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(11) Patent Number: K.E 527   

(45) Date of grant: 15/03/2013   
           
(51) Int.CI.8:       

(73) Owner:   
A 61K 31/435, A 61P 25/00, 25/16,    SANOFI of Patent Department, 17 4 A venue de France,   
25/18,25/22, 25/24, 25/28, 3/04    F-75013 Paris, France   

(21)Application Number:    KElP/ 2011/001334

(72) Inventors:    GAO, Zhongli,  c/o Sanofi-Aventis U.S. 1041 Route 202-    206 Mail Code: BWD-303A Bridgewater, New Jersey   

(22) Filing Date:        08807, US; HARTUNG, Ryan, c/o Sanofi-Aventis U.S.   
04/12/2009        1041 Route 202-206 Mail Code: BWD-303A   
        Bridgewater, New Jersey 08807 US and HALL, Daniel,   
(30) Priority data:        c/o Sanofi-Aventis U.S. 1041 Route 202-206 Mail Code:   
095 5431  31/07/2009  FR and    BWD-303A Bridgewater, New Jersey 08807, US   
611120,088  05/12/2008  us   

(74) Agent/address for correspondence:   
           
(86)  PCT data        Kaplan & Stratton Advocates, P.O. Box 40111-00100,   
PCT/US09/066673    04/12/2009    Nairobi   
wo 2010/065803    10/06/2010           


(54)    Title:

SUBSTITUTED PIPERIDINE SPIRO PYRROLIDINONE AND PIPERIDINONES USED AS H3 MODULATORS

•(57) Abstract:

The present invention discloses and claims a series of substituted N-phenyl-bipyrrolidine carboxamides of formula (I), wherein R1, R2, R3, m, nand pare as described herein. More specifically, the compounds of this invention are modulators of H3 receptors and are, therefore, useful as pharmaceutical agents, especially in the treatment and/or prevention of a variety of diseases modulated by H3 receptors including diseases associated with the central nervous system. Additionally, this invention also discloses methods of preparation of substituted N-phenyl-bipyrrolidine carboxamides and intermediates therefor.
 







SUBSTITUTED  PIPERIDINE  SPIRO  PYRROLIDINONE  AND  PIPERIDINONES  USED  AS  H3

MODULATORS


5





BACKGROUND OF THE INVENTION

Field of the Invention

10 The present invention relates to a series of substituted piperidine spiro pyrrolidinone and piperidinone derivatives. The compounds of this invention are modulators of H3 receptors and are, therefore, useful as pharmaceutical agents, especially in the treatment and/or prevention of a variety of diseases modulated by H3 receptors including diseases associated with the central nervous system.

15    Additionally, this invention also relates to methods of preparation of substituted piperidine spiro pyrrolidinone and piperidinone and intermediates therefor. Description of the Art
Histamine  is  a ubiquitous  messenger  molecule  released  from  mast cells,

enterochromaffin-like cells, and neurons.  The physiological actions of histamine are

20    mediated by four pharmacologically defined receptors (H 1, H2, H3 and H4 ). All histamine receptors exhibit seven transmembrane domains and are members of the G-protein-coupled receptor superfamily (GPCRs).

The H1 receptor was the first member of the histamine receptor family to be pharmacologically defined, with the development of classical antihistamines

25    (antagonists), such as diphenhydramine and fexofenadine.  While antagonism of the
.....
H1  receptor of the immune system is commonly used for the treatment of allergic

reactions, the H1 receptor is also expressed in various peripheral tissues and the central nervous system (CNS). In the b~~tn; H1 is involved in the control of

wakefulness, mood, appetite and hormone secretion.

30 The H2 receptor is also expressed in the CNS, where it may modulate several processes, including cognition. However, H2 receptor antagonists have primarily been developed to ameliorate gastric ulcers by inhibiting histamine-mediated gastric
 

2


acid secretion by parietal cells. Classic H2 antagonists include cimetidine, ranitidine, and famotidine.

It should further be noted that H4 receptor function remains poorly defined, but may involve immune regulation and inflammatory processes.

5 On the other hand, H3 receptors have also been pharmacologically identified in the CNS, heart, lung, and stomach. The H3 receptor differs significantly from other histamine receptors, exhibiting low sequence homology (H1 :~ 22%, H2: 21%, H4: 35%). H3 is a presynaptic autoreceptor on histamine neurons in the brain and a presynaptic heteroreceptor in nonhistamine-containing neurons in both.,.-~he~cehfr~l~-c

10    and peripheral nervous systems.  In addition to histamine, H3 a~s?-'-;odulates the

~    .  -
release    and/or  synthesis  of  other  neurotransmitters,  inclupif:lg  acet)!lc.holir:~,E,?,,~~
I• I H  (    C);:; J\r;.;.d ;.;<
dopamine, norepinepherin and serotonin.  Of particular note, pres~0,aptic,fT-(o9!,1JC!.tion,.,
~\1.,:\--',_)o. -~..  '"•'   •-..!•'"   ~ _..r•  .  • ~  .. '
of histamine release by H3 allows significant regulation of H1 and ~f2-,Jt3~eptor~~ifi-'"rrie:....
••::;-::z.,• ..,~.--.-•--_-'---, .....

brain.  Modulating multiple neurotransmitter signaling pathways, H3 may ctdn~fti6Ste7t6:3'

15    varied physiological processes. Indeed, extensive preclinical evidence indicates that H3 plays a role in cognition, sleep-wake cycle and energy homeostasis.

Modulators of H3 function may be useful in the treatment of obesity and central nervous system disorders (Schizophrenia, Alzheimer's disease, attention-deficit

hyperactivity  disorder,  Parkinson's disease,  depression,  and  epilepsy),  sleep

20    disorders (narcolepsy and insomnia), cardiovascular disorders (acute myocardial infarction), respiratory disorders (asthma), and gastrointestinal disorders. See generally, Hancock. Biochem. Pharmacal. 2006 Apr 14;71 (8):11 03-13 and Esbenshade et al. Mollnterv. 2006 Apr;6(2):77-88, 59.
U.S.  Patent  No.  7,223,788  discloses  a  series  of  compounds,  including

25    substituted bis-pyrrolidines, having melanin concentrating hormone (MCH) receptor antagonists. But the compounds disclosed therein are not reported to be active at the H3 receptor site.

All of the references described herein are incorporated herein by reference in

their entirety.

30    Accordingly, it is an object of this invention to provide a series of substituted

piperidine spiro pyrrolidinone and piperidinone as selective H3 receptor ligands for

treatment of H3 receptor regulated CNS disorders.
 

4


In other aspects of this invention there are also provided various pharmaceutical compositions comprising one or more compounds of formula (I) as well as their therapeutic use in alleviating various diseases which are mediated in-part and/or fully by H3 receptors.

5 DETAILED DESCRIPTION OF THE INVENTION The terms as used herein have the following meanings:
As used herein, the expression "(C1- C6)alkyl" includes methyl and ethyl groups, and straight-chained or branched propyl, and butyl groups. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl and tert-butyl. Derived expressions such
10    as "(C1- C6)alkoxy", "(Cr C6)alkoxy(C1- C6)alkyl", or "hydroxy(C1- C6)alkyl" are to be construed accordingly.

As used herein, the expression "cycloalkyl" includes all of the known cyclic

radicals.    Representative  examples  of "cycloalkyl"  include without  any  limitation

cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

15    Derived expressions such as "cycloalkoxy", "cycloalkylalkyl", "cycloalkylaryl", "cycloalkylcarbonyl" are to be construed accordingly.
As used herein, the expression "(C1-Ce)perfluoroalkyl" means that all of the

hydrogen atoms in said alkyl group are replaced with fluorine atoms. Illustrative examples include trifluoromethyl and pentafluoroethyl, and straight-chained or

20 branched heptafluoropropyl, nonafluorobutyl, undecafluoropentyl and tridecafluorohexyl groups. Derived expression, "(C1-Cs)perfluoroalkoxy", is to be construed accordingly.

As used herein, the expression "(Ce-C1o)aryl" means substituted or unsubstituted phenyl or naphthyl. Specific examples of substituted phenyl or

25    naphthyl include o-, p-, m-tolyl, 1 ,2-, 1,3-, 1,4-xylyl, 1-methylnaphthyl, 2-methylnaphthyl, etc. "Substituted phenyl" or "substituted naphthyl" also include any of

the possible substituents as further defined herein or one known in the art. Derived expression, "(C6-C1o)arylsulfonyl," is to be construed accordingly.

As  used  herein,  the  expression  "(Ce-C10)aryi(C1-C4)alkyl"  means  that  the

30    (C6-C10)aryl as defined herein is further attached to (CrC4)alkyl as defined herein. Representative examples include benzyl, phenylethyl, 2-phenylpropyl, 1-naphthylmethyl, 2-naphthylmethyl and the like. Similarly, the expression
 

5


"(C6-C10 )arylcarbonyl" shall be construed accordingly. Representative examples include benzoyl, naphthylcarbonyl, and the like.

As used herein, the expression "heteroaryl" includes all of the known heteroatom containing aromatic radicals. Representative 5-membered heteroaryl

5    radicals include furanyl, thienyl or thiophenyl, pyrrolyl, isopyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isothiazolyl, and the like. Representative 6-membered heteroaryl radicals include pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and

the like radicals.   Representative examples of bicyclic heteroaryl radicals  include,

benzofuranyl,    benzothiophenyl,    indolyl,    quinolinyl.,    isoquinolinyl,   cinnolyl,

10    benzimidazolyl, indazolyl, pyridofuranyl, pyridothienyl, and the like radicals. Derived expression "heteroarylcarbonyl" shall be construed accordingly, e.g., pyridinecarbonyl, furancarbonyl, and the like.

As used herein, the expression "heterocycle" includes all of the known reduced

heteroatom  containing  cyclic  radicals.   Representative  5-membered  heterocycle

15    radicals include tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, 2:.thiazolinyl, tetrahydrothiazolyl, tetrahydrooxazolyl, and the like. Representative 6-membered

heterocycle  radicals  include  piperidinyl,  piperazinyl,  morpholinyl,  thiomorpholinyl,

tetrahydropyranyl, and the like.  Various other heterocycle radicals include, without

any  limitation,  aziridinyl,  azepanyl,  diazepanyl,  diazabicyclo[2.2.1]hept-2-yl,  and

20    triazocanyl, and the like. Derived expression "heterocyclecarbonyl" and "heterocycloalkyi(C1-Cs)alkyl" shall be construed accordingly.
"Halogen" or "halo" means chloro, fluoro, bromo, and iodo.

As used herein, "patient" means a warm blooded animal, such as for example rat, mice, dogs, cats, guinea pigs, and primates such as humans.

25 As used herein, the expression "pharmaceutically acceptable carrier" means a non-toxic solvent, dispersant, excipient, adjuvant, or other material which is mixed with the compound of the present invention in order to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to the patient. One example of such a carrier is pharmaceutically acceptable oil typically

30    used for parenteral administration.

The term "pharmaceutically acceptable salts" as used herein means that the salts of the compounds of the present invention can be used in medicinal preparations. Other salts may, however, be useful in the preparation of the
 

6


compounds according to the invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable

5    acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfamic acid, sulfuric acid, methanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, hydroxymaleic acid, malic acid, ascorbic acid, succinic acid, glutaric acid, acetic acid, propionic acid, salicylic acid, cinnamic acid, 2-

phenoxybenzoic acid, hydroxybenzoic acid, phenylacetic acid, benzoic acid, oxalic

10    acid, citric acid, tartaric acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, carbonic acid or phosphoric acid. The acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate can also be formed. Also, the salts so formed may present either as mono- or di- acid salts and can exist substantially anhydrous or can be hydrated. Furthermore, where the compounds of

15    the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts, and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.

The expression "stereoisomers" is a general term used for all isomers of the

20    individual  molecules  that  differ only  in  the  orientation  of their  atoms  in  space.

Typically it includes mirror image isomers that are usually formed due to a!)~~a;s;ty'&fe asymmetric center, (enantiomers). Where the compounds according to1ff~S:rnv~ntion

possess two or more asymmetric centers, they may addition~~( exi~t,(J~9 diastereoisomers, also certain individual molecules may exist as geo~~~Q.iSof.neJ:~

25    (cis/trans). Similarly, certain compounds of this invention may exist in~~~] two or more structurally distinct forms that are in rapid equilibrium, commonl~wr as tautomers. Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is

to be understood that all such isomers and mixtures thereof in any proportion are

30    encompassed within the scope of the present invention.

As used herein, 'R'and 'S'are used as commonly used terms in organic chemistry to denote specific configuration of a chiral center. The term 'R'(rectus) refers to that configuration of a chiral center with a clockwise relationship of group
 

7


priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The term 'S'(sinister) refers to that configuration of a chiral center with a counterclockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The priority of groups is

5    based upon sequence rules wherein prioritization is first based on atomic number (in order of decreasing atomic number). A listing and discussion of priorities is contained in Stereochemistry of Organic Compounds, Ernest L. Eliel, Samuel H. Wilen and Lewis N. Mander, editors, Wiley-lnterscience, John Wiley & Sons, Inc., New York,
1994.

10 In addition to the (R)-(S) system, the older D-L system may also be used herein to denote absolute configuration, especially with reference to amino acids. In this system a Fischer projection formula is oriented so that the number 1 carbon of the main chain is at the top. The prefix 'D'is used to represent the absolute configuration of the isomer in which the functional (determining) group is on the right

15    side of the carbon at the chiral center and 'L',that of the isomer in which it is on the left.


In a broad sense, the term "substituted" is contemplated to include all permissible substituents of organic compounds. In a few of the specific embodiments as disclosed herein, the term "substituted" means substituted with one or more

20    substituents independently selected from the group consisting of (C1-Cs)alkyl, (C2-C6)alkenyl, (C1-Cs)perfluoroalkyl, phenyl, hydroxy, -C02H, an ester, an amide, (C1-C6)alkoxy, (C1-Cs)thioalkyl, (C1-Cs)perfluoroalkoxy, -NH2, Cl, Br, I, F, -NH-Iower alkyl, and -N(Iower alkyl)2. However, any of the other suitable substituents known to one

skilled in the art can also be used in these embodiments.

25 "Therapeutically effective amount" means an amount of the compound which is effective in treating the named disease, disorder or condition.

The term "treating" refers to:

(i) preventing a disease, disorder or condition from occurring in a patient that may be predisposed to the disease, disorder and/or condition, but has not yet

30    been diagnosed as having it;

(ii)    inhibiting the disease, disorder or condition, i.e., arresting its development; and
 

8


(iii)    relieving the disease, disorder or condition, i.e., causing regression of the disease, disorder and/or condition.

Thus, in accordance with the practice of this invention there is provided a compound of the formula 1:

5 This invention further includes various salts of the compounds of formula (I) including various enantiomers or diastereomers of compounds of formula (I).
In other aspects of this invention there are also provided various pharmaceutical compositions comprising one or more compounds of formula (I) as well as their therapeutic use in alleviating various diseases which are mediated in-

10    part and/or fully by H3 receptors.

Thus,  in  accordance with the practice of this  invention there  is provided  a

compound of the formula 1:









(I)

15    wherein

m is 1 or 2; n is 1 or 2;

pis 1 or 2;

R1 is hydrogen, (C1-C4)alkyl, CF3, (C1-C4)alkoxy-(C1-C4)alkyl; and

20    R2 is hydrogen, halogen, (C1-C4)alkyl or CFs;
R3 is hydrogen, (C1-Ce)alkyl, (C1-Ce)alkyloxycarbonyl, such as tert-butyloxycarbonyl, (C3-C7)cycloalkyi(C1-Ce)alkyl, substituted or unsubstituted heterocycle, such as tetrahydropyranyl, substituted or unsubstituted heterocycloalkyi(C1-C6 )alkyl, such as tetrahydropyranylmethyl, substituted or unsubstituted 5- or 6-

25    membered ring heteroaryi(C1-Ce)alkyl, such as furanylmethyl, substituted or unsubstituted benzyl, (C1-C4)alkoxymethylcarbonyl, substituted or unsubstituted (C3-C7 )cycloalkanecarbonyl, substituted or unsubstituted benzylcarbonyl, substituted or unsubstituted (Ce-C10)arylcarbonyl, such as naphthylcarbonyl, benzoyl, etc., substituted or unsubstituted 5 or 6-membered
 

9


ring heteroarylcarbonyl, such as pyridinecarbonyl or furancarbonyl, substituted or unsubstituted heterocyclecarbonyl, such as tetrahydropyrancarbonyl, substituted or unsubstituted benzenesulfonyl, wherein the substituents are selected from halogen, trifluoromethoxy, (C1-C4)alkoxy, (C1-C4)alkyl or CF3.

s This invention further includes various salts of the compounds of formula (I) including various enantiomers or diastereomers of compounds of formula (1). As noted hereinabove and by way of specific examples hereafter all of the salts that can be formed including pharmaceutically acceptable salts are part of this invention. As also noted hereinabove and hereafter all of th!3 conceivable enantiomeric and

10    diastereomeric forms of compounds of formula (I) are part of this invention.

In one of the embodiments, there is also provided the compounds of formula

(I) wherein

n, p and mare 1;

R1 is methyl, ethyl, isopropyl, n-propyl or methoxymethyl;

15    R2 is hydrogen, fluorine, chlorine, methyl,. ethyl or CF3; and
R3 is hydrogen, methoxymethylcarbonyl, tert-butyloxycarbonyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, tetrahydropyranyl, benzyl, furanylmethyl, cyclopentane-carbonyl, cyclohexanecarbonyl, trifluoromethoxybenzoyl, fluorobenzoyl,

benzyl-carbonyl,  naphthylcarbonyl,  benzenesulfonyl,  fluorobenzene  sulfonyl  or

20    methoxybenzenesulfonyl.

In another embodiment of this invention there is also provided a compound of formula (I), wherein n is 2 and m is 1; or n is 1 and m is 2; p is 1 or 2;

R1 is methyl or ethyl;

R2  is hydrogen, fluorine, chlorine, methyl, ethyl or CF3; and

25    R3 is hydrogen, isopropyl, tert-butyloxycarbonyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, tetrahydropyranyl, benzyl, furanylmethyl,

tetrahydropyranylmethyl, cyclopentanecarbonyl, cyclohexanecarbonyl, tetrahydropyrancarbonyl, benzoyl, trifluoromethoxybenzoyl, fluorobenzoyl, benzyl-carbonyl, naphthylcarbonyl, pyridinecarbonyl, furancarbonyl or benzenesulfonyl.

30 In a further aspect of this invention the following compounds encompassed by the scope of this invention without any limitation may be enumerated: 2-[2-methyi-4-((2R,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-1-oxo-2,8-diaza-
spiro[4.5]decane-8-carboxylic acid tert-butyl ester;
 

10


2-[2-methyi-4-((2R,3'R)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester;

2-[2-methyi-4-((28,3'R)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester;

5 2-[2-methyl-4-( (28,3'8)- 2-methyl-[1 ,3']bipyrrolidinyl-1'-yl)-phenyl]-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester;

2-[2 -methyl-4-(2 -methyl-[1 ,3']bipyrrolid inyl-1 '-yl)- phenyl]-1-oxo-2,8-d iaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester

2-[2-methyl-4-( (28 ,3'8)- 2-methyl-[1 ,3']bipyrrolidinyl-1'-yl)-phenyl]-1-oxo2,9--d iaza-

10 spiro[5.5]undecane-9-carboxylic acid tert-butyl ester; 2-[4-((28,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-1-oxo-2,9-diaza-
spiro[5.5]undecane-9-carboxylic acid tert-butyl ester;

4-{[2 -fluoro-4-( (28 ,3 '8)- 2-methyl-[1 ,3']bipyrrolid inyl-1 '-yl)- phenyl]-methyl-carbamoyl}-4-propyl-piperidine-1-carboxylic acid tert-butyl ester;

15 2-{4-[4-(28-2-methyl-pyrrolidin-1-yl)-piperidin-1-yl]-phenyl}-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester;

2-{4-[4-(28-2-methyl-pyrrolidin-1-yl)-piperidin-1-yl]-2-trifluoromethyl-phenyl}-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester;

2-{4-[4-(28-2-methyl-pyrrolidin-1-yl)-piperidin-1-yl]-2-fluoro-phenyl}-1-oxo-2,8-diaza-

20 spiro[4.5]decane-8-carboxylic acid tert-butyl ester; 2-{4-[3-((28,3'8)-2-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-phenyl}-1-oxo-2,8-diaza-

spiro[4.5]decane-8-carboxylic acid tert-butyl ester;

2-{4-[3-( (28 ,3'8)-2-methyl-piperidin-1-yl)- pyrrolidin-1-yl]-2-trifl uoromethyl-phenyl}-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester;

25 2-{4-[3-( (28 ,3'8)-2-methyl-piperidin-1-yl)-pyrrolid in-1-yl]-2-fluoro-phenyl}-1-oxo-2 ,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester;

2-[2-methyl-4-((28,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;

8-cyclopentylmethyl-2-[2-methyl-4-(2-methyl-[1 ,3']bipyrrolidinyl-1'-1)-phenyl]-2,8-diaza-

30    spiro[4.5]decan-1-one;

2-[2-methyl-4-( (28,3'8)- 2-methyl-[1 ,3']bipyrrolidinyl-1'-yl)-phenyl]-8-4(-trifl uoromethoxy-benzoyl )-2,8-d iaza-spiro[ 4 .5]decan-1-one;
 

11


8-benzenesulfonyl-2-{4-[4-(28-2-methyl-pyrrol id in-1-yl )-piperidin-1-yl]-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;

8-(4-methoxy-benzenesulfonyl)-2-[4-((28,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-2-trifl uoromethyl-phenyl]-2 ,8-d iaza-spiro[4 .5]d ecan-1-one;

5 2-[4-( (28,3'8)- 2-methyl-[1 ,3']bipyrrolidinyl-1'-yl)-2-trifluoromethyl-phenyl]-82,-diaza-spiro[4.5]decan-1-one

2-[2-methyl-4-((28,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;
2-[2-methyi-4-((2R,3'R)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-2,8-diaza-lO spiro[4.5]decan-1-one Hydrochloride;

2-[2-methyi-4-((2R,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one Hydrochloride;

2-[2-methyi-4-((28,3'R)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one Hydrochloride;

15 8-cyclopentylmethyl-2-[2-methyi-4-((2R,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-1)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;

8-cyclopentylmethyl-2-[2-methyl-4-( (2R,3'R)-2-methyl-[1,3']bipyrrolid inyl-1 '-)I-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;

8-cyclopentyl methyl-2-[2-methyl-4-( (28,3'R)- 2-methyl-[1 ,3']bipyrrolid inyl-1'-1)-phenyl]-

20 2,8-diaza-spiro[4.5]decan-1-one; 8-cyclopentylmethyl-2-[2-methyl-4-((28,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-1)-phenyl]-

2,8-diaza-spiro[4.5]decan-1-one; 2-[2-methyi-4-((2R,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-8-(4-

trifluoromethoxy-benzoyl)-2,8-diaza-spiro[4.5]decan-1-one;

25 2-[2-methyi-4-((2R,3'R)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-8-(4-trifluoromethoxy-benzoyl)-2,8-diaza-spiro[4.5]decan-1-one;

2-[2-methyi-4-((28,3'R)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-8-(4-trifluoromethoxy-benzoyl)-2,8-diaza-spiro[4.5]decan-1-one;

2-[2-methyl-4-(2-methyl-[1 ,3']bipyrrolidinyl-1'-yl)-phenyl]-8-(4-trifluoromethoxy-

30 benzoyl)-2,8-diaza-spiro[4.5]decan-1-one; 3-[2-methyl-4-((28,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-2,9-diaza-
spiro[5.5]undecan-1-one;
 

12


3-[4-((28,318)-2-methyl-[1 ,31]bipyrrolidinyl-1 ~-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-

1-one;

1    1
3-[2-fluoro-4-( (28 ,3 8)-2-methyl-[1 ,3 ] bipyrrol id inyl-1 I -yl)-phenyl]-2,9-d iaza-spiro[5.5]undecan-1-one;

5 3-[2-methyl-4-( (28,318)-2-methyl-[1 ,31]bipyrrolidinyl-1 ~-yl )-phenyl]-9-(pyridine-4-carbonyl)-2,9-diaza-spiro[5.5]undecan-1-one;

9-(furan-3-carbonyl)-2-[2-methyl-4-((28,318)-2-methyl-[1 ,31]bipyrrolidinyl-1 ~-yl)-phenyl]-

2,9-diaza-spiro[5.5]undecan-1-one;

9-benzoyl-2-[4-((28,318)-2-methyl-[1 ,31]bipyrrolidinyl-1 ~-yl)-phenyl]-2,9-diaza-

10    spiro[5.5]undecan-1-one;

9-( 4-fl uoro-benzoyl-2-[4-( (28 ,318)-2-methyl-[1 ,31]bipyrrol id inyl-1 '-yl)- phenyl]-2,9-d iaza-spiro[5.5]undecan-1-one;

9-cyclohexanecarbonyl-2-[2-fluoro-4-((2S,318)-2-methyl-[1 ,31]bipyrrolidinyl-1 1-yl)-phenyl]-2 ,9-d iaza-spiro[5.5]undecan-1-one;

15 2-[2-fluoro-4-((28,318)-2-methyl-[1 ,31]bipyrrolidinyl-1 1-yl)-phenyl]-9-(tetrahydro-pyran-4-carbonyl )-2,9-diaza-spiro[5.5]undecan-1-one;
1    1
9-isopropyl-2-[2-methyl-4-( (28,3 8 )-2-methyl-[1 ,3 ] bipyrrol id inyl-1 I -yl )-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;

9-cyclohexylmethyl-2-[2-methyl-4-((28,31S)-2-methyl-[1 ,31]bipyrrolidinyl-1 1-yl)-phenyl]-

20 2,9-diaza-spiro[5.5]undecan-1-one; 9-cyclopropylmethyl-2-[4-((28,318)-2-methyl-[1 ,31]bipyrrolidinyl-1 1-yl)-phenyl]-2,9-
diaza-spiro[5.5]undecan-1-one;

2-[4-((28,318)-2-methyl-[1 ,31]bipyrrolidinyl-1 ~-yl)-phenyl]-9-(tetrahydro-pyran-4-yl)-2,9-diaza-spiro[5.5]undecan-1-one;

25 9-benzyl-2-[2-fluoro-4-((28,3'S)-2-methyl-[1,31]bipyrrolidinyl.-1 1-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;

2-[2-fluoro-4-((28,3'8)-2-methyl-[1,31]bipyrrolidinyl-1 ~-yl)-phenyl]-9-furan-2-ylmethyl-

2,9-diaza-spiro[5.5]undecan-1-one;

2-{4-[4-(28-2-methyl-pyrrol id in-1-yl)-piperid in-1-yl]-phenyl}-2 ,8-diaza-spiro[4.5]decan-

30 1-one; 2-{4-[4-(2S-2-methyl-pyrrolidin-1-yl)-piperidin-1-yl]-2-trifluoromethyl-phenyl}-2,8-diaza-


spiro[4.5]decan-1-one;
 

13


2-{4-[4-(28-2-methyl-pyrrol id in-1-yl )-piperidin-1-yl]-2-fl uoro-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;

2-{4-[3-( (28 ,3'8)- 2-methyl-piperid in-1-yl )-pyrrol id in-1-yl]-phenyl}-2,8-d iaza-spiro[4.5]decan-1-one;

5 2 -{4-[3-( (28 ,3'8)- 2-methyl-piperid in-1-yl )-pyrrol id in-1-yl]-2-trifl uoromethyl-ph enyl}-2,8-diaza-spiro[4.5]decan-1-one;
2-{4-[3-( (28 ,3'8)- 2 -methyl-piperid in-1-yl)-pyrrol id in-1-yl]-2-fluoro-phenyl}-2, 8-d iaza-spiro[4.5]decan-1-one;

8-( 4-fluoro-benzoyl )-2-{4-[ 4-(28-2-methyl-pyrrol id in-1-yl)-piperid in-1-yl]-phenyl}-2,8-

10 diaza-spiro[4.5]decan-1-one; 8-cyclohexanecarbonyl-2-{2-fluoro-4-[4-(28-2-methyl-pyrrolidin-1-yl)-piperidin-1-yl]-

phenyl}-2,8-diaza-spiro[4.5]decan-1-one; 8-(4-tluoro-benzenesulfonyl)-2-{4-[3-((28,3'8)-2-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-
phenyl}-2,8-diaza-spiro[4.5]decan-1-one;

15 2-{4-[3-((28,3'8)-2-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-phenyl}-8-(tetrahydro-pyran-4-carbonyl)-2,8-diaza-spiro[4.5]decan-1-one;

8-cyclopentanecarbonyl-2-{4-[3-( (28,3 '8)- 2-methyl-piperid in-1-yl )-pyrrolidin-1-yl]-2-trifl uoromethyl-phenyl}-2,8-d iaza-spiro[4 .5]decan-1-one;

8-cyclopropylmethyl-2-{2-fl uoro-4-[4-(28-2-methyl-pyrrol id in-1-yl )-piperid in-1-yl]-

20 phenyl}-2,8-diaza-spiro[4.5]decan-1-one; 8-cyclopentylmethyl-2-{2-fluoro-4-[4-(2S-2-methyl-pyrrolidin-1-yl)-piperidin-1-yl]-

phenyl}-2,8-diaza-spiro[4.5]decan-1-one; 8-cyclohexylmethyl-2-{4-[3-((28,3'8)-2-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-2-
trifluoromethyl-phenyl}-2,8-d iaza-spiro[4 .5]decan-1-one;

25 2-{2-fluoro-4-[3-( (28,3'8)-2-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-phenyl}-8-(tetrahydro-pyran-4-ylmethyl)-2,8-diaza-spiro[4.5]decan-1-one;

2-[4-((28,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-2-trifluoromethyl-phenyl]-8-phenylacetyl-2,8-diaza-spiro[4.5]decan-1-one;

8-(2-methoxy-acetyl)-2-[4-((28,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-2-

30 trifluoromethyl-phenyl]-2 ,8-diaza-spiro[4.5]decan-1-one; 2-[4-((28,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-2-trifluoromethyl-phenyl]-8-
(naphthalene-2-carbonyl)-2,8-diaza-spiro[4.5]decan-1-one;
 

    14       
    8-benzoyl-2-[4-((28,318)-2-methyl-[1 ,31]bipyrrolidinyl-1 ~-yl)-2-trifluoromethyl-phenyl]-
    2,8-diaza-spiro[ 4.5]decan-1-one;       
    8-(furan-3-carbonyl)-2-[4-((28,318)-2-methyl-[1 ,31]bipyrrolidinyl-1 1-yl)-2-trifluoromethyl-
    phenyl]-2,8-d iaza-spiro[4.5]decan-1-one;       
5    8-furan-2-ylmethyi-2-[4-((2S,31S)-2-methyl-[1 ,31]bipyrrolidinyl-1 1-yl)-2-trifluoromethyl-
    ph enyl]-2 ,8-d iaza-spiro[4 .5]decan-1-one;       
    1    1    1
    8-cyclopropyl methyl-2-[4-( (28 ,3 8)-2-methyl-[1 ,3    ]  bipyrrolid inyl-1 -yl )-2-trifluoromethyl-
    phenyl]-2,8-d iaza-spiro[4.5]decan-1-one;       
    2-[4-((28,318)-2-methyl-[1 ,31]bipyrrolidinyl-1 ~-yl)-2-trifluoromethyl-phenyl]-8-
10    (tetrahydro-pyran-4-ylmethyl)-2,8-diaza-spiro[4.5]decan-1-one; and
    2-[4-( (28,318 )-2-methyl-[1 ,31]bipyrrolidinyl-1 I -yl )-2-trifl uoromethyl-phenyl]-2,8-d iaza-
    spiro[4.5]decan-1-one .       
    All of the above compounds may also include corresponding salts wherever
    possible including the pharmaceutically acceptable salts thereof.
15    In another aspect of this invention the following compounds encompassed by
    compound of formula (I) of this invention without any limitation may be enumerated:
    8-cyclopentylmethyl-2-[2-methyl-4-( (2R,318 )-2-methyl-[ 1 ,31]bipyrrol id inyl-1 1-l )-phenyl]-
    2,8-diaza-spiro[4.5]decan-1-one;       
    8-cyclopentyl methyl-2-[2-methyl-4-( (2R,31 R)-2-methyl-[1 ,31]bipyrrol idinyl-1 I -1 )-phenyl]-
20    2,8-diaza-spiro[4.5]decan-1-one;       
    8-cyclopentylmethyl-2-[2-methyi-4-((2S,31R)-2-methyl-[1 ,31]bipyrrolidinyl-1 1-l)-phenyl]-
    2,8-diaza-spiro[4.5]decan-1-one;       
    8-cyclopentylmethyl-2-[2-methyl-4-((28,318)-2-methyl-[1 ,31]bipyrrolidinyl-1 1-l)-phenyl]-
    2,8-diaza-spiro[ 4.5]decan-1-one;       
25    2-[2-methyl-4-( (2R,318)-2-methyl-[1 ,3']bipyrrolidinyl-1I- yl)-phenyl]-8-( 4,..
    trifluoromethoxy-benzoyl)-2,8-diaza-spiro[4.5]decan-1-one;.('•.-•:•
    2-[2-methyl-4-( (2R,3'R)-2-methyl-[1,3 1]bipyrrol idinyl-1 ~-yl )-pheny1J+~~f4-
            (.""'.
    trifluoromethoxy-benzoyl )-2 ,8-d iaza-spiro[ 4 .5]decan-1-one ;•~
    2-[2-methyi-4-((2S,31R)-2-methyl-[1 ,31]bipyrrolidinyl-1 1-yl)-phenyl]-8-(4-'
30    trifluoromethoxy-benzoyl)-2,8-diaza-spiro[4.5]decan-1-one;
    2-[2-methyl-4-(2-methyl-[1 ,31]bipyrrolidinyl-1 '-yl)-phenyl]-8-(4-trifluoromethoxy-
    benzoyl)-2,8-diaza-spiro[4 .5]decan-1-one;   
 

15


3-[2-methyl-4-((28,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;

3-[4-((28,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;


5 3-[2-fluoro-4-((28,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;

9-isopropyl-2-[2-methyl-4-( (28,3'8)- 2-methyl-[1 ,3']bipyrrolid inyl-1'-yl)- phenyl]-2, 9-diaza-spiro[5.5]undecan-1-one;

9-cyclohexylmethyl-2-[2-methyl-4-((28,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-

10 2,9-diaza-spiro[5.5]undecan-1-one; 9-cyclopropylmethyl-2-[4-((28,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-2,9-
diaza-spiro[5.5]undecan-1-one; 2-[4-((28,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-9-(tetrahydro-pyran-4-yl)-2,9-

diaza-spiro[5.5]undecan-1-one;

15 9-benzyl-2-[2-fluoro-4-((28,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;

2-[2-fluoro-4-( (28 ,3'8)-2-methyl-[1,3']bipyrrolid inyl-1'-yl)-phenyl]-9furan--2-ylrnethyl-2,9-diaza-spiro[5.5]undecan-1-one;

8-cyclopropylmethyl-2-{2-fluoro-4-[4-(28-2-methyl-pyrrolidin-1-yl)-piperidin-1-yl]-

20    phenyl}-2,8-diaza-spiro[4.5]decan-1-one;

8-cyclopentyl methyl-2-{2-fluoro-4-[4-(28-2-methyl-pyrrol id in-1-yl)-piperidin-1-yl]-phenyl}-2,8-diaza-spiro[4 .5]decan-1-one;

2 -{2-fluoro-4-[3-( (28 ,3'8)- 2-methyl-piperidin-1-yl )-pyrrol idin-1-yl]-phenyl}-8-(tetrahydro-pyran-4-ylmethyl)-2,8-diaza-spiro[4.5]decan-1-one;

25 8-furan-2-ylmethyl-2-[4-( (28 ,3'8)- 2-methyl-[1 ,3']bipyrrolid inyl-1'-yl)- 2-trifluoromethyl-phenyl]-2,8-d iaza-spiro[4 .5]decan-1-one;

8-cyclopropylmethyl-2-[4-((28,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-2-trifluoromethyl-phenyl]-2,8-diaza-spiro[4.5]decan-1-one; and

2-[4-((28,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-2-trifluoromethyl-phenyl]-8-

30    (tetrahydro-pyran-4-ylmethyl)-2,8-diaza-spiro[4.5]decan-1-one;

Again all of the conceivable salts of the above noted compounds including the pharmaceutically acceptable salts are part of this invention.
 

16


In another aspect of this invention the compound of this invention may be represented by a specific stereoisomeric form of formula (II):
0    N<r)    NQ''N~       
    )    )-V)p    (II)   
    n    R1,       

Wherein R1,  Rz, Rs, m, n and p are as defined hereinabove.

5 The compounds of this invention can be synthesized by any of the procedures known to one skilled in the art. Specifically, several of the starting materials used in the preparation of the compounds of this invention are known or are themselves commercially available. The compounds of this invention and several of the precursor compounds may also be prepared by methods used to prepare similar

10    compounds as reported in the literature and as further described herein. For instance, see R. C. Larock, "Comprehensive Organic Transformations," VCH publishers, 1989.

It is also well known that in various organic reactions it may be necessary to

protect reactive functional groups, such as for example, amino groups, to avoid their

15    unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice and known to one of skilled in the art, for example, see T. \IV. Greene and P. G. M. Wuts in "Protective Groups in Organic Chemistry" John Wiley and Sons, Inc., 1991. For example, suitable amine protecting

groups    include   without   any   limitation   sulfonyl   (e.g.,   tosyl),   acyl   (e.g.,

20    benzyloxycarbonyl or t-butoxycarbonyl) and arylalkyl (e.g., benzyl), which may be removed subsequently by hydrolysis or hydrogenation as appropriate. Other suitable amine protecting groups include trifluoroacetyl [-C(=O)CFs] which may be removed by

base catalyzed hydrolysis, or a solid phase resin  bound benzyl group, such as a

Merrifield resin bound 2,6-dimethoxybenzyl group (Ellman linker) or a 2,6-dimethoxy-

25    4-[2-(polystyrylmethoxy)ethoxy]benzyl, which may be removed by acid catalyzed hydrolysis, for example with TFA.
More specifically,  the  compounds  disclosed  herein  and various  precursors

used therefor can be synthesized according to the following procedures of Schemes

1 - 5, wherein R1, Rz, Rs, m and n are as defined for Formula I unless otherwise

30    indicated.
 

17


For instance, Scheme 1 illustrates the preparation of the intermediate [1, 3']-pyrrolidinyl-pyrrolidine of formula (4 ), wherein R is as defined herein. First, in step 1, Scheme 1, suitably protected (for example tert-butyloxycarbonyl (boc)) pyrrolidinone of formula (1) is condensed with a desired substituted pyrrolidine of formula (2) by

5    any of the known reductive amination procedures to form an intermediate of formula

(3).   For instance,  such  condensation  reactions  are generally carried  out in the

presence of reducing agents such as triacetoxyborohydride in an inert atmosphere,

such as nitrogen atmosphere.  The reaction can be carried out either at sub-ambient,

ambient or super-ambient reaction  temperatures  and  pressures.   Typically,  such

10    reactions are carried out at room temperature at atmospheric pressure of nitrogen. The reaction mixture is then worked-up using procedures known to skilled in the art to isolate the intermediate of formula (3).

In step 2, Scheme 1, the intermediate (3) is then de-protected to form the

desired [1, 3']-pyrrolidinyl-pyrrolidineof formula (4 ).  Such de protection reactions are

15    generally  carried  out  under  acidic  conditions,  for  example,  in  the  presence  of

hydrochloric acid at sub-ambient to ambient temperatures, for example in the temperature range of about -1 ooc to room temperature. However, other suitable reaction temperatures can also be used depending upon the nature of the intermediate of formula (3).

20        Scheme 1           
boc __jf~o +    y step1    . boc           
    HN    )p        m    }p   
                )~~-9       
(1)    (2)    R1        R1       
                (3)       
                       

step 2
)lo    HNQ--9)p

m,p=1,2    (4)   R1

Scheme 2 illustrates preparation of enantiomerically pure isomers of the [1 ,3'] pyrrolidinyl-pyrrolidine of formula (9), wherein R is as defined herein. In step 1, Scheme 2, suitably protected (for example boc) pyrrolidine or piperidine alcohol of

25    formula (5) is treated with p-toluene sulfonyl chloride to form intermediate of formula
 

18


(6). This reaction can be carried out using any of the procedures known to one skilled in the art, such as for example carrying out the reaction in the presence of a suitable base such as triethylamine and DMAP in a suitable organic solvent, preferably an aprotic solvent such as dichloromethane at sub-ambient or ambient

5    temperature conditions.

In step 2, Scheme 2, the intermediate of formula (6) is condensed with a desired pyrrolidine or piperidine of formula (7). Again, such condensation reactions can be carried out using any of the procedures known to one skilled in the art in order to obtain the intermediate of formula (8). Typically, such condensation reactions are

10    carried out in the presence of a base such as potassium carbonate in the presence of solvents such as acetonitrile at ambient to super-ambient temperature conditions.

In step 3, Scheme 2, the_ intermediate of formula (8) is then reacted with an acid, such as hydrochloric acid in a suitable solvent, such as dioxane, to form the desired stereospecific isomer of intermediate of formula (9). It has now been found

15    that the intermediates of formula (9) can be readily formed in accordance with the process of this invention with high enantiomeric purity, specific details of which are

provided hereinbelow by way of various examples. In general, the enantiomeric purity can be determined by chiral HPLC.

    Scheme 2
step 1    step 2
boc-~~OHNf\   TsCI

(5)

    boc,.....NQ••,,omN    step 3       
            m'N   
               
    (8)    R/•••) P        HNQ•••o   
            (9)Rr•••) p   
               
20    m, p =1, 2           

Scheme 3 illustrates the preparation of the intermediate of formula (13). In step 1, Scheme 3, commercially available piperidine-1 ,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester, of formula (10) is treated with suitable base, such as nBuli in presence of HMPA in THF, followed by alkenyl halides, to form intermediate of
 

19


formula (12). This reaction can be carried out using any of the procedures known to one skilled in the art, such as reported in the literature (Nagumo, S.; Matoba A.; et al, Tetrahedron, 2002, 58(49), 9871-9877; Stafford, J. A.; Heathcock, C. H. J. Org. Chern., 1990, 55(20), 5433-5434). In step 2, Scheme 3, the alkene (12) is cleaved

5 with Os04 and Nai04 in propanol and water to form aldehyde (13). Scheme 3

                    Step 1       
                           
                    nBuLi       
                    HMPA       
        (11)        THF    n   
(10)                   
                       
        Step2            (12)   
                           
        Nal04               
        Os04               
        iPrOH        n       
        H20               
X= I, Br            (13)           
n = 1, 2                       

Scheme 4 illustrates the preparation of compounds of this invention. The aldehyde of formula (13) is condensed with a desired commercially available bromide

10    of formula (16) by any of the known reductive amination procedures to form an intermediate of formula (17). For instance, such condensation reactions are generally carried out in the presence of reducing agents such as triacetoxyborohydride in an
inert atmosphere, such as nitrogen atmosphere.  The reaction can be carried out

either  at  sub-ambient,  ambient  or  super-ambient  reaction  temperatures  and

15    pressures. Typically, such reactions are carried out at room temperature at atmospheric pressure of nitrogen. The reaction mixture is then worked-up using procedures known to skilled in the art to isolate the intermediate of formula (17). The cyclization is then initiated by catalytic amount of base, such as potassium t-butoxide

in aprotic solvents, such THF, to form compounds of formula (18). The intermediate

20 of formula (18) is then condensed with the amine intermediate (4) or (9) prepared according to Scheme 1 and 2 to form the compounds of this invention (19).
Scheme 4
 

20




                    2   
    Rz}yBr    NaBH(OAc)3    O  <ffR Br   
+    ~    DCE        ~  ""'   
                   
    HN        ~lo N    1.0   
    2            n  N   
                   
    (16)        I    (17)   
                   





(4) or(9)






n,m,p=1,2

Scheme 5 illustrates further derivatization from the compound of formula (19). Removal of the protection group yields the amine (20). This amine can be alkylated under reductive amination conditions or acylated with carboxylic or sulfonic acid or its
s    acid chloride or acid anhydride to form am ides or sufonamides.
 






























As already noted hereinabove, the compounds of this invention can readily be converted into salts. More particularly, the compounds of the present invention are
 

21


basic, and as such compounds of this invention are useful in the form of the free base or in the form of a pharmaceutically acceptable acid addition salt thereof. Acid addition salts may be a more convenient form for use; and, in practice, use of the salt form inherently amounts to use of the free base form. The acids which can be used

5    to prepare the acid addition salts include preferably those which produce, when combined with the free base, pharmaceutically acceptable salts, that is, salts whose anions are non-toxic to the patient in pharmaceutical doses of the salts, so that the beneficial inhibitory effects inherent in the free base are not vitiated by side effects ascribable to the anions. Although pharmaceutically acceptable salts of said basic

10    compound is preferred, all acid addition salts are useful as sources of the free base form even if the particular salt, per se, is desired only as an intermediate product as, for example, when the salt is formed only for purposes of purification, and identification, or when it is used as intermediate in preparing a pharmaceutically

acceptable salt by ion exchange procedures.

15 In another aspect of this embodiment, a specific disease, a disorder or a condition that can be prevented and/or treated with the compound of this invention include, without any limitation the following: sleep-related disorders (specific examples include without any limitation narcolepsy, attentional deficits, circadian rhythm sleep disorders, obstructive sleep apnea, periodic limb movement and

20    restless leg syndrome, excessive sleepiness and drowsiness due to medication side-effect, etc.), neurological disorders (specific examples that may be enumerated include but not limited to dementia, Alzheimer'sdisease, multiple sclerosis, epilepsy

and  neuropathic pain),  neuropsychological  and  cognitive disorders  (a few of the

specific  examples  include  without  any  limitation  include  schizophrenia,  attention

25    deficit/hyperactivity disorder, Alzheimer's disease, depression, seasonal affective disorder, and cognitive impairment). Certain of the disorders also include cognitive impairment •associated with schizophrenia (CIAS), anxiety disorders such as generalized anxiety, panic disorder and post-traumatic stress disorder, and major depressive disorder. Other disorders include dementia of Alzheimer type (OAT),

30    cognitive deficits related to neurological diseases such as Alzheimer, Parkinson, Huntington, age related cognitive impairment, mild cognitive impairment, vascular dementia, Lewis Body dementia and any other cognition associated to cognitive deficits.
 

22


As described hereinbelow by way of specific examples, the compounds of formula (I) bind to the H3 receptors and demonstrate inverse agonism versus H3 functional activity. Therefore, the compounds of this invention may have utility in the treatment of diseases or conditions ameliorated with H3 receptor ligands. More

5    specifically, the compounds of the present invention are H3 receptor ligands that modulate function of the H3 receptor by antagonizing the activity of the receptor. Further, the compounds of this invention may be inverse agonists that inhibit the basal activity of the receptor or they may be antagonists that completely block the

action of receptor.:activating agonists.  Additionally, the compounds of this invention

10    may also be partial agonists that partially block or partially activate the H3 receptor or they may be agonists that activate the receptor. Thus the compounds of this

invention may act differentially as antagonists, inverse agonists and/or partial agonists depending on functional output, histamine tone and or tissue context. Accordingly, the differential activities of these compounds may allow for utility to

15    ameliorate multiple disease states as specifically enumerated above.

Thus in one aspect of this invention there is provided a method of treating a disease in a patient, said disease selected from the group consisting of sleep related disorder, dementia, Alzheimer's disease, multiple sclerosis, cognitive disorder, attention deficit hyperactivity disorder and depression, comprising administering to

20    said patient a therapeutically effective amount of a compound of formula (I).

One of skill in the art readily appreciates that the pathologies and disease states expressly stated herein are not intended to be limiting rather to illustrate the efficacy of the compounds of the present invention. Thus it is to be understood that the compounds of this invention may be used to treat any disease caused by the

25    effects of H3 receptors. That is, as noted above, the compounds of the present invention are modulators of H3 receptors and may be effectively administered to

ameliorate any disease state which is mediated all or in part by H3 receptors.

All of the various embodiments of the compounds of this invention as disclosed herein can be used in the method of treating various disease states as described

30    herein. As stated herein, the compounds used in the method of this invention are capable of inhibiting the effects of H3 receptor and thereby alleviating the effects and/or conditions caused due to the activity of H3.
 

23


In another embodiment of the method of this invention, the compounds of this invention can be administered by any of the methods known in the art. Specifically, the compounds of this invention can be administered by oral, intramuscular, subcutaneous, rectal, intratracheal, intranasal, intraperitoneal or topical route.

5 Finally, in yet another embodiment of this invention, there is also provided a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula (I), including enantiomers, stereo isomers, and tautomers of said compound and pharmaceutically acceptable salts, solvates or derivatives thereof, with said compound having the general structure shown in formula I as described

10    herein.

As described herein, the pharmaceutical compositions of this invention feature H3 inhibitory activity and thus are useful in treating -any disease, condition or a disorder caused due to the effects of H3 in a patient. Again, as described above, all of the preferred embodiments of the compounds of this invention as disclosed herein

15 can be used in preparing the pharmaceutical compositions as described herein. Preferably the pharmaceutical compositions of this invention are in unit dosage
forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto-injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal

20    administration, or for administration by inhalation or insufflation.  Alternatively, the

    compositions may be presented in a form suitable for once-weekly or once-monthly
    administration; for example, an insoluble salt of the active compound,__....swetr•-as-~the,
    ,..,-~    ..,•:.•",:  .•    ...' ,   •,.,
    decanoate salt, may be adapted to provide a depot preparation /6r intrafnuscular
    injection.  An erodible polymer containing the active ingredient ni~qy be en~isaged. _
    •,...,. .        !I : .._ ; .-I    .
25    For preparing solid compositions such as tablets, the principal acJi've ingredient    is
    I..,  .....  ',    ..,    •   
    mixed with a pharmaceutical carrier, e.g. conventional tableting ingh~cllents _?uch _as•
        '    -   
    corn  starch,  lactose,  sucrose,  sorbitol,  talc,  stearic  acid,  magnesium  stearate,

dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound

30    of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such
 

24


as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. Flavored unit dosage forms contain from 1 to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg, of the

5    active ingredient. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of

prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to

10    resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and

cellulose acetate.

15 The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil; as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents

20    for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.

The pharmaceutical compositions of this invention can be administered by any

of the methods known in the art.  In general, the pharmaceutical compositions of this

25    invention can be administered by oral, intramuscular, subcutaneous, rectal, intratracheal, intranasal, intraperitoneal or topical route. The preferred administrations of the pharmaceutical composition of this invention are by oral and

intranasal routes. Any of the known methods to administer pharmaceutical compositions by an oral or an intranasal route can be used to administer the

30    composition of this invention.

In the treatment of various disease states as described herein, a suitable dosage level is about 0.01 to 250 mg/kg per day, preferably about 0.05 to 100 mg/kg
 

25


per day, and especially about 0.05 to 20 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day.

This invention is further illustrated by the following examples which are provided for illustration purposes and in no way limit the scope of the present

5    invention.

Examples (General)

As used in the examples and preparations that follow, the terms used therein shall have the meanings indicated: "kg" refers to kilograms, "g" refers to grams, "mg" refers to milligrams, ")lg" refers to micrograms, "pg" refers to picograms, "lb" refers to

10    pounds, "oz" refers to ounces, "mol" refers to moles, "mmol" refers to millimoles, ")lmole" refers to micromoles, "nmole" refers to nanomoles, "L" refers to liters, "ml" or "ml" refers to milliliters, ").LL" refers to microliters, "gal" refers to gallons, "°C" refers to degrees Celsius, "Rf" refers to retention factor, "mp" or "m.p." refers to melting point,

"dec" refers to decomposition, "bp" or "b.p." refers to boiling point, "mm of Hg" refers

15    to pressure in millimeters of mercury, "em" refers to centimeters, "nm" refers to nanometers, "abs." refers to absolute, "cone." refers to concentrated, "c" refers to concentration in g/ml, "OMSO" refers to dimethyl sulfoxide, "DMF" refers to N,N-
dimethylformamide,    "COl" refers to  1, 1'-carbonyldiimidazole, "OCM" or "CH2CI2"

refers  to  dichloromethane,  "OCE"  refers  to  1,2-dichloroethane,  "HCI"  refers  to

20    hydrochloric acid, "EtOAc" refers to ethyl acetate, "PBS" refers to Phosphate Buffered

Saline, "IBMX" refers to 3-isobutyl-1-methylxanthine, "PEG" refers to polyethylene glycol, "MeOH" refers to methanol, "MeNH2" refers to methyl amine, "N2" refers to nitrogen gas, "iPrOH" refers to isopropyl alcohol, "Et20" refers to ethyl ether, "LAH" refers to lithium aluminum hydride, "heptane" refers to n-heptane, "HMBA-AM" resin

25    refers to 4-hydroxymethylbenzoic acid amino methyl resin, "PdCb(dppf)2" refers to 1, 1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride OCM complex, "HBTU"

refers to 2-(1 H-benzotriazol-1 yl)-1, 1 ,3,3-tetramethyluronium hexafluorophosphate, "OlEA" refers to diisopropylethylamine, "CsF" refers to cesium fluoride, "Mel" refers to methyl iodide, "AcN," "MeCN" or "CHsCN"refers to acetonitrile, ''TFA"refers to

30    trifluoroacetic acid, "THF" refers to tetrahydrofuran, "NMP" refers to 1-methyl-2-pyrrolidinone, "H20" refers to water, "BOG" refers to t-butyloxycarbonyl, "brine" refers to a saturated aqueous sodium chloride solution, "M" refers to molar, "mM" refers to millimolar, ").LM" refers to micromolar, "nM" refers to nanomolar, "N" refers to normal,
 

26


"TLC" refers to thin layer chromatography, "HPLC" refers to high performance liquid chromatography, "HRMS" refers to high resolution mass spectrum, "L.O.D." refers to loss on drying, "J.lCi" refers to microcuries, "i.p." refers to intraperitoneally, "i.v." refers to intravenously, anhyd = anhydrous; aq = aqueous; min = minute; hr = hour; d = day;

5    sat. = saturated; s = singlet, d = doublet; t = triplet; q = quartet; m = multiplet; dd = doublet of doublets; br =broad; LC =liquid chromatograph; MS =mass spectrograph; ESI/MS = electrospray ionization/mass spectrograph; RT = retention time; M = molecular ion, "-" = approximately.

Reactions generally are run under a nitrogen atmosphere.  Solvents are dried

10    over magnesium sulfate and are evaporated under vacuum on a rotary evaporator. TLC analyses are performed with EM Science silica gel 60 F254 plates with

visualization by UV irradiation. Flash chromatography is performed using Alltech prepacked silica gel cartridges. The 1H NMR spectra are run at 300 MHz on a Gemini 300 or Varian Mercury 300 spectrometer with an ASW 5 mm probe, and
15    usually recorded at ambient temperature in a deuterated solvent, such. as 0 20, OM SO-Ds or CDCb unless otherwise noted. Chemical shifts values ( ) are indicated in parts per million (ppm) with reference to tetramethylsilane (TMS) as the internal standard.


High   Pressure   Liquid   Chromatography-Mass   Spectrometry   (LCMS)

20    experiments to determine retention times (Rr) and associated mass ions are performed using one of the following methods:
Mass Spectra (MS) are recorded using a Micromass mass spectrometer. Generally, the method used was positive electro-spray ionization, scanning mass m/z from 100

to 1000.  Liquid chromatography was performed on a Hewlett Packard 1100 Series

25    •Binary Pump & Degasser; Auxiliary detectors used were: Hewlett Packard 1100 Series UV detector, wavelength = 220 nm and Sedere SEDEX 75 Evaporative Light Scattering (ELS) detector temperature = 46°C, N2 pressure = 4 bar.

LCT: Grad (AcN+0.05% TFA):(H20+0.05% TFA) = 5:95 (0 min) to 95:5 (2.5 min) to

95:5 (3 min). Column: YMC Jsphere 33x2 4 1-JM, 1 ml/min

30    MUX: Column: YMC Jsphere 33x2, 1 ml/min

Grad (AcN+0.05% TFA):(H20+0.05% TFA) = 5:95 (0 min) to 95:5 (3.4 min) to 95:5 (4.4 min).
 

    27   
    LCT2: YMC Jsphere 33x2 4 !-JM, (AcN+0.05% TFA):(H20+0.05% TFA) = 5:95 (0 min)
    to 95:5 (3.4 min) to 95:5 (4.4 min)   
    QU: YMC Jsphere 33x2 1 ml/min, (AcN+0.08% formic acid):(H20+0.1% formic acid) =
    5:95 (0 min) to 95:5 (2.5min) to 95:5 (3.0min)   
5    The following examples describe the procedures used for the preparation of
    various  starting  materials  employed  in  the  preparation  of the  compounds of this
    invention.   
    INTERMEDIATES   
    Intermediate (i)   
10    2-Methyl-[1 ,3']bipyrrolidinyl-1'-carboxylicacid tert-butyl ester
    ~q   
    o==(    3

0
Hc-fcH3
3

CH3

To a solution of N-BOC-3-pyrrolidinone (4.22g, 22.9 mmol) and 2-methylpyrroline (1.95 g, 22.9 mmol) (HCI salt was made by addition of 22.9 ml of 1 M HCI in ether into the DCM solution of 2-methylpyrroline, then evaporated) in DCE (60
15    ml) was added powdered sodium triacetoxyborohydride slowly under N2 at r.t. The yellowish milky solution was stirred at r.t. overnight. LC/MS - m/z 255 and 199 (base

and M-tBu).

The reaction was quenched with aq. NaHC03 solution (1 00 ml). The two layers were separated, and the aqueous layer was extracted with DCM (20 mL x 2).

20    The combined DCM extracts were washed with sodium bicarbonate (1 0 ml), and brine (5 mlx2), dried (anhydrous potassium carbonate), filtered, and concentrated in vacuo. The crude product was purified on a silica gel column, eluted with DCM and 7.5% MeOH in DCM to get 5.50 g (yield: 94%) of the title compound as a liquid. MS:
255 (M+H+); TLC: 0.5 (1 0% MeOH in DCM).

25    Intermediate (ii)

2-Methyl-[1 ,3']bipyrrolidinyl hydrochloride
 

28





•2HCI



2-Methyl-[1 ,3']bipyrrolidinyl-1'-carboxylicacid tert-butyl ester (5.50 g , 21.62 mmol) was treated with 20 ml of 4 M HCI in dioxane at 0°C. The solution was stirred under nitrogen at r.t. overnight. TLC (10% MeOH in DCM) did not detect the starting

5    material. Nz was passed through the solution with stirring. The outlet was passed through KOH solution to absorb HCI for 30 min. The solvent was removed by evaporation to dryness to get the title compound as a hygroscopic gummy material,

5.3    g (-1 00 %).  This material was used without further purification in subsequent

steps as illustrated below.  LCMS: Rr = 0.35 minutes, MS: 155 (M+H).

10    1H NMR (DzO, 300MHz): 4.30 (m), 3.85 (m), 3.76 (s), 3.5 (m), 3.46 (m), 3.32 (m), 2.66 (m), 2.28 (m), 2.10 (m), 1.46 (bs).

Intermediate (iii)

(R)-3-(Toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester











15 To a 2L round-bottom flask equipped with a mechanical stirring rod and a 250m! addition funnel was added p-tosyl chloride (58g, 305mmol, 1.5eq) and 600ml of anhydrous DCM. The solution was cooled with ice-water bath. EtsN (65ml) and DMAP (2.65g) were added. A solution of (R)-3-(-)-N-Boc-hydroxy pyrrolidine (38g, 203 mmol, 1.0eq) in 200 ml of DCM was added slowly. The reaction mixture was

20    allowed to stir at room temperature over night. TLC showed completion of the reaction. The product had an Rt value of 0.3 (TLC developed in DCM). The reaction was cooled by ice-water bath. Polymer-supported trisamine (32g) was added and

stirred for 30 min. Trisamine bead was filtered and rinsed with 300-400 mL of DCM. The organic solution was washed with 200 ml of H3P04 (1M) solution twice, followed

25    by saturated NaHC03 solution (200 ml), and brine (200 ml). The organic phase was dried over K2C03. After concentration, the crude product was purified by a 750g
 

29


silica gel cartridge (DCM to 5% MeOH in DCM) to afford the title compound as a beige oil (52g, 75%).
MS: 363 (M+Na+); TLC (DCM) Rf = 0.3.

1H NMR (CDCI3, 300MHz), 8 (ppm): 7.80 (d, 9.0Hz, 2H), 7.35 (d, 7.8Hz, 2H), 5.04 s (bs, 1 H), 3.45 (m, 4H), 2.46 (bs, 3H), 2.05 (m, 2H), 1.43 (s, 9H).

Intermediate (iv)

( S )-3-(Tol uene-4-su lfonyloxy)-pyrrol id ine-1-carboxyl ic acid tert -butyl ester











A round bottomed flask was charged with 80 ml of anhydrous DCM.  The

10    solvent was evacuated and purged with nitrogen. To this solvent was added (38)-1-BOC-3-pyrrolidinol (obtained from Astatech), (16.32 g, 33.8 mmol), DMAP (0.4g). The solution was cooled to an ice-water bath. To this cold solution was added a solution of p-toluene-sulfonyl chloride (9.67 g, 50.87 mmol, 1.5 equiv.) in 20 ml of DCM. The ice-water bath was removed and the solution was stirred under nitrogen

15    overnight. TLC (5% MeOH in DCM for SM, 12 visualization; DCM for product, UV) showed the completion of the reaction. The reaction was quenched by addition of polymer-supported amine (4.5 g), stirred 30 min. 50 ml of DCM was added and filtered. The filtration pad was washed with DCM. The organic was washed with
H3P04  (1M, 2 x 50ml), followed by NaHC03 (50 ml, brine (50 ml), dried (K2C03),

20    filtered and concentrated to a liquid. This was purified on a 110 g silica gel column on Analogix using 0-2% MeOH in DCM to obtain pure product, 8.82 g (77% yield).
TLC (DCM) Rf = 0.3. LC: Rt = 3.55 min, 100% pure based on total ion, MS: 363 (M+Na); 342, 327, 286 (base).
1H NMR (300MHz, CDCI3), 8 (ppm): 7.81  (d, 8.7Hz, 2H), 7.37 (d, 8.7Hz, 2H), 5.04

25 (bs, 1 H), 3.45 (m, 4H), 2.46 (s, 3H), 1 .44 (s, 9H). Intermediate (v)
(2S,3'S)-2-Methyl-[1,3']bipyrrolidinyl-1'-carboxylicacid tert-butyl ester
 

30













The tosylate (52g, 0.15mol, 1.0eq), (28)-2-methyl pyrrolidine (25.2g, 0.3 mol, 2.0eq), anhydrous CHsCN (500ml), and dry K2C03 powder (50g, 36 mmol, 2.4eq) were added to a 2L round-bottom flask equipped with a mechanical stirrer and a

5    reflux condenser. The resulting suspension was stirred at 75°C for 20h. The heating block was set at 88 °C.
LC/MS showed a trivial amount of starting material at m/z 363.  The reaction mixture

was concentrated in  vacuo.  The residue was partitioned between 200 ml of water

and 400 ml of DCM.  The aqueous layer was washed with 50 ml of DCM twice. The
10    organic extracts were combined and washed with 150 ml of saturated NaHC03 solution, 150 ml of brine, and dried over K2C03. The crude was purified by silica gel column, eluted with 5-10% MeOH in DCM. The product still had weak UV absorption at 254 nm and 280 nm. A pale yellow oil was obtained. Yield: 24.5g (64%).

LCMS: Rr = 1.27 minutes, MS: 255 (M+H).

15    1H NMR (300 MHz, CDCI3), 8 (ppm): 3.15 (m, 2H), 3.3 (m, 3H), 2.97 (m, 1H), 2.71 (m,
    1 H), 2.47 (m, 1 H), 1.98 (m, 2H), 1.96-1.67 (m, 4H), 1.46 (s, 9H), 1.06 (d, 6.2Hz, 3H).
    Intermediate (vi)
    (2R,3'S)-2-Methyl-[1,3']bipyrrolidinyl-1'-carboxylicacid tert-butyl ester











20 The title compound was prepared in a manner substantially the same as intermediate (2R,3'S)-2-Methyl-[1,3']bipyrrolidinyl-1'-carboxylicacid tert-butyl ester by condensing 3-(3R)-(toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester with R-(-)-2-methylpiperindine (obtained from Advanced Asymmetries). LCMS: Rr = 1.05 minutes, MS: 255 (M+H).
 

31


1H NMR (300 MHz, CDCis), 8 (ppm): 3.30 (m, 1H), 3.14 (bs, 2H), 2.91 (m, 1H), 2.75 (m, 1 H), 2.51 (m, 1H), 2.07-1.69 (m, 6H), 1.46 (s, 9H), 1.10 (d, 6.0Hz, 3H).

Intermediate (vii) (2S,3'R)-2-Methyl-[1,3']bipyrrolidinyl-1'-carboxylicacid tert-butyl ester









5

3-(38)-(Toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (6.82 g, 19.97 mmol, 1 equiv. ) and S-(+)-2-methyl-piperindine (obtained from Advanced Asymmetries), (3.40 g, 40 mmol, 2 equiv.) were dissolved in anhydrous CH3CN (65 ml). To this colorless solution was added powder KzCOs (powder, 325

10    mess, 98+%, 6.1 Og, 44.2 mmol, 2.2 equiv.) at r.t. The suspension was heated with stirring under nitrogen over an oil bath maintained at 80°C for 24h. TLC (3% MeOH in DCM for SM, 7.5% MeOH in DCM for product) showed the SM was consumed almost completely. LC/MS showed very little amount of SM at m/z 363.

The suspension was concentrated to dryness.  The residue was taken in water

15    (25ml) and DCM (80 ml). The two layers were separated, and the aqueous layer was extracted with DCM (20 mlx2). The combined DCM extracts were washed with sodium bicarbonate (25 ml), and brine (25 ml), dried (anhydrous potassium

carbonate), filtered, and concentrated in vacuo. The crude product was purified on a silica gel column (70 g) on Analogix, eluted with MeOH in DCM (0 to 7.5%) to obtain

20    4.08g (80.3%) of the title compound as a gummy material.  LCMS: RT = 1.14 minutes,

MS: 255 (M+H).

1 H NMR (300 MHz, CDCI 3),  8 (ppm): 3.30 (m, 1H), 3.14 (bs, 2H), 2.91 (m, 1H),  2.75

    (m, 1H), 2.51 (m, 1H), 2.07-1.69 (m, 6H),  1.46 (s, 9H), 1.10 (d, 6.0Hz, 3H).
    Intermediate (viii)
25    (2R,3'R)-2-Methyl-[1,3']bipyrrolidinyl-1'-carboxylicacid tert-butyl ester
 

32













The  title compound was  prepared  in  a manner substantially the  same as

intermediate (2R,3'S)-2-Methyl-[1,3']bipyrrolidinyl-'1- carboxylicacid tert-butyl ester by

condensing    3-(3S)-(toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic   acid   tert-butyl

5    ester and R-(-)-2-methylpiperindine (obtained from Advanced Asymmetries). LCMS: RT = 1.09 minutes, MS: 255 (M+H).

1 H NMR (300 MHz, CDCI3), 8 (ppm): 3.15 (m, 2H), 3.3 (m, 3H), 2.97 (m, 1H), 2.71 (m, 1H), 2.47 (m, 1 H), 1.98 (m, 2H), 1.96-1.67 (m, 4H), 1.46 (s, 9H), 1.06 (d, 6.2Hz, 3H).

Intermediate (ix)

10    (2S,3'R)-2-Methyl-[1,3']bipyrrolidinyldihydrochloride

~r;

~_j - •2HCI H CH3

2(2S)-Methyi-[1,3'(3'R)]bipyrrolidinyl-'1- carboxylicacid tert-butyl ester (7.91 g , 31 .14 mmol) was treated with 28.8 ml of HCI in dioxane at 0°C. The solution was stirred under nitrogen at r.t. overnight. Both TLC (10% MeOH in DCM) and LC/MS
15    did not detect the starting material.  The reaction was judged complete.

N2 was passed through the solution with stirring. The outlet was passed through KOH solution to absorb HCI for 1h. The solvent was removed by evaporation to dryness to get the title compound as a hygroscopic very thick gummy (2HCI salt, hydrated- Exact composition unknown), 8.07 g (-1 00 %). MS: 155 (M+H).

20    1H NMR: (020, 300 MHz), 8 (ppm): 11.6 (bs, 1H), 9.1 (bs, 1H) 4.12 ( m, 1H) 3.5, (m, 2H), 3.3-3.1 ( m, 3H), 2.4-2.1 (m, 4H), 2.4(m, 2H), 1.6 (m, 1 H), 1.4(d, 6.0 Hz,3H).

Intermediate (x) (28,3'8)-2-Methyl-[1,3']bipyrrolidinyldihydrochloride
 

33





•2HCI


(28,3'8)-2-Methyl-[1,3']bipyrrolidinyl-1'-carboxylic acid tert-butyl ester (24.5g) was dissolved in 30 ml of dry 1 ,4-dioxane. HCI solution (85ml, 4M in dioxane) was added at oac, and allowed to stir at room temperature. Brown gum appeared after

5    about 20 minutes. After 4 h, the reaction was complete. N2 was passed through the flask for 1h with stirring. The outlet passed though KOH solution to absorb HCI. The

solvent was removed by vacuum to afford 29g of hygroscopic beige gum. LCM8: Rr =0.37 minutes, M8: 155 (M+H).
1 H NMR: (020, 300 MHz), o (ppm): 11.6 (bs, 1 H), 9.1 (bs, 1H) 4.12 ( m, 1H) 3.5, (m,

10 2H), 3.3-3.1 (m, 3H), 2.4-2.1 (m, 4H), 2.4(m, 2H), 1.6 (m, 1 H), 1.4(d, 6.0 Hz,3H) Intermediate (xi)
(2R,3'8)-2-Methyl-[1,3']bipyrrolidinyldihydrochloride

O•"l:(  •2HCI
H    CH3

The  title compound  was  prepared  in  a manner substantially the same  as

15    intermediate (28,3'R)-2-Methyl-[1,3']bipyrrolidinyl dihydrochloride by acid hydrolysis of 2(2R)-methyl-[1 ,3'(3'8)]bipyrrolidinyl'-1- carboxylicacid tert-butyl ester.

M8: 155 (M+H).
1 H NMR: (020, 300 MHz), o (ppm): 11.6 (bs, 1 H), 9.1 (bs, 1 H) 4.12 ( m, 1H) 3.5, (m, 2H), 3.3-3.1 ( m, 3H), 2.4-2.1 (m, 4H), 2.4(m, 2H), 1.6 (m, 1 H), 1.4(d, 6.0 Hz,3H).
20    Intermediate (xii)

(2R,3'R)-2-Methyl-[1,3']bipyrrolidinyldihydrochloride
e;{( . •2HCI

H    CH3

The title compound was prepared in a manner substantially the same as intermediate (28,3'R)-2-Methyl-[1,3']bipyrrolidinyl dihydrochloride by acid hydrolysis
25    of 2-(2R)-methyl-[1 ,3'(3'R)]bipyrrolidinyl'-1- carboxylicacid tert-butyl ester.
 

34


MS: 155 (fvl+H).

1 H NMR: (020, 300 fvlHz), 8 (ppm): 11.6 (bs, 1 H), 9.1 (bs, 1 H) 4.12 ( m, 1H) 3.5, (m, 2H), 3.3-3.1 (m, 3H), 2.4-2.1 (m, 4H), 2.4(m, 2H), 1.6 (m, 1 H), 1.4(d, 6.0 Hz,3H)

Intermediate (xiii)

5    4-AIIyl-piperidine-1 ,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester










In a 250-ml RBF was weighed 6.1 g (60 mmol) of diisopropylamine and dissolved in THF. This solution was cooled to -78°C. To this was added 24 ml of 2.5 fv1 (60 mmol) of butyllithium in hexane and stirred for 15 min, warmed up to 0°C for 20

10 min, re-cooled to -78°C. To this was added piperidine-1 ,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (12.87g, 50 mmol) in THF (10 mL). There was almost no color change. This was stirred at -78oC for 45 min. Then, a mixture of 5g of HMPA and 10.92 g of allyl iodide was added via cannula. The solution was still clear, very light in yellow. This mixture was stirred at -78°C for 20 min, then, the dry ice bath

15 was removed and the stirring was continued to allow the reaction mixture warm to r.t. over 40 min. The reaction mixture was poured into ice (-50 g), sat'dNH4CI aq. (50
ml) and ether (50 ml). The two layers were separated, the aqueous layer was extracted with ether (3x50 mL). The combined organic layers were washed with brine, dried (K2C03), filtered, and concentrated in vacuo to obtain 15g (1 00%) of the

20    title compound as a yellow liquid,

LC Rr = 3.45  min, MS: 198, 242 (fvl-tBu).

NMR (300M Hz, CDCI3) 8: NMR (300M Hz, CDCI3): 5.68 (m, 1H); 5.07 (, bs, 1 H), 5.04 (d, 10.2Hz, 1 H), 4.17 (q, 7.2, 2H), 3.88 (broad d, 9Hz, 2H), 2.9 (broad t, 12.9Hz, 2H),
2.27 (d, 7.8Hz, 2H), 2.1 (broad d, 13.2Hz), 1.45 (s, 9H), 1.26 (t, 7.2Hz, 3H).

25    Intermediate (xiv)

4-(2-0xo-ethyl)-piperidine-1 ,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester
 

35






~

0 CH 3 H

0

4-AIIyl-piperidine-1 ,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (2.97g, 10 mmol) was dissolved in iPrOH (50.0 ml) and H20 (1 0.0 ml). To this was added a aqueous solution of Nai04 (4.68g, 21.8mmol) in water (40.0 ml), followed by addition
5    of Os04 (8.4 mg, crystals, in one portion) at rt,. The solution was stirred at rt. After 30 min, milky cloudy formed. Stirring was continued overnight. TLC and LC/MS did not detect the SM, but it is still very milky. The reaction mixture was poured into ice water (20 ml) and EtOAc (30 ml). The two layers were separated and the aqueous layer was extracted with EtOAc (3x 15 ml). The combined extracts were washed

10    with brine, and concentrated to dryness to get a liquid. The liquid was subject a reduced distillation to remove isopropanol. The remaining liquid was purified on a 50-g silica gel column, eluted with MeOH in DCM (0-5%). Note: the product is not UV active. Anisaldehyde visualization was used. The product fractions were collected and concentrated to yield 1.03 g (34% yield) of the title compound as a liquid.

15    LC/MS:  RT = 2.84 min, MS: 300.

NMR (300MHz, CDCI3) 8: 9.73 (t, 1.8Hz, 1 H), 4.22 (q, 7.2Hz, 2H), 3.69 (m, 2H), 3.20

    (m, 2H), 2.68 (m, 2H), 2.12 (m, 2H), 1.52 (m, 2H), 1.49 (s, 9H), 1.27 (t, 7.2Hz, 3H).   
    Intermediate (xv)       
    4-[2-( 4-Bromo-2-methyl-phenylamino )-ethyl]-piperid ine-1 ,4-dicarboxyl ic   
20    acid 1-tert-butyl ester 4-ethyl ester   
    H C   
    H3c-J~JlC(o3    )   
    H C    0 H3 C   
    3    ~--0-Bc   
           
    2-Methyl-4-bromo-aniline (0.637g, 3.427 mmol) was dissolved in DCE (15 ml);   
    to  this  solution  was  transferred  a  solution    of  4-(2-oxo-ethyl)-piperidine-1 ,4-   
    dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (1.03g, 3.425 mmol) in DCE (35 ml).   
25    The flask was submerged in a water bath at rt.  To this clear solution was then added   
 

36
 


acetic acid (0.647g, 10.8 mmol, 3.1 equiv), followed by NaBH(OAc)3 (2.18 g, 10.3 mmol, 3 equiv.) under N2 at r.t. suspension was stirred at r.t. overnight. LC/MS showed m/z min. along with small amount of aniline sm at 2.103 (186/188).
 


addition of powder The yellowish milky 469/471 at t = 4.930 TLC (5% of MeOH in
 

5    DCM) showed no SM. of aldehyde, but aniline. The reaction was diluted with DCM (20 ml), cooled to ice-water bath, and quenched with 10 ml of 1 N NH40H. The two

layers were separated, and the aqueous layer was extracted with DCM (15 ml x 3).

The combined DCM extracts were washed with sodium bicarbonate (1 0 ml), and

brine (1 0 ml), dried (anhydrous potassium carbonate), filtered,  and concentrated.

10    The product was purified on a 40g-silica gel column eluted with 0-2% of MeOH in

DCM to get 0.65g (41 %) of the title compound as an oil. LC/MS Rr =3.96 min, MS: 469/471 (M+H+)

NMR (300MHz, CDCI3) 8: 7.21-7.13 (m, 2H), 6.42 (d, 8.4Hz, 1H), 4.15 (q, ?.2Hz,

2H), 3.88 (m, 3H), 3.13 (m, 2H), 2.93 (m, 2H), 2.16 (bd, 2H), 2.26 (s, 3H), 1.88 (m,

15 2H), 1.46 (s, 9H), 1.43 (m, 2H), 1.42 (t, ?.2Hz, 3H). Intermediate (xvi)

4-[2-( 4-Bromo:.phenylamino )-ethyl]-piperidine-1 ,4-dicarboxyl ic acid 1-tert-butyl ester 4-ethyl ester
CH03ANCCo JH3
H3c-}
H3C    .  o

~-o-Br

20 This intermediate was synthesized in substantially the same way as described above from 1.75 g of the desired aldehyde to get 1.45g (54% yield) of the title product as a colorless liquid.
LC/MS: Rr =3.81 mins; MS:  455/457

Intermediate (xvii)

25 4-[2-(4-Bromo-2-trifluoromethyl-phenylamino )-ethyl]-piperidine-1 ,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester
 

37













This intermediate was synthesized in substantially the same way as described above from 1.75 g of the desired aldehyde to get 2.03 g (66 % yield) of the title product as a yellow liquid.
5    LC/MS: Rr =4.18 mins; MS:  523/525.

Intermediate (xviii) 4-[2-(4-Bromo-2-fluoro-phenylamino)-ethyl]-piperidine-1 ,4-dicarboxylic acid 1-tert-

butyl ester 4-ethyl ester
CH3 ANLl2o
H3C+0    JHs
HsC    o

~-p-Br

F

10 This intermediate was synthesized in substantially the same way as described above from 1.75 g of the desired aldehyde to get 1.97g (71% yield) of the title product as an amber liquid.
LC/MS: Rr =3.95 mins; MS: 473/475.

Intermediate (xix)

15 2-(4-Bromo-2-methyl-phenyl)-1-oxo-2, 8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester
+3  )l0_NOO"0H3 C ~Br
H3 C    0    N -\_d
CH3

To a clear solution of 4-[2-(4-Bromo-2-methyl-phenylamino)-ethyl]-piperidine-1 ,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (3.42 mmol) in THF (40 ml) was

20    added a solution of potassium t-butoxide (1M in THF) 1 ml (1 mmol, 0.3 equiv.) at r.t. (water bath at rt). The clear solution turned a little bit cloudy. After 30 min, TLC (5% MeOH in DCM) showed the reaction is complete (spot to spot), LC/MS detected the
 

38


product peak of 423/425 (t 3.267 min). The reaction was cooled in an ice-water bath, diluted with 100 ml of DCM, quenched with 20 ml of water. The two layers were separated. The aqueous layer was extracted with DCM (2x20 ml). The combined DCM extracts were washed with brine, and concentrated on rotavap to yield 0.90 g

5    (63% yield) of the title compound as a white solid. LC Rr = 4.00 min, MS: 423/425 ;

NMR (300M Hz, CDCI3) 8: 7.42 (m, 1H), 7.35 (m, 1 H), 7.00 (d, 8.4Hz, 1 H), 4.03 (m, 2H), 3.64 (t, 6.9Hz, 2H), 3.06 (m, 2H), 2.17 (s, 3H), 2.13 (m, 2H), 1.96 (m, 2H), 1.57
(m, 2H), 1.47 (s, 9H).

10    Intermediate (xx)

2-(4-Bromo-phenyl)-1-oxo-2, 8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester
H C   )l0_NCDo --0-~
3_j_    Br
Hp~;-o    N    -
H3C

This intermediate is synthesized  in the same way as described above from

15    1.44 g of the desired aniline to get 0.955g (74 % yield) of the title product as a beige solid.


LC/MS: 4.13 mins./409.09

    Intermediate (xxi)
    2-( 4-Bromo-2-trifl uoromethyl-phenyl )-1-oxo-2,8-d iaza-spiro[ 4 .5]decane-8-carboxyl ic
20    acid tert-butyl ester

H CH:i-~~0 J__NCDOFtF, Br
3    N-O-
CH3

This intermediate is synthesized in the same way as described above from 2.04 g of the desired aniline to get 1.79g (97% yield) of the title product as a yellow solid.

25    LC/MS: Rr= 4.13 mins./ MS: 477

Intermediate (xxii) 2-(4-Bromo-2-fluoro-phenyl)-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester
 

39


H C        0    .    F
3l _    )l_NC\80    ~~Br
H3C~/    -o        N~
H3C

This intermediate is synthesized in the same way as described above from 1.98 g of the desired aniline to get 1.75g (98 % yield) of the title product as a brown solid.

s    LC/MS: Rr = 3.98 mins.  MS: 427

Intermediate (xxiii)

4-But-3-enyl-piperidine-1 ,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester

CH3    0
H3C+O)l_N~
H3C    o.-"""CH3


:--
CH2

A mixture of THF (160 ml) and diisopropyl amine (9.92 ml, 70.8 mmol, 1.2

10    eq) was cooled to -78°C and a 2.5 M solution of n-Buli in heptanes (28.3 ml, 70.8 mmol, 1.2 eq) was added slowly. The solution was stirred for 15 min, warmed to 0°C for 20 min and cooled back to -78 °C. Ethyl N-Bocpiperidine-4-carboxylate (11 ml, 59 mmol, 1 eq.) in 10 ml of THF was added drop-wise and stirred for 40 min before it

was  warmed  to  rt.   The  reaction  mixture was  stirred  for  12 h, transferred  to  a

15    separatory funnel, quenched with 500 ml of water and extracted with ethyl acetate (2 x 300 ml). The combined organics were dried over Na2S04 and concentrated under

vacuum to give the title compound as a yellow oil (13.9 g, 76%). LC/MS: Rr =4.15 mins. MS: 312

NMR (300MHz, CDCI3) 8: 5.75 (ddt, 1H), 5.02 (d, 1H), 4.96 (t, 1H), 4.18 (q, 2H),

20    3.89-3.86 (m, 2H), 2.88 (t, 2H), 2.11 (d, 2H), 1.99-1.93 (m, 2H), 1.66-1.57 (m, 2H), 1.45 (s, 9H), 1.43-1.32 (m, 2H), 1.27 (t, 3H)

Intermediate (xxiv)

4-(3-0xo-propyl)-piperidine-1 ,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester
 

40












4-But-3-enyl-piperidine-1 ,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (13.5 g, 43.48 mmol, 1 eq) was dissolved in i-PrOH (217 ml) and a solution of Nal04 (20.23 g, 94.6 mmol, 2.18 eq) in 217 ml of water was added followed by Os04 (37

5    mg, 0.144 mmol, 0.003 eq). The reaction mixture was vigorously stirred for 6 h. The reaction mixture was then quenched with 1500 ml of water, transferred to a separatory funnel and extracted with ethyl acetate (3 x 200 ml). The combined organics were dried over Na2S04 and purified by column chromatography on silica gel (300 g column, 30% EtOAc in heptanes; 50 ml!min). This gave 8.5 g (63%) of

10    the title compound as a beige oil. LC Rr = 3.62 min, MS: 314;

NMR (300M Hz, CDCI3) 8: 9.75 (s, 1H), 4.17 (q, 2H), 4.16-4.14 (m, 2H), 2.87 (t, 2H),

2.43 (dt, 2H), 2.10 (d, 2H), 1.85 (t, 2H), 1.45 (s, 9H), 1.36 (dd, 2H), 1.27 (t, 3H). Intermediate (xxv)

15 4-[3-( 4-Bromo-2-methyl-phenylamino )-propyl]-piperidine-1 ,4-dicarhoxvlic acid 1-tert-butyl ester 4-ethyl ester
CH  o
H3C+03 )l_~NCH3
H C    )    H C

3    0    ~_3:_o-Br

2-Methyl-4-bromo-aniline (1.68 g, 9.05 mmol, 1 eq) was dissolved in 1,2-dichloroethane (95 ml). A solution of 4-(3-0xo-propyl)-piperidine-1 ,4-dicarboxylic

20    acid 1-tert-butyl ester 4-ethyl ester (2.8 g, 9.05 mmol, 1 eq) in 95 ml of 1,2-dichloroethane was added to the previous solution followed by glacial acetic

anhydride (1.74 g, 28.05 mol, 3.1 eq) and NaBH(OAc)3 (5.76 g, 27.15 mmol, 3 eq). The reaction mixture was stirred for 48 h, quenched with 200 mL of water, transferred to a separatory funnel and extracted with dichloromethane (2 x 100 mL). The

25    combined organics were dried over Na2S04 and purified by column chromatography
 

41


on silica gel (200 g column, 25% EtOAc in heptanes; 50 mL/min). This gave 3.78 g (86%) of the title compound as a beige gum.
LC RT = 4.82 min, MS:  383;

NMR (300MHz, CDCI3) 8:7.16 (dd, 1H), 7.15 (s, 1H), 6.40 (d, 1H), 4.16 (q, 2H), 3.87

5 (d, 2H), 3.41 (s, 1 H), 3.09-3.09 (m, 2H), 2.89 (t, 2H), 2.13 (s, 1 H), 2.09 (s, 3H), 1.66-1.52 (m, 3H), 1.45 (s, 9H), 1.26 (d, 3H), 1.27-1.17 (m, 2H), 0.88 (t, 3H)

Intermediate (xxvi)

4-[3-(4-Bromo-phenylamino )-propyl]-piperidine-1 ,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester
CH  o

H3Cf03 Jl~NoJH3
H3C    o

~-o-Br
10

This intermediate was synthesized in substantially the same way as above. LC RT = 4.65 min, MS: 469 (M+H);

NMR (300MHz, CDCI3) 8: 7.23 (d, 2H), 6.44 (d, 2H), 4.16 (q, 2H), 3.87 (d, 2H), 3.61 (s, 1 H), 3.04 (t, 2HO, 2.88 (t, 2H), 2.10 (d, 2H), 1.63-1.48 (m, 3H), 1.45 (s, 9H), 1.26

15    (d, 3H), 0.88 (t, 3H)

Intermediate (xxvii) 4-[3-(4-Bromo-2-fluoro-phenylamino)-propyl]-piperidine-1 ,4-dicarboxylic acid 1-tert-









20 This intermediate was synthesized in substantially the same way as above. LC RT = 4.82 min, MS: 487 (M+H);

NMR (300MHz, CDCI3) 8:7.16-7.03 (m, 2H), 6.65 (t, 1H), 4.16 (q, 2H), 3.84-3.72 (m, 2H), 3.08 (q, 2H), 2.88 (t, 2H), 2.10 (d, 2H), 1.66-1.52 (m, 3H), 1.45 (s, 9H), 1.40-1.34 (m, 1 H), 1.26 (d, 3H), 0.88 (t, 3H).

25    Intermediate (xxviii)

2-( 4-Bromo-2-methyl-phenyl )-1-oxo-2, 9-d iaza-spiro[5.5]undecane-9-carboxyl ic acid tert-butyl ester
 

42









4-[3-( 4-Bromo-2-methyl-phenylam ino )-propyl]-piperid ine-1 ,4-d icarboxyl ic acid 1-tert-butyl ester 4-ethyl ester (3.78 g, 7.81 mmol, 1 eq) was dissolved in THF (80 ml). A 1M solution of NaOt-Bu in THF (7.8 ml, 7.8 mmol, 1 eq) was added and the

5    reaction mixture was stirred for 2 h at rt. The reaction mixture was stirred for 48 h, quenched with 250 ml of water, transferred to a separatory funnel and extracted with dichloromethane (2 x 150 mL). The combined organics were dried over Na2S04 and

purified  by  column  chromatography on  silica  gel  (200 g  column,  50%  EtOAc  in

heptanes; 50 ml/min).  This gave 2.49 g (73%) of the title compound as a beige gum.

10    LC Rr =  4.08 min, MS: 437 (M+H);

NMR (300M Hz, CDCI3) 8: 7.40 (s, 1 H), 7.35 (dd, 1 H), 6.96 (d, 1 H), 3 ..85-3.71 (m, 2H), 3.60-3.54 (m, 1 H), 3.39-3.22 (m, 3H), 2.21-2.04 (m, 3H), 2.12 (s, 3H}, 1.97-1.88

(m, 3H), 1.45 (s, 9H), 1.31-1.24 (m, 2H). Intermediate (xxix)

15 2-(4-Bromo-phenyl)-1-oxo-2,9-diaza-spiro[5.5]undecane-9-carboxylic acid tert-butyl ester









This intermediate was synthesized in substantially the same way as above. LC Rr = 3.97 min, MS: 423 (M+H);

20    NMR (300MHz, CDCI3) 8: 7.49 (d, 2H), 7.09 (d, 2H), 3.83-3.75 (m, 2H), 3.64-3.60 (m, 2H), 3.31-3.22 (m, 2H), 2.18-2.04 (m, 2H), 1.98-1.90 (m, 4H), 1.46 (s, 9H), 1.31-1.24
    (m, 2H).
    Intermediate (xxx)
    2-(4-Bromo-2-fluoro-phenyl)-1-oxo-2,9-diaza-spiro[5.5]undecane-9-carboxylic acid
25    tert-butyl ester
 

43









This intermediate was synthesized in substantially the same way as above. LC Rr = 4.05 min, MS: 441 (M+H);

NMR (300MHz, CDC13) 8: 7.33-7.28 (m, 2H), 7.09 (t, 1H), 3.80-3.72 (m, 2H), 3.59-

5 3.55 (m, 2H), 3.36-3.27 (m, 2H), 2.16-2.04 (m, 2H), 1.99-1.90 (m, 4H), 1.46 (s, 9H), 1.31-1.24 (m, 2H)

Example 1 2-[2-Methyi-4-((2R,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-1-oxo-2,8-diaza-

spiro[4.5]decane-8-carboxylic acid tert-butyl ester
H C   JL_    0   H3C       
H3    ;to    ~\)lN~N8.    X>   
    CH3    '--A_j       

10    H3 C

The HCI salt of (2R,3'S)-2-Methyl-[1,3']bipyrrolidinylwas dissolved in 2 ml of MeOH with the aid of sonication. To the solution was added 50 ml of DCM. The solution was cooled to an ice-water bath. To this solution was added powder KOH (0.5g, 9.5 mmol, 2.6 equiv. to the amine salt) with stirring under N2. The stirring was

15    continued for 1h. 0.5g of powder K2C03 was added with stirring to form a nice suspension. The suspension was filtered through a Cellite pad, rinsed with DCM until no amine was leach out by TLC (20% MeOH in DCM, anisaldehyde visualization,

white spot just above the origin). The solution was concentrated to dryness; the residue was further dried under high vacuum with stirring for 1h, re-dissolved in

20    anhydrous toluene and ready to use.

An 20-ml vial containing a stir bar was charged with Pd2(dba)3 (0.01 equiv., 0.002036 mmol, 2 mg.), 2-dicyclohexylphosphino-2',4',6'-triisopropyl-biphenyl(0.05 equiv., 0.01018 mmol, 5 mg.), and sodium t-butoxide (2.5 equiv., 0.509 mmol, 50 mg.). The vial was de-gassed and refilled with N2 three cycles. A solution of 2-(4-

25    bromo-2-methyl-phenyl)-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (86 mg, 0.2 mmol; prepared from 0.82g dissolved in 9.5 ml of toluene, 1 ml was used for each reaction) was introduced and the red solution was stirred for 1 min
 

44


at rt, then the amine in toluene (1.11 equiv., 1 ml each, corresponding to 60 mg, 0.22 mmol of bipyrrolidine) was introduced. The flask was evacuated and backfilled with N2. The reaction was heated in an oil bath set at 90°C for 2.5h, allowed to cool down to room temperature. Toluene was evaporated under reduced pressure. The residue

5    was re-dissolved in DCM (1 0 ml) and aq. NaHC03 (2 ml). The two layers were separated and the aqueous layer was extracted with DCM (3 x 5 ml). The combined

    DCM extracts were washed with sodium bicarbonate (5 ml), and brine (5 ml), dried
    (anhydrous potassium carbonate), filtered, and concentrated.  The crude product was
    purified on a 1 0-g silica gel column eluted with DCM and 5% of 7N NH3 MeOH in
10    DCM to obtain the title compound as a semi-solid.
    LC, RT =2.63 mins; MS: 497.   
    1H NMR (CDCI 3,  300 MHz), o (ppm):    6.96 (m, 1 H), 6.39 (m, 2H), 4.04 (m, 2H), 3.59
    (t, 6.6Hz, 2H), 3.45-3.17 (m, 5H), 3.02 (m, 3H), 2.79 (m, 1H), 2.54 (q, 6.0Hz, 1H),
    2.30-1.90 (m, 9H), 1.76 (m, 3H), 1.62-1.39 (m, 12H), 1.14 (d, 6.3Hz, 3H).
15            Example 2
    2-[2-Methyl~4-( (2R,3'R)-2-methyl-[1 ,3']bipyrrolid inyl-1'-yl)-phenyl]-1-oxo-2,8-diaza-
    spiro[4.5]decane-8-carboxylic acid tert-butyl ester
    H C    )L_    0   H3C
    H,~to    ()(J:_o-N/j
    CH3        )=>
            H3 C
    The  title  compound  was  prepared  in  a manner substantially the  same  as
20    Example 1 to obtain the title compound as a semi-solid.
    LC, RT = 2.66 mins; MS: 497.   
    1H NMR (CDCI3,  300 MHz), o (ppm):    6.96 (m, 1 H), 6.39 (m, 2H), 4.04 (m, 2H), 3.59
    (t, 6.6Hz, 2H), 3.50 (t, 7.2Hz, 1H), 3.37 (dt, 2.2Hz, 9.3Hz, 1 H), 3.245 (m, 3H), 3.04
    (m, 3H), 2.77 (m, 1 H), 2.54 (q, 6.0Hz, 1 H), 2.17-1.90 (m, 9H), 1.76 (m, 3H), 1.62-1.39
25    (m, 12H), 1.14 (d, 6.3Hz, 3H).   
            Example 3

2-[2-Methyl-4-( (2S,3'R)-2-methyl-[1,3']bipyrrol idinyl-1'-yl)- phenyl]-1-oxo-2 ,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester
 

                45   
    H3C   )L_    0    H3 C   
    H,cto    ()bZ>--/1
    CH3                u
                    H3c''
    The title  compound  was  prepared  in  a manner substantially the  same  as
    Example 1 to obtain the title compound as a semi-solid.
    LC, RT = 2.56 mins; M8: 497.           
5    1H NMR (CDCI 3,  300 MHz), o (ppm):  6.96 (m, 1 H), 6.39 (m, 2H), 4.04 (m, 2H), 3.59
    (t, 6.6Hz, 2H), 3.45-3.17 (m, 5H), 3.02 (m, 3H), 2.79 (m, 1 H), 2.54 (q, 6.0Hz, 1 H),
    2.30-1.90 (m, 9H), 1.76 (m, 3H), 1.62-1.39 (m, 12H), 1.14 (d, 6.3Hz, 3H).
            Example 4   
    2-[2-Methyl-4-( (28,3'8)-2-methyl-[1,3']bipyrrolidinyl-1 '-yl)-phenyl]-1-oxo-2,8-diaza-
10    spiro[4.5]decane-8-carboxylic acid tert-butyl ester
    H C    J_    0    H3C   
    H3;to        ~{\)lN~N8.
    CH,        l....J\_j    ••.o
                    H 3 c'
    The  title  compound  was  prepared  in  a manner substantially the same  as
    Example 1 to obtain the title compound as a semi-solid.
    LC, RT = 2.61 mins; M8: 497.           
15    1H NMR (CDCI 3, 300 MHz), o (ppm):  6.96 (m, 1 H), 6.39 (m, 2H), 4.04 (m, 2H), 3.59
    (t, 6.6Hz, 2H), 3.50 (t, 7.2Hz, 1H), 3.37 (dt, 2.2Hz, 9.3Hz, 1 H), 3.245 (m, 3H), 3.04
    (m, 3H), 2.77 (m, 1H), 2.54 (q, 6.0Hz, 1H), 2.17-1.90 (m, 9H), 1.76 (m, 3H), 1.62-1.39
    (m, 12H), 1.14 (d, 6.3Hz, 3H).           

Example 5

20 2-[2-Methyl-4-(2-methyl-[1 ,3']bipyrrolidinyl-1'-yl)-phenyl]-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester
H C   )L_    0   H3C
H,;to  ~"\)..NZ>-<:l
CH3    ~    ~

H3C
 

46


The title compound was prepared in a manner substantially the same as Example 1 to obtain the title compound as a semi-solid.

LC, RT = 2.62 mins; MS: 497.

1H NMR (CDCI3 , 300 MHz), 8 (ppm):  Two sets of spectra were observed.

5    Example 6

2-[2-Methyl-4-((28,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-2,8-diaza-

spiro[4.5]decan-1-one

0    H3C
H~\)lN~N/"'"j,
~    0.,,.0

H3 c'

2-[2-Methyl-4-( (2S ,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-1-oxo-2,8-

10    diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (150 mg) was treated with 1 ml (excess) of 4M HCI in dioxane at oac. The stirring was continued at rt for 1h. The solvent was evaporated and the solid was further dried under high vacuum at rt for 2h to obtain the title compound as a tan solid.

LC, RT = 1.41 mins; MS: 397.

15    Example 7

2-[2-Methyi-4-((2R,3'R)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one Hydrochloride

Hob~N~

HCI    HCD
3

The  title  compound  was  prepared  in  a manner substantially the  same  as

20    Example 1 .

LC, RT = 1.38 mins; MS: 397.

Example 8 2-[2-Methyi-4-((2R,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one Hydrochloride
 

47











The title compound was prepared in a manner substantially the same as Example 1
LC, RT =1.4 mins; MS: 397.

5    Example 9

2-[2-Methyi-4-((2S,3'R)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one Hydrochloride








The title  compound was  prepared  in  a manner substantially the same as

10    Example 1.

LC, RT =1.35 mins; MS: 397.

Example 10 8-Cyclopentylmethyl-2-[2-methyi-4-((2R,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-l)-phenyl]-

2,8-diaza-spiro[4.5]decan-1-one

ON~b-N8.X>

15    H3C

To 2-[2-methyi-4-((2R,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one (40 mg, 0.1 mmol) was added a solution of cyclopentane-carboxaldehyde (CAS 872-53-7, MW 98.14) (30 mg, 0.3 mmol) in 5 mL, followed by powder sodium triacetoxyborohydride under N2 at r.t. The yellowish milky

20    suspension was stirred at r.t. overnight. The reaction was quenched with DCM (5 ml), NaHC03 aq. (2 ml) and NaOH (1 N, 1 ml). The two layers were separated, and the aqueous layer was extracted with DCM (5 ml). The combined DCM extracts were washed with sodium bicarbonate (5 ml), and brine (5 ml), dried (anhydrous
 

    48
    potassium  carbonate),  filtered,  and  the  solution  was  directly loaded  onto  a  1 0-g
    waters silica gel column, eluted with DCM, followed by 5% of 7N NH3 I MeOH  in
    DCM.  The collection of the fractions was evaporated to obtain a solid.
    LC, Rr = 1.65 mins; MS: 479.
5    1H NMR (CDCI3, 300 MHz), 8 (ppm):  6.96 (m, 1 H), 6.39 (m, 2H), 3.55 (t, 7.2Hz, 2H),
    3.45-3.17 (m, 5H), 3.44-3.19 (m, 3H), 2.53 (q, 8.1Hz, 1H), 2.25 (m, 3H), 2.07-1.91 (m,
    8H), 1.74 (m, 4H), 1.62-1.41 (m, 12H), 1.20 (m, 2H), 1.14 (d, 6.3Hz, 3H).
    Example 11
    8-Cyclopentyl methyl-2-[2-methyl-4-( (2 R,3'R)-2-methyl-[1,3']bipyrrol id inyl-1 '-)I-phenyl]-
10    2,8-diaza-spiro[4.5]decan-1-one









The title compound was prepared in a manner substantially the same as Example 1.
LC, Rr = 1.68 mins; MS: 479.

15    1H NMR (CDCI3, 300 MHz), 8 (ppm): 6.96 (m, 1 H), 6.39 (m, 2H), 2.55 (t, 7.2Hz, 2H), 3.50 (t, 7.2Hz, 1 H), 3.45-3.10 (m, 4H), 3.01 (m, 1H), 2.89 (m, bs, 1 H), 2.78 (sextet, 6.9Hz, 1 H), 2.50 (q, 8.4Hz, 1 H), 2.27 (m, 3H), 2.07-1.91 (m, 8H), 1.74 (m, 4H), 1.62-

1.41 (m, 12H), 1.20 (m, 2H), 1.13 (d, 6.3Hz, 3H). Example 12

20 8-Cyclopentylmethyl-2-[2-methyi-4-((2S,3'R)-2-methyl-[1,3']bipyrrolidinyl-1'-l)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one







The title compound was prepared in a manner substantially the same as Example 1.
25    LC, Rr = 1.7 mins; MS: 479.
 

49


1H NMR (CDCI 3, 300 MHz), o (ppm): 6.96 (m, 1 H), 6.39 (m, 2H), 3.55 (t, 7.2Hz, 2H), 3.45-3.17 (m, 5H), 3.44-3.19 (m, 3H), 2.53 (q, 8.1Hz, 1H), 2.25 (m, 3H), 2.07-1.91 (m, 8H), 1.74 (m, 4H), 1.62-1.41 (m, 12H), 1.20 (m, 2H), 1.14 (d, 6.3Hz, 3H).

Example 13

s 8-Cyclopentylmethyl-2-[2-methyi-4-((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-1)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one
0    H3C

o()b~{),,_o

H 3 c'

The title compound was prepared in a manner substantially the same as Example 1.
10    LC, RT = 1.67 mins; MS: 479.

1H NMR (CDCI 3, 300 MHz), o (ppm): 6.96 (m, 1 H), 6.39 (m, 2H), 2.55 (t, 7.2Hz, 2H), 3.50 (t, 7.2Hz, 1 H), 3.45-3.10 (m, 4H), 3.01 (m, 1H), 2.89 (m, bs, 1 H), 2.78 (sextet, 6.9Hz, 1 H), 2.50 (q, 8.4Hz, 1 H), 2.27 (m, 3H), 2.07-1.91 (m, 8H), 1.74 (m, 4H), 1.62-

1.41 (m, 12H), 1.20 (m, 2H), 1.13 (d, 6.3Hz, 3H).

15    Example 14

8-Cyclopentylmethyl-2 -[2-methyl-4-(2-methyl-[1 ,3']bipyrrolidinyl-1 '-1) -phenyl]-2,8-

diaza-spiro[4.5]decan-1-one

o H3C

ON~Z}-N~N
HCD
3

The title compound  was  prepared  in  a manner substantially the  same  as

20    Example 1.

LC, RT =1.63 mins; MS: 479.

1H NMR (CDCis,  300  MHz),  8 (ppm):   two sets of spectra  were observed.  It is

ambiguous to assign the spectra.

Example 15

25 2-[2-Methyl-4-( (2R,3'S)- 2-methy! -[1 ,3']bipyrrolid inyl-1 '-yl)- phenyl]-8-( 4-trifluoromethoxy-benzoyl)-2,8-diaza-spiro[4.5]decan-1-one
 

50










To a solution of acid chloride in DCM was added 2-[2-methyi-4-((2S,3'S)-2-methyl-[1 ,3']bipyrrolidinyl-1'-yl)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one( - 20 mg, 0.06 mmol) followed by potassium carbonate (40 mg, excess). The colorless

s suspension was allowed to stir under nitrogen overnight at rt. The reaction was quenched with DCM (5 ml) and aq. sodium bicarbonate solution (2 ml). The two layers were separated. The aqueous layer was extracted with DCM (5 ml). The combined DCM solution was dried over K2C03, directly loaded onto a 10-g silica gel column, eluted with DCM and 5% 7N NH3 solution of MeOH in DCM to get the

10    product, as in the table.

LC, RT = 2.52 mins; MS: 585.

1H NMR (CDCb, 300 MHz), 8 (ppm):  7.49 (d, 8.4Hz, 2H), 7.25 (d, 8.4Hz, 2H), 6.95

(m, 1H), 6.39 (m, 2H), 3.62 (m, 2H), 3.45-3.21 (m, 5H), 2.99 (m, 1H), 2.80 (m, 1H), 2.54 (q; 8.4Hz, 1H), 2.24 (m, 1H), 2.19-1.91 (m, 8H), 1.87-1.39 (m, 1OH), 1.15 (d,

15    6.3Hz, 3H).

Example 16 2-[2-Methyi-4-((2R,3'R)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-8-(4-

trifluoromethoxy-benzoyl)-2,8-diaza-spiro[4.5]decan-1-one








20 The title compound was prepared in a manner substantially the same as Example 15.


l-C, RT = 2.62 mins; MS: 585.

1H NMR (CDCI3 , 300 MHz), 8 (ppm): 7.49 (d, 8.4Hz, 2H), 7.25 (d, 8.4Hz, 2H), 6.95 (m, 1H), 6.39 (m, 2H), 3.62 (m, 2H), 3.51 (t, 7.2Hz, 1H), 3.42-3.20 (m, 4H), 3.02 (m,

25    1H), 2.78 (m, 1H), 2.54 (q, 8.4Hz, 1H), 2.24-1.92 (m, 9H), 1.87-1.39 (m, 10H), 1.14 (d, 6.3Hz, 3H).

Example 17•
 

51


2-[2-Methyi-4-((28,3'R)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-8-(4-trifluoromethoxy-benzoyl)-2,8-diaza-spiro[4.5]decan-1-one
~~Fodc~J~N~,,.0
H3C

The  title  compound  was  prepared  in  a manner substantially the  same  as

5    Example 15.

LC, Rr = 2.62 mins; MS: 585.

    1H NMR (CDCI3,  300 MHz), 8 (ppm):  7.49 (d, 8.4Hz, 2H), 7.25 (d, 8.4Hz, 2H), 6.95
    (m, 1 H), 6.39 (m, 2H), 3.62 (m, 2H), 3.45-3.21 (m, 5H), 2.99 (m, 1 H), 2.80 (m, 1 H),
    2.54 (q, 8.4Hz, 1H), 2.24 (m, 1H),    2.19-1.91  (m,    8H), 1.87-1.39 (m, 10H), 1.15 (d,
10    6.3Hz, 3H).       
        Example 18   
    2-[2 -M ethyl-4-(2-m ethyl-[ 1 ,3']b ipyrrol id inyl-1 '-yl)- phenyl]-8-( 4-trifl u oro methoxy-
    benzoyl)-2,8-diaza-spiro[4 .5]decan-1-one
    odNaj~{J,N
    F~        D
    FF        H3C
15    The  title  compound  was  prepared  in  a manner substantially the same as
    Example 15.       
    LC, Rr =2.62 mins; M8: 585.       
    1H  NMR (CDCI 3,  300  MHz),  8 (ppm):   two sets of spectra were observed.  It is
    ambiguous to assign the spectra.       
20        Example 19   
    2-[2-Methyl-4-((28,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-8-(4-
    trifl uoromethoxy-benzoyl )-2 ,8-di aza-sp iro [4 .5]decan-1-on e
    o    o  H3C   
    ~\ )lN:_o-N~J,
    0 ff l_/\_j    '0
    ~~F        H C'''
 
3
 

52


The  title  compound  was  prepared  in  a  manner substantially the  same  as

Example 15.

LC RT =  2.55 min, MS: 585 (M+H).

1H NMR (300MHz, CDCI3) 8 (ppm):  7.49 (d, 8.4Hz, 2H), 7.25 (d, 8.4Hz, 2H), 6.95 (m,

5    1 H), 6.39 (m, 2H), 3.62 (m, 2H), 3.51 (t, 7.2Hz, 1 H), 3.42-3.20 (m, 4H), 3.02 (m, 1 H), 2.78 (m, 1H), 2.54 (q, 8.4Hz, 1H), 2.24-1.92 (m, 9H), 1.87-1.39 (m, 10H), 1.14 (d,

6.3Hz, 3H).

Example 20


10 2-[2-Methyl-4-( (2S ,3'8)-2-methyl-[1,3']bipyrrolid inyl-1 '-yl)-phenyl]-1-oxo-2,9-diaza-spiro[5.5]undecane-9-carboxylic acid tert-butyl ester









The title compound was prepared in a manner substantially the same as Example 1.
15    LC RT = 4.88 min, MS: 511 (M+H).

1 H NMR (300M Hz, CDCI3) 8 (ppm): 6.92 (d, 1 H), 6.39-6.37 (m, 2H), 3.81-3.73 (m, 2H), 3.59-3.40 (m, 2H), 3.36-3.20 (m, ?H), 3.01-2.9 (m, 1 H), 2.79-2.76 (m, 1 H), 2.52 (q, 1H), 2.17-2.13 (m, 2H), 2.10 (s, 3H), 2.04-1.51 (m, 13H), 1.45 (s, 9H), 1.13 (d,

    3H).
20    Example 21

2-[4-((2S,3'S)-2-Methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-1-oxo-2,9-diaza-spiro[5.5]undecane-9-carboxylic acid tert-butyl ester








The  title  compound  was  prepared  in  a manner substantially the  same  as

25    Example 1 .

LC RT = 4.68 min, MS: 497 (M+H).
 

53


1H NMR (300MHz, CDC13) 8 (ppm): 7.01  (d, 2H); 6.52 (d, 2H), 3.83-3.75 (m, 2H),

3.58    (t, 2H), 3.50 (t, 1 H), 3.38-3.19 (m, 7H), 3.04-2.98 (m, 1 H), 2.79-2.75 (m, 1 H),
2.53    (q, 1 H), 2.19-2.10 (m, 4H), 2.03-1.71 (m, 7H), 1.52-1.47 (m, 2H), 1.45 (s, 9H),
1.13(d,3H)
5    Example 22
    4-{[2-Fiuoro-4-( (28,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)- phenyl]-
    methyl-carbamoyl}-4-propyl-piperidine-1-carboxylic acid tert-butyl ester











The  title  compound  was  prepared  in  a manner substantially the  same  as

10    Example 1.

LC RT = 4.9 min, M8: 515 (M+H).

1 H NMR (300M Hz, CDCI3) 8 (ppm):  6.98 (t, 1 H), 6.30-6.23 (m, 2H), 3.79-3.72 (m,

2H), 3.54 (t, 2H), 3.47 (t, 1 H), 3.36-3.19 (m, 7H), 3.00(dt, 1 H), 2.77 (q, 1 H), 2.51 (q, 1 H), 2.17-2.09 (m, 4H), 2.03-1.75 (m, 7H), 1.52-1.46 (m, 2H), 1.45 (s, 9H), 1.12 (d,

15    3H).

Example 23 3-[2-Methyl-4-((28,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one Hydrochloride

~OH,C
-cN--0-(J.::.o
 

    HgC    .HCI
20    The title  compound  was  prepared  in  a manner substantially the  same  as
    Example 1.   
    LC RT =  1.72 min, M8: 411 (M+H).   
 

54


1H NMR (300MHz, CDCis) 8 (ppm): 7.01 (d, 1 H), 6.63-6.60 (m, 2H), 4.16 (t, 1 H), 3.81-3.21 (m, 17H), 3.31 (s, 3H), 2.60-2.45 (m, 1 H), 2.38-2.28 (m, 2H), 2.16-2.01 (m, 5H), 1.86-1.77 (m, 3H), 1.50 (d, 3H).

Example 24

5 3-[4-((28,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one Hydrochloride
~:-o-N8..
,,,'0
H3C    .HCI

The title compound was prepared in a manner substantially the same as Example 1.
10    LC Rr =  1.59 min, MS: 397 (M+H).

1H NMR (300MHz, CDCis) 8 (ppm): 7.09 (d, 2H), 6.74 (d, 2H), 4.16 (t, 1H), 3.81-3.19 (m, 17H), 2.60-2.4 7 (m, 1 H), 2.38-2.27 (m, 2H), 2.15-1.97 (m, 5H), 1.84-1.76 (m, 3H),

1.50 (d, 3H).

Example 25

15 3-[2-Fiuoro-4-((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one Hydrochloride

~-b-N8..,,,'0

H3C    .HCI

The title compound was prepared in a manner substantially the same as Example 1.
20    LC Rr = 1.74 min, MS: 415 (M+H).

1H NMR (300MHz, CDCis) 8 (ppm): 7.13 (t, 1H), 6.53-6.49 (m, 2H), 4.21 (t, 1H), 3.76-3.21 (m, 17H), 2.57-2.50 (m, 1 H), 2.36-2.26 (m, 2H), 2.12-1.97 (m, 5H), 1.84-

1.77 (m, 3H), 1.50 (d, 3H).

Example 26
 

55


3-[2-Methyl-4-((28,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-9-(pyridine~4-

carbonyl)-2,9-diaza-spiro[5.5]undecan-1-one

N~:
<t;:b-{J,
,,,'0
H3C

The  title compound  was  prepared  in  a manner substantially the  same  as

5    Example 1.

LC Rr = 2.42 min, MS: 516 (M+H).

1H NMR (300MHz, CDCI3) 8 (ppm):  8.67-8.63 (m, 2H), 7.77-7.73 (m, 1H), 7.34 (dd,

1 H), 6.93-6.91 (m, 1 H), 6.40-6.38 (m, 2H), 4.20-3.88 (m, 4H), 3.60-3.21 (m, 7H), 3.05-3.02 (m, 1H), 2.81 (q, 1H), 2.55 (q, 1H), 2.13-1.46 (m, 17H), 1.15 (d, 3H).
10    Example 27

9-(Furan-3-carbonyl )-2-[2-methyl-4-( (2S ,3'8)-2-methyl-[1 ,3']bipyrrolid inyl-1 '-yl)-phenyl]-2,9-d iaza-spiro[5 .5]u ndecan-1-one

~0
~ ();,pH,ch
--cN~-/i <J..::.o

H3C

The  title  compound  was  prepared  in  a manner substantially  the  same  as

15    Example 1 .

LC Rr = 2.65 min, MS: 505 (M+H).

1H NMR (300MHz, CDCI3) 8 (ppm): 7.68 (s, 1 H), 7.40 (t, 1 H), 6.92 (d, 1 H), 6.55 (s, 1 H), 6.40-6.38 (m, 2H)4.05-3.91 (m, 2H), 3.64-3.56 (m, 4H), 3.42-3.30 (m, 2H), 3.27-3.21 (m, 2H), 3.02 (dt, 1H), 2.79 (q, 1H), 2.53 (q, 1H), 2.10 (s, 3H), 2.17-1.74 (m,

20    1OH), 1.62-1.48 (m, 4H), 1.13 (d, 3H).

Example 28 9-Benzoyl-2-[4-((28,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one
 

56













The  title compound  was  prepared  in  a manner substantially the  same  as

Example 1.

LC RT = 2.67 min, MS: 501 (M+H).

5    1H NMR (300MHz, CDC!s) 8 (ppm): 7.31 (m, 5H), 7.22 (d, 2H), 6.94 (d, 2H), 4.00-3.90 (m, 1H), 3.68 (m, 2H), 3.50-3.15 (m, 9H), 2.96 (q, 1H), 2.65 (q, 1H), 2.10-1.67

    (m, 11 H), 1.59-1.54 (m, 2H), 1.37-1.23 (m, 1H), 1.17 (d, 3H).
    Example 29
    9-(4-Fiuoro-benzoyi-2-[4-((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-2,9-
10    diaza-spiro[5.5]undecan-1-one










    The  title compound  was  prepared  in  a manner substantially the  same as
    Example 1.   
    LC RT = 2.74 min, MS: 519 (M+H).   
15    1H NMR (300MHz, CDCI3) 8 (ppm):    7.34 (dt, 2H), 7.00 (t, 2H), 6.94 (d, 2H), 6.45 (d,
    2H), 4.01-3.90 (m, 1H), 3.80-3.61    (m, 2H), 3.52 (t, 2H), 3.43 (t, 1H), 3.33-3.15 (m,
    5H), 2.94 (dt, 1 H), 2.72 (q, 1H), 2.46 (q, 1H), 2.10-1.37 (m, 14H), 1.06 (d, 3H).
        Example 30
    9-Cyclohexanecarbonyl-2-[2-fluoro-4-((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-
20    phenyl]-2,9-d iaza-spiro[5.5]undecan-1-one
 

57












    The  title compound  was  prepared  in  a manner substantially the same as
    Example 1.
    LC RT = 2.97 min, M8: 525 (M+H).
5    1H NMR (300MHz, CDCis) 8 (ppm):  6.92 (t, 1H), 6.22-6.18 (m, 2H), 3.84-3.70 (m,
    2H), 3.49-3.18 (m, 10H), 3.91 (q, 1H), 2.62 (q, 1H), 2.50-2.33 (m, 1H), 2.15-1.18 (m,
    24H), 1.12 (d, 3H).
    Example 31
    2-[2-Fiuoro-4-((28,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-9-(tetrahydro-pyran-
10    4-carbonyl)-2,9-diaza-spiro[5.5]undecan-1-one









    The title  compound was  prepared  in  a manner substantially the same as
    Example 1.
    LC RT = 2.45 min, M8: 527 (M+H).
15    1H NMR (300MHz, CDCis) 8 (ppm):  6.93 (t, 1H), 6.24-6.18 (m, 2H), 3.95-3.75 (m,
    6H), 3.48-3.30 (m, 10H), 3.19-3.13 (m, 2H), 3.04 (q, 1H), 2.74-2.67 (m, 2H), 2.40-
    2.32 (m, 1H), 2.13-1.43 (m, 15H), 1.17 (d, 3H).
    Example 32
    9-lsopropyl-2-[2-methyl-4-((28,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-2,9-
20    diaza-spiro[5.5]undecan-1-one
 

58


The title compound was prepared in a manner substantially the same as Example 1.

LC RT =  1.77 min, MS: 453 (M+H).

1 H NMR (300M Hz, CDC!s) 8 (ppm):  6.91  (d, 1 H), 6.39-6.36 (m, 2H), 3.53-3.48 (m,

5 2H), 3.38-3.18 *m, 5H), 2.99 (dt, 1H), 2.86-2.69 (m, 4H), 2.55-2.44 (m, 4H), 2.27-2.14 (m, 2H), 2.10 (s, 3H), 2.03-1.52 (m, 11H), 1.12 (d, 3H), 1.05 (d, 6H).

Example 33 9-Cyclohexylmethyl-2-[2-methyi-4-((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one









10

The title compound was prepared in a manner substantially the same as Example 1.
LC RT =  2.29 min, MS: 507 (M+H).

1 H NMR (300M Hz, CDC!s) 8 (ppm):  6.91  (d, 1 H), 6.38-6.36 (m, 2H), 3.54-3.48 .(m,

15    2H), 3.39-3.18 (m, 5H), 2.99 (dt, 1 H), 2.77-2.66 (m, 4H), 2.51 (q, 1 H), 2.23 (d, 2H), 2.13 (d, 2H), 2.09 (s, 3H), 2.03-1.43 (m, 17H), 1.24-1.16 (m, 4H), 1.12 (d, 3H), 0.91-

    0.83 (m, 3H).
    Example 34
    9-Cyclopropylmethyi-2-[4-((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-2,9-
20    diaza-spiro[5.5]undecan-1-one
 









The title compound was prepared in a manner substantially the same as Example 1.
LC RT = 3.33 min, MS: 451 (M+H).
 

59


1 H NMR (300MHz, CDCI3) 8 (ppm): 6.93 (d, 2H), 6.43 (d, 2H), 3.48 (t, 2H), 3.41 (t, 1 H), 3.29-3.12 (m, 4H), 2.91 (dt, 1H), 2.82-2.77 (m, 2H), 2.69-2.67 (m, 2H), 2.43 (q, 1H), 2.35-2.31 (m, 1H), 2.20 (d, 2H), 2.17-1.48 (m, 14H), 1.04 (d, 3H), 0.84-0.73 (m, 1 H), 0.42 (m, 2H), 0.01 (m, 2H).

5    Example 35

2-[4-((28,3'8)-2-Methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-9-(tetrahydro-pyran-4-yl)-2,9-diaza-spiro[5.5]undecan-1-one










The  title  compound  was  prepared  in  a manner substantially the  same  as

10    Example 1.

LC Rr = 3.24 min, M8: 481 (M+H).

1H NMR (300MHz, CDCI3) 8    (ppm):  7.01 (d, 2H), 6.51 (d, 2H), 4.00 (dd, 2H), 3.56 (t,
2H), 3.49    (t, 1 H), 3.40-3.20 (m, 7H), 2.99 (dt, 1 H), 2.99-2.83 (m, 2H), 2.76 (q, 1 H),
2.53-2.44    (m, 5H), 2.28-1.54    (m, 16H), 1.12 (d, 3H).
15        Example 36
9-Benzyl-2-[2-fluoro-4-((28,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-2,9-diaza-
        spiro[5.5]undecan-1-one

~N
<t;:-Q-o.,.o

    H,c'
    The  title  compound  was  prepared  in  a manner  substantially the same  as
20    Example 1.
    LC Rr = 2.14 min, M8: 505 (M+H).
    1H NMR (300MHz, CDC!s) 8 (ppm):  7.37-7.24 (m, 5H), 7.00 (t, 1 H), 6.31-6.24 (m,
    2H), 3.54-3.46 (m, 4H), 3.36-3.20 (m, 4H), 3.00 (dt, 1 H), 2.79-2.74 (m, 3H), 2.52 (q,
    1 H), 2.35-2.27 (m, 4H), 2.04-1.76 (m, 1 OH), 1.60-1.54 (m, 3H), 1.13 (d, 3H).
25    Example 37
 

60


2-[2-Fiuoro-4-((28,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-9-furan-2-ylmethyl-2,9-diaza-spiro[5.5]undecan-1-one









The  title  compound  was  prepared  in  a manner substantially the same  as

s    Example 1.

LC RT = 2 min, MS: 495 (M+H).

1H NMR (300MHz, CDCI3) 8 (ppm):  7.37 (d, 1H), 6.98 (t, 1H), 6.31-6.23 (m, 3H), 6.18

(d, 1H), 3.56-3.44 (m, 5H), 3.35-3.18 (m, 4H), 2.99 (dt, 1H), 2.78-2.72 (m, 3H), 2.53-2.42 (m, 3H), 2.30-2.24 (m, 2H), 2.19-2.05 (m, 1 H), 1.99-1.77 (m, 8H), 1.62-1.40 (m,

10    3H), 1.11 (d, 3H).

Example 38 2-{4-[4-(2S-2-Methyl-pyrrolidin-1-yl)-piperidin-1-yl]-phenyl}-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester








15 The title compound was prepared in a manner substantially the same as Example 1.

LC RT = 2.61 min, MS: 497 (M+H).

1H NMR (300MHz, CDCI3) 8 (ppm): 7.49 (d, 2H), 6.94 (d, 2H), 4.04 (d, 2H), 3.78-3.67 (m, 4H), 3.04 (t, 2H), 2.92 (dd, 2H), 2.83-2.50 (m, 4H), 2.07 (t, 2H), 1.98-1.6 (m, 12H),

20    1.45 (s, 9H), 1.3 (d, 3H).

Example 39

2-{4-[4-(28-2-Methyl-pyrrol idin-1-yl)-piperidin-1-yl]-2-trifluoromethyl-phenyl}-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester
 

61











    The  title  compound  was  prepared  in  a  manner substantially the  same  as
    Example 1.
    LC Rr = 2.75 min, MS: 565 (M+H).
5    1H NMR (300MHz, CDCb) 8 (ppm):  7.16 (d, 1H), 7.04 (2,H), 3.96 (d, 2H), 3.74 (d,
    2H), 3.60 (d, 2H), 3.12-3.01 (m, 4H), 2.87 (m, 3H), 2.66 (dd, 1H), 2.10 (t,2H), 2.0-1.82
    (m, 8H), 1.77-1.61 (m, 2H), 1.5 (d, 2H), 1.4 (s, 9H), 1.1 (d, 3H).
    Example 40
    2-{4-[4-(2S-2-Methyl-pyrrolidin-1-yl)-piperidin-1-yl]-2-tluoro-phenyl}-1-oxo-2,8-diaza-
10    spiro[4.5]decane-8-carboxylic acid tert-butyl ester








The title compound was prepared in a manner substantially the same as Example 1.
LC Rr = 2.71 min, MS: 516 (M+H).

15 1 H NMR (300M Hz, CDCis) 8 (ppm): 7.17 (t, 1 H), 6.65 (dd, 2H), 3.99 (d, 2H) 3.68 (m, 4H), 3.09 (t, 2H), 2.95 (d, 2H), 2.74 (m, 4H), 2.09 (t, 2H), 1.99- 1.62 (m, 1OH), 1.54-1.41 (m, 11 H), 1.09 (d, 3H).

                Example 41   
    2-{4-[3-((2S,3'S)-2-Methyl-piperidin-1-yl)-pyrrolidin-1-yl]-phenyl}-1-oxo-2,8-diaza-
20    spiro[4.5]decane-8-carboxylic acid tert-butyl ester
    H,::ra    c>Qa F'Yf).... ~O
    H3C    \__N    N~    -$'
        r            HsC
        0           

The title compound was prepared in a manner substantially the same as Example 1.
LC Rr = 2.74 min, MS: 497 (M+H).
 

62


1H NMR (300MHz, CDCI3) 8 (ppm): 7.37 (d,2H), 6.47 (d, 2H), 3.93 (d, 2H), 3.66 (t, 2H), 3.52 (t, 1 H), 3.43-3.30(m, 2H), 3.19 (dd, 2H), 2.96 (t, 1H), 2.79 (m, 1 H), 2.62 (m, 1H), 2.31 (m, 1 H), 2.01-1.82 (m, 7H), 1.67 (m, 1 H), 1.58 (d, 2H), 1.50-1.30 (m, 13H), 1.10 (d,3H).

5    Example 42

2-{4-[3-((28,3'8)-2-Methyl-piperidin-1-yl)-pyrrolidin-1-yl]-2-trifluoromethyl-phenyl}-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester








The title  compound  was  prepared  in  a manner substantially the  same as

10    Example 1.

LC RT = 2.97 min, M8: 565 (M+H).

1H NMR (300MHz, CDCI3) 8 (ppm): 7.05 (d, 1 H), 6.76 (d, 1 H), 6.63 (dd, 1 H), 3.98 (d, 2H), 3.66-3.40 (m, 5H), 3.32 (t, 1 H), 3.23 (dd, 1 H), 3.11 (t, 2H), 2.88 (m, 1 H), 2.69 (m, 1H), 2.38 (m, 1H), 2.10-2.00 (m, 4H), 1.98-1.94 (m,2H), 1.78-1.70 (m, 1H), 1.60-1.40

15    (m, 13H), 1.08 9d, 3H).

Example 43

2-{4-[3-( (28 ,3'8)- 2-Methyl-piperid in-1-yl )-pyrrol id in-1-yl]-2-fluoro-phenyl}-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester






20 The title compound was prepared in a manner substantially the same as Example 1.

LC RT = 2.66 min, M8: 515 (M+H).

1H NMR (300MHz, CDCI3) 8 (ppm): 7.14 (t, 1 H), 6.26-6.23 (m, 2H), 3.99 (d, 2H), 3.65 (t, 2H), 3.58 (dd, 1H), 3.49-3.34 (m, 2H), 3.30-3.04 (m, 4H), 2.86 (m, 1 H), 2.65 (m,

25 1H), 2.36 (m, 1H), 2.11-1.93 (m, 7H), 1.78 (m, 1H), 1.65-1.43 (m, 15), 1.10 (d, 3H). Example 44
 

63


2-{4-[4-(28-2-Methyl-pyrrol idin-1-yl )-piperid in-1-yl]-phenyl}-2 ,8-d iaza-spiro[4 .5]decan-1-one Hydrochloride







The  title  compound  was  prepared  in  a manner substantially the  same  as

5    Example 1.

LC Rr =  2.43 min, MS: 397 (M+H).

1H NMR (300MHz, CDsOD) o (ppm): 7.86 (d, 2H), 7.73 (d, 2H), 3.93-3.84 (m 5H), 3.67 (m, 2H), 3.60-3.56 (m, 2H), 2.50-2.35 (m, 4H), 2.24 (t, 2H), 2.13-2.09 (m, 4H),

1.88-1.80 (m, 4H), 1.53 (d, 3H).

10    Example 45

2-{4-[4-(28-2-Methyl-pyrrolidin-1-yl)-piperidin-1-yl]-2-trifluoromethyl-phenyl}-2,8-diaza-spiro[4.5]decan-1-one Hydrochloride









The  title  compound  was  prepared  in  a manner substantially the  same  as

15    Example 1 .

LC Rr =  1.89 min, MS: 465 (M+H).

1H NMR (300MHz, CD30D) o (ppm): 7.57 (d, 2H), 7.44 (d, 1 ), 4.01 (d, 2H), 3.83 (m, 1 H),•3.73 (t, 2H), 3.61-3.50 (m, 4H), 3.25-3.20 (m, 4H), 2.33-2.25 (m, 5H), 2.12-2.08 (m, 5H), 1.93-1.75 (m, 4H), 1.50 (d, 3H).

20    Example 46

2 -{4-[ 4-(28-2-Methyl-pyrrol id in-1-yl )-piperidin-1-yl]-2-fl uoro-pheify!}f2,8-Cfi9,~­ spiro[4.5]decan-1-one Hydrochloride
 

64


The title compound was prepared in a manner substantially the same as Example 1.

LC Rr =  3.19 min, M8: 415 (M+H).

1H NMR (300MHz, CD30D) 8 (ppm):  7.34 (t, 1 H), 7.06 (dd, 2H), 3.91 (d, 2H), 3.86-

5 3.80 (m, 1 H), 3.75 (t, 2H), 3.60-3.49 (m, 5H), 3.26-3.21 (m, 2H), 3.18-3.10 (m, 2H), 2.35-2.23 (m, 4H), 2.18-1.78 (m, 8H), 1.53 (d, 3H).

Example 47

2-{4-[3-( (28 ,3'8)- 2-Methyl-piperid in-1-yl)-pyrrol id in-1-yl]-phenyl}-2,8-d iaza-spiro[4.5]decan-1-one Hydrochloride
rYlJ... ,,IINO
    HN    N~    ~,•       
10    cO    H3 c''    .HCI   
    The  title  compound  was  prepared  in  a manner substantially the  same  as
    Example 1.               
    LC Rr = 2.56 min, M8: 397 (M+H).           
    1H NMR (300MHz, CD30D) 8 (ppm):  7.42 (dd, 2H), 6.72 (t, 2H), 3.84    (m, 3H), 3.61-
15    3.49 (m, 6H), 3.24-3.19 (m, 3H), 2.47 (dd, 1 H), 2.20 (t, 3H), 2.18-2.07    (m, 3H), 1.95-
    1.88 (m, 6H), 1.79-1.68 (m, 3H), 1.47 (t, 3H).           
        Example 48           

2-{4-[3-((28 ,3'8)- 2-Methyl-piperidin-1-yl )-pyrrol id in-1-yl]-2-trifl uoromethyl-phenyl}-2,8-diaza-spiro[4.5]decan-1-one Hydrochloride







20

The title compound was prepared in a manner substantially the same as Example 1.
LC Rr = 2.9 min, M8: 465 (M+H).

1H NMR (300MHz, CD30D) 8 (ppm):  7.27 (dd, 1H), 6.94 (d, 2H), 3.75-2.68 (m, 3H),

25    3.60-3.48 (m, 6H), 3.24-3.20 (m, 3H), 2.51 (dd, 1 H), 2.25 (t, 3H), 2.15-2.07 (m, 3H), 1.92-1.79 (m, ?H), 1.70-1.63 (m , 3H), 1.48 (t, 3H).
 

Example49
 

65


2-{4-[3-((28,3'8)-2-Methyl-piperidin-1-yl)-pyrrolidin-1-yl]-2-fluoro-phenyl}-2,8-diaza-spiro[4.5]decan-1-one Hydrochloride
O    ylJ..,IlNO
HNN    ~ l    ,,
oQ        H C.s-
        3
    F    .HCI

The  title  compound  was  prepared  in  a manner substantially  the  same  as

5    Example 1.

LC RT = 2.61 min, M8: 415 (M+H).

1H NMR (300MHz, CD30D) 8 (ppm):  7.23-7.19 (m, 1 H), 6.51 (t, 2H), 3.76-3.70 (m,

3H), 3.61-3.51 (m, 6H), 3.25-3.21 (m, 3H), 2.48 (m, 1 H), 2.26-2.20 (m, 3H), 2.17-2.09 (m, 3H), 1.91-1.76 (m, 7H), 1.68-1.60 (m, 3H), 1.47 (t, 3H).

10    Example 50

8-Benzenesu lfonyl-2-{4-[4-(28-2-m ethyl-pyrrol id in-1-yl )-piperid in-1-yl]-phenyl}-2,8-diaza-spiro[4.5]decan-1-one







The  title  compound  was  prepared  in  a manner substantially the  same  as

15    Example 1 .

LC RT =  4.99 min, M8: 537 (M+H).

1H NMR (300MHz, CD30D) 8 (ppm):  7.79 (d, 2H), 7.69-7.60 (m , 3H), 7.38 (d, 2H),

7.1    (d, 2H), 3.85-3.80 (m, 3H), 3.74 (t, 1 H), 3.68-3.64 (m , 3H), 3.25-3.20 (m, 3H),

2.79    (t, 2H), 2.66 (t, 2H), 2.28-1.80 (m, 14H), 1.65 (m, 1 H), 1.47 (d, 3H).

20    Example 51

8-(4-Fiuoro-benzoyl)-2-{4-[4-(28-2-methyl-pyrrol id in-1-yl )-piperid in-1-yl]-phenyl}-2,8-

diaza-spiro[4.5]decan-1-one
 

66


The title compound was prepared in a manner substantially the same as Example 1.
LC RT =  4.59 min, MS: 519 (M+H).

1H NMR (300MHz, CDsOD) 8 (ppm):  7.52-7.44 (m, 4H), 7.21  (t, 2H), 7.03 (d, 2H),

5 3.86-3.82 (m, 6H), 3.48-3.30 (m, 3H), 3.2 (m, 3H), 2.8 (t, 2H), 2.35-1.98 (m, 8H), 1.90-1.77 (m, 6H), 1.45 (d, 3H).

Example 52

8-Cyclohexanecarbonyl-2-{2-fl uoro-4-[4-(28-2-methyl-pyrrol idin-1-yl )-piperid in-1-yl]-phenyl}-2,8-diaza-spiro[4.5]decan-1-one






10

The title compound was prepared in a manner substantially the same as Example 1.

LC RT = 4.96 min, MS: 525 (M+H).

1H NMR (300MHz, CDsOD) 8 (ppm):  7.20 (t, 1H), 6.81  (d, 2H), 4.35-4.30 (m, 1 H),

15    4.05-4.00 (m, 1H), 3.94-3.86 (m, 4H), 3.73 (t, 3H), 3.51-3.42 (m, 3H), 3.17-3~08 (m, 1 H), 2.91-2.83 (m, 3H), 2.68 (m, 1 H), 2.32-2.19 (m, 5H), 2.11-2.04 (m, 4H), 1.89-160

    (m, 13H) 1.44 (d, 3H).
    Example 53
    8-(4-Fiuoro-benzenesulfonyi)-2-{4-[3-((2S,3'S)-2-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-
20    phenyl}-2,8-diaza-spiro[4.5]decan-1-one






The title compound was prepared in a manner substantially the same as Example 1.

LC RT = 5.3 min, MS: 555 (M+H).

25 1H NMR (300MHz, CDsOD) 8 (ppm): 7.88-7.84 (m, 2H), 7.42-7.33 (m, 4H), 6.67 (d, 2H), 4.30-4.26 (m, 1 H), 3.75 (t, 2H), 3.67-3.56 (m, 6H), 3.38-3.33 (m, 2H), 2.69 (t, 2H), 2.48-2.32 (m, 4H), 2.06-1.78 (m, 8H), 1.75 (m, 3H), 1.45 (d, 3H).

Example 54
 

67


2-{4-[3-( (2S ,3'S)- 2-Methyl-piperid in-1-yl )-pyrrol id in-1-yl]-phenyl}-8-(tetrahydro-pyran-4-carbonyl )-2,8-d iaza-spiro [4 .5]decan-1-one







The  title  compound  was  prepared  in  a manner substantially the same  as

5    Example 1.

LC Rr = 4.26 min, MS: 509 (M+H).

1H NMR (300MHz, CD30D) 8 (ppm): 7.39 (d, 2H), 6.67 (d, 2H), 4.39 (m,1H), 4.15 (m, 1 H), 3.97 (m, 2H), 3.83 (t, 2H), 3.66.3.47 (m, 7H), 3.03-2.98 (m, 3H), 2.5-2.35 (m, 2H) 2.21 (t, 2H), 2.10-2.00 (m, 1 H), 1.88-1.79 (m, 1 OH), 1.65-1.60 (m, 6H), 1.45 (d, 3H).

10    Example 55

8-Cyclopentanecarbonyi-2-{4-[3-((2S,3'S)-2-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-2-

trifluoromethyl-phenyl}-2,8-diaza-spiro[4.5]decan-1-one








The  title  compound  was  prepared  in  a manner substantially the  same  as

15    Example 1.

LC Rr = 5.24 min, MS: 561 (M+H).

1H NMR (300M Hz, CD30D) 8 (ppm):  7.21 (d, 1 H), 6.93 (m, 2H), 4.38-4.28 (m, 1 H),

4.10-4.06 (m, 1 H), 3.79-3.63 (m, 8H), 3.43-3.40 (m,3H), 2.50-2.50 (m,2H), 2.25 (m, 2H), 2.07 (m, 2H), 1.88-1.64 (m, 15H), 1.47 (d, 3H).
20    Example 56

8-Cyclopropylmethyl-2-{2-fluoro-4-[4-(28-2-methyl-pyrrol id in-1-yl )-piperid in-1-yl]-

phenyl}-2,8-diaza-spiro[4 .5]decan-1-one
 

68


The  title  compound  was  prepared  in  a manner  substantially the same  as

Example 1.

LC RT =  1.92 min, MS: 469 (M+H).

1H NMR (300MHz, CD300) o (ppm):  7.22 (t, 1 H), 6.85 (d, 2H), 3.94-3.82 (m, 3H),

5    3.77-3.70 (t, 2H), 3.68-3.60 (m, 2H), 3.53-3.42 (m, 2H), 3.36 (s, 2H), 3.27-3.19 (m, 2H), 3.02 (d, 2H), 2.91-2.83 (m, 2H), 2.32-1.79 (m,13H), 1.43 (d, 3H), 1.10-1.06 (m,

    1 H), 0.75 (s, 2H), 0.43 (d, 2H).
    Example 57
    8-Cyclopentyl methyl-2-{2-fluoro-4-[4-(28-2-methyl-pyrrol idin-1-yl)-piperid in-1-yl]-
10    phenyl}-2,8-diaza-spiro[4.5]decan-1-one
 













15








20
 







The title compound was prepared in a manner substantially the same as Example 1.

LC RT =  3.91 min, MS: 497 (M+H).

1H NMR (300MHz, C030D) o (ppm): 7.21 (t, 1 H), 6.82 (d, 2H), 3.86 (d, 2H), 3.70 (t, 2H), 3.67-3.54 (m, 1 H),3.34 (s, 2H), 3.23 (m, 1 H), 3.18-3.09 (m, 4H), 2.88-2.78 (m, 2H), 2.57-2.39 (m, 4H), 2.20-1.45 (m, 20H), 1.40-1.17 (m, 5H).

Example 58

8-Cyclohexylmethyl-2-{4-[3-( (2S ,3'S)- 2-methyl-piperid in-1-yl)-pyrrol id in-1-yl]-2-
trifluoromethyl-phenyl}-2,8-diaza-spiro[4.5]decan-1-one
Q oOO yl:)...,,No
N    N   ~ h    .,•
H3C

F  F  F
 

The title compound was prepared in a manner substantially the same as Example 1.

LC RT = 4.41 min, MS: 561 (M+H).

25 1H NMR (300M Hz, CD300) o (ppm): 7.11 (d, 1 H), 6.81 (m, 2H), 3.65-3.62 (m, 3H), 3.60-3.46 (m, 2H), 3.35 (s, 2H), 3.25 (m, 1 H), 2.92-2.84 (m, 4H), 2.71 (m, 1 H), 2.46
 

69


(m, 1 H), 2.19-2.08 (m, 8H), 2.01-1.94 (m, 2H), 1.82-1.45 (m, 13H), 1.35-1.24 (m, 2H), 1.15 (d, 3H), 0.93 (dd, 2H).
Example 59

2-{2-Fiuoro-4-[3-( (28 ,3'8)-2-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-phenyl}-8-

5    (tetrahydro-pyran-4-ylmethyl)-2,8-diaza-spiro[4.5]decan-1-one







The title compound was prepared in a manner substantially the same as Example 1.
LC Rr = 3.61 min, M8: 513 (M+H).

10 1H NMR (300MHz, C0300) 8 (ppm): 7.08 (t, 1 H), 6.40-6.32 (m, 2H), 3.95-3.90 (m, 2H), 3.68-3.58 (m, 3H), 3.51-3.34 (m, 4H), 3.33 (s, 2H), 3.25 (m, 1 H), 2.89 (d, 4H),

2.69    (m, 1 H), 2.45 (m, 1 H), 2.22-1.90 (m, 11 H), 1.89-1.40 (m, 8H), 1.38-1.20 (m, 2H),

1.15    (d, 3H).

Example 60

15 2-[4-((28,3'8)-2-Methyl-[1,3']bipyrrolidinyl-1'-yl)-2-trifluoromethyl-phenyl]-8-phenylacetyl-2,8-diaza-spiro[4.5]decan-1-one








The title compound was prepared in a manner substantially the same as Example 1.

20    LC Rr = 3.01 min, M8: 569 (M+H).

1H NMR (300MHz, CDCI3) 8 (ppm): 7.98-7.91 (m, 4H), 7.60-7.50 (m, 3H), 7.17 (d, 1 H), 6.82-6.80 (m, 2H), 4.48 (m, 1 H), 3.81 (m, 1 H), 3.67 (m, 2H), 3.58 (t, 1 H), 3.46-

3.34    (m, 4H), 3.27-3.21  (m, 2H), 3.04-2.97 (m, 1 H), 2.92-2.82 (q, 2H), 2.65 (q, 1H),

2.25    (m, 2H), 2.10-1.95 (m, 3H), 1.83-1.78 (m, 3H), 1.68-1.40 (m, 3H), 1.18 (d, 3H).

25
 

Example 61 8-(2-Methoxy-acetyl)-2-[4-((28,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-2-trifluoromethyl-phenyl]-2,8-d iaza-spiro[4.5]decan-1-one
 

70











The title compound was prepared in a manner substantially the same as Example 1.

LC Rr = 4.31 min, M8: 523 (M+H).

5 1H NMR (300MHz, CDCis) 8 (ppm): 7.21 (d, 1 H), 6.90 (d, 2H), 4.30 (m, 1 H), 4.21 (d, 2H), 4.05-3.97 (m, 1 H), 3.93-3.75 (m, 2H), 3.69 (t, 2H), 3.61-3.57 (m, 2H), 3.41 (s, 3H), 3.36-3.33 (m, 2H), 3.22-3.15 (m, 2H), 2.53-2.45 (m, 1 H), 2.27-2.24 (m, 5H),

2.10-2.04 (m, 2H), 1.95-1.65 (m, 6H), 1.42 (d, 3H).


10    Example 62

2-[4-((28,3'8)-2-Methyl-[1,3']bipyrrolidinyl-1'-yl)-2-trifluoromethyl-phenyl]-8-( naphthalene-2-carbonyl )-2 ,8-d iaza-spiro[4.5]decan-1-one








The  title compound  was  prepared  in  a manner  substantially the  same  as

15    Example 1.

LC Rr = 3.21 min, M8: 605 (M+H).

1H NMR (300MHz, CDCis) 8 (ppm): 7.98-7.91 (m, 4H), 7.60-7.50 (m, 3H), 7.17 (d, 1 H), 6.82-6.80 (m, 2H), 4.48 (m, 1 H), 3.81 (m, 1 H), 3.67 (m, 2H), 3.58 (t, 1 H), 3.46-3.34 (m, 4H), 3.27-3.21 (m, 2H), 3.04-2.97 (m, 1 H), 2.92-2.82 (q, 2H), 2.65 (q, 1 H),

20    2.25 (m, 2H), 2.10-1.95 (m, 3H), 1.83-1.78 (m, 3H), 1.68-1.40 (m, 3H), 1.18 (d, 3H).


Example 63

8-Benzoyl-2-[4-( (28,3'8)- 2-methyl-[1 ,3']bipyrrolid inyl-1 '-yl)- 2-trifluoromethyl-phenyl]-2,8-diaza-spiro[4.5]decan-1-one
 

71










The  title  compound  was  prepared  in  a  manner  substantially the  same  as

Example 1.

LC Rr =  2.93 min, MS: 555 (M+H).

5    1H NMR (300MHz, CD30D) 8 (ppm): 7.49-7.44 (m, 5H), 7.21 (d, 2), 6.93 (m, 2H), 4.42 (m, 1H), 4.16-4.11 (m, 1 H), 3.83-3.54 (m, 6H), 3.38-3.34 (m, 2H), 3.24-3.20 (m, 2H), 2.60-2.53 (rn, 2H), 2.36-2.22 (m, 5H), 2.15-2.10 (m, 3H), 1.97-1.78 (m, 4H), 1.47

(d, 3H).

Example 64

10 8-(Furan-3-carbonyi)-2-[4-((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-2-trifluoromethyl-phenyl]-2, 8-diaza-spiro[4 .5]decan-1-one








The title compound was prepared in a manner substantially the same as Example 1.
15    LC Rr = 2.75 min, MS: 545 (M+H).

1H NMR (300MHz, CDCI3) 8 (ppm): 7.88 (s, 1 H), 7.60 (s, 1 H), 7.21 (d, 1 H), 6.87 (s, 2H), 6.64 (s, 1 H), 4.38-4.06 (m, 2H), 3.82-3.66 (m, 4H), 3.58-3.52 (m, 1 H), 3.43-3.33 (m, 5H), 3.01-2.92 (q, 1H), 2.39-2.28 (m, 1 H), 2.26-2.05 (m, 5H), 1.99-1.80 (m, 4H),

1.74-1.60 (m, 3H), 1.35 (d, 3H).

20    Example 65

8-( 4-Methoxy-benzenesulfonyl )-2-[4-( (2S ,3'S)- 2-methyl-[1 ,3']bipyrrolid inyl-1'-yl)-2-trifluoromethyl-phenyl]-2,8-d iaza-spiro[4 .5]decan-1-one
 

72


The  title  compound  was  prepared  in  a manner  substantially the same  as

Example 1.

LC RT = 3.19 min, M8: 621 (M+H).

1H NMR (300MHz, CDsOD) 8 (ppm):  7.74 (d, 2H), 7.18-7.04 (m, 3H), 6.89 (m, 2H),

s    4.02 (m, 1 H), 3.88 (s, 3H), 3.78-3.72 (m, 1 H), 3.63-3.55 (m, 8H), 3.23 (m, 2H), 2.75-2.68 (m, 2H), 2.54-2.48 (m, 1 H), 2.35-2.29 (m, 2H), 2.10-1.95 (m, 6H), 1.80-1.65 (m,

    3H), 1.45 (d, 3H).
    Example 66
    8-Furan-2-ylmethyl-2-[4-( (28 ,3'8)-2-methyl-[1 ,3']bipyrrolidinyl-1 '-yl)-2-trifluoromethyl-
10    phenyl]-2,8-diaza-spiro[4.5]decan-1-one








The title compound was prepared in a manner substantially the same as Example 1.
LC RT =  2.22 min, M8: 531 (M+H).

15 1H NMR (300MHz, CDCI3) 8 (ppm): 7.56 (s, 1 H), 7.23 (d, 1 H), 6.93 (d, 2H), 6.50 (s, 1 H), 6.44 (s, 1 H), 4.09-4.07 (m, 1 H), 3.95-3.93 (s, 2H), 3.81-3.49 (m, 8H), 3.19-3.15 (m, 2H), 2.74-2.68 (m 2H), 2.54-2.49 (m, 2H), 2.36-2.17 (m, 4H), 2.15-2.07 (m, 4H), 1.82-1.74 (m, 3H), 1.47 (d, 3H).

Example 67

20 8-Cyclopropylmethyl-2-[4-( (28 ,3'8)-2-methyl-[1 ,3']bipyrrolid inyl-1 '-yl)- 2 -trifluoromethyl-phenyl]-2,8-diaza-spiro[4.5]decan-1-one







The title compound was prepared in a manner substantially the same as Example 1.
25    LC RT = 3.72 min, M8: 505 (M+H).

1H NMR (300MHz, CD30D) 8 (ppm): 7.29 (d, 1 H), 6.94 (d, 2H), 4.15-4.10 (m, 1 H), 3.80-3.53 (m, 8H), 3.40-3.33 (m, 2H), 3.04 (d, 2H), 2.55 (m, 2H), 2.39-2.17 (m, 6H),
 

    73
2.13    (t, 1H), 2.08-2.00 (m, 3H), 1.83-1.76 (m, 1H), 1.47 (d, 3H), 1.2-1.15 (m, 1H),
0.79    (d, 2H), 0.49 (d, 2H).
    Example 68
    2-[4-((2S,3'S)-2-Methyl-[1,3']bipyrrolidinyl-'1- yl)-2-trifluoromethyl-phenyl]-8-
5    (tetrahyd ro-pyran-4-ylmethyl )-2,8-diaza-spiro[4 .5]decan-1-one








The title compound was prepared in a manner substantially the same as Example 1.
LC Rr = 3.68 min, MS: 549 (M+H).

10    1 H NMR (300MHz, CD300) 8 (ppm): 7.29 (d, 1H), 6.96 (d, 2H), 4.17 (m, 2H), 3.97-3.93 (d, 4H), 3.85-3.77 (m, 2H), 3.72-3.32 (m, 8H), 3.25-3.22 (m, 2H), 3.03 (d, 2H), 2.592.53 (m, 1), 2.38-2.11 (m, 8H), 2.08-1.95 (m, 2H), 1.83-1.74 (m, 4H), 1.44 (d,

3H), 1.44-1.35 (m, 2H).

Example 69

15 2-[4-((2S,3'S)-2-Methyl-[1,3']bipyrrolidinyl'-1- yl)-2-trifluoromethyl-phenyl]-2,8-diaza-spiro[4.5]decan-1-one Hydrochloride

HN~y~INCJ..p

H3C
F
F  F    .HCI

The title compound was prepared in a manner substantially the same as Example 1.
20    LC Rr = 3.4 min, MS: 451 (M+H).

1H NMR (300MHz, CD30D) 8 (ppm):  7.6 (d, 1H), 6.95 (m, 2H), 4.24-4.2,1jm:; ~1 H),
    .;,.J  ••,.    .'
    3.86-3.80 (m, 1H), 3.75-3.67 (m, 3H), 3.56-3.48 (m, 3H), 3.40-3.34 (m, 2,8};~i26-3:~1-:
    1li .' ;,_.~ I    1!.:.1 <-.-
    (m, 2H), 2.63-2.57 (m, 1H), 2.42-2.23 (m, 5H), 2.15-2.08 (m, 4H), 1.91-1 :e~~~(m,-4:H);,
    1.52 (d, 3H).   
25    Biological Examples   
    Example 70   
 

74


This Example 70 demonstrates the efficacy of the compounds of this invention as H3 receptor ligands. The compounds of this invention have been demonstrated to displace [3 H]-methylhistamine radioligand binding to mammalian cell membranes expressing rhesus (Macacca Mulatta) H3 receptor. These compounds display rhesus

5    H3 affinity constants (Ki) in the range of 1 ,uM to <1 nM. Additionally, the compounds of this invention have been demonstrated by GTPyS radioligand binding assay to inhibit rhesus H3 constitutive function?! activity in cell membranes. This inhibition of

basal rhesus H3-mediated GTPyS radioligand binding demonstrates that the compounds of this invention find utility as inverse agonists. These compounds

10 decreased rhesus H3 GTPyS radioligand binding by 0-40% below basal levels. Rhesus H3 membranes were prepared from the Flp-ln T-REx 293 Cell Line
(Invitrogen) stably transfected with pcDNA5/FRT/TO (Invitrogen) containing the rhesus monkey (Macacca Mulatta) 445 amino acid H3 receptor. (Genbank #AY231164). Stably transfected cultures were amplified in tissue culture flasks by

15    standard tissue culture methods and induced to express rhesus H3 by exposure to 500 ng/ml tetracycline (Cellgro) for 24 hours. After induction, cells were dissociated from flasks utilizing Cell Stripper (Cellgro). Cells were centrifuged (1 K x g, 5 min) and

pellet frozen in an ethanol-dry ice bath to disrupt cell membranes.  Frozen cell pellet

was  re-suspended  in  5  mM  HEPES  (pH  7.4,  Invitrogen)  at  1Oml/1 000  cm2  of

20    harvested cells. The cell suspension was drawn through an 18 gauge needle (2-3x) followed by a 23 gauge needle (2-3x) to further disrupt cell membranes. The cell suspension was centrifuged (40K x g, 30 min). Cell membrane pellet was re-suspended in 5 mM HEPES (pH 7.4, Invitrogen) at a final protein concentration of 10

mg/ml.  Rhesus H3 membranes were stored under liquid nitrogen prior to use in [3H]-

25    Methylhistamine and GTP  S radioligand binding assays.

Rhesus H3 radioligand binding assay was performed using rhesus H3 receptor membranes (prepared as described above), [3H]-Methylhistamine (Perkin Elmer) and WGA SPA beads (wheat germ agglutinin scintillation proximity assay) beads (Amersham). The assay was performed in 96-well Opti-Piates (Packard). Each

30    reaction contained 50 pJ rhesus H3 membranes (20-30 p.g total protein), 50 p.l WGA SPA beads (0.1 ).!g) and 50 p.l of 83Ci/mmol [3H]-Methylhistamine (final concentration 2 nM) and 50 ).!1 of tested compound. The compounds of this invention and/or vehicle were diluted with binding buffer from 10 mM DMSO stocks. Assay plates were
 

75


sealed with TopSeal (Perkin Elmer) and mixed on shaker (25°C, 1 hour). Assay plates were read on TopCount scintillation counter (Packard). Results were analyzed by Hill transformation and Ki values were determined by Cheng-Prusoff equation. The observed binding data for a few of the representative compounds of this

s    invention are summarized in Table 1.

    TABLE 1   
               
Example    Rhesus H3    Inverse Agonism:%   
No.    binding ki (nM)    inhibition of Basal   
            GTPyS binding in   
            Rhesus H3   
               
1    132        -24   
               
2    248        -30   
               
3    7        -23   
               
4    43        -31   
               
5    18        -13   
               
6    11        -22   
               
7    15        -22   
               
8    0.8        -26   
               
9    0.6        -35   
               
10    12        -26   
               
11    22        -29   
               
12    0.8        -20   
               
13    0.8        -37   
               
14    5.6        -31   
               
15    118        -14   
               
               
16    100        -13   
               
17    1.4        -9   
               
18    6.2        -10   
               
               
               
19    1.4        -19   
               
20    6.8        -18   
               
21    7.3        -28   
               
 

                                76       
                                       
            Example        Rhesus H3        Inverse Agonism:%   
            No.        binding ki (nM)        inhibition of Basal   
                                    GTPyS binding in   
                                       
                                    Rhesus H3   
                                       
    22            0.03        -27   
                                       
    23            0.07        -19   
                                       
    24            0.1        -13   
                                       
    25            0.06        -22   
                           
                                       
    26            4        -17   
                                       
            27            1.6        -19   
                                       
            28            0.5        -15   
                                       
                                       
            29            0.4        -17   
                                       
            30            0.7        -22   
                                       
                                       
            31            0.4        -19   
                                   
                                       
            32            0.4        -14   
                                       
                                       
            33            0.2        -14   
                                       
            34            0.2        -16   
                                   
                                       
            35            0.04        -18   
                                       
            36            0.06        -13   
                                       
            37            0.1        -17   
                                       
            38            0.008        -25   
                                       
            39            0.9        -22   
                                       
            40            0.3        -21   
                                       
            41            5.6        -14   
                                   
                                   
            42            64        -15   
                               
        43            4.3        -19   
                               
            44            0.1        -19   
                                   
            45            0.15        -19   
                               
            46            0.1        -24   
                               
            47            0.4        -17   
                               
            48            0.6        -24   
                               
        49            0.5        -22   
                               
                                       
 

                    77       
                           
    Example        Rhesus H3        Inverse Agonism:%   
    No.        binding ki (nM)        inhibition of Basal   
                        GTPyS binding in   
                           
                        Rhesus H3   
                           
                           
    50        0.24        -23   
                           
    51            0.08        -17   
                           
    52        0.2        -24   
                           
    53        1.9        -13   
                           
    54        3.3        -24   
                           
    55        2.1        -27   
                       
                       
    56        0.04        -23   
                       
    57        0.1        -21   
                       
    58        0.15        -19   
                       
    59        4.6        -19   
                       
    60        144        -19   
                       
                       
    61        193        -7   
                       
    62        8.1        -19   
                       
    63        64        -18   
                       
                           
    64        9.6        -19   
                       
                       
    65        10.6        -18   
                       
    66        5.5        -19   
                       
    67        1.4        -12   
                       
    68        4.2        -19   
                       
    69        0.09        -28   
                           
Example 71

This Example illustrates the study of efficacy of the compounds of this invention in increasing the wakefulness in animal models.
Male Sprague Dawley rats (Charles River, France) weighing 250 ± 10 g were

s    anaesthetized with ZOLETIL R 50 (60 mg/kg ip) and mounted in a stereotaxic apparatus. Cortical electrodes (small stainless steel screw electrodes of 0.9 mm in diameter) were screwed into the bone over the sensorimotor cortex (1.5 mm lateral to the median suture and 1.5 mm behind the fronto-parietal suture), the visual cortex (1.5 mm lateral to the median suture and 1.5 mm in front of the parieto-occipital
 

78


suture) and over the cerebellum (reference electrode). Cortical electrodes were attached to a connector (Winchester, 7-lead) and fixed with dental cement to the cranium.

After  three  weeks  of  post-operative  recovery,  animals  were  placed  in

5    plexiglass cylinders (60 em diameter) with free access to food and water. The temperature of the room was kept constant (21 ± 1 oc) and lights were on from 7 a.m. to 7 p.m. The rats were recorded from 10 a.m. to 4 p.m. during three consecutive days: control day (01 ), drug day (02) and post drug day (03). Vehicle (01 and 03)

or drug (02) were administered 15 min before the recording.

10 Activity in sensorimotor and visual cortices were recorded by comparison with the reference electrode placed over the cerebellar cortex. Three stages were differentiated:

-    wakefulness  (W)  characterized  by  low voltage fast  electrocortical  (ECoG)

activity;

15    NREM sleep (non rapid eye movement or slow wave sleep: SWS) characterized by an increase in electrocortical activity; development of high-amplitude slow waves with some bursts of sleep spindles;

REM sleep (rapid eye movement or paradoxical sleep: PS) characterized by hypersynchronization of the theta rhythm in the visual area.

20 Analysis of the ECoG signal was performed automatically by means of a computerized system discriminating between the various sleep phases using sequential spectral analysis of ten seconds periods (Oeltamed's software "Coherence").

The compounds of this invention were dissolved  in 0.6% MTC tween  and

25    administered by oral route (po). The volume of injection was 0.5ml/1 OOg of body weight.
Two types of analysis were used to quantify the effects of the compounds of this invention on sleep-wakefulness variables: the one hour-period and the six hour-

period analysis.

30 The results are expressed in minutes (one hour-period analysis) or as the percentage of the control values (1 00% ). Statistical analysis of the data was carried out using the Student's test for paired values to determine significant variations from control values.
 

79


Example 72

Stress-induced ultrasonic vocalizations test in adult rats

This Example illustrates the study of efficacy of the compounds of this invention as antidepressive agents in animal models.

s The procedure used was adapted from the technique described by Van Der Poe! A.M, Noach E.J.K, Miczek K.A (1989) Temporal patterning of ultrasonic distress calls in the adult rat: effects of morphine and benzodiazepines. Psychopharmacology

97:147-8. Rats were placed for a training session in a cage with a stainless steel grid floor (MED Associates, Inc., St. Albans, VT). Four electric shocks (0.8 mA, 3s) were

10    delivered every 7s and ultrasonic vocalizations (UV, 22KHz) were subsequently recorded with the Ultravox system (Noldus, Wageningen, The Netherlands) during 2 min. A modified ultrasound detector (Mini-3 bat model) connected to a microphone was used to transform ultrasonic sound into audible sound. The signal was then

filtered and sent to a computer where the Ultravox software recorded each bout of UV

15    that lasted more than 1Oms. Rats were selected on the basis of their UV duration (>40s) and subjected to the test, 4h after training. For the test, rats were placed in the same cage as that used for training. One electric shock (0.8 mA, 3s) was delivered and UV (duration and frequency) were subsequently recorded with the

Ultravox system during 2 min.  The compounds of this invention were administered

20    p.o. 60 min before testing.

Example 73 Forced-swimming test in rats

This Example further illustrates the study of efficacy of the compounds of this invention as antidepressive agents in animal models.

25 The procedure was a modification of that described by Porsolt et al. (1977) Depression: a new animal model sensitive to antidepressant treatments. Nature
266:730-2. Rats were placed in individual glass cylinder (40 em height, 17 em diameter) containing water (21 oc) to a height of 30 em. Two swimming sessions were conducted (a 15-min training session followed 24h later by a 6-min test). After

30    each swimming session, rats were placed under a heating lamp to avoid hypothermia. The duration of immobility was measured during the 6-min test. The compounds of this invention were administered p.o. twice (15 min after training session and 60 min before the test).
 

80




Although the invention has been illustrated by certain of the preceding examples, it is not to be construed as being limited thereby; but rather, the invention encompasses the generic area as hereinbefore disclosed. Various modifications and

5    embodiments can be made without departing from the spirit and scope thereof.
 

81


CLAIMS

What is claimed is:


1.    A compound of formula (I):








5


wherein

m is 1 or 2;

n is 1 or 2;

10    pis 1 or 2;

R1 is hydrogen, (C1-C4)alkyl, CF3, (C1-C4)alkoxy-(C1-C4)alkyl;

R2 is hydrogen, halogen, (C1-C4)alkyl or CF3; and
R3 is hydrogen, (C1-C4)alkyl, (C1-C5)alkyloxycarbonyl, (C3-C7)cycloalkyi(C1-C5)alkyl, substituted or unsubstituted heterocycle,

15    substituted or unsubstituted heterocycloalkyi(C1-C5)alkyl, substituted or
    unsubstituted 5- or 6-membered ring heteroaryi(C1-C5)alkyl, substituted
    or unsubstituted benzyl, (C1-C4)alkoxymethylcarbonyl, substituted or
    unsubstituted (C3-C7)cycloalkanecarbonyl, substituted or unsubstituted
    benzylcarbonyl, substituted or unsubstituted (C5-C1o)arylcarbonyl,
20    substituted or unsubstituted 5 or 6-membered ring heteroarylcarbonyl,
    substituted or unsubstituted heterocyclecarbonyl, substituted or
    unsubstituted benzenesulfonyl, wherein the substituents are selected

from halogen, trifluoromethoxy, (C1-C4)alkoxy, (C1-C4)alkyl or CF3.; or an enantiomer or a diastereomer thereof.

25

2.    The compound according to claim 1, wherein

n, p, and mare 1;

R1 is methyl, ethyl, isopropyl, n-propyl or methoxymethyl; R2 is hydrogen, fluorine, chlorine, methyl, ethyl or CF3; and
 

82


R3 is hydrogen, metho:xyethylcarbonyl, tert-butyloxycarbonyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, tetrahydropyranyl, benzyl, furanylmethyl, cyclopentane-carbonyl, cyclohexanecarbonyl, trifluoromethoxybenzoyl, fluorobenzoyl, benzyl-

5    carbonyl, naphthylcarbonyl, benzenesulfonyl, fluorobenzene sulfonyl or methoxybenzenesulfonyl.



3.    The compound according to claim 1, wherein n is 2 and m is 1; or

10    n is 1 and m is 2; pis 1 or 2;

R1 is methyl or ethyl;

R2 is hydrogen, fluorine, chlorine, methyl, ethyl or CF3; and

R3  is hydrogen, isopropyl, tert-butyloxycarbonyl, cyclopropylmethyl,
 

15








20








25








30
 

cyclopentylmethyl, cyclohexylmethyl, tetrahydropyranyl, benzyl, furanylmethyl, tetrahydropyranylmethyl, cyclopentane carbonyl, cyclohexane carbonyl, tetrahydropyran carbonyl, benzoyl, trifluoromethoxybenzoyl, fluorobenzoyl, benzyl carbonyl, naphthyl carbonyl, pyridine carbonyl or furan carbonyl.

4.    The compound of claim 1 selected from the group consisting of: 2-[2-methyl-4-( (2R,3'S)-2-methyl~[1 ,3']bipyrrolidinyl-1'-yl)-phenyl]-1-oxo-2,8-

diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester;

2-[2-methyi-4-((2R,3'R)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester;

2-[2-methyl-4-( (2S ,3'R)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester;

2-[2-methyl-4-( (2S ,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester;

2-[2-methyl-4-(2-methyl-[1 ,3']bipyrrolidinyl-1'-yl)-phenyl]-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester
2-[2-methyi-4-((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-1-oxo-2,9-diaza-spiro[5.5]undecane-9-carboxylic acid tert-butyl ester;
 

83


2-[4-((28,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-1-oxo-2,9-diaza-spiro[5.5]undecane-9-carboxylic acid tert-butyl ester;

4-{[2-fluoro-4-((28,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-methyl-carbamoyl}-4-propyl-piperidine-1-carboxylic acid tert-butyl ester;

5 2-{4-[4-(28-2-methyl-pyrrolidin-1-yl)-piperidin-1-yl]-phenyl}-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester;

2-{4-[4-(28-2-methyl-pyrrolidin-1-yl)-piperidin-1-yl]-2-trifluoromethyl-phenyl}-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester; 2-{4-[4-(28-2-methyl-pyrrolidin-1-yl)-piperidin-1-yl]-2-fluoro-phenyl}-1-oxo-2,8-

10    diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester;

2-{4-[3-( (28,3'8)-2-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-phenyl}-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester;

2-{4-[3-((28,3'8)-2-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-2-trifluoromethyl-phenyl}-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl

15 ester; 2-{4-[3-((28,3'8)-2-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-2-fluoro-phenyl}-1-oxo-


2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester; 2 -[2-methyl-4-( (28 ,3'8)-2-methyl-[1,3']bipyrrol id inyl-1'-yl)-phenyl]-2,8-diaza-

spiro[4.5]decan-1-one;

20 8-cyclopentylmethyl-2-[2-methyl-4-(2-methyl-[1 ,3']bipyrrolidinyl-1'-l)-phenyl]-2,8-diaza-spiro[ 4.5]decari-1-one;

2-[2-methyl-4-( (28 ,3'8)- 2-methyl-[1 ,3']bipyrrolid inyl-1'-yl)- phenyl]-8-( 4-trifluoromethoxy-benzoyl)-2,8-diaza-spiro[4.5]decan-1-one;

8-benzenesulfonyl-2-{4-[4-(28-2-methyl-pyrrol id in-1-yl)-piperid in-1-yl]-phenyl}-

25 2,8-diaza-spiro[ 4.5]decan-1-one; 8-(4-methoxy-benzenesulfonyl)-2-[4-((28,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-
yl)-2-trifluoromethyl-phenyl]-2,8-diaza-spiro[4.5]decan-1-one; 2-[4-((28,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-2-trifluoromethyl-phenyl]-2,8-

diaza-spiro[4.5]decan-1-one

30 2-[2-methyl-4-((28,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;

2-[2-methyl-4-( (2R,3'R)-2-methyl-[1 ,3']bipyrrolid inyl-1'-yl)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one Hydrochloride;
 

    84
    2-[2-methyi-4-((2R,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-2,8-diaza-
    spiro[4 .5]decan-1-one Hydrochloride;
    2-[2-methyi-4-((28,3'R)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-2,8-diaza-
    spiro[4 .5]decan-1-one Hydrochloride;
5    8-cyclopentylmethyl-2-[2-methyi-4-((2R,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-l)-
    phenyl]-2,8-diaza-spiro[4.5]decan-1-one;
    8-cyclopentylmethyl-2-[2-methyi-4-((2R,3'R)-2-methyl-[1,3']bipyrrolidinyl-1'-l)-
    phenyl]-2,8-d iaza-spiro[4 .5]decan-1-one;
    8-cyclopentylmethyl-2-[2-methyi-4-((28,3'R)-2-methyl-[1,3']bipyrrolidinyi-1'-I)-
10    phenyl]-2,8-diaza-spiro[4.5]decan-1-one;
    8-cyclopentylmethyl-2-[2-methyl-4-((28,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-l)-
    phenyl]-2,8-diaza-spiro[4.5]decan-1-one;
    2-[2-methyi-4-((2R,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-8-(4-
    trifluoromethoxy-benzoyl)-2,8-diaza-spiro[4.5]decan-1-one;
15    2-[2-methyi-4-((2R,3'R)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-8-(4-
    trifluoromethoxy-benzoyl)-2,8-diaza-spiro[4.5]decan-1-one;
    2-[2-methyi-4-((28,3'R)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-8-(4-
    trifluoromethoxy-benzoyl)-2,8-diaza-spiro[4.5]decan-1-one;
    2-[2-methyl-4-(2-methyl-[1 ,3']bipyrrolidinyl-1'-yl)-phenyl]-8-(4-trifluoromethoxy-
20    benzoyl)-2,8-diaza-spiro[4.5]decan-1-one;
    3-[2-m ethyl-4-( (28 ,3'8)- 2-methyl-[1 ,3']bipyrrol id inyl-1'-yl)- phenyl]-2,9-diaza-
    spiro[S .5]undecan-1-one;
    3-[4-((28,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-2,9-diaza-
    spiro[5.5]undecan-1-one;
25    3-[2-fluoro-4-((28,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-2,9-diaza-
    spiro[5.5]undecan-1-one;
    3-[2-methyl-4-((28,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-9-(pyridine-4-
    carbonyl)-2,9-diaza-spiro[5.5]undecan-1-one;
    9-(furan-3-carbonyl)-2-[2-methyl-4-((28,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-yi)-
30    phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;
    9-benzoyl-2-[4-( (28 ,3'8)- 2-methyl-[1 ,3']bipyrrolid inyl-1'-yl)- phenyl]-2,9-d iaza-
    spiro[5.5]undecan-1-one;
 

85


9-(4-fluoro-benzoyl-2-[4-((28,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;

9-cyclohexanecarbonyl-2-[2-fluoro-4-( (28 ,3'8)- 2-methyl-[1 ,3']bipyrrol idi nyl-1'-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;

5 2-[2-fluoro-4-((28,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-9-(tetrahydro-pyran-4-carbonyl)-2,9-diaza-spiro[5.5]undecan-1-one;

9-isopropyl-2-[2-methyl-4-( (28,3'8)- 2 -methyl-[1 ,3']bipyrrol id inyl-1'-yl)- phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;

9-cyclohexylmethyl-2-[2-methyl-4-((28,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-lO phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;

9-cyclopropylmethyl-2-[4-((28,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;

2-[4-((28,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-9-(tetrahydro-pyran-4-yl)-2,9-diaza-spiro[5.5]undecan-1-one;

15 9-benzyl-2-[2-fluoro-4-((28,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;

2-[2-fluoro-4-( (28 ,3'8)- 2-methyl-[1 ,3']bipyrrolidinyl-1'-)yl-phenyl]-9-furan-2-ylmethyl-2,9-diaza-spiro[5.5]undecan-1-one;

2-{4-[4-(28-2-methyl-pyrrolidin-1-yl)-piperidin-1-yl]-phenyl}-2,8-diaza-

20 spiro[4.5]decan-1-one; 2-{4-[4-(28-2-methyl-pyrrolidin-1-yl)-piperidin-1-yl]-2-trifluoromethyl-phenyl}-

2,8-diaza-spiro[4.5]decan-1-one;

2-{4-[4-(28-2-methyl-pyrrolid in-1-yl )-piperidin-1-yl]-2-fl uoro-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;

25 2-{4-[3-( (28,3'8)-2-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;

2-{4-[3-( (28 ,3'8)- 2-methyl-piperid in-1-yl )-pyrrol id in-1-yl]-2-trifl uoromethyl-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;

2-{4-[3-( (28 ,3'8)- 2-methyl-piperid in-1-yl )-pyrrol id in-1-yl]-2-fluoro-phenyl}-2 ,8-

30    diaza-spiro[4.5]decan-1-one;

8-( 4-fl uoro-benzoyl )-2-{4-[4-(28-2-methyl-pyrrol id in-1-yl)-piperid in-1-yl]-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;
 

    86
    8-cyclohexanecarbonyl-2-{2-fluoro-4-[4-(2S-2-methyl-pyrrolidin-1-yl)-piperidin-
    1-yl]-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;
    8-(4-fluoro-benzenesulfonyi)-2-{4-[3-((2S,3'S)-2-methyl-piperidin-1-yl)-
    pyrrolidin-1-yl]-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;
5    2-{4-[3-((2S,3'S)-2-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-phenyl}-8-(tetrahydro-
    pyran-4-carbonyl )-2,8-d iaza-spiro[4.5]d ecan-1-one;
    8-cyclopentanecarbonyl-2-{4-[3-( (2S,3'S)-2-methyl-piperidin-1-yl)-pyrrol idin-1-
    yl]-2-trifluoromethyl-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;
    8-cyclopropylmethyl-2-{2-fluoro-4-[4-(2S-2-methyl-pyrrolidin-1-yl)-piperidin-1-
10    yl]-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;
    8-cyclopentylmethyl-2-{2-fluoro-4-[4-(2S-2-methyl-pyrrolidin-1-yl)-piperidin-1-
    yl]-phenyl}-2,8-diaza-spiro[4 .5]decan-1-one;
    8-cyclohexylmethyi-2-{4-[3-((2S,3'S)-2-methyl-piperidin-1-yl)-pyrrolidin-1-yl]-2-
    trifluoromethyl-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;
15    2-{2-fluoro-4-[3-( (2S ,3'S)- 2-methyl-piperid in-1-yl )-pyrrol idin-1-yl]-phenyl}-8-
    (tetrahydro-pyran-4-ylmethyl)-2,8-diaza-spiro[4.5]deca~-1-one;
    2-[4-((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-2-trifluoromethyl-phenyl]-8-
    phenylacetyl-2,8-diaza-spiro[4.5]decan-1-one;
    8-(2-methoxy-acetyi)-2-[4-((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yi)-2-
20    trifluoromethyl-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;
    2-[4-((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-2-trifluoromethyl-phenyl]-8-
    ( naphthalene-2-carbonyl )-2,8-d iaza-spiro[ 4 .5]decan-1-one;
    8-benzoyi-2-[4-((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-2-trifluorometh_vl..,-
    phenyl]-2,8-diaza-spiro[4.5]decan-1-one;
25    8-(furan-3-carbonyi)-2-[4-((2S,3'S)-2-methyl-[1,3']bipyrrolidinvl-.~•~vl)-2-
    trifluoromethyl-phenyl]-2,8-diaza-spiro[4.5]decan-1-ol,r:!, •••",
    8-furan-2-ylmethyi-2-[4-((2S,3'S)-2-methyl-[1,3']bipyrrolidinyi-1'~)(J~:?:~ -
    trifl uoromethyl-phenyl]-2,8-d iaza-spiro[4.5]decan-1-one;
    8-cyclopropylmethyi-2-[4-((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yi)-2-
30    trifluoromethyl-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;
    2-[4-((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-2-trifluoromethyl-phenyl]-8-
    (tetrahydro-pyran-4-ylmethyl)-2,8-diaza-spiro[4.5]decan-1-one; and
 

        87
        2-[4-((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-2-trifluoromethyl-phenyl]-2,8-
        diaza-spiro[4.5]decan-1-one;
        or a salt thereof.
5    5.    The compound of claim 1 selected from the group consisting of:
        8-cyclopentylmethyl-2-[2-methyi-4-((2R,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-l)-
        phenyl]-2,8-diaza-spiro[4.5]decan-1-one;
        8-cyclopentylmethyl-2-[2-methyi-4-((2R,3'R)-2-methyl-[1,3']bipyrrolidinyl-1'-l)-
        phenyl]-2,8-diaza-spiro[4.5]decan-1-one;
10        8-cyclopentylmethyl-2-[2-methyi-4-((2S,3'R)-2-methyl-[1,3']bipyrrolidinyl-1'-l)-
        phenyl]-2,8-diaza-spiro[4.5]decan-1-one;
        8-cyclopentylmethyl-2-[2-methyi-4-((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-l)-
        phenyl]-2,8-diaza-spiro[4.5]decan-1-one;
        2-[2-methyl-4-( (2R,3'S )-2-methyl-[1,3']bipyrrolid inyl-1'-yl)- phenyl]-8-( 4-
15        trifluoromethoxy-benzoyl)-2,8-diaza-spiro[4.5]decan-1-one;
        2-[2-methyi-4-((2R,3'R)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-8-(4-
        trifl uoromethoxy-benzoyl )-2,8-d iaza-spiro[4 .5]decan-1-one;
        2-[2-methyl-4-( (2S,3'R)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-48--(
        trifluoromethoxy-benzoyl)-2,8-diaza-spiro[4.5]decan-1-one;
20        2-[2-methyl-4-(2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-8-(4-trifluoromethoxy-
        benzoyl)-2,8-diaza-spiro[4.5]decan-1-one;
        3-[2-methyl-4-( (2S ,3'S)- 2-methyl-[1,3']bipyrrol id inyl-1'-yl)- phenyl]-2,9-diaza-
        spiro[5.5]undecan-1-one;
        3-[4-((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-2,9-diaza-
25        spiro[5.5]undecan-1-one;
        3-[2-fluoro-4-( (2S ,3'S)- 2-methyl-[1,3']bipyrrolidinyl-1'-yl)- phenyl]-2,9-d iaza-
        spiro[5.5]undecan-1-one;
        9-isopropyl-2-[2-methyi-4-((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-
        2,9-diaza-spiro[5.5]undecan-1-one;
30        9-cyclohexylmethyl-2-[2-methyi-4-((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-
        phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;

9-cyclopropyl methyl-2-[4-( (2S,3'S)- 2-methyl-[1,3']bipyrrolid inyl-1'-yl)-phenyl]-2,9-diaza-spiro[5.5]undecan-1-one;
 

    88
    2-[4-((28,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-9-(tetrahydro-pyran-4-
    yl)-2,9-diaza-spiro[5.5]undecan-1-one;
    9-benzyl-2-[2-fluoro-4-((28,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-2,9-
    diaza-spiro[5.5]undecan-1-one;
5    2-[2-fluoro-4-( (28 ,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-)yl-phenyl]-9-furan-2-
    ylmethyl-2,9-diaza-spiro[5.5]undecan-1-one;
    8-cyclopropylmethyl-2-{2 -fl uoro-4-[4-(28-:2-methyl-pyrrol idin-1-yl )-piperidin-1-
    yl]-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;
    8-cyclopentylmethyl-2-{2-fluoro-4-[4-(28-2-methyl-pyrrolidin-1-yl)-piperidin-1-
10    yl]-phenyl}-2,8-diaza-spiro[4.5]decan-1-one;
    2-{2-fl uoro-4-[3-( (28 ,3'8)- 2-methyl-piperid in-1-yl )-pyrrol idin-1-yl]-phenyl}-8-
    (tetrahydro-pyran-4-ylmethyl)-2,8-diaza-spiro[4.5]decan-1-one;
    8-furan-2-ylmethyl-2-[4-((28 ,3'8)- 2-methyl-[1 ,3']bipyrrolid inyl-1 '-yl)- 2-
    trifluoromethyl-phenyl]-2,8-diaza-spiro[4.5]decan-1-one;
15    8-cyclopropylmethyl-2-[4-((28,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-2-
    trifluoromethyl-phenyl]-2,8-diaza-spiro[4.5]decan-1-one; and
    2-[4-((28,3'8)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-2-trifluoromethyl-phenyl]-8-

(tetrahydro-pyran-4-ylmethyl)-2,8-diaza-spiro[4.5]decan-1-one; or a salt thereof.

20

6.    The compound according or claim 1 which is having the formula (II):






(II)

wherein R1, Rz, R3, m and n are as defined in claim 1.


25    7. A pharmaceutical composition comprising one or more compounds of any of claims 1 to 6 or a pharmaceutically acceptable salt, an enantiomer, or a diastereomer thereof in combination with one or more pharmaceutically acceptable carriers, diluents or excipients.
 

89


8.    Use of a compound of any of claims 1 to 6 or a pharmaceutically acceptable salt, an enantiomer, or a diastereomer thereof for the preparation of a pharmaceutical composition, which compound is capable of modulating H3 receptor function for treating cognitive impairment associated with

5    schizophrenia (CIAS), anxiety disorders such as generalized anxiety, panic disorder and post-traumatic stress disorder, major depressive disorder,

dementia of Alzheimer type (OAT), cognitive deficits related to neurological diseases chosen from Alzheimer, Parkinson or Huntington, age related cognitive impairment, mild cognitive impairment, vascular dementia, Lewis
10    Body dementia, cognition associated with cognitive deficits, sleep related disorders, attention deficit hyperactivity disorder and depression, and obesity.

9.    Use according to claim 8, wherein the sleep disorder is selected from the group consisting of narcolepsy, circadian rhythm sleep disorder, obstructive

15    sleep apnea, periodic limb movement and restless leg syndrome, excessive sleepiness and drowsiness due to medication side-effect.

10.    Use according to claim 8, wherein the sleep disorder is narcolepsy.


20    11. Use according to claim 8, wherein the disease is cognitive impairment associated with schizophrenia (CIAS).

12.    Use according to claim 8, wherein the disease is dementia of Alzheimer type (OAT).

25

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