean a Ci-C 8 alkyl radical attached to the sulfur of a sulfoxide radical having the formula: -S(O)- wherein the alkyl radical has the same definition as described herein.
  • Examples include, but are not limited to, methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, /jo-propylsulf ⁇ nyl, «-butylsulfinyl, jec-burylsulfinyl, iso- butylsulfinyl, f-butylsulf ⁇ nyl, and the like.
  • Ci-C 8 alkylsulfonamide is intended to mean the groups shown below: wherein Cj-C 8 alkyl has the same definition as described herein.
  • Cj-C 8 alkylsulfonyl is intended to mean a C]-C 8 alkyl radical attached to the sulfur of a sulfone radical having the formula: -S(O) 2 - wherein the alkyl radical has the same definition as described herein. Examples include, but are not limited to, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, /so-propylsulfonyl, n-butylsulfonyl, sec-butylsulfonyl, iso- butylsulfonyl, ⁇ -butylsulfonyl, and the like.
  • Ci-C 8 alkylthio is intended to mean a Cj -C 8 alkyl radical attached to a sulfur atom (i.e., -S-) wherein the alkyl radical has the same definition as described herein. Examples include, but are not limited to, methylsulfanyl (i.e., CH 3 S-), ethylsulfanyl, n-propylsulfanyl, iso- propylsulfanyl, re-butylsulfanyl, jec-butylsulfanyl, zs ⁇ -butylsulfanyl, f-butylsulfanyl, and the like.
  • methylsulfanyl i.e., CH 3 S-
  • ethylsulfanyl ethylsulfanyl
  • n-propylsulfanyl iso- propylsulfanyl
  • re-butylsulfanyl
  • Ci-C 8 alkylureyl is intended to mean the group of the formula: -NC(O)N- wherein one are both of the nitrogens are substituted with the same or different Q-C 8 alkyl group wherein alkyl has the same definition as described herein.
  • alkylureyl include, but are not limited to, CH 3 NHC(O)NH-, NH 2 C(O)NCH 3 -, (CH 3 ) 2 NC(O)NH-, (CHs) 2 NC(O)NCH 3 -, CH 3 CH 2 NHC(O)NH-, CH 3 CH 2 NHC(O)NCH 3 - and the like.
  • C 2 -C 8 alkynyl is intended to mean a radical containing 2 to 8 carbons and at least one carbon-carbon triple bond, some embodiments are 2 to 4 carbons, some embodiments are 2 to 3 carbons, and some embodiments have 2 carbons.
  • alkynyl examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2- ⁇ entynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and the like.
  • alkynyl includes di- and tri-ynes.
  • amino is intended to mean the group -NH 2 .
  • Ci-C 8 alkylamino is intended to mean one alkyl radical attached to a -NH- radical wherein the alkyl radical has the same meaning as described herein. Some examples include, but are not limited to, methylamino, ethylamino, /z-propylamino, ⁇ o-propylamino, n- butylamino, .sec-butylamino, wo-butylamino, f-butylamino, and the like. Some embodiments are "C 1 -C 2 alkylamino.”
  • aryl is intended to mean an aromatic ring radical containing 6 to 10 ring carbons. Examples include phenyl and naphthyl.
  • tricyclic is intended to mean one C 4 -C 7 cycloalkyl or C 4 -C 7 cycloalkenyl group together with a C 4 -C 7 cycloalkyl, aryl or heteroaryl group wherein both groups share two ring carbons thus forming either a fused or bridged ring system.
  • Bicyclic examples include, but are not limited to, bicyclo[l.l.l]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.1.1]heptyl, bicyclo[3.2.1]octyl, 1,2,3,4-tetrahydro-naphthalenyl, indanyl, octahydro-pentalenyl, and the like.
  • carbo-Ci-C ⁇ -alkoxy is intended to mean a Ci-C 6 alkyl ester of a carboxylic acid, wherein the alkyl group is as defined herein.
  • carboxylic acid group is intended to mean the group -CONH 2 .
  • carboxy or “carboxyl” is intended to mean the group -CO 2 H; also referred to as a carboxylic acid group.
  • cyano is intended to mean the group -CN.
  • C 4 -C 7 cycloalkenyl is intended to mean a non-aromatic ring radical containing 4 to 7 ring carbons and at least one double bond; some embodiments contain 4 carbons. Examples include cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and the like.
  • C 3 -C 7 cycloalkyl is intended to mean a saturated ring radical containing 3 to 7 carbons; some embodiments contain 3 to 6 carbons; some embodiments contain 3 to 5 carbons; some embodiments contain 5 to 7 carbons; some embodiments contain 3 to 4 carbons. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • C 3 -C 7 cycloalkylenyl is intended to mean a saturated ring di-radical containing 3 to 7 carbons; some embodiments contain 3 to 6 carbons; some embodiments contain 3 to 5 carbons; some embodiments contain 5 to 7 carbons; some embodiments contain 3 to 4 carbons. Examples include cyclopropylenyl, cyclobutylenyl, cyclopentylenyl, cyclohexylenyl, cycloheptylenyl and the like.
  • the C 3 -C 7 cycloalkylenyl di-radical may be 1,2 disubstituted, for example 1,2-cyclopropyl, 1 ,2-cyclobutyl, 1,2- cyclopentyl, 1,2-cyclohexyl, 1,2-cyclohe ⁇ ryl and the like.
  • C 2 -C 8 dialkylamino is intended to mean an amino substituted with two of the same or different Ci-C 4 alkyl radicals wherein alkyl radical has the same definition as described herein. Some examples include, but are not limited to, dimethylamino, methylethylamino, diethylamino, methylpropylamino, methylisopropylamino, ethylpropylamino, ethylisopropylamino, dipropylamino, propylisopropylamino and the like. Some embodiments are "C 2 -C 4 dialkylamino.”
  • C 2 -C 8 dialkylcarboxamido or "C 2 -C 8 dialkylcarboxamide” is intended to mean two alkyl radicals, that are the same or different, attached to an amide group, wherein alkyl has the same definition as described herein.
  • a C 2 -C 8 dialkylcarboxamido may be represented by the following groups:
  • dialkylcarboxamide examples include, but are not limited to, N ⁇ V-dimethylcarboxamide, N-methyl-N-ethylcarboxarnide, N 5 N- diethylcarboxamide, N-methyl-N-isopropylcarboxamide, and the like.
  • C 2 -C 8 dialkylsulfonamide is intended to mean one of the following groups shown below:
  • Ci-C 4 has the same definition as described herein, for example but not limited to, methyl, ethyl, n-propyl, isopropyl, and the like.
  • C r C 6 haloalkoxy is intended to mean a C 1 -C 6 haloalkyl, as defined herein, which is directly attached to an oxygen atom. Examples include, but are not limited to, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy and the like.
  • C 1 -C 6 haloalkyl is intended to mean a Ci-C 6 alkyl group, defined herein, wherein the alkyl is substituted with one halogen up to fully substituted and a fully substituted C]-C 6 haloalkyl can be represented by the formula C n L 2n+I wherein L is a halogen and "n" is 1, 2, 3, 4, 5 or 6; when more than one halogen is present then they may be the same or different and selected from the group consisting of F, Cl, Br and I, preferably F, some embodiments are 1 to 5 carbons, some embodiments are 1 to 4 carbons, some embodiments are 1 to 3 carbons, and some embodiments are 1 or 2 carbons.
  • haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, 2,2,2- trifluoroethyl, pentafluoroethyl and the like.
  • C 1 -C 6 haloalkylsuliinyl is intended to mean a C 1 -C 6 haloalkyl radical attached to the sulfur atom of a sulfoxide group having the formula: -S(O)- wherein the haloalkyl radical has the same definition as described herein. Examples include, but are not limited to, trifluoromethylsulfinyl, 2,2,2-trifluoroethylsulfinyl, 2,2-difluoroethylsulfinyl and the like.
  • C 1 -C 6 haloalkylsulfonyl is intended to mean a C 1 -C 6 haloalkyl radical attached to the sulfur atom of a sulfone group having the formula: -S(O) 2 - wherein haloalkyl has the same definition as described herein. Examples include, but are not limited to, trifluoromethylsulfonyl, 2,2,2-trifluoroethylsulfonyl, 2,2-difluoroethylsulfonyl and the like.
  • Ci-C 6 haloalkylthio is intended to mean a Ci -C 6 haloalkyl radical directly attached to a sulfur wherein the haloalkyl has the same meaning as described herein. Examples include, but are not limited to, trifluoromefhylthio (i.e., CF 3 S-, also referred to as trifluoromethylsulfanyl), 1,1-difluoroethylthio, 2,2,2-trifluoroethylthio and the like.
  • halogen or halo is intended to mean to a fluoro, chloro, bromo or iodo group.
  • heteroaryl is intended to mean an aromatic ring system that may be a single ring, two fused rings or three fused rings wherein at least one ring carbon is replaced with a heteroatom selected from, but not limited to, the group consisting of O, S and N wherein the N can be optionally substituted with H, Ci-C 4 acyl or Cj-C 4 alkyl.
  • heteroaryl groups include, but are not limited to, pyridyl, benzofuranyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, quinolinyl, benzoxazolyl, benzothiazolyl, lH-benzimidazolyl,-isoquinolinyl, quinazolinyl, quinoxalinyl and the like.
  • the heteroatom is selected from, but not limited to, the group consisting of O, S and N, wherein N is substituted with H (i.e., NH), examples include, but are not limited to, pyrrolyl, indolyl, lH-benzoimidazol-2-yl, and the like.
  • one of the rings is aromatic.
  • heterobicyclic group examples include, but are not limited to, 2,5- diaza-bicyclo[2.2.1]hept-2-yl, 7-aza-bicyclo[2.2.1]hept-7-yl, 1,3-dihydro-isoindolyl, 3,4- dihydro-lH-isoquinolinyl, octahydro-cyclopenta[c]pyrrolyl and the like.
  • the nitrogen is optionally substituted with C 1 -C 4 acyl or Ci-C 4 alkyl, and ring carbon atoms are optionally substituted with oxo or a thiooxo thus forming a carbonyl or thiocarbonyl group.
  • the heterocyclic group can be attached/bonded to any available ring atom, for example, ring carbon, ring nitrogen, and the like.
  • the heterocyclic group is a 3-, 4-, 5-, 6- or 7-membered ring.
  • heterocyclic group examples include, but are not limited to, aziridin-1-yl, aziridin-2-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, piperidin-1- yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, morpholin-2-yl, morpholin-3-yl, morpholin-4- yl, piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, piperazin-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, [l,3]-dioxolan-2-yl, thiomorpholin-4-yl, [l,4]oxazepan-4-yl, 1,1-dioxo-l ⁇ 6 - thiomorpholin-4-yl, azepan
  • hydroxyl is intended to mean the group -OH.
  • nitro is intended to mean the group -NO 2 .
  • phenyl is intended to mean the group C 6 Hs-.
  • sulfonamide is intended to mean the group -SO 3 NH 2 .
  • thiol is intended to mean the group -SH.
  • One aspect of the present invention pertains to certain compounds as shown in Formula (Ia):
  • the compounds of the present invention are other than N-(3- cyanopheny ⁇ -N-p- ⁇ '-fK ⁇ l-dimethylethylJaminoJsulfonylJflJ'-biphenylj ⁇ -ylJethylJ-glycine methyl ester, represented by the formula below:
  • the compounds of the present invention are other than N-[[4'-[2- oxo-2-(phenylarnino)ethyI] [1,1 '-biphenyl]-4-yl] sulfonyl]-D-valine 1 , 1 -dimethylethyl ester, represented by the formula below:
  • the compounds of the present invention are other than N-[[4'-[2- oxo-2-[(phenylmethyl)amino]ethyl] [1,1 '-biphenyl] -4-yl]sulfonyl] -D-valine 1 , 1 -dimethylethyl ester, represented by the formula below:
  • the compounds of the present invention are other than iV-[[4'-[2- oxo-2-(phenylamino)ethyl][l,l'-biphenyl]-4-yl]sulfonyl]-D-valine
  • the compounds of the present invention are other than N-[[4'-[2- oxo-2-[(phenylmethyl)amino]ethyl][l,r-biphenyl]-4-yl]sulfonyl]-D-valine represented by the formula below:
  • substituted indicates that at least one hydrogen atom of the chemical group is replaced by a non-hydrogen substituent or group, the non-hydrogen substituent or group can be monovalent or divalent. When the substituent or group is divalent, then it is understood that this group is further substituted with another substituent or group.
  • a chemical group herein when a chemical group herein is "substituted" it may have up to the full valance of substitution; for example, a methyl group can be substituted by 1, 2, or 3 substituents, a methylene group can be substituted by 1 or 2 substituents, a phenyl group can be substituted by 1, 2, 3, 4, or 5 substituents, a naphthyl group can be substituted by 1, 2, 3, 4, 5, 6, or 7 substituents and the like.
  • substituted with one or more substituents refers to the substitution of a group with one substituent up to the total number of substituents physically allowed by the group. Further, when a group is substituted with more than one group they can be identical or they can be different.
  • Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. It is understood that the various tautomeric forms are within the scope of the compounds of the present invention.
  • Compounds of the invention can also include all isotopes of atoms occurring in the intermediates and/or final compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include deuterium and tritium.
  • compounds of Formula (Ia) and Formulae related thereto may have two or more chiral centers, and therefore can exist as enantiomers and/or diastereomers. The invention is understood to extend to and embrace all such enantiomers, diastereomers and mixtures thereof, including but not limited to racemates.
  • compounds of the present invention have two stereochemical centers and both are R.
  • compounds of the present invention have two stereochemical centers and both are S.
  • compounds of the present invention have two stereochemical centers wherein one stereochemical center is R and one stereochemical center is S. In another embodiment, compounds of the present invention have three stereochemical centers wherein all stereochemical centers are R. In another embodiment, compounds of the present invention have three stereochemical centers wherein all stereochemical centers are S. In another embodiment, compounds of the present invention have three stereochemical centers wherein two stereochemical centers- are R and the third stereochemical center is S. In another embodiment, compounds of the present invention have three stereochemical centers wherein two stereochemical centers are S and the third stereochemical center is R. It is understood that compounds of Formula (Ia) and formulae used throughout this disclosure are intended to represent all individual enantiomers and mixtures thereof, unless stated or shown otherwise. One aspect of the present invention pertains to certain compounds as shown in Formula
  • R 1 and R 2 are each selected independently from the group consisting of H, Ci-Cs alkyl,
  • each R 1 and R 2 is optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting OfC]-C 6 acyl, Q-C 6 acyloxy, C 2 -C 8 alkenyl, Q-C 6 alkoxy, Ci-C 8 alkyl, Ci-C 8 alkylcarboxamide, C 2 -C 8 alkynyl, Ci-C 8 alkylsulfonamide, Ci-C 8 alkylsulfinyl, C]-C 8 alkylsulfon
  • J is -CH 2 CH 2 - or a l,2-C 3 -C 7 -cycloalkylenyl group, each optionally substituted with 1, 2, 3 or 4 substituents selected independently from the group consisting Of C 1 -C 3 alkyl, C]-C 4 alkoxy, carboxy, cyano, C]-C 3 haloalkyl, halogen, hydroxyl and oxo;
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , R 1 ' and R 12 are each selected independently from the group consisting of H, Ci-C 6 acyl, Ci-C 6 acyloxy, C 2 -C 8 alkenyl, Ci-C 6 alkoxy, Ci-C 8 alkyl, Ci-C 8 alkylcarboxamide, C 2 -C 8 alkynyl, Ci-Cs alkylsulfonamide, C]-C 8 alkylsulfinyl, C 1 -C 8
  • R 8 and R 9 together with the nitrogen atom to which they are both bonded form a C 3 -C 7 heterocyclyl or a C 5 -C 10 heterobicyclyl group each optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected independently from the group consisting of Cj-Ce acyl, Cj-C 6 acyloxy, C 2 - C 8 alkenyl, Cj-C 6 alkoxy, Cj-C 8 alkyl, Ci-C 8 alkylcarboxamide, C 2 -C 8 alkynyl, Ci-C 8 alkylsulfonamide, Cj-C 8 alkylsulfinyl, Cj-C 8 alkylsulfonyl, Q-C 8 alkylthio, Ci-C 8 alkylureyl, amino, C]-C 8 alkylamino, C 2 -C 8 dialkylamino, carbo-Ci-C 6 -alkoxy, carboxamide, carboxy, cyan
  • each R 1 and R 2 is selected independently from the group consisting of H, Ci-C 8 alkyl, C 3 -C 7 cycloalkyl, aryl, heterocyclyl, aryl-Ci-G f -alkylenyl, heteroaryl-Ci-Q-alkylenyl and aryloxy-Q-Q-alkylenyl, and each R 1 and R 2 is optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting of Ci-C 6 alkoxy, Ci-C 8 alkyl, C 3 -C 7 cycloalkyl, halogen, C 1 -C 6 haloalkyl and hydroxyl.
  • each R 1 and R 2 is selected independently from the group consisting of H, Ci-C 8 alkyl, C 3 -C 7 cycloalkyl, aryl, heterocyclyl, aryl-d-C 4 -alkylenyl, heteroaryl-Cj-C 4 -alkylenyl and aryloxy-Ci-C 4 -alkylenyl, and each R 1 and R 2 is optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting of methoxy, ethoxy, isopropoxy, cyclopropyl, cyclohexyl, hydroxyl, fluoro, methyl, chloro and trifluoromethyl.
  • each R 1 and R 2 is selected independently from the group consisting of H, methyl, ethyl, n-propyl, isopropyl, t-butyl, 1-propyl-butyl, cyclopropyl.
  • cyclobutyl cyclopentyl, cyclohexyl, phenyl, tetrahydropyran-4-yl, benzyl, pyridin-2-ylmethyl, 2-phenoxy-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, 2-isopropoxyethyl, cyclopropylmethyl, cyclohexylmethyl, 2-hydroxyethyl, 4-fluoro-phenyl, 4-methyl-benzyl, 4-methoxy-benzyl, A- fluoro-benzyl, 4-chloro-benzyl and 4-trifluoromethyl-benzyl.
  • R 1 is H or Ci-C 8 alkyl and R 2 is C]-C 8 alkyl, C 3 -C 7 cycloalkyl, aryl, heterocyclyl, aryl-Ci-C 4 -alkylenyl, aryl-Ci-C 4 -alkylenyl, heteroaryl-Ci-C 4 -alkylenyl or aryloxy-Ci-C 4 -alkylenyl, and each R 2 is optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting of C]-Ce alkoxy, Ci-C 8 alkyl, C 3 -C 7 cycloalkyl, halogen, C 1 -C 6 haloalkyl and hydroxyl.
  • R 1 is H or Cj-C 8 alkyl and R 2 is Cj-C 8 alkyl, C 3 -C 7 cycloalkyl, aryl, heterocyclyl, aryl-Cj -Gj-alkylenyl, aryl-Ci-C 4 -alkylenyl, heteroaryl-Cj-C 4 -alkylenyl or aryloxy-Ci-C 4 -alkylenyl, and each R 2 is optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting of methoxy, ethoxy, isopropoxy, cyclopropyl, cyclohexyl, hydroxyl, fluoro, methyl, chloro and trifluoromethyl.
  • R 1 is H, methyl or ethyl and R 2 is H 3 methyl, ethyl, n-propyl, isopropyl, t-butyl, 1-propyl-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, tetrahydropyran-4-yl, benzyl, pyridin-2-ylmethyl, 2-phenoxy-ethyl, 2-methoxy-ethyl, 2-ethoxy- ethyl, 2-isopropoxyethyl, cyclopropylmethyl, cyclohexylmethyl, 2-hydroxyethyl, 4-fluoro- phenyl, 4-methyl-benzyl, 4-methoxy-benzyl, 4-fluoro-benzyl, 4-chloro-benzyl or 4- trifluoromethyl-benzyl.
  • R 1 and R 2 together with the nitrogen atom to which they are both bonded form a C 3 -C 7 heterocyclyl or a C 5 -Ci 0 heterobicyclyl group. In some embodiments, R 1 and R 2 together with the nitrogen atom to which they are both bonded form azetidin-1-yl, pyrrolidin-l-yl, piperidin-1-yl, morpholin-4-yl, 1,1-dioxo- thiomorpholin-4-yl, 2,3-dihydro-lH-isoindol-2-yl or l,2,3,4-tetrahydro-isoquinolin-2-yl.
  • each R 1 and R 2 is selected independently from the group consisting of ⁇ , Ci-C 8 alkyl, C 3 -C 7 cycloalkyl, aryl, heterocyclyl, aryl-Ci-C 4 -alkylenyl, amino, heteroaryl-Ci-Gj-alkylenyl, aryloxy-Ci-C 4 -alkylenyl and Ci-C 6 acyl, and each R : andR 2 is optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting OfC]-C 6 alkoxy, Ci-C 8 alkyl, aryl, carbo-Ci-Cg-alkoxy, C 3 -C 7 cycloalkyl, halogen, Ci-C 6 haloalkyl, hydroxyl, Ci-C 6 acyl, Ci-C 6 acyloxy, Ci-C 6 haloalkoxy and heterocyclyl; wherein each Ci-C 8 alkyl, C
  • R 1 andR 2 together with the nitrogen atom to which they are both bonded form a C 3 -C 7 heterocyclyl or a C 5 -C 10 heterobicyclyl group each optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting OfC 1 -C 6 acyl, Ci-C 8 alkyl, Ci-C 8 alkylcarboxamide, C]-C 6 acyloxy, carboxy and hydroxy; and wherein each Ci-C 8 alkyl and carboxy may be further substituted with Ci-C 6 acyloxy, Ci-C 6 alkoxy, aryl-Ci-C 4 -alkylenyl or hydroxy.
  • R 1 and R 2 are each selected independently from the group consisting of ⁇ , methyl, ethyl, n-propyl, isopropyl, t-butyl, 1-propyl-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, tetrahydropyran-4-yl, benzyl, pyridin-2-ylmethyl, 2-phenoxy-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, 2-isopropoxyethyl, cyclopropylmethyl, cyclohexylmethyl, 2-hydroxyethyl, 4-fluoro-phenyl, 4-methyl-benzyl, 4-methoxy-benzyl, 4- fluoro-benzyl, 4-chloro-benzyl, 4-trifluoromethyl-benzyl, amino, 2-methoxy-l -methyl-ethyl, iso
  • R 1 andR 2 together with the nitrogen atom to which they are both bonded form azetidin- 1-yl, pyrrolidin-l-yl, piperidin-1-yl, morpholin-4-yl, l,l-dioxo-thiomorphoIm-4-yl, 2,3-dihydro- lH-isoindol-2-yl, l,2,3,4-tetrahydro-isoquinolin-2-yl, 3-hydroxy-pyrrolidin-l-yl, 3- hydroxymethyl-pi ⁇ eridin-1-yl, aziridinl-yl, 2-methoxymethyl-pyrrolidin-l-yl, 3-hydroxy- piperidin-l-yl, 2-hydroxymethyl-pyrrolidin-l-yl, 4-(benzyloxycarbonyl)piperidin-l-yl, 4- (propionyloxy-methyl)-piperidin-.l-yl, 2-(propionyloxy-methyl)
  • each R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , R 1 ' and R 12 is selected independently from H or halogen. In some embodiments, R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , R 1 ' and R 12 are H.
  • J is -CH 2 CH 2 - optionally substituted with 1, 2, 3 or 4 substituents selected independently from the group consisting OfCi-C 3 alkyl, Ci-C 4 alkoxy, carboxy, cyano, C 1 -C 3 haloalkyl, halogen, hydroxyl and oxo.
  • J is -CH2CH2-.
  • each R 8 and R 9 is selected independently from the group consisting of H, Ci-C 8 alkyl, C 3 -C 7 cycloalkyl, aryl, heterocyclyl, aryl-C 1 -C 4 -alkylenyl, heteroaryl-Ci-C 4 -alkylenyl and aryloxy-Ci-C 4 -alkylenyl, and each R 8 andR 9 is optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting of Ci-C 6 alkoxy, Ci-C 8 alkyl, C 3 -C 7 cycloalkyl, halogen, C]-Ce haloalkyl and hydroxyl.
  • each R 8 and R 9 is selected independently from the group consisting of H, C]-Cs alkyl, C 3 -C 7 cycloalkyl, aryl, heterocyclyl, aryl-C]-C 4 -alkylenyl, heteroaryl-Ci-C 4 -alkylenyl and aryloxy-Ci-C 4 -alkylenyl, and each R 8 andR 9 is optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting of methoxy, ethoxy, isopropoxy, cyclopropyl, cyclohexyl, hydroxyl, fluoro, methyl, chloro and trifluoromethyl.
  • each R 8 and R 9 is selected independently from the group consisting of H, methyl, ethyl, n-propyl, isopropyl, t-butyl, 1-propyl-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, tetrahydropyran-4-yl, benzyl, pyridin-2-ylmethyl, 2-phenoxy-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, 2-isopropoxyethyl, cyclopropylmethyl, cyclohexylmethyl, 2-hydroxyethyl, 4-fluoro-phenyl, 4-methyl-benzyl, 4-methoxy-benzyl, 4- fiuoro-benzyl, 4-chloro-benzyl and 4-trifluoromethyl-benzyl.
  • R 8 and R 9 together with the nitrogen
  • R 8 and R 9 together with the nitrogen atom to which they are both bonded form a C 3 -C 7 heterocyclyl group optionally substituted with methyl. In some embodiments, R 8 and R 9 together with the nitrogen atom to which they are both bonded form pyrrolidin-1-yl optionally substituted with methyl.
  • R 8 and R 9 together with the nitrogen atom to which they are both bonded form 2-methyl-pyrrolidin-l-yl.
  • R 8 and R 9 together with the nitrogen atom to which they are both bonded form (i?)-2-methyl-pyrrolidin-l -yl.
  • R 8 and R 9 together with the nitrogen atom to which they are both bonded form (iS)-2-methyl-pyrrolidin-l-yl.
  • Some embodiments of the present invention pertain to compounds of Formula (Ig):
  • R 1 is H or C]-C 8 alkyl and R 2 is C]-Cg alkyl, C 3 -C 7 cycloalkyl, aryl, heterocyclyl,* aryl- Ci-C 4 -alkylenyl, heteroaryl-C]-C 4 -alkylenyl or aryloxy-Cj-Gralkylenyl, and each R 2 is optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting Of Cj-C 6 alkoxy, Cj-C 8 alkyl, C 3 -C 7 cycloalkyl, halogen, Cj-C 6 haloalkyl and hydroxyl; or
  • R 1 and R 2 together with the nitrogen atom to which they are both bonded form a C 3 -C 7 heterocyclyl or a C 5 -C 10 heterobicyclyl group;
  • J is -CH 2 CH 2 -; and R 8 and R 9 together with the nitrogen atom to which they are both bonded form a C 3 -C 7 heterocyclyl group optionally substituted with Cj-C 8 alkyl.
  • Some embodiments of the present invention pertain to compounds of Formula (Ig), supra, or a pharmaceutically acceptable salt, hydrate or solvate thereof; wherein R 1 is H, methyl or ethyl and R 2 is H, methyl, ethyl, n-propyl, isopropyl, t-butyl, 1- propyl-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, tetrahydropyran-4-yl, benzyl, pyridin-2-ylmethyl, 2-phenoxy-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, 2- isopropoxyethyl, cyclopropylmethyl, cyclohexylmethyl, 2-hydroxyethyl, 4-fluoro-phenyl, 4- methyl-benzyl, 4-methoxy-benzyl, 4-fluoro-benzyl, 4-
  • R 1 and R 2 together with the nitrogen atom to which they are both bonded form azetidin- 1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, l,l-dioxo-thiomorpholin-4-yl, 2,3-dihydro- lH-isoindol-2-yl or l,2,3,4-tetrahydro-isoquinolin-2-yl;
  • R 8 and R 9 together with the nitrogen atom to which they are both bonded form 2-methyl- pyrrolidin-1-yl.
  • Some embodiments of the present invention pertain to compounds of Formula (Ii):
  • R 1 is H or Ci-Cs alkyl and R 2 is C]-C 8 alkyl, C 3 -C 7 cycloalkyl, aryl, heterocyclyl, aryl- Ci-C 4 -alkylenyl, heteroaryl-Ci-C 4 -alkylenyl or aryloxy-Ci-C 4 -alkylenyl and each R 2 is optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting OfCi-C 6 alkoxy, Cj-C 8 alkyl, C 3 -C 7 cycloalkyl, halogen, Ci-C 6 haloalkyl and hydroxyl; or
  • R 1 and R 2 together with the nitrogen atom to which they are both bonded form a C 3 -C 7 heterocyclyl or a Cs-Qo heterobicyclyl group; J is -CH 2 CH 2 -; and
  • R 8 and R 9 together with the nitrogen atom to which they are both bonded form a C 3 -C 7 heterocyclyl group optionally substituted with Ci-Cg alkyl.
  • Some embodiments of the present invention pertain to compounds of Formula (Ii), supra, or a pharmaceutically acceptable salt, hydrate or solvate thereof; wherein:
  • R 1 is H, methyl or ethyl and R 2 is H, methyl, ethyl, n-propyl, isopropyl, t-butyl, 1- propyl-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, tetrahydropyran-4-yl, benzyl, pyridin-2-ylmethyl, 2-phenoxy-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, 2- isopropoxyethyl, cyclopropylmethyl, cyclohexylmethyl, 2-hydroxyethyl, 4-fluoro-phenyl, A- methyl-benzyl, 4-methoxy-benzyl, 4-fluoro-benzyl, 4-chloro-benzyl or 4-trifluoromethyl- benzyl; or R 1 and R 2 together with the nitrogen atom to which they
  • R 8 and R 9 together with the nitrogen atom to which they are both bonded form 2-methyl-. pyrrolidin-1-yl.
  • Some embodiments of the present invention pertain to compounds selected from compounds of Formula (Ig) and pharmaceutically acceptable salts, hydrates and solvates thereof:
  • R 1 is selected from the group consisting of H, Ci-C 6 acyl and Ci-C 8 alkyl optionally substituted with 1, 2, 3, 4 or 5 suhstituents selected independently from the group consisting of Ci-C 6 alkoxy and hydroxy;
  • R 2 is selected from the group consisting of H, Ci-C 8 alkyl, C 3 -C 7 cycloalkyl, aryl, heterocyclyl, aryl-Ci-C 4 -alkylenyl, amino, heteroaryl-Ci-C 4 -alkylenyl, aryloxy-Ci-C 4 -alkylenyI and C
  • R 1 and R 2 together with the nitrogen atom to which they are both bonded form a C 3 -C 7 heterocyclyl or a C 3 -C ]0 heterobicyclyl group each optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting Of C]-C 6 acyl, C]-C 8 alkyl, Cj-C 8 alkylcarboxamide, C]-C 6 acyloxy, carboxy and hydroxy; and wherein each C 1 -C 8 alkyl and carboxy may be further substituted with C r C 6 acyloxy, C]-C 6 alkoxy, aryl-Ci-C 4 -alkylenyl or hydroxy;
  • R s and R 9 together with the nitrogen atom to which they are both bonded form a C 3 -C 7 heterocyclyl group optionally substituted with Ci-C 8 alkyl.
  • Some embodiments of the present invention pertain to compounds selected from compounds of Formula (Ig) and pharmaceutically acceptable salts, hydrates and solvates thereof:
  • R 1 is H, methyl, ethyl, 2-hydroxy-ethyl, 2-methoxy-ethyl or acetyl
  • R 2 is selected from the group consisting of H, methyl, ethyl, n-propyl, isopropyl, t-butyl, 1-propyl-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, tetrahydropyran-4-yl, benzyl, pyridin-2-ylmethyl, 2-phenoxy-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, 2- isopropoxyethyl, cyclopropylmethyl, cyclohexylmethyl, 2-hydroxyethyl, 4-fluoro-phenyl, 4- methyl-benzyl, 4-methoxy-benzyl, 4-fmoro-benzyl, 4-chlord-
  • R 1 and R 2 together with the nitrogen atom to which they are both bonded form azetidin- 1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, l,l-dioxo-thiomorpholin-4-yl, 2,3-dihydro- lH-isoindol-2-yl, l,2,3,4-tetrahydro-isoquinolin-2-yl, 3-hydroxy-pyrrolidin-l-yl, 3- hydroxymethyl-piperidin-1-yl, aziridinl-yl, 2-methoxymethyl-pyrrolidin-l-yl, 3-hydroxy- piperidin-1-yl, 2-hydroxymethyl-pyrroIidin-l-yl, 4-(benzyloxycarbonyl)piperidin-l-yl, 4- (propionyloxy-methyl)-piperidin-l -yl, 2-(propionyloxy-methyl)-pyrrolidin
  • R s and R 9 together with the nitrogen atom to which they are both bonded form pyrrolidin-1-yl or 2-methyl-pyrrolidin-l-yl.
  • R 1 , R 3 , R 4 , R s , R 6 , R 7 , R 8 , R 10 , R 11 and R 12 are all H and R 9 is phenyl or benzyl then R 2 is a moiety other than C]-Cs alkyl substituted with carbo-Ci-C6- alkoxy.
  • R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 10 , R 11 and R 12 are all H and R 9 is phenyl or benzyl then R 2 is a moiety other than Ci-C 8 alkyl substituted with carboxy.
  • R 1 , R 3 , R 4 , R s , R 6 , R 7 , R 10 , R 11 andR 12 are all H; and R 2 is tert-butyl; and R 8 is Ci-Cs alkyl substituted with carbo-C]-C 6 -alkoxy; then R 9 is a moiety other than aryl substituted with cyano.
  • Some embodiments of the present invention include every combination of one or more compounds selected from the following group shown in TABLE A.
  • Some embodiments of the present invention include every combination of one or more compounds selected from the following group shown in TABLE B.
  • individual compounds and chemical genera of the present invention encompass all pharmaceutically acceptable salts, solvates, and particularly hydrates, thereof.
  • the compounds of the Formula (Ia) of the present invention may be prepared according to relevant published literature procedures that are used by one skilled in the art. Exemplary reagents and procedures for these reactions appear hereinafter in the working Examples. Protection and deprotection may be carried out by procedures generally known in the art (see, for example, Greene, T. W. and Wuts, P. G. M., Protecting Groups in Organic Synthesis, 3 rd Edition, 1999 [Wiley]; incorporated herein by reference in its entirety).
  • the present invention embraces each diastereomer, each enantiomer and mixtures thereof of each compound and generic Formulae disclosed herein just as if they were each individually disclosed with the specific stereochemical designation for each chiral carbon. Separation of the individual isomers (such as by chiral HPLC, recrystallization of diastereomeric mixtures and the like) or selective synthesis (such as by enantiomeric selective syntheses and the like) of the individual isomers is accomplished by application of various methods which are well known to practitioners in the art. Representative examples are shown here in.
  • GPCRs G-protein coupled receptors
  • Rat and human histamine H3-receptors also show constitutive activity which means that they can transduce a signal even in the absence of a ligand. Histamine H3-receptors also function as heteroceptors, modulating the release of a number of other transmitter substances including serotonin, acetylcholine, dopamine and noradrenaline (see: Brown et al. Prog. Neurobiol. 2001, 63, 637-672).
  • the ligand functions as either an antagonist or inverse agonist (for reviews see: Leurs et al. Nat. Rev. Drug. Discov. 2005, 4, 107-120; Passani et a Trends Pharmacol. ScL 2004, 25, 618-625).
  • histamine H3-receptor antagonists and inverse agonists such as compounds of the present invention.
  • the compounds disclosed herein are believed to be useful in the treatment and/or prevention of several diseases and disorders, and in the amelioration of symptoms thereof. These compounds can be used alone or in combination with other compounds for the treatment and/or prevention of diseases and disorders. Without limitation, these diseases and disorders include the following. Histamine H3-rece ⁇ tor antagonists have been shown to increase wakefulness (e.g. Lin J. S. et al. Brain Research 1990, 523, 325-330).
  • H3-receptor antagonists can be useful for disorders of sleep and wakefulness (Parmentier et al. JNeurosci. 2002, 22, 7695-7711; Ligneau et al. J. Pharmacol. Exp. Ther. 1998, 287, 658-666).
  • histamine H3-receptor antagonists and inverse agonists can be used to treat the somnolence syndrome associated with different pathological conditions, for example, sleep apnea and Parkinson's disease or circumstances associated with lifestyle, for example, daytime somnolence from sleep deprivation as a result of nocturnal jobs, overwork, or jet-lag (see Passani et al., Trends Pharmacol. ScL 2004, 25, 618-625). Somnolence is one of the major problems of public health because of its high prevalence (19-37% of the general population) and risk for causing work and traffic accidents.
  • Sleep apnea is a common sleep disorder characterized by brief interruptions of breathing during sleep. These episodes, called apneas, last 10 seconds or more and occur repeatedly throughout the night. People with sleep apnea partially awaken as they struggle to breathe, but in the morning they may not be aware of the disturbances in their sleep.
  • the most common type of sleep apnea is obstructive sleep apnea (OSA), caused by relaxation of soft tissue in the back of the throat that blocks the passage of air.
  • OSA obstructive sleep apnea
  • CSA Central sleep apnea
  • the hallmark symptom of the disorder is excessive daytime sleepiness.
  • sleep apnea Additional symptoms of sleep apnea include restless sleep, loud snoring (with periods of silence followed by gasps), falling asleep during the day, morning headaches, trouble concentrating, irritability, forgetfulness, mood or behaviour changes, weight gain, increased heart rate, anxiety, and depression.
  • methylxanthine theophylline (chemically similar to caffeine) can reduce the number of episodes of apnea, but can also produce side effects such as palpitations and insomnia.
  • Theophylline is generally ineffective in adults with OSA, but is sometimes used to treat CSA, and infants and children with apnea.
  • some neuroactive drugs particularly modern-generation antidepressants including mirtazapine, have been reported to reduce incidences of obstructive sleep apnea.
  • histamine H3-receptor antagonists and inverse agonists can be used to treat narcolepsy (Tedford et al. Soc. Neurosci. Abstr. 1999, 25, 460.3).
  • Narcolepsy is a neurological condition most characterized by Excessive Daytime Sleepiness (EDS), episodes of sleep and disorder of REM or rapid eye movement sleep.
  • EDS Excessive Daytime Sleepiness
  • the main characteristic of narcolepsy is overwhelming Excessive Daytime Sleepiness (EDS), even after adequate nighttime sleep.
  • a person with narcolepsy is likely to become drowsy or to fall asleep, often at inappropriate times and places.
  • nighttime sleep may be fragmented with frequent wakenings.
  • Classic symptoms of narcolepsy include, for example, cataplexy which is sudden episodes of loss of muscle function, ranging from slight weakness (such as limpness at the neck or knees, sagging facial muscles, or inability to speak clearly) to complete body collapse. Episodes may be triggered by sudden emotional reactions such as laughter, anger, surprise, or fear, and may last from a few seconds to several minutes.
  • Another symptom of narcolepsy is sleep paralysis, which is the temporary inability to talk or move when waking up.
  • hypnagogic hallucinations which are vivid, often frightening, dream-like experiences that occur while dozing, falling asleep and/or while awakening, and automatic behaviour which occurs when a person continues to function (talking, putting things away, etc.) during sleep episodes, but awakens with no memory of performing such activities.
  • Daytime sleepiness, sleep paralysis, and hypnagogic hallucinations also occur in people who do not have narcolepsy, such as in people who are suffering from extreme lack of sleep. Cataplexy is generally considered unique to narcolepsy.
  • narcolepsy treat the symptoms, but not the underlying cause.
  • antidepressant medications and other drugs that suppress REM sleep are prescribed.
  • the drowsiness is normally treated using stimulants such as methylphenidate (Ritalin), amphetamines (Adderall), dextroamphetamine (Dexedrine), methamphetamine (Desoxyn), modafinil (Provigil), etc.
  • Other medications used are codeine and selegiline.
  • the cataplexy is treated using clomipramine, imipramine, or protriptyline but this need only be done in severe cases.
  • a new medication is gamma-hydroxybutyrate (GHB) (Xyrem), recently approved in the USA by the Food and Drug Administration. It is thought to be effective because it increases the quality of nocturnal sleep.
  • GLB gamma-hydroxybutyrate
  • histamine H3-receptor antagonists and inverse agonists can be used for the treatment and/or prevention of conditions associated with excessive daytime sleepiness such as hypersomnia, narcolepsy, sleep apnea, time zone change disorder, and other disorders which are associated with excessive daytime sleepiness such as fibromyalgia, and multiple sclerosis
  • histamine H3 -receptor antagonists and inverse agonists have been shown to improve cognitive performance in various animal models (Hancock and Fox in Milestones in Drug Therapy, ed. Buccafusco, 2003). These compounds can be used as pro-cognitive agents and can increase vigilance. Therefore, histamine H3 -receptor antagonists and inverse agonists can be used in aging or degenerative disorders in which vigilance, attention and memory are impaired, for example, as in Alzheimer's disease or other dementias.
  • AD Alzheimer's disease
  • cognitive impairment extends to the domains of language, skilled movements, recognition and functions closely related to the frontal and temporal lobes of the brain such as decision-making and planning.
  • drugs which offer symptomatic benefit, specifically with respect to short-term memory impairment.
  • acetylcholinesterase inhibitors such as donepezil (Aricept), galantamine (Razadyne) and rivastigmine (Exelon) and NMDA antagonists such as memantine.
  • Histamine H3-receptor antagonists and inverse agonists can be used to treat or prevent cognitive disorders (Passani et al. Trends Pharmacol. Sci. 2004, 25, 618-625), epilepsy (Vohora et al. Pharmacol. Biochem. Behav. 2001, 68, 735-741), depression (Perez-Garcia et al. Psychopharmacol. 1999, 142, 215-220), attention deficit hyperactivity disorder (ADHD), (Fox et al. Behav. Brain Res.
  • ADHD attention deficit hyperactivity disorder
  • histamine H3-receptor antagonists and inverse agonists can be used to treat or prevent epilepsy.
  • Epilepsy (often referred to as a seizure disorder) is a chronic neurological condition characterized by recurrent unprovoked seizures. In terms of their pattern of activity, seizures may be described as either partial (focal) or generalized. Partial seizures only involve a localized part of the brain, whereas generalized seizures involve the entire cortex.
  • epilepsy syndromes each presenting with its own unique combination of seizure type, typical age of onset, EEG findings, treatment, and prognosis.
  • Some common seizure syndromes include, for example, infantile spasms (West syndrome), childhood absence epilepsy, and benign focal epilepsy of childhood (Benign Rolandic epilepsy), juvenile myoclonic epilepsy, temporal lobe epilepsy, frontal lobe epilepsy and Lennox-Gastaut syndrome.
  • compounds of the present invention can be used in combination with various known drugs.
  • compounds of the present invention can be used with one or more drugs that prevent seizures or reduce seizure frequency: these include carbamazepine (common brand name Tegretol), clobazam (Frisium), clonazepam (Klonopin), ethosuximide (Zarontin), felbamate (Felbatol), fosphenytoin (Cerebyx), flurazepam (Dalmane), gabapentin (Neurontin), lamotrigine (Lamictal), levetiracetam (Keppra), oxcarbazepine (Trileptal), mephenytoin (Mesantoin), phenobarbital (Luminal), phenytoin (Dilantin), pregabalin (Lyrica), primidone (Mysoline), sodium valproate (Epilim), tiagabine (Gabitril), topiramate (
  • Drugs used only in the treatment of refractory status epilepticus include paraldehyde (Paral) and pentobarbital (Nembutal).
  • a histamine H3-receptor antagonist or inverse agonist can be used the sole agent of treatment or can be used in combination with other agents.
  • Vohora et al. show that a histamine H3-receptor antagonist can work as an anti-epilepsy, anti-seizure drug and also showed effect with sub-effective doses of the H3 -receptor antagonist in combination with sub-effective doses of known anti-epileptic drugs (Vohora et al. Pharmacol. Biochem. Behav. 2001, 68, 735-741).
  • Perez-Garcia et al. (Perez-Garcia et al. Psychopharmacol. 1999, 142, 215-220) tested the ability of a histamine H3 -receptor agonist and antagonist on experimental mouse models of anxiety (elevated plus-maze) and depression (forced swimming test). They found that while the compounds did not have a significant effect on the model of anxiety, a H3-receptor antagonist did have a significant dose-dependent effect in the model of depression. Thus, histamine H3- receptor antagonists or inverse agonists can have antidepressant effects.
  • Clinical depression is a state of sadness or melancholia that has advanced to the point of being disruptive to an individual's social functioning and/or activities of daily living. Clinical depression affects about 16% of the population on at least one occasion in their lives. Clinical depression is currently the leading cause of disability in the U.S. as well as other countries, and is expected to become the second leading cause of disability worldwide (after heart disease) by the year 2020, according to the World Health Organization.
  • compounds of the present invention can be used in combination with various known drugs.
  • compounds of the present invention can be used with one or more of the drugs currently available that can relieve the symptoms of depression.
  • They include, for example, monoamine oxidase inhibitors (MAOIs) such as Nardil or Moclobemide (Manerix), tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (Prozac), paroxetine (Paxil), escitalopram (Lexapro), and sertraline (Zoloft), norepinephrine reuptake inhibitors such as reboxetine (Edronax), and serotonin-norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine (Effexor) and duloxetine (Cymbal ta)
  • MAOIs monoamine oxidase inhibitors
  • SSRIs selective serotonin reuptake
  • histamine H3 -receptor antagonists and inverse agonists can be used to treat or prevent attention deficit hyperactivity disorder (ADHD).
  • ADHD attention deficit hyperactivity disorder
  • the first-line medications used to treat ADHD are mostly stimulants, which work by stimulating the areas of the brain responsible for focus, attention, and impulse control.
  • the use of stimulants to treat a syndrome often characterized by hyperactivity is sometimes referred to as a paradoxical effect, but there is no real paradox in that stimulants activate brain inhibitory and self-organizing mechanisms permitting the individual to have greater self-regulation.
  • the stimulants used include, for example, methylphenidate (sold as Ritalin, Ritalin SR and Ritalin LA), Metadate, Metadate ER, Metadate CD, Concerta, Focalin, Focalin XR or Methylin.
  • the stimulants also include, for example, amphetamines such dextroamphetamine , sold as
  • Dexedrine, Dexedrine Spansules, Adderall, and Adderall XR a trade name for a mixture of dextroamphetamine and laevoamphetamine salts, methamphetamine sold as Desoxyn, bupropion, a dopamine and norepinephrine reuptake inhibitor, marketed under the brand name Wellbutrin.
  • a non-stimulant medication to treat ADHD is Atomoxetine (sold as Strattera) a norepinephrine reuptake inhibitor.
  • Other drugs sometimes used for ADHD include, for example, benzphetamine, Provigil/Alertec/modaf ⁇ nil and clonidine.
  • a histamine H3-receptor antagonist was at least as effective as methylphenidate (Ritalin) (Hancock and Fox in Milestones in Drug Therapy, ed. Buccafusco, 2003).
  • Compounds of the present invention can be used in combination with various known drugs.
  • compounds of the present invention can be used with one or more of the drugs used to treat ADHD and related disorders.
  • histamine H3 -receptor antagonists and inverse agonists can be used to treat or prevent schizophrenia.
  • Schizophrenia is a psychiatric diagnosis that describes a mental disorder characterized by impairments in the perception or expression of reality and by significant social or occupational dysfunction.
  • a person experiencing untreated schizophrenia is typically characterized as demonstrating disorganized thinking, and as experiencing delusions or auditory hallucinations. Although the disorder is primarily thought to affect cognition, it can also contribute to chronic problems with behavior and emotion. Schizophrenia is often described in terms of "positive” and “negative” symptoms. Positive symptoms include delusions, auditory hallucinations and thought disorder, and are typically regarded as manifestations of psychosis. Negative symptoms are so named because they are considered to be the loss or absence of normal traits or abilities, and include features such as flat, blunted or constricted affect and emotion, poverty of speech and lack of motivation.
  • Some models of schizophrenia include formal thought disorder and planning difficulties in a third group, a "disorganization syndrome.”
  • the first line pharmacological therapy for schizophrenia is usually the use of antipsychotic medication.
  • Antipsychotic drugs are only thought to provide symptomatic relief from the positive symptoms of psychosis.
  • the newer atypical antipsychotic medications (such as clozapine, risperidone, olanzapine, quetiapine, ziprasidone and aripiprazole) are usually preferred over older typical antipsychotic medications (such as chlorpromazine and haloperidol) due to their favorable side-effect profile.
  • atypical antipsychotics are associated with less extra pyramidal side-effects and tardive dyskinesia than the conventional antipsychotics
  • some of the agents in this class appear to be associated with metabolic side effects such as weight gain, hyperglycemia and hypertriglyceridemia that must be considered when choosing appropriate pharmacotherapy.
  • Histamine H3-receptor antagonists or inverse agonists can be used to treat obesity
  • histamine H3-receptor antagonists have been investigated in various preclinical models of obesity and have shown to be effective in reducing food intake, reducing weight, and decreasing total body fat in mice (Hancock, et a Eur. J. Pharmacol. 2004, 487,
  • Histamine H3 -receptor antagonists or inverse agonists can also be used to treat upper airway allergic responses (U.S. Pat. Nos. 5,217,986; 5,352,707 and 5,869,479) including allergic rhinitis and nasal congestion. Allergic rhinitis is a frequently occurring chronic disease that affects a large number of people. Recent analysis of histamine H3-receptor expression in the periphery by quantitative PCR revealed that H3-receptor mRNA is abundantly expressed in human nasal mucosa (Varty et al. Eur. J. Pharmacol. 2004, 484, 83-89).
  • histamine H3-receptor antagonists in a cat model of nasal decongestion, a combination of histamine H3-receptor antagonists with the Hl receptor antagonist chlorpheniramine resulted in significant nasal decongestion without the hypertensive effect seen with adrenergic agonists.
  • histamine H3-receptor antagonists or inverse agonists can be used alone or in combination with Hl receptor blockage for the treatment of allergic rhinitis and nasal congestion. Histamine H3-receptor antagonists or inverse agonists have therapeutic potential for the treatment of pain (Medhurst et al. Biochemical Pharmacology (2007), 73(8), 1182-1194).
  • a further aspect of the present invention pertains to pharmaceutical compositions comprising one or more compounds as described herein and one or more pharmaceutically acceptable carriers. Some embodiments pertain to pharmaceutical compositions comprising a compound of the present invention and a pharmaceutically acceptable carrier.
  • Some embodiments of the present invention include a method of producing a pharmaceutical composition comprising admixing at least one compound according to any of the compound embodiments disclosed herein and a pharmaceutically acceptable carrier.
  • Formulations may be prepared by any suitable method, typically by uniformly mixing the active compound(s) with liquids or finely divided solid carriers, or both, in the required proportions, and then, if necessary, forming the resulting mixture into a desired shape.
  • Liquid preparations for oral administration may be in the form of solutions, emulsions, aqueous or oily suspensions, and syrups.
  • the oral preparations may be in the form of dry powder that can be reconstituted with water or another suitable liquid vehicle before use. Additional additives such as suspending or emulsifying agents, non-aqueous vehicles (including edible oils), preservatives, and flavorings and colorants may be added to the liquid preparations.
  • Parenteral dosage forms may be prepared by dissolving the compound of the invention in a suitable liquid vehicle and filter sterilizing the solution before filling and sealing an appropriate vial or ampule: These are just a few examples of the many appropriate methods well known in the art for preparing dosage forms.
  • a compound of the present invention can be formulated into pharmaceutical compositions using techniques well known to those in the art. Suitable pharmaceutically- acceptable carriers, outside those mentioned herein, are known in the art; for example, see
  • a compound of the invention may, in an alternative use, be administered as a raw or pure chemical, it is preferable however to present the compound or active ingredient as a pharmaceutical formulation or composition further comprising a pharmaceutically acceptable carrier.
  • the invention thus further provides pharmaceutical formulations comprising a compound of the invention or a pharmaceutically acceptable salt or derivative thereof together with one or more pharmaceutically acceptable carriers thereof and/or prophylactic ingredients.
  • the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not overly deleterious to the recipient thereof.
  • Transdermal patches dispense a drug at a controlled rate by presenting the drug for absorption in an efficient manner with a minimum of degradation of the drug.
  • transdermal patches comprise an impermeable backing layer, a single pressure sensitive adhesive and a removable protective layer with a release liner.
  • the compounds of the invention may thus be placed into the form of pharmaceutical formulations and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, gels or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use.
  • Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
  • the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid.
  • the pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient.
  • dosage units are capsules, tablets, powders, granules or a suspension, with conventional additives such as lactose, mannitol, corn starch or potato starch; with binders such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins; with disintegrators such as corn starch, potato starch or sodium carboxymethyl-cellulose; and with lubricants such as talc or magnesium stearate.
  • the active ingredient may also be administered by injection as a composition wherein, for example, saline, dextrose or water may be used as a suitable pharmaceutically acceptable carrier.
  • active ingredient is defined in the context of a "pharmaceutical composition” and is intended to mean a component of a pharmaceutical composition that provides the primary pharmacological effect, as opposed to an "inactive ingredient” which would generally be recognized as providing no pharmaceutical benefit.
  • the dose when using the compounds of the present invention can vary within wide limits, and as is customary and is known to the physician, it is to be tailored to the individual conditions in each individual case.
  • doses of the present invention include, but not limited to, about 0.001 mg to about 5000 mg, about 0.001 mg to about 2500 mg, about 0.001 mg to about 1000 mg, 0.001 mg to about 500 mg, 0.001 mg to about 250 mg, about 0.001 mg to 100 mg, about 0.001 mg to about 50 mg, and about 0.001 mg to about 25 mg.
  • Multiple doses may be administered during the day, especially when relatively large amounts are deemed to be needed, for example 2, 3 or 4, doses. Depending on the individual and as deemed appropriate from the patient's physician or care-giver it may be necessary to deviate upward or downward from the doses described herein.
  • the amount of active ingredient, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will ultimately be at the discretion of the attendant physician or clinician.
  • a model system typically an animal model
  • these extrapolations may merely be based on the weight of the animal model in comparison to another, such as a mammal, preferably a human, however, more often, these extrapolations are not simply based on weights, but rather incorporate a variety of factors.
  • compositions of this invention are selected in accordance with a variety factors as cited above.
  • the actual dosage regimen employed may vary widely and therefore may deviate from a preferred dosage regimen and one skilled in the art will recognize that dosage and dosage regimen outside these typical ranges can be tested and, where appropriate, may be used in the methods of this invention.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
  • the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations.
  • the daily dose can be divided, especially when relatively large amounts are administered as deemed appropriate, into several, for example 2, 3 or 4, part administrations. If appropriate, depending on individual behavior, it may be necessary to deviate upward or downward from the daily dose indicated.
  • the compounds of the present invention can be administrated in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise, as the active component, either a compound of the invention or a pharmaceutically acceptable salt of a compound of the invention.
  • a suitable pharmaceutically acceptable carrier can be either solid, liquid or a mixture of both.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier can be one or more substances, which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier is a finely divided solid, which is in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted to the desire shape and size.
  • the powders and tablets may contain varying percentage amounts of the active compound.
  • a representative amount in a powder or tablet may contain from 0.5 to about 90 percent of the active compound; however, an artisan would know when amounts outside of this range are necessary.
  • Suitable carriers for powders and tablets are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • the term "preparation" is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.
  • a low melting wax such as an admixture of fatty acid glycerides or cocoa butter
  • the active component is dispersed homogeneously therein, as by stirring.
  • the molten homogenous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions.
  • parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.
  • injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the compounds according to the present invention may thus be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-f ⁇ lled syringes, small volume infusion or in multi-dose containers with an added preservative.
  • the pharmaceutical compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-firee water, before use.
  • Aqueous formulations suitable for oral use can be prepared by dissolving or suspending the active component in water and adding suitable colorants, flavors, stabilizing and thickening agents, as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration.
  • liquid forms include solutions, suspensions, and emulsions.
  • These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • the compounds according to the invention may be formulated as ointments, creams or lotions, or as a transdermal patch.
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.
  • Formulations suitable for topical administration in the mouth include lozenges comprising active agent in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray.
  • the formulations may be provided in single or multi-dose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomizing spray pump.
  • Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurized pack with a suitable propellant.
  • the compounds of the present invention or pharmaceutical compositions comprising them are administered as aerosols, for example as nasal aerosols or by inhalation, this can be carried out, for example, using a spray, a nebulizer, a pump nebulizer, an inhalation apparatus, a metered inhaler or a dry powder inhaler.
  • Pharmaceutical forms for administration of the compounds of the present invention as an aerosol can be prepared by processes well- known to the person skilled in the art.
  • solutions or dispersions of the compounds of the present invention in water, water/alcohol mixtures or suitable saline solutions can be employed using customary additives, for example benzyl alcohol or other suitable preservatives, absorption enhancers for increasing the bioavailability, solubilizers, dispersants and others, and, if appropriate, customary propellants, for example include carbon dioxide, CFCs, such as, dichlorodifiuoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane; and the like.
  • the aerosol may conveniently also contain a surfactant such as lecithin.
  • the dose of drug may be controlled by provision of a metered valve.
  • the compound In formulations intended for administration to the respiratory tract, including intranasal formulations, the compound will generally have a small particle size for example of the order of 10 microns or less. Such a particle size may be obtained by means known in the art, for example by micronization. When desired, formulations adapted to give sustained release of the active ingredient may be employed.
  • the active ingredients may be provided in the form of a dry powder, for example, a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
  • a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
  • the powder carrier will form a gel in the nasal cavity.
  • the powder composition may be presented in unit dose form for example in capsules or cartridges of, e.g., gelatin, or blister packs from which the powder may be administered by means of an inhaler.
  • the pharmaceutical preparations are preferably in unit dosage forms.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form. Tablets or capsules for oral administration and liquids for intravenous administration are preferred compositions.
  • the compounds according to the invention may optionally exist as pharmaceutically acceptable salts including pharmaceutically acceptable acid addition salts prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids.
  • Representative acids include, but are not limited to, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, oxalic, p-toluenesulfonic and the like, such as those pharmaceutically acceptable salts listed in Journal of Pharmaceutical Sciences, 66:1-19 (1977); incorporated herein by reference in its entirety.
  • the acid addition salts may be obtained as the direct products of compound synthesis.
  • the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.
  • the compounds of this invention may form solvates with standard low molecular weight solvents using methods known to the skilled artisan, such as those described in Polymorphism in Pharmaceutical solids, edited by Harry G. Brittain, Marcel Dekker, New York, 1999, which is incorporated herein by reference in its entirety.
  • Pro-drugs refers to compounds that have been modified with specific chemical groups known in the art and when administered into an individual these groups undergo biotransformation to give the parent compound. Pro-drugs can thus be viewed as compounds of the invention containing one or more specialized non-toxic protective groups used in a transient manner to alter or to eliminate a property of the compound. In one general aspect, the "pro-drug” approach is utilized to facilitate oral absorption.
  • T. Higuchi and V. Stella Pro- drugs as Novel Delivery Systems Vol. 14 of the A.C.S. Symposium Series; and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are hereby incorporated by reference in their entirety.
  • Some embodiments of the present invention include a method of producing a pharmaceutical composition for "combination-therapy" comprising admixing at least one compound according to any of the compound embodiments disclosed herein, together with at least one known pharmaceutical agent as described herein and a pharmaceutically acceptable carrier.
  • histamine H3-receptor modulators are utilized as active ingredients in a pharmaceutical composition, these are not intended for use only in humans, but in other non-human mammals as well. Indeed, recent advances in the area of animal health-care mandate that consideration be given for the use of active agents, such as histamine H3 -receptor modulators, for the treatment of an H3-receptor associated disease or disorder in domestic animals (e.g., cats and dogs) and in other domestic animals (e.g., cows, chickens, fish, etc.). Those of ordinary skill in the art are readily credited with understanding the utility of such compounds in such settings.
  • Another object of the present invention relates to radio-labeled compounds of the present invention that would be useful not only in radio-imaging but also in assays, both in vitro and in vivo, for localizing and quantitating the histamine H3-receptor in tissue samples, including human, and for identifying histamine H3-receptor ligands by inhibition binding of a radio-labeled compound. It is a farther object of this invention to develop novel H3-receptor assays of which comprise such radio-labeled compounds.
  • the present invention embraces isotopically-labeled compounds of the present invention.
  • An “isotopically” or “radio-labeled” compounds are those that are identical to compounds disclosed herein, but for the fact that one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.
  • Suitable radionuclides that may be incorporated in compounds of the present invention include but are not limited to 2 H (also written as D for deuterium), 3 H (also written as T for tritium), 11 C, 13 C, 14 C, 13 N, 15 N, 15 O 5 17 0, 18 0, 18 F, 35 S, 36 Cl, 82 Br, 7S Br, 76 Br, 77 Br, 123 I, 124 1, 125 I and 131 I.
  • the radionuclide that is incorporated in the instant radio-labeled compounds will depend on the specific application of that radio-labeled compound.
  • Radionuclide that has incorporated at least one radionuclide; in some embodiments the radionuclide is selected from the group consisting of 3 H, 14 C, 125 1 , 35 S and 82 Br.
  • isotopically-labeled compounds of the present invention are useful in compound and/or substrate tissue distribution assays.
  • the radionuclide 3 H and/or 14 C isotopes are useful in these studies.
  • substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
  • Isotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the Drawings and Examples infra, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • Synthetic methods for incorporating activity levels of 125 I into target molecules include:
  • a radiolabeled histamine H3 -receptor compound of Formula (Ia) can be used in a screening assay to identify/evaluate compounds.
  • a newly synthesized or identified compound i.e., test compound
  • test compound can be evaluated for its ability to reduce binding of the "radio-labeled compound of Formula (Ia)" to the H3-receptor. Accordingly, the ability of a test compound to compete with the "radio-labeled compound of Formula (Ia)" for the binding to the histamine H3 -receptor directly correlates to its binding affinity.
  • the labeled compounds of the present invention bind to the histamine H3-receptor.
  • the labeled compound has an IC 50 less than about 500 ⁇ M
  • the labeled compound has an ICs 0 less than about 100 ⁇ M
  • the labeled compound has an ICs 0 less than about 10 ⁇ M
  • the labeled compound has an IC 50 less than about 1 ⁇ M
  • the labeled inhibitor has an IC 50 less than about 0.1 ⁇ M.
  • TLC Thin-layer chromatography
  • PK6F silica gel 60 A 1 mm plates (Whatman)
  • column chromatography was carried out on a silica gel column using Kieselgel 60, 0.063- • 0.200 mm (Merck).
  • Evaporation was done under reduced pressure on a B ⁇ chi rotary evaporator.
  • Celite 545 ® was used during palladium filtrations.
  • LCMS specs 1) PC: HPLC-pumps: LC-IOAD VP, Shimadzu Inc.; HPLC system controller: SCL-IOA VP, Shimadzu Lie; UV-Detector: SPD-IOA VP, Shimadzu Lie; Autosampler: CTC HTS, PAL, Leap Scientific; Mass spectrometer: API 150EX with Turbo Ion Spray source, AB/MDS Sciex; Software: Analyst 1.2. 2) Mac: HPLC-pumps: LC-8A VP,
  • Example 1.1 Preparation of Intermediate ( ⁇ )-4-(2-(2-Methy]pyrrolidin-l- yl)ethyl)phenylboronic Acid.
  • Step A Preparation of Intermediate 4-Bromophenethyl Methanesulfonate.
  • Step B Preparation of Intermediate ( J R)-l-(4-Bromophenethyl)-2- methylpyrrolidine.
  • the crude oil was further purified by silica column chromatography eluting with ethyl acetate followed by 0-10% methanol in ethyl acetate to give the title compound (8.85 g, 75%) as a pale yellow oil; 98% ee (by chiral HPLC; column: 25 cm Chiral Tech AD-H, analytical; eluent: 1% isopropanol in hexanes, isocratic; flow Rate: 0.5 mL/min; wavelength: 220 nM).
  • Step C Preparation of Intermediate ( ⁇ )-4-(2-(2-MethylpyrroIidin-l- yl)ethyl)phenylboronic Acid.
  • (i?)-l-(4-Bromophenethyl)-2 -methylpyrrolidine (2.16 g, 8.04 mmol) was dissolved in
  • aqueous solution was made basic (pH ⁇ 8) with 50% sodium hydroxide and extracted twice with ethyl acetate (50 mL each), plus three times with DCM (50 mL each).
  • the combined organic phases were dried with magnesium sulfate, filtered, and concentrated to give 1.70 g of a yellow foam.
  • the foam was triturated with diethyl ether (20 mL) twice, and dried under high vacuum to give the title compound (1.19 g, 64% yield) as a pale yellow solid.
  • Step A Preparation of Intermediate 4-Bromo-iV-cyclopentylbenzenesulfonamide.
  • Step B Preparation of 4'-[2-(( J R)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonic Acid Cyclopentylamide (Compound 32).
  • the resulting yellow organic phase was separated and the clear aqueous layer was extracted with ethyl acetate (2 x 5 mL).
  • the organic phases were combined, dried over magnesium sulfate, and filtered. The solvent was removed under reduced pressure.
  • the resulting crude residue was dissolved in a mixture of acetonitrile and acetic acid and purified by preparative HPLC (0.1% TFA in acetonitrile/0.1% TFA in water). The product containing fractions from HPLC were combined and the acetonitrile was removed under reduced pressure.
  • the resulting aqueous solution was made basic (pH ⁇ 10) with 2 M sodium carbonate solution and extracted with ethyl acetate (50 mL).
  • Example 1.3 Preparation of 4'-[2-((jR)-2-Methyl-pyrrolidin-l-yl)-ethylJ-biphenyl-4- sulfonic Acid Cyclopropylmethyl-amide (Compound 31).
  • the title compound was prepared in a similar manner as described in Example 1.2, using 4-bromo- ⁇ r -(cyclopropylmethyl)benzenesulfonamide (125 mg, 0.43 mmol), and ( ⁇ )-4-(2- (2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (100 mg, 0.43 mmol), to give 159 mg of the HCl salt in 85% yield.
  • Example 1.4 Preparation of 4'-[2-(( ⁇ )-2-Methyl-pyrroIidin-l-yl)-ethyl]-biphenyl-4- sulfonic Acid Phenylamide (Compound 30).
  • Example 1.6 Preparation of 4'-[2-((i.)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonic Acid Cyclohexylmethyl-amide (Compound 28).
  • the title compound was prepared in a similar manner as described in Example 1.2, using 4-bromo-iV-(cyclohexylmethyl)benzenesulfonamide (152 mg, 0.43 mmol), and (i?)-4-(2- (2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (100 mg, 0.43 mmol), to give 169 mg of the HCl salt in 77% yield.
  • Example 1.7 Preparation of 4'-[2-((-R)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonic Acid (l-Propyl-butyl)-amide (Compound 27).
  • Example 1.8 Preparation of 4'-[2-(( ⁇ )-2-Methyl-pyrrolidin-l-yI)-ethyl]-biphenyl-4- sultonic Acid (2-Hydroxy-ethyl)-am ⁇ de (Compound 25).
  • the title compound was prepared in a similar manner as described in Example 1.2, using 4-bromo-//-(2-hydroxyethyl)benzenesulfonamide (129 mg, 0.43 mmol), and (i?)-4-(2-(2- methylpyrrolidin-l-yl)ethyl)phenylboronic acid (100 mg, 0.43 mmol), to give 119 mg of the HCl salt in 61% yield.
  • Example 1.9 Preparation of 4'-[2-((i?)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonic Acid 4-ChIoro-benzylamide (Compound 24).
  • the title compound was prepared in a similar manner as described in Example 1.2, using iV-(4-chloroben2yl)-4-bromobenzenesulfonamide (155 mg, 0.43 mmol), and (fl)-4-(2-(2- methylpyrrolidin-l-yl)ethyl)phenylboronic acid (100 mg, 0.43 mmol), to give 168 mg of the HCl salt in 78% yield.
  • the title compound was prepared in a similar manner as described in Example 1.2, using ⁇ '-(4-fluorobenzyl)-4-bromobenzenesulfonamide (151 mg, 0.43 mmol), and (/?)-4-(2-(2- methylpyrrolidin-l-yl)ethyl)phenylboronic acid (100 mg, 0.43 mmol), to give 156 mg of the HCl salt in 73% yield.
  • Example 1.11 Preparation of 4'-[2-((2-)-2-Methyl-pyrroUdin-l-yl)-ethyl]-biphenyl-4- sulfonic Acid (4-FIuoro-phenyl)-amide (Compound 22).
  • Example 1.12 Preparation of 4'-[2-((l?)-2-Methyl-pyrroIidin-l-yl)-ethyl]-biphenyl-4- sulfonic Acid 4-Trifluoromethyl-benzylamide (Compound 14).
  • Example 1.13 Preparation of 4'-[2-((R)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonic Acid Benzyl-ethyl-amide (Compound 13).
  • Example 1.14 Preparation of 4'-I2-((fi)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyI-4- sulfonic Acid (2-Isopropoxy-ethyl)-amide (Compound 7).
  • the title compound was prepared in a similar manner as described in Example 1.2, using 4-bromo-N-(2-isopropoxyethyl)benzenesulfonamide (144 mg, 0.43 mmol), and (R)-4-(2- (2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (100 mg, 0.43 mmol), to give 113 mg of the HCl salt in 54% yield.
  • Example 1.15 Preparation of 4'-[2-((/?)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonic Acid (Pyridin-2-ylmethyl)-amide (Compound 3).
  • the title compound was prepared in a similar manner as described in Example 1.2, using 4-bromo-N-(pyridin-2-ylmethyl)benzenesulfonamide (150 mg, 0.43 mmol), and ( ⁇ )-4-(2- (2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (100 mg, 0.43 mmol), to give 128 mg of the HCl salt in 59% yield.
  • Example 1.16 Preparation of 2- ⁇ 4'-[2-(( ⁇ )-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- suIfonyI ⁇ -2,3-dihydro-lfl r -isoindole (Compound 2).
  • Example 1.17 Preparation of 4'-[2-((i?)-2-Methyl-pyrrolidin-l-yl)-ethyI]-biphenyl-4- sulfonic Acid (Tetrahydro-pyran-4-yl>amide (Compound 1).
  • the title compound was prepared in a similar manner as described in Example 1.2, using 4-bromo-N-(tetrahydro-2H-pyran-4-yl)benzenesulfonamide (144 mg, 0.43 mmol), and (i2)-4-(2-(2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (100 mg, 0.43 mmol), to give 51 mg of the HCl salt in 24% yield.
  • Example 1.18 Preparation of 2- ⁇ 4 t -[2-(( ⁇ )-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonyl ⁇ -l,2,3,4-tetrahydro-isoquinoline (Compound 12).
  • the title compound was prepared in a similar manner as described in Example 1.2, using 2-(4- brornophenylsulfonyl)-l,2,3,4-tetrahydroisoquinoline (157 mg, 0.43 mmol), and (i?)-4-(2-(2- methylpyrrolidin-l-yl)ethyl)phenylboronic acid (100 mg, 0.43 mmol), to give 185 mg of the HCl salt in 83% yield.
  • Example 1.19 Preparation of 4'-[2-(( ⁇ )-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-3-sulfonic Acid Dimethylamide (Compound 42). To a microwave synthesizer vial was added (i?)-l-(4-bromophenethyl)-2- methylpyrrolidine (50.0 mg, 0.186 mmol), 3-( ⁇ N-dimethylsulfamoyl)phenylboronic acid (64.0 mg, 0.280 mmol), aq.
  • Example 1.20 Preparation of 4'-[2-((l?)-2-Methyl-pyrroUdin-l-yl)-ethyl]-biphenyl-3- sulfonic Acid Diethylamide (Compound 41).
  • Example 1.21 Preparation of 4'-[2-((jR)-2-Methyl-pyrroKdi ⁇ -l-yl)-ethyl]-biphenyl-4- sulfonic Acid Ethylamide (Compound 37).
  • the title compound was prepared in a similar manner as described in Example 1.19, using (/ ⁇ )-l-(4-bromophenethyl)-2-methylpj ⁇ olidine (50.0 mg, 0.186 mmol), and 4-(N- cyclopropylsulfamoyl)phenylboronic acid (67.4 mg, 0.280 mmol) as starting materials, to give a clear solid (TFA salt) in 7% yield.
  • Example 1.23 Preparation of 4'-[2-((i?)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonic Acid Amide (Compound 35). To a microwave synthesizer vial was added (i?)-l-(4-bromophenethyl)-2- methylpyrrolidine (200 mg, 0.746 mmol), 4-sulfamoylphenylboronic acid (195 mg, 0.969 mmol), aq.
  • Example 1.28 Preparation of 4- ⁇ 4*-[2-(( ⁇ )-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonyl ⁇ -morpholine (Compound 33).
  • the title compound was prepared in a similar manner as described in Example 1.23, using (7?)-l-(4-bromophenethyl)-2-methylpyrrolidine (200 mg, 0.746 mmol), and 4- (morpholinosulfonyl)phenylboronic acid (263 mg, 0.970 mmol) as starting materials, to give a white solid (HCl salt) in 11% yield.
  • the title compound was prepared in a similar manner as described in Example 1.2, using ( ⁇ )-4-(2-(2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (200 mg, 0.858 mmol), and 4- bromo-N-(2-methoxyethyl)benzenesulfonamide (252 mg, 0.858 mmol) as starting materials, to give a white solid (HCl salt) in 29% yield.
  • Example 1.30 Preparation of ( J R)-2-Methyl-l- ⁇ 2-[4'-(pyrrolidine-l-sulfonyl)-biphenyl-4-yl]- ethyl ⁇ -pyrrolidine (Compound 11).
  • the title compound was prepared in a similar manner as described in Example 1.2, using (i-)-4-(2-(2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (100 mg, 0.429 mmol), and 1- (4-bromophenylsulfonyl)pyrrolidine (125 mg, 0.429 mmol) as starting materials, to give a white solid (HCl salt) in 64% yield.
  • Example 1.31 Preparation of 4*-[2-(( ⁇ )-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4-sulfonic Acid Cyclohexylamide (Compound 10).
  • the title compound was prepared in a similar manner as described in Example 1.2, using (i-)-4-(2-(2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (100 mg, 0.429 mmol), and 4- bromo- ⁇ f-cyclohexylbenzenesulfonamide (137 mg, 0.429 mmol) as starting materials, to give a white solid (HCl salt) in 47% yield.
  • Example 1.32 Preparation of 4- ⁇ 4'-[2-((i?)-2-Methyl-pyrrolidin-l-yl)-ethyl ⁇ -biphenyl-4- sulfonylj-thiomorpholine 1,1-Dioxide (Compound 6).
  • the title compound was prepared in a similar manner as described in Example 1.2, using (i2)-4-(2-(2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (300 mg, 1.29 mmol), and 4- (4 ⁇ bromo-benzenesulfonyl)-thiomorpholine 1,1-dioxide (593 ing, 1.67 mmol) as starting materials, to give a white solid (HCl salt) in 25% yield.
  • Example 133 Preparation of 4'-[2-((jR)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4-sulfonic Acid (2-Ethoxy-ethyl)-amide (Compound 5).
  • the title compound was prepared in a similar manner as described in Example 1.2, using (i?)-4-(2-(2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (100 mg, 0.429 mmol), and 4- bromo-N-(2-ethoxyethyl)benzenesulfonamide (198 mg, 0.644 mmol) as starting materials, to give a white solid (HCl salt) in 24% yield.
  • Example 1.35 Preparation of 4'-[2-((i?)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonic Acid Methylamide (Compound 20).
  • the title compound was prepared in a similar manner as described in Example 1.2, using 4-bromo-N-methylbenzenesulfonamide (127 mg, 0.506 mmol), and (R)-4-(2-(2- methylpyrrolidin-l-yl)ethyl)phenylboronic acid (118 mg, 0.506 mmol) as starting materials, to give a white solid (HCl salt) in 65% yield.
  • Example 1.36 Preparation of 4'-[2-(( ⁇ )-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonic Acid Isopropylamide (Compound 19).
  • the title compound was prepared in a similar manner as described in Example 1.2, using 4-bromo-N-isopr ⁇ pylbe ⁇ zenesulfonamide (151 mg, 0.545 mmol) and (i?)-4-(2-(2- methylpyrrolidm-l-yl)ethyl)phenylboronic acid (127 mg, 0.545 mmol) as starting materials, to give a white solid (HCl salt) in 76% yield.
  • Example 1.37 Preparation of 4'-[2-((i?)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonic Acid Propylamide (Compound 18).
  • the title compound was prepared in a similar manner as described in Example 1.2, using 4-bromo-N-/ert-butylbenzenesulfonamide (154 mg, 0.528 mmol) and (R)-4-(2-(2 ⁇ methylpyrrolidin-l-yl)ethyl)phenylboronic acid (123 mg, 0.528 mmol) as starting materials, to give a white solid (HCl salt) in 54% yield.
  • the title compound was prepared in a similar manner as described in Example 1.2, using 4-bromo-N-cyclobutylbenzenesulfonamide (158 mg 5 0.545 mmol) and ( ⁇ )-4-(2-(2- methylpyrrolidin-l-yl)ethyl)phenylboronic acid (127 mg, 0.545 mmol) as starting materials, to give a white solid (HCl salt) in 73% yield.
  • Example 1.40 Preparation of (/?)-l- ⁇ 2-[4'-(Azetidine-l-sulfonyl)-biphenyl-4-yl]-ethyl ⁇ -2- methyl-pyrrolidine (Compound 15).
  • the title compound was prepared in a similar manner as described in Example 1.2, using l-(4-bromophenylsulfonyl)azetidine (135 mg, 0.489 mmol) and (i?)-4-(2-(2- methylpyrrolidin-l-yl)ethyl)phenylboronic acid (114 mg, 0.489 mmol) as starting materials, to give a white solid (HCl salt) in 70% yield.
  • Example 1.41 Preparation of 4'- ⁇ 2-((/?)-2-Methyl-pyrroIidin-l-yl)-ethyl]-biphenyI-4- sulfonic Acid 4-Methoxy-benzylamide (Compound 9).
  • Example 1.42 Preparation of 4'-[2-((i?)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonic Acid (2-Phenoxy-ethyI)-amide (Compound 8).
  • the title compound was prepared in a similar manner as described in Example 1.2, using 4-bromo-N-(2-phenoxyethyl)benzenesulfonarnide (171 mg, 0.481 mmol), and (i?)-4-(2-(2- methylpyrrolidin-l-yl)ethyl)phenylboronic acid (112 mg, 0.481 mmol) as starting materials, to give a white solid (HCl salt) in 53% yield.
  • Example 1.43 Preparation of 4'-[2-((R)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonic Acid Diethylamide (Compound 26).
  • the title compound was prepared in a similar manner as described in Example 1.23, using (i?)-l-[2-(4-bromo-phenyl)-ethyl]-2-methyl-pyrrolidine (200 mg, 0.746 mmol), and A- (N,N-diethylsulfamoyl)phenylboronic acid (249 mg, 0.969 mmol) as starting materials, to give a white solid (HCl salt) in 12% yield.
  • the ethyl acetate layer was extracted an additional three times with 1 M HCl (30 mL each).
  • the aqueous layers were combined and adjusted to pH 10 by the addition of sodium carbonate.
  • the basic aqueous layer was extracted with DCM (100 mL).
  • 50% Sodium hydroxide (1 mL) was added to the aqueous layer, which was then extracted with DCM (3 x 50 mL).
  • the combined DCM layers were dried with sodium sulfate and the solvent was removed under reduced pressure, yielding 11.25 g (91%) of yellow oil.
  • the crude product was purified by silica chromatography eluting with ethyl acetate followed by 0-10% methanol in ethyl acetate, yielding 9.62 g (78%) as a pale yellow oil; 98% ee (by chiral HPLC; column: 25 cm Chiral Tech AD-H, analytical; eluent: 1% isopropanol in hexanes, isocratic; flow Rate: 0.5 mL/min; wavelength: 220 nM).
  • the title compound was prepared in a similar manner as described in Example 1.23, using 4-(N-ethylsulfamoyl)phenylboronic acid (128 mg, 0.559 mrnol) and (5)-l-(4- bromophenethyl)-2-methylpyrrolidine (150 mg, 0.559 mol) as starting materials, to give a white solid (HCl salt) in 70% yield.
  • Step A Preparation of (R)-tert-Butyl 2-Methylpyrrolidine-l-carboxylate.
  • N-Boc-L-prolinol (Omega Chem, Qu ⁇ bec, Canada; catalog no. BP-5319; 98% ee) (30.1 g, 150 mmol) was dissolved in dichloromethane (150 mL). Triethylamine (52.1 mL, 374 mmol) was added and the mixture was cooled in an ice bath. Methanesulfonyl chloride (12.2 mL, 157 mmol) was added dropwise via an addition funnel over 30 min. The ice bath was removed and the mixture was stirred.
  • Methanesulfonyl chloride (1.25 mL, 16 mmol) was added twice at 30 min intervals until TLC (2:1, ethyl acetate/hexanes) showed no more starting materials left.
  • the reaction mixture was then diluted with ethyl acetate (800 mL) and washed with 1 M HCl (2 x 100 mL), brine (100 mL), saturated sodium carbonate (2 x 100 mL), and brine (100 mL).
  • the ethyl acetate layer was dried with sodium sulfate and the solvent was removed under reduced pressure.
  • the crude reaction mixture was suspended in DCM (750 mL) and water (150 mL) in a seperatory funnel. The water layer was removed and the organic layer was washed with water (100 mL). The combined water layers were washed with DCM (2 x 50 mL). The combined organic phase was dried over magnesium sulfate and filtered. The solvent was removed under reduced pressure to give a crude residue (30.75 g). The crude residue was purified by flash chromatography using 10% ethyl acetate in hexanes followed by 20% ethyl acetate in hexanes. The product containing fractions were pooled and the solvent was removed under reduced pressure.
  • Step B (i ⁇ )-2-Methylpyrrolidine Hydrochloride.
  • the title compound was prepared in a similar manner as described in Example 1.2, using 2-(4-bromophenylsulfonyl)-6,7-dimethoxy-l,2,3,4-tetrahydroisoquinoline (180 mg, 0.44 mmol) and ( ⁇ )-4-(2-(2-methyl ⁇ yrrolidin-l-yl)ethyl)phenylboronic acid (102 mg, 0.44 mmol) to give 153 mg of the HCl salt in 63% yield.
  • Example 2.2 Preparation of 4'-[2-((i?>2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonic acid 4-trifluoromethoxy-benzylamide (Compound 106).
  • Example 2.3 Preparation of 7- ⁇ 4-[2-((jR)-2-Methyl-pyrrolidin-l-yl)-ethyl]-phenyl ⁇ -3,4- dihydro-2//-benzo[b][l,2,5]oxathiazepine 1,1-Dioxide (Compound 76).
  • the title compound was prepared in a similar manner as described in Example 1.2, using 7-bromo-3,4-dihydro-2H-5,l,2-benzoxathiaze ⁇ ine 1,1-dioxide (124 mg, 0.45 mmol) and ( ⁇ )-4-(2-(2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (104 mg, 0.45 mmol) to give 58 mg of the HCl salt in 30% yield.
  • the title compound was prepared in a similar manner as described in Example 1.2, using 2-(l-(4-bromophenylsulfonyl)piperidin-4-yl)ethanol (317 mg, 0.91 mmol) and ( ⁇ )-4-(2- (2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (212 mg, 0.91 mmol) to give 206 mg of the HCl salt in 46% yield.
  • the product containing fractions were pooled and the acetonitrile removed under reduced pressure.
  • the resulting aqueous layer was made basic (pH ⁇ 10) with 2 M sodium carbonate solution and extracted with ethyl acetate (50 mL).
  • the aqueous layer was then saturated with sodium chloride and extracted with ethyl acetate (2 x 25 mL).
  • the ethyl acetate extracts were combined, dried with magnesium sulfate, and filtered. 1 M HCl in diethyl ether (1.5eq.) was added and the solvent removed under reduced pressure to give 125 mg of the HCl salt as a white solid (41% yield).
  • Example 2.10 Preparation of 4'-[2-(( ⁇ >2-Methyl-pyrroIidin-l-yl)-ethyl]-biphenyI-4- sulfonic acid ((-S)-2 ⁇ methoxy-l-methyl-ethyl)-amide (Compound 95).
  • Example 2.12 Preparation of 4'-[2-((i?)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonic Acid (( ⁇ )-2-Hydroxy-l-methyl-ethyl)-amide (Compound 83).
  • the title compound was prepared in a similar manner as described in Example 2.9, using (i.)-2-aminopropan-l-ol (48 mg, 0.64 mmol) and (i?)-4'-(2-(2-methylpyrrolidin-l- yl)ethyl)biphenyl-4-sulfonyl chloride (210 mg, 0.58 mmol) to give 19 mg of the HCl salt in 7% yield.
  • the product containing fractions were pooled and the acetonitrile removed under reduced pressure.
  • the resulting aqueous layer was made basic (pH ⁇ 10) with 2 M sodium carbonate solution and extracted with ethyl acetate (50 mL).
  • the aqueous layer was then saturated with sodium chloride and extracted with ethyl acetate (2 x 25 mL).
  • the ethyl acetate extracts were combined, dried with magnesium sulfate, and filtered. 1 M HCl in diethyl ether (1.5 eq.) was added and the solvent removed under reduced pressure to give 9.3 mg of the HCl salt as a white solid (8% yield).
  • Example 2.15 Preparation of 4'-[2-(( ⁇ )-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonic acid (tetrahydro-pyran-4-ylmethyl)-amide (Compound 67).
  • the title compound was prepared in a similar manner as described in Example 2.9, using (tetrahydro-2H-pyran-4-yl)methanamine (54 mg, 0.47 mmol) and (i?)-4'-(2-(2- methylpyrrolidin-l-yl)ethyl)biphenyl-4-sulfonyl chloride (156 mg, 0.43 mmol) to give 64 mg of the HCl salt in 31% yield.
  • Example 2.16 Preparation of 4-Methoxymethyl-l- ⁇ 4'-[2-((i?)-2-methyI-pyrroIidin-l-yl)- ethyl]-biphenyl-4-sulfonyI ⁇ -piperidine (Compound 128).
  • Example 2.17 Preparation of 4-(2-Methoxy-ethyI)-l- ⁇ 4'-[2-(( ⁇ )-2-methyl-pyrrolidin-l-yl)- ethyI]-biphenyl-4-sulfonyl ⁇ -piperidine (Compound 126).
  • the title compound was prepared in a similar manner as described in Example 1.2, using l-(4-bromophenylsulfonyl)-4-(2-methoxyethyl)piperidine (326 mg, 0.90 mmol) and (R)A- (2-(2-methylpyrrolidin-l-yl)ethyl) ⁇ henylboronic acid (210 mg, 0.90 mmol) to give 247 mg of the HCl salt in 54% yield.
  • Example 2.18 Preparation of l- ⁇ 4'-[2-(( ⁇ )-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonyl ⁇ -p ⁇ peridin-4-ol (Compound 120).
  • the title compound was prepared in a similar manner as described in Example 1.2, using l-(4-bromophenylsulfonyl)piperidin-4-ol (284 mg, 0.89 mmol) and ( ⁇ )-4-(2-(2- methylpyrrolidin-l-yl)ethyl)phenylboronic acid (207 mg, 0.89 mmol) to give 232 mg of the HCl salt in 56% yield.
  • Example 2.19 Preparation of 3,5-Dimethyl-4- ⁇ 4'-[2-((fi)-2-methyl-pyrrolidin-l-yl)-ethyl]- biphenyl-4-sulfonyl ⁇ -morpholine (Compound 118).
  • the title compound was prepared in a similar manner as described in Example 1.2, using 4-(4-bromophenylsulfonyl)-3,5-dimethylmorpholine (291 mg, 0.87 mmol) and (i?)-4-(2- (2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (203 mg. 0.87 mmol) to give 304 mg of the HCl salt in 73% yield.
  • Example 2.20 Preparation of 4- ⁇ 4'-[2-((i?)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- suIfonyIJ-piperazin-2-one (Compound 114).
  • Example 2.21 Preparation of 4'-[2-(( ⁇ )-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonic Acid Bis-(2-hydroxy-ethyl)-amide (Compound 78).
  • the title compound was prepared in a similar manner as described in Example 1.2, using 4-bromo-N v /V-bis(2-hydroxyethyl)benzenesulfonamide (285 mg, 0.88 mmol) and (R)-4-(2- (2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (205 mg, 0.88 mmol) to give 270 mg of the HCl salt in 66% yield.
  • Example 2.22 Preparation of 4'-[2-((i ⁇ )-2-Methyl-pyrrolidin-l-yI)-ethyl]-biphenyI-4- sulfonic Acid (2-Hydroxy-l,l-dimethyl-ethyl)-amide (Compound 73).
  • Example 2.24 Preparation of Propionic acid 2-(l- ⁇ 4'-[2-((2?)-2-methyl-pyrrolidin-l-yl)- ethyl]-biphenyl-4-sulfonyl ⁇ -piperidin-4-yl)-ethyl Ester (Compound 63).
  • the title compound was prepared in a similar manner as described in Example 1.2, using 2-(l-(4-bromophenylsulfonyl)piperidin-4-yl)ethyl propionate (212 mg, 0.52 mmol) and (i?)-4-(2-(2-methylpyrrolidin-l -yl)ethyl)phenylboronic acid (122 mg, 0.52 mmol) to give 191 mg of the HCl salt in 66% yield.
  • the title compound was prepared in a similar manner as described in Example 1.2, using ( ⁇ )-(l-(4-bromophenylsulfonyl)pyrrolidin-2-yl)methanol (164 mg, 0.51 mmol) and ( ⁇ )-4- (2-(2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (119 mg, 0.51 mmol) to give 45.4 mg of the HCl salt in 19% yield.
  • Example 2.26 Preparation of ((5)-l- ⁇ 4'-[2-((iR)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl- S 4-suIfonyl ⁇ -pyrroIidin-2-yl)-methanol (Compound 59).
  • the title compound was prepared in a similar manner as described in Example 1.2, using l-(4-bromophenylsulfonyl)piperidin-4-yl propionate (179 mg, 0.48 mmol) and (R)-4-(2-0 (2-methylpyrrolidin-l -yl)ethyl)phenylboronic acid (111 mg, 0.48 mmol) to give 62 mg of the HCl salt in 25% yield.
  • Example 2.28 Preparation of ( ⁇ )-2-(Methoxymethyl)-l-(4'-(2-(( ⁇ )-2-methylpyrrolidin-l- yl)ethyl)biphenyl-4-ylsulfonyl)pyrrolidine (Compound 48).
  • the title compound was prepared in a similar manner as described in Example 1.2, using (5)-l-(4-bromophenylsulfonyl)-2-(methoxymethyl)pyrrolidine (174 mg, 0.52 mmol) and ( ⁇ )-4-(2-(2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (121 mg, 0.52 mmol) to give 165 mg of the HCl salt in 66% yield.
  • the title compound was prepared in a similar manner as described in Example 1.2, using (i?)-l-(4-bromophenylsulfonyl)pyrrolidin-3-ol (154 mg, 0.50 mmol) and (i?)-4-(2-(2- methylpyrrolidin-l-yl)ethyl)phenylboronic acid (117 mg, 0.50 mmol) to give 127 mg of the HCl salt in 56% yield.
  • the title compound was prepared in a similar manner as described in Example 1.2, using (>S)-(l-(4-bromophenylsulfonyl)pyrrolidm-2-yl)methyl propionate (181 mg, 0.48 mmol) and (i?)-4-(2-(2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (112 mg, 0.48 mmol) to give 165 mg of the HCl salt in 66% yield.
  • Example 2.33 Preparation of Propionic Acid 2-(Methyl- ⁇ 4'-[2-(( ⁇ )-2-methyl-pyrrolidin-l- yl)-ethyI]-biphenyl-4-sulfonyI ⁇ amino)-ethyl Ester (Compound 69).
  • the title compound was prepared in a similar manner as described in Example 1-2, using 2-(4-bromo-N-methylphenylsulfonamido)ethyl propionate (159 mg, 0.45 mmol) and (R)- 4-(2-(2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (106 mg, 0.45 mmol) to give 142 mg of the HCl salt in 63% yield.
  • Example 2.34 Preparation of (5)-l- ⁇ 4'-[2-((/ir)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl- 4-sulfonyl ⁇ -pyrrolidin-3-ol (Compound 45).
  • Example 2.35 Preparation of Propionic Acid (A>l- ⁇ 4'-[2-((2.>2-methyI-pyrrolidin-l-yl)- ethyl]-biphenyl-4-sulfonyl ⁇ -pyrroIidin-3-yl Ester (Compound 119).
  • Example 2.36 Preparation of Propionic Acid 2-Methyl-2- ⁇ 4'-[2-((i?)-2-methyl-pyrrolidin- l-yl)-ethyl]-biphenyl-4-sulfonylamino ⁇ -propyl Ester (Compound 121).
  • Example 2.37 Preparation of Propionic Acid (-S)-l- ⁇ 4'-[2-((R>2-Methyl-pyrrolidin-l-yl)- ethyl]-biphenyl-4-suIfonyl ⁇ -pyrrolidin-3-yI Ester (Compound 127).
  • Example 2.40 Preparation of (l- ⁇ 4'-[2-((i ⁇ )-2-Metliyl-pyrrolidin-l-yl)-ethyl]-biphenyI-4- sulfonyl ⁇ -piperidin-2-yl)-methanoI (Compound 104).
  • Example 2.42 Preparation of l-(4- ⁇ 4'-[2-((i?)-2-Methyl-pyrroIidin-l-yl)-ethyI]-biphenyI-4- sulfonyl ⁇ -piperazin-l-yl)-propan-l-one (Compound 92).
  • the title compound was prepared in a similar manner as described in Example 2.9, using l-(piperazin-l-yl)propan-l-one hydrochloride (105 mg, 0.59 mmol) and (fl)-4'-(2-(2- methyl ⁇ yrrolidin-l-yl)ethyl)biphenyl-4-sulfonyl chloride (214 mg, 0.59 mmol) to give 70 mg of the HCl salt in 24% yield.
  • Example 2.43 Preparation of 4'-[2-((JR)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonic Acid Benzyl-(2-methoxy-ethyl)-amide (Compound 86).
  • the resulting aqueous layer was made basic (pH ⁇ 10) with 2 M sodium carbonate solution and extracted with ethyl acetate (50 mL). The aqueous layer was then saturated with sodium chloride and extracted with ethyl acetate (2 x 25 mL). The ethyl acetate extracts were combined, dried with magnesium sulfate, and filtered. 1 M HCl in diethyl ether (1.5 eq.) was added and the solvent removed under reduced pressure to yield 54 mg of the HCl salt as a white solid (16% yield).
  • Example 2.44 Preparation of 4'-[2-(( ⁇ )-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonic Acid Isopropyl-(2-methoxy-ethyl)-amide (Compound 80).
  • Example 2.45 Preparation of 4'-[2-(( ⁇ )-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonic Acid Isobutyl-(2-methoxy-ethyl)-amide (Compound 75).
  • the title compound was prepared in a similar manner as described in Example 2.43, using 1 -bro ⁇ no-2-methylpropane (104 mg, 0.76 mmol) and ((i?)-N-(2-methoxyethyl)-4'-(2-(2- methylpyrrolidin-l-yl)ethyl)biphenyl-4-sulfonamide hydrochloride (222 mg, 0.51 mmol) to give 117 mg of the HCl salt in 47% yield.
  • the title compound was prepared in a similar manner as described in Example 2.43, using 4-(bromomethyl)tetrahydro-2i7-pyran (146 mg, 0.81 mmol) and ((/.)-N-(2-methoxyethyl)- 4'-(2-(2-methylpyrrolidin-l-yl)ethyl)biphenyl-4-sulfonamide hydrochloride (238 mg, 0.54 mmol) to give 127 mg of the HCl salt in 44% yield.
  • Example 2.47 Preparation of Acetic Acid 2-(AcetyI- ⁇ 4'-[2-(( J R)-2-methyl-pyrrolidin-l-yI)- ethyl]-biphenyl-4-sulfonyI ⁇ -amino)-ethyl Ester (Compound 65).
  • the title compound was prepared in a similar manner as described in Example 1.2, using 2-(N-(4-bromophenylsulfonyl)acetamido)ethyl acetate (195 mg, 0.54 mmol) and (i?)-4-(2- (2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (125 mg, 0.54 mmol) to give 123 mg of the HCl salt in 45% yield.
  • Example 2.48 Preparation of 4'-[2-((R)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- s ⁇ lfonic Acid Acetyl-(2-hydroxy-ethyl)-amide (Compound 60).
  • the title compound was prepared in a similar manner as described in Example 1.2, using 2-(N-(4-bromophenylsulfonyl)acetamido)ethyl acetate (195 mg, 0.54 mmol) and ( ⁇ )-4-(2- (2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (125 mg, 0.54 mmol) to give 57 mg of the HCl salt in 23% yield.
  • Example 2.49 Preparation of 4'-[2-(( ⁇ )-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonic Acid Benzyl-(2-hydroxy-ethyl)-amide (Compound 57).
  • the title compound was prepared in a similar manner as described in Example 1.2, using 7V-benzyl-4-bromo-N-(2-hydroxyethyl)benzenesulfonamide (205 mg, 0.55 mmol) and (R)- 4-(2-(2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (129 mg, 0.55 mmol) to give 158 mg of the HCl salt in 55% yield.
  • Example 2.50 Preparation of (.S)-l- ⁇ 4'-[2-((if)-2-MethyI-pyrrolidin-l-yl)-ethyl]-biphenyl- 4-sulfonyl ⁇ -piperidin-3-oI (Compound 54).
  • the title compound was prepared in a similar manner as described in Example 1.2, using (5)-l-(4-bromophenylsulfonyl)piperidin-3-ol (177 mg, 0.55 mmol) and ( ⁇ )-4-(2-(2 ⁇ methylpyrrolidin-l-yl)ethyl)phenylboronic acid (129 mg, 0.55 mmol) to give 185 mg of the HCl salt in 72% yield.
  • Example 2.56 Preparation of (it)-l-(2-(4'-((iS)-3-Methoxypyrrolidin-l-ylsulfonyI)biphenyl- 4-yl)ethyl)-2-methylpyrrolidine (Compound 105).
  • Example 2.57 Preparation of ( ⁇ f)-3-Methoxy-l- ⁇ 4'-[2-(( ⁇ )-2-methyI-pyrrolidin-l-yI)- ethyl]-biphenyI-4-sulfonyl ⁇ -piperidine (Compound 99).
  • Example 2.58 Preparation of CR)-3-Methoxymethyl-l- ⁇ 4'-[2-((i?)-2-methyI-pyrrolidin-l- yl)-ethyl]-biphenyl-4-sulfonyI ⁇ -piperidine (Compound 93).
  • the title compound was prepared in a similar manner as described in Example 1.2, using (i?)-l-(4-bromophenylsulfonyl)-3-(methoxymethyl)piperidine (169 mg, 0.49 mmol) and (i?)-4-(2-(2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (113 mg, 0.49 mmol) to give 165 mg of the HCl salt in 69% yield.
  • Example 2.60 Preparation of 4'-[2-(( J R)-2-Methyl-pyrrolidin-l-yl)-ethylJ-biphenyl-4- sulfonic Acid (2-Hydroxy-ethyI)-isopropyI-amide (Compound 81).
  • the title compound was prepared in a similar manner as described in Example 1.2, using 4-bromo-N-(2-hydroxyethyl)-N-isopropylbenzenesulfonamide (167 mg, 0.52 mmol) and (i-)-4-(2-(2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (121 mg, 0.52 mmol) to give 123 mg of the HCl salt in 51% yield.
  • Example 2.61 Preparation of 4'-[2-((i ⁇ )-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonic Acid ((_S)-2-Hydroxy-l-methyl-ethyl)-amide (Compound 62).
  • Example 2.62 Preparation of l- ⁇ 4'-[2-(( ⁇ )-2-Methyl-pyrrolidin-l-yl)-ethyI]-biphenyl-4- suIfonyl ⁇ -piperidine-4-carboxylic Acid Ethyl Ester (Compound 90).
  • Step A Preparation of Intermediate 2-Biphenyl-4-yl-ethanoI.
  • Step B Preparation of Intermediate Methanesulfonic Acid 2-Biphenyl-4-yI-ethyl Ester.
  • 2-bi ⁇ henyl-4-yl-ethanol 5.00 g, 25.2 mmol
  • dichloromethane 50 mL
  • triefhylamine 3.52 mL, 25.2 mmol
  • mesyl chloride 2.16 mL, 27.7 mmol
  • Step C Preparation of Intermediate ( ⁇ )-l-(2-Biphenyl-4-yI-ethyl)-2-methyl- pyrrolidine.
  • Example 2.68 Preparation of 4'-[2-(( ⁇ )-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonic Acid [2-(2-Oxo-imidazolidin-l-yl)-ethyl]-amide (Compound 84).
  • Example 2.69 Preparation of ⁇ 4'-[2-((-R)-2-Methyl-pyrrolid ⁇ n-l-yl)-ethyl]-biphenyl-4- sulfonylamino ⁇ -acetic Acid Isopropyl Ester (Compound 115).
  • Example 2.71 Preparation of 4'-[2-((-8)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonic Acid [3-(2-Oxo-pyrrolidin-l-yl)-propyl]-amide (Compound 85).
  • reaction mixture was purified by prep HPLC (0.1% TFA in acetonitrile/0.1% TFA in water) to furnish the title compound (0.012 g, 5% yield) as a yellow oil after concentration.
  • Example 2.75 Preparation of 4'-[2-(( ⁇ )-2-Methyl-pyrroIidin-l-yl)-ethyl]-biphenyI-4- sulfonic Acid (Pyridin-3-ylmethyl)-amide (Compound 100).
  • the title compound was prepared in a similar manner as described in Example 1.2, using 4-bromo- ⁇ r -(pyridin-3-ylmethyl)benzenesulfonamide (140 mg, 0.429 mmol) and (R)-A-(I- (2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (100 mg, 0.429 mmol) as starting materials, to give a white solid (HCl salt) in 37% yield.
  • the title compound was prepared in a similar manner as described in Example 1,2, using 4-bromo-N-(pyridin-4-ylmethyl)benzenesulfonamide (140 mg, 0.429 mmol) and (/.)-4-(2- (2-methylpyrrolidm-l-yl)ethyl)phenylboronic acid (100 mg, 0.429 mmol) as starting materials, to give a white solid (HCl salt) in 67% yield.
  • the title compound was prepared in a similar manner as described in Example 1.2, using 4-bromo-N-phenethylbenzenesulfonamide (148 mg, 0.436 mmol) and ( ⁇ )-4-(2-(2- methyl ⁇ yrrolidin-l-yl)ethyl)phenylboronic acid (102 mg, 0.436 mmol) as starting materials, to give a white solid (HCl salt) in 70% yield.
  • Example 2.78 Preparation of 4'-[2-((i.)-2-Methyl-pyrrolidiii-l-yl)-ethyl]-biphenyI-4- sulfonic Acid (3-PhenyI-propyl)-amide (Compound 82).
  • the title compound was prepared in a similar manner as described in Example 1.2, using 4-bromo-N-(3-phenylpropyl)benzenesulfonamide (170 mg, 0.479 mmol) and (i?)-4-(2 ⁇ (2- methylpyrrolidin-l-yl)ethyl)phenylboronic acid (112 mg, 0.479 mmol) as starting materials, to give a white solid (HCl salt) in 73% yield.
  • Example 2.80 Preparation of 4'-[2-((i?)-2-Methyl-pyrroIidin-l-yl)-ethyl]-biphenyI-4- sulfonic Acid 3,5-DichIoro-benzylamide (Compound 58).
  • Example 2-81 Preparation of 4'-(2-Pyrrolidin-l-yl-ethyI)-biphenyl-4-sulfonic Acid Ethylamide (Compound 55).
  • the title compound was prepared in a similar manner as described in Example 1.18, using 4-(N-ethylsulfamoyl)phenylboronic acid (176 mg, 0.767 mmol) and l-(4- bromophenethyl)pyrrolidine (150 mg, 0.590 mmol) as starting materials, to give a white solid (HCl salt) in 40% yield.
  • Example 2.82 Preparation of 4-Methoxy-l- ⁇ 4'-[2-((jR)-2-methyl-pyrroIidin-l-yl)-ethyl]- biphenyl-4-sulfonyl ⁇ -piperidine (Compound 113).
  • the title compound was prepared in a similar manner as described in Example 1.2, using l-(4-bromophenylsulfonyl)-4-methoxypiperidine (156 mg, 0.468 mmol) and (S)-4-(2-(2- methylpyrrolidin-l-yl)ethyl)phenylboronic acid (109 mg, 0.468 mmol) as starting materials, to give a white solid (HCl salt) in 56% yield.
  • Example 2.86 Preparation of 4-(2-Ethoxy-ethyl)-l- ⁇ 4'-[2-((i?)-2-metliyl-pvrrolidin-l-yl)- ethyl]-biphenyl-4-suIfonyl ⁇ -piperidine(Compound 91).
  • the histamine receptor binding assay was conducted using standard laboratory procedures as described below.
  • Certain other compounds of the invention had activity values ranging from about 5 ⁇ M to about 50 pM in this assay.
  • Rats Male Sprague-Dawley rats (225-350 g) (Harlan, San Diego, CA) were singly housed and maintained in a humidity- (30-70%) and temperature- (20-22 0 C) controlled facility on a 12 h:12 h light/dark cycle (lights on at 6:30 A.M.) with free access to food (Harlan-Teklad Western Res., Orange, CA, Rodent Diet 8604) and water. Rats were allowed at least three days of habituation to the animal facility before surgery. Procedures: Rats were anaesthetized with a ketamine/xylazine mixture, and surgically prepared for
  • rats were habituated to polypropylene test cages for at least three days. On test days, the rats were placed in the test chambers and habituated overnight. At 10 am the next day, the rats were administered the test compound, connected to the recording apparatus, and placed back into the test chambers for 3 h.
  • EEG and EMG data were digitized and stored in 10 s epochs over the three hour test period. These data were then visually scored, and each 10 s epoch characterized as either a non- REM sleep, REM sleep, or waking episode. Total wake time over the three hour period was . calculated for each rat after either vehicle administration or test compound. Percent increase in wakefulness was then derived for each rat.
  • the following table shows the observed percent increase in wakefulness over 3 h after oral administration of a representative compound at 1 mg/kg.
  • EXAMPLE 5 Human Histamine H3-Receptor Binding Assay - MDS Pharma Services (Taiwan). Compounds of the invention were tested for their ability to bind to the human histamine
  • H3 agonists such as ⁇ - ⁇ -methyl-histamine (RAMH) .
  • RAMH ⁇ - ⁇ -methyl-histamine
  • Blockade of RAMH-induced drinking can therefore be utilized as an in vivo assay for functional H3 antagonist activity.
  • male Sprague Dawley rats 250-350 g were housed three per cage and maintained under a reverse 12 h light cycle (lights off at 11:30 h).
  • rats were individually housed in new cages and food was removed. 120 min later, rats were administered test article (vehicle or H3 antagonist, 0.3 mg/kg PO).
  • RAMH vehicle or RAMH 3 mg/kg salt SC
  • 10 min after administration of RAMH weighed water bottles were placed in the cages, and drinking was allowed for 20 min. Water consumption was determined for each animal by weighing each bottle to the nearest 0.1 g. Data is expressed as percentage reduction in water intake according to the following formula:

Abstract

The present invention relates to certain biphenyl sulfonamide derivatives of Formula (Ia) and pharmaceutical compositions thereof that modulate the activity of the histamine H3-receptor. Compounds and pharmaceutical compositions thereof are directed to methods useful in the treatment of histamine H3-receptor associated disorders, such as, cognitive disorders, epilepsy, brain trauma, depression, obesity, disorders of sleep and wakefulness such as narcolepsy, hypersomnia, somnolence syndrome, jet lag, sleep apnea and the like, attention deficit hyperactivity disorder (ADHD), schizophrenia, allergies, allergic responses in the upper airway, allergic rhinitis, nasal congestion, dementia, Alzheimer's disease and the like.

Description

MODULATORS OF THE HISTAMINE H3-RECEPTOR USEFUL FOR THE TREATMENT OF DISORDERS RELATED THERETO
FIELD OF THE INVENTION The present invention relates to certain compounds of Formula (Ia) and pharmaceutical compositions thereof that modulate the activity of the histamine H3-receptor. Compounds of the present invention and pharmaceutical compositions thereof are directed to methods useful in the treatment of histamine H3-receptor associated disorders, such as, cognitive disorders, epilepsy, brain trauma, depression, obesity, disorders of sleep and wakefulness such as narcolepsy, hypersomnia, somnolence syndrome, jet lag, sleep apnea and the like, attention deficit hyperactivity disorder (ADHD), schizophrenia, allergies, allergic responses in the upper airway, allergic rhinitis, nasal congestion, dementia, Alzheimer's disease and the like.
SUMMARY OF THE INVENTION One aspect of the present invention pertains to certain compounds selected from compounds as shown in Formula (Ia):
Ca) and pharmaceutically acceptable salts, hydrates and solvates thereof; wherein: R1 andR2 are each selected independently from the group consisting of H, C]-C6 acyl,
C]-Cg alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloalkyl, aryl, heterocyclyl, heteroaryl, aryl- C]-C4-alkylenyl, aryloxy-C]-C4-alkylenyl, heteroaryl-Ci-C4-alkylenyl and heteroaryloxy-Cj-C4- alkylenyl, and each R1 andR2 is optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting OfCi-C6 acyl, Cj-C6 acyloxy, C2-C8 alkenyl, Cj-C6 alkoxy, Ci-C8 alkyl, Ci-C8 alkylcarboxamide, C2-C8 alkynyl, Cj-C8 alkylsulfonamide, C]-C8 alkylsulfmyl, CrC8 alkylsulfonyl, C]-C8 alkylthio, Ci-C8 alkylureyl, amino, aryl, Ci-C8 alkylamino, C2-C8 dialkylamino, carbo-C]-C6-alkoxy, carboxamide, carboxy, cyano, C3-C7 cycloalkyl, C2-C8 dialkylcarboxamide, C2-C8 dialkylsulfonamide, halogen, CrC6 haloalkoxy, Ci-C6 haloalkyl, Q-C6 haloalkylsulfmyl, Cj-C6 haloalkylsulfonyl, C3-C6 haloalkylthio, heterocyclyl, hydroxyl, thiol, nitro and sulfonamide; wherein each Ci-C8 alkyl may be further substituted with hydroxy; or R1 and R2 together with the nitrogen atom to which they are both bonded form a C3-C7 heterocyclyl or a C5-C]0 heterobicyclyl group each optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected independently from the group consisting OfC1-C6 acyl, Ci-C6 acyloxy, C2- C8 alkenyl, Ci-C6 alkoxy 5 C]-C8 alkyl, C1-C8 alkylcarboxamide, C2-C8 alkynyl, Ci-C8 alkylsulfonamide, Ci-C8 alkylsulfinyl, CpC8 alkylsulfonyl, C]-C8 alkylthio, Ci-C8 alkylureyl, amino, Ci-C8 alkylamino, C2-C8 dialkylamino, carbo-Ci-C6~alkoxy, carboxamide, carboxy, cyano, C3-C7 cycloalkyl, C2-C8 dialkylcarboxamide, C2-C8 dialkylsulfonamide, halogen, Ci-C6 haloalkoxy, Ci-C6 haloalkyl, Ci-C6 haloalkylsulfinyl, Ci-C6 haloalkylsulfonyl, Ci-C6 haloalkylthio, hydroxyl, thiol, nitro, oxo and sulfonamide; wherein each C]-C8 alkyl and carboxy may be further substituted with Ci-C6 acyloxy, Ci-C6 alkoxy, aryl-Ci-C4-alkylenyl, or hydroxy; or
R2 is selected independently from the group consisting of H, Ci-C6 acyl, C]-C8 alkyl, C2- C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloalkyl, aryl, heterocyclyl, heteroaryl, aryl-Q-C4-alkylenyl, aryloxy-Q-C4-alkylenyl, heteroaryl-Ci-C4-alkylenyl and heteroaryloxy-Q-Q-alkylenyl, and each R2 is optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting OfCi-C6 acyl, Ci-C6 acyloxy, C2-C8 alkenyl, C]-C6 alkoxy, Ci-C8 alkyl, CrC8 alkylcarboxamide, C2-C8 alkynyl, Cj-C8 alkylsulfonamide, Q-C8 alkylsulfinyl, C]-C8 alkylsulfonyl, C]-C8 alkylthio, CrC8 alkylureyl, amino, aryl, Ci-C8 alkylamino, C2-C8 dialkylamino, carbo-Cj-C6-alkoxy, carboxamide, carboxy, cyano, C3-C7 cycloalkyl, C2-C8 dialkylcarboxamide, C2-C8 dialkylsulfonamide, halogen, Ci-C6 haloalkoxy, Ci-C6 haloalkyl, Q- C6 haloalkylsulfinyl, Ci-C6 haloalkylsulfonyl, Cj-C6 haloalkylthio, heterocyclyl, hydroxyl, thiol, nitro and sulfonamide; and R1 and R12 together with the atoms to which they are both bonded form a C6-C8 heterocyclyl group optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting OfCj-C6 acyl, C]-C6 acyloxy, C2-C8 alkenyl, Ci-C6 alkoxy, C]-C8 alkyl, Cj-C8 alkylcarboxamide, C2-C8 alkynyl, Cj-C8 alkylsulfonamide, C]-C8 alkylsulfinyl, Q- C8 alkylsulfonyl, Ci-C8 alkylthio, Ci-C8 alkylureyl, amino, aryl, Cj-C8 alkylamino, C2-C8 dialkylamino, carbo-Q-Cg-alkoxy, carboxamide, carboxy, cyano, C3-C7 cycloalkyl, C2-C8 dialkylcarboxamide, C2-C8 dialkylsulfonamide, halogen, Ci-C6 haloalkoxy, C]-C6 haloalkyl, Q- C6 haloalkylsulfinyl, C]-Cg haloalkylsulfonyl, Cj-C6 haloalkylthio, heterocyclyl, hydroxyl, thiol, nitro and sulfonamide;
J is -CH2CH2- or a l,2-C}-C7-cycloalkylenyl group, each optionally substituted with 1, 2, 3 or 4 substituents selected independently from the group consisting OfCi-C3 alkyl, Q-C4 alkoxy, carboxy, cyano, C]-C3 haloalkyl, halogen, hydroxyl and oxo; R3, R4, R5, R6, R7, R10, R11 and R12 are each selected independently from the group consisting of H, Ci-C6 acyl, Ci-C6 acyloxy, C2-C8 alkenyl, Ci-C6 alkoxy, Ci-C8 alkyl, C1-C8 alkylcarboxamide, C2-C8 alkynyl, Ci-C8 alkylsulfonamide, CrC8 alkylsulfinyl, Ci-C8 alkylsulfonyl, Ci-C8 alkylthio, Ci-C8 alkylureyl, amino, Ci-C8 alkylamino, C2-C8 dialkylamino, carbo-Ci-Cβ-alkoxy, carboxamide, carboxy, cyano, C3-C7 cycloalkyl, C2-C8 dialkylcarboxamide, C2-C8 dialkylsulfonamide, halogen, CrC6 haloalkoxy, Ci-C6 haloalkyl, Ci-C6 haloalkylsulfϊnyl, Ci-C6 haloalkylsulfonyl, Q-C6 haloalkylthio, hydroxyl, thiol, nitro and sulfonamide; and R8 and R9 are each selected independently from the group consisting of H, Ci-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloalkyl, aryl, heterocyclyl, heteroaryl, aryl-Cj-C4- alkylenyl, aryloxy-Ci-C4-alkylenyl, heteroaryl-Ci-C4-alkylenyI and heteroaryloxy-Ci-C4- alkylenyl, and each R8 and R9 is optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting Of Ci-C6 acyl, C]-C6 acyloxy, C2-C8 alkenyl, C]-C6 alkoxy, Cj-C8 alkyl, C]-C8 alkylcarboxamide, C2-C8 alkynyl, Ci-C8 alkylsulfonamide, C]-C8 alkylsulfinyl, Ci-C8 alkylsulfonyl, Ci-C8 alkylthio, Cj-C8 alkylureyl, amino, Ci-C8 alkylamino, C2-C8 dialkylamino, carbo-C]-C6-alkoxy, carboxamide, carboxy, cyano, C3-C7 cycloalkyl, C2-C8 dialkylcarboxamide, C2-C8 dialkylsulfonamide, halogen, Cj-C6 haloalkoxy, Cj-C6 haloalkyl, C1- C6 haloalkylsulfmyl, C]-C6 haloalkylsulfonyl, Cj-C6 haloalkylthio, hydroxyl, thiol, nitro and sulfonamide; or
R8 and R9 together with the nitrogen atom to which they are both bonded form a C3-C7 heterocyclyl or a Cj-Ci0 heterobicyclyl group each optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected independently from the group consisting OfCj-C6 acyl, Cj-C6 acyloxy, C2- C8 alkenyl, Ci-C6 alkoxy, C1-C8 alkyl, Cj-C8 alkylcarboxamide, C2-C8 alkynyl, Cj-C8 alkylsulfonamide, Cj-C8 alkylsulfinyl, Cj-C8 alkylsulfonyl, Cj-C8 alkylthio, Cj-C8 alkylureyl, amino, Cj-C8 alkylamino, C2-C8 dialkylamino, carbo-Cj-C6-alkoxy, carboxamide, carboxy, cyano, C3-C7 cycloalkyl, C2-C8 dialkylcarboxamide, C2-C8 dialkylsulfonamide, halogen, Cj-C6 haloalkoxy, Cj-C6 haloalkyl, Cj-C6 haloalkylsulfinyl, C1-C6 haloalkylsulfonyl, CrC6 haloalkylthio, hydroxyl, thiol, nitro, oxo and sulfonamide. One aspect of the present invention pertains to pharmaceutical compositions comprising a compound of the present invention and a pharmaceutically acceptable carrier.
One aspect of the present invention pertains to methods for treating histamine H3- receptor associated disorders in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.
One aspect of the present invention pertains to methods for treating histamine H3- receptor associated disorders selected from the group consisting of cognitive disorders, epilepsy, brain trauma, depression, obesity, disorders of sleep and wakefulness such as narcolepsy, hypersomnia, somnolence syndrome, jet lag, sleep apnea and the like, attention deficit hyperactivity disorder (ADHD), schizophrenia, allergies, allergic responses in the upper airway, allergic rhinitis, nasal congestion, dementia and Alzheimer's disease. One aspect of the present invention pertains to methods for treating disorders of sleep and wakefulness in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.
One aspect of the present invention pertains to methods for treating cognitive disorders in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.
One aspect of the present invention pertains to methods for inducing wakefulness in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.
One aspect of the present invention pertains to methods for treating pain in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.
One aspect of the present invention pertains to the use of compounds of the present invention for production of a medicament for use in the treatment of a histamine H3-receptor associated disorder.
One aspect of the present invention pertains to the use of compounds of the present invention for production of a medicament for use in the treatment of a histamine H3-receptor associated disorder selected from the group consisting of cognitive disorders, epilepsy, brain trauma, depression, obesity, disorders of sleep and wakefulness such as narcolepsy, hypersomnia, somnolence syndrome, jet lag, sleep apnea and the like, attention deficit hyperactivity disorder (ADHD), schizophrenia, allergies, allergic responses in the upper airway, allergic rhinitis, nasal congestion, dementia and Alzheimer's disease.
One aspect of the present invention pertains to the use of compounds of the present invention for production of a medicament for use in the treatment of disorders of sleep and wakefulness.
One aspect of the present invention pertains to the use of compounds of the present invention for production of a medicament for use in the treatment of cognitive disorders.
One aspect of the present invention pertains to the use of compounds of the present invention for production of a medicament for use in inducing wakefulness.
One aspect of the present invention pertains to the use of compounds of the present invention for production of a medicament for use in treating pain. One aspect of the present invention pertains to compounds of the present invention for use in a method of treatment of the human or animal body by therapy.
One aspect of the present invention pertains to compounds of the present invention for use in a method for the treatment of a histamine H3-receptor associated disorder in the human or animal body by therapy.
One aspect of the present invention pertains to compounds of the present invention for use in a method for the treatment of a histamine H3-receptor associated disorder selected from the group consisting of cognitive disorders, epilepsy, brain trauma, depression, obesity, disorders of sleep and wakefulness such as narcolepsy, hypersomnia, somnolence syndrome, jet lag, sleep apnea and the like, attention deficit hyperactivity disorder (ADHD), schizophrenia, allergies, allergic responses in the upper airway, allergic rhinitis, nasal congestion, dementia and Alzheimer's disease in the human or animal body by therapy.
One aspect of the present invention pertains to compounds of the present invention for use in a method for the treatment of a disorder of sleep or wakefulness in the human or animal body by therapy.
One aspect of the present invention pertains to compounds of the present invention for use in a method for the treatment of a cognitive disorder in the human or animal body by therapy.
One aspect of the present invention pertains to compounds of the present invention for use in a method of inducing wakefulness in the human or animal body by therapy.
One aspect of the present invention pertains to compounds of the present invention for use in a method for the treatment of pain in the human or animal body by therapy.
One aspect of the present invention pertains to processes for preparing a composition comprising admixing a compound of the present invention and a pharmaceutically acceptable carrier.
These and other aspects of the invention disclosed herein will be set forth in greater detail as the patent disclosure proceeds.
BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows, a general synthetic scheme for the synthesis of (i?)-2-methylpyrrolidine via reduction of L-prolinol and for its subsequent conversion into (ϋ)-l-(4-bromophenethyl)-2- methylpyrrolidine and (i?)-4-(2-(2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid.
Figure 2 shows a general synthetic scheme for preparation of compounds of the present invention by microwave mediated, palladium catalyzed Suzuki reaction between a phenylboronic acid, and a phenyl sulfonamide substituted with a leaving group such as halogen or triflate. The sulfonamide is prepared by reaction of a precursor containing a suitable leaving group with an amine. The boronic acid is prepared in two steps from a precursor containing two leaving groups. The first step involves reaction with an amine. The second step involves reaction with a trialkyl borate.
Figure 3 shows a general synthetic scheme for preparation of compounds of the present invention by microwave mediated, palladium catalyzed Suzuki reaction between a phenyl halide or triflate or the like and a phenylboronic acid substituted with a sulfonamide.
Figure 4 shows a general synthetic scheme for preparation of compounds of the present invention. Starting from a biaryl acetic acid the carboxylic acid function is reduced and the resulting alcohol is converted to a leaving group. This is then alkylated with an amine in the presence of a base and the biaryl group is sulfonylated using a halosulfonic acid. The final step is reaction of the sulfonyl halide with an amine in the presence of a base.
Figure 5 shows two general methods for preparing compounds of the present invention. The first method involves the alkylation of a secondary amine. In the second method, a sulfonyl halide is first alkylated with a secondary amine in which one of the substituents bears a protecting group. Subsequent deprotection provides compounds of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
DEFINITIONS
For clarity and consistency, the following definitions will be used throughout this patent document.
The term "agonists" is intended to mean moieties that interact and activate the receptor, such as the histamine H3-receptor, and initiate a physiological or pharmacological response characteristic of that receptor. For example, when moieties activate the intracellular response upon binding to the receptor, or enhance GTP binding to membranes.
The term "antagonists" is intended to mean moieties that competitively bind to the receptor at the same site as agonists (for example, the endogenous ligand), but which do not activate the intracellular response initiated by the active form of the receptor, and can thereby inhibit the intracellular responses by agonists or partial agonists. Antagonists do not diminish the baseline intracellular response in the absence of an agonist or partial agonist.
The term "contact or contacting" is intended to mean bringing the indicated moieties together, whether in an in vitro system or an in vivo system. Thus, "contacting" a histamine H3- receptor with a compound of the invention includes the administration of a compound of the present invention to an individual, preferably a human, having a histamine H3 -receptor, as well as, for example, introducing a compound of the invention into a sample containing a cellular or more purified preparation containing a histamine H3 -receptor.
The term "in need of treatment" and the term "in need thereof when referring to treatment are used interchangeably to mean a judgment made by a caregiver (e.g. physician, nurse, nurse practitioner, etc. in the case of humans; veterinarian in the case of animals, including non-human mammals) that an individual or animal requires or will benefit from treatment. This judgment is made based on a variety of factors that are in the realm of a caregiver's expertise, but that includes the knowledge that the individual or animal is ill, or will become ill, as the result of a disease, condition or disorder that is treatable by the compounds of the invention. Accordingly, the compounds of the invention can be used in a protective or preventive manner; or compounds of the invention can be used to alleviate, inhibit or ameliorate the disease, condition or disorder.
The term "individual" is intended to mean any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
The term "inverse agonists" is intended to mean moieties that bind to the endogenous form of the receptor or to the constitutively activated form of the receptor, and which inhibit the baseline intracellular response initiated by the active form of the receptor below the normal base level of activity which is observed in the absence of agonists or partial agonists, or decrease GTP binding to membranes. Preferably, the baseline intracellular response is inhibited in the presence of the inverse agonist by at least 30%, more preferably by at least 50%, and most preferably by at least 75%, as compared with the baseline response in the absence of the inverse agonist.
The term "modulate or modulating" is intended to mean an increase or decrease in the amount, quality, response or effect of a particular activity, function or molecule. The term "pharmaceutical composition" is intended to mean a composition comprising at least one active ingredient; including but not limited to, salts, solvates and hydrates of compounds of the present invention; whereby the composition is amenable to investigation for a specified, efficacious outcome in a mammal (for example, without limitation, a human). Those of ordinary skill in the art will understand and appreciate the techniques appropriate for determining whether an active ingredient has a desired efficacious outcome based upon the needs of the artisan. The term "therapeutically effective amount" is intended to mean the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following: (1) Preventing the disease, for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease; (2) Inhibiting the disease, for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology); and (3) Ameliorating the disease, for example, ameliorating a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology).
CHEMICAL GROUP, MOIETY OR RADICAL The term "Ci-Ce acyl" is intended to mean a Ci-Ce alkyl radical attached to the carbon of a carbonyl group wherein the definition of alkyl has the same definition as described herein; some examples include, but are not limited to, acetyl, propionyl, n-butanoyl, sec-butanoyl, pivaloyl, pentanoyl and the like.
The term "Cj-Ce acyloxy" is intended to mean an acyl radical attached to an oxygen atom wherein acyl has the same definition has described herein; some embodiments are when acyloxy is Ci-C5 acyloxy, some embodiments are when acyloxy is C]-C4 acyloxy. Some examples include, but are not limited to, acetyloxy, propionyloxy, butanoyloxy, iso- butanoyloxy, pentanoyloxy, hexanoyloxy and the like.
The term "C2-C8 alkenyl" is intended to mean a radical containing 2 to 8 carbons wherein at least one carbon-carbon double bond is present, some embodiments are 2 to 7 carbons, some embodiments are 2 to 6 carbons, some embodiments are 2 to 5 carbons, some embodiments are 2 to 4 carbons, some embodiments are 2 to 3 carbons, and some embodiments have 2 carbons. Both E and Z isomers are embraced by the term "alkenyl." Furthermore, the term "alkenyl" includes di- and tri-alkenyls. Accordingly, if more than one double bond is present then the bonds may be all E or all Z or a mixture thereof. Examples of an alkenyl include vinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-ρentenyl, 4-pentenyl, 2-hexenyl, 3- hexenyl, 4-hexenyl, 5-hexanyl, 2,4-hexadienyl and the like.
The term "Ci-C6 alkoxy" is intended to mean a C]-C6 alkyl radical, as defined herein, attached directly to an oxygen atom, some embodiments are 1 to 5 carbons, some embodiments are 1 to 4 carbons, some embodiments are 1 to 3 carbons, and some embodiments are 1 or 2 carbons. Examples include methoxy, ethoxy, /z-propoxy, iso-propoxy, «-butoxy, f-butoxy, iso- butoxy, sec-butoxy and the like.
The term "Ci-C8 alkyl" is intended to mean a straight or branched carbon radical containing 1 to 8 carbons, some embodiments are 1 to 7 carbons, some embodiments are 1 to 6 carbons, some embodiments are 1 to 5 carbons, some embodiments are 1 to 4 carbons, some embodiments are 1 to 3 carbons, and some embodiments are 1 or 2 carbons. Examples of an alkyl include, but not limited to, methyl, ethyl, M-propyl, iso-propyl, n-butyl, sec-butyl, iso- butyl, f-butyl, pentyl, isσ-pentyl, f-pentyl, neo-pentyl, 1-methylbutyl [i.e.,
-CH(CH3)CH2CH2CH3], 2-methylbutyl [i.e., -CH2CH(CH3)CH2CH3], n-hexyl, «-heptyl, n-octyl and the like.
The term "Ci-C8 alkylcarboxamido" or "C1-C8 alkylcarboxamide" is intended to mean a single Cj-C8 alkyl group attached to either the carbon or the nitrogen of an amide group, wherein alkyl has the same definition as found herein. The C1-Cs alkylcarboxamido may be represented by the following:
alkyl
Examples include, but are not limited to, N-methylcarboxamide, N-ethylcarboxamide, N-n-propylcarboxamide, N- £sσ-propylcarboxamide, N-H-butylcarboxamide, N-sec- butylcarboxamide, N- /so-butylcarboxamide, N-f-butylcarboxamide and the like.
The term "Ci-C4-alkyIenyl" is intended to mean a C]-C4 divalent straight carbon group containing 1 to 4 carbons, some embodiments are 1 to 3 carbons, and some embodiments are 1 to 2 carbons. In some embodiments, alkylenyl refers to, for example, -CH2-, -CH2CH2-, - CH2CH2CH2-, and/or -CH2CH2CH2CH2-.
The term "aryloxy" is intended to mean an aromatic ring radical as defined herein, attached directly to an oxygen atom. Examples include phenoxy, naphthyloxy and the like.
The term "heteroaryloxy" is intended to mean a heteroaryl radical as defined herein, attached directly to an oxygen atom. Examples include pyridyloxy, benzofuranyloxy, pyrazinyloxy, pyridazinyloxy, pyrimidinyloxy, triazinyloxy, quinolinyloxy, benzoxazolyloxy, benzothiazolyloxy, lH-benzimidazolyloxy, isoquinolinyloxy, quinazolinyloxy, quinoxalinyloxy and the like.
The term "aryl-Ci-Graϊkylenyl" is intended to mean a Cj-C4 alkylene group bonded to an aryl group, each as defined herein. In some embodiments aryl-Ci-C4 alkylenyl refers to, for example, benzyl (-CΗ2-phenyl), phenylethyl (-CH2CH2-phenyl), and the like.
The term "heteroaryl-Ci-C4-alkylenyl" is intended to mean a C1-C4 alkylene group bonded to a heteroaryl group, each as defined herein. In so.me embodiments, heteroaryl-Cj-C4~ alkyleneyl refers to, for example, pyridinylmethyl (-CH2-pyridinyl) and the like.
The term "aryloxy-Ci-C4-alkylenyl" is intended to mean a Cj-C4 alkylene group bonded to an aryloxy group, each as defined herein. Ih some embodiments, aryloxy-Cj-C4- alkylenyl refers to, for example, 2-phenoxy-ethyl, phenoxy-methyl and the like.
The term "heteroaryloxy-Ci-Q-alkylenyl" is intended to mean a Cj-C4 alkylene group bonded to a heteroaryloxy group, each as defined herein. In some embodiments, heteroaryloxy- Cj-Cj-alkylenyl refers to, for example 2-(pyridin-2-yloxy)ethyl, (pyridin-2-yloxy)methyl and the like. The term "Cj-C8 alkylsulfinyl" is intended to mean a Ci-C8 alkyl radical attached to the sulfur of a sulfoxide radical having the formula: -S(O)- wherein the alkyl radical has the same definition as described herein. Examples include, but are not limited to, methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, /jo-propylsulfϊnyl, «-butylsulfinyl, jec-burylsulfinyl, iso- butylsulfinyl, f-butylsulfϊnyl, and the like.
The term "Ci-C8 alkylsulfonamide" is intended to mean the groups shown below: wherein Cj-C8 alkyl has the same definition as described herein.
The term "Cj-C8 alkylsulfonyl" is intended to mean a C]-C8 alkyl radical attached to the sulfur of a sulfone radical having the formula: -S(O)2- wherein the alkyl radical has the same definition as described herein. Examples include, but are not limited to, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, /so-propylsulfonyl, n-butylsulfonyl, sec-butylsulfonyl, iso- butylsulfonyl, ^-butylsulfonyl, and the like.
The term "Ci-C8 alkylthio" is intended to mean a Cj -C8 alkyl radical attached to a sulfur atom (i.e., -S-) wherein the alkyl radical has the same definition as described herein. Examples include, but are not limited to, methylsulfanyl (i.e., CH3S-), ethylsulfanyl, n-propylsulfanyl, iso- propylsulfanyl, re-butylsulfanyl, jec-butylsulfanyl, zsø-butylsulfanyl, f-butylsulfanyl, and the like.
The term "Ci-C8 alkylureyl" is intended to mean the group of the formula: -NC(O)N- wherein one are both of the nitrogens are substituted with the same or different Q-C8 alkyl group wherein alkyl has the same definition as described herein. Examples of an alkylureyl include, but are not limited to, CH3NHC(O)NH-, NH2C(O)NCH3-, (CH3)2NC(O)NH-, (CHs)2NC(O)NCH3-, CH3CH2NHC(O)NH-, CH3CH2NHC(O)NCH3- and the like.
The term "C2-C8 alkynyl" is intended to mean a radical containing 2 to 8 carbons and at least one carbon-carbon triple bond, some embodiments are 2 to 4 carbons, some embodiments are 2 to 3 carbons, and some embodiments have 2 carbons. Examples of an alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-ρentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and the like. The term "alkynyl" includes di- and tri-ynes. The term "amino" is intended to mean the group -NH2.
The term "Ci-C8 alkylamino" is intended to mean one alkyl radical attached to a -NH- radical wherein the alkyl radical has the same meaning as described herein. Some examples include, but are not limited to, methylamino, ethylamino, /z-propylamino, ώo-propylamino, n- butylamino, .sec-butylamino, wo-butylamino, f-butylamino, and the like. Some embodiments are "C1-C2 alkylamino." The term "aryl" is intended to mean an aromatic ring radical containing 6 to 10 ring carbons. Examples include phenyl and naphthyl.
The term "tricyclic" is intended to mean one C4-C7 cycloalkyl or C4-C7 cycloalkenyl group together with a C4-C7 cycloalkyl, aryl or heteroaryl group wherein both groups share two ring carbons thus forming either a fused or bridged ring system. Bicyclic examples include, but are not limited to, bicyclo[l.l.l]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.1.1]heptyl, bicyclo[3.2.1]octyl, 1,2,3,4-tetrahydro-naphthalenyl, indanyl, octahydro-pentalenyl, and the like.
The term "carbo-Ci-Cβ-alkoxy" is intended to mean a Ci-C6 alkyl ester of a carboxylic acid, wherein the alkyl group is as defined herein. Examples include, but are not limited to, carbomethoxy [-C(=O)OCH3]5 carboethoxy, carbopropoxy, carboisopropoxy, carbobutoxy, carbo-sec-butoxy, carbo-wo-butoxy, carbo-f-butoxy, carbo-n-pentoxy, carbo-wo-pentoxy, carbo- /-pentoxy, carbo-raeo-pentoxy, carbo-n-hexyloxy, and the like.
The term "carboxamide" is intended to mean the group -CONH2. The term "carboxy" or "carboxyl" is intended to mean the group -CO2H; also referred to as a carboxylic acid group.
The term "cyano" is intended to mean the group -CN.
The term "C4-C7 cycloalkenyl" is intended to mean a non-aromatic ring radical containing 4 to 7 ring carbons and at least one double bond; some embodiments contain 4 carbons. Examples include cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and the like.
The term "C3-C7 cycloalkyl" is intended to mean a saturated ring radical containing 3 to 7 carbons; some embodiments contain 3 to 6 carbons; some embodiments contain 3 to 5 carbons; some embodiments contain 5 to 7 carbons; some embodiments contain 3 to 4 carbons. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
The term "C3-C7 cycloalkylenyl" is intended to mean a saturated ring di-radical containing 3 to 7 carbons; some embodiments contain 3 to 6 carbons; some embodiments contain 3 to 5 carbons; some embodiments contain 5 to 7 carbons; some embodiments contain 3 to 4 carbons. Examples include cyclopropylenyl, cyclobutylenyl, cyclopentylenyl, cyclohexylenyl, cycloheptylenyl and the like. In some embodiments the C3-C7 cycloalkylenyl di-radical may be 1,2 disubstituted, for example 1,2-cyclopropyl, 1 ,2-cyclobutyl, 1,2- cyclopentyl, 1,2-cyclohexyl, 1,2-cycloheρryl and the like.
The term "C2-C8 dialkylamino" is intended to mean an amino substituted with two of the same or different Ci-C4 alkyl radicals wherein alkyl radical has the same definition as described herein. Some examples include, but are not limited to, dimethylamino, methylethylamino, diethylamino, methylpropylamino, methylisopropylamino, ethylpropylamino, ethylisopropylamino, dipropylamino, propylisopropylamino and the like. Some embodiments are "C2-C4 dialkylamino."
The term "C2-C8 dialkylcarboxamido" or "C2-C8 dialkylcarboxamide" is intended to mean two alkyl radicals, that are the same or different, attached to an amide group, wherein alkyl has the same definition as described herein. A C2-C8 dialkylcarboxamido may be represented by the following groups:
„ , alkyl
C1-C4 alkyi C1-C4 alkyl wherein Ci-C4 has the same definition as described herein. Examples of a dialkylcarboxamide include, but are not limited to, N^V-dimethylcarboxamide, N-methyl-N-ethylcarboxarnide, N5N- diethylcarboxamide, N-methyl-N-isopropylcarboxamide, and the like.
The term "C2-C8 dialkylsulfonamide" is intended to mean one of the following groups shown below:
wherein Ci-C4 has the same definition as described herein, for example but not limited to, methyl, ethyl, n-propyl, isopropyl, and the like.
The term "CrC6 haloalkoxy" is intended to mean a C1-C6 haloalkyl, as defined herein, which is directly attached to an oxygen atom. Examples include, but are not limited to, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy and the like.
The term "C1-C6 haloalkyl" is intended to mean a Ci-C6 alkyl group, defined herein, wherein the alkyl is substituted with one halogen up to fully substituted and a fully substituted C]-C6 haloalkyl can be represented by the formula CnL2n+I wherein L is a halogen and "n" is 1, 2, 3, 4, 5 or 6; when more than one halogen is present then they may be the same or different and selected from the group consisting of F, Cl, Br and I, preferably F, some embodiments are 1 to 5 carbons, some embodiments are 1 to 4 carbons, some embodiments are 1 to 3 carbons, and some embodiments are 1 or 2 carbons. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, 2,2,2- trifluoroethyl, pentafluoroethyl and the like.
The term "C1-C6 haloalkylsuliinyl" is intended to mean a C1-C6 haloalkyl radical attached to the sulfur atom of a sulfoxide group having the formula: -S(O)- wherein the haloalkyl radical has the same definition as described herein. Examples include, but are not limited to, trifluoromethylsulfinyl, 2,2,2-trifluoroethylsulfinyl, 2,2-difluoroethylsulfinyl and the like. The term "C1-C6 haloalkylsulfonyl" is intended to mean a C1-C6 haloalkyl radical attached to the sulfur atom of a sulfone group having the formula: -S(O)2- wherein haloalkyl has the same definition as described herein. Examples include, but are not limited to, trifluoromethylsulfonyl, 2,2,2-trifluoroethylsulfonyl, 2,2-difluoroethylsulfonyl and the like. The term "Ci-C6 haloalkylthio" is intended to mean a Ci -C6 haloalkyl radical directly attached to a sulfur wherein the haloalkyl has the same meaning as described herein. Examples include, but are not limited to, trifluoromefhylthio (i.e., CF3S-, also referred to as trifluoromethylsulfanyl), 1,1-difluoroethylthio, 2,2,2-trifluoroethylthio and the like.
The term "halogen" or "halo" is intended to mean to a fluoro, chloro, bromo or iodo group.
The term "heteroaryl" is intended to mean an aromatic ring system that may be a single ring, two fused rings or three fused rings wherein at least one ring carbon is replaced with a heteroatom selected from, but not limited to, the group consisting of O, S and N wherein the N can be optionally substituted with H, Ci-C4 acyl or Cj-C4 alkyl. Examples of heteroaryl groups include, but are not limited to, pyridyl, benzofuranyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, quinolinyl, benzoxazolyl, benzothiazolyl, lH-benzimidazolyl,-isoquinolinyl, quinazolinyl, quinoxalinyl and the like. In some embodiments, the heteroatom is selected from, but not limited to, the group consisting of O, S and N, wherein N is substituted with H (i.e., NH), examples include, but are not limited to, pyrrolyl, indolyl, lH-benzoimidazol-2-yl, and the like.
The term "C5-CiO heterobicyclic" is intended to mean a bicyclic ring, as described herein, wherein 1 , 2, or 3 ring carbons are replaced with a heteroatom or group selected from, but not limited to, the group consisting of O, S, S(=O), S(=O)2, and NH, wherein the nitrogen is optionally substituted, and 1 or 2 ring carbons are optionally substituted with oxo or thiooxo thus together forming a carbonyl or thiocarbonyl group respectively. In some embodiments, one of the rings is aromatic. Examples of a heterobicyclic group include, but are not limited to, 2,5- diaza-bicyclo[2.2.1]hept-2-yl, 7-aza-bicyclo[2.2.1]hept-7-yl, 1,3-dihydro-isoindolyl, 3,4- dihydro-lH-isoquinolinyl, octahydro-cyclopenta[c]pyrrolyl and the like.
The term "C3-C7 heterocyclic" or "C3-C7 heterocyclyl" is intended to mean a non- aromatic carbon ring (i.e., C3-C7 cycloalkyl or C4-C7 cycloalkenyl as defined herein) wherein one, two or three ring carbons are replaced by a heteroatom selected from, but not limited to, the group consisting of O, S, S(=O), S(=O)2, NH, wherein the N can be optionally substituted as described herein. Li some embodiments, the nitrogen is optionally substituted with C1-C4 acyl or Ci-C4 alkyl, and ring carbon atoms are optionally substituted with oxo or a thiooxo thus forming a carbonyl or thiocarbonyl group. The heterocyclic group can be attached/bonded to any available ring atom, for example, ring carbon, ring nitrogen, and the like. The heterocyclic group is a 3-, 4-, 5-, 6- or 7-membered ring. Examples of a heterocyclic group include, but are not limited to, aziridin-1-yl, aziridin-2-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, piperidin-1- yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, morpholin-2-yl, morpholin-3-yl, morpholin-4- yl, piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, piperazin-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, [l,3]-dioxolan-2-yl, thiomorpholin-4-yl, [l,4]oxazepan-4-yl, 1,1-dioxo-lλ6- thiomorpholin-4-yl, azepan-1-yl, azepan-2-yl, azepan-3-yl, azepan-4-yl, tetrahydro-furan-2-yl, tetrahydro-naran-3-yl, and the like.
The term "hydroxyl" is intended to mean the group -OH.
The term "nitro" is intended to mean the group -NO2.
The term "oxo" is intended to mean the substituent =O, accordingly, as a result, when a carbon is substituted by an "oxo" group the new group resulting from the carbon and oxo together is a carbonyl group.
The term "phenyl" is intended to mean the group C6Hs-.
The term "sulfonamide" is intended to mean the group -SO3NH2.
The term "thiol" is intended to mean the group -SH.
COMPOUNDS OF THE INVENTION:
One aspect of the present invention pertains to certain compounds as shown in Formula (Ia):
(Ia) or a pharmaceutically acceptable salt, hydrate or solvate thereof; wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12 and J have the same definitions as described herein, supra and infra. In some embodiments the compounds of the present invention are other than N-(3- cyanopheny^-N-p-^'-fK^l-dimethylethylJaminoJsulfonylJflJ'-biphenylj^-ylJethylJ-glycine methyl ester, represented by the formula below:
In some embodiments, the compounds of the present invention are other than N-[[4'-[2- oxo-2-(phenylarnino)ethyI] [1,1 '-biphenyl]-4-yl] sulfonyl]-D-valine 1 , 1 -dimethylethyl ester, represented by the formula below:
In some embodiments, the compounds of the present invention are other than N-[[4'-[2- oxo-2-[(phenylmethyl)amino]ethyl] [1,1 '-biphenyl] -4-yl]sulfonyl] -D-valine 1 , 1 -dimethylethyl ester, represented by the formula below:
In some embodiments the compounds of the present invention are other than iV-[[4'-[2- oxo-2-(phenylamino)ethyl][l,l'-biphenyl]-4-yl]sulfonyl]-D-valine
In some embodiments, the compounds of the present invention are other than N-[[4'-[2- oxo-2-[(phenylmethyl)amino]ethyl][l,r-biphenyl]-4-yl]sulfonyl]-D-valine represented by the formula below:
It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. All combinations of the embodiments pertaining to the chemical groups represented by the variables (e.g., R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12 and J) contained within the generic chemical formulae described herein [e.g. (Ia), (Ic), (Ie), etc.] are specifically embraced by the present invention just as if they were explicitly disclosed, to the extent that such combinations embrace compounds that result in stable compounds (i.e., compounds that can be isolated, characterized and tested for biological activity). It is understood that compounds of the present invention including all subcombinations of the chemical groups related thereto embrace pharmaceutically acceptable salts, solvates and hydrates thereof. In addition, all subcombinations of the chemical groups listed in the embodiments describing such variables, as well as all subcombinations of uses andmedical indications described herein, are also specifically embraced by the present invention just as if each of such subcombination of chemical groups and subcombϊnation of uses and medical indications were explicitly disclosed herein. As used herein, "substituted" indicates that at least one hydrogen atom of the chemical group is replaced by a non-hydrogen substituent or group, the non-hydrogen substituent or group can be monovalent or divalent. When the substituent or group is divalent, then it is understood that this group is further substituted with another substituent or group. When a chemical group herein is "substituted" it may have up to the full valance of substitution; for example, a methyl group can be substituted by 1, 2, or 3 substituents, a methylene group can be substituted by 1 or 2 substituents, a phenyl group can be substituted by 1, 2, 3, 4, or 5 substituents, a naphthyl group can be substituted by 1, 2, 3, 4, 5, 6, or 7 substituents and the like. Likewise, "substituted with one or more substituents" refers to the substitution of a group with one substituent up to the total number of substituents physically allowed by the group. Further, when a group is substituted with more than one group they can be identical or they can be different.
Compounds of the invention can also include tautomeric forms, such as keto-enol tautomers, and the like. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. It is understood that the various tautomeric forms are within the scope of the compounds of the present invention.
Compounds of the invention can also include all isotopes of atoms occurring in the intermediates and/or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include deuterium and tritium. It is understood and appreciated that compounds of Formula (Ia) and Formulae related thereto may have two or more chiral centers, and therefore can exist as enantiomers and/or diastereomers. The invention is understood to extend to and embrace all such enantiomers, diastereomers and mixtures thereof, including but not limited to racemates. In another embodiment, compounds of the present invention have two stereochemical centers and both are R. In another embodiment, compounds of the present invention have two stereochemical centers and both are S. In another embodiment, compounds of the present invention have two stereochemical centers wherein one stereochemical center is R and one stereochemical center is S. In another embodiment, compounds of the present invention have three stereochemical centers wherein all stereochemical centers are R. In another embodiment, compounds of the present invention have three stereochemical centers wherein all stereochemical centers are S. In another embodiment, compounds of the present invention have three stereochemical centers wherein two stereochemical centers- are R and the third stereochemical center is S. In another embodiment, compounds of the present invention have three stereochemical centers wherein two stereochemical centers are S and the third stereochemical center is R. It is understood that compounds of Formula (Ia) and formulae used throughout this disclosure are intended to represent all individual enantiomers and mixtures thereof, unless stated or shown otherwise. One aspect of the present invention pertains to certain compounds as shown in Formula
(Ia):
(Ia) or a pharmaceutically acceptable salt, hydrate or solvate thereof; wherein: R1 and R2 are each selected independently from the group consisting of H, Ci-Cs alkyl,
C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloalkyl, aryl, heterocyclyl, heteroaryl, aryl-Ci-G,- alkylenyl, aryloxy-Ci-Gj-alkylenyl, heteroaryl-Ci-Gralkylenyl and heteroaryloxy-Ci-C4- alkylenyl, and each R1 and R2 is optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting OfC]-C6 acyl, Q-C6 acyloxy, C2-C8 alkenyl, Q-C6 alkoxy, Ci-C8 alkyl, Ci-C8 alkylcarboxamide, C2-C8 alkynyl, Ci-C8 alkylsulfonamide, Ci-C8 alkylsulfinyl, C]-C8 alkylsulfonyl, Ci-Cg alkylthio, Ci-C8 alkylureyl, amino, Ci-C8 alkylamino, C2-C8 dialkylamino, carbo-Ci-C6-alkoxy, carboxamide, carboxy, cyano, C3-C7 cycloalkyl, C2-C8 dialkylcarboxamide, C2-C8 dialkylsulfonamide, halogen, C]-C6 haloalkoxy, C]-C6 haloalkyl, Q- C6 haloalkylsulfmyl, Ci-C6 haloalkylsulfonyl, Ci-C6 haloalkylthio, hydroxyl, thiol, nitro and sulfonamide; or
R > i1 and R2 together with the nitrogen atom to which they are both bonded form a C3-C7 heterocyclyl or a C5-CI0 heterobicyclyl group each optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected independently from the group consisting OfCi-C6 acyl, Ci-C6 acyloxy, C2- C8 alkenyl, Ci-Ce alkoxy, Ci-C8 alkyl, Cj-C8 alkylcarboxamide, C2-C8 alkynyl, C1-C8 alkylsulfonamide, C]-C8 alkylsulfinyl, Ci-C8 alkylsulfonyl, Cj-C8 alkylthio, C]-C8 alkylureyl, amino, Ci-C8 alkylamino, C2-C8 dialkylamino, carbo-C]-C6-alkoxy, carboxamide, carboxy, cyano, C3-C7 cycloalkyl, C2-C8 dialkylcarboxamide, C2-C8 dialkylsulfonamide, halogen, CrC6 haloalkoxy, Ci-C6 haloalkyl, Ci-C6 haloalkylsulfmyl, Ci-C6 haloalkylsulfonyl, Ci-C6 haloalkylthio, hydroxyl, thiol, nitro, oxo and sulfonamide;
J is -CH2CH2- or a l,2-C3-C7-cycloalkylenyl group, each optionally substituted with 1, 2, 3 or 4 substituents selected independently from the group consisting Of C1-C3 alkyl, C]-C4 alkoxy, carboxy, cyano, C]-C3 haloalkyl, halogen, hydroxyl and oxo; R3, R4, R5, R6, R7, R10, R1 ' and R12 are each selected independently from the group consisting of H, Ci-C6 acyl, Ci-C6 acyloxy, C2-C8 alkenyl, Ci-C6 alkoxy, Ci-C8 alkyl, Ci-C8 alkylcarboxamide, C2-C8 alkynyl, Ci-Cs alkylsulfonamide, C]-C8 alkylsulfinyl, C1-C8 alkylsulfonyl, Ci-C8 alkylthio, Ci-C8 alkylureyl, amino, Cj-C8 alkylamino, C2-C8 dialkylamino, carbo-Ci-Cβ-alkoxy, carboxamide, carboxy, cyano, C3-C7 cycloalkyl, C2-Cg dialkylcarboxamide, C2-C8 dialkylsulfonamide, halogen, Cj-C6 haloalkoxy, Cj-C6 haloalkyl, C]-C6 haloalkylsulfϊnyl, Ci-C6 haloalkylsulfonyl, Ci-C6 haloalkylthio, hydroxyl, thiol, nitro and sulfonamide; and R8 and R9 are each selected independently from the group consisting of H, Ci-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloalkyl, aryl, heterocyclyl, heteroaryl, aryl-Cj-Gr alkylenyl, aryloxy-Ci-C4-alkylenyl, and heteroaryloxy-Q-G;- alkylenyl, and each R8 and R9 is optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting Of Ci-C6 acyl, Cj-C6 acyloxy, C2-C8 alkenyl, Cj-C6 alkoxy, Cj-C8 alkyl, C]-C8 alkylcarboxamide, C2-C8 alkynyl, C]-C8 alkylsulfonamide, C]-C8 alkylsulfinyl, Cj-C8 alkylsulfonyl, C1-C8 alkylthio, Ci-C8 alkylureyl, amino, Ci-C8 alkylamino, C2-C8 dialkylamino, carbo-Ci-Cβ-alkoxy, carboxamide, carboxy, cyano, C3-C7 cycloalkyl, C2-C8 dialkylcarboxamide, C2-C8 dialkylsulfonamide, halogen, C]-C6 haloalkoxy, C1-C6 haloalkyl, C1- C6 haloalkylsulfϊnyl, C1-C6 haloalkylsulfonyl, Ci-C6 haloalkylthio, hydroxyl, thiol, nitro and sulfonamide; or
R8 and R9 together with the nitrogen atom to which they are both bonded form a C3-C7 heterocyclyl or a C5-C10 heterobicyclyl group each optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected independently from the group consisting of Cj-Ce acyl, Cj-C6 acyloxy, C2- C8 alkenyl, Cj-C6 alkoxy, Cj-C8 alkyl, Ci-C8 alkylcarboxamide, C2-C8 alkynyl, Ci-C8 alkylsulfonamide, Cj-C8 alkylsulfinyl, Cj-C8 alkylsulfonyl, Q-C8 alkylthio, Ci-C8 alkylureyl, amino, C]-C8 alkylamino, C2-C8 dialkylamino, carbo-Ci-C6-alkoxy, carboxamide, carboxy, cyano, C3-C7 cycloalkyl, C2-C8 dialkylcarboxamide, C2-C8 dialkylsulfonamide, halogen, C]-C6 haloalkoxy, Cj-C6 haloalkyl, C1-C6 haloalkylsulfinyl, C1-C6 haloalkylsulfonyl, C1-C6 haloalkylthio, hydroxyl, thiol, nitro, oxo and sulfonamide. Some embodiments of the present invention pertain to compounds of Formula (Ic):
(Ic) Some embodiments of the present invention pertain to compounds of Formula (Ie):
(Ie)
In some embodiments, each R1 and R2 is selected independently from the group consisting of H, Ci-C8 alkyl, C3-C7 cycloalkyl, aryl, heterocyclyl, aryl-Ci-Gf-alkylenyl, heteroaryl-Ci-Q-alkylenyl and aryloxy-Q-Q-alkylenyl, and each R1 and R2 is optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting of Ci-C6 alkoxy, Ci-C8 alkyl, C3-C7 cycloalkyl, halogen, C1-C6 haloalkyl and hydroxyl.
In some embodiments, each R1 and R2 is selected independently from the group consisting of H, Ci-C8 alkyl, C3-C7 cycloalkyl, aryl, heterocyclyl, aryl-d-C4-alkylenyl, heteroaryl-Cj-C4-alkylenyl and aryloxy-Ci-C4-alkylenyl, and each R1 and R2 is optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting of methoxy, ethoxy, isopropoxy, cyclopropyl, cyclohexyl, hydroxyl, fluoro, methyl, chloro and trifluoromethyl.
In some embodiments, each R1 and R2 is selected independently from the group consisting of H, methyl, ethyl, n-propyl, isopropyl, t-butyl, 1-propyl-butyl, cyclopropyl. cyclobutyl, cyclopentyl, cyclohexyl, phenyl, tetrahydropyran-4-yl, benzyl, pyridin-2-ylmethyl, 2-phenoxy-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, 2-isopropoxyethyl, cyclopropylmethyl, cyclohexylmethyl, 2-hydroxyethyl, 4-fluoro-phenyl, 4-methyl-benzyl, 4-methoxy-benzyl, A- fluoro-benzyl, 4-chloro-benzyl and 4-trifluoromethyl-benzyl.
In some embodiments, R1 is H or Ci-C8 alkyl and R2 is C]-C8 alkyl, C3-C7 cycloalkyl, aryl, heterocyclyl, aryl-Ci-C4-alkylenyl, aryl-Ci-C4-alkylenyl, heteroaryl-Ci-C4-alkylenyl or aryloxy-Ci-C4-alkylenyl, and each R2 is optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting of C]-Ce alkoxy, Ci-C8 alkyl, C3-C7 cycloalkyl, halogen, C1-C6 haloalkyl and hydroxyl.
In some embodiments, R1 is H or Cj-C8 alkyl and R2 is Cj-C8 alkyl, C3-C7 cycloalkyl, aryl, heterocyclyl, aryl-Cj -Gj-alkylenyl, aryl-Ci-C4-alkylenyl, heteroaryl-Cj-C4-alkylenyl or aryloxy-Ci-C4-alkylenyl, and each R2 is optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting of methoxy, ethoxy, isopropoxy, cyclopropyl, cyclohexyl, hydroxyl, fluoro, methyl, chloro and trifluoromethyl.
In some embodiments, R1 is H, methyl or ethyl and R2 is H3 methyl, ethyl, n-propyl, isopropyl, t-butyl, 1-propyl-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, tetrahydropyran-4-yl, benzyl, pyridin-2-ylmethyl, 2-phenoxy-ethyl, 2-methoxy-ethyl, 2-ethoxy- ethyl, 2-isopropoxyethyl, cyclopropylmethyl, cyclohexylmethyl, 2-hydroxyethyl, 4-fluoro- phenyl, 4-methyl-benzyl, 4-methoxy-benzyl, 4-fluoro-benzyl, 4-chloro-benzyl or 4- trifluoromethyl-benzyl.
In some embodiments, R1 and R2 together with the nitrogen atom to which they are both bonded form a C3-C7 heterocyclyl or a C5-Ci0 heterobicyclyl group. In some embodiments, R1 and R2 together with the nitrogen atom to which they are both bonded form azetidin-1-yl, pyrrolidin-l-yl, piperidin-1-yl, morpholin-4-yl, 1,1-dioxo- thiomorpholin-4-yl, 2,3-dihydro-lH-isoindol-2-yl or l,2,3,4-tetrahydro-isoquinolin-2-yl. In some embodiments, each R1 and R2 is selected independently from the group consisting of Η, Ci-C8 alkyl, C3-C7 cycloalkyl, aryl, heterocyclyl, aryl-Ci-C4-alkylenyl, amino, heteroaryl-Ci-Gj-alkylenyl, aryloxy-Ci-C4-alkylenyl and Ci-C6 acyl, and each R: andR2 is optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting OfC]-C6 alkoxy, Ci-C8 alkyl, aryl, carbo-Ci-Cg-alkoxy, C3-C7 cycloalkyl, halogen, Ci-C6 haloalkyl, hydroxyl, Ci-C6 acyl, Ci-C6 acyloxy, Ci-C6 haloalkoxy and heterocyclyl; wherein each Ci-C8 alkyl may be further substituted with hydroxy; or
R1 andR2 together with the nitrogen atom to which they are both bonded form a C3-C7 heterocyclyl or a C5-C10 heterobicyclyl group each optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting OfC1-C6 acyl, Ci-C8 alkyl, Ci-C8 alkylcarboxamide, C]-C6 acyloxy, carboxy and hydroxy; and wherein each Ci-C8 alkyl and carboxy may be further substituted with Ci-C6 acyloxy, Ci-C6 alkoxy, aryl-Ci-C4-alkylenyl or hydroxy.
In some embodiments, R1 and R2 are each selected independently from the group consisting of Η, methyl, ethyl, n-propyl, isopropyl, t-butyl, 1-propyl-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, tetrahydropyran-4-yl, benzyl, pyridin-2-ylmethyl, 2-phenoxy-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, 2-isopropoxyethyl, cyclopropylmethyl, cyclohexylmethyl, 2-hydroxyethyl, 4-fluoro-phenyl, 4-methyl-benzyl, 4-methoxy-benzyl, 4- fluoro-benzyl, 4-chloro-benzyl, 4-trifluoromethyl-benzyl, amino, 2-methoxy-l -methyl-ethyl, propionyloxyl, 3,5-dichlorobenzyl, acetyl, 3,4-dichlorobenzyl, 2-hydroxy-l -methyl-ethyl, 2- acetoxyethyl, 4-fluoro-phenyl-ethyl, tetrahydro-pyran-4-ylmethyl, 2-propionyloxy-ethyl, diphenyl-methyl, 2-hydroxy- 1,1 -dimethyl-ethyl, isobutyl, 3-phenyl-propyl, 2-oxo-imidazolidin- 1-yl-ethyl, phenyl-ethyl, ρyridin-4-yl-methyl, 3-methoxy-3-oxopropyl, pyridin-3-yl-methyl, 1- methoxy-l-oxopropan-2-yl, l-(hydroxymethyl)cyclopentyl, 4-(trifluoromethoxy)-benzyl, 2- methoxy-3-oxoethyl, l-isopropoxy-l-oxopropan-2-yl, 2-isopropoxy-2-oxoethyl, 2-methyl-l- (propionyloxy)propan-2-yl, l-tert-butoxy-l-oxopropan-2-yl and 2-fe/7-butoxy-2-oxoethyl; or
R1 andR2 together with the nitrogen atom to which they are both bonded form azetidin- 1-yl, pyrrolidin-l-yl, piperidin-1-yl, morpholin-4-yl, l,l-dioxo-thiomorphoIm-4-yl, 2,3-dihydro- lH-isoindol-2-yl, l,2,3,4-tetrahydro-isoquinolin-2-yl, 3-hydroxy-pyrrolidin-l-yl, 3- hydroxymethyl-piρeridin-1-yl, aziridinl-yl, 2-methoxymethyl-pyrrolidin-l-yl, 3-hydroxy- piperidin-l-yl, 2-hydroxymethyl-pyrrolidin-l-yl, 4-(benzyloxycarbonyl)piperidin-l-yl, 4- (propionyloxy-methyl)-piperidin-.l-yl, 2-(propionyloxy-methyl)-pyrrolidin-l -yl, 3- methoxymethyl-ρiperidin-1-yl, 4-hydroxymethyl-piperidin-l -yl, 4-(ethoxycarbonyl)piperidin-l- yl, 4-(2-ethoxy-ethyl)piperidin-l-yl, 4-propionyl-piperazin-l-yl, 4-(ethoxy-methyl)-piperidin-l- yl, 3-methoxy-piperidin-l-yl, 4-(2-hydroxy-ethyl)-piperidin-l-yl, 2-hydroxymethyl-piperidin-l- yl, 3-methoxy-pyrrolidin-l-yl, 2-carboxy-pyrrolidin-l-yl, 6,7-dimethoxy-3,4- dihydroisoquinolin-2(lH)-yl, 4-methoxy-piperidin-l-yl, 3-oxo-piperazin-l-yl, 2- (methylcarbamoyl)pyrrolidin-l-yl, 3,5-dimethyl-morpholin-4-yl, 3-propionyloxy-pyrrolidin-l- yl, 4-hydroxy-piperidin-l-yl, 4-carboxy-piperidin-l-yl, 4-hydroxy-2-(methoxycarbonyl)- pyrrolidin-1-yl, 4-(2-methoxy-ethyl)-piperidin-l-yl or 4-(methoxymethyl)-piperidin-l-yl.
In some embodiments, each R3, R4, R5, R6, R7, R10, R1 ' and R12 is selected independently from H or halogen. In some embodiments, R3, R4, R5, R6, R7, R10, R1 ' and R12 are H.
In some embodiments, J is -CH2CH2- optionally substituted with 1, 2, 3 or 4 substituents selected independently from the group consisting OfCi-C3 alkyl, Ci-C4 alkoxy, carboxy, cyano, C1-C3 haloalkyl, halogen, hydroxyl and oxo. In some embodiments, J is -CH2CH2-. In some embodiments, each R8 and R9 is selected independently from the group consisting of H, Ci-C8 alkyl, C3-C7 cycloalkyl, aryl, heterocyclyl, aryl-C1-C4-alkylenyl, heteroaryl-Ci-C4-alkylenyl and aryloxy-Ci-C4-alkylenyl, and each R8andR9 is optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting of Ci-C6 alkoxy, Ci-C8 alkyl, C3-C7 cycloalkyl, halogen, C]-Ce haloalkyl and hydroxyl. In some embodiments, each R8 and R9 is selected independently from the group consisting of H, C]-Cs alkyl, C3-C7 cycloalkyl, aryl, heterocyclyl, aryl-C]-C4-alkylenyl, heteroaryl-Ci-C4-alkylenyl and aryloxy-Ci-C4-alkylenyl, and each R8andR9 is optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting of methoxy, ethoxy, isopropoxy, cyclopropyl, cyclohexyl, hydroxyl, fluoro, methyl, chloro and trifluoromethyl.
In some embodiments, each R8 and R9 is selected independently from the group consisting of H, methyl, ethyl, n-propyl, isopropyl, t-butyl, 1-propyl-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, tetrahydropyran-4-yl, benzyl, pyridin-2-ylmethyl, 2-phenoxy-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, 2-isopropoxyethyl, cyclopropylmethyl, cyclohexylmethyl, 2-hydroxyethyl, 4-fluoro-phenyl, 4-methyl-benzyl, 4-methoxy-benzyl, 4- fiuoro-benzyl, 4-chloro-benzyl and 4-trifluoromethyl-benzyl. In some embodiments, R8 and R9 together with the nitrogen atom to which they are both bonded form a C3-C7 heterocyclyl group optionally substituted with C]-C8 alkyl.
In some embodiments, R8 and R9 together with the nitrogen atom to which they are both bonded form a C3-C7 heterocyclyl group optionally substituted with methyl. In some embodiments, R8 and R9 together with the nitrogen atom to which they are both bonded form pyrrolidin-1-yl optionally substituted with methyl.
In some embodiments, R8 and R9 together with the nitrogen atom to which they are both bonded form 2-methyl-pyrrolidin-l-yl.
In some embodiments, R8 and R9 together with the nitrogen atom to which they are both bonded form (i?)-2-methyl-pyrrolidin-l -yl.
In some embodiments, R8 and R9 together with the nitrogen atom to which they are both bonded form (iS)-2-methyl-pyrrolidin-l-yl.
Some embodiments of the present invention pertain to compounds of Formula (Ig):
(Ig) or a pharmaceutically acceptable salt, hydrate or solvate thereof; wherein:
R1 is H or C]-C8 alkyl and R2 is C]-Cg alkyl, C3-C7 cycloalkyl, aryl, heterocyclyl,* aryl- Ci-C4-alkylenyl, heteroaryl-C]-C4-alkylenyl or aryloxy-Cj-Gralkylenyl, and each R2 is optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting Of Cj-C6 alkoxy, Cj-C8 alkyl, C3-C7 cycloalkyl, halogen, Cj-C6 haloalkyl and hydroxyl; or
R1 and R2 together with the nitrogen atom to which they are both bonded form a C3-C7 heterocyclyl or a C5-C10 heterobicyclyl group;
J is -CH2CH2-; and R8 and R9 together with the nitrogen atom to which they are both bonded form a C3-C7 heterocyclyl group optionally substituted with Cj-C8 alkyl.
Some embodiments of the present invention pertain to compounds of Formula (Ig), supra, or a pharmaceutically acceptable salt, hydrate or solvate thereof; wherein R1 is H, methyl or ethyl and R2 is H, methyl, ethyl, n-propyl, isopropyl, t-butyl, 1- propyl-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, tetrahydropyran-4-yl, benzyl, pyridin-2-ylmethyl, 2-phenoxy-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, 2- isopropoxyethyl, cyclopropylmethyl, cyclohexylmethyl, 2-hydroxyethyl, 4-fluoro-phenyl, 4- methyl-benzyl, 4-methoxy-benzyl, 4-fluoro-benzyl, 4-chloro-benzyl or 4-trifluoromethyl- benzyl; or
R1 and R2 together with the nitrogen atom to which they are both bonded form azetidin- 1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, l,l-dioxo-thiomorpholin-4-yl, 2,3-dihydro- lH-isoindol-2-yl or l,2,3,4-tetrahydro-isoquinolin-2-yl;
J is -CH2CH2-; and
R8 and R9 together with the nitrogen atom to which they are both bonded form 2-methyl- pyrrolidin-1-yl.
Some embodiments of the present invention pertain to compounds of Formula (Ii):
(B) or a pharmaceutically acceptable salt, hydrate or solvate thereof; wherein:
R1 is H or Ci-Cs alkyl and R2 is C]-C8 alkyl, C3-C7 cycloalkyl, aryl, heterocyclyl, aryl- Ci-C4-alkylenyl, heteroaryl-Ci-C4-alkylenyl or aryloxy-Ci-C4-alkylenyl and each R2 is optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting OfCi-C6 alkoxy, Cj-C8 alkyl, C3-C7 cycloalkyl, halogen, Ci-C6 haloalkyl and hydroxyl; or
R1 and R2 together with the nitrogen atom to which they are both bonded form a C3-C7 heterocyclyl or a Cs-Qo heterobicyclyl group; J is -CH2CH2-; and
R8 and R9 together with the nitrogen atom to which they are both bonded form a C3-C7 heterocyclyl group optionally substituted with Ci-Cg alkyl.
Some embodiments of the present invention pertain to compounds of Formula (Ii), supra, or a pharmaceutically acceptable salt, hydrate or solvate thereof; wherein:
R1 is H, methyl or ethyl and R2 is H, methyl, ethyl, n-propyl, isopropyl, t-butyl, 1- propyl-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, tetrahydropyran-4-yl, benzyl, pyridin-2-ylmethyl, 2-phenoxy-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, 2- isopropoxyethyl, cyclopropylmethyl, cyclohexylmethyl, 2-hydroxyethyl, 4-fluoro-phenyl, A- methyl-benzyl, 4-methoxy-benzyl, 4-fluoro-benzyl, 4-chloro-benzyl or 4-trifluoromethyl- benzyl; or R1 and R2 together with the nitrogen atom to which they are both bonded form azetidin- 1-yl, pyrrolidin-1-yl, ρiperidin-1-yl, moφholin-4-yl, l,l-dioxo-thiomorpholin-4-yl, 2,3-dihydro- lH-isoindol-2-yl or l,2,3,4-tetrahydro-isoquinolin-2-yl;
J is -CH2CH2-; and
R8 and R9 together with the nitrogen atom to which they are both bonded form 2-methyl-. pyrrolidin-1-yl.
Some embodiments of the present invention pertain to compounds selected from compounds of Formula (Ig) and pharmaceutically acceptable salts, hydrates and solvates thereof:
wherein:
R1 is selected from the group consisting of H, Ci-C6 acyl and Ci-C8 alkyl optionally substituted with 1, 2, 3, 4 or 5 suhstituents selected independently from the group consisting of Ci-C6 alkoxy and hydroxy; R2 is selected from the group consisting of H, Ci-C8 alkyl, C3-C7 cycloalkyl, aryl, heterocyclyl, aryl-Ci-C4-alkylenyl, amino, heteroaryl-Ci-C4-alkylenyl, aryloxy-Ci-C4-alkylenyI and C|-Cβ acyl, and each R2 is optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting of C]-Q5 alkoxy, Ci-C8 alkyl, aryl, carbo-Q -Cβ-alkoxy, C3-C7 cycloalkyl, halogen, Q-C6 haloalkyl, hydroxyl, Ci-C6 acyl, Ci-C6 acyloxy, Ci-C6 haloalkoxy and heterocyclyl; wherein each Ci-C8 alkyl may be further substituted with hydroxy; or
R1 and R2 together with the nitrogen atom to which they are both bonded form a C3-C7 heterocyclyl or a C3-C]0 heterobicyclyl group each optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting Of C]-C6 acyl, C]-C8 alkyl, Cj-C8 alkylcarboxamide, C]-C6 acyloxy, carboxy and hydroxy; and wherein each C1-C8 alkyl and carboxy may be further substituted with CrC6 acyloxy, C]-C6 alkoxy, aryl-Ci-C4-alkylenyl or hydroxy;
J is -CH2CH2-; and
Rs and R9 together with the nitrogen atom to which they are both bonded form a C3-C7 heterocyclyl group optionally substituted with Ci-C8 alkyl.
Some embodiments of the present invention pertain to compounds selected from compounds of Formula (Ig) and pharmaceutically acceptable salts, hydrates and solvates thereof:
(Ig) wherein:
R1 is H, methyl, ethyl, 2-hydroxy-ethyl, 2-methoxy-ethyl or acetyl; R2 is selected from the group consisting of H, methyl, ethyl, n-propyl, isopropyl, t-butyl, 1-propyl-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, tetrahydropyran-4-yl, benzyl, pyridin-2-ylmethyl, 2-phenoxy-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, 2- isopropoxyethyl, cyclopropylmethyl, cyclohexylmethyl, 2-hydroxyethyl, 4-fluoro-phenyl, 4- methyl-benzyl, 4-methoxy-benzyl, 4-fmoro-benzyl, 4-chlord-benzyl, 4-trifluoromethyl-ben2yl, amino, 2-methoxy-l -methyl-ethyl, propionyloxyl, 3,5-dichlorobenzyl, acetyl, 3,4- dichlorobenzyl, 2-hydroxy-l -methyl -ethyl, 2-acetoxyethyl, 4-fluoro-phenyl-ethyl, tetrahydro- ρyran-4-ylmethyl, 2-propionyloxy-ethyl, diphenyl-methyl, 2-hydroxy-l, 1 -dimethyl -ethyl, isobutyl, 3 -phenyl-propyl, 2-oxo-imidazolidin-l-yl-ethyl, phenyl-ethyl, pyridin-4-yl-methyl, 3- methoxy-3-oxopropyl, pyridin-3-yl-methyl, l-methoxy-l-oxopropan-2-yl, 1- (hydroxymethyl)cyclopentyl, 4-(trifluoromethoxy)-benzyl, 2-methoxy-3-oxoethyl, 1- isopropoxy-l-oxopropaπ-2-yl, 2-isopropoxy-2-oxoethyl, 2-methyl-l-(propionyloxy)propan-2-yl, l-ter/-butoxy-l-oxopropan-2-yl and 2-tert-butoxy-2-oxoethyl; or
R1 and R2 together with the nitrogen atom to which they are both bonded form azetidin- 1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, l,l-dioxo-thiomorpholin-4-yl, 2,3-dihydro- lH-isoindol-2-yl, l,2,3,4-tetrahydro-isoquinolin-2-yl, 3-hydroxy-pyrrolidin-l-yl, 3- hydroxymethyl-piperidin-1-yl, aziridinl-yl, 2-methoxymethyl-pyrrolidin-l-yl, 3-hydroxy- piperidin-1-yl, 2-hydroxymethyl-pyrroIidin-l-yl, 4-(benzyloxycarbonyl)piperidin-l-yl, 4- (propionyloxy-methyl)-piperidin-l -yl, 2-(propionyloxy-methyl)-pyrrolidin- 1 -yl, 3- methoxymethyl-piperidin- 1 -yl, 4-hydroxymethyl-piperidin- 1 -yl, 4-(ethoxycarbonyl)piρeridin- 1 - yl, 4-(2-ethoxy-ethyl)piperidin-l-yl, 4-propionyl-piperazin-l-yl, 4-(ethoxy-methyl)-piperidin-l- yl, 3-methoxy-piperidin-l-yl, 4-(2-hydroxy-ethyl)-piperidin-l-yl, 2-hydroxymethyl-piperidin-l- yl, 3-methoxy-pyrrolidin-l-yl, 2-carboxy-pyrrolidin-l-yl, 6,7-dimethoxy-3,4- dihydroisoquinolin-2(lH)-yl, 4-methoxy-piperidin-l-yl, 3-oxo-piperazin-l-yl, 2- (methylcarbamoyl)ρyrrolidin-l-yl, 3,5-dimethyl-morpholin-4-yl, 3-propionyloxy-pyrrolidin-l - yl, 4-hydroxy-piperidin-l-yl, 4-carboxy-piperidin-l-yl, 4-hydroxy-2-(methoxycarbonyI)- pyrrolidin-1-yl, 4-(2-methoxy-ethyl)-piperidin-l-yl or 4-(methoxymethyl)-piperidin-l-yl; J is -CH2CH2-; and
Rs and R9 together with the nitrogen atom to which they are both bonded form pyrrolidin-1-yl or 2-methyl-pyrrolidin-l-yl. In some embodiments, where R1, R3, R4, Rs, R6, R7, R8, R10, R11 and R12 are all H and R9 is phenyl or benzyl then R2 is a moiety other than C]-Cs alkyl substituted with carbo-Ci-C6- alkoxy.
In some embodiments, where R1, R3, R4, R5, R6, R7, R8, R10, R11 and R12 are all H and R9 is phenyl or benzyl then R2 is a moiety other than Ci-C8 alkyl substituted with carboxy.
In some embodiments, where R1, R3, R4, Rs, R6, R7, R10, R11 andR12 are all H; and R2 is tert-butyl; and R8 is Ci-Cs alkyl substituted with carbo-C]-C6-alkoxy; then R9 is a moiety other than aryl substituted with cyano.
Some embodiments of the present invention include every combination of one or more compounds selected from the following group shown in TABLE A.
TABLE A
Cmpd
Chemical Structure Chemical Name No.
4'-[2-((Λ)-2-Methyl- pyrrolidm-l-yl)-ethyl]- biphenyl-4-sulfonic acid
(tetrahydro-pyran-4-yl)- amide
2- {4'-[2-(P)-2-Methyl- pyrrolidin-l -yl)-ethyl] - biphenyl-4-sul fonyl } -2,3 - dihy dro- 1 H-i soindole
4'-[2-((i?)-2-Methyl- pyrrolidin- 1 -yl)-ethyl] - biρhenyl-4-sulfonic acid
(pyridin-2-ylmethyl)-amide
4'-[2-((i?)-2-Methyl- pyrrolidin-l-yl)-ethyl]- biρhenyl-4-sulfonic acid 4- methyl-benzylamide
4'-[2-((7?)-2-Methyl- pyrrolidin- 1 -yl)-ethyl] - biphenyl-4-sulfonic acid (2- ethoxy-ethyl)-amide
Some embodiments of the present invention include every combination of one or more compounds selected from the following group shown in TABLE B.
TABLE B ■
-
-
} -
- -
-
Additionally, individual compounds and chemical genera of the present invention, for example those compounds found in TABLE A and TABLE B including diastereomers and enantiomers thereof, encompass all pharmaceutically acceptable salts, solvates, and particularly hydrates, thereof. The compounds of the Formula (Ia) of the present invention may be prepared according to relevant published literature procedures that are used by one skilled in the art. Exemplary reagents and procedures for these reactions appear hereinafter in the working Examples. Protection and deprotection may be carried out by procedures generally known in the art (see, for example, Greene, T. W. and Wuts, P. G. M., Protecting Groups in Organic Synthesis, 3rd Edition, 1999 [Wiley]; incorporated herein by reference in its entirety).
It is understood that the present invention embraces each diastereomer, each enantiomer and mixtures thereof of each compound and generic Formulae disclosed herein just as if they were each individually disclosed with the specific stereochemical designation for each chiral carbon. Separation of the individual isomers (such as by chiral HPLC, recrystallization of diastereomeric mixtures and the like) or selective synthesis (such as by enantiomeric selective syntheses and the like) of the individual isomers is accomplished by application of various methods which are well known to practitioners in the art. Representative examples are shown here in.
INDICATIONS AND METHODS OF PROPHYLAXIS AND/OR TREATMENT
Histamine [2-(imidazol-4-yl)ethylamine] exerts its physiological effects through four distinct G-protein coupled receptors (GPCRs), termed Hl3 H2, H3 and H4. The histamine H3- receptor was first identified in 1983, when it was determined that the H3-receptor acted as an autoreceptor controlling both the synthesis and release of histamine (see: Arrang et al. Nature 1983, 302, 832-7). At least four human and three rat splice variants have proven functional activity in pharmacological assays (Passani et al., Trends in Pharmacol. Sd.2004, 25, 618-625). Rat and human histamine H3-receptors also show constitutive activity which means that they can transduce a signal even in the absence of a ligand. Histamine H3-receptors also function as heteroceptors, modulating the release of a number of other transmitter substances including serotonin, acetylcholine, dopamine and noradrenaline (see: Brown et al. Prog. Neurobiol. 2001, 63, 637-672). Thus, there are a number of therapeutic applications for ligands which target the histamine H3-receptor, where the ligand functions as either an antagonist or inverse agonist (for reviews see: Leurs et al. Nat. Rev. Drug. Discov. 2005, 4, 107-120; Passani et a Trends Pharmacol. ScL 2004, 25, 618-625).
Accordingly, preclinical studies have identified a number of indications which are amenable to treatment with histamine H3-receptor antagonists and inverse agonists, such as compounds of the present invention. The compounds disclosed herein are believed to be useful in the treatment and/or prevention of several diseases and disorders, and in the amelioration of symptoms thereof. These compounds can be used alone or in combination with other compounds for the treatment and/or prevention of diseases and disorders. Without limitation, these diseases and disorders include the following. Histamine H3-receρtor antagonists have been shown to increase wakefulness (e.g. Lin J. S. et al. Brain Research 1990, 523, 325-330). This effect demonstrates that H3-receptor antagonists can be useful for disorders of sleep and wakefulness (Parmentier et al. JNeurosci. 2002, 22, 7695-7711; Ligneau et al. J. Pharmacol. Exp. Ther. 1998, 287, 658-666). For example, histamine H3-receptor antagonists and inverse agonists can be used to treat the somnolence syndrome associated with different pathological conditions, for example, sleep apnea and Parkinson's disease or circumstances associated with lifestyle, for example, daytime somnolence from sleep deprivation as a result of nocturnal jobs, overwork, or jet-lag (see Passani et al., Trends Pharmacol. ScL 2004, 25, 618-625). Somnolence is one of the major problems of public health because of its high prevalence (19-37% of the general population) and risk for causing work and traffic accidents.
Sleep apnea (alternatively sleep apnoea) is a common sleep disorder characterized by brief interruptions of breathing during sleep. These episodes, called apneas, last 10 seconds or more and occur repeatedly throughout the night. People with sleep apnea partially awaken as they struggle to breathe, but in the morning they may not be aware of the disturbances in their sleep. The most common type of sleep apnea is obstructive sleep apnea (OSA), caused by relaxation of soft tissue in the back of the throat that blocks the passage of air. Central sleep apnea (CSA) is caused by irregularities in the brain's normal signals to breathe. The hallmark symptom of the disorder is excessive daytime sleepiness. Additional symptoms of sleep apnea include restless sleep, loud snoring (with periods of silence followed by gasps), falling asleep during the day, morning headaches, trouble concentrating, irritability, forgetfulness, mood or behaviour changes, weight gain, increased heart rate, anxiety, and depression.
Few drug-based treatments of obstructive sleep apnea are known despite over two decades of research and tests. Oral administration of the methylxanthine theophylline (chemically similar to caffeine) can reduce the number of episodes of apnea, but can also produce side effects such as palpitations and insomnia. Theophylline is generally ineffective in adults with OSA, but is sometimes used to treat CSA, and infants and children with apnea. In 2003 and 2004, some neuroactive drugs, particularly modern-generation antidepressants including mirtazapine, have been reported to reduce incidences of obstructive sleep apnea. When other treatments do not completely treat the OSA, drugs are sometimes prescribed to treat a patient's daytime sleepiness or somnolence. These range from stimulants such as amphetamines to modern anti-narcoleptic medicines. The anti-narcoleptic modafinil is seeing increased use in this role as of 2004.
In addition, for example, histamine H3-receptor antagonists and inverse agonists can be used to treat narcolepsy (Tedford et al. Soc. Neurosci. Abstr. 1999, 25, 460.3). Narcolepsy is a neurological condition most characterized by Excessive Daytime Sleepiness (EDS), episodes of sleep and disorder of REM or rapid eye movement sleep. The main characteristic of narcolepsy is overwhelming Excessive Daytime Sleepiness (EDS), even after adequate nighttime sleep. A person with narcolepsy is likely to become drowsy or to fall asleep, often at inappropriate times and places. In addition, nighttime sleep may be fragmented with frequent wakenings. Classic symptoms of narcolepsy include, for example, cataplexy which is sudden episodes of loss of muscle function, ranging from slight weakness (such as limpness at the neck or knees, sagging facial muscles, or inability to speak clearly) to complete body collapse. Episodes may be triggered by sudden emotional reactions such as laughter, anger, surprise, or fear, and may last from a few seconds to several minutes. Another symptom of narcolepsy is sleep paralysis, which is the temporary inability to talk or move when waking up. Other symptoms include, for example, hypnagogic hallucinations which are vivid, often frightening, dream-like experiences that occur while dozing, falling asleep and/or while awakening, and automatic behaviour which occurs when a person continues to function (talking, putting things away, etc.) during sleep episodes, but awakens with no memory of performing such activities. Daytime sleepiness, sleep paralysis, and hypnagogic hallucinations also occur in people who do not have narcolepsy, such as in people who are suffering from extreme lack of sleep. Cataplexy is generally considered unique to narcolepsy.
Currently the treatments available for narcolepsy treat the symptoms, but not the underlying cause. For cataplexy and other REM-sleep symptoms, antidepressant medications and other drugs that suppress REM sleep are prescribed. The drowsiness is normally treated using stimulants such as methylphenidate (Ritalin), amphetamines (Adderall), dextroamphetamine (Dexedrine), methamphetamine (Desoxyn), modafinil (Provigil), etc. Other medications used are codeine and selegiline. The cataplexy is treated using clomipramine, imipramine, or protriptyline but this need only be done in severe cases. A new medication is gamma-hydroxybutyrate (GHB) (Xyrem), recently approved in the USA by the Food and Drug Administration. It is thought to be effective because it increases the quality of nocturnal sleep.
Interestingly, modafinil (Provigil) has recently been shown to increase hypothalamic histamine release (Ishizuka et al. Nenrosci. Lett. 2003, 339, 143-146).
In addition, recent studies using the classic Doberman model of narcolepsy with a non- imidazole histamine H3-receptor antagonist showed that a histamine H3-receptor antagonist can reduce the number of cataplectic attacks and the duration of the attacks (Carruthers Ann. Meet. Eur. Histamine Res. Soc. 2004, Abs. p31).
In summary, histamine H3-receptor antagonists and inverse agonists can be used for the treatment and/or prevention of conditions associated with excessive daytime sleepiness such as hypersomnia, narcolepsy, sleep apnea, time zone change disorder, and other disorders which are associated with excessive daytime sleepiness such as fibromyalgia, and multiple sclerosis
(Parmentier et al., J. NeuroscL 2002, 22, 7695-7711; Ligneau et al. J. Pharmacol. Exp. Ther. 1998, 287, 658-666). Other conditions include excessive sleepiness due to shift work, medical disorders, psychiatric disorders, narcolepsy, primary hypersomnia, and the like. Histamine H3- receptor antagonists and inverse agonists can also be used occasionally to promote wakefulness or vigilance in shift workers, sleep deprivation, post anesthesia grogginess, drowsiness as a side effect from a medication, military use and the like. In addition, wakefulness is a prerequisite for several brain functions including attention, learning, and memory and is required for appropriate behaviours in response to environmental challenges. Histamine H3 -receptor antagonists and inverse agonists have been shown to improve cognitive performance in various animal models (Hancock and Fox in Milestones in Drug Therapy, ed. Buccafusco, 2003). These compounds can be used as pro-cognitive agents and can increase vigilance. Therefore, histamine H3 -receptor antagonists and inverse agonists can be used in aging or degenerative disorders in which vigilance, attention and memory are impaired, for example, as in Alzheimer's disease or other dementias.
Alzheimer's disease (AD), a neurodegenerative disorder, is the most common cause of dementia. It is characterized clinically by progressive cognitive deterioration together with neuropsychiatric symptoms and behavioural changes. The most striking early symptom is memory loss, which usually manifests as minor forgetfulness that becomes steadily more pronounced with illness progression, with relative preservation of older memories. As the disorder progresses, cognitive (intellectual) impairment extends to the domains of language, skilled movements, recognition and functions closely related to the frontal and temporal lobes of the brain such as decision-making and planning. There is currently no cure for AD, although there are drugs which offer symptomatic benefit, specifically with respect to short-term memory impairment. These drugs include acetylcholinesterase inhibitors such as donepezil (Aricept), galantamine (Razadyne) and rivastigmine (Exelon) and NMDA antagonists such as memantine. Histamine H3-receptor antagonists and inverse agonists can be used to treat or prevent cognitive disorders (Passani et al. Trends Pharmacol. Sci. 2004, 25, 618-625), epilepsy (Vohora et al. Pharmacol. Biochem. Behav. 2001, 68, 735-741), depression (Perez-Garcia et al. Psychopharmacol. 1999, 142, 215-220), attention deficit hyperactivity disorder (ADHD), (Fox et al. Behav. Brain Res. 2002, 131, 151-61), and schizophrenia (Fox et al. J. Pharmacol. Exp. Ther. 2005, 313, 176-190). These indications are described briefly below. For additional information, see reviews by Leurs et al., in Leurs et al. Nat. Rev. Drug. Discov. 2005, 4, 107- 120, and Vohora Investigational Drugs 2004, 7, 667-673). Histamine H3-receptor antagonists or inverse agonists can also be used as a novel therapeutic approach to restore cortical activation in comatose or brain-traumatized patients (Passani et al., Trends in Pharmacol. Sci. 2004, 25, 618-625). As stated above, histamine H3-receptor antagonists and inverse agonists can be used to treat or prevent epilepsy. Epilepsy (often referred to as a seizure disorder) is a chronic neurological condition characterized by recurrent unprovoked seizures. In terms of their pattern of activity, seizures may be described as either partial (focal) or generalized. Partial seizures only involve a localized part of the brain, whereas generalized seizures involve the entire cortex. There are many different epilepsy syndromes, each presenting with its own unique combination of seizure type, typical age of onset, EEG findings, treatment, and prognosis. Some common seizure syndromes include, for example, infantile spasms (West syndrome), childhood absence epilepsy, and benign focal epilepsy of childhood (Benign Rolandic epilepsy), juvenile myoclonic epilepsy, temporal lobe epilepsy, frontal lobe epilepsy and Lennox-Gastaut syndrome.
Compounds of the present invention can be used in combination with various known drugs. For example, compounds of the present invention can be used with one or more drugs that prevent seizures or reduce seizure frequency: these include carbamazepine (common brand name Tegretol), clobazam (Frisium), clonazepam (Klonopin), ethosuximide (Zarontin), felbamate (Felbatol), fosphenytoin (Cerebyx), flurazepam (Dalmane), gabapentin (Neurontin), lamotrigine (Lamictal), levetiracetam (Keppra), oxcarbazepine (Trileptal), mephenytoin (Mesantoin), phenobarbital (Luminal), phenytoin (Dilantin), pregabalin (Lyrica), primidone (Mysoline), sodium valproate (Epilim), tiagabine (Gabitril), topiramate (Topamax), valproate semisodium (Depakote), valproic acid (Depakene, Convulex), and vigabatrin (Sabril). Other drugs are commonly used to abort an active seizure or interrupt a seizure flurry; these include diazepam (Valium) and lorazepam (Ativan). Drugs used only in the treatment of refractory status epilepticus include paraldehyde (Paral) and pentobarbital (Nembutal).
As stated above, a histamine H3-receptor antagonist or inverse agonist can be used the sole agent of treatment or can be used in combination with other agents. For example, Vohora et al. show that a histamine H3-receptor antagonist can work as an anti-epilepsy, anti-seizure drug and also showed effect with sub-effective doses of the H3 -receptor antagonist in combination with sub-effective doses of known anti-epileptic drugs (Vohora et al. Pharmacol. Biochem. Behav. 2001, 68, 735-741).
Perez-Garcia et al. (Perez-Garcia et al. Psychopharmacol. 1999, 142, 215-220) tested the ability of a histamine H3 -receptor agonist and antagonist on experimental mouse models of anxiety (elevated plus-maze) and depression (forced swimming test). They found that while the compounds did not have a significant effect on the model of anxiety, a H3-receptor antagonist did have a significant dose-dependent effect in the model of depression. Thus, histamine H3- receptor antagonists or inverse agonists can have antidepressant effects.
Clinical depression is a state of sadness or melancholia that has advanced to the point of being disruptive to an individual's social functioning and/or activities of daily living. Clinical depression affects about 16% of the population on at least one occasion in their lives. Clinical depression is currently the leading cause of disability in the U.S. as well as other countries, and is expected to become the second leading cause of disability worldwide (after heart disease) by the year 2020, according to the World Health Organization.
Compounds of the present invention can be used in combination with various known drugs. For example, compounds of the present invention can be used with one or more of the drugs currently available that can relieve the symptoms of depression. They include, for example, monoamine oxidase inhibitors (MAOIs) such as Nardil or Moclobemide (Manerix), tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (Prozac), paroxetine (Paxil), escitalopram (Lexapro), and sertraline (Zoloft), norepinephrine reuptake inhibitors such as reboxetine (Edronax), and serotonin-norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine (Effexor) and duloxetine (Cymbal ta)
As stated above, histamine H3 -receptor antagonists and inverse agonists can be used to treat or prevent attention deficit hyperactivity disorder (ADHD). According to the Diagnostic and Statistical Manual of Mental Disorders-IV-TR, ADHD is a developmental disorder that arises in childhood, in most cases before the age of 7 years, is characterized by developmentally inappropriate levels of inattention and/or hyperactive-impulsive behavior, and results in impairment in one or more major life activities, such as family, peer, educational, occupational, social, or adaptive functioning. ADHD can also be diagnosed in adulthood.
The first-line medications used to treat ADHD are mostly stimulants, which work by stimulating the areas of the brain responsible for focus, attention, and impulse control. The use of stimulants to treat a syndrome often characterized by hyperactivity is sometimes referred to as a paradoxical effect, but there is no real paradox in that stimulants activate brain inhibitory and self-organizing mechanisms permitting the individual to have greater self-regulation. The stimulants used include, for example, methylphenidate (sold as Ritalin, Ritalin SR and Ritalin LA), Metadate, Metadate ER, Metadate CD, Concerta, Focalin, Focalin XR or Methylin. The stimulants also include, for example, amphetamines such dextroamphetamine , sold as
Dexedrine, Dexedrine Spansules, Adderall, and Adderall XR, a trade name for a mixture of dextroamphetamine and laevoamphetamine salts, methamphetamine sold as Desoxyn, bupropion, a dopamine and norepinephrine reuptake inhibitor, marketed under the brand name Wellbutrin. A non-stimulant medication to treat ADHD is Atomoxetine (sold as Strattera) a norepinephrine reuptake inhibitor. Other drugs sometimes used for ADHD include, for example, benzphetamine, Provigil/Alertec/modafϊnil and clonidine. Recently it has been reported that in a rat pup model for ADHD, a histamine H3-receptor antagonist was at least as effective as methylphenidate (Ritalin) (Hancock and Fox in Milestones in Drug Therapy, ed. Buccafusco, 2003). Compounds of the present invention can be used in combination with various known drugs. For example, compounds of the present invention can be used with one or more of the drugs used to treat ADHD and related disorders. As stated above, histamine H3 -receptor antagonists and inverse agonists can be used to treat or prevent schizophrenia. Schizophrenia is a psychiatric diagnosis that describes a mental disorder characterized by impairments in the perception or expression of reality and by significant social or occupational dysfunction. A person experiencing untreated schizophrenia is typically characterized as demonstrating disorganized thinking, and as experiencing delusions or auditory hallucinations. Although the disorder is primarily thought to affect cognition, it can also contribute to chronic problems with behavior and emotion. Schizophrenia is often described in terms of "positive" and "negative" symptoms. Positive symptoms include delusions, auditory hallucinations and thought disorder, and are typically regarded as manifestations of psychosis. Negative symptoms are so named because they are considered to be the loss or absence of normal traits or abilities, and include features such as flat, blunted or constricted affect and emotion, poverty of speech and lack of motivation. Some models of schizophrenia include formal thought disorder and planning difficulties in a third group, a "disorganization syndrome." The first line pharmacological therapy for schizophrenia is usually the use of antipsychotic medication. Antipsychotic drugs are only thought to provide symptomatic relief from the positive symptoms of psychosis. The newer atypical antipsychotic medications (such as clozapine, risperidone, olanzapine, quetiapine, ziprasidone and aripiprazole) are usually preferred over older typical antipsychotic medications (such as chlorpromazine and haloperidol) due to their favorable side-effect profile. While the atypical antipsychotics are associated with less extra pyramidal side-effects and tardive dyskinesia than the conventional antipsychotics, some of the agents in this class (especially olanzapine and clozapine) appear to be associated with metabolic side effects such as weight gain, hyperglycemia and hypertriglyceridemia that must be considered when choosing appropriate pharmacotherapy. Histamine H3-receptor antagonists or inverse agonists can be used to treat obesity
(Hancock, Curr. Opin. Investig. Drugs 2003, 4, 1190-1197). The role of neuronal histamine in food intake has been established for many years and neuronal histamine release and/or signalling has been implicated in the anorectic actions of known mediators in the feeding cycle such as leptin, amylin and bombesin. In the brain, the H3-receptor is implicated in the regulation of histamine release in the hypothalamus. Moreover, in situ hybridization studies have revealed histamine H3-receptor mRNA expression in rat brown adipose tissue, indicating a role in the regulation of thermogenesis (Karlstedt et ah, MoI. Cell. Neurosci. 2003, 24, 614- 622). Furthermore, histamine H3-receptor antagonists have been investigated in various preclinical models of obesity and have shown to be effective in reducing food intake, reducing weight, and decreasing total body fat in mice (Hancock, et a Eur. J. Pharmacol. 2004, 487,
183-197). The most common drugs used for the treatment of obesity are sibutramine (Meridia) and orlistat (Xenical), both of which have limited effectiveness and significant side effects. Therefore, novel anti-obesity agents, such as histamine H3 -receptor antagonists or inverse agonists, are needed.
Histamine H3 -receptor antagonists or inverse agonists can also be used to treat upper airway allergic responses (U.S. Pat. Nos. 5,217,986; 5,352,707 and 5,869,479) including allergic rhinitis and nasal congestion. Allergic rhinitis is a frequently occurring chronic disease that affects a large number of people. Recent analysis of histamine H3-receptor expression in the periphery by quantitative PCR revealed that H3-receptor mRNA is abundantly expressed in human nasal mucosa (Varty et al. Eur. J. Pharmacol. 2004, 484, 83-89). In addition, in a cat model of nasal decongestion, a combination of histamine H3-receptor antagonists with the Hl receptor antagonist chlorpheniramine resulted in significant nasal decongestion without the hypertensive effect seen with adrenergic agonists. (McLeod et al. Am. J. Rhinol. 1999, 13, 391- 399). Thus, histamine H3-receptor antagonists or inverse agonists can be used alone or in combination with Hl receptor blockage for the treatment of allergic rhinitis and nasal congestion. Histamine H3-receptor antagonists or inverse agonists have therapeutic potential for the treatment of pain (Medhurst et al. Biochemical Pharmacology (2007), 73(8), 1182-1194).
PHARMACEUTICAL COMPOSITIONS
A further aspect of the present invention pertains to pharmaceutical compositions comprising one or more compounds as described herein and one or more pharmaceutically acceptable carriers. Some embodiments pertain to pharmaceutical compositions comprising a compound of the present invention and a pharmaceutically acceptable carrier.
Some embodiments of the present invention include a method of producing a pharmaceutical composition comprising admixing at least one compound according to any of the compound embodiments disclosed herein and a pharmaceutically acceptable carrier.
Formulations may be prepared by any suitable method, typically by uniformly mixing the active compound(s) with liquids or finely divided solid carriers, or both, in the required proportions, and then, if necessary, forming the resulting mixture into a desired shape.
Conventional excipients, such as binding agents, fillers, acceptable wetting agents, tabletting lubricants, and disintegrants may be used in tablets and capsules for oral administration. Liquid preparations for oral administration may be in the form of solutions, emulsions, aqueous or oily suspensions, and syrups. Alternatively, the oral preparations may be in the form of dry powder that can be reconstituted with water or another suitable liquid vehicle before use. Additional additives such as suspending or emulsifying agents, non-aqueous vehicles (including edible oils), preservatives, and flavorings and colorants may be added to the liquid preparations. Parenteral dosage forms may be prepared by dissolving the compound of the invention in a suitable liquid vehicle and filter sterilizing the solution before filling and sealing an appropriate vial or ampule: These are just a few examples of the many appropriate methods well known in the art for preparing dosage forms.
A compound of the present invention can be formulated into pharmaceutical compositions using techniques well known to those in the art. Suitable pharmaceutically- acceptable carriers, outside those mentioned herein, are known in the art; for example, see
Remington, The Science and Practice of Pharmacy, 20th Edition, 2000, Lippincott Williams & Wilkins, (Editors: Gennaro et al.).
While it is possible that, for use in the prophylaxis or treatment, a compound of the invention may, in an alternative use, be administered as a raw or pure chemical, it is preferable however to present the compound or active ingredient as a pharmaceutical formulation or composition further comprising a pharmaceutically acceptable carrier.
The invention thus further provides pharmaceutical formulations comprising a compound of the invention or a pharmaceutically acceptable salt or derivative thereof together with one or more pharmaceutically acceptable carriers thereof and/or prophylactic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not overly deleterious to the recipient thereof.
Pharmaceutical formulations include those suitable for oral, rectal, nasal, topical (including buccal and sub-lingual), vaginal or parenteral (including intramuscular, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation, insufflation or by a transdermal patch. Transdermal patches dispense a drug at a controlled rate by presenting the drug for absorption in an efficient manner with a minimum of degradation of the drug. Typically, transdermal patches comprise an impermeable backing layer, a single pressure sensitive adhesive and a removable protective layer with a release liner. One of ordinary skill in the art will understand and appreciate the techniques appropriate for manufacturing a desired efficacious transdermal patch based upon the needs of the artisan. The compounds of the invention, together with a conventional adjuvant, carrier, or diluent, may thus be placed into the form of pharmaceutical formulations and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, gels or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use. Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units are capsules, tablets, powders, granules or a suspension, with conventional additives such as lactose, mannitol, corn starch or potato starch; with binders such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins; with disintegrators such as corn starch, potato starch or sodium carboxymethyl-cellulose; and with lubricants such as talc or magnesium stearate. The active ingredient may also be administered by injection as a composition wherein, for example, saline, dextrose or water may be used as a suitable pharmaceutically acceptable carrier.
Compounds of the present invention or a solvate or physiologically functional derivative thereof can be used as active ingredients in pharmaceutical compositions, specifically as histamine H3-receptor modulators. By the term "active ingredient" is defined in the context of a "pharmaceutical composition" and is intended to mean a component of a pharmaceutical composition that provides the primary pharmacological effect, as opposed to an "inactive ingredient" which would generally be recognized as providing no pharmaceutical benefit. The dose when using the compounds of the present invention can vary within wide limits, and as is customary and is known to the physician, it is to be tailored to the individual conditions in each individual case. It depends, for example, on the nature and severity of the illness to be treated, on the condition of the patient, on the compound employed or on whether an acute or chronic disease state is treated or prophylaxis is conducted or on whether further active compounds are administered in addition to the compounds of the present invention. Representative doses of the present invention include, but not limited to, about 0.001 mg to about 5000 mg, about 0.001 mg to about 2500 mg, about 0.001 mg to about 1000 mg, 0.001 mg to about 500 mg, 0.001 mg to about 250 mg, about 0.001 mg to 100 mg, about 0.001 mg to about 50 mg, and about 0.001 mg to about 25 mg. Multiple doses may be administered during the day, especially when relatively large amounts are deemed to be needed, for example 2, 3 or 4, doses. Depending on the individual and as deemed appropriate from the patient's physician or care-giver it may be necessary to deviate upward or downward from the doses described herein.
The amount of active ingredient, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will ultimately be at the discretion of the attendant physician or clinician. In general, one skilled in the art understands how to extrapolate in vivo data obtained in a model system, typically an animal model, to another, such as a human. In some circumstances, these extrapolations may merely be based on the weight of the animal model in comparison to another, such as a mammal, preferably a human, however, more often, these extrapolations are not simply based on weights, but rather incorporate a variety of factors. Representative factors include the type, age, weight, sex, diet and medical condition of the patient, the severity of the disease, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetic and toxicology profiles of the particular compound employed, whether a drug delivery system is utilized, on whether an acute or chronic disease state is being treated or prophylaxis is conducted or on whether further active compounds are administered in addition to the compounds of the present invention and as part of a drug combination. The dosage regimen for treating a disease condition with the compounds and/or compositions of this invention is selected in accordance with a variety factors as cited above. Thus, the actual dosage regimen employed may vary widely and therefore may deviate from a preferred dosage regimen and one skilled in the art will recognize that dosage and dosage regimen outside these typical ranges can be tested and, where appropriate, may be used in the methods of this invention.
The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations. The daily dose can be divided, especially when relatively large amounts are administered as deemed appropriate, into several, for example 2, 3 or 4, part administrations. If appropriate, depending on individual behavior, it may be necessary to deviate upward or downward from the daily dose indicated.
The compounds of the present invention can be administrated in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise, as the active component, either a compound of the invention or a pharmaceutically acceptable salt of a compound of the invention.
For preparing pharmaceutical compositions from the compounds of the present invention, the selection of a suitable pharmaceutically acceptable carrier can be either solid, liquid or a mixture of both. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances, which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active component.
In tablets, the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted to the desire shape and size.
The powders and tablets may contain varying percentage amounts of the active compound. A representative amount in a powder or tablet may contain from 0.5 to about 90 percent of the active compound; however, an artisan would know when amounts outside of this range are necessary. Suitable carriers for powders and tablets are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.
For preparing suppositories, a low melting wax, such as an admixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogenous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions. For example, parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. Ih addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compounds according to the present invention may thus be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-fϊlled syringes, small volume infusion or in multi-dose containers with an added preservative. The pharmaceutical compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-firee water, before use. Aqueous formulations suitable for oral use can be prepared by dissolving or suspending the active component in water and adding suitable colorants, flavors, stabilizing and thickening agents, as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents.
Also included are solid form preparations, which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
For topical administration to the epidermis the compounds according to the invention may be formulated as ointments, creams or lotions, or as a transdermal patch.
Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Formulations suitable for topical administration in the mouth include lozenges comprising active agent in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray. The formulations may be provided in single or multi-dose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomizing spray pump. Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurized pack with a suitable propellant. If the compounds of the present invention or pharmaceutical compositions comprising them are administered as aerosols, for example as nasal aerosols or by inhalation, this can be carried out, for example, using a spray, a nebulizer, a pump nebulizer, an inhalation apparatus, a metered inhaler or a dry powder inhaler. Pharmaceutical forms for administration of the compounds of the present invention as an aerosol can be prepared by processes well- known to the person skilled in the art. For their preparation, for example, solutions or dispersions of the compounds of the present invention in water, water/alcohol mixtures or suitable saline solutions can be employed using customary additives, for example benzyl alcohol or other suitable preservatives, absorption enhancers for increasing the bioavailability, solubilizers, dispersants and others, and, if appropriate, customary propellants, for example include carbon dioxide, CFCs, such as, dichlorodifiuoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane; and the like. The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug may be controlled by provision of a metered valve.
In formulations intended for administration to the respiratory tract, including intranasal formulations, the compound will generally have a small particle size for example of the order of 10 microns or less. Such a particle size may be obtained by means known in the art, for example by micronization. When desired, formulations adapted to give sustained release of the active ingredient may be employed.
Alternatively the active ingredients may be provided in the form of a dry powder, for example, a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
Conveniently the powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form for example in capsules or cartridges of, e.g., gelatin, or blister packs from which the powder may be administered by means of an inhaler.
The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form. Tablets or capsules for oral administration and liquids for intravenous administration are preferred compositions.
The compounds according to the invention may optionally exist as pharmaceutically acceptable salts including pharmaceutically acceptable acid addition salts prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids. Representative acids include, but are not limited to, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, oxalic, p-toluenesulfonic and the like, such as those pharmaceutically acceptable salts listed in Journal of Pharmaceutical Sciences, 66:1-19 (1977); incorporated herein by reference in its entirety.
The acid addition salts may be obtained as the direct products of compound synthesis. In the alternative, the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent. The compounds of this invention may form solvates with standard low molecular weight solvents using methods known to the skilled artisan, such as those described in Polymorphism in Pharmaceutical solids, edited by Harry G. Brittain, Marcel Dekker, New York, 1999, which is incorporated herein by reference in its entirety.
Compounds of the present invention can be converted to "pro-drugs." The term "prodrugs" refers to compounds that have been modified with specific chemical groups known in the art and when administered into an individual these groups undergo biotransformation to give the parent compound. Pro-drugs can thus be viewed as compounds of the invention containing one or more specialized non-toxic protective groups used in a transient manner to alter or to eliminate a property of the compound. In one general aspect, the "pro-drug" approach is utilized to facilitate oral absorption. A thorough discussion is provided in T. Higuchi and V. Stella, Pro- drugs as Novel Delivery Systems Vol. 14 of the A.C.S. Symposium Series; and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are hereby incorporated by reference in their entirety.
Some embodiments of the present invention include a method of producing a pharmaceutical composition for "combination-therapy" comprising admixing at least one compound according to any of the compound embodiments disclosed herein, together with at least one known pharmaceutical agent as described herein and a pharmaceutically acceptable carrier.
It is noted that when the histamine H3-receptor modulators are utilized as active ingredients in a pharmaceutical composition, these are not intended for use only in humans, but in other non-human mammals as well. Indeed, recent advances in the area of animal health-care mandate that consideration be given for the use of active agents, such as histamine H3 -receptor modulators, for the treatment of an H3-receptor associated disease or disorder in domestic animals (e.g., cats and dogs) and in other domestic animals (e.g., cows, chickens, fish, etc.). Those of ordinary skill in the art are readily credited with understanding the utility of such compounds in such settings.
OTHER UTILITIES
Another object of the present invention relates to radio-labeled compounds of the present invention that would be useful not only in radio-imaging but also in assays, both in vitro and in vivo, for localizing and quantitating the histamine H3-receptor in tissue samples, including human, and for identifying histamine H3-receptor ligands by inhibition binding of a radio-labeled compound. It is a farther object of this invention to develop novel H3-receptor assays of which comprise such radio-labeled compounds.
The present invention embraces isotopically-labeled compounds of the present invention. An "isotopically" or "radio-labeled" compounds are those that are identical to compounds disclosed herein, but for the fact that one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature. Suitable radionuclides that may be incorporated in compounds of the present invention include but are not limited to 2H (also written as D for deuterium), 3H (also written as T for tritium), 11C, 13C, 14C, 13N, 15N, 15O5 170, 180, 18F, 35S, 36Cl, 82Br, 7SBr, 76Br, 77Br, 123I, 1241, 125I and 131I. The radionuclide that is incorporated in the instant radio-labeled compounds will depend on the specific application of that radio-labeled compound. For example, for in vitro histamine H3 -receptor labeling and competition assays, compounds that incorporate 3H, 14C, 82Br, 1251, 131I or 35S will generally be most useful. For radio-imaging applications 11C, 18F, 1251, 1231, 1241, 131I, 75Br, 76Br or 77Br will generally be most useful. It is understood that a "radio-labeled " or "labeled compound" is a compound of
Formula (Ia) that has incorporated at least one radionuclide; in some embodiments the radionuclide is selected from the group consisting of 3H, 14C, 1251 , 35S and 82Br.
Certain isotopically-labeled compounds of the present invention are useful in compound and/or substrate tissue distribution assays. In some embodiments the radionuclide 3H and/or 14C isotopes are useful in these studies. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the Drawings and Examples infra, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. Other synthetic methods that are useful are discussed infra. Moreover, it should be understood that all of the atoms represented in the compounds of the invention can be either the most commonly occurring isotope of such atoms or the more scarce radio-isotope or nonradioactive isotope. Synthetic methods for incorporating radio-isotopes into organic compounds are applicable to compounds of the invention and are well known in the art. These synthetic methods, for example, incorporating activity levels of tritium into target molecules, are as follows:
A. Catalytic Reduction with Tritium Gas - This procedure normally yields high specific activity products and requires halogenated or unsaturated precursors.
B. Reduction with Sodium Borohydride [3H] - This procedure is rather inexpensive and requires precursors containing reducible functional groups such as aldehydes, ketones, lactones, esters, and the like.
C. Reduction with Lithium Aluminum Hydride [3H] - This procedure offers products at almost theoretical specific activities. It also requires precursors containing reducible functional groups such as aldehydes, ketones, lactones, esters, and the like. D. Tritium Gas Exposure Labeling - This procedure involves exposing precursors containing exchangeable protons to tritium gas in the presence of a suitable catalyst.
E. N-Methylation using Methyl Iodide [3H] - This procedure is usually employed to prepare O-methyl or N-methyl (3H) products by treating appropriate precursors with high specific activity methyl iodide (3H). This method in general allows for higher specific activity, such as for example, about 70-90 Ci/mmol.
Synthetic methods for incorporating activity levels of 125I into target molecules include:
A. Sandmeyer and like reactions — This procedure transforms an aryl or heteroaryl amine into a diazonium salt, such as a tetrafluoroborate salt, and subsequently to 12SI labeled compound using Na125I. A represented procedure was reported by Zhu, G-D. and co-workers in J. Org. Chem., 2002, 67, 943-948.
B. Ortho 125Iodination of phenols — This procedure allows for the incorporation of 125I at the ortho position of a phenol as reported by Collier, T. L. and co-workers in J. Labelled Compd. Radiopharm., 1999, 42, S264-S266. C. Aryl and heteroaryl bromide exchange with 125I - This method is generally a two step process. The first step is the conversion of the aryl or heteroaryl bromide to the corresponding tri-alkyltin intermediate using for example, a Pd catalyzed reaction [i.e. Pd(Ph3P)4] or through an aryl or heteroaryl lithium, in the presence of a tri-alkyltinhalide or hexaalkylditin [e.g., (CH3)3SnSn(CH3)3]. A representative procedure was reported by Le Bas, M.-D. and co-workers in J. Labelled Compd. Radiopharm. 2001, 44, S280-S282.
A radiolabeled histamine H3 -receptor compound of Formula (Ia) can be used in a screening assay to identify/evaluate compounds. In general terms, a newly synthesized or identified compound (i.e., test compound) can be evaluated for its ability to reduce binding of the "radio-labeled compound of Formula (Ia)" to the H3-receptor. Accordingly, the ability of a test compound to compete with the "radio-labeled compound of Formula (Ia)" for the binding to the histamine H3 -receptor directly correlates to its binding affinity.
The labeled compounds of the present invention bind to the histamine H3-receptor. In one embodiment the labeled compound has an IC50 less than about 500 μM, in another embodiment the labeled compound has an ICs0 less than about 100 μM, in yet another embodiment the labeled compound has an ICs0 less than about 10 μM, in yet another embodiment the labeled compound has an IC50 less than about 1 μM, and in still yet another embodiment the labeled inhibitor has an IC50 less than about 0.1 μM.
Other uses of the disclosed receptors and methods will become apparent to those in the art based upon, inter alia, a review of this disclosure. As will be recognized, the steps of the methods of the present invention need not be performed any particular number of times or in any particular sequence. Additional objects, advantages, and novel features of this invention will become apparent to those skilled in the art upon examination of the following examples thereof, which are intended to be illustrative and not intended to be limiting.
EXAMPLES EXAMPLE 1 : Syntheses of compounds of the present invention.
Illustrated syntheses for compounds of the present invention are shown in Figures 1 through 5 where the symbols have the same definitions as used throughout this disclosure.
The compounds of the invention and their synthesis are further illustrated by the following examples. The following examples are provided to further define the invention without, however, limiting the invention to the particulars of these examples. The compounds described herein, supra and infra, are named according to the CS ChemDraw Ultra Version 7.0.1, AutoNom version 2.2, or ChemDraw Ultra version 9.0.3. In certain instances common names are used and it is understood that these common names would be recognized by those skilled in the art. Chemistry: Proton nuclear magnetic resonance (1H NMR) spectra were recorded on a
Varian Mercury Vx-400 equipped with a 4 nucleus auto switchable probe and z-gradient or a Bruker Avance-400 equipped with a QNP (Quad Nucleus Probe) or a BBI (Broad Band Inverse) and z-gradient. Chemical shifts are given in parts per million (ppm) with the residual solvent signal used as reference. NMR abbreviations are used as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. Microwave irradiations were carried out using a Smith Synthesizer™ or an Emrys Optimizer™ (Personal Chemistry). Thin-layer chromatography (TLC) was performed on silica gel 60 F2s4 (Merck), preparatory thin-layer chromatography (prep TLC) was preformed on PK6F silica gel 60 A 1 mm plates (Whatman), and column chromatography was carried out on a silica gel column using Kieselgel 60, 0.063- • 0.200 mm (Merck). Evaporation was done under reduced pressure on a Bϋchi rotary evaporator. Celite 545 ® was used during palladium filtrations.
LCMS specs: 1) PC: HPLC-pumps: LC-IOAD VP, Shimadzu Inc.; HPLC system controller: SCL-IOA VP, Shimadzu Lie; UV-Detector: SPD-IOA VP, Shimadzu Lie; Autosampler: CTC HTS, PAL, Leap Scientific; Mass spectrometer: API 150EX with Turbo Ion Spray source, AB/MDS Sciex; Software: Analyst 1.2. 2) Mac: HPLC-pumps: LC-8A VP,
Shimadzu Jhc; HPLC system controller: SCL-IOA VP, Shimadzu Inc. UV-Detector: SPD-IOA VP, Shimadzu Inc; Autosampler: 215 Liquid Handler, Gilson Inc; Mass spectrometer: API 150EX with Turbo Ion Spray source, AB/MDS Sciex Software: MassChrom 1.5.2.
Example 1.1: Preparation of Intermediate (Λ)-4-(2-(2-Methy]pyrrolidin-l- yl)ethyl)phenylboronic Acid. Step A: Preparation of Intermediate 4-Bromophenethyl Methanesulfonate.
4-Bromophenethyl alcohol (38.9 g, 193 mmol) was dissolved in DCM (193 mL). Triethylamine (40.4 mL, 290 mmol) was added and the mixture was cooled in an ice bath. Methanesulfonyl chloride (18 mL, 232 mmol) was added dropwise via an addition funnel. The ice bath was removed and the mixture was stirred for 30 min. The reaction mixture was diluted with 200 mL DCM, washed with 1 M HCl twice (100 mL each), followed by brine, saturated sodium bicarbonate, and brine. The organic phase was dried with sodium sulfate and filtered. Solvent was removed under reduced pressure to give the title compound (54.0 g) in quantitative yield. 1H NMR (400 MHz, CDCl3) δ 2.89 (s, 3 H), 3.02 (t, 7= 6.82 Hz, 2 H), 4.40 (t, J= 6.82 Hz, 2 H), 7.03 - 7.17 (m, 2 H), 7.43 - 7.47 (m, 2 H).
Step B: Preparation of Intermediate (JR)-l-(4-Bromophenethyl)-2- methylpyrrolidine.
4-Bromophenethyl methanesulfonate (12.2 g, 43.8 mmol) was dissolved in acetonitrile (88 mL). Sodium carbonate (6.04 g, 57.0 mmol) was added, followed by (R)-(-)-2- methylpyrrolidine (Advanced Asymmetries, Millstadt, IL; catalog no. 67085; [α] -15.8 °) (4.48 g, 52.6 mmol). The reaction mixture was warmed to 80 0C and stirred overnight. The sodium carbonate was filtered and solvent was removed under reduced pressure. The crude residue was re-suspended in ethyl acetate (~200 mL), extracted with 1 M HCl (75 mL). The ethyl acetate was extracted an additional three times with 1 M HCl (30 mL each). The HCl layers were combined and made pH~10 by addition of sodium carbonate. The basic aqueous layer was extracted with.DCM (100 mL). 1 mL of 50% sodium hydroxide was added to the aqueous layer, which was then extracted three times with DCM (50 mL each). DCM layers were combined, dried with sodium sulfate and filtered. Solvent was removed under reduced pressure to give a yellow oil (10.2 g, 87% crude yield). The crude oil was further purified by silica column chromatography eluting with ethyl acetate followed by 0-10% methanol in ethyl acetate to give the title compound (8.85 g, 75%) as a pale yellow oil; 98% ee (by chiral HPLC; column: 25 cm Chiral Tech AD-H, analytical; eluent: 1% isopropanol in hexanes, isocratic; flow Rate: 0.5 mL/min; wavelength: 220 nM). Exact mass calculated for C13H]8BrN: 267.1, Found: LCMS m/z = 268.0 (M+H+); 1H NMR (400 MHz, Methanol-^) δ 1.15 (d, /= 6.06 Hz, 3 H), 1.37 - 1.53 (m, 1 H), 1.73 - 1.86 (m, 2 H), 1.94 - 2.07 (m, 1 H), 2.21 - 2.35 (m, 2 H), 2.35 - 2.48 (m, 1 H), 2.68 - 2.91 (m, 2 H), 2.98 - 3.11 (m, 1 H), 3.18 - 3.29 (m, 1 H), 7.14 - 7.20 (m, 2 H), 7.38 - 7.48 (m, 2 H).
Step C: Preparation of Intermediate (Λ)-4-(2-(2-MethylpyrroIidin-l- yl)ethyl)phenylboronic Acid. (i?)-l-(4-Bromophenethyl)-2 -methylpyrrolidine (2.16 g, 8.04 mmol) was dissolved in
THF (20 mL) under argon. The reaction mixture was cooled to -78 0C and n-butyllithium (1.6 M in hexanes, 6.53 mL, 10.4 mmol) was added slowly. After 1.5 h of stirring, trusopropylborate (7.42 mL, 32.1 mmol) was added. The reaction was kept at -78 0C for 2 h. It was allowed to warm to room temperature and stirred for 1.5 h. The cloudy reaction mixture was quenched with 1 M HCl (40 mL). THF was removed under reduced pressure. The remaining aqueous solution was made basic (pH~8) with 50% sodium hydroxide and extracted twice with ethyl acetate (50 mL each), plus three times with DCM (50 mL each). The combined organic phases were dried with magnesium sulfate, filtered, and concentrated to give 1.70 g of a yellow foam. The foam was triturated with diethyl ether (20 mL) twice, and dried under high vacuum to give the title compound (1.19 g, 64% yield) as a pale yellow solid. Exact mass calculated for C13H20BNO2: 233.1 , Found: LCMS mlz = 234.2 (IVH-H+); 1H NMR (400 MHz, Methanol-^) δ 1.25 (d, J= 6.32 Hz, 3 H), 1.49 - 1.61 (m, 1 H), 1.80 - 1.97 (m, 2 H), 2.04 - 2.18 (m, 1 H), 2.61 - 2.74 (m, 2 H), 2.76 - 2.98 (m, 3 H), 3.19 - 3.45 (m, 2 H), 7.16 (d, 2 H)3 7.48 - 7.62 (m, 2 H).
Example 1.2: Preparation of 4'-[2-((Λ)-2-Methyl-pyrrolidiii-l-yl)-ethyl]-biphenyl-4- sulfonic Acid Cyclopentylamide (Compound 32).
Step A: Preparation of Intermediate 4-Bromo-iV-cyclopentylbenzenesulfonamide.
4-Bromobenzene-l-sulfonyl chloride (1.00 g, 3.91 mmol) was dissolved in THF (16 mL). DIPEA (1.34 mL, 7.66 mmol) was added followed by cyclopentanamine (0.454 mL, 4.60 mmol). The reaction mixture was allowed to stir overnight. The reaction mixture was diluted with ethyl acetate (100 mL), and washed first with 1 M HCl (20 mL once, 10 mL once), and then brine (10 mL). The organic phase was dried with sodium sulfate and the solvent was removed under reduced pressure to give the title compound (quantitative yield) as a white solid. Exact mass calculated for CnHi4BrNO2S: 303.0, Found: LCMS mlz = 304.1 (M+H* 78Br, 100), 306.2 (M-HH+ 80Br, 97); 1HNMR (400 MHz, DMSO-^6) δ 1.21 - 1.44 (m, 4 H), 1.47 - 1.65 (m, 4 H), 3.35 - 3.45 (m, 1 H), 7.70 - 7.79 (m, 3 H), 7.79 - 7.84 (m, 2 H).
Step B: Preparation of 4'-[2-((JR)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonic Acid Cyclopentylamide (Compound 32).
To a microwave synthesizer vial was added 4-bromo-N-cyclopentylbenzenesulfonarnide (196 mg, 0.64 mmol), (i?)-4-(2-(2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (150 mg, 0.64 mmol), and Pd(PPh3)4 (19.3 mg, 0.019 mmol). To this mixture was added benzene (3.0 mL), EtOH (1.0 mL) and sodium carbonate (2 M, 0.64 mL, 1.29 mmol). The resulting reaction mixture was heated in the microwave synthesizer at 100 0C for 60 min. The resulting yellow organic phase was separated and the clear aqueous layer was extracted with ethyl acetate (2 x 5 mL). The organic phases were combined, dried over magnesium sulfate, and filtered. The solvent was removed under reduced pressure. The resulting crude residue was dissolved in a mixture of acetonitrile and acetic acid and purified by preparative HPLC (0.1% TFA in acetonitrile/0.1% TFA in water). The product containing fractions from HPLC were combined and the acetonitrile was removed under reduced pressure. The resulting aqueous solution was made basic (pH~10) with 2 M sodium carbonate solution and extracted with ethyl acetate (50 mL). The solution was then saturated with sodium chloride and extracted with ethyl acetate (2 x 25 mL). The ethyl acetate extracts were combined, dried over magnesium sulfate, and filtered. I M HCl in diethyl ether (1.5 eq.) was added to the filtrate and solvent was removed under reduced pressure to give the HCl salt of the title compound (0.245 g, 85% yield) as a white solid. Exact mass calculated for C24H32N2O2S: 412.6, Found: LCMS mlz = 413.7 (M+HT); 1H NMR (400 MHz, Methanol-**,) δ 1.33 - 1.46 (m, 2.3 H), 1.48 - 1.54 (m, 4.7 H), 1.60 - 1.84 (m, 5 H)5 2.04 - 2.24 (m, 2 H), 2.32 - 2.44 (m, 1 H), 3.08 - 3.25 (m, 2 H), 3.26 - 3.33 (m, 2 H), 3.51 - 3.61 (m, 2 H), 3.63 - 3.72 (m, 1 H), 3.74 - 3.84 (m, 1 H), 7.49 (d, J= 8.34 Hz, 2 H), 7.70 - 7.74 (m, 2 H), 7.80 - 7.85 (m, 2 H), 7.91 - 7.97 (m, 3 H).
Example 1.3: Preparation of 4'-[2-((jR)-2-Methyl-pyrrolidin-l-yl)-ethylJ-biphenyl-4- sulfonic Acid Cyclopropylmethyl-amide (Compound 31). The title compound was prepared in a similar manner as described in Example 1.2, using 4-bromo-Λr-(cyclopropylmethyl)benzenesulfonamide (125 mg, 0.43 mmol), and (Λ)-4-(2- (2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (100 mg, 0.43 mmol), to give 159 mg of the HCl salt in 85% yield. Exact mass calculated for C23H30N2O2S: 398.2, Found: LCMS mlz = 399.4 (M+BT); 1H NMR (400 MHz, Methanol-^) δ -0.05 - 0.05 (m, 2 H), 0.29 - 0.36 (m, 2 H), 0.70 - 0.82 (m, 1 H), 1.23 (d, J= 6.82 Hz5 0.3 H), 1.39 (d, J= 6.32 Hz, 2.7 H), 1.60 - 1.74 (m, 1 H), 1.93 - 2.11 (m, 2 H), 2.18 - 2.33 (m, 1 H), 2.67 (d, J= 6.82 Hz, 2 H)5 2.96 - 3.12 (m, 2 H), 3.14 - 3.19 (m, 2 H), 3.41 - 3.49 (m, 1 H), 3.49 - 3.60 (m, 1 H), 3.62 - 3.72 (m, 1 H), 7.36 (d, J= 8.34 Hz5 2 H), 7.59 (d, J= 8.34 Hz, 2 H), 7.67 - 7.72 (m, 2 H)5 7.79 - 7.83 (m, 3 H).
Example 1.4: Preparation of 4'-[2-((Λ)-2-Methyl-pyrroIidin-l-yl)-ethyl]-biphenyl-4- sulfonic Acid Phenylamide (Compound 30).
The title compound was prepared in a similar manner as described in Example 1.2, using 4-bromo-N-phenylbenzenesulfonamide (135 mg, 0.43 mmol), and (/?)-4-(2-(2- methylpyrrolidin-l-yl)ethyl)phenylboronic acid (100 mg, 0.43 mmol), to give 179 mg of the HCl salt in 90% yield. Exact mass calculated for C25H28N2O2S: 420.2, Found: LCMS mlz = 421.3 (M+H4"); 1H NMR (400 MHz, Methanol-ό,) δ 1.34 (d, J= 6.82 Hz, 0.3 H), 1.50 (d, J= 6.32 Hz, 2.7 H), 1.72 - 1.83 (m, 1 H), 2.04 - 2.24 (m, 2 H), 2.31 - 2.44 (m, 1 H), 3.04 - 3.22 (m, 2 H), 3.24 - 3.31 (m, 2 H), 3.49 - 3.59 (m, 1 H)5 3.61 - 3.69 (m, 1 H)5 3.73 - 3.81 (m, 1 H), 7.04 - 7.10 (m, 1 H), 7.12 - 7.16 (m, 2 H), 7.20 - 7.27 (m, 2 H)5 7.45 (d, J= 8.34 Hz, 2 H), 7.65 (d, J= 8.34 Hz5 2 H)5 7.71 - 7.75 (m, 2 H), 7.80 - 7.85 (m, 2 H), 7.92 (s, 1 H). Example 1.5: Preparation of 4'-[2-((i.)-2-Methyl-pyrrolidiii-l-yl)-ethyl]-biphenyl-4- sulfonic Acid Benzylamide (Compound 29).
The title compound was prepared in a similar manner as described in Example 1.2, using N-benzyl-4-bromobenzenesulfonamide (142 mg, 0.43 mmol), and (R)-4-(2-(2- methylpyrrolidin-l-yl)ethyl)phenylboronic acid (100 mg, 0.43 mmol), to give 152 mg of the HCl salt in 74% yield. Exact mass calculated for C26H30N2O2S: 434.2, Found: LCMS mlz = 435.4 01+H+); 1H NMR (400 MHz, Methanol-^) δ 1.35 (d, J= 6.82 Hz, 0.3 H), 1.51 (d, J = 6.57 Hz, 2.7 H), 1.73 - 1.85 (m, 1 H), 2.06 - 2.25 (m, 2 H), 2.33 - 2.43 (m, 1 H), 3.08 - 3.25 (m, 2 H), 3.26 - 3.32 (m, 2 H), 3.51 - 3.61 (m, 1 H), 3.62 - 3.73 (m, 1 H), 3.75 - 3.82 (m, 1 H), 4.11 (s, 2 H), 7.19 - 7.27 (m, 5 H), 7.49 (d, J= 8.34 Hz, 2 H), 7.69 (d, J= 8.34 Hz, 2 H), 7.75 - 7.80 (m, 2 H), 7.87 - 7.93 (m, 3 H).
Example 1.6: Preparation of 4'-[2-((i.)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonic Acid Cyclohexylmethyl-amide (Compound 28). The title compound was prepared in a similar manner as described in Example 1.2, using 4-bromo-iV-(cyclohexylmethyl)benzenesulfonamide (152 mg, 0.43 mmol), and (i?)-4-(2- (2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (100 mg, 0.43 mmol), to give 169 mg of the HCl salt in 77% yield. Exact mass calculated for C26H36N2O2S: 440.3, Found: LCMS mlz = 441.3 OVB-H+); 1H NMR (400 MHz, Methanol-^) δ 0.84 - 0.95 (m, 2 H), 1.15 - 1.25 (m, 3 H), 1.35 (d, J = 6.82 Hz, 0.3 H), 1.37 - 1.46 (rn, 1 H), 1.51 (d, J= 6.57 Hz, 2.7 H), 1.61 - 1.84 (m,- 6 H), 2.05 - 2.23 (m, 2 H), 2.30 - 2.45 (m, 1 H), 2.71 (d, J= 6.82 Hz, 2 H), 3.10 - 3.23 (m, 2 H), 3.25 - 3.31 (m, 2 H), 3.53 - 3.60 (m, 1 H), 3.62 - 3.72 (m, 1 H), 3.74 - 3.83 (m, 1 H), 7.49 (d, J= 8.34 Hz, 2 H), 7.71 (d, J= 8.34 Hz, 2 H), 7.80 - 7.85 (m, 2 H), 7.89 - 7.94 (m, 3 H).
Example 1.7: Preparation of 4'-[2-((-R)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonic Acid (l-Propyl-butyl)-amide (Compound 27).
The title compound was prepared in a similar manner as described in Example 1.2, using 4-bromo-N-(heptan-4-yl)benzenesulfonamide (146 mg, 0.43 mmol), and (Λ)-4-(2-(2- methylpyrrolidin-l-yl)ethyl)phenylboronic acid (100 mg, 0.43 mmol), to give 142 mg of the HCl salt in 68% yield. Exact mass calculated for C26H38N2O2S: 442.3, Found: LCMS mlz =
443.3 01+H+); 1H NMR (400 MHz, Methanol-^) δ 0.75 (t, J= 7.20 Hz, 6 H), 1.12 - 1.40 (m, 8 H), 1.32 (d, J= 6.82 Hz, 0.3 H), 1.48 (d, J= 6.57 Hz, 2.7 H), 1.70 - 1.81 (m, 1 H), 2.02 - 2.20 (m, 2 H), 2.29 - 2.40 (m, 1 H), 3.06 - 3.22 (m, 3 H), 3.23 - 3.29 (m, 1 H), 3.50 - 3.58 (m, 1 H), 3.60 - 3.69 (m, 1 H), 3.71 - 3.79 (m, 1 H), 7.46 (d, J= 8.34 Hz, 2 H)5 7.68 (d, J= 8.08 Hz, 2 H), 7.79 (d, J = 8.59 Hz, 2 H), 7.88 - 7.93 (m, 3 H). Example 1.8: Preparation of 4'-[2-((Λ)-2-Methyl-pyrrolidin-l-yI)-ethyl]-biphenyl-4- sultonic Acid (2-Hydroxy-ethyl)-amϊde (Compound 25).
The title compound was prepared in a similar manner as described in Example 1.2, using 4-bromo-//-(2-hydroxyethyl)benzenesulfonamide (129 mg, 0.43 mmol), and (i?)-4-(2-(2- methylpyrrolidin-l-yl)ethyl)phenylboronic acid (100 mg, 0.43 mmol), to give 119 mg of the HCl salt in 61% yield. Exact mass calculated for C2IH28N2O3S: 388.2, Found: LCMS mlz = 389.4 (M+H4); 1H NMR (400 MHz, Methanol--*,) δ 1.35 (d, J = 6.82 Hz, 0.3 H)5 1.51 (d, J= 6.57 Hz, 2.7 H), 1.73 - 1.85 (m, 1 H)5 2.03 - 2.22 (m, 2 H), 2.33 - 2.43 (m, 1 H), 3.01 (t, J= 5.94 Hz, 2 H)5 3.09 - 3.24 (m, 2 H), 3.26 - 3.31 (m, 2 H), 3.53 - 3.61 (m, 3 H), 3.62 - 3.72 (m, 1 H), 3.73 - 3.84 (m, 1 H), 7.49 (d, J= 8.08 Hz, 2 H), 7.71 (d, J= 8.08 Hz, 2 H), 7.83 (d, J= 8.59 Hz, 2 H), 7.92 - 7.97 (m, 2 H).
Example 1.9: Preparation of 4'-[2-((i?)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonic Acid 4-ChIoro-benzylamide (Compound 24). The title compound was prepared in a similar manner as described in Example 1.2, using iV-(4-chloroben2yl)-4-bromobenzenesulfonamide (155 mg, 0.43 mmol), and (fl)-4-(2-(2- methylpyrrolidin-l-yl)ethyl)phenylboronic acid (100 mg, 0.43 mmol), to give 168 mg of the HCl salt in 78% yield. Exact mass calculated for C26H29ClN2O2S: 468.2, Found: LCMS mlz = 469.6 (M-HH+ 35Cl, 100), 471.5 (M+H* 37Cl, 37); 1H NMR (400 MHz, Methanol-^) δ 1.35 (d, J = 6.82 Hz, 0.3 H), 1.51 (d, J= 6.57 Hz, 2.7 H), 1.73 - 1.85 (m, 1 H), 2.03 - 2.25 (m, 2 H), 2.32.- 2.44 (m, 1 H), 3.07 - 3.25 (m, 2 H), 3.26 - 3.33 (m, 2 H), 3.52 - 3.61 (m, 1 H), 3.62 - 3.72 (m, 1 H), 3.75 - 3.83 (m, 1 H), 4.11 (s, 2 H), 7.22 (d, J= 1.52 Hz, 4 H), 7.49 (d, J= 8.34 Hz, 2 H), 7.69 (d, J= 8.34 Hz, 2 H), 7.75 (d, J= 8.59 Hz, 2 H), 7.84 - 7.88 (m, 2 H).
Example 1.10: Preparation of 4'-[2-((if)-2-Metliyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonic Acid 4-Fluoro-benzylamide (Compound 23).
The title compound was prepared in a similar manner as described in Example 1.2, using Λ'-(4-fluorobenzyl)-4-bromobenzenesulfonamide (151 mg, 0.43 mmol), and (/?)-4-(2-(2- methylpyrrolidin-l-yl)ethyl)phenylboronic acid (100 mg, 0.43 mmol), to give 156 mg of the HCl salt in 73% yield. Exact mass calculated for C26H29FN2O2S: 452.2, Found: LCMS mlz = 453.3 (M+H4); 1H NMR (400 MHz, Methanol-^) δ 1.35 (d, J= 6.82 Hz, 0.3 H), 1.51 (d, J= 6.57 Hz, 2.7 H), 1.73 - 1.86 (m, 1 H), 2.03 - 2.26 (m, 2 H), 2.32 - 2.44 (m, 1 H), 3.08 - 3.24 (m, 2 H), 3.26 - 3.32 (m, 2 H), 3.53 - 3.60 (m, 1 H), 3.63 - 3.71 (m, 1 H), 3.75 - 3.84 (m, 1 H), 4.08 - 4.12 (m, 2 H), 6.93 - 7.00 (m, 2 H), 7.21 - 7.28 (m, 2 H)5 7.49 (d, J= 8.34 Hz, 2 H), 7.69 (d, J= 8.08 Hz, 2 H), 7.74 - 7.79 (m, 2 H), 7.85 - 7.90 (m, 2 H). Example 1.11: Preparation of 4'-[2-((2-)-2-Methyl-pyrroUdin-l-yl)-ethyl]-biphenyl-4- sulfonic Acid (4-FIuoro-phenyl)-amide (Compound 22).
The title compoiand was prepared in a similar manner as described in Example 1.2, using 4-bromo-N-(4-fluorophenyl)benzenesulfonamide (139 mg, 0.43 mmol), and (β)-4-(2-(2- methylpyrrolidin-l-yl)ethyl)phenylboronic acid (100 mg, 0.43 mmol), to give 163 mg of the HCl salt in 78% yield. Exact mass calculated for C25H27FN2O2S: 438.2, Found: LCMS mlz = 439.4 (MB-H+); 1H KIMR (400 MHz, Methanol-^) δ 1.34 (d, J= 6.82 Hz, 0.3 H), 1.50 (d, J= 6.57 Hz, 2.7 H), 1.72 - 1.85 (m, 1 H), 2.02 - 2.25 (m, 2 H), 2.32 - 2.43 (m, 1 H), 3.06 - 3.23 (m, 2 H), 3.24 - 3.32 (m, 2 H), 3.51 - 3.70 (m, 2 H), 3.72 - 3.83 (m, 1 H), 6.95 - 7.03 (m, 2 H), 7.09 - 7.16 (m, 2 H), 7.46 (d, J= 8.34 Hz, 2 H), 7.66 (d, J= 8.34 Hz, 2 H), 7.72 - 7.82 (m, 4 H).
Example 1.12: Preparation of 4'-[2-((l?)-2-Methyl-pyrroIidin-l-yl)-ethyl]-biphenyl-4- sulfonic Acid 4-Trifluoromethyl-benzylamide (Compound 14).
The title compound was prepared in a similar manner as described in Example 1.2, usmgN-(4-(trifluoromethyl)benzyl)-4-bromobenzenesulfonamide (172 mg, 0.43 mmol), and (i?)-4-(2-(2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (100 mg, 0.43 mmol), to give 160 mg of the HCl salt in 68% yield. Exact mass calculated for C27H29F3N2O2S: 505.2, Found: LCMS mlz = 503.3 (M+lT); 1H NMR (400 MHz, Methanol-^) δ 1.34 (d, J= 6.82 Hz, 0.3 H),
1.50 (d, J= 5.81 Hz, 2.7 H), 1.74 - 1.87 (m, 1 H), 2.08 - 2.22 (m, 2 H), 2.35 (d, J= 7.33 Hz, 1 H), 3.08 - 3.24 (m, 2 H), 3.27 - 3.32 (m, 2 H), 3.51 - 3.85 (m, 3 H), 4.22 (s, 2 H), 7.44 (m, 2 H),
7.48 (m, 2 H)5 7.51 - 7.56 (m, 2 H), 7.68 (m, 2 H), 7.75 (d, J= 8.59 Hz, 2 H), 7.85 - 7.89 (m, 2 H).
Example 1.13: Preparation of 4'-[2-((R)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonic Acid Benzyl-ethyl-amide (Compound 13).
The title compound was prepared in a similar manner as described in Example 1.2, using N-benzyl-4-bromo-Λ'-ethylbenzenesulfonamide (155 mg, 0.43 mmol), and (R)-4-(2-(2- methylpyrrolidin-l-yl)ethyl)phenylboronic acid (100 mg, 0.43 mmol), to give 160 mg of the HCl salt in 73% yield. Exact mass calculated for C28H34N2O2S: 462.2, Found: LCMS mlz = 463.4 QVH-H+); 1H NMR (400 MHz, Methanol-^) δ 0.95 (t, 3 H), 1.35 (d, J= 6.82 Hz, 0.3 H),
1.51 (d, /= 6.57 Hz, 2.7 H), 1.72 - 1.85 (m, 1 H), 2.03 - 2.23 (m, 2 H), 2.32 - 2.44 (m, 1 H), 3.04 - 3.32 (m, 6 H), 3.53 - 3.62 (m, 1 H), 3.62 - 3.73 (m, 1 H), 3.74 - 3.84 (m, 1 H), 4.41 (s, 1 H)5 7.27 - 7.39 (m, 5 H), 7.50 (d, J= 8.34 Hz, 2 H), 7.73 (d, J= 8.08 Hz, 2 H), 7.86 (d, 2 H), 7.95 (d, 2 H).
Example 1.14: Preparation of 4'-I2-((fi)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyI-4- sulfonic Acid (2-Isopropoxy-ethyl)-amide (Compound 7). The title compound was prepared in a similar manner as described in Example 1.2, using 4-bromo-N-(2-isopropoxyethyl)benzenesulfonamide (144 mg, 0.43 mmol), and (R)-4-(2- (2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (100 mg, 0.43 mmol), to give 113 mg of the HCl salt in 54% yield. Exact mass calculated for C24H34N2O3S: 430.2, Found: LCMS mlz = 431.5 (M-HH+); 1H NMR (400 MHz, Methanol-**,) δ 0.94 - 1.02 (m, 6 H), 1.24 (d, J = 7.07 Hz, 0.3 H), 1.40 (d, J= 6.32 Hz, 2.7 H), 1.62 - 1.73 (m, 2 H), 1.92 - 2.15 (m, 2 H), 2.21 - 2.33 (m, 1 H), 2.96 (t, J= 5.68 Hz, 2 H), 2.99 - 3.13 (m, 2 H), 3.15 - 3.21 (m, 1 H), 3.33 (t, J = 5.81 Hz, 2 H), 3.36 - 3.50 (m, 2 H), 3.51 - 3.62 (m, 1 H), 3.63 - 3.73 (m, 1 H), 7.38 (d, J= 8.34 Hz, 2 H), 7.60 (d, J= 8.34 Hz, 2 H), 7.69 - 7.74 (m, 2 H)3 7.81 - 7.86 (m, 2 H).
Example 1.15: Preparation of 4'-[2-((/?)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonic Acid (Pyridin-2-ylmethyl)-amide (Compound 3).
The title compound was prepared in a similar manner as described in Example 1.2, using 4-bromo-N-(pyridin-2-ylmethyl)benzenesulfonamide (150 mg, 0.43 mmol), and (Λ)-4-(2- (2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (100 mg, 0.43 mmol), to give 128 mg of the HCl salt in 59% yield. Exact mass calculated for C25H29N3O2S: 435.2, Found: LCMS mlz = 436.5 (M+H4); 1H NMR (400 MHz, Methanol-^) δ 1.35 (d, J= 6.82 Hz, 0.3 H), 1.53 (t, J= 7.07 Hz, 2.7 H), 1.74 - 1.86 (m, 1 H), 2.03 - 2.27 (m, 2 H), 2.31 - 2.45 (m, 1 H), 3.09 - 3.25 (m, 2 H), 3.27 - 3.33 (m, 2 H), 3.53 - 3.74 (m, 2 H), 3.74 - 3.86 (m, 1 H), 4.51 - 4.56 (m, 2 H), 7.52 (d, J= 8.08 Hz, 2 H), 7.73 (d, J= 8.08 Hz, 2 H), 7.89 (d, J= 8.59 Hz, 2 H), 7.96 - 8.05 (m, 3 H), 8.11 (d, J= 8.08 Hz, 1 H), 8.58 - 8.64 (m, 1 H), 8.80 (d, J= 5.81 Hz, 1 H).
Example 1.16: Preparation of 2-{4'-[2-((Λ)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- suIfonyI}-2,3-dihydro-lflr-isoindole (Compound 2). The title compound was prepared in a similar manner as described in Example 1.2, using 2-(4-bromophenylsulfonyl)isoindoline (148 mg, 0.43 mmol), and (i?)-4-(2-(2- methylpyrrolidin-l-yl)ethyl)phenylboronic acid (100 mg, 0.43 mmol), to give 143 mg of the HCl salt in 68% yield. Exact mass calculated for C27H30N2O2S: 446.2, Found: LCMS mlz = 447.3 (M+H÷); 1H NMR (400 MHz, Methanol-^) δ 1.33 (d, J= 6.82 Hz, 0.3 H), 1.50 (d, J= 6.57 Hz, 2.7 H), 1.71 - 1.84 (m, 1 H), 2.02 - 2.23 (m, 2 H), 2.31 - 2.43 (m, 1 H), 3.06 - 3.22 (m, 2 H), 3.24 - 3.32 (m, 2 H), 3.50 - 3.60 (m, 1 H), 3.59 - 3.71 (m, 1 H), 3.72 - 3.82 (m, 1 H)3 4.62 - 4.68 (m, 4 H), 7.23 (m, 4 H), 7.46 (d, J= 8.08 Hz, 2 H), 7.68 (d, J= 8.08 Hz, 2 H), 7.84 (d, J= 8.59 Hz, 2 H), 7.97 (d, J= 8.34 Hz, 2 H).
Example 1.17: Preparation of 4'-[2-((i?)-2-Methyl-pyrrolidin-l-yl)-ethyI]-biphenyl-4- sulfonic Acid (Tetrahydro-pyran-4-yl>amide (Compound 1). The title compound was prepared in a similar manner as described in Example 1.2, using 4-bromo-N-(tetrahydro-2H-pyran-4-yl)benzenesulfonamide (144 mg, 0.43 mmol), and (i2)-4-(2-(2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (100 mg, 0.43 mmol), to give 51 mg of the HCl salt in 24% yield. Exact mass calculated for C24H32N2O3S: 428.2, Found: LCMS mlz = 429.4 (M^-H+); 1H NMR (400 MHz, Methanol-^) δ 0.90 - 1.02 (m, 1 H), 1.15 - 1.25 (m, 1 H), 1.35 (d, J= 6.82 Hz, 0.3 H), 1.50 (t, J= 6.82 Hz, 2.7 H), 1.64 - 1.73 (m, 2 H), 1.73 - 1.86 (m, 1 H), 2.05 - 2.25 (m, 2 H), 2.31 - 2.44 (m, 1 H), 3.07 - 3.25 (m, 2 H), 3.26 - 3.41 (m, 4 H), 3.51 - 3.90 (m, 6 H), 7.49 (d, J= 8.08 Hz, 2 H), 7.72 (d, J= 8.08 Hz, 2 H), 7.83 (d, J= 8.59 Hz, 2 H), 7.96 (d, J= 8.34 Hz, 2 H).
Example 1.18: Preparation of 2-{4t-[2-((Λ)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonyl}-l,2,3,4-tetrahydro-isoquinoline (Compound 12).
The title compound was prepared in a similar manner as described in Example 1.2, using 2-(4- brornophenylsulfonyl)-l,2,3,4-tetrahydroisoquinoline (157 mg, 0.43 mmol), and (i?)-4-(2-(2- methylpyrrolidin-l-yl)ethyl)phenylboronic acid (100 mg, 0.43 mmol), to give 185 mg of the HCl salt in 83% yield. Exact mass calculated for C28H32N2O2S: 460.2, Found: LCMS mlz = 461.5 01+H+); 1H NMR (400 MHz, Methanol-^) δ 1.34 (d, J= 6.82 Hz, 0.3 H), 1.50 (d, J= 6.57 Hz, 2.7 H), 1.73 - 1.85 (m, 1 H), 2.04 - 2.23 (m, 2 H), 2.31 - 2.42 (m, 1 H), 2.92 (t, J= 5.81 Hz, 3 H), 3.07 - 3.23 (m, 2 H), 3.25 - 3.32 (m, 1 H), 3.41 (t, J= 6.06 Hz, 2 H), 3.50 - 3.60 (m, 1 H), 3.61 - 3.71 (m, 1 H), 3.73 - 3.84 (m, 1 H), 4.29 (s, 2 H), 7.07 - 7.18 (m, 4 H), 7.48 (d, J= 8.34 Hz, 2 H), 7.70 (d, J= 8.34 Hz, 2 H), 7.83 - 7.88 (m, 2 H), 7.91 - 7.96 (m, 2 H).
Example 1.19: Preparation of 4'-[2-((Λ)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-3-sulfonic Acid Dimethylamide (Compound 42). To a microwave synthesizer vial was added (i?)-l-(4-bromophenethyl)-2- methylpyrrolidine (50.0 mg, 0.186 mmol), 3-(ΛζN-dimethylsulfamoyl)phenylboronic acid (64.0 mg, 0.280 mmol), aq. Na2CO3 (0.186 mL, 0.373 mmol, 2 M solution), and Pd(PPh3)4 (6.00 mg, 0.006 mmol) in a mixture of EtOH (0.25 mL) and benzene (0.75 mL). The resulting reaction mixture was heated in a microwave synthesizer at 100 0C for 30 min. The reaction mixture was concentrated, dissolved in DMSO, filtered, and purified by HPLC (0.1 % TFA in acetonitrile/0.1% TFA in water) to yield the title compound (32.0 mg, 0.062 mmol, 33% yield) as a clear solid (TFA salt). Exact mass calculated for C2iH28N2O2S: 372.2, Found: LCMS mlz = 373.1 04+H+); 1H NMR (400 MHz, Methanol-^) δ 1.33 (d, J= 6.82 Hz, 0.3 H), 1.48 (d, J= 6.57 Hz, 2.7 H), 1.70 - 1.82 (m, 1 H), 2.01 - 2.19 (m, 2 H), 2.30 - 2.40 (m, 1 H), 2.70 - 2.74 (m, 6 H), 3.02 - 3.20 (m, 2 H), 3.20 - 3.30 (m, 2 H), 3.50 - 3.60 (m, 1 H), 3.61 - 3.70 (m, 1 H), 3.73 - 3.85 (m, 1 H), 7.4037 - 7.53 (m, 2 H), 7.61 - 7.83 (m, 4 H), 7.90 - 8.02 (m, 2 H). Example 1.20: Preparation of 4'-[2-((l?)-2-Methyl-pyrroUdin-l-yl)-ethyl]-biphenyl-3- sulfonic Acid Diethylamide (Compound 41).
The title compound was prepared in a similar manner as described in Example 1.19, using (i?)-l-(4-bromophenethyl)-2-methylpyrrolidine (50.0 mg, 0.186 mmol), and 3-(N,N- diethylsulfamoyl)phenylboronic acid (71.9 mg, 0.280 mmol) as starting materials, to give a clear solid (TFA salt) in 9% yield. Exact mass calculated for C23H32N2O2S: 400.2, Found: LCMS mlz = 401.1 (MH-H+); 1H NMR (400 MHz, Methanol-^) δ 1.05 - 1.20 (m, 6 H), 1.33 (d, J= 6.57 Hz, 0.3 H), 1.43 - 1.53 (m, 2.7 H), 1.67 - 1.84 (m, 1 H), 2.00 - 2.26 (m, 2 H), 2.30 - 2.43 (m, 1 H),. 3.01 - 3.30 (m, 8 H), 3.47 - 3.60 (m, 1 H), 3.60 - 3.71 (m, 1 H), 3.71 - 3.84 (m, 1 H), 7.45 - 7.53 (m, 2 H), 7.61 - 7.71 (m, 3 H), 7.76 - 7.94 (m, 2 H), 7.99 (s, 1 H).
Example 1.21: Preparation of 4'-[2-((jR)-2-Methyl-pyrroKdiπ-l-yl)-ethyl]-biphenyl-4- sulfonic Acid Ethylamide (Compound 37).
The title compound was prepared in a similar manner as described in Example 1.19, using (i?)-l-(4-bromophenethyl)-2-methylpyrrolidine (50.0 mg, 0.186 mmol), and 4-(N- ethylsulfamoyl)phenylboronic acid (64.1 mg, 0.280 mmol) as starting materials, to give a clear solid (TFA salt) in 42% yield. Exact mass calculated for C2iH2gΝ2O2S: 372.2, Found: LCMS mlz = 373.2 (M+H4); 1H NMR (400 MHz, Methanol-^) δ 1.08 (t, J= 7.20 Hz, 3 H), 1.33 (d, J= 6.82 Hz, 0.3 H), 1.48 (d, J= 6.57 Hz, 2.7 H), 1.70 - 1.83 (m, 1 H), 2.00 - 2.25 (m, 2 H), 2.30 - 2.42 (m, 1 H), 2.93 (q, J= 7.16 Hz, 2 H), 3.06 - 3.30 (m, 4 H), 3.48 - 3.59 (m, 1 H), 3.59 - 3.69 (m, 1 H), 3.70 - 3.81 (m, 1 H), 7.42 - 7.51 (m, 2 H), 7.67 - 7.73 (m, 2 H), 7.78 - 7.84 (m, 2 H), 7.88 - 7.94 (m, 2 H).
Example 1.22: Preparation of 4'-[2-((i?)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonic Acid Cyclopropylamide (Compound 36).
The title compound was prepared in a similar manner as described in Example 1.19, using (/ϋ)-l-(4-bromophenethyl)-2-methylpjττolidine (50.0 mg, 0.186 mmol), and 4-(N- cyclopropylsulfamoyl)phenylboronic acid (67.4 mg, 0.280 mmol) as starting materials, to give a clear solid (TFA salt) in 7% yield. Exact mass calculated for C22H28N2O2S: 384.2, Found: LCMS mlz = 385.2 OVH-H+); 1H NMR (400 MHz, Methanol-ώ,) δ 0.45 - 0.61 (m, 4 H)3 1.33 (d, J= 6.82 Hz3 0.3 H), 1.48 (d, J= 6.57 Hz, 2.7 H), 1.68 - 1.81 (m, 1 H), 2.01 - 2.25 (m, 3 H), 2.30 - 2.41 (m, 1 H), 3.01 - 3.22 (m, 2 H), 3.22 - 3.30 (m, 2 H), 3.45 - 3.59 (m, 1 H), 3.59 - 3.71 (m3 1 H), 3.71 - 3.82 (m, 1 H), 7.46 (d, J= 8.08 Hz, 2 H), 7.71 (d, J - 8.08 Hz, 2 H)3 7.79 - 7.87 (m, 2 H), 7.94 (d, /- 8.34 Hz, 2 H).
Example 1.23: Preparation of 4'-[2-((i?)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonic Acid Amide (Compound 35). To a microwave synthesizer vial was added (i?)-l-(4-bromophenethyl)-2- methylpyrrolidine (200 mg, 0.746 mmol), 4-sulfamoylphenylboronic acid (195 mg, 0.969 mmol), aq. Na2CO3 (0.746 mL, 1.49 mmol, 2 M solution), and Pd(PPh3)4 (21.5 mg, 0.019 mmol) in a mixture of EtOH (0.75 mL) and benzene (2.25 mL). The resulting reaction mixture was heated in a microwave synthesizer at 100 0C for 30 min. The reaction mixture was concentrated, dissolved in DMSO, filtered, and purified by HPLC (0.1% TFA in acetonitrile/0.1% TFA in water). The combined fractions were basified with 1 N NaOH and extracted 3 times with EtOAc. The combined organics were dried over MgSO4, filtered, and concentrated. To the resulting residue was added 2 mL MeOH and 0.30 mL of 1 M HCl in Et2O. The resulting mixture was concentrated to yield the title compound (108 mg, 0.284 mmol, • 38% yield) as a white solid (HCl salt). Exact mass calculated for Ci9H24N2O2S: 344.2, Found: LCMS m/z = 345.3 (M+H+); 1H NMR (400 MHz, Methanol-^) δ 1.48 (d, J= 5.81 Hz, 3 H), 1.73 - 1.86 (m, 1 H), 2.00 - 2.22 (m, 2 H), 2.30 - 2.40 (m, 1 H), 3.04 - 3.22 (m, 2 H), 3.22 - 3.30 (m, 2 H), 3.47 - 3.70 (m, 2 H), 3.70 - 3.82 (m, 1 H), 7.46 (d, J= 8.34 Hz, 2 H), 7.65 - 7.71 (m, 2 H), 7.74 - 7.83 (m, 2 H), 7.90 - 8.02 (m, 2 H).
Example 1.24: Preparation of 4'-[2-((/.)-2-Metliyl-pyrrolidin-l-yl)-ethyI]-biphenyl-3-sulfonic Acid Ethylamide (Compound 40).
The title compound was prepared in a similar manner as described in Example 1.19, using (R)- 1 -(4-bromophenethyl)-2-methylpyrrolidine (50.0 mg, 0.186 mmol), and 3-(N- ethylsulfamoyl)phenylboronic acid (64.1 mg, 0.280 mmol) as starting materials, to give a clear solid (TFA salt) in 12% yield. Exact mass calculated for C2]H28N2O2S: 372.2, Found: LCMS m/z = 373.1 (M+H÷); 1H NMR (400 MHz, Methanol-^) δ 1.09 (t, J = 7.33 Hz, 3 H), 1.35 (d, J= 6.82 Hz, 0.3 H), 1.46 - 1.53 (m, 2.7 H), 1.72 - 1.83 (m, 1 H), 2.03 - 2.24 (m, 2 H), 2.33 - 2.44 (m, 1 H)5 2.95 (q, J = 7.16 Hz, 2 H), 3.05 - 3.24 (m, 2 H), 3.25 - 3.32 (m, 2 H), 3.51 - 3.61 (m, 1 H), 3.63 - 3.73 (m, 1
H), 3.75 - 3.83 (m, 1 H), 7.49 (d, J= 8.08 Hz, 2 H), 7.64 - 7.74 (m, 3 H), 7.82 - 7.93 (m, 2 H)5 8.04 - 8.11 (m, I H).
Example 1.25: Preparation of 4'-[2-((JR)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-3-sulfonic Acid Isopropylamide (Compound 39).
The title compound was prepared in a similar manner as described in Example 1.19, using (i?)-l-(4-bromophenethyl)-2-methylpyrrolidine (50.0 mg, 0.186 mmol), and 3-(N- isoproρylsulfamoyl)ρhenylboronic acid (68.0 mg, 0.280 mmol) as starting materials, to give a clear solid (TFA salt) in 6% yield. Exact mass calculated for C22H30N2O2S: 386.2, Found: LCMS mlz = 387.1 (M+H+); 1H NMR (400 MHz5 Methanol-^) δ 1.03 - 1.11 (m, 6 H), 1.35 (d, J= 6.82 Hz, 0.3
H), 1.50 (d, J= 6.57 Hz, 2.7 H)5 1-71 - 1.84 (m5 1 H)52.03 - 2.24 (m, 2 H), 2.32 - 2.43 (m, 1 H), 3.05 - 3.24 (m, 2 H)5 3.25 - 3.31 (m, 2 H), 3.38 - 3.47 (m, 1 H), 3.51 - 3.61 (m, 1 H), 3.63 - 3.73 (m5 1 H), 3.75 - 3.83 (m, 1 H), 7.49 (d, J= 8.34 Hz, 2 H), 7.63 - 7.74 (m, 3 H), 7.84 - 7.92 (m, 2 H), 8.09 - 8.14 (m, 1 H).
Example 1.26: Preparation of l-{4'-[2-(CR)-2-Methyl-pyrrolidin-l-yl)-ethyI]-biphenyl-3- sulfonyl}-piperidine (Compound 38).
The title compound was prepared in a similar manner as described in Example 1.19, using (Λ)-l-(4-bromophenethyl)-2-methylpyrrolidine (50.0 mg, 0.186 mmol), and 3-(piperidin-l- ylsulfonyl)phenylboronic acid (75.3 mg, 0.280 mmol) as starting materials, to give a clear solid (TFA salt) in 14% yield. Exact mass calculated for C24H32N2O2S: 412.2, Found: LCMS m/z - 413.2 (M+fT); 1H NMR (400 MHz, Methanol-^) δ 1.35 (d, / = 6.82 Hz, 0.3 H), 1.42 - 1.54 (m, 4.7 H),
1.62 - 1.71 (m, 4 H), 1.72 - 1.84 (m, 1 H), 2.03 - 2.25 (m, 2 H), 2.33 - 2.44 (m, 1 H), 3.00 - 3.07 (m, 4 H), 3.07 - 3.25 (m, 2 H), 3.25 - 3.31 (m, 2 H), 3.51 - 3.62 (m, 1 H), 3.64 - 3.73 (m, 1 H), 3.74 - 3.83 (m, 1 H), 7.49 (d, J= 8.08 Hz, 2 H), 7.67 - 7.80 (m, 4 H), 7.92 - 7.98 (m, 2 H).
Example 1.27: Preparation of l-{4'-[2-((JR)-2-Methyl-pyrrolidin-l-yl)-ethyl]-bϊphenyl-4- sulfonyl}-piperidine (Compound 34).
The title compound was prepared in a similar manner as described in Example 1.19, using (i?)-l-(4-bromophenethyl)-2-methylpyrrolidine (200 mg, 0.746 mmol), and 4-(piperidin-l- ylsulfonyl)phenylboronic acid (261 mg, 0.970 mmol) as starting materials, to give a clear solid (TFA salt) in 8% yield. Exact mass calculated for C24H32N2O2S: 412.2, Found: LCMS m/z = 413.2 (M+H4); 1H NMR (400 MHz, Methanol-^) δ 1.35 (d, J= 6.82 Hz, 0.3 H), 1.43 - 1.53 (m, 4.7 H),
1.63 - 1.71 (m, 4 H), 1.72 - 1.83 (m, 1 H), 2.04 - 2.24 (m, 2 H), 2.33 - 2.43 (m, 1 H), 3.01 - 3.05 (m, 4 H), 3.06 - 3.24 (m, 2 H), 3.26 - 3.31 (m, 2 H), 3.51 - 3.61 (m, 1 H), 3.64 - 3.73 (m, 1 H), 3.74 - 3.82 (m, 1 H), 7.47 - 7.51 (m, 2 H), 7.71 - 7.76 (m, 2 H), 7.83 - 7.90 (m, 4 H).
Example 1.28: Preparation of 4-{4*-[2-((Λ)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonyl}-morpholine (Compound 33).
The title compound was prepared in a similar manner as described in Example 1.23, using (7?)-l-(4-bromophenethyl)-2-methylpyrrolidine (200 mg, 0.746 mmol), and 4- (morpholinosulfonyl)phenylboronic acid (263 mg, 0.970 mmol) as starting materials, to give a white solid (HCl salt) in 11% yield. Exact mass calculated for C23HSoN2O3S: 414.2, Found: LCMS m/z = 415.1 (MH-H+); 1H NMR (400 MHz, Methanol-^) δ 1.35 (d, 0.3 H), 1.51 (d, J= 6.32 Hz, 2.7 H), 1.73 - 1.84 (m, 1 H)5 2.05 - 2.24 (m, 2 H), 2.33 - 2.43 (m, 1 H), 2.99 - 3.05 (m, 4 H), 3.08 - 3.25 (m, 2 H), 3.26 - 3.32 (m, 2 H), 3.53 - 3.60 (m, 1 H), 3.63 - 3.72 (m, 1 H), 3.72 - 3.76 (m, 4 H), 3.76 - 3.83 (m, 1 H), 7.48 - 7.52 (m, 2 H), 7.72 - 7.77 (m, 2 H), 7.84 - 7.93 (m, 4 H). Example 1.29: Preparation of 4'-[2-((2-)-2-Methyl-pyrroIidin-l-yl)-ethyl]-biphenyl-4-suIfonic Acid (2-Methoxy-ethyl)-amide (Compound 21).
The title compound was prepared in a similar manner as described in Example 1.2, using (Λ)-4-(2-(2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (200 mg, 0.858 mmol), and 4- bromo-N-(2-methoxyethyl)benzenesulfonamide (252 mg, 0.858 mmol) as starting materials, to give a white solid (HCl salt) in 29% yield. Exact mass calculated for C22H30N2O3S: 402.2, Found: LCMS mlz = 403.4 (M+H*); 1H NMR (400 MHz, Methanol-^) δ 1.23 (d, J= 6.82 Hz3 0.3 H), 1.39 (d, J= 6.57 Hz, 2.7 H)5 1.61 - 1.72 (m, 1 H), 1.92 - 2.11 (m, 2 H), 2.21 - 2.31 (m, 1 H), 2.96 (t, J= 5.56Hz32 H)32.99 - 3.12 (m, 2 H), 3.15 (s, 3 H), 3.16 - 3.19 (m, 2 H)3 3.29 (t,J = 5.43 Hz, 2 H), 3.39 - 3.50 (m, 1 H), 3.51 - 3.59 (m, 1 H), 3.63 - 3.71 (m, 1 H), 7.37 (d, J = 8.34 Hz, 2 H), 7.59 (d, J= 8.08 Hz, 2 H), 7.69 - 7.73 (m, 2 H), 7.80 - 7.84 (m, 2 H).
Example 1.30: Preparation of (JR)-2-Methyl-l-{2-[4'-(pyrrolidine-l-sulfonyl)-biphenyl-4-yl]- ethyl}-pyrrolidine (Compound 11). The title compound was prepared in a similar manner as described in Example 1.2, using (i-)-4-(2-(2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (100 mg, 0.429 mmol), and 1- (4-bromophenylsulfonyl)pyrrolidine (125 mg, 0.429 mmol) as starting materials, to give a white solid (HCl salt) in 64% yield. Exact mass calculated for C23H30N2O2S: 398.2, Found: LCMS mlz = 399.2 (M+lT); 1H NMR (400 MHz, Methanol-^) δ 1.18 (d, 3 H), 1.43 - 1.54 (m, 1 H), 1.75 - 1.88 (m, 6 H), 1.98 - 2.09 (m, 1 H), 2.28 - 2.52 (m, 3 H), 2.82 - 3.00 (m, 2 H), 3.07 - 3.16 (m, 1 H), 3.26 - 3.32 (m, 5 H), 7.37 - 7.42 (m, 2 H), 7.64 - 7.68 (m, 2 H), 7.84 - 7.94 (m, 4 H).
Example 1.31: Preparation of 4*-[2-((Λ)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4-sulfonic Acid Cyclohexylamide (Compound 10). The title compound was prepared in a similar manner as described in Example 1.2, using (i-)-4-(2-(2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (100 mg, 0.429 mmol), and 4- bromo-Λf-cyclohexylbenzenesulfonamide (137 mg, 0.429 mmol) as starting materials, to give a white solid (HCl salt) in 47% yield. Exact mass calculated for C25H34N2O2S: 426.2, Found: LCMS mlz = 427.0 (M+If); 1H NMR (400 MHz, Methanol-^) 1H NMR (400 MHz, Methanol- dA) δ ppm 1.10 - 1.27 (m, 8 H) 1.42 - 1.58 (nα, 2 H) 1.64 - 1.87 (m, 6 H) 1.97 - 2.07 (m, I H) 2.27 - 2.49 (m, 3 H) 2.81 - 2.98 (m, 2 H) 3.02 - 3.14 (m, 2 H) 3.24 - 3.31 (m, 1 H) 7.35 - 7.39 (m, 2 H) 7.62 - 7.67 (m, 2 H) 7.78 - 7.82 (m, 2 H) 7.91 - 7.95 (m, 2 H).
Example 1.32: Preparation of 4-{4'-[2-((i?)-2-Methyl-pyrrolidin-l-yl)-ethyl}-biphenyl-4- sulfonylj-thiomorpholine 1,1-Dioxide (Compound 6).
The title compound was prepared in a similar manner as described in Example 1.2, using (i2)-4-(2-(2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (300 mg, 1.29 mmol), and 4- (4~bromo-benzenesulfonyl)-thiomorpholine 1,1-dioxide (593 ing, 1.67 mmol) as starting materials, to give a white solid (HCl salt) in 25% yield. Exact mass calculated for C23H30N2O4S2: 462.2, Found: LCMS mlz = 463.4 (NB-H+); 1H NMR (400 MHz, Methanol-^) δ 1.35 (d, J= 6.82 Hz, 0.3 H) 1.51 (d, J= 6.57 Hz, 2.7 H) 1.73 - 1.85 (m, 1 H) 2.04 - 2.23 (m, 2 H) 2.33 - 2.43 (m, 1 H) 3.09 - 3.22 (m, 2 H) 3.22 - 3.27 (m, 4 H) 3.27 - 3.31 (m, 2 H) 3.52 - 3.62 (m, 1 H) 3.62 - 3.71 (m, 5 H) 3.75 - 3.83 (m, 1 H) 7.50 (d, J= 8.08 Hz, 2 H) 7.74 (d, J= 7.83 Hz, 2 H) 7.88 - 7.95 (m, 4 H).
Example 133: Preparation of 4'-[2-((jR)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4-sulfonic Acid (2-Ethoxy-ethyl)-amide (Compound 5).
The title compound was prepared in a similar manner as described in Example 1.2, using (i?)-4-(2-(2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (100 mg, 0.429 mmol), and 4- bromo-N-(2-ethoxyethyl)benzenesulfonamide (198 mg, 0.644 mmol) as starting materials, to give a white solid (HCl salt) in 24% yield. Exact mass calculated for C23H32N2O3S: 416.2, Found: LCMS mlz = All A (M+H4); 1H NMR (400 MHz, Methanol-^) δ 1.13 (t, J= 7.07 Hz, 3 H), 1.35 (d, J= 6.82 Hz, 0.3 H), 1.51 (d, J= 6.32 Hz, 2.7 H), 1.73 - 1.85 (m, 1 H)3 2.04 - 2.24 (m, 2 H), 2.33 - 2.43 (m, 1 H)5 3.09 (t, J= 5.68 Hz, 2 H), 3.11 - 3.24 (m, 2 H), 3.26 - 3.31 (m, 2 H), 3.39 - 3.47 (m, 4 H), 3.52 - 3.62 (m, 1 H), 3.63 - 3.71 (m, 1 H), 3.75 - 3.83 (m, 1 H), 7.46 - 7.51 (m, 2 H), 7.69 - 7.73 (m, 2 H), 7.81 - 7.85 (m, 2 H), 7.92 - 7.97 (m, 2 H).
Example 1.34: Preparation of 4'-[2-((jR)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4-sulfonic Acid 4-Methyl-benzylamide (Compound 4).
The title compound was prepared in a similar manner as described in Example 1.2, using (i?)-4-(2-(2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (100 mg, 0.644 mmol), and 4- bromo-N-(4-methyl-benzyl)-benzenesulfonamide as starting materials (219 mg, 0.644 mmol), to give a white solid (HCl salt) in 32% yield. Exact mass calculated for C27H32N2O2S: 448.2, Found: LCMS mlz = 449 A (M+H4); 1H NMR (400 MHz, Methanol-^) δ 1.23 (d, J= 6.57 Hz, 0.3 H) 1.40 (d, J= 6.32 Hz, 2.7 H) 1.62 - 1.73 (m, 1 H) 1.93 - 2.10 (m, 2 H) 2.14 (s, 3 H) 2.20 - 2.31 (m, 1 H) 2.97 - 3.13 (m, 2 H) 3.14 - 3.19 (m, 2 H) 3.41 - 3.49 (m, 1 H) 3.50 - 3.60 (m, 1 H) 3.63 - 3.72 (m, 1 H) 3.94 (s, 2 H) 6.91 - 7.00 (m, 4 H) 7.37 (d, J= 7.83 Hz, 2 H) 7.56 (d, J= 7.83 Hz, 2 H) 7.63 (d, J= 8.34 Hz3 2 H) 7.75 (d, J= 8.08 Hz, 2 H).
Example 1.35: Preparation of 4'-[2-((i?)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonic Acid Methylamide (Compound 20). The title compound was prepared in a similar manner as described in Example 1.2, using 4-bromo-N-methylbenzenesulfonamide (127 mg, 0.506 mmol), and (R)-4-(2-(2- methylpyrrolidin-l-yl)ethyl)phenylboronic acid (118 mg, 0.506 mmol) as starting materials, to give a white solid (HCl salt) in 65% yield. Exact mass calculated for C20H26N2O2S: 358.2, Found: LCMS mlz = 359.5 (M+H4); 1H NMR (400 MHz, Methanol-^) δ 1.33 (d, J = 6.82 Hz3 0.3 H), 1.50 (d, J= 6.57 Hz5 2.7 H), 1.71 - 1.84 (m, 1 H), 2.03 - 2.20 (m, 2 H), 2.31 - 2.40 (m, 1 H), 2.53 - 2.58 (m, 3 H), 3.08 - 3.24 (m, 2 H), 3.24 - 3.38 (m, 2 H), 3.50 - 3.70 (m, 2 H), 3.73 - 3.81 (m, 1 H), 7.47 (d, J= 8.08 Hz, 2 H), 7.69 (d, J= 8.08 Hz, 2 H), 7.79 - 7.84 (m, 2 H), 7.87 - 7.92 (m, 2 H).
Example 1.36: Preparation of 4'-[2-((Λ)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonic Acid Isopropylamide (Compound 19). The title compound was prepared in a similar manner as described in Example 1.2, using 4-bromo-N-isoprόpylbeήzenesulfonamide (151 mg, 0.545 mmol) and (i?)-4-(2-(2- methylpyrrolidm-l-yl)ethyl)phenylboronic acid (127 mg, 0.545 mmol) as starting materials, to give a white solid (HCl salt) in 76% yield. Exact mass calculated for C22H30N2O2S: 386.2, Found: LCMS mlz = 387.4 (M+H4); 1H NMR (400 MHz, Methanol-^) δ 1.01 - 1.08 (m, 6 H)5 1.33 (d, J= 6.82 Hz, 0.3 H), 1.50 (d, J= 6.32 Hz, 2.7 H), 1.71 - 1.83 (m, 1 H), 2.02 - 2.20 (m, 2 H), 2.30 - 2.40 (m, 1 H), 3.07 - 3.20 (m, 2 H), 3.23 - 3.43 (m, 3 H), 3.51 - 3.69 (m, 2 H), 3.72 - 3.82 (m, 1 H), 7.46 (d, /= 8.08 Hz5 2 H), 7.68 (d, J= 8.08 Hz5 2 H), 7.80 (d, J= 8.59 Hz, 2 H), 7.92 (d, 7= 8.59 Hz, 2 H).
Example 1.37: Preparation of 4'-[2-((i?)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonic Acid Propylamide (Compound 18).
The title compound was prepared in a similar manner as described in Example 1.2, using 4-bromo-N-propylbenzenesulfonamide (143 mg, 0.515 mmol) and (if)-4-(2-(2- methylpyrrolidin-l-yl)ethyl)phenylboronic acid (120 mg, 0.515 mmol) as starting materials, to give a white solid (HCl salt) in 44% yield. Exact mass calculated for C22H30N2O2S: 386.2,
Found: LCMS mlz = 387.6 (M+H4); 1H NMR (400 MHz, Methanol-^) δ 0.83 - 0.93 (m, 3 H), 1.33 (d, y= 6.82 Hz, 0.3 H), 1.42 - 1.53 (m, 4.7 H), 1.77 (dd, J= 13.01, 8.46 Hz, 1 H), 2.02 - 2.21 (m, 2 H), 2.30 - 2.42 (m, 1 H), 2.83 (t, J= 7.07 Hz5 2 H)5 3.07 - 3.21 (m5 2 H), 3.23 - 3.36 (m, 2 H), 3.50 - 3.70 (m5 2 H), 3.73 - 3.82 (m, 1 H)7 7.47 (d, J= 7.83 Hz, 2 H), 7.68 (d, J= 7.83 Hz, 2 H), 7.80 (d, J = 8.59 Hz5 2 H), 7.87 - 7.92 (m, 2 H).
Example 1.38: Preparation of 4f-[2-((JR)-2-Methyl-pyrroIidin-l-yl)-ethyl]-biphenyl-4- sulfonic Acid tørf-Butylamide (Compound 17).
The title compound was prepared in a similar manner as described in Example 1.2, using 4-bromo-N-/ert-butylbenzenesulfonamide (154 mg, 0.528 mmol) and (R)-4-(2-(2~ methylpyrrolidin-l-yl)ethyl)phenylboronic acid (123 mg, 0.528 mmol) as starting materials, to give a white solid (HCl salt) in 54% yield. Exact mass calculated for C23H32N2O2S: 400.2, Found: LCMS m/z = 401.6 (M+H4); 1H NMR (400 MHz5 Methanol-^) δ 1.20 (s, 9 H), 1.33 (d, J= 6.57 Hz, 0.3 H), 1.50 (d, J= 6.32 Hz, 2.7 H), 1.77 (dd, J= 8.34 Hz5 1 H)52.04 - 2.21 (m, 2 H), 2.30 - 2.40 (m, 1 H), 3.09 - 3.20 (m, 2 H), 3.24 - 3.34 (m, 2 H), 3.49 - 3.69 (m, 2 H), 3.72 - 3.82 (m, 1 H)57.46 (d, J= 8.08 Hz, 2 H)5 7.68 (d5 J= 7.83 Hz, 2 H), 7.78 (d, J= 8.59 Hz52 H), 7.94 (d, J= 8.34 Hz5 2 H).
Example 1.39: Preparation of 4'-[2-((i?)-2-Methyl-pyrrolidiu-l-yl)-ethyl]-biphenyl-4- sulfonic Acid Cyclobutylamide (Compound 16).
The title compound was prepared in a similar manner as described in Example 1.2, using 4-bromo-N-cyclobutylbenzenesulfonamide (158 mg50.545 mmol) and (Λ)-4-(2-(2- methylpyrrolidin-l-yl)ethyl)phenylboronic acid (127 mg, 0.545 mmol) as starting materials, to give a white solid (HCl salt) in 73% yield. Exact mass calculated for C23H30N2O2S: 398.2, Found: LCMS m/z = 399.4 (M+H4); 1H NMR (400 MHz, Methanol-^) δ 1.33 (d, J= 6.82 Hz, 0.3 H)5 1.50 (t, J= 5.81 Hz52.7 H), 1.52 - 1.63 (m, 2 H), 1.72 - 1.89 (m, 3 H), 1.98 - 2.19 (m, 4 H), 2.29 - 2.41 (m, 1 H), 3.06 - 3.21 (m, 2 H), 3.23 - 3.34 (m, 2 H), 3.50 - 3.70 (m, 2 H), 3.70 - 3.82 (m, 2 H), 7.46 (d, J= 8.08 Hz, 2 H), 7.68 (d, J= 8.08 Hz, 2 H), 7.75 - 7.82 (m, 2 H)5 7.86 - 7.93 (m, 2 H).
Example 1.40: Preparation of (/?)-l-{2-[4'-(Azetidine-l-sulfonyl)-biphenyl-4-yl]-ethyl}-2- methyl-pyrrolidine (Compound 15).
The title compound was prepared in a similar manner as described in Example 1.2, using l-(4-bromophenylsulfonyl)azetidine (135 mg, 0.489 mmol) and (i?)-4-(2-(2- methylpyrrolidin-l-yl)ethyl)phenylboronic acid (114 mg, 0.489 mmol) as starting materials, to give a white solid (HCl salt) in 70% yield. Exact mass calculated for C22H28N2O2S: 384.2, Found: LCMS m/z = 385.3 (M+H*); 1H NMR (400 MHz, Methanol-^) δ 1.33 (d, J= 6.82 Hz, 0.3 H), 1.50 (d5 J= 6.57 Hz, 2.7 H), 1.71 - 1.83 (m, 1 H), 1.86 - 1.96 (m5 2 H)5 2.02 - 2.22 (m, 2 H)5 2.30 - 2.41 (m, 1 H), 3.03 (t, J= 6.69 Hz, 2 H)5 3.08 - 3.21 (m, 2 H)5 3.23 - 3.34 (m, 2 H), 3.50 - 3.70 (m, 4 H)5 3.72 - 3.82 (m, 1 H)5 7.47 (d5 J= 8.08 Hz5 2 H), 7.68 (d, J= 8.08 Hz, 2 H), 7.81 (d, J= 8.59 Hz, 2 H), 7.89 - 7.94 (m, 2 H).
Example 1.41: Preparation of 4'-{2-((/?)-2-Methyl-pyrroIidin-l-yl)-ethyl]-biphenyI-4- sulfonic Acid 4-Methoxy-benzylamide (Compound 9).
The title compound was prepared in a similar manner as described in Example 1.2, using N-(4-methoxybenzyl)-4-bromobenzenesulfonamide (158 mg, 0.468 mmol), and (i?)-4-(2- (2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (127 mg, 0.468 mmol) as starting materials, to give a white solid (HCl salt) in 51% yield. Exact mass calculated for C27H32N2O3S: 464.2, Found: LCMS m/z = 465.4 (M+H*); 1H NMR (400 MHz, Methanol-^) δ 1.33 (d, J= 6.82 Hz, 0.3 H), 1.50 (d, J= 5.31 Hz, 2.7 H), 1.78 (s, 1 H), 2.10 (s, 2 H), 2.35 (s, 1 H), 3.15 (s, 2 H)3 3.23
- 3.37 (m, 2 H), 3.49 - 3.82 (m, 6 H), 4.83 - 4.92 (m, 2 H), 6.76 (d, J= 8.59 Hz, 2 H), 7.10 (d, J = 8.34 Hz, 2 H), 7.47 (d, J= 7.33 Hz, 2 H), 7.67 (d, J= 7.33 Hz, 2 H), 7.73 (d, J= 8.34 Hz, 2 H), 7.84 (d, J= 8.08 Hz, 2 H).
Example 1.42: Preparation of 4'-[2-((i?)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonic Acid (2-Phenoxy-ethyI)-amide (Compound 8).
The title compound was prepared in a similar manner as described in Example 1.2, using 4-bromo-N-(2-phenoxyethyl)benzenesulfonarnide (171 mg, 0.481 mmol), and (i?)-4-(2-(2- methylpyrrolidin-l-yl)ethyl)phenylboronic acid (112 mg, 0.481 mmol) as starting materials, to give a white solid (HCl salt) in 53% yield. Exact mass calculated for C27H32N2O3S: 464.2, Found: LCMS mlz = 465.4 (M+H+); 1H NMR (400 MHz, Methanol-^) δ 1.33 (d, J= 5.81 Hz, 0.3 H), 1.50 (d, J= 5.31 Hz, 2.7 H), 1.78 (s, 1 H), 2.10 (s, 2 H), 2.35 (s, 1 H), 3.15 (s, 2 H), 3.22
- 3.38 (m, 4 H), 3.63 (d, J= 11.87 Hz, 2 H)5 3.77 (s, 1 H), 3.93 (t, J= 5.31 Hz, 2 H), 6.78 (d, J= 8.08 Hz, 2 H), 6.87 (t, J= 7.33 Hz, 1 H), 7.18 (t, J= 7.96 Hz, 2 H), 7.46 (d, J= 7.58 Hz, 2 H),
7.63 (d, J= 7.33 Hz, 2 H), 7.74 (d, J= 8.08 Hz, 2 H), 7.89 - 7.95 (m, 2 H).
Example 1.43: Preparation of 4'-[2-((R)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonic Acid Diethylamide (Compound 26). The title compound was prepared in a similar manner as described in Example 1.23, using (i?)-l-[2-(4-bromo-phenyl)-ethyl]-2-methyl-pyrrolidine (200 mg, 0.746 mmol), and A- (N,N-diethylsulfamoyl)phenylboronic acid (249 mg, 0.969 mmol) as starting materials, to give a white solid (HCl salt) in 12% yield. Exact mass calculated for C23H32N2O2S: 400.2, Found: LCMS m/z = 401.4 (M+H""); 1H NMR (400 MHz, Methanol-^) δ 1.08 - 1.21 (m, 6 H), 1.32 (d, J = 6.82 Hz, 0.3 H), 1.50 (d, J= 6.32 Hz, 2.7 H), 1.71 - 1.85 (m, 1 H), 2.03 - 2.21 (m, 2 H), 2.30 - 2.41 (m, 1 H), 3.07 - 3.21 (m, 2 H), 3.20 - 3.29 (m, 6 H), 3.49 - 3.59 (m, 1 H), 3.59 - 3.70 (m, 1 H), 3.72 - 3.83 (m, 1 H), 7.46 (d, J= 8.08 Hz, 2 H)5 7.67 (d, J= 8.08 Hz5 2 H), 7.73 - 7.83 (m, 2 H), 7.84 - 7.90 (m, 2 H).
Example 1.44: Synthesis of (5)-l-(4-Bromophenethyl)-2-methylpyrrolidiπe.
4-Bromophenethyl methanesulfonate (12.84 g, 46mmol) was dissolved in acetonitrile (94 mL, 0.5 M). Sodium carbonate (6.34 g, 60 mmol) was added, followed by (5)-(+)-2- methylpyrrolidine (Advanced Asymmetries, Millstadt, IL; catalog no. 83022; [α] +16.4 °) (4.7 g, 55mmol). The reaction mixture was warmed to 80 0C and stirred overnight. The sodium carbonate was removed by filtration and the solvent was removed under reduced pressure. The crude product was dissolved in ethyl acetate (200 mL) and extracted with 1 M HCl (75 mL). The ethyl acetate layer was extracted an additional three times with 1 M HCl (30 mL each). The aqueous layers were combined and adjusted to pH 10 by the addition of sodium carbonate. The basic aqueous layer was extracted with DCM (100 mL). 50% Sodium hydroxide (1 mL) was added to the aqueous layer, which was then extracted with DCM (3 x 50 mL). The combined DCM layers were dried with sodium sulfate and the solvent was removed under reduced pressure, yielding 11.25 g (91%) of yellow oil. The crude product was purified by silica chromatography eluting with ethyl acetate followed by 0-10% methanol in ethyl acetate, yielding 9.62 g (78%) as a pale yellow oil; 98% ee (by chiral HPLC; column: 25 cm Chiral Tech AD-H, analytical; eluent: 1% isopropanol in hexanes, isocratic; flow Rate: 0.5 mL/min; wavelength: 220 nM). Exact mass calculated for CnHjgBrN: 267.06, Found: LCMS mlz = 268.0 01+H+ 78Br, 100), 270.2 (M+H÷ 80Br, 97); 1H NMR (400 MHz, Methanol-^) δ ppm 1.15 (d, J= 6.32 Hz, 3 H) 1.40 - 1.51 (m, 1 H) 1.75 - 1.85 (m, 2 H) 1.95 - 2.06 (m, 1 H) 2.22 - 2.35 (m, 2 H) 2.36 - 2.47 (m, 1 H) 2.72 - 2.89 (m, 2 H) 2.99 - 3.09 (m, 1 H) 3.20 - 3.28 (m, 1 H) 7.15 - 7.20 (m, 2 H) 7.41 - 7.47 (m, 2 H).
Example 1.45: Preparation of 4'-[2-((5)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyI-4- sulfonic Acid Ethylamide (Compound 43).
The title compound was prepared in a similar manner as described in Example 1.23, using 4-(N-ethylsulfamoyl)phenylboronic acid (128 mg, 0.559 mrnol) and (5)-l-(4- bromophenethyl)-2-methylpyrrolidine (150 mg, 0.559 mol) as starting materials, to give a white solid (HCl salt) in 70% yield. Exact mass calculated for C2IH28N2O2S: 372.2, Found: LCMS mlz = 373.2 (M+lT); 1H NMR (400 MHz, Methanol-^) δ 1.08 (t, J= 7.20 Hz, 3 H), 1.33 (d, J= 6.82 Hz, 0.3 H), 1.49 (d, J= 6.57 Hz, 2.7 H), 1.77 (dd, J= 13.01, 7.96 Hz, 1 H), 2.01 - 2.24 (m, 2 H), 2.30 - 2.41 (m, 1 H), 2.92 (q, J= 7.16 Hz5 2 H), 3.07 - 3.23 (m, 2 H)5 3.23 - 3.35 (m, 2 H)3 3.50 - 3.59 (m, 1 H)5 3.59 - 3.70 (m, 1 H), 3.71 - 3.82 (m, 1 H), 7.46 (d, J= 8.34 Hz, 2 H), 7.68 (d5 J= 8.34 Hz, 2 H), 7.77 - 7.83 (m, 2 H), 7.87 - 7.93 (m, 2 H).
Example 1.46: (Λ^-Methylpyrrolidine Hydrochloride.
Step A: Preparation of (R)-tert-Butyl 2-Methylpyrrolidine-l-carboxylate.
N-Boc-L-prolinol (Omega Chem, Quέbec, Canada; catalog no. BP-5319; 98% ee) (30.1 g, 150 mmol) was dissolved in dichloromethane (150 mL). Triethylamine (52.1 mL, 374 mmol) was added and the mixture was cooled in an ice bath. Methanesulfonyl chloride (12.2 mL, 157 mmol) was added dropwise via an addition funnel over 30 min. The ice bath was removed and the mixture was stirred. Methanesulfonyl chloride (1.25 mL, 16 mmol) was added twice at 30 min intervals until TLC (2:1, ethyl acetate/hexanes) showed no more starting materials left. The reaction mixture was then diluted with ethyl acetate (800 mL) and washed with 1 M HCl (2 x 100 mL), brine (100 mL), saturated sodium carbonate (2 x 100 mL), and brine (100 mL). The ethyl acetate layer was dried with sodium sulfate and the solvent was removed under reduced pressure. The crude (S)-tert~butyl 2-((methylsuIfonyloxy)methyl)pyrrolidine-l-carboxylate (41.8 g, 150 mmol) was dissolved in THF (300 mL, 0.5 M) and cooled in an ice bath. Lithium triethylborohydride (1 M in THF, 314 mL, 314 mmol) was added slowly after which the ice bath was removed and the mixture was stirred for 2 h. TLC (2:1, ethyl acetate/hexanes) showed no starting materials. Methanol (100 mL) was added slowly to quench the reaction and the organic solvent was removed under reduced pressure. The crude reaction mixture was suspended in DCM (750 mL) and water (150 mL) in a seperatory funnel. The water layer was removed and the organic layer was washed with water (100 mL). The combined water layers were washed with DCM (2 x 50 mL). The combined organic phase was dried over magnesium sulfate and filtered. The solvent was removed under reduced pressure to give a crude residue (30.75 g). The crude residue was purified by flash chromatography using 10% ethyl acetate in hexanes followed by 20% ethyl acetate in hexanes. The product containing fractions were pooled and the solvent was removed under reduced pressure. The product was dried overnight under reduced pressure to give the title compound (22.76 g) in 82% yield. 1H NMR (400 MHz, CDCl3) δ 1.12 - 1.18 (m, 3 H), 1.46 (s, 9 H), 1.55 (d, J= 6.06 Hz, 1 H), 1.73 - 2.05 (m, 3 H), 3.29 - 3.40 (m, 2 H), 3.77 - 3.96 (m, 1 H).
Step B: (iϊ)-2-Methylpyrrolidine Hydrochloride.
(i?)-ter/-Butyl 2-methylpyrrolidine-l-carboxylate (22.7 g, 123 mmol) was dissolved in a 4 M hydrogen chloride solution in dioxane (100 mL) and the reaction was stirred for 30 min. TLC (2:1, ethyl acetate/hexanes) confirmed that there was no starting material left. The solvent was removed under reduced pressure. The crude residue was dissolved in acetonitrile and toluene. The solvent was removed under reduced pressure and the resulting white powder was dried overnight under reduced pressure to give the title compound (14.6 g) in 98% yield. 1H NMR (400 MHz, CDCl3) δ 1.55 (d, J= 6.57 Hz, 3 H), 1.66 - 1.77 (m, 1 H), 1.95 - 2.04 (m, 1 H), 2.05 - 2.23 (m, 2 H), 3.25 - 3.36 (m, 1 H), 3.37 - 3.48 (m, 1 H), 3.62 - 3.74 (m, 1 H), 9.38 (s, 1 H), 9.86 (s, 1 H).
Example 2.1: Preparation of 6,7-Dimethoxy-2-{4'-[2-((iS!)-2-methyl-pyrrolidin-l-yl)-ethyI]- biphenyl-4-suIfonyJ}-l,2,3,4-tetrahydro-isoquinoline (Compound 112). The title compound was prepared in a similar manner as described in Example 1.2, using 2-(4-bromophenylsulfonyl)-6,7-dimethoxy-l,2,3,4-tetrahydroisoquinoline (180 mg, 0.44 mmol) and (Λ)-4-(2-(2-methylρyrrolidin-l-yl)ethyl)phenylboronic acid (102 mg, 0.44 mmol) to give 153 mg of the HCl salt in 63% yield. Exact mass calculated for C30H36N2O4S: 520.2, Found: LCMS m/z = 521.5 (M+H1); 1H NMR (400 MHz, Methanol-ώ,) δ 1.35 (d, .3 H), 1.50 (d, 7= 6.32 Hz, 2.7 H), 1.71 - 1.84 (m, 1 H), 2.03 - 2.23 (m, 2 H), 2.31 - 2.43 (m, 1 H), 2.83 (t, J= 5.68 Hz, 2 H), 3.07 - 3.23 (m, 2 H), 3.25 - 3.33 (m, 2 H), 3.35 - 3.42 (m, 2 H), 3.51 - 3.71 (m, 2 H)3 3.73 - 3.83 (m, 7 H), 4.22 (s, 2 H), 6.67 (d, J= 13.64 Hz, 2 H), 7.48 (d, J= 8.08 Hz, 2 H), 7.67 - 7.72 (m, 2 H), 7.84 (d, J= 8.59 Hz, 2 H), 7.89 - 7.95 (m, 2 H).
Example 2.2: Preparation of 4'-[2-((i?>2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonic acid 4-trifluoromethoxy-benzylamide (Compound 106).
The title compound was prepared in a similar manner as described in Example 1.2, using 4-bromo-N-(4-(trifluoromethoxy)benzyl)benzenesulfonamide (183 mg, 0.45 mmol) and (i?)-4-(2-(2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (104 mg, 0.45 mmol) to give 169 mg of the HCl salt in 68% yield. Exact mass calculated for C27H29F3N2O3S: 518.2, Found: LCMS mlz = 519.4 (M+H*); 1H NMR (400 MHz, Methanol-d4) δ 1.50 (d, J - 6.06 Hz, 3 H),
1.73 - 1.85 (m, 1 H), 2.05 - 2.21 (m, 2 H), 2.32 - 2.43 (m, 1 H), 3.09 - 3.23 (m, 2 H), 3.27 - 3.36 (m, 2 H), 3.72 (d, J= 49.77 Hz, 3 H), 4.13 - 4.18 (m, 2 H), 7.15 (d, J= 8.08 Hz, 2 H), 7.32 - 7.36 (m, 2 H), 7.49 (d, J= 8.08 Hz, 2 H), 7.69 (d, J= 8.34 Hz, 2 H), 7.75 - 7.79 (m, 2 H), 7.86 - 7.90 (m, 2 H).
Example 2.3: Preparation of 7-{4-[2-((jR)-2-Methyl-pyrrolidin-l-yl)-ethyl]-phenyl}-3,4- dihydro-2//-benzo[b][l,2,5]oxathiazepine 1,1-Dioxide (Compound 76).
The title compound was prepared in a similar manner as described in Example 1.2, using 7-bromo-3,4-dihydro-2H-5,l,2-benzoxathiazeρine 1,1-dioxide (124 mg, 0.45 mmol) and (Λ)-4-(2-(2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (104 mg, 0.45 mmol) to give 58 mg of the HCl salt in 30% yield. Exact mass calculated for C2JH26N2O3S: 386.2, Found: LCMS mlz = 387.3 (M+H4); 1H NMR (400 MHz, Methanol-^) δ 1.50 (d, J= 5.81 Hz, 3 H)5 1.73 - 1.85 (m, 1 H), 2.06 - 2.22 (m, 2 H), 2.32 - 2.42 (m, 1 H), 3.06 - 3.24 (m, 2 H), 3.25 - 3.39 (m, 2 H), 3.48 - 3.72 (m, 5 H), 3.72 - 3.81 (m, 1 H), 4.20 - 4.24 (m, 2 H), 7.45 - 7.49 (m, 3 H), 7.53 (dd, J = 8.34, 1.77 Hz, 1 H), 7.69 (d, J= 8.34 Hz, 2 H), 7.88 (d, J= 8.34 Hz, 1 H).
Example 2.4: Preparation of 4'-[2-((i.)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyI-4- sulfonic Acid Benzhydryl-amide (Compound 71).
The title compound was prepared in a similar manner as described in Example 1.2, using iV-benzhydryl-4-bromobenzenesulfonamide (176 mg, 0.44 mmol) and (J?)-4-(2-(2- methylpyrrolidin-l-yl)ethyl)phenylboronic acid (102 mg, 0.44 mmol) to give 161 mg of the HCl salt in 67% yield. Exact mass calculated for C32H34N2O2S: 510.2, Found: LCMS mlz = 511.5 (MH-H+); 1H NMR (400 MHz, Methanol-^) δ 1.35 (d, J= 6.82 Hz, 0.3H) 1.51 (d, J= 6.57 Hz,
2.7 H), 1.73 - 1.85 (m, 1 H), 2.04 - 2.25 (m, 2 H), 2.32 - 2.43 (m, 1 H), 3.07 - 3.22 (m, 2 H), 3.26 - 3.36 (m, 2 H), 3.53 - 3.60 (m, 1 H), 3.63 - 3.72 (m, 1 H), 3.74 - 3.83 (m, 1 H), 5.61 (s, 1
H), 7.12 - 7.22 (m, 10 H), 7.47 (d, J= 8.34 Hz, 2 H), 7.55 (d, J= 8.59 Hz, 2 H), 7.61 (d, J=
8.08 Hz, 2 H), 7.70 (d, J= 8.59 Hz, 2 H). Example 2.5: Preparation of 4'-[2-((i?)-2-Methyl-pyrrolidin-l-yI)-ethyI]-biphenyl-4- sulfonic acid [2-(4-fluoro-pheoyl)-ethyl]-amide (Compound 66).
The title compound was prepared in a similar manner as described in Example 1.2, using 4-bromo-N-(4-fluorophenethyl)benzenesulfonamide (164 mg, 0.46 mmol) and (R)A-(2- (2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (107 mg, 0.46 mmol) to give 158 mg of the HCl salt in 68% yield. Exact mass calculated for C27H31FN2O2S: 466.2, Found: LCMS mlz = 467.4 (M+H4); 1H NMR (400 MHz, Methanol-^,) δ 1.35 (d, J= 6.82 Hz, 0.3H) 1.48 - 1.54 (m, 2.7 H), 1.73 - 1.84 (m, 1 H), 2.05 - 2.25 (m, 2 H), 2.33 - 2.42 (m, 1 H), 2.75 (t, J= 7.20 Hz, 2 H), 3.10 - 3.22 (m, 4 H), 3.26 - 3.36 (m, 2 H), 3.53 - 3.61 (m, 1 H), 3.62 - 3.71 (m, 1 H), 3.75 - 3.83 (m, 1 H), 6.92 - 6.99 (m, 2 H), 7.12 - 7.17 (m, 2 H), 7.48 (d, J= 8.08 Hz, 2 H), 7.71 (d, J= 8.34 Hz, 2 H), 7.77 - 7.81 (m, 2 H), 7.85 - 7.89 (m, 2 H).
Example 2.6: Preparation of 4'-[2-((i?)-2-MethyI-pyrrolidin-l-yl)-etliyl]-biphenyl-4- sulfonic acid (2-methoxy-ethyl)-methyl-amide (Compound SO).
The title compound was prepared in a similar manner as described in Example 1.2, using 4-bromo-N-(2-methoxyethyl)-N-methylbenzenesulfonamide (132 mg, 0.43 mmol) and (Λ)-4-(2-(2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (100 mg, 0.43 mmol) to give 125 mg of the HCl salt in 64% yield. Exact mass calculated for C23H32N2O3S: 416.2, Found: LCMS 02/.^ 417.4 (M+!!4); 1H NMR (400 MHz, Methanol-^) δ 1.35 (d, J= 6.82 Hz, 0.3H) 1.49 (d, J = 6.57 Hz, 2.7 H), 1.71 - 1.81 (m, 1 H), 2.03 - 2.18 (m, 2 H), 2.30 - 2.40 (m, 1 H), 2.82 - 2.84 (m, 3 H), 3.06 - 3.19 (m, 2 H), 3.21 - 3.32 (m, 7 H), 3.50 - 3.57 (m, 3 H), 3.60 - 3.69 (m, 1 H), 3.72 - 3.80 (m, 1 H), 7.46 (d, J= 8.08 Hz, 2 H), 7.69 (d, J = 8.34 Hz, 2 H), 7.81 - 7.88 (m, 4 H).
Example 2.7: Preparation of 4'-[2-((i?)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonic acid (2-methoxy-l-methyl-ethyl)-amide (Compound 44).
The title compound was prepared in a similar manner as described in Example 1.2, using 4-bromo-N-(l-methoxypropan-2-yl)benzenesulfonamide (135 mg, 0.44 mmol) and (R)-4- (2-(2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (102 mg, 0.44 mmol) to give 118 mg of the HCl salt in 60% yield. Exact mass calculated for C23H32N2O3S: 416.2, Found: LCMS mlz = 417.4 (M+H*); 1H NMR (400 MHz, Methanol-^) δ 1.02 (d, J= 6.82 Hz, 3 H), 1.32 (d, J= 6.82 Hz, 0.3 H), 1.49 (d, J= 6.57 Hz, 2.7 H), 1.70 - 1.82 (m, 1 H), 2.02 - 2.19 (m, 2 H), 2.30 - 2.40 (m, 1 H), 3.07 - 3.21 (m, 6 H), 3.23 - 3.33 (m, 3 H), 3.39 - 3.46 (m, 1 H), 3.50 - 3.58 (m, 1 H), 3.60 - 3.68 (m, 1 H), 3.72 - 3.79 (m, 1 H), 7.45 (d, J= 8.08 Hz, 2 H), 7.68 (d, J= 8.08 Hz, 2 H), 7.79 (d, J= 8.59 Hz, 2 H)3 7.92 (d, J= 8.59 Hz, 2 H). Example 2.8: Preparation of 2-(l-{4'-[2-((i?)-2-Methyl-pyrrolidin-l-yl)-ethyI]-biphenyl-4- sulfonyl}-piperidin-4-yl)-ethanol (Compound 101).
The title compound was prepared in a similar manner as described in Example 1.2, using 2-(l-(4-bromophenylsulfonyl)piperidin-4-yl)ethanol (317 mg, 0.91 mmol) and (Λ)-4-(2- (2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (212 mg, 0.91 mmol) to give 206 mg of the HCl salt in 46% yield. Exact mass calculated for C26H36N2O3S: 456.2, Found: LCMS mlz - 457.4 (MR-H+); 1HNMR (400 MHz, Methanol-^) δ 1.19 - 1.34 (m, 3 H), 1.43 (t, J= 6.32 Hz, 2 H), 1.49 (d, J= 6.32 Hz, 3 H), 1.71 - 1.82 (m, 3 H), 2.02 - 2.19 (m, 2 H), 2.26 - 2.40 (m, 3 H),
3.06 - 3.22 (m, 2 H), 3.24 - 3.32 (m, 2 H), 3.51 - 3.57 (m, 3 H), 3.60 - 3.69 (m, 1 H), 3.71 - 3.80 (m, 3 H), 7.47 (d, J= 8.08 Hz, 2 H), 7.69 (d, J= 8.08 Hz, 2 H), 7.79 - 7.86 (m, 4 H).
Example 2.9: Preparation of (iS)-4-Hydroxy-l-{4'-[2-((i.)-2-methyl-pyrrolidin-l-yl)-ethyl]- biphenyl-4-sulfonyl}-pyrrolidine-2-carboxylic Acid Methyl Ester (Compound 125).
(2S)-Methyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride (148 mg, 0.82 mmol) and (/ϊ)-4'-(2-(2-methylpyrrolidin- 1 -yl)ethyl)biphenyl-4-sulfonyl chloride (270 mg, 0.74 mmol) were combined in a round bottom flask and dissolved in dichloromethane. To this mixture was added diisopropylethylamine (288 mg, 2.23 mmol) and the mixture was stirred 1 h at room temperature, the solvent was then removed under reduced pressure. The resulting crude mixture was dissolved in acetonitrile and diluted acetic acid and purified by preparative HPLC. The product containing fractions were pooled and the acetonitrile removed under reduced pressure. The resulting aqueous layer was made basic (pH~10) with 2 M sodium carbonate solution and extracted with ethyl acetate (50 mL). The aqueous layer was then saturated with sodium chloride and extracted with ethyl acetate (2 x 25 mL). The ethyl acetate extracts were combined, dried with magnesium sulfate, and filtered. 1 M HCl in diethyl ether (1.5eq.) was added and the solvent removed under reduced pressure to give 125 mg of the HCl salt as a white solid (41% yield). Exact mass calculated for C25H32N2O5S: 472.2, Found: LCMS mlz = 473.5 CMH-H+); 1H NMR (400 MHz, Methanol-^) δ 1.32 (d, J= 6.82 Hz, 0.3 H), 1.48 (d, J= 6.32 Hz,
2.7 H), 1.70 - 1.82 (m, 1 H), 2.01 - 2.20 (m, 4 H), 2.30 - 2.40 (m, 1 H), 3.05 - 3.21 (m, 2 H), 3.22 - 3.36 (m, 3 H), 3.50 - 3.69 (m, 3 H), 3.71 - 3.80 (m, 4 H), 4.27 - 4.37 (m, 2 H), 7.46 (d, J= 8.08 Hz, 2 H), 7.69 (d, J = 8.34 Hz, 2 H), 7.80 - 7.84 (m, 2 H), 7.89 - 7.93 (m, 2 H).
Example 2.10: Preparation of 4'-[2-((Λ>2-Methyl-pyrroIidin-l-yl)-ethyl]-biphenyI-4- sulfonic acid ((-S)-2~methoxy-l-methyl-ethyl)-amide (Compound 95).
The title compound was prepared in a similar manner as described in Example 2.9, using (ιS)-l-methoxypropan-2-amine (58 mg, 0.65 mmol) and (i?)-4'-(2-(2-methylpyrτolidin-l- yl)ethyl)biphenyl-4-sulfonyl chloride (215 mg, 0.59 mmol) to give 32 mg of the HCl salt in 12% yield. Exact mass calculated for C23H32N2O3S: 416.6, Found: LCMS mlz = All.2 QVM-H+); 1H NMR (400 MHz5 Methanol-^) δ 1.02 (d, J= 6.82 Hz, 3 H), 1.32 (d, J= 6.82 Hz, 0.3 H), 1.48 (d, J = 6.57 Hz, 2.7 H), 1.71 - 1.82 (m, 1 H), 2.00 - 2.21 (m, 2 H), 2.29 - 2.39 (m, 1 H), 3.08 - 3.21 (m, 6 H), 3.23 - 3.31 (m, 3 H), 3.39 - 3.46 (m, 1 H), 3.49 - 3.58 (m, 1 H), 3.59 - 3.68 (m, 1 H), 3.72 - 3.80 (m, 1 H), 7.46 (d, J= 8.08 Hz, 2 H), 7.69 (d, J= 8.08 Hz, 2 H), 7.79 (d, J= 8.59 Hz, 2 H), 7.93 (d, J= 8.59 Hz, 2 H).
Example 2.11: Preparation of (l-{4r-[2-((i.)-2-Methyl-pyrrolidlin-l-yI)-ethyl]-biphenyI-4- sulfonyl}-piperidin-4-yl)-methanol (Compound 89).
The title compound was prepared in a similar manner as described in Example 1.2, using (l-(4-bromophenylsulfonyl)piperidin-4-yl)methanol (280 mg, 0.84 mmol) and (i?)-4-(2- (2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (195 mg, 0.84 mmol) to give 293 mg of the HCl salt in 73% yield. Exact mass calculated for C25H34N2O3S: 442.2, Found: LCMS mlz = 443.4 (1VH-H+); 1H NMR (400 MHz, Methanol-^) δ 1.20 - 1.43 (m, 3 H), 1.49 (d, J = 6.57 Hz, 3 H), 1.70 - 1.83 (m, 3 H), 2.01 - 2.20 (m, 2 H), 2.27 - 2.40 (m, 3 H), 3.07 - 3.22 (m, 2 H), 3.24 - 3.32 (m, 2 H), 3.36 (d, J= 6.06 Hz, 2 H), 3.50 - 3.58 (m, 1 H), 3.60 - 3.69 (m, 1 H), 3.73 - 3.83 (m, 3 H), 7.47 (d, J= 8.08 Hz, 2 H), 7.69 (d, J= 8.08 Hz, 2 H), 7.79 - 7.86 (m, 4 H).
Example 2.12: Preparation of 4'-[2-((i?)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonic Acid ((Λ)-2-Hydroxy-l-methyl-ethyl)-amide (Compound 83). The title compound was prepared in a similar manner as described in Example 2.9, using (i.)-2-aminopropan-l-ol (48 mg, 0.64 mmol) and (i?)-4'-(2-(2-methylpyrrolidin-l- yl)ethyl)biphenyl-4-sulfonyl chloride (210 mg, 0.58 mmol) to give 19 mg of the HCl salt in 7% yield. Exact mass calculated for C22H30N2O3S: 402.2, Found: LCMS mlz = 403.4 (M+H1); 1H NMR (400 MHz, Methanol-^) δ 1.00 (d, J= 6.57 Hz, 3 H), 1.32 (d, J= 6.82 Hz, 0.3 H), 1.49 (d, J= 6.32 Hz, 2.7 H), 1.70 - 1.83 (m, 1 H), 2.01 - 2.21 (m, 2 H), 2.29 - 2.40 (m, 1 H), 3.07 - 3.22 (m, 2 H), 3.22 - 3.35 (m, 3 H), 3.41 - 3.48 (m, 2 H), 3.50 - 3.58 (m, 1 H), 3.59 - 3.69 (m, 1 H), 3.72 - 3.81 (m, 1 H), 7.46 (d, J= 8.08 Hz, 2 H), 7.68 (d, J= 8.08 Hz, 2 H), 7.79 (d, J= 8.34 Hz, 2 H), 7.93 (d, J= 8.34 Hz, 2 H).
Example 2.13: Preparation of 4'-[2-((Λ>2-Methyl-pyrrolidin-l-yl)-ethyI]-biphenyI-4- sulfonic Acid (2-Hydroxy-ethyl)-methyl-amide (Compound 77).
The title compound was prepared in a similar manner as described in Example 1.2, using 4-bromo-N-(2-hydroxyethyl)-N-methylbenzenesulfonamide (143 mg, 0.49 mmol) and (R)- 4-(2-(2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (113 mg, 0.49 mmol) to give 163 mg of the HCl salt in 77% yield. Exact mass calculated for C22H30N2O3S: 402.2, Found: LCMS mlz = 403.4 OVH-H+); 1H NMR (400 MHz, Methanol-^) δ 1.49 (d, J = 6.57 Hz, 3 H), 1.70 - 1.82 (m, 1 H), 2.03 - 2.20 (m, 2 H), 2.29 - 2.40 (m, 1 H), 2.80 - 2.86 (m, 3 H), 3.08 - 3.21 (m, 4 H), 3.23 - 3.33 (m, 2 H), 3.49 - 3.58 (m, 1 H)5 3.60 - 3.71 (m, 3 H), 3.72 - 3.81 (m, 1 H), 7.46 (d, J = 8.34 Hz, 2 H), 7.68 (d, J= 8.34 Hz, 2 H), 7.81 - 7.88 (m, 4 H).
Example 2.14: Preparation of 2-Methyl-7-{4-[2-((Λ)-2-methyI-pyrrolidin-l-yl)-ethyl]- phenyl}-3,4-dihydro-2Jϊ-benzo[b][l,2,5]oxatliiazepine 1,1-Dioxide (Compound 72).
In a round-bottomed flask was placed 7-{4-[2-((i?)-2-methyl-pyrrolidin-l-yl)-ethyl]- phenyl}-3,4-dihydro-2H-benzo[b][l,2,5]oxathiazepine 1,1-dioxide (Example 2.3) (103 mg, 0.27 mmol) dissolved in THF (1.3 mL). To this was added iodomethane (151 mg, 1.07 mmol) followed by diisopropylethylamine (69 mg, 0.53 mmol). This mixture was allowed to stir for 18 h at room temperature. LCMS showed no starting materials left. The crude mixture was purified by preparative HPLC. The product containing fractions were pooled and the acetonitrile removed under reduced pressure. The resulting aqueous layer was made basic (pH ~ 10) with 2 M sodium carbonate solution and extracted with ethyl acetate (50 mL). The aqueous layer was then saturated with sodium chloride and extracted with ethyl acetate (2 x 25 mL). The ethyl acetate extracts were combined, dried with magnesium sulfate, and filtered. 1 M HCl in diethyl ether (1.5 eq.) was added and the solvent removed under reduced pressure to give 9.3 mg of the HCl salt as a white solid (8% yield). Exact mass calculated for C22H28N2O3S: 400.2, Found: LCMS mlz = 401.4 (M-HH+); 1H NMR (400 MHz, Methanol-^) δ 1.43 (d, J= 6.57 Hz, 3 H), 1.90 - 2.02 (m, 1 H), 2.10 - 2.22 (m, 2 H), 2.35 - 2.45 (m, 1 H), 2.97 (s, 2 H), 3.10 - 3.47 (m, 4 H), 3.51 - 3.93 (m, 6 H), 4.17 - 4.22 (m, 2 H), 7.42 - 7.52 (m, 4 H), 7.65 (d, J= 8.08 Hz, 2 H), 7.84 (d, J= 8.08 Hz, I H).
Example 2.15: Preparation of 4'-[2-((Λ)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonic acid (tetrahydro-pyran-4-ylmethyl)-amide (Compound 67). The title compound was prepared in a similar manner as described in Example 2.9, using (tetrahydro-2H-pyran-4-yl)methanamine (54 mg, 0.47 mmol) and (i?)-4'-(2-(2- methylpyrrolidin-l-yl)ethyl)biphenyl-4-sulfonyl chloride (156 mg, 0.43 mmol) to give 64 mg of the HCl salt in 31% yield. Exact mass calculated for C25H34N2O3S: 442.2, Found: LCMS mlz = 443.3 (M+H*); 1H NMR (400 MHz, Methanol-**,) δ 1.13 - 1.26 (m, 2 H), 1.33 (d, J= 6.82 Hz, 0.3 H)3 1.48 (d, J= 6.57 Hz, 2.7 H), 1.57 - 1.82 (m, 4 H), 2.00 - 2.19 (m, 2 H), 2.29 - 2.40 (m, 1 H), 2.75 (d, J= 6.82 Hz, 2 H), 3.05 - 3.22 (m, 2 H)5 3.23 - 3.38 (m, 4 H), 3.49 - 3.58 (m, 1 H), 3.59 - 3.68 (m, 1 H), 3.71 - 3.81 (m, 1 H), 3.89 (dd, J= 10.99, 3.41 Hz, 2 H), 7.46 (d, J= 8.08 Hz, 2 H), 7.68 (d, J= 8.08 Hz, 2 H), 7.80 (d, J= 8.59 Hz, 2 H), 7.88 - 7.92 (m, 2 H).
Example 2.16: Preparation of 4-Methoxymethyl-l-{4'-[2-((i?)-2-methyI-pyrroIidin-l-yl)- ethyl]-biphenyl-4-sulfonyI}-piperidine (Compound 128). The title compound was prepared in a similar manner as described in Example 1.2, using l-(4-bromophenylsulf6nyl)-4-(methoxymethyl)piperidine (324 mg, 0.93 mmol) and (R)-4- (2-(2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (217 mg, 0.93 mmol) to give 254 mg of the HCl salt in 55% yield. Exact mass calculated for C26H36N2O3S: 456.2, Found: LCMS mlz = 457.4 (M+H4); 1H NMR (400 MHz, Methanol-^,) δ 1.23 - 1.36 (m, 2 H), 1.49 (d, J = 6.57 Hz, 3 H), 1.71 - 1.81 (m, 3 H), 2.01 - 2.19 (m, 2 H), 2.26 - 2.39 (m, 3 H), 3.06 - 3.22 (m, 4 H), 3.28 - 3.31 (m, 6 H), 3.49 - 3.58 (m, 1 H), 3.59 - 3.70 (m, 1 H), 3.72 - 3.82 (m, 3 H), 7.47 (d, J= 8.34 Hz, 2 H), 7.69 (d, J= 8.34 Hz, 2 H), 7.78 - 7.87 (m, 4 H).
Example 2.17: Preparation of 4-(2-Methoxy-ethyI)-l-{4'-[2-((Λ)-2-methyl-pyrrolidin-l-yl)- ethyI]-biphenyl-4-sulfonyl}-piperidine (Compound 126).
The title compound was prepared in a similar manner as described in Example 1.2, using l-(4-bromophenylsulfonyl)-4-(2-methoxyethyl)piperidine (326 mg, 0.90 mmol) and (R)A- (2-(2-methylpyrrolidin-l-yl)ethyl)ρhenylboronic acid (210 mg, 0.90 mmol) to give 247 mg of the HCl salt in 54% yield. Exact mass calculated for C27H38N2O3S: 470.2, Found: LCMS mlz = 471.4 (M+H+); 1H NMR (400 MHz, Methanol-^) δ 1.19 - 1.36 (m, 3 H), 1.43 - 1.51 (m, 4 H), 1.69 - 1.83 (m, 3 H), 2.01 - 2.20 (m, 2 H), 2.24 - 2.41 (m, 3 H), 3.06 - 3.20 (m, 2 H), 3.28 - 3.31 (m, 6 H), 3.38 (t, J= 6.32 Hz, 2 H), 3.49 - 3.58 (m, 1 H), 3.59 - 3.69 (m, 1 H), 3.71 - 3.81 (m, 3 H), 7.47 (d, J= 8.34 Hz, 2 H), 7.69 (d, J= 8.08 Hz, 2 H), 7.79 - 7.86 (m, 4 H).
Example 2.18: Preparation of l-{4'-[2-((Λ)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonyl}-pϊperidin-4-ol (Compound 120).
The title compound was prepared in a similar manner as described in Example 1.2, using l-(4-bromophenylsulfonyl)piperidin-4-ol (284 mg, 0.89 mmol) and (ϋ)-4-(2-(2- methylpyrrolidin-l-yl)ethyl)phenylboronic acid (207 mg, 0.89 mmol) to give 232 mg of the HCl salt in 56% yield. Exact mass calculated for C24H32N2O3S: 428.2, Found: LCMS mlz = 429.6 (M+H4); 1H NMR (400 MHz, Methanol-^) δ 1.32 (d, J= 6.82 Hz, 0.3 H), 1.49 (d, J= 6.57 Hz, 2.7 H), 1.52 - 1.62 (m, 2 H), 1.70 - 1.82 (m, 1 H), 1.83 - 1.92 (m, 2 H), 2.01 - 2.20 (m, 2 H), 2.29 - 2.40 (m, 1 H), 2.75 - 2.87 (m, 2 H), 3.07 - 3.22 (m, 2 H), 3.23 - 3.33 (m, 2 H), 3.33 - 3.42 (m, 2 H), 3.49 - 3.58 (m, 1 H), 3.59 - 3.69 (m, 2 H), 3.72 - 3.82 (m, 1 H), 7.46 (d, J= 8.08 Hz, 2 H), 7.68 (d, J= 8.08 Hz, 2 H), 7.80 - 7.86 (m, 4 H).
Example 2.19: Preparation of 3,5-Dimethyl-4-{4'-[2-((fi)-2-methyl-pyrrolidin-l-yl)-ethyl]- biphenyl-4-sulfonyl}-morpholine (Compound 118). The title compound was prepared in a similar manner as described in Example 1.2, using 4-(4-bromophenylsulfonyl)-3,5-dimethylmorpholine (291 mg, 0.87 mmol) and (i?)-4-(2- (2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (203 mg. 0.87 mmol) to give 304 mg of the HCl salt in 73% yield. Exact mass calculated for C25H34N2O3S: 442.2, Found: LCMS mlz = 443.1 (M+JT); 1H NMR (400 MHz, Methanol-^) δ 1.12 (t, J= 6.95 Hz, 6 H)3 1.32 (d, J= 6.82 Hz, 0.3 H), 1.49 (d, J= 6.32 Hz5 2.7 H), 1.70 - 1.82 (m, 1 H), 1.90 - 1.99 (m, 2 H), 2.02 - 2.21 (m, 2 H), 2.29 - 2.40 (m, 1 H), 3.06 - 3.23 (m, 2 H), 3.22 - 3.32 (m, 2 H), 3.50 - 3.72 (m, 6 H)3 3.72 - 3.81 (m, 1 H), 7.47 (d, J= 8.34 Hz, 2 H), 7.71 (d, J= 8.34 Hz, 2 H), 7.80 - 7.89 (m, 4 H).
Example 2.20: Preparation of 4-{4'-[2-((i?)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- suIfonyIJ-piperazin-2-one (Compound 114).
The title compound was prepared in a similar manner as described in Example 1.2, using 4-(4-bromophenylsulfonyl)piperazin-2-one (279 mg, 0.88 mmol) and (i?)-4-(2-(2- methylpyrrolidin-l-yl)ethyl)phenylboronic acid (204 mg, 0.88 mmol) to give 190 mg of the HCl salt in 47% yield. Exact mass calculated for C23H29N3O3S: 427.2, Found: LCMS mlz = 428.2 (M+H÷); 1H NMR (400 MHz, Methanol-^) δ 1.32 (d, /= 6.82 Hz3 0.3 H), 1.49 (d, J= 6.57 Hz, 2.7 H), 1.70 - 1.83 (m, 1 H), 2.02 - 2.19 (m, 2 H), 2.30 - 2.40 (m, 1 H), 3.07 - 3.21 (m, 2 H), 3.23 - 3.32 (m, 2 H), 3.32 - 3.37 (m, 4 H), 3.49 - 3.58 (m, 1 H), 3.59 - 3.70 (m, 3 H), 3.72 - 3.81 (m, 1 H), 7.47 (d, J= 8.34 Hz, 2 H), 7.70 (d, J= 8.08 Hz, 2 H), 7.85 - 7.92 (m, 4 H).
Example 2.21: Preparation of 4'-[2-((Λ)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonic Acid Bis-(2-hydroxy-ethyl)-amide (Compound 78). The title compound was prepared in a similar manner as described in Example 1.2, using 4-bromo-Nv/V-bis(2-hydroxyethyl)benzenesulfonamide (285 mg, 0.88 mmol) and (R)-4-(2- (2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (205 mg, 0.88 mmol) to give 270 mg of the HCl salt in 66% yield. Exact mass calculated for C23H32N2O4S: 432.2, Found: LCMS mlz = 433.1 (M+ff*); 1H NMR (400 MHz, Methanol-^) δ 1.32 (d, J= 6.82 Hz, 0.3 H), 1.49 (d, J = 6.57 Hz, 2.7 H), 1.70 - 1.82 (m, 1 H), 2.00 - 2.19 (m, 2 H), 2.29 - 2.41 (m, 1 H), 3.05 - 3.22 (m, 2 H), 3.23 - 3.36 (m, 6 H), 3.52 (d, J= 7.07 Hz, 1 H), 3.59 - 3.69 (m, 1 H), 3.69 - 3.81 (m, 5 H), 7.46 (d, J= 8.08 Hz, 2 H), 7.69 (d, J= 8.08 Hz, 2 H), 7.79 - 7.83 (m, 2 H), 7.89 - 7.92 (m32 H).
Example 2.22: Preparation of 4'-[2-((iϊ)-2-Methyl-pyrrolidin-l-yI)-ethyl]-biphenyI-4- sulfonic Acid (2-Hydroxy-l,l-dimethyl-ethyl)-amide (Compound 73).
The title compound was prepared in a similar manner as described in Example 1.2, using 4-bromo-N-(l-hydroxy-2-methylpropan-2-yl)benzenesulfonamide (278 mg, 0.90 mmol) and (R)-4-(2-(2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (210 mg, 0.90 mmol) to give 192 mg of the HCl salt in 47% yield. Exact mass calculated for C23H32N2O3S: 416.2, Found: LCMS mlz = 417 A (M+H4); 1H NMR (400 MHz, Methanol-^) δ 1.11 - 1.15 (m, 6 H), 1.32 (d, J = 6.82 Hz, I H), 1.48 (d, J= 6.57 Hz, 3 H), 1.70 - 1.82 (m, 1 H), 2.02 - 2.19 (m, 2 H), 2.29 - 2.40 (m, 1 H), 3.06 - 3.22 (m, 2 H), 3.22 - 3.32 (m, 2 H), 3.37 - 3.40 (m, 2 H), 3.50 - 3.58 (m, 1 H), 3.59 - 3.69 (m, 1 H), 3.71 - 3.80 (m, 1 H), 7.45 (d, J= 8.34 Hz, 2 H), 7.68 (d, J= 8.08 Hz, 2 H), 7.76 - 7.79 (m, 2 H), 7.93 - 7.96 (m, 2 H).
Example 2.23: Preparation of Propionic acid l-{4'-[2-((i?)-2-methyl-pyrrolidin-l-yl)-ethyl]- biphenyl-4-sulfonyl}-piperidin-4-ylmethyl Ester (Compound 68).
The title compound was prepared in a similar manner as described in Example 1.2, using (l-(4-bromophenylsulfonyl)piperidin-4-yl)methyl propionate (208 mg, 0.53 mmol) and (i?)-4-(2-(2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (124 mg, 0.53 mmol) to give 206 mg of the HCl salt in 72% yield. Exact mass calculated for C28H38N2O4S: 498.3, Found: LCMS mlz = 499.7 (M-I-H+); 1H NMR (400 MHz, Methanol-^,) δ 1.07 (t, J= 7.58 Hz, 3 H), 1.28 - 1.41 (m, 2 H), 1.48 (d, J= 6.57 Hz, 3 H), 1.57 - 1.68 (m, 1 H), 1.71 - 1.82 (m, 3 H), 2.01 - 2.21 (m, 2 H), 2.25 - 2.41 (m, 5 H), 3.05 - 3.22 (m, 2 H), 3.23 - 3.33 (m, 2 H), 3.49 - 3.59 (m, 1 H), 3.60 - 3.69 (m, 1 H), 3.72 - 3.85 (m, 3 H), 3.91 (d, J= 6.06 Hz, 2 H), 7.47 (d, J= 8.08 Hz, 2 H), 7.70 (d, J= 8.34 Hz, 2 H), 7.80 - 7.88 (m, 4 H).
Example 2.24: Preparation of Propionic acid 2-(l-{4'-[2-((2?)-2-methyl-pyrrolidin-l-yl)- ethyl]-biphenyl-4-sulfonyl}-piperidin-4-yl)-ethyl Ester (Compound 63).
The title compound was prepared in a similar manner as described in Example 1.2, using 2-(l-(4-bromophenylsulfonyl)piperidin-4-yl)ethyl propionate (212 mg, 0.52 mmol) and (i?)-4-(2-(2-methylpyrrolidin-l -yl)ethyl)phenylboronic acid (122 mg, 0.52 mmol) to give 191 mg of the HCl salt in 66% yield. Exact mass calculated for C29H40N2O4S: 512.3, Found: LCMS mlz = 513.7 (M+lT); 1H NMR (400 MHz, Methanol-^) δ 1.06 (t, J= 7.58 Hz, 3 H), 1.31 (d, J= 7.33 Hz, 3 H), 1.48 (d, J= 6.57 Hz, 3 H), 1.55 (q, J= 6.32 Hz, 2 H), 1.71 - 1.82 (m, 3 H), 2.02 - 2.21 (m, 2 H), 2.23 - 2.41 (m, 5 H), 3.06 - 3.21 (m, 2 H), 3.22 - 3.34 (m, 2 H), 3.49 - 3.59 (m, 1 H), 3.60 - 3.70 (m, 1 H), 3.71 - 3.80 (m, 3 H), 4.08 (t, J= 6.69 Hz, 2 H), 7.47 (d, J= 8.34 Hz, 2 H), 7.70 (d,J= 8.08 Hz, 2 H), 7.80 - 7.87 (m, 4 H).
Example 2.25: Preparation of ((JR)-l-{4'-[2-((fi)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl- 4-sulfonyl}-pyrrolidin-2-yϊ)-methanoI (Compound 56). The title compound was prepared in a similar manner as described in Example 1.2, using (Λ)-(l-(4-bromophenylsulfonyl)pyrrolidin-2-yl)methanol (164 mg, 0.51 mmol) and (Λ)-4- (2-(2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (119 mg, 0.51 mmol) to give 45.4 mg of the HCl salt in 19% yield. Exact mass calculated for C24H32N2O3S: 428.2, Found: LCMS mlz = 429.4 (M+ET1); 1H NMR (400 MHz, Methanol-^) δ 1.33 (d, J = 6.82 Hz, 0.3 H), 1.47 (d, J= 6.57 Hz, 2.7 H)3 1.50 - 1.64 (m, 2 H), 1.69 - 1.92 (m, 3 H), 2.00 - 2.19 (m, 2 H), 2.29 - 2.40 (m, 1 H), 3.02 - 3.30 (m, 5 H), 3.38 - 3.46 (m, 1 H), 3.55 (dd, J= 10.48, 7.20 Hz, 2 H), 3.59 - 3.81 (m, 4 H), 7.45 (d, J= 8.08 Hz, 2 H), 7.69 (d, J= 8.34 Hz, 2 H), 7.83 - 7.86 (m, 2 H), 7.90 - 7.93 (m, 2 H).
Example 2.26: Preparation of ((5)-l-{4'-[2-((iR)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl- S 4-suIfonyl}-pyrroIidin-2-yl)-methanol (Compound 59).
The title compound was prepared in a similar manner as described in Example 1.2, using (5)-(l-(4-bromophenylsulfonyl)pyrrolidin-2-yl)methanol (170 mg, 0.53 mmol) and (R)A- (2-(2-methylpyrrolidin-l-yl)ethyl)pheπylboroπic acid (124 mg, 0.53 mmol) to give 32 mg of the HCl salt in 13% yield. Exact mass calculated for C24H32N2O3S: 428.2, Found: LCMS m/z = 0 429.4 (M+HT); 1H NMR (400 MHz5 Methanol-^) δ 1.31 (d, J = 6.82 Hz, 0.3 H), 1.47 (d, J = 6.57 Hz, 2.7 H), 1.51 - 1.62 (m, 2 H), 1.69 - 1.91 (m, 3 H), 2.01 - 2.20 (m, 2 H), 2.34 (t, J= 12.63 Hz, 1 H), 3.03 - 3.29 (m, 5 H), 3.42 (dd, 1 H), 3.55 (dd, J= 10.48, 7.20 Hz, 2 H), 3.60 - 3.70 (m, 2 H), 3.70 - 3.80 (m, 2 H), 7.46 (d, J = 8.08 Hz, 2 H), 7.70 (d, J= 8.34 Hz, 2 H), 7.83 - 7.87 (m, 2 H), 7.90 - 7.94 (m, 2 H). 5
Example 2.27: Preparation of Propionic acid l-{4'-[2-((2?)-2-methyl-pyrrolidin-l-yl)-ethyI]- biphenyl-4-sulfonyI}-piperidin-4-yl Ester (Compound 53).
The title compound was prepared in a similar manner as described in Example 1.2, using l-(4-bromophenylsulfonyl)piperidin-4-yl propionate (179 mg, 0.48 mmol) and (R)-4-(2-0 (2-methylpyrrolidin-l -yl)ethyl)phenylboronic acid (111 mg, 0.48 mmol) to give 62 mg of the HCl salt in 25% yield. Exact mass calculated for C27H36N2O4S: 484.2, Found: LCMS m/z = 485.4 (M+H+); 1H NMR (400 MHz, Methanol-^) δ 1.01 (t, J= 7.58 Hz, 3 H), 1.33 (d, J= 6.82 Hz, 0.3 H), 1.48 (d, J= 6.57 Hz, 2.7 H), 1.68 - 1.82 (m, 3 H), 1.89 - 2.00 (m, 2 H), 2.02 - 2.19 (m, 2 H), 2.24 (q, J= 7.58 Hz, 2 H), 2.30 - 2.39 (m, 1 H), 2.97 - 3.05 (m, 2 H), 3.08 - 3.19 (m, 25 H), 3.21 - 3.30 (m, 4 H), 3.51 - 3.58 (m, 1 H), 3.60 - 3.70 (m, 1 H), 3.71 - 3.80 (m, 1 H), 4.74 - 4.82 (m, 1 H), 7.47 (d, J= 8.08 Hz, 2 H), 7.70 (d, J= 8.08 Hz, 2 H), 7.82 - 7.88 (m, 4 H).
Example 2.28: Preparation of (Λ)-2-(Methoxymethyl)-l-(4'-(2-((Λ)-2-methylpyrrolidin-l- yl)ethyl)biphenyl-4-ylsulfonyl)pyrrolidine (Compound 48). 0 The title compound was prepared in a similar manner as described in Example 1.2, using (R)-I -(4-bromophenylsulfonyl)-2-(methoxymethyl)pyrrolidine (174 mg, 0.52 mmol) and (iϊ)-4-(2-(2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (121 mg, 0.52 mmol) to give 155 mg of the HCl salt in 62% yield. Exact mass calculated for C25H34N2O3S: 442.2, Found: LCMS m/z = 443.4 (M+lT); 1H NMR (400 MHz, Methanol-^) δ 1.32 (d, J = 6.82 Hz, 0.3 H)5 1.48 (d,5 J= 6.32 Hz, 2.7 H), 1.57 (d, J= 12.88 Hz, 2 H), 1.70 - 1.90 (m, 3 H), 2.01 - 2.20 (m, 2 H), 2.35 (d, J= 8.08 Hz, 1 H), 3.05 - 3.23 (m, 3 H), 3.23 - 3.31 (m, 2 H), 3.36 (s, 3 H), 3.37 - 3.43 (m, 2 H)3 3.49 - 3.69 (m, 3 H)3 3.72 - 3.80 (m, 2 H)3 7.46 (d, J= 8.08 Hz3 2 H)3 7.70 (d, J= 8.08 Hz3 2 H), 7.83 - 7.87 (m, 2 H), 7.90 - 7.93 (m, 2 H).
Example 2.29: Preparation of (S)-2-(Methoxymethyl)-l-(4'-(2-((i?)-2-methylpyrrolidin-l- yI)ethyI)biphenyl-4-yIsuIfonyl)pyrrolidine (Compound 51).
The title compound was prepared in a similar manner as described in Example 1.2, using (5)-l-(4-bromophenylsulfonyl)-2-(methoxymethyl)pyrrolidine (174 mg, 0.52 mmol) and (Λ)-4-(2-(2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (121 mg, 0.52 mmol) to give 165 mg of the HCl salt in 66% yield. Exact mass calculated for C25H34N2O3S: 442.2, Found: LCMS mlz = 443.6 (M+H4); 1H NMR (400 MHz, Methanol-^) δ 1.32 (d, J = 6.82 Hz, 0.3 H), 1.49 (d, J= 6.57 Hz, 2.7 H), 1.52 - 1.62 (m, 2 H), 1.72 - 1.89 (m, 3 H), 2.03 - 2.20 (m, 2 H), 2.30 - 2.39 (m, 1 H), 3.07 - 3.22 (m, 3 H), 3.22 - 3.31 (m, 2 H), 3.36 (s, 3 H), 3.37 - 3.43 (m, 2 H), 3.50 - 3.69 (m, 3 H), 3.72 - 3.80 (m, 2 H), 7.46 (d, J= 8.08 Hz3 2 H)3 7.69 (d, J= 8.08 Hz, 2 H), 7.83 - 7.86 (m, 2 H), 7.89 - 7.93 (m, 2 H).
Example 2.30: Preparation of (Λ)-l-{4'-[2-((Λ)-2-Methyl-pyrrolidin-l-yl)-ethyI]-biphenyI- 4-sulfonyl}-pyrrolidin-3-oI (Compound 129).
The title compound was prepared in a similar manner as described in Example 1.2, using (i?)-l-(4-bromophenylsulfonyl)pyrrolidin-3-ol (154 mg, 0.50 mmol) and (i?)-4-(2-(2- methylpyrrolidin-l-yl)ethyl)phenylboronic acid (117 mg, 0.50 mmol) to give 127 mg of the HCl salt in 56% yield. Exact mass calculated for C23H30N2O3S: 414.2, Found: LCMS mlz = 415.2 (M+H^); 1H NMR (400 MHz, Methanol-^) δ 1.32 (d, J= 6.82 Hz, 0.3 H), 1.49 (d, J= 6.32 Hz, 2.7 H), 1.72 - 1.82 (m, 2 H)5 1.82 - 1.93 (m, 1 H), 2.02 - 2.21 (m, 2 H), 2.29 - 2.40 (m, 1 H), 3.07 - 3.22 (m, 3 H), 3.23 - 3.32 (m, 2 H), 3.34 - 3.42 (m, 3 H)3 3.49 - 3.58 (m, 2 H), 3.59 - 3.69 (m, 1 H)3 3.72 - 3.81 (m, 1 H), 4.26 - 4.30 (m3 1 H), 7.46 (d, J= 8.08 Hz, 2 H), 7.68 (d, J= 8.34 Hz, 2 H), 7.81 - 7.84 (m, 2 H), 7.87 - 7.90 (m, 2 H).
Example 2.31: Preparation of Propionic Acid (fi)-l-{4l-[2-((i?)-2-Methyl-pyrrolidin-l-yl)- ethyl]-biphenyl-4-sulfonyl}-pyrrolidin-2-ylmethyl Ester (Compound 74). The title compound was prepared in a similar manner as described in Example 1.2, using (JR)-(l-(4-bromophenylsulfonyl)pyrrolidin-2-yl)methyl propionate (191 mg, 0.51 mmol) and (R)-4-(2-(2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (118 mg, 0.51 mmol) to give 176 mg of the HCl salt in 67% yield. Exact mass calculated for C27H36N2O4S: 484.2, Found: LCMS mlz = 485.4 (M+H*); 1H NMR (400 MHz, Methanol-^) δ 1.11 (t, J= 7.45 Hz, 3 H), 1.32 (d, J= 6.82 Hz, 0.3 H), 1.48 (d, J= 6.57 Hz, 2.7 H), 1.51 - 1.71 (m, 3 H), 1.72 - 1.81 (m, 2 H), 1.82 - 1.95 (m3 1 H), 2.07 (s, 2 H), 2.35 (q, J= 7.41 Hz, 3 H), 3.05 - 3.21 (m, 2 H)3 3.23 - 3.32 (m3 2 H), 3.38 - 3.49 (m, 1 H), 3.50 - 3.59 (m, 1 H), 3.59 - 3.70 (m, 1 H), 3.71 - 3.81 (m, 1 H), 3.89 - 3.97 (m, 1 H)3 4.09 - 4.16 (m, 1 H), 4.18 - 4.25 (m, 1 H), 7.47 (d, J= 8.08 Hz, 2 H), 7.70 (d, J= 8.08 Hz, 2 H), 7.83 - 7.87 (m, 2 H), 7.90 - 7.94 (m, 2 H).
Example 2.32: Preparation of Propionic Acid (5)-l-{4'-[2-((JR)-2-Methyl-pyrro]idin-l-yl)- ethyIl-biphenyl-4-sulfonyl}-pyrrolidin-2-ylmethyl Ester (Compound 79).
The title compound was prepared in a similar manner as described in Example 1.2, using (>S)-(l-(4-bromophenylsulfonyl)pyrrolidm-2-yl)methyl propionate (181 mg, 0.48 mmol) and (i?)-4-(2-(2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (112 mg, 0.48 mmol) to give 165 mg of the HCl salt in 66% yield. Exact mass calculated for C27H36N2O4S: 484.2, Found: LCMS mlz = 485.5 (M+Hf); 1H NMR (400 MHz, Methanol-^,) δ 1.08 - 1.14 (m, 3 H), 1.32 (d, J = 6.82 Hz, 0.3 H), 1.46 - 1.50 (m, 2.7 H), 1.53 - 1.70 (m, 3 H), 1.72 - 1.81 (m, 2 H), 1.83 - 1.94 (m, 1 H)3 2.01 - 2.20 (m, 2 H)3 2.30 - 2.40 (m, 3 H)3 3.06 - 3.21 (m, 2 H)3 3.22 - 3.33 (m, 2 H)3 3.40 - 3.48 (m, 1 H), 3.50 - 3.58 (m, 1 H), 3.60 - 3.69 (m, 1 H), 3.72 - 3.81 (m, 1 H), 3.89 - 3.97 (m, 1 H), 4.09 - 4.16 (m, 1 H), 4.19 - 4.25 (m, 1 H), 7.47 (d, J= 8.08 Hz, 2 H), 7.70 (d, J= 8.34 Hz, 2 H), 7.83 - 7.86 (m, 2 H), 7.90 - 7.93 (m, 2 H).
Example 2.33: Preparation of Propionic Acid 2-(Methyl-{4'-[2-((Λ)-2-methyl-pyrrolidin-l- yl)-ethyI]-biphenyl-4-sulfonyI}~amino)-ethyl Ester (Compound 69).
The title compound was prepared in a similar manner as described in Example 1-2, using 2-(4-bromo-N-methylphenylsulfonamido)ethyl propionate (159 mg, 0.45 mmol) and (R)- 4-(2-(2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (106 mg, 0.45 mmol) to give 142 mg of the HCl salt in 63% yield. Exact mass calculated for C25H34N2O4S: 458.2, Found: LCMS mlz = 459.6 (M+ϊt); 1H NMR (400 MHz, Methanol-^) δ 1.09 (t, J- 7.58 Hz, 3 H), 1.32 (d, J= 7.07 Hz, 0.3 H), 1.48 (d, J= 6.57 Hz, 2.7 H), 1.71 - 1.82 (m, 1 H), 2.02 - 2.19 (m, 2 H), 2.28 - 2.40 (m, 3 H), 2.84 (s, 3 H), 3.07 - 3.20 (m, 2 H), 3.23 - 3.32 (m, 2 H), 3.30 - 3.36 (m, 2 H), 3.53 (s, 1 H), 3.59 - 3.69 (m, 1 H), 3.71 - 3.81 (m, 1 H), 4.22 (t, J= 5.43 Hz, 2 H), 7.47 (d, J= 8.34 Hz, 2 H), 7.69 (d, J= 8.08 Hz, 2 H)3 7.81 - 7.88 (m, 4 H).
Example 2.34: Preparation of (5)-l-{4'-[2-((/ir)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl- 4-sulfonyl}-pyrrolidin-3-ol (Compound 45).
The title compound was prepared in a similar mariner as described in Example 1.2, using (S)-I -(4-bromophenylsulfonyl)pyrrolidin-3-ol (147 mg, 0.48 mmol) and (Z?)-4-(2-(2- methylpyrrolidin-l-yl)ethyl)plienylboronic acid (112 mg, 0.48 mmol) to give 161 mg of the HCl salt in 74% yield. Exact mass calculated for C23H30N2O3S: 414.2, Found: LCMS mlz - 415.2 (M+KT); 1H NMR (400 MHz, Methanol-^) δ 1.32 (d, J= 6.82 Hz, 0.3 H)3 1.49 (d, J= 6.57 Hz, 2.7 H), 1.72 - 1.82 (m, 2 H), 1.82 - 1.94 (m, 1 H), 2.01 - 2.19 (m, 2 H), 2.30 - 2.40 (m, 1 H), 3.06 - 3.22 (m, 3 H), 3.23 - 3.32 (m, 2 H), 3.34 - 3.41 (m, 3 H), 3.50 - 3.58 (m, 1 H), 3.60 - 3.69 (m, 1 H), 3.72 - 3.81 (m, 1 H), 4.26 - 4.32 (m, 1 H), 7.46 (d, J= 8.34 Hz, 2 H), 7.68 (d, J = 8.08 Hz, 2 H), 7.81 - 7.85 (m, 2 H), 7.87 - 7.91 (m, 2 H).
Example 2.35: Preparation of Propionic Acid (A>l-{4'-[2-((2.>2-methyI-pyrrolidin-l-yl)- ethyl]-biphenyl-4-sulfonyl}-pyrroIidin-3-yl Ester (Compound 119).
The title compound was prepared in a similar manner as described in Example 1.2, using (Λ)-l-(4-bromophenylsulfonyl)pyrrolidin-3-yl propionate (174 mg, 0.48 mmol) and (R)-4- (2-(2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (112 mg, 0.48 mmol) to give 96 mg of the HCl salt in 39% yield. Exact mass calculated for C26H34N2O4S: 470.2, Found: LCMS mlz = 471.7 (TvH-H+); 1H NMR (400 MHz, Methanol-^) δ 0.84 (t, J= 7.58 Hz, 3 H), 1.32 (d, J= 6.82 Hz, 0.3 H), 1.49 (d, J= 6.57 Hz, 2.7 H), 1.69 - 2.18 (m, 7 H), 2.30 - 2.41 (m, 1 H), 3.05 - 3.22 (m, 2 H), 3.23 - 3.40 (m, 4 H), 3.45 - 3.58 (m, 3 H), 3.61 - 3.70 (m, 1 H), 3.72 - 3.82 (m, 1 H), 5.10 (t, J= 4.29 Hz, 1 H), 7.47 (d, J= 8.08 Hz, 2 H), 7.69 (d, J= 8.08 Hz, 2 H), 7.84 - 7.92 (m, 4 H).
Example 2.36: Preparation of Propionic Acid 2-Methyl-2-{4'-[2-((i?)-2-methyl-pyrrolidin- l-yl)-ethyl]-biphenyl-4-sulfonylamino}-propyl Ester (Compound 121).
The title compound was prepared in a similar manner as described in Example 1.2, using 2-(4-bromophenylsulfonamido)-2-methylpropyl propionate (186 mg, 0.51 mmol) and (R)- 4-(2-(2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (119 mg, 0.51 mmol) to give 167 mg of the HCl salt in 64% yield. Exact mass calculated for C26H36N2O4S: 472.2, Found: LCMS mlz = 473.7 (M+H÷); 1H NMR (400 MHz, Methanol-^) δ 1.00 (t, J= 7.58 Hz, 3 H), 1.22 (s, 6 H), 1.32 (d, J = 6.82 Hz, 0.3 H), 1.49 (d, J= 6.57 Hz, 2.7 H), 1.71 - 1.83 (m, 1 H), 2.01 - 2.24 (m, 4 H), 2.29 - 2.40 (m, 1 H), 3.06 - 3.20 (m, 2 H), 3.23 - 3.33 (m, 2 H), 3.50 - 3.58 (m, 1 H)5 3.59 - 3.69 (m, 1 H), 3.72 - 3.80 (m, 1 H), 3.94 (s, 2 H), 7.45 (d, J= 8.08 Hz, 2 H), 7.67 (d, J= 8.34 Hz, 2 H), 7.76 (d, J= 8.59 Hz, 2 H), 7.92 (d, J= 8.59 Hz, 2 H).
Example 2.37: Preparation of Propionic Acid (-S)-l-{4'-[2-((R>2-Methyl-pyrrolidin-l-yl)- ethyl]-biphenyl-4-suIfonyl}-pyrrolidin-3-yI Ester (Compound 127). The title compound was prepared in a similar manner as described in Example 1.2, using (,S)-l-(4-bromophenylsulfonyl)pyrrolidin-3-yl propionate (182 mg, 0.50 mmol) and (R)-4- (2-(2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (117 mg, 0.50 mmol) to give 182 mg of the HCl salt in 72% yield. Exact mass calculated for C26H34N2O4S: 470.2, Found: LCMS mlz = AlU (MfH+); 1H NMR (400 MHz, Methanol-^) δ 0.81 - 0.86 (m, 3 H), 1.32 (d, J= 6.82 Hz, 0.3 H), 1.49 (d, J= 6.57 Hz, 2.7 H), 1.71 - 2.21 (m, 7 H), 2.29 - 2.41 (m, 1 H), 3.08 - 3.23 (m, 2 H), 3.23 - 3.40 (m, 4 H), 3.45 - 3.58 (m, 3 H), 3.60 - 3.69 (m, 1 H), 3.72 - 3.81 (m, 1 H), 5.09 (t, J= 4.29 Hz, 1 H), 7.47 (d, J= 8.08 Hz, 2 H), 7.68 (d, J= 8.08 Hz, 2 H), 7.88 (q, J= 8.59 Hz, 4 H).
Example 2.38: Preparation of (5)-l-{4f-[2-((Λ>2-MethyI-pyrrolid[in-l-yl)-ethyl]-biphenyl- 4-sulfonyl}-pyrrolidine-2-carboxylic Acid Methylamide (Compound 116).
The title compound was prepared in a similar manner as described in Example 2.9, using (5)-N-methylpyrrolidine-2-carboxamide hydrochloride (110 mg, 0.67 mmol) and (R)-A'- (2-(2-methylpyrrolidin-l-yl)ethyl)biphenyl-4-sulfonyl chloride (0.221 mg, 0.61 mmol) to give 183 mg of the HCl salt in 61% yield. Exact mass calculated for C25H33N3O3S: 455.2, Found: LCMS mlz = 456.4 (IVB-H+); 1H NMR (400 MHz, Methanol-^) δ 1-32 (d, J= 6.82 Hz, 0.3 H), 1.49 (d, J= 6.32 Hz, 2.7 H), 1.58 - 1.66 (m, 1 H), 1.71 - 1.96 (m, 4 H), 2.00 - 2.20 (m, 2 H), 2.29 - 2.41 (m, 1 H), 2.78 (s, 3 H), 3.23 - 3.34 (m, 5 H), 3.50 - 3.68 (m, 3 H), 3.72 - 3.81 (m, 1 H), 4.07 (dd, J= 8.21, 3.66 Hz, 1 H), 7.47 (d, J= 8.08 Hz, 2 H), 7.69 (d, J= 8.08 Hz, 2 H), 7.84 - 7.88 (m, 2 H), 7.91 - 7.94 (m, 2 H).
Example 2.39: Preparation of (5)-l-{4f-[2-((ϋ;>-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl- 4-sulfonyl}-pyrrolidine-2-carboxylic Acid (Compound 110).
The title compound was prepared in a similar manner as described in Example 2.9, using (iS)-methyl pyrrolidine-2-carboxylate hydrochloride (108 mg, 0.65 mmol) and (i?)-4'-(2- (2-methylpyrrolidin-l-yl)ethyl)biphenyl-4-sulfonyl chloride (216 mg, 0.59 mmol) to give 118 mg of the HCl salt in 40% yield. Exact mass calculated for C24H30N2O4S: 442.2, Found: LCMS mlz = 443.6 (M+H4); 1H NMR (400 MHz, Methanol-^) δ 1.38 (d, J= 6.82 Hz, 0.3 H), 1.50 (d, J= 6.57 Hz, 2.7 H), 1.65 - 1.85 (m, 2 H), 1.86 - 2.18 (m, 6 H), 2.29 - 2.40 (m, 1 H), 3.11 - 3.21 (m, 2 H), 3.22 - 3.36 (m, 2 H), 3.46 - 3.68 (m, 3 H), 3.73 - 3.81 (m, 1 H), 4.20 - 4.27 (m, 1 H), 7.48 (d, J= 8.34 Hz, 2 H), 7.69 (d, J= 8.34 Hz, 2 H), 7.83 - 7.87 (m, 2 H), 7.92 - 7.95 (m, 2 H).
Example 2.40: Preparation of (l-{4'-[2-((iϊ)-2-Metliyl-pyrrolidin-l-yl)-ethyl]-biphenyI-4- sulfonyl}-piperidin-2-yl)-methanoI (Compound 104).
The title compound was prepared in a similar manner as described in Example 2.9, using piperidin-2-ylmethanol (66 mg, 0.57 mmol) and (i-)-4'-(2-(2-methylpyrrolidin-l- yl)ethyl)biphenyl-4-sulfonyl chloride (209 mg, 0.57 mmol) to give 134 mg of the HCl salt in 49% yield. Exact mass calculated for C25H34N2O3S: 442.2, Found: LCMS mlz - AAS1 A (M+H1"); 'H NMR (400 MHz, Methanol-^) δ 1.19 - 1.44 (m, 2 H), 1.45 - 1.58 (m, 6 H), 1.70 - 1.82 (m, 2 H), 2.01 - 2.20 (m, 2 H), 2.30 - 2.40 (m, 1 H), 3.00 - 3.21 (m, 3 H), 3.23 - 3.33 (m, 2 H), 3.50 - 3.69 (m, 4 H)5 3.72 - 3.82 (m, 2 H), 4.02 - 4.10 (m, 1 H), 7.46 (d, J= 8.08 Hz, 2 H), 7.68 (d, J= 8.08 Hz, 2 H), 7.80 (d, J= 8.59 Hz, 2 H), 7.90 - 7.92 (m, 2 H). Example 2.41: Preparation of (l-{4'-[2-((i?)-2-Methyl-pyrrolidin-l-yl)-ethyI]-biphenyl-4- sulfonyl}-piperidin-3-yl)-methanol (Compound 98).
The title compound was prepared in a similar manner as described in Example 2.9, using pipεridin-3-yImethanol (71 mg, 0.62 mmol) and (R)-4'-(2-(2-methylpyrrolidm-l- yl)ethyl)biphenyl-4-sulfonyl chloride (225 mg, 0.62 mmol) to give 109 mg of the HCl salt in 37% yield. Exact mass calculated for C25H34N2O3S: 442.2, Found: LCMS mlz = 443.6 04+H+); 1H NMR (400 MHz, Methanol-^Methanol-^ethanol-ώ,) δ 0.90 - 1.04 (m, 1 H), 1.32 (d, J= 6.82 Hz, 0.3 H), 1.49 (d, J = 6.57 Hz, 2.7 H), 1.54 - 1.70 (m, 2 H), 1.72 - 1.82 (m, 3 H), 2.02 - 2.21 (m, 3 H), 2.29 - 2.41 (m, 2 H), 3.06 - 3.22 (m, 2 H), 3.22 - 3.36 (m, 3 H), 3.50 - 3.58 (m, 2 H), 3.58 - 3.69 (m, 2 H), 3.71 - 3.81 (m, 2 H), 7.47 (d, J= 8.08 Hz, 2 H)5 7.69 (d, J= 8.34 Hz, 2 H), 7.80 - 7.86 (m, 4 H).
Example 2.42: Preparation of l-(4-{4'-[2-((i?)-2-Methyl-pyrroIidin-l-yl)-ethyI]-biphenyI-4- sulfonyl}-piperazin-l-yl)-propan-l-one (Compound 92). The title compound was prepared in a similar manner as described in Example 2.9, using l-(piperazin-l-yl)propan-l-one hydrochloride (105 mg, 0.59 mmol) and (fl)-4'-(2-(2- methylρyrrolidin-l-yl)ethyl)biphenyl-4-sulfonyl chloride (214 mg, 0.59 mmol) to give 70 mg of the HCl salt in 24% yield. Exact mass calculated for C26H35N3O3S: 469.2, Found: LCMS mlz = 470.6 (MH-H+); 1H NMR (400 MHz, Methanol-^) δ 1.02 (t, J= 7.45 Hz, 3 H), 1.32 (d, J= 6.82 Hz, 0.3 H), 1.48 (d, J= 6.32 Hz, 2.7 H), 1.70 - 1.83 (m, 1 H), 2.02 - 2.18 (m, 2 H), 2.30 - 2.39 (m, 3 H), 2.97 - 3.07 (m, 4 H), 3.08 - 3.21 (m, 2 H), 3.22 - 3.34 (m, 2 H), 3.50 - 3.57 (m, 1 H), 3.58 - 3.69 (m, 5 H), 3.71 - 3.80 (m, 1 H), 7.47 (d, J= 8.34 Hz, 2 H), 7.69 (d, J= 8.08 Hz, 2 H), 7.81 - 7.88 (m, 4 H).-
Example 2.43: Preparation of 4'-[2-((JR)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonic Acid Benzyl-(2-methoxy-ethyl)-amide (Compound 86).
(Λ)-N-(2-methoxyethyl)-4'-(2-(2-methylpyrrolidin-l-yl)ethyl)biphenyl-4-sulfonamide hydrochloride (277 mg, 0.63 mmol), and sodium hydride, 60% dispersion in mineral oil (76.1 mg, 1.89 mmol) were combined in a dry round bottom flask under argon. Anhydrous dimethylformamide (4 mL) was added followed by (bromomethyl)benzene (130 mg, 0.76 mmol), and the mixture stirred overnight. The resulting crude was dissolved in dilute acetic acid and purified by preparative HPLC. The product containing fractions were pooled and the acetonitrile removed under reduced pressure. The resulting aqueous layer was made basic (pH ~ 10) with 2 M sodium carbonate solution and extracted with ethyl acetate (50 mL). The aqueous layer was then saturated with sodium chloride and extracted with ethyl acetate (2 x 25 mL). The ethyl acetate extracts were combined, dried with magnesium sulfate, and filtered. 1 M HCl in diethyl ether (1.5 eq.) was added and the solvent removed under reduced pressure to yield 54 mg of the HCl salt as a white solid (16% yield). Exact mass calculated for C29H36N2O3S: 492.2, Found: LCMS mlz = 493.5 QVH-H+); 1H NMR (400 MHz, Methanol-ώ^VIethanol-ό,) δ 1.32 (d, J = 6.82 Hz5 0.3 H), 1.49 (d, J= 6.57 Hz, 2.7 H), 1.71 - 1.83 (m, 1 H), 2.02 - 2.21 (m, 2 H), 2.29 - 2.42 (m, 1 H), 3.07 (s, 3 H), 3.09 - 3.21 (m, 2 H), 3.23 - 3.35 (m, 6 H), 3.49 - 3.58 (m, 1 H), 3.59 - 3.69 (m, 1 H), 3.72 - 3.81 (m, 1 H), 4.44 (s, 2 H), 7.24 - 7.33 (m, 5 H), 7.47 (d, J= 8.08 Hz, 2 H), 7.68 (d, J= 7.58 Hz, 2 H), 7.81 (d, J= 8.34 Hz, 2 H), 7.91 (d, 7= 8.34 Hz, 2 H).
Example 2.44: Preparation of 4'-[2-((Λ)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonic Acid Isopropyl-(2-methoxy-ethyl)-amide (Compound 80). The title compound was prepared in a similar manner as described in Example 2.43, using 2-iodopropane (128 mg, 0.76 mmol) and ((i?)-N-(2-methoxyethyl)-4'-(2-(2- methylpyrrolidin-l-yl)ethyl)biphenyl-4-sulfonamide hydrochloride (221 mg, 0.50 mmol) to give 46 mg of the HCl salt in 19% yield. Exact mass calculated for C25H36N2O3S: 444.2, Found: LCMS mlz = 445.7 (M+lT); 1H NMR (400 MHz, Methanol-**,,) δ 1.04 (d, J = 6.82 Hz, 6 H), 1.32 (d, J= 6.82 Hz, 0.3 H), 1.48 (d, J= 6.57 Hz, 2.7 H), 1.70 - 1.83 (m, 1 H), 2.01 - 2.20 (m, 2 H), 2.28 - 2.41 (m, 1 H), 3.06 - 3.21 (m, 2 H), 3.22 - 3.38 (m, 7 H), 3.50 - 3.69 (m, 4 H), 3.71 -
3.81 (m, 1 H), 4.01 - 4.13 (m, 1 H), 7.46 (d, J= 8.08 Hz, 2 H), 7.68 (d, J= 8.08 Hz, 2 H), 7.79 -
7.82 (m, 2 H), 7.88 - 7.91 (m, 2 H).
Example 2.45: Preparation of 4'-[2-((Λ)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonic Acid Isobutyl-(2-methoxy-ethyl)-amide (Compound 75).
The title compound was prepared in a similar manner as described in Example 2.43, using 1 -broτno-2-methylpropane (104 mg, 0.76 mmol) and ((i?)-N-(2-methoxyethyl)-4'-(2-(2- methylpyrrolidin-l-yl)ethyl)biphenyl-4-sulfonamide hydrochloride (222 mg, 0.51 mmol) to give 117 mg of the HCl salt in 47% yield. Exact mass calculated for C26H38N2O3S: 458.3, Found: LCMS mlz = 459.6 (M-I-H+); 1H NMR (400 MHz, Methanol-^) δ 0.94 (d, J = 6.82 Hz, 6 H), 1.35 (d, J = 6.82 Hz, 0.3 H)3 1.51 (d, J= 6.57 Hz, 2.7 H), 1.72 - 1.84 (m, I H), 1.93 - 2.02 (m, 1 H), 2.04 - 2.22 (m, 2 H), 2.33 - 2.43 (m, 1 H), 3.01 (d, J= 7.58 Hz, 2 H), 3.07 - 3.22 (m, 2 H), 3.26 (s, 3 H), 3.28 - 3.36 (m, 4 H), 3.48 - 3.59 (m, 3 H), 3.63 - 3.72 (m, 1 H), 3.74 - 3.83 (m, 1 H), 7.49 (d, J= 8.08 Hz, 2 H), 7.73 (d, J= 8.08 Hz, 2 H), 7.83 - 7.86 (m, 2 H), 7.89 - 7.93 (m, 2 H).
Example 2.46: Preparation of 4T-[2-((JR)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonic Acid (2~Methoxy-ethyl)-(tetrahydro-pyran-4-ylmethyl)-amide (Compound 70). The title compound was prepared in a similar manner as described in Example 2.43, using 4-(bromomethyl)tetrahydro-2i7-pyran (146 mg, 0.81 mmol) and ((/.)-N-(2-methoxyethyl)- 4'-(2-(2-methylpyrrolidin-l-yl)ethyl)biphenyl-4-sulfonamide hydrochloride (238 mg, 0.54 mmol) to give 127 mg of the HCl salt in 44% yield. Exact mass calculated for C2SH40N2O4S: 500.3, Found: LCMS m/z = 501.5 (M+H4); 1H NMR (400 MHz, Methanol-^) δ 1.20 - 1.32 (m, 2 H), 1.35 (d, J= 6.82 Hz, 0.3 H), 1.51 (d, J= 6.57 Hz, 2.7 H), 1.68 (dd, J= 12.88, 1.77 Hz, 2 H), 1.73 - 1.86 (m, 1 H), 1.92 - 2.03 (m, 1 H), 2.05 - 2.22 (m, 2 H), 2.31 - 2.44 (m, 1 H), 3.08 - 3.10 (m, 2 H), 3.12 - 3.23 (m, 2 H), 3.24 - 3.45 (m, 9 H), 3.49 - 3.60 (m, 3 H), 3.62 - 3.72 (m, 1 H), 3.74 - 3.84 (m, 1 H), 3.95 (dd, J= 11.49, 2.65 Hz, 2 H), 7.49 (d, J= 8.08 Hz, 2 H), 7.71 (d, J = 8.34 Hz, 2 H), 7.83 - 7.86 (m, 2 H), 7.90 - 7.93 (m, 2 H).
Example 2.47: Preparation of Acetic Acid 2-(AcetyI-{4'-[2-((JR)-2-methyl-pyrrolidin-l-yI)- ethyl]-biphenyl-4-sulfonyI}-amino)-ethyl Ester (Compound 65).
The title compound was prepared in a similar manner as described in Example 1.2, using 2-(N-(4-bromophenylsulfonyl)acetamido)ethyl acetate (195 mg, 0.54 mmol) and (i?)-4-(2- (2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (125 mg, 0.54 mmol) to give 123 mg of the HCl salt in 45% yield. Exact mass calculated for C25H32N2O5S: 472.2, Found: LCMS mlz = 473.6 (M+H*); 1H NMR (400 MHz, Methanol-^) δ 1.32 (d, J= 6.82 Hz, 0.3 H), 1.49 (d, J= 6.57 Hz, 2.7 H), 1.70 - 1.82 (ni, 1 H), 2.03 (s, 3 H), 2.04 - 2.21 (m, 2 H), 2.29 - 2.40 (m, 4 H), 3.07 - 3.22 (m, 2 H), 3.22 - 3.33 (m, 2 H), 3.50 - 3.58 (m, 1 H), 3.59 - 3.69 (m, 1 H), 3.72 - 3.81 (m, 1 H), 4.14 (t, J= 5.43 Hz, 2 H), 4.32 (t, J= 5.43 Hz, 2 H), 7.47 (d, J= 8.34 Hz, 2 H), 7.70 (d, J= 8.08 Hz, 2 H), 7.84 - 7.88 (m, 2 H), 7.99 - 8.03 (m, 2 H).
Example 2.48: Preparation of 4'-[2-((R)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sυlfonic Acid Acetyl-(2-hydroxy-ethyl)-amide (Compound 60).
The title compound was prepared in a similar manner as described in Example 1.2, using 2-(N-(4-bromophenylsulfonyl)acetamido)ethyl acetate (195 mg, 0.54 mmol) and (Λ)-4-(2- (2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (125 mg, 0.54 mmol) to give 57 mg of the HCl salt in 23% yield. Exact mass calculated for C23H30N2O4S: 430.2, Found: LCMS mlz = 431.5 (M+H"1"); 1H NMR (400 MHz, Methanol-^) δ 1.32 (d, J= 6.82 Hz, 0.3 H), 1.48 (t, J= 6.06 Hz, 2.7 H), 1.70 - 1.82 (m, 1 H), 1.95 (s, 3 H), 2.01 - 2.21 (m, 2 H), 2.29 - 2.40 (m, 1 H), 3.06 - 3.21 (m, 4 H), 3.23 - 3.35 (m, 2 H), 3.49 - 3.58 (m, 1 H), 3.59 - 3.69 (m, 1 H), 3.72 - 3.81 (m, 1 H), 4.02 - 4.07 (m, 2 H), 7.46 (d, J= 8.34 Hz, 2 H), 7.68 (d, J= 8.34 Hz, 2 H), 7.79 - 7.82 (m, 2 H), 7.89 - 7.93 (m, 2 H).
Example 2.49: Preparation of 4'-[2-((Λ)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonic Acid Benzyl-(2-hydroxy-ethyl)-amide (Compound 57). The title compound was prepared in a similar manner as described in Example 1.2, using 7V-benzyl-4-bromo-N-(2-hydroxyethyl)benzenesulfonamide (205 mg, 0.55 mmol) and (R)- 4-(2-(2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (129 mg, 0.55 mmol) to give 158 mg of the HCl salt in 55% yield. Exact mass calculated for C28H34N2O3S: 478.2, Found: LCMS mlz = 479.4 (M+H+); 1H NMR (400 MHz, Methanol-^) δ 1.32 (d, J= 6.82 Hz, 0.3 H), 1.49 (d, J= 6.32 Hz, 2.7 H), 1.70 - 1.83 (m, 2 H), 2.01 - 2.21 (m, 2 H), 2.30 - 2.40 (m, 1 H), 3.06 - 3.20 (m, 2 H), 3.21 - 3.33 (m, 3 H), 3.41 (t, J= 6.82 Hz, 2 H), 3.49 - 3.58 (m, 1 H), 3.60 - 3.70 (m, 1 H), 3.72 - 3.82 (m, 1 H), 4.42 (s, 2 H), 7.24 - 7.34 (m, 5 H), 7.47 (d, J= 8.34 Hz, 2 H), 7.70 (d, J= 8.08 Hz, 2 H), 7.83 (d, J= 8.59 Hz, 2 H), 7.91 - 7.95 (m, 2 H).
Example 2.50: Preparation of (.S)-l-{4'-[2-((if)-2-MethyI-pyrrolidin-l-yl)-ethyl]-biphenyl- 4-sulfonyl}-piperidin-3-oI (Compound 54). The title compound was prepared in a similar manner as described in Example 1.2, using (5)-l-(4-bromophenylsulfonyl)piperidin-3-ol (177 mg, 0.55 mmol) and (Λ)-4-(2-(2~ methylpyrrolidin-l-yl)ethyl)phenylboronic acid (129 mg, 0.55 mmol) to give 185 mg of the HCl salt in 72% yield. Exact mass calculated for C24H32N2O3S: 428.2, Found: LCMS mlz = 429.4 (M+H4); 'H NMR (400 MHz, Methanol-^) δ 1.17 - 1.29 (m, 1 H), 1.32 (d, J= 6.82 Hz, 0.3 H), 1.48 (d, J= 6.32 Hz, 2.7 H)5 1.52 - 1.64 (m, 1 H), 1.70 - 1.88 (m, 3 H), 2.00 - 2.21 (m, 2 H),
2.29 - 2.41 (m, 2 H), 2.47 - 2.56 (m, 1 H), 3.07 - 3.21 (m, 2 H), 3.23 - 3.32 (m, 2 H), 3.35 - 3.43 (m, 1 H), 3.49 - 3.58 (m, 2 H), 3.60 - 3.81 (m, 3 H), 7.47 (d, J= 8.08 Hz, 2 H), 7.70 (d, J= 8.34 Hz, 2 H), 7.80 - 7.87 (m, 4 H).
Example 2.51 : Preparation of (Λ)-l-{4'-[2-((i?)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl- 4-sulfonyl}-piperidin-3-oI (Compound 52).
The title compound was prepared in a similar manner as described in Example 1.2, using (i?)-l-(4-bromophenylsulfonyl)piperidin-3-ol (180 mg, 0.56 mmol) and (R)~4-(2-(2- methylρyrrolidin-l-yl)ethyl)phenylboronic acid (131 mg, 0.56 mmol) to give 184 mg of the HCl salt in 70% yield. Exact mass calculated for C24H32N2O3S: 428.2, Found: LCMS mlz = 429.4 (M+H4); 1H NMR (400 MHz, Methanol-^) δ 1.16 - 1.29 (m, 1 H), 1.32 (d, J= 6.82 Hz, 0.3 H), 1.48 (d, J= 6.57 Hz, 2.7 H), 1.51 - 1.65 (m, 1 H), 1.70 - 1.88 (m, 3 H), 2.02 - 2.20 (m, 2 H),
2.30 - 2.40 (m, 2 H)5 2.48 - 2.56 (m, 1 H), 3.06 - 3.22 (m, 2 H), 3.23 - 3.32 (m, 2 H), 3.35 - 3.43 (m, 1 H), 3.49 - 3.59 (m, 2 H), 3.59 - 3.82 (m, 3 H), 7.47 (d, J= 8.08 Hz, 2 H), 7.70 (d, J= 8.08 Hz, 2 H), 7.80 - 7.87 (m, 4 H).
Example 2.52: Preparation of ((5)-l-{4r-[2-((JR)-2-Methyl-pyrrolidin-l-yl)-ethyI]-biphenyl- 4-sulfonyl}-piperidin-3-yl)-methanol (Compound 49).
The title compound was prepared in a similar manner as described in Example 1.2, using (-S)-(I -(4-bromophenylsulfonyl)piperidin-3-yl)methanol (174 mg, 0.52 mmol) and (R)-4- (2-(2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (121 mg, 0.52 mmol) to give 121 mg of the HCl salt in 49% yield. Exact mass calculated for C25H34N2O3S: 442.2, Found: LCMS mlz = 443.6 (M+H*), 1H NMR (400 MHz, Methanol-^) δ 0.90 - 1.03 (m, 1 H), 1.32 (d, J= 6.82 Hz, 0.3 H), 1.48 (d, J= 6.57 Hz, 2.7 H), 1.55 - 1.71 (m, 2 H), 1.72 - 1.83 (m, 3 H), 2.01 - 2.21 (m, 3 H), 2.30 - 2.40 (m, 2 H), 3.05 - 3.22 (m, 2 H), 3.23 - 3.37 (m, 3 H), 3.42 - 3.57 (m, 2 H), 3.59 -
3.70 (m, 2 H), 3.72 - 3.82 (m, 2 H), 7.47 (d, J= 8.34 Hz, 2 H), 7.69 (d, J= 8.34 Hz, 2 H), 7.80 - 7.87 (m, 4 H).
Example 2.53: Preparation of ((JR)-l-{4'-[2-((JR)-2-Methyl-pyrrolidin-l-yI)-ethyl]-biphenyl- 4-sulfonyl}-piperidin-3-yl)-methanol (Compound 46).
The title compound was prepared in a similar manner as described in Example 1.2, using (i?)-(l-(4-bromophenylsulfonyl)piperidin-3-yl)methanol (175 mg, 0.52 mmol) and (R)A- (2-(2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (122 mg, 0.52 mmol) to give 206 mg of the HCl salt in 82% yield. Exact mass calculated for C25H34N2O3S: 442.2, Found: LCMS mlz = 443.6 01+H+); 1H NMR (400 MHz, Methanol-^) δ 0.93 - 1.06 (m, 1 H), 1.35 (d, J= 6.82 Hz, 0.3 H), 1.52 (d, J= 6.57 Hz, 2.7 H), 1.57 - 1.74 (m, 2 H), 1.75 - 1.86 (m, 3 H), 2.07 - 2.22 (m, 3 H), 2.33 - 2.44 (m, 2 H), 3.09 - 3.24 (m, 2 H), 3.25 - 3.37 (m, 3 H), 3.49 (dd, /= 10.99, 5.18 Hz, 1 H), 3.53 - 3.61 (m, 1 H)5 3.61 - 3.72 (m, 2 H), 3.75 - 3.84 (m, 2 H), 7.50 (d, J= 8.34 Hz, 2 H),
7.71 (d, J= 8.08 Hz, 2 H), 7.82 - 7.89 (m, 4 H).
Example 2.54: Preparation of (JR)-l-(2-(4'-((i.)-3-methoxypyrrolidin-l-ylsulfonyl)biphenyl- 4-yl)ethyl)-2-methylpyrrolidine (Compound 117).
The title compound was prepared in a similar manner as described in Example 1.2, using (i?)-l-(4-bromophenylsulfonyl)-3-methoxypyrrolidine (157 mg, 0.49 mmol) and (iϊ)-4-(2- (2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (114 mg, 0.49 mmol) to give 169 mg of the HCl salt in 74% yield. Exact mass calculated for C24H32N2O3S: 428.2, Found: LCMS mlz = 429.4 (M+H"); 1H NMR (400 MHz, Methanol-^) δ 1.23 (d, J= 6.82 Hz, 0.3 H), 1.39 (d, /=
6.57 Hz, 2.7 H), 1.61 - 1.87 (m, 3 H), 1.91 - 2.13 (m, 2 H)5 2.20 - 2.33 (m, 1 H), 2.97 - 3.11 (m, 5 H), 3.12 - 3.33 (m, 6 H), 3.40 - 3.49 (m, 1 H), 3.50 - 3.60 (m, 1 H), 3.63 - 3.71 (m, 1 H), 3.76 - 3.82 (m, 1 H), 7.37 (d, J= 8.34 Hz, 2 H), 7.60 (d, J= 8.34 Hz, 2 H), 7.73 - 7.76 (m, 2 H)5 7.78 - 7.82 (m, 2 H).
Example 2.55: Preparation of (S)-3-Methoxy-l-{4'-[2-((i?)-2-methyl-pyrrolidin-l-yl)-ethyl]- biphenyl-4-sulfonyl}-piperidine (Compound 111).
The title compound was prepared in a similar manner as described in Example 1.2, using (iS)-l-(4-bromophenylsulfonyl)-3-methoxypiperidine (161 mg, 0.48 mmol) and (R)-4-(2- (2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (112 mg, 0.48 mmol) to give 171 mg of the HCl salt in 74% yield. Exact mass calculated for C25H34N2O3S: 442.2, Found: LCMS mlz = 443.4 (M+H1"); 1H NMR (400 MHz, Methanol-^) δ 1.32 - 1.44 (m, 1 H), 1.48 - 1.63 (m, 4 H), 1.73 - 1.92 (m, 3 H), 2.04 - 2.23 (m, 2 H), 2.33 - 2.43 (m, 1 H), 2.72 - 2.88 (m, 2 H), 3.09 - 3.24 (m, 3 H), 3.26 - 3.44 (m, 7 H), 3.52 - 3.60 (m, 1 H), 3.62 - 3.73 (m, 1 H), 3.75 - 3.83 (m, 1 H)5 7.50 (d, J= 8.08 Hz, 2 H), 7.72 (d, J= 8.34 Hz, 2 H), 7.84 - 7.90 (m, 4 H).
Example 2.56: Preparation of (it)-l-(2-(4'-((iS)-3-Methoxypyrrolidin-l-ylsulfonyI)biphenyl- 4-yl)ethyl)-2-methylpyrrolidine (Compound 105).
The title compound was prepared in a similar manner as described in Example 1.2, using (S)-I -(4-bromophenylsulfonyl)-3-methoxypyrrolidine (157 mg, 0.49 mmol) and (R)-4-(2- (2-methylpyrrolidin-l~yl)ethyl)phenylboronic acid (114 mg, 0.49 mmol) to give 156 mg of the HCl salt in 69% yield. Exact mass calculated for C24H32N2O3S: 428.2, Found: LCMS mlz = 429.1 (M+IT); 1H NMR (400 MHz, Methanol-^) δ 1.35 (d, J= 6.82 Hz, 0.3 H), 1.52 (d, J= 6.57 Hz, 2.7 H), 1.73 - 1.98 (m, 3 H), 2.04 - 2.23 (m, 2 H), 2.32 - 2.45 (m, 1 H), 3.09 - 3.22 (m, 5 H), 3.24 - 3.45 (m, 6 H), 3.52 - 3.62 (m, 1 H), 3.63 - 3.72 (m, 1 H), 3.75 - 3.84 (m, 1 H), 3.88 - 3.94 (m, 1 H), 7.49 (d, J= 8.34 Hz, 2 H), 7.71 (d, J= 8.34 Hz, 2 H), 7.83 - 7.94 (m, 4 H).
Example 2.57: Preparation of (ϋf)-3-Methoxy-l-{4'-[2-((Λ)-2-methyI-pyrrolidin-l-yI)- ethyl]-biphenyI-4-sulfonyl}-piperidine (Compound 99).
The title compound was prepared in a similar manner as described in Example 1.2, using (i?)-l-(4-bromophenylsulfonyl)-3-methoxypiperidine (161 mg, 0.48 mmol) and (i?)-4-(2- (2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (112 mg, 0.48 mmol) to give 157 mg of the HCl salt in 68% yield. Exact mass calculated for C25H34N2O3S: 442.2, Found: LCMS mlz = 443.6 (M+H4); 1H NMR (400 MHz, Methanol-^) δ 1.31 - 1.43 (m, 1 H), 1.51 (d, J= 6.57 Hz, 3 H), 1.54 - 1.63 (m, 1 H), 1.74 - 1.90 (m, 3 H), 2.05 - 2.22 (m, 2 H), 2.32 - 2.43 (m, 1 H), 2.73 - 2.87 (m, 2 H), 3.09 - 3.25 (m, 3 H), 3.26 - 3.44 (m, 7 H), 3.53 - 3.60 (m, 1 H), 3.62 - 3.72 (m, 1 H), 3.75 - 3.84 (m, 1 H), 7.50 (d, J= 8.34 Hz, 2 H)3 7.72 (d, J= 8.34 Hz, 2 H), 7.84 - 7.90 (m, 4 H).
Example 2.58: Preparation of CR)-3-Methoxymethyl-l-{4'-[2-((i?)-2-methyI-pyrrolidin-l- yl)-ethyl]-biphenyl-4-sulfonyI}-piperidine (Compound 93). The title compound was prepared in a similar manner as described in Example 1.2, using (i?)-l-(4-bromophenylsulfonyl)-3-(methoxymethyl)piperidine (169 mg, 0.49 mmol) and (i?)-4-(2-(2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (113 mg, 0.49 mmol) to give 165 mg of the HCl salt in 69% yield. Exact mass calculated for C26H36N2O3S: 456.2, Found: LCMS mlz = 457.3 (M+H*); 1H NMR (400 MHz, Methanol-^) δ 0.96 - 1.10 (m, 1 H), 1.35 (d, J = 6.82 Hz, 0.3 H), 1.52 (d, J= 6.57 Hz, 2.7 H), 1.57 - 1.72 (m, 2 H), 1.73 - 1.85 (m, 2 H), 1.87 - 1.98 (m, 1 H), 2.04 - 2.26 (m, 3 H), 2.32 - 2.48 (m, 2 H), 3.09 - 3.25 (m, 3 H), 3.26 - 3.41 (m, 6 H), 3.52 - 3.85 (m, 5 H), 7.49 (d, J= 8.34 Hz, 2 H), 7.71 (d, J= 8.08 Hz, 2 H), 7.81 - 7.89 (m, 4 H). Example 2.59: Preparation of (5)-3-Methoxymethyl-l-{4'-[2-((JR)-2-methyl-pyrroUdin-l- yl)-ethyl]-biphenyl-4-sulfonyl}-piperidiπe (Compound 87).
The title compound was prepared in a similar manner as described in Example 1.2, using (S)-I -(4-bromophenylsulfonyl)-3-(methoxymethyl)piperidine (170 mg, 0.49 mmol) and (i?)-4-(2-(2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (114 mg, 0.49 mmol) to give 190 mg of the HCl salt in 79% yield. Exact mass calculated for C26H36N2O3S: 456.2, Found: LCMS mlz = 457.3 (M+H4); 1H NMR (400 MHz, Methanol-^) δ 0.98 - 1.09 (m, 1 H), 1.35 (d, J= 6.82 Hz5 0.3 H), 1.52 (d, J= 6.57 Hz, 2.7 H), 1.57 - 1.71 (m, 2 H), 1.73 - 1.84 (m, 2 H), 1.87 - 1.98 (m, 1 H), 2.04 - 2.25 (m, 3 H), 2.31 - 2.47 (m, 2 H), 3.09 - 3.25 (m, 3 H), 3.26 - 3.36 (m, 6 H), 3.52 - 3.84 (m, 5 H), 7.49 (d, J= 8.34 Hz, 2 H), 7.71 (d, J= 8.34 Hz, 2 H), 7.81 - 7.89 (m, 4 H).
Example 2.60: Preparation of 4'-[2-((JR)-2-Methyl-pyrrolidin-l-yl)-ethylJ-biphenyl-4- sulfonic Acid (2-Hydroxy-ethyI)-isopropyI-amide (Compound 81). The title compound was prepared in a similar manner as described in Example 1.2, using 4-bromo-N-(2-hydroxyethyl)-N-isopropylbenzenesulfonamide (167 mg, 0.52 mmol) and (i-)-4-(2-(2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (121 mg, 0.52 mmol) to give 123 mg of the HCl salt in 51% yield. Exact mass calculated for C24H34N2O3S: 430.2, Found: LCMS mlz = 431.5 (M+H+); 1H NMR (400 MHz, Methanol-^) δ 1.06 (d, J = 6.82 Hz, 6 H), 1.33 - 1.37 (m, 0.3 H), 1.49 - 1.53 (m, 2.7 H), 1.73 - 1.86 (m, 1 H), 2.05 - 2.23 (m, 2 H), 2.32 - 2.43 (m, 1 H)5 3.07 - 3.22 (m, 2 H), 3.22 - 3.35 (m, 4 H), 3.52 - 3.60 (m, 1 H), 3.62 - 3.72 (m, 1 H), 3.72 - 3.83 (m, 3 H), 4.07 - 4.17 (m, 1 H), 7.49 (d, J= 8.34 Hz, 2 H), 7.71 (d, J= 8.34 Hz, 2 H), 7.82 - 7.86 (m, 2 H), 7.91 - 7.95 (m, 2 H).
Example 2.61: Preparation of 4'-[2-((iϋ)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonic Acid ((_S)-2-Hydroxy-l-methyl-ethyl)-amide (Compound 62).
The title compound was prepared in a similar manner as described in Example 2.9, using (S)-2-aminopropan-l-ol (48 mg, 0.64 mmol) and (i-)-4'-(2-(2-methylpyrrolidin-l- yl)ethyl)biphenyl-4-sulfonyl chloride (210 mg, 0.58 mmol) to give 11 mg of the HCl salt in 4% yield. Exact mass calculated for C22H30N2O3S: 402.2, Found: LCMS mlz = 403.4 (M+H4}; 1H NMR (400 MHz, Methanol-^) δ 1.00 (d, J= 6.32 Hz, 3 H), 1.33 (d, J= 6.82 Hz, 0.3 H), 1.49 (d, J= 6.32 Hz, 2.7 H)3 1.77 (s, 1 H), 2.02 - 2.19 (m, 2 H), 2.28 - 2.40 (m, 1 H), 3.14 (s, 2 H), 3.23 - 3.37 (m, 4 H), 3.39 - 3.48 (m, 1 H), 3.49 - 3.59 (m, 1 H), 3.58 - 3.69 (m, 1 H), 3.73 - 3.81 (m, 1 H), 7.46 (d, J= 7.83 Hz, 2 H), 7.68 (d, J= 7.83 Hz, 2 H), 7.80 (d, J= 8.34 Hz, 2 H), 7.93 (d, J= 8.08 Hz, 2 H). Example 2.62: Preparation of l-{4'-[2-((Λ)-2-Methyl-pyrrolidin-l-yl)-ethyI]-biphenyl-4- suIfonyl}-piperidine-4-carboxylic Acid Ethyl Ester (Compound 90). Step A: Preparation of Intermediate 2-Biphenyl-4-yl-ethanoI.
To a 1000 mL round-bottomed flask containing 4-biphenylacetic acid (20.0 g, 94.2 mmol) in THF (250 mL) at 0 0C was added borane THF complex (240 mL, 240 mmol) via an addition funnel. The reaction was then heated to 65 0C for 3 h and then cooled to 0 0C. The reaction was slowly quenched with MeOH (250 mL) and concentrated. The product was diluted with EtOAc (500 mL) and washed with 1 M HCl (200 mL), saturated NaHCO3 (200 mL) and brine (200 mL). The organics were dried with MgSO4, filtered and concentrated to furnish the title compound (18.0 g, 96% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 2.92 (t, J= 6.44 Hz, 2 H), 3.91 (t, /= 6.57 Hz, 2 H), 7.29 - 7.37 (m, 3 H), 7.40 - 7.47 (m, 2 H), 7.52 - 7.61 (m, 4 H).
Step B: Preparation of Intermediate Methanesulfonic Acid 2-Biphenyl-4-yI-ethyl Ester. To a 250 mL round-bottomed flask containing 2-biρhenyl-4-yl-ethanol (5.00 g, 25.2 mmol) in dichloromethane (50 mL) was added triefhylamine (3.52 mL, 25.2 mmol) and mesyl chloride (2.16 mL, 27.7 mmol). This was stirred at -30 0C allowing to warm to 25 0C over 2 h. The reaction was filtered and diluted with EtOAc (100 mL). This was washed with water (50 mL), 1 M HCl (50 mL), saturated NaHCO3 (50 mL) and brine (50 mL). The organics were dried with MgSO4, filtered and concentrated to furnish title compound as a cream colored solid (5.93 g, 85% yield). 1H NMR (400 MHz, CDCl3) δ 2.89 (s, 3 H), 3.11 (t, J= 6.82 Hz, 2 H), 4.46 (t, J= 6.95 Hz, 2 H), 7.29 - 7.34 (m, 2 H), 7.34 - 7.38 (m, 1 H), 7.41 - 7.47 (m, 2 H), 7.54 - 7.60 (m, 4 H).
Step C: Preparation of Intermediate (Λ)-l-(2-Biphenyl-4-yI-ethyl)-2-methyl- pyrrolidine.
To 3-neck 250 mL round-bottomed flask equipped with a condenser was charged sodium carbonate (14.6 g, 137.4 mol) and (Λ)-2-methyl-pyrroIidine hydrochloride (5.57 g, 45.8 mmol) in acetonitrile (30 mL). The mixture was allowed to stir at 25 0C for 10 min, and methanesulfonic acid 2-biphenyl-4-yl-ethyl ester (14.5 g, 52.7 mmol) in acetonitrile (50 mL) was added. The mixture was then heated to reflux and stirred for 16 h. The reaction was filtered and concentrated to yield a dark brown oil. This was dissolved in EtOAc (125 mL) and extracted with 1 M HCl (4 x 25 mL). The aqueous layers were combined and made basic by addition of 50% NaOH (20 mL). The aqueous layer was extracted with dichloromethane (7 x 25 mL), the organic layers were combined, dried over Na2SO4, filtered and concentrated. The crude reaction mixture was purified by column chromatography (Biotage column 65M, 2-
20%MeOH/DCM) to furnish the title compound (10.1 g, 82%) as an orange oil. Exact mass calculated for Cj9H23N: 265.18, Found: LCMS mlz = 266.18 (M+H+); 1H NMR (400 MHz, CDCl3) δ 1.13 (d, J= 6.06 Hz3 3 H), 1.40 - 1.51 (m, 1 H), 1.66 - 1.78 (m, 1 H), 1.78 - 1.88 (m, 1 H), 1.88 - 1.99 (m, 1 H), 2.21 (q, /= 8.84 Hz, 1 H), 2.28 - 2.39 (m, 2 H), 2.79 - 2.94 (m, 2 H)5 3.07 (td, J= 11.24, 6.06 Hz, 1 H), 3.27 (dt, J= 8.65, 2.65 Hz, 1 H), 7.29 (d, J= 8.34 Hz, 2 H), 7.31 - 7.35 (m, 1 H), 7.38 - 7.46 (m, 2 H), 7.49 - 7.54 (m, 2 H), 7.55 - 7.62 (m, 2 H). Step D: Preparation of Intermediate (JR)-4'-[2-(2-Methyl-pyrrolidin-l-yl)-ethyl]- biphenyl-4-sulfonyl Chloride.
(i?)-l-(2-Biphenyl-4-yl-ethyl)-2-methyl-pyrrolidine (0.703 g, 2.65 ramol) in a 100 mL round-bottomed flask was dissolved in dichloromethane (10 mL) and cooled to 0 0C. Chlorosulfonic acid (1.76 mL, 26.5 mmol) in dichloromethane (10 mL) was added dropwise over 10 min and the reaction allowed to stir for 3 h while slowly warming to 25 0C. The reaction was quenched by dropwise addition into an ice-cold solution of 50% saturated NaHCO3 (10 mL) adding additional ice to keep the solution cold. This was diluted with dichloromethane (20 mL) and the layers separated. The aqueous layer was extracted with dichloromethane (2 x 40 mL). The combined organics, were dried over Na2SO4, filtered and concentrated to furnish title compound (0.74 g, 74%) as yellow solid. Exact mass calculated for Ci9H2ZClNO2S:
363.11, Found: LCMS mlz = 364.11 (M+H+); 1H NMR (400 MHz, DMSO-J6) δ 1.21 (d, /= 7.07 Hz, 0.3 H)5 1.40 (d, J= 6.57 Hz, 2.7 H), 1.62 (s, 1 H), 1.96 (s, 2 H), 2.14 - 2.27 (m, 1 H), 2.98 - 3.12 (m, 2 H), 3.14 - 3.28 (m, 2 H), 3.44 (s, 1 H), 3.49 - 3.59 (m, 1 H), 3.59 - 3.69 (m, 1 H), 7.42 (d, J= 8.34 Hz, 2 H), 7.59 - 7.64 (m, 2 H), 7.64 - 7.70 (m, 4 H). Step E: Preparation of (Λ)-Ethyl l-(4'-(2-(2-MethyϊpyrroIidin-l-yl)ethyl)biphenyl-
4-ylsulfonyl)piperidine-4-carboxylate Hydrochloride Salt.
Ethyl isonipecotate (0.22 mL, 1.43 mmol) and triethylamine (0.66 mL, 4.77 mmol) were dissolved in DMF (4 mL) and the resulting solution added to a 25 mL flask containing (i?)-4'-(2- (2-methylpyrrolidin-l-yl)ethyl)biphenyl-4-sulfonyl chloride (0.382 g, 0.95 mmol). The resulting solution was stirred at 25 0C for 16 h. The reaction mixture was purified by preparative HPLC (0.1% TFA in acetonitrile/0.1% TFA in water). The fractions were neutralized with saturated potassium carbonate (10 mL) and extracted with dichloromethane (2 x 30 mL). To this solution was added 1.0 M HCl in ether (3 mL), which was concentrated to furnish the title compound as a cream colored solid (0.203 g, 40%). Exact mass calculated for C27H36N2O4S: 484.2, Found: LCMS m/∑ = 485.2 (M+lT); 1H NMR (400 MHz, DMSO-^6) δ 1.10 - 1.15 (m, 3 H)5 1.19 - 1.22 (m, 0.3 H), 1.44 (d, J= 6.57 Hz, 2.7 H), 1.52 - 1.71 (m, 3 H)5 1.86 - 2.02 (m, 4 H)5 2.14 - 2.25 (m, 1 H), 2.35 - 2.44 (m, 1 H), 2.44 - 2.49 (m, 2 H), 3.05 - 3.24 (m, 4 H), 3.36 - 3.48 (m, 1 H), 3.49 - 3.58 (m, 3 H), 3.59 - 3.67 (m, 1 H), 4.03 (q, J= 7.07 Hz, 2 H), 7.47 (d, J= 8.08 Hz, 2 H), 7.75 (d, J= 8.34 Hz, 2 H), 7.80 (d, J= 8.34 Hz, 2 H), 7.94 (d, J= 8.59 Hz, 2 H). Example 2.63: Preparation of {4'-[2-((i?)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonylamino}-acetic Acid te/tf-Butyl Ester (Compound 124).
The title compound was prepared in a similar manner as described in Example 2.62, using (i?)-4'-(2-(2-methylpyrrolidin-l-yl)ethyl)biphenyl-4-sulfonyl chloride (0.064 g, 0.16 mmol), and glycine f-butyl ester acetic acid salt (0.037 g, 0.19 mmol), to give 12 mg of the trifluoroacetate salt. Exact mass calculated for C2SH34N2O4S: 458.2, Found: LCMS m/z = 459.2 (M+H1).
Example 2.64: Preparation of (5)-2-{4'-[2-((JR)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl- 4-sulfonylamino}-propionic Acid tert-Butyl Ester (Compound 122).
The title compound was prepared in a similar manner as described in Example 2.62, using (i?)-4'-(2-(2-methylpyrrolidin-l-yl)ethyl)biphenyl-4-sulfonyl chloride (0.064 g, 0.16 mmol), and L-alanine £-butyl ester hydrochloride (0.035 g, 0.19 mmol), to give 14 mg of the trifluoroacetate salt. Exact mass calculated for C2SH36N2O4S: 472.2, Found: LCMS m/z — 473.2 (M+H4).
Example 2.65: Preparation of {4'-[2-((Λ)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonylamino}-acetic Acid Methyl Ester (Compound 108).
The title compound was prepared in a similar manner as described in Example 2.62, using (i?)-4'-(2-(2-methylpyrrolidin-l-yl)ethyl)biphenyl-4-sulfonyl chloride (0.10 g, 0.25 mmol), and glycine methyl ester hydrochloride (0.047 g, 0.37 mmol), to give 6 mg of the trifluoroacetate salt. Exact mass calculated for C22H2SN2O4S: 416.2, Found: LCMS mfz = 417.2 (M+H1").
Example 2.66: Preparation of (.S)-2-{4'-[2-((Λ)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl- 4-sulfonylamino}-propionic Acid Methyl Ester (Compound 102).
The title compound was prepared in a similar manner as described in Example 2.62, using (i?)-4'-(2-(2-methylpyrrolidin-l-yl)ethyl)biphenyl-4-sulfonyl chloride (0.10 g, 0.25 mmol), and L-alanine methyl ester hydrochloride (0.052 g, 0.37 mmol), to give the trifluoroacetate salt. Exact mass calculated for C23H30N2O4S: 430.2, Found: LCMS m/z = 431.2 (M+Kf).
Example 2.67: Preparation of 3-{4'-[2-((JR)-2-Methyl-pyrroIidin-l-yl)-ethyl]-biphenyl-4- sulfonylaminoj-propionic Acid Methyl Ester (Compound 96).
The title compound was prepared in a similar manner as described in Example 2.62, using (-/-)-4l-(2-(2-methylpyrrolidin-l-yl)ethyl)biphenyl-4-sulfonyl chloride (0.10 g, 0.25 mmol), and β-alanine methyl ester hydrochloride (0.052 g, 0.37 mmol), to give 8 mg of the trifluoroacetate salt. Exact mass calculated for C23H30N2O4S: 430.2, Found: LCMS mlz = 431.2 01+H+).
Example 2.68: Preparation of 4'-[2-((β)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonic Acid [2-(2-Oxo-imidazolidin-l-yl)-ethyl]-amide (Compound 84).
The title compound was prepared in a similar manner as described in Example 2.62, using (i?)-4'-(2-(2-methylpyrrolidin-l-yl)ethyl)biphenyl-4-sulfonyl chloride (0.10 g, 0.25 mmol), and l-(2-aminoethyl)imidazolidin-2-one (0.048 g, 0.37 mmol), to give 9 mg of the trifluoroacetate salt. Exact mass calculated for C24H32N4O3S: 456.2, Found: LCMS mlz = 457.2 (M+H+).
Example 2.69: Preparation of {4'-[2-((-R)-2-Methyl-pyrrolidϊn-l-yl)-ethyl]-biphenyl-4- sulfonylamino}-acetic Acid Isopropyl Ester (Compound 115).
The title compound was prepared in a similar manner as described in Example 2.62, using (i?)-4'-(2-(2-methylpyrrolidin-l-yl)ethyl)biphenyl-4-sulfonyl chloride (0.30 g, 0.75 mmol), and glycine isopropyl ester hydrochloride (0.138 g, 0.90 mmol), to give 231 mg of the hydrochloride salt. Exact mass calculated for C24H32N2O4S: 444.2, Found: LCMS m/z = 445.2 (M+H1); 1H NMR (400 MHz, Methanol-^) δ 1.10 (d, J= 6.32 Hz, 6 H), 1.33 (d, J = 6.57 Hz, 0.3 H), 1.50 (d, J= 6.57 Hz, 2.7 H), 1.71 - 1.84 (m, 1 H), 2.00 - 2.21 (m, 2 H), 2.28 - 2.41 (m, 1 H), 3.09 - 3.21 (m, 2 H), 3.24 - 3.37 (m, 3 H), 3.50 - 3.59 (m, 1 H), 3.60 - 3.70 (m, 1 H), 3.72 - 3.83 (m, 3 H), 4.78 - 4.87 (m, 1 H), 7.46 (d, J= 7.83 Hz, 2 H), 7.64 (d, /= 7.83 Hz, 2 H), 7.77 (d, J= 8.34 Hz, 2 H), 7.89 (d, J= 8.34 Hz, 2 H).
Example 2.70: Preparation of (-$)-2-{4t-[2-((JR)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl- 4-sulfonyIamino}-propionic Acid Isopropyl Ester (Compound 109).
The title compound was prepared in a similar manner as described in Example 2.62, using (Λ)-4'-(2-(2-methylpyrrolidin-l-yl)ethyl)biphenyl-4-sulfonyl chloride (0.30 g, 0.75 mmol), and L-alanine isopropyl ester hydrochloride (0.151 g, 0.90 mmol), to give 292 mg of the hydrochloride salt. Exact mass calculated for C25H34N2O4S: 458.2, Found: LCMS mlz = 459.2 (M+H*); 1HNMR (400 MHz, Methanol-^) δ 1.02 - 1.07 (m, 6 H), 1.30 (d, J= 7.33 Hz, 3 H),
1.50 (d, J= 6.32 Hz, 3 H), 1.71 - 1.84 (m, 1 H), 2.01 - 2.21 (m, 2 H), 2.29 - 2.41 (m, 1 H), 3.24 - 3.33 (m, 2 H), 3.35 (s, 3 H), 3.50 - 3.59 (m, 1 H), 3.60 - 3.69 (m, 1 H), 3.73 - 3.83 (m, 1 H), 3.93 (q, /= 7.07 Hz, 1 H), 4.65 - 4.76 (m, 1 H), 7.46 (d, J= 7.83 Hz, 2 H), 7.64 (d, J= 7.83 Hz, 2 H), 7.76 (d, J= 8.34 Hz, 2 H), 7.88 (d, J = 8.34 Hz, 2 H).
Example 2.71: Preparation of 4'-[2-((-8)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonic Acid [3-(2-Oxo-pyrrolidin-l-yl)-propyl]-amide (Compound 85). The title compound was prepared in a similar manner as described in Example 2.62, using (i?)-4'-(2-(2-methylpyrrolidin-l-yl)ethyl)biphenyl-4-sulfonyl chloride (0.30 g, 0.75 mmol), and l-(3-aminopropyl)pyrrolidin-2-one (0.13 mg, 0.90 mmol), to give 331 mg of the hydrochloride salt. Exact mass calculated for C26H35N3O3S: 469.2, Found: LCMS mlz = 470.2 (M+H4); 1H NMR (400 MHz, Methanol-^) δ 1.33 (d, J = 6.82 Hz, 0.3 H), 1.50 (d, /= 6.32 Hz, 2.7 H), 1.66 - 1.75 (m, 2 H), 1.74 - 1.84 (m, 1 H), 1.95 - 2.05 (m, 2 H), 2.06 - 2.21 (m, 2 H), 2.30 - 2.41 (m, 3 H), 2.87 (t, J= 6.82 Hz, 2 H), 3.08 - 3.22 (in, 2 H)5 3.24 - 3.29 (m, 4 H), 3.42 (t, J= 6.95 Hz, 2 H), 3.51 - 3.59 (m, 1 H), 3.60 - 3.69 (m, 1 H), 3.73 - 3.83 (m, 1 H), 7.46 (d, J= 7.83 Hz, 2 H)5 7.67 (d, J= 7.83 Hz, 2 H), 7.80 (m, 2 H), 7.89 (d, J= 8.08 Hz, 2 H).
Example 2.72: Preparation of l-{4'-[2-((Λ)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyI-4- sulfonyl}-piperidine-4-carboxylic Acid Benzyl Ester (Compound 64).
The title compound was prepared in a similar manner as described in Example 2.62, using (i?)-4'-(2-(2-methylpyrτolidin-l-yl)ethyl)biphenyl-4-sulfonyl chloride (0.587 g, 1.46 mmol), and benzyl piperidine-4-carboxylate hydrochloride (0.31 mg, 0.90 mmol), to give 501 mg of the title compound as an off-white solid. Exact mass calculated for C32H38N2O4S: 546.3, Found: LCMS mlz = 547.3 (M+H÷).
Example 2.73: Preparation of l-{4'-[2-((i?)-2-Methyl-pyrro-idin-l-yl)-ethyl3-biplienyl-4- sulfonyl}-piperidine-4-carboxylic Acid (Compound 123).
A 250 mL round-bottomed flask was charged with (Λ)-benzyl l-(4'-(2-(2- methylpyrrolidin-l-yl)ethyl)biphenyl-4-ylsulfonyl)piperidine-4-carboxylate (300 mg, 0.549 mmol), 50 mL MeOH5 and 10% palladium/carbon (0.060 g). This was evacuated and purged with H2 (3x) followed by stirring for 72 h at 25 0C. The reaction was filtered through celite and concentrated. The product was recrystallized from MeOH/1 : 1 EtOAc/hexanes to form an off- white solid. This was dissolved in dichloromethane and 1.0 M HCl in ether (0.5 mL) was added, which after concentration furnished the title compound (0.079 g, 30%) as a white solid. Exact mass calculated for C25H32N2O4S: 456.2, Found: LCMS mlz = 457.2 (M+H*>
Example 2.74: Preparation of (-»)-l-{2-[4'-(Aziridine-l-sulfonyl)-biphenyl-4-yl]-ethyl}-2- methyl-pyrrolidine (Compound 47).
To a 100 mL round-bottomed flask containing (i?)-l-(2-biphenyl-4-yl-ethyl)-2-methyl- pyrrolidine (0.20 g, 0.66 mmol) in dichloromethane (10 mL) was added chlorosulfonic acid (0.44 mL, 6.6 mmol). This was stirred at 0 0C for addition and warmed to 25 0C stirring for 2 h. The reaction was quenched with 2-bromoethylamine hydrobromide (2.03 g, 9.94 mmol) at 0 0C and stirred for 2 h. The reaction was diluted with 15% NaOH (20 mL) and extracted with EtOAc (2 x 25 mL). The organics were dried with MgSO4, filtered and concentrated. The reaction mixture was purified by prep HPLC (0.1% TFA in acetonitrile/0.1% TFA in water) to furnish the title compound (0.012 g, 5% yield) as a yellow oil after concentration. Exact mass calculated for C2IH26N2O2S: 370.1, Found: LCMS m/z = 371.3 (M+H1); 1H NMR (400 MHz, Methanol-^,) δ 1.17 (m, 1 H), 1.24 (m, 2 H), 1.32 (m, 2 H), 1.43 - 1.54 (m, 1 H), 1.77 - 1.87 (m, 2 H), 2.30 - 2.45 (m, 2 H), 2.45 - 2.57 (m, 1 H), 2.90 (d, 2 H), 3.13 (m, 1 H), 3.27 (t, 2 H), 3.38 (m, 4 H), 7.38 (d, J= 8.08 Hz3 2 H), 7.60 - 7.66 (m, 2 H), 7.94 (d, J= 8.34 Hz, 2 H).
Example 2.75: Preparation of 4'-[2-((Λ)-2-Methyl-pyrroIidin-l-yl)-ethyl]-biphenyI-4- sulfonic Acid (Pyridin-3-ylmethyl)-amide (Compound 100). The title compound was prepared in a similar manner as described in Example 1.2, using 4-bromo-Λr-(pyridin-3-ylmethyl)benzenesulfonamide (140 mg, 0.429 mmol) and (R)-A-(I- (2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (100 mg, 0.429 mmol) as starting materials, to give a white solid (HCl salt) in 37% yield. Exact mass calculated for C25H29N3O2S: 435.2, Found: LCMS m/z = 436.3 (M+H"); 1H NMR (400 MHz, Methanol-^) δ 1.33 (d, 7= 6.82 Hz, 0.3 H), 1.51 (d, J= 5.56 Hz, 2.7 H), 1.79 (s, 1 H), 2.12 (s, 2 H), 2.35 (s, 1 H), 3.09 - 3.23 (m, 2 H), 3.24 - 3.36 (m, 2 H), 3.51 - 3.70 (m, 2 H), 3.79 (s, 1 H), 4.38 (s, 2 H), 7.49 (d, J= 7.07 Hz, 2 H), 7.70 (d, J= 7.07 Hz, 2 H), 7.83 (d, J= 7.83 Hz, 2 H), 7.95 (d, J= 7.83 Hz, 2 H), 8.07 (t, J= 12.63 Hz, 1 H), 8.63 (d, 7= 7.58 Hz, 1 H), 8.78 (d, J= 5.05 Hz, 1 H), 8.86 (s, 1 H).
Example 2.76: Preparation of 4'-[2-((Λ)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonic Acid (Pyridin-4-yImethyI)-amide (Compound 94).
The title compound was prepared in a similar manner as described in Example 1,2, using 4-bromo-N-(pyridin-4-ylmethyl)benzenesulfonamide (140 mg, 0.429 mmol) and (/.)-4-(2- (2-methylpyrrolidm-l-yl)ethyl)phenylboronic acid (100 mg, 0.429 mmol) as starting materials, to give a white solid (HCl salt) in 67% yield. Exact mass calculated for C25H2SN3O2S: 435.2, Found: LCMS m/z = 436.5 (M+ET); 1H NMR (400 MHz, Methanol-**,) δ 1.33 (d, J= 6.82 Hz, 0.3 H), 1.50 (d, J= 6.19 Hz, 2.7 H), 1.78 (dd, J= 12.88, 8.08 Hz, 1 H), 2.02 - 2.21 (m, 2 H), 2.30 - 2.41 (m, 1 H), 3.11 - 3.23 (m, 2 H), 3.24 - 3.37 (m, 2 H), 3.49 - 3.71 (m, 2 H), 3.72 - 3.83 (m, 1 H), 4.46 (s, 2 H), 7.49 (d, J= 8.08 Hz, 2 H)3 7.70 (d, J= 8.08 Hz, 2 H), 7.84 (d, J= 8.34 Hz, 2 H), 7.96 (d, J= 8.34 Hz, 2 H)3 8.11 (d, J= 6.32 Hz3 2 H), 8.80 (d, J= 6.57 Hz, 2 H).
Example 2.77: Preparation of 4'-[2-((i?)-2-MethyI-pyrrolidin-l-yl)-ethyl]-biphenyI-4- sulfonic Acid Phenethyl-amide (Compound 88).
The title compound was prepared in a similar manner as described in Example 1.2, using 4-bromo-N-phenethylbenzenesulfonamide (148 mg, 0.436 mmol) and (Λ)-4-(2-(2- methylρyrrolidin-l-yl)ethyl)phenylboronic acid (102 mg, 0.436 mmol) as starting materials, to give a white solid (HCl salt) in 70% yield. Exact mass calculated for C27H32N2O2S: 448.2, Found: LCMS mlz = 449.3 (M+H÷); 1H NMR (400 MHz, Methanol-^) δ 1.32 (d, J= 6.82 Hz, 0.3 H), 1.49 (d, J= 6.57 Hz, 2.7 H), 1.71 - 1.82 (m, 1 H), 1.97 - 2.20 (m, 2 H), 2.30 - 2.40 (m, 1 H), 2.74 (t, J= 7.45 Hz, 2 H), 3.07 - 3.18 (m, 4 H), 3.23 - 3.33 (m, 2 H), 3.50 - 3.69 (m, 2 H), 3.72 - 3.81 (m, 1 H), 7.09 - 7.18 (m, 3 H), 7.19 - 7.25 (m, 2 H), 7.46 (d, J= 8.08 Hz, 2 H), 7.67 (d, 7= 8.08 Hz, 2 H), 7.74 - 7.79 (m, 2 H), 7.83 - 7.88 (m, 2 H).
Example 2.78: Preparation of 4'-[2-((i.)-2-Methyl-pyrrolidiii-l-yl)-ethyl]-biphenyI-4- sulfonic Acid (3-PhenyI-propyl)-amide (Compound 82).
The title compound was prepared in a similar manner as described in Example 1.2, using 4-bromo-N-(3-phenylpropyl)benzenesulfonamide (170 mg, 0.479 mmol) and (i?)-4-(2~(2- methylpyrrolidin-l-yl)ethyl)phenylboronic acid (112 mg, 0.479 mmol) as starting materials, to give a white solid (HCl salt) in 73% yield. Exact mass calculated for C2SH34N2O2S: 462.2, Found: LCMS mlz = 463.3 (M+H4); 1H NMR (400 MHz, Methanol-.*,) δ 1.33 (d, J= 6.82 Hz, 0.3 H), 1.49 (d, J= 6.32 Hz, 2.7 H), 1.68 - 1.82 (m, 3 H), 2.00 - 2.19 (m, 2 H), 2.30 - 2.40 (m, 1 H), 2.58 (t, 2 H), 2.89 (t, J= 6.95 Hz, 2 H). 3.07 - 3.21 (m, 2 H), 3.23 - 3.34 (m, 2 H), 3.49 -
3.71 (m, 2 H), 3.72 - 3.82 (m, 1 H), 7.05 - 7.14 (m, 3 H), 7.16 - 7.22 (m, 2 H), 7.47 (d, J= 8.34 Hz, 2 H), 7.68 (d, J= 8.34 Hz, 2 H), 7.76 - 7.81 (m, 2 H), 7.86 - 7.91 (m, 2 H).
Example 2.79: Preparation of 4'-[2-((jR)-2-Methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonic Acid 3,4-DichIoro-benzylamide (Compound 61).
The title compound was prepared in a similar manner as described in Example 1.2, using N-(3;4-dichlorobenzyl)-4-bromobenzenesulfonamide (204 mg, 0.517 mmol) and (i?)-4-(2- (2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (120 mg, 0.517 mmol) as starting materials, to give a white solid (HCl salt) in 48% yield. Exact mass calculated for C26H28Cl2N2O2S: 502.1, Found: LCMS mlz = 503.1 (M+H*); 1H NMR (400 MHz, Methanol-^) δ 1.33 (d, J= 6.82 Hz, 0.3 H), 1.50 (d, J= 6.32 Hz, 2.7 H), 1.71 - 1.83 (m, 1 H), 2.02 - 2.20 (m, 2 H), 2.29 - 2.40 (m, 1 H), 3.08 - 3.22 (m, 2 H), 3.23 - 3.34 (m, 2 H), 3.49 - 3.71 (m, 2 H), 3.72 - 3.82 (m, 1 H), 4.11 (s, 2 H), 7.14 (dd, J= 8.08, 2.02 Hz, 1 H), 7.28 (d, J= 2.02 Hz, 1 H), 7.34 (d, J= 8.34 Hz, 1 H), 7.46 (d, J= 8.08 Hz, 2 H), 7.65 (d, J= 8.08 Hz, 2 H), 7.70 (d, J= 8.34 Hz, 2 H), 7.81 (d, J= 8.59 Hz, 2 H).
Example 2.80: Preparation of 4'-[2-((i?)-2-Methyl-pyrroIidin-l-yl)-ethyl]-biphenyI-4- sulfonic Acid 3,5-DichIoro-benzylamide (Compound 58).
The title compound was prepared in a similar manner as described in Example 1.2, using N-(3,5-dichlorobenzyl)-4-bromobenzenesulfonamide (201 mg, 0.509 mmol) and (i?)-4-(2- (2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (119 mg, 0.509 mmol) as starting materials, to give a white solid (HCl salt) in 46% yield. Exact mass calculated for C26H28Cl2N2O2S: 502.1, Found: LCMS mlz = 503.1 (M+H4); 1H NMR (400 MHz, Methanol-^) δ 1.30 - 1.37 (m, 0.3 H), 1.50 (d, J= 6.57 Hz, 2.7 H), 1.77 (dd, J= 13.14, 8.08 Hz, 1 H), 2.01 - 2.22 (m, 2 H), 2.29 - 2.42 (m, 1 H), 3.06 - 3.23 (m, 2 H), 3.23 - 3.35 (m, 2 H), 3.50 - 3.71 (m, 2 H), 3.72 - 3.83 (m, 1 H), 4.13 (s, 2 H), 7.13 (d, J= 1.77 Hz, 2 H), 7.19 (t, J= 1.89 Hz, 1 H), 7.46 (d, J= 8.08 Hz, 2 H), 7.64 (d, J = 8.08 Hz, 2 H), 7.68 - 7.74 (m, 2 H), 7.79 - 7.84 (m, 2 H).
Example 2-81: Preparation of 4'-(2-Pyrrolidin-l-yl-ethyI)-biphenyl-4-sulfonic Acid Ethylamide (Compound 55).
The title compound was prepared in a similar manner as described in Example 1.18, using 4-(N-ethylsulfamoyl)phenylboronic acid (176 mg, 0.767 mmol) and l-(4- bromophenethyl)pyrrolidine (150 mg, 0.590 mmol) as starting materials, to give a white solid (HCl salt) in 40% yield. Exact mass calculated for C20H26N2O2S: 358.2, Found: LCMS mlz = 359.3 01+H+); 1H NMR (400 MHz, Methanol-^) δ 1.08 (t, J= 7.20 Hz, 3 H), 2.05 (t, J= 6.06 Hz, 2 H), 2.18 (s, 2 H), 2.92 (q, J= 7.33 Hz, 2 H), 3.07 - 3.23 (m, 4 H), 3.45 - 3.54 (m, 2 H), 3.65 - 3.77 (m, 2 H), 7.45 (d, J= 8.08 Hz, 2 H), 7.68 (d, J= 7.83 Hz, 2 H), 7.80 (d, J= 8.34 Hz, 2 H), 7.87 - 7.93 (m, 2 H).
Example 2.82: Preparation of 4-Methoxy-l-{4'-[2-((jR)-2-methyl-pyrroIidin-l-yl)-ethyl]- biphenyl-4-sulfonyl}-piperidine (Compound 113). The title compound was prepared in a similar manner as described in Example 1.2, using l-(4-bromophenylsulfonyl)-4-methoxypiperidine (156 mg, 0.468 mmol) and (S)-4-(2-(2- methylpyrrolidin-l-yl)ethyl)phenylboronic acid (109 mg, 0.468 mmol) as starting materials, to give a white solid (HCl salt) in 56% yield. Exact mass calculated for C2SH34N2O3S: 442.2, Found: LCMS mlz = 443.3 (M+ff1); 1H NMR (400 MHz, Methanol-^) δ 1.33 (d, J= 6.32 Hz, 0.3 H), 1.50 (d, J= 6.06 Hz, 2.7 H), 1.60 - 1.83 (m, 3 H), 1.85 - 1.95 (m, 2 H), 2.11 (s, 2 H),
2.35 (s, 1 H)32.89 - 2.99 (m, 2 H), 3.08 - 3.37 (m, 10 H), 3.64 (s, 2 H), 3.77 (s, 1 H), 7.48 (d, J= 7.83 Hz, 2 H), 7.70 (d, J= 7.58 Hz, 2 H), 7.84 (dd, 4 H).
Example 2.83: Preparation of 4f-[2-((JR)-2-Methyl-pyrrolidin-l-yl)-ethyI]-biphenyI-4- sulfonic Acid Bis-(2-methoxy-ethyl)-amide (Compound 107)
The title compound was prepared in a similar manner as described in Example 1.2, using 4-bromo-N,N-bis(2-methoxyethyl)benzenesulfonamide (151 mg, 0.429 mmol) and (i?)-4- (2-(2-methylpyrrolidin-l~yl)ethyl)ρhenylboronic acid (100 mg, 0.429 mmol) as starting materials, to give a white solid (HCl salt) in 40% yield. Exact mass calculated for C2SH36N2O4S: 460.2, Found: LCMS m/z = 461.4 (M+H*); 1H NMR (400 MHz5 Methanol-^) δ 1.33 (d, J=
6.82 Hz, 0.3 H)3 1.49 (d, J= 6.57 Hz, 2.7 H), 1.70 - 1.82 (m, 1 H), 2.11 (d, J= 31.58 Hz, 2 H), 2.34 (d, J= 5.56 Hz, 1 H), 3.06 - 3.22 (m, 2 H), 3.24 - 3.34 (m, 9 H), 3.42 (t, J= 5.68 Hz, 4 H), 3.53 (t, J = 5.68 Hz, 4 H), 3.59 - 3.82 (m, 2 H), 7.47 (d, J = 8.34 Hz, 2 H), 7.70 (d, J= 8.08 Hz, 2 H), 7.79 - 7.85 (m, 2 H), 7.88 - 7.93 (m, 2 H).
Example 2.84: Preparation of 4'-[2-((Λ>2-Methyl-pyrroHdin-l-yl)-ethyl]-biphenyl-4- 5 sulfonic Acid (l-Hydroxymethyl-cyclopentyl)-amide (Compound 103)
The title compound was prepared in a similar manner as described in Example 1.2, using 4-bromo-N-(l-(hydroxymethyl)cyclopentyl)benzenesulfonamide (143 mg, 0.429 mmol) and (Λ)-4-(2-(2-methylpyrrolidin-l-yl)ethyl)phenylboronic acid (100 mg, 0.429 mmol) as starting materials, to give a white solid (HCl salt) in 56% yield. Exact mass calculated for
10 C25H34N2O3S: 442.2, Found: LCMS mlz = 443.5 (M+H+); 1H NMR (400 MHz, Methanol-^) δ 1.27 - 1.36 (in, 0.3 H), 1.41 - 1.55 (m, 6.7 H), 1.57 - 1.69 (m;2 H), 1.72 - 1.87 (m, 3 H), 1.99 - 2.23 (m, 2 H), 2.34 (d, J= 5.05 Hz, 1 H), 3.06 - 3.24 (m, 2 H), 3.23 - 3.37 (m, 2 H), 3.55 (s, 3 H), 3.59 - 3.70 (m, 1 H), 3.72 - 3.83 (m, 1 H), 7.46 (d, J= 8.08 Hz, 2 H), 7.69 (d, J = 7.83 Hz, 2 H), 7.78 (d, J= 8.59 Hz, 2 H), 7.95 (d, J= 8.59 Hz, 2 H).
15
Example 2.85: Preparation of 4-Ethoxymethyl-l-{4'-[2-((i.)-2-methyl-pyrrolidin-l-yl)- ethyl]-biphenyl-4-sulfonyI}-piperidine (Compound 97).
The title compound was prepared in a similar manner as described in Example 1.2, using l-(4-bromoρhenylsulfonyl)-4-(ethoxymethyl)piperidine (179 mg, 0.493 mmol) and (R)-4-
20 (2-(2-methylpyπOlidin-l-yl)ethyl)phenylboronic acid (115 mg, 0.493 mmol) as starting materials, to give a white solid (HCl salt) in 58% yield. Exact mass calculated for C27H38N2O3S: 470.3, Found: LCMS mlz = 471.4 (M+H4); 1H NMR (400 MHz, Methanol-c?4) δ 1.13 (t, J= 6.95 Hz, 3 H), 1.22 - 1.38 (m, 3 H), 1.49 (d, J= 6.57 Hz, 4 H), 1.77 (s, 3 H), 2.10 (s, 2 H), 2.25 - 2.41 (m, 3 H), 3.08 - 3.21 (m, 2 H), 3.21 - 3.34 (m, 3 H), 3.43 (q, J= 7.07 Hz, 2 H), 3.64 (s, 2 H),
25. 3.77 (s, 3 H)3 7.47 (d, /= 8.08 Hz, 2 H), 7.70 (d, J= 8.34 Hz, 2 H), 7.80 - 7.88 (m, 4 H).
Example 2.86: Preparation of 4-(2-Ethoxy-ethyl)-l-{4'-[2-((i?)-2-metliyl-pvrrolidin-l-yl)- ethyl]-biphenyl-4-suIfonyl}-piperidine(Compound 91).
The title compound was prepared in a similar manner as described in Example 1.2, 30 using (191 mg, 0.506 mmol) and (R)-4-(2 -(2 -methylpyrrolidin-l-yl)ethyl)phenylboronic acid (118 mg, 0.506 mmol) as starting materials, to give a white solid (HCl salt) in 63% yield. Exact mass calculated for C28H40N2O3S: 484.3, Found: LCMS Wz = 485.4 (M+H1"); 1H NMR (400 MHz, Methanol-^) δ 1.13 (t, J= 7.07 Hz, 3 H), 1.28 (d, J= 3.28 Hz, 4 H), 1.43 - 1.53 (m, 5 H), 1.76 (s, 3 H), 2.07 (s, 2 H), 2.25 - 2.40 (m, 3 H), 3.07 - 3.22 (m, 2 H), 3.23 - 3.35 (m, 1 H), 3.38 35 - 3.48 (m, 4 H), 3.49 - 3.70 (m, 2 H), 3.77 (s, 3 H), 7.47 (d, J= 8.08 Hz, 2 H), 7.70 (d, J= 8.08 Hz, 2 H), 7.79 - 7.88 (m, 4 H). EXAMPLE 3: [3Hl iV-Alpha-Methyl-Histamine Competitive Histamine H3-receptor Binding Assay
The histamine receptor binding assay was conducted using standard laboratory procedures as described below. A crude membrane fraction was prepared from whole rat brain cortex using a polytron to homogenize the tissue followed by differential centrifugation in a HEPES-based buffer containing protease inhibitors. Membranes where frozen at -80 0C until needed. Frozen membranes were thawed and resuspended in ice-cold assay buffer consisting of 50 mM TRIS containing 5 mM EDTA (pH = 7.4). 50 micrograms (μg) of membrane protein was added to each well of a 96-well assay plate along with test compound and [3H]-N-o>rnethyl- histamine (1 nanomolar (nM) final assay concentration). Imetit was used as an assay positive control at varying concentrations. The plate was incubated for 30 min at room temperature. The assay was terminated by rapid filtration through a 96-well glass fiber filtration plate (GF/C) using a cell harvester (Perkin-Elmer). Captured membranes were washed three times with cold assay buffer and plates were dried at 50 0C. 35 microliters (μL) of scintillation cocktail was added to each well and membrane-bound radioactivity was recorded using a TopCount 96-well plate scintillation counter (Perkin-Elmer).
The following table shows the observed activities for certain compounds of the present invention.
Certain other compounds of the invention had activity values ranging from about 5 μM to about 50 pM in this assay.
EXAMPLE 4: Rat Polysomnography Protocol
Animals: Male Sprague-Dawley rats (225-350 g) (Harlan, San Diego, CA) were singly housed and maintained in a humidity- (30-70%) and temperature- (20-22 0C) controlled facility on a 12 h:12 h light/dark cycle (lights on at 6:30 A.M.) with free access to food (Harlan-Teklad Western Res., Orange, CA, Rodent Diet 8604) and water. Rats were allowed at least three days of habituation to the animal facility before surgery. Procedures: Rats were anaesthetized with a ketamine/xylazine mixture, and surgically prepared for
EEG and EMG recording. After 2-3 weeks of post-surgical recovery, rats were habituated to polypropylene test cages for at least three days. On test days, the rats were placed in the test chambers and habituated overnight. At 10 am the next day, the rats were administered the test compound, connected to the recording apparatus, and placed back into the test chambers for 3 h.
Data analysis
EEG and EMG data were digitized and stored in 10 s epochs over the three hour test period. These data were then visually scored, and each 10 s epoch characterized as either a non- REM sleep, REM sleep, or waking episode. Total wake time over the three hour period was . calculated for each rat after either vehicle administration or test compound. Percent increase in wakefulness was then derived for each rat.
The following table shows the observed percent increase in wakefulness over 3 h after oral administration of a representative compound at 1 mg/kg.
EXAMPLE 5: Human Histamine H3-Receptor Binding Assay - MDS Pharma Services (Taiwan). Compounds of the invention were tested for their ability to bind to the human histamine
H3-receptor using the MDS Pharma Services (Taiwan) assay, Catalogue No. 239810. Certain compounds of the present invention and their corresponding activity values are shown in following table.
EXAMPLE 6: Blockade of RAMH-Induced Drinking Assay
When administered to rodents, H3 agonists such as Λ-α-methyl-histamine (RAMH) . induce a drinking response that is sensitive to reversal with an H3 antagonist. Blockade of RAMH-induced drinking can therefore be utilized as an in vivo assay for functional H3 antagonist activity. In this assay, male Sprague Dawley rats (250-350 g) were housed three per cage and maintained under a reverse 12 h light cycle (lights off at 11:30 h). At 10:30 h on the day of test, rats were individually housed in new cages and food was removed. 120 min later, rats were administered test article (vehicle or H3 antagonist, 0.3 mg/kg PO). 30 min later, water was removed, and RAMH (vehicle or RAMH 3 mg/kg salt SC) was administered. 10 min after administration of RAMH, weighed water bottles were placed in the cages, and drinking was allowed for 20 min. Water consumption was determined for each animal by weighing each bottle to the nearest 0.1 g. Data is expressed as percentage reduction in water intake according to the following formula:
[l-[(antagonist/RAMH) - (vehicle/RAMH) / (vehicle/RAMH) - (vehicle/vehicle)]]* 100
Those skilled in the art will recognize that various modifications, additions, substitutions, and variations to the illustrative examples set forth herein can be made without departing from the spirit of the invention and are, therefore, considered within the scope of the invention. All documents referenced above, including, but not limited to, printed publications, and provisional and regular patent applications, are incorporated herein by reference in their entirety.

Claims

What is claimed is:
1. A compound selected from compounds of Formula (Ia):
Ota) and pharmaceutically acceptable salts, hydrates and solvates thereof; wherein:
R1 and R2 are each selected independently from the group consisting of H, C]-C6 acyl, C]-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloalkyl, aryl, heterocyclyl, heteroaryl, aryl-Ci-C4-alkylenyl, aryloxy-Ci-C4-alkylenyl, heteroaryl-Ci-C4-alkylenyl and heteroaryloxy-Ci-Ct-alkylenyl, and each R1 and R2 is optionally substituted with 1,
2, 3, 4 or 5 substituents selected independently from the group consisting of Ci-Ce acyl, Ci-C6 acyloxy, C2-C8 alkenyl, Cj-C6 alkoxy, Ci-C8 alkyl, Cj-C8 alkylcarboxamide, C2- C8 alkynyl, Ci-C8 alkylsulfonamide, Cj-C8 alkylsulfmyl, Cj-C8 alkylsulfonyl, Ci-C8 alkylthio, Ci-C8 alkylureyl, amino, aryl, C1-C8 alkylamino, C2-C8 dialkylamino, carbo- / Cj -C6-alkoxy, carboxamide, carboxy, cyano, C3-C7 cycloalkyl, C2-C8 dialkylcarboxamide, C2-C8 dialkylsulfonamide, halogen, Cj-C6 haloalkoxy, Ci-C6 haloalkyl, Ci-C6 haloalkylsulfinyl, Cj-C6 haloalkylsulfonyl, Ci-C6 haloalkylthio, heterocyclyl, hydroxyl, thiol, nitro and sulfonamide; wherein each Cj-C8 alkyl may be further substituted with hydroxy; or
R1 and R2 together with the nitrogen atom to which they are both bonded form a C3-C7 heterocyclyl or a Cs-C]0 heterobicyclyl group each optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected independently from the group consisting Of Ci-C6 acyl, Ci-C6 acyloxy, C2-C8 alkenyl, Cj-C6 alkoxy, Ci-C8 alkyl, Cj-C8 alkylcarboxamide, C2-C8 alkynyl, C]-C8 alkylsulfonamide, Cj-C8 alkylsulfinyl, C1-C8 alkylsulfonyl, C]-C8 alkylthio, Cj-C8 alkylureyl, amino, Ci-C8 alkylamino, C2-C8 dialkylamino, carbo-Cj-Q- alkoxy, carboxamide, carboxy, cyano, C3-C7 cycloalkyl, C2-C8 dialkylcarboxamide, C2- C8 dialkylsulfonamide, halogen, Cj-C6 haloalkoxy, Cj-C6 haloalkyl, Ci-C6 haloalkylsulfinyl, Cj-C6 haloalkylsulfonyl, Ci-C6 haloalkylthio, hydroxyl, thiol, nitro, oxo and sulfonamide; wherein each Cj-C8 alkyl and carboxy may be further substituted with Cj-C6 acyloxy, Ci-C6 alkoxy, aryl-Cj-C4-alkylenyl, or hydroxy; or R2 is selected independently from the group consisting of H, Ci-C6 acyl, C]-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloalkyl, aryl, heterocyclyl, heteroaryl, aryl-Ci-C4-alkylenyl, aryloxy-Ci-C4-alkylenyl, heteroaryl-C]-C4-alkylenyl and and each R2 is optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting OfCi-C6 acyl, Cj-C6 acyloxy, C2-C8 alkenyl, C1-C6 alkoxy, Ci-C8 alkyl, Ci-C8 alkylcarboxamide, C2-C8 alkynyl, Ci-C8 alkylsulfonamide, Ci-C8 alkylsulfiπyl, Ci-C8 alkylsulfonyl, C]-C8 alkylthio, C]-C8 alkylureyl, amino, aryl, Ci-C8 alkylamino, C2-C8 dialkylamino, carbo- Cj-Cβ-alkoxy, carboxamide, carboxy, cyano, C3-C7 cycloalkyl, C2-Cs dialkylcarboxamide, C2-C8 dialkylsulfonamide, halogen, Cj-C6 haloalkoxy, Cj-C6 haloalkyl, Cj-C6 haloalkylsulfϊnyl, Cj-C6 haloalkylsulfonyl, Ci-C6 haloalkylthio, heterocyclyl, hydroxyl, thiol, nitro and sulfonamide; and R1 and R12 together with the atoms to which they are both bonded form a C6-C8 heterocyclyl group optionally substituted with 1, 2, 3, 4 or 5 substituents selected- independently from the group consisting of Cj-C6 acyl, Ci-C6 acyloxy, C2-C8 alkenyl, Cj-C6 alkoxy, Cj-C8 alkyl, Cj-C8 alkylcarboxamide, C2-C8 alkynyl, Q-C8 alkylsulfonamide, C]-C8 alkylsulfinyl, Cj-C8 alkylsulfonyl, Cj-C8 alkylthio, Cj-C8 alkylureyl, amino, aryl, Cj-C8 alkylamino, C2-C8 dialkylamino, carbo-Ci-C6-alkoxy, carboxamide, carboxy, cyano, C3-C7 cycloalkyl, C2-C8 dialkylcarboxamide, C2-C8 dialkylsulfonamide, halogen, Cj-C6 haloalkoxy, Cj-C6 haloalkyl, Cj-C6 haloalkylsulfinyl, CrC6 haloalkylsulfonyl, Cj-Cg haloalkylthio, heterocyclyl, hydroxyl, thiol, nitro and sulfonamide;
J is -CH2CH2- or a 1 ,2-C3-C7-cycloalkylenyl group, each optionally substituted with 1, 2, 3 or 4 substituents selected independently from the group consisting OfCi-C3 alkyl, C]-C4 alkoxy, carboxy, cyano, Ci-C3 haloalkyl, halogen, hydroxyl and oxo; R3, R4, R5, R6, R7, R10, R1 ' and R12 are each selected independently from the group consisting of H, Ci-C6 acyl, Ci-C6 acyloxy, C2-C8 alkenyl, Ci-C6 alkoxy, CrC8 alkyl, C]-C8 alkylcarboxamide, C2-C8 alkynyl, Cj-C8 alkylsulfonamide, Cj-C8 alkylsulfinyl, Cj-C8 alkylsulfonyl, C]-C8 alkylthio, Cj-C8 alkylureyl, amino, Cj-C8 alkylamino, C2-C8 dialkylamino, carbo-Q-Cc-alkoxy, carboxamide, carboxy, cyano, C3- C7 cycloalkyl, C2-C8 dialkylcarboxamide, C2-C8 dialkylsulfonamide, halogen, Cj-C6 haloalkoxy, Cj-C6 haloalkyl, Cj-C6 haloalkylsulfinyl, Cj-C6 haloalkylsulfonyl, Ci-C6 haloalkylthio, hydroxyl, thiol, nitro and sulfonamide; and
R8 and R9 are each selected independently from the group consisting of H, Cj-C8 alkyl, C2-C5 alkenyl, C2-C8 alkynyl, C3-C7 cycloalkyl, aryl, heterocyclyl, heteroaryl, aryl-Ci-Gi-alkylenyl, heteroaryl-Ci-Q-alkylenyl and heteroaryloxy-C1-C4-alkylenyl, and each R8 andR9 is optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting OfC1-C6 acyl, Q- Cg acyloxy, C2-C8 alkenyl, Ci-C6 alkoxy, C,-C8 alkyl, Ci-C8 alkylcarboxamide, C2-C8 alkynyl, Ci-C8 alkylsulfonamide, C1-C8 alkylsulfinyl, CrC8 alkylsulfonyl, Ci-C8 alkylthio, Ci-C8 alkylureyl, amino, Ci-C8 alkylamino. C2-C8 dialkylamino, carbo-Ci-C6- alkoxy, carboxamide, carboxy, cyano, C3-C7 cycloalkyl, C2-C8 dialkylcarboxamide, C2- C8 dialkylsulfonamide, halogen, Ci-C6 haloalkoxy, CrC6 haloalkyl, Ci-C6 haloalkylsulfinyl, Ci-C6 haloalkylsulfonyl, Ci-C6 haloalkylthio, hydroxyl, thiol, nitro and sulfonamide; or
R8 and R9 together with the nitrogen atom to which they are both bonded form a C3-C7 heterocyclyl or a C5-Ci0 heterobicyclyl group each optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected independently from the group consisting OfCi-C6 acyl, Ci-C6 acyloxy, C2-C8 alkenyl, Cj-C6 alkoxy, Ci-C8 alkyl, C]-C8 alkylcarboxamide,
C2-C8 alkynyl, Ci-C8 alkylsulfonamide, Ci-C8 alkylsulfinyl, Ci-C8 alkylsulfonyl, Ci-C8 alkylthio, C]-Cg alkylureyl, amino, Ci-C8 alkylamino, Ca-C8 dialkylamino, carbo-Ci-C6- alkoxy, carboxamide, carboxy, cyano, C3-C7 cycloalkyl, C2-C8 dialkylcarboxamide, C2- C8 dialkylsulfonamide, halogen, Ci-C6 haloalkoxy, Ci-C6 haloalkyl, Ci-C6 haloalkylsulfinyl, Ci-C6 haloalkylsulfonyl, C1-C6 haloalkylthio, hydroxyl, thiol, nitro, oxo and sulfonamide; provided that said compound is other than:
-Y-CS-cyanopheny^-N-P-^'-CfCUl-dimethylethyOaminolsulfonyyClJ1- biphenyl]-4-yl]ethyl]-glycine methyl ester;
N-[[4'-[2-oxo-2-(phenylamino)ethyl][l,r-biphenyl]-4-yl]sulfonyl]-D-valine 1,1- dimethylethylester;
N-[[4'-[2-oxo-2-[(phenylmethyl)amino]ethyl] [1,1 '-biphenyl]-4-yl jsulfonyl]-D- valine 1,1-dimethylethyl ester;
N-[[4'-[2-oxo-2-(phenylamino)ethyl][l,r-biphenyl]-4-yl]sulfonyl]-D-valme; or N-[[4'-[2-oxo-2-[(phenylmethyl)amino]ethyl][l,r-biphenyl]-4-yl]sulfonyl]-D-valine.
2. The compound according to claim 1, wherein:
R1 and R2 are each selected independently from the group consisting of H, Ci-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C7 cycloalkyl, aryl, heterocyclyl, heteroaryl, aryl-C1-C4-alkylenyl, aryloxy-Ci-Q-alkylenyl, heteroaryl-Ci-C4-alkylenyl and heteroaryloxy-Ci-C^alkylenyl, and each R1 and R2 is optionally substituted with 1, 2, 3,
4 or 5 substituents selected independently from the group consisting OfC1-C6 acyl, Ci- C6 acyloxy, C2-C8 alkenyl, Q-C6 alkoxy, Ci-C8 alkyl, Ci-C3 alkylcarboxamide, C2-C8 alkynyl, CrC8 alkylsulfonamide, C1-C8 alkylsulfrnyl, Cj-C8 alkylsulfonyl, CrC8 alkylthio, C]-C8 alkylureyl, amino, Ci-C8 alkylamino, C2-C8 dialkylamino, carbo-Ci-C6- alkoxy, carboxamide, carboxy, cyano, C3-C7 cycloalkyl, C2-C8 dialkylcarboxamide, C2- C8 dialkylsulfonamide, halogen, C]-Ce haloalkoxy, Ci-C6 haloalkyl, Ci-C6 haloalkylsulfinyl, Ci-C6 haloalkylsulfonyl, Ci-C6 haloalkylthio, hydroxyl, thiol, nitro and sulfonamide; or
R1 and R2 together with the nitrogen atom to which they are both bonded form a C3-C7 heterocyclyl or a C5-Ci0 heterobicyclyl group each optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected independently from the group consisting Of C]-C6 acyl, Ci-C6 acyloxy, C2-C8 alkenyl, Ci-C6 alkoxy, Ci-C8 alkyl, Ci-C8 alkylcarboxamide, C2-C8 alkynyl, Ci-C8 alkylsulfonamide, CpC8 alkylsulfinyl, Ci-C8 alkylsulfonyl, Ci-C8 alkylthio, Ci-C8 alkylureyl, amino, Ci-C8 alkylamino, C2-C8 dialkylamino, carbo-C]-C6- alkoxy, carboxamide, carboxy, cyano, C3-C7 cycloalkyl, C2-C8 dialkylcarboxamide, C2- C8 dialkylsulfonamide, halogen, Ci-C6 haloalkoxy, C]-C6 haloalkyl, C]-C6 haloalkylsulfinyl, CrC6 haloalkylsulfonyl, Cj-C6 haloalkylthio, hydroxyl, thiol, nitro, oxo and sulfonamide.
3. The compound according to claim 2, selected from compounds having Formula (Tc) and pharmaceutically acceptable salts, hydrates and solvates thereof:
4. The compound according to claim 2, selected from compounds having Formula (Ie) and pharmaceutically acceptable salts, hydrates and solvates thereof:
(Ie)
5. The compound according to any one of claims 2 to 4, wherein each R1 and R2 is selected independently from the group consisting of H, Q-C8 alkyl, C3-C7 cycloalkyl, aryl, heterocyclyl, aryl-C|-C4-alkylenyl, heteroaryl-d-C4-alkylenyl and aryloxy-C,-C4- alkylenyl, and each R1 and R2 is optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting OfCi-C6 alkoxy, Ci-C8 alkyl, C3-C7 cycloalkyl, halogen, Ci-C6 haloalkyl and hydroxyl.
6. The compound according to any one of claims 2 to 4, wherein each R1 and R2 is selected independently from the group consisting of H, Ci-C8 alkyl, C3-C7 cycloalkyl, aryl, heterocyclyl, aryl-Ci-C4-alkylenyl, heteroaryl-C1-C4-alkylenyl and aryloxy-Ci-C4- alkylenyl, and each R1 and R2 is optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting of methoxy, ethoxy, isopropoxy, cyclopropyl, cyclohexyl, hydroxyl, fluoro, methyl, chloro and trifluoromethyl.
7. The compound according to any one of claims 2 to 4, wherein each R1 and R2 is selected independently from the group consisting of H, methyl, ethyl, n-propyl, isopropyl, t- butyl, 1-propyl-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, tetrahydropyran-4-yl, benzyl, pyridin-2-ylmethyl, 2-phenoxy-ethyl, 2-methoxy-ethyl, 2- ethoxy-ethyl, 2-isopropoxyethyl, cyclopropylmethyl, cyclohexylmethyl, 2- hydroxyethyl, 4-fluoro-phenyl, 4-methyl-benzyl, 4-methoxy-benzyl, 4-fluoro-benzyl, 4- chloro-benzyl and 4-trifluoromethyl-benzyl.
8. The compound according to any one of claims 2 to 4, wherein R1 is H or Ci-C8 alkyl and R2 is C]-C8 alkyl, C3-C7 cycloalkyl, aryl, heterocyclyl, aryl-Ci-C4-alkylenyl, aryl- Ci-C4-alkylenyl, heteroaryl-Ci-C4-alkylenyl or aryloxy-Ci-C4-alkylenyl, and each R2 is optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting Of Ci-C6 alkoxy, Ci-C8 alkyl, C3-C7 cycloalkyl, halogen, Ci-C5 haloalkyl and hydroxyl.
9. The compound according to any one of claims 2 to 4, wherein R1 is H or Ci-C8 alkyl and R2 is Ci-C8 alkyl, C3-C7 cycloalkyl, aryl, heterocyclyl, aryl-Ci-C4-alkylenyl, aryl- Ci-C4-alkylenyl, heteroaryl-C,-C4-alkylenyl or aryloxy-Ci-C4-alkylenyl, and each R2 is optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting of methoxy, ethoxy, isopropoxy, cyclopropyl, cyclohexyl, hydroxyl, fluoro, methyl, chloro and trifluoromethyl.
10. The compound according to any one of claims 2 to 4, wherein R1 is H, methyl or ethyl and R2 is H, methyl, ethyl, n-propyl, isopropyl, t-butyl, 1-propyl-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, tetrahydropyran-4-yl, benzyl, pyridin-2- ylmethyl, 2-phenoxy-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, 2-isopropoxyethyl, cyclopropylmethyl, cyclohexylmethyl, 2-hydroxyethyl, 4-fluoro-phenyl, 4-methyl- benzyl, 4-methoxy-benzyl, 4-fluoro-benzyl, 4-chloro-benzyl or 4-trifluorornethyl- benzyl.
11. The compound according to any one of claims 2 to 4, wherein R1 and R2 together with the nitrogen atom to which they are both bonded form a C3-C7 heterocyclyl or a C5-C10 heterobicyclyl group.
12. The compound according to any one of claims 2 to 4, wherein R1 and R2 together with the nitrogen atom to which they are both bonded form azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, l,l-dioxo-thiomorpholin-4-yl, 2,3-dihydro-l//-isoindol- 2-yl or l,2,3,4-tetrahydro-isoquinolin-2-yl.
13. The compound according to any one of claims 2 to 12, wherein each R3, R4, R5, R6, R7, R10, R11 and R12 is selected independently from H or halogen.
14. The compound according to any one of claims 2 to 12, wherein R3, R4, R5, R6, R7, R10, Rπ andR12 are H.
15. The compound according to any one of claims 2 to 14, wherein J is -CH2CH2- optionally substituted with 1, 2, 3 or 4 substituents selected independently from the group consisting Of Ci-C3 alkyl, Ci-C4 alkoxy, carboxy, cyano, Ci-C3 haloalkyl, halogen, hydroxyl and oxo.
16. The compound according to any one of claims 2 to 14, wherein J is -CH2CH2-.
17. The compound according to any one of claims 2 to 16, wherein each R8 and R9 is selected independently from the group consisting of H, Ci-Cs alkyl, C3-C7 cycloalkyl, aryl, heterocyclyl, aryl-Ci-C4-alkylenyl, heteroaryl-Ci-C4-alkylenyl and aryloxy-Cj-C-r alkylenyl, and each R8 andR9 is optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting of Cj -C6 alkoxy, Cj -C8 alkyl, C3-C7 cycloalkyl, halogen, C1-Q; haloalkyl and hydroxyl.
18. The compound according to any one of claims 2 to 16, wherein each R8 and R9 is selected independently from the group consisting of H, C]-C8 alkyl, C3-C7 cycloalkyl, aryl, heterocyclyl, aryl-CrC4-alkylenyl, heteroaryl-Ci-C4-alkylenyl and aryloxy-CrC4- alkylenyl, and each R8 and R9 is optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting of methoxy, ethoxy, isopropoxy, cyclopropyl, cyclohexyl, hydroxyl, fluoro, methyl, chloro and trifluoromethyl.
19. The compound according to any one of claims 2 to 16, wherein each R8 and R9 is selected independently from the group consisting of H, methyl, ethyl, n-propyl, isopropyl, t-butyl, 1-propyl-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, tetrahydropyran-4-yl, benzyl, pyridin-2-ylmethyl, 2-phenoxy-ethyl, 2-methoxy- ethyl, 2-ethoxy-ethyl, 2-isopropoxyethyl, cyclopropylmethyl, cyclohexylmethyl, 2- hydroxyethyl, 4-fluoro-phenyl, 4-methyl-benzyl, 4-methoxy-benzyl, 4-fluoro-benzyl, 4- chloro-benzyl and 4-trifluoromethyl-benzyl.
20. The compound according to any one of claims 2 to 16, wherein R8 and R9 together with the nitrogen atom to which they are both bonded form a C3-C7 heterocyclyl group optionally substituted with Ci-C8 alkyl.
21. The compound according to any one of claims 2 to 16, wherein R8 and R9 together with the nitrogen atom to which they are both bonded form a C3-C7 heterocyclyl group optionally substituted with methyl.
22. The compound according to any one of claims 2 to 16, wherein R8 andR9 together with the nitrogen atom to which they are both bonded form pyrrolidin-l-yl optionally substituted with methyl.
23. The compound according to any one of claims 2 to 16, wherein R8 and R9 together with the nitrogen atom to which they are both bonded form 2-methyl-pyrrolidin-l-yl.
24. The compound according to any one of claims 2 to 16, wherein R8 and R9 together with the nitrogen atom to which they are both bonded form (Λ)-2-methyl-pyrrolidin-l-yl.
25. The compound according to any one of claims 2 to 16, wherein R8 and R9 together with the nitrogen atom to which they are both bonded form (ιS)-2-methyl-ρyrrolidin-l-yl.
26. The compound according to claim 1, selected from compounds of Formula (Ig) and pharmaceutically acceptable salts, hydrates and solvates thereof: wherein:
R1 is H or C1-C8 alkyl and R2 is C1-C8 alkyl, C3-C7 cycloalkyl, aryl, • heterocyclyl, aryl-CrC4-alkylenyl, heteroaryl-Ci-C4-alkylenyl or aryloxy-Cι-C4- alkylenyl, and each R2 is optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting of CrC6 alkoxy, Ci-C8 alkyl, C3-C7 cycloalkyl, halogen, Ci-C6 haloalkyl andhydroxyl; or
R1 and R2 together with the nitrogen atom to which they are both bonded form a C3-C7 heterocyclyl or a Cs-Cj0 heterobicyclyl group; J is -CH2CH2-; and
R8 and R9 together with the nitrogen atom to which they are both bonded form a C3-C7 heterocyclyl group optionally substituted with C1-Cg alkyl.
27. The compound according to claim 1 , selected from compounds of Formula (Ig) and pharmaceutically acceptable salts, hydrates and solvates thereof:
(Ig) wherein
R1 is H, methyl or ethyl and R2 is H, methyl, ethyl, n-propyl, isopropyl, t-butyl, 1-ρropyl-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, tetrahydropyran-4-yl, benzyl, pyridin-2-ylmethyl, 2-phenoxy-ethyl, 2-methoxy-ethyl, 2- ethoxy-ethyl, 2-isopropoxyethyl, cyclopropylmethyl, cyclohexylmethyl, 2- hydroxyethyl, 4-fluoro-phenyl, 4-methyl-benzyl, 4-methoxy-benzyl, 4-fiuoro-benzyl, 4- chloro-benzyl or 4-trifluoromethyl-benzyl; or
R1 and R2 together with the nitrogen atom to which they are both bonded form azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, 1, 1-dioxo-thiomorpholin-
4-yl, 2,3-dihydro-lH-isoindol-2-yl or l,2,3,4-tetrahydro-isoquinolin-2-yl; J is -CH2CH2-; and
R8 and R9 together with the nitrogen atom to which they are both bonded form 2-methyl-pyrrolidin- 1 -yl .
28. The compound according to claim 1, selected from compounds of Formula (Ii) and pharmaceutically acceptable salts, hydrates and solvates thereof:
(K) wherein: R1 is H or Ci-C8 alkyl and R2 is C1-C8 alkyl, C3-C7 cycloalkyl, aryl, heterocyclyl, aryl-Ci-Q-alkylenyl, heteroaryl-Ci-C4-alkylenyl or aryloxy-C i-C4- alkylenyl and each R2 is optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting of Ci-C6 alkoxy, Cj-C8 alkyl, C3-C7 cycloalkyl, halogen, Ci-C6 haloalkyl and hydroxyl; or R1 and R2 together with the nitrogen atom to which they are both bonded form a
C3-C7 heterocyclyl or a C5-C]0 heterobicyclyl group; J is -CH2CH2-; and
R8 and R9 together with the nitrogen atom to which they are both bonded form a C3-C7 heterocyclyl group optionally substituted with Ci-C8 alkyl.
29. The compound according to claim 1, selected from compounds of Formula (Ii) and pharmaceutically acceptable salts, hydrates and solvates thereof:
(B) wherein: R1 is H, methyl or ethyl and R2 is H, methyl, ethyl, n-propyl, isopropyl, t-butyl,
1-propyl-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, tetrahydropyran-4-yl, benzyl, pyridin-2-ylmethyl, 2-phenoxy-ethyl, 2-methoxy-ethyl, 2- ethoxy-ethyl, 2-isopropoxyethyl, cyclopropylmethyl, cyclohexylmethyl, 2- hydroxyethyl, 4-fluoro-phenyl, 4-methyl-benzyl, 4-methoxy-benzyl, 4-fiuoro-benzyl, A- chloro-benzyl or 4-trifluoromethyl-benzyl; or
R1 and R2 together with the nitrogen atom to which they are both bonded form azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, 1,1-dioxo-thiomorpholin- 4-yl, 2,3-dihydro-l//-isoindol-2-yl or l,2,3,4-tetrahydro-isoquinolin-2-yl; J is -CH2CH2-; and Rs and R9 together with the nitrogen atom to which they are both bonded form 2-methyl-pyrrolidin-l-yl.
30. The compound according to claim 1, selected from the following compounds and pharmaceutically acceptable salts, hydrates and solvates thereof:
4'-[2-(2-methyl-pyrrolidin-l -yl)-ethyl]-biphenyl-4-sulfonic acid (tetrahydro- pyran-4-yl)-amide;
2- {4'-[2-(2-methyl-pyrrolidm-l -yl)-ethyl]-biphenyl-4-sulfonyl} -2,3-dihydro- lH-isoindole; 4'-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4-sulfonic acid (pyridin-2- ylmethyl)-amide;
4'-[2-(2-methyl-pyrrolidin-l -yl)-ethyI]-biphenyl-4-sulfonic acid 4-methyl- benzylamide;
4'-[2-(2-methyl-pyrrolidin-l -yl)-ethyl]-biphenyl~4-sulfonic acid (2-ethoxy- ethyl)-amide;
4- {4'-[2-(2-methyl-pyrrolidin-l -yl)-ethyl]-biphenyl-4-sulfonyl} -thiomorpholine 1,1 -dioxide;
4'-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4-sulfonic acid (2-isopropoxy- ethyl)-amide; 4'-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4-sulfonic acid (2-phenoxy- ethyl)-amide;
4'-[2-(2-methyl-pyrrolidin- 1 -yl)-ethyl]-biphenyl-4-sulfonic acid 4-methoxy- benzylamide;
4'-[2-(2-methyl-pyrrolidiπ-l -yl)-ethyl]-biphenyl-4-sulfonic acid cyclohexylamide;
2-methyl- 1 - {2-[4'-(pyrrolidine- 1 -sulfonyl)-biphenyl-4-yl]-ethyl } -pyrrolidine; 2-{4'-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4-sulfonyl}-l,2,3:i4- tetrahydro-isoquinoline;
4'-[2-(2-methyl-pyrrolidin-l -yl)-ethyl]-biphenyl-4-sulfonic acid benzyl-ethyl- amide;
4'-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4-sulfonic acid 4- trifluorornethyl-benzylamide;
1 - {2-[4'-(azetidine-l -sulfonyl)-biphenyl-4-yl]-ethyl } -2-methyl-pyrrolidine; 4'-[2-(2-methyl-pyrrolidin-l -yl)-ethyl]-biphenyl-4-sulfonic acid cyclobutylamide;
4'-[2-(2-methyl-pyrrolidin-l -yl)-ethyl]-biphenyl-4-sulfonic acid tert- butylamide; 4'-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4-sulfonic acid propylamide; 4'-[2<2-methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4-sulfonic acid isopropylamide;
4'-[2-(2-methyl-pyrrolidin- l-yl)-ethyl]-biphenyl-4-sulfonic acid methylamide; 4'-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4-sulfonic acid (2-methoxy- ethyl)-amide;
4'-[2-(2-methyl-pyπOlidin-l-yl)-ethyl]-biphenyl-4-sulfonic acid (4-fluoro- phenyl)-amide;
4'-[2-(2-methyl-pyrrolidin-l -yl)-ethyl]-biphenyl-4-sulfonic acid 4-fluoro- benzylamide;
4'-[2-(2-methyl-pyrτolidin-l -yl)-ethyl]-biphenyl-4-sulfonic acid 4-chloro- benzylamide;
4'-[2-(2-methyl-pyiτolidin-l-yl)-ethyl]-biphenyl-4-sulfonic acid (2-hydroxy- ethyl)-amide; 4'-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4-sulfonic acid diethylamide;
4'-[2-(2-methyl-pyττolidin-l-yl)-ethyl]-biphenyl-4-sulfonic acid (1-propyl- butyl)-amide;
4'-[2-(2-methyl-pyrτolidin-l -yl)-ethyl]-biphenyl-4-sulfonic acid cyclohexylmethyl-amide; 4'-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4-sulfonic acid ben2ylamide;
4'-[2-(2-meth.yl-pyrrolidin- 1 -yl)-ethyl] -biphenyl-4-sulfonic acid phenylamide; 4'-[2-(2-methyl-pyrrolidin-l-yl)-etliyl]-biphenyl-4-sulfonic acid cyclopropylmethyl-amide;
4'-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4-sulfonic acid cyclopentylamide;
4-{4'-[2-(2-inethyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4-sulfonyl}-morρholine; l-{4'-[2-(2-methyl-pyrrolidm-l-yl)-ethyl]-biphenyl-4-sulfonyl}-piperidine; 4'-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4-sulfonic acid amide; 4'-[2-(2-methyl-pyrrolidin-l -yl)-ethyl]-biphenyl-4-sulfonic acid cyclopropylamide; and
4l-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4-sulfonic acid ethylamide.
31. The compound according to claim 1, selected from the following compounds and pharmaceutically acceptable salts, hydrates and solvates thereof: l-{4'-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-3-sulfonyl}-piperidine;
4'-[2-(methyl-ρyrrolidin-l-yl)-ethyl]-biphenyl-3-sulfonic acid isopropylamide; 4'-[2-(methyl-pyrrolidin-l-yl)-ethyl]-biρhenyl-3-sulfonic acid ethylamide; 4'-[2-(2-methyl-pyrrol idin- 1 -yl)-ethyl]-biphenyl-3 -sulfonic acid diethylamide; and
4'-[2-(methyl-pyrrolidin- 1 -yl)-ethyl] -biphenyl-3 -sulfonic acid dimethylamide .
32. The compound according to claim 1, wherein:
R1 and R2 are each selected independently from the group consisting of H, Q- C8 alkyl, C3-C7 cycloalkyl, aryl, heterocyclyl, aryl-Ci-C4-alkylenyl, amino, heteroaryl- Ci-C4-alkylenyl, aryloxy-Ci-C4-alkylenyl and Q-C6 acyl, and each R1 andR2 is optionally substituted with I, 2, 3, 4 or 5 substituents selected independently from the group consisting OfQ-C6 alkoxy, Ci-C8 alkyl, aryl, carbo-Q-C6-alkoxy, C3-C7 cycloalkyl, halogen, Ci-Ce haloalkyl, hydroxyl, C1-C6 acyl, Ci-C6 acyloxy, Ci-C6 haloalkoxy and heterocyclyl; wherein each Ci-C8 alkyl may be further substituted with hydroxy; or R1 andR2 together with the nitrogen atom to which they are both bonded form a
C3-C7 heterocyclyl or a C5-Q0 heterobicyclyl group each optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting of Ci-Cg acyl, C]-C8 alkyl, Ci-Cs alkylcarboxamide, Ci-C6 acyloxy, carboxy and hydroxy; and wherein each Ci-C8 alkyl and carboxy may be further substituted with Cj-C6 acyloxy, Ci-C6 alkoxy, aryl-Q-C^alkylenyl or hydroxy.
33. The compound according to claim 1, wherein:
R1 and R2 are each selected independently from the group consisting of H, methyl, ethyl, n-propyl, isopropyl, t-butyl, 1 -propyl-butyl, cyclopropyl, cyclobutyl, . cyclopentyl, cyclohexyl, phenyl, tetrahydropyran-4-yl, benzyl, pyridm-2-ylmethyl, 2- phenoxy-ethyl, 2-methoxy-ethyl, 2-ethoxy-ethyl, 2-isoproρoxyethyl, cyclopropylmethyl, cyclohexylmethyl, 2-hydroxyethyl, 4-fluoro-phenyl, 4-methyl-benzyl, 4-methoxy- benzyl, 4-fluoro-benzyl, 4-chloro-benzyl, 4-trifluoromethyl-benzyl, amino, 2-methoxy- 1 -methyl-ethyl, propionyloxyl, 3,5-dichlorobenzyl, acetyl, 3,4-dichlorobenzyl, 2- hydroxy-1 -methyl-ethyl, 2-acetoxyethyl, 4-fluoro-phenyl-ethyl, tetrahydro-pyran-4- ylmethyl, 2-propionyloxy-ethyl, diphenyl-methyl, 2-hydroxy-l,l -dimethyl-ethyl, isobutyl, 3-phenyl-propyl, 2-oxo-imidazolidin-l-yl-ethyl, phenyl-ethyl, pyridin-4-yl- methyl, 3-methoxy-3-oxopropyl, pyridin-3-yl -methyl, l-methoxy-l-oxopropan-2-yl, 1- (hydroxymethyl)cyclopentyl, 4-(trifluoromethoxy)-benzyl, 2-methoxy-3-oxoethyl, 1- isopropoxy- 1 -oxopropan-2-yl, 2-isopropoxy-2-oxoethyl, 2-methyl- 1 -
(propionyloxy)propan-2-yl, 1-tert-bvAoxy-l -oxopropan-2-yl and 2-fert-butoxy-2- oxoethyl; or
R1 and R2 together with the nitrogen atom to which they are both bonded form azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, 1,1-dioxo-thiomorpholin- 4-yl, 2,3-dihydro-lH-isoindol-2-yl, l,2,3,4-tetrahydro-isoquinolin-2-yl, 3-hydroxy- pyrrolidin-1-yl, 3-hydroxymethyl -piperidin-1-yl, aziridinl-yl, 2-methoxymethyl- pyrrolidin-1-yl, 3-hydroxy-piperidin-l-yl, 2-hydroxyτnethyl-pyrrolidin-l-yl, 4- (benzyloxycarbonyl)piperidin-l-yl. 4-(propionyloxy-methyl)-piperidin-l-yl, 2- (propionyloxy-methyl)-pyrrolidin-l-yl, 3-methoxymethyl-piperidin-l -yl, 4- hydroxymethyl-piperidin-1 -yl, 4-(ethoxycarbonyl)piperidin- 1 -yl, 4-(2-ethoxy- ethyl)piperidin-l-yl, 4-proρionyl-piperazin-l-yl, 4-(ethoxy-methyl)-ρiperidin-l-yl, 3- methoxy-piperidin-1 -yl, 4-(2-hydroxy-ethyl)-piperidin-l-yl, 2-hydroxymethyl- piperidin-1-yl, 3-methoxy-pyrrolidin-l-yl, 2-carboxy-pyrrolidin-l-yl, 6,7-dimethoxy- 3,4-dihydroisoquinolin-2(lH)-yl, 4-methoxy-piperidin-l-yl, 3-oxo-piperazin-l-yl, 2- (methylcarbamoyl)pyrrolidin-l-yl, 3,5-dimethyl-morpholin-4-yl, 3-propionyloxy- pyrrolidin-l-yl,.4-hydroxy-piperidin-l-yl, 4-carboxy-piperidin-l-yl, 4-hydroxy-2-
(methoxycarbonyl)-pyrrolidm-l-yl, 4-(2-methqxy-ethyl)-piperidin-l-yl or 4- (methoxymethyl)-piperidin-l -yl.
34. The compound according to any one of claims 1 , 32 and 33, wherein R3, R4, R5, R6, R7, R10,Rπ andRI2 are Η.
35. The compound according to any one of claims 1 and 32 to 34, wherein J is -CH2CH2-.
36. The compound according to any one of claims 1 and 32 to 35, wherein R8 andR9 together with the nitrogen atom to which they are both bonded form pyrrolidin-1-yl optionally substituted with methyl.
37. The compound according to any one of claims 1 and 32 to 35, wherein R8 andR9 together with the nitrogen atom to which they are both bonded form 2-methyl- pyrrolidin-1-yl.
38. The compound according to any one of claims 1 and 32 to 35, wherein Rs and R9 together with the nitrogen atom to which they are both bonded form (7?)-2-methyl- pyrrolidin-1-yl.
39. The compound according to claim 1, selected from compounds of Formula (Ig) and pharmaceutically acceptable salts, hydrates and solvates thereof:
(Ig) wherein:
R1 is selected from the group consisting of H, C1-C6 acyl and Ci-C8 alkyl optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting of Ci-C6 alkoxy and hydroxy;
R2 is selected from the group consisting of H, Q-C8 alkyl, C3-C7 cycloalkyl, aryl, heterocyclyl, aryl-Cj-C4-alkylenyl, amino, heteroaryl-Ci-Gj-alkylenyl, aryloxy-C)- Cj-alkylenyl and Ci-C6 acyl, and each R2 is optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from the group consisting OfC)-C6 alkoxy, Cj-C8 alkyl, aryl, carbo-C]-C6-alkoxy, C3-C7 cycloalkyl, halogen, Cj-C6 haloalkyl, hydroxyl,
C]-C6 acyl, Ci-C6 acyloxy, C1-C6 haloalkoxy and heterocyclyl; wherein each C1-C8 alkyl may be further substituted with hydroxy; or
R1 and R2 together with the nitrogen atom to which they are both bonded form a C3-C7 heterocyclyl or a C5-Ci0 heterobicyclyl group each optionally substituted with 1,
2, 3, 4 or 5 substituents selected independently from the group consisting OfCi-C6 acyl, C1-C8 alkyl, C1-C8 alkylcarboxamide, Ci-C6 acyloxy, carboxy and hydroxy; and wherein each C1-C8 alkyl and carboxy may be further substituted with C1-C6 acyloxy, Cj-C6 alkoxy, aryl-Cj-C4-alkylenyl or hydroxy; J is -CH2CH2-; and
R8 and R9 together with the nitrogen atom to which they are both bonded form a C3-C7 heterocyclyl group optionally substituted with Cj-C8 alkyl.
40. The compound according to claim 1, selected from compounds of Formula (Ig) and pharmaceutically acceptable salts, hydrates and solvates thereof:
wherein:
R1 is H, methyl, ethyl, 2-hydroxy-ethyl, 2-methoxy-ethyl or acetyl;
R2 is selected from the group consisting of H, methyl, ethyl, n-propyl, isopropyl, t-butyl, 1-propyl-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, tetrahydropyran-4-yl, benzyl, pyridin-2-ylmethyl, 2-phenoxy-ethyl, 2-methoxy- ethyl, 2-ethoxy-ethyl, 2-isopropoxyethyl, cyclopropylmethyl, cyclohexylmethyl, 2- hydroxyeihyl, 4-fluoro-phenyl, 4-methyl-benzyl, 4-methoxy-benzyl, 4-fluoro-benzyl, A- chloro-benzyl, 4-trifluoromethyl-benzyl, amino, 2-methoxy-l -methyl-ethyl, propionyloxyl, 3,5-dichlorobenzyl, acetyl, 3,4-dichlorobenzyl, 2-hydroxy-l-methyl- ethyl, 2-acetoxyethyl, 4-fluoro-phenyl-ethyl, tetrahydro-pyran-4-ylmethyl, 2- propionyloxy-ethyl, diphenyl-methyl, 2-hydroxy- 1,1 -dimethyl-ethyl, isobutyl, 3-phenyl- propyl, 2-oxo-imidazolidin-l-yl-ethyl, phenyl-ethyl, pyridin-4-yl-methyl, 3-methoxy-3- oxopropyl, pyridin-3-yl -methyl, l-methoxy-l-oxopropan-2-yl, 1- (hydroxymethyl)cyclopentyl, 4-(trifluoromethoxy)-benzyl, 2-methoxy-3-oxoethyl, 1- isopropoxy-l-oxopropan-2-yl, 2-isopropoxy-2-oxoethyl, 2-methyl-l-
(propionyloxy)propan-2-yl, l-tert-butoxy-l-oxopropan-2-yl and 2-/er/-butoxy-2- oxoethyl; or R1 and R2 together with the nitrogen atom to which they are both bonded form azetidin- 1 -yl, pyrrolidin- 1 -yl, piperidin- 1 -yl, morpholin-4-yl, 1 , 1 -dioxo-thiomorpholin-
4-yl, 2,3-dihydro-lH-isoindol-2-yl, l,2,3,4-tetrahydro-isoquinolin-2-yl3 3-hydroxy- pyrrolidin-1-yl, 3-hydroxymethyl-piperidin-l-yl, aziridinl-yl, 2-methoxymethyl- pyrrolidin-1-yl, 3-hydroxy-piperidin-l-yl, 2-hydroxymethyl-pyrrolidin-l-yl, A- (ben2yloxycarbonyl)piperidin-l-yl, 4-(propionyloxy-methyl)-piperidin-l -yl, 2- (propionyloxy-methyl)-pyrrolidin-l-yl, 3-methoxymethyl-piperidin-l-yl, A- hydroxymethyl-piperidin-1-yl, 4-(ethoxycarbonyl)piperidin-l-yl, 4-(2-ethoxy- ethyl)piperidin-l-yl, 4-propionyl-piperazin-l-yl, 4-(ethoxy-methyl)-ρiperidin-l-yl, 3- methoxy-piperidin-1 -yl, 4-(2-hydroxy-ethyl)-piperidin-l-yl, 2-hydroxymethyl- piperidin-1-yl, 3-methoxy-pyrrolidin-l-yl, 2-carboxy-pyrrolidin-l-yl, 6,7-dimethoxy- 3,4-dihydroisoquinolin-2(lH)-yl, 4-methoxy-piperidm-l-yl, 3-oxo-piperazin-l-yl, 2-
(methylcarbamoyl)pyrrolidin-l-yl, 3,5-dimethyl-morpholin-4-yl, 3-propionyIoxy- pyrrolidin-1-yl, 4-hydroxy-piperidin-l-yl3 4-carboxy-piperidin-l-yl, 4-hydroxy-2- (methoxycarbonyl)-pyrrolidin-l-yl, 4-(2-methoxy-ethyl)-piperidin-l-yl or A- (methoxymethyl)-piperidin- 1 -yl; J is -CH2CH2-; and
R8 and R9 together with the nitrogen atom to which they are both bonded form pyrrolidin- 1-yl or 2-methyl-pyrrolidin-l-yl.
41. The compound according to claim 1 selected from the following compounds and pharmaceutically acceptable salts, hydrates and solvates thereof:
4'-[2-(2-methyl -pyrrolidin- 1 -yl)-ethyl]-biphenyl-4-sulfonic acid (2-methoxy-l - methyl-ethyl)-amide; l-{4'-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4-sulfonyl}-pyrrolidin-3-ol;
(l-{4'-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4-sulfonyl}-piperidin-3- yl)-methanol; l-{2-[4'-(aziridine-l-sulfonyl)-biphenyl-4-yl]-ethyl}-2-methyl-pyτrolidine; 2-(methoxymethyl)-l-(4'-(2-(2-methylpyrrolidin-l-yl)ethyl)biphenyl-4- ylsulfonyl)pyrrolidine;
4'-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4-sulfonic acid (2-methoxy- ethyl)-methyl-amide; l-{4'-[2-(2-methyl-pyrrolidm-l-yl)-ethyl]-biphenyl-4-sulfonyl}-piperidin-3-ol; propionic acid l-{4'-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4-sulfonyl}- piperidin-4-yl ester;
4'-(2-pyrrolidin-l-yl-ethyl)-biphenyl-4-sulfonic acid ethylamide;
( 1 - {4'-[2-(2-methyl-pyrrolidin- 1 -yl)-ethyl]-biphenyl-4-sulfonyl } -pyrrolidin-2 - yl)-methanol; 4'-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4-sulfonic acid benzyl-(2- hydroxy-ethyl)-amide;
4'-[2-(2-methyl-pyrrolidin-l -yl)-ethyl]-biphenyl-4-sulfonic acid 3,5-dichloro- benzylamide;
4'-[2-(2-methyl-pyrrolidm-l -yl)-ethyl]-biphenyl-4-sulfonic acid acetyI-(2- hydroxy-ethyl)-amide;
4'-[2-(2-methyl-pyrrolidin-l -yl)-ethyl]-biphenyl-4-sulfonic acid 3,4-dichloro- benzylamide;
4'-[2-(2-methyl-pyrrolidin-l -yl)-ethyl]-biρhenyl-4-sulfonic acid (2-hydroxy-l - methyl-ethyl)-amide; propionic acid 2-(l-{4'-[2-(2-methyl-pyrrolidin-l-yI)-ethyl]-biρlienyl-4- sulfonyl } -piperidin-4-yl)-ethyl ester; l-{4'-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4-sulfonyl}-piperidine-4- carboxylic acid benzyl ester; acetic acid 2-(acetyl-{4'-[2-(2-met]iyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonyl}-amino)-ethyl ester;
4'-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4-sulfonic acid [2-(4-fluoro- . phenyl)-ethyl]-amide;
4'-[2-(2-methyl-pyrrolidin-l -yl)-ethyl]-biphenyl-4-sulfonic acid (tetrahydro- pyran-4-ylmethyl)-amide; propionic acid l-{4'-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4-sulfonyl}- piperidin-4-yl methyl ester; propionic acid 2-(methyl- {4'-[2-(2-methyl-pyrrolidin- 1 -yl)-ethyl] -biphenyl-4- sulfonyl}-amino)-ethyl ester;
4'-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4-sulfonic acid (2-methoxy- ethyl)-(tetrahydro-pyran-4-ylmethyl)-amide; 4'-[2-(2-methyl-pyrrolidin-l -yl)-ethyl]-biphenyl-4-sulfonic acid benzhydryl- amide;
2-methyl-7-{4-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-phenyl}-3,4-dihydro-2H- benzo[b][l ,4,5]oxathiazepine 1,1-dioxide;
4'-[2-(2-methyl-pyτrolidin-l-yl)-ethyl]-biphenyl-4-sulfonic acid (2-hydroxy- 1,1- dimethyl-ethyl)-amide; propionic acid l-{4'-[2-(2-πiethyl-pyiτolidin-l-yl)-ethyl]-biphenyl-4-sulfonyl}- pyrrolidin-2-ylmethyl ester;
4'-[2-(2-methyl-pyrrolidin- 1 -yl)-ethyl]-biphenyl-4-sulfonic acid isobutyl-(2- methoxy-ethyl)-amide; 7-{4-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-phenyl}-3,4-dihydro-2//- benzo[b] [ 1 ,4,5]oxathiazepine 1 , 1 -dioxide;
4'-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4-sulfonic acid (2-hydroxy- ethyl)-methyl-amide;
4'-[2-(2-methyl-pyrrolidin-l -yl)-ethyl]-biphenyl-4-sulfonic acid bis-(2-hydroxy- ethyl)-amide;
4'-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4-sulfonic acid isopropyl-(2- methoxy-ethyl)-amide;
4'-[2-(2-methyl-pyrrolidin- 1 -yl)-ethyl]-biphenyl-4-sulfonic acid (2-hydroxy- ethyl)-isopropyl-amide; 4'-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4-sulfonic acid (3-phenyl- propyl)-amide;
4'-[2-(2-methyl-pyrrolidin- 1 -yl)-ethyl]-biphenyl-4-sulfonic acid [2-(2-oxo- imidazolidin-l-yl)-ethyl]-amide;
4I-[2-(2-methyl-pyrrolidin- 1 -yl)-ethyl]-biphenyl-4-sulfonic acid [3-(2-oxo- pyrrolidin-l-yl)-propyl] -amide;
4'-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4-sulfonic acid benzyl-(2- methoxy-ethyl)-amide;
3-methoxymethyl-l - {4'-[2-(2-methyl-pyrrolidin-l -yl)-ethyl]-biphenyl-4- sulfonyl} -piperidine; 4'-[2-(2-methyl-pyrrolidin- l-yl)-ethyl]-biphenyl-4-sulfonic acid phenethyl- amide; ( 1 - {4'-[2-(2-methyl-pyrrolidin-l -yl)-ethyl]-biphenyl-4-sulfonyl} -piperidin-4- yl)-methanol; l-{4'-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4-sulfonyl}-piperidine-4- carboxylic acid ethyl ester; 4-(2-ethoxy-ethyl)-l-{4'-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonyl}-piperidme; l-(4-{4'-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4-sulfonyl}-piperazin-l- yl)-propan-l -one;
4'-[2-(2-methyl-pyrrolidin-l -yl)-ethyl]-biphenyl-4-sulfonic acid (pyridin-4- ylmethyl)-aτnide;
3- {4'-[2-(2-methyl-pyrrolidin-l -yl)-ethyl]-biphenyl-4-sulfonylamino} -propionic acid methyl ester;
4-ethoxymethyl-l-{4'-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonyl} -piperidine; (l-{4l-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4-sulfonyl}-piperidin-3- yl)-methanol;
3-methoxy-l-{4'-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4-sulfonyl}- piperidine;
4'-[2-(2-methyl-pyrrolidin- 1 -yl)-ethyl]-biphenyl-4-sulfonic acid (pyridin-3 - ylmethyl)-amide;
2-(l-{4'-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4-sulfonyl}-piperidin-4- yl)-ethanol;
2- {4'-[2-(2-methyl-pyrrolidiii-l -yl)-ethyl]-biphenyl-4-sulfonylamino} -propionic acid methyl ester; 4'-[2-(2-methyl-pyrrolidin- 1 -yl)-ethyl]-biphenyl-4-sulfonic acid ( 1 - hydroxymethyl-cyclopentyl)-amide;
(l-{4'-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4-suIfonyl}-piperidin-2- yl)-methanol;
1 -(2-(4'-(3 -methoxypyrrolidin- 1 -ylsulfonyl)biphenyl-4-yl)ethyl)-2- methylpyrrolidine;
4'-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4-sulfoτiic acid 4- trifluoromethoxy-benzylamide;
4'-[2-(2-methyl-pyrrolidin-l -yl)-ethyl]-biphenyl-4-sulfonic acid bis-(2-methoxy- ethyl)-amide; {4'-[2-(2-methyl-pyrrolidin- 1 -yl)-ethyl]-biphenyl-4-sulfonylamino} -acetic acid methyl ester; 2-{4l-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4-sulfonylamino}-propionic acid isopropyl ester; l-l^-p-CZ-methyl-pyrrolidin-l-y^-ethylJ-biphenyM-sulfonyll-pyrrolidine^- carboxylic acid; . 6,7-dimethoxy-2- {4'-[2-(2-methyl-pyrrolidin- 1 -yl)-ethyl]-biphenyl-4-sulfonyl} -
1 ,2,3 ,4-tetrahydro-isoquinoline;
4-methoxy-l-{4'-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4-sulfonyl}- piperidine;
4-{4'-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4-sulfonyl}-piperazin-2- one;
{4'-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4-sulfonylamino}-acetic acid isopropyl ester; l-{4'-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4-sulfonyl}-pyrrolidine-2- carboxylic acid methylamide; 3,5-dimethyl-4-{4'-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4-sulfonyl}- morpholine; propionic acid l-{4'-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4-sulfonyl}- pyrrolidin-3-yl ester; l-{4'-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4-sulfonyl}-piperidm-4-oI;' propionic acid 2-methyl-2-{4'-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonylamino} -propyl ester;
2-{4'-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4-sulfonylamino}-propionic acid tert-butyl ester;
1 -{4'-[2-(2-methyl-pyrrolidin-l -yl)-ethyl]-biphenyl~4-sulfonyl} -piperidine-4- carboxylic acid;
{4l-[2-(2-methyl-pyrrolidin-l -yl)-ethyl]-biphenyl-4-sulfonylamino} -acetic acid tert-butyl ester;
4-hydroxy-l - {4'-[2-(2-methyl-pyrrolidin-l -yl)-ethyl]-biphenyl-4-sulfonyl } - pyrrolidine-2-carboxylic acid methyl ester; 4-(2-methoxy-ethyl)-l - {4'-[2-(2-methyl-pyrrolidin- 1 -yl)-ethyl]-biphenyl-4- sulfonyl}-piperidine; and
4-methoxymethyl-l-{4'-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4- sulfonyl} -piperidine.
42. A pharmaceutical composition comprising a compound according to any one of claims 1 to 41 and a pharmaceutically acceptable carrier.
43. A method for treating a histamine H3-receptor associated disorder in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 41 or a pharmaceutical composition according to claim 42.
44. The method according to claim 43, wherein said histamine H3-receptor associated disorder is selected from the group consisting of a cognitive disorder, epilepsy, brain trauma, depression, obesity, disorders of sleep and wakefulness such as narcolepsy, hypersomnia, somnolence syndrome, jet lag, sleep apnea and the like, attention deficit hyperactivity disorder (ADHD), schizophrenia, allergies, allergic responses in the upper airway, allergic rhinitis, nasal congestion, dementia and Alzheimer's disease.
45. The method according to claim 44, wherein said histamine H3 -receptor associated disorder is a disorder of sleep or wakefulness.
46. The method according to claim 44, wherein said histamine H3-receptor associated disorder is a cognitive disorder.
47. A method of inducing wakefulness in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according . to any one of claims 1 to 41 or a pharmaceutical composition according to claim 42.
48. A method for treating pain in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 41 or a pharmaceutical composition according to claim 42.
49. Use of a compound according to any one of claims 1 to 41 for production of a medicament for use in the treatment of a histamine H3-receptor associated disorder.
50. The use according to claim 49, wherein said histamine H3-receptor associated disorder is selected from the group consisting of a cognitive disorder, epilepsy, brain trauma, depression, obesity, disorders of sleep and wakefulness such as narcolepsy, hypersomnia, somnolence syndrome, jet lag, sleep apnea and the like, attention deficit hyperactivity disorder (ADHD), schizophrenia, allergies, allergic responses in the upper airway, allergic rhinitis, nasal congestion, dementia and Alzheimer's disease.
51. The use according to claim 49, wherein said histamine H3-receptor associated disorder is a disorder of sleep or wakefulness.
52. The use according to claim 49, wherein said histamine H3-receptor associated disorder is a cognitive disorder.
53. Use of a compound according to any one of claims 1 to 41 for production of a medicament for use in inducing wakefulness.
54. Use of a compound according to any one of claims 1 to 41 for production of a medicament for use in the treatment of pain.
55. A compound according to any one of claims 1 to 41 for use in a method of treatment of the human or animal body by therapy.
56. A compound according to any one of claims 1 to 41 for use in a method for the treatment of a histamine H3-receptor associated disorder in the human or animal body by therapy.
57. A compound according to any one of claims 1 to 41 for use in a method for the treatment of a histamine H3-receptor associated disorder selected from the group consisting of a cognitive disorder, epilepsy, brain trauma, depression, obesity, disorders of sleep and wakefulness such as narcolepsy, hypersomnia, somnolence syndrome, jet lag, sleep apnea and the like, attention deficit hyperactivity disorder (ADHD), schizophrenia, allergies, allergic responses in the upper airway, allergic rhinitis, nasal congestion, dementia and Alzheimer's disease in the human or animal body by therapy.
58. A compound according to any one of claims 1 to 41 for use in a method for the treatment of a disorder of sleep or wakefulness.
59. A compound according to any one of claims 1 to 41 for use in a method for the treatment of a cognitive disorder.
60. A compound according to any one of claims 1 to 41 for use in a method of inducing wakefulness.
61. A compound according to any one of claims 1 to 41 for use in a method for the treatment of pain.
62. A process for preparing a composition comprising admixing a compound according to any one of claims 1 to 41 and a pharmaceutically acceptable carrier.
EP07796576A 2006-06-29 2007-06-28 Modulators of the histamine h3-receptor useful for the treatment of disorders related thereto Withdrawn EP2035372A1 (en)

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