CA2690737A1 - 6.5-pyrrolopiperidine tachykinin receptor antagonists - Google Patents

Abstract

The present invention is directed to certain hydroxymethyl ether hydroisoindoline compounds which are useful as neurokinin-1 (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.

Description

TITLE OF THE INVENTION
6.5 -PYRROLOPIPERIDINE TACHYKININ RECEPTOR ANTAGONISTS
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 neurokinin A and neurokinin B. The current nomenclature designates the receptors for substance P, neurokinin A, and neurokinin B as neurokinin- I(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 particular substance P, activity, including disorders of the central nervous system, nociception and pain, gastrointestinal disorders, disorders of bladder fiinction and respiratory diseases.
SUMMARY OF THE INVENTION
The present invention is directed to certain hydroxymethyl ether hydroisoindoline 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 forinulations in the treatment of certain disorders, including emesis, urinary incontinence, LUTS, depression, and anxiety.

DETAILED DESCRIPTION OF TI-IE INVENTION
In one embodiment the present invention is directed to coznpou.nds of the formula F3C ~ CF3 /
R~ R3 x R4 N Q

R'5 N
I
R' and pharmaceutically acceptable salts thereof aald individual enantiomers and diastereomers thereof, wherein:
X is N or CH;
RI is selected from the group consisting of (1) hydrogen, (2) C X-6alkyl, which is unsubstituted or substituted with halogen, hydroxyl, -COOH, or phenyl, (3) cyclopentenone, (4) -(CO)-C I _6alkyl, which is optionally substituted with hydroxyl, (5) -(CO)-NH2, (6) -(CO)-NHC I _6alkyl, (7) --(C O)-N(C 1..6alkyl)(C I _6alkyl), (8) -CI..4alkyl-(CO)-NH2, (9) -C I..4alkyl-(CO)-NHC I ..6alkyl, (10) -C 1 _q.alkyl-(C O)-N(C i _&alkyl)(C 1 -6alkyl), ( I 1) -(C O)-O-C I_6alkyl, (12) -(CO)-C3_6cycloalkyl, N_.~~ -\
0~ ~O or Ci or oro N~~A
~~ or (13) O
(14) -(CO)-HET, wherein HET is selected from the group consisting of Ra 0 NH 0--Rb o X
N
OD and HD
Wherein Ra is selected from H, and C I_3alkyl and Rb is selected fromH, C
1_4alkyl, -(CO)-CH3 and -(CO)-NH2, R2, R3, R4 and R5 are each independently selected from the group consisting of:
(1) hydrogen, and (2) methyl;
R6 is independently selected from the group consisting of:
(1) hydrogen, and (2) fluorine.
Within this embodiment there is a genus of compound of formula Ia:

R? Rs N ~0-N
I
R' Za wherein RI, R2, R3, R4, R5, R6, and X are defined herein, 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 R1 is selected from the group consisting ofl (1) hydrogen, (2) C 1 -3 alkyl, which is unsubstituted or substituted with hydroxyl or phenyl, (3) cyclopent-2-en-J.-one, which is unsubstituted or substituted with hydroxyl, (4) -(CO)-C1-3alkyl, (5) --(CO)-NH2, (6) =-(CO)TNHC 1-3 alkyl, (7) =-(CO)-N(C 1-3alkyl)(C 1-3 alkyl), and N

O_-~O
(8) 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 R1 is selected from the group consisting of:
(1) hydrogen, (2) cyclopent-2-en-l-one, (3) 1,2-oxazol-4(51-1')-one, (4) 2,2-dimethylpropanoyl, (5) nzethylpropanoyl, (6) CH3NH-(CO)-, (7) (CH3)2-N-(CO)-, and O N
~O
~g) Within this embodiment there is a genus of compounds of Formula I wherein R6 is hydrogen.

Withzn this embodiment there is a genus of compounds of Formula I wherein R6 is fluorine.

Within this embodiment there is a genus of compounds of Foz-znula I wherein R5 is hydrogen.

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 :

N X' O

N
I
R' Ia or a pharinaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof wherein R1 is selected from the group consisting of:
(1) hydrogen, (2) cyclopent-2-en- I -one, (3) 1,2-oxazoZ-4(5H)-one, (4) 2,2-dimethylpropazaoyl, (5) methylpropanoyl, (6) CH3NH-(CO)-, (7) (CH3)2-N-(CO)-, and O~[O
(8) 9 R6 is independently selected from the group consisting of ( I ) hydrogen, and (2) fluorine;
R5 is independently selected from the group consisting of:
(1) hydrogen,and (2) methyl.

Within this embodiment, it is preferred that X is N.
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 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 phan-naceutically 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 inixtu.res, 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 asyznmetric 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 compoun.ds. Formula I shows the stracture of the class of compounds without preferred stereochemistry. The independent syntheses of these 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 coinpounds may be 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 enantiornerically 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 confzguration by methods well known in the art.
There are several acceptable methods of naming the compounds discussed herein:

,OH

~ ~ CH~
0 ~ CH3 For example, the above compound can be named either as "(3aR,4R,5S,7aR) tert-butyl-5-hydroxy-4-(2-zn.ethylphenyl)octahydro-2H-isoindole-2-carboxylate" or "tert-butyl (3aR,4R,5S,7aR)-5-hydroxy-4-phenyloctahydro-2H-isoandole-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, C i_g, as in C
1_6alkyl is defined to identify the group as having 1, 2, 3, 4, 5 or 6 carbons in a linear or branched arrangement, such that Cl_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 ternm "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum, amm.onium, 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, 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, ethylenediatnine, N-ethyl-morpholine, N-ethylpiperidine, glucarnine, 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 phannaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, funa.aric, gluconic, glutarnic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, _7..

nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fu.nlaric, 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 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.
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 particularly depressive disorders, for example, single episodic or recurrent major depressive disorders and dysthymic disorders, or bipolar disorders, for example, bipolar I disorder, bipolar Il 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 anirn.al phobias, social phobias, obsessive-coin.pul,sive disorder, stress disorders 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 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-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, arnphetamines (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 abuse, intoxication, withdrawal, intoxication deleriwn, 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 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 chron.ic cerebrovascular damage such as cerebral infarction, subarachnoid haen-iorrhage or 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, zxa.usculo-skeletal 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, peripheral neuropathies, tic douloureux, atypical facial pain, nerve root daixaage, 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 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;
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 ezematoid 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 carcinomas such as small cell lung cancer.
Tachykinin, and in particular substance P, antagonists may also be of use in the treatment of gastrointestinal (GT) 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 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 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 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 finiction such as cystitis, bladder detrusor hyper-reflexia, 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 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 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 disorders.
The coinpounds 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 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 emetogenic cancer chemotherapy, including high-dose cisplatin. Most especially, the compounds of the present invention are of use in the treatment of einesis induced by antineoplastic (cytotoxic) agents, including those routinely used in cancer chemotherapy, and emesis induced by 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 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,4dvances, 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, mechlorethamine, streptozocin, cyclophosphamide, carmustine (BCNU), loinustine (CCNU), doxorubicin (adriamycin), daunorubicin, procarbazine, mitomycin, cytarabine, etoposide, methotrexate, 5-fluorouracil, vinblastine, vincristine, bleomycin and chlorainbucil [R. T. Gralla et al in Cancer Treatment Reports (1984) f 8(1), 163-1721.
A fu.rther aspect of the present invention comprises the use of a compound of the present invention for achieving a clr.ronobiologic (circadian rhythm phase-shifting) effect and alleviating circadian rhytlun 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 m.arnrnal.
A ftuther aspect of the present invention comprises the use of a compound of the 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 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 fizrther directed to the use of a compound of the present invention or a phamxaceutically acceptable salt thereof, for enhancing or improving sleep quality as well as preventing and treating sleep disorders and sleep disturbances in a mammal. hi 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 pharmaceutically acceptable salt thereof The present invention is useful for the treatment of sleep disorders, including Disorders of Initiating aiid Maintaining Sleep (insomnias) ("DTMS") which can arise from psychophysiological causes, as a consequence of psychiatric disorders (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 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 neurolc.inin:-1 receptors in a mammal comprising combining a compound of the present invention with a phara.naceutical carrier or diluent. The present invention is further directed to a method for the manufacture of amedicajuent 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 d.iluent.
The present invention also provides a method for the treatrnent or prevention of physiological disorders associated with an excess of tachykinins, especially substance P, which method coinprises 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 "treatrnent" or "to treat" refers to the administration of 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 terrn "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 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 treatment. This activity can be demonstrated by the following assays.
Rece tor Ex ression in COS: To express the cloned human neurokinin-l receptor (NK1R) transiently in COS, the eDNA 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.
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 NaC1, 1.2 mM CaC12, 1.2 mM MgC12, 2.4 mM K2HPO4, 0.6 mM KH2PO4, 10 mM glucose, 10 mM HEPES pH 7.4) at 260 V and uF using the IBI GENEZAPPER (IBI, New Haven, CT). The cells were incubated in 10% fetal calf serum, 2 mM glutarnine, 100U/ml penlcillin-streptomycin, and 90 / DMEM
media (GBCO, Grand Island, NY) in 5% C02 at 37 C for three days before the binding assay.
Stable Expression in CHO: To establish a stable cell line expressin.g the cloned human NK1 R, the eDNA was subeloned into the vector pRcCMV (INVTTROGEN).
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-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 NKXR
expressed in either COS or CHO cells is based on the use of 1251-substance F(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, 150 mM NaCI, 0.04 mg/ml bacitracin, 0.004 rng/ml leupeptin, 0.2 rng/rnl BSA, 0.01 mM
phosphoramidon) such that 200 ul of the cell suspension would give rise to about 10,000 cpm of specific 1251-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 1251_SP and 20 ul of unlabeled substance P or any other test compound. The tubes were incubated at 4 C or at room temperature for 1 hour with gentle shaking. The bound radioactivity was separated from unbou.nd 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 rnM MnCl2, 150 mM NaCI) tl-uee times and its radioactivity was determined by gamma counter. The activation of phospholipase C by NKIR may also be measured in CHO
cells 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 Ck10 media for 4 days, cells are loaded with 0.025 uCi/ml of 3H-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 test compound, and incubation is continued at 37 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 C, the media is removed and 0.1 N HCl is added. Each well is sonicated at 4 C and extracted with CHC13/methanol (1:1). The aqueous phase is applied to a 1 ml Dowex AG 1X$
ion exchange column. The colunin 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-0.1 N formic acid and quantitated by beta counter.
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 M. The Examples hereinunder were found to have the following activity:

Example TC50 nM Exam Ie IC50 (nM) Example 1C50 (nM) 1 1.7 13 0.083 25 0.052 2 0.25 14 00.044 26 0.031 3 12. 15 0.071 27 ----4 0.17 16 0.152 28 0.077 5 15 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 0.066 22 0.089 34 0.048 11 0.060 23 0.094 35 0.111 12 0.043 24 --~W 36 0.108 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 ftarther 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 in need of a reduction of the ainount 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 ainounts 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 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 i-odirectly, 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 unifortnly 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 phartnaceutical composition the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases.
Accordingly, the pharmaceu.tical 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 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 admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the ma.nufactYre 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 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 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 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 fonn of suppositories for rectal administration. For topical use, 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 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 inethods well known in the art of pharmacy. The terzn "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 administration, single dose vials for injection, or suppositories for rectal administration. This list of unit dosage forms is not intended to be limiting in airy 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 ingredients, carriers, diluents, and the like, are provided with instructions for preparation of the actual dosage foran 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.
By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the forrnulation 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 in a form that can be introduced into that individuals body in a therapeutically useful form and therapeutically effective ainount, 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.
The term "therapeutically effective amount" refers to a sufficient quantity of the compounds of the present invention, in a suitable composition, and in a suitable dosage fon-n. to treat or prevent the noted disease conditions.
The cor.n.pou.nds 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 the present invention.
Accordingly, in the prevention or treatinent of emesis, a compound of the present invention may be used in conjunction with other anti-emetic agents, especially 5HT3 receptor 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 5HT1 agonists, 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 inhibitars (SSRIs), monoamine oxidase inhibitors (MAGIs), reversible inhibitors of m.onoan-iine oxidase (RIMAs), scrotonin and noradrenaline reuptake inhibitors (SNRIs), a-adrenoreceptor antagonists, atypical anti-depressants, benzodiazepines, 5-HTzA 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 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 antiinflam.matory 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 iiihibitor, such as an intexleukin-1 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 antiinflana.a.natory agent.

For the treatment of urinary incontinence and LUTS, a compound of the invention may be used in combination with a 03 adrenergic receptor ([33AR) agonist ((33 agonist), and/or an anti-muscatinic and optionally an alpha-1 adrenergic antagonist, or a steroid type 115-alpha-reductase inhibitor.

For purposes of this specification the 03 agonist is intended to include N-[4-[2-[[2-hydroxy-2-(pyridin-3-yl)ethyl]amino]ethyl)phenyl]-4-[4-(3-cyclopentylpropyl)-5-tetrazolon-1-yl] benzenesulfonamide.
2N-[4-[2-[[2-hydroxy-2-(pyridin-3-yl)ethyl] amino]ethyllphenyl]-4-[4-[4-(trifluoromethyl)phenyl]thiazol-2-=yl]benzenesulfonarnide. Appropriate daily amounts of the 03 agonist include 10mg, 25,mg, 50mg, 100mg, 125mg, 200mg, 250mg and 375mg. These beta 3 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.

For purposes of this specification, anti-musearinc agents included, but are not limited to tolterodine, oxybutynin, trospium, vaanicamide, solifenacin, propiverine, S-oxybutynin, temiverine, sanctura, staybla, fesoterodine, SVT40776, 202405 by GlaxoSmithKline, TD6301, RBX9841, DDP200, axad PLD179. See, for example, US
5,382,600;
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 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, solifenacin, propiverine, S-oxybutynin, temiverine, sanctura, staybla, fesoterodine, SVT40776, 202405 by GlaxoSnzathKlin.e, 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 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.
For purposes of this specification the 5-alpha reductase inhibitor includes, but is not limited to finasteride, dutasteride, turosteride and epristeride.

By the term "fnasteride" as used here is meant the compound as designated by 4-azaandrost-l-ene-17-carboxamide, N-(1,1-dirnethylethyl)-3-oxo-,(5 a,17B). FDA
approved doses for finasteride are 1 mg and 5mg, once a day.

By the term "dutasteride" as used herein is meant the compound as designated by (5 a, 17i3)-N-{2, 5 bis(trifluoromethyl)phen.yl}-3-oxo-4-azaandrost-l-ene-17-carboxamide. FDA
approved doses for f nasteride are 1 mg 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.

For purposes of this specification the alpha- adrenergic receptor antagonist is selected from amsulosin, terazosin, doxazosin, alfuzosin, indoramin and prazosin.

By the teri-n "amsulosin" (e.g. Flomax or tamsulosin hydrochloride) as used herein is meant the compound designated as (-)-(R)-5-[2-[[2-(O-ethoxyphenoxy)ethyl]amino]propyl]-2-methoxyben.zenesulf 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.
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.
By the term doxazosin as used herein is meant the compound 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-[(2,3-dihydro-l,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.
By the term "alfuzosin" (e.g. Uroxatral) as used herein is meant the compound N-[3-[(4-amino-6,7-dimethoxy-2-quinazolinyl)methylaznino]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.
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-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 wheii using any combination described herein, both the compound of the present invention and the other active agent(s) will be administered to a patient, within a reasonable period of time. The compowads may be in the same pharmaceutically acceptable carrier and therefore administered simultaneonsly. They may be in separate pharnnaceutical carriers such as conventional oral dosage fonns which are taken simultaneously.
The term "combination" also refers to the case where the compounds are provided in separate dosage fornas 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 second active component may be administered either as an oral dosage forzn such as a tablet or a fast-dissolving oral dosage form. By a "fast dissolving oral fonnulation" is meant, an oral delivery fornn 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 within one hour, the second active component should be administered, either in the same type of dosage fornn, or another dosage form which provides effective delivery of the medicaznent.
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 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.
In the treatrnent 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 adininistered in single or multiple doses. Preferably, 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 eveia 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 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 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 herein. All ~H NMR spectra were obtained on instrumentation at field strength of 400 or 500 MHz.

N O

F
O
3- 3aSR 4RS 7aSR -5- 3 5-bis trifluorometh 1 hen 1 ace 1-4- 4-fluoro hen 1 octah dro-2H
rrolo 3 4-c idin-2- 1 e clo ent-2-en-l-one Step A: N-[(1E)-(4-fluorophenyl)methyl ne]-1-[(trimethylsilyl)oxylethylenaminc F
N
is E~0--~

To a stirred solution of 41 mL(41 msnol, in hexanes) LHMDS in 60 rnL dry ether under nitrogen atmosphere at 0 C 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 mL, 41 mmol). After 5 min, cold bath was removed and the mixture was allowed to stirred at rt for 2.5 hr. Then, TMSCI (5.19 mL, 41 mrnol) was added to quench the reaction.
After 10 min, the mixture was filtered of1'the white solid through a cake of celite. The solution was removed all volatiles to give a yellow oil as the title compound.
'H NMR (CDC13, ppm): $ 7.82 - 7.88 (m, 2H), 7.14 (t, 21-1), 4.69 (s, 1 H), 4.34 (s, 1 H).

Step dinxethyl (2RS,3RS, 4SR)-2-(4-fluorophenyl)-6-oxopiperid'rne-3,4-dicarboxylate F

NH "O'CO2CH3 A solution of N-[(1E)-(4-fluorophenyl)methylene]-1-[(trixnethylsilyl)oxy]ethylenarn.ine (1.65 g, 6.95 mmol, step A) and dimethyl fizmarate (1.0 g, 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 3 5 mL of methanol. After stirring at rt for 10 min, the white suspension was filtered to give the title compound as a white solid.lV1S: 310 (M+1).

Step C: tert-butyl(2RS,3RS,4SR)-2-(4-fluorophenyl)-3,4Tbis(hydroxymethyl)piperidine-l-carboxylate F
( \
O ~
-O~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 0 C was added LiBH4 (6.6 mL, 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 HCl and stirred at rt for 21ir. Then v latiles were removed under vacuum. The residue was dried with toluene (3x) and was added 50 mL of THF and BH3-SMe2 (8.25 mL, 16.5 mmol, as a 2N solution in THF). The mixture was heated to reflux under N2 for 2 hr and was cooled to rt. Upon removal of volatiles, the residue 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)20 (0.72 g, 3.29 mmol) at rt. After 20 rnin, it was removed of volatiles and was worked up with EtOAc/NaHCOa/NaCI.
The organic phase was dried with NaZSO4 and was filtered. Upon removal of solvent, it was purified by Horizon MPLC using a gradient eluting system of 0-5% methanol in CH2CI.2 to afford the title compound. MS: 362 (M+Na).

Stet~ D: tert-butyl (3aSR,4RS,7aSR)-2-benzyl-4-(4Wfluorophenyl)octahydro-5H-pyrrolo [3,4-c]pyri dine-5-carboxylate F

0 / \
~-O--N
N
A solution of tert-butyl(2RS,3RS,4SR)-2-(4-fluorophenyl)-3,4--bis(hydroxymethyl)piperidine-1-carboxylate (0.38 g, 1.12 rrunol), DMAP (3.4 mg, 0.28 mmol), triethylamine (0.070 mL, 5.04 zmxa.oi) in 12 mL of CH202 was added MsC1(0.26 mL, 3.36 mmol) at 0 C. After 25 nn.in, the reaction was quenched with NaHCO3. The mixture was worked up with EtOAc/NaHCO3/NaC1. The organic phase was dried with Na2SO4 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 inmo1). The mixture was heated in a 102 C oil bath for 7 hrs.
It was worked up with EtOAc/NaOH/NaC1 and was dried with NaZSO4 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
NH3 in rnethanol- 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

N
A solution of tert-butyl (3aSR,4RS,7aSR)-2-benzyl-4-(4-fluorophenyl)octahydro-5FT pyrrolo[3,4-c]pyridine-5-carboxylate (0.20 g, 0.48 rnzn.ol) in 12 mL of 4 M HC1 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).

St~: (3aSR,4RS,7aSR)-2-benzyl-4-(4-flnorophenyl)octahydro-lH-pyrrolo[3,4-c]pyridine F
F
F F

F O
F ~
N
F

To a solution of (3aSR,4RS,7aSR)-2-benzyl-4-(4-fluorophenyl)octahydro-1H-pyrrolo[3,4-c]pyridine (62.8 mg, 0.056 mmol, intermediate step E) and DMAP (2 mg) and N-(3-dinmethylam.inopropyl)-N'-ethylcarbodiimide hydrochloride (21.2 mg, 0.11 mmol) and 3,5-bis(trifluorozxa.ethyl)-bez-zzeneacetic acid (30 mg, 0.11 mmol) in 3 mL of CH2CI7 was added N, N-diisopropylethylanaine (0.33 mmol, 0.058 mL) and the mixture was stiired at rt for 1 hr. Upon removal of volatiles, it was purified by reverse phase HPLC to give the title compouxzd. MS: 565 (M+1).

Step G: (3aS'R,4RS,7aSR)-5-~[3,5-bis(trifluoromethyl)phenyl)acetyl}-4-(4-fluorophenyl)octahydro-1 H-pyrrolo [3,4-c]pyridine F
F
F F

O
F N
F NH
F

a solution oi'(3aSR,4RS,7aS'R)-2-benzyl-4-(4-fluoz-ophenyl)octahydro-lH-pyrarolo[3,4-c]pyridin.e (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 reinoval of methanol. MS: 475 (M+1), St ep H: 3--[(3aSR,4RS,7a,SR)-5-~[3,5-bis(trifluoromethyl)phenyl]acetyl}-4-(4T
fluorophenyl)octahydro-2H pyrrolo[3,4-c]pyridan-2-yl]cyclopez,it-2-en-1-one / ( \ CF3 N O

F
O

A solution of (3aS'R,4RS,7aSR)-5-{[3,5-bis(trifluoromethyl)phenyl]acetyl}-4T(4-fluorophenyl)octahydro-lH-pyrrolo[3,4-c]pyridine (0.032 g, 0.054 man.ol), TsOH
monohydrate (2.7 mg) and 1,3-cyclopentanedione (8 mg, 0.082 mzxa.ol) in 3 mL of toluene was heated in 100 C oil bath for 3 hrs. Afi:er removal of volatiles, the residue was purified by reverse phase HPLC
to afford the title compound. MS: 555 (M+1).
EXAMPLE 2, EXAMPLE 3, and EXAMPLE 4 3-l(3aSR,4RS,7aSR)-5-12-[3,5-bis trifluoromethyl phenXljpropanoyI}-4(4-fluoro heig 1 octah dro-2H- rrolo 3 4-c idin-2- 1 c clo ent-2-en-l-one F
Q

/ I

~ CF3 N O
CI:''~~ F

3 W 3aSR 4RS 7aSR -5- 2- 3 5-bis trifluorometh 1 hen 1-2-meth 1 ro ano 1-4- 4-fluorohcLi 1 octah dro-2H rrolo 3 4-c ridin-2- 1 c c1o ent-2-en-l-one A solution of 3-[(3aSR,4RS,7aSR)-5-{[3,5-bis(trifluoronlethyl)phenyl]acetyll-4-(4-fluorophenyl)octahydro-2Hpyrrolo[3,4-c]pyridin-2-yl]cyclopent-2-en-l-one (27 rng, 0.049 mmol) in 2 mL of THF was added LHMDS (0.1.36 mmol, 0.136 mL in THF) at -78 C
and was stirred at -78 C for 10 inin. Then iodomethane (0.0095 mL, 0. 15 mmol) was added. After 30 rnin, the reaction was quei-iched with HOAc. Upon removal of volatiles, the title compounds were isolated by reverse phase HPLC. The first and third fractions as the monoalkylation products, MS: 568 (M+l). The second fraction as the dimethylation product, MS:
583 (M+1).
EXA.MPLE 5 N O

F
O~

CL

3-12-[(3aSR,4RS,7aSR)-5-1[3,5-bis(trifluoromethyl)phen lly 1ace . ityJ-4-(4-fluorophenyl)octahydro-2H pyrroloF3,4-c]pyridzn-2-yl1-2-oxoeth_yl}-1,3-oxazolidin-2-one The title compound was prepared from 3 aSR,4RS, 7aSR)-5 - ~ [3,5 -bis(trifluorornethyl)phenyllacetyl}-4-(4-fluorophenyl)octahydro-1H pyrrolo[3,4-c]pyridine and (2-oxo-l,3-oxazolidin-3-yl)acetic acid by the procedure in Example 1, step F.
MS: 602 (M+1).

N

N~O
N-=I /
F
O
(3aSR, 4RS, 7aSR)-1V-11-[3,5Tbis(trifluoromethyl phen 1~]ethyll-4-~4-fluorophenyl)-N-meth,r (3-oxocyclopent-l-en-1-yl octah_ydro-5H-py~TOlo[3,4-c]pyridine-5-carboxan~ide St~pe ,,,V,,, A: ~ 1-[3,5-bis(triflnorornethyl)phenyl]ethyl}methylcarbamac chloride N
CI'1~1, O

A solution of 1-[3,5-bis(trifluoromethyl)phenyl]-N-methylethan.amine (0.54 g, 1.99 mmol) in chloroform (18 mL) was added a solution of Cs2CO3 (3.90 g, 11.9 mmol) in 8 mL
of water. To this suspension at OoC was added a solution of phosgene (4.2 znL, 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 Na2SO4, filtered and concentrated to afford the title compound.
1 HNMR (CDC13, ppM): & 7.89 (s, 1H), 7.77 (s, 2H), 5.77-5.78 (m, 1H), 2.91 and 2.81 (s, 311).
1.72 and 1.70 (s, 314).

Step B: (3aSR,4RS,7aSR)-2-benzyl-.N-~ 1-[3,5-bis(trifluorarnethyl)phenyl]ethyl}-4-(4-fluorophenyl)-N-methylactahydro-5H-pyrrolo [3 ,4-c] pyridine- 5 -carboxan-iide N
No N--'~ F

A solution of 11J3,5-bis(trifluoromethyl)phenyl]ethyl}methylcarbanlic chloride (0.18 g, 0.53 nunal), DMAP (2 mg), N, N-diisopropylethylainine (0.23 mL, 1.34 mmol) and 3aSR,4RS,7aSR)-2-benzyl-4-(4-fluorophenyl)octahydra-1H pyrrolo[3,4-c]pyridii-ie (0.083 g, 0.27 mmol) in methylene chloride (10 rnL) 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+l).
St .e~C (3aSR, 4RS,7aSR)-N-{1-[3,5-bis(triflnorornethyl)phenyl]ethyl1 -4-(4-fluoraphenyl)-N-niethyloctahydro-5H-pyrrola[3,4-c]pyridine-5-carboxamide cF3 CF3 N
N"~o NH-~ F

The title compound was prepared from 3aSR,4RS,7aSR)-2-benzyl-N{1-[3,5-bis(trifluorornethyl)phenyl]ethyl}-4-(4-fluorophenyl)-N rnethyloctahydraT5H
pyrrolo[3,4-c]pyridine-5-carboxamide by the procedure in Example 1, step G. MS: 518 (M+1).

Step D: (3aSR,4RS,7aSR)-N {1-[3,5-bis(trifluoromethyl)phenyllethyl~-4-(4-fluorophenyl)-N methyl-2-(3-oxocyclopent-l-en-l-yl)octahydro-5H pyrrolo[3,4-c]pyridine-5-carboxamide N
NQ

F
O
The title compound was prepared from (3aSR,4RS,7aSR)-N-j1-[3,5-bis(trifluoromcthyl)phcnyl]ethyl}-4-(4-fluorophenyl)-11r methyloctahydro-5H
pyrrolo[3,4-c]pyridine-5-carboxarnide by the procedure in Example 1, step H. MS: 598 (M+1).

(3aSR,4RS,7aSR)-N- 1-f.3,5-bis(trifluorometllyl)phenylIet11y1~4-(4-fluorophenyl)-1~ meth r1-2-tetrah clro-2H- an-4- lcarbon 1 octah dro-5,11- nolo 3 4-c rid'zne-5-carboxamide 'N
NO

F
o The title compound was prepared from (3aSR,4RS,7aSR)-N-{1-[3,5-bis(trifluorometb.yl)phenyl]e-thyl}-4-(4-flnorophenyl)-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+I).

EXAMPLE 8 (L-001946286) O
c~ N ~N ~~ -3aS 4R 7-2-be . 1-N- 1R -1- 3 5-bis trifluorozneth 1 hen 1 eth 1-N-z-neth 1-4 methylplaoyl)octahydro-5H pyrroloL3,4-clp,~ridiiae-5-carboxarmide Step A: NN [(lE)-(2-methylphenyl)methylene]-1-[(trimethylsilyl)oxy]ethylenamine The title compound was prepared according to Example 1, step A.
'H NMR (CDC13, ppm): Fi 4.71 (s, IH), 4.35 (s, IH), 2.57 (s, 3H), 0.34 (s, 9H).

St~pe _Bw dimethyl (2RS,3RS,4SR)-2-(2-methylphenyl)-6-oxopiperidine-3,4-dicarboxylate ~ \
~
~~ .,CO2CH3 The title compound was prepared from N[(1L)-(2-methylphenyl)methylene]-1.-[(trimethyisilyl)oxy]ethylenamine azid dimethyl fumarate according to Example 1, step B. MS:
306 (M+ l).

Step C: tert-bntyl (2RS,3RS,4SR)-3,4-bis(hydroxymethyl)-2-(2-methylphenyl)piperidine-1-carboxylate O
~O~N OH
OH

The title compound was prepared from dimethyl (2RS,3RS,4SR)-2-(2-rza.ethylphenyl)-6-oxopiperidin.e-3,4-dicaxboxylate according to Exwnple 1, step C.
MS: 358 (M+Na).

Step D: tert-butyl (3aSR,4RS,7aSR)-2-benzyl-4-(2-methylphenyl)octahydro-5H=
pyrrolo[3,4-clpyridine-5-carboxylate )0X N\ -N
The title compound was prepared from tert-butyl (2RS,3RS,4SR)-3,4-bis(hyd.roxymethyl)-2-(2-methylphenyl)piperidine-l-carboxylate according to Example 1, step D.
MS: 407 (M+1).

Step E: (3aSR,4RS,7aSR)-2-benzyl-4-(2-methylphenyl)octahydro-lI-1-pyrrolo[3,4-c]pyridine NH ~
N
The title compound was prepared from tert-butyl (3aSR,4RS,7aSR)-2-benzyl-4-(2-methylphenyl)octahydro-SH-pyr.rolo[3,4-c]pyridine-5-carboxylate according to Example 1, step E. MS: 307 (M+I).

Step F: {(1R)-1-[3,5-bis(trifluorornethyl)phenyl]ethylI nlethylcarbainic chloride 'N' CIO
The title compound was prepared from (1R)-1-[3,5-bis(trifluoromethyl)phenyl]-N-methylethanan-iine according to Example 6, step A.

Step G: (3aS,4R,7aS)-2-benzyl-N- {(1R)-1-[3,5-bis(trifluoroam.ethyl)phenyl]ethyl~-.N-rnethyl-4-(2-methylphenyl)octahydro-5H-pyrrolo [3 ,4-e] pyridine- 5-carboxana.ide o CF
N N ~N -A solution of {(1R)-I-[3,5-bis(trifluoromethyl)phenyl]ethyl) methylcarbamic chloride (3.3 g, 9.9 mmol), DMAP (20 mg), N, N-diisopropylethylamine (2.1 inL, 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 inL) 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 hexanes to afford the title cornpowid as the fast fraction. MS: 604 (M+1).

I
o I \Nf!

3aS 4R 7-N 1R -1- 3 5-bis trifluorometh 1 hen 1 eth 1-N-meth 1-4- 2-meth 1 hen 1 octah dro-5H- rrolo 3 4-c idine-5-carboxamide The title compound was prepared from 3aS,4R,7aS)-2-benzyl-N {(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]-N methyl-4-(2-methylphenyl)octahydroW5H-pyrrolo[3,4-c]pyridine-5-carboxamide (Example 8, Step G) with the same method as in Example 1, step E.
MS: 514 (M+1).

CF3 \ CF3 N/
NO

(3 a~S,4R,7a,D-N-{(1 R)-l-j3,5-bis(trifluoramethyl)aheUI1 ethyl } -N-metlZyl-4-(2-meth.ylpheziyl)-2-(3-oxacyclopen.t-l-en-1-~)actahydra-SH-pMala[3,4-elpyrid'zne-5-caxboxan aide The title compaund was prepared from(3aS,4R,7aS')-N-{(1R)- 1- [3,5-bis(trifluoromethyl)phenyl]ethyl}-N-methyl-4-(2-zn.ethylpheny1)octahydra-SH
pyrrolo[3,4-e]pyyridine-5-carbaxamide (Example 9) with the same method as in Example 1, step E. MS: 594 (M+1)=

EXAMPLE 11 and EXAMPLE 12 CF3 CF'3 'N.

N -~--O
N-~
N}~2-~

3aS 4R 7-N'- 1R -1- 3 5-bis trifluororneth 1 hen 1 eth 1-N5-n-ieth 1-4- 2-meth 1 hen 1 tetrah dro-1H- rrolo 3 4-c idine-2 5 3H4 -dicarboxamide _33_ ( N
N~O

N-=I /
O-~
N
O
3aS 4R 7-N- 1R -1- 3 5-bis trifluororneth 1 hen i eth 1-N-meth 1-4- 2-zneth 1 hen 1-2-4-oxo-4 5-dih dro-1 3-oxazol-2- 1 octah dro-5H- rrolo 3 4-c idine-5-carboxamide A solution of (3aS,4R,7aS)-N=1 (1R)-1-(3,5-bis(trifluorpmethyl)phenyl]ethyl}-N-methyl-4-(2-methylphenyl)octahydro-5H pyrrolo[3,4-c]pyridine-5-carboxarnide (27 mg, 0.051 mmol) in methylene chloride (5 mL) was added chloroacetyl isocyanate (0.009 znL, 0,11 mmol) at rt. After 30 nain, 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 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.).

N.
N'~a N --~I /
O
fl 3aS4R 7-N 1R -1- 3 5-bis trifluorometh 1 hen 1 eth 1-Nmeth 1-4- 2-meth 1 hen 1-5-axo-2 5-dih drofuran-3- 1 octah dro-5H- rrola 3 4-c ridine-5-carboxamide A solution of (3a.S`,4R,7aS)-N {(1R)-1-[3,5-bis(trifluoromethyl)phenyl]cthyl) -N-methyl-4-(2-znethylphenyl)octahydro-5FI pyrrolo[3,4-c]pyridine-5-carboxamide (24 mg, 0.047 zntxiol) and tetronic acid (15 mg, 0.15 mmol) in 2-propanol (3 mL) was heated at reflux for 3 hrs.

Upon removal of volatiles. The residue was purified by reverse phase HPLC to give the title compound. MS: 596 (M+1).

'N.

N --'--3aS4R 7--N 1R -1- 3 5-bis trifluororneth 1 hen 1 eth 1-2-iso ro1-N-meth 1-4- 2 meth 1 hen 1 octah dro-5H rrolo 3 4-c rzdine-5-carboxamide A solution of (3aS,4R,7a.S)-N f(IR)-1-[3,5-bis(trifluaromethyl)phenyl]ethyl}-N
inethyl-4-(2-methylphenyl)actahydro-5H pyr.rolo[3,4-c]pyridine-5-carboxamide (20 mg, 0.039 nunol), acetone (0.011 mL, 0.15 m-inol) and NaB(OAc)3H 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).

EXAMPLE 15 and EXAMPLE 16 ~, N

N ~O
N-=

~Q

(3aS,4R,7at~)-2-(2-ainino-2-oxoethyl)-N-I(1R)-1-[3,5-bis(nifluoraznethyl)ullenylIeth, 1N
methyl-4=(2-meth ~lpheLiyl)oCtahydro-5H-pyrralo[3 ,4-c] pyridine-5Tcarboxamide 'N.
N --~-O
N----~

3aS 4R 7 -5- 1R -1- 3 5-bis trifluorometh 1 hen 1 eth 1 meth 1 amino carbon 1-meth 1 hen 1 octah dr -2H ol0 3 4-c din-2- 1 acetic acid A solution of (3 aS,4R,7aS)-N {(1R)-1-[3,5-bis(triflnoromethyl)phenyl] ethyl}-N-fnethyl-4-(2-rnethyllahenyl)octahydro-5H Pyrrolo[3,4-c]pyridine-5-carboxamide (25mg, 0.039 m.znol), chloroacetamide (9 mg, 0.097 mmol) and Cs2CO3 (33mg, 0.097 mmol) in 2 mL of dioxane was heated in a 100 C oil bath for 16 hrs. Upon removal of volatiles.
The residue was 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+1).

CF3 z ~
N --~-O

OH
3aS4R 7-N- 1R -1- 3 5-bis trifluorometh 1 hen 1 eth 1-2- 2-2-h drox ro an a 1-N-meth i-4- 2-meth 1 hen 1 octah dro-5H rrolo 3 4-c ridine-5Wcaz'boxamide 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]pyridineW5-carboxamide (Example 9) and (2S)-2-(acetyloxy)pxapanoic acid with the same method as in Example 1, step F.

MS: 586 (M+l).

EXAMI'LE 18 N

N~o O

(3aS,4R,7an-2-ace ,tYl-N {(1R)-l- 3,5-bis trifluoromethyl)uhenyl]ethyl} -N-methyl-4-(2-rnethylphenyl)octahydro-5H-uyrrolo f 3,4-c]pyridine-5-carboxamzde The title compound was prepared from(3aS,4R,7aS)-N-{(1R)-1-[3,5-bis(trifluorornethyl)phenyl]ethyl]-N-methyl-4-(2-methylphenyl)octahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxatnide (Example 9) with the same method as in Example l, step F. MS; 556 (M+1).

EXA.MPLE 19 NNa N

3aS 4R 7-N 1R -l- 3 5--bis trifluorometh 1 hen 1 eth 1-.11T aneth 1-2- 1-meth oxa i erzdin-3- 1 carborz 1-4- 2-meth 1 hen 1 octah dro-5H- rrolo 3 4-c ridine-carboxarnide 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_ clpyridine-5-carboxanaide (Example 9) and 1-methyl-6-oxopiperidine-3-carboxylic acid with the same method as in Example 1, step F. MS: 653 (M+1).

N
NO
O

N
~ -NH2 O

3aS 4R 7 -2- 1-faminocarboLiyl)piperidin-4-yllcarboUl.1-N-.tf 1R -1- 3 5-bis trifluorameth 1 hen 1 eth 1-N metb 1-4- 2-meth 1 hen 1 octah dro-5H- rrolo cl pyridin.e-5-carboxamide The title compound was prepared from(3aS,4R,7aS')-N f (1R)-1-[3,5-bis(triflnororn.ethyl)phenyl]ethylI -N-methyl-4-(2-rnethylphenyl)octahydro-5H
pyrrolo[3,4-c]pyridine-5-carboxamide (Example 9) and 1-(aminocarbonyl)piperidineW4-carboxylic acid with the same method as in Example 1, step F. MS: 668 (M+1).

N

Na a 3aS4R 7-N- i.R -1- 3 5-bis trifluorometh 1 b.en 1 eth 1-N-meth 1-4- 2-m.eth 1 hen 1-2-tetrah dro-2H- ran-4- i octah dro-5H rrolo 34-c idine-5-carboxamide The title compound was prepared 1'rona.(3aS,4R,7aS)-N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyllethyl } -N-methyl-4-(2-methylphenyl )octahydra-5H-pyrrolo [3,4-c]pyridine-5-carboxamide (Example 9) with the same method as in Example 14.
MS: 598 (M+1).

N-'~'d N
O~

3aS4R 7 -2- 1-ace 1 i eridin-4- I-N- lR -1- 3 5Tbis trifluorometh 1hen 1 eth 1-.N
meth 1-4- 2-meth I hen 1 octah dro-5H o10 3 4-c ridine-5-ca.rboxamide The title compowld was prepared from(3aS,4R,7aS)-1V {(1R)- 1- [3,5-bis(trifluoromethyl)phenyl]ethylI -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+1).

CF3 \ CF3 N~ /

O
OH

3aS4R 7-N 1 R -1- 3 5-bis trifluorometh 1 hen 1 eth -2- 1- 3-h drox -2 2-dimeth 1 ro 1 i eridin-4- 1-N-rneLb 1-4- 2-meth 1 hen 1 octah dro-5H oIo 3 4 clpvridine-5-caxbox.amide St~A: tert-butyl (3aSR,4RS,7aSR)-2-(3-hydroxy-2,2-dimethylpropyl)-4-(2-rnethylphenyl)octahydro-5H-pyrrolo [3,4-c]pyrxdine-5-carboxylate o oH
,)-0 The title compound was prepared from tert-butyl (2RS',3RS,4SR)-3,4-bis(hydroxymethyl)-2-(2-rnethylphenyl)piperidine-l-carboxylate according to Example 1, step D.
MS: 403 (M+l).

St~B tert-butyl (3aSR,4RS,7aSR)-2-[3-(acetyloxy)-2,2-dimethylpropyl]-4-(2-methylphenyl)octahydro-5H pyrrolo[3,4-c]pyridine-5-carboxylate ~-~
0 ~ Q
)-0 ~ o ~1 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-caz'boxylate (84 mg, 0.21 mmol), Ae20 (0.104 rnL, 1.05 mmol) and DAMP (2 mg) in 5 mL of pyridine was stirred at rt for 1 hr. Upon removal of volatiles, the crude was purified by preparative TLC (MeOH/CH?,CI2 = 5:95) to afford the title compound. MS: 445 (M+l).

Step C: 3-[(3aS,4R,7aS)-5-{[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl ~ (methyl)amino] carbonyl} -4-(2-methylphenyl)octahydro-2H pyrrolo[3,4-c]pyridin-2-yl]-2,2-dirnethylpropyl acetate o4 F F o 0 F I N ~ N
F ~
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-carboxylate according to and Eample 1, step E and Example 8, step G. MS: 642 (M+1).

Step D: tert-butyl (3aS,4R,7aS)-2-(3-hydroxy-2,2-dzmethylpropyl)-4-(2-methylphenyl)octahydro-5H-pyrro lo[3,4-c]pyridine-5-carboxylate A solution of 3-[(3aS,4R,7a.S`)-5-1[{(1R)-1-[3,5-bis(trifluoromethyl) 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+l).

N

O

3aS 4R 7-2- 1- 3-amino-2 2-dimeth 1-3-oxo ro l i eridin-4- 1-N 1R -1- 3 5-bis trifluorometh 1 hen 1 eth 1-N-meth 1-4- 2-meth 1 hen 1 octah dro-5H zTolo capyridine-5--carboxamide The title compound was prepared from tert-butyl (2RS,3RS,4SR)-3,4-bis(hydroxymethyl)-2-(2-methylphenyl)piperidine-l-carboxylate and 3-amino-2,2-dimethylpropanaznide according to steps in Example 8. MS: 613 (M+I).

(3aS,4R,7a.S;)-2-benzyl-N ((1R)-1-G3,5-bis(trifluoronaethjl)pheUl, ethI}-4T(4-fluoro-2-methylphenyl -N-methyloctahydro-5H-prolo[3,4-elpyridine-5-carboxamide F
o CF
N~N ~N -The title compound was prepared according to steps in Example 8. MS: 622 (M+l ).

3aS 4R 7 -N 1R -1- 3 5-bis trifluorormeth 1 hen 1 eth 1-4- 4-fluoro-2-rneth 1 hen 1-N-meth loctah dro-5H- rolo 3 4-c idine-5-carboxamide F
o C3 NN ~
NFi The title compound was prepared from (3aS,4R,7aS)-2-benzyl-N {(lR)-1-[3,5-bi s(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).

Nl-~, O

N--'~ F
O

3aS 4R 7-N- 1R -1- 3 5-bis trifluorometh 1 hen 1 eth 1-4- 4-fluora-2-meth 1 hen I TN
rneth 1-2- 3-oxoc cla ent-l-en-1- 1 actah dro-SH- rrolo 3 4-c ridine-5-carboxamide The title compound was prepared from (3aS,4R,7aS)-1V {(1R)-1-[3,5-bis(trifluoromethyl)phenyl] ethyl I -4 W (4-fluoro-2-methylphenyl)-N-rnethyloctahydro- 5H-pyrrolo[3,4-c]pyridine-5-carboxamide with the same method as in Example 1, step H. MS: 612 (M+ 1).

N

NO
N---' F
N

O
(3aS,4R,7a@-N {..(1R)-l-[3,5-bis(trifluoraxn.ethyl)nen~lethyX-4-(4-fluc~ra-2-meth ly phenyX)-N
meth,yl-2-(4-oxo-4,5-dihydro-143-oxazal-2-yl octahydra-5H-pyrrolo[3,4-c].pyridine-5-carboxamide The title compound was prepared with the same procedure as Example 12. MS:
615 (M+1).

N

NO
N-~ F

O
3aS 4R 7-N- 1R -1- 3 5-bis trifluorometh 1 hen 1 eth 1-4- 4-fluoro-2-meth 1 hen 1-N-meth 1-2- 5-oxo-2 5-dih drof-uran-3- 1 octah dro-5H rrolo 3 4-~c idine-5-carboxamide The title compound was prepared from (3aS,4R,7aS)-N-I(1R)-l-[3,5-bis(trifluoromethyl)phenyl] ethyl) -4-(4-fluoro-2-rnethylphenyl)-N
rnethyloctahydro-5H-pyrrolo[3,4-c]pyridzne-5-carboxatnide with the same method as in Example 13.
MS: 614 (M+1).

~, N
NO

H

3aS4R 7-N- 1R -1- 3 5-bis triflnorometh 1 hen 1 eth 1-4- 4-fluoro-2-meth 1 hen 2-2-h drox ra ano l-N meth loctah dro-5H- ola 3 4-c idine-5-carboxamide The title compound was prepared from (3aS,4R,7axS')-N-{(1R)-1-[3,5-bis(triflnoromethyl)phenyl] ethyl) -4-(4-fluoro-2-methylphenyl)-N methyl octahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxamide with the same method as in Example 1, step F. MS: 604 (M+l).

_44..

N

NO
N--0~', OH

(3 aS,4R, 7aS)-N- {(1R)-1- f3,5 -bis(trifluoromethyl)phen~llethyll-4-(4 Wfluoro-2-met.liyll2herayl)-2-2R -2-h drox ro ano l-N-meth loctah dro-5H rrolo 3 4Wc xxdine-5-carboxamide The title compound was prepared from (3aS,4R,7aS)-N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyt]ethyl}-4-(4-fluoro-2-methylphenyl)-N
methyloctahydro-51-1-pyrrolo[3,4-c]pyridine-5-carboxamxde with the same method as in Example 1, step F. MS: 604 (M+1).

F F
F F
F F
~N

N-~-O

F
o=~

(3a.S',4R,7aq-2-acetyZ-N-f (1R)-1- 3,5-bis~trifluoromethyl)pheUljqhy1l-4-(4-fl.uoro-2-nra ethylpheUl)-N-meLhyloctahydro-SH-tayr.rolo[3 24-cjayridxne-5-carboxamxde The title compound was prepared from (3aS,4R,7aS)-N-{(1R)-1-[3,5-bis(trzfluorometiryl)phenyl]etb.yi}-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:574 (M+1).

F F
F
F
F
F
'N

No F

3aS 4R 7-N 1R -1- 3 S-bis trifluorometh 1 hen 1 eth I-2- 2 2-dianeth 1 ro ano fluoro-2-meth 1 hen 1-N-meth loctah dro-5H- ol0 3 4-c idine-5-carboxam.ide The title compound was prepared from (3aS,4R,7aS)-N f(1R)-1-[3,S-bis(trifluorornethyl)phenyl] ethyl } -4-(4-fluoro-2-methylphenyl)-N-methyloctahydro-5H-pyrrolo[3,4-c]pyridine-5-carboxana.ide with the same method as in Example 1, step F. MS 616 (M+1).

F F
F F
F F
N

N-~-O

F

O
3aS4R 7-N- 1R -1- 3 STbis trifluorometh 1 hen 1 eth i-4- 4-fluoro-2-meth 1 hen meth 1-2- tetrah dro-2H ran-4- lcarbon 1 octah dro-SH- ol0 3 4-c ridine-S-carboxamide The title compound was prepared from (3aS,4R,7aS)-N {(1R)-1-[3,5-bi,s(trifluoromethyl)phenyl]ethylI -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: 644 (M+1)=

F F
F
F

N
N -~-O

F

3aS 4R 7-N 1R -1- 3 5-bis trifluorometh 1 hen 1 eth 1-4- 4-fluoro-2-meth 1 hen meth I-2- tetrah dro-2H ran-4- I octah dro-5I-f- 010 3 4-c 'rdine-5-carboxamide The title compound was prepared from (3aS,4R,7aS)-N-{(1R)-l-[3,5-bis(trifluoromethyl)phenyl] ethyl } -4-(4-fluoro-2-methylphenyl)-N-methyloctahydro-5H-pyrrolo[3,4-clpyridine-5-carboxamide with the same method as in Example 14.
MS: 616 (M+1).

F F
F
F

1~ N
Na N-~ F
N
O:-, (3aS,4R,7aS)-2-(1-acetylpiperidin.-4-yl)-N f(1R)-I-j3 5-bis trifluoromethyl)phenyl ethyl}-4-(4-fluoro-2Tmethylphenyl)-N-metl loctahydro-5.H-pyrrolo[3,4-c]pyridine-5-carboxamide The title compound was prepared from (3aS,4R,7aS)-1V {(1R)-1-[3,5-bis(trifluoromethyi)phenyl] ethyl } -4-(4--fluaro-2-methylphenyl)-N-methyloctahydro-5H
pyrroio[3,4-c]pyridine-5-carboxamide with the same method as in Example 14.
MS: 658 (M+1).

While the inventzon 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 consequence of variations in responsiveness of the mammal being treated for any of the indications with the compounds of the invention indicated above.

Claims (18)

1. A compound of the formula I:
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, (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, (6) -(CO)-NHC1-6alkyl, (7) -(CO)-N(C1-6alkyl)(C1-6alkyl), (8) -C1-4alkyl-(CO)-NH2, (9) -C1-4alkyl-(CO)-NHC1-6alkyl, (10)-C1-4alkyl-(CO)-N(C1-6alkyl)(C1-6alkyl), (11) -(CO)-O-C1-6alkyl, (12) -(CO)-C3-6cycloalkyl, (14) -(CO)-HET, wherein HET is selected from the group consisting of Wherein Ra is selected from H, and C1-3alkyl and Rb is selected from H, C1-4alkyl, -(CO)-CH3 and -(CO)-NH2, R2, R3, R4 and R5 are each independently selected from the group consisting of:
(1) hydrogen, and (2) methyl;
R6 is independently selected from the group consisting of:
(1) hydrogen, and (2) fluorine.

2. The compound of Claim l of the formula Ia:
wherein R1, R2, R3, R4, R5, R6, and X are defined herein, or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof.

3. A compound according to Claim 1 wherein R1 is selected from the group consisting of R1 is selected from the group consisting of:
(1) hydrogen, (2) C1-3alkyl, 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, (5) -(CO)-NH2, (6) -(CO)-NHC1-3alkyl, (7) -(CO)-N(C1-3alkyl)(C1-3alkyl), and wherein the alkyl portion of choices (4),(6) and (7) of R1 are optionally substituted with halo, hydroxyl or phenyl.

4. The compound of Claim 1 wherein R1 is selected from the group consisting of:
(1) hydrogen, (2) cyclopent-2-en-1-one, (3) 1,2-oxazol-4(5H)-one, (4) 2,2-dimethylpropanoyl, (5) methylpropanoyl, (6) CH3NH-(CO)-, (7) (CH3)2-N-(CO)-, and

5. The compound of Claim 1 wherein R6 is hydrogen.

6. The compound of Claim 1 wherein R6 is fluorine.

7. The compound of Claim 1 wherein R5 is hydrogen.

8. The compound of Claim 1 wherein R5 is methyl.

9. The compound of Claim 1 wherein X is N.

10. The compound of Claim 1 of the formula Ia:
or a pharmaceutically acceptable salt thereof and individual enantiomers and diastereomers thereof wherein X is N or CH, R1 is selected from the group consisting of:
(1) hydrogen, (2) cyclopent-2-en-1-one, (3) 1,2-oxazol-4(5H)-one, (4) 2,2-dimethylpropanoyl, (5) methylpropanoyl, (6) CH3NH-(CO)-, (7) (CH3)2-N-(CO)-, and R6 is independently selected from the group consisting of:
(1) hydrogen, and (2) fluorine;
R5 is independently selected from the group consisting of:
(1) hydrogen, and (2) methyl.

11. A cornpotund according to claim 10 wherein X is N.

12. A compound which is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof

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

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

16. A method of antagonizing the effect of substance P at its receptor site or for the blockade of neurokinin-1 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 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 1 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 or a pharmaceutically acceptable salt thereof with a pharmaceutical carrier or diluent.