WO2007061741A2 - Modulators of the h3 receptor useful for the treatment of disorders related thereto - Google Patents

Modulators of the h3 receptor useful for the treatment of disorders related thereto Download PDF

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Publication number
WO2007061741A2
WO2007061741A2 PCT/US2006/044479 US2006044479W WO2007061741A2 WO 2007061741 A2 WO2007061741 A2 WO 2007061741A2 US 2006044479 W US2006044479 W US 2006044479W WO 2007061741 A2 WO2007061741 A2 WO 2007061741A2
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Prior art keywords
pyrrolidin
phenyl
ethyl
cyclopenta
hexahydro
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PCT/US2006/044479
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French (fr)
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WO2007061741A3 (en
Inventor
Vincent J. Santora
Jonathan A. Covel
Rena Hayashi
Robert R. Webb
Albert S. Ren
Weichao G. Chen
Jonathan J. Duffield
Jason B. Ibarra
Michelle Pulley
Graeme Semple
Michael I. Weinhouse
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Arena Pharmaceuticals, Inc.
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Priority to CA002628527A priority Critical patent/CA2628527A1/en
Priority to AU2006316609A priority patent/AU2006316609A1/en
Priority to EP06837763A priority patent/EP1948605A2/en
Priority to JP2008541338A priority patent/JP2009515989A/en
Publication of WO2007061741A2 publication Critical patent/WO2007061741A2/en
Publication of WO2007061741A3 publication Critical patent/WO2007061741A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
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    • 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
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • 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
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
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    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D401/06—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 carbon chain containing only aliphatic carbon atoms
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    • 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
    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond
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    • 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
    • C07D403/06—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 carbon chain containing only aliphatic carbon atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
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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
    • C07D405/14—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 three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D417/04—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 directly linked by a ring-member-to-ring-member bond

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-associated disorders, such as, cognitive disorders, epilepsy, brain trauma, depression, obesity, motion sickness and vertigo, disorders of sleep and wakefulness such as narcolepsy, shift-work syndrome, drowsiness as a side effect from a medication, maintenance of vigilance to aid in completion of tasks and the like, cataplexy, 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
  • One aspect of the present invention pertains to certain compounds as shown in Formula (Ia):
  • G is CR 7 or C, provided that when G is CR 7 then - - is a single bond, wherein R 3 is H and R 7 is H or OH, and when G is C then - - is a double bond and R 3 is absent;
  • E is C(R 8 R 9 ) or C(RV)C(R 10 R 11 ), wherein R 8 , R 9 , R 10 , and R 11 are each selected independently from the group consisting of H, Ci -3 alkyl, Ci -4 alkoxy, carboxy, cyano, Ci -3 haloalkyl, and halogen;
  • K is Ci_ 4 alkylene optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 substituents selected independently from the group consisting OfCi -3 alkyl, Ci -4 alkoxy, carboxy, cyano, C 1-3 haloalkyl, halogen, hydroxyl, and oxo;
  • R 1' is " selected from the group consisting of H, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, Ci -4 alkylene-Q.rcycloalkyl, C 3-7 heterocyclyl, aryl, Ci -4 alkylene-aryl, heteroaryl, and Ci -4 alkylene-heteroaryl, and each of said Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkyny
  • R 2 is H, halogen or Ci -3 alkyl
  • R 4 and R 5 are each independently selected from the group consisting of H, C 1-6 alkyl, C 2- ⁇ alkenyl, C 2-6 alkynyl, and C 3-7 cycloalkyl, and wherein each of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-7 cycloalkyl groups are optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected independently from the group consisting OfC 1-6 acyl, Ci -6 acyloxy, C 2-6 alkenyl, C 1-6 alkoxy, C 1-6 alkyl, Ci -6 alkylcarboxamide, C 2-6 alkynyl, Ci -6 alkylsulfonamide, Ci -6 alkylsulfmyl, Ci -6 alkylsulfonyl, Ci -6 alkylthio, Ci -6 alkylureyl, amino, Ci -6 alkylamino, C 2-8 dialkylamino, carbo-C
  • R 4 and R 5 together with the nitrogen atom to which they are both bonded form a C 3-7 heterocyclyl or C 5-10 heterobicyclyl group optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected independently from the group consisting OfC 1-6 acyl, C 1-6 acyloxy, C 2-6 alkenyl, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 alkylcarboxamide, C 2-6 alkynyl, C 1-6 alkylsulfonamide, Ci -6 alkylsulfmyl, Ci -6 alkylsulfonyl, C 1-6 alkylthio, C 1-6 alkylureyl, amino, C 1-6 alkylamino, C 2-8 dialkylamino, carbo-C 1-6 -alkoxy, carboxamide, carboxy, cyano, C 3-7 cycloalkyl, C 2-8 dialkylcarboxamide, C 2-8 dialkylsulfonamide, halogen, C
  • Ar is phenyl, pyridinyl, or pyrimidinyl, each optionally substituted with 1, 2, 3, or 4 substituents selected independently from the group consisting of C ]-6 acyl, Ci -6 acyloxy, C 2-6 alkenyl, Ci -6 alkoxy, Ci -6 alkyl, Ci -6 alkylcarboxamide, C 2-6 alkynyl, Q -6 alkylsulfonamide, Ci -6 alkylsulfmyl, C 1-6 alkylsulfonyl, Ci -6 alkylthio, Ci -6 alkylureyl, amino, Ci -6 alkylamino, C 2-8 dialkylamino, carbo-Ci -6 -alkoxy, carboxamide, carboxy, cyano, C 3-7 cycloalkyl, C 2-8 C 1-6 haloalkyl, C 1-6 haloalkylsulfinyl, C 1-6 haloalkylsulfony
  • R 1 is selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 1-4 alkylene-C 3-7 -cycloalkyl, C 3-7 heterocyclyl, aryl, C 1-4 alkylene-aryl, heteroaryl, and C 1-4 alkylene-heteroaryl, and each of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 1-4 alkylene-C 3-7 -cycloalkyl, C 3-7 heterocyclyl, aryl, C 1-4 alkylene-aryl, heteroaryl, and C 1-4 alkylene-heteroaryl groups are optionally substituted with
  • R 4 and R 5 are each independently selected from the group consisting of H, C 1-6 alkyl, C 2- ⁇ alkenyl, C 2-6 alkynyl, and C 3-7 cycloalkyl, and wherein each of said Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-7 cycloalkyl groups are optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected independently from the group consisting Of Ci -6 acyl, Ci -6 acyloxy, C 2-6 alkenyl, Ci -6 5 alkoxy, Ci -6 alkyl, Ci -6 alkylcarboxamide, C 2-6 alkynyl, C 1-6 alkylsulfonamide, C 1-6 alkylsulfmyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, Ci -6 alkylureyl, amino, Ci -6 alkylamino, C 2-8 dialkylamino, carbo-
  • 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 modulating the activity of a
  • H3 receptor by contacting the receptor with a compound according to any of the embodiments described herein or a pharmaceutical composition.
  • One aspect of the present invention pertains to methods for treating H3 -receptor associated disorders in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound according to any of the embodiments described herein or a pharmaceutical composition thereof.
  • One aspect of the present invention pertains to methods for treating H3 -receptor associated disorders selected from the group consisting of cognitive disorders, epilepsy, depression, narcolepsy, obesity, motion sickness, vertigo, a sleep/wake disorder, insomnia, jet lag, sleep apnea, attention deficit hyperactivity disorder (ADHD), schizophrenia, allergies, allergic responses in the upper airway, allergic rhinitis, bipolar disorders, manic disorders, neurogenic inflammation, migraine, eating disorders, dementia, and Alzheimer's disease in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound according to any of the embodiments described herein or a pharmaceutical composition thereof.
  • cognitive disorders selected from the group consisting of cognitive disorders, epilepsy, depression, narcolepsy, obesity, motion sickness, vertigo, a sleep/wake disorder, insomnia, jet lag, sleep apnea, attention deficit hyperactivity disorder (ADHD), schizophrenia, allergies, allergic responses in the upper airway, allergic rhinitis, bi
  • One aspect of the present invention pertains to methods for treating sleep/wake disorders in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound according to any of the embodiments described herein 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 according to any of the embodiments described herein or a pharmaceutical composition thereof.
  • One aspect of the present invention pertains to the use of compounds according to any of the embodiments described herein for production of a medicament for use in the treatment of a H3 -receptor associated disorder.
  • One aspect of the present invention pertains to the use of compounds according to any of the embodiments described herein for production of a medicament for use in the treatment of a H3-receptor associated disorder is selected from the group consisting of cognitive disorders, epilepsy, depression, narcolepsy, obesity, motion sickness, vertigo, a sleep/wake disorder, insomnia, jet lag, sleep apnea, attention deficit hyperactivity disorder (ADHD), schizophrenia, allergies, allergic responses in the upper airway, allergic rhinitis, bipolar disorders, manic dTiso/rdJeUrsS, ne ⁇ urBoge/ni.Nch inNfbla i HmI"7ma9tion, mi .grai .ne, ea .ti.ng d A i.sord ,ers, d ,emen + ti.a, and A A A1 lz ,hei .mer , s disease.
  • ADHD attention deficit hyperactivity disorder
  • One aspect of the present invention pertains to the use of compounds according to any of the embodiments described herein for production of a medicament for use in the treatment of sleep/wake disorders.
  • One aspect of the present invention pertains to the use of compounds according to any of the embodiments described herein for production of a medicament for use in inducing wakefulness.
  • One aspect of the present invention pertains to compounds according to any of the embodiments described herein for use in a method of treatment of the human or animal body by therapy.
  • One aspect of the present invention pertains to compounds according to any of the embodiments described herein for use in a method of treatment of a H3 -receptor associated disorder in the human or animal body by therapy.
  • One aspect of the present invention pertains to compounds according to any of the embodiments described herein for use in a method of treatment of a H3 -receptor associated disorder selected from the group consisting of cognitive disorders, epilepsy, depression, narcolepsy, obesity, motion sickness, vertigo, a sleep/wake disorder, insomnia, jet lag, sleep apnea, attention deficit hyperactivity disorder (ADHD), schizophrenia, allergies, allergic responses in the upper airway, allergic rhinitis, bipolar disorders, manic disorders, neurogenic inflammation, migraine, eating disorders, dementia, and Alzheimer's disease in the human or animal body by therapy.
  • ADHD attention deficit hyperactivity disorder
  • One aspect of the present invention pertains to compounds according to any of the embodiments described herein for use in a method of treatment of a sleep/wake disorder in the human or animal body by therapy.
  • One aspect of the present invention pertains to compounds according to any of the embodiments described herein for use in a method for inducing wakefulness 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 according any embodiments described herein and pharmaceutically acceptable carrier.
  • R a at each occurrence is independently Ci -6 alkyl, R b i Ts e/ithe Wr aB pr Oote Bcti /ng iH gMro4u J p I + (i7.e. ' , 9 PG]) or R b is Ri as described herein, and PG 2 is a protecting group which can be the same or different compared to PGj.
  • Protecting groups may be required for various functionality or functionalities during the synthesis of some of the compounds of the invention.
  • a suitable nitrogen protecting group such as, benzyl, Boc, Cbz, Moz, Alloc, Fmoc and the like
  • Deprotection can be achieved using standard reagents familiar to one skilled in the art (these might include TFA, a mineral acid, Palladium/hydrogen gas and the like in an alcoholic or ethereal solvent system chosen from methanol, ethanol, fert-butanol, TBF, 1,4-dioxane, and the like).
  • an orthogonal protection strategy may be adopted.
  • Figure 1 shows the general synthetic scheme for the preparation of compounds of the present invention.
  • Figure 1 illustrates a general method for preparing compounds of the present invention with a variety of groups.
  • Figure 2 shows the general synthetic scheme for the preparation of compounds of the present invention.
  • Figure 2 illustrates a general method for preparing compounds of the present invention wherein the NR 4 R 5 group is introduced in the last step.
  • Figure 3 shows the general synthetic schemes for the preparation of compounds of the present invention.
  • Figure 3 illustrates general methods for preparing compounds of the present invention comprising deprotection and the introduction of -D-R 1 group in the last step. It is understood that protection of the 3° alcohol may be necessary for compounds of Formula N prior to introducing the -D-R 1 group, for example, Methods B, C, D, E, or F.
  • Figure 4 shows the general synthetic schemes for the preparation of compounds of the present invention.
  • Figure 4 illustrates the general methods for preparing compounds of the present invention using Method B (reductive animation using, for example, an aldehyde or a ketone), Method C (amide and carbamate formation using, using for example, an acid chloride or a chloroformate respectively) and Method D (urea formation using, for example, an isocyanate).
  • Method B reductive animation using, for example, an aldehyde or a ketone
  • Method C amide and carbamate formation using, using for example, an acid chloride or a chloroformate respectively
  • Method D urea formation using, for example, an isocyanate
  • Figure 5 shows the general synthetic schemes for the preparation of compounds of the present invention.
  • Figure 5 illustrates the general methods for preparing compounds of the present invention using Method E (arylation or heteroarylation using, for example, an aryl/heteroaryl-halide with a base, such as, potassium ⁇ -butoxide under microwave irradiation conditions) and Method F (amide formation using, using for example, a carboxylic acid and a coupling reagent, such as, DCC).
  • Figure 6 snows a general synthetic scheme for prepa ⁇ ng compounds of the present invention via a Suzuki reaction.
  • the cyclic ketone B is converted in three steps to the corresponding halide. This is coupled with an aryl boronic acid prepared from an aryl halide.
  • Figure 7 shows four general methods for preparing compounds of the present invention.
  • the first method involves the reaction of a secondary bicyclic amine with an alkyl moiety bearing a leaving group to form a tertiary amine.
  • the second method involves the reaction of a secondary bicyclic amine with a carboxylic acid in the presence of a coupling agent such as HATU to form an amide.
  • the third method involves the reaction of a secondary bicyclic amine with a sulfonyl chloride to form a sulfonamide.
  • the last method involves the oxidation of an amine to form an amine-oxide.
  • Figure 8 shows two general methods for preparing intermediates of compounds of the present invention.
  • the first method involves reaction of a bicyclic ketone with a strong base and an alkyl halide to alkylate the bicyclic ketone at the ⁇ -position.
  • the second method involves the Suzuki reaction of a bicyclic vinyl triflate with a boronic acid.
  • agonists is intended to mean moieties that interact and activate the receptor, such as the H3 receptor, and initiates 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.
  • Ci -6 acyl is intended to mean a Ci -6 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, is ⁇ -butanoyl, pivaloyl, pentanoyl, hexanoyl and the like.
  • Cj -6 acyloxy is intended to mean an acyl radical attached to an oxygen atom wherein acyl has the same definition as described herein; some embodiments are when acyloxy is Ci -5 acyloxy, some embodiments are when acyloxy is Ci -4 acyloxy.
  • C 2-6 alkenyl is intended to mean a radical containing 2 to 6 carbons wherein at least one carbon-carbon double bond is present, some embodiments are 2 to 4 carbons, some embodiments are 2 to 3 carbons, and some embodiments have 2 carbons.
  • alkenyl Both E and Z isomers afe ' emtfra ' ce ⁇ 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-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexanyl, 2,4-hexadienyl and the like.
  • Ci -6 alkoxy is intended to mean an 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, ra-propoxy, ⁇ o-propoxy, H-butoxy, Z-butoxy, ⁇ o-butoxy, sec-butoxy and the like.
  • C 1-6 alkyl is intended to mean a straight or branched carbon radical containing 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, «-propyl, zso-propyl, H-butyl, sec-butyl, iso-butyl, ⁇ -butyl, pentyl, ⁇ -pentyl, r-pentyl, r ⁇ e ⁇ -pentyl, 1-methylbutyl [i.e.,
  • C -6 alkylcarboxamido or "C 1-6 alkylcarboxamide” is intended to mean a single Q -6 alkyl group attached to either the carbon or the nitrogen of an amide group, wherein alkyl has the same definition as found herein.
  • the Cj -6 alkylcarboxamido may be represented by the following:
  • C 1-4 alkylene is intended to mean a Ci -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.
  • alkylene 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 -.
  • C 1-4 alkylene-aryl is intended to mean a C M alkylene group bonded to an aryl group, each as defined herein.
  • Cj -4 alkylene-aryl refers to, for example, benzyl (-CH 2 -phenyl), phenylethyl (-CH 2 CH 2 -phenyl), and the like.
  • C 1-4 alkylene-C 3-7 -cycloalkyl is intended to mean a Ci -4 alkylene group bonded to a C 3- 7-cycloalkyl group, each as defined herein.
  • ' " C 3-7 -cycl6al ⁇ yl refers to, for example, cyclopropylmethyl (-CH ⁇ cyclopropyl), cyclopropylethyl
  • C 1-4 alkylene-heteroaryl is intended to mean a Ci -4 alkylene group bonded to a heteroaryl group, each as defined herein.
  • Q -4 alkylene-heteroaryl refers to, for example, pyridinylmethyl (-CH 2 -pyridinyl) and the like.
  • C 1-6 alkylsulfinyl is intended to mean a Ci -6 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, methylsulf ⁇ nyl, ethylsulfinyl, w-propylsulfinyl, zs ⁇ -propylsulfinyl, w-butylsulfinyl, sec-butylsulfinyl, iso- butylsulfinyl, ⁇ -butylsulfinyl, and the like.
  • C 1-6 alkylsulfonamide is intended to mean the groups shown below:
  • Ci -6 alkyl has the same definition as described herein.
  • Ci -6 alkylsulfonyl is intended to mean a Ci -6 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, zs ⁇ -propylsulfonyl, ⁇ -butylsulfonyl, sec-butylsulfonyl, iso- butylsulfonyl, £-butylsulfonyl, and the like.
  • Ci -6 alkylthio is intended to mean a Ci -6 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, ra-propylsulfanyl, iso- propylsulfanyl, ra-butylsulfanyl, sec-butylsulfanyl, zs ⁇ -butylsulfanyl, r-butylsulfanyl, and the like.
  • methylsulfanyl i.e., CH 3 S-
  • ethylsulfanyl ethylsulfanyl
  • ra-propylsulfanyl iso- propylsulfanyl
  • ra-butylsulfanyl sec-
  • Ci -6 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 Ci -6 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-, (CH 3 ) 2 NC(O)NH-, (CH 3 ) 2 NC(O)NCH 3 -, CH 3 CH 2 NHC(O)NH-, CH 3 CH 2 NHC(O)NCH 3 -, and the like.
  • C 2-6 alkynyl is intended to mean a radical containing 2 to 6 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-pentynyl, 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 .
  • C 1-6 alkylammo 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 not limited to, methylamino, ethylamino, /z-propylamino, z-s ⁇ -propylamino, n- butylamino, see-butylamino, zso-butylamino, f-butylamino, and the like.
  • Some embodiments are "C 1-2 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 4-7 cycloalkyl or C 4-7 cycloalkenyl group together with a C 4-7 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 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.
  • 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 4-7 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 to 6 carbons; some embodiments contain 4 to 5 carbons; some embodiments contain 4 carbons. Examples include cyclobutenyl, cyclopentenyl, cyclopentenyl, cyclohexenyl, and the like.
  • C 3-7 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 2-8 dialkylamino is intended to mean an amino substituted with two of the same or different Ci -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.
  • C 2-8 dialkylcarboxamido or "C 2-8 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 2-8 dialkylcarboxamido may be represented by the following groups:
  • Ci -4 has the same definition as described herein.
  • Examples of a dialkylcarboxamide include, but are not limited to, N,N-dimethylcarboxamide, N-methyl-N-ethylcarboxamide, N,N- diethylcarboxamide, N-methyl-N-isopropylcarboxamide, and the like.
  • C 2-8 dialkylsulfonamide is intended to mean one of the following groups shown below:
  • Ci -4 has the same definition as described herein, for example but not limited to, methyl, ethyl, «-propyl, isopropyl, and the like.
  • C 2-8 dialkylthiocarboxamido or "C 2-8 dialkylthiocarboxamide” is intended to mean two alkyl radicals, that are the same or different, attached to a thioamide group, wherein alkyl has the same definition as described herein.
  • a C 2-8 dialkylthiocarboxamido or C 2-8 dialkylthiocarboxamide may be represented by the following groups:
  • C 1-4 alkyl Ci -4 alkyl examples include, but are not limited to, NN- dimethylthiocarboxamide, N-methyl-N-ethylthiocarboxamide and the like.
  • Ci -6 haloalkoxy is intended to mean a Ci -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.
  • Ci -6 haloalkyl is intended to mean an Ci -6 alkyl group, defined herein, wherein the alkyl is substituted with one halogen up to fully substituted and a fully substituted Ci -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, Et, ⁇ f / u ⁇ f]i IR 1 ./ 114,114.114.79
  • Cj -6 haloalkylsulfinyl is intended to mean a C 1-6 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, trifluoromethylsulfmyl, 2,2,2-trifluoroethylsulf ⁇ nyl, 2,2-difluoroethylsulfinyl and the like.
  • Ci -6 haloalkylsulfonyl is intended to mean a Ci -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 -6 haloalkylthio is intended to mean a Cj -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, trifluoromethylthio (i.e., CF 3 S-, also referred to as trifluoromethylsulfanyl), 1,1-difluoroethylthio, 2,2,2-trifluoroethylthio and the like.
  • 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 -4 acyl or Ci -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 ⁇ (i.e., NH), examples include, but are not limited to, pyrrolyl, indolyl, lH-benzoimidazol-2-yl, and the like. Other examples include, but are not limited to, those in TABLES A-E, and the like.
  • 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.
  • C 3-7 heterocyclic or "C 3-7 heterocyclyl” is intended to mean a non-aromatic carbon ring (i.e., C 3-7 cycloalkyl or C 4-7 cycloalkenyl as defined herein) wherein one, two or three ring carbons are replaced by a heteroatom selected from, but are not limited to, the group ip> f " x / ij
  • 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-, A-, 5-, 6- or 7-membered containing 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, piperzin-1-yl, piperzin-2-yl, piperzin-3-yl, piperzin-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, [1,3]- dioxolan-2-yl, thiomorpholin-4-yl, [l,4]oxazepan-4-yl, l,l-dioxo-l ⁇ ⁇ -thiomorpholin-4-yl, azepan-1
  • 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 H 5 -.
  • sulfonamide is intended to mean the group -SO 3 NH 2 .
  • thiol is intended to mean the group -SH.
  • contacting is intended to mean bringing the indicated moieties together, whether in an in vitro system or an in vivo system.
  • "contacting" a 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 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 H3 receptor.
  • the term "in need of treatment” is intended 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.
  • 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 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.
  • 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 Formula (Ia); 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:
  • 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,
  • 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).
  • 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 there from 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. In another embodiment, compounds of the present invention have four stereochemical centers wherein three stereochemical centers are as described previously and the fourth stereochemical center is S.
  • compounds of the present invention have four stereochemical centers wherein three stereochemical centers are as described previously and the fourth stereochemical center is R. In another embodiment, compounds of the present invention have five stereochemical centers wherein four stereochemical centers are as described previously and the fifth stereochemical center is S. In another embodiment, compounds of the present invention have five stereochemical centers wherein four stereochemical centers are as described previously and the fifth 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 encompasses N-oxides of compounds of Formula (Ia).
  • E is C(R 8 R 9 ).
  • R 8 and R 9 are each H.
  • the present invention pertains to certain compounds as shown in the following Formula (Ic):
  • G is CR 7 and - - is a single bond; wherein R 7 is H or OH.
  • the present invention pertains to certain compounds as shown in the following Formula (Ie):
  • the present invention pertains to certain compounds as shown in the following Formula (Ig):
  • E is C(RV)C(R 10 R 11 ).
  • the present invention pertains to certain compounds as shown in the following Formula (Ii):
  • R 10 , and R 11 are each H. In some embodiments, R 8 , R 9 , R 10 , and R 11 are each H.
  • G is CR 7 an _ ⁇ _ is a single bond; wherein R 7 is H or OH.
  • the present invention pertains to certain compounds as shown in the following Formula (Ik):
  • G is C and — is a double bond.
  • the present invention pertains to certain compounds as shown in the following Formula (Im):
  • the present invention pertains to certain compounds as shown in the following Formula QLo): P CT,/" IJi SO IB / NMM
  • D is absent.
  • J is O.
  • J is NR 12 , wherein R 12 is H or Ci -6 alkyl. In some embodiments, J is absent.
  • K is the same as described herein for compounds of Formula (Ia) and/or subgenera thereof, provided that when K is substituted with oxo, then the carbon of the resulting carbonyl group is not directly bonded to the nitrogen of the NR 4 R 5 group.
  • K is C 1-4 alkylene optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 substituents selected independently from the group consisting of Cu alkyl, Ci -4 alkoxy, carboxy, cyano, Ci -3 haloalkyl, halogen, and hydroxyl. In some embodiments, K is -CH 2 CH 2 -.
  • R 1 is selected from the group consisting of H, Ci -6 alkyl, C 3-7 cycloalkyl, Ci -4 alkylene-C 3-7 -cycloalkyl, aryl, Q -4 alkylene-aryl, heteroaryl, and Ci -4 alkylene- heteroaryl, and each of said Ci -6 alkyl and Ci -4 alkylene-aryl, groups are optionally substituted with 1 or 2 substituents selected independently from the group consisting OfCi -6 alkoxy, Ci -6 alkyl, amino, Ci -6 alkylamino, C 2 -s dialkylamino, C 3-7 cycloalkyl, formyl, halogen, C 1-6 haloalkoxy, C 1-6 haloalkyl, and hydroxyl.
  • R 1 is selected from the group consisting of H, Ci -6 alkyl, C 3-7 cycloalkyl, Ci -4 alkylene-C 3-7 -cycloalkyl, aryl, Ci -4 alkylene-aryl, heteroaryl, and C 1-4 alkylene- heteroaryl, and each of said Ci -6 alkyl and C 1-4 alkylene-aryl, groups are optionally substituted with 1 or 2 substituents selected independently from the group consisting of C 1-6 alkoxy, C 1-6 alkyl, amino, C 1-6 alkylamino, C 2- g dialkylamino, C 3-7 cycloalkyl, halogen, C 1-6 haloalkoxy, C 1-6 haloalkyl, and hydroxyl.
  • R 1 is selected from the group consisting of H, benzyl, cyclopropylmethyl, isobutyl, isopropyl, 4-trifluoromethoxy-benzyl, 2,4-dimethoxy-benzyl, cyclohexyl, cyclopentyl, methyl, ethyl, t-butyl, 4-methoxy-benzyl, 4-trifluoromethylbenzyl, cyclobutyl, 3-hydroxy-prop-2-yl, 4-hydroxy-benzyl, cyclopropyl, phenyl, py ⁇ dm-2-yl, hydroxymethyl, tetrahydro-furan-3-yl, tetrahydropyran-4-yl, pyridin-3-yl, pyrazin-2-yl, 2- fluoroethyl, trifluoromethyl, thiophen-2-ylmethyl, tetrahydropyran-4-ylmethyl, pyrimadin
  • R 1 is selected from the group consisting of H, benzyl, cyclopropylmethyl, isobutyl, isopropyl, 4-trifluoromethoxy-benzyl, 2,4-dimethoxy-benzyl, cyclohexyl, cyclopentyl, methyl, ethyl, t-butyl, 4-methoxy-benzyl, cyclobutyl, 3-hydroxy-prop- 2-yl, 4-hydroxy-benzyl, cyclopropyl, phenyl, pyridin-2-yl, hydroxymethyl and tetrahydro-furan- 3-yl.
  • R 2 is H or Ci -6 alkyl
  • R 2 is H or methyl. In some embodiments, R 2 is H.
  • R 4 and R 5 are each independently H or Q -6 alkyl; or
  • R 4 and R 5 together with the nitrogen atom to which they are both bonded form a C 3 .. 7 heterocyclyl or C 5-10 heterobicyclyl optionally substituted with 1 or 2 substituents selected independently from the group consisting of Cj -S alkyl, halogen, hydroxyl, oxo and phenyl; and said Ci -6 alkyl, is optionally substituted with 1 or 2 substituents selected independently from C 1-6 alkoxy and hydroxyl.
  • R 4 and R 5 are each independently H or Ci -6 alkyl; or
  • R 4 and R 5 together with the nitrogen atom to which they are both bonded form a C 3-7 heterocyclyl or C 5-I0 heterobicyclyl optionally substituted with 1 or 2 substituents selected independently from the group consisting OfCi -6 alkyl, halogen, and hydroxyl; and said C 1-6 alkyl, is optionally substituted with hydroxyl.
  • R 4 and R 5 are each independently H, methyl or isopropyl.
  • R 4 and R 5 are each independently H or methyl.
  • R 4 and R 5 together with the nitrogen atom to which they are both bonded form a group selected from the group consisting of pyrrolidin-1-yl, 2-methyl-pyrrolidin- 1-yl, 2-methyl-piperidin-l-yl, 4-methyl-piperazin-l-yl, 2,5-dimethyl-pyrrolidin-l-yl, dimethyl- amino, 2,2-dimethyl-pyrrolidin-l-yl, morpholin-4-yl, 2-hydroxymethyl-pyrrolidin-l-yl, 3- hydroxy-pyrrolidin-1-yl, 3,3-difluoro-pyrrolidin-l-yl, azetidin-1-yl, 3,3-difluoro-piperidin-l-yl, 2,3-dihydro-isoindol-2-yl, 3,4-dihydro-lH-isoquinolin-2-yl, 2,3-dihydro-indol-l
  • R 4 and R together with the nitrogen atom to which they are both bonded form a group selected from the group consisting of pyrrolidin-1-yl, 2-methyl-pyrrolidin- 1-yl, 2-methyl-piperidin-l-yl, 4-methyl-piperazin-l-yl, 2,5-dimethyl-pyrrolidin-l-yl, dimethyl- amino, 2,2-dimethyl-pyrrolidin-l-yl, morpholin-4-yl, 2-hydroxymethyl-pyrrolidin-l-yl, 3- hydroxyl-pyrrolidin-1-yl, 3,3-difluoro-pyrrolidin-l-yl, azetidin-1-yl, 3,3-difluoro-pipe
  • Ar is 1,4-phenylene, 1,3-phenylene or 2,5-pyridinylene.
  • the present invention pertains to certain 3-phenyl-pyrazole derivatives as shown in Formula (Ia):
  • D is C(O), OC(O), NR 6 C(O), S(O) 2 , or absent, wherein R 6 is H or CH 3 ;
  • G is CR 7 or C, provided that when G is CR 7 then - - is a single bond, wherein R 3 is H and R 7 is H or OH, and when G is C then - - is a double bond and R 3 is absent; R 2 is H or methyl;
  • E is -CH 2 - or -CH 2 CH 2 -;
  • K is -CH 2 CH 2 -;
  • R 1 is selected from the group consisting of H, benzyl, cyclopropylmethyl, isobutyl, isopropyl, 4-trifluoromethoxy-benzyl, 2,4-dimethoxy-benzyl, cyclohexyl, cyclopentyl, methyl, ethyl, t-butyl, 4-methoxy-benzyl, 4-trifluoromethylbenzyl, cyclobutyl, 3-hydroxy-prop-2-yl, 4- hydroxy-benzyl, cyclopropyl, phenyl, pyridin-2-yl, hydroxymethyl, tetrahydiO-furan-3-yl, tetrahydropyran-4-yl, pyridin-3-yl, pyrazin-2-yl, 2-fluoroethyl, trifluoromethyl, thiophen-2- ylmethyl, tetrahydropyran-4-ylmethyl, pyrimadin-5
  • R 4 and R 5 are each independently H, methyl or isopropyl; or
  • R 4 and R 5 together with the nitrogen atom to which they are both bonded form a group selected from the group consisting of pyrrolidin-1-yl, 2-methyl-pyrrolidin-l-yl, 2-methyl- piperidin-l-yl, 4-methyl-piperazin-l-yl, 2,5-dimethyl-pyrrolidin-l-yl, dimethyl-amino, 2,2- dimethyl-pyrrolidin-l-yl, morpholin-4-yl, 2-hydroxymethyl-pyrrolidin-l-yl, 3-hydroxy- pyrrolidin-1-yl, 3,3-difluoro-pyrrolidin-l-yl, azetidin-1-yl, 3,3-difluoro-piperidin-l-yl, 2,3- ,...,,,, ,.. excited Needles
  • the present invention pertains to certain 3-phenyl- ⁇ yrazole derivatives as shown in Formula (Iq):
  • G is CR 7 or C, provided that when G is CR 7 then - - is a single bond, wherein R 3 is H and R 7 is H or OH, and when G is C then - - is a double bond and R 3 is absent;
  • K is -CH 2 CH 2 -;
  • R 1 is selected from the group consisting of H, benzyl, cyclopropylmethyl, isobutyl, isopropyl, 4-trifluoromethoxy-benzyl, 2,4-dimethoxy-benzyl, cyclohexyl, cyclopentyl, methyl, ethyl, t-butyl, 4-methoxy-benzyl, cyclobutyl, 3-hydroxy-prop-2-yl, 4-hydroxy-benzyl, cyclopropyl, phenyl, pyridin-2-yl, hydroxymethyl and tetrahydro-furan-3-yl;
  • R 4 and R 5 together with the nitrogen atom to which they are both bonded form a group selected from the group consisting of pyrrolidin-1-yl, 2-methyl-pyrrolidin-l-yl, 2-methyl- piperidin-1-yl, 4-methyl-piperazin-l-yl, 2,5-dimethyl-pyrrolidin-l-yl, dimethyl-amino, 2,2- dimethyl-pyrrolidin-1-yl, morpholin-4-yl, 2-hydroxymethyl-pyrrolidin-l-yl, 3-hydroxyl- pyrrolidin-1-yl, 3,3-difluoro-pyrrolidin-l-yl, azetidin-1-yl, 3,3-difluoro-piperidin-l-yl, 2,3- dihydro-isoindol-2-yl, 3,4-dihydro-lH-isoquinolin-2-yl, 2,3-dihydro-indol-l-yl,
  • the present invention pertains to certain 3-phenyl-pyrazole derivatives as shown in Formula (Is):
  • R 7 is H or OH;
  • J is O or absent;
  • K is -CH 2 CH 2 -;
  • R 1 is selected from the group consisting of H, benzyl, cyclopropylmethyl, isobutyl, isopropyl, 4-trifluoromethoxy-ben2yl, 2,4-dimethoxy-benzyl, cyclohexyl, cyclopentyl, methyl, ethyl, t-butyl, 4-methoxy-benzyl, cyclobutyl, 3-hydroxy-prop-2-yl, 4-hydroxy-benzyl, cyclopropyl, hydroxymethyl and tetrahydro-furan-3-yl;
  • R 4 and R 5 together with the nitrogen atom to which they are both bonded form a group selected from the group consisting of pyrrolidin-1-yl and 2-methyl-pyrrolidin-l-yl; and Ar is 1,4-phenylene or 2,5-pyridinylene.
  • the present invention pertains to certain 3-phenyl-pyrazole derivatives as shown in Formula (Iu):
  • R 1 is selected from the group consisting of H, benzyl, cyclopropylmethyl, isobutyl, isopropyl, 4-trifluoromethoxy-benzyl, 2,4-dimethoxy-benzyl, cyclohexyl, cyclopentyl, methyl, ethyl, 4-methoxy-benzyl, cyclobutyl, 3-hydroxy-prop-2-yl, 4-hydroxy-benzyl, cyclopropyl, phenyl, pyridin-2-yl, hydroxymethyl and tetrahydro-furan-3-yl;
  • R 4 and R 5 together with the nitrogen atom to which they are both bonded form a group selected from the group consisting of pyrrolidin-1-yl, 2-methyl-pyrrolidin-l-yl, 2-methyl- piperidin-1-yl, 4-methyl-piperazin-l-yl, 2,5-dimethyl-pyrrolidin-l-yl, dimethyl-amino, 2,2- P CTV" U Si Ol IB/ I Ml-NhNl":/' ' 9
  • Ar is 1,4-phenylene, 1,3-phenylene or 2,5-pyridinylene.
  • the present invention pertains to certain 3-phenyl-pyrazole derivatives as shown in (Iw):
  • R 7 is H or OH
  • K is -CH 2 CH 2 -;
  • R 1 is selected from the group consisting of H, isopropyl, cyclopentyl, methyl, or cyclopropyl;
  • R 4 and R 5 together with the nitrogen atom to which they are both bonded form pyrrolidin-1-yl
  • Ar is 1,4-phenylene.
  • the present invention pertains to certain 3-phenyl-pyrazole derivatives as shown in Formula (Iy):
  • K is -CH 2 CH 2 -;
  • R 1 is selected from the group consisting of H, benzyl, isopropyl, cyclopentyl, methyl, or cyclopropyl; ' R an ⁇ ' R together with ' the nitrogen atom to which they are both bonded form pyrrolidin-1-yl; and
  • Ar is 1,4-phenylene.
  • Some embodiments of the present invention include every combination of one or more compounds selected from the following group shown in the TABLES A through E.
  • 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 the general synthetic schemes in Figures 1 through 8 as well as 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, chiral HPLC, recrystallization of diastereomeric mixtures, and the like) or selective synthesis (such as, 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. It is understood that compounds of the present invention, where the two hydrogens assigned as H a and H b are cis with respect to each other, have the following stereochemistry represented by Formula (Ha) and Formula (lie):
  • the compounds of the present invention have the stereochemical designations as represented by Formula (Ha):
  • the compounds of the present invention have the stereochemical designations as represented by Formula (He):
  • the compounds of the present invention have the stereochemical designations as represented by Formula (lie):
  • the compounds of the present invention have the stereochemical designations as represented by Formula (Ilg): ⁇ )
  • the compounds of the present invention have the stereochemical designations as represented by Formula (ED):
  • the compounds of the present invention have the stereochemical designations as represented by Formula (Ilk):
  • compounds of the present invention have the stereochemical designations of (3aS,6aS) wherein the carbons assigned as 3a and 6a and the stereochemistry are represented in Formula (TLm) :
  • compounds of the present invention have the stereochemical designations of (3aR,6aR) wherein the carbons assigned as 3a and 6a and the stereochemistry are represented in Formula (Ho):
  • the compounds disclosed herein are believed to be useful in the treatment of several additional diseases and disorders, and in the amelioration of symptoms thereof. Without limitation, these include the following.
  • Histamine [2-(imidazol-4-yl)ethylamine] is a transmitter substance present in both the central and peripheral nervous system.
  • CNS central nervous system
  • TMN tuberomammillary nuclei
  • Histaminergic neurons extend from the TMN to innervate all major areas of the brain, suggesting involvement in a wide variety of physiological processes (see: Haas and Panula in Nat. Rev. Neurosci. 2003, 4, 121-130).
  • H1-H4 histamine exerts its physiological effects through four distinct G-protein coupled receptors (GPCRs), termed H1-H4.
  • GPCRs G-protein coupled receptors
  • the 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). 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 2003, 63, 637-672).
  • H3 antagonists and inverse agonists such as compounds of the present invention.
  • These include cognitive disorders (Passani et al. Trends Pharmacol Sci 2004, 25, 618-624), epilepsy (Vohora et al. Pharmacol BiochemBehav 2001, 68, 735-741), depression (Perez-Garcia et a. Psychopharmacol 1999, 142, 215-220), narcolepsy (Tedford et al. Soc Neurosci Abstr 2000, 26, 460.3), obesity (Hancock, Curr Opin Investig Drugs 2003, 4, 1190- 1197), motion sickness and vertigo (Pan et al. Methods Find Exp Clin Pharmacol. 1998, 20, 771-777), disorders of sleep and wakefulness (Parmentier et al. J Neurosci. 2002, 22, 7695-
  • H3 antagonists have been shown to increase wakefulness (e.g. Lin J. S. et al. Brain Research 1990, 523, 325-330).
  • H3 antagonists can also be useful for conditions associated with excessive daytime sleepiness such as narcolepsy, sleep apnea, time zone change disorder, fibromyalgia, and multiple " sclefosis (Parmentier R, et al., J Neurosci. 2002, 22, 7695-7711 ; Ligneau X. et al. J Pharmacol Exp Ther. 1998, 287, 658-666).
  • sclefosis Parmentier R, et al., J Neurosci. 2002, 22, 7695-7711 ; Ligneau X. et al. J Pharmacol Exp Ther. 1998, 287, 658-666.
  • Leurs et al. in Nat Rev Drug Discov 2005, 4, 107-120, and Vohora, 2004, Investigational Drugs 7, 667- 673.
  • 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 often 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.
  • the drug gamma-hydroxybutyrate (GHB) (Xyrem) is approved in the USA by the Food and Drug Administration to treat both the cataplexy and excessive daytime sleepiness associated with narcolepsy.
  • 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 can also be used occasionally to promote wakefulness or vigilance in shift workers, slepp deprivation, post anesthesia grogginess, drowiness as a side effect from a medication, military use and the like. Ia 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 Tlierapy, 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. ScL 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 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. Sd. 2004, 25, 618-625).
  • 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 P t.. on iy ' iiftfM' a ⁇ '&daliled part'of ⁇ he 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 (
  • a histamine H3 -receptor antagonist or inverse agonist can be used as the sole agent of treatment or can be used in combination with other agents. For example, Vohora et al.
  • H3-receptor antagonist can work as an anti-epilepsy, antiseizure 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. 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. IP f f / 1
  • compounds of me 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 (Cymbalta).
  • MAOIs monoamine oxidase inhibitors
  • SSRIs selective serotonin reuptake inhibitor
  • 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.
  • 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 sTign 4ifiMcanBt s OociIBal/ orH ocMcMuHpMa!t;i;o?n' 1 a 1 ;!l d.ysfunction.
  • a person experi .enci .ng untreated schizophreni .a i .s typically characterized as demonstrating disorganized thinking, and as experiencing delusions or auditory hallucinations.
  • 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.
  • 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.
  • the H3 -receptor is implicated in the regulation of histamine release in the hypothalamus.
  • histamine H3-receptor mKNA expression in rat brown adipose tissue indicating a role in the regulation of thermogenesis (Karlstedt et al., MoI. Cell. Neuwsci. 2003, 24, 614-622).
  • 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 al. Eur. J. Pharmacol. 2004, 487, 183-197).
  • H3 -receptor mRNA is abundantly expressed in human nasal mucosa (Varty et al. Eur. J. Pharmacol. 2004, 484, 83-89).
  • histamine H3 -receptor antagonists with the Hl receptor antagonist chlo ⁇ heniramine 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.
  • H3 -associated disorders such as, cognitive disorders, epilepsy, brain trauma, depression, obesity, motion sickness and vertigo, disorders of sleep and wakefulness such as narcolepsy, shift-work syndrome, drowsiness as a side effect from a medication, maintenance of vigilance to aid in completion of tasks and the like, cataplexy, 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
  • 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
  • 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 Remington, The Science and Practice of Pharmacy, 20th Edition, 2000, Lippincott Williams & Wilkins, (Editors: Gennaro, A. R., et al.).
  • 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 u Tni.t ⁇ do Usa Sge P for Bms/ m HayMH cHon 1 +ta?in 1 9 any sui .ta,b_,le e « ff.ecti.ve amoun + t o TMi th.e ac + ti-ve i •ngred ,i.ent 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. 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.
  • one skilled in the art understands how to extrapolate in vivo data obtained in a model system, »
  • 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.
  • 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.
  • pCT/ U TSheO poBwd/er i s' ⁇ aNndbM tahbJlet' ⁇ st may contai .n varying percentage amounts o r f t u he acti .ve 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 maybe 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-filled 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 IP C T / Ii 1 "S O ⁇ , ⁇ ⁇ '" 1 H! Ni- "+ 7 ' '9
  • 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.
  • 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, tor 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, dichlorodifluoromethane, 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).
  • PVP polyvinylpyrrolidone
  • 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 Science, 66, 2 (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 ID if" "]! ' " .- ⁇ " IJi S Cl! Fi 1 ,./ ' 11..11 " "”I W7 '9
  • the compounds of this invention may form solvates with standard low molecular weight solvents using methods known to the skilled artisan.
  • Pro-drugs can be converted to "pro-drugs.”
  • the term "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.
  • 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.
  • 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 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.
  • 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 H3 receptor in tissue samples, including human, and for identifying H3 receptor ligands by inhibition binding of a radio-labeled compound. It is a further 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 which are identical to compounds disclosed herein, but for the fact that one or more atoms are replaced or substituted or mass num u ber d ⁇ ifferent fr ,om t .he a + tomi ⁇ c mass or mass number typically found in nature (i.e., naturally occurring).
  • 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 0, 17 O, 18 0, 18 F, 35 S, 36 Cl, 82 Br, 75 Br, 76 Br, 77 Br, 123 1, 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. For example, for in vitro H3 receptor labeling and competition assays, compounds that incorporate 3 H, 14 C, 82 Br, 125 1 , 131 1, 35 S or will generally be most useful. For radio-imaging applications 11 C, 18 F, 125 1, 123 1, 124 1, 131 I, 75 Br, 76 Br or 77 Br will generally be most useful.
  • 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 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 Schemes supra and Examples infra, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • 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.
  • Synthetic methods for incorporating activity levels of 125 I into target molecules include:
  • a radio-labeled 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
  • the ability of a test compound to compete with the "radio-labeled compound of Formula (Ia)" for the binding to the H3 receptor directly correlates to its binding affinity.
  • the labeled compounds of the present invention bind to the H3 receptor.
  • the labeled compound has an IC 50 less than about 500 ⁇ M, in another embodiment the labeled compound has an IC 50 less than about 100 ⁇ M, in yet another embodiment the labeled compound has an IC 50 less than about 10 ⁇ M, in yet another embodiment the labeled compound has an IC 50 less than about 1 ⁇ M, and in still yet another embodiment 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 in vacuo 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 Inc; UV-Detector: SPD-IOA VP, Shimadzu Lie; Autosampler: CTC HTS, PAL, Leap Scientific; Mass spectrometer: API 150EX with Turbo Ion Spray source, ABMDS Sciex; Software: Analyst 1.2. 2) Mac: HPLC-pumps: LC-8A VP, Shimadzu Inc; 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 ( ⁇ )-2-Ben2yl-hexahydro-cycIopenta[c]pyrrol-4-one.
  • the salt was recrystallized twice from isopropanol to leave (3aS,6aR)-2- benzylhexahydrocyclopenta[c]pyrrol-4(5H)-one-di-p-toluoyl-L-tartrate as a white crystalline solid. This was partitioned between dichloromethane (100 mL) and 3.5% aqueous sodium bicarbonate (200 mL), the lower layer was removed and the upper layer was extracted with dichloromethane (100 mL).
  • Example 1.2 Preparation of l-[2-(4-Bromo-phenyl)-ethyl]-pyrrolidine.
  • Example 1.3 Preparation of ( ⁇ )-2-Benzyl-4-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]- octahydro-cyclopenta[c]pyrrol-4-ol.
  • Example 1.4 Preparation of 2-Benzyl-4- ⁇ 4 ⁇ (2-[(2S)-2-methyl-pyrrolidin ⁇ l-yl]-ethyl)- phenyl ⁇ -octahydro-cyclopenta[c]pyrrol-4-ol.
  • Example 1.1 The title compound was obtained using the method described in Example 1.3 starting with l-[2-(4-Bromo-phenyl)-ethyl]-2-methyl pyrrolidine.
  • the enantiomerically pure isomers of this compound (3aS,6aR and 3aR,6aS) were obtained by the same method starting from the corresponding single isomer ketones in Example 1.1.
  • Example 1.5 Preparation of ( ⁇ )-2-Benzyl-4-[4-(2 ⁇ pyrrolidin-l-yl-ethyl)-phenyl]- octahydro-cyclopenta[c]pyrrole Dihydrochloride.
  • Example 1.6 Preparation of ( ⁇ )-4-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-octahydro- cyclopenta[c]pyrrol-4-ol.
  • Example 1.7 Preparation of ( ⁇ )-6-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-l,2,3,3a,4,6a- hexahydro-cyclopenta[c]pyrrole Dihydrochloride.
  • Example 1.8 Preparation of [2-(4-bromo-phenyl)-ethoxy]-t ⁇ rt-butyl-dimethyl-silane.
  • Example 1.10 ( ⁇ )-Preparation of 2-BenzyI-6- ⁇ 4-[2-(te ⁇ t-butyl-dimethyl-silanyloxy)-ethyl]- phenyl ⁇ -l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole.
  • Example 1.12 Preparation of ( ⁇ )-Methanesulfonic acid 2-[4-(2-benzyl-l,2,3,3a,6,6a- hexahydro-cyclopenta[c]pyrrol-4-yl)-phenyl]-ethyl ester.
  • Example 1.14 Preparation of ( ⁇ )-2-Benzyl-6-[4-(2-piperidin-l-yl-ethyl)-phenyl]- l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride.
  • Example 1.15 Preparation of ( ⁇ )-2-Benzyl-6- ⁇ 4-[2-(2-methyl-piperidin-l-yl)-ethyl]- phenyI ⁇ -l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride.
  • Example 1.16 Preparation of ( ⁇ )-2-Ben2yl-6- ⁇ 4-[2-(4-methyl-piperazin-l-yl)-ethyl]- phenyl ⁇ -l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride.
  • Example 1.17 Preparation of (3aRS,6aRS )-2-Benzyl-6- ⁇ 4-[2-((2R,6S)-2,6-dimethyl- piperidin-1-yl)-ethyl!-phenyl$-1,2,3,3a,46aa-hexahydro-cyclopentalcJpyrrole Dihydrochloride.
  • Example 1.18 Preparation of ( ⁇ )-2-BenzyI-6- ⁇ 4-[2-(2,5-dimethyl-pyrrolidin-l-yl)-ethyl]- phenyl ⁇ -l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride.
  • Example 1.20 Preparation of (2aR ,6aR)-2-Benzyl-6- ⁇ 4-(2-[(2S)-2-methyl-pyrrolidin-l-yl]- ethyl)-phenyl ⁇ -l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride.
  • Example 1.21 Preparation of ( ⁇ )-2-Benzyl-6- ⁇ 4-[2-(2,2-dimethyl-pyrrolidin-l-yl)-ethyl]- phenyl ⁇ -l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole DihydrochIoride.
  • Example 1.22 Preparation of (2afi,6al?)-2-Benzyl-6- ⁇ 4-(2-[(2i?)-2-methyl-pyrrolidin-l-yl]- ethyl)-phenyl ⁇ -l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride.
  • Example 1.23 Preparation of ( ⁇ )-2-Benzyl-6-[4-(2-morpholin-4-yl-ethyl)-phenyl]- l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride.
  • Example 1.24 Preparation of (l- ⁇ 2-[4-(2-Benzyl-l,2,3,3a,6,6a-hexahydro- cyclopenta[c]pyrrol-4-yl)-phenyl]-ethyl ⁇ -pyrrolidin-2-yl)-(fi)-methanol Dihydrochloride.
  • Example 1.25 Preparation of (l- ⁇ 2-[4-(2-BenzyI-l,2,3,3a,6,6a-hexahydro- cyclopenta[c]pyrrol-4-yl)-phenyl]-ethyl ⁇ -pyrrolidin-2-yl)-(iS)-methanoI Dihydrochloride.
  • Example 1.27 Preparation of ( ⁇ )-2-Benzyl-6- ⁇ 4-[2-(3,3-difluoro-pyrrolidin-l-yl)-ethyl]- phenyl ⁇ -l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride.
  • Example 1.28 Preparation of ( ⁇ )-6-[4-(2-Azetidin ⁇ l-yl-ethyl)-phenyl]-2-benzyl- l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride.
  • Example 1.29 Preparation of ( ⁇ )-2-Benzyl-6- ⁇ 4-[2-(3,3-difluoro-piperidin-l-yl)-ethyl]- phenyl ⁇ -l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride.
  • Example 1.30 Preparation of ( ⁇ )-2- ⁇ 2-[4-(2-Benzyl-l,2,3,3a,6,6a-hexahydro- cyclopenta[c]pyrrol-4-yl)-phenyl]-ethyl ⁇ -2,3-dihydro-lH-isoindole Dihydrochloride.
  • Example 1.31 Preparation of ( ⁇ )-2- ⁇ 2-[4-(2-Benzyl-l,2,3,3a,6,6a-hexahydro- cyclopenta[c]pyrrol-4-yl)-phenyl]-ethyl ⁇ -l,2,3,4-tetrahydro-isoquinoIine Dihydrochloride.
  • Example 1.32 Preparation of l- ⁇ 2-[4-(2-Benzyl-l,2,3,3a,6,6a-hexahydro- cyclopenta[c]pyrrol-4-yl)-phenyl]-ethyl ⁇ -(3iS)-pyrrolidin-3-ol Dihydrochloride.
  • Example 1.33 Preparation of ( ⁇ )-l- ⁇ 2-[4-(2-Benzyl-l,2,3,3a,6,6a-hexahydro- cyclopenta[c]pyrrol-4-yl)-phenyl]-ethyl ⁇ -2,3-dihydro-lH-indole Dihydrochloride.
  • Example 1.7 The compound in Example 1.7 (0.200 g, 0.708 mmol) and cyclopentanone (0.060 g, 0.708 mmol) were mixed in dichloromethane (5 mL), and then treated with sodium triacetoxyborohydride (0.210 g, 0.991 mmol), and AcOH (0.043 g, 0.708 mmol). The mixture was stirred at room temperature under a N 2 atmosphere for 24h until the reactants were consumed as determined by LC/MS. The reaction mixture was quenched by adding 1 N NaOH, and the product was extracted with EtOAc. The organic extract was washed with brine and dried (MgSO 4 ). The solvent was removed at reduced pressure leaving the crude product.
  • Example 1.35 Preparation of (3aS 6aS)-2-CyclopropyImethyl-6-[4-(2-pyrrolidin-l-yl- ethyl)-phenyl]-l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride.
  • Example 1.36 Preparation of (3a5 r ,6a5)-2-Cyclopentyl-6-[4-(2-pyrrolidin-l-yl-ethyl)- phenyl]-l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride.
  • Example 1.37 Preparation of (3a5 r ,6a.S)-2-(4-Methoxy-benzyl)-6-[4-(2-pyrrolidiii-l-yl- ethyl)-phenyl]-l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride.
  • Example 1.39 Preparation of ( ⁇ )-2-Cyclobutyl-6-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]- l,2,3,3a,4,6a-hexahydro-cycIopenta[c]pyrrole Dihydrochloride.
  • Example 1.40 Preparation of ( ⁇ )-2- ⁇ 6-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-3,3a,4,6a- tetrahydro-lH-cyclopenta[c]pyrrol-2-yl ⁇ -propan-l-ol Dihydrochloride.
  • Example 1.42 Preparation of ( ⁇ )-4- ⁇ 6-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-3,3a,4,6a- tetrahydro-lH-cyclopenta[c]pyrrol-2-ylmethyl ⁇ -phenol Dihydrochloride.
  • Example 1.43 Preparation of ( ⁇ )-2-CyclohexyI-6-[4-(2-pyrroIidin-l-yl-ethyl)-phenyl]- l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride.
  • Example 1.44 Preparation of ( ⁇ )-2-Methyl-6-[4-(2-pyrroIidin-l-yl-ethyl)-phenyl]- 1,2,3,3a,4,6a-hexahydro-cyclopenta[cpyrroleDihydrochloride.
  • Example 1.45 Preparation of ( ⁇ )-2-Isopropyl-6-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]- l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride.
  • Example 1.46 Preparation of ( ⁇ )-2-Isobutyl-6-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]- 1 ,2,3,3a,4,6a-hexahydro-cyclopenta [c] pyrrole Dihydrochloride.
  • Example 1.47 Preparation of ( ⁇ )-2-(2,4-Dimethoxy-benzyl)-6-[4-(2-pyrrolidin-l-yl-ethyl)- phenyl]-1 ,2,3,3a,46a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride.
  • Example 1.48 Preparation of ( ⁇ )-6-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-2-(4- trifluoromethoxy-benzyl)-l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrroIe Dihydrochloride.
  • Example 1.50 Preparation of (3aS,6aS)-Cyclopropyl- ⁇ 6-[4-(2-pyrrolidin-l-yl-ethyl)- phenyl]-3,3a,4,6a-tetrahydro-lH-cyclopenta[c ⁇ pyrrol-2-yl ⁇ - lmethanone Hydrochloride.
  • Example 1.51 Preparation of (3aS,6aS)-2-Methyl-l- ⁇ 6-[4-(2-pyrrolidin-l-yl-ethyl)- phenyl]-3,3a,4,6a-tetrahydro-lH-cyclopenta[c]pyrrol-2-yl ⁇ -propan-l-one Hydrochloride.
  • Example 1.52 Preparation of (3a.S',6a5)-Cyclopentyl- ⁇ 6-[4-(2-pyrrolidin-l-yl-ethyl)- phenyl]-3,3a,4,6a-tetrahydro-lH-cyclopenta[c]pyrro ⁇ -yl ⁇ -methanone Hydrochloride.
  • Example 1.53 Preparation of ( ⁇ )-6-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-3,3a,4,6a- tetrahydro-lH-cyclopenta[c]pyrrole Dihydrochloride-2-carboxylic acid ethyl ester Hydrochloride.
  • Example 1.54 Preparation of ( ⁇ )-4-Hydroxy-4-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]- hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester.
  • Example 1.55 Preparation of ( ⁇ )-4-[4-(2-PyrroUdm-l-yl-ethyl)-phenyl]-octahydro- cyclopenta[c]pyrrole Dihydrochloride.
  • Example 1.56 Preparation of ( ⁇ )-2-CycIopropylmethyl-4-[4-(2-pyrrolidin-l-yl-ethyl)- phenyl]-octahydro-cyclopenta[c]pyrrole Dihydrochloride.
  • Example 1.57 Preparation of ( ⁇ )-2-Isopropyl-4-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]- octahydro-cyclopenta[c]pyrrole Dihydrochloride.
  • Example 1.58 Treparkiori of ( ⁇ )-2-Cyclopentyl-4-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]- octahydro-cycIopenta[c]pyrroIe Dihydrochloride.
  • Example 1.59 Preparation of ( ⁇ )-2-(2,4-Dimethoxy-benzyl)-4-[4-(2-pyrrolidin-l-yl-ethyl)- phenyl] -octahydro-cyclopenta [c] pyrrole Dihydrochloride.
  • Example 1.60 Preparation of ( ⁇ )-2-Cyclohexyl-4-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]- octahydro-cyclopenta[c]pyrrole Dihydrochloride.
  • Example 1.62 Preparation of (3ai?,4i?,6a5)-4- ⁇ 4-[4-(2-PyrroIidin-l-yl-ethyl)-phenyl]- hexahydro-cyclopenta[c]pyrroI-2-yImethyl]-phenoI.
  • Example 1.63 Preparation of (3ai?,4i?,6a5)-2-Cyclobutyl-4-[4-(2-pyrrolidin-l-yl-ethyl)- phenyl]-octahydro-cyclopenta[c]pyrrole Dihydrochloride.
  • Example 1.64 Preparation of (3aR ,4R ,6a i S)-2- ⁇ 4-[4-(2-Pyrrolidra-l-yl-ethyl)-phenyl]- hexahydro-cycIopenta[c]pyrrol-2-yl ⁇ -propan-l-ol dihydrocholride.
  • Example 1.65 Preparation of ( ⁇ )-2-Isobutyl-4-[4-(2-pyrrolidin-l-yI-ethyl)-phenyl]- octahydro-cyclopenta[c]pyrrole DihydrochIoride.
  • Example 1.66 Preparation of ( ⁇ )-l- ⁇ 7-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-l,3,3a,4,5,7a- hexahydro-isoindol-2-yl ⁇ -ethanone.
  • Example 1.68 Preparation of ( ⁇ )-4-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-2-(4- trifluoromethoxy-benzyl)-octahydro-cyclopenta[c]pyrrole Dihydrochloride.
  • Example 1.69 Preparation of ( ⁇ )-4- ⁇ 4-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-hexahydro- cyclopenta[c]pyrroI-2-y ⁇ methyl]-phenolDihydrochloride.
  • Example 1.70 Preparation of (3a/?,4i?,6aS)-2-Benzyl-4-[4-(2-pyrroIidin-l-yl-ethyl)- phenyl]-octahydro-cyclopenta[c]pyrrole Dihydrochloride.
  • Example 1.71 Preparation of ( ⁇ )-2- ⁇ 4-[4-(2-PyrroHdin-l-yl-ethyl)-phenyl]-hexahydro- cyclopenta[c]pyrroI-2-yl ⁇ -propan-l-ol Dihydrochloride.
  • Example 1.72 Preparation of ( ⁇ )-l- ⁇ 4-[4-(2-PyrroHdin-l-yl-ethyl)-phenyl]-hexahydro- cyclopenta[c]pyrrol-2-yl ⁇ -ethanone Hydrochloride.
  • Example 1.73 Preparation of ( ⁇ )-2-Methyl-l- ⁇ 4-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]- hexahydro-cyclopentafcjpyrrol ⁇ -ylj-propan-l-one Hydrochloride.
  • Example 1.74 Preparation of ( ⁇ )-CydopropyI- ⁇ 4-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]- hexahydro-cydopenta[c]pyrrol-2-yl ⁇ -methanone Hydrochloride.
  • Example 1.75 Preparation of ( ⁇ )-Cyclopentyl- ⁇ 4-[4-(2-pyrrolidin-l-yl-ethyl)-phenyI]- hexahydro-cyclopenta[c]pyrrol-2-yl ⁇ -methanone Hydrochloride.
  • Example 1.76 Preparation of ( ⁇ )-4-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyI]-hexahydro- cyclopenta[c]pyrrole-2-carboxylic acid ethyl ester Hydrochloride.
  • Example 1.77 Preparation of ( ⁇ )-2-(4-Methoxy-benzyl)-4-[4-(2-pyrrolidin-l-yl-ethyl)- phenyl]-octahydro-cycIopenta[c]pyrrol-4-ol.
  • Example 1.78 Preparation of ( ⁇ )-2-Cyclopropylmethyl-4-[4-(2-pyrrolidin-l-yl-ethyl)- phenyl]-octahydro-cyclopenta[c]pyrrol-4-ol.
  • Example 1.79 Preparation of ( ⁇ )-2-IsobutyI-4-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]- octahydro-cyclopenta[c]pyrrol-4-ol.
  • Example 1.80 Preparation of ( ⁇ )-2-Isopropyl-4-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]- octahydro-cyclopenta[c]pyrroI-4-ol.
  • Example 1.81 Preparation of ( ⁇ )-4-[4-(2-Pyrrolidin-l-yI-ethyl)-phenyl]-2-(4- trifluoromethoxy-benzyl)-octahydro-cycIopenta[c]pyrrol-4-ol.
  • Example 1.82 Preparation of ( ⁇ )-2-(2,4-Dimethoxy-benzyl)-4-[4-(2-pyrrolidin-l-yl-ethyI)- phenyl]-octahydro-cyclopenta[c]pyrrol-4-ol.
  • Example 1.83 Preparation of ( ⁇ )-2-Cyclohexyl-4-[4-(2-pyrrolidin ⁇ l-yl-ethyl)-phenyl] ⁇ octahydro-cyclopenta[c]pyrrol-4-oI.
  • Example 1.84 Preparation of ( ⁇ )-2-Cydopentyl-4-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]- octahydro-cyclopenta[c]pyrrol-4-olcarboxylic acid tert-butyl ester.
  • Example 1.86 Preparation of (3aS,6aS)-6-[4-(2-Pyrrolidin-1-yl-ethyl)-phenyl]-3,3a,4,6a- tetrahydro-lH-cyclopenta[c]pyrrole-2-carboxylic acid cyclopentylamide.
  • IQ a 5 mL glass tube were placed the compound described in Example 1.7 (0.200 g, 0.708 mmol), bromobenzene (0.074, 0.472 mmol), potassium t-butoxide (0.079 g, 0.708 mmol), 3 mL of methyl sulfoxide, and a magnetic stir bar.
  • the vessel was sealed with a septum and placed into a microwave cavity. With microwave irradiation, the temperature was ramped from room temperature to 200 0 C and held for 5 min. After the mixture was allowed to cool to room temperature, the reaction vessel was opened and the reaction mixture was filtered. The mixture was purified via preparative HPLC.
  • Example 1.88 Preparation of ( ⁇ )-2-Pyridin-2-yI-6-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]- l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride.
  • Example 1.90 Preparation of ( ⁇ )-2-Hydroxy-l- ⁇ 4-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]- hexahydro-cyclopenta[c]pyrrol-2-yl ⁇ ethanone.
  • Example 1.91 Preparation of ( ⁇ )-2-Hydroxy-2-methyl-l- ⁇ 6-[4-(2-pyrrolidin-l-yl-ethyl)- phenyl]-3,3a,4,6a-tetrahydro-lH-cyclopenta[c]pyrrol-2-yl ⁇ -propan-l-one.
  • the crude mixture was diluted with EtOAc and washed with water.
  • the organic layer was concentrated, and diluted with DMSO for purification on the HPLC, using method 10-60% over 25 min.
  • the pure fractions were combined, neutralized with saturated solution of sodium bicarbonate, and extracted with EtOAc.
  • the organic layers were combined and concentrated (0.112g, 67%).
  • Example 1.96 Preparation of ( ⁇ )-4-Hydroxy-4-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]- hexahydro-cyc!openta[c]pyrroIe-2-carboxylic acid ethyl ester.
  • Example 1.100 Preparation of ( ⁇ )-2-Benzyl-6-[6-(2-pyrrolidin-l-yl-ethyl)-pyridin-3-yl]- l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride.
  • Example 1.101 Preparation of ( ⁇ )-2-Benzyl-4-[4-(2 ⁇ pyrrolidin-l-yl-ethoxy)-phenyl]- octahydro-cyclopenta[c]pyrrol-4-ol.
  • Example 1.102 Preparation of ( ⁇ )-2-Benzyl-6-[4-(2-pyrrolidin-l-yl-ethoxy)-phenyl]- l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride.
  • Example 1.101 The compound described in Example 1.101 (250.00mg, 615 ⁇ mol) was dissolved in 5 mL of DCM. Methanesulfonyl chloride (95.2 ⁇ l, 1230 ⁇ mol) and triethylamine (171 ⁇ l, 1230 ⁇ mol) were added. The mixture was stirred at 25 0 C for 24 hr in a sealed vial. The reaction was quenched with water and extracted with DCM. The combined organic layers were dried over MgSO 4 and concentrated at reduced pressure. Purification by silica gel chromatography (EtOAc/ 5%MeOH/NH 3 in DCM) gave the title compound as a yellow oil (1 lO.Omg, 46.0%).
  • Example 1.105 Preparation of ( ⁇ )-2-Benzyl-6-[3-(2-pyrrolidin-l-yl-ethoxy)-phenyl]- l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride.
  • Example 1.108 Preparation of ( ⁇ )-2-Benzyl-4-[5-(2-pyrroIidin-l-yl-ethyl)-pyridin-2-yl]- octahydro-cyclopenta[c]pyrrol-4-ol.
  • Example 1.109 Preparation of ( ⁇ )-2-Benzyl-6-[5-(2-pyrrolidin-l-yl-ethyI)-pyridin-2-yI]- l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole DihydrochIoride.
  • Example 1.112 Preparation of ( ⁇ )-2-Benzyl-7-[4-(2-pyrroIidin-l-yl-ethyl)-phenyl]- 2,3,3a,4,5,7a-hexahydro-lH-isoindole.
  • Example 1.113 Preparation of ( ⁇ )-7-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-2,3,3a,4,5,7a- hexahydro-lH-isoindole.
  • EXAMPLE 2 Syntheses of compounds of the present invention.
  • Step A Preparation of Intermediate 4-Bromophenethyl Methanesulfonate.
  • Step B Preparation of Intermediate (i?)-l-(4-BromophenethyI)-2- methylpyrrolidine. 4-Bromophenethyl methanesulfonate (12.2 g, 43.8 mmol) was dissolved in acetonitrile
  • 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 organics were dried over MgSO 4 , filtered, and concentrated to give 1.70 g of a yellow foam. The foam was triturated with 20 mL diethyl ether twice, and dried under high vacuum to give the title compound(1.19g,64%yield) as a pale yellow solid.
  • Example 2.2 Preparation of 2-Hydroxy-2-methyl-l- ⁇ 6-[4-(2-pyrroIidin-l-yl ⁇ ethyl)- phenyl]-3,3a,4,6a-tetrahydro-lH-cyclopenta[c]pyrrol-2-yl ⁇ -propan-l-one.
  • Example 1.7 The compound from Example 1.7 (0.200 g, 0.708 mmol) and hydroxyisobutyric acid (0.073 g, 0.708 mmol) were mixed in DCM (10 mL), and treated with N.N.N' N'-tetramethyl-O- (7-azabenzotriazol-l-yl)uronium hexafluorophosphate (0.323 g, 0.849 mmol), and triethylamine (0.125 g, 1.24 mmol). The mixture was stirred at 40 0 C under N 2 atmosphere for l ⁇ h until the reactants were consumed as determined by LC/MS. The reaction mixture was diluted with DCM (20 mL) and quenched with distilled water (20 mL).
  • Example 2.5 Preparation of 2-Pyridin-4-yl-6-[4-(2-pyrrolidin-l-yI-ethyl)-phenyI]- l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole.
  • Example 2.6 Preparation of 3- ⁇ 6-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-3,3a,4,6a- tetrahydro-lH-cyclopentafcJpyrrol ⁇ -ylJ-benzaldehyde.
  • Example 2.8 Preparation of 6-[4-(2-PyrroIidin-l-yl-ethyI)-phenyl]-2-thiazoI-2-yl- l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole.
  • Example 2.9 Preparation of 2-Pyrazm-2-y ⁇ -6-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]- l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole.
  • Example 2.10 Preparation of 2-Pyrimidin-2-yl-6-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]- l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole.
  • Example 2.11 Preparation of 2-Pyrimidin-5-yl-6-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]- l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole.
  • reaction vessel was opened and the reaction mixture was filtered through a small column of Celite.
  • the mixture was purified by preparative HPLC to afford the TFA salt of the title compound (0.025 g, 19.5%) as an orange solid.
  • Example 2.12 Preparation of 2-(3,5-Difluoro ⁇ phenyl)-6-[4-(2-pyrrolidin-l ⁇ yl-ethyl)- phenyl]-1,2,3,3a,4,6a-hexahydro-cyclopentatcJpyrrole.
  • Example 2.13 Preparation of 3- ⁇ 6-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-3,3a,4,6a- tetrahydro-lH-cyclopenta[c]pyrrol-2-yl ⁇ -benzonitrile.
  • Example 1.7 In a 5 mL glass tube were placed the compound from Example 1.7 (0.070 g, 0.248 mmol), 3-bromobenzonitrile (0.045 g, 0.248 mmol), palladium dibenzylideneacetone (0.011 g, 0.0 12mmol),sodiumtert-butoxide (0.035 g, 0.372 mmol), 2 ⁇ (dicyclohexylphosphino) biphenyl (1.75 mg, 5.00 ⁇ mol) and a magnetic stir bar.
  • the vessel was sealed with a septum and placed into a microwave cavity. With microwave irradiation, the temperature was ramped from room temperature to 110 0 C and held for 6 h.
  • reaction vessel was opened and the reaction mixture was filtered through a small column of Celite.
  • the mixture was purified by preparative HPLC to afford the TFA salt of the title compound (0.025 g, 26.3%) as an orange solid.
  • Example 2.14 Preparation of Cyclopropyl-((3aR,4R,6aS)-4- ⁇ 4-[2-((R)-2-methyl- pyrrolidin-l-yl)-ethyl]-phenyl ⁇ -hexahydro-cyclopenta[c ⁇ pyrrol-2-yl-2-yl)-methanone.
  • Step A Preparation of (3aR,4R,6aS)-4-(4-(2-((R)-2-Methylpyrrolidin-l- yl)ethyl)pheny ⁇ )octahydrocyclopenta[c]pyrrole
  • Step B Preparation of Cyclopropyl-((3aR,4R,6aS)-4- ⁇ 4-[2-((R)-2-methyl- pyrrolidin-l-yl)-ethyl]-phenyl ⁇ -hexahydro-cyclopenta[c-pyrrol-2-yl)-methanone
  • reaction vessel was opened and the reaction mixture was filtered through a small column of silica.
  • the mixture was purified by preparative HPLC to afford the TFA salt of the title compound (0.063 g, 40.1%) as a white solid.
  • Example 2.15 Preparation of (3aS,6aS)-6- ⁇ 4-[2-((R)-2-Methyl-pyrroIidin-l-yl)-ethyI]- phenyl ⁇ -2-(6-trifluoromethyl-pyridin-3-yl)-l,2,3,3a,4,6a-hexahydro-cycIopenta[c]pyrrole (Compound C102).
  • Step A Preparation of (3aS,6aS)-6-(4-(2-((R)-2-Methylpyrrolidin-l- ytyethytypheny ⁇ -l ⁇ jSjSa ⁇ a-hexahydrocyclopentaJclpyrrole
  • Step B Preparation of (3aS,6aS)-6- ⁇ 4-[2-((R)-2-Methyl-pyrroKdin-l-yl)-ethyl]- phenyl ⁇ -2-(6-trifluoromethyl-pyridin-3-yl)-l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole
  • the vessel was sealed with a septum and placed into a microwave cavity. With microwave irradiation, the temperature was ramped from room temperature to 110 0 C and held for 6 h. After the mixture was allowed to cool to room temperature, the reaction vessel was opened and the reaction mixture was filtered through a small column of Celite. The mixture was purified by preparative HPLC to afford the TFA salt of the title compound (0.020 g, 8.4%) as an orange solid.
  • Example 2.16 Preparation of 5-((3aS,6aS)-6- ⁇ 4-[2-((R)-2-Methyl-pyrrolidin-l-yl)-ethyl]- phenyl ⁇ -3,3a,4,6a-tetrahydro-lH-cyclopenta[c]pyrrol-2-yl)-pyridine-2-carbonitrile.
  • Example 2.17 Preparation of 2-Methyl-l-((3aR,4R,6aS)-4- ⁇ 4-[2-((R)-2-methyl-pyrrolidin- 1-yl)-ethyl]-phenyl ⁇ -hexahydro-cycIopenta[c]pyrrol-2-yl)- propan-l-one.
  • Example 2.18 Preparation of ((3aR,4R,6aS)-4- ⁇ 4-[2-((R)-2-Methyl-pyrrolidin-l-yl)-ethyl]- phenyl ⁇ -hexahydro-cycIopenta[c]pyrrol-2-yl)-pyridin-3-yl-methanone.
  • Example 2.19 Preparation of ((3aR,4R,6aS)-4- ⁇ 4-[2-((R)-2-Methyl-pyrroIidin-l-yl)-ethyl]- phenylj-hexahydro-cyclopentalcjpyrrol-2-yl)-pyrazin ⁇ -yl-methanone.
  • Example 2.20 Preparation of (3aR,4R,6aS)-2-(2-Fluoro-ethyl)-4- ⁇ 4-[2-((R)-2-methyl- pyrrolidin-l-yl)-ethyl]-phenyl ⁇ -octahydro-cyclopenta[c]pyrrole.
  • the temperature was ramped from room temperature to 120 0 C and held for 3 h. After the mixture was allowed to cool to room temperature, the reaction vessel was opened and the reaction mixture was filtered through a small column of silica. The mixture was purified by preparative HPLC to afford the TFA salt of the title compound (0.025 g, 21.7%) as a yellow, viscous solid.
  • Example 2.21 Preparation of 2,2,2-Trifluoro-l-((3aR,4R,6aS)-4- ⁇ 4-[2-((R)-2-methyl- pyrrolidin-1-yl-ethyl]-phenyl ⁇ -hexahydro-cyclopenta[c]pyrrol-2-yl)-ethanone.
  • Example 2.22 Preparation of ((3aR,4R,6aS)-4- ⁇ 4-[2-((R)-2-Methyl-pyrrolidin-l-yl)-ethyI]- phenyl ⁇ -hexahydro-cyclopenta[c]pyrrol-2-yl)-pyrimidin-5-yl-methanone.
  • Example 2.24 Preparation of (3aR,4R,6aS)-4- ⁇ 4-[2-((R)-2-Methyl-pyrrolidin-l-yl)-ethyl]- phenyl ⁇ -2-(2,2,2-trifluoro-ethyl)-octahydro-cyclopenta[c]pyrrole.
  • the temperature was ramped from room temperature to 120 0 C and held for 3h. After the mixture was allowed to cool to room 0 temperature, the reaction vessel was opened and the reaction mixture was filtered through a small column of silica. The mixture was purified by preparative HPLC to afford the TFA salt of the title compound (0.023 g, 16.7%) as a white solid.
  • Example 2.25 Preparation of ((3aR,4R,6aS)-4- ⁇ 4-[2-((R)-2-Methyl-pyrrolidin-l-yl)-ethyl]- phenylj-hexahydro-cyclopentatcjpyrrol ⁇ -ylj- ⁇ etrahydro-pyran ⁇ -y ⁇ -methanone.
  • Step A Preparation of Intermediate (R)-l-(4-Bromobenzyl)-2-methylpyrrolidine
  • dichloroethane 10 mL
  • (R)-2-methylpyrrolidinium chloride 0.32 g, 2.7 mmol
  • sodium triacetoxyborohydride 0.79 g, 3.7 mmol
  • the reaction was stirred at room temperature for 18 h.
  • the reaction was quenched with water (5 mL) and treated with NaOH (pH 8).
  • the volatile solvents were evaporated under reduced pressure and the aqueous slurry was extracted with DCM.
  • the combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated under reduced pressure to leave the title compound which was used without further purification.
  • Step B Preparation of Intermediate (3aR, 6aS)-2-BenzyI-4-(4-(((R)-2- methyIpyrrolidin-l-yl)methyl)phenyl)octahydrocyclopenta[c]pyrrol-4-ol
  • Step C Preparation of (3aS, 6aS)-2-Benzyl-6-[4-((l?)-2-methyl-pyrrolidm-l- ylmethyl)-phenyl]-1,2,3,3a,46 a-hexahydro-cycIopentafclpyrrole (3aR, 6aS)-2-Benzyl-4-(4-(((R)-2-methylpyrrolidin-l- yl)methyl)phenyl)octahydrocyclopenta[c]pyrrol-4-ol (0.18 g, 0.46 mmol) from Step B above was dissolved in isopropyl alcohol (5 mL) and then an anhydrous solution of hydrogen chloride (4.0 M in dioxane, 5 mL) was added. The mixture was heated at 60 0 C for 16 h and then the ip I ⁇ T / ⁇ i ft Fi; in i! ;:; i ⁇ • ⁇ " Ni-NH-
  • Step B Preparation of 2-BenzyloctahydrocycIopenta[c]pyrrol-4-yl Methanesulfonate.
  • Step C Preparation of 2-Benzyl-4-iodooctahydrocycIopenta[c]pyrrole.
  • Step D Preparation of 2-Benzyl-4-(4-(2-(pyrrolidin-l- yl)ethyl)phenyl)octahydrocyclopenta[c]pyrrole.
  • Step E Preparation of 4-(4-(2-(Pyrrolidin-l- yl)ethyl)phenyl)octahydrocyclopenta[c]pyrrole. PHI f / 1
  • Step F Preparation of Racemic Mixture of (3aR, 4R, 6aS) and (3aS, 4S, 6aR)-2- Methyl-l-4-[4-(2-pyrrolidin-l-yl-ethyI)-phenyl]-hexahydro-cyclopenta[c]pyrrol-2-yl ⁇ - propan-1-one.
  • Example 2.28 Preparation of CycIopentyl-((3aR,4R,6aS)-4- ⁇ 4-[2-((R)-2-methyI-pyrrolidin- l-yl)-ethyl]-phenyl ⁇ -hexahydro-cyclopenta[c]pyrrol-2-yl)-methanone.
  • Example 2.29 Preparation of CyclopropyI-((3aR,4S,6aS)-4- ⁇ 4-[2-((R)-2-methyl-pyrrolidin- l-yl)-ethyl]-phenyl ⁇ -hexahydro-cyclopenta[c]pyrrol-2-(lH)-yI)-methanone.
  • Step A Preparation of (3aR,4S,6aS)-2-Benzyl-4-bromo- octahydrocyclopenta[c]pyrrole.
  • Step B Preparation of (3aR,4S,6aS)-2-Benzyl-4-(4-(2-((R)-2-methylpyrrolidin-l- yl)ethyl)phenyl)-octahydrocyclopenta[c]pyrrole.
  • Step C Preparation of (3aR,4S,6aS)-4-(4-(2-((R)-2-Methylpyrrolidin-l- yl)ethyl)phenyl)-octahydrocyclopenta[c]pyrrole.
  • Step D Preparation of CycIopropyl-((3aR,4S,6aS)-4- ⁇ 4-[2-((R)-2-methyI- pyrrolidin-l-yl)-ethyl]-phenyl ⁇ -hexahydro-cyclopenta[c]pyrrol-2-(lH)-yl)-methanone.
  • Example 2.30 Preparation of Cyclopentyl-((3aR,4S,6aS)-4- ⁇ 4-[2-((R)-2-methyl-pyrroIidin- l-yl)-ethyl]-phenyl ⁇ -hexahydro-cyclopenta[c]pyrrol-2-(lH)-yl)-methanone (Compound B28).
  • Example 2.31 Preparation of ((3aR,4S,6aS)-4- ⁇ 4-[2-((R)-2-Methyl-pyrrolidin-l-yl)-ethyl]- phenyl ⁇ -hexahydro-cyclopenta[c]pyrrol-2-(lH)-yl)-(tetrahydro-pyran-4-yl)-methanone (Compound B26).
  • Example 2.32 Preparation of ((3aR,4R,6aS)-444-[2-((R)-2-Methyl-l-oxy-pyrrolidin-l-yl)- ethyI]-phenyI ⁇ -hexahydro-cyclopenta[c]pyrrol-2-yl)-(tetrahydro-pyran-4-yl)-methanone.
  • Example 2.33 Preparation of 4-(2-Benzyl-l,2,3,3a,6,6a-hexahydro-cyclopenta[c]pyrrol-4- yl)-N-methyl-benzamide.
  • Example 2.34 Preparation of ((3aR,4R,6aS)-4- ⁇ 4-[2-((R)-2-Methyl-pyrrolidin-l-yl)-ethyl]- phenyl ⁇ -hexahydro-cyclopentalcjpyrrol ⁇ -ylj-phenyl-methanone.
  • Example 2.35 Preparation of 2-(4-Methoxy-benzyl)-6-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]- l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole.
  • Example 2.36 Preparation of (3aR,7aR)-4-(4-(2-((R)-2-methylpyrrolidin-l- yl)ethyl)phenyl)-2,3,3a,6,7,7a-hexahydro-lH-isoindole.
  • Step A Preparation of (3aS,7aR)-2-benzyl-4-(4-(2-((R)-2-methylpyrrolidin-l- yl)ethyl)phenyl)-octahydro-lH-isoindol-4-ol.
  • (3aS, 7aR)-2-Benzylhexahydro-lH-isoindol-4(2H)-one was prepared via the method described in Example 1.1 using cyclohexenone as the starting material and resolving the product using di-p-toluoyl-d-tartaric acid. Analysis of (3aS, 7ai.)-2-Benzylhexahydro-lH-isomdol-4(2H)-one via Chiral
  • Step B Preparation of (3aS,7aR)-4-(4-(2-((R)-2-methylpyrrolidin-l- yl)ethyl)phenyl)-octahydro-lH-isoindol-4-ol.
  • Step C Preparation of (3aR,7aR)-4-(4-(2-((R)-2-methylpyrrolidin-l- yl)ethyl)phenyl)-2,3,3a,6,7,7a-hexahydro-lH-isoindole.
  • Step D Preparation of (3aS,7aR)-4-(4-(2-((R)-2-methylpyrrolidin-l- yl)ethyl)phenyl)-octahydro-lH-isoindoIe.
  • Example 2.37 Preparation of ⁇ 7-[4-(2-PyrroKdin-l-yI-ethyl)-phenyI]-l,3,3a,4,5,7a- hexahydro-isoindoI ⁇ 2-yl ⁇ -(tetrahydro-furan-3-yl)-methanone.
  • Example 2.38 Preparation of Pyridin-3-yl- ⁇ 7-[4-(2-pyrrolidin-l-yI-ethyl)-phenyl]- l,3,3a,4,5,7a-hexahydro-isoindol-2-yl ⁇ -methanone.
  • Example 2.40 Preparation of ⁇ 4-[4-(2-PyrroKdin-l-yl-ethyl)-phenyl]-octahydro-isoindol-2- yl ⁇ -(tetrahydro-furan-3-yl)-methanone.
  • Example 2.41 Preparation of l-(4- ⁇ 4-[2-((S)-2-Methyl-pyrrolidin-l-y ⁇ )-ethyl]-phenyl ⁇ - octahydro-isoindoI-2-yl)-ethanone.
  • Example 2.42 Preparation of 2-Methyl-l- ⁇ (3aS,7aS)-7-[4-(2-pyrrolidin-l-yl-ethyl)- phenyl]-l,3,3a,4,5,7a-hexahydro-isoindol-2-yl ⁇ -propan-l-one.
  • Example 2.43 Preparation of (3aS,7aS)-2-Cyclopropanesulfonyl-7-[4-(2-pyrrolidin-l-yl- ethyl)-phenyl]-2,3,3a,4,5,7a-hexahydro-lH-isoindole.
  • Example 2.44 Preparation of (3aS,7aS)-2-(Propane-2-sulfonyl)-7-[4-(2-pyrroIidin-l-yl- ethyl)-phenyl]-2,3,3a,4,5,7a-hexahydro-lH-isoindole.
  • Example 2.45 Preparation of 2-Methyl-l-((3aS,7aS)-7- ⁇ 4-[2-((R)-2-methyl-pyrrolidin-l- yl)-ethyl]-phenyl ⁇ -l,3,3a,4,5,7a-hexahydro-isoindol-2-yl)-propan-l-one.
  • E exxaammppllee 2 Z.A46b P Prreeppaarraattiioonn ooff CCyclopropyl-((3aS,7aS)-7- ⁇ 4-[2-((R)-2-methyl-pyrroIidin-l- yl)-ethyl]-phenyl ⁇ -l,3,3a,4,5,7a-hexahydro-isoindol-2-yl)-methanone.
  • Example 2.47 Preparation of Cyclopentyl-((3aS,7aS)-7- ⁇ 4-[2-((R)-2-methyl-pyrroKdin-l- yI)-ethyl]-phenyl ⁇ -l,3,3a,4,5,7a-hexahydro-isoindol-2-yl)-methanone.
  • Example 2.48 Preparation of l-(7- ⁇ 4-[2-((R)-2-Methyl-pyrrolidin-l-yl)-ethyl]-phenyl ⁇ - l,3,3a,4,5,7a-hexahydro-isoindol-2-yl)-ethanone.
  • Example 2.49 Preparation of l-((3aS,7aS)-7- ⁇ 4-[2-((R)-2-Methyl-pyrrolidin-l-yl)-ethyl]- phenyl ⁇ -l,3,3a,4,5,7a-hexahydro-isoindol-2-yl)-2-phenyl-ethanone.
  • Example 2.50 Preparation of ((3aR,7aR)-7- ⁇ 4-[2-((R)-2-Methyl-pyrroUdin-l-yl)-ethyl]- phenyl ⁇ -l,3,3a,4,5,7a-hexahydro-isoindol-2-yl)-(tetrahydro-furan-3-yl)-methanone.
  • Example 2.51 Preparation of (3aR,7aR)-2-Benzyl-7- ⁇ 4-[2-((R)-2-methyl-pyrrolidin-l-yl)- ethyl]-phenyl ⁇ -2,3,3a,4,5,7a-hexahydro-lH-isoindole.
  • Example 2.52 Preparation of ⁇ (3aS,7aS)-7-[4-(2-Pyrrolidin-l ⁇ yl-ethyl)-phenyl]- l,3,3a,4,5,7a-hexahydro-isoindol-2-yl ⁇ -(tetrahydro-furan-3-yl)-methanone.
  • Example 2.53 Preparation of ((3aS,7aS)-7- ⁇ 4-[2-((R)-2-Methyl-pyrrolidin-l-yl)-ethyl]- phenyl ⁇ -l,3,3a,4,5,7a-hexahydro-isoindol-2-yl)-(tetrahydro-furan-3-yl)-methanone.
  • Example 2.54 Preparation of ((3aS,7aR)-4- ⁇ 4-[2-((R)-2-Methyl-pyrrolidin-l-yl)-ethyl]- phenyl ⁇ -octahydro-isoindol-2-yl)-(tetrahydro-furan-3-yl)-methanone.
  • Example 2.55 Preparation of ((3aR,7aS)-4- ⁇ 4-[2-((R)-2-Methyl-pyrrolidin-l-yI)-ethyl]- phenyl ⁇ -octahydro-isoindol-2-yl)-(tetrahydro-furan-3-yl)-methanone.
  • Example 2.56 Preparation of 2-MethyI-l-((3aS,7aR)-4- ⁇ 4-[2-((R)-2-methyl-pyrrolidin-l- yl)-ethy ⁇ ]-phenyl ⁇ -octahydro-isoindol-2-yl)-propan-l-one.
  • Example 2.58 Preparation of ((3aS,7aR)-4- ⁇ 4-[2-((R)-2-Methyl-pyrrolidin-l-yl)-ethyl]- phenyl ⁇ -octahydro-isoindol-2-yl)-(tetrahydro-pyran-4-yl)-methanone.

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Abstract

The present invention relates to certain fused heterobicyclic derivatives of Formula (Ia) and pharmaceutical compositions thereof that modulate the activity of the H3 receptor. Compounds and pharmaceutical compositions thereof are directed to methods useful in the treatment of H3-associated disorders, such as, cognitive disorders, epilepsy, brain trauma, depression, obesity, motion sickness and vertigo, disorders of sleep and wakefulness such as narcolepsy, shift-work syndrome, drowsiness as a side effect from a medication, maintenance of vigilance to aid in completion of tasks and the like, cataplexy, 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

IP' ϋ"': T/ JULS O IS / NMHMMl"1?' «9
B MODULATORS OF THE 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-associated disorders, such as, cognitive disorders, epilepsy, brain trauma, depression, obesity, motion sickness and vertigo, disorders of sleep and wakefulness such as narcolepsy, shift-work syndrome, drowsiness as a side effect from a medication, maintenance of vigilance to aid in completion of tasks and the like, cataplexy, 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 as shown in Formula (Ia):
Figure imgf000003_0001
(ϊa) or a pharmaceutically acceptable salt, hydrate or solvate thereof; wherein:
D is C(=O), OC(=O), NR6C(=O), S(=O)2, or absent, wherein R6 is H or C1-6 alkyl;
G is CR7 or C, provided that when G is CR7 then - - is a single bond, wherein R3 is H and R7 is H or OH, and when G is C then - - is a double bond and R3 is absent;
E is C(R8R9) or C(RV)C(R10R11), wherein R8, R9, R10, and R11 are each selected independently from the group consisting of H, Ci-3 alkyl, Ci-4 alkoxy, carboxy, cyano, Ci-3 haloalkyl, and halogen;
J is O, S, S(=O), S(=O)2, NR12, or absent, wherein R12 is H or Ci-6 alkyl; K is Ci_4 alkylene optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 substituents selected independently from the group consisting OfCi-3 alkyl, Ci-4 alkoxy, carboxy, cyano, C1-3 haloalkyl, halogen, hydroxyl, and oxo; "R1' is "selected from the group consisting of H, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, Ci-4 alkylene-Q.rcycloalkyl, C3-7 heterocyclyl, aryl, Ci-4 alkylene-aryl, heteroaryl, and Ci-4 alkylene-heteroaryl, and each of said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, Ci-4 alkylene-C3-7-cycloalkyl, C3-7 heterocyclyl, aryl, Ci-4 alkylene-aryl, heteroaryl, and C]-4 alkylene-heteroaryl groups are optionally substituted with 1, 2, 3, 4, 5, 6, or 7 substituents selected independently from the group consisting of Ci-6 acyl, Ci-6 acyloxy, C2-6 alkenyl, Ci-6 alkoxy, Ci-6 alkyl, Ci-6 alkylcarboxamide, C2-6 alkynyl, Ci-6 alkylsulfonamide, Ci-6 alkylsulfmyl, Ci-6 alkylsulfonyl, Ci-6 alkylthio, Ci-6 alkylureyl, amino, C1-6 alkylamino, C2-8 dialkylamino, carbo-Ci-6-alkoxy, carboxamide, carboxy, cyano, C3-7 cycloalkyl, C2-8 dialkylcarboxamide, C2-8 dialkylsulfonamide, formyl, halogen, Ci-6 haloalkoxy, Ci-6 haloalkyl, Ci-6 haloalkylsulfinyl, Ci-6 haloalkylsulfonyl, Ci-6 haloalkylthio, hydroxyl, thiol, nitro, and sulfonamide;
R2 is H, halogen or Ci-3 alkyl;
R4 and R5 are each independently selected from the group consisting of H, C1-6 alkyl, C2- β alkenyl, C2-6 alkynyl, and C3-7 cycloalkyl, and wherein each of said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-7 cycloalkyl groups are optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected independently from the group consisting OfC1-6 acyl, Ci-6 acyloxy, C2-6 alkenyl, C1-6 alkoxy, C1-6 alkyl, Ci-6 alkylcarboxamide, C2-6 alkynyl, Ci-6 alkylsulfonamide, Ci-6 alkylsulfmyl, Ci-6 alkylsulfonyl, Ci-6 alkylthio, Ci-6 alkylureyl, amino, Ci-6 alkylamino, C2-8 dialkylamino, carbo-Ci-6-alkoxy, carboxamide, carboxy, cyano, C3-7 cycloalkyl, C2-8 dialkylcarboxamide, C2-8 dialkylsulfonamide, halogen, Ci-6 haloalkoxy, Ci-6 haloalkyl, Ci-6 haloalkylsulfinyl, Ci-6 haloalkylsulfonyl, C1-6 haloalkylthio, hydroxyl, thiol, nitro, and sulfonamide; or
R4 and R5 together with the nitrogen atom to which they are both bonded form a C3-7 heterocyclyl or C5-10 heterobicyclyl group optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected independently from the group consisting OfC1-6 acyl, C1-6 acyloxy, C2-6 alkenyl, C1-6 alkoxy, C1-6 alkyl, C1-6 alkylcarboxamide, C2-6 alkynyl, C1-6 alkylsulfonamide, Ci-6 alkylsulfmyl, Ci-6 alkylsulfonyl, C1-6 alkylthio, C1-6 alkylureyl, amino, C1-6 alkylamino, C2-8 dialkylamino, carbo-C1-6-alkoxy, carboxamide, carboxy, cyano, C3-7 cycloalkyl, C2-8 dialkylcarboxamide, C2-8 dialkylsulfonamide, halogen, C1-6 haloalkoxy, C1-6 haloalkyl, Q-6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, C1-6 haloalkylthio, hydroxyl, thiol, nitro, oxo, phenyl, and sulfonamide, and said C1-6 alkyl, is optionally substituted with 1 or 2 substituents selected independently from C1-6 alkoxy and hydroxyl; and
Ar is phenyl, pyridinyl, or pyrimidinyl, each optionally substituted with 1, 2, 3, or 4 substituents selected independently from the group consisting of C]-6 acyl, Ci-6 acyloxy, C2-6 alkenyl, Ci-6 alkoxy, Ci-6 alkyl, Ci-6 alkylcarboxamide, C2-6 alkynyl, Q-6 alkylsulfonamide, Ci-6 alkylsulfmyl, C1-6 alkylsulfonyl, Ci-6 alkylthio, Ci-6 alkylureyl, amino, Ci-6 alkylamino, C2-8 dialkylamino, carbo-Ci-6-alkoxy, carboxamide, carboxy, cyano, C3-7 cycloalkyl, C2-8
Figure imgf000005_0001
C1-6 haloalkyl, C1-6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, C1-6 haloalkylthio, hydroxyl, thiol, nitro, and sulfonamide; provided that: G and J are not bonded to adjacent ring carbons of said Ar group; and when E is C(R8R9), then Ha and Hb are cis with respect to each other. One aspect of the present invention pertains to compounds wherein: D is C(=O), OC(O), NR6C(O), or absent, wherein R6 is H or C1-6 alkyl; R1 is selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C1-4 alkylene-C3-7-cycloalkyl, C3-7 heterocyclyl, aryl, C1-4 alkylene-aryl, heteroaryl, and C1-4 alkylene-heteroaryl, and each of said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C1-4 alkylene-C3-7-cycloalkyl, C3-7 heterocyclyl, aryl, C1-4 alkylene-aryl, heteroaryl, and C1-4 alkylene-heteroaryl groups are optionally substituted with 1, 2, 3, 4, 5, 6, or 7 substituents selected independently from the group consisting of C1-6 acyl, C1-6 acyloxy, C2-6 alkenyl, C1-6 alkoxy, C1-6 alkyl, C1-6 alkylcarboxamide, C2-6 alkynyl, C1-6 alkylsulfonamide, C1-6 alkylsulfmyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C1-6 alkylureyl, amino, Ci-6 alkylamino, C2-S dialkylamino, carbo-Ci-6-alkoxy, carboxamide, carboxy, cyano, C3-7 cycloalkyl, C2-8 dialkylcarboxamide, C2-8 dialkylsulfonamide, halogen, C1-6 haloalkoxy, C1-6 haloalkyl, C1-6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, C1-6 haloalkylthio, hydroxyl, thiol, nitro, and sulfonamide; and
R4 and R5 are each independently selected from the group consisting of H, C1-6 alkyl, C2- β alkenyl, C2-6 alkynyl, and C3-7 cycloalkyl, and wherein each of said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-7 cycloalkyl groups are optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected independently from the group consisting Of Ci-6 acyl, Ci-6 acyloxy, C2-6 alkenyl, Ci-6 5 alkoxy, Ci-6 alkyl, Ci-6 alkylcarboxamide, C2-6 alkynyl, C1-6 alkylsulfonamide, C1-6 alkylsulfmyl, C1-6 alkylsulfonyl, C1-6 alkylthio, Ci-6 alkylureyl, amino, Ci-6 alkylamino, C2-8 dialkylamino, carbo-Ci-6-alkoxy, carboxamide, carboxy, cyano, C3-7 cycloalkyl, C2-8 dialkylcarboxamide, C2-8 dialkylsulfonamide, halogen, Ci-6 haloalkoxy, Ci-6 haloalkyl, C]-6 haloalkylsulfinyl, Ci-6 haloalkylsulfonyl, Ci-6 haloalkylthio, hydroxyl, thiol, nitro, and sulfonamide; or 0 R4 and R5 together with the nitrogen atom to which they are both bonded form a C3-7 heterocyclyl or C5-I0 heterobicyclyl group optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected independently from the group consisting Of Ci-6 acyl, C1-6 acyloxy, C2-6 alkenyl, Ci-6 alkoxy, Ci-6 alkyl, Ci-6 alkylcarboxamide, C2-6 alkynyl, Ci-6 alkylsulfonamide, C1-6 alkylsulfmyl, C1-6 alkylsulfonyl, C1-6 alkylthio, Ci-6 alkylureyl, amino, Ci-6 alkylamino, C2-8 5 dialkylamino, carbo-C1-6-alkoxy, carboxamide, carboxy, cyano, C3-7 cycloalkyl, C2-8 dialkylcarboxamide, C2-8 dialkylsulfonamide, halogen, C1-6 haloalkoxy, C1-6 haloalkyl, Ci-6 p r T / i| 1 FiIIl iFii / «4.114.14.7 "1,
"'"halόallcylsulfinyl, Ci-6 haloalkylsulfonyl, C1-6 haloalkylthio, hydroxyl, thiol, nitro, and sulfonamide, and said C)-6 alkyl, is optionally substituted with hydroxyl.
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 modulating the activity of a
H3 receptor by contacting the receptor with a compound according to any of the embodiments described herein or a pharmaceutical composition.
One aspect of the present invention pertains to methods for treating H3 -receptor associated disorders in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound according to any of the embodiments described herein or a pharmaceutical composition thereof.
One aspect of the present invention pertains to methods for treating H3 -receptor associated disorders selected from the group consisting of cognitive disorders, epilepsy, depression, narcolepsy, obesity, motion sickness, vertigo, a sleep/wake disorder, insomnia, jet lag, sleep apnea, attention deficit hyperactivity disorder (ADHD), schizophrenia, allergies, allergic responses in the upper airway, allergic rhinitis, bipolar disorders, manic disorders, neurogenic inflammation, migraine, eating disorders, dementia, and Alzheimer's disease in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound according to any of the embodiments described herein or a pharmaceutical composition thereof.
One aspect of the present invention pertains to methods for treating sleep/wake disorders in an individual comprising administering to the individual in need thereof a therapeutically effective amount of a compound according to any of the embodiments described herein 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 according to any of the embodiments described herein or a pharmaceutical composition thereof.
One aspect of the present invention pertains to the use of compounds according to any of the embodiments described herein for production of a medicament for use in the treatment of a H3 -receptor associated disorder.
One aspect of the present invention pertains to the use of compounds according to any of the embodiments described herein for production of a medicament for use in the treatment of a H3-receptor associated disorder is selected from the group consisting of cognitive disorders, epilepsy, depression, narcolepsy, obesity, motion sickness, vertigo, a sleep/wake disorder, insomnia, jet lag, sleep apnea, attention deficit hyperactivity disorder (ADHD), schizophrenia, allergies, allergic responses in the upper airway, allergic rhinitis, bipolar disorders, manic dTiso/rdJeUrsS, neαurBoge/ni.Nch inNfblaiHmI"7ma9tion, mi .grai .ne, ea .ti.ng d Ai.sord ,ers, d ,emen +ti.a, and A A A1lz ,hei .mer , s disease.
One aspect of the present invention pertains to the use of compounds according to any of the embodiments described herein for production of a medicament for use in the treatment of sleep/wake disorders.
One aspect of the present invention pertains to the use of compounds according to any of the embodiments described herein for production of a medicament for use in inducing wakefulness.
One aspect of the present invention pertains to compounds according to any of the embodiments described herein for use in a method of treatment of the human or animal body by therapy.
One aspect of the present invention pertains to compounds according to any of the embodiments described herein for use in a method of treatment of a H3 -receptor associated disorder in the human or animal body by therapy. One aspect of the present invention pertains to compounds according to any of the embodiments described herein for use in a method of treatment of a H3 -receptor associated disorder selected from the group consisting of cognitive disorders, epilepsy, depression, narcolepsy, obesity, motion sickness, vertigo, a sleep/wake disorder, insomnia, jet lag, sleep apnea, attention deficit hyperactivity disorder (ADHD), schizophrenia, allergies, allergic responses in the upper airway, allergic rhinitis, bipolar disorders, manic disorders, neurogenic inflammation, migraine, eating disorders, dementia, and Alzheimer's disease in the human or animal body by therapy.
One aspect of the present invention pertains to compounds according to any of the embodiments described herein for use in a method of treatment of a sleep/wake disorder in the human or animal body by therapy.
One aspect of the present invention pertains to compounds according to any of the embodiments described herein for use in a method for inducing wakefulness 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 according any embodiments described herein and 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
The variables described in the figures herein have the same definitions as described throughout this disclosure with the exception, Ra at each occurrence is independently Ci-6 alkyl, Rb i Ts e/ithe Wr aB pr Oote Bcti /ng iH gMro4uJpI+ (i7.e.', 9 PG]) or Rb is Ri as described herein, and PG2 is a protecting group which can be the same or different compared to PGj.
Protecting groups may be required for various functionality or functionalities during the synthesis of some of the compounds of the invention. In certain reactions, use of a suitable nitrogen protecting group (such as, benzyl, Boc, Cbz, Moz, Alloc, Fmoc and the like) may be necessary during further chemical modification of the core. Deprotection can be achieved using standard reagents familiar to one skilled in the art (these might include TFA, a mineral acid, Palladium/hydrogen gas and the like in an alcoholic or ethereal solvent system chosen from methanol, ethanol, fert-butanol, TBF, 1,4-dioxane, and the like). On occasion wherein the target molecule contains 2 protecting groups, an orthogonal protection strategy may be adopted.
Representative protecting groups that are suitable for a wide variety of synthetic transformations are disclosed in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York, 1999, the disclosure of which is incorporated herein by reference in its entirety. Figure 1 shows the general synthetic scheme for the preparation of compounds of the present invention. Figure 1 illustrates a general method for preparing compounds of the present invention with a variety of groups.
Figure 2 shows the general synthetic scheme for the preparation of compounds of the present invention. Figure 2 illustrates a general method for preparing compounds of the present invention wherein the NR4R5 group is introduced in the last step.
Figure 3 shows the general synthetic schemes for the preparation of compounds of the present invention. Figure 3 illustrates general methods for preparing compounds of the present invention comprising deprotection and the introduction of -D-R1 group in the last step. It is understood that protection of the 3° alcohol may be necessary for compounds of Formula N prior to introducing the -D-R1 group, for example, Methods B, C, D, E, or F.
Figure 4 shows the general synthetic schemes for the preparation of compounds of the present invention. Figure 4 illustrates the general methods for preparing compounds of the present invention using Method B (reductive animation using, for example, an aldehyde or a ketone), Method C (amide and carbamate formation using, using for example, an acid chloride or a chloroformate respectively) and Method D (urea formation using, for example, an isocyanate).
Figure 5 shows the general synthetic schemes for the preparation of compounds of the present invention. Figure 5 illustrates the general methods for preparing compounds of the present invention using Method E (arylation or heteroarylation using, for example, an aryl/heteroaryl-halide with a base, such as, potassium ^-butoxide under microwave irradiation conditions) and Method F (amide formation using, using for example, a carboxylic acid and a coupling reagent, such as, DCC). Figure 6 snows a general synthetic scheme for prepaπng compounds of the present invention via a Suzuki reaction. The cyclic ketone B is converted in three steps to the corresponding halide. This is coupled with an aryl boronic acid prepared from an aryl halide.
Figure 7 shows four general methods for preparing compounds of the present invention. The first method involves the reaction of a secondary bicyclic amine with an alkyl moiety bearing a leaving group to form a tertiary amine. The second method involves the reaction of a secondary bicyclic amine with a carboxylic acid in the presence of a coupling agent such as HATU to form an amide. The third method involves the reaction of a secondary bicyclic amine with a sulfonyl chloride to form a sulfonamide. The last method involves the oxidation of an amine to form an amine-oxide.
Figure 8 shows two general methods for preparing intermediates of compounds of the present invention. The first method involves reaction of a bicyclic ketone with a strong base and an alkyl halide to alkylate the bicyclic ketone at the α-position. The second method involves the Suzuki reaction of a bicyclic vinyl triflate with a boronic acid.
DEFINITIONS:
The term "agonists" is intended to mean moieties that interact and activate the receptor, such as the H3 receptor, and initiates 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 "Ci-6 acyl" is intended to mean a Ci-6 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, isø-butanoyl, pivaloyl, pentanoyl, hexanoyl and the like. The term "Cj-6 acyloxy" is intended to mean an acyl radical attached to an oxygen atom wherein acyl has the same definition as described herein; some embodiments are when acyloxy is Ci-5 acyloxy, some embodiments are when acyloxy is Ci-4 acyloxy. Some examples include, but are not limited to, acetyloxy, propionyloxy, w-butanoyloxy, zso-butanoyloxy, pivaloyloxy, pentanoyloxy, hexanoyloxy and the like. The term "C2-6 alkenyl" is intended to mean a radical containing 2 to 6 carbons wherein at least one carbon-carbon double bond is present, 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 afe'emtfra'ceα 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-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexanyl, 2,4-hexadienyl and the like.
The term "Ci-6 alkoxy" is intended to mean an 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, ra-propoxy, ώo-propoxy, H-butoxy, Z-butoxy, ώo-butoxy, sec-butoxy and the like.
The term "C1-6 alkyl" is intended to mean a straight or branched carbon radical containing 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, «-propyl, zso-propyl, H-butyl, sec-butyl, iso-butyl, ^-butyl, pentyl, ώø-pentyl, r-pentyl, røeø-pentyl, 1-methylbutyl [i.e.,
-CH(CH3)CH2CH2CH3], 2-methylbutyl [i.e., -CH2CH(CH3)CH2CH3], w-hexyl and the like.
The term "Ci-6 alkylcarboxamido" or "C1-6 alkylcarboxamide" is intended to mean a single Q-6 alkyl group attached to either the carbon or the nitrogen of an amide group, wherein alkyl has the same definition as found herein. The Cj-6 alkylcarboxamido may be represented by the following:
O O
% N N C1-6 alkyl
Examples include, but are not limited to, N-methylcarboxamide, N-ethylcarboxamide, N-n- propylcarboxamide, N- zso-propylcarboxamide, N-«-butylcarboxamide, N-sec- butylcarboxamide, N- zsø-butylcarboxamide, N-r'-butylcarboxamide and the like. The term "C1-4 alkylene" is intended to mean a Ci-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. In some embodiments alkylene refers to, for example, -CH2-, -CH2CH2-, - CH2CH2CH2-, and/or -CH2CH2CH2CH2-.
The term "C1-4 alkylene-aryl" is intended to mean a CM alkylene group bonded to an aryl group, each as defined herein. In some embodiments Cj-4 alkylene-aryl refers to, for example, benzyl (-CH2-phenyl), phenylethyl (-CH2CH2-phenyl), and the like.
The term "C1-4 alkylene-C3-7-cycloalkyl" is intended to mean a Ci-4 alkylene group bonded to a C3-7-cycloalkyl group, each as defined herein. In some embodiments Ci-4 alkylene- ,,,,,j . y JjJ1 g pr y j!+L|.!!,,|,7- g| '" C3-7-cycl6alκyl refers to, for example, cyclopropylmethyl (-CH^cyclopropyl), cyclopropylethyl
(-CH2CH2-CyCIoPrOPyI), cyclobutylmethyl (-CH2-cyclobutyl), and the like.
The term "C1-4 alkylene-heteroaryl" is intended to mean a Ci-4 alkylene group bonded to a heteroaryl group, each as defined herein. In some embodiments Q-4 alkylene-heteroaryl refers to, for example, pyridinylmethyl (-CH2-pyridinyl) and the like.
The term "C1-6 alkylsulfinyl" is intended to mean a Ci-6 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, methylsulfϊnyl, ethylsulfinyl, w-propylsulfinyl, zsø-propylsulfinyl, w-butylsulfinyl, sec-butylsulfinyl, iso- butylsulfinyl, ^-butylsulfinyl, and the like.
The term "C1-6 alkylsulfonamide" is intended to mean the groups shown below:
alkyl
Figure imgf000011_0001
wherein Ci-6 alkyl has the same definition as described herein.
The term "Ci-6 alkylsulfonyl" is intended to mean a Ci-6 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, zsø-propylsulfonyl, κ-butylsulfonyl, sec-butylsulfonyl, iso- butylsulfonyl, £-butylsulfonyl, and the like.
The term "Ci-6 alkylthio" is intended to mean a Ci-6 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, ra-propylsulfanyl, iso- propylsulfanyl, ra-butylsulfanyl, sec-butylsulfanyl, zsø-butylsulfanyl, r-butylsulfanyl, and the like.
The term "Ci-6 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 Ci-6 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-, (CH3)2NC(O)NH-, (CH3)2NC(O)NCH3-, CH3CH2NHC(O)NH-, CH3CH2NHC(O)NCH3-, and the like.
The term "C2-6 alkynyl" is intended to mean a radical containing 2 to 6 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-pentynyl, 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 C1-6 alkylammo 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 not limited to, methylamino, ethylamino, /z-propylamino, z-sø-propylamino, n- butylamino, see-butylamino, zso-butylamino, f-butylamino, and the like. Some embodiments are "C1-2 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 C4-7 cycloalkyl or C4-7 cycloalkenyl group together with a C4-7 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 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-C1-6-alkoxy" is intended to mean a C1-6 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], carboethoxy, carbopropoxy, carboisopropoxy, carbobutoxy, carbo-sec-butoxy, carbo-zsobutoxy, carbo-r'-butoxy, carbo-n-pentoxy, carbo-zsø-pentoxy, carbo- f-pentoxy, carbo-neø-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 "C4-7 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 to 6 carbons; some embodiments contain 4 to 5 carbons; some embodiments contain 4 carbons. Examples include cyclobutenyl, cyclopentenyl, cyclopentenyl, cyclohexenyl, and the like.
The term "C3-7 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.
The term "C2-8 dialkylamino" is intended to mean an amino substituted with two of the same or different Ci-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 "C2-4 dialkylamino." f /i| ILSOR /4-4'"4'7 ^ ' " The term "C2-8 dialkylcarboxamido" or "C2-8 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 C2-8 dialkylcarboxamido may be represented by the following groups:
Figure imgf000013_0001
wherein Ci-4 has the same definition as described herein. Examples of a dialkylcarboxamide include, but are not limited to, N,N-dimethylcarboxamide, N-methyl-N-ethylcarboxamide, N,N- diethylcarboxamide, N-methyl-N-isopropylcarboxamide, and the like.
The term "C2-8 dialkylsulfonamide" is intended to mean one of the following groups shown below:
Figure imgf000013_0002
wherein Ci-4 has the same definition as described herein, for example but not limited to, methyl, ethyl, «-propyl, isopropyl, and the like.
The term "C2-8 dialkylthiocarboxamido" or "C2-8 dialkylthiocarboxamide" is intended to mean two alkyl radicals, that are the same or different, attached to a thioamide group, wherein alkyl has the same definition as described herein. A C2-8 dialkylthiocarboxamido or C2-8 dialkylthiocarboxamide may be represented by the following groups:
S S
<£ Ν Ν C1-4 alkyl
C1-4 alkyl Ci-4 alkyl Examples of a dialkylthiocarboxamide include, but are not limited to, NN- dimethylthiocarboxamide, N-methyl-N-ethylthiocarboxamide and the like.
The term "Ci-6 haloalkoxy" is intended to mean a Ci-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. The term "Ci-6 haloalkyl" is intended to mean an Ci-6 alkyl group, defined herein, wherein the alkyl is substituted with one halogen up to fully substituted and a fully substituted Ci-6 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, Et, ξ f / u^ f]i IR1 ./ 114,114.114.79
""'fluόrorfiemyX αifluoromethyl, trifluoromethyl, chlorodifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl and the like.
The term "Cj-6 haloalkylsulfinyl" is intended to mean a C1-6 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, trifluoromethylsulfmyl, 2,2,2-trifluoroethylsulfϊnyl, 2,2-difluoroethylsulfinyl and the like.
The term "Ci-6 haloalkylsulfonyl" is intended to mean a Ci-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. The term "Ci-6 haloalkylthio" is intended to mean a Cj-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, trifluoromethylthio (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-4 acyl or Ci-4 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 Η (i.e., NH), examples include, but are not limited to, pyrrolyl, indolyl, lH-benzoimidazol-2-yl, and the like. Other examples include, but are not limited to, those in TABLES A-E, and the like.
The term "C5-I0 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 are not limited to, the group consisting of O, S, S(=O), S(=O)2, and NH, wherein the nitrogen can be optionally substituted, and 1 or 2 ring carbons can be optionally substituted with oxo or thiooxo thus together form a carbonyl or thiocarbonyl group respectively. 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 "C3-7 heterocyclic" or "C3-7 heterocyclyl" is intended to mean a non-aromatic carbon ring (i.e., C3-7 cycloalkyl or C4-7 cycloalkenyl as defined herein) wherein one, two or three ring carbons are replaced by a heteroatom selected from, but are not limited to, the group ip> f " x / ij || s O B / NHLiJ+'7 "3
'* '"' consisting of O, S, S(=O), S(=O)2, NH, wherein the N can be optionally substituted as described herein, in some embodiments, the nitrogen is optionally substituted with C1-4 acyl or Ci-4 alkyl, and ring carbon atoms 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-, A-, 5-, 6- or 7-membered containing 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, piperzin-1-yl, piperzin-2-yl, piperzin-3-yl, piperzin-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, [1,3]- dioxolan-2-yl, thiomorpholin-4-yl, [l,4]oxazepan-4-yl, l,l-dioxo-lλδ-thiomorpholin-4-yl, azepan-1-yl, azepan-2-yl, azepan-3-yl, azepan-4-yl, tetrahydro-furan-2-yl, tetrahydro-furan-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 C6H5-. The term "sulfonamide" is intended to mean the group -SO3NH2. The term "thiol" is intended to mean the group -SH.
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 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 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 H3 receptor.
The term "in need of treatment" is intended 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. p IF r / uis o Hi / |Nm-i|+79
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 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 Formula (Ia); 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).
COMPOUNDS OF THE INVENTION: One aspect of the present invention pertains to certain compounds as shown in Formula
Figure imgf000017_0001
(Ia) or a pharmaceutically acceptable salt, hydrate or solvate thereof; wherein Ri, Ra, R3, R4, R5, D, E, G, J, K and Ar have the same definitions as described herein, supra and infra.
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, D, E, G, J, K and Ar) 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). In addition, all subcombinations of the chemical groups listed in the embodiments describing such variables, as well as all subcombinations of uses and medical indications described herein, are also specifically embraced by the present invention just as if each of such subcombination of chemical groups and subcombination 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. PC T/ UBDB/ W}Wc7 % n . . . .. . + fi . . ,
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 there from 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. Li 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. In another embodiment, compounds of the present invention have four stereochemical centers wherein three stereochemical centers are as described previously and the fourth stereochemical center is S. In another embodiment, compounds of the present invention have four stereochemical centers wherein three stereochemical centers are as described previously and the fourth stereochemical center is R. In another embodiment, compounds of the present invention have five stereochemical centers wherein four stereochemical centers are as described previously and the fifth stereochemical center is S. In another embodiment, compounds of the present invention have five stereochemical centers wherein four stereochemical centers are as described previously and the fifth 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 encompasses N-oxides of compounds of Formula (Ia).
In some embodiments, E is C(R8R9).
In some embodiments, R8 and R9 are each H. In some embodiments the present invention pertains to certain compounds as shown in the following Formula (Ic):
Figure imgf000019_0001
(Ic) wherein each variable in Formula (Ic) has the same meaning as described herein, supra and infra.
In some embodiments, G is CR7 and - - is a single bond; wherein R7 is H or OH.
In some embodiments the present invention pertains to certain compounds as shown in the following Formula (Ie):
Figure imgf000019_0002
(Ie) wherein each variable in Formula (Ie) has the same meaning as described herein, supra and infra. In some embodiments, G is C and - - is a double bond.
In some embodiments the present invention pertains to certain compounds as shown in the following Formula (Ig):
Figure imgf000019_0003
(Ig) wherein each variable in Formula (Ig) has the same meaning as described herein, supra and infra.
In some embodiments, E is C(RV)C(R10R11).
In some embodiments the present invention pertains to certain compounds as shown in the following Formula (Ii):
Figure imgf000020_0001
(Ii) wherein each variable in Formula (Ii) has the same meaning as described herein, supra and infra.
In some embodiments, R10, and R11 are each H. In some embodiments, R8, R9, R10, and R11 are each H.
In some embodiments, G is CR7 an _^÷_ is a single bond; wherein R7 is H or OH. In some embodiments the present invention pertains to certain compounds as shown in the following Formula (Ik):
Figure imgf000020_0002
(Ik) wherein each variable in Formula (Ik) has the same meaning as described herein, supra and infra.
In some embodiments, G is C and — is a double bond.
In some embodiments the present invention pertains to certain compounds as shown in the following Formula (Im):
Figure imgf000020_0003
wherein each variable in Formula (Im) has the same meaning as described herein, supra and infra.
In some embodiments, D is S(=O)2.
Li some embodiments, D is C(=O). In some embodiments the present invention pertains to certain compounds as shown in the following Formula QLo): P CT,/" IJi SO IB / NMM
Figure imgf000021_0001
Qfo) wherein each variable in Formula (Io) has the same meaning as described herein, supra and infra.
In some embodiments, D is OC(=O). In some embodiments, D is NHC(=O).
In some embodiments, D is absent. In some embodiments, J is O. In some embodiments, J is S, S(=O), or S(=0)2. In some embodiments, J is NR12, wherein R12 is H or Ci-6 alkyl. In some embodiments, J is absent.
In some embodiments, K is the same as described herein for compounds of Formula (Ia) and/or subgenera thereof, provided that when K is substituted with oxo, then the carbon of the resulting carbonyl group is not directly bonded to the nitrogen of the NR4R5 group.
In some embodiments, K is C1-4 alkylene optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 substituents selected independently from the group consisting of Cu alkyl, Ci-4 alkoxy, carboxy, cyano, Ci-3 haloalkyl, halogen, and hydroxyl. In some embodiments, K is -CH2CH2-.
In some embodiments, R1 is selected from the group consisting of H, Ci-6 alkyl, C3-7 cycloalkyl, Ci-4 alkylene-C3-7-cycloalkyl, aryl, Q-4 alkylene-aryl, heteroaryl, and Ci-4 alkylene- heteroaryl, and each of said Ci-6 alkyl and Ci-4 alkylene-aryl, groups are optionally substituted with 1 or 2 substituents selected independently from the group consisting OfCi-6 alkoxy, Ci-6 alkyl, amino, Ci-6 alkylamino, C2-s dialkylamino, C3-7 cycloalkyl, formyl, halogen, C1-6 haloalkoxy, C1-6 haloalkyl, and hydroxyl.
In some embodiments, R1 is selected from the group consisting of H, Ci-6 alkyl, C3-7 cycloalkyl, Ci-4 alkylene-C3-7-cycloalkyl, aryl, Ci-4 alkylene-aryl, heteroaryl, and C1-4 alkylene- heteroaryl, and each of said Ci-6 alkyl and C1-4 alkylene-aryl, groups are optionally substituted with 1 or 2 substituents selected independently from the group consisting of C1-6 alkoxy, C1-6 alkyl, amino, C1-6 alkylamino, C2-g dialkylamino, C3-7 cycloalkyl, halogen, C1-6 haloalkoxy, C1-6 haloalkyl, and hydroxyl. In some embodiments, R1 is selected from the group consisting of H, benzyl, cyclopropylmethyl, isobutyl, isopropyl, 4-trifluoromethoxy-benzyl, 2,4-dimethoxy-benzyl, cyclohexyl, cyclopentyl, methyl, ethyl, t-butyl, 4-methoxy-benzyl, 4-trifluoromethylbenzyl, cyclobutyl, 3-hydroxy-prop-2-yl, 4-hydroxy-benzyl, cyclopropyl, phenyl, pyπdm-2-yl, hydroxymethyl, tetrahydro-furan-3-yl, tetrahydropyran-4-yl, pyridin-3-yl, pyrazin-2-yl, 2- fluoroethyl, trifluoromethyl, thiophen-2-ylmethyl, tetrahydropyran-4-ylmethyl, pyrimadin-5-yl, methoxymethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-hydroxypropan-2-yl, cyclopentylmethyl, thiophen-2-yl, pyridin-4-yl, furan-2-yl, morpholin-4-yl, 3-formylphenyl, thiazol-2-yl, pyrimadin-2-yl, isoxazol-5-yl, 3,5-difluorophenyl, 3-cyanophenyl, 6- trifluoromethylpyridin-3-yl, and 6-cyanopyridin-3-yl.
In some embodiments, R1 is selected from the group consisting of H, benzyl, cyclopropylmethyl, isobutyl, isopropyl, 4-trifluoromethoxy-benzyl, 2,4-dimethoxy-benzyl, cyclohexyl, cyclopentyl, methyl, ethyl, t-butyl, 4-methoxy-benzyl, cyclobutyl, 3-hydroxy-prop- 2-yl, 4-hydroxy-benzyl, cyclopropyl, phenyl, pyridin-2-yl, hydroxymethyl and tetrahydro-furan- 3-yl.
In some embodiments, R2 is H or Ci-6 alkyl
Ih some embodiments, R2 is H or methyl. In some embodiments, R2 is H.
In some embodiments, R4 and R5 are each independently H or Q-6 alkyl; or
R4 and R5 together with the nitrogen atom to which they are both bonded form a C3..7 heterocyclyl or C5-10 heterobicyclyl optionally substituted with 1 or 2 substituents selected independently from the group consisting of Cj-S alkyl, halogen, hydroxyl, oxo and phenyl; and said Ci-6 alkyl, is optionally substituted with 1 or 2 substituents selected independently from C1-6 alkoxy and hydroxyl.
Li some embodiments, R4 and R5 are each independently H or Ci-6 alkyl; or
R4 and R5 together with the nitrogen atom to which they are both bonded form a C3-7 heterocyclyl or C5-I0 heterobicyclyl optionally substituted with 1 or 2 substituents selected independently from the group consisting OfCi-6 alkyl, halogen, and hydroxyl; and said C1-6 alkyl, is optionally substituted with hydroxyl.
In some embodiments, R4 and R5 are each independently H, methyl or isopropyl.
In some embodiments, R4 and R5 are each independently H or methyl.
In some embodiments, R4 and R5 together with the nitrogen atom to which they are both bonded form a group selected from the group consisting of pyrrolidin-1-yl, 2-methyl-pyrrolidin- 1-yl, 2-methyl-piperidin-l-yl, 4-methyl-piperazin-l-yl, 2,5-dimethyl-pyrrolidin-l-yl, dimethyl- amino, 2,2-dimethyl-pyrrolidin-l-yl, morpholin-4-yl, 2-hydroxymethyl-pyrrolidin-l-yl, 3- hydroxy-pyrrolidin-1-yl, 3,3-difluoro-pyrrolidin-l-yl, azetidin-1-yl, 3,3-difluoro-piperidin-l-yl, 2,3-dihydro-isoindol-2-yl, 3,4-dihydro-lH-isoquinolin-2-yl, 2,3-dihydro-indol-l-yl, 2- methoxymethyl-pyrrolidin- 1 -yl, 2-carbamoylpyrrolidin- 1 -yl, 2-(methylcarbamoyl)pyrrolidin- 1 - yl, piperidin-1-yl, 2-oxopyrrolidin-l-yl, 3-phenylpyrrolidin-l-yl, 2-isopropylpyrrolidin-l-yl, 2- trifluoromethylpyrrolidin-1-yl, and 2-phenylpyrrolidin-l-yl. ,lf !„„„ ..|, ^. j| J ^u Ig1 y ii,,|,,u,,jj,,|L,||,,";;ii' g In some embodiments, R4 and R together with the nitrogen atom to which they are both bonded form a group selected from the group consisting of pyrrolidin-1-yl, 2-methyl-pyrrolidin- 1-yl, 2-methyl-piperidin-l-yl, 4-methyl-piperazin-l-yl, 2,5-dimethyl-pyrrolidin-l-yl, dimethyl- amino, 2,2-dimethyl-pyrrolidin-l-yl, morpholin-4-yl, 2-hydroxymethyl-pyrrolidin-l-yl, 3- hydroxyl-pyrrolidin-1-yl, 3,3-difluoro-pyrrolidin-l-yl, azetidin-1-yl, 3,3-difluoro-piperidin-l-yl, 2,3-dihydro-isoindol-2-yl, 3,4-dihydro-lH-isoquinolin-2-yl, 2,3-dihydro-indol-l-yl, and amino.
In some embodiments, Ar is 1,4-phenylene, 1,3-phenylene or 2,5-pyridinylene.
In some embodiments, the present invention pertains to certain 3-phenyl-pyrazole derivatives as shown in Formula (Ia):
Figure imgf000023_0001
0») or a pharmaceutically acceptable salt, hydrate or solvate thereof; wherein:
D is C(O), OC(O), NR6C(O), S(O)2, or absent, wherein R6 is H or CH3;
G is CR7 or C, provided that when G is CR7 then - - is a single bond, wherein R3 is H and R7 is H or OH, and when G is C then - - is a double bond and R3 is absent; R2 is H or methyl;
E is -CH2- or -CH2CH2-;
J is O or absent;
K is -CH2CH2-;
R1 is selected from the group consisting of H, benzyl, cyclopropylmethyl, isobutyl, isopropyl, 4-trifluoromethoxy-benzyl, 2,4-dimethoxy-benzyl, cyclohexyl, cyclopentyl, methyl, ethyl, t-butyl, 4-methoxy-benzyl, 4-trifluoromethylbenzyl, cyclobutyl, 3-hydroxy-prop-2-yl, 4- hydroxy-benzyl, cyclopropyl, phenyl, pyridin-2-yl, hydroxymethyl, tetrahydiO-furan-3-yl, tetrahydropyran-4-yl, pyridin-3-yl, pyrazin-2-yl, 2-fluoroethyl, trifluoromethyl, thiophen-2- ylmethyl, tetrahydropyran-4-ylmethyl, pyrimadin-5-yl, methoxymethyl, 2,2-difluoroethyl, 2,2,2- trifluoroethyl, 2-hydroxypropan-2-yl, cyclopentylmethyl, thiophen-2-yl, pyridin-4-yl, furan-2-yl, morpholin-4-yl, 3-formylphenyl, thiazol-2-yl, pyrimadin-2-yl, isoxazol-5-yl, 3,5-difluorophenyl, 3-cyanophenyl, 6-trifluoromethylpyridin-3-yl, and 6-cyanopyridin-3-yl;
R4 and R5 are each independently H, methyl or isopropyl; or
R4 and R5 together with the nitrogen atom to which they are both bonded form a group selected from the group consisting of pyrrolidin-1-yl, 2-methyl-pyrrolidin-l-yl, 2-methyl- piperidin-l-yl, 4-methyl-piperazin-l-yl, 2,5-dimethyl-pyrrolidin-l-yl, dimethyl-amino, 2,2- dimethyl-pyrrolidin-l-yl, morpholin-4-yl, 2-hydroxymethyl-pyrrolidin-l-yl, 3-hydroxy- pyrrolidin-1-yl, 3,3-difluoro-pyrrolidin-l-yl, azetidin-1-yl, 3,3-difluoro-piperidin-l-yl, 2,3- ,...,,, ,,..„ ».|p ,,.. J! I ,!;;;■. |"jj |:;» / |j,,|U|,,|[,, ||,,jjπ '"H' Cjj
1H u'dmydrδ-iiomdδl-2-yl, 3;4-dihydro-lH-isoquinolin-2-yl, 2,3-dihydro-indol-l-yl, 2- methoxymethyl-pyrrolidin-1-yl, 2-carbamoylpyrrolidin-l-yl, 2-(methylcarbamoyl)pyrrolidin-l- yl, piperidin-1-yl, 2-oxopyrrolidin-l-yl, 3-phenylpyrrolidin-l-yl, 2-isopropylpyrrolidin-l-yl, 2- trifluoromethylpyrrolidin-1-yl, and 2-phenylpyrrolidin-l-yl; and Ar is 1,4-phenylene, 1,3-phenylene or 2,5-pyridinylene.
In some embodiments, the present invention pertains to certain 3-phenyl-ρyrazole derivatives as shown in Formula (Iq):
Figure imgf000024_0001
(iq) or a pharmaceutically acceptable salt, hydrate or solvate thereof; wherein:
D is C(=O), OC(=O), NR6C(=O), or absent, wherein R6 is H or CH3; G is CR7 or C, provided that when G is CR7 then - - is a single bond, wherein R3 is H and R7 is H or OH, and when G is C then - - is a double bond and R3 is absent;
E iS -CH2- Or -CH2CH2-; J is O or absent;
K is -CH2CH2-;
R1 is selected from the group consisting of H, benzyl, cyclopropylmethyl, isobutyl, isopropyl, 4-trifluoromethoxy-benzyl, 2,4-dimethoxy-benzyl, cyclohexyl, cyclopentyl, methyl, ethyl, t-butyl, 4-methoxy-benzyl, cyclobutyl, 3-hydroxy-prop-2-yl, 4-hydroxy-benzyl, cyclopropyl, phenyl, pyridin-2-yl, hydroxymethyl and tetrahydro-furan-3-yl;
R4 and R5 together with the nitrogen atom to which they are both bonded form a group selected from the group consisting of pyrrolidin-1-yl, 2-methyl-pyrrolidin-l-yl, 2-methyl- piperidin-1-yl, 4-methyl-piperazin-l-yl, 2,5-dimethyl-pyrrolidin-l-yl, dimethyl-amino, 2,2- dimethyl-pyrrolidin-1-yl, morpholin-4-yl, 2-hydroxymethyl-pyrrolidin-l-yl, 3-hydroxyl- pyrrolidin-1-yl, 3,3-difluoro-pyrrolidin-l-yl, azetidin-1-yl, 3,3-difluoro-piperidin-l-yl, 2,3- dihydro-isoindol-2-yl, 3,4-dihydro-lH-isoquinolin-2-yl, 2,3-dihydro-indol-l-yl, and amino; and Ar is 1,4-phenylene, 1,3-phenylene or 2,5-pyridinylene.
In some embodiments, the present invention pertains to certain 3-phenyl-pyrazole derivatives as shown in Formula (Is):
Figure imgf000025_0001
(Is) or a pharmaceutically acceptable salt, hydrate or solvate thereof; wherein:
D is C(=O), OC(=O), or absent; R7 is H or OH;
J is O or absent; K is -CH2CH2-;
R1 is selected from the group consisting of H, benzyl, cyclopropylmethyl, isobutyl, isopropyl, 4-trifluoromethoxy-ben2yl, 2,4-dimethoxy-benzyl, cyclohexyl, cyclopentyl, methyl, ethyl, t-butyl, 4-methoxy-benzyl, cyclobutyl, 3-hydroxy-prop-2-yl, 4-hydroxy-benzyl, cyclopropyl, hydroxymethyl and tetrahydro-furan-3-yl;
R4 and R5 together with the nitrogen atom to which they are both bonded form a group selected from the group consisting of pyrrolidin-1-yl and 2-methyl-pyrrolidin-l-yl; and Ar is 1,4-phenylene or 2,5-pyridinylene.
In some embodiments, the present invention pertains to certain 3-phenyl-pyrazole derivatives as shown in Formula (Iu):
Figure imgf000025_0002
σ«) or a pharmaceutically acceptable salt, hydrate or solvate thereof; wherein:
D is C(=O), OC(=O), NHC(=O), or absent; J is O or absent; K iS -CH2CH2-;
R1 is selected from the group consisting of H, benzyl, cyclopropylmethyl, isobutyl, isopropyl, 4-trifluoromethoxy-benzyl, 2,4-dimethoxy-benzyl, cyclohexyl, cyclopentyl, methyl, ethyl, 4-methoxy-benzyl, cyclobutyl, 3-hydroxy-prop-2-yl, 4-hydroxy-benzyl, cyclopropyl, phenyl, pyridin-2-yl, hydroxymethyl and tetrahydro-furan-3-yl;
R4 and R5 together with the nitrogen atom to which they are both bonded form a group selected from the group consisting of pyrrolidin-1-yl, 2-methyl-pyrrolidin-l-yl, 2-methyl- piperidin-1-yl, 4-methyl-piperazin-l-yl, 2,5-dimethyl-pyrrolidin-l-yl, dimethyl-amino, 2,2- P CTV" U Si Ol IB/ IMl-NhNl":/'' 9
" '" dimethyl-pyrrolidin-l-yt, morpholin-4-yl, 2-hydroxymethyl-pyrrolidin-l-yl, 3-hydroxyl- pyrrolidin-1-yl, 3,3-difluoro-pyrrolidin-l-yl, azetidin-1-yl, 3,3-difluoro-piperidin-l-yl, 2,3- diliydro-isoindol-2-yl, 3,4-dihydro-lH-isoquinolin-2-yl, 2,3-dihydro-indol-l-yl, and amino; and
Ar is 1,4-phenylene, 1,3-phenylene or 2,5-pyridinylene. In some embodiments, the present invention pertains to certain 3-phenyl-pyrazole derivatives as shown in (Iw):
Figure imgf000026_0001
(Iw) or a pharmaceutically acceptable salt, hydrate or solvate thereof; wherein: D is C(=O) or NR6C(=O), wherein R6 is H or CH3;
R7 is H or OH;
J is absent;
K is -CH2CH2-;
R1 is selected from the group consisting of H, isopropyl, cyclopentyl, methyl, or cyclopropyl;
R4 and R5 together with the nitrogen atom to which they are both bonded form pyrrolidin-1-yl; and
Ar is 1,4-phenylene.
In some embodiments, the present invention pertains to certain 3-phenyl-pyrazole derivatives as shown in Formula (Iy):
Figure imgf000026_0002
(iy) or a pharmaceutically acceptable salt, hydrate or solvate thereof; wherein:
D is C(O) or NR6C(=0), wherein R6 is H or CH3; J is absent;
K is -CH2CH2-;
R1 is selected from the group consisting of H, benzyl, isopropyl, cyclopentyl, methyl, or cyclopropyl; ' R anα'R together with'the nitrogen atom to which they are both bonded form pyrrolidin-1-yl; and
Ar is 1,4-phenylene.
Some embodiments of the present invention include every combination of one or more compounds selected from the following group shown in the TABLES A through E.
TABLE A
Figure imgf000027_0001
Figure imgf000028_0001
-
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
TABLEB
Figure imgf000031_0002
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
TABLEC
Figure imgf000041_0002
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
I
Figure imgf000045_0002
Figure imgf000045_0001
Figure imgf000046_0001
per/
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
-
-
-
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
-
Figure imgf000061_0001
Figure imgf000062_0001
TABLED
Figure imgf000062_0002
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
■••'■ "1Ii1" ..'■ ii ϋ «:":> r ..-11..'7 Q
-
Figure imgf000068_0001
Additionally, individual compounds and chemical genera of the present invention, for example those compounds found in TABLES A through E 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 the general synthetic schemes in Figures 1 through 8 as well as 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, chiral HPLC, recrystallization of diastereomeric mixtures, and the like) or selective synthesis (such as, 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. It is understood that compounds of the present invention, where the two hydrogens assigned as Ha and Hb are cis with respect to each other, have the following stereochemistry represented by Formula (Ha) and Formula (lie):
Figure imgf000069_0001
(Ha) (Hc)
In some embodiments, the compounds of the present invention have the stereochemical designations as represented by Formula (Ha):
Figure imgf000069_0002
(Ha)
In some embodiments, the compounds of the present invention have the stereochemical designations as represented by Formula (He):
Figure imgf000069_0003
(Hc)
In some embodiments, the compounds of the present invention have the stereochemical designations as represented by Formula (lie):
Figure imgf000069_0004
(He)
In some embodiments, the compounds of the present invention have the stereochemical designations as represented by Formula (Ilg):
Figure imgf000070_0001
α§)
In some embodiments, the compounds of the present invention have the stereochemical designations as represented by Formula (ED):
Figure imgf000070_0002
In some embodiments, the compounds of the present invention have the stereochemical designations as represented by Formula (Ilk):
Figure imgf000070_0003
In some embodiments, compounds of the present invention have the stereochemical designations of (3aS,6aS) wherein the carbons assigned as 3a and 6a and the stereochemistry are represented in Formula (TLm) :
Figure imgf000070_0004
(urn)
In some embodiments, compounds of the present invention have the stereochemical designations of (3aR,6aR) wherein the carbons assigned as 3a and 6a and the stereochemistry are represented in Formula (Ho):
Figure imgf000070_0005
T/ US O B / MHHMHk/" '9
INDICATIONS AND METHODS OF PROPHYLAXIS AND/OR TREATMENT
In addition to the foregoing beneficial uses for the modulators of H3 receptor activity disclosed herein, the compounds disclosed herein are believed to be useful in the treatment of several additional diseases and disorders, and in the amelioration of symptoms thereof. Without limitation, these include the following.
Histamine [2-(imidazol-4-yl)ethylamine] is a transmitter substance present in both the central and peripheral nervous system. In the central nervous system (CNS) cell bodies of histaminergic neurons are located almost exclusively in the tuberomammillary nuclei (TMN) of the posterior hypothalamus. Histaminergic neurons extend from the TMN to innervate all major areas of the brain, suggesting involvement in a wide variety of physiological processes (see: Haas and Panula in Nat. Rev. Neurosci. 2003, 4, 121-130).
Histamine exerts its physiological effects through four distinct G-protein coupled receptors (GPCRs), termed H1-H4. The 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). 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 2003, 63, 637-672). Thus, there are a number of therapeutic applications for ligands which target the 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 al. Trends Pharmacol Sci 2004, 25, 618-624).
Accordingly, preclinical studies have identified a number of indications which are amenable to treatment with H3 antagonists and inverse agonists, such as compounds of the present invention. These include cognitive disorders (Passani et al. Trends Pharmacol Sci 2004, 25, 618-624), epilepsy (Vohora et al. Pharmacol BiochemBehav 2001, 68, 735-741), depression (Perez-Garcia et a. Psychopharmacol 1999, 142, 215-220), narcolepsy (Tedford et al. Soc Neurosci Abstr 2000, 26, 460.3), obesity (Hancock, Curr Opin Investig Drugs 2003, 4, 1190- 1197), motion sickness and vertigo (Pan et al. Methods Find Exp Clin Pharmacol. 1998, 20, 771-777), disorders of sleep and wakefulness (Parmentier et al. J Neurosci. 2002, 22, 7695-
7711; Ligneau et al. J Pharmacol Exp Ther. 1998, 287, 658-666), attention deficit hyperactivity disorder (ADHD), (Fox et al. Behav Brain Res. 2002, 131, 151-61), schizophrenia (Fox et al. J Pharmacol Exp Ther. 2005, 313, 176-190), and treatment of upper airway allergic responses (U.S. Pat. Nos. 5,217,986; 5,352,707 and 5,869,479). H3 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 antagonists can also be useful for conditions associated with excessive daytime sleepiness such as narcolepsy, sleep apnea, time zone change disorder, fibromyalgia, and multiple "sclefosis (Parmentier R, et al., J Neurosci. 2002, 22, 7695-7711 ; Ligneau X. et al. J Pharmacol Exp Ther. 1998, 287, 658-666). For additional information, see reviews by Leurs et al., in Nat Rev Drug Discov 2005, 4, 107-120, and Vohora, 2004, Investigational Drugs 7, 667- 673. 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 drug 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 often 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 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. The drug gamma-hydroxybutyrate (GHB) (Xyrem) is approved in the USA by the Food and Drug Administration to treat both the cataplexy and excessive daytime sleepiness associated with narcolepsy.
Interestingly, modafinil (Provigil) has recently been shown to increase hypothalamic histamine release (Ishizuka et al. Neurosci. 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 narcoleptic 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. Neurosci. 2002, 22, 7695-7711; Ligneau et al. J. Pharmacol. Exp. Titer. 1998, 287, 658-666). Other conditions include excessive sleepiness due to shift work, medical ril .,...„ «•«- / ij i c; i"! C" / ||,,)Ul,|.,llnL"7 C|
Ir' 'WϊsόrdersXpsycmatric 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, slepp deprivation, post anesthesia grogginess, drowiness as a side effect from a medication, military use and the like. Ia 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 Tlierapy, 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. ScL 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., 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. Sd. 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 P t..oniy' iiftfM' a ϊ'&daliled part'of ϊhe 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 as 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, antiseizure 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. (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. IP f f / 1 |t Cj; |[°|i ip|, / ii,,|μι.|..!i.,|.'7 q
'' ' Compounds of me present invention can be used in combination with various known drugs. For examples, 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 (Cymbalta).
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/modafinil 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 examples, 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 sTign 4ifiMcanBt s OociIBal/ orH ocMcMuHpMa!t;i;o?n'1a1;!l d.ysfunction. A person experi .enci .ng untreated schizophreni .a i .s 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 mKNA expression in rat brown adipose tissue, indicating a role in the regulation of thermogenesis (Karlstedt et al., MoI. Cell. Neuwsci. 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 al. 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.
Figure imgf000078_0001
agoni .sts can a ,lso , be used J to ^ trea +t 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 chloφheniramine 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.
Compounds of the present invention described herein may be used in combination with modafinil (Provigil) for the treatment of H3 -associated disorders such as, cognitive disorders, epilepsy, brain trauma, depression, obesity, motion sickness and vertigo, disorders of sleep and wakefulness such as narcolepsy, shift-work syndrome, drowsiness as a side effect from a medication, maintenance of vigilance to aid in completion of tasks and the like, cataplexy, 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.
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, A. R., 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 u Tni.tΛ do Usa Sge P for Bms/ m HayMH cHon1+ta?in19 any sui .ta,b_,le e«ff.ecti.ve amoun +t o ™i th.e ac +ti-ve i •ngred ,i.ent 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 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, »|» .,. I || ,,:;;J. IJ...JJ |;» / ||,,|, !J,|, H,|,, ^1 C|| 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. pCT/ U TSheO poBwd/eris'Ψ aNndbM tahbJlet'ζst may contai .n varying percentage amounts o rf tuhe acti .ve 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 maybe 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. In 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-filled 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 IP C T / Ii1 "S O ε ,■■'" 1H!" Ni- "+ 7' '9
""sterile solid or by ϊyophilization "from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free 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, tor 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, dichlorodifluoromethane, 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 Science, 66, 2 (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 ID if" "]!'" .-■" IJi S Cl! Fi1 ,./' 11..11"""I W7 '9
""'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.
Compounds of the present invention can be converted to "pro-drugs." The term "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. 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 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 H3 receptor modulators, for the treatment of a IB-associated disease or disorder in domestic animals (e.g., cats and dogs) and in other domestic animals (e.g., such as 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 H3 receptor in tissue samples, including human, and for identifying H3 receptor ligands by inhibition binding of a radio-labeled compound. It is a further 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 which are identical to compounds disclosed herein, but for the fact that one or more atoms are replaced or substituted
Figure imgf000086_0001
or mass num uber d ^ifferent fr ,om t .he a +tomi ■c mass or mass number typically found in nature (i.e., naturally occurring). 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, 150, 17O, 180, 18F, 35S, 36Cl, 82Br, 75Br, 76Br, 77Br, 1231, 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 H3 receptor labeling and competition assays, compounds that incorporate 3H, 14C, 82Br, 1251 , 1311, 35S or 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 Schemes supra 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 a scarcer 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. Tπtmm 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 125I labeled compound using Na125I. A represented procedure was reported by Zhu, D.-G. 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. Labeled Cornpd. 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 represented procedure was reported by Bas, M.-D. and co-workers in J. Labeled Compd. Radiopharm. 2001, 44, S280-S282.
A radio-labeled 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 H3 receptor directly correlates to its binding affinity.
The labeled compounds of the present invention bind to the H3 receptor. In one embodiment the labeled compound has an IC50 less than about 500 μM, in another embodiment the labeled compound has an IC50 less than about 100 μM, in yet another embodiment the labeled compound has an IC50 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 P C T/ U SCt Ei, ,/' IjMMy,!.:?' 9 ^ , 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 8 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 Chem Draw Ultra Version 7.0.1, AutoNom version 2.2. 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 = multiplex, br = broad. Microwave irradiations were carried out using the Emrys Synthesizer (Personal Chemistry). Thin-layer chromatography (TLC) was performed on silica gel 60 F254 (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 in vacuo 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 Inc; UV-Detector: SPD-IOA VP, Shimadzu Lie; Autosampler: CTC HTS, PAL, Leap Scientific; Mass spectrometer: API 150EX with Turbo Ion Spray source, ABMDS Sciex; Software: Analyst 1.2. 2) Mac: HPLC-pumps: LC-8A VP, Shimadzu Inc; 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 (±)-2-Ben2yl-hexahydro-cycIopenta[c]pyrrol-4-one.
Figure imgf000088_0001
p ji"- "'I" / 1 | II;::J; |;"| p;, / ϋ,,jμ!,,|Ul,,|, 71 C|
'"" To a' solution of N-(methoxymethyl)-N-(trimethylsilylmet]iyl)benzyl amine (5O g, 0.210 mol) in acetonitrile (134 mL) was added cyclopentenone (17.2g, 0.210 mol). The mixture was stirred under nitrogen and heated at 42-450C for 3.5 h. The reaction mixture was cooled to room temperature and acetonitrile was removed under reduced pressure. The crude residue was purified by vacuum distillation at 126-130 °C/1 Torr to obtain the title compound (30.93g,
68.5%). MS m/z 216.2, (M+H); 1H NMR (400 MHz, CD3OD) δ 7.20-7.32 (m, 5H), 3.55 (dd, J
= 52.0, 13.1 Hz, 2H), 3.02 (dd, J= 9.4, 1.8 Hz, IH), 2.84-2.93 (m, IH), 2.67 (dd, J = 9.4, 2.6
Hz, IH), 2.61 (m, IH), 2.47 (dd, J = 9.6, 7.3 Hz, IH), 2.36-2.47 (m, 2H), 2.23-2.32 (m, IH),
2.07-2.17 (m, IH), 1.75-1.83 (m, IH). Resolution via Chiral HPLC
Column: Chiralpak AD-H, 150 x 2.1 mm, 5 μm particle size
Eluent: 95% Hexane/5% Isopropanol
Gradient: Isocratic
Flow: 1 mL/minute Detector: 254 nm
Retention Times: 3aR,6aS - 5.70 min.; 3aS,6ai? - 6.90 min.
Resolution of (3aSr,6aΛ)-2-Benzylhexahydro-cyclopenta[c]pyrrol-4(5BT)-one via
Diastereomeric Salt Formation.
Figure imgf000089_0001
To a stirred solution of (±)-2-benzylhexahydrocyclopenta[c]pyrrol-4(5H)-one (10 g,
46.4 mmol) in isopropanol (30 mL) at 60 0C was added a solution of di-p-toluoyl-L-tartaric acid in isopropanol (30 mL). Heating was continued at 6O0C to until a clear solution was obtained, at which point the mixture was cooled to 50 0C and then seeded with (3aS,6aR)-2- benzylhexahydro-cyclopenta[c]pyrrol-4(5H)-one-di-p-toluoyl-L-tartrate (30% ee). This suspension was allowed to cool to room temperature over 16 hours and the solids were collected by vacuum filtration. The salt was recrystallized twice from isopropanol to leave (3aS,6aR)-2- benzylhexahydrocyclopenta[c]pyrrol-4(5H)-one-di-p-toluoyl-L-tartrate as a white crystalline solid. This was partitioned between dichloromethane (100 mL) and 3.5% aqueous sodium bicarbonate (200 mL), the lower layer was removed and the upper layer was extracted with dichloromethane (100 mL). The combined organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure to leave the title compound as a pale orange oil (2.28 g, 46%) with an ee of 99.5% as determined by chiral HPLC. MS m/z 216.2, (M+H).
Example 1.2: Preparation of l-[2-(4-Bromo-phenyl)-ethyl]-pyrrolidine.
Figure imgf000090_0001
To a suspension of 4-bromo-phenyl-ethyl alcohol (2.00 g, 9.95 mmol) and triethylamine (1.39 mL, 9.95 mmol) in dichloromethane was added methanesulfonyl chloride (1.25g, 10.9 mmol) at 00C. The reaction was stirred for 1 h and concentrated to give the crude bromophenyl mesylate intermediate (MS m/z 280.2, (M+H)). Pyrrolidine (5.9 mL, 72 mmol) was diluted with acetonitrile and potassium carbonate (22 g, 158 mmol) was added and stirred for 1 h at ambient temperature. To the solution was added Methanesulfonic acid 2-(4-bromo-phenyl)-ethyl ester (20.0 g, 72 mmol). The reaction mixture was stirred overnight at 50 0C. After cooling to room temperature, the mixture was filtered and concentrated. The crude material was purified by silica gel column eluting with 80% EtOAc/hexane followed by 6% 2.0 M ammonia in methanol/dichloromethane to give the title compound (17 g, 93%). MS m/z 256, (M+H); 1H NMR (400 MHz, CDCl3) δ ppm 7.39 (d, J = 8.59 Hz, 2 H) 7.08 (d, J = 8.08 Hz, 2 H) 4.07 - 4.16 (m, 1 H) 2.75 - 2.85 (m, 2 H) 2.65 - 2.73 (m, 2 H) 2.55 - 2.64 (m, 3 H) 1.77 - 1.86 (m, 4 H).
Example 1.3: Preparation of (±)-2-Benzyl-4-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]- octahydro-cyclopenta[c]pyrrol-4-ol.
Figure imgf000090_0002
To a solution of l-[2-(4-Bromo-phenyl)-ethyl]-pyrrolidine (2.54 g, 9.99 mmol) in THF (27 mL) at -78 0C was added n-BuLi (7.25 mL, 11.6 mmol, 1.6M in hexanes) with stirring. After 1 h at -78 0C, the ketone from Example 1.1 (2.036 g, 9.46 mmol) dissolved in THF (10 mL) was added to the reaction mixture via cannula. After 2 hr, the reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over MgSO4 and concentrated at reduced pressure The crude product was purified through a silica gel column with 15% Acetone/ 85% Hexanes then with 10% MeOH/ 90% dichloromethane to give a product as yellow solid (2.43 g, 65.8%). The enantiomerically pure isomers of this compound (3aS,6aR and 3aR,6aS) were obtained by the same method starting from the corresponding single isomer ketones in Example 1.1. MS m/z 391, (M+H); 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 8.3 Hz, 2H), 7.22-7.33 (m, 5H), 7.15 (d, J = 7.8 Hz, 2H), 3.73 (d, J = U.I Hz, IH), 3.45-3.52 (m, 2H), 3.00 (d, J = 9.3 Hz, IH), 2.57-2.88 (m, 10H), 2.12-2.21 (m, 3H), 1.79-2.07 (m, 7H), 1.57-1.68 (m, IH). F" I"" T / 1| Jl S P IB / 8+tt+iι+'7' 9
"Example 1.4: Preparation of 2-Benzyl-4-{4~(2-[(2S)-2-methyl-pyrrolidin~l-yl]-ethyl)- phenyl}-octahydro-cyclopenta[c]pyrrol-4-ol.
Figure imgf000091_0001
The title compound was obtained using the method described in Example 1.3 starting with l-[2-(4-Bromo-phenyl)-ethyl]-2-methyl pyrrolidine. The enantiomerically pure isomers of this compound (3aS,6aR and 3aR,6aS) were obtained by the same method starting from the corresponding single isomer ketones in Example 1.1. MS m/z 405, (M+H); 1H NMR (400 MHz, DMSO-J6) δ 7.20-7.61 (m, 9H), 4.46 (dd, J = 12.7, 3.4 Hz, 2H), 4.34 (d, J = 4.9 Hz, 2H), 4.12 (dd, J = 12.9, 7.6 Hz, 2H), 3.78-3.90 (m, 2H), 3.56-3.65 (m, IH), 2.82-3.44 (m, 9H), 1.80- 2.24 (m, 4H), 1.57-1.69 (m, 2H), 1.39 (d, J = 6.4 Hz, 3H).
Example 1.5: Preparation of (±)-2-Benzyl-4-[4-(2~pyrrolidin-l-yl-ethyl)-phenyl]- octahydro-cyclopenta[c]pyrrole Dihydrochloride.
Figure imgf000091_0002
A solution of the compound described in Example 1.3 (0.2Og, 0.51mmol) in glacial acetic acid (3.0 mL) was added to 10% palladium on carbon (0.055g) in a Parr hydrogenation bottle. Perchloric acid (70%, 0.25 mL, 2.9mmol) was added to the mixture and the bottle was placed onto the Parr shaker under hydrogen at 55 psi for 16h. The catalyst was carefully filtered off using MeOH to wash the crude product through. The filtrate was concentrated at reduced pressure and the residue was diluted with EtOAc and water, then adjusted with aq. NaOH to pH = 10. The mixture was extracted into EtOAc and the combined organics were washed with brine and dried over anhydrous sodium sulfate. The solvent was removed at reduced pressure to give the title compound (0.19 g, 98%). MS m/z 375.6 (M+H); 1H NMR (400 MHz, MeOH-^) δ 7.28-7.18 (m, 5H), 7.16 (d, J= 8.1 Hz, 2H), 7.11 (d, J= 8.1 Hz, 2H), 3.44 (ABq, JM = 29.0, J= 12.6 Hz, 2H), 3.16 (ddd, J= 13.1, 8.0, 5.7, Hz, IH), 3.08-2.95 (m, 2H), 2.81-2.65 (m, 5H), 2.65- 2.58 (m, 4H), 2.39 (dddd, J= 9.0, 9.0, 0.0, 0.0 Hz, IH), 2.05-1.57 (m, 10H).
Example 1.6: Preparation of (±)-4-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-octahydro- cyclopenta[c]pyrrol-4-ol.
Figure imgf000092_0001
A solution of the compound described in Example 1.3 (2.294 g, 5.874 mmol), Ammonium formate (1.910 g, 30.29 mmol), and Pd(OH)2 (454.3 mg, 20% Pd/C, Pearlman's catalyst) in MeOH (12.0 mL) was heated to reflux for 50 min. After cooling to room temperature, the reaction mixture was filtered through a short column of Celite with MeOH. The solution was concentrated to give the title compound which was purified by preparative HPLC. The enantiomerically pure isomers of this compound (3aS,6aR and 3aR,6aS) were obtained by the same method starting from the corresponding single isomer ketones in Example 1.1. MS m/z 301.2, (M+H); 1HNMR (400 MHz, CDCl3) δ 7.47 (d, J= 8.3 Hz, 2H), 7.19 (d, J= 8.3 Hz, 2H), 3.28 (br s, IH), 3.23-3.19 (m, 2H), 2.92-2.76 (m, 5H), 2.74-2.68 (m, 2H), 2.65-2.56 (m, 5H), 2.55-2.50 (m, IH), 2.21 (ddd, J= 15.5, 7.6, 7.6 Hz, IH), 2.07-1.97 (m, IH), 1.93-1.87 (m, IH), 1.84-1.79 (m, 3H), 1.64 (ddd, J= 19.7, 13.3, 6.7 Hz, IH).
Example 1.7: Preparation of (±)-6-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-l,2,3,3a,4,6a- hexahydro-cyclopenta[c]pyrrole Dihydrochloride.
Figure imgf000092_0002
To a solution of the compound described in Example 1.6 (1.919 g, 6.39 mmol) in isopropyl alcohol (32.0 mL) was added HCl (16.0 mL, 64.0 mmol, 4M in 1,4-dioxane). The resulting reaction mixture was heated to 60 0C. After 3 h, the reaction mixture was concentrated at reduced pressure and neutralized with 10% NaOH solution. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with H2O, brine, dried over MgSθ4 and concentrated at reduced pressure The product obtained was pure enough to carry on to next step without purification (1.89 g, 100%). The enantiomerically pure isomers of this compound (3aS,6aR and 3aR,6aS) were obtained by the same method starting from the corresponding single isomer ketones in Example 1.1. MS m/z 283, (M+H); 1H NMR (400 MHz, CD3OD) δ 7.43 (d, J= 8.3 Hz, 2H), 7.31 (d, J= 8.3 Hz, 2H), 6.19 (bs, IH), 4.03-4.11 (m, IH), 3.41-3.72 (m, 6H), 2.89-3.17 (m, 7H), 2.46 (dd, J = 18.5, 2.4 Hz, IH), 1.96-2.22 (m, 5H).
Example 1.8: Preparation of [2-(4-bromo-phenyl)-ethoxy]-tørt-butyl-dimethyl-silane.
Figure imgf000093_0001
To a solution of alcohol (2Og, 99.5mmol) in 250 mL DCM was added a solution of imidazole (16.9g, 248.9 mmol) in 150 mL DCM. The mixture was stirred at room temperature for 5 minutes and a solution of TBDMS-Chloride (15g, 99.5 mmol) was added slowly. The mixture was stirred for 2 h at room temperature. Water (200 mL) was added followed by 10% HCl (150 mL). The organic phase was separated, washed with brine, dried with Na2SO4 and concentrated at reduced pressure. Chromatographic purification (silica gel, 10% EtOAc in Hexanes) gave the title compound as an oil. MS m/z 316, (M+H).
Example 1.9: (±)-Preparation of 2-Benzyl-4-{4-[2-(tert-butyl-dimethyl-saanyloxy)-ethyl]- phenyI}-octahydro-cyclopenta[c]pyrrol-4-ol.
Figure imgf000093_0002
To a solution of [2-(4-bromo-phenyl)-ethoxy]-tert-butyl-dimethyl-silane (1.74g, 5.52mmol) in THF (15 mL) at -78° C was added n-BuLi (3.0 mL, 7.50mmol, 2.5M in hexanes). After Ih at -78° C, 2-benzyl-hexahydrocyclopenta[c]pyrrol-4(5H)-one (1.06g, 4.92mmol) dissolved in THF (10 mL) was added to reaction mixture. The reaction was allowed to stir at - 78° C for 2h. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried with MgSO41 filtered and concentrated at reduced pressure. The product was purified by flash chromatography (silica gel, 10% EtOAc in hexane). The combined fractions were concentrated at reduced pressure to yield product as a clear liquid (1.42g, 64%). The enantiomerically pure isomers of this compound (3aS,6aR and 3aR,6aS) were obtained by the same method starting from the corresponding single isomer ketones in Example 1.1. MS m/z 453, (M+H).
Example 1.10: (±)-Preparation of 2-BenzyI-6-{4-[2-(teιt-butyl-dimethyl-silanyloxy)-ethyl]- phenyl}-l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole.
Figure imgf000093_0003
p in: T / i VH in B ..■•■" im»».ji"»-i»';;;!i' 9
To absolution of Burgess Reagent (828.8mg, 3.48mmol) in benzene (3.5 mL) was added 2-Benzyl-4-{4-[2-(fert-butyl-dimethyl-silanyloxy)-ethyl]-phenyl}-octahydro- cyclopenta[c]pyrrol-4-ol (1.42g, 3.14mmol) dissolved in benzene (2 mL). The mixture was heated to 50° C and allowed to stir for 2h. The reaction mixture was cooled to room temperature, quenched with water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried with MgSO4, filtered and concentrated at reduced pressure. The product was purified by flash chromatography (silica gel, 20% EtOAc in hexane). The combined fractions were concentrated at reduced pressure to yield product as a clear liquid (356mg, 26%). The enantiomerically pure isomers of this compound (3aS,6aR and 3aR,6aS) were obtained by the same method starting from the corresponding single isomer ketones in Example 1.1. MS m/z 434, (M+H).
Example 1.11: Preparation of (±)-2-[4-(2-Benzyl-l,2,3,3a,6,6a-hexahydro- cyclopenta[c]pyrrol-4-yl)-phenyl]-ethanoL
Figure imgf000094_0001
To a solution of 2-Benzyl-6-{4-[2-(ter/-butyl-dimethyl-silanyloxy)-ethyl]-phenyl}- l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole (356mg, 0.821mmol) in THF (4.0 mL) was added TBAF (1.60 mL, 1.60mmol, 1.0M in THF). The mixture was allowed to stir at room temperature for 3h. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried with MgSO4, filtered and concentrated at reduced pressure. The product was purified by flash chromatography (silica gel, 100% EtOAc). The combined fractions were concentrated at reduced pressure. The product was then purified by HPLC (0.1% TFA in acetonitrile, 0.1 % TFA in water). The combined fractions were dried under lyophilizer. The salt product was washed with saturated NaHCO3 to yield the free base (190mg, 72%). The enantiomerically pure isomers of this compound
(3aS,6aR and 3aR,6aS) were obtained by the same method starting from the corresponding single isomer ketones in Example 1.1. MS m/z 320, (M+H).
Example 1.12: Preparation of (±)-Methanesulfonic acid 2-[4-(2-benzyl-l,2,3,3a,6,6a- hexahydro-cyclopenta[c]pyrrol-4-yl)-phenyl]-ethyl ester.
Figure imgf000094_0002
P C I" / IJUiS O B / ''HM-P+?' 9
' " To a solution of 2-[4-(2-Benzyl-l,2,3,3a,6,6a-hexahydro-cyclopenta[c]pyrrol-4-yl)- phenyl]-ethanol (0.5Og, 1.57mmol) in 8 mL DCM was added Et3N (1.65 mL, 1.2g, 11.8 mmol) followed by MsCl (0.4 mL, 0.0.592g, 5.17mmol). The mixture was stirred at room temp for 2.5 h, diluted with 75 mL EtOAc and washed with saturated sodium bicarbonate and brine. The organic layer was dried with Na2SO4 and concentrated at reduced pressure. Purification via silica gel chromatography (20-50%EtOAc in Hexanes) gave the title compound as an oil, 51 lmg, 82%. The enantiomerically pure isomers of this compound (3aS,6aR and 3aR,6aS) were obtained by the same method starting from the corresponding single isomer ketones in Example 1.1. MS m/z 398, (M+H).
Example 1.13 - General Method A
Preparation of (±)-2-Benzyl-6-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-l,2,3,3a,4,6a-hexahydro- cyclopenta[c]pyrrole DihydrochIoride.
Figure imgf000095_0001
A solution of the compound described in Example 1.12 (455.4 mg, 1.146 mmol), pyrrolidine (0.21 mL, 2.5 mmol), and Na2CO3 (307.3 mg, 2.90 mmol) in 6.3 mL OfCH3CN was heated to 120 0C for 3 hr under microwave irradiation in a heavy walled sealed tube. The reaction mixture was quenched with H2O and extracted with EtOAc. The combined organic layers were washed with H2O, brine, dried over MgSO4 and concentrated at reduced pressure The crude product obtained was filtered through a pad of silica gel with 10% MeOH/ 90% EtOAc then purified by HPLC. The combined HPLC fractions were basifϊed with NaOH, extracted with EtOAc, and concentrated. The resulting material was dissolved in 5 mL of ether, 2 equivalents of HCl in ether was added and the resulting mixture concentrated under vacuum to give the title compound as pale yellow solid (106 mg, 25%). The enantiomerically pure isomers of this compound (3aS,6aR and 3aR,6aS) were obtained by the same method starting from the corresponding single isomer ketones in Example 1.1. MS m/z 373, (M+H); 1H NMR (400 MHz, DMSO-^5) δ 7.50-7.59 (m, 2H), 7.40-7.46 (m, 5H), 7.27 (d, J = 8.1 Hz, 2H), 6.24-6.29 (m, IH), 4.25-4.39 (m, 2H), 3.80-4.10 (m, 2H), 3.60-3.69 (m, IH), 3.48-3.57 (m, 2H), 3.28-3.37 (m, 2H), 3.15-3.24 (m, 2H)5 2.96-3.07 (m, 4H), 2.66-2.88 (m, 2H), 2.32-2.48 (m, IH), 1.81-2.06 (m, 4H).
Example 1.14: Preparation of (±)-2-Benzyl-6-[4-(2-piperidin-l-yl-ethyl)-phenyl]- l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride.
Figure imgf000096_0001
The title compound was obtained using general method A. MS m/z 387.2, (M+H); 1H NMR (400 MHz, CD3OD) δ 7.36-7.46 (m, 7H), 7.27 (d, J= 7.05 Hz, 2H), 6.20 (s, IH), 4.33 (s, 2H), 4.18 (m, IH) 3.97 (m, IH), 3.78 (t, J = 9.2 Hz, IH), 3.60 (d, J = 12.4 Hz, 4H), 2.80-3.80 (m, 6H), 2.46 (d, J = 18.4 Hz, IH), 1.97 (d, J= 15.2 Hz, IH), 1.71-1.89 (m, 5H), 1.45-1.58 (m, 2H).
Example 1.15: Preparation of (±)-2-Benzyl-6-{4-[2-(2-methyl-piperidin-l-yl)-ethyl]- phenyI}-l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride.
Figure imgf000096_0002
The title compound was obtained using general method A. MS m/z 401.2, (M+H); 1H NMR (400 MHz, CD3OD) δ 7.37-7.48 (m, 7H), 7.29 (d, J = 5.6 Hz, 2H), 6.20 (s, IH), 4.33 (s, 2H), 4.17 (m, IH) 3.97 (m, IH), 3.78 (m, IH), 3.67 (m, IH), 3.40-3.54 (m, 3H), 2.81-3.16 (m, 7H), 2.46 (d, J = 18.4 Hz, IH), 1.72-2.05 (m, 4H), 1.56-1.67 (m, 2H), 1.34-1.45 (m, 3H).
Example 1.16: Preparation of (±)-2-Ben2yl-6-{4-[2-(4-methyl-piperazin-l-yl)-ethyl]- phenyl}-l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride.
Figure imgf000096_0003
The title compound was obtained using general method A. MS m/z 402.2, (M+H); 1H NMR (400 MHz, CD3OD) δ 7.34-7.50 (m, 7H), 7.26 (s, 2H), 6.19 (s, IH), 4.33 (s, 2H), 4.10- 4.20 (m, IH), 3.97 (m, IH), 3.70-3.80 (m, IH), 3.32-3.58 (m, 7H), 3.18-3.30 (m, 5H), 2.98 (m, 4H), 2.83-2.94 (m, 3H), 2.46 (d, J= 17.6 Hz, IH).
Example 1.17: Preparation of (3aRS,6aRS )-2-Benzyl-6-{4-[2-((2R,6S)-2,6-dimethyl- piperidin-1-yl)-ethyl!-phenyl$-1,2,3,3a,46aa-hexahydro-cyclopentalcJpyrrole Dihydrochloride.
Figure imgf000097_0001
The title compound was obtained using general method A. MS m/z 415.4, (M+H); 1H NMR (400 MHz, CD3OD) δ 7.41-7.50 (m, 7H), 7.32 (d, J = 6.8 Hz, 2H), 6.23 (s, IH), 4.28-4.42 (m, 2H), 3.75-4.25 (m, 2H), 3.44 (d, J = 7.2 Hz, 5H), 3.20-3.25 (m, IH), 2.81-3.07 (m, 4H), 2.47 (d, J= 18.8 Hz, IH), 2.03 (d, J = 12.0 Hz, 2H), 1.56-1.89 (m, 5H), 1.37-1.50 (m, 6H).
Example 1.18: Preparation of (±)-2-BenzyI-6-{4-[2-(2,5-dimethyl-pyrrolidin-l-yl)-ethyl]- phenyl}-l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride.
Figure imgf000097_0002
The title compound was obtained using general method A. MS m/z 401.2, (M+H); 1H NMR (400 MHz, CD3OD) 7.40-7.5 (m, 7H), 7.33 (d, J = 5.6 Hz, 2H), 6.22 (s, IH), 4.35 (s, 2H), 3.98-4.25 (m, 2H), 3.62-3.85 (m, 2H), 3.35-3.58 (m, 4H), 3.21 (s, IH), 2.80-3.10 (m, 4H), 2.47 (d, J = 18.4 Hz, IH), 2.19-2.36 (m, 2H), 1.75-1.86 (m, 2H), 1.43-1.53 (m, 5H), 1.36 (d, J = 5.6 Hz, IH).
Example 1.19: Preparation of (±)-2-[4-(2-Benzyl-l,2,3,3a,6,6a-hexahydro- cyclopenta[c]pyrrol-4-yl)-phenyl]-ethyl}-dimethyl-amine Dihydrochloride.
Figure imgf000097_0003
The title compound was obtained using general method A. MS m/z 347.2, (M+H); 1H NMR (400 MHz, CD3OD) δ 7.39-7.50 (m, 7H), 7.30 (d, J = 6.8 Hz, 2H), 6.22 (s, IH), 4.35 (s, 2H), 3.75-4.25 (m, 2H), 3.32-3.59 (m, 5H), 3.14-3.27 (m, IH), 3.00-3.10 (m, 2H), 2.94 (s, 6H), 2.80-2.90 (m, IH), 2.47 (d, J= 18.4 Hz, IH).
Example 1.20: Preparation of (2aR ,6aR)-2-Benzyl-6-{4-(2-[(2S)-2-methyl-pyrrolidin-l-yl]- ethyl)-phenyl}-l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride.
Figure imgf000098_0001
The title compound was obtained using general method A. MS m/z 387, (M+H); 1H NMR (400 MHz, CD3OD) δ 7.27-7.52 (m, 9H), 6.21-6.26 (m, IH)5 4.15-4.42 (m, 2H), 3.93-4.03 (m, IH), 3.68-3.83 (m, 2H), 2.80-3.67 (m, HH), 2.43-2.52 (m, IH), 2.29-2.40 (m, IH), 2.00- 2.18 (m, 2H), 1.70-1.81 (m, IH), 1.44-1.49 (m, 3H).
Example 1.21: Preparation of (±)-2-Benzyl-6-{4-[2-(2,2-dimethyl-pyrrolidin-l-yl)-ethyl]- phenyl}-l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole DihydrochIoride.
Figure imgf000098_0002
The title compound was obtained using general method A. MS m/z 401, (M+H); 1H
NMR (400 MHz, DMSO-^) δ 7.48-7.57 (m, 2H), 7.40-7.46 (m, 5H), 7.28-7.33 (m, 2H), 6.24- 6.29 (m, IH), 4.26-4.41 (m, 2H), 3.81-3.89 (m, IH), 3.61-3.71 (m, 2H), 2.30-3.36 (m, 11H), 1.86-2.03 (m, 4H), 1.48 (d, J = 2.5 Hz, 3H), 1.17 (d, J = 3.2 Hz, 3H).
Example 1.22: Preparation of (2afi,6al?)-2-Benzyl-6-{4-(2-[(2i?)-2-methyl-pyrrolidin-l-yl]- ethyl)-phenyl}-l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride.
Figure imgf000098_0003
The title compound was obtained using general method A. MS m/z 387, (M+H); 1H NMR (400 MHz, DMSO-^) δ 7.48-7.58 (m, 2H), 7.37-7.44 (m, 5H), 7.28 (d, J= 8.3 Hz, 2H), 6.25 (bs, IH), 4.25-4.39 (m, 2H), 3.79-4.10 (m, 2H), 3.54-3.70 (m, IH), 2.96-3.53 (m, 9H), 2.66-2.87 (m, 2H), 2.34-2.48 (m, IH), 2.14-2.26 (m, IH), 1.86-2.04 (m, 2H), 1.58-1.70 (m, IH), 1.38-1.44 (m, 3H).
Example 1.23: Preparation of (±)-2-Benzyl-6-[4-(2-morpholin-4-yl-ethyl)-phenyl]- l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride.
Figure imgf000099_0001
The title compound was obtained using general method A. MS m/z 389, (M+H); 1H NMR (400 MHz, CD3OD) δ 7.25-7.35 (m, 7H), 7.17 (d, J = 8.2 Hz, 2H), 6.05-6.08 (d d, J = 4.0, 2.5 Hz, IH), 3.62-3.82 (m, 7H), 2.99-3.23 (m, 3H), 2.73-2.84 (m, 3H), 2.52-2.63 (m, 6H), 2.25-2.36 (m, 3H).
Example 1.24: Preparation of (l-{2-[4-(2-Benzyl-l,2,3,3a,6,6a-hexahydro- cyclopenta[c]pyrrol-4-yl)-phenyl]-ethyl}-pyrrolidin-2-yl)-(fi)-methanol Dihydrochloride.
Figure imgf000099_0002
The title compound was obtained using general method A. MS m/z 403.4, (M+H); 1H
NMR (400 MHz, MeOH-^) δ ppm 1.83 - 2.09 (m, 2 H) 2.09 - 2.33 (m, 2 H) 2.43 - 2.53 (m, 1 H) 2.80 - 3.15 (m, 5 H) 3.17 - 3.28 (m, 1 H) 3.34 - 3.58 (m, 2 H) 3.61 - 3.83 (m, 5 H) 3.86 - 4.25 (m, 3 H) 4.29 - 4.43 (m, 2 H) 6.17 - 6.27 (m, 1 H) 7.25 - 7.36 (m, 2 H) 7.38 - 7.54 (m, 7 H)
Example 1.25: Preparation of (l-{2-[4-(2-BenzyI-l,2,3,3a,6,6a-hexahydro- cyclopenta[c]pyrrol-4-yl)-phenyl]-ethyl}-pyrrolidin-2-yl)-(iS)-methanoI Dihydrochloride.
Figure imgf000099_0003
The title compound was obtained using general method A. MS m/z 403.5, (M+H); 1H NMR (400 MHz, MeOH-rf,) δ ppm 1.85 - 1.95 (m, 1 H) 2.01 - 2.08 (m, 1 H) 2.10 - 2.31 (m, 2 H) 2.42 - 2.51 (m, 1 H) 2.80 - 3.14 (m, 5 H) 3.17 - 3.27 (m, 1 H) 3.32 - 3.58 (m, 2 H) 3.60 - 3.84 (m, 5 H) 3.87 - 4.25 (m, 3 H) 4.30 - 4.42 (m, 2 H) 6.18 - 6.28 (m, 1 H) 7.24 - 7.36 (m, 2 H) 7.39 - 7.54 (m, 7 H)
Example 1.26: Preparation of l-{2-[4-(2-Benzyl-l,2,3,3a,6,6a-hexahydro- cyclopenta[c]pyrrol-4-yl)-phenyl]-ethyI}-(3i2)-pyrrolidin-3-ol Dihydrochloride. P «:::;: τ/ use e / H-H- H
Figure imgf000100_0001
The title compound was obtained using general method A. MS m/z 389.5, (M+H); 1H NMR (400 MHz, MeOEW,) δ ppm 1.98 - 2.16 (m, 2 H) 2.29 - 2.54 (m, 2 H) 2.81 - 3.10 (m, 4 H) 3.15 - 3.28 (m, 2 H) 3.35 - 3.63 (m, 4 H) 3.70 - 3.88 (m, 2 H) 3.90 - 4.26 (m, 2 H) 4.30 - 4.44 (m, 2 H) 4.50 - 4.63 (m, 1 H) 6.18 - 6.28 (m, 1 H) 7.26 - 7.36 (m, 2 H) 7.38 - 7.54 (m, 7 H)
Example 1.27: Preparation of (±)-2-Benzyl-6-{4-[2-(3,3-difluoro-pyrrolidin-l-yl)-ethyl]- phenyl}-l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride.
Figure imgf000100_0002
The title compound was obtained using general method A. MS m/z 409.3, (M+H); 1H NMR (400 MHz, MeOH-d,) δ ppm 2.41 - 2.54 (m, 1 H) 2.62 - 2.78 (m, 2 H) 2.80 - 3.01 (m, 2 H) 3.02 - 3.14 (m, 2 H) 3.17 - 3.26 (m, 1 H) 3.35 - 3.48 (m, 1 H) 3.50 - 3.61 (m, 3 H) 3.74 - 3.82 (m, 2 H) 3.91 - 4.25 (m, 3 H) 4.30 - 4.41 (m, 3 H) 6.18 - 6.27 (m, 1 H) 7.29 - 7.37 (m, 2 H) 7.40 - 7.54 (m, 7 H)
Example 1.28: Preparation of (±)-6-[4-(2-Azetidin~l-yl-ethyl)-phenyl]-2-benzyl- l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride.
Figure imgf000100_0003
The title compound was obtained using general method A. MS m/z 359 A, (M+H); 1H NMR (400 MHz, MeOH-J,) δ ppm 2.06 - 2.64 (m, 3 H) 2.77 - 3.07 (m, 4 H) 3.11 - 3.27 (m, 2 H) 3.33 - 3.62 (m, 4 H) 3.71 - 3.85 (m, 1 H) 3.92 - 4.23 (m, 5 H) 4.25 - 4.42 (m, 2 H) 7.24 - 7.35 (m, 2 H) 7.38 - 7.56 (m, 7 H)
Example 1.29: Preparation of (±)-2-Benzyl-6-{4-[2-(3,3-difluoro-piperidin-l-yl)-ethyl]- phenyl}-l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride.
Figure imgf000101_0001
The title compound was obtained using general method A. MS m/z 423.2, (M+H); 1H NMR (400 MHz, MeOH-^) δ ppm 2.00 - 2.40 (m, 4 H) 2.42 - 2.55 (m, 1 H) 2.80 - 3.16 (m, 5 H) 3.18 - 3.29 (m, 1 H) 3.37 - 3.82 (m, 7 H) 3.91 - 4.24 (m, 2 H) 4.29 - 4.46 (m, 2 H) 6.18 - 6.26 (m, 1 H) 7.25 - 7.37 (m, 2 H) 7.40 - 7.57 (m, 7 H)
Example 1.30: Preparation of (±)-2-{2-[4-(2-Benzyl-l,2,3,3a,6,6a-hexahydro- cyclopenta[c]pyrrol-4-yl)-phenyl]-ethyl}-2,3-dihydro-lH-isoindole Dihydrochloride.
Figure imgf000101_0002
The title compound was obtained using general method A. MS m/z 421.4, (M+H); 1H
NMR (400 MHz, MeOH-^) δ ppm 2.40 - 2.59 (m, 1 H) 2.79 - 3.06 (m, 2 H) 3.13 - 3.22 (m, 2 H) 3.23 - 3.63 (m, 2 H) 3.66 - 3.87 (m, 3 H) 3.97 - 4.27 (m, 2 H) 4.31 - 4.46 (m, 2 H) 4.59 - 4.76 (m, 2 H) 4.92 - 5.04 (m, 2 H) 6.19 - 6.31 (m, 1 H) 7.31 - 7.59 (m, 13 H)
Example 1.31: Preparation of (±)-2-{2-[4-(2-Benzyl-l,2,3,3a,6,6a-hexahydro- cyclopenta[c]pyrrol-4-yl)-phenyl]-ethyl}-l,2,3,4-tetrahydro-isoquinoIine Dihydrochloride.
Figure imgf000101_0003
The title compound was obtained using general method A. MS m/z 435.5, (M+H); 1H NMR (400 MHz, MeOH-^) δ ppm 2.41 - 2.56 (m, 1 H) 2.82 - 3.06 (m, 3 H) 3.12 - 3.27 (m, 4 H) 3.42 - 3.64 (m, 5 H) 3.70 - 4.29 (m, 3 H) 4.32 - 4.50 (m, 3 H) 4.65 - 4.83 (m, 1 H) 6.19 - 6.33 (m, I H) 7.19 - 7.60 (m, 13 H)
Example 1.32: Preparation of l-{2-[4-(2-Benzyl-l,2,3,3a,6,6a-hexahydro- cyclopenta[c]pyrrol-4-yl)-phenyl]-ethyl}-(3iS)-pyrrolidin-3-ol Dihydrochloride.
Figure imgf000102_0001
The title compound was obtained using general method A. MS m/z 389.5, (M+H); 1H NMR (400 MHz, MeOEW,) δ ppm 1.14 - 1.31 (m, 2 H) 2.05 - 2.21 (m, 1 H) 2.35 - 2.55 (m, 2 H) 2.83 - 3.65 (m, 9 H) 3.73 - 3.89 (m, 2 H) 3.94 - 4.28 (m, 2 H) 4.32 - 4.46 (m, 2 H) 4.52 - 4.65 (m, 1 H) 6.20 - 6.30 (m, 1 H) 7.28 - 7.37 (m, 2 H) 7.40 - 7.56 (m, 7 H)
Example 1.33: Preparation of (±)-l-{2-[4-(2-Benzyl-l,2,3,3a,6,6a-hexahydro- cyclopenta[c]pyrrol-4-yl)-phenyl]-ethyl}-2,3-dihydro-lH-indole Dihydrochloride.
Figure imgf000102_0002
The title compound was obtained using general method A. MS m/z 421.3, (M+H); 1H
NMR (400 MHz, MeOH-^) δ ppm 2.41 - 2.59 (m, 1 H) 2.80 - 3.04 (m, 2 H) 3.08 - 3.19 (m, 2 H) 3.20 - 3.63 (m, 5 H) 3.72 - 3.86 (m, 2 H) 3.93 - 4.27 (m, 4 H) 4.31 - 4.44 (m, 2 H) 6.18 - 6.31 (m, I H) 7.29 - 7.62 (m, 13 H).
Example 1.34 - General Method B
Preparation of (±)-2-Cyclopentyl-6-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-l,2,3,3a,4,6a- hexahydro-cyclopenta[c]pyrrole Dihydrochloride
Figure imgf000102_0003
The compound in Example 1.7 (0.200 g, 0.708 mmol) and cyclopentanone (0.060 g, 0.708 mmol) were mixed in dichloromethane (5 mL), and then treated with sodium triacetoxyborohydride (0.210 g, 0.991 mmol), and AcOH (0.043 g, 0.708 mmol). The mixture was stirred at room temperature under a N2 atmosphere for 24h until the reactants were consumed as determined by LC/MS. The reaction mixture was quenched by adding 1 N NaOH, and the product was extracted with EtOAc. The organic extract was washed with brine and dried (MgSO4). The solvent was removed at reduced pressure leaving the crude product. The crude product was filtered through a silica gel plug using 5% 2 M NH3ZMeOH in dichloromethane. Purification as described in Example 1.13 afforded the title compound as a
Figure imgf000103_0001
yellow sond. The enantiometrically pure isomers of this compound (3aS,6aR and 3aR,6aS) were obtained by the same method starting from the corresponding single isomer ketones in Example 1.1. MS m/z 351.3, (MfH); 1H NMR (400 MHz, CD3OD) δ 7.36 (d, J= 8.0 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 6.04 (s, IH), 3.79-3.69 (m, IH), 3.21 (t, J= 8.0 Hz, IH), 3.13-3.05 (m, IH), 3.03- 2.97 (m, IH), 2.86-2.77 (m, 3H), 2.76-2.69 (m, 3H), 2.64 (br s, 4H), 2.41 (t, J= 8.0 Hz, IH), 2.31 (dd, J= 17.6, 2.8 Hz, IH), 2.16 (q, J= 7.9 Hz, IH), 1.91-1.75 (m, 5H), 1.75-1.62 (m, 2H), 1.59-1.48 (m, 2H), 1.47-1.36 (m, 2H).
Example 1.35: Preparation of (3aS 6aS)-2-CyclopropyImethyl-6-[4-(2-pyrrolidin-l-yl- ethyl)-phenyl]-l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride.
Figure imgf000103_0002
The title compound was obtained using general method B. MS m/z 337, (M+H); 1H NMR (400 MHz, CD3OD) δ 7.47 (dd, J = 11.8, 8.2 Hz, 2H), 7.34 (dd, J = 8.0, 4.6 Hz, 2H), 6.24 (d, J = 32.6 Hz, IH), 4.14-4.25 (m, IH), 3.95-4.09 (m, IH), 3.63-3.72 (m, 2H), 3.39-3.60 (m, 5H), 3.01-3.18 (m, 6H), 2.72-2.93 (m, 2H), 2.42-2.57 (m, IH), 1.96-2.23 (m, 4H), 1.02-1.14 (m, IH), 0.64-0.75 (m, 2H), 0.32-0.44 (m, 2H).
Example 1.36: Preparation of (3a5r,6a5)-2-Cyclopentyl-6-[4-(2-pyrrolidin-l-yl-ethyl)- phenyl]-l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride.
Figure imgf000103_0003
The title compound was obtained using general method B. MS m/z 351, (M+H).
Example 1.37: Preparation of (3a5r,6a.S)-2-(4-Methoxy-benzyl)-6-[4-(2-pyrrolidiii-l-yl- ethyl)-phenyl]-l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride.
Figure imgf000103_0004
The title compound was obtained using general method B. MS m/z 403, (M+H); 1H NMR (400 MHz, CH3OD) δ 7.28-7.45 (m, 6H), 6.98 (dd, J = 8.6, 2.0 Hz, 2H), 6.22 (d, J = 11.4 Hz IH), 4.14-4.34 (m, 2H), 3.90-4.04 (m, IH), 3.63-3.86 (m, 6H), 3.20-3.55 (m, 4H), 2.78-3.18 Example 1.38: Preparation of (3a5',6a5)-2-Isopropyl-6-[4-(2-pyrroIidin-l-yl-ethyl)- phenyl]-l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride.
Figure imgf000104_0001
The title compound was obtained using general method B. MS m/z 325, (M+H); 1H NMR (400 MHz, OMSO-d6) δ 7.45 (d, J = 8.1 Hz, 2H), 7.25-7.32 (m, 2H), 6.23-6.30 (m, IH), 3.96-4.15 (m, IH), 3.25-3.57 (m, 6H), 2.98-3.08 (m, 5H), 2.53-2.89 (m, 3H), 2.31-2.40 (m, IH), 1.83-2.06 (m, 5H), 1.21-1.29 (m, 6H).
Example 1.39: Preparation of (±)-2-Cyclobutyl-6-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]- l,2,3,3a,4,6a-hexahydro-cycIopenta[c]pyrrole Dihydrochloride.
Figure imgf000104_0002
The title compound was obtained using general method B. MS m/z 337.6, (M+H); 1H NMR (400 MHz, CD3OD) δ 7.45 (t, J= 8.0 Hz, 2H), 7.37-7.29 (m, 2H), 6.30-6.16 (m, IH), 4.17 (br s, IH), 4.13-3.98 (m, IH), 3.81 (q, J= 8.0 Hz, 2H), 3.68 (br s, 2H), 3.50-3.37 (m, 4H), 3.20-
2.94 (m, 4H), 2.92-2.81 (m, IH), 2.73-2.58 (m, IH), 2.56-2.40 (m, IH), 2.36-2.10 (m, 6H), 2.09-
1.95 (m, 2H), 1.94-1.76 (m, 2H).
Example 1.40: Preparation of (±)-2-{6-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-3,3a,4,6a- tetrahydro-lH-cyclopenta[c]pyrrol-2-yl}-propan-l-ol Dihydrochloride.
Figure imgf000104_0003
The title compound was obtained using general method B. MS m/z 341.4, (M+H); 1H NMR (400 MHz, CD3OD) δ 7.48 (dd, J= 8.0, 8.0 Hz, 2H), 7.36 (d, J= 8.0 Hz, 2H), 6.31-6.18 (m, IH), 4.27-413 (m, IH), 4.09-3.79 (m, 2H), 3.76-3.66 (m, 2H), 3.65-3.52 (m, 2H), 3.50-3.41 (m, 3H), 3.22-3.05 (m, 5H), 2.95-2.79 (m, 2H), 2.61-2.44 (m, IH), 2.19 (s, 2H), 2.12-1.99 (m, 2H), 1.45-1.30 (m, 3H), 1.19 (t, J= 8.0 Hz, IH).
Figure imgf000105_0001
phenyl]-l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride.
Figure imgf000105_0002
The title compound was obtained using general method B. MS m/z 337.5, (M+H); 1H NMR (400 MHz, CD3OD) δ 7.46, (d, J= 8.0 Hz, 2H), 7.34 (d, J= 8.0 Hz, 2H), 6.22 (s, IH), 4.14-4.04 (m, IH), 3.86 (br s, IH), 3.79-3.68 (m, IH), 2.46-3.33 (m, 7H), 3.11-2.99 (m, 6H), 2.97-2.88 (m, IH), 2.50 (br d, J= 16.0 Hz, IH), 2.09 (t, J= 4.0 Hz, 4H), 1.14-1.04 (m, IH), 0.69 (d, J= 8.0 Hz, 2H), 0.38 (br s, 2H).
Example 1.42: : Preparation of (±)-4-{6-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-3,3a,4,6a- tetrahydro-lH-cyclopenta[c]pyrrol-2-ylmethyl}-phenol Dihydrochloride.
Figure imgf000105_0003
The title compound was obtained using general method B. MS m/z 389.6, (M+H); 1H NMR (400 MHz, CD3OD) δ 7.35 (d, J= 8.0 Hz, 2H), 7.19 (d, J= 8.0 Hz, 2H), 7.11 (d, J= 8.0 Hz, 2H), 6.71 (d, J= 8.0 Hz, 2H), 6.06 (s, IH), 3.73 (br d, J= 8.0 Hz, IH), 3.52 (q, J= 21.3 Hz, 2H), 3.14 (t, J= 8.0 Hz, IH), 3.08-2.95 (m, 2H), 2.94-2.69 (m, 9H), 2.31 (br d, J= 20.0 Hz, 2H), 2.26-2.14 (m, 2H), 1.89 (s, 4H).
Example 1.43: Preparation of (±)-2-CyclohexyI-6-[4-(2-pyrroIidin-l-yl-ethyl)-phenyl]- l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride.
Figure imgf000105_0004
The title compound was obtained using general method B. MS m/z 365.5, (M+H); 1H NMR (400 MHz, CDCl3) δ 7.32 (d, J= 8.2 Hz, 2H), 7.16 (d, J= 8.2 Hz, 2H), 6.00-5.97 (m, IH), 3.74-3.63 (m, IH), 3.29 (ddd, J= 8.8, 8.8, 0.0 Hz, IH), 3.16 (ddd, J= 8.2, 8.2, 0.0 Hz, IH), 3.03-2.93 (m, IH), 2.85-2.65 (m, 5H), 2.60-2.54 (m, 4H), 2.33-2.25 (m, IH), 2.14-2.04 (m, 2H), 1.98-1.85 (m, 5H), 1.84-1.77 (m, 4H), 1.75-1.67 (m, 2H), 1.60-1.54 (m, IH), 1.23-1.10 (m, 3H).
Example 1.44: Preparation of (±)-2-Methyl-6-[4-(2-pyrroIidin-l-yl-ethyl)-phenyl]- 1,2,3,3a,4,6a-hexahydro-cyclopenta[cpyrroleDihydrochloride.
Figure imgf000106_0001
The title compound was obtained using general method B. MS m/z 291 A, (M+H); 1H NMR (400 MHz, CD3OD) δ 7.69 (s, IH), 7.60 (s, IH), 7.45 (s, IH), 7.34 (s, IH), 6.16-6.30 (m, IH), 4.21(s, IH), 3.70 (s, IH), 3.35-3.60 (m, 2H), 2.95-3.25 (m, 2H), 2.90 (s, 2H), 2.20 (s, IH), 2.05 (s, IH), 1.20-1.50 (m, 9H), .80-1.00 (m, 3H)
Example 1.45: Preparation of (±)-2-Isopropyl-6-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]- l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride.
Figure imgf000106_0002
The title compound was obtained using general method B. MS m/z 325.6, (M+H); 1H NMR (400 MHz, CD3OD) δ 7.45 (s, 2H), 7.35 (s, 2H), 6.14-6.30 (m, IH), 3.87-4.30 (m, 2H), 3.37-3.80 (m, 5H), 2.99-3.25 (m, 5H), 2.40-2.90 (m, 3H), 1.97-2.30 (m, 4H), 1.30-1.50 (m, 6H), .80-1.00 (m, 2H).
Example 1.46: Preparation of (±)-2-Isobutyl-6-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]- 1 ,2,3,3a,4,6a-hexahydro-cyclopenta [c] pyrrole Dihydrochloride.
Figure imgf000106_0003
The title compound was obtained using general method B. MS m/z 339.4, (M+H); 1H NMR (400 MHz, CD3OD) δ 7.44 (s, 2H), 7.33 (s, 2H), 6.15-6.24 (m, IH), 4.19 (s, IH), 4.05 (s, IH), 3.95 (s, IH), 3.69 (s, 2H), 3.35-3.55 (m, 3H), 2.91-3.20 (m, 7H), 2.40-2.90 (m, 3H), 2.17 (s, 2H), 2.04 (s, 3H), .90-1.10 (m, 6H).
Example 1.47: Preparation of (±)-2-(2,4-Dimethoxy-benzyl)-6-[4-(2-pyrrolidin-l-yl-ethyl)- phenyl]-1 ,2,3,3a,46a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride.
Figure imgf000107_0001
The title compound was obtained using general method B. MS m/z 433.5, (M+H); 1H NMR (400 MHz, CD3OD) δ 7.40 (dd, J1 = 7.6 Hz, J2 = 2.8 Hz, 2H), 7.24-7.36 (m, 2H), 7.22 (dd, J1 = 8.4 Hz, J2 = 2.4 Hz, IH), 6.50-6.62 (m, 2H), 6.20 (d, J = 11.6 Hz, IH), 4.27 (d, / = 16.0 Hz, IH), 3.904.05 (m, IH), 3.70-3.85 (m, 7H), 3.65-3.68 (m, 2H), 3.45-3.60 (m, 4H), 3.02-3.27 (m, 5H), 2.79-3.00 (m, 2H), 2.45 (d, J = 16.0 Hz, IH), 2.10-2.32 (m, 2H), 1.96-2.10 (m, 2H).
Example 1.48: Preparation of (±)-6-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-2-(4- trifluoromethoxy-benzyl)-l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrroIe Dihydrochloride.
Figure imgf000107_0002
The title compound was obtained using general method B. MS m/z 457 'A, (M+H); 1H NMR (400 MHz, CD3OD) δ 7.48-7.67 (m, 2H), 7.38-7.46 (m, 2H), 7.26-7.38 (m, 4H), 6.21 (d, J = 8.8 Hz, IH), 4.40 (d, J = 10.0 Hz, IH), 3.95-4.05 (m, IH), 3.72-3.82 (m, IH), 3.63-3.71 (m, 2H), 3.35-3.62 (m, 4H), 2.80-3.20 (m, 9H), 2.42-2.52 (m, IH), 1.92-2.23 (m, 4H).
Example 1.49 - General Method C
Preparation of (±)-l-{6-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-3,3a,4,6a-tetrahydro-lH- cyclopenta[c] pyrrol-2-yl}-ethanone Hydrochloride.
Figure imgf000107_0003
To a stirring solution of the compound described in Example 1.7 (0.090 g, 0.319 mmol) in dichloromethane (10 mL) was added acetyl chloride (0.052 g, 0.478 mmol) and triethylamine (0.035 mg, 0.351 mmol). The mixture was stirred at room temperature for 2h until the reactants were consumed as determined by LC/MS. The reaction mixture was diluted with dichloromethane (15 mL) and quenched with distilled water (20 mL). The organic extract was washed with brine and dried (MgSO4). The solvent was removed at reduced pressure leaving the crude product. The crude product was purified by passing through a silica gel column using 5% 2 M NH3MeOH in dichloromethane. Purification as described in Example 1.13 afforded the title coumpo (0.0u90n g, d 52.3% a ysield a). T yhe eenalntlioomewrically s pourel isiodmers of this compound (3aS,6aR and 3aR,6aS) were obtained by the same method starting from the corresponding single isomer ketones in Example 1.1. MS m/z 325.5, (M+H); 1H NMR (400 MHz, CD3OD) δ 7.40 (t, J= 8.0 Hz, 2H), 7.30 (t, J= 8.0 Hz, 2H), 6.10 (br s, IH), 3.97-3.81 (m, 2H), 3.80-3.72 (m, IH), 3.71-3.62 (m, IH), 3.51-3.41 (m, 3H), 3.23 (q, J= 6.7 Hz, 2H), 3.13 (q, J= 8.0 Hz, 2H), 3.08-3.01 (m, 2H), 2.81 (dd, J= 16.0, 8.0 Hz, IH), 2.45-2.34 (m, IH), 2.22- 2.10 (m, 2H), 2.07 (s, 2H), 2.05-1.99 (m, 2H), 1.97 (s, 2H).
Example 1.50: Preparation of (3aS,6aS)-Cyclopropyl-{6-[4-(2-pyrrolidin-l-yl-ethyl)- phenyl]-3,3a,4,6a-tetrahydro-lH-cyclopenta[c}pyrrol-2-yl }- lmethanone Hydrochloride.
Figure imgf000108_0001
The title compound was obtained using general method C. MS m/z 351, (M+H); 1H NMR (400 MHz, CH3OD) δ 7.41 (dd, J = 9.1, 9.1 Hz, 2H), 7.30 (dd, J = 8.0, 8.0 Hz, 2H), 6.09- 6.12 (m, IH), 4.06 (dd, /= 18.8, 9.1 Hz, IH), 3.63-3.99 (m, 4H), 3.42-3.52 (m, 3H), 3.02-3.26 (m, 6H), 2.76-2.88 (m, IH), 2.34-2.46 (m, IH), 1.96-2.21 (m, 4H), 1.61-1.83 (m, IH), 0.65-0.89 (m, 4H).
Example 1.51: Preparation of (3aS,6aS)-2-Methyl-l-{6-[4-(2-pyrrolidin-l-yl-ethyl)- phenyl]-3,3a,4,6a-tetrahydro-lH-cyclopenta[c]pyrrol-2-yl}-propan-l-one Hydrochloride.
Figure imgf000108_0002
The title compound was obtained using general method C. MS m/z 353, (M+H); 1H NMR (400 MHz, CH3OD) δ 7.41 (dd, J = 8.0, 6.1 Hz, 2H), 7.30 (dd, J = 7.4, 7.4 Hz, 2H), 6.10 (bs, IH), 3.63-3.96 (m, 5H), 3.42-3.56 (m, 3H), 3.02-3.36 (m, 6H), 2.73-2.86 (m, 2H), 2.33-2.43 (m, IH), 2.10-2.22 (m, 2H), 1.95-2.08 (m, 2H), 1.08 (d, J = 6.8 Hz, 2H), 1.04 (d,J= 6.8 Hz, IH), 1.03 (d, J = 6.8 Hz, 2H), 0.85 (d, J = 6.8 Hz, IH).
Example 1.52: Preparation of (3a.S',6a5)-Cyclopentyl-{6-[4-(2-pyrrolidin-l-yl-ethyl)- phenyl]-3,3a,4,6a-tetrahydro-lH-cyclopenta[c]pyrro}-yl}-methanone Hydrochloride.
Figure imgf000109_0001
The title compound was obtained using general method C. MS m/z 319, (M+H); 1H NMR (400 MHz, CH3OD) δ 7.40 (dd, J = 7.8, 6.1 Hz, 2H), 7.30 (dd, J = 7.8, 7.8 Hz, 2H), 6.10 (bs, IH), 3.63-3.96 (m, 5H), 3.42-3.58 (m, 3H), 3.02-3.37 (m, 6H), 2.70-2.96 (m, 2H), 2.33-2.43 (m, IH), 1.42-1.91 (m, 8H).
Example 1.53: Preparation of (±)-6-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-3,3a,4,6a- tetrahydro-lH-cyclopenta[c]pyrrole Dihydrochloride-2-carboxylic acid ethyl ester Hydrochloride.
Figure imgf000109_0002
The title compound was obtained using general method C. MS m/z 355.3, (M+H); 1H NMR (400 MHz, CD3OD) δ 7.32 (d, J= 8.0 Hz, 2H), 7.21 (d, J= 8.0 Hz, 2H), 6.04 (s, IH), 4.04 (br s, 2H), 3.80 (br s, IH), 3.75-3.61 (m, 2H), 3.38-3.31 (m, IH), 3.18-3.02 (m, 2H), 2.81 (dd, J= 18.0, 6.0 Hz, 4H), 2.72 (s, 5H), 2.33 (d, J= 16.0, IH), 1.91-1.81 (m, 4H), 1.25-1.11 (m, 3H).
Example 1.54: Preparation of (±)-4-Hydroxy-4-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]- hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester.
Figure imgf000109_0003
The title compound was obtained using general method C starting from the title compound in Example 1.6. MS m/z 401.4, (M+H); 1H NMR (400 MHz, MeOEW,) δ ppm 1.45 (s, 9 H) 1.76 - 1.87 (m, 5 H) 2.01 - 2.28 (m, 4 H) 2.63 - 2.69 (m, 4 H) 2.70 - 2.77 (m, 2 H) 2.78 - 2.86 (m, 2 H) 2.86 - 2.97 (m, 2 H) 3.11 - 3.24 (m, 1 H) 3.46 - 3.56 (m, 1 H) 3.59 - 3.73 (m, 1 H) 7.16 - 7.22 (m, 2 H) 7.38 - 7.43 (m, 2 H).
Example 1.55: Preparation of (±)-4-[4-(2-PyrroUdm-l-yl-ethyl)-phenyl]-octahydro- cyclopenta[c]pyrrole Dihydrochloride.
Figure imgf000110_0001
To a solution of the compound described in Example 1.13 (0.100 g, 0.268 mmol) in methanol (5 mL) was added ammonium formate (0.085 g, 1.342 mmol) and Pearlman's catalyst (0.020 g). The mixture was stirred at reflux for 15 min until the reactants were consumed as determined by LC/MS. The mixture was filtered to remove the catalyst, concentrated by rotary evaporation and purified by preparative HPLC to give the title compound. The enantiomerically pure isomers of this compound (3aS,6aR and 3aR,6aS) were obtained by the same method starting from the corresponding single isomer ketones in Example 1.1. MS m/z 285.4 (M+H)
Example 1.56: Preparation of (±)-2-CycIopropylmethyl-4-[4-(2-pyrrolidin-l-yl-ethyl)- phenyl]-octahydro-cyclopenta[c]pyrrole Dihydrochloride.
Figure imgf000110_0002
The title compound was obtained using general method B starting from the title compound in Example 1.55. MS m/z 339.4, (M+H); 1H NMR (400 MHz, CD3OD) δ 7.19-7.43 (m, 4H), 3.85-4.05 (m, IH), 3.59-3.75 (m, 2H), 3.34-3.53 (m, 3H), 2.90-3.25 (m, 10H), 2.38- 2.80 (m, IH), 1.67-2.60 (m, 9H), .60-.8O (m, 2H), .30-.5O (m, 2H).
Example 1.57: Preparation of (±)-2-Isopropyl-4-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]- octahydro-cyclopenta[c]pyrrole Dihydrochloride.
Figure imgf000110_0003
The title compound was obtained using general method B starting from the title compound in Example 1.55. MS m/z 327.3, (M+H); 1H NMR (400 MHz, CD3OD) δ 7.31 (dd, J = 14.0, 10.0 Hz, 4H), 3.92 (t, J= 10.0 Hz, IH), 3.74-3.63 (m, 2H), 3.52-3.40 (m, 2H), 3.39-3.33 (m, IH), 3.24 (dd, J= 20.0, 8.0 Hz, IH), 3.19-3.09 (m, 2H), 3.08-2.99 (m, 2H), 2.71 (dd, J= 10.0, 10.0 Hz, IH), 2.40 (dd, J= 10.0, 10.0 Hz, IH), 2.23-2.09 (m, 3H), 2.08-1.95 (m, 3H), 1.94-1.84 (m, IH), 1.81-1.72 (m, IH), 1.46-1.36 (m, IH), 1.33 (d, J= 8.0 Hz, 3H), 1.30-1.26 (m, IH), 1.24 (d, J= 4.0 Hz, 3H). IP |C If / I B 'R ft R / 111, 11+ 11+ "7 C'.||
11 Example 1.58: Treparkiori of (±)-2-Cyclopentyl-4-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]- octahydro-cycIopenta[c]pyrroIe Dihydrochloride.
Figure imgf000111_0001
The title compound was obtained using general method B starting from the title compound in Example 1.55. MS m/z 320.3, (M+H); 1H NMR (400 MHz, CD3OD) δ 7.29 (dd, / = 16.0, 8.0 Hz, 4H)5 3.90 (t, J= 10.0 Hz, IH), 3.73-3.63 (m, 2H), 3.45-3.37 (m, 3H), 3.36-3.32 (m, IH), 3.28-3.17 (m, 2H), 3.12 (tar dd, J= 20.0, 8.0 Hz, 2H), 3.06-2.98 (m, 3H), 2.97-2.87 (m, IH), 2.70 (dd, J= 12.0, 12.0 Hz, IH), 2.40 (dd, J= 12.0, 12.0 Hz, IH), 2.21-1.96 (m, 8H), 1.93- 1.83 (m, IH), 1.81-1.70 (m, 3H), 1.69-1.49 (m, 3H).
Example 1.59: Preparation of (±)-2-(2,4-Dimethoxy-benzyl)-4-[4-(2-pyrrolidin-l-yl-ethyl)- phenyl] -octahydro-cyclopenta [c] pyrrole Dihydrochloride.
Figure imgf000111_0002
The title compound was obtained using general method B starting from the title compound in Example 1.55. MS m/z 435.4, (M+H); 1H NMR (400 MHz, CDCl3) δ 7.18-7.08 (m, 5H), 6.43-6.38 (m, 2H), 3.78 (s, 3H), 3.70 (s, 3H), 3.40 (ABq, JΛB = 25.7, J= 13.3 Hz, 2H), 3.16-2.94 (m, 3H), 2.83-2.72 (m, 3H), 2.70-2.64 (m, 2H), 2.60-2.54 (m, 4H), 2.50-2.44 (m, IH), 2.04-1.66 (m, 9H), 1.62-1.55 (m, IH).
Example 1.60: Preparation of (±)-2-Cyclohexyl-4-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]- octahydro-cyclopenta[c]pyrrole Dihydrochloride.
Figure imgf000111_0003
The title compound was obtained using general method B starting from the title compound in Example 1.55. MS m/z 367.3, (M+H); 1H NMR (400 MHz, MeOH-^) δ 7.21- 7.12 (m, 4H), 3.39 (dd, J = 8.8, 8.8 Hz, IH), 3.23-3.15 (m, IH), 3.01 (dddd, J = 8.6, 8.6, 8.6, 8.6 Hz, IH), 2.84-2.60 (m, HH), 1.97-1.53 (m, 14H), 1.30-1.00 (m, 6H). o f" T ••'" Il I "-?n IF1IL,/" Nt-Nl-11+'/ "-ill • " ΕxampieiM: W^^^ ethyl)-phenyl]-octahydro-cyclopenta[c]pyrroleDihydrochloride.
Figure imgf000112_0001
The title compound was obtained using general method B starting from the title compound in Example 1.55. MS m/z 339.4 (M+H); Η NMR (400 MHz, CDCl3) δ 7.17 (d, J= 8.2 Hz, 2H), 7.12, (d, J= 8.2 Hz, 2H), 3.30 (ddd, J= 8.7, 8.7, 0.0 Hz, IH), 3.18-3.10 (m, IH), 3.04 (dddd, J= 8.4, 8.4, 8.4, 8.4 Hz, IH), 2.87-2.78 (m, 3H), 2.72-2.54 (m, 8H), 2.31-2.24 (m, 2H), 2.01 (dd, J= 12.2, 7.2 Hz, IH), 1.96-1.67 (m, 6H), 1.62-1.52 (m, 2H), 0.88-0.76 (m, IH), 0.50-0.36 (m, 2H), 0.11—0.04 (m, 2H).
Example 1.62: Preparation of (3ai?,4i?,6a5)-4-{4-[4-(2-PyrroIidin-l-yl-ethyl)-phenyl]- hexahydro-cyclopenta[c]pyrroI-2-yImethyl]-phenoI.
Figure imgf000112_0002
The title compound was obtained using general method B starting from the title compound in Example 1.55. MS m/z 391.2 (M+H); 1H NMR (400 MHz, CDCl3) δ 8.18 (br s, IH), 7.10-6.95 (m, 6H), 6.78 (d, J= 8.5 Hz, 2H), 3.91 (d, J= 12.9 Hz, IH), 3.62 (d, J= 12.9 Hz, IH), 3.35 (ddd, J= 9.4, 9.4, 0.0 Hz, IH), 3.25-2.28 (m, 13H), 2.68-2.60 (m, IH), 2.43-2.35 (m, IH), 2.05-1.61 (m, 7H).
Example 1.63: Preparation of (3ai?,4i?,6a5)-2-Cyclobutyl-4-[4-(2-pyrrolidin-l-yl-ethyl)- phenyl]-octahydro-cyclopenta[c]pyrrole Dihydrochloride.
Figure imgf000112_0003
The title compound was obtained using general method B starting from the title compound in Example 1.55. MS m/z 339.3 (M+H); 1H NMR (400 MHz, CDCl3) δ 7.15 (d, J= 8.3 Hz, 2H), 7.13 (d, J= 8.3 Hz, 2H), 3.17-3.07 (m, 2H), 3.02 (dddd, J- 8.4, 8.4, 8.4, 8.4 Hz, IH), 2.86-2.75 (m, 3H), 2.73-2.62 (m, 3H), 2.61-2.52 (m, 4H), 2.47 (ddd, J= 8.8, 8.8, 0.0 Hz, IH), 1.97-1.54 (m, 15H), 1.43 (ddd, J= 9.2, 9.2, 0.0 Hz, IH). Example 1.64: Preparation of (3aR ,4R ,6aiS)-2-{4-[4-(2-Pyrrolidra-l-yl-ethyl)-phenyl]- hexahydro-cycIopenta[c]pyrrol-2-yl}-propan-l-ol dihydrocholride.
Figure imgf000113_0001
The title compound was obtained using general method B starting from material in Example 1.55. MS m/z 343.4 (M+H); 1HNMR (400 MHz, MeOH-d4,) δ 7.21-7.10 (m, 4H), 3.58-2.52 (m, 16H), 2.48-1.00 (m, 13H).
Example 1.65: Preparation of (±)-2-Isobutyl-4-[4-(2-pyrrolidin-l-yI-ethyl)-phenyl]- octahydro-cyclopenta[c]pyrrole DihydrochIoride.
Figure imgf000113_0002
The title compound was obtained using general method B starting from the title compound in Example 1.55. MS m/z 341.4, (M+H); 1H NMR (400 MHz, CD3OD) 8 7.20-7.40 (m, 4H), 3.82-3.98 (m, IH), 3.62-3.74 (m, 2H), 3.33-3.51 (m, 3H), 2.87-3.46 (m, 10), 2.37-2.63 (m, IH), 1.70-2.42 (m, 9H), .92-1.21 (m, 6H).
Example 1.66: Preparation of (±)-l-{7-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-l,3,3a,4,5,7a- hexahydro-isoindol-2-yl}-ethanone.
Figure imgf000113_0003
The title compound was prepared in a similar manner as described in General Method C. LC-MS m/z 387.5 (M+H); 1H NMR (400 MHz, Methanol-^) δ ppm 7.41 (dd, J= 11.70, 7.80 Hz, 2 H) 7.26 - 7.35 (m, 2 H) 6.14 - 6.26 (m, 1 H) 3.76 - 4.03 (m, 2 H) 3.57 - 3.76 (m, 4 H) 3.40 - 3.57 (m, 3 H) 3.02 - 3.23 (m, 5 H) 2.61 (dd, J= 32.18, 5.85 Hz, 1 H) 2.26 - 2.40 (m, 3 H) 2.12 - 2.26 (m, 3 H) 1.98 - 2.12 (m, 2 H) 1.72 - 1.92 (m, 1 H) 1.49 - 1.67 (m, 1 H).
Example 1.67: Preparation of (±)-2-(4-Methoxy-benzyl)-4-[4-(2-pyrrolidin-l-yl-ethyl)- phenyl]-octahydro-cyclopenta[c]pyrroϊe Dihydrochloride.
- Ill -
Figure imgf000114_0001
The title compound was obtained using general method B starting from the title compound in Example 1.55. MS m/z 405.7, (M+H); 1H NMR (400 MHz, CD3OD) δ 7.41-7.55 (m, IH), 7.20-7.41 (m, 5H), 6.92-7.05 (m, 2H), 4.15-4.41 (m, 2H), 3.78-3.88 (m, 3H), 3.62-3.78 (m, 3H), 3.22-3.52 (m, 3H), 2.90-3.22 (m, 7H), 2.49-2.87 (m, 2H), 1.94-2.26 (m, 6H), 1.90-1.94 (m, 2H).
Example 1.68: Preparation of (±)-4-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-2-(4- trifluoromethoxy-benzyl)-octahydro-cyclopenta[c]pyrrole Dihydrochloride.
Figure imgf000114_0002
The title compound was obtained using general method B starting from the title compound in Example 1.55. MS m/z 459.5, (M+H); 1H NMR (400 MHz, CD3OD) δ 7.44-7.80 (m, 2H), 7.19-7.24 (m, 6H), 4.27-4.50 (m, 2H), 3.60-3.80 (m, 3H), 3.30-3.51 (m, 3H), 2.90-3.20 (m, 6H), 2.50-2.90 (m, 2H), 1.70-2.27 (m, 8H).
Example 1.69: Preparation of (±)-4-{4-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-hexahydro- cyclopenta[c]pyrroI-2-yϊmethyl]-phenolDihydrochloride.
Figure imgf000114_0003
The title compound was obtained using general method B starting from the title compound in Example 1.55. MS m/z 391.7, (M+H); 1H NMR (400 MHz, CD3OD) δ 7.23-7.42 (m, 6H), 6.70-6.88 (m, 2H), 4.14-4.39 (m, 2H), 3.55-3.79 (m, 3H), 3.33-3.50 (m, 3H), 2.87-3.27 (m, 7H), 2.43-2.86 (m, 2H), 1.69-2.27 (m, 8H).
Example 1.70: Preparation of (3a/?,4i?,6aS)-2-Benzyl-4-[4-(2-pyrroIidin-l-yl-ethyl)- phenyl]-octahydro-cyclopenta[c]pyrrole Dihydrochloride.
Figure imgf000115_0001
The title compound was obtained using general method B starting from the title compound in Example 1.55. MS m/z 375.6 (M+H); 1H NMR (400 MHz, MeOH-^) δ 7.28-7.18 (m, 5H), 7.16 (d, J= 8.1 Hz, 2H), 7.11 (d, J= 8.1 Hz, 2H), 3.44 (ABq, JM = 29.0, J= 12.6 Hz, 2H), 3.16 (ddd, J= 13.1, 8.0, 5.7, Hz, IH), 3.08-2.95 (m, 2H), 2.81-2.65 (m, 5H), 2.65-2.58 (m, 4H), 2.39 (dddd, J= 9.0, 9.0, 0.0, 0.0 Hz, IH), 2.05-1.57 (m, 10H).
Example 1.71: Preparation of (±)-2-{4-[4-(2-PyrroHdin-l-yl-ethyl)-phenyl]-hexahydro- cyclopenta[c]pyrroI-2-yl}-propan-l-ol Dihydrochloride.
Figure imgf000115_0002
The title compound was obtained using general method B starting from the title compound in Example 1.55. MS m/z 343.3, (M+H); 1H NMR (400 MHz, CD3OD) δ 7.10-7.50 (bra, 4H), 3.60-3.80 (m, 2H), 3.25-3.55 (m, 7H), 2.90-3.25 (m, 4H), 1.60-2.30 (m, HH), 1.10- 1.50 (m, 6H), .80-1.00 (m, 2H).
Example 1.72: Preparation of (±)-l-{4-[4-(2-PyrroHdin-l-yl-ethyl)-phenyl]-hexahydro- cyclopenta[c]pyrrol-2-yl}-ethanone Hydrochloride.
Figure imgf000115_0003
The title compound was obtained using general method C starting from the title compound in Example 1.55. MS m/z 327.3, (M+H); 1H NMR (400 MHz, CD3OD) δ 7.23-7.30 (m, 4H), 3.60-3.82 (m, IH), 3.10-3.50 (m, 10H), 2.85-3.08 (m, 4H), 1.94-2.25 (m, 9H), 1.85 (s, IH), 1.62-1.75 (m, IH).
Example 1.73: Preparation of (±)-2-Methyl-l-{4-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]- hexahydro-cyclopentafcjpyrrol^-ylj-propan-l-one Hydrochloride.
Figure imgf000116_0001
The title compound was obtained using general method C starting from the title compound in Example 1.55.
MS m/z 355.5, (M+H); 1HNMR (400 MHz, CD3OD) δ 7.24 (s, 4H), 3.80-3.90 (m, IH), 3.60- 3.75 (m, 3H), 3.35-3.55 (m, 4H), 2.75-3.28 (m, 8H), 1.90-2.25 (m, 7H), 1.60-1.72 (m, IH), .95- 1.15 (m, 6H).
Example 1.74: Preparation of (±)-CydopropyI-{4-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]- hexahydro-cydopenta[c]pyrrol-2-yl}-methanone Hydrochloride.
Figure imgf000116_0002
The title compound was obtained using general method C starting from the title compound in Example 1.55. MS m/z 353.4, (M+H); 1HNMR (400 MHz, CD3OD) δ 7.25 (s, 4H), 3.88-4.12 (m, IH), 3.60-3.75 (m, 3H), 3.35-3.50 (m, 4H), 2.75-3.28 (m, 7H), 1.95-2.25 (m, 7H), 1.60-1.90 (m, 2H), .70-.95 (m, 4H).
Example 1.75: Preparation of (±)-Cyclopentyl-{4-[4-(2-pyrrolidin-l-yl-ethyl)-phenyI]- hexahydro-cyclopenta[c]pyrrol-2-yl}-methanone Hydrochloride.
Figure imgf000116_0003
The title compound was obtained using general method C starting from the title compound in Example 1.55. MS m/z 381.4, (M+H); 1H NMR (400 MHz, CD3OD) δ 7.25 (s, 4H), 3.82-3.95 (m, IH), 3.55-3.75 (m, 3H), 3.35-3.50 (m, 4H), 2.75-3.28 (m, 7H), 1.85-2.25 (m, 9H), 1.60-1.85 (m, 8H).
Example 1.76: Preparation of (±)-4-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyI]-hexahydro- cyclopenta[c]pyrrole-2-carboxylic acid ethyl ester Hydrochloride.
Figure imgf000117_0001
The title compound was obtained using general method C starting from the title compound in Example 1.55. MS m/z 357.4, (M+H); 1H NMR (400 MHz, CD3OD) δ 7.17 (s, 4H), 4.14-4.08 (m, IH), 4.03 (br s, IH), 3.59 (dd, J= 16.0, 8.0 Hz, IH), 3.15-3.05 (m, 2H), 2.91-2.77 (m, 4H), 2.76-2.68 (m, 2H), 2.64 (br s, 4H), 2.22-2.10 (m, IH), 2.07-1.91 (m, 3H), 1.84 (s, 4H), 1.69-1.56 (m, IH), 1.30-1.09 (m, 3H).
Example 1.77: Preparation of (±)-2-(4-Methoxy-benzyl)-4-[4-(2-pyrrolidin-l-yl-ethyl)- phenyl]-octahydro-cycIopenta[c]pyrrol-4-ol.
Figure imgf000117_0002
The title compound was obtained using general method B starting from the title compound in Example 1.6. MS m/z 403.4, 421.5, (M+H); 1H NMR (400 MHz, DMSO-d6) δ 7.43 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 7.2 Hz, 2H), 7.22-7.32 (m, 2H), 6.98 (d, J = 7.6 Hz, 2H), 4.47 (d, / = 12.0 Hz, IH), 4.33 (s, IH), 4.02 (d, J = 12.4 Hz, IH), 3.82 (s, 3H) 3.80 (s, IH), 3.60-3.72 (m, 2H), 3.54 (d, J = 10.0 Hz, IH), 3.34-3.44 (m, 3H), 2.90-3.19 (m, 7H), 1.90-2.24 (m, 8H).
Example 1.78: Preparation of (±)-2-Cyclopropylmethyl-4-[4-(2-pyrrolidin-l-yl-ethyl)- phenyl]-octahydro-cyclopenta[c]pyrrol-4-ol.
Figure imgf000117_0003
The title compound was obtained using general method B starting from the title compound in Example 1.6. MS m/z 355.5, (M+H); 1H NMR (400 MHz, CHLOROFORM-*/) δ ppm 7.49 (d, J = 8.59 Hz, 2 H) 7.19 (d, J = 8.08 Hz, 2 H) 3.11 (d, J = 9.60 Hz, 1 H) 2.66 - 2.96 (m, 9 H) 2.54 - 2.63 (m, 1 H) 2.12 - 2.39 (m, 5 H) 1.80 - 2.03 (m, 7 H) 1.59 - 1.74 (m, 1 H) 0.82 - 0.99 (m, 1 H) 0.43 - 0.56 (m, 2 H) 0.04 - 0.17 (m, 2 H). Example 1.79: Preparation of (±)-2-IsobutyI-4-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]- octahydro-cyclopenta[c]pyrrol-4-ol.
Figure imgf000118_0001
The title compound was obtained using general method B starting from the title compound in Example 1.6. MS m/z 357.5, (M+H); 1H NMR (400 MHz, MeOHW,) δ ppm 7.45 (d, J = 8.08 Hz, 2 H) 7.18 (d, J = 8.08 Hz, 2 H) 2.93 (d, J = 9.09 Hz, 1 H) 2.72 - 2.89 (m, 4 H) 2.56 - 2.72 (m, 7 H) 2.15 - 2.30 (m, 4 H) 1.98 - 2.11 (m, 2 H) 1.72 - 1.90 (m, 6 H) 1.52 - 1.66 (m, 1 H) 0.89 - 0.99 (m, 6 H).
Example 1.80: Preparation of (±)-2-Isopropyl-4-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]- octahydro-cyclopenta[c]pyrroI-4-ol.
Figure imgf000118_0002
The title compound was obtained using general method B starting from the title compound in Example 1.6. MS m/z 343.2, (M+H); 1H NMR (400 MHz, MeOH-^) δ ppm 7.43 (d, J = 8.59 Hz, 2 H) 7.18 (d, J = 8.08 Hz, 2 H) 2.94 (d, / = 9.09 Hz, 1 H) 2.73 - 2.88 (m, 3 H) 2.56 - 2.72 (m, 8 H) 2.38 - 2.56 (m, 2 H) 2.26 (dd, J= 9.35, 6.32 Hz, 1 H) 1.95 - 2.19 (m, 2 H) 1.75 - 1.92 (m, 5 H) 1.12 (d, J= 6.06 Hz, 6 H).
Example 1.81: Preparation of (±)-4-[4-(2-Pyrrolidin-l-yI-ethyl)-phenyl]-2-(4- trifluoromethoxy-benzyl)-octahydro-cycIopenta[c]pyrrol-4-ol.
Figure imgf000118_0003
The title compound was obtained using general method B starting from the title compound in Example 1.6. MS m/z 3432, (M+H); 1H NMR (400 MHz, MeOH-^) δ ppm 7.35 - 7.44 (m, 4 H) 7.23 (d, J = 8.59 Hz, 2 H) 7.15 (d, J = 8.08 Hz, 2 H) 3.55 - 3.71 (m, 2 H) 2.71 - 2.93 (m, 4 H) 2.52 - 2.70 (m, 8 H) 2.33 - 2.43 (m, 1 H) 1.95 - 2.22 (m, 3 H) 1.74 - 1.91 (m, 5 H) 1.49 - 1.63 (m, I H). IP C T/ 1,1 S Cl G/ !i+l!+!!+7ni3
Example 1.82: Preparation of (±)-2-(2,4-Dimethoxy-benzyl)-4-[4-(2-pyrrolidin-l-yl-ethyI)- phenyl]-octahydro-cyclopenta[c]pyrrol-4-ol.
Figure imgf000119_0001
The title compound was obtained using general method B starting from the title compound in Example 1.6. MS m/z 351.2, (M+H); 1H NMR (400 MHz, MeOH-J,) δ ppm 7.39 (d, J = 8.08 Hz, 2 H) 7.14 (d, J = 8.08 Hz, 2 H) 7.08 (d, J = 8.0.8 Hz, 1 H) 6.53 (d, / = 2.53 Hz, 1 H) 6.45 (dd, J = 8.08, 2.53 Hz, 1 H) 3.81 (s, 3 H) 3.78 (s, 3 H) 3.45 - 3.63 (m, 2 H) 2.72 - 2.89 (m, 4 H) 2.51 - 2.70 (m, 8 H) 2.31 (t, J= 8.59 Hz, 1 H) 1.94 - 2.18 (m, 3 H) 1.74 - 1.86 (m, 4 H) 1.42 - 1.58 (m, I H).
Example 1.83: Preparation of (±)-2-Cyclohexyl-4-[4-(2-pyrrolidin~l-yl-ethyl)-phenyl]~ octahydro-cyclopenta[c]pyrrol-4-oI.
Figure imgf000119_0002
The title compound was obtained using general method B starting from the title compound in Example 1.6.
MS m/z 383.6, (M+H); 1H NMR (400 MHz, MeOH-J,) δ ppm 1.25 - 1.36 (m, 5 H) 1.55 - 1.65 (m, 2 H) 1.70 - 1.97 (m, 9 H) 1.99 - 2.36 (m, 4 H) 2.47 - 2.73 (m, 8 H) 2.75 - 2.86 (m, 4 H) 2.98 - 3.11 (m, 1 H) 7.14 - 7.21 (m, 2 H) 7.41 - 7.47 (m, 2 H)
Example 1.84: Preparation of (±)-2-Cydopentyl-4-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]- octahydro-cyclopenta[c]pyrrol-4-olcarboxylic acid tert-butyl ester.
Figure imgf000119_0003
The title compound was obtained using general method B starting from the title "''compound in Example 1.6. MS' m/z 369.4, (M+H); 1H NMR (400 MHz, MeOH-d4) δ ppm 1.45 - 1.66 (m, 5 H) 1.68 - 1.77 (m, 2 H) 1.80 - 1.93 (m, 7 H) 1.98 - 2.18 (m, 2 H) 2.26 (dd, 1 H) 2.48 - 2.59 (m, 1 H) 2.59 - 2.65 (m, 5 H) 2.69 (s, 4 H) 2.76 - 2.89 (m, 3 H) 2.90 - 3.04 (m, 1 H) 7.14 - 7.23 (m, 2 H) 7.33 - 7.52 (m, 2 H)
Example 1.85- General Method D
Preparation of (3aS,6aS)-6-[4-(2-Pyrrolidin-1-yl-ethy^-phenyl]-3,3a,4,6a-tetrahydro-lH- cyclopenta[c]-pyrrole-2-carboxylic acid isopropylamide Hydrochloride.
Figure imgf000120_0001
To a solution of the compound described in Example 1.7 (160.5 mg, 568 μmol) in dichloromethane (3.0 mL) was added isopropyl isocyanate (61.4 μl, 625 μmol) and stirred at room temperature for 1.5 hr. Upon completion, the reaction mixture was filtered through a short column of silica gel with MeOH and concentrated at reduced pressure. The crude product was purified by HPLC. The product (76.7 mg, 36.7%) obtained was made into an HCl salt. The enantiomerically pure isomers of this compound (3aS,6aR and 3aR,6aS) were obtained by the same method starting from the corresponding single isomer ketones in Example 1.1. MS m/z 368, (M+H); 1H NMR (400 MHz, CH3OD) δ 7.38 (d, J = 7.8 Hz, 2H), 7.28 (d, / = 8.3 Hz, 2H), 6.08 (d, J = 2.0 Hz, IH), 3.79-3.90 (m, 2H), 3.63-3.74 (m, 4H), 3.40-3.47 (m, 2H),' 3.32-3.37 (m, IH), 3.01-3.19 (m, 6H), 2.75-2.84 (m, IH), 2.34-2.42 (m, IH), 1.96-2.22 (m, 5H), 1.09-1.14 (m, 6H).
Example 1.86: Preparation of (3aS,6aS)-6-[4-(2-Pyrrolidin-1-yl-ethyl)-phenyl]-3,3a,4,6a- tetrahydro-lH-cyclopenta[c]pyrrole-2-carboxylic acid cyclopentylamide.
Figure imgf000120_0002
The title compound was obtained using general method D. MS m/z 394, (M+H); 1H
NMR (400 MHz, CH3OD) δ 7.38 (dd, / = 8.0, 1.7 Hz, 2H), 7.27 (dd, J = 8.0, 1.7 Hz, 2H), 6.06- 6.10 (m, IH), 3.90-3.99 (m, IH), 3.80-3.88 (m, IH), 3.41-3.47 (m, 2H), 3.28-3.36 (m, IH), 3.01- 3.17 (m, 6H), 2.75-2.83 (m, 2H), 2.34-2.42 (m, IH), 1.95-2.22 (m, 4H), 1.83-1.94 (m, 2H), 1.35- 1.74 (m, 6H).
Example 1.87- General Method E pi;VrepaMlώ hexahydro-cycIopenta[c]pyrrole Dihydrochloride.
Figure imgf000121_0001
IQ a 5 mL glass tube were placed the compound described in Example 1.7 (0.200 g, 0.708 mmol), bromobenzene (0.074, 0.472 mmol), potassium t-butoxide (0.079 g, 0.708 mmol), 3 mL of methyl sulfoxide, and a magnetic stir bar. The vessel was sealed with a septum and placed into a microwave cavity. With microwave irradiation, the temperature was ramped from room temperature to 2000C and held for 5 min. After the mixture was allowed to cool to room temperature, the reaction vessel was opened and the reaction mixture was filtered. The mixture was purified via preparative HPLC. Purification afforded 0.021 g (12.4%) of the title compound as a yellow viscous solid. The enantiomerically pure isomers of this compound (3aS,6aR and 3aR,6aS) were obtained by the same method starting from the corresponding single isomer ketones in Example 1.1. MS m/z 359.2, (M+H); 1H NMR (400 MHz, CD3OD) δ 7.39 (d, J= 8.0 Hz, 2H), 7.21 (d, J= 8.0 Hz, 2H), 7.12 (t, J= 8.0 Hz, 2H), 6.65-6.55 (m, 3H), 6.06 (s, IH), 4.59 (br s, IH), 3.91 (br s, IH), 3.63-3.51 (m, 2H) 3.24-3.15 (m, IH), 3.09 (dd, J= 8.0, 4.0 Hz, IH), 3.04 (dd, J= 8.0, 4.0 Hz, IH), 2.91-2.76 (m, 5H), 2.72 (br s, 4H), 2.43 (dd, J= 20.0, 4.0 Hz, IH), 1.89-1.82 (m, 3H).
Example 1.88: Preparation of (±)-2-Pyridin-2-yI-6-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]- l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride.
Figure imgf000121_0002
The title compound was obtained using general method E. MS m/z 360.3, (M+H); 1H NMR (400 MHz, CD3OD) δ 7.91 (dd, J= 8.0, 8.0Hz, 2H), 7.84 (d, J= 4.0 Hz, 2H), 7.33 (d, J= 8.0 Hz, 2H), 7.02 (d, J= 8.0 Hz, IH), 6.87 (t, J= 8.0 Hz, IH), 6.15 (s, IH)5 4.12 (br s, IH), 4.04-3.94 (m, 2H), 3.67 (br s, 2H), 3.58 (dd, J= 12.0, 4.0 Hz, IH), 3.48-3.33 (m, 4H), 3.22-3.03 (m, 4H), 2.94-2.83 (m, IH), 2.52 (d, J= 16.0 Hz, IH), 2.12 (br s, 4H).
Example 1.89- General Method F
Preparation of (3ai-»,6a5)-2-Hydroxy-l-{6-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-3,3a,4,6a- tetrahydro-lH-cyclopentafcJpyrrol^-ylJ-ethanone.
Figure imgf000122_0001
A solution of acid (118.0 mg, 1.55 mmol) and PS-DCC (1.44 g, 1.44 mmol) in dichloromethane (14.0 mL) and DMF (1.0 mL) was stirred for 10 min before adding the amine from Example 1.7 (186.0 mg, 0.659 mmol) dissolved in 5 mL of dichloromethane. After 12 h, the resin was filtered and washed with dichloromethane and MeOH. The solution was concentrated. The over-coupled ester product was treated with NaOH in MeOH for 1 hr. Upon completion, the reaction mixture was acidified with TFA and concentrated. The crude product was purified by HPLC (57 mg, 25.4%) and made into an HCl salt. The enantiomerically pure isomers of this compound (3aS,6aR and 3aR,6aS) were obtained by the same method starting from the corresponding single isomer ketones in Example 1.1. MS m/z 341, (M+H); 1H NMR (400 MHz, CH3OD) δ 7.40 (d, J = 8.2 Hz, 2H), 7.30 (dd, J= 8.0, 3.9 Hz, 2H), 6.08-6.12 (m IH), 4.04-4.15 (m, 2H), 3.63-3.96 (m, 6H), 3.42-3.54 (m, 3H), 3.02-3.35 (m, 6H), 2.76-2.86 (m, IH), 2.35-2.43 (m, IH), 1.95-2.23 (m, 4H).
Example 1.90: Preparation of (±)-2-Hydroxy-l-{4-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]- hexahydro-cyclopenta[c]pyrrol-2-yl}~ethanone.
Figure imgf000122_0002
The title compound was obtained using general method F. MS m/z 343.3, (M+H); 1H NMR (400 MHz, CD3OD) δ 7.05-7.15 (m, 4H), 4.05-4.25 (m, IH), 3.85-4.00 (m, IH), 3.55-3.75 (m, 3H), 3.35-3.50 (m, 4H), 2.80-3.25 (m, 6H), 1.90-2.25 (m, 7H), 1.60-1.90 (m, 2H), 1.10-1.50 (m, IH), .80-1.00 (m, IH).
Example 1.91: Preparation of (±)-2-Hydroxy-2-methyl-l-{6-[4-(2-pyrrolidin-l-yl-ethyl)- phenyl]-3,3a,4,6a-tetrahydro-lH-cyclopenta[c]pyrrol-2-yl}-propan-l-one.
Figure imgf000122_0003
The title compound was obtained using general method F. MS m/z 369.2, (M+H); 1H NMR (400 MHz, CD3OD) δ 7.33 (d, J= 8.0 Hz, 2H), 7.20 (d, J= 8.0 Hz, 2H), 6.04 (s, IH), 4.27-4.01 (m, IH), 4.00-3.68 (m, 3H), 3.66-3.56 (m, IH), 3.52-3.37 (m, IH), 3.19-2.94 (m, IH), lf '4i5-2:73'tm; 3H)1, 2.72-2.66 (m, 2H), 2.60 (s, 4H), 2.35 (d, J= 16.0 Hz, IH), 1.85-1.79 (m, 4H), 1.37 (dd, J= 8.0 Hz, 3H), 1.28 (s, 2H), 1.10 (s, IH).
Example 1.92- General Method G Preparation of (±)-4-(2-Benzyl-l,2,3,3a,6,6a-hexahydro-cyclopenta[c]pyrrol-4-yl)- phenylamine.
Figure imgf000123_0001
To a microwave vial was added trifluoromethanesulfonic acid 2-benzyl-l,2,3,3a,6,6a- hexahydro-cyclopenta[c]pyrrol-4-yl ester (0.20Og, 0.586 mmol), 4-aminophenylboronic ester (0.253g, 1.15 mmol), tetrakis palladium triphenylphosphine (0.067g, 0.058 mmol), 2.0 M sodium carbonate in water (0.575 mL) dissolved in toluene:EtOH (2:1) and sealed under argon. The reaction was stirred at 1000C for 5400s on the smith synthesizer. The crude mixture was diluted with EtOAc and washed with water. The organic layer was concentrated, and diluted with DMSO for purification on the HPLC, using method 10-60% over 25 min. The pure fractions were combined, neutralized with saturated solution of sodium bicarbonate, and extracted with EtOAc. The organic layers were combined and concentrated (0.112g, 67%). MS m/z 291.0, (MfH); 1H NMR (400 MHz, DMSO-J6) δ ppm 7.39 - 7.52 (m, 6 H) 7.34 (d, J = 8.08 Hz, 2 H) 6.93 (d, J = 8.59 Hz, 2 H) 6.66 (d, J = 7.58 Hz, 1 H) 6.10 (s, 1 H) 4.26 - 4.43 (m, 2 H) 3.74 - 4.08 (m, 2 H) 3.68 (t, J= 9.09 Hz, 1 H) 3.01 - 3.55 (m, 2 H) 2.65 - 2.88 (m, 1 H) 2.36 (d, J = 18.19 Hz, I H).
Example 1.93: Preparation of (±)-5-(2-Benzyl-l,2,3,3a,6,6a-hexahydro- cyclopenta[c]pyrrol-4-yl)-pyridin-2-ylamine.
Figure imgf000123_0002
The title compound was obtained using general method G. MS m/z 292.1 , (M+H); 1H
NMR (400 MHz, DMSO-^6) δ ppm 7.28 - 8.12 (m, 7 H) 6.67 - 6.98 (m, 1 H) 6.16 (s, 1 H) 4.14 ■ 4.51 (m, 2 H) 2.17 - 4.01 (m, 8 H) 0.96 - 1.18 (m, 1 H).
Example 1.94: Preparation of (±)-2-[4-(2-Benzyl-l,2,3,3a,6,6a-hexahydro- cyclopenta[c]pyrrol-4-yl)-phenyl]-ethylamine.
Figure imgf000124_0001
The title compound was obtained using general method G. MS m/z 319.2, (M+H).
Example 1.95: Preparation of (±)-l-{4-Hydroxy-4-[4-(2-pyrroIidin-l-yl-ethyl)-phenyl]- hexahydro-cyclopenta[c]pyrrol-2-yl}-ethanone.
Figure imgf000124_0002
The title compound was obtained using general method C starting from the title compound in Example 1.6. MS m/z 343.1, (M+H); 1H NMR (400 MHz, MeOH-^) δ ppm 1.77 - 1.91 (m, 5 H) 2.00 - 2.05 (m, 3 H) 2.06 - 2.30 (m, 3 H) 2.60 - 2.68 (m, 4 H) 2.67 - 2.77 (m, 2 H) 2.78 - 2.87 (m, 2 H) 2.87 - 3.11 (m, 2 H) 3.33 - 3.58 (m, 2 H) 3.61 - 3.71 (m, 1 H) 3.71 - 3.90 (m, 1 H) 7.14 - 7.24 (m, 2 H) 7.35 - 7.49 (m, 2 H)
Example 1.96: Preparation of (±)-4-Hydroxy-4-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]- hexahydro-cyc!openta[c]pyrroIe-2-carboxylic acid ethyl ester.
Figure imgf000124_0003
The title compound was obtained using general method C starting from the title compound in Example 1.6. MS m/z 373.3, (M+H); 1H NMR (400 MHz, MeOH-^) δ ppm 1.20 - 1.30 (m, 3 H) 1.81 - 1.87 (m, 4 H) 2.05 - 2.14 (m, 2 H) 2.14 - 2.29 (m, 1 H) 2.61 - 2.70 (m, 4 H) 2.71 - 2.78 (m, 2 H) 2.78 - 2.87 (m, 2 H) 2.88 - 3.00 (m, 2 H) 3.18 - 3.27 (m, 1 H) 3.32 - 3.39 (m, 1 H) 3.53 - 3.62 (m, 1 H) 3.63 - 3.75 (m, 1 H) 4.04 - 4.13 (m, 2 H) 7.14 - 7.26 (m, 2 H) 7.35 - 7.46 (m, 2 H).
Example 1.97: Preparation of 2-vinyl-3-bromopyridine.
Figure imgf000124_0004
A solution of 2,5-dibromopyridine (4800 mg, 20.3 mmol), tributyl(vinyl)tin (6.43 g,
20.3 mmol), tetrakis(triphenylphosphine) palladium (0) (1.17 g, 1.01 mmol) in 15 mL of toluene p ir I" / 1 ISfS K ,■■" «4. B+ ii+ 7' qi
1 "'"was heated to 170 0C for 0.1*5 hf under microwave irradiation in a heavy walled sealed tube. The suspension was extracted with 500 mL of toluene, treated with KF solution, followed by NaOH solution. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure to afford a yellow viscous solid as product. Compound was purified by silica column eluted with (0-5% EtOAc/n-hexane) to afford a white viscous solid. (2.25g, 60.3%). 1H NMR (400 MHz, OMSO-d6) δ 8.83 (d, J = 2.3 Hz, IH), 8.02 (dd, J = 8.44, 2.35 Hz, IH), 7.49 (d, J = 2.3 Hz, IH), 6.79 (dd, J =16.00, 12.29 Hz, IH), 6.23 (dd, J = 16.00, 1.48 Hz, IH), 5.52 (dά,J =12.29, 1.48Hz, IU).
Example 1.98: Preparation of 2-(2-pyrrolidin-l-yl-ethyl)-5-bromopyridine.
Figure imgf000125_0001
To a solution of 2-vmyl-3-bromopyridine (2.25 g, 12 mmol) in 10 mL of anhydrous THF was added pyrrolidine (1.0 mL, 12 mmol) and sodium tert-butoxide (1.2 g, 12 mmol). The mixture was heated to 80 0C for 24 hr under pressure in a heavy walled sealed tube. After 24 hours, reaction was quenched with water, the product was extracted into DCM and washed with 2M HCl. The aqueous layer was then basified with solid Na2CO3 to pH=10.0 and extracted with DCM. The combined organic layers was dried (MgSO4) and concentrated at reduced pressure to give the title compound as a yellow solid (1.82g, 58.0%). MS m/z 357.3, (M+H); 1H NMR (400 MHz, DMSO-J6) δ 8.58 (d, J = 2.36 Hz, IH), 7.93 ( dd, J = 8.33, 2.36 Hz, IH), 7.30 (d, J = 8.33 Hz, IH), 2.87 (t, 2H), 2.76 (t, 2H), 2.50 (m, 8H).
Example 1.99: Preparation of (±)-2-Benzyl-4-[5-(2-pyrrolidin-l-yl-ethyl)-pyridin-3-yl]- octahydro-cyclopenta[c]pyrrol-4-ol.
Figure imgf000125_0002
2-(2-Pyrrolidin-l-yl-ethyl)-5-bromopyridme (800.0mg, 3.1 mmol) was dissolved in anhydrous THF under N2 and cooled to -780C. n-BuLi (2.5M in THF, 1.6 mL, 4.1 mmol) was added dropwise at the same temperature and the mixture was stirred for 15 minutes. The compound described in Example 1.1 (0.68 g, 3.1 mmol) dissolved in 20 mL of THF was added dropwise at -78°C and the mixture was stirred at -78°C for 3 hours, then allowed to warm to room temperature. The mixture was quenched with water and the volatiles were removed under reduced pressure. The product was taken up in DCM and washed with water and sat. aq. i
Figure imgf000126_0001
d|;lried over MgSO4, concentrated under reduced pressure to afford brown viscous oil as final product. Purification by HPLC afforded the title compound as a yellow viscous oil (LOg, 81.0%). MS m/z 392.4, (M+H); 1H NMR (400 MHz, CDCl3) δ 8.79 (m, IH), 8.20-8.25 (m, IH), 7.70-7.74 (m, IH), 7.23-7.43 (m, 5H), 4.23 (d, IH), 4.30-4.20 (t, 2H), 4.17 (m, 2H), 4.00(d, IH), 3.45-3.70 (m, 2H), 3.20-3.40 (m, 2H), 3.00-3.20 (m, 4H), 2.95 (m, IH), 2.40-2.50 (m, 2H), 2.15-2.30 (m, 2H), 2.00-2.20 (m, 4H), 1.80-2.00 (m, IH).
Example 1.100: Preparation of (±)-2-Benzyl-6-[6-(2-pyrrolidin-l-yl-ethyl)-pyridin-3-yl]- l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride.
Figure imgf000126_0002
To a solution of the compound described in Example 1.99 (200mg, 511 μmol) in 5 mL of DCM was added Et3N (107 μl, 766 μmol) and methanesulfonyl chloride (59.3 μl, 766 μmol). The mixture was stirred at room temperature for 24 hr in a sealed vial, quenched with water and extracted with DCM. The product was extracted with IN HCl, the aqueous layer was isolated, treated with Na2CO3 then extracted with DCM. The organic layer was dried over MgSO4, volatiles were removed under reduced pressure and the crude was purified by silica gel chromatography: eluted with EtOAc/5%MeOH/NH3 in DCM to afford the title compound as a yellow viscous liquid. MS m/z 374.3, (M+H); 1H NMR (400 MHz, CDCl3) δ 8.52 (d, IH), 7.56 (dd, IH), 7.57-7.18 (m, 5H), 7.09 (d, IH), 6.09 (m, IH), 3.67 (m, IH), 3.65 (d, IH) 3.45 (d, IH), 3.00-3.30 (m, IH), 3.00 (m, 3H), 2.95 (m, IH), 2.80 (t, 2H), 2.65-2.75 (m, IH), 2.58 (m, 4H), 2.25-2.35 (m, IH), 2.16(m, 2H), 1.76 (m,4H).
Example 1.101: Preparation of (±)-2-Benzyl-4-[4-(2~pyrrolidin-l-yl-ethoxy)-phenyl]- octahydro-cyclopenta[c]pyrrol-4-ol.
Figure imgf000126_0003
4-(2-pyrrolidinoethoxy)phenyl bromide (439 mg, 1626 μmol) was dissolved in anhydrous THF under N2, stirred at room temperature for a 10 min., then cooled to -780C. n- BuLi (2.5 M in hexanes, 0.845 mL, 2.1 mmol) was added dropwise and the mixture was stirred for 1 hour. The ketone described in Example 1.1 (350mg, 1.6 mmol), dissolved in 10 mL of THF was added dropwise. The resulting mixture was stirred at -78°C for 3 hours then allowed r> in "T ■" ii !lEϊ[ It'lf lFii ••'" »+Ni»LIK7 l|;;ii
''"' 'HoVarffl to fόom'temperature overnight. The mixture was quenched with water and the volatiles were removed under reduced pressure. The product was taken up in DCM, washed with water, dried over MgSO4, and then concentrated to afford a yellow oil. Purified by column chromatography (EtOAc, 10%NH3-MeOH in DCM) to afford the title compound as a yellow oil (0.25g, 37.8%). MS m/z 407.2, (M+H); 1H NMR (400 MHz, CDCl3) δ 7.22-7.37 (d, 2H), 7.13- 7.21 (m, 5H), 6.85-6.77 (m, 3H), 4.02 (t, 2H), 3.65 (d, IH) 3.29 (d, IH), 3.90 (d, IH)5 2.70-2.80 (t, 2H), 2.65 (m, IH), 2.60 (m, IH), 2.50-2.60 (m, 4H), 2.20 (d, IH), 2.00(m, 2H), 1.90 (m, IH), 1.80 (m, 2H), 1.60-1.70(m, 4H), 1.50 (m, IH).
Example 1.102: Preparation of (±)-2-Benzyl-6-[4-(2-pyrrolidin-l-yl-ethoxy)-phenyl]- l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride.
Figure imgf000127_0001
The compound described in Example 1.101 (250.00mg, 615 μmol) was dissolved in 5 mL of DCM. Methanesulfonyl chloride (95.2 μl, 1230 μmol) and triethylamine (171 μl, 1230 μmol) were added. The mixture was stirred at 25 0C for 24 hr in a sealed vial. The reaction was quenched with water and extracted with DCM. The combined organic layers were dried over MgSO4 and concentrated at reduced pressure. Purification by silica gel chromatography (EtOAc/ 5%MeOH/NH3 in DCM) gave the title compound as a yellow oil (1 lO.Omg, 46.0%). MS tn/z 389.3, (M+H); 1H NMR (400 MHz, CDCl3) δ 7.25-7.34 (m, 7H), 6.89 (d, 2H), 5.94 (m, IH), 4.14 (t, 2H), 3.66 (m, IH), 3.63 (d, IH), 3.52 (d, IH), 3.14 (t, IH), 2.99 (m, 2H), 2.91 (t, 2H), 2.79 (m, 2H), 2.75 (m, 4H), 2.35 (m, 2H), 1.83 (m, 4H).
Example 1.103: Preparation of 3~(2-pyrrolidinoethoxy)phenyl bromide.
Figure imgf000127_0002
To a stirred solution of 3-bromophenol (2.00 g, 11.6 mmol) in 2.0 mL of anhydrous
DMF at room temperature was added solid NaH (2.77 g, 116 mmol) in small portions, then reaction mixture was stirred at 70 0C for 5 minutes, then a solution of l-(2- chloroethyl)pyrrolidine (7.86 g, 46.2 mmol) in 3 mL of anhydrous DMF was added and the mixture was stirred at the same temperature. The reaction was quenched with water and extracted with EtOAc. The combined organic layers were dried over MgSO4, then concentrated to afford brown viscous oil. Purification by silica gel chromatography (EtOAc) gave the title compound as a red oil (1.54g, 49.3%). MS m/z 272.0, (M+H); 1H NMR (400 MHz, CDCl3 ) δ 7.11-7.04 (m, 3H), 6.84 ( m, IH), 4.08 (t, 2H), 2.93 (t, 2H), 2.76 (m, 4H), 1.80 (m, 4H). p if jj- / 1| I ic if! pji / 114.114.114. "7 ig
'Example i'ϊoi: Preparation of (±)-2-Benzyl-4-[3-(2-pyrrolidin-l-yl-ethoxy)-phenyl]- octahydro-cyclopenta[c]pyrrol-4-ol.
Figure imgf000128_0001
A solution of 3-(2-pyrrolidinoethoxy)phenyl bromide (500mg, 1.85 mmol) in 50 mL anhydrous TBDF under N2 was cooled at -780C. n-BuLi (2.5 M in hexanes, 1.02 mL, 2.5 mmol) was added dropwise at the and the mixture stirred for 1 hour. The ketone from Example 1.1 (500 mg, 2.3 mmol) dissolved in 10 mL of THF was then added dropwise. The mixture was stirred at -780C for 3 hours, and allowed to warm to room temperature over night. The reaction was quenched with water and concentrated. The product was dissolved in EtOAc and washed with water, dried with MgSθ4 and concentrated to afford a yellow oil. Purification by silica gel chromatography (EtOAc/10%NH3-MeOH in DCM) gave the title compound as a yellow oil. MS m/z 407.2, (M+H); 1H NMR (400 MHz, CDCl3) δ 7.04-7.28 (m, 6H), 7.02 (m, IH), 6.87 (m, IH), 6.73 (m,lH), 4.08 (t, 2H), 3.67 (d, IH) 3.42 (d, IH), 2.95 (d, IH), 2.80-2.90 (t, 2H), 2.75 (m, IH), 2.65 (m, IH), 2.50-2.60 (m, 4H),2.50 (m,2H), 2.20 (m, 2H), 2.00(m, IH), 1.95 (m, 2H), 1.70-1.80 (m, 4H), 1.50 (m, IH).
Example 1.105: Preparation of (±)-2-Benzyl-6-[3-(2-pyrrolidin-l-yl-ethoxy)-phenyl]- l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride.
Figure imgf000128_0002
The title compound was obtained using the method described in Example 1.101. MS m/z 389.5, (M+H); 1H NMR (400 MHz, CDCl3) δ 7.13-7.42 (m, 5H), 7.29 (m, IH), 6.80-7.00( m, 3H),6.10 (m, IH), 4.50 (t, 2H), 3.66 (m, IH), 4.00-4.20 (m, 4H), 3.90 (m, 2H), 3.80 (t, IH), 3.60 (m, 2H), 3.50 (m, IH), 3.10 (m, 2H), 2.60 (m, 2H),2.40(m, IH), 2.00-2.20 (m, 4H).
Example 1.106: Preparation of 2-Bromo-5-(2-methoxyvinyl)-pyridine.
Figure imgf000128_0003
In a 500 mL Round-bottomed flask equipped with a stir bar and a nitrogen inlet was placed (methoxy-methyl)triphenylphosphonium chloride (9.2g, 27 mmol) and 40 mL of anhydrous THF. The mixture was cooled to O0C and n-BuLi (2.5M in THF, 11.0 mL, 27.5mmol) was added dropwise to the suspension under N2. After Ih at O0C, the solid P " f su rsp /en!&sio&n& tur Bned ,/ i.'n Ntol-1H ak b"r+ow 7n "iis|h solution. A solution of 2-bromo-3-pyridylcarboxaldehyde
(5.Og, 27mmol) in 15 mL anhydrous THF was added dropwise into the solution at O0C. After 3h at O0C, the mixture was stirred at room temperature overnight before being quenched with H2O. The reaction mixture was extracted with EtOAc and the organic extract was dried and concentrated to give the crude product as an oil. Purification by silica gel chromatography gave the title compound as mixture of both E and Z isomers (2.9g, 50%). MS m/z 214.0 (M+H); 1H NMR (400 MHz, CDCl3) δ 8.42 (d, IH), 8.23 (d, IH), 7.87 (dd, IH), 7.40(m, 3H), 7.09 (d, IH), 6.30(d, IH), 5.71(d, IH), 5.17 (d, IH), 3.84 (s, 3H), 3.73 (s, 3H).
Example 1.107: Preparation of 2-bromo-5-(2-pyrrolidin-l-yI-ethyl)-pyridine.
Figure imgf000129_0001
To a solution of the compound described in Example 1.106 (2.5g, 12 mmol) in 7.5 mL of 10:1 acetonitrile/H2O was added a solution of 4M HCl (5.0 mL, 23mmol) in dioxane. The mixture was stirred at 230C for 3h. After removal of the solvent under vacuum, the oil residue was dissolved in dichloromethane and washed with H2O. The organic extract was dried and concentrated to give 2.3 g of the crude aldehyde intermediate. The intermediate was dissolved in 20 mL THF and pyrrolidine (0.818g, 11.5mmol) was added. The mixture was stirred for about 30 min and sodium triacetoxyborohydride (4.87g, 23.0mmol) was added in small portions. The reaction mixture was stirred at room temperature for 1 h then quenched with H2O. After adjusting to pH ~11 with aqueous NaOH, the desired product was extracted with EtOAc. The combined organic layers were dried, concentrated at reduced pressure and purified by column chromatography to give the title compound. MS m/z 255.0 (M+H); 1H NMR (400 MHz, CDCl3) δ 8.23 (d, IH), 7.41 (m, 2H), 2.79(m, 2H), 2.67 (m, 2H), 2.55 (m, 4H), 1.81 (m, 4H).
Example 1.108: Preparation of (±)-2-Benzyl-4-[5-(2-pyrroIidin-l-yl-ethyl)-pyridin-2-yl]- octahydro-cyclopenta[c]pyrrol-4-ol.
Figure imgf000129_0002
In a sealed scintillation vial under N2 was placed the compound described in Example 1.107 0.228g, 0.894mmol) and anhydrous THF (5 mL). A solution of 2.5M BuLi in THF (0.465 mL) was added dropwise at -780C. The mixture was stirred for Ih at -780C under N2 and the ketone described in Example 1.1 (192mg, 0.894mmol) dissolved in 1 mL of dry THF was added C d TroVpw" IiJse STT Hhe 6 "re /su"l 1It.Iin-4g" m1''!ix"1?tu1r 1e1UiU was stirred for 2h at the same temperature then quenched with
H2O. After extraction with CH2C12/H2O, the combined organics were dried and concentrated. The crude product was purified by silica gel chromatography to give the title compound (190 mg, 54%). MS m/z 392.3 (M+H); 1H NMR (400 MHz, CDCl3) δ 8.39 (d, IH), 7.71 (d, IH), 7.50 (m, IH), 7.31 (m, 5H), 4.12 (d, IH), 3.74 (m, IH)5 3.71 (s, IH), 3.02 (m, IH), 2.66-2.92 (m, 9H) 2.57 (m, 4H), 2.17-2.28 (m, 4H), 1.79 (m, 4H).
Example 1.109: Preparation of (±)-2-Benzyl-6-[5-(2-pyrrolidin-l-yl-ethyI)-pyridin-2-yI]- l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole DihydrochIoride.
Figure imgf000130_0001
The title compound was obtained by the method described in Example 1.102 starting with the compound described in Example 1.108. MS m/z 374.5 (M+H); 1H NMR (400 MHz, CDCl3) δ 8.80 (m, IH), 8.10 (m, IH), 7.82 (m, IH), 7.32-7.42 (m, 5H), 6.71 (m, IH), 4.00-4.45 (m, 3H), 3.75-3.96 (m, 4H), 3.25-3.45 (m,4H), 3.20 (m, 3H), 2.90 (m, 4H), 2.1 l(m, 4H).
Example 1.110: Preparation of (±)-2-benzyl-octahydro-isoindol-4-one.
Figure imgf000130_0002
The title compound was prepared in a similar manner as described in Example 1.1, starting with cyclohexenone. LC-MS m/z 230.5 (M+H); 1H NMR (400 MHz, MeOH-cQ δ ppm 7.00 - 7.58 (m, 5 H) 3.59 (s, 2 H) 2.65 - 2.97 (m, 5 H) 2.13 - 2.46 (m, 3 H) 1.73 - 1.96 (m, 3 H) 1.30 - 1.48 (m, I H).
Example 1.111: Preparation of (±)-2-Benzyl-4-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]- octahydro-isoindol-4-ol
Figure imgf000130_0003
The title compound was prepared in a similar manner as described in Example 1.3. LC- MS m/z 405.7 (M+H); 1H NMR (400 MHz, Methanol-^) δ ppm 7.35 - 7.42 (m, 2 H) 7.20 - 7.35 (m, 5 H) 7.09 - 7.15 (m, 2 H) 3.72 (s, 2 H) 2.84 - 2.92 (m, 1 H) 2.55 - 2.83 (m, 12 H) 2.42 - 2.50 lL(nl, ϊ &γ±l4 -±37 Cm, 1 Hj \.7S - 1.99 (m, 5 H) 1.67 - 1..175 (m, 2 H) 1.58 - 1.66 (m, 1 H) 1.36 - 1.47 (m, 1 H).
Example 1.112: Preparation of (±)-2-Benzyl-7-[4-(2-pyrroIidin-l-yl-ethyl)-phenyl]- 2,3,3a,4,5,7a-hexahydro-lH-isoindole.
Figure imgf000131_0001
The title compound was prepared in a similar manner as described in Example 1.7. LC- MS m/z 387.5 (M+H); 1H NMR (400 MHz, MeOH-^) δ ppm 7.19 - 7.32 (m, 7 H) 7.13 (d, J=8.08 Hz, 2 H) 6.08 (t, /=3.79 Hz, 1 H) 3.57 (s, 2 H) 3.08 - 3.17 (m, 1 H) 2.93 - 3.01 (m, 1 H) 2.74 - 2.84 (m, 2 H) 2.63 - 2.72 (m, 2 H) 2.43 - 2.63 (m, 6 H) 2.24 - 2.32 (m, 1 H) 2.09 - 2.20 (m, 2 H) 2.02 (t, /=9.35 Hz, 1 H) 1.76 - 1.86 (m, 4 H) 1.64 - 1.75 (m, 1 H) 1.42 - 1.57 (m, 1 H).
Example 1.113: Preparation of (±)-7-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-2,3,3a,4,5,7a- hexahydro-lH-isoindole.
Figure imgf000131_0002
The title compound was prepared in a similar manner as described in Examples 1.6 and 1.7. LC-MS m/z 297.3 (M+H); 1H NMR (400 MHz, MeOH-^) δ ppm 7.20 - 7.47 (m, 4 H) 6.22 (t, /=3.79 Hz, 1 H) 3.60 - 3.80 (m, 2 H) 3.39 - 3.60 (m, 5 H) 3.22 (dd, /=12.13, 4.04 Hz, 1 H) 2.99 - 3.18 (m, 4 H) 2.81 - 2.94 (m, 1 H) 2.60 - 2.77 (m, 1 H) 2.24 - 2.38 (m, 2 H) 2.09 - 2.22 (m, 2 H) 1.95 - 2.09 (m, 2 H) 1.78 - 1.89 (m, 1 H) 1.48 - 1.63 (m, 1 H).
EXAMPLE 2: Syntheses of compounds of the present invention.
Example 2.1: Preparation of (i?)-4-(2-(2-Methylpyrrolidin-l-yl)ethyl)phenylboronic Acid.
Figure imgf000131_0003
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. P IT" T --'" Il P 'FaOfii / NHMI-1MI"/1' C|f
■' Methariesulfoiiyl 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 DCM (200 mL), 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. The 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, 3H), 3.02 (t, J= 6.82 Hz, 2H)5 4.40 (t, J= 6.82 Hz, 2H), 7.03 - 7.17 (m, 2H), 7.43 - 7.47 (m, 2H).
Step B: Preparation of Intermediate (i?)-l-(4-BromophenethyI)-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 (4.48 g, 52.6 mmol). The reaction mixture was warmed to 80 0C and stirred overnight. The sodium carbonate was filtered and the 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). HCl layers were combined and made basic (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 over Na2SO4 and filtered. The 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. MS m/z = 268.0 (M+H); 1H NMR (400 MHz, CD3OD) δ 1.15 (d, J= 6.06 Hz, 3H), 1.37 - 1.53 (m, IH), 1.73 - 1.86 (m, 2H), 1.94 - 2.07 (m, IH), 2.21 - 2.35 (m, 2H), 2.35 - 2.48 (m, IH), 2.68 - 2.91 (m, 2H), 2.98 - 3.11 (m, IH), 3.18 - 3.29 (m, IH), 7.14 - 7.20 (m, 2H), 7.38 - 7.48 (m, 2H). Step C: Preparation of (i?)-4-(2-(2-Methylpyrrolidin-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 90 min of stirring, triisopropylborate (7.42 mL, 32.1 mmol) was added. The reaction was kept at -78 0C for 2 hours. It was allowed to warm to room temperature and stirred for 1.5 h. The cloudy reaction mixture was quenched with 40 mL of 1 M HCl. 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 organics were dried over MgSO4, filtered, and concentrated to give 1.70 g of a yellow foam. The foam was triturated with 20 mL diethyl ether twice, and dried under high vacuum to
Figure imgf000133_0001
give the title compound(1.19g,64%yield) as a pale yellow solid. MS m/z = 234.2 (M+H); 1H NMR (400 MHz, CD3OD) δ 1.25 (d,J=6.32 Hz, 3H), 1.49 - 1.61 (m, IH), 1.80 - 1.97 (m, 2H), 2.04 - 2.18 (m, IH), 2.61 - 2.74 (m, 2H), 2.76 - 2.98 (m, 3H), 3.19 - 3.45 (m, 2H), 7.16 (d, 2H), 7.48 - 7.62 (m, 2H).
Example 2.2: Preparation of 2-Hydroxy-2-methyl-l-{6-[4-(2-pyrroIidin-l-yl~ethyl)- phenyl]-3,3a,4,6a-tetrahydro-lH-cyclopenta[c]pyrrol-2-yl}-propan-l-one.
Figure imgf000133_0002
The compound from Example 1.7 (0.200 g, 0.708 mmol) and hydroxyisobutyric acid (0.073 g, 0.708 mmol) were mixed in DCM (10 mL), and treated with N.N.N' N'-tetramethyl-O- (7-azabenzotriazol-l-yl)uronium hexafluorophosphate (0.323 g, 0.849 mmol), and triethylamine (0.125 g, 1.24 mmol). The mixture was stirred at 40 0C under N2 atmosphere for lδ h until the reactants were consumed as determined by LC/MS. The reaction mixture was diluted with DCM (20 mL) and quenched with distilled water (20 mL). The organic extract was washed with brine and dried over MgSO4 The solvent was removed under reduced pressure to leave a crude residue. The crude residue was purified by preparative HPLC to afford the TFA salt of the title compound (0.027 g, 10.3%) as a white solid. MS m/z 369.2, (M+H); 1HNMR (400 MHz, CD3OD) O l.l l (s, IH), 1.18 (t, J= 7.07 Hz, IH), 1.28 (s, IH), 1.37 (d, J = 6.06 Hz, 3H), 1.80 - 1.85 (m, 4H), 2.31 - 2.40 (m, IH), 2.58 - 2.64 (m, 4H), 2.66 - 2.72 (m, 2H), 2.78 - 2.85 (m, 3H), 3.29 - 3.32 (m, 3H), 3.49 (q, J = 7.07 Hz, IH), 3.74 (s, 3H), 6.04 (s, IH), 7.20 (d, J = 8.08 Hz, 2H), 7.33 (d, J= 8.08 Hz, 2H).
Example 2.3: Preparation of 2-Methoxy-l-((3aR,4R,6aS)-4-{4-[2-((R)-2-methyl-pyrrolidin- l-yl)-ethyl]-phenyl}-hexahydro-cyclopenta[cl]pyrrol-2-yl)-ethanone
Figure imgf000133_0003
The title compound was obtained using general method C starting from (3aR,4R,6aS)-4-(4-(2- ((R)-2-methylpyrrolidin-l-yl)ethyl)phenyl)-octahydrocyclopenta[c]pyrrole. MS m/z 371, (M+H); 1H NMR (400 MHz, CD3OD) δ 1.45-1.49 (m, 3H), 1.64-1.82 (m, 2H), 1.89-2.24 (m, 5H), 2.29-2.39 (m, IH), 2.85-3.90 (m, 17H), 3.99-4.14 (m, 2H), 7.25-7.31 (m, 4H).
Figure imgf000134_0001
l,2,3,3a,,4.,6a-hexahydro-cyclopenta[c]pyrrole.
Figure imgf000134_0002
The title compound was obtained using general method E. MS m/z 360.3, (M+H); 1H NMR (400 MHz, CD3OD) δ 2.12 (bs, 4H), 2.52 (d, J= 16.0 Hz, IH), 2.94-2.83 (m, IH), 3.22- 3.03 (m, 4H), 3.48-3.33 (m, 4H), 3.58 (dd, J= 12.0, 4.0 Hz, IH), 3.67 (bs, 2H), 4.04-3.94 (m, 2H), 4.12 (bs, IH), 6.15 (s, IH), 6.87 (t, J= 8.0 Hz, IH), 7.02 (d, J= 8.0 Hz, IH), 7.33 (d, J= 8.0 Hz, 2H), 7.84 (d, J= 4.0 Hz, 2H), 7.91 (dd, J= 8.0 Hz, 2H).
Example 2.5: Preparation of 2-Pyridin-4-yl-6-[4-(2-pyrrolidin-l-yI-ethyl)-phenyI]- l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole.
Figure imgf000134_0003
The title compound was obtained using general method E. MS m/z 360.5, (M+H); 1H NMR (400 MHz, CD3OD) δ 1.99 - 2.07 (m, 2H), 2.12 - 2.20 (m, 2H), 2.47 - 2.54 (m, IH), 2.85 - 2.93 (m, IH), 3.05 - 3.17 (m, 4H), 3.31 - 3.38 (m, IH), 3.41 - 3.56 (m, 4H), 3.65 - 3.72 (m, 2H), 3.92 - 4.01 (m, 2H), 4.05 - 4.12 (m, IH), 6.13 - 6.15 (m, IH), 6.75 - 6.79 (m, IH), 6.85 - 6.89 (m, IH), 7.30 - 7.35 (m, 2H), 7.41 - 7.45 (m, 2H), 8.01 - 8.10 (m, 2H).
Example 2.6: Preparation of 3-{6-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-3,3a,4,6a- tetrahydro-lH-cyclopentafcJpyrrol^-ylJ-benzaldehyde.
Figure imgf000134_0004
The title compound was obtained using general method E. MS m/z 387.5, (M+H); 1H NMR (400 MHz, CD3OD) δ 0.68 - 0.73 (m, 3H), 1.02 - 1.13 (m, 2H), 2.46 - 2.53 (m, 2H), 3.02 - 3.10 (m, 7H), 3.40 - 3.52 (m, 7H), 6.23 - 6.26 (m, IH), 7.31 - 7.35 (m, 4H), 7.44 - 7.48 (m, 4H). !l" !LExam'plrf:7: Preparation of 2-(3-Methoxy-phenyl)-6-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]- l^^jSa^^a-hexahydro-cyclopentalclpyrrole.
Figure imgf000135_0001
The title compound was obtained using general method E. MS m/z 389.5, (M+H); 1H NMR (400 MHz, CD3OD) δ 1.94 - 2.00 (m, IH), 2.41 - 2.49 (m, IH), 2.82 - 2.90 (m, IH), 2.92 - 3.01 (m, 3H), 3.03 - 3.14 (m, 9H), 3.20 - 3.27 (m, 2H), 3.32 - 3.39 (m, 2H), 3.74 - 3.81 (m, 3H), 3.97 - 4.04 (m, IH), 6.09 - 6.11 (m, IH), 6.58 - 6.60 (m, IH), 7.05 - 7.07 (m, IH), 7.24 - 7.27 (m, 3H), 7.37 - 7.40 (m, 3H).
Example 2.8: Preparation of 6-[4-(2-PyrroIidin-l-yl-ethyI)-phenyl]-2-thiazoI-2-yl- l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole.
Figure imgf000135_0002
The title compound was obtained using general method E. MS m/z 366.3, (M+H); 1H NMR (400 MHz, CD3OD) δ 1.95 - 2.00 (m, 5H), 2.41 - 2.48 (m, IH), 2.92 - 2.99 (m/3H), 3.03 - 3.13 (m, 9H), 3.20 - 3.27 (m, IH), 3.33 - 3.39 (m, IH), 3.73 - 3.80 (m, 2H), 7.06 (m, IH), 7.24 - 7.28 (m, 2H), 7.37 - 7.40 (m, 2H).
Example 2.9: Preparation of 2-Pyrazm-2-yϊ-6-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]- l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole.
Figure imgf000135_0003
In a 5 mL glass tube were placed the compound from Example 1.7 (0.150 g, 0.531 mmol), 2-chloropyrazine (0.243 g, 2.12 mmol), triethylamine (0.215 g, 2.12 mmol), and a magnetic stir bar. The vessel was sealed with a septum and placed into a microwave cavity. With microwave irradiation, the temperature was ramped from room temperature to 200 0C and held for 5 min. After the mixture was allowed to cool to room temperature, the reaction vessel was opened and the reaction mixture was filtered. The mixture was purified by preparative HPLC to afford the TFA salt of the title compound (0.080 g, 41.8%) as a yellow-white solid. P
Figure imgf000136_0001
1.26 - 1.30 (m, IH), 1.81 - 1.87 (m, 4H), 2.41 - 2.51 (m, IH), 2.60 - 2.66 (m, 4H), 2.68 - 2.75 (m, 2H), 2.80 - 2.90 (m, 3H), 3.23 - 3.28 (m, IH), 3.43 - 3.52 (m, IH), 3.78 - 3.91 (m, 2H), 3.93 - 4.02 (m, IH), 6.05 - 6.08 (m, IH), 7.19 - 7.23 (m, 2H), 7.34 - 7.39 (m, 2H), 7.67 - 7.70 (m, IH), 7.84 - 7.87 (m, IH), 7.95 - 7.99 (m, IH).
Example 2.10: Preparation of 2-Pyrimidin-2-yl-6-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]- l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole.
Figure imgf000136_0002
In a 5 mL glass tube were placed the compound from Example 1.7 (0.113 g, 0.400 mmol), 2-chloropyrimidine (0.183 g, 1.60 mmol), triethylamine (0.162 g, 1.60 mmol), and a magnetic stir bar. The vessel was sealed with a septum and placed into a microwave cavity. With microwave irradiation, the temperature was ramped from room temperature to 200 0C and held for 5 min. After the mixture was allowed to cool to room temperature, the reaction vessel was opened and the reaction mixture was filtered. The mixture was purified by preparative HPLC to afford the TFA salt of the title compound (0.020 g, 13.8%) as a yellow-white solid. MS m/z 360.4 (M+H); 1H NMR (400 MHz, CD3OD) δ 1.15 - 1.21 (m, IH), 1.88 - 1.94 (m, 3H), 2.03 (s, IH), 2.40 - 2.47 (m, IH), 2.79 - 2.96 (m, 8H), 3.17 - 3.25 (m, IH), 3.46 - 3.52 (m, IH), 3.55 - 3.60 (m, IH), 3.82 - 3.88 (m, IH), 3.90 - 3.96 (m, 2H), 6.06 - 6.08 (m, IH), 6.55 (t, J = 4.93 Hz, IH), 7.23 (d, J = 8.08 Hz, 2H), 7.38 (d, J = 8.34 Hz, 2H), 8.24 (d, J = 4.80 Hz, 2H).
Example 2.11: Preparation of 2-Pyrimidin-5-yl-6-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]- l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole.
Figure imgf000136_0003
In a 5 mL glass tube were placed the compound from Example 1.7 (0.100 g, 0.354 mmol), 5-bromopyrimidine (0.056 g, 0.354 mmol), palladium dibenzylideneacetone (0.016 g, 0.017 mmol), sodium tert-butoxide (0.051 g 0.531 mmol), 2-(dicyclohexylphosphino) biphenyl (1.75 mg, 5.00 μmol) and a magnetic stir bar. The vessel was sealed with a septum and placed into a microwave cavity. With microwave irradiation, the temperature was ramped from room temperature to 1100C and held for 6 h. After the mixture was allowed to cool to room temperature, the reaction vessel was opened and the reaction mixture was filtered through a small column of Celite. The mixture was purified by preparative HPLC to afford the TFA salt of the title compound (0.025 g, 19.5%) as an orange solid. MS m/z 361 A, (M+H); 1H NMR (400 MHz, CD3OD) δ 1.85 - 1.91 (m, 5H), 2.43 - 2.51 (m, IH), 2.73 - 2.78 (m, 4H), 2.83 - 2.91 (m, 5H), 3.12 - 3.17 (m, IH)5 3.21 - 3.29 (m, IH), 3.64 - 3.73 (m, 2H), 3.96 - 4.04 (m, IH), 6.07 - 6.09 (m, IH)5 7.21 - 7.24 (m, 2H), 7.37 - 7.40 (m, 2H), 8.08 - 8.09 (m, 2H), 8.39 - 8.40 (m, IH).
Example 2.12: Preparation of 2-(3,5-Difluoro~phenyl)-6-[4-(2-pyrrolidin-l~yl-ethyl)- phenyl]-1,2,3,3a,4,6a-hexahydro-cyclopentatcJpyrrole.
Figure imgf000137_0001
In a 5 mL glass tube were placed the compound from Example 1.7 (0.070 g, 0.248 mmol), l-bromo-3,5-difluorobenzene (0.048 g, 0.248 mmol), palladium dibenzylideneacetone (0.011 g, 0.012 mmol), sodium tert-butoxide (0.035 g 0.372 mmol), 2-(dicyclohexylphosphino) biphenyl (1.75 mg, 5.00 μmol) and a magnetic stir bar. The vessel was sealed with a septum and placed into a microwave cavity. With microwave irradiation, the temperature was ramped from room temperature to 110 0C and held for 6 h. After the mixture was allowed to cool to room temperature, the reaction vessel was opened and the reaction mixture was filtered through a small column of Celite. The mixture was purified by preparative HPLC to afford the TFA salt of the title compound (0.030 g, 30.6%) as an orange solid. MS m/z 395.4, (M+H); 1H NMR
(400 MHz, CD3OD) δ 2.00 - 2.08 (m, IH), 2.11 - 2.23 (m, 3H), 2.83 - 2.94 (m, IH)5 3.05 - 3.22 (m, 5H)5 3.34 - 3.37 (m, 3H), 3.42 - 3.50 (m, 2H), 3.64 - 3.80 (m, 4H), 4.01 (s, IH), 6.15 (s, IH)5 6.26 - 6.39 (m, 3H)5 7.32 (d, /= 7.83 Hz, 2H), 7.44 (d, /= 7.83 Hz, 2H).
Example 2.13: Preparation of 3-{6-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-3,3a,4,6a- tetrahydro-lH-cyclopenta[c]pyrrol-2-yl}-benzonitrile.
Figure imgf000137_0002
In a 5 mL glass tube were placed the compound from Example 1.7 (0.070 g, 0.248 mmol), 3-bromobenzonitrile (0.045 g, 0.248 mmol), palladium dibenzylideneacetone (0.011 g, 0.0
Figure imgf000138_0001
12mmol),sodiumtert-butoxide (0.035 g, 0.372 mmol), 2~(dicyclohexylphosphino) biphenyl (1.75 mg, 5.00 μmol) and a magnetic stir bar. The vessel was sealed with a septum and placed into a microwave cavity. With microwave irradiation, the temperature was ramped from room temperature to 110 0C and held for 6 h. After the mixture was allowed to cool to room temperature, the reaction vessel was opened and the reaction mixture was filtered through a small column of Celite. The mixture was purified by preparative HPLC to afford the TFA salt of the title compound (0.025 g, 26.3%) as an orange solid. MS m/z 384.3, (M+H); 1H NMR (400 MHz, CD3OD) δ 1.50 - 1.58 (m, 2H), 1.95 - 2.08 (m, 2H), 2.11 - 2.23 (m, 3H), 2.82 - 2.93 (m, IH), 3.05 - 3.21 (m, 5H), 3.42 - 3.50 (m, 2H), 3.63 - 3.81 (m, 4H), 3.96 - 4.07 (m, IH), 6.15 (s, IH), 6.34 (d, J=7.83 Hz, 4H), 7.32 (d, J=7.83 Hz, 2H), 7.44 (d, J=7.83 Hz, 2H).
Example 2.14: Preparation of Cyclopropyl-((3aR,4R,6aS)-4-{4-[2-((R)-2-methyl- pyrrolidin-l-yl)-ethyl]-phenyl}-hexahydro-cyclopenta[c}pyrrol-2-yl-2-yl)-methanone. Step A: Preparation of (3aR,4R,6aS)-4-(4-(2-((R)-2-Methylpyrrolidin-l- yl)ethyl)phenyϊ)octahydrocyclopenta[c]pyrrole
Figure imgf000138_0002
To a solution of (3aS, 6aS)-2-benzyl-6-(4-(2-((R)-2-methylpyrrolidin-l- yl)ethyl)phenyl)-1,2,3,3a,4,6a -hexahydrocyclopentafcjpvrrole (4.21 g, 10.89 mmol) obtained using general method A starting from the corresponding single isomer ketone from example 1.1 in MeOH (31.0 mL) was added ammonium formate (3.592 g, 56.97 mmol), and Pd(OH)2 (862.3 mg, 20% Pd/C, Pearlman's catalyst). The reaction mixture was heated to reflux for 30 min. After cooled to room temperature, the reaction mixture was filtered through a short column of Celite with MeOH and concentrated to afford the title compound as a yellow amorphous solid (3.429 g). The product obtained was used in next step without further purification. MS m/z 299.4, (M+H).
Step B: Preparation of Cyclopropyl-((3aR,4R,6aS)-4-{4-[2-((R)-2-methyl- pyrrolidin-l-yl)-ethyl]-phenyl}-hexahydro-cyclopenta[c-pyrrol-2-yl)-methanone
Figure imgf000138_0003
In a 5 mL glass tube were placed (3aR, 4R, 6aS)-4-(4-(2-((i?)-2-methylpyrrolidin-l- yl)ethyl)phenyl)-octahydrocyclopenta[c]pyrrole (0.129 g, 0.432 mmol), 2,2-difluoroethyl i::;"
Figure imgf000139_0001
sodium carbonate (0.071 g, 0.670 mmol)) and a magnetic stir bar. The vessel was sealed with a septum and placed into a microwave cavity. With microwave irradiation, the temperature was ramped from room temperature to 120 0C and held for 3 h. After the mixture was allowed to cool to room temperature, the reaction vessel was opened and the reaction mixture was filtered through a small column of silica. The mixture was purified by preparative HPLC to afford the TFA salt of the title compound (0.063 g, 40.1%) as a white solid. MS m/z 363.6, (M+H); 1H NMR (400 MHz, CD3OD) δ 1.28 (s, 2H), 1.28 (s, 2H), 1.34 - 1.41 (m, 2H), 1.52 (s, 3H), 1.61 (s, 2H), 2.13 - 2.21 (m, 3H), 3.02 - 3.19 (m, 3H), 3.24 - 3.28 (m, IH), 3.35 - 3.42 (m, IH), 3.42 - 3.51 (m, 3H), 3.51 - 3.61 (m, 5H), 3.60 - 3.71 (m, 3H), 7.35 - 7.50 (m, 3H), 7.72 - 7.82 (m, IH).
Example 2.15: Preparation of (3aS,6aS)-6-{4-[2-((R)-2-Methyl-pyrroIidin-l-yl)-ethyI]- phenyl}-2-(6-trifluoromethyl-pyridin-3-yl)-l,2,3,3a,4,6a-hexahydro-cycIopenta[c]pyrrole (Compound C102). Step A: Preparation of (3aS,6aS)-6-(4-(2-((R)-2-Methylpyrrolidin-l- ytyethytypheny^-l^jSjSa^όa-hexahydrocyclopentaJclpyrrole
Figure imgf000139_0002
To a solution of (3aR, 6aS)-4-(4-(2-((R)-2-methylpyrrolidin-l-yl)ethyl)phenyl)- octahydrocyclopenta[c]pyrrol-4-ol (2.74 g, 8.71 mmol) in isopropyl alcohol (45.0 mL), prepared in a similar manner as described in example 1.6 starting from the corresponding single isomer ketone from example 1.1, was added HCl (22.0 mL, 88.0 mmol, 4M in 1,4-dioxane). The resulting reaction mixture was heated at 60 0C. After 16 h, the reaction was cooled to room temperature and extracted with DCM for any organic impurities. The aqueous layer obtained was neutralized with 10% NaOH solution to ~pH12 and extracted with DCM. The organic layer was washed with H2O, brine, dried over MgSO4 and concentrated to afford the title compound as a yellow amorphous solid (2.18 g, 84%). The product was used in next step without further purification. MS m/z 297.3, (M+H).
Step B: Preparation of (3aS,6aS)-6-{4-[2-((R)-2-Methyl-pyrroKdin-l-yl)-ethyl]- phenyl}-2-(6-trifluoromethyl-pyridin-3-yl)-l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole
Figure imgf000140_0001
In a 5 mL glass tube were placed (3aS,6aS)-6-(4-(2-((R)-2-memylpyrrolidin-l- yl)ethyl)phenylH,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole (0.160 g, 0.540 mmol), 5-bromo- 2-(trifluoromethyl) pyridine (0.183 g, 0.810 mmol), palladium dibenzylideneacetone (0.025 g, 0.027 mmol), sodium tert-butoxide (0.078 g, 0.810 mmol), 2-(dicyclohexylphosphino) biphenyl (1.75 mg, 5.00 μmol) and a magnetic stir bar. The vessel was sealed with a septum and placed into a microwave cavity. With microwave irradiation, the temperature was ramped from room temperature to 110 0C and held for 6 h. After the mixture was allowed to cool to room temperature, the reaction vessel was opened and the reaction mixture was filtered through a small column of Celite. The mixture was purified by preparative HPLC to afford the TFA salt of the title compound (0.020 g, 8.4%) as an orange solid. MS m/z 442.5 (M+H); 1H NMR (400 MHz, CD3OD) δ 1.44 - 1.47 (m, 3H), 1.68 - 1.80 (m, IH), 2.01 - 2.17 (m, 2H), 2.29 - 2.39 (m, IH), 2.45 - 2.52 (m, IH), 2.84 - 2.93 (m, 2H), 2.97 - 3.28 (m, 6H), 3.46 - 3.56 (m, IH), 3.56 - 3.66 (m, IH), 3.70 - 3.79 (m, 3H), 3.98 - 4.05 (m, IH), 6.13 (d, J = 1.77 Hz, IH), 7.01 (dd, J = 8.72, 2.65 Hz, IH), 7.32 (d, J = 8.08 Hz, 2H), 7.45 (d, J = 8.34 Hz, 2H), 7.52 (d, J = 8.84 Hz, IH), 7.91 (d, J = 2.78 Hz, IH).
Example 2.16: Preparation of 5-((3aS,6aS)-6-{4-[2-((R)-2-Methyl-pyrrolidin-l-yl)-ethyl]- phenyl}-3,3a,4,6a-tetrahydro-lH-cyclopenta[c]pyrrol-2-yl)-pyridine-2-carbonitrile.
Figure imgf000140_0002
The title compound was obtained using general method E starting from (3aS, 6aiS)-6-(4- (2-((R)-2-methylpyrrolidin-l-yl)ethyl)phenyl)-l,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole. MS m/z 399.2, (M+H); 1H NMR (400 MHz, CD3OD) δ 1.18 - 1.31 (m, 4H), 1.48 - 1.63 (m, IH), 1.90 (bs, 2H), 2.04 - 2.18 (m, IH), 2.43 - 2.57 (m, 2H), 2.81 - 2.99 (m, 4H), 3.10 - 3.25 (m, 3H),3.44-3.54(m,2H),3.73 - 3.86 (m, 2H), 4.02 (bs, IH), 6.09 (s, IH), 6.90 - 6.99 (m, IH), 7.21 - 7.31 (m, 2H), 7.39 (d, J = 8.34 Hz, 2H), 7.54 (d, J = 8.59 Hz, IH), 7.91 - 7.99 (m, IH).
Example 2.17: Preparation of 2-Methyl-l-((3aR,4R,6aS)-4-{4-[2-((R)-2-methyl-pyrrolidin- 1-yl)-ethyl]-phenyl}-hexahydro-cycIopenta[c]pyrrol-2-yl)- propan-l-one.
Figure imgf000141_0001
The title compound was obtained using general method C starting from (3ai?, AR, 6aS)- 4-4-(2-((R )-2-methylpyrrolidin-l -yl)ethyl)phenyl)-octahydrocyclopenta[c]pyrrole. MS m/z 369.2, (M+H); 1H NMR (400 MHz, CD3OD) δ 0.92 - 0.98 (m, 2H), 1.02 - 1.08 (m, 3H), 1.11 - 1.15 (m, 3H), 1.38 - 1.51 (m, IH), 1.61 - 1.70 (m, IH), 1.72 - 1.84 (m, 2H), 1.94 - 2.05 (m, 3H), 2.22 - 2.34 (m, 2H), 2.35 - 2.47 (m, 2H), 2.70 - 2.89 (m, 3H), 2.90 - 3.05 (m, 3H), 3.05 - 3.15 (m, IH), 3.15 - 3.27 (m, 2H), 3.33 - 3.40 (m, IH), 3.44 - 3.51 (m, IH), 3.58 - 3.66 (m, IH), 3.76 - 3.84 (m, IH), 7.13 - 7.21 (m, 4H).
Example 2.18: Preparation of ((3aR,4R,6aS)-4-{4-[2-((R)-2-Methyl-pyrrolidin-l-yl)-ethyl]- phenyl}-hexahydro-cycIopenta[c]pyrrol-2-yl)-pyridin-3-yl-methanone.
Figure imgf000141_0002
The title compound was obtained using general method C starting from (3aR , 4R, 6aS)- 4-4-(2-((R )-2-methylpyrrolidin-l -yl)ethyl)phenyl)-octahydrocyclopenta[c]pyrrole. MS m/z 404.8, (M+H); 1H NMR (400 MHz, CD3OD) δ 1.09 - 1.16 (m, 3H), 1.38 - 1.50 (m, IH), 1.79
(dd, J= 6.32, 2.78 Hz, 3H), 1.95 - 2.05 (m, 3H), 2.15 - 2.34 (m, 2H), 2.36 - 2.46 (m, IH), 2.61 - 2.86 (m, 3H), 2.88 - 2.96 (m, 2H), 2.97 - 3.14 (m, 2H), 3.16 - 3.28 (m, 2H), 3.33 - 3.49 (m, IH), 3.63 (dd, J = 12.63, 4.04 Hz, IH), 3.75 - 3.89 (m, IH), 7.01 - 7.09 (m, 2H), 7.16 - 7.27 (m, 2H), 7.35 - 7.54 (m, IH), 7.87 (dd, J = 62.27, 7.71 Hz, IH), 8.49 - 8.54 (m, IH), 8.60 - 8.67 (m, IH).
Example 2.19: Preparation of ((3aR,4R,6aS)-4-{4-[2-((R)-2-Methyl-pyrroIidin-l-yl)-ethyl]- phenylj-hexahydro-cyclopentalcjpyrrol-2-yl)-pyrazin^-yl-methanone.
Figure imgf000142_0001
The title compound was obtained using general method C starting from (3aR, AR, 6aS)- 4-4-(2-((i?)-2-methylpyrrolidin-l-yl)ethyl)phenyl)-octahydrocyclopenta[c]pyrrole. MS m/z 405.5, (M+H); 1H NMR (400 MHz, CD3OD) δ 1.41 - 1.50 (m, 3H), 1.62 - 1.84 (m, 2H), 2.01 - 2.09 (m, 2H), 2.29 - 2.39 (m, IH), 2.85 - 3.08 (m, 4H), 3.11 - 3.28 (m, 5H), 3.31 - 3.57 (m, 4H), 3.56 - 3.68 (m, IH), 3.68 - 3.79 (m, 2H), 3.84 - 4.01 (m, IH), 7.12 - 7.18 (m, 2H), 7.25 - 7.34 (m, 3H), 8.64 - 8.72 (m, IH), 8.81 - 8.98 (m, IH).
Example 2.20: Preparation of (3aR,4R,6aS)-2-(2-Fluoro-ethyl)-4-{4-[2-((R)-2-methyl- pyrrolidin-l-yl)-ethyl]-phenyl}-octahydro-cyclopenta[c]pyrrole.
Figure imgf000142_0002
In a 5 mL glass tube were placed (3ai?, AR, 6aιS)-4-4-(2-((i?)-2-methylpyrrolidin-l- yl)ethyl)phenyl)-octahydrocyclopenta[c]pyrrole (0.100 g, 0.335 mmol), 2-fluoroethyl methanesulfonate (0.071 g, 0.503 mmol), sodium carbonate (0.036 g, 0.335 mmol) and a magnetic stir bar in acetonitrile (6 mL). The vessel was sealed with a septum and placed into a microwave cavity. With microwave irradiation, the temperature was ramped from room temperature to 120 0C and held for 3 h. After the mixture was allowed to cool to room temperature, the reaction vessel was opened and the reaction mixture was filtered through a small column of silica. The mixture was purified by preparative HPLC to afford the TFA salt of the title compound (0.025 g, 21.7%) as a yellow, viscous solid. MS m/z 345.1, (M+H); 1H NMR (400 MHz, CD3OD) δ 1.16 (d, J = 6.06 Hz, 3H), 1.42 - 1.53 (m, IH), 1.59 - 1.68 (m, 2H), 1.75 - 1.94 (m, 5H), 1.94 - 2.07 (m, 2H), 2.30 - 2.41 (m, 2H), 2.47 - 2.62 (m, 4H), 2.63 - 2.68 (m, IH), 2.71 - 2.88 (m, 4H), 3.00 - 3.12 (m, IH), 3.14 - 3.24 (m, IH), 3.24 - 3.29 (m, IH), 4.38 (t, J = 4.93 Hz, IH), 4.47 - 4.53 (m, IH), 7.12 - 7.22 (m, 4H).
Example 2.21: Preparation of 2,2,2-Trifluoro-l-((3aR,4R,6aS)-4-{4-[2-((R)-2-methyl- pyrrolidin-1-yl-ethyl]-phenyl}-hexahydro-cyclopenta[c]pyrrol-2-yl)-ethanone.
Figure imgf000143_0001
The title compound was obtained using general method F starting from (3aR, AR, 6aS)- 4-(4-(2-((i?)-2-methylpyrrolidin-l -yl)ethyl)phenyl)-octahydrocyclopenta[c]pyrrole. MS m/z 395.2, (M+H); 1H NMR (400 MHz, CD3OD) δ 1.15 - 1.29 (m, 3H), 1.46 - 1.62 (m, IH), 1.61 - 1.77 (m, IH), 1.82 - 1.92 (m, 3H), 1.97 - 2.17 (m, 4H), 2.55 (bs, 2H), 2.76 - 2.98 (m, 3H), 2.99 - 3.23 (m, 4H), 3.38 - 3.53 (m, 2H), 3.53 - 3.66 (m, IH), 3.75 - 3.93 (m, IH), 7.18 - 7.26 (m, 4H).
Example 2.22: Preparation of ((3aR,4R,6aS)-4-{4-[2-((R)-2-Methyl-pyrrolidin-l-yl)-ethyI]- phenyl}-hexahydro-cyclopenta[c]pyrrol-2-yl)-pyrimidin-5-yl-methanone.
Figure imgf000143_0002
The title compound was obtained using general method F starting from (3aR, AR, 6aS)-
4-4-(2-((i?)-2-methylpyrrolidin-l-yl)ethyl)phenyl)-octahydrocyclopenta[c]pyrrole. MS m/z 405.5, (M+H); 1H NMR (400 MHz, CD3OD) δ 1.13 - 1.18 (m, 4H), 1.40 - 1.51 (m, IH), 1.76 - 1.88 (m, 3H), 1.96 - 2.08 (m, 5H), 2.25 - 2.40 (m, 2H), 2.48 (bs, IH), 2.64 - 2.88 (m, 2H), 2.90 - 15 3.00 (m, IH), 3.07 - 3.18 (m, IH), 3.18 - 3.27 (m, IH), 3.34 - 3.43 (m, 2H), 3.58 - 3.64 (m, IH), 3.82 - 3.89 (m, IH), 7.04 - 7.09 (m, 2H), 7.18 - 7.27 (m, 2H), 8.73 - 8.75 (m, IH), 8.91 - 8.92 (m, IH), 9.10 - 9.23 (m, IH).
Example 2.23: Preparation of (3aR,4R,6aS)-2-(2,2-Difluoro-ethyl)-4-{4-[2-((R)-2-methyl-
20 pyrrolidin-l-yl)-ethyl]-phenyl}-octahydro-cyclopenta[c]pyrrole.
HF2
Figure imgf000143_0003
In a 5 mL glass tube were placed (3aR, AR, 6a£)-4-4-(2-((R)-2-methylpyrrolidin-l- yl)ethyl)phenyl)-octahydrocyclopenta[c]pyrrole (0.129 g, 0.432 mmol), 2,2-difluoroethyl methanesulfonate (0.242 g, 1.51 mmol), sodium carbonate (0.046 g, 0.432 mmol) and a
25 magnetic stir bar in acetonitrile (6 mL). The vessel was sealed with a septum and placed into a jp C ''m'i<&M4$l3 Jvity"'. VfWfecroWaVe iiradiation, the temperature was ramped from room temperature to 120 0C and held for 3 h. After the mixture was allowed to cool to room temperature, the reaction vessel was opened and the reaction mixture was filtered through a small column of silica. The mixture was purified by preparative HPLC to afford the TFA salt of
5 the title compound (0.063 g, 40.1%) as a white solid. MS m/z 345.1 (M+H); 1H NMR (400 MHz, CD3OD) δ 1.41 - 1.51 (m, 3H), 1.69 - 1.82 (m, 2H), 1.84 - 1.97 (m, IH), 1.98 - 2.20 (m, 4H), 2.28 - 2.39 (m, IH), 2.55 - 2.66 (m, IH), 2.81 - 2.90 (m, IH), 2.98 - 3.13 (m, 4H), 3.17 - 3.28 (m, 3H), 3.34 - 3.45 (m, IH), 3.45 - 3.61 (m, 2H), 3.64 - 3.77 (m, 3H), 3.96 - 4.05 (m, IH), 6.14 - 6.44 (m, IH), 7.25 - 7.36 (m, 4H). 0
Example 2.24: Preparation of (3aR,4R,6aS)-4-{4-[2-((R)-2-Methyl-pyrrolidin-l-yl)-ethyl]- phenyl}-2-(2,2,2-trifluoro-ethyl)-octahydro-cyclopenta[c]pyrrole.
Figure imgf000144_0001
In a 5 mL glass tube were placed (3aR, 4R, 6a5)-4-(4-(2-((i?)-2-methylpyrrolidin-l- 5 yl)ethyl)phenyl)-octahydrocyclopenta[c]pyrrole (0.108 g, 0.362 mmol), 2,2,2-trifluoroethyl methanesulfonate (0.226 g, 1.27 mmol), sodium carbonate (0.038 g, 0.362 mmol) and a magnetic stir bar in acetonitrile (6 mL). The vessel was sealed with a septum and placed into a microwave cavity. With microwave irradiation, the temperature was ramped from room temperature to 120 0C and held for 3h. After the mixture was allowed to cool to room 0 temperature, the reaction vessel was opened and the reaction mixture was filtered through a small column of silica. The mixture was purified by preparative HPLC to afford the TFA salt of the title compound (0.023 g, 16.7%) as a white solid. MS m/z 381.2, (M+H); 1H NMR (400 MHz, CD3OD) δ 1.45 - 1.50 (m, 3H), 1.71 - 1.82 (m, 2H), 1.87 - 2.25 (m, 4H), 2.29 - 2.39 (m, IH), 2.67 - 2.74 (m, IH), 2.91 - 3.15 (m, 3H), 3.17 - 3.28 (m, 2H), 3.32 - 3.46 (m, 2H), 3.48 - 5 3.61 (m, 2H), 3.69 - 3.77 (m, IH), 3.99 - 4.06 (m, IH), 4.17 - 4.28 (m, 2H), 7.30 - 7.36 (m, 7H).
Example 2.25: Preparation of ((3aR,4R,6aS)-4-{4-[2-((R)-2-Methyl-pyrrolidin-l-yl)-ethyl]- phenylj-hexahydro-cyclopentatcjpyrrol^-ylj-^etrahydro-pyran^-y^-methanone.
Figure imgf000144_0002
The title compound was obtained using general method C starting from (3aR,4R,6aS)-4-(4-(2-
((R)-2-methylpyrrolidin-l-yl)ethyl)phenyl)-octahydrocyclopenta[c]pyrrole. MS m/z 411, (M+H); 1H NMR (400 MHz, CD3OD) δ 1.44-1.49 (m, 3H), 1.55-1.80 (m, 6H), 1.89-2.25 (m, 5H), 2.29-2.46 (m, IH), 2.72-2.84 (m, IH), 2.89-4.01 (m, 18H), 7.25-7.29 (m, 4H).
Example 2.26: Preparation of (3aS,6aS)-2-Benzyl-6-[4-((R)-2-methyl-pyrrolidin-l- ylmethyl)-phenyl-1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole.
Figure imgf000145_0001
Step A: Preparation of Intermediate (R)-l-(4-Bromobenzyl)-2-methylpyrrolidine To a solution of 4-bromobenzaldehyde (0.50 g5 2.7 mmol) in dichloroethane (10 mL) was added (R)-2-methylpyrrolidinium chloride (0.32 g, 2.7 mmol) and sodium triacetoxyborohydride (0.79 g, 3.7 mmol). The mixture was stirred at room temperature for 18 h. The reaction was quenched with water (5 mL) and treated with NaOH (pH 8). The volatile solvents were evaporated under reduced pressure and the aqueous slurry was extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to leave the title compound which was used without further purification. MS m/z 254, (M+H).
Step B: Preparation of Intermediate (3aR, 6aS)-2-BenzyI-4-(4-(((R)-2- methyIpyrrolidin-l-yl)methyl)phenyl)octahydrocyclopenta[c]pyrrol-4-ol The crude (R)-I -(4-Bromobenzyl)-2-methylpyrrolidine (0.24 g, 0.93 mmol) from Step
A above was dissolved in THF (3.0 mL) and the solution was cooled to -78 0C. nBuLi was added and the mixture was stirred for 1 h at -78 0C. A solution of (3aR, 6aS)-2- benzylhexahydrocyclopenta[c]pyrrol-4(5H)-one (0.20 g, 0.93 mmol) in THF (1.5 mL) was added and the mixture was stirred for 2 h at -78 0C. The reaction was quenched with water and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to afford the title compound. MS m/z 391, (M+H).
Step C: Preparation of (3aS, 6aS)-2-Benzyl-6-[4-((l?)-2-methyl-pyrrolidm-l- ylmethyl)-phenyl]-1,2,3,3a,46 a-hexahydro-cycIopentafclpyrrole (3aR, 6aS)-2-Benzyl-4-(4-(((R)-2-methylpyrrolidin-l- yl)methyl)phenyl)octahydrocyclopenta[c]pyrrol-4-ol (0.18 g, 0.46 mmol) from Step B above was dissolved in isopropyl alcohol (5 mL) and then an anhydrous solution of hydrogen chloride (4.0 M in dioxane, 5 mL) was added. The mixture was heated at 60 0C for 16 h and then the ip IΓ T /■ i ft Fi; in i!;:;iι •■■" Ni-NH-t/11 "3
'' ""solvents were evaporated. The residue was dissolved in ethyl acetate and treated with NaOH (pH 10). The aqueous slurry was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated at reduced pressure. The residue was purified by HPLC (0.1% TFA in acetonitrile, 0.1 % TFA in water). The combined fractions were lyophilized and treated with HCl to afford the dihydrochloride salt of the title compound. MS m/z 373, (M+H); 1H NMR (400 MHz, CDCl3) δ 1.18 (d, J= 6.0 Hz, 3H), 1.42-1.55 (m, IH), 1.57-1.82 (m, 3H), 1.87-2.02 (m, IH), 2.05-2.60 (m, 4H), 2.68-2.80 (m, IH), 2.88-3.07 (m, 3H), 3.10-3.25 (m, 2H), 3.58 (ABq, J= 38.4, 12.9 Hz, 2H), 3.67-3.80 (m, IH), 4.02 (d, J= 12.8 Hz, IH), 6.08 (s, IH), 7.20-7.36 (m, 9H).
Example 2.27: Preparation of Racemic Mixture of (3aR, 4R, 6aS) and (3aS, 4S, 6aR)-2-
Methyl-l-4-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-hexahydro-cyclopenta[c]pyrrol-2-yI}- propan-1-one.
Figure imgf000146_0001
Racemic Mixture Step A: Preparation of 2-BenzyI-octahydro-cyclopenta[c]pyrrol-4-ol.
2-Benzyl-hexahydro-cyclopenta[c]pyrrol-4-one (2.50 g, 11.6 mmol) was dissolved in ethanol (25 mL) and sodium borohydride (0.44 g, 11.6 mmol) was added. The reaction was stirred at room temperature for 16 h. The mixture was diluted with water (25 mL) and the product was extracted into DCM (2 x 50 mL). The organic phase was dried (MgSO4) and filtered and the solvent was removed under reduced pressure to leave the title compound (2.50 g, 99%) which was used without further purification. MS m/z 218.1 (M+H).
Step B: Preparation of 2-BenzyloctahydrocycIopenta[c]pyrrol-4-yl Methanesulfonate.
2-Benzyl-octahydro-cyclopenta[c]pyrrol-4-ol (1.00 g, 4.6 mmol) was dissolved in DCM (25 mL) and N,N-diisopropylethylamine (1.04 mL, 6.0 mmol) was added. The reaction was cooled to 0 0C and methanesulfonyl chloride (0.43 mL, 5.5 mmol) was added dropwise over 5 min. The reaction was stirred at 0 0C for 3 hours and then quenched with the addition of saturated aqueous NaHCO3 (25 mL). The product was extracted into DCM (2 x 25 mL), the organic layer was dried (MgSO4) and filtered and the solvent was removed under reduced pressure. The residue was purified by column chromatography (50-100% EtOAc/hexane) to leave the title compound (1.05 g, 77%) as a colorless oil. MS m/z 296.2 (M+H); 1HNMR (400 MHz, CDCl3) 8 1.55-1.61 (m, IH), 1.68-1.80 (m, IH), 1.96-2.04 (m, IH), 2.07-2.19 (m, IH), p IIS / ιi-PφMI-71" "31
L
Figure imgf000147_0001
IH)5 2.52-2.57 (m, IH), 2.63-2.69 (m, IH), 2.70-2.79 (m, 2H), 2.85-2.92 (m, IH),
3.00 (s, 3H), 3.60 (t, J= 12.8 Hz, 2H), 4.95-5.02 (m, IH), 7.23-7.36 (m, 5H).
Step C: Preparation of 2-Benzyl-4-iodooctahydrocycIopenta[c]pyrrole.
2-Benzyloctahydrocyclopenta[c]pyrrol-4-yl methanesulfonate (0.57 g, 1.9 mmol) was dissolved in THF (4 mL). Sodium bromide (1. 97 g, 1.9 mmol) was added and the reaction was stirred at 65 0C for 24 h. No change was observed by LCMS. More NaBr (1.60 g, 8 eq.) was added followed by acetone (4 mL) and the reaction was heated to reflux for 24 h. TLC showed mostly starting material, with a small amount of product. The reaction was cooled to room temperature, filtered and concentrated under reduced pressure. The residue was dissolved in THF (5 mL), lithium iodide (0.51 g, 2 eq.) was added and the mixture was heated to reflux for 24 h. After cooling to room temperature, water was added and the mixture was extracted with DCM. The organic phase was dried, filtered and concentrated to a brown oil. This was purified by column chromatography (0-90% EtOAc/n-hexane) to leave the title compound (0.52 g, 83% yield) as a colorless oil. MS m/z 328.2 (M+H); 1H NMR (400 MHz, CDCl3) δ 1.38-1.47 (m, IH), 1.92-2.12 (m, 2H), 2.19-2.25 (m, IH), 2.37-2.51 (m, 4H), 2.64-2.73 (m, IH), 2.98-3.04 (m, IH), 3.60 (dd, J= 13.6, 17.6 Hz, 2H), 4.09-4.15 (m, IH), 7.25-7.37 (m, 5H).
Step D: Preparation of 2-Benzyl-4-(4-(2-(pyrrolidin-l- yl)ethyl)phenyl)octahydrocyclopenta[c]pyrrole.
4-(2-(Pyrrolidin-l-yl)ethyl)phenylboronic acid was prepared in a similar manner as described in Example 2.1, Step C, using l-[2-(4-bromo-phenyl)ethyl]-pyrrolidine from Example 1.2. To a 4 mL vial was place 4-(2-(pyrrolidin-l-yl)ethyl)phenylboronic acid (99.6 mg, 455 μmol), 4,7-diphenyl-l,10-phenanthroline (10.1 mg, 30 μmol), bis(l,5-cyclooctadiene)m'ckel (0) (4.2 mg, 15 μmol) and potassium tert-butoxide (68.0 mg, 606 μmol). The vial was flushed with nitrogen and 2-butanol (2.3 mL) was added. The mixture was stirred at room temperature for 10 min. Next, 2-benzyl-4-iodooctahydrocyclopenta[c]pyrrole (124 mg, 379 μmol) in 2-butanol (0.2 mL) was added and the reaction was heated to 60 °C for 5 h. The mixture was cooled to room temperature, concentrated and purified by RPHPLC (5-95% ACN/water/0.1%TFA). The fractions containing product were basified to pH 8 and extracted with DCM. The organic phase was dried, filtered and concentrated to a colorless oil (24 mg). The oil residue (10 mg) was dissolved in MeOH (1 mL) and 1.25 M HCl in MeOH (0.03 mL) was added. The mixture was concentrated to a white solid, dissolved in warm water (10 mL) and lyophilized to leave a white solid (6 mg). MS m/z = 375.5 (M+H); 1H NMR (400 MHz, Methanol-^) δ 1.05-1.15 (m, 2H), 1.31-1.42 (m, IH), 1.51-1.62 (m, IH), 1.70-1.77 (m, 2H), 1.88-1.97 (m, 4H), 2.33-2.47 (m, 4H), 2.53-2.58 (m, 2H), 2.60-2.75 (m, 4H), 3.18-3.22 (m, 2H), 3.35-3.41 (m, IH), 3.49-3.52(m, IH), 3.96-4.02 (m, IH), 7.00-7.02 (m, 4H), 7.13-7.17 (m, IH), 7.18-7.26 (m, 4H).
Step E: Preparation of 4-(4-(2-(Pyrrolidin-l- yl)ethyl)phenyl)octahydrocyclopenta[c]pyrrole. PHI f / 1| |i Cy1K §;:J( / UJAU.71' qi
'' 2LB'enzyl-4-(4-(2-(pyrrόlidin-l-yl)ethyl)phenyl)octahydrocyclopenta[c]pyrrole (14.0 mg, 37 μmol) was dissolved in methanol (1 mL). Ammonium formate (12.0 mg, 187 μmol) and 20% palladium hydroxide on carbon powder (5.2 mg, 8 μmol) were added and the reaction was stirred at 65 0C for 18 h. The mixture was filtered through 0.45 micron Teflon and used without further purification. MS m/z 285.2 (M+H).
Step F: Preparation of Racemic Mixture of (3aR, 4R, 6aS) and (3aS, 4S, 6aR)-2- Methyl-l-4-[4-(2-pyrrolidin-l-yl-ethyI)-phenyl]-hexahydro-cyclopenta[c]pyrrol-2-yl}- propan-1-one.
4-(4-(2-(Pyrrolidin-l-yl)ethyl)phenyl)octahydrocyclopenta[c]pyrrole (6 mg, 21 μmol) was dissolved in DCM (1 mL) and triethylamine (2 mg, 21 μmol) and isobutyryl chloride (2 mg, 21 μmol) were added. After 1 h the reaction was quenched by the addition of water and the product was extracted into DCM. The organic phase was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography 1/9/89 ammonium hydroxide/methanol/DCM to give the title compound (4 mg, 53%). MS m/z 355.3 (M+H); 1H NMR (400 MHz, CD3OD) δ 0.92-1.05 (m, 6H), 1.44-1.55 (m, IH), 1.66-1.78 (m, IH), 1.86-2.14 (m, 6H), 2.51-2.75 (m, 4H), 2.75-2.80 (m, IH), 2.84-2.93 (m, 2H), 2.96-3.10 (m, 2H), 3.22-3.45 (m, 4H), 3.50-3.63 (m, 2H), 3.67-3.74 (m, IH), 7.12-7.20 (m, 4H).
Example 2.28: Preparation of CycIopentyl-((3aR,4R,6aS)-4-{4-[2-((R)-2-methyI-pyrrolidin- l-yl)-ethyl]-phenyl}-hexahydro-cyclopenta[c]pyrrol-2-yl)-methanone.
Figure imgf000148_0001
The title compound was obtained using general method C starting from (3ai?, AR, 6aS)- 4-4-(2-((i?)-2-methylpyrrolidin-l-yl)ethyl)phenyl)-octahydrocyclopenta[c]pyrrole. MS m/z
395.0, (M+H); 1H NMR (400 MHz, CD3OD) δ 1.09 - 1.16 (m, 3 H), 1.39 - 1.52 (m, 2 H), 1.55 - 1.73 (m, 8 H), 1.74 - 1.83 (m, 3 H), 1.83 - 1.91 (m, 1 H), 1.93 - 2.05 (m, 2 H), 2.22 - 2.34 (m, 2 H), 2.35 - 2.45 (m, 1 H), 2.51 - 2.66 (m, 1 H), 2.70 - 3.06 (m, 6 H), 3.14 - 3.27 (m, 2 H), 3.33 - 3.54 (m, 2 H), 3.57 - 3.83 (m, 1 H), 7.12 - 7.20 (m, 4 H).
Example 2.29: Preparation of CyclopropyI-((3aR,4S,6aS)-4-{4-[2-((R)-2-methyl-pyrrolidin- l-yl)-ethyl]-phenyl}-hexahydro-cyclopenta[c]pyrrol-2-(lH)-yI)-methanone.
Figure imgf000149_0001
Step A: Preparation of (3aR,4S,6aS)-2-Benzyl-4-bromo- octahydrocyclopenta[c]pyrrole.
(3aR,4R,6aS)-2-Benzyl-octahydrocyclopenta[c]pyrrol-4-yl methanesulfonate (1.77 g, 6 mmol) was dissolved in THF (20 mL). Lithium bromide (0.90 mL, 36 mmol) was added and the reaction was stirred at reflux for 48 h. The mixture was filtered, the filtrate was diluted with DCM and water was added. The organic phase was removed and the aqueous phase was reextracted with more DCM. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to leave a yellow oil. This was purified by column chromatography (0-50% EtOAc/n-hexane) to leave the title compound (1.05 g, 62%) as a colorless oil. MS m/z 280.2, 282.3 (M+H); 1H NMR (400 MHz, CDCl3) δ 1.40-1.49 (m, IH), 1.90-1.98 (m, IH), 2.08-2.17 (m, IH), 2.22-2.32 (m, IH), 2.38-2.48 (m, 4H), 2.70-2.80 (m, IH), 2.87-2.95 (m, IH), 3.51 (bs, 2H), 4.13-4.18 (m, IH), 7.22-7.34 (m, 5H).
Step B: Preparation of (3aR,4S,6aS)-2-Benzyl-4-(4-(2-((R)-2-methylpyrrolidin-l- yl)ethyl)phenyl)-octahydrocyclopenta[c]pyrrole.
(R)-4-(2-(2-Methylpyrrolidin-l-yl)ethyl)phenylboronic acid (233 mg, 1 mmol), bis(l,5- cyclooctadiene)nickel (0) (11 mg, 40 μmol), 4,7-diphenyl-l,10-phenanthroline (27 mg, 80 μmol), and potassium tert-butoxide (179 mg, 1.6 mmol) were charged to a 20 mL vial. The vial was purged with nitrogen and 2-butanol (5 mL) was added. The mixture was stirred at room temperature for 30 minutes and then (3aR,4S,6aS)-2-benzyl-4-bromo- octahydrocyclopenta[c]pyrrole (280 mg, 1 mmol) in 2-butanol (1 mL) was added. The reaction was stirred at 60 °C for 3 h and monitored for disappearance of the boronic acid by LCMS. On completion of the reaction the mixture was cooled to room temperature and concentrated to a brown oil. This was purified by HPLC (5-95% ACN/water/0.1%TFA) to leave the title compound (267 mg, 69%) as a colorless oil. MS m/z 389.4 (M+H4); 1H NMR (400 MHz,
CDCl3) S 1.51 (d, J= 7.6 Hz, 3H), 1.66-1.71 (m, IH), 1.87-1.95 (m, IH), 1.99-2.11 (m, 2H), 2.12-2.29 (m, 3H), 2.55-2.70 (m, IH), 2.73-2.82 (m, IH), 2.86-3.06 (m, 7H), 3.10-3.18 (m, IH), 3.18-3.26 (m, IH), 3.43-3.57 (m, IH), 3.60-3.67 (m, IH), 3.77-3.88 (m, IH), 3.91-4.00 (m, IH), 4.17-4.29 (m, IH), 4.33-4.40 (m, IH), 7.04-7.08 (m, IH), 7.10-7.17 (m, 4H), 7.38-7.45 (m, 4H). Step C: Preparation of (3aR,4S,6aS)-4-(4-(2-((R)-2-Methylpyrrolidin-l- yl)ethyl)phenyl)-octahydrocyclopenta[c]pyrrole.
(3aR,4S,6aS)-2-Benzyl-4-(4-(2-((R)-2-methylpyrrolidin-l-yl)ethyl)phenyl)- octahydrocyclopenta[c]pyrrole (267 mg, 687 μmol) was dissolved in methanol (10 mL). The reaction was purged with nitrogen and 20% palladium hydroxide on carbon powder (121 mg, B "> π ' 1 T72S μm Uo Sl) w Oas B ad /de Hd. lk Th "•*e■ r 7ea 'c9tion was stirred under a hydrogen balloon for 4 h. The mixture was filtered through 0.45 micron Teflon and concentrated to a colorless oil (172 mg, 84%), which was used without further purification. MS m/z 299.5 (M+H).
Step D: Preparation of CycIopropyl-((3aR,4S,6aS)-4-{4-[2-((R)-2-methyI- pyrrolidin-l-yl)-ethyl]-phenyl}-hexahydro-cyclopenta[c]pyrrol-2-(lH)-yl)-methanone.
(3aR,4S,6aS)-4-(4-(2-((R)-2-Methylpyrrolidin-l-yl)ethyl)phenyl)- octahydrocyclopenta[c]pyrrole (30 mg, 101 μmol) in DCM (1 mL) was charged to a 2 mL vial. Triethylamine (21.2 μl, 151 μmol) was added followed by cyclopropanecarbonyl chloride (15.8 mg, 151 μmol). The reaction was stirred at room temperature for 1 h and then quenched with the addition of saturated aqueous NaHCO3 (1 mL). The mixture was extracted with DCM (2 x 1 mL) and the organic phase was concentrated under reduced pressure to leave a colorless oil. This was dissolved in DMSO (1 mL) and purified by RPHPLC (5-95%). The product- containing fractions were lyophilized to leave the title compound as a colorless oil (16.6 mg, 45%). MS m/z 367.3 (M+H).
Example 2.30: Preparation of Cyclopentyl-((3aR,4S,6aS)-4-{4-[2-((R)-2-methyl-pyrroIidin- l-yl)-ethyl]-phenyl}-hexahydro-cyclopenta[c]pyrrol-2-(lH)-yl)-methanone (Compound B28).
Figure imgf000150_0001
The title compound (12.7 mg, 32%) was prepared in a manner analogous to Example
2.29. MS m/z 395.4 (M+H).
Example 2.31: Preparation of ((3aR,4S,6aS)-4-{4-[2-((R)-2-Methyl-pyrrolidin-l-yl)-ethyl]- phenyl}-hexahydro-cyclopenta[c]pyrrol-2-(lH)-yl)-(tetrahydro-pyran-4-yl)-methanone (Compound B26).
Figure imgf000150_0002
The title compound (18.0 mg, 44%) was prepared in a manner analogous to Example 2.29. MS /fi/z 411.5 (M+Η). Example 2.32: Preparation of ((3aR,4R,6aS)-444-[2-((R)-2-Methyl-l-oxy-pyrrolidin-l-yl)- ethyI]-phenyI}-hexahydro-cyclopenta[c]pyrrol-2-yl)-(tetrahydro-pyran-4-yl)-methanone.
Figure imgf000151_0001
((3aR, 4S, 6aS)-4-{4-[2-((R)-2-Methyl-pyrrolidin-l-yl)-ethyl]-phenyl}-hexahydro- cyclopenta[c]pyrrol-2-yl)-(tetrahydro-pyran^-y^-methanone (10 mg, 24 μmol) was dissolved in methanol (1 mL). Sodium hydroxide (2 N) (24 μl, 49 μmol) and hydrogen peroxide (12 μl, 122 μmol) were added and the mixture was stirred at 50 0C for 24 h. The mixture was concentrated and purified by preparative HPLC to leave the title compound (6 mg, 58%) as an orange oil. MS m/z 427.3 (M+H).
Example 2.33: Preparation of 4-(2-Benzyl-l,2,3,3a,6,6a-hexahydro-cyclopenta[c]pyrrol-4- yl)-N-methyl-benzamide.
Figure imgf000151_0002
The title compound was obtained using general method G. MS m/z 333.4, (M+H); 1H NMR (400 MHz, CD3OD) δ 2.37 (d, J = 15.6 Hz, 3H), 2.87 - 2.97 (m, 4H), 3.00 - 3.15 (m, 2H), 3.17 - 3.27 (m, IH), 3.71 (dd, J1=12.4 Hz, J2=16.8 Hz, 2H), 3.83 (d, J= 4.0 Hz, IH), 6.27 (d, J = 1.6 Hz, IH), 7.25 - 7.29 (m, 2H), 7.32 (d, J = 4.0 Hz, 3H), 7.49 (d, J = 8.4 Hz, 2H), 7.75 (d, J = 8.8 Hz, 2H).
Example 2.34: Preparation of ((3aR,4R,6aS)-4-{4-[2-((R)-2-Methyl-pyrrolidin-l-yl)-ethyl]- phenyl}-hexahydro-cyclopentalcjpyrrol^-ylj-phenyl-methanone.
Figure imgf000151_0003
A mixture of benzoic acid (120.5 mg, 0.9867 mmol) and PS-Carbodiimide (1.01 g, 1.01 mmol) in DCM (10.0 mL) was stirred for 10 min and added (3aR,4R,6aS)-4-(4-(2-((R)-2- iP'irT ■■'"! PFi(ClJB / H+iψ»+7' 9 'metnylpyi&6lϊdih-l-yl)ethyl)phehyl)-octahydrocyclopenta[c]pyrrole (152 nig, 0.510 mmol) dissolved in DCM (5.0 mL). After 14 h, the resin was filtered and washed with DCM and MeOH. The solution was concentrated. The residue was purified by preparative HPLC, lyophilized, and treated with HCl to afford the hydrochloride salt of the title compound (115.9 mg). MS m/z 403, (M+H); 1H NMR (400 MHz, CD3OD) δ 1.41-1.49 (m, 3H), 1.53-1.84 (m, 2H), 1.94-2.20 (m, 5H), 2.28-2.39 (m, IH), 2.86-3.91 (m, 14H), 7.10-7.54 (m, 9H).
Example 2.35: Preparation of 2-(4-Methoxy-benzyl)-6-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]- l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole.
Figure imgf000152_0001
To a solution of 2-(4-methoxy-benzyl)-4-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]- octahydro-cyclopenta[c]pyrrol~4-ol (0.189 g, 0.45 mmol) in isopropyl alcohol (3.5 mL) was added HCl (1.58 mL, 6.3 mmol, 4M in 1,4-dioxane). The reaction mixture was heated to 60 0C. After 24 h, the mixture was concentrated under reduced pressure and neutralized with 10% NaOH solution. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with H2O, brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified through a silica gel column with 10% MeOH/ 90% DCM to afford the title compound (0.105 g, 60%) as a yellow oil. MS m/z 403.5, (M+H); 1H NMR (400 MHz, CD3OD) δ 1.95-2.20 (m, 4H), 2.40-2.50 (m, IH), 2.75-3.25 (m, 7H), 3.30-3.55 (m, 4H), 3.60-3.75 (m, 2H), 3.78 (s, IH), 3.80 (s, 3H), 3.90-4.05 (m, IH), 4.20-4.35 (m, 2H), 6.20 (d, J = 10.8 Hz, IH), 6.95 (d, J = 8.4 Hz, 2H), 7.26-7.32 (m, 2H), 7.34-7.44 (m, 4H).
Example 2.36: Preparation of (3aR,7aR)-4-(4-(2-((R)-2-methylpyrrolidin-l- yl)ethyl)phenyl)-2,3,3a,6,7,7a-hexahydro-lH-isoindole. Step A: Preparation of (3aS,7aR)-2-benzyl-4-(4-(2-((R)-2-methylpyrrolidin-l- yl)ethyl)phenyl)-octahydro-lH-isoindol-4-ol.
Figure imgf000152_0002
" The title compound was prepared in the same manner as descπbed m Example 1.3 starting from (3aS, 7ai?)-2-benzylhexahydro-lH-isoindol-4(2H)-one. MS m/z 419.5 (M+Η); 1H
NMR (400 MHz, CDCl3) δ 1.13 (d, J=6.06 Hz, 3 H), 1.38 - 1.51 (m, 2 H), 1.62 - 2.04 (m, 8 H),
2.17 - 2.39 (m, 5 H), 2.46 - 2.53 (m, 1 H), 2.56 - 2.66 (m, 1 H), 2.74 - 2.91 (m, 4 H), 3.00 - 3.09 (m, 1 H), 3.24 - 3.31 (m, 1 H), 3.58 (d, /=12.63 Hz, 1 H), 3.76 (d, J=I 3.14 Hz, 1 H), 7.16 (d,
J=8.59 Hz, 2 H), 7.23 - 7.35 (m, 5 H), 7.44 - 7.48 (m, 2 H).
(3aS, 7aR)-2-Benzylhexahydro-lH-isoindol-4(2H)-one was prepared via the method described in Example 1.1 using cyclohexenone as the starting material and resolving the product using di-p-toluoyl-d-tartaric acid. Analysis of (3aS, 7ai.)-2-Benzylhexahydro-lH-isomdol-4(2H)-one via Chiral
ΗPLC:
Column: Chiralpak AD-Η, 150 x 2.1 mm, 5 μm particle size
Eluent: 95% Ηexane/5% Isopropanol
Gradient: Isocratic Flow: 1 mL/minute
Detector: 254 nm
Retention Times: 3aR,7aS - 15.2 min.; 3aS,7ai? - 16.0 min.
Step B: Preparation of (3aS,7aR)-4-(4-(2-((R)-2-methylpyrrolidin-l- yl)ethyl)phenyl)-octahydro-lH-isoindol-4-ol.
Figure imgf000153_0001
The title compound was prepared in the same manner as described in Example 1.6 starting from (3aS,7aR)-2-benzyl-4-(4-(2-((R)-2-methylpyrrolidin-l-yl)ethyl)phenyl)-octahydro- lH-isoindol-4-ol. MS m/z 329.4 (M+H); 1H NMR (400 MHz, CDCl3) δ 1.17 - 1.25 (m, 1 H), 1.36 - 1.42 (m, 3 H), 1.44 - 1.51 (m, 1 H), 1.68 - 1.84 (m, 5 H), 1.88 - 2.23 (m, 4 H), 2.46 - 2.52 (m, 1 H), 2.54 - 2.65 (m, 1 H), 2.83 - 3.12 (m, 6 H), 3.15 - 3.38 (m, 4 H), 3.61 - 3.70 (m, 1 H), 7.18 (d, J=8.59 Hz, 2 H), 7.39 (d, J=8.08 Hz, 2 H).
Step C: Preparation of (3aR,7aR)-4-(4-(2-((R)-2-methylpyrrolidin-l- yl)ethyl)phenyl)-2,3,3a,6,7,7a-hexahydro-lH-isoindole.
Figure imgf000153_0002
"'" l '' '" The 'title compound was'prepared in the same manner as described in Example 1.7 starting from (3aS, 7aR)-4-(4-(2-((R)-2-methylpyrrolidm-l-yl)ethyl)phenyl)-octahydro-lH- isoindol-4-ol. LC-MS m/z 311.5 (M+H); 1H NMR (400 MHz, CDCl3) δ 1.09 - 1.14 (m, 3 H), 1.19 - 1.28 (m, 1 H), 1.39 - 1.52 (m, 2 H), 1.66 - 1.86 (m, 4 H), 1.87 - 1.98 (m, 2 H), 2.15 - 2.22 (m, 3 H), 2.24 - 2.41 (m, 3 H), 2.50 - 2.55 (m, 1 H), 2.73 - 2.87 (m, 3 H), 2.97 - 3.29 (m, 4 H), 7.16 (d, J=7.58 Hz5 2 H), 7.25 - 7.31 (m, 2 H).
Step D: Preparation of (3aS,7aR)-4-(4-(2-((R)-2-methylpyrrolidin-l- yl)ethyl)phenyl)-octahydro-lH-isoindoIe.
Figure imgf000154_0001
A mixture of (3aR, 7aR)-4-(4-(2-((i?)-2-methylpyrrolidm-l-yl)ethyl)phenyl)-
2,3,3a,6,7,7a-hexahydro-lH-isoindole, and 10% palladium on carbon was dissolved in methanol. The scintillation vial was evacuated and purged with hydrogen three times. The reaction mixture was stirred over night under hydrogen at room temperature. The mixture was filtered and concentrated to afford the title compound. LC-MS m/z 313.0 (M+H); 1H NMR (400 MHz, CDCl3) δ 1.12 (d, J=6.06 Hz, 3H), 1.31 - 1.52 (m, 3H), 1.73 (d, J=3.03 Hz, 5H), 1.88 -
2.01 (m, 2H), 2.13 - 2.35 (m, 5H), 2.48 - 2.65 (m, 2H), 2.69 - 3.29 (m, 8H), 7.03 - 7.21 (m, 4H).
Example 2.37: Preparation of {7-[4-(2-PyrroKdin-l-yI-ethyl)-phenyI]-l,3,3a,4,5,7a- hexahydro-isoindoI~2-yl}-(tetrahydro-furan-3-yl)-methanone.
Figure imgf000154_0002
To a stirring solution of PS-Carbodiimide polymer-bound coupling agent (1.168 g, 1.484 mmol) and tetrahydrofuran-3-carboxylic acid (0.1063 mL, 1.113 mmol) in DCM was added 4-(4-(2-(pyrrolidin-l-yl)ethyl)phenyl)-2,3,3a,6,7,7a-hexahydro-lH-isoindole (0.220 g, 0.742 mmol). The reaction mixture was stirred at room temperature for 8 h. The reaction mixture was filtered, rinsed with DCM, and concentrated. The crude residue was purified by HPLC using 10-85% ACN/H2O over 35 min. The combined fractions were made basic with 10% aqueous sodium hydroxide, and extracted with ethyl acetate. The organic layer was dried over Na2S(It, and concentrated to afford the title compound which was made into a hydrochloride salt using 1.0 M HCl in ether. MS m/z 395.4 (M+H); 1H NMR (400 MHz, CD3OD) δ 1.43 - 1.57 (m, IH), 1.68 - 1.80 (m, IH), 1.83 (d, J= 3.54 Hz, 3H), 1.89 - 1.99 (m, ip ii I" / y Sf IB ■''" II+H-IW"'?1 l!;:ilι
||... ii,,,^, 2:ιd(T- ΪW(in, mj, Ϊ$A - 2.34 (m, 2H), 2.40 - 2.56 (m, IH), 2.62 (s, 4H), 2.67 - 2.76 (m, 2H), 2.78 - 2.87 (m, 2H), 2.95 - 3.24 (m, 2H), 3.28 - 3.39 (m, 2H), 3.42 - 3.65 (m, 2H)3 3.66 - 3.89 (m, 4H), 6.08 - 6.18 (m, IH), 7.14 - 7.24 (m, 2H), 7.29 - 7.39 (m, 2H).
Example 2.38: Preparation of Pyridin-3-yl-{7-[4-(2-pyrrolidin-l-yI-ethyl)-phenyl]- l,3,3a,4,5,7a-hexahydro-isoindol-2-yl}-methanone.
Figure imgf000155_0001
The title compound was obtained using general method C. MS m/z 389.5 (M+H); 1H NMR (400 MHz, CD3OD) δ 1.48 - 1.63 (m, IH), 1.66 - 1.90 (m, 2H), 1.96 - 2.21 (m, 4H), 2.27 - 2.40 (m, IH), 2.51 - 2.65 (m, IH), 2.97 - 3.20 (m, 4H), 3.24 - 3.59 (m, 6H), 3.59 - 3.76 (m, 2H), 3.88 - 4.02 (m, IH), 6.13 - 6.28 (m, IH), 7.19 - 7.49 (m, 4H), 8.06 - 8.25 (m, IH), 8.69 - 9.17 (m, 3H).
Example 2.39: Preparation of l-(7-{4-[2-((S)-2-Methyl-pyrrolidin-l-yl)-ethyl]-phenyl}- l,3,3a,4,5,7a-hexahydro
Figure imgf000155_0002
The title compound was obtained using general method A. MS m/z 353.4 (M+H).
Example 2.40: Preparation of {4-[4-(2-PyrroKdin-l-yl-ethyl)-phenyl]-octahydro-isoindol-2- yl}-(tetrahydro-furan-3-yl)-methanone.
Figure imgf000155_0003
A mixture of (7-(4-(2-(pyrrolidin- 1 -yl)ethyl)phenyl)- 1 ,3 a,4,7a-tetrahydro- 1 H-isoindol- 2(6H)-yl)(tetrahydrofuran-3-yl)methanone (0.020 g, 0.051 mmol), and 10% palladium on carbon (0.020 g, 0.19 mmol) was dissolved in methanol. The scintillation vial was evacuated and purged with hydrogen three times. The reaction mixture was stirred over night under hydrogen at room temperature. The mixture was filtered and concentrated to afford the title i!<" *" compound. MS m/z 397.4, (M+B); 1H NMR (400 MHz, CDCl3) B 1.12 - 1.30 (m, IH), 1.37 - 1.46 (m, IH), 1.65 - 1.81 (m, 3H), 1.90 - 2.00 (m, 4H), 2.04 - 2.36 (m, 5H), 2.51 - 2.74 (m, IH), 2.88 - 3.13 (m, 4H), 3.17 - 3.42 (m, 3H), 3.70 - 4.06 (m, 10H), 7.05 - 7.21 (m, 4H).
Example 2.41 : Preparation of l-(4-{4-[2-((S)-2-Methyl-pyrrolidin-l-yϊ)-ethyl]-phenyl}- octahydro-isoindoI-2-yl)-ethanone.
Figure imgf000156_0001
The title compound was obtained using general method A. MS m/z 355.5 (M+H); 1H NMR (400 MHz, CD3OD) δ 1.15 - 1.40 (m, 2H), 1.50 (d, J = 6.06 Hz, 3H), 1.61 - 2.19 (m, 6H), 2.29 - 2.48 (m, 2H), 2.51 - 2.85 (m, IH), 2.90 - 3.00 (m, 2H), 3.04 - 3.15 (m, 3H), 3.19 - 3.38 (m, 8H), 3.47 - 3.84 (m, 3H), 7.21 - 7.41 (m, 4H).
Example 2.42: Preparation of 2-Methyl-l-{(3aS,7aS)-7-[4-(2-pyrrolidin-l-yl-ethyl)- phenyl]-l,3,3a,4,5,7a-hexahydro-isoindol-2-yl}-propan-l-one.
Figure imgf000156_0002
The title compound was obtained using general method C. MS m/z 367.4 (M+H); 1H NMR (400 MHz, CDCl3) δ 0.99 - 1.17 (m, 6H), 1.43 - 1.61 (m, IH), 1.71 - 1.81 (m, IH), 2.03 - 2.15 (m, 2H), 2.19 - 2.32 (m, 4H), 2.38 - 2.56 (m, IH), 2.61 - 2.72 (m, IH), 2.77 - 2.91 (m, 2H), 3.0r - 3.48 (m, 8H), 3.52 - 3.90 (m, 3H), 6.09 - 6.15 (m, IH), 7.16 - 7.26 (m, 2H), 7.27 - 7.35 (m, 2H).
Example 2.43: Preparation of (3aS,7aS)-2-Cyclopropanesulfonyl-7-[4-(2-pyrrolidin-l-yl- ethyl)-phenyl]-2,3,3a,4,5,7a-hexahydro-lH-isoindole.
Figure imgf000156_0003
ιn> it1"" "1If" / It Il I|:;;[U[""|! IR / n+im»ii»||..'7 l!:'l ll"' L" " " " To a solution of (3aέ,7a'S)-4-(4-(2-(pyrrolidin-l-yl)ethyl)phenyl)-2,3,3a,6,7,7a- hexahydro-lH-isoindole (0.100 g, 0.337 mmol) in DCM (5.0 ml) was added triethylamine (0.0940 ml, 0.675 mmol) followed by cyclopropanesulfonyl chloride (0.0474 g, 0.337 mmol). The reaction mixture was stirred at 25 0C for 1.5 h. Upon completion, the reaction mixture was concentrated. The residue was purified by preparative HPLC using 10-95% ACNTH2O over 50 min. MS m/z 401.3, (M+H); 1H NMR (400 MHz, CDCl3) δ 0.98 - 1.06 (m, 5H), 1.13 - 1.22 (m, 2H), 1.73 - 1.88 (m, 4H), 2.24 - 2.36 (m, 3H), 2.47 - 2.62 (m, 4H), 2.65 - 2.75 (m, 2H), 2.79 - 2.87 (m, 2H), 3.01 - 3.08 (m, IH), 3.30 - 3.41 (m, 2H), 3.64 - 3.74 (m, 2H), 6.08 - 6.15 (m, IH), 7.15 - 7.19 (m, 2H), 7.23 - 7.26 (m, 2H).
Example 2.44: Preparation of (3aS,7aS)-2-(Propane-2-sulfonyl)-7-[4-(2-pyrroIidin-l-yl- ethyl)-phenyl]-2,3,3a,4,5,7a-hexahydro-lH-isoindole.
Figure imgf000157_0001
The title compound was prepared in a similar manner as described in Example 2.43. MS m/z 403.3 (M+H); 1H NMR (400 MHz, CDCl3) δ 1.32 (d, J = 6.57 Hz, 6H), 1.51 - 1.66 (m, IH), 1.73 - 1.84 (m, IH), 2.19 - 2.34 (m, 5H), 2.44 - 2.55 (m, IH), 2.44 - 2.56 (m, IH), 2.78 - 2.91 (m, 2H), 2.98 - 3.07 (m, IH), 3.14 - 3.38 (m, 7H), 3.62 - 3.76 (m, 2H), 3.80 - 3.93 (m, 2H), 6.10 (t, J= 3.79 Hz, IH), 7.15 - 7.23 (m, 2H), 7.28 (d, J = 7.58 Hz, 2H).
Example 2.45: Preparation of 2-Methyl-l-((3aS,7aS)-7-{4-[2-((R)-2-methyl-pyrrolidin-l- yl)-ethyl]-phenyl}-l,3,3a,4,5,7a-hexahydro-isoindol-2-yl)-propan-l-one.
Figure imgf000157_0002
The title compound was obtained using general method C. MS m/z 381.4 (M+H); 1H NMR (400 MHz, CD3OD) δ 0.95 - 0.99 (m, IH), 1.01 - 1.04 (m, IH), 1.08 (dd, J= 6.57, 4.04 Hz, 4H), 1.28 - 1.34 (m, 2H), 1.43 (d, J= 6.06 Hz, 3H), 1.52 (dd, J = 12.38, 3.79 Hz, IH), 1.71 - 1.82 (m, 2H), 2.02 - 2.12 (m, 2H), 2.26 - 2.33 (m, 2H), 2.51 - 2.59 (m, IH), 2.75 - 2.83 (m, IH), 2.96 - 3.08 (m, 2H), 3.15 - 3.21 (m, 2H), 3.34 - 3.42 (m, IH), 3.44 - 3.63 (m, 4H), 3.67 - 3.86 (m, 2H), 6.14 - 6.17 (m, IH), 7.27 - 7.31 (m, 2H), 7.37 - 7.42 (m, 2H). E exxaammppllee 2 Z.A46b:: P Prreeppaarraattiioonn ooff CCyclopropyl-((3aS,7aS)-7-{4-[2-((R)-2-methyl-pyrroIidin-l- yl)-ethyl]-phenyl}-l,3,3a,4,5,7a-hexahydro-isoindol-2-yl)-methanone.
Figure imgf000158_0001
The title compound was obtained using general method C. MS m/z 379.5, (M+H); 1H NMR (400 MHz, CDCl3) δ 0.57 - 0.71 (m, 2H), 0.79 - 0.95 (m, 2H), 1.16 - 1.28 (m, 2H), 1.28 - 1.33 (m, 2H), 1.37 - 1.61 (m, 3H), 1.64 - 1.76 (m, 2H), 1.85 (d, / = 15.66 Hz, IH), 1.95 - 2.06 (m, 5H), 2.31 - 2.52 (m, IH), 2.67 - 2.78 (m, 2H), 2.83 - 2.92 (m, IH), 2.96 - 3.05 (m, IH), 3.16 - 3.37 (m, 2H), 3.48 - 3.64 (m, 2H), 3.77 - 3.87 (m, IH), 6.02 - 6.07 (m, IH), 7.07 - 7.16 (m, 2H), 7.19 - 7.27 (m, 2H).
Example 2.47: Preparation of Cyclopentyl-((3aS,7aS)-7-{4-[2-((R)-2-methyl-pyrroKdin-l- yI)-ethyl]-phenyl}-l,3,3a,4,5,7a-hexahydro-isoindol-2-yl)-methanone.
Figure imgf000158_0002
The title compound was obtained using general method C. MS m/z 407.5, (M+H); 1H NMR (400 MHz, CDCl3) δ 1.17 - 1.35 (m, 2H), 1.42 - 1.86 (m, 9H), 1.95 - 2.08 (m, 3H), 2.18 - 2.32 (m, 4H), 2.37 - 2.55 (m, IH), 2.58 - 2.66 (m, IH), 2.73 - 2.80 (m, IH), 2.83 - 2.94 (m, 2H), 2.99 - 3.41 (m, 5H), 3.53 - 3.66 (m, 2H), 3.68 - 3.86 (m, 2H), 4.01 (s, IH), 6.09 - 6.14 (m, IH), 7.15 - 7.24 (m, 2H), 7.31 (t, J = 8.34 Hz, 2H).
Example 2.48: Preparation of l-(7-{4-[2-((R)-2-Methyl-pyrrolidin-l-yl)-ethyl]-phenyl}- l,3,3a,4,5,7a-hexahydro-isoindol-2-yl)-ethanone.
Figure imgf000158_0003
To the solution of 2-(4-(2-acetyl-2,3,3a,6,7,7a-hexahydro-lH-isoindol-4-yl)phenyl)ethyl methanesulfonate (0.125 g, 0.3439 mmol) in acetonitrile was added R-methylpyrrolidine (0.04100 g, 0.4815 mmol) and sodium carbonate (0.08019 g, 0.7566 mmol). The reaction was stirred at 50 0C overnight. The reaction mixture was filtered and concentrated under reduced p Il If" ■"" If Kill B ■••" iMMMI-NI"/' 9
11 '""'pressure. "The residue was purified by HPLC using 20-95% ACN/H2O over 50 min. The pure fractions were combined, and neutralized with a saturated solution of sodium bicarbonate. The product was extracted with ethyl acetate, dried over Na2SO4, and concentrated to afford the title compound. MS m/z 353.4, (M+H).
Example 2.49: Preparation of l-((3aS,7aS)-7-{4-[2-((R)-2-Methyl-pyrrolidin-l-yl)-ethyl]- phenyl}-l,3,3a,4,5,7a-hexahydro-isoindol-2-yl)-2-phenyl-ethanone.
Figure imgf000159_0001
The title compound was prepared in a similar manner as described in Example 2.37. MS m/z 429.5, (M+H); 1H NMR (400 MHz, CDCl3) δ 1.12 (dd, J = 5.81, 2.27 Hz, 3H), 1.40 - 1.51 (m, 2H), 1.61 - 1.84 (m, 4H), 1.89 - 1.99 (m, IH), 2.15 - 2.34 (m, 5H), 2.40 - 2.48 (m, IH), 2.66 - 2.89 (m, 3H), 2.97 - 3.16 (m, 2H), 3.20 - 3.29 (m, IH), 3.33 - 3.41 (m, IH), 3.49 - 3.60 (m, IH), 3.64 - 3.77 (m, 2H), 3.83 - 3.93 (m, IH), 7.03 - 7.35 (m, 9H).
Example 2.50: Preparation of ((3aR,7aR)-7-{4-[2-((R)-2-Methyl-pyrroUdin-l-yl)-ethyl]- phenyl}-l,3,3a,4,5,7a-hexahydro-isoindol-2-yl)-(tetrahydro-furan-3-yl)-methanone.
Figure imgf000159_0002
The title compound was prepared in a similar manner as described in Example 2.37. MS m/z 409.5, (M+H); 1H NMR (400 MHz, CDCl3) δ 1.13 (d, J = 6.06 Hz, 3H), 1.41 - 1.60 (m, 2H), 1.70 - 2.15 (m, 6H), 2.17 - 2.39 (m, 6H), 2.41 - 2.55 (m, IH), 2.76 - 2.91 (m, 2H), 2.94 - 3.21 (m, 3H), 3.24 - 3.31 (m, IH), 3.36 - 3.48 (m, IH), 3.54 - 3.98 (m, 6H), 6.08 - 6.13 (m, IH), 7.13 - 7.22 (m, 2H), 7.25 - 7.30 (m, 2H).
Example 2.51: Preparation of (3aR,7aR)-2-Benzyl-7-{4-[2-((R)-2-methyl-pyrrolidin-l-yl)- ethyl]-phenyl}-2,3,3a,4,5,7a-hexahydro-lH-isoindole.
Figure imgf000160_0001
The title compound was prepared in a similar manner as described in Example 1.7. MS m/z 401.3 (M+H); 1H NMR (400 MHz, CD3OD) δ 1.47 (d, J = 6.06 Hz, 3H), 1.57 - 1.69 (m, IH), 1.70 - 1.84 (m, IH), 1.86 - 1.95 (m, IH), 2.02 - 2.21 (m, 2H), 2.24 - 2.39 (m, 3H), 2.69 - 2.93 (m, 2H), 3.00 - 3.16 (m, 3H), 3.18 - 3.28 (m, 2H), 3.45 - 3.64 (m, 4H), 3.67 - 3.87 (m, 2H), 4.28 - 4.47 (m, 2H), 6.26 (s, IH), 7.24 - 7.59 (m, 9H).
Example 2.52: Preparation of {(3aS,7aS)-7-[4-(2-Pyrrolidin-l~yl-ethyl)-phenyl]- l,3,3a,4,5,7a-hexahydro-isoindol-2-yl}-(tetrahydro-furan-3-yl)-methanone.
Figure imgf000160_0002
The title compound was prepared in a similar manner as described in Example 2.37. MS m/z 395 A (M+H); 1HNMR (400 MHz, CDCl3) δ 1.53 - 1.68 (m, 4H), 1.72 - 1.78 (m, 2H), 1.84 (s, 2H), 1.92 - 2.07 (m, 2H), 2.08 - 2.23 (m, 2H), 2.25 - 2.32 (m, IH), 2.33 - 2.39 (m, IH), 2.57 - 2.70 (m, IH), 2.75 (s, 2H), 2.81 - 2.89 (m, 2H), 2.91 - 3.00 (m, 2H), 3.05 - 3.31 (m, 2H), 3.34 - 3.50 (m, IH), 3.53 - 3.98 (m, 5H), 6.08 - 6.12 (m, IH), 7.13 - 7.22 (m, 2H), 7.24 - 7.29 (m, 2H).
Example 2.53: Preparation of ((3aS,7aS)-7-{4-[2-((R)-2-Methyl-pyrrolidin-l-yl)-ethyl]- phenyl}-l,3,3a,4,5,7a-hexahydro-isoindol-2-yl)-(tetrahydro-furan-3-yl)-methanone.
Figure imgf000160_0003
The title compound was prepared in a similar manner as described in Example 2.37. MS m/z 409.5 (M+H); 1H NMR (400 MHz, CDCl3) δ 1.17 (dd, J = 6.06, 2.53 Hz, 3H), 1.44 - 1.56 (m, 2H), 1.71 - 2.03 (m, 4H), 2.07 - 2.49 (m, 8H), 2.79 - 2.89 (m, 2H), 2.95 - 3.48 (m, 6H), 3.54 - 3.96 (m, 6H), 6.10 (t, J = 3.79 Hz, IH), 7.12 - 7.22 (m, 2H), 7.25 - 7.30 (m, 2H). Example 2.54: Preparation of ((3aS,7aR)-4-{4-[2-((R)-2-Methyl-pyrrolidin-l-yl)-ethyl]- phenyl}-octahydro-isoindol-2-yl)-(tetrahydro-furan-3-yl)-methanone.
Figure imgf000161_0001
The title compound was prepared in a similar manner as described in Example 2.40.
MS m/z AWA, (M+H); 1H NMR (400 MHz, CDCl3) δ 1.10 - 1.32 (m, IH), 1.35 - 1.56 (m, IH), 1.58 - 1.85 (m, 6H), 1.88 - 2.39 (m, 8H), 2.50 - 2.75 (m, IH), 2.84 - 3.62 (m, 12H), 3.67 - 4.10 (m, 5H), 7.09 - 7.27 (m, 4H).
Example 2.55: Preparation of ((3aR,7aS)-4-{4-[2-((R)-2-Methyl-pyrrolidin-l-yI)-ethyl]- phenyl}-octahydro-isoindol-2-yl)-(tetrahydro-furan-3-yl)-methanone.
Figure imgf000161_0002
The title compound was prepared in a similar manner as described in Example 2.40. MS m/z 411.4 (M+H); 1H NMR (400 MHz, CDCl3) δ 1.15 - 1.35 (m, IH), 1.40 - 1.56 (m, 3H), 1.66 - 1.80 (m, 3H), 1.84 - 2.20 (m, 7H), 2.25 - 2.42 (m, 2H), 2.59 - 2.79 (m, IH), 2.87 - 3.16
(m, 5H), 3.17 - 3.30 (m, 4H), 3.36 - 3.45 (m, IH), 3.46 - 3.67 (m, 3H), 3.46 - 3.66 (m, 4H),7.20 - 7.34 (m, 4H).
Example 2.56: Preparation of 2-MethyI-l-((3aS,7aR)-4-{4-[2-((R)-2-methyl-pyrrolidin-l- yl)-ethyϊ]-phenyl}-octahydro-isoindol-2-yl)-propan-l-one.
Figure imgf000161_0003
The title compound was prepared in a similar manner as described in general method C. LC-MS m/z 383.4 (M+H); 1H NMR (400 MHz, CDCl3) δ 0.98 - 1.17 (m, 5H), 1.20 - 1.32 (m, IH), 1.37 - 1.49 (m, IH), 1.57 (s, 3H), 1.64 - 1.85 (m, 3H), 1.89 - 2.09 (m, 3H), 2.18 - 2.36 (m, 3H), 2.45 - 2.69 (m, 2H), 2.88 - 3.17 (m, 5H), 3.18 - 3.58 (m, 6H), 3.59 - 3.87 (m, 2H), 7.09 -
7.33 (m, 4H). Example 2.57: Preparation of Cyclopentyl-((3aS,7aR)-4-{4-[2-((R)-2-methyl-pyrrolidin-l- yl)-ethyl]-phenyI}-octahydro-isoindol-2-yl)-methanone.
Figure imgf000162_0001
The title compound was prepared in a similar manner as described in general method C. MS m/z 409.5 (M+H); IH NMR (400 MHz, CDCl3) δ 1.11 - 1.30 (m, IH), 1.37 - 1.47 (m, 2H), 1.51 - 1.95 (m, 14H), 1.99 - 2.12 (m, 2H), 2.17 - 2.37 (m, 3H), 2.49 - 2.79 (m, 3H), 2.88 - 3.60 (m, 10H), 3.88 - 4.09 (m, IH), 7.08 - 7.27 (m, 4H).
Example 2.58: Preparation of ((3aS,7aR)-4-{4-[2-((R)-2-Methyl-pyrrolidin-l-yl)-ethyl]- phenyl}-octahydro-isoindol-2-yl)-(tetrahydro-pyran-4-yl)-methanone.
Figure imgf000162_0002
The title compound was prepared in a similar manner as described in general method C. MS m/z 425.3 (M+H); IHNMR (400 MHz, CDCl3) δ 1.10 - 1.28 (m, IH), 1.37 - 1.48 (m, IH), 1.54 (d, J = 6.06 Hz, 3H), 1.58 - 2.09 (m, 9H), 2.15 - 2.73 (m, 6H), 2.88 - 3.12 (m, 5H), 3.21 - 3.49 (m, 7H), 3.50 - 3.62 (m, IH), 3.66 - 3.79 (m, IH), 3.94 - 4.05 (m, 2H), 7.06 - 7.28 (m, 4H).
Example 2.59: Preparation of {(3aS,7aR)-4-[4-(2-Pyrrolidin-l-yl-ethyI)-phenyl]-octahydro- isoindol-2-yl}-(tetrahydro-furan-3-yl)-methanone.
Figure imgf000162_0003
The title compound was prepared in the same manner as described in Example 2.37. MS m/z 397.4 (M+H); IHNMR (400 MHz, CDCl3) δ 1.12 - 1.30 (m, IH), 1.37 - 1.46 (m, IH), 1.65 - 1.81 (m, 3H), 1.90 - 2.00 (m, 4H), 2.04 - 2.36 (m, 5H), 2.51 - 2.74 (m, IH), 2.88 - 3.13 (m, 4H), 3.17 - 3.42 (m, 3H), 3.70 - 4.06 (m, 10H), 7.05 - 7.21 (m, 4H).
Example 2.60: General Method K Pre paration of 2--Methyl-i-(6-|4-[2-(3-phenyl-pyrrolidin-l-yl)-ethyl]-phenyl}-3,3a,4,6a- tetrahydro-lH-cyclopentalclpyrrol-^-yϊJ-propan-l-one.
Step A: Preparation of Intermediate l-(4-(4-(2-(tert-
ButyldimethyIsilyloxy)ethyl)phenyl)-4-hydroxyhexahydrocyclopenta[c]pyrrol-2(lH)-yI)-2- methylpropan-l-one
Figure imgf000163_0001
Starting with compound from Example 1.9, reduction of the N-benzyl was performed as described in Example 1.6, followed by acylation as general route C afforded the title compound. MS m/z = 432.2 (M+H); 1HNMR (400 MHz, CD3OD) δ 0 (s, 6H), 0.89 (s, 9H), 1.07 - 1.19 (m, 6H), 1.84 (dd, J = 7.96, 2.65 Hz, IH), 2.09 - 2.34 (m, 3H), 2.74 - 2.85 (m, 3H), 2.91 - 3.12 (m, 2H), 3.35 - 3.58 (m, 2H), 3.66 - 3.98 (m, 4H), 7.19 - 7.25 (m, 2H), 7.39 - 7.48 (m, 2H).
Step B: Preparation of Intermediate 4-(2-IsobutyryI~l,2,3,3a,6,6a- hexahydrocyclopenta[c]pyrrol-4-yl)phenethyl Methanesulfonate
Figure imgf000163_0002
Starting with compound from Step A above, followed by deprotection and elimination described for Example 1.7, followed by mesylation as described in Example 1.12 afforded the title compound. MS m/z = 378.0 (M+H); 1H NMR (400 MHz, CD3OD) 8 0.84 - 0.89 (m, 1.5H), 1.02 - 1.12 (m, 4.5H), 2.34 - 2.45 (m, IH), 2.56 - 2.66 (m, 0.5H), 2.74 - 2.88 (m, 0.5H), 2.92 - 2.98 (m, 3H), 3.03 - 3.07 (m, 2H), 3.45 - 3.60 (m, IH), 3.71 - 3.99 (m, 3H), 4.40 - 4.47 (m, 2H), 6.10 (s, IH), 7.29 (t, J = 7.33 Hz, 2H), 7.35 - 7.42 (m, 5H).
Step C: Preparation of 2-Methyl-l-(6-{4-[2-(3-phenyl-pyrrolidin-l-yl)-ethyl]- phenyl}-3,3a,4,6a-tetrahydro-lH-cyclopenta[c]pyrrol-2-yl)-propan-l-one
Figure imgf000163_0003
Starting with material from Step B above, the title compound was obtained using general method A. MS m/z = 429.1 (M+H); 1H NMR (400 MHz, CD3OD) δ 1.00 - 1.15 (m, 6H), 2.22 - 2.45 (m, 2H), 2.46 - 2.65 (m, 2H), 2.73 - 2.90 (m, 2H), 3.07 - 3.16 (m, 2H), 3.19 - 332 (m, 1H), 3.4 23.66(m,5H), 3.68 - 4.04 (m, 6H), 6.12 (d, J= 1.77 Hz, IH), 7.26 - 7.47 (m, 9H).
Example 2.61: Preparation of 2-Methyl-l-{(3aR,4R,6aS)-4-[4-(2-pyrrolidin-l-yl-ethyl)- phenyI]-hexahydro-cyclopenta[c]pyrrol-2-yl}-propan-l-one.
Figure imgf000164_0001
Starting with material from example 2.60, step B, displacement as described in general method A led to title compound. MS m/z = 355.2 (M+H); 1H NMR (400 MHz, CD3OD) δ 0.94 - 1.14 (m, 6H), 1.65 - 1.74 (m, IH), 1.95 - 2.24 (m, 6H), 2.40 - 2.50 (m, IH), 2.72 - 2.83 (m, IH), 2.88 - 3.29 (m, 6H), 3.35 - 3.54 (m, 5H), 3.62 - 3.76 (m, 3H), 3.79 - 3.87 (m, IH), 7.23 - 7.34 (m, 4H).
Example 2.62: Preparation of (3aS,6aS)-2-Methanesulfonyl-6-[4-(2-pyrrolidin-l-yl-ethyl)- phenyl]-l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole.
Figure imgf000164_0002
The title compound was obtained using general method C. MS m/z = 361.3 (M+H); 1H NMR (400 MHz, CD3OD) δ 1.99 - 2.09 (m, 2H), 2.19 (s, 2H), 2.38 - 2.47 (m, IH), 2.82 - 2.93 (m, 4H), 3.03 - 3.24 (m, 7H), 3.44 - 3.50 (m, 2H), 3.54 - 3.63 (m, 2H), 3.65 - 3.73 (m, 2H), 3.90 - 3.98 (m, IH), 6.18 (d, J = 1.77 Hz, IH), 7.32 (d, J= 8.08 Hz, 2H), 7.44 (d, J= 8.08 Hz, 2H).
Example 2.63: Preparation of l-{2-[4-(2~Benzyl-l,2,3,3a,6,6a-hexahydro- cyclopenta[c]pyrrol-4-yl)-phenyl]-ethyl}-pyrrolidin-2-one.
Figure imgf000164_0003
The title compound was obtained using general method A. MS m/z = 387.3 (M+H); 1H
NMR (400 MHz, CD3OD) δ 1.96 - 2.07 (m, 3H), 2.37 (t, J = 8.08 Hz, 3H), 2.65 - 2.74 (m, 2H),
Figure imgf000165_0001
2.81-2.90(m,3H),3.31-3.44(m,4H), 2H), 3.72 - 3.83 (m, IH), 3.95 - 4.04 (m, IH), 4.04 - 4.14 (m, IH), 4.17 - 4.27 (m, IH), 6.04 - 6.19 (m, IH), 7.14 - 7.35 (m, 4H), 7.38 - 7.57 (m, 4H).
Example 2.64: Preparation of 1-(6-{4-[2-(2-Isopropyl-pyrrolidin-1-yI)-ethyl]-phenyl}- 3,3a,46a-tetrahydro-lH-cyclopenta[c]pyrrol-2-yl)-2--methyl-propan-l-one.
Figure imgf000165_0002
The title compound was obtained using general method K. MS m/z = 395.2 (M+H); 1H NMR (400 MHz, CD3OD) δ 0.85 - 1.15 (m, 12H), 1.84 - 1.96 (m, IH), 1.99 - 2.28 (m, 4H), 2.34 - 2.45 (m, IH), 2.55 - 2.88 (m, 2H), 3.06 - 3.17 (m, 3H), 3.24 - 3.36 (m, 2H), 3.38 - 3.59 (m, 4H), 3.63 - 4.01 (m, 4H), 6.09 - 6.14 (m, IH), 7.29 - 7.37 (m, 2H), 7.39 - 7.46 (m, 2H).
Example 2.65: Preparation of 2-Benzyl-6-{4-[2-(2-trifluoromethyl-pyrrolidin-l-yl)-ethyl]- phenyl}-l,2,3,3a,4,6a-hexahydro-cyclopenta[c|pyrrole.
Figure imgf000165_0003
The title compound was obtained using general method A. MS m/z = 441.4 (M+H); 1H NMR (400 MHz, CD3OD) δ 2.06 - 2.33 (m, 4H), 2.45 - 2.56 (m, 2H), 2.82 - 2.96 (m, 2H), 3.00 - 3.18 (m, 2H), 3.36 - 3.63 (m, 4H), 3.73 - 4.07 (m, 3H), 4.16 - 4.26 (m, IH), 4.32 - 4.43 (m, 2H), 4.49 - 4.65 (m, IH), 6.19 - 6.29 (m, IH), 7.21 - 7.57 (m, 9H).
Example 2.66: Preparation of 2-Methyl-l-(6-{4-[2-(2-phenyl-pyrrolidin-l-yl)-ethyl]- phenyl}-3,3a,4,6a-tetrahydro-lH-cyclopenta[c]pyrrol-2-yl) -propan-l-one.
Figure imgf000165_0004
The title compound was obtained using general method K. MS m/z = 429.3 (M+H); 1H NMR (400 MHz, CD3OD) δ 0.81 - 1.12 (m, 6H), 2.27 - 2.45 (m, 4H), 2.51 - 3.13 (m, 7H), 3.19 3.31 (m,2H)), 3.37- 3.55 (m, 2H), 3.67 - 4.01 (m, 4H), 4.47 - 4.56 (m, IH), 6.05 - 6.11 (m,
IH), 7.11 - 7.21 (m, 2H), 7.30 - 7.40 (m, 2H), 7.49 - 7.57 (m, 3H), 7.58 - 7.66 (m, 2H).
Example 2.67: Preparation of 2-Methyl-1-(6-{4-[2-((S)-2-methyl-pyrrolidin-1-yl)-ethyl]- phenyl}-3,3a,4,6a-tetrahydro-lH-cyclopenta[c]pyrrol-2-yl)propan-1-one.
Figure imgf000166_0001
The title compound was obtained using general method K. MS m/z = 367.3 (M+H); 1H NMR (400 MHz, CD3OD) δ 0.85 - 1.14 (m, 6H), 1.45 - 1.53 (m, 3H), 1.71 - 1.85 (m, IH), 2.03 - 2.19 (m, 2H), 2.31 - 2.46 (m, 2H), 2.55 - 2.87 (m, 2H), 3.03 - 3.18 (m, 2H), 3.18 - 3.41 (m, 4H), 3.42 - 3.67 (m, 3H), 3.70 - 4.03 (m, 4H), 6.09 - 6.16 (m, IH), 7.30 - 7.37 (m, 2H), 7.38 - 7.46 (m, 2H).
Example 2.68: Preparation of 2-Methyl-1-(6-{4-[2-((R)-2-methyl-pyrrolidin-1-yl)-ethyl]- phenyl}-3,3a,4,6a-tetrahydro-lH-cyclopenta[c]pyrrol-2-yl)-propan-l-one.
Figure imgf000166_0002
The title compound was obtained using general method K. MS m/z = 367.0 (M+H); 1H NMR (400 MHz, CD3OD) δ 0.84 - 1.15 (m, 6H), 1.44 - 1.54 (m, 3H), 1.72 - 1.84 (m, IH), 2.03 - 2.21 (m, 2H), 2.30 - 2.48 (m, 2H), 2.54 - 2.89 (m, 2H), 3.01 - 3.17 (m, 2H), 3.18 - 3.40 (m, 4H), 3.44 - 3.66 (m, 3H), 3.70 - 4.00 (m, 4H), 6.09 - 6.14 (m, IH), 7.30 - 7.38 (m, 2H), 7.38 - 7.47 (m, 2H).
Example 2.69: Preparation of l-(6-{4-[2-((S)-2-Hydroxymethyl-pyrrolidin-l-yl)-ethyl]- phenyl}-3,3a,4,6atetrahydro-lH-cycIopenta[c]pyrrol-2-yl)-2-methyl-propan-l-one.
Figure imgf000166_0003
" The 'title compound was obtained using general method K. MS m/z = 383.1 (M+H); 1H
NMR (400 MHz, CD3OD) δ 0.82 - 1.14 (m, 6H), 1.87 - 1.98 (m, IH), 2.00 - 2.10 (m, IH), 2.11 - 2.32 (m, 2H), 2.33 - 2.46 (m, IH), 2.56 - 2.89 (m, 2H), 3.06-3.15 (m, 2H), 3.17 - 3.41 (m, 5H), 3.44 - 3.60 (m, IH), 3.63 - 4.00 (m, 8H), 6.09 - 6.15 (m, IH), 7.28 - 7.36 (m, 2H), 7.37 - 7.46 (m, 2H).
Example 2.70: Preparation of l-(6-{4-[2-(2,5-Dimethyl-pyrroIidin-l-yl)-ethyl]-phenyl}- 3,3a,4,6a-tetrahydro-lH-cyclopenta[c]pyrrol-2-yl)-2- -methyl-propan-l-one.
Figure imgf000167_0001
The title compound was obtained using general method K. MS m/z = 381.4 (M+H); 1H
NMR (400 MHz, CD3OD) δ 0.81 - 1.10 (m, 6H), 1.32 - 1.54 (m, 6H), 1.70 - 1.94 (m, 2H), 2.21 - 2.48 (m, 3H), 2.53 - 2.85 (m, 2H), 3.02 - 3.14 (m, 2H), 3.16 - 3.36 (m, 2H), 3.37 - 3.57 (m, 2H), 3.62 - 4.15 (m, 6H), 6.08 - 6.13 (m, IH), 7.29 - 7.35 (m, 2H), 7.37 - 7.44 (m, 2H).
Example 2.71: Preparation of l-(6-{4-[2-((2R,5R)-2,5-Dimethyl-pyrrolidin-l-yl)-ethyl]- phenyl}-3,3a,4,6a-tetrahydro-lH-cycIopenta[c]pyrrol-2-yl)-2-methyl-propan-l-one.
Figure imgf000167_0002
The title compound was obtained using general method K. MS m/z = 381.2 (M+H); 1H NMR (400 MHz, CD3OD) δ 0.81 - 1.11 (m, 6H), 1.31 - 1.55 (m, 6H), 2.19 - 2.48 (m, 4H), 2.53 - 2.86 (m, 2H), 3.00 - 3.13 (m, 3H), 3.19 - 3.34 (m, 2H), 3.36 - 3.49 (m, 2H), 3.61 - 3.97 (m, 5H), 4.02 - 4.14 (m, IH), 6.07 - 6.11 (m, IH), 7.28 - 7.36 (m, 2H), 7.38 - 7.46 (m, 2H).
Example 2.72: Preparation of 2-Benzyl-5-methyl-6-{4-[2-((R)-2-methyl-pyrrolidin-l-yl)- ethyl]-phenyl}-1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole. Step A: Preparation of Intermediate 2-Benzyl-5- methylhexahydrocyclopenta [c] pyrrol-4(5H)-one
Figure imgf000167_0003
To a solution of 2-benzyl-hexahydro-cyclopenta[c]pyrrol-4-one from Example 1.1 dissolved in THF (2 mL) was added lithium diisopropylamine solution made in situ by adding 1.6 M n-butyllitbium in hexanes (2.00 mL) to diisopropylamine dissolved in THF (5 mL) at -78 0C. The reaction mixture was stirred 30 min at -780C before iodomethane was added and stirred another 30 min at -780C. The reaction was then warmed to -200C and stirred 1 h until no starting materials remained as determined by LCMS. The mixture was diluted with ethyl acetate (50 mL), extracted with water (10 mL), washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC to afford the TFA salt of the title compound (148 mg). MS m/z = 230.3 (M+H); 1H NMR (400 MHz, CDCl3) δ 1.05 - 1.11 (m, 3H), 1.24 - 1.36 (m, IH), 1.62 - 1.74 (m, IH), 2.21 - 2.30 (m, IH), 2.32 - 2.43 (m, IH), 2.47 - 2.59 (m, IH), 2.61 - 2.77 (m, 2H), 2.93 (dd, J = 9.22, 1.89 Hz, IH), 3.15 (d, J= 9.35 Hz, IH), 3.41 - 3.70 (m, 2H), 7.18 - 7.34 (m, 5H).
Step B: Preparation of 2-Benzyl-5-methyI-6-{4-[2-((R)-2-methyl-pyrrolidin-l-yl)- ethyll-phenyty-l.ljSjSa^jόa-hexahydro-cyclopentalcJpyrrole
Figure imgf000168_0001
The title compound was obtained using material prepared in Step A above, coupling as desribed in Example 1.03, followed by elimination as desribed in Example 1.7. MS m/z = 401.4 (M+H); 1H NMR (400 MHz, CD3OD) δ 1.19 - 1.31 (m, 3H), 1.49 - 1.64 (m, 3H), 1.77 - 2.00 (m, 2H), 2.07 - 2.35 (m, 2H), 2.52 - 2.95 (m, 5H), 2.97 - 3.20 (m, 4H), 3.23 - 3.59 (m, 5H), 3.81 - 4.23 (m, 3H), 7.02 - 7.33 (m, 9H).
Example 2.73: Preparation of Cyclopentyl-(5-methyl-6-{4-[2-((R)-2-methyI-pyrrolidin-l- y^-ethyll-phenylJ-SjSa^jόa-tetrahydro-lH-cyclopentalcJpyrrol^-y^-methanone.
Figure imgf000168_0002
The title compound was obtained using material prepared in Example 2.72, followed by deprotection of the benzyl as Example 1.6, followed by acylation as in general route B. MS m/z = 407.3 (M+H), 1H NMR (400 MHz, CD3OD) δ 1.41 - 1.55 (m, 5H), 1.56 - 1.94 (m, 10H), 2.03 - 2.21 (m, 2H), 2.28 - 2.45 (m, 2H), 2.73 - 2.83 (m, IH), 2.85 - 3.00 (m, IH), 3.02 - 3.33 (m, 6H), 3.35 - 3.67 (m, 4H), 3.70 - 3.96 (m, 3H), 7.19 - 7.28 (m, 2H), 7.32 - 7.40 (m, 2H). Example 2.74: Preparation of CycIopentyl-(5-methyl-4-{4-[2-((R)-2-methyl-pyrrolidin-l- yl)-ethyl]-phenyl}-hexahydro-cyclopenta[c]pyrrol-2-yl)-methanone.
Figure imgf000169_0001
The title compound was obtained using material prepared in Example 2.73, followed by catalytic hydrogenation of the double bond as described in Example 2.40. MS m/z = 409.4 (M+H), 1HNMR (400 MHz, CD3OD) δ 0.65 - 0.78 (m, 3H), 1.19 - 1.89 (m, 7H), 1.95 - 2.12 (m, 2H), 2.20 - 2.36 (m, 3H), 2.41 - 2.57 (m, IH), 2.63 - 3.05 (m, 5H), 3.08 - 3.24 (m, 4H), 3.25 - 3.74 (m, 10H), 7.01 - 7.09 (m, 2H), 7.10 - 7.31 (m, 3H).
Example 2.75: General Method L
Preparation of ((3aR,4R,6aS)-4-{4-[2-((S)-2-Hydroxymethyl-pyrrolidin-1-yl)-ethyl]- phenyl}-hexahydro-cyclopentalclpyrrol---yl)-(tetrahydro-pyran-4-yl)-methanone.
Step A: Preparation of Intermediate ((3aR,6aS)- 4-(4-(2-(tert- Butyldimethylsilyloxy)ethyl)phenyl)-4-hydroxyhexahydrocyclopenta[c]pyrrol-2(lH)- yl)(tetrahydro-2H-pyran-4-yl)methanone.
Figure imgf000169_0002
Starting with enantiomerically pure isomer (3aR,6aS) of compound from Example 1.9, reduction of the N-benzyl was performed as described in Example 1.6, followed by acylation as general route C afforded the title compound. MS m/z = 474.3 (M+H).
Step B: Preparation of ((3aS,6aS)-4-(4-(2-hydroxyethyl)phenyl)-3,3a,6,6a- tetrahydrocyclopenta[c]pyrrol-2(lB)-yl)(tetrahydro-2H-pyran-4-yl)methanone
Figure imgf000169_0003
Starting with compound from Step A above, deprotection and elimination as described for Example 1.7, afforded the title compound. MS m/z = 342.2 (M+H).
Step C: Preparation of 4-(3aR,6aS)-(2-(tetrahydro-2H-pyran-4- carbonyl)octahydrocyclopenta[c]pyrrol-4-yl)phenethyl methanesulfonate
Figure imgf000170_0001
Starting with compound from Step B above, followed by catalytic hydrogenation of the double bond as described for example 2.40, followed by mesylation as described in Example 1.12 afforded the title compound. MS m/z = 422.1 (M+H), 1H NMR (400 MHz, CD3OD) δ 1.42 - 1.82 (m, 5H), 1.93 - 2.19 (m, 3H), 2.40 - 2.51 (m, 0.5H)5 2.73 - 2.83 (m, 0.5H), 2.92 (s, 3H), 2.94 - 3.28 (m, 5H), 3.34 - 3.56 (m, 5H), 3.62 - 4.02 (m, 3H), 4.38 - 4.48 (m, 2H), 7.18 - 7.30 (m, 4H).
Step D: Preparation of ((3aR,4R,6aS)-4-{4-[2-((S)-2-HydroxymethyI-pyrrolidin-l- yl)-ethyl]-phenyl}-hexahydro-cyclopenta[c]pyrroI-2-yl)-(tetrahydro-pyran-4-yl)- niethanone
Figure imgf000170_0002
Starting with material from Step C above, the title compound was obtained using general method A. MS m/z = 427.4 (M+H); 1H NMR (400 MHz, CD3OD) δ 1.38 - 1.81 (m, 5H), 1.87 - 2.31 (m, 7H), 2.74 - 3.16 (m, 6H), 3.17 - 3.59 (m, 7H), 3.63 - 3.80 (m, 5H), 3.81 - 4.02 (m, 4H), 7.23 - 7.33 (m, 4H).
Example 2.76: Preparation of ((3aR,4R,6aS)-4-{4-[2-((S)-2-Methoxymethyl-pyrrolidin-l- yl)-ethyI]-phenyl}-hexahydro-cyclopenta[c]pyrrol-2-yl)-(tetrahydro-pyran-4-yl)- methanone.
Figure imgf000170_0003
The title compound was obtained using general method G. MS m/z = 441.7 (M+H); 1H NMR (400 MHz, CD3OD) δ 1.38 - 1.82 (m, 5H), 1.85 - 2.22 (m, 6H), 2.23 - 2.50 (m, 2H), 2.73 - 3.17 (m, 6H), 3.18 - 3.59 (m, 9H), 3.58 - 4.03 (m, 8H), 7.22 - 7.34 (m, 4H).
Example 2.77: Preparation of (S)-l-(2-{4-[(3aR,4R,6aS)-2-(Tetrahydro-pyran-4-carbonyl)- octahydro-cydopenta[c]pyrrol-4-yI]-phenyl}-ethyl)-pyrrolidine-2-carboxylic acid amide.
Figure imgf000171_0001
The title compound was obtained using general method L. MS m/z = 440.6 (M+H); 1H NMR (400 MHz, CD3OD) δ 1.40 - 1.83 (m, 5H), 1.92 - 2.28 (m, 6H), 2.39 - 2.86 (m, 2H), 2.87 - 3.16 (m, 4H), 3.15 - 3.58 (m, 9H), 3.64 - 4.02 (m, 4H), 4.22 - 4.37 (m, IH), 7.20 - 7.33 (m, 4H).
Example 2.78: Preparation of ((3aR,4R,6aS)-4-{4-[2-((R)-2-Methoxymethyl-pyrroUdin-l- yl)-ethyI]-phenyI}-hexahydro-cyclopenta[c]pyrrol-2-yl)-(tetrahydro-pyran-4-yl)- methanone.
Figure imgf000171_0002
The title compound was obtained using general method L. MS m/z = 441.6 (M+H); 1H NMR (400 MHz, CD3OD) δ 1.40 - 1.80 (m, 5H), 1.81 - 2.22 (m, 6H), 2.23 - 2.49 (m, 2H), 2.75 - 3.16 (m, 4H), 3.17 - 3.57 (m, HH), 3.59 - 4.03 (m, 8H), 7.23 - 7.33 (m, 4H).
Example 2.79: Preparation of (S)-l-(2-{4-[(3aR,4R,6aS)-2-(Tetrahydro-pyran-4-carbonyl)- octahydro-cycIopenta[c]pyrrol-4-yl]-phenyl}-ethyl)-pyrrolidine-2-carboxylic add methylamide.
Figure imgf000171_0003
The title compound was obtained using general method L. MS m/z = 455.4 (M+H); 1H NMR (400 MHz, CD3OD) δ 1.36 - 1.83 (m, 5H), 1.92 - 2.29 (m, 6H), 2.37 - 2.88 (m, 5H), 2.89 - 3.10 (m, 4H), 3.11 - 3.72 (m, 9H), 3.77 - 4.02 (m, 4H), 4.13 - 4.30 (m, IH), 7.21 - 7.31 (m, 4H).
Example 2.80: Preparation of {(3aR,4R,6aS)-4-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]- hexahydro-cyclopenta[c]pyrrol-2-yl}-(tetrahydro-pyran-4-yl)-methanone.
Figure imgf000172_0001
The title compound was obtained using general method L. MS m/z = 397.2 (M+H); 1H NMR (400 MHz, CD3OD) δ 1.42 - 1.82 (m, 5H), 1.94 - 2.23 (m, 7H), 2.41 - 2.84 (m, IH), 2.87 - 3.30 (m, 8H), 3.33 - 3.60 (m, 6H), 3.64 - 3.77 (m, 2H)5 3.81 - 4.01 (m, 3H), 7.23 - 7.33 (m, 4H).
Example 2.81: Preparation of {(3aR,4R,6aS)-4-[4-(2-Piperidin-l-yl-ethyI)-phenyl]- hexahydro-cyclopenta[c]pyrrol-2-yl}-(tetrahydro-pyran-4-yl)πmethanone.
Figure imgf000172_0002
The title compound was obtained using general method L. MS m/z = 411.4 (M+H); 1H
NMR (400 MHz, CD3OD) δ 1.40 - 2.19 (m, J= 5.00 Hz, 15H), 2.39 - 2.85 (m, IH), 2.88 - 3.17 (m, 7H), 3.18 - 3.56 (m, 6H), 3.58 - 3.70 (m, 2H), 3.79 - 4.01 (m, 3H)5 7.24 - 7.32 (m, 4H).
Example 2.82: Preparation of {(3aR,4R,6aS)-4-[4-(2-Diisopropylamino-ethyl)-phenyl]- hexahydro-cyclopenta[c]pyrroI-2-yI}-(tetrahydro-pyran-4-yl)-methanone.
Figure imgf000172_0003
The title compound was obtained using general method L. MS m/z = 427.6 (M+H); 1H NMR (400 MHz, CD3OD) δ 1.40 - 1.51 (m, 12H), 1.54 - 1.81 (m, 5H), 1.91 - 2.17 (m, 3H), 2.39 - 2.83 (m, IH)5 2.89 - 3.27 (m, 6H), 3.28 - 3.59 (m, 6H), 3.63 - 4.00 (m, 5H), 7.23 - 7.34 (m, 4H).
Example 2.83: Preparation of {(3aR,4R,6aS)-4-[4-(2-Morpholin-4-yI-ethyl)-phenyl]- hexahydro-cyclopentalcJpyrroW-ylJ-^etrahydro-pyran^-y^-methanone.
Figure imgf000172_0004
The title compound was obtained using general method L. MS m/z = 413.7 (M+H); 1H
NMR (400 MHz, CD3OD) δ 1.40 - 1.82 (m, 5H), 1.93 - 2.17 (m, 3H), 2.38 - 2.85 (m, IH), 2.87 - 3.16 (m, 5H), 3.16 - 3.30 (m, 3H), 3.30 - 3.73 (m, 8H), 3.77 - 4.01 (m, 5H), 4.06 - 4.15 (m, 2H), 7.25 - 7.33 (m, 4H).
Example 2.84: Preparation of ((3aR,4R,6aS)-4-{4-[2-((R)-3-Hydroxy-pyrroIidin-l-yl)- ethyl]-phenyl}-hexahydro-cyclopenta[c]pyrrol-2-yl)-(tetrahydro-pyran-4-yl)-methanone.
Figure imgf000173_0001
The title compound was obtained using general method L. MS m/z = 413.3 (M+H); 1H
NMR (400 MHz, CD3OD) δ 1.40 - 1.82 (m, 5H), 1.92 - 2.19 (m, 5H), 2.33 - 2.51 (m, IH), 2.74 - 3.62 (m, 15H), 3.63 - 4.02 (m, 5H), 4.53 - 4.64 (m, IH), 7.24 - 7.33 (m, 4H).
Example 2.85: Preparation of ((3aR,4R,6aS)-4-{4-[2-(3,3-Difluoro-pyrrolidin-l-yl)-ethyl]- phenyl}-hexahydro-cyclopenta[c]pyrrol-2-yl)-(tetrahydro-pyran^-y^-methanone.
Figure imgf000173_0002
The title compound was obtained using general method L. MS m/z = 433.3 (M+H); 1H NMR (400 -Hz, CD3OD) δ 1.39 - 1.83 (m, 5H), 1.91 - 2.21 (m, 4H), 2.36 - 2.87 (m, 3H), 2.88 - 3.29 (m, 6H), 3.33 - 3.73 (m, 7H), 3.77 - 4.27 (m, 5H), 7.24 - 7.36 (m, 4H).
Example 2.86: Preparation of 4-(2-Benzyl-l,2,3,3a,6,6a-hexahydro-cyclopenta[c]pyrrol-4- yl)-benzylamine.
Figure imgf000173_0003
To a reaction vial was added 2-benzyl-l,2,3,3a,6,6a-hexahydrocyclopenta[c]pyrrol-4-yl trifluoromethanesulfonate (152.4 mg, 0.439 mmol), 4-(aminomethyl)phenylboronic acid hydrochloride (163.2 mg, 0.871 mmol), Na2CO3 (0.648 ml, 1.30 mmol, 2 M solution in H2O) and tetrakis(triphenylphosphine)palladium (0) (30.6 mg, 0.026 mmol) in a mixture of EtOH '''"' ""■(O.T'8 mTfand toluene (3.0 ml). The reaction mixture was heated at 100 0C for 1.5 h. Upon completion, the reaction mixture was washed with H2O, and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, and concentrated. The residue was purified by preparative HPLC to afford the title compound (16 mg, 12%) as a TFA salt. MS m/z 305, (M+H); 1H NMR (400 MHz, CD3OD) δ 2.48 (dd, J= 18.4, 2.0 Hz, IH), 2.79-3.05 (m, 2H), 3.14-3.84 (m, 3H), 3.92-4.38 (m, 6H), 6.27 (bs, IH), 7.38-7.50 (m, 9H).
Example 2.87: Preparation of 3-(2-Benzyl-l,2,3,3a,6,6a-hexahydro-cyclopenta[c]pyrrol-4- yl)-benzylamine.
Figure imgf000174_0001
To a reaction vial was added 2-benzyl-l,2,3,3a,6,6a-hexahydrocyclopenta[c]pyrrol-4-yl trifluoromethanesulfonate (153.4 mg, 0.442 rnmol), 3-(aminomethyl)phenylboronic acid hydrochloride (163.3 mg, 0.871 mmol), Na2CO3 (0.648 ml, 1.30 mmol, 2 M solution in H2O) and tetrakis(triphenylphosphine)palladium (0) (32.6 mg, 0.028 mmol) in a mixture of EtOH (0.78 ml) and toluene (3.0 ml). The reaction mixture was heated at 100 0C for 1.5 h. Upon completion, the reaction mixture was washed with H2O, and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, and concentrated. The residue was purified by preparative HPLC to afford the title compound (8 mg, 6%) as a TFA salt. MS m/z 305, (M+H); 1H NMR (400 MHz, CH3OD) δ 2.48 (dd, J = 18.4, 2.0 Hz, IH), 2.79-3.04 (m, 2H), 3.14-3.84 (m, 3H), 3.96-4.40 (m, 6H), 6.27 (bs, IH), 7.31-7.53 (m, 9H).
Example 2.88: Preparation of (3aR, 6aS)-2-Benzyl-6-{4-[2-((R)-2-methyl-pyrrolidin-l-yl)- ethyll-phenyty-l^S^ay^βa-hexahydro-cyclopentafclpyrrole.
Step A: Preparation of (3aS, 6aR)-2-Benzyϊ-4{4-[2-(2-methyI-pyrrolidin-l-yl)- ethyl]-phenyl}-octahydro-cyclopenta[c]pyrroϊ-4-ol
Figure imgf000174_0002
The title compound was prepared in a manner analogous to Example 1.3, using (3aS, 6aR)-2-benzylhexahydro-cyclopenta[c]pyrrol-4(5H)-one and (±)-2-methylpyrrolidine. MS m/z 405, (M+H). ,,.,,,f .,..,, ..,,.. / I. Ii q. ,|».|. p; / ||JfJ,,||,J,.L'7l Q
!f" Ll !l ' 1 kep yfprepaAtion oϊ'(3aR, 6aS)-2-Benzyl-6-{4-[2-((R)-2-methyl-pyrrolidin-l-yl)- ethyl]-phenyl}-l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole
Figure imgf000175_0001
The title compound was obtained by elimination as described for Example 1.7 starting from the compound of Step A, followed by chiral separation using chiral chromatography. Separation of the R-isomer and S-isomers was accomplished by using the semi-prep Chiralpak AD-H column and conditions as follows: Solvent: 99 hexane/1 methanol/0.05 DEA, Method: Isocratic 6.5 mL/min over 72 min, Wavelength: 254 nm, Amount: 6 mg at lmg/mL. Peak 1: 43.715 min, Peak 2: 49.742 min. MS m/z 387.5 (M+H).
Example 2.89: Preparation of 2-Benzyl-6-{4-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-phenyl}- l,2,3,3a,4,6a~hexahydro-eyclopenta[c]pyrrole.
Figure imgf000175_0002
The title compound was obtained using general method A. MS m/z 386, (M+H); 1H NMR (400 MHz, CD3OD) δ 1.44 (d, J = 5.7 Hz, 3H), 19 (s, IH), 1.99-2.19 (m, 2H), 2.25-2.38 (m, IH), 2.43 (dd, J= 18.3, 2.5 Hz, IH), 2.80-3.30 (m, 7H), 3.40-3.80 (m, 6H), 3.90-4.24 (m, 3H), 61.68-1.81 (m, IH), 7.30 (d, J = 8.2 Hz, 2H), 7.37-7.45 (m, 7H).
Example 2.90: Preparation of 6-{4-[2-(2-Methyl-pyrrolidin-l-yl)-ethyl]-phenyl}-3,3a,4,6a- tetrahydro-lH-cyclopenta[c]pyrrole-2-carboxyIic acid ethyl ester.
Figure imgf000175_0003
In a 5 mL glass tube were placed 6-(4-(2-(2-methylpyrrolidin-l-yl)ethyl)phenyl)- l,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole, ethyl chloroformate (0.042 g, 0.388 mmol), and a magnetic stir bar in benzene (3 mL). The vessel was sealed with a septum and placed into a microwave cavity. With microwave irradiation, the temperature was ramped from room temperature to 120 0C and held for 3 h. After the mixture was allowed to cool to room "'temperature, "the reaction vessel was opened and the reaction mixture was filtered. The mixture was purified by preparative HPLC to afford the TFA salt of the title compound (0.009 g, 9.45%) as a yellow oil. MS m/z 369.2, (M+H); 1H NMR (400 MHz3 CD3OD) δ 0.87 (bs, 2H), 1.094 (s, 6H), 1.24-1.42 (m, IH), 1.72 (s, 2H), 1.82-2.02 (m, IH), 2.24-2.35 (m, IH), 2.45-2.54 (m, 2H), 2.65-2.85 (m, 3H), 2.96-3.10 (m, 2H), 3.10-3.24 (m, 2H), 3.62 (dd, J= 10.0, 6.0 Hz, 2H), 3.68- 3.80 (m, IH), 3.84-4.00 (m, 2H), 6.09 (s, IH), 7.16-7.25 (m, 2H), 7.27-7.36 (m, 2H).
Example 2.91: Preparation of (3aS,6aS)-2-Benzyl-6-{4-[2-((S)-2-methyl-pyrrolidin-l-yl)- ethyl]-phenyl}-1,2,3,3a,4,6a-hexahydro-cyclopentatclpyrrole.
Figure imgf000176_0001
To a solution of (3aR,6aS)-2-benzyl-4-(4-(2-((S)-2-methylpyrrolidin-l-yl)ethyl)phenyl)- octahydrocyclopenta[c]pyrrol-4-ol (236 mg, 0.583 mmol) in isopropyl alcohol (3.2 mL) was added HCl (1.5 mL, 2 M in ether) and heated to 40 0C. Additional HCl in ether was added in ~1 mL portion to the reaction mixture until the reaction was complete. To the reaction mixture were added EtOAc and H2O. The organic layer was separated from the aqueous layer. The aqueous layer was washed with EtOAc and neutralized with saturated NaHCO3. The aqueous layer was extracted with EtOAc and Et2O. The combined organic layers were washed with H2O, brine and dried over MgSO4 and concentrated. The residue was purified by preparative HPLC to afford the title compound (74 mg, 33%) as a TFA salt. MS m/z 386, (M+H); 1H NMR (400 MHz, CD3OD) δ 1.45-1.49 (m, 3H), 1.70-1.81 (m, IH), 2.00-2.19 (m, 2H), 2.28-2.39 (m, IH), 2.42-2.51 (m, IH), 2.80-3.62 (m, HH), 3.67-3.82 (m, IH), 3.92-4.23 (m, 2H), 4.28-4.41 (m, 2H), 6.17-6.24 (m, IH), 7.30 (dd, J= 8.0, 8.0 Hz, 2H), 7.38-7.51 (m, 7H)..
Example 2.92: Preparation of (3aR,6aR)-2-Benzyl-6-{4-[2-(2,2-dimethyl-pyrrolidin-l-yl)- ethyl]-phenyl}-l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole.
Figure imgf000176_0002
To a solution of (3aS, 6aR)-2-benzyl-4-(4-(2-(2,2-dimethylpyrrolidin-l- yl)ethyl)phenyl)-octahydrocyclopenta[c]pyrrol-4-ol (456 mg, 1.09 mmol) in DCM (5.5 mL) was IPMΓ '"!" «•■" I P ""* 11 Fit ■'" NM1+11+ 7 "i r added friethylamine (0.304 ml, 2.18 mmol) at 25 0C. The reaction mixture was cooled to -20 0C and methanesulfonyl chloride (0.170 ml, 2.20 mmol) was added. The reaction mixture was kept at below -20 0C for 30 min before warmed to 25 0C and stirred for another 1 h. The reaction mixture was quenched with saturated NaHCO3 and extracted with DCM. The combined organic layers were washed with H2O, brine, dried over MgSO4 and concentrated. The residue was purified by preparative HPLC, lyophilized, and treated with HCl to afford the hydrochloride salt of the title compound (81.7 mg). MS m/z 401, (M+H); 1H NMR (400 MHz, CD3OD) δ 1.17 (d, J = 3.5 Hz, 3H), 1.50 (d, J = 3.8 Hz, 3H), 1.86-2.03 (m, 4H), 2.32-2.41 (m, IH), 2.64-2.86 (m, 4H), 2.92-3.56 (m, 5H), 3.60-3.71 (m, 2H), 3.78-4.10 (m, 2H), 4.25-4.39 (m, 2H), 6.25 (bs, IH), 7.27-7.36 (m, 2H), 7.39-7.45 (m, 5H), 7.52-7.61 (m, 2H).
Example 2.93: Preparation of (3aS,6aS)-6-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-3,3a,4,6a- tetrahydro-lH-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide.
Figure imgf000177_0001
The title compound was obtained using general method C. MS m/z 354, (M+H); 1H
NMR (400 MHz, CD3OD) δ 1.96-2.08 (m, 2H), 2.10-2.22 (m, 2H), 2.33-2.41 (m, IH), 2.74- 2.83 (m, 7H), 3.02-3.18 (m, 5H), 3.20-3.30 (m, 2H), 3.42-3.48 (m, 2H), 3.64-3.71 (m, 3H), 3.74- 3.85 (m, 2H), 6.08-6.11 (m, IH), 7.29 (d, J= SA Hz, 2H), 7.41 (d, J = 8.1 Hz, 2H).
Example 2.94: Preparation of (3aS,6aS)-2-Cyclopentylmethyl-6-[4-(2-pyrrolidm~l-yl- ethyl)-phenyl]-l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole.
Figure imgf000177_0002
The title compound was obtained using general method B. MS m/z 365, (M+H); 1H NMR (400 MHz, CD3OD) δ 1.20-1.31 (m, 2H), 1.54-2.25 (m, 11H), 2.42-2.55 (m, IH), 2.72- 2.92 (m, 2H), 3.03-3.19 (m, 7H), 3.41-3.52 (m, 4H), 3.65-3.72 (m, 2H), 3.93-4.07 (m, IH), 4.16- 4.25 (m, IH), 6.19-6.28 (m, IH), 7.31-7.35 (m, 2H), 7.43-7.49 (m, 2H).
Example 2.95: Preparation of {(3aS,6aS)-6-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-3,3a,4,6a- tetrahydro-lH-cyclopentatclpyrrol^-ylJ-thiophen-Z-yl-methanone.
Figure imgf000178_0001
The title compound was obtained using general method C. MS m/z 393, (M+H); 1H NMR (400 MHz, CD3OD) δ 1.95-2.07 (m, 2H), 2.10-2.22 (m, 2H), 2.39-2.47 (m, IH), 2.77- 2.88 (m, IH), 3.00-3.18 (m, 5H), 3.40-3.80 (m, 6H), 3.86-4.25 (m, 3H), 6.11-6.14 (m, IH), 7.00- 7.17 (m, IH), 7.26-7.34 (m, 2H), 131-1 Al (m, 2H), 7.53-7.67 (m, 2H).
Example 2.96: Preparation of Furan-2-yl-{(3aS,6aS)-6~[4-(2-pyrrolidm-l-yl-ethyl)-phenyl]- 3,3a,4,6a-tetrahydro-lH-eyclopenta[c]pyrrol-2-yl}-methanone.
Figure imgf000178_0002
The title compound was obtained using general method C. MS m/z 377, (M+H); 1H NMR (400 MHz, CD3OD) δ 1.95-2.07 (m, 2H), 2.10-2.22 (m, 2H), 2.39-2.47 (m, IH), 2.79- 2.87 (m, IH), 3.01-3.18 (m, 5H), 3.23-3.32 (m, IH), 3.41-3.49 (m, 2H), 3.61-3.72 (m, 3H), 3.81- 4.04 (m, 2H), 4.17-4.28 (m, IH), 6.10-6.13 (m, IH), 6.50-6.61 (m, IH), 6.99-7.11 (m, IH), 7.27- 7.33 (m, 2H), 7.38-7.45 (m, 2H), 7.59-7.72 (m, IH).
Example 2.97: Preparation of Pyridin-4-yl-{(3aS,6aS)-6-[4-(2-pyrrolidin-l-yl-ethyl)- phenyl]-3,3a,4,6a-tetrahydro-lH-cyclopenta[c]pyrrol-2-yl}-methanone.
Figure imgf000178_0003
The title compound was obtained using general method C. MS m/z 388, (M+H); 1H NMR (400 MHz, CD3OD) δ 1.97-2.09 (m, 2H), 2.10-2.22 (m, 2H), 2.28-2.52 (m, IH), 2.74- 2.92 (m, IH), 2.99-3.29 (m, 6H), 3.38-3.50 (m, 2H), 3.52-3.73 (m, 3H), 3.75-3.88 (m, IH), 3.90- 4.11 (m, 2H), 6.12-6.18 (m, IH), 7.22-7.48 (m, 4H), 8.01-8.20 (m, 2H), 8.86-9.00 (m, 2H).
Example 2.98: Preparation of Morpholin-4-yl-{(3aS,6aS)-6-[4-(2-pyrrolidin-l-yl-ethyl)- phenyl] -3,3a,4,6a-tetrahydro-1H-cyclopenta[c]pyrrol-2-yl}-methanone.
Figure imgf000179_0001
The title compound was obtained using general method C. MS m/z 396, (M+H); 1H NMR (400 MHz, CD3OD) δ 1.97-2.08 (m, 2H), 2.12-2.22 (m, 2H), 2.33-2.41 (m, IH), 2.74- 2.83 (m, IH), 3.01-3.08 (m, 3H), 3.09-3.30 (m, 8H), 3.42-3.83 (m, HH), 6.07-6.10 (m, IH), 7.29 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 8.2 Hz, 2H).
Example 2.99: Preparation of Pyridin-3-yl-{(3aS,6aS)-6-[4-(2-pyrrolidin-l-yl-ethyl)- phenyl]-3,3a,4,6 }-tetrahydro-lH-cyclopenta[elpyrrol- 2-yl}- methanone.
Figure imgf000179_0002
The title compound was obtained using general method C. MS m/z 388, (M+H); 1H NMR (400 MHz, CD3OD) δ 1.96-2.10 (m , 2H), 2.11-2.22 (m, 2H), 2.31-2.52 (m, IH), 2.74- 2.92 (m, IH), 2.99-3.26 (m, 5H), 3.35-3.59 (m, 3H), 3.62-3.73 (m, 3H), 3.84-4.01 (m, 2H), 4.03- 4.13 (m, IH), 6.12-6.18 (m, IH), 122-1 Al (m, 4H), 8.03-8.20 (m, IH), 8.59-8.79 (m, IH), 8.86- 9.10 (m, 2H).
Example 2.100: Preparation of Pyridin-2-yl-{(3aS,6aS)-6-[4-(2-pyrrolidin-l-yl-ethyl)- phenyl]-3,3a,4,6a-tetrahydro-lH-cyclopenta[c]pyrrol-2-yl}-methanone.
Figure imgf000179_0003
The title compound was obtained using general method C. MS m/z 388, (M+H); 1H NMR (400 MHz, CD3OD) δ 1.97-2.08 (m , 2H), 2.11-2.22 (m, 2H), 2.33-2.52 (m, IH), 2.75- 2.92 (m, IH), 2.98-3.25 (m, 5H), 3.37-3.60 (m, 3H), 3.63-3.72 (m, 3H), 3.93-4.15 (m, 3H), 6.12- 6.17 (m, IH), 1.22-1 Al (m, 4H), 7.89-8.21 (m, 2H), 8.36-8.56 (m, IH), 8.73-8.86 (m, IH). n> C" "1II'" / il Il c» 111 IK. ■■■" ii+H+iUI.. /" Q
'' l! Εxampie'llOΪ: Preparation of Cyclohexyl-{(3aS,6aS)-6-[4-(2-pyrrolidin-l-yl-ethyl)~ phenyl]-3,3a,4,6a-tetrahydro-lH-cyclopenta[c]pyrrol-2-yl}-methanone.
Figure imgf000180_0001
The title compound was obtained using general method C. MS m/z 393, (M+H); 1H NMR (400 MHz, CD3OD) δ 1.06-1.45 (m, 5H), 1.57-1.81 (m, 5H), 1.96-2.08 (m, 2H), 2.10- 2.22 (m, 2H), 2.25-2.53 (m, 2H), 2.76-2.85 (m, IH), 3.01-3.28 (m, 6H), 3.41-3.55 (m, 3H), 3.61- 3.96 (m, 5H), 6.07-6.12 (m, IH), 1.21-134 (m, 2H), 7.36-7.43 (m, 2H).
Example 2.102: Preparation of {(3aS,6aS)-6-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-3,3a,4,6a- tetrahydro-lH-cyclopenta[c]pyrrol-2-yl}-(tetrahydro-furan-3-yl)-methanone.
Figure imgf000180_0002
A mixture of tetrahydrofuran-3-carboxylic acid (64.3 μl, 0.672 mmol) and PS- Carbodiimide (710 mg, 0.710 mmol) in DCM (7.0 mL) was stirred for 10 min and added (3aS,6aS)-6-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole (102.1 mg, 0.362 mmol) dissolved in DCM (3.0 mL). After 18 h, the resin was filtered and washed with DCM and MeOH. The solution was concentrated. The residue was purified by preparative HPLC, lyophilized, and treated with HCl to afford the hydrochloride salt of the title compound (54.2 mg). MS m/z 381, (M+H); 1H MVIR (400 MHz, CD3OD) δ 1.95-2.22 (m, 6H), 2.34-2.44 (m, IH), 2.77-2.86 (m, IH), 3.02-3.24 (m, 6H), 3.24-3.60 (m, 4H), 3.62-3.99 (m, 9H), 6.08-6.13 (m, IH), 7.27-7.34 (m, 2H), 7.37-7.44 (m, 2H).
Example 2.103: Preparation of Phenyl-{(3aS,6aS)-6-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]- S^a^jόa-tetrahydro-lH-cyclopentafclpyrrol^-ylJ-methanone.
Figure imgf000180_0003
„. .,..„. ...«» ,. I! .J q. ipji p. _,,• i| iMπ|jm,,'7 Q f IL,,. it .. !UA"'mixUe of benzoic acid (89.6 mg, 0.7337 mmol) and PS-Carbodiiraide (702.2 mg,
0.702 mmol) in DCM (7.0 mL) was stirred for 10 min and added (3aS,6aS)-6-[4-(2-Pyrrolidin- l-yl-ethy^-phenylj-l^jSβa^jόa-hexahydro-cyclopentatclpyrrole (101 mg, 0.358 mmol) dissolved in DCM (3.0 ml). After 23 h, the resin was filtered and washed with DCM and MeOH. The solution was concentrated. The residue was purified by preparative HPLC, lyophilized, and treated with HCl to afford the hydrochloride salt of the title compound (69.3 mg). MS m/z 387, (M+H); 1H NMR (400 MHz, CD3OD) δ 1.95-2.08 (m, 2H), 2.10-2.21 (m, 2H), 2.24-2.49 (m, IH), 2.70-2.91 (m, IH), 2.99-3.21 (m, 5H), 3.36-3.50 (m, 3H), 3.56-3.72 (m, 3H), 3.75-4.03 (m, 3H), 6.10-6.15 (m, IH), 7.20-7.49 (m, 9H).
Example 2.104: Preparation of 2-Phenyl-l-{(3aS,6aS)-6-[4-(2-pyrrolidin-l-yl-ethyl)- phenyl]-3,3a,4,6a-tetrahydro-lH-cyclopenta[c]pyrrol-2-yl}-ethanone.
Figure imgf000181_0001
A mixture of 2-phenylacetic acid (94.4 mg, 0.6934 mmol) and PS-Carbodiimide (717.0 mg, 0.717 mmol) in DCM (7.0 mL) was stirred for 10 min and added (3aS,6aS)-6-[4-(2-
Pyrrolidin-l-yl-ethyl)-phenyl]-l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole (101 mg, 0.358 mmol) dissolved in DCM (3.0 mL). After 23 h, the resin was filtered and washed with DCM and MeOH. The solution was concentrated. The residue was purified by preparative HPLC, lyophilized, and treated with HCl to afford the hydrochloride salt of the title compound (60.6 mg). MS m/z 401, (M+H); 1H NMR (400 MHz, CD3OD) δ 1.96-2.08 (m, 2H), 2.11-2.21 (m, 2H), 2.22-2.40 (m, IH), 2.71-2.84 (m, IH), 3.02-3.18 (m, 5H), 3.42-3.91 (m, HH), 6.03-6.08 (m, IH), 7.05-7.40 (m, 9H).
Example 2.105: Preparation of (3aS,6aS)-2-(Propane-2-sulfonyl)-6-[4-(2-pyrrolidin~l-yl- ethyl)-phenyl]-l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole.
Figure imgf000181_0002
To a solution of (3aS,6aS)-6-[4-(2-Pyrrolidm-l-yl-ethyl)-phenyl]-l,2,3,3a,4,6a- hexahydro-cyclopenta[c]pyrrole (202 mg, 0.715 mmol) in DCM (10.0 mL) was added «' " tπethyTamme ('O.Ϊ96 τnl, 1.4l mmol) followed by 2-propanesulfonyl chloride (0.159 ml, 1.42 mmol). The resulting reaction mixture was stirred at 25 0C for 3.0 h. Upon completion, the reaction mixture was concentrated. The residue was purified by preparative HPLC, lyophilized, and treated with HCl to afford the hydrochloride salt of the title compound (86.3 mg). MS m/z 389, (M+H); 1H NMR (400 MHz, CD3OD) δ 1.24 (d, J = 6.8 Hz, 3H), 1.25 (d, J = 6.8 Hz, 3H), 1.96-2.09 (m, 2H), 2.09-2.21 (m, 2H), 2.34-2.42 (m, IH), 2.77-2.87 (m, IH), 3.03-3.28 (m, 8H), 3.41-3.47 (m, 2H), 3.59-3.71 (m, 4H), 3.84-3.91 (m, IH), 6.11-6.15 (m, IH), 7.30 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 8.2 Hz, 2H).
Example 2.106: Preparation of (3aS,6aS)-2-Benzenesulfonyl-6-[4-(2-pyrrolidin-l-yl-ethyl)- phenyl]-l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole.
Figure imgf000182_0001
To a solution of (3aS,6aS)-6-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-l,2,3,3a,4,6a- hexahydro-cyclopenta[c]pyrrole (101.4 mg, 0.359 mmol) in DCM (5.0 mL) was added triethylamine (98.2 μl, 0.7045 mmol) followed by benzenesulfonyl chloride (67.8 μl, 0.5313 mmol). The resulting reaction mixture was stirred at 25 0C for 1.5 h. Upon completion, the reaction mixture was concentrated. The residue was purified by preparative HPLC, lyophilized, and treated with HCl to afford the hydrochloride salt of the title compound (60.5 mg). MS m/z 423, (M+H); 1H NMR (400 MHz, CD3OD) δ 1.96-2.08 (m, 2H), 2.11-2.22 (m, 2H), 2.25-2.33 (m, IH), 2.73-2.82 (m, IH), 2.94-3.08 (m, 5H), 3.10-3.18 (m, 2H), 3.25-3.35 (m, 2H), 3.42-3.49 (m, 2H), 3.64-3.71 (m, 2H), 3.73-3.80 (m, IH), 6.03-6.07 (m, IH), 7.27 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 8.3 Hz, 2H), 7.54-7.59 (m, 2H), 7.63-7.68 (m, IH), 7.71-7.75 (m, 2H).
Example 2.107: Preparation of (3aS,6aS)-2-Phenylmethanesulfonyl-6-[4-(2-pyrrolidin~l-yl- ethyl)-phenyl]-l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole.
Figure imgf000182_0002
hexahydro-cyclopenta[c]pyrrole (99.4 mg, 0.352 mmol) in DCM (5.0 mL) was added triethylamine (98.2 μl, 0.7045 mmol) followed by phenylmethanesulfonyl chloride (107.9 mg, 0.5660 mmol). The resulting reaction mixture was stirred at 25 0C for 16.5 h. Upon completion, the reaction mixture was concentrated. The residue was purified by preparative HPLC, lyophilized, and treated with HCl to afford the hydrochloride salt of the title compound (64.1 mg). MS m/z 437, (M+H); 1H NMR (400 MHz, CD3OD) 8 1.98-2.05 (m, 2H), 2.13-2.20 (m, 2H), 2.26-2.35 (m, IH), 2.72-2.82 (m, IH), 2.97-3.18 (m, 7H), 3.42-3.54 (m, 4H), 3.63-3.71 (m, 2H), 3.78-3.85 (m, IH), 4.295 (d, J = 2.8 Hz, 2H), 6.10-6.14 (m, IH), 7.27-7.39 (m, 9H).
Example 2.108: Preparation of Pyrazin-2-yI-{(3aS,6aS)-6-[4-(2-pyrrolidin-l-yl-ethyI)- phenyl]-3,3a,4,6a-tetrahydro-lH-cyclopenta[c}pyrrol-l-2-yll-2-yl2-yl}methanone.
Figure imgf000183_0001
A mixture of 2-pyrazinecarboxylic acid (89.2 mg, 0.7188 mmol) and PS-Carbodiimide (707.7 mg, 0.708 mmol) in DCM (7.0 mL) was stirred for 10 min and added (3aS,6aS)-6-[4-(2- Pyrrolidin-l-yl-ethyl)-phenyy-1,2,3,3a 4,6a-hexahydro-cyclopenta[c]pyrrole (106.0 mg, 0.375 mmol) dissolved in DCM (3.0 mL). After 16.5 h, the temperature of the reaction mixture was raised to 30 0C. After 73.5 h at 30 0C, the resin was filtered and washed with CH2Cl2 and MeOH. The solution was concentrated. The residue was purified by preparative HPLC, lyophilized, and treated with HCl to afford the hydrochloride salt of the title compound (13.3 mg). MS m/z 389, (M+H); 1HNMR (400 MHz, CD3OD) δ 1.97-2.08 (m, 2H), 2.10-2.22 (m, 2H), 2.32-2.50 (m, IH), 2.74-2.90 (m, IH), 2.99-3.24 (m, 5H), 3.39-3.61 (m, 3H), 3.63-3.72 (m, 3H), 3.88-3.96 (m, IH), 3.99-4.12 (m, 2H), 6.10-6.14 (m, IH), 7.22-7 '.47 (m, 4H), 8.50-8.72 (m, 2H), 8.82-8.95 (m, IH).
Example 2.109: Preparation of Isoxazol-5-yl-{(3aS,6aS)-6-[4-(2-pyrrolidin-l-yl-ethyl)- phenyl]-3,3a,4,6a-tetrahydro-lH-cyclopentalclpyrrol^-ylJ-methanone.
Figure imgf000183_0002
P IL',: i /
Figure imgf000184_0001
'compountwai obtained using general method C. MS m/z 378, (M+H); 1H NMR (400 MHz, CD3OD) δ 1.95-2.07 (m, 2H), 2.10-2.21 (m, 2H), 2.38-2.48 (m, IH), 2.78- 2.89 (m, IH), 3.00-3.32 (m, 5H), 3.40-3.50 (m, 2H), 3.56-3.71 (m, 3H), 3.79-4.05 (m, 3H), 4.13- 4.23 (m, IH), 6.11-6.14 (m, IH), 6.81-6.91 (m, IH), 7.26-7.33 (m, 2H), 7.37-7.45 (m, 2H), 8.41- 8.51 (m, IH).
Example 2.110: Preparation of 2-Pyridin-3-yl-l-{(3aS,6aS)-6-[4-(2-pyrrolidin-l-yl-ethyl)- phenyl]-3,3a,4,6a-tetrahydro-lH-cydopenta[c]pyrrol-2-yI}-ethanone.
Figure imgf000184_0002
A solution of 3-pyridylacetic acid hydrochloride (120.3 mg, 0.693 mmol) in DCM (7.0 ml) was added triethylamine (0.150 ml, 1.076 mmol) and stirred at room temperature. After 45 min, PS-Carbodiimide (720 mg, 0.720 mmol) was added to the reaction mixture and further stirred for 10 min before (3aS,6aS)-6-[4~(2-Pyrrolidin-l-yl~ethyl)-phenyl]-l,2,3,3a,4,6a- hexahydro-cyclopenta[c]pyrrole (99.8 mg, 0.353 mmol) dissolved in DCM (3.0 mL) was added. After 19 h, the resin was filtered and washed with DCM and MeOH. The solution was concentrated. The residue was purified by preparative HPLC, lyophilized, and treated with HCl to afford the hydrochloride salt of the title compound (64.9 mg). MS m/z 402, (M+H); 1H NMR (400 MHz, CD3OD) δ 1.97-2.09 (m, 2H), 2.11-2.21 (m, 2H), 2.36-2.51 (m, IH), 2.79-2.90 (m, IH), 3.00-3.19 (m, 5H), 3.41-3.53 (m, 3H), 3.58-3.73 (m, 3H), 3.76-3.93 (m, 2H), 3.97-4.11 (m, 3H), 6.12-6.15 (m, IH), 7.27-7.35 (m, 2H), 7.38-7.46 (m, 2H), 7.99-8.07 (m, IH), 8.44-8.54 (m, IH), 8.72-8.78 (m, 2H).
Example 2.111: Preparation of (3aS,6aS)-2-Ethanesulfonyl-6-[4-(2-pyrroIidin-l-yl-ethyl)- phenyll-l^jSaAόa-hexahydro-cyclopentatclpyrrole.
Figure imgf000184_0003
To a solution of (3aS,6aS)-6-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-l,2,3,3a,4,6a- hexahydro-cyclopenta[c]pyrrole (99.8 mg, 0.353 mmol) in DCM (5.0 mL) was added triethylamine (98.2 μl, 0.705 mmol) followed by ethanesulfonyl chloride (50.3 μl, 0.531 mmol). The resulting reaction mixture was stirred at 25 0C for 1.5 h. Upon completion, the reaction
Figure imgf000185_0001
and treated with HCl to afford the hydrochloride salt of the title compound (56.8 mg). MS m/z 375, (M+H); 1H NMR (400 MHz, CD3OD) δ 1.25 (t, J = 7.4 Hz, 3H), 1.96-2.07 (m, 2H), 2.12-2.22 (m, 2H), 2.36-2.43 (m, IH), 2.79-2.88 (m, IH), 2.96-3.08 (m, 4H), 3.09-3.19 (m, 5H), 3.42-3.49 (m, 2H), 3.56-3.70 (m, 4H), 3.87-3.94 (m, IH), 6.14-6.16 (m, IH), 7.295 (d, J = 8.3 Hz, 2H), 7.41 (d, J = 8.2 Hz, 2H).
Example 2.112: Preparation of 2-Pyridin-2-yl-l-{(3aS,6aS)-6-[4-(2-pyrrolidm-l-yI-ethyl)- phenylJ-SjSa^jδa-tetrahydro-lH-cyclopentatclpyrrol^-ylJ-ethanone.
Figure imgf000185_0002
A solution of 2-pyridylacetic acid hydrochloride (117.2 mg, 0.675 mmol) in DCM (7.0 mL) was added triethylamine (0.150 ml, 1.076 mmol) and stirred at room temperature. After 1 h, PS-Carbodiimide (711.5 mg, 0.712 mmol) was added to the reaction mixture and further stirred for 10 min before (3aS,6aS)-6-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-l,2,3,3a,4,6a- hexahydro-cyclopenta[c]pyrrole (99.6 mg, 0.353 mmol) dissolved in DCM (3.0 mL) was added. After 19.5 h, the resin was filtered and washed with DCM and MeOH. The solution was concentrated. The residue was purified by preparative HPLC, lyophilized, and treated with HCl to afford the hydrochloride salt of the title compound (58.8 mg). MS m/z 402, (M+H); 1H NMR (400 MHz, CD3OD) δ 1.97-2.09 (m, 2H), 2.10-2.22 (m, 2H), 2.37-2.52 (m, IH), 2.79-2.91 (m, IH), 3.02-3.30 (m, 5H), 3.40-3.95 (m, 7H), 4.01-4.15 (m, 2H), 4.22-4.34 (m, 2H), 6.13-6.17 (m, IH), 7.30 (d, / = 8.0 Hz, IH), 7.34 (d, J = 7.8 Hz, IH), 7.40 (d, J = 8.1 Hz, IH), 7.45 (d, J = 8.4 Hz, IH), 7.90-8.01 (m, 2H), 8.52-8.59 (m, IH), 8.77-8.81 (m, IH).
Example 2.113: Preparation of 2-Pyridin-4-yl-l-{(3aS,6aS)-6-[4-(2-pyrrolidin-l-yl-ethyl)- phenyll-SjSa^joa-tetrahydro-lH-cyclopentafcJpyrrol^-yty-ethanone.
Figure imgf000185_0003
A solution of 4-pyridylacetic acid hydrochloride (117 mg, 0.676 mmol) in DCM (7.0 mL) was added triethylamine (0.150 ml, 1.076 mmol) and stirred at room temperature. After 45 min, PS-Carbodiimide (712.3 mg, 0.712 mmol) was added to the reaction mixture and further
Figure imgf000186_0001
hexahydro-cyclopenta[c]pyrrole (101.0 nig, 0.358 mmol) dissolved in DCM (3.0 mL) was added. After 20 h, the resin was filtered and washed with DCM and MeOH. The solution was concentrated. The residue was purified by preparative HPLC5 lyophilized, and treated with HCl to afford the hydrochloride salt of the title compound (37.4 mg). MS m/z 402, (M+H); 1H NMR (400 MHz, CD3OD) δ 1.97-2.22 (m, 4H), 2.35-2.50 (m, IH), 2.77-2.88 (m, IH), 3.04-3.30 (m, 5H), 3.40-3.61 (m, 4H), 3.64-3.74 (m, 2H), 3.76-3.92 (m, 2H), 3.95-4.20 (m, 3H), 6.10-6.14 (m, IH), 7.30 (d, J = 8.0 Hz, IH), 7.32 (d, J = 7.0 Hz, IH), 7.39 (d, J = 8.1 Hz, 2H), 7.92 (d, J = 6.4 Hz, IH), 7.99 (d, J = 6.5 Hz, IH), 8.715 (d, J = 6.5 Hz, IH), 8.775 (d, J = 6.5 Hz, IH).
Example 2.114: Preparation of (3aS,6aS)-2-Cyclopropanesulfonyl~6-[4-(2-pyrrolidin-l-yl- ethyl)-phenyl]-l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole.
Figure imgf000186_0002
To a solution of (3aS,6aS)-6-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-l,2,3,3a,4,6a- hexahydro-cyclopenta[c]pyrrole (99.3 mg, 0.352 mmol) in DCM (5.0 mL) was added triethylamine (98.2 μl, 0.705 mmol) followed by cyclopropanesulfonyl chloride (54.1 μl, 0.531 mmol). The resulting reaction mixture was stirred at 25 0C for 1.5 h. Upon completion, the reaction mixture was concentrated. The residue was purified by preparative HPLC, lyophilized, and treated with HCl to afford the hydrochloride salt of the title compound (67.5 mg). MS m/z 387, (M+H); 1H NMR (400 MHz, CD3OD) δ 0.89-1.03 (m, 4H), 1.97-2.07 (m, 2H), 2.12-2.21 (m, 2H), 2.36-2.49 (m, 2H), 2.80-2.89 (m, IH), 3.02-3.20 (m, 7H), 3.42-3.50 (m, 2H), 3.59-3.70 (m, 4H), 3.88-3.95 (m, IH), 6.14-6.18 (m, IH), 7.30 (d, J = 8.2 Hz, 2H), 7.42 (d, J = 8.2 Hz, 2H).
Example 2.115: Preparation of 2-Methyl-l-((3aS,6aS)-6-{4-[2-((R)-2-methyl-pyrrolidin-l- yl)-ethyl]-phenyl}-3,3a,4,6a-tetrahydro-lH-cyclopenta[c]pyrrol-2-yl)-propan-l-one.
Figure imgf000186_0003
p IiJ. if /
Figure imgf000187_0001
method C using (3aS,6aS)-6-(4-(2-((R)- 2-methylpyrrolidin-l-yl)ethyl)phenyl)-l,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole. MS m/z 367, (M+H); 1H NMR (400 MHz, CD3OD) δ 0.85-1.11 (m, 6H), 1.48 (d, J= 6.4 Hz, 3H), 1.70- 1.82 (m, IH), 2.00-2.19 (m, 2H), 2.29-2.44 (m, 2H), 2.57-2.86 (m, 2H), 3.02-3.38 (m, 6H), 3.44- 3.64 (m, 3H), 3.71-3.98 (m, 4H), 6.09-6.12 (m, IH), 7.29-7.36 (m, 2H), 7.37-7.43 (m, 2H).
Example 2.116: Preparation of Cyclopropyl-((3aS,6aS)-6-{4-[2-((R)-2-methyl-pyrrolidin-l- yI)-ethyl]-phenyl}-3,3a,4,6a-tetrahydro-lH-cydopenta[c]pyrrol-2-yl)-methanone.
The title compound was obtained using general method C using (3aS,6aS)-6-(4-(2-((R)-
2-methylpyrrolidin- 1 -yl)ethyl)phenyl)- 1 ,2,3 ,3 a,4,6a-hexahydrocyclopenta[c]pyrrole. MS m/z 365, (M+H); 1H NMR (400 MHz, CD3OD) δ 0.65-0.90 (m, 4H), 1.475 (d, J = 6.5 Hz, 3H), 1.61-1.87 (m, 2H), 2.01-2.18 (m, 2H), 2.28-2.47 (m, 2H), 2.76-2.86 (m, IH), 3.02-3.30 (m, 5H), 3.44-4.12 (m, 8H), 6.09-6.12 (m, IH), 7.29-7.45 (m, 4H).
Example 2.117: Preparation of (3aS,6aS)-2-Cyclopropanesulfonyl-6-{4-[2-((R)-2-methyl- pyrrolidin-l-y^-ethyll-phenylJ-l^jSjSa^jόa-hexahydro-cyclopentalcJpyrrole.
Figure imgf000187_0003
To a solution of (3aS,6aS)-6-(4-(2-((R)-2-methylpyrrolidin-l-yl)ethyl)phenyl)- 0 l,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole (98.9 mg, 0.334 mmol) in DCM (5.0 mL) was added triethylamine (93.5 μl, 0.671 mmol) followed by cyclopropanesulfonyl chloride (51.5 μl, 0.506 mmol). The resulting reaction mixture was stirred at 25 0C for 1.5 h. Upon completion, the reaction mixture was concentrated. The residue was purified by preparative HPLC. The HPLC fractions were lyophilized to give the title compound as a TFA salt. MS m/z 401, 5 (M+H); 1H NMR (400 MHz, CD3OD) δ 0.90-1.03 (m, 4H), 1.45 (d, J = 6.6 Hz, 3H), 1.68-1.80 (m, IH), 2.00-2.18 (m, 2H), 2.29-2.49 (m, 3H), 2.81-2.89 (m, IH), 2.96-3.29 (m, 7H), 3.46-3.77 (m, 5H), 3.88-3.95 (m, IH), 6.14-6.18 (m, IH), 7.30 (d, J= 8.2 Hz, 2H), 7.42 (d, J = 8.2 Hz, 2H).
Figure imgf000188_0001
phenyl}-2-(propane-2-sulfonyl)-l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole.
Figure imgf000188_0002
To a solution of (3aS,6aS)-6-(4-(2-((R)-2-methylpyrrolidin-l-yl)ethyl)phenyl)- 1 ^ΛSaAόa-hexahyάrocyclopentatcjpyrrole (100.6 mg, 0.339 mmol) in DCM (5.0 ml) was added triethylamine (93.5 μl, 0.671 mmol) followed by 2-propanesulfonyl chloride (56.8 μl, 0.506 mmol). The resulting reaction mixture was stirred at 25 °C for 1.5 h. Upon completion, the reaction mixture was concentrated. The residue was purified by preparative HPLC. The HPLC fractions were lyophilized to give the title compound as a TFA salt. MS m/z 403, (M+H); 1H NMR (400 MHz, CH3OD) δ 1.23 (d, J = 4.1 Hz, 3H), 1.25 (d, J = 4.1 Hz, 3H), 1.45 (d, J = 6.5 Hz, 3H), 1.68-1.79 (m, IH), 2.00-2.15 (m, 2H), 2.28-2.42 (m, 2H), 2.78-2.87 (m, IH), 2.95-3.28 (m, 8H), 3.46-3.77 (m, 5H), 3.85-3.92 (m, IH), 6.11-6.15 (m, IH), 7.30 (d, J = 8.3 Hz, 2H), 7.40 (d, J = 8.3 Hz, 2H).
Example 2.119: Preparation of ((3aS,6aS)-6-{4-[2-((R)-2-Methyl-pyrrolidin-l-yl)-ethyl]- phenyll-S^a^jόa-tetrahydro-lH-cyclopentafclpyrrol^-y^-pyridin-S-yl-methanone.
Figure imgf000188_0003
The title compound was obtained using general method C using (3aS,6aS)-6-(4-(2-((R)- 2-methylpyrrolidin-l-yl)ethyl)phenyl)-l,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole. MS m/z 402, (M+H); 1H NMR (400 MHz, CD3OD) δ 1.45-1.50 (m , 3H), 1.70-1.82 (m, IH), 2.01-2.22 (m, 2H), 2.30-2.52 (m, 2H), 2.73-2.92 (m, IH), 3.00-3.15 (m, 2H), 3.16-3.42 (m, 3H), 3.46-3.79 (m, 5H), 3.86-4.13 (m, 3H), 6.12-6.18 (m, IH), 7.23-7.48 (m, 4H), 8.07-8.22 (m, IH), 8.62-8.81 (m, IH), 8.88-9.11 (m, 2H).
5 Example 2.120: Preparation of Cyclopentyl-((3aS,6aS)-6-{4-[2-((R)-2-methyl-pyrrolidin-l- yl)-ethyl]-phenyl}-3,3a,4,6a-tetrahydro-lH-cyclopenta[c]pyrrol-2-yl)-methanone.
Figure imgf000189_0001
The title compound was obtained using general method C using (3aS,6aS)-6-(4-(2-((R)- 2-methylpyrrolidin-l-yl)ethyl)phenyl)-l,2,3,3a,4,6a-hexahydrocycloρenta[c]pyrrole. MS m/z 393, (M+H); 1H NMR (400 MHz, CD3OD) δ 1.44-1.92 (m, 13H), 2.00-2.43 (m, 4H), 2.69-2.97 (m, 2H), 3.01-3.38 (m, 5H), 3.44-3.63 (m, 3H), 3.69-3.97 (m, 4H), 6.08-6.11 (bs, IH), 7.28-7.41 (m, 4H).
Example 2.121: Preparation of ((3aS,6aS)-6-{4-[2-((R)-2-Methyl-pyrrolidin-l-yl)-ethyl]- phenylJ-S^a^jόa-tetrahydro-lH-cyclopentafclpyrrol^-y^-^etrahydro-furan-S-yl)- methanone.
Figure imgf000189_0002
A mixture of tetrahydroruran-3-carboxylic acid (0.368 ml, 3.85 mmol) and PS- Carbodiimide (4.04 g, 4.04 mmol) in DCM (40.0 ml) was stirred for 10 min and added (3aS,6aS)-6-(4-(2-((R)-2-methylpyrrolidin-l-yl)ethyl)phenyl)-l,2,3,3a,4,6a- hexahydrocyclopenta[c]pyrrole (600 mg, 2.03 mmol) dissolved in DCM (5.0 mL). After 12.5 h, the resin was filtered and washed with DCM and MeOH. The solution was concentrated. The residue was purified by preparative HPLC. The HPLC fractions were lyophilized to give the title compound as a TFA salt. MS m/z 395, (M+H); 1H NMR (400 MHz, CH3OD) δ 1.44-1.48 (m, 3H), 1.68-1.79 (m, IH), 1.96-2.23 (m, 4H), 2.29-2.44 (m, 2H), 2.77-2.86 (m, IH), 2.96-3.15 (m, 3H), 3.18-3.39 (m, 3H), 3.44-3.99 (m, 12H), 6.09-6.13 (m, IH), 7.28-7.35 (m, 2H), 7.38- 7.44 (m, 2H).
Example 2.122: Preparation of l-((3aS,6aS)-6-{4-[2-((R)-2-Methyl-pyrrolidin-l-yl)-ethyl]- phenyI}-33a,4,6a-tetrahydro-lH-eyclopenta[c]pyrrol-2-yl)-2-phenyl-ethanone.
Figure imgf000189_0003
A mixture of 2-phenylacetic acid (130.2 mg, 0.9563 mmol) and PS-Carbodiimide (996 mg, 0.996 mmol) in DCM (10.0 ml) was stirred for 10 min and added (3aS,6aS)-6-(4-(2-((R)-2- methylpyrrolidin- 1 -yl)ethyl)phenyl)- 1 ,2,3 ,3 a,4,6a-hexahydrocyclopenta[c]pyrrole ( 147.3 mg, 0.497 mmol) dissolved in DCM (3.0 mL). After 23 h, the resin was filtered and washed with DCM and MeOH. The solution was concentrated. The residue was purified by preparative HPLC, lyophilized, and treated with HCl to afford the hydrochloride salt of the title compound (70.5 mg). MS m/z 415, (M+H); 1H NMR (400 MHz, CD3OD) δ 1.44-1.49 (m, 3H), 1.70-1.81 (m, IH), 2.00-2.17 (m, 2H), 2.22-2.40 (m, 2H), 2.70-2.84 (m, IH), 3.01-3.35 (m, 6H), 3.47-3.63 (m, 4H), 3.69-3.93 (m, 5H), 6.03-6.08 (m, IH), 7.04-7.40 (m, 9H).
Example 2.123: Preparation of ((3aR,4R,6aS)-4-{4-[2-((R)-2-Methyl-pyrrolidin-l-yl)- ethyl]-phenyl}-hexahydro-cyclopenta[c]pyrrol-2-yl)-(tetrahydro-furan-3-yl)-methanone.
Figure imgf000190_0001
A mixture of tetrahydrofuran-3-carboxylic acid (0.122 ml, 1.28 mmol) and PS- 5 Carbodiimide (1.40 g, 1.40 mmol) in DCM (15.0 ml) was stirred for 15 min and added
(3aR,4R,6aS)-4-(4-(2-((R)-2-methylpyrrolidin-l-yl)ethyl)phenyl)- octahydrocyclopenta[c]pyrrole (204.4 mg, 0.685 mmol) dissolved in DCM (5.0 mL). After 66 h, the resin was filtered and washed with DCM and MeOH. The solution was concentrated.
The residue was purified by preparative HPLC, lyophilized, and treated with HCl to afford the 0 hydrochloride salt of the title compound (127.6 mg). MS m/z 397, (M+H); 1H NMR (400 MHz,
CD3OD) δ 1.44-1.48 (m, 3H), 1.64-1.80 (m, 2H), 1.90-2.22 (m, 8H), 2.29-2.40 (m, IH), 2.88-
4.01 (m, 18H), 7.25-7.30 (m, 4H).
Example 2.124: Preparation of ((3aS,6aS)-6-{4-[2-((R)-2-Methyl-pyrrolidin-l-yl)-ethyl]- 5 phenyl}-3,3a,4,6a-tetrahydro-lH-cycIopenta[c-pyrrol-2-yl)-phenyl-methanone.
Figure imgf000190_0002
A mixture of benzoic acid (158.2 mg, 1.295 mmol) and PS-Carbodiimide (1.359 g, 1.359 mmol) in DCM (13.5 mL) was stirred for 10 min and added (3aS,6aS)-6-(4-(2-((R)-2- methylpyrrolidin-l-yl)phenyl)-1,2,3,3a4,6a-hexahydrocyclopenta[c]pyrrole (201.7 mg, P C
Figure imgf000191_0001
mL). After 16.5 h, the resin was filtered and washed with DCM and MeOH. The solution was concentrated. The crude product was purified by HPLC. The residue was purified by preparative HPLC, lyophilized, and treated with HCl to afford the hydrochloride salt of the title compound (144 mg). MS m/z 401, (M+H); 1H NMR (400 MHz, CD3OD) δ 1.43-1.49 (m, 3H), 1.69-1.81 (m, IH), 2.00-2.18 (m, 2H), 2.24-2.50 (m, 2H), 2.71- 2.92 (m, IH), 2.95-3.42 (m, 6H), 3.46-4.03 (m, 7H), 6.10-6.15 (m, IH), 7.22-7.49 (m, 9H).
Example 2.125: Preparation of ((3aS,6aS)-6-{4-[2-((R)-2-Methyl-pyrrolidin-l-yl)-ethyl]- phenyI}-3,3a,4,6a-tetrahydro-lH-cyclopenta[c]pyrroI-2-yl)-(tetrahydro-pyran-4-yl)- methanone.
Figure imgf000191_0002
The title compound was obtained using general method C using (3aS,6aS)-6-(4-(2-((R)- 2-methylpyrrolidin-l-yl)ethyl)phenyl)-l,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole. MS m/z 409, (M+H); 1H NMR (400 MHz, CD3OD) δ 1.45-1.49 (m, 3H), 1.52-1.81 (m, 5H), 2.00-2.20 (m, 2H), 2.28-2.44 (m, 2H), 2.56-2.87 (m, 2H), 2.98-3.29 (m, 6H), 3.30-3.64 (m, 5H), 3.70-3.86 (m, 3H), 3.88-4.00 (m, 3H), 6.08-6.12 (m, IH), 7.29-7.35 (m, 2H), 7.37-7.43 (m, 2H).
Example 2.126: Preparation of CycIohexyl-((3aR,4R,6aS)-4-{4-[2-((R)-2-methyl- pyrrolidin-l-y^-ethylj-phenylj-hexahydro-cyclopentalcjpyrrol^-y^-methanone.
Figure imgf000191_0003
The title compound was obtained using general method C starting from (3aR,4R,6aS)-4-
(4-(2-((R)-2-memylpyrrolidin-l-yl)ethyl)phenyl)-octahydrocyclopenta[c]pyrrole. MS m/z 409, (M+H); 1H NMR (400 MHz, CD3OD) δ 1.09-1.50 (m, 8H), 1.52-1.84 (m, 7H), 1.89-2.24 (m, 5H), 2.27-2.40 (m, IH), 2.43-2.53 (m, IH), 2.86-3.84 (m, 14H), 7.22-7.32 (m, 4H). 5
Example 2.127: Preparation of 3-Methyl-l-((3aR,4R,6aS)-4-{4-[2-((R)-2-methyl- pyrrolidin-l-y^-ethyll-phenylj-hexahydro-cyclopentalcjpyrrol^-y^-butan-l-one.
Figure imgf000192_0001
The title compound was obtained using general method C starting from (3aR,4R,6aS)-4- (4-(2-((R)-2-methylpyrrolidin-l-yl)ethyl)phenyl)-octahydrocyclopenta[c]pyrrole. MS m/z 383, (M+H); 1H NMR (400 MHz, CD3OD) δ 0.85-1.03 (m, 6H), 1.48 (d, J= 6.2 Hz, 3H), 1.64-1.83 (m, 2H), 1.90-2.39 (m, 9H), 2.90-3.62 (m, 12H), 3.69-3.80 (m, IH), 3.82-3.90 (m, IH), 7.24- 7.33 (m, 4H).
Example 2.128: Preparation of l-((3aR,4R,6aS)-4-{4-[2-((R)-2-Methyl-pyrrolidin-l-yl)~ ethyl]-phenyI}-hexahydro-cyclopenta[c]pyrrol-2-yl)-2-thiophen-2-yl-ethanone.
Figure imgf000192_0002
The title compound was obtained using general method C starting from (3aR,4R,6aS)-4-
(4-(2-((R)-2-methylpyrrolidin-l-yl)ethyl)phenyl)-octahydrocyclopenta[c]pyrrole. MS m/z 423, (M+H); 1H NMR (400 MHz, CD3OD) δ 1.44-1.49 (m, 3H), 1.52-1.66 (m, IH), 1.69-2.26 (m, 6H), 2.28-2.39 (m, IH), 2.58-4.02 (m, 16H), 6.75-7.01 (m, 2H), 7.09-7.34 (m, 5H). 5
Example 2.129: Preparation of 2,2-Dimethyl-l-((3aR,4R,6aS)-4-{4-[2-((R)-2-methyl- pyrrolidin-l-y^-ethyll-pheny^-hexahydro-cyclopentafclpyrrol^-y^-propan-l-one.
Figure imgf000192_0003
The title compound was obtained using general method C starting from (3aR,4R,6aS)-4- 0 (4-(2-((R)-2-methylpyrrolidin-l-yl)ethyl)phenyl)-octahydrocyclopenta[c]pyrrole. MS m/z 383, (M+H); 1H NMR (400 MHz5 CD3OD) δ 1.12-1.26 (m, 9H), 1.46 (d, /= 6.5 Hz, 3H), 1.62-1.83 (m, 2H), 1.88-2.24 (m, 5H), 2.29-2.39 (m, IH), 2.83-3.14 (m, 5H), 3.16-3.42 (m, 4H), 3.45-3.83 (m, 5H), 7.27 (bs, 4H). P
Figure imgf000193_0001
ethyl]-phenyl}-hexahydro-cyclopenta[c]pyrrol-2-yl)-ethanone.
Figure imgf000193_0002
The title compound was obtained using general method C starting from (3aR,4R,6aS)-4- 5 (4-(2-((R)-2-methylpyrrolidin-l-yl)ethyl)phenyl)-octahydrocyclopenta[c]pyrrole. MS m/z 341, (M+H); 1H NMR (400 MHz, CD3OD) δ 1.47 (dd, J = 6.5, 1.8 Hz, 3H), 1.66-1.81 (m, 2H), 1.96-2.27 (m, 8H), 2.29-2.39 (m, IH), 2.92-3.14 (m, 4H), 3.15-3.30 (m, 3H), 3.34-3.63 (m, 5H), 3.69-3.79 (m, IH), 3.83-3.91 (m, IH), 7.26-7.30 (m, 4H).
0 Example 2.131: Preparation of l-((3aR,4R,6aS)-4-{4-[2-((R)-2-Methyl-pyrrolidin-l-yl)- ethyl]-phenyl}-hexahydro-cyclopenta[c]pyrrol-2-yI)-2-phenyl-ethanone.
Figure imgf000193_0003
A mixture of 2-phenylacetic acid (176.7 mg, 1.298 mmol) and PS-Carbodiimide (1.352 g, 1.352 mmol) in DCM (15.0 mL) was stirred for 10 min and added (3aR,4R,6aS)-4-(4-(2-((R)- 5 2-methylpyrrolidin-l-yl)ethyl)phenyl)-octahydrocyclopenta[c]pyrrole (203 mg, 0.680 mmol) dissolved in DCM (5.0 mL). After 18 h, the resin was filtered and washed with DCM and MeOH. The solution was concentrated. The residue was purified by preparative HPLC, lyophilized, and treated with HCl to afford the hydrochloride salt of the title compound (165.6 mg). MS rn/z 417, (M+H); 1H NMR (400 MHz, CD3OD) δ 1.42-1.62 (m, 4H), 1.68-2.24 (m, 0 6H), 2.28-2.38 (m, IH), 2.83-3.27 (m, 7H), 3.27-3.78 (m, 9H), 6.98-7.36 (m, 9H).
Example 2.132: Preparation of l-((3aR,4R,6aS)-4-{4-[2-((R)-2-Methyl-pyrrolidin-l-yl)- ethyl]-phenyl}-hexahydro-cydopenta[c]pyrrol-2-yl)-2-(tetrahydro-pyran-4-yl)-ethanone.
Figure imgf000193_0004
O I '■ 1"ir"'/
Figure imgf000194_0001
acid (194.1 mg, 1.346 mmol) and PS-
Carbodiimide (1.359 g, 1.359 mmol) in DCM (15.0 mL) was stirred for 10 min and added (3aRJ4R,6aS)-4-(4-(2-((R)-2-methylpyrrolidin-l-yl)ethyl)phenyl)- octahydrocyclopenta[c]pyrrole (203 mg, 0.680 mmol) dissolved in DCM (5.0 mL). After 19 h, the resin was filtered and washed with DCM and MeOH. The solution was concentrated. The residue was purified by preparative HPLC, lyophilized, and treated with HCl to afford the hydrochloride salt of the title compound (143.0 mg). MS m/z 425, (M+H); 1H NMR (400 MHz, CD3OD) δ 1.14-1.44 (m, 3H), 1.46-1.85 (m, 7H), 1.88-2.42 (m, 9H), 2.90-3.96 (m, 17H), 7.28 (bs, 4H).
EXAMPLE 3: [3H] N-ALPHA-METHYL-HISTAMINE COMPETITIVE 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 -8O0C until needed. Frozen membranes were thawed and resuspended in ice-cold assay buffer consisting of 5OmM TRIS containing 5mM 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-α-methyl- histamine (1 nanomolar (nM) final assay concentration). Imetit was used as an assay positive control at varying concentrations. The plate was incubated for 30 minutes 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 where washed three times with cold assay buffer and plates were dried at 5O0C. 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.
Figure imgf000194_0002
0 Certain other compounds of the invention had activity values ranging from about 5 μM to about 50 pM in this assay.
EXAMPLE 4: (UE)-N-ALPHA-METHYL-HISTAMINE (RAMH) PROTOCOL. ψ C T/ U HIJitø:' Hall''kpfagiϊe-Dawley rats (225-35Og) (Harlan, San Diego, CA) were housed two to three per cage and maintained in a humidity- (30-70%) and temperature- (20-22°C) controlled facility on a 12 hr:12 hr 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 5 allowed at least three days of habituation to the animal facility before testing.
Procedure: Rats were placed into individual cages with wire grid bottoms, with free access to water and no food. After 90min of habituation, rats were injected with vehicle or test compound. 30-60min later (depending on PK/route of test compound), water was removed, and vehicle or R-α-methyl-histamine dihydrochloride was injected (20mg/kg salt, SC, lcc/kg 0 dissolved in water). lOmin later, water was returned to cages. Water intake over 20min was then measured.
Data analysis: RAMH-induced drinking was confirmed by comparison of vehicle+vehicle group versus vehicle+RAMH group. % Inhibition of RAMH-induced drinking was calculated for each individual animal as follows: [l-(D-V)/(R-V)]*100 where D = the 5 individual animal's water intake, V = the mean water intake of the vehicle+vehicle group, and R = the mean water intake of the vehicle+RAMH group. Mean ± SEM % inhibition for test compound groups was then obtained from the % inhibition values of individual animals.
The following table shows the observed percent inhibition of RAMH-induced drinking for certain compounds of the present invention administered at 3 mg/Kg subcutaneous. 0
Figure imgf000195_0001
Example 5: Human H3-RECEPTOR Binding Assay - MDS Pharma Services (Taiwan).
Compounds of the invention were tested for their ability to bind to the human H3- receptor using the MDS .Pharma Services (Taiwan) assay, Catalogue No. 239810. Certain 5 compounds of the present invention and their corresponding activity values are shown in following table.
Figure imgf000195_0002
Figure imgf000196_0001
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 one hour after administration of two representative compounds.
Figure imgf000196_0002
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. AU 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

P C T / U S O 6 ,/ »ΨN-H-7 «3 CLAIMS
What is claimed is:
1. A compound of Formula (Ia) :
Figure imgf000197_0001
(Ia) or a pharmaceutically acceptable salt, hydrate or solvate thereof; wherein:
D is C(=O), OC(=O), NR6C(=O), S(O)2, or absent, wherein R6 is H or C1-6 alkyl;
G is CR7 or C, provided that when G is CR7 then — is a single bond, wherein R3 is H and R7 is H or OH, and when G is C then - - is a double bond and R3 is absent;
E is C(R8R9) or C(RsR9)C(R10Rπ), wherein R8, R9, R10, and R11 are each selected independently from the group consisting of H, Q-3 alkyl, Ci-4 alkoxy, carboxy, cyano, Ci-3 haloalkyl, and halogen;
J is O, S, S(=0), S(O)2, NR12, or absent, wherein R12 is H or C1-6 alkyl; K is C1-4 alkylene optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 substituents selected independently from the group consisting of C1-3 alkyl, C1-4 alkoxy, carboxy, cyano, C1-3 haloalkyl, halogen, hydroxyl, and oxo;
R1 is selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C1-4 alkylene-C3-7-cycloalkyl, C3-7 heterocyclyl, aryl, C1-4 0 alkylene-aryl, heteroaryl, and C1-4 alkylene-heteroaryl, and each of said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C1-4 alkylene-C3-7-cycloalkyl, C3-7 heterocyclyl, aryl, C1-4 alkylene-aryl, heteroaryl, and C1-4 alkylene-heteroaryl groups are optionally substituted with 1, 2, 3, 4, 5, 6, or 7 substituents selected independently from the group consisting Of C1-6 acyl, C1-6 acyloxy, C2-6 alkenyl, C1-6 alkoxy, C1-6 alkyl, C1-6 5 alkylcarboxamide, C2-6 alkynyl, C1-6 alkylsulfonamide, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C1-6 alkylthio, C1-6 alkylureyl, amino, C1-6 alkylamino, C2-8 dialkylamino, carbo-C1-6-alkoxy, carboxamide, carboxy, cyano, C3-7 cycloalkyl, C2-8 dialkylcarboxamide, C2-8 dialkylsulfonamide, formyl, halogen, C1-6 haloalkoxy, C1-6 haloalkyl, C1-6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, C1-6 haloalkylthio, hydroxyl, 0 thiol, nitro, and sulfonamide;
R2 is H, halogen or Ci-3 alkyl; P !!',::: I / U
Figure imgf000198_0001
from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-7 cycloalkyl, and wherein each of said Ci-6 alkyl, C2-5 alkenyl, C2-6 alkynyl, and C3-7 cycloalkyl groups are optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected independently from the group consisting of Ci-6 acyl, Ci-6 acyloxy, C2-6 alkenyl, Ci-6 alkoxy, Ci-6 alkyl, Ci-6 alkylcarboxamide, C2-6 alkynyl,
Ci-6 alkylsulfonamide, Ci-6 alkylsulfinyl, C1-6 alkylsulfonyl, Ci-6 alkylthio, Ci-6 alkylureyl, amino, Ci-6 alkylamino, C2-8 dialkylamino, carbo-Ci-6-alkoxy, carboxamide, carboxy, cyano, C3-7 cycloalkyl, C2-8 dialkylcarboxamide, C2-8 dialkylsulfonamide, halogen, C1-6 haloalkoxy, Ci-6 haloalkyl, C1-6 haloalkylsulfinyl, Ci-6 haloalkylsulfonyl, C]-6 haloalkylthio, hydroxyl, thiol, nitro, and sulfonamide; or
R4 and R5 together with the nitrogen atom to which they are both bonded form a C3-7 heterocyclyl or C5-I0 heterobicyclyl group optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected independently from the group consisting of Ci-6 acyl, Ci-6 acyloxy, C2-6 alkenyl, Ci-6 alkoxy, Ci-6 alkyl, Ci-6 alkylcarboxamide, C2-6 alkynyl, Ci-6 alkylsulfonamide, Ci-6 alkylsulfinyl, C1-6 alkylsulfonyl, Ci-6 alkylthio, C1-6 alkylureyl, amino, C1-6 alkylamino, C2-8 dialkylamino, carbo-C1-6-alkoxy, carboxamide, carboxy, cyano, C3-7 cycloalkyl, C2-8 dialkylcarboxamide, C2-8 dialkylsulfonamide, halogen, C1-6 haloalkoxy, C1-6 haloalkyl, C1-6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, C1-6 haloalkylthio, hydroxyl, thiol, nitro, oxo, phenyl, and sulfonamide, and said C1-6 alkyl, is optionally substituted with 1 or 2 substituents selected independently from C1-6 alkoxy and hydroxyl; and
Ar is phenyl, pyridinyl, or pyrimidinyl, each optionally substituted with 1, 2, 3, or 4 substituents selected independently from the group consisting OfC1-6 acyl, Cx-6 acyloxy, C2-6 alkenyl, Ci-6 alkoxy, Ci-6 alkyl, Ci-6 alkylcarboxamide, C2-6 alkynyl, C1-6 alkylsulfonamide, C1-6 alkylsulfinyl, Ci-6 alkylsulfonyl, C1-6 alkylthio, C1-6 alkylureyl, amino, C1-6 alkylamino, C2-8 dialkylamino, carbo-C1-6-alkoxy, carboxamide, carboxy, cyano, C3-7 cycloalkyl, C2-8 dialkylcarboxamide, C2-8 dialkylsulfonamide, halogen, Ci-6 haloalkoxy, C1-6 haloalkyl, Ci-6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, C1-6 haloalkylthio, hydroxyl, thiol, nitro, and sulfonamide; 0 provided that:
G and J are not bonded to adjacent ring carbons of said Ar group; and when E is C(R8R9), then Ha and Hb are cis with respect to each other.
2. The compound according to claim 1, wherein: 5 D is C(O), OC(O), NR6C(=O), or absent, wherein R6 is H or Cj-6 alkyl;
R1 is selected from the group consisting of H, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, Ci-4 alkylene-C3-7-cycloalkyl, C3-7 heterocyclyl, aryl, C1-4 « iu IS " Llall<yTene-aryl, heteroaryl, and C1-4 alkylene-heteroaryl, and each of said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, Q-4 alkylene-C3-7-cycloalkyl, C3-7 heterocyclyl, aryl, Ci-4 alkylene-aryl, heteroaryl, and Ci-4 alkylene-heteroaryl groups are optionally substituted with 1, 2, 3, 4, 5, 6, or 7 substituents selected independently from the group consisting Of Ci-6 acyl, Ci-6 acyloxy, C2-6 alkenyl, Ci-6 alkoxy, Ci-6 alkyl, Ci-6 alkylcarboxamide, C2-6 alkynyl, Ci-6 alkylsulfonamide, Ci-6 alkylsulfmyl, Ci-6 alkylsulfonyl, Ci-6 alkylthio, Ci-6 alkylureyl, amino, Ci-6 alkylamino, C2-8 dialkylamino, carbo-Ci_6-alkoxy, carboxamide, carboxy, cyano, C3-7 cycloalkyl, C2-8 dialkylcarboxamide, C2-8 dialkylsulfonamide, halogen, Ci-6 haloalkoxy, Ci-6 haloalkyl, Ci-6 haloalkylsulfinyl, Ci-6 haloalkylsulfonyl, Ci-6 haloalkylthio, hydroxyl, thiol, nitro, and sulfonamide; and
R4 and R5 are each independently selected from the group consisting of H, Ci-6 alkyl, C2-6 alkenyl, C2.6 alkynyl, and C3-7 cycloalkyl, and wherein each of said Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-7 cycloalkyl groups are optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected independently from the group consisting of Ci-6 acyl,
Ci-6 acyloxy, C2-6 alkenyl, Ci-6 alkoxy, Ci-6 alkyl, Ci-6 alkylcarboxamide, C2-6 alkynyl, Ci-6 alkylsulfonamide, Q-6 alkylsulfmyl, Ci-6 alkylsulfonyl, Ci-6 alkylthio, C1-6 alkylureyl, amino, Ci-6 alkylamino, C2-8 dialkylamino, carbo-Ci-6-alkoxy, carboxamide, carboxy, cyano, C3-7 cycloalkyl, C2-8 dialkylcarboxamide, C2-8 dialkylsulfonamide, halogen, Ci-6 haloalkoxy, Ci-6 haloalkyl, Ci-6 haloalkylsulfinyl, C]-6 haloalkylsulfonyl,
Ci-6 haloalkylthio, hydroxyl, thiol, nitro, and sulfonamide; or
R4 and R5 together with the nitrogen atom to which they are both bonded form a C3-7 heterocyclyl or C5-I0 heterobicyclyl group optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected independently from the group consisting of Ci-6 acyl, Ci-6 acyloxy, C2-6 alkenyl, Ci-6 alkoxy, Ci-6 alkyl, Ci-6 alkylcarboxamide, C2-6 alkynyl, Ci-6 alkylsulfonamide, Ci-6 alkylsulfmyl, Q-6 alkylsulfonyl, Ci-6 alkylthio, Ci-6 alkylureyl, amino, Ci-6 alkylamino, C2-8 dialkylamino, carbo-Ci-6-alkoxy, carboxamide, carboxy, cyano, C3-7 cycloalkyl, C2-8 dialkylcarboxamide, C2-8 dialkylsulfonamide, halogen, Ci-6 haloalkoxy, Ci-6 haloalkyl, Ci-6 haloalkylsulfinyl, Ci-6 haloalkylsulfonyl, Ci-6 haloalkylthio, hydroxyl, thiol, nitro, and sulfonamide, and said Ci-6 alkyl, is optionally substituted with hydroxyl.
3. The compound according to claim 2, wherein E is C(R8R9).
4. The compound according to claim 2 or 3, wherein R8 and R9 are each H. TH Ii f / |! fiC; Hi IR, / !i..p4JΨ'7 "''I 7 i'" * 5'! " u'Tht'compound according to any one of claims 2 to 4, wherein G is CR7 and ^. is a single bond; wherein R7 is H or OH.
6. The compound according to any one of claims 2 to 4, wherein G is C and - - is a double bond.
7. The compound according to claim 2, wherein E is C(R8R9)C(R10Rn).
8. The compound according to claim 2 or 7, wherein R10, and Rn are each H.
9. The compound according to claim 2, 7 or 8, wherein R8, R9, R10, and R11 are each H.
10. The compound according to claim 2, 7, 8 or 9, wherein G is CR7 and - - is a single bond; wherein R7 is H or OH.
11. The compound according to claim 2, 7, 8 or 9, wherein G is C and - - is a double bond.
12. The compound according to claim 1, wherein D is S(=O)2.
13. The compound according to any one of claims 2 to 11 , wherein D is C(=O).
14. The compound according to any one of claims 2 to 11, wherein D is OC(=O).
15. The compound according to any one of claims 2 to 11 , wherein D is NHC(=O) .
16. The compound according to any one of claims 2 to 11, wherein D is absent.
17. The compound according to any one of claims 2 to 11, or 13 to 16, wherein J is O.
18. The compound according to any one of claims 2 to 11, or 13 to 16 wherein J is S, S(=O), or S(=O)2.
19. The compound according to any one of claims 2 to 11, or 13 to 16, wherein J is NR12, wherein R12 is H or C1-6 alkyl.
20. The compound according to any one of claims 2 to 11, or 13 to 16, wherein J is absent. p C T/ U S O B/ Ii+11+11+?19
21. The compound according to any one of claims 2 to 11 , or 13 to 20, wherein K is -CH2CH2-.
22. The compound according to claims 1 or 12, wherein R1 is selected from the group consisting of H, Ci_6 alkyl, C3-7 cycloalkyl, Ci-4 alkylene-C3-7-cycloalkyl, aryl, Q-4 alkylene-aryl, heteroaryl, and C1-4 alkylene-heteroaryl, and each of said Ci-6 alkyl and C1-4 alkylene-aryl, groups are optionally substituted with 1 or 2 substituents selected independently from the group consisting Of C1-6 alkoxy, C1-6 alkyl, amino, Cj-6 alkylamino, C2-8 dialkylamino, C3-7 cycloalkyl, foπfiyl, halogen, C1-6 haloalkoxy, Ci-6 haloalkyl, and hydroxyl.
23. The compound according to any one of claims 2 to 11 or 13 to 21, wherein R1 is selected from the group consisting of H, Ci-6 alkyl, C3-7 cycloalkyl, Ci-4 alkylene-C3-7- cycloalkyl, aryl, Ci-4 alkylene-aryl, heteroaryl, and C1-4 alkylene-heteroaryl, and each of said Ci-6 alkyl and Ci-4 alkylene-aryl, groups are optionally substituted with 1 or 2 substituents selected independently from the group consisting OfC1-6 alkoxy, Ci-6 alkyl, amino, C1-6 alkylamino, C2-s dialkylamino, C3-7 cycloalkyl, halogen, Ci-6 haloalkoxy, Q- 6 haloalkyl, and hydroxyl.
24. The compound according to any one of claims 1, 12 or 22, wherein R1 is selected from the group consisting of H, benzyl, cyclopropylmethyl, isobutyl, isopropyl, 4- trifluoromethoxy-benzyl, 2,4-dimethoxy-benzyl, cyclohexyl, cyclopentyl, methyl, ethyl, t-butyl, 4-methoxy-benzyl, 4-trifluoromethylbenzyl, cyclobutyl, 3-hydroxy-prop-2-yl, 4- hydroxy-benzyl, cyclopropyl, phenyl, pyridin-2-yl, hydroxymethyl, tetrahydro-furan-3- yl, tetrahydropyran-4-yl, pyridin-3-yl, pyrazin-2-yl, 2-fluoroethyl, trifluoromethyl, thiophen-2-ylmethyl, tetrahydropyran-4-ylmethyl, pyrimadin-5-yl, methoxymethyl, 2,2- difluoroethyl, 2,2,2-trifluoroethyl, 2-hydroxypropan-2-yl, cyclopentylmethyl, thiophen- 2-yl, pyridin-4-yl, furan-2-yl, morpholin-4-yl, 3-formylphenyl, thiazol-2-yl, pyrimadin- 2-yl, isoxazol-5-yl, 3,5-difluorophenyl, 3-cyanophenyl, 6-trifluoromethylpyridin-3-yl, and 6-cyanopyridin-3-yl.
25. The compound according to any one of claims 2 to 11, 13 to 21, or 23, wherein R1 is selected from the group consisting of H, benzyl, cyclopropylmethyl, isobutyl, isopropyl, 4-trifluoromethoxy-benzyl, 2,4-dimethoxy-benzyl, cyclohexyl, cyclopentyl, methyl, ethyl, t-butyl, 4-methoxy-benzyl, cyclobutyl, 3-hydroxy-prop-2-yl, 4-hydroxy-benzyl, cyclopropyl, phenyl, pyridin-2-yl, hydroxymethyl and tetrahydro-furan-3-yl. p C T/ US O B / Nl- 1MM1+ 7 '9
26. The compound according to any one of claims 1, 12, 22, or 24, wherein R2 is H or Cj-6 alkyl
27. The compound according to any one of claims 1, 12, 22, 24, or 26, wherein R2 is H or methyl.
28. The compound according to any one of claims 2 to 11, 13 to 21, 23 or 25, wherein R2 is H.
29. The compound according claim 1, 12, 22, 24, 26, or 27, wherein R4 and R5 are each independently H or Ci-6 alkyl; or
R4 and R5 together with the nitrogen atom to which they are both bonded form a C3-7 heterocyclyl or C5-I0 heterobicyclyl optionally substituted with 1 or 2 substituents selected independently from the group consisting OfC1-6 alkyl, halogen, hydroxyl, oxo and phenyl; and said C1-6 alkyl, is optionally substituted with 1 or 2 substituents selected independently from Ci-6 alkoxy and hydroxyl.
30. The compound according to any one of claims 2 to 11, 13 to 21, 23, 25, or 28, wherein R4 and R5 are each independently H or C1-6 alkyl; or
R4 and R5 together with the nitrogen atom to which they are both bonded form a C3-7 heterocyclyl or C5-10 heterobicyclyl optionally substituted with 1 or 2 substituents selected independently from the group consisting of Ci-6 alkyl, halogen, and hydroxyl; and said C1-6 alkyl, is optionally substituted with hydroxyl.
31. The compound according to any one of claims 1, 12, 22, 24, 26, 27, or 29, wherein R4 and R5 are each independently H, methyl or isopropyl.
32. The compound according to any one of claims 2 to 11, 13 to 21, 23, 25, 28, or 30, wherein R4 and R5 are each independently H or methyl.
33. The compound according to any one of claims 1, 12, 22, 24, 26, 27, 29, or 31, wherein R4 and R5 together with the nitrogen atom to which they are both bonded form a group selected from the group consisting of pyrrolidin-1-yl, 2-methyl-pyrrolidin-l-yl, 2- methyl-piperidin-1-yl, 4-methyl-piperazin-l-yl, 2,5-dimethyl-pyrrolidin-l-yl, dimethyl- amino, 2,2-dimethyl-pyrrolidin-l-yl, morpholin-4-yl, 2-hydroxymethyl-pyrrolidin-l-yl, 3-hydroxy-pyrrolidin-l-yl, 3,3-difluoro-pyrrolidin-l-yl, azetidin-1-yl, 3,3-difluoro- l rii i! il l"!! / »+»*'»-|l" / "w "' pϊpehd'm-1-yl, 2,3-dihydro-isoindol-2-yl, 3,4-dihydro-lH-isoquinolin-2-yl, 2,3-dihydro- indol-1-yl, 2-methoxymethyl-pyrrolidin-l-yl, 2-carbamoylpyrrolidin-l-yl, 2- (methylcarbamoyl)pyrrolidin-l-yl, piperidin-1-yl, 2-oxopyrrolidin-l-yl, 3- phenylpyrrolidin-1-yl, 2-isopropylpyrrolidin-l-yl, 2-trifluoromethylpyrrolidin-l-yl, and 2-phenylpyrrolidin-l-yl.
34. The compound according to any one of claims 2 to 11, 13 to 21, 23, 25, 28, 30, or 32, wherein R4 and R5 together with the nitrogen atom to which they are both bonded form a group selected from the group consisting of pyrrolidin-1-yl, 2-methyl-pyrrolidin-l-yl, 2- methyl-piperidin-1-yl, 4-methyl-piperazin-l-yl, 2,5-dimethyl-pyrrolidin-l-yl, dimethyl- amino, 2,2-dimethyl-pyrrolidin-l-yl, morpholin-4-yl, 2-hydroxymethyl-pyrrolidin-l-yl, 3-hydroxyl-pyrrolidin-l-yl, 3,3-difluoro-pyrrolidin-l-yl, azetidin-1-yl, 3,3-difluoro- piperidin-1-yl, 2,3-dihydro-isoindol-2-yl, 3,4-dihydro-lH-isoquinolin-2-yl, 2,3-dihydro- indol-1-yl, and amino.
35. The compound according to any one of claims 2 to 11, 13 to 21, 23, 25, 28, 30, 32, or 34, wherein Ar is 1,4-phenylene, 1,3-phenylene or 2,5-pyridinylene.
36. The compound according to claim 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof; wherein:
D is C(=O), OC(=O), NR6C(=O), S(O)2, or absent, wherein R6 is H or CH3;
G is CR7 or C, provided that when G is CR7 then - - is a single bond, wherein R3 is H and R7 is H or OH, and when G is C then - - is a double bond and R3 is absent;
R2 is H or methyl; E is -CH2- or -CH2CH2-;
J is O or absent;
K is -CH2CH2-;
R1 is selected from the group consisting of H, benzyl, cyclopropylmethyl, isobutyl, isopropyl, 4-trifluoromethoxy-benzyl, 2,4-dimethoxy-benzyl, cyclohexyl, cyclopentyl, methyl, ethyl, t-butyl, 4-methoxy-benzyl, 4-trifluoromethylbenzyl, cyclobutyl, 3-hydroxy-prop-2-yl, 4-hydroxy-benzyl, cyclopropyl, phenyl, pyridin-2-yl, hydroxymethyl, tetrahydro-furan-3-yl, tetrahydropyran-4-yl, pyridin-3-yl, pyrazin-2-yl, 2-fluoroethyl, trifluoromethyl, thiophen-2-ylmethyl, tetrahydropyran-4-ylmethyl, pyrimadin-5-yl, methoxymethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2- hydroxypropan-2-yl, cyclopentylmethyl, thiophen-2-yl, pyridin-4-yl, furan-2-yl, morpholin-4-yl, 3-formylphenyl, thiazol-2-yl, pyrimadin-2-yl, isoxazol-5-yl, 3,5- difluorophenyl, 3-cyanophenyl, 6-trifluoromethylpyridin-3-yl, and 6-cyanopyridin-3-yl; P C T / βS O E V'ffitlg'l, independently H, mΛyl or isopropyl; or
R4 and R5 together with the nitrogen atom to which they are both bonded form a group selected from the group consisting of pyrrolidin-1-yl, 2-methyl-pyrrolidin-l-yl, 2- methyl-piρeridin-1-yl, 4-methyl-piperazin-l-yl, 2,5-dimethyl-ρyrrolidin-l-yl, dimethyl- amino, 2,2-dimethyl-pyrrolidin-l -yl, morpholin-4-yl, 2-hydroxymethyl-pyrrolidin-l -yl,
3-hydroxy-pyrrolidih-l-yl, 3,3-difluoro-pyrrolidin-l-yl, azetidin-1-yl, 3,3-difluoro- piperidin-1-yl, 2,3-dihydro-isoindol-2-yl, 3,4-dihydro-lH-isoquinolin-2-yl, 2,3-dihydro- indol-1-yl, 2-methoxymethyl-pyrrolidin-l-yl, 2-carbamoylpyrrolidin-l-yl, 2- (methylcarbamoyl)pyrrolidin-l-yl, piperidin-1-yl, 2-oxopyrrolidin-l-yl, 3- phenylpyrrolidin-1-yl, 2-isopropylpyrrolidin-l-yl, 2-trifluoromethylpyrrolidin-l-yl, and
2-phenylpyrrolidin-l-yl; and
Ar is 1,4-phenylene, 1,3-phenylene or 2,5-pyridinylene.
37. The compound according to claim 2 having Formula (Iq):
Figure imgf000204_0001
(iq) or a pharmaceutically acceptable salt, hydrate or solvate thereof; wherein:
D is C(=O), OC(=O), NR6C(=O), or absent, wherein R6 is H or CH3;
G is CR7 or C, provided that when G is CR7 then - - is a single bond, wherein R3 is H and R7 is H or OH, and when G is C then - - is a double bond and R3 is absent;
E is -CH2- or -CH2CH2-;
J is O or absent;
K iS -CH2CH2-;
R1 is selected from the group consisting of H, benzyl, cyclopropylmethyl, isobutyl, isopropyl, 4-trifluoromethoxy-benzyl, 2,4-dimethoxy-benzyl, cyclohexyl, cyclopentyl, methyl, ethyl, t-butyl, 4-methoxy-benzyl, cyclobutyl, 3-hydroxy-ρrop-2-yl, 4-hydroxy-benzyl, cyclopropyl, phenyl, pyridin-2-yl, hydroxymethyl and tetrahydro- furan-3-yl;
R4 and R5 together with the nitrogen atom to which they are both bonded form a group selected from the group consisting of pyrrolidin-1-yl, 2-methyl-pyrrolidin-l-yl, 2- methyl-piperidin-1-yl, 4-methyl-piperazin-l-yl, 2,5-dimethyl-pyrrolidin-l-yl, dimethyl- ammo, 2,2-dimethyl-pyrrolidin-l -yl, morpholin-4-yl, 2-hydroxymethyl-pyrrolidin-l -yl,
3-hydroxyl-pyrrolidin-l-yl, 3,3-difluoro-pyrrolidin-l-yl, azetidin-1-yl, 3,3-difluoro- in. f "f / 1 J! Cu |"| |"i, / ψMHMK?' 1Ql
' "" ' ' "' p'ϊpeπαm-1-yl, 2,3-dihydro-isoindol-2-yl, 3,4-dihydro-lH-isoquinolin-2-yl, 2,3-dihydro- indol-1-yl, and amino; and
Ar is 1,4-phenylene, l,3-phenylene or 2,5-pyridinylene.
38. The compound according to claim 2 having Formula (Is):
Figure imgf000205_0001
(Is) or a pharmaceutically acceptable salt, hydrate or solvate thereof; wherein:
D is C(O), 0C(=0), or absent; R7 is H or OH;
J is O or absent; K is -CH2CH2-;
R1 is selected from the group consisting of H, benzyl, cyclopropylmethyl, isobutyl, isopropyl, 4-trifluoromethoxy-benzyl, 2,4-dimethoxy-benzyl, cyclohexyl, cyclopentyl, methyl, ethyl, t-butyl, 4-methoxy-benzyl, cyclobutyl, 3-hydroxy-prop-2-yl,
4-hydroxy-benzyl, cyclopropyl, hydroxymethyl and tetrahydro-furan-3-yl;
R4 and R5 together with the nitrogen atom to which they are both bonded form a group selected from the group consisting of pyrrolidin-1-yl and 2-methyl-pyrrolidin-l- yi; and
Ar is 1,4-phenylene or 2,5-pyridinylene.
39. The compound according to claim 2 having Formula (Iu):
Figure imgf000205_0002
(Iu) or ■ a pharmaceutically acceptable salt, hydrate or solvate thereof; wherein:
D is C(=O), OC(=O), NHC(=0), or absent;
J i ;s O or absent;
K is -CH2CH2-; o !|iiHi T / 1| I S ft IFi / NH1+ Ml- 7 '9 i! ' K is selected from the group consisting of H, benzyl, cyclopropylmethyl, isobutyl, isopropyl, 4-trifluoromethoxy-benzyl, 2,4-dimethoxy-benzyl, cyclohexyl, cyclopentyl, methyl, ethyl, 4-methoxy-benzyl, cyclobutyl, 3-hydroxy-prop-2-yl, 4- hydroxy-benzyl, cyclopropyl, phenyl, pyridin-2-yl, hydroxymethyl and tetrahydro- furan-3-yl;
R4 and R5 together with the nitrogen atom to which they are both bonded form a group selected from the group consisting of pyrrolidin-1-yl, 2-methyl-pyrrolidin-l-yl, 2- methyl-piperidin-1-yl, 4-methyl-piperazin-l-yl, 2,5-dimethyl-pyrrolidin-l-yl, dimethyl- amino, 2,2-dimethyl-pyrrolidin-l-yl, morpholin-4-yl, 2-hydroxymethyl-pyrrolidin-l-yl, 3-hydroxyl-pyrrolidin-l-yl, 3,3-difluoro-pyrrolidin-l-yl, azetidin-1-yl, 3,3-difluoro- piperidin-1-yl, 2,3-dihydro-isoindol-2-yl, 3,4-dihydro-lH-isoquinolin-2-yl, 2,3-dihydro- indol-1-yl, and amino; and
Ar is 1,4-phenylene, 1,3-phenylene or 2,5-pyridinylene.
40. The compound according to claim 2 having Formula (Iw):
Figure imgf000206_0001
(Iw) or a pharmaceutically acceptable salt, hydrate or solvate thereof; wherein:
D is C(=O) or NR6C(O), wherein R6 is H or CH3; R7 is H or OH;
J is absent; K is -CH2CH2-;
R1 is selected from the group consisting of H, isopropyl, cyclopentyl, methyl, or cyclopropyl; R4 and R5 together with the nitrogen atom to which they are both bonded form pyrrolidin-1-yl; and
Ar is 1,4-phenylene.
41. The compound according to claim 2 having Formula (Iy): pCT/USOB
Figure imgf000207_0001
(Iy) or a pharmaceutically acceptable salt, hydrate or solvate thereof; wherein:
D is C(=O) or NR6C(=0), wherein R6 is H or CH3; J is absent;
Figure imgf000207_0002
R1 is selected from the group consisting of H, benzyl, isopropyl, cyclopentyl, methyl, or cyclopropyl;
R4 and R5 together with the nitrogen atom to which they are both bonded form pyrrolidin-1-yl; and
Ar is 1,4-phenylene.
42. The compound according to claim 2, wherein said compound is selected from the group consisting of: 2-Benzyl-4-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-octahydro-cyclopenta[c]pyrrol-
4-ol;
2-Benzyl-4-{4-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-phenyl}-octahydro- cyclopenta[c]pyrrol-4-ol;
4-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-octahydro-cyclopenta[c]pyrrol-4-ol; 2-Cyclopropylmethyl-4-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-octahydro- cyclopenta[c]pyrrol-4-ol;
2-Isobutyl-4-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-octahydro- cyclopenta[c]pyrrol-4-ol;
2-Isopropyl-4-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-octahydro- cyclopenta[c]pyrrol-4-ol;
4-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-2-(4-trifluoromethoxy-benzyl)- octahydro-cyclopenta[c]pyrrol-4-ol;
2-(2,4-Dimethoxy-ben2yl)-4-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-octahydro- cyclopenta[c]pyrrol-4-ol; 2-Cyclohexyl-4-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-octahydro- cyclopenta[c]pyrrol-4-ol;
2-Cyclopentyl-4-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-octahydro- cyclopenta[c]pyrrol-4-ol; H-1E if'l IK1 ,•" IiA 11+ 11+ "7 Cfl '•ω! J'"'t !l"J^{4iHydrrøy4-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-hexahydro- cyclopenta[c]pyrrol-2-yl}-ethanone;
4-Hydroxy-4-[4-(2-pyrrolidin- 1 -yl-ethyl)-phenyl] -hexahydro- cyclopenta[c]ρyrrole-2-carboxylic acid ethyl ester; 4-Hydroxy-4-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-hexahydro- cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester;
2-Benzyl-4-[6-(2-pyrrolidin-l-yl-ethyl)-pyridin-3-yl]-octahydro- cyclopenta[c]pyrrol-4-ol;
2-Benzyl-4-[4-(2-pyrrolidin-l-yl-ethoxy)-phenyl]-octahydro- cyclopenta[c]pyrrol-4-ol;
2-Benzyl-4-[5 -(2-pyrrolidin- 1 -yl-ethyl)-pyridin-2-yl] -octahydro- cyclopenta[c]pyrrol-4-ol;
2-Benzyl-4-[4-(2-pyrrolidin- 1 -yl-ethyl)-phenyl] -octahydro- cyclopenta[c]pyrrole; 4-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-octariydro-cyclopenta[c]pyrrole;
2-Cyclopropylmethyl-4-[4-(2-pyrrolidin-l-yl-ethyl)-plienyl]-octahydro- cyclopenta[c]pyrrole;
2-Isopropyl-4-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-octahydro- cyclopenta[c]pyrrole; 2-Cyclopentyl-4-[4-(2-pyrrolidin- 1 -yl-ethyl)-phenyl] -octahydro- cyclopenta[c]pyrrole;
2-(2,4-Dimethoxy-benzyl)-4-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-octahydro- cyclopenta[c]pyrrole;
2-Cyclohexyl-4-[4-(2-pyrrolidin-l -yl-ethyl)-phenyl] -octahydro- cyclopenta[c]pyrrole;
4-{4-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-hexahydro-cyclopenta[c]pyrrol-2- ylmethyl} -phenol;
2-Cyclobutyl-4-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-octahydro- cyclopenta[c]pyrrole; 2-{4-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-hexahydro-cyclopenta[c]pyrrol-2-yl}- propan-1-ol;
2-Isobutyl-4-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-octahydro- cyclopenta[c]pyrrole;
2-(4-Methoxy-benzyl)-4-[4-(2-pyrrolidin- 1 -yl-ethyl)-phenyl] -octahydro- cyclopenta[c]pyrrole;
4-[4-(2-Pyrrolidin- 1 -yl-ethyl)-phenyl] -2-(4-trifluoromethoxy-benzyl)- octahydro-cyclopenta[c]pyrrole; !Ϊ:;:H I C1 / l!.|,,l!,,|,l|..7 C CJl rblidin-l-yl-ethyl)-phenyl]-hexahydro-cyclopenta[c]pyrrol-2- ylmethyl } -phenol; l-{4.[4.(2-Pyrrolidm-l-yl-ethyl)-phenyl]-hexahydro-cyclopenta[c]pyrrol-2-yl}- ethanone; 2-Methyl-l-{4-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-hexahydro- cyclopenta[c]pyrrol-2-yl}-propan-l-one;
Cyclopropyl- {4-[4-(2-pyrrolidin- 1 -yl-ethyl)-phenyl] -hexahydro- cyclopenta[c]pyrrol-2-yl}-methanone;
Cyclopentyl-{4-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-hexahydro- cyclopenta[c]pyrrol-2-yl} -methanone;
4-[4-(2-Pyrrolidin-l-yl-ethyl)-plienyl]-hexahydro-cyclopenta[c]pyrrole-2- carboxylic acid ethyl ester;
2-Hydroxy- 1 - {4-[4-(2-pyrrolidin- 1 -yl-ethyl)-phenyl] -hexahydro- cyclopenta[c]pyrrol-2-yl}-ethanone; 6-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-l,2,3,3a,4,6a-hexahydro- cyclopenta[c]pyrrole;
2-Benzyl-6-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-l,2,3,3a,4,6a-hexahydro- cyclopenta[c]pyrrole;
2-Benzyl-6-{4-[2-(2-methyl-piperidin-l-yl)-ethyl]-phenyl}-l,2,3,3a,4,6a- hexahydro-cyclopenta[c]pyrrole;
2-Benzyl-6-{4-[2-(4-methyl-piperazin-l -yl)-ethyl]-phenyl} -1 ,2,3,3a,4,6a- hexahydro-cyclopenta[c]pyrrole;
2-Benzyl-6-{4-[2-(2,5-dimethyl-pyrrolidin-l-yl)-ethyl]-phenyl}-l,2,3,3a,4,6a- hexahydro-cyclopenta[c]pyrrole; {2-[4-(2-Benzyl-l,2,3,3a,6,6a-hexahydro-cyclopenta[c]pyrrol-4-yl)-phenyl]- ethyl} -dimethyl-amine;
2-Benzyl-6-{4-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-phenyl}-l,2,3,3a,4,6a- hexahydro-cyclopenta[c]pyrrole;
2-Benzyl-6-{4-[2-(2,2-dimethyl-pyrrolidin-l-yl)-ethyl]-phenyl}-l,2,3,3a,4,6a- hexahydro-cyclopenta[c]pyrrole;
2-Benzyl-6-[4-(2-morpholin-4-yl-ethyl)-phenyl]-l,2,3,3a,4,6a-hexahydro- cyclopenta[c]pyrrole;
(l-{2-[4-(2-Benzyl-l,2,3,3a,6,6a-hexahydro-cyclopenta[c]pyrrol-4-yl)-phenyl]- ethyl} -pyrrolidin-2-yl)-methanol; l-{2-[4-(2-Benzyl-l,2,3,3a,6,6a-hexahydro-cyclopenta[c]pyrrol-4-yl)-phenyl]- ethyl } -pyrrolidin-3 -ol; ' U "!2-Berizyl-6-t4-f2-(3;3-difluoro-pyrrolidm-l-yl)-ethyl3-phenyl}-l,2,3,3a;4,6a- hexahydro-cyclopenta[c]pyrrole;
6-[4-(2-Azetidin-l-yl-ethyl)-phenyl]-2-benzyl-l,2,3,3a,4,6a-hexahydro- cyclopenta[c]pyrrole; 2-Benzyl-6-{4-[2-(3,3-difluoro-ρiperidm-l-yl)-ethyl]-phenyl}-l,2,353a,4,6a- hexahydro-cyclopenta[c]pyrrole;
2-{2-[4-(2-Benzyl-l,2,3,3a,6,6a-hexahydro-cyclopenta[c]pyrrol-4-yl)-phenyl]- ethyl}-2,3-dihydro-lH-isoindole;
2-{2-[4-(2-Benzyl-l,2,3,3a,6,6a-hexahydro-cyclopenta[c]pyrrol-4-yl)-phenyl]- ethyl} - 1,2,3 ,4-tetrahydro-isoquinoline; l-{2-[4-(2-Benzyl-l,2,3,3a,6,6a-hexahydro-cyclopenta[c]pyrrol-4-yl)-phenyl]- ethyl} -2,3-dihydro-lH-indole;
2-Cyclopropylmethyl-6-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-l,2,3,3a,4,6a- hexahydro-cyclopenta[c]pyrrole; 2-Cyclopentyl-6-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-l,2,3,3a,4,6a-hexahydro- cyclopenta[c]pyrrole;
2-(4-Methoxy-benzyl)-6-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-l,2,3,3a,4,6a- hexahydro-cyclopenta[c]pyrrole;
2-Isopropyl-6-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-l,2,3,3a,4,6a-hexahydro- cyclopenta[c]pyrrole;
2-Cyclobutyl-6-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-l,2,3,3a,4,6a-hexahydro- cyclopenta[c]pyrrole;
2-{6-[4-(2-Pyrrolidin-l-yl-ethyl)-p]ienyl]-3,3a,4,6a-tetraliydro-lH- cyclopenta[c]pyrrol-2-yl} -propan- 1 -ol; 4-{6-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-3,3a,4,6a-tetrahydro-lH- cyclopenta[c]pyrrol-2-ylmethyl}-phenol;
2-Cyclohexyl-6-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-l,2,3,3a,4,6a-hexahydro- cyclopenta[c]pyrrole;
2-Methyl-6-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-l,2,3,3a,4,6a-hexahydro- cyclopenta[c]pyrrole;
2-Isobutyl-6-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-l,2,3,3a,4,6a-hexahydro- cyclopenta[c]pyrrole;
2-(2,4-Dimethoxy-ben2yl)-6-[4-(2-pyrrolidm-l-yl-ethyl)-phenyl]-l,2,3,3a,4,6a- hexahydro-cyclopenta[c]pyrrole; 6-[4-(2-Pyrrolidin-l -yl-ethyl)-phenyl] -2-(4-trifluoromethoxy-benzyl)- l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole; "■ ' "' " CyclopropCl-{6-[4-(2-pyrrolidm-l-yl-ethyl)-plienyl]-3,3a,4,6a-tetrahydro-lH- cyclopenta[c]pyrrol-2-yl}-methanone;
2-Methyl-l-{6-[4-(2-pyrrolidin-l-yl-ethyl)-ρhenyl]-3,3a,4,6a-tetrahydro-lH- cyclopenta[c]pyrrol-2-yl} -propan-1 -one; Cyclopentyl- {6-[4-(2-pyrrolidin-l -yl-ethyl)-phenyl]-3,3a,4,6a-tetrahydro~lH- cyclopenta[c]pyrrol-2-yl}-methanone;
6-[4-(2-Pyrrolidin-l-yl-ethyl)-ρhenyl]-3,3a,4,6a-tetrahydro-lH- cyclopenta[c]pyrrole-2-carboxylic acid ethyl ester;
6-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-3,3a,4,6a-tetrahydro-lH- cyclopenta[c]pyrrole-2-carboxylic acid isopropylamide;
6-[4-(2-Pyrrolidin-l-yl-ethyl)-plienyl]-3,3a,4,6a-tetrahydro-lH- cyclopenta[c]pyrrole-2-carboxylic acid cyclopentylamide;
2-Pyridin-2-yl-6-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-l,2,3,3a,4,6a-hexahydro- cyclopenta[c]pyrrole; 2-Hydroxy-l-{6-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-3,3a,4,6a-tetrahydro-lH- cyclopenta[c]pyrrol-2-yl}-ethanone;
2-[4-(2-Benzyl-l,2,3,3a,6,6a-hexahydro-cyclopenta[c]pyrrol-4-yl)-phenyl]- ethylamine;
2-Benzyl-6-[6-(2-pyrrolidin-l-yl-ethyl)-pyridin-3-yl]-l,2,3,3a,4,6a-hexahydro- cyclopenta[c]pyrrole;
2-Benzyl-6-[4-(2-pyrrolidm-l-yl-ethoxy)-phenyl]-l,2,3,3a,4,6a-hexahydro- cyclopenta[c]pyrrole;
2-Benzyl-6-[3-(2-pyrrolidin-l-yl-ethoxy)-phenyl]-l,2,3,3a,4,6a-hexaliydro- cyclopenta[c]pyrrole; 2-Benzyl-6-[5-(2-pyrrolidin-l-yl-ethyl)-pyridin-2-yl]-l,2,3,3a,4,6a-hexahydro- cyclopenta[c]pyrrole; l-{6-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-3,3a,4,6a-tetraliydro-m- cyclopenta[c]pyrrol-2-yl}-ethanone;
(6-{4-[2-(2-Methyl-pyrrolidin-l-yl)-ethyl]-phenyl}-3,3a,4,6a-tetrahydro-lH- cyclopentafcjpyrrol^-y^-^etrahydro-furan-S -yl)-methanone;
2-Ben2yl-7-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-2,3,3a,4,5,7a-hexahydro-lH- isoindole;
7-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-2,3,3a,4,5,7a-hexahydro-lH-isoindole; l-{7-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-l,3,3a,4,5,7a-hexahydro-isoindol-2- yl}-ethanone;
2-Methyl-l-{7-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-l,3,3a,4,5,7a-hexahydro- isoindol-2-yl } -propan-1 -one; n Ii'"" "1Ii"1 / 1 i «5 in IR / H..|l« 8.11» IMI- "7 '»»11
""' llra" " " Cyclopropyl-{7-[4-(2-pyrrolidm-l-yl-ethyl)-phenyl]-l,3,3a,4,5,7a-hexahydro- isoindol-2-yl} -methanone;
7-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-l,3,3a,4,5,7a-hexahydro-isoindole-2- carboxylic acid dimethylamide; 7-[4-(2-Pyrrolidin-l -yl-ethyl)-phenyl]-l ,3,3a,4,5,7a-hexahydro-isoindole-2- carboxylic acid isopropylamide;
7-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-l,3,3a,4,5,7a-hexahydro-isoindole-2- carboxylic acid cyclopentylamide;
4-[4-(2-Pyrrolidin- 1 -yl-ethyl)-phenyl] -octahydro-isoindole; l-{4-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-octahydro-isoindol-2-yl}-et]ianone;
2-Methyl-l-{4-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-octahydro-isoindol-2-yl}- propan-1-one;
Cyclopropyl-{4-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-octahydro-isoindol-2-yl}- methanone; 4-[4-(2-Pyrrolidin- 1 -yl-emyty-phenylj-octahydro-isoindole-^-carboxylic acid dimethylamide;
4-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-octahydro-isoindole-2-carboxylic acid isopropylamide; and
4-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-octahydro-isoindole-2-carboxylic acid cyclopentylamide; or a pharmaceutically acceptable salt, hydrate or solvate thereof.
43. The compound according to claim 1, wherein said compound is selected from the group consisting of: 2-(4-Methoxy-benzyl)-4-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-octahydro- cyclopenta[c]pyrrol-4-ol;
4-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-2-(4-trifluoromethyl-benzyl)-octahydro- cyclopenta[c]pyrrol-4-ol;
2-Methyl-4-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-octahydro-cyclopenta[c]pyrrol- 4-ol;
2-Ethyl-4-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-octahydro-cyclopenta[c]pyrrol-4- ol;
2-Cyclobutyl-4-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-octahydro- cyclopenta[c]pyrrol-4-ol; 2-Benzyl-4-[3-(2-pyrrolidin-l-yl-ethoxy)-phenyl]-octahydro- cyclopenta[c]pyrrol-4-ol; 4-4-(2-Pyrrolidin-1
Figure imgf000213_0001
-yl-ethyl)-phenyl-2-(4-trifluoromethyl-benzyl)-octahydro- cyclopenta[c]pyrrole;
2-Methyl-4-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-octahydro- cyclopenta[c]pyrrole; 2-Ethyl-4-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-octahydro-cyclopenta[c]pyrrole;
(4-{4-[2-(2-Methyl-pyrrolidin-l-yl)-etliyl]-phenyl}-hexahydro- cyclopenta[c]pyrrol-2-yl)-(tetrahydro-furan-3-yl)-methanone;
Cyclopropyl-(4-{4-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-phenyl}-hexahydro- cyclopenta[c]pyrrol-2-yl)-methanone; (4-{4-[2-(2-Methyl-pyrrolidin-l-yl)-ethyl]-phenyl}-hexahydro- cyclopenta[c]pyrrol-2-yl)-tetrahydro-pyran-4-yl)-metlianone;
2-Methyl-l -(4- {4-[2-(2-methyl-pyrrolidin-l -yl)-ethyl]-phenyl} -hexahydro- cyclopenta[c]pyrrol-2-yl)-propan-l-one;
Cyclopentyl-(4- {4-[2-(2-methyl-pyrrolidin-l -yl)-ethyl]-phenyl} -hexahydro- cyclopenta[c]pyrrol-2-yl)-methanone;
(4-{4-[2-(2-Methyl-pyrrolidin-l-yl)-ethyl]-phenyl}-hexahydro- cyclopenta[c]pyrrol-2-yl)-pyridm-3-yl-metlianone;
(4- {4-[2-(2-Methyl-pyrrolidin- 1 -yl)-ethyl] -phenyl} -hexahydro- cyclopenta[c]pyrrol-2-yl)-pyrazin-2-yl-methanone; Cyclohexyl-(4-{4-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-phenyl}-hexaliydro- cyclopenta[c]pyrrol-2-yl)-methanone;
2-(2-Fluoro-ethyl)-4-{4-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-phenyl}- octahydro-cyclopenta[c]pyrrole;
3-Methyl-l-(4-{4-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-phenyl}-hexahydro- cyclopenta[c]pyrrol-2-yl)-butan-l -one;
2,2,2-Trifluoro-l-(4-{4-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-phenyl}- hexahydro-cyclopenta[c]pyrrol-2-yl)-ethanone; l-(4-{4-[2-(2-Methyl-pyrrolidin-l-yl)-ethyl]-phenyl}-hexahydro- cyclopenta[c]pyrrol-2-yl)-2--thiophen-2-yl-ethanone; Cyclopentyl-(5-methyl-4-{4-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-plienyl}- hexahydro-cyclopenta[c-pyrrol-2-yl)-methanone;
2,2-Dimethyl-l-(4-{4-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-phenyl}-hexaliydro- cyclopenta[c]pyrrol-2-yl)-propan- 1 -one; l-(4-{4-[2-(2-Methyl-pyrrolidin-l-yl)-ethyl]-phenyl}-hexahydro- cyclopenta[c]pyrrol-2-yl)-ethanone;
1 -(4- {4-[2-(2-Methyl-pyrrolidin-l -yl)-ethyl]-phenyl} -hexahydro- cyclopenta[c]pyrrol-2-yl)-2-phenyl-ethanone; 1-(4-{4-[2-(2-Methyl-pyrrolidin-l-yl)-etliyl]-phenyl}-hexahydro- cyclopenta[c]pyrrol-2-yl)-2-(tetrahydro-pyran-4-yl)-ethanone;
(4-{4-[2-(2-Methyl-pyrrolidin-l-yl)-ethhl]-phenyl}-hexahydro- cyclopenta[c]pyrrol-2-yl)-pyrimidin-5-yl-methanone; 2-Methoxy-l -(4- {4-[2-(2-methyl-pyrrolidin-l -yl)-ethyl]-phenyl} -hexahydro- cyclopenta[c]pyrrol-2-yl)-ethanone;
2-(2,2-Difluoro-ethyl)-4-{4-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-phenyl}- octahydro-cyclopenta[c]pyrrole;
(4- {4-[2-(2-Methyl-pyrrolidin- 1 -yl)-ethyl] -phenyl} -hexahydro- cyclopenta[c]pyrrol-2-yl)-phenyl-methanone;
4-{4-[2-(2-Methyl-pyrrolidin-l-yl)-ethyl]-phenyl}-2-(2,2,2-trifluoro-ethyl)- octahydro-cyclopenta[c]pyrrole;
(4-{4-[2-(2-Hydroxymethyl-pyrrolidin-l-yl)-ethyl]-phenyl}-hexahydro- cyclopenta[c]pyrrol-2-yl)-(tetrahydro-pyran-4-yl)-methanone; (4-{4-[2-(2-Methoxymethyl-pyrrolidin-l-yl)-ethyl]-phenyl}-hexahydro- cyclopenta[c]pyrrol-2-yl)-(t etrahydro-pyran^-y^-methanone;
1 -(2- {4-[2-(Tetrahydro-pyran-4-carbonyl)-octahydro-cyclopenta[c]pyrrol-4-yl] - phenyl} -ethyl)-pyrrolidine-2-carboxylic acid amide; l-(2-{4-[2-(Tetrahydro-pyran-4-carbonyl)-octahydro-cyclopenta[c]pyrrol-4-yl]- phenyl} -ethyl)-pyrrolidine-2-carboxylic acid methylamide;
{4-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-hexahydro-cyclopenta[c]pyrrol-2-yl}- (tetrahydro-pyran-4-yl)-methanone;
{4-[4-(2-Piperidin-l-yl-ethyl)-phenyl]-hexahydro-cyclopenta[c]pyrrol-2-yl}- (tetrahydro-pyran-4-yl)-methanone; {4-[4-(2-Diisopropylamino-ethyl)-phenyl]-hexahydro-cyclopenta[c]pyrrol-2- yl } -(tetrahydro-pyran-4-yl)-methanone;
{4-[4-(2-Morpholin-4-yl-ethyl)-phenyl]-hexahydro-cyclopenta[c]pyrrol-2-yl}- (tetrahydro-pyran-4-yl)-methanone;
(4- {4-[2-(3 -Hydroxy-pyrrolidin-1 -yl)-ethyl]-phenyl} -hexahydro- cyclopenta[c]pyrrol-2-yl)-(tetrahydro-pyran-4-yl)-methanone;
(4-{4-[2-(3,3-Difluoro-pyrrolidin-l-yl)-ethyl]-phenyl}-hexahydro- cyclopenta[c]pyrrol-2-yl)-(tetrahydro-pyran-4-yl)-methanone;
4-(2-Benzyl-l,2,3,3a,6,6a-hexahydro-cyclopenta[c]pyrrol-4-yl)-N-methyl- benzamide; Cyclopentyl-(5-methyl-6-{4-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-phenyl}-
3,3a,4,6 a-tetrahydro-lH-cyclopenta[c-pyrrol-2-yl)-methanone;
4-(2-Benzyl-l,2,3,3a,6,6a-hexahydro-cyclopenta[c]pyrrol-4-yl)-benzylamine; 3-(2-Benzyl-1,2,3,3a,6,6a-hexahydro-cyclopenta[c]pyrrol-4yl)-benzylamine;
2-Benzyl-6-[4-(2-piperidin-l-yl-ethyl)-phenyl]-l,2,3,3a,4,6a-hexahydro- cyclopenta[c]pyrrole;
2-Ethyl-6-[4-(2-pyrrolidm-l-yl-ethyl)-phenyl]-l,2,3,3a,4,6a-hexahydro- cyclopenta[c]pyrrole;
2-Hydroxy-2-methyl-l-{6-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-3,3a,4,6a- tetrahydro- 1 H-cyclopenta[c]pyrrol-2-yl } -propan- 1 -one;
2-Phenyl-6-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-l,2,3,3a,4,6a-hexahydro- cyclopenta[c]pyrrole; 6-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-3,3a,4,6a-tetrahydro-lH- cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide;
2-Cyclopentylmethyl-6-[4-(2-pyrrolidin-l-yl-etliyl)-phenyl]-l,2,3,3a,4,6a- hexahydro-cyclopenta[c]pyrrole;
{6-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-3,3a,4,6a-tetrahydro-lH- cyclopenta[c]pyrrol-2-yl} -thiophen-2-yl-methanone;
2-Pyridm-3-yl-6-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-l,2,3,3a,4,6a-hexahydro- cyclopenta[c]pyrrole;
2-Pyridin-4-yl-6-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-l,2,3,3a,4,6a-hexahydro- cyclopenta[c]pyrrole; F uran-2-yl-{6-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-3,3a,4,6a-tetrahydro-lH- cyclopenta[c]pyrrol-2-yl}-methanone;
Morpholin-4-yl-{6-[4-(2-pyrrolidm-l-yl-ethyl)-phenyl]-3,3a,4,6a-tetrahydro- lH-cyclopenta[c]pyrrol-2-yl}-methanone;
2-(3-Methoxy-phenyl)-6-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-l,2,3,3a,4,6a- hexahydro-cyclopenta[c]pyrrole;
6-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-2-thiazol-2-yl-l,2,3,3a,4,6a-hexahydro- cyclopenta[c]pyrrole;
Pyridin-3-yl-{6-[4-(2-pyrrolidm-l-yl-ethyl)-phenyl]-3,3a,4,6a-tetrahydro-lH- cyclopenta[c]pyrrol-2-yl}-methanone; Pyridin-2-yl-{6-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-3,3a,4,6a-tetrahydro-lH- cyclopenta[c]pyrrol-2-yl}-methanone;
Cyclohexyl- {6-[4-(2-pyrrolidin- 1 -yl-ethyl)-phenyl]-3 ,3 a,4,6a-tetrahydro- 1 H- cyclopenta[c]pyrrol-2-yl}-2-yl-2-yl-m( ethanone;
{6-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-3,3a,4,6a-tetrahydro-lH- cyclopenta[c-pyrrol-2-yl}-(etrahydro-furan-3-yl)-methanone;
2-Pyrazin-2-yl-6-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-l,2,3,3a,4,6a-hexahydro- cyclopenta[c]pyrrole; Phenyl-[6-[4-(2 -pyrrolidin-l-yl-ethyl-phenyl]6--3,3a4,6a-tetrahydro-1H- cyclopenta[c]pyrrol-2-yl}-methanone;
2-Phenyl-1-{6-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl]-3,3a,4,6a-tetrahydro-1H- cyclopenta[c]pyrrol-2~yl}-ethanone; Pyrazin-2-yl-{6-[4-(2-pyrrolidm-l-yl-ethyl)-ρhenyl]-3,3a,4,6a-tetrahydro-1H- cyclopenta[c]pyrrol-2-yl}-methanone;
2-Pyrimidm-2-yl-6-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-l,2,3,3a,4,6a- hexahydro-cyclopenta[c]pyrrole;
2-Methyl-l -(6- {4-[2-(3-phenyl-ρyrrolidin- 1 -yl)-ethyl]-phenyl} -3 ,3 a,4,6a- tetrahydro-lH-cyclopenta[c]pyrrol-2-yl) -propan-l-one; l-(6-{4-[2-(2-Isopropyl-pyrrolidin-l-yl)-ethyl]-phenyl}-3,3a,4,6a-tetrahydro- lH-cyclopenta[c]pyrrol-2-yl)-2--methyl-propan-l-one;
2-Benzyl-6-{4-[2-(2-trifluoromethyl-pyrrolidin-l-yl)-ethyl]-phenyl}- l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole; 2-Methyl-l-(6-{4-[2-(2-phenyl-pyrrolidin-1-yl)-ethyl]-phenyl}-3,3a,4,6a- tetrahydro-lH-cyclopenta[c]pyrrol-2-yl)-propan-l-one;
2-Methyl-l-(6-{4-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-phenyl}-3,3a,4,6a- tetrahydro-lH-cyclopenta[c]pyrrol-2-yl )--propan-l-one;
Isoxazol-5-yl-{6-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl]-3,3a,4,6a-tetrahydro-1H- cyclopenta[c]pyrrol-2-yl} -methanone;
2-Pyridin-3-yl-1-{6-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl]-3,3a,4,6a-tetrahydro- lH-cyclopenta[c]pyrrol-2-yl}-ethanone;
2-Pyridin-2-yl-1-{6-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-3,3a;4,6a-tetrahydro- lH-cyclopenta[c]pyrrol-2-yl}-ethanone; 1-(6-{4-[2-(2-Hydroxymethyl-pyrrolidin-l-yl)-ethyl]-phenyl}-3,3a,4,6a- tetrahydro-lH-cyclopenta[c]pyrrol-2-yl)-2-methyl-propan-l-one;
2-Pyridin-4-yl-1-{6-[4-(2-pyrrolidin-l-yl-etliyl)-phenyl]-3,3a,4,6a-tetrahydro- lH-cyclopenta[c]pyrrol-2-yl}-ethanone;
2-Pyrimidm-5-yl-6-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-1,2,3,3a,4,6a- hexahydro-cyclopenta[c]pyrrole;
Cyclopropyl-(6-{4-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-phenyl}-3,3a,4,6a- tetrahydro-lH-cyclopenta[c]pyrrol-2-yl)-methanone;
(6-{4-[2-(2-Methyl-pyrrolidin-l-yl)-ethyl]-phenyl}-3,3a:,4,6a-tetrahydro-1H- cyclopenta[c]pyrrol-2-yl)-pyridin-3-yl-methanone; Cyclopentyl-(6-{4-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-phenyl}-3,3a,4,6a- tetrahydro-lH-cyclopenta[c]pyrrol-2-yl)--methanone; '1-(6-1-(6-}4-[2-Methyl-pyrrolidin-l-yl)-ethyl]-phenyl}-3,3a,4,6a-tetrahydro-m- cyclopenta[c]pyrrol-2-yl)-2-phenyl-ethanone;
2-(3,5-Difluoro-phenyl)-6-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-l,2,3,3a,4,6a- hexahydro-cyclopenta[c]pyrrole; 3-{6-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-3,3a,4,6a-tetrahydro-m- cyclopenta[c]pyrrol-2-yl}-benzonitrile; l-(6-{4-[2-(2,5-Dimethyl-pyrrolidin-l-yl)-ethyl]-phenyl}-3,3a,4,6a-tetrahydro- lH-cyclopentafcJpyrrol^-y^^-methyl-propan-l-one;
(6-{4-[2-(2-Methyl-pyrrolidin-l-yl)-ethyl]-phenyl}-3,3a,4,6a-tetrahydro-lH- cyclopenta[c]pyrrol-2-yl)-phenyl-methanone;
6-{4-[2-(2-Methyl-pyrrolidin-l-yl)-ethyl]-phenyl}-2-(6-trifluoromethyl-pyridm- 3-yl)-1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole;
5-(6-{4-[2-(2-Methyl-pyrrolidin-l-yl)-ethyl]-phenyl}-3,3a,4,6a-tetrahydro-lH- cyclopenta[c]pyrrol-2-yl)-pyridine-2-carbonitrile; (6-{4-[2-(2-Methyl-pyrrolidin-l-yl)-etliyl]-phenyl}-3,3a,4,6a-tetrahydro-lH- cyclopenta[c]pyrrol-2-yl)-(tetrahydro-pyran-4-yl)-methanone;
2-Benzyl-5-methyl-6-{4-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-phenyl}- 1,2,3 ,3a,4,6a-hexahydro-cyclopenta[c]pyrrole;
2-Benzyl-6-[4-(2-methyl-pyrrolidin-l-ylmethyl)-phenyl]-l,2,3,3a,4,6a- hexahydro-cyclopenta[c]pyrrole;
6-{4-[2-(2-Methyl-pyrrolidin-l-yl)-ethyl]-phenyl}-3,3a,4,6a-tetrahydro-lH- cyclopenta[c]pyrrole-2-carboxylic acid ethyl ester;
Pyridin-4-yl-{6-[4-(2-pyrrolidm-l-yl-ethyl)-phenyl]-3,3a,4,6a-tetrahydro-lH- cyclopenta[c]pyrrol-2-yl}-methanone; {7-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-l,3,3a,4,5,7a-hexahydro-isoindol-2-yl}-
(tetrahydro-furan-3 -yl)-methanone;
Pyridin-3-yl-{7-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-l,3,3a,4,5,7a-hexahydro- isoindol-2-yl} -methanone; l-(7-{4-[2-(2-Methyl-pyrrolidin-l-yl)-ethyl]-phenyl}-l,3,3a,4,5,7a-hexahydro- isoindol-2-yl)-ethanone;
2-Methyl-l-(7-{4-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-phenyl}-l,3,3a,4,5,7a- hexahydro-isoindol-2-yl)-propan-l-one;
Cyclopropyl-(7-{4-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-phenyl}-l,3,3a,4,5,7a- hexahydro-isoindol-2-yl)-methanone; Cyclopentyl-(7-{4-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-phenyl}-l,3,3a,4,5,7a- hexahydro-isoindol-2-yl)-methanone; 1-(7-{4-[2-(2-Methyl-pyrrolidin-1-yl)-ethyl-phenyl}-1,3,3a,4,5,7a-hexahydro- isoindol-2-yl)-2~phenyl-ethanone;
(7-{4-[2-(2-Methyl-pyrrolidin-l-yl)-ethyl]-phenyl}-l,3,3a,4,5,7a-hexahydro- isoindol-2-yl)-(tetrahydro-furan-3-yl)-methanone; 2-Ben2yl-7-{4-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-phenyl}-2,3,3a,4,5,7a- hexahydro-lH-isoindole;
{4-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-octahydro-isoindol-2-yl}-(tetrahydro- furan-3 -yl)-methanone;
1 -(4- {4-[2-(2-Methyl-pyrrolidin-l -yl)-ethyl]-phenyl} -octahydro-isoindol-2-yl)- ethanone;
(4-{4-[2-(2-Methyl-pyrrolidin-l-yl)-ethyl]-phenyl}-octahydro-isoindol-2-yl)- (tetrahydro-ftiran-3 -yl)-methanone;
2-Methyl-l-(4-{4-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-phenyl}-octahydro- isoindol-2-yl)-propan-l -one; Cyclopentyl-(4-{4-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-phenyl}-octahydro- isoindol-2-yl)-methanone;
(4-{4-[2-(2-Metliyl-pyrrolidin-l-yl)-ethyl]-phenyl}-octaliydro-isoindol-2-yl)- (tetrahydro-pyran-4-yl)-methanone; l-{2-[4-(2-Benzyl-l,2,3,3a,6,6a-hexahydro-cyclopenta[c]pyrrol-4-yl)-phenyl]- ethyl} -pyrrolidin-2-one;
3-{6-[4-(2-Pyrrolidin-l-yl-ethyl)-phenyl]-3,3a,4,6a-tetrahydro-lH- cyclopenta[c]pyrrol-2-yl}-benzaldehyde;
2-Methanesulfonyl-6-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-l,2,3,3a,4,6a- hexahydro-cyclopenta[c]pyrrole; 2-(Propane-2-sulfonyl)-6-[4-(2-pyrrolidin-l -yl-ethyl)-phenyl]-l ,2,3,3a,4,6a- hexahydro-cyclopenta[c]pyrrole;
2-Benzenesulfonyl-6-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-l,2,3,3a,4,6a- hexahydro-cyclopenta[c]pyrrole;
2-Phenylmethanesulfonyl-6-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-l,2,3,3a,4,6a- hexahydro-cyclopenta[c]pyrrole;
2-Ethanesulfonyl-6-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-l,2,3,3a,4,6a- hexahydro-cyclopenta[c]pyrrole;
2-Cyclopropanesulfonyl-6-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-l,2,3,3a,4,6a- hexahydro-cyclopenta[c]pyrrole; 2-Cyclopropanesulfonyl-6-{4-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-phenyl}- l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole; IP C IF / W& O ^^^f^ l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole;
2-(Propane-2-sulfonyl)-7-[4-(2-pyrrolidin-l-yl-ethyl)-phenyl]-2,3,3a,4,5,7a- hexahydro-lH-isoindole; and 2-Cyclopropanesulfonyl-7-[4-(2-pyrrolidm-l-yl-ethyl)-phenyl]-2,3,3a,4,5,7a- hexahydro-lH-isoindole; or a pharmaceutically acceptable salt, hydrate or solvate thereof.
44. A pharmaceutical composition comprising a compound according to any one of claims 1 to 43 and a pharmaceutically acceptable carrier.
45. A method for treating a 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 43 or a pharmaceutical composition according to claim 44.
46. The method according to claim 45, wherein said H3-receptor associated disorder is selected from the group consisting of cognitive disorders, epilepsy, depression, narcolepsy, obesity, motion sickness, vertigo, a sleep/wake disorder, insomnia, jet lag, sleep apnea, attention deficit hyperactivity disorder (ADHD), schizophrenia, allergies, allergic responses in the upper airway, allergic rhinitis, bipolar disorders, manic disorders, neurogenic inflammation, migraine, eating disorders, dementia, and Alzheimer's disease.
47. The method according to claim 45, wherein said H3-receptor associated disorder is a sleep/wake disorder.
48. 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 43 or a pharmaceutical composition according to claim 44.
49. Use of a compound according to any one of claims 1 to 43 for production of a medicament for use in the treatment of a H3 -receptor associated disorder.
50. The use according to claim 49, wherein said H3-receptor associated disorder is selected from the group consisting of cognitive disorders, epilepsy, depression, narcolepsy, obesity, motion sickness, vertigo, a sleep/wake disorder, insomnia, jet lag, sleep apnea, in, r - 1T / It lϊ 1R 111 IR ■■■" fcP-P|..'7 «'."!
Il «,„, ii , '-'atffeήϊion 'deficit hyperactivity disorder (ADHD), schizophrenia, allergies, allergic responses in the upper airway, allergic rhinitis, bipolar disorders, manic disorders, neurogenic inflammation, migraine, eating disorders, dementia, and Alzheimer's disease.
51. The use according to claim 49, wherein said H3 -receptor associated disorder is a sleep/wake disorder.
52. Use of a compound according to any one of claims 1 to 43 for production of a medicament for use in inducing wakefulness.
53. A compound according to any one of claims 1 to 43 for use in a method of treatment of the human or animal body by therapy.
54. A compound according to any one of claims 1 to 43 for use in a method for the treatment of a H3 -receptor associated disorder in the human or animal body by therapy.
55. A compound according to any one of claims 1 to 43 for use in a method for the treatment of a H3-receptor associated disorder is selected from the group consisting of cognitive disorders, epilepsy, depression, narcolepsy, obesity, motion sickness, vertigo, a sleep/wake disorder, insomnia, jet lag, sleep apnea, attention deficit hyperactivity disorder (ADHD), schizophrenia, allergies, allergic responses in the upper airway, allergic rhinitis, bipolar disorders, manic disorders, neurogenic inflammation, migraine, eating disorders, dementia, and Alzheimer's disease in the human or animal body by therapy.
56. A compound according to any one of claims 1 to 43 for use in a method for the treatment of a sleep/wake disorder in the human or animal body by therapy.
57. A compound according to any one of claims 1 to 43 for use in a method for inducing wakefulness in the human or animal body by therapy.
58. A process for preparing a composition comprising admixing a compound according to any one of claims 1 to 43 and a pharmaceutically acceptable carrier. lr 59. A pharmaceutical composition compπsmg a compound according to any one of claims 2 to 11, 13 to 21, 23, 25, 28, 30, 32, 34, 35, or 37 to 42, and a pharmaceutically acceptable carrier.
60. A method for treating a 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 2 to 11, 13 to 21, 23, 25, 28, 30, 32, 34, 35, or 37 to 42, or a pharmaceutical composition according to claim 59.
61. The method according to claim 60, wherein said H3-receptor associated disorder is selected from the group consisting of cognitive disorders, epilepsy, depression, narcolepsy, obesity, motion sickness, vertigo, a sleep/wake disorder, insomnia, jet lag, sleep apnea, attention deficit hyperactivity disorder (ADHD), schizophrenia, allergies, allergic responses in the upper airway, allergic rhinitis, bipolar disorders, manic disorders, neurogenic inflammation, migraine, eating disorders, dementia, and
Alzheimer's disease.
62. The method according to claim 60, wherein said H3-receptor associated disorder is a sleep/wake disorder.
63. 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 2 to 11, 13 to 21, 23, 25, 28, 30, 32, 34, 35, or 37 to 42, or a pharmaceutical composition according to claim 59.
64. Use of a compound according to any one of claims 2 to 11, 13 to 21, 23, 25, 28, 30, 32, 34, 35, or 37 to 42, for production of a medicament for use in the treatment of a IB- receptor associated disorder.
65. The use according to claim 64, wherein said H3-receptor associated disorder is selected from the group consisting of cognitive disorders, epilepsy, depression, narcolepsy, obesity, motion sickness, vertigo, a sleep/wake disorder, insomnia, jet lag, sleep apnea, attention deficit hyperactivity disorder (ADHD), schizophrenia, allergies, allergic responses in the upper airway, allergic rhinitis, bipolar disorders, manic disorders, neurogenic inflammation, migraine, eating disorders, dementia, and Alzheimer's disease. i If-11 IL6I1 /
Figure imgf000222_0001
wherein said H3-receptor associated disorder is a sleep/wake disorder.
67. Use of a compound according to any one of claims 2 to 11, 13 to 21, 23, 25, 28, 30, 32, 34, 35, or 37 to 42, for production of a medicament for use in inducing wakefulness.
68. A compound according to any one of claims 2 to 11, 13 to 21, 23, 25, 28, 30, 32, 34, 35, or 37 to 42, for use in a method of treatment of the human or animal body by therapy.
69. A compound according to any one of claims 2 to 11, 13 to 21, 23, 25, 28, 30, 32, 34, 35, or 37 to 42, for use in a method for the treatment of a H3-receptor associated disorder in the human or animal body by therapy.
70. A compound according to any one of claims 2 to 11, 13 to 21, 23, 25, 28, 30, 32, 34, 35, or 37 to 42, for use in a method for the treatment of a H3 -receptor associated disorder is selected from the group consisting of cognitive disorders, epilepsy, depression, narcolepsy, obesity, motion sickness, vertigo, a sleep/wake disorder, insomnia, jet lag, sleep apnea, attention deficit hyperactivity disorder (ADHD), schizophrenia, allergies, allergic responses in the upper airway, allergic rhinitis, bipolar disorders, manic disorders, neurogenic inflammation, migraine, eating disorders, dementia, and
Alzheimer's disease in the human or animal body by therapy.
71. A compound according to any one of claims 2 to 11, 13 to 21, 23, 25, 28, 30, 32, 34, 35, or 37 to 42, for use in a method for the treatment of a sleep/wake disorder.
72. A compound according to any one of claims 2 to 11, 13 to 21, 23, 25, 28, 30, 32, 34, 35, or 37 to 42, for use in a method for the treatment of inducing wakefulness.
73. A process for preparing a composition comprising admixing a compound according to any one of claims 2 to 11, 13 to 21, 23, 25, 28, 30, 32, 34, 35, or 37 to 42, and a pharmaceutically acceptable carrier.
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