AU2008268667A1 - 6.5-pyrrolopiperidine tachykinin receptor antagonists - Google Patents

Description

WO 2009/002770 PCT/US2008/067270 TITLE OF THE INVENTION 6.5 -PYRROLOPIPERIDINE TACHYKININ RECEPTOR ANTAGONISTS 5 BACKGROUND OF THE INVENTION Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being so-named because of their prompt contractile action on extravascular smooth muscle tissue. The tachykinins are distinguished by a conserved carboxyl terminal sequence. In addition to substance P, the known mammalian tachykinins include 10 neurokinin A and neurokinin B. The current nomenclature designates the receptors for substance P, neurokinin A, and neurokinin B as neurokinin-l (NK-1), neurokinin-2 (NK-2), and neurokinin-3 (NK-3), respectively. Tachykinin, and in particular substance P, antagonists are useful in the treatment of clinical conditions which are characterized by the presence of an excess of tachykinin, in 15 particular substance P, activity, including disorders of the central nervous system, nociception and pain, gastrointestinal disorders, disorders of bladder function and respiratory diseases. SUMMARY OF THE INVENTION The present invention is directed to certain hydroxymethyl ether hydroisoindoline 20 compounds of Formula (I) which are useful as neurokinin-l (NK-1) receptor antagonists, and inhibitors of tachykinin and in particular substance P. The invention is also concerned with pharmaceutical formulations comprising these compounds as active ingredients and the use of the compounds and their formulations in the treatment of certain disorders, including emesis, urinary incontinence, LUTS, depression, and anxiety. 25 - 1- WO 2009/002770 PCT/US2008/067270 DETAILED DESCRIPTION OF THE INVENTION In one embodiment the present invention is directed to compounds of the formula I:

F

3 C CF 3 R R3 X R? 4 N O __

R

5 N R1 5 and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof, wherein: X is N or CH;

R

1 is selected from the group consisting of: (1) hydrogen, 10 (2) C1-6alkyl, which is unsubstituted or substituted with halogen, hydroxyl, -COOH, or phenyl, (3) cyclopentenone, (4) -(CO)-C1 -6alkYl, which is optionally substituted with hydroxyl, (5) -(CO)-NH2, 15 (6) -(CO)-NHC I -6alkyl, (7) -(CO)-N(C 1-6alkyl)(C1I-6alkyl), (8) -Ci-4alkyl-(CO)-NH2, (9) -C1 -4alkyl-(CO)-NHC 1 -6alkyl, (10) -Ci-4alkyl-(CO)-N(CI-6alkyl)(C1-6alkyl), 20 (11) -(CO)-O-Cl-6alkyl, (12) -(CO)-C3-6cycloalkyl, -2- WO 2009/002770 PCT/US2008/067270 Q or or or or (13) 0 (14) -(CO)-HET, wherein HET is selected from the group consisting of Ra O NH N0-Rb N 0 and HO Wherein Ra is selected from H, and C -3alkyl and Rb is selected fromH, C -4alkyl, -(CO)-CH3 5 and -(CO)-NH2,

R

2 , R 3 , R 4 and R 5 are each independently selected from the group consisting of: (1) hydrogen, and (2) methyl;

R

6 is independently selected from the group consisting of: 10 (1) hydrogen, and (2) fluorine. Within this embodiment there is a genus of compound of formula Ia:

F

3 C

CF

3 R2 R3 X R 4 N Ot_ __ //R R5 N

R

1 Ia wherein RI, R 2 , R 3 , R 4 , R 5 , R 6 , and X are defined herein, -3- WO 2009/002770 PCT/US2008/067270 or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof. Within this embodiment there is a genus of compounds of Formula I wherein 5 R 1 is selected from the group consisting of: (1) hydrogen, (2) Cp-3alkyl, which is unsubstituted or substituted with hydroxyl or phenyl, (3) cyclopent-2-en-1-one, which is unsubstituted or substituted with hydroxyl, (4) -(CO)-C1-3alkyl, 10 (5) -(CO)-NH2, (6) -(CO)-NHC1-3alkyl, (7) -(CO)-N(Ci-3alkyl)(Cj-3alkyl), and (8) 0 15 wherein the alkyl portion of choices (4), (6) and (7) of R1 are optionally substituted with halo, hydroxyl or phenyl. Within this embodiment there is a genus of compounds of Formula I wherein RI is selected from the group consisting of: 20 (1) hydrogen, (2) cyclopent-2-en- 1-one, (3) 1,2-oxazol-4(5H)-one, (4) 2,2-dimethylpropanoyl, (5) methylpropanoyl, 25 (6) CH3NH-(CO)-, (7) (CH3)2-N-(CO)-, and (8) 0 30 Within this embodiment there is a genus of compounds of Formula I wherein R 6 is hydrogen. Within this embodiment there is a genus of compounds of Formula I wherein R 6 is fluorine. -4- WO 2009/002770 PCT/US2008/067270 Within this embodiment there is a genus of compounds of Formula I wherein R 5 is hydrogen. 5 Within this embodiment there is a genus of compounds of Formula I wherein R5 is methyl. Within this embodiment there is a genus of compounds of formula Ia:

F

3 C

CF

3 R 2 R 3 X R 4 N O - _ R 6 R5 N

R

1 Ia 10 or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof wherein RI is selected from the group consisting of: (1) hydrogen, (2) cyclopent-2-en- 1-one, 15 (3) 1,2-oxazol-4(5H)-one, (4) 2,2-dimethylpropanoyl, (5) methylpropanoyl, (6) CH3NH-(CO)-, (7) (CH3)2-N-(CO)-, and 0 Nzo_ 20 (8)

R

6 is independently selected from the group consisting of: (1) hydrogen, and (2) fluorine;

R

5 is independently selected from the group consisting of: 25 (1) hydrogen, and -5- WO 2009/002770 PCT/US2008/067270 (2) methyl. Within this embodiment, it is preferred that X is N. Specific embodiments of the present invention include a compound which is 5 selected from the group consisting of the subject compounds of the Examples herein and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof. Specific embodiments of the present invention include a compound which is selected from the group consisting of the subject compounds of the Examples herein and 10 phannaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof. The compounds of the present invention may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such 15 asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the ambit of this invention. The present invention is meant to comprehend all such isomeric forms of these compounds. Formula I shows the structure of the class of compounds without preferred stereochemistry. The independent syntheses of these 20 diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. If desired, racemic mixtures of the compounds may be 25 separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is often the formation of salts using an enantiomerically 30 pure acid or base. The diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art. Alternatively, any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known 35 configuration by methods well known in the art. There are several acceptable methods of naming the compounds discussed herein. -6- WO 2009/002770 PCT/US2008/067270 ,OH N

CH

3

CH

3 0O

OCH

3 For example, the above compound can be named either as "(3aR,4R,5S,7aR) tert butyl-5-hydroxy-4-(2-methylphenyl)octahydro-2H-isoindole-2-carboxylate" or "tert-butyl 5 (3aR,4R,5S,7aR)-5-hydroxy-4-phenyloctahydro-2H-isoindole-2-carboxylate". The core structure may be generally referred to as octahydroisoindole, hexahydroisoindoline, perhydroisoindoline, hydroisoindoline, or hydroisoindole compounds. As appreciated by those of skill in the art, halo or halogen as used herein are intended to include fluoro, chloro, bromo and iodo. Similarly, Cl-6, as in C1-6alkyl is defined to 10 identify the group as having 1, 2, 3, 4, 5 or 6 carbons in a linear or branched arrangement, such that CI-8alkyl specifically includes methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert butyl, pentyl, and hexyl. A group which is designated as being independently substituted with substituents may be independently substituted with multiple numbers of such substituents. The term "pharmaceutically acceptable salts" refers to salts prepared from 15 pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts in the solid form may exist in more than one crystal structure, 20 and may also be in the form of hydrates. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylene-diamine, diethylamine, 2 diethylaminoethanol, 2-dimethylamino-ethanol, ethanolamine, ethylenediamine, N-ethyl 25 morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, 30 benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, -7- WO 2009/002770 PCT/US2008/067270 nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids. It will be understood that, as used herein, references to the compounds of the present invention are meant to also include the pharmaceutically acceptable 5 salts. Exemplifying the invention is the use of the compounds disclosed in the Examples and herein. Specific compounds within the present invention include a compound which selected from the group consisting of the compounds disclosed in the following Examples and pharmaceutically acceptable salts thereof and individual diastereomers thereof. 10 The compounds of the present invention are useful in the prevention and treatment of a wide variety of clinical conditions which are characterized by the presence of an excess of tachykinin, in particular substance P, activity. Thus, for example, an excess of tachykinin, and in particular substance P, activity is implicated in a variety of disorders of the central nervous system. Such disorders include mood disorders, such as depression or more 15 particularly depressive disorders, for example, single episodic or recurrent major depressive disorders and dysthymic disorders, or bipolar disorders, for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder; anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobias, for example, specific animal phobias, social phobias, obsessive-compulsive disorder, stress disorders 20 including post-traumatic stress disorder and acute stress disorder, and generalised anxiety disorders; schizophrenia and other psychotic disorders, for example, schizophreniform disorders, schizoaffective disorders, delusional disorders, brief psychotic disorders, shared psychotic disorders and psychotic disorders with delusions or hallucinations; delerium, dementia, and amnestic and other cognitive or neurodegenerative disorders, such as Alzheimer's disease, senile 25 dementia, dementia of the Alzheimer's type, vascular dementia, and other dementias, for example, due to HIV disease, head trauma, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, or due to multiple aetiologies; Parkinson's disease and other extra-pyramidal movement disorders such as medication-induced movement disorders, for example, neuroleptic-induced parkinsonism, neuroleptic malignant syndrome, neuroleptic 30 induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-induced tardive dyskinesia and medication-induced postural tremour; substance-related disorders arising from the use of alcohol, amphetamines (or amphetamine-like substances) caffeine, cannabis, cocaine, hallucinogens, inhalants and aerosol propellants, nicotine, opioids, phenylglycidine derivatives, sedatives, hypnotics, and anxiolytics, which substance-related disorders include dependence and 35 abuse, intoxication, withdrawal, intoxication delerium, withdrawal delerium, persisting dementia, psychotic disorders, mood disorders, anxiety disorders, sexual dysfunction and sleep disorders; epilepsy; Down's syndrome; demyelinating diseases such as MS and ALS and other -8- WO 2009/002770 PCT/US2008/067270 neuropathological disorders such as peripheral neuropathy, for example diabetic and chemotherapy-induced neuropathy, and postherpetic neuralgia, trigeminal neuralgia, segmental or intercostal neuralgia and other neuralgias; and cerebral vascular disorders due to acute or chronic cerebrovascular damage such as cerebral infarction, subarachnoid haemorrhage or 5 cerebral oedema. Tachykinin, and in particular substance P, activity is also involved in nociception and pain. The compounds of the present invention will therefore be of use in the prevention or treatment of diseases and conditions in which pain predominates, including soft tissue and peripheral damage, such as acute trauma, osteoarthritis, rheumatoid arthritis, musculo-skeletal 10 pain, particularly after trauma, spinal pain, myofascial pain syndromes, headache, episiotomy pain, and burns; deep and visceral pain, such as heart pain, muscle pain, eye pain, orofacial pain, for example, odontalgia, abdominal pain, gynaecological pain, for example, dysmenorrhoea, and labour pain; pain associated with nerve and root damage, such as pain associated with peripheral nerve disorders, for example, nerve entrapment and brachial plexus avulsions, amputation, 15 peripheral neuropathies, tic douloureux, atypical facial pain, nerve root damage, and arachnoiditis; pain associated with carcinoma, often referred to as cancer pain; central nervous system pain, such as pain due to spinal cord or brain stem damage; low back pain; sciatica; ankylosing spondylitis, gout; and scar pain. Tachykinin, and in particular substance P, antagonists may also be of use in the 20 treatment of respiratory diseases, particularly those associated with excess mucus secretion, such as chronic obstructive airways disease, bronchopneumonia, chronic bronchitis, cystic fibrosis and asthma, adult respiratory distress syndrome, and bronchospasm; inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis, rheumatoid arthritis, pruritis and sunburn; allergies such as eczema and rhinitis; hypersensitivity disorders such as poison ivy; 25 ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like; ophthalmic conditions associated with cell proliferation such as proliferative vitreoretinopathy; cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria, and other eczematoid dermatitis. Tachykinin, and in particular substance P, antagonists may also be of use in the treatment of neoplasms, including breast tumours, neuroganglioblastomas and small cell 30 carcinomas such as small cell lung cancer. Tachykinin, and in particular substance P, antagonists may also be of use in the treatment of gastrointestinal (GI) disorders, including inflammatory disorders and diseases of the GI tract such as gastritis, gastroduodenal ulcers, gastric carcinomas, gastric lymphomas, disorders associated with the neuronal control of viscera, ulcerative colitis, Crohn's disease, irritable bowel 35 syndrome and emesis, including acute, delayed or anticipatory emesis such as emesis induced by chemotherapy, radiation, toxins, viral or bacterial infections, pregnancy, vestibular disorders, for example, motion sickness, vertigo, dizziness and Meniere's disease, surgery, migraine, variations -9- WO 2009/002770 PCT/US2008/067270 in intercranial pressure, gastro-oesophageal reflux disease, acid indigestion, over indulgence in food or drink, acid stomach, waterbrash or regurgitation, heartburn, for example, episodic, nocturnal or meal-induced heartburn, and dyspepsia. Tachykinin, and in particular substance P, antagonists may also be of use in the 5 treatment of a variety of other conditions including stress related somatic disorders; reflex sympathetic dystrophy such as shoulder/hand syndrome; adverse immunological reactions such as rejection of transplanted tissues and disorders related to immune enhancement or suppression such as systemic lupus erythematosus; plasma extravasation resulting from cytokine chemotherapy, disorders of bladder function such as cystitis, bladder detrusor hyper-reflexia, 10 frequent urination, urinary incontinence and LUTS, including the prevention or treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and frequency; fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis; disorders of blood flow caused by vasodilation and vasospastic diseases such as angina, vascular headache, migraine and Reynaud's disease; and pain or nociception attributable to or associated with any of 15 the foregoing conditions, especially the transmission of pain in migraine. As used herein, the term "urinary incontinence" is intended to include a range of conditions including urge incontinence, stress incontinence, overflow incontinence, functional incontinence, neurogenic incontinence, post-prostatectomy incontinence, urinary frequency, urinary urgency, nocturia, enuresis, and related conditions in mammalian subjects. In more 20 detailed embodiments, the lower urinary tract disorder, or targeted symptoms for treatment arising therefrom, may include overactive bladder, including neurogenic and non-neurogenic overactive bladder, interstitial cystitis, prostatitis, prostadynia, and benign prostatic hyperplasia. In further embodiments, the methods and compositions of the invention are effective for preventing or treating excessive micturition in subjects suffering from lower urinary tract 25 disorders. The compounds of the present invention are also of value in the treatment of a combination of the above conditions, in particular in the treatment of combined post-operative pain and post-operative nausea and vomiting. The compounds of the present invention are particularly useful in the prevention 30 or treatment of emesis, including acute, delayed or anticipatory emesis, such as emesis induced by chemotherapy, radiation, toxins, pregnancy, vestibular disorders, motion, surgery, migraine, and variations in intercranial pressure. For example, the compounds of the present invention are of use optionally in combination with other antiemetic agents for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderate or highly 35 emetogenic cancer chemotherapy, including high-dose cisplatin. Most especially, the compounds of the present invention are of use in the treatment of emesis induced by antineoplastic (cytotoxic) agents, including those routinely used in cancer chemotherapy, and emesis induced by - 10 - WO 2009/002770 PCT/US2008/067270 other pharmacological agents, for example, rolipram. Examples of such chemotherapeutic agents include alkylating agents, for example, ethyleneimine compounds, alkyl sulphonates and other compounds with an alkylating action such as nitrosoureas, cisplatin and dacarbazine; antimetabolites, for example, folic acid, purine or pyrimidine antagonists; mitotic inhibitors, for 5 example, vinca alkaloids and derivatives of podophyllotoxin; and cytotoxic antibiotics. Particular examples of chemotherapeutic agents are described, for instance, by D. J. Stewart in Nausea and Vomiting: Recent Research and Clinical Advances, Eds. J. Kucharczyk et al, CRC Press Inc., Boca Raton, Florida, USA (1991) pages 177-203, especially page 188. Commonly used chemotherapeutic agents include cisplatin, dacarbazine (DTIC), dactinomycin, 10 mechlorethamine, streptozocin, cyclophosphamide, carmustine (BCNU), lomustine (CCNU), doxorubicin (adriamycin), daunorubicin, procarbazine, mitomycin, cytarabine, etoposide, methotrexate, 5-fluorouracil, vinblastine, vincristine, bleomycin and chlorambucil [R. J. Gralla et al in Cancer Treatment Reports (1984) 6(l), 163-172]. A further aspect of the present invention comprises the use of a compound of the 15 present invention for achieving a chronobiologic (circadian rhythm phase-shifting) effect and alleviating circadian rhythm disorders in a mammal. The present invention is further directed to the use of a compound of the present invention for blocking the phase-shifting effects of light in a mammal. A further aspect of the present invention comprises the use of a compound of the 20 present invention in the treatment of Lower urinary tract symptoms (LUTS). LUTS in men include, but are not, restricted to a complex of obstructive (voiding) and irritative (storage or filling) symptoms, which include increased frequency, nocturia, poor urinary stream and hesitancy or delay in starting urinary flow. LUTS are recognized as arising from changes in urethral resistance induced by the enlarging prostate as well as contraction of the prostatic 25 smooth muscle. The resulting increase in urethral resistance restricts the outflow of urine and causes secondary changes are induced in the bladder. A characteristic pattern of unstable bladder contractions, also known as irritable bladder, is often observed in men with morphological BPH. The present invention is further directed to the use of a compound of the present invention or a pharmaceutically acceptable salt thereof, for enhancing or improving sleep quality 30 as well as preventing and treating sleep disorders and sleep disturbances in a mammal. In particular, the present invention provides a method for enhancing or improving sleep quality by increasing sleep efficiency and augmenting sleep maintenance. In addition, the present invention provides a method for preventing and treating sleep disorders and sleep disturbances in a mammal which comprising the administration of a compound of the present invention or a 35 pharmaceutically acceptable salt thereof. The present invention is useful for the treatment of sleep disorders, including Disorders of Initiating and Maintaining Sleep (insomnias) ("DIMS") which can arise from psychophysiological causes, as a consequence of psychiatric disorders - 11 - WO 2009/002770 PCT/US2008/067270 (particularly related to anxiety), from drugs and alcohol use and abuse (particularly during withdrawal stages), childhood onset DIMS, nocturnal myoclonus and restless legs and non specific REM disturbances as seen in ageing. The particularly preferred embodiments of the instant invention are the treatment 5 of emesis, urinary incontinence, depression or anxiety by administration of the compounds of the present invention to a subject (human or animal) in need of such treatment. The present invention is directed to a method for the manufacture of a medicament for antagonizing the effect of substance P at its receptor site or for the blockade of neurokinin-1 receptors in a mammal comprising combining a compound of the present invention 10 with a phannaceutical carrier or diluent. The present invention is further directed to a method for the manufacture of a medicament for the treatment of a physiological disorder associated with an excess of tachykinins in a mammal comprising combining a compound of the present invention with a pharmaceutical carrier or diluent. The present invention also provides a method for the treatment or prevention of 15 physiological disorders associated with an excess of tachykinins, especially substance P, which method comprises administration to a patient in need thereof of a tachykinin reducing amount of a compound of the present invention or a composition comprising a compound of the present invention. As used herein, the term "treatment" or "to treat" refers to the administration of 20 the compounds of the present invention to reduce, ameliorate, or eliminate either the symptoms or underlying cause of the noted disease conditions, in a subject (human or animal) that suffers from that condition or displays clinical indicators thereof. The term "prevention" or "to prevent" refers to the administration of the compounds of the present invention to reduce, ameliorate, or eliminate the risk or likelihood of 25 occurrence of the noted disease conditions, in a subject (human or animal) susceptible or predisposed to that condition. The compounds of this invention are useful for antagonizing tachykinins, in particular substance P in the treatment of gastrointestinal disorders, central nervous system disorders, inflammatory diseases, pain or migraine and asthma in a mammal in need of such 30 treatment. This activity can be demonstrated by the following assays. Receptor Expression in COS: To express the cloned human neurokinin-1 receptor (NKIR) transiently in COS, the cDNA for the human NK1R was cloned into the expression vector pCDM9 which was derived from pCDM8 (INVITROGEN) by inserting the ampicillin resistance gene (nucleotide 1973 to 2964 from BLUESCRIPT SK+) into the Sac II site. 35 Transfection of 20 ug of the plasmid DNA into 10 million COS cells was achieved by electroporation in 800 ul of transfection buffer (135 mM NaCl, 1.2 mM CaCl2, 1.2 mM MgCI2, 2.4 mM K2HPO4, 0.6 mM KH2PO4, 10 mM glucose, 10 mM HEPES pH 7.4) at 260 V and 950 -12- WO 2009/002770 PCT/US2008/067270 uF using the IBI GENEZAPPER (IBI, New Haven, CT). The cells were incubated in 10% fetal calf serum, 2 mM glutamine, I OOU/ml penicillin-streptomycin, and 90% DMEM media (GIBCO, Grand Island, NY) in 5% C02 at 37 0 C for three days before the binding assay. Stable Expression in CHO: To establish a stable cell line expressing the cloned 5 human NK1R, the cDNA was subeloned into the vector pRcCMV (INVITROGEN). Transfection of 20 ug of the plasmid DNA into CHO cells was achieved by electroporation in 800 ul of transfection buffer suplemented with 0.625 mg/ml Herring sperm DNA at 300 V and 950 uF using the IBI GENEZAPPER (IBI). The transfected cells were incubated in CHO media [10 % fetal calf serum, 100 U/ml pennicilin-streptomycin, 2 mM glutamine, 1/500 hypoxanthine 10 thymidine (ATCC), 90% IMDM media (JRH BIOSCIENCES, Lenexa, KS), 0.7 mg/ml G418 (GIBCO)] in 5% .C02 at 37*C until colonies were visible. Each colony was separated and propagated. The cell clone with the highest number of human NKIR was selected for subsequent applications such as drug screening. Assay Protocol using COS or CHO: The binding assay of human NK1R 15 expressed in either COS or CH-lO cells is based on the use of 12 5 1-substance P (1251-SP, from DU PONT, Boston, MA) as a radioactively labeled ligand which competes with unlabeled substance P or any other ligand for binding to the human NKI R. Monolayer cell cultures of COS or CHO were dissociated by the non-enzymatic solution (SPECIALTY MEDIA, Lavallette, NJ) and resuspended in appropriate volume of the binding buffer (50 mM Tris pH 7.5, 5 mM MnC12, 20 150 mM NaCl, 0.04 mg/ml bacitracin, 0.004 mg/ml leupeptin, 0.2 mg/mI BSA, 0.01 mM phosphoramidon) such that 200 ul of the cell suspension would give rise to about 10,000 cpm of specific 125I-SP binding (approximately 50,000 to 200,000 cells). In the binding assay, 200 ul of cells were added to a tube containing 20 ul of 1.5 to 2.5 nM of 125I-SP and 20 ul of unlabeled substance P or any other test compound. The tubes were incubated at 44C or at room 25 temperature for 1 hour with gentle shaking. The bound radioactivity was separated from unbound radioactivity by GF/C filter (BRANDEL, Gaithersburg, MD) which was pre-wetted with 0.1 % polyethylenimine. The filter was washed with 3 ml of wash buffer (50 mM Tris pH 7.5, 5 mM MnCl2, 150 mM NaCI) three times and its radioactivity was determined by gamma counter. The activation of phospholipase C by NKIR may also be measured in CHO cells 30 expressing the human NK1 R by determining the accumulation of inositol monophosphate which is a degradation product of IP3. CHO cells are seeded in 12-well plate at 250,000 cells per well. After incubating in CHO media for 4 days, cells are loaded with 0.025 uCi/ml of 3 H-myoinositol by overnight incubation. The extracellular radioactivity is removed by washing with phosphate buffered saline. LiCl is added to the well at final concentration of 0.1 mM with or without the 35 test compound, and incubation is continued at 37 0 C for 15 min. Substance P is added to the well at final concentration of 0.3 nM to activate the human NK1R. After 30 min of incubation at 37 0 C, the media is removed and 0.1 N HCl is added. Each well is sonicated at 4 0 C and extracted - 13 - WO 2009/002770 PCT/US2008/067270 with CHCl3/methanol (1:1). The aqueous phase is applied to a 1 ml Dowex AG IX8 ion exchange column. The column is washed with 0.1 N formic acid followed by 0.025 M ammonium formate-0. 1 N formic acid. The inositol monophosphate is eluted with 0.2 M ammonium formate-0. I N formic acid and quantitated by beta counter. 5 In particular, the intrinsic tachykinin receptor antagonist activities of the compounds of the present invention may be demonstrated by this assay. The compounds of the invention have activity in the aforementioned assay in the range of 0.05 nM to 10 pM. The Examples hereinunder were found to have the following activity: Example IC50 (nM) Example IC50 (nM) Example IC50 (nM) 1 1.7 13 0.083 25 0.052 2 0.25 14 0.044 26 0.031 3 12. 15 0.071 27 4 0.17 16 0.152 28 0.077 5 3.5 17 0.081 29 0.115 6 0.16 18 0.068 30 0.072 7 0.53 19 0.090 31 0.057 8 1.19 20 0.185 32 - 9 0.041 21 0.085 33 0.066 10 0.066 22 0.089 34 0.048 11 0.060 23 0.094 35 0.111 12 0.043 24 - 36 0.108 10 The activity of the present compounds may also be demonstrated by the assay disclosed by Lei, et al., British J. Phannacol., 105, 261-262 (1992). According to a further or alternative aspect, the present invention provides a compound of the present invention for use as a composition that may be administered to a subject 15 in need of a reduction of the amount of tachykinin or substance P in their body. The term "composition" as used herein is intended to encompass a product comprising specified ingredients in predetermined amounts or proportions, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. This term in relation to pharmaceutical compositions is intended to 20 encompass a product comprising one or more active ingredients, and an optional carrier comprising inert ingredients, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. In general, pharmaceutical compositions are prepared by - 14 - WO 2009/002770 PCT/US2008/067270 uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. 5 Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier. By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. 10 Pharmaceutical compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in 15 admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or 20 talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. Compositions for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient 25 is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil. Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Oily suspensions may be formulated by suspending the active ingredient in a suitable oil. Oil-in-water emulsions may also be employed. Dispersible powders and granules suitable for preparation of an aqueous suspension by the 30 addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Pharmaceutical compositions of the present compounds may be in the form of a sterile injectable aqueous or oleagenous suspension. The compounds of the present invention may also be administered in the form of suppositories for rectal administration. For topical use, 35 creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention may be employed. The compounds of the present invention may also be - 15 - WO 2009/002770 PCT/US2008/067270 formulated for administered by inhalation. The compounds of the present invention may also be administered by a transdermal patch by methods known in the art. The compositions containing compounds of the present invention may be presented in unit dosage form and may be prepared by any of the methods well known in the art 5 of pharmacy. The term "unit dosage form" is taken to mean a single dose wherein all active and inactive ingredients are combined in a suitable system, such that the patient or person adminstering the drug to the patient can open a single container or package with the entire dose contained therein, and does not have to mix any components together from two or more containers or packages. Typical examples of unit dosage forms are tablets or capsules for oral 10 administration, single dose vials for injection, or suppositories for rectal administration. This list of unit dosage forms is not intended to be limiting in any way, but merely to represent typical examples in the pharmacy arts of unit dosage forms. The compositions containing compounds of the present invention may also be presented as a kit, whereby two or more components, which may be active or inactive 15 ingredients, carriers, diluents, and the like, are provided with instructions for preparation of the actual dosage form by the patient or person administering the drug to the patient. Such kits may be provided with all necessary materials and ingredients contained therein, or they may contain instructions for using or making materials or components that must be obtained independently by the patient or person administering the drug to the patient. 20 By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The terms "administration of' or "administering a" compound should be understood to mean providing a compound of the invention to the individual in need of treatment 25 in a form that can be introduced into that individuals body in a therapeutically useful form and therapeutically effective amount, including, but not limited to: oral dosage forms, such as tablets, capsules, syrups, suspensions, and the like; injectable dosage forms, such as IV, IM, or IP, and the like; transdermal dosage forms, including creams, jellies, powders, or patches; buccal dosage forms; inhalation powders, sprays, suspensions, and the like; and rectal suppositories. 30 The tern "therapeutically effective amount" refers to a sufficient quantity of the compounds of the present invention, in a suitable composition, and in a suitable dosage form to treat or prevent the noted disease conditions. The compounds of the present invention may be administered in combination with another substance that has a complimentary effect to the tachykinin and substance P inhibitors of 35 the present invention. Accordingly, in the prevention or treatment of emesis, a compound of the present invention may be used in conjunction with other anti-emetic agents, especially 5HT3 receptor -16- WO 2009/002770 PCT/US2008/067270 antagonists, such as ondansetron, granisetron, tropisetron, palenosetron and zatisetron, a corticosteroid, such as dexamethasone, or GABAB receptor agonists, such as baclofen. Likewise, for the prevention or treatment of migraine a compound of the present invention may be used in conjunction with other anti-migraine agents, such as ergotamines or 5HTI agonists, 5 especially sumatriptan, naratriptan, zolmatriptan or rizatriptan. It will be appreciated that for the treatment of depression or anxiety, a compound of the present invention may be used in conjunction with other anti-depressant or anti-anxiety agents, such as norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase 10 (RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRIs), a-adrenoreceptor antagonists, atypical anti-depressants, benzodiazepines, 5-HT1A agonists or antagonists, especially 5-HTiA partial agonists, corticotropin releasing factor (CRF) antagonists, and pharmaceutically acceptable salts thereof. For the treatment or prevention of eating disorders, including obesity, bulimia nervosa and compulsive eating disorders, a compound of the present 15 invention may be used in conjunction with other anorectic agents. It will be appreciated that for the treatment or prevention of pain or nociception or inflammatory diseases, a compound of the present invention may be used in conjunction with an antiinflammatory or analgesic agent such as an opiate agonist, a lipoxygenase inhibitor, such as an inhibitor of 5-lipoxygenase, a cyclooxygenase inhibitor, such as a cyclooxygenase-2 inhibitor, an interleukin inhibitor, such as 20 an interleukin- I inhibitor, an NMDA antagonist, an inhibitor of nitric oxide or an inhibitor of the synthesis of nitric oxide, a non-steroidal antiinflammatory agent, or a cytokine-suppressing antiinflammatory agent. For the treatment of urinary incontinence and LUTS, a compound of the invention 25 may be used in combination with a p3 adrenergic receptor (p3AR) agonist (P3 agonist), and/or an anti-muscatinic and optionally an alpha-1 adrenergic antagonist, or a steroid type II 5-alpha reductase inhibitor. For purposes of this specification the p3 agonist is intended to include N-[4-[2 30 [[2-hydroxy-2-(pyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-[4-(3-cyclopentylpropyl)-5-tetrazolon 1-yl]benzenesulfonamide. 2N-[4- -[[[[2-hydroxy-2-(pyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-[4-[4 (trifluoromethyl)phenyl]thiazol-2-yl]benzenesulfonamide. Appropriate daily amounts of the D3 agonist include 10mg, 25,mg, 50mg, 100mg, 125mg, 200mg, 250mg and 375mg. These beta 3 35 agonists are discussed and may be prepared as disclosed in US 5,561,142 and US 6,011,048, which are hereby incorporated by reference. - 17 - WO 2009/002770 PCT/US2008/067270 For purposes of this specification, anti-muscarinc agents included, but are not limited to tolterodine, oxybutynin, trospium, vamicamide, solifenacin, propiverine, S oxybutynin, temiverine, sanctura, staybla, fesoterodine, SVT40776, 202405 by GlaxoSmithKline, TD6301, RBX9841, DDP200, and PLD179. See, for example, US 5,382,600; 5 US 3,176,019; US 3,480,626; US 4,564,621; US 5,096,890; US 6,017,927; US 6,174,896; US 5,036,098; US 5,932,607; US 6,713,464; US 6,858,650; and DD 106643. See also, US 6,103,747; US 6,630,162; US 6,770,295; US 6,911,217; US 5,164,190; US 5,601,839; US 5,834,010; US 6,743,441; W02002000652; W0200400414853. These also include trospium chloride, darifenacin and imidafenacin (KRP-197). As will be appreciate by those of skill in the 10 art, these drugs may be administered orally or topically in standard or extended release forms, such as extended release tolterodine, extended relesase oxybutynin and transdermal oxybutynin. Within the aspect of the invention discussed above, there is a genus wherein the anti-muscarinic agent is selected from tolterodine, oxybutynin, trospium, vamicamide, 15 solifenacin, propiverine, S-oxybutynin, temiverine, sanctura, staybla, fesoterodine, SVT40776, 202405 by GlaxoSmithKline, TD6301, RBX9841, DDP200, and PLD179. Within the aspect of the invention discussed above, there is a genus wherein the anti-muscarinic agent is selected from the group consisting of trospium chloride, darifenacin and 20 imidafenacin. Within the aspect of the invention discussed above, there is a genus wherein the anti-muscarinic agent is selected from the group consisting of extended release tolterodine, extended relsease oxybutynin and transdermal oxybutynin. 25 For purposes of this specification the 5-alpha reductase inhibitor includes, but is not limited to finasteride, dutasteride, turosteride and epristeride. By the term "finasteride" as used here is meant the compound as designated by 4 30 azaandrost-1-ene-17-carboxamide, N-(1,1-dimethylethyl)-3-oxo-,(5 a,171). FDA approved doses for finasteride are 1mg and 5mg, once a day. By the term "dutasteride" as used herein is meant the compound as designated by (5 a, 178)-N-{2, 5 bis(trifluoromethyl)phenyl}-3-oxo-4-azaandrost-l-ene-17-carboxamide. FDA 35 approved doses for finasteride are 1mg and 5mg, once a day. The FDA approved dose for dutasteride is 0.5mg, once a day. The FDA approved dose for dutasteride is 0.5mg, once a day. - 18 - WO 2009/002770 PCT/US2008/067270 For purposes of this specification the alpha- adrenergic receptor antagonist is selected from amsulosin, terazosin, doxazosin, alfuzosin, indoramin and prazosin. By the term "amsulosin" (e.g. Flomax or tamsulosin hydrochloride) as used herein 5 is meant the compound designated as (-)-(R)-5-[2-[[2-(O-ethoxyphenoxy)ethyljamino]propyl]-2 methoxybenzenesulf onamide and salts, hydrates and solvates thereof. Amsulosin is disclosed in U.S. Pat. No. 4,703,063 and claimed in U.S. Pat. No. 4,987,152 as being useful in treating lower urinary tract dysfunction. FDA approved doses include 0.4mg once a day for tamsulosin hydrochloride. 10 By the term "terazosin" as used herein is meant the compound 1-(4-amino-6,7 dimethoxy-2quinazolinyl)-4-[(tetrahydro-2-furoyl)carbonyl]p iperazine and salts, hydrates and solvates thereof. Terazosin is disclosed in U.S. Pat. No. 4,251,532. FDA approved doses include 1, 2, 5 and 10mg once a day for terazosin hydrochloride. 15 By the term doxazosin as used herein is meant the compound 1-(4-amino-6,7 dimethoxy-2-quinazolinyl)-4-[(2,3-dihydro-1,4-benzodioxin-2 -yl)carbonyl]-piperazine and salts, hydrates and solvates thereof Doxazosin is disclosed in U.S. Pat. No. 4,188,390. FDA approved doses include 1, 2, 4 and 8 mg once a day for doxazosin mesylate. 20 By the term "alfuzosin" (e.g. Uroxatral) as used herein is meant the compound N [3-[(4-amino-6,7-dimethoxy-2-quinazolinyl)methylamino]propyl]tetrahydro- 2 furancarboxamide and salts, hydrates and solvates thereof. Alfuzosin is disclosed in U.S. Pat. No. 4,315,007. FDA approved doses include 10 mg once a day for alfuzosin hydrochloride. 25 By the term "indoramin" as used herein is meant the compound N-[[1-[2-(1H indol-3-yl)ethyl]-4-piperidinyl]benzamine. Indoramin is disclosed in U.S. Pat. No. 3,527,761. By the term "prazosin" as used herein is meant a compound of the formula 1-(4 30 amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-furanylcarbonyl)piperazine. and solvates thereof. Prazosin is disclosed in U.S. Pat. No. 3,511,836. FDA approved doses include 1, 2 and 5 mg once a day for prazosin hydrochloride. It will be appreciated that when using any combination described herein, both the 35 compound of the present invention and the other active agent(s) will be administered to a patient, within a reasonable period of time. The compounds may be in the same pharmaceutically acceptable carrier and therefore administered simultaneously. They may be in separate -19- WO 2009/002770 PCT/US2008/067270 pharmaceutical carriers such as conventional oral dosage forms which are taken simultaneously. The term "combination" also refers to the case where the compounds are provided in separate dosage forms and are administered sequentially. Therefore, by way of example, one active component may be administered as a tablet and then, within a reasonable period of time, the 5 second active component may be administered either as an oral dosage form such as a tablet or a fast-dissolving oral dosage form. By a "fast dissolving oral formulation" is meant, an oral delivery form which when placed on the tongue of a patient, dissolves within about 10 seconds. By "reasonable period of time" is meant a time period that is not in excess of about 1 hour. That is, for example, if the first active component is provided as a tablet, then 10 within one hour, the second active component should be administered, either in the same type of dosage form, or another dosage form which provides effective delivery of the medicament. The compounds of this invention may be administered to patients (animals and humans) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. It will be appreciated that the dose required for use in any particular application will vary from 15 patient to patient, not only with the particular compound or composition selected, but also with the route of administration, the nature of the condition being treated, the age and condition of the patient, concurrent medication or special diets then being followed by the patient, and other factors which those skilled in the art will recognize, with the appropriate dosage ultimately being at the discretion of the attendant physician. 20 In the treatment of the conditions associated with an excess of tachykinins, a suitable dosage level of the compounds of the present invention, or pharmaceutically acceptable salts thereof, is about 0.001 to 50 mg/kg per day, in particular about 0.01 to about 25 mg/kg, such as from about 0.05 to about 10 mg/kg per day. The dosage range will generally be about 0.5 to 1000 mg per patient per day, which may be administered in single or multiple doses. Preferably, 25 the dosage range will be about 0.5 mg to 500 mg per patient per day; more preferably about 0.5 mg to 200 mg per patient per day; and even more preferably about 5 mg to 50 mg per patient per day. Specific dosages of the compounds of the present invention, or pharmaceutically acceptable salts thereof, for administration include 1 mg, 5 mg, 10 mg, 30 mg, 100 mg, and 500 mg. Pharmaceutical compositions of the present invention may be provided in a 30 formulation comprising about 0.5 mg to 1000 mg active ingredient; more preferably comprising about 0.5 mg to 500 mg active ingredient; or 0.5 mg to 250 mg active ingredient; or 1 mg to 100 mg active ingredient. Specific pharmaceutical compositions for treatment or prevention of excess tachykinins comprise about 1 mg, 5 mg, 10 mg, 30 mg, 100 mg, and 500 mg of active ingredient. Several methods for preparing the compounds of this invention are illustrated in 35 the following Examples. Starting materials and the requisite intermediates are in some cases commercially available, or can be prepared according to literature procedures or as illustrated -20 - WO 2009/002770 PCT/US2008/067270 herein. All 'H NMR spectra were obtained on instrumentation at field strength of 400 or 500 MHz. EXAMPLE 1 CF3 CF3 NO F 0 5 3-[(3aSR,4RS,7aSR)-5.-{[3,5-bis(trifluoromethyl)phenyl]acetyl)-4-(4-fluoroph-enylloctahydro-2H pyrolo[3,4-clpyridin-2- yl]cyclogpent-2-en-1 -one Step A: N-[(1E)-(4-fluorophenyl)methylene]-1-[(trimethylsilyl)oxy]ethylenamine 10 F N To a stirred solution of 41 mL(41 mmol, in hexanes) LHMDS in 60 mL dry ether under nitrogen atmosphere at 0C was added 4.4 mL (41 mmol) of 4-fluorobenzaldehyde. After 1 hr, to this mixture was added a triethylamine (6.4 mL, 45.5 mmol) and acetyl chloride (2.92 15 mL, 41 mmol). After 5 min, cold bath was removed and the mixture was allowed to stirred at rt for 2.5 hr. Then, TMSCl (5.19 mL, 41 rnmol) was added to quench the reaction. After 10 min, the mixture was filtered off the white solid through a cake of celite. The solution was removed all volatiles to give a yellow oil as the title compound. 1H NMR (CDCl 3 , ppm): 8 7.82 -7.88 (m, 2H), 7.14 (t, 2H), 4.69 (s, 1H), 4.34 (s, 1H). 20 -21- WO 2009/002770 PCT/US2008/067270 Step B: dimethyl (2RS,3RS, 4SR)-2-(4-fluorophenyl)-6-oxopiperidine-3,4-dicarboxylate F NH 'CO2CH3 0 CO2CH3 A solution of N-[(lE)-(4-fluorophenyl)methylene]-l [(trimethylsilyl)oxy]ethylenamine (1.65 g, 6.95 mmol, step A) and dimethyl fumarate (1.0 g, 5 6.95 mmol) in 20 mL of toluene was heated under N2 in a 80 *C oil bath for 16 hr. Toluene was removed by vacuum and the residue was added 35 mL of methanol. After stirring at rt for 10 min, the white suspension was filtered to give the title compound as a white solid. MS: 310 (M+1). 10 Step C: tert-butyl (2RS,3RS,4SR)-2-(4-fluorophenyl)-3,4-bis(hydroxymethyl)piperidine- 1 carboxylate F 0 0 N ' " OH OH A solution of dimethyl (2RS,3RS,4SR)-2-(4-fluorophenyl)-6-oxopiperidine-3,4 dicarboxylate (0.51 g, 1.65 mmol, step B) in 50 mL of THF at 04C was added LiBH44 (6.6 mL, 15 13.2 mmol, 2N solution in THF). Then the cold bath was removed and the mixture was allowed to stir at rt for 16 hr. The reaction was added with 10 mL 2N HCI and stirred at rt for 2hr. Then volatiles were removed under vacuum. The residue was dried with toluene (3x) and was added 50 mL of THF and BH 3 SMe 2 (8.25 mL, 16.5 mmol, as a 2N solution in THF). The mixture was heated to reflux under N 2 for 2 hr and was cooled to rt. Upon removal of volatiles, the residue 20 was dissolved in 20 mL of ethanol and was heated in 96 C oil bath for 2 hr. Upon removal of volatiles, the residue was dissolved in mixture of dioxzne and water (15 mL, 2:1 by volume) and was added triethylamine (0.70 mL, 4.95 mmol) and (Boc) 2 0 (0.72 g, 3.29 mmol) at rt. After 20 min, it was removed of volatiles and was worked up with EtOAc/NaHCO 3 /NaCl. The organic phase was dried with Na 2

SO

4 and was filtered. Upon removal of solvent, it was purified by 25 Horizon MPLC using a gradient eluting system of 0-5% methanol in CH2Cl 2 to afford the title compound. MS: 362 (M+Na). - 22 - WO 2009/002770 PCT/US2008/067270 SWpD; tert-butyl (3aSR,4RS,7aSR)-2-benzyl-4-(4-fluorophenyl)octahydro-5H pyrrolo[3,4-c]pyridine-5-carboxylate F O N 0 A0 5 A solution of tert-butyl (2RS,3RS,4SR)-2-(4-fluorophenyl)-3,4 bis(hydroxymethyl)piperidine-1-carboxylate (0.38 g, 1.12 mmol), DMAP (3.4 mg, 0.28 mmol), triethylamine (0.070 mL, 5.04 mmol) in 12 mL of CH 2 C1 2 was added MsCl (0.26 mL, 3.36 mmol) at 0 *C. After 25 min, the reaction was quenched with NaHCO 3 . The mixture was worked 10 up with EtOAc/NaHCO 3 /NaCl. The organic phase was dried with Na 2

SO

4 and was filtered. Upon removal of solvent, it was dissolved in 30 mL of n-butyl alcohol and was added benzylamine (0.73 ml, 6.7 mmol). The mixture was heated in a 102 *C oil bath for 7 hrs. It was worked up with EtOAc/NaOH/NaCl and was dried with Na 2

SO

4 and was filtered. Upon removal of solvent, it was purified by Horizon MPLC using a gradient eluting system of 0 to 50% (EtOAc/Hex/ 2N 15 NH 3 in methanol = 10 : 10 : 1) in hexanes to afford the title compound. MS: 411 (M+1). Step E: (3aSR,4RS,7aSR)-2-benzyl-4-(4-fluorophenyl)octahydro-IH-pyrrolo[3,4 c]pyridine F NH N 20 A solution of tert-butyl (3aSR,4RS,7aSR)-2-benzyl-4-(4-fluorophenyl)octahydro 5H-pyrrolo[3,4-c]pyridine-5-carboxylate (0.20 g, 0.48 mmol) in 12 mL of 4 M HCI in dioxane was stirred at rt for 2 hr and was removed volatiles to give the title compound as HCl salt. MS: 311 (M+1). - 23 - WO 2009/002770 PCT/US2008/067270 Step F: (3aSR,4RS,7aSR)-2-benzyl-4-(4-fluorophenyl)octahydro-1H-pyrrolo[3,4 c]pyridine F F F F F F 0 N F To a solution of (3aSR,4RS,7aSR)-2-benzyl-4-(4-fluorophenyl)octahydro-1H 5 pyrrolo[3,4-c]pyridine (62.8 mg, 0.056 mmol, intermediate step E) and DMAP (2 mg) and N-(3 dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (21.2 mg, 0.11 mmol) and 3,5 bis(trifluoromethyl)-benzeneacetic acid (30 mg, 0.11 mmol) in 3 mL of CH 2 C1 2 was added N, N diisopropylethylamine (0.33 mmol, 0.058 mL) and the mixture was stiired at r for 1 hr. Upon removal of volatiles, it was purified by reverse phase HPLC to give the title compound. MS: 565 10 (M+1). Step G: (3aSR,4RS,7aSR)-5-{ [3,5-bis(trifluoromethyl)phenyljacetyl}-4-(4 fluorophenyl)octahydro-1H-pyrrolo[3,4-c]pyridine F F F F F~N ' N'NH F 15 a solution of (3aSR,4RS,7aSR)-2-benzyl-4-(4-fluorophenyl)octahydro-1H-pyrrolo[3,4-c]pyridine (115 mg, 0.17 mmol, intermediate step F) in 10 mL of MeOH was added Pd(OH) 2 (80 mg, 20% Pd on carbon) and the mixture was shaken under 50 psi of hydrogen for 1 hr. It was filtered 0.2 micron PTFE filter. The title compound was obtained after removal of methanol. MS: 475 (M+1). 20 - 24 - WO 2009/002770 PCT/US2008/067270 Step H: 3-[(3aSR,4RS,7aSR)-5-{ [3,5-bis(trifluoromethyl)phenyl]acetyl}-4-(4 fluorophenyl)octahydro-2H-pyrrolo[3,4-c]pyridin-2-yl]cyclopent-2-en- 1-one CF3 CF3 N 0 F 0 5 A solution of (3aSR,4RS,7aSR)-5- [3,5-bis(trifluoromethyl)phenyl]acetyl} -4-(4 fluorophenyl)octahydro-1H-pyrrolo[3,4-c]pyridine (0.032 g, 0.054 nmol), TsOH monohydrate (2.7 mg) and 1,3-cyclopentanedione (8 mg, 0.082 mmol) in 3 mL of toluene was heated in 100 C oil bath for 3 hrs. After removal of volatiles, the residue was purified by reverse phase HPLC to afford the title compound. MS: 555 (M+1). 10 EXAMPLE 2- EXAMPLE 3. and EXAMPLE 4 3-[(3aSR,4RS,7aSR)-5-{2-[3,5-bis(trifluoromethyl)phenylpropanovl }-4-(4 fluorophenlyoctahydro-2H-pyrrolo[3,4-clpyridin-2-vlleclopent-2-en-1-one 15 CF3 CF3 NO N F F 0 - 25 - WO 2009/002770 PCT/US2008/067270 CF3 t-6 CF3 'N F 3-[(3aSR,4RS,7aSR)-5-{2-[3,5-bis(trifluoromethyl )phenyl)-2-methylpropanov l}-4-4 fluorophenyl)octahydro-2H-pyrrolo[3,4-cjpyridin-2-yll cclopent-2-en- 1-one 5 A solution of 3-[(3aSR,4RS,7aSR)-5- {[3,5-bis(trifluoromethyl)phenyl]acetyl}-4 (4-fluorophenyl)octahydro-2H-pyrrolo[3,4-c]pyridin-2-yl]cyclopent-2-en- 1-one (27 mg, 0.049 mmol) in 2 mL of THF was added LHMDS (0.136 mmol, 0.136 mL in THF) at -78 "C and was stirred at -78 C for 10 min. Then iodomethane (0.0095 mL, 0.15 mmol) was added. After 30 min, the reaction was quenched with HOAc. Upon removal of volatiles, the title compounds 10 were isolated by reverse phase HPLC. The first and third fractions as the monoalkylation products, MS: 568 (M+I). The second fraction as the dimethylation product, MS: 583 (M+1). EXAMPLE 5 CF3 CF3 N 0 NZ/ O F 0 15 0 0 3-{2-[(3aSR.4RS.7aSR)-5-{[3,5-bis(trifluoromethyl)phenyllacetyl}-44 fluorophenyl)octahydro-2H-pyrrolo[3.4-clpyridin-2-yll-2-oxoethyl}-1,3-oxazolidin-2-one The title compound was prepared from 3aSR,4RS,7aSR)-5-{[3,5 20 bis(trifluoromethyl)phenyl]acetyl}-4-(4-fluorophenyl)octahydro-IH-pyrrolo[3,4-c]pyridine and (2-oxo-1,3-oxazolidin-3-yl)acetic acid by the procedure in Example 1, step F. MS: 602 (M+1). - 26 - WO 2009/002770 PCT/US2008/067270 EXAMPLE 6 CF3 CF3 N N 0 N~ A F 0," (3aSR, 4RS, 7aSR)-N-{1-13,5-bis(trifluoromethyl)phenyl]ethyl}-4-(4-fluorophenyl)-N-methyl-2 (3-oxocyclopent-1-en-1-yl)octahydro-5H-pyrrolo[3,4-clpyridine-5-carboxanide 5 Step.A: 1- [3,5-bis(trifluoromethyl)phenyl] ethyl} methylcarbamic chloride CF3 CF3 N A solution of 1-[3,5-bis(trifluoromethyl)phenyl]-N-methylethanamine (0.54 g, 1.99 mmol) in chloroform (18 mL) was added a solution of Cs 2

CO

3 (3.90 g, 11.9 mmol) in 8 mL 10 of water. To this suspension at OoC was added a solution of phosgene (4.2 mL, 7.97 mmol, 20 % in toluene). The mixture was stirred at rt for 1 hr. The mixture was diluted with water and extracted with methylene chloride (2x50 mL). The organic phase was dried with Na 2 S0 4 , filtered and concentrated to afford the title compound. 1H NMR (CDCl 3 , ppm): 8 7.89 (s, IH), 7.77 (s, 2H), 5.77-5.78 (m, 1H), 2.91 and 2.81 (s, 31). 15 1.72 and 1.70 (s, 31). - 27 - WO 2009/002770 PCT/US2008/067270 Step B: (3aSR,4RS,7aSR)-2-benzyl-N- { 1- [3,5 -bis(trifluoromethyl)phenyl] ethyl } -4-(4 fluorophenyl)-N-methyloctahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxamide CF3 CF3 N Nt0 Nz F 5 A solution of {1-[3,5-bis(trifluoromethyl)phenyl]ethyl}methylcarbamic chloride (0.18 g, 0.53 mmnol), DMAP (2 mg), N, N-diisopropylethylamine (0.23 mL, 1.34 mmol) and 3aSR,4RS,7aSR)-2-benzyl-4-(4-fluorophenyl)octahydro-1H-pyrrolo[3,4-c]pyridine (0.083 g, 0.27 mmol) in methylene chloride (10 mL) was stirred at rt for 72 hrs. Upon removal of solvent, it was purified by reverse phase HPLC to afford the title compound. MS: 608 (M+1). 10 Step C: (3aSR, 4RS,7aSR)-N- {I -[3,5-bis(trifluoromethyl)phenyl] ethyl } -4-(4 fluorophenyl)-N-methyloctahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxamide CF3 CF3 N N N F 15 The title compound was prepared from 3aSR,4RS,7aSR)-2-benzyl-N-{ 1-[3,5 bis(trifluoromethyl)phenyl] ethyl } -4-(4-fluorophenyl)-N-methyloctahydro-5H-pyrrolo [3,4 c]pyridine-5-carboxamide by the procedure in Example 1, step G. MS: 518 (M+1). -28- WO 2009/002770 PCT/US2008/067270 Step D: (3aSR,4RS,7aSR)-N-{1-[3,5-bis(trifluoromethyl)phenyljethyl}-4-(4-fluorophenyl) N-methyl-2-(3-oxocyclopent-1-en-1-yl)octahydro-5H-pyrrolo[3,4-c]pyridine-5 carboxamide CF3 CF3 N 0 N- z F 5 The title compound was prepared from (3aSR,4RS,7aSR)-N-{l-[3,5 bis(trifluoromethyl)phenyl]ethyl} -4-(4-fluorophenyl)-N-methyloctahydro-5H-pyrrolo[3,4 c]pyridine-5-carboxamide by the procedure in Example 1, step H. MS: 598 (M+1). EXAMPLE 7 10 (3aSR,4RS,7aSR)-N-{1-[3,5-bis(trifluoromethyl)phenlethyl} -4-(4-fluorophenyl)-N-methyl-2 (tetrahydro-2H-pyran-4-ylcarbonyl)octahydro-5H-pyrrolo[3,4-clpyridine-5-carboxamide CF3 CF3 N N O F 0 15 The title compound was prepared from (3aSR,4RS,7aSR)-N-{l-[3,5 bis(trifluoromethyl)phenyl]ethyl}-4-(4-fluorophenyl)-N-methyloctahydro-5H-pyrrolo[3,4 c]pyridine-5-carboxamide and tetrahydro-2H-pyran-4-carboxylic acid by the procedure in Example 1, step F. MS: 630 (M+l). -29- WO 2009/002770 PCT/US2008/067270 EXAMPLE 8 (L-001946286) 0 CF N'<N 3 N N N CF3 (3aS,4R,7aS)-2-benzyl-N-{(lR)-1 -[3,5-bis(trifluoromethyl)phenyH ethyl}-N-methyl-4-(2 5 methylphenyl)octahydro-5H-pyrrolo[3,4-clpyridine-5-carboxamide Step A: N-[(1E)-(2-methylphenyl)methylene]-1-[(trimethylsilyl)oxy]ethylenamine 10 The title compound was prepared according to Example 1, step A. 'H NMR (CDCl 3 , ppm): 6 4.71 (s, 1H), 4.35 (s, IH), 2.57 (s, 3H), 0.34 (s, 9H). StpB: dimethyl (2RS,3RS,4SR)-2-(2-methylphenyl)-6-oxopiperidine-3,4-dicarboxylate NH ''CO2CH3 O CO2CH3 15 The title compound was prepared from N- [(I E)-(2-methylphenyl)methylene] -1 [(trimethylsilyl)oxy]ethylenamine and dimethyl fumarate according to Example 1, step B. MS: 306 (M+1). -30- WO 2009/002770 PCT/US2008/067270 Step C: tert-butyl (2RS,3RS,4SR)-3,4-bis(hydroxymethyl)-2-(2-methylphenyl)piperidine-1 carboxylate 0 O N OH OH 5 The title compound was prepared from dimethyl (2RS,3RS,4SR)-2-(2 methylphenyl)-6-oxopiperidine-3,4-dicarboxylate according to Example 1, step C. MS: 358 (M+Na). Step D: tert-butyl (3aSR,4RS,7aSR)-2-benzyl-4-(2-methylphenyl)octahydro-5H 10 pyrrolo[3,4-clpyridine-5-carboxylate 0 N The title compound was prepared from tert-butyl (2RS,3RS,4SR)-3,4 bis(hydroxymethyl)-2-(2-methylphenyl)piperidine- I -carboxylate according to Example 1, step D. 15 MS: 407 (M+1). Step E: (3aSR,4RS,7aSR)-2-benzyl-4-(2-methylphenyl)octahydro- 1H-pyrrolo[3,4 c]pyridine N H N 20 The title compound was prepared from tert-butyl (3aSR,4RS,7aSR)-2-benzyl-4-(2 methylphenyl)octahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylate according to Example 1, step E. MS: 307 (M+l). -31- WO 2009/002770 PCT/US2008/067270 Step F: { (1 R)-1 -[3,5-bis(trifluoromethyl)phenyl] ethyl } methylcarbamic chloride CF3 CF3 'N CI 0 The title compound was prepared from (lR)-1-[3,5-bis(trifluoromethyl)phenyl]-N 5 methylethanamine according to Example 6, step A. StepG: (3 aS,4R,7aS)-2-benzyl-N- {(R)- 1 -[3,5 -bis(trifluoromethyl)phenyl] ethyl } -N methyl-4-(2-methylphenyl)octahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxamide 0 S NN CF3 10 A solution of { (1R)- 1 -[3,5 -bis(trifluoromethyl)phenyl] ethyl} methylcarbamic chloride (3.3 g, 9.9 mmol), DMAP (20 mg), N, N-diisopropylethylamine (2.1 mL, 12 mmol) and 3aSR,4RS,7aSR)-2-benzyl-4-(4-fluorophenyl)octahydro-1H-pyrrolo[3,4-c]pyridine (1.5 g, 4.9 mmol) in methylene chloride (50 mL) was stirred at rt for 72 hrs. Upon removal of volatiles, the residue was purified by Horizon MPLC using a gradient eluting system of 30 -100% EtOAc in 15 hexanes to afford the title compound as the fast fraction. MS: 604 (M+1). EXAMPLE 9 0 C N N INH CF3 (3aS,4R,7aS)-N-{(R)-1-[3,5-bis(trifluoromethyl)phenvl]ethyl} I-N-methyl-4-(2 20 methylphenvloctahydro-5H-pyrrolof3,4-c pyidine-5-carboxamide The title compound was prepared from 3aS,4R,7aS)-2-benzyl-N-{(lR)-1-[3,5 bis(trifluoromethyl)phenyl]ethyl} -N-methyl-4-(2-methylphenyl)octahydro-5H-pyrrolo[3,4 - 32 - WO 2009/002770 PCT/US2008/067270 c]pyridine-5-carboxamide (Example 8, Step G) with the same method as in Example 1, step E. MS: 514 (M+1). EXAMPLE 10 CF3 CF3 I NZ -K 5 0 (3aS,4R,7aS)-N-{(!R)-1-[3,5-bis(trifluoromethyl)phenyllethyl}-N-methyl-4-(2-methylphenvl)-2 (3-oxocyclopent-1-en-1-vl)octahydro-5H-pvrrolo[3,4-c]pyridine-5-carboxamide The title compound was prepared from(3aS,4R,7aS)-N-{(IR)-1-[3,5 10 bis(trifluoromethyl)phenyl]ethyl}-N-methyl-4-(2-methylphenyl)octahydro-5H-pyrrolo[3,4 c]pyridine-5-carboxamide (Example 9) with the same method as in Example 1, step E. MS: 594 (M+1). EXAMPLE 11 and EXAMPLE 12 CF3 CF3 Nt NH2-- 15 0 (3aS,4R.7aS)-N 5 -I(IR)-1-[3,5-bis(trifluoromethyl)phenethyl } -N -methyl-4-(2 methylphenyl)tetrahydro-1H-pyrrolo[3,4-c pyridine-2,5(3H,4H)-dicarboxamide -33 - WO 2009/002770 PCT/US2008/067270 CF3 CF3 NO N -" O

N

N 0 (3aS,4R7aS)-N-{(1R)-1 -[3,5-bis(trifluoromethl)phenyl ethyl }-N-methyl-4-(2-methylphenyl-2 (4-oxo-4,5-dihydro-1,3-oxazol-2-vlloctahydro-5H-pyrrolof3,4-cjpyridine-5-carboxamide 5 A solution of (3aS,4R,7aS)-N- { (1R)- 1-[3,5 -bis(trifluoromethyl)phenyl] ethyl } -N methyl-4-(2-methylphenyl)octahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxamide (27 mg, 0.051 mmol) in methylene chloride (5 mL) was added chloroacetyl isocyanate (0.009 mL, 0.11 mmol) at rt. After 30 min, volatile was removed and the residue was added 10 mL of water. The mixture was heated in a 100 'C oil bath for 1 h. Upon removal of volatiles. The residue was purified by 10 reverse phase HPLC to give the title compounds. The first fraction is the dicarboxamide, MS: 557 (M+1). The second fraction is the oxazolone, MS: 597 (M+1). EXAMPLE 13 CF3 CF3 N 15 0 (3aS,4R,7aS)-N-{ (1R)-1-[3,5-bis(trifluoromethyl)phenvl]ethyl}-N-methyl-4-(2-methylphenyl)-2 (5-oxo-2,5-dihydrofuran-3-vl)octahydro-5H-pyrrolo[3,4-clpyridine-5-carboxamide A solution of (3aS,4R,7aS)-N- { (1R)- 1-[3,5-bis(trifluoromethyl)phenyl]ethyl} -N methyl-4-(2-methylphenyl)octahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxamide (24 mg, 0.047 20 rnmol) and tetronic acid (15 mg, 0.15 mmol) in 2-propanol (3 mL) was heated at reflux for 3 hrs. - 34 - WO 2009/002770 PCT/US2008/067270 Upon removal of volatiles. The residue was purified by reverse phase HPLC to give the title compound. MS: 596 (M+1). EXAMPLE 14 CF3 CF3 N N 0 NK 5 (3aS4R,7aS)-N-{(lR)-1 -[3,5-bis(trifluoromethyl)pheniyll ethyl}1-2-isopropyvl-N-m-ethl-4-(2 methylphenyl)octahyro-5Hf-pyrrolo[3,4-clpyridine-5-carboxamide A solution of (3aS,4R,7aS)-N-{(IR)-1-[3,5-bis(trifluoromethyl)phenyljethyl}-N 10 methyl-4-(2-methylphenyl)octahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxamide (20 mg, 0.039 mmol), acetone (0.011 mL, 0.15 mmol) and NaB(OAc) 3 H in methylene chloride (5 mL) was stirred at rt for 16 hrs. Upon removal of volatiles. The residue was purified by reverse phase HPLC to give the title compound. MS: 556 (M+1). 15 EXAMPLE 15 and EXAMPLE 16 CF3 CF3 N N O

N

NH2 (3aS,4R,7aS)-2-(2-amino-2-oxoethyfl-N-{(1R)-1-[35-bis(trifluoromethllphenl] ethyl I -N methyl-4-(2-methylphenyl)octahydro-5H-pyrrolo[3.4-c]pyridine-5-carboxamide -35- WO 2009/002770 PCT/US2008/067270 CF3 CF3 N N -'-O NI Z C02H [(3aS,4R,7aS)-5- [{(R)-1-[3,5-bis(trifluoromethyl)phenvl]ethyl)(methyl)amino]carbonyl}-4-(2 methylphenvl)octahydro-2H-pyrrolo [3,4-c] pyridin-2-vllacetic acid 5 A solution of (3 aS,4R,7aS)-N- {(1 R)- 1- [3,5-bis(trifluoromethyl)phenyl]ethyl} -N methyl-4-(2-methylphenyl)octahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxamide (25mg, 0.039 mmol), chloroacetamide (9 mg, 0.097 mmol) and Cs 2

CO

3 (33mg, 0.097 mmol) in 2 mL of dioxane was heated in a 100 4C oil bath for 16 hrs. Upon removal of volatiles. The residue was 10 purified by reverse phase HPLC to give the title compounds. The first faction is the amide, MS: (571). The second fraction is the acid, MS: 572 (M+l). EXAMPLE 17 CF3 CF3 N

I-

N O OH 15 (3aS,4R,7aS-N-{(.lR)-l-[3,5-bis(trifluoromethyl)phenyll ethyl}-2-[(2S)-2-hydroxypropanovl -N me thyl-4-(2-methylphenvl)octahydro-.5H-pyrrolo[3,4-c]pyridine-5-carboxamide The title compound was prepared from(3aS,4R,7aS)-N-{(tR)-l-[3,5 20 bis(trifluoromethyl)phenyl] ethyl } -N-methyl-4-(2-methylphenyl)octahydro-5H-pyrrolo [3,4 c]pyridine-5-carboxamide (Example 9) and (2S)-2-(acetyloxy)propanoic acid with the same method as in Example 1, step F. - 36 - WO 2009/002770 PCT/US2008/067270 MS: 586 (M+1). EXAMPLE 18 CF3 CF3 N N 0

N

o 5 (3aS,4R,7aS)-2-acetyl-N-{(lR)-1-[3,5-bis(trifluoromethylphenvl]ethyl}-N-methyl-4(2 methylphenvll)octahydro-5H-pyrrolo[3,4-clpyridine-5-carboxamide The title compound was prepared from(3aS,4R,7aS)-N-{(IR)-1-[3,5 10 bis(trifluoromethyl)phenyl]ethyl } -N-methyl-4-(2-methylphenyl)octahydro-5H-pyrrolo [3,4 c]pyridine-5-carboxamide (Example 9) with the same method as in Example 1, step F. MS: 556 (M+1). EXAMPLE 19 CF3 CF3 N0 N- N N 15 0 (3aS,4R,7aS-N-{(lR)-1-[3,5-bis(trifluoromethyl)phenvfllethyl}-N-methyl-2-[(1-methyl-6 oxopiperidin-3-yl)carbonyll-4-(2-methylphenylboctahydro-5H-pyrrolof3,4-c]pyridine-5 carboxamide 20 The title compound was prepared from(3aS,4R,7aS)-N-{(1R)-1-[3,5 bis(trifluoromethyl)phenyl] ethyl} -N-methyl-4-(2-methylphenyl)octahydro-5H-pyrrolo [3,4 -37- WO 2009/002770 PCT/US2008/067270 c]pyridine-5-carboxamide (Example 9) and 1-methyl-6-oxopiperidine-3-carboxylic acid with the same method as in Example 1, step F. MS: 653 (M+1). EXAMPLE 20 CF3 CF3

W

0 N /NH2 5 0 (3aS,4R,7aS)-2-[ 1-(aminocarbonvll)piperidin-4-y]carbonyl)-N-{(1 lR)-i-[3.5 bis(trifluoromethyl)phenv1]ethyl -N-methyl-4-(2-methylphenvl)octahydro-5H-pyrrolo [3,4 c]pyridine-5-carboxamide 10 The title compound was prepared from(3aS,4R,7aS)-N-{(1R)-1-[3,5 bis(trifluoromethyl)phenyl] ethyl) -N-methyl-4-(2-methylphenyl)octahydro-5H-pyrrolo[3,4 c]pyridine-5-carboxamide (Example 9) and 1-(aminocarbonyl)piperidine-4-carboxylic acid with the same method as in Example 1, step F. MS: 668 (M+l). 15 EXAMPLE 21 CF3 CF3 N

N

0 (3aS,4R,7aS)-N-(IlR)-1-[3,5-bis(trifluoromethyl)phenvllethyl}-N-methyl-4-(2-methylphenvl)-2 20 (tetrahydro-2H-pyran-4-yl)octahydro-5H-pyrrolof3,4-c]pyridine-5-carboxamide -38- WO 2009/002770 PCT/US2008/067270 The title compound was prepared from(3aS,4R,7aS)-N-{(1R)-1-[3,5 bis(trifluoromethyl)phenylethyl}-N-methyl-4-(2-methylphenyl)octahydro-5H-pyrrolo[3,4 c]pyridine-5-carboxamide (Example 9) with the same method as in Example 14. MS: 598 (M+I). 5 EXAMPLE 22 CF3 CF3 NN 0 (3aS,4R,7aS)-2-(1-acetylpiperidin-4-yl)-N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-N methyl-4-(2-methylphenyl)octahydro-5H-pyrrolo[3,4-clpyridine-5-carboxamide 10 The title compound was prepared from(3aS,4R,7aS)-N-{(IR)-1-[3,5 bis(trifluoromethyl)phenyl] ethyl } -N-methyl-4-(2-methylphenyl)octahydro-5H-pyrrolo [3,4 c]pyridine-5-carboxamide (Example 9) with the same method as in Example 14. MS: 639 (M+I). 15 EXAMPLE 23 CF3 CF3 Nz OH (3aS,4R,7 aS)-N-{(1R)-I-[3,5-bis(trifluoromethyl)phenyljethyl -2-Fl-(3-hydroxy-2,2 dimethylpropyllpiperidin-4-yll-N-methyl-4-(2-methylphen1l)octahydro-5H-pyrrolo[3,4 20 c]pyridine-5-carboxamide -39- WO 2009/002770 PCT/US2008/067270 Step A: tert-butyl (3aSR,4RS,7aSR)-2-(3-hydroxy-2,2-dimethylpropyl)-4-(2 methylphenyl)octahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylate 0 OH O N &'\N O The title compound was prepared from tert-butyl (2RS,3RS,4SR)-3,4 5 bis(hydroxymethyl)-2-(2-methylphenyl)piperi dine-I -carboxylate according to Example 1, step D. MS: 403 (M+1). Step B: tert-butyl (3aSR,4RS,7aSR)-2-[3-(acetyloxy)-2,2-dimethylpropylj-4-(2 methylphenyl)octahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylate O N \N 10 10 A solution of tert-butyl (3aSR,4RS,7aSR)-2-(3-hydroxy-2,2-dimethylpropyl)-4-(2 methylphenyl)octahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylate (84 mg, 0.21 mmol), Ac 2 0 (0.104 mL, 1.05 mmol) and DAMP (2 mg) in 5 mL of pyridine was stirred at rt for 1 hr. Upon 15 removal of volatiles, the crude was purified by preparative TLC (MeOH/CH2C0 2 = 5:95) to afford the title compound. MS: 445 (M+1). Step C: 3-[(3aS,4R,7aS)-5-{[{(lR)-1-[3,5 bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl)-4-(2 20 methylphenyl)octahydro-2H-pyrrolo[3,4-c]pyridin-2-yl]-2,2-dimethylpropyl acetate 04 F F 0 F NX N F F'F IiN F r F The title compound was prepared from tert-butyl (3aSR, 4RS,7aSR)-2-[3 (acetyloxy)-2,2-dimethylpropyl]-4-(2-methylphenyl)octahydro-5H-pyrrolo[3,4-c]pyridine-5 25 carboxylate according to and Eample 1, step E and Example 8, step G. MS: 642 (M+1). -40 - WO 2009/002770 PCT/US2008/067270 Step D: tert-butyl (3aS,4R,7aS)-2-(3-hydroxy-2,2-dimethylpropyl)-4-(2 methylphenyl)octahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxylate A solution of 3-[(3aS,4R,7aS)-5-{[{(R)-1-[3,5-bis(trifluoromethyl) 5 phenyl] ethyl) (methyl)amino]carbonyl} -4-(2-methylphenyl)octahydro-2H-pyrrolo [3,4-c]pyridin 2-yl]-2,2-dimethylpropyl acetate (32 mg, 0.05 mmol) in 3 mL of methanol was added 3 drops of 2N NaOH solution. The mixture was stirred at rt for 3 hrs. Upon removal of volatiles, the crude was purified by reverse phase HPLC to afford the title compound. MS: 600 (M+I). 10 EXAMPLE 24 CF3 CF3 N NN 0 NH2 (3aS,4R,7aS)-2-[1-(3-amino-2,2-dimethyl-3-oxopropvl)piperidin-4-vll -N-{(IR)-l-[3,5 bis(trifluoromethyl)phenyllethyl}-N-methyl-4-(2-methylphenvl)octahydro-5H-pyrrolo[3,4 15 c]pyridine-5-carboxamide The title compound was prepared from tert-butyl (2RS,3RS,4SR)-3,4 bis(hydroxymethyl)-2-(2-methylphenyl)piperidine- 1 -carboxylate and 3-amino-2,2 dimethylpropanamide according to steps in Example 8. MS: 613 (M+I). 20 -41- WO 2009/002770 PCT/US2008/067270 EXAMPLE 25 (3aS,4R,7aS)-2-benzyl-N-{(1R)-1-[3.5-bis(trifluoromethyl)phenyllethvl}-4-(4-fluoro-2 methylphenyl)-N-methyloctahydro-5H-pyrrolo[3,4-clpyridine-5-carboxamide 5 F CF2 3 ( N N 0'\ CF3 The title compound was prepared according to steps in Example 8. MS: 622 (M+1). 10 EXAMPLE 26 (3aS,4R,7aS)-N-{(1R)-1I-[3,5-bis(trifluoromethyl)phenyllethyl}-4-(4-fluoro-2-methyIphenv)-N methyloctahydro-5H-pyrrolo[3,4-c lpyridine-5-carboxamide F 0 CF NXN "\ NH CF3 15 The title compound was prepared from (3aS,4R,7aS)-2-benzyl-N-{(1R)-1-[3,5 bis(trifluoromethyl)phenyl] ethyl } -4-(4-fluoro-2-methylphenyl)-N-methyloctahydro-5H pyrrolo[3,4-c]pyridine-5-carboxamide with the same method as in Example 1, step E. MS: 532 (M+1). 20 - 42 - WO 2009/002770 PCT/US2008/067270 EXAMPLE 27 CF3 CF3 ~N N- F (3aS,4R,7a5S)-N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethy l-4-(4-fluoro-2-methylphenvl)-N 5 methyl-2-(3-oxocyclopent-1-en-1-yl)octahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxamide The title compound was prepared from (3aS,4R,7aS)-N-{(1R)-1-[3,5 bis(trifluoromethyl)phenyl] ethyl } -4-(4-fluoro-2-methylphenyl)-N-methyloctahydro-5H pyrrolo[3,4-c]pyridine-5-carboxamide with the same method as in Example 1, step H. MS: 612 10 (M+1). EXAMPLE 28 CF3 CF3 N F N 0 15 (3aS,4R,7aS)-N-{(1R)-1-[3,5-bis(trifluoromethyllphenyllethyl}-4-(4-fluoro-2-methylphenyl)-N methyl-2-(4-oxo-4,5-dihydro-1,3-oxazol-2-ylloctahydro-5H-pyrrolo[3,4-cjpyridine-5 carboxamide The title compound was prepared with the same procedure as Example 12. MS: 20 615 (M+1). - 43 - WO 2009/002770 PCT/US2008/067270 EXAMPLE 29 CF3 CF3 N Nt0 N- F 0 0 (3aS,4R,7aS)-N-{(1 R)-1-[3,5-bis(trifluoromethyv)phenvilethyl -4-(4-fluoro-2-methylphenyl)-N 5 methyl-2-(5-oxo-2,5-dihydrofuran-3-yl)octahydro-5H-pyrrolo[3,4-c] pyridine-5-carboxamide The title compound was prepared from (3aS,4R,7aS)-N-{(lR)-l-[3,5 bis(trifluoromethyl)phenyl] ethyl} -4-(4-fluoro-2-methylphenyl)-N-methyloctahydro-5H pyrrolo[3,4-c]pyridine-5-carboxamide with the same method as in Example 13. MS: 614 (M+l). 10 EXAMPLE 30 CF3 CF3 N Nt0 N- z N F o -OH (3aS,4R,7aS)-N-{(R)-1 -[3.5-bis(trifluoromethyl)phenyl]ethyl}-4-(4-fluoro-2-methylphenvyl)-2 15 j((S-2-hydroxypropanovll-N-methyloctahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxamide The title compound was prepared from (3aS,4R,7aS)-N-{(IR)-1-[3,5 bis(trifluoromethyl)phenyl] ethyl) -4-(4-fluoro-2-methylphenyl)-N-methyloctahydro-5H pyrrolo[3,4-c]pyridine-5-carboxamide with the same method as in Example 1, step F. MS: 604 20 (M+1). -44- WO 2009/002770 PCT/US2008/067270 EXAMPLE 31 CF3 CF3 N N (o N'F O H (3aS,4R,7aS)-N-{1 R)-1-[3,5-bis(trifluoromethyl)phenyljethyl}-4-(4-fluoro-2-methylphenyl)-2 5 [(2R)-2-hydroxvpropanoyl]-N-methyloctahydro-5H-pyrrolo[3,4-cjpyridine-5-carboxamide The title compound was prepared from (3aS,4R,7aS)-N-{(1R)-1-[3,5 bis(trifluoromethyl)phenyl] ethyl) -4-(4-fluoro-2-methylphenyl)-N-methyloctahydro-5H pyrrolo[3,4-c]pyridine-5-carboxamide with the same method as in Example 1, step F. MS: 604 10 (M+1). EXAMPLE 32 F F F F F F N NO Nz F 0= 15 (3aS,4R.7aS)-2-acet1yl-N-{ (iR)-1-[3,5-bis(trifluoronethyl)phenvljethyl}-4-(4-fluoro-2 methylphenvl)-N-methyloctahydro-5H-pyrolo[3,4-clpyridine-5-carboxamide The title compound was prepared from (3aS,4R,7aS)-N-{(1R)-I-[3,5 bis(trifluoromethyl)phenyl]ethyl}-4-(4-fluoro-2-methylphenyl)-N-methyloctahydro-5H 20 pyrrolo[3,4-c]pyridine-5-carboxamide with the same method as in Example 1, step F. MS:574 (M+1). -45- WO 2009/002770 PCT/US2008/067270 EXAMPLE 33 F F F F F N. F N N 0 F (3aS,4R,7aS)-N-{(1R)-1 -[3,5-bis(trifluoromethyl)phenyl]ethyl I-2-(22-dimethylpropanovl)-4-(4 5 fluoro-2-methylphenl)-N-methyloctahydro-5H-pyrrolo[3,4-clpyridine-5-carboxamide The title compound was prepared from (3aS,4R,7aS)-N-{(1R)-1-[3,5 bis(trifluoromethyl)phenyl] ethyl } -4-(4-fluoro-2-methylphenyl)-N-methyloctahydro-5H pyrrolo[3,4-c]pyridine-5-carboxamide with the same method as in Example 1, step F. MS 616 10 (M+1). EXAMPLE 34 F F F F F F N N0 F 0 15 (3aS,4R,7aS)-N-( (1lR)-1-[3,5-bis(trifluoromethyl)phenl]ethyl}-4-(4-fluoro-2-methylphenyl)-N methyl-2-(tetrahydro-2H-pyran-4-ylcarbonylloctahydro-5H-pyrrolo[3 ,4-c]pyridine-5 carboxamide The title compound was prepared from (3aS,4R,7aS)-N-{(1R)-1-[3,5 20 bis(trifluoromethyl)phenyl]ethyl } -4-(4-fluoro-2-methylphenyl)-N-methyloctahydro-5H - 46 - WO 2009/002770 PCT/US2008/067270 pyrrolo[3,4-c]pyridine-5-carboxamide with the same method as in Example 1, step F. MS: 644 (M+1). EXAMPLE 35 F F F F N 50 (3aS,4R,7aS)-N-((1R)-i-[3,5-bis(trifluoromethyl)iphenyllethyl}-4-(4-fluoro-2-methylphenvl)-N methyl-2-(tetrahydro-2H-pyran-4-yl)octahydro-5H-rrolo[3.4-clpyridine-5-carboxamide 10 The title compound was prepared from (3aS,4R,7aS)-N-{(1R)-1-[3,5 bis(trifluoromethyl)phenyl] ethyl} -4-(4-fluoro-2-methylphenyl)-N-methyloctahydro-5H pyrrolo[3,4-cjpyridine-5-carboxamide with the same method as in Example 14. MS: 616 (M+i). EXAMPLE 36 F F F F Nt0 N- F N 0: 15 (3aS,4R,7aS)-2-(1-acetylpiperidin-4-yl)-N-{(R)-I-[3,5-bis(trifluoromethyl)phenyl] ethyl -4-(4 fluoro-2-methylphenvl)-N-methyloctahydro-5H-pyrrolo[3,4-clpvridine-5-carboxamide - 47 - WO 2009/002770 PCT/US2008/067270 The title compound was prepared from (3aS,4R,7aS)-N-{(lR)-l-[3,5 bis(trifluoromethyl)phenyl] ethyl }-4-(4-fluoro-2-methylphenyl)-N-methyloctahydro-5H pyrrolo[3,4-c]pyridine-5-carboxamide with the same method as in Example 14. MS: 658 (M+1). 5 While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various adaptations, changes, modifications, substitutions, deletions, or additions of procedures and protocols may be made without departing from the spirit and scope of the invention. For example, effective dosages other than the particular dosages as set forth herein above may be applicable as a 10 consequence of variations in responsiveness of the mammal being treated for any of the indications with the compounds of the invention indicated above. -48 -

Claims (18)

1. A compound of the formula I: F 3 C CF 3 R 2 R3 X R 4 N O / R6 R 5 N I R ' 5 and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof, wherein: X is N or CH, R1 is selected from the group consisting of: (1) hydrogen, 10 (2) C -6alkyl, which is unsubstituted or substituted with halogen, hydroxyl, -COOH, or phenyl, (3) cyclopentenone, (4) -(CO)-C1-6alkyl, which is optionally substituted with hydroxyl, (5) -(CO)-NH2, 15 (6) -(CO)-NHC1-6alkyl, (7) -(CO)-N(C1 -6alkyl)(C 1 -6alkyl), (8) -C1 -4alkyl-(CO)-NH2, (9) -C -4alkyl-(CO)-NHC 1 -6alkyl, (10) -C -4alkyl-(CO)-N(C 1 -6alkyl)(C 1 -6alkyl), 20 (11) -(CO)-O-Cl-6alkyl, (12) -(CO)-C3-6cycloalkyl, -49- WO 2009/002770 PCT/US2008/067270 Q or or or 00 0 0 or (13) 0 (14) -(CO)-HET, wherein HET is selected from the group consisting of Ra O NH N-Rb 0X N 0 and HO Wherein Ra is selected from H, and C1-3alkyl and Rb is selected fromH, Cp-4alkyl, -(CO)-CH3 5 and -(CO)-NH2, R 2 , R 3 , R 4 and R 5 are each independently selected from the group consisting of: (1) hydrogen, and (2) methyl; R 6 is independently selected from the group consisting of: 10 (1) hydrogen, and (2) fluorine.

2. The compound of Claim 1 of the formula Ia: F

3 C CF 3 R 2 R 3 X R

4 N O1 __ Re R 5 N RI La - 50 - WO 2009/002770 PCT/US2008/067270 wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and X are defined herein, or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof. 5 3. A compound according to Claim 1 wherein R 1 is selected from the group consisting of: RI is selected from the group consisting of: (1) hydrogen, (2) C1-3alkyl, which is unsubstituted or substituted with hydroxyl or phenyl, 10 (3) cyclopent-2-en-1-one, which is unsubstituted or substituted with hydroxyl, (4) -(CO)-Cl-3alkyl, (5) -(CO)-NH2, (6) -(CO)-NHC1-3alkyl, (7) -(CO)-N(C 1-3 alkyl)(C 1-3 alkyl), and 15 (8) 0 wherein the alkyl portion of choices (4), (6) and (7) of RJ are optionally substituted with halo, hydroxyl or phenyl. 20 4. The compound of Claim 1 wherein RI is selected from the group consisting of: (1) hydrogen, (2) cyclopent-2-en- 1-one, (3) 1,2-oxazol-4(5H)-one, 25 (4) 2,2-dimethylpropanoyl, (5) methylpropanoyl, (6) CH3NH-(CO)-, (7) (CH3)2-N-(CO)-, and (8) 0O 0 30

5. The compound of Claim I wherein R 6 is hydrogen.

6. The compound of Claim I wherein R 6 is fluorine. -51- WO 2009/002770 PCT/US2008/067270

7. The compound of Claim 1 wherein R 5 is hydrogen.

8. The compound of Claim I wherein R5 is methyl. 5

9. The compound of Claim I wherein X is N.

10. The compound of Claim 1 of the formula Ia: F 3 C CF 3 FR 3 X R 4 N O_ R5 N R 1 Ia or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers 10 thereof wherein X is N or CH, R1 is selected from the group consisting of: (1) hydrogen, (2) cyclopent-2-en- 1 -one, 15 (3) 1,2-oxazol-4(5H)-one, (4) 2,2-dimethylpropanoyl, (5) methylpropanoyl, (6) CH3NH-(CO)-, (7) (CH3)2-N-(CO)-, and 20 (8) O R 6 is independently selected from the group consisting of: (1) hydrogen, and (2) fluorine; R 5 is independently selected from the group consisting of: 25 (1) hydrogen, and - 52 - WO 2009/002770 PCT/US2008/067270 (2) methyl.

11. A compound according to claim 10 wherein X is N. 5

12. A compound which is selected from the group consisting of: CF3 CF3 CF3 CF3 N 'N N F F 0 0 CF3 CC3 CF33 ' CF3 F N'NO ONO N O0 0 -F3 CF3 'NNCR3 CF3 N' N 1 0 N N0 F 0 N-~ I' F 0 0 - 53 - WO 2009/002770 PCT/US2008/067270 00 N N N C3. N N NH XI I NH F3 0F3 0F3 CFS CF3 CF3 N O N O NH2 0 0 CF3 CF3 CF3 CF3 NNN NN 0 o 0 CF3 CF3 CF3 CF3 NN 0 N H2 5 -54- WO 2009/002770 PCT/US2008/067270 CF3 CF3 CFS CFZ N " O NK K N<O OH A C02H CF3 CF3 CF3 CF3 NLO N NXO N 0 NIN O CF3 CF3 CF3 CF3 NO N -N N O 0 N NN SNH2 5 0-5 -55 - WO 2009/002770 PCT/US2008/067270 CF3 CF3 CF3 CF3 N N -s OH N N--O NA0 O NN CFC CF3 NN N N CF A CF5 C3 CF3 F N 3N N NO J NH CF3 0 - 56 - WO 2009/002770 PCT/US2008/067270 CF3 CF3 CF3 CF3 N N N 0N N 0 F F N O 0 0 CF3 CF3 CF3 CF3 NNN N 'N 0 N 0 F 69 F O=_ OH F"OH F F F F F F F F 'N F O' F F - 5 NO 'N0 N NN 0 F FF (NF ' F 0 0 - 57 - WO 2009/002770 PCT/US2008/067270 F F F F Nt N O NF or a pharmaceutically acceptable salt thereof

13. A pharmaceutical composition which comprises an inert carrier and a 5 compound of Claim 1.

14. A method for the treatment of pain or inflammation, migraine, emesis, postherpetic neuralgia, depression, anxiety or urinary incontenence, and LUTS which method comprises administration to a patient in need thereof a therapeutically effective amount of the 10 compound of Claim 1.

15. A method according to Claim 14 for the treatment of urinary incontinence or LUTS. 15

16. A method of antagonizing the effect of substance P at its receptor site or for the blockade of neurokinin- I receptors in a patient in need thereof comprising administration to said patient a therapeutically effective amount of the compound of Claim 1.

17. A method of treating a physiological disorder associated with an excess of 20 tachykinins in a patient in need thereof comprising administration to said patient a therapeutically effective amount of a compound of Claim 1.

18. Use of a compound according to Claim I for the manufacture of a medicament for antagonizing the effect of substance P at its receptor site or for the blockade of 25 neurokinin-1 receptors in a mammal comprising combining a compound of the present invention or a pharmaceutically acceptable salt thereof with a pharmaceutical carrier or diluent. -58-