BRPI0922843A2 - piperidine spiro pyrrolidinone and substituted piperidinone, preparation and therapeutic application thereof - Google Patents

Abstract

Substituted piperidine spiro pyrrolidinone and piperidinone, preparation and therapeutic application thereof The present invention relates to a series of substituted n-phenyl bipyrrolidine carboxamides of formula (I). wherein r1, r2, r3, m, n and p are as described herein in this patent application. more specifically, the compounds of this invention are h3 receptor modulators and therefore are useful as pharmaceutical agents, especially in the treatment and / or prevention of a variety of h3 receptor modulated diseases including diseases associated with the central nervous system. In addition, this invention also describes methods of preparing substituted n-phenyl bipyrrolidine carboxamides and intermediates therefor.

Description

Invention Patent Descriptive Report for '“PIPERIDINE SPIRUS PIRROLIDINONE AND SUBSTITUTED PIPERIDINONE ,. PREPARATION AND THERAPEUTIC APPLICATION OF THE SAME ”.

Background of the Invention

Field of invention

The present invention relates to a series of substituted piperidine spiro pyrrolidinone and piperidinone derivatives. The compounds of this invention are H3 receptor modifiers 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 relates to methods of preparing substituted and intermediate piperidine spiro pyrrolidinone and piperidinone for that purpose.

□ escriçàod ^ lecntçi ··

Histamine is a ubiquitous messenger molecule released by mast cells, cells similar to enterochromaffin, and neurons. The physiological actions of nystamine are mediated by four defined pharmaeologicamerite receptors (H1, Hz, H3 and H4). All histamine receptors have 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 classic antihistamines (antagonists), such as diphenhydramine and fexc-phenadine. Although antagonism of the immune system's Hi receptor is commonly used for the treatment of allergic reactions, the H1 lick receptor is expressed in various peripheral and central nervous system (CNS) tissues. In the brain, H1 is involved in the control of alertness. of mood, appetite and hormonal secretion

The H2 receptor is also expressed in the central nervous system, where it can modulate various processes, including cognition. However, H2 receptor antagonists have been developed essentially to improve gastric ulcers by inhibiting the secretion of gastric acid by hylstamine-mediated parieial cells. Classic H2 antagonists include cimetidine, ranitidine. and famotidine.

It should be noted in advance that the function of H4 receptors remains more defined, but may involve immune regulation and prayers5 inflate matters

On the other hand, H3 receptors have also been identified pharmacologically in the central nervous system, heart, lung, and stomach. The H3 receptor differs significantly from other histamine receptors, presenting low sequencer homology (HI: 22%, Η2 · 21%, H4 : 10 35%). Η3 is a presynaptic autoneceptor over bisiamine neurons in the brain and a presynaptic hetererreceptor in neurons that do not contain histamma neurons in both the central and peripheral nervous systems. In addition to hlstamina. H3 also modulates the release and / or synthesis of other neurotransmitters. including acetiicoline, dopamine, norepinefn15 na and serotonin. Noteworthy in particular, the pre-synaptic modulation of histamine release by H3 has significant regulation of H1 and H2 receptors in the brain, modulating signaling pathways of multiple neurotransmitters, H3 may contribute to various physiological processes. -dlnrca indicates that H3 has a role in cognition, in the sane and wake cycle and in energy riomeoslase.

Modelers of H3 function may be useful in the treatment of obesity and central nervous system disorders (Schizophrenia, Zdzheimer's disease, hyperactivity disorder and attention deficit disorder, Parkinson's disease, depression, and epilepsy), sleep disorders ( rareolepsy and insomnia), cardiovascular disorders (acute myocardial infarction), respiratory disorders (asthma), and gastrointestinal disorders. See generally speaking, Hancock. Biochem. Pharmacol, 2Q06.Apr 14: 71 (8): 1103-13 and Esbenshade ef a /. Mol Interv, 2006 Apr; 6 (2); 77-88, 59.

U.S. Patent Number 7,223.788 ⁹ depicts a series of 30 composite including substituted bis-pírrolldínas, antagonists melanins tent-concentrating hormone receptor (MCH). But the compounds described therein are not reported to be active at the H3 receptor site.

fairy art references described here, in this patent application. are incorporated here, in this patent application, by reference in their entirety.

Therefore, it is an object of this invention to provide a series of piperidine spiro pyrrolidinone and pipendmone substituted as selective H3 receptors for the treatment of central nervous system disorders regulated by H3 receptors.

It is also an object of this invention to provide processes for the preparation of spiro pmolidinone and substituted piperidinone pipendin as described herein, in this patent application.

Other objects and additional scope of the applicability of the present invention will become evident from the following detailed description.

Summary of the Invention '15 It has now been seen that the compounds of formula (?) Are useful for inverse H3 receptor antagonists and / or 'agonies'. In this way ·, according to the practice of this invention, a compound of formula (I) · is provided

m that:

m is 1 or u 2;

n is 1 or 2;

p is 1 or 2;

R: it's hydrogen, (C _} - C _s ) alkyl, CF _{3 <} (C _r Ce) ahòoxi- (C> 25 CíÇaiquila: e

R? is hydrogen. haiogenide, (C _r Qqalkyl or QF ₃ ;

R _{3 is} hydrogen, (Cr C $) alkyl. (C3-G _? ) Cytochloride, te? Cbmitoxicarbauite, (Gi-CzjcicloalquiKGr Cçjaiquila, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted, substituted or unsubstituted, substituted or substituted furanylmethyl, substituted or substituted ) alkoxymethyl carbonyl, (C- _S -C?) substituted or unsubstituted cycloácano cruboniia, substituted or unsubstituted benzoyl, substituted or unsubstituted benzyl carbonyl, substituted or unsubstituted carbonyl naphthyl, substituted or unsubstituted carbonyl, substituted furan carbonyl or unsubstituted tetrahydrofuran hldropkano carbonyl substituted or unsubstituted, blessed 'sulfunila substituted or unsubstituted, wherein substituents are selected from es balogeneto, trifluoromethoxy, (CrQJalcóxi, _(C? cC 10) alkyl or-CF j, benziloxícarboniia.

This invention additionally includes various salts of the compounds of formula (I) including various enanimers 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 application in alleviating various diseases which are partially mediated and / or topophalmerite by H3 receptors. Dã.êcúção Detailed, da.] Nyençãg

The spas as used here, cars have a patent application, 20 have the following meanings'.

as used here, in this patent application, the expression "(Cr C6) a! quila ^! 'includes methyl and ethyl groups. and groups of straight or branched prupíla chains, and butia. Particular alchi groups are media, etda, n-propyl, isopropyl and tert-butyl Expressions derived from such name 25 '' (Ch-C-6) alkoxy ''. ”(Cr C6) alcòxí (C _} ·· CõjalquilaE or '' hydroxy (C _r · CSialkila ') must be interpreted accordingly.

As used herein, in this patent application, the expression ^f 'aioioaiquila ^<! includes all known cyclic radicals. Representative examples of "cyhaloalkyl" include without limitation cyclopropyl, cyclobutyl, oiclopentyl, cyclic hexiia, cycloheptyl, ketoethyl, and the like. Expressions such as cyclo - derived "," ^{cycloalkylalkyl, \!;} cycloalkylaryl ”, '' clcloalkylarbonyl '' must be interpreted accordingly.

As used herein, in this patent application, the expression (Cr Cdperfluoroalkite ' ⁴ means that all hydrogen atoms in said alkyl group are replaced with fiber atoms. Illustrative examples include trlfluoromethyl to pentaflucroethyl clusters, and ·· 5 chain minds straight or branched heptafiuuropropíla, aonafiucrobutíla undecafiuoropentiía and tridecaflàor-hexHa. The derived expression, "((> C ^ perfiucroaoxy"), must be interpreted accordingly.

As used herein, in this patent application, the expression (C ^ -C flaute means unsubstituted substituted phenyl or naphthyl. 10 Specific examples of substituted slit or naphthia Include o-, p-, mtolite, 1.2 ··. 1.3-, 1.4-xiliia. 1-methylnatete. 2-mefilnafiila, etc. Substituted or substituted naphthylite also includes any of the possible subsiitmentes as defined further here, in this patent application, or as is technically known. The derived expression, (Ce · · 15 Cv-Janlsulfoníia, must be interpreted accordingly.

As used aqm. in this patent application, the expression "(Ce-Ct £)) aryl (Cr-C \) alquHa means that (C _and -Ci _f? } aryl as defined here, in this patent application, is additionally attached to {C _; -C <<) alkyl as defined herein, in this patent application. Representative examples 20 include benzyl, pheniethyl, 2-femipropyl, 1-naphthylmetite.

2-naphthylmethyl and the like. Similarly, the expression (Cs-C ^ danlcai bonila 'should be interpreted accordingly. Representative examples include benzoyl, nalkylcarbonyl, and the like.

As used herein, in this patent application, the expressions are 'heteroanla' including all known heteroatom-containing aromatic radicals. Representative 5-membered heteroanl radicals include turanite, phienyl or thiophenyl, pbroil, isopyrrole, piraxolyl, iridazolite, oxazolite. ttezobía. Isothiazolyl, and the like. Representative 6-membered heferearite radicals include pyridimla, pindazínte. ptemidímisr pyraziniia. triaziniia, and 30 similar radicals Representative examples of heieroaryl b; ayloyl radicals include, benzofuranyl, benzothiophene. indoilla, quinolinyl, isoquinolimla, cinolila, benzrmidazotHa ,. indazolite. pyridofuranite, pindothead, and similar β / 92 radicals. The derivative expression ’’ ‘heteroanlcarborãla '* should be interpreted accordingly, for example, pyridinecarbonyl, furancvrarboniis, and the like.

As used herein, in this patent application, the expression is hetero-cyclo ”includes all known cyclic fillers containing reduced heteroatorrjo. Representative 5-membered heterocyclic radicals include tetrahydrofuranyl. tetrahydrophiophenyl. pyrrdidyl, .2-thiazoyl, tetrahydrothiaxyl, tetrahydrooxazaiyl, and the like. Representative 6-membered heterocyclic radicals include piperidmüa, piperaziníla, morpholínda, ho10 rnorfoliniía, tetra ·· hydropiranila, and the like. Various other heterocycle radicals include, without limitation, aziridine, azepanyl, diazepanyl, diazabicide 2.1] heptyl, and triazocanyl, and the like. The derivative expression '' heterocyclocarbonyl and heterocyclicalkyl (C _r C ',) Alchemy ^K should be interpreted: accordingly.

Halogen or halo ”means chlorine, fluoro, bromo, and iodo.

As used here. in this patent application, 'patient' means a warm-blooded animal, such as, for example, rat, mice, dogs, cats, guinea pigs, and primulas such as humans.

As used herein, in this patent application, expression is a pharmaceutically acceptable carrier ”means a solvent. dispersant, exeipient, adjuvant. or other non-toxic material which is mixed with the compound of the present invention to allow the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to the patient. An example of a similar carrier is pharmaceutically acceptable oil typically used for parenteral administration.

The term pharmaceutically acceptable salts as used herein, in this patent application, means that the compounds of the present invention can be used in medicinal preparations. Quires salts, however, can be useful in the preparation of the compounds according to the invention or their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which can be formed, for example, by mixing

7/92 yields a solution of the compound according to the invention as a solution of a pharmaceutically acceptable acid such as hydrochloric acid, oromidric acid, nitric acid, sulfamic acid, sulfuric acid. methanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, fumaric acid, msleic acid, hydroxymalelic acid, amino acid, asoorbic acid, suooinic acid. glutaric acid, acetic acid, prupionic acid, salicylic acid, cinnamic acid, 2-phenoxyberzoic acid, hydroxybenzoic acid, phenoxyacetic acid, benzoic acid, oxalic acid. citric acid, tartaric acid, glycolic acid. lactic acid, pyruvic acid, malonic acid, carbonic acid or 10 phosphoric acid. Metal salts of lais acid such as sodium monohydrogen orphophosphate and potassium hydrogen sulfate can also be formed. In addition, salts formed in this way can be present either as mono- or di-acid salts and can exist substantially anhydrous or can be hydrated. Furthermore, where the compounds of the invention carry an acidic portion. familial and acceptable acceptable salts thereof may include salts of alkali metals, for example, sodium or potassium salts; alkaline earth metal salts, for example, calcium or magnesium salts, and salts formed with suitable organic binders, for example, quaternary ammonium.

The expression ^>! stereoisomers' ^! is a general term used for all isomers of individual molecules that differ only in the orientation of their atoms in space. Typically induces mirror image isres that are usually formed due to at least one asymmetric center, (enantiomers). Where the compounds according to invention 25 have two or more asymmetric centers, they can additionally exist as dlastereôrneros. also, some individual molecules may exist as geometric isomers (cis / kans). Similarly, some compounds of this invention can exist in a mixture of two or more structurally distinct forms that are in rapid equilibrium, commonly known as tautomers. Representative examples of tautomers include cefo-enel tautomers, phenol-tautomers, nitrous-extreme tautomers, imine-enamine lauomers, ele. It should be understood that all of these

8/92 mere and mixtures thereof in any proportion are included within the scope of the present invention.

As used here, in the patent application, 'R' and Έ 'are used as terms commonly used in organic chemistry to note the specific configuration of a chiral center. The term 'R ^! (straight) refers to the configuration of a chiral center with a clockwise relationship of the priority group (highest to lowest second) when viewed along the link towards the lowest priority group. The term 'S' (sdíteter) refers to the configuration of a chiral center with an anti-clockwise ratio of the priority group (highest to lowest second) when viewed along the link towards the lowest priority group. The priority group is based on sequence rules in which prioritization is first based on the atomic number (out of fear of reducing the atomic number). A list and discussion of priorities 15 is included in Sfemuc /? Em? Sfry of Organic Compounds, Ernest L Eliel.

Samuel H. Wílen and Lewis N Mender. editors, Wíley-lntotsoience. John Wiley & Sons, inc., New York, 1994.

In addition to the (R) - (S) system. the oldest D-L system can also be used here, in this patent application, to desolute the absolute contradiction, specifically with reference to amino acids. In this system a Fischer projection formula is oriented so that the number 1 carbon in the main chain tics at the top. The prefix 'D' is used to represent the absolute configuration of the isomer in which the functional group (determinant) is on the right side of the carbon in the center chirai and Ί.Λ to 25 of the isomer to which it is on the left.

In a broad sense, the term "substituted" is contemplated to include all permissible substances of organic compounds. In some of the specific embodiments as described here, in this patent application, the term substituted ”means substituted with one or more 35 substituents selected independently from the group consisting of (C ',. C, _:: ;;) alchemy, (Cg -C ^ alkenyl, (C- _; .GY) perfluamaiquia, phenyl, hsdrdxi. CO? H, an ester, an amide, (C <-CeJalcoxy, (C _r Ce) thioalkyl _! ((A

9/92

Ce) peifluoroalkoxyl -Ni-R, CL Br, I, F, -NH-lower alkyl. and -N (Ir-lower alkyl) _; >. However, can any of the other suitable substitutions of knowledge of a person skilled in the art also be used in these modalities?

"Therapeutically effective amount means an amount of the compound which is effective in treating the so-called disease, disorder or condition.

The terms treatment ”refers to;

(í) preventing a disease, disorder or condition from occurring in a patient who may be predisposed to the disease, disorder and / or condition, but has not yet been diagnosed as having it;

(ii) inhibit the disease, disorder or condition, that is. stop its development; and (iii) alleviate the disease, disorder or condition, that is, cause the regression of? disease, disorder and / or condition.

Therefore, according to the practice of this invention, a compound of formula I is provided:

This invention additionally includes various salts of the compounds of formula (1) including several enantiomers or dastomeres 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 (1) as well as their therapeutic application in the alleviation of various diseases which are mediated in part and / or totally by H3 receptors.

Therefore, according to the practice of this invention, a compound of the formula 1 is provided:

millstone 1 ου 2; ng I or 2; p 1 or 2:

R ·; is hydrogen, (Ci-C ₄ ) alkyl, CF _S. (C 1 -C 4 alkoxy-fCrC 4 alquita;

and

R; <is hydrogen. haiogenide, {Ch-C ^ lquHa or Qfo;

Rj is hydrogen, (C _r C§) aíquíla, (Ci-C ^ alquiloxsoarbanila such uterus horn-butiioxicarboniia, (C3-C7) cinícalquÍ! (C _r Cf,) alkyl, substituted or unsubstituted heterociolo such as tetra- hydropyranyl, heierocidoaquií ·· 10 (Cí Cs) substituted or unsubstituted aiquila, such as tetrahydropyranyl · menla, heternarií (C <-C6) substituted or unsubstituted 5 or 6-membered ring aliquia, such as furanitmethyl. benzyl substituted or unsubstituted. (Cr-Cálaiooxymethylcarbonila substituted or unsubstituted, (Cs ~ Cz) cyclic ·· aioanooarbonila substituted or unsubstituted, substituted or unsubstituted benzylarbonrla, (Cç-C ^ substituted or unsubstituted, t;? J J such as nafoícarbomla, benzoyl, etc., substituted or unsubstituted 5- or 6-membered ring heteroancarbonyl, such as pyridinecarbonyl or fbrancsrbomla, substituted or unsubstituted heterocyclocarbon, such a tetrahydropyrancarbonyl, benzen substituted or unsubstituted ossulfonsla.in 20 the substituents are selected from halegenefo, irifluorometóxi.

(Cv-C ^ aicóxi, {(te-Cqtaiquiía or CF ·. ·.

This invention further includes various salts of the compounds of formula (!) Including various enamphomers or diastereomers of compounds of formula (I). As noted above and by way of specific examples in the following parts, all salts that can be formed including pharmaceutically acceptable salts are part of this invention. As also observed, and in the following parts, all conceivable en diastereomeric forms of compounds of formula (h are pads; of this invention.

In one of the branches. iambérn are provided the compounds of form (i) in which: n., p and m are l;

11/92

R; it's methyl. ethyl, isopropyl, a-propyl or methoxymethyl:

R ₂ is hydrogen, fluorine, chlorine, methyl, ethyl or CFy. and

R _{5 is} hydrogen, methoxymethylearbonyl, ferc-butyloxycarbonyl. clclopropilmetiía. oiclnpenhlmethyl, cellohexylmethyl, tetrahydropvanlla, benzyl, 5 furanimethyl. ciciopentane-carbonyl, cyolohexanocarbonyl, trifiuoromethoxybenzoyl, tluorobenzoyl, benzyl-oarbonite, naphthylcarbonate, beazenesulfonyl, fluorobenzene sulfonyl or methoxybenzenesulfonyl,

In another embodiment of this invention there is also provided a compound of formula (· :), where n is 2 and m is 1: or n is 1 and rn is 2; p is 1 or 10 2:

R: it's methyl or atyl,

R ₂ is hydrogen, floor, chlorine, methyl, erila or CF% and

R _{3 is} hydrogen, isopropyl, tert-butyloxycarbonyl, oiciopropiimethyl, cyclopentylmethyl, cycle ·· hexiimmethyl, tefra-hydropyrar-iIa, benziIa, turanílmeti15 ia, tetra • hydropilylmethyl, cyclic-cyclohexyl-cyclohexyl-carbonyl-cyclohexanecarbonate , fluorobenzoyl, benzyl-carbonyl, naphthylcarbon, pyridinecarbonyl, furanocarbunHa or benzene-sulfonyl.

As an additional aspect of this invention, the following fields20 encompassed by the scope of this invention without any limitation can be enumerated:

acid tert-butyl ester> 2 * Ρ-Γπβ1ϋ · 4 - ((2Η, 3 · Β) -2-Γηβ1ro1,3 '| bipyrroiidiaill'-ii) -phenin-1-oxa-2,8-d: aza-esplrQ [4,5] deaanG · 8-earboxylioo;

2- (2-N-methyl-4 - ((2R, 3'R) -2-methyl- [1.3 '| 25 bipyrrciidinii-1'il) -pheni0-1 oxc-2.8-diaza-spiro [i-butyl acid ester] 4 51decane-8-carboKiHco:

2-ρΕΓΠ ^ ίΙ · -4 · - ((2δ, 3ΊΒ) ·· 9 ··? · ηη111- (1,3'Jb ipirm I idinli ·· 1 '-ii) -fenii] tert-butiiic ester -1 oxc-2.8-diaza-spiroF4,5Jdeca no-8 carboxylic:

2 '[2-methyl-4- (Ç? S _; 3'S) -2-meiii · (1,3'J · blpirrolidiml-1 ^, i!) - phenyl] -1-oxo-2 tert-butyl ester _! 8 “díaza - espiro {4 5jdeasnu -8-carboxi'Íico:

2- {2-Methyl-4 (2 · methyl) NOOObipiuolidiml acid tert-butyl ester ·

1 'li) ·· ten i I] -1 -oxo -2,8 diaza -pirate [4,5} deeano-8-carboxylic;

2- {2-ίηοίίΙ · 4 ·· ((2ο ·, 3 ^! 8) -2-ηΊ0ΐί: tert-butyl ester:

(Ί, 3'jbjpírroHdsnil · ί '-B) -fe-nM j-1 -axo-2,9daza-spiro (5.51undecane-9-carbo · xitox ester ferc-butylic acid 2- (4 - (( 23.75) -2- ^ 655 (1.3 ^ 510 (00lidinyl-1 ^! -J) -phenyl] -1 -oxo ~ 2,9-diaza -spire [5. .Jundeaana -ü-carboxy:

4 - {[2-number-4 - ((2S, 335) -2 ~ niethyl- [1,3; 'bi · pyrrolidini-ri!) - feidl] -mei: i-carbamaiQ- 4-propyl-pipendin-1-carboxyco;

2- {4 - (4- (2S-2-renne | -pyrroiidin-1 ~ si) piperidin -1 -il j-phenis} -1 · oxo - 2 ₍ tert-bidyl ester) -1 · oxo - 2 ₍ 8-diaza-spiro (4.5] -S-oarboxylic dean;

2-44- (4 - (28--2-methyl-pyrridyl-1-yl) pipendin-1-yl-2-triHaorornetd-tenil} -1-oxo-2.8-dísza-espíío tert-butyl ester ? 4.5ldeírano-8-cafboxiiioo:

2- {4- (4- (2S-2-methyl-pyrrolidin-1-yl) pipendin-1yl | -2- ^ uor-phenyl} -1-oxo-2,8-diaza “ € spiro [4.5] deoana-8-carboxihco:

acid tert-butyl ester 2 - (4- (3 - ((28,3'3) - 2-methyl-piper id in -1 il) -piiTohdío- 1-i |] -phenü} 1 -oxo- 2,8-díaza-espíro [4,3] decano-8-aafbaxilico:

tefo-butyl acid ester 244- [3 ((2S _s 3 ^! S) “2-metü-piperidin» 1il) pinoiid in -1-yl-2 - trifiuorornethyl-thioyl) -1 -oxo-2,8-diaza -spifo [4,5jdecane-8aarboxylic;

2- {4- (3 - ((2S ₍ 3'S) -2-rnetii-piperidia-1 - ü) pyrrolidyl-1-yl] -2-fluoro-phenyl} -1-oxo-2, tert-butyl ester B-diaza-espirepl. Sjdecano-b-oatbaxilica;

2 '(2rrietil-4 - ((2S, 37S) - 2 - axdsl- [1.3Jbipírrnlidinií-V - íl) - feriil | -2.8 - díaza-espíro [4.5] deuan ~ 1 -ona ;

8-cyclopentylmeül-2 [2-methyl | -4- (2-methyl- (1,3lbipyrrolidinib1'-í) - rénírj2,8-diaza-espiro (4.5] decan-1-one;

2- [2-rneti54 - ((2S, 3'S) -2-melii- [1,3 '] b ipirroiid in i I-1' -sibíerdíl-8 (4-In titíarometòxí-benzoi0-2 _; 8-diaza- -spiro (4.5] deaarj - 1 -year:

8-benzenes $ cfenyl-2- {4 [4- (2S-2-niethyl-pyrralidin-1di) -pipendin-1d] -phenyl} 2,8-diaza-spiro [4 SJdecan-1-one;

8- (4-metôxbberrzenosulfQnil) “2“ [4 “(((2S _> 3 ^, $») - 2-metd- [1,3'lbipirro lidinií-1 -diaza -espiro [4.5 Jdecan-1 -ona _:

2- (4 - ((2S, 31o) - 2-rneíil- [l.33bipirralidini! · 1'-ίΙ) - 2-ίΓΝοθΓοι · ηη1ΐΙ · -ί6ηίΟ · 2,8 -diaza-espiro (4.5} decan -1 -one

2- (2-metd-4 - ((28,3'8) · 2-melll · (1,31bipirrahdfoil · · 1'-il) -eniQ-2,8díaza-e & píro {4.5] deaan- 1 -ona;

Chloride of 2- (2-methyl-4 - {(2R, 3'R) -2-metd- [1,3'lbipkrohdind- 1MÍ) phenií] -2 _s 8-diaza-65pko (4,51decaa-1 - ona;

2-22 meiii-4 - (((2R, 3 ^! 5) -2 ηΐ6ΐίΙ- (1.S'jbipkrohdjnii-Γ-Η) FeuiΠ-2,8-d iaza-espkoK 5] decion 1-one decon;

Cloudraio de 242-0 ^ 1.: 1-4 - ((28,317) -2-methyl · (1,3'Ibipyrroiidiπií-1 -R) fenií -2 -2-diaza-espiro (4,5] denan ~ 1- ona.

8-OiaÍDpent) ímetd-2- (2-rnatiM - ((2R _> 3 ^! S) -2-met)! F1.Olbipyrrolidinií10 1 ^ 1) 400 (11-2,8-0) 323-6 ^^^ 0 (4,5jdecan-1-one;

8-οίαΙορηΓ41 ^ <442 ·· (2 · ΠΊθ1ίΙ-4 ·· (((2 (<3Ί2) -2-ΓΓίηίίΙ41 _! 3 ^> 1Ρ) ρίίΤθίΙ8ίίΐί5- '-Ι) 4οηί!] - 2,8- <ϋκζ3- « δρί? ο [4.5] Ροοοη-1 -ona;

-οΙοΕ> ρο ^ 4ίΙπ ^ 3ΐίΙ-2- [2-π) 6 () ί '· -4 - ((25, 3 ⁱ R) -2-met) l- (1 _! 3'] bipirroi) din) l · ^! -IMenyl | -2,8-diaza-o $ píío (4 .SJdeean -1 -one;

8-610 ^ 601) 1010111-2- (2 ^ 1651-4 - ((25,3 ^! S) -2-mstil- (1,3 '| bipyrrolidin) 11 ^: -ij-pheni)) - 2,8 -d (aza-ospírn [4,5] deoan-1 -one,

2- (2-methyl-4 ((2R, 3'S) -2-metphí (t, 3'jbipkro (idiayl · -T-yl) -phenH} -8- (4in8uoromethoxide (-benzo: l) -2 _: 8 -d) aza-espíro (4.5] deca) ') - 1-one;

2- (2-meul-4 - ((2R, 3'R} · 2-renne-íl Glbipirrohdüfe-I ¹ - - (j} -fersin-8- (42.0?) Fuo) 'Ofnetoxy (-benzail) - 2,8-d: sza · spiro (4.5 Jdeoan-1-one;

- (2- rneiii-4 ((2S, 3'R) -2-methyl- [1 // 'jblpinalidiali-1' -ii) -tenyl] -8- (4 ~ tnf) uoromethoxy-b6nzo) l) “ 2 ₍ 8-diaza-espko [4.5] decan-1-one;

2- (2-melií-4- (2-metií (1 _; 33bipkroh'diní (-1 '·· ί () 4οηίΓρ8- (4 h1fh.) Ornmetõxi-benzoii) -2.8-diaza-espíra [4,5] decan ~ 1-one;

3- (2-01 ^ (11-4 - ((28,378) -2-) 065 (- (1,3Jbipifrul (dinirin-fen (iJ-2,9diaza-espk o (5.5 | undecan-1 -ono _:

3- (4 - ((2.8.3 ^: 8) -2 -maübf 1.3 '| bipir) olid (η (I-1 ^: · ii) · fen 1 ((- 2.9 díazaespko [5.51 u ndecaπ -1 -ena, (2-800) -4 - ((28,37 ^ -2- ^ 65 (- (1.3 '] bipin'oiidinii-1 ^ 046) 55-2,9- diaza-espko (5 .Sjundecan -1 -one;

3- (2-016 (8-4 - ((28,373) -2-01651- (1,3 '] bipín'o5diiii (· 1' -iO-pheniN · -9 (pyridine-4 oarbomi) - 2.9 -diazaaspif o (5.5 | undeoan-1-one,

9- [ίυΓυη ·· 3 ·· οη4) οηϋ) 2- [2ηιοϋΙ “4 - ((28,2 ^! 8) · -2- (π © 1ΙΙ- [1,3 ^: ] bipyrroiidinil- 1 '· ίΙ) -ίυηΗ] ·· 2,9-diaza espiro [5.5] undecan-1-ona:

9-benzoii-2 - [4 - (((2S, 3 ^! S) -2-niefil- [1,3 ^: Ibipiírníldiml - 1'-il) -pheniH-2,9diaza-espko [5 5] undecan-1 -one,

9 '- (4-ίΙύ0Μ ^ ηζοίί'2- [4 · (((23,3 ^, δ) -2 ··? ΗείΙΙ · [ΐ _! 3 ^, ^ ΐρίποΙί6ίηΗ-Γ-ίΙ) · fenii] -2,9- daza-espko [5.5] undecan-1-one;

9-oiclohexanocarbonií -2- [2-fluoro-4 - ((28,3'54) -2 methyl ·] 1,3'jbipsrrolid inii-1 '-ii) -fcnil] -2. 9-diaza-e $ piro {5, 5] undecan -1 ona '.

2-1,2 - fluorine ~ 4 - ((2S _: 3'8) -2-rne ti bí 1,3 '] bipi u olid i π i I - 1' -yl) -phenylj -9 - (tetra10 hydro-pyran-4 carbond) --2,9-diaza ~ loop [5. bjundecan-1 -ona:

9-isopropyl-2- [2-metii-4 - ((28,3 ^, S) -2-rnetd- [1,3 ^! ] Beep! Rrolidinyl -Γ-ΙΙ) fend] -2,9-daza-spiro [5 5 (undacan-1-one:

9-cick> nexdmeílb2- {2 -mat il - 4- ((28, 3'8) - 2-rnatil -ft G ^ hipinOlidinil · · il) -4énii} -2,9-dsaza-espiro [5 bjundecan - l-ona,

9cidopropiinietd-2- [4 ((2S, 3'S) -2rriefii- [1.31bipim> lidinyl-r - yl) ferdíl-2 ₍ 9-diaza-spiro [5.5 | undecan-1-one;

2- [4 - ((2S.3 ^! S) -2-met.il- [1 ₎ 3Jbipiffoiidinii-r-il) 4erHÍ} -9- (teüa-nidropíraη -4 H) -2.9-diaza espkaí5.5lundenan- 1-one;

9-bqrrzíl-2- [2 - (^ 0 ^ - 4 - ((28,385,0-2-0 ^ 1111- (1.3801 ^ 1101101011--1-11) -10 (1 ^ -20 2.9- diaza-espim [5 5lundecan 1 -one _:

2-42-1100 (-4 - ((. 28.3 ^: S) 2 ·· methyl-f 1,3'jbipinolidi n il 1 '-4) -phenylp9-furarl · 2n-ilmntil-2.9-- diaxs-nspiru (5.5] undeean-1-one;

2-44 - (4 - (28-2 -mutil-p ir ro lidin -1 - II) - piperidin-1 -ü] -phenyl} -2 ₍ 3 ~ diazaes pi ro [4, íi [dock n -1 -aaa:

2- {4 - (4 - (2 8-2 -matii-pluOiidín-1 H) -pipsridin -1 -ii] -2-tafluommetilfenii} - 2 _í 8-diaza-espiro [4.5] deaaa-t- -now;

2- {4 - (4- (2 8-2-matil-pinalidin -1 - II) -piperidin -1 - i!] - 2-fiúor-pheníi} -2,8d: 'aza-espi (o [4 , 5] decan -1 -one:

2- {4- [3 - ((2S, 3 ^! S) -2 -metii -pipmidin-1 il) -pyridio-1 - li] feη11} -2,830 d iazaespu o [4,5] decan-1 -one:

2 ·· {4 ·· [3 ·· (((5? 8.3 ^! 8} -2-Γηυ1ί8ρίρθΓί6ίη-1- · ΙΙ) -ρίΓΓοΙίαίΠ-1 · 41 | '· 2- (Γί1ΙηαΓθmetil-fenil} -2,8- diaza-espif o [4, Sidecars-1-one:

2 - (4- (3 - ((28,3 ^) - 2--0 ^ 11-pipeddin-1 - ií) -pirrGiidire1 ~ i!] - 2fiúur - feri: 'i} · -2 , 8 • dteza-espfro ^ .Sjdeean ·· 1 -ona;

8- (4 ~ 0úor-benzoyl) 244- (4- (2S-2-rneüi - piuolidin-1-yl) -pipendin-1-1] teniíV2,8-diaza-ospiro [4. Sidecan-1 -ona ;

8-c? Ciohexanocarbonil-2 [2-fluoro -4 - (4- (28-2-metrl-pyrrdidin-1-yl) ·· piperídin-1 -1] -femQ-2 _: 8-diaza ~ spir'o (4.51decan - 1-one;

8 - (4-fluoro-benzenesulfonyl) -2- {4434 (2S _i 3 ^Í ) -2-motil-pipeédin · -1yl) -pin'alidin-1 yl] -phenyl) -2.8'diaza-espiro ( 4 5decan ~ 1-aua _;

2- (4-4 3 - ((28 _; 3 * S) -2-methyl-pipend in-1 -yl) -p; rrolid in ·· 1 4} -phen1} -8 - (tetra 10 hydro-pyran -4earbonyl) -2 _! 8-diaza-espire44.5] deoan-1-one _:

8 - ci! DapsrriannGarban.ii - 2 - {4- [3 - ((2S, 3 ^> S) -2-rnefii-piperidin'1 - ii) ·· pirroHdin-1-iij-2-tnfjuoromebl -phenyl} -2 _t 8-diaza-e5piro (4.5) decan-1-one:

8-οΐ € ^ ') ρΓορίΙη'' _: οΡΐ-2- {2 ·· ίΚκ · ϊΓ-4 · 44 · - (25 ·· 2 · ηΊ € 3Η · ρΙ: · ΓαΗΡϊη · 1-1ί · ρίροΐ'ΐdin -ldlJ-phenylJ ^^ Bteiaza-espiroH.Sjdfôcan-l-one;

8-ciciopentiimedl-2- {2 “fluoro-4- [4- (2.S-2-methyl-pyrrolidine -1-yl) • pipendin- 1 dj-phenyl} -2,8-daza-spiro (4.5] decan-1-one;

8 ~ € ίοΙα-Η © χΐΐΓηβϋί-2- {4- [3 - ((2δ _! 3Ό) ·· 2 ·· ηΊβ! ΊΙ ~ ρίρρΓ5άΙη- · 14Ι) -ρί? Ίθϋάΐη ·

-íip ^ triíluorcmetii-fenilJ- ^ JJ •• diazaespi? o | 4.5Jdfòcan - ’! - ona:

/ '{z-fluoro · -4 - (3 - ((28,3 ^, S) -2-methyl-piperidin-1-: l) -pírralidÓ! -' l-íi}: eni '} ··

2ü 8- (tef.ra-hidf'o-piran'4-ilmetii) -2,8-day £ a-espiroí4.5} decan-t-ona:

2- [4 - ((2S.3'S) -2-metH- _(1: ^3, w) ^e-1 ípkroiidínü -ii) -2 - tnfiuc-Romet-1-phenyl} 'íeniiao £ 8-2-JTD _: 8-diaza-fóspiro [4.5Jdecafi-bona;

8- (2-methaxy-anethyl) -2- (4 - ((2S _< 3'S) -2-meUl- [1 Qlbipyrrolidirúl-l ^ 4) -2tnfleoromethyl-phenyl-2, S-diaza-eapirolA .SJdeuan-1 -one;

2- (4 - ((28.3'S) -2-methyl- [1, .33bipyrridylsii-r - yl) -2-tr4luuromethyl-phenyl] 8- (naphthaene-2-carbond) -2,8-daza- spiff [4,5jdecan-1-one;

8-benznil-2- (4 - ((2S, 3'S) -2-metll | 1,3 '] blpir? Olk.liriil - 1 ^< -íiy2 - tdfiuorr) meíii-phenyl] -2,8-díaza -spiro (4,5] deGan-1-one _: ·

8 ·· (! Υ {· 0Γ ^ · 3 · αοΓ5 () Πί <} - 2 · Ι4 · (('253 _: 3 ^, 8) ·' 2- · η · ΐ € 1ίί- [1 .Tlbipinulídir ^ (1-T-yl) 30 2 - fluorineethyl-phenyl-2 _: 8-diaza-cspirc (4.5} decan-1-one;

8-furan-Q-iimethyl-2- (4 - ((28478) -2-5 ^ 0 (11 - (-: .S'jhipi-'roiidinyl-l'-yl / Q 'tfif: uor0rnetil-phenílj- 2 ₅ 8-diaz3-spirG {4,5] deean-1-one:

8-cyclopropylmethyl-2- (4 - ((2S _; 3'S) -2-meiil4 ¹ > 3 '] b ίρ i red idinii -1 ^! Ui-zirifiuorumetii-phenin-.SB-diaxa-e & pIrcjfT.bjdecan-l-una :

2- (4 - ((28, 3 ^! 8} -2πιβ1ίΙ · [1 _! 3 ^< ] οΐρΐΓ? · ΟίίάίΠίΙ-1 ^! -ΙΙ) · 2-1πΙΙυ0Γθπ · »οΐϋ · 4οπί |] 8 (tetrahydro-piran ~ 4-iimethyl} -2,8'diaza-spirof4,5jdecan-1-one; and

2- (4 - '((2S _; 3T ^}. 2 - methyl - [1 _! 31bípirroÍidiníl-r-yl) -24rifluoson> 0tll - ferjsH · 2 _; 8-diaza-espiro (4. 5] dacan -1 -one.

All of the above compounds may also include corresponding salts where possible including the pharmaceutically acceptable salts thereof.

In another aspect of this invention the following compounds encompassed by the compound of formula (i) of this invention without any limitation can be enumerated;

8-οΙοΙοροηΙίΙποίίΙ · 2- [2-methyl-4 - ((2R, 3'S) -2-methyl 1 ^ (bipyrrelidinll1 '-l) -phenyl] -2,8-disza ~ espíro [4.5] deGan-1 -one;

8 · ρίοΐορ0ηϋΙ? Ηδίϋ'2- (2-ΓΠθ111 · 4 - ((2Α, 3'Η) -2-ΓηοΙίΙ4Τ3Ί8! Ρΐ ^ οΙΙοίπίΙ1 '-!) - fenü] -2,8-diaza-espiro (4 .Sjdecan -1 -one;

8-ci'dopenliimel.ii-2- [2-metiT4 - ((2S, 3'R) -S-melil-p ^ 'jbipirmhdinii1'-l) -phenH] -2,8-diaza-espiro (4. S] decan-1-one;

8-cidopentilnjel.il-2 - [2-methyl-4 · (((2S, 3'S) -2-methyl-1 _: 3 '| b ipi rra lid ini I1'-ij-phenyl) -2 ₍ 8-diaza -spiroM, 5] decan-1-one;

2- [2-metii-4 - ((2R, 3'S} -2 meUl - {1.3'jbipirrdidiail-l '-yl) -phenyl] -8- í4-fri · tluoromethoxy-benzoü) -2 _> 8-daza- spirof4.51decaH-1-one;

2- [2-me! Íl-44 (2R, 3TT) - 2-metin _! 3 ⁱ -bipyrrolidia; ⁽ 1-1 ^< -yl) - 'teni] -8- (4-trl · fluoromethoxy'-benzai) -2 _> 8-diaza-spiroK Sldecaa - 1-one;

2.-ρ-ΓηηΙίΙ-4 - ({2, $ _; 3 ^! Η) '· 2 · ϊηοΙΙΙ ·· Π, 3'jbipirmlidinii-Γ-il) -fenii] -8 (4 -Influarornetoxi-benzoiíi-VuTdíaza- Sjdecan -1-one species;

2- [2-methyl-4- (2-methyl- (1,3 ^: ] bipir m lidimi-1 ^> -ii) 'ténd | -8- (4-trifluoromatáxi'oenzoil; -2.8dlaza-espiío [4.5'jdecau-1-one;

3- Γ2 -! 'ΗοϋΙ-4 - ((2 $, 3 ^! 3) · 2-ίηοϋΙ4Τ3' ^ ίρίΓ ^ Ιί8ίπίΜ'-ΙΙ) - [οηΙφ2 _> 3- d iaza-espiro [5.5 lundecan -1 -orja;

304 -. ((28,353) -2-methyl [1,3'lbipirmlidinii · 1 ¹ -il) -phenlll-2,9-diazaespi ro (5.5 Jund ecan -1 -us,

342-fluoro-4 - {(2S, 3'S) - 2-met.il- [1, 3'lbi pyrroid ini I-1 '-il; -pheni?] - 2,9day-spiro (5. 5] undecan-1 nude.

9 - isopropyl - 2 - [2 - methyl-4 - ((2S.3 ^! S) 2-methyl - (1,3 '] bipyrToh'd ini I-1 * -H) ferM] -2,9-diaza-eapka [5.5] uadecan-1-one;

9-cyclohexylmethyl-2- [2-methyl-4 - ((2S, 3'S) -2-rnelyl (1 _: 3 ^t ] bipyrrolidinyl1 '-yl) -phenyl] -2 _; 9 - diaza - spiru [e. 5] undecan-1-one;

9-dcl opropi kneti I-2 - (4 - ((25,373) -2 -i rseti H <3 'jbipi rroíid in i I -1 Ml) ten il] -2 _; 9 -d iaza-espko [5.5] undecan-1-one;

2-í 44 (25,3'8) -2-methyl- [1,3'jbipyrroiidinyl-t-li-feriilj-b-ttetrahydric10 piran-4 ~ ii) -2,9-disza-spiriro [5.5 ] undefX3n-1 -ana;

9-benzi-2- (2 -f! Uor-4 - ((2S, 3'S) -2-matil- [1.S'jbipirroiidiml-1 Ml) -pheniij2,9-diaza-espiro [5 5] undecan - 1-one;

- [2- 8úor-4 - ((2S.3 ^! S) -2- metib [13 '] bipyrrolid ind -1 ^! - ii) -fen üj - 9 - furan 2-iÍmeül-2,9-diaza- espíraí5,5] undecan-1-one,

3cyclopropylmethyl! -2- {2-80or-4 (4- (2S2-methyls-pyrrhydin-1-yl) -piperidin -1 -yl) - 'phenyl} 2,8-diaza-ospiío [4. Sldecan-1-one;

8 ~ C: c! Opentiimetn''2 '' {2-'fiúor4- (4 ™ {S? S'-2 ~ metH''pirroHdin “1 * M) ~ piperi dk> -14íj4enil} -2,8- diaxa ~ and $ piro [4.5] deaan-1 ~ ana ·.

- {2 ~ fiúor-4- (3 - ((2S ₎ 3 ^, S) - 2 -υ'ΐηΡί-ρ sporidia -1 · -il) -pirrnlid in-1 - il] 4e π ¢ 1 (20 8 '(tetrahydrG-pyran-4-4metji) -2,8-diaza-eapiro (4.5] decan-i-one:

84υ {· 3η · 2-! Ϊ́π3θϋΙ-2- [4 - (((23 _ί 3'8) -2-π ' _ί αίίΙ · · [1 _! 3 ^< 1 ^ ρί ^ οΐίάίηϊΙ-1 ^, -ϋ) · 2ldfluaromeUI- fen! n-2,8-díaza-spiro [4.5] decan-1-one;

-cyclop: opilrnelü-2 (4 ((2S, 3'S) -2 -matil (1,3 ^! ] biplrroiidinü -1 ^: - d) - 2irifiuGrorneUI “ferHn-2.8“ diaza-espiro [4.5] decan - 1 “Ona ; and

2- (4 - ((2 S, 3'S) - 2-matil (1,3 ^! Ibípirrolid In 11-1 '-il) -zirif luorometii - phenyl] ··

8 - (tetrahydride "piran-4ilmeUi) 2,6-diaza-ei? PirQ [4.5] decan-1 - one;

Again, the conceivable salts of the aforementioned compounds including the salable pharmaeeotioamonle salts are part of this invention,

In another aspect of this invention, the compound of this invention can be represented by a specific stereomeric form of

Where R _b R ₂ , R _s . m, nep are as defined above.

The compounds of this invention can be synthesized by any of the procedures known to a person skilled in the art. Specifically, several of the starting materials used in the preparation of the compounds of the invention are known or are available in the cornerchamber itself. The compounds of this invention and non-precursor stations can also be prepared by methods used to prepare similar compounds as reported in the literature and as further described herein, in this patent application. For example, see R. C. Larock, Comprehensive Organic Transformations VC-H publishers, 1989.

It is also well known that in several organic reactions it may be necessary to protect reactive functional groups, such as, for example, amino groups, to avoid their uncontrolled participation in the reactions. Conventional protection groups can be used in accordance with the routine practice and knowledge of a person skilled in the art, for example, see TW .Greene, and P. G M. Wats in Protective Groups in Organic Chemistry ”John WHey and Sons, Inc., 1991. For example, suitable amine protection groups include, without limitation, sutphonyl (eg, tosyl), deferred (eg, benzyloxycarbonyl or t-butoxycarbonyl) and cnalkal (eg benzHa), o which can be removed subsequently by hydrolysis or hydrogenation as appropriate. Other suitable amine protection groups include iriflucroacefila [-C (- O) CF ^ which can be removed by base catalyzed hydrolysis, or a benzyl group linked to solid phase resin, such as a 2.6-dimethoxy group> enzila bonded to Merrifield resin (Ellman's chain) or a 2.6-ύί? · πΡΐ.όχΙ-4- [2- (ροΙΐ5 (ίηΙίη ^ 1όχΙ) β (οχφοηζίΐ3, which can be removed by hydrolyzed by 'acid, for example, TF A sound.

More specifically, the compounds described here, in this patent application, and various precursors used for that purpose may have been synthesized in accordance with the following procedures of Schemes 1 to 5, where R <. Rs, R _; ?. <rn en are as defined for Formula I unless otherwise indicated.

For example, Scheme 1 illustrates the preparation of the intermediate [1, 3 ^! ] -pyrrolidinyl-pyrrolidine of formula (4), where R is as defined οροί, in this patent application. First, in step 1, Scheme 1, appropriately protected pyrroiidinone of formula (1) (e.g., ferebutyloxycarbonyl (boc)) is condensed with a desired substituted pyrrolidine of formula (2) by any of the reductive smining procedures known to form an intermediate of formula (3). For example, the condensation reactions referred to are generally carried out in the presence of drafting agents such as triaceloxyborohydride in an inert atmosphere, such as a nitrogen atmosphere. The reaction can be carried out either at reaction temperatures and sub-ambient, ambient or super-ambient pressures. Typically, the reactions referred to are performed at ambient temperatures under atmospheric pressure of nitrogen. The reaction mixture is then prepared using procedures known to a person skilled in the art to isolate the intermediate of formula (3).

In step 2. Scheme 1, intermediate (3) is then deprotected to form the desired [1, 1-ptoolideinsl-pyrrolidine of formula (4). The reactions gave mentioned deprotection are generally carried sat acidic conditions, for example in the presence of hydrochloric acid in subenvironment ambient temperatures, for example in cerna temperature range ^{-10; I} C to room temperature. However, other suitable reaction temperatures can also be used depending on the nature of the intermediate of formula (3).

Scheme 2 illustrates the preparation of enantiumerically pure isomers of (1.3] pyrrolidinyl-pyrrolidine of formula (9), where R is as defined here, in this patent application. In step 1, Scheme 2, 5 pyrrolidine alcohol or piperidine oonvenieníernenfe protected (for example, bocj of formula (5) is treated with p-toluene chloride suifomia to form ^- the intermediate of formula (6). This reaction can be carried out using any of the procedures known to ^- a person skilled in the art, such as, for example, carrying out the reaction in the presence of an adequate base such as triethylamine and DMAP in a suitable organic solvent, preferably an aprotic solvent such as dichlorornethane under sub-ambient or ambient temperature conditions.

In step 2, Scheme 2, the intermediate of formula (6) is condensed with a desired pyrrolidine or plpendin of formula (7). Referidasονοί 5, the aforementioned condensation reactions can be carried out using any of the procedures known to a person skilled in the art in order to obtain the intermediate of formula (8). Typically, the said condensation reactions are carried out in the presence of a base such as potassium carbonate in the presence of solvents such as acetorútula in 2.0 conditions from room temperature to super-room.

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 pacific isomer of intermediate of formula (9). It has now been seen that the intermediates of formula (9) can be readily formed according to the process of this invention with high enantiomedical purity, the specific details of which are provided below by means of several examples. In general, the enanphonomical purity can be determined per HPLC quirai.

Layout 2

te i-Su *, TsCl teoi

J ...

te b J w \ ..... -------- ........

/ \ (9) X

6) Scheme 3 illustrates the preparation of the intermediate of formula (13). In step 1, Scheme 3, 4-ethyl ester of plperidine-1,4-diaarboxy acid ester 1-commercially available, of formula (10) is treated with an appropriate basis, such as aBulJ in the presence of HMPA in THE. followed by haietos of aiquenila, to form the intermediate of formula (12). This reaction can be carried out using any of the procedures known to a person skilled in the art, as reported in the literature (Nagumo, S .; Matoba A ,; ef a / .. Tetrahedron, 2002, 58 (49), 9871-9877;

Stafford. J. A; Heathcock, C. H, J. Qrg. Cham., 1990, 35 (20). 5433-5434).

Scheme 2. In step 3 _have the alkene (12) , and with ciivado QsCA and NaIO <and propanol and water to aldehyde former (13)

Layout.3

Vf

Scheme 4 illustrates the preparation of compounds of this invention. The aldehyde of formula (13) is condensed with a commercially available bromide of formula (16) by any of the known reductive amination procedures to form an intermediate of formula (17). For example, the condensation reactions referred to are generally carried out in the presence of reducing agents such as tnacetoxiborohydrate in an inert atmosphere, such as a nitrogen atmosphere. The reaction can be carried out, either at reaction temperatures and sub-ambient, ambient or super-ambient pressures. Typically. the referred reactions are carried out at room temperature under atmospheric pressure of nitrogen. The reaction mixture is then elaborated using procedures known to a person skilled in the art to isolate the formula intermediate (17). Theiolization is then initiated by catalytic amount of base, such as potassium t-butoxide in aprotic solvents, such as THE. to form the formula (13) oompostus. The Intermediate 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),

73/92

Layout 4

/..a í-m ψ *

Scheme 5 further illustrates derivation of the compound of formula (19). Removing the protection group produces the amsna (20). This amine can be alkylated under conditions of reductive or asylum amination with carboxylic or sulfonic acid and its acid chloride or acid anhydride to form amides or sufonamides.

As noted above, the compounds of this invention can be readily poured into salts. More particularly, the compounds of the present invention are basic, and thus the 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 can be a more convenient form of application; and, in practice, the use of the exit form inherently corresponds to the use of the free base form. The acids that can be used to prepare the acid addition salts preferably include those which they produce. when combined with the base hvre. six pharmaceutically acceptable, that is, salts whose only ones are non-toxic to the patient in pharmaceutical dosages of the salts, so that the beneficial irritation effects inherent in the free base are not addicted by side effects attributable to anics. Although pharmaceutically acceptable salts of the said basic compound are preferred, all acid addition salts are useful as sources of the free base form even if it comes out in particular, per se. it is desired only with an intermediate product such as, for example, when salt is formed for purification and identification purposes only, or when used as an intermediate in the preparation of a pharmaceutically acceptable salt by ion exchange procedures.

In another aspect of this embodiment, a specific disease, a disorder or ^one a condition that can be prevented and / or treated with COM20 put this invention include, without limitation, the following: disorders related sane (specific examples include without any narcolepsy limitation, attention deficits, disturbances of circadian rhythm of sleep, abstract sleep apnea, periodic limb movements and restless legs syndrome, excessive drowsiness and numbness due to medication side effects, etc.), neurological disorders (specific examples) which can be enumerated include, but are not limited to, dementia, Alzheimer's disease, multiple echelosis, epilepsy and aeuropathic pain), neuropsychological and cognitive disorders (some of the specific examples include without limitation schizophrenia, deficiency of the disease / hyperactivity 30 disorder, disease Alzheimer's disease, depression, seasonal affective disorder, ed sPARTICULAR PURPOSE cognitive). Some of the disorders also include cognitive impairment associated with schizophrenia (CIA.S), anxiety disorders such as generalized anxiety, panic disorder and post-traumatic stress disorders, and major depressive disorder. Other disorders include Alzheimer's-type dementia (DAT), cognitive deficits related to neurological diseases such as Alzheimer's, Parkinson's, Huntington's, age-related cognitive distension, mild cognitive impairment, vascular dementia, Lewis body dementia and any other deficits factors associated with cognition

As described lower? through specific examples, the compounds of formula (I) bind to H3 receptors and demonstrate inverse agonism versus functional H3 activity. Therefore, the compounds of this invention may be useful in the treatment of diseases or conditions improved with H3 receptor antigens. More specifically, the compounds of the present invention are H3 receptor ligands that modulate H3 receptor function by antagonizing the activity of the receptor. In addition, the compounds of this invention may be inverse agonists that inhibit the basal activity of the receptor or may be antagonists that completely block the action of receptor activating agonists. In addition, the compounds of this invention can also be partial agonists that sparrowly block or partially activate the H3 receptor or can be agonists that activate the receptor. Therefore, the compounds of this invention can differentially act as antagonists, inverse agonists and / / partial agonists depending on the functional potency, the histarnine tone and / or the teddual context. Therefore, the differential activities of these compounds may enable the utility to improve multiple disease states as spherically listed above.

Therefore in one aspect of this invention there is provided a method of treating a disease in a patient, the said disease selected from the group consisting of sleep related disorder, dementia. Alzheimer's disease, multiple scterosis, cognitive impairment, attention deficit hyperactivity disorder and depression, comprising administering to such a patient a therapeutically effective amount of a compound of formula (I).

A person skilled in the art will profoundly recognize that the pathologies and disease states exoressively determined herein, in this patent application, are not intended to be humming but preferably to illustrate the effectiveness of the compounds of the present invention. Therefore, it should be understood that the compounds of this invention can be used to treat any disease caused by the effects of H3 receptors. That is, as noted above, the compounds of the present invention are H3 receptor modulators and can be administered effectively to improve 'any stay of illness which is mediated in the fedo or in pan by H3 receptors,

All of the various embodiments of the compounds of this invention as described herein, in this patent application, can be used in the method of treating various illnesses as described herein. As determined herein, in this patent application, the compounds used in the method of this invention are capable of inhibiting the effects of the H3 receptor in order to alleviate the effects and / or conditions caused due to the H3 activity.

In another embodiment of the method of this invention, the compounds of this invention can be administered by any of the canine methods in the Specific-American technique, the compounds of this invention can be administered orally, intramuscularly, subcutaneously, ratally, intratracheally, intranasally, intraperitoneally, topically.

Finally, in yet another embodiment of this invention, there is also provided a pharmaceutical composition comprising a fannaceulically acceptable carrier and a compound of formula (h, including enantiomers, stereoisomers, 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 here, in this patent application

Conforms? described herein, in this patent application, the pharmaceutical compositions of this invention feature H3 inhibitory activity and are therefore useful in the treatment of any disease, condition or disorder caused due to the effects of H3 in a patient. Again. as described above, all preferred embodiments of the compounds of this invention as described herein, in this patent application, can be used in the preparation of pharmaceutical compositions as described herein, in this patent application.

Preferably, the pharmaceutical compositions of this invention are in unit dosage forms such as tablets, pills, capsules, powders. sterile granules, sterile solutions or suspensions, calibrated aerosol or liquid sprays, germs, ampoules. auioin10 jector or suppository devices; for oral, parenteral, iniranasal administration. sublingual or ratal, or for administration by brotherhood or insufflation. Alternatively, the compositions can be presented in a form suitable for administration once a week or once a month; for example, an insoluble salt of the atsvo compound, such as the decanaate salt, can be adapted to provide a depot preparation for Intramuscular Injection. An erodible polymer containing the active ingredient can be predicted. To prepare solid compositions such as tablets, the main active ingredient is mixed with a pharmaceutical carrier, for example, conventional tablet-making ingredients such as cornstarch, lactose, sucrose. sorbitol, laic, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, for example, water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutical salt acceptable value. When referring to these homogeneous preformulation compositions, it is indicated that the active ingredient is dispersed uniformly throughout the composition so that the composition can be readily subdivided into equally effective dosage unit forms such as tablets, pills and capsules This preformulation composition is then subdivided into 30 dosage unit 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 active ingredient. The tablets or pills of the new composition can be coated or combined differently to provide a dosage form providing the advantage of prolonged action. For example, the tablet or pill can comprise an internal dosage component and an external dosage component, the latter being in the form of an envelope over the precedent. The two components can be separated into an enteric layer which serves to resist disintegration in the stomach and allows the internal component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for similar layers; or euphoric coatings, the aforementioned materials including a series of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetitic alcohol and cellulose acetate.

The liquid forms in which the new compositions of the present invention can be incorporated for administration by oral route or injection include aqueous solutions, conveniently flavored syrups, aqueous or oil suspensions, and aromatic emulsions with edible oils such as cotton oil. sesame oil, cuckoo oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Dispersing or suspending agents suitable for aqueous suspensions include synthetic and natural gums such as imgacants, acacia, alginate, dextran, sodium carboxylmethylcellulose. methylcellulase. polyvinyl-pyrrolidone or gelatin.

The pharmaceutical compositions of this invention can be used in any of the methods known in the art. In general, the pharmaceutical compositions of this invention can be administered orally, intramuscularly, subeutaneously. rectal, iniratmquesl, intranasal, intraperitoneal or topical. Preferred administrations of the pharmaceutical composition of this invention are oral and intranasal routes. Any of the known methods for administering pharmaceutical compositions by an oral route or an intranasal route can be used to administer the composition of this invention.

28/92

In the treatment of various disease states as described here, in this patent application, an appropriate dosage level is about 0.01 to 250 mgfkg per day, preferably about 0.05 to 100 mgZkg per day, and especially about 0.05 at 20 mg / kg per day. The 5 posts can be administered on a 1 to 4 times a day basis.

This invention is further illustrated by the following examples which are provided for purposes of illustration and do not in any way limit the scope of the present invention,

E xemp los (Ge ruis>

As used in the following examples and preparations, the terms used therein must have the meanings indicated · kg refers to kilograms. g refers to grams, mg refers to milligrams, ”pu refers to micrograms. pg refers to picograms. ib refers to pounds, oz refers to ounces, mol ”refers to mole, mmoi refers to mi15 limnols, pmo 'refers to rioromols. 'nmol ”refers to nanomols, L” refers to liters, “ml. or ml “refers to milliliters, μΙ. refers to micrometers, gal refers to gallons, 'C refers to degrees Celsius, ”R ₅ · refers to holding force,“ mp or “rn p. refers to melting point, dec "refers to decomposition .." bp "or bp refers to boiling point, mm Hg if it hurts the pressure in millimeters of mercury," cm refers to centimeters, "nm" refers to nanometers, abs. refers to absolute, conc. refers to concentrate, ”c” refers to the concentration in g / mL, DMSO refers to dirnetyl sulfoxide, DMF refers to Ν, Ν-dimethylformamide, CDI refers to H'-carboniidi-imidazok DCM ”or CH _Ã Clj refers to dichloromethane, ”DCE” refers to 1,2-dichloroethane, HCI ”refers to hydrochloric acid,“ EtOAo ”refers to ethyl acetate, PRE refers to phosphate buffered saline,“ IBMX refers to 3 -isobutyl-1-methixanthin, “PEG refers to pnlretifenu glfeol,“ MeOH refers to methanol, MeNH / refers to methyl amine, N / refers to nitrogen gas, ΊΡγΟΗ ”refers to isopropyl alcohol, EtaO re3Q hurts the ellether, Ί..ΑΚ refers to Ütio aluminum halide, heptane refers to n-heptane, HMBA-AM resin refers to 4-hydroxymethylbenzoic acid amino metry resin, ” ^:? d (2b {dppf)? _: refers to di complex

30/92 chloride of 1 _; 1'-bis (difeniifasfino) ferrocene paiádiu (II) DCM HBTLF hexafluorophosphate refers to 2- (1H-benzotriazol-1yl) -l1,3,3-tetramethyluronium hexafluorophosphate, "DIEA refers to ^{dlasopropitelilamlna,!} 'CsF ^<! refers to cesium fluoride, Mel "refers to iadeto of mefila, ACN, CH3CN or MeCN refers to acetonia trite, 1 FA" refers to trifluoroacetic acid, ^'THF! refers to tetrahydrofuran, NMP "refers to 1-methyl-2-pyrrulidinone, ^<: HaO refers to water," BOC refers to t-butyoxycarhonyl, brine refers to a saturated aqueous solution of sodium chloride, M " refers to molar, rnM refers to molecular, “pM refers to molecular, nM“ refers to nanomplar, 10 “N refers to normal, TLC refers to thin layer chromatography, 01PLC” refers to liquid orography high performance, HRMS refers to high resolution mass and spectrum, LOD refers to loss on drying, “uCí refers to microcuries, ^>! i.p. refers to intraperitoneally, '' iv refers to via intravartuse, snhyd - anhydrous; aq - aqueous; min ~ 15 minutes; h - hour; d - day; leaves. - saturated; s ~ singlet, d - doublet; i ··· tripe; q ~ quartet; rn - ruultipieto; dd ~ doublet of doublets; br - ample; LC ™ liquid crematography; MS ~ mass spectrograph, ESI / MS - ionization for electrospray / mass spectrography; Tr - retention time; M - molecular ion, ~ approximately.

The reactions are usually carried out under a nitrogen atmosphere. The solvents are dried over magnesium sulphate and evaporated in vacuo over a rotary evaporator. TLC analyzes are performed with 60 F254 slides of silica gel i-.M Science with visualization by LJV irradiation, chromatography by cinthylation is performed using alltech pre-comprised gel cartridges. Ή NMR spectra are performed at 300 MHz. On a Gemsni 300 or Vanan Mercury 300 spectrometer with a 5 mm ASW probe, and generally recorded at room temperature in a doctoral solvent, such as D> u} corne, or mono CDUl ₃ which is differently driven. Chemical substitution values () are indicated in parts per million (ppm) with reference to teframethylsilane (TMS) as the internal standard.

High Pressure Liquid Chromatography Experiments

31/92 pectrome of mass (LCMS) to determine the retention times (Tr) and associated mass ions are performed using one of the following methods:

Mass spectra (MS) are recorded using a Micromass mass spectrometer. In general, the method used was positive electrospray ionization, mass scan m / z from 100 to 1000, Liquid chromatography was performed on a Hewlett Packard 1100 Series Binary Pump &Degasser; the auxiliary detectors used were: UV detector Hewlett Packard 1100 Series, wavelength ~ 220 nm and Sedere SEDEX 75 Evaporative Light Scattering (ELS) detector temperature ~ 46%), N ₂ pressure ~ 400 KPa (4 bar).

LOT: Grad (AcNH.U) 5% TEA) :( H.O + OO5% TEA) ~ 5:95 (0 min) at 95: 5 (2.5 min) at 93: 5 (3 min) . Ooluna; YMC Jsphere 33x2 4 pM. 1 mi / rmn

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

Grad (AcNHL05% TEA). (H2CH 0.05% TEA) ~ 5.95 (0 min) at 95: 5 (3.4 min) at 95.5 (4.4 min).

LOTS- YMC Jsphere 33x2 4 pM, (AcN + 0.05% TEA): (Η2Ο · ι · 0 _; 05% TP.A) ~ 5 95 (0 min) at 95: 5 (3.4 min) 95: 5 (4.4 rain)

QU: YMC Jsphere 33x2 1 mi / min, (AcN + 0.08% formic acid) :( H2O'i'0.1% formic acid) - 5:95 (0 min) at 95. 5 (2, 5 min) to 95: 5 (3.0 min)

The following examples describe the procedures used for the preparation of various starting materials used in the preparation of the compounds of this invention.

INTERMEDIARIES lDlermediàno. {:} Z ’.- mettef ^ SIbipiiTOlidintLV-cafboxylic acid tert-butyl ester

.................................................. .........................

Ο

H..C ...... Á -CH, ch ₃

The sister solution of N-8OC-3-pyrrolidinne (4.22 eq, 22.9 mmols) 5 and 2-methylpyrroline (1.95 g, .22.9 mmols) (HCI salt was prepared by adding 22.9 ml., 1 M HCI in ether in the DCM solution of 2-methylpyrroin (and then evaporated) in DOE (69 ml) was added sodium triacetoxyborohydride slowly sprayed under bb at room temperature.

The yellowish milky solution was stirred at room temperature overnight. I..C / MS ~ rn / z 255 and 199 (base and M-tBu).

The reaction was quenched with aqueous NaHCO; · solution (160 ml).

The two layers are separated, and the aqueous layer has been extracted with

DGM (29 mL x 2). The combined DCM extracts were washed with sodium bicarbonate (10 mL), and brine (5 mLx.2), dried (anhydrous sodium carbonate), filtered, and concentrated in vacuo. The crude product was purified on a column of sica-gel, eluted with DCM and 7.591; of MeOH in DCM to obtain 5.50 g (yield · 94%} of the title compound as a liquid .. MS: 255 (Ι9ΗΗΊ: TLC: 6.5 (10% MeOH in DCM). l (Àt9íl139ÓÈAic .. (lÜ

2-Methyl-yl _: 3 ^: terobutyl ester _: 3-pyrrolidmyl-Γ-carboxylic acid (5.50 g <21.62 mmols) was treated with 2.0 ml of 4 M HCl in dioxane at 0 ° C. The solution was stirred under nitrogen at room temperature overnight. TLC (10% MeOH in DCM) did not detect the starting material. N ₂ was passed through the solution with stirring. The outlet was passed through the KOH solution to absorb HCl for 30 min. The sclveuf was removed by evaporation until drying to obtain the title compound as a hygroscopic gummy material, 5..3 g (-10 ()%) East material was used without further purification in subsequent steps as shown below. LCMS; Three ^ 0.35 minutes. MS: 155 (M + H).

Ί-Ι NMR (D _? O. 300 MHz): 4.30 (m), 3.85 (m), 3.76 (s). 3.5 (m),

3.46 (rn) _; 3.32 (m). 2.66 (m). 2.28 (m). 2.10 (m). 1.46 (bs).

ίΠ .. <ο.Φ3Α.ό.ΐ4 ^ λ.ίίί? 1 ester ........ terg-butnioo ........ de ........ acted ... ..... íRh34lpluenp ₂ 4-suifpniloxí) -girruíidina - 1carboxiliao

To a 2 L redundant bottom flask equipped with a mechanical stirring stick and a 256 ml addition funnel was added p-tosyl chloride (58 eq. 305 mmols, 1.5 eq) and 600 ml amdric DCM. The solution was cooled with an ice water bath. EtjN (65 ml) and DMAP (2.65 eq) were added. A solution of (Ri-SfjN-Boc-lihydroxy pinolidine (38 eq, 203 mmols, 1.0 eq) in 200 ml of DCM was added slowly.The reaction mixture was allowed to stir at room temperature overnight. ., TLC showed the completion of the reaction The product had a Río boil of 0.3 (TL.C developed in DCM), The reaction was cooled by an ice water bath Trisarnine on polymer support (32 eu) was added and water for 30 mm Trisarnin bead was filtered and rinsed with 300-400 ml DCM The organic solution was washed with 200 ml HsPO ^ solution (1 M) twice, followed by saturated NaHCOx solution (200 ml)

34/92 ml), and brine (200 ml). The organic phase was dry score ΚΑΚΑ. After concentration, a crude product was purified by a 759 eq sDoa-gel cartridge (OCM 5% MeOH in OCM) to provide the title compound as a beige oil (52 eq, 75%).

MS: 363 (NHNa *); UNCLE (DOM) Rí - 0.3.

^S H NMR (CDCh, 300 MHz), 3 (ppm): 7.80 (d, 9.0Hz, 2H), 7.35 (d, 7.8Hz, 2H). 5.04 (bs. 1H). 3/15 (m, 4H), 2.46 (bs, 3H), 2.05 (m, 2H), 1.43 (s, 9H).

ester ........ tert-butiijco ........ of ........ acid. (8) -3- (toiueno-4su; phenyloxy) -pyrralidine-1caroxy

A round bottom flask was loaded with 80 ml of anhydrous DCM. The solvent was evacuated and purged with nitrogen. To this solvent was added (3S} -1 BOC-3-pyrrclidinoi (obtained from Astatech), (16.32 g, 33.8 mmols), DMAP (0.4 eq). The solution was cooled to a water bath To this cold solution, a solution of p-toluenesulfoniia chloride (9.57 g, 50.87 rums, 1.5 equiv) in 20 ml of DCM was added. The ice water bath was removed and the solution was stirred under nitrogen overnight TLC (5% MeOi I in DCM for starting material, visualization 2; DCM for product, UV) showed the completion of the reaction. The reaction is extinguished by adding amine on polymer support (4.5 g't, stirred 30 min 50 ml. of DCM was added to the filtrate. The filtration block was washed with DEM (organic 3 was washed with H3PO4 (1M, 2 x 50mL), followed by NaHCO ·; (50 ml ... brine (50 ml), dried (K _; XXA). Filtered and concentrated to a liquid. This was purified on a 110 g column of Analogs * silica gel using 0-2% MeOH in DCM to obtain pr udu35 / 92 to pure, 8.82 g (77% yield).

TLQ (DCM) Rf 0.3. I..C: Tf ~ 3.55 min, 100% pure with full ion ring base, MS · 363 (M + Na): 342, 327, 286 (base)

Ή NMR (300 MHz, CDCI ₃ ), δ (ppm) '7.31 (d, 8.7Hz .. 2H), 7.37 (d. 8.7Hz, 2H), 5.04 (bs. 1H), 3, 45 (m, 4H), 2.46 (s, 3H), 1.44 (s, 9H).

Intermediate (v) water tert-butyl ester (28.3 ^): 2: 01011141.JTbipyrrplidinylV-carbnxyl

<) tosiide (52 eq, O.lbmnl 1.0 eq), (2S) -2-methyl pyrroteite (25.2 eq. 0.3 mni, 2.0 eq), anhydrous CH3 CN (500 ml), and dry K ^ CCA powder (59 eq, 36 mmols, 2.4 oq) were added to a 2 liter melting flask equipped with a mechanical stirrer and a reflux condenser. The resulting suspension was stirred at 75 ° C for 20 hours. The heating block was adjusted to 88X.

LC / MS showed a trivial amount of starting material in m / z 363. The reaction mixture was concentrated in vacuo. The residue was partitioned between 200 ml., Water and 400 ml. of DCM. The aqueous layer was washed with 60 ml. of DOM twice The organic extracts were combined and washed with 150 ml. of saturated NaHCOs solution. 150 ml. brine, and dried over K2CO3. The crude was purified by silica gel column, euthanized with 5 to 10% MeOH in Π0Μ. The product still had weak IJV absorption at 254 nm and 280 nm. A ciara-yellow oil was obtained. Yield: 24.5 eq (64%)

ICMS: Tr ~ 1.27 minutes. MS: 255 (M H I).

• H NMR (300 MHz. CDCI4, 3 (ppm): 3.15 (nm, 2H). 3.3 (m, 3H), 2.97 (m. 1H). .2.71 (m, 1H), 2.47 (m , 1H). 1.98 (m, 2H), 1.96-1.67 (m, 4H),

1.46 (s. 9H), 1.06 (d, 6.2Hz, 3H).

36/92 èste £ terc: .but0.igp.de.acido (2Ρ _! 3 ^< 8) -2- ^ β! ΊΙ- [1 _! 316ίρΙποΙί0ΙηΠ · Α ^^ οχΗίοο

The title compound was prepared in a substantially the same way as the intermediate tert-butyl ester of (2R.3'S) -2'5 methyl- [1 J ^ bipiriOiidinii-T-cafboxylic by condensation of 3- butyric acid ester of 3- (3R) - (toluanu-d -sulfonyloxy) -plrohydine-1-carbuxii with R () -2 methylpipenndine (obtained from Advanced Asymmetries). LCMS: Tr ··· 1.05 minutes. MS; 255 (Nh-H).

Ή NMR (300 MHz, CDCb), Ô (pprn). 3.30 (m, 1H). 3.14 (bs, 2H>, 10 2.91 (m, 1H). 2.75 (mn, 1H). 2.51 (m, 1H), 2.07-1.69 (m, 6H). 1.46 (s. 9H).

1.10 (d, 6.0Hz, 3H).

Intermediate (vii) tert-butyl ester of (2S _: 3 ^; R) -2 methyl- | 1, S'lbipyrrolidinyl-V-ciarbgxiHcp

3- (33) - (Toluene-4-sulfonuoxy) acid tert-butyl baler 15 pyrrolidine-1-carbaxllic (6.82 g, 19.97 mmoís. 1 eq) and S - (+) - 2-mefil · · piporindin (obtained from Advanced Asymmetries), (3.40 g, 40 mmols, 2 eq) were dissolved in anhydrous CHj.CN (65 ml). To this colorless solution was added KjCCb powder (powder, .325 mesh, 98 *%. 6.19 eq <44.2 mmols, 2.2 equiv) at room temperature. The suspension was heated with stirring 20 under nitrogen over an oil bath maintained at 80 * C for 24h, TLC (336 Me-OH in DOM for starting material, 7.5% MeOH in DCM for product) showed that the matter! of departure was almost completely consumed. LC / MS showed very little starting material at m / z 363.

The suspension was concentrated to dryness. The residue was made up in water (25mL) and DCM (80 mL). The two layers were separated, and the aqueous layer was extracted with DCM (20 ml..x2). 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) over Anslogix, elutriated with MeOH in DCM (0 to 7.5%) to obtain 4.08 eq (80.3%) of the title compound as a gummy material. LCMS: Tr ~ 1.14 minutes, MS; 255 (M * H).

H NMR (300 MHz, CDCh), δ (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, OH), 1.10 (d, 6.0 Hz, 3.H).

.Íüte.tii'bbdiÁr.i9..íy> teril-butyl ester of (2R.313) -2-methyl- (1,3 ”bip.irroiidirHI-1 ^, -carbcxiiico

The title compound was prepared in a manner substantially the same as that of the intermediate · tert-butyl acid ester (2R, 3'S) -2meiirfl, 3Jbipirn.didini; -1 '' - carcitite by condensation of tert-butyl ester of 3- (3S) - (toiueno - 4-suiphaniloxy) -pyrridine-1-carbuxiic acid and R - (-) - 2mettyptperindine (obtained from Advanced Asymmetries). L.OMS; Tr - 1.09 minutes, MS: 255

Ή NMR (300 MHz, CDCI *), δ (ppm): 3.15 (m, 2H), 3., 3 (m, 3H), 2.97 (rn, 1H), 2.71 (m, 1H ), 2.47 (m, ΓΗ), 1.98 (m. 2H), 1.96-1.67 (m, 4H),

1.46 (s, 9H), 1.06 (d. 6.2Hz, 3H).

38/92

Intermediate (lx) didpndrafo .de (28.31 ^) - 2-1005111,37biplrr <? Lidinila

2HCI

2 (2S) -Methyl- [1,3 ^! (3 ^f R)] bipyrrolidinylcarboxyl (7.91 g, 31.14 microls) was treated with 28.8 ml HC! in dioxane a (FC. The solution was stirred under nitrogen at room temperature overnight, 1 auto TLC (10% MeOH in DCM) as LC / MS did not detect the starting material, the reaction was considered complete,

We were passed through the stirred solution. The outlet was passed through the K.QH solution to absorb HCl for 1 hour. The solvent was removed by evaporation to dryness to obtain the title compound as a very thick gummy hygroscopic (2HCI salt, hydrate exact unknown composition), 8.97 g (--100%), MS: 155 (M-i-H).

1 H NMR. (D ₂ Q, 300 MHz), -S (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 (nm, 1H), 1., 4 (d, 8.0 Hz, 3H).

hitei: m ^^. OP..x).

giiclg.ryjrglo. of (28,3'8) -2-ηιη9Ι- [1,3 ^! ] biMr: ohdinila

Tero-buhhco of acid (2S, 3 ^) - 2.-016111- (1.31bipyrralid lRJ-1'carboxylic acid (24.5 g) was dissolved in 30 ml of dry 1.4-dioxane. HC solution; (85 ml , 4 M in dioxane) was added to 0 ^: 'C-. O left to stir at room temperature' Brown range appeared after about 29 minutes After 4 hours, ts reaction was complete, R _; , was passed through the flask for one hour with stirring. The salt passed through a solution of

39/92

KOH to absorb HCI. The solvent was removed by vacuum to provide 29 g of hygroscopic beige gum.

LCMS: Tr ~ 0.37 minutes, MS: 155 (ΜΗΉ).

’Η NMR: (CbO. 300 MHz), 3 (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 (rn, 2H), 1.6 (m _f 1H), 1.4 (0, 6.0, Hz, .3H) l {<teíínedíárig. (XAl dicluridratu de ί2Η., 3Έ) 2 mgtjl41,3dbipirrqiidirsM vsssssr

U --- ’η: · :::::

| 2HCI ch ₃

The tltuio compound was prepared in a manner, substantially the same as the (2S <3'R) -2-metü (1,3 '] biphroiidirsla dihydrochloride by? 2 (2R) tert-butyl ester hydrolysis ) rnetiM'1,3 '(3'S)] bipyrroidine-1-carboxylic.

MS: 155 (M-rH).

Ή NMR: (DsO. 300 MHz), 6 (ppm): 11.6 (bs. 1H), 9.1 (ba, 1H)

4.12 (m, 1H) 3.5, (rn, 2H), 3.3-3.1 (rn, 3H), 2., 4-2.1 (m, 4H), 2.4 (m, 2H }, 1.6 (m, 1H), 1.4 (d, 6.0 Hz, 3H).

(2R, 3 ^? R) -2-methyl dichlorohydrate 1,3 ^! 1bipyrrglidinyl

The title compound was prepared in a substantially the same way as the (2S, 3 ^: R) -2-methylΠ, 3'lbipyrrulidinyl hydrochloride intermediate by 2 ~ (2R) methyl-f-tert-butyl ester hydrochloride 1,3 ^: (3 ^: R)] bipirrui'idini? -1 '--carboxy'hco.

MS: 155 (M-rH).

* H NMR: (EoO, 300 MHz), 3 (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 (ro, 4H), 2.4 (m, 2H) , 1,6 (m, 1Η}, 1,4 (4, 6,0 Hz, 3H) ester ...... 4 strokes ..... of ...... ester ...... .1-ierc-butylic _____ of ...... acid ^ -aiyl-pipendsna-l .4disarboxylic ° CFL,

CH

In a 250 ml round bottom flask I weighed 6.1 g (60 mmols) of diisopropylamine and dissolved in THF. This solution was cooled to -78'Ό. To this was added 24 ml of 2.5 M (60 ml) of butyl lithium in hexane and stirred for 15 min, heated to 0 ^:> C for 20 min, cooled to 78X. To this was added 4-ethyl ester of 1-tert-butyl ester of piperidine-1A-dicarboxylic acid (12.87 g, 50 mmols) in THF (W ml). Almost 10 there was no color change. This was stirred at · 78 ^: Ε for 45 min. Then, a mixture of δ g of HMPA and 10.92 g of a.Ma iodide was added via cannula. The solution was still clear, very light yellow. This mixture was stirred at · 78 ^φ Ο for 20 mm, then the dry ice bath was removed and stirring was continued to allow the reaction mixture to warm to room temperature for 40 min. The reaction mixture was poured into ice (-50 g), saturated aqueous NH4 Cl (50 ml) and ether (50 ml). The two layers were separated, the aqueous layer was extracted with ether (3x58 ml), The combined organic layers were washed with brine, bags (K2CO3), filtered, and concentrated in vacuo to obtain 15 g (100¾) of the title compound 2.0 like a yellow liquid,

LC Tr - · 3.45 min, MS. 198, 242 (M-iBu)

NMR (300 MHz <CDC13) 5: NMR (300 MHz. CDC13). 5.68 (m,

1H); 5.07 (.bs, 1H). 5.04 (d, 10.2Hz, 1 Η). 4.17 (q, 7.2, 2H). 3.88 (wide d, 9Hz, 2H), 2.9 (wide L 12.9Hz, 2H), 2.27 (d, 7.8Hz, 2H), 2.1 (wide d, 25 13.2Hz), 1.45 (s. 9H ), 1.26 (t, 7.2 Hz, 3H).

èste 4-eiÜico ester? 4- (2-oxo-ethyl) -pipeddin3-1.4dfearbaxilicu 1-tero-butyl acid

T-allyl-piperidine5 1,4-dicarboxylic acid 1-teru-butyl ester 4-ethyl ester (2.97 g, 10 ml) was dissolved in iPrOH (50.0 ml) and H2Q (10.0 ml) . To this was added an aqueous solution of NaiO, <(4.68 eq, 21.8 mm) in water (40.0 ml.), Followed by the addition of OsO, <(8.4 mg, crystals, in one portion ) at room temperature, The solution was stirred at room temperature. After 30 min, milky turbidity formed. The agitation was continued overnight. TI..C and t.C / MS did not detect the breeding material, but it is still very milky. The reaction mixture was poured into ice water (20 mb) and EtOAc (30 ml). The two layers were separated and the aqueous layer was extracted with EiOAc (3x 15 ml). The combined extracts were washed with brine, and concentrated to dryness to obtain a liquid. Liquid gas was subjected to reduced distillation to remove isopropanol. The remaining liquid was purified on a 50 g silica gel column fed with MeOH in DCM (0 to 5%). Note: the product is not UV active. Anisaldehyde visualization was used. The product fractions were collected and concentrated to produce 1.03 g (34% yield) of the title compound as a liquid.

LC / MS: Tr ~ 2.84 min, MS: 300.

NMR (300 MHz, CDCl3) 8; 9.73 (t, 1.8Hz, 1H), 4.22 (q. 7.2Hz, 2H), 3.69 (m. 2H), 3.20 (m, 2H), 2.58 (m, 2H). 2.12 (m, 2H), 1.52 (rn, 2H), 1.49 (S, 9H), 1.27 (t, 7.2 Hz, 3H), .25 intermediate (xv)

Oster 4-etelçg ..... de ..... ester ...... 1.te. (. Ç .-. Bu.li.í.i.çG ..... de ... ..adde ..... 4J2- (4-brrjntg-2 methyl · ί ^ πΗ ^ ΓϊΊί \ ΓΪ017 ^ 1 ^ ϋΛ · Ρ, ΪΡθί ^ ίΠ. <·? ”. 1Λ ^”. ^ .. ί ^ . ·; ^. Θ -? <ΊΙί <2?>

^ -Methyl-A-bromoaniline (0.637 g, 3.427 mmols) was dissolved in

DCE (15 ml): this solution was transferred with a solution of 4- {2 .-- oxQ - efíl) -plperidine · 1,4-dicarboxylic acid 4-ethyl ester of 4 {{2 .-- oxQ - efyll) - 1,4-dicarboxylic acid (1, 03

g. 3.425 mmols) in DCE (35 ml.) The vial was submerged in a water bath at room temperature. To this dara solution was then added acetic acid (0.647 g, 10.8 mmol, 3.1 eq). followed by the addition of 10 NaBH (O.Ac) 3 powder (2.18 g. 10.3 mmois, 3 eq) sub N2 at ambient temperature. The yellowish milky suspension was stirred at room temperature for one day for other. LC / MS showed m / z 469/471 in t - · 4,930 min along with a small amount of a.inhibition of the starting material in 2.103 (186/188}, TLC (53¾ MeOH in DCM) did not show starting material of 15 aideldo, but anllina The reaction was diluted with DCM (20 ml ..), cooled to an ice-water bath, and quenched with 10 ml. Of 1 N NH4OH. The two layers were separated, and the aqueous layer was separated. extracted with DCM (15 ml. x 3), The combined DCM extracts were washed with sodium bicarbonate (10 ml), and brine (10 ml), dried (anhydrous potassium carbonate).

filtered, and concentrated. The product was purified on a 40 g silica gel column eluted with 0 to 2% MeOH in DCM to obtain 0.65 g (41%) of the title compound as an oil.

LC / MS Tr ~ '3.96 min, MS: 469/471 (M + H *)

NMR (300 MHz, CDCl3) 8: 7.21-7.13 (m. 2H), 5.42 (d, 8.4Hz. 25 1H). 4.15 (q, 7.2 Hz, 2H), 3.88 (such as 3H). 3.13 (rn, 2H). 2.93 (m, 2H), 2.16 (bd,

2H), 2.26 (s, 3H), 1.88 (m, 2H), 1.46 (s, 9H). 1.43 (m. 2H), 1.42 (17.2 Hz. 3H).

43/92 intermediate. (Xy.ü 4-ethyl ester 1-tert-butyl acid 4- | 2 - (4-bipmo-phenylamino) -ethyl piper idioa-1.4-diçarbc> xílíçp

This intermediate was synthesized in substantially the same way as described above from 1/75 g of the desired aideide to obtain 1.45 g (54% of production) of the title product as a colorless liquid.

LC / MS, Tr '3.81 min; MS: 455/457

Intermediate (xvii) d-ethylteodeether ester 1-has-butyl acid ... 4-í2- (4-brg? Ng-2-trifiugmmeiifenílamino) -ethiH-piperjdina · t4-dicarboxiiica

r

This intermediate was substantially synthesized in the method as described above from 1.75 g of the desired aideide to obtain 2.03 g (66% of production) of the titanium product as a yellow liquid.

LC / MS: Tr ~ 4.18 min: MS: 523/525.

Intermediate (xviií) ester ...... 4-ellico ..... of ..... ester ...... IdermbutHiço ..... of ..... acid ..... .4 [244-bromo-2-OúoE feoHamin ^

44/92.

This intermediate was synthesized in substantially the same way as described above from 1.75 g of the desired aldehyde to obtain 1.97 g (71% yield) of the title product as an amber liquid.

LG / MS: Tr - · 3.95 min; MS: 473/475.

Intermediate (xix) 2- (4-Bromo ~ 2-methyl4enyl) -1-oxo-2 acid-butyl acid ester. 8-d? Azae $ piro [4 _: 5jdecana-8-carboxy

To a solution of 4-ethyl ester of 4-ethyl ester of 4-methyl (4-bromO “2“ methyl4eniiammo} ~ ethylppiperidine -1,4-dicarboxyic acid (3.42 10 mmols) in THF (40 ml ) a 1 ml solution of potassium t-buloxide (1 M in Ti ll) (1 mmol, 0.3 eq) was added at room temperature (water bath at room temperature). The clear solution became a little cloudy. rle 30 min, TLC (5% MeOH in DCM) showed that the reaction was complete (point to point) LC / .MS detected the 15 423/425 prong pin (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 concentrates on rotavap to produce 0.90 g (53% yield) of title compound 20 as a white solid.

LC Tf - 4, DO min, MS: 42.3 / 425;

NMR (300 MHz. CDCI3) δ: 7., 42 (m, 1H), 7.35 (m, IHk 7.00 (d. 8.4Hz, 1H). 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).

intermediate ίχχ) estert ^ c-bytHico of .......... acid .......... 2- (4-bmmo-phenii) -1-C: Xo-2, .. ......... tetíiazaespifo [4,5idecanu-8-ca? boxniup

This intermediate is synthesized in the same way as described above from 1.4-4 g of the desired amine to obtain 0.955 g (74% of production) of the title product as a beige solid.

LC / MS: 4.13 mm. /409.09 intermediate (x.xi) termbutyl acid ester 2-; 4-taurrio - 2 - trifluprpraetyl-fonyl) -1; UXO-2.8 - diaza1Q eapiru [4.5 | decano-8-carbuxnicu

F

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

t.C / MS: R- - 4.13 min / MS: 477 intermediate (xxii) tert-butyl acid ester Sitebronig-S-flitordegilM-Oxg-Zatojaz ^ spirof4,5] decane-8-carboxyl

This intermediate is synthesized in the same way as described above at 1.98 g of the desired andean to obtain 1.75 g (98% of production) of the title product as a brown solid.

I..Q / MS: Tr = 3.98 min MS: 427

46/92

Intermediate (xxiii) 4-ppt-3-enii-piperidine-4-ethyl-de-piperidine-1.4-dicarbgxlltço acid ester 4-ethylphogester. α

-'OH :,

........................::::: ..................... ....: ............................................. .................................................. ........................ : : : : : :................ : : ,Ç . .................................................. .................................................. ...............................: ........

A mixture of THE (160 ml) and diisopropyl amine (9.92 ml,

70.8 mmols, 1.2 eq) was cooled to -78 ^<: C and a 2.5 M solution of n-BuLI in heptanes (28.3 ml, 70.8 mmols, 1.2 eq) was added slowly. The solution was stirred for 15 min. X heated for 20 min and cooled back to ^-78; C N ^s Bocpiperidina-4-carboxylate Ethyl (. 11 ml 59 mmol 1 eq) in 10 mL of THF was added dropwise and stirred for 40 min before being warmed to room temperature The reaction mixture was stirred for 12 h. transferred to a separatory funnel, extinguished with 500 ml. of water and extracted with ethyl acetate (2 x 300 ml ..). The combined organics were dried over Na2SO4 and concentrated under vacuum to give the title compound as a yellow oil (13.9 g, 76%),

LC / MS: Tr - 4.15 in MS: 3'12

NMR (300 MHz, CDCl3) 5. 5.75 (ddt. 1H), 5.02 (d, 1H), 4.96 (L, 1H). 4.18 (q, 2.H), 3.89-3.86 (nm, 2H), 2.88 (t, 2H), 2.11 (d, 2H), 1.99-1.93 (m. 2M), 1.66-1.57 (m, 2H), 1.45 (s, 9H), 1.43-1.32 (m. 2H), 1.27 (t, 3H) Intermediate (xxiv) 4- (3 oxa-propyl) piperidine-1,4-tert-butyl ester 4-elyl ester

4-but-3-eaipiparidine-1,4 dicarboxylic acid 4-butyl ester 4-stiiicu (13.5 g, 43.45 mmol, 1 eq) was dissolved in i ·· PrOH (217 ml) and a solution of NalO4 (20.23 g, 94.6 mmois, 2.18 eq) in 217 ml of water was added followed by Os04 (37 mg, 0.144 mmoí, 0.003 eq), The reaction mixture was vigorously stirred for 6 h, A The reaction mixture 6 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 Na2SO4 and purified by column chromatography on silica gel (300 g column, 30% EoOAo in heptanes; 50 mL / min). This gave 8.5 g (63%) of the title compound as a beige oil.

LC Tr 3.02 min, MS: 314;

NMR (300 MHz, CDCl3) m 9.75 (s. 1H), 4.17 (q. 2H). 4.16-4.14 (m. 2H), 2.87 (I, 2H), 2.43 (dt <2H), 2.10 (d, 2H). 1.85 (I, 2H). 1.45 (s. 9H), 1.36 (dd, 2H), 1.27 (t. 3H).

Intermediate (xxv) 4-affiliated ester ..... of ..... ester ...... 4-13- (4-0romo-2-methyl - 1-fer-butyric acid)

2-MetiM-bromo-aniline (1.68 g, 9.05 mmols. 1 eq) was dissolved in 1.2 dichloroane (95 ml). A 4-efiyl ester solution of 4--tert-butyl ester of 4- (3-oxo-propyl) -piperidine-1,4-diecarboxylic (2.8 g, 9.05 mmoles, 1 eq) in 95 ml., 1,2-dichloroethane was added to the previous solution followed by anhydride glacial aetic (1.74 g, 28.05 mol, 3.1 eq) and NaBH (OAc) 3 (5.76 g, 27.15 mmols, 3 eq). The reaction mixture was stirred for 48 h, quenched with 200 ml of water, transferred to a separatory funnel and extracted with dkduromethane (2 x 109 ml.). The combined organics were 25 dried over Na2SO4 and purified by column crumstugraphy on silica gel (200 g column. 25'7; LILiOAc in heptanes; 50 ml./min). This gave 3.78 g (86%) of the title compound as a beige gum.

LC Tr - 4.82 min, MS: 383;

NMR (300 MHz, CDGI3) m 7.16 (dd, 1H). 7.15 (s, 1H), 5.40 (d, 1H). 4.16 (q, 2H), 3.8? (d. 2H). 3.41 (s. 1H), 3.09-3.09 (m, 2H), 2.89 (t, 2H), 2.13 (s. 1H), 2.09 (a, 3H), 1 , 66-1.52 (m. 3H), 1.45 (s, 9H), 1.26 (d. 3H), 1,271.17 (m, 2H). 0.88 (1., 3H)

Intermediate ίχχνό fester ..4-4- [3- (4 ~ bmmo-thenylamino) propyl | -pipendina'i fester 1-tert-butyl acid fester _; 4-diçarboxsíico

This intermediary was synthesized in substantially the same way as above,

T0 LC Tr 4.65 min, MS: 469 (MHt);

NMR (300 MHz, CDCl3) 3 7.23 (d, 2H). 6.44 (d. 2H), 4.16 (q,

2H). 3.67 (d. 2.H), 3.01 (s, 1H) <3.04 (t, 2HQ, 2.88 (t, 2H), 2.10 (d, 2H), 1,631.48 (m, 1.45 (s, 9H), 1.26 (d, 3H), 6.88 (i, 3H) integral ^^^

1S fester ..... 4-ethyl ..... of ..... ester ..... t-tero-butylic ..... of 4 '{3-j4-brpmo-2- acid fiúor.fenilamino) - propjl | -piperidine-l., 4-dicart> oxylic cm n

This intermediary was synthesized in substance the same way as above.

LG Tr 4.82 min, MS; 487 (M-i-H);

NMR (300 MHz. CDCl3) δ: 7.16-7.03 (m. 2H), 6.65 (t, 1H), 4.16 (q, 2H), 3.84-3.72 (m. 2H), 3.08 (q, 2H), 2.80 (t. 2H). 2.18 (d, 2H), 1.66-1.82 (m, 3H). 1.45 (s, 9H). 1.40-1.34 (rn, 1H), 1.26 (d, 3H), 0.88 (t. 3H}.

I nterm ed i á rig .. (x χ viii) ester .t§m.-buti.! Icode ....... acid _____ 2 - (4 -Bromo - 2methyl ~ phenyl) 1 ~ oxo-2.9d iassesp? rof5 _; 5lundeçanQ-9narboxilico

4- (3- (4-bromine-2-5 methyl-phenylamino ^ proptippiperidine-1-dinarboxylic acid) l-ferric-butyl ester (3.78 g. 7, -St mmols, 1 eg ) was dissolved in THF (80 ml ..) A 1 M solution of NaGt-Bu ern THF (7.8 ml, 7.8 mmols, 1 eq) was added and the reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was stirred for h, quenched with 250 ml of water, transferred to a separatory funnel and extracted with didoromeiarro (2 x 150 ml ..). The combined organics were dried over N & 2SO4 and purified by actuation chromatography. on silica ·· gel (200 g column, 50% EtOAo in heptanes: 50 mL / min) This gave 2.49 g (73%) of the title compound as a beige gum.

LC Tr »4.03 min. MS: 437 (M-rH);

NMR (300 MHz. CDCl3) δ: 7.40 (s, 1H), 7.35 (dd, 1H). 6.96 (d,

1H), 3.85-3.71 (m, 2H), 3.60-3.54 (nm, 1H). 3.39-3.22 (m, 3H), 2.21-2.04 (m, 3H), 2.12 (s, 3H), 1.97-1.88 (nm, 3H). 1.45 (s. 9H), 1.31-1.24 (nm, 2H). ί9ΐθ. (. 01. ^ 1Ε2.1ί <? ... (>% ΐ-4ί ester ............ lerc-butíliçe ............. of ___. 2d4rBrQpig-phenyl) 1-uxo-2.9-diaza20 asplroF5,5lundecanu-9-çarbuxilíçg

This intermediary was synthesized in subsiancial 0 the same changes as above.

LC Tr 3.97 min, MS: 423 (M * H):

NMR (300 Mliz. CDCl3) 5: 7.49 (d, 2H), 7.09 (d, 2H), 3.83-3.75 (m, 2H). 3.64-3.60 (rn, 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).

InlermediánsJxxxi ester ....... terc-butiilco ........ de ....... áçjdo ......... iLil-Biomo; ^ spirQ [5 _? 5 | undecano-9-carboxyHpo

This intermediary was synthesized in subsiancialmonte the same way as above ...

LC Rt 4.05 min, MS. 441 (M-H);

R, MN (300 MHz, CDCl3) 3: 7.33-7.28 (nm, 2H), 7.09 (t, 1H), 3,803.72 (m, 2Hh 3.50-3.55 (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.l

242-0101114 acid tert-butyl ester - ((2 ^, 3 ^): 2411 ^ 5115370 ^ 1001161011-5ii) -tenH51-oxa-2,8-diaxa-spiro; 4.5] dacano-8-sarboxihuo

H _S G

(2R, 3'8) -2-methyl [1 _; 3 ^: ] bipinoHdinil was dissolved in 2 ml of MeOH with the aid of sonication. To the solution, 50 ml was added. of DCM. The solution was (cooled to an ice-water bath. To this solution, powdered KOH (0.5 g <9.5 mmols, 2.6 eg to the amine salt) was added with seb H2 agitation. Stirring was continued for 1 hour, 0.5 g of K2CO3 powder was added with stirring to form a delicate suspension The suspension was filtered through a pad of Celite, rinsed with DCM until no more leached amine was per TLC (20% MeOH in DCM, visualization by anisaldehyde, white dot just above the origin), The solution was concentrated to dryness: the residue was further dried under high vacuum with stirring for one hour, redissible in light anhydrous and ready to use

A 20 ml bottle. containing a stir bar was loaded with Pd2 (dba) 3 (0.01 equiv., 0.002036 mmol, 2 mg.), 2-dicyclor: exylphosphine-2 ^< , 4 ^> , 6 ^< triisopropyl-biphenyl (0, 05 eq, 0.81018 mmol, 5 mg), and sodium tbutoxide (2.5 eq, 0.509 mmois, 50 mg). The flask was degassed and refilled with three cycles of N2. A solution of 2- (4-bromine-2-methylmethyl) -1-QXo-2,8-diaza-spiro [4,5] decanu-8 ·· carboxilya tert-butyl ester (86 mg, 9.2 mmol; prepared from 0.8.2 g dissolved in 9.5 ml. of foluene (1 ml was used for each reaction) was introduced and the red solution was stirred for 1 min at room temperature, then the arnica in toluene (1.11 eq. 1 ml each, corresponding to 60 mg, 6.22 mmol of bipyrrolidine) was introduced. The flask was evacuated and filled with N2. The reaction was heated in an oil bath adjusted to 9Ü ^r 'C for 2.5 hours, left to cool to room temperature, Toluene was evaporated under reduced pressure, The residue was re-dissolved in DCM (16 mb) and aqueous MaHCO3 (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 (carbonate). anhydrous potassium), filtered, and concentrated. The crude product was purified on a 10 g silica gel column and eluted with DCM and 5% 7 N NH3 MeOH in DCM to obtain the title compound as a semi-solid.

L.C, Tr ~ 2.63 min; MS: 497.

Ή R.MN (CDCh, 360 MHz), § (pprn): 6.96 (rn, 1H), 6.39 (rn, 2H), 4.04 (rn, 2H), 3.59 (f, 6 , 6Hz, 2H), 3.45-3.1? (rn, 5H), 3.02 (rn, 3H), 2.79 (rn, 1H), 2.54 (q, 5.0Hz, 1H), 2.30-1.90 (m, 9H). 1.76 (m. 3H), 1.62-1.39 (m, 12H), 1.14 (d. 6.3Hz, 3H).

52/92

2- | 2-MethiM - ((2R, 3 ^< R) -2-methyl- | 1 .SlbipúroHciinü-1 ^; H) -phen {n-1-oxG-2 _> 8-diaza- tert-butyl ester espiro (4 _t 51deaano-8 - oarb0x | Hcp

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

LC, Tr - 2.66 min; MS: 497 ..

h-1 NMR (CDCte 300 MHz), 6 (ppm): 6.96 (m. 1H), 6.39 (m. 2H). 4.04 (rn. 2H), 3.69 (I, 6.6Hz, 2H), 3.50 (t, 7.2Hz, 1H). 3.3? (dt, 2.2Hz, 9.3Hz, W 1H), 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). Exempted

ELster.i ^ rc-; byt (hoo ... of ... acid. 2-12ÍQ: .Í9.n.ÜlJ.Hb \ Q ^

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

LC. Tr 2.56 min; MS: 497.

Η NMR (CDCb, 300 MHzj, 6 (ppm). 6.96 (m. 1H), 6.39 (m, 2H).

2.0 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> 1.76 (rn, 3H) _; 1.62-1.39 (m,

12H), 1.14 (d, 6.3Hz, 3H).

53/92.

Example 4

2T2m ^ dfoH tert-butyl ether (^ ΐΜθθί (Ε.1 ^^^

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

LC, Tr - 2.61 min; MS: 497.

H NMR (CDCh. 300 MHz), δ (ppm): 6.96 (m, 1H), 6.39 (m, 2H), 4.04 (m, 2H), 3.59 (i, 6.6Hz, 2H), 3.50 (t, 7.2Hz. 1H), 3.37 (dt, 2.2Hz. 9.3Hz. 1H), 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, 3HK 1.62-1.39 (m, 12H). 1.14 (d, 6.3Hz, 3H). ΕχθηΐρΙο.5

2 "[2metH. ~ 4T2-m ^ | 4t _> 3ΊbipiΓroüdinil · T-yl) 4-enyl butyl acid ester

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

LC. Tr - 2.62 min; MS: 497.

-Η NMR (CDCh. 300 MHz). ô (ppm); Two series of spectra were observed.

54/92

Example 6 ^ φίΛΡΐ ^^ ί ^ ϋΙίνΙζ ^ η ^

HN

H. ₅ C '' 2- [2-methyl-4 - ((2SJ'S) -2-methyl (1.3 '] bipifrolidind-1 -ib-tenii] -1-oxo-2 ₍ 8-) tero-biotic ester daza-spiro [4,5] decane · 8-carboxylic (150 mg) was treated with 1 ml. (excess) of 4 M HCI in dioxane a (FC. The stirring was -onfinished at room temperature for 1h. The solvent was evaporated and the solid was further dried under high vacuum at room temperature for two hours to obtain the title compound as a brown solid

LC. Tr ~ 1.41 min; MS: 397.

Exerppto.7 .Qofterato ..... de ..... 242-η ^ ΐίΜ '((2Η, 314) 2 - η ^ 1ΐί-Π, 315; ρΙποη6ίπί6Γ4Η- · ίβπίΙΙ; 2,8 ;;

.Φί47 / 17.9. ^

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

LC, Tr - 1.38 min; MS; 397.

55/92

Example 8

Çíoddratq ..... of .....

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

LC. Tr - 1.4 mm; MS: 397.

Example 9

Hydrochloride ...... of ...... 2d2cmeWídHÍ2S, .3 ^ featespim [4 _Â 5jdecan-1mna

The title compound was prepared in a substantially the same manner as Example 1. LC, Tr ~ 1.35 min: MS: 397.

Example.1.0. ^ E-diazg-espE

A 242-methyl - ((2R.3'S) -2-methylH1.3 ^< ] bipyrrohydine-T-ii) -phenyl] -2 _; 8diaza-spirofo.bldecan-l-one (40 mg, 0.1 mmoi) a solution of ciaiapentann-carboxaideide (CAS 872-53-7, molecular weight 98.14) (30 mg, 0.3 mmol) in 5 ml was added .., followed by powdered sodium tnacetoxiborohydride under N2 at room temperature, The yellowish milky suspension was stirred at room temperature overnight, The reaction was quenched with DCM (5 ml), aqueous NaHCG3 (2 ml .) and NaOH (1 N, 1 ml ..) .. The two layers were separated, and the aqueous layer was extracted with DCM (5 5 ml). The combined DCM extracts were washed with sodium bicarbonate (5 mb) and brine (5 ml), dried (anhydrous potassium carbonate), filtered, and the solution was directly loaded onto a waters column of 1D g of silica gel , elutriated with DCM, followed by 5% 7 N NH3 / MeOH in DOM. The compilation of the fractions was evaporated to obtain a solid, 0 LC, Tr ~ 1.65 min; MS; 479.

H NMR (CDCK 300 MHz), o (ppm): 6.96 (m, 1H), 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, 6.3 Hz, 3H).

Example 11

8-Cídopentümetii - 242-nretíl-4 - ((2R, 3 ^Í R) -2metiÍ- (1 _Í 3 ^< lbipirralidinii-ri) fer ^ n-

2,8-day za -spiro (4, Sldecan-1-one

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

LC, Tr 1.68 min; MS: 479.

1 H NMR (CDCI _S; 300 MHz), 8 (ppm): 8.96 (m, 1H), 6.39 (m, 2H),

2.55 (t, 7.2 Hz, 2H). 3.50 (t <7.2Hz, 1H), 3.45-3.10 (rn, 4H), 3.01 (m, 1H), 2.89 (m. Bs, 1H), 2.78 ( sextet, 6.9Hz, 1H>, 2.50 (q, 8.4Hz, 1H), 2.27 (m, 3H), 2.07-1.91 (rn, 8H), 1.74 (m, 4H) , 1.52-1.41 (m, 12H)., 1.20 (m, 2H) <1.13 (d,

57/92

Example 12

B-Ciolopenhlmetil-S-R-metiM-ttgS.S'Rr ^ -metii-fl.SlbipirrGiidinii-T-O-phenill2.8diaza-eepiro [4,5 | deean-1-one

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

LC, Tr ~ 1.7 min; MS: 479.

Ή NMR (CDCh, 300 MHz). Ò (ppm): 6.96 (m, 1H), 6.39 (m, 2H),

3.55 (t, 7.2 Hz, 2H). 3.45-3.17 (m, 5H), 3.44-3.19 (m. 3H). 2.53 (q, 8.1 Hz, 1H). 2.25 (m, 3H) _: 2.07-1.91 (rn, 8H), 1.74 (m, 4H), 1.62-1.41 (m. 12H), 1.20 (m, 2H), 1 , 14 (d, 6.3 Hz, 3H).

Example 13 8- € ί € ΐορβπίίΙΙ η ^ Ι “242 ^^ ίΙ ·· 4 · - (((23. _< 3 ^ί β) ·· 2 ·. · .Πΐ6ΐιΙ4.1., 3. ^< | 6.ίρίσοΙί6ίπίΙ '1 ^< -!) 4βηίΐ] -

2.8-diaza-espiro (4.51 from Gan10na

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

LC, Tr - 1.67 min; MS: 479.

• H NMR (CDCh, 300 MHz). ô (ppm). 6.96 (m. ΊΗ), 6.39 (m, 2H),

2.55 (t, 7.2Hz, 2H), 3.50 (t. 7.2Hz, 1H), 3.45-3.10 (m, 4H), 3.01 (m _? 1H), 2.89 (rn , bs, 1H), 2.78 (sextet. 6.9Hz, 1H), 2.50 (q, 8.4Hz. 1H), 2.27 (m, 3H), 2.07-1.91 (m, 8H) , 1.74 (m. 4H), 1.6.2-1.41 (m, 12H), 1.20 (m, 2H), 1.13 (d, 6.3Hz, 3H).

58/92

Example 14

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

LC, Tr ~ 1.53 min; MS: 479.

Η NMR (CDCh, 300 MHzi, 8 (ppm): Two series of spectra were observed, It is ambiguous to assign the spectra.

Exernofo..l5:

2 · 12-Μο1ίΕ4 ((2R, 3 ⁱ S) -2-tethyl41.33bipit'roiidiitil-1j-ii) -phenin “8- (4-trinuqrqmet0xi ·· beriZoil) -2,8-diaza-espiro (4.5] decan-1-one

To a solution of acid chloride in DEM was added 2- (2nefe-4- ((25, OO ^ -methyl-p, 3'jb ipirru I idirnl-1 Ml) -phenyl] -2, S-dlaza-espíro ( 4.5] decan ~ 1-one (~ 20 mg, 0.06 mmol) followed by potassium carbonate (40 mg, excess). The Colorless suspension was left to stir under nitrogen overnight at room temperature The reaction was quenched with DCM (5 ml.) And aqueous sodium bicarbonate solution (2 ml). The two layers were separated. The heated layer was extracted with DCM (5 ml). The combined DCM solution was dried over K2CO3, directly washed with a column of 10 g of silica gel, elutriated with DCM and 5% solution of 7 N NH3 MeOH in DCM to obtain the product, as shown in the table.

LC, Tr - 2.52 mm; MS: 585.

59/92 • H NMR (COCb, 300 MHz), Ô (ppm): 7.49 (d, 8.4 Hz, 2H), 7.25 (d, 8.4Hz, 2H), 6.95 (m, 1H ), 6.35 (m, 2H), 3.62 (m, 2H), 3.45-3.21 (m. 5H), 2.99 (m. 1H), 2.80 (m, 1H), 2 , 54 (q, 8.4 Hz., 1H), 2.24 (m, 1H), 2.19-1.91 (m, 8H), 1.87-1.39 (m, 10H), 1, 15 (d, 6.3 Hz., 3H).

ExemsteJS

242-1 ^^ (1-4 - ((2 ^, 3 ^) - 2. ^ 6111- (1 .S ^ blpirTolidinyl-1-iQ-pheni ^ -S - ^ - frifluoromethoxy. ·. · Benzoyl) - 2,8-diaz: a-esp1ro [4, S Idacan-1 -ana

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

LC, Tr - 2.62 min; MS: 585.

1 H NMR (CDCh, 300 MHz), 8 (ppmi; 7.49 (d. 8.4Hz. 2H), 7.25 (d, 8.4Hz, 2.H), 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 , 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, 6.3 Hz, 3H).

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

LC, Tf - 2.62 min; MS; 585.

1 H NMR (CDCl., 300 MHz), 5 (ppm): 7.49 (d, 8.4Hz, 2H), 7.25 (d, 8.4Hz, 2H), 6.95 (m, 1H), 6.39 (m, 2H). 3.62 (nm, 2.H), 3.45-3.21 (m. 5H), 2.99 (m, 1H), 2.80 (m, 1H). 2.54 (q. 8.4 Hz, 1H), 2.24 (m, 1H), 2.19-1.91 (nm, 8H), 1.87-1.39 (m. 10H). 1.15 (d, 6.3 Hz, 3H).

242-Mehi-4- (2-met> l4 1,3! Biph roRd i π M-1 ^s -il) -fen = 118- (4-trifluoromethoxy · benzoyl) -

2.8-diaza-espiroi4,5ideaan-1-una

The title compound was prepared in a substance similar to Example 15,

LC, Tr “2.62 min; MS: 585.

^! H NMR (CDCh, 300 MHz), b (ppm): Two series of spectra were observed, E ambiguous to assign the spectra.

Example 19

242-Metí 1-4 - ((28,3; S) -2-metiM1> 315ίρί ^ οΙιΡΙη? ΕΓ: ίΙΕίοηίΙΙ-8- (4- (ύίΙυοίριροίόχρ benzorí} ~ 2.8-diaza-espiro | 4.5ldeçan-l-ona

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

LC Tr ”2.55 min, MS: 585 (M * H).

• H NMR (300 MHz, CDCb) δ (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, 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).

61/92

Acid 2 tert-butyl ester 2 (2-4 / 114 - / (23.3 ^) - 2-0) 011541 _; 3lbipkroh <jinü ~ 1 ^τ ~

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

LC Tr - 4.88 min, MS; 511 (M t H).

^! H NMR (300 MHz, COCI-4 δ (ppm); 6.92 (d, 1H), 8.39-6.37 (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, 1H). 2.79-2.76 (m, 1H), 2., 52 (q, 1H), 2.17--2.13 (m, 2H), 2.10 (s, 3H), 2.041.51 (m, 13H). 1.45 (s, 9H) , 1.13 (d, 3H).

ExernpÍQ.21

È.ster..te (Ç-buÍÍ.IicP of acid 2- (4 - ((28,3 ^! S) -2-meiii- (1,33bipsrrelidinyl-1 ^f -to-phenii] ··

RR p- <o

X í iVr · p

The title compound was prepared in a substance way that is the same as Example 1.

LC Tr “4.68 min, MS: 497 (M-H).

Ή NMR (300 MHz, CDCl3) ô (ppm); 7.01 (d, 2H), 6.52 (d. 2.H), 3.83-3.75 (m, 2H), 3.58 (f. 2H), 3.50 (t, 1H) <3.38-3.19 (m, 7H), 3.04-2.98 (m, 1H), 2.79-2.75 (m, 1H), 2.53 (q, 1H), 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 )

62/92

Example 22

4 - {(2-l ^:: lúaMq (2S.3'S) 2-met4- [1 .Olbipyrrolidinyl-Ti!} - phenii] -methyl-earbanioil} -4-prepil-piperidine-1- earboxiliao

The title compound was prepared in an aubstantial manner, the same as that of Example 1.

C Tr - 4.9 min, MS: 515 (M + H).

Ή NMR (300 MHz, CDCl3) 3 (ppm). 6.98 (t, 1 H) _: 6.30-6.23 (m, 2H), 3 / 79--3.72 (m, 2H), 3.54 (i, 2H), 3.4 ' 7 ft 1H), 3.36-3.19 (m. 7H), 3.00 (dt, 1H). 2.77 (q, 1H), 2.51 (q, 1H), 2.17-2.09 (m, 4H), 2.93-1.75 (m. 7H), 1.5210 1.46 (m , 2H), 1.45 (s, 9H), 1.12 (d, 3H).

Example 23

Clpndrate of 3- (2-010111--4 - ((23.3 ^) - 2 - ^^ 111 - (1.3 Ibipyrrojidinibl diaza-spirqí S, 5] undecan ~ 1-one

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

LC Tr 1.72 min, MS: 411

Ή NMR (300 MHz., CDCI $) δ (ppm): 7.01 (d. 1H), 6.63-6.60 (m,

2.H). 4.16 (t. 1H), 3.81-3.21 (m, 17H), 3.31 (a. 3H), 2.60-2.45 (m, 1H), 2.38-

2.28 (m. 2H), 2.16-2.01 (m, 5H). 1.86-1.77 (m. 3H), 1.50 (d, 3H).

63/92

344 - ((2S _! 3 ^Í 9) -2-methyl-71,3 ^Í ] bipiuolidinyl-T-yl) -phen || -2.9-diazaespiro (5.51undecan-1On.a

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

LC Tr - 1.59 min, MS: 397 (M * H).

1 H NMR (300 MHz, CDChO 6 (ppm): 7.09 (d, 2H), 6.74 (d, 2H), 4.16 (t, 1H), 3.81 - 3.19 (m, 17H) 2.60-2.47 (m, 1H), 2.38-2.27 (rn, 2H), 2,151.97 (m, 5H), 1.84-1.76 (rn, 3H) <1.50 (d. 3H).

Example25

Hydrochloride ...... of ...... 3424100 ^ 4 - ((23.3 ^) - 2 ^ 051-41.3 '| bipyrmlsdinyl-1-in-phenill-2,9-

^H * ^c '.HCI

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

LC Tr - 1.74 min, MS: 415 (M * H).

Ί-1 NMR (300 MHz, COCI ₃ ) ê- (ppm): 7.13 (,, 1H), 6.53-6.49 (m.

214), 4.21 (t, 1H), 3.76-3.21 (m. 17H), 2.57-2.50 (m, 1H) <2.36-2.26 (m, 2H), 2 , 12-1.97 (m, 5H). 1.84-1.77 (m, 3H) „1.50 (d. 3H).

64/92

Example 28

3- [2-Methyl-4 - ((28..3 ^< 8) -27mei-n, 3 ^> lbipin'olidinR-T-íl) -tenin-9- (pyridine-4Ρ.ΕΦ.9.Ο .. Ι ^^^

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

LC Tr - 2.42 min. MS; 516 (M * H),

H NMR (300 MHz, CDCh) 5 (ppm): 8.67-8.63 (m. 2H). 7.77-7.73 (m, 1H). 7.34 (dd. 1H), 8.93-6.91 (m, 1H), 6.40-6.38 (m, 2H). 4.20-3.88 (m, 4H), 3.60-3.21 (m. 7H), 3.65-3.02 (m. 1H), 2.81 (q. 1H). 2.55 (q, 1H), 2.1310 1.46 (m, 17H), 1.15 (d, 3H).

Example.27

97 (^^ 30: 3-03. ^ 00.0) .- 242 -.-. 0) 6111-4 - ((28.3 ^) - 2 ^ 6111- (13113 ^ 1 ^ 011 (11011-1-11 ) -

: rp

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

LC Tr ~ 2.65 mm. MS '505 (M4-H).

1 H NMR (300 MHz, GDCi ₃ ) 8 (ppm). 7.68 (s. 1H), 7.40 (t, 1H). 6.92 (d, 1H), 6.55 (s, 1H), 6.40-8.38 (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. 10H), 1.82-1.48 (m, 4H), 1.13 (d. 3H).

65/92

Example 28

9-300 ^ 011-2- (4 - ((28, ^ 8) -2- ^ 0111- (1.31610 ^ 0116 ^ 11--1 H) feni.ll - 2.9 - diaz ^ · spirp [5..5Iundeean-1-one

Ν'Χ ^: í <· ......... .......................

;> O

X — J: V ......> ^: 6. The title compound was prepared in a substantive manner in addition to the same as Example 1.

LC Tf 2.67 mio, MS? 501 (M + H).

1 H NMR (300 ΜΉζ, CDCI ₃ ) 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, 11H), 1.59-1.54 (nm, 2H), 1.37-1.23 (nm, 1H), 10 1.17 (d. 3H).

Example 29

9- (4-FI0Qf-benxgiL2- [4 ~ n2S _: .3 ^j S) -2 “mehl41,31bipirrDlidinlt-r-il) -phenili ~ 2.9diaza-espiro [5 _> 5] un6ecan - 1-one

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

LC Tr 2.74 min, MS: 519 (M * H).

• H NMR (300 MHz. COCh) δ (ppm): 7.34 (dt, 2H). 7.00 (t. 2H), 6.94 (d, 2H), 6.45 (d, 2H), 4..01-3.90 (nm, 1H). 3.80-3.61 (m _v 2.H.), 3.52. (t, 2H), 3.43 (t, 1H), 3.33-3.15 (m, 5H), 2.94 (dt, 1H). 2.72 (q, 1H). 2.46 (q, 1H). 2.1020 1.37 (m. 14H). 1.06 (d. 3H).

66/92 .Express 30

The title compound was prepared in a subsiancial way using the example 1,

LC Tr 2.97 min, MS. ' 525 (ΜΉ l).

• H NMR (300 MHz. CDCR) δ (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), 2,502.33 (rn, 1H), 2.15-1.18 (rn, 24H), 1.12 (d , 3H).

Exernplg 3t

242-Húor-4 -Ú2S, 3'S) -2-methyl-f1,31-bipyrrolidinyl-1 MI) -phenyl-9- {tetrahydrg-pirap4-carbonyl) -2,9-diaza-eapi rol 5.51 u ndecan -1 -one

K.

O57777777777Í77777777

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

LC Tr 2.45 min, MS: 527 (M + H), 1 H NMR (300 MHz. CDCl 3) 8 (ppm): 6.93 (t, 1H), 6.24-8.18 (rn,

2H). 3.95-3.75 (m, 6H), 3.48-3.30 (m, 10H), 3.19-3.13 (nm, 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),

67/92

Example 32

9Ί5ΡΡΓαρΗ7242: - ^^ ίΜ- · (((23 _! 3 ^< 8) - 2- ^ οίίΜ13Ί6φ1ίΎθΗ6ίηίμΐ ^ί · -ΙΠ ·· ίοΓΗη ·· 2.9 ·· dto- ^

The title compound was prepared in an incubative manner the same as Example 1.

LC Tf - 1.77 min, MS: 453 (M + H).

1 H NMR (300 MHz, CDCl ₃ ) 3 (ppm): 6.91 (d, 1H), 6.39-6.36 (m, 2H), 3.53-3.48 (m, 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 10 (d. 3H), 1.05 (d, 6H).

9? 6 · Ϊ9ΐθ ~ ΟόΧθΜΗ ~ 2-ί2-Π) θίίΜ - (((23,3Έ) · -2 - ΓΠΘ11Ι-Π.3 ^, ] ΟΙρΐΓΓθΙΙάΙπ1Ι- · 1 ^, ~ ίΙ) - · ί0ηί112 _; 9 ~ diaza.-spirgí5,5hjndeuan-1-una

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

LC Tr = 2.29 min, MS: 507 'H NMR (300 MHz. CDCLO 6 (ppm); 6.91 (d, 1H) _S 6.38-6.36 (m, 2H), 3.54-3, 48 (nm, 2H), 3.39-3.18 (m. 5H), 2.99 (dt 1H), 2.77-2.66 (m, 4H). 2.51 (q, 1H), 2. , 23 (d, 2H), 2.1.3 (d, 2.H). 2.09 (s, 3H), 2.03-1.43 (rn, 17H), 20 1.24-1.10 (m. 4H) , 1.12 (d, 3H), 0.91-0.83 (m. 3H).

68/92

Example 34

9-ΟίοΙορη ~) ρίΙ? Ηη8ί - 2 '{4 - ((26,3 ^? 8) -2 ^ οΙΙΙ-Γ1,310ΙρΗ · ι · αΙίΡ1ίν1 · r-iJ) -feran-2.9-diaza: /// //: /////////// 1: ϊ |: ϊκ |: ϊϊϊ <ίϊ; | Βθϊϊϊϊϊϊϊϊϊίϊ |: |: ϊίϊϊϊϊϊϊϊϊϊϊϊ |: ^

ΪΪΪΪΪΪΪΪΪΪΪΪΪΪΪΪΪΪΪΪΪΪΪΪΚΪΪΪΪΪΪΪ

The title compound was prepared in a substantive manner 5 exactly the same as Example 1.

I..C Tr 3.33 mln _f MS. 451 (M + H).

1 H NMR (300 MHz, CDCb) 3 (pprn); 6.93 (d. 2H), 6.43 (d, 2H).

3.48 (t, 2H), 3.41 (t 1H), 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 10 (m, 14H). 1.04 (d. 3H), 0.84--0.73 (m, 1H), 0.42 (m, 2H). 0.01 (m. 2H).

Example 35

244 - ((28, ^ 3 ^) - 2-106841,314 ^^ 01 ^ 100-1 ^ -11) 460111--9- (161 ^ - ^^^ 01 ^ 0-4-11) -2, 9-diaza-espim [5 <5] undeaan-1-one

11 /:

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

LC Tr 3.24 min, MS: 481 (M-i-H).

1 H NMR (300 MHz, CDCl ₃ ) δ (ppm): 7.01 (d, 2H), 6.51 (d, 2H), 4.00 (dd. 2H). 3.56 (t. 2H). 3.49 (t, 1H). 3.40-3.20 (m <7H). 2.99 (dt, 1H), 2.99-2.83 (m. 2H), 2.76 (q. 1H), 2.53-2.44 (m, 5H). 2.28-1.54 (rn, 16H), 1.12 20 (d „3H),

69/92

Example 36

9-Βοηζϋ-242-ΗύθΓ-4 - (((28.3 ^> 5) -2 ^ 61) Ι41.3Ί6ίρίΓΓθίίά) ΠίΙ · Γ-ΐΙ) -ίθηϋ1-2 _ί 9-άΙοζΗ-

It is composed of the title tbi prepared in a substantially the same manner as Example 1.

LC Tr * = 2/14 min, MS: 505 (M-tel).

Ui NMR (300 MHz, CDCh) 6 (ppm): 7.37-7.24 (m, 5H), 7.00 (t, 1H), 6.31-6.24 (m, 2H), 3.54-3, 46 (m, 4H), 3.36-3.20 (m, 4H), 3x00 (di, 1H), 2.79-2.74 (m, 3H), 2.52 (q. 1H), 2.35 -2.27 (m, 4H), 2.04-1.76 (m. 10H), 1.6010 1.54 (m. 3H), 1.13 (d, 3H),

Bxempip 37

2- (27ΕΙ.ύθΕ4 .- ((23 ₁ 3 ^, 8) -2- ^ βΙίΙ-Π, 3 ^ ίρίΓΓθΙίύίηΐΙ-1. ^, .4Ι). ·· ίοπίΙ1-94υΓ8.η-2-ίΙηιθΰ | ·· 2 , 9-

/ ................. Then ..... f:

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

LC Tr 2 min, MS: 495 (M * H),

Ή NMR (300 MHz, CCCR) 5 (ppm): 7.37 (d, 1H), 6.98 it, 1H). 6.3K23 (m. 3H), 6.18 (d, 1H), 3.56-3.44 (rn, 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, 2.H), 2.19-2.05 (m, 1 Η), 1.99-1.77 (m, 8H), 1.62-1.40 (m, 3H), 1.11 (d, 3H).

7W92

Example 38

2- {4-j4- (2S-2-pyrrolidin-l-in-pipendin-1-ΙΠ ··phenyl} 1-oxO “2.8-diaza-spiroH.5] tert-butyl ester of <^ na -8-carboxy <........ | y |||||||||||||||||| ^ |||||||||||| í ||| _{g |} |||||| g ^ ........

HC-À α, —x H r ^ \ .... m / ⁵ '5- / s jq; · *> \ G ^:

Í'ÇC λ''Η X 4 ÇU-í to \ ....... / \ /

............................................ W ..... ...................

The title compound was prepared in a substantive manner similar to that of Example 1.

LC Tr - 2.61 min, MS: 497 (M + H).

⁵ H NMR (300 MHz, CDCh.) Â (ppm): 7.49 (d. 2H), 6.94 (d, 2H),

4.04 (d. 2H), 3.78-3.67 (m. 4H). 3.04 (L 2.H), 2.92 (dd, 2H), 2.83-2.50 (m,

4H). 2.07 (t, 2H), 1.98-1.6 (m.12H). 1.45 (s, 9H), 1.3 (d, 3H).

Example 39

2- {4 '(4 -' (2S-2-met4'Pyrralidin-1-ii} -piperidin-1-in-.2 trffiuQrometHfenii} .1 “.axp -.- 2,8 -diaza-esprro [4, Sldecana8-carboxiiicp

H, c q / \, ...- laughs ...

n — 4 il / <”'/ < ^: <><' ............ <: <<<'\<< .............. .;.> y <: <: <: <..... <7 <: <ΐΐ <<<< .......

o ^: \ ......

........................ ........ ........ .......... ...... _::::

....... ........ <<<<<<<<<< ^ ........................ ..... <<< ^ ...... <<<<< _: £ Χ <: <: <: ................... <<<<<<<:<< ^ ................... ..............

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

LC Tr ~ 2.75 min, MS: 565 'H NMR (300 MHz. CDCh) δ (ppm): 7.16 (d, 1H), 7.04 (2, Hj, 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),

2- {4-ί4- (2β ~ 2 ^ πβΗΙ-ρίίτοΐίόίπ-1 -ín-pioeridin-l ill-2 ·· fíúor ~ fe π i I} -1 -xo-2,8- d íaza-spirofd, 6Jderiaao ~ 8-c-arbox jiico ^H s ^c ; o 7 VK .2

H.C - V-0 .-— '. Ò / Y

Τοοοοοοοοουοοοοοοο ... YοοογίΤ; ..... YfooffLYfooojYiooo ^ f ^ / LçOol ^ Tfo / íofoooo ^ oooorX. ^ Ioooooo / Ã ^

H _S C? ^ '·' · Ν XJ / MlX

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

LC Tr 271 min, MS; 516 (M * H).

1 H NMR (300 MHz, CDCb) 5 (ppm): 7.17 (t. 1H), 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), 1.9 $) - 1.62 (m, 10H), 1.54 - 1.41 (m, 11 H), 1.09 (d, 3H).

OfômpM.4.1 ester. g ^ IYifgSYSTgmietil ^ piperidin-l-ylFpyrrelidin-lill-phenylD-1-oxo ^ .e ^ diaz-spkoH ^ ldecane-S-carboxyco acid termbutllicp

HC

The title compound was prepared in a substance manner similar to Example 1,

LC Tr - 2.74 min, MS: 497 (M-H), 'H NMR (30Q MHz, CDCl3) § (ppm), 7.37 (d, 2H). 6.47 (d ,. 2H), 3.93 (d, 2H), 3.66 (t, 2H), 3.52 (t, 1H), 3.43-3.30 (m, 2H), 3.19 (dd, 2H) <2.96 (t, 1H), 2.79 (m, 1H). 2.62 (m, 1H), 2.31 (m, 1H), 2.01-1.82 (m, 7H), 1.67 (m, 1H), 1.58 (d., 2H), 1.50-1.30 (m, 13H), 1.10 (d, 3H),

72/92

2- (4- (3 - ((2S, S'Sj-g-mebl-piperidln-l -iO-pyrrole acid ester) dΐn-1iIl · ^ 2trrΠuorαπ} etí: feπil} -1: pxO: 2 _! 8: diaza: spiro (4 _i 5] decano-S-carboxylic

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

LC Tr - 2.97 min, MS: 565 (M + H).

Ή NMR (300 MHz, CDCh) δ (ppm). 7.05 (d, 1H), 6.76 (d, 1H), 6.63 (dd, 1H), 3.98 (d, 2H). 3.66-3.40 (m, 5H), 3.32 (t, ΊΗ), 3.23 (dd, 1H), 3.11 (t 2H), 2.88 (m, 1H), 2, 69 (rn, 1H), 2.38 (m. 1H), 2.10-2.00 (m, 4H) <10 1.98-1.94 (m, 2H), 1.78-1.70 (m „1 Η), 1.60-1.41) (m, 13H), 1.08 9d, 3H).

Example 43

2- (4- (3 - ((25.79) -2-methyl-piperidin-Vil) -pinplidm-1yl] -2-fluoro-phenyl} -1 - <> xo - 2-tert-butyl ester _; 8 - diazaespirp [4,51decana-8-carboxy |

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

LC Tr - 2.66 min, MS: 515 (M + H).

1 H NMR (300 MHz, CDCl _s ) 8 (ppm): 7.14 (t, 1H), 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, 1H), 2.65 (m, 1H), 2.36 (rn, 1K), 2.11-1.93 (m, 7H), 1.78 20 (m, 1H), 1.65-1.43 (m, 15), 1.10 (d, 3H).

Example 44

2.44- (4- (2S-2-methyl ~ pyrrhenium] idin-1-yl) -piperidla-1-in-feriill-2.8-diazospiro (4,5IdeDan-1-one)

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

LC Tr ~ 2.43 min, MS: 39? (Mi-H).

Ή NMR (300 MHz, CDjOD) 3 (ppm): 7.86 (d, 2H), 7.73 (d. 2H), 3.93-3.84 (m 5H). 3.67 (rn. 2H), 3.60-3.56 (rn. 2H), 2.50-2.35 (m, 4H), 2.24 (t. 2H), 2.13-2.09 ( rn, 4H), 1.88-1.80 (m, 4H). 1.53 (d. 3H),

Example 45

2- {4-1'4- (2S ~ 2-methyl-pyrrole idin-1-yl} -piperidin-1-yl] -2-tnfluoromethyl · feri i |} 2,8-d iaza-spifoH ondlondrate, 5 jdacan -1 - ona

..HCl

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

LC Tr 1.89 average. MS: 465 (M * H).

1 H NMR (300 MHz, CD ₃ OD) 5 (ppm): 7.57 (d, 2H), 7.44 (d, 1), 4.01 (d, 2H), 3.83 (m, 1H), 3.73 ft, 2.H), 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).

74/92

Example 46

Cloõdmto ............ 2- {4- [4- (2S-2-mefil-pi _< Tolidin-1-yl) -pipendin-1àll-2-náor-phenylV2. & Diaza-fòspiro (4, Sldecan-1 ~ Gna

^f .HCl

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

LC Tr - 3.19 min, MS: 415 • H NMR (300 MHz, CD ^ OD) § (ppm): 7.34 (t, 1H), 7.03 (dd, 2H),

3.91 (d. 2H). 3.86-3.89 (m, 1H), 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).

θ 47

Hydrochloride ..... of ..... 2j.4i; Hí2S ^

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

LC Tr _? - - 2.56 min, MS: 397 (M + H).

1 H NMR (300 MHz, CD ₃ OD) 8 (ppm): 7.42 (dd, 2H), 6.72 (t, 2H), 3.84 (m, 3H), 3.61-3.49 (m, 6H), 3.24-3.19 (rn, 3H), 2.47 (dd, 1H), 2.20 (t, 3H), 2.18-2.07 (m. 3H), 1.95-1.83 (m, 6H). 1.79-1.68 (m, 3H). 1.47 (t, 3H).

75/92

Example.48

_______________ of ______________ 2 · '- {4- (3 - (((23,3 · $) - 2-ι · ηοΙΙΙ · ί6ίΓί ·· 1 ·· ίΙ) ρίΓΓαΙίάίπ-1-111--2-trifl uonametil-feni 1) hydrochloride -2,3-diaza-espi ra | 4,5] deca η-1 -on a

^F ..HCI

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

LC Tr ~ 2.9 min, MS: 465 (M * H).

Ή NMR (300 MHz, CD ₂ OD) δ (ppm): 7.27 (dd, 1H). 6.94 (d, 2H). 3.75-2.68 (m, 3H). 3.60-3.48 (m, 6H), 3.24-3.20 (m, 3H), 2.51 (dd, 1H), 2.25 (t. 3H), 2.15-2, 07 (m, 3H), 1.92-1.79 (m, 7H), 1.70-1.63 (m, 3H). 1.48 (t, 3H).

Example 49

Hydrochloride ....... of ........ 2- (443 - ((23 _χ 3 ^>) - 2-Γηο0Ι-ρίρ6ηάίΠ-1 · 4Ι) -ρ {ΓΓθ08ΐπ ·· 1ΐΠ-2 ·· ίΙύθΓ-

The title compound was prepared in an understatement manner the same as Example 1.

LC Tr 2.61 min, MS: 415

Ή NMR (300 MHz, CDjOD) 8 (ppm): 7.23-7.19 (m. 1H), 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. 1H), 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 (L3H).

Example 50

8Benzenesossfonil2- {4- [4- (2S-2-methylpyrrolidin-1-yl} -pfperldin ~ 1-in-fenn> 2,8 · diaza-espirpH.Sldecan-l-pna

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

LC Tr ~ 4.99 min. MS: 537 (Μ · * · Η).

1 H NMR (300 MHz, CD? OD) δ (ppm): 7.79 (d, 2H), 7.69-7.60 (m,

3H), 7.38 (d, 2H). 7.01 (d, 2H). 3.85-3.80 (nm, 3H). 3.74 (t. 1H), 3.68-3.64 (m,

3H), 3.25-3.2.0 (m, 3H), 2.79 (t. 2H), 2.66 (t, 2H). 2.28-1.80 (m. UH), 1.65 10 (m. 1H), 1.47 (d., 3H).

Example.51

8 ·· (4-ΕΙύθΓ · 6βηζοίΙ) · -2 ·· {4 ·· | 4 (23 ·· 2 · ^ Β5Ι ·· ρίσοΙΪ £ ϋη ·· 1 ·· ϋ) -ρΐρθπύίη-1.-ΙΙΕ ^ η (ΙΤ ·: 2 _χ 8day- _; spiro (4,5 Ideua m1 ona

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

LC Tr ~ 4.59 min, MS: 519 (M-r-H).

1 H NMR (300 MHz. CLHOD) 8 (ppm): 7.52-7.44 (m <4H). 7.21 (t. 2H), 7.03 (d, 2H), 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 (nm, 6H), 1.45 (d, 3H).

an

77/92 .52

B-Cido-hexan0cait) aniL2- {2-60or-4- [4- (2S-2-methyl-pyrrolidin ~ 1-yl) piperidin-1 <n-phenyl} -2.8 ~ diaza-spiff [4.5] deqan- 1.-Qna

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

LC Tr - 4.96 min. MS; 525 (M-HI).

Ή NMR (300 MHz, CD ₃ OD) δ (ppm). 7.20 (t. 1H). 6.81 (d, 2H), 4.35-4.30 (m, 1H), 4.05-4.00 (m, 1H), 3.94-3.86 (m, 4H), 3, 73 (t, 3H), 3,513.42 (m, 3H). 3.17-3.08 (m, 1H), 2.91-2.83 (m. 3H), 2.88 (m; 1H), 2., 32-2.19 IQ (m, 5H), 2, 11-2.04 (m, 4H), 1.89-160 (m. 13H) 1.44 (d, 3H).

8- (4-ΕΙύθΓ-6βπζ0παρβοΙίοηΐΙ) -2- {443 - ((28 _; 3 ^ί 8) -2-? ΗοΙίΟρίρθίίΟίη-1-ίϊ) -ρίίΓθΙΐηίη1 -ílMenil 1-2,8-diaza-spirof4,5ldeçan- -one

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

LC Tr ~ 5.3 min, MS: 555

Ή NMR (300 MHz. CD ₃ OD) 5 (ppm): 7.88-7.84 (m, 2H), 7,427.33 (m. 4H). 6.67 (d, 2H). 4.30-4.26 (m, 1H). 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 20 (m, 3H), 1.45 (d. 3H).

78/92

Example 54 {4 ··! 3 · ((28 _! 8 ^, 3> · 2 ··? Ηβ | ιΤρίΡβ? 1 <ϋη-1-ίϋ-βίΓΓ0ίίξϋη ~ 1 ~ ί! 1-ΓβηΙ! Ν8-ίΐ61Γ3-ΚΙ8? σ · ρΐΓ3Π4-carbpml) -2 <S-diaza-espimlA, 5] decan-1-one

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

LC Tr ”4.26 min, MS: 509’ H NMR (300 MHz, CD3OD) δ (ppm) :. 7.39 (d, 2H), 6.67 (d, 2H), 4.39 (m, 1H), 4.15 (m, 1H) „3.97 (m, 2H), 3.83 (t , 2Hk 3.66.3.47 (m. 7H), 3.032.98 (rn, 3H), 2.5-2.35 (rn, 2H) 2.21 (t. 2H), 2.10-2.00 (m. 1H), 1.88-1.79 (nm, 10H), 1.65-1.60 (m, 6H), 1.45 (d. 3H).

Example 55 8-ÇicÍppent.anncamQnil-2- {4-f3 - ((22L3 ^, £ 1) - 2-mel.il - piperidin-1-sl) -pyrrolidin-1-in · 2tOAtegron ^^^

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

LC Tr ~ 5.24 min, MS: 561 H NMR (300 MHz, CD2 OD) 3 (ppm): 7.21 (d, 1H). 6.93 (nm, 2H), 4.38-4.28 (m. 1H), 4.10-4.06 (m. 1H), 3.79-3.83 (m, 8H). 3.43-3.40 (m, 3H), 2.50-2.50 (m.2H). 2.25 (m, 2H), 2.07 (rn, 2H), 1.88-1.64 (m, 15H), 1.47 (d,

79/92

Example 56

MhZâdfe

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

LC Tr “1, 92 min, MS: 459 (M r-H).

^S H NMR (300 MHz, CD ₃ O0) 5 (ppm): 7.22 (t, 1H). 6.85 (d. 2H), 3.94-3.82 (m, 3H). 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), 2.32-179 10 (m, 13H), 1.43 (d, 3H), 1.10-1.06 (m, 1H). 0.75 (s, 2H), 0.43 (d, 2.H).

Example 57

8-C ientlpentilmat iI> 2 {2.4l.ÚGr4I4-12S-2-m

Mk ^

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

LC Tr - 3.91 nm, MS: 497 (M + H).

Ti NMR (300 MHz, CD _S OD) 3 (ppm): 7.21 (t, 1H). 6.82 (d, 2H),

3.86 (d, 2H), 3.70 (t, 2H), 3.67-3.64 (m, 1H), 3.34 (s, 2H), 3.23 (m. 1H), 3,183.09 (m, 4H), 2.88-2.78 (m, 2H), 2.57-2.39 (rn, 4H), 2.20-1.45 (m, 20H), 1.4020 1.17 (m. 5H).

80/92 .E.xe _: mpplp.58

8-Cicio- ΚοχίΐΓΠθΟΕ2 {4-ί3 - ((25 _ί 3Ό) -2Πϊθ1Η ~ Ρίρβπάΐη ~ 1 -ib ~ pí noHdín-1 · ill 2tòfíuarometil-femll-2, 8díaza-espirpJ4 _t 5] deaan-1 -una

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

LC Tr ~ 4 <41 min, MS: 661 (M * H).

H NMR (300 MHz. CD3OD) 8 (ppm): 7.11 (d, 1H), 8.81 (m, 2H), 3.85-3.62 (nm, 3H), 3.60-3.46 (m. 2K) . 3.35 (s <2H), 3.26 (m, 1H), 2.92-2.84 (m, 4H) <2.71 (m. 1H), 2.46 (nm, 1H), 2.19-2.08 (nm, 8H), 2.01-1.94 (m, 2H), 1.82-1.45 (nm. 13H), 1.35-1.24 (m, 2H). 1.15 (d. 3H). 0.93 (dd, 2H).

Example 59

O-fE-iHüoM-fS- ^ SS.SO ^ -methyl-piperidin-1-yl-pyrrolidin-HlMémiEBHteVã '' hidrg _; .piran-4-ylmethyl) -2,8-díaza-g-spirQf4,5] decan-1-ana

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

LC Tr ~ 3.61 min. MS; 513 (M + H).

Ί-Ι NMR (300 MHz. CD ₃ OD) 8 (ppm) :. 7.08 (t, 1H), 8.40-6.32 (nm, 2H), 3.95-3.00 (m, 2H). 3.68-3.58 (m, 3H), 3.51-3.34 (m, 4H), 3.33 (s. 2H), 3.25 (m, 1H), 2.89 (d, 4H). 2.69 (m _; 1H), 2.45 (m. 1H), 2.22-1.90 (nm, 11H), 1.89-1.40 (m, 8H), 1.38-1.20 (m, 2H), 1.15 (d, 3H).

81/92

Example 60

2- (4 - ((28.3 ^) 72 - ^) 051- (1.318101 ^ 1181011-1-11) -240900 ^ 0091-1001118-1401 ^ 00111.2,8-6 (^

Τ '' f \ F F

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

LC Tr ~ 3.01 min, MS: 869 (M4H).

^! H NMR (300 MHz, CDCl ₃ ) 0 (ppm): 7.98-7.91 (m, 4H), 7.60-7.50 (nm, 3H), 7.17 (d, 1H) <6.82 -6.80 (m, 2H), 4.48 (m, 1H), 3.81 (m, 1Hi, 3.67 (m,

2.H), 3.68 (t, 18), 3.46-3.34 (m. 4H), 3.2.7-3.21 (m. 2H), 3.04-2.97 (m, 1H).

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).

8- (2-Methoxy-acetii) -2- (4 - ((2S, 3 ^ S) -2-methyl- [131bipyrrolidini.l-11ül2-trifluorpmetii-í ^: enin-2 _Í 8-diaza-spirgí4,51deGaa -1-one

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

LC Tr 4.31 min, MS. 523 (M + H).

’H NMR (300 MHz, CDCh) ô (ppm): 7.21 (d, 1H), 6.90 (d. 2H),

4.30 (m. 1H), 4.2.1 (d, 2H), 4.05-3.97 (m. 1H), 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). 2.532.45 (m. 1H). 2.27-2.24 (m, 5H), 2.10-2.04 (m, 2H), 1.95-1.85 (m. 6H), 1.42 (d, 3H).

82/92

Example 62

25 ^ ad> onii) 2 _> 8díaza- ^ spiroí4 _< $ ldecan-1-one

The title compound was prepared in a substantive manner approximately the same as Example 1,

LC Tr 3.21 min, MS: 605 (M * H).

'H NMR (300 MHz, CDCfe) δ (ppn >> ·. 7.98-7.91 (m, 4H), 7.60-7.50 (m, 3H), 7.17 (d, 1H) , 6.82-6.80 (m. 2H). 4.48 (m, 1H), 3.81 (m, 1Hj, 3.67 (m, 2H), 3.58 (t, 1H), 3.46 -3.34 (m, 4H}, 3.27-3.21 (m, 2H), 3.04-2.97 (m, 1H), 10 2.92-2.82 (q, 2H), 2., 65 (q, 1H), 2.25 (rn, 2H), 2.10-1.95 (m, 3H), 1.83-1.78 (m, 3H), 1.68-1.40 (m , 3H), 1.18 (d, 3H),

Example; S3

6 :: ^ 11490 :: 14 :: ((2 ^ 2 ^): 2: ^ 08141 Jlbipyrrolidinil-T-in-B-tniluprornetil-phenill2,8 - díaza-espirg | 4,5ldec-an-1-ppa

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

LC Tr 2.93 min, MS: 555 (IvR H).

1 H NMR (300 MHz, CD ₃ OD) 8 (ppm); 7.49-7.44 (m, 5H), 7.21 (d,

2), 6.93 (m, 2H), 4.42 (m. 1H), 4.16-4.11 (rn, 1H), 3.83-3.54 (m. 6H), 3.3820 3.34 (m. 2H). 3.24-3.20 (m, 2H), 2.80-2.53 (m, 2H). 2.36-2.22 (m, 5H), 2.152.10 (rn, 3H), 1.97-1.78 (m, 4H), 1.47 (d, 3H).

2/83

Example 64

8 - (^ 0 ^ 0-3-0 ^ 00011) -2- (4 - ((28 ^ 8) -2-016111- (1 _> 3'l0ipiirolidioil-rH) -24rifluofo.01681460111-2,8-0 . ^ 6.-.- 650 ^ 014, .5106060 -.- .. 1.-0.0¾

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

LC Tr ~ 2.75 min. MS; 545 (M + H).

1 H NMR (300 MHz, CDCb) 3 (ppm): 7.88 (s. 1H), 7.60 (s. 1H}, 7.21 (d, 1H). 0.87 (s, 2H). 6.64 (s. 1.38-4.06 (m, 2H). 3.82-3.66 (m, 4H), 3.58-3.52 (m. 1H), 3.43-3.33 ( m. 5H), 3.01-2.92 (q, 1H), 2.39-2.28 (m. 1H), 2.26-2.05 (m. 5H), 1.99-1.80 (m. 4H), 1.74 -1.60 (m. 3H), 1.35 (d, 3H).

Example 65

8- (4- ^ 610) (1-0602600550110010-244 - ((28. ^ 8) -2 + 0611141,310101001101011-141) -2-tn8uorometiLfenill-2.8-díaza-espko [4,5 '| decao-l -paa

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

LC-Tr ~ 3.19 min, MS; 621 (M-rH) ..

1 H NMR (300 MHz, COjOD) δ (ppm): 7, .74 (d, 2H), 7.18-7.04 (m. 3H). 6.89 (m, 2H), 4.02 (m, 1H), 3.86 (s, 3H). 3.78-3.72 (m, 1H), 3.63-3.55 (m _s 8H), 3.23 (m, 2H), 2.75-2.68 (m, 2H), 2.54- 2.48 (m, 1H), 2.35-2.29 (m. 2H), 2.16-1.95 (nm, 6H), 1.80-1.65 (m, 3H), 1.45 ( d, 3H).

84/92 .Example .66

8 ~ ΕυΓ8η-2-ΙΐΓηό.ΐΗ ·· 244 ·· (((26 _ί 3 * 8} ·· 2 ·· ΠΊβϋΙ ·· ί1.3 ^< ^ ίρίπΌΗάίπίΜ ^< -ίΙ) -24ΓίίΙυοΓθΓηθ ^ ί fenin-2,8 ~ d iaza-e $ píroí4 _; 51decan- 1 -ona

The title compound was prepared in a substantive manner similar to Example 1.

LC Tr ”2.22 min, MS: 531 (M + H).

Ή NMR (300 MHz, CDCI ₃ ) 8 (ppm): 7.56 (s, 1H), 7.23 (d, 1H), 6.93 (d, 2H), 6.50 (s, 1H), 6.44 (s, 1H), 4.09-4.07 (m, 1H), 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. 3'H)

8-CidopropílmetíE2-l4 - (((2S, 3 ^> Sb2-methyl-1,3,3 ^r lbipírrolidíníl-r-íri-2 “tnfloofomfôbí * fe.njn-2 _A 8: diazaespíro | 4,5ldecan-1-one

The title oompoate was prepared in a substartoi / 15 manner similar to Example 1.

LC Tr 3.72 min, MS: 505 (M + H).

1 H NMR (300 MHz, CD _S OD) 5 (ppm): 7.29 (d, 1H), 6.94 (d, 2H),

4.15-4.10 (m, 1H), 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). 2.13 (t. 1H), 2.68-2.00 (m, 3H), 1.83-1.76 (nm, 20 1H), 1.47 (d, 3H). 1.2-1.15 (m, 1H), 0.79 (d, 2H), 0.49 (d, 2H).

85/92

Example 68

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

LC Tr 3.68 min, MS: 549 (M * H).

H NMR (300 MHz, CD ₃ OD) 3 (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), 3,253.22 (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).

ExemfiloSà ciondra.to..d.ê..2> {4r {(2S _! 3 ^, S} ~ 2-metiEn, 3 ^> lbipinOlidinil “1 ^> -4l) -2-tnfluorometiEfenin ~

Hi

HCI

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

LC Tr ™ 3.4 min, MS: 451 (ΜΉΙ),

Ή NMR (300 MHz, CD3OD) 5 (ppm). 7.6 (d. 1H). 6.95 (m, 2H). 4.24-4.21 (m. 1H). 3.86-3.80 (m. 1H), 3.75-3.67 (m, 3H). 3.56-3.48 (m, 3H). 3.40-3.34 (m. 2H). 3.26-3.21 (m. 2.H), 2.63-2.57 (m, 1H). .2.42-2.23 (nm, 5H).

2.15-2.08 (m, 4H), 1.91-1.81 (m, 4H), 1.52 (d, 3H).

Biological Examples

EqCAMmFfeT

This Example 70 demonstrates the effectiveness of the compounds of this invention in ligating H3 receptors. It has been shown that compounds

86.:92 of this invention displace ^ Hj-methylhistamine radioligand binding to mammalian cell membranes expressing R3 H3 receptor (Macacca mu / afia). These compounds have affinity constants (Kl) for H3 in the range from 1 μΜ to <1 nM. Additionally. it has been demonstrated by proof of GTPyS radioactive binding that the compounds of this invention inhibit the functional constitutive activity of H3 resus in cell membranes. This inhibition of HTP-mediated HTP radioligand binding demonstrates that the compounds of this invention find utility as inverse agonists, These compounds decreased the H3-mediated radioactive bonding of R3 by 0 to 40% below baseline levels.

Rhesus H3 membranes were prepared from the Flp-ln T-REx 293 cell line (infrared) stably transfected with pcDNA5 / FRT / TO (infitrogen) containing the 443 rhesus monkey amino acid H3 receptor (Macacca mu / ada). (Genbank rT AY231154). Transfected cultures were stably amplified in tissue culture flasks by routine tissue culture methods and induced to express R3 H3 by exposure to 500 ng / ml tetracycline (Cellgro) for 24 floras. After induction, the cells were dissociated from the phrases using Ceil Stripper (Cellgro). The cells were centrifuged (1K xg, 5 min) and frozen in 20 pellets in an ethanol dry ice bath to break cell membranes. The pellet of frozen cells was resuspended in 5 mM HEPES (pH 7.4, invitrogen) at 10 ml / 1000 cm '^; of cells harvested, The cell suspension was extracted through an 18 gauge needle (2 to 3 times) followed by a 23 gauge needle (2 to 3 times) to further disrupt the white cell mem2.5. The cell suspension was centrifuged (40K xg, 30 min). The cell membrane pellet was resuspended in 5 mM HEPES (pH 7.4, Invstrogen) at a final protein concentration of 10 mg / ml. Rhesus H3 membranes were stored under liquid nitrogen prior to use in radioligand binding tests GTPyS and [3H] -Meti-histamine, 30 The radioligand binding test of rhesus was performed using rhesus H3 receptor membranes (prepared as described above), [3H] -Methylhistamine (Perkin Elmer) and VVGA SPA beads (proof of

8'7 / 07 proximity to scintillation of frige germ agglutinin) (Amersham), The test was carried out in 96-well OpK-Plates (Packard). Each reaction contained 50 pi of H3 membranes from rhesus (20 to 30 pg of total protein), SO μΙ of WGA SPA beads (0.1 pg) and 50 pi of 83Ci / mmols of [Yft-Methyl-histamine (final concentration of 2 nM) and 50 μί of tested compound. The compounds of this invention and / or vehicle were diluted with 10 mM DMSO stock binding buffer. The test slides were sealed with TopSeaí (Perkin Elmer) and mixed with a shaker (25 ° C, one hour). The test slides were read in a TopCount scintillation counter (Packard). The results were analyzed by Hill transformation and the Ki values were determined by the Cheng-Prusoff equation. The binding data observed for some representative compounds of this invention are summarized in Table 1.

TABLE 1

FP. of the Ex-i ki of the H3 bond of i Inverse Agonism:% inhibition iple | Reso (nM) i Basal GTPvS binding in Reso H3 i

....................... < i 1 -24 i 248 30 | 3 .............................. .................... ....................... ♦> “3

| 43 j - 31 j í 5 (18 i -13 í

Ι1 | 999999999 ||||| 99999 | 9 ||: ||| 9 || ^

I ||||||||||||| í ||||||||||; |||||||||| ^

F ™ —----------------.................

||||||||||| g ||||| g ||||||||: |: |||||||||||| ^ [9I 0.6 | -35 i

........ ςςτςςΙ ίί1 ·· 1ΙΙΙ11 ·

I 1: 2: _{;;:; ί;} ····· _;;: ~ 20 ... ,,. J l ||| ll | lf ||||| l | l | f ||||||| (lBIIIII | i ^ ............ | g || çil |

Σ ........................... ”—— .......... g

Jf ___________________________ j _..... _____________________i ___________...................... YJ ..... J

88/92

i NT do Ex- I ki of the er link π H3 of [Reverse agonism:% inhibition i emplo i Rose (nM) 1 GTPyS Basal connection in 1 H3 of Rhesus | 16 | 108 1-13 I 17 I 1.4 ί _g | 18 I 6.2 „... j, O _:: __________ ______________________ ______J

ϊ 19 i 1.4 I -19

I 20) 6.8I -13 ί 21 I 7 3 I -28

122 I 0.03J-27

I 23 I 0.07 1-19

31 1 I ........................................? ........ ......... 0.4 _______I -19 _______________________ — ____________ | ii ||||||||| l | 0.4 1 -14 1 33 I 0.2 | -14 [34. : | 0.2 j -w. .........................- Í ββιβ 0.04 ί -18 0.06 _________ 1 37 1 0.1 $ t .............

[38 .............................. [0.008 [-25

x> £? 0.9 I -22 40 / 777777 ^ 2277 / ::::::::::: 0.3 Í ^ '71 41 / ^ << / ^ / ^ / <> t </ ^ / ^ / ^ / ^ < c <* < 0.0 11111111 42 64 I -15 43 4.3 I -19

89/92

Example NT ki of the H3 connection of Rhesus (nM) Inverse agonism; % of Basal GTPyS binding inhibition in H3 of Rhesus 44 45 ......... 9.15 46 ΙΙΙΙΙΙΙΙΙΙΙΙΙΐ · ΐΙΙ ^ 47 ................................. ΡΛ ................ ................ -17 4B77 49 -22 56 lllllllllliilllilillll fliililililillill .............. 0.08 -17 52 0.2 • 24 lililllillllli 54 3.3 -24 55 2.1 Iftlllllllllli 57 0.1 • 21 58 0.15 w 11111 ^^ -19 60 144 lllllllllllllilill it. ' 193 62 8.1 19 i | l | li |||| i | liiiiiiilllliillllli 9.6 -19 iBÉ ..... 10.6 66 5.5 -19 i 67 68 4.2 -19 .69 0.99 .................................................. .......................................

Example 71

This Example illustrates the study of the effectiveness of the compounds in this

90/92 invention in increasing wakefulness in animal models.

Male Sprague Dawley rafts (Charles River. France) weighing 250; i: 10 g were anesthetized with ZOLETIL? 50 (60 rng / kg ip) and mounted on a stereotactic device. Cortical electrodes (small electrodes of 5 stainless steel thread 0.9 mm in diameter) were apparatized inside the bone over the sensorimotor cortex (1.5 mm lateral to the median suture and 1.5 mm behind the frontoparietal suture), the visual cortex (1.5 mm lateral to the median saturation and 1.5 mm in front of the parietooccipital suture) and on the cerebellum (reference electrode) Cortial electrodes were attached to a connector 10 (Winchester, 7-lead) and fixed with dental cement to the skull.

After three weeks of postoperative recovery, the animals were placed inside plexiglass cylinders (60 cm in diameter) with free access to food and water. The room temperature was kept constant (21 ± 1 ^t: C) and the lights were turned on from 7 am to 7 pm at 3 pm. Rats recorded bore 10 am to 4 pm during three consecutive days: control day (D1) _are drug day (D2) and pósfármacc- day (D3). Vehicle (D1 and D3) or drug (D2) were administered 15 min before registration.

Activity in the sensorimotor and visual cortices was recorded by comparison with the columnar reference electrode over a cerebellar cortex.

Three stages were distinguished:

- wakefulness (W) characterized by rapid low voltage electrocortical activity (ECoG);

- NREM sleep (slow eye movement or slow 25 wave sound: SWS) characterized by an increase in eietrocortical activity; development of slow waves of high amplitude with some explosions of sound spindles;

- REM sana (rapid eye movement or paradoxical sana · PS) characterized by hypersynaranization of the theta rhythm in the visual area.

A. Analysis of the IcCoG signal was performed automatically by means of a computerized system discriminating between the various phases of sleep using sequential spectral analysis of ten-second periods

91/92 (Deltamed Coherence software).

The compounds of this invention were dissolved in 0.6% MTC tween and administered orally (po). The injection volume was 9.5 ml / WO g of body weight.

Two types of analysis were used to quantify the effects of the compounds of this invention on sleep-wake variables - the analysis of the one hour period and the analysis of the six hour period.

The results are expressed in minutes (analysis of the hourly period) or as a percentage of the control values (100%). Statistical analysis of the data was performed using the Student's t test for paired values to determine significant variations in the control values. Exen} .pip..72

Test of stress-induced idiosyncratic vocalizations in adult rats

This Example illustrates the study of the effectiveness of the compounds of this invention as antidepressant agents in animal models.

The procedure used was adapted from the technique described by Van Der Poel A.M, Noach E.J.K, Miczek K.A (1989) Temporal paffemfog of t / ffrasortie rástress caf / s fo the adb / f rah effects of morphfoe and benzodiazepines. (Temporal standardization of ultrasonic cries of distress in adult rafo: e20 made from morphine and benz.odiaz.epinas) Psycfoop / wrrtacofogy 97: 147-9. The rats were placed for a training session in a cage with a stainless steel grid floor (ME D Associates, lnc, <St. Albans, VT). Four electric shocks (0.8 mA, 3 seconds) were released every 7 seconds and the ultrasonic vocalizations (UV, 22 KHz) were then recorded with the Ultravox system (Noldus, Wageningen, Netherlands) for 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 UV crisis that lasted for 10 30 ms. The rats were selected based on their UV duration (> 4Gs) and subjected to the test, 4 hours after training. For the test, the rats were placed in the same cage that was used for training. a

92/92 electric shock (0.8 mA, 3 seconds) was released and the UV (duration and frequency) were then recorded with the Ultravox system for 2 min. The compounds of this invention were administered orally 60 min before the test,

Exenipln 73

Forced swimming test in rats

This Example further illustrates the study of the effectiveness of the compounds of this invention as antidepressant agents in animal models,

The procedure was a modification of that described by Porsolt et af. (1977) Depression; a. new anirna / mode / sensfove fo anffdepressanf freafmenfs. (Depression, a new animate model sensitive to antidepressant treatments) A / afure 266: 730-2. The rates were placed in an individual glass cylinder (40 cm high, 17 cm in diameter) containing water (2ΓΟ) up to a height of 30 cm. Two swimming sessions were conducted (a 15-minute training session followed 24 hours later by a 6-minute test). After each swimming session, the rats were placed under a heating lamp to avoid hypothermia. The duration of immobility was measured during the 6-minute test. The compounds of this invention were administered orally twice (15 minutes after the training session and 60 minutes before the test).

Although the invention has been illustrated by some of the preceding examples, it should not be considered to be limited by them; but preferably, the invention encompasses the generic area as described above. Can several modifications and modalities be made? move away from the spine and its scope.

Claims (11)

1. Toast compound (I):

v.) where 5 m is 1 or 2; π is 1 or 2; foot 1 or 2; R- _: is hydrogen, (C ^ C ^ lalquita, CF _{S (} (C1-C ^ falcoxy-CC ^ -C ^ alkyl; (¾ is hydrogen, halide, (C _r C ^ jalkyl or CF »; and WR; _} is hydrogen, (CrC ^ alkyl, (Ci-Cg) alkyloxycarbonyl, (C; rC?) alkylidalkyl (CvCs) alkyl, substituted or unsubstituted beferocicio, heterocidoalkyl (CrCf,) substituted or unsubstituted alkyl, heteroari; (CrCg) substituted or unsubstituted 5- and 6-membered alkyl, substituted or unsubstituted benzyl, (CrC ^ alkoxymethylGarbonyl, 15 (substituted or unsubstituted Cs-Cycloalkanecarbonyl, substituted or unsubstituted benzylcarbonyl, (substituted or unsubstituted Cg-C ^ arylcarbonyl, substituted or unsubstituted 5- or 6-membered heteroancarbonyl, substituted or unsubstituted heterocyclocarbonyl, substituted or unsubstituted benzenesulfonyl substituted, in which the substituents are selected from halide, trifluoromethoxy, (CvCC alkoxy, (CrC ^)) akylia or CF _; <; or an enantiomer or diastereomer thereof. A compound according to claim 1, wherein m p, and rn are 1, R _{5 is} media, atyl, isopropyl, r-propyl or methoxyeda; .25 R _? is hydrogen, fluorine, chlorine, methyl, ethyl or CFç and R: í is hydrogen, methoxyethylarbonyl, tert-butyloxycarbonyl. cyclopropylmethyl, cyclopentylmethyl. cido-hexylmethyl, lyric-hydropyrania, benzyl, furardylmethyl. cyclopentane-catbonyl, cyclohexanecarbonlla, trifluorometuxi · benzoyl. fluorobenzoyl, benzyl-carbonia. naftücarbomía. benzenesulfonyl, fluorobenzene sulfonyl or methoxybenzenesultbnyl. A compound according to claim 1, wherein n and 2 and m is 1; or n is 1 and 2; p is 1 or 2; R <is methyl or ethyl; R _{s is} hydrogen, fluorine, chlorine, methyl, ethyl or CF _S ; and 10 Rs is hydrogen, isopropyl. tert-butyloxycarbonyl, cyclopropylmethyl, cyclopenylimethyl, cyclohexylmethyl, tetrahydropyranyl. benzyl, furanylmethyl, tetrahydropyranilmethyl, oiclopentane carbonyl, cyclohexane carbonyl. carbonyl tetrahydropyran. banzaria, tnfluoromethoxybenzia, tluorobenzoyl, benzd carbonda, nafiil carbonia, pyridia carbonia or furan carbonda. A compound according to claim 1 selected from the group consisting of a 242-methyl-4 - ((2R.3'S) -2-methyl · tarc-butyl ester) · · [1.33bipolar in 11-1 ^! - il) -phenyl 1 -oxo ~ 2,8-diaza ~ spiroH. 5) decane-8-carboxylic; 2 .- (2-0 ^ 0 (11-4 - ((217,347) -2 ^ 0011120 [1.3 ') bipyrroid i π i ~ ~ il) -phen i I] -1 -oxo -2,8-diaza-espiro (4.5] dean-8 ~ carboxylum: acid tert ester butlhco Matii-2- {2-4 - ((2S, 3'R) -2-methyl ~ [1.3 ^I] beep rrolidiniM ^4l!) 'phenyl) -1-oxo-2,8- diaza-espiro (4.5] decano-8'Carboxílíoa; Lerc-butyl acid ester 2- (2-metd ~ 4 - ((2S, 3'S) ~ 2.-meiii (1,3 ^: ] bipirro Íidini; -T-ii) -phenyl-1oxo-2,8 - diaza -spiro (4.5] dean-8-earboxliiaa: 25 2- (2-methyl -4- (2 - methyl-; 1.3 ^f ) bjpyrrolidinyl-yl) -phenyl] -1 oxo-2 <8-diaza-spiral (4.5) decan- tert-butyl ester 8-carboxyl: tert-butyl ester of 2- (2-methyl-4 - ((2S, 3'S) _-2-metili1: 3: bipirrolidird.l-1 -yl) -1} -ferdl ^{"UXO-2,9-diaza-!} spiru (5.51undecano-9'-rx3rboxi'hQo; 2 (4 - ((2S.3'S) -2-methyl) (1 .Tlbipyrmlidinyl30 r-yl) - phenyl) - '1-oxo-2,9'diaza'espíro (5.5] uadecane tert-butyl ester -9-carboxylic; 4 - {[2-fluor-4 - ((2S _! 3 ^, S) ~ 2-methyl (1 .Slbipyrralidinyl-T-yl) -phenyl} -methyl-Garbamoii} -4-propyl tert-butyl ester -piperidine-1-'Carbc-xylicu: 3/9 2- {444- (2S-2'rnetH-pyrrolidin ~ 1 h) acid teFC-butyl ester ~ 1 h-piperidin-1-ylJ-pheniQ-1-oxG ^ .S-diaza-espiFG ^ .Sjdecano-S- carboxylic; 2- {4- (442S-2-me1: yl ~ pIFFolidin-1 ~ yl) -pipeFidin ~ 1-ii] ~ 2-trl9uorornetiHeail} -1-GX0-2,8-diaza-spirc44 acid tefc-butyl acid .5] daaano-8-caFbGXylic; 2- {4- [4- (2S-2-methyl-pínndin-1-yl) · pipend'in-1-yl] ~ 2-fluofen-phenyl} -1 ~ ox0--2 tert-baptic acid ester , 8-diazole-spiro (4.5] decanO'8-carbox9jcG; 244- [3 - {(28 _! 3 ^, 8) -2-πΊθΐϋ-ρΙρ0πΟίη-1 ~ ii) -pyrrolidin-1-yl) -pheni (} - 1-oxG-2,8- diaza-espiro [4.5] decar) o-3carboxnico: acid tert-butyl ester 244434 (2S.3'S) - 2-me9l-pipendin-1yl) -pyrrolidin-1 Ül-2tmluoFOfnfôtil-feniQ-1-cxo ~ 2 _} 8 ~ diaza-espíro [4.5] decano-8 “ carboxylic; butyl acid ester 244- (3 - ((28,3 ^c S) -2-me9l-piperidirl · · 1-11) · plaolídin ~ 1-yl] ~ 2-fluoro-phenyl} -1-oxo-2 _t 8-diazospiro [4.5] deoano-8-carboxylic; 242- ^ tH-4 - ((2S _t 3 \ S) -2-meW41 Jlbipyrratidinyl-10-O-fenslK? ^ Diaza-espira [4.5] deoan-1-one; 8-aidapeatilmetll-242-methyl ~ 4- (2-rnetii41,3 '] bipinalidinyl-1 ^> -1) -phenii] ~ 2.8- daza spir0 (4.5jdeean-1-one; 2 (2 - methyl -4 - ((28 _f 3'S) -2-methyl- [1,3'lbipin'oiidinyl-1 ^! -Yl) -phenyl) -8 - (4-trb fluoromethoxy-benzoii) -2, 8-diaza-breath (4.5) decan-1-one; S-benzcacssuífuail-2 {4- (4- (2S-2-fnet: 1-pirfohdin-1 -i) -piperidiπ-1 i] -phenyl} -2 _t 8-diaza-e & piroí4.5jdecan - 1-- 0na; 8 ~ (4-π) © 1όχΙ-6οηζοηοδδΡΐ (οπίΙ) -2- [4 · ((28,3'5) -2-Γηο9ΐ- (1,3> ΐρΐΓΓθίίdiral-1ís) -2-iriflu> ofometíl ~ phenyl ] -2.8 ~ diaza-spiro [4.5jdecan-1-hollow; 244 - ((25 _t 3 ^, S) -2-methyl- [1 _f 31bipkrulidinyl-Tyl) -2-trifiuar0met.il-phenyl] - 2.8- db.za -spiro (4, S | deoan-1-one 242-metiM - ((28 _t 3'S) -2-methyl- [1 .S'Jbipyrrolidinyl-y-iij-phenEllS.ediaza-espira (4.5 ideca η-1 -o na; 2- {2-Methyl-44 (2R, 3'R) -2-meH-ily31b; pyrrulidinyl; ~ 1 ⁱ -yl) phenyl - 2,8-diaza-spire [4.5] decan-l -una; Oloridrato metll-242-4 - ((2R 3S) -2-methyl-I1.3 ^{<jbipirrolidínii-1 _'yl!)} Phenyl-2.8-diaza-espÍFo [4.5] decan1- <phosphine; OlonoVafo de 242-0 ^ 91-4 - ((28,374) -2-00111-11,3> ipirrolidind ~ 1 ‘-H) ·· 4/9 tonil | -2,8-diaz. “FèspitP (4,51decan-l-0na; 8 ~ c) dapentjifnetíl-2- (2rnetíl-4 - ({2R, 3'S) -2-meiíl- (1,3 ^, ] bíptrroiidjnil1 M) -phenH] -2,8-d) aza ~ espiro [4,5 ] decan-1-one: 8-C) dopenWmethyl-2- (2 ~ methyl-4 - ((2R _> 3 ^, R) -2-metn- [1 _< 3 *] b) pinolidinyl5 1 Mf-phenOH, 8-draza-espi) o ( 4 .djdecan-1 -ona: 8- ddopenfHmet) l ~ 242 ~ mfôt6-4 - ((2S _! 3 ^! R) -2 ~ rneü5-í1,3 ^! ] BÈpinObd) ní (- 1 ~ n-phenii] ~ 2.8 "diaza-spiro (4.5 | decan-1-one; 3 <; ίοΙορ © πΙίΙπΊβΙϋ-2 (2-ΓΠ ^ 5Ι-4 ·· (((28 _ι 3 ^, 3) -2-? ΗρϋΗ1 _! 310ίρίσ0ΐΙ _! 310ίρίσ0ΐΙ <ίίηϋ ·· 1'l) -ffôníl] -2,8-díaza-spiro (4,5) decan-1-one; 10 2- [2-me6l-4 - ((2R. 3'S) -2-meW- [1,3'Jbipí rrolidínil- 1 'ip-phenin-8- (4-trifluor0mtôt6xi-benzoii) -2 ₍ 8-díaza -spiro [4.5) decan-1-Gna; 2 ~ ί2-ηΊΜΗ-4 - ((2Ρ ₎ 312) -2-πι © ΙίΙ-Π>318ίρίπΌΠ8ίπΤΤ'ίΙ) · ί0ηίΙ] ·· 8 ·· (44π ·· 6uorGmetóxi-benzoii) -2,8-d) aza-0spiro [4.5] deoan-1 ~ one; 2 · {2 ·· ίηβίίί · 4 ·· {(2δ _> 3 ^) - 2 ··) ηβϋΙ · {1 _! 3 ^, } όΐρΐποΙί <Ιίπί! ~ Γ-1Ι) -ί © ηΐί] -8- (4- (π15 fiuDrGmetôxi-benzoyl) -2,8-dfaza-espír0 [4,5] deoan-1 -ona; 242-) 00654 - (2-meW- [1 _Γ 3 ^ 5) ρί) ο4κοπί51 'H) -phenH] -8 ~ (44.rifluoromethoxy-benzoyl) -2,8-diazs-espko (4,5] decan -1 -one; 342-010 () 1-4 - ((28.3 ^) - 2-) 0061- (1,3lbjpinolidinR-1'-h) -phenH] ~ 2.9-drazaespko (5.5] undeean-1-one; 20 3- (4 - ((28,3'S) -2-nie6i- [1,3 '] bipkrol) dynil · 1' -il) -phenyl] -2,9-daza -spjfo [5.5] ondecan -1 - ona; 342-fiúor-4 - ((28,3 ^) - 2-) 0061- (1,3 ^ 1 ^^ 0 ^) 011-1-10- ^ 0) 1) -2,9-61323espko (5.5] uodecan-1-one; 3 - (2 rned-4 - ((2S _; 3'S) -2-me6l- {1,3,3 *) beep krolidi n si-1 -H) -fen h | -9- (pyrine 25 dine · 4 · € 3) Ροπ) 1) -2 ₍ 9-6ί3Ζ3- & 5ρίΓθ (5.5] υπ6βοοη-1 -ona; 9- (furan-3-ca) boníl) -2 · (2 ·· ίηβ <ί54 - ((2,8. S'SVz-metsi-FLSlbipkTohdi- nií-l '-) l) -pheníO2,9-díaza -espka (5.5) undecan-1-one; 9-80) ^ 0) 52- (4 - ((28,31S) -2-n) SlK - (1 _.; 3 '] bipirr () hdiaH-V-ii) -tnnji] - 2, < ) ~ diaz-spiro [5.5) undecan-1-one; 30 9- (48úe) -benzd52- (4 - ((28,358) -2-metH- {1. S'jbipFfQlidiniU 1 Ml) phenyl] -2,9-d iaza-esp)) G <5.51undecan -1 -one; 9-ρίοΙο-Ιι © Χ3ηαΡ3Γ60ΠίΙ-242-ΠΰϋΓ-4 ”((28,3'8) -2-ΓΠΘί {! - (1 _> 3 ^, ] 8ΐρΐΓΓ0Ηb / 9 dsnil · 1 * -H) -phenyl] -2 , 9-diaza-espko [5.5lundeGan-1-one _; S- [Z-fluor-4 - ((2S _> 3'S) -2-metii (1 _> 3'Jbíp? ÍToHd _: iníJ ~ 1 '~ H) -fenH)''<3 ~ (teira ~ hidro-píran ^ -caíixjntl ^^ foiaza-espíroIS.SJundeoan-l-ona; $) 4δορΓορίΙ-2- (2-ΓηοϋΙ-4 - ((28 _; 3'δ) -2-meiil- [1,3 ^: ] 0ΙρίσοΗάίπϋ ·· 1 '· il) 5 feniO-2, 9-diaza-espiro {5. 5] undeoan-1 -ana; 9-CiGk> hexHmetü-2 - (2 -metH-4 - ((2S, 3'S) -2-methyl- (1,3 ‘) bipkrolidinil · 1 ^, -0) -phenH] -2 _J 9-diaza-espka (5.5jundecap -1 one; 9-ciolopropiimetil-2- {4,3'JbipinoHdinil-1 ‘-ÍI} fenh] -2,9-diaza-espiro [5.5] undecan-1-Ona; 10 2 · (4 - ((2S, 3'S) -2 ~ rne $ - (1, Tfbipirralid inyl-1 'àQ-phenH ^ - (tetrahydropyran-4il) -2,9-daza-espíro (5.5} undeoan -canvas; 9-bfônzil-2- (2-fluoro-4 - ((2S, 3'S) -2-rne5i (1.3jbípírrQlidinil-1'-ü) -phenyl] 2.9 ~ diaza-espiro [5.5] u ndeaan -1 one ; 2- (2 · ί1ύϋΓ · 4 ·· ((2δ _< 3 ^, δ) ·· 2-ΓΠβίΐί- [1 _< 3 ^, 15ίρΐπ · οΗάΙπίΙ · 1 ^> -ίϊ) ·· ίοπίΙ] ·· 9-ίυΓηπ ·· 15 2-ilmetii-2.9-diaz-eâpífu (5. 5] undecan-1-one; 2- {4 - [4- (2S-2-niethyl-p? Tolidin-1-i}} pipend I n-1-8-diazaespko (4,5] decan-1-cna; 2- {4- [4- (2S-2 ~ methyl-pyrrGlidin “1-ü) -piperidin-1-ii] ~ 2-tdfluoromeiil · fenü} -2.8-aiaza ~ espíro [4.5] dfôGan-1-one; 20 2- {4-i4- (2S-2 mfôtil-pírraüdín-1 -il) -piperídin-1 -ii -2-fluúDr-faniQ-2,8diaza-es piro (4.5] deca n -1 -one ; 2 ·· {4 ··! 3 ·· (((28 _< 3 ^! Δ) -2-ίη © ΙΙΙρίρυί ^ ίη1 · 'ίί) · -ρίηυ ^ Ιπ ·· 1ίΠ ·· (υηίβ-2,8 ·· diaza -specific (4.5] decan-1-one; 2- (4- (3 - ((28.3 ^) - 2-mety-pyruridin-1 - 1) -pineOidin-1-yl] -2-fluorine 25 methyl I - phenyl-2 _; 8-diaza -spiro (4.5) decan-1-one; 2- {4- (3 - ((28,3 ^ί 8) -2-ηΊ © ΙίΟρίρ0ΓίΡί'η1-ίί) · -ρίπ'οίΜίη-1-ίΠ · '2 · -ί1ύθΓ · 4 ^: υπΙί} ·· 2.8 diazaespiro (4.5) dec: an-1-one; 8 (4-fhXsr ~ benzoyl) -2- {4- (4- (2S-2-methyl-pyrrolidin-1-yl) ~ piperidin - 1-yl] phenit} -2,8-djaza-espko [4.5 ] decan-1-one, ' 30 8 - ddO'hexanoca? Boni? -2- {2-flúoM44- (2S-2a ^ ethyl-pírroHdin-l-! L) · pip6ndm-1-íl] 4enH} -2,8-díaza-te5pko [ 4.5] decan-1-ana; 8- (4-11úor - benzenesulfontl) ~ 2- {4 - (3 - ((2S, 3'S) -2-metd-pipeddín-1 6/9 PQ-pyrrolidine in-1] (phen) 1} -2,8-diaza-6spiro [4.5] decan- · 1-one; Z ^ -P-CCSS ^ ’Sy-S-meiiipiperidln-lill-pkroHdinl-in-phenill-S · (tetra • hydro-p« an-4GarbonH) -2,8 ~ diaza-espíP [4.5ldecan-1Ona; 8-cyclopeaten0cafboni52- {443 - ((2S, 3'S) -2 ~ metii ~ piperidia ~ 1-yl) -pir ”rôlidin - 1 ~ 51-2-triflooromethyl ~ phenyl} -2 ₁ 8-diaza ~ spiro (4.5 ) deoan-1-one; 8+; ícl0prQpHmeb52-42 ~ fluoro-4- (4- (2S “2-nietíTpirrGiidin ~ 1 ~ il) -pipeddin-1 -5] ~ fen) l} -2 _: 8-diaz.a6apiro (4.51decan-l -one; 8Cid0p6n5lm6t) l-.2- {241òor-4- (4- (2S - 2-me55p) roll) din-1-ii) -p) pe ~ nd) n-1-) 1-fea) í) - 2,8-diaz3-6sp) ra [4. Sldeoaa-l-one; 8-cjdChexilmetíi-2- {4 -p- ^ S ^ ’Sl ^ motii-pipendin-l-in-pyrrohdin- 1- il] -2tnflüorome5lphenyl) -2 _! 8díaza-espíra (4.5] de0an-l-0na; 2- {2Rúor-4 (3 ((2S _< 3 ^< S) -2-me8lpíperídín-1il) -pinoi »din-1-íO-phenyl} 8- (tehahidrap) / an-4-5metil) - 2, 8 - díaza-0spiro [4.51decan-1-one; 2- (4- ((2 S, 3'8) -2-81015- (1,3 '] b ipirroüdi niM -5) -2-1 / iflaorornetil - feail] ·· 8-fen5aceti5 ~ 2.8 ~ d) aza-spiro (4.5) decan - 1-one; 3- (2-016 ^ 1--0001))) - 2- (4 - ((28.3 ^) - 2-8161) 1- (1.316) 05801) 6) 575-10 ^) - 2trifl uaromethyl fen i I] -2,8 -diaza -spiro (4.5] deca to -1one; 2 - (4 ((28.3 ^) - 2- / 005) - (1.310) 0) ^ 0 ^ 6) 0) 51 ^ -) 0-2-10500008101: 1 -fend] 8 - (03 ^ 31080-2- ^ 000))) - 2,8 - diaza- 'spiro (4,5] deean - 1-one; 8--60 ^^ 0) 1--2- (4 - ((28.3 ^) - 2- / 005) - (1.31650) 00)) 5) / 51-T-) l) - 2fdfluororr? Etí5fer5l} -2,8 ~ diaza-a = spir0 {4 SJdecan-l-ona; 8- (fi5 / an ~ 3-carbon5) -2 .- (4 ~ ((2S ₍ 3 ^! S) -2-m655 [1.3>) ρ) σαΙκ & 551 ^S -H) - 2- bit uGros7ieb8fen5] 2,8-diaza ~ spiro (4.5] decan-1-one; 8-drilling ~ 2-5m0t) 52- (4 ~ ((28,3'8) -2 + net) 5 [1,31b) pyrroiidini51 ^ -) 1) -2tnfh.fôrom655fe! 7) 1-2,3 6) aza-osp) ro (45] decan-1-one; 8-0) 0100/00) 1/061.) 1-2- (4 - ((28458) -2-01055 (1,316) 0) 0011550) 1-8-) 1) -2-tafluorGmeti5phenyl] -2, 8-diaza-esp) ro [45 Mecan-1-one; 2 - (4 - ((28.3T>) - 2-01655 (1, .31b '; 0irrol) dso) 51 ^! -))) - 2-5': 11ηο / 0ηιρ5ί'ίοπίΗ · 8 ~ (t6tra -h) dí'op) ran-4-5oiet) l) -2., 8 ~ d) aza-spir6 (4.5] decan-1-one; and 2- (4 - ((28,358) -2- / 0085 (1,316) 0) // 0)) - 5) 0) 51-) 1) -2-5150010 / 001) 1- (00512, S-diaza- es0) / o (455] decaa-1-one; or oni I left them 7/9 5. .Composition of .according to .. Claim 1 selected from the group consisting of: 8-oiclopentylmethyl-2 [2-methyl - ((2R, 3'S) “2-methyl {1 ₍ 3 '] bipyrrohydini]' ·· I) -phenylJ - ^. B-diaza-spiraH. Bldecan-1-one; 8-ciak> pentylmethyl-2- (2-methyl-4 ~ ((2R _; 3'R) -2-methylH1,3 ^! ] BipyrroHdinyl1 '·· D-phenyl] - 2.8-diazã ”spiro [4.5] decan- 1-one; S-ciatopentiimetil - ^ - j ^ -methylM-ti ^ S.TRhí-methyl-íl. Ibipyrrolidinyl · · 1 l) -phenyl] ~ 2 _} 8-diaza-spiro [4.5) decan-1-one; 8- cyclopemílmeÜi-2- (2rnfôtil-4 - ((2S.3'S) -2 ~ metii- [1 _} 3 '] bípírrolidinil- 1 M) "phenin" 2,8 <liaza ~ espiro [4.5] decan ·· 1 ona; 242-ηιο (ίΙ-4 - (((2Η, 3 ^ΐ 8} 2-ηΊο8Ι - (1,3 ^: ] bipioolidinyl-1 ^: -yl) -phenyl] -8- (4-tritluaromethoxy-benzoyl) -2 _í 8 -diaza-spiro [4,5] decan-1 one; 2- (2-methyl ~ 4 "((2R, 3'R) -2-methyl- [1 ₍ 3 ^, ] bipyrrolidinyl-Tyl) -phenyl] 8- (4 ~ tn- f] uoramethoxy-beozoH) -2,8-diazospiro [4,5 Jdecan-1-one; 242-οιο1ίΙ · 4 - ((28,3Ή) -2-oiethyl-fl .3 '] bipyrrolidinyl - 1' -st) -phenyl] -8 ~ (4-tritluoromethoxy-benzoyl) ~ 2,8-d! aza-espíro [4.5] decan -1 -one; 242-methyl-4 '- (2-nieül- (1 _{ 3'] bipyrrolidinyl r -yl) -phenyl] -8- (4-4rif! UorometóKi-benzail) -2,8-diaza-spire (4.5] decan -1 -one; 3- 12 -01051-4 - ((28.3 ^) - 2-010111- (1 _t 3 ^: ] bi-pyridyl-1 ^: -yl) -phenyl] -2,9-diazospiro (5.5] undecan-1-one ; 3- (4-- ((28.3'8) -2-methyl- (1.3 '] beep irrolidated in il-1' -ií) ~ phenyl | -2.9-diaza -spiro [5.5] undecan-1 -one; 342411 ^ -4 - ((28.3 ^) - 2-010111- (1,3 ^^ 1 ^ 01 ^ 1011-1 ~ il) -fenll] -2,3-diaza · 'espim (5.5] undecao-1 - ona; S-isopropyl ^ M ^ methyl-4 - ((28,3'S) -2-meil- [1,3 '] ΜρΐΓΓαμ8ίοίΙ-1' -ií) phenyl] -2 _: 9-díaza ~ espíro [5. Sluodecao -1 -coa; 9- cyclohexyl.methyl-2- [2'-methyl'4 4 (2S.3'S) -2 ~ methyl41 .SJbipinoididine- 1 '~ i!} ~ Phenyl] -2 _t 9-dlaza-loop (5.S] undecan-1-one; 9-cyclopropylraethyl-244 - ((2S, 3'S) -2-mat: 'l {1,3 ^t ] bipifrolidinyl ~ 1 ^< -yl) t and ii] -2,9-diaz.a-esp'so (5.5 ] undecan-1-one; 2- (4 - ((28,3'5) “2'rr5ethyl41,3'jbipyrrolidinyl-1 ^< -yl) -phenyl] ~ 9- (tetrahydfupiran-A ~ 4) ~ 2, $) ~ diaza ~ spiro [5.5] uodecan-1-one; 8/9 9 ~ 0οηζ5ΐ-2 ~ [2-ίΙύοΜ - ((2.8.3'3) -2-πϊθ * 5ί- [1,3 ^ 5ρ5ΓΓθϋά5η5ΐ-Τ-ϋ) -ί6ΠίΙ] 2.9-diaza - espiro [5.5) undecan -1 -one; 2 - {2-fluor-4 - ((2S, 373) -2 methyl (1, 3 ') bipyrrhydryl-1' -yl) -fe.n ii] -9-furan2-ylmethyl-2 _! 9-diaza-espira (5.5] und ^ an'1 one; 5 8-cyclopropylmethyl-2- {24lüor-4- (4- (2S-2-methylpyrrhydric5-1-ib-piperi '· din-1 -in-pheniQ - ^. S-diaza-espiro ^ .- Sjdecari-l -a-N-A: S-uííJoper-itílíTíetil ^ qS-fluoro-á-H- ^ S ^ -áíethyl-pyrroiidifv- l-yl) -piperi · din-l ~ íl) ~ phenyl} -2,3-dlaza-espiro [4.Sjdecan -1 -one; 2- (2-fluor'4- [3 - ({2S.3'S) -2-methyl-piperidin ~ 1 -10-pyrrotidin-1-yl) -phenyl} 10 8- (tetrahydro-piraa- 4-ylmethyl) -2., 8-diazax? Spiro (4.5] decan-1 -una: 8-furan-2-iimethyl-2- (4 - ((2S, 3'S) -2-methyl- (1,3 '] btpirroiidinyl-1 - /) - 2trifluoromethyl-phen i I) - 2,8 -diaza - spiro [4.5) decan 1-one; 8-dcícpropiímetil-2 [4 - ((2S, 3TS) -2-methyl- (1 pB ^ bipyrrolídiail-T-ib-Ctrífkíoromethyl-pheniI) - 2,8 diaza-spiro (4..5] decan-1 one ; O 15 2-l4 - ((2S, 3 \ S) -2metH- [1,3 '] bípínnlidmí! -Ri>) - 2-trifiuoromethyl -fem] 8- (tetra ~ h5dro ~ pyran-4-5lmethyl) ~ 2 , 8 ~ diaza-esp! Ro (4.5] decan ~ 1-one; or one leaves them .. A compound according to claim 1 which is having the formula (ih:

20 wherein R ^ ₍ R _; >, R ^ ₍ men are as defined in claim 1. Pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 6 or a pharmaceutically acceptable salt, an enantiomer, or a diastereomer thereof in combination with one or more vehicles, diluents or excipients 25 pharmaceutically acceptable. Use of a compound according to quaique - one of claims 1 to 6 or a pharmaceutically acceptable salt, an enantiomer, or a diastereomers thereof for the preparation of a pharmaceutical composition, a compound compound and capable of modulating H3 receptor function for treating cognitive impairment associated with schizophrenia (CIAS), anxiety disorders such as generalized anxiety, panic disorder and post-traumatic stress disorders, major depressive disorder, Alzheimer's-type dementia (DAT), cognitive deficits related to neurological diseases chosen among Alzheimer's, Parkinson's or Huntington's, age-related cognitive impairment, mild cognitive impairment, vascular dementia, Lewis corpus dementia, cognition associated with cognitive deficits, sleep-related disorders, attention deficit hyperactivity disorder and depression, and obesity , 9. Use according to claim 8, in which the sleep disorder is selected from the group consisting of narcalepsy, circadian sleep disturbance, obstructive sleep apnea, periodic limb movements and restless leg syndrome, excessive sleepiness and numbness due to side effect of medication, 10. Use according to claim 8, wherein the sleep disorder is narcolepsy 11. Use according to claim 8, wherein the disease is cognitive impairment associated with schizophrenia (CiAS). 1.2. Use according to claim 8, wherein the disease is Alzheimer's-type dementia (DAT),