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AU2006316609A1 - 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
AU2006316609A1
AU2006316609A1 AU2006316609A AU2006316609A AU2006316609A1 AU 2006316609 A1 AU2006316609 A1 AU 2006316609A1 AU 2006316609 A AU2006316609 A AU 2006316609A AU 2006316609 A AU2006316609 A AU 2006316609A AU 2006316609 A1 AU2006316609 A1 AU 2006316609A1
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AU
Australia
Prior art keywords
pyrrolidin
phenyl
ethyl
cyclopenta
hexahydro
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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AU2006316609A
Inventor
Weichao G. Chen
Jonathan A. Covel
Jonathan J. Duffield
Rena Hayashi
Jason B. Ibarra
Michelle Pulley
Albert S. Ren
Vincent J. Santora
Graeme Semple
Robert R. Webb
Michael I. Weinhouse
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Arena Pharmaceuticals Inc
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Arena Pharmaceuticals Inc
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Filing date
Publication date
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Publication of AU2006316609A1 publication Critical patent/AU2006316609A1/en
Abandoned legal-status Critical Current

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    • 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
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
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    • 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
    • C07D401/04—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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    • 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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    • 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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    • 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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    • 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
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    • 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
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    • 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

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Description

WO 2007/061741 PCT/US2006/044479 S M ULATORS OF THE H3 RECEPTOR USEFUL FOR THE TREATMENT OF DISORDERS RELATED THERETO 5 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 H 3 -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 10 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 15 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): RI--D\ N Ha GArj K N R5 II Hb E R 3
R
4 R2 20 (Ia) or a pharmaceutically acceptable salt, hydrate or solvate thereof; wherein: D is C(=O), OC(=O), NR 6 C(=O), S(=0) 2 , or absent, wherein R 6 is H or C 1
.
6 alkyl; G is CR 7 or C, provided that when G is CR 7 then - - is a single bond, wherein R is H 25 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(RR 9 ) or C(RR 9 )C(RIoR"), wherein R 8 , R 9 , R 1 o, and R" are each selected independently from the group consisting of H, C 1
.
3 alkyl, C1-4 alkoxy, carboxy, cyano, C 1 -3 haloalkyl, and halogen; J is O, S, S(=O), S(=O)2, NR 12, or absent, wherein R 12 is H or C.1- 6 alkyl; 30 K is C14 alkylene optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 substituents selected independently from the group consisting of C 1
.
3 alkyl, C1-4 alkoxy, carboxy, cyano, C 1 -3 haloalkyl, halogen, hydroxyl, and oxo; -1- WO 2007/061741 PCT/US2006/044479 ii::: t 1: 'Ti tL !,,tJ 1 t ./ , l ll.. ,of H, l k is selected from the group consisting of H, CI.
6 alkyl, C 2
.-
6 alkenyl, C2-.
6 alkynyl, C3-7 cycloalkyl, C 1
.-
4 alkylene-C 3
.-
7 -cycloalkyl, C 3
.
7 heterocyclyl, aryl, C.
4 allkylene-aryl, heteroaryl, and C14 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 14 alkylene-aryl, heteroaryl, 5 and C 1
-
4 alkylene-heteroaryl groups are optionally substituted with 1, 2, 3, 4, 5, 6, or 7 substituents selected independently from the group consisting of C 1
.
6 acyl, C 1 .- 6 acyloxy, C 2 -6 alkenyl, C-6 alkoxy, C 1
.
6 alkyl, Cz.
6 alkylcarboxamide, C 2
.
6 alkynyl, CI-6 alkylsulfonamide, C 1 .- 6 alkylsulfinyl, C.
6 alkylsulfonyl, C 1
.
6 allkylthio, 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 10 dialklcylcarboxamide, C 2
-
8 dialkylsulfonamide, formyl, halogen, C.
6 haloalkoxy, C.
6 haloalkyl,
C
1 .- 6 haloalkylsulfinyl, C 1 .- 6 haloalkylsulfonyl, C 1
.
6 haloalkylthio, hydroxyl, thiol, nitro, and sulfonamide;
R
2 is H, halogen or C- 3 alkyl;
R
4 and R 5 are each independently selected from the group consisting of H, Cz.
6 alkyl, C2 15 6 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 C 1 -6 acyl, C.
6 acyloxy, C 2
.-
6 alkenyl, Cl-6 alkoxy, C.
6 alkyl, C 1
.
6 alkylcarboxamide, C2- 6 alkynyl, C 1 ..- 6 alkylsulfonamide, C 1
.-
6 alkylsulfinyl,
C
1
I-
6 alkylsulfonyl, C 1
_
6 alkylthio, C 1 .- 6 alkylureyl, amino, C.
6 alkylamino, C2- 8 dialkylamino, 20 carbo-Cl.
6 -alkoxy, carboxamide, carboxy, cyano, C 3
.
7 cycloalkyl, C2-.
8 dialkylcarboxamide, C 2 -8 dialkylsulfonamide, halogen, C 1
,
6 haloalkoxy, C.
6 haloalkyl, C 1
.
6 haloalkylsulfinyl, C_ 6 haloalkylsulfonyl, C 1
.
6 haloalkylthio, hydroxyl, thiol, nitro, and sulfonamide; or
R
4 and R together with the nitrogen atom to which they are both bonded form a C 3 -7 heterocyclyl or Cs- 10 heterobicyclyl group optionally substituted with 1, 2, 3, 4, 5, or 6 25 substituents selected independently from the group consisting of C 1
.-
6 acyl, C1-.
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, C 1 -6 alkylsulfinyl, 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 1 .- 6 haloalkoxy, C.
6 haloalkyl, C 1
.
6 30 haloalkylsulfinyl, C1-. haloalkylsulfonyl, C 1
.
6 haloalkylthio, hydroxyl, thiol, nitro, oxo, phenyl, and sulfonamide, and said C 1 .- 6 alkyl, is optionally substituted with 1 or 2 substituents selected independently from C..
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, C 2 -6 35 alkenyl, C 1
.
6 alkoxy, C 1 -6 alkyl, C 1
.
6 alkylcarboxamide, C2-.
6 alkynyl, C 1 -6 alkylsulfonamide, C.-6 alkylsulfinyl, C.
6 alkylsulfonyl, C.
6 alkylthio, C 1
.
6 alkylureyl, amino, Ci-6 alkylamino, C 2
-.
8 dialkylamino, carbo-C 1
.
6 -alkoxy, carboxamide, carboxy, cyano, C 3
.
7 cycloalkyl, C 2 -8 -2- WO 2007/061741 PCT/US2006/044479 PC 1C 1 d 1 bi " 2 ulfonamide, halogen, C.
6 haloalkoxy, C 1
.
6 haloalkyl, C 1
,
6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, CI-6 haloalkylthio, hydroxyl, thiol, nitro, and sulfonamide; provided that: 5 G and J are not bonded to adjacent ring carbons of said Ar group; and when E is C(RR?), 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), NR 6 C(=O), or absent, wherein R 6 is H or CI-6 alkyl;
R
1 is selected from the group consisting of H, C.-6 alkyl, C 2
.
6 alkenyl, C 2
.
6 alkynyl, C 3 -7 10 cycloalkyl, C 1
-
4 alkylene-C 3
.
7 -cycloalkyl, C3- 7 heterocyclyl, aryl, C.
4 alkylene-aryl, heteroaryl, and C 14 alkylene-heteroaryl, and each of said C 1
.
6 alkyl, C2- 6 alkenyl, C 2
-
6 alkynyl, C 3
.
7 cycloalkyl, C 14 alkylene-C 3
.
7 -cycloalkyl, C 3
.
7 heterocyclyl, aryl, Cz-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 C 1 -6 acyl, C 1
.
6 acyloxy, C2-.
6 15 alkenyl, C 1 -6 alkoxy, C 1
.
6 alkyl, C.I-6 alkylcarboxamide, C 2
-
6 alkynyl, C1- 6 alkylsulfonamide, C- 1
.
6 alkylsulfinyl, C 1
-
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.
6 haloalkoxy, C 1
,
6 haloalkyl, C.
6 haloalkylsulfinyl, C 1 -6 haloalkylsulfonyl, C1- 6 haloalkylthio, hydroxyl, thiol, nitro, and 20 sulfonamide; and
R
4 and R are each independently selected from the group consisting of H, C1.-6 alkyl, C 2 6 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 of C 1
.
6 acyl, C1- 6 acyloxy, C2- 6 alkenyl, C 1
_
6 25 alkoxy, C 1 -6 alkyl, C 1
.
6 alkylcarboxamide, C 2 -6 alkynyl, C 1 -6 alkylsulfonamide, C 1 a.
6 alkylsulfinyl,
C
1
-.
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, C2- 8 dialkylcarboxamide, C 2
-
8 dialkylsulfonamide, halogen, C.- 6 haloalkoxy, C.
6 haloalkyl, C 1
.
6 haloalkylsulfinyl, C 1
-.
6 haloalkylsulfonyl, C1- 6 haloalkylthio, hydroxyl, thiol, nitro, and sulfonamide; or 30 R 4 and R 5 together with the nitrogen atom to which they are both bonded form a C 3
.
7 heterocyclyl or Cs-Io 0 heterobicyclyl group optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected independently from the group consisting of C 1
.
6 acyl, C 1
.
6 acyloxy, C 2
-
6 alkenyl, C 1 ., alkoxy, C 1
.
6 alkyl, C 1
.-
6 alkylcarboxamide, C 2 -6 alkynyl, C1-.
6 alkylsulfonamide, C 1
.
6 alkylsulfinyl, C 1
.
6 alkylsulfonyl, C 1 .a alkylthio, C1- 6 alkylureyl, amino, C 1
.
6 alkylamino, C 2
-
8 35 dialkylamino, carbo-C.
6 -alkoxy, carboxamide, carboxy, cyano, C 3
.
7 cycloalkyl, C 2 -8 dialkylcarboxamide, C 2
.
8 dialkylsulfonamide, halogen, C 1
-
6 haloalkoxy, C 1
.
6 haloalkyl, C 1
.
6 -3- WO 2007/061741 PCT/US2006/044479 1 haloalls1 i;, C 1 1 6 haloalkyls lfonyl, C.6 haloalkylthio, hydroxyl, thiol, nitro, and sulfonamide, and said Cl- 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. 5 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 10 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 15 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 20 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. 25 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 30 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, 35 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 -4- WO 2007/061741 PCT/US2006/044479 V~ ~ ~~~1 II... .. . .. I 1 it 1'" f disorders, neurogemc milammaion, migraine, eating disorders, dementia, and Alzheimer'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 5 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 10 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. 15 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 20 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 25 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 30 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. 35 BRIEF DESCRIPTION OF THIE 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 C 1
-
6 alkyl, Rb -5- WO 2007/061741 PCT/US2006/044479 is either a protecting group (i.e., PG 1 ) or Rb is R 1 as described herein, and PG 2 is a protecting group which can be the same or different compared to PG. 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 5 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, tert-butanol, THF, 1,4-dioxane, and the like). On occasion wherein the target 10 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. 15 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 20 invention wherein the NR 4 Rs 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 group in the last step. It is understood that protection of the 30 alcohol may be necessary for compounds of Formula N 25 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 amination using, for example, an aldehyde or a ketone), Method C (amide and carbamate formation using, using for example, an acid chloride 30 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 35 aryl/heteroaryl-halide with a base, such as, potassium t-butoxide under microwave irradiation conditions) and Method F (amide formation using, using for example, a carboxylic acid and a coupling reagent, such as, DCC). -6- WO 2007/061741 PCT/US2006/044479 :igiire 6 shows a general synthetic scheme for preparing 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. 5 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 10 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 a-position. The second method involves the Suzuki reaction of a bicyclic vinyl triflate with a boronic acid. 15 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 20 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 25 the baseline intracellular response in the absence of an agonist or partial agonist. The term "C 1
.
6 acyl" is intended to mean a C 1
-
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, iso-butanoyl, pivaloyl, pentanoyl, hexanoyl and the like. 30 The term "C 1
.
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-s acyloxy, some embodiments are when acyloxy is C 1
.
4 acyloxy. Some examples include, but are not limited to, acetyloxy, propionyloxy, n-butanoyloxy, iso-butanoyloxy, pivaloyloxy, pentanoyloxy, hexanoyloxy and the like. 35 The term "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. Both E and Z isomers -7- WO 2007/061741 PCT/US2006/044479 PCare e"fbraced " he term "alkeiyl." 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 5 and the like. The term "C 1 z 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, n-propoxy, iso-propoxy, n-butoxy, t-butoxy, iso-butoxy, 10 sec-butoxy and the like. The term "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, n-propyl, iso-propyl, n-butyl, 15 sec-butyl, iso-butyl, t-butyl, pentyl, iso-pentyl, t-pentyl, neo-pentyl, 1-methylbutyl [i.e.,
-CH(CH
3
)CH
2
CH
2
CH
3 ], 2-methylbutyl [i.e., -CH 2
CH(CH
3
)CH
2
CH
3 ], n-hexyl and the like. The term "C 1 .-6 alkylcarboxamido" or "C 1
-
6 alkylcarboxamide" is intended to mean a single C1-6 alkyl group attached to either the carbon or the nitrogen of an amide group, wherein alkyl has the same definition as found herein. The C.1-6 alkylcarboxamido may be represented by 20 the following: O O N 01_6 alkyl N 'KC1-6 alkyl • H H Examples include, but are not limited to, N-methylcarboxamide, N-ethylcarboxamide, N-n propylcarboxamide, N- iso-propylcarboxamide, N-n-butylcarboxamide, N-sec butylcarboxamide, N- iso-butylcarboxamide, N-t-butylcarboxamide and the like. 25 The term "C.4 alkylene" is intended to mean a C1-4 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, -CH 2 -, -CH 2
CH
2 -, CH 2
CH
2
CH
2 -, and/or -CH 2
CH
2
CH
2 CH2-. The term "C 1
-
4 alkylene-aryl" is intended to mean a C 14 alkylene group bonded to an 30 aryl group, each as defined herein. In some embodiments C 1 .4 alkylene-aryl refers to, for example, benzyl (-CH 2 -phenyl), phenylethyl (-CH 2
CH
2 -phenyl), and the like. The term "C1-4 alkylene-C 3
.
7 -cycloalkyl" is intended to mean a C 1 4 alkylene group bonded to a C 3
.-
7 -cycloalkyl group, each as defined herein. In some embodiments C 14 alkylene -8- WO 2007/061741 PCT/US2006/044479 r" " '" ' .. I C:', f' i::f , ' 11.11.1 ,11 it, : I 1C-cyloalt refers to, for example, cyclopropylmethyl (-CH2-cyclopropyl), cyclopropylethyl
(-CH
2 CH2-cyclopropyl), cyclobutylmethyl (-CH 2 -cyclobutyl), and the like. The term "C 14 alkylene-heteroaryl" is intended to mean a CI 4 alkylene group bonded to a heteroaryl group, each as defined herein. In some embodiments C 1 4 alkylene-heteroaryl 5 refers to, for example, pyridinylmethyl (-CH 2 -pyridinyl) and the like. The term "C 1 6 alkylsulfinyl" is intended to mean a C 1 -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, methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, iso-propylsulfinyl, n-butylsulfmyl, sec-butylsulfinyl, iso 10 butylsulfinyl, t-butylsulfinyl, and the like. The term "C 1 .- 6 alkylsulfonamide" is intended to mean the groups shown below: 00 00 NS C 6 alkylN S C akS 1-6 alkyl H H wherein C 1
-
6 alkyl has the same definition as described herein. The term "C 1
.
6 alkylsulfonyl" is intended to mean a C 1 -6 alkyl radical attached to the 15 sulfur of a sulfone radical having the formula: -S(0) 2 - wherein the alkyl radical has the same definition as described herein. Examples include, but are not limited to, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, iso-propylsulfonyl, n-butylsulfonyl, sec-butylsulfonyl, iso butylsulfonyl, t-butylsulfonyl, and the like. The term "C 1 -6 alkylthio" is intended to mean a C1- 6 alkyl radical attached to a sulfur 20 atom (i.e., -S-) wherein the alkyl radical has the same definition as described herein. Examples include, but are not limited to, methylsulfanyl (i.e., CH 3 S-), ethylsulfanyl, n-propylsulfanyl, iso propylsulfanyl, n-butylsulfanyl, sec-butylsulfanyl, iso-butylsulfanyl, t-butylsulfanyl, and the like. The term "C 1 6 alkylureyl" is intended to mean the group of the formula: -NC(O)N 25 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, CH 3 NHC(0)NH-, NH2C(0)NCH 3 -, (CH 3
)
2 NC(0)NH-, (CH3) 2 NC(0)NH-,
(CH
3
)
2 NC(0)NCH 3 -, CH 3 CH2NHC(O)NHI-, CH 3
CH
2 NHC(0)NCH 3 -, and the like. The term "C 2
.
6 alkynyl" is intended to mean a radical containing 2 to 6 carbons and at 30 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. 35 The term "amino" is intended to mean the group -NHi 2 . -9- WO 2007/061741 PCT/US2006/044479 *te er ':C/ 6 alky.amno" 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, n-propylamino, iso-propylamino, n butylamino, sec-butylamino, iso-butylamino, t-butylamino, and the like. Some embodiments are 5 "C- 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 "bicyclic" 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 10 carbons thus forming either a fused or bridged ring system. Bicyclic examples include, but not limited to, bicyclo[1.1.1]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-C.
6 -alkoxy" is intended to mean a CI.
6 alkyl ester of a carboxylic 15 acid, wherein the alkyl group is as defined herein. Examples include, but are not limited to, carbomethoxy [-C(=O)OCH 3 ], carboethoxy, carbopropoxy, carboisopropoxy, carbobutoxy, carbo-sec-butoxy, carbo-iso-butoxy, carbo-t-butoxy, carbo-n-pentoxy, carbo-iso-pentoxy, carbo t-pentoxy, carbo-neo-pentoxy, carbo-n-hexyloxy, and the like. The term "carboxamide" is intended to mean the group -CONH2. 20 The term "carboxy" or "carboxyl" is intended to mean the group -C0 2 H; 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 25 carbons; some embodiments contain 4 to 5 carbons; some embodiments contain 4 carbons. Examples include cyclobutenyl, cyclopentenyl, cyclopentenyl, cyclohexenyl, and the like. The term "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. 30 Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. The term "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, 35 ethylisopropylamino, dipropylamino, propylisopropylamino and the like. Some embodiments are "C 2
.
4 dialkylamino." - 10- WO 2007/061741 PCT/US2006/044479 .:":"",." " netrmC 2..s a l1ca rboxamido" 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: O O N.C-4 alkyl NN C 1
-
4 alkyl 5 C 1
-
4 alkyl C1-4 alkyl wherein C 14 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 "C 2 8 dialkylsulfonamide" is intended to mean one of the following groups 10 shown below: 00 00 SNC1- 4 alkyl N C 1 4 alkyl
C
1
-
4 alkyl C1- 4 alkyl wherein C 14 has the same definition as described herein, for example but not limited to, methyl, ethyl, n-propyl, isopropyl, and the like. The term "C 2 -8 dialkylthiocarboxamido" or "C 2 .s 8 dialkylthiocarboxamide" is 15 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 -s dialkylthiocarboxamido or C 2
-
8 dialkylthiocarboxamide may be represented by the following groups: S S , C1-4 alkyl S NA CI-4 alkyl
C
1
-
4 alkyl C 1
-
4 alkyl 20 Examples of a dialkylthiocarboxamide include, but are not limited to, N,N dimethylthiocarboxamide, N-methyl-N-ethylthiocarboxamide and the like. The term "C.
6 haloalkoxy" is intended to mean a C 1 -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. 25 The term "C 1
.
6 haloalkyl" is intended to mean an C 1
.
6 alkyl group, defined-herein, wherein the alkyl is substituted with one halogen up to fully substituted and a fully substituted
C
1
.-
6 haloalkyl can be represented by the formula CnL 2 n+ 1 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, C1, Br and I, preferably F, some embodiments are 1 to 5 30 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, -11- WO 2007/061741 PCT/US2006/044479 l~o, t: ... IiU ,,,i "I",.; f 1 11 .101141"; 11.. :... f Iu6 roiiif, dfltuorometh12, tlfluoromethyl, chlorodifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl and the like. The term "C.
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 5 has the same definition as described herein. Examples include, but are not limited to, trifluoromethylsulfinyl, 2,2,2-trifluoroethylsulfinyl, 2 ,2-difluoroethylsulfinyl and the like. The term "C 1
.
6 haloalkylsulfonyl" is intended to mean a C 1
.-
6 haloalkyl radical attached to the sulfur atom of a sulfone group having the formula: -S(0)2- wherein haloalkyl has the same definition as described herein. Examples include, but are not limited to, 10 trifluoromethylsulfonyl, 2,2,2-trifluoroethylsulfonyl, 2,2-difluoroethylsulfonyl and the like. The term "C 1 .- 6 haloalkylthio" is intended to mean a C 1
.-
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. 15 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 20 can be optionally substituted with H, C1-4 acyl or C 14 alkyl. Examples of heteroaryl groups include, but are not limited to, pyridyl, benzofuranyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, quinolinyl, benzoxazolyl, benzothiazolyl, 1H-benzimidazolyl, isoquinolinyl, quinazolinyl, quinoxalinyl and the like. In some embodiments, the heteroatom is selected from, but not limited to, the group consisting of 0, S and N, wherein N is substituted with H (i.e., 25 NH), examples include, but are not limited to, pyrrolyl, indolyl, 1H-benzoimidazol-2-yl, and the like. Other examples include, but are not limited to, those in TABLES A-E, and the like. The term "Cs- 1 0 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(=0) 2 , and NH, wherein the nitrogen can be 30 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. I ]hept-2-yl, 7-aza bicyclo[2.2.1]hept-7-yl, 1,3-dihydro-isoindolyl, 3,4-dihydro-1H-isoquinolinyl, octahydro cyclopenta[c]pyrrolyl and the like. 35 The term "C 3
.
7 heterocyclic" or "C 3
.
7 heterocyclyl" is intended to mean a non-aromatic carbon ring (i.e., C3- 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 - 12- WO 2007/061741 PCT/US2006/044479 co is in 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 C 1
-
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, 5 for example, ring carbon, ring nitrogen, and the like. The heterocyclic group is a 3-, 4-, 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-1l-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] 10 dioxolan-2-yl, thiomorpholin-4-yl, [1,4]oxazepan-4-yl, 1,1-dioxo-1 6 -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 -NO 2 . 15 The term "oxo" is intended to mean the substituent =0, 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 C 6 Hs-. The term "sulfonamide" is intended to mean the group -SO 3
NH
2 . 20 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, 25 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 30 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 35 the disease, condition or disorder. - 13 - WO 2007/061741 PCT/US2006/044479 11'1 ,i PEI I.t. -:,,l lro ] o ' I j j .e 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 5 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 10 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 15 compounds of Formula (la); 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 20 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 25 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 30 (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: 35 One aspect of the present invention pertains to certain compounds as shown in Formula (la): - 14- WO 2007/061741 PCT/US2006/044479
R
1 \ .... , ... ... , ! ,j °, L ,;' R N Ha G Ar K
NR
5 Hb E R 3 R4
R
2 (la) or a pharmaceutically acceptable salt, hydrate or solvate thereof; wherein Ri, R 2 , R 3 , R 4 , Rs, 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 5 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., R 1 , R 2 , R 3 , R 4 , Rs, D, E, G, J, K and Ar) contained within the 10 generic chemical formulae described herein [e.g. (la), (Ic), (le), 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 15 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 20 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 25 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. 30 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. -15- WO 2007/061741 PCT/US2006/044479 :"6 '../ .. i ds 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. 5 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. In another embodiment, compounds of the present invention have two stereochemical centers and both are 10 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 15 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 20 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 25 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 30 enantiomers and mixtures thereof, unless stated or shown otherwise. One aspect of the present invention encompasses N-oxides of compounds of Formula (la). In some embodiments, E is C(RR 9 ). In some embodiments, R 8 and R are each H. 35 In some embodiments the present invention pertains to certain compounds as shown in the following Formula (Ic): -16- WO 2007/061741 PCT/US2006/044479 P:t i[,.1" ',::.::i!:ll,:, R R N .Ha GAr K'NR HbR3 R R
R
9
R
2 (Ic) wherein each variable in Formula (Ic) has the same meaning as described herein, supra and infra. In some embodiments, G is CR 7 and - - is a single bond; wherein R' is H or OH. 5 In some embodiments the present invention pertains to certain compounds as shown in the following Formula (le): R1DN Ha ArN " K R5 R Hb H R
R
8
R
9 R (le) wherein each variable in Formula (le) has the same meaning as described herein, supra and infra. 10 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): R1 -D\ N Ha Ar K R 5 Hb 4 R8 R9 R2 (Ig) wherein each variable in Formula (Ig) has the same meaning as described herein, supra and 15 infra. In some embodiments, E is C(RR 9 )C(RoR"). In some embodiments the present invention pertains to certain compounds as shown in the following Formula (Ii): -17- WO 2007/061741 PCT/US2006/044479 ... l ... ... It,, !, t "tii,'' 'l ': ' N ...
R
1 \ N Ha Ar IK NR 5 GN % R 3 R4 Hb 2
R
8 F R
R
9
R
10
R
11 (i) wherein each variable in Formula (li) has the same meaning as described herein, supra and infra. In some embodiments, R i 0 , and R" are each H. 5 In some embodiments, R 8 , R 9 , R'
I
o, and R 1 ' are each H. In some embodiments, G is CR 7 an - - is a single bond; wherein R 7 is H or OH. In some embodiments the present invention pertains to certain compounds as shown in the following Formula (Ik): R N Ha AR ,
NR
5 FR;' N R3 R 4 Hb8 R RR
R
9 Ro R11 (Ik) 10 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): N Ha ArN K N R 5 \ N Hb R2
R
8
R
9
R
10 R11 15 (Im) wherein each variable in Formula (Im) has the same meaning as described herein, supra and infra. In some embodiments, D is S(=0) 2 . In some embodiments, D is C(=O). 20 In some embodiments the present invention pertains to certain compounds as shown in the following Formula (lo): -18- WO 2007/061741 PCT/US2006/044479 R1\ N Ha GAr, K NR 5 Hb E R 3 4 R2 (lo) wherein each variable in Formula (lo) has the same meaning as described herein, supra and infra. In some embodiments, D is OC(=O). 5 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 NR 1 2 , wherein R 1 2 is H or C.
6 alkyl. 10 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 NR 4
R
s group. In some embodiments, K is C 1 4 alkylene optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 15 8 substituents selected independently from the group consisting of C 1
.
3 alkyl, C14 alkoxy, carboxy, cyano, C 1
.
3 haloalkyl, halogen, and hydroxyl. In some embodiments, K is -CH 2 CH2-. In some embodiments, R' is selected from the group consisting of H, C 1 -6 alkyl, C 3 -7 cycloalkyl, C1- 4 alkylene-C 3
-
7 -cycloalkyl, aryl, C 1
-
4 alkylene-aryl, heteroaryl, and C 14 alkylene 20 heteroaryl, and each of said C 1
.
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, Cl-6 alkyl, amino, C 1
.
6 alkylamino, C 2 -8 dialkylamino, C 3
.-
7 cycloalkyl, formyl, halogen, C 1 .- 6 haloalkoxy, C 1 .- 6 haloalkyl, and hydroxyl. In some embodiments, R' is selected from the group consisting of H, CI- 6 alkyl, C 3
-.
7 25 cycloalkyl, C 14 alkylene-C 3
.
7 -cycloalkyl, aryl, C 14 alkylene-aryl, heteroaryl, and C 1 4 alkylene heteroaryl, and each of said C.
6 alkyl and C1- 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._ 6 alkylamino, C 2
.-
8 dialkylamino, C 3
.-
7 cycloalkyl, halogen, C_ 6 haloalkoxy, C.-6 haloalkyl, and hydroxyl. 30 In some embodiments, R! 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, -19- WO 2007/061741 PCT/US2006/044479 " r...t" 11R1;: " I L 11.1[" 1 1 . "; W 11: cycobutyl, i-hdloxy-prop-2-yl, 4-hydroxy-benzyl, cyclopropyl, phenyl, pyridin-2-yl, hydroxymethyl, tetrahydro-fiuran-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, 5 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, R' is selected from the group consisting of H, benzyl, cyclopropylmethyl, isobutyl, isopropyl, 4-trifluoromethoxy-benzyl, 2,4-dimethoxy-benzyl, 10 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, R 2 is H or C 1 6 alkyl In some embodiments, R 2 is H or methyl. 15 In some embodiments, R 2 is H. In some embodiments, R 4 and R' are each independently H or C1-6 alkyl; or
R
4 and R s together with the nitrogen atom to which they are both bonded form a C 3
.
7 heterocyclyl or Cs- 10 heterobicyclyl optionally substituted with 1 or 2 substituents selected independently from the group consisting of C1-6 alkyl, halogen, hydroxyl, oxo and phenyl; and 20 said C 1
.
6 alkyl, is optionally substituted with 1 or 2 substituents selected independently from C 1
.
6 alkoxy and hydroxyl. In some embodiments, R 4 and R s are each independently H or C1-.
6 alkyl; or
R
4 and R together with the nitrogen atom to which they are both bonded form a C 3 -7 heterocyclyl or Cs 5
.-
1 0 heterobicyclyl optionally substituted with 1 or 2 substituents selected 25 independently from the group consisting of Ca-6 alkyl, halogen, and hydroxyl; and said CI-6 alkyl, is optionally substituted with hydroxyl. In some embodiments, R 4 and R 5 are each independently H, methyl or isopropyl. In some embodiments, R 4 and R s are each independently H or methyl. In some embodiments, R 4 and R s together with the nitrogen atom to which they are both 30 bonded form a group selected from the group consisting ofpyrrolidin-1-yl, 2-methyl-pyrrolidin 1-yl, 2-methyl-piperidin-1-yl, 4-methyl-piperazin-1-yl, 2,5-dimethyl-pyrrolidin-1-yl, dimethyl amino, 2,2-dimethyl-pyrrolidin-1-yl, morpholin-4-yl, 2-hydroxymethyl-pyrrolidin-1-yl, 3 hydroxy-pyrrolidin-1-yl, 3,3-difluoro-pyrrolidin-1-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 35 methoxymethyl-pyrrolidin-1-yl, 2-carbamoylpyrrolidin-l1-yl, 2-(methylcarbamoyl)pyrrolidin-1 yl, piperidin-1-yl, 2-oxopyrrolidin-1-yl, 3-phenylpyrrolidin-1-yl, 2-isopropylpyrrolidin-1-yl, 2 trifluoromethylpyrrolidin-1-yl, and 2-phenylpyrrolidin-1-yl. -20- WO 2007/061741 PCT/US2006/044479 ' "' m e. si embodiments, 4 and R s together with the nitrogen atom to which they are both bonded form a group selected from the group consisting of pyrrolidin-l1-yl, 2-methyl-pyrrolidin 1-yl, 2-methyl-piperidin-1-yl, 4-methyl-piperazin-l1-yl, 2,5-dimethyl-pyrrolidin-1-yl, dimethyl amino, 2,2-dimethyl-pyrrolidin-1-yl, morpholin-4-yl, 2-hydroxymethyl-pyrrolidin-1-yl, 3 5 hydroxyl-pyrrolidin-l1-yl, 3,3-difluoro-pyrrolidin-1l-yl, azetidin-l1-yl, 3,3-difluoro-piperidin-1-yl, 2,3-dihydro-isoindol-2-yl, 3,4-dihydro-1H-isoquinolin-2-yl, 2,3-dihydro-indol-1-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 (la): R N Ha Ar K R 5 Hb E R 3 R
R
2 10 (Ia) or a pharmaceutically acceptable salt, hydrate or solvate thereof; wherein: D is C(=0), OC(=O), NR 6 C(=O), S(=O) 2 , or absent, wherein R 6 is H or CH3; 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; 15 R 2 is H or methyl; E is -CH 2 -or -CH 2
CH
2 -; J is O or absent; K is -CH 2
CH
2 -; R' is selected from the group consisting of H, benzyl, cyclopropylmethyl, isobutyl, 20 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 25 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;
R
4 and R 5 are each independently H, methyl or isopropyl; or
R
4 and R s together with the nitrogen atom to which they are both bonded form a group 30 selected from the group consisting of pyrrolidin-l -yl, 2-methyl-pyrrolidin-1 -yl, 2-methyl piperidin-1-yl, 4-methyl-piperazin-1-yl, 2,5-dimethyl-pyrrolidin-1-yl, dimethyl-amino, 2,2 dimethyl-pyrrolidin-1-yl, morpholin-4-yl, 2-hydroxymethyl-pyrrolidin-1-yl, 3-hydroxy pyrrolidin-1-yl, 3,3-difluoro-pyrrolidin-1-yl, azetidin-1-yl, 3,3-difluoro-piperidin-1-yl, 2,3 -21- WO 2007/061741 PCT/US2006/044479 p "", U/ I,1 1!Ei :IIiiii i', i .,11" 11.11. 11:::1 dihyro-isomdol-2-yl, 3,4-dihydro-1lH-isoquinolin-2-yl, 2,3-dihydro-indol-1-yl, 2 methoxymethyl-pyrrolidin-1-yl, 2-carbamoylpyrrolidin-1-yl, 2-(methylcarbamoyl)pyrrolidin- 1 yl, piperidin-1-yl, 2-oxopyrrolidin-1-yl, 3-phenylpyrrolidin-1-yl, 2-isopropylpyrrolidin-1-yl, 2 trifluoromethylpyrrolidin-1-yl, and 2-phenylpyrrolidin-l1-yl; and 5 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 (Iq): RD\ N Ha Ar K K R 5 H E R 3 R4 H (Iq) or a pharmaceutically acceptable salt, hydrate or solvate thereof; 10 wherein: D is C(-O), OC(=O), NR 6 C(=O), 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; E is -CH 2 - or -CH 2
CH
2 -; 15 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-benzyl, 2,4-dimethoxy-benzyl, cyclohexyl, cyclopentyl, methyl, ethyl, t-butyl, 4-methoxy-benzyl, cyclobutyl, 3-hydroxy-prop-2-yl, 4-hydroxy-benzyl, 20 cyclopropyl, phenyl, pyridin-2-yl, hydroxymethyl and tetrahydro-furan-3-yl; R4 and R s 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-1-yl, 4-methyl-piperazin-1-yl, 2,5-dimethyl-pyrrolidin-1-yl, dimethyl-amino, 2,2 dimethyl-pyrrolidin-1-yl, morpholin-4-yl, 2-hydroxymethyl-pyrrolidin-1-yl, 3-hydroxyl 25 pyrrolidin-1l-yl, 3,3-difluoro-pyrrolidin-1-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. In some embodiments, the present invention pertains to certain 3-phenyl-pyrazole derivatives as shown in Formula (Is): - 22- WO 2007/061741 PCT/US2006/044479 RI..-D\ N Ha Ar K NR 5 R7 Hb R4 (Is) or a pharmaceutically acceptable salt, hydrate or solvate thereof; wherein: D is C(=O), OC(=O), or absent; 5 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-benzyl, 2,4-dimethoxy-benzyl, cyclohexyl, cyclopentyl, methyl, 10 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 Rs together with the nitrogen atom to which they are both bonded form a group selected from the group consisting of pyrrolidin-l1-yl and 2-methyl-pyrrolidin-l1-yl; and 15 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): NR Ha Ar K R5 / I Hb R (Iu) or a pharmaceutically acceptable salt, hydrate or solvate thereof; 20 wherein: D is C(=0), OC(=0), NHC(=0), or absent; J is O or absent; K is -CH 2
CH
2 -;
R
1 is selected from the group consisting of H, benzyl, cyclopropylmethyl, isobutyl, 25 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- 1-yl, 2-methyl 30 piperidin-1-yl, 4-methyl-piperazin-l1-yl, 2,5-dimethyl-pyrrolidin-l1-yl, dimethyl-amino, 2,2 -23 - WO 2007/061741 PCT/US2006/044479 W1.: me -pyro I thl-yroldi di tlil-pyrrodin--yl, morphliolin-4-yl, 2 -hydroxymethyl-pyrrolidin-l-yl, 3-hydroxyl pyrrolidin-1-yl, 3,3-difluoro-pyrrolidin-1-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. 5 In some embodiments, the present invention pertains to certain 3-phenyl-pyrazole derivatives as shown in (Iw): R N Ha Ar , KN
R
5 -J N R7 I Hb R (Iw) or a pharmaceutically acceptable salt, hydrate or solvate thereof; wherein: 10 D is C(=O) or NR 6 C(=O), wherein R is H or CH 3 ;
R
7 is H or OH; J is absent; K is -CH 2
CH
2 -;
R
1 is selected from the group consisting of H, isopropyl, cyclopentyl, methyl, or 15 cyclopropyl;
R
4 and R s together with the nitrogen atom to which they are both bonded form pyrrolidin-l1-yl; and Ar is 1,4-phenylene. In some embodiments, the present invention pertains to certain 3-phenyl-pyrazole 20 derivatives as shown in Formula (Iy): RD N Ha Ar jK N R 5 -J N H R4 Hb (Iy) or a pharmaceutically acceptable salt, hydrate or solvate thereof; wherein: D is C(=O) or NR 6 C(=O), wherein R 6 is H or CH 3 ; 25 J is absent; K is -CH 2
CH
2 -; R' is selected from the group consisting of H, benzyl, isopropyl, cyclopentyl, methyl, or cyclopropyl; -24 - WO 2007/061741 PCT/US2006/044479 and together witi'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 5 compounds selected from the following group shown in the TABLES A through E. TABLE A Cmpd No. Chemical Structure Chemical Name 2-Benzyl-4-[4-(2 AN pyrrolidin-1-yl-ethyl) N phenyl]-octahydro OH cyclopenta[c]pyrrol-4-ol 2-Benzyl-4-{4-[2-(2 N methyl-pyrrolidin-1-yl) Ni ethyl]-phenyl}-octahydro OH cyclopenta[c]pyrrol-4-ol H 4-[4-(2-Pyrrolidin-l1-yl N A3 N ethyl)-phenyl]-octahydro OH cyclopenta[c]pyrrol-4-ol 2-Cyclopropylmethyl-4 [4-(2-pyrrolidin-1-yl A4 N N ethyl)-phenyl]-octahydro OH cyclopenta[c]pyrrol-4-ol -25- WO 2007/061741 PCT/US2006/044479 ~tipd ~. hemical Structure Chemical Name 2-Isobutyl-4-[4-(2 A5 Npyrrolidin- 1 -yl-ethyl) N/ phenyl]-octahydro cyclopenta[c]pyrrol-4-ol OH 2-Isopropylb4-[4-(2 phenyll-octahydro OH cyclopenta[c]pyrrol-4-ol
F
3 CO /4-[4-(2-Pyrrolidin-1 -yl -0 -1 ethyl)-phenyl]-2-(4 A7 N NIJ trifluoromethoxy-benzyl) NH octahydro OH cyclopenta[clpyrrol-4-ol H3O
OCH
3 2-(2,4-Dimethoxy
H
3 00 /benzyl)-4-[4-(2-pyrrolidin A8 ND 1-yl-ethyl)-phenyl] ~ I octahydro OH cyclopenta[c]pyrrol-4-ol 2-Cyclohexyl-4-[4-(2 r pyrrolidin-1 -yl-ethyl) A9N , phenylil-octahydro OH cyclopenta[cllpyrrol-4-ol - 26 - WO 2007/061741 PCT/US2006/044479 ~~:" 0i;: Chemical. S-ructhre Chmcal IName 2-Cyclopentyl-4-[4-(2 Al9 pyrrolidin-1I -yl-ethyl) A1 phenyl]-octahydro OH cyclopenta[c]pyrrol-4-ol 1- {4-Hydroxy-4-[4-(2 pyrrolidin-1 -yl-ethyl) All N phenyl]-hexahydro "N cyclopenta[c]pyrrol-2-yl} OH ethanone 4-Jlydroxy-4-[4-(2 pyrrolidin-1 -yl-ethyl) A12 Nphenyl]-hexahydro & OC~rcyclopenta[c]pyrrole-2 carboxylic acid ethyl ester 4-Hydroxy-4-[4-(2 0o- 0 pyrrolidin-1-yl-ethyl) A13 phenyl]-hexahydro A13 Ncyclopenta[c]pyrrole-2 OH carboxylic acid tert-butyl ester 2-Benzyl-4-[6-(2 A14 N 'Dpyrrolidin-1-yl-ethyl) N pyridin-3-yl]-octahydro OH cyclopenta[c]pyrrol-4-ol -27 - WO 2007/061741 PCT/US2006/044479 Chemical Structure Chemical Name / 2-Benzyl- 4
-[
4
-(
2 A15 N pyrrolidin-l-Y-ethoxy) 0 ' phenyl]-octahydro O0H cyclopenta[c]pyrrol- 4 -ol 2-Benzyl-4-[5-(2 A16 N pyrrolidin-1 -yl-ethyl) A16 / pyridin-2-yl]-octahydro OH cyclopenta[c]pyrrol-4-ol
H
3 COel / 2-(4-Methoxy-benzyl)-4 A17 N r\ [4-(2--pytrolidil- 1 -yl NI) ethyl)-phenyl]-octahydro OH cyclopentaI~c]pyrro1-4-ol
F
3 C /4-[4-(2-Pyrrolidim-1 -yl ethyl)-phenyl]-2-(4 A18
NDN
17 trifluoromethyl-benzyl) ~N octahydro OH cyclopenta[c]pyrrol-4-ol 2-Methyl-4-[4-(2 N rDyrrolidin-1-yl-ethyl) A19 N phenyl]-octahydro O H cyclopentallclpyrrol-4-ol 2-Ethyl-4-[4-(2-pyrrolidin N20 NNI 1-yl-ethyl)-phenyl] 'N. octahydro OH cyclopenta[c]pyrrol- 4 -ol -28- WO 2007/061741 PCT/US2006/044479 Cmpd No. Chemical Structure Chemical Name 2-Cyclobutyl-4-[4-(2 N pyrrolidin-l1-yl-ethyl) phenyl]-octahydro OH cyclopenta[c]pyrrol-4-ol N 2-Benzyl-4-[3-(2
O
f pyrrolidin-l1-yl-ethoxy) A22 N OH phenyl]-octahydro cyclopenta[c]pyrrol-4-ol OH TABLE B Cmpd No. Chemical Structure Chemical Name No 2-Benzyl-4-[4-(2 BN1 pyrrolidin-1-yl-ethyl) B * phenyl]-octahydro cyclopenta[c]pyrrole 4-[4-(2-Pyrrolidin-1-yl B2 N ethyl)-phenyl] B2 H octahydro cyclopenta[c]pyrrole 2-Cyclopropylmethyl No 4-[4-(2-pyrrolidin-1-yl B3 N ethyl)-phenyl] octahydro cyclopenta[c]pyrrole -29 - WO 2007/061741 PCT/US2006/044479 Cmpd No. Chemical Structure Chemical Name 2-Isopropyl-4-[4-(2 No pyrrolidin-1-yl-ethyl) B4 phenyl]-octahydro cyclopenta[c]pyrrole 2-Cyclopentyl-4-[4-(2 pyrrolidin-1-yl-ethyl) B5 N phenyl]-octahydro cyclopenta[c]pyrrole 2-(2,4-Dimethoxy OMe NF benzyl)-4-[4-(2 B6 I N pyrrolidin-1 -yl-ethyl) MeO phenyl]-octahydro cyclopenta[c]pyrrole 2-Cyclohexyl-4-[4-(2 B7 pyrrolidin-1-yl-ethyl) phenyl]-octahydro cyclopenta[c]pyrrole 4- {4-[4-(2-Pyrrolidin .N 1-yl-ethyl)-phenyl] B8 N hexahydro cyclopenta[c]pyrrol-2 ylmethyl} -phenol S 2-Cyclobutyl-4-[4-(2 No pyrrolidin-1 -yl-ethyl) B9 phenyl]-octahydro cyclopenta[c]pyrrole -30- WO 2007/061741 PCT/US2006/044479 It: :: : ~ i F:"t'" , L .!!i I I ! V:;, < I qI, ,,i, - :; 1::1 Cmpd No. Chemical Structure Chemical Name 2- { 4 -[4-(2-Pyrrolidin HO' N C 1-yl-ethyl)-phenyl] B10 N hexahydro cyclopenta[c]pyrrol-2 yl}-propan-1l-ol 2-Isobutyl-4-[4-(2 B11 N pyrrolidin-1-yl-ethyl) phenyl]-octahydro cyclopenta[c]pyrrole 2-(4-Methoxy-benzyl) N0 4-[4-(2-pyrrolidin-1-yl B12 HCN Oethyl)-phenyl]
H
3 CO octahydro cyclopenta[c]pyrrole 4-[4-(2-Pyrrolidin-1-yl N ethyl)-phenyl]-2-(4 B 13 F N trifluoromethoxy
F
3 CO benzyl)-octahydro cyclopenta[c]pyrrole 4- {4-[4-(2-Pyrrolidin 4No 1-yl-ethyl)-phenyl] B14 N hexahydro cyclopenta[c]pyrrol-2 ylmethyl}-phenol 1- {4-[4-(2-Pyrrolidin 0 N401-yl-ethyl)-phenyl] B15 N I hexahydro cyclopenta[c]pyrrol-2 yl} -ethanone -31- WO 2007/061741 PCT/US2006/044479 II: " N " t I:' I,, -!.! :::,,i !! . ,!! 1i .1 " 11.1 ":;,'.' 11:::11 Cmpd No. Chemical Structure Chemical Name 2-Methyl-1- {4-[4-(2 O N pyrrolidin-1-yl-ethyl) B16 N I phenyl]-hexahydro cyclopenta[c]pyrrol-2 yl}-propan-1l-one Cyclopropyl- {4-[4-(2 O No pyrrolidin-1-yl-ethyl) B17 N phenyl]-hexahydro cyclopenta[c]pyrrol-2 yl}-methanone Cyclopentyl- {4-[4-(2 O- NK pyrrolidin-1-yl-ethyl) B 18 N phenyl]-hexahydro cyclopenta[c]pyrrol-2 yl}-methanone 4-[4-(2-Pyrrolidin-1-yl o NO ethyl)-phenyl] B19
O
1 N hexahydro cyclopenta[c]pyrrole-2 carboxylic acid ethyl ester 2-Hydroxy-1- {4-[4-(2 HO 0L N pyrrolidin-1-yl-ethyl) B20 N phenyl]-hexahydro cyclopenta[c]pyrrol-2 yl} -ethanone 4-[4-(2-Pyrrolidin-1 -yl No 2 ethyl)-phenyl]-2-(4 B21 F N trifluoromethyl FC benzyl)-octahydro cyclopenta[c]pyrrole - 32 - WO 2007/061741 PCT/US2006/044479 11 ~ 11 ll 1::, RR , I q:::11 Cmpd No. Chemical Structure Chemical Name No 2-Methyl-4-[4-(2 B22 N pyrrolidin-l1-yl-ethyl) phenyl]-octahydro cyclopenta[c]pyrrole 2-Ethyl-4-[4-(2 B23 'N N pyrrolidin-1-yl-ethyl) phenyl]-octahydro cyclopenta[c]pyrrole (4- {4-[2-(2-Methyl pyrrolidin-1 -yl)-ethyl] 0 B24 N phenyl}-hexahydro BO N cyclopenta[c]pyrrol-2 yl)-(tetrahydro-furan-3 yl)-methanone Cyclopropyl-(4- {4-[2 (2-methyl-pyrrolidin-1 B25N yl)-ethyl]-phenyl} B25 hexahydro cyclopenta[c]pyrrol-2 yl)-methanone (4- {4-[2-(2-Methyl pyrrolidin-1-yl)-ethyl] SN phenyl}-hexahydro B26 OB26 N cyclopenta[c]pyrrol-2 yl)-(tetrahydro-pyran 4-yl)-methanone 2-Methyl-l-(4-{4-[2 I (2-methyl-pyrrolidin- 1 B 0' N yl)-ethyl]-phenyl} B27 N hexahydro cyclopenta[c]pyrrol-2 yl)-propan-1l-one -33- WO 2007/061741 PCT/US2006/044479 Cmpd No. Chemical Structure Chemical Name Cyclopentyl-(4- {4-[2 (2-methyl-pyrrolidin-1 0 B28 N yl)-ethyl]-phenyl } BJ"hexahydro cyclopenta[c]pyrrol-2 yl)-methanone (4-{4-[2-(2-Methyl pyrrolidin-1-yl)-ethyl] O B29 N phenyl}-hexahydro B29 NN I " cyclopenta[c]pyrrol-2 yl)-pyridin-3-yl methanone (4-{4-[2-(2-Methyl pyrrolidin-1-yl)-ethyl] O B3N phenyl}-hexahydro B30 N cyclopenta[c]pyrrol-2 yl)-pyrazin-2-yl methanone Cyclohexyl-(4- {4-[2 (2-methyl-pyrrolidin-1 0 B31 N yl)-ethyl]-phenyl} B31 N N hexahydro cyclopenta[c]pyrrol-2 yl)-methanone 2-(2-Fluoro-ethyl)-4 F32- N {4-[2-(2-methyl B32 pyrrolidin-1-yl)-ethyl] phenyl}-octahydro cyclopenta[c]pyrrole - 34 - WO 2007/061741 PCT/US2006/044479 Cmpd No. Chemical Structure Chemical Name 3-Methyl-l-(4- {4-[2 ' (2-methyl-pyrrolidin- 1 B33 N yl)-ethyl]-phenyl} B33 N hexahydro cyclopenta[c]pyrrol-2 yl)-butan-1l-one 2,2,2-Trifluoro-1 -(4 {4-[2-(2-methyl 0 FaC NN pyrrolidin-1-yl)-ethyl] B34 phenyl}-hexahydro cyclopenta[c]pyrrol-2 yl)-ethanone 1-(4- {4-[2-(2-Methyl pyrrolidin-1-yl)-ethyl] B35 N phenyl}-hexahydro B35 N cyclopenta[c]pyrrol-2 yl)-2-thiophen-2-yl ethanone Cyclopentyl-(5-methyl 4- {4-[2-(2-methyl N36 N pyrrolidin-1-yl)-ethyl] B36 (-"N I B phenyl} -hexahydro cyclopenta[c]pyrrol-2 yl)-methanone 2,2-Dimethyl-1l-(4- {4 [2-(2-methyl B N pyrrolidin-1-yl)-ethyl] B37 3 phenyl} -hexahydro cyclopenta[c]pyrrol-2 yl)-propan-1l-one -35- WO 2007/061741 PCT/US2006/044479 Cmpd No. Chemical Structure Chemical Name 1-(4-{4-[2-(2-Methyl O N pyrrolidin-1-yl)-ethyl] B38 N phenyl}-hexahydro cyclopenta[c]pyrrol-2 yl)-ethanone 1-(4- {4-[2-(2-Methyl pyrrolidin-1-yl)-ethyl] B39 NIk phenyl}-hexahydro cyclopenta[c]pyrrol-2 yl)-2-phenyl-ethanone 1-(4- {4-[2-(2-Methyl pyrrolidin-1-yl)-ethyl] B40 phenyl}-hexahydro B40 cyclopenta[c]pyrrol-2 yl)-2-(tetrahydro pyran-4-yl)-ethanone (4- {4-[2-(2-Methyl pyrrolidin-1-yl)-ethyl] ON N phenyl}-hexahydro B41 cyclopenta[c]pyrrol-2 N yl)-pyrimidin-5-yl methanone 2-Methoxy-1-(4- {4-[2 (2-methyl-pyrrolidin- 1 B42 O yl)-ethyl]-phenyl} hexahydro cyclopenta[c]pyrrol- 2 yl)-ethanone - 36 - WO 2007/061741 PCT/US2006/044479 I ;: ' ~ ~ ~ ~ ~ ... [,,'' ."f
'
," tl I::iit i;i ... ..ii "" I ' I Cmpd No. Chemical Structure Chemical Name 2-(2,2-Difluoro-ethyl) Fi N 4-{4-[2-(2-methyl B43 pyrrolidin-1-yl)-ethyl] F phenyl}-octahydro cyclopenta[c]pyrrole (4- {4-[2-(2-Methyl O Npyrrolidin-1-yl)-ethyl] B44 N phenyl}-hexahydro cyclopenta[c]pyrrol-2 yl)-phenyl-methanone 4- {4-[2-(2-Methyl pyrrolidin-1-yl)-ethyl] 4 N phenyl}-2-(2,2,2 B45 F trifluoro-ethyl) octahydro cyclopenta[c]pyrrole (4- {4-[2-(2-Methyl- 1 oxy-pyrrolidin-1-yl) O N ethyl]-phenyl} B46 O hexahydro o 0 cyclopenta[c]pyrrol-2 yl)-(tetrahydro-pyran 4-yl)-methanone (4-{4-[2-(2 Hydroxymethyl O HO pyrrolidin-1-yl)-ethyl] B47 O N phenyl}-hexahydro cyclopenta[c]pyrrol-2 yl)-(tetrahydro-pyran 4-yl)-methanone -37- WO 2007/061741 PCT/US2006/044479 Cmpd No. Chemical Structure Chemical Name (4-{4-[2-(2 Methoxymethyl O pyrrolidin-1-yl)-ethyl] B48 N phenyl}-hexahydro cyclopenta[c]pyrrol-2 yl)-(tetrahydro-pyran 4-yl)-methanone 1-(2- {4-[2-(Tetrahydro 0 pyran-4-carbonyl)
H
2 N octahydro 0 B49 O N cyclopenta[c]pyrrol-4 O \yl]-phenyl}-ethyl) pyrrolidine-2 carboxylic acid amide 1-(2-{4-[2-(Tetrahydro pyran-4-carbonyl) O N octahydro 0 H cyclopenta[c]pyrrol-4 B50N yl]-phenyl}-ethyl) pyrrolidine-2 carboxylic acid methylamide {4-[4-(2-Pyrrolidin- 1 N yl-ethyl)-phenyl] B51 hexahydro B51 NOcyclopenta[c]pyrrol-2 yl} -(tetrahydro-pyran 4-yl)-methanone {4-[4-(2-Piperidin-1-yl ethyl)-phenyl] O B52 N hexahydro B52 O cyclopenta[c]pyrrol-2 yl} -(tetrahydro-pyran 4-yl)-methanone -38- WO 2007/061741 PCT/US2006/044479 Cmpd No. Chemical Structure Chemical Name {4-[4-(2 Diisopropylamino O ethyl)-phenyl] B53 Nhexahydro cyclopenta[c]pyrrol-2 yl} -(tetrahydro-pyran 4-yl)-methanone {4-[4-(2-Morpholin-4 ("O yl-ethyl)-phenyl] O N,) hexahydro B54 ON ' cyclopenta[c]pyrrol-2 yl} -(tetrahydro-pyran 4-yl)-methanone (4- {4-[2-(3-Hydroxy H Spyrrolidin-1-yl)-ethyl] B55 N phenyl}-hexahydro BN5cyclopenta[c]pyrrol-2 yl)-(tetrahydro-pyran 4-yl)-methanone (4- {4-[2-(3,3-Difluoro F pyrrolidin-1-yl)-ethyl] O phenyl}-hexahydro B56 0.
" N cyclopenta[c]pyrrol-2 yl)-(tetrahydro-pyran 4-yl)-methanone TABLE C pd "Chemical Structure Chemical Name No. - 39 - WO 2007/061741 PCT/US2006/044479 CmpdChemical Structure Chemical Name No. 6-[4-(2-Pyrrolidin-1 yl-ethyl)-phenyl] Ci N 1,2,3,3a,4,6a HN I hexahydro I cyclopenta[c]pyrrole 2-Benzyl-6-[4-(2 Nr2~ pyrrolidin-1 -yl-ethyl) 'NN C2 I N phenyl]-1,2,3,3a,4,6a I hexahydro cyclopenta[c]pyrrole 2-Benzyl-6-{4-[2-(2 methyl-piperidin-1 -yl) C3N N? ethyl]-phenyl} N 1,2,3,3a,4,6a I hexahydro cyclopenta[c]pyrrole 2-Benzyl-6-{4-12-(4 r N methyl-piperazin-1 N yl)-ethylll-phenyl} C4 I 1,2,3,3a,4,6a hexahydro cyclopenta[c]pyrrole 2-B enzyl-6- {4-[2-(2,5 dimethyl-pyrrolidin- 1 C5N yl)-ethyl]-phenyl} C 1 ,2,3,3a,4,6a hexahydro cyclopenta[c]pyrrole {2-[4-(2-Benzyl I 1,2,3,3a,6,6a If N N ~ hexahydro C6 cyclopentalclpyrrol- 4 yl)-phenyl] -ethyl} dimethyl-amine -40- WO 2007/061741 PCT/US2006/044479 Chemical Structure Chemical Name No. 2-Benzyl-6-{4-[2-(2 methyl-pyrrolidin-1 C7 N" N yl)-ethyl] -phenyl} 1,2,3,3a,4,6a hexahydro cyclopenta[c]pyrrole 2-Benzyl-6-{4-[2-(2,2 dimethyl-pyrrolidin-1 C8 N yl)-ethyl]-phenyl} 1,2,3,3a,4,6a hexahydro cyclopenta[c]pyrrole 2-Benzyl-6-[4-(2 r o morpholin-4-yl-ethyl) C9 /fr"Nphenyl]-1 ,2,3,3a,4,6a hexahydro cyclopenta[c]pyrrole (1- {2-[4-(2-Benzyl 1,2,3,3a,6,6a hexahydro CloN cyclopenta[clpyrrol-4 HO yl)-phenyl] -ethyl} pyrrolidin-2-yl) methanol I- {2-[4-(2-Benzyl OH 1,2,3,3a,6,6a C1i f hexahydro I " NN cyclopenta[c]pyrrol-4 -~ yl)-phenyl] -ethyl} pyrrolidin-3-ol WO 2007/061741 PCT/US2006/044479 1 11::::; IF"I II:: Chemical Structure Chemical Name No. 2-Benzyl-6- {4-[2-(3,3 7J<F difluoro-pyrrolidin-1 C12 I N Iyl)-ethylll-phenyl} C1 1,2,3,3a,4,6a hexahydro cyclopenta[c~pyrrole 6-[4-(2-Azetidin-1 -yl N'III1 ethyl)-phenyl] -2 C13 1~f~N benzyl-1,2,3,3a,4,6a I hexahydro cyclopenta[c]pyrrole 2-B enzyl-6- {4-[2-(3,3 difluoro-piperidin-1 C4NN F ZF yl)-ethyl]-phenyl} C r 1,2,3,3a,4,6a I hexahydro cyclopenta[c]pyrrole 2- {2-[4-(2-Benzyl C15P hexahydro cyclopenta[c]pyrrol-4 I yl)-phenyl]-ethyl} -2,3 dihydro-il-isoindole 2- {2-[4-(2-Benzyl 1 ,2,3,3a,6,6a Kji) hexahydro C16 /~'N cyclopenta[c]pyrrol-4 yl)-phenyl] -ethyl} 1 ,2,3,4-tetrahydro isoquinoline, -42 - WO 2007/061741 PCT/US2006/044479 Chemical Structure Chemical Name No. 1- {2-[4-(2-Benzyl 1,2,3,3a,6,6a NN / hexahydro C1 -b Cl7 cyclopenta[c]pyrrol-4 yl)-phenyl] -ethyl) -2,3 dihydro-1H-indole 4-(2-Benzyl 0 1,2,3,3a,6,6a C18 ~Nhexahydro C18 N Hcyclopenta[c]pyrrol-4 yl)-N-methyl benzamide 2-Cyclopropylmethyl 6-[4-(2-pyrrolidin-1 No yl-.ethyl)-phenyl] C19 N N~1,2,3,3a,4,6a hexahydro cyclopenta[c]pyrrole 2-Cyclopentyl-6-[4-(2 pyrrolidin-1 -yl-ethyl) C20 Nphenylj.-l,2,3,3a,4,6a I hexahydro cyclopenta[c]pyrrole 2-(4-Methoxy-benzyl) 6-[4-(2-pyrrolidin-1 C21 N yl-ethyl)-phenyl]
H
3 COO _1 1 ,2,3,3a,4,6a hexahyciro cyclopenta[c]pyrrole 2-Isopropyl-6-[4-(2 C22 N Iphenyl]-l,2,3,3a,4,6a I hexahydro cyclopenta[c]pyrrole -43 - WO 2007/061741 PCT/US2006/044479 ~ ~~~~~l II 11: il . Chemical Structure Chemical Name No. 2-Cyclobutyl-6-[4-(2 pyrrolidin-1-yl-ethyl) C23 Nphenyl]-1 ,2, 3,3a,4, 6a I hexahydro cyclopenta[c]pyrrole 2- {6-[4-(2-Pyrrolidin N4 1 -yl-ethyl)-phenyl] C24 HO3,3a,4,6a-tetrahydro 111 I cyclopenta[c]pyrrol-2 yl}-propan-1-ol Pyridin-4-yl- f{6-[4-(2 N pyrrolidin-1 -yl-ethyl) C25 Dphenyl]-3 ,3a,4,6a C25 N tetrahydro-1H cyclopenta[c]pyrrol-2 yl} -methanone 4- {6-[4-(2-Pyrrolidin No 1-yl-ethyl)-phenyl] C26 IN NN/' 3,3a,4,6a-tetrahydro I cyclopenta[c]pyrrol-2 ylmethyl} -phenol 2-Cyclolaexyl-6-[4-(2 6") NO7 pyrrolidin-1-yl-ethyl) C27 "'"'NIphenyl]-1,2,3,3a,4,6a hexahydro cyclopenta[c]pyrrole 2-Methyl-6-[4-(2 NoI& pyrrolidin-1 -yl-ethyl) C28 "N Iphenyl]-1,2,3,3a,4,6a I hexahydro cyclopenta[clpyrrole -44 - WO 2007/061741 PCT/US2006/044479 (npdChemical Structure Chemical Name No. Cyclopentyl-(5 methyl-6- {4-[2-(2 0N methylbpyrrolidin-1 C29 ~y)-ethyl] -phenyl} C29 3,3a,4,6a-tetrahydro 111 cyclopenta[c]pyrrol-2 yl)-methanone 2-Isobutyl-6-[4-(2
N~
2 ~ pyrrolidin-1 -yl-ethyl) C30 N Iphenyl]-l ,2,3,3a,4,6a hexahydro cyclopenta[c]pyrrole 2-(2,4-Dimethoxy OMe NoI& benzyl)-6-[4-(2 C31 Npyrrolidin-1 -yl-ethyl) MeO~d :b phenyl]-1,2,3,3a,4,6a hexahydro cyclopenta[c]pyrrole 6-[4-(2-Pyrrolidin-l C32 I N Itrifluoromethoxy
F
3 CO-0 - benzyl)-1 ,2,3,3a,4,6a hexahydro cyclopenta[clpyrrole Cyclopropyl- {6-[4-(2 0 Nr2~ pyrrolidin-1-yl-ethyl) C33 0'~ ND phenyl]-3,3a,4,6a tetrahydro-1H cyclopenta[c]pyrrol-2 yl} -methanone -45 - WO 2007/061741 PCT/US2006/044479 mp Chemical Structure Chemical Name No. 2-Methyl-1 -{6-[4-(2 -I pyrrolidin-1-yl-ethyl) O N phenyl]-3,3a,4,6a C34 tetrahydro-1H cyclopenta[c]pyrrol-2 yl} -propan-1l-one Cyclopentyl- {6-[4-(2 pyrrolidin-1-yl-ethyl) 0 No phenyl]-3,3a,4,6a C35 N_ C35 tetrahydro-1H cyclopenta[c]pyrrol-2 yl} -methanone 6-[4-(2-Pyrrolidin-1 yl-ethyl)-phenyl] O 3,3a,4,6a-tetrahydro C36 .o-. N 1H 3 cyclopenta[c]pyrrole 2-carboxylic acid ethyl ester 6-[4-(2-Pyrrolidin- 1 yl-ethyl)-phenyl] 0 No 3,3a,4,6a-tetrahydro C37 H N 1H p cyclopenta[c]pyrrole 2-carboxylic acid isopropylamide 6-[4-(2-Pyrrolidin- 1 yl-ethyl)-phenyl] 0 No 3,3a,4,6a-tetrahydro C38 N N 1H cyclopenta[c]pyrrole 2-carboxylic acid cyclopentylamide -46 - WO 2007/061741 PCT/US2006/044479 CmpdChemical Structure Chemical Name No. 2-Pyridin-2-yl-6-[4-(2 No 2 pyrrolidin-l-yl-ethyl) C39 N~ phenylj-1,2,3,3a,4,6a I hexahydro cyclopenta[c]pyrrole 2-ilydroxy- 1 - {6-[4-(2 pyrrolidin-l -yl-ethyl) 0 ND C40 HO,A(N- phenyl]-3,3a,4,6a tetrahydro-1H cyclopenta[c]pyrrol-2 yl} -ethanone 2-[4-(2-Benzyl
NH
2 1,2,3,3a,6,6a C41 I N hexahydro cyclopenta[c]pyrrol-4 yl)-phenyl]-ethylamine 2-Benzyl-6-[6-(2 pyrrolidin-1-yl-ethyl) N NV pyridin-3-yl] C4 IN~ N I1,2,3,3a 4,6a I hexahydro cyclopenta[c]pyrrole 2-Benzyl-6-[4-(2 pyrrolidin- i-yb N ethoxy)-phenyl] C43 ~ J l,2,3,3a,4,6a hexahydro cyclopenta[c]pyrrole 2-Benzyl-6-[3-(2 pyrrolidin-1 -yl C44 N NOethoxy)-phenyl] 0 1,2,3,3a,4,6a hexahydro cyclopenta[c]pyrrole -47 - WO 2007/061741 PCT/US2006/044479 LmclChemical Structure Chemical Name No. 2-Benzyl-6-[5-(2 pyrrolidin-1 -yl-ethyl) C45 N~ ~ N ,2,3,3a,4,6a hexahydro cyclopenta[c]pyrrole 1- {6-[4-(2-Pyrrolidin 1 -yl-ethyl)-phenyllj C46 NV3,3a,4,6a-tetrahydro I cyclopenta[c]pyrrol-2 yl} -ethanone (6- {4-[2-(2-Methyl pyrrolidin-1 -yl)-ethyll 0NrhI phenyl} -3,3a,4,6a C47 Oc~Ntetrahydro-1H cyclopenta[c]pyrrol-2 yl)-(tetrahydro-furan 3-yl)-methanone 4-(2-Benzyl
NNH
2 1,2,3,3a,6,6a C48 hexahydro I cyclopentailcjpyrrol-4 yl)-benzylamine 3-(2-Benzyl C4 1 ( N NH~ 1,2,3,3a,6,6a I cyclopenta[c]pyrrol-4 yl)-benzylamine 2-Benzyl-6-[4-(2 piperidin-1 -yl-ethyl) C50 N N phenyl]-1,2,3,3a,4,6a I cyclopenta[c]pyrrole -48 - WO 2007/061741 PCT/US2006/044479 Cp Chemical Structure Chemical Name No. 2-Ethyl-6-[4-(2 N pyrrolidin-1-yl-ethyl) C51 N phenyl]-1,2,3,3a,4,6a hexahydro cyclopenta[c]pyrrole 6- {4-[2-(2-Methyl O O N pyrrolidin-1-yl)-ethyl] phenyl} -3,3a,4,6a C52 tetrahydro-lH cyclopenta[c]pyrrole 2-carboxylic acid ethyl ester 2-Hydroxy-2-methyl O 1- {6-[4-(2-pyrrolidin ' N 1-yl-ethyl)-phenyl] C53 HO 3,3a,4,6a-tetrahydro 1H cyclopenta[c]pyrrol-2 yl} -propan-1l-one 2-Phenyl-6-[4-(2 S.pyrrolidin-1-yl-ethyl) C54 N phenyl]-1,2,3,3a,4,6a hexahydro cyclopenta[c]pyrrole 6-[4-(2-Pyrrolidin-1 O No yl-ethyl)-phenyl] 3,3a,4,6a-tetrahydro I C55 1H cyclopenta[c]pyrrole 2-carboxylic acid dimethylamide -49 - WO 2007/061741 PCT/US2006/044479 Chemical Structure Chemical Name No. 2-Cyclopentylmethyl No 6-[4-(2-pyrrolidin-1 C56 6> NNN yl-ethyl)-phenyl] l,2,3,3a,4,6a hexahydro cyclopenta[c]pyrrole 1 -{2-[4-(2-Benzyl 0 1,2,3,3a,6,6a C57 hexahydro C5I cyclopenta[c]pyrrol-4 I yl)-phenyl]-ethyl} pyrrolidin-2-one {6-[4-(2-Pyrrolidin-l 0 No yl-ethyl)-phenyl] /s N 3,3a,4,6a-tetrahydro C58 I lH cyclopenta[clpyrrol-2 yl} -thiophen-2-yl methanone 2-Pyridin-3 -yl-6-[4-(2 N Nr~ pyrrolidin-1-yl-ethyl) C59 Nphenyll-1 ,2,3 ,3a,4,6a hexahydro cyclopenta[c]pyrrole 2-Pyridin-4-yl-6-[4-(2 No pyrrolidin-1-yl-ethyl) C60 N phenyl]-l,2,3,3a,4,6a cyclopenta[c]pyrrole -50- WO 2007/061741 PCT/US2006/044479 lr I:, 11 1 [::: H I mpChemical Structure Chemical Name No. Furan-2-yl- {6-[4-(2 0 NoIQ pyrrolidin-l -yl-ethyl) C61 ' / Nphenyl]-3,3a,4,6a C61 tetrahydro-lil cyclopenta[c]pyrrol-2 yl} -methanone Morpholin-4-yl-{6-[4 o NoII (2-pyrrolidin-1 -yl rK-\NA' ethyl)-phenyl] C62 G )3,3a,4,6a-tetrahydro 111 cyclopenta[c]pyffol-2 yl} -methanone 3- {6-[4-(2-Pyrrolidin OHC~& NI&~ 1-yl-ethyl)-phenyl]- C63 OC NN 3,3a,4,6a-tetrahydro 111 cyclopenta[c]pyrrol-2 yl} -benzaldehyde 2-(3-Methoxy-phenyl) NDII 6-[4-(2-pyrrolidin-1 C64 H 3 CO%). N--\ yl-ethyl)-phenyl] 1,2,3,3a,4,6a hexahydro cyclopenta[c]pyrrole 6-[4-(2-Pyrrolidin-l Nr2 yl-ethyl)-phenyl] -2 C65 N'NIthiazol-2-yl 1,2,3,3a,4,6a hexahydro cyclopenta[c]pyrrole WO 2007/061741 PCT/US2006/044479 dn Chemical Structure Chemical Name No. Pyridin-3-yl-{6-[4-(2 0 No 2 pyrrolidin- 1-yl-ethyl) C66 I Nphenyl]-3,3a,4,6a N tetrahydro-lil cyclopenta[c]pyrrol-2 yl} -methanone Pyridin-2-yl- {6-[4-(2 N 0 NI pyrrolidin-1-yl-ethyl) C67 I Nphenyl]-3,3a,4,6a N--N tetrahydro-1H cyclopenta[c]pyrrol-2 yl} -methanone Cyclohexyl- {6-[4-(2 o pyrrolidin-1-yl-ethyl) N N~vphenyl]-3,3a,4,6a C68 O tetrahyciro-lil cyclopenta[c]pyrrol-2 yl} -methanone {6-[4-(2-Pyrrolidin-1 o0r2 yl-ethyl)-phenyll oo A) -- 3,3a,4,6a-tetrahydro C69 111 cyclopenta[c]pyrrol-2 yl} -(tetrahydro-furan 3-yl)-methanone 2-Pyrazin-2-yl-6-[4-(2 N NKI0 pyrrolidin-l1 -yl-ethyl) C70 ~ C - phenyl]-1,2,3,3a,4,6a hexahydro cyclopenta[c]py-rrole - 52 - WO 2007/061741 PCT/US2006/044479 Chemical Structure Chemical Name Phenyl- {6-[4-(2 0 pyrrolidin-1-yl-ethyl) C71 phenyl]-3,3a,4,6a-. C71 K>tetrahydro-il cyclopenta[c]pyrrol-2 yl} -methanone 2-Phenyl-1l-{6-[4-(2 (~oND pyrrolidin-1 -yl-ethyl) C7 N phenyl]-3,3a,4,6a tetrahydro-1H cyclopenta[c]pyrrol-2 yl} -ethanone 2-Methanesulfonyl-6 00 [4-(2-pyrrolidin-1 -yl C73 N ethyl)-phenyl] 1,2,3,3a,4,6a hexahydro cyclopenta[c]pyrrole 2-(Propane-2 0,p r2 sulfonyl)-6-[4-(2 C74 , ,Npyrrolidin-1 -yl-ethyl) phenyl]-1,2,3,3a,4,6a hexahydro cyclopenta[clpyrrole 2-Benzenesulfonyl-6 0 K'>N [4-(2-pyrrolidin-1 -yl N.~- ethyl)-phenyl] C75 S-'N hexahydro cyclopenta[c]pyrrole - 53 - WO 2007/061741 PCT/US2006/044479 Chemical Structure Chemical Name No. 2 00 IPhenylmethanesulfony N 1-6-[4-(2-pyrrolidin-1 C76 yl-ethyl)-phenyl] 1,2,3,3a,4,6a hexahydro cyclopenta[c]pyrrole Pyrazin-2-yl- {6-[4-(2 O NC pyrrolidin-1-yl-ethyl) C7 phenyl]-3,3a,4,6a C77 N tetrahydro-lH cyclopenta[c]pyrrol-2 yl} -methanone 2-Pyrimidin-2-yl-6-[4 (N No2 (2-pyrrolidin-1-yl C78 N ethyl)-phenyl] C78 1,2,3,3a,4,6a hexahydro cyclopenta[c]pyrrole 2-Methyl-l-(6-{4-[2 O NO yO (3-phenyl-pyrrolidin-1 N yl)-ethyl]-phenyl} C79 3,3a,4,6a-tetrahydro 1H cyclopenta[c]pyrrol-2 yl)-propan-1l-one 1-(6-{4-[2-(2 Isopropyl-pyrrolidin-1 0No yl)-ethyl]-phenyl} C80 N 3,3a,4,6a-tetrahydro 111 cyclopenta[c]pyrrol-2 yl)-2-methyl-propan-1 one - 54- WO 2007/061741 PCT/US2006/044479 p Chemical Structure Chemical Name No. 2-Benzyl-6- {4-[2-(2
F
3 C trifluoromethyl C81pyrrolidin-1-yl)-ethyl] 081 Nphenyl}-1,2,3,3a,4,6a hexahydro cyclopenta[c]pyrrole 2-Methyl-l-(6-{4-[2 0 (2-phenyl-pyrrolidin- 1 N yl)-ethyl]-phenyl} C82 3,3a,4,6a-tetrahydro 1H cyclopenta[c]pyrrol-2 yl)-propan-1l-one 2-Methyl-l-(6- {4-[2 (2-methyl-pyrrolidin SN 1-yl)-ethyl]-phenyl } C83 N 3,3a,4,6a-tetrahydro 1H cyclopenta[c]pyrrol-2 yl)-propan-1l-one Isoxazol-5-yl- {6-[4-(2 0 Npyrrolidin-1-yl-ethyl) C084 N N phenyl]-3,3a,4,6a C84 NL ". tetrahydro-lH cyclopenta[c]pyrrol-2 yl} -methanone 2-Pyridin-3-yl-1- {6-[4 N 0,1AO ND(2-pyrrolidin-1-yl N ethyl)-phenyl] C85 3,3a,4,6a-tetrahydro 1H cyclopenta[c]pyrrol-2 yl}-ethanone - 55 - WO 2007/061741 PCT/US2006/044479 MPu Chemical Structure Chemical Name No. 2-Ethanesulfonyl-6-[4 00 N ~~ (2-pyrrolidin-1-yl C86 Nl NN ethyl)-phenylj I 1,2,3,3a,4,6a hexahydro cyclopenta[c]pyrrole 2-Pyridin-2-yl--f {6-[4 - 0 0 (2-pyrrolidin-1-yl N N~ ethyl)-phenyl] C87 3 ,3a,4,6a-tetrahydro 1W cyclopenta[c]pyrrol-2 yl} -ethanone HO Hydroxymethyl 0N, pyrrolidin-1-yl)-ethyl] N88 phenyl}-3,3a,4,6a C88 I tetrahyclro-1H cyclopenta[c]pyrrol-2 yl)-2-methyl-propa-n-1 one 2-Pyridin-4-yl-1 -{6-[4 IJ N ethyl)-phenyl] C89 3 ,3a,4,6a-tetrahydro 111 cyclopenta[c]pyrrol-2 yl} -ethanone 2 0 0~ Cyclopropanesulfonyl X-~ N 6-[4-(2-pyrrolidin-1 C90 yl-ethyl)-phenyl] 1 ,2,3,3a,4,6a hexahydro cyclopenta[c]pyrrole -56- WO 2007/061741 PCT/US2006/044479 Chemical Structure Chemical Name No. 2-Pyrimidin-5-yl-6-[4 Nr2 (2-pyrrolidin-1-yl C9 1 N 4 ethyl)-phenyl] -1,2,3,3a,4,6a hexahydro cyclopenta[c]pyrrole Cyclopropyl-(6-f 4-[2 (2-methyl-pyrrolidin 0No I-yl)-ethyl]-phenyl} C92 3 ,3a,4,6a-tetrahydro cyclopenta[c]pyrrol-2 yl)-methanone 2 0 Cyclopropanesulfonyl 9~pN 6-{44[2-(2-methyl C93 N pyrrolidin-1 -yl)-ethyl] I phenyl}-1,2,3,3a,4,6a hexahydro cyclopenta[c]pyrrole 6- {4-[2-(2-Methyl pyrrolidin-1 -yl)-ethyl] phenyl} -2-(propane-2 0 C94 'y~ONsulfonyl) N I 1,2,3,3a,4,6a I hexahydro cyclopenta[c]pyrrole (6- {4-[2-(2-Methyl 0 ~pyrrolidin- 1 -yl)-ethyl] N phenyl}-3,3a,4,6a C95 ~ N iN . tetrahydro-1IH I cyclopenta[c]pyrrol-2 yl)-pyridin-3 -yl methanone - 57 - WO 2007/061741 PCT/US2006/044479 N.Chemical Structure Chemical Name Cyclopentyl-(6- {4-{2 0 (2-methyl-pyrrolidin C6N 1-yl)-ethyl]-phenyl} C96 J~ N3,3a,4,6a-tetrahydro cyclopenta[clpyrrol-2 yl)-methanone 1 -(6-{4-[2-(2-Methyl >-\ Pyrrolidin-1 -yl)-ethyl] C97 0 1"J N N phenyl}-3,3a,4,6a tetrahydro-1H I cYclopenta[clpyrrol-2 Yl)-2-phenyl-ethanone 2-(3,5-Difluoro F phenyl)-6-[4-(2 C98 Nopyrrolidin-1-yl-ethyl) N Iphenyl]-1,2,3,3a,4,6a I hexahydro cyclopenta[clpyrrole 3- {6-[4-(2-Pyrrolidin NC-'I1Q No> 1-yl-ethyl)-phenyl] C99 NNy 3,3a,4,6a-tetrahyclro I111 cyclopenta[c]pyrrol-2 yl} -benzonitrile 0 Dimethyl-pyrrolidin-1 _N yl)-ethyl]-phenyl} N10 3,3a,4,6a-tetrahydro 111 cyclopenta[clpyrrol-2 yl)-2-methyl-propan-1 one -58- WO 2007/061741 PCT/US2006/044479 Chemical Structure Chemical Name No. (6-{4-[2-(2-Methyl pyrrolidin-l1-yl)-ethyl] O S0N phenyl}-3,3a,4,6a C11 /(I tetrahydro-lH cyclopenta[c]pyrrol-2 yl)-phenyl-methanone 6-{4-[2-(2-Methyl
F
3 C pyrrolidin-1-yl)-ethyl] N phenyl}-2-(6 N12trifluoromethyl C102 pyridin-3-yl) 1,2,3,3a,4,6a hexahydro cyclopenta[c]pyrrole 5-(6- {4-[2-(2-Methyl NC pyrrolidin-1-yl)-ethyl] N phenyl} -3,3a,4,6a C103 tetrahydro-lH cyclopenta[c]pyrrol-2 yl)-pyridine-2 carbonitrile (6- {4-[2-(2-Methyl pyrrolidin-1-yl)-ethyl] 0 N I N phenyl}-3,3a,4,6a C104 00 tetrahydro-IH cyclopenta[c]pyrrol-2 yl)-(tetrahydro-pyran 4-yl)-methanone 2-Benzyl-5-methyl-6 {4-[2-(2-methyl ,NN pyrrolidin-1-yl)-ethyl] C107/ N I phenyl}-1,2,3,3a,4,6a hexahydro cyclopenta[c]pyrrole - 59- WO 2007/061741 PCT/US2006/044479 Chemical Structure Chemical Name No. 2-Benzyl-6-[4-(2 jN6 methyl-pyrrolidin-1 C106 ylmethyl)-phenyl] C10 1,2,3,3a,4,6a hexahydro cyclopenta[c]pyrrole TABLE D Cmpd No. Chemical Structure Chemical Name 2-Benzyl-7-[4-(2 Spyrrolidin-1 -yl-ethyl) Dl N phenyl]-2,3,3a,4,5,7a hexahydro-lH isoindole 7-[4-(2-Pyrrolidin-1-yl HN - N ethyl)-phenyl] D2 2,3,3a,4,5,7a hexahydro-lH isoindole 1-{7-[4-(2-Pyrrolidin-1 0 N4 yl-ethyl)-phenyl] D3 1,3,3a,4,5,7a hexahydro-isoindol-2 yl}-ethanone -60 - WO 2007/061741 PCT/US2006/044479 Cmpd No. Chemical Structure Chemical Name 2-Methyl-1- {7-[4-(2 NQ0 pyrrolidin-1-yl-ethyl) D4 phenyl]-1,3,3a,4,5,7a hexahydro-isoindol-2 yl}-propan-l-one Cyclopropyl- {7-[4-(2 O [N pyrrolidin-1-yl-ethyl) N/N D5 phenyl]-1,3,3a,4,5,7a I hexahydro-isoindol-2 yl}-methanone 7-[4-(2-Pyrrolidin-1-yl O ethyl)-phenyl] D6/ N N 1,3,3a,4,5,7a D6hexahydro-isoindole-2 carboxylic acid dimethylamide 7-[4-(2-Pyrrolidin-1-yl - 0 ethyl)-phenyl] HN N 1,3,3a,4,5,7a D7 I \7hexahydro-isoindole-2 carboxylic acid isopropylamide 7-[4-(2-Pyrrolidin-l1-yl 0 , ethyl)-phenyl] D8 N~ HN 1,3,3a,4,5,7a | hexahydro-isoindole-2 I carboxylic acid cyclopentylamide - 61 - WO 2007/061741 PCT/US2006/044479 Cmpd No. Chemical Structure Chemical Name {7-[4-(2-Pyrrolidin-1 0 yl-ethyl)-phenyl] D 0 N ND 1,3,3a,4,5,7a hexahydro-isoindol-2 yl} -(tetrahydro-furan-3 yl)-methanone N 0 Pyridin-3 -yl- {7-[4-(2 N NQ& pyrrolidin-1-yl-ethyl) D10O phenyl]-1 ,3,3a,4,5 ,7a hexahydro-isoindol-2 yl} -methanone 01 -(7- {4-[2-(2-Methyl -- <N pyrrolidin-1-yl)-ethyl] D11 N phenyl}-1,3,3a,4,5,7a hexahydro-isoindol-2 yl)-ethanone 2-(Propane-2-sulfonyl) 0 7-[4-(2-pyrrolidin-1 -yl D2 ND2 ethyl)-phenyl] N 2,3,3a,4,5,7a hexahydro-lil isoindole 2 Cyclopropanesulfonyl 0 D13 N- ethyl)-phenyl] N 2,3,3a,4,5,7a hexahydro-lil isoindole, -62 - WO 2007/061741 PCT/US2006/044479 Cmpd No. Chemical Sinictare Chemical Name 2-Methyl-i -(7- {4-[2-(2 0 methyl-pyrrolidin-1 D14 N N.2 yl)-ethyl]-phenyl} 1,3,3a,4,5,7a I hexahyclro-isoindol-2 yl)-propan-l -one Cyclopropyl-(7- {4-[2 0 (2-methyl-pyrrolidin-1 N1 N yl)-ethyl]-phenyl} D15 1,3,3a,4,5,7a hexahydro-isoindol-2 yl)-methanone Cyclopentyl-(7- {4-[2 0 (2-methyl-pyrrolidin-1 D16 N Nyl)-ethyl]-phenyl} D16 N1,3,3a,4,5,7a hexahydro-isoindol-2 yl)-methanone 1 -(7- {4-1j2-(2-Methyl 4 / 0 pyrrolidin-1-yl)-ethyl] D17 N , * N phenyl}-1,3,3a,4,5,7a hexahydro-isoindol-2 yl)-2-phenyl-ethanone (7- {4-[2-(2-Methyl 0 pyrrolidin-1 -yl)-ethyll D8 0- ,N .. N phenyl}-1,3,3a,4,5,7a Dl 8'-.-hexahydro-isoindol-2 yl)-(tetrahydro-faran-3 yl)-methanone -63 - WO 2007/061741 PCT/US2006/044479 Cmpd No. Chemical Structure Chemical Name 2-Benzyl-7-{4-[2-(2 methyl-pyrrolidin-1 D19 N .Nyl)-ethyl]-phenyl} D19 2 ,3,3a,4,5,7a hexahydro-lH isoindole TABLE E Cmpd No. Chemical Structure Chemical Name NN 4-[4-(2-Pyrrolidin-l1-yl El ethyl)-phenyl] octahydro-isoindole O 1- {4-[4-(2-Pyrrolidin-1 N yl-ethyl)-phenyl] E2 octahydro-isoindol-2 yl} -ethanone 2-Methyl-l- {4-[4-(2 -NF pyrrolidin-1-yl-ethyl) E3 phenyl]-octahydro isoindol-2-yl} -propan 1-one Cyclopropyl- {4-[4-(2 O0 pyrrolidin-1-yl-ethyl) E4 - N phenyl]-octahydro NI isoindol-2-yl} methanone - 64- WO 2007/061741 PCT/US2006/044479 Cmpd No. Chemical Structure Chemical Name 4-[4-(2-Pyrrolidin-1-yl N ethyl)-phenyl] E5 octahydro-isoindole-2 carboxylic acid dimethylamide 4-[4-(2-Pyrrolidin-1-yl HN OD ethyl)-phenyl] N/ E6 octahydro-isoindole-2 carboxylic acid isopropylamide Q 4-[4-(2-Pyrrolidin-1-yl HN ethyl)-phenyl] E7 N N octahydro-isoindole-2 carboxylic acid cyclopentylamide {4-[4-(2-Pyrrolidin- 1 N)NO yl-ethyl)-phenyl] E8 octahydro-isoindol-2 yl}-(tetrahydro-furan-3 yl)-methanone o 1-(4-{4-[2-(2-Methyl 9N Npyrrolidin-1-yl)-ethyl] E9 phenyl}-octahydro isoindol-2-yl)-ethanone (4-{4-[2-(2-Methyl O _ pyrrolidin-1-yl)-ethyl] ElO N N phenyl}-octahydro N0isoindol-2-yl) (tetrahydro-furan-3-yl) methanone - 65 - WO 2007/061741 PCT/US2006/044479 Cmpd No. Chemical Structure Chemical Name 2-Methyl-l-(4- {4-[2-(2 N methyl-pyrrolidin-1-yl) El N ethyl]-phenyl} octahydro-isoindol-2 yl)-propan-l-one Cyclopentyl-(4- {4-[2 E-2N N (2-methyl-pyrrolidin- l E12 I yl)-ethyl]-phenyl} octahydro-isoindol-2 yl)-methanone (4- {4-[2-(2-Methyl Spyrrolidin-1 -yl)-ethyl] 0E13 N phenyl}-octahydro E13 Nisoindol-2-yl) (tetrahydro-pyran-4-yl) methanone 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 5 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 10 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, 3r 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 15 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 20 here in. - 66- WO 2007/061741 PCT/US2006/044479 It s 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 (HIa) and Formula (Hec):
R
1 D\ R"" D N NHa R1 N /Ha G -Arj . K N R 5 G Ar K NR5 Hb E R3 Hb E R3 R4
R
2
R
2 (Ha) (Hc) 5 In some embodiments, the compounds of the present invention have the stereochemical designations as represented by Formula (Ha): R1 D\N. Ha N \H ' Ar K R iG "1J 'N H E- R3
R
2 (Ha) In some embodiments, the compounds of the present invention have the stereochemical designations as represented by Formula (He): R1 D\ N Ha GArG K 'NR5 Hb E R 3 R4 R2 10 (HIc) In some embodiments, the compounds of the present invention have the stereochemical designations as represented by Formula (He): N H R1"A D\ KNR \\\r,,, r_..5 SR7 H E R3 R 4 R2E (Ie) In some embodiments, the compounds of the present invention have the stereochemical 15 designations as represented by Formula (Hg): - 67 - WO 2007/061741 PCT/US2006/044479 NH N H"-"'j N SAr 5 H E R3 R
R
2 (ig) In some embodiments, the compounds of the present invention have the stereochemical designations as represented by Formula (IHi): RI1 ,D\ - H N H 11ArN . K 'N R R7 HE IR3 R 4
R
2 (IIi) 5 In some embodiments, the compounds of the present invention have the stereochemical designations as represented by Formula (Hik): R1" D\ H NH Ar" K N. R 5 H E: R 3
R
4 R2 (lk) 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 10 represented in Formula (HIm): 3a 6 Hb 4 5 R 2 R4 R2 (Hlm) 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): R1-D\ 2 1 N .Ha 3 (R a 6 A r , K N R R). 6 N~j Hb 4 5 R2
R
4
R
2 15 (IIo) -68- WO 2007/061741 PCT/US2006/044479 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 5 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 10 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 15 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 20 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 25 present invention. These include cognitive disorders (Passani et al. Trends Pharmacol Sci 2004, 25, 618-624), epilepsy (Vohora et al. Pharmacol Biochem Behav 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, 30 771-777), 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 35 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, - 69 - WO 2007/061741 PCT/US2006/044479 I: ' E " . 11" / V C ! t, ,, " l ,It., l , i," ii aC Admutlie Iosis (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. 5 Histamine H113-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. Sci. 2004, 25, 618-625). Somnolence is one of the major 10 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 15 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 20 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 25 (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. 30 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 35 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 - 70 - WO 2007/061741 PCT/US2006/044479 "narcolepsy is overwhelmmg 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 5 episodes of loss of muscle function, ranging from slight wealmkness (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 10 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 15 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 20 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 25 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 30 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 35 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. Ther. 1998, 287, 658-666). Other conditions include excessive sleepiness due to shift work, medical -71- WO 2007/061741 PCT/US2006/044479 SC rdb , itric dsorrsfiarcolepsy, 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. 5 In addition, wakefulness is a prerequisite for several brain functions including attention, learning, and memory and is required for appropriate behaviours in response to environmental challenges. Histamine H3-receptor antagonists and inverse agonists have been shown to improve cognitive performance in various animal models (Hancock and Fox in Milestones in Drug Therapy, ed. Buccafusco, 2003). These compounds can be used as pro-cognitive agents 10 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 15 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 20 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 25 cognitive disorders (Passani et al. Trends Pharmnacol. Sci. 2004, 25, 618-625), epilepsy (Vohora et al. Pharmnacol. Biochemn. 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 30 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 Pharmnacol. Sci. 2004, 25, 618-625). As stated above, histamine H3-receptor antagonists and inverse agonists can be used to 35 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 - 72 - WO 2007/061741 PCT/US2006/044479 jP.. ol i l a ie pa te 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 5 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 10 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 15 (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). 20 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, anti seizure drug and also showed effect with sub-effective doses of the H3-receptor antagonist in combination with sub-effective doses of known anti-epileptic drugs (Vohora et al. Pharmacol. 25 Biochem. Behav. 2001, 68, 735-741). Perez-Garcia et al. (Psychophannacol. 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 30 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 35 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. - 73 - WO 2007/061741 PCT/US2006/044479 C compounds of he 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), 5 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 10 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, 15 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 20 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 25 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 30 reported that in a rat pup model for ADHD, a histamine H113-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. 35 As stated above, histamine H113-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 -74- WO 2007/061741 PCT/US2006/044479 "iit sigifincan social or occupational dysfunction. A person experiencing untreated schizophrenia is typically characterized as demonstrating disorganized thinking, and as experiencing delusions or auditory hallucinations. Although the disorder is primarily thought to affect cognition, it can also contribute to chronic problems with behavior and emotion. Schizophrenia is often 5 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 10 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 15 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 20 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 25 signalling has been implicated in the anorectic actions of known mediators in the feeding cycle such as leptin, amylin and bombesin. In the brain, the H3-receptor is implicated in the regulation of histamine release in the hypothalamus. Moreover, in situ hybridization studies have revealed histamine H3-receptor mRNA expression in rat brown adipose tissue, indicating a role in the regulation of thermogenesis (Karlstedt et al., Mol. Cell. Neurosci. 2003, 24, 614-622). 30 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, 35 novel anti-obesity agents, such as histamine H3-receptor antagonists or inverse agonists, are needed. - 75 - WO 2007/061741 PCT/US2006/044479 istanulne H3-receptor antagonists or inverse agonists can also be used to treat upper airway allergic responses (U.S. Pat. Nos. 5,217,986; 5,352,707 and 5,869,479) including allergic rhinitis and nasal congestion. Allergic rhinitis is a frequently occurring chronic disease that affects a large number of people. Recent analysis of histamine H3-receptor expression in the 5 periphery by quantitative PCR revealed that H3-receptor mRNA is abundantly expressed in human nasal mucosa (Varty et al. Eur. 1. Pharmacol. 2004, 484, 83-89). In addition, in a cat model of nasal decongestion, a combination of histamine H3-receptor antagonists with the H1 receptor antagonist chlorpheniramine resulted in significant nasal decongestion without the hypertensive effect seen with adrenergic agonists. (McLeod et al. Am. J. Rhinol. 1999, 13, 391 10 399). Thus, histamine H3-receptor antagonists or inverse agonists can be used alone or in combination with H1 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, 15 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, 20 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 25 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. 30 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 35 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 - 76 - WO 2007/061741 PCT/US2006/044479 bef6rei use. ditional 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 5 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 10 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 15 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 20 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, sub cutaneous 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 25 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. 30 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 35 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 - 77 - WO 2007/061741 PCT/US2006/044479 umii dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably 5 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 10 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 15 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 20 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. 25 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 30 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 35 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, -78- WO 2007/061741 PCT/US2006/044479 ypcay 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 5 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 10 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 15 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 20 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 25 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, 30 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. 35 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. - 79 - WO 2007/061741 PCT/US2006/044479 11: ! 1..'.. " , It 11! ll:::0-1 ,ll. t+ ' J;t Theiaers and tblets may contain varying percentage amounts of the active compound. A representative amount in a powder or tablet may contain from 0.5 to about 90 percent of the active compound; however, an artisan would know when amounts outside of this range are necessary. Suitable carriers for powders and tablets are magnesium carbonate, 5 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, 10 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 15 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, 20 water or water-propylene glycol solutions. For example, parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic 25 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 30 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 35 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 - 80- WO 2007/061741 PCT/US2006/044479 IF:'It ' '"''" !,solution,'.,',for suitable ,, stenle sohd or y lyophilization 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 5 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 10 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 15 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. 20 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, 25 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 30 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 35 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 -81 - WO 2007/061741 PCT/US2006/044479 suifable lsane solutions can be employed using customary additives, for example benzyl alcohol or other suitable preservatives, absorption enhancers for increasing the bioavailability, solubilizers, dispersants and others, and, if appropriate, customary propellants, for example include carbon dioxide, CFCs, such as, dichlorodifluoromethane, trichlorofluoromethane, or 5 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 10 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). 15 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 20 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 25 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, 30 camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfiric, 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 35 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 - 82 - WO 2007/061741 PCT/US2006/044479 :a iZrain the solvento otherwise at n 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 5 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 10 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. 15 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. 20 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 H3-associated disease or disorder in domestic animals (e.g., cats and dogs) and in 25 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 30 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. 35 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 - 83 - WO 2007/061741 PCT/US2006/044479 by an aom having an atomic mass or mass number different from the atomic 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), "C, 1 3 C, 14C, 1 3 N, 1 5 N, 150, 170, 5 18O, 8 F, 35 S, 36 C1, 82 Br, 75 r 76 Br, 77 Br, 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, 1 4 C, 82 Br, 1251, 131I, 35 S or will generally be most useful. For radio-imaging applications "1C, 1 8 F, 125, 1231, 1241, 1311 75 Br, 76 Br or 7 7 Br will generally be 10 most useful. It is understood that a "radio-labeled" or "labeled compound" is a compound of Formula (Ta) that has incorporated at least one radionuclide; in some embodiments the radionuclide is selected from the group consisting of "H, 1 4 C, 125, 35S and 82 Br. Certain isotopically-labeled compounds of the present invention are useful in compound 15 and/or substrate tissue distribution assays. In some embodiments the radionuclide 3H and/or 14 C 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 20 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 25 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: 30 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 [H] - This procedure is rather inexpensive and requires precursors containing reducible functional groups such as aldehydes, ketones, lactones, esters, and the like. 35 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. - 84- WO 2007/061741 PCT/US2006/044479 D. TritiIum 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 ['H] -This procedure is usually employed to prepare O-methyl or N-methyl (H) products by treating appropriate precursors with high 5 specific activity methyl iodide (RH). 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 1251 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 1251 labeled 10 compound using Na 1 25 I. A represented procedure was reported by Zhu, D.-G. and co-workers in J. Org. Chem. 2002, 67, 943-948. B. Ortho 1 25 Iodination 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 Comnpd. Radiopharm. 1999, 42, S264-S266. 15 C. Aryl and heteroaryl bromide exchange with 1251 - 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(Ph 3 P)4] or through an aryl or heteroaryl lithium, in the presence of a tri-alkyltinhalide or hexaalkylditin [e.g., (CH 3
)
3 SnSn(CH 3
)
3 ]. A represented procedure was reported by Bas, M.-D. 20 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 25 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 IC 5 0 less than about 500 pM, in another embodiment the labeled compound has an IC 50 less than about 100 PM, in yet another embodiment the 30 labeled compound has an IC 50 less than about 10 pM, in yet another embodiment the labeled compound has an IC 50 less than about 1 gM, and in still yet another embodiment the labeled inhibitor has an IC 5 0 less than about 0.1 pM. 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. 35 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 - 85 - WO 2007/061741 PCT/US2006/044479 upon examination of the following examples thereof which are intended to be illustrative and not intended to be limiting. EXAMPLES 5 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 10 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 15 Varian Mercury Vx-400 equipped with a 4 nucleus auto switchable probe and z-gradient or a Bruker Avance-400 equipped with a QNP (Quad Nucleus Probe) or a BBI (Broad Band Inverse) and z-gradient. Chemical shifts are given in parts per million (ppm) with the residual solvent signal used as reference. NMR abbreviations are used as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. Microwave irradiations were carried out using the 20 Emrys Synthesizer (Personal Chemistry). Thin-layer chromatography (TLC) was performed on silica gel 60 F 2 s 4 (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 Btichi rotary evaporator. Celite 545 @ was used during palladium filtrations. 25 LCMS specs: 1) PC: HPLC-pumps: LC-10AD VP, Shimadzu Inc.; HPLC system controller: SCL-O10A VP, Shimadzu Inc; UV-Detector: SPD-10A VP, Shimadzu Inc; Autosampler: CTC HTS, PAL, Leap Scientific; Mass spectrometer: API 150EX with Turbo Ion Spray source, AB/MDS Sciex; Software: Analyst 1.2. 2) Mac: HPLC-pumps: LC-8A VP, Shimadzu Inc; HPLC system controller: SCL-10A VP, Shimadzu Inc. UV-Detector: SPD-10A 30 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-Benzyl-hexahydro-cyclopenta[c]pyrrol-4-one. N8 35 N -86- WO 2007/061741 PCT/US2006/044479 T6 a'stion of iN-(etfioxymethyl)-N-(trimethylsilylmethyl)benzyl amine (50 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 42-45 0 C for 3.5 h. The reaction mixture was cooled to room temperature and acetonitrile was removed under reduced pressure. The crude residue was 5 purified by vacuum distillation at 126-130 oC/1 Torr to obtain the title compound (30.93g, 68.5%). MS m/z 216.2, (M+H); 1H NMR (400 MHz, CD 3 OD) 8 7.20-7.32 (mn, 5H), 3.55 (dd, J = 52.0, 13.1 Hz, 2H), 3.02 (dd, J= 9.4, 1.8 Hz, 1H), 2.84-2.93 (m, 1H), 2.67 (dd, J = 9.4, 2.6 Hz, 1H), 2.61 (mn, 1H), 2.47 (dd, J = 9.6, 7.3 Hz, 1H), 2.36-2.47 (mn, 2H), 2.23-2.32 (mn, 1H), 2.07-2.17 (mn, 1H), 1.75-1.83 (mn, 1H). 10 Resolution via Chiral HPLC Column: Chiralpak AD-H, 150 x 2.1 mm, 5 pm particle size Eluent: 95% Hexane/5% Isopropanol Gradient: Isocratic Flow: 1 mL/minute 15 Detector: 254nm Retention Times: 3aR,6aS - 5.70 min.; 3aS,6aR? - 6.90 min. Resolution of (3aS,6aR)-2-Benzylhexahydro-cyclopenta[clpyrrol-4(5H)-one via Diastereomeric Salt Formation. NS5 H Z6a 6 20 To a stirred solution of ( 4 )-2-benzylhexahydrocyclopenta[c]pyrrol-4(5H)-one (10 g, 46.4 mmol) in isopropanol (30 mL) at 60 oC was added a solution of di-p-toluoyl-L-tartaric acid in isopropanol (30 mL). Heating was continued at 60 0 C to until a clear solution was obtained, at which point the mixture was cooled to 50 oC and then seeded with (3aS,6aR)-2 benzylhexahydro-cyclopenta[c]pyrrol-4(5H)-one-di-p-toluoyl-L-tartrate (30% ee). This 25 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 30 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 nm/z 216.2, (M+H). Example 1.2: Preparation of 1-[2-(4-Bromo-phenyl)-ethyl]-pyrrolidine. - 87- WO 2007/061741 PCT/US2006/044479 Br, 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 0 0 C. The reaction was stirred for 1 h and concentrated to give the crude bromophenyl 5 mesylate intermediate (MS inm/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 oC. After cooling to room temperature, the mixture was filtered and concentrated. The crude material was purified by 10 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 nm/z 256, (M+H); 1H NMR (400 MHz, CDC1 3 ) 6 ppm 7.39 (d, J = 8.59 Hz, 2 H) 7.08 (d, J = 8.08 Hz, 2 H) 4.07 4.16 (min, 1 H) 2.75 - 2.85 (mn, 2 H) 2.65- 2.73 (mn, 2 H) 2.55 - 2.64 (mn, 3 H) 1.77 - 1.86 (mn, 4 H). 15 Example 1.3: Preparation of (-)-2-Benzyl-4-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl] octahydro-cyclopenta[c]pyrrol-4-ol. N N OH To a solution of 1-[2-(4-Bromo-phenyl)-ethyl]-pyrrolidine (2.54 g, 9.99 mmol) in THF (27 mL) at -78 oC was added n-BuLi (7.25 mL, 11.6 mmol, 1.6M in hexanes) with stirring. 20 After 1 h at -78 oC, 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 MgSO 4 and concentrated at reduced pressure The crude product was purified through a silica gel column with 15% Acetone/ 85% Hexanes then with 10% 25 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); 1 H NMR (400 MHz, CDC1 3 ) 6 7.43 (d, J= 8.3 Hz, 2H), 7.22-7.33 (mn, 5H), 7.15 (d, J= 7.8 Hz, 2H), 3.73 (d, J = 12.7 Hz, 1H), 3.45-3.52 (mn, 2H), 3.00 (d, J = 9.3 Hz, 1H), 30 2.57-2.88 (min, 10H), 2.12-2.21 (mn, 3H), 1.79-2.07 (mn, 7H), 1.57-1.68 (mn, 1H). - 88 - WO 2007/061741 PCT/US2006/044479 Example'.: Preparation of 2-Benzyl-4-{4-(2-[(2S)-2-methyl-pyrrolidin-1-yl]-ethyl) phenyl}-octahydro-cyclopenta[c]pyrrol-4-ol. NN OH The title compound was obtained using the method described in Example 1.3 starting 5 with 1-[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 nm/z 405, (M+H); 'H NMR (400 MHz, DMSO-d 6 ) 8 7.20-7.61 (mn, 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 (mn, 2H), 3.56-3.65 (mn, 1H), 2.82-3.44 (in, 9H), 1.80 10 2.24 (mn, 4H), 1.57-1.69 (min, 2H), 1.39 (d, J= 6.4 Hz, 3H). Example 1.5: Preparation of (:)-2-Benzyl-4-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl] octahydro-cyclopenta[c]pyrrole Dihydrochloride. N No 15 A solution of the compound described in Example 1.3 (0.20g, 0.5 1mmol) 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 20 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 nm/z 375.6 (M+H); 1H NMR (400 MHz, MeOH-d 4 ) 8 7.28-7.18 (min, 5H11), 7.16 (d, J= 8.1 Hz, 2H), 7.11 (d, J= 8.1 Hz, 2H11), 3.44 (ABq, J = 29.0, J= 25 12.6 Hz, 2H11), 3.16 (ddd, J= 13.1, 8.0, 5.7, Hz, 1H11), 3.08-2.95 (mn, 2H11), 2.81-2.65 (mn, 5H), 2.65 2.58 (min, 4H), 2.39 (dddd, J= 9.0, 9.0, 0.0, 0.0 Hz, 1H), 2.05-1.57 (in, 10H). Example 1.6: Preparation of (h)-4-[4-(2-Pyrrolidin-1-yl-ethyl)-phenyl]-octahydro cyclopenta[clpyrrol-4-ol. - 89- WO 2007/061741 PCT/US2006/044479 H N N OH 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 mniL) was heated to reflux for 50 min. After cooling to room 5 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); 1 HNMR (400 MHz, CDC1 3 ) & 7.47 (d, J= 8.3 Hz, 2H), 7.19 (d, J= 10 8.3 Hz, 2H), 3.28 (br s, 1H), 3.23-3.19 (mn, 2H), 2.92-2.76 (mn, 5H), 2.74-2.68 (mn, 2H), 2.65-2.56 (mn, 5H), 2.55-2.50 (min, 1H), 2.21 (ddd, J= 15.5, 7.6, 7.6 Hz, 1H), 2.07-1.97 (mn, 1H), 1.93-1.87 (m, 1H), 1.84-1.79 (mn, 3H), 1.64 (ddd, J= 19.7, 13.3, 6.7 Hz, 1H). Example 1.7: Preparation of (±)-6-[4-(2-Pyrrolidin-1-yl-ethyl)-phenyll-1,2,3,3a,4,6a 15 hexahydro-cyclopenta[c]pyrrole Dihydrochloride. NF2D HN IY 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 HC1 (16.0 mL, 64.0 mmol, 4M in 1,4-dioxane). The resulting reaction mixture was heated to 60 oC. After 3 h, the reaction mixture was concentrated 20 at reduced pressure and neutralized with 10% NaOH solution. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with H20, brine, dried over MgSO 4 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 25 corresponding single isomer ketones in Example 1.1. MS inm/z 283, (M+H); 1H NMR (400 MHz, CD 3 OD) ( 7.43 (d, J= 8.3 Hz, 2H), 7.31 (d, J = 8.3 Hz, 2H), 6.19 (bs, 1H), 4.03-4.11 (inm, 1H), 3.41-3.72 (mn, 6H), 2.89-3.17 (min, 7H), 2.46 (dd, J = 18.5, 2.4 Hz, 1H), 1.96-2.22 (mn, 5H). Example 1.8: Preparation of [2-(4-bromo-phenyl)-ethoxy]-tert-butyl-dimethyl-silane. - 90 - WO 2007/061741 PCT/US2006/044479 Br Si To a solution of alcohol (20g, 99.5mmol) in 250 mL DCM was added a solution of imidazole (1 6
.
9 g, 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 mnimol) was added slowly. The 5 mixture was stirred for 2 h at room temperature. Water (200 mL) was added followed by 10% HC1 (150 mnL). The organic phase was separated, washed with brine, dried with Na 2
SO
4 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). 10 Example 1.9: (±)-Preparation of 2-Benzyl-4-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethyll phenyl}-octahydro-cyclopenta[c]pyrrol-4-ol. N OS,/ OH To a solution of [2-(4-bromo-phenyl)-ethoxy]-tert-butyl-dimethyl-silane (1.74g, 5.52mmol) in THF (15 mL) at -780 C was added n-BuLi (3.0 mL, 7.50mmol, 2.5M in hexanes). 15 After lh 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 780 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 MgSO 4 , filtered and concentrated at reduced pressure. The product was purified by flash chromatography (silica gel, 20 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 nim/z 453, (M+H). 25 Example 1.10: (-)-Preparation of 2-Benzyl-6-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl] phenyl}-1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole. N O1 -91- WO 2007/061741 PCT/US2006/044479 I o sot ion of Burgess Reagent (828.8mg, 3.48mmol) in benzene (3.5 mL) was added 2-Benzyl-4- {4-[2-(tert-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 500 C and allowed to stir for 2h. The reaction mixture was cooled to room 5 temperature, quenched with water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried with MgSO 4 , 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) 10 were obtained by the same method starting from the corresponding single isomer ketones in Example 1.1. MS nm/z 434, (M+H). Example 1.11: Preparation of (±)-2-[4-(2-Benzyl-1,2,3,3a,6,6a-hexahydro cyclopenta[c]lpyrrol-4-yl)-phenyll-ethanol. N OH 15 To a solution of 2-Benzyl-6-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-phenyl} 1,2,3,3a,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. 20 The combined organic layers were washed with water, brine, dried with MgSO 4 , 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 NaHCO 3 to 25 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 nm/z 320, (M+H). Example 1.12: Preparation of (±)-Methanesulfonic acid 2-[4-(2-benzyl-1,2,3,3a,6,6a 30 hexahydro-cyclopenta[c]pyrrol-4-yl)-phenyl]-ethyl ester. N9OMs N - 92 - WO 2007/061741 PCT/US2006/044479 "o oIuon of [ 2-I(enzyl-1l, 2
,
3
,
3 a, 6
,
6 a-hexahydro-cyclopenta[c]pyrrol-4-yl) phenyl]-ethanol (0.50g, 1.57mmol) in 8 mL DCM was added Et 3 N (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 5 organic layer was dried with Na 2
SO
4 and concentrated at reduced pressure. Purification via silica gel chromatography (20-50%EtOAc in Hexanes) gave the title compound as an oil, 51 1mg, 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). 10 Example 1.13 - General Method A Preparation of (±)- 2 -Benzyl- 6
-[
4
-(
2 -pyrrolidin-1-yl-ethyl)-phenyl]-1,2,3,3a,4,6a-hexahydro cyclopenta[c]pyrrole Dihydrochloride. 15 A solution of the compound described in Example 1.12 (455.4 mg, 1.146 mmol), pyrrolidine (0.21 mL, 2.5 mmol), and Na 2
CO
3 (307.3 mg, 2.90 mmol) in 6.3 mniL of CH 3 CN was heated to 120 'C for 3 hr under microwave irradiation in a heavy walled sealed tube. The reaction mixture was quenched with H20 and extracted with EtOAc. The combined organic layers were washed with H20, brine, dried over MgSO 4 and concentrated at reduced pressure 20 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 basified with NaOH, extracted with EtOAc, and concentrated. The resulting material was dissolved in 5 mL of ether, 2 equivalents of HC1 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 25 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); 111 NMR (400 MHz, DMSO-d 6 ) 6 7.50-7.59 (m, 2H11), 7.40-7.46 (min, 5H), 7.27 (d, J = 8.1 Hz, 2H), 6.24-6.29 (mn, 1H), 4.25-4.39 (mn, 2H11), 3.80-4.10 (mn, 211), 3.60-3.69 (mn, 1H1), 3.48-3.57 (mn, 2H), 3.28-3.37 (mn, 2H), 3.15-3.24 (m, 2H), 2.96-3.07 (mn, 4H), 2.66-2.88 (mn, 2H), 2.32-2.48 (mn, 1H11), 1.81-2.06 30 (m, 4H). Example 1.14: Preparation of (±)-2-Benzyl-6-[4-(2-piperidin-1-yl-ethyl)-phenyl] 1, 2
,
3
,
3 a, 4 ,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride. - 93 - WO 2007/061741 PCT/US2006/044479 N,, / The title compound was obtained using general method A. MS m/z 387.2, (M+H); 'H NMR (400 MHz, CD 3 OD) 6 7.36-7.46 (m, 7H), 7.27 (d, J = 7.05 Hz, 2H), 6.20 (s, 1H), 4.33 (s, 2H11), 4.18 (m, 1H) 3.97 (m, 1H), 3.78 (t, J = 9.2 Hz, 1H), 3.60 (d, J= 12.4 Hz, 4H), 2.80-3.80 5 (m, 6H11), 2.46 (d, J = 18.4 Hz, 1H), 1.97 (d,J= 15.2 Hz, 1H11), 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-1-yl)-ethyl] phenyl}-1, 2 ,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride. N N 10 The title compound was obtained using general method A. MS m/z 401.2, (M+H); 'H NMR (400 MHz, CD 3 OD) 8 7.37-7.48 (m, 7H11), 7.29 (d, J = 5.6 Hz, 2H11), 6.20 (s, 1H), 4.33 (s, 2H), 4.17 (m, 1H) 3.97 (m, 1H11), 3.78 (m, 1H), 3.67 (m, 1H11), 3.40-3.54 (m, 3H), 2.81-3.16 (m, 7H), 2.46 (d, J = 18.4 Hz, 1H), 1.72-2.05 (m, 4H), 1.56-1.67 (m, 2H11), 1.34-1.45 (m, 3H1). 15 Example 1.16: Preparation of (±)- 2 -Benzyl-6-{4-[2-(4-methyl-piperazin-1-yl)-ethyl] phenyl}-l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride. N N N The title compound was obtained using general method A. MS m/z 402.2, (M+H); 'H 20 NMR (400 MHz, CD 3 OD) 8 7.34-7.50 (m, 7H11), 7.26 (s, 2H), 6.19 (s, 1H), 4.33 (s, 2H11), 4.10 4.20 (m, 111), 3.97 (m, 1H11), 3.70-3.80 (m, 1H), 3.32-3.58 (m, 7H), 3.18-3.30 (m, 5H11), 2.98 (m, 4H), 2.83-2.94 (m, 3H11), 2.46 (d, J = 17.6 Hz, 1H). Example 1.17: Preparation of ( 3 aRS,6aRS)-2-Benzyl-6-{4-[2-((2R,6S)-2,6-dimethyl 25 piperidin-l-yl)-ethyl]-phenyl}-1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride. -94 - WO 2007/061741 PCT/US2006/044479 N N The title compound was obtained using general method A. MS m/z 415.4, (M+H); 'H NMR (400 MHz, CD30D) 6 7.41-7.50 (m, 7H), 7.32 (d, J = 6.8 Hz, 2H), 6.23 (s, 1H11), 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, 1H11), 2.81-3.07 (m, 4H), 5 2.47 (d, J= 18.8 Hz, 1H), 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-Benzyl-6-{4-[2-(2,5-dimethyl-pyrrolidin-1-yl)-ethyl] phenyl}-1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride. N N /N 10 The title compound was obtained using general method A. MS nm/z 401.2, (M+H); 'H NMR (400 MHz, CD30D) 7.40-7.5 (m, 7H), 7.33 (d, J = 5.6 Hz, 2H), 6.22 (s, 1H), 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, 1H11), 2.80-3.10 (m, 4H), 2.47 (d,J= 18.4 Hz, 1H11), 2.19-2.36 (m, 211), 1.75-1.86 (m, 2H), 1.43-1.53 (m, 5H), 1.36 (d,J= 5.6 Hz, 1H). 15 Example 1.19: Preparation of (-)-2-[4-(2-Benzyl-1,2,3,3a,6,6a-hexahydro cyclopenta[cl]pyrrol-4-yl)-phenyl]-ethyl}-dimethyl-amine Dihydrochloride. N N II The title compound was obtained using general method A. MS m/z 347.2, (M+H); 'H 20 NMR (400 MHz, CD 3 OD) 6 7.39-7.50 (m, 7H), 7.30 (d, J= 6.8 Hz, 2H), 6.22 (s, 1H), 4.35 (s, 2H), 3.75-4.25 (m, 2H), 3.32-3.59 (m, 5H), 3.14-3.27 (m, 1H), 3.00-3.10 (m, 2H), 2.94 (s, 6H), 2.80-2.90 (m, 1H), 2.47 (d,J= 18.4 Hz, 1H). Example 1.20: Preparation of (2aR,6aR)-2-Benzyl-6-{4-(2-[(2S)-2-methyl-pyrrolidin-1-yl] 25 ethyl)-phenyl}-1,2,3,3a,4,6a-hexahydro-cyclopenta[el]pyrrole Dihydrochloride. - 95 - WO 2007/061741 PCT/US2006/044479 N HN H The title compound was obtained using general method A. MS m/z 387, (M+H); 'H NMR (400 MHz, CD 3 OD) 6 7.27-7.52 (m, 9H11), 6.21-6.26 (m, IH), 4.15-4.42 (m, 2H11), 3.93-4.03 (m, 111), 3.68-3.83 (m, 2H), 2.80-3.67 (m, 11H), 2.43-2.52 (m, 1H), 2.29-2.40 (m, 111), 2.00 5 2.18 (m, 2H), 1.70-1.81 (m, 1H), 1.44-1.49 (m, 3H). Example 1.21: Preparation of ( )-2-Benzyl-6-{4-[2-(2,2-dimethyl-pyrrolidin-1-yl)-ethyl
]
phenyl}-1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride. N NFI I 10 The title compound was obtained using general method A. MS m/z 401, (M+H11); 'H NMR (400 MHz, DMSO-d 6 ) 6 7.48-7.57 (m, 2H), 7.40-7.46 (m, 5H), 7.28-7.33 (m, 2H11), 6.24 6.29 (m, 1H), 4.26-4.41 (m, 2H), 3.81-3.89 (m, 1H), 3.61-3.71 (m, 2H11), 2.30-3.36 (m, 1111), 1.86-2.03 (m, 4H), 1.48 (d, J= 2.5 Hz, 3H), 1.17 (d, J= 3.2 Hz, 3H). 15 Example 1.22: Preparation of ( 2 aR,6aR)-2-Benzyl-6-{4-(2-[(2R)-2-methyl-pyrrolidin-1-yl] ethyl)-phenyl}-1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride. N H N H The title compound was obtained using general method A. MS m/z 387, (M+H); 11H NMR (400 MI-Iz, DMSO-d 6 ) 6 7.48-7.58 (m, 2H11), 7.37-7.44 (m, 5H11), 7.28 (d, J = 8.3 Hz, 2H), 20 6.25 (bs, 1H11), 4.25-4.39 (m, 2H11), 3.79-4.10 (m, 2H), 3.54-3.70 (m, 1H), 2.96-3.53 (m, 9H11), 2.66-2.87 (m, 2H11), 2.34-2.48 (m, 1H), 2.14-2.26 (m, 1H11), 1.86-2.04 (m, 2H11), 1.58-1.70 (m, 1H), 1.38-1.44 (m, 3H11). Example 1.23: Preparation of (=)-2-Benzyl-6-[ 4
-(
2 -morpholin-4-yl-ethyl)-phenyl] 25 1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride. - 96 - WO 2007/061741 PCT/US2006/044479 0 N N N The title compound was obtained using general method A. MS m/z 389, (M+H); 11H NMR (400 MHz, CD 3 OD) 3 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, 1H11), 3.62-3.82 (m, 7H11), 2.99-3.23 (m, 3H11), 2.73-2.84 (m, 3H), 2.52-2.63 (m, 6H), 5 2.25-2.36 (m, 3H11). Example 1.24: Preparation of (1-{2-[ 4
-(
2 -Benzyl-1,2,3,3a,6,6a-hexahydro cyclopenta[c]pyrrol-4-yl)-phenyl]-ethyl}-pyrrolidin-2-yl)-(R)-methanol Dihydrochloride. HO N N I 10 The title compound was obtained using general method A. MS nm/z 403.4, (M+H); 11H NMR (400 MHz, MeOH-d 4 ) 3 ppm 1.83 - 2.09 (m, 2 H) 2.09 - 2.33 (m, 2 H) 2.43 - 2.53 (m, 1 H) 2
.
8 0- 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) 15 Example 1.25: Preparation of (1-{2-[4-(2-Benzyl-1,2,3,3a,6,6a-hexahydro cyclopenta[c]pyrrol-4-yl)-phenyl]-ethyl}-pyrrolidin-2-yl)-(S)-methanol Dihydrochloride. H O ' /,, ' NN The title compound was obtained using general method A. MS m/z 403.5, (M+H); 1H NMR (400 MHz, MeOH-d 4 ) 3 ppm 1.85 - 1.95 (mn, 1 H) 2.01 - 2.08 (m, 1 H) 2.10 - 2.31 (m, 2 20 H) 2.42- 2.51 (m, 1 H) 2
.
8 0 - 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
.
2 5 (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 (mn, 7 H) Example 1.26: Preparation of 1-{2-[4-(2-Benzyl-1,2,3,3a,6,6a-hexahydro 25 cyclopenta[c]pyrrol-4-yl)-phenyl]-ethyl}-(3R)-pyrrolidin-3-ol Dihydrochloride. -97 - WO 2007/061741 PCT/US2006/044479 OH N No
-
NJ / The title compound was obtained using general method A. MS nm/z 389.5, (M+H); 1H NMR (400 MHz, MeOH-d 4 ) 8 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
.
2 8 (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 5 (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-1-yl)-ethyl] phenyl}-1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride. N N F NN 10 The title compound was obtained using general method A. MS m/z 409.3, (M+H); 'H NMR (400 MHz, MeOH-d 4 ) 8 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) 15 Example 1.28: Preparation of (±)- 6
-[
4 -(2-Azetidin-1-yl-ethyl)-phenyl]-2-benzyl 1, 2 ,3,3a,4,6a-hexahydro-cyclopenta[clpyrrole Dihydrochloride. N N'II NN I The title compound was obtained using general method A. MS tnm/z 359.4, (M+H); 1H 20 NMR (400 MHz, MeOH-d 4 ) 8 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-1-yl)-ethyl] 25 phenyl}-1,2,3,3a,4,6a-hexahydro-cyclopenta[c]lpyrrole Dihydrochloride. - 98 - WO 2007/061741 PCT/US2006/044479 NaF C N F The title compound was obtained using general method A. MS m/z 423.2, (M+H); 'H NMR (400 MHz, MeOH-d 4 ) 6 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 (mn, 1 H) 3.37 - 3.82 (mn, 7 H) 3.91 - 4.24 (m, 2 H) 4.29 - 4.46 (m, 2 H) 6.18 - 6.26 5 (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-1,2,3,3a,6,6a-hexahydro cyclopenta[c]pyrrol-4-yl)-phenyl]-ethyl}-2,3-dihydro-1H-isoindole Dihydrochloride. N N N 10 The title compound was obtained using general method A. MS nm/z 421.4, (M+H); 'H NMR (400 MHz, MeOH-d 4 ) 6 ppm 2.40 - 2.59 (m, 1 H) 2.79 - 3.06 (mn, 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) 15 Example 1.31: Preparation of (±)- 2
-{
2
-[
4
-(
2 -Benzyl-1,2,3,3a,6,6a-hexahydro cyclopenta[c]pyrrol- 4 -yl)-phenyl]-ethyl}-1,2,3,4-tetrahydro-isoquinoline Dihydrochloride. N N The title compound was obtained using general method A. MS m/z 435.5, (M+H); 'H NMR (400 MHz, MeOH-d 4 ) 6 ppm 2.41 - 2.56 (m, 1 H) 2.82 - 3.06 (m, 3 H) 3.12 - 3.27 (m, 4 20 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, 1 H) 7.19- 7.60 (m, 13 H) Example 1.32: Preparation of 1-{ 2
-[
4
-(
2 -Benzyl-1,2,3,3a,6,6a-hexahydro cyclopenta[c]pyrrol-4-yl)-phenyl]-ethyl}-(3S)-pyrrolidin-3-ol Dihydrochloride. - 99 - WO 2007/061741 PCT/US2006/044479 j l":: i w'"/ ' l il::: , ol, HI l. , O H H N N // The title compound was obtained using general method A. MS m/z 389.5, (M+H); 'H NMR (400 MHz, MeOH-d 4 ) 5 ppm 1.14 - 1.31 (mn, 2 H) 2.05 - 2.21 (mn, 1 H) 2.35 - 2.55 (mn, 2 H) 2.83 - 3.65 (min, 9 H) 3.73 - 3.89 (min, 2 H) 3.94 - 4.28 (min, 2 H) 4.32 - 4.46 (min, 2 H) 4.52 - 4.65 5 (min, 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-1,2,3,3a,6,6a-hexahydro cyclopenta[c]pyrrol-4-yl)-phenyl]-ethyl}-2,3-dihydro-1H-indole Dihydrochloride. N N/ 10 The title compound was obtained using general method A. MS m/z 421.3, (M+H); 'H NMR (400 MHz, MeOH-d 4 ) 5 ppm 2.41 - 2.59 (mn, 1 H) 2.80 - 3.04 (min, 2 H) 3.08 - 3.19 (mn, 2 H) 3
.
2 0 - 3
.
6 3 (mi, 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 (mn, 1 H) 7.29 - 7.62 (min, 13 H). 15 Example 1.34 - General Method B Preparation of (:)- 2 -Cyclopentyl-6-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl]-1,2,3,3a,4,6a hexahydro-cyclopenta[c]pyrrole Dihydrochloride NNC The compound in Example 1.7 (0.200 g, 0.708 mmol) and cyclopentanone (0.060 g, 20 0.708 mimol) 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 25 dried (MgSO 4 ). 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 NH 3 /MeOH in dichliloromethane. Purification as described in Example 1.13 afforded the title compound as a -100- WO 2007/061741 PCT/US2006/044479 .,:::2 1.040 . ennt o icily 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 nm/z 351.3, (M+H); 'H NMR (400 MHz, CD 3 OD) 6 7.36 (d,J= 8.0 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 6.04 (s, 1H), 3.79-3.69 (m, 1H), 3.21 (t, J= 8.0 Hz, 1H), 3.13-3.05 (m, 1H), 3.03 5 2.97 (m, 1H), 2.86-2.77 (m, 3H), 2.76-2.69 (m, 3H), 2.64 (br s, 4H), 2.41 (t, J= 8.0 Hz, 1H), 2.31 (dd, J= 17.6,2.8 Hz, 1H), 2.16 (q, J= 7.9 Hz, 1H), 1.91-1.75 (m, 5H), 1.75-1.62 (m, 2H), 1.59-1.48 (m, 2H11), 1.47-1.36 (mn, 2H). Example 1.35: Preparation of ( 3 aS, 6 aS)-2-Cyclopropylmethyl-6-[4-(2-pyrrolidin-l-yl 10 ethyl)-phenyl]-1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride. N H NoI _H' The title compound was obtained using general method B. MS nm/z 337, (M+H); 1H NMR (400 MHz, CD 3 OD) 6 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, 1H), 4.14-4.25 (m, 1H), 3.95-4.09 (m, 1H), 3.63-3.72 (m, 2H), 3.39-3.60 (m, 15 5H), 3.01-3.18 (m, 6H), 2.72-2.93 (m, 2H), 2.42-2.57 (m, 1H), 1.96-2.23 (m, 4H), 1.02-1.14 (m, 1H), 0.64-0.75 (m, 2H), 0.32-0.44 (m, 2H). Example 1.36: Preparation of ( 3 aS, 6 aS)-2-Cyclopentyl-6-[4-(2-pyrrolidin-l-yl-ethyl) phenyl]-1, 2
,
3
,
3 a,4,6a-hexahydro-cyclopenta[c]lpyrrole Dihydrochloride. N H 20 H The title compound was obtained using general method B. MS nm/z 351, (M+H). Example 1.37: Preparation of ( 3 aS, 6 aS)-2-(4-Methoxy-benzyl)-6-[4-(2-pyrrolidin-.l-yl ethyl)-phenyl]-1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride. MeO ) N H 25 H The title compound was obtained using general method B. MS inm/z 403, (M+H); 'H NMR (400 MHz, CH 3 OD) 6 7.28-7.45 (m, 6H), 6.98 (dd, J= 8.6, 2.0 Hz, 2H), 6.22 (d, J= 11.4 Hz 1H), 4.14-4.34 (m, 2H), 3.90-4.04 (m, 1H), 3.63-3.86 (m, 6H), 3.20-3.55 (m, 4H), 2.78-3.18 -101 - WO 2007/061741 PCT/US2006/044479 If"'' "m,' J,214 -2'5'1(in, 1H), .1.97-2.22 (in, 411). Example 1.38: Preparation of ( 3 aS, 6 aS)- 2 -Isopropyl-6-[4-(2-pyrrolidin-1-yl-ethyl) phenyl]-1,2,3,3a,4,6a-hexahydro-cyclopenta[cl]pyrrole Dihydrochloride. NNH 5 H The title compound was obtained using general method B. MS inm/z 325, (M+H); 1H NMR (400 MHz, DMSO-d 6 ) 6 7.45 (d, J= 8.1 Hz, 2H), 7.25-7.32 (mn, 2H), 6.23-6.30 (m, 1H), 3.96-4.15 (m, 111), 3.25-3.57 (m, 6H), 2.98-3.08 (m, 5H), 2.53-2.89 (m, 3H), 2.31-2.40 (m, 1H), 1.83-2.06 (mn, 5H), 1.21-1.29 (mn, 6H). 10 Example 1.39: Preparation of (±)- 2 -Cyclobutyl-6-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl]. 1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride. N The title compound was obtained using general method B. MS nm/z 337.6, (M+H); 1H 15 NMR (400 MHz, CD 3 OD) 8 7.45 (t, J= 8.0 Hz, 2H), 7.37-7.29 (mn, 2H11), 6.30-6.16 (mn, 1H), 4.17 (br s, 1H), 4.13-3.98 (m, 1H11), 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, 1H), 2.73-2.58 (m, 1H), 2.56-2.40 (m, 1H), 2.36-2.10 (m, 6H11), 2.09 1.95 (m, 2H), 1.94-1.76 (mn, 2H). 20 Example 1.40: Preparation of (=)-2-{6-[4-(2-Pyrrolidin-1-yl-ethyl)-phenyl]-3,3a,4,6a tetrahydro-lH-cyclopenta[c]lpyrrol-2-yl}-propan-l-ol Dihydrochloride. HO The title compound was obtained using general method B. MS nm/z 341.4, (M+H); 1H NMR (400 MHz, CD 3 OD) 6 7.48 (dd, J= 8.0, 8.0 Hz, 2H), 7.36 (d, J= 8.0 Hz, 2H11), 6.31-6.18 25 (m, 1H11), 4.27-413 (mn, 1H), 4.09-3.79 (mn, 2H), 3.76-3.66 (mn, 2H), 3.65-3.52 (mn, 2H11), 3.50-3.41 (mn, 3H), 3.22-3.05 (mn, 5H), 2.95-2.79 (m, 2H), 2.61-2.44 (mn, 1H), 2.19 (s, 2H), 2.12-1.99 (m, 2H), 1.45-1.30 (mn, 3H), 1.19 (t,J= 8.0 Hz, 1H). - 102 - WO 2007/061741 PCT/US2006/044479 IP" .4Prerit of (±)-2-Cyclopropylmethyl-6-1[4-(2-pyrrolidin-1-yl-ethyl) phenyl]-l,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride. N2o The title compound was obtained using general method B. MS m/z 337.5, (M+H); 1H 5 NMR (400 MHz, CD 3 OD) 8 7.46, (d, J= 8.0 Hz, 2H), 7.34 (d, J= 8.0 Hz, 2H), 6.22 (s, 1H11), 4.14-4.04 (m, 1H), 3.86 (br s, 1H), 3.79-3.68 (m, 1H), 2.46-3.33 (m, 7H), 3.11-2.99 (m, 6H), 2.97-2.88 (m, 1H), 2.50 (br d, J= 16.0 Hz, 1H), 2.09 (t, J= 4.0 Hz, 4H), 1.14-1.04 (m, 1H), 0.69 (d, J= 8.0 Hz, 2H), 0.38 (br s, 2H). 10 Example 1.42: : Preparation of (±)- 4
-{
6
-[
4
-(
2 -Pyrrolidin-1-yl-ethyl)-phenyl]-3,3a,4,6a tetrahydro-1H-cyclopenta[cl]pyrrol-2-ylmethyl}-phenol Dihydrochloride. HO / NN The title compound was obtained using general method B. MS m/z 389.6, (M+H); 'H NMR (400 MHz, CD 3 OD) 6 7.35 (d, J= 8.0 Hz, 2H11), 7.19 (d, J= 8.0 Hz, 2H), 7.11 (d, J= 8.0 15 Hz, 2H), 6.71 (d, J= 8.0 Hz, 2H), 6.06 (s, 1H), 3.73 (br d, J= 8.0 Hz, 1H), 3.52 (q, J= 21.3 Hz, 2H), 3.14 (t, J= 8.0 Hz, 1H), 3.08-2.95 (m, 2H11), 2.94-2.69 (m, 9H), 2.31 (br d, J= 20.0 Hz, 2H), 2.26-2.14 (m, 2H), 1.89 (s, 4H11). Example 1.43: Preparation of (±)- 2 -Cyclohexyl-6-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl] 20 1, 2
,
3 ,3a,4,6a-hexahydro-cyclopenta[cl]pyrrole Dihydrochloride. N I The title compound was obtained using general method B. MS m/z 365.5, (M+H); 'H NMR (400 MHz, CDC1 3 ) 5 7.32 (d, J= 8.2 Hz, 2H11), 7.16 (d, J= 8.2 Hz, 2H), 6.00-5.97 (m, 1H), 3.74-3.63 (m, 1H), 3.29 (ddd, J= 8.8, 8.8, 0.0 Hz, 1H11), 3.16 (ddd, J= 8.2, 8.2, 0.0 Hz, 1H), 25 3.03-2.93 (m, 1H), 2.85-2.65 (m, 5H), 2.60-2.54 (m, 4H), 2.33-2.25 (m, 1H), 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, 1H11), 1.23-1.10 (m, 3H). Example 1.44: Preparation of (-)- 2 -Methyl-6-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl] - 103 - WO 2007/061741 PCT/US2006/044479 ' ,l Iii ,,,, 1: ',. 1 ,, 11II 1,2,,a,4a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride. N The title compound was obtained using general method B. MS m/z 297.4, (M+H); 'H NMR (400 MHz, CD30D) 8 7.69 (s, 1H), 7.60 (s, 1H11), 7.45 (s, 1H11), 7.34 (s, 1H11), 6.16-6.30 (m, 5 111), 4.21(s, 1H11), 3.70 (s, 1H11), 3.35-3.60 (m, 2H11), 2.95-3.25 (m, 2H11), 2.90 (s, 2H), 2.20 (s, 1H), 2.05 (s, 1H11), 1.20-1.50 (m, 9H), .80-1.00 (mn, 311H) Example 1.45: Preparation of (±)- 2 -Isopropyl- 6
-[
4
-(
2 -pyrrolidin-1-yl-ethyl)-phenyl] 1, 2
,
3
,
3 a, 4
,
6 a-hexahydro-cyclopentafc]pyrrole Dihydrochloride. IN 10 The title compound was obtained using general method B. MS m/z 325.6, (M+H); 1H NMR (400 MHz, CD 3 OD) 6 7.45 (s, 2H11), 7.35 (s, 2H), 6.14-6.30 (m, 1H), 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, 4H11), 1.30-1.50 (m, 6H1), .80-1.00 (m, 2H). 15 Example 1.46: Preparation of (:)- 2 -Isobutyl-6-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl]. 1, 2
,
3
,
3 a, 4 ,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride. INN The title compound was obtained using general method B. MS mn/z 339.4, (M+H); 'H 20 NMR (400 MHz, CD 3 OD) 6 7.44 (s, 2H), 7.33 (s, 2H11), 6.15-6.24 (m, 1H), 4.19 (s, 1H11), 4.05 (s, 1H1), 3.95 (s, 1H1), 3.69 (s, 2H), 3.35-3.55 (m, 3H11), 2.91-3.20 (m, 7H), 2.40-2.90 (m, 3H11), 2.17 (s, 2H11), 2.04 (s, 3H), .90-1.10 (m, 6H). Example 1.47: Preparation of (±)- 2
-(
2
,
4 -Dimethoxy-benzyl)-6-[4-(2-pyrrolidin-1-yl-ethyl) 25 phenyl]-1, 2
,
3
,
3 a, 4
,
6 a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride. -104- WO 2007/061741 PCT/US2006/044479 !r , : , i:,:1t",., IL, !! 41 -11 I t-II,. I lq ,7 tl;, M e ~~NC> MeO \ NN / The title compound was obtained using general method B. MS m/z 433.5, (M+H); 'H NMR (400 MHz, CD 3 OD) 6 7.40 (dd, J1 = 7.6 Hz, J 2 = 2.8 Hz, 2H), 7.24-7.36 (mn, 2H1), 7.22 (dd, J = 8.4 Hz, J 2 = 2.4 Hz, 1H), 6.50-6.62 (min, 2H), 6.20 (d, J = 11.6 Hz, 1H), 4.27 (d, J = 5 16.0 Hz, 1H), 3.90-4.05 (mn, 1H11), 3.70-3.85 (mn, 7H), 3.65-3.68 (mn, 2H), 3.45-3.60 (mn, 4H), 3.02-3.27 (mn, 5H11), 2.79-3.00 (min, 2H), 2.45 (d, J= 16.0 Hz, 1H), 2.10-2.32 (mn, 2H), 1.96-2.10 (mn, 2H). Example 1.48: Preparation of (+)-6-[4-(2-Pyrrolidin-1-yl-ethyl)-phenyl]-2-(4 10 trifluoromethoxy-benzyl)-1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride.
F
3 CO0N N / The title compound was obtained using general method B. MS nm/z 457.4, (M+H); 1H NMR (400 MHz, CD30D) 6 7.48-7.67 (mn, 2H), 7.38-7.46 (mn, 2H1), 7.26-7.38 (mn, 4H11), 6.21 (d, J = 8.8 Hz, 1H1), 4.40 (d, J = 10.0 Hz, 1H1), 3.95-4.05 (mn, 1H), 3.72-3.82 (min, 1H), 3.63-3.71 (inm, 15 2H1), 3.35-3.62 (min, 4H11), 2.80-3.20 (mn, 9H), 2.42-2.52 (mn, 1H), 1.92-2.23 (in, 4H). Example 1.49 - General Method C Preparation of (A)-l-{6-[4-(2-Pyrrolidin-1-yl-ethyl)-phenyl]-3,3a,4,6a-tetrahydro-lH cyclopenta[c]pyrrol-2-yl}-ethanone Hydrochloride. 200 NC >~ 20 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 25 dichloromethane (15 mL) and quenched with distilled water (20 mL). The organic extract was washed with brine and dried (MgSO 4 ). 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 NH 3 /MeOH in dichloromethane. Purification as described in Example 1.13 afforded - 105 - WO 2007/061741 PCT/US2006/044479 1-' ..... .. " ": ii "" "' J 11;;;11 Jtir . the title compound as a yellow solid (0.090 g, 52.3% yield). 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 325.5, (M+H); 'H NMR (400 MHz, CD 3 OD) 6 7.40 (t, J= 8.0 Hz, 2H), 7.30 (t, J= 8.0 Hz, 2H), 6.10 (br s, 1H), 3.97-3.81 (m, 5 2H), 3.80-3.72 (m, 1H), 3.71-3.62 (m, 1H), 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, 1H), 2.45-2.34 (m, 1H), 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-1-yl-ethyl) 10 phenyl]- 3 ,3a,4,6a-tetrahydro-1H-cyclopenta[e]pyrrol-2-yl}-methanone Hydrochloride. H NC>~i H The title compound was obtained using general method C. MS m/z 351, (M+H); 'H NMR (400 VMHIz, CH 3 0D) 5 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, 1H), 4.06 (dd, J= 18.8, 9.1 Hz, 1H), 3.63-3.99 (m, 4H), 3.42-3.52 (m, 3H), 3.02-3.26 15 (m, 6H), 2.76-2.88 (m, 1H), 2.34-2.46 (m, 1H), 1.96-2.21 (m, 4H), 1.61-1.83 (m, 1H), 0.65-0.89 (m, 4H). Example 1.51: Preparation of ( 3 aS,6aS)-2-Methyl-1-{6-[4-(2-pyrrolidin-1-yl-ethyl) phenyl]- 3
,
3 a, 4
,
6 a-tetrahydro-1H-cyclopenta[elcpyrrol-2-yl}-propan-l-one Hydrochloride. 200 NH 20 H The title compound was obtained using general method C. MS m/z 353, (M+H); 1H NMR (400 MHz, CH30D) 5 7.41 (dd, J 8.0, 6.1 Hz, 2H), 7.30 (dd, J= 7.4, 7.4 Hz, 2H), 6.10 (bs, 1H), 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, 1H11), 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, 25 1H), 1.03 (d, J = 6.8 Hz, 2H), 0.85 (d, J= 6.8 Hz, 1H). Example 1.52: Preparation of ( 3 aS, 6 aS)-Cyclopentyl-{6-[4-(2-pyrrolidin-1-yl-ethyl) phenyl]- 3
,
3 a, 4
,
6 a-tetrahydro-1H-cyclopenta[c]pyrrol-.2-yl}-methanone Hydrochloride. -106- WO 2007/061741 PCT/US2006/044479 N H
H
Z The title compound was obtained using general method C. MS nm/z 379, (M+H); '11 NMR (400 MHz, CH30D) 6 7.40 (dd, J= 7.8, 6.1 Hz, 2H11), 7.30 (dd, J = 7.8, 7.8 Hz, 2H), 6.10 (bs, 1H11), 3.63-3.96 (m, 5H11), 3.42-3.58 (m, 3H), 3.02-3.37 (m, 6H), 2.70-2.96 (m, 2H), 2.33-2.43 5 (m, 1H), 1.42-1.91 (m, 8H). Example 1.53: Preparation of (±)-6-[ 4 -(2-Pyrrolidin-1-yl-ethyl)-phenyl]-3,3a,4,6a tetrahydro-1H-cyclopenta[c]pyrrole Dihydrochloride-2-carboxylic acid ethyl ester Hydrochloride. 0 No 10 The title compound was obtained using general method C. MS nm/z 355.3, (M+H); 1H NMR (400 MHz, CD 3 OD) 8 7.32 (d, J= 8.0 Hz, 2H11), 7.21 (d, J= 8.0 Hz, 2H11), 6.04 (s, 1H), 4.04 (br s, 2H), 3.80 (br s, 1H), 3.75-3.61 (m, 2H), 3.38-3.31 (m, 1H), 3.18-3.02 (m, 2H11), 2.81 (dd, J= 18.0, 6.0 Hz, 4H), 2.72 (s, 5H1), 2.33 (d, J= 16.0, 1H11), 1.91-1.81 (m, 4H), 1.25-1.11 (m, 15 3H). Example 1.54: Preparation of (±)- 4 -Hydroxy-4-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl] hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester. O N N O OH 20 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); '11 NMR (400 MHz, MeOH-d 4 ) 8 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). 25 Example 1.55: Preparation of (-)- 4 -[4-(2-Pyrrolidin-1-yl-ethyl)-phenyl]-octahydro cyclopenta[c]pyrrole Dihydrochloride. - 107 - WO 2007/061741 PCT/US2006/044479 .. IL ....... . .'1-"1=. 1 .... , 1~t4, ;T 11::,11 HN 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 5 determined by LC/MS. The mixture was filtered to remove the catalyst, concentrated by rotary evaporation and purified by preparative IHIPLC 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) 10 Example 1.56: Preparation of (=)- 2 -Cyclopropylmethyl-4-[4-(2-pyrrolidin-1-yl-ethyl) phenyl]-octahydro-cyclopenta[c]pyrrole Dihydrochloride. V-- NN N2o The title compound was obtained using general method B starting from the title compound in Example 1.55. MS nm/z 339.4, (M+H); 1H NMR (400 MHz, CD30D) 6 7.19-7.43 15 (min, 4H), 3.85-4.05 (in, 1H), 3.59-3.75 (min, 2H), 3.34-3.53 (in, 3H), 2.90-3.25 (in, 10H), 2.38 2.80 (min, 1H), 1.67-2.60 (min, 9H), .60-.80 (min, 2H), .30-.50 (min, 2H1). Example 1.57: Preparation of (±)-2-Isopropyl-4-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl] octahydro-cyclopenta[c]pyrrole Dihydrochloride. N 20 The title compound was obtained using general method B starting from the title compound in Example 1.55. MS inm/z 327.3, (M+H); 'H NMR (400 MHz, CD 3 OD) 8 7.31 (dd, J = 14.0, 10.0 Hz, 4H11), 3.92 (t, J= 10.0 Hz, 1H), 3.74-3.63 (mn, 2H11), 3.52-3.40 (mn, 2H), 3.39-3.33 (mn, 1H), 3.24 (dd, J= 20.0, 8.0 Hz, 1H11), 3.19-3.09 (in, 2H11), 3.08-2.99 (mn, 2H11), 2.71 (dd, J= 25 10.0, 10.0 Hz, 1H11), 2.40 (dd, J= 10.0, 10.0 Hz, 1H), 2.23-2.09 (mn, 3H), 2.08-1.95 (in, 3H), 1.94-1.84 (min, 1H), 1.81-1.72 (in, 1H), 1.46-1.36 (min, 1H), 1.33 (d, J= 8.0 Hz, 3H), 1.30-1.26 (mn, 1H), 1.24 (d, J= 4.0 Hz, 3H). -108- WO 2007/061741 PCT/US2006/044479 P xampe 1C:Preparation of (±)- 2 -Cyclopentyl-4-[ 4
-(
2 -pyrrolidin-1-yl-ethyl)-phenyl] octahydro-cyclopenta[clpyrrole Dihydrochloride. N The title compound was obtained using general method B starting from the title 5 compound in Example 1.55. MS m/z 320.3, (M+H); 1H NMR (400 MHz, CD 3 OD) 3 7.29 (dd, J = 16.0, 8.0 Hz, 4H), 3.90 (t, J= 10.0 Hz, 1H), 3.73-3.63 (m, 2H), 3.45-3.37 (m, 3H), 3.36-3.32 (m, 1H), 3.28-3.17 (m, 2H), 3.12 (br dd, J= 20.0, 8.0 Hz, 2H), 3.06-2.98 (m, 3H11), 2.97-2.87 (m, 1H1), 2.70 (dd, J= 12.0, 12.0 Hz, 1H), 2.40 (dd, J= 12.0, 12.0 Hz, 111), 2.21-1.96 (m, 8H11), 1.93 1.83 (m, 1H), 1.81-1.70 (m, 3H), 1.69-1.49 (m, 3H). 10 Example 1.59: Preparation of (±)- 2 -(2,4-Dimethoxy-benzyl)-4-[4-(2-pyrrolidin-1-yl-ethyl) phenyl]-octahydro-cyclopenta[c]pyrrole Dihydrochloride. MeO N The title compound was obtained using general method B starting from the title 15 compound in Example 1.55. MS m/z 435.4, (M+H); 1H NMR (400 MHz, CDC1 3 ) 6 7.18-7.08 (m, 5H), 6.43-6.38 (m, 2H), 3.78 (s, 3H), 3.70 (s, 3H), 3.40 (ABq, JB = 25.7, J= 13.3 Hz, 2H11), 3.16-2.94 (m, 3H), 2.83-2.72 (m, 3H), 2.70-2.64 (m, 2H11), 2.60-2.54 (m, 4H), 2.50-2.44 (m, 1H11), 2.04-1.66 (m, 9H), 1.62-1.55 (m, 1H). 20 Example 1.60: Preparation of (A)-2-Cyclohexyl-4-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl] octahydro-cyclopenta[c]pyrrole Dihydrochloride. N N 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-d 4 ) 6 7.21 25 7.12 (m, 4H), 3.39 (dd, J= 8.8, 8.8 Hz, 1H), 3.23-3.15 (m, 1H), 3.01 (dddd, J= 8.6, 8.6, 8.6, 8.6 Hz, 1H), 2.84-2.60 (m, 1111), 1.97-1.53 (m, 14H), 1.30-1.00 (m, 6H11). -109- WO 2007/061741 PCT/US2006/044479 E x .mle : Prepartioii of(3aR,4R,6aS)-2-Cyclopropylmethyl-4-[4-(2-pyrrolidin-1-yl ethyl)-phenyl]-octahydro-cyclopenta[c]pyrrole Dihydrochloride. The title compound was obtained using general method B starting from the title 5 compound in Example 1.55. MS m/z 339.4 (M+H); 'H NMR (400 MHz, CDC1 3 ) 8 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, 1H), 3.18-3.10 (m, 111), 3.04 (dddd, J= 8.4, 8.4, 8.4, 8.4 Hz, 1H), 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, 1H11), 1.96-1.67 (m, 6H), 1.62-1.52 (m, 2H), 0.88-0.76 (m, 1H11), 0.50-0.36 (m, 2H), 0.11-0.04 (m, 2H). 10 Example 1.62: Preparation of (3aR,4R,6aS)-4-{4-[4-(2-Pyrrolidin-1-yl-ethyl)-phenyl] hexahydro-cyclopenta[c]pyrrol-2-ylmethyl]-phenol. HO ' N The title compound was obtained using general method B starting from the title 15 compound in Example 1.55. MS m/z 391.2 (M+H); 1H NMR (400 MHz, CDC1 3 ) 6 8.18 (br s, 1H), 7.10-6.95 (m, 6H), 6.78 (d, J= 8.5 Hz, 2H), 3.91 (d, J= 12.9 Hz, 1H), 3.62 (d, J= 12.9 Hz, 1H), 3.35 (ddd, J= 9.4, 9.4, 0.0 Hz, 1H), 3.25-2.28 (m, 13H), 2.68-2.60 (m, 1H), 2.43-2.35 (m, 1H), 2.05-1.61 (m, 7H). 20 Example 1.63: Preparation of (3aR,4R,6aS)-2-Cyclobutyl-4-[4-(2-pyrrolidin-1-yl-ethyl) phenyl]-octahydro-cyclopenta[elpyrrole Dihydrochloride. The title compound was obtained using general method B starting from the title compound in Example 1.55. MS nm/z 339.3 (M+H); 'H NMR (400 MHz, CDC1 3 ) 5 7.15 (d, J= 25 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, 1H1), 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, 1H1), 1.97-1.54 (m, 15H), 1.43 (ddd, J= 9.2, 9.2, 0.0 Hz, 1H). -110- WO 2007/061741 PCT/US2006/044479 P"'txamniiAe,.4:"'Preparatio , of"3aR,4R,6aS)-2-{4-[4-(2-Pyrrolidin-1-yl-ethyl)-phenyl] hexahydro-cyclopenta[c]pyrrol-2-yl}-propan-.1-ol dihydrocholride. OH N The title compound was obtained using general method B starting from material in 5 Example 1.55. MS nm/z 343.4 (M+H); 1H NMR (400 MHz, MeOH-d 4 ) 5 7.21-7.10 (m, 4H11), 3.58-2.52 (m, 16H), 2.48-1.00 (m, 13H11). Example 1.65: Preparation of (±)- 2 -Isobutyl-4-[4-(2-pyrrolidin-l-yl-ethyl)-phenyll octahydro-cyclopenta[c]pyrrole Dihydrochloride. N 10 The title compound was obtained using general method B starting from the title compound in Example 1.55. MS nm/z 341.4, (M+H); 1H NMR (400 MHz, CD 3 OD) 8 7.20-7.40 (m, 4H1), 3.82-3.98 (m, 1H), 3.62-3.74 (m, 2H), 3.33-3.51 (m, 3H11), 2.87-3.46 (m, 10), 2.37-2.63 (m, 1H), 1.70-2.42 (m, 9H), .92-1.21 (m, 6H). 15 Example 1.66: Preparation of (±)-l-{7-[4-(2-Pyrrolidin-1-yl-ethyl)-phenyll-1,3,3a,4,5,7a hexahydro-isoindol-2-yl}-ethanone. O N/N The title compound was prepared in a similar manner as described in General Method 20 C. LC-MS m/z 387.5 (M+H); 1H NMR (400 MHz, Methanol-d 4 ) 4 ppm 7.41 (dd, J= 11.70, 7
.
8 0 Hz, 2 H) 7.
2 6 -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). 25 Example 1.67: Preparation of (±)- 2
-(
4 -Methoxy-benzyl)-4-[4-(2-pyrrolidin-1-yl-ethyl) phenyl]-octahydro-cyclopenta[c]pyrrole Dihydrochloride. -111- WO 2007/061741 PCT/US2006/044479 MeO N N The title compound was obtained using general method B starting from the title compound in Example 1.55. MS nm/z 405.7, (M+H); 'H NMR (400 MHz, CD 3 OD) 6 7.41-7.55 (m, 1H), 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 5 (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-1-yl-ethyl)-phenyl]-2-(4 trifluoromethoxy-benzyl)-octahydro-cyclopenta[c]pyrrole Dihydrochloride. INo
F
3 CO -N 10 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); 'H NMR (400 MHz, CD 3 OD) 6 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). 15 Example 1.69: Preparation of (±)- 4
-{
4
-[
4 -(2-Pyrrolidin-1-yl-ethyl)-phenyl]-hexahydro cyclopenta[c]lpyrrol-2-ylmethyl]-phenol Dihydrochloride. N N HO(r The title compound was obtained using general method B starting from the title 20 compound in Example 1.55. MS m/z 391.7, (M+H); 'H NMR (400 MHz, CD 3 OD) 8 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 (3aR,4R,6aS)-2-Benzyl-4-[4-(2-pyrrolidin-1-yl-ethyl) 25 phenyl]-octahydro-cyclopenta[c]pyrrole Dihydrochloride. -112- WO 2007/061741 PCT/US2006/044479 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); 'H NMR (400 MHz, MeOH-d 4 ) 6 7.28-7.18 (m, 5H), 7.16 (d, J= 8.1 Hz, 2H), 7.11 (d, J= 8.1 Hz, 2H11), 3.44 (ABq, JAB = 29.0, J= 12.6 Hz, 5 2H1), 3.16 (ddd, J= 13.1, 8.0, 5.7, Hz, 1H11), 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, 1H), 2.05-1.57 (m, 10H). Example 1.71: Preparation of (-)- 2
-{
4
-[
4 -(2-Pyrrolidin-1-yl-ethyl)-phenyl]-hexahydro cyclopenta[cl]pyrrol-2-yl}-propan-l-ol Dihydrochloride. OH NC> N 10 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); 'H NMR (400 MHz, CD 3 OD) 6 7.10-7.50 (brs, 4H11), 3.60-3.80 (m, 2H), 3.25-3.55 (m, 7H), 2.90-3.25 (m, 4H11), 1.60-2.30 (m, 11H), 1.10 1.50 (m, 6H), .80-1.00 (m, 2H). 15 Example 1.72: Preparation of (+)-l-{ 4
-[
4
-(
2 -Pyrrolidin-1-yl-ethyl)-phenyl-hexahydro cyclopenta[c]pyrrol-2-yl}-ethanone Hydrochloride. N N C The title compound was obtained using general method C starting from the title 20 compound in Example 1.55. MS nm/z 327.3, (M+H); 'H NMR (400 MHz, CD 3 OD) 3 7.23-7.30 (m, 4H11), 3.60-3.82 (m, 1H11), 3.10-3.50 (m, 10H), 2.85-3.08 (m, 4H), 1.94-2.25 (m, 9H), 1.85 (s, 1H), 1.62-1.75 (m, 1H). Example 1.73: Preparation of (±)- 2 -Methyl-1-{4-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl] 25 hexahydro-eyclopenta[c]pyrrol-2-yl}-propan-l-one Hydrochloride. - 113 - WO 2007/061741 PCT/US2006/044479 N N The title compound was obtained using general method C starting from the title compound in Example 1.55. MS nm/z 355.5, (M+H); 'H NMR (400 MHz, CD 3 OD) 0 7.24 (s, 4H), 3.80-3.90 (min, 1H), 3.60 5 3.75 (mn, 3H), 3.35-3.55 (mn, 4H11), 2.75-3.28 (mn, 8H), 1.90-2.25 (mn, 7H11), 1.60-1.72 (mn, 1H), .95 1.15 (min, 6H11). Example 1.74: Preparation of (-)-Cyclopropyl-{4-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl] hexahydro-cyclopenta[c]pyrrol-2-yl}-methanone Hydrochloride. 0 N VANr 10 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); 1H NMR (400 MHz, CD 3 OD) 0 7.25 (s, 4H), 3.88-4.12 (min, 1H), 3.60-3.75 (mn, 3H), 3.35-3.50 (mn, 4H), 2.75-3.28 (mn, 7H), 1.95-2.25 (inm, 7H11), 1.60-1.90 (min, 2H11), .70-.95 (min, 4H). 15 Example 1.75: Preparation of (+)-Cyclopentyl-{4-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl] hexahydro-cyclopenta[c]pyrrol-2-yl}-methanone Hydrochloride. N NC The title compound was obtained using general method C starting from the title 20 compound in Example 1.55. MS nm/z 381.4, (M+H); H11 NMR (400 MHz, CD 3 OD) 0 7.25 (s, 4H), 3.82-3.95 (mn, 1H), 3.55-3.75 (mn, 3H), 3.35-3.50 (mn, 4H11), 2.75-3.28 (mn, 7H), 1.85-2.25 (inm, 9H11), 1.60-1.85 (mn, 8H). Example 1.76: Preparation of (±)- 4
-[
4
-(
2 -Pyrrolidin-1-yl-ethyl)-phenyl]-hexahydro 25 cyclopenta[c]pyrrole-2-carboxylic acid ethyl ester Hydrochloride. -114- WO 2007/061741 PCT/US2006/044479 OA N The title compound was obtained using general method C starting from the title compound in Example 1.55. MS nm/z 357.4, (M+H); 1H NMR (400 MHz, CD 3 OD) 6 7.17 (s, 4H), 4.14-4.08 (m, 1H), 4.03 (br s, 1H11), 3.59 (dd, J= 16.0, 8.0 Hz, 1H), 3.15-3.05 (m, 2H11), 5 2.91-2.77 (m, 4H), 2.76-2.68 (m, 2H11), 2.64 (br s, 4H), 2.22-2.10 (m, 1H11), 2.07-1.91 (m, 3H), 1.84 (s, 4H), 1.69-1.56 (m, 1H), 1.30-1.09 (m, 3H). Example 1.77: Preparation of (A)- 2
-(
4 -Methoxy-benzyl)-4-[4-(2-pyrrolidin-1-yl-ethyl) phenyl]-octahydro-cyclopenta[cl]pyrrol-4-ol. MeO\ 10 OH 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); 'H NMR (400 MHz, DMSO-d 6 ) 6 7.43 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 7.2 Hz, 2H11), 7.22-7.32 (m, 2H11), 6.98 (d, J= 7.6 Hz, 2H), 4.47 (d, J = 12.0 Hz, 111), 4.33 (s, 1H), 4.02 (d, J = 12.4 Hz, 1H), 3.82 (s, 3H11) 3.80 (s, 1H), 15 3.60-3.72 (m, 2H), 3.54 (d, J= 10.0 Hz, 111), 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-1-yl-ethyl) phenyl]-octahydro-cyclopenta[c]pyrrol-4-ol. N N 20 OH The title compound was obtained using general method B starting from the title compound in Example 1.6. MS inm/z 355.5, (M+H); 1H NMR (400 MHz, CHLOROFORM-d) 3 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 25 - 0.99 (m, 1 H) 0.
4 3- 0.56 (m, 2 H) 0.04- 0.17 (m, 2 H). - 115- WO 2007/061741 PCT/US2006/044479 xample 1.7: Preparation of ()-2-Isobutyl-4-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl] octahydro-cyclopenta[c]pyrrol-4-ol. NN SOH The title compound was obtained using general method B starting from the title 5 compound in Example 1.6. MS m/z 357.5, (M+H); 1H NMR (400 MHz, MeOH-d 4 ) 6 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). 10 Example 1.80: Preparation of (-)- 2 -Isopropyl-4-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl] octahydro-cyclopenta[c]pyrrol-4-ol. N N OH 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-d 4 ) 6 ppm 7.43 15 (d, J= 8.59 Hz, 2 H) 7.18 (d, J = 8.08 Hz, 2 H) 2.94 (d, J= 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-1-yl-ethyl)-phenyl]-2-(4 20 trifluoromethoxy-benzyl)-octahydro-cyclopenta[c]pyrrol-4-ol.
F
3CO / N NNI~I OH The title compound was obtained using general method B starting from the title compound in Example 1.6. MS nm/z 343.2, (M+H); 'H NMR (400 MHz, MeOH-d 4 ) 6 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 25 2
.
93 (m, 4 H) 2
.
52
-
2
.
7 0 (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, 1 H). -116- WO 2007/061741 PCT/US2006/044479 Example 1.82: Preparation of (-)- 2 -(2,4-Dimethoxy-benzyl)-4-[4-(2-pyrrolidin-1-yl-ethyl) phenyl]-octahydro-cyclopenta[cl]pyrrol-4-ol. OMe MeO N OH 5 The title compound was obtained using general method B starting from the title compound in Example 1.6. MS inm/z 351.2, (M+H); 'H NMR (400 MHz, MeOH-d 4 ) 8 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, J= 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) 10 1.42 - 1.58 (m, 1 H). Example 1.83: Preparation of (±)- 2 -Cyclohexyl-4-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl] octahydro-cyclopenta[c]pyrrol-4-ol. NN OH 15 The title compound was obtained using general method B starting from the title compound in Example 1.6. MS nm/z 383.6, (M+H); 'H NMR (400 MHz, MeOH-d 4 ) 5 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) 20 Example 1.84: Preparation of (-)-2-Cyclopentyl-4-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl] octahydro-cyclopenta[c]pyrrol-4-olcarboxylic acid tert-butyl ester. N N OH The title compound was obtained using general method B starting from the title -117- WO 2007/061741 PCT/US2006/044479 compouM in ample 1.. I/z 369.4, (M+H); 'H NMR (400 MHz, MeOH-d 4 ) 3 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 (mn, 2 H) 2.26 (dd, 1 H) 2.48 - 2.59 (min, 1 H) 2.59 - 2.65 (min, 5 H) 2.69 (s, 4 H) 2.76 -2.89 (min, 3 H) 2.90 -3.04 (in, 1 H) 7.14 7.23 (m, 2 H) 7.33- 7.52 (m, 2 H) 5 Example 1.85- General Method D Preparation of ( 3 aS, 6 aS)-6-[4-(2-Pyrrolidin-1-yl-ethyl)-phenyl]-3,3a,4,6a-tetrahydro-1H cyclopenta[c]-pyrrole-2-carboxylic acid isopropylamide Hydrochloride. N ND HN H H. o © H 10 To a solution of the compound described in Example 1.7 (160.5 mg, 568 gmol) in dichloromethane (3.0 mL) was added isopropyl isocyanate (61.4 1gl, 625 pmol) 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 HC1 salt. The 15 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 mn/z 368, (M+H); 1H NMR (400 MHz, CH 3 OD) ( 7.38 (d, J= 7.8 Hz, 2H), 7.28 (d, J= 8.3 Hz, 2H), 6.08 (d, J= 2.0 Hz, 1H), 3.79-3.90 (min, 2H), 3.63-3.74 (mn, 4H11), 3.40-3.47 (mn, 2H), 3.32-3.37 (mn, 1H), 3.01-3.19 (min, 6H), 2.75-2.84 (mn, 1H11), 2.34-2.42 (mn, 1H), 1.96-2.22 (mn, 5H), 1.09-1.14 20 (min, 6H11). Example 1.86: Preparation of ( 3 aS, 6 aS)- 6 -[4-(2-Pyrrolidin-1-yl-ethyl)-phenyl]-3,3a,4,6a tetrahydro-1H-cyclopenta[c]pyrrole-2-carboxylic acid cyclopentylamide. N0 No HN H H 25 The title compound was obtained using general method D. MS m/z 394, (M+H); 1H NMR (400 MHz, CH 3 OD) 8 7.38 (dd, J= 8.0, 1.7 Hz, 2H), 7.27 (dd, J = 8.0, 1.7 Hz, 2H), 6.06 6.10 (in, 1H), 3.90-3.99 (mn, 1H11), 3.80-3.88 (mn, 1H1), 3.41-3.47 (in, 2H), 3.28-3.36 (mn, 1H), 3.01 3.17 (in, 611), 2.75-2.83 (mn, 2H11), 2.34-2.42 (mn, 1H), 1.95-2.22 (mn, 4H11), 1.83-1.94 (mn, 2H11), 1.35 1.74 (min, 6H). 30 Example 1.87- General Method E -118- WO 2007/061741 PCT/US2006/044479 PreparAtiono (A)-2-Phenyil-6-4-(2-pyrrolidin-1-yl-ethyl)-phenyl]-1,2,3,3a,4,6a hexahydro-cyclopenta[c]lpyrrole Dihydrochloride. 1 IN In a 5 mL glass tube were placed the compound described in Example 1.7 (0.200 g, 5 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 10 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 nm/z 359.2, (M+H); 'H NMR (400 MHz, CD 3 OD) 6 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 (mn, 3H), 6.06 (s, 1H), 4.59 15 (br s, 1H), 3.91 (br s, 1H), 3.63-3.51 (mn, 2H) 3.24-3.15 (mn, 1H), 3.09 (dd, J= 8.0, 4.0 Hz, 1H), 3.04 (dd, J= 8.0, 4.0 Hz, 1H), 2.91-2.76 (mn, 5H), 2.72 (br s, 4H), 2.43 (dd, J= 20.0, 4.0 Hz, 1H), 1.89-1.82 (min, 3H). Example 1.88: Preparation of (±)- 2 -Pyridin-2-yl-6-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl] 20 1, 2
,
3
,
3 a,4, 6 a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride. IN The title compound was obtained using general method E. MS m/z 360.3, (M+H); 1 H NMR (400 MHz, CD 3 OD) 3 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, 1H), 6.87 (t, J= 8.0 Hz, 1H), 6.15 (s, 1H), 4.12 (br s, 1H), 25 4.04-3.94 (min, 2H), 3.67 (br s, 2H), 3.58 (dd, J= 12.0, 4.0 Hz, 1H), 3.48-3.33 (mn, 4H), 3.22-3.03 (mn, 4H), 2.94-2.83 (mn, 1H), 2.52 (d, J= 16.0 Hz, 1H), 2.12 (br s, 4H). Example 1.89- General Method F Preparation of ( 3 aS, 6 aS)- 2 -Hydroxy-1-{6-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl]-3,3a,4,6a 30 tetrahydro-1H-cyclopenta[c]pyrrol-2-yl}-ethanone. -119- WO 2007/061741 PCT/US2006/044479 HOO N NH H A solution of acid (118.0 mg, 1.55 mmol) and PS-DCC (1.44 g, 1.44 rmol) 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 mniL of dichloromethane. After 12 h, 5 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 IHIPLC (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 10 from the corresponding single isomer ketones in Example 1.1. MS nm/z 341, (M+H); 1H NMR (400 MHz, CH 3 OD) 3 7.40 (d, J = 8.2 Hz, 2H), 7.30 (dd, J= 8.0, 3.9 Hz, 2H), 6.08-6.12 (m 1H), 4.04-4.15 (min, 2H), 3.63-3.96 (min, 6H), 3.42-3.54 (min, 3H1), 3.02-3.35 (mn, 6H), 2.76-2.86 (inm, 1H), 2.35-2.43 (mn, 1H), 1.95-2.23 (mn, 4H). 15 Example 1.90: Preparation of (+)- 2 -Hydroxy-1-{4-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl hexahydro-cyclopenta[e]pyrrol-2-yl}-ethanone. 0 HO, No "N The title compound was obtained using general method F. MS m/z 343.3, (M+H); 'H NMR (400 MHz, CD 3 OD) 5 7.05-7.15 (min, 4H), 4.05-4.25 (min, 1H11), 3.85-4.00 (mn, 1H), 3.55-3.75 20 (min, 3H), 3.35-3.50 (min, 4H), 2.80-3.25 (mn, 6H), 1.90-2.25 (mn, 7H), 1.60-1.90 (mn, 2H), 1.10-1.50 (mn, 1H), .80-1.00 (mn, 1H). Example 1.91: Preparation of (-)- 2 -Hydroxy-2-methyl-1-{6-[4-(2-pyrrolidin-1-yl-ethyl) phenyl]- 3
,
3 a, 4
,
6 a-tetrahydro-1lH-cyclopenta[c]pyrrol-2-yl}-propan-1-one. 0 HO ONN 25 The title compound was obtained using general method F. MS m/z 369.2, (M+H); 1H NMR (400 MHz, CD 3 OD) 6 7.33 (d, J= 8.0 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H1), 6.04 (s, 1H), 4.27-4.01 (min, 1H), 4.00-3.68 (mn, 3H), 3.66-3.56 (mn, 1H), 3.52-3.37 (mn, 1H11), 3.19-2.94 (mn, 1H), -120- WO 2007/061741 PCT/US2006/044479
S
2 5 2 ,73 ,, 2.2-2.6 (, 2H), 2.60 (s, 4H11), 2.35 (d, J= 16.0 Hz, 111), 1.85-1.79 (m, 4H), 1.37 (dd, J= 8.0 Hz, 3H), 1.28 (s, 2H), 1.10 (s, 1H). Example 1.92- General Method G 5 Preparation of (±)- 4
-(
2 -Benzyl-l, 2 ,3,3a,6,6a-hexahydro-cyclopentafc]pyrrol-4-yl) phenylamine. NN
NH
2 I I To a microwave vial was added trifluoromethanesulfonic acid 2-benzyl-1,2,3,3a,6,6a hexahydro-cyclopenta[c]pyrrol-4-yl ester (0.200g, 0.586 mmol), 4-aminophenylboronic ester 10 (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 100 0 C 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 I-IPLC, using method 10-60% over 25 min. The pure 15 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 nzm/z 291.0, (M+H); 1H NMR (400 MHz, DMSO-d 6 ) 3 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) 20 2.36 (d, J= 18.19 Hz, 1 H). Example 1.93: Preparation of (d)-5-(2-Benzyl-1,2,3,3a,6,6a-hexahydro cyclopenta[c]pyrrol-4-yl)-pyridin-2-ylamine. N \ N NH 2 25 The title compound was obtained using general method G. MS m/z 292.1, (M+H); 'H NMR (400 MHz, DMSO-d 6 ) 5 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-1,2,3,3a,6,6a-hexahydro 30 cyclopenta[c]pyrrol-4-yl)-phenyl]-ethylamine. - 121 - WO 2007/061741 PCT/US2006/044479 N
NH
2 NO / 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-pyrrolidin-1-yl-ethyl)-phenyl] 5 hexahydro-cyclopenta[elpyrrol-2-yl}-ethanone. NN OH 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-d 4 ) 6 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 10 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-1-yl-ethyl)-phenyl] hexahydro-cyclopenta[cl]pyrrole-2-carboxylic acid ethyl ester. NN 15 OH 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-d 4 ) 6 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 20 (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. Br 25 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 - 122 - WO 2007/061741 PCT/US2006/044479 was 'eateUo '/ C for 0.- 1 h 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 MgSO 4 and the solvent was removed under reduced pressure to afford a yellow viscous solid as product. Compound was purified by silica 5 column eluted with (0-5% EtOAc/n-hexane) to afford a white viscous solid. (2.25g, 60.3%). 'H NMR (400 MHz, DMSO-d 6 ) 8 8.83 (d, J = 2.3 Hz, 1H), 8.02 (dd, J= 8.44, 2.35 Hz, 1H), 7.49 (d, J= 2.3 Hz, 1H), 6.79 (dd, J=16.00, 12.29 Hz, 1H), 6.23 (dd, J= 1 6 .00,1.48 Hz, 1H), 5.52 (dd, J =12.29, 1.48 Hz, 1H). 10 Example 1.98: Preparation of 2
-(
2 -pyrrolidin-1-yl-ethyl)-5-bromopyridine. Br N To a solution of 2-vinyl-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 oC for 24 hr under pressure in a heavy walled sealed tube. After 24 15 hours, reaction was quenched with water, the product was extracted into DCM and washed with 2M HC1. The aqueous layer was then basified with solid Na 2
CO
3 to pH=10.0 and extracted with DCM. The combined organic layers was dried (MgSO 4 ) 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); 'H NMR (400 MHz, DMSO-d 6 ) 6 8.58 (d, J= 2.36 Hz, 1H), 7.93 (dd, J= 8.33, 2.36 Hz, 1H), 7.30 (d, J 20 8.33 Hz, 1H), 2.87 (t, 2H), 2.76 (t, 2H), 2.50 (mn, 8H). Example 1.99: Preparation of (+)- 2 -Benzyl-4-[5-(2-pyrrolidin-1-yl-ethyl)-pyridin-3-yl] octahydro-cyclopenta[c]pyrrol-4-ol. 0-,- ' N NN N OH 25 2-(2-Pyrrolidin-1-yl-ethyl)-5-bromopyridine (800.0mg, 3.1 mmol) was dissolved in anhydrous THF under N 2 and cooled to -78 0 C. 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 0 C and the mixture was stirred at -78 0 C for 3 hours, then allowed to warm to 30 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. - 123 - WO 2007/061741 PCT/US2006/044479 '4 n orgamc ayer was died over MgSO 4 , concentrated under reduced pressure to afford brown viscous oil as final product. Purification by HPLC afforded the title compound as a yellow viscous oil (1.0g, 81.0%). MS mn/z 392.4, (M+H); 1H NMR (400 MHz, CDC13) 6 8.79 (min, 1H), 8.20-8.25 (min, 1H11), 7.70-7.74 (m, 1H), 7.23-7.43 (mn, 5H), 4.23 (d, 1H), 4.30-4.20 (t, 5 2H), 4.17 (mn, 2H), 4.00(d, 1H11), 3.45-3.70 (mn, 2H), 3.20-3.40 (mn, 2H11), 3.00-3.20 (mn, 4H11), 2.95 (mn, 1H), 2.40-2.50 (min, 2H), 2.15-2.30 (in, 2H), 2.00-2.20 (min, 4H), 1.80-2.00 (mn, 1H). Example 1.100: Preparation of (±)-2-Benzyl-6-[6-(2-pyrrolidin-1-yl-ethyl)-pyridin-3-yl] 1, 2
,
3
,
3 a, 4 ,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride. N NN N 10 To a solution of the compound described in Example 1.99 (200mg, 511 gmol) in 5 mL of DCM was added Et 3 N (107 1gl, 766 Rmol) and methanesulfonyl chloride (59.3 1gl, 766 pmol). 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 HC1, the aqueous layer was isolated, 15 treated with Na 2
CO
3 then extracted with DCM. The organic layer was dried over MgSO 4 , volatiles were removed under reduced pressure and the crude was purified by silica gel chromatography: eluted with EtOAc/5%MeOH/NH 3 in DCM to afford the title compound as a yellow viscous liquid. MS m/z 374.3, (M+H); 'H NMR (400 MHz, CDC1 3 ) 6 8.52 (d, 1H), 7.56 (dd, 1H), 7.57-7.18 (min, 5H), 7.09 (d, 1H11), 6.09 (min, 1H11), 3.67 (min, 1H), 3.65 (d, 1H11) 3.45 (d, 1H), 20 3.00-3.30 (min, 1H11), 3.00 (min, 3H), 2.95 (mn, 1H), 2.80 (t, 2H), 2.65-2.75 (mn, 1H), 2.58 (mn, 4H), 2.25-2.35 (min, 1H), 2.16(m, 2H), 1.76 (m,4H). Example 1.101: Preparation of (-)-2-Benzyl-4-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl] octahydro-cyclopenta[c]pyrrol-4-ol. N N 25 OH 4-(2-pyrrolidinoethoxy)phenyl bromide (439 mg, 1626 gmol) was dissolved in anhydrous TIF under N 2 , stirred at room temperature for a 10 min., then cooled to -78 0 C. 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 30 THF was added dropwise. The resulting mixture was stirred at -78 0 C for 3 hours then allowed -124- WO 2007/061741 PCT/US2006/044479 0 o t roomtemperaure 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 MgSO 4 , 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 5 (0.25g, 37.8%). MS nm/z 407.2, (M+H); 1H NMR (400 MHz, CDC1 3 ) 6 7.22-7.37 (d, 2H), 7.13 7.21 (min, 5H), 6.85-6.77 (min, 3H), 4.02 (t, 2H), 3.65 (d, 1H) 3.29 (d, 1H), 3.90 (d, 1H), 2.70-2.80 (t, 2H), 2.65 (mn, 1H), 2.60 (mn, 1H), 2.50-2.60 (min, 4H), 2.20 (d, 1H), 2.00(m, 2H), 1.90 (mn, 1H), 1.80 (m, 2H), 1.60-1.70(m, 4H), 1.50 (in, 1H). 10 Example 1.102: Preparation of (±)- 2 -Benzyl-6-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl] 1, 2
,
3 ,3a,4,6a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride. N O The compound described in Example 1.101 (250.00mg, 615 pmol) was dissolved in 5 mL of DCM. Methanesulfonyl chloride (95.2 pl, 1230 gmol) and triethylamine (171 pl, 1230 15 gmol) were added. The mixture was stirred at 25 '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 (110.0mg, 46.0%). MS m/z 389.3, (M+H); 'H NMR (400 MHz, CDC1 3 ) 6 7.25-7.34 (mn, 7H), 6.89 (d, 2H), 5.94 (inm, 20 1H), 4.14 (t, 2H), 3.66 (mn, 1H), 3.63 (d, 1H), 3.52 (d, 1H), 3.14 (t, 1H), 2.99 (mn, 2H), 2.91 (t, 2H), 2.79 (min, 2H), 2.75 (min, 4H), 2.35 (min, 2H),1.83 (mn, 4H). Example 1.103: Preparation of 3-(2-pyrrolidinoethoxy)phenyl bromide. Br O o 25 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 Nail (2.77 g, 116 mmol) in small portions, then reaction mixture was stirred at 70 oC for 5 minutes, then a solution of 1-(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 30 extracted with EtOAc. The combined organic layers were dried over MgSO 4 , 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 nm/z 272.0, (M+H); 1H NMR (400 MHz, CDC13) 6 7.11-7.04 (min, 3H), 6.84 (min, 1H), 4.08 (t, 2H), 2.93 (t, 2H), 2.76 (min, 4H), 1.80 (mn, 4H). - 125 - WO 2007/061741 PCT/US2006/044479 '," ~ 11..... "'l ::: I: .11 ;;PJ,,0L ." Exam 6 l.104: 'Preparation of ()-2-Benzyl-4-[3-(2-pyrrolidin-1-yl-ethoxy)-phenyl] octahydro-cyclopenta[c]pyrrol-4-ol. N \NO OH A solution of 3-(2-pyrrolidinoethoxy)phenyl bromide (500mg, 1.85 mmol) in 50 mL 5 anhydrous THF under N 2 was cooled at -78 0 C. 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 -78 0 C 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 10 with water, dried with MgSO 4 and concentrated to afford a yellow oil. Purification by silica gel chromatography (EtOAc/10%NH 3 -MeOH in DCM) gave the title compound as a yellow oil. MS nm/z 407.2, (M+H); 1H NMR (400 MHz, CDCl 3 ) 8 7.04-7.28 (m, 6H), 7.02 (m, 1H), 6.87 (m, 1H), 6.73 (m,1H), 4.08 (t, 2H11), 3.67 (d, 1H) 3.42 (d, 1H11), 2.95 (d, 1H1), 2.80-2.90 (t, 2H), 2.75 (m, 1H), 2.65 (m, 1H), 2.50-2.60 (m, 4H),2.50 (m,2H1), 2.20 (m, 2H), 2.00(m, 1H), 1.95 (m, 2H), 15 1.70-1.80 (m, 4H), 1.50 (m, 1H). Example 1.105: Preparation of (=)- 2 -Benzyl-6-[3-(2-pyrrolidin-1-yl-ethoxy)-phenyl] 1,2,3,3a,4,6a-hexahydro-cyclopenta[c]lpyrrole Dihydrochloride. IN ~ N 20 The title compound was obtained using the method described in Example 1.101. MS m/z 389.5, (M+H); 1H NMR (400 MHz, CDC1 3 ) 8 7.13-7.42 (m, 5H11), 7.29 (m, 1H11), 6.80-7.00( m, 3H),6.10 (m, 1H11), 4.50 (t, 2H11), 3.66 (m, 1H11), 4.00-4.20 (m, 4H1), 3.90 (m, 2H11), 3.80 (t, 1H11), 3.60 (m, 2H), 3.50 (m, 1H), 3.10 (m, 2H), 2.60 (m, 2H),2.40(m, 1H), 2.00-2.20 (m, 4H). 25 Example 1.106: Preparation of 2-Bromo-5-(2-methoxyvinyl)-pyridine. OMe Br N 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 0 0 C and n-BuLi (2.5M in THF, 11.0 mnL, 30 27.5mmol) was added dropwise to the suspension under N 2 . After lh at 0 0 C, the solid -126- WO 2007/061741 PCT/US2006/044479 suspension rne' into a wboirnish solution. A solution of 2-bromo-3-pyridylcarboxaldehyde (5.0g, 27mmol) in 15 mL anhydrous THF was added dropwise into the solution at 0oC. After 3h at 0OC, the mixture was stirred at room temperature overnight before being quenched with H20. The reaction mixture was extracted with EtOAc and the organic extract was dried and 5 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 tn/z 214.0 (M+H); 1 H NMR (400 MHz, CDC1 3 ) 6 8.42 (d, 111), 8.23 (d, 1H1), 7.87 (dd, 1H), 7.40(m, 3H), 7.09 (d, 1H11), 6.30(d, 1H11), 5.71(d, 1H11), 5.17 (d, 1H11), 3.84 (s, 3H), 3.73 (s, 3H11). 10 Example 1.107: Preparation of 2 -bromo-5-(2-pyrrolidin-1-yl-ethyl)-pyridine. NN2D Br N To a solution of the compound described in Example 1.106 (2.5g, 12 mmol) in 7.5 mL of 10:1 acetonitrile/11 2 0 was added a solution of4M HC1 (5.0 mL, 23mmol) in dioxane. The mixture was stirred at 23oC for 3h. After removal of the solvent under vacuum, the oil residue 15 was dissolved in dichloromethane and washed with 1H20. 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.
8 7g, 23.0mmol) was added in small portions. The reaction mixture was stirred at room temperature for 1 h then quenched with H20. After 20 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 nm/z 255.0 (M+H); 'H NMR (400 MHz, CDC1 3 ) 6 8.23 (d, 1IH), 7.41 (mn, 2H), 2.79(m, 2H11), 2.67 (m, 2H11), 2.55 (m, 4H), 1.81 (m, 4H1). 25 Example 1.108: Preparation of (+)- 2 -Benzyl-4-[5-(2-pyrrolidin-1-yl-ethyl)-pyridin-2-yl]. octahydro-cyclopenta[c]pyrrol-4-ol. N ND7 OH In a sealed scintillation vial under N 2 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 TI-IF (0.465 30 mL) was added dropwise at -78oC. The mixture was stirred for lh at -78 0 C under N 2 and the ketone described in Example 1.1 (192mg, 0.894mmol) dissolved in 1 mL of dry THF was added -127- WO 2007/061741 PCT/US2006/044479 Sdropwise. The re'sultmg mixture was stirred for 2h at the same temperature then quenched with H20. After extraction with CH2C 2 /11 2 0, 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 nm/z 392.3 (M+H); 'H NMR (400 MHz, CDC1 3 ) 8 8.39 (d, 1H), 7.71 (d, 1H), 5 7.50 (m, 1H11), 7.31 (m, 5H), 4.12 (d, 1H11), 3.74 (m, 1H), 3.71 (s, 1H11), 3.02 (m, 1H11), 2.66-2.92 (m, 911) 2.57 (m, 4H), 2.17-2.28 (m, 4H11), 1.79 (m, 4H11). Example 1.109: Preparation of (±)- 2 -Benzyl-6-[5-(2-pyrrolidin-1-yl-ethyl)-pyridin-2-yl] 1, 2
,
3
,
3 a, 4
,
6 a-hexahydro-cyclopenta[c]pyrrole Dihydrochloride. N1N N 10 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); 'H NMR (400 MHz, CDC1 3 ) 8 8.80 (m, 1H11), 8.10 (m, 1H11), 7.82 (m, 1H), 7.32-7.42 (m, 5H11), 6.71 (m, 1H11), 4.00-4.45 (m, 3H), 3.75-3.96 (m, 4H11), 3.25-3.45 (m,4H), 3.20 (m, 3H), 2.90 (m, 4H11), 2.11(m, 4H11). 15 Example 1.110: Preparation of (d)-2-benzyl-octahydro-isoindol-4-one. 0 N 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+H11); 'H NMR (400 MHz, MeOH-d 4 ) 8 ppm 20 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, 1 H). Example 1.111: Preparation of ()-2-Benzyl-4-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl] octahydro-isoindol-4-ol -\N OH 25 N The title compound was prepared in a similar manner as described in Example 1.3. LC MS nm/z 405.7 (M+H); 1H NMR (400 MHz, Methanol-d4) 8 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 -128- WO 2007/061741 PCT/US2006/044479 , 2 .29 .7m 1 H1. - 1.99 (m, 5 H)1.67 - 1.75(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-pyrrolidin-1-yl-ethyl)-phenyl] 5 2,3,3a,4,5,7a-hexahydro-1H-isoindole. N/N The title compound was prepared in a similar manner as described in Example 1.7. LC MS m/z 387.5 (M+H); 1 H NMR (400 MHz, MeOH-d 4 ) & ppm 7.19 - 7.32 (m, 7 H) 7.13 (d, J=8.08 Hz, 2 H) 6.08 (t, J=3.79 Hz, 1 H) 3.57 (s, 2 H) 3.08 - 3.17 (m, 1 H) 2.93 - 3.01 (m, 1 H) 10 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, J=9.35 Hz, 1 H) 1.76- 1.86 (mn, 4 H) 1.64 - 1.75 (m, 1 Hi) 1.42 - 1.57 (m, 1 H). Example 1.113: Preparation of (±)-7-[4-(2-Pyrrolidin-1-yl-ethyl)-phenyl]-2,3,3a,4,5,7a hexahydro-1H-isoindole. HNN HN No 15 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); 1 H NMR (400 MHz, MeOH-d 4 ) 6 ppm 7.20 - 7.47 (m, 4 H) 6.22 (t, J=3.79 Hz, 1 H) 3.60 - 3.80 (m, 2 H) 3.39 - 3.60 (m, 5 H) 3.22 (dd, J=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 20 (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 (R)- 4
-(
2
-(
2 -Methylpyrrolidin-1-yl)ethyl)phenylboronic Acid. 25
(HO)
2 B N 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. -129- WO 2007/061741 PCT/US2006/044479 Metaesoni chore ( 1 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 HC1 twice (100 mL each), followed by brine, saturated sodium bicarbonate, and brine. The organic phase was dried with sodium sulfate and filtered. 5 The solvent was removed under reduced pressure to give the title compound (54.0 g) in quantitative yield. 'H NMR (400 MHz, CDC1 3 ) 8 2.89 (s, 3H), 3.02 (t, J= 6.82 Hz, 2H11), 4.40 (t, J= 6.82 Hz, 2H), 7.03 - 7.17 (min, 2H), 7.43 - 7.47 (min, 2H). Step B: Preparation of Intermediate (R)-l-(4-Bromophenethyl)-2 methylpyrrolidine. 10 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 'C 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 15 HC1 (75 mL). The ethyl acetate was extracted an additional three times with 1 M HC1 (30 mL each). HC1 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 Na 2
SO
4 and filtered. The solvent was removed under 20 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 mn/z = 268.0 (M+H); 'H NMR (400 MHz, CD 3 0D) 6 1.15 (d, J= 6.06 Hz, 3H), 1.37 - 1.53 (in, 1H11), 1.73 - 1.86 (mn, 2H), 1.94 - 2.07 (mn, 1H), 2.21 - 2.35 (mn, 2H11), 2.35 - 2.48 (mn, 1H11), 2.68 - 2.91 25 (min, 2H), 2.98 - 3.11 (in, 1H), 3.18 - 3.29 (mn, 1H), 7.14 - 7.20 (mn, 2H), 7.38 - 7.48 (mn, 2H). Step C: Preparation of (R)- 4
-(
2 -(2-Methylpyrrolidin-1-yl)ethyl)phenylboronic Acid. (R)-1-(4-Bromophenethyl)-2-methylpyrrolidine (2.16 g, 8.04 immol) was dissolved in TIF (20 mL) under Argon. The reaction mixture was cooled to -78 'C and n-butyllithium (1.6 30 M in hexanes, 6.53 mniL, 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 oC 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 mnL of 1 M HC1. THF was removed under reduced pressure. The remaining aqueous solution was made basic (pH-8) with 50% sodium hydroxide and 35 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 -130- WO 2007/061741 PCT/US2006/044479 0t1tecomour 1. , 9 64 % yield) as a pale yellow solid. MS nm/z = 234.2 (M+H); 'H NMR (400 MHz, CD 3 OD) 8 1.25 (d, J=6.32 Hz, 3H), 1.49 - 1.61 (min, 1H), 1.80 - 1.97 (mn, 2H), 2.04 - 2.18 (min, 1H), 2.61 - 2.74 (min, 2H), 2.76 - 2.98 (mn, 3H11), 3.19 - 3.45 (min, 2H), 7.16 (d, 2H11), 7
.
4 8
-
7 .62 (m, 2H1). 5 Example 2.2: Preparation of 2 -Hydroxy- 2 -methyl-1-{6-[4-(2-pyrrolidin-1-yl-ethyl) phenyl]- 3
,
3 a,4,6a-tetrahydro-1H-cyclopenta[c]pyrrol-2-yl}-propan-.1-one. N No HO The compound from Example 1.7 (0.200 g, 0.708 mmol) and hydroxyisobutyric acid 10 (0.073 g, 0.708 mmol) were mixed in DCM (10 mnL), and treated with N,NNNV-tetramethyl-O (7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.323 g, 0.849 mmol), and triethylamine (0.125 g, 1.24 mmol). The mixture was stirred at 40 oC under N 2 atmosphere for 16 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 15 brine and dried over MgSO 4 . 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 nm/z 369.2, (M+H); '11 NMR (400 MHz,
CD
3 OD) 1.11 (s, 1H), 1.18 (t,J=7.07 Hz, 1H), 1.28(s, 1H), 1.37 (d,J=6.06 Hz, 3H), 1.80 1.85 (mn, 4H11), 2.31 - 2.40 (mn, 1H), 2.58 - 2.64 (mn, 4H), 2.66 - 2.72 (in, 2H11), 2.78 - 2.85 (mn, 3H), 20 3.29 - 3.32 (min, 3H), 3.49 (q, J= 7.07 Hz, 1H11), 3.74 (s, 3H11), 6.04 (s, 1H), 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 1-yl)-ethyl]-phenyl}-hexahydro-cyclopenta[c]pyrrol-2-yl)-ethanone. 0 O N H 25 H - N h The title compound was obtained using general method C starting from (3aR,4R,6aS)-4-(4-(2 ((R)-2-methylpyrrolidin-1-yl)ethyl)phenyl)-octahydrocyclopenta[c]pyrrole. MS m/z 371, (M+H); 'H NMR (400 MHz, CD 3 OD) 3 1.45-1.49 (mn, 3H11), 1.64-1.82 (mn, 2H), 1.89-2.24 (inm, 5H), 2.29-2.39 (min, 1H), 2.85-3.90 (mn, 17H), 3.99-4.14 (mn, 2H11), 7.25-7.31 (mn, 4H). 30 - 131 - WO 2007/061741 PCT/US2006/044479 xnp1 2.4 l'liparaffbn**f 2=Pyridin-3-yl-6-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl] 1, 2
,
3
,
3 a, 4
,
6 a-hexahydro-cyclopenta[clpyrrole. NQ/J II The title compound was obtained using general method E. MS m/z 360.3, (M+H); 'H 5 NMR (400 MHz, CD30D) 8 2.12 (bs, 4H), 2.52 (d, J= 16.0 Hz, 1H), 2.94-2.83 (m, 1H), 3.22 3.03 (m, 4H), 3.48-3.33 (m, 4H), 3.58 (dd, J= 12.0, 4.0 Hz, 1H), 3.67 (bs, 2H), 4.04-3.94 (m, 2H11), 4.12 (bs, 1H), 6.15 (s, 1H), 6.87 (t, J= 8.0 Hz, 1H), 7.02 (d, J= 8.0 Hz, 1H11), 7.33 (d, J= 8.0 Hz, 2H), 7.84 (d, J= 4.0 Hz, 2H), 7.91 (dd, J= 8.0 Hz, 2H). 10 Example 2.5: Preparation of 2 -Pyridin- 4 -yl-6-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl]. 1, 2
,
3
,
3 a, 4
,
6 a-hexahydro-cyclopenta[c]pyrrole. I N I The title compound was obtained using general method E. MS m/z 360.5, (M+H); 'H NMR (400 MHz, CD 3 OD) 8 1.99 - 2.07 (m, 2H), 2.12 - 2.20 (m, 2H), 2.47 - 2.54 (m, 1H11), 2.85 15 - 2.93 (m, 1H11), 3.05 - 3.17 (m, 4H), 3.31 - 3.38 (m, 1H), 3.41 - 3.56 (m, 4H), 3.65 -3.72 (m, 2H), 3.92 -4.01 (m, 2H), 4.05- 4.12 (m, 1H11), 6.13 - 6.15 (m, 1H), 6.75 - 6.79 (m, 1H11), 6.85 6.89 (m, 1H), 7.30 - 7.35 (m, 2H11), 7.41 - 7.45 (m, 2H), 8.01 - 8.10 (m, 2H). Example 2.6: Preparation of 3
-{
6
-[
4
-(
2 -Pyrrolidin-1-yl-ethyl)-phenyl]-3,3a,4,6a 20 tetrahydro-1H-cyclopenta[c]pyrrol-2-yl}-benzaldehyde. H N The title compound was obtained using general method E. MS m/z 387.5, (M+H); 1H NMR (400 MHz, CD 3 OD) 8 0.68 - 0.73 (m, 3H11), 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, 1H), 7.31 - 7.35 (m, 4H), 7.44 - 7.48 (m, 25 4H). -132- WO 2007/061741 PCT/US2006/044479 4E aeparation of 2(3-Methoxy-phenyl)-6-14-(2-pyrrolidin-1-yl-ethyl)-phenyl] 1, 2
,
3
,
3 a, 4
,
6 a-hexahydro-cyclopenta[c]pyrrole. MeO N N / The title compound was obtained using general method E. MS m/z 389.5, (M+H); 1 H 5 NMR (400 MHz, CD 3 OD) 6 1.94 - 2.00 (mn, 1H11), 2.41 - 2.49 (mn, 1H11), 2.82 - 2.90 (mn, 1H), 2.92 -3.01 (min, 3H), 3.03- 3.14 (min, 9H), 3.20 - 3.27 (mn, 2H), 3.32 - 3.39 (mn, 2H), 3.74- 3.81 (inm, 3H11), 3.97 -4.04 (m, 1H11), 6.09- 6.11 (mn, 1H), 6.58- 6.60 (mn, 1H), 7.05- 7.07 (mn, 1H), 7.24 7.27 (min, 3H), 7.37 - 7.40 (min, 3H). 10 Example 2.8: Preparation of 6-[4-(2-Pyrrolidin-1-yl-ethyl)-phenyl]-2-thiazol-2-yl 1, 2
,
3
,
3 a, 4
,
6 a-hexahydro-cyclopenta[c]pyrrole. N / The title compound was obtained using general method E. MS m/z 366.3, (M+H); 1H NMR (400 MHz, CD 3 OD) 8 1.95 - 2.00 (mn, 5H), 2.41 - 2.48 (mn, 1H11), 2.92 - 2.99 (m, 3H), 3.03 15 - 3.13 (min, 9H), 3.20 - 3.27 (min, 1H), 3.33 - 3.39 (min, 1H), 3.73 - 3.80 (mn, 2H11), 7.06 (mn, 1I), 7.24 - 7.28 (min, 2H), 7.37 - 7.40 (mn, 2H). Example 2.9: Preparation of 2 -Pyrazin-2-yl-6-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl] 1, 2 ,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole. N N No N 20 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 'C and 25 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. - 133 - WO 2007/061741 PCT/US2006/044479 IP' i:.. n ~l 4o. 400 MHz, CD 3 OD) 8 1.26 - 1.30 (mn, 1H), 1.81 - 1.87 (inm, 4H), 2.41 - 2.51 (min, 1H), 2.60 - 2.66 (min, 4H), 2.68 - 2.75 (in, 2H), 2.80 - 2.90 (mn, 3H), 3.23 3.28 (min, 1H), 3.43 - 3.52 (mn, 1H), 3.78 - 3.91 (min, 2H), 3.93 - 4.02 (mn, 1H), 6.05 - 6.08 (mn, 1H), 7.19 - 7.23 (mn, 2H), 7.34 - 7.39 (mn, 2H), 7.67 - 7.70 (min, 1H), 7.84 - 7.87 (mn, 1H), 7.95 - 7.99 5 (mn, 1H). Example 2.10: Preparation of 2 -Pyrimidin-2-yl-6-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl] 1, 2
,
3
,
3 a, 4 ,6a-hexahydro-cyclopenta[c]pyrrole. NN 10 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 oC and held for 5 min. After the mixture was allowed to cool to room temperature, the reaction vessel 15 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 min/z 360.4 (M+H); 1 H NMR(400 MHz, CD 3 OD) 6 1.15- 1.21 (min, 1H), 1.88 - 1.94 (mn, 3H), 2.03 (s, 1H), 2.40- 2.47 (in, 1H), 2.79 - 2.96 (min, 8H), 3.17 - 3.25 (mn, 1H), 3.46 - 3.52 (mn, 1H), 3.55- 3.60 (min, 1H), 3.82 - 3.88 (min, 1H), 3.90- 3.96 (mn, 2H), 6.06 - 6.08 (mn, 1H), 6.55 (t, J= 20 4.93 Hz, 1H), 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-1-yl-ethyl)-phenyl] 1, 2 ,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole. r NJ I 25 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 rmol), 2-(dicyclohexylphosphino) biphenyl (1.75 mg, 5.00 pmol) 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 30 temperature to 110 oC and held for 6 h. After the mixture was allowed to cool to room -134- WO 2007/061741 PCT/US2006/044479 P tef e:'t Fcel as 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 nim/z 361.4, (M+H); 'H NMR (400 MHz, CD 3 0D) 8 1.85 - 1.91 (in, 511), 2.43 - 2.51 (mn, 1H), 2.73 - 2.78 (mn, 4H11), 2.83 - 2.91 5 (in, 5H), 3.12 - 3.17 (min, 1H11), 3.21 - 3.29 (min, 1H), 3.64 - 3.73 (in, 2H11), 3.96- 4.04 (mn, 111), 6.07 - 6.09 (min, 1H11), 7.21 - 7.24 (min, 2H), 7.37 - 7.40 (min, 2H), 8.08 - 8.09 (mn, 2H11), 8.39 - 8.40 (inm, 1H1). Example 2.12: Preparation of 2
-(
3 ,5-Difluoro-phenyl)-6-[4-(2-pyrrolidin-1-yl-ethyl) 10 phenyl]-l, 2
,
3 ,3a,4,6a-hexahydro-cyclopenta[c]pyrrole. F F-- No In a 5 mL glass tube were placed the compound from Example 1.7 (0.070 g, 0.248 mmol), 1-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) 15 biphenyl (1.75 mg, 5.00 pmol) 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 oC 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 20 of the title compound (0.030 g, 30.6%) as an orange solid. MS nm/z 395.4, (M+H); 'H NMR (400 MHz, CD 3 OD) 6 2.00 - 2.08 (mn, 1H), 2.11 - 2.23 (mn, 3H), 2.83 - 2.94 (m, 1H), 3.05 - 3.22 (mn, 5H), 3.34 - 3.37 (min, 3H), 3.42 - 3.50 (mn, 2H), 3.64 - 3.80 (mn, 4H11), 4.01 (s, 1H11), 6.15 (s, 1H), 6.26 - 6.39 (mn, 3H), 7.32 (d, J= 7.83 Hz, 2H11), 7.44 (d, J = 7.83 Hz, 2H). 25 Example 2.13: Preparation of 3
-{
6
-[
4
-(
2 -Pyrrolidin-1-yl-ethyl)-phenyl]-3,3a,4,6a tetrahydro-lH-cyclopenta[c]pyrrol-2-yl}-benzonitrile. CN NN 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, - 135 - WO 2007/061741 PCT/US2006/044479 Pi. IC l 1 3 '-8u ettoxe (0.035 g, 0.372 mmol), 2-(dicyclohexylphosphino) biphenyl (1.75 mg, 5.00 pmol) 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 'C and held for 6 h. After the mixture was allowed to cool to room 5 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); 'H NMR (400 MHz, CD 3 OD) 5 1.50 - 1.58 (min, 2H), 1.95- 2.08 (min, 2H11), 2.11- 2.23 (m, 3H), 2.82 -2.93 (mn, 1H), 3.05 - 3.21 (m, 5H), 3.42- 3.50 (mn, 2H), 3.63 - 3.81 (m, 4H11), 3.96 -4.07 (m, 1H), 6.15 10 (s, 1H), 6.34 (d, J=7.83 Hz, 4H11), 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-1-yl)-ethyl]-phenyl}-hexahydro-cyclopenta[c]pyrrol-2-yl)-methanone. Step A: Preparation of ( 3 aR, 4
R,
6 aS)-4-(4-(2-((R)-2-Methylpyrrolidin-1 15 yl)ethyl)phenyl)octahydrocyclopenta[clpyrrole H N H To a solution of (3aS, 6 aS)-2-benzyl-6-(4-(2-((R)-2-methylpyrrolidin-1 yl)ethyl)phenyl)-1, 2
,
3
,
3 a, 4 ,6a-hexahydrocyclopenta[c]pyrrole (4.21 g, 10.89 mmol) obtained using general method A starting from the corresponding single isomer ketone from example 1.1 20 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 mn/z 25 299.4, (M+H). Step B: Preparation of Cyclopropyl-((3aR,4R,6aS)-4-{4-[2-((R)-2-methyl pyrrolidin-1-yl)-ethyl]-phenyl}-hexahydro-cyclopenta[c]pyrrol-2-yl)-methanone N H In a 5 mL glass tube were placed (3aR, 4R, 6 aS)- 4 -(4-(2-((R)-2-methylpyrrolidin-1 30 yl)ethyl)phenyl)-octahydrocyclopenta[c]pyrrole (0.129 g, 0.432 mmol), 2,2-difluoroethyl - 136 - WO 2007/061741 PCT/US2006/044479 ea:s t:0 g . ol), 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 oC and held for 3 h. After the mixture was allowed to cool to room temperature, the reaction vessel was 5 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); 'H NMR (400 MHz, CD30D) 3 1.28 (s, 2H), 1.28 (s, 2H), 1.34 - 1.41 (mn, 2H11), 1.52 (s, 3H), 1.61 (s, 2H), 2.13 - 2.21 (mn, 3H), 3.02 - 3.19 (mn, 3H), 3.24 3.28 (min, 1H), 3.35 - 3.42 (mn, 1H), 3.42 - 3.51 (mn, 3H11), 3.51 - 3.61 (mn, 5H11), 3.60 - 3.71 (mn, 3H), 10 7.35 - 7.50 (min, 3H11), 7.72 - 7.82 (min, 1H). Example 2.15: Preparation of (3aS,6aS)-6-{4-[2-((R)-2-Methyl-pyrrolidin-1-yl)-ethyl] phenyl}- 2
-(
6 -trifluoromethyl-pyridin-3-yl)-1,2,3,3a,4,6a-hexahydro-cyclopenta[clpyrrole (Compound C102). 15 Step A: Preparation of (3aS,6aS)-6-(4-(2-((R)-2-Methylpyrrolidin-1 yl)ethyl)phenyl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole H N <i H HH NC To a solution of (3aR, 6 aS)-4-(4-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)phenyl) octahydrocyclopenta[c]pyrrol-4-ol (2.74 g, 8.71 mmol) in isopropyl alcohol (45.0 mL), prepared 20 in a similar manner as described in example 1.6 starting from the corresponding single isomer ketone from example 1.1, was added HC1 (22.0 mniL, 88.0 mmol, 4M in 1,4-dioxane). The resulting reaction mixture was heated at 60 oC. 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 25 was washed with H20, brine, dried over MgSO 4 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 inm/z 297.3, (M+H). Step B: Preparation of ( 3 aS, 6 aS)-6-{4-[2-((R)-2-Methyl-pyrrolidin-1-yl)-ethyl] phenyl}- 2
-(
6 -trifluoromethyl-pyridin-3-yl)-1,2,3,3a,4,6a-hexahydro-eyelopenta[clpyrrole -137- WO 2007/061741 PCT/US2006/044479 F3 N N In a 5 mL glass tube were placed ( 3 aS,6aS)- 6
-(
4 -(2-((R)-2-methylpyrrolidin-1 yl)ethyl)phenyl)-1,2,3,3a,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, 5 0.027 mmol), sodium tert-butoxide (0.078 g, 0.810 mmol), 2-(dicyclohexylphosphino) biphenyl (1.75 mg, 5.00 gmol) 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 oC 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 10 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); 'H NMR (400 MHz, CD 3 OD) 8 1.44 - 1.47 (m, 3H), 1.68 - 1.80 (m, 1I), 2.01 - 2.17 (m, 2H), 2.29 - 2.39 (m, 1H), 2.45 - 2.52 (m, 1H), 2.84 - 2.93 (m, 2H), 2.97 - 3.28 (m, 6H), 3.46 - 3.56 (m, 1H), 3.56 3.66 (m, 1H), 3.70 - 3.79 (m, 3H), 3.98 - 4.05 (m, 1H11), 6.13 (d, J= 1.77 Hz, 1H), 7.01 (dd, J= 15 8.72, 2.65 Hz, 1H11), 7.32 (d, J = 8.08 Hz, 2H), 7.45 (d, J = 8.34 Hz, 2H), 7.52 (d, J= 8.84 Hz, 1H), 7.91 (d, J = 2.78 Hz, 1H). Example 2.16: Preparation of 5 -((3aS,6aS)-6-{4-[2-((R)-2-Methyl-pyrrolidin-1-yl)-ethyl] phenyl}- 3
,
3 a, 4
,
6 a-tetrahydro-1H-yclopenta[c]pyrrol-2-yl)-pyridine-2-carbonitrile. NC -N N H 20 N The title compound was obtained using general method E starting from (3aS, 6aS)-6-(4 (2-((R)-2-methylpyrrolidin-1-yl)ethyl)phenyl)-1, 2 ,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole. MS nm/z 399.2, (M+H); 'H NMR (400 MHz, CD 3 OD) 8 1.18 - 1.31 (m, 4H), 1.48 - 1.63 (m, 1H), 1.90 (bs, 2H), 2.04 - 2.18 (m, 1H), 2.43- 2.57 (m, 2H), 2.81 -2.99 (m, 4H), 3.10 - 3.25 (m, - 138 - WO 2007/061741 PCT/US2006/044479 )~ (3 ,) - .86 (m, 2H), 4.02 (bs, 1H11), 6.09 (s, 1H), 6.90 - 6.99 (m, 1H11), 7.21 - 7.31 (m, 2H11), 7.39 (d, J 8.34 Hz, 2H11), 7.54 (d, J= 8.59 Hz, 1H11), 7.91 - 7.99 (m, 1H11). Example 2.17: Preparation of 2 -Methyl-1-((3aR,4R,6aS)-4-{4-[2-((R)-2-methyl-pyrrolidin 5 1-yl)-ethyl]-phenyl}-hexahydro-cyclopenta[c]pyrrol-2-yl)-propan-l-one. )5- N H H 0 / NJ The title compound was obtained using general method C starting from (3aR, 4R, 6aS) 4
-
4
-(
2 -((R)-2-methylpyrrolidin-1 -yl)ethyl)phenyl)-octahydrocyclopenta[c]pyrrole. MS m/z 369.2, (M+H); 'H NMR (400 MHz, CD 3 OD) 6 0.92 -0.98 (m, 2H), 1.02 - 1.08 (m, 3H), 1.11 10 1.15 (m, 3H11), 1.38 - 1.51 (m, 1H), 1.61 - 1.70 (m, 1H), 1.72 - 1.84 (m, 2H11), 1.94- 2.05 (m, 3H), 2.22 - 2.34 (m, 2H11), 2.35 - 2.47 (m, 2H), 2.70 - 2.89 (m, 3H11), 2.90 - 3.05 (m, 311), 3.05 - 3.15 (m, 1H), 3.15- 3.27 (m, 2H), 3.33 - 3.40 (m, 1H11), 3.44 -3.51 (m, 1H11), 3.58 - 3.66 (m, 1H), 3.76 -3.84 (m, 1H), 7.13 - 7.21 (m, 4H). 15 Example 2.18: Preparation of ((3aR,4R,6aS)-4-{4-[2-((R)-2-Methyl-pyrrolidin-1-yl)-ethyl] phenyl}-hexahydro-cyclopenta[c]pyrrol-2-yl)-pyridin-.3.-yl-methanone. 0 N NJ H H '"s N . The title compound was obtained using general method C starting from (3aR, 4R, 6aS) 4-4-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)phenyl)-octahydrocyclopenta[c]pyrrole. MS mn/z 20 404.8, (M+H); 'H NMR (400 MHz, CD 3 OD) 3 1.09- 1.16 (m, 3H), 1.38- 1.50 (m, 1H), 1.79 (dd, J = 6.32, 2.78 Hz, 3H), 1.95 - 2.05 (m, 3H), 2.15 - 2.34 (m, 2H11), 2.36 - 2.46 (m, 1H), 2.61 2.86 (m, 3H), 2.88 -2.96 (m, 2H), 2.97 - 3.14 (m, 2H), 3.16 - 3.28 (m, 2H11), 3.33 - 3.49 (m, 1H11), 3.63 (dd, J= 12.63, 4.04 Hz, 1H), 3.75 - 3.89 (m, 1H), 7.01 - 7.09 (m, 2H), 7.16 - 7.27 (m, 2H), 7.35 - 7.54 (m, 1H), 7.87 (dd, J= 62.27, 7.71 Hz, 1H), 8.49 - 8.54 (m, 1H11), 8.60 - 8.67 (m, 1H). 25 Example 2.19: Preparation of (( 3 aR, 4 R,6aS)-4-{4-[2-((R)-2-Methyl-pyrrolidin-1-yl)-ethyl] phenyl}-hexahydro-cyclopenta[c]pyrrol-2-yl)-pyrazin-2-yl-methanone. -139- WO 2007/061741 PCT/US2006/044479 N H H ,V N' The title compound was obtained using general method C starting from (3aR, 4R, 6aS) 4
-
4
-(
2 -((R)-2-methylpyrrolidin-1 -yl)ethyl)phenyl)-octahydrocyclopenta[c]pyrrole. MS m/z 405.5, (M+H); 1 1HNMR (400 MHz, CD 3 OD) 8 1.41 - 1.50 (mn, 3H11), 1.62 - 1.84 (mn, 2H11), 2.01 5 2.09 (min, 2H11), 2.29- 2.39 (mn, 1H11), 2.85 - 3.08 (mn, 4H), 3.11- 3.28 (mn, 511), 3.31- 3.57 (mn, 4H), 3.56 - 3.68 (min, 1H), 3.68 - 3.79 (mn, 2H), 3.84 -4.01 (mn, 1H), 7.12 - 7.18 (mn, 2H), 7.25 - 7.34 (mn, 3H), 8.64 - 8.72 (min, 1H), 8.81 - 8.98 (mn, 1H11). Example 2.20: Preparation of (3aR,4R,6aS)-2-(2-Fluoro-ethyl)-4-{4-[2-((R)-2-methyl 10 pyrrolidin-l-yl)-ethyl]-phenyl}-octahydro-cyclopenta [c]pyrrole. F N H< AH H .,ii In a 5 mL glass tube were placed (3aR, 4R, 6aS)-4-4-(2-((R)-2-methylpyrrolidin-1 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 15 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 '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 IPLC to afford the TFA salt of 20 the title compound (0.025 g, 21.7%) as a yellow, viscous solid. MS m/z 345.1, (M+H); 'H NMR (400 MHz, CD 3 OD) 6 1.16 (d, J= 6.06 Hz, 3H), 1.42 - 1.53 (mn, 1H), 1.59 - 1.68 (mn, 2H11), 1.75 - 1.94 (min, 5H11), 1.94 - 2.07 (m, 2H11), 2.30 - 2.41 (mn, 2H), 2.47 - 2.62 (mn, 4H11), 2.63 - 2.68 (inm, 1H1), 2.71 - 2.88 (min, 4H11), 3.00 - 3.12 (min, 1H), 3.14 - 3.24 (mn, 1H11), 3.24 - 3.29 (min, 1H11), 4.38 (t, J = 4.93 Hz, 1H11), 4.47 - 4.53 (mn, 1H11), 7.12 - 7.22 (mn, 4H). 25 Example 2.21: Preparation of 2
,
2 ,2-Trifluoro-1-((3aR,4R,6aS)-4-{4-[2-((R)-2-methyl pyrrolidin-l-yl)-ethyl]-phenyl}-hexahydro-cyclopenta[c]lpyrrol-2-yl)-ethanone. -140- WO 2007/061741 PCT/US2006/044479 F3C N H _ H ,,l N The title compound was obtained using general method F starting from (3aR, 4R, 6aS) 4
-(
4
-(
2 -((R)-2-methylpyrrolidin-1 -yl)ethyl)phenyl)-octahydrocyclopenta[c]pyrrole. MS m/z 395.2, (M+H); 1H NMR (400 MHz, CD 3 OD) 6 1.15 - 1.29 (m, 3H), 1.46 - 1.62 (m, 1H11), 1.61 5 1.77 (m, 1H), 1.82 - 1.92 (m, 3H), 1.97- 2.17 (m, 4H11), 2.55 (bs, 2H), 2.76- 2.98 (m, 3H), 2.99 3.23 (m, 4H11), 3.38- 3.53 (m, 2H11), 3.53 - 3.66 (m, 1H), 3.75 - 3.93 (m, 1H11), 7.18 - 7.26 (m, 4H). Example 2.22: Preparation of ((3aR,4R,6aS)-4-{4-[2-((R)-2-Methyl-pyrrolidin-1-yl)-ethyl] phenyl}-hexahydro-cyclopenta[c]pyrrol-2-yl)-pyrimidin-5-yl-methanone. N 10 N 10 H$F.ag\ NG The title compound was obtained using general method F starting from (3aR, 4R, 6aS) 4-4-(2-((R)-2-methylpyrrolidin-1 -yl)ethyl)phenyl)-octahydrocyclopenta[c]pyrrole. MS min/z 405.5, (M+H); 'H NMR (400 MHz, CD30D) 3 1.13 -1.18 (m, 4H), 1.40 -1.51 (m, 1H), 1.76 1.88 (m, 3H), 1.96- 2.08 (m, 5H11), 2.25- 2.40 (m, 2H1), 2.48 (bs, 1H), 2.64 -2.88 (m, 2H1), 2.90 15 3.00 (m, 1H11), 3.07- 3.18 (m, 1H), 3.18- 3.27 (mn, 1H11), 3.34- 3.43 (m, 2H), 3.58 - 3.64 (m, 1H), 3.82 - 3.89 (m, 1H), 7.04 - 7.09 (m, 2H), 7.18 - 7.27 (m, 2H), 8.73 - 8.75 (m, 1H), 8.91 - 8.92 (m, 1H), 9.10- 9.23 (m, 1H). 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.
HF
2
C-
N H In a 5 mL glass tube were placed (3aR, 4R, 6 aS)- 4 -4-(2-((R)-2-methylpyrrolidin-1 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 - 141 - WO 2007/061741 PCT/US2006/044479 t: "id i t. "iI i' 4 rave irradiation, the temperature was ramped from room temperature to 120 OC 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); 'H NMR (400 MHz, CD 3 OD) 6 1.41- 1.51 (mn, 3H11), 1.69 - 1.82 (m, 2H), 1.84- 1.97 (m, 1H11), 1.98 -2.20 (m, 4H), 2.28 - 2.39 (min, 1H), 2.55 - 2.66 (mn, 1H), 2.81 - 2.90 (mn, 1H), 2.98 - 3.13 (mn, 4H11), 3.17 3.28 (min, 3H11), 3.34 - 3.45 (in, 1H11), 3.45 - 3.61 (mn, 2H11), 3.64 - 3.77 (mn, 3H), 3.96 - 4.05 (in, 1H), 6.14- 6.44 (min, 1H), 7.25- 7.36 (mn, 4H). 10 Example 2.24: Preparation of ( 3 aR, 4 R,6aS)-4-{4-[2-((R)-2-Methyl-pyrrolidin-1-yl)-ethyl].
phenyl}- 2
-(
2
,
2
,
2 -trifluoro-ethyl)-octahydro-cyclopenta[c]pyrrole.
F
3 C N H In a 5 mL glass tube were placed (3aR, 4R, 6 aS)-4-(4-(2-((R)-2-methylpyrrolidin-1 15 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 'C and held for 3h. After the mixture was allowed to cool to room 20 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 nm/z 381.2, (M+H); 1H NMR (400 MHz, CD 3 OD) 8 1.45 - 1.50 (mn, 3H), 1.71 - 1.82 (mn, 2H), 1.87 - 2.25 (mn, 4H), 2.29 - 2.39 (inm, 1H), 2.67 - 2.74 (in, 1H), 2.91- 3.15 (mn, 3H), 3.17 - 3.28 (mn, 2H11), 3.32- 3.46 (mn, 2H), 3.48 25 3.61 (min, 2H), 3.69 -3.77 (mn, 1H), 3.99- 4.06 (min, 1H1), 4.17 - 4.28 (mn, 2H), 7.30 - 7.36 (mn, 7H). Example 2.25: Preparation of ((3aR,4R,6aS)-4-{4-[2-((R)-2-Methyl-pyrrolidin-1-yl)-ethyl] phenyl}-hexahydro-cyclopenta[ce]pyrrol-2-yl)-(tetrahydro-pyran-.4-yl).-methanone. N H - 142- WO 2007/061741 PCT/US2006/044479 Ke tile compound was obtained using general method C starting from (3aR,4R,6aS)-4-(4-(2 ((R)-2-methylpyrrolidin-1-yl)ethyl)phenyl)-octahydrocyclopenta[c]pyrrole. MS mn/z 411, (M+H); 1H NMR (400 MHz, CD 3 OD) 8 1.44-1.49 (min, 3H11), 1.55-1.80 (min, 6H), 1.89-2.25 (inm, 5H), 2.29-2.46 (min, 1H), 2.72-2.84 (min, 1H), 2.89-4.01 (mn, 18H), 7.25-7.29 (mn, 4H). 5 Example 2.26: Preparation of ( 3 aS,6aS)-2-Benzyl-6-[4-((R)-2-methyl-pyrrolidin-1 ylmethyl)-phenyl]-1,2,3,3a,4,6a-hexahydro-cyclopenta[elpyrrole. N H H / Step A: Preparation of Intermediate (R)-1-(4-Bromobenzyl)-2-methylpyrrolidine 10 To a solution of 4-bromobenzaldehyde (0.50 g, 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 15 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. MS m/z 254, (M+H). Step B: Preparation of Intermediate (3aR, 6aS)-2-Benzyl-4-(4-(((R)-2 methylpyrrolidin-1-yl)methyl)phenyl)octahydrocyclopenta[c]pyrrol-4-ol 20 The crude (R)-1l-( 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 'C. nBuLi was added and the mixture was stirred for 1 h at -78 oC. 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 oC. The reaction was quenched with water and 25 then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na 2
SO
4 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-((R)-2-methyl-pyrrolidin-1 ylmethyl)-phenyll-1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole 30 (3aR, 6 aS)-2-Benzyl-4-(4-(((R)-2-methylpyrrolidin-1 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 'C for 16 h and then the - 143 - WO 2007/061741 PCT/US2006/044479 vens were evaporate . he 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 Na 2
SO
4 and concentrated at reduced pressure. The residue was purified by HPLC (0.1% TFA in acetonitrile, 0.1 % TFA in water). The combined fractions 5 were lyophilized and treated with HCI to afford the dihydrochloride salt of the title compound. MS nm/z 373, (M+H); 1H NMR (400 MHz, CDC1 3 ) 6 1.18 (d, J= 6.0 Hz, 3H), 1.42-1.55 (inm, 1H), 1.57-1.82 (in, 3H), 1.87-2.02 (mn, 1H), 2.05-2.60 (m, 4H), 2.68-2.80 (mn, 1H), 2.88-3.07 (inm, 3H), 3.10-3.25 (mn, 2H), 3.58 (ABq, J= 38.4, 12.9 Hz, 2H), 3.67-3.80 (m, 1H), 4.02 (d, J= 12.8 Hz, 1H), 6.08 (s, 1H), 7.20-7.36 (min, 9H). 10 Example 2.27: Preparation of Racemic Mixture of (3aR, 4R, 6aS) and (3aS, 4S, 6aR)-2 Methyl-l- 4 -[4-(2-pyrrolidin-1-yl-ethyl)-phenyl]-hexahydro-cyclopenta[c]pyrrol-2-yl} propan-1-one. >0 >0 N N (R) H NS) H H (S (s)\ /H\R)( \/NQ7 Racemic Mixture 15 Step A: Preparation of 2-Benzyl-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 (MgSO 4 ) and 20 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 nm/z 218.1 (M+H). Step B: Preparation of 2 -Benzyloctahydrocyclopenta[c]pyrrol-4-yl Methanesulfonate. 2 -Benzyl-octahydro-cyclopenta[c]pyrrol-4-ol (1.00 g, 4.6 mmol) was dissolved in DCM 25 (25 mL) and N,N-diisopropylethylamine (1.04 mL, 6.0 mmol) was added. The reaction was cooled to 0 oC and methanesulfonyl chloride (0.43 mL, 5.5 mmol) was added dropwise over 5 min. The reaction was stirred at 0 oC for 3 hours and then quenched with the addition of saturated aqueous NaHCO 3 (25 mnL). The product was extracted into DCM (2 x 25 mL), the organic layer was dried (MgSO 4 ) and filtered and the solvent was removed under reduced 30 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 nm/z 296.2 (M+H); 'H NMR (400 MHz, CDC1 3 ) 8 1.55-1.61 (min, 1H), 1.68-1.80 (mn, 1H), 1.96-2.04 (mn, 1H), 2.07-2.19 (m, 1H), -144- WO 2007/061741 PCT/US2006/044479 '2. . -. ' ; 1, 2.52-2.57 (m' 1H-), 2.63-2.69 (m, 1H), 2.70-2.79 (m, 2H), 2.85-2.92 (m, 1H), 3.00 (s, 3H), 3.60 (t, J= 12.8 Hz, 2H), 4.95-5.02 (mn, 1H), 7.23-7.36 (min, 5H1). Step C: Preparation of 2 -Benzyl- 4 -iodooctahydrocyclopenta[c]pyrrole. 2-Benzyloctahydrocyclopenta[c]pyrrol-4-yl methanesulfonate (0.57 g, 1.9 mmol) was 5 dissolved in THF (4 mL). Sodium bromide (1. 97 g, 1.9 mmol) was added and the reaction was stirred at 65 oC 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 10 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 nm/z 328.2 (M+H); 'H NMR (400 MHz, CDC1 3 ) 6 1.38-1.47 (inm, 15 1H), 1.92-2.12 (mn, 2H), 2.19-2.25 (mn, 1H), 2.37-2.51 (mn, 4H), 2.64-2.73 (mn, 1H), 2.98-3.04 (inm, 1H), 3.60 (dd, J= 13.6, 17.6 Hz, 2H), 4.09-4.15 (mn, 1H), 7.25-7.37 (mn, 5H). Step D: Preparation of 2-Benzyl-4-(4-(2-(pyrrolidin-1 yl)ethyl)phenyl)octahydrocyclopentalclpyrrole. 4-(2-(Pyrrolidin-1-yl)ethyl)phenylboronic acid was prepared in a similar manner as 20 described in Example 2.1, Step C, using 1-[2-(4-bromo-phenyl)ethyl]-pyrrolidine from Example 1.2. To a 4 mL vial was place 4-(2-(pyrrolidin-1-yl)ethyl)phenylboronic acid (99.6 mg, 455 gmol), 4,7-diphenyl-1,10-phenanthroline (10.1 mng, 30 jmol), bis(1,5-cyclooctadiene)nickel (0) (4.2 mg, 15 tmol) and potassium tert-butoxide (68.0 mg, 606 Rmol). The vial was flushed with nitrogen and 2-butanol (2.3 mL) was added. The mixture was stirred at room temperature for 10 25 min. Next, 2 -benzyl-4-iodooctahydrocyclopenta[c]pyrrole (124 mg, 379 gmol) in 2-butanol (0.2 mL) was added and the reaction was heated to 60 oC 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 30 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 nm/z = 375.5 (M+H); 1H NMR (400 MHz, Methanol-d4) 6 1.05-1.15 (mn, 2H), 1.31-1.42 (min, 1H), 1.51-1.62 (min, 1H), 1.70-1.77 (mn, 2H), 1.88-1.97 (mn, 4H), 2.33-2.47 (mn, 4H), 2.53-2.58 (min, 2H), 2.60-2.75 (min, 4H), 3.18-3.22 (mn, 2H), 3.35-3.41 (min, 1H), 3.49-3.52(m, 1H), 35 3.96-4.02 (min, 1H), 7.00-7.02 (min, 4H), 7.13-7.17 (min, 1H), 7.18-7.26 (mn, 4H). Step E: Preparation of 4-(4-(2-(Pyrrolidin-1 yl)ethyl)phenyl)octahydrocyclopenta[c]pyrrole. - 145 - WO 2007/061741 PCT/US2006/044479 -- 'enzy-4-(4-(2-(pyrroldin-1-yl)ethyl)phenyl)octahydrocyclopenta[c]pyrrole (14.0 mg, 37 pmol) was dissolved in methanol (1 mL). Ammonium formate (12.0 mg, 187 pmol) and 20% palladium hydroxide on carbon powder (5.2 mg, 8 gmol) were added and the reaction was stirred at 65 'C for 18 h. The mixture was filtered through 0.45 micron Teflon and used without 5 further purification. MS nm/z 285.2 (M1+H). Step F: Preparation of Racemic Mixture of (3aR, 4R, 6aS) and (3aS, 4S, 6aR)-2 Methyl-l- 4
-[
4 -(2-pyrrolidin-1-yl-ethyl)-phenyl]-hexahydro-cyclopenta[c]pyrrol-2-yl} propan-1-one. 4-(4-(2-(Pyrrolidin-1 -yl)ethyl)phenyl)octahydrocyclopenta[c]pyrrole (6 mg, 21 Pmol) 10 was dissolved in DCM (1 mL) and triethylamine (2 mg, 21 pmol) and isobutyryl chloride (2 mg, 21 pmol) 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 (MgSO 4 ), 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 mn/z 15 355.3 (M+H); 'H NMR (400 MIIz, CD 3 OD) 6 0.92-1.05 (mn, 6H), 1.44-1.55 (mn, 1H), 1.66-1.78 (mn, 1H), 1.86-2.14 (min, 6H), 2.51-2.75 (min, 4H), 2.75-2.80 (mn, 1H), 2.84-2.93 (mn, 2H11), 2.96-3.10 (min, 2H11), 3.22-3.45 (min, 4H11), 3.50-3.63 (min, 2H), 3.67-3.74 (min, 1H), 7.12-7.20 (mn, 4H). Example 2.28: Preparation of Cyclopentyl-((3aR,4R,6aS)-4-{4-[2-((R)-2-methyl-pyrrolidin 20 1-yl)-ethyl]-phenyl}-hexahydro-cyclopenta[cl]pyrrol-2-yl)-methanone. 0 N H< .H The title compound was obtained using general method C starting from (3aR, 4R, 6aS) 25 4-4-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)phenyl)-octahydr cyclopenta[c]pyrrole. MS m/z 395.0, (M+H); 'H NMR (400 MHz, CD 3 OD) 6 1.09 - 1.16 (m, 3 H), 1.39 - 1.52 (m, 2 H), 1.55 1.73 (in, 8 H), 1.74 - 1.83 (mn, 3 H), 1.83 - 1.91 (mn, 1 H), 1.93 - 2.05 (mn, 2 H), 2.22 - 2.34 (mn, 2 H), 2.35 - 2.45 (min, 1 H), 2.51 - 2.66 (mn, 1 H), 2.70- 3.06 (mn, 6 H), 3.14- 3.27 (min, 2 H), 3.33 3.54 (mn, 2 H), 3.57 - 3.83 (mn, 1 H), 7.12- 7.20 (mn, 4 H). 30 Example 2.29: Preparation of Cyclopropyl-((3aR,4S,6aS)-4-{4-[2-((R)-2-methyl-pyrrolidin 1-yl)-ethyl]-phenyl}-hexahydro-cyclopenta[c]lpyrrol-2-(1H)-yl)-methanone. -146- WO 2007/061741 PCT/US2006/044479 iP' IF::: '"l'"/' L,!t i2,1 jii l. 11.,l!,, 1-iI.. 7,l;;i: H N Step A: Preparation of (3aR,4S,6aS)-2-Benzyl-4-bromo octahydrocyclopenta[c]pyrrole.
(
3 aR,4R,6aS)-2-Benzyl-octahydrocyclopenta[c]pyrrol-4-yl methanesulfonate (1.77 g, 6 5 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 MgSO 4 , filtered and concentrated under reduced pressure to leave a yellow oil. This was purified by column 10 chromatography (0-50% EtOAc/n-hexane) to leave the title compound (1.05 g, 62%) as a colorless oil. MS nm/z 280.2, 282.3 (M+H); 'H NMR (400 MHz, CDC13) 6 1.40-1.49 (mn, 1H), 1.90-1.98 (min, 1H), 2.08-2.17 (min, 1H), 2.22-2.32 (min, 1H1), 2.38-2.48 (mn, 4H), 2.70-2.80 (m, 1H), 2.87-2.95 (mn, 1H), 3.51 (bs, 2H), 4.13-4.18 (min, 1H), 7.22-7.34 (mn, 5H). Step B: Preparation of ( 3 aR, 4 S,6aS)-2-Benzyl-4-(4-(2-((R)-2-methylpyrrolidin-1 15 yl)ethyl)phenyl)-octahydrocyclopenta[c]pyrrole. (R)-4-(2-(2-Methylpyrrolidin-1l-yl)ethyl)phenylboronic acid (233 mg, 1 mmol), bis(1,5 cyclooctadiene)nickel (0) (11 mg, 40 Rmol), 4 ,7-diphenyl-1,10-phenanthroline (27 mg, 80 pmol), 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 20 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 oC 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 25 compound (267 mg, 69%) as a colorless oil. MS m/z 389.4 (M+H); 1H NMR (400 MHz, CDC13) 6 1.51 (d, J= 7.6 Hz, 3H11), 1.66-1.71 (mn, 1H11), 1.87-1.95 (m, 1H11), 1.99-2.11 (m, 2H), 2.12-2.29 (min, 3H11), 2.55-2.70 (mn, 1H11), 2.73-2.82 (min, 1H11), 2.86-3.06 (mn, 7H11), 3.10-3.18 (in, 1H), 3.18-3.26 (min, 1H), 3.43-3.57 (in, 1H), 3.60-3.67 (min, 1H), 3.77-3.88 (min, 1H), 3.91-4.00 (mn, 1H11), 4.17-4.29 (min, 1H11), 4.33-4.40 (min, 1H), 7.04-7.08 (min, 1H), 7.10-7.17 (min, 4H), 7.38-7.45 (mn, 4H11). 30 Step C: Preparation of ( 3 aR, 4 S,6aS)-4-(4-(2-((R)-2-Methylpyrrolidin-1 yl)ethyl)phenyl)-octahydrocyclopenta[c]pyrrole.
(
3 aR, 4
S,
6 aS)- 2 -Benzyl-4-(4-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)phenyl) octahydrocyclopenta[c]pyrrole (267 mg, 687 jtmol) was dissolved in methanol (10 mL). The reaction was purged with nitrogen and 20% palladium hydroxide on carbon powder (121 mg, -147- WO 2007/061741 PCT/US2006/044479 172 gpiol wasadded. The reaction 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 nm/z 299.5 (M+H). Step D: Preparation of Cyclopropyl-((3aR,4S,6aS)-4-{4-[2-((R)-2-methyl 5 pyrrolidin-1-yl)-ethyl]-phenyl}-hexahydro-cyclo penta[c]pyrro-2-(1 )-yl)-methanone.
(
3 aR, 4
S,
6 aS)-4-(4-(2-((R)-2-Methylpyrrolidin-l -yl)ethyl)phenyl) octahydrocyclopenta[c]pyrrole (30 mg, 101 gmol) in DCM (1 mL) was charged to a 2 mL vial. Triethylamine (21.2 pl, 151 tmol) was added followed by cyclopropanecarbonyl chloride (15.8 mg, 151 jmol). The reaction was stirred at room temperature for 1 h and then quenched with 10 the addition of saturated aqueous NaIHICO 3 (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). 15 Example 2.30: Preparation of Cyclopentyl-((3aR,4S,6aS)-4-{4-[2-((R)-2-methyl-pyrrolidin 1-yl)-ethyl]-phenyl}-hexahydro-cyclopenta[el]pyrrol-2-(1H)-yl)-methanone (Compound B28). N : H 20 The title compound (12.7 mg, 32%) was prepared in a manner analogous to Example 2.29. MS nm/z 395.4 (M+H). Example 2.31: Preparation of (( 3 aR, 4
S,
6 aS)- 4 -{4-[2-((R)-2-Methyl-pyrrolidin-1-yl)-ethyl] phenyl}-hexahydro-cyclopenta[clpyrrol-2-(..)-yl)-(tetrahydro-pyran-4-yl)-methanone 25 (Compound B26). H N The title compound (18.0 mg, 44%) was prepared in a manner analogous to Example 2.29. MS m/z 411.5 (M+H). - 148- WO 2007/061741 PCT/US2006/044479 xap .2: reparation of (( 3 aR, 4 R,6aS)-4-{4-[2-((R)-2-Methyl-1-oxy-pyrrolidin-1-yl) ethyl]-phenyl}-hexahydro-cyclopenta[c]pyrrol-2-yl)-(tetrahydro-pyran-4-yl)-methanone. O O ~NH HO 0 ((3aR, 4S, 6aS)-4- { 4
-[
2 -((R)-2-Methyl-pyrrolidin-1-yl)-ethyl]-phenyl} -hexahydro 5 cyclopenta[c]pyrrol-2-yl)-(tetrahydro-pyran-4-yl)-methanone (10 mg, 24 gmol) was dissolved in methanol (1 mL). Sodium hydroxide (2 N) (24 gl, 49 pLmol) and hydrogen peroxide (12 pl, 122 ptmol) were added and the mixture was stirred at 50 'C 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). 10 Example 2.33: Preparation of 4
-(
2 -Benzyl-1,2,3,3a,6,6a-hexahydro-cyclopenta[]pyrrol-4 yl)-N-methyl-benzamide. N - 0
HN
The title compound was obtained using general method G. MS m/z 333.4, (M+H); 'H 15 NMR (400 MHz, CD30D) 2.37 (d, J= 15.6 Hz, 3 H), 2.87 - 2.97 (m, 4H), 3.00 - 3.15 (inm, 2H), 3.17 - 3.27 (mn, 1H), 3.71 (dd, J;=12.4 Hz, J 2 =16.8 Hz, 2H1), 3.83 (d, J = 4.0 Hz, 1H), 6.27 (d, J= 1.6 Hz, 1H), 7.25 - 7.29 (mn, 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). 20 Example 2.34: Preparation of (( 3 aR,4R,6aS)-4-{4-[2-((R)-2-Methyl-pyrrolidin-1-yl)-ethyl] phenyl}-hexahydro-cyclopenta[c]pyrrol-2-yl)-phenyl-methanone.
°
0 N H 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 -149- WO 2007/061741 PCT/US2006/044479 Smer phenyl)-octahydrocyclopenta[c]pyrrole (152 mg, 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 HC1 to afford the hydrochloride salt of the title compound (115.9 5 mg). MS m/z 403, (M+H); 1H NMR (400 MHz, CD 3 OD) 6 1.41-1.49 (m, 3H), 1.53-1.84 (m, 2H), 1.94-2.20 (m, 5H), 2.28-2.39 (m, 1H), 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-1-yl-ethyl)-phenyl] 1, 2
,
3
,
3 a, 4 ,6a-hexahydro-cyclopenta[c]pyrrole.
H
3 CO / N 10 / To a solution of 2 -(4-methoxy-benzy1)-4-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl] octahydro-cyclopenta[c]pyrrol-4-ol (0.189 g, 0.45 mmol) in isopropyl alcohol (3.5 mL) was added HC1 (1.58 mL, 6.3 mmol, 4M in 1,4-dioxane). The reaction mixture was heated to 60 'C. After 24 h, the mixture was concentrated under reduced pressure and neutralized with 10% 15 NaOH solution. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with H20, brine, dried over MgSO 4 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 nm/z 403.5, (M+H); 1H NMR (400 MHz, CD 3 OD) <. 1.95-2.20 (m, 4H), 2.40-2.50 (m, 1H), 2.75-3.25 (m, 7H), 3.30-3.55 (m, 4H), 3.60-3.75 (m, 20 2H), 3.78 (s, 1H), 3.80 (s, 3H), 3.90-4.05 (m, 1H), 4.20-4.35 (m, 2H), 6.20 (d, J = 10.8 Hz, 1H), 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 ( 3 aR,7aR)-4-(4-(2-((R)-2-methylpyrrolidin-1 yl)ethyl)phenyl)-2,3,3a,6,7,7a-hexahydro-lH-isoindole. 25 Step A: Preparation of (3aS,7aR)-2-benzyl-4-(4-(2-((R)-2-methylpyrrolidin-1 yl)ethyl)phenyl)-octahydro-1H-isoindol-4-ol. N OHHN -150- WO 2007/061741 PCT/US2006/044479 hecompound was prepared in the same manner as described in Example 1.3 starting from (3aS, 7aR)-2-benzylhexahydro-lH-isoindol-4(2H)-one. MS m/z 419.5 (M+H); 1H NMR (400 MHz, CDC1 3 ) 6 1.13 (d, J=6.06 Hz, 3 H), 1.38 - 1.51 (m, 2 H), 1.62 - 2.04 (mn, 8 H), 2.17 - 2.39 (mn, 5 H), 2.46 - 2.53 (m, 1 H), 2.56 - 2.66 (mn, 1 H), 2.74 - 2.91 (mn, 4 H), 3.00 - 3.09 5 (m, 1 H), 3.24 - 3.31 (m, 1 H), 3.58 (d, J=12.63 Hz, 1 H), 3.76 (d, J=13.14 Hz, 1 H), 7.16 (d, J=8.59 Hz, 2 H), 7.23 - 7.35 (mn, 5 H), 7.44 - 7.48 (m, 2 H). (3aS, 7aR)-2-Benzylhexahydro-1H-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. 10 Analysis of (3aS, 7aR)-2-Benzylhexahydro-1H-isoindol-4(2H)-one via Chiral HPLC: Column: Chiralpak AD-H, 150 x 2.1 mm, 5 gm particle size Eluent: 95% Hexane/5% Isopropanol Gradient: Isocratic 15 Flow: 1 mL/minute Detector: 254 nm Retention Times: 3aR,7aS - 15.2 min.; 3aS,7aR - 16.0 min. Step B: Preparation of ( 3 aS,7aR)-4-(4-(2-((R)-2-methylpyrrolidin-1 20 yl)ethyl)phenyl)-octahydro-1H-isoindol-4-ol. H N H OHI, NO The title compound was prepared in the same manner as described in Example 1.6 starting from ( 3 aS, 7 aR)- 2 -benzyl-4-(4-(2-((R)-2-methylpyrrolidin.-1-yl)ethyl)phenyl)-octahydro 1H-isoindol-4-ol. MS nm/z 329.4 (M+H); 'H NMR (400 MHz, CDC1 3 ) 6 1.17 - 1.25 (mn, 1 H), 25 1.36 - 1.42 (m, 3 H), 1.44 - 1.51 (mn, 1 H), 1.68 - 1.84 (mi, 5 H), 1.88 - 2.23 (m, 4 H), 2.46 - 2.52 (m, 1 H), 2 .54- 2
.
6 5 (mi, 1 H), 2.83- 3.12 (mi, 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 ( 3 aR,7aR)-4-(4-(2-((R)-2-methylpyrrolidin-1 yl)ethyl)phenyl)-2,3,3a,6,7,7a-hexahydro-1H-isoindole. H N 30 N -151 - WO 2007/061741 PCT/US2006/044479 rneitlecompound was prepared in the same manner as described in Example 1.7 starting from (3aS, 7 aR)-4-(4-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)phenyl)-octahydro- 1H isoindol-4-ol. LC-MS nm/z 311.5 (M+H); 'H NMR (400 MHz, CDC1 3 ) 6 1.09 - 1.14 (mn, 3 H), 1.19- 1.28 (min, 1 H), 1.39 - 1.52 (mn, 2 H), 1.66 - 1.86 (mn, 4 H), 1.87 - 1.98 (mn, 2 H), 2.15 - 2.22 5 (mn, 3 H), 2.24 - 2.41 (min, 3 H), 2.50 - 2.55 (mn, 1 H), 2.73 - 2.87 (mn, 3 H), 2.97 - 3.29 (mn, 4 H), 7.16 (d, J=7.58 Hz, 2 H), 7.25 - 7.31 (min, 2 H). Step D: Preparation of (3aS,7aR)-4-(4-(2-((R)-2-methylpyrrolidin-1 yl)ethyl)phenyl)-octahydro-1H-isoindole. H N N( 10 A mixture of (3aR, 7aR)-4-(4-(2-((R)-2-methylpyrrolidin- 1-yl)ethyl)phenyl) 2
,
3
,
3 a, 6 ,7,7a-hexahydro-1H-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 nm/z 313.0 (M+H); 'H NMR (400 15 MHz, CDC1 3 ) 6 1.12 (d, J=6.06 Hz, 3H), 1.31 - 1.52 (mn, 3H), 1.73 (d, J=3.03 Hz, 5H), 1.88 2.01 (min, 2H), 2.13 - 2.35 (mn, 5H), 2.48 - 2.65 (mn, 2H), 2.69 - 3.29 (mn, 8H), 7.03 - 7.21 (mn, 4H). Example 2.37: Preparation of { 7
-[
4
-(
2 -Pyrrolidin-1-yl-ethyl)-phenyll-1,3,3a,4,5,7a hexahydro-isoindol-2-yl}-(tetrahydro-furan-3-yl)-methanone. 200 QNN 20 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-1-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 25 mixture was filtered, rinsed with DCM, and concentrated. The crude residue was purified by HPLC using 10-85% ACN/H 2 0 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 Na 2
SO
4 , and concentrated to afford the title compound which was made into a hydrochloride salt using 1.0 M HCl in ether. MS inm/z 395.4 (M+H); 1H NMR (400 MHz, 30 CD 3 OD) 6 1.43 - 1.57 (min, 1H), 1.68 - 1.80 (mn, 1H), 1.83 (d, J= 3.54 Hz, 3H), 1.89 - 1.99 (inm, -152- WO 2007/061741 PCT/US2006/044479 1 ),2 .- n,"12.24 - 2.34 (m, 2H), 2.40 -2.56 (m, 1H), 2.62 (s, 4H), 2.67 - 2.76 (m, 2H), 2.78 - 2.87 (in, 2H), 2.95 - 3.24 (in, 2H), 3.28 - 3.39 (mn, 2H), 3.42 - 3.65 (min, 2H), 3.66 3.89 (min, 4H), 6.08 - 6.18 (mn, 1H), 7.14 - 7.24 (mn, 2H), 7.29 - 7.39 (mn, 2H). 5 Example 2.38: Preparation of Pyridin-3-yl-{7-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl] 1, 3
,
3 a, 4
,
5 ,7a-hexahydro-isoindol-2-yl}-methanone. 0-N The title compound was obtained using general method C. MS nm/z 389.5 (M+H); 1H NMR (400 MHz, CD 3 OD) 3 1.48 - 1.63 (min, 1H), 1.66 - 1.90 (mn, 2H), 1.96 - 2.21 (min, 4H), 2.27 10 - 2.40 (min, 1H), 2.51- 2.65 (mn, 1H), 2.97- 3.20 (mn, 4H), 3.24- 3.59 (min, 6H), 3.59- 3.76 (inm, 2H), 3.88 -4.02 (min, 1H), 6.13 - 6.28 (min, 1H), 7.19 - 7.49 (mn, 4H), 8.06 - 8.25 (mn, 1H), 8.69 9.17 (min, 3H). Example 2.39: Preparation of 1-( 7
-{
4
-[
2 -((S)-2-Methyl-pyrrolidin-1-yl)-ethyl]-phenyl}.
15 1,3,3a, 4 ,5,7a-hexahydro-isoindol-2-yl)-ethanone. N O The title compound was obtained using general method A. MS nm/z 353.4 (M+H). Example 2.40: Preparation of { 4
-[
4
-(
2 -Pyrroidin-1-yl-ethyl)-phenyl]-octahydro-isoindol-2.
20 yl}-(tetrahydro-furan-3-yl)-methanone. 0 A mixture of (7-(4-(2-(pyrrolidin-1-yl)ethyl)phenyl)-1,3a,4,7a-tetrahydro-1H-isoindol 2
(
6 H)-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 25 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 - 153 - WO 2007/061741 PCT/US2006/044479 ;y compound. ih/z 39 ,i( H NMR (400 MHz, CDC1 3 ) 8 1.12- 1.30 (m, 1H), 1.37 1.46 (m, 1H11), 1.65 - 1.81 (m, 3H), 1.90 - 2.00 (m, 4H), 2.04 - 2.36 (m, 5H), 2.51 - 2.74 (m, 1H), 2.88 - 3.13 (m, 4H), 3.17- 3.42 (m, 3H11), 3.70- 4.06 (m, 10H11), 7.05- 7.21 (m, 4H). 5 Example 2.41: Preparation of 1-( 4
-{
4 -[2-((S)-2-Methyl-pyrrolidin-1-yl)-ethyl]-phenyl}.
octahydro-isoindol-2-yl)-ethanone. N/N 0 ~O The title compound was obtained using general method A. MS m/z 355.5 (M+H); 1H NMR (400 MHz, CD 3 OD) S 1.15 - 1.40 (m, 2H), 1.50 (d, J= 6.06 Hz, 3H), 1.61 -2.19 (m, 10 6H1), 2.29 - 2.48 (m, 2H), 2.51 - 2.85 (m, 1H), 2.90 - 3.00 (m, 2H), 3.04 - 3.15 (m, 3H), 3.19 3.38 (m, 8H11), 3.47 - 3.84 (m, 3H), 7.21 - 7.41 (m, 4H11). Example 2.42: Preparation of 2 -Methyl-1-{(3aS,7aS)-7-[4-(2-pyrrolidin-1-yl-ethyl) phenyl]-l, 3 ,3a,4,5,7a-hexahydro-isoindol-2-yl}-propan-l-one. '/H 15 The title compound was obtained using general method C. MS nm/z 367.4 (M+H); 'H NMR (400 MHz, CDC1 3 ) 6 0.99 - 1.17 (m, 6H), 1.43 - 1.61 (m, 1H), 1.71 - 1.81 (m, 1H11), 2.03 2.15 (m, 2H11), 2.19 - 2.32 (m, 4H), 2.38 - 2.56 (m, 1H), 2.61 - 2.72 (m, 1H11), 2.77 - 2.91 (m, 2H11), 3.01 - 3.48 (m, 8H), 3.52 - 3.90 (m, 3H), 6.09 - 6.15 (m, 1H), 7.16 - 7.26 (m, 2H), 7.27 - 7.35 20 (m, 2H11). Example 2.43: Preparation of ( 3 aS,7aS)-2-Cyclopropanesulfonyl-7-[4-(2-pyrrolidin-l-yl ethyl)-phenyl]-2,3,3a,4,5,7a-hexahydro-lH-isoindole. H H N o4 - 154 - WO 2007/061741 PCT/US2006/044479 To a solution o (3aS,7aS)-4-(4-(2-(pyrrolidin-1-yl)ethyl)phenyl)-2,3,3a,6,7,7a hexahydro-1H-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 oC for 1.5 h. Upon completion, the reaction mixture was 5 concentrated. The residue was purified by preparative HPLC using 10-95% ACN/H 2 0 over 50 min. MS nm/z 401.3, (M+H); 'H NMR (400 MHz, CDC1 3 ) 5 0.98 - 1.06 (mn, 5H), 1.13 - 1.22 (min, 2H11), 1.73 - 1.88 (min, 4H11), 2.24 - 2.36 (min, 3H11), 2.47 - 2.62 (min, 4H), 2.65 - 2.75 (mn, 2H), 2.79 - 2.87 (min, 2H11), 3.01 - 3.08 (mn, 1H11), 3.30 - 3.41 (mn, 2H), 3.64 - 3.74 (min, 2H), 6.08 - 6.15 (inm, 1H), 7.15 - 7.19 (min, 2H), 7.23 - 7.26 (mn, 2H). 10 Example 2.44: Preparation of ( 3 aS,7aS)-2-(Propane-2-sulfonyl)-7-[4-(2-pyrrolidin-1-yl ethyl)-phenyl]-2,3,3a,4,5,7a-hexahydro-lH-isoindole. H& H "H N/ The title compound was prepared in a similar manner as described in Example 2.43. 15 MS m/z403.3(M+H); 'HNMR(400 MHz, CDC1 3 ) 6 1.32 (d, J= 6.57 Hz, 6H), 1.51 - 1.66 (m, 1H), 1.73 - 1.84 (mn, 1H), 2.19 - 2.34 (mn, 5H), 2.44 - 2.55 (mn, 1H), 2.44 - 2.56 (mn, 1H11), 2.78 2.91 (min, 2H11), 2.98- 3.07 (mn, 1H), 3.14 - 3.38 (min, 7H), 3.62- 3.76 (in, 2H), 3.80- 3.93 (mn, 2H), 6.10 (t, J= 3.79 Hz, 1H), 7.15 -7.23 (min, 2H), 7.28 (d, J = 7.58 Hz, 2H). 20 Example 2.45: Preparation of 2 -Methyl-1-((3aS,7aS)-7-{4-[2-((R)-2-methyl-pyrrolidin-1 yl)-ethyl]-phenyl}-,3,3a,4,5,7a-hexahydro-isoindol-2-yl)-propan-l.-one. N - N O HN The title compound was obtained using general method C. MS inm/z 381.4 (M+H); 'H NMR (400 MHz, CD 3 OD) 6 0.95 -0.99 (m, 1H), 1.01 - 1.04 (m, 1H), 1.08 (dd, J 6.57, 4.04 25 Hz, 4H), 1.28 - 1.34 (m, 2H), 1.43 (d,J= 6.06Hz, 3H), 1.52 (dd,J= 12.38, 3.79 Hz, 1H), 1.71 - 1.82 (min, 2H1), 2.02- 2.12 (mn, 2H), 2.26 - 2.33 (mn, 2H), 2.51- 2.59 (in, 1H), 2.75- 2.83 (inm, 1H), 2.96 - 3.08 (mn, 2H11), 3.15- 3.21 (in, 2H), 3.34 - 3.42 (mn, 1H), 3.44- 3.63 (mn, 4H11), 3.67 3.86 (min, 2H11), 6.14 - 6.17 (mn, 1H), 7.27 - 7.31 (mn, 2H), 7.37 - 7.42 (mn, 2H). -155- WO 2007/061741 PCT/US2006/044479 t Yampe :reparation of tyclopropyl-((3aS,7aS)-7-{4-[2-((R)-2-methyl-pyrrolidin-1 yl)-ethyl]-phenyl}-1, 3 ,3a,4,5,7a-hexahydro-isoindol-2-yl)-methanone. Q/ N '/H The title compound was obtained using general method C. MS rn/z 379.5, (M+H); 'H 5 NMR (400 MHz, CDC1 3 ) 8 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, J = 15.66 Hz, 1H), 1.95 - 2.06 (m, 5H), 2.31 - 2.52 (m, 1H1), 2.67- 2.78 (m, 2H), 2.83 - 2.92 (m, 1H), 2.96- 3.05 (m, 1H), 3.16 - 3.37 (m, 2H), 3.48 - 3.64 (m, 2H), 3.77 - 3.87 (m, 1H), 6.02 - 6.07 (m, 1H), 7.07 - 7.16 (m, 2H), 7.19 - 7.27 (m, 2H). 10 Example 2.47: Preparation of Cyclopentyl-((3aS,7aS)-7-{4-[2-((R)-2-methyl-pyrrolidin-1 yl)-ethyl]-phenyl}-1,3,3a,4,5,7a-hexahydro-isoindol-2-yl)-methanone. 0 N N 'H/H The title compound was obtained using general method C. MS nm/z 407.5, (M+H); 'H 15 NMR (400 MHz, CDC1 3 ) 8 1.17 - 1.35 (m, 2H), 1.42 - 1.86 (mn, 9H), 1.95 - 2.08 (m, 3H), 2.18 2.32 (m, 4H), 2.37 - 2.55 (m, 1H), 2.58 - 2.66 (m, 1H), 2.73 - 2.80 (m, 1H), 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, 1H), 6.09 - 6.14 (m, 1H), 7.15 - 7.24 (m, 2H), 7.31 (t, J= 8.34 Hz, 2H). 20 Example 2.48: Preparation of 1-( 7
-{
4
-[
2 -((R)-2-Methyl-pyrrolidin-1-yl)-ethyl]-phenyl} 1, 3
,
3 a, 4
,
5 ,7a-hexahydro-isoindol-2-yl)-ethanone. N C To the solution of 2 -(4-(2-acetyl-2,3,3a, 6
,
7
,
7 a-hexahydro-1H-isoindol4-yl)phenyl)ethyl methanesulfonate (0.125 g, 0.3439 mmol) in acetonitrile was added R-methylpyrrolidine 25 (0.04100 g, 0.4815 mmol) and sodium carbonate (0.08019 g, 0.7566 mmol). The reaction was stirred at 50 oC overnight. The reaction mixture was filtered and concentrated under reduced -156- WO 2007/061741 PCT/US2006/044479 11' -f ....... "! -, 11:. 11::: ,,I !. [ Ir ::i1 pressure. Te residue was purified by HPLC using 20-95% ACN/H 2 0 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 Na 2
SO
4 , and concentrated to afford the title compound. MS m/z 353.4, (M+H). 5 Example 2.49: Preparation of 1-(( 3 aS, 7 aS)-7-{ 4 -[2-((R)-2-Methyl-pyrrolidin-1-yl)-ethyl] phenyl}-1,3,3a,4,5,7a-hexahydro-isoindol-2-yl)-2-phenyl-ethanone. ONI H S N 0 H The title compound was prepared in a similar manner as described in Example 2.37. 10 MS m/z 429.5, (M+H); 1 'H NMR (400 MHz, CDC13) 8 1.12 (dd, J = 5.81, 2.27 Hz, 3H), 1.40 1.51 (m, 2H11), 1.61 - 1.84 (m, 4H), 1.89 - 1.99 (m, 1H11), 2.15 - 2.34 (m, 5H), 2.40- 2.48 (m, 1H), 2.66 - 2.89 (m, 3H11), 2.97 - 3.16 (m, 2H), 3.20 - 3.29 (m, 1H1), 3.33 - 3.41 (m, 1H), 3.49 - 3.60 (m, 1H1), 3.64 - 3.77 (m, 2H11), 3.83 - 3.93 (m, 1H), 7.03 - 7.35 (m, 9H11). 15 Example 2.50: Preparation of ((3aR,7aR)-7-{4-[2-((R)-2-Methyl-pyrrolidin-1-yl)-ethyl] phenyl}-1, 3
,
3 a, 4 ,5,7a-hexahydro-isoindovl-2-yl)-(tetrahydro-furan-3-yl)-methanone. 0 N/ NO - NIH H The title compound was prepared in a similar manner as described in Example 2.37. MS nm/z 409.5, (M+H); 'H NMR (400 MHz, CDC1 3 ) 8 1.13 (d, J = 6.06 Hz, 3H), 1.41 - 1.60 (m, 20 2H), 1.70 -2.15 (m, 6H), 2.17 - 2.39 (m, 6H), 2.41 -2.55 (m, 1H), 2.76- 2.91 (m, 2H), 2.94 3.21 (m, 3H), 3.24 - 3.31 (m, 1H), 3.36- 3.48 (m, 1H11), 3.54 - 3.98 (m, 6H), 6.08 - 6.13 (m, 1H11), 7.13 - 7.22 (m, 2H), 7.25 - 7.30 (m, 2H11). Example 2.51: Preparation of ( 3 aR,7aR)-2-Benzyl-7-{4-[2-((R)-2-methyl-pyrrolidin-1-yl) 25 ethyl]-phenyl}-2,3,3a,4,5,7a-hexahydro-1H.-isoindole. -157- WO 2007/061741 PCT/US2006/044479 HI N /lo No The title compound was prepared in a similar manner as described in Example 1.7. MS nm/z 401.3 (M+H); 1H NMR (400 MHz, CD 3 OD) 8 1.47 (d, J =6.06 Hz, 3H), 1.57 -1.69 (m, 1H), 1.70 - 1.84 (m, 1H), 1.86 - 1.95 (m, 111), 2.02 - 2.21 (m, 2H), 2.24 - 2.39 (m, 3H), 2.69 5 2.93 (m, 2H), 3 .00 -3.16 (m, 3H), 3.18 - 3.28 (m, 2H1), 3.45 - 3 .64 (m, 4H), 3.67 -3.87 (m, 2H), 4.28 - 4.47 (m, 2H), 6.26 (s, 1H), 7.24 - 7.59 (m, 91H). Example 2.52: Preparation of {(3aS,7aS)-7-[4-(2-Pyrrolidin-1-yl-ethyl)-phenyl] 1, 3
,
3 a, 4 ,5, 7 a-hexahydro-isoindol-2-yl}-(tetrahydro-furan-3-yl)-methanone. 0 ONN H,& 'H 10 The title compound was prepared in a similar manner as described in Example 2.37. MS m/z 395.4 (M+H); '11H NMR (400 MHz, CDC1 3 ) 6 1.53 - 1.68 (m, 4H), 1.72 - 1.78 (m, 2H), 1.84 (s, 2H), 1.92 - 2.07 (mn, 2H), 2.08 - 2.23 (m, 2H11), 2.25 - 2.32 (m, 1H11), 2.33 - 2.39 (m, 1H11), 2.57- 2.70 (m, 1H), 2.75 (s, 2H), 2.81- 2.89 (m, 2H11), 2.91 - 3.00 (m, 2H), 3.05 - 3.31 (mn, 2H), 15 3.34 - 3.50 (m, 1H), 3.53 - 3.98 (m, 5H), 6.08 - 6.12 (m, 1H), 7.13 - 7.22 (mn, 2H1), 7.24 - 7.29 (m, 2H). Example 2.53: Preparation of (( 3 aS,7aS)-7-{4-[2-((R)-2-Methyl-pyrrolidin-1-yl)-ethyl] phenyl}-1, 3
,
3 a, 4 ,5,7a-hexahydro-isoindol-2-yl)-(tetrahydro-furan-3-yl)-methanone. oNO N 200 20 0 The title compound was prepared in a similar manner as described in Example 2.37. MS mn/z 409.5 (M+H); 'H NMR (400 MHz, CDC13) 6 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 (mn, 8H1), 2.79 - 2.89 (m, 2H), 2.95 - 3.48 (m, 6H11), 3.54 - 3.96 (m, 6H11), 6.10 (t, J= 3.79 Hz, 1H11), 7.12 - 7.22 (m, 2H11), 7.25 - 7.30 (m, 2H). - 158 - WO 2007/061741 PCT/US2006/044479 Example 2.54: Preparation of ((3aS,7aR)-4-{4-[2-((R)- 2 -Methyl-pyrrolidin-1-yl)-ethyl] phenyl}-octahydro-isoindol-2-yl)-(tetrahydro-furan-3-yl)-methanone. \ H a N 5 The title compound was prepared in a similar manner as described in Example 2.40. MS nm/z 411.4, (M+H); 1'H NMR (400 MHz, CDC1 3 ) 6 1.10 - 1.32 (m, 1H), 1.35 - 1.56 (m, 1H), 1.58 - 1.85 (m, 6H), 1.88- 2.39 (mn, 8H), 2.50- 2.75 (m, 1H), 2.84 - 3.62 (m, 12H), 3.67 - 4.10 (m, 5H), 7.09 - 7.27 (mn, 4H). 10 Example 2.55: Preparation of (( 3 aR,7aS)-4-{4-[2-((R)-2-Methyl-pyrrolidin-1-yl)-ethyl] phenyl}-octahydro-isoindol-2-yl)-(tetrahydro-furan-3-yl)-methanone. H I * H ' The title compound was prepared in a similar manner as described in Example 2.40. MS mn/z 411.4 (M+H); 1H NMR (400 MHz, CDC1 3 ) 5 1.15 - 1.35 (m, 1H), 1.40 - 1.56 (m, 3H), 15 1.66 - 1.80 (m, 3H), 1.84 - 2.20 (m, 7H), 2.25 - 2.42 (m, 2H), 2.59 - 2.79 (m, 1H), 2.87 - 3.16 (m, 5H), 3.17 - 3.30 (m, 4H), 3.36 - 3.45 (m, 1H), 3.46 - 3.67 (m, 3H), 3.46 - 3.66 (m, 4H),7.20 7.34 (m, 4H). Example 2.56: Preparation of 2 -Methyl-1-((3aS,7aR)-4-{4-[2-((R)-2-methyl-pyrrolidin-1 20 yl)-ethyl]-phenyl}-octahydro-isoindol-2-yl)-propan-l-one. H\\H 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, CDCl 3 ) 8 0.98 - 1.17 (m, 5H), 1.20 - 1.32 (m, 1H), 1.37 - 1.49 (m, 1H), 1.57 (s, 3H), 1.64 - 1.85 (m, 3H), 1.89 - 2.09 (m, 3H), 2.18 - 2.36 (m, 25 3H), 2.45 - 2
.
6 9 (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). -159- WO 2007/061741 PCT/US2006/044479 Example 2.57: Preparation of Cyclopentyl-((3aS,7aR)-4-{4-[2-((R)-2-methyl-pyrrolidin-1 yl)-ethyl]-phenyl}-octahydro-isoindol-2-yl)-methanone. ,<H NN 0 5 The title compound was prepared in a similar manner as described in general method C. MS m/z 409.5 (M+H); 1H NMR (400 MHz, CDC1 3 ) 3 1.11 -1.30 (m, 1H), 1.37 -1.47 (m, 2H), 1.51 - 1.95 (m, 14H), 1.99 -2.12 (m, 2H11), 2.17 -2.37 (m, 3H11), 2.49- 2.79 (m, 3H11), 2.88- 3.60 (m, 10H), 3.88 - 4.09 (m, 1H11), 7.08 - 7.27 (m, 4H). 10 Example 2.58: Preparation of ((3aS,7aR)-4-{4-[2-((R)-2-Methyl-pyrrolidin-1-yl)-ethyl] phenyl}-octahydro-isoindol-2-yl)-(tetrahydro-pyran-4-yl)-methanone. ,11 H N N. The title compound was prepared in a similar manner as described in general method C. MS mnz/z425.3 (M+H); 1HNMR (400 MHz, CDC1 3 ) 6 1.10- 1.28 (m, 1H), 1.37- 1.48 (m, 1H), 15 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, 7H11), 3.50 - 3.62 (m, 1H), 3.66 - 3.79 (m, 1H11), 3.94- 4.05 (m, 2H11), 7.06 - 7.28 (m, 41H). Example 2.59: Preparation of {( 3 aS, 7 aR)-4-[4-(2-Pyrrolidin-1-yl-ethyl)-phenyl]-octahydro isoindol-2-yl}-(tetrahydro-furan-3-yl)-methanone. H\V NN INN 20 0 o The title compound was prepared in the same manner as described in Example 2.37. MS nzm/z 397.4 (M+H); 1H NMR (400 MHz, CDC1 3 ) 8 1.12 - 1.30 (m, 1H11), 1.37 - 1.46 (m, 1H), 1.65 - 1.81 (m, 3H11), 1.90- 2.00 (m, 4H), 2.04- 2.36 (m, 5H11), 2.51 - 2.74 (m, 1H11), 2.88 - 3.13 (m, 4H), 3.17 - 3.42 (m, 3H), 3.70 - 4.06 (m, 10H11), 7.05 - 7.21 (m, 4H11). 25 Example 2.60: General Method K -160- WO 2007/061741 PCT/US2006/044479 PrtpaatiOof 2- et]y--L-(64-[2-(3-phenyl-pyrrolidin--lyl)-ethyl]-phenyl}-3,3a,4,6a tetrahydro-1H-cyclopenta[clpyrrol-2-yl)-propan-l-one. Step A: Preparation of Intermediate 1-(4-(4-(2-(tert Butyldimethylsilyloxy)ethyl)phenyl)-4-hydroxyhexahydrocyclopenta[c]pyrrol-2(1H)-yl)-2 5 methylpropan-1-one 0 N OH O i 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); 1H NMR (400 MHz, CD 3 OD) 3 0 (s, 6H), 0.89 (s, 9H), 1.07 - 1.19 (m, 10 6H), 1.84 (dd, J = 7.96, 2.65 Hz, 1H), 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, 2H11), 7.39 - 7.48 (m, 2H). Step B: Preparation of Intermediate 4-(2-Isobutyryl-1,2,3,3a,6,6a hexahydrocyclopenta[c]pyrrol-4-yl)phenethyl Methanesulfonate 0 N 0S 15 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); 'H NMR (400 MHz, CD30D) 3 0.84 - 0.89 (m, 1.5H), 1.02 - 1.12 (m, 4.5H), 2.34 - 2.45 (m, 1H), 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, 1H11), 3.71 - 3.99 (m, 3H), 4.40 - 4.47 (m, 2H11), 20 6.10 (s, 1H), 7.29 (t, J = 7.33 Hz, 2H11), 7.35 - 7.42 (m, 5H). Step C: Preparation of 2-Methyl-1-(6-{4-[2-(3-phenyl-pyrrolidin-1-yl)-ethyl] phenyl}- 3
,
3 a, 4
,
6 a-tetrahydro-lH-cyclopenta[c]pyrrol-2-yl)-propan-.-one 0 NN Starting with material from Step B above, the title compound was obtained using 25 general method A. MS m/z = 429.1 (M+H); 'H NMR (400 MHz, CD 3 OD) 3 1.00 - 1.15 (m, 6H11), 2.22 - 2.45 (m, 2H11), 2.46 - 2.65 (m, 2H), 2.73 - 2.90 (m, 2H), 3.07 - 3.16 (m, 2H11), 3.19 - 161 - WO 2007/061741 PCT/US2006/044479 3- .66 (, 511), 3.68- 4.04 (m, 6H), 6.12 (d, J 1.77 Hz, 1H), 7.26 - 7.47 (mn, 9H). Example 2.61: Preparation of 2 -Methyl-1-{(3aR,4R,6aS)-4-[4-(2-pyrrolidin-1-yl-ethyl) 5 phenyl]-hexahydro-cyclopenta[c]pyrrol-2-yl}-propan-l.-one. H\ 0 Starting with material from example 2.60, step B, displacement as described in general method A led to title compound. MS nm/z = 355.2 (M+H); 1H NMR (400 MHz, CD 3 OD) 8 0.94 10 - 1.14 (m, 6H), 1.65 -1.74 (m, 1H), 1.95 - 2.24 (m, 6H), 2.40 - 2.50 (mn, 1H), 2.72- 2.83 (m, 1H), 2.88 - 3.29 (mn, 6H), 3.35 - 3.54 (m, 5H), 3.62 - 3.76 (mn, 3H), 3.79 - 3.87 (m, 1H), 7.23 7.34 (m, 4H). Example 2.62: Preparation of (3aS,6aS)-2-Methanesulfonyl-6-[4-(2-pyrrolidin-1-yl-ethyl) 15 phenyl]-l, 2
,
3 ,3a,4,6a-hexahydro-cyclopenta[c]lpyrrole. ON S, H //'N H The title compound was obtained using general method C. MS m/z = 361.3 (M+H); 'H NMR (400 MHz, CD 3 OD) 8 1.99 - 2.09 (m, 2H), 2.19 (s, 2H), 2.38 - 2.47 (m, 1H), 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 (mn, 2H), 3.90 20 - 3.98 (m, 1H), 6.18 (d, J= 1.77 Hz, 1H), 7.32 (d, J= 8.08 Hz, 2H), 7.44 (d, J= 8.08 Hz, 2H). Example 2.63: Preparation of 1-{2-[4-(2-Benzyl-1,2,3,3a,6,6a-hexahydro cyclopenta[c]lpyrrol-4-yl)-phenyl]-ethyl}-pyrrolidin-2-one. - N0 25 The title compound was obtained using general method A. MS m/z= 387.3 (M+H); 1H NMR (400 MHz, CD 3 OD) 6 1.96 - 2.07 (mn, 3H), 2.37 (t, J= 8.08 Hz, 3H), 2.65 - 2.74 (m, 2H), -162- WO 2007/061741 PCT/US2006/044479 . - , .""44 " (m, 4H11), 3.49 - 3.56 (m, 2H), 3.72 - 3.83 (m, 1H), 3.95 - 4.04 (m, 1H), 4.04 - 4.14 (m, 1H1), 4.17 - 4.27 (m, 1H11), 6.04 - 6.19 (m, 1H1), 7.14 -7.35 (m, 4H11), 7.38 -7.57 (m, 4H1). 5 Example 2.64: Preparation of 1-( 6
-{
4
-[
2
-(
2 -Isopropyl-pyrrolidin-1-yl)-ethyl]-phenyl} 3
,
3 a, 4
,
6 a-tetrahydro-1H-cyclopenta[c]pyrrol-2-yl)-2-methyl-propan-.1-one. I 0 N The title compound was obtained using general method K. MS m/z = 395.2 (M+H); 'H NMR (400 MHz, CD 3 OD) 8 0.85 -1.15 (m, 12H), 1.84 -1.96 (m, 1H), 1.99 - 2.28 (m, 4H), 10 2.34 -2.45 (m, 1H), 2.55 - 2.88 (m, 2H), 3.06 - 3.17 (m, 3H11), 3.24 - 3.36 (mn, 2H), 3.38 - 3.59 (m, 4H1), 3.63 - 4.01 (m, 4H), 6.09- 6.14 (m, 1H), 7.29 - 7.37 (m, 2H11), 7.39 - 7.46 (m, 2H). Example 2.65: Preparation of 2 -Benzyl-6-{4-[2-(2-trifluoromethyl-pyrrolidin-1-yl)-ethyl] phenyl}-l,2,3,3a,4,6a-hexahydro-cyclopenta[c]lpyrrole. N F F F N 15 The title compound was obtained using general method A. MS m/z = 441.4 (M1+H); 'H NMR (400 MHz, CD 3 OD) 8 2.06 - 2.33 (m, 4H11), 2.45 - 2.56 (m, 2H11), 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, 1H), 4.32 - 4.43 (m, 2H), 4.49 - 4.65 (m, 1H), 6.19 - 6.29 (m, 1H), 7.21 - 7.57 (m, 9H11). 20 Example 2.66: Preparation of 2 -Methyl-1-(6-{4-[2-(2-phenyl-pyrrolidin-1-yl)-ethyl] phenyl}- 3
,
3 a, 4
,
6 a-tetrahydro-1H-cyclopenta[c]pyrrol-2-yl)-propan-l-one. N O The title compound was obtained using general method K. MS m/z = 429.3 (M+H11); 1H 25 NMR (400 MHz, CD 3 OD) 8 0.81 - 1.12 (m, 6H), 2.27 - 2.45 (m, 4H), 2.51 - 3.13 (m, 7H), 3.19 - 163 - WO 2007/061741 PCT/US2006/044479 3- 1 (hm ),.37-3.55 (, 2 -),3.67 -4.01(m, 4H),4.47-4.56(m, lH),6.05 -6.11(m, 1H1), 7.11- 7.21 (m, 2H11), 7.30- 7.40 (m, 2H11), 7.49- 7.57 (m, 3H11), 7.58- 7.66 (m, 2H). Example 2.67: Preparation of 2 -Methyl-1-(6-{4-[2-((S)-2-methyl-pyrrolidin-1-yl)-ethyl]-. 5 phenyl}- 3
,
3 a,4,6a-tetrahydro-1H-cyclopenta[e]pyrrol-2-yl)-propan-1-one. 0 The title compound was obtained using general method K. MS nm/z = 367.3 (M+H); 1H NMR (400 MHz, CD 3 OD) 8 0.85 - 1.14 (m, 6H), 1.45 - 1.53 (m, 3H), 1.71 - 1.85 (m, 1H), 2.03 - 2.19 (m, 2H), 2.31 - 2.46 (m, 2H11), 2.55 - 2.87 (m, 2H), 3.03 - 3.18 (m, 2H), 3.18 - 3.41 (m, 10 4H), 3.42 - 3.67 (m, 3H), 3.70 - 4.03 (m, 4H), 6.09 - 6.16 (m, 1H11), 7.30 - 7.37 (m, 2H), 7.38 7.46 (m, 2H11). Example 2.68: Preparation of 2 -Methyl-1-(6-{4-[2-((R)-2-methyl-pyrrolidin-1-yl)-ethyl]. phenyl}- 3 ,3a,4,6a-tetrahydro-1H-cyclopenta[lc]pyrrol-2-yl)-propan-l-one. O CNN 15 N The title compound was obtained using general method K. MS nm/z = 367.0 (M+H); 111 NMR (400 MHz, CD 3 OD) 8 0.84 - 1.15 (m, 6H), 1.44 - 1.54 (m, 3H), 1.72 - 1.84 (m, 1H), 2.03 - 2.21 (m, 2H11), 2.30- 2.48 (m, 2H11), 2.54- 2.89 (m, 2H11), 3.01 - 3.17 (m, 2H), 3.18- 3.40 (m, 4H11), 3.44- 3.66 (m, 3H), 3.70 - 4.00 (m, 4H), 6.09 - 6.14 (m, 1H11), 7.30 - 7.38 (m, 2H), 7.38 20 7.47 (m, 2H11). Example 2.69: Preparation of 1-( 6
-{
4
-[
2 -((S)-2-Hydroxymethyl-pyrrolidin-1-yl)-ethyl] phenyl}- 3
,
3 a, 4
,
6 a-tetrahydro-1H-cyclopenta[c]pyrrol-2-yl)-2-methyl-propan-l-one. -164 - 164 - WO 2007/061741 PCT/US2006/044479 The title compound was obtained using general method K. MS m/z = 383.1 (M+H); 1H NMR (400 MHz, CD30D) 6 0.82 - 1.14 (m, 6H), 1.87 - 1.98 (m, 1H11), 2.00 - 2.10 (m, 1H), 2.11 -2.32 (m, 2H), 2.33- 2.46 (m, 1H), 2.56- 2.89 (m, 2H), 3.06-3.15 (m, 2H), 3.17 - 3.41 (m, 5H), 3.44 - 3.60 (in, 1H), 3.63 - 4.00 (in, 8H), 6.09 - 6.15 (m, 1H), 7.28 - 7.36 (m, 2H), 7.37 - 7.46 5 (m, 2H). Example 2.70: Preparation of 1-( 6
-{
4 -[2-(2,5-Dimethyl-pyrrolidin-1-yl)-ethyl]-phenyl} 3
,
3 a, 4
,
6 a-tetrahydro-1H-cyclopenta[cl]pyrrol-2-yl)-2-methyl-propan-l-one. 0 N 10 The title compound was obtained using general method K. MS nm/z = 381.4 (M+H); 1H NMR (400 MHz, CD 3 OD) 5 0.81 - 1.10 (m, 6H), 1.32 - 1.54 (m, 6H11), 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, 2H11), 3.37 -3.57 (m, 2H), 3.62- 4.15 (m, 6H11), 6.08 - 6.13 (mn, 1H11), 7.29 - 7.35 (m, 2H11), 7.37 - 7.44 (m, 2H11). 15 Example 2.71: Preparation of 1-(6-{4-[2-((2R,5R)-2,5-Dimethyl-pyrrolidin-1-yl)-ethyll phenyl}- 3
,
3 a, 4
,
6 a-tetrahydro-1H-cyclopenta[c]pyrrol-2-yl)-2-methyl-propan-l-one. 0 The title compound was obtained using general method K. MS mn/z = 381.2 (M+H); 1H NMR (400 MHz, CD 3 OD) 8 0.81 -1.11 (m, 6H), 1.31 -1.55 (m, 6H1), 2.19 -2.48 (m, 4H11), 2.53 20 - 2.86 (mn, 2H11), 3.00 -3.13 (m, 3H), 3.19 -3.34 (m, 2H1), 3.36 -3.49 (m, 2H11), 3.61- 3.97 (m, 5H), 4.02- 4.14 (m, 1H), 6.07 - 6.11 (m, 1H11), 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-1-.yl) ethyl]-phenyl}-1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole. 25 Step A: Preparation of Intermediate 2-Benzyl-5 methylhexahydrocyclopenta[c]pyrrol-4(5H)-one NO - 165 - WO 2007/061741 PCT/US2006/044479 T6o 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-butyllithium in hexanes (2.00 mL) to diisopropylamine dissolved in THF (5 mL) at -78 oC. The reaction mixture was stirred 30 min at -78 'C before iodomethane was added and 5 stirred another 30 min at -78 'C. The reaction was then warmed to -20 oC 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 Na 2
SO
4 . 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 nm/z = 230.3 (M+H); 1H NMR (400 10 MHz, CDC13) 8 1.05 - 1.11 (m, 3H), 1.24 - 1.36 (m, 1H), 1.62 - 1.74 (m, 1H), 2.21 - 2.30 (m, 1H), 2.32- 2.43 (m, 1H), 2.47 - 2.59 (m, 1H), 2.61- 2.77 (m, 2H), 2.93 (dd, J = 9.22, 1.89 Hz, 1H), 3.15 (d, J= 9.35 Hz, 1H), 3.41 - 3.70 (m, 2H11), 7.18 - 7.34 (m, 5H). Step B: Preparation of 2 -Benzyl-5-methyl-6-{4-[2-((R)-2-methyl-pyrrolidin-1-yl) ethyl]-phenyl}-1,2,3,3a,4,6a-hexahydro-eyclopenta[c]pyrrole N 15 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 nm/z = 401.4 (M+H); 'H NMR (400 MHz, CD 3 OD) 8 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, 5H11), 2.97 - 3.20 (m, 4H), 3.23 - 3.59 (m, 5H), 3.81 20 - 4.23 (m, 3H), 7.02 - 7.33 (m, 9H). Example 2.73: Preparation of Cyclopentyl-(5-methyl-6-{4-[2-((R)-2-methyl-pyrrolidin-1 yl)-ethyl]-phenyl}- 3
,
3 a, 4 ,6a-tetrahydro-1H-cyclopenta[c]pyrrol-2-yl)-methanone. ONN 25 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 mn/z = 407.3 (M+H), 1H NMR (400 MHz, CD 3 OD) 8 1.41 - 1.55 (m, 5H), 1.56 - 1.94 (m, 10H1), 2.03 - 2.21 (m, 2H), 2.28 - 2.45 (m, 2H), 2.73 - 2.83 (m, 1H), 2.85 - 3.00 (m, 1H11), 3.02 - 3.33 (m, 6H), 3.35 - 3.67 (m, 4H11), 3.70 - 3.96 (m, 3H11), 7.19 - 7.28 (m, 2H), 7.32 - 7.40 (m, 2H11). -166- WO 2007/061741 PCT/US2006/044479 I 7 I ..
-
/ i11+ Example 2.74: Preparation of Cyclopentyl-(5-methyl-4-{4-[2-((R)-2-methyl-pyrrolidin-1.
yl)-ethyl]-phenyl}-hexahydro-cyclopenta[c]pyrrol-2-yl)-methanone. 5 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, CD 3 OD) 5 0.65 - 0.78 (m, 3H), 1.19 - 1.89 (m, 7H), 1.95 - 2.12 (mn, 2H), 2.20 - 2.36 (m, 3H1), 2.41 - 2.57 (m, 1H), 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). 10 Example 2.75: General Method L Preparation of (( 3 aR, 4 R,6aS)-4-{4-[2-((S)-2-Hydroxymethyl-pyrrolidin-1-yl)-ethyl] phenyl}-hexahydro-cyclopenta[c]pyrrol-2-yl)-(tetrahydro-pyran-4-yl)-methanone. Step A: Preparation of Intermediate ((3aR,6aS)- 4-(4-(2-(tert 15 Butyldimethylsilyloxy)ethyl)phenyl)-4-hydroxyhexahydrocyclopenta[c]pyrrol.-2(1H) yl)(tetrahydro-2H-pyran-4-yl)methanone. 0 Oc i NH 0 H OH H /H 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 20 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]lpyrrol-2(1H)-yl)(tetrahydro-2H-pyran-4-yl)methanone 0 OO SN H OH H Starting with compound from Step A above, deprotection and elimination as described 25 for Example 1.7, afforded the title compound. MS m/z = 342.2 (M+H). Step C: Preparation of 4
-(
3 aR, 6 aS)-(2-(tetrahydro-2H-pyran-4 carbonyl)octahydrocyclopenta[cj]pyrrol-4-yl)phenethyl methanesulfonate -167- WO 2007/061741 PCT/US2006/044479 O N H OS N"'O -- 00 H 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 mn/z= 422.1 (M+H), 1H NMR (400 MHz, CD 3 OD) 8 5 1.42 - 1.82 (m, 5H), 1.93 - 2.19 (m, 3H), 2.40- 2.51 (m, 0.5H), 2.73- 2.83 (m, 0.5H), 2.92 (s, 3H),2.94 - 3.28 (m, 5H), 3.34 - 3.56 (mn, 5H), 3.62- 4.02 (m, 3H), 4.38- 4.48 (m, 2H), 7.18 7.30 (m, 4H). Step D: Preparation of (( 3 aR, 4
R,
6 aS)- 4
-{
4 -[2-((S)-2-Hydroxymethyl-pyrrolidin-1 yl)-et hyl -phenyl}-hexahydro-cyclopenta[cpyrrol-2.-yl)-(tetrahydro-pyran-4-yl) 10 methanone OQ O OH N H Starting with material from Step C above, the title compound was obtained using general method A. MS m/z= 427.4 (M+H); 'H NMR (400 MHz, CD30D) a 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 15 4.02 (m, 4H), 7.23 - 7.33 (m, 4H). Example 2.76: Preparation of (( 3 aR, 4 R,6aS)-4-{4-[2-((S)-2-Methoxymethyl-pyrrolidin-1 yl)-ethyl]-phenyl}-hexahydro-cyclopenta[c]pyrrol-2-yl)-(tetrahydro-pyran-4-yl) methanone. 20 The title compound was obtained using general method G. MS m/z = 441.7 (M+H); 1H NMR (400 MHz, CD 3 OD) 3 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). 25 Example 2.77: Preparation of (S)-l-( 2
-{
4 -[(3aR,4R,6aS)-2-(Tetrahydro-pyran-4-carbonyl) octahydro-cyclopenta[c]pyrrol-4-yl]-phenyl}.-ethyl)-pyrrolidine-2-carboxylic acid amide. - 168 - WO 2007/061741 PCT/US2006/044479 O NH 2 The title compound was obtained using general method L. MS nm/z = 440.6 (M+H); 1 H NMR (400 MHz, CD 3 OD) 8 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, 1H), 7.20 - 7.33 (m, 5 4H). Example 2.78: Preparation of ((3aR,4R,6aS)-4-{4-[2-((R)-2-Methoxymethyl-pyrrolidin-1 yl)-ethyl]-phenyl}-hexahydro-cyclopenta[c]pyrrol-2-yl)-(tetrahydro-pyran-4-yl) methanone. 100 10 Hs\ The title compound was obtained using general method L. MS nm/z = 441.6 (M+H); 1H NMR (400 MHz, CD 3 OD) 6 1.40 - 1.80 (m, 5H), 1.81 - 2.22 (m, 6H11), 2.23 - 2.49 (m, 2H), 2.75 - 3.16 (m, 4H), 3.17 - 3.57 (m, 11H), 3.59 -4.03 (m, 8H11), 7.23- 7.33 (m, 4H). 15 Example 2.79: Preparation of (S)-1-(2-{4-[(3aR,4R,6aS)-2-(Tetrahydro-pyran-4-carbonyl) octahydro-cyclopenta[c]lpyrrol-4-yl]-phenyl}-ethyl)-pyrrolidine-2-carboxylic acid methylamide. 0 ,, N \"N "0 H The title compound was obtained using general method L. MS m/z = 455.4 (M+H); 'H 20 NMR (400 MHz, CD 3 OD) 6 1.36 - 1.83 (m, 5H11), 1.92 - 2.29 (m, 6H), 2.37 - 2.88 (m, 5H11), 2.89 - 3.10 (m, 4H11), 3.11 - 3.72 (m, 9H), 3.77 - 4.02 (m, 4H), 4.13- 4.30 (m, 1H), 7.21 - 7.31 (m, 4H1). Example 2.80: Preparation of {(3aR,4R,6aS)-4-[4-(2-Pyrrolidin-1-yl-ethyl)-phenyll 25 hexahydro-cyclopenta[c]lpyrrol-2-yl}-(tetrahydro-pyran-4-yl)-methanone. -169- WO 2007/061741 PCT/US2006/044479 ON The title compound was obtained using general method L. MS mn/z = 397.2 (M+H); 'H NMR (400 MHz, CD 3 OD) 6 1.42 -1.82 (m, 5H), 1.94 - 2.23 (m, 7H), 2.41- 2.84 (m, 1H11), 2.87 - 3.30 (m, 8H11), 3.33 - 3.60 (m, 6H), 3.64 - 3.77 (m, 2H11), 3.81- 4.01 (m, 3H), 7.23 - 7.33 (in, 5 4H). Example 2.81: Preparation of {(3aR,4R,6aS)-4-[4-(2-Piperidin-1-yl-ethyl)-phenyl] hexahydro-cyclopenta[c]pyrrol-2-yl}-(tetrahydro-pyran-4-yl)-methanone. H O/ 10 The title compound was obtained using general method L. MS inm/z = 411.4 (M+H); 1H NMR (400 MHz, CD30D) 6 1.40 - 2.19 (m, J = 5.00 Hz, 15H), 2.39 - 2.85 (m, 1H), 2.88 - 3.17 (m, 7H11), 3.18 - 3.56 (m, 6H), 3.58 - 3.70 (m, 2H11), 3.79 - 4.01 (m, 3H), 7.24 - 7.32 (m, 4H). Example 2.82: Preparation of {(3aR,4R,6aS)-4-[4-(2-Diisopropylamino-ethyl)-phenyl] 15 hexahydro-cyclopenta[el]pyrrol-2-yl}-(tetrahydro-pyran-4-yl)-methanone. OO? N The title compound was obtained using general method L. MS nm/z = 427.6 (M+H); 'H NMR (400 MHz, CD30D) 6 1.40 - 1.51 (m, 12H), 1.54 - 1.81 (m, 5H), 1.91 - 2.17 (m, 3H), 2.39 - 2.83 (m, 1H11), 2.89 - 3.27 (m, 6H), 3.28 - 3.59 (m, 6H), 3.63 - 4.00 (m, 5H), 7.23 - 7.34 20 (m, 4H11). Example 2.83: Preparation of {(3aR,4R,6aS)-4-[4-(2-Morpholin-4-yl-ethyl)-phenyl] hexahydro-cyclopentalclpyrrol-2-yl}-(tetrahydro-pyran-4-yl)-methanone. 07 H O - 170 - WO 2007/061741 PCT/US2006/044479 Te title compound was obtained using general method L. MS m/z = 413.7 (M+H); 1H NMR (400 MHz, CD 3 OD) 5 1.40 -1.82 (m, 5H), 1.93 - 2.17 (m, 3H), 2.38 - 2.85 (m, 1H), 2.87 -3.16 (m, 5H), 3.16- 3.30 (m, 3H), 3.30 - 3.73 (m, 8H), 3.77 - 4.01 (m, 51H), 4.06 - 4.15 (m, 211), 7.25 - 7.33 (m, 4H11). 5 Example 2.84: Preparation of ((3aR,4R,6aS)-4-{4-[2-((R)-3-Hydroxy-pyrrolidin-1-yl) ethyl]-phenyl}-hexahydro-cyclopenta[c]pyrrol-2-yl)-(tetrahydro-pyran-4-yl)-methanone. O OH 10 The title compound was obtained using general method L. MS m/z = 413.3 (M+H); 111 NMR (400 MHz, CD 3 OD) 8 1.40 - 1.82 (m, 5H11), 1.92 - 2.19 (m, 5H), 2.33 - 2.51 (m, 1H11), 2.74 - 3.62 (m, 15H), 3.63 - 4.02 (m, 5H), 4.53 - 4.64 (m, 1H), 7.24 - 7.33 (m, 4H11). Example 2.85: Preparation of ((3aR,4R,6aS)-4-{4-[2-(3,3-Difluoro-pyrrolidin-1-yl)-ethyl] 15 phenyl}-hexahydro-cyclopenta[c]pyrrol-2-yl)-(tetrahydro-pyran-4-yl)-methanone. OO F H ^N H F The title compound was obtained using general method L. MS m/z = 433.3 (M+H); 1H NMR (400 MHz, CD 3 OD) 8 1.39 - 1.83 (m, 5H), 1.91 - 2.21 (m, 4H), 2.36 - 2.87 (m, 3H), 2.88 - 3.29 (m, 6H11), 3.33 - 3.73 (m, 7H), 3.77 - 4.27 (m, 5H), 7.24 - 7.36 (m, 4H). 20 Example 2.86: Preparation of 4-(2-Benzyl-1,2,3,3a,6,6a-hexahydro-cyclopenta[clpyrrol-4 yl)-benzylamine. N - NH 2 To a reaction vial was added 2-benzyl-1,2,3,3a,6,6a-hexahydrocyclopenta[c]pyrrol-4-yl 25 trifluoromethanesulfonate (152.4 mg, 0.439 mmol), 4-(aminomethyl)phenylboronic acid hydrochloride (163.2 mg, 0.871 mmol), Na 2
CO
3 (0.648 ml, 1.30 mmol, 2 M solution in H20) and tetrakis(triphenylphosphine)palladium (0) (30.6 mg, 0.026 mmol) in a mixture of EtOH - 171 - WO 2007/061741 PCT/US2006/044479 1(08 ril) an tlene (3.0 ml). the reaction mixture was heated at 100 oC for 1.5 h. Upon completion, the reaction mixture was washed with H20, and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO 4 , and concentrated. The residue was purified by preparative HPLC to afford the title compound (16 mg, 12%) as a TFA 5 salt. MS m/z 305, (M+H); 'H NMR (400 MHz, CD 3 OD) 6 2.48 (dd, J = 18.4, 2.0 Hz, 1H), 2.79-3.05 (min, 2H), 3.14-3.84 (m, 3H), 3.92-4.38 (min, 6H), 6.27 (bs, 1H), 7.38-7.50 (mn, 9H). Example 2.87: Preparation of 3-(2-Benzyl-1,2,3,3a,6,6a-hexahydro-cyclopenta[c]pyrrol-4 yl)-benzylamine. N
NH
2 10 To a reaction vial was added 2-benzyl-1,2,3,3a,6,6a-hexahydrocyclopenta[c]pyrrol-4-yl trifluoromethanesulfonate (153.4 mg, 0.442 mmol), 3-(aminomethyl)phenylboronic acid hydrochloride (163.3 mg, 0.871 mmol), Na 2
CO
3 (0.648 mil, 1.30 mmol, 2 M solution in H20) and tetrakis(triphenylphosphine)palladium (0) (32.6 mg, 0.028 mmol) in a mixture of EtOH 15 (0.78 ml) and toluene (3.0 ml). The reaction mixture was heated at 100 oC for 1.5 h. Upon completion, the reaction mixture was washed with H 2 0, and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO 4 , and concentrated. The residue was purified by preparative HPLC to afford the title compound (8 mg, 6%) as a TFA salt. MS nm/z 305, (M+H); 1H NMR (400 MHz, CH 3 OD) 5 2.48 (dd, J = 18.4, 2.0 Hz, 1H), 20 2.79-3.04 (min, 2H), 3.14-3.84 (min, 3H), 3.96-4.40 (mn, 6H), 6.27 (bs, 1H), 7.31-7.53 (mn, 9H). Example 2.88: Preparation of (3aR, 6aS)-2-Benzyl-6-{4-[2-((R)-2-methyl-pyrrolidin-1-yl) ethyl]-phenyl}-1,2,3,3a,4,6a-hexahydro-cyelopenta[c]pyrrole. Step A: Preparation of (3aS, 6aR)-2-Benzyl-4{4-[2-(2-methyl-pyrrolidin-1-yl) 25 ethyl]-phenyl}-octahydro-cyclopenta[c]pyrrol-4-ol
NT
N H HO 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). -172- WO 2007/061741 PCT/US2006/044479 S.. SiteI":"Preparation of (3aR, 6aS)-2-Benzyl-6-{4-[2-((R)-2-methyl-pyrrolidin-1-yl) ethyl]-phenyl}-1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole
N/
QN H H The title compound was obtained by elimination as described for Example 1.7 starting 5 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). 10 Example 2.89: Preparation of 2-Benzyl-6-{4-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-phenyl} 1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole. N The title compound was obtained using general method A. MS mn/z 386, (M+H); 1'H 15 NMR (400 MHz, CD30D) 8 1.44 (d, J = 5.7 Hz, 3H11), 19 (s, 1H), 1.99-2.19 (m, 2H), 2.25-2.38 (m, 1H11), 2.43 (dd, J= 18.3, 2.5 Hz, 1H11), 2.80-3.30 (m, 7H11), 3.40-3.80 (m, 6H), 3.90-4.24 (m, 3H), 61.68-1.81 (m, 1H), 7.30 (d, J= 8.2 Hz, 2H11), 7.37-7.45 (m, 7H). Example 2.90: Preparation of 6-{4-[2-(2-Methyl-pyrrolidin-1-yl)-ethyl]-phenyl}-3,3a,4,6a 20 tetrahydro-1H-cyclopenta[c]pyrrole-2-carboxylic acid ethyl ester. 0 NN In a 5 mL glass tube were placed 6 -(4-(2-(2-methylpyrrolidin-1-yl)ethyl)phenyl) 1,2,3,3a,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 25 microwave cavity. With microwave irradiation, the temperature was ramped from room temperature to 120 'C and held for 3 h. After the mixture was allowed to cool to room - 173 - WO 2007/061741 PCT/US2006/044479 stemperatue t eacfion vssel 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); 'H NMR (400 MHz, CD 3 OD) 6 0.87 (bs, 2H11), 1.094 (s, 6H), 1.24-1.42 (min, 1H), 1.72 (s, 2H11), 1.82-2.02 (min, 1H), 2.24-2.35 (min, 1H), 2.45-2.54 (mn, 2H), 5 2.65-2.85 (min, 3H), 2.96-3.10 (mn, 2H), 3.10-3.24 (min, 2H), 3.62 (dd, J= 10.0, 6.0 Hz, 2H), 3.68 3.80 (min, 1H), 3.84-4.00 (min, 2H11), 6.09 (s, 1H), 7.16-7.25 (min, 2H11), 7.27-7.36 (min, 2H11). Example 2.91: Preparation of (3aS,6aS)-2-Benzyl-6-{4-[2-((S)-2-methyl-pyrrolidin-1-yl) ethyl]-phenyl}-1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole. N H N~J 10 To a solution of (3aR,6aS)-2-benzyl-4-(4-(2-((S)-2-methylpyrrolidin-1-yl)ethyl)phenyl) octahydrocyclopenta[c]pyrrol- 4 -ol (236 mg, 0.583 mmol) in isopropyl alcohol (3.2 mL) was added HC1 (1.5 mL, 2 M in ether) and heated to 40 oC. Additional HC1 in ether was added in -1 mL portion to the reaction mixture until the reaction was complete. To the reaction mixture 15 were added EtOAc and H20. The organic layer was separated from the aqueous layer. The aqueous layer was washed with EtOAc and neutralized with saturated NaHCO 3 . The aqueous layer was extracted with EtOAc and Et 2 0. The combined organic layers were washed with H20, brine and dried over MgSO 4 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); 'H NMR 20 (400 MHz, CD 3 OD) 6 1.45-1.49 (min, 3H), 1.70-1.81 (min, 1H), 2.00-2.19 (mn, 2H11), 2.28-2.39 (inm, 1H1), 2.42-2.51 (min, 1H), 2.80-3.62 (min, 1111), 3.67-3.82 (min, 1H11), 3.92-4.23 (mn, 2H11), 4.28-4.41 (min, 2H11), 6.17-6.24 (min, 1H11), 7.30 (dd, J = 8.0, 8.0 Hz, 211), 7.38-7.51 (min, 7H).. Example 2.92: Preparation of (3aR,6aR)-2-Benzyl-6-{4-[2-(2,2-dimethyl-pyrrolidin-l-yl) 25 ethyl]-phenyl}-1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole. N H N To a solution of (3aS, 6aR)-2-benzyl-4-(4-(2-(2,2-dimethylpyrrolidin-1 yl)ethyl)phenyl)-octahydrocyclopenta[c]pyrrol-4-ol (456 mg, 1.09 mmol) in DCM (5.5 mL) was -174- WO 2007/061741 PCT/US2006/044479 !: I t" ' "°l '. I" ! ',: if", I ,f"- ". ll~ ~t~l:'; Rll c aad 1 .e1ylamine (.304 ml, 2.18 mmol) at 25 C. The reaction mixture was cooled to -20 oC and methanesulfonyl chloride (0.170 ml, 2.20 mmol) was added. The reaction mixture was kept at below -20 oC for 30 min before warmed to 25 oC and stirred for another 1 h. The reaction mixture was quenched with saturated NaHCO 3 and extracted with DCM. The combined organic 5 layers were washed with H20, brine, dried over MgSO 4 and concentrated. The residue was purified by preparative HPLC, lyophilized, and treated with HC1 to afford the hydrochloride salt of the title compound (81.7 mg). MS nm/z 401, (M+H); 'H NMR (400 MHz, CD 3 OD) 5 1.17 (d, J 3.5 Hz, 3H11), 1.50 (d, J= 3.8 Hz, 3H), 1.86-2.03 (mn, 4H), 2.32-2.41 (min, 1H), 2.64-2.86 (inm, 4H11), 2.92-3.56 (min, 511), 3.60-3.71 (min, 2H11), 3.78-4.10 (min, 2H11), 4.25-4.39 (min, 2H), 6.25 (bs, 1H), 10 7.27-7.36 (min, 2H), 7.39-7.45 (min, 5H), 7.52-7.61 (min, 2H). Example 2.93: Preparation of (3aS,6aS)-6-[4-(2-Pyrrolidin-1-yl-ethyl)-phenyll-3,3a,4,6a tetrahydro-1H-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide. \ 0 N H 15 The title compound was obtained using general method C. MS m/z 354, (M+H); 'H NMR (400 MHz, CD 3 OD) & 1.96-2.08 (min, 2H), 2.10-2.22 (min, 2H), 2.33-2.41 (mn, 1H), 2.74 2.83 (min, 7H), 3.02-3.18 (min, 5H), 3.20-3.30 (min, 2H11), 3.42-3.48 (min, 2H11), 3.64-3.71 (mn, 3H), 3.74 3.85 (mn, 2H), 6.08-6.11 (mn, 1H11), 7.29 (d, J= 8.1 Hz, 2H), 7.41 (d, J = 8.1 Hz, 2H11). 20 Example 2.94: Preparation of (3aS,6aS)-2-Cyclopentylmethyl-6-[4-(2-pyrrolidin-1-yl ethyl)-phenyl]-1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole. N H N_ The title compound was obtained using general method B. MS nm/z 365, (M+H); 'H NMR (400 MHz, CD 3 OD) 6 1.20-1.31 (min, 2H), 1.54-2.25 (min, 1111), 2.42-2.55 (mn, 1H11), 2.72 25 2.92 (min, 2H), 3.03-3.19 (min, 7H), 3.41-3.52 (m, 4H11), 3.65-3.72 (min, 2H), 3.93-4.07 (in, 1H), 4.16 4.25 (min, 1H11), 6.19-6.28 (min, 1H), 7.31-7.35 (min, 2H), 7.43-7.49 (min, 2H). Example 2.95: Preparation of {(3aS,6aS)-6-[4-(2-Pyrrolidin-1-yl-ethyl)-phenyl]-3,3a,4,6a tetrahydro-1H-cyclopenta[c]pyrrol-2-yl}-thiophen-2-yl-methanone. - 175 - WO 2007/061741 PCT/US2006/044479 ~N H NN H / 3 The title compound was obtained using general method C. MS m/z 393, (M+H); 1H NMR (400 MHz, CD 3 OD) 8 1.95-2.07 (m, 2H), 2.10-2.22 (m, 2H), 2.39-2.47 (m, 1H), 2.77 2.88 (m, 1H), 3.00-3.18 (m, 5H), 3.40-3.80 (mn, 6H), 3.86-4.25 (mn, 3H), 6.11-6.14 (m, 1H), 7.00 5 7.17 (m, 1H), 7.26-7.34 (m, 2H), 7.37-7.47 (m, 2H), 7.53-7.67 (m, 2H). Example 2.96: Preparation of Furan-2-yl-{(3aS,6aS)-6-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl] 3,3a,4,6a-tetrahydro-1H-cyclopenta[c]pyrrol-2-yl}-methanone. N H H NQJ 10 The title compound was obtained using general method C. MS nm/z 377, (M+H); 'H NMR (400 MHz, CD 3 OD) 8 1.95-2.07 (m, 2H), 2.10-2.22 (m, 2H), 2.39-2.47 (m, 1H), 2.79 2.87 (m, 1H), 3.01-3.18 (m, 5H), 3.23-3.32 (m, 1H), 3.41-3.49 (m, 2H), 3.61-3.72 (m, 3H), 3.81 4.04 (m, 2H), 4.17-4.28 (m, 1H), 6.10-6.13 (m, 1H), 6.50-6.61 (m, 1H), 6.99-7.11 (m, 1H), 7.27 7.33 (m, 2H), 7.38-7.45 (m, 2H), 7.59-7.72 (m, 1H). 15 Example 2.97: Preparation of Pyridin-4-yl-{(3aS,6aS)-6-[4-(2-pyrrolidin-1-yl-ethyl) phenyl]-3,3a,4,6a-tetrahydro-1H-cyclopenta[c]pyrrol-2-yl}-methanone. N N H H NO The title compound was obtained using general method C. MS m/z 388, (M+H); 1H 20 NMR (400 MHz, CD 3 OD) 8 1.97-2.09 (m, 2H), 2.10-2.22 (m, 2H), 2.28-2.52 (m, 1H), 2.74 2.92 (m, 1H), 2.99-3.29 (m, 6H), 3.38-3.50 (m, 2H), 3.52-3.73 (m, 3H), 3.75-3.88 (m, 1H), 3.90 4.11 (m, 2H), 6.12-6.18 (m, 1H), 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-1-yl-ethyl) -176- WO 2007/061741 PCT/US2006/044479 ' e] 4-tetra yro-l-cyclopenta[c]pyrrol-2-yl}-methanone. 0
N
N H HW C The title compound was obtained using general method C. MS nm/z 396, (M+H); 1H NMR (400 MHz, CD 3 OD) 8 1.97-2.08 (m, 2H), 2.12-2.22 (m, 2H), 2.33-2.41 (m, 1H), 2.74 5 2.83 (m, 1H), 3.01-3.08 (m, 3H), 3.09-3.30 (m, 8H), 3.42-3.83 (m, 11H), 6.07-6.10 (m, 1H), 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-1-yl-ethyl) phenyl]-3,3a,4,6a-tetrahydro-1H-cyclopenta[c]pyrrol-2-yl}-methanone. N H 10 H N The title compound was obtained using general method C. MS m/z 388, (M+H); H NMR (400 MHIz, CD 3 OD) 5 1.96-2.10 (m, 2H), 2.11-2.22 (m, 2H), 2.31-2.52 (m, 1H), 2.74 2.92 (m, 1H), 2.99-3.26 (mn, 5H), 3.35-3.59 (m, 3H), 3.62-3.73 (m, 3H), 3.84-4.01 (m, 2H), 4.03 4.13 (mn, 1H), 6.12-6.18 (m, 1H), 7.22-7.47 (m, 4H), 8.03-8.20 (m, 1H), 8.59-8.79 (m, 1H), 8.86 15 9.10 (m, 2H). Example 2.100: Preparation of Pyridin-2-yl-{(3aS,6aS)-6-[4-(2-pyrrolidin-1-yl-ethyl) phenyl]-3,3a,4,6a-tetrahydro-H-cyclopenta[c]pyrrol-2-yl}-methanone. -N 0 N H H 20 The title compound was obtained using general method C. MS m/z 388, (M+H11); 1H NMR (400 MHz, CD 3 OD) 6 1.97-2.08 (m, 2H), 2.11-2.22 (m, 2H), 2.33-2.52 (m, 1H), 2.75 2.92 (m, 1H), 2.98-3.25 (m, 511), 3.37-3.60 (m, 3H), 3.63-3.72 (m, 3H), 3.93-4.15 (m, 3H), 6.12 6.17 (m, 1H), 7.22-7.47 (m, 4H), 7.89-8.21 (m, 2H), 8.36-8.56 (m, 1H), 8.73-8.86 (m, 1H). -177- WO 2007/061741 PCT/US2006/044479 S x i , Preparation o Cyclohexyl-{(3aS,6aS)-6-[4-(2-pyrrolidin-1-yl-ethyl) phenyl]-3,3a,4,6a-tetrahydro-1H-cyclopenta[]cpyrrol-2-yl}-methanone. 0 0 N H ___ H / The title compound was obtained using general method C. MS nm/z 393, (M+H); 'H 5 NMR (400 MHz, CD 3 OD) 8 1.06-1.45 (m, 5H), 1.57-1.81 (m, 5H), 1.96-2.08 (m, 2H), 2.10 2.22 (in, 2H), 2.25-2.53 (m, 2H), 2.76-2.85 (mn, 1H), 3.01-3.28 (m, 6H), 3.41-3.55 (m, 3H), 3.61 3.96 (m, 5H), 6.07-6.12 (m, 1H), 7.27-7.34 (mn, 2H), 7.36-7.43 (m, 2H). Example 2.102: Preparation of {(3aS,6aS)-6-[4-(2-Pyrrolidin-1-yl-ethyl)-phenyl]-3,3a,4,6a 10 tetrahydro-1H-cyclopenta[c]pyrrol-2-yl}-(tetrahydro-furan-3-yl)-methanone. N H H NCj A mixture of tetrahydrofuran-3-carboxylic acid (64.3 p1, 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-1 -yl-ethyl)-phenyl]-1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole 15 (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 HC1 to afford the hydrochloride salt of the title compound (54.2 mg). MS nm/z 381, (M+H); 1H NMR (400 MHz, CD 3 OD) 6 1.95-2.22 (m, 6H), 2.34-2.44 (m, 1H), 2.77-2.86 (m, 1H), 3.02-3.24 (m, 6H), 3.24-3.60 (m, 4H), 3.62-3.99 (m, 9H), 20 6.08-6.13 (m, 1H), 7.27-7.34 (m, 2H), 7.37-7.44 (m, 2H). Example 2.103: Preparation of Phenyl-{(3aS,6aS)-6-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl] 3,3a,4,6a-tetrahydro-H-cyclopenta[c]pyrrol-2-yl}-methanone.
°
0 N H H - 178 - WO 2007/061741 PCT/US2006/044479 C "' .. A ft ii ooenzoi6 aci a(89.6 mg, 0.7337 mmol) and PS-Carbodiimide (702.2 mg, 0.702 mmol) in DCM (7.0 mL) was stirred for 10 min and added (3aS,6aS)-6-[4-(2-Pyrrolidin 1-yl-ethyl)-phenyl]-1,2,3,3a,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 5 MeOH. The solution was concentrated. The residue was purified by preparative HPLC, lyophilized, and treated with HC1 to afford the hydrochloride salt of the title compound (69.3 mg). MS m/z 387, (M+H); 'H NMR (400 MHz, CD 3 OD) 5 1.95-2.08 (min, 2H), 2.10-2.21 (inm, 2H), 2.24-2.49 (min, 1H), 2.70-2.91 (min, 1H), 2.99-3.21 (min, 5H), 3.36-3.50 (min, 3H), 3.56-3.72 (inm, 3H), 3.75-4.03 (min, 3H), 6.10-6.15 (min, 1H), 7.20-7.49 (min, 9H). 10 Example 2.104: Preparation of 2-Phenyl-l-{(3aS,6aS)-6-[4-(2-pyrrolidin-1-yl-ethyl) phenyl]-3,3a,4,6a-tetrahydro-1H-cyclopenta[c]pyrrol-2-yl}-ethanone. 0 N H H NC] A mixture of 2-phenylacetic acid (94.4 mg, 0.6934 mmol) and PS-Carbodiimide (717.0 15 mg, 0.717 mmol) in DCM (7.0 mL) was stirred for 10 min and added (3aS,6aS)-6-[4-(2 Pyrrolidin-1-yl-ethyl)-phenyl]-1,2,3,3a,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 HCI to afford the hydrochloride salt of the title compound (60.6 20 mg). MS nm/z 401, (M+H); 1H NMR (400 MHz, CD 3 OD) 6 1.96-2.08 (min, 2H), 2.11-2.21 (inm, 2H), 2.22-2.40 (min, 1H), 2.71-2.84 (min, 1H), 3.02-3.18 (min, 5H), 3.42-3.91 (mn, 11H), 6.03-6.08 (min, 1H), 7.05-7.40 (min, 9H). Example 2.105: Preparation of (3aS,6aS)-2-(Propane-2-sulfonyl)-6-[4-(2-pyrrolidin-l-yl 25 ethyl)-phenyl]-1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole. Os N H H NO To a solution of (3aS,6aS)-6-[4-(2-Pyrrolidin-1-yl-ethyl)-phenyl]-1,2,3,3a,4,6a hexahydro-cyclopenta[c]pyrrole (202 mg, 0.715 mmol) in DCM (10.0 mL) was added -179- WO 2007/061741 PCT/US2006/044479 yiamine (0.196 l, 1.41 nnol) followed by 2 -propanesulfonyl chloride (0.159 ml, 1.42 mmol). The resulting reaction mixture was stirred at 25 oC for 3.0 h. Upon completion, the reaction mixture was concentrated. The residue was purified by preparative HPLC, lyophilized, and treated with HC1 to afford the hydrochloride salt of the title compound (86.3 mg). MS m/z 5 389, (M+H); 'H NMR (400 MHz, CD 3 OD) 1.24 (d, J= 6.8 Hz, 3H), 1.25 (d, J= 6.8 Hz, 3H), 1.96-2.09 (min, 2H), 2.09-2.21 (min, 2H), 2.34-2.42 (min, 1H), 2.77-2.87 (min, 1H), 3.03-3.28 (min, 8H), 3.41-3.47 (min, 2H), 3.59-3.71 (min, 4H), 3.84-3.91 (min, 1H11), 6.11-6.15 (min, 1H), 7.30 (d, J= 8.2 Hz, 2H), 7.40 (d, J = 8.2 Hz, 2H11). 10 Example 2.106: Preparation of (3aS,6aS)-2-Benzenesulfonyl-6-[4-(2-pyrrolidin-1-yl-ethyl) phenyl]-1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole. 0o OsS N H H / J To a solution of (3aS,6aS)-6-[4-(2-Pyrrolidin-1-yl-ethyl)-phenyl]-1,2,3,3a,4,6a hexahydro-cyclopenta[c]pyrrole (101.4 mg, 0.359 mmol) in DCM (5.0 mL) was added 15 triethylamine (98.2 pl, 0.7045 mmol) followed by benzenesulfonyl chloride (67.8 1 l, 0.5313 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, lyophilized, and treated with HC1 to afford the hydrochloride salt of the title compound (60.5 mg). MS m/z 423, (M+H); 1H NMR (400 MHz, CD 3 OD) 6 1.96-2.08 (min, 2H), 2.11-2.22 (min, 2H11), 2.25-2.33 20 (min, 1H), 2.73-2.82 (min, 1H), 2.94-3.08 (min, 5H), 3.10-3.18 (min, 2H), 3.25-3.35 (m, 2H), 3.42-3.49 (min, 2H), 3.64-3.71 (min, 2H), 3.73-3.80 (min, 1H11), 6.03-6.07 (min, 1H), 7.27 (d, J= 8.3 Hz, 2H), 7.34 (d, J = 8.3 Hz, 2H11), 7.54-7.59 (min, 2H), 7.63-7.68 (min, 1H11), 7.71-7.75 (min, 2H). Example 2.107: Preparation of (3aS,6aS)-2-Phenylmethanesulfonyl-6-[4-(2-pyrrolidin-l-yl 25 ethyl)-phenyl]-1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole. -18O N H H -180- WO 2007/061741 PCT/US2006/044479 i;::::[;: " i" 1..,1 , i ° [j I 3ll" )-6-[4-(2-Pyrrolidin-1-yl-ethyl)-phenyl]-1,2,3,3a,4,6a hexahydro-cyclopenta[c]pyrrole (99.4 mg, 0.352 mmol) in DCM (5.0 mL) was added triethylamine (98.2 pl, 0.7045 mmol) followed by phenylmethanesulfonyl chloride (107.9 mg, 0.5660 mmol). The resulting reaction mixture was stirred at 25 oC for 16.5 h. Upon 5 completion, the reaction mixture was concentrated. The residue was purified by preparative HPLC, lyophilized, and treated with HC1 to afford the hydrochloride salt of the title compound (64.1 mg). MS m/z 437, (M+H); 'H NMR (400 MHz, CD 3 OD) 6 1.98-2.05 (min, 2H), 2.13-2.20 (min, 2H), 2.26-2.35 (min, 1H), 2.72-2.82 (min, 1H), 2.97-3.18 (min, 7H), 3.42-3.54 (min, 4H), 3.63-3.71 (min, 2H), 3.78-3.85 (min, 1H11), 4.295 (d, J = 2.8 Hz, 2H), 6.10-6.14 (min, 1H), 7.27-7.39 (min, 9H). 10 Example 2.108: Preparation of Pyrazin-2-yl-{(3aS,6aS)-6-[4-(2-pyrrolidin-1-yl-ethyl) phenyl]-3,3a,4,6a-tetrahydro-1H-cyclopenta[c]pyrrol-2-yl}-methanone. N 0 N N H H NGI A mixture of 2-pyrazinecarboxylic acid (89.2 mg, 0.7188 mmol) and PS-Carbodiimide 15 (707.7 mg, 0.708 mmol) in DCM (7.0 mL) was stirred for 10 min and added (3aS,6aS)-6-[4-(2 Pyrrolidin-1-yl-ethyl)-phenyl]-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 'C. After 73.5 h at 30 oC, the resin was filtered and washed with CH2C1 2 and MeOH. The solution was concentrated. The residue was purified by preparative HPLC, 20 lyophilized, and treated with HC1 to afford the hydrochloride salt of the title compound (13.3 mg). MS nm/z 389, (M+H); '1H NMR (400 MHz, CD 3 OD) 5 1.97-2.08 (min, 2H), 2.10-2.22 (inm, 2H), 2.32-2.50 (min, 1H), 2.74-2.90 (min, 1H), 2.99-3.24 (min, 5H), 3.39-3.61 (min, 3H), 3.63-3.72 (inm, 3H), 3.88-3.96 (min, 1H), 3.99-4.12 (min, 2H), 6.10-6.14 (mn, 1H11), 7.22-7.47 (min, 4H), 8.50-8.72 (in, 2H), 8.82-8.95 (min, 1H). 25 Example 2.109: Preparation of Isoxazol-5-yl-{(3aS,6aS)-6-[4-(2-pyrrolidin-1-yl-ethyl) phenyl]-3,3a,4,6a-tetrahydro-lH-cyclopenta c]pyrrol-2-yl}-methanone.
N-
0 O N H NC - 181 - WO 2007/061741 PCT/US2006/044479 S e 16"a &ompoun obtained using general method C. MS nm/z 378, (M+H); 1H NMR (400 MHz, CD 3 OD) 6 1.95-2.07 (min, 2H), 2.10-2.21 (min, 2H), 2.38-2.48 (min, 1H), 2.78 2.89 (min, 1H), 3.00-3.32 (min, 5H), 3.40-3.50 (mn, 2H), 3.56-3.71 (mn, 3H), 3.79-4.05 (mn, 3H), 4.13 4.23 (min, 1H), 6.11-6.14 (min, 1H), 6.81-6.91 (mn, 1H), 7.26-7.33 (min, 2H), 7.37-7.45 (mn, 2H), 8.41 5 8.51 (min, 1H). Example 2.110: Preparation of 2-Pyridin-3-yl-1-{(3aS,6aS)-6-[4-(2-pyrrolidin-1-yl-ethyl) phenyl]-3,3a,4,6a-tetrahydro-lH-cyclopenta[c]pyrrol-2-yl}-ethanone. 0 N H N H / NO] 10 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-1-yl-ethyl)-phenyl]-1,2,3,3a,4,6a hexahydro-cyclopenta[c]pyrrole (99.8 mg, 0.353 mmol) dissolved in DCM (3.0 mL) was added. 15 After 19 h, the resin was filtered and washed with DCM and MeOH. The solution was concentrated. The residue was purified by preparative IHIPLC, lyophilized, and treated with HC1 to afford the hydrochloride salt of the title compound (64.9 mg). MS m/z 402, (M+H); 1H NMR (400 MHz, CD 3 OD) 6 1.97-2.09 (min, 2H), 2.11-2.21 (min, 2H), 2.36-2.51 (min, 1H), 2.79-2.90 (inm, 1H), 3.00-3.19 (min, 5H), 3.41-3.53 (min, 3H), 3.58-3.73 (mn, 3H), 3.76-3.93 (mn, 2H), 3.97-4.11 (inm, 20 3H), 6.12-6.15 (min, 1H), 7.27-7.35 (mn, 2H), 7.38-7.46 (min, 2H), 7.99-8.07 (mn, 1H), 8.44-8.54 (inm, 1H), 8.72-8.78 (min, 2H). Example 2.111: Preparation of (3aS,6aS)-2-Ethanesulfonyl-6-[4-(2-pyrrolidin-1-yl-ethyl) phenyl]-1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole. o0 N H H / NO 25 To a solution of (3aS,6aS)-6-[4-(2-Pyrrolidin-1-yl-ethyl)-phenyl]-1,2,3,3a,4,6a hexahydro-cyclopenta[c]pyrrole (99.8 mg, 0.353 mmol) in DCM (5.0 mL) was added triethylamine (98.2 gl, 0.705 mmol) followed by ethanesulfonyl chloride (50.3 p1, 0.531 mmol). The resulting reaction mixture was stirred at 25 'C for 1.5 h. Upon completion, the reaction -182- WO 2007/061741 PCT/US2006/044479 "c mei idenda ereue was purified by preparative HPLC, lyophilized, 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, CD 3 OD) 3 1.25 (t, J = 7.4 Hz, 3H), 1.96-2.07 (min, 2H), 2.12-2.22 (min, 2H), 2.36-2.43 (min, 1H), 2.79-2.88 (in, 1H), 2.96-3.08 (min, 4H), 3.09-3.19 (min, 511), 3.42-3.49 5 (min, 2H11), 3.56-3.70 (min, 4H), 3.87-3.94 (min, 1H11), 6.14-6.16 (min, 1H), 7.295 (d, J= 8.3 Hz, 2H11), 7.41 (d, J= 8.2 Hz, 2H). Example 2.112: Preparation of 2-Pyridin-2-yl-1-{(3aS,6aS)-6-[4-(2-pyrrolidin-1-yl-ethyl) phenyl]-3,3a,4,6a-tetrahydro-1IH-cyclopenta[c]pyrrol-2-yl}-ethanone. O N \N H H G 10 H N 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-1-yl-ethyl)-phenyl]-1,2,3,3a,4,6a 15 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 IPLC, lyophilized, and treated with HC1 to afford the hydrochloride salt of the title compound (58.8 mg). MS m/z 402, (M+H); 1H NMR (400 MHz, CD 3 OD) 8 1.97-2.09 (min, 2H), 2.10-2.22 (min, 2H11), 2.37-2.52 (min, 1H), 2.79-2.91 (inm, 20 1H1), 3.02-3.30 (min, 5H), 3.40-3.95 (min, 7H11), 4.01-4.15 (mn, 2H), 4.22-4.34 (mn, 2H11), 6.13-6.17 (inm, 1H), 7.30 (d, J= 8.0 Hz, 1H), 7.34 (d, J= 7.8 Hz, 1H), 7.40 (d, J= 8.1 Hz, 1H), 7.45 (d, J= 8.4 Hz, 1H), 7.90-8.01 (min, 211), 8.52-8.59 (min, 1H), 8.77-8.81 (in, 1H). Example 2.113: Preparation of 2-Pyridin-4-yl-1-{(3aS,6aS)-6-[4-(2-pyrrolidin-1-yl-ethyl) 25 phenyl]-3,3a,4,6a-tetrahydro-H-cyclopenta[e]pyrrol-2-yl}-ethanone. 0 N HN 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 - 183 - WO 2007/061741 PCT/US2006/044479 "Por 6d' " 1 '',S-6-[4-(2-Pyrrolidin-1-yl-ethyl)-phenyl]-1,2,3,3a,4,6a hexahydro-cyclopenta[c]pyrrole (101.0 mg, 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 HPLC, lyophilized, and treated with HC1 5 to afford the hydrochloride salt of the title compound (37.4 mg). MS m/z 402, (M+H); 'H NMR (400 MHz, CD 3 OD) 8 1.97-2.22 (min, 4H), 2.35-2.50 (min, 1H), 2.77-2.88 (min, 1H), 3.04-3.30 (inm, 5H), 3.40-3.61 (min, 4H), 3.64-3.74 (m, 2H), 3.76-3.92 (min, 2H), 3.95-4.20 (min, 3H), 6.10-6.14 (inm, 1H), 7.30 (d, J= 8.0 Hz, 1H11), 7.32 (d, J = 7.0 Hz, 1H), 7.39 (d, J= 8.1 Hz, 2H11), 7.92 (d, J= 6.4 Hz, 1H), 7.99 (d, J= 6.5 Hz, 1H), 8.715 (d, J = 6.5 Hz, 1H11), 8.775 (d, J = 6.5 Hz, 1H). 10 Example 2.114: Preparation of (3aS,6aS)-2-Cyclopropanesulfonyl-6-[4-(2-pyrrolidin-1-yl ethyl)-phenyl]-1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole. 0sSO N H NC H / To a solution of (3aS,6aS)-6-[4-(2-Pyrrolidin-1-yl-ethyl)-phenyl]-1,2,3,3a,4,6a 15 hexahydro-cyclopenta[c]pyrrole (99.3 mg, 0.352 mmol) in DCM (5.0 mL) was added triethylamine (98.2 il, 0.705 mmol) followed by cyclopropanesulfonyl chloride (54.1 1gl, 0.531 mmol). The resulting reaction mixture was stirred at 25 oC for 1.5 h. Upon completion, the reaction mixture was concentrated. The residue was purified by preparative HPLC, lyophilized, and treated with HC1 to afford the hydrochloride salt of the title compound (67.5 mg). MS mn/z 20 387, (M+H); 'H NMR (400 MHz, CD 3 OD) 6 0.89-1.03 (m, 4H), 1.97-2.07 (min, 2H), 2.12-2.21 (m, 2H), 2.36-2.49 (min, 2H), 2.80-2.89 (m, 1H), 3.02-3.20 (min, 7H), 3.42-3.50 (m, 2H), 3.59-3.70 (min, 4H11), 3.88-3.95 (min, 1H), 6.14-6.18 (min, 1H), 7.30 (d, J= 8.2 Hz, 2H), 7.42 (d, J= 8.2 Hz, 2H). 25 Example 2.115: Preparation of 2-Methyl-l-((3aS,6aS)-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. N H H N -184- WO 2007/061741 PCT/US2006/044479 i:::R I, " ,ijrbopu obtai ned using general method C using (3aS,6aS)-6-(4-(2-((R) 2-methylpyrrolidin-1 -yl)ethyl)phenyl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole. MS mn/z 367, (M+H); 'H NMR (400 MHz, CD 3 OD) 5 0.85-1.11 (in, 6H), 1.48 (d, J= 6.4 Hz, 3H), 1.70 1.82 (m, 1H), 2.00-2.19 (m, 2H), 2.29-2.44 (m, 2H), 2.57-2.86 (min, 2H), 3.02-3.38 (mn, 6H), 3.44 5 3.64 (min, 3H), 3.71-3.98 (m, 4H), 6.09-6.12 (min, 1H), 7.29-7.36 (min, 2H), 7.37-7.43 (mn, 2H). Example 2.116: Preparation of Cyclopropyl-((3aS,6aS)-6-{4-[2-((R)-2-methyl-pyrrolidin-1 yl)-ethyl]-phenyl}-3,3a,4,6a-tetrahydro-1H-cyclopenta[c]pyrrol-2-yl)-methanone. N H H / NO] 10 The title compound was obtained using general method C using (3aS,6aS)-6-(4-(2-((R) 2-methylpyrrolidin-1 -yl)ethyl)phenyl)-1 ,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole. MS mn/z 365, (M+H); 1H NMR (400 MHz, CD 3 OD) 8 0.65-0.90 (min, 4H), 1.475 (d, J= 6.5 Hz, 3H), 1.61-1.87 (min, 2H), 2.01-2.18 (mn, 2H), 2.28-2.47 (min, 2H), 2.76-2.86 (min, 1H), 3.02-3.30 (min, 5H), 3.44-4.12 (min, 8H), 6.09-6.12 (min, 1H), 7.29-7.45 (mn, 4H). 15 Example 2.117: Preparation of (3aS,6aS)-2-Cyclopropanesulfonyl-6-{4-[2-((R)-2-methyl pyrrolidin-1-yl)-ethyl]-phenyl}-1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole. 0 1/40 N H _ HW To a solution of (3aS,6aS)-6-(4-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)phenyl) 20 1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole (98.9 mg, 0.334 mmol) in DCM (5.0 mL) was added triethylamine (93.5 pl, 0.671 mmol) followed by cyclopropanesulfonyl chloride (51.5 l1, 0.506 mmol). The resulting reaction mixture was stirred at 25 oC 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 nm/z 401, 25 (M+H); 'H NMR (400 MHz, CD 3 OD) 5 0.90-1.03 (mn, 4H), 1.45 (d, J = 6.6 Hz, 3H), 1.68-1.80 (min, 1H), 2.00-2.18 (min, 2H), 2.29-2.49 (min, 3H), 2.81-2.89 (min, 1H), 2.96-3.29 (in, 7H), 3.46-3.77 (m, 5H), 3.88-3.95 (min, 1H), 6.14-6.18 (min, 1H), 7.30 (d, J = 8.2 Hz, 2H), 7.42 (d, J = 8.2 Hz, 2H). - 185 - WO 2007/061741 PCT/US2006/044479 . 8: Prepar (3aS,6aS)-6- {4-[2-((R)-2-Methyl-pyrrolidin-1-yl)-ethyl] phenyl}-2-(propane-2-sulfonyl)-1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole. )0 N H H NO To a solution of (3aS,6aS)-6-(4-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)phenyl) 5 1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole (100.6 mg, 0.339 mmol) in DCM (5.0 ml) was added triethylamine (93.5 1l, 0.671 mmol) followed by 2-propanesulfonyl chloride (56.8 g1, 0.506 mmol). The resulting reaction mixture was stirred at 25 oC 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 nm/z 403, 10 (M+H); 1H NMR (400 MHz, CH 3 OD) 8 1.23 (d, J= 4.1 Hz, 3H), 1.25 (d, J = 4.1 Hz, 3H), 1.45 (d, J= 6.5 Hz, 3H11), 1.68-1.79 (m, 1H), 2.00-2.15 (m, 2H), 2.28-2.42 (m, 2H), 2.78-2.87 (m, 1H), 2.95-3.28 (m, 8H11), 3.46-3.77 (m, 5H), 3.85-3.92 (m, 1H), 6.11-6.15 (m, 1H), 7.30 (d, J 8.3 Hz, 2H), 7.40 (d, J = 8.3 Hz, 2H11). 15 Example 2.119: Preparation of ((3aS,6aS)-6-{4-[2-((R)-2-Methyl-pyrrolidin-1-yl)-ethyl] phenyl}-3,3a,4,6a-tetrahydro-1H-cyclopenta[e]pyrrol-2-yl)-pyridin-3-yl-methanone. N N < H HH The title compound was obtained using general method C using (3aS,6aS)-6-(4-(2-((R) 2-methylpyrrolidin-1 -yl)ethyl)phenyl)-1 ,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole. MS m/z 20 402, (M+H); 1 H NMR (400 MHz, CD 3 OD) 8 1.45-1.50 (m, 3H11), 1.70-1.82 (m, 1H), 2.01-2.22 (m, 2H), 2.30-2.52 (m, 2H), 2.73-2.92 (m, 1H), 3.00-3.15 (m, 2H11), 3.16-3.42 (m, 3H11), 3.46-3.79 (m, 5H), 3.86-4.13 (m, 3H11), 6.12-6.18 (m, 1H), 7.23-7.48 (m, 4H), 8.07-8.22 (m, 1H), 8.62-8.81 (m, 1H), 8.88-9.11 (m, 2H). 25 Example 2.120: Preparation of Cyclopentyl-((3aS,6aS)-6-{4-[2-((R)-2-methyl-pyrrolidin-1 yl)-ethyl]-phenyl}-3,3a,4,6a-tetrahydro-1H-cyclopenta[c]pyrrol-2-yl)-methanone. - 186- WO 2007/061741 PCT/US2006/044479 N H H /tNG: The title compound was obtained using general method C using (3aS,6aS)-6-(4-(2-((R) 2-methylpyrrolidin-1-yl)ethyl)phenyl)-1 ,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole. MS mn/z 393, (M+H); 1H NMR (400 MHz, CD 3 OD) 5 1.44-1.92 (min, 13H), 2.00-2.43 (min, 4H11), 2.69-2.97 5 (in, 2H11), 3.01-3.38 (m, 5H11), 3.44-3.63 (min, 3H), 3.69-3.97 (m, 4H), 6.08-6.11 (bs, 1H11), 7.28-7.41 (min, 4H). Example 2.121: Preparation of ((3aS,6aS)-6-{4-[2-((R)-2-Methyl-pyrrolidin-1-yl)-ethyl] phenyl}-3,3a,4,6a-tetrahydro-1H-cyclopenta[cl]pyrrol-2-yl)-(tetrahydro-furan-3-yl) 10 methanone. N H H NC] A mixture of tetrahydrofuran-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-1-yl)ethyl)phenyl)-1,2,3,3a,4,6a 15 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 THPLC fractions were lyophilized to give the title compound as a TFA salt. MS m/z 395, (M+H); 1H NMR (400 MHz, CH 3 OD) a 1.44-1.48 (m, 3H), 1.68-1.79 (mn, 1H), 1.96-2.23 (in, 4H), 2.29-2.44 (in, 2H), 2.77-2.86 (mn, 1H), 2.96-3.15 20 (mn, 3H), 3.18-3.39 (min, 3H), 3.44-3.99 (m, 12H), 6.09-6.13 (mn, 1H), 7.28-7.35 (mn, 2H), 7.38 7.44 (m, 2H). Example 2.122: Preparation of 1-((3aS,6aS)-6-{4-[2-((R)-2-Methyl-pyrrolidin-1-yl)-ethyl] phenyl}-3,3a,4,6a-tetrahydro-1H-cyclopenta[c]lpyrrol-2-yl)-2-phenyl-ethanone. 0 N H H NJ 25 -187- WO 2007/061741 PCT/US2006/044479 : 1 A 'e '/' Iltl o 2-p i yla c etic 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)-1,2,3,3a,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 5 DCM and MeOH. The solution was concentrated. The residue was purified by preparative HIPLC, lyophilized, and treated with HC1 to afford the hydrochloride salt of the title compound (70.5 mg). MS nm/z 415, (M+H); H NMR (400 MHz, CD 3 OD) 6 1.44-1.49 (min, 3H), 1.70-1.81 (min, 1H), 2.00-2.17 (min, 2H), 2.22-2.40 (min, 2H), 2.70-2.84 (min, 1H), 3.01-3.35 (mn, 6H), 3.47-3.63 (min, 4H), 3.69-3.93 (min, 5H), 6.03-6.08 (min, 1H), 7.04-7.40 (min, 9H). 10 Example 2.123: Preparation of ((3aR,4R,6aS)-4-{4-[2-((R)-2-Methyl-pyrrolidin-1-yl) ethyl]-phenyl}-hexahydro-cyclopenta[c]pyrrol-2-yl)-(tetrahydro-furan-3-yl)-methanone. N H HH A mixture of tetrahydrofuran-3-carboxylic acid (0.122 ml, 1.28 mmol) and PS 15 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-1-yl)ethyl)phenyl) octahydrocyclopenta[c]pyrrole (204.4 mg, 0.685 mmol) dissolved in DCM (5.0 mniL). 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 HC1 to afford the 20 hydrochloride salt of the title compound (127.6 mg). MS m/z 397, (M+H); 'H NMR (400 MHz,
CD
3 OD) 5 1.44-1.48 (min, 3H), 1.64-1.80 (min, 2H), 1.90-2.22 (min, 8H), 2.29-2.40 (min, 1H), 2.88 4.01 (min, 18H), 7.25-7.30 (min, 4H). Example 2.124: Preparation of ((3aS,6aS)-6-{4-[2-((R)-2-Methyl-pyrrolidin-1-yl)-ethyl] 25 phenyl}-3,3a,4,6a-tetrahydro-1H-cyclopentalclpyrrol-2-yl)-phenyl-methanone. N H H 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-1-yl)ethyl)phenyl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole (201.7 mg, - 188 - WO 2007/061741 PCT/US2006/044479 P 8 ::: ~ tW'.N'iW 3.0 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 HC1 to afford the hydrochloride salt of the title compound (144 mg). MS m/z 401, (M+H); 1H NMR (400 MHz, 5 CD 3 OD) 8 1.43-1.49 (min, 3H), 1.69-1.81 (mn, 1H), 2.00-2.18 (m, 2H11), 2.24-2.50 (min, 2H11), 2.71 2.92 (min, 1H), 2.95-3.42 (min, 6H), 3.46-4.03 (mn, 7H), 6.10-6.15 (mn, 1H), 7.22-7.49 (mn, 9H11). Example 2.125: Preparation of ((3aS,6aS)-6-{4-[2-((R)-2-Methyl-pyrrolidin-l-yl)-ethyll] phenyl}-3,3a,4,6a-tetrahydro-1H-cyclopenta[clpyrrol-2-yl)-(tetrahydro-pyran- 4 -yl) 10 methanone. N H H N J The title compound was obtained using general method C using (3aS,6aS)-6-(4-(2-((R) 2-methylpyrrolidin-1-yl)ethyl)phenyl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole. MS min/z 409, (M+H); 1 H NMR (400 MHz, CD 3 OD) 8 1.45-1.49 (min, 3H), 1.52-1.81 (m, 5H), 2.00-2.20 15 (min, 2H11), 2.28-2.44 (min, 2H), 2.56-2.87 (m, 2H), 2.98-3.29 (m, 6H11), 3.30-3.64 (min, 511), 3.70-3.86 (m,-3H11), 3.88-4.00 (min, 3H), 6.08-6.12 (m, 1H), 7.29-7.35 (mn, 2H), 7.37-7.43 (mn, 2H). Example 2.126: Preparation of Cyclohexyl-((3aR,4R,6aS)-4-{4-[2-((R)-2-methyl pyrrolidin-1-yl)-ethyll-phenyl}-hexahydro-cyclopenta[clpyrrol-2-yl)-methanone. H H .0 N 20 The title compound was obtained using general method C starting from (3aR,4R,6aS)-4 (4-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)phenyl)-octahydrocyclopenta[c]pyrrole. MS mn/z 409, (M+H); 11H NMR (400 MHz, CD 3 OD) 8 1.09-1.50 (min, 8H11), 1.52-1.84 (min, 7H), 1.89-2.24 (m, 5H11), 2.27-2.40 (min, 1H11), 2.43-2.53 (min, 1H11), 2.86-3.84 (min, 14H), 7.22-7.32 (m, 4H). 25 Example 2.127: Preparation of 3-Methyl-1-((3aR,4R,6aS)-4-{4-[2-((R)-2-methyl pyrrolidin-1-yl)-ethyl]-phenyl}-hexahydro-cyclopenta[c]pyrrol-2-yl)-butan-l-one. -189- WO 2007/061741 PCT/US2006/044479 N H H C/ N The title compound was obtained using general method C starting from (3aR,4R,6aS)-4 (4-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)phenyl)-octahydrocyclopenta[c]pyrrole. MS nm/z 383, (M+H); 11H NMR (400 MHz, CD 3 OD) 8 0.85-1.03 (m, 6H), 1.48 (d, J = 6.2 Hz, 3H), 1.64-1.83 5 (m, 2H), 1.90-2.39 (m, 9H), 2.90-3.62 (m, 12H), 3.69-3.80 (m, 1H), 3.82-3.90 (m, 1H), 7.24 7.33 (m, 4H). Example 2.128: Preparation of 1-((3aR,4R,6aS)-4-{4-[2-((R)-2-Methyl-pyrrolidin-1-yl) ethyl]-phenyl}-hexahydro-cyclopenta[cl]pyrrol-2-yl)-2-thiophen-2-yl-ethanone. 0 10 H .I NC] The title compound was obtained using general method C starting from (3aR,4R,6aS)-4 (4-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)phenyl)-octahydrocyclopenta[c]pyrrole. MS nm/z 423, (M+H); 'H NMR (400 MHz, CD 3 OD) 8 1.44-1.49 (m, 3H), 1.52-1.66 (m, 1H), 1.69-2.26 (m, 6H), 2.28-2.39 (m, 1H), 2.58-4.02 (m, 16H), 6.75-7.01 (m, 2H), 7.09-7.34 (m, 5H). 15 Example 2.129: Preparation of 2,2-Dimethyl-1-((3aR,4R,6aS)-4-{4-[2-((R)-2-methyl pyrrolidin-1-yl)-ethyl]-phenyl}-hexahydro-cyclopenta[c]pyrrol-2-yl)-propan-1-one. N H The title compound was obtained using general method C starting from (3aR,4R,6aS)-4 20 (4-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)phenyl)-octahydrocyclopenta[c]pyrrole. MS im/z 383, (M+H); '1H NMR (400 MHz, CD 3 OD) 8 1.12-1.26 (m, 9H11), 1.46 (d, J = 6.5 Hz, 3H), 1.62-1.83 (m, 2H11), 1.88-2.24 (m, 5H), 2.29-2.39 (m, 1H11), 2.83-3.14 (m, 5H), 3.16-3.42 (m, 4H11), 3.45-3.83 (m, 5H), 7.27 (bs, 4H11). - 190- WO 2007/061741 PCT/US2006/044479 CT r~a . xal '1 r bf 1-((3aR,4R,6aS)-4-{4-[2-((R)-2-Methyl-pyrrolidin-1-yl) ethyl]-phenyl}-hexahydro-eyclopenta[c]pyrrol-2-yl)-ethanone. N H The title compound was obtained using general method C starting from (3aR,4R,6aS)-4 5 (4-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)phenyl)-octahydrocyclopenta[c]pyrrole. MS nm/z 341, (M+H); 'H NMR (400 MHz, CD 3 OD) 8 1.47 (dd, J= 6.5, 1.8 Hz, 3H), 1.66-1.81 (min, 2H), 1.96-2.27 (min, 8H), 2.29-2.39 (min, 1H), 2.92-3.14 (min, 4H), 3.15-3.30 (min, 3H), 3.34-3.63 (min, 5H11), 3.69-3.79 (min, 1H11), 3.83-3.91 (m, 1H11), 7.26-7.30 (min, 4H11). 10 Example 2.131: Preparation of 1-((3aR,4R,6aS)-4-{4-[2-((R)-2-Methyl-pyrrolidin-1-yl) ethyl]-phenyl}-hexahydro-cyclopenta[c]pyrrol-2-yl)-2-phenyl-ethanone. 0 N H H .11 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) 15 2-methylpyrrolidin-1-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 HC1 to afford the hydrochloride salt of the title compound (165.6 mg). MS m/z 417, (M+H); 1H NMR (400 MHz, CD 3 OD) 8 1.42-1.62 (in, 4H11), 1.68-2.24 (inm, 20 6H11), 2.28-2.38 (min, 1H), 2.83-3.27 (min, 71H1), 3.27-3.78 (min, 9H), 6.98-7.36 (min, 911). Example 2.132: Preparation of 1-((3aR,4R,6aS)-4-{4-[2-((R)-2-Methyl-pyrrolidin-1-yl) ethyl]-phenyl}-hexahydro-cyclopenta[e]lpyrrol-2-yl)-2-(tetrahydro-pyran-4-yl)-ethanone. O N O- NH - 191 - WO 2007/061741 PCT/US2006/044479 g it:: 'i7.""' ll., 2~Ijtie o te "ro-2H-pyran-4-yl)acetic 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 (3aR,4R,6aS)-4-(4-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)phenyl) octahydrocyclopenta[c]pyrrole (203 mg, 0.680 mmol) dissolved in DCM (5.0 mL). After 19 h, 5 the resin was filtered and washed with DCM and MeOH. The solution was concentrated. The residue was purified by preparative IHIPLC, lyophilized, and treated with HC1 to afford the hydrochloride salt of the title compound (143.0 mg). MS m/z 425, (M+H); 'H NMR (400 MHz,
CD
3 OD) 6 1.14-1.44 (min, 3H), 1.46-1.85 (min, 7H), 1.88-2.42 (min, 9H), 2.90-3.96 (min, 17H), 7.28 (bs, 4H). 10 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 15 cortex using a polytron to homogenize the tissue followed by differential centrifugation in a HEPES-based buffer containing protease inhibitors. Membranes where frozen at -80 0 C until needed. Frozen membranes were thawed and resuspended in ice-cold assay buffer consisting of 50mM TRIS containing 5mM EDTA (pH=7.
4 ). 50 micrograms (ttg) of membrane protein was added to each well of a 96-well assay plate along with test compound and [H]-N-a-methyl 20 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 50oC. 35 microliters (pL) of scintillation cocktail was 25 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. Compound No. Ki Binding Assay (nM) (±)-C46 5.7 (n= 4) (3aS,6aS)-C37 28.0 (n= 3) (+)-C26 128.0 (n= 3) 30 Certain other compounds of the invention had activity values ranging from about 5 gM to about 50 pM in this assay. EXAMPLE 4: (R)-N-ALPHA-METHYL-HISTAMINE (RAMH) PROTOCOL. -192- WO 2007/061741 PCT/US2006/044479 ~ ... / 1,,.11, I~a e i age-Dawley rats ( 2 25-350g) (Harlan, San Diego, CA) were housed two to three per cage and maintained in a humidity- (30-70%) and temperature- (20-22oC) controlled facility on a 12 hr:12 hr light/dark cycle (lights on at 6:30 A.M.) with free access to food (Harlan-Teldad 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-a-methyl-histamine dihydrochloride was injected (20mg/kg salt, SC, lcc/kg 10 dissolved in water). 10min 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 RAMHII-induced drinking was calculated for each individual animal as follows: [1-(D-V)/(R-V)]*100 where D = the 15 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. 20 Cmpd No.* % Inhibition +/- s.e. (+)-C30 101.9 +/- 10.9 (±)-C23 110.4 +/- 12.7 (:)-C19 86.5 +/- 10.8 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 H113 receptor using the MDS.Pharma Services (Taiwan) assay, Catalogue No. 239810. Certain 25 compounds of the present invention and their corresponding activity values are shown in following table. Compound No. Binding Assay (nM) (3as,6aS)-C2 0.6 (3as,6aS)-C8 2.8 ()-C8 3.5 - 193 - WO 2007/061741 PCT/US2006/044479 l xi:I
'
ThLl 11 g EiA i ly lyoinifgraphy 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 oC) 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 5 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 10 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 thenext 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 15 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 20 after administration of two representative compounds. Dose and route % Increase in Cmpd No. of administration wakefulness +/- s.e. (±)-C7 (Example 2.89) 1.0 mg/kg SC 38 ± 15 B26 (Example 2.31) 3.0 mg/kg PO 47 ± 20 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 25 departing from the spirit of the invention and are, therefore, considered within the scope of the invention. All documents referenced above, including, but not limited to, printed publications, and provisional and regular patent applications, are incorporated herein by reference in their entirety. -194-

Claims (56)

1. A compound of Formula (Ia): R 1 D RI N Ha GAr ,K N R5 3 4 Hb E R R 2 (la) 5 or a pharmaceutically acceptable salt, hydrate or solvate thereof; wherein: D is C(=O), OC(=O), NR 6 C(=O), S(=0) 2 , or absent, wherein R 6 is H or C 1 .- 6 alkyl; G is CR 7 or C, provided that when G is CR 7 then - - is a single bond, wherein 10 R' is H and R7 is H or OH, and when G is C then - - is a double bond and R is absent; E is C(RR 9 ) or C(RRg)C(R' 0 R"), wherein R, R, R 1 0 , and R" are each selected independently from the group consisting of H, C1-. 3 alkyl, C 14 alkoxy, carboxy, cyano, C- 3 haloalkyl, and halogen; J is O, S, S(=O), S(=O) 2 , NR 12, or absent, wherein R 1 2 is H or C 1 .alkyl; 15 K is C 14 alkylene optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 substituents selected independently from the group consisting of C1-. 3 alkyl, C4 alkoxy, carboxy, cyano, C 1 .- 3 haloalkyl, halogen, hydroxyl, and oxo; R' 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 14 20 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- 4 alkylene-heteroaryl groups are optionally substituted with 1, 2, 3, 4, 5, 6, or 7 substituents selected independently from the group consisting of C 1 . 6 acyl, C 1 .6 acyloxy, C 2 .- 6 alkenyl, C 1 - 6 alkoxy, C. 6 alkyl, C 1 . 6 25 alkylcarboxamide, C 2 - 6 alkynyl, C 1 - 6 alkylsulfonamide, C 1 .- 6 alkylsulfinyl, C 1 . 6 alkylsulfonyl, C 1 .- 6 alkylthio, C 1 .- 6 alkylureyl, amino, C 1 . 6 alkylamino, C 2 - 8 dialkylamino, carbo-Cl. 6 -alkoxy, carboxamide, carboxy, cyano, C 3 .7 cycloalkyl, C 2 -8 dialkylcarboxamide, C 2 - 8 dialkylsulfonamide, formyl, halogen, C 1 . 6 haloalkoxy, C 1 -. 6 haloalkyl, C 1 . 6 haloalkylsulfinyl, C. 6 haloalkylsulfonyl, C 1 . 6 haloalkylthio, hydroxyl, 30 thiol, nitro, and sulfonamide; R 2 is H, halogen or C 1 - 3 alkyl; - 195 - WO 2007/061741 PCT/US2006/044479 II.... ' RIl an d R e each independently selected from the group consisting of H, C. 6 alkyl, C2- 6 alkenyl, C 2 . 6 alkynyl, and C 3 . 7 cycloalkyl, and wherein each of said C. 6 alkyl, C 2 -. 6 alkenyl, C2- 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 C 1 . 6 acyl, 5 C 1 -6 acyloxy, C 2 .- 6 alkenyl, C 1 . 6 alkoxy, CI. 6 alkyl, C 1 . 6 alkylcarboxamide, C2-. 6 alkynyl, C 1 . 6 alkylsulfonamide, C 1 .- 6 alkylsulfinyl, C. 6 alkylsulfonyl, C 1 . 6 alkylthio, C 1 . 6 alkylureyl, amino, C 1 . 6 alkylamino, C 2 .- 8 dialkylamino, carbo-C1. 6 -alkoxy, carboxamide, carboxy, cyano, C 3 .- 7 cycloalkyl, C 2 .8 dialkylcarboxamide, C 2 . 8 dialkylsulfonamide, halogen, C 1 .- 6 haloalkoxy, CI.6 haloalkyl, C 1 . 6 haloalkylsulfinyl, C 1 .- 6 haloalkylsulfonyl, 10 C 1 .- 6 haloalkylthio, hydroxyl, thiol, nitro, and sulfonamide; or R 4 and R s together with the nitrogen atom to which they are both bonded form a C 3 - 7 heterocyclyl or Cs-. 1 0 o heterobicyclyl group optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected independently from the group consisting of C1- 6 acyl, C 1 .. 6 acyloxy, C2-6 alkenyl, C 1 -6 alkoxy, C 1 -6 alkyl, C 1 - 6 alkylcarboxamide, C2- 6 alkynyl, C 1 -. 6 15 alkylsulfonamide, C 1 . 6 alkylsulfinyl, C 1 -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 1 -6 haloalkoxy, C 1 . 6 haloalkyl, C1- 6 haloalkylsulfinyl, C1- 6 haloalkylsulfonyl, C 1 . 6 haloalkylthio, hydroxyl, thiol, nitro, oxo, phenyl, and sulfonamide, and said C 1 -6 alkyl, is 20 optionally substituted with 1 or 2 substituents selected independently from C 1 .-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 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 25 alkylsulfonamide, CI_ 6 alkylsulfinyl, C 1 .- 6 alkylsulfonyl, C 1 . 6 alkylthio, C. 6 alkylureyl, amino, CI- 6 alkylamino, C 2 -8 dialkylamino, carbo-C 1 .- 6 -alkoxy, carboxamide, carboxy, cyano, C 3 .- 7 cycloalkyl, C 2 s dialkylcarboxamide, C 2 -8 dialkylsulfonamide, halogen, C. 6 haloalkoxy, C 1 .- 6 haloalkyl, C 1 .- 6 haloalkylsulfinyl, C 1 . 6 haloalkylsulfonyl, C 1 .- 6 haloalkylthio, hydroxyl, thiol, nitro, and sulfonamide; 30 provided that: G and J are not bonded to adjacent ring carbons of said Ar group; and when E is C(RgRg), then Ha and Hb are cis with respect to each other.
2. The compound according to claim 1, wherein: 35 D is C(=0), OC(=O), NRC(=O), or absent, wherein R 6 is H or C 1 - 6 alkyl; R' is selected from the group consisting of H, C 1 . 6 alkyl, C 2 - 6 alkenyl, C2-. 6 alkynyl, C 3 . 7 cycloalkyl, C1- 4 alkylene-C 3 . 7 -cycloalkyl, C 3 7 heterocyclyl, aryl, CI-4 -196- WO 2007/061741 PCT/US2006/044479 y: : l i-aryl, heteraryl, and C. 4 alkylene-heteroaryl, and each of said Cb-6 alkyl, C2-6 alkenyl, C2.-6 alkynyl, C 3 .- 7 cycloalkyl, C 1 .- 4 alkylene-C 3 . 7 -cycloalkyl, C3.7 heterocyclyl, aryl, C1-4 alkylene-aryl, heteroaryl, and C 1 .- 4 alkylene-heteroaryl groups are optionally substituted with 1, 2, 3, 4, 5, 6, or 7 substituents selected independently from the group 5 consisting of CI.6 acyl, CI-6 acyloxy, C 2 - 6 alkenyl, C1-.6 alkoxy, C 1 . 6 alkyl, C 1 . 6 alkylcarboxamide, C2-. 6 alkynyl, C 1 . 6 alkylsulfonamide, C1.6 allkylsulfinyl, C 1 . 6 alkylsulfonyl, C 1 . 6 alkylthio, C.. 6 alkylureyl, amino, C.6 alkylamino, C2-8 dialkylamino, carbo-C 1 . 6 -alkoxy, carboxamide, carboxy, cyano, C3. cycloalkyl, C2-.8 dialkylcarboxamide, C2-. 8 dialkylsulfonamide, halogen, C.. 6 haloalkoxy, C.6 haloalkyl, 10 C.6 haloalkylsulfinyl, C1.6 haloalkylsulfonyl, C 1 . 6 haloalkylthio, hydroxyl, thiol, nitro, and sulfonamide; and R 4 and R s are each independently selected from the group consisting of H, C.6 alkyl, C2-6 alkenyl, C2.-6 alkynyl, and C3-7 cycloalkyl, and wherein each of said C1.6 alkyl, C2.- alkenyl, C2.6 alkynyl, and C3-7 cycloalkyl groups are optionally substituted with 1, 2, 15 3, 4, 5, or 6 substituents selected independently from the group consisting of C1-6 acyl, C1-6 acyloxy, C2-6 alkenyl, C1.6 alkoxy, C1.6 alkyl, C.-6 alkylcarboxamide, C2.6 alkynyl, CI-6 alkylsulfonamide, C.-6 alkylsulfinyl, C.-6 alkylsulfonyl, C1-6 alkylthio, C1-6 alkylureyl, amino, C1.6 alkylamino, C2-8 dialkylamino, carbo-Cl- 6 -alkoxy, carboxamide, carboxy, cyano, C3.7 cycloalkyl, C2-8 dialkylcarboxamide, C2-8 dialkylsulfonamide, 20 halogen, C1-6 haloalkoxy, C1-6 haloalkyl, C1.-6 haloalkylsulfinyl, C1-6 haloalkylsulfonyl, C-6 haloalkylthio, hydroxyl, thiol, nitro, and sulfonamide; or R 4 and R 5 together with the nitrogen atom to which they are both bonded form a C3.7 heterocyclyl or Cs-10 heterobicyclyl group optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected independently from the group consisting of C-.6 acyl, C6 25 acyloxy, C2-6 alkenyl, C1-6 alkoxy, CI-6 alkyl, C1.6 alkylcarboxamide, C2-6 alkynyl, C1-6 alkylsulfonamide, C.6 alkylsulfinyl, C1-6 alkylsulfonyl, C1-6 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, halogen, C-.6 haloalkoxy, C0.6 haloalkyl, C1.6 haloalkylsulfinyl, C.6 haloalkylsulfonyl, C-.6 30 haloalkylthio, hydroxyl, thiol, nitro, and sulfonamide, and said C1.6 alkyl, is optionally substituted with hydroxyl.
3. The compound according to claim 2, wherein E is C(RRg). 35 4. The compound according to claim 2 or 3, wherein R 8 and R 9 are each H. -197- WO 2007/061741 PCT/US2006/044479 c Ie m pound accoiding to any one of claims 2 to 4, wherein G is CR and - - is a single bond; wherein R 7 is H or OH.
6. The compound according to any one of claims 2 to 4, wherein G is C and - - is a 5 double bond.
7. The compound according to claim 2, wherein E is C(RRg)C(R'ioR").
8. The compound according to claim 2 or 7, wherein Ro, and R" 1 are each H. 10
9. The compound according to claim 2, 7 or 8, wherein R 8 , R 9 , Ro, and R 1 are each H.
10. The compound according to claim 2, 7, 8 or 9, wherein G is CR 7 and -- is a single bond; wherein R' is H or OH. 15
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(=0) 2 . 20
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). 25 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. 30
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 NR 12 35 wherein R 12 is H or C 1 . 6 alkyl.
20. The compound according to any one of claims 2 to 11, or 13 to 16, wherein J is absent. - 198 - WO 2007/061741 PCT/US2006/044479
21. The compound according to any one of claims 2 to 11, or 13 to 20, wherein K is -CHzCH 2 -. 5 22. The compound according to claims 1 or 12, wherein R 1 is selected from the group consisting of H, C 1 . 6 alkyl, C3- 7 cycloalkyl, C 1 .- 4 alkylene-C 3 . 7 -cycloalkyl, aryl, C 1 -4 alkylene-aryl, heteroaryl, and C 1 - 4 alkylene-heteroaryl, and each of said C1- 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 10 alkylamino, C2-8 dialkylamino, C 3 - 7 cycloalkyl, fornfAyl, halogen, C 1 -6 haloalkoxy, C 1 . 6 haloalkyl, and hydroxyl.
23. The compound according to any one of claims 2 to 11 or 13 to 21, wherein R 1 is selected from the group consisting of H, C 1 . 6 alkyl, C 3 . 7 cycloalkyl, C1- 4 alkylene-C 3 7 15 cycloalkyl, aryl, C 1 - 4 alkylene-aryl, heteroaryl, and C4 alkylene-heteroaryl, and each of said C.-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, C1- 6 alkylamino, C 2 -8 dialkylamino, C 3 - 7 cycloalkyl, halogen, C 1 -6 haloalkoxy, C 6 haloalkyl, and hydroxyl. 20
24. The compound according to any one of claims 1, 12 or 22, wherein 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 25 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 30 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 R 1 is selected from the group consisting of H, benzyl, cyclopropylmethyl, isobutyl, isopropyl, 35 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. -199- WO 2007/061741 PCT/US2006/044479
26. The compound according to any one of claims 1, 12, 22, or 24, wherein R 2 is H or C 1 -6 alkyl 5 27. The compound according to any one of claims 1, 12, 22, 24, or 26, wherein R 2 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. 10
29. The compound according claim 1, 12, 22, 24, 26, or 27, wherein R 4 and Rs are each independently H or C 1 . 6 alkyl; or R 4 and Rs together with the nitrogen atom to which they are both bonded form a C 3 . 7 heterocyclyl or C 5 .- 1 0 heterobicyclyl optionally substituted with 1 or 2 substituents 15 selected independently from the group consisting of CI. 6 alkyl, halogen, hydroxyl, oxo and phenyl; and said C1- 6 alkyl, is optionally substituted with 1 or 2 substituents selected independently from C1- 6 alkoxy and hydroxyl.
30. The compound according to any one of claims 2 to 11, 13 to 21, 23, 25, or 28, wherein 20 R 4 and R 5 are each independently H or C 1 . 6 alkyl; or R 4 and Rs together with the nitrogen atom to which they are both bonded form a C 3 .- 7 heterocyclyl or C5-.o heterobicyclyl optionally substituted with 1 or 2 substituents selected independently from the group consisting of C 1 . 6 alkyl, halogen, and hydroxyl; and said CI-6 alkyl, is optionally substituted with hydroxyl. 25
31. The compound according to any one of claims 1, 12, 22, 24, 26, 27, or 29, wherein R 4 and R 5 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, 30 wherein R 4 and Rs 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 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 35 methyl-piperidin-1-yl, 4-methyl-piperazin-1-yl, 2,5-dimethyl-pyrrolidin-1-yl, dimethyl amino, 2,2-dimethyl-pyrrolidin-1-yl, morpholin-4-yl, 2-hydroxymethyl-pyrrolidin-1-yl, 3-hydroxy-pyrrolidin-1-yl, 3,3-difluoro-pyrrolidin-1-yl, azetidin-1-yl, 3,3-difluoro - 200 - WO 2007/061741 PCT/US2006/044479 i'ppe-i : -y, , 3-dihydro-isoindol-2-yl, 3,4-dihydro-1H-isoquinolin-2-yl, 2,3-dihydro indol-1-yl, 2-methoxymethy1-pyrrolidin-1-yl, 2-carbamoylpyrrolidin-1-yl, 2 (methylcarbamoyl)pyrrolidin-1 -yl, piperidin-1 -yl, 2-oxopyrrolidin-1 -yl, 3 phenylpyrrolidin-1-yl, 2-isopropylpyrrolidin-1-yl, 2-trifluoromethylpyrrolidin-1-yl, and 5 2-phenylpyrrolidin-1-yl.
34. The compound according to any one of claims 2 to 11, 13 to 21, 23, 25, 28, 30, or 32, wherein R 4 and Rs 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 10 methyl-piperidin-1-yl, 4-methyl-piperazin-1-yl, 2,5-dimethyl-pyrrolidin-1-yl, dimethyl amino, 2,2-dimethyl-pyrrolidin-1-yl, morpholin-4-yl, 2-hydroxymethyl-pyrrolidin-1-yl, 3-hydroxyl-pyrrolidin-1-yl, 3,3-difluoro-pyrrolidin-1-yl, azetidin-1-yl, 3,3-difluoro piperidin-l1-yl, 2,3-dihydro-isoindol-2-yl, 3,4-dihydro-lH-isoquinolin-2-yl, 2,3-dihydro indol-1-yl, and amino. 15
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 20 solvate thereof; wherein: 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? is H and R7 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; 25 E is -CH 2 -or -CH 2 CH 2 -; J is O or absent; K is -CH 2 CH 2 -; R' is selected from the group consisting of H, benzyl, cyclopropylmethyl, isobutyl, isopropyl, 4-trifluoromethoxy-benzyl, 2,4-dimethoxy-benzyl, cyclohexyl, 30 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 35 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; -201- WO 2007/061741 PCT/US2006/044479 ... [ i,::: W ,:k4 and K are each independently H, methyl or isopropyl; or R 4 and Rs 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-1-yl, 4-methyl-piperazin-1-yl, 2,5-dimethyl-pyrrolidin-1-yl, dimethyl 5 amino, 2,2-dimethyl-pyrrolidin-1-yl, morpholin-4-yl, 2-hydroxymethyl-pyrrolidin-l1-yl, 3-hydroxy-pyrrolidif-1-yl, 3,3-difluoro-pyrrolidin-1-yl, azetidin-1-yl, 3,3-difluoro piperidin-l1-yl, 2,3-dihydro-isoindol-2-yl, 3,4-dihydro-1H-isoquinolin-2-yl, 2,3-dihydro indol-1-yl, 2-methoxymethyl-pyrrolidin-1-yl, 2-carbamoylpyrrolidin-1-yl, 2 (methylcarbamoyl)pyrrolidin- 1-yl, piperidin- 1-yl, 2-oxopyrrolidin-1 -yl, 3 10 phenylpyrrolidin-1-yl, 2-isopropylpyrrolidin-1-yl, 2-trifluoromethylpyrrolidin-1-yl, and 2-phenylpyrrolidin-1-yl; and Ar is 1,4-phenylene, 1,3-phenylene or 2,5-pyridinylene.
37. The compound according to claim 2 having Formula (Iq): R1 D\ N Ha .Ar K NR 5 G J N Hb E R 3 H 15 (Iq) or a pharmaceutically acceptable salt, hydrate or solvate thereof; wherein: D is C(=O), OC(=O), NR 6 C(=O), 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 20 R is H and R 7 is H or OH, and when G is C then - - is a double bond and R is absent; E is -CH 2 - or -CH 2 CH 2 -; J is O or absent; K is -CH 2 CH 2 -; R' is selected from the group consisting of H, benzyl, cyclopropylmethyl, 25 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 Rs together with the nitrogen atom to which they are both bonded form a 30 group selected from the group consisting of pyrrolidin-1-yl, 2-methyl-pyrrolidin-1-yl, 2 methyl-piperidin-1-yl, 4-methyl-piperazin-1-yl, 2,5-dimethyl-pyrrolidin-1-yl, dimethyl amino, 2,2-dimethyl-pyrrolidin-1-yl, morpholin-4-yl, 2-hydroxymethyl-pyrrolidin-1-yl, 3-hydroxyl-pyrrolidin-1-yl, 3,3-difluoro-pyrrolidin-l1-yl, azetidin-l1-yl, 3,3-difluoro - 202 - WO 2007/061741 PCT/US2006/044479 piperin-l-y, 2,3-dhydro-isoindol-2-yl, 3 , 4 -dihydro-1H-isoquinolin-2-yl, 2,3-dihydro indol-1 -yl, and amino; and Ar is 1,4-phenylene, 1,3-phenylene or 2,5-pyridinylene. 5 38. The compound according to claim 2 having Formula (Is): R DN Ha Ar // 1A K .N R5 r K,R Hb kR4 (Is) or a pharmaceutically acceptable salt, hydrate or solvate thereof; wherein: D is C(=O), OC(=O), or absent; 10 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-benzyl, 2,4-dimethoxy-benzyl, cyclohexyl, 15 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 s 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-1 yl; 20 and Ar is 1,4-phenylene or 2,5-pyridinylene.
39. The compound according to claim 2 having Formula (Iu): R1..-D\ NH Ar K 'NR 5 j- N Hb R (Iu) 25 or a pharmaceutically acceptable salt, hydrate or solvate thereof; wherein: D is C(=0), OC(=O), NHC(=O), or absent; J is O or absent; K is -CH 2 CH 2 -; - 203 - WO 2007/061741 PCT/US2006/044479 Cis 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 5 furan-3-yl; R 4 and Rs 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-1-yl, 4-methyl-piperazin-1-yl, 2,5-dimethyl-pyrrolidin-1-yl, dimethyl amino, 2,2-dimethyl-pyrrolidin-1-yl, morpholin-4-yl, 2-hydroxymethyl-pyrrolidin-1-yl, 10 3-hydroxyl-pyrrolidin-1-yl, 3,3-difluoro-pyrrolidin-1-yl, azetidin-1-yl, 3,3-difluoro piperidin-1-yl, 2,3-dihydro-isoindol-2-yl, 3,4-dihydro-1H-isoquinolin-2-yl, 2,3-dihydro indol-1-yl, and amino; and Ar is 1,4-phenylene, 1,3-phenylene or 2,5-pyridinylene. 15 40. The compound according to claim 2 having Formula (Iw): R1j- D\Nf Ar-j I K IN RD N Ha Ar ,K NR 5 R7 R4 Hb (1w) or a pharmaceutically acceptable salt, hydrate or solvate thereof; wherein: D is C(=O) or NRC(=O), wherein R is H or CH 3 ; 20 R 7 is H or OH; J is absent; K is -CH 2 CH 2 -; R' is selected from the group consisting of H, isopropyl, cyclopentyl, methyl, or cyclopropyl; 25 R 4 and R 5 together with the nitrogen atom to which they are both bonded form pyrrolidin-l-yl; and Ar is 1,4-phenylene.
41. The compound according to claim 2 having Formula (Iy): - 204 - WO 2007/061741 PCT/US2006/044479 N Ha Ar '- ,K',N ,R5 \ R4 Hb (iy) or a pharmaceutically acceptable salt, hydrate or solvate thereof; wherein: D is C(=O) or NR 6 C(=O), wherein R 6 is H or CH3; 5 J is absent; K is -CH 2 CH 2 -; R' is selected from the group consisting of H, benzyl, isopropyl, cyclopentyl, methyl, or cyclopropyl; R 4 and R s together with the nitrogen atom to which they are both bonded form 10 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: 15 2-Benzyl-4-[4-(2-pyrrolidin-1 -yl-ethyl)-phenyl]-octahydro-cyclopenta[c]pyrrol 4-ol; 2-Benzyl-4- {4-[2-(2-methyl-pyrrolidin-1 -yl)-ethyl]-phenyl}-octahydro cyclopenta[c]pyrrol-4-ol; 4-[4-(2-Pyrrolidin-1-yl-ethyl)-phenyl]-octahydro-cyclopenta[c]pyrrol-4-ol; 20 2-Cyclopropylmethyl-4-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl]-octahydro cyclopenta[c]pyrrol-4-ol; 2-Isobutyl-4-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl]-octahydro cyclopenta[c]pyrrol-4-ol; 2-Isopropyl-4-[4-(2-pyrrolidin-1 -yl-ethyl)-phenyl]-octahydro 25 cyclopenta[c]pyrrol-4-ol; 4-[4-(2-Pyrrolidin-1-yl-ethyl)-phenyl]-2-(4-trifluoromethoxy-benzyl) octahydro-cyclopenta[c]pyrrol-4-ol; 2-(2,4-Dimethoxy-benzyl)-4-[4-(2-pyrrolidin-l1-yl-ethyl)-phenyl]-octahydro cyclopenta[c]pyrrol-4-ol; 30 2-Cyclohexyl-4-[4-(2-pyrrolidin-l1-yl-ethyl)-phenyl]-octahydro cyclopenta[c]pyrrol-4-ol; 2-Cyclopentyl-4-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl]-octahydro cyclopenta[c]pyrrol-4-ol; - 205 - WO 2007/061741 PCT/US2006/044479 1'{4Iydroky-4-[4-(2-pyrrolidin-1 -yl-ethyl)-phenyl] -hexahydro cyclopenta[c]pyrrol-2-yl} -ethanone; 4-Hydroxy-4-[4-(2-pyrrolidin-1 -yl-ethyl)-phenyl]-hexahydro cyclopenta[c]pyrrole-2-carboxylic acid ethyl ester; 5 4-Ilydroxy-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-1 -yl-ethoxy)-phenyl]-octahydro 10 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; 15 4-[4-(2-Pyrrolidin-1 -yl-ethyl)-phenyl]-octahydro-cyclopenta[c]pyrrole; 2-Cyclopropylmethyl-4-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl]-octahydro cyclopenta[c]pyrrole; 2-Isopropyl-4-[4-(2-pyrrolidin-1 -yl-ethyl)-phenyl]-octahydro cyclopenta[c]pyrrole; 20 2-Cyclopentyl-4-[4-(2-pyrrolidin-1 -yl-ethyl)-phenylll-octahydro cyclopenta[c]pyrrole; 2-(2,4-Dimethoxy-benzyl)-4-[4-(2-pyrrolidin-1 -yl-ethyl)-phenyl]-octahydro cyclopenta[c]pyrrole; 2-Cyclohexyl-4-[4-(2-pyrrolidin-1 -yl-ethyl)-phenyl] -octahydro 25 cyclopenta[cjpyrrole; 4- {4-[4-(2-Pyrrolidin-1 -yl-ethyl)-phenyl]-hexahydro-cyclopenta[clpyrrol-2 ylmethyl} -phenol; 2-Gyclobutyl-4-[4-(2-pyrrolidin-1 -yl-ethyl)-phenyl]-octahydro cyclopenta[c]pyrrole; 30 2- {4-[4-(2-Pyrrolidin-1 -yl-ethyl)-phenyl]-hexahydro-cyclopenta[clpyrrol-2-yl} propan-1-ol; 2-Isobutyl-4-[4-(2-pyrrolidin-1 -yl-ethyl)-phenyl]-octahydro cyclopenta[cjpyrrole; 2-(4-Methoxy-benzyl)-4-[4-(2-pyrrolidin-l -yl-ethyl)-phenyl]-octahydro 35 cyclopenta[c]pyrrole; 4-[4-(2-Pyrrolidin-1 -yl-ethyl)-phenyl]-2-(4-trifluoromethoxy-benzyl) octahydro-cyclopenta[c]pyrrole; - 206 - WO 2007/061741 PCT/US2006/044479 .;:.:'- {4-[4-(2-yrroh ! idin-1-yl-ethyl)-phenyl]-hexahydro-cyclopenta[c]pyrrol-2 ylmethyl } -phenol; 1- {4-[4-(2-Pyrrolidin-l1-yl-ethyl)-phenyl]-hexahydro-cyclopenta[c]pyrrol-2-yl} ethanone; 5 2-Methyl-I -{4-[4-(2-pyrrolidin-1 -yl-ethyl)-phenyl]-hexahydro cyclopenta[c]pyrrol-2-yl} -propan-1 -one; Cyclopropyl- {4-[4-(2-pyrrolidin-1 -yl-ethyl)-phenyl]-hexahydro cyclopenta[c]pyrrol-2-yl}-methanone; Cyclopentyl- {4-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl]-hexahydro 10 cyclopenta[c]pyrrol-2-yl} -methanone; 4-[4-(2-Pyrrolidin-1 -yl-ethyl)-phenyl]-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; 15 6-[4-(2-Pyrrolidin-1-yl-ethyl)-phenyl]-1,2,3,3a,4,6a-hexahydro cyclopenta[c]pyrrole; 2-Benzyl-6-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl]-1,2,3,3a,4,6a-hexahydro cyclopenta[c]pyrrole; 2-Benzyl-6-{4-[2-(2-methyl-piperidin-1 -yl)-ethyl]-phenyl} -1,2,3,3a,4,6a 20 hexahydro-cyclopenta[c]pyrrole; 2-Benzyl-6- {4-[2-(4-methyl-piperazin-1 -yl)-ethyl]-phenyl} -1,2,3,3a,4,6a hexahydro-cyclopenta[c]pyrrole; 2-Benzyl-6- {4-[2-(2,5-dimethyl-pyrrolidin-1 -yl)-ethyl]-phenyl} -1,2,3,3a,4,6a hexahydro-cyclopenta[c]pyrrole; 25 {2-[4-(2-Benzyl-1,2,3,3a,6,6a-hexahydro-cyclopenta[c]pyrrol-4-yl)-phenyl] ethyl}-dimethyl-amine; 2-Benzyl-6- {4-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-phenyl}-1,2,3,3a,4,6a hexahydro-cyclopenta[c]pyrrole; 2-Benzyl-6- {4-[2-(2,2-dimethyl-pyrrolidin-1 -yl)-ethyl]-phenyl} -1,2,3,3a,4,6a 30 hexahydro-cyclopenta[c]pyrrole; 2-Benzyl-6-[4-(2-morpholin-4-yl-ethyl)-phenyl]-1,2,3,3a,4,6a-hexahydro cyclopenta[c]pyrrole; (1- {2-[4-(2-Benzyl-1,2,3,3a,6,6a-hexahydro-cyclopenta[c]pyrrol-4-yl)-phenyl] ethyl}-pyrrolidin-2-yl)-minethanol; 35 1-{2-[4-(2-Benzyl-1,2,3,3a,6,6a-hexahydro-cyclopenta[c]pyrrol-4-yl)-phenyl] ethyl}-pyrrolidin-3-ol; - 207- WO 2007/061741 PCT/US2006/044479 '-i I~Ben2, h'4r2(33difluoropyrrolidin-1-yl)-ethyll-phenyl} -1,2,3 ,3a,4,6a hexahyclro-cyclopenta[c]pyrrole; 6-[4-(2-Azetidin-1 -yl-ethyl)-phenyl]-2-benzyl-1 ,2,3,3a,4,6a-hexahydro cyclopenta[c]pyrrole; 5 2-Benzyl-6- {4-[2-(3,3-difluoro-piperidin-1 -yl)-ethyl]-phenyl} -1 ,2,3,3a,4,6a hexahydro-cyclopenta[c]pyrrole; 2- {2-[4-(2-Benzyl-1 ,2,3 ,3a,6,6a-hexahydro-cyclopenta[c]pyrrol-4-yl)-phenyl] ethyl} -2,3-dihydro-lil-isoindole; 2- {2-[4-(2-Benzyl-1 ,2,3,3a,6,6a-hexahydro-cyclopenta[c]pyrrol-4-yl)-phenyl] 10 ethyl} -1,2,3,4-tetrahydro-isoquinoline; 1- {2-[4-(2-Benzyl-1 ,2,3,3a,6,6a-hexahydro-cyclopenta[c]pyrrol-4-yl)-phenyl] ethyl) -2,3-dihydro-1H-indole; 2-Cyclopropylmethyl-6-[4-(2-pyrrolidin-1 -yl-ethyl)-phenyll-1,2,3,3a,4,6a hexahydro-cyclopenta[c]pyrrole; 15 2-Cyclopentyl-6-[4-(2-pyrrolidin-1 -yl-ethyl)-phenyl]-1 ,2,3,3a,4,6a-hexahydro cyclopenta[c]pyrrole; 2-(4-Methoxy-benzyl)-6-[4-(2-pyrrolidin-1 -yl-ethyl)-phenyll-1 ,2,3,3a,4,6a hexahydro-cyclopenta[c]pyrrole; 2-Jsopropyl-6-[4-(2-pyrrolidin-1 -yl-ethyl)-phenyl]-1 ,2,3 ,3a,4,6a-hexahyclro 20 cyclopenta[c]pyrrole; 2-Cyclobutyl-6-[4-(2-pyrrolidin-1 -yl-ethyl)-phenyl]-1 ,2,3,3a,4,6a-hexahydro cyclopenta[c]pyrrole; 2- {6-[4-(2-Pyrrolidin-1 -yl-ethyl)-phenyl]-3,3a,4,6a-tetrahydro-1H cyclopenta[c]pyrrol-2-yl} -propan-1 -ol; 25 4- {6-[4-(2-Pyrrolidin-1 -yl-ethyl)-phenyl]-3,3a,4,6a-tetrahydro-flH cyclopenta[c]pyrrol-2-ylmethyl} -phenol; 2-Cyclohexyl-6-[4-(2-pyrrolidin-1 -yl-ethyl)-phenyl]-1 ,2,3,3a,4,6a-hexahydro cyclopenta[c]pyrrole; 2-Methyl-6-[4-(2-pyrrolidin-1 -yl-ethyl)-phenyl]-1 ,2,3 ,3a,4,6a-hexahydro 30 cyclopenta[c]pyrrole; 2-Isobutyl-6-[4-(2-pyrrolidin-1 -yl-ethyl)-phenyl]-1 ,2,3,3a,4,6a-hexahydro cyclopenta[c]pyrrole; 2-(2,4-Dimethoxy-benzyl)-6-[4-(2-pyrrolidin-1 -yl-ethyl)-phenyl]-1 ,2,3 ,3a,4,6a hexahydro-cyclopenta[c~pyrrole; 35 6-[4-(2-Pyrrolidin-1 -yl-ethyl)-phenyl] -2-(4-trifluoromethoxy-benzyl) 1 ,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole; - 208 - WO 2007/061741 PCT/US2006/044479 Cyclopropyl- {6-[4-(2-pyrrolidin-1 -yl-ethyl)-phenyl]-3,3a,4,6a-tetrahydro-1H cyclopenta[c]pyrrol-2-yl} -methanone; 2-Methyl-1 - {6-[4-(2-pyrrolidin-1 -yl-ethyl)-phenyl]-3,3a,4,6a-tetrahydro-1H cyclopenta[c]pyrrol-2-yl}-propan-1 -one; 5 Cyclopentyl- {6-[4-(2-pyrrolidin-1 -yl-ethyl)-phenyl]-3,3a,4,6a-tetrahydro-1H cyclopenta[c]pyrrol-2-yl}-methanone; 6-[4-(2-Pyrrolidin-1-yl-ethyl)-phenyl]-3,3a,4,6a-tetrahydro-1H cyclopenta[c]pyrrole-2-carboxylic acid ethyl ester; 6-[4-(2-Pyrrolidin-1-yl-ethyl)-phenyl]-3,3a,4,6a-tetrahydro-1H 10 cyclopenta[c]pyrrole-2-carboxylic acid isopropylamide; 6-[4-(2-Pyrrolidin-1 -yl-ethyl)-phenyl]-3,3a,4,6a-tetrahydro-1H cyclopenta[c]pyrrole-2-carboxylic acid cyclopentylamide; 2-Pyridin-2-yl-6-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl]-1l,2,3,3a,4,6a-hexahydro cyclopenta[c]pyrrole; 15 2-Hydroxy-1 -{6-[4-(2-pyrrolidin-1 -yl-ethyl)-phenyl]-3,3a,4,6a-tetrahydro-1H cyclopenta[c]pyrrol-2-yl}-ethanone; 2-[4-(2-Benzyl-1,2,3,3a,6,6a-hexahydro-cyclopenta[c]pyrrol-4-yl)-phenyl] ethylamine; 2-Benzyl-6-[6-(2-pyrrolidin-l1-yl-ethyl)-pyridin-3-yl]-1,2,3,3a,4,6a-hexahydro 20 cyclopenta[c]pyrrole; 2-Benzyl-6-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1,2,3,3a,4,6a-hexahydro cyclopenta[c]pyrrole; 2-Benzyl-6-[3-(2-pyrrolidin-l1-yl-ethoxy)-phenyl]-1,2,3,3a,4,6a-hexahydro cyclopenta[c]pyrrole; 25 2-Benzyl-6-[5-(2-pyrrolidin-1-yl-ethyl)-pyridin-2-yl]-1,2,3,3a,4,6a-hexahydro cyclopenta[c]pyrrole; 1- {6-[4-(2-Pyrrolidin-1-yl-ethyl)-phenyl]-3,3a,4,6a-tetrahydro-1H cyclopenta[c]pyrrol-2-yl}-ethanone; (6- {4-[2-(2-Methyl-pyrrolidin-1 -yl)-ethyl]-phenyl} -3,3a,4,6a-tetrahydro-1H 30 cyclopenta[c]pyrrol-2-yl)-(tetrahydro-furan-3-yl)-methanone; 2-Benzyl-7-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl]-2,3,3a,4,5,7a-hexahydro-1H isoindole; 7-[4-(2-Pyrrolidin-1-yl-ethyl)-phenyl]-2,3,3a,4,5,7a-hexahydro-1H-isoindole; 1 -{7-[4-(2-Pyrrolidin-1-yl-ethyl)-phenyl]-1,3,3a,4,5,7a-hexahydro-isoindol-2 35 yl}-ethanone; 2-Methyl-1-{7-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl]-1,3,3a,4,5,7a-hexahydro isoindol-2-yl}-propan-1 -one; - 209 - WO 2007/061741 PCT/US2006/044479 "" . Cyclopropyl {7-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl]-1,3,3a,4,5,7a-hexahydro isoindol-2-yl} -methanone; 7-[4-(2-Pyrrolidin-1-yl-ethyl)-phenyl]-1,3,3a,4,5,7a-hexahydro-isoindole-2 carboxylic acid dimethylamide; 5 7-[4-(2-Pyrrolidin-1-yl-ethyl)-phenyl]-1,3,3a,4,5,7a-hexahydro-isoindole-2 carboxylic acid isopropylamide; 7-[4-(2-Pyrrolidin-1-yl-ethyl)-phenyl]-1,3,3a,4,5,7a-hexahydro-isoindole-2 carboxylic acid cyclopentylamide; 4-[4-(2-Pyrrolidin-1-yl-ethyl)-phenyl]-octahydro-isoindole; 10 1-{4-[4-(2-Pyrrolidin-1-yl-ethyl)-phenyl]-octahydro-isoindol-2-yl}-ethanone; 2-Methyl-1 -{4-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl]-octahydro-isoindol-2-yl} propan-l-one; Cyclopropyl-{4-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl]-octahydro-isoindol-2-yl} methanone; 15 4-[4-(2-Pyrrolidin-1-yl-ethyl)-phenyl]-octahydro-isoindole-2-carboxylic acid dimethylamide; 4-[4-(2-Pyrrolidin-1-yl-ethyl)-phenyl]-octahydro-isoindole-2-carboxylic acid isopropylamide; and 4-[4-(2-Pyrrolidin-1-yl-ethyl)-phenyl]-octahydro-isoindole-2-carboxylic acid 20 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: 25 2-(4-Methoxy-benzyl)-4-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl]-octahydro cyclopenta[c]pyrrol-4-ol; 4-[4-(2-Pyrrolidin-1-yl-ethyl)-phenyl]-2-(4-trifluoromethyl-benzyl)-octahydro cyclopenta[c]pyrrol-4-ol; 2-Methyl-4-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl]-octahydro-cyclopenta[c]pyrrol 30 4-ol; 2-Ethyl-4-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl]-octahydro-cyclopenta[c]pyrrol-4 ol; 2-Cyclobutyl-4-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl]-octahydro cyclopenta[c]pyrrol-4-ol; 35 2-Benzyl-4-[3-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-octahydro cyclopenta[c]pyrrol-4-ol; -210- WO 2007/061741 PCT/US2006/044479 4-4(-yrr61idin-1 -yl-ethyl)-phenyl]-2-(4-trifluoromethyl-benzyl)-octahydro cyclopenta[c]pyrrole; 2-Methyl-4-[4-(2-pyrrolidin-1 -yl-ethyl)-phenyl]-octahydro cyclopenta[c]pyrrole; 5 2-Ethyl-4-[4-(2-pyrrolidin-1 -yl-ethyl)-phenyl]-octahydro-cyclopenta[c]pyrrole; (4-{4-[2-(2-Methy-pynrolidin-1 -yl)-ethyl]-phenyl} -hexahydro cyclopenta[c]pyrrol-2-yl)-(tetrahydro-furan-3-yl)-methanone; Cyclopropyl-(4- {4-[2-(2-methyl-pyrrolidin-1 -yl)-ethyi]-phenyl} -hexahydro cyclopenta[c]pyrrol-2-yl)-methanone; 10 (4-{4-[2-(2-Methyl-pyrrolidin-1 -yl)-ethyl]-phenyl} -hexahydro cyclopenta[c]pyrrol-2-yl)-(tetrahydro-pyran-4-yl)-methanone; 2-Methyl-i -(4- {4-[2-(2-methyl-pyrrolidin-1 -yl)-ethyl]-phenyi} -hexahydro cyclopenta[c]pyrrol-2-yl)-propan-1 -one; Cyclopentyl-(4- {4-[2-(2-methyl-pyrrolidin-1 -yl)-ethyl]-phenyl} -hexahydro 15 cyclopenta[c]pyrrol-2-yl)-methanone; (4- {4-[2-(2-Methyl-pyrrolidin-1 -yl)-ethyl]-phenyl} -hexahyciro cyclopenta[c]pyrrol-2-yl)-pyridin-3-yl-methanone; (4- {4-[2-(2-Methyl-pyrrolidin-1 -yl)-ethyl] -phenyi} -hexahydro cyclopenta[c]pyrrol-2-yi)-pyrazin-2-yl-methanone; 20 - Cyclohexyl-(4- {4-[2-(2-methyl-pyrrolidin-1 -yl)-ethyl]-phenyl} -hexahydro cyciopenta[c]pyrrol-2-yl)-methanone; 2-(2-Fluoro-ethyl)-4-{4-[2-(2-methyl-pyrrolidin-1 -yl)-ethyl] -phenyl} octahydro-cyclopenta[c]pyrrole; 3-Methyl-i -(4- {4-[2-(2-methyl-pyrrolidin-1 -yl)-ethyl] -phenyl} -hexahydro 25 cyclopenta[c]pyrrol-2-yl)-butan-1 -one; 2,2,2-Trifluoro-1 -(4- {4-[2-(2-methyl-pyrrolidin-1 -yl)-ethyl] -phenyl} hexahydro-cyclopenta[c]pyrrol-2-yl)-ethanone; 1-(4-{4-[2-(2-Methyl-pyrrolidin-1 -yl)-ethyl]-phenyl} -hexahydro cyclopenta[c]pyrrol-2-yl)-2-thiophen-2-yl-ethanone; 30 Cyclopentyl-(5-methyl-4-{4-[2-(2-methyl-pyffolidin-1 -yl)-ethyl]-phenyl} hexahydro-cyclopenta[c]pyrrol-2-yl)-rnlethanone; 2,2-Dimethyl-1 -(4- {4-[2-(2-methyl-pyrrolidin-l -yl)-ethyl]-phenyl} -hexahydro cyclopenta[c]pyrrol-2-yl)-propan-1 -one; 1 -(4- {4-[2-(2-Methyl-pyrrolidin-1 -yl)-ethyl]-phenyl} -hexahydro 35 cyclopenta[c]pyrrol-2-yl)-ethanone; 1 -(4- {4-[2-(2-Methyl-pyrrolidin-1 -yl)-ethyl]-phenyl} -hexahydro cyclopenta[c]pyrrol-2-yl)-2-phenyl-ethanone; -211- WO 2007/061741 PCT/US2006/044479 1.4 4f2-(I-Mie' thy1-pyrrolidin-1 -yI)-ethyl]-phenyl} -hexahydro cyclopenta[c]pyrrol-2-yl)-2-(tetrahydro-pyran-4-yl)-ethanone; (4- {4-[2-(2-Methyl-pyrrolidin-1 -yl)-ethyl]-phenyl} -hexahydro cyclopenta[c]pyrrol-2-yl)-pyrimiidin-5-yl-methanone; 5 2-Methoxy-1 -(4- {4-[2-(2-methyl-pyrrolidin-1 -yl)-ethyl]-phenyl} -hexahydro cyclopenta[clpyrrol-2-yl)-ethanone; 2-(2,2-Difluoro-ethyl)-4-{4-[2-(2-methyl-pyrrolidin-1 -yl)-ethyl]-phenyl} octahydro-cyclopenta[c]pyrrole; (4- {4-[2-(2-Methyl-pyrrolidin-1 -yl)-ethyl]-phenyl} -hexahydro 10 cyclopenta[c]pyrrol-2-yl)-phenyl-methanone; 4-{4-[2-(2-Methyl-pyrrolidin-1 -yl)-ethyl]-phenyl} -2-(2,2,2-trifluoro-ethyl) octahydro-cyclopenta[c]pyrrole; (4- {4-[2-(2-llydroxymethyl-pyrrolidin-1 -yl)-ethyl]-phenyl} -hexahydro cyclopenta[c]pyrrol-2-yl)-(tetrahydro-pyran-4-yl)-methanone; 15 (4- {4-[2-(2-Methoxymethyl-pyrrolidin-1 -yl)-ethyl]-phenyl} -hexahydro cyclopenta[c]pyrrol-2-yl)-(tetrahydro-pyran-4-yl)-methanone; 1 -(2-{4-[2-(Tetrahydro-pyran-4-carbonyl)-octahydro-cyclopenta[c]pyrrol-4-yl] phenyl} -ethyl)-pyrrolidine-2-carboxylic acid amide; 1 -(2- {4-[2-(Tetrahydro-pyran-4-carbonyl)-octahydro-cyclopenta[c]pyrrol-4-yl] 20 phenyl} -ethyl)-pyrrolidine-2-carboxylic acid methylamide; {4-[4-(2-Pyrrolidin-1 -yl-ethyl)-phenyl]-hexahydro-cyclopenta[c]pyrrol-2-yl} (tetrahydro-pyran-4-yl)-methanone; {4-[4-(2-Piperidin-1 -yl-ethyl)-phenyl]-hexahydro-cyclopenta[c]pyrrol-2-yl} (tetrahydro-pyran-4-yl)-methanone; 25 {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[cjpyrrol-2-yl} (tetrahydro-pyran-4-yl)-methanone; (4- {4-[2-(3 -Hydroxy-pyrrolidin-1 -yl)-ethyl] -phenyl} -hexahydro 30 cyclopenta[c]pyrrol-2-yl)-(tetrahydro-pyran-4-yl)-methanone; (4- {4-[2-(3,3-Difluoro-pyrrolidin-1 -yl)-ethyl] -phenyl} -hexahydro cyclopenta[c]pyrrol-2-yl)-(tetrahydro-pyra-n-4-yl)-methanone; 4-(2-Benzyl-1 ,2,3 ,3a,6, 6a-hexahydro-cyclopenta[c]pyrrol-4-yl)-N-methyl benzamfide; 35 Cyclopentyl-(5-methyl-6- {4-[2-(2-methyl-pyrrolidin-1 -yl)-ethyl]-phenyl} 3,3a,4,6a-tetrahydro-ll-cyclopenta[c]pyr-rol-2-yl)-methanone;, 4-(2-Benzyl-1 ,2,3 ,3a,6,6a-hexahydro-cyclopenta[c]pyrrol-4-yl)-benzylamine; -212- WO 2007/061741 PCT/US2006/044479 en 1,2 4' ,3a, 6, 6a-hexahydro-cyclopenta[c]pyrrol-4-yl)-benzylamine; 2-Benzyl-6-[4-(2-piperidin-1 -yl-ethyl)-phenyl]-1 ,2,3,3a,4,6a-hexahyclro cyclopenta[c]pyrrole; 2-Ethyl-6-[4-(2-pyrrolidin-1 -yl-ethyl)-phenyl]-1 ,2,3,3a,4, 6a-hexahydro 5 cyclopenta[c]pyrrole; 2-IHydroxy-2-methyl- - {6-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl]-3,3a,4,6a tetrahydro-1H-cyclopenta[c]pyrrol-2-yl} -propan-1 -one; 2-Phenyl-6-[4-(2-pyrrolidin-1 -yl-ethyl)-phenyl]-1 ,2,3,3a,4,6a-hexahydro cyclopenta[c]pyrrole; 10 6-[4-(2-Pyrrolidin-1 -yl-ethyl)-phenyl]-3 ,3a,4,6a-tetrahydro-1H cyclopenta[c]pyrrole-2-carboxylic acid dimethylam-ide; 2-Cyclopentylmethyl-6-[4-(2-pyrrolidin-1 -yl-ethyl)-phenyl]-1 ,2,3,3a,4,6a hexahydro-cyclopenta[c]pyrrole; {6-[4-(2-Pyrrolidin-1 -yl-ethyl)-phenyl]-3,3a,4,6a-tetrahydro-1H 15 cyclopenta[c]pyrrol-2-yl} -thiophen-2-yl-methanone; 2-Pyridin-3-yl-6-[4-(2-pyrrolidin-1 -yl-ethyl)-phenyl]-1 ,2,3 ,3a,4,6a-hexahydro cyclopenta[c]pyrrole; 2-Pyridin-4-yl-6-[4-(2-pyrrolidin- 1 -yl-ethyl)-phenyl] -1 ,2,3,3 a,4,6a-hexahydro cyclopenta[c]pyrrole; 20 Furan-2-yl- {6-[4-(2-pyrrolidin-1 -yl-ethyl)-phenyl]-3 ,3a,4,6a-tetrahydro-1H cyclopenta[clpyrrol-2-yl} -methanone; Morpholin-4-yl-{f6-[4-(2-pyrrolidin- 1 -yl-ethyl)-phenyl]-3,3 a,4,6a-tetrahydro 1IH-cyclopenta[c]pyrrol-2-yl}-methanone; 2-(3,-Methoxy-phenyl)-6-[4-(2-pyrrolidin-1 -yl-ethyl)-phenyl]- 1,2,3,3 a,4,6a 25 hexahydro-cyclopenta[c]pyrrole; 6-[4-(2-Pyrrolidin-1 -yl-ethyl)-phenyl]-2-thiazol-2-yl-1 ,2,3,3a,4,6a-hexahydro cyclopenta[c]pyrrole; Pyridin-3 -yl- f{6-[4-(2-pyrrolidin- 1 -yl-ethyl)-phenyl] -3,3 a,4,6a-tetrahydro-1IH cyclopenta[c]pyrrol-2-yl} -methanone; 30 Pyridin-2-yl- {6-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl]-3,3a,4,6a-tetrahydro-1H cyclopenta[c]pyrrol-2-yl} -methanone; Cyclohexyl-{f6-[4-(2-pyrrolidin-I -yl-ethyl)-phenyl]-3,3 a,4,6a-tetrahydro-1T1 cyclopenta[clpyrrol-2-yl} -methanone; {6-[4-(2-Pyrrolidin-1 -yl-ethyl)-phenyl]-3,3a,4,6a-tetrahydro-fIH 35 cyclopenta[c]pyrrol-2-yl} -(tetrahydro-furan-3 -yl)-methanone; 2-Pyrazin-2-yl-6-[4-(2-pyrrolidin-1 -yl-ethyl)-phenyl]-1 ,2,3 ,3a,4,6a-hexahydro cyclopenta[c]pyrrole; -213- WO 2007/061741 PCT/US2006/044479 ii::: t. I~ili i Vi ~'n y-ty1-hny]33,,attaacr-H hn- 61 .--(Z2-pyrrolidi1ylehlphy]-,a46ttrydoH' cyclopenta[c]pyrrol-2-yl} -methanone; 2-Phenyl- 1 -{16-[4-(2-pyrrolidin-1 -yl-ethyl)-phenyl] -3,3 a,4,6a-tetrahydro-fIH cyclopenta[c]pyrrol-2-yl} -ethanone; 5 Pyrazin-2-yl- {6-[4-(2-pyrrolidin-1 -yl-ethyl)-phenyl]-3 ,3a,4,6a-tetrahydro-1H cyclopenta[c]pyrrol-2-yl} -methanone; 2-Pyrimidin-2-yl-6-[4-(2-pyrrolidin-l -yl-ethyl)-phenyl]-1 ,2 ,3 ,3a,4,6a hexahydro-cyclopentalpyrrole; 2-Methyl-i -(6- {4-[2-(3-phenyl-pyrrolidin- 1 -yl)-ethyl]-phenyl} -3,3 a,4,6a 10 tetrahydro-1H-cyclopenta[c]pyrrol-2-yl)-propan-l -one; 1 -(6- {4-[2-(2-Isopropyl-pyrrolidin-1 -yl)-ethyl]-phenyl} -3 ,3a,4,6a-tetrahydro fl{-cyclopenta[c]pyrrol-2-yl)-2-methyl-propan-l -one; 2-B enzyl-6- {4-[2-(2-trifluoromethyl-pyrrolidin-1 -yl)-ethyl]-phenyl} 1,2,3,3a,4,6a-hexahydro-cyclopenta[clpyrrole; 15 2-Methyl-i -(6- {4-[2-(2-phenyl-pyrrolidin-1 -yl)-ethyl]-phenyl} -3,3a,4,6a tetrahyclro-1IH-cyclopenta[c]pyrrol-2-yl)-propan-l -one; 2-Methyl-i -(6- {4-[2-(2-methyl-pyrrolidin-i -yl)-ethyl]-phenyl} -3 ,3a,4,6a tetrahydro-iH-cyclopenta[cjpyrrol-2-y1)-propan-I -one; Isoxazol-5-yl- {6-[4-(2-pyrrolidin-1 -yl-ethyl)-phenyl]-3,3a,4,6a-tetrahydro-flH 20 cyelopenta[c]pyrrol-2-yl} -methanone; 2-Pyridin-3 -yl-1 - {6-[4-(2-pyrrolidin-I -yl-ethyl)-phenyl]-3,3 a,4,6a-tetrahydro 1ll-cyclopenta[c]pyrrol-2-yl} -ethanone; 2-Pyridin-2-yl-i1 - {6-[4-(2-pyrrolidin-1 -yi-ethyl)-phenyl]I-3,3 a,4,6a-tetrahydro iH-cyclopenta[c]pyrrol-2-yl} -ethanone; 25 1 -(6- {4-[2-(2-Hyclroxymethyl-pyrrolidin-1I -yl)-ethyi]-phenyi} -3,3 a,4,6a tetrahydro-1IH-cyclopenta~c]pyrro1-2-yl)-2-methyl-propan-1I -one; 2-Pyridin-4-yl-i - {6-[4-(2-pyrrolidin-I -yl-ethy1)-phenylI]-3,3 a,4,6a-tetrahydro iH-cyclopenta~c]pyrrol-2-yl} -ethanone; 2-Pyrimidin-5-yl-6-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl]-i ,2,3 ,3a,4, 6a 30 hexahydro-cyclopenta[c]pyrrole; Gyciopropyl-(6- {4-[2-(2-methyl-pyrrolidin-i -yl)-ethyl]-phenyl} -3,3a,4,6a tetrahydro-1H-cyclopenta[cjpyrro1-2-yl)-methanone; (6- {4-[2-(2-Methyl-pyrrolidin-1 -yl)-ethyl]-phenyl} -3 ,3a,4,6a-tetrahydro-ill cyclopenta[c]pyrrol-2-yl)-pyridin-3-yl-inethanone; 35 Cyclopentyl-(6- {4-[2-(2-methyl-pyrrolidin-i -yl)-ethyl]-phenyl} -3 ,3a,4,6a tetrahydro-IH-cyclopenta[c]pyrrol-2-yl)-methanone; -214- WO 2007/061741 PCT/US2006/044479 l1 1-(6-. W(-Mthyl-pyrrolidin-1 -yl)-ethyl]-phenyl} -3,3a,4,6a-tetrahydro-1H cyclopenta[c]pyrrol-2-yl)-2-phenyl-ethanone; 2-(3,5-Difluoro-phenyl)-6-[4-(2-pyrrolidin-1 -yl-ethyl)-phenyl]-1,2,3,3a,4,6a hexahydro-cyclopenta[c]pyrrole; 5 3- {6-[4-(2-Pyrrolidin- 1 -yl-ethyl)-phenyl]-3,3a,4,6a-tetrahydro-1H cyclopenta[c]pyrrol-2-yl} -benzonitrile; 1-(6- {4-[2-(2,5-Dimethyl-pyrrolidin-1 -yl)-ethyl]-phenyl} -3,3a,4,6a-tetrahydro 1H-cyclopenta[c]pyrrol-2-yl)-2-methyl-propan-1 -one; (6- {4-[2-(2-Methyl-pyrrolidin-1 -yl)-ethyl]-phenyl} -3,3a,4,6a-tetrahydro-1H 10 cyclopenta[c]pyrrol-2-yl)-phenyl-methanone; 6- {4-[2-(2-Methyl-pyrrolidin-1 -yl)-ethyl]-phenyl} -2-(6-trifluoromethyl-pyridin 3-yl)-1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole; 5-(6- {4-[2-(2-Methyl-pyrrolidin-1 -yl)-ethyl]-phenyl} -3,3a,4,6a-tetrahydro-lH cyclopenta[c]pyrrol-2-yl)-pyridine-2-carbonitrile; 15 (6- {4-[2-(2-Methyl-pyrrolidin-1 -yl)-ethyl]-phenyl} -3,3a,4,6a-tetrahydro-1H cyclopenta[c]pyrrol-2-yl)-(tetrahydro-pyran-4-yl)-methanone; 2-Benzyl-5-methyl-6-{4-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-phenyl} 1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole; 2-Benzyl-6-[4-(2-methyl-pyrrolidin-1-ylmethyl)-phenyl]-1,2,3,3a,4,6a 20 hexahydro-cyclopenta[c]pyrrole; 6-{4-[2-(2-Methyl-pyrrolidin-1-yl)-ethyl]-phenyl} -3,3a,4,6a-tetrahydro-1H cyclopenta[c]pyrrole-2-carboxylic acid ethyl ester; Pyridin-4-yl- {6-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl]-3,3a,4,6a-tetrahydro-1lH cyclopenta[c]pyrrol-2-yl} -methanone; 25 {7-[4-(2-Pyrrolidin-1 -yl-ethyl)-phenyl]-1,3,3a,4,5,7a-hexahydro-isoindol-2-yl} (tetrahydro-furan-3-yl)-methanone; Pyridin-3-yl- {7-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl]-1,3,3a,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 30 isoindol-2-yl)-ethanone; 2-Methyl-1 -(7- {4-[2-(2-methyl-pyrrolidin-1 -yl)-ethyl]-phenyl} -1,3,3a,4,5,7a hexahydro-isoindol-2-yl)-propan-1 -one; Cyclopropyl-(7- {4-[2-(2-methyl-pyrrolidin-1 -yl)-ethyl]-phenyl} -1,3,3a,4,5,7a hexahydro-isoindol-2-yl)-methanone; 35 Cyclopentyl-(7- {4-[2-(2-methyl-pyrrolidin-1 -yl)-ethyl]-phenyl} -1,3,3a,4,5,7a hexahydro-isoindol-2-yl)-methanone; -215- WO 2007/061741 PCT/US2006/044479 1 ( ~- (2-M7thy1-pyrrolidin-1 -yl)-ethyl]-phenyl} -1 ,3,3a,4,5,7a-hexahydro isoindol-2-yl)-2-phenyl-ethanone; (7- {4-[2-(2-Methyl-pyrrolidin-1 -yl)-ethyl]-phenyl} -1 ,3,3a,4,5,7a-hexahydro isoindol-2-yl)-(tetrahydro-furan-3 -yl)-methanone; 5 2-Benzyl-7- {4-[2-(2-methyl-pyrrolidin-1 -yl)-ethyl]-phenyl} -2,3,3a,4,5,7a hexahydro-1H-isoindole; {4-[4-(2-Pyrrolidin-1 -yl-ethyl)-phenyl]-octahydro-isoindol-2-yl} -(tetrahydro furan-3-yl)-methanone; 1 -(4- {4-[2-(2-Methyl-pyrrolidin-1 -yl)-ethyl]-phenyl} -octahyclro-isoindol-2-yl) 10 ethanone; (4- {4-[2-(2-Methyl-pyrrolidin-1 -yl)-ethyl]-phenyl} -octahydro-isoindol-2-yl) (tetrahydro-furan-3-yl)-methanone; 2-Methyl-i -(4- {4-[2-(2-methyl-pyrrolidin-1 -yl)-ethyl]-phenyl} -octahydro isoindol-2-yl)-propan-1 -one; 15 Cyclopentyl-(4-{4-12-(2-methyl-pyrrolidin-l -yl)-ethyl]-phenyl} -octahydro isoindol-2-yl)-methanone; (4- {4-[2-(2-Methiyl-pyrrolidin-1 -yl)-ethyl-phenyl} -octahydro-isoindol-2-yl) (tetrahydro-pyran-4-yl)-methanone; 1 -{2-[4-(2-Benzyl-1 ,2,3,3a,6,6a-hexahydro-cyclopenta[c]pyrrol-4-yl)-phenyl] 20 ethyl} -pyrrolidin-2-one; 3- {6-[4-(2-Pyrrolidin-1 -yl-ethyl)-phenyl]-3,3a,4,6a-tetrahylro-IH cyclopenta[cllpyrrol-2-yl} -benzaldehyde; 2-Methanesulfonyl-6-[4-(2-pyrrolidin-1 -yl-ethyl)-phenyl]-1 ,2,3,3a,4,6a hexahydro-cyclopentallclpyrrole; 25 2-(Propane-2-sulfonyl)-6-[4-(2-pyrrolidin-1 -yl-ethyl)-phenyl]-1 ,2,3,3 a,4,6a hexahydro-cyclopenta[c]pyrrole; 2-Benzenesulfonyl-6-[4-(2-pyrrolidi-n-1 -yl-ethyl)-phenyl]- 1,2,3,3a,4,6a hexahydro-eyclopenta[c]pyrrole; 2-Phenylmethanesulfonyl-6-[4-(2-pyrrolidin-1 -yl-ethyl)-phenyl]-1 ,2,3 ,3a,4,6a 30 hexahydro-cyclopentaliclpyrrole; 2-Ethanesulfonyl-6-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl]-1 ,2,3,3a,4,6a hexahydro-cyclopenta[c]pyrrole; 2-Cyclopropanesulfonyl-6-[4-(2-pyrrolidin-1-yl-ethyl)-phenyll-l,2,3,3a,4,6a hexahydro-cyclopenta[c]pyrrole; 35 2-Cyclopropanesulfonyl-6- {4-[2-(2-methyl-pyrrolidin-1 -yl)-ethyl]-phenyll 1,2,3, 3a,4, 6a-hexahydro-cyclopenta[c]pyrrole; -216- WO 2007/061741 PCT/US2006/044479 C-{4-S E 1 2 et ld-pyrrolidin-1-yl)-ethyl]-phenyl}-2-(propane-2-sulfonyl) 1,2,3,3a,4,6a-hexahydro-cyclopenta[c]pyrrole; 2-(Propane-2-sulfonyl)-7-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl]-2,3,3a,4,5,7a hexahydro-1H-isoindole; and 5 2-Cyclopropanesulfonyl-7-[4-(2-pyrrolidin-1-yl-ethyl)-phenyl]-2,3,3a,4,5,7a hexahydro-1H-isoindole; or a pharmaceutically acceptable salt, hydrate or solvate thereof.
44. A pharmaceutical composition comprising a compound according to any one of claims 10 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 15 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, 20 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. 25 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 30 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. 35 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, -217- WO 2007/061741 PCT/US2006/044479 > aen'""o/ aeficJ hyperacivity 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. 5
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 10 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. 15 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 20 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 25 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. 30 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. 35 -218- WO 2007/061741 PCT/US2006/044479 I I 1 iarmaceu ical comp sition comprising 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. 5 60. A method for treating a H113-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. 10 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 15 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. 20
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. 25
64. Use of a compound according to anyone 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 H3 receptor associated disorder. 30 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, 35 neurogenic inflammation, migraine, eating disorders, dementia, and Alzheimer's disease. -219- WO 2007/061741 PCT/US2006/044479 PC / :: i. el s 1 ~ 1 'n ,l b 64, 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, 5 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. 10 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, 15 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 20 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. 25
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 30 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. - 220 -
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