MXPA06009685A - Alpha aryl or heteroaryl methyl beta piperidino propanoic acid compounds as orl1-receptor antagonists - Google Patents

Abstract

This invention provides the compounds of formula (I):or a pharmaceutically acceptable ester of such compound, or a pharmaceutically acceptable salt thereof, wherein R1 and R2 independently represent a hydrogen atom or the like;R3 represents an aryl group having from 6 to 10 ring atoms or the like;X represents an oxygen atom , or the like;Y represents an oxygen atom or the like;and n represents an integer 0, 1 or 2. These compounds have ORL1-receptor antagonists activity;and therefore, are useful to treat diseases or conditions such as pain, various CNS diseases etc.

Description

ACID COMPOUNDS ALPHA ARIL OR HETEROARIL METHYL BETA PIPERIDINE PROPANOIC AS RECEPTOR ANTAGONISTS ORL1 Field of the Invention This invention relates to compounds of alpha aryl or heteroaryl methyl beta piperidino propanoic acid and to pharmaceutically acceptable esters or pharmaceutically acceptable salts and solvates thereof and to the medical use thereof. Furthermore, this invention relates to a pharmaceutical composition comprising said compound or its pharmaceutically acceptable ester or pharmaceutically acceptable salt. The compounds of this invention have binding affinity for the ORL-1 receptor. In particular, the compounds of this invention have antagonist activity for said receptor. The compounds of this invention are useful in the treatment or prevention of disorders or medical conditions selected from pain, a CNS disorder and the like, which are mediated by overactivation of said receptor. Background of the Invention Three types of opioid receptors have been identified, μ (mu), d (delta) and K (kappa). These receptors can be indicated with combinations of OP (abbreviation of opioid peptides) and numerical subscripts as suggested by the International Union of Pharmacology (IUPHAR). Specifically, OPL OP2 and OP3 correspond respectively to the receivers d, K and μ. It has been discovered that they belong to the receptors coupled to the G protein and are distributed in the central nervous system (CNS), peripheries and organs in a mammal. As ligands of the receptors, endogenous and synthetic opioids are known. It is believed that an endogenous opioid peptide produces its effect through an interaction with the major classes of opioid receptors.

For example, endorphins have been purified as endogenous opioid peptides and bind both the d and μ receptors. Morphine is a well-known non-peptide opioid analgesic and has binding affinity mainly for the μ receptor. Opioids have been widely used as pharmacological agents, but drugs such as morphine and heroin induce some side effects such as drug addiction and euphoria. Meunier et al. reported the isolation of a seventeen-amino acid peptide of rat brain length as an endogenous ligand for an orphan opioid receptor (Nature, Vol. 337, pp. 532-535, October 12, 1995), and now said receptor is known as "Type 1 opioid receptor" (abbreviated as ORL-1 receptor). In the same report, the endogenous opioid ligand has been introduced as an agonist for the ORL-1 receptor and is termed "nociceptin (abbreviated as NC)". In addition, the same ligand was designated "orphanin FQ (abbreviated as OFQ or oFQ)" by Reinscheid et al. (Science, Vol. 270, pp. 792-794, 1995). This receptor can be indicated as OP4 according to a recommendation of IUPHAR in 1998 (British Journal of Pharmacology, Vol. 129, p.1261-1283, 2000). International Patent Application Number (WO) 9429309 discloses various spiro-substituted azacyclo compounds, which are neurokinin antagonists useful in the treatment of pain. In addition, International Patent Application Number (WO) 9825605 discloses various spiro-substituted azacyclo compounds, which are antagonists of the modulator of chemokine receptor activity. In addition, International Patent Application Number (WO) 0226714 discloses various spiropiperidine compounds that show binding affinity to a nociceptin receptor.

In addition, International Patent Application Number (WO) 03064425 describes various spiropiperidine compounds, which are ORL1 antagonists, for example, compound (i) shown below: Compound (i) shows potent activity in the dofetilide binding assay. There is a need to provide new ORL1 antagonists that are good drug candidates. In particular, the preferred compounds should bind strongly to the ORL1 receptor and display functional activity as antagonists while showing little affinity for other receptors. They must be well absorbed from the gastrointestinal tract, be metabolically stable and have favorable pharmacokinetic properties and less drug-drug interaction. They should not be toxic and should show few side effects. In addition, the ideal drug candidate will exist in a physical form that is stable, non-hygroscopic and easily formulated. In particular, it will be desirable to provide an ORL1 antagonist with lower inhibitory activity in the potassium channel HERG. SUMMARY OF THE INVENTION Surprisingly, it has now been discovered that the alpha aryl or heteroaryl methyl beta piperidino propanamide compounds of the present invention are ORL1 antagonists with analgesic activity, particularly when delivered by systemic administration. Less inhibitory activity has also been observed in the HERG channel in the selected compounds. The inhibitory activity in the HERG channel was estimated from the affinity for the HERG potassium channel by measuring the binding to [3H] dofetilide, which can predict the inhibitory activity in the HERG channel (Eur. J. Pharmacol., 430, pp. 147-148, 2001). Selected compounds with low [3H] dofetilide binding activity were evaluated in the IHERG assay to check their activity in the HERG channel. The selected compounds of the present invention showed a shorter QT prolongation. The present invention provides a compound of the following formula (I): 0) or a pharmaceutically acceptable ester of such a compound, or a pharmaceutically acceptable salt thereof, wherein R1 and R2 independently represent a hydrogen atom, a halogen atom or an alkyl group having from 1 to 3 carbon atoms; R3 represents a phenyl group or a heteroaryl group and said heteroaryl group is a 5- or 6-membered heteroaromatic group having from 1 to 4 ring nitrogen heteroatoms or 1 or 2 nitrogen ring heteroatoms and 1 oxygen heteroatom or 1 heteroatom of sulfur in the ring; said phenyl group and heteroaryl group are optionally substituted with 1 to 3 groups selected from a halogen atom, a hydroxy group, an alkyl group having from 1 to 3 carbon atoms, an alkoxy group having from 1 to 3 carbon atoms, an alkoxyalkyl group having a total of 2 to 6 carbon atoms, a hydroxyalkyl group having from 1 to 3 carbon atoms, an amino group, a mono- or di-alkylamino group each alkyl part having from 1 to 3 carbon atoms; carbon, an aminocarbonyl group, a mono- or di-alkylaminocarbonyl group having from 1 to 3 carbon atoms in each alkyl group, an alkanoylamino group having from 2 to 3 carbon atoms and an alkylsulfonylamino group having from 1 to 3 carbon atoms; -XY- represents a group of formula -N (R4) C (= O) -, -C (= O) N (R4) -, -N (R4) CH2-, - CH2N (R4) -, -N ( R4) SO2-, -SO2N (R4) -, -CH2CH2-, -CH = CH-, -CH (CH2OH) CH2-, -CH2CH (CH2OH) -, -CH2CH (OH) -, -CH (OH) CH2 -, -C (R4) (R5) -O- or -OC (R4) (R5) -; R4 represents a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms; R5 represents a hydrogen atom, an alkyl group having from 1 to 3 carbon atoms or a hydroxyalkyl group having from 1 to 3 carbon atoms; and n represents an integer 0, 1 or 2. The compounds of the present invention are antagonists of the ORL1 receptor and have various therapeutic applications, particularly in the treatment of pain, sleep disorders, eating disorders including anorexia and bulimia; anxiety and stress states; diseases of the immune system; locomotor disorders; memory loss, cognitive disorders and dementia including senile dementia, Alzheimer's disease, Parkinson's disease or other neurodegenerative pathologies; epilepsy or seizure and symptoms associated with them; a central nervous system disorder related to the action of glutamate release, anti-epileptic action, alteration of spatial memory, release of serotonin, anxiolytic action, mesolimbic dopaminergic transmission, welfare properties of drugs of abuse, modulation of the effects of striated muscle and the effects of glutamate on locomotor activity; cardiovascular disorders including hypotension, bradycardia and stroke; kidney disorders including water excretion, sodium ion excretion and syndrome of inappropriate secretion of antidiuretic hormone (SIADH); gastrointestinal disorders; respiratory tract disorders including respiratory distress syndrome in adults (ARDS); autonomic disorders including suppression of the micturition reflex; metabolic disorders including obesity; cirrhosis with ascites; sexual dysfunctions; altered pulmonary function including obstructive pulmonary disease and tolerance or dependence to a narcotic analgesic or similar. The compounds of the present invention are useful for the general treatment of pain. Physiological pain is an important protective mechanism designed to warn of the danger of potentially damaging stimuli from the external environment. The system works through a specific set of primary sensory neurons and is activated exclusively by noxious stimuli by means of peripheral transduction mechanisms (Millan 1999 Prog. Neurobio, 57: 1-164 for a full review). These sensory fibers are known as nociceptors and are characterized by small diameter axons with low conduction velocities. Nociceptors encode the intensity, duration and quality of the noxious stimulus and, by means of its topographically organized projection towards the spinal cord, the location of the stimulus. Nociceptors are found in nociceptive nerve fibers of which there are two main types, A-delta fibers (myelinated) and C fibers (unmyelinated). The activity generated by the entrance of the nociceptor is transferred after a complex processing in the dorsal horn, directly or by nuclei of relay from the stem of the brain to the ventrobasal thalamus and later to the cortex, where the sensation of pain is generated. Severe acute pain and chronic pain may involve the same pathways directed by pathophysiological procedures and as such may fail to provide a protective mechanism and instead contribute to weakening the debilitating symptoms associated with a wide range of diseases. Pain is a feature of many disease states and injuries. When a substantial injury to body tissue occurs due to disease or trauma, the characteristics of nociceptor activation are altered. Sensitization occurs in the periphery, locally around the lesion and centrally where the nociceptors end. This leads to a hypersensitivity at the site of the injury and in nearby normal tissue. In acute pain these mechanisms may be useful and may allow the repair procedure to take place and the hypersensitivity returns to normal when the lesion has healed. However, in many chronic pain states, hypersensitivity lasts longer than the healing procedure and this is usually due to a nervous system injury. This injury usually leads to maladaptation of the afferent fibers (Woolf & amp;; Salter 2000 Science 288: 1765-1768). Clinical pain is present when discomfort and abnormal sensitivity are among the patient's symptoms. Patients tend to be quite heterogeneous and may exhibit various pain symptoms. There are several typical subtypes of pain: 1) spontaneous pain that can be dull, burning or throbbing; 2) painful responses to noxious stimuli are exaggerated (hyperalgesia); 3) the pain is produced by normally innocuous stimuli (allodynia) (Meyer et al., 1994 Textbook of Pain 13-44). Although patients with back pain, arthritis pain, CNS trauma or neuropathic pain may have similar symptoms, the underlying mechanisms are different and, therefore, may require different treatment strategies. Therefore, pain can be divided into several different areas due to its different pathophysiologies, these include nociceptive, inflammatory, neuropathic pain, etc. It should be noted that some types of pain have multiple etiologies and therefore can be classified in more than one area, for example, back pain, cancer pain has both nociceptive and neuropathic components. Nociceptive pain is induced by tissue injury or intense stimuli that have the potential to cause injury. Pain afferents are activated by transduction of stimuli by the nociceptors at the site of the lesion and sensitize the spinal cord to the level of its termination. It is then transmitted through the spinal tract to the brain where pain is perceived (Meyer et al., 1994 Textbook of Pain 13-44). Activation of nociceptors activates two types of afferent nerve fibers. Myelinated A-delta fibers transmit rapidly and are responsible for the sensations of sharp, throbbing pain, while unmyelinated C fibers transmit at lower velocity and lead to dull or sharp pain. Acute nociceptive pain of moderate to severe is a prominent feature, but without limitation, of sprained / twisted pain, post-operative pain (pain after any type of surgical procedure), post-traumatic pain, burns, myocardial infarction, pancreatitis acute and renal colic. In addition, acute pain syndromes related to cancer are usually due to therapeutic interactions such as chemotherapy toxicity, immunotherapy, hormone therapy and radiation therapy. Moderate to severe acute nociceptive pain is a prominent feature, but without limitation, of cancer pain that may be pain related to tumors (eg bone pain, headache and facial pain, visceral pain) or associated with anti-cancer therapy. cancer (eg, post-chemotherapy syndromes, post-surgical chronic pain syndromes, post-radiation syndromes), back pain that may be due to ruptured or herniated intervertebral discs, or joint abnormalities of the lumbar facet, sacroiliac joints, paraspinal muscles, or longitudinal ligament later. Neuropathic pain is defined as pain initiated or caused by a lesion or primary dysfunction in the nervous system (IASP definition). The injury to the nerve can be caused by trauma and disease and thus the term "neuropathic pain" encompasses many disorders with various etiologies. These include, but are not limited to, diabetic neuropathy, post herpetic neuralgia, back pain, cancer neuropathy, HIV neuropathy, phantom limb pain, carpal tunnel syndrome, chronic alcoholism, hypothyroidism, trigeminal neuralgia, uremia, or vitamin deficiencies. Neuropathic pain is pathological because it does not have a protective role. It is usually present long after the original cause has dissipated, usually lasting for years, significantly reducing the quality of life of patients (Woolf and Mannion 1999 Lancet 353: 1959-1964). The symptoms of neuropathic pain are difficult to treat since they are usually heterogeneous even among patients with the same disease (Woolf & amp;; Decosterd 1999 Pain Supp. 6: S141-S147; Woolf and Mannion 1999 Lancet 353: 1959-1964). They include spontaneous pain, which may be continuous or paroxysmal and abnormal evoked pain, such as hyperalgesia (increased sensitivity to a noxious stimulus) and allodynia (sensitivity to a normally harmless stimulus). The inflammatory procedure is a complex series of biochemical and cellular events activated in response to tissue injury or the presence of foreign substances, which results in swelling and pain (Levine and Taiwo 1994: Textbook of Pain 45-56). Arthritic pain makes up most of the inflammatory pains of the population. Rheumatoid disease is one of the most common chronic inflammatory conditions in developed countries and rheumatoid arthritis is a common cause of disability. The exact etiology of RA is unknown but current hypotheses suggest that both genetic and microbiological factors may be important (Grennan &Jayson 1994 Textbook of Pain 397-407). It has been estimated that nearly 16 million Americans have symptomatic osteoarthritis (OA) or a degenerative joint disease, most of which are over 60 years old and this number is expected to increase to 40 million as the age of the population increases , making this a public health problem of enormous magnitude (Houge &Mersfelder 2002 Ann Pharmacother, 36: 679-686, McCarthy et al., 1994 Textbook of Pain 387-395). Most patients with OA seek medical attention due to pain. Arthritis has a significant impact on psychosocial and physical function and is known to be the leading cause of disability in advanced stages of life. Other types of inflammatory pain include, but are not limited to, inflammatory bowel diseases (IBD). Other types of pain include, but are not limited to: - Musculoskeletal disorders including, but not limited to, myalgia, fibromyalgia, spondylitis, sero-negative (non-rheumatoid) arthropathies, non-joint rheumatism, dystrophinopathy, glycogenolysis, polymyositis, pyomyositis. - Central pain or "thalamic pain" defined as pain caused by injury or dysfunction of the nervous system including, but not limited to, central post-stroke pain, multiple sclerosis, spinal cord injury, Parkinson's disease and epilepsy. - Heart and vascular pain including, but not limited to, angina, myocardial infarction, mitral stenosis, pericarditis, Raynaud's phenomenon, scleroderma, skeletal muscle ischemia. - Visceral pain and gastrointestinal disorders. The viscera encompass the organs of the abdominal cavity. These organs include the sexual organs, spleen and part of the digestive system. The pain associated with the viscera can be divided into visceral digestive pain and non-digestive visceral pain. Gastrointestinal (Gl) disorders usually found include functional bowel disorders (FBD) and inflammatory bowel diseases (IBD). These Gl disorders include a wide variety of disease states that are currently only moderately controlled, including, for FBD, gastroesophageal reflux, dyspepsia, irritable bowel syndrome (IBS) and abdominal functional pain syndrome (FAPS) and -for IBD, Crohn's disease, ileitis and ulcerative colitis, all of which regularly produce visceral pain. Other types of visceral pain include pain associated with dysmenorrhea, pelvic pain, cystitis, and pancreatitis. - Headache including, but not limited to, migraine, migraine with aura, migraine without aura, headache in accumulations, tension-type headache. - Orofacial pain including, but not limited to, dental pain, temporomandibular myofascial pain. Thus, in a further aspect of the present invention, there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt or ester thereof, in the manufacture of a medicament for the treatment of pain. As an alternative aspect, a method for pain treatment is provided, comprising administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or ester thereof, to a mammal in need of such treatment. Detailed Description of the Invention As used herein, the term "halogen" means fluoro, chloro, bromo and iodo, preferably fluoro or chloro. As used herein, the term "alkyl" means saturated straight or branched chain radicals, including, but not limited to, methyl, ethyl, n-propyl, isopropyl. As used herein, the term "alkoxy" means alkyl-O-, including, but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy. As used herein, the term "alkanoyl" means a group having carbonyl such as R'-C (O) - where R 'is H, C? -5 alkyl, phenyl or C3-6 cycloalkyl, including, but without limitation, formyl, acetyl, ethyl-C (O) -, n-propyl-C (O) -, isopropyl-C (O) -, A7-butyl-C (O) -, iso-butyl-C (O ) -, secondary butyl-C (O) -, tertiary butyl-C (O) -, cyclopropyl-C (O) -, cyclobutyl-C (O) -, cyclopentyl-C (O) -, cyclohexyl-C (O ) - and similar. As used herein, the term "aryl" means a monocyclic or bicyclic aromatic carbocyclic ring of 6 to 10 carbon atoms; including, but not limited to, phenyl or naphthyl, preferably phenyl. As used herein, the term "cycloalkyl" means a saturated carbocyclic radical ring of 3 to 6 carbon atoms, including, but not limited to, cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. As used herein, the term "heteroaryl" means a heteroaromatic group attached by C having from 1 to 4 ring nitrogen heteroatoms or 1 or 2 nitrogen ring heteroatoms and 1 oxygen heteroatom or 1 sulfur heteroatom in the ring including, but not limited to, pyrazolyl, furyl, thienyl, oxazolyl, isoxazolyl, tetrazolyl, thiazolyl, isothiazolyl, imidazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrrolyl, thiophenyl, pyrazinyl, pyridazinyl, isooxazolyl, isothiazolyl, triazolyl, furazanyl, quinolyl , isoquinolyl, midazopyridyl, benzimidazolyl, indolyl and the like. As used herein, the term "haloalkyl", as used herein, means an alkyl radical that is substituted with halogen atoms as defined above including, but not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2- groups fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 3-fluoropropyl, 4-fluorobutyl, chloromethyl, trichloromethyl, iodomethyl and bromomethyl and the like. When the compounds of formula (I) contain hydroxy groups, they can form esters. Examples of such esters include esters with a hydroxy group and esters with a carboxy group. The ester moiety can be a conventional protecting group or a protective group which can be cleaved in vivo by a biological method such as hydrolysis. The term "protecting group" means a group that can be cleaved by a chemical process such as hydrogenolysis, hydrolysis, electrolysis or photolysis. The term "treat", as used herein, refers to reversing, alleviating, inhibiting the progress of or preventing the disorder or condition, for which said term applies, or one or more symptoms of said disorder or condition. The term "treatment", as used herein, refers to the act of treating, as "treating" has been defined in the immediately preceding definition. In a preferred aspect (A), the invention provides a compound of formula (I), or a pharmaceutically acceptable ester or salt thereof, wherein R1 and R2 independently represent a hydrogen atom or a fluorine atom. More preferably, R1 and R2 represent a hydrogen atom, or R1 represents a hydrogen atom and R2 represents a fluorine atom and R3, X, Y and n are as defined above. In another preferred aspect (B), the invention provides a compound of formula (I), or a pharmaceutically acceptable ester or salt thereof, wherein R1 and R2 are as defined above, in their broadest aspect or in a preferred aspect , most preferred or most preferred in (A), R3 represents a phenyl group or a heteroaryl group and said heteroaryl group is a 5-6 membered heteroaromatic group containing from 1 to 2 nitrogen heteroatoms or 1 or 2 nitrogen heteroatoms and 1 oxygen atom or 1 sulfur atom; said phenyl group and heteroaryl group are optionally substituted with 1 to 3 groups selected from a halogen atom, a hydroxy group, an alkyl group having from 1 to 3 carbon atoms, an alkyl group having from 1 to 6 carbon atoms interrupted by an oxygen atom, a hydroxyalkyl group having from 1 to 3 carbon atoms, an amino group and an alkylsulfonylamino group having from 1 to 3 carbon atoms. More preferably, R3 represents a phenyl group or a heteroaryl group selected from a pyridyl group, a thiazolyl group, a pyrazolyl group and an oxazolyl group; said phenyl group is optionally substituted with 1 to 3 groups selected from a fluorine atom, a chlorine atom, a hydroxy group, a methyl group, a methoxymethyl group, a hydroxymethyl group, an amino group and methanesulfonylamino. Most preferably, R3 represents a pyridyl group, a thiazolyl group and a pyrazolyl group and X, Y and n are as defined above. In another preferred aspect (C), the invention provides a compound of formula (I), or a pharmaceutically acceptable ester or salt thereof, wherein R1 and R2 are as defined above, in their broadest aspect or in a preferred aspect , more preferred or most preferred in (A), or (B), R3 is as defined above, in the broadest aspect or in a preferred or more preferred aspect in (B), -XY- represents a group of formula -N (R4) C (= O) -, -C (= O) N (R4) -, -N (R4) CH2-, -CH2N (R4) -, -N (R4) SO2-, - SO2N (R4) -, -CH2CH2-, -CH = CH-, -CH (CH2OH) CH2-, -CH2CH (CH2OH) -, -CH2CH (OH) -, -CH (OH) CH2-, -C (R4) (R5) -O- or -OC (R4) (R5) -. More preferably, -X-Y- represents a group of formula -N (CH3) C (= O) -, -CH2O-, -CH (CH3) O-, C (CH3) 2O- or -CH2CH2-. n is as defined above. In another preferred aspect (D), the invention provides a compound of formula (I), or a pharmaceutically acceptable ester or salt thereof, wherein R1 and R2 are as defined above, in their broadest aspect or in one aspect Preferred, most preferred or most preferred in (A), (B) or (C), R3 is as defined above, in the broadest aspect or in a preferred aspect or in a more preferred aspect in (B) or (C), -XY- is as defined above, in its broadest aspect or in a preferred aspect or in a more preferred aspect of (C), n represents an integer 0. Preferred individual groups R1 to R3 and X, Y and n are those defined by the groups R1 to R3 and X, Y and n in the Examples section below.

Particularly preferred compounds of the invention include those in which each variable in Formula (I) is selected from among the preferred groups for each variable. Even more preferable compounds of the invention include those in which each variable in Formula (I) is selected from more preferred or most preferred groups of each variable.

A specific compound according to the invention is selected from the consisting of: 2-benzyl-3- (2,3-dihydro-1 ^ -spiro [inden-1,4, -piperidin trifluoroacetate. ] -1 '-yl) propanoic; 2- (2-Chlorobenzyl) -3- (1α, 3H-spiro [2-benzofuran-1,4'-piperidin] -1'-yl) propanoic acid trifluoroacetate; 2- (5- { [Ferric-butyl (dimethyl) silyl] oxy} -2-fluorobenzyl) -3- (1?, 3 H-spiro [2-benzofuran-1,4'-p] acid trifluoroacetate Peridin] -1 '-yl) propanoic; 2- (2-Chloro-5-hydroxybenzyl) -3- (1?, 3-spiro [2-benzofuran-1,4'-pyrperidin] -1'-yl) propanoic acid; 2- (2-Chlorobenzyl) -3- (1-methyl-2-oxo-1,2-dihydro-1? -spiro [indole-3,4'-piperidine] -1'-I) propanoic acid; 2- (2-Chlorobenzyl) -3- (5-fluoro-1-methyl-1,2-dihydro-1 '/ 7-spiro [indol-S ^' -piperidin-1-i-propanoic acid; (2-fluoro-5-hydroxybenzyl) -3- (1-methyl-2-oxo-1,2-dihydro-1'H-spiroIindol-S ^ '-piperidin-1-i-Opropanoic acid; - (2-chlorobenzyl) -3- (6-fluoro-1α, 3H-spiro [2-benzofuran-1,4'-piperidin] -1'-yl) propanoic acid 2- (2-chloro-5-) hydroxybenzyl) -3- (1-methyl-2-oxo-1,2-dihydro-1'H-espirotindol-S ^ '-piperidin-1-l) propanoic acid trifluoroacetate 2- (5-. . [ert-Butyl (dimethyl] silyl] oxy] -2-fluorobenzyl) -3- (5-fluoro-1-methyl-1,2-dihydro-1 '-espirophenol-S ^' -piperidine) -l '-il) propanoic; 2- (5-. {[[Ferc-butyl (dimethyl [) silyl] oxy} -2-chlorobenzyl) -3- (5-fluoro-1-methyl-1,2-dihydro-1 'acid trifluoroacetate H-spiroIindol-S ^ '-piperidin-J'-yl) propanoic; 2- (2-Chloro-5-hydroxybenzyl) -3- (5-fluoro-1-methyl-2-oxo-1,2-dihydro-1'H-spiro-indol-S ^ '-piperidin-1'-acid il) propanoic; 2- (2-Fluoro-5-hydroxybenzyl) -3- (5-fluoro-1-methyl-2-oxo-1,2-dihydro-1? -spiroIindol-S ^ '-piperidin-1-yl) acid) propanoic; 2- (2-Chloro-5-hydroxybenzyl) -3- (2-hydroxy-2,3-dihydro-1? -spiro [inden-1,4'-piperidin] -1'-yl) propanoic acid; 2- (2-Chloro-5-hydroxybenzyl) -3- (3-methyl-1'H, 3H-spiro [2-benzofuran-1,4'-pperide] -1'-I) acid propanoic; 2- (2-Chloro-5-hydroxy-benzyl) -3- [3- (hydroxymethyl) -2,3-dihydro-1? -spiro [inden-1,4'-p-peridin] -1 '- acid iljpropanoic; 2- (2-Chloro-5-hydroxybenzyl) -3- (3-hydroxy-2,3-dhydro-1? -spiro [inden-1,4'-piperidine] -1'-yl acid propanoic; 2- (2-Chloro-5-hydroxybenzyl) -3- (5-fluoro-1'H, 3 H-spiro [2-benzofuran-1,4'-piperidin] -1'-yl) propanoic acid; 3- (3-Methyl-1?, 3 H-spiro [2-benzofuran-1,4'-piperidin] -1 '-yl) -2- (pyridin-2-ylmethyl) propanoic acid; 3- (3-Methyl-1α, 3H-spiro [2-benzofuran-1,4'-piperidin] -1'-yl) -2- (1,3-thiazol-4-ylmethyl) propanoic acid trifluoroacetate; 3- (3,4-Dihydro-1, / - / - spiro [isocromen-1,4, -piperidin] -1 '-yl) -2- (1,3-thiazol-4-ylmethyl) propanoic acid trifluoroacetate; 3- (5-Fluoro-1-methyl-2-oxo-1,2-dihydro-1'H-spiro [indol-3,4'-p¡peridin] -1'-yl) -2- trifluoroacetate - (1,3-thiazol-4-ylmethyl) propane; 3- (2,3-Dihydro-1? -spiro [inden-1,4'-piperidin] -1'-yl) -2- (1,3-thiazol-4-ylmethyl) propanoic acid trifluoroacetate; 3- (2,3-Dihydro-1'H-spiro [inden-1,4] -piperidine] -1'-yl) -2- (1 H-pyrazol-1-ylmethyl) propanoic acid; 3- (6-Fluoro-3,4-dihydro-1 '/ V-spiro [isocromen-1,4'-piperidin] -1-yl) -2- (1 H -pyrazol-1-ylmethyl) propanoic acid; and 3- (6-Fluoro-3,4-dihydro-1 '- / - spiro [isocromeno-1 ^ -piperidin] -!' - yl) -2- (1,3-thiazole-4) trifluoroacetate -ylmethyl) propanoic; or a pharmaceutically acceptable ester thereof. or a pharmaceutically acceptable salt thereof. General Synthesis: The compounds of formula I of the present invention can be prepared according to known preparation procedures or General Methods illustrated in the following reaction schemes. Unless otherwise indicated from R1 to R6 and X, Y, and n in the reaction schemes and in the analysis that follows, they are defined as defined above. The term "protecting group", as used hereinafter, means a hydroxy or amino protecting group selected from the typical hydroxy or amino protecting groups described in Protective Groups in Organic Synthesis edited by TW Greene et al. . (John Wiley &; Sons, 1999); The following reaction schemes illustrate the preparation of compounds of formula (I). Scheme 1: This scheme illustrates the preparation of compounds of formula (I). Scheme 1 L1 3 Stage 1A 1-1 1-2 1-7 Stage 1H (I) In the above formula, G represents a hydrogen atom or a hydroxy group. Ra represents an alkyl group having 1 to 4 carbon atoms. L1 represents a leaving group. Examples of suitable leaving groups include: halogen atoms, such as chlorine, bromine and iodine; sulphonic esters such as TfO (triflates), MsO (mesylates), TsO (tosylates); and similar. Step 1A In this step, a compound of formula 1-2 in which L1 represents a halogen atom can be prepared by halogenating the compound of formula I-1 in which G represents a hydrogen atom under halogenation conditions with a halogenation reagent in an inert solvent in the reaction. Examples of suitable solvents include: tetrahydrofuran, 1,4-dioxane, / V,? / - dimethylformamide, acetonitrile; alcohols, such as methanol or ethanol; halogenated hydrocarbons, such as dichloromethane, 1,2-dichloroethane, chloroform or carbon tetrachloride and acetic acid. Suitable halogenation reagents include, for example, bromine, chlorine, iodine, N-chlorosuccimide, N-bromosuccimide, 1,3-dibromo-5,5-dimethylhydantoin, bis (dimethylacetamide) hydrogen tribromide, tetrabutylammonium tribromide, bromodimethyl bromide. , hydrogen bromide-hydrogen peroxide, nitrodibromoacetonitrile or copper (II) bromide. The reaction can be carried out at a temperature of 0 ° C to 200 ° C, more preferably 20 ° C to 120 ° C. The reaction times are, in general, from 5 minutes to 48 hours, more preferably from 30 minutes to 24 hours, it will normally be sufficient. The compound of formula 1-2 wherein L 1 represents a halogen atom or a sulfonic ester may also be prepared by halogenating or sulfonating the compound of formula 1-1 wherein G represents a hydroxy group under conditions known to those skilled in the art. . For example, the hydroxy group of the compound of formula 1-1 can be transformed to the halogen atom by using a halogenating agent in the presence or absence of an inert solvent in the reaction. Preferred halogenating agents include: chlorinating agents, such as thionyl chloride, oxalyl chloride, p-toluenesulfonyl chloride, methanesulfonyl chloride, hydrogen chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride or phosphorus reagents such as triphenylphosphine, tributylphosphine or triphenylphosphite in the presence of a halogen source such as carbon tetrachloride, chlorine, N-chlorosuccinimide (NCS); brominating agents, such as hydrogen bromide,? / -bromosuccinimide (NBS), phosphorus tribromide, trimethylsilyl bromide or phosphorus reagents such as triphenylphosphine, tributylphosphine or triphenylphosphite in the presence of a halogen source such as carbon tetrabromide, bromine or NBS; and iodinating agents such as hydroiodic acid, phosphorus triiodide or phosphorus reagents such as triphenylphosphine, tributylphosphine or triphenylphosphite in the presence of a halogen source such as iodine. Examples of suitable solvents include: aliphatic hydrocarbons, such as hexane, heptane and petroleum ether; aromatic hydrocarbons, such as benzene, toluene, o-dichlorobenzene, nitrobenzene, pyridine and xylene; halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; and ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran and 1,4-dioxane. This reaction can be carried out at a temperature in the range of -100 ° C to 250 ° C, more preferably 0 ° C at the reflux temperature for a period of 1 minute to a day, more preferably 20 minutes to 5 hours. As an alternative, the hydroxy group of the compound of formula 1-1 can be converted to the sulfonate group using a sulfonating agent in the presence or absence of a base. Examples of such sulfonation agents include: p-toluenesulfonyl chloride, p-toluenesulfonic anhydride, methanesulfonyl chloride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride or the like in the presence or absence of an inert solvent in the reaction. Examples of such bases include: an alkali metal or alkaline earth metal hydroxide, alkoxide, carbonate, halide or hydride, such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium fer- t-butoxide, sodium carbonate, potassium carbonate, potassium fluoride. , sodium hydride or potassium hydride, or an amine such as triethylamine, tributylamine, diisopropylethylamine, pyridine or dimethylaminopyridine in the presence or absence of an inert solvent in the reaction. Examples of suitable solvents include: aliphatic hydrocarbons, such as hexane, heptane and petroleum ether; aromatic hydrocarbons, such as benzene, toluene, o-dichlorobenzene, nitrobenzene, pyridine and xylene; halogenated hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride and 1,2-dichloroethane; and ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran and 1,4-dioxane; ? /,? / - dimethylformamide, and dimethyl sulfoxide. This reaction can be carried out at a temperature in the range of -50 ° C to 100 ° C, more preferably -10 ° C to 50 ° C for a period of 1 minute to a day, more preferably 20 minutes to 5 hours. Step 1B In this step, a compound of formula 1-4 can be prepared by alkylation of a compound of formula 1-3 with the alkylating agent 1-2 in the presence of a base in a solvent inert in the reaction. Examples of suitable solvents include: tetrahydrofuran,? /,? / - dimethylformamide, dimethyl sulfoxide, diethyl ether, toluene, ethylene glycol dimethyl ether generally or 1,4-dioxane. Examples of suitable bases include: alkylthioes, such as n-butyllithium, sec-butyllithium or fer-butyllithium; arillithiums, such as phenyllithium or lithium naphthylide; metallamides such as sodium amide or lithium diisopropylamide; and alkali metals such as potassium hydride or sodium hydride. This reaction can be carried out at a temperature in the range of -50 ° C to 200 ° C, usually -10 ° C to 100 ° C for a period of 5 minutes to 72 hours, usually 30 minutes to 36 hours. Step 1C In this step, a compound of formula 1-6 can be prepared by aldol condensation of a compound of formula 1-3 with an aldehyde compound 1-5 in the presence of a base in a solvent inert in the reaction. Examples of suitable solvents include: tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide, ether, toluene, ethylene glycol dimethyl ether or 1,4-dioxane. Examples of suitable bases include: lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, cesium carbonate, thallium carbonate (I), sodium ethoxide, potassium fe / c-butoxide , potassium acetate, cesium fluoride, tetrabutylammonium fluoride, tetrabutylammonium chloride, tetrabutylammonium iodide, pyridine, picoline, 4 - (? /,? / - dimethylamino) pyridine, triethylamine, tributylamine, diisopropylethylamine,? / - methylmorphoryn and? / - methylpiperidine. This reaction can be carried out at a temperature in the range of -50 ° C to 250 ° C, usually -10 ° C to 150 ° C for a period of 5 minutes to 72 hours, usually 30 minutes to 24 hours. Step 1D In this step, the compound of formula 1-4 can be prepared by reduction of the olefin compound of formula 1-6 with a reducing agent in an inert solvent. Examples of suitable solvents include: methanol, ethanol, ethyl acetate, tetrahydrofuran (THF) or mixtures thereof. The reduction can be carried out under known hydrogenation conditions in the presence of a metal catalyst, for example nickel catalysts such as Raney nickel, palladium catalysts such as Pd-C, platinum catalysts such as Pt? 2 or ruthenium catalysts such as RuCI2 (Ph3P) 3 in a hydrogen atmosphere or in the presence of hydrogen sources such as hydrazine or formic acid. If desired, the reaction is carried out under acidic conditions, for example in the presence of hydrochloric acid or acetic acid. This reaction can be carried out at a temperature in the range of -50 ° C to 200 ° C, usually -10 ° C to 100 ° C for a period of 5 minutes to 72 hours, usually 30 minutes to 36 hours. Step 1E In this step, a compound of formula 1-7 can be prepared by reaction of Horner-Emmons of the compound of formula 1-4 with formaldehyde or paraformaldehyde in the presence of a base in a solvent inert in the reaction. Examples of suitable solvents include: tetrahydrofuran, / V, / V-dimethylformamide, dimethisulfoxide, diethyl ether, toluene, ethylene glycol dimethyl ether, water or 1,4-dioxane. Examples of suitable bases include: lithium hydroxidesodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, cesium carbonate, thallium carbonate (I), sodium methoxide, sodium ethoxide, potassium urea-butoxide, potassium hydride or sodium hydride. This reaction can be carried out at a temperature in the range of 0 ° C to 200 ° C, usually 50 ° C to 150 ° C for a period of 5 minutes to 72 hours, usually 30 minutes to 50 hours. Step 1 F In this step, a compound of formula 1-10 can be prepared by the Michael reaction of a compound of formula 1-8 with an enone compound of formula 1-9 in the presence of a base in an inert solvent in the reaction . Examples of suitable solvents include: acetonitrile, tetrahydrofuran, / V,? / - d -methylformamide, dimethyl sulfoxide, ether, toluene, ethylene glycol dimethyl ether, water or 1,4-dioxane. Examples of suitable bases include: triethylamine, tributylamine, diisopropylethylamine, pyridine, picoline, N-methylmorforin and? / - methylpiperidine, sodium carbonate, potassium carbonate, sodium bicarbonate, cesium carbonate. This reaction can be carried out at a temperature in the range of 0 ° C to 200 ° C, usually 25 ° C to 100 ° C for a period of 5 minutes to 60 hours, usually 30 minutes to 30 hours. Step 1G In this step, a compound of formula 1-11 can be prepared by alkylation of a compound of formula 1-10 with alkylating agent 1-2 in the presence of a base in a solvent inert in the reaction. Examples of suitable solvents include: tetrahydrofuran, diethyl ether, toluene, generally ethylene glycol dimethyl ether or 1,4-dioxane. Examples of suitable bases include: lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, metallamide such as sodium amide or lithium diisopropylamide.; and alkali metals such as potassium hydride or sodium hydride. If desired, this reaction can be carried out in the presence or absence of an additive such as? /,? / '- dimethylpropyleneurea (DMPU), hexamethylphosphoramide (HMPA), N, N, N', N-tetramethylethylenediamine (TMEDA). This reaction can be carried out at a temperature in the range of -100 ° C to 200 ° C, usually -80 ° C to 100 ° C for a period of 5 minutes to 72 hours, usually 30 minutes to 36 hours. Step 1H In this step, the compound of formula 1-11 can be prepared by the Michael reaction of the compound of formula 1-8 with the enone compound of formula 1-7 in the presence or absence of a base in an inert solvent in the reaction . Examples of suitable solvents include: methanol, ethanol, tetrahydrofuran,? /,? / - dimethymamide, dimethyl suide, diethylether, toluene, ethylene glycol dimethyl ether, water or 1,4-dioxane. Examples of suitable bases include: triethylamine, tributylamine, diisopropylethylamine, pyridine, picoline, / V-methylmorforin and N-methylpiperidine. This reaction can be carried out at a temperature in the range of 0 ° C to 200 ° C, usually 25 ° C to 100 ° C for a period of 1 hour to 2 weeks, usually 5 hours to 10 days. Step 11 In this step, an acid compound of formula 1-12 can be prepared by hydrolysis of the ester compound of formula 1-11 in a solvent. The hydrolysis can be carried out by conventional methods. In a typical procedure, the hydrolysis is carried out under basic conditions, for example, in the presence of sodium hydroxide, potassium hydroxide or lithium hydroxide. Suitable solvents include, for example, alcohols such as methanol, ethanol, propanol, butanol, 2-methoxyethanol and ethylene glycol; ethers such as tetrahydrofuran (THF), 1,2-dimethoxyethane (DME) and 1,4-dioxane; amides such as? /, / V-dimethymamide (DMF) and hexamethylphospholypromide; and suides such as dimethisuide (DMSO). This reaction can be carried out at a temperature in the range of -20 ° C to 100 ° C, usually 20 ° C to 75 ° C for a period of 30 minutes to 48 hours, usually 60 minutes to 30 hours. The hydrolysis can also be carried out under acidic conditions, for example in the presence of hydrogen halides such as hydrogen chloride and hydrogen bromide; suic acids such as p-toluenesuic acid and benzenesuic acid; pyridium p-toluenesuate; and carboxylic acid, such as acetic acid and trifluoroacetic acid. Suitable solvents include, for example, alcohols such as methanol, ethanol, propanol, butanol, 2-methoxyethanol and ethylene glycol; ethers such as tetrahydrofuran (THF), 1,2-dimethoxyethane (DME) and 1,4-dioxane; halogenated hydrocarbons, such as dichloromethane, 1,2-dichloroethane, amides such as? /,? / - dimethymamide (DMF) and hexamethylphospholypromide; and suides such as dimethisuide (DMSO). This reaction can be carried out at a temperature in the range of -20 ° C to 100 ° C, usually 0 ° C to 65 ° C for a period of 30 minutes to 24 hours, usually 60 minutes to 10 hours. Scheme 2 1-8 2-2 2-3 In the previous formula, Ray L1 are as defined above. Step 2A In this step, a compound of formula 2-2 can be prepared by the Michael reaction of the compound of formula 1-8 with an enone compound of formula 2-1. This reaction is essentially the same and can be carried out in the same way and using the same reagents and reaction conditions as in Step 1 H in Scheme 1. Step 2B In this step, the compound of formula 2-3 can be converted into a compound with a leaving group L1 of formula 2-2 under conditions known to those skilled in the art. This reaction is essentially the same and can be carried out in the same way and using the same reagents and reaction conditions as in Step 1A in Scheme 1. Step 2C. In this step, a compound of formula 2-4 can be prepared by replacement of the leaving group of the compound of formula 2-3 with the compound of formula R 3 H in the presence of a base in a solvent inert in the reaction. Examples of suitable solvents include: acetonitrile, tetrahydrofuran, / V,? / - dimethylformamide, dimethisulfoxide, ether, toluene, ethylene glycol dimethyl ether or 1,4-dioxane. Examples of suitable bases include: lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, cesium carbonate, thallium carbonate (I), sodium ethoxide, potassium ferc-butoxide, acetate potassium, cesium fluoride, tetrabutylammonium fluoride, tetrabutylammonium chloride, tetrabutylammonium iodide, pyridine, picoline, 4- (N, N-dimethylamino) pyridine, triethylamine, tributylamine, diisopropylethylamine, N-methylmorphoryn and? / - methylpiperidine. This reaction can be carried out at a temperature in the range of 0 ° C to 250 ° C, usually from -10 ° C to 150 ° C for a period of 5 minutes to 72 hours, usually 30 minutes to 36 hours. Step 2D In this step, a compound of formula (I) can be prepared by hydrolysis of the compound of formula 2-4. This reaction is essentially the same and can be carried out in the same way and using the same reagents and reaction conditions as in Step 11 in Scheme 1.

In the above Schemes 1 to 3, examples of suitable solvents include a mixture of two or more of the any solvents described in each step. The starting materials in the general syntheses mentioned above are commercially available or can be obtained by conventional procedures known to those skilled in the art.

The compounds of formula (I) and the aforementioned intermediate preparation methods can be isolated and purified by conventional procedures, such as recrystallization or chromatographic purification. The various general procedures described above can be useful for the introduction of the desired groups at any step of the step formation of the required compound and it will be appreciated that these general procedures can be combined in different ways in such multi-step procedures. The sequence of the reactions in the multi-step procedures should, of course, be selected so that the reaction conditions used do not affect groups in the molecule that are desired in the final product. Procedure for evaluating biological activities: It has been found that compounds of Formula (I) have an affinity for ORL-1 receptors and antagonistic activity by the ORL-1 receptor. In this way, these compounds are useful as analgesic, antiinflammatory, diuretic, anesthetic, neuroprotective, anti-hypertensive and anti-anxiety agents and the like, in mammalian subjects, especially humans in need of such agents. The affinity, antagonistic activities and analgesic activity can be demonstrated by means of the following tests respectively.

Affinity for ORL1 receptors: ORL1 Receptor Binding Assay: The membranes of HEK-293 cells transfected with the human ORL1 receptor (PerkinElmer) were incubated for 45 minutes at room temperature with [3H] nociceptin 0, 4 nM, 1.0 mg of SPA beads coated with wheat germ agglutinin (WGA) and various concentrations of test compounds in a final volume of 200 μl of 50 mM HEPES buffer pH 7.4 containing 10 mM MgCfe and EDTA 1 mM. The non-specific binding (NSB) was determined by the addition of unlabeled nociceptin 1 μM. After the reaction, the assay plate was centrifuged at 1,000 rpm for 1 min and then the radioactivity was measured by WALLAC 1450 MicroBeta Trilux. Receptor Binding Assay u: The membranes of CHO-K1 cells transfected with the human Mu receptor (PerkinElmer) were incubated for 45 minutes at room temperature with 1.0 nM [3H] DAMGO, 1.0 mg of SPA beads coated with WGA and various concentrations of test compounds in a final volume of 200 μl of 50 mM Tris-HCl pH 7.4 buffer containing 25 mM MgCl. The NSB was determined by the addition of unlabeled DAMGO 1 μM. After the reaction, the assay plate was centrifuged at 1,000 rpm for 1 minute and then the radioactivity was measured by WALLAC 1450 MicroBata Trilux. Each percentage of NSB obtained in this way was plotted as a function of the concentration of the compound. A sigmoidal curve was used to determine the 50% bonds (ie Clso values) - In this test, the preferred compounds prepared in the working examples that appear later in this document showed a higher binding affinity for the receptors. ORL-1 than by the Mu receptors.

CI5o (receptors ORL1) nM / Cl50 (mu receptors) nM < 1.0 Functional Assay of ORL1 Receptor: Membranes of HEK-293 cells transfected with the human ORL1 receptor were incubated with [35 S] GTP? S 400 pM, 10 nM nociceptin and various concentrations of test compounds in assay buffer (HEPES 20 mM, 100 mM NaCl, 25 mM MgCl, 1 mM EDTA, 5 μM GDP, 1 mM DTT, pH 7.4) containing 1.5 mg of SPA beads coated with WGA for 90 minutes at room temperature in a final volume of 200 μl. The basal junction was evaluated in the absence of nociceptin and the NSB was defined by the addition of unlabeled 10 μM GTP? S. The membrane bound radioactivity was detected by a liquid scintillation counter Wallac 1450 MicroBeta. Analgesic Assays: Tail Queue Test in Mice: The latency time to remove the tail of a heat radiation stimulus is recorded before and after the administration of test compounds. Cutting time is set at 8 seconds. Twist Test with Acetic Acid in Mice: 0.7% (v / v) acetic acid saline solution (0.16 ml / 10 g body weight) was injected intraperitoneally into mice. The test compounds are administered before the injection of acetic acid. As soon as acetic acid is injected, the animals are placed in a 1-liter beaker and twist recorded for 15 minutes. Licking Test with Formalin in Mice: licking of the hind paw induced with formalin is initiated by a subcutaneous injection of 20 μl of a formalin solution 2% in a back leg of mice. The test compounds are administered before the formalin injection. The total licking time is recorded for 45 minutes after the formalin injection. Mechanical Hyperalqesia Assay induced with Carrageenan in Rats: The response to the mechanical nociceptive stimulus is measured using an algesiometer (Ugo Basile, Italy). Pressure is placed on the leg until the rats remove the hind leg. Lambda-carrageenan saline solution of 1% (w / v) is injected subcutaneously in the hind paw and the response of the withdrawal is measured before and after the injection. The test compounds are administered in a suitable period of time. Carrageenan-Induced Hyperalgesia Assay in Rats: The response to the term nociceptive stimulus is measured using a plantar test apparatus (Ugo Basile, Italy). The radiant heat stimuli are applied to the leg until the rats remove the hind leg. Lambda-carrageenan saline solution of 2% (w / v) is injected subcutaneously in the hind paw and the response of the withdrawal is measured before and after the injection. This test procedure is described in K. Hargreaves, et al., Pain 32: 77-88, 1988. Chronic Constriction Injury Model (CCI Model): Chronic constriction injury is performed according to Bennett's procedure (Bennett and Xie, Pain 33: 87-107, 1988). Tactile allodynia in rats is evaluated using the von Frey filaments (Stoelting, IL) before and after the administration of test compounds. Partial Ligation Model of the Sciatic Nerve (PSL): This assay can be performed according to similar procedures described by Z. Seitzer, et al. (Pain, 43: 205-218, 1990) (Title: A novel behavioral model of neuropathic pain disorders produced in rats by partial sciatic nerve injury).

Dofetilide Binding Assay: The paste of HEK-293 cells expressing the HERG product can be suspended in a 10-fold volume of 50 mM Tris buffer adjusted to pH 7.5 at 25 ° C with 2 M HCl containing 21 mM MgCl, 10 mM KCl. The cells were homogenized using a Polytron homogenizer (at maximum power for 20 seconds) and centrifuged at 48,000 g for 20 minutes at 4 ° C. The pellet was resuspended, homogenized and centrifuged once more in the same manner. The resulting supernatant was discarded and the final pellet was resuspended (10-fold volume of 50 mM Tris buffer) and homogenized at maximum power for 20 seconds. The membrane homogenate was divided into aliquots and stored at -80 ° C until use. An aliquot was used to determine the protein concentration using a rapid protein assay kit and an ARVO SX plate reader (Wallac). All the manipulation, mother solution and equipment were kept on ice at all times. For the saturation tests, experiments were performed in a total volume of 200 μl. Saturation was determined by incubating 20 μl of [3 H] -dofetilide and 160 μl of membrane homogenates (20-30 μg of protein per well) for 60 minutes at room temperature in the absence or presence of 10 μM dofetilide at final concentrations (20 μl ) for the total or non-specific union, respectively. All incubations were terminated by rapid vacuum filtration on glass fiber filter papers soaked in PEI using a Skatron cell harvester followed by two washes with 50 mM Tris buffer (pH 7.5 at 25 ° C). The receptor-bound radioactivity was quantified by liquid scintillation counting using a Packard LS counter. For the competition assay, the compounds were diluted in 96-well polypropylene plates in the form of 4-point dilutions in a semi-logarithmic format. All dilutions were first made in DMSO and then transferred to 50 mM Tris buffer (pH 7.5 at 25 ° C) containing 1 mM MgCl 2, 10 mM KCl so that the final concentration of DMSO was equal to 1% . The compounds were dispensed in triplicate into assay plates (4 μl). The pockets of total binding and non-specific binding were fixed in 6 wells as vehicle and final concentration of 10 μM dofetilide, respectively. The radioligand was prepared at 5.6 x final concentration and this solution was added to each well (36 μl). The assay was initiated by the addition of SPA beads of poly-L-lysine YSi (50 μl, 1 mg / well) and membranes (110 μl, 20 μg / well). Incubation continued for 60 minutes at room temperature. The plates were incubated for an additional 3 hours at room temperature so that the beads sedimented. The radioactivity bound to the receptor was quantified using a Wallac MicroBeta plate counter. IHFRR assay HEK 293 cells stably expressing the HERG potassium channel were used for an electrophysiological study. The methodology for stable transfection of this channel in HEK cells can be found in other references (Z. Zhou et al., 1998, Biophysical journal, 74, pp. 230-241). Before the day of the experiment, the cells were harvested from the culture flasks and plated on glass coverslips in conventional MEM medium with 10% FCS. Cells grown on plates were stored in an incubator at 37 ° C maintained in an atmosphere of 95% O2 / 5% CO2. The cells were studied between 15-28 hours after collection. HERG currents were studied using conventional "patch clamp" techniques in the whole cell mode. During the experiment the cells were superfused with an external standard solution of the following composition (mM); NaCl, 130; KCl, 4; CaCl2, 2; MgCl2, 1; Glucose, 10; HEPES, 5; pH 7.4 with NaOH. Whole cell logs were made using a voltage clamp amplifier and patch pipettes having a resistance of 1-3 MOhm when filled with the internal standard solution of the following composition (mM); KCl, 130; MgATP, 5; MgCl2, 1.0; HEPES, 10; EGTA, 5, pH 7.2 with KOH. Only cells with access resistance below 15 MO and resistance to closure > 1 GO The compensation of series resistors was applied up to a maximum of 80%. No escape subtraction was made. However, the acceptable access resistance depended on the size of the recorded currents and the level of compensation of series resistors that can be safely used. After achieving the whole cell configuration and sufficient dialysis of the cell with pipette solution (> 5 min), a conventional voltage protocol was applied to the cell to cause membrane currents. The voltage protocol is as follows. The membrane was depolarized from a holding potential of -80 mV to +20 mV for 1000 ms. This was followed by a voltage drop ramp (speed 0.5 mV ms "1) up to the maintenance potential.The voltage protocol was applied to a cell continuously during the experiment every 4 seconds (0.25 Hz) The amplitude of the maximum current induced was measured at approximately -40 mV during the ramp.After stable current responses elicited in the external solution were obtained, vehicle was applied (0.5% DMSO in the standard external solution). for 10-20 minutes by means of a peristaltic pump Whenever there were minimal changes in the amplitude of the current response caused in the vehicle control state, the test compound of 0.3, 1, 3 or 10 μM was applied during A period of 10 minutes The 10 minute period included the time during which the supply solution was passing through the tube from the solution tank to the recording chamber by means of the pump. the cells to the compound solution was greater than 5 minutes after the concentration of the drug in the chamber reached the intended concentration well. There was reversibility. Finally, the cells were exposed to a high dose of dofetilide (5 μM), a specific blocker of IKr, to assess the endogenous insensitive current. All the experiments were carried out at room temperature (23 ± 1 ° C). The evoked membrane currents were recorded in real time in a computer, filtered at 500-1 KHz (Bessel -3dB) and sampled at 1-2 KHz using the voltage clamp amplifier and a specific software for data analysis. The amplitude of the maximum current, which took place around -40 mV, was measured later in the computer. The arithmetic mean of the ten amplitude values was calculated under control conditions and in the presence of drug. The percentage reduction of IN in each experiment was obtained by means of the normalized current value using the following formula: IN = (1 - ID IC) X100, where is the mean value of current in the presence of drug e is the mean value of current under control conditions. Different experiments were performed for each drug concentration or corresponding control with time and the arithmetic mean of each experiment is defined as the result of the study. The pharmaceutically acceptable salts of the compounds of formula (I) include the acid addition salts and bases thereof. Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include acetate salts, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, edisilate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybienate, hydrochloride / chloride, hydrobromide / bromide, iodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate. Suitable basic salts are formed from bases that form non-toxic salts. Examples include the aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. For an analysis of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection and Use" by Stahl and Wermuth, (Wiley-VCH, Weinheim, Germany, 2002). A pharmaceutically acceptable salt of a compound of formula (I) can be prepared easily by mixing together solutions of the compound of formula (I) and the desired base or acid, as appropriate. The salt can be precipitated from a solution and can be collected by filtration or recovered by evaporation of the solvent. The degree of ionization in the salt can vary from completely ionized to almost non-ionized. The compounds of the invention can exist in both solvated and unsolvated forms. The term "solvate" is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term "hydrate" is used when said solvent is water.

Included within the scope of the invention are complexes such as clathrates, drug-host inclusion complexes in which, unlike the solvates mentioned above, the drug and the host are present in stoichiometric or non-stoichiometric amounts. Also included are complexes of drugs that contain two or more organic and / or inorganic components that may be in stoichiometric or non-stoichiometric amounts. The resulting complexes can be ionized, partially ionized or non-ionized. For an analysis of such complexes see J Pharm Sci, 64 (8), 1269-1288 of Haleblian (August 1975). In the following, all references to compounds of formula (I) include references to salts, solvates and complexes thereof and to solvates and salt complexes thereof. The compounds of this invention include compounds of formula (I) as defined hereinbefore, polymorphs, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as defined hereinafter and isotopically-labeled compounds of formula (I). As indicated, the invention includes all polymorphs of the compounds of formula (I) as defined hereinabove. The so-called "prodrugs" of the compounds of formula (I) are also within the scope of the invention. In this way, certain derivatives of compounds of formula (I) which may have little or no pharmacological activity per se may, when administered in or on the body, be converted to compounds of formula (I) having the desired activity, example, by hydrolytic cleavage. Such derivatives are referred to as "prodrugs". Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and in "Bioreversible Carriers in Drug Design ", Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association). Prodrugs according to the invention can be produced, for example, by replacing appropriate functionalities present in the compounds of formula (I) with certain residues known to those skilled in the art as "pro-residues" as described, for example, in "Design of Prodrugs "by H Bundgaard (Elsevier, 1985) Some examples of prodrugs according to the invention include: (i) when the compound of formula (I) contains a carboxylic acid functionality (-COOH), an ester thereof, for example, replacement of the hydrogen with alkyl (Ci-Cs) (ii) when the compound of formula (I) contains an alcohol functionality (-OH), an ether thereof, for example, replacement of the hydrogen with alkanoyloxymethyl (Ct- Cß), and (ii) when the compound of formula (I) contains a primary or secondary amino functionality (-NH2 or -NHR where R? H), an amide thereof, for example, replacement of one or both hydrogens with alkanoyl (CIC-IO) In the references mentioned above, other examples of replacement groups can be found according to the above examples and examples of other types of prodrugs Finally, certain compounds of formula (I) can act on their own as prof macos of other compounds of formula (I).

The term "ester" or "amide" means a protecting group that can be cleaved in vivo by a biological process such as hydrolysis and forms a free acid or a free amine or salt thereof. It can be determined whether a compound is such a derivative or not by administering it by intravenous injection to an experimental animal, such as a rat or a mouse and then studying the body fluids of the animal to determine whether the compound or a pharmaceutically acceptable salt thereof can detected or not. Preferred examples of groups for forming an ester with a hydroxy group and for forming an amide with an amino group include: (1) aliphatic alkanoyl groups, for example: alkanoyl groups such as the formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl, decanoyl, 3-methylnonanoyl, 8-methylnonanoyl, 3-ethyl-octanoyl, 3,7- dimethyloctanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, 1-methylpentadecanoyl, 14-methylpentadecanoyl, 13,13-dimethyltetradecanoyl, heptadecanoyl, 15-methylhexadecanoyl, octadecanoyl, 1-methylheptadecanoyl, nonadecanoyl, cosanoyl and henicosanoyl; halogenated alkylcarbonyl groups such as the chloroacetyl, dichloroacetyl, trichloroacetyl and trifluoroacetyl groups; alkoxyalkanoyl groups such as the methoxyacetyl group; and unsaturated alkanoyl groups such as the acryloyl, propioloyl, methacryloyl, crotonoyl, isocrotonoyl, and (£) -2-methyl-2-buteneyl groups; (2) aromatic alkanoyl groups, for example: arylcarbonyl groups such as the benzoyl, α-naphthoyl and β-naphthoyl groups; halogenated arylcarbonyl groups such as the 2-bromobenzoyl and 4-chlorobenzoyl groups; alkylated arylcarbonyl groups such as the 2,4,6-trimethylbenzoyl groups and 4-toluoyl groups; alkoxylated arylcarbonyl groups such as the 4-anisoyl group; nitro-arylcarbonyl groups such as the 4-nitrobenzoyl and 2-nitrobenzoyl groups; arylcarbonyl alkoxycarbonyl groups such as the 2- (methoxycarbonyl) benzoyl group; and arylated arylcarbonyl groups such as the 4-phenylbenzoyl group; (3) alkoxycarbonyl groups, for example: alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, sec-butoxycarbonyl, l-butoxycarbonyl and isobutoxycarbonyl groups; and halogen- or tri (alkyl) silyl substituted alkoxycarbonyl groups such as the 2,2,2-trichloroethoxycarbonyl and 2-trimethylsilylethoxycarbonyl groups; tetrahydropyranyl or tetrahydrothiopyranyl groups such as: tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl, and 4-methoxytetrahydrothiopyran-4-yl; tetrahydrofuranyl or tetrahydrothiofuranyl groups such as: tetrahydrofuran-2-yl and tetrahydrothiophen-2-yl; (5) silyl groups, for example: tri (alkyl) silyl groups such as the trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, f-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl and triisopropylsilyl groups; and silyl groups substituted with one or more aryl and alkyl groups such as the diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl and phenyldiisopropylsilyl groups; (6) alkoxymethyl groups, for example: alkoxymethyl groups such as methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl and f-butoxymethyl groups; alkoxylated alkoxymethyl groups such as the 2-methoxyethoxymethyl group; and halo (alkoxy) methyl groups such as the 2,2,2-trichloroethoxymethyl and bis (2-chloroethoxy) methyl groups; (7) substituted ethyl groups, for example: alkoxylated ethyl group such as the 1-ethoxyethyl and 1- (isopropoxy) ethyl groups; and halogenated ethyl group such as 2,2,2-trichloroethyl groups; (8) aralkyl groups, for example: alkyl groups substituted with 1 to 3 aryl groups such as benzyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl and 9-anthrylmethyl groups; alkyl groups substituted with 1 to 3 substituted aryl groups, wherein one or more of the aryl groups is substituted with one or more alkyl, alkoxy, nitro, halogen or cyano substituents such as the 4-methylbenzyl, 2,4,6-trimethylbenzyl groups , 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl and 4-cyanobenzyl; alkenyloxycarbonyl groups such as the vinyloxycarbonyl group; aryloxycarbonyl groups such as phenoxycarbonyl; and aralkyloxycarbonyl groups wherein the aryl ring may be substituted with 1 or 2 alkoxy or nitro groups such as benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl. The compounds of formula (I) containing one or more asymmetric carbon atoms can exist in the form of two or more stereoisomers. When a compound of formula (I) contains an alkenyl or alkenylene group, cis / trans (or Z / E) geometric isomers are possible. When the compound contains, for example, a keto or oxime group, or an aromatic moiety, tautomeric isomerism ("tautomerism") can be produced. From this it must be understood that a single compound can show more a type of isomerism. Included within the scope of this invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of formula (I), including compounds that show more than one type of isomerism and mixtures of one or more thereof. Also included are acid addition salts and bases wherein the counter ion is optically active, for example, D-lactate or L-lysine, or racemic, for example, DL-tartrate or DL-arginine.

The cis / trans isomers can be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include the chiral synthesis of a suitable optically pure precursor or the resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography.

(HPLC). Alternatively, the racemate (or a racemic precursor) can be reacted with a suitable optically active compound, for example, an alcohol or, in the case where the compound of formula (I) contains an acid or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine. The resulting diastereomeric mixture can be separated by chromatography and / or fractional crystallization and one or both diastereoisomers can be converted to the corresponding pure enantiomer (s) by means well known to one skilled in the art. The chiral compounds of the invention (and chiral precursors thereof) can be obtained in enantiomerically enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing 0 to 50% isopropanol, typically 2 to 20% and 0 to 5% of an alkylamine, typically 0.1% diethylamine. The concentration of the eluate provides the enriched mixture. Stereoisomeric conglomerates can be separated by conventional techniques known to those skilled in the art - see, for example, "Stereochemistry of Organic Compounds" by E L Eliel (Wiley, New York, 1994).

The present invention includes all isotopically pharmaceutically acceptable labeled compounds of formula (I) wherein one or more atoms are replaced by atoms having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number that is normally found In nature. Examples of suitable isotopes for inclusion in the compounds of the invention include hydrogen isotopes such as 2H and 3H, carbon, such as 11C, 13C and 14C, chloro, such as 36CI, fluorine, such as 18F, iodine, such as 123l and 125l, nitrogen, such as 13N and 15N, oxygen, such as 15O, 17O and 18O, phosphorus, such as 32P, and sulfur, such as 35S. Certain isotopically-labeled compounds of formula (I), for example, those incorporating radioactive isotopes are useful in studies of tissue distribution of drug and / or substrate. The radioactive isotopes titrio, ie 3H and carbon-14, that is, 14C, are particularly useful for this purpose in view of their easy incorporation and easy means of detection. Substitution with heavier isotopes such as deuterium, that is, 2H, can provide certain therapeutic benefits resulting from increased metabolic stability, for example, increase in half-life in vivo or reduction of dosage requirements and, therefore, may be preferred in some circumstances. Substitution with positron emitting isotopes, such as 11C, 18F, 15O, and 13N, may be useful in Positron Emission Topography (PET) studies to examine receptor occupancy in the substrate. The isotopically-labeled compounds of formula (I) can be prepared generally by conventional techniques known to those skilled in the art or by methods analogous to those described in the appended Examples and Preparations using appropriate isotopically labeled reagents in place of the unlabeled reagent employed above. The pharmaceutically acceptable solvates according to the invention include those in which the crystallization solvent can be substituted isotopically, for example, D2O, d6-acetone, d6-DMSO. The compounds of the invention directed to pharmaceutical use can be administered in the form of crystalline or amorphous products. They can be obtained, for example, in the form of short solid beds, powders or films by processes such as precipitation, crystallization, lyophilization, spray drying or evaporative drying. Microwave or radiofrequency drying can be used for this purpose. They can be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or in the form of any combination thereof). Generally, they will be administered in formulation form in conjunction with one or more pharmaceutically acceptable excipients. The term "excipient" is used herein to describe any ingredient other than the compound or compounds of the invention. The choice of excipient will depend to a large extent on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. The compounds of the invention can be administered in combination, separately, simultaneously or sequentially with one or more other pharmacologically active agents. Suitable agents, particularly for the treatment of pain, include: (i) opioid analgesics, for example morphine, heroin, hydromorphone, oxymorphone, levorphanol, levalorfan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene , nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine and pentazocine; (ii) non-steroidal anti-inflammatory drugs (NSAIDs), for example aspirin, diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxaprozin, phenylbutazone , piroxicam, sulindac, tolmetin, zomepirac and their pharmaceutically acceptable salts; (iii) barbiturate sedatives, for example amobarbital, aprobarbital, butabarbital, butabital, mephobarbital, metharbital, methohexital, pentobarbital, phenobarbital, secobarbital, talbutal, teamilal, thiopental and their pharmaceutically acceptable salts; (iv) benzodiazepines having a sedative action, for example chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam, triazolam and their pharmaceutically acceptable salts, (v) Hi antagonists having sedative action, for example diphenhydramine, pyrilamine, promethazine, chlorpheniramine, chlorcyclizine and their pharmaceutically acceptable salts; (vi) miscellaneous sedatives such as glutethimide, meprobamate, methaqualone, dicloralfepazone and their pharmaceutically acceptable salts; (vii) musculoskeletal relaxants, for example baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol, orfrenadine and their pharmaceutically acceptable salts, (viii) alpha-2-delta ligands, for example, gabapentin and pregabalin; (ix) alpha-adrenergic active compounds, for example doxazosin, tamsulosin, clonidine and 4-amino-6,7-dimethoxy-2- (5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl) -5 - (2-pyridyl) quinazoline; (x) tricyclic antidepressants, for example desipramine, imipramine, amitriptyline and nortriptyline; (xi) anticonvulsants, for example carbamazepine and valproate; (xii) serotonin reuptake inhibitors, for example fluoxetine, paroxetine, citalopram and sertraline; (xiii) mixed serotonin-noradrenaline reuptake inhibitors, for example milnacipran, venlafaxine and duloxetine; (xiv) noradrenaline reuptake inhibitors, for example reboxetine; (xv) tachykinin (NK) antagonists, particularly NK-3, NK-2 and NK-1 antagonists, for example (R, 9R) -7- [3,5-bs (trifluoromethyl) benzyl] -8,9,10,11-tetrahydro-9-methyl-5- (4-methylphenyl) -7H- [1,4] diazocino [2,1-g] [1,7] naphthyridine -6,13-dione (TAK-637), 5 - [[(2f?, 3S) -2 - [(íf?) - 1- [3,5-bis (trifluoromethyl) phenyl] ethoxy-3 (4-fluorophenyl) -4-morpholinyl] methyl] -1,2-dihydro-3H-1,2,4-triazol-3-one (MK-869), lanepitant, dapitant and 3 - [[2-methoxy] 5- (trifluoromethoxy) phenyl] methylamino] -2-phenylpiperidine (2S, 3S) (xvi) muscarinic antagonists, for example oxybutin, tolterodine, propiverine, tropsium chloride and darifenacin; (xvii) COX-2 inhibitors, for example celecoxib, rofecoxib and valdecoxib; (xviii) non-selective COX inhibitors (preferably with Gl protection), for example nitroflurbiprofen (HCT-1026); (xix) analgesics of coal tar, in particular, paracetamol; (xx) neuroleptics, such as droperidol; (xxi) vanilloid receptor agonists, for example resinferatoxin; (xxii) beta-adrenergic compounds such as propranolol; (xxiii) local anesthetics such as mexiletine; (xxiv) corticosteroids, such as dexamethasone (xxv) agonists and serotonin receptor antagonists; (xxvi) cholinergic (nicotinic) analgesics; and (xxvii) miscellaneous analgesic agents such as Tramadol®; (xxviii) NMDA receptor antagonists, for example dextromethorphan ((+) - 3-hydroxy- / V-methylmorfinan) and its metabolite dextrorphan ((+) - 3-hydroxy -? / - methylmorphinan), ketamine, memantine, pyrroloquinoline quinone and c / s-4- (phosphonomethyl) -2-piperidinecarboxylic acid and its pharmaceutically acceptable salts; (xxix) EP4 receptor agonists and antagonists of prostaglandin (xxx) PDEV inhibitors, such as sildenafil, vardenafil or taladafilo; Thus, the invention further provides a combination comprising a compound of the invention or a pharmaceutically acceptable salt, solvate or prodrug thereof and a compound or class of compounds selected from the group (i) - (xxx) above. Also provided is a pharmaceutical composition comprising such combination, together with a pharmaceutically acceptable excipient, diluent or carrier, particularly for the treatment of a disease in which an ORL1 antagonist is involved.

Pharmaceutical compositions suitable for the administration of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in "Remington's Pharmaceutical Sciences", 19th Edition (Mack Publishing Company, 1995). ORAL ADMINISTRATION The compounds of the invention can be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract or buccal or sublingual administration may be employed, whereby the compound enters directly into the bloodstream from the mouth. Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particles, liquids or powders, dragees (including liquid-filled ones), chewing gums, multi- and nano-particles, gels, solid solution, liposomes, films (including muco-adhesives), ovules, sprays and liquid formulations. Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in hard or soft capsules and typically comprise a carrier, for example water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or a suitable oil and one or more emulsifying agents and / or suspending agents. Liquid formulations can also be prepared by reconstituting a solid, for example, from a seal. The compounds of the invention can also be used in rapid dissolution and disintegration dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986 by Liang and Chen (2001). For dosage forms in tablets, depending on the dose, the drug can be from 1% by weight to 80% by weight of the dosage form, more typically from 5% by weight to 60% by weight of the dosage form. In addition to the drug, the tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, hydroxypropylcellulose substituted with lower alkyl, starch, pregelatinized starch and sodium alginate. Generally, the disintegrant will comprise from 1% by weight to 25% by weight, preferably from 5% by weight to 20% by weight of the dosage form. Binders are generally used to impart cohesion qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropylcellulose and hydroxypropylmethylcellulose. The tablets may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate. The tablets may also optionally comprise surfactants such as sodium lauryl sulfate and polysorbate 80 and glidants such as silicon dioxide and talc. When present, the surfactants may comprise from 0.2 wt% to 5 wt% of the tablet and the glidants may comprise from 0.2 wt% to 1 wt% of the tablet. The tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate and mixtures of magnesium stearate with sodium lauryl sulfate.

The lubricants generally comprise from 0.25% by weight to 10% by weight, preferably from 0.5% by weight to 3% by weight of the tablet. Other possible ingredients include anti-oxidants, colorants, flavoring agents, preservatives and taste masking agents. Exemplary tablets contain up to about 80% drug, from about 10% by weight to about 90% by weight binder, from about 0% by weight to about 85% by weight of diluent, about 2% by weight. % by weight to about 10% by weight of disintegrant and from about 0.25% by weight to about 10% by weight of lubricant. Tablet blends can be compressed directly or with a roller to form tablets. Blends of tablets or portions of mixtures may alternatively be wet granulated, dry or melt, freeze in the molten state, or extruded prior to tablet formation. The final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated. Tablet formulation is discussed in "Pharmaceutical Dosage Forms: Tablets, Vol. 1", by H. Lieberman and L. Lachman, Marcel Dekker, N.Y., N.Y., 1980 (ISBN 0-8247-6918-X).

Solid formulations for oral administration can be formulated to be immediate and / or modified controlled release. Modified release formulations include delayed, sustained, pulsed, controlled, directed and programmed release. Modified release formulations suitable for the purposes of the invention are described in U.S. Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are found in Verma et al., Pharmaceutical Technology On-line, 25 (2), 1-14 (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298. PARENTERAL ADMINISTRATION The compounds of the invention can also be administered directly into the blood stream, into the muscle or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Devices suitable for parenteral administration include needle injectors (including microneedles), needleless injectors, and infusion techniques. Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably at a pH of 3 to 9) but, for some applications, may be formulated more appropriately as a non-aqueous sterile solution or in the form of dry powder to use together with a suitable vehicle such as sterile pyrogen-free water. The preparation of parenteral formulations under sterile conditions, for example, by lyophilization, can be carried out easily using conventional pharmaceutical techniques well known to those skilled in the art. The solubility of compounds of formula (I) used in the preparation of parenteral solutions can be increased by the use of appropriate formulation techniques such as, the incorporation of agents that improve solubility. Formulations for use with administration by needleless injection comprise a compound of the invention in powder form together with a suitable vehicle such as sterile, pyrogen-free water. Formulations for parenteral administration can be formulated to be immediate and / or modified controlled release. Modified release formulations include delayed, sustained, pulsed, controlled, directed and programmed release. In this way, the compounds of the invention can be formulated as a solid, semi-solid or thixotropic liquid for administration in the form of an implanted reservoir that provides modified release of the active compound. Examples of such formulations include drug-coated stents and PGLA microspheres. TOPICAL ADMINISTRATION The compounds of the invention can also be administered topically to the skin or mucosa., this is by dermal or transdermal route. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, fine powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes can also be used. Typical vehicles include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated - see, for example, J Pharm Sci, 88 (10) 955-958 by Finnin and Morgan (October 1999). Other means of topical administration include administration by electroporation, iontophoresis, phonophoresis, sonophoresis, and microneedle or needle-free injection (e.g., PowderJect ™, Bioject ™, etc.). Formulations for topical administration can be formulated to be immediate and / or modified controlled release. Modified release formulations include delayed, sustained, pulsed, controlled, directed and programmed release. INHALED / INTRANASAL ADMINISTRATION The compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (alone or as a mixture, for example, in a dry mixture with lactose or in the form of a mixed component particle, for example , mixed with phospholipids such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, sprayer, atomizer (preferably an atomizer that uses electrohydrodynamics to produce a fine mist) or nebulizer, with or without the use of a suitable propellant such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example chitosan or cyclodextrin. The pressurized container, pump, spray, atomizer or nebulizer contains a solution or suspension of the compound or compounds of the invention comprising, for example, ethanol, aqueous ethanol or an alternative agent suitable for dispersion, solubilization or extension of the release of the active agent, a propellant (s) as solvent and an optional surfactant such as sorbitan trioleate, oleic acid or an oligolactic acid. Before use in a dry powder or suspension formulation, the drug product is micronized to a size suitable for administration by inhalation (typically less than 5 microns). This can be achieved by any suitable grinding process such as spiral jet grinding, fluid bed jet grinding, supercritical fluid processing to form nanoparticles, high pressure homogenization or spray drying. Capsules (made, for example, with gelatin or HPMC), blisters and cartridges for use in an inhaler or insufflator can be formulated to contain a powder mixture of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as / -leucine, mannitol or magnesium stearate. The lactose may be anhydrous or in the monohydrate form, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose. A solution formulation suitable for use in an atomizer that uses electrohydrodynamics to produce a fine mist may contain from 1 μg to 20 mg of the compound of the invention per actuation and the actuation volume may vary from 1 μl to 100 μl. A typical formulation may comprise a compound of formula (I), propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents that can be used in place of propylene glycol include glycerol and polyethylene glycol. Suitable flavors such as menthol and levomenthol or sweeteners such as saccharin or sodium saccharin can be added to the formulations of the invention intended for inhaled / intranasal administration.

Formulations for inhaled / intranasal administration can be formulated to be immediate and / or modified controlled release using, for example, poly (DL-lactic-coglycolic acid) (PGLA). Modified release formulations include delayed, sustained, pulsed, controlled, directed and programmed release. In the case of inhalers and dry powder aerosols, the dosage unit is determined by means of a valve that delivers a measured quantity. The units according to the invention are typically arranged to deliver a metered dose or "puff containing from 1 μg to 10 mg of the compound of formula (I)." The total daily dose will typically be in the range of 1 μg to 10 mg it can be administered in a single dose or, more usually, in divided doses throughout the day.RECTAL / INTRAVAGINAL ADMINISTRATION The compounds of the invention can be administered rectally or vaginally, for example, in the form of a suppository, pessary or enema. Cocoa butter is a traditional suppository base but various alternatives can be used as appropriate Formulations for rectal / vaginal administration can be formulated to be immediate and / or modified controlled release Modified release formulations include delayed, sustained release, in pulses, controlled, directed and programmed EYE / AURAL ADMINISTRATION The compounds of the invention can also administ directly in the eye or ear, typically in the form of drops of a suspension or micronized solution in sterile isotonic saline with adjusted pH. Other formulations suitable for ocular and aural administration include ointments, biodegradable (e.g. sponges with absorbable gels, collagen) and non-biodegradable (e.g., silicone) implants, wafers, lenses and particulate or vesicle systems such as niosomes or liposomes. A polymer such as crosslinked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose or methylcellulose or a heteropolysaccharide polymer, for example, gellan gum, can be incorporated together with a preservative such as benzalkonium chloride. Such formulations can also be administered by iontophoresis. Formulations for ocular / aural administration can be formulated to be immediate and / or modified controlled release. Modified release formulations include delayed, sustained, pulsed, controlled, directed or programmed release. OTHER TECHNOLOGIES The compounds of the invention may be combined with soluble macromolecular entities such as cyclodextrin and suitable derivatives thereof or polymers containing polyethylene glycol to improve their solubility, dissolution rate, taste masking, bioavailability and / or stability for use in any of the modes of administration mentioned above. It is discovered that drug-cyclodextrin complexes, for example, are generally useful for most dosage forms and routes of administration. Both inclusion and non-inclusion complexes can be used. As an alternative to direct complexation with the drug, the cyclodextrin can be used as an auxiliary additive, that is, as a carrier, diluent or solubilizer. The most commonly used for these purposes are alpha, beta and gamma cyclodextrins, examples of which can be found in International Patent Applications No. WO 91/11172, WO 94/02518 and WO 98/55148. PARTS KIT While it is desirable to administer a combination of active compounds, for example, for the purpose of treating a particular disease or condition, it is within the scope of the invention that two or more pharmaceutical compositions can be conveniently combined, at least one of which contains a compound according to the invention, in the form of a kit suitable for the co-administration of the compositions. Thus, the kit of the invention comprises two or more different pharmaceutical compositions, at least one of which contains a compound of formula (I) according to the invention and means for separately storing said compositions, such as a container, divided bottle or divided aluminum container. An example of such a kit is the known blister-type container used for the packaging of tablets, capsules and the like. The kit of the invention is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the different compositions in different dosage ranges or for evaluating the different compositions from each other. To encourage acceptance, the kit typically comprises instructions for administration and can be provided with a so-called reminder system. DOSAGE For administration to human patients, the total daily dose of the compounds of the invention is typically in the range of 0.1 mg to 3000 mg, preferably 1 mg to 500 mg, depending, of course, on the mode of administration. administration. For example, oral administration may require a total daily dose of 0.1 mg to 3000 mg, preferably 1 mg to 500 mg, while an intravenous dose may require only 0.1 mg to 1000 mg, preferably 0, 1 mg to 300 mg. The total daily dose can be administered in a single dose or in divided doses. These dosages are based on an average human subject with a weight of approximately 65 kg to 70 kg. The doctor can easily determine the doses for subjects whose weight falls outside this range, such as children and the elderly. For the avoidance of doubt, the references in this document to "treatment" include references to curative, palliative and prophylactic treatment. EXAMPLES The invention is illustrated by the following non-limiting examples in which, unless otherwise indicated: all operations were performed at room temperature, i.e. in the range of 18-25 ° C; the evaporation of the solvent was carried out using a rotovapor under reduced pressure with a bath at a temperature of up to 60 ° C; the reactions were monitored by thin layer chromatography (TLC); the given melting points (pf) are not corrected (the polymorphism can give rise to different melting points); The structure and purity of all the isolated compounds were checked by at least one of the following techniques: TLC (pre-coated TLC plates with Merck 60 F254 silica gel or TLC plates pre-coated with Merck NH2 gel (a silica coated with amine) F254s), mass spectrometry, nuclear magnetic resonance spectrum (NMR), infrared absorption (IR) spectra. The returns are given for illustrative purposes only. The treatment with a cation exchange column was performed using an SCX cartridge (Varian BondElute) which was previously conditioned with methanol. Flash column chromatography was performed using Merck 60 silica gel (63-200 μm), Wako 300HG silica gel (40-60 μm), NH Fuji Silysia gel (silica gel coated with amine) (30-50 μm). ), Biotage KP-SIL (32-63 μm) or Biotage AMINOSILICA (a silica gel coated with amine) (40-75 μm). Preparative TLC was performed using TLC plates precoated with Merck 60 F254 silica gel (0.5 or 1.0 mm thickness). The low resolution mass spectrum (IE) data were obtained in an Integrity mass spectrometer (Waters). The low resolution mass spectrum data (I EN) were obtained in a ZMD mass spectrometer (Micromass). The NMR data were determined at 270 MHz (JEOL JNM-LA 270 spectrometer) or 300 MHz (JEOL JNM-LA 300 spectrometer) or 600 MHz (Bruker AVANCE 600 spectrometer) using deuterated chloroform (99.8% D) or dimethylsulfoxide ( 99.9% D) as solvent unless otherwise indicated, in relation to tetramethylsilane (TMS) as an internal standard in parts per million (ppm); The conventional abbreviations used are: s = singlet, d = doublet, t = triplet, c = quadruplet, quint = quintuplet, m = multiplet, a = width, etc. The IR spectra were measured with a Shimazu infrared spectrometer (IR-470). Chemical symbols have their usual meanings; I (liter (s)), ml (milliliter (s)), g (gram (s)), mg (milligram (s)), mol (moles), mmol (millimoles), eq. (equivalent (s)), quant. (quantitative performance). EXAMPLE 1 2-Benzyl-3- (2,3-dihydro-1? -espirofinden-1,4'-piperidin-1 '-Q-propanoic acid trifluoroacetate STAGE 1. 3- (2,3-Dihydro-1? -espyrorinden-1,4'-piperidin-1-l) fer-butyl propanoate A solution of 2,3-dihydrospiro [inden-1] , 4'-piperidine] (3.0 g, 13 mmol), fer-butyl acrylate (3.1 g, 24 mmol) and triethylamine (4.5 mL, 32 mmol) in tetrahydrofuran (60 mL) was stirred at room temperature. 70 ° C in a nitrogen atmosphere for 1 day. The organic phase was washed with an aqueous solution of saturated sodium bicarbonate (100 ml). The aqueous phase was extracted with ethyl acetate (150 ml x 2). The combined organic phases were washed with brine (50 ml), dried over sodium sulfate, and evaporated. The residue was purified by column chromatography on silica gel eluting with hexane / acetone (4/1) to yield 2.8 g (66%) of the title compound as a yellow oil: 1 H-NMR (CDCl 3) d 7 , 19-7.12 (4H, m), 2.92-2.85 (4H, m), 2.74-2.69 (2H, m), 2.50-2.45 (2H,), 2.26-2.17 (2H, m), 2.02-1.87 (4H, m), 1.76-1.67 (1H, m), 1.56-1.52 (1H, m), 1, 46 (9H, s). STEP 2. 2-Benzyl-3- (2,3-dihydro-1'H-spirounden-1,4'-piperidin-1-ferro-butyl dpropanoate To a stirred solution of S ^ .S-dihydro-I ? -spirofinden-l ^ '- piperidin] -1'-yl) propane-butyl ester (step 1, 200 mg, 0.63 mmol) in tetrahydrofuran (2 ml) was added dropwise a 1.0 solution M of lithium bis (trimethylsilyl) amide in tetrahydrofuran (0.76 ml, 0.76 mmol) at -78 ° C and the mixture was stirred for 30 minutes at the same temperature. To the mixture was added 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone (92 μl, 0.76 mmol) at -78 ° C and stirred for 30 minutes at room temperature. same temperature. To the resulting mixture was added benzyl bromide (130 mg, 0.76 mmol) and the reaction mixture was stirred at the same temperature for 1 hour and then at 0 ° C for 1 hour. The reaction mixture is quenched by the addition of an aqueous solution of saturated ammonium chloride. The mixture was extracted with ethyl acetate (20 ml x 3) and then the combined organic phases were washed with brine (50 ml), dried over sodium sulfate, and evaporated. The residue was purified by column chromatography on silica gel eluting with hexane / ethyl acetate (8/1) to yield 88 mg (34%) of the title compound as a colorless oil: 1 H-NMR (CDCl 3) d 7 , 30-7.11 (9H, m), 2.93-2.66 (8H, m), 2.48-2.41 (1H, m), 2.28-2.10 (2H, m) , 2.04-1.82 (4H, m), 1.53-1.39 (2H, m), 1.36 (9H, s). STAGE 3. 2-Benzyl-3- (2,3-dihydro-1'H-espirofinden-1,4'-pperidin-1'-dihydro-1-d-propanoic acid trifluoroacetate To a stirred solution of 2-benzyl-3- (2,3- Ferric-butyl dihydro-1? -spiro [nden-1,4'-piperidin] -1'-yl) propanoate (step 2, 88 mg, 0.22 mmol) in dichloromethane (1 ml) was added with acid trifluoroacetic (1 ml) and stirred at room temperature for 2 hours.The reaction mixture was evaporated to dryness yielding 181 mg (quant.) of the title compound as a yellow oil: 1 H-NMR (CDCl 3) d 8, 22 (1H, sa), 7.43-7.04 (9H, m), 3.75-3.25 (5H, m), 3.11-2.74 (6H, m), 2.32- 2.13 (2H, m), 2.02-1.97 (2H, m), 1.76-1.71 (2H, m) EXAMPLE 2 2-Benzyl-3- (1?) Acid trifluoroacetate. 3H-SpiroF2-benzofuran-1,4'-piperidin-1'-diDPAenoic STEP 1. 2-Benzyl-3- (1 '/7.3rt-spiro-2-benzofuran-1, 4'-pi? Eridin-1'-di-tert-butyl-d-propanoate The title compound was prepared according to the procedure described in US Pat. step 2 of Example 1 from 3- (1'H, 3H-spiro [2-benzofuran-1'-piperidin-J-1-di-d-propane-fer-butyl and benzyl bromide: 1H-NMR (CDCl3) d) 7.32-7.08 (9H, m), 5.06 (2H, s), 2.96-2.69 (6H, m), 2.55-2.31 (3H, m), 2, 00-1, 84 (2H, m), 1, 80-1, 68 (2H, m), 1, 35 (9H, s); MS (ESI) 408 (M + H) +. STAGE 2. Trifluoroacetate 2-Benzyl-3- (1? .3H-Spiroyl-2-benzofuran-1,4'-piperidin-1'-di-propane) acid The title compound was prepared according to the procedure described in step 3 of example 1 from 2-Benzyl-3- (1 '/ - /, 3 H-spiro [2-benzofuran-1,4'-piperidin] -1'-yl) propane-butyl stearate (step 1): 1 H-NMR (CDCl 3) d 7.35-7.10 (9H, m), 5.04 (2H, s), 3.70-2.69 (9H, m), 2.50-2.30 (2H, m), 1 90-1.80 (2H, m); MS (ESI) 352 (M + H) +, 350 (M-H). 'EXAMPLE 3 Acid trifluoroacetate or 2- (3-methoxybenzyd-3- (1?, 3 H-spiro-2-benzofuran-1, 4'-piperidn) -1'-Dpropanoic STEP 1. 2- (3-Methoxybenzid-3- (1?, 3 H-spiro-2-benzofuran-1,4'-piperidin-1'-di-tert-butyl dicarboxy) The title compound was prepared according to the procedure described in step 2 of Example 1 from 3- (1'H, 3H-spiro [2-benzofuran-1,4'-piperidin] -r-yl) -tributyl-butyl propanoate (WO 2003064425) and 1- (bromomethyl) - 3-methoxybenzene: 1 H-NMR (CDCl 3) d 7.30-7.08 (5H, m), 6.84-6.70 (3H, m), 5.06 (2H, s), 3.79 (3H, s), 2.90-2.68 (6H, m), 2.54-2.32 (3H, m), 1.98-1.84 (2H, m), 1.80-1 68 (2H, m), 1.38 (9H, s); MS (ESI) 438 (M + H) +. STAGE 2. 2- (3-Methoxybenzyl-P-3- (1'H.3H-espyror2-benzofuran-1,4'-piperidinH'-propanoic acid trifluoroacetate The title compound was prepared according to the procedure described in step 3 of Example 1 starting from 2- (3-methoxybenzyl) -3- (1 'H, 3 H-spiro [2-benzofuran-1,4'-piperidine] -1'- il) ferric butyl propanoate (step 1): 1 H-NMR (CDCl 3) d 7.35-7.05 (5H, m), 6.84-6.70 (3H, m), 5.04 (2H , s), 3.79 (3H, s), 3.66-3.50 (3H, m), 3.49-3.20 (3H, m), 3.08-3.24 (2H, m), 2.76-2 64 (1H, m), 2.48-2.25 (2H, m), 1.94-1.78 (2H, m); MS (ESI) 382 (M + H) +, 380 (M-H) _. EXAMPLE 4 2-Benzyl-3- (5-fluoro-1-methyl-1,2-dihydro-1β-es-pyrolindole-3,4'-p-peridin-1'-di-d-propane) acid STEP 1. 5-Fluoro-1,2-dihydro-1? -espirop'ndol-3,4'-piperidin-1'-benzylcarboxylate The title compound was prepared according to the procedure described in the literature (Tetrahedron 1997, 53, 10983-10992.) From (4-fluorophenyl) hydrazine hydrochloride: 1 H-NMR (CDCl 3) d 7.39-7.32 (5H, m), 6.78-6.72 (2H, m), 6.67-6.63 (1H, m), .16 (2H, s), 4.16 (2H, ma), 3.64 (1H, ma), 3.49 (2H, s), 2.97 (2H, ma), 1.74 (4H , ma); MS (ESI) 341 (M + H) +. STEP 2. 5-Fluoro-1-methyl-1,2-dihydro-1? -spirorindole-3,4'-piperidin-1'-benzyl carboxylate To a stirred solution of 5-fluoro-1,2-dihydro-1? -spiro [indol-3,4'-piperidine] -1'-benzylcarboxylate (step 1, 1.27 g, 3.72 mmol), aqueous 37% formaldehyde solution (1.4 ml, 18.6 mmol), and sodium cyanoborohydride (701 mg, 11.1 mmol) in methanol (30 ml) was added acetic acid (1.06 ml, 18.6 mmol) at room temperature. After stirring for 20 hours, the mixture was quenched by the addition of an aqueous solution of dilute sodium hydroxide, and then concentrated to give a brown syrup. The crude material was partitioned between ethyl acetate and an aqueous solution of dilute sodium hydroxide, and then the organic phase was washed with brine, dried over sodium sulfate, and evaporated yielding 1.38 g of the title compounds in the form of a yellow syrup: 1 H-NMR (CDCl 3) d 7.39-7.32 (5H, m), 6.93-6.69 (2H, m), 6.40-6.36 (1H, m) , 5.16 (2H, s), 4.13 (2H, ma), 3.23 (2H, s), 3.00 (2H, ma), 2.73 (3H, s), 1.73 ( 4H, ma); MS (ESI) 354 (M + H) +. STEP 3. 5-Fluoro-1-methyl-1,2-dihydrospirophenol-3,4'-piperidine1 A solution of 5-fluoro-1-methyl-1,2-dihydro-1'-rV-spiro [indol-3, 4'-piperidine] -1'-benzylcarboxylate (step 2, 1.38 g, 3.90 mmol) in trifluoroacetic acid (10 ml) was heated to reflux for 4.5 hours. The reaction mixture was evaporated to give a brown syrup. This crude material was divided between diclpromethane and an aqueous solution of dilute sodium hydroxide, and then the organic phase was dried over sodium sulfate and evaporated. The residue was purified by column chromatography on silica gel coated with amine (70 g) eluting with dichloromethane, then dichloromethane / methanol (50/1) yielding 814 mg (95%) of the title compound as a brown solid. light: MS (ESI) 221 (M + H) + STAGE 4. 2-Benzyl-3- (5-fluoro-1-methyl-1,2-dihydro-1'f7-espirorindole-3,4'-piperidin) -1'-ethyl-D-Propanoate A solution of 5-f luoro-1-methyl-1,2-dihydrospiro [indole-3,4'-piperidine] (step 3, 399 mg, 1.81 mmol) and ethyl 2-benzylacrylate (Tetrahedron Lett. 1997, 19, 3753-3756., 376 mg, 1.97 mmol) in methanol (19 mL) was stirred at room temperature for 8 days. The reaction mixture was evaporated giving a light yellow syrup. The residue was purified by column chromatography on silica gel (35 g) eluting with hexane / ethyl acetate (1/1) yielding 421 mg (57%) of the title compound as a colorless syrup: 1 H-NMR ( CDCl 3) d 7.38-7.17 (5H, m), 6.80-6.72 (2H, m), 6.37-6.32 (1H, m), 4.16-4.04 ( 2H, m), 3.15 (2H, s), 2.97-2.73 (6H, m), 2.71 (3H, s), 2.47-2.41 (1H, m), 2 , 20-2.03 (2H, m), 1.86-1.75 (2H, m), 1.68-1.64 (2H, m), 1.15 (3H, t, J = 7.2 Hz); MS (ESI) 411 (M + H) +. STEP 5. Acid 2-benzyl-3- (5-fluoro-1-methyl-1,2-dihydro-1? -espirophenol-3,4'-piperidin-1'-D-propanoic A mixture of 2-benzyl-3- ( Ethyl 5-fluoro-1-methyl-1,2-dihydro-1 '/ -spiro [indol-3,4'-piperidin] -1'-yl) propanoate (step 4, 421 mg, 1.03 mmol) and lithium hydroxide (131 mg, 16.4 mmol) in tetrahydrofuran / methanol / water (6 ml / 2 ml / 2 ml) was stirred at room temperature for 22 hours.The mixture was poured into tetraborate buffer (pH = 9, 18.45 ml) and extracted with 1-butanol / toluene (3/1, 40 ml) The organic phase was dried over sodium sulfate and evaporated, the residue was purified by column chromatography on silica gel (35 g. ) eluting with dichloromethane / methanol (50/1) yielding 282 mg (72%) of the title compound as a colorless solid: 1 H-NMR (CDCl 3) d 7.33-7.20 (5H, m), 6.83-6.76 (1H, m), 6, 71-6.67 (1H, m), 6.38-6.34 (1H, m), 3.38-3.31 (2H, m), 3.13 (2H, s), 3.01-2.84 (5H, m), 2, 69 (3H, s), 2.71-2.45 (5H, m), 2.09-1.98 (2H, m), 1.82-1.75 (2H, m); MS (ESI) 383 (M + Hf, 381 (M-H) '. EXAMPLE 5 2- (2-ChlorobenzD-3- (1? .3H-Spiror-2-benzofuran-1.4'-piperidin-1' - trifluoroacetate Dpropanoic STEP 1. 2- (2-ChlorobenzD-3- (1? .3H-spiro-2-benzofuran-1,4'-piperidin-1'-di-tert-butyl dicarboxylate) The title compound was prepared according to the procedure described in US Pat. step 2 of Example 1 from 3- (1'H, 3H-spiro [2-benzofuran-1,4'-piperidin] -1'-yl) propane-butyl ester (WO 2003064425) and 1- ( bromomethyl) -2-chlorobenzene: 1 H-NMR (CDCl 3) d 7.36-7.10 (8H, m), 5.06 (2H, s), 3.10-2.36 (9H, m), 1 95-1.70 (4H, m) 1.35 (9H, s); MS (ESI) 442 (M + H) + STAGE 2. 2- (2-ChlorobenzD-3- (1) trifluoroacetate ? 3H-esp.ror2-benzofuran-1.4'-piperidin-1'-di-propane The title compound was prepared according to the procedure described in step 3 of Example 1 from 2- (2-chlorobenzyl) -3 - (1 'H, 3H-Spiro [2-benzofuran-1,4'-piperidin] -1'-yl) propane-butyl ester (step 1): 1 H-NMR (CDCl 3) d 7, 41-7.11 (8H, m), 5.06 (2H, s), 3.75-2.93 (9H, m), 2.58-2.23 (2H, m), 1.97- 1.79 (2H, m); MS (ESI) 386 (M + Hf) EXAMPLE 6 2-Benzyl-3- (5-fluoro-1-m) acid til-2-oxo-1, 2-dihydro-1? 7-espirorindol-3,4'-piperidin-1'-Dpropanoic STAGE 1. 5-Fluoro-2-oxo-1,2-dihydro-1? -esp Ropndol-3,4'-piperidinal-1'-fer-butylcarboxylate To a stirred solution of 5-fluoro-1,3-dihydro-2H-indole-2-one (1.80 g, 11.9 mmol) in tetrahydrofuran (30 ml) was added dropwise a 1 M solution of bis (trimethylsilyl) sodium amide in tetrahydrofuran (35.7 ml, 35.7 mmol) at -78 ° C for 15 minutes and the mixture was stirred for 1, 5 hours at the same temperature. To the mixture was added dropwise a solution of fer-butyl bis (2-chloroethyl) carbamate (2.88 g, 11.9 mmol) in tetrahydrofuran (10 ml) at -78 ° C, then this resulting mixture it was slowly warmed to room temperature and stirred for 19 hours at the same temperature. The reaction mixture was quenched by the addition of an aqueous solution of ammonium chloride, and concentrated to give a brown residue. The crude material was partitioned between ethyl acetate and water, and then the organic phase was washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by column chromatography on silica gel (100 g) eluting with hexane / acetopa (3/1) yielding 356 mg (15%) of the title compound as a light brown syrup: 1 H-NMR (CDCl 3 ) d 8.56 (1H, sa), 7.03-6.83 (3H, m), 3.89-3.69 (4H, m), 1.92-1.72 (4H, m), 1.50 (9H, s); MS (! EN) 319 (M-H) -.

STEP 2. 5-Fluoro-1-methyl-2-oxo-1,2-dihydro-1? -espirophenol-3,4'-p-peridin-1'-carboxylic acid-ferric ester To a stirred solution of 5-fluoro-2-oxo-1,2-dihydro-1? -spiro [indole-3,4'-piperidine] -1'-ferro-butylcarboxylate (step 1, 166 mg, 0.518 mmol) in? / , / V-dimethylformamide (4 ml) was added 70% sodium hydride in mineral oil (27 mg, 0.777 mmol) at 0 ° C and the mixture was stirred for 10 minutes at the same temperature. To the mixture was added methyl iodide (147 mg, 1.04 mmol) at 0 ° C, then this resulting mixture was slowly warmed to room temperature and stirred for 18 hours at the same temperature. The reaction mixture was diluted with toluene / ethyl acetate (1/3), then washed with water twice, and then the organic phase was washed with brine, dried over sodium sulfate, and evaporated yielding 130 mg (75 mL). %) of the title compound as a light yellow solid: 1 H-NMR (CDCl 3) d 7.05-6.96 (2H, m), 6.79-6.75 (1H, m), 3.90 -3.73 (4H, m), 3.19 (3H, s), 1.87-1.68 (4H, m), 1.50 (9H, s). STAGE 3. 5-Fluoro-1-methylspirophenol-3,4'-p? 'Peridin1-2 (1 / -7) -one A solution of 5-fluoro-1-methyl-2-oxo-1,2 -dihydro-1 '- / - spiro [indole-3,4'-piperidine] -1'-ferrobutylcarboxylate (step 2, 130 mg, 0.389 mmol) in a solution of 10% hydrochloric acid in methanol ( 5 ml) was stirred for 4 days. The reaction mixture was evaporated giving a yellow syrup. This crude material was partitioned between diethyl ether and an aqueous solution of 0.4 N sodium hydroxide and then the organic phase was dried over sodium sulfate, and evaporated yielding 70 mg (77%) of the title compound as a solid colorless: MS (ESI) 235 (M + Hf. STEP 4. 2-Benzyl-3- (5-fluoro-1-methyl-2-oxo-1,2-dihydro-1 '- esopyrofindol-3,4'-piperidin-1' Ethyl-D -propanoate The title compound was prepared according to the procedure described in step 4 of Example 4 from 5-fluoro-1-methylepiro [indole-3,4'-pi? eridin] -2 ( 1 H) -one (step 3) and ethyl 2-benzylacrylate (Tetrahedron Lett. 1997, 19, 3753-3756): 1 H-NMR (CDCl 3) d 7.31-7.11 (6H, m), 7.00-6.93 (1H, m), 6.76-6.71 ( 1H, m), 4.16-4.06 (2H, m), 3.17 (3H, s), 3.01-2.80 (6H, m), 2.74-2.65 (1H, m), 2, 61-2.55 (2H, m), 1.98-1.88 (2H, m), 1.76-1.66 (2H, m), 1.17 (3H, t, J = 7.3) Hz); MS (ESI) 425 (M + Hf. STAGE 5. 2-Benzyl-3- (5-fluoro-1-methylene-2-oxo-1,2-dihydro-1 '/ V-espyrorindol- 3,4'-piperidin-1'-iDpropanoic The title compound was prepared according to the procedure described in step 5 of example 4 from 2-benzyl-3- (5-fluoro-1-methyl-2- oxo-1, ethyl 2-dihydro-1? -spiro [indol-3,4'-piperidin] -1 '-iDpropanoate (stage 4): MS (ESI) 397 (M + Hf, 395 (M-H). "EXAMPLE 7 2- (2-Fluorobenzyd-3- (1? .3 -spiror2-benzofuran- 1.4'- acid trifluoroacetate. piperidinl-1 '-iDpropanoic STEP 1. 2- (2-FluorobenzD-3- (1? 3 H-spiro-2-benzofuran-1,4'-piperidin-1'-Ferrobutyl-D -propanoate) The title compound was prepared according to the procedure described in step 2 of Example 1 from 3- (1'H, 3-spiro [2-benzofuran-1,4'-piperidin] -1'-yl) propane-butyl ester (WO 2003064425) and 1- (bromomethyl) ) -2-fluorobenzene: 1 H-NMR (CDCl 3) d 7.30-6.97 (8H, m), 5.06 (2H, s), 3.02-2.69 (6H, m), 2, 53-2.33 (3H, m), 1, 97-1.84 (2H, m), 1.80-1.66 (2H, m), 1.35 (9H, s), MS (I EN ) 426 (M + Hf. STAGE 2. 2- (2-FluorobenzD-3- (1'rV.3H-Spiror2-benzofuran-1,4'-piperidin] -1'-D-Propanoic acid trifluoroacetate The title compound was prepared according to the procedure described in step 3 of Example 1 starting from 2- (2-fluorobenzyl) -3- (1'H, 3H-spiro [2-benzofuran-1,4'-piperidine] -1 '- Ferric-butyl iDpropanoate (stage 1): 1 H-NMR (CDCl 3) d 7.88-7.02 (8H, m), 5.06 (2H, s), 3.86-2.89 (9H, m), 2.54-2.36 ( 2H, m), 1, 96-1, 81 (2H, m); MS (ESI) 370 (M + Hf, 368 (M-Hf EXAMPLE 8 2- (2-MethoxybenzD-3- (1Yi3 / 7-spiro-2-benzofuran-1,4'-piperidin-1'-) trifluoroacetate iDpropanoic STEP 1. 2- (2-MethylbenzD-3- (1'H.3H-espyr2-benzofuran-1.4'-piperidin-1'-d-Ferrobutyl Dpropanoate The title compound was prepared in accordance with procedure described in step 2 of example 1 from 3- (177,3H-spiro [2-benzofuran-1,4'-piperidin] -1'-yl) propane butyl ferric acid (WO 2003064425) and 1- (bromomethyl) -2-methylbenzene: 1 H-NMR (CDCl 3) d 7.29-7.08 (8H, m), 5.05 (2H, s), 3.92-2.37 (9H, m), 2.33 (3H, s), 1.97-1.84 (2H, m), 1.80-1.68 (2H, m), 1.35 (9H, s); MS (ESI) 422 (M + Hf. STAGE 2. 2- (2-Methylbenzyl-3- (1'H.3 -spiror2-benzofuran-1,4'-piperidin-1'-di-propane) trifluoroacetate The title compound was prepared according to the procedure described in step 3 of Example 1 from 2- (2-methylbenzyl) -3- (1'H, 3H-spiro [2-benzofuran-1,4'-piperidin ] -1'-Di-butyl-butyl ester (step 1): 1 H-NMR (CDCl 3) d 7.38-6.92 (8H, m), 5.07 (2H, s), 3.84-2, 16 (11H, m), 2.38 (3H, s), 1.93-1, 85 (2H, m); MS (ESI) 366 (M + Hf, 364 (M-H). 'EXAMPLE 9 Trifluoroacetate of 2- (5- {, butyl-butyl (dimethyldnol) -2-fluorobenzyd-3- (1?, 3H-espirof2-benzofuran-1,4'-piperidin-1 '-iDpropanoic STEP 1. ferc-Butyl (4-fluoro-3-methylphenolDdimethylol) To a stirred solution of 4-fluoro-3-methylphenol (15 g, 0.12 mol) and Midazole (18 g, 0.26 mol) in? /, / V-dimethylformamide (100 ml) was added tert-butyl (chloro) dimethylsilane (20 g, 0.13 mol) at 0 ° C. The reaction mixture was stirred at room temperature for 20 hours, and was quenched by the addition of water.

The aqueous phase was extracted with diethyl ether (400 ml). The combined organic phases were washed with water and brine, dried over magnesium sulfate, and evaporated yielding 30 g (quant.) Of the title compound as a yellow oil: 1 H-NMR (CDCl 3) d 6.84 ( 1H, t, J = 8.7 Hz), 6.66-6.54 (2H, m), 2.21 (3H, d, J = 2.1 Hz), 0.97 (9H, s), 0.17 (6H, s). STEP 2. f3- (Bromomet®-4-fluorophenoxy (ferc-butiDdimethylslane) A mixture of fer-butyl (4-fluoro-3-methylphenoxy) dimethylsilane (step 1, 30 g, 0.12 mol),? -bromosuccinimide (24 g, 0.13 mol) and benzoylperoxide (1.5 g, 6.2 mmol) in carbon tetrachloride (75 ml) was heated to reflux under a nitrogen atmosphere for 4 hours. cooled to 0 ° C, and the white precipitate was filtered. The filtrate was washed with an aqueous solution of sodium bicarbonate, dried over magnesium sulfate, and evaporated. The residue was purified by column chromatography on silica gel eluting with hexane yielding 25 g (65%) of the title compound as a colorless oil: 1 H-NMR (CDCl 3) d 6.91 (1H, t, J = 9.2 Hz), 6.84 (1H, dd, J = 6.2, 2.9 Hz), 6.77-6.68 (1H, m), 4.44 (2H, s), 0, 97 (9H, s), 0.18 (6H, s). STAGE 3. 2- (5- (rferc-Butyl (d-methylsilinoxy) -2-fluorobenzD-3- (1'H.3 / - / - spiroF2-benzofuran-1,4'-piperidin-1 Ferric-butyl dpropanoate The title compound was prepared according to the procedure described in step 2 of Example 1 from 3- (1α, 3H-spiro [2-benzofuran-1,4'-piperidine] -1'-Di-butyl-butyl ester (WO 2003064425) and [3- (bromomethyl) -4-fluorophenoxy] (fer-butyl) dimethylsilane (step 2): 1 H-NMR (CDCl 3) d 7.28- 7.08 (4H, m), 6.85 (1H, t, J = 9.2 Hz), 6.69-6.58 (2H, m), 5.06 (2H, s), 2.92 -2.66 (6H, m), 2.53-2.33 (3H, m), 1.98-1.84 (2H, m), 1.77-1.68 (2H, m), 1.38 (9H, s), 0.97 (9H, s), 0.17 (6H, s); MS (lEN) 556 (M + Hf. STEP 4. 2- (5-Ffferc-butyl (dimethylsilylpoxy) -2-fluorobenzyd-3- (1? .3H-espiror2-benzofuran-1,4 'trifluoroacetate. -pperidin1-1 '-iDpropanoic The title compound was prepared according to the procedure described in step 3 of Example 1 from 2- (5- { [ferc-butyl (dimethyl) silyl] oxy} - 2-fluorobenzyl) -3- (1?, 3H-spiro [2-benzofuran-1,4'-piperidin] -1'-yl) -propanoate ferric-butyl ester (step 3): 1H-NMR (CDCl3 ) d 7.34-6.66 (7H, m), 5.06 (2H, s), 3.78-2.32 (11H, m), 1.91-1.31 (2H, m), 0.97 (9H, s), 0.17 (6H, s); MS (ESI) 500 (M + Hf, 498 (M-Hf EXAMPLE 10 2-Benzyl-3- (1-methylene-2) acid -oxo-1,2-d and H-d-1'H-spiro [indol-3,4'-piperidin-1 '-iD-propanoic acid STEP 1. 2-Oxo-l .2-dihydro-1? -espirofindol-3,4'-piperidin-1'-ferrobutylcarboxylate The title compound was prepared according to the procedure described in step 1 of Example 6 from 1,3-dihydro-2H-indol-2-one: 1 H-NMR (CDCl 3) d 7.92 (1H, sa), 7.29-7.21 (2H, m), 7, 07-7.02 (1H, m), 6.92-6.89 (1H, m), 3.90-3.75 (4H, m), 1, 92-1, 71 (4H, m) , 1.50 (9H, s); MS (ESI) 301 (M-H)? STEP 2. 1 -Methyl-2-oxo-1,2-dihydro-1? -espirophenol-3,4'-piperidin-1'-ferrobutylcarboxylate The title compound was prepared according to the procedure described in step 2 of Example 6 from 2-oxo-1,2-dihydro-1'A / -spiro [indole-3,4'-piperidine] -1 '- ferric-butyl carboxylate (step 1): 1 H-NMR (CDCl 3) d 7.32-7.26 (2H, m), 7.09-7.04 (1H, m), 6.87-6.85 (1H, m), 3.91-3.74 (4H, m), 3.21 (3H, s), 1.87-1.71 (4H, m), 1.50 (9H, s). STEP 3. 1-Methylspirophenol-3,4'-p-peridin-1-2 (1rV) -one The title compound was prepared according to the procedure described in step 3 of Example 6 from 1-methyl-2-oxo- 1,2-dihydro-1'A / -spiro [indol-3,4'-piperidin] -1'-ferro-butylcarboxylate (step 2): 1 H-NMR (CDCl 3) d 7,45-7,42 (1H, m), 7.32-7.25 (1H, m), 7.10-7.05 (1H, m), 6.87-6.84 (1H, m), 3.43-3 , 34 (2H, m), 3.12-3.03 (2H, m), 1.90-1.81 (2H, m), 1.76-1.68 (2H, m); MS (ESI) 217 (M + Hf. STEP 4. 2-Benzyl-3- (1-methyl-2-oxo-1,2-dihydro-1β-espyroindond-3.4'-p-peridin-1) 1'-Ethyl D -propanoate The title compound was prepared according to the procedure described in step 4 of Example 4 from 1-methylspiro [indole-3,4'-piperidine] -2 (1 H) -one ( step 3) and ethyl 2-benzylacrylate (Tetrahedron Lett. 1997, 19, 3753-3756): 1 H-NMR (CDCl 3) d 7.39 (1 H, da, J = 7.0 Hz), 7.30-7.18 (6H, m), 7.07-7 , 01 (1H, m), 6.84 (1H, da, J = 7.7 Hz), 4.14-4.06 (2H, m), 3.19 (3H, s), 3.02-2, 81 (6H, m), 2.77-2.69 (1H, m), 2.66-2.56 (2H, m), 1.98-1.90 (2H, m), 1.77- 1.70 (2H, m), 1, 17 (3H, t, J = 7.0 Hz); MS (ESI) 407 (M + Hf. STAGE 5. 2-Benzyl-3- (1-methylene-2-oxo-1,2-dihydro-1 '-espyrorindole-3,4'-piperidiri) - 1-D-Propanoic The title compound was prepared according to the procedure described in step 5 of Example 4 from 2-benzyl-3- (1-methyl-2-oxo-1,2-dihydro-1 ' Ethyl H-spiro [ipdol-3,4'-pperidin] -1'-yl) propanoate (step 4): MS (ESI) 379 (M + Hf, 377 (M-H). "EXAMPLE 11 Trifluoroacetate of 2- (5-rferc-butyl (dimethylDsilyl) -2-chlorobenzyl-3- (1? .3H-spiro-2-benzofuran-1,4'-piperidin-1'-di-propane) STAGE 1. 2- (5-Trferc-Butyl (dimethylsiliconx) -2-chlorobenzyl-3- (1'H.3H-spiro-2-benzofuran-1.4'-pperiod1-1'- L) fer-t-butyl propanoate The title compound was prepared according to the procedure described in step 2 of example 1 from 3- (1 '/ - /, 3 H-spiro [2-benzofuran-1,4] Ferrobutyl propanoate -piperidin-1-yl) propane (WO 2003064425) and [3- (bromomethyl) -4-chlorophenoxy] (fer-butyl) dimethylsilane (J. Org. Chem. 1996, 61, 6974): 1 H-NMR (CDCl 3) d 7.28-7.09 (5H, m), 6.74 (1H, d, J = 3.0 Hz), 6.62 (1H, dd, J = 8.7, 3.0 Hz), 5.06 (2H, s), 3.49-2.69 (6H, m), 2.52-2.38 (3H, m), 1.93-1.70 (4H , m), 1.39 (9H, s), 0.96 (9H, s), 0.18 (6H, s), EM (IEN) 572 (M + Hf. STAGE 2. 2- (2-trifluoroacetate) 5- (rferc-butyl (dimethyldisloxy) -2-chlorobenzyl-3- (1? .3H-spiro-2-benzofuran-1,4'-piperidin-1'-di-dopanoic The title compound was prepared according to the procedure described in step 3 of Example 1 starting from 2- (5- { [ferc-butyl (dimethyl) silyl] oxy} -2-chlorobenzyl) -3- (1?, 3H-spiro [2-benzofuran-1, 4'-piperidin] -1'-yl) propane-butyl stearate (step 1): 1 H-NMR (CDCl 3 ) d 7.85-7.01 (5H, m), 6.78-6.65 (2H, m), 5.06 (2H, s), 3.79-2.71 (9H, m), 2.61-2.28 (2H, m), 1.92-1.72 (2H, m), 0.96 (9H, s), 0.18 (6H, s); MS (ESI) 516 (M + H) EXAMPLE 12 2- (2,6-d.fluorobenzyd-3- (1W, 3 H -spiror-2-benzofuran-1,4'-piperidin-1'-di-d-propanoic acid trifluoroacetate.

STEP 1. 2- (2,6-DifluorobenzD-3- (1? .3A / -spiror2-benzofuran-1,4'-piperidin-1'-dicarboxylic acid) The title compound was prepared according to the procedure described in Step 2 of Example 1 from 3- (1?, 3 H-spiro [2-benzofuran-1,4'-piperidine] -1'-di-d-butpanoic acid ester (WO 2003064425) and 2- (bromomethyl) -1 , 3-difluorobenzene: 1 H-NMR (CDCl 3) d 7.30-7.05 (5H, m), 6.90-6.80 (2H, m), 5.05 (2H, s), 2.96 -2.70 (6H, m), 2.56-2.34 (3H, m), 1.96-1.68 (4H, m), 1.37 (9H, s); MS (IEN) 444 (M + Hf. STAGE 2. 2- (2,6-difluorobenzyl-3- (1? .3H-spiroy2-benzofuran-1,4'-piperidine [-1'-.Ppropane] trifluoroacetate The compound of title was prepared according to the procedure described in step 3 of example 1 from 2- (2,6-difluorobenzyl) -3- (17-, 3H-spiro [2-benzofuran-1,4'-piperidine] -1'-Di-butyl-butyl ester (step 1): 1 H-NMR (CDCl 3) d 7.45-6.86 (7H, m), 5.06 (2H, s), 3.76-2.90 (9H, m), 2.49-2.31 (2H, m), 1, 98-1.81 (2H, m); MS (IEN ) 388 (M + Hf, 386 (M-Hf EXAMPLE 13 2- (4-rferc-butyl (dimethylsilyloxy) -2-chlorobenzyl-3- (1? .3H-espyrof2-benzofuran-1.4'- acid trifluoroacetate. piperidin-1 '-Dpropanoic STAGE 1. (4-Ffferc-Butyl (dimethylsilyoxy) -2-chlorophenolmethanol To a stirred solution of 4-. {[[Ferc-butyl (dimethyl) silyl] oxy} -2- chlorobenzaldehyde (WO 2003051797, 1.58 g, 5.83 mmol) in methanol (5 ml) was added sodium borohydride (264 mg, 7.00 mmol) at 0 ° C. The mixture was stirred at room temperature for 3 hours The mixture was extracted with ethyl acetate (200 ml) and the organic phase was washed with brine, dried over sodium sulfate and evaporated, and the residue was purified by chromatography. column on silica gel (100 g) eluting with hexane / ethyl acetate (20/1 to 10/1) to afford 1.51 g (95%) of the title compound as a colorless oil: 1 H-NMR (CDCl 3 ) d 7.30 (1 H, d, J = 8.5 Hz), 6.87 (1 H, d, J = 2.4 Hz), 6.74 (1 H, dd, J = 8.5 , 2.4 Hz), 4.70 (2H, sa), 0.98 (9H, s), 0.20 (6H, s), EM (IEN) 255 (M + Hf. STAGE 2. ferc-Butiir3 -chloro-4- (chloromethyl-phenoxy-1,4-dimethylsil) to a solution stirring of ferc-butyl [3-chloro-4- (chloromethyl) phenoxy] dimethylsilane (step 1, 500 mg, 1.83 mmol) in dichloromethane (5 ml) was added triethylamine (0.139 ml, 2.75 mmol) and Methanesulfonyl chloride (231 mg, 2.02 mmol) at room temperature. The mixture was stirred for 2 hours at the same temperature. The mixture was diluted with ethyl acetate (100 ml), and the mixture was washed with water and brine, dried over sodium sulfate and evaporated. The residue was purified by chromatography on silica gel (40 g) eluting with hexane / ethyl acetate (10/1) yielding 580 mg (quant.) Of the title compound as a colorless oil: 1 H-NMR (CDCl 3) d 7.87-7.26 (1H, m), 6.93-6.71 (2H, m), 4.66 (2H, s), 0.97 (9H, s), 0.21 (6H , s). STAGE 3. 2- (4-érferc-But¡l (dimetiDsilillox¡ >; -2-chlorobenzD-3- (1 'H, 3H-spiro-2-benzofuran-1,4'-piperidin-1'-di-tert-butyl dicarboxy) The title compound was prepared according to the procedure described in step 2 of Example 1 from 3- (1'H, 3H-spiro [2-benzofuran-1,4'-piperidin] -1'-di-d-butpanoate of fer-butyl (WO 2003064425) and fer-butyl [3-chloro- 4- (chloromethyl) phenoxy] dimethylsilane (step 2): 1 H-NMR (CDCl 3) d 7.38-6.61 (7H, m), 5.06 (2H, s), 3.00-2.33 ( 9H, m), 2.04-1.65 (4H, m), 1.86 (9H, s), 0.97 (9H, 's), 0.18 (6H, s); MS (ESI) 572 (M + Hf. STEP 4. 2- (4-urea-butyl (dimethyldinosilyoxy-2-chlorobenzD-3- (1'-Y.3f-spiro [2-benzofuran-1, 4 '] trifluoroacetate. -piperidin-1 '-iDpropanoic The title compound was prepared according to the procedure described in step 3 of Example 1 from 2- (4-. {[[fer-butyl (dimethyl] silyl] oxy]} -2-chlorobenzyl) -3- (1?, 3 7-spiro [2-benzofuran-1,4'-piperidine] -1'-di-butyl butyl ester (step 3): 1 H-NMR (CDCl 3) d 7.83-6.69 (7H, m), 5.06 (2H, s), 3.78-2.78 (9H, m), 2.54-2.31 (2H, m), 2 , 00-1, 80 (2H, m), 0.97 (9H, s), 0.20 (6H, s); MS (IEN) 516 (M + Hf, 514 (M-H) - EXAMPLE 14 2- (2,6-D-fluoro-3-hydroxybenzD-3- (1 '. 3 H-spiro 2-benzofuran-1,4'-piperidin-1'-D-propaneic acid trifluoroacetate STEP 1. 2.4-D-Fluoro-3- (hydroxyethyl) phenol To a stirred solution of fer-butyl (2,4-difluorophenoxy) dimethylsilane (J. Med. Chem. 1993, 36, 3947., 1.50 g, 6, 14 mmol) in tetrahydrofuran (30 ml) was added a 1.57 M solution of n-butyllithium in hexane (4.69 ml, 7.37 mmol) at -78 ° C for 10 minutes, and the mixture was stirred under stirring. -78 ° C for 2 hours To the mixture,? /,? / - dimethylformamide (0.950 ml, 2.28 mmol) was added at -78 ° C. The mixture was stirred at -78 ° C for 1 hour, it was allowed to warm to room temperature and stand at room temperature for 16 hours The mixture was diluted with methanol (20 ml), and sodium borohydride (696 mg, 18.4 mmol) was added to the mixture at 0 ° C. The reaction was quenched by addition of aqueous ammonium chloride at 0 ° C until pH = 7. The mixture was extracted with diethyl ether (200 ml) and the organic phase was washed with brine, dried over magnesium sulfate and evaporated. was purified by column chromatography on silica gel (100 g) eluting with hexane / ethyl acetate (2/1) yielding 410 mg (42%) of the title compound as a colorless oil: 1 H-NMR (CDCl 3) d 6.93 (1H, td, J = 9.2, 5.3 Hz), 6.81 (1H, td, J = 9.2, 1.8 Hz), 4.80 (2H, s), 0.98 (9H, s), 0.20 (6H, s); MS (EI) 160 (Mp STEP 2. 3- (Bromometyl-2,4-difluorophenol To a stirred solution of 2,4-difluoro-3- (hydroxymethyl) phenol (step 1, 410 mg, 256 mmol) in ether diethyl ether (4 ml) and dichloromethane (1 ml) was added phosphorus tribromide (0.257 ml, 2.71 mmol) at 0 ° C. The mixture was stirred for 30 minutes and then the mixture was poured over aqueous sodium bicarbonate in ice The mixture was extracted with ethyl acetate (200 ml), and the organic phase was washed with water and brine, dried over magnesium sulfate and evaporated yielding 266 mg (47%) of the title compound as an oil. colorless, which was used in the next step without purification: 1H-NMR (CDCl3) d 6.95 (1H, td, J = 9.0, 5.4 Hz), 6.81 (1H, td, J = 9 , 0, 1.8 Hz), 4.52 (2H, s) STAGE 3. 2- (2,6-difluoro-3-hydroxybenzD-3- (1 'H.3H-espyr2-benzofuran-1.4'- piperidn -1-1'-Ferro-butyl dpropanoate The title compound was prepared according to the procedure described in step 2 of example 1 to of 3- (17V, 3H-spiro [2-benzofuran-1,4'-piperidin] -1'-yl) propane-butyl ester and 3- (bromomethyl) -2,4-difluorophenol (stage 2): 1 H-NMR (CDCl 3) d 7.30-7.18 (3H, m), 7.12-7.06 (1H, m), 6.82 (1H, td, J = 9.1, .3 Hz), 6.73 (1H, td, J = 9.1, 1.5 Hz), 5.05 (2H, m), 2.96-2.38 (9H, m), 1, 97-69 (4H, m), 1.87 (9H, s); MS (ESI) 460 (M + Hf, 458 (M-H) \ STEP 4. 2- (2,6-Difluoro-3-hydroxybenzD-3- (1'H.3H-Spiror2-benzofuran-1,4'-) trifluoroacetate piperidin] -1'-iDpropanoic The title compound was prepared according to the procedure described in step 3 of Example 1 from 2- (2,6-difluoro-3-hydroxybenzyl) -3- (17- /, 3H-spiro [2-benzofuran-1,4'-piperidin] -1'-yl) propane-butyl stearate (step 3): 1 H-NMR (CDCl 3) d 7.84-7.10 (4H, m) 6.93-6.84 (1H, m), 6.78-6.70 (1H, m), .06 (2H, s), 3.71-3.58 (3H, m), 3.39-2.89 (6H, m), 2.47-2.29 (2H, m), 1, 94-83 (2H, m); MS (ESI) 404 (M + Hf. EXAMPLE 15 2- (2-Chloro-5-hydroxybenzDi-3- (1?. 3 H-spiro | 2-benzofuran-1,4'-piperidin-1'-acid! Dpropanoic STEP 1. 2- (2-Chloro-5-hydroxybenzyd-3- (1? .3H-spiro-2-benzofuran-1,4'-piperidin-1'-di-d-propanoic fer-butyl ester To a solution of 2- (5- {. [ferc-butyl (dimethyl) silyl] oxy} -2-cyclobenzyl) -3- (1?, 3 H-spiro [2-benzofuran-1,4'-piperidine] -1'-yl. ) ferric-butyl propanoate (step 1 of example 11, 2.5 g, 4.3 mmol) in tetrahydrofuran was added a solution of tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 4.3 ml, 4.3 mmol). ) and the mixture was stirred at room temperature for 3 hours Water (50 ml) was added to the mixture and the mixture was extracted with ethyl acetate (50 ml x 3) .The combined organic phases were washed with brine (50 ml). ml), dried over magnesium sulfate and evaporated The residue was purified by column chromatography on silica gel eluting with hexane / ethyl acetate (3/1) yielding 1.8 g (94%) of the title compound. in the form of a white powder: 1 H-NMR (CDCl 3) d 7.32-7.04 (5H, m), 6.76 (1H, d, J = 3.0 Hz,), 6.63 (1H, dd, J = 8.6, 3.0 Hz), 5.06 (2H, s), 3.08-2.71 (6H, m), 2.60-2.37 (3H, m), 2.02- 1.84 (2H, m), 1.80-1.67 (2H, m), 1.38 (9H, s). STEP 2. 2- (2-Chloro-5-hydroxybenzyd-3- (1'H, 3H-spiro-2-benzofuran-1,4'-piperidin-1'-di-dopanoic acid To a solution of 2- (2- Chloro-5-hydroxybenzyl) -3- (1?, 3H-Spiro [2-benzofuran-1,4'-pyrperidin] -1'-yl) propane-butyl ester (stage 1, 1,8 g, 4.0 mmol) in dichloromethane was added trifluoroacetic acid (4.0 ml) and the mixture was stirred at room temperature for 4 hours.The volatile materials were removed to give a residue, which was dissolved in dichloromethane. Amine-coated silica gel (30-50 μm, 20 g) was added to the solution and the resulting suspension was filtered.The amine-coated silica gel was washed with dichloromethane / methanol (10/1) .The combined organic phases were concentrated The powder was washed with isopropyl alcohol yielding 0.92 g (57%) of the title compound: 1 H-NMR (DMSO-cfe) d 9.50 (1H, sa), 7.23-6 , 98 (5H, m), 6.66-6.48 (2H, m), 4.84 (2H, s), 2.86-2.53 (6H, m), 2.46-2.12 (3H, m), 1, 84-1.63 (2H, m ), 1.59-1.43 (2H, m) EXAMPLE 16 2-R 2 - (Methoxymethyl-P-benzyl-3- (1? .3 / - / - Spiror-2-benzofuran-1,4'-piperidinyl) trifluoroacetate -1 '-iDpropanoic STEP 1. 2-f2- (MethoxymethiDbencin-3- (1'H.3H-Spiror2-benzofuran-1,4'-piperidin-1'-d-Ferrobutyl-D -propanoate) The title compound was prepared according to the procedure described in US Pat. Stage 2 of Example 1 from 3- (1?, 3 H-spiro [2-benzofuran-1,4'-piperidine] -1'-di-d-butpanoate of fer-butyl (WO 2003064425) and 1- (bromomethyl) - 2- (methoxymethyl) benzene (WO 2003106443): 1 H-NMR (CDCl 3) d 7.35-7.07 (8H, m), 5.06 (2H, s), 4.56 (1H, d, J = 11, 5 Hz), 4. 45 (1H, d, J = 11.5 Hz), 3.41 (3H, s), 2.96-2.71 (6H, m), 2.54-2.33 (3H, m), 1 , 98-1.68 (4H, m), 1.35 (9H, s); MS (ESI) 452 (M + Hf. STAGE 2. 2-R 2 - (methoxymethyl) D-benzyl-3-trifluoroacetate (1W, 3rt-spiro-2-benzofuran-1,4'-piperidin-1'-D-propane) The title compound was prepared according to the procedure described in step 3 of Example 1 from 2- [2- (methoxymethyl) benzyl] -3- (1'H, 3/7-spiro [2-benzofuran- Tert-butyl 1, 4'-piperidin] -1'-yl) propanoate (step 1): 1 H-NMR (CDCl 3) d 7.39-7.06 (8H, m), 5.04 (2H, s), 4.51 (1H, d, J = 10.9 Hz), 4. 46 (1H, d, J = 10.9 Hz), 3.71-2.75 (9H, m), 3.45 (3H, s), 2.47-2.27 (2H, m), 1 , 92-1.77 (2H, m); MS (ESI) 396 (M + Hf, 394 (M-Hf EXAMPLE 17 2- (2-ChlorobenzD-3- (1-methyl-2-oxo-1,2-dihydro-1? -espyrorindole-3,4) '-piperidin-1' -Dpropanoic STEP 1. Ethyl 3- (2-chloropheniD-2- (diethoxyphosphorylpropanoate To a stirred solution of ethyl (diethoxyphosphoryl) acetate (10.0 g, 44.6 mmol) in? /,? -dimethylformamide (100 ml) 60% sodium hydride in mineral oil (1.96 g, 49.1 mmol) was added at 0 ° C and the mixture was stirred for 1 hour at the same temperature, to which was added 1- (bromomethyl). -2-chlorobenzene (6.35 ml, 49.1 mmol) at 0 ° C and the resulting mixture was stirred for 18 hours at room temperature.The reaction mixture was quenched by the addition of water, then extracted with diethyl ether (200 ml x 2) and the combined organic phases were washed with water (100 ml) and brine (100 ml), dried over sodium sulfate, and evaporated. The residue was purified by column chromatography on silica gel (500 g) eluting with hexane / ethyl acetate (1/1) yielding 14.6 g (93%) of the title compound as a colorless oil: 1H- NMR (CDCl 3) d 7.36-7.09 (4H, m), 4.26-4.06 (6H, m), 3.52-3.27 (3H, m), 1, 39-1, 33 (6H, m), 1.15 (3H, t, J = 7.0 Hz). STEP 2. 2- (2-Chlorobenzyl) Ethyl Diacrylate To a stirred mixture of ethyl 3- (2-chlorophenyl) -2- (diethoxyphosphoryl) propanoate (step 1, 14.6 g, 41.9 mmol) and formaldehyde 37% in water (20 ml) was added a solution of potassium carbonate (17.4 g) in water (80 ml) at room temperature and the mixture was stirred for 6 hours at 90 ° C. After cooling to room temperature At room temperature, the mixture was extracted with diethyl ether (300 ml), and then the organic phase was washed with brine (100 ml), dried over magnesium sulfate, and evaporated.The residue was purified by gel column chromatography. silica (300 g) eluting with hexane / ethyl acetate (30/1) to afford 6.57 g (70%) of the title compound as a colorless oil: 1 H-NMR (CDCl 3) d 7.39-7, 36 (1H, m), 7.25-7.16 (3H, m), 6.27 (1H, c, J = 1.3 Hz), 5.33 (1H, c, J = 1.7 Hz), 4.22 (2H, c, J = 7.2 Hz), 3.76 (2H, t, J = 1.4 Hz) , 1.29 (3H, t, J = 6.0 Hz). STEP 3. 2- (2-ChlorobenzD-3- (1-methyl-2-oxo-1,2-dihydro-1? -espirofindole-3,4'-piperidin-1'-ethyl-D -propanoate The title compound was prepared from according to the procedure described in step 4 of example 4 from 1-methylspiro [indole-3,4'-piperidine] -2 (1A7) -one (step 3 of example 10) and 2- (2-chlorobenzyl) ethyl acrylate (step 2): 1 H-NMR (CDCl 3) d 7.41-7.02 (7H, m), 6.85-6.80 (1H, m), 4.14-4.02 (2H , m), 3.19-2.59 (12H, m), 1.98-1.68 (4H, m), 1, 18-1, 12 (3H, m); MS (IEN) 441 (M + Hf. STAGE 4. 2- (2-Chlorobenzyl-D-3- (1-methyl-2-oxo-1,2-dihydro-1'H-espiropndol-3,4'-piperidin-1'-PPpropanoic acid) Compound The title was prepared according to the procedure described in step 5 of Example 4 starting from 2- (2-chlorobenzyl) -3- (1-methyI-2-oxo-1,2-dihydro-1 '-spiro [indole -3,4'-piperidin] -1'-ethyl-di-propane (step 3): MS (ESI) 413 (M + Hf, 411 (M-Hf EXAMPLE 18 2- (2-Chlorobenzyl-3- (5-fluoro-1-methyl-1,2-dihydro-1? -espyrolindol-) 3.4 'piperidinl-1' -iDpropanoic STAGE 1. 2- (2-ChlorobenzD-3- (5-fluoro-1-methyl-1,2-dihydro-1'H-espiropndol- 3.4'-piperidin-1'-! Ethyl Dpropanoate The title compound was prepared according to the procedure described in step 4 of Example 4 from ethyl 2- (2-chlorobenzyl) acrylate (step 2 of example 17): 1 H-NMR (CDCl 3) d 7.36-7.33 (1H, m), 7.23-7.14 (3H, m), 6.80-6.82 (2H , m), 6.35 (1H, dd, J = 8.4, 3.9 Hz), 4.14-4.03 (2H, m), 3.16 (2H, s), 3.13-3.05 ( 2H, m), 2.95-2.72 (4H, m), 2.71 (3H, s), 2.49 (1H, dd, J = 12.3, 5.9 Hz), 2.12 -2.06 (2H, m), 1.80 (2H, td, J = 12.6, 4.2 Hz), 1.66 (2H, da, J = 14.1 Hz), 1.15 ( 3H, t, J = 7.1 Hz); MS (ESI) 445 (M + Hf. STEP 2. 2- (2-ChlorobenzD-3- (5-fluoro-1-methyl-1,2-dihydro-1'H-spiroUndol-3,4'-piper) acid Din] -1'-D -propanoic The title compound was prepared according to the procedure described in step 5 of Example 4 starting from 2- (2-chlorobenzyl) -3- (5-fluoro-1-methyl). Ethyl l-1, 2-dihydro-1? -spiro [indol-3,4'-piperidin] -1'-yl) propane (step 1): MS (ESI) 417 (M + Hf, 415 (M-Hf EXAMPLE 19 2- (2-Fluoro-5-hydroxybenzDi-3- (1-methyl-2-oxo-1,2-dihydro-1? espirof indole- 3.4'-piperidin-1 '' -iDpropanoic STAGE 3r (5- (rferc-Butyl (dimethyDsilylpoxy) -2-fluoropheniP-2- (ethyl diethoxyphosphorylpropanoate) The title compound was prepared according to the procedure described in step 1 of example 17 from [ 3- (bromomethyl) -4-fluorophenoxy] (fer-butyl) dimethylsilane (step 2 of example 9): 1 H-NMR (CDCl 3) d 6.86 (1H, t, J = 6.9 Hz), 6.68 -6.81 (2H, m), 4.24-4.06 (6H, m), 3.37-3.12 (3H, m), 1.38-1.33 (6H, m), 1 , 18 (3H, t, J = 7.2 Hz), 0.96 (9H, s), 0.15 (6H, s). STEP 2. 2- (5-Ffferc-Butyl (ethyl) -Dys-linoxy-2-fluorobenzylcarbonate The title compound was prepared according to the procedure described in step 2 of example 17 from 3- (5-. {[[ferc-butyl (dimethyl) silyl] oxy] -2. fluorophenyl) -2- (ethyl diethoxyphosphorylpropanoate (step 1): 1H-NMR (CDCl3) d 6.91-6.85 (1H, m), 6.67-6.62 (2H, m), 6.25 (1H, d, J = 1.1) Hz), 5.44-5.42 (1H, m), 4.21 (2H, c, J = 7.2 Hz), 3.59 (2H, s), 1, 28 (3H, t, J = 7.2 Hz), 0.96 (9H, s), 0.16 (6H, s). STAGE 3. 2- (5-rferc-Butyl (d-methyl) -Dsilynoxy-T-2-fluorobenzD-3- (1-methyl-2-oxo-1,2-dihydro-1? -espirofindol-3,4'-piperidin-V1 '-iD-propanoate ethyl ester The title compound was prepared according to the procedure described in step 4 of example 4 from 1-methylspiro [indole-3,4'-piperidine] -2 (1H) -one (step 3 of example 10 ) and ethyl 2- (5- { [fer-butyl (dimethyl) silyl] oxy]., 2-fluorobenzyl) acrylate (step 2): 1 H-NMR (CDCl 3) d 7.39 (1H, d, J = 7.1 Hz), 7.31-7.25 (1H, m), 7.04 (1H, t, J = 7.8 Hz), 6.89-6.82 (2H, m ), 6.68-6.61 (2H, m), 4.13 (2H, c, J = 7.1 Hz), 3.19 (3H, s), 3.03-2.57 (9H, m), 1.98-1.69 (4H, m), 1.21 (3H, t, J = 7.4 Hz), 0.97 (9H, s), 0.17 (6H, s); MS (ESI) 555 (M + Hf. STEP 4. 2- (2-Fluoro-5-hydroxybenzyl-3- (1-methyl-2-oxo-1,2-dihydro-177-espiropndol-3) acid., 4'-piperidin-1'-diDPAnoic The title compound was prepared according to the procedure described in step 5 of Example 4 from 2- (5- { [Ferc-butyl (d-methyl) ) silyl] oxy] -2.-fluorobenzyl) -3- (1-methyl-2-oxo-1,2-dihydro-1? -espyrro [Ido-3,4'-piperidine] Ethyl-1'-dDiopanoate (step 3): MS (ESI) 413 (M + Hf, 411 (M-H). "EXAMPLE 20 2- (6-Chloro-2-fluoro-3-hydroxybenzide) trifluoroacetate 3- (1? .3H-Spiror2-benzofuran-1, 4'-piperidin-1'-diD-dopanoic) STEP 1. ferc-Butyl (4-chloro-2-fluorophenoxyD-dimethylsilane) The title compound was prepared according to the procedure described in step 1 of example 9 from 4-chloro-2-fluorophenol: 1 H-NMR (CDCl 3) d 7.08 (1H, dd, J = 10.3, 2.4 Hz), 6.97 (1H, ddd, J = 8.7, 2.4, 1.5 Hz), 6.83 (1H, t, J = 8.7 Hz), 0.99 (9H, s), 0.18 (6H, s). STEP 2. ferc-Butyl (4-chloro-2-fluoro-phenoxypdimethylsilane) The title compound was prepared according to the procedure described in step 1 of example 14 from fer-butyl (4-cyclo-2-fluorophenoxypdimethylsilane ( step 1): 1 H-NMR (CDCl 3) d 7.05 (1 H, dd, J = 8.7, 1.8 Hz), 6.82 (1 H, d, J = 8.7 Hz), 4.83 (2H, dd, J = 6.8, 2.3 Hz), 1.00 (9H, s), 0.19 (3H, s), 0.19 (3H, s); MS (EI) 233 (M-* Buf STEP 3. r3- (BromometiD-4-chloro-2-fluorophenoxy (ferc-butiD-dimethylsilane) The title compound was prepared according to the procedure described in step 2 of example 14 a from fer-butyl (4-chloro-2-fluorophenoxy) dimethylsilane (step 2): 1 H-NMR (CDCl 3) d 7.06 (1H, dd, J = 8.7, 1.6 Hz), 6.83 (1H, t, J = 8.7 Hz), 4.61 (2H, d, J = 2.0 Hz), 1.00 (9H, s), 0.19 (6H, s). STEP 4. 2- (6-Chloro-2-fluoro-3-hydroxybenzyl-D-3- (1'-trifluoromethyl-3-spiro-benzofuran-1,4'-piperidin-1'-di-ferrobutyl) The title compound was prepared according to the procedure described in step 2 of example 1 from 3- (1 'H, 3-spiro [2-benzofuran-1,4'-piperidin] -1'-di-d-butpanoate of fer-butyl (WO 2003064425) and [3- (bromomethyl) -4-chloro-2-fluorophenoxy] (fer-butyl) dimethylsilane (step 3): 1 H-NMR (CDCl 3) d 7.29-7.17 (3H, m) , 7.11-7.06 (1H, m), 7.02 (1H, dd, J = 8.8, 1.8 Hz), 6.80 (1H, t, J = 8.8 Hz), 5.05 (2H, s), 3.07-2.73 (6H,), 2.56-2.37 (3H, m), 1.95-1.65 (4H, m), 1.39 (9H, s); MS (ESI) 476 (M + Hf, 474 (M-Hf STEP 5. 2- (6-Chloro-2-fluoro-3-hydroxybenzD-3- (1?. 3 H -spirof2-benzofuran-1, trifluoroacetate, 4'-piperidiñl-1 '-iDpropanoic The title compound was prepared according to the procedure described in step 3 of example 1 from 2- (6-chloro-2-fluoro-3-hydroxybenzyl) -3- ( 1?, 3 H-spiro [2-benzofuran-1, 4'-piperidin] -1'-yl) propane-butyl stearate (step 4): 1 H-NMR (CDCl 3) d 9.63 (1H, sa), 7.45-6.84 (6H, m), 5.07 (2H, s), 3.79-2.90 (9H, m), 2.58-1, 78 (4H, m); IEN) 420 (M + Hf, 418 (M-H). "EXAMPLE 21 3- (2,3-Dihydro-1? -espiropnden-1,4'-piperidin-1'-iD-2- (pyridin-2-trifluoroacetate) ilmetiDpropanoico STAGE 1. 3- (2,3-Dihydro-1? -esp¡rofinden-1,4'-piper¡d¡n1-1'-D-2- (pyridin-2-ylmethylpropanoate of fer-butyl The title compound was prepared according to the procedure described in step 2 of example 1 from 3- (2,3-dihydro-1 'V-spiro [inden-1,4'-piperidin] -1'-dihydroxypropionate). butyl (WO 2003064425) and 2- (bromomethyl) pyridine: 1 H-NMR (CDCl 3) d 8.58-8.51 (1H, m), 7.64-7.52 (1H, m), 7.29- 7.06 (6H, m), 3.20-1.32 (17H, m), 1.38 (9H, m); MS (ESI) 407 (M + Hf. STEP 2. Trifluoroacetate of 3- (2,3-dihydro-1 '- espyrn-n-1,4'-piperidine M'-D-2- (pyridin-2-ylmet Dopropanoic The title compound was prepared according to the procedure described in step 3 of Example 1 from 3- (2,3-dihydro-1'H-spiro [inden-1'-piperidin-1-yl]. iD ^ -Ir-butyl ylpyridin-ylmethylppropanoate (step 1). 1 H-NMR (CDCl 3) d 8.74-7.83 (4H, m), 7.29-7.11 (4H, m), 3 , 92-2.03 (15H, m), 1.89-1.74 (2H, m); MS (ESI) 351 (M + Hf, 349 (M-H) '. EXAMPLE 22 2- (5-. {Rferc-butyl (dimethylsilyoxy) -2-methylbenzyd- acid trifluoroacetate 3- (1? .3H-Spiro-2-benzofuran-1.4'-piperidin-1'-diD-dopanoic) TFA STEP 1. Methyl 5-hydroxy-2-methylbenzoate To a stirred solution of 5-hydroxy-2-methylbenzoic acid (WO 9619437, 1.11 g, 6.69 mmol), in dichloromethane (6 ml) and methanol ( 6 ml) was added a 2.0 M solution of (trimethylsilyl) diazomethane in diethyl ether (7.31 ml, 14.7 mmol) at 0 ° C. The mixture was stirred at room temperature for 3 days and the mixture was diluted with dichloromethane (200 ml). The solution was washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was purified by column chromatography on silica gel (40 g) eluting with hexane / ethyl acetate (10/1) yielding 545 mg (49%) of the title compound: 1 H-NMR (CDCl 3) d 7.42. (1H, d, J = 2.8 Hz), 7.12 (1H, d, J = 8.4 Hz), 6.91 (1H, dd, J = 8.4, 2.8 Hz), 3 , 89 (3H, s), 2.51 (3H, s); MS (EI) 166 (Mf. STAGE 2. 5- (Methyl fferc-Butyl (dimethyldysinoxy) -2-methylbenzoate The title compound was prepared according to the procedure described in step 1 of Example 9 from methyl 5-hydroxy-2-methylbenzoate (step 1): 1 H-NMR (CDCl 3) d 7.87 (1H, d, J = 2.6 Hz), 7.09 (1H, d, J = 8.3 Hz), 6.89 (1H, dd, J = 8.3, 2.6 Hz), 3.88 (3H, s), 2.51 (3H, s), 0.98 ( 9H, s), 0.19 (6H, s) STEP 3. (5-Ffferc-Butyl (dimethylDs-lipoxfl-2-methylene) methanol To a stirred solution of 5- { [Fer-butyl ( methyl dimethyl) silyl] oxy.} -2-methylbenzoate (step 2, 810 mg, 2.89 mmol) in dichloromethane (15 ml) was added a 0.95 M solution of diisobutylaluminum hydride in hexane (6, 69 ml, 6.35 mmol) at -78 ° C. The mixture was stirred at -78 ° C. for 2 hours.The reaction was quenched by the addition of water (6.7 ml) at -78 ° C. The mixture was dried with dichloromethane (50 ml) and hexane (50 ml), and the mixture was stirred at room temperature for 16 hours. MgSO 4 and concentrated to yield 724 mg (99%) of the title compound as a colorless oil: 1 H-NMR (CDCl 3) d 7.02 (1H, d, J = 8.1 Hz), 6, 88 (1H, d, J = 2.6 Hz), 6.68 (1H, dd, J = 8.1, 2.6 Hz), 4.64 (2H, d, J = 5.6 Hz), 2.26 (3H, s), 1.48 (1H, t, J = 5.6 Hz), 0.98 (9H, s), 0.19 (6H, s). STEP 4. f3- (Bromometho-P-4-methylphenoxy1 (ferc-butiD-dimethylsilane) The title compound was prepared according to the procedure described in step 2 of example 14 from (5-. {[[Fer-butyl ( dimethyl) silyl] oxy} - 2-methylphenyl) methanol (step 3). 1 H-NMR (CDCl 3) d 7.02 (1 H, d, J = 8.3 Hz), 6.80 (1 H, d, J = 2.6 Hz), 6.70 (1 H, dd, J = 8.3, 2.6 Hz), 4.44 (2H, s), 2.32 (3H, s) 0.98 (9H, s), 0.18 (6H, s) STEP 5. 2- (5-flferc-butyl (dimethydisilypoxy) -2-methylbenzyl-3- (1'H) .3H-Spiror-2-benzofuran-1,4'-piperidin-1'-di-tert-butyl-d-propane The title compound was prepared according to the procedure described in step 2 of Example 1 from 3- (1 'H, 3H-spiro [2-benzofuran-1,4'-piperidine] -1'-di-d-propane-butyl ester (WO 2003064425) and [3- (bromomethyl) -4-methylphenoxy] (fer-butyl) dimethylsilane ( step 4): 1 H-NMR (CDCl 3) d 7.30-7.07 (4H, m), 6.96 (1H, d, J = 8.2 Hz), 6.67 (1H, d, J = 2.6 Hz), 6.58 (1H, dd, J = 8.2, 2.6 Hz), 5.06 (2H, s), 2.92-2.70 (6H, m), 2, 52-2.32 (3H, m), 2.24 (3H, s), 1, 99-1.83 (2H, m), 1.78-1.68 (2H, m), 1.39 ( 9H, s), 0.97 (9H, s), 0.17 (6H, s); MS (ESI) 552 (M + H) STEP 6. Trifluoroacetate of 2- (5-ffferc-butyl (dimethylDsilyloxy) -2-methylbenzyl-3- (1? .3H-espiror2-benzofuran-1.4'-p Peridin-1-d-D-propane The title compound was prepared according to the procedure described in step 3 of Example 1 starting from 2- (5- { [Ferc-butyl (dimethyl) silyl] oxy} - 2-methylbenzyl) -3- (1?, 3AY-spiro [2-benzofuran-1, 4'-pi? Er¡d¡n] -1'-di-d-butpanoate of fer-butyl (step 5): 1H -NRM (CDCb) d 7.38-6.79 (5H, m), 6.67 (1H, dd, J = 8.3, 2.6 Hz), 6.59 (1H, d, J = 2 , 6 Hz), 5.04 (2H, s), 3.69-2.14 (11H, m), 2.26 (3H, s), 1.91-1.76 (2H, m), 0 98 (9H, s), 0.18 (6H, s); MS (ESI) 496 (M + Hf) EXAMPLE 23 2- (2-ChlorobenzD-3- (6-fluoro-1 '- .3H-) acid espirof2-benzofuran-1, 4'-piperidin | - 1 '-iDpropanoic STEP 1. 2- (2-ChlorobenzD-3- (6-fluoro-1'H.3H-espíror2-benzofuran-1.4'-piperidinl-1'-di-d-propane-ethyl ester The title compound was prepared according to the procedure described in step 4 of example 4 from 6-fluoro-3/7-spiro [2-benzofuran -1,4'-piperidine] (J. Med. Chem. 1995, 38, 2009.) and 2- ( 2-chlorobenzyl) ethyl acrylate (step 2 of example 17): 1 H-NMR (CDCl 3) d 7.36-7.32 (1H, m), 7.24-7.10 (4H, m), 6, 95 (1H, dt, J = 8.8, 2.2 Hz), 6.79 (1H, dd, J = 8.4, 2.2 Hz), 5.00 (2H, s), 4.16-4.04 (2H, m), 3, 15- 3.05 (2H, m), 2.95-2.76 (4H, m), 2.56-2.33 (3H, m), 1.86 (2H, dt, J = 12.5 , 4.8 Hz), 1.75-1.69 (2H, m), 1.14 (3H, t, J = 7.2 Hz); MS (ESI) 432 (M + Hf. STAGE 2. 2- (2-ChlorobenzD-3- (6-fluoro-1?. 3 H -sp-2-benzofuran-1,4'-piperidin-1'-di-d-propanoic acid of the title was prepared according to the procedure described in step 5 of example 4 from 2- (2-chlorobenzyl) -3- (6-fluoro-1'H, 3H-spiro [2-benzofuran-1, 4 Ethyl '-piperidine] -1'-iDpropanoate (step 1): 1 H-NMR (DMSO-6) d 7.42-7.35 (2H, m), 7.30-7.04 (5H, m) , 4.91 (2H, s), 3.65-3.27 (1H, m), 2.58-2.50 (5H, m), 2.39-2.14 (3H, m), 1 , 93-1.74 (2H, m), 1.61-1.53 (2H, m); MS (ESI) 404 (M + Hf, 402 (M-H). "EXAMPLE 24 2- (2-Acid) -fluoro-5-hydroxybenzyd-3- (6-fluoro-1? .3H-espiror2-benzofuran-1.4'-piperidin-1 '-Dpropanoic acid STAGE 1. 2- (5- (rferc-Butyl (dimethylsulfonyl) -2-fluorobenzyl-3- (6-fluoro-1'H.3H-espiror2-benzofuran-1.4'- ethyl pyridinyl-1'-yl) propanoate The title compound was prepared according to the procedure described in step 4 of example 4 from 6-fluoro-3A / -spiro [2-benzofuran- 1,4'-piperidine] (J. Med. Chem. 1995, 38, 2009.) and 2- (5- { [Ferc-butyl (dimethyl) syl] oxy] -2-fluorobenzyl) ethyl acrylate (step 2 of Example 19): 1 H-NMR (CDCl 3) d 7.12 (1 H, dd, J = 8.3, 4.8 Hz), 6.98-6.77 (3H, m), 6.67-6.60 (2H, m), 5.00 (2H, s), 4.24-4.05 (2H, m), 2.98-2.72 (6H, m) , 2.52-2.32 (3H, m), 1.91-1.82 (2H, m), 1.76-1, 68 (2H, m), 1.19 (3H, t, J = 7.2 Hz), 0.97 (9H, s), 0.17 (6H, s), EM (IEN) 546 (M + Hf. STAGE 2. 2- (2-Fluoro-5-hydroxybenzyl) -3- (6-fluoro-1'R3H-spiro-2-benzofuran-1.4'-piperidin-1'-diD-dopanoic The title compound was prepared according to the procedure described in step 5 of example 4 from 2- ( 5- { [Ferc-butyl (dimet l) silyl] oxy] .2. - 2-fluorobenzyl) -3- (6-fIuoro-1 '/ -, 3-spiro [2-benzofuran-1,4'-piperidine] -1' - l) ethyl propanoate (step 1): 1 H-NMR (DMSO-cfe) d 9.28 (1H, s), 7.29 (1H, dd, J = 8.3, 5.0 Hz), 7, 18 (1H, dd, J = 9.1, 2.1 Hz), 7.12-7.06 (1H, m), 6.93 (1H, dd, J = 9.8, 8.9 Hz) , 6.66-6.56 (2H, m), 4.93 (2H, s), 3.74-3.28 (1H, m), 2.93-2.64 (6H, m), 2 , 52-2.25 (3H, m), 1.96-1.82 (2H, m), 1.67-1.57 (2H, m); MS (ESI) 404 (M + Hf, 402 (M-H). "EXAMPLE 25 2-Benzyl-3- (6-fluoro-17 - /, 3-spiro-2-benzofuran-1,4'-piperidinyl) trifluoroacetate -1 '-iDpropanoic STEP 1. 2-Benzyl-3- (6-fluoro-1'H.3H-spiro-2-benzofuran-1,4'-piperidn-1'-di-tert-butyl dicarboxylate The title compound was prepared in accordance with the procedure described in step 4 of example 4 from 6-fluoro-3-spiro [2-benzofuran-1,4'-piperidine] (J. Med. Chem. 1995, 38, 2009.) and 2- ferric butyl benzylacrylate (Tetrahedron Lett, 1990, 31, 4413.): 1 H-NMR (CDCl 3) d 7.30-7.11 (6H, m), 6.98-6.92 (1H, m), 6.78 (1H, dd, J = 8.3, 2.3 Hz), 5.01 (2H, s), 2.89-2.69 (6H, m), 2.50-2.32 (3H, m), 1, 92-1, 71 (4H , m), 1.36 (9H, s); MS (ESI) 426 (M + Hf. STAGE 2. 2-Benzyl-3- (6-fluoro-1'H 3 -spiror-2-benzofuran-1,4'-piperidin-N-di-d-propanoic acid trifluoroacetate The title compound was prepared according to the procedure described in step 3 of example 1 from 2-benzyl-3- (6-fluoro-1'H, 3H-spiroP-benzofuran-1'-piperidin-1-di-D-propanoate). fer-butyl (step 1): 1 H-NMR (CDCl 3) d 7.38-7.29 (3H, m), 7.21-7.14 (3H, m), 7.05-6.99 (1H , m), 6.79 (1H, dd, J = 8.1, 2.2 Hz), 5.01 (2H, s), 3.70-3.53 (3H, m), 3.42- 3.24 (3H, m), 3.03-2.70 (3H, m), 2.42-2.28 (2H, m), 1.94-1, 84 (2H, m); ESI) 370 (M + Hf, 368 (M-H). "EXAMPLE 26 2- (2-Chloro-5-hydroxybenzDi-3- (1-methyl-2-oxo-1,2-dihydro-1 '/ -) acid espirofindol-3. 4'-piperidin1-1 '-Dpropanoic STEP 1. 2- (5-Fert-Butyl (d-methyldinosilyoxy) -2-chlorobenzyd-3- (1-methyl-2-oxo-1,2-dihydro-1β-esopyridol-3,4'-piperidin) 1'-ethylpropanoate The title compound was prepared according to the procedure described in step 4 of example 4 from 1-methylspiro [indole-3,4'-piperidine] -2 (1H) -one ( step 3 of example 10) and 2- (5-. {[[ferc-butyl] (dimethyl) silyl] oxyl] -2-chlorobenzyl) ethyl acrylate (step 2 of example 30): 1H -NRM (CDCI3) d 7.39 (1H, d, J = 6.6 Hz), 7.31-7.25 (1H, m), 7.18 (d, J = 8.7) Hz), 7.04 (1H, dt, J = 7.5, 1.0 Hz), 6.84 (1H, d, J = 7.6 Hz), 6.73-6.70 (1H, m ), 6.64 (1H, dd, J = 8.6, 3.0 Hz), 4.26-4.04 (2H, m), 3.19 (3H, s), 3.12-2, 58 (9H, m), 1.98-1.87 (2H, m), 1.79-1.69 (2H, m), 0.97 (9H, s), 0.18 (6H, s); MS (ESI) 571 (M + Hf. STEP 2. 2- (2-Chloro-5-hydroxybenzDi-3- (1-methyl-2-oxo-1,2-dihydro-1'rV-espirorindol-3,4'-piperidin-1) -1'-iPpropanoic The title compound was prepared according to the procedure described in step 4 of example 30 from 2- (2-chlorobenzyl) -3- (1-methyl-2-oxo-1, 2- Dihydro-1? -espyrro [indol-3,4'-piperidin] -1'-dihydroacetate (step 1): MS (lEN) 429 (M + Hf, 427 (M-Hf EXAMPLE 27 Trifluoroacetate of 2- (2-chloro-5-fluorobenzyd-3- (1'ry.3H-espyr2-benzofuran-1,4'-piperidin-1'-D-propanoic acid STEP 1. 2- (2-Chloro-5-fluorobenzyl-3- (1'H.3H-espyr2-benzofuran-1,4'-piperidin-1-di-d-propane-fer-butyl) The title compound was prepared from according to the procedure described in step 2 of example 1 starting with 3- (1'H, 3H-spiro [2-benzofuran-1,4'-piperidin] -1'-yl) propane-butyl ester and - (bromomethyl) -1-chloro-4-fluorobenzene (J. Heterocyclic Chem. 1997, 34, 27.): 1 H-NMR (CDCl 3) d 7.36-7.09 (5H, m), 7.01 ( 1 H, dd, J = 9.2, 3.0 Hz), 6.88 (1H, td, J = 8.3, 3.0 Hz), 5.06 (2H, s), 3.08- 2.70 (6H, m), 2.55-2.37 (3H, m), 1.97- 1.67 (4H, m), 1.38 (9H, s), MS (IEN) 460 ( M + Hf. STAGE 2. 2- (2-Chloro-5-fluorobenzyd-3- (1'H, 3 / - / - esp.ror2-benzofuran-1.4'-pperidin1-1 'trifluoroacetate. -Dpropanoic The title compound was prepared according to the procedure described in step 3 of example 1 starting from 2- (2-cyoro-5-fluorobenzyl) -3- (1'H, 3 -spiro [2 -benzofuran-1,4'-piperidine] -1'-di-d-butpanoate of fer-butyl (step 1): 1 H-NMR (CDCl 3) d 7,37-7,1 0 (5H, m), 7.05-6.91 (2H, m), 5.07 (2H, s), 3.76- 3.57 (3H, m), 3.48-3.09 ( 4H, m), 3.00-2.87 (2H, m), 2.54-2.27 (2H, m), 1.98-1.80 (2H, m); MS (ESI) 404 (M + Hf. EXAMPLE 28 2- (5-Ifferc-butyl (dimethylsilyoxy > -2-fluorobenzyl) -3- (5-f-1-methyl-1,2-dihydro) trifluoroacetate -1? -esp¡rorindol-3,4'-piperidin1-1 '-Dpropanoic STEP 1. 3- (5-Fluoro-1-methyl-1,2-dihydro-1? 7-espiropndol-3,4'-p.peridinyl-1'-di-d-butpanoate) The title compound was prepared in accordance with the procedure described in step 1 of example 1 from 5-fluoro-1-methyl-1,2-dihydrospiro [indole-3,4'-piperidine] (step 3 of example 4): 1 H-NMR (CDCl 3) d 6.81-6.74 (2H, m), 6.36 (1H, dd, J = 8.0, 4.2 Hz), 3.18 (2H, s), 2.89-2.82 (2H, m), 2.72 (3H, s), 2.68 (2H, d, J = 7.8 Hz), 2.45 (2H, t, J = 7.4) Hz), 2.14 (2H, dt, J = 11.8, 2.7 Hz), 1.86 (2H, dt, J = 12.7, 3.8 Hz), 1.71 (2H, da , J = 12.0 Hz), 1.46 (9H, s); MS (ESI) 349 (M + Hf. STEP 2. 2- (5- { Rferc-Butyl (dimethylsinoxy) -2-fluorobenzyl-3- (5-fluoro-1-methyl) 1,2-dihydro-1? -espirophenol-3,4'-piperidin-1'-di-tert-butyl ester The title compound was prepared according to the procedure described in step 2 of example 1 from 3- (5 -fluoro-1-methyl-1, 2-dihydro-1'H-spiro [indol-3,4'-pyrperidin] -1'-yl) propane-butyl ester (stage 1) and [3- ( bromometyl) -4-fluorophenoxy] (fer-butyl) dimethylsilane (step 2 of example 9): 1 H-NMR (CDCl 3) d 6.91-6.59 (5H, m), 6.35 (1H, dd , J = 8.3, 4.1 Hz), 3.16 (2H, s), 2.93-2.64 (9H, m), 2.42 (1H, dd, J = 12.1, 5 , 7 Hz), 2.20-2.04 (2H, m), 1.86-1, 76 (2H, m), 1.69-1, 63 (2H, m), 1.38 (9H, s), 0.97 (9H, s), 0.17 (6H, s), MS (ESI) 587 (M + Hf. STEP 3. Trifluoroacetate of 2- (5-flferc-butyl (d.methyl-Silypoxy) 2-FluorobenzD-3- (5-fluoro-1-methyl-1,2-dihydro-1? -espyrofindole-3,4'-pperiodin-1'-di-propane) The title compound was prepared in accordance with The p procedure described in step 3 of example 1 from 2- (5-. { [ferc-butyl (dimethyl) silyl] oxy} -2-fluorobenzyl) -3- (5-fluoro-1-methyl-1,2-dihydro-1? -spiro [indol-3,4'-piperidin] -1'-di-d-butpanoate of fer-butyl (step 2) : MS (ESI) 531 (M + Hf, 529 (M-H)? EXAMPLE 29 2- (5- { Rferc-butyl (dirnetiDsilylpoxy!) -2-c! Orobenzyl) trifluoroacetate - 3- (5-fluoro-1-methyl-1,2-dihydro-1'-tf-espyropndol-3,4'-piperidin-1'-di-propane) STEP 1. 2- (5- (f-Fert-Butyl (d-methylsilynoxy> -2-chlorobenzyl-3- (5-fluoro-1-methyl-1,2-dihydro-1? -espirophenol-3,4'-piperidyl) n1-1'-Di-butyl butyl dpropanoate The title compound was prepared according to the procedure described in step 2 of Example 1 from 3- (5-fluoro-1-methyl-1,2-dihydro-177 - spiro [indole-3,4'-piperidn] -1'-yl) propane-butyl ester (step 1 of example 28) and [3- (bromomethyl) -4-chlorophenoxy] (fer-butyl) dimethylsilane (J. Org. Chem. 1996, 61, 6974): 1 H-NMR (CDCl 3) d 7.17 (1 H, d, J = 8.6 Hz), 6.80-6.71 (3H, m ), 6.63 (1H, dd, J = 8.6, 2.9 Hz), 6.35 (1H, dd, J = 8.3, 4.1 Hz), 3.16 (2H, s) , 2.95-2.66 (9H, m), 2.43 (1H, dd, J = 12.2, 5.6 Hz), 2.21-2.08 (2H, m), 1.86 -1.75 (2H, m), 1.70- 1.63 (2H, m), 1.39 (9H, s), 0.97 (9H, s), 0.18 (6H, s); MS (ESI) 603 (M + Hf. STEP 2. 2- (5-Ffferc-butyl) trifluoroacetate (dimethylsilyoxy-2-chlorobenzyl-3- (5-fluoro-1-methyl-1,2-dihydro-1? -spiror Ndol-3.4'-p¡peridin1-1 '- Dpropanoic The compuest or the title was prepared according to the procedure described in step 3 of example 1 from 2- (5-. { [fer-butyl (dimethyl) silyl] oxy} - 2-chlorobenzyl) -3- (5-fluoro-1-methyl-1,2-dihydro-1? -spiro [indoI-3,4'-piperidin] -1'-ferrobutyl-di-propane-dopa (step 1): MS (ESI) 547 (M + Hf, 545 (M-H) 'EXAMPLE 30 2- (2-Chloro-5-hydroxybenzyl-3- (5-fluoro-1-methyl-2-oxo- 1,2-dihydro-1 '/ • / - espiropndol-3,4'-piperidin-1'-iDpropanoic acid (ethyl diethyphosphorylpropanoate) The title compound was prepared according to the procedure described in step 1 of example 17 from [3- (bromomethyl) -4-chlorophenoxy] (fer-butyl) d -methyl-silane (J. Org. Chem. 1996, 61, 6974.): 1 H-NMR (CDCl 3) d 7.18 (1 H, d, J = 8.6 Hz), 6.75 (1 H, d, J = 2.8 Hz) , 6.65 (1H, dd, J = 8.6, 2.8 Hz), 4.30-4.02 (6H, m), 3.50-3.10 (3H, m), 1.37 (3H, t, J = 7.1 Hz), 1.36 (3H, t, J = 7.1 Hz), 1.19 (3H, t, J = 7.1 Hz), 0.96 (9H , s), 0.17 (6H, s) STEP 2. 2- (5-ffferc-Butyl (dimethylDsilylpoxy) -2-chlorobenzyl-ethyl acrylate The title compound was prepared according to the procedure described in step 2 of Example 17 from ethyl 3- (5-. {[ethyl-ethyl-butyl (dimethyl) SiIyl] oxy} -2-chlorophenyl) -2- (diethoxyphosphoryl) propane (step 1): 1H -NMR (CDCl 3) d 7.21 (1H, d, J = 8.6 Hz), 6.72 (1H, d, J = 2.8 Hz), 6.66 (1H, dd, J = 8, 6, 2.8 Hz), 6.28-6.25 (1H, m), 5.36-5.32 (1H, m), 4.22 (2H, c, J = 7.1 Hz), 3.68 (2H, s), 1, 29 (3H, t, J = 7 , 1 Hz), 0.96 (9H, s), 0.17 (6H, s). STEP 3. 2- (5-f-rferc-Butyl (dimethyldsilynoxy) -2-chlorobenzyl-3- (5-fluoro-1-methyl-2-oxo-1,2-dihydro-1? ethylpyrrolidol-3,4'-piperidin-1'-ethylpropanoate The title compound was prepared according to the procedure described in step 4 of example 4 from 5-fluoro-1 -methylspiro [indole-3,4'-piperidine] -2 (1 W) -one (step 3 of example 6) and 2- (5- { [ferc-butyl (dimethyl) silyl] oxy] -2. -chlorobenzyl) ethyl acrylate (step 2): 1 H-NMR (CDCl 3) d 7.18 (1H, d, J = 8.6 Hz), 7.14 (1H, dd, J = 8.3, 2, 4 Hz), 7.02-6.93 (1H, m), 6.77-6.70 (2H, m), 6.64 (1H, dd, J = 8.6, 2.9 Hz), 4.20-4.00 (2H, m), 3.18 (3H, s), 3.15-2.80 (6H, m), 2.75-2.50 (3H, m), 2, 00-1.85 (2H, m), 1.75-1.60 (2H, m), 1.20 (3H, t, J = 7.2 Hz), 0.97 (9H, s), 0 18 (6H, s) MS (ESI) 589 (M + Hf. STAGE 4. 2- (2-Chloro-5-hydroxybenzDi-3- (5-fluoro-1-methyl-2-oxo-1,2- dihydro-1? -espyrorindole-3,4'-piperidin-1'-di-dopanoic acid To a stirred solution of 2- (5- { [ferc-butyl (dimethyl) silyl] oxy} -2-chloro benzyl) -3- (5-fluoro-1-methyl-2-oxo-1,2-dihydro-1? -espyr [indol-3,4'-piperidin] -1'-ethylpropanoate (stage 3, 0.79 g, 1.3 mmol) in tetrahydrofuran (5 ml) and methanol (3 ml) was added a 2N aqueous sodium hydroxide solution (3.5 ml) at room temperature. The reaction mixture was stirred at room temperature for 20 hours, evaporated to remove methanol, and acidified with an aqueous solution of sodium hydrogen phosphate (pH = 4-5). The aqueous phase was extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate, and evaporated yielding 0.65 g (quant.) Of the title compound as a white solid: 1H-NMR (DMSO-d6) d 9.62 (1H, s), 7.53-7.43 (1H, m), 7.20 (1H, d, J = 7.9 Hz), 7.17-7.08 (1H, m), 7 , 07-6.98 (1 H, m), 6.74 (1 H, d, J = 2.5 Hz), 6.65 (1 H, dd, J = 7.9, 2.5 Hz) , 3.11 (3H, s), 3.10-2.60 (9H, m), 1.98-1.60 (4H, m); MS (ESI) 447 (M + H, 445 (M-Hf EXAMPLE 31 2- (2-Fluoro-5-hydroxybenzD-3- (5-fluoro-1-methyl-2-oxo-1.2- dihydro-1? -espyrorindole-3,4'-piperidinH'-Dpropanoic acid STEP 1. 2- (5-frferc-Butyl (dimethylsilylxoxy> -2-fluorobenzyl-3- (5-fluoro-1-methyl-2-oxo-1,2-dyrh-1-esopyridol- Ethyl 3,4'-piperidin-1'-dihydroxypropionate The title compound was prepared according to the procedure described in step 4 of Example 4 from 5-fluoro-1-methylspiro [indole-3,4'- piperidine] -2 (1 ^) -one (stage 3 of example 6) and 2- (5- { [ferric-butyl (dimethyl) silyl] oxy] .2-fluorobenzyl) acrylate ethyl (step 2 of example 19): 1 H-NMR (CDCl 3) d 7.14 (1H, dd, J = 8.3, 2.4 Hz), 7.02-6.93 (1H, m), 6 , 90-6.82 (1H, m), 6.74 (1H, dd, J = 8.5, 4.1 Hz), 6.68-6.59 (2H, m), 4.18-4.04 (2H, m ), 3.18 (3H, s), 3.07-2.53 (9H, m), 2.00-1, 85 (2H, m), 1.77-1.63 (2H, m), 1.20 (3H, t, J = 7.2 Hz), 0.97 (9H, s), 0.17 (6H, s); MS (ESI) 573 (M + Hf. STEP 2. 2- (2-Fluoro-5-hydroxybenzyl-3- (5-fluoro-1-methyl-2-oxo-1,2-dihydro-1? -espyrorindole) -3,4'-piperidin-1 '' -iDpropanoic The title compound was prepared according to the procedure described in step 5 of Example 4 from 2- (5- { [P-butyl (dimethyl) silyl) ] oxy.} - 2-f luorobenzyl) -3- (5-fluoro-1-methyl-2-oxo-1,2-dihydro-1? -spiro [indole-3,4'-piperidin] - 1'-yl) ethyl propanoate (step 1): 1 H-NMR (DMSO-cfe) d 9.27 (1H, s), 7.52-7.43 (1H, m), 7.19-7 , 08 (1H, m), 7.02 (1H, dd, J = 8.2, 4.2 Hz), 6.93 (1H, t, J = 9.1 Hz), 6.69-6, 55 (2H, m), 3.11 (3H, s), 3.05-2.45 (9H, m), 1.88-1.58 (4H, m); MS (IEN) 431 (M + Hf, 429 (M-Hf.) EXAMPLE 32 3- (1? .3H-Spiro-2-benzofuran-1,4'-piperidin-1'-iD-2- (1,3-thiazol-4-ethyl) trifluoroacetate. Dpropanoic STAGE 1. 3-ñ? 3H-Espir-2-benzofuran-1,4'-piperidin-1 '-iD-2- (1,3-thiazol-4-ylmethylpropanoate) ferric-butyl A mixture of 4-methyl-1, 3-thiazole (505 mg, 5.09 mmol), N-bromosuccinimide (952 mg, 5.35 mmol) and 2,2'-azobisisobutyronitrile (83.5 mg, 0.509 mmol) in carbon tetrachloride (20 ml. ) was heated to reflux in a nitrogen atmosphere for 2 hours.The reaction mixture was cooled to room temperature, and the resulting white precipitate was filtered.The filtrate was diluted with toluene and partially evaporated yielding 4- (bromomethyl) -1 , Crude 3-thiazole as a solution in toluene, which was used in the next step without purification, to a stirred solution of 3- (1α, 3H-spiro [2-benzofuran-1,4'-piperidine] - 1 '-Di-butyl dpropanoate (WO 2003064425, 450 mg, 1.42 mmol) in tetrahydrofuran (10 ml) was added dropwise a 1.0 M solution of lithium bis (trimethylsilyl) amide. in tetrahydrofuran (1.84 ml, 1.84 mmol) at -78 ° C and the mixture was stirred 30 minutes at the same temperature. To the mixture was added 1,3-d.methyl-3,4,5,6-tetrahydro-2 (1 /) -pyrimidinone (0.223 ml, 1.84 mmol) at -78 ° C and it was stirred for 30 minutes at the same temperature. To the resulting mixture was added a solution of crude 4- (bromomethyl) -1,3-thiazole in tetrahydrofuran (2 ml) and the reaction mixture was stirred at the same temperature for 30 minutes and then at -30 ° C. for 2 hours. The reaction mixture is quenched by the addition of an aqueous solution of saturated ammonium chloride. The mixture was extracted with ethyl acetate (150 ml), and then the combined organic phases were washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by column chromatography on silica gel (40 g) eluting with hexane / ethyl acetate (2/1) to yield 181 mg (31%) of the title compound as a yellow oil: 1 H-NMR ( CDCl 3) d 8.75 (1 H, d, J = 1.7 Hz), 7.33-7.07 (4H, m), 7.03 (1 H, d, J = 1.7 Hz), 5.06 (2H, m), 3.16-2.68 (6H, m), 2.57-2.32 (3H,), 1.99-1.86 (2H, m), 1.82 -1.67 (2H, m), 1, 39 (9H, s); MS (ESI) 415 (M + Hf. STEP 2. Trifluoroacetate of 3- (1α, 3f / -espyrol2-benzofuran-1,4'-piperidin-1'-yl) -2- (1,3-thiazole-4) -methyl) propanoic The title compound was prepared according to the procedure described in step 3 of example 1 from 3- (1? 3 7-spiro [2-benzofuran-1,4'-piperidine] -1 '-yl) -2- (1,3-thiazol-4-ylmethyl) propane-butyl ester (step 1): 1 H-NMR (CDCl 3) d 9.20 (1H, s), 7.54 (1H, s), 7.47-7.11 (4H, m), 5.09 (2H, s), 3.89-3.19 (9H, m), 2.48-2.27 (2H, m) 2.03-1.84 (2H, m); MS (ESI) 359 (M + Hf, 357 (M-H). 'EXAMPLE 33 3- (6-Fluoro-1? .3H-Spiror2-benzofuran -1.4'-p1peridin1-1 '-D-2- (pyridin-2-ylmethylpropanoic acid) STEP 1. 3- (6-Fluoro-1'H.3H-Spiror2-benzofuran-1.4'-piperidin-1'-p-2- (ethyl pyridin-2-ylmethylpropanoate) The title compound was prepared in accordance with the procedure described in step 4 of example 4 from 6-fluoro-3H-spiro [2-benzofuran-1,4'-piperidine] (J. Med. Chem. 1995, 38, 2009.) and 2- ( pyridin-2-ylmethyl) ethyl acrylate (Polym, J. 2000, 32, 173.): 1 H-NMR (CDCl 3) d 8.56-8.50 (1H, m), 7.63-7.53 ( 1H, m), 7.19-7.08 (3H, m), 6.99-6.90 (1H, m), 6.77 (1H, dd, J = 8.6, 2.2 Hz) , 5.00 (2H, s), 4.18-4.04 (2H, m), 3.33-3.20 (1H, m), 3.15-2.70 (5H, m), 2 , 57-2.28 (3H, m), 1.92-1.60 (4H, m), 1.17 (3H, t, J = 7.2 Hz), MS (IEN) 399 (M + Hf STAGE 2. 3- (6-Fluoro-1'H.3H-Spiror2-benzofuran-1.4'-piperidin1-1'-iP-2- (pyridin-2-ylmethylpropanoic acid To a stirred solution of 3- (6- fluoro-1?, 3 H-spiro [2-benzofuran-1, 4'-piperidin] -1'-iD-2- (pyridin-2-ylmethyl) propanoate of ethyl (step 1, 2.0 g, , 1 mmol) in tetrahydrofuran (10 ml) and ethanol (15 ml) was added hydroxy Sodium 2 N (10 ml) at room temperature. The reaction mixture was stirred at room temperature for 16 hours, evaporated to remove the ethanol, and neutralized by the addition of an aqueous 2N hydrochloric acid solution (10 ml). The aqueous mixture was evaporated to remove the water, then diluted with toluene (10 ml), and concentrated to dryness. The residue was dissolved with ethyl acetate (100 ml), and filtered. The filtrate was evaporated yielding 1.9 g (quant.) Of the title compound as a colorless amorphous solid: 1 H-NMR (CDCl 3) d 8.52-8.46 (1H, m), 7.62-7 , 54 (1H, m), 7.28-7.22 (1H, m), 7.17-7.06 (2H, m), 7.00-6.91 (1H, m), 6.82 (1H, dd, J = 8.3, 2.2 Hz), 4.99 (2H, s), 3.47-3.36 (1H, m), 3.30-3.14 (2H, m ), 3.02-2.40 (6H, m), 2.13-1.90 (2H, m), 1.84-1.70 (2H, m); MS (ESI) 371 (M + H) EXAMPLE 34 2- (2-Chloro-5-hydroxybenzyd-3- (3,3-dimethyl-1 '/ y, 3 / -espirof2-benzofuran- 1, 4'- piperidin1-1 '-iDpropanoic STEP 1. 2- (2-Bromophen-Dopropan-2-ol) To a stirred solution of ethyl 2-bromobenzoate (10 g, 46.5 mmol) in tetrahydrofuran (80 mL) was added dropwise a solution 3, 0 M of methylmagnesium chloride in tetrahydrofuran (39 ml, 0.116 mol) at room temperature and the mixture was stirred for 19 hours at the same temperature.The reaction mixture was quenched by the addition of an aqueous 2N hydrochloric acid solution, and concentrated giving a colorless residue.The crude material was partitioned between diethyl ether and water, and then the organic phase was washed with brine, dried over sodium sulfate, and evaporated.The residue was purified by gel column chromatography. of silica (150 g) eluting with hexane / ethyl acetate (15/1) yielding 6.91 g (69%) of the title compound as a colorless oil: 1 H-NMR (CDCl 3) d 7.68-7 , 57 (2H, m), 7.33-7.25 (1H, m), 7.13-7.07 (1H, m), 1.75 (6H, s). STEP 2. 4-r2- (1-Hydroxy-1-methylethylphen-p-1-methylpperidin-4-ol) To a stirred solution of 2- (2-bromophenyl) propan-2-yl (step 1) , 6.91 g, 32.1 mmol) in tetrahydrofuran (32 ml) was added dropwise a 1.59 M solution of butyllithium in tetrahydrofuran (46.5 ml, 73.9 mmol) at -78 ° C during 20 minutes and the mixture was stirred for 1 hour at the same temperature.To the mixture was added dropwise a solution of 1-methylpiperidin-4-one (5.09 g, 45.0 mmol) in tetrahydrofuran ( 18 ml) at -78 ° C for 10 minutes.This resulting mixture was slowly warmed to room temperature and stirred for 18 hours at the same temperature.The reaction mixture was quenched by the addition of water, and concentrated giving an orange residue. The crude material was partitioned between diethyl ether and water, and then the organic phase was washed with brine, dried over sodium sulfate, and evaporated The residue was purified by column chromatography on silica gel (150 g) eluted with hexane / ethyl acetate (5/1), dichloromethane / methanol (10/1), then dichloromethane / methanol / triethylamine (10/1/1) yielding 4.62 g (58%) of the title compound in the form of light yellow syrup: MS (ESI) 250 (M + Hf. STAGE 3. 1 ', 3,3-Trimethyl-3H-spiro-2-benzofuran-1,4'-piperidinal To a stirred solution of 4- [2- (1-hydroxy-1-methylethyl) phenyl] -1-methylpiperidin-4-ol ( step 2, 4.62 g, 18.5 mmol) in benzene (200 ml) was added dropwise boron trifluoride diethyl etherate (11.0 ml, 86.8 mmol) at room temperature and the mixture was stirred for 40 hours at the same temperature. The reaction mixture was quenched by the addition of water (200 ml) and an aqueous 2N sodium hydroxide solution (200 ml), and the benzene phase was separated. The aqueous phase was extracted with diethyl ether, and then the combined organic phase was washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by column chromatography on silica gel coated with amine (100 g) eluting with dichloromethane yielding 2.39 g (56%) of the title compound as a colorless solid: 1 H-NMR (CDCl 3) d 7 , 30-7.24 (2H, m), 7.12-7.07 (2H, m), 2.81-2.72 (2H, m), 2.51-2.42 (2H, m) , 2.37 (3H, s), 2.07-1, 97 (2H, m), 1.73-1.67 (2H, m), 1.50 (6H, s); MS (ESI) 233 (M + Hf. STAGE 4. 3.3-D-methy1-3H-espyr2-benzofuran-1.4'-piperidine1 To a stirred solution of 1, 3,3-trimethyl-3H-spiro [ 2-benzofuran-1,4'-piperidine] (step 3, 2.39 g, 10.3 mmol) in 1,2-dichloroethane (50 ml) was added dropwise 1-chloroethyl chloroformate (2.68 g.) ml, 24.8 mmol) at 0 ° C and the mixture was stirred for 15 minutes at the same temperature.This resulting mixture was heated at reflux for 21 hours.After cooling to room temperature, the mixture was concentrated to give a yellow solid Clear.

This crude material was dissolved in methanol (30 ml), and heated to reflux for 19.5 hours. After cooling to room temperature, the mixture was concentrated to give a pale yellow solid. The crude material was partitioned between diethyl ether and an aqueous 1N sodium hydroxide solution, and then the organic phase was washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by column chromatography on silica gel coated with amine (50 g) eluting with dichloromethane to yield 1.02 g (45%) of the title compound as a light yellow solid: 1 H-NMR (CDCl 3) d 7.31-7.24 (2H, m), 7.13-7.09 (2H, m), 3.17-3.08 (2H, m), 3.03-2.97 (2H, m ), 1, 93-1, 83 (2H, m), 1, 70-1, 65 (2H, m), 1.51 (6H, s); MS (ESI) 218 (M + Hf.

STAGE 5. 2- (2-Chloro-5-hydroxybenzDi-3- (3,3-dimethyl-1 '/ y.3 / y-esopyr2-benzofuran-1.4'-p-peridin-1'-ethyl-D-propanoate and 2- (5-ffferc-butyl (dimethylsulfonyl) -2-chlorobenzyl-3- (3,3-dimethyl-1,3,3-espiror-2-benzofuran) ethyl-piperidinM '-iDpropanoate The title compounds were prepared according to the procedure described in step 4 of Example 4 from 3,3-dimethyl-3H-spiro [2-benzofuran-1,4'-p] peridin] (step 4) and 2- (5-. {[[ferc-butyl (dimethyI) syl] oxy] -2-chlorobenzyl) ethyl acrylate (step 2 of example 30) 2- (2 Chloro-5-hydroxybenzyl) -3- (3,3-dimethyl-1β, 3H-spiro [2-benzofuran-1,4'-piperidin] -1'-yl) propanoate ethyl: 1H -NMR (CDCl 3) d 7.29-7.21 (2H, m), 7.15 (1H, d, J = 8.4 Hz), 7.09-7.03 (2H, m), 6, 72 (1H, d, J = 2.9 Hz), 6.65 (1H, dd, J = 8.4, 2.9 Hz), 4.11-4.02 (2H, m), 3.19 -3.09 (1H, m), 3.02-2.78 (5H, m), 2.62-2.46 (3H, m), 2.02-1.92 (2H, m), 1 67-1.62 (2H, m), 1.48 (6H, s), 1.14 (3H, t, J = 7.2 Hz), MS (ESI) 458 (M + Hf. 2- ( 5 - { [ferc-Butyl (dimethyl) silyl] oxy} -2-chlorobenzyl-3- (3,3-dimethyl-1α, 3H-spiro [2-benzofuran-1,4'-piperidine] -1'-l) ethyl propanoate: 1 H-NMR (CDCl 3) d 7.28-7.25 (2H, m), 7.18 (1H, d, J = 8.4 Hz), 7.10-7.07 (2H, m), 6.72 (1H, d, J = 2.9 Hz), 6.64 (1H, dd, J = 8.4, 2.9 Hz), 4.17-4.04 (2H, m), 3.12-2.99 (2H) , m), 2.89-2.75 (4H, m), 2.58-2.42 (3H, m), 1.98-1.88 (2H, m), 1.67-1.63. (2H, m), 1.49 (6H, s), 1.20 (3H, t, J = 7.2 Hz), 0.97 (9H, s), 0.18 (6H, s); MS (ESI) 572 (M + Hf. STEP 6. 2- (2-Chloro-5-hydroxybenzyd-3- (3,3-dimethyl-1'H.3H-spiro-2-benzofuran-1,4'-piperidin) - 1'-D-Propanoic The title compound was prepared according to the procedure described in step 5 of Example 4 from 2- (2-chloro-5-hydroxybenzyl) -3- (3,3-dimethyl-1'rV Ethyl 3H-espyro [2-benzofuran-1, 4'-piperidin] -1'-yl) propanoate (step 5) and 2- (5- { [Ferc-butyl (dimethyl) s) Lyl] oxy.} -2-chlorobenzyl) -3- (3,3-dimethyl-1α, 3H-spiro [2-benzofuran-1,4'-piperidin] -1'-dihydroxyethyl ( step 5). 1 H-NMR (CDCl 3) d 7.32-7.29 (2H, m), 7.13 (1H, d, J = 8.6 Hz), 7.13-7.08 (2H, m), 6.81 (1H, d, J = 2.9 Hz), 6.69 (1H, dd, J = 8.6, 2.9 Hz), 3.48-3.42 (1H, m ), 3.25-3.19 (1H, m), 3.04-2.92 (3H, m), 2.86-2.65 (4H, m), 2.19-2.01 (2H) , m), 1.78-1.73 (2H, m), 1.46 (6H, s), MS (ESI) 430 (M + Hf. EXAMPLE 35 2- (2-chloro-5-h) DroxibenciD-3- (2-hydroxy-2,3-dihydro-1? -espyrorinden-1,4'-piperidin-1 '-Dpropanoic acid STAGE 1. 2- (5-frferc-Butyl (dιmeDsilynoxy) -2-chlorobenzyl-3- (2-hydroxy-2,3-dihydro-1 'f -spirorinden-1,4') Ethyl-piperidin-1 '-iD-propanoate The title compound was prepared as a mixture of diastereomers according to the procedure described in step 4 of Example 4 from 2,3-dihydrospray [inden-1,4]. '-piperidine] -2-ol (Tetrahedron: Asymmetry 1999, 10, 1787.) and 2- (5-. {[[ferc-butyl (dimethyl) silyl] oxy} -2-chlorobenzyl) ethyl acrylate ( step 2 of example 30): 1 H-NMR (CDCl 3) d 7.23-7.16 (5H, m), 6.72-6.62 (2H, m), 4.46-4.44 (1H, m), 4.18-4.13 (2H, m), 3.33-3.25 (1H, m), 3.12-2.98 (2H, m), 2.91-2.71 ( 5H, m), 2.54-2.30 (2H, m), 2.02-1.93 (1H, m), 1.71-1.44 (4H, m), 1.22-1, 15 (3H, m), 0.97 (9H, s), 0.18 (6H, s); MS (ESI) 558 (M + Hf.

STEP 2. 2- (2-Chloro-5-hydroxybenzDiD-3- (2-hydroxy-2,3-dihydro-1'H-spiro-finden-1,4'-piperidin-1'-Dpropanoic acid The title compound is prepared in the form of a mixture of diastereomers according to the procedure described in step 4 of Example 30 from 2- (5-. {[[fer-butyl (dimethyl) silyl] oxy] -2-chlorobenzyl. ) -3- (Ethyl 2-hydroxy-2,3-dihydro-17-espiro [inden-1,4'-piperidin] -1'-dihydroxypropionate) (step 1): MS (ESI) 416 (M + Hf, 414 (M-Hf EXAMPLE 36 2- (2-Chloro-5-hydroxybenzDi-3- (3-methyl-1? .3H-spiro-2-benzofuran) 1.4'-piperidinl-1 '-iDpropanoic STEP 1. 1- (2-Bromopheni-Ethanol) To a stirred solution of 1- (2-bromophenyl) ethanone (5 g, 25.1 mmol) in methanol (50 mL) was added sodium borohydride (1.43 g, 37%). 7 mmol) at room temperature and the mixture was stirred for 24 hours at the same temperature.The reaction mixture was quenched by the addition of water, and concentrated to give a colorless residue.The crude material was partitioned between diethyl ether and water , and then the organic phase was washed with brine, dried over sodium sulfate, and evaporated The residue was purified by column chromatography on silica gel (100 g) eluting with hexane / ethyl acetate (5/1) yielding 5.4 g (quant.) Of the title compound as a colorless oil: 1 H-NMR (CDCl 3) d 7.62-7.50 (2H, m), 7.37-7.32 (1H, m ), 7.16-7.10 (1H, m), 5.28-5.21 (1H, de, J = 3.5, 6.4 Hz), 1.96 (1H, d, J = 3 , 5 Hz), 1.49 (3H, d, J = 6.4 Hz) STEP 2. 4-Hydroxy-4-r2- (1-hydroxyethylDfeniflpiperidin-1-ethylcarboxylate To a stirred solution). to 1- (2-bromophenyl) ethanol (step 1, 5.4 g, 25.1 mmol) in tetrahydrofuran (25 ml) was added dropwise a 1.59 M solution of butyllithium in tetrahydrofuran (33 ml, 51.5 mmol) at -78 ° C for 20 minutes and the mixture was stirred for 2 hours at the same temperature. To the mixture was added dropwise a solution of ethyl 4-oxopiperidin-1-carboxylate (4.73 g, 27.6 mmol) in tetrahydrofuran (10 ml) at -78 ° C for 15 minutes. This resulting mixture was slowly warmed to room temperature and stirred for 19 hours at the same temperature. The reaction mixture was quenched by the addition of an aqueous solution of saturated ammonium chloride, and then the organic phase was washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by column chromatography on silica gel (150 g) eluting with hexane / ethyl acetate (2/1), then hexane / ethyl acetate (1/1) yielding 1.37 g (19%) of the compound of the title in the form of a light yellow syrup: 1 H-NMR (CDCl 3) d 7.60-7.57 (1H, m), 7.33-7.23 (3H, m), 5.80-5, 75 (1H, m), 4.17-4.05 (4H, m), 3.32 (2H, ma), 3.08 (1H, sa), 2.37 (1H, sa), 1.99 -1.87 (2H, m), 1.58 (3H, t, J = 6.4 Hz), 1.29-1.23 (4H, m). STEP 3. S-Methyl-l '/ iSH-spirore-benzofuran-1'-piperidin-1'-ethylcarboxylate To a stirred solution of 4-hydroxy-4- [2- (1-hydroxyethyl) ethyl phenyl] piperidine-1-carboxylate (step 2, 1.37 g, 4.67 mmol) in dichloromethane (30 ml), triethylamine (1 ml) and pyridine (3 ml) was added dropwise to methanesulfonyl chloride (0.54 ml, 7.01 mmol) at 0 ° C for 15 minutes. This resulting mixture was slowly warmed to room temperature and stirred for 45 minutes at the same temperature, then heated to reflux for 3 hours. The reaction mixture was washed with water, 2 N hydrochloric acid aqueous solution, dried over sodium sulfate, and evaporated. The residue was purified by column chromatography on silica gel (70 g) eluting with hexane / ethyl acetate (5/1) to afford the crude title compound as a light yellow syrup. This material was dissolved in diethyl ether (20 ml) and ethyl acetate (20 ml), then washed with saturated aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, and evaporated yielding 1.32 g (79%). ) of the title compound in the form of a light yellow syrup: 1 H-NMR (CDCl 3) d 7.32-7.26 (2H, m), 7.16-7.03 (1H, m), 7.08- 7.05 (1H, m), 5.30 (1H, c, J = 6.2 Hz), 4.20-4.04 (4H, m), 3.31-3.19 (2H, m) , 2.01-1.91 (2H, m), 1.75-1.58 (3H, m), 1.50 (3H, d, J = 6.4 Hz), 1.28 (3H, t , J = 7.2 Hz). STAGE 4. 3-Methyl-3H-spiro-2-benzofuran-1.4'-piperidine1 A solution of 3-methyl-1α, 3H-spiro [2-benzofuran-1,4'-p¡peridin] -1'-carboxylate from ethyl (step 3, 1.02 g, 3.70 mmol) in 4 M aqueous sodium hydroxide solution (10 ml) and ethanol (20 ml) was heated to reflux for 2 days. The reaction mixture was concentrated to give a colorless residue. The crude material was partitioned between diethyl ether and water, and the organic phase was washed with brine, dried over sodium sulfate, and evaporated yielding 732 mg (97%) of the title compound as a light yellow syrup: 1H -NRM (CDCI3) d 7.29-7.26 (2H, m), 7.16-7.12 (2H, m), 5.29 (1H, c, J = 6.4 Hz), 3, 16-2.96 (4H, m), 2.02-1.92 (1H, m), 1.78-1.63 (3H, m), 1.50 (3H, d, J = 6.4) Hz); MS (ESI) 204 (M + Hf.

STAGE 5. 2- (2-Chloro-5-hydroxybenzyl-3- (3-methyl-1? .3H-spiro-2-benzofuran-1.4'-piperidin-1'-di-d-propane-2-ethyl 2- (5- crude-butyl (dimethylsilyl) -2-chlorobenzyl-3- (3-methyl-1 '/-/.3H-espirof2-benzofuran-1.4'-piperidin1-1' -iDpropanoate ethyl The compounds of the title were prepared according to the procedure described in step 4 of example 4 from 3-methyl-3H-spiro [2-benzofuran-1,4'-piperidine] (step 4) and 2- (5 -. {[[ferc-butyl (dimethyl] silyl] oxy} - 2-chlorobenzyl) ethyl acrylate (step 2 of example 30) 2- (2-chloro-5-hydroxybenzyl) -3- ( 3-methyl-1 ^, 3 -spiro [2-benzofuran-1,4-piperidin] -1'-yl) ethyl propanoate: MS (ESI) 444 (M + H, 2- (5-. [ferc-butyl (dimethyl) syl] oxy] -2-chlorobenzyl) -3- (3-methyl-1α, 3H-spiro [2-benzofuran-1,4'-piperidine] -1 '-yl) ethyl propanoate: 1 H-NMR (CDCl 3) d 7.28-7.25 (2H, m), 7.17 (1H, d, J = 8.6 Hz), 7.13-7, 09 (2H, m), 6.72 (1 H, d, J = 2.9 Hz), 6.63 (1 H, dd, J = 8.6, 2.9 Hz), 5.27 (1 H, c, J = 6.4 Hz), 3.07-2.99 (2H, m), 2.88-2.75 (4H, m), 2.55-2.36 (3H, m), 2.08-1.98 ( 1H, m), 1.86-1.76 (1H, m), 1.71-1.65 (2H, m), 1.48 (3H, d, J = 6.4 Hz), 1.19 (3H, t, J = 7.2 Hz), 0.97 (9H, s), 0.18 (6H, s); MS (ESI) 558 (M + Hf. STEP 6. 2- (2-Chloro-5-hydroxybenzDi-3- (3-methyl-1'H.3H-spiro-2-benzofuran-1,4'-piperidin-1 '- iDpropanoic The title compound was prepared according to the procedure described in step 5 of Example 4 from 2- (2-chloro-5-hydroxybenzyl) -3- (3-methyl-1α, 3H-spiro [2 -benzofuran-1,4'-piperidine] -1'-dihydroxyethyl-2- (5-. {[[ferc-butyl (dimethyl) silyl] oxy} -2-chlorobenzyl) -3- (3- methyl-1'H, 3H-spiro [2-benzofuran-1,4'-piperidine] -1'-dihydroxyethyl (step 5): MS (ESI) 416 (M + Hf, 414 (M-H)? EXAMPLE 37 2- (2-Chloro-5-hydroxybenzDi-3- (5,7-difluoro-1-methyl-1,2-dihydro-1β-espyrorindol-3,4'-piperidin-1'-diDropanoic acid STEP 1. 5.7-Difluoro-1,2-dihydro-1? -espiophenol-3,4'-piperidine-1'-benzylcarboxylate The title compound was prepared according to the procedure described in step 1 of example 4 from (2,4-difluorophenyl) hydrazine hydrochloride: 1 H-NMR (CDCl 3) d 7.39-7.32 (5H, m), 6.65-6.51 (2H, m), 5.16 (2H, s), 4.16 (2H, m.a), 3.25 (2H, s), 2.97 (2H, m.a), 1.72 (4H, m.a). STEP 2. 5.7-Difluoro-1-methyl-1,2-dihydro-1'-rV-espirorindol-3,4'-pperidene-1'-carboxylic acid benzyl ester The title compound was prepared according to the procedure described in step 2 of Example 4 from 5,7-difluoro-1,2-dihydro-1? -spiro [indole-3,4'-piperidine] -1'-benzylcarboxylate (step 1): 1H- NMR (CDCl 3) d 7.39-7.31 (5H, m), 6.65-6.51 (2H, m), 5.16 (2H, s), 4.16 (2H, m.a), 3.24 (2H, s), 2.95 (2H, m.a), 2.92 (3H, s), 1.72 (4H, m.a); MS (ESI) 373 (M + Hf. STAGE 3. 5.7-Difluoro-1-methyl-1,2-dihydroespyridol-3,4'-piperidinal The title compound was prepared according to the procedure described in step 3 of Example 4 from 5,7-difluoro-1-methyl-1,2-dihydro-1'H-spiro [indole-3,4'-piperidine] -1'-benzylcarboxylate (step 2): MS ( IEN) 234 (M + Hf.

STEP 4. 2- (5 rferc-butyl (dimethylsinoxyV-2-ciorobenzyd-3- (5,7-difluoro-1-methyl-1,2-dihydro-1? -espyrorindole-3,4'-piperidine M ' Ethyl-Doppanoate The title compound was prepared according to the procedure described in step 4 of Example 4 from 5,7-difluoro-1-methyl-1,2-dihydrospiro [indole-3,4'- piperidine] (step 3) and 2- (5-. {[[ferc-butyl (d-methyl) silyl] oxy] -2- chlorobenzyl) ethyl acrylate (step 2 of example 30): 1 H-NMR ( CDCl 3) d 7.17 (1H, d, J = 8.6 Hz), 6.70-6.58 (3H, m), 6.56 (1H, d, J = 8.6 Hz), 4.15-4.03 (2H, m), 3.16 (2H, s), 3.06-2.69 (6H, m), 2.89 (3H, s), 2.48-2.43 (1H, m), 2.18-2.01 (2H, m), 1.82-1.63 (4H, m), 1.18 (3H, t, J = 7 , 2 Hz), 0.96 (9H, s), 0.17 (6H, s); MS (ESI) 593 (M + Hf. STAGE 5. 2- (2-Chloro-5-hydroxybenzDi-3- (5,7-d-fluoro-1-methyl-1,2-dihydro-1? -espirofindol-3,4) '-piperidin1-1' -iDpropanoic The title compound was prepared according to the procedure described in step 4 of Example 30 from 2- (5-. {[[ferc-butyl (dimethyl) silyl] oxy}. -2-chlorobenzyl) -3- (5,7-difluoro-1-methyl-1,2-dihydro-1? -spiro [indol-3,4'-piperidin] -1'-di-d-propane-ethyl ester (stage 4 ): MS (ESI) 451 (M + Hf, 449 (M-H) EXAMPLE 38 2- (2-Chloro-5-hydroxybenzDi-3- (1-methyl-2,2-dioxodo-1 H.1) acid ? -spiroß, 1-benzo-isot-azole-3,4'-piperidin-1 '-iD-propanoic acid STEP 1. 2.2-1-methyl-1,3-dihydro-2,1-benzoisothiazole dioxide A mixture of 1,3-dihydro-2,1-benzoisothiazole 2,2-dioxide (J. Heterocyclic Chem. 1986, 23, 1645., 401 mg, 2.37 mmol), methyl iodide (0.6 ml, 9.48 mmol) and potassium carbonate (328 mg, 2.37 mmol) in N, N-dimethylformamide (7 ml). it was stirred for 4 hours at room temperature. The reaction mixture was diluted with toluene / ethyl acetate (1/3), then washed with water twice, and then the organic phase was washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by preparative silica gel thin layer chromatography developed with hexane / ethyl acetate (2/1) to yield 272 mg (63%) of the title compound as a light brown syrup: 1 H-NMR (CDCl 3 ) d 7.33-7.17 (2H, m), 7.03-6.95 (1H, m), 6.70 (1H, d, J = 7.9 Hz), 4.80 (2H, s), 3.09 (3H, s). STAGE 2. 2.2-1-methyl-1H-H-spiroR, 1-benzoisothiazole-3,4'-piperidinyl-1'-benzylcarboxylate dioxide To a stirred solution of 1-methyl-2,2-dioxide 1,3-dihydro-2,1-benzisothiazole (step 1, 272 mg, 1.48 mmol) and benzyl bis (2-bromoethyl) carbamate (Bioorg, Med Chem. Let. 1997, 7, 1311., 595 mg, 1.63 mmol) in N, N-dimethylformamide (5 ml) was added 70% sodium hydride in mineral oil (112 mg, 3.27 mmol) at 0 ° C and the mixture was stirred for 1 hr. the same temperature, then slowly warmed to room temperature and stirred for 1.5 hours at the same temperature. The reaction mixture was diluted with toluene / ethyl acetate (1/3), then washed with water three times, and then the organic phase was washed with brine, dried over sodium sulfate and evaporated. The residue was purified by preparative silica gel thin layer chromatography developed with hexane / ethyl acetate (2/1) yielding 288 mg (50%) of the title compound as a brown syrup: 1 H-NMR (CDCl 3) d 7.39-7.29 (7H, m), 7.12-7.01 (2H, m), 6.72 (1H, d, J = 7.9 Hz), 5.18 (2H, s) ), 4.23 (2H, ma), 3.48 (2H, ma), 3.13 (3H, s), 2.40-2.35 (2H, m), 2.01 (2H, ma) .

STAGE 3. 2.2-1-Methyl-1 H-espyror2.1-benzoisothiazole-3,4'-piperidine dioxide A mixture of 2,2-dioxide of 1-methyl-1 H, 1'H-spiro [2, 1-BenzoisothiazoI-3,4'-piperidine] -1'-benzylcarboxylate (step 2, 288 mg, 0.745 mmol) and 10% palladium on carbon (50 mg) in methanol (10 ml) was stirred under an atmosphere of hydrogen at room temperature for 8 hours. The catalyst was removed by filtration, and then the filtrate was concentrated to give 201 mg (quant.) Of the title compound as a yellow solid: 1 H-NMR (CDCl 3) d 7.33-7.23 (2H, m) , 7.06-7.02 (1H, m), 6.70 (1H, d, J = 7.9 Hz), 3.36-3.20 (4H, m), 3.13 (3H, s ), 2.42-2.37 (2H, m), 2.24-2.17 (2H, m); MS (ESI) 253 (M + Hf. STEP 4. 2- (5-urea-Butyl (dimethylDsilyloxy) -2-chlorobenzD-3- (1-methyl-2,2-dioxide-1 H, 1β-esopyrol 1 -benzo Sothiazole-3,4'-piperidin-1'-ethylpropanoate The title compound was prepared according to the procedure described in step 4 of example 4 from 2,2-dioxide of 1-methyl-1 / - -spiro [2,1-benzoisothiazole-3,4'-piperidine] (step 3) and 2- (5- { [ferric-butyl (dimethyl) siyl] oxy]. chlorobenzyl) ethyl acrylate (step 2 of example 30): 1 H-NMR (CDCl 3) d 7.32-7.27 (1H, m), 7.20-7.16 (2H, m), 7, 04-6.99 (1H, m), 6.71-6.62 (3H, m), 4.17-4.05 (2H, m), 3.12 (3H, s), 3.08- 2.52 (9H, m), 2.89-2.83 (2H, m), 2.11-2.00 (2H, m), 1.20 (3H, t, J = 7.2 Hz) 0.97 (9H, s), 0.18 (6H, s); MS (ESI) 607 (M + Hf. STAGE 5. 2- (2-Chloro-5-hydroxybenzDi-3- (1-methyl) -2.2-dioxide-1H.1'H-spiro [2,1-benzoisothiazole-3,4'-piperidin-1'-diDPA-naic acid The title compound was prepared according to the procedure described in step 4 of the example 30 from 2- (5-. { [fer-butyl (dimethyl] silyl] oxy} -2-chlorobenzyl) -3- (1-methyl-2,2-dioxido-1ri1'H-spiro [2,1-benzoisothiazol-3,4'-piperidin] -1'-di-d-propane-ethyl ester (stage 4 ): MS (ESI) 465 (M + Hf, 463 (M-H). "EXAMPLE 39 3- (6-Fluoro-17 - /, 3f7-spiro-2-benzofuran-1,4 'piperidin-1'-iP-2) trifluoroacetate -f3- (hydroxymethiDbencinpropanoic STEP 1. (r3- (Bromomethobenzene)> (ferc-butiDdimethylsilane To a mixture of [3- ( { [Ferc-butyl (dimethyl) silyl] oxy} methyl) phenyl] methanol (J. .

Med. Chem. 1996, 25, 4871., 4.39 g, 17 mmol) and carbon tetrabromide (8.95 g, 27 mmol) in tetrahydrofuran (60 ml) was added triphenylphosphine (6.82 g, 26 mmol) in two portions at 0 ° C and the mixture was stirred for 3 hours at room temperature. The mixture was neutralized with aqueous sodium hydrogencarbonate and extracted with dichloromethane. The organic phase was concentrated.

The residue was taken up in hexane and the resulting mixture was filtered, and concentrated. The residue was purified by column chromatography on silica gel eluting with hexane / dichloromethane (10/1) yielding 760 mg (14%) of the title compound as a colorless oil: 1 H-NMR (CDCl 3) d 7.40 -7.20 (4H, m), 4.72 (2H, s), 4.49 (2H, s), 0.93 (9H, s), 0.09 (6H, s). STEP 2. 3- (6-Fluoro-1? .3H-Spirol2-benzofuran-1,4'-piperidin-1'-di-butyl-di-d-propane The title compound was prepared according to the procedure described in step 1 of the example 1 from 6-fluoro-3? -spiro [2-benzofuran-1,4'-piperidine] (J. Med. Chem. 1995, 38, 2009.): 1 H-NMR (CDCl 3) d 7.14 ( 1H, dd, J = 8.3, 5.0 Hz), 6.96 (1H, dt, J = 8.3, 2.4 Hz), 6.80 (1H, dd, J = 8.4, 2.2 Hz), 5.02 (2H, s), 2.90-2.70 (4H, m), 2.55-2.35 ( 4H, m), 2.00-1.70 (4H, m), 1.47 (9H, s). STEP 3. 2-f3- ( { Rferc-Butyl (dimethylsilyoxy> methybenzene-3- (6-fluoro-1'H.3H-spiro [2-benzofuran-1,4'-piperidin-1 ' -I-Ferro-butyl dpropanoate The title compound was prepared according to the procedure described in step 2 of Example 1 from { [3- (bromomethyl) benzyl] oxy} - (fer-butyl) dimethylsilane ( Step 1) and fer-butyl 3- (6-fluoro-1? 3 H-spiro [2-benzofuran-1,4'-piperidin] -1'-yl) propanoate (step 2): 1 H-NMR (CDCl 3) d 7.30-7.02 (5H, m), 6.98-6.88 (1H, m), 6.80-6.72 (1H, m), 4.99 (2H, s), 4.69 (2H, s), 2.95-2.60 (6H, m), 2.55-2.25 (3H, m), 1.95-1, 65 (4H, m), 1.34 (9H, s), 0.92 (9H, s), 0.08 (6H, s); MS (ESI) 570 (M + Hf. STAGE 4. 3- (6-fluoro-1?, 3? / - espíror2-benzofuran-1.4 'piperidin-1' -iD-2-f3- (hydroxymethylbenzyl) trifluoroacetate. npropanoic The title compound was prepared according to the procedure described in step 3 of Example 1 from 2- [3- ( { [ferric-butyl (dimethyl) silyl] oxy] methyl) benzyl ] -3- (6-Fluoro-1?, 3 H-spiro [2-benzofuran-1,4'-piperidin] -1'-yl) -propanoate of fer-butyl (step 3): MS (ESI) 400 (M + Hf EXAMPLE 40 2- (2-Chloro-4-hydroxybenzyd-3- (1?, 3 H-spiro-2-benzofuran-1,4'-piperidin-1'-1-di-propane) acid STEP 1. 2- (2-Chloro-4-hydroxybenzyl-3- (1'H.3H-spiro-2-benzofuran-1,4'-piperidin-1'-di-tert-butylbutyl) The title compound was prepared in accordance with procedure described in step 1 of example 15 from 2- (4-. {[[tert-butyl (dimethyI) silyl] oxy} -2-cyorobenzD-3- (1?, 3 H-spiro [2- ferz-butyl benzofuran-1, 4'-piperidin] -1'-yl) propanoate (step 3 of Example 13): 1 H-NMR (CDCl 3) d 7.32-7.16 (3H, m), 7, 12-6.98 (2H, m), 6.64 (1H, d, J = 2.6 Hz), 6.47 (1H, dd, J = 8.4, 2.6 Hz), 5.06 (2H, s), 3.10-2.75 (6H, m), 2.63-2.42 (3H, m), 2.10-1, 82 (2H, m), 1.80-1 , 67 (2H, m), 1.43 (9H, s); MS (ESI) 458, 460 (M + Hf, 456, 458 (M-Hf STEP 2. 2- (2-Chloro-4-hydroxybenzyl) -3- (1? .3H-Spiror2-benzof? Ran-1.4'-piperidin-1'-diDPAnoic The title compound was prepared according to the procedure described in step 2 of Example 15 from 2- (2 -chloro-4-hydroxybenzyl) -3- (1?, 3H-spiro [2-benzofuran-1,4'-piperidin] -1'-di-d-butpanoate of fer-butyl ester (stage 1): 1 H-NMR (DMSO-cfe) d 9.71 (1H, sa), 7.33-7.18 (4H, m), 7.11 (1H, d, J = 8.1 Hz), 6.83-6.76 (1H, m), 6.70-6.62 (1H, m), 4.95 (2H, s), 2.93-2.62 (6H, m), 2, 55-2.20 (3H, m), 1, 90-1.73 (2H, m), 1.67-1.52 (2H, m). EXAMPLE 41 2- (2-Chloro-5-hydroxybenzD-3-f3- (hydroxyethyl) -2,3-dihydro-1'H-espiropnden-1,4'-piperidn-1'-illpropanoic acid and 2- (2-chloro-5-hydroxybenzDi-3- (3-hydroxy-2,3-dihydro-1'-trifluor-1,4'-p-peridin-1'-diDropanoic acid) STAGE 1. 3-Oxo-2.3-dihydro-1? -espirofinden-1,4'-piperidn-1'-ethylcarboxylate To a stirred suspension of spirohydrochloride [inden-1,4'-piperidine] - 3 (2H) -one (WO9937642, 592 mg, 2.5 mmol) in dichloromethane (20 mL) was added triethylamine (1.04 mL, 7.5 mmol) and ethyl chloroformate (0.29 mL, 3, 0 mmol) at 0 ° C and the mixture was stirred for 6 hours at room temperature. The reaction was quenched by the addition of an aqueous solution of 10% citric acid (50 ml). The aqueous phase was extracted with ethyl acetate (200 ml), and the combined organic phases were washed with saturated aqueous sodium bicarbonate solution (50 ml) and brine (100 ml), dried over sodium sulfate, and evaporated yielding 672 g. mg (99%) of the title compounds as a colorless oil: 1 H-NMR (CDCl 3) d 7.77-7.74 (1H, m), 7.68-7.63 (1H, m), 7.51-7.48 (1H, m), 7.45-7.40 (1H, m), 4.34-4.23 (2H, m), 4.19 (2H, c, J = 7 , 1 Hz), 2.91 (2H, ta, J = 12.9 Hz), 2.65 (2H, s), 2.00 (2H, dt, J = 12.8, 4.2 Hz), 1.53 (2H, da, J = 12.7 Hz), 1.30 (3H, t, J = 7.2 Hz); MS (ESI) 274 (M + Hf. STEP 2. 2.3-D-Hydrospirophen-1,4'-piperidin-3-ylmethanol v 2.3-dihydrospiroinden-1,4'-piperidin-3-ol To a stirred mixture of (methoxymethyl) chloride ) triphenylphosphonium (2.1 g, 6.1 mmol) and potassium ferc-butoxide (689 mg, 6.1 mmol) in 1,4-dioxane (50 ml) was added a solution of 3-oxo-2,3-dihydro-1? -spiro [ inden-1,4'-piperidine] -1'-ethyl carboxylate (670 mg, 2.5 mmol) in 1,4-dioxane (50 ml) at room temperature and the mixture was stirred for 36 hours at the same temperature . The mixture was quenched by the addition of water (100 ml). The 1,4-dioxane was removed under reduced pressure. The aqueous phase was extracted with ethyl acetate (200 ml), and the organic phase was washed with brine (50 ml), dried over sodium sulfate, and evaporated. The residue was purified by column chromatography on silica gel (200 g) eluting with hexane / ethyl acetate (10/1 to 2/1) to yield a colorless oil (680 mg). This oil was dissolved in acetone (25 ml). To the solution was added concentrated hydrochloric acid (0.5 ml) and the mixture was heated to reflux for 3 hours. After cooling to room temperature, the mixture was basified by the addition of an aqueous solution of saturated sodium bicarbonate. The mixture was extracted with ethyl acetate (250 ml). The organic phase was washed with brine (50 ml), dried over sodium sulfate, and evaporated to yield a yellow oil (682 mg). This oil was dissolved in methanol (10 ml). To the solution was added sodium borohydride (103 mg, 2.7 mmol) at 0 ° C and the mixture was stirred for 3 hours at room temperature. The reaction was quenched by the addition of water (30 ml). The mixture was extracted with ethyl acetate (200 ml), and the organic phase was washed with an aqueous solution of 10% citric acid (20 ml) and an aqueous solution of saturated sodium bicarbonate (20 ml), dried over sulphate sodium, and evaporated. The residue was purified by column chromatography on silica gel (40 g) eluting with hexane / ethyl acetate (1/1) to yield a colorless oil (257 mg). This oil was dissolved in ethanol. To the solution was added an aqueous solution of 5 N sodium hydroxide (1.8 ml) at room temperature and the reaction mixture was heated to reflux for 20 hours. After cooling to room temperature, the ethanol was removed under reduced pressure. The aqueous phase was extracted with dichloromethane (100 ml x 2). The combined organic phases were dried over sodium sulfate, and evaporated yielding 205 mg of mixture of the title compounds as a colorless oil: MS (ESI) 218 and 204 (M + Hf.

STAGE 3. 2- (5- (rferc-Butyl (dimethylsilyloxy> -2-chlorobenzyl-3-r3- (hydroxymethiD-2.3-dihydro-1? -espyrrorin-1.4'-pperidin-1'-! Ethyl npropanoate and 2- (5-. {fferc-butyl (dimethylDsilynoxy) -2-chlorobenzyd-3- (3-hydroxy-2,3-dihydro-1? -espyrofonide- 1,4 Ethyl d-propionate The ethyl ester mixture was prepared according to the procedure described in step 4 of example 4 starting from 2., 3-dihydrospiro [inden-1,4'-piperidin] -3-ylmethanol and 2,3-dihydrospiro [inden-1,4'-piperidin-3-ol (stage 2) and 2- (5-. [ethyl-butyl (dimethyl) silyl] oxy] -2-chlorobenzyl) acrylate (step 2 of Example 30): MS (I ES) 572 and 558 (M + Hf. STEP 4. 2- (2-Acid) -chloro-5-hydroxybenzyd-3-r3- (hydroxymethiD-2,3-dihydro-1? -spiro (inden-1,4'-piperidin-1'-Dpropanoic acid and 2- (2-chloro-5-hydroxybenzyd-3-) (3-hydroxy-2,3-dihydro-1'H-spiroNnden-1,4'-piperidin-1'-Dpropanoic The mixture of the title compounds was prepared according to the procedure described in step 4 of Example 30 from 2- (5- { [ferc-butyl (dimethyl) silyl] oxy] -2-chlorobenzyl) -3- [3- (hydroxymethyl) -2.3 -dihydro-1'H-spiro [inden-1,4'-pperidin] -1'-yl] propanoate of ethyl and 2- (5- { [fer (; -butyl (dimethyI) silyl] oxy} -2-chlorobenzyl) -3- (3-hydroxy-2,3-dihydro-1'H-spiro [inden-1,4'-piperidin] -1'-yl) propanoate ethyl (step 3): MS (ESI) 430 and 416 (M + Hf, 428 and 414 (M-H)? EXAMPLE 42 2- (2-Chloro-5-hydroxybenzDi-3- (5-fluoro-1?. 3 H-spiro-2-benzofuran) -1.4'-piperidinl-1 '-iDpropanoic STAGE 1. 2- (5-. {Fferc-butyl (dimethylsilyloxyV2-chlorobenzD-3- (5-fluoro-1? .3H-espirof2-benzofuran-1, 4'-piperidin-1'-ethylpropanoate The title compound was prepared according to the procedure described in step 4 of example 4 from 5-fluoro-3 H-spiro [2-benzofuran-1,4'-piperidine] (WO 2002088089) and 2- (5- . {[[ethyl-butyl (dimethyl) silyl] oxy} -2-chlorobenzyl) ethyl acrylate (step 2 of example 30): 1 H-NMR (CDCl 3) d 7.18 (1H, d, J = 8.6 Hz), 7.08-6.83 (3H, m), 6.72 (1H, d, J = 2.8 Hz), 6.64 (1H, dd, J = 8.6, 2.8 Hz), 5.01 (2H, s), 4.18-4.00 (2H, m), 3, 15-2.97 (2H, m), 2.93-2.70 (4H, m), 2.58-2.30 (3H, m), 1.95-1.78 (2H, m), 1.77-1.63 (2H, m), 1.19 (3H, t, J = 7.1 Hz), 0.97 (9H, s), 0.18 (6H, s); MS (ESI) 562 (M + Hf. STEP 2. 2- (2-Chloro-5-hydroxybenzyd-3- (5-fluoro-1'f. 3 H-espyr2-benzofuran-1, 4'-piperidin-1'-di-propane The title compound was prepared according to the procedure described in step 4 of example 30 from 2- (5- { [Ferc-butyl (dimethyl) s) 1,11,22-chlorobenzyl) -3- (5-fluoro-1?, 3 H-spiro [2-benzofuran-1,4'-piperidin] -1'-dihydroxyethyl ester (step 1): MS (ESI) 420 (M + Hf, 418 (M-H)? EXAMPLE 43 2-R 2- (Ethoxycarbonylbenzyl-3- (1'H 3 H-esp 2-benzofuran) acid trifluoroacetate 1, 4'-piperidin1-1 '-iDpropanoic STEP 1. Ethyl 2-r3-ferc-Butoxy-3-oxo-2- (1?. 3 H -spirof2-benzofuran-1,4'-piperidin-1'-ylmethylpropylbenzoate) The title compound was prepared in accordance with the procedure described in step 2 of example 1 from 3- (1?, 3 H-spiro [2-benzofuran-1, 4'-piperidn] -1'-di-d-propanoate ferric-butyl (WO 2003064425 ) and ethyl 2- (bromomethyl) benzoate (J. Org. Chem. 1985, 50, 2128.): 1 H-NMR (CDCl 3) d 7.93-7.89 (1H, m), 7.41-7 , 36 (1H, m), 7.29-7.18 (5H, m), 7.11-7.08 (1H, m), 5.05 (2H, s), 4.37 (2H, c , J = 7.2 Hz), 3.36-3.32 (1H, m), 3.03-2.87 (3H, m), 2.79-2.72 (2H, m), 2, 54-2.45 (2H, m), 2.40-2.31 (1H, m), 1.95-1.82 (2H, m), 1.75-1.68 (2H, m), 1.41 (3H, t, J = 7.2 Hz), 1.34 (9H, s), EM (IEN) 480 (M + Hf. STAGE 2. 2-f2- (ethoxycarbon) Dibenzyl-2-trifluoroacetate n-3- (1'r7.3 / -spiro [2-benzofuran-1,4'-piperidin] -1'-diDPAnoic The title compound was prepared according to the procedure described in step 3 of example 1 to starting from 2- [3-ferc-butoxy-3-oxo-2- (1'H, ethyl 3H-spiro [2-benzofuran-1, 4'-piperidin] -1'-ylmethyl) propyl] benzoate (step 1): 1 H-NMR (CDCl 3) d 8.04 (1H, d , J = 7.7 Hz), 7.51 (1H, t, J = 7.5 Hz), 7.41-7.21 (5H, m), 7.11-7.09 (1H, m) , 5.08 (2H, s), 4.37 (2H, c, J = 7.2 Hz), 3.79-3.65 (3H, m), 3.53-3.16 (5H, m ), 2.43-2.25 (2H, m), 1.96-1.88 (2H, m), 1.41 (3H, t, J = 7.1 Hz); MS (ESI) 424 (M + Hf, 422 (M-Hf EXAMPLE 44 3- (6-Fluoro-1? 3 H-spiro-2-benzofuran-1,4'-piperidin-1'-yl) -2- trifluoroacetate (1, 3-t-azole-4-lmethyl-PPpropanoic acid TFA STEP 1. 2- (Dietoxyphosphoric acid) D-3- (1,3-thiazoi-4-d-propanoate) A mixture of 4-methylthiazole (5.85 g, 59 mmol),? / - bromosuccinimide (11 g, 62 mmol) and 2,2'-azobisisobutyronitrile (968 mg, 5.9 mmol) in carbon tetrachloride (200 ml) was refluxed for 5 hours, after cooling, the mixture was filtered. To the filtrate was added toluene (100 ml) and the mixture was concentrated yielding a toluene solution of 4- (bromomethyl) -1,3-thiazole (27 g) to a solution of ferric-butyl diethylphosphonoacetate (15.6 g). g, 62 mmol) in dimethylformamide (50 ml) was added sodium hydride (60% dispersion in mineral oil, 2.48 g, 62 mmol) at 0 ° C under a nitrogen atmosphere. A solution of 4- (bromomethyl) -1,3-thiazole in toluene (27 g) was added to the mixture.The mixture was stirred at room temperature overnight.The mixture was quenched with water and extracted with toluene / ethyl acetate. ethyl (1/3) The combined organic phase was washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by column chromatography on silica gel eluting with hexane / ethyl acetate (1/2 to 100% ethyl acetate) yielding 7.17 g (35%) of the title compound as a colorless oil. : 1 H-NMR (CDCl 3) d 8, 74 (1H, d, J = 2.0 Hz), 7.06 (1H, d, J = 1.8 Hz), 4.24-4.08 (4H, m), 3.55-3, 24 (3H, m), 1, 45-1, 30 (15H, m). STAGE 2. 2- (1,3-Thiazol-4-ylmethyl) butyl dichloride To a stirred solution of ferrous butyl 2- (diethoxyphosphoryl) -3- (1,3-thiazol-4-yl) propanoate (step 1, 7.17 g, 20.5 mmol) in tetrahydrofuran (100 ml) was added sodium hydride (60% dispersion in mineral oil, 820 mg, 20.5 mmol) at 0 ° C under a nitrogen atmosphere. 10 minutes, paraformaldehyde (1.85 g, 61.5 mmol) was added to the mixture and the mixture was stirred at room temperature for 45 minutes, the mixture was quenched with aqueous sodium hydrogencarbonate and extracted with ethyl acetate. The combined organic phase was washed with brine, dried over sodium sulfate, and evaporated The residue was purified by column chromatography on silica gel eluting with hexane / ethyl acetate (3/1) yielding 4.25 g (92%) ) of the title compound as a colorless oil: 1 H-NMR (CDCl 3) d 8.77 (1H, d, J = 2.0 Hz), 7.04 (1H, d, J = 2.0 Hz) 6.23-6.20 (1H, m), 5.52 (1H, c, J = 1, 3 Hz), 3.83 (2H, s), 1.44 (9H, s); MS (ESI) 226 (M + Hf. STAGE 3. 3- (6-Fluoro-1'H.3H-spiro-2-benzofuran-1.4'-p1peridin1-1 '-iD-2- (1,3-thiazole-4 Ferric-butyl-ethylmethylpropanoate The title compound was prepared according to the procedure described in step 4 of Example 4 from 6-fluoro-3H-spiro [2-benzofuran-1,4'-piperidine] (J. Med. Chem. 1995, 38, 2009.) and fer-butyl 2- (1,3-thiazol-4-ylmethyl) acrylate (step 2): 1 H-NMR (CDCl 3) d 8.75 (1H, d, J = 2.0 Hz), 7.13 (1H, dd, J = 8.3, 4.8 Hz), 7.03 (1H, d, J = 2.0 Hz), 6.95 (1H, dt, J = 9.0, 2.4 Hz), 6.77 (1H, dd, J = 8.3, 2.2 Hz), 5.01 (2H, sa), 3.14-2.99 (3H, m), 2.90-2.84 (1H, m), 2.84-2.65 (2H, m), 2.56-2.28 (3H, m), 1.95-1 , 66 (4H, m), 1.39 (9H, s); MS (ESI) 433 (M + Hf. STEP 4. Trifluoroacetate of 3- (6-fluoro-1? 3H-esp.ror2-benzofuran- 1.4'-piperidin1-1'-iD-2- (1,3-thiazol-4-ylmethylpropanoic acid) The title compound was prepared according to the procedure described in step 3 of example 1 from 3- (6-fluoro) -1?, 3H-spiro [2-ben zofuran-1, 4'-piperidin] -1'-yl) -2- (1, 3-thiazol-4-ylmethyl) propane-butyl ester (step 3): 1 H-NMR (DMSO-de) d 9.09 (1H, s), 7.48 (1H, s), 7.38-7.30 (1H, m), 7.22-7.10 (1H, m), 7.05-6.95 (1H, m), 4.99 (2H, sa), 3.95-3.10 (9H, m), 2.28-2.10 (2H) , m), 1, 93-1.78 (2H, m); MS (ESI) 377 (M + Hf, 375 (M-Hf EXAMPLE 45 2- (2-Chloro-5-hydroxybenzD-3-f3- (hydroxymetho-1? .3H-spiro-2-benzofuran-1.4 'piperidinM' -illpropanoic STEP 1. 1- (2-Bromophene) -Pethane-1,2-diol To a stirred solution of 1-bromo-2-vinylbenzene (4.14 g, 22.6 mmol) and? / - 4-methylmorpholine oxide in acetonitrile (20 ml) and water (10 ml) was added a 2.5% solution of osmium tetraoxide in 2-methyl-2-propanol (2 ml) at room temperature and the mixture was stirred for 24 hours at room temperature. The reaction mixture was quenched by the addition of sodium hydrosulfate, and was diluted with water, then extracted with ethyl acetate.The organic phase was washed with an aqueous solution of dilute hydrochloric acid and brine, dried over sodium sulfate. , and evaporated yielding 5.01 g (quant.) of the title compound as a brown solid: 1 H-NMR (CDCl 3) d 7.53 (1H, d, J = 7.7 Hz), 7.41 (1H, d, J = 8.1 Hz), 7.26-7.21 (1 H, m), 7.06-7.00 (1 H, m), 5.02 (1 H, m) 3.76-3.72 (1 H, m), 3.40-3.33 (1 H, m) STEP 2. 1 - (2-Bromophen-D-2-ffferc-butyl (diphenhydroxyethyl) stirred solution of 1- (2-bromophenyl) ethano- 1,2-diol (step 1, 5.01 g, 22.6 mmol) and in dichloromethane (20 ml) and imidazole (2.31 g, 33.9 mmol) in? /, / V-dimethylformamide (20 ml ) was added ferc-butyldiphenylsilyl chloride (6.53 g, 23.8 mmol) at 0 ° C and the mixture was stirred for 19 hours at the same temperature. The reaction mixture was diluted with toluene / ethyl acetate (1/3), then washed with water three times and brine, dried over sodium sulfate, and evaporated. The residue was purified by column chromatography on silica gel (100 g) eluting with hexane / ethyl acetate (10/1) to yield 7.05 g (68%) of the title compound as a colorless syrup: 1H- NMR (CDCl 3) d 7.70-7.67 (2H, m), 7.61-7.57 (3H, m), 7.47-7.28 (8H, m), 7.14-7, 08 (1H, m), 5.21-5.26 (1H, m), 3.98-3.94 (1H, m), 3.57-3.51 (1H, m), 3.17 ( 1H, d, J = 2.9 Hz), 1.03 (9H, s). STAGE 3, 4-f2- (2-l-dibenyl-butyl (d-phenylsidinoxy) -1-hydroxyethyl-4-hydroxypiperidin-1-ethylcarboxylate To a stirred solution of 1- (2-bromophenyl) ) -2-. {[[Ferc-butyl (diphenyl) silyl] oxy] ethanol (step 2, 5.63 g, 12.4 mmol) in tetrahydrofuran (36 ml) was added dropwise a solution 1 , 59 M of butyllithium in tetrahydrofuran (15.9 ml, 25.3 mmol) at -78 ° C for 5 minutes and the mixture was stirred for 5 hours at the same temperature. A solution was added dropwise to the mixture. of ethyl 4-oxopiperidin-1-carboxylate (2.33 g, 13.6 mmol) in tetrahydrofuran (10 mL) at -78 ° C and the mixture was stirred for 2 hours at the same temperature. slowly to room temperature and stirred for 16 hours at the same temperature.The reaction mixture was quenched by the addition of a saturated aqueous solution of ammonium chloride, and concentrated giving a yellow residue. The crude material was partitioned between ethyl acetate and water, and then the organic phase was washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by column chromatography on silica gel (150 g) eluting with hexane / ethyl acetate (2/1) to yield 1.76 g (26%) of the title compound as a colorless solid: 1H- NMR (CDCl 3) d 7.57-7.25 (14H, m), 5.72 (1H, m), 4.19-4.08 (2H, m), 3.96-3.75 (2H, m), 3.34-3.14 (1H, m), 1.89-1, 72 (2H, m), 1.53-1.43 (3H, m), 1.34-1.23 ( 2H, m), 1.28 (3H, t, J = 6.9 Hz), 1.03 (9H, s). STAGE 4. 3-fflferc-butyl (d-phenylDsilyloxy) metiD-1? .3H-Spiror2-benzofuran-1.4'- piperidinM'-ethylcarboxylate To a stirred solution of 4- [2- (2-. { [ethyl fer- tic-butyl (diphen-I) -silyl] oxy} - 1-hydroxyethyl) phenyl] -4-hydroxypiperidine-1-carboxylate (step 3, 1.76 g, 3.21 mmol) and triethylamine (1.34 ml, 9.64 mmol) in dichloromethane (15 ml) was added dropwise methanesulfonyl chloride (552 mg, 4.82 mmol) at 0 ° C for 5 minutes. This resulting mixture was slowly warmed to room temperature and stirred for 18 hours at the same temperature, then at 50 ° C for 2 hours. The reaction mixture was washed with water, dried over sodium sulfate, and evaporated. The residue was purified by column chromatography on silica gel (100 g) eluting with hexane / ethyl acetate (5/1) to yield 1.39 g (79%) of the title compound as a colorless syrup: 1H- NMR (CDCl 3) d 7.65-7.61 (4H, m), 7.45-7.23 (9H, m), 7.10-7.05 (1H, m), 5.32 (1H, t, J = 4.6 Hz), 4.20-4.04 (4H, m), 3.94-3.84 (2H, m), 3.23 (2H, ma), 2.04-1 , 66 (4H, m), 1.28 (3H, t, J = 6.4 Hz), 0.99 (9H, s). STAGE 5. 3H-Spiror2-benzofuran-1.4'-piperid and 3-methanol A solution of 3- ( { [Fer- butyl (diphenyl) silyl] oxy} methyl) -1'H, 3H I -spiro [ethyl 2-benzofuran-1, 4'-piperidine] -1'-carboxylate (step 4, 1.39 g, 2.63 mmol) in 5 M sodium hydroxide aqueous solution (10 ml) and ethanol ( 10 ml) was heated to reflux for 40 hours. The reaction mixture was concentrated to give a brown residue. The crude material was partitioned between diethyl ether and water, and the organic phase was washed with brine, dried over sodium sulfate, and evaporated yielding 100 mg (17%) of the title compound as a colorless solid: MS ( IEN) 220 (M + Hf. STAGE 6. 2- (5- ^ -ferc-Butyl) (dimethyldinoxy) -2-chlorobenzyd-3-r3- (hydroxyethyl) -1, 3H-spiro2 ethylbenzofuran-1, 4'-piperidin-N '-illpropanoate The title compound was prepared according to the procedure described in step 4 of example 4 from 3 / -spiro [2-benzofuran-1, 4'-piperidin] -3-ylmethanol (step 5) and ethyl 2- (5-. {[[(Ethyl-butyl (dimethyl) silyl] oxy} -2-chlorobenzyl) acrylate (step 2 of the example 30): 1 H-NMR (CDCl 3) d 7.31-7.10 (5H, m), 6.71 (1H, d, J = 2.8 Hz), 6.64 (1H, dd, J = 8.6, 2.8 Hz), 5.27 (1H, m), 4.19-4.00 (2H, m), 3.95-3.90 (1H, m), 3.76- 3.63 (1H, m), 3.12-2.99 (2H, m), 2.88-2.76 (4H, m), 2.55-2.39 (3H, m), 2.09-1 , 80 (2H, m), 1.71-1.66 (2H, m), 1.18 (3H, t, J = 7.2 Hz), 0.96 (9H, s), 0.17 (6H, s); MS (ESI) 574 (M + Hf. STAGE 7. 2- (2-Chloro-5-hydroxybenzD-3-r3- (hydroxymethiD-1? .3H-spiro-2-benzofuran-1, 4'- pyrididin-1-ylpropanoic The title compound was prepared according to the procedure described in step 4 of example 30 from 2- (5-. {[[ferc-butyl (dimethyl) silyl] oxy}. -2-chlorobenzyl) -3- [3- (hydroxymethyl) -1?, 3H-espyro [ethyl 2-benzofuran-1, 4'-piperidin] -1'-yljpropanoate (step 6): MS ( ESI) 432 (M + Hf, 430 (M-Hf EXAMPLE 46 3- (5-Fluoro-1-methyl-2-oxo-1,2-dihydro-1-esopropyl-3,4'-piperidine) -1 '-D- 2- (pyridin-2-ylmethylpropanoic acid STEP 1. 3- (5-Fluoro-1-methyl) -2-oxo-1,2-dihydro-1'H-espiropndol-3,4'-piperidin-1'-D-2- (pyridin-2) ethyl-ethylmethylpropanoate The title compound was prepared according to the procedure described in step 4 of example 4 from 5-fluoro-1-methylspiro [indole-3,4'-piperidine] -2 (1 - /) -one (step 3 of example 6) and ethyl 2- (pyridin-2-ylmethyl) acrolylate (Polym J. 2000, 32, 173.): 1 H-NMR (CDCl 3) d 8.57-8, 51 (1H, m), 7.64-7.54 (1H, m), 7.22-7.08 (3H, m), 7.02-6.92 (1H, m), 6.74 (1H, dd, J = 8.4, 4.3 Hz), 4.18-4.06 (2H, m), 3.38- 3.23 (1H, m), 3.17 (3H, s), 3.13-2.82 (5H, m), 2.77-2.54 (3H, m), 1.98-1, 85 (2H, m), 1.75-1.60 (2H, m), 1.19 (3H, t, J = 7.1 Hz); MS (ESI) 426 (M + Hf. STAGE 2. 3- (5-Fluoro-1-methyl-2-oxo-1,2-dihydro-1'H-espirorindole-3,4'p-peridin-1-acid. '-P-2- (pyridin-2-ylmethylpropanoic acid) The title compound was prepared according to the procedure described in step 4 of example 30 from 3- (5-fluoro-1-methyl-2-oxo- Ethyl 1,2-dihydro-1? -spiro [4dol-3,4'-piperidin] -1'-yl) -2- (pyridin-2-ylmethyl) propanoate (step 1): 1 H-NMR (CDCl 3 ) d 8.57-8.49 (1H, m), 7.65-7.56 (1H, m), 7.34-7.26 (1H, m), 7.19-7.10 (1H , m), 7.04-6.92 (2H, m), 6.80-6.72 (1H, m), 3.62-3.13 (7H, m), 3.17 (3H, s), 2.98-2.82 (2H, m), 2.45-2.25 (2H, m), 1.95-1.75 (2H, m); MS (ESI) 398 (M + H) EXAMPLE 47 3- (3,3-Dimethyl-1? 3 H-spiro-2-benzofuran-1,4'-p.peridin-1'-di-2- (pyridin-2-ylmethyl-propanenoic acid STAGE 1. 3- (3,3-Dimethyl-1?. 3 H-spiro-r 2 -benzofuran-1,4'-piperidin-1'-D-2- (ethyl pyridin-2-ylmethylpropanoate The title compound was prepared in accordance with the procedure described in step 4 of Example 4 starting from 3,3-dimethyl-3H-spiro [2-benzofuran-1,4'-piperidine] (step 4 of example 34) and 2- (pyridin-2) ylmethyl) ethyl acrylate (Polym, J. 2000, 32, 173): 1 H-NMR (CDCl 3) d 8.57-8.50 (1H, m), 7.63-7.53 (1H, m), 7.33-7.02 (6H, m), 4.19-4.04 (2H, m), 3.33-3.20 (1H, m), 3.16-2.97 (2H, m), 2.94-2.68 (3H, m ), 2.62-2.36 (3H, m), 1.98-1.82 (2H, m) "1, 78-1.57 (2H, m), 1.48 (6H, s), 1, 18 (3H, t, J = 7.1 Hz); MS (ESI) 409 (M + Hf. STEP 2. Acid 3- (3,3-d.methyl-1?, 3 H -spec.-2-benzofuran-1,4'-piperidin-1'-iD-2- (pyridine -2-ilmetiDpropanoic The title compound was prepared according to the procedure described in step 2 of Example 33 from 3- (3,3-dimethyl-1'H, 3H-spiro [2-benzofuran-1] ^ '- piperidinj-l'-iD ^ -ıpiridin ^ -ilmetippropanoate ethyl (stage 1): 1H-NMR (CDCI3) d 8.56-8.48 (1H, m), 7.70-7.59 ( 1H, m), 7.40-7.23 (3H, m), 7.21-7.02 (3H, m), 3.58-3.44 (2H, m), 3.43-2.83 (7H, m), 2.48-2.28 (2H, m ), 1.83-1.68 (2H, m), 1.17 (6H, s); MS (ESI) 381 (M + H) EXAMPLE 48 3- (3-Methyl-1?. 3 H-Spiro-2-benzofuran-1,4'-piperidin-1-yl) -2- (py-din-2-) ImetiDpropanoico STAGE 1. 3- (3-Met-1-1?, 3-pyrroxy-benzofuran-1, 4'-piperid-1-1-iP-2- (pyridin-2-methyl Ethyl Dpropanoate The title compound was prepared as a mixture of diastereomers according to the procedure described in step 4 of Example 4 from 3-methyl-3H-spiro [2-benzofuran-1, 4'- piperidine] (step 4 of example 36) and ethyl 2- (pyridin-2-ylmethyl) acrylate (Polym, J. 2000, 32, 173.): 1 H-NMR (CDCl 3) d 8.57-8.50 ( 1H, m), 7.63-7.53 (1H, m), 7.33-7.03 (6H, m), .27 (1H, c, J = 6.4 Hz), 4.21-4.01 (2H, m), 3.35-3.20 (1H, m), 3.16-2.97 ( 2H, m), 2.95-2.68 (3H, m), 2.62-2.32 (3H, m), 2.08-1.93 (1H, m), 1.88-1, 60 (3H, m), 1, 48 (3H, d, J = 6.4 Hz), 1, 27-1, 07 (3H, m); MS (ESI) 395 (M + H, STEP 2. Acid 3- (3-methylene-1'H, 3H-spiro-2-benzofuran-1,4'-piperidn -1-1'-D- 2- (pyridin-2-ylmethyl) propanoic The title compound was prepared as a mixture of diastereomers according to the procedure described in step 2 of example 33 from 3- (3-methyl-1'H, 3 H-spiro [2-benzofuran-1,4'-piperidn] -1'-iD-2- (pyridin-2-ylmethyl) propanoate ethyl (step 1): MS (ESI) 367 (M + Hf. EXAMPLE 49 3- (3-Methyl-1? .3H-Spiro-2-benzofuran-1,4'-piperidin-1 '-iD-2- (1,3-thiazol-4-ylmethylpropanoic acid) trifluoroacetate STAGE 1. 3- (3-Methyl-1'H.3H-spiroF2-benzofuran-1.4'-piperidin-1'-D-2- (1,3-thiazole-4-ylmethylpropanoate of fer-butyl The The title compound was prepared according to the procedure described in step 4 of example 4 from 3-methyl-3W-spiro [2-benzofuran-1,4'-piperidine] (step 4 of example 36) and 2- (1,3-thiazole-4-ylmethyl) fer-butyl acrylate (step 2 of example 44): 1 H-NMR (CDCl 3) d 8.75 (1H, d, J = 2.0 Hz), 7.31 -7.05 (4H, m), 7.03 (1H, d, J = 2.0 Hz), 5.28 (1H, c, J = 6.4 Hz), 3.16-2.65 (6H, m), 2.62-2.30 (3H, m), 2, 12-1, 62 (4H, m), 1, 49 (3H, d, J = 6.4 Hz), 1, 39 (9H, s); MS (ESI) 429 (M + Hf. STAGE 2. 3- (3-Methyl-1'f / .3H-Spiro-2-benzofuran-1,4'-piperidin-1'-iD-2- (1-3) Trifluoroacetate -t-azole-4-ylmethylpropanoic The title compound was prepared according to the procedure described in step 3 of example 1 from 3- (3-methyl-1'H, 3 / - / - spiro [2- Ferric-butyl benzofuran-1,4'-piperidin] -1'-yl) -2- (1,3-thiazol-4-ylmethyl) propanoate (step 1): MS (ESI) 373 (M + H) EXAMPLE 50 Trifluoroacetate of 3- (3,4-dihydro-1? -espiropsochromen-1,4'-piperidin-1'-iD-2- (1.3 -thiazole-4-ylmethylpropanoic acid TFA STAGE 1. 3- (3,4-dihydro-1 'H-spiro-cyclohexene-1,4'-piperidin-1'-yl) -2- (1,3-thiazole-4-ylmethylpropanoate of fer-butyl) The title compound was prepared in accordance with the procedure described in step 4 of example 4 from 3,4-dihydrospiro [isochromeno-1,4'-p-peridine] (WO 9528389) and 2- (1,3-thiazol-4-ylmethyl) acrylate of fer-butyl (step 2 of example 44): 1 H-NMR (CDCl 3) d 8.75 (1H, d, J = 2.0 Hz), 7.25-7.05 (4H, m), 7.03 (1H, d, J = 2.0 Hz), 3.89 (2H, t, J = 5.5 Hz), 3.17-3.03 (3H, m), 2.90-2.62 (3H, m), 2, 82 (2H, t, J = 5.5 Hz), 2.57-2.30 (3H, m), 2.05-1.75 (4H, m), 1.40 (9H, s); MS (ESI) 429 (M + Hf. STAGE 2. 3- (3,4-Dihydro-1? -spyror-1-methyl-1,4'-piperidin-1-yl) -2- (3-3-) trifluoroacetate thiazol-4-ylmethylpropanoic The title compound was prepared according to the procedure described in step 3 of example 1 from 3- (3,4-dihydro-1'H-spiro [isochromen-1, 4'-piperidin ] -1'-yl) -2- (1,3-thiazol-4-ylmethyl) -propanebutyl propanoate (step 1): EXAMPLE 51 3- (5-Fluoro-1? .3H-Spiror2- trifluoroacetate benzofuran-1,4'-piperidin-1 '-iD-2- (1,3-thiazol-4-ylmethylpropanoic acid) STAGE 1. 3- (5-Fluoro-1'H.3fí-espiror2-benzofuran-1.4'-piperidin1-1 '-D-2- (1,3-thiazole-4-ylmethyl) propane-butyl ester The title compound was prepared according to the procedure described in step 4 of Example 4 from 5-fluoro-3 H-spiro [2-benzofuran-1,4'-piperidine] and 2- (1,3-thiazole). 4-ylmethyl) ferric butyl acrylate (stage 2 of Example 44): 1 H-NMR (CDCl 3) d 8.75 (1H, d, J = 2.0 Hz), 7.07-6.85 (4H, m), 5.02 (2H, s) , 3.17-3.02 (3H, m), 2.97-2.85 (1H, m), 2.83-2.67 (2H, m), 2.56-2.30 (3H, m) ), 1, 95-1, 80 (2H, m), 1, 78-1, 65 (2H, m), 1.38 (9H, s); MS (ESI) 433 (M + Hf. STEP 2. Trifluoroacetate of 3- (5-fluoro-1? .3H-spiro-2-benzofuran-1,4'-p-peridin-1-yl) -2- ( 1,3-thiazole-4-ylmethyl-D-propane The title compound was prepared according to the procedure described in step 3 of Example 1 from 3- (5-fluoro-1α, 3H-spiro [2-benzofuran] -1, 4'-piperidin] -1'-yl) -2- (1, 3-thiazol-4-ylmethyl) propanoate of fer-butyl (step 1): MS (ESI) 377 (M + Hf EXAMPLE 52 3- (7-fluoro-1?, 3 / - / - spiro [2-benzofuran-1,4'-piperidin-1'-trifluoroacetate] D-2- (1, 3-t! Azo! -4-i! MethyDpropanoic STAGE 1. 3- (7-Fluoro-1'H.3H-Spiror2-benzofuran-1.4'-piperidin-1'-D-2- (1,3-thiazole-4-ylmethylpropanoate of fer-butyl) The compound of title was prepared according to the procedure described in step 4 of example 4 from 7-fluoro-3 H-spiro [2-benzofuran-1,4'-piperidine] (J. Med. Chem. 1995, 38, 2009 .) and 2- (1, 3-thiazoI-4-ylmethyl) ferricbutyl acrylate (step 2 of example 44): H-NMR (CDCl 3) d 8.75 (1H, d, J = 2.0 Hz), 7.26-7.17 (1H, m), 7.03 (1H, d, J = 2.0 Hz) ), 6.99-6.85 (2H, m), 5.07 (2H, s), 3.17-2.90 (4H, m), 2.82-2.66 (2H, m), 2.55-2.15 (5H, m), 1.80-1, 66 (2H, m), 1.39 (9H, s); MS (ESI) 433 (M + Hf. STEP 2. Trifluoroacetate of 3- (7-fluoro-1? .3H-spiro-2-benzofuran-1,4'-piperidin-1'-D-2- (1, 3-thiazol-4-i! MetiPpropanoic The title compound was prepared according to the procedure described in step 3 of Example 1 from 3- (7-fluoro-1'H, 3H-spiro [2-benzofuran- 1, 4'-piperidin] -1'-yl) -2- (1,3-thiazol-4-ylmethyl) propane-butyl ester (step 1): MS (ESI) 377 (M + Hf. EXAMPLE 53 Trifluoroacetate of 3- (5-fluoro-1-methyl-2-oxo-1,2-dihydro-1? -espirophenol-3,4'-piperidin-1'-yl) -2- (1,3-thiazole- 4-ilmetiDpropanoic STAGE 1. 3- (5-Fluoro-1-methyl-2-oxo-1,2-d, 1-d-1-esopyrone-3,4'-piperidin-1'-iD-2- (1,3-t) Azole-4-ylmethylpropanoate The title compound was prepared according to the procedure described in step 4 of Example 4 from 5-fluoro-1-methiospiro [indole-3,4'- piperidine] -2 (1H) -one (step 3 of example 6) and fer-butyl 2- (1,3-thiazol-4-ylmethyl) acrylate (step 2 of example 44): 1 H-NMR (CDCl 3 ) d 8.76 (1H, d, J = 2.0 Hz), 7.14 (1H, dd, J = 8.4, 2.4 Hz), 7.04 (1H, d, J = 2, 0 Hz), 7.02-6.93 (1H, m), 6.75 (1H, dd, J = 8.4, 4.4 Hz), 3.25-2.50 (12H, m), 2.00-1.85 (2H, m), 1.84-1.64 (2H, m), 1.40 (9H, s); MS (ESI) 460 (M + Hf. STAGE 2. 3- (5-Fluoro-1-methy1-2-oxo-1,2-dihydro-1? -espyrofindol-3,4'-p-peridin-3-trifluoroacetate) -1'-iP-2- (1,3-thiazol-4-methyl) propanoic The title compound was prepared according to the procedure described in step 3 of example 1 from 3- (5-fluoro-1-) Methyl-2-oxo-1,2-dihydro-1? -spiro [indol-3,4'-piperidin] -1'-yl) -2- (1,3-thiazoI-4-ylmethyl) propanoate ferric butyl (step 1): MS (ESI) 404 (M + Hf EXAMPLE 54 Trifluoroacetate of 3- (2,3-dihydro-1? -espirofinden-1,4'-piperidin-1'-iP-2- (1, 3- t-azole-4-ethyl-D-propane STAGE 1. 3- (2,3-Dihydro-1 'H-espirorinden-1.4'-piperidin1-1' -iP-2- (1,3-thiazole-4) Ferric-butyl ImethiPpropanoate The title compound was prepared according to the procedure described in step 4 of Example 4 from 2,3-dihydrospiro [inden-1,4'-piperidine] and 2- (1, 3 -thiazol-4-ylmethyl) ferricbutyl acrylate (step 2 of the example 44): 1 H-NMR (CDCl 3) d 8.75 (1H, d, J = 2.0 Hz), 7.16-7.11 (2H, m), 7.02 (1H, d, J = 2 , 0 Hz), 6.88-6.82 (2H, m), 3.13-2.95 (5H, m), 2.75-2.31 (4H, m), 2.19-2, 01 (2H, m), 1.71-1, 60 (6H, m), 1.38 (9H, s); MS (ESI) 419 (M + Hf. STEP 2. Trifluoroacetate of 3- (2,3-dihydro-1'H-spiro-n-1,4'-piperidin-1'-yl) -2- (1, 3-t) Azol-4-ylmethylD-propanoic acid The title compound was prepared according to the procedure described in step 3 of Example 1 from 3- (2,3-dihydro-1'H-spiro [ l ^ '- piperidinl-l-iD ^ -lI.S-thiazoM-ylmethylpropanoate of fer-butyl (step 1): 1 H-NMR (CDCl 3) d 9.67 (1H, d, J = 2.2 Hz) , 7.90 (1H, d, J = 2.4 Hz), 7.26-7.20 (3H, m), 7.11-7.08 (1H, m), 3.85-3.05 (9H, m), 2.97 (2H, t, J = 7.3 Hz), 2.33-2.16 (2H, m), 2.08 (2H, t, J = 7.2 Hz) 1.80 (2H, da, J = 14.9 Hz); MS (ESI) 357 (M + Hf) EXAMPLE 55 3- (6-Fluoro-1'-.3H-spiro-2-benzofuran-1.4'- piperidin-1 '-D-2- (1 H-pyrazole-1-methylmethylpropanoic acid) STEP 1. 3- (6-Fluoro-1'H.3 / 7-spiro-2-benzofuran-1,4'-piperidin-1'-ethyl-D-2- (hydroxymethyl) propanoate The title compound was prepared from according to the procedure described in step 4 of Example 4 starting from 6-fluoro-3 H-spiro [2-benzofuran-1,4'-pperiod] (J. Med. Chem. 1995, 38 , 2009.) and ethyl 2- (hydroxymethyl) acrylate: 1 H-NMR (CDCl 3) d 7.14 (1H, dd, J = 8.2, 5.0 Hz), 7.03-6.93 (1H , m), 6.79 (1H, dd, J = 8.2, 2.2 Hz), 5.01 (2H, s), 4.15 (2H, c, J = 7.1 Hz), 4 , 05-3.88 (2H, m), 3.12-2.80 (5H, m), 2.70-2.55 (1H, m), 2.47-2.31 (1H, m) , 2.00-1.70 (4H, m), 1.27 (3H, t, J = 7.1 Hz); MS (ESI) 338 (M + Hf. STEP 2. 3- (6-Fluoro-1'H.3H-spiro-2-benzofuran-1.4'-p-peridin-1'-iP-2- (1H-pyrazole-1) ethyl-ethylmethylpropanoate To a stirred solution of 3- (6-fIuoro-1'H, 3H-spiro [2-benzofuran-1,4'-piperidin] -1'-yl) -2- (hydroxymethyl) propanoate of ethyl (stage 1) and triethylamine in dichloromethane was added methanesulfonyl chloride at 0 ° C. The reaction mixture was stirred at the same temperature for 1 hour, and was quenched by the addition of an aqueous solution of sodium bicarbonate. The mixture was extracted with dichloromethane The combined organic phases were dried over magnesium sulfate and evaporated The residue was dissolved with acetonitrile, and potassium carbonate and pyrazole were added to the solution The mixture was stirred at 80 ° C for 16 hours , quenched by the addition of water, and extracted with ethyl acetate.The combined organic phases were washed with brine, dried over magnesium sulfate, and evaporated.The residue was purified by chromat column chromatography on silica gel eluting with ethyl acetate / methanol (10/1) to yield the title compound as a colorless oil: 1 H-NMR (CDCl 3) d 7.54-7.49 (1H, m) , 7.45-7.40 (1H, m), 7.17-7.10 (1H, m), 7.00-6.90 (1H, m), 6.83-6.75 (1H, m), 6.25-6.20 (1H, m), 5.01 (2H, s), 4.48-4.35 (2H, m), 4.20-4.06 (2H, m) , 3.37-3.23 (1H, m), 2.90-2.30 (6H, m), 1.98-1.65 (4H, m), 1.27-1.15 (3H, m); MS (ESI) 388 (M + Hf. STAGE 3. 3- (6-Fluoro-1'H.3H-spiro-2-benzofuran-1.4'-p-peridin-1-l-D-2- (1 H-pyrazole-1-methylmethylpropanoic The title compound was prepared according to the procedure described in step 2 of example 33 from 3- (6-fluoro-17 - /, 3H-spiro [2-benzofuran- 1, 4'-piperidin] -1'-yl) -2- (1 H-pyrrazol-1-ylmethyl) propanoate ethyl (step 1): MS (ESI) 360 (M + Hf, 358 (M- Hf EXAMPLE 56 3- (1? .3H-Spiro-2-benzofuran-1,4'-pyrimidine-1'-iD-2- (1,3-thiazole-4-methyl-D-propanoic acid trifluoroacetate STEP 1. 3- (1 'H 3 H-Spiro-2-benzofuran-1,4'-piperidin-1'-yl) -2- (1, 3-thiazol-4-ylmethylpropanoate of fer-butyl) The title compound was prepared from according to the procedure described in step 4 of example 4 starting from 3H-spiro [2-benzofuran-1,4'-piperidine] and fer-butyl 2- (1,3-thiazol-4-ylmethyl) acrylate ( stage 2 of the example 44): 1 H-NMR (CDCl 3) d 8.79-8.72 (1H, m), 7.32-7.15 (3H, m), 7.14-7.06 (1H, m), 7.05-6.99 (1H, m), 5.06 (2H, s), 3.15-3.00 (3H, m), 2.99-2.87 (1H, m), 2, 84-2.67 (2H, m), 2.58-2.30 (3H, m), 1.99-1.83 (2H, m), 1.81-1.67 (2H, m), 1.39 (9H, s); MS (ESI) 415 (M + Hf. STAGE 2. 3- (1'fí.3H-Spiro-2-benzofuran-1,4'-pjperidin-1'-di-2- (1,3-thiazol-4-ylmethylpropanoic acid trifluoroacetate The title compound was prepared according to the procedure described in step 4 of example 44 from 3- (1'H, 3H-spiro [2-benzofuran-1. ^ - piperid? nl-l'--2 - (1, 3-thiazole-4-ylmethyl) propane-butyl ester (step 1) and trifluoroacetic acid: 1 H-NMR (CDCl 3) d 11.99 (1H, sa), 9.63-9.54 (1H , m), 8.86-8.55 (1H, ma), 7.90-7.80 (1H, m), 7.40-7.21 (3H, m), 7.17-7.07 (1H, m), 5.11 (2H, s), 3, 90- 3.18 (9H, m), 2.50-2.20 (2H, m), 2.07-1.90 (2H, m). EXAMPLE 57 3- (2,3-Hydro-1? -espyrorinden-1,4'-piperidin-1'-iD-2- (1-fluoro-pyrazole-1-Imethylpropanoic acid STEP 1. 2- (1H-Pyrazole-1-ethyl-ethyl acrylate A mixture of ethyl 2- (hydroxymethyl) acrylate (4.1 g, 32 mmol), pyrazole (2.6 g, 38 mmol) and potassium carbonate (11 g, 79 mmol) in acetonitrile (30 mL) was heated to reflux for 20 hours, quenched by the addition of water (100 mL), and extracted with ethyl acetate. ethyl (40 ml x 2). The combined organic phases were washed with brine, dried over magnesium sulfate, and evaporated. The residue was purified by column chromatography on silica gel eluting with hexane / ethyl acetate (7/1) affording 1.0 g (18%) of the title compound as a colorless oil: 1 H-NMR (CDCl 3) d 7.57-7.53 (1H, m), 7.48-7.45 (1H, m), 6.36-6.32 (1H, m), 6.28 (1H, t, J = 2.0 Hz), 5.48-5.44 (1H, m), 5.01 (2H, s), 4.24 (2H, c, J = 7.1 Hz), 1.30 (3H, t, J = 7 , 1 Hz). STEP 2. 3- (2,3-Dihydro-1'H-espyropnden-1,4'-pperidin-1-l-iD-2- (1H-pyrazol-1-ylmethylpropanoate ethyl The title compound was prepared according to the procedure described in step 4 of example 4 from 2,3-dihydrospiro [inden-1,4'-piperidine] and ethyl 2- (1 H-pyrazol-1-ylmethyl) acrylate (step 1) ): 1 H-NMR (CDCl 3) d 7.55-7.48 (1H, m), 7.44-7.38 (1H, m), 7.25-7.10 (4H, m), 6, 25-6.18 (1H, m), 4.48-4.38 (2H, m), 4.23 ^, 05 (2H, m), 3.38-3.22 (1H, m), 2 , 95-2.77 (2H, m), 2.88 (2H, t, J = 7.3 Hz), 2.73-2.61 (1H, m), 2.58-2.46 (1H , m), 2.30-2.15 (2H, m), 1.98 (2H, t, J = 7.3 Hz), 1.96-1.80 (2H, m), 1.58- 1.45 (2H, m), 1, 25 (3H, t, J = 7.3 Hz); MS (ESI) 368 (M + Hf. STEP 3. 3- (2,3-Dihydro-1'H-espiropnden-1,4'-p-peridin-1'-iP-2- (1-pyrazole-1 - ilmetiPpropanoic The title compound was prepared according to the procedure described in step 4 of example 30 from 3- (2,3-dihydro-1'H-spiro [inden-1,4'-piperidine] -1 ' ethyl) -2- (1 H-pyrazol-1-ylmethyl) propanoate (step 2): MS (ESI) 340 (M + Hf, 338 (M-Hf EXAMPLE 58 3- (3,4-dihydro-1) ? -esp¡rorisocromeno-1, 4'-piperidin] -1 '-il) -2- (1 H-pyrazol-1-ylmethylpropropanoic acid) STEP 1. 3- (3,4-Dihydro-1 W-spiro-chromocose-1,4'-piperidin] -1'-iP-2- (1 H -pyrazol-1-ylmethylpropanoate ethyl) The title compound was prepared according to the procedure described in step 4 of example 4 from 3,4-dihydrospiro [isochromeno-1,4'-piperidine] and 2- (1 / - / - pyrazol-1-ethylmethacrylate) ( stage 1 of the example 57): 1 H-NMR (CDCl 3) d 7.51 (1 H, d, J = 2.0 Hz), 7.40 (1 H, d, J = 2.0 Hz), 7.25-7.05 (4H, m), 6.21 (1H, t, J = 2.0 Hz), 4.48-4.36 (2H, m), 4.24-4.05 (2H, m), 3, 88 (2H, t, J = 5.5 Hz), 3.36-3.23 (1H, m), 2.82 (2H, t, J = 5.5 Hz), 2.78-2.62 ( 3H, m), 2.58-2.38 (3H, m), 2.05-1.85 (4H, m), 1.22 (3H, t, J = 7.2 Hz); MS (ESI) 384 (M + Hf. STAGE 2. 3- (3,4-d, H-d-1-H-pyrophoschromene-1,4'-piperidin-1'-iP-2- (1 H-pyrazole -1-methylpropanoic The title compound was prepared according to the procedure described in step 4 of Example 30 from 3- (3,4-dihydro-1β-spiro [isocromen-1,4'-piperidine] - 1'-ethyl) -2- (1 H-pyrazol-1-ylmethyl) propanoate (step 1): MS (ESI) 356 (M + Hf, 354 (M-Hf EXAMPLE 59 Trifluoroacetate of 3- (7 -fluoro-3,4-d¡h¡dro-1'rV-esp¡ropsocromeno-1.4'-piperidinl-1 '-il) -2- (1,3-t¡azol-4-ilmet¡Dpropanoico STEP 1. 2- (2-Bromo-4-fluorofeniDetanol To a solution of (2-bromo-4-fluorophenyl) acetic acid (1.5 g, 6.44 mmol) in tetrahydrofuran (10 mL) was added a solution. 1 M borane-tetrahydrofuran complex in tetrahydrofuran (9.66 ml, 9.66 mmol) at 0 ° C. The mixture was warmed to room temperature and stirred for 3 hours.The reaction mixture was quenched by the addition of acid 2 N hydrochloric acid (50 ml) was extracted with ethyl acetate (200 ml), the organic phase was washed with brine (50 ml), dried over sodium sulfate and evaporated, the residue was purified by column chromatography on silica gel (100 g) eluting with hexane / ethyl acetate (5/1) to yield 1.30 g (92%) of the title compound as a colorless oil: 1 H-NMR (CDCl 3) d 7.33- 7.23 (2H, m), 6.99 (1H, dt, J = 8.3, 2.6 Hz), 3.87 (2H, t, J = 6.6 Hz), 3.00 (2H, t, J = 6.7 Hz). STEP 2. Ethyl 4-r5-Fluoro-2- (2-hydroxyethylDfenip-4-hydroxypiperidin-1-carboxylate) The title compound was prepared according to the procedure described in step 2 of example 36 from 2 - (2-bromo-4-fluorophenyl): 1 H-NMR (CDCl 3) d 7.18 (1 H, dd, J = 8.4, 6.2 Hz), 7.01 (1H, dd, J = 11 , 4, 2.6 Hz), 6.95 (1H, dt, J = 8.0, 2.7 Hz), 4.18-4.02 (4H, m), 3.94 (2H, t, J = 5.8 Hz), 3.40-3.28 (4H, m), 2.01-1, 83 (4H, m), 1.28 (3H, t, J = 7.2 Hz); MS (ESI) 310 (M-Hf STEP 3. 7-Fluoro-3,4-dihydro-1? -espiropsochromen-1,4-piperidin-1-ethyl carboxylate The title compound was prepared according to the procedure described in step 3 of example 36 from 7-fluoro-3,4-dihydro-1? -spiro [isochromen-1,4'-piperidine] -1'-ethyl carboxylate (step 2): 1 H-NMR (CDCl 3) d 7 , 07 (1H, dd, J = 8.4, 5.9 Hz), 6.87 (1H, dt, J = 8.4, 2.6 Hz), 6.78 (1H, dd, J = 10 , 1, 2.6 Hz), 4.17 (2H, c, J = 7.2 Hz), 4.07 (2H, sa), 3.90 (2H, t, J = 5.5 Hz), 3.25-3.14 (2H, m), 2.79 (2H, t, J = 5.4 Hz), 1.92-1.77 (4H, m), 1.29 (3H, t, J = 7.1 Hz); MS (ESI) 294 (M + Hf. STEP 4. 7-Fluoro-3,4-dihydrospirofisocromen-1,4-piperidinal) The title compound was prepared according to the procedure described in step 4 of example 36 from 7- fluoro-3,4-dihydro-1'H-spiro [isocromen-1, 4-piperidin] -1'-ethyl carboxylate (step 3): 1 H-NMR (CDCl 3) d 7.05 (1H, dd, J = 8.3, 5.9 Hz), 6.91-6.82 (2H, m), 3.89 (2H, t, J = 5.5 Hz), 3.12-3.03 (2H, m), 2.95-2.89 (2H, m), 2.78 (2H, t, J = 5.5 Hz), 1.91-1.83 (4H, m); MS (ESI) 222 (M + Hf. STAGE 5. 3- (7-Fluoro-3,4-dihydro-17-p-spyrol-so-methyl-1, 4'-piperidin-1'-ID-2- (1.3 -thiazole-4-i! ferd-butylmethylpropanoate The title compound was prepared according to the procedure described in step 4 of example 4 from 7-fluoro-3,4-dih-sparospiro [isocromen-1, 4-piperidine] (step 4) and fer-butyl 2- (1,3-thiazol-4-ylmethyl) acrylate (step 2 of example 44): 1 H-NMR- (CDCl 3) d 8.75 (1H, d , J = 2.0 Hz), 7.06-7.01 (2H, m), 6.88-6.78 (2H, m), 3.86 (2H, t, J = 5.5 Hz) , 3.11-3.03 (3H, m), 2.85-2.64 (5H, m), 2.52-2.33 (3H, m), 1.95-1.82 (4H, m), 1.40 (9H, s); MS (ES) 447 (M + H) STEP 6. Trifluoroacetate of 3- (7-fluoro-3,4-dihydro-1? -espyrolyl isocromen-1,4'-piperidin-1'-iP-2- (1, 3-thiazol-4-ylmethylpropanoic The title compound was prepared according to the procedure described in step 3 of Example 1 from 3- (7-fluoro-3,4-dihydro-1'H-spiro [isocromeno- Ferric-butyl 1,4'-piperidin] -1 '-yl) -2- (1,3-thiazole-4-ylmethyl) propanoate (step 5): MS (ESI) 391 (M + H) EXAMPLE 60 3- (7-Fluoro-3,4-dihydro-1 '- esopharomisocromen-1, 4'-pyrimidin-1'-yl) -2- (1 H -pyrazol-1-ylmethylpropropanoic acid) STEP 1. 3- (7-Fluoro-3,4-dihydro-1? -espirofisocromeno-1,4'-piperidin-1-l-iP-2- (1H-p¡razol-1-methylmethyl) propanoate ethyl The title compound was prepared according to the procedure described in step 4 of example 4 from 7-fluoro-3,4-dihydrospiro [sochromen-1,4-piperidine] (step 4 of example 60) and 2- (1H- pyrazoyl-1-ylmethyl) ethyl acrylate (step 1 of example 58): 1 H-NMR (CDCl 3) d 7.51 (1H, d, J = 1.8 Hz), 7.40 (1H, d, J = 2.4 Hz), 7.07-7.02 (1H, m), 6.88-6.82 (2H, m), 6.21 (1H, t, J = 1.8 Hz), 4.43-4.41 (2H, m), 4, 18- 4.09 (2H, m), 3.86 (2H, t, J = 5.4 Hz), 3.34-3.25 (1H, m), 2.78-2.65 (5H, m), 2.55-2.38 (3H, m), 1.97-1, 81 (4H, m), 1.22 (3H, t, J = 7.0 Hz); MS (ESI) 402 (M + Hf. STAGE 2. 3- (7-Fluoro-3,4-dihydro-1 '- espiropsochromen-1,4'-piperidin-1'-iD-2- (1H-pyrazole-1) acid The title compound was prepared according to the procedure described in step 4 of Example 30 from 3- (7-fluoro-3,4-dihydro-1'H-spiro [isochromen-1, 4]. '-piperidin] -1' -yl) -2- (1 H-pyrazol-1-ylmethyl) propanoate ethyl (step 1): MS (ESI) 374 (M + Hf, 372 (M-Hf EXAMPLE 61 Acid 3 - (6-fluoro-3,4-dihydro-1 'f / - esopyrol-so-methyl-1, 4'-piperidinM' -D-2- (1 H -pyrazole-1-methylmethylpropanoic acid STEP 1. 2- (2-Bromo-5-fluoropheniDetanol To a solution of (2-bromo-5-fluorophenyl) acetic acid (1.29 g, 5.54 mmol) in tetrahydrofuran (15 mL) was added hydride. lithium and aluminum (210 mg, 5.54 mmol) at 0 ° C. The mixture was warmed to room temperature and stirred for 3 hours.After cooling to 0 ° C, the reaction mixture was quenched by the addition of acid 2 N hydrochloric acid (30 ml) was extracted with diethyl ether (200 ml), the organic phase was washed with water (50 ml) and brine (50 ml), dried over magnesium sulphate and evaporated. purified by column chromatography on silica gel (40 g) eluting with hexane / ethyl acetate (5/1) yielding 247 mg (20%) of the title compound as a colorless oil: 1 H-NMR (CDCl 3) d 7.51 (1H, dd, J = 8.8, 5.4 Hz), 7.04 (1H, dd, J = 9.2, 3.1 Hz), 6.84 (1H, dt, J = 8.4, 3.1 Hz), 3.93-3.87 (2H, m), 3.01 (2H, t, J = 6.6 Hz ), 1.44 (1H, t, J = 5.7 Hz). STEP 2. Ethyl 4-r4-Fluoro-2- (2-hydroxyetiDfenin-4-hydroxypiperidin-1-carboxylate) The title compound was prepared according to the procedure described in step 2 of example 36 from 2 - (2-bromo-5-fluorophenyl) ethanol (step 1): 1 H-NMR (CDCl 3) d 7.30-7.25 (1H, m), 6.95-6.86 (2H, m), 4 , 18-3.96 (6H, m), 3.83 (1H, sa), 3.40-3.30 (2H, m), 2.01-1.82 (4H, m), 1.27 (3H, t, J = 7.2 Hz); MS (ESI) 310 (M-Hf STEP 3. 6-Fluoro-3,4-dihydro-1? -espiropsochromeno-1,4'-piperidin-1'-carboxylate ethyl The title compound was prepared according to the procedure described in step 3 of Example 36 from 4- [4-fluoro-2- (2-hydroxyethyl) phenyI] -4-hydroxypiperidin-1-ethylcarboxylate (step 2): 1H-NMR (CDCl3) d 7.06-7.01 (1H, m), 6.89 (1H, dt, J = 8.5, 2.6 Hz), 6.80 (1H, dd, J = 9.3, 2.7 Hz), 4.17 (2H, c, J = 7.0 Hz), 4.05 (2H, sa), 3.90 (2H, t, J = 5.5 Hz), 3.19 (2H, sa), 2.82 (2H, t, J = 5.5 Hz), 1.87-1.82 (4H, m), 1.29 (3H, t, J = 7.2 Hz); MS (ESI) 294 (M + Hf. STAGE 4. 6-Fluoro-3,4-d-hydroxypyrrochromocenne-1,4'-piperidine] The title compound was prepared according to the procedure described in step 4 of the example 36 from 6-fluoro-3,4-dihydro-1β-spiro [isocromen-1,4'-piperidine] -1'-ethyl carboxylate (step 3): 1 H-NMR (CDCl 3) d 7.14 (1H, dd, J = 8.7, 5.6 Hz), 6.89 (1H, dt, J = 8.7, 2.5 Hz), 6.79 (1 H, dd, J = 9, 4, 2.8 Hz), 3.90 (2H, t, J = 5.6 Hz), 3.12-3.02 (2H, m), 2.93-2.87 (2H, m), 2.81 (2H, t, J = 5.4 Hz), 1.87-1.83 (4H, m); MS (ESI) 222 (M + Hf. STEP 5. 3- (6-Fluoro-3,4-dihydro-1'rV-spiro-cycloso-1,4'-piperidin-1'-iD-2- (1H-pyrazole-1) Ethyl limetiDpropanoate The title compound was prepared according to the procedure described in step 4 of Example 4 from 6-fluoro-3,4-dihydrospiro [isochromen-1,4'-piperidine] (step 4) and 2- (1H-pyrazolo-1-ylmethyl) ethyl acrylate (step 1 of example 57): 1 H-NMR (CDCl 3) d 7.51 (1H, d, J = 1.8 Hz), 7.40 ( 1H, d, J = 2.4 Hz), 7.09 (1H, dd, J = 8.7, 5.6 Hz), 6.88 (1H, dt, J = 8.5, 2.8 Hz ), 6.78 (1H, dd, J = 9.4, 2.6 Hz), 6.21 (1H, t, J = 2.1 Hz), 4.44-4.40 (2H, m) , 4.19-4.09 (2H, m), 3.87 (2H, t, J = 5.6 Hz), 3.34-3.24 (1H, m), 2.80 (2H, t , J = 5.5 Hz), 2.72-2.65 (3H, m), 2.55-2.38 (3H, m), 2.00-1.81 (4H, m), 1 1 (3H, t, J = 7.2 Hz); MS (IEN) 402 (M + Hf. STAGE 6. 3- (6-Fluoro-3,4-dhydro-1'H-espyropsochromen-1,4 'acid) -piperidin-1'-yl) -2- (1 H -pyrazole-1-ylmethylpropanoic acid The title compound was prepared according to the procedure described in step 4 of example 30 starting from 3- (6-fluoro-3,4-dihydro-1'H-spiro [isochromen-1, 4'-piperidin] -1 '-il) -2- (1 Ethyl H-pyrazol-1-ylmethyl) propanoate (step 5): MS (ESI) 374 (M + Hf, 372 (M-Hf EXAMPLE 62 3- (4,5-dihydro-1'H.3H-) trifluoroacetate espirof2-benzoxepin-1.4'- piperidinl-1 '-il) -2- (1,3-thiazol-4-ylmethyl-D-propane) STEP 1. Ethyl 4-hydroxy-4-f2- (3-hydroxypropyl Dfenanpiperidin-1-carboxylate) The title compound was prepared according to the procedure described in step 2 of example 36 a from 3- (2-bromophenyl) propan-1-ol (J. Am. Chem. Soc. 2003, 125, 3509) and ethyl 4-oxopiperidin-1-carboxylate: 1 H-NMR (CDCl 3) d 7.34-7.10 (4H, m), 4.20-3.90 (2H, m), 4.14 (2H, c, J = 7.1 Hz), 3.63 (2H, t, J = 5.9 Hz), 3.45-3.25 (2H, m), 3.12 (2H, t, J = 7.6 Hz), 2, 10-1, 85 (6H, m), 1, 26 (3H, t, J = 7.1 Hz). STEP 2. 4.5-D-Hydro-1'H.3H-espyror2-benzoxepin-1.4'-pperidin-1'-ethylcarboxylate The title compound was prepared according to the procedure described in step 3 of Example 36 from 4-hydroxy-4- [2- (3-hydroxypropyl) phenyl] piperidine-1-carboxylic acid ethyl ester (step 1): 1 H-NMR (CDCl 3) d 7.37-7.14 (4H, m), 4.22-3.95 (2H, m), 4.15 (2H, c, J = 7.1) Hz), 3.64 (2H, t, J = 6.4 Hz), 3.45-3.25 (2H, m), 3.20-3.08 (2H, m), 2.18-1 90 (6H, m), 1, 27 (3H, t, J = 7.1 Hz). STEP 3. 4,5-Dihydro-3 H-spiro-2-benzoxepin-1,4'-p-peridinal The title compound was prepared according to the procedure described in step 4 of example 36 from 4,5-dihydro -1'H, 3H-spiro [ethyl 2-benzoxepin-1, 4'-piperidin] -1'-carboxylate (step 2): MS (ESI) 218 (M + Hf. STAGE 4. 3- (4.5- Dihydro-1'H.3H-Spiror2-benzoxepin-1,4'-pperidineM'-iD-2- (1,3-thiazole-4-methylmethylpropanoate) The title compound was prepared in accordance with the procedure described in step 4 of Example 4 from 4,5-dihydro-3 H-spiro [2-benzoxepin-1,4'-piperidine] (step 3) and 2- (1,3-thiazole-4-) ylmethyl) ferric butyl acrylate (step 2 of example 44): 1 H-NMR (CDCl 3) d 8.75 (1 H, d, J = 2.0 Hz), 7.25-7.03 (4H, m ), 7.02 (1 H, d, J = 2.0 Hz), 3.66 (2H, t, J = 6.6 Hz), 3.16-2.90 (5H, m), 2, 88-2.63 (3H, m), 2.58-2.35 (3H, m), 2.05-1, 80 (6H, m), 1.38 (9H, s), MS (IEN) 443 (M + Hf. STEP 5. Trifluoroacetate of 3- (4,5-dihydro-1'H.3H-espiror2-benzoxepin-1, 4'-piperidin] -1 '-yl) -2- (1,3-thiazol-4-ylmethyl) propanoic The title compound was prepared according to the procedure described in step 3 of example 1 from 3- (4 , 5-dihydro-1'H, 3H-spiro [2-benzoxepin-1,4-piperidin-1-yl] -2- (1, 3-thiazol-4-ylmethyl) propane-butyl ester (step 4) ): MS (ESI) 387 (M + Hf. EXAMPLE 63 3- (6-Fluoro-3,4-dihydro-1'H-espiropsochromeno-1,4'-piperidin-1'-D-2- (1,3-thiazol-4-ylmethylpropanoic acid) trifluoroacetate STAGE 1. 3- (6-Fluoro-3,4-dihydro-1? -spirorisocromeno-1,4'-piperidin-1'-di-2- (1,3-thiazole-4-ylmethylpropanoate, ferric-butyl) The compound of the title was prepared according to the procedure described in step 4 of example 4 from 6-fluoro-3,4-dihydroespyrro [isocromen-1,4'-piperidine] (step 4 of the Example 61) and fer-butyl 2- (1,3-thiazol-4-ylmethyl) acrylate (step 2 of example 44): 1 H-NMR (CDCl 3) d 8.75 (1H, d, J = 2.0 Hz), 7.06 (1H, dd, J = 8.7, 5.6 Hz), 7.02 (1H, d, J = 1.8 Hz), 6.88 (1H, dt, J = 8.6, 2.7 Hz), 6.78 (1H, dd, J = 9.3, 2.7 Hz), 3.87 (2H, t, J = 5.5 Hz), 3.11-3.02 (3H, m), 2.84-2.65 (5H, m), 2.52-2 , 33 (3H, m), 1.97-1, 80 (4H, m), 1.39 (9H, s); MS (ESI) 402 (M + Hf. STEP 2. Trifluoroacetate of 3- (6-fluoro-3,4-dihydro-1'H-espirorisocromeno-1.4'-pjperidin1-1 '-iP-2- (1.3-t) azol-4-ylmethylpropanoic The title compound was prepared according to the procedure described in step 3 of example 1 from 3- (6-fluoro-3,4-dihydro-1'H-spiro [isocromen-1, 4'-piperidin] -1'-yl) -2- (1, 3-thiazol-4-ylmethyl) propane-ferro-butyl ester (step 1): MS (ESI) 374 (M + Hf, 372 (M-Hf) EXAMPLE 64 3- (5-Fluoro-1-methyl-1,2-dihydro-1'H-espirophenol-3,4'-piperidin-1'-di-2- (1,3-thiazole-4) acid trifluoroacetate -ilmetiDpropanoic STAGE 1. 3- (5-Fluoro-1-methyl-1,2-dihydro-1'H-espirorindol-3,4'-piperidin-1'-di-2- (1,3-thiazole-4-ylmethyl-propenoate-ferro-butyl) The title compound was prepared according to the procedure described in step 1 of example 32 from 3- (5-fluoro-1-methyl-1,2-dihydro-1? -spiro [indole-3,4 ' -piperidin] -1'-yl) fer-butyl propanoate (step 1 of example 28): 1 H-NMR (CDCl 3) d 8.75 (1H, d, J = 2.0 Hz), 7.02 (1H , d, J = 2.0 Hz), 6.81-6.70 (2H, m), 6.37-6.33 (1H, m), 3.18-2.67 (7H, m), 2.49-2.43 (2H, m), 2.22-2 , 01 (2H, m), 1.87-1.61 (4H, m), 1.49-1.22 (12H, m).

STAGE 2. 3- (5-Fluoro-1-methyl-1,2-dihydro-1'-H-espyrorindol-3,4'-piperidin-1'-iD-2- (1,3-t-azole-4-) trifluoroacetate The title compound was prepared according to the procedure described in step 3 of Example 1 from 3- (5-fluoro-1-methyl-1,2-dihydro-1'H-spiro). [Ndol-3,4'-piperidin] -1'-yl) -2- (1,3-thiazol-4-ylmethyl) propane-butyl-tert-butyl ester (step 1): MS (ESI) 390 (M + Hf, 388 (M-Hf EXAMPLE 65 ACID 2- (2-CHLOROBENCIL) -3- (2.3-DIHYDRO-1'H-ESPIRORINDEN-1.4'-PlPERlDlN1-1'-lL) PROPANOIC STEP 1. 2- (2-chlorobenzD-3- (2,3-dihydro-1'-H-espirorinden-1,4'-pperidin-1'-ethyl-D -propanoate) The title compound was prepared according to the procedure described in step 4 of Example 4 from 2,3-dihydrospiro [inden-1,4'-piperidine] and ethyl 2- (2-chlorobenzyl) acrylate (step 2 of example 17): 1 H-NMR (CDCl 3) d 7.36-7.30 (1H, m), 7.24-7.10 (7H, m), 4.15-3.98 (2H, m), 3.15-3.05 (2H, m), 2.95-2.74 (6H, m), 2.55-2.48 (1H, m), 2.27-2.12 (2H, m), 2.03-1.81 ( 4H, m), 1, 51-1.45 (2H, m), 1.14 (3H, t, J = 7.3 Hz), MS (ESI) 412 (M + Hf. STAGE 2. Acid 2- (2-chlorobenzyl) -3- (2,3-dihydro-1'H-espyrrornide-1,4'-piperidin-1'-diDNA) The title compound was prepared according to the procedure described in step 4 of Example 30 from ethyl 2- (2-chlorobenzyl) -3- (2,3-dihydro-1'H-spiro [inden-1,4'-piperidin] -1'-yl) propanoate (stage 1 ): IR (KBr) v 3400, 1709 crn'1; 1 H-NMR (CDCl 3) d 7.38-7.33 (2H, m), 7.23-7.14 (6H, m), 3.57 (1H, dd, J = 14.1, 5.1 Hz), 3.22 (1H, da, J = 12.6 Hz), 3.06-2.53 (8H, m), 2.35-2.23 (1H, m ), 2.09-1.91 (4H, m), 1.68-1.61 (2H, m); MS (ESI) 384 (M + Hf, 382 (M-H) "; Anal, caled, for C23H26CINO2: C, 71.96; H, 6.83; N, 3.65 Found: C, 71.56, H, 6.86; N, 3.45;

Claims (15)

.CLAIMS 1. A compound of the following formula (I) (?) or a pharmaceutically acceptable ester of such a compound, or a pharmaceutically acceptable salt or solvates thereof, wherein R1 and R2 independently represent a hydrogen atom, a halogen atom or an alkyl group having from 1 to 3 carbon atoms;
1. R3 represents an aryl group having 6 to 10 ring atoms or a heteroaryl group and said heteroaryl group is a 5- to 10-membered heteroaromatic group containing from 1 to 3 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom; said aryl group and heteroaryl group are optionally substituted with 1 to 3 groups selected from a halogen atom, a hydroxy group, an alkyl group having from 1 to 3 carbon atoms, an alkoxy group having from 1 to 3 carbon atoms , an alkyl group having from 1 to 6 carbon atoms interrupted by an oxygen atom, a hydroxyalkyl group having from 1 to 3 carbon atoms, an amino group, a mono- or di-alkylamino group having from 1 to 3 carbon atoms, an aminocarbonyl group, a mono- or dialkylaminocarbonyl group having from 1 to 3 carbon atoms in each dialkylaminocarbonyl group having from 1 to 3 carbon atoms in each alkyl group, an alkanoylamino group having from 1 to 3 carbon atoms and an alkylsulfonylamino group having from 1 to 3 carbon atoms; -XY- represents a group of formula -N (R4) C (= O) -, -C (= O) N (R4) -, - N (R4) CH2-, -CH2N (R4) -, -N ( R4) SO2-, -SO2N (R4) -, -CH2CH2-, -CH = CH-, - CH (CH2OH) CH2-, -CH2CH (CH2OH) -, -CH2CH (OH) -, -CH (OH) CH2 -, -C (R4) (R5) - O- or -OC (R) (R5) -; R4 represents a hydrogen atom or an alkyl group having from 1 to 3 carbon atoms; R5 represents a hydrogen atom, an alkyl group having from 1 to 3 carbon atoms or a hydroxyalkyl group having from 1 to 3 carbon atoms; n represents an integer 0, 1 or 2.
2. 2. A compound according to claim 1, wherein R1 and R2 independently represent a hydrogen atom or a fluorine atom.
3. 3. A compound according to any one of claims 1 to 2 wherein R3 represents a phenyl group or a heteroaryl group and said heteroaryl group is a 5-6 membered heteroaromatic group containing from 1 to 2 heteroatoms of nitrogen or i or 2 nitrogen heteroatoms and 1 oxygen atom or 1 sulfur atom; said phenyl group and heteroaryl group are optionally substituted with 1 to 3 groups selected from a halogen atom, a hydroxyl group, an alkyl group having from 1 to 3 carbon atoms, an alkyl group having from 1 to 6 carbon atoms interrupted by an oxygen atom, a hydroxyalkyl group having from 1 to 3 carbon atoms, an amino group and an alkylsulfonylamino group having from 1 to 3 carbon atoms.
4. 4. A compound according to any one of claims 1 to 3 wherein R3 represents a phenyl group or a heteroaryl group selected from a pyridyl group, a thiazolyl group, a pyrazolyl group and an oxazolyl group; said phenyl group is optionally substituted with 1 to 3 groups selected from a fluorine atom, a chlorine atom, a hydroxy group, a methyl group, a methoxymethyl group, a hydroxymethyl group, an amino group and methanesulfonylamino.
5. 5. A compound according to any one of claims 1 to 4 wherein -XY- represents a group of the formula N (CH3) C (= O) -, -N (CH3) CH2-, -N (CH3) SO2 -, -CH2O-, -CH (CH3) O-, -C (CH3) 2O-, -CH (CH2OH) O-, -CH2CH2-, -CH (CH2OH) CH2-, -CH (OH) CH2-, -CH = CH-, or -CH2CH (OH) -.
6. 6. A compound according to any one of claims 1 to 5, wherein -X-Y- represents a group of formula -N (CH3) C (= O) -, -CH2O-, -CH (CH3) O-,
7. 7. A compound according to any one of claims 1 to 6 wherein n represents an integer 0.
8. 8. A compound according to claim 1 selected from: 2-Benzyl-3- (2,3-dhydro-1'H-spiro [inden-1,4'-piperidin] -1'-iDpropanoic acid trifluoroacetate; 2- (2-chlorobenzyl) acid trifluoroacetate - 3- (1'H, 3H-spiro [2-benzofuran-1,4'-piperidin] -1'-iDpropanoic acid trifluoroacetate 2- (5- { [Ferc-butyl (dimethyl)) silyl] oxy} -2-fluorobenzyl) -3- (1'H, 3H-spiro [2-benzofuran-1,4'-piperidin] -1'-yl) propanoic acid; 2- (2-chloro- 5-hydroxybenzyl) -3- (1α, 3H-spiro [2-benzofuran-1,4'-piperidine] -1'-iDpropanoic acid, 2- (2-chlorobenzyl) -3- (1 -methyl-2- oxo-1, 2-dihydro-1 'H-spiro [indole-3,4'-piperidin] -1'-iDpropanoic acid, 2- (2-chlorobenzyl) -3- (5-fluoro-1-methyl-1) , 2-dihydro-1 'H-spiro [indole-3,4'-piperidin] -1'-yl) propanoic acid 2- (2-fluoro-5-hydroxybenzyl) -3- (1 -methyl-2- oxo-1, 2-dihydro-1 'H-spiro [indole-3,4'-piperidin] -1'-yl) propanoic acid 2- (2-chlorobenzyl) -3- (6-fluoro-1'H) , 3 H-spiro [2-benzofuran-1, 4'-pperidin] -1'-iDpropanoic acid, 2- (2-chloro-5-hydroxybenzyl) -3- (1-methyl-2-oxo-1, 2-dihydro-1 'H-spiro [i ndol-3,4'-piperidin] -1'-yl) propanoic acid; 2- (5-. {[[Ferc-butyl (dimethyl) siIyl] oxy} -2-fluorobenzyl) -3- (5-fluoro-1-methyl-1,2-dihydro-1'H) trifluoroacetate -spiro [indol-3,4'-piperidin] -1 '-yl) propanoic; 2- (5-. {[[Ferc-butyl (dimethyl) silyl] oxy] -2- chlorobenzyl) -3- (5-fluoro-1-methyl-1,2-dihydro-) acid trifluoroacetate 1 'H-spiro [indole-3,4'-piperidin] -1'-iDpropanoic acid 2- (2-chloro-5-hydroxybenzyl) -3- (5-fluoro-1-methyl-2-oxo) -1,2-dihydro-1? -spiro [indole-3,4'-pperidin] -1'-di-dopanoic acid 2- (2-fluoro-5-hydroxybenzyl) -3- (5-fluoro-1-methyl-2-oxo-1,2-dihydro-1'-H-spiro [indol-3,4'-piperidin] -1'-yl) propanoic acid; 2- (2-Chloro-5-hydroxybenzyl) -3- (2-hydroxy-2,3-dihydro-1'H-spiro [inden-1,4'-piperidin] -1'-iD-propanenoic acid; 2- (2-chloro-5-hydroxybenzyl) acid; (2-Chloro-5-hydroxybenzyl) -3- (3-methyl-1'H, 3H-spiro [2-benzofuran-1,4'-piperidin] -1'-diDPAnoic acid; 2- (2-chloro- 5-hydroxybenzyl) -3- [3- (hydroxymethyl) -2,3-dihydro-1'H-spiro [inden-1,4'-piperidin] -1'-yl] propanoic; 2- (2-acid) -chloro-5-hydroxybenzyl) -3- (3-hydroxy-2,3-dihydro-1'H-spiro [inden-1,4'-piperidin] -1'-iD-propanoic acid; 2- (2- Chloro-5-hydroxybenzyl) -3- (5-fluoro-1 'H, 3H-spiro [2-benzofuran-1,4'-piperidin] -1'-diDPAnoic acid; 3- (3-methyl-1? 3H-spiro [2-benzofuran-1,4'-piperidin] -1'-yl) -2- (pyridin-2-ylmethyl) propanoic acid trifluoroacetate 3- (3-methyl-1'H, 3H-spiro [2-benzofuran-1,4'-piperidin] -1 '-yl) -2- (1,3-thiazol-4-ylmethyl) propanoic; 3- (3,4-Dihydro-1'H-) trifluoroacetate Spiro [Isochromene-1,4'-piperidine] -1 '-yl) -2- (1,3-thiazol-4-ylmethyl) propanoic acid; 3- (5-fluoro-1-methyl-2-trifluoroacetate) -oxo-1,2-dihydro-1'H- spiro [indole-3,4'-piperidin] -1'-iD-2- (1,3-thiazol-4-ylmethyl) propanoic acid; 3- (2,3-Dihydro-1'H-spiro [inden-1,4'-piperidin] -1'-yl) -2- (1,3-thiazol-4-ylmethyl) propanoic acid trifluoroacetate; 3- (2,3-Dihydro-1'H-spiro [inden-1,4'-piperidin] -1'-yl) -2- (1 H-pyrazol-1-ylmethyl) propanoic acid; 3- (6-Fluoro-3,4-dihydro-1'H-spiro [isocromen-1,4'-piperidin] -1-yl) - - (1 H -pyrazol-1-ylmethyl) propanoic acid; and 3- (6-Fluoro-3,4-dihydro-1'H-spiro [, socromen-, 4'-piperidin] -1-yl) -2- (1,3-thiazol-4-ylmethyl) trifluoroacetate propanoic; or a pharmaceutically acceptable ester thereof or a pharmaceutically acceptable salt thereof.
9. 9. A pharmaceutical composition which includes a compound of formula (I) or a pharmaceutically acceptable ester or salt thereof, as defined in any one of claims 1 to 8, together with a pharmaceutically acceptable excipient.
10. 10. The use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof, as defined in any one of claims 1 to 8 and 9, respectively, for the manufacture of a medicament for treating a disease for the one that indicates an ORLL antagonist
11. 11. A use according to claim 10 wherein the disease is selected from pain, sleep disorders, eating disorders including anorexia and bulimia; anxiety and stress states; diseases of the immune system; locomotor disorders; memory loss, cognitive disorders and dementia including senile dementia, Alzheimer's disease, Parkinson's disease or other neurodegenerative pathologies; epilepsy or seizure and symptoms associated with them; a central nervous system disorder related to the action of glutamate release, anti-epileptic action, alteration of spatial memory, release of serotonin, anxiolytic action, mesolimbic dopaminergic transmission, welfare properties of drugs of abuse, modulation of the effects of striated muscle and the effects of glutamate on locomotor activity; cardiovascular disorders including hypotension, bradycardia and stroke; kidney disorders including water excretion, sodium ion excretion and syndrome of inappropriate secretion of antidiuretic hormone (SIADH); gastrointestinal disorders; respiratory tract disorders including respiratory distress syndrome in adults (ARDS); autonomic disorders including suppression of the micturition reflex; metabolic disorders including obesity; cirrhosis with ascites; sexual dysfunctions; altered lung function including obstructive pulmonary disease; and tolerance or dependence on a narcotic analgesic.
12. 12. A use according to claim 10 or claim 11 wherein the disease is pain, sleep disorders, eating disorders including anorexia and bulimia; stress states; memory loss, cognitive disorders, gastrointestinal disorders; sexual dysfunctions; tolerance or dependence to a narcotic analgesic.
13. 13. A method of treating a mammal, including a human, to treat a disease for which an ORL1 antagonist is indicated, including treating said mammal with an effective amount of a compound of formula (I) or with a salt, solvate or pharmaceutically acceptable composition thereof, as defined in any one of claims 1 to 7 and 8, respectively.
14. 14. A method according to claim 13 wherein the disease is selected from pain; sleep disorders, eating disorders including anorexia and bulimia; anxiety and stress states; diseases of the immune system; locomotor disorders; memory loss, cognitive disorders and dementia including senile dementia, Alzheimer's disease, Parkinson's disease or other neurodegenerative pathologies; epilepsy or seizure and symptoms associated with them; a central nervous system disorder related to the action of glutamate release, anti-epileptic action, alteration of spatial memory, release of serotonin, anxiolytic action, mesolimbic dopaminergic transmission, welfare properties of drugs of abuse, modulation of the effects of striated muscle and the effects of glutamate on locomotor activity; cardiovascular disorders including hypotension, bradycardia and stroke; kidney disorders including water excretion, sodium ion excretion and syndrome of inappropriate secretion of antidiuretic hormone (SIADH); gastrointestinal disorders; respiratory tract disorders including respiratory distress syndrome in adults (ARDS); autonomic disorders including suppression of the micturition reflex; metabolic disorders including obesity; cirrhosis with ascites; sexual dysfunctions; altered lung function including obstructive pulmonary disease; and tolerance or dependence on a narcotic analgesic.
15. 15. A method according to claim 13 or claim 14 wherein the disease is selected from pain, sleep disorders, eating disorders including anorexia and bulimia; stress states; memory loss, cognitive disorders, gastrointestinal disorders; sexual dysfunctions; tolerance or dependence to a narcotic analgesic.