WO2004064764A2 - Substituted alkyl amido piperidines - Google Patents

Substituted alkyl amido piperidines Download PDF

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Publication number
WO2004064764A2
WO2004064764A2 PCT/US2004/000175 US2004000175W WO2004064764A2 WO 2004064764 A2 WO2004064764 A2 WO 2004064764A2 US 2004000175 W US2004000175 W US 2004000175W WO 2004064764 A2 WO2004064764 A2 WO 2004064764A2
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WO
WIPO (PCT)
Prior art keywords
compound
piperidinyl
phenyl
alkyl
branched
Prior art date
Application number
PCT/US2004/000175
Other languages
French (fr)
Other versions
WO2004064764A3 (en
Inventor
Mohammad R. Marzabadi
John M. Wetzel
Chien-An Chen
Yu Jiang
Kai Lu
Original Assignee
H. Lundbeck A/S
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to US10/541,991 priority Critical patent/US20060217418A1/en
Priority to EP04700366A priority patent/EP1590326A4/en
Priority to AU2004206794A priority patent/AU2004206794A1/en
Priority to EA200501122A priority patent/EA009818B1/en
Application filed by H. Lundbeck A/S filed Critical H. Lundbeck A/S
Priority to MXPA05006956A priority patent/MXPA05006956A/en
Priority to BR0406725-8A priority patent/BRPI0406725A/en
Priority to NZ540366A priority patent/NZ540366A/en
Priority to JP2006500796A priority patent/JP2006515618A/en
Priority to CA002509456A priority patent/CA2509456A1/en
Priority to UAA200506356A priority patent/UA79659C2/en
Publication of WO2004064764A2 publication Critical patent/WO2004064764A2/en
Publication of WO2004064764A3 publication Critical patent/WO2004064764A3/en
Priority to IS7860A priority patent/IS7860A/en
Priority to IL169637A priority patent/IL169637A0/en
Priority to NO20053838A priority patent/NO20053838L/en

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Definitions

  • MCH Melanin-concentrating hormone
  • MCH has been reported to participate in a variety of processes including feeding, water balance, energy metabolism, general arousal/attention state, memory and cognitive functions, and psychiatric disorders (for reviews, see Baker, 1991; Baker, 1994; Nahon, 1994; Knigge et al., 1996). Its role in feeding or body weight regulation is supported by a recent Nature publication (Qu et al., 1996) demonstrating that MCH is overexpressed in the hypothalamus of ob/ob mice compared with ob/+ mice, and that fasting further increased MCH mRNA in both obese and normal mice during fasting. MCH also stimulated feeding in normal rats when injected into the lateral ventricles (Rossi et al., 1997).
  • MCH also has been reported to functionally antagonize the behavioral effects of ⁇ -MSH (Miller et al., 1993; Gonzalez et al, 1996; Sanchez et al., 1997); in addition, stress has been shown to increase POMC mRNA levels while decreasing the MCH precursor preproMCH (ppMCH) mRNA levels (Presse et al., 1992).
  • MCH may serve as an integrative neuropeptide involved in the reaction to stress, as well as in the regulation of feeding and sexual activity (Baker, 1991 ; Knigge et al., 1996).
  • MCH tritiated ligand
  • Radioiodination of the tyrosine at position thirteen resulted in a ligand with dramatically reduced biological activity (see Drozdz and Eberle, 1995).
  • the radioiodination of the MCH analogue [Phe 13 ,Tyr 19 ]-MCH was successful (Drozdz et al., 1995); the ligand retained biological activity and exhibited specific binding to a variety of cell lines including mouse melanoma (B16-F1, G4F, and G4F-7), PC12, and COS cells.
  • the K D the K D
  • MCH methylcellulose
  • lateral hypothalamus a brain area implicated in the regulation of thirst and hunger (Grillon et al., 1997); recently orexins A and B, which are potent orexigenic agents, have been shown to have very similar localization to MCH in the lateral hypothalamus (Sakurai et al., 1998).
  • MCH mRNA levels in this brain region are increased in rats after 24 hours of food-deprivation (Herve and Fellman, 1997); after insulin injection, a significant increase in the abundance and staining intensity of MCH immunoreactive perikarya and fibres was observed concurrent with a significant increase in the level of MCH mRNA (Bahjaoui-Bouhaddi et al., 1994).
  • MCH melanocortin
  • the MCH cell group occupies a rather constant location in those areas of the lateral hypothalamus and subthalamus where they lie and may be a part of some of the so-called "extrapyramidal" motor circuits. These involve substantial striato- and pallidofugal pathways involving the thalamus and cerebral cortex, hypothalamic areas, and reciprocal connections to subthalamic nucleus, substantia nigra, and mid-brain centers (Bittencourt et al., 1992). In their location, the MCH cell group may offer a bridge or mechanism for expressing hypothalamic visceral activity with appropriate and coordinated motor activity. Clinically it may be of some value to consider the involvement of this MCH system in movement disorders, such as Parkinson's disease and Huntingdon's Chorea in which extrapyramidal circuits are known to be involved.
  • Locus 12q23-24 coincides with a locus to which autosomal dominant cerebellar ataxia type II (SCA2) has been mapped (Auburger et al., 1992; Twells et al., 1992).
  • SCA2 autosomal dominant cerebellar ataxia type II
  • This disease comprises neurodegenerative disorders, including an olivopontocerebellar atrophy.
  • the gene for Darier's disease has been mapped to locus 12q23-24 (Craddock et al., 1993).
  • Darier's disease is characterized by abnormalities I keratinocyte adhesion and mental illnesses in some families.
  • the MCH gene may represent a good candidate for SCA2 or Darier's disease.
  • diseases with high social impact have been mapped to this locus.
  • the gene responsible for chronic or acute forms of spinal muscular atrophies has been assigned to chromosome 5q12-13 using genetic linkage analysis (Melki et al., 1990; Westbrook et al., 1992).
  • MCH may regulate reproductive functions in male and female rats.
  • MCH transcripts and MCH peptide were found within germ cells in testes of adult rats, suggesting that MCH may participate in stem cell renewal and/or differentiation of early spermatocytes (Hervieu et al., 1996).
  • MCH injected directly into the medial preoptic area (MPOA) or ventromedial nucleus (VMN) stimulated sexual activity in female rats (Gonzalez et al., 1996).
  • MCH stimulated luteinizing hormone
  • anti-MCH antiserum inhibited LH release
  • the zona incerta which contains a large population of MCH cell bodies, has previously been identified as a regulatory site for the pre-ovulatory LH surge (MacKenzie et al., 1984).
  • MCH has been reported to influence release of pituitary hormones including ACTH and oxytocin.
  • MCH analogues may also be useful in treating epilepsy.
  • MCH has also been observed to affect behavioral correlates of cognitive functions. MCH treatment hastened extinction of the passive avoidance response in rats (McBride et al., 1994), raising the possibility that MCH receptor antagonists may be beneficial for memory storage and/or retention. A possible role for MCH in the modulation or perception of pain is supported by the dense innervation of the periaqueductal grey (PAG) by MCH-positive fibers. Finally, MCH may participate in the regulation of fluid intake.
  • PAG periaqueductal grey
  • MCH may be an important peptide involved in the central control of fluid homeostasis in mammals.
  • MCH-1 G-protein coupled receptor
  • MCH-1 knockout mice Two groups have shown independently (Marsh et al, 2002; Chen et al, 2002) that the targeted disruption of the MCH-1 receptor gene (MCH-1 knockout) in mice results in animals that are hyperphagic but are lean and have decreased body mass relative to wild-type littermates. The decrease in body mass is attributed to an increase in metabolism. Each group demonstrated that the MCH-1 knockout mice are resistant to diet-induced obesity, and generally exhibit weights similar to littermates maintained on regular chow.
  • MCH1 antagonists are useful to treat obesity, depression, anxiety, as well as urinary disorders.
  • the term "antagonist” refers to a compound which binds to, and decreases the activity of, a receptor in the presence of an agonist.
  • activation may be measured using any appropriate second messenger system which is coupled to the receptor in a cell or tissue in which the receptor is expressed.
  • second messenger systems are adenylate cyclase, intracellular calcium mobilization, ion channel activation, guanylate cyclase and inositol phospholipid hydrolysis.
  • agonist refers to a compound which binds to, and increases activity of, a receptor as compared with the activity of the receptor in the absence of any agonist.
  • the synthesis of novel compounds which bind selectively to the cloned human melanin-concentrating hormone-1 (MCH1) receptor, compared to other cloned G-protein coupled receptors, and inhibit the activation of the cloned receptors as measured in in vitro assays is disclosed.
  • the in vitro receptor binding assays described hereinafter were performed using various cultured cell lines, each transfected with and expressing only a single cloned receptor.
  • the compounds of the present invention may also be used to treat abnormal conditions such as feeding disorders (obesity, bulimia and bulimia nervosa), sexual/reproductive disorders, depression, anxiety, depression and anxiety, epileptic seizure, hypertension, cerebral hemorrhage, congestive heart failure, sleep disturbances, or any condition in which antagonism of an MCH1 receptor may be beneficial.
  • feeding disorders ovalbumina, bulimia and bulimia nervosa
  • sexual/reproductive disorders depression, anxiety, depression and anxiety
  • epileptic seizure hypertension
  • cerebral hemorrhage congestive heart failure
  • sleep disturbances sleep disturbances
  • the compounds of the present invention may be used to reduce the body mass of a subject.
  • the compounds of the present invention may be used to treat urinary disorders.
  • the present invention provides a compound having the structure:
  • each R ⁇ is independently hydrogen; -F; -Cl; -Br; -I; -CN; -NO 2; straight chained or branched C C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl; C3-C7 cycloalkyl or C 5 -C 7 cycloalkenyl; aryl; heteroaryl; -N(R 5 ) 2 ; -(CH 2 ) m OR 5 ; -COR 5 ; -CO 2 R 5 ; -OCOR 5 ; -CON(R 5 ) 2 ; -N(R 5 )COR 5 ; -N(R 5 )CON(R 5 )2; -OCON(R 5 ) 2 or -N(R 5 )CO 2 R 5 ;
  • R 2 is hydrogen; -F; -Cl; -Br; -I; -CN; -(CH 2 ) m OR 5 ; -(CH 2 ) m SR 5 ; -NH 2 ; straight chained or branched C C 7 alkyl, monofluoroalkyl, polyfluoroalkyl; aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more R ⁇
  • R 3 is hydrogen; -F; -Cl; -Br; -I; -CN; -(CH 2 ) m OR 5 ; -(CH 2 ) m SR5; straight chained or branched C C 7 alkyl, monofluoroalkyl, polyfluoroalkyl; aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more Ri; or wherein R 2 and R 3 together can be - (CH 2 ) P -;
  • R 4 is straight chained or branched C C 7 alkyl, monofluoroalkyl or polyfluoroalkyl, C 3 - C 6 cycloalkyl, , C C 7 alkyl - C 3 -C 6 cycloalkyl; -N(R 5 ) 2 or -(CH 2 ) m OR 5 ;
  • each R 5 is independently hydrogen; aryl; heteroaryl or straight chained or branched C 1 -C 7 alkyl, wherein the alkyl may be substituted with an aryl or heteroaryl;
  • each R 6 is independently hydrogen; straight chained or branched C C 7 alkyl;
  • each R 7 is independently hydrogen; phenyl or straight chained or branched C C 7 alkyl, wherein the alkyl may be substituted with a phenyl;
  • each m is independently an integer from 0 to 5 inclusive;
  • n is an integer from 1 to 5 inclusive
  • each X is independently CRi or N, provided that if one X is N then the remaining X are CR ⁇ or a pharmaceutically acceptable salt thereof.
  • the compound is selected from one of the specific compounds disclosed in the Detailed Description of the Invention.
  • the compound is enantiomercially pure. In another embodiment of the invention, the compound is diastereomerically pure. In a further embodiment, the compound is enantiomercially and diastereomerically pure.
  • the present invention further provides a pharmaceutical composition that comprises a therapeutically effective amount of a compound of the present invention and a pharmaceutically acceptable carrier.
  • the present invention further provides a pharmaceutical composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
  • the present invention also provides a process for making a pharmaceutical composition comprising admixing a compound of the present invention and a pharmaceutically acceptable carrier.
  • the invention further provides a method of treating a subject suffering from an affective disorder selected from the group consisting of depression, major depression, bipolar disorder, agoraphobia, specific phobia, social phobia, obsessive-compulsive disorder, post- traumatic stress disorder, acute stress disorder and anxiety comprising administering to the subject a therapeutically effective amount of the compound of the invention.
  • an affective disorder selected from the group consisting of depression, major depression, bipolar disorder, agoraphobia, specific phobia, social phobia, obsessive-compulsive disorder, post- traumatic stress disorder, acute stress disorder and anxiety comprising administering to the subject a therapeutically effective amount of the compound of the invention.
  • the disorder is depression or anxiety.
  • the invention further provides a method of treating a subject suffering from a urinary disorder selected from the group consisting of urinary incontinence, urge incontinence, urinary frequency, urinary urgency, nocturia or enuresis comprising administering to the subject a therapeutically effective amount of the compound of the invention.
  • a urinary disorder selected from the group consisting of urinary incontinence, urge incontinence, urinary frequency, urinary urgency, nocturia or enuresis comprising administering to the subject a therapeutically effective amount of the compound of the invention.
  • the disorder is urinary incontinence.
  • the invention further provides a method of treating a subject suffering from an eating disorder selected from the group consisting of obesity, bulimia, bulimia nervosa or anorexia nervosa comprising administering to the subject a therapeutically effective amount of the compound of the invention.
  • the disorder is obesity.
  • heteroaryl is used to include five and six membered unsaturated rings that may contain one or more oxygen, sulfur, or nitrogen atoms.
  • heteroaryl groups include, but are not limited to, carbazole, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl.
  • heteroaryl is used to include fused bicyclic ring systems that may contain one or more heteroatoms such as oxygen, sulfur and nitrogen.
  • heteroaryl groups include, but are not limited to, indolizinyl, indolyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzimidazolyl, purinyl, benzoxazolyl, benzisoxazolyl, benzo[b]thiazolyl, imidazo[2,1-b]thiazolyl, cinnolinyl, quinazolinyl, quinoxalinyl, 1 ,8- naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, phthalimidyl and 2,1 ,3-benzothiazolyl.
  • heteroaryl also includes those chemical moieties recited above which may be substituted with one or more of the following: -F, -Cl, -Br, -I, CN, -NO 2 , straight chained or branched C C 7 alkyl, straight chained or branched C 1 -C7 monofluoroalkyl, straight chained or branched C C 7 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 7 alkynyl; C 3 -C 7 cycloalkyl, C 3 -C 7 monofluorocycloalkyl, C 3 -C 7 polyfluorocycloalkyl, C 5 -C 7 cycloalkenyl.
  • heteroaryl further includes the N-oxides of those chemical moieties recited above which include at least one nitrogen atom.
  • aryl is phenyl or naphthyl.
  • straight chained or branched C C alkyl refers to a saturated hydrocarbon having from one to seven carbon atoms inclusive, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methly-2-propyl and 2-methly-1 -propyl.
  • alkenyl and alkynyl respectively, designate such groups having from two to seven carbon atoms, including one double bond and triple bond respectively, such as ethenyl, propenyl, butenyl, ethynyl, propynyl, and butynyl.
  • C 3 -C 7 cycloalkyl designates a monocyclic carbocycle having three to seven carbon atoms, such as cyclopropyl, cyclopentyl, cyclohexyl, etc.
  • C C 7 alkyl-C 3 -C 6 cycloalkyl designates a saturated alkyl hydrocarbon substituted with a monocyclic carbocycle ring having three to seven carbon atoms attached via the C r C alkyl moiety, such as methyl-cyclopropyl, ethyl-cyclopentyl, n-propyl-cyclohexyl, etc.
  • stereoisomers may include enantiomers, diastereomers, or E or Z alkene or imine isomers.
  • the invention also provides for stereoisomeric mixtures, including racemic mixtures, diastereomeric mixtures, or E/Z isomeric mixtures.
  • Stereoisomers can be synthesized in pure form (N ⁇ gradi, M.; Stereoselective Synthesis. (1987) VCH Editor Ebel, H.
  • the compounds of the present invention are preferably 80% pure, more preferably 90% pure, and most preferably 95% pure. Included in this invention are pharmaceutically acceptable salts and complexes of all of the compounds described herein.
  • the acids and bases from which these salts are prepared include but are not limited to the acids and bases listed herein.
  • the acids include, but are not limited to, the following inorganic acids: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and boric acid.
  • the acids include, but are not limited to, the following organic acids: acetic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, maleic acid, citric acid, methanesulfonic acid, benzoic acid, glycolic acid, lactic acid and mandelic acid.
  • the bases include, but are not limited to ammonia, methylamine, ethylamine, propylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, ethylenediamine, hydroxyethylamine, morpholine, piperazine and guanidine.
  • This invention further provides for the hydrates and poiymorphs of all of the compounds described herein.
  • the present invention includes within its scope prodrugs of the compounds of the invention.
  • prodrugs will be functional derivatives of the compounds of the invention which are readily convertible in vivo into the required compound.
  • the term "administering" shall encompass the treatment of the various conditions described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.
  • the present invention further includes metabolites of the compounds of the present invention. Metabolites include active species produced upon introduction of compounds of this invention into the biological milieu.
  • This invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the compound of the invention and a pharmaceutically acceptable carrier.
  • the amount of the compound is from about 0.01 mg to about 800 mg. In another embodiment, the amount of the compound is from about 0.01 mg to about 500 mg. In yet another embodiment, the amount of the compound is from about 0.1 mg to about 250 mg. In another embodiment, the amount of the compound is from about 0.1 mg to about 60 mg. In yet another embodiment, the amount of the compound is from about 1 mg to about 20 mg.
  • the carrier is a liquid and the composition is a solution. In another embodiment, the carrier is a solid and the composition is a tablet.
  • the carrier is a gel and the composition is a capsule, suppository or a cream.
  • the compound may be formulated as a part of a pharmaceutically acceptable transdermal patch.
  • the compound may be delivered to the subject by means of a spray or inhalant..
  • This invention also provides a pharmaceutical composition made by combining a therapeutically effective amount of the compound of this invention and a pharmaceutically acceptable carrier.
  • This invention provides a process for making a pharmaceutical composition comprising combining a therapeutically effective amount of the compound of this invention and a pharmaceutically acceptable carrier.
  • a solid carrier can include one or more substances which may also act as endogenous carriers (e.g. nutrient or micronutrient carriers), flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material.
  • the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.
  • the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient.
  • Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
  • Liquid carriers are used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions.
  • the active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats.
  • the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, coloring agents, viscosity regulators, stabilizers or osmoregulators.
  • suitable examples of liquid carriers for oral and parenteral administration include water (partially containing additives as above, e.g.
  • cellulose derivatives preferably sodium carboxymethyl cellulose solution
  • alcohols including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil).
  • the carrier can also be an oily ester such as ethyl oleate or isopropyl myristate.
  • Sterile liquid carriers are useful in sterile liquid form compositions for parenteral administration.
  • the liquid carrier for pressurized compositions can be a halogenated hydrocarbon or other pharmaceutically acceptable propellent.
  • Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by for example, intramuscular, intrathecal, epidural, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously.
  • the compounds may be prepared as a sterile solid composition which may be dissolved or suspended at the time of administration using sterile water, saline, or other appropriate sterile injectable medium.
  • Carriers are intended to include necessary and inert binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings.
  • the compound can be administered orally in the form of a sterile solution or suspension containing other solutes or suspending agents (for example, enough saline or glucose to make the solution isotonic), bile salts, acacia, gelatin, sorbitan monoleate, polysorbate 80 (oleate esters of sorbitol and its anhydrides copolymerized with ethylene oxide) and the like.
  • solutes or suspending agents for example, enough saline or glucose to make the solution isotonic
  • bile salts for example, enough saline or glucose to make the solution isotonic
  • acacia gelatin
  • sorbitan monoleate sorbitan monoleate
  • polysorbate 80 oleate esters of sorbitol and its anhydrides copolymerized with ethylene oxide
  • compositions suitable for oral administration include solid forms, such as pills, capsules, granules, tablets, and powders, and liquid forms, such as solutions, syrups, elixirs, and suspensions.
  • forms useful for parenteral administration include sterile solutions, emulsions, and suspensions.
  • Optimal dosages to be administered may be determined by those skilled in the art, and will vary with the particular compound in use, the strength of the preparation, the mode of administration, and the advancement of the disease condition. Additional factors depending on the particular subject being treated will result in a need to adjust dosages, including subject age, weight, gender, diet, and time of administration.
  • a "therapeutically effective amount” is any amount of a compound which, when administered to a subject suffering from a disease against which the compounds are effective, causes reduction, remission, or regression of the disease.
  • a "subject” is a vertebrate, a mammal or a human.
  • This invention provides a method of treating a subject suffering from an abnormality wherein the abnormality is alleviated by decreasing the activity of an MCH1 receptor which comprises administering to the subject an amount of a compound of the invention which is an MCH1 receptor antagonist effective to treat the subject's abnormality.
  • the abnormality is a regulation of a steroid or pituitary hormone disorder, an epinephrine release disorder, a gastrointestinal disorder, a cardiovascular disorder, an electrolyte balance disorder, hypertension, diabetes, a respiratory disorder, asthma, a reproductive function disorder, an immune disorder, an endocrine disorder, a musculoskeletal disorder, a neuroendocrine disorder, a cognitive disorder, a memory disorder such as Alzheimer's disease, a sensory modulation and transmission disorder, a motor coordination disorder, a sensory integration disorder, a motor integration disorder, a dopaminergic function disorder such as Parkinson's disease, a sensory transmission disorder, an olfaction disorder, a sympathetic innervation disorder, an affective disorder such as depression and anxiety, a stress-related disorder, a fluid-balance disorder, a seizure disorder, pain, psychotic behavior such as schizophrenia, morphine tolerance, opiate addiction, migraine or a urinary disorder such as urinary incontinence.
  • an affective disorder such as depression and
  • depressive and anxiety disorders are for the purpose of illustrating the utility of the compounds of this invention.
  • the definitions of depressive and anxiety disorders given below are those listed in Diagnostic and Statistical Manual of Mental Disorders. 4th ed. (DSM-IV; American Psychiatric Association, 1994a) or Diagnostic and Statistical Manual of Mental Disorders. 3rd ed. Revised (DSM-III-R; American Psychiatric Association, 1987). Additional information regarding these disorders can be found in this reference, as well as the others cited below, all of which are incorporated herein by reference.
  • Depressive disorders include major depressive disorder and dysthymic disorder (American Psychiatric Association, 1994a; American Psychiatric Association, 1994b).
  • Major depressive disorder is characterized by the occurrence of one or more major depressive episodes without manic or hypomanic episodes.
  • a major depressive episode is defined as a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it should include at least 4 of the following 8 symptoms: change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation (Medical Economics Company, 2002).
  • Dysthymic disorder involves a type of depression that is not severe enough to be called a major depressive episode, but that lasts much longer than major depressive disorder, without high phases.
  • the compounds of this invention will be effective in treating depression in patients who have been diagnosed with depression by administration of any of the following tests: Hamilton Depression Rating Scale (HDRS), Hamilton depressed mood item, Clinical Global Impressions (CGI)-Severity of Illness. It is further contemplated that the compounds of the invention will be effective in inducing improvements in certain of the factors measured in these tests, such as the HDRS subfactor scores, including the depressed mood item, sleep disturbance factor and anxiety factor, and the CGl-Severity of Illness rating. It is also contemplated that the compounds of this invention will be effective in preventing relapse of major depressive episodes.
  • HDRS Hamilton Depression Rating Scale
  • CGI Clinical Global Impressions
  • Anxiety disorders include panic disorder, agoraphobia with or without history of panic disorder, specific phobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder and generalized anxiety disorder. It is contemplated that the compounds of this invention will be effective in treating any of all of these disorders in patients who have been diagnosed with these disorders.
  • Obsessive compulsive disorder is characterized by recurrent and persistent ideas, thoughts, impulses or images (obsessions) that are ego-dystonic and/or repetitive, purposeful and intentional behaviors (compulsions) that are recognized by the person as excessive or unreasonable (American Psychiatric Association, 1994a). The obsessions or compulsions cause marked distress, are time-consuming, or significantly interfere with social or occupational functioning.
  • the compounds of this invention will be effective in treating obsessions and compulsions in patients who have been diagnosed with obsessive compulsive disorder by administration of appropriate tests, which may include, but are not limited to any of the following: Yale Brown Obsessive Compulsive Scale (YBOCS) (Goodman, 1989) (for adults), National Institute of Mental Health Global OCD Scale (NIMH GOCS), CGl-Severity of Illness scale. It is further contemplated that the compounds of the invention will be effective in inducing improvements in certain of the factors measured in these tests, such as a reduction of several points in the YBOCS total score. It is also contemplated that the compounds of this invention will be effective in preventing relapse of obsessive compulsive disorder.
  • Panic disorder is characterized by recurrent unexpected panic attacks and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a significant change in behavior related to the attacks (American Psychiatric
  • a panic attack is defined as a discrete period of intense fear or discomfort in which four (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings of unreality) or depersonalization (being detached from oneself); fear of losing control; (11) fear of dying;
  • Panic disorder may or may not be associated with agoraphobia, or an irrational and often disabling fear of being out in public. It is contemplated that the compounds of this invention will be effective in treating panic disorder in patients who have been diagnosed with panic disorder on the basis of frequency of occurrence of panic attacks, or by means of the CGl-Severity of Illness scale.
  • the compounds of the invention will be effective in inducing improvements in certain of the factors measured in these evaluations, such as a reduction in frequency or elimination of panic attacks, an improvement in the CGl-Severity of Illness scale or a CGI-Global Improvement score of 1 (very much improved), 2 (much improved) or 3 (minimally improved). It is also contemplated that the compounds of this invention will be effective in preventing relapse of panic disorder.
  • Social anxiety disorder also known as social phobia
  • social phobia is characterized by a marked and persistent fear of one or more social or performance situations in which the person is exposed to unfamiliar people or to possible scrutiny by others (American Psychiatric Association, 1994a). Exposure to the feared situation almost invariably provokes anxiety, which may approach the intensity of a panic attack. The feared situations are avoided or endured with intense anxiety or distress. The avoidance, anxious anticipation, or distress in the feared situation(s) interferes significantly with the person's normal routine, occupational or academic functioning, or social activities or relationships, or there is marked distress about having the phobias. Lesser degrees of performance anxiety or shyness generally do not require psychopharmacological treatment.
  • the compounds of this invention will be effective in treating social anxiety disorder in patients who have been diagnosed with social anxiety disorder by administration of any of the following tests: the Liebowitz Social Anxiety Scale (LSAS), the CGl-Severity of Illness scale, the Hamilton Rating Scale for Anxiety (HAM-A), the Hamilton Rating Scale for Depression (HAM-D), the axis V Social and Occupational Functioning Assessment Scale of DSM-IV, the axis II (ICD-10) World Health Organization Disability Assessment, Schedule 2 (DAS-2), the Sheehan Disability Scales, the Schneier Disability Profile, the World Health Organization Quality of Life-100 (WHOQOL-100), or other tests as described in Bobes, 1998, which is incorporated herein by reference.
  • LSAS Liebowitz Social Anxiety Scale
  • HAM-A Hamilton Rating Scale for Anxiety
  • HAM-D Hamilton Rating Scale for Depression
  • ICD-10 World Health Organization Disability Assessment
  • DAS-2 the Sheehan Disability Scales
  • the compounds of the invention will be effective in inducing improvements as measured by these tests, such as the a change from baseline in the Liebowitz Social Anxiety Scale (LSAS), or a CGI- Global Improvement score of 1 (very much improved), 2 (much improved) or 3 (minimally improved). It is also contemplated that the compounds of this invention will be effective in preventing relapse of social anxiety disorder.
  • LSAS Liebowitz Social Anxiety Scale
  • CGI- Global Improvement score of 1 (very much improved), 2 (much improved) or 3 (minimally improved). It is also contemplated that the compounds of this invention will be effective in preventing relapse of social anxiety disorder.
  • Generalized anxiety disorder is characterized by excessive anxiety and worry (apprehensive expectation) that is persistent for at least 6 months and which the person finds difficult to control (American Psychiatric Association, 1994a). It must be associated with at least 3 of the following 6 symptoms: restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, sleep disturbance.
  • the diagnostic criteria for this disorder are described in further detail in DSM- IV, which is incorporated herein by reference (American Psychiatric Association, 1994a). It is contemplated that the compounds of this invention will be effective in treating generalized anxiety disorder in patients who have been diagnosed with this disorder according to the diagnostic criteria described in DSM-IV.
  • the compounds of the invention will be effective in reducing symptoms of this disorder, such as the following: excessive worry and anxiety, difficulty controlling worry, restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, or sleep disturbance. It is also contemplated that the compounds of this invention will be effective in preventing relapse of general anxiety disorder.
  • Post-traumatic stress disorder as defined by DSM-III-R/IV (American Psychiatric Association, 1987, American Psychiatric Association, 1994a), requires exposure to a traumatic event that involved actual or threatened death or serious injury, or threat to the physical integrity of self or others, and a response which involves intense fear, helplessness, or horror.
  • Symptoms that occur as a result of exposure to the traumatic event include re- experiencing of the event in the form of intrusive thoughts, flashbacks or dreams, and intense psychological distress and physiological reactivity on exposure to cues to the event; avoidance of situations reminiscent of the traumatic event, inability to recall details of the event, and/or numbing of general responsiveness manifested as diminished interest in significant activities, estrangement from others, restricted range of affect, or sense of foreshortened future; and symptoms of autonomic arousal including hypervigilance, exaggerated startle response, sleep disturbance, impaired concentration, and irritability or outbursts of anger.
  • a PTSD diagnosis requires that the symptoms are present for at least a month and that they cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. It is contemplated that the compounds of this invention will be effective in treating PTSD in patients who have been diagnosed with PTSD by administration of any of the following tests: Clinician-Administered PTSD Scale Part 2 (CAPS), the patient-rated Impact of Event Scale (IES) (Medical Economics Company, 2002, p. 2752). It is further contemplated that the compounds of the invention will be effective in inducing improvements in the scores of the CAPS, IES, CGl-Severity of Illness or CGI-Global Improvement tests. It is also contemplated that the compounds of this invention will be effective in preventing relapse of PTSD.
  • CAPS Clinician-Administered PTSD Scale Part 2
  • IES patient-rated Impact of Event Scale
  • CGI-Global Improvement tests It is also contemplated that the compounds of this invention will be effective in preventing relapse of PTSD.
  • the subject invention provides a method of treatment or management of the following indications: depressive disorders, anxiety disorders, eating/body weight disorders, and urinary disorders.
  • depressive disorders are major depressive disorder or dysthymic disorder.
  • anxiety disorders are panic disorder, agoraphobia without history of panic disorder, specific phobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder or generalized anxiety disorder.
  • eating/body weight disorders are obesity, weight gain, bulimia, bulimia nervosa or anorexia nervosa.
  • urinary disorders include, but are not limited to urinary incontinence overactive bladder, urge incontinence, urinary frequency, urinary urgency, nocturia or enuresis. Overactive bladder and urinary urgency may or may not be associated with benign prostatic hyperplasia.
  • This invention provides a method of modifying the feeding behavior of a subject, which comprises administering to the subject an amount of a compound of the invention effective to decrease the consumption of food by the subject.
  • This invention also provides a method of treating an eating disorder in a subject, which comprises administering to the subject an amount of a compound of the invention effective to treat the eating disorder.
  • the eating disorder is obesity, bulimia, bulimia nervosa or anorexia nervosa.
  • the present invention further provides a method of reducing the body mass of a subject, which comprises administering to the subject an amount of a compound of the invention effective to reduce the body mass of the subject.
  • This invention also provides a method of managing obesity in a subject in need of weight loss, which comprises administering to the subject an amount of a compound of the invention effective to induce weight loss in the subject.
  • This invention also provides a method of managing obesity in a subject who has experienced weight loss, which comprises administering to the subject an amount of a compound of the invention effective to maintain such weight loss in the subject.
  • the present invention also provides a method of treating depression in a subject, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject's depression.
  • This invention also provides a method of treating anxiety in a subject, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject's anxiety.
  • This invention also provides a method of treating depression and anxiety in a subject, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject's depression and anxiety.
  • This invention alsp provides a method of treating major depressive disorder in a subject, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject's major depressive disorder.
  • This invention also provides a method of treating dysthymic disorder in a subject, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject's dysthymic disorder.
  • This invention also provides a method of treating obsessions and compulsions in a subject with obsessive compulsive disorder, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject's obsessions and compulsions.
  • This invention also provides a method of treating panic disorder, with or without agoraphobia, in a subject, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject's panic disorder.
  • This invention also provides a method of treating social anxiety disorder in a subject, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject's social anxiety disorder.
  • This invention also provides a method of treating generalized anxiety disorder in a subject, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject's generalized anxiety disorder.
  • This invention also provides a method of treating post-traumatic stress disorder in a subject, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject's post-traumatic stress disorder.
  • the compounds of this invention will be effective in treating obesity, including weight loss and maintenance of weight loss in patients, who have been diagnosed with obesity by the one or more of the following measurements: an increased body mass index, increased waist circumference (an indicator of intra-adominal fat), Dual Energy X-Ray Absorptiometry (DEXA) and nestal (android) fat mass. It is further contemplated that the compounds of the invention will be effective in inducing improvements in certain factors measured in these tests.
  • the compounds of this invention will be effective in treating urinary disorders in patients who have urge or mixed (with a predominance of urge) incontinence as evidenced by the number of unnecessary episodes per week, the number of unnecessary micturitions per day and a low volume voided per micturition. It is further contemplated that the compounds of the invention will be effective in inducing improvements in certain factors measured in these tests.
  • the present invention also provides a method of treating a subject suffering from bipolar I or II disorder, schizoaffective disorder, a cognitive disorder with depressed mood, a personality disorder, insomnia, hypersomnia, narcolepsy, circadian rhythm sleep disorder, nightmare disorder, sleep terror disorder or sleepwalking disorder.
  • the present invention provides a method of treating overactive bladder with symptoms of urge urinary incontinence, urgency and/or frequency in a subject, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject's overactive bladder.
  • This invention also provides a method of alleviating urge urinary incontinence in a subject suffering from overactive bladder, which comprises administering to the subject an amount of a compound of the invention effective to alleviate the subject's urge urinary incontinence.
  • This invention further provides a method of alleviating urinary urgency in a subject suffering from overactive bladder, which comprises administering to the subject an amount of a compound of the invention effective to alleviate the subject's urinary urgency.
  • this invention provides a method of alleviating urinary frequency in a subject suffering from overactive bladder, which comprises administering to the subject an amount of a compound of the invention effective to alleviate the subject's urinary frequency.
  • the present invention also provides a method of treating a subject suffering from a urinary disorder, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject's urinary disorder.
  • the urinary disorder is urinary incontinence, overactive bladder, urge incontinence, urinary frequency, urinary urgency, nocturia or enuresis.
  • the present invention provides a method of alleviating the symptoms of a disorder in a subject, which comprises administering to the subject an amount of an MCH1 antagonist effective to alleviate the symptoms, wherein the MCH1 antagonist is any of the compounds of the invention.
  • the subject is a vertebrate, a mammal, a human or a canine.
  • the compound is administered orally.
  • the compound is administered in combination with food.
  • the subject invention provides a method of treatment for the following indications: depression, anxiety, eating/body weight disorders, and urinary disorders.
  • Examples of eating/body weight disorders are obesity, bulimia, or bulimia nervosa.
  • urinary disorders include, but are not limited to, urinary incontinence, overactive bladder, urge incontinence, urinary frequency, urinary urgency, nocturia, or enuresis. Overactive bladder and urinary urgency may or may not be associated with benign prostatic hyperplasia.
  • This invention provides a method of modifying the feeding behavior of a subject which comprises administering to the subject an amount of a compound of the invention effective to decrease the consumption of food by the subject.
  • This invention also provides a method of treating an eating disorder in a subject which comprises administering to the subject an amount of a compound of this invention effective to decrease the consumption of food by the subject.
  • the eating disorder is bulimia, obesity or bulimia nervosa.
  • the subject is a vertebrate, a mammal, a human or a canine.
  • the compound is administered in combination with food.
  • the present invention further provides a method of reducing the body mass of a subject which comprises administering to the subject an amount of a compound of the invention effective to reduce the body mass of the subject.
  • the present invention also provides a method of treating a subject suffering from depression which comprises administering to the subject an amount of a compound of this invention effective to treat the subject's depression.
  • the present invention further provides a method of treating a subject suffering from anxiety which comprises administering to the subject an amount of a compound of this invention effective to treat the subject's anxiety.
  • the present invention also provides a method of treating a subject suffering from depression and anxiety which comprises administering to the subject an amount of a compound of this invention effective to treat the subject's depression and anxiety.
  • the present invention also provides a method of treating a subject suffering from major depressive disorder, dysthymic disorder, bipolar I and II disorders, schizoaffective disorder, cognitive disorders with depressed mood, personality disorders, insomnia, hypersomnia, narcolepsy, circadian rhythm sleep disorder, nightmare disorder, sleep terror disorder, sleepwalking disorder, obsessive-compulsive disorder, panic disorder, with or without agoraphobia, posttraumatic stress disorder, social anxiety disorder, social phobia and generalized anxiety disorder.
  • the present invention also provides a method of treating a subject suffering from a urinary disorder which comprises administering to the subject an amount of a compound of this invention effective to treat the subject's a urinary disorder.
  • the urinary disorder is urinary incontinence, overactive bladder, urge incontinence, urinary frequency, urinary urgency, nocturia, or enuresis.
  • the present invention further provides for a compound having the structure:
  • each R-i is independently hydrogen; -F; -Cl; -Br; -I; -CN; -NO 2; straight chained or branched C C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl; C 3 -C 7 cycloalkyl or C 5 -C 7 cycloalkenyl; aryl; heteroaryl; -N(R 5 ) 2 ; -(CH 2 ) m OR 5 ; -COR 5 ; -CO 2 R 5 ; -OCOR 5 ; -CON(R 5 ) 2 ; -N(R 5 )COR 5 ; -N(R 5 )CON(R 5 ) 2 ; -OCON(R 5 ) 2 or -N(R 5 )CO 2 R 5 ;
  • R 2 and R 3 are independently hydrogen; -F; -Cl; -Br; -I; -CN; -(CH 2 ) m OR 5 ; -(CH 2 ) m SR 5 ; straight chained or branched C C 7 alkyl, monofluoroalkyl, polyfluoroalkyl; aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more Ri; or
  • R 2 and R 3 together can be -(CH 2 ) P -;
  • R 4 is hydrogen; straight chained or branched C C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; C 3 -C 6 cycloalkyl; -N(R 5 ) 2 or -(CH 2 ) m OR 5 ; wherein each R 5 is independently hydrogen; aryl; heteroaryl or straight chained or branched d-C 7 alkyl, wherein the alkyl may be substituted with aryl or heteroaryl;
  • each R 6 is independently hydrogen; straight chained or branched C C 7 alkyl;
  • each R 7 is independently hydrogen; phenyl or straight chained or branched C r C 7 alkyl, wherein the alkyl may be substituted with phenyl;
  • R 8 is hydrogen or straight chained C C 7 alkyl
  • R and R 8 together can be -(CH 2 ) r -;
  • each m is independently an integer from 0 to 5 inclusive;
  • n is an integer from 1 to 5 inclusive
  • p is an integer from 2 to 7 inclusive
  • q is an integer from 0 to 2 inclusive
  • each X is independently CH or N;
  • Z is CO; SO 2 or may be absent
  • the compound has the structure:
  • the compound has the structure:
  • each R 1 is independently hydrogen; -F; -Cl; -Br; -I; -CN; -NO 2; straight chained or branched C C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl; C 3 -C 7 cycloalkyl or C 5 -C 7 cycloalkenyl; aryl; heteroaryl; -N(R 5 ) 2 ; -(CH 2 ) OR 5 ; -COR 5 ;
  • R 5 is independently hydrogen; -F; -Cl; -Br; -I; -CN; -(CH 2 ) m OR 5 ; -(CH 2 ) m SR 5 ; straight chained or branched C C 7 alkyl, monofluoroalkyl, polyfluoroalkyl; aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more R- t ; or
  • R 2 and R 3 together can be -(CH 2 ) P -;
  • R 4 is straight chained or branched C C 7 alkyl, monofluoroalkyl or polyfluoroalkyl, C 3 - C 6 cycloalkyl, C C 7 alkyI-C 3 -C 6 cycloalkyl -N(R 5 ) 2 or -(CH 2 ) m OR 5 ;
  • each R 5 is independently hydrogen; aryl; heteroaryl or straight chained or branched C C 7 alkyl, wherein the alkyl may be substituted with aryl or heteroaryl;
  • each R 6 is independently hydrogen; straight chained or branched C C 7 alkyl;
  • each R 7 is independently hydrogen; phenyl or straight chained or branched C C 7 alkyl, wherein the alkyl may be substituted with phenyl;
  • each m is independently an integer from 0 to 5 inclusive; wherein n is an integer from 1 to 5 inclusive; wherein p is an integer from 2 to 7 inclusive; wherein q is an integer from 0 to 2 inclusive; wherein X is CH or N;
  • each R ⁇ is independently hydrogen; straight chained or branched C C 7 alkyl; -F; -Cl; -Br; -I; -CN; -NO 2 ; straight chained or branched C C 4 alkyl or polyfluoroalkyl; -(CH 2 ) m OR 5 ; -COR 5 ; -CO 2 R 5 ; -OCOR 5 ; - CON(R 5 ) 2 ; -N(R 5 )COR 5 or-N(R 5 )CON(R 5 ) 2 ;
  • R 2 and R 3 are independently hydrogen; -F; -Cl; -Br; -I; -CN; -(CH 2 ) m SR 5 ; straight chained or branched C C 7 alkyl; aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more Ri; or
  • R 2 and R 3 together can be -(CH 2 ) P -;
  • R is straight chained or branched C C 7 alkyl; C 3 -C 6 cycloalkyl; -N(R 5 ) 2 or - (CH 2 ) m OR 5 ;
  • each R 5 is independently hydrogen or straight chained or branched C C 3 alkyl, wherein the alkyl may be substituted with phenyl; wherein m is 0 to 3; wherein n is 1 to 3; wherein p is an integer from 2 to 5 inclusive; wherein q is 0; and wherein X is CH.
  • each R 5 is independently hydrogen or straight chained or branched C C 3 alkyl, wherein the alkyl may be substituted with a phenyl;
  • R 7 is independently hydrogen or straight chained or branched C C 7 alkyl; and
  • R 4 is straight chained or branched C C 7 alkyl.
  • each Ri is independently hydrogen; -F; -Cl; -Br; -I or straight chained or branched C C 7 alkyl; and wherein R 2 is hydrogen or straight chained or branched C C 7 alkyl.
  • n 2.
  • R ⁇ is hydrogen; -F; -Cl; -Br; -I or straight chained or branched C C 7 alkyl; and
  • R 2 is hydrogen or straight chained or branched C C 7 alkyl.
  • R 2 is hydrogen
  • R 3 is OH.
  • R 4 is C 3 -C 6 cycloalkyl.
  • each R 2 and R 3 are independently hydrogen; -F; -Br or straight chained or branched C C 7 alkyl.
  • R 2 and R 3 are independently hydrogen or straight chained or branched C C 7 alkyl.
  • R 2 and R 3 are independently hydrogen; -F or -Br.
  • R 2 and R 3 together are -(CH 2 ) P -;
  • the compound has the structure:
  • each Ri is independently hydrogen; -F; -Cl; -Br; -I or straight chained or branched C C 7 alkyl; and wherein R 2 is hydrogen or straight chained or branched C C 7 alkyl.
  • R 4 is straight chained or branched C C 7 alkyl.
  • the compound has the following structure:
  • the compound has the following structure:
  • each R 5 is independently hydrogen or straight chained or branched CrC 3 alkyl, wherein the alkyl may be substituted with a phenyl;
  • R 7 is independently hydrogen or straight chained or branched C C 7 alkyl; and
  • R is straight chained or branched C C 7 alkyl.
  • each R ⁇ is independently hydrogen; -F; -Cl; -Br; -I or straight chained or branched C C 7 alkyl.
  • X is N.
  • X is CRi.
  • R 2 is OH
  • the compound has the following structure:
  • R 5 and R 7 are independently hydrogen or straight chained or branched C C 7 alkyl; and R 4 is straight chained or branched d-C 7 alkyl.
  • R 2 is hydrogen; straight chained or branched C C 7 alkyl; or -OH.
  • the compound is diastereomerically pure.
  • the compound is enantiomerically and diastereomerically pure.
  • the present invention also provides a pharmaceutical composition that comprises a therapeutically effective amount of a compound of the present invention and a pharmaceutically acceptable carrier.
  • the present invention further provides a pharmaceutical composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
  • the present invention also provides a process for making a pharmaceutical composition comprising admixing a compound of the present invention and a pharmaceutically acceptable carrier.
  • the present invention also provides a method for treating a subject suffering from a disorder mediated by the MCH1 receptor comprising administering to the subject a therapeutically effective amount of a compound of the present invention.
  • the therapeutically effective amount is between about 0.03 and about 300 mg.
  • the disorder is depression, anxiety, obesity or urge incontinence.
  • the present invention also provides a method of treating a subject suffering from a disorder selected from the group consisting of depression, anxiety, urge incontinence or obesity comprising administering to the subject a therapeutically effective amount of a compound of the present invention.
  • Preparative thin-layer chromatography was carried out on glass sheets precoated with silica gel GF (2 mm, Analtech). Flash column chromatography was performed on Merck silica gel 60 (230 - 400 mesh). Melting points (mp) were determined in open capillary tubes on a Mel-Temp apparatus and are uncorrected.
  • reaction mixture was cooled to -78 °C and te/f-butyl 4-oxo-1 -piperidinecarboxylate (Aldrich Chemical Company, 40.0 mmol) in THF (40 mL) was added dropwise to the reaction mixture, which was then stirred for 30 minutes.
  • Tf 2 NPh (42.0 mmol, 15.0 g) in THF (40 mL) was added dropwise to the reaction mixture and stirred at 0 °C overnight.
  • the reaction mixture was concentrated in vacuo, re-dissolved in hexanes.EtOAc (9:1), passed through a plug of alumina and the alumina plug was washed with hexanes:EtOAc (9:1). The combined extracts were concentrated to yield 16.5 g of the desired product that was contaminated with some starting Tf 2 NPh.
  • TEftT-BUTYL 4-(3-AMINOPHENYL)-3,6-DIHYDRO-1(2W)-PYRIDINECARBOXYLATE A degassed mixture of 2 M aqueous Na 2 C0 3 solution (4.2 mL), te/f-butyl 4- ⁇ [(trifluoromethyl)sulfonyl]oxy ⁇ -3,6-dihydro-1(2-4)-pyridinecarboxylate (0.500 g, 1.51 mmol), 3- aminophenylboronic acid hemisulfate (0.393 g, 2.11 mmol), lithium chloride (0.191 g, 4.50 mmol) and tetrakis-triphenylphosphine palladium (0) (0.080 g, 0.075 mmol) in dimethoxyethane (5 mL) was heated at reflux temperature for 3 hours under an inert atmosphere.
  • TERT-BUTYL 4-[3-(AMINO)PHENYL]-1-PIPERIDINECARBOXYLATE A mixture of 3.10 g of te/f-butyl 4-(3-aminophenyI)-3,6-dihydro-1(2H)-pyridinecarboxylate (11.3 mmol) and 1.0 g of 10% Pd/C in 200 mL of ethanol was hydrogenated at room temperature using the balloon method for 2 days. The reaction mixture was filtered through Celite and washed with ethanol.
  • TERT-BUJYl 4-[3-(ACETYLAMINO)PHENYL]-1-PIPERIDINECARBOXYLATE Into a solution of 14.6 g (52.6 mmol) of te/f-butyl 4-[3-(amino)phenyl]-1 -piperidinecarboxylate and 14.7 mL (105 mmol) of triethylamine in 120 mL THF at 0 °C was slowly added 4.5 mL (63.1 mmol) of acetyl chloride. The reaction mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The residue was dissolved in CH CI 2 and washed with H 2 O, followed by brine.
  • 1,4-dioxane at 0 °C was bubbled HCI gas for 10 minutes.
  • the reaction mixture was allowed to warm to room temperature and the bubbling of the HCI gas was continued for 1 hour.
  • the aqueous solution was extracted with 3 X 80 mL of dichloromethane. The combined organic extracts were dried (MgSO ), filtered and concentrated in vacuo.
  • PYRIDINE CARBOXYLATE To a 50-mL RB-flask containing te/f-butyl 4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate (500 mg, 1.62 mmol), K 2 CO 3 (670 mg, 4.86 mmol) and PdCI 2 dppf (0.190 mmol, 155 mg) was added a solution of N-(3-bromo-4-methylphenyl)-2-methylpropanamide (415 mg, 1.62 mmol) in DMF (10.0 mL) at room temperature under argon.
  • TERT-BUTYL 4-[5-AMINO-2-METHOXYPHENYL]-1-PIPERIDINECARBOXYLATE A solution of te f-butyl 4-(2-methoxy-5-nitrophenyl)-3,6-dihydro-1(2/-/)-pyridinecarboxylate (1.30 g, 3.90 mmol) and 10% Pd/C (200.0 mg) in MeOH:EtOAc (1:4, 100 mL) was hydrogenated at room temperature for 72 h using the hydrogen balloon method. The reaction mixture was filtered through Celite and washed with ethanol (3 x 100 mL).
  • TERT-BUTYL 3-BROMOPROPYLCARBAMATE A solution of 3-bromopropylamine hydrobromide (10.9 g, 49.8 mmol), BOC 2 O (11.4 g, 52.3 mmol) and K 2 C0 3 (20.6 g, 149.4 mmol) in ethanol (100 ml) were stirred at room temperature overnight. The precipitated salts were removed by filtration and the filtrate was concentrated in vacuo. The residue was dissolved in dichloromethane and washed with water, followed by brine.
  • TERT-BUTYL 3- ⁇ 4-[3-(ACETYLAMINO)PHENYL]-1-PIPERIDINYL ⁇ PROPYLCARBAMATE A mixture of ⁇ /-[3-(4-piperidyl)phenyl]acetamide (550 mg, 2.1 mmol), tert-butyl 3- bromopropylcarbamate (550 mg, 2.3 mmol), K 2 CO 3 (1.10 g, 8.9 mmol), diisopropylethyl amine (1.50 mL) and a few crystals of Kl in dioxane (20 mL) was heated at reflux temperature for 2 days.
  • Trifluoroacetic acid (1.0 mL) was added to a solution of tert-butyl 3- ⁇ 4-[3-(acetylamino)phenyl]-1 -piperidinyl ⁇ propylcarbamate (340 mg) in dry dichloromethane (10 mL) and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was basified to pH 12 by addition of a 10% aqueous solution of KOH and then the dichloromethane was removed in vacuo.
  • Step 2 Deprotection of the N-(n-phthalimidoalkyl)piperidine from step 1 was accomplished by heating a solution of phthalimide-protected amine 2 with excess hydrazine hydrate (10 eq) in ethanol (0.5-1.0 M) at 90 °C for 4 h. The reaction mixture was monitored by TLC to completion. Upon completion of the reaction, the mixture was cooled to room temperature, the insoluble by-products were removed by filtration through Celite and the filtrate was concentrated in vacuo. The crude product was chromatographed (dichloromethane- methanol-isopropylamine) to give the desired N-(n-aminoalkyl)piperidine 3.
  • Step l N-(3- ⁇ 1-[(3R)-3-HYDROXY-3-PHENYLPROPYL]-4-PIPERIDINYL ⁇ PHENYL)-2-
  • reaction mixture was cooled to room temperature and poured into water (50 mL) and the aqueous layer was extracted with methylene chloride (3 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried over Na 2 SO 4 and concentrated under reduced pressure.
  • Step 1
  • reaction mixture was cooled to room temperature, poured into water (50 mL) and the aqueous layer was extracted with methylene chloride (3 x 30 mL). The combined organic extracts were washed with brine (30 mL), dried over MgSO 4 and concentrated under reduced pressure.
  • Step 3 See Scheme 3/ Method B for general deprotection conditions.
  • Step 4 See general coupling conditions in Schemes 8-10.
  • BIS(4-FLUOROPHENYL)ACETIC ACID Fluorobenzene (13.6 g, 0.142 mol) and glyoxylic acid monohydrate (2.35 g, 0.0255 mol) were dissolved in warm acetic acid (30.0 mL). The mixture was cooled in an ice/water bath and concentrated sulfuric acid (20.0 mL) was added dropwise over 0.5 h. The resulting thick red suspension was stirred at 80 °C for 12 h and then cooled to room temperature. Water (300 mL) was added and the pH was adjusted to 3 with potassium hydroxide pellets and 10% KOH solution.
  • BIS(4-METHYLPHENYL)ACETIC ACID To a 250 mL RB-flask was added 4,4'- dimethylbenzhydrol (1.06 g, 5.00 mmol) and 97% sulfuric acid (44.0 mL). The mixture was cooled to 15 °C by an ice/water bath and formic acid (12.0 mL) was added dropwise via an addition funnel over 0.5 h. The resulting foaming solution was stirred at 15 °C for 2 h. Water (300 mL) was added and the pH was adjusted to 3 with potassium hydroxide pellets and 10% KOH solution.
  • a library of amides was constructed in polypropylene Robbins "Reactor Blocks", 48 well plates.
  • PS-CDI resin 300 mg, 2.00 eq, purchased from Argonaut Technologies
  • the Reactor Blocks were sealed and rotated in a Robbins oven (FlexChem) at room temperature for 12 h.
  • the solutions were filtered in parallel into Robbins receiving plates and the resin was washed with CH 2 CI 2 (2.0 mL) and MeOH (1.0 mL).
  • the filtrate and washings were concentrated under reduced pressure to give the desired product, which was analyzed by 1 H NMR and ESMS.
  • (4S)-3-[(4-fluorophenyl)acetyl]-4-isopropyl-1 ,3-oxazolidin-2-one To a solution of (4S)-4- isopropyl-1 ,3-oxazolidin-2-one (2.0 g, 15.5 mmol) in dry THF (20 mL) at -78°C under argon, was added dropwise a 2.5M solution of ⁇ -BuLi in hexanes (6.2 mL, 15.5 mmol). After stirring at -78°C for 15 min, (4-fluorophenyl)acetyl chloride (2.55 mL, 18.6 mmol) was added.
  • (4S)-3-[(4-chlorophenyl)acetyl]-4-isopropyI-1 ,3-oxazolidin-2-one To a solution of (4S)-4-iso propyl-1 ,3-oxazolidin-2-one (2.0 g, 15.5 mmol) in dry THF (20 mL) at -78°C under argon, was added dropwise a 2.5M solution of n-BuLi in hexanes (6.2 mL, 15.5 mmol). After stirring at -78°C for 15 min, (4-chlorophenyl)acetyl chloride (2.70 mL, 21.8 mmol) was added.
  • (4R)-3-[(4-fluorophenyl)acetyl]-4-isopropyl-1 ,3-oxazolidin-2-one To a solution of (4R)-4- isopropyl-1 ,3-oxazolidin-2-one (5.2 g, 40.3 mmol) in dry THF (100 mL) at -78°C under argon, was added dropwise a 2.5M solution of ⁇ -BuLi in hexanes (17.0 mL, 42.5 mmol). After stirring at -78°C for 15 min, (4-fluorophenyl)acetyl chloride (6.34 mL, 46.4 mmol) was added.
  • (4R)-3-[(4-chlorophenyl)acetyl]-4-isopropyl-1,3-oxazolidin-2-one To a solution of (4R)-4- isopropyl-1 ,3-oxazolidin-2-one (5.3 g, 41.1 mmol) in dry THF (100 mL) at -78°C under argon, was added dropwise a 2.5M solution of n-BuLi in hexanes (17.0 mL, 42.5 mmol). After stirring at -78°C for 15 min, (4-chlorophenyl)acetyl chloride (2.70 mL, 21.8 mmol) was added.
  • (4S)-3-[(2S)-2-(4-fluorophenyI)propanoyl]-4-isopropyl-1 ,3-oxazolidin-2-one To a solution of (4S)-3-[(4-fluorophenyl)acetyl]-4-isopropyl-1 ,3-oxazolidin-2-one (2.81 g, 10.6 mmol) in dry THF (40 mL) at -78°C under argon, was added dropwise 1.0M solution of NaHMDS in THF (117 mL, 11.7 mmol) over a period of 10 min.
  • (4S)-3-[(2S)-2-(4-chIorophenyl)propanoyl]-4-isopropyl-1 ,3-oxazolidin-2-one To a solution of (4S)-3-[(4-chlorophenyl)acetyl]-4-isopropyl-1 ,3-oxazolidin-2-one (1.07 g, 3.81 mmol) in dry THF (30 mL) at -78°C under argon, was added dropwise 1.0M solution of NaHMDS in THF (4.20 mL, 4.20 mmol) over a period of 10 min.
  • (4R)-3-[(2R)-2-(4-fluorophenyl)propanoyl]-4-isopropyl-1 ,3-oxazolidin-2-one To a solution of (4R)-3-[(4-fluorophenyl)acetyl]-4-isopropyl-1,3-oxazolidin-2-one (4.24 g, 16.0 mmol) in dry THF (80 mL) at -78°C under argon, was added dropwise 1.0M solution of NaHMDS in THF (17.6 mL, 17.6 mmol) over a period of 10 min. After stirring at -78°C for 1 h, Mel (5.0 mL, 80.0 mmol) was added.
  • (4R)-3-[(2R)-2-(4-chlorophenyl)propanoyl]-4-isopropyl-1 ,3-oxazolidin-2-one To a solution of (4R)-3-[(4-chlorophenyl)acetyl]-4-isopropyl-1 ,3-oxazolidin-2-one (2.80 g, 9.96 mmol) in dry THF (80 mL) at -78°C under argon, was added dropwise 1.0M solution of NaHMDS in THF (11.0 mL, 11.0 mmol) over a period of 10 min. After stirring at -78°C for 1 h, Mel (1.9 mL, 30.0 mmol) was added.
  • (2S)-2-(4-fluorophenyl)propanoic acid To a solution of (4S)-3-[(2S)-2-(4-fluorophenyl) propanoyl]-4-isopropyl-1 ,3-oxazolidin-2-one (2.40 g, 8.60 mmol) in 160 mL THF/ H 2 0 (3:1) at 0°C, was added 30% H 2 0 2 (7.8 mL, 68.8 mmol) followed by LiOH (722 mg, 17.2 mmol).
  • (2S)-2-(4-chlorophenyl)propanoic acid To a solution of (4S)-3-[(2S)-2-(4-chlorophenyl) propanoyl]-4-isopropyl-1 ,3-oxazolidin-2-one (678 mg, 2.30 mmol) in 45 mL THF/ H 2 0 (3:1) at 0°C, was added 30% H 2 0 2 (2.1 mL, 18.4 mmol) followed by LiOH (193 mg, 4.6 mmol). The resulting mixture was stirred at 0°C for 2 h and the excess peroxide was quenched at 0°C with 1.5 N aqueous Na 2 S0 3 (15 mL).
  • the oxazolidone chiral auxiliary was recovered by EtOAc extraction (50 mL x 3). The aqueous layer was acidified with 3N HCI and extracted with EtOAc.
  • (2R)-2-(4-fluorophenyl)propanoic acid To a solution of (4R)-3-[(2R)-2-(4-fluorophenyl )propanoyl]-4-isopropyl-1 ,3-oxazolidin-2-one (2.59 g, 9.28 mmol) in 160 mL THF/ H 2 0 (3:1) at 0°C, was added 30% H 2 0 2 (8.4 mL, 74.2 mmol) followed by LiOH (780 mg, 18.6 mmol). The resulting mixture was stirred at 0°C for 2 h and the excess peroxide was quenched at 0°C with 1.5 N aqueous Na 2 S0 3 (54 mL).
  • the oxazolidone chiral auxiliary was recovered by EtOAc extraction (50 mL x 3). The aqueous layer was acidified with 3N HCI and extracted with EtOAc.
  • (2R)-2-(4-chlorophenyl)propanoic acid To a solution of (4R)-3-[(2R)-2-(4-chlorophenyl) propanoyl]-4-isopropyl-1 ,3-oxazolidin-2-one (1.58 g, 5.35 mmol) in 45 mL THF/ H 2 0 (3:1) at 0°C, was added 30% H 2 0 2 (4.9 mL, 42.8 mmol) followed by LiOH (449 mg, 10.7 mmol). The resulting mixture was stirred at 0°C for 2 h and the excess peroxide was quenched at 0°C with 1.5 N aqueous Na 2 S0 3 (31 mL).
  • the oxazolidone chiral auxiliary was recovered by EtOAc extraction (50 mL x 3). The aqueous layer was acidified with 3N HCI and extracted with EtOAc.
  • RCOOH For intermediate RCOOH are available from commercial sources or alternatively may be prepared from a variety of intermediates known to those skilled in the art.
  • ⁇ - substituted aryl acetic acid can be prepared by hydrolysis of corresponding ⁇ -substituted arylacetonitriles or ⁇ -substituted aryl acetic esters (Rieu, et al., 1986. Tetrahedron 42(15) 4095-4131 and references cited therein).
  • Enantiomerically pure-substituted aryl acetic acid can be prepared by asymmetric syntheses or enzymatic kinetic resolution (Evans, in Asymmetric Synthesis, ed. Morrison 1984. Vol 3, Academic Press, New York; Li, ef al., 2001. Tetrahedron: Asymmetry 12, 3305-3312 and references cited therein).
  • Enantiomerically pure ⁇ -hydroxy carboxylic acid can be prepared by asymmetric syntheses or kinetic resolution (Chang, ef al., 1999. Org. Lett. 13 2061-2063; Deng, et al., 2002. J. Am. Chem. Soc. 124(12) 2870-2871 ; Bull, et al., 2003. Tetrahedron: Asymmetry 14, 1407- 1446 and references cited therein).
  • N-(3-BROMOPROPYL)-2,2-DIPHENYLACETAMIDE N-(3-BROMOPROPYL)-2,2-DIPHENYLACETAMIDE.
  • 3- bromopropylamine hydrobromide (2.91 g, 13.3 mmol) in 10 mL of CH 2 CI 2 was added 2.8 mL of triethylamine (20.0 mmol).
  • the reaction mixture was stirred at room temperature for 10 minutes, followed by addition of diphenyl acetyl chloride (2.56 g, 11.1 mmol) and triethylamine (2.8 L, 20 mmol) in CH 2 CI 2 (10 mL).
  • the reaction mixture was stirred for 40 minutes at room temperature and then diluted with 200 mL of CH 2 CI 2 .
  • N-[4-(1- ⁇ 3-[(DIPHENYLACETYL)AMINO]PROPYL ⁇ -4-PIPERIDINYL)PHENYL]-2- METHYLPROPANAMIDE A mixture of 2-methyl-N-[4-(4-piperidinyl)phenyl]propanamide (50.0 mg, 2.0 mmol), N-(3-bromopropyl)-2,2-diphenylacetamide (64.2 mg, 0.2 mmol), K 2 C0 3 (55.0 mg, 4.0 mmol), and Nal (45.0 mg, 0.3 mmol) in 2 mL of DMF was stirred at room temperature for 10 minutes followed by heating to 80-90 °C for 12h.
  • N- ⁇ 3-[4-(3-AMINOPHENYL)-1-PIPERIDINYL] ⁇ -2,2-DIPHENYLACETAMIDE A 25mL RB- flask, equipped with a balloon of hydrogen, was charged with benzyl 3-(1- ⁇ 3- [(diphenylacetyl)amino]propyl ⁇ -4-piperidinyl] phenylcarbamate (787 mg, 0.140 mmol), Pd/C (10 mol%, 14.8 mg) and ethanol (2.00 mL) at room temperature. The mixture was stirred at room temperature for 12 h and filtered through a plug of Celite.
  • 1-bromo-2,4-difluoro-5-nitrobenzene To a suspension of 1-bromo-2,4-difluorobenzene (6.0 mL, 53.0 mmol) in coned H 2 S0 4 (38.5 mL) at 0°C was added dropwise coned HN0 3 (34.0 mL) maintaining an internal temperature below 20°C. The resulting mixture was stirred for 30 min at 0°C, then poured slowly into ice water with vigorous stirring. The aqueous phase was separated and extracted with EtOAc.
  • 5-bromo-2,4-difluoroaniline To a solution of 1-bromo-2,4-difluoro-5-nitrobenzene (5.04 g, 21.3 mmol) in EtOH (100 mL), THF (50 mL), NH 4 CI ( ⁇ aq (25 mL) and H 2 0 (25 mL) was added iron powder (5.0 g, 89.5 mmol). The mixture was refluxed for 2 h and filtered through celite. The filter pad was washed with EtOAc (3 x 50 mL). The filtrate was concentrated and the residue was partitioned between EtOAc and brine. The organic layer was dried over MgS0 and concentrated.
  • tert-butyl 4-[2,4-difluoro-5-(isobutyrylamino)phenyl]-3,6-dihydro-1 (2H)-pyridine carboxylate To a 250-mL RB flask containing tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 3,6-dihydro-1(2H)-pyridinecarboxylate (3.31 g, 107 mmol), K 2 C0 3 (4.44 g, 32.1 mmol) and PdCI dppf (870 mg, 1.07 mmol) was added a solution of N-(5-bromo-2,4-difluorophenyl)-2- methylpropanamide (3.28 g, 11.8 mmol) in DMF (100 mL) at room temperature under argon.
  • DMF 100 mL
  • tert-butyl 4-[2,4-difluoro-5-(isobutyrylamino)phenyl]-1-piperidinecarboxylate A solution of tert- butyl 4-[2,4-difluoro-5-(isobutyrylamino)phenyl]-3,6-dihydro-1 (2H)-pyridinecarboxylate (2.40 g, 6.31 mmol) and 10% Pd/C (500 mg) in EtOAc (40.0 mL) and MeOH (10.0 mL) was hydrogenated (200 psi) at room temperature overnight. The reaction mixture was filtered through celite and washed with ethanol (3 x 10 mL).
  • Example 9 was prepared from bromo (phenyl)aceticacid and N- ⁇ 3-[1-(3-aminopropyl)-4-piperidinyl] phenyl ⁇ -2-methylpropanamide according to the procedures described in Scheme 9: ESMS m/e: 500.0 (M + H) + .
  • Example 10 was prepared from bromo(phenyl)acetic acid and N- ⁇ 3-[1-(3-aminopropyl)-4-piperidinyl]phenyl ⁇ propanamide according to the procedures described in Scheme 10: ESMS m/e: 486.1 (M + H) + .
  • Example 14 was prepared from mesityl(phenyl) acetic acid and N- ⁇ 3-[1-(3- aminopropyl)-4-piperidinyl]phenyl ⁇ propanamide according to the procedures described in Scheme 9: ESMS m/e: 526.3 (M + H) + .
  • Example 16 was prepared from (ethylsulfanyl) (diphenyl)acetic acid and N- ⁇ 3-[1-(3-amino propyl)-4-piperidinyl]phenyl ⁇ -2-methylpropan amide according to the procedures described in Scheme 9: ESMS m/e: 658.6 (M + H) + .
  • Example 18 was prepared from diphenylacetyl chloride and N- ⁇ 3-[1-(3-aminopropyl)-4-piperidinyl]phenyl ⁇ -2,2-di methylpropanamide according to the procedures described in Scheme 8: 1 H NMR (400 MHz, CDCI 3 ) ⁇ 7.51-7.41 (s, 1H), 7.34-7.10 (m, 13H), 6.99-6.80 (m, 2H), 4.81 (s, 1 H), 3.40-3.26 (m, 2H), 2.96-278 (m, 2H), 2.50-2.25 (m, 3H), 1.98-1.82 (m, 2H), 179-1.68 (m, 2H), 1.68-1.45 (m, 4H), 1.23 (s, 9H);
  • Example 20 was prepared from diphenyl acetyl chloride and N- ⁇ 3-[1-(3-aminopropyl)-4-piperidinyl]-4-methoxyphenyl ⁇ -2-methylpropanamide according to the procedures described in Scheme 8: ESMS m/e: 528.3 (M + H) + .
  • Example 21 was prepared from bis(4-fluorophenyl)acetic acid and N- ⁇ 3-[1-(3-aminopropyl)-4-piperidinyl] phenyl ⁇ propanamide according to the procedures described in Scheme 10: ESMS m/e: 520.3 (M + H) + .
  • Example 22 was prepared from diphenyl acetyl chloride and N- ⁇ 3-[1-(3- aminopropyl)-4-piperidinyl]-4-methoxyphenyl ⁇ butanamide according to the procedures described in Scheme 8: ESMS m/e: 528.4 (M + H) + .
  • Example 23 was prepared from bis(4- fluorophenyl)acetic acid and N- ⁇ 3-[1-(3-aminopropyl)-4-piperidinyl]-4-methoxyphenyl ⁇ -2- methylpropanamide according to the procedures described in Scheme 9: ESMS m/e: 564.4 (M + H) + .
  • Example 26 was prepared from bis(4-fluorophenyl) acetic acid and N- ⁇ 3-[1-(3-aminopropyl)-4-piperidinyl]-4-methoxyphenyl ⁇ butanamide according to the procedures described in Scheme 9: ESMS m/e: 564.4 (M + H) + .
  • Example 29 was prepared from .
  • Example 43 was prepared from 1-(4- chlorophenyl)cyclobutanecarboxylic acid and N- ⁇ 3-[1-(3-aminopropyl)-4-piperidinyl]phenyl ⁇ -2- methylpropanamide according to the procedures described in Scheme 9: 1 H NMR (400 MHz, CDCI 3 ) ⁇ 7.56 (s, 1H), 7.41 (s, 1 H), 7.34-7.21 (m, 6H), 6.93 (s, 1H), 6.48 (s, 1H), 3.31-3.24 (m, 2H), 2.94-2.86 (m, 2H), 2.86-276 (m, 2H), 2.57-2.37 (m, 4H), 2.33-2.26 (m, 2H), 2.12- 2.0
  • Example 46 was prepared from 2-(4-fluoro phenyl)propanoic acid and N- ⁇ 5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl ⁇ -2-methyl propanamide according to the procedures described in Scheme 9: 1 H NMR (400 MHz, CDCI 3 ) ⁇ 8.38-8.23 (m, 1H), 7.48-7.27 (m, 3H), 7.13-6.94 (m, 4H), 6.94-6.82 (m, 1H), 3.62- 3.46 (m, 1H), 3.41-3.26 (m, 2H), 3.17-3.03 (m, 1H), 3.02-2.91 (m, 1H), 2.67-2.35 (m, 4H),
  • Example 47 was prepared from 1-(4-chlorophenyl)cyclopropanecarboxylic acid and N- ⁇ 5-[1-(3-aminopropyl)-4-piperidinyl]-2- fluorophenyl ⁇ -2-methylpropanamide according to the procedures described in Scheme 9: 1 H NMR (400 MHz, CDCI 3 ) ⁇ 8.32-8.18 (m, 1H), 7.43-7.25 (m, 5H), 7.08-6.93 (m, 1H), 6.93-679 (br, 1H), 574-5.59 (br, 1H), 3.35-3.15 (m, 2H), 3.93-275 (m, 2H), 2.65-2.49 (m, 1H),
  • Example 48 was prepared from bis(4- fluorophenyl) acetic acid and N- ⁇ 5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl ⁇ -2- methylpropanamide according to the procedures described in Scheme 9: ESMS m/e: 552.3 (M + H) + .
  • Example 49 was prepared from 2-(4- chlorophenyl)-2-methylpropanoic acid and N- ⁇ 5-[1-(3-aminopropyl)-4-piperidinyl]-2- fluorophenyl ⁇ -2-methylpropanamide according to the procedures described in Scheme 9: 1 H NMR (400 MHz, CDCI 3 ) ⁇ 8.34-8.20 (m, 1H), 7.46-7.14 (m, 5H), 7.10-6.95 (m, 1H), 6.92-677 (br, 1H), 674-6.59 (br, 1H), 3.39-3.25 (m, 2H), 3.00-2.82 (m, 2H), 2.67-2.51 (m, 1H), 2.51- 2.40 (m, 1H), 2.40-2.27 (m, 2H), 2.03-1.86 (m, 2H), 1.85-171 (m, 2H), 171-1.57 ( , 4
  • Example 51 was prepared from 2,2-diphenylpropanoic acid and N- ⁇ 5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl ⁇ -2-methylpropanamide according to the procedures described in Scheme 9: 1 H NMR (400 MHz, CDCI 3 ) ⁇ 8.27-8.13 (m, 1H), 8.04 (s, 1H), 7.62 (s, 1H), 7.50-7.39 (m, 1H), 7.39-7.16 (m, 7H), 7.12-6.90 (m, 2H), 679-6.60 (br, 1H), 4.94-4.61 (br, 1H), 3.60-3.22 (m, 4H), 2.89-276 (m, 2H), 276-2.55 (
  • Example 56 was prepared from diphenylacetyl chloride and N- ⁇ 5-
  • Example 57 was prepared from bis(4-chlorophenyl)acetic acid and N- ⁇ 3-[1-(3-aminopropyl)-4-piperidinyl]phenyl ⁇ propanamide according to the procedures described in Scheme 10: ESMS m/e: 552.2 (M + H) + .
  • Example 58 was prepared from 1-(4-chloro phenyl)cyclobutanecarboxylic acid and N- ⁇ 3-[1-(3-aminopropyl)-4-piperidinyl]phenyl ⁇ propan amide according to the procedures described in Scheme 10: ESMS m/e: 482.3 (M + H) + .
  • Example 59
  • Example 60 was prepared from 1-(4- fluorophenyl)cyclopentanecarboxylic acid and N- ⁇ 3-[1-(3-aminopropyl)-4-piperidinyl] phenyl ⁇ propanamide according to the procedures described in Scheme 10: ESMS m/e: 480.4 (M + H) + .
  • Example 61 was prepared from 1-(4-fluoro phenyl)cyclohexanecarboxylic acid and N- ⁇ 3-[1-(3-aminopropyl)-4-piperidinyl]phenyl ⁇ propanamide according to the procedures described in Scheme 10: ESMS m/e: 494.4 (M + H) + .
  • Example 62 was prepared from 1-(4-chloro phenyl)cyclopentanecarboxylic acid and N- ⁇ 3-[1-(3-aminopropyl)-4-piperidinyl]phenyl ⁇ propanamide according to the procedures described in Scheme 10: ESMS m/e: 496.4 (M + H) + .
  • Example 63 was prepared from 1-(4- chlorophenyl)cyclopropanecarboxylic acid and N- ⁇ 3-[1-(3-aminopropyl)-4-piperidinyl]phenyl ⁇ propanamide according to the procedures described in Scheme 10: ESMS m/e: 468.3 (M + H) + .
  • Example 64 was prepared from 2-(4-fluorophenyl)propanoic acid and N- ⁇ 3-[1-(3-aminopropyl)-4-piperidinyl]phenyl ⁇ propanamide according to the procedures described in Scheme 10: ESMS m/e: 440.4 (M + H) + .
  • Example 65 was prepared from diphenylacetyl chloride and N- ⁇ 5-[1-(3- aminopropyl)-4-piperidinyl]-2-fluorophenyl ⁇ butanamide according to the procedures described in Scheme 8: 1 H NMR (400 MHz, CDCI 3 ) ⁇ 8.33-8.18 (m, 1H), 7.49-7.10 (m, 12H), 7.10-6.93 (m, 1 H), 6.90-676 (br, 1H), 4.87 (s, 1 H), 3.44-3.28 (m, 2H), 3.06-2.89 (m, 2H), 2.56-2.40 (m, 3H), 2.40-2.31 (m, 2H), 2.13-1.93 (m, 2H), 1.86-1.52 (m, 8H), 1.01 (t,
  • Example 80 was prepared from 2-(4-chlorophenyl)- 2-methylpropanoic acid and N- ⁇ 3-[1-(3-aminopropyl)-4-piperidinyl]phenyl ⁇ butanamide according to the procedures described in Scheme 9: ESMS m/e: 484.3 (M + H) + .
  • Example 104 was prepared from bis(4-fluoro phenyl)acetic acid and N- ⁇ 5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl ⁇ butanamide according to the procedures described in Scheme 10: 1 H NMR (400 MHz, CDCI 3 ) ⁇ 8.33-8.14 (m, 1H), 7.89-7.67 (br, 1H), 7.51-6.60 (m, 10H), 4.98-479 (br, 1H), 4.75 (s, 1H), 3.46-3.29 (m, 2H), 3.29-3.08 (m, 2H), 279-2.63 (m, 2H), 2.63-2.46 (m, 1H), 2.46-2.21 (m,
  • Example 107 was prepared from 1- (4-fluorophenyl)cyclopentanecarboxylic acid and N- ⁇ 5-[1-(3-aminopropyl)-4-piperidinyl]-2- fluorophenyljbutanamide according to the procedures described in Scheme 10: 1 H NMR (400 MHz, CDCI 3 ) ⁇ 8.30-8.13 (m, 1H), 8.09-7.95 (br, 1H), 7.47-7.26 (m, 3H), 7.08-6.87 (m, 3H), 675-6.54 (br, 1H), 3.30-3.07 (m, 4H), 2.59-2.44 (m, 3H), 2.44-2.33 (m, 2H), 2.33-2.19
  • Example 108 was prepared from bis(4-chlorophenyl) acetic acid and N- ⁇ 5-[1-(3-aminopropyl)-4-piperidinyl]-2-fiuorophenyl ⁇ butan amide according to the procedures described in Scheme 10: ESMS m/e: 584.2 (M + H) + .
  • Example 10 prepared from bis(4-methylphenyl)acetic acid and N- ⁇ 5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl ⁇ butanamide according to the procedures described in Scheme 10: 1 H NMR (400 MHz, CDCI 3 ) ⁇ 8.30-8.13 (m, 1H), 8.08- 7.92 (br, 1H), 7.43-6.89 (m, 9H), 676-6.61 (br, 1H), 4.98-479 (br, 1H), 4.70 (s, 1H), 3.39- 3.16 (m, 4H), 2.83-2.63 (m, 2H), 2.63-2.47 (m, 1H), 2.45-2.12 (m, 4H), 2.27
  • Example 110 was prepared from 2-(4- chlorophenyl)-2-methylpropanoic acid and N- ⁇ 5-[1-(3-aminopropyl)-4-piperidinyl]-2- fluorophenyl ⁇ butanamide according to the procedures described in Scheme 10: 1 H NMR (400 MHz, CDCI 3 ) 8.31-8.12 (m, 1H), 7.44-7.15 (m, 5H), 7.12-6.94 (m, 1H), 675-6.61 (br, 1H), 6.61-6.46 (br, 1H), 3.35-3.12 (m, 4H), 270-2.47 (m, 3H), 2.46-2.35 (m, 2H), 2.35-2.21 (m,
  • Example 111 was prepared from bis(4- methylphenyl)acetic acid and N- ⁇ 3-[1-(3-aminopropyl)-4-piperidinyl]phenyl ⁇ cyclo propanecarboxamide according to the procedures described in Scheme 10: 1 H NMR (400 MHz, CDCI 3 ) ⁇ 8.24-8.04 (br, 1H), 8.04-7.95 (br, 1H), 7.59-6.92 (m, 10H), 6.90-676 (m, 1H),
  • Example 112 was prepared from 1-(4-chlorophenyl)cyclopentanecarboxylic acid and N- ⁇ 3-[1-(3-aminopropyl)-4- piperidinyl]phenyl ⁇ cyclopropanecarboxamide according to the procedures described in Scheme 10: 1 H NMR (400 MHz, CDCI 3 ) ⁇ 8.03-7.87 (br, 1H), 7.56-7.02 (m, 8H), 6.91-6.65 (br, 1H), 3.30-3.05 (m, 4H), 2.62-2.38 (m, 3H), 2.38-2.21 (m, 2H), 1.98-1.51 (m, 15H), 1.14- 1.01 (m, 2H
  • Example 113 was prepared from bis(4- chlorophenyl)acetic acid and N- ⁇ 3-[1-(3-aminopropyl)-4-piperidinyl]phenyl ⁇ cyclo propanecarboxamide according to the procedures described in Scheme 10: 1 H NMR (400 MHz, CDCI 3 ) ⁇ 7.84-7.80 (br, 1H), 7.80-7.69 (br, 1H), 7.64-7.46 (br, 1H), 7.40-6.90 (m, 9H), 6.85-6.66 (m, 1H), 4.94-474 (br, 1 H), 4.69 (s, 1H), 3.41-3.25 (m, 2H), 3.25-3.07 (m, 2H), 277-2.61
  • Example 114 was prepared from triphenylacetic acid and N- ⁇ 3-[1-(3-aminopropyl)-4-piperidinyl] phenylcyclopropanecarboxamide according to the procedures described in Scheme 10: ESMS m/e: 572.3 (M + H) + .
  • Example 116 was prepared from 2-(4- chlorophenyl)propanoic acid and N- ⁇ 3-[1-(3-aminopropyl)-4-piperidinyl]phenyl
  • Example 119 was prepared from 1-(2-chloro-4-fluorophenyl)cyclopentanecarboxylic acid and N- ⁇ 3-[1-(3- aminopropyl)-4-piperidinyl]phenyl ⁇ cyclopropane carboxamide according to the procedures described in Scheme 10: ESMS m/e: 526.2 (M + H) + .
  • Example 120 was prepared from bis(4- fluorophenyl)acetic acid and N- ⁇ 3-[1-(3-aminopropyl)-4-piperidinyl]phenyl ⁇ cyclopro panecarboxamide according to the procedures described in Scheme 10: 1 H NMR (400 MHz, CDCI 3 ) ⁇ 7.64-7.55 (s, 1H), 7.55-7.47 (s, 1H), 7.47-7.37 (br, 1H), 7.36-7.17 (m, 6H), 7.05- 6.95 (m, 4H), 6.95-6.87 (br, 1H), 4.81 (s, 1H), 3.47-3.35 (m, 2H), 3.07-2.94 (m, 2H), 2.58- 2.41
  • Example 123 was prepared from 2,2-diphenylpropanoic acid and N- ⁇ 3-[1-(3-aminopropyl)-4-piperidinyl] phenyljcyclopropanecarboxamide according to the procedures described in Scheme 10: ESMS m/e: 510.3 (M + H) + .
  • Example 127 was prepared from 2-(4- chlorophenyl)-2-methylpropanoic acid and N- ⁇ 3-[1-(3-aminopropyl)-4-piperidinyl]-4- fluorophenyl ⁇ -2-methylpropanamide according to the procedures described in Scheme 9: 1 H NMR (400 MHz, CDCI 3 ) ⁇ 7.95 (s, 1H), 7.73 (s, 1 H), 7.68 (s, 1 H), 7.43-7.38 (m, 1 H), 7.37- 7.26 (m, 3H), 6.93-6.83 (m, 2H), 3.96-3.61 (m, 1H), 3.26-3.02 (m, 4H), 2.69-2.59 (m, 1H), 2.51-2.
  • Example 132 was prepared from bis(4- methylphenyl)acetic acid and N- ⁇ 3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl ⁇ -2- methylpropanamide according to the procedures described in Scheme 9: 1 H NMR (400 MHz,
  • CDCI 3 CDCI 3 ) ⁇ 7.72 (s, 1H), 7.36-7.31 (m, 1H), 7.28-7.21 (m, 1H), 7.12-7.07 (m, 3H), 7.03-6.99 (m,
  • Example 137 was prepared from 1-(2-chloro-4-fluorophenyl)cyclopentanecarboxylic acid and N- ⁇ 3-[1-(3- aminopropyl)-4-piperidinyI]-4-fluorophenyl ⁇ -2-methylpropanamide according to the procedures described in Scheme 9: ESMS m/e: 546.1 (M + H) + .
  • Example 139 was prepared from bis(4-fluoro phenyl)acetic acid and N'- ⁇ 3-[1-(3-aminopropyl)-4-piperidinyl]phenyl ⁇ -N,N-dimethylurea according to the procedures described in Scheme 9: ESMS m/e: 535.4 (M + H) + .
  • Example 140 was prepared from diphenylacetyl chloride and benzyl 3-[1-(3-aminopropyl)-4- piperidinyljphenyl carbamate according to the procedures described in Scheme 8: ESMS m/e: 562.5 (M + H) + .
  • Example 141 was prepared from bis(4-fluorophenyl)acetic acid and benzyl 3-[1-(3-amino propyl)-4-piperidinyl]phenylcarbamate according to the procedures described in Scheme 9: ESMS m/e: 598.5 (M + H) + .
  • Example 147 was prepared from 1-(2-chloro-4-fluorophenyl)cyclohexanecarboxylic acid and isopropyl 3-[1-(3-amino propyl)-4- piperidinyl]phenyl carbamate according to the procedures described in Scheme 9: ESMS m/e: 558.1 (M + H) + .
  • Example 148 was prepared from N-(3-bromopropyl)-2,2-diphenyl acetamide and 2-methyl-N-[4-(4-piperidinyl) phenyl] propanamide according to the procedures described in Scheme 14: ESMS m/e: 498.3 (M + H) + .
  • Example 149 was prepared from N-(3-bromopropyl)-2,2-diphenylacetamide and N- [4-(4-piperidinyl)phenyl]butanamide according to the procedures described in Scheme 14: ESMS m/e: 498.3 (M + H) + .
  • Example 151 was prepared from 3,3-diphenylpropanoic acid and N- ⁇ 3-[1-(3-aminopropyl)-4-piperidinyl] phenyl ⁇ cyclopropane carboxamide according to the procedures described in Scheme 9: ESMS m/e: 510.4 (M + H) + .
  • Example 152 was prepared via hydrogenation of benzyl 3-(1- ⁇ 3-[(diphenylacetyl)amino] propyl ⁇ -4-piperidinyl)phenylcarbamate according to the procedures described in Scheme 15: ESMS m/e: 428.3 (M + H) + .
  • Example 153 was prepared from (3,4-difluorophenyl)(hydroxy)acetic acid and N- ⁇ 3-[1 -(3-aminopropyl)-4-piperidinyl]-4-methylphenyl ⁇ -2-methylpropanamide according to the procedures described in Scheme 12: ESMS m/e: 488.3 (M + H) + .
  • N- ⁇ 3-[1-(3- ⁇ [hydroxy(diphenyl)acetyl]amino ⁇ propyl)-4-piperidinyl]-4-methylphenyl ⁇ -2-methyl propanamide A mixture of hydroxy(diphenyl)acetic acid (100 mg, 0.44 mmol) and 1 ,1'- carbonyldiimidazole (78 mg, 0.48 mmol) in CH 2 CI 2 (5 mL) was stirred at room temperature for 3 h, then a solution of N- ⁇ 3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl ⁇ -2-methyl propanamide (140 mg, 0.44 mmol) in CH 2 CI 2 (5 mL) was added.
  • Example 156 was prepared from bis(4-fluorophenyl)(hydroxy)acetic acid and N- ⁇ 3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl ⁇ -2-methylpropanamide according to the procedures described in Scheme 12: 1 H NMR (400 MHz, CDCI 3 ) ⁇ 9.44 (s, br, 1 H), 8.18 (s, 1 H), 7.62-7.48 (m, 4 H), 7.32 (s, 1 H), 7.07-7.00 (m, 1 H), 7.00-6.89 (m, 4 H), 672-6.53 (m, 1 H), 5.96-571 (br, 1 H), 3.55-3.44 (m, 2 H), 3.14-3.02 (m, 2 H), 2.8
  • Example 158 was prepared from bis(2-chlorophenyl)(hydroxy)acetic acid and N- ⁇ 3-[1 -(3-aminopropyl)-4-piperidinyl]-4-methylphenyl ⁇ -2-methylpropanamide according to the procedures described in Scheme 12:
  • Example 160 was prepared from bis(4-fluoro phenyl) (hydroxy)acetic acid and N- ⁇ 5-[1-(3-aminopropyl)-4-piperidinyl]-2,4-difluoro phenyl ⁇ -2-methyl propanamide according to the procedures described in Scheme 12:
  • Example 161 was prepared from (2S)-2-phenylpropanoic acid and N- ⁇ 3-[1-(3- aminopropyl)-4-piperidinyl]-4-methyIphenyl ⁇ -2-methylpropanamide according to the procedures described in Scheme 12:
  • Example 170 was prepared from N-(3-bromopropyl)-2,2-diphenylacetamide and 2-methyl-N- [5-(4-piperidinyl)-3-pyridinyl]propanamide according to the procedures described in Scheme 14: 1 H NMR (400 MHz, CDCI 3 ) ⁇ 8.47-8.42 (m, 1 H), 8.21-8.16 (m, 1 H), 8.09 (s, 1 H), 7.59 (s, 1 H), 7.35-7.20 (m, 10 H), 6.87 (s, 1 H), 4.91 (s, 1 H), 3.46-3.36 (m, 2 H), 3.01-2.92 (m, 2 H), 2.62-2.47 (m, 2 H), 2.47-2.37 (m, 2 H), 2.11-1.94 (m, 4 H), 1.86
  • Example 171 was prepared from N-(3-bromopropyl)-2,2-diphenylacetamide and 2- methyl-N-[2,4,6-trifluoro-3-(4-piperidinyl)phenyl]propanamide according to the procedures described in Scheme 14; ESMS m/e: 552.3 (M + H) + .
  • Example 172 was prepared from N-(3-bromopropyl)-2,2-bis(4-fluoro phenyl) acetamide and 2-methyl-N-[5-(4-piperidinyl)-3-pyridinyl]propanamide according to the procedures described in Scheme 14: 1 H NMR (400 MHz, CDCI 3 ) ⁇ 8.39 (s, 1 H), 8.19 (s, 1 H), 8.17 (S, 1 H), 7.95 (s, 1 H), 7.31-7.20 (m, 5 H), 7.04-6.94 (m, 4 H), 4.82 (s, 1 H), 3.46- 3.35 (m, 2 H), 2.98-2.92 (m, 2 H), 2.62-2.48 (m, 2 H), 2.48-2.38 (m, 2
  • Example 173 was prepared from N-(3-bromopropyl)-2,2-bis(4-fluoro phenyl)acetamide and 2-methyl-N-[2,4,6-trifluoro-3-(4-piperidinyl)phenyl]propanamide according to the procedures described in Scheme 14; ESMS m/e: 588.3 (M + H) + .
  • Example 174 was prepared from amino(diphenyl)acetic acid and ⁇ /- ⁇ 3-[1-(3- aminopropyl)-4-piperidinyl]-4-fluorophenyl ⁇ cyclopropanecarboxamide according to the procedures described in Scheme 12; ESMS m/e: 529.4 (M + H) + .
  • Example 176 was prepared from hydroxy(diphenyl)acetic acid and ⁇ /- ⁇ 5-[1-(3- aminopropyl)-4-piperidinyl]-3-pyridinyl ⁇ -2-methylpropanamide according procedures described in Scheme 12; ESMS m/e: 515.4 (M + H) + .
  • Example 177 was prepared from bis(4-fluorophenyl) (hydroxy)acetic acid and ⁇ /- ⁇ 5-[1-(3-aminopropyl)-4-piperidinyl]-3-pyridinyl ⁇ -2-methylpropan amide according procedures described in Scheme 12; ESMS m/e: 551.3 (M + H) + .
  • Example 178 was prepared from hydroxy[bis(4-methylphenyl)]acetic acid and ⁇ /- ⁇ 5-[1-(3-aminopropyl)-4-piperidinyl]-3-pyridinyl ⁇ -2-methyl propanamide according procedures described in Scheme 12; ESMS m/e: 543.4 (M + H) + .
  • an oral composition of a compound of this invention 100 mg of one of the compounds described herein is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 hard gel capsule.
  • a broad variety of host cells can be used to study heterologously expressed proteins. These cells include but are not restricted to assorted mammalian lines such as: Cos-7, CHO, LM(tk- ), HEK293, Peak rapid 293, etc.; insect cell lines such as: Sf9, Sf21, etc.; amphibian cells such as xenopus oocytes; and others.
  • COS 7 cells are grown on 150 mm plates in DMEM with supplements (Dulbecco's Modified Eagle Medium with 10% bovine calf serum, 4 mM glutamine, 100 units/ml penicillin/100 Fg/ml streptomycin) at 37°C, 5% C0 2 .
  • Peak rapid 293 (Peakr293) cells are grown on 150 mm plates in DMEM with supplements (10% fetal bovine serum, 10% L-glutamine, 50 Fg/ml gentamycin) at 37°C, 5% C0 2 .
  • Stock plates of Peak rapid 293 cells are trypsinized and split 1 :12 every 3- 4 days.
  • Mouse fibroblast LM(tk-) cells are grown on 150 mm plates in DMEM with supplements (Dulbecco's Modified Eagle Medium with 10% bovine calf serum, 4 mM glutamine, 100 units/ml penicillin/100 Fg/ml streptomycin) at 37°C, 5% C0 2 .
  • LM(tk-) cells Stock plates of LM(tk-) cells are trypsinized and split 1:10 every 3-4 days.
  • Stock plates of CHO cells are trypsinized and split 1:8 every 3-4 days.
  • Stock plates of NIH-3T3 cells are trypsinized and split 1 :15 every 3-4 days.
  • Sf9 and Sf21 cells are grown in monolayers on 150 mm tissue culture dishes in TMN-FH media supplemented with 10% fetal calf serum, at 27°C, no C0 2 .
  • High Five insect cells are grown on 150 mm tissue culture dishes in Ex-Cell 400TM medium supplemented with L-Glutamine, also at 27°C, no C0 2 .
  • cell lines that grow as adherent monolayers can be converted to suspension culture to increase cell yield and provide large batches of uniform assay material for routine receptor screening projects.
  • DNA encoding proteins to be studied can be transiently expressed in a variety of mammalian, insect, amphibian and other cell lines by several methods including but not restricted to; calcium phosphate-mediated, DEAE-dextran mediated, Liposomal-mediated, viral-mediated, electroporation-mediated and microinjection delivery. Each of these methods may require optimization of assorted experimental parameters depending on the DNA, cell line, and the type of assay to be subsequently employed.
  • a typical protocol for the calcium phosphate method as applied to Peak rapid 293 cells is described as follows: Adherent cells are harvested approximately twenty-four hours before transfection and replated at a density of 3.5 x 10 6 cells/dish in a 150 mm tissue culture dish and allowed to incubate over night at
  • 250 FI of a mixture of CaCI 2 and DNA (15 Fg DNA in 250 mM CaCI 2 ) is added to a 5 ml plastic tube and 500 FI of 2X HBS (280 mM NaCl, 10 mM KCI, 1.5 mM Na 2 HP0 4 , 12 mM dextrose, 50 mM HEPES) is slowly added with gentle mixing. The mixture is allowed to incubate for 20 minutes at room temperature to allow a DNA precipitate to form. The DNA precipitate mixture is then added to the culture medium in each plate and incubated for 5 hours at 37°C, 5% C0 2 .
  • 2X HBS 280 mM NaCl, 10 mM KCI, 1.5 mM Na 2 HP0 4 , 12 mM dextrose, 50 mM HEPES
  • G ⁇ protein expression vector, reporter construct, antibiotic resistance marker, mock vector, etc. are added to 9 ml of complete DMEM plus DEAE-dextran mixture (10 mg/ml in PBS).
  • Cos-7 cells plated into a T225 flask (sub-confluent) are washed once with PBS and the DNA mixture is added to each flask. The cells are allowed to incubate for 30 minutes at 37°C, 5% C0 2 . Following the incubation, 36 ml of complete DMEM with 80 FM chloroquine is added to each flask and allowed to incubate an additional 3 hours. The medium is then aspirated and 24 ml of complete medium containing 10% DMSO for exactly 2 minutes and then aspirated.
  • the cells are then washed 2 times with PBS and 30 ml of complete DMEM added to each flask. The cells are then allowed to incubate over night. The next day the cells are harvested by trypsinization and reseeded as needed depending upon the type of assay to be performed.
  • a typical protocol for liposomal-mediated transfection as applied to CHO cells is described as follows; Cells to be used for transfection are split 24 hours prior to the transfection to provide flasks which are 70-80% confluent at the time of transfection. A total of 10Fg of DNA which may include varying ratios of receptor DNA plus any additional DNA needed (e.g. G ⁇ protein expression vector, reporter construct, antibiotic resistance marker, mock vector, etc.) is used to transfect each 75 cm 2 flask of cells. Liposomal mediated transfection is carried out according to the manufacturer's recommendations (LipofectAMINE, GibcoBRL, Bethesda, MD).
  • Transfected cells are harvested 24 hours post transfection and used or reseeded according the requirements of the assay to be employed.
  • a typical protocol for the electroporation method as applied to Cos-7 cells is described as follows; Cells to be used for transfection are split 24 hours prior to the transfection to provide flasks which are subconfluent at the time of transfection. The cells are harvested by trypsinization resuspended in their growth media and counted. 4 x 10 6 cells are suspended in 300 FI of DMEM and placed into an electroporation cuvette. 8 Fg of receptor DNA plus 8 Fg of any additional DNA needed (e.g.
  • G ⁇ protein expression vector, reporter construct, antibiotic resistance marker, mock vector, etc. is added to the cell suspension, the cuvette is placed into a BioRad Gene Pulser and subjected to an electrical pulse (Gene Pulser settings: 0.25 kV voltage, 950 FF capacitance). Following the pulse, 800 FI of complete DMEM is added to each cuvette and the suspension transferred to a sterile tube. Complete medium is added to each tube to bring the final cell concentration to 1 x 10 5 cells/100 FI. The cells are then plated as needed depending upon the type of assay to be performed.
  • a typical protocol for viral mediated expression of heterologous proteins is described as follows for baculovirus infection of insect Sf9 cells.
  • the coding region of DNA encoding the receptor disclosed herein may be subcloned into pBlueBaclll into existing restriction sites or sites engineered into sequences 5' and 3' to the coding region of the polypeptides.
  • Heterologous DNA can be stably incorporated into host cells, causing the cell to perpetually express a foreign protein.
  • Methods for the delivery of the DNA into the cell are similar to those described above for transient expression but require the co-transfection of an ancillary gene to confer drug resistance on the targeted host cell. The ensuing drug resistance can be exploited to select and maintain cells that have taken up the heterologous DNA.
  • An assortment of resistance genes are available including but not restricted to Neomycin, Kanamycin, and Hygromycin.
  • stable expression of a heterologous receptor protein is carried out in, but not necessarily restricted to, mammalian cells including, CHO, HEK293, LM(tk-), etc.
  • pellets of transfected cells are suspended in ice-cold buffer (20 mM Tris. HCI, 5 mM EDTA, pH 7.4) and homogenized by sonication for 7 sec.
  • the cell lysates are centrifuged at 200 x g for 5 min at 4°C.
  • the supernatants are then centrifuged at 40,000 x g for 20 min at 4°C.
  • the resulting pellets are washed once in the homogenization buffer and suspended in binding buffer (see methods for radioligand binding). Protein concentrations are determined by the method of Bradford (1976) using bovine serum albumin as the standard. Binding assays are usually performed immediately, however it is possible to prepare membranes in batch and store frozen in liquid nitrogen for future use.
  • Plasmid pcDNA3.1-rMCH1-f comprises the regulatory elements necessary for expression of DNA in a mammalian cell operatively linked to DNA encoding the rat MCH1 receptor so as to permit expression thereof. Plasmid pcDNA3.1-rMCH1-f was deposited on July 05, 2001, with the American Type Culture Collection (ATCC), 12301 Parklawn Drive, Rockville, Maryland 20852, U.S.A.
  • Binding assays can also be performed as described hereinafter using plasmid pEXJ.HR-TL231 (ATCC Accession No. 203197) Plasmid pEXJ.HR-TL231 encodes the human MCH1 receptor and was deposited on September 17, 1998, with the American Type Culture Collection (ATCC), 12301 Parklawn Drive, Rockville, Maryland 20852, U.S.A.

Abstract

This invention is directed to compounds which are selective antagonists for melanin concentrating hormone-1 (MCH1) receptors. The invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of the invention and a pharmaceutically acceptable carrier. This invention provides a pharmaceutical composition made by combining a therapeutically effective amount of the compound of this invention and a pharmaceutically acceptable carrier. This invention further provides a process for making a pharmaceutical composition comprising combining a therapeutically effective amount of the compound of the invention and a pharmaceutically acceptable carrier. This invention also provides a method of reducing the body mass of a subject which comprises administering to the subject an amount of a compound of the invention effective to reduce the body mass of the subject. This invention further provides a method of treating a subject suffering from depression and/or anxiety which comprises administering to the subject an amount of a compound of the invention effective to treat the subject's depression and/or anxiety.

Description

SUBSTITUTED ALKYL A IDO PIPERID1NES
BACKGROUND OF THE INVENTION
Melanin-concentrating hormone (MCH) is a cyclic peptide originally isolated from salmonid (teleost fish) pituitaries (Kawauchi et al., 1983). In fish, the 17 amino acid peptide causes aggregation of melanin within the melanophores and inhibits the release of ACTH, acting as a functional antagonist of α-MSH. Mammalian MCH (19 amino acids) is highly conserved between rat, mouse, and human, exhibiting 100% amino acid identity, but its physiological roles are less clear. MCH has been reported to participate in a variety of processes including feeding, water balance, energy metabolism, general arousal/attention state, memory and cognitive functions, and psychiatric disorders (for reviews, see Baker, 1991; Baker, 1994; Nahon, 1994; Knigge et al., 1996). Its role in feeding or body weight regulation is supported by a recent Nature publication (Qu et al., 1996) demonstrating that MCH is overexpressed in the hypothalamus of ob/ob mice compared with ob/+ mice, and that fasting further increased MCH mRNA in both obese and normal mice during fasting. MCH also stimulated feeding in normal rats when injected into the lateral ventricles (Rossi et al., 1997). MCH also has been reported to functionally antagonize the behavioral effects of α-MSH (Miller et al., 1993; Gonzalez et al, 1996; Sanchez et al., 1997); in addition, stress has been shown to increase POMC mRNA levels while decreasing the MCH precursor preproMCH (ppMCH) mRNA levels (Presse et al., 1992). Thus MCH may serve as an integrative neuropeptide involved in the reaction to stress, as well as in the regulation of feeding and sexual activity (Baker, 1991 ; Knigge et al., 1996).
Although the biological effects of MCH are believed to be mediated by specific receptors, binding sites for MCH have not been well described. A tritiated ligand ([3H]-MCH) was reported to exhibit specific binding to brain membranes but was unusable for saturation analyses, so neither affinity nor Bmax were determined (Drozdz and Eberle, 1995).
Radioiodination of the tyrosine at position thirteen resulted in a ligand with dramatically reduced biological activity (see Drozdz and Eberle, 1995). In contrast, the radioiodination of the MCH analogue [Phe13,Tyr19]-MCH was successful (Drozdz et al., 1995); the ligand retained biological activity and exhibited specific binding to a variety of cell lines including mouse melanoma (B16-F1, G4F, and G4F-7), PC12, and COS cells. In G4F-7 cells, the KD
= 0.118nM and the Bmax -1100 sites/cell. Importantly, the binding was not inhibited by α-
MSH but was weakly inhibited by rat ANF (Ki = 116 nM vs. 12 nM for native MCH) (Drozdz et al., 1995). More recently specific MCH binding was reported in transformed keratinocytes
(Burgaud et al., 1997) and melanoma cells (Drozdz et al., 1998), where photo-crosslinking studies suggest that the receptor is a membrane protein with an apparent molecular weight of 45-50 kDaltons, compatible with the molecular weight range of the GPCR superfamily of receptors. No radioautoradiographic studies of MCH receptor localization using this ligand have been reported as yet.
The localization and biological activities of MCH peptide suggest that the modulation of MCH receptor activity may be useful in a number of therapeutic applications. The role of MCH in feeding is the best characterized of its potential clinical uses. MCH is expressed in the lateral hypothalamus, a brain area implicated in the regulation of thirst and hunger (Grillon et al., 1997); recently orexins A and B, which are potent orexigenic agents, have been shown to have very similar localization to MCH in the lateral hypothalamus (Sakurai et al., 1998). MCH mRNA levels in this brain region are increased in rats after 24 hours of food-deprivation (Herve and Fellman, 1997); after insulin injection, a significant increase in the abundance and staining intensity of MCH immunoreactive perikarya and fibres was observed concurrent with a significant increase in the level of MCH mRNA (Bahjaoui-Bouhaddi et al., 1994). Consistent with the ability of MCH to stimulate feeding in rats (Rossi et al., 1997) is the observation that MCH mRNA levels are upregulated in the hypothalami of obese ob/ob mice (Qu et al., 1996), and decreased in the hypothalami of rats treated with leptin, whose food intake and body weight gains are also decreased (Sahu, 1998). MCH appears to act as a functional antagonist of the melanocortin system in its effects on food intake and on hormone secretion within the HPA (hypothalamopituitary/adrenal axis) (Ludwig et al., 1998). Together these data suggest a role for endogenous MCH in the regulation of energy balance and response to stress, and provide a rationale for the development of specific compounds acting at MCH receptors for use in the treatment of obesity and stress-related disorders.
In all species studied to date, a major portion of the neurons of the MCH cell group occupies a rather constant location in those areas of the lateral hypothalamus and subthalamus where they lie and may be a part of some of the so-called "extrapyramidal" motor circuits. These involve substantial striato- and pallidofugal pathways involving the thalamus and cerebral cortex, hypothalamic areas, and reciprocal connections to subthalamic nucleus, substantia nigra, and mid-brain centers (Bittencourt et al., 1992). In their location, the MCH cell group may offer a bridge or mechanism for expressing hypothalamic visceral activity with appropriate and coordinated motor activity. Clinically it may be of some value to consider the involvement of this MCH system in movement disorders, such as Parkinson's disease and Huntingdon's Chorea in which extrapyramidal circuits are known to be involved.
Human genetic linkage studies have located authentic hMCH loci on chromosome 12 (12q23-24) and the variant hMCH loci on chromosome 5 (5q12-13) (Pedeutour et al., 1994). Locus 12q23-24 coincides with a locus to which autosomal dominant cerebellar ataxia type II (SCA2) has been mapped (Auburger et al., 1992; Twells et al., 1992). This disease comprises neurodegenerative disorders, including an olivopontocerebellar atrophy. Furthermore, the gene for Darier's disease, has been mapped to locus 12q23-24 (Craddock et al., 1993). Darier's disease is characterized by abnormalities I keratinocyte adhesion and mental illnesses in some families. In view of the functional and neuroanatomical patterns of the MCH neural system in the rat and human brains, the MCH gene may represent a good candidate for SCA2 or Darier's disease. Interestingly, diseases with high social impact have been mapped to this locus. Indeed, the gene responsible for chronic or acute forms of spinal muscular atrophies has been assigned to chromosome 5q12-13 using genetic linkage analysis (Melki et al., 1990; Westbrook et al., 1992). Furthermore, independent lines of evidence support the assignment of a major schizophrenia locus to chromosome 5q11.2- 13.3 (Sherrington et al., 1988; Bassett et al., 1988; Gilliam et al., 1989). The above studies suggest that MCH may play a role in neurodegenerative diseases and disorders of emotion.
Additional therapeutic applications for MCH-related compounds are suggested by the observed effects of MCH in other biological systems. For example, MCH may regulate reproductive functions in male and female rats. MCH transcripts and MCH peptide were found within germ cells in testes of adult rats, suggesting that MCH may participate in stem cell renewal and/or differentiation of early spermatocytes (Hervieu et al., 1996). MCH injected directly into the medial preoptic area (MPOA) or ventromedial nucleus (VMN) stimulated sexual activity in female rats (Gonzalez et al., 1996). In ovariectomized rats primed with estradiol, MCH stimulated luteinizing hormone (LH) release while anti-MCH antiserum inhibited LH release (Gonzalez et al., 1997). The zona incerta, which contains a large population of MCH cell bodies, has previously been identified as a regulatory site for the pre-ovulatory LH surge (MacKenzie et al., 1984). MCH has been reported to influence release of pituitary hormones including ACTH and oxytocin. MCH analogues may also be useful in treating epilepsy. In the PTZ seizure model, injection of MCH prior to seizure induction prevented seizure activity in both rats and guinea pigs, suggesting that MCH- containing neurons may participate in the neural circuitry underlying PTZ-induced seizure (Knigge and Wagner, 1997). MCH has also been observed to affect behavioral correlates of cognitive functions. MCH treatment hastened extinction of the passive avoidance response in rats (McBride et al., 1994), raising the possibility that MCH receptor antagonists may be beneficial for memory storage and/or retention. A possible role for MCH in the modulation or perception of pain is supported by the dense innervation of the periaqueductal grey (PAG) by MCH-positive fibers. Finally, MCH may participate in the regulation of fluid intake. ICV infusion of MCH in conscious sheep produced diuretic, natriuretic, and kaliuretic changes in response to increased plasma volume (Parkes, 1996). Together with anatomical data reporting the presence of MCH in fluid regulatory areas of the brain, the results indicate that MCH may be an important peptide involved in the central control of fluid homeostasis in mammals.
The identification of a G-protein coupled receptor for MCH has recently been published (Chambers et al., 1999; Saito et al., 1999). These groups identified MCH as the endogenous ligand for the human orphan G-protein coupled receptor SLC-1 (Lakaye et al., 1998). The rat homologue of this receptor (now called MCH-1 ) was reported to be localized in regions of the rat brain associated with feeding behavior (e.g. dorsomedial and ventromedial hypothalamus). The link between MCH-1 and the effects of MCH on feeding has been strengthened by recent reports on the phenotype of MCH-1 knockout mice. Two groups have shown independently (Marsh et al, 2002; Chen et al, 2002) that the targeted disruption of the MCH-1 receptor gene (MCH-1 knockout) in mice results in animals that are hyperphagic but are lean and have decreased body mass relative to wild-type littermates. The decrease in body mass is attributed to an increase in metabolism. Each group demonstrated that the MCH-1 knockout mice are resistant to diet-induced obesity, and generally exhibit weights similar to littermates maintained on regular chow.
Finally, synthetic antagonist molecules for the MCH-1 receptor have now been described in the literature. Bednarek et al. (Bednarek et al. 2002) have reported on the synthesis of high affinity peptide antagonists of MCH-1. In addition, a small molecule antagonist of MCH-1 has been described by Takekawa et al. (Takekawa et al., 2002). This compound, T-226296, exhibits high affinity for the MCH-1 receptor (~ 5-9 nM for rat and human MCH-1), and was shown to inhibit food intake induced by the intracerebroventricular application of MCH. These data validate the strategy of using an MCH-1 receptor antagonist to treat obesity.
Furthermore, in our own studies, we have tested MCH1 antagonists in several animal models that are well known as predictive for the efficacy of compounds in humans, see Borowsky, et al. (2002). These experiments indicate that MCH1 antagonists are useful to treat obesity, depression, anxiety, as well as urinary disorders.
As used in this invention, the term "antagonist" refers to a compound which binds to, and decreases the activity of, a receptor in the presence of an agonist. In the case of a G-protein coupled receptor, activation may be measured using any appropriate second messenger system which is coupled to the receptor in a cell or tissue in which the receptor is expressed. Some specific, but by no means limiting, examples of well-known second messenger systems are adenylate cyclase, intracellular calcium mobilization, ion channel activation, guanylate cyclase and inositol phospholipid hydrolysis. Conversely, the term "agonist" refers to a compound which binds to, and increases activity of, a receptor as compared with the activity of the receptor in the absence of any agonist.
In one embodiment of this invention, the synthesis of novel compounds which bind selectively to the cloned human melanin-concentrating hormone-1 (MCH1) receptor, compared to other cloned G-protein coupled receptors, and inhibit the activation of the cloned receptors as measured in in vitro assays is disclosed. The in vitro receptor binding assays described hereinafter were performed using various cultured cell lines, each transfected with and expressing only a single cloned receptor.
Furthermore, the compounds of the present invention may also be used to treat abnormal conditions such as feeding disorders (obesity, bulimia and bulimia nervosa), sexual/reproductive disorders, depression, anxiety, depression and anxiety, epileptic seizure, hypertension, cerebral hemorrhage, congestive heart failure, sleep disturbances, or any condition in which antagonism of an MCH1 receptor may be beneficial. In addition, the compounds of the present invention may be used to reduce the body mass of a subject. Furthermore, the compounds of the present invention may be used to treat urinary disorders.
SUMMARY OF THE INVENTION
The present invention provides a compound having the structure:
Figure imgf000007_0001
wherein each R^ is independently hydrogen; -F; -Cl; -Br; -I; -CN; -NO2; straight chained or branched C C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl; C3-C7 cycloalkyl or C5-C7 cycloalkenyl; aryl; heteroaryl; -N(R5)2; -(CH2)mOR5; -COR5; -CO2R5; -OCOR5; -CON(R5)2; -N(R5)COR5; -N(R5)CON(R5)2; -OCON(R5)2 or -N(R5)CO2R5;
wherein R2 is hydrogen; -F; -Cl; -Br; -I; -CN; -(CH2)mOR5; -(CH2)mSR5; -NH2; straight chained or branched C C7 alkyl, monofluoroalkyl, polyfluoroalkyl; aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more R^
wherein R3 is hydrogen; -F; -Cl; -Br; -I; -CN; -(CH2)mOR5; -(CH2)mSR5; straight chained or branched C C7 alkyl, monofluoroalkyl, polyfluoroalkyl; aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more Ri; or wherein R2 and R3 together can be - (CH2)P-;
wherein R4 is straight chained or branched C C7 alkyl, monofluoroalkyl or polyfluoroalkyl, C3- C6 cycloalkyl, , C C7 alkyl - C3-C6 cycloalkyl; -N(R5)2 or -(CH2)mOR5;
wherein each R5 is independently hydrogen; aryl; heteroaryl or straight chained or branched C1-C7 alkyl, wherein the alkyl may be substituted with an aryl or heteroaryl;
wherein each R6 is independently hydrogen; straight chained or branched C C7 alkyl;
wherein each R7 is independently hydrogen; phenyl or straight chained or branched C C7 alkyl, wherein the alkyl may be substituted with a phenyl;
wherein each m is independently an integer from 0 to 5 inclusive;
wherein n is an integer from 1 to 5 inclusive;
wherein p is an integer from 2 to 7 inclusive; wherein q is an integer from 0 to 2 inclusive; and
wherein each X is independently CRi or N, provided that if one X is N then the remaining X are CR^ or a pharmaceutically acceptable salt thereof. In one embodiment of the invention, the compound is selected from one of the specific compounds disclosed in the Detailed Description of the Invention.
In an embodiment of the present invention the compound is enantiomercially pure. In another embodiment of the invention, the compound is diastereomerically pure. In a further embodiment, the compound is enantiomercially and diastereomerically pure.
The present invention further provides a pharmaceutical composition that comprises a therapeutically effective amount of a compound of the present invention and a pharmaceutically acceptable carrier.
The present invention further provides a pharmaceutical composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
The present invention also provides a process for making a pharmaceutical composition comprising admixing a compound of the present invention and a pharmaceutically acceptable carrier.
The invention further provides a method of treating a subject suffering from an affective disorder selected from the group consisting of depression, major depression, bipolar disorder, agoraphobia, specific phobia, social phobia, obsessive-compulsive disorder, post- traumatic stress disorder, acute stress disorder and anxiety comprising administering to the subject a therapeutically effective amount of the compound of the invention. In a separate embodiment of the invention, the disorder is depression or anxiety.
Additionally, the invention further provides a method of treating a subject suffering from a urinary disorder selected from the group consisting of urinary incontinence, urge incontinence, urinary frequency, urinary urgency, nocturia or enuresis comprising administering to the subject a therapeutically effective amount of the compound of the invention. In a separate embodiment of the invention, the disorder is urinary incontinence.
The invention further provides a method of treating a subject suffering from an eating disorder selected from the group consisting of obesity, bulimia, bulimia nervosa or anorexia nervosa comprising administering to the subject a therapeutically effective amount of the compound of the invention. In a separate embodiment of the invention, the disorder is obesity. DETAILED DESCRIPTION OF THE INVENTION
As used in the present invention, the term "heteroaryl" is used to include five and six membered unsaturated rings that may contain one or more oxygen, sulfur, or nitrogen atoms. Examples of heteroaryl groups include, but are not limited to, carbazole, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl. In addition, the term "heteroaryl" is used to include fused bicyclic ring systems that may contain one or more heteroatoms such as oxygen, sulfur and nitrogen. Examples of such heteroaryl groups include, but are not limited to, indolizinyl, indolyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzimidazolyl, purinyl, benzoxazolyl, benzisoxazolyl, benzo[b]thiazolyl, imidazo[2,1-b]thiazolyl, cinnolinyl, quinazolinyl, quinoxalinyl, 1 ,8- naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, phthalimidyl and 2,1 ,3-benzothiazolyl. The term "heteroaryl" also includes those chemical moieties recited above which may be substituted with one or more of the following: -F, -Cl, -Br, -I, CN, -NO2, straight chained or branched C C7 alkyl, straight chained or branched C1-C7 monofluoroalkyl, straight chained or branched C C7 polyfluoroalkyl, straight chained or branched C2-C7 alkenyl, straight chained or branched C2-C7 alkynyl; C3-C7 cycloalkyl, C3-C7 monofluorocycloalkyl, C3-C7 polyfluorocycloalkyl, C5-C7 cycloalkenyl. The term "heteroaryl" further includes the N-oxides of those chemical moieties recited above which include at least one nitrogen atom.
In the present invention, the term "aryl" is phenyl or naphthyl.
In the present invention, the term straight chained or branched C C alkyl refers to a saturated hydrocarbon having from one to seven carbon atoms inclusive, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methly-2-propyl and 2-methly-1 -propyl. Similarily, alkenyl and alkynyl, respectively, designate such groups having from two to seven carbon atoms, including one double bond and triple bond respectively, such as ethenyl, propenyl, butenyl, ethynyl, propynyl, and butynyl. The term, C3-C7 cycloalkyl designates a monocyclic carbocycle having three to seven carbon atoms, such as cyclopropyl, cyclopentyl, cyclohexyl, etc. The term, C C7 alkyl-C3-C6 cycloalkyl designates a saturated alkyl hydrocarbon substituted with a monocyclic carbocycle ring having three to seven carbon atoms attached via the CrC alkyl moiety, such as methyl-cyclopropyl, ethyl-cyclopentyl, n-propyl-cyclohexyl, etc.
The invention provides for each pure stereoisomer of any of the compounds described herein. Such stereoisomers may include enantiomers, diastereomers, or E or Z alkene or imine isomers. The invention also provides for stereoisomeric mixtures, including racemic mixtures, diastereomeric mixtures, or E/Z isomeric mixtures. Stereoisomers can be synthesized in pure form (Nόgradi, M.; Stereoselective Synthesis. (1987) VCH Editor Ebel, H. and Asymmetric Synthesis, Volumes 3 B 5, (1983) Academic Press, Editor Morrison, J.) or they can be resolved by a variety of methods such as crystallization and chromatographic techniques (Jaques, J.; Collet, A.; Wilen, S.; Enantiomer, Racemates. and Resolutions, 1981 , John Wiley and Sons and Asymmetric Synthesis, Vol. 2, 1983, Academic Press, Editor Morrison, J). In addition the compounds of the present invention may be present as ensantiomers, diasteriomers, isomers or two or more of the compounds may be present to form a racemic or diastereomeric mixture.
The compounds of the present invention are preferably 80% pure, more preferably 90% pure, and most preferably 95% pure. Included in this invention are pharmaceutically acceptable salts and complexes of all of the compounds described herein. The acids and bases from which these salts are prepared include but are not limited to the acids and bases listed herein. The acids include, but are not limited to, the following inorganic acids: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and boric acid. The acids include, but are not limited to, the following organic acids: acetic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, maleic acid, citric acid, methanesulfonic acid, benzoic acid, glycolic acid, lactic acid and mandelic acid. The bases include, but are not limited to ammonia, methylamine, ethylamine, propylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, ethylenediamine, hydroxyethylamine, morpholine, piperazine and guanidine. This invention further provides for the hydrates and poiymorphs of all of the compounds described herein.
The present invention includes within its scope prodrugs of the compounds of the invention. In general, such prodrugs will be functional derivatives of the compounds of the invention which are readily convertible in vivo into the required compound. Thus, in the present invention, the term "administering" shall encompass the treatment of the various conditions described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985. The present invention further includes metabolites of the compounds of the present invention. Metabolites include active species produced upon introduction of compounds of this invention into the biological milieu.
This invention further provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of the invention and a pharmaceutically acceptable carrier. In one embodiment, the amount of the compound is from about 0.01 mg to about 800 mg. In another embodiment, the amount of the compound is from about 0.01 mg to about 500 mg. In yet another embodiment, the amount of the compound is from about 0.1 mg to about 250 mg. In another embodiment, the amount of the compound is from about 0.1 mg to about 60 mg. In yet another embodiment, the amount of the compound is from about 1 mg to about 20 mg. In a further embodiment, the carrier is a liquid and the composition is a solution. In another embodiment, the carrier is a solid and the composition is a tablet. In another embodiment, the carrier is a gel and the composition is a capsule, suppository or a cream. In a further embodiment the compound may be formulated as a part of a pharmaceutically acceptable transdermal patch. In yet a further embodiment, the compound may be delivered to the subject by means of a spray or inhalant.. This invention also provides a pharmaceutical composition made by combining a therapeutically effective amount of the compound of this invention and a pharmaceutically acceptable carrier. This invention provides a process for making a pharmaceutical composition comprising combining a therapeutically effective amount of the compound of this invention and a pharmaceutically acceptable carrier.
A solid carrier can include one or more substances which may also act as endogenous carriers (e.g. nutrient or micronutrient carriers), flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
Liquid carriers are used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, coloring agents, viscosity regulators, stabilizers or osmoregulators. Suitable examples of liquid carriers for oral and parenteral administration include water (partially containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration, the carrier can also be an oily ester such as ethyl oleate or isopropyl myristate. Sterile liquid carriers are useful in sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions can be a halogenated hydrocarbon or other pharmaceutically acceptable propellent.
Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by for example, intramuscular, intrathecal, epidural, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. The compounds may be prepared as a sterile solid composition which may be dissolved or suspended at the time of administration using sterile water, saline, or other appropriate sterile injectable medium. Carriers are intended to include necessary and inert binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings. The compound can be administered orally in the form of a sterile solution or suspension containing other solutes or suspending agents (for example, enough saline or glucose to make the solution isotonic), bile salts, acacia, gelatin, sorbitan monoleate, polysorbate 80 (oleate esters of sorbitol and its anhydrides copolymerized with ethylene oxide) and the like.
The compound can also be administered orally either in liquid or solid composition form. Compositions suitable for oral administration include solid forms, such as pills, capsules, granules, tablets, and powders, and liquid forms, such as solutions, syrups, elixirs, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions, and suspensions. Optimal dosages to be administered may be determined by those skilled in the art, and will vary with the particular compound in use, the strength of the preparation, the mode of administration, and the advancement of the disease condition. Additional factors depending on the particular subject being treated will result in a need to adjust dosages, including subject age, weight, gender, diet, and time of administration. In the subject application a "therapeutically effective amount" is any amount of a compound which, when administered to a subject suffering from a disease against which the compounds are effective, causes reduction, remission, or regression of the disease. In a subject application, a "subject" is a vertebrate, a mammal or a human.
This invention provides a method of treating a subject suffering from an abnormality wherein the abnormality is alleviated by decreasing the activity of an MCH1 receptor which comprises administering to the subject an amount of a compound of the invention which is an MCH1 receptor antagonist effective to treat the subject's abnormality. In separate embodiments, the abnormality is a regulation of a steroid or pituitary hormone disorder, an epinephrine release disorder, a gastrointestinal disorder, a cardiovascular disorder, an electrolyte balance disorder, hypertension, diabetes, a respiratory disorder, asthma, a reproductive function disorder, an immune disorder, an endocrine disorder, a musculoskeletal disorder, a neuroendocrine disorder, a cognitive disorder, a memory disorder such as Alzheimer's disease, a sensory modulation and transmission disorder, a motor coordination disorder, a sensory integration disorder, a motor integration disorder, a dopaminergic function disorder such as Parkinson's disease, a sensory transmission disorder, an olfaction disorder, a sympathetic innervation disorder, an affective disorder such as depression and anxiety, a stress-related disorder, a fluid-balance disorder, a seizure disorder, pain, psychotic behavior such as schizophrenia, morphine tolerance, opiate addiction, migraine or a urinary disorder such as urinary incontinence.
The following description of depressive and anxiety disorders is for the purpose of illustrating the utility of the compounds of this invention. The definitions of depressive and anxiety disorders given below are those listed in Diagnostic and Statistical Manual of Mental Disorders. 4th ed. (DSM-IV; American Psychiatric Association, 1994a) or Diagnostic and Statistical Manual of Mental Disorders. 3rd ed. Revised (DSM-III-R; American Psychiatric Association, 1987). Additional information regarding these disorders can be found in this reference, as well as the others cited below, all of which are incorporated herein by reference. Depressive disorders include major depressive disorder and dysthymic disorder (American Psychiatric Association, 1994a; American Psychiatric Association, 1994b). Major depressive disorder is characterized by the occurrence of one or more major depressive episodes without manic or hypomanic episodes. A major depressive episode is defined as a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it should include at least 4 of the following 8 symptoms: change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation (Medical Economics Company, 2002). Dysthymic disorder involves a type of depression that is not severe enough to be called a major depressive episode, but that lasts much longer than major depressive disorder, without high phases.
It is contemplated that the compounds of this invention will be effective in treating depression in patients who have been diagnosed with depression by administration of any of the following tests: Hamilton Depression Rating Scale (HDRS), Hamilton depressed mood item, Clinical Global Impressions (CGI)-Severity of Illness. It is further contemplated that the compounds of the invention will be effective in inducing improvements in certain of the factors measured in these tests, such as the HDRS subfactor scores, including the depressed mood item, sleep disturbance factor and anxiety factor, and the CGl-Severity of Illness rating. It is also contemplated that the compounds of this invention will be effective in preventing relapse of major depressive episodes. Anxiety disorders include panic disorder, agoraphobia with or without history of panic disorder, specific phobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder and generalized anxiety disorder. It is contemplated that the compounds of this invention will be effective in treating any of all of these disorders in patients who have been diagnosed with these disorders. Obsessive compulsive disorder is characterized by recurrent and persistent ideas, thoughts, impulses or images (obsessions) that are ego-dystonic and/or repetitive, purposeful and intentional behaviors (compulsions) that are recognized by the person as excessive or unreasonable (American Psychiatric Association, 1994a). The obsessions or compulsions cause marked distress, are time-consuming, or significantly interfere with social or occupational functioning. It is contemplated that the compounds of this invention will be effective in treating obsessions and compulsions in patients who have been diagnosed with obsessive compulsive disorder by administration of appropriate tests, which may include, but are not limited to any of the following: Yale Brown Obsessive Compulsive Scale (YBOCS) (Goodman, 1989) (for adults), National Institute of Mental Health Global OCD Scale (NIMH GOCS), CGl-Severity of Illness scale. It is further contemplated that the compounds of the invention will be effective in inducing improvements in certain of the factors measured in these tests, such as a reduction of several points in the YBOCS total score. It is also contemplated that the compounds of this invention will be effective in preventing relapse of obsessive compulsive disorder.
Panic disorder is characterized by recurrent unexpected panic attacks and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a significant change in behavior related to the attacks (American Psychiatric
Association, 1994a). A panic attack is defined as a discrete period of intense fear or discomfort in which four (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings of unreality) or depersonalization (being detached from oneself); fear of losing control; (11) fear of dying;
(12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes. Panic disorder may or may not be associated with agoraphobia, or an irrational and often disabling fear of being out in public. It is contemplated that the compounds of this invention will be effective in treating panic disorder in patients who have been diagnosed with panic disorder on the basis of frequency of occurrence of panic attacks, or by means of the CGl-Severity of Illness scale. It is further contemplated that the compounds of the invention will be effective in inducing improvements in certain of the factors measured in these evaluations, such as a reduction in frequency or elimination of panic attacks, an improvement in the CGl-Severity of Illness scale or a CGI-Global Improvement score of 1 (very much improved), 2 (much improved) or 3 (minimally improved). It is also contemplated that the compounds of this invention will be effective in preventing relapse of panic disorder.
Social anxiety disorder, also known as social phobia, is characterized by a marked and persistent fear of one or more social or performance situations in which the person is exposed to unfamiliar people or to possible scrutiny by others (American Psychiatric Association, 1994a). Exposure to the feared situation almost invariably provokes anxiety, which may approach the intensity of a panic attack. The feared situations are avoided or endured with intense anxiety or distress. The avoidance, anxious anticipation, or distress in the feared situation(s) interferes significantly with the person's normal routine, occupational or academic functioning, or social activities or relationships, or there is marked distress about having the phobias. Lesser degrees of performance anxiety or shyness generally do not require psychopharmacological treatment. It is contemplated that the compounds of this invention will be effective in treating social anxiety disorder in patients who have been diagnosed with social anxiety disorder by administration of any of the following tests: the Liebowitz Social Anxiety Scale (LSAS), the CGl-Severity of Illness scale, the Hamilton Rating Scale for Anxiety (HAM-A), the Hamilton Rating Scale for Depression (HAM-D), the axis V Social and Occupational Functioning Assessment Scale of DSM-IV, the axis II (ICD-10) World Health Organization Disability Assessment, Schedule 2 (DAS-2), the Sheehan Disability Scales, the Schneier Disability Profile, the World Health Organization Quality of Life-100 (WHOQOL-100), or other tests as described in Bobes, 1998, which is incorporated herein by reference. It is further contemplated that the compounds of the invention will be effective in inducing improvements as measured by these tests, such as the a change from baseline in the Liebowitz Social Anxiety Scale (LSAS), or a CGI- Global Improvement score of 1 (very much improved), 2 (much improved) or 3 (minimally improved). It is also contemplated that the compounds of this invention will be effective in preventing relapse of social anxiety disorder.
Generalized anxiety disorder is characterized by excessive anxiety and worry (apprehensive expectation) that is persistent for at least 6 months and which the person finds difficult to control (American Psychiatric Association, 1994a). It must be associated with at least 3 of the following 6 symptoms: restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, sleep disturbance. The diagnostic criteria for this disorder are described in further detail in DSM- IV, which is incorporated herein by reference (American Psychiatric Association, 1994a). It is contemplated that the compounds of this invention will be effective in treating generalized anxiety disorder in patients who have been diagnosed with this disorder according to the diagnostic criteria described in DSM-IV. It is further contemplated that the compounds of the invention will be effective in reducing symptoms of this disorder, such as the following: excessive worry and anxiety, difficulty controlling worry, restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, or sleep disturbance. It is also contemplated that the compounds of this invention will be effective in preventing relapse of general anxiety disorder.
Post-traumatic stress disorder (PTSD), as defined by DSM-III-R/IV (American Psychiatric Association, 1987, American Psychiatric Association, 1994a), requires exposure to a traumatic event that involved actual or threatened death or serious injury, or threat to the physical integrity of self or others, and a response which involves intense fear, helplessness, or horror. Symptoms that occur as a result of exposure to the traumatic event include re- experiencing of the event in the form of intrusive thoughts, flashbacks or dreams, and intense psychological distress and physiological reactivity on exposure to cues to the event; avoidance of situations reminiscent of the traumatic event, inability to recall details of the event, and/or numbing of general responsiveness manifested as diminished interest in significant activities, estrangement from others, restricted range of affect, or sense of foreshortened future; and symptoms of autonomic arousal including hypervigilance, exaggerated startle response, sleep disturbance, impaired concentration, and irritability or outbursts of anger. A PTSD diagnosis requires that the symptoms are present for at least a month and that they cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. It is contemplated that the compounds of this invention will be effective in treating PTSD in patients who have been diagnosed with PTSD by administration of any of the following tests: Clinician-Administered PTSD Scale Part 2 (CAPS), the patient-rated Impact of Event Scale (IES) (Medical Economics Company, 2002, p. 2752). It is further contemplated that the compounds of the invention will be effective in inducing improvements in the scores of the CAPS, IES, CGl-Severity of Illness or CGI-Global Improvement tests. It is also contemplated that the compounds of this invention will be effective in preventing relapse of PTSD.
In a preferred embodiment, the subject invention provides a method of treatment or management of the following indications: depressive disorders, anxiety disorders, eating/body weight disorders, and urinary disorders. Examples of depressive disorders are major depressive disorder or dysthymic disorder. Examples of anxiety disorders are panic disorder, agoraphobia without history of panic disorder, specific phobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder or generalized anxiety disorder. Examples of eating/body weight disorders are obesity, weight gain, bulimia, bulimia nervosa or anorexia nervosa. Examples of urinary disorders include, but are not limited to urinary incontinence overactive bladder, urge incontinence, urinary frequency, urinary urgency, nocturia or enuresis. Overactive bladder and urinary urgency may or may not be associated with benign prostatic hyperplasia. This invention provides a method of modifying the feeding behavior of a subject, which comprises administering to the subject an amount of a compound of the invention effective to decrease the consumption of food by the subject. This invention also provides a method of treating an eating disorder in a subject, which comprises administering to the subject an amount of a compound of the invention effective to treat the eating disorder. In an embodiment of the present invention, the eating disorder is obesity, bulimia, bulimia nervosa or anorexia nervosa.
The present invention further provides a method of reducing the body mass of a subject, which comprises administering to the subject an amount of a compound of the invention effective to reduce the body mass of the subject. This invention also provides a method of managing obesity in a subject in need of weight loss, which comprises administering to the subject an amount of a compound of the invention effective to induce weight loss in the subject. This invention also provides a method of managing obesity in a subject who has experienced weight loss, which comprises administering to the subject an amount of a compound of the invention effective to maintain such weight loss in the subject. The present invention also provides a method of treating depression in a subject, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject's depression. This invention also provides a method of treating anxiety in a subject, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject's anxiety. This invention also provides a method of treating depression and anxiety in a subject, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject's depression and anxiety. This invention alsp provides a method of treating major depressive disorder in a subject, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject's major depressive disorder. This invention also provides a method of treating dysthymic disorder in a subject, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject's dysthymic disorder. This invention also provides a method of treating obsessions and compulsions in a subject with obsessive compulsive disorder, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject's obsessions and compulsions. This invention also provides a method of treating panic disorder, with or without agoraphobia, in a subject, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject's panic disorder. This invention also provides a method of treating social anxiety disorder in a subject, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject's social anxiety disorder. This invention also provides a method of treating generalized anxiety disorder in a subject, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject's generalized anxiety disorder. This invention also provides a method of treating post-traumatic stress disorder in a subject, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject's post-traumatic stress disorder.
It is contemplated that the compounds of this invention will be effective in treating obesity, including weight loss and maintenance of weight loss in patients, who have been diagnosed with obesity by the one or more of the following measurements: an increased body mass index, increased waist circumference (an indicator of intra-adominal fat), Dual Energy X-Ray Absorptiometry (DEXA) and trucal (android) fat mass. It is further contemplated that the compounds of the invention will be effective in inducing improvements in certain factors measured in these tests. It is contemplated that the compounds of this invention will be effective in treating urinary disorders in patients who have urge or mixed (with a predominance of urge) incontinence as evidenced by the number of unnecessary episodes per week, the number of unnecessary micturitions per day and a low volume voided per micturition. It is further contemplated that the compounds of the invention will be effective in inducing improvements in certain factors measured in these tests.
The present invention also provides a method of treating a subject suffering from bipolar I or II disorder, schizoaffective disorder, a cognitive disorder with depressed mood, a personality disorder, insomnia, hypersomnia, narcolepsy, circadian rhythm sleep disorder, nightmare disorder, sleep terror disorder or sleepwalking disorder.
The present invention provides a method of treating overactive bladder with symptoms of urge urinary incontinence, urgency and/or frequency in a subject, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject's overactive bladder. This invention also provides a method of alleviating urge urinary incontinence in a subject suffering from overactive bladder, which comprises administering to the subject an amount of a compound of the invention effective to alleviate the subject's urge urinary incontinence. This invention further provides a method of alleviating urinary urgency in a subject suffering from overactive bladder, which comprises administering to the subject an amount of a compound of the invention effective to alleviate the subject's urinary urgency. Additionally, this invention provides a method of alleviating urinary frequency in a subject suffering from overactive bladder, which comprises administering to the subject an amount of a compound of the invention effective to alleviate the subject's urinary frequency. The present invention also provides a method of treating a subject suffering from a urinary disorder, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject's urinary disorder. In some embodiments the urinary disorder is urinary incontinence, overactive bladder, urge incontinence, urinary frequency, urinary urgency, nocturia or enuresis. The present invention provides a method of alleviating the symptoms of a disorder in a subject, which comprises administering to the subject an amount of an MCH1 antagonist effective to alleviate the symptoms, wherein the MCH1 antagonist is any of the compounds of the invention.
In an embodiment of the invention, the subject is a vertebrate, a mammal, a human or a canine. In another embodiment, the compound is administered orally. In yet another embodiment, the compound is administered in combination with food. In a preferred embodiment, the subject invention provides a method of treatment for the following indications: depression, anxiety, eating/body weight disorders, and urinary disorders.
Examples of eating/body weight disorders are obesity, bulimia, or bulimia nervosa. Examples of urinary disorders include, but are not limited to, urinary incontinence, overactive bladder, urge incontinence, urinary frequency, urinary urgency, nocturia, or enuresis. Overactive bladder and urinary urgency may or may not be associated with benign prostatic hyperplasia. This invention provides a method of modifying the feeding behavior of a subject which comprises administering to the subject an amount of a compound of the invention effective to decrease the consumption of food by the subject. This invention also provides a method of treating an eating disorder in a subject which comprises administering to the subject an amount of a compound of this invention effective to decrease the consumption of food by the subject. In an embodiment of the present invention, the eating disorder is bulimia, obesity or bulimia nervosa. In an embodiment of the present invention, the subject is a vertebrate, a mammal, a human or a canine. In a further embodiment, the compound is administered in combination with food. The present invention further provides a method of reducing the body mass of a subject which comprises administering to the subject an amount of a compound of the invention effective to reduce the body mass of the subject. The present invention also provides a method of treating a subject suffering from depression which comprises administering to the subject an amount of a compound of this invention effective to treat the subject's depression. The present invention further provides a method of treating a subject suffering from anxiety which comprises administering to the subject an amount of a compound of this invention effective to treat the subject's anxiety. The present invention also provides a method of treating a subject suffering from depression and anxiety which comprises administering to the subject an amount of a compound of this invention effective to treat the subject's depression and anxiety.
The present invention also provides a method of treating a subject suffering from major depressive disorder, dysthymic disorder, bipolar I and II disorders, schizoaffective disorder, cognitive disorders with depressed mood, personality disorders, insomnia, hypersomnia, narcolepsy, circadian rhythm sleep disorder, nightmare disorder, sleep terror disorder, sleepwalking disorder, obsessive-compulsive disorder, panic disorder, with or without agoraphobia, posttraumatic stress disorder, social anxiety disorder, social phobia and generalized anxiety disorder. The present invention also provides a method of treating a subject suffering from a urinary disorder which comprises administering to the subject an amount of a compound of this invention effective to treat the subject's a urinary disorder. In some embodiments, the urinary disorder is urinary incontinence, overactive bladder, urge incontinence, urinary frequency, urinary urgency, nocturia, or enuresis.
The present invention further provides for a compound having the structure:
Figure imgf000020_0001
wherein each R-i is independently hydrogen; -F; -Cl; -Br; -I; -CN; -NO2; straight chained or branched C C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl; C3-C7 cycloalkyl or C5-C7 cycloalkenyl; aryl; heteroaryl; -N(R5)2; -(CH2)mOR5; -COR5; -CO2R5; -OCOR5; -CON(R5)2; -N(R5)COR5; -N(R5)CON(R5)2; -OCON(R5)2 or -N(R5)CO2R5;
wherein R2 and R3 are independently hydrogen; -F; -Cl; -Br; -I; -CN; -(CH2)mOR5; -(CH2)mSR5; straight chained or branched C C7 alkyl, monofluoroalkyl, polyfluoroalkyl; aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more Ri; or
wherein R2 and R3 together can be -(CH2)P-;
wherein R4 is hydrogen; straight chained or branched C C7 alkyl, monofluoroalkyl or polyfluoroalkyl; C3-C6 cycloalkyl; -N(R5)2 or -(CH2)mOR5; wherein each R5 is independently hydrogen; aryl; heteroaryl or straight chained or branched d-C7 alkyl, wherein the alkyl may be substituted with aryl or heteroaryl;
wherein each R6 is independently hydrogen; straight chained or branched C C7 alkyl;
wherein each R7 is independently hydrogen; phenyl or straight chained or branched CrC7 alkyl, wherein the alkyl may be substituted with phenyl;
wherein R8 is hydrogen or straight chained C C7 alkyl;
wherein R and R8 together can be -(CH2)r-;
wherein each m is independently an integer from 0 to 5 inclusive;
wherein n is an integer from 1 to 5 inclusive;
wherein p is an integer from 2 to 7 inclusive;
wherein q is an integer from 0 to 2 inclusive;
wherein each X is independently CH or N;
wherein Z is CO; SO2 or may be absent
or a pharmaceutically acceptable salt thereof.
In one embodiment of the invention, the compound has the structure:
Figure imgf000021_0001
In another embodiment of the invention, the compound has the structure:
Figure imgf000021_0002
wherein each R1 is independently hydrogen; -F; -Cl; -Br; -I; -CN; -NO2; straight chained or branched C C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl; C3-C7 cycloalkyl or C5-C7 cycloalkenyl; aryl; heteroaryl; -N(R5)2; -(CH2) OR5; -COR5;
-CO2R5; -OCOR5; -CON(R5)2; -N(R5)COR5; -N(R5)CON(R5)2; -OCON(R5)2 or -N(R5)C02R5; wherein R2 and R3 are independently hydrogen; -F; -Cl; -Br; -I; -CN; -(CH2)mOR5; -(CH2)mSR5; straight chained or branched C C7 alkyl, monofluoroalkyl, polyfluoroalkyl; aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more R-t; or
wherein R2 and R3 together can be -(CH2)P-;
wherein R4 is straight chained or branched C C7 alkyl, monofluoroalkyl or polyfluoroalkyl, C3- C6 cycloalkyl, C C7 alkyI-C3-C6 cycloalkyl -N(R5)2 or -(CH2)mOR5;
wherein each R5 is independently hydrogen; aryl; heteroaryl or straight chained or branched C C7 alkyl, wherein the alkyl may be substituted with aryl or heteroaryl;
wherein each R6 is independently hydrogen; straight chained or branched C C7 alkyl;
wherein each R7 is independently hydrogen; phenyl or straight chained or branched C C7 alkyl, wherein the alkyl may be substituted with phenyl;
wherein each m is independently an integer from 0 to 5 inclusive; wherein n is an integer from 1 to 5 inclusive; wherein p is an integer from 2 to 7 inclusive; wherein q is an integer from 0 to 2 inclusive; wherein X is CH or N;
or a pharmaceutically acceptable salt thereof.
In a sub-class of the invention, are the compounds wherein each R^ is independently hydrogen; straight chained or branched C C7 alkyl; -F; -Cl; -Br; -I; -CN; -NO2; straight chained or branched C C4 alkyl or polyfluoroalkyl; -(CH2)mOR5; -COR5; -CO2R5; -OCOR5; - CON(R5)2; -N(R5)COR5 or-N(R5)CON(R5)2;
wherein R2 and R3 are independently hydrogen; -F; -Cl; -Br; -I; -CN; -(CH2)mSR5; straight chained or branched C C7 alkyl; aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more Ri; or
wherein R2 and R3 together can be -(CH2)P-;
wherein R is straight chained or branched C C7 alkyl; C3-C6 cycloalkyl; -N(R5)2 or - (CH2)mOR5;
wherein each R5 is independently hydrogen or straight chained or branched C C3 alkyl, wherein the alkyl may be substituted with phenyl; wherein m is 0 to 3; wherein n is 1 to 3; wherein p is an integer from 2 to 5 inclusive; wherein q is 0; and wherein X is CH.
In a subclass of the invention, the compounds have the formula:
Figure imgf000023_0001
In one embodiment of the invention, the compounds having the following structure:
Figure imgf000023_0002
In one embodiment of the invention, each R5 is independently hydrogen or straight chained or branched C C3 alkyl, wherein the alkyl may be substituted with a phenyl; R7 is independently hydrogen or straight chained or branched C C7 alkyl; and R4 is straight chained or branched C C7 alkyl.
In one embodiment of the invention, each Ri is independently hydrogen; -F; -Cl; -Br; -I or straight chained or branched C C7 alkyl; and wherein R2 is hydrogen or straight chained or branched C C7 alkyl.
In one embodiment, n = 2.
In one embodiment of the invention, R^ is hydrogen; -F; -Cl; -Br; -I or straight chained or branched C C7 alkyl; and
R2 is hydrogen or straight chained or branched C C7 alkyl.
In one embodiment of the invention, R2 is hydrogen.
In one embodiment, R3 is OH.
In a subclass of the invention are the compounds of the formula:
Figure imgf000023_0003
In one embodiment of the invention, R4 is C3-C6 cycloalkyl. In one embodiment of the invention, each R2 and R3 are independently hydrogen; -F; -Br or straight chained or branched C C7 alkyl.
In one embodiment of the invention, R2 and R3 are independently hydrogen or straight chained or branched C C7 alkyl.
In one embodiment of the invention, R2 and R3 are independently hydrogen; -F or -Br.
In one embodiment of the invention, R2 and R3 together are -(CH2)P-;
In one embodiment of the invention, the compound has the structure:
Figure imgf000024_0001
In one embodiment of the invention, R5 and R7 are independently hydrogen or straight chained or branched C C7 alkyl.
In one embodiment of the invention, each Ri is independently hydrogen; -F; -Cl; -Br; -I or straight chained or branched C C7 alkyl; and wherein R2 is hydrogen or straight chained or branched C C7 alkyl.
In one embodiment of the invention, R4 is straight chained or branched C C7 alkyl.
In one embodiment of the invention, the compound has the following structure:
Figure imgf000024_0002
In one embodiment of the invention, the compound has the following structure:
Figure imgf000024_0003
In one embodiment R2 is hydrogen or -OH; wherein R3 is phenyl substituted with one or more R- moieties; and q = 0.
In one embodiment each R5 is independently hydrogen or straight chained or branched CrC3 alkyl, wherein the alkyl may be substituted with a phenyl; R7 is independently hydrogen or straight chained or branched C C7 alkyl; and R is straight chained or branched C C7 alkyl. In one embodiment, each R^ is independently hydrogen; -F; -Cl; -Br; -I or straight chained or branched C C7 alkyl.
In one embodiment, X is N.
In one embodiment, X is CRi.
In one embodiment, R2 is OH.
In one embodiment of the invention, the compound has the following structure:
Figure imgf000025_0001
In one embodiment R3 is phenyl substituted with one or more R1 moieties; and q = 0.
In one embodiment, R5 and R7 are independently hydrogen or straight chained or branched C C7 alkyl; and R4 is straight chained or branched d-C7 alkyl.
In one embodiment, R2 is hydrogen; straight chained or branched C C7 alkyl; or -OH.
In one embodiment of the invention, the compound is enantiomerically pure.
In one embodiment of the invention, the compound is diastereomerically pure.
In one embodiment of the invention, the compound is enantiomerically and diastereomerically pure.
The present invention also provides a pharmaceutical composition that comprises a therapeutically effective amount of a compound of the present invention and a pharmaceutically acceptable carrier.
The present invention further provides a pharmaceutical composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
The present invention also provides a process for making a pharmaceutical composition comprising admixing a compound of the present invention and a pharmaceutically acceptable carrier. The present invention also provides a method for treating a subject suffering from a disorder mediated by the MCH1 receptor comprising administering to the subject a therapeutically effective amount of a compound of the present invention.
In one embodiment, the therapeutically effective amount is between about 0.03 and about 300 mg.
In one embodiment, the disorder is depression, anxiety, obesity or urge incontinence.
The present invention also provides a method of treating a subject suffering from a disorder selected from the group consisting of depression, anxiety, urge incontinence or obesity comprising administering to the subject a therapeutically effective amount of a compound of the present invention.
The invention will be better understood from the Experimental Details which follow. However, one skilled in the art will readily appreciate that the specific methods and results discussed are merely illustrative of the invention as described more fully in the claims which follow thereafter.
Experimental Section
I. Synthetic Methods for Examples
General Methods: All reactions (except for those done by parallel synthesis reaction arrays) were performed under an Argon atmosphere and the reagents, neat or in appropriate solvents, were transferred to the reaction vessel via syringe and cannula techniques. The parallel synthesis reaction arrays were performed in vials (without an inert atmosphere) using -KEM heating shakers (Saint Louis, MO). Anhydrous solvents were purchased from Aldrich Chemical Company and used as received. The compounds described herein were named using ACD/Name program (version 4.0, Advanced Chemistry Development Inc., Toronto, Ontario, M5H2L3, Canada). The 1H NMR spectra were recorded at 400 MHz using a Brϋker Avance spectrometer with tetramethylsilane as internal standard. Splitting patterns were designated as follows: s = singlet; d = doublet; t = triplet; q = quartet; quintet; sextet; septet; br = broad; m = multiplet. Elemental analyses were performed by Robertson Microlit Laboratories, Inc. Mass spectra were obtained on a Platform II (Fisons) or Quattro Micro (Micromass) spectrometer with electrospray (ESMS) ionization and MH+ is reported. Thin- layer chromatography (TLC) was carried out on glass plates precoated with silica gel 60 F254 (0.25 mm, EM Separations Tech.). Preparative thin-layer chromatography was carried out on glass sheets precoated with silica gel GF (2 mm, Analtech). Flash column chromatography was performed on Merck silica gel 60 (230 - 400 mesh). Melting points (mp) were determined in open capillary tubes on a Mel-Temp apparatus and are uncorrected.
The examples described in the experimental section are merely illustrative of the methods used to synthesize MCH1 antagonists. A more detailed description of each reaction is represented by the procedures following the schemes. Additional compounds of the invention can be obtained by the general synthetic procedures described herein or by incorporating variations into these methods. The definitions of the variables depicted in the below-identified schemes are defined in the Summary of the Invention. For example, the variable R may be straight chained or branched C C7 alkyl, monofluoroalkyl or polyfluoroalkyl, C3-C6 cycloalkyl, C C7 alkyl-C3-C6 -cycloalkyl ; -N(R5)2 or -(CH2)mOR5. Additionally, for clarity purposes, the number of moieties (R off phenyl have been limited in number to one.
SCHEME 1
Figure imgf000028_0001
(a) LDA/ PhNTf2 / THF/ -78 °C then 0°C overnight, (b) Aminophenylboronic acid / Pd(PPh)4/ LiCI/ Na2C03/ DME-H2O/ reflux 3h. (c) 10% Pd/C / H2/ EtOH/ rt 24-48h. (d) Acid chloride or carbamoyl chloride or chloroformate/ base/ THF/ 0°C then rt 2-3h. (e) 4M HCI in 1 ,4-dioxane/ rt 1 h or TFA/ CH2CI2/ rt 1-2h.
SCHEME 2
Method A
Figure imgf000028_0002
Method B
Figure imgf000028_0003
(a) Bis(pinacolato)diboron/ KOAc/ PdCI2dppf/ dppf/ 80°C overnight, (b) K2C03/ PdCI2dppf/ DMF/ 80°C overnight, (c) 10% Pd/C / H2/ EtOH/ rt 24h-72h. (d) 4M HCI in 1 ,4-dioxane/ rt 1 h or TFA/ CH2CI2/ rt 1-2h. (e) Acid chloride/ Et3N/ THF/ 0°C then rt 2-3h.
SCHEME 3 Method A
B ^^ NH2.HBr Br"
Figure imgf000029_0001
Method B
Figure imgf000029_0002
(a) Di-tert-butyl dicarbonate/ K2CO3/ EtOH/ rt overnight, (b) terf-Butyl N-(3-bromopropyl) carbamate / K2Cθ3 / Nal/ DMF/ 80-100 °C overnight, (c) 4M HCI in 1 ,4-dioxane/ 0 °C 1 h or TFA CH2CI2/ rt 1-2h. (d) N-(n-bromoalkyl) phthalimide/ K2C03 / Nal/ DMF/ 90 °C 5h. (e) N-(n-bro oalkyl) phthalimide/ diisopropylethylamine/ BU4NI/ dioxane/ 100 °C 24h. (f) hydrazine hydrate/ EtOH/ reflux 4h.
SCHEME 4
Figure imgf000029_0003
(a) Nal/ K2CO3/ DMF/ 80-100°C overnight or diisopropylethylamine/ Bu-tNI/ dioxane/ 100°C 3h. (b) acid chloride/ base/ CH2CIZ/ rt 2h. (c) acid/ coupling reagent/ DMF/ CH2C-2/ rt overnight.
SCHEME 5
Figure imgf000030_0001
diisopropylethylamine/ Bu NI/ dioxane/ reflux overnight (c) hydrazine hydrate/ EtOH/ reflux 4h (d) Acid chloride or carbamoyl chloride or chloroformate/ base/ THF/ 0°C then rt 2-3h (e) acid/ coupling reagent DMF/ CH2CI2/ rt overnight
SCHEME 6
Figure imgf000030_0002
(a) HOAc/ H2S04/ 80°C overnight
Reference for the procedure Clarke, L F , Hegarty, A F , O'Neill, P J Org Chem 1992, 57, 362-36β
SCHEME 7
Figure imgf000030_0003
(a) H2S04/ 15°C/Zh
Reference for the procedure Takahashi, Y , Yoneda N , Nagai, H Chem Lett 1985, 1733-173 .
SCHEME 8
Figure imgf000031_0001
(a) Acid chlonde or carbamoyl chloride or chloroformate/ base/ CH2CI2 or THF/ 0°C then rt 12h
SCHEME 9
Figure imgf000031_0002
(a) EDC/ DMAP/ DMF/ CH2CI2/ rt overnight
SCHEME 10
Figure imgf000031_0003
(a) PS Carbodiimide/ DMAP/ DMF/ CH2CI2/ rt overnight
SCHEME 11
Figure imgf000031_0004
(a) (COCI)2 or SOCI2 (b) (4S)-(-)-4-lsopropyl-2-oxazolldinone/ n-BuLI/ THF/ -78°C to 0° (c) LHMDS/THF/ -78°C to 0°/ Mel (d) LIOH/ H202/ THF/ H20/ rt
SCHEME 12
Figure imgf000032_0001
(a) General coupling methods are shown as following:
1,1 '-carbonyldiimidazole/ CH2CI2/ rt overnight, or SOCI2/ Et3N/ CH2CI2/ rt overnight, or DCC/ HOBt/ Base/ CH2CI2/ rt overnight, or EDCI/ DMAP/ CH2CI2/ rt overnight, or EDCI/ HOBt/ Et3N/ CH2CI2/ rt overnight, or isobutyl chloroformate/ NMP/ CH2CI2/-20°C for 1 h.
SCHEME 13
Figure imgf000032_0002
(a) Etl/ t-BuONa/ THF/ rt overnight, (b) RCOOH/ EDC/ DMAP/ CH2CI2 / DMF.
SCHEME 14
Figure imgf000032_0003
(a) Et3N/ CH2CI2/ rt 0 min. (b) K2C03/ Nal/ DMF/ 80-100°C overnight.
SCHEME 15
Figure imgf000032_0004
(a) H2, Pd/C, EtOH, rt 12h. SCHEME 16
Figure imgf000033_0001
H2S04/HN03 pd(OH)2fethanol
0°C cyclohexene/heat
Figure imgf000033_0002
Figure imgf000033_0004
Figure imgf000033_0003
Figure imgf000033_0005
(a) K2C03/ PdCI2dppf/ DMF/ 80°C overnight, (b) 10% Pd/C / H2/ HOAc rt 24h-72h. (c) 4M HCI in 1 ,4-dioxane/ rt 1 h or TFA/ CH2CI2/ rt 1-2h.
SCHEME 17
Figure imgf000034_0001
(a) DPPA/ Et3N/ BnOH/ toluene reflux overnight, (b) K2Cθ3/ PdCI2dppf/ DMF/ 80°C overnight, (c) 10% Pd/C / H2/ EtOAc/ rt 24h-72h. (d) 4M HCI in 1 ,4-dioxane/ rt 1 h or TFA/ CH2CI2/ rt 1 -2h. (e) isobutyryl chloride/ Et3N/ THF/ 0°C then rt 2-3h.
Figure imgf000034_0002
Synthesis 1990, 499-501 Synth. Commun. 1990, 19, 2965-2970 Bioorg. Med. Chem Lett, 2000, 10, 1559-1562 Bull Chem. Soc. Jpn., 1993, 66, 797-803
Figure imgf000034_0003
SCHEME 18
Figure imgf000034_0004
(a) KOH/ 50% EtOH(aq)/ reflux overnight.
SCHEME 19
General Methods for the Syntheses of Carboxylic Acids
Figure imgf000035_0001
b. cyanation (KCN, NH4CI); followed by HCI, MeOH; See. e-9- WEBER, E.; DOERPINGHAUS, N.; CSOEREGH, I.; d KOH MeOH then HCI Cnem Soc' Perkin Traπs 2 [JCPKBH] 1990, (12), 2167-2177.
Gilman, H.; Gaj, B. J.; J Org Chem [JOCEAH] 1963, 28, 1725.
Figure imgf000035_0002
See, e.g., Brain, E. G.; Doyle, F. P.; Hardy, K.; J Chem Soc [JCSOA9] 1962, 1445.
SCHEME 20
General Methods for the Syntheses of Carboxylic Acids
Figure imgf000035_0003
Cl (Br,I)
Figure imgf000035_0004
a. p-CH3PhS02CI (tosyl chloride), Et3N; followed by cyanation (KCN, NH CI); followed by HCI, MeOH; b. cyanation (KCN, NH4CI); followed by HCI, MeOH; c. base such as NaH, halogen-CH2(CH2)mCH2-halogen; d. KOH, MeOH then HCI
See, e.g., TATARINOVA, V. I.; VASIL'EV, A. A.; PETROSYAN, V. A.; Izv Akad Nauk SSSR, Ser Khim [IASKA6] 1990, (11), 2646-2648. TODO, Y.; TAKAGI, H.; UNO, F.; FUKUOKA, Y.; IKEDA, Y.; TANAKA, K.; SAIKAWA, I.; NARITA, H.; Chem Pharm Bull [CPBTAL] 1994, 42 (10), 2049-2054. Jaouen, G.; Meyer, A.; Simonneaux, G.; J Chem Soc, Chem Commun [JCCCAT] 1975, 813. Ann N Y Acad Sci [ANYAA9] 1977, 295, 59. Semmelhack, M. F.; Ann N Y Acad Sci [ANYAA9] 1977, 295, 36. SCHEME 21
Syntheses of Diphenylalkyl Acetic Acid Derivatives
Figure imgf000036_0001
YONEZAWA, N.; HINO, T.; KINUNO, T.; MATSUKI, T.; IKEDA, T.; Synth Commun [SYNCAV] 1999, 29 (10), 1687-1695. YAMAZAKI, T.; SAITO, S.; OHWADA, T.; SHUDO, K.; Tetrahedron Lett [TELEAY] 1995, 36 (32), 5749-5752. Patai, S.; Dayagi, S.; J Chem Soc [JCSOA9] 1958, 3058.
Figure imgf000036_0002
Watanabe, Y.; Kadokura, M.; Mitsudo, T.; J Chem Soc, Chem Commun [JCCCAT] 1986, 1539.
Figure imgf000036_0003
Takahashi, Y.; Nagai, H.; Yoneda, N.; Chem Lett [CMLTAG] 1985, 1733.
Figure imgf000036_0004
Pohmakotr, M.; Phinyocheep, P.; Tetrahedron Lett [TELEAY] 1984, 25 (21), 2249. Trost, B. M.; Salzmann, T. N.; Hiroi, K.; J Am Chem Soc [JACSAT] 1976, 98, 4887. Bockmuhl, M.; Ehrhart, G.; Justus Liebigs Ann Chem [JLACBF] 1948, 561, 52.
GENERAL PROCEDURE FOR PIPE IDINE SIDE CHAIN SYNTHESIS (SCHEME 1):
TERT-BUTYL 4-{[(TRIFLUOROMETHYL)SULFONYL]OXY}-3,6-DIHYDRO-1(2/-/)-PYRIDINE CARBOXYLATE: n-Butyl lithium (17.6 mL, 44.2 mmol, 2.5 M in hexanes) was added to a solution of diisopropyl amine (96.2 mL, 44.2 mmol) in 40 mL of dry THF at 0 °C and the resulting mixture was stirred for 20 minutes. The reaction mixture was cooled to -78 °C and te/f-butyl 4-oxo-1 -piperidinecarboxylate (Aldrich Chemical Company, 40.0 mmol) in THF (40 mL) was added dropwise to the reaction mixture, which was then stirred for 30 minutes. Tf2NPh (42.0 mmol, 15.0 g) in THF (40 mL) was added dropwise to the reaction mixture and stirred at 0 °C overnight. The reaction mixture was concentrated in vacuo, re-dissolved in hexanes.EtOAc (9:1), passed through a plug of alumina and the alumina plug was washed with hexanes:EtOAc (9:1). The combined extracts were concentrated to yield 16.5 g of the desired product that was contaminated with some starting Tf2NPh.
TEftT-BUTYL 4-(3-AMINOPHENYL)-3,6-DIHYDRO-1(2W)-PYRIDINECARBOXYLATE: A degassed mixture of 2 M aqueous Na2C03 solution (4.2 mL), te/f-butyl 4- {[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydro-1(2-4)-pyridinecarboxylate (0.500 g, 1.51 mmol), 3- aminophenylboronic acid hemisulfate (0.393 g, 2.11 mmol), lithium chloride (0.191 g, 4.50 mmol) and tetrakis-triphenylphosphine palladium (0) (0.080 g, 0.075 mmol) in dimethoxyethane (5 mL) was heated at reflux temperature for 3 hours under an inert atmosphere. The organic layer of the cooled reaction mixture was separated and the aqueous layer was washed with ethyl acetate (3 X 50 mL). The combined organic solutions were dried and concentrated in vacuo. The crude product was chromatographed (silica, hexanes: EtOAc: dichloromethane = 6: 1 : 1 with 1% added isopropylamine) to give 0.330 g of the desired product in 81% yield. ESMS m/e : 275.2 (M + H)+.
TERT-BUTYL 4-[3-(AMINO)PHENYL]-1-PIPERIDINECARBOXYLATE: A mixture of 3.10 g of te/f-butyl 4-(3-aminophenyI)-3,6-dihydro-1(2H)-pyridinecarboxylate (11.3 mmol) and 1.0 g of 10% Pd/C in 200 mL of ethanol was hydrogenated at room temperature using the balloon method for 2 days. The reaction mixture was filtered through Celite and washed with ethanol. The combined ethanol extracts were concentrated in vacuo and the residue was chromatographed on silica (dichloromethane: methanol: isopropylamine = 95: 5: 1) to give 2.63 g of the desired product (84%): ESMS m/e : 277.2 (M + H)+.
TERT-BUJYl 4-[3-(ACETYLAMINO)PHENYL]-1-PIPERIDINECARBOXYLATE. Into a solution of 14.6 g (52.6 mmol) of te/f-butyl 4-[3-(amino)phenyl]-1 -piperidinecarboxylate and 14.7 mL (105 mmol) of triethylamine in 120 mL THF at 0 °C was slowly added 4.5 mL (63.1 mmol) of acetyl chloride. The reaction mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The residue was dissolved in CH CI2 and washed with H2O, followed by brine. The organic layer was dried over MgSO4 and concentrated in vacuo to give 16.6 g (52.1 mmol, 99%) of desired product: 1H NMR (400 MHz, CDCI3) δ 7.41-7.20 (m, 3H), 6.94 (d, 1 H, J = 7.5 Hz), 4.21 (m, 2H), 2.75 (m, 2H), 2.62 (m, 1H), 2.16 (s, 3H), 1.78 (m, 2H), 1.56 (m, 2H), 1.48 (s, 9H).
Λ/-[3-(4-PIPERIDYL)PHENYL]ACETAMIDE: A solution of HCI in dioxane (4N, 5 mL) was added to fe/f-butyl 4-[3-(acetylamino)phenyl]-1 -piperidinecarboxylate (660 mg) in dry dichloromethane (15 mL). The reaction mixture was stirred at room temperature overnight and concentrated in vacuo, giving the HCI salt of the desired product (550 mg): 1H NMR (400 MHz, CDCI3) δ 2.02 (d, J = 13.2 Hz, 2H), 2.11-2.45 (m, 5H), 2.67-2.77 (m, 1H), 3.00-3.10 (m, 2H), 3.51 (d, J = 10.5 Hz, 2H), 6.94 (d, J = 7.5 Hz, 1H), 7.20-7.46 (m, 3H), 7.60 (s, 1H).
TERT-BUTYL 4-[3-(ISOBUTYRYLAMINO)PHENYL]-3,6-DIHYDRO-1 (2H)-PYRIDINE
CARBOXYLATE: Anal. Calc. for C20H28N2O3+0.175 CHCI3: C, 66.33; H, 7.77; N, 7.67.
Found: C, 66.20; H, 7.41; N, 7.88. and TERT-BUTYL 4-[3-(ISOBUTYRYLAMINO)PHENYL]-
1-PIPERIDINECARBOXYLATE: ESMS m/e : 347.2 (M + H)+ . These intermediates were synthesized as illustrated by the methods above.
2-METHYL-Λ/-[3-(4-PIPERIDINYL)PHENYL]PROPANAMIDE: Into a stirred solution of 2.20 g
(6.50 mmol) of te/f-butyl 4-[3-(isobutyrylamino)phenyl]-1 -piperidinecarboxylate in 100 ml of
1,4-dioxane at 0 °C was bubbled HCI gas for 10 minutes. The reaction mixture was allowed to warm to room temperature and the bubbling of the HCI gas was continued for 1 hour. The solvent was removed in vacuo, the residue was dissolved in 50 mL of water and was basified to pH = 13 by addition of KOH pellets. The aqueous solution was extracted with 3 X 80 mL of dichloromethane. The combined organic extracts were dried (MgSO ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 9 : 1 : 0.1 = dichloromethane : methanol : isopropyl amine) to afford 0.700 g (46% yield) of the desired product: ESMS m/e : 247.2 (M + H)+.
Using the methods described above, the following intermediates were further synthesized. TERT-BUTYL 4-[3-(PROPIONYLAMINO)PHENYL]-1-PIPERIDINECARBOXYLATE: ESMS m/e: 333.4 (M + H)+; Λ/-[3-(4-PIPERIDINYL)PHENYL]PROPANAMIDE: ESMS m/e: 233.1 (M + H)+. TERΓ-BUTYL4-{3-[(CYCLOPROPYLCARBONYL)AMINO]PHENYL}-1-PIPERIDINE CARBOXYLATE: ESMS m/e: 345.5 (M + H)+; Λ/-[3-(4-PIPERIDINYL)
PHENYL]CYCLOPROPANECARBOXAMIDE: ESMS m/e: 245.0 (M+ H)+; Λ/-[3-(4- PIPERIDINYL )PHENYL]BUTANAMIDE: ESMS m/e: 247.3 (M + H)+; Λ/,Λ/-DIMETHYL-/V'-[3- (4-PIPERIDINYL) PHENYL]UREA: ESMS m/e: 248.2 (M + H)+; ISOPROPYL 3-(4- PIPERIDINYL)PHENYL CARBAMATE: ESMS m/e 263.4 (M + H)+; BENZYL 3-(4- PIPERIDINYL)PHENY LCARBAMATE: ESMS m/e 311.3 (M + H)+; 2-METHYL-Λ/-[4-(4- PIPERIDINYL )PHENYL]PROPANAMIDE: ESMS m/e: 247.1 (M + H)+; Λ/-[4-(4- PIPERIDINYL)PHENYL]BUTANAMIDE: ESMS m/e: 247.2 (M + H)+.
GENERAL PROCEDURE FOR THE SYNTHESIS OF 4-ARYL PIPERIDINES (SCHEME 2)
TERT-BUTYL 4-(4,4,5,5-TETRAMETHYL-1 ,3,2-DIOXABOROLAN-2-YL)-3,6-DIHYDRO- 1(2H)-PYRIDINECARBOXYLATE: To a 50-mL RB-flask, charged with bis(pinacolato)diboron (422 mg, 1.66 mmol), KOAc (444 mg, 4.53 mmol), PdCI2dppf (37.0 mg, 3.00 mol%) and dppf (25.0 mg, 3.00 mol%) was added a solution of te/f-butyl 4- {[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydro-1(2H)-pyridinecarboxylate (500 mg, 1.51 mmol) in 1,4-dioxane (10.0 mL) at room temperature under argon. The mixture was heated at 80 °C overnight. After cooling to room temperature, the mixture was filtered through Celite and the Celite was washed with EtOAc (3 x 20 mL). The filtrates were concentrated in vacuo. The resulting residue was dissolved in EtOAc and washed with H2O and brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (1 :9 EtOAc:hexane) to give te/f-butyl 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3,6- dihydro-1(2/- )-pyridinecarboxylate (355 mg, 76%): 1H NMR (400 MHz, CDCI3) δ 6.60-6.34 (br, 1H), 4.06-3.86 (br, 2H), 3.55-3.34 (br, 2H), 2.35-2.09 (br, 2H), 1.46 (s, 9H), 1.26 (s, 12H); ESMS m/e: 310.4 (M + H)+.
Method A (Scheme 2)
N-(3-BROMO-4-METHYLPHENYL)-2-METHYLPROPANAMIDE: Into a solution of 1.0 g
(5.40 mmol) of 3-bromo-4-methylaniline and 0.91 mL (6.50 mmol) of triethylamine in 10 mL THF at 0 °C was slowly added 0.68 L (6.50 mmol) of 2-methylpropanoyl chloride. The reaction mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The residue was dissolved in CH2CI2 and washed with H2O, followed by brine. The organic layer was dried over MgSO and concentrated in vacuo to give .37 g (5.35 mmol, 99%) of the desired product: ESMS m/e: 255.9 (M + H)+.
Using the methods described above, the following intermediates were further synthesized. N-(3-BROMO-2-METHYLPHENYL)-2-METHYLPROPANAMIDE: ESMS m/e: 255.9 (M + H)+. Λ/-(6-BROMO-2-PYRIDINYL)-2-METHYLPROPANAMIDE: ESMS m/e: 242.8 (M + H)+.
TERT-BUTYL 4-[5-(ISOBUTYRYLAMINO)-2-METHYLPHENYL]-3,6-DIHYDRO-1(2H)-
PYRIDINE CARBOXYLATE: To a 50-mL RB-flask containing te/f-butyl 4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate (500 mg, 1.62 mmol), K2CO3 (670 mg, 4.86 mmol) and PdCI2dppf (0.190 mmol, 155 mg) was added a solution of N-(3-bromo-4-methylphenyl)-2-methylpropanamide (415 mg, 1.62 mmol) in DMF (10.0 mL) at room temperature under argon. The mixture was heated to 80 °C under argon overnight. After cooling to room temperature, the mixture was filtered through Celite and the Celite was washed with EtOAc (3 x 20 mL). The filtrates were washed with H20 (20 mL), brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified flash chromatography (20% EtOAc/ hexane) to give tert-butyl 4-[5-(isobutyrylamino)- 2-methylphenyl]-3,6-dihydro-1(2H)-pyridinecarboxylate (360 mg, 62%): ESMS m/e: 303.0 (M-56 + H)+.
TERT-BUTYL 4-[5-(ISOBUTYRYLAMINO)-2-METHYLPHENYL]-1-PIPERIDINE
CARBOXYLATE: A mixture of tert-butyl 4-[5-(isobutyrylamino)-2-methylphenyl]-3,6-dihydro- 1(2H)-pyridinecarboxylate (335 mg, 0.93 mmol) and 10% Pd/C (35.0 mg) in EtOH (20.0 mL) was hydrogenated at room temperature overnight using the hydrogen balloon method. The reaction mixture was filtered through Celite and washed with ethanol (3 x 10 mL). The combined extracts were concentrated in vacuo to afford tert-butyl 4-[5-(isobutyrylamino)-2- methylphenyl]-1 -piperidinecarboxylate (335 mg, 100%): ESMS m/e: 361.4 (M + H)+.
2-METHYL-Λ/-[4-METHYL-3-(4-PIPERIDINYL)PHENYL] PROPANAMIDE: Into a solution of tert-butyl 4-[5-(isobutyrylamino)-2-methylphenyl]-1-piperidinecarboxylate (335 mg, 0.930 mmol) in CH2CI2 (10.0 mL) was added TFA (10.0 mL) at room temperature. The reaction mixture was stirred for 2 h and concentrated in vacuo. The residue was dissolved in 20 mL of CHCI3//-PrOH (3:1) and was basified with 5% KOH solution (10 mL). The aqueous layer was extracted with CHCI3//-PrOH (3:1 , 3 x 10 mL). The combined organic extracts were washed with brine, dried over MgS0 , filtered and concentrated in vacuo to give 2-methy!-Λ/-[4-methyl-3-(4- pipeπdinyl)phenyl]propanamide (190 mg, 78%): ESMS m/e: 261.0 (M + H)+.
Using the methods described above, the following intermediates were further synthesized. 2-METHYL-Λ/-[2-METHYL-3-(4-PIPERIDINYL)PHENYL]PROPANAMIDE: ESMS m/e: 261.3 (M + H)+. 2-METHYL-Λ/-[6-(4-PIPERIDINYL)-2-PYRIDINYL]PROPANAMIDE: ESMS m/e: 248.1 (M + H)+. Method B (Scheme 2)
TERT-BUTYL 4-(2-METHOXY-5-NITROPHENYL)-3,6-DIHYDRO-1(2H)-PYRIDINE
CARBOXYLATE: To a 250-mL RB-flask containing te/f-butyl 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate (3.09 g, 10.0 mmol), K2CO3 (4.14 g, 30.0 mmol) and PdCI2dppf (419 mg) was added a solution of 2-bromo-4-nitroanisole (2.30 g, 10 mmol) in DMF (10.0 mL) at room temperature under argon. The mixture was heated to 80 °C under argon overnight. After copied to room temperature, water (500 mL) was added to the mixture. The aqueous layer was extracted with EtOAc (2 x 200 mL) and the combined organic extracts were dried over K2CO3, filtered and concentrated in vacuo. The crude material was purified on flash chromatography (20% EtOAc/hexane) to give te/f-butyl 4-(2- methoxy-5-nitrophenyl)-3,6-dihydro-1(2/-/)-pyridinecarboxylate (1.51 g, 46%): ESMS m/e: 334.9 (M + H)+.
TERT-BUTYL 4-[5-AMINO-2-METHOXYPHENYL]-1-PIPERIDINECARBOXYLATE: A solution of te f-butyl 4-(2-methoxy-5-nitrophenyl)-3,6-dihydro-1(2/-/)-pyridinecarboxylate (1.30 g, 3.90 mmol) and 10% Pd/C (200.0 mg) in MeOH:EtOAc (1:4, 100 mL) was hydrogenated at room temperature for 72 h using the hydrogen balloon method. The reaction mixture was filtered through Celite and washed with ethanol (3 x 100 mL). The combined organic filtrates were concentrated in vacuo to afford terf-butyi 4-[5-amino-2-methoxyphenyl]-1- piperidinecarboxylate (1.00 g, 84%): ESMS m/e: 307.2 (M + H)+.
te f-Butyl 4-[5-(ISOBUTYRYLAMINO)-2-METHOXYPHENYL]-1-
PIPERIDINECARBOXYLATE: 1H NMR (400 MHz, CDCI3) δ 7.39 (dd, 1 H, J = 8.8, 2.8 Hz), 7.25 (br, 1H), 6.80 (d, 1 H, J = 8.4 Hz), 4.23 (br, 2H), 3.80 (s, 3H), 3.07 (tt, 1H, J = 11.8, 4.1 Hz), 2.89-2.73 (m, 2H), 2.49 (septet, 1H, J = 6.7 Hz), 1.77 (d, 2H, J = 11.6 Hz), 1.64-1.52 (m, 3H), 1.48 (s, 9H), 1.25 (d, 6H, J = 6.8 Hz).
Using the methods described above, the following additional intermediates were synthesized. Λ/-[4-METHOXY-3-(4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: ESMS m/e: 277.2 (M + H)+. Λ/-[4-FLUORO-3-(4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMIDE: ESMS m/e: 265.2 (M + H)+. Λ/-[2-FLUORO-5-(4-PIPERIDINYL)PHENYL]-2- METHYLPROPANAMIDE: ESMS m/e: 265.4 (M + H)+. Λ/-[4-FLUORO-3-(4- PIPERIDINYL)PHENYL]BUTANAMIDE: ESMS m/e: 265.2 (M + H)+. Λ/-[2-FLUORO-5-(4- PlPERIDINYL)PHENYL]BUTANAMIDE: ESMS m/e: 265.4 (M + H)+. Λ/-[4-METHOXY-3-(4- PIPERIDINYL)PHENYL]BUTANAMIDE: 1H NMR (400 MHz, CD3OD) δ 7.34 (dd, 1 H, J = 8.1 , 3.3 Hz), 7.25 (d, 1 H, J = 3.3 Hz), 6.82 (d, 1H, J = 8.1 Hz), 3.76 (s, 3H), 3.10-2.92 (m, 4H), 2.66 (dt, 2H, J = 12.6, 2.6 Hz), 2.64-2.56 (m, 1 H), 2.27 (t, 2H, J = 7.4 Hz), 1.76-1.44 (m, 6H), 0.95 (t, 3H, J = 7.4 Hz).
Λ/-[2-HYDROXY-5-(4-PIPERIDINYL)PHENYL]-2-METHYLPROPANAMlDE: Prepared by the procedure for Λ/-[4-methoxy-3-(4-piperidinyl)phenyl]-2-methylpropanamide using tert-butyl 4- (4,4,5,5-tetramethyI-1 ,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate and 4- bromo-2-nitrophenol and acylating with isobutyryl chloride: ESMS m/e: 263.4 (M + H)+.
GENERAL PROCEDURES FOR N-(n-AMINOALKYL)PIPERlDINE SYNTHESIS (SCHEME 31
Method A (Scheme 3)
TERT-BUTYL 3-BROMOPROPYLCARBAMATE: A solution of 3-bromopropylamine hydrobromide (10.9 g, 49.8 mmol), BOC2O (11.4 g, 52.3 mmol) and K2C03 (20.6 g, 149.4 mmol) in ethanol (100 ml) were stirred at room temperature overnight. The precipitated salts were removed by filtration and the filtrate was concentrated in vacuo. The residue was dissolved in dichloromethane and washed with water, followed by brine. The organic layer was dried over MgSO and concentrated in vacuo to give 11.2 g (46.9 mmol, 94%) of the desired product: 1H NMR (400 MHz, CDCI3) δ 5.07 (br, 1H), 3.31 (t, 2H, J = 6.6 Hz), 3.12 (apparent br q, 2H, J = 6.0 Hz), 1.92 (quintet, 2H, J = 6.6 Hz), 1.30 (s, 9H).
TERT-BUTYL 3-{4-[3-(ACETYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYLCARBAMATE: A mixture of Λ/-[3-(4-piperidyl)phenyl]acetamide (550 mg, 2.1 mmol), tert-butyl 3- bromopropylcarbamate (550 mg, 2.3 mmol), K2CO3 (1.10 g, 8.9 mmol), diisopropylethyl amine (1.50 mL) and a few crystals of Kl in dioxane (20 mL) was heated at reflux temperature for 2 days. The precipitated salts were removed by filtration, the filtrate was concentrated in vacuo and the crude product was chromatographed on silica to give the desired product (340 mg; 43%): ESMS m/e: 376.2 (M + H)+.
Λ/-{3-[1-(3-AMINOPROPYL)-4-PIPERIDINYL]PHENYL}ACETAMIDE: Trifluoroacetic acid (1.0 mL) was added to a solution of tert-butyl 3-{4-[3-(acetylamino)phenyl]-1 -piperidinyl} propylcarbamate (340 mg) in dry dichloromethane (10 mL) and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was basified to pH 12 by addition of a 10% aqueous solution of KOH and then the dichloromethane was removed in vacuo. The aqueous layer was frozen and lyophilized to give a solid, which was extracted with methanol. Removal of the solvent gave the desired product (120 mg) as an oil: 1H NMR (400 MHz, CDCI3) δ 7.48 (m, 1H), 7.38 (d, 1H, J = 7.7 Hz), 7.24 (t, 1H, J = 7.7 Hz), 6.99 (d, 1H, J = 7.7 Hz), 3.11 (d, 2H, J = 11.6 Hz), 2.84 (t, 2H, J = 6.6 Hz), 2.59-2.52 (m, 1 H), 2.50 (t, 2H, J = 6.6 Hz), 2.18-2.09 (m, 2H), 2.13 (s, 3H), 1.90-1.72 (m, 6H).
Using the methods described above, the following additional intermediates were synthesized. N-{3-[1-(3-AMINOPROPYL)-4-PIPERIDINYL]PHENYL}BUTANAMIDE. ESMS m/e: 304.3 (M + H)+. Λ/-{3-[1-(3-AMINOPROPYL)-4-PIPERIDINYL]-4-METHYLPHENYL}-2-METHYL PRO PANAMIDE. ESMS m/e: 318.3 (M + H)+. Λ/-{3-[1-(3-AMINOPROPYL)-4-PIPERIDINYL]-4- FLUOROPHENYL}-2-METHYL PROPANAMIDE. ESMS m/e: 322.4 (M + H)+. Λ/-{6-[1-(3- AMINOPROPYL)-4-PIPERIDINYL]-2-PYRIDINYL}-2-METHYLPROPANAMIDE. ESMS m/e: 305.2 (M + H)+. Λ/-{5-[1-(3-AMINOPROPYL)-4-PIPERIDINYL]-2-FLUOROPHENYL}-2- METHYLPROPANAMIDE. ESMS m/e: 322.4 (M + H)+. Λ/-{5-[1-(3-AMINOPROPYL)-4- PIPERIDINYL]-2-FLUOROPHENYL}BUTANAMIDE. ESMS m/e: 322.3 (M + H)+.
Method B (Scheme 3) Step 1 : A mixture of piperidine 1 (1.00 eq, 0.0226 mmol), Λ/-(n-bromoalkyl)phthalimide (1.50 eq, 0.0338 mmol), Bu4NI (200 mg) and diisopropylethylamine (5.00 eq, 0.113 mmol) in dioxane (200 mL) was heated at 99 °C for 24 h. The reaction was monitored by TLC analysis (95:5 CH2CI2:methanol). If necessary, additional 0.0113 mmol of the appropriate bromoalkylphthalimide was added to the reaction mixture and heating was continued for an additional 48 h. The reaction mixture was cooled to room temperature, the ammonium salts were filtered out and the solvent was removed under reduced pressure. The crude product was chromatographed (silica) to give the desired N-(n-phthalimidoalkyl)piperidine 2.
Step 2: Deprotection of the N-(n-phthalimidoalkyl)piperidine from step 1 was accomplished by heating a solution of phthalimide-protected amine 2 with excess hydrazine hydrate (10 eq) in ethanol (0.5-1.0 M) at 90 °C for 4 h. The reaction mixture was monitored by TLC to completion. Upon completion of the reaction, the mixture was cooled to room temperature, the insoluble by-products were removed by filtration through Celite and the filtrate was concentrated in vacuo. The crude product was chromatographed (dichloromethane- methanol-isopropylamine) to give the desired N-(n-aminoalkyl)piperidine 3.
Using the methods described above, the following additional intermediates were synthesized. Λ/-(3-{1-[2-(1,3-DIOXO-1,3-DIHYDRO-2HISOINDOL-2-YL)ETHYL]-4- PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE. ESMS m/e: 420.2 (M + H)+. N-(3-{1- [3-(1 ,3-DIOXO-1 ,3-DIHYDRO-2H-ISOINDOL-2-YL)PROPYL]-4-PIPERIDINYL}PHENYL)-2- METHYLPROPANAMIDE: ESMS m/e: 434.4 (M + H)+. N-(3-{1-[4-(1,3-DIOXO-1 ,3- DIHYDRO-2H-ISOINDOL-2-YL)BUTYL]-4-PIPERIDINYL}PHENYL)-2- METHYLPROPANAMIDE: ESMS m/e: 448.4 (M + H)+. /-(3-{1-[5-(1 ,3-DIOXO-1 ,3- DIHYDRO-2tf-ISOINDOL-2-YL)PENTYL]-4-PIPERIDINYL}PHENYL)-2- METHYLPROPANAMIDE. ESMS m/e: 462.4 (M + H)+. N-(3-{1-[6-(1,3-DIOXO-1 ,3- DIHYDRO-2H-ISOINDOL-2-YL)HEXYL]-4-PIPERIDINYL}PHENYL)-2- METHYLPROPANAMIDE: ESMS m/e: 476.4 (M + H)+.
Λ/-{3-[1-(2-AMINOETHYL)-4-PIPERIDINYL]PHENYL}-2-METHYLPROPANAMIDE: Prepared according to step 2 of Method B (Scheme 3) using N-(3-{1-[2-(1,3-dioxo-1 ,3-dihydro-2H- isoindol-2-yl)ethyl]-4-piperidinyl}phenyl)-2-methylpropanamide and hydrazine hydrate; ESMS m/e: 290.2 (M + H)+.
Using the methods described above, the following additional intermediates were synthesized. Λ/-{3-[1-(3-AMINOPROPYL)-4-PIPERIDINYL]PHENYL}-2-METHYLPROPANAMIDE: ESMS m/e: 304.1 (M + H)+. Λ/-{3-[1-(4-AMINOBUTYL)-4-PIPERIDINYL]PHENYL}-2- METHYLPROPANAMIDE: ESMS m/e: 318.2 (M + H)+. Λ/-{3-[1-(5-AMINOPENTYL)-4- PIPERIDINYL]PHENYL}-2-METHYLPROPANAMIDE: ESMS m/e: 332.2 (M + H)+. Λ/-{3-[1- (6-AMINOHEXYL)-4-PIPERIDINYL]PHENYL}-2-METHYLPROPANAMIDE: ESMS m/e: 346.3 (M + H)+. Λ/-{3-[1-(3-AMINOPROPYL)-4-PIPERIDINYL]PHENYL}PROPANAMIDE: 1H NMR (400 MHz, CDCI3) δ 7.37-7.29 (m, 2H), 7.14 (t, 1H, J = 7.9 Hz), 6.90 (d, 1H, J = 7.9 Hz), 3.27 (s, 2H), 3.06-2.97 (m, 2H), 2.63 (t, 2H, J = 6.8 Hz), 2.50-2.26 (m, 6H), 2.04 (dt, 2H, J = 12.1 , 2.7 Hz), 1.81 (m, 3H), 1.80-1.60 (m, 6H). Λ/-{3-[1-(3-AMINOPROPYL)-4- PIPERIDINYL] PHENYL}CYCLOPROPANECARBOXAMIDE: ESMS m/e: 302.3 (M + H)+. N- {3-[1-(3-AMINOPROPYL)-4-PIPERIDINYL]PHENYL}-2,2-DIMETHYLPROPANAMIDE: ESMS m/e: 318.3 (M + H)+. Λ/-{3-[1-(3-AMINOPROPYL)-4-PIPERIDINYL]PHENYL}-3-METHYL BUTANAMIDE: ESMS m/e 318.3 (M + H)+. Λ/-{3-[1-(3-AMINOPROPYL)-4-PIPERIDINYL ]PHENYL}-3,3-DIMETHYLBUTANAMIDE: ESMS m/e: 332.3 (M + H)+.
Using the methods described above, the following additional intermediates were synthesized. Λ/'-{3-[1-(3-AMINOPROPYL)-4-PIPERIDINYL]PHENYL}-Λ/,Λ/-DIMETHYLUREA: 1H NMR (400 MHz, CD3OD) δ 7.36 (s, 1 H), 7.32-7.25 (m, 1H), 7.21 (t, 1H, J = 7.9 Hz), 6.92 (d, 1 H, J = 7 Hz), 3.33 (s, 6H), 3.17-3.07 (m, 2H), 2.75 (t, 2H, J = 6,9), 2.58-2.44 (m, 3H), 2.14 (dt, 2H, J = 11.8, 2.7 Hz), 1.93-1.67 (m, 8H). ISOPROPYL 3-[1-(3-AMINOPROPYL)-4-PIPERIDINYL] PHENYLCARBAMATE: 1H NMR (400 MHz, CDCI3) δ 7.20 (broad s, 1H), 7.16 (d, 1 H, J = 5.3 Hz), 7.08 (t, 1H, J = 8.3 Hz), 6.80 (d, 1H, J = 7.4 Hz), 4.89-4.79 (m, 1H), 3.21 (quintet, 1 H, J = 1.6 Hz), 3.03-2.95 (m, 2H), 2.61 (t, 2H, 6.8 Hz), 2.46-2.31 (m, 3H), 2.01 (dt, 2H, J = 117, 2.8 Hz), 1.78-1.57 (m, 7H), 1.19 (d, 6H, J = 6.2 Hz). BENZYL 3-[1-(3-AMINOPROPYL)-4- PIPERIDINYL]PHENYLCARBAMATE: 1H NMR (400 MHz, CDCI3) δ 7.60-7.30 (m, 9H), 7.08 (dt, 1H, J = 7.5, 1.4 Hz), 5.34 (s, 2H), 4.09 (quintet, 1H, J = 5.7 Hz), 3.30-3.10 (m, 4H), 2.65
(t, 2H, J = 7.8 Hz), 2.28 (dt, 2H, J = 12, 1.4 Hz), 2.07-1.85 (m, 7H). Λ/-{3-[1-(3-
AMINOPROPYL)-4-PIPERIDlNYL]-4-METHOXYPHENYL}-2-METHYLPROPANAMIDE:
ESMS m/e: 334.6 (M + H)+.Λ/-{3-[1-(3-AMINOPROPYL)-4-PIPERIDINYL]-4- METHOXYPHENYLJBUTANAMIDE: 1H NMR (400 MHz, CD3OD) δ 7.46-7.57 (m, 1H), 6.97
(s, 1H), 6.77 (d, 1H, J = 8.8 Hz), 3.88-3.80 (m, 2H), 3.78 (s, 3H), 3.12-2.74 (m, 4H), 2.46 (t,
2H, J = 6.6 Hz), 2.39 (t, 2H, J = 7.3 Hz), 2.07-1.94 (m, 2H), 1.87-1.44 (m, 9H), 1.02 (t, 3H, J
7.4 Hz). Λ/-{5-[1-(3-AMINOPROPYL)-4-PIPERIDINYL]-2-HYDROXYPHENYL}-2-
METHYLPROPANAMIDE: 1H NMR (400 MHz, CD3OD) δ 8.12-8.08 (m, 1 H), 7.70-7.66 (m, 2H), 7.44 (d, 1H, J = 2.2 Hz), 2.79-2.55 (m, 3H), 2.39-2.28 (m, 3H), 2.26 (d, 2H, J = 11.6 Hz),
1.98 (dt, 2H, J = 12, 2.5 Hz), 1.74-1.53 (m, 6H), 1.11 (d, 6H, J = 6.8 Hz).
General procedure for Scheme 4
Step l N-(3-{1-[(3R)-3-HYDROXY-3-PHENYLPROPYL]-4-PIPERIDINYL}PHENYL)-2-
METHYLPROPANAMIDE: Into a 25-mL RB-flask was added (R)-(+)-3-chloro-1-phenyl-1- propanol (0.545 g, 3.19 mmol, 99%ee, Aldrich Chemical Co.), 2-methyl-Λ/-[3-(4- piperidinyl)phenyl]propanamide (0.748 g, 3.04 mmol), potassium carbonate (0.420 g, 3.04 mmol), sodium iodide (0.684 g, 4.56 mmol) and DMF (6.0 mL) at room temperature. After stirring at 100 °C for 3 hrs, TLC showed that the reaction was complete. The reaction mixture was cooled to room temperature and poured into water (50 mL) and the aqueous layer was extracted with methylene chloride (3 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (1 : 1 = hexane : ethyl acetate with 1% isopropylamine) to afford the desired product (1.09 g, 94% yield) as a light-yellow solid: 1H NMR (400 MHz, CDCI3) δ 8.10 (s, 1H), 7.46-7.35 (m, 6H), 7.27 (m, 2H), 6.98 (apparent d, 1H, J = 7.6 Hz), 5.02 (apparent dd, 1H, J = 4.4, 8.1 Hz), 3.18 (apparent dd, 2H, J = 2.5, 12.5 Hz), 2.74 (m, 2H), 2.50 (m, 2H), 2.30-2.10 (m, 6H), 1.80 (m, 2H), 1.25 (d, 6H, J = 7.1 Hz); ESMS m/e: 381.2 (M + H)+. ' Step 2: See general coupling conditions in Schemes 8-10.
General procedure for Scheme 5
Step 1 :
2-[(1S)-3-CHLORO-1-PHENYLPROPYL]-1/-/-ISOINDOLE-1,3(2H)-DIONE: Prepared according to the general procedure described in Srebnik, M.; Ramachandran, PN.; Brown,
H.C. J. Org. Chem. 1988, 53, 2916-2920. A mixture of phthalimide (0.147 g, 1.0 mmol), (R)- (+)-3-chloro-1-phenyl-1-propanol (0.171 g, 1.0 mmol), triphenylphosphine (0.262 g, 1.0 mmol) and diethyl azodicarboxylate (0.174 g, 1.0 mmol) in 5.0 mL of THF was stirred at room temperature for 24 h. The reaction mixture was concentrated in vacuo. The residue was washed with pentane (3 x 50 mL) and the combined pentane extracts were concentrated and chromatographed (silica, hexanes : EtOAc = 8 : 1 as the eluent) to give the desired product (0.121 g, 50%) as a yellow solid: 1H NMR (400 MHz, CDCI3) δ 7.82 (apparent dd, 2H, J = 2.9 Hz), 7.70 (apparent dd, 2H, J = 2.9 Hz), 7.56 (m, 2H), 7.39-7.27 (m, 3H), 5.64 (apparent dd, 1H, J = 7.0, 9.2 Hz), 3.57 (m, 2H), 3.05 (m, 1H), 2.82 (septet, 1H, J = 7.0 Hz); ESMS m/e: 300.1 (M + H)+.
Step 2:
N-(3-{1-[(3S)-3-(1,3-DIOXO-1 ,3-DIHYDRO-2H-ISOINDOL-2-YL)-3-PHENYLPROPYL]-4- PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE: A mixture of potassium carbonate (29.2 mg, 0.211 mmol), sodium iodide (47.5 mg, 0.317 mmol), 2-methyl-/V-[3-(4- piperidinyl)phenyl]propanamide (51.8 mg, 0.211 mmol) and 2-[(1S)-3-chloro-1-phenylpropyl]- 1H-isoindole-1 ,3(2H)-dione (63.1 mg, 0.211 mmol) in DMF (5.0 mL) was stirred at 100 °C for 3 hrs, at which time TLC indicated that the reaction was complete. The reaction mixture was cooled to room temperature, poured into water (50 mL) and the aqueous layer was extracted with methylene chloride (3 x 30 mL). The combined organic extracts were washed with brine (30 mL), dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by preparative TLC [2.5% NH3 (2.0 M in methanol) in CHCI3] to give the desired product (74.1 mg, 77%) as a thick oil: 1H NMR (400 MHz, CDCI3) δ 7.83 (apparent dd, 2H, J = 2.9 Hz), 7.69 (apparent dd, 2H, J = 2.9 Hz), 7.56 (apparent dt, 3H, J = 2.9, 7.3 Hz), 7.33 (m, 4H), 7.21 (t, 1 H, J = 7.8 Hz), 7.09 (s, 1H), 6.81 (apparent d, 1 H, J = 7.8 Hz), 5.49 (apparent dd, 1H, J = 5.5, 9.5 Hz), 2.98 (d, 1H, J = 9.5 Hz), 2.87 (m, 2H), 2.50 (septet, 1H, J = 6.7 Hz), 2.40-2.35 (m, 4H), 1.94 (m, 2H), 1.70-1.50 (m, 4H), 1.25 (d, 6H, J = 7.9 Hz); ESMS m/e: 510.4 (M+H)+.
Step 3: See Scheme 3/ Method B for general deprotection conditions. Step 4: See general coupling conditions in Schemes 8-10.
General procedure for Scheme 6
BIS(4-FLUOROPHENYL)ACETIC ACID. Fluorobenzene (13.6 g, 0.142 mol) and glyoxylic acid monohydrate (2.35 g, 0.0255 mol) were dissolved in warm acetic acid (30.0 mL). The mixture was cooled in an ice/water bath and concentrated sulfuric acid (20.0 mL) was added dropwise over 0.5 h. The resulting thick red suspension was stirred at 80 °C for 12 h and then cooled to room temperature. Water (300 mL) was added and the pH was adjusted to 3 with potassium hydroxide pellets and 10% KOH solution. The aqueous solution was extracted with ethyl acetate (3 x 100 mL) and the combined organic extracts were washed with brine (100 mL) and dried over sodium sulfate, filtered and concentrated in vacuo to give the desired product (5.18 g, 82%) as a red solid, which was used in the subsequent step without further purification: 1H NMR (400 MHz, CD3OD) δ 9.45 (br s, 1H), 7.31-7.25 (m, 4H), 7.06-7.0 (m, 4H), 5.01 (s, 1H).
General procedure for Scheme 7
BIS(4-METHYLPHENYL)ACETIC ACID. To a 250 mL RB-flask was added 4,4'- dimethylbenzhydrol (1.06 g, 5.00 mmol) and 97% sulfuric acid (44.0 mL). The mixture was cooled to 15 °C by an ice/water bath and formic acid (12.0 mL) was added dropwise via an addition funnel over 0.5 h. The resulting foaming solution was stirred at 15 °C for 2 h. Water (300 mL) was added and the pH was adjusted to 3 with potassium hydroxide pellets and 10% KOH solution. The aqueous solution was extracted with ethyl acetate (3 x 100 mL) and the combined organic extracts were washed with brine (100 mL) and dried over sodium sulfate, filtered and concentrated in vacuo to give the desired product (0.281 g, 26%) as a pale yellow solid, which was used in the subsequent step without further purification: 1H NMR (400 MHz, CD3OD) δ 7.28-6.99 (m, 8H), 6.96 (br s, 1H), 4.94 (s, 1 H), 2.29 (s, 6H).
General procedure for Scheme 8
Λ/-[3-(1-{3-[(DIPHENYLACETYL)AMINO]PROPYL}-4-PIPERIDINYL)PHENYL]-2- METHYLPROPANAMIDE. A mixture of 2,2-diphenylacetyl chloride (0.300 mmol, 69.2 mg), Λ/-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide (0.250 mmol, 75.8 mg) and triethylamine (0.500 mmol, 50.5 mg) was dissolved in THF (2.00 mL) and the mixture was shaken on an Orbital J-KEM Shaker at room temperature for 12 h. The reaction mixture was concentrated in vacuo, and the residue was purified by preparative TLC [silica, CH2CI2: ammonia (2.0 M in methanol) 100:5] to afford the desired product (83.3 mg, 62% yield): 1H NMR (400 MHz, CDCI3) δ 7.51 (s, 1H), 7.33-7.21 (m, 13H), 6.94 (m, 2H), 4.88 (s, 1 H), 3.39 (t, 2H, J = 5.6 Hz), 2.93 (d, 2H, J = 11.3 Hz), 2.52-2.36 (m, 4H), 1.97 (t, 2H, J = 11.3 Hz), 1.83-1.58 (m, 6H), 1.24 (d, 6H, J = 7.6 Hz); Anal. Calcd for C32H39N3O2+HCI+0.19CHCI3: C, 69.44; H, 7.27; N, 7.55. Found: C, 69.44; H, 7.43; N, 7.43; ESMS m/e: 498.4 (M+H)+.
General procedure for Scheme 9
Λ/-(3-{4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-2,2-DIPHENYL PROPANAMIDE. A mixture of 2,2-diphenylpropionic acid (0.200 mmol, 45.2 mg), Λ/-{3-[1-(3- aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide (0.200 mmol, 60.7 mg), 1-[3- (dimethylamino)propyl]3-ethylcarbodiimide (EDC, 0.400 mmol, 62.0 mg) and 4- dimethylaminopyridine (5.00 mg) was dissolved in CH2CI2/DMF (1.00/0.100 mL) and the mixture was shaken on an orbital J-KEM shaker at room temperature for 12 h. The reaction mixture was concentrated in vacuo, purified by preparative TLC [silica, CH2CI2:ammonia (2.0 M in methanol) 100:5] to afford the desired product (43.8 mg, 42% yield): 1H NMR (400 MHz, CDCI3) δ 7.50-7.43 (br, 1H), 7.43-7.39 (br, 1H), 7.39-7.18 (m, 12H), 6.89 (d, 1H, J = 7.7 Hz), 6.23 (br, 1H) 3.42-3.32 (m, 2H), 2.85 (d, 2H, J = 10.8 Hz), 2.50 (quintet, 1H, J = 7.4 Hz), 2.45-2.36 (m, 1H), 2.28 (t, 2H, J = 6.4 Hz), 1.99 (s, 3H), 1.96-1.82 (m, 2H), 178-1.60 (m, 4H), 1.60-1.47 (m, 2H), 1.23 (d, 6H, J = 7.0 Hz); ESMS m/e: 512.4 [M + Hf.
General procedure for Scheme 10
A library of amides was constructed in polypropylene Robbins "Reactor Blocks", 48 well plates. PS-CDI resin (300 mg, 2.00 eq, purchased from Argonaut Technologies) was placed in each well of the "Reactor Blocks" 48 well plates. To each well was added an amine (0.200 mmol) and a carboxylic acid (0.22 mmol) in 3.00 mL of CH2CI2 and DMF (10:1). The Reactor Blocks were sealed and rotated in a Robbins oven (FlexChem) at room temperature for 12 h. The solutions were filtered in parallel into Robbins receiving plates and the resin was washed with CH2CI2 (2.0 mL) and MeOH (1.0 mL). The filtrate and washings were concentrated under reduced pressure to give the desired product, which was analyzed by 1H NMR and ESMS.
2-(4-CHLOROPHENYL)-2-METHYL-Λ/-(3-{4-[3-(PROPIONYLAMINO)PHENYL]-1- PIPERIDINYL}PROPYL)PROPANAMlDE: Prepared according to the general procedure outlined in Scheme 10 using 2-(4-chlorophenyl)-2-methylpropanoic acid and N-{3-[1-(3- aminopropyl)-4-piperidinyl]phenyl}propanamide: 1H NMR (400 MHz, CDCI3) δ 7.86 (s, 1H), 7.50 (s, 1 H), 7.34-7.19 (m, 6H), 6.96 (d, 1H, J = 7.8 Hz), 672-6.67 (m, 1H), 3.42 (q, 2H, J = 7.1 Hz), 3.31 (q, 3H, J = 5.4 Hz), 2.49-2.35 (m, 5H), 2.08-1.95 (m, 2H), 1.82-174 (m, 2H), 171-1.62 (m, 3H), 1.56 (s, 6H), 1.24 (t, 3H, J = 7.8 Hz); ESMS m/e: 470.3 [M + H]+.
General procedure for Scheme 11
(4S)-3-[(4-fluorophenyl)acetyl]-4-isopropyl-1 ,3-oxazolidin-2-one: To a solution of (4S)-4- isopropyl-1 ,3-oxazolidin-2-one (2.0 g, 15.5 mmol) in dry THF (20 mL) at -78°C under argon, was added dropwise a 2.5M solution of π-BuLi in hexanes (6.2 mL, 15.5 mmol). After stirring at -78°C for 15 min, (4-fluorophenyl)acetyl chloride (2.55 mL, 18.6 mmol) was added. The resulting reaction mixture was stirred at -78°C for 30 min and 0°C for 15 min, quenched with saturated NH CI (5 mL) and concentrated in vacuo. The residue was dissolved in EtOAc (100 mL) and washed with saturated Na2CO3 following by brine, dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (10%- 15% EtOAc/ hexane) to give 2.83 g (10.7 mmol, 69%) of (4S)-3-[(4-fluorophenyI)acetyl]-4- isopropyl-1,3-oxazolidin-2-one: 1H NMR (400 MHz, CDCI3) δ 7.30-7.25 (m, 2 H), 7.10 (t, 2 H, J = 8.5 Hz), 4.46-4.41 (m, 1 H), 4.36-4.15 (m, 4 H), 2.40-2.28 (m, 1 H), 0.88 (d, 3 H, J = 7.6 Hz), 0.79 (d, 3 H, J = 7.6 Hz); ESMS m/e: 266.2 (M + H)+.
(4S)-3-[(4-chlorophenyl)acetyl]-4-isopropyI-1 ,3-oxazolidin-2-one: To a solution of (4S)-4-iso propyl-1 ,3-oxazolidin-2-one (2.0 g, 15.5 mmol) in dry THF (20 mL) at -78°C under argon, was added dropwise a 2.5M solution of n-BuLi in hexanes (6.2 mL, 15.5 mmol). After stirring at -78°C for 15 min, (4-chlorophenyl)acetyl chloride (2.70 mL, 21.8 mmol) was added. The resulting reaction mixture was stirred at -78°C for 30 min and 0°C for 15 min, quenched with saturated NH CI (5 mL) and concentrated in vacuo. The residue was dissolved in EtOAc (100 mL) and washed with saturated Na2C03 following by brine, dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (10%- 15% EtOAc/ hexane) to give 2.33 g (8.29 mmol, 53%) of (4S)-3-[(4-chlorophenyl)acetyl]-4- isopropyl-1,3-oxazolidin-2-one: 1H NMR (400 MHz, CDCI3) δ 7.31-7.22 (m, 4 H), 4.45-4.41 (m, 1 H), 4.35-4.16 (m, 4 H), 2.39-2.29 (m, 1 H), 0.89 d, 3 H, J = 7.2 Hz), 0.80 (d, 3 H, J = 7.2 Hz); ESMS m/e: 282.2 (M + H)+.
(4R)-3-[(4-fluorophenyl)acetyl]-4-isopropyl-1 ,3-oxazolidin-2-one: To a solution of (4R)-4- isopropyl-1 ,3-oxazolidin-2-one (5.2 g, 40.3 mmol) in dry THF (100 mL) at -78°C under argon, was added dropwise a 2.5M solution of π-BuLi in hexanes (17.0 mL, 42.5 mmol). After stirring at -78°C for 15 min, (4-fluorophenyl)acetyl chloride (6.34 mL, 46.4 mmol) was added. The resulting reaction mixture was stirred at -78°C for 30 min and 0°C for 15 min, quenched with saturated NH4CI (15 mL) and concentrated in vacuo. The residue was dissolved in EtOAc (200 mL) and washed with saturated Na2CO3 following by brine, dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (10%-15% EtOAc/ hexane) to give 8.35 g (31.5 mmol, 78%) of (4R)-3-[(4- fluorophenyl)acetyl]-4-isopropyl-1 ,3-oxazolidin-2-one: 1H NMR (400 MHz, CDCI3) δ 7.30-7.25 (m, 2 H), 7.10 (t, 2 H, J = 8.5 Hz), 4.46-4.41 (m, 1 H), 4.36-4.15 (m, 4 H), 2.40-2.28 (m, 1 H), 0.88 (d, 3 H, J = 7.6 Hz), 0.79 (d, 3 H, J = 7.6 Hz); ESMS m/e: 266.1 (M + H)+.
(4R)-3-[(4-chlorophenyl)acetyl]-4-isopropyl-1,3-oxazolidin-2-one: To a solution of (4R)-4- isopropyl-1 ,3-oxazolidin-2-one (5.3 g, 41.1 mmol) in dry THF (100 mL) at -78°C under argon, was added dropwise a 2.5M solution of n-BuLi in hexanes (17.0 mL, 42.5 mmol). After stirring at -78°C for 15 min, (4-chlorophenyl)acetyl chloride (2.70 mL, 21.8 mmol) was added. The resulting reaction mixture was stirred at -78°C for 30 min and 0°C for 15 min, quenched with saturated NH4CI (15 mL) and concentrated in vacuo. The residue was dissolved in EtOAc (200 mL) and washed with saturated Na2CO3 following by brine, dried over MgSO , filtered and concentrated in vacuo. The crude material was purified by flash chromatography (10%-15% EtOAc/ hexane) to give 6.48 g (23.1 mmol, 56%) of (4R)-3-[(4- chlorophenyl)acetyl]-4-isopropyl-1,3-oxazolidin-2-one: 1H NMR (400 MHz, CDCI3) δ 7.31-7.22 (m, 4 H), 4.45-4.41 (m, 1 H), 4.35-4.16 (m, 4 H), 2.39-2.29 (m, 1 H), 0.89 d, 3 H, J = 7.2 Hz), 0.80 (d, 3 H, J = 7.2 Hz); ESMS m/e: 282.1 (M + H)+.
(4S)-3-[(2S)-2-(4-fluorophenyI)propanoyl]-4-isopropyl-1 ,3-oxazolidin-2-one: To a solution of (4S)-3-[(4-fluorophenyl)acetyl]-4-isopropyl-1 ,3-oxazolidin-2-one (2.81 g, 10.6 mmol) in dry THF (40 mL) at -78°C under argon, was added dropwise 1.0M solution of NaHMDS in THF (117 mL, 11.7 mmol) over a period of 10 min. After stirring at -78°C for 1 h, Mel (3.30 mL, 53.0 mmol) was added. The resulting reaction mixture was stirred at -78°C for 1 h and - 40°C for 2 h, quenched with HOAc (32 mmol) in ether (20 mL), filtered over celite. The filtrate was concentrated in vacuo and the residue was dissolved in CH2CI2 (100 mL) and washed with H20 following by brine, dried over MgS04, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (5%-10% EtOAc in hexane) to give 2.40 g (8.60 mmol, 81%) of (4S)-3-[(2S)-2-(4-fluorophenyl)propanoyl]-4-isopropyl-1 ,3- oxazolidin-2-one: 1H NMR (400 MHz, CDCI3) δ 7.34-7.31 (m, 2 H), 7.02-6.96 (m, 2 H), 5.13 (q, 1 H, J = 7.7 Hz), 4.38-4.33 (m, 1 H), 4.18-4.13 (m, 2 H), 2.48-2.37 (m, 1 H), 1.49 (d, 3;H, J = 7.3 Hz), 0.91 (apparent t, 6 H, J = 6.9 Hz); ESMS m/e: 280.2 (M + H)+.
(4S)-3-[(2S)-2-(4-chIorophenyl)propanoyl]-4-isopropyl-1 ,3-oxazolidin-2-one: To a solution of (4S)-3-[(4-chlorophenyl)acetyl]-4-isopropyl-1 ,3-oxazolidin-2-one (1.07 g, 3.81 mmol) in dry THF (30 mL) at -78°C under argon, was added dropwise 1.0M solution of NaHMDS in THF (4.20 mL, 4.20 mmol) over a period of 10 min. After stirring at -78°C for 1 h, Mel (1.19 mL, 19.1 mmol) was added. The resulting reaction mixture was stirred at -78°C for 1 h and - 40°C for 2 h, quenched with HOAc (11.4 mmol) in ether (20 mL), filtered over celite. The filtrate was concentrated in vacuo and the residue was dissolved in CH2CI2 (50 mL) and washed with H20 following by brine, dried over MgS04, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (5%-10% EtOAc in hexane) to give 0.68 g (2.30 mmol, 60%) of (4S)-3-[(2S)-2-(4-chlorophenyl)propanoyl]-4-isopropyl-1 ,3- oxazolidin-2-one: 1H NMR (400 MHz, CDCI3) δ 7.30-7.23 (m, 4 H), 5.11 (q, 1 H, J = 7.9 Hz), 4.35 (quintet, 1 H, J = 37 Hz), 4.16-4.09 (m, 2 H), 2.46-2.36 (m, 1 H), 1.49 (d, 3 H, J = 7.3 Hz), 0.91 (apparent t, 6 H, J = 6.9 Hz); ESMS m/e: 296.2 (M + H)+.
(4R)-3-[(2R)-2-(4-fluorophenyl)propanoyl]-4-isopropyl-1 ,3-oxazolidin-2-one: To a solution of (4R)-3-[(4-fluorophenyl)acetyl]-4-isopropyl-1,3-oxazolidin-2-one (4.24 g, 16.0 mmol) in dry THF (80 mL) at -78°C under argon, was added dropwise 1.0M solution of NaHMDS in THF (17.6 mL, 17.6 mmol) over a period of 10 min. After stirring at -78°C for 1 h, Mel (5.0 mL, 80.0 mmol) was added. The resulting reaction mixture was stirred at -78°C for 1 h and - 40°C for 2 h, quenched with HOAc (48 mmol) in ether (20 mL), filtered over celite. The filtrate was concentrated in vacuo and the residue was dissolved in CH2CI2 (200 mL) and washed with H20 following by brine, dried over MgS0 , filtered and concentrated in vacuo. The crude material was purified by flash chromatography (5%-10% EtOAc in hexane) to give 2.59 g (9.28 mmol, 58%) of (4R)-3-[(2R)-2-(4-fluorophenyl)propanoyl]-4-isopropyI-1 ,3- oxazolidin-2-one: 1H NMR (400 MHz, CDCI3) δ 7.34-7.31 (m, 2 H), 7.02-6.96 (m, 2 H), 5.13 (q, 1 H, J = 7.7 Hz), 4.38-4.33 (m, 1 H), 4.18-4.13 (m, 2 H), 2.48-2.37 (m, 1 H), 1.49 (d, 3 H, J = 7.3 Hz), 0.91 (apparent t, 6 H, J = 6.9 Hz); ESMS m/e: 280.2 (M + H)+.
(4R)-3-[(2R)-2-(4-chlorophenyl)propanoyl]-4-isopropyl-1 ,3-oxazolidin-2-one: To a solution of (4R)-3-[(4-chlorophenyl)acetyl]-4-isopropyl-1 ,3-oxazolidin-2-one (2.80 g, 9.96 mmol) in dry THF (80 mL) at -78°C under argon, was added dropwise 1.0M solution of NaHMDS in THF (11.0 mL, 11.0 mmol) over a period of 10 min. After stirring at -78°C for 1 h, Mel (1.9 mL, 30.0 mmol) was added. The resulting reaction mixture was stirred at -78°C for 1 h and - 40°C for 2 h, quenched with HOAc (30.0 mmol) in ether (20 mL), filtered over celite. The filtrate was concentrated in vacuo and the residue was dissolved in CH2CI2 (100 mL) and washed with H20 following by brine, dried over MgS0 , filtered and concentrated in vacuo. The crude material was purified by flash chromatography (5%-10% EtOAc in hexane) to give 1.58 g (5.35 mmol, 54%) of (4R)-3-[(2R)-2-(4-chlorophenyl)propanoyl]-4-isopropyl-1 ,3- oxazolidin-2-one: 1H NMR (400 MHz, CDCI3) δ 7.30-7.23 (m, 4 H), 5.11 (q, 1 H, J = 7.9 Hz), 4.35 (quintet, 1 H, J = 3.7 Hz), 4.16-4.09 (m, 2 H), 2.46-2.36 (m, 1 H), 1.49 (d, 3 H, J = 7.3 Hz), 0.91 (apparent t, 6 H, J = 6.9 Hz); ESMS m/e: 296.1 (M + H)+.
(2S)-2-(4-fluorophenyl)propanoic acid: To a solution of (4S)-3-[(2S)-2-(4-fluorophenyl) propanoyl]-4-isopropyl-1 ,3-oxazolidin-2-one (2.40 g, 8.60 mmol) in 160 mL THF/ H20 (3:1) at 0°C, was added 30% H202 (7.8 mL, 68.8 mmol) followed by LiOH (722 mg, 17.2 mmol). The resulting mixture was stirred at 0°C for 2 h and the excess peroxide was quenched at 0°C with 1.5 N aqueous Na2S03 (51 mL). After buffering to pH 9-10 with aqueous NaHC03 and evaporation of the THF, the oxazolidone chiral auxiliary was recovered by EtOAc extraction (50 mL x 3). The aqueous layer was acidified with 3N HCI and extracted with EtOAc. The organic layer was washed with brine, dried over MgS04, filtered and concentrated in vacuo to give 0.92 g (5.47 mmol, 64%) of (2S)-2-(4-fluorophenyl)propanoic acid; [α]D = + 70° (C=1 , MeOH): 1H NMR (400 MHz, CDCI3) δ 12.2-11.4 (br, 1 H), 7.31-7.24 (m, 2 H), 7.04-6.97 (m, 2 H), 372 (q, 1 H, J = 7.3 Hz), 1.49 (d, 3 H, J = 7.3 Hz); ESMS m/e: 167.2 (M - H)+.
(2S)-2-(4-chlorophenyl)propanoic acid: To a solution of (4S)-3-[(2S)-2-(4-chlorophenyl) propanoyl]-4-isopropyl-1 ,3-oxazolidin-2-one (678 mg, 2.30 mmol) in 45 mL THF/ H20 (3:1) at 0°C, was added 30% H202 (2.1 mL, 18.4 mmol) followed by LiOH (193 mg, 4.6 mmol). The resulting mixture was stirred at 0°C for 2 h and the excess peroxide was quenched at 0°C with 1.5 N aqueous Na2S03 (15 mL). After buffering to pH 9-10 with aqueous NaHC03 and evaporation of the THF, the oxazolidone chiral auxiliary was recovered by EtOAc extraction (50 mL x 3). The aqueous layer was acidified with 3N HCI and extracted with EtOAc. The organic layer was washed with brine, dried over MgS04, filtered and concentrated in vacuo to give 0.36 g (1.96 mmol, 85%) of (2S)-2-(4-chlorophenyl)propanoic acid; [α]D = + 67° (C=1 , MeOH): 1H NMR (400 MHz, CDCI3) δ 12.2-10.8 (br, 1 H), 7.32-7.23 (m, 4 H), 3.72 (q, 1 H, J = 7.3 Hz), 1.50 (d, 3 H, J = 7.3 Hz); ESMS m/e: 183.2 (M - H)+.
(2R)-2-(4-fluorophenyl)propanoic acid: To a solution of (4R)-3-[(2R)-2-(4-fluorophenyl )propanoyl]-4-isopropyl-1 ,3-oxazolidin-2-one (2.59 g, 9.28 mmol) in 160 mL THF/ H20 (3:1) at 0°C, was added 30% H202 (8.4 mL, 74.2 mmol) followed by LiOH (780 mg, 18.6 mmol). The resulting mixture was stirred at 0°C for 2 h and the excess peroxide was quenched at 0°C with 1.5 N aqueous Na2S03 (54 mL). After buffering to pH 9-10 with aqueous NaHC03 and evaporation of the THF, the oxazolidone chiral auxiliary was recovered by EtOAc extraction (50 mL x 3). The aqueous layer was acidified with 3N HCI and extracted with EtOAc. The organic layer was washed with brine, dried over MgS04, filtered and concentrated in vacuo to give 1.43 g (8.51 mmol, 92%) of (2R)-2-(4-fluorophenyl)propanoic acid; [α]D = - 61.5° (C=1.04, MeOH): 1H NMR (400 MHz, CDCI3) δ 12.2-11.4 (br, 1 H), 7.31- 7.24 (m, 2 H), 7.04-6.97 (m, 2 H), 372 (q, 1 H, J = 7.3 Hz), 1.49 (d, 3 H, J = 7.3 Hz); ESMS m/e: 167.2 (M - H)+.
(2R)-2-(4-chlorophenyl)propanoic acid: To a solution of (4R)-3-[(2R)-2-(4-chlorophenyl) propanoyl]-4-isopropyl-1 ,3-oxazolidin-2-one (1.58 g, 5.35 mmol) in 45 mL THF/ H20 (3:1) at 0°C, was added 30% H202 (4.9 mL, 42.8 mmol) followed by LiOH (449 mg, 10.7 mmol). The resulting mixture was stirred at 0°C for 2 h and the excess peroxide was quenched at 0°C with 1.5 N aqueous Na2S03 (31 mL). After buffering to pH 9-10 with aqueous NaHC03 and evaporation of the THF, the oxazolidone chiral auxiliary was recovered by EtOAc extraction (50 mL x 3). The aqueous layer was acidified with 3N HCI and extracted with EtOAc. The organic layer was washed with brine, dried over MgS04, filtered and concentrated in vacuo to give 0.97 g (5.27 mmol, 98%) of (2R)-2-(4-chlorophenyl)propanoic acid; [α]D = - 64.8° (C=1.05, MeOH): 1H NMR (400 MHz, CDCI3) δ 12.2-10.8 (br, 1 H), 7.32-7.23 (m, 4 H), 3.72 (q, 1 H, J = 7.3 Hz), 1.50 (d, 3 H, J = 7.3 Hz); ESMS m/e: 183.2 (M - H)+.
General procedure for Scheme 12
For intermediate RCOOH are available from commercial sources or alternatively may be prepared from a variety of intermediates known to those skilled in the art. For example, α- substituted aryl acetic acid can be prepared by hydrolysis of corresponding α -substituted arylacetonitriles or α -substituted aryl acetic esters (Rieu, et al., 1986. Tetrahedron 42(15) 4095-4131 and references cited therein).
Enantiomerically pure-substituted aryl acetic acid can be prepared by asymmetric syntheses or enzymatic kinetic resolution (Evans, in Asymmetric Synthesis, ed. Morrison 1984. Vol 3, Academic Press, New York; Li, ef al., 2001. Tetrahedron: Asymmetry 12, 3305-3312 and references cited therein).
Enantiomerically pure α-hydroxy carboxylic acid can be prepared by asymmetric syntheses or kinetic resolution (Chang, ef al., 1999. Org. Lett. 13 2061-2063; Deng, et al., 2002. J. Am. Chem. Soc. 124(12) 2870-2871 ; Bull, et al., 2003. Tetrahedron: Asymmetry 14, 1407- 1446 and references cited therein).
The enantiomeric purity is determined by NMR or HPLC (Parker, 1991. Chem. Rev. 91 1441-1457 and references cited therein). Many other methods to produce acid intermediates are known in the literature and may be utilized by those skilled in the art for their preparation.
General procedure for Scheme 13 Step l
A 25 mL RB-flask was charged with ethyl iodide (1.00 mmol, 156 mg), Λ/-{3-[1-(3- aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide (1.00 mmol, 303 mg), sodium tert- butoxide (2.00 mmol, 192 mg) and THF (5.00 mL). The mixture was shaken on an J-KEM orbital shaker at room temperature for 12 h. The reaction mixture was concentrated in vacuo and purified by preparative TLC [silica, CH2CI2:ammonia (2.0 M in methanol) 100:5] to afford the desired product (28.5 mg, 9% yield): 1H NMR (400 MHz, CDCI3) δ 7.47 (s, 1H), 7.40-7.30 (m, 1H), 7.23-7.19 (m, 1 H), 7.01-6.95 (m, 2H), 370 (q, 2H, J = 6.0 Hz), 3.10-3.02 (m, 2H), 2.81-275 (m, 2H), 2.50-2.41 (m, 4H), 2.09-2.01 (m, 2H), 1.83-1.67 (m, 6H), 1.24 (d, 7H, J = 6.0 Hz), 1.08 (t, 3H, J = 6.0 Hz). Step 2: See Scheme 9.
General procedure for Scheme 14
N-(3-BROMOPROPYL)-2,2-DIPHENYLACETAMIDE. To a stirred mixture of 3- bromopropylamine hydrobromide (2.91 g, 13.3 mmol) in 10 mL of CH2CI2 was added 2.8 mL of triethylamine (20.0 mmol). The reaction mixture was stirred at room temperature for 10 minutes, followed by addition of diphenyl acetyl chloride (2.56 g, 11.1 mmol) and triethylamine (2.8 L, 20 mmol) in CH2CI2 (10 mL). The reaction mixture was stirred for 40 minutes at room temperature and then diluted with 200 mL of CH2CI2. The solution was washed with aqueous 0.5 N HCI (100 mL x 3), water (50 mL), NaHC03 (sat, 100 mL) and NaCl (sat), dried over MgS04. Removal of solvent gave the crude product as a light yellow solid that was used in the next step without further purification (3.33 g, 91%): 1H NMR (400 MHz, CDCI3) δ 7.56-7.45 (m,.10H), 5.88-5.69 (br, 1H), 4.92 (s, 1H), 3.47-3.39 (m, 2H), 3.35 (t, 2H, J = 6.4 Hz), 2.16-1.98 (m, 2H).
N-[4-(1-{3-[(DIPHENYLACETYL)AMINO]PROPYL}-4-PIPERIDINYL)PHENYL]-2- METHYLPROPANAMIDE: A mixture of 2-methyl-N-[4-(4-piperidinyl)phenyl]propanamide (50.0 mg, 2.0 mmol), N-(3-bromopropyl)-2,2-diphenylacetamide (64.2 mg, 0.2 mmol), K2C03 (55.0 mg, 4.0 mmol), and Nal (45.0 mg, 0.3 mmol) in 2 mL of DMF was stirred at room temperature for 10 minutes followed by heating to 80-90 °C for 12h. The reaction mixture was cooled to room temperature and purified by preparative TLC (silica gel, EtOAc/NH3 (2 M in MeOH); 95:5) to afford N-[4-(1-{3-[(diphenylacetyl)amino]propyl}-4-piperidinyl)phenyl]-2- methylpropanamide as a colorless oil (15.7 mg, 32%): ESMS m/e 498.3 (M + H)+.
General procedure for Scheme 15
N-{3-[4-(3-AMINOPHENYL)-1-PIPERIDINYL]}-2,2-DIPHENYLACETAMIDE: A 25mL RB- flask, equipped with a balloon of hydrogen, was charged with benzyl 3-(1-{3- [(diphenylacetyl)amino]propyl}-4-piperidinyl] phenylcarbamate (787 mg, 0.140 mmol), Pd/C (10 mol%, 14.8 mg) and ethanol (2.00 mL) at room temperature. The mixture was stirred at room temperature for 12 h and filtered through a plug of Celite. The Celite was washed with methylene chloride (3 x 5 mL) and the filtrate was concentrated in vacuo. The residue was purified by preparative TLC [silica, CH2CI2: ammonia (2.0 M in methanol) 100:5] to afford N- {3-[4-(3-aminophenyl)-1-piperidinyl]}-2,2-diphenylacetamide: 1H NMR (400 MHz, CDCI3) δ 7.34-7.08 ( , 15H), 4.59 (s, 1 H), 3.38-3.31 (m, 1H), 3.24-3.15 (m, 2H), 271-2.64 (m, 1H), 2.49-2.28 (m, 3H), 2.08-1.89 (m, 3H), 1.84-1.49 (m, 6H); ESMS m/e: 428.3 (M + H)+. General procedure for Scheme 16
1-bromo-2,4-difluoro-5-nitrobenzene: To a suspension of 1-bromo-2,4-difluorobenzene (6.0 mL, 53.0 mmol) in coned H2S04 (38.5 mL) at 0°C was added dropwise coned HN03 (34.0 mL) maintaining an internal temperature below 20°C. The resulting mixture was stirred for 30 min at 0°C, then poured slowly into ice water with vigorous stirring. The aqueous phase was separated and extracted with EtOAc. The combined organic extrats were washed with 5% aqueous KOH and brine, dried over MgS0 and concentrated to give 12.2 g (51.5 mmol, 97%) of 1-bromo-2,4-difluoro-5-nitrobenzene: 1H NMR (400 MHz, CDCI3) δ 8.39 (t, 1 H, J = 7.4 Hz), 7.13 (dd, 1 H, J = 7.7, 10.3 Hz).
2-bromo-1 ,3,5-trifluoro-4-nitrobenzene: 1H NMR (400 MHz, CDCI3) δ 7.05-6.98 (m, 1 H); ESMS m/e: 256.2 (M + H)+.
5-bromo-2,4-difluoroaniline: To a solution of 1-bromo-2,4-difluoro-5-nitrobenzene (5.04 g, 21.3 mmol) in EtOH (100 mL), THF (50 mL), NH4CI (βaq (25 mL) and H20 (25 mL) was added iron powder (5.0 g, 89.5 mmol). The mixture was refluxed for 2 h and filtered through celite. The filter pad was washed with EtOAc (3 x 50 mL). The filtrate was concentrated and the residue was partitioned between EtOAc and brine. The organic layer was dried over MgS0 and concentrated. Purification by flash chromatography (5-10% EtOAc/ Hexane) provided 2.6 g (59 %) of 5-bromo-2,4-difluoroaniline: ESMS m/e: 208.2 (M + H)+.
3-bromo-2,4,6-trifluoroaniline: 1H NMR (400 MHz, CDCI3) δ 6.85-676 (m, 1 H), 378-3.51 (br, 2 H).
N-(5-bromo-2,4-difluorophenyl)-2-methylpropanamide:
Into a solution of 2.6 g (12.6 mmol) of 5-bromo-2,4-difluoroaniline and 2.1 mL (15.1 mmol) of triethylamine in 50 mL THF at 0 °C was slowly added 1.6 mL (15.1 mmol) of isobutyryl chloride. The reaction mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The residue was dissolved in EtOAc and washed with H20, saturated aqueous Na2C03 and brine. The organic layer was dried over MgS04 and concentrated in vacuo to give 3.3 g (11.8 mmol, 94%) of N-(5-bromo-2,4-difluorophenyl)-2-methylpropanamide: ESMS m/e: 278.1 (M + H)+.
N-(3-bromo-2,4,6-trifluorophenyl)-2-methylpropanamide: ESMS m/e: 296.3 (M + H)+.
tert-butyl 4-[2,4-difluoro-5-(isobutyrylamino)phenyl]-3,6-dihydro-1 (2H)-pyridine carboxylate: To a 250-mL RB flask containing tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 3,6-dihydro-1(2H)-pyridinecarboxylate (3.31 g, 107 mmol), K2C03 (4.44 g, 32.1 mmol) and PdCI dppf (870 mg, 1.07 mmol) was added a solution of N-(5-bromo-2,4-difluorophenyl)-2- methylpropanamide (3.28 g, 11.8 mmol) in DMF (100 mL) at room temperature under argon. The mixture was heated to 80 °C under argon overnight, cooled to room temperature, filtered through celite and the celite was washed with EtOAc (3 x 20 mL). The filtrates were washed with H20 (20 mL), brine (20 mL), dried over MgS04, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (10%-20% EtOAc/ hexane) to give 2.4 g (6.31 mmol, 59%) of tert-butyl 4-[2,4-difluoro-5-(isobutyrylamino)phenyl]-3,6-dihydro-1(2H)- pyridine carboxylate: ESMS m/e: 379.3 (M - H)+.
tert-butyl 4-[2,4,6-trifluoro-3-(isobutyrylamino)phenyl]-3,6-dihydro-1 (2H)-pyridinecarboxylate: ESMS m/e: 397.6 (M - H)+.
tert-butyl 4-[2,4-difluoro-5-(isobutyrylamino)phenyl]-1-piperidinecarboxylate: A solution of tert- butyl 4-[2,4-difluoro-5-(isobutyrylamino)phenyl]-3,6-dihydro-1 (2H)-pyridinecarboxylate (2.40 g, 6.31 mmol) and 10% Pd/C (500 mg) in EtOAc (40.0 mL) and MeOH (10.0 mL) was hydrogenated (200 psi) at room temperature overnight. The reaction mixture was filtered through celite and washed with ethanol (3 x 10 mL). The combined extracts were concentrated in vacuo to afford 2.04 g (5.34 mmol, 85%) of tert-butyl 4-[2,4-difluoro-5- (isobutyryiamino)phenyl]-1 -piperidinecarboxylate: ESMS m/e: 383.2 (M + H)+.
N-[2,4-difluoro-5-(4-piperidinyl)phenyl]-2-methylpropanamide: Into a solution of tert-butyl 4-
[2,4-difluoro-5-(isobutyrylamino)phenyl]-1-piperidinecarboxylate (6.54 g, 17.1 mmol) in 1 ,4- dioxane (40.0 mL) was added 4M HCI in 1,4-dioxane (160 mL) at room temperature. The reaction mixture was stirred for 1 h and concentrated in vacuo. The residue was dissolved in 100 mL of H20 and was basified with 10% KOH solution (50 mL). The aqueous layer was extracted with CHCI3/i-PrOH (3:1 , 3 x 150 mL). The combined organic extracts were washed with brine, dried over MgS0 , filtered and concentrated in vacuo to give 4.72 g (16.7 mmol,
98%) of N-[2,4-difluoro-5-(4-piperidinyl)phenyl]-2-methylpropanamide: ESMS m/e: 283.3 (M
+ H)+.
2-methyl-N-[2,4,6-trifluoro-3-(1 ,2,3,6-tetrahydro-4-pyridinyl)phenyl]propanamide: ESMS m/e:
299.5 (M + H)+. 2-methyl-N-[2,4,6-trifluoro-3-(4-piperidinyl)phenyl] propanamide: ESMS m/e:
301.3 (M + H)+.
General procedure for Scheme 17 benzyl 5-bromo-3-pyridinylcarbamate: To a suspension of 5-bromonicotinic acid (20.0 g, 99.0 mmol) in toluene (200 mL) was added diphenylphosphoryl azide (25.6 mL, 118.8 mmol) and Et3N (16.6 mL, 118.8 mmol). After stirring at room temperature for 30 min, benzyl alcohol (15.4 mL, 148.5 mmol) was added. The mixture was stirred at room temperature for 1 h then refluxed overnight. The cold reaction mixture was washed with H20, NaHC03 and brine, dried over MgS04 and concentrated. Purification by flash chromatography (15-50% EtOAc/ Hexane) provided 22.2 g (72.5 mmol, 73 %) of benzyl 5-bromo-3-pyridinylcarbamate: ESMS m/e: 307.0 (M + H)+.
tert-butyl 4-{5-[(phenylmethoxy)carbonylamino]-3-pyridyl}-1 ,2,5,6- tetrahyd ropy rid i necarboxylate:
ESMS m/e: 410.2 (M + H)+. tert-butyl 4-(5-amino-3-pyridinyl)-1 -piperidinecarboxylate: ESMS m/e: 278.3 (M + H)+. tert-butyl 4-[5-(isobutyrylamino)-3-pyridinyl]-1-piperidine carboxylate: ESMS m/e: 348.3 (M + H)+. 2-methyl-N-[5-(4-pipehdinyl)-3-pyridinyl]propanamide: ESMS m/e: 248.3 (M + H)+.
General procedure for Scheme 18 Bis(4-fluorophenyl)(hydroxy)acetic acid:
To a solution prepared from 10.2 g of KOH and 50 ml of 50% EtOH was added 1,2-bis(4- fluorophenyl)-1 ,2-ethanedione ( 10.0 g, 40.6 mmol) and the mixture was heated at reflux temperature overnight. After cooling to room temperature, the mixture was washed with ether (100 mL x 2). The aqueous layer was cooled to 0°C, acidified with 12 N HCI (20 mL) and extracted with CH2CI2 (150 mL x 2). The combined organic layers were washed with brine, dried over MgS0 , filtered and concentrated in vacuo to give 9.15 g (34.7 mmol, 85%) of bis(4-fluorophenyl)(hydroxy)acetic acid: ESMS m/e: 263.2 (M - H)+.
Hydroxy[bis(4-methylphenyl)]acetic acid: To a solution prepared from 10.6 g of KOH and 50 ml of 50% EtOH was added 1 ,2-bis(4- methylphenyl)-1 ,2-ethanedione ( 10.0 g, 42.0 mmol) and the mixture was heated at reflux temperature overnight. After cooled to room temperature, the mixture was washed with ether (100 mL x 2). The aqueous layer was cooled to 0°C, acidified with 12 N HCI (20 mL) and extracted with CH2CI2 (150 mL x 2). The combined organic layers were washed with brine, dried over MgS04, filtered and concentrated in vacuo to give 9.56 g (37.3 mmol, 89%) of hydroxy[bis(4-methylphenyl)]acetic acid: ESMS m/e: 255.3 (M - H)+. Example 1
Figure imgf000058_0001
Λ/-{3-[1-(3-{[BIS(4-FLUOROPHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL] PHENYL}-2-METHYLPROPANAMIDE: Example 1 was prepared from bis(4-fluorophenyl) acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCI3) δ 7.63 (s, 1H), 7.39-7.31 (m, 3H), 7.29-7.21 (m, 5H), 7.02-6.96 (m, 4H), 4.80 (s, 1H), 3.40 (q, 2H, J = 4.5 Hz), 2.94 (d, 2H, J = 10.2 Hz), 2.51-2.38 (m, 4H), 1.97(dt, 2H, J = 1.8, 10.4 Hz), 1.81 (m, 2H), 1.68 (quintet, 2H, J = 6.8 Hz,), 1.59 (m, 3H), 1.23 (d, 6H, J = 6.9 Hz); ESMS m/e: 534.3 (M + H)+; Anal. Calc. For (HCI salt) C32H37F2N302 • HCI • 0.20 CHCI3: C, 65.11 ; H, 6.48; N, 7.07. Found: C, 65.30; H, 6.50; N, 6.96.
Example 2
Figure imgf000058_0002
Λ/-{3-[1-(3-{[BIS(4-CHLOROPHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL]
PHENYL}-2-METHYLPROPANAMIDE: Example 2 was prepared from bis(4-chlorophenyl) acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl] phenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCI3) δ 7.64 (s, 1H), 7.34-7.13 (m, 12H), 4.75 (s, 1H), 3.41 (q, 2H, J = 4.5 Hz), 2.94 (d, 2H, J = 10.2 Hz),
2.51-2.40 ( , 4H), 1.97 (m, 2H), 1.82 (m, 2H), 1.68 (quintet, 2H, J = 6.8 Hz), 1.59 (m, 3H),
1.25 (d, 6H, J = 6.8 Hz); ESMS m/e: 566.2 (M + H)+.
Example 3
Figure imgf000058_0003
Λ/-(3-{4-[3-(acetylamino)phenyl]-1-piperidinyl}propyl)-2,2-diphenylacetamide: Example 3 was prepared from diphenylacetyl chloride and N-{3-[1-(3-aminopropyl)-4-piperidinyl ]phenyl}acetamide according to the procedures described in Scheme 8: H NMR (400 MHz, CDCI3) δ 770 (s, 1H), 7.40 (s, 1H), 7.32-7.20 (m, 12H), 6.96 (t, 1H, J = 4.8 Hz), 6.91 (d, 1H, J = 7.6 Hz), 4.87 (s, 1H), 3.39 (dd, 2H, J = 6.0, 12.4 Hz), 2.90 (d, 2H, J = 11.6 Hz), 2.43 (m, 1H), 2.36 (t, 2H, J = 6.4 Hz), 2.11 (s, 3H), 1.94 (m, 2H), 1.76 (d, 2H, J = 12.4 Hz), 1.68 (t, 2H, J = 6.8 Hz), 1.60 (dd, 2H, J = 1.2, 8.4 Hz); ESMS m/e: 470.3 (M + H)+.
Example 4
Figure imgf000059_0001
Λ/-[3-(1-{3-[(DIPHENYLACETYL)AMINO]PROPYL}-4-PIPERIDINYL)-4-METHYL PHENYL] - 2-METHYLPROPANAMIDE: Example 4 was prepared from diphenyl acetyl chloride and N- {3-[1-(3-aminopropyl)-4-piperidinyl]-4-methyl phenyl}-2-methylpropanamide according to the procedures described in Scheme 8: 1H NMR (400 MHz, CDCI3) δ 7.39-7.23 (m, 12H), 7.14 (br, 1H), 7.08 (d, 1H, J = 8.4 Hz), 6.90 (br, 1H), 4.91 (s, 1H), 3.41 (dd, 2H, J = 6.4, 12.4 Hz), 2.95 (d, 2H, J = 12.4 Hz), 2.66 (m, 1H), 2.47 (m, 1H), 2.40 (t, 2H, J = 6.4 Hz), 2.28 (s, 3H), 2.03-1.97 (m, 2H), 174-1.62 (m, 6H), 1.22 (d, 6H, J = 7.2 Hz); ESMS m/e: 512.3 (M + H)+.
Example 5
Figure imgf000059_0002
Λ/-[3-(1-{3-[(2,2-DIPHENYLACETYL)AMINO]PROPYL}-4-PIPERIDINYL)PHENYL] BUTANAMIDE: Example 5 was prepared from diphenylacetyl chloride and N-{3-[1-(3-amino propyl)-4-piperidinyl]phenyl}butanamide according to the procedures described in Scheme 8: 1H NMR (400 MHz, CDCI3) δ 7.49 (s, 1H), 7.35-7.23 (m, 12H), 7.20 (s, 1H), 6.95 (d, 2H, J = 7.6 Hz), 4.90 (s, 1 H), 3.41 (dd, 2H, J = 5.6, 11.6 Hz), 2.94 (d, 2H, J = 11.6 Hz), 2.48 (m, 1H), 2.40 (t, 2H, J = 6.4 Hz), 2.34 (t, 2H, J = 7.2 Hz), 1.98 (t, 2H, J = 11.2 Hz), 1.82-1.60 (m, 8H), 1.02 (t, 3H, J = 7.2 Hz); ESMS m/e: 498.3 (M + H)+.
Example 6 Λ/-[6-(1-{3-[(DIPHENYLACETYL)AMINO]PROPYL}-4-PIPERIDINYL)-2-PYRIDINYL]-2-
Figure imgf000059_0003
METHYLPROPANAMIDE: Example 6 was prepared from diphenylacetyl chloride and N-{6- [1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamide according to the procedures described in Scheme 8: 1H NMR (400 MHz, CDCI3).δ 8.07 (d, 1H, J = 8.0 Hz), 771-7.63 (m, 3H), 7.42-7.23 (m, 10H), 6.89 (d, 1H, J = 7.6 Hz), 4.96 (s, 1H), 3.41 (dd, 2H, J = 5.6, 7.6 Hz), 3.00 (d, 2H, J = 11.6 Hz), 2.60 (m, 1H), 2.47 (t, 2H, J = 6.4 Hz), 2.45 (m, 1H), 2.06-2.01 (m, 2H), 1.89-1.64 (m, 6H), 1.13 (d, 6H, J = 6.8 Hz); ESMS m/e: 499.3 (M + H)+. Example 7
Figure imgf000060_0001
2-(4-CHLOROPHENYL)-2-METHYL-/V-(3-{4-[3-(PROPIONYLAMINO)PHENYL]-1- PIPERIDINYL}PROPYL)PROPANAMIDE: Example 7 was prepared from 2-(4-chloro phenyl)-2-methylpropanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}propan amide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 7.86 (s, 1H), 7.50 (s, 1H), 7.34-7.19 (m, 6H), 6.96 (d, 1H, J = 7.8 Hz), 672-6.67 (m, 1H), 3.42 (q, 2H, J = 7.1 Hz), 3.31 (q, 3H, J = 5.4 Hz), 2.49-2.35 (m, 5H), 2.08-1.95 (m, 2H), 1.82-174 ( , 2H), 171-1.62 (m, 3H), 1.56 (s, 6H), 1.24 (t, 3H, J = 7.8 Hz); ESMS m/e: 470.3 (M + H)+.
Example 8
Figure imgf000060_0002
2-(4-CHLOROPHENYL)-Λ/-(3-{4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL} PROPYL)-2-METHYLPROPANAMIDE: Example 8 was prepared from 2-(4-chlorophenyl)-2- methylpropanoic acid and N-{3-[1-(3-amino propyl)-4-piperidinyl]phenyl}-2-methylpropan amide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCI3) δ 7.53 (s, 1H), 7.32-7.24 (m, 7H), 6.91 (d, 1H, J = 7.2 Hz), 6.67 (m, 1H), 3.31 (q, 2H, J = 5.5 Hz), 2.92-2.85 (m, 2H), 2.53 (septet, 1H, J = 6.7 Hz), 2.43 (tt, 1H, J = 11.6, 3.0 Hz), 2.33 (t, 2H, J = 6.7 Hz), 1.91 (dt, 2H, J = 11.7, 1.8 Hz), 178-172 (m, 2H), 1.65-1.59 (m, 2H), 1.56 (s, 6H), 1.52-1.45 (m, 2H), 1.25 (d, 6H, J = 6.7 Hz); ESMS m/e: 484.3 (M + H)+; Anal. Calc. for (HCI salt) C28H38CIN302 • HCI • 0.30 CHCI3: C, 61.10; H, 7.12; N, 7.55. Found: C, 60.90; H, 7.20; N, 7.64.
Example 9
Figure imgf000060_0003
Λ/-{3-[1-(3-{[BROMO(PHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL] PHENYL}-2- METHYLPROPANAMIDE: Example 9 was prepared from bromo (phenyl)aceticacid and N- {3-[1-(3-aminopropyl)-4-piperidinyl] phenyl}-2-methylpropanamide according to the procedures described in Scheme 9: ESMS m/e: 500.0 (M + H)+.
Example 10
Figure imgf000060_0004
Λ/-[3-(1-{3-[(2-BROMO-2-PHENYLACETYL)AMINO]PROPYL}-4-PIPERIDINYL) PHENYLJPROPANAMIDE: Example 10 was prepared from bromo(phenyl)acetic acid and N- {3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}propanamide according to the procedures described in Scheme 10: ESMS m/e: 486.1 (M + H)+.
Example 1 π
Figure imgf000061_0001
Λ/-(3-{4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-2,2-DI PHENYLHEPTANAMIDE: Example 11 was prepared from 2,2-diphenyl heptanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCI3) δ 7.65 (s, 1H), 7.45 (s, 1 H), 7.40 (m, 1H), 7.37-7.19 (m, 11H), 6.88 (d, 1H, J = 7.3 Hz), 6.34 (t, 1H, J = 4.5 Hz), 3.34-3.27 (m, 3H), 2.94-2.87 (m, 2H), 2.52 (septet, 1 H, J = 6.9 Hz), 2.46-2.34 (m, 4H), 2.27 (t, 2H, J = 6.9 Hz), 2.00-1.91 (m, 2H), 177-1.69 (m, 2H), 1.69-1.52, (m, 5H), 1.30-1.20 (m, 12H); ESMS m/e: 568.4 (M + H)+.
Example 12
Figure imgf000061_0002
Λ/-(3-{4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-2,2-DIPHENYL BUTANAMIDE: Example 12 was prepared from 2,2-diphenylbutanoic acid and N-{3-[1-(3- aminopropyl)-4-piperidinyl]phenyl}-2-methyl propanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCI3) δ 7.45 (s, 1H), 7.44-7.39 (m, 2H), 7.37- 7.28 (m, 8H), 7.27-7.20 (m, 3H), 6.89 (d, 1H, J = 7.4 Hz), 6.43 (t, 1H, J = 4.5 Hz), 3.35-3.27 (m, 2H), 2.90-2.82 (m, 2H), 2.51 (septet, 1H, J = 6.8 Hz), 2.49-2.35 (m, 4H), 2.24 (t, 2H, J = 6.3 Hz), 1.89 (t, 2H, J = 10.2 Hz), 175-1.68 (m, 2H), 1.66-1.58 (m, 2H), 1.57-1.45 (m, 2H), 1.24 (d, 6H, J = 6.7 Hz), 1.27-1.23 (m, 2H); ESMS m/e: 526.3 (M + H)+.
Example 13
Figure imgf000061_0003
Λ/-[3-(1-{3-[(DIPHENYLACETYL)AMINO]PROPYL}-4-PIPERIDINYL)PHENYL]-3-METHYL BUTANAMIDE: Example 13 was prepared from diphenylacetyl chloride and N-{3-[1-(3- aminopropyl)-4-piperidinyl]phenyl}-3-methylbutanamide according to the procedures described in Scheme 8: H NMR (400 MHz, CDCI3) δ 1079-10.51 (br, 1H), 8.85-8.67 (m, 1 H), 8.01.-7.81 (br, 1H), 7.70 (d, 1H, J = 7.2 Hz), 7.47-7.14 (m, 11H), 6.89 (d, 1H, J = 7.2 Hz), 5.03 (s, 1H), 3.53-3.26 (m, 4H), 2.96-2.80 (m, 2H), 278-2.52 (m, 3H), 2.44-2.14 (m, 2H), 2.26 (d, 2H, J = 6.0 Hz), 2.14-1.94 (m, 3H), 1.94-176 (m, 2H), 1.10 (d, 6H, J = 6.4 Hz); ESMS m/e: 512.3 (M + H)+; Anal. Calc. (HCI salt) C33H42CIN3O2O.60CH2CI2: C, 67.36; H, 7.27; N, 7.01. Found: C, 67.08; H, 7.57; N, 7.36.
Figure imgf000062_0001
Λ/-[3-(1-{3-[(2-MESITYL-2-PHENYLACETYL)AMINO]PROPYL}-4-PIPERIDINYL)PHENYL] PROPANAMIDE: Example 14 was prepared from mesityl(phenyl) acetic acid and N-{3-[1-(3- aminopropyl)-4-piperidinyl]phenyl} propanamide according to the procedures described in Scheme 9: ESMS m/e: 526.3 (M + H)+.
Example 15
Figure imgf000062_0002
2,2-DIPHENYL-Λ/-(3-{4-[3-(PROPIONYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL) BUTANAMIDE: Example 15 was prepared from 2,2-diphenylbutanoic acid and N-{3-[1-(3- aminopropyl)-4-piperidinyl] phenyljpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 7.43-7.38 (m, 1H), 7.37-7.29 (m, 9H), 7.28-7.21 (m, 4H), 6.90 (d, 1H, J = 8.2 Hz), 6.43 (t, 1H, J = 4.1), 3.32 (q, 2H, J = 6.5 Hz), 2.95-2.89 (m, 2H), 2.45 (q, 2H, J = 7.9 Hz), 2.43-2.35 (m, 3H), 2.27 (t, 2H, J = 6.5 Hz), 2.01-1.92 (m, 2H), 178-1.59 (m, 6H), 1.24 (t, 3H, J = 7.9 Hz), 079 (t, 3H, J = 6.5 Hz); ESMS m/e: 512.3 (M + H)+.
Example 16
Figure imgf000062_0003
Λ/-{3-[1-(3-{[(ETHYLSULFANYL)(DIPHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL] PHENYL}-2-METHYLPROPANAMIDE: Example 16 was prepared from (ethylsulfanyl) (diphenyl)acetic acid and N-{3-[1-(3-amino propyl)-4-piperidinyl]phenyl}-2-methylpropan amide according to the procedures described in Scheme 9: ESMS m/e: 658.6 (M + H)+.
Example 17
Figure imgf000063_0001
Λ/-[3-(1-{3-[(2,2-DIPHENYLACETYL)AMlNO]PROPYL}-4-PIPERIDINYL)PHENYL] CYCLO PROPANECARBOXAMIDE: Example 17 was prepared from diphenylacetyl chloride and N- {3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclo propanecarboxamide according to the procedures described in Scheme 8: 1H NMR (400 MHz, CDCI3) δ 9.26-9.09 (br, 1H), 8.12- 7.91 (br, 1H), 7.69 (d, 1H, J = 7.2 Hz), 7.63-7.42 (br, 1H), 7.43-7.12 (m, 11H), 6.88 (d, 1 H, J = 7.2 Hz), 5.03 (s, 1H), 3.53-3.27 (m, 4H), 2.99-2.84 (m, 2H), 2.84-2.58 (m, 3H), 2.40-2.16 (m, 2H), 2.16-1.98 (m, 2H), 1.98-1.83 (m, 2H), 178-1.64 (m, 1H), 1.10-0.97 (m, 2H), 0.90- 076 (m, 2H); ESMS m/e: 496.3 (M + H)+.
Example 18
Figure imgf000063_0002
Λ/-[3-(1-{3-[(DIPHENYLACETYL)AMINO]PROPYL}-4-PIPERIDINYL)PHENYL]-2,2- DIMETHYLPROPANAMIDE: Example 18 was prepared from diphenylacetyl chloride and N- {3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2,2-di methylpropanamide according to the procedures described in Scheme 8: 1H NMR (400 MHz, CDCI3) δ 7.51-7.41 (s, 1H), 7.34-7.10 (m, 13H), 6.99-6.80 (m, 2H), 4.81 (s, 1 H), 3.40-3.26 (m, 2H), 2.96-278 (m, 2H), 2.50-2.25 (m, 3H), 1.98-1.82 (m, 2H), 179-1.68 (m, 2H), 1.68-1.45 (m, 4H), 1.23 (s, 9H); ESMS m/e: 512.3 (M + H)+.
Example 19
Figure imgf000063_0003
Λ/-[3-(1-{3-[(DIPHENYLACETYL)AMINO]PROPYL}-4-PIPERIDINYL)PHENYL]-3,3- DIMETHYLBUTANAMIDE: Example 19 was prepared from diphenylacetyl chloride and N-{3- [1-(3-aminopropyl)-4-piperidinyl]phenyl}-3,3-dimethylbutanamide according procedures described in Scheme 8: 1H NMR (400 MHz, CDCI3) δ 1073-10.50 (br, 1H), 8.63-8.48 (m, 1H), 7.97-777 (br, 1H), 7.70 (d, 1 H, J = 7.2 Hz), 7.45-7.11 (m, 11H), 6.89 (d, 1H, J = 7.2 Hz), 5.01 (s, 1H), 3.46-3.26 (m, 4H), 2.97-277 (m, 2H), 277-2.50 (m, 3H), 2.42-2.17 (m, 2H), 2.25 (s, 2H), 2.14-1.94 (m, 2H), 1.93-178 (m, 2H), 1.00 (s, 9H); ESMS m/e: 526.4 (M + H)+; Anal. Calc. (HCI salt) C34H44CIN302O.31CHCI3: C, 68.77; H, 7.45; N, 7.01. Found: C, 68.51 ; H, 7.40; N, 7.39. Example 20
Figure imgf000064_0001
Λ/-[3-(1-{3-[(DIPHENYLACETYL)AMINO]PROPYL}-4-PIPERIDINYL)-4-METHOXY PHENYL] -2-METHYLPROPANAMIDE: Example 20 was prepared from diphenyl acetyl chloride and N- {3-[1-(3-aminopropyl)-4-piperidinyl]-4-methoxyphenyl}-2-methylpropanamide according to the procedures described in Scheme 8: ESMS m/e: 528.3 (M + H)+.
Example 21
Figure imgf000064_0002
Λ/-{3-[1-(3-{[2,2-BIS(4-FLUOROPHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL]
PHENYL}PROPANAMIDE: Example 21 was prepared from bis(4-fluorophenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl] phenyl}propanamide according to the procedures described in Scheme 10: ESMS m/e: 520.3 (M + H)+.
Example 22
Figure imgf000064_0003
Λ/-[3-(1-{3-[(DIPHENYLACETYL)AMINO]PROPYL}-4-PIPERIDINYL)-4-METHOXYPHENYL] BUTANAMIDE: Example 22 was prepared from diphenyl acetyl chloride and N-{3-[1-(3- aminopropyl)-4-piperidinyl]-4-methoxyphenyl}butanamide according to the procedures described in Scheme 8: ESMS m/e: 528.4 (M + H)+.
Example 23
Figure imgf000064_0004
Λ/-{3-[1-(3-{[BIS(4-FLUOROPHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL]-4- METHOXYPHENYLJ-2-METHYLPROPANAMIDE: Example 23 was prepared from bis(4- fluorophenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methoxyphenyl}-2- methylpropanamide according to the procedures described in Scheme 9: ESMS m/e: 564.4 (M + H)+.
Example 24
Figure imgf000065_0001
Λ/-[3-(1-{3-[(DIPHENYLACETYL)AMINO]PROPYL}-4-PIPERIDINYL)-4-FLUOROPHENYL]-2- METHYLPROPANAMIDE: Example 24 was prepared from diphenylacetyl chloride and N-{3- [1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 8: 1H NMR (400 MHz, CDCI3) δ 7.95 (s, 1H), 7.47 (dd, 1H, J = 2.4, 6.4 Hz), 7.34-7.21 (m, 11H), 7.06 (t, 1H, J = 4.8 Hz), 6.91 (t, 1H, J = 10.0 Hz), 4.90 (s, 1 H), 3.38 (dd, 2H, J = 6.0, 11.6 Hz), 2.90-2.87 (m, 2H), 2.74 (m, 1H), 2.50 (m, 1H), 2.36 (t, 2H, J = 6.8 Hz), 1.96 (dt, 2H, J = 2.8, 12.0 Hz), 173-1.62 (m, 6H), 1.20 (d, 6H, J = 6.8 Hz); ESMS m/e: 516.3 (M + H)+.
Example 25
Figure imgf000065_0002
Λ/-[3-(1-{3-[(DIPHENYLACETYL)AMINO]PROPYL}-4-PIPERIDINYL)-4-FLUOROPHENYL] BUTANAMIDE: Example 25 was prepared from diphenylacetyl chloride and N-{3-[1-(3- aminopropyl)-4-piperidinyl]-4-fluorophenyl} butanamide according to the procedures described in Scheme 8: 1H NMR (400 MHz, CDCI3) δ 7.71 (s, 1H), 7.39 (dd, 1H, J = 2.8, 6.8 Hz), 7.33-7.21 (m, 11H), 7.00 (t, 1 H, J = 5.6 Hz), 6.92 (t, 1H, J = 9.2 Hz), 4.89 (s, 1H), 3.38 (dd, 2H, J = 6.4, 12.0 Hz), 2.91-2.88 (m, 2H), 2.74 (m, 1H), 2.36 (t, 2H, J = 6.4 Hz), 2.29 (t, 2H, J = 7.6 Hz), 1.97 (dt, 2H, J = 2.4, 11.6 Hz), 177-1.62 (m, 8H), 0.97 (t, 3H, J = 7.2 Hz); ESMS m/e: 516.3 (M + H)+.
Example 26
Figure imgf000065_0003
Λ/-{3-[1-(3-{[BIS(4-FLUOROPHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL]-4- METHOXYPHENYLJBUTANAMIDE: Example 26 was prepared from bis(4-fluorophenyl) acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methoxyphenyl}butanamide according to the procedures described in Scheme 9: ESMS m/e: 564.4 (M + H)+.
Example 27
Figure imgf000065_0004
Λ/-{3-[1-(3-{[2,2-BIS(4-FLUOROPHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL] PHENYLJBUTANAMIDE: Example 27 was prepared from bis(4-fluorophenyl) acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl] phenyljbutanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 8.14 (s, 1H), 7.69 (t, 1H, J = 5.2 Hz), 7.52 (s, 1H), 7.38 (d, 1H, J = 8.0 Hz), 7.30-7.27 (m, 4H), 7.20 (t, 1H, J = 8.0 Hz), 7.00-6.95 (m, 4H), 6.89 (d, 1H, J = 8.0 Hz), 4.90 (s, 1H), 3.37 (dd, 2H, J = 6.0, 11.6 Hz), 3.05 (d, 2H, J = 11.2 Hz), 2.55 (t, 2H, J = 6.8 Hz), 2.49 (m, 1H), 2.33 (t, 2H, J = 7.2 Hz), 2.17 (m, 2H), 1.79- 1.69 (m, 8H), 0.97 (t, 3H, J = 7.6 Hz); ESMS m/e: 534.4 (M + H)+.
Example 28
Figure imgf000066_0001
Λ/-(3-{4-[3-(acetylamino)phenyl]-1-piperidinyl}propyl)-2,2-bis(4-fluorophenyl)acetamide: Example 28 was prepared from bis(4-fluorophenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4- piperidinyl] phenyl}acetamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 8.25 (s, 1H), 7.83 (br s, 1H), 7.41-7.85 (m, 12H), 4.90 (s, 1H), 3.36 (dd, 2H, J = 5.6, 12.0 Hz), 3.18 (d, 2H, J = 11.6 Hz), 2.69 (t, 2H, J = 6.4 Hz), 2.53 (m, 1H), 2.34 (m, 2H), 2.15 (s, 3H), 1.96-179 (m, 6H); ESMS m/e: 506.4 (M + H)+.
Example 29
Figure imgf000066_0002
Λ/-{6-[1-(3-{[BIS(4-FLUOROPHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL]-2- PYRIDINYLJ-2-METHYLPROPANAMIDE: Example 29 was prepared from . bis(4- fluorophenyl)acetic acid and N-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2- methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 8.06 (d, 1H, J = 8.4 Hz), 7.99 (m, 1H), 7.84 (s, 1H), 7.63 (t, 1H, J = 8.0 Hz), 7.39-7.32 (m, 4H), 7.03-6.97 (m, 4H), 6.87 (d, 1H, J = 7.6 Hz), 4.91 (s, 1H), 3.39 (dd, 2H, J = 5.2, 11.2 Hz), 3.07 (d, 2H, J = 11.6 Hz), 2.62 (m, 1H), 2.55 (t, 2H, J = 6.4 Hz), 2.34 (m, 1H), 2.16 (t, 2H, J = 11.2 Hz), 1.93-173 (m, 6H), 1.16 (d, 6H, J = 6.8 Hz); ESMS m/e: 535.4 (M + H)+.
Example 30
Figure imgf000067_0001
Λ/-(3-{4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-2,2-DIPHENYL PROPANAMIDE: Example 30 was prepared from 2,2-diphenylpropanoic acid and N-{3-[1-(3- aminopropyl)-4-piperidinyl] phenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCI3) δ 7.46 (s, 1H), 7.42 (s, 1 H), 7.39-7.18 (m, 12H), 6.89 (d, 1H, J = 7.7 Hz), 6.23 (m, 1H), 3.35 (q, 2H, J = 6.4), 2.85 (d, 2H, J = 10.8 Hz), 2.5 (quintet, 1H, J = 7.4 Hz), 2.45-2.36 (m, 1H), 2.28 (t, 2H, J = 6.4 Hz), 1.99 (s, 3H), 1.91- 1.82 (m, 2H), 175-1.68 (m, 2H), 1.65 (t, 2H, J = 6.4 Hz), 1.60-1.47 (m, 2H), 1.23 (d, 6H, J = 7.0 Hz); ESMS m/e: 512.4 (M + H)+.
Example 31
Figure imgf000067_0002
1-(4-CHLOROPHENYL)-Λ/-(3-{4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL} PROPYL)CYCLOPENTANECARBOXAMIDE: Example 31 was prepared from 1-(4-chloro phenyl)cyclopentanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyI}-2- methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCI3) δ 7.45-7.42 (m,1H), 7.33-7.24 (m, 7H), 6.94 (d, 1H, J = 7.1 Hz), 6.58-6.52 (m, 1H), 3.26 (q, 2H, J = 6.1 Hz), 2.90 (d, 2H, J = 10.8 Hz), 2.56-2.40 (m, 4H), 2.29 (t, 2H, J = 6.3 Hz), 2.03-1.87 (m, 6H), 1.83-176 (m, 4H), 1.60 (dd, 4H, J = 6.8, 4.6 Hz), 1.25 (d, 6H, J = 6.8 Hz); ESMS m/e: 510.4 (M + H)+.
Example 32
Figure imgf000067_0003
Λ/-{3-[1-(3-{[BIS(4-FLUOROPHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL]-4- METHYLPHENYLJ-2-METHYLPROPANAMIDE: Example 32 was prepared from bis(4- fluorophenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2- methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCI3) δ 8.09 (s, 1 H), 7.98 (s, 1H), 7.59 (d, 1H, J = 1.8 Hz), 7.54-7.51 (m, 1H), 7.32 (m, 3H), 7.21-7.18 (m, 1H), 6.99-6.94 (m, 5H), 4.87 (s, 1H), 3.36 (q, 2H, J = 5.8 Hz), 2.92-2.97 (m, 2H), 2.68-2.58 (m, 1H), 2.5 (quintet, 1 H, J = 7.2 Hz), 2.37 (t, 2H, J = 5.7 Hz), 2.25 (s, 3H), 2.01-1.92 ( , 2H), 171-1.52 (m, 6H), 1.16 (d, 6H, J = 7.2 Hz); ESMS m/e: 548.4 (M + H)+. Example 33
Figure imgf000068_0001
Λ/-[3-(1-{3-[(DIPHENYLACETYL)AMINO]PROPYL}-4-PIPERIDINYL)-2-METHYL PHENYL]- 2-METHYLPROPANAMIDE: Example 33 was prepared from diphenyl acetyl chloride and N- {3-[1-(3-aminopropyl)-4-piperidinyl]-2-methyl phenyl}-2-methylpropanamide according to the procedures described in Scheme 8: 1H NMR (400 MHz, CDCI3) δ 7.49 (d, 1 H, J = 8.0 Hz), 7.35-7.19 (m, 11H), 7.09-7.02 (m, 3H), 4.90 (s, 1H), 3.41 (dd, 2H, J = 5.6, 11.6 Hz), 2.99 (d, 2H, J = 12.8 Hz), 2.72 (m, 1H), 2.59 (m, 1 H), 2.43 (t, 2H, J = 6.4 Hz), 2.19 (s, 3H), 2.06-2.00 (m, 2H), 175-1.60 (m, 6H), 1.30 (d, 6H, J = 6.8 Hz); ESMS m/e: 512.5 (M + H)+.
Example 34
Figure imgf000068_0002
Λ/-{3-[1-(3-{[BIS(4-METHYLPHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL] PHENYL} -2-METHYLPROPANAMIDE: Example 34 was prepared from bis(4-methylphenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl] phenyl} -2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCI3) δ 7.50 (s, 1H), 7.29 (d, 2H, J = 6.1 Hz), 7.13 (m, 8H), 6.93 (d, 1H, J = 7.5 Hz), 6.83-678 (m, 1H), 7.27-7.21 (m, 1H), 4.81 (s, 1H), 3.40-3.34 (m, 2H), 2.91 (d, 2H, J = 11.6 Hz), 2.53-2.41 (m, 2H), 2.36 (t, 2H, J = 6.6 Hz), 2.29 (s, 6H), 1.99-1.88 (m, 2H), 178 (d, 3H, J = 12.9 Hz), 1.67 (t, 2H, J = 6.6 Hz), 1.62- 1.56 (m, 1H), 1.24 (d, 6H, J = 6.8 Hz); ESMS m/e: 526.4 (M + H)+.
Example 35
Figure imgf000068_0003
Λ/-{3-[1-(3-{[bis(4-fluorophenyl)acetyl]amino}propyl)-4-piperidinyl]-4-fluorophenyl}-2-methyl propanamide: Example 35 was prepared from bis(4-fluorophenyl)acetic acid and N-{3-[1-(3- aminopropyl)-4-piperidinyl]-4-fiuorophenyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 7.58 (dd, 1H, J = 2.8, 6.4 Hz), 7.53 (s, 1H), 7.49 (br s, 1 H), 7.31-6.92 (m, 10H), 4.81 (s, 1H), 3.40 (dd, 2H, J = 5.6, 11.2 Hz), 2.93 (d, 2H, J = 11.6 Hz), 2.76 (m, 1H), 2.49 (m, 1H), 2.42 (t, 2H, J = 6.0 Hz), 2.02-1.96 (m, 2H), 1.77 (d, 2H, J = 11.6 Hz), 1.69-1.62 (m, 4H), 1.22 (d, 6H, J = 6.8 Hz); ESMS m/e: 552.3 (M + H)+.
Example 36
^ ^
1-(4-FLUOROPHENYL)-Λ/-(3-{4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL} PROPYL)CYCLOPENTANECARBOXAMIDE: Example 36 was prepared from 1-(4-fluoro phenyl)cyclopentanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyi]phenyl}-2- methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCI3) δ 7.53 (s, 1H), 7.33 (dd, 2H, J = 5.8, 3.6 Hz,), 7.29-7.26 (m, 2H), 7.25-7.20 (m, 1H), 7.02-6.95 (m, 2H), 6.93 (d, 1H, J = 7.1 Hz), 6.54-6.49 (m, 1H), 3.26 (q, 2H, J = 6.5 Hz), 3.22- 3.14 (m, 1H), 2.90 (d, 1H, J = 12.0 Hz), 2.55-2.37 (m, 4H), 2.29 (t, 2H, J = 6.5 Hz), 2.06 (s, 4H), 2.00-1.90 (m, 3H), 1.82-175 (m, 4H), 173-1.66 (m, 3H), 1.65-1.57 (m, 4H), 1.25 (d, 6H, J = 6.7 Hz); ESMS m/e: 494.3 (M + H)+; Anal. Calc. for C3oH40FN302 • 0.10 CHCI3 • 0.650 DMF: C, 70.92; H, 8.27; N, 8.64. Found: C, 70.83; H, 8.11 ; N, 8.93.
Example 37
Figure imgf000069_0001
2-(4-CHLOROPHENYL)-Λ/-(3-{4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL} PROPYL)PROPANAMIDE: Example 37 was prepared from 2-(4-chlorophenyl)propanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCI3) δ 7.61 (d, 2H, J = 6.5 Hz), 7.26 (s, 6H), 7.05-6.99 (m, 1H), 6.94 (d, 1H, J = 7.1 Hz), 3.37-3.25 (m, 2H), 2.89 (d, 1H, J = 9.6 Hz), 2.57-2.43 (m, 2H), 2.37 (t, 2H, J = 6.1 Hz), 2.22-2.16 (m, 2H), 2.00-1.91 (m, 2H), 1.89-177 (m, 2H), 1.69-1.58 (m, 4H), 1.48 (d, 3H, J = 7.0 Hz), 1.24 (d, 6H, J = 7.0 Hz); ESMS m/e: 470.3 (M + H)+.
Example 38
Figure imgf000069_0002
1-(2-CHLORO-4-FLUOROPHENYL)-Λ/-(3-{4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-
PIPERIDINYL}PROPYL)CYCLOPENTANECARBOXAMIDE: Example 38 was prepared from 1-(2-chloro-4-fluorophenyl)cyclopentanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4- piperidinyl]phenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCI3) δ 7.58(s, 1H), 7.52 (s, 1H), 7.45-7.36 (m, 1H), 7.34-7.29 (m, 1H), 7.23 (t, 1H, J = 8.0 Hz), 7.177.13 (m, 1H), 6.95-6.90 (m, 2H), 6.00-5.94 (m, 1 H), 3.30 (q, 2H, J = 6.4 Hz), 2.92-2.84 (m, 2H), 2.57-2.38 (m, 3H), 2.47-2.39 (m, 1H), 2.31 (t, 1H, J = 7.2 Hz), 1.95-173 (m, 7H), 1.68-1.48 (m, 8H), 1.24 (d, 6H, J = 7.2 Hz); ESMS m/e: 528.3 (M + H)+.
Example 39
Figure imgf000070_0001
Λ/-{3-[1-(3-{[(3,4-DICHLOROPHENYL)(METHOXY)ACETYL]AMINO}PROPYL)-4- PIPERIDINYL]PHENYL}-2-METHYLPROPANAMIDE: Example 39 was prepared from (3,4- dichlorophenyl)(methoxy)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2- methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCI3) δ 8.02-7.94 (m, 1H), 7.54 (d, 2H, J = 10.1 Hz), 7.41 (d, 1H, J = 8.5 Hz), 7.34-7.19 (m, 4H), 6.97 (d, 1H, J = 7.0 Hz), 4.56 (s, 1H), 3.83 (s, 3H), 3.09-3.01 (m, 2H), 2.55-2.39 (m, 4H), 2.17 (s, 1H), 2.08-1.95 (m, 3H), 1.91-177 (m, 4H), 174-165 (m, 2H), 1.22 (d, 6H, J = 6.6 Hz); ESMS m/e: 520.2 (M + H)+.
Example 40
Figure imgf000070_0002
1-(4-FLUOROPHENYL)-Λ/-(3-{4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL}
PROPYL)CYCLOHEXANECARBOXAMIDE: Example 40 was prepared from 1-(4-fluoro phenyl)cyclohexanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl] phenyl}-2- methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCIs) δ 7.56 (s, 2H), 7.42-7.36 (m, 2H), 7.30-7.20 (m, 2H), 7.05-6.96 (m, 3H), 6.85-679 (m, 1H), 3.28 (q, 2H, J = 6.3 Hz), 2.95-2.87 (m, 2H), 2.57-2.41 (m, 2H), 2.36-2.28 (m, 4H), 2.06 (s, 1H), 1.96-1.84 (m, 4H), 1.83-175 (m, 2H), 171-1.54 (m, 9H), 1.24 (d, 6H, J = 7.1 Hz); ESMS m/e: 508.3 (M + H)+.
Example 41
Figure imgf000070_0003
1-(2,4-DICHLOROPHENYL)-Λ/-(3-{4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL} PROPYL)CYCLOPROPANECARBOXAMIDE: Example 41 was prepared from 1-(2,4- dichlorophenyl)cyclopropanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl] phenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCI3) δ 7.67 (s, 1H), 7.49 (s, 1H), 7.44 (d, 1H, J = 2.0 Hz), 7.35 (s, 1H), 7.28- 7.19 (m, 3H), 6.92 (d, 1H, J = 7.6 Hz), 5.69-5.62 (m, 1H), 3.26 (q, 2H, J = 6.7 Hz), 2.89-2.82 (m, 2H), 2.54 (quintet, 1 H, J = 67 Hz), 2.47-2.37 (m, 1H), 2.32-2.26 (m, 3H), 1.97-1.88 (m, 2H), 179-1.69 (m, 4H), 1.66-1.56 (m, 4H), 1.24 (d, 6H, J = 6.7 Hz), 1.05-1.01 (m, 1H); ESMS m/e: 516.2 (M + H)+; Anal. Calc. for C28H35CI2N302 • 0.048 CHCI3: C, 64.51 ; H, 6.76; N, 8.05. Found: C, 64.51 ; H, 6.60; N, 8.15.
Example 42
Figure imgf000071_0001
2-(4-FLUOROPHENYL)-Λ/-(3-{4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL} PROPYL)PROPANAMIDE: Example 42 was prepared from 2-(4-fluoro phenyl)propanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methyl propanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCI3) δ 7.58 (s, 2H), 7.32-7.22 (m, 4H), 7.01-6.92 (m, 3H), 6.90-6.83 (m, 1H), 3.50 (q, 1H, J = 7.1 Hz), 3.39-3.26 (m, 2H), 2.93- 2.86 (m, 1 H), 2.55-2.42 (m, 2H), 2.40-2.34 (m, 2H), 2.16 (s, 1H), 2.01-1.91 (m, 2H), 1.89- 1.77 (m, 2H), 172-1.54 (m, 4H), 1.49 (d, 3H, J = 7.0 Hz), 1.24 (d, 6H, J = 7.0 Hz); ESMS m/e: 454.3 (M + H)+; Anal. Calc. for C27H36FN302 • 1.1 CH3OH: C, 69.04; H, 8.33; N, 8.60. Found: C, 69.06; H, 8.61 ; N, 8.79.
Example 43
"- -/f x. -»' XXX( f_
1-(4-CHLOROPHENYL)-/V-(3-{4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL} PROPYL)CYCLOBUTANECARBOXAMIDE: Example 43 was prepared from 1-(4- chlorophenyl)cyclobutanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2- methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCI3) δ 7.56 (s, 1H), 7.41 (s, 1 H), 7.34-7.21 (m, 6H), 6.93 (s, 1H), 6.48 (s, 1H), 3.31-3.24 (m, 2H), 2.94-2.86 (m, 2H), 2.86-276 (m, 2H), 2.57-2.37 (m, 4H), 2.33-2.26 (m, 2H), 2.12- 2.02 (m, 1H), 1.97-1.87 (m, 3H), 1.82 (s, 1H), 179 (s, 1H), 170-1.56 (m, 4H), 1.24 (d, 6H, J = 7.2 Hz); ESMS m/e: 496.3 (M + H)+; Anal. Calc. for C29H38CIN302 • 0.550 CHCI3: C, 63.18; H, 6.92; N, 7.48. Found: C, 63.22; H, 6.90; N, 7.48.
Example 44
Figure imgf000072_0001
1-(4-CHLOROPHENYL)-Λ/-(3-{4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL} PROPYL)CYCLOPROPANECARBOXAMIDE: Example 44 was prepared from 1-(4- chlorophenyl)cyclopropanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}- 2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCI3) δ 7.47 (s, 1H), 7.40 (s, 1H), 7.36-7.30 (m, 5H), 7.27-7.20 (m, 1H), 6.93 (d, 1H, J = 7.6 Hz), 570-5.63 (m, 1 H), 3.24 (q, 2H, J = 6.6 Hz), 2.84 (d, 2H, J = 11.4 Hz), 2.52 (quintet, 1H, J = 7.2 Hz), 2.47-2.37 (m, 1H), 2.26 (t, 2H, J = 7.2 Hz), 1.92 (t, 2H, J = 11.6 Hz), 1.75 (d, 2H, J = 12.5 Hz), 1.65-1.53 (m, 6H), 1.25 (d, 6H, J = 7.2 Hz), 1.00 (q, 2H, J = 2.9 Hz); ESMS m/e: 482.3 (M + H)+; Anal. Calc. for C28H36CIN302 • 0.540 CH2CI3: C, 64.93; H, 7.08; N, 7.96. Found: C, 65.00; H, 7.22; N, 7.81.
Figure imgf000072_0002
1-(4-CHLOROPHENYL)-Λ/-(3-{4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL}
PROPYL)CYCLOHEXANECARBOXAMIDE: Example 45 was prepared from 1-(4-chloro phenyl) cyclohexanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2- methyl propanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCI3) δ 7.57 (s, 1H), 7.52 (s,1H), 7.38-7.35 (m, 2H), 7.30-7.21 (m, 4H), 6.93 (d, 1 H, J = 7.2 Hz), 6.88-6.83 (m, 1H), 3.28 (q, 2H, J = 5.6 Hz), 2.95-2.88 (m, 2H), 2.56-2.41 (m, 2H), 2.35-2.26 (m, 3H), 2.07 (s, 1H), 1.96-1.84 (m, 4H), 1.83-176 (m, 2H), 170-1.53 (m, 10H), 1.24 (d, 6H, J = 7.1 Hz); ESMS m/e: 524.3 (M + H)+.
Figure imgf000072_0003
Λ/-(3-{4-[4-FLUORO-3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-2-(4- FLUOROPHENYL)PROPANAMIDE: Example 46 was prepared from 2-(4-fluoro phenyl)propanoic acid and N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}-2-methyl propanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCI3) δ 8.38-8.23 (m, 1H), 7.48-7.27 (m, 3H), 7.13-6.94 (m, 4H), 6.94-6.82 (m, 1H), 3.62- 3.46 (m, 1H), 3.41-3.26 (m, 2H), 3.17-3.03 (m, 1H), 3.02-2.91 (m, 1H), 2.67-2.35 (m, 4H), 2.24-1.97 (m, 2H), 1.95-1.62 (m, 6H), 1.49 (d, 3H, J = 7.2 Hz), 1.27 (d, 6H, J = 6.8 Hz); ESMS m/e: 472.4 (M + H)+. Example 47
Figure imgf000073_0001
1-(4-CHLOROPHENYL)-Λ/-(3-{4-[4-FLUORO-3-(ISOBUTYRYLAMINO)PHENYL]-1- PIPERIDINYL}PROPYL)CYCLOPROPANECARBOXAMIDE: Example 47 was prepared from 1-(4-chlorophenyl)cyclopropanecarboxylic acid and N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2- fluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCI3) δ 8.32-8.18 (m, 1H), 7.43-7.25 (m, 5H), 7.08-6.93 (m, 1H), 6.93-679 (br, 1H), 574-5.59 (br, 1H), 3.35-3.15 (m, 2H), 3.93-275 (m, 2H), 2.65-2.49 (m, 1H), 2.49- 2.34 (m, 1H), 2.34-2.19 (m, 2H), 2.00-1.83 (m, 2H), 1.82-1.68 (m, 2H), 1.68-1.48 (m, 4H), 1.36-1.17 (m, 2H), 1.27 (d, 6H, J = 6.8 Hz), 1.0 (s, 2H); ESMS m/e: 500.3 (M + H)+; Anal. Calc. for (HCI salt) C28H36C.2FN302 0.45CHCI3: C, 57.85; H, 6.22; N, 7.11. Found: C, 57.61 ; H, 6.37; N, 7.30.
Example 48
Figure imgf000073_0002
Λ/-{5-[1-(3-{[BIS(4-FLU0R0PHENYL)ACETYL]AMIN0}PR0PYL)-4-PIPERIDINYL]-2- FLUORO PHENYL}-2-METHYLPROPANAMIDE: Example 48 was prepared from bis(4- fluorophenyl) acetic acid and N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}-2- methylpropanamide according to the procedures described in Scheme 9: ESMS m/e: 552.3 (M + H)+.
Example 49
Figure imgf000073_0003
2-(4-CHLOROPHENYL)-Λ/-(3-{4-[4-FLUORO-3-(ISOBUTYRYLAMINO)PHENYL]-1-
PIPERIDINYL}PROPYL)-2-METHYLPROPANAMIDE: Example 49 was prepared from 2-(4- chlorophenyl)-2-methylpropanoic acid and N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2- fluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCI3) δ 8.34-8.20 (m, 1H), 7.46-7.14 (m, 5H), 7.10-6.95 (m, 1H), 6.92-677 (br, 1H), 674-6.59 (br, 1H), 3.39-3.25 (m, 2H), 3.00-2.82 (m, 2H), 2.67-2.51 (m, 1H), 2.51- 2.40 (m, 1H), 2.40-2.27 (m, 2H), 2.03-1.86 (m, 2H), 1.85-171 (m, 2H), 171-1.57 ( , 4H), 1.56 (s, 6H), 1.27 (d, 6H, J = 6.8 Hz); ESMS m/e: 502.3 (M + H)+. Example 50
Figure imgf000074_0001
Λ/-{6-[1-(3-{[BIS(4-CHLOROPHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL]-2- PYRIDINYLJ-2-METHYLPROPANAMIDE: Example 50 was prepared from bis(4- chlorophenyl)acetic acid and N-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2- methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 8.06 (d, 1 H, J = 8.0 Hz), 7.96 (br s, 1H), 7.77 (s, 1H), 7.64 (t, 1H, J = 8.4 Hz), 7.31-7.26 (m, 8H), 6.88 (dd, 1H, J = 0.8, 7.6 Hz), 4.84 (s, 1H), 3.39 (dd, 2H, J = 5.6, 11.6 Hz), 2.99 (d, 2H, J = 11.6 Hz), 2.59 (m, 1H), 2.47 (t, 2H, J = 6.0 Hz), 2.28 (m, 1H), 2.07-2.00 (m, 2H), 1.89 (dd, 2H, J = 2.0, 12.4 Hz), 176-1.67 (m, 4H), 1.14 (d, 6H, J = 6.8 Hz); ESMS m/e: 567.3 (M + H)+.
Example 51
Figure imgf000074_0002
Λ/-(3-{4-[4-FLUORO-3-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-2,2- DIPHENYLPROPANAMIDE: Example 51 was prepared from 2,2-diphenylpropanoic acid and N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCI3) δ 8.27-8.13 (m, 1H), 8.04 (s, 1H), 7.62 (s, 1H), 7.50-7.39 (m, 1H), 7.39-7.16 (m, 7H), 7.12-6.90 (m, 2H), 679-6.60 (br, 1H), 4.94-4.61 (br, 1H), 3.60-3.22 (m, 4H), 2.89-276 (m, 2H), 276-2.55 (m, 4H), 2.55-2.34 (m, 3H), 2.14-1.82 (m, 3H), 2.00 (s, 3H), 1.26 (d, 6H, J = 6.4 Hz); ESMS m/e: 530.4 (M + H)+; Anal. Calc. for (HCI salt) C33H41CIFN302O.24CHCI3O.96H20: C, 65.23; H, 7.11; N, 6.86. Found: C, 64.96; H, 7.36; N, 6.87.
Example 52
Figure imgf000074_0003
Λ/-{3-[1-(3-{[BIS(4-CHLOROPHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL]-4- METHYLPHENYL}-2-METHYLPROPANAMIDE: Example 52 was prepared from bis(4- chlorophenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2- methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCI3) δ 7.65 (s, 1H), 7.62 (d, 1H, J = 2.4 Hz), 7.53 (t, 1H, J = 4.8 Hz), 7.28-7.22 (m, 8H), 7.12 (dd, 1H, J = 2.0, 8.4 Hz), 7.03 (d, 1H, J = 8.0 Hz), 4.80 (s, 1H), 3.36 (dd, 2H, J = 6.0, 11.6 Hz), 2.91 (d, 2H, J = 14.0 Hz), 2.64 (m, 1H), 2.47 (m, 1 H), 2.38 (t, 2H, J = 5.6 Hz), 2.24 (s, 3H), 2.00-1.93 (m, 2H), 170-1.56 (m, 6H), 1.16 (d, 6H, J = 7.2 Hz); ESMS m/e: 580.3 (M + H)+.
Example 53
Figure imgf000075_0001
/-{3-[1-(3-{[2,2-BIS(4-CHLOROPHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL]
PHENYLJBUTANAMIDE: Example 53 was prepared from bis(4-chlorophenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}butanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 7.67 (s, 1H), 7.58 (s, 1H), 7.49 (br s, 1H), 7.28-7.21 (m, 10H), 6.91 (m, 1H), 4.77 (s, 1H), 3.38 (dd, 2H, J = 6.0, 11.6 Hz), 2.93 (d, 2H, J = 11.6 Hz), 2.46 (m, 1H), 2.41 (t, 2H, J = 6.0 Hz), 2.31 (t, 2H, J = 7.2 Hz), 1.96 (dt, 2H, J = 1.6, 12.0 Hz); 1.82-1.66 (m, 6H), 1.58-1.54 (m, 2H), 0.98 (t, 3H, J = 7.6 Hz); ESMS m/e: 566.3 (M + H)+.
Example 54
Figure imgf000075_0002
/V-{3-[1-(3-{[BIS(4-CHLOROPHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL]-4-
FLUOROPHENYL}-2-METHYLPROPANAMIDE: Example 54 was prepared from bis(4- chlorophenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl}-2- methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 7.62-7.57 (m, 3H), 7.27 (s, 8H), 7.23-7.19 (m, 1H), 6.94 (dd, 1H, J = 8.8, 10.0
Hz), 4.78 (s, 1H), 3.39 (dd, 2H, J = 6.0, 11.6 Hz), 2.93 (d, 2H, J = 11.6 Hz), 2.77 (m, 1H),
2.48 (m, 1H), 2.42 (t, 2H, J = 6.0 Hz), 1.99 (dt, 2H, J = 1.6, 11.6 Hz), 177 (d, 2H, J = 11.2
Hz), 1.69-1.61 (m, 4H), 1.22 (d, 6H, J = 6.8 Hz); ESMS m/e: 584.2 (M + H)+.
Example 55
Figure imgf000075_0003
Λ/-(3-{4-[3-(ACETYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-2,2-BIS(4-CHLORO PHENYL)ACETAMIDE: Example 55 was prepared from bis(4-chlorophenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide according procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 7.48 (s, 1H), 7.39 (br s, 1H), 7.31-7.22 (m, 11H), 6.94-6.92 (m, 1H), 476 (s, 1H), 3.39 (dd, 2H, J = 6.4, 12.0 Hz), 2.97 (d, 2H, J = 10.0 Hz), 2.49 (m, 1H), 2.44 (t, 2H, J = 6.4 Hz), 2.17 (s, 3H), 2.05-1.99 (m, 2H), 1.83 (d, 2H, J = 13.2 Hz), 1.71 (m, 2H), 1.61 (m, 2H); ESMS m/e: 538.3 (M + H)+.
Example 56
Figure imgf000076_0001
Λ/-[5-(1-{3-[(DIPHENYLACETYL)AMINO]PROPYL}-4-PIPERIDINYL)-2-FLUOROPHENYL]-2-
METHYLPROPANAMIDE: Example 56 was prepared from diphenylacetyl chloride and N-{5-
[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 8: 1H NMR (400 MHz, CD3OD,) δ 7.80-7.64 (m, 1H), 7.37- 7.09 (m, 12H), 7.08-6.98 (m, 1H), 6.98-6.88 (br, 1H), 4.90 (s, 1H), 3.47-3.33 (m, 2H), 3.33-
3.18 (m, 2H), 3.01-2.81 (m, 4H), 2.81-2.69 (m, 1H), 2.69-2.54 (m, 1H), 2.10-1.66 (m, 6H),
1.10 (d, 6H, J = 6.4 Hz); ESMS m/e: 516.4 (M + H)+. Anal. Calc. For (HCI salt)
C32H39CIFN302O.16CHCI3: C, 67.68; H, 6.92; N, 7.36. Found: C, 67.43; H, 6.85; N, 7.17.
Example 57
Figure imgf000076_0002
/V-{3-[1-(3-{[2,2-BIS(4-CHLOROPHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL] PHENYLJPROPANAMIDE: Example 57 was prepared from bis(4-chlorophenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}propanamide according to the procedures described in Scheme 10: ESMS m/e: 552.2 (M + H)+.
Example 58
Figure imgf000076_0003
1-(4-CHLOROPHENYL)-Λ/-(3-{4-[3-(PROPIONYLAMINO)PHENYL]-1-PIPERIDINYL} PROPYL)CYCLOBUTANECARBOXAMIDE: Example 58 was prepared from 1-(4-chloro phenyl)cyclobutanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl} propan amide according to the procedures described in Scheme 10: ESMS m/e: 482.3 (M + H)+. Example 59
Figure imgf000077_0001
2-METHYL-/V-[3-(1-{3-[(TRIPHENYLACETYL)AMINO]PROPYL}-4-PIPERIDINYL)PHENYL] PROPANAMIDE: Example 59 was prepared from triphenylacetic acid and N-{3-[1-(3- aminopropyI)-4-piperidinyl]phenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCI3) δ 7.40 (d, 2H, J = 10.8 Hz), 7.32-7.17 (m, 17H), 6.87 (d, 1H, J = 7.7 Hz), 6.32-6.26 (m, 1H), 3.41 (q, 2H, J = 6.0 Hz), 2.83 (d, 2H, J = 10.5 Hz), 2.48 (quintet, 1H, J = 6.7 Hz), 2.43-2.33 (m, 1H), 2.26 (t, 2H, J = 6.7 Hz), 1.89 (t, 2H, J = 11.5 Hz), 173-1.62 (m, 4H), 1.56-1.44 (m, 2H), 1.22 (d, 6H, J = 6.7 Hz); ESMS m/e: 574.3 (M + H)+; Anal. Calc. for C38H43N302 • 0.730 CHCI3: C, 70.38; H, 6.67; N, 6.36. Found: C, 70.42; H, 6.57; N, 6.47.
Example 60
Figure imgf000077_0002
1-(4-FLUOROPHENYL)-Λ/-(3-{4-[3-(PROPIONYLAMINO)PHENYL]-1-PIPERIDINYL}
PROPYL)CYCLOPENTANECARBOXAMIDE: Example 60 was prepared from 1-(4- fluorophenyl)cyclopentanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl] phenyl}propanamide according to the procedures described in Scheme 10: ESMS m/e: 480.4 (M + H)+.
Example 61
Figure imgf000077_0003
1-(4-FLUOROPHENYL)-Λ/-(3-{4-[3-(PROPIONYLAMINO)PHENYL]-1-PIPERIDINYL} PROPYL)CYCLOHEXANECARBOXAMIDE: Example 61 was prepared from 1-(4-fluoro phenyl)cyclohexanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl} propanamide according to the procedures described in Scheme 10: ESMS m/e: 494.4 (M + H)+.
Example 62
Figure imgf000078_0001
1-(4-CHLOROPHENYL)-Λ/-(3-{4-[3-(PROPIONYLAMINO)PHENYL]-1-PIPERIDINYL} PROPYL)CYCLOPENTANECARBOXAMIDE: Example 62 was prepared from 1-(4-chloro phenyl)cyclopentanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl} propanamide according to the procedures described in Scheme 10: ESMS m/e: 496.4 (M + H)+.
Example 63
Figure imgf000078_0002
1-(4-CHLOROPHENYL)-/V-(3-{4-[3-(PROPIONYLAMINO)PHENYL]-1-PIPERIDINYL}
PROPYL)CYCLOPROPANECARBOXAMIDE: Example 63 was prepared from 1-(4- chlorophenyl)cyclopropanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl} propanamide according to the procedures described in Scheme 10: ESMS m/e: 468.3 (M + H)+.
Example 64
Figure imgf000078_0003
2-(4-FLUOROPHENYL)-Λ/-(3-{4-[3-(PROPIONYLAMINO)PHENYL]-1-PIPERIDINYL} PROPYL) PROPANAMIDE: Example 64 was prepared from 2-(4-fluorophenyl)propanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}propanamide according to the procedures described in Scheme 10: ESMS m/e: 440.4 (M + H)+.
Example 65
Figure imgf000078_0004
Λ/-[5-(1-{3-[(DIPHENYLACETYL)AMINO]PROPYL}-4-PIPERIDINYL)-2-FLUOROPHENYL] BUTANAMIDE: Example 65 was prepared from diphenylacetyl chloride and N-{5-[1-(3- aminopropyl)-4-piperidinyl]-2-fluorophenyl}butanamide according to the procedures described in Scheme 8: 1H NMR (400 MHz, CDCI3) δ 8.33-8.18 (m, 1H), 7.49-7.10 (m, 12H), 7.10-6.93 (m, 1 H), 6.90-676 (br, 1H), 4.87 (s, 1 H), 3.44-3.28 (m, 2H), 3.06-2.89 (m, 2H), 2.56-2.40 (m, 3H), 2.40-2.31 (m, 2H), 2.13-1.93 (m, 2H), 1.86-1.52 (m, 8H), 1.01 (t, 3H, J = 7.6 Hz); ESMS m/e: 516.6 (M + H)+; Anal. Calc. For (HCI salt) C32H39CIFN302- 0.25CHCI3 .00H2O: C, 64.49; H, 6.93; N, 6.99. Found: C, 64.23; H, 7.21; N, 6.99.
Example 66
Figure imgf000079_0001
1-(4-FLUOROPHENYL)-Λ/-(3-{4-[6-(ISOBUTYRYLAMINO)-2-pyridinyl]-1-piperidinyl}propyl) cyclopentanecarboxamide: Example 66 was prepared from 1-(4-fluorophenyl) cyclopentanecarboxylic acid and N-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2- methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 8.06 (d, 1H, J = 8.4 Hz), 7.79 (s, 1H), 7.64 (t, 1H, J = 7.6 Hz), 7.38-7.34 (m, 2H), 7.01-6.97 (m, 2H), 6.88 (d, 1H, J = 7.2 Hz), 6.53 (br s, 1H), 3.27 (dd, 2H, J = 6.0, 12.4 Hz), 2.94 (d, 2H, J = 14.0 Hz), 2.54-2.48 (m, 4H), 2.32 (t, 2H, J = 6.4 Hz), 1.99-1.60 (m, 14H), 1.25 (d, 6H, J = 7.2 Hz); ESMS m/e: 495.3 (M + H)+.
Example 67
Figure imgf000079_0002
1-(4-CHLOROPHENYL)-Λ/-(3-{4-[6-(ISOBUTYRYLAMINO)-2-PYRIDINYL]-1-PIPERIDINYL} PROPYL)CYCLOHEXANECARBOXAMIDE: Example 67 was prepared from 1-(4- chlorophenyl)cyclohexanecarboxylic acid and N-{6-[1-(3-aminopropyl)-4-piperidinyl]-2- pyridinyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 8.06 (d, 1H, J = 8.4 Hz), 7.78 (br s, 1H), 7.65 (t, 1H, J = 8.0 Hz), 7.40-7.38 (m, 2H), 7.30-7.27 (m, 2H), 6.88 (d, 2H, J = 7.6 Hz), 3.29 (dd, 2H, J = 6.0, 11.6 Hz), 2.96 (m, 2H), 2.56-2.49 (m, 2H), 2.36-2.30 (m, 4H), 2.00-175 (m, 8H), 1.64-1.59 (m, 8H), 1.25 (d, 6H, J = 6.8 Hz); ESMS m/e: 525.3 (M + H)+.
Example 68
Figure imgf000079_0003
1-(4-FLUOROPHENYL)-Λ/-(3-{4-[6-(ISOBUTYRYLAMINO)-2-PYRIDINYL]-1-PIPERIDINYL} PROPYL)CYCLOHEXANECARBOXAMIDE: Example 68 was prepared from 1-(4- fluorophenyl)cyclohexanecarboxylic acid and N-{6-[1-(3-aminopropyl)-4-piperidinyl]-2- pyridinyl}-2-methylpropanamide according to the procedures described in Scheme 10: H NMR (400 MHz, CDCI3) δ 8.07 (d, 1H, J = 8.0 Hz), 7.79 (br s, 1H), 7.66 (t, 1H, J = 8.0 Hz), 7.45-7.41 (m, 2H), 7.04-7.00 (m, 2H), 6.89 (d, 1H, J = 7.6 Hz), 6.85 (br s, 1 H), 3.30 (dd, 2H, J = 6.0, 12.0 Hz), 2.97 (d, 2H, J = 11.6 Hz), 2.57-2.50 (m, 2H), 2.37-2.32 (m, 4H), 2.01-177 (m, 8H), 1.65-1.60 (m, 8H), 1.27 (d, 6H, J = 7.2 Hz); ESMS m/e: 509.3 (M + H)+.
Example 69
Figure imgf000080_0001
Λ/-(3-{4-[3-(butyrylamino)phenyl]-1-piperidinyl}propyl)-1-(4-chlorophenyl)cyclopropane carboxamide: Example 69 was prepared from 1-(4-chlorophenyl) cyclopropanecarboxylic acid and N-{3-[1-(3-amino propyl)-4-piperidinyl]phenyl}butanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 7.53 (s, 1H), 7.45 (s, 1H), 7.36-7.34 (m, 5H), 7.24 (t, 1H, J = 8.0 Hz), 6.94 (d, 1H, J = 7.6 Hz), 5.69 (br s, 1 H), 3.25 (dd, 2H, J = 6.8, 12.8 Hz), 2.87 (d, 2H, J = 11.6 Hz), 2.44 (m, 1H), 2.35 (t, 2H, J = 7.2 Hz), 2.29 (t, 2H, J = 6.8 Hz), 1.95 (t, 2H, J = 11.2 Hz), 1.80-174 (m, 4H), 1.63-1.59 (m, 6H), 1.03-1.00 (m, 5H); ESMS m/e: 482.3 (M + H)+.
Example 70
Figure imgf000080_0002
Λ/-(3-{4-[3-(ACETYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-1-(4-FLUORO PHENYL )CYCLOHEXANECARBOXAMIDE: Example 70 was prepared from 1-(4- fluorophenyl)cyclohexanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl }acetamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 7.47 (m, 2H), 7.43-7.39 (m, 2H), 7.30-7.27 (m, 2H), 7.04-7.00 (m, 2H), 6.96 (d, 1H, J = 7.2 Hz), 6.77 (br s, 1 H), 3.30 (dd, 2H, J = 5.6, 11.6 Hz), 2.95 (d, 2H, J = 11.6 Hz), 2.49 (m, 1 H), 2.34 (t, 4H, J = 6.4 Hz), 2.19 (s, 3H), 1.99-1.80 (m, 6H), 173-1.60 (m, 10H); ESMS m/e: 480.3 (M + H)+.
Example 71
Figure imgf000080_0003
Λ/-(3-{4-[3-(ACETYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-1-(4-CHLORO PHENYL) CYCLOPROPANECARBOXAMIDE: Example 71 was prepared from 1-(4-chlorophenyl)cyclo propanecarboxylic acid and N-{3-[1-(3-amino propyl)-4-piperidinyl]phenyl}acetamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 7.51 (s, 1H), 7.39-7.34 (m, 6H), 7.26 (t, 1H, J = 7.2 Hz), 6.96 (d, 1H, J = 7.6 Hz), 5.68 (br s, 1H), 3.26 (dd, 2H, J = 6.8, 12.8 Hz), 2.88 (d, 2H, J = 13.2 Hz), 2.45 (m, 1H), 2.30 (t, 2H, J = 7.2 Hz), 2.19 (s, 3H), 1.96 (t, 2H, J = 11.6 Hz), 1.78 (d, 2H, J = 12.8 Hz), 1.65-1.58 (m, 6H), 1.02 (dd, 2H, J = 3.6, 6.8 Hz); ESMS m/e: 454.2 (M + H)+.
Example 72
Figure imgf000081_0001
Λ/-(3-{4-[3-(ACETYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-1-(4-FLUOROPHENYL) CYCLOPENTANECARBOXAMIDE: Example 72 was prepared from 1-(4-fluorophenyl) cyclopentanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 7.44 (s, 1H), 7.38-7.25 (m, 5H), 7.03-6.97 (m, 3H), 6.49 (br s, 1H), 3.29 (dd, 2H, J = 5.6, 12.0 Hz), 2.98-2.94 (m, 2H), 2.55-2.49 (m, 3H), 2.33 (t, 2H, J = 6.8 Hz), 2.20 (s, 3H), 2.01-1.95 (m, 4H), 1.86-.162 (m, 10H); ESMS m/e: 466.2 (M + H)+.
Example 73
Figure imgf000081_0002
1-(4-CHLOROPHENYL)-Λ/-(3-{4-[6-(ISOBUTYRYLAMINO)-2-PYRIDINYL]-1-PIPERIDINYL} PROPYL)CYCLOBUTANECARBOXAMIDE: Example 73 was prepared from 1-(4- chlorophenyl)cyclobutanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-2- pyridinyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 8.07 (d, 1 H, J = 8.0 Hz), 7.78 (br s, 1H), 7.66 (t, 1H, J = 7.6 Hz), 7.37-7.32 (m, 4H), 6.90 (d, 1H, J = 7.6 Hz), 6.65 (br s, 1H), 3.30 (dd, 2H, J = 5.6, 11.6 Hz), 2.98 (d, 2H, J = 11.2 Hz), 2.88-2.81 (m, 2H), 2.58-2.43 (m, 4H), 2.36 (t, 2H, J = 6.4 Hz), 2.10- 1.96 (m, 4H), 1.92-178 (m, 4H), 1.64 (m, 2H), 1.25 (d, 6H, J = 6.8 Hz); ESMS m/e: 497.2 (M + H)+.
Example 74
Figure imgf000081_0003
Λ/-(3-{4-[3-(ACETYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-1-(4-CHLOROPHENYL) CYCLOBUTANECARBOXAMIDE: Example 74 was prepared from 1-(4-chlorophenyl)cyclo butanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) ,δ 7.55 (s, 1H), 7.36- 7.26 (m, 7H), 6.97 (d, 1H, J = 7.2 Hz), 6.50 (br s, 1H), 3.30 (dd, 2H, J = 6.0, 12.0 Hz), 2.98- 2.95 (m, 2H), 2.87-2.80 (m, 2H), 2.53-2.42 (m, 3H), 2.34 (t, 2H, J = 6.4 Hz), 2.20 (s, 3H), 2.15-1.82 (m, 6H), 174-.161 (m, 4H); ESMS m/e: 468.2 (M + H)+.
Example 75
Figure imgf000082_0001
Λ/-(3-{4-[3-(ACETYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-1-(4-CHLOROPHENYL) CYCLOHEXANECARBOXAMIDE: Example 75 was prepared from 1-(4-chlorophenyl) cyclohexanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 7.47 (s, 1H), 7.44 (s, 1H), 7.40-7.37 (m, 2H), 7.32-7.25 (m, 4H), 6.96 (d, 1H, J = 7.2 Hz), 6.81 (br s, 1H), 3.30 (dd, 2H, J = 5.6, 11.6 Hz), 2.94 (d, 2H, J = 12.4 Hz), 2.49 (m, 1H), 2.34 (t, 4H, J = 6.4 Hz), 2.20 (s, 3H), 1.99-1.81 (m, 6H), 172-1.55 (m, 10H); ESMS m/e: 496.2 (M + H)+.
Example 76
Figure imgf000082_0002
1-(4-CHLOROPHENYL)-/V-(3-{4-[6-(ISOBUTYRYLAMINO)-2-PYRIDINYL]-1-PIPERIDINYL} PROPYL)CYCLOPROPANECARBOXAMIDE: Example 76 was prepared from 1-(4- chlorophenyl)cyclopropanecarboxylic acid and N-{6-[1-(3-aminopropyl)-4-piperidinyl]-2- pyridinyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 8.06 (d, 1H, J = 8.0 Hz), 7.83 (s, 1H), 7.64 (t, 1H, J = 7.6 Hz), 7.38- 7.33 (m, 4H), 6.89 (d, 1H, J = 7.6 Hz), 5.68 (br s, 1 H), 3.26 (dd, 2H, J = 6.0, 12.4 Hz), 2.90 (d, 2H, J = 11.6 Hz), 2.58-2.52 (m, 2H), 2.31 (t, 2H, J = 6.8 Hz), 1.99 (t, 2H, J = 12.0 Hz), 1.85 (d, 2H, J = 12.8 Hz), 170-1.59 (m, 6H), 1.28 (d, 6H, J = 6.8 Hz), 1.01 (dd, 2H, J = 3.6, 6.4 Hz); ESMS m/e: 483.3 (M + H)+.
Example 77
Figure imgf000083_0001
Λ/-{3-[1-(3-{[2-(4-CHLOROPHENYL)PROPANOYL]AMINO}PROPYL)-4-PIPERIDINYL] PHENYLJBUTANAMIDE: Example 77 was prepared from 2-(4-chlorophenyl)propanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}butanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 7.56 (s, 1 H), 7.41 (s, 1H), 7.30-7.27 (m, 6H), 6.96 (m, 2H), 3.51 (q, 1H, J = 7.2 Hz), 3.50-3.30 (m, 2H), 3.02 (d, 1H, J = 10.8 Hz), 2.92 (d, 1H, J = 13.6 Hz), 2.50 (m, 1H), 2.41-2.34 (m, 4H), 1.99-1.94 (m, 2H), 1.86-1.58 (m, 8H), 1.51 (d, 3H, J = 7.2 Hz), 1.02 (t, 3H, J = 7.6 Hz); ESMS m/e: 470.3 (M + H)+.
Example 78
Figure imgf000083_0002
Λ/-(3-{4-[3-(ACETYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-1-(4-CHLOROPHENYL) CYCLOPENTANECARBOXAMIDE: Example 78 was prepared from 1-(4-chlorophenyl) cyclopentanecarboxylic acid and N-{3-[1-(3-amino propyl)-4-piperidinyl]phenyl}acetamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 7.44 (s, 1H), 7.34-7.26 (m, 7H), 6.97 (d, 1H, J = 7.6 Hz), 6.54 (br s, 1 H), 3.28 (dd, 2H, J = 5.6, 12.0 Hz), 2.95 (d, 2H, J = 12.0 Hz), 2.54-2.48 (m, 3H), 2.33 (t, 2H, J = 6.8 Hz), 2.20 (s, 3H), 2.00- 1.95 (m, 4H), 1.84-1.60 (m, 10H); ESMS m/e: 482.2 (M + H)+.
Example 79
Figure imgf000083_0003
Λ/-(3-{4-[3-(ACETYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-2-(4-CHLORO PHENYL)- 2-METHYLPROPANAMIDE: Example 79 was prepared from 2-(4-chlorophenyl)-2-methyl propanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 7.43 (s, 2H), 7.34-7.25 (m, 6H), 6.95 (d, 1H, J = 7.2 Hz), 6.65 (br s, 1H), 3.33 (dd, 2H, J = 6.0, 12.0 Hz), 2.92 (d, 2H, J = 12.0 Hz), 2.45 (m, 1H), 2.36 (t, 2H, J = 6.0 Hz), 2.20 (s, 3H), 1.94 (t, 2H, J = 12.4 Hz), 178 (d, 2H, J = 13.2 Hz), 1.65 (m, 2H), 1.57 (s, 6H), 1.55-1.46 (m, 2H); ESMS m/e: 456.2 (M + H)+.
Example 80
Figure imgf000084_0001
Λ/-{3-[1-(3-{[2-(4-CHLOROPHENYL)-2-METHYLPROPANOYL]AMINO}PROPYL)-4- PIPERIDINYL]PHENYL}BUTANAMIDE: Example 80 was prepared from 2-(4-chlorophenyl)- 2-methylpropanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}butanamide according to the procedures described in Scheme 9: ESMS m/e: 484.3 (M + H)+.
Example 81
Figure imgf000084_0002
1-(4-CHLOROPHENYL)-Λ/-(3-{4-[5-(ISOBUTYRYLAMINO)-2-METHYLPHENYL]-1- PIPERIDINYL}PROPYL)CYCLOPENTANECARBOXAMIDE: Example 81 was prepared from 1-(4-chlorophenyl)cyclopentanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4- methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 7.44 (d, 1H, J = 2.0 Hz), 7.37-7.34 (m, 2H), 7.31-7.25 (m, 4H), 7.09 (d, 1H, J = 8.0 Hz), 6.50 (br s, 1H), 3.29 (dd, 2H, J = 6.4, 12.0 Hz), 2.92 (d, 2H,,J = 11.6 Hz), 2.66 (m, 1H), 2.54-2.48 (m, 3H), 2.33-2.29 (m, 5H), 2.03-1.94 (m, 4H), 1.83-1.59 (m, 10H), 1.26 (d, 6H, J = 6.8 Hz); ESMS m/e: 524.3 (M + H)+.
Example 82
Figure imgf000084_0003
2-METHYL-/V-[6-(1-{3-[(TRIPHENYLACETYL)AMINO]PROPYL}-4-PIPERIDINYL)-2-
PYRIDINYL]PROPANAMIDE: Example 82 was prepared from triphenyl acetic acid and N- {6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 8.05 (d, 1H, J = 8.0 Hz), 7.81 (s, 1H), 7.63 (t, 1H, J = 7.6 Hz), 7.30-7.24 (m, 15H), 6.84 (d, 1H, J = 7.2 Hz), 6.33 (br s, 1H), 3.44 (dd, 2H, J = 6.4, 12.4 Hz), 2.89 (d, 2H, J = 11.6 Hz), 2.57-2.49 (m, 2H), 2.31 (t, 2H, J = 6.8 Hz), 1.95 (t, 2H, J = 12.0 Hz), 179-1.58 (m, 6H), 1.27 (d, 6H, J = 6.8 Hz); ESMS m/e: 575.3 (M + H)+.
Example 83
Figure imgf000085_0001
Λ/-(3-{4-[6-(ISOBUTYRYLAMINO)-2-PYRIDINYL]-1-PIPERIDINYL}PROPYL)-2,2- DIPHENYLPROPANAMIDE: Example 83 was prepared from 2,2-diphenylpropanoic acid and N-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 8.05 (d, 1H, J = 8.0 Hz), 7.80 (s, 1H), 7.63 (t, 1H, j = 7.6 Hz), 7.35-7.24 (m, 10H), 6.85 (d, 1H, J = 8.0 Hz), 6.26 (t, 1H, J = 4.8 Hz), 3.38 (dd, 2H, J = 6.4, 12.4 Hz), 2.92-2.89 (m, 2H), 2.55-2.48 (m, 2H), 2.32 (t, 2H, J = 6.8 Hz), 2.00 (s, 3H), 1.96 (t, 2H, J = 11.2 Hz), 1.79 (d, 2H, j = 11.6 Hz), 172-1.61 (m, 4H), 1.27 (d, 6H, 6.8 Hz); ESMS m/e: 513.3 (M + H)+.
Example 84
Figure imgf000085_0002
1-(4-CHLOROPHENYL)-Λ/-(3-{4-[6-(ISOBUTYRYLAMINO)-2-PYRIDINYL]-1- PIPERIDINYL}PROPYL)CYCLOPENTANECARBOXAMIDE: Example 84 was prepared from 1-(4-chlorophenyl)cyclopentanecarboxyIic acid and N-{6-[1-(3-aminopropyl)-4-piperidinyl]-2- pyridinyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 8.07 (d, 1H, J = 8.4 Hz), 7.81 (s, 1H), 7.66 (t, 1H, J = 7.6 Hz), 7.36- 7.33 (m, 2H), 7.30-7.27 (m, 2H), 6.90 (d, 1H, J = 6.8 Hz), 6.60 (br s, 1H), 3.28 (dd, 2H, J = 5.6, 12.0 Hz), 2.95 (d, 2H, J = 11.6 Hz), 2.55-2.49 (m, 4H), 2.33 (t, 2H, J = 6.4 Hz), 2.00-1.61 (m, 14H), 1.26 (d, 6H, J = 6.8 Hz); ESMS m/e: 511.3 (M + H)+.
Example 85
Figure imgf000085_0003
1-(4-CHLOROPHENYL)-Λ/-(3-{4-[5-(ISOBUTYRYLAMINO)-2-METHYLPHENYL]-1- PIPERIDINYL}PROPYL)CYCLOHEXANECARBOXAMIDE: Example 85 was prepared from 1-(4-chlorophenyl)cyclohexanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4- methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 7.46 (d, 1 H, J = 1.6 Hz), 7.42-7.39 (m, 2H), 7.31-7.21 (m, 4H), 7.08 (d, 1 H, J = 8.0 Hz), 6.78 (br s, 1H), 3.29 (dd, 2H, J = 6.0, 12.0 Hz), 2.93 (d, 2H, J = 11.6 Hz), 2.65 (m, 1H), 2.50 (m, 1 H), 2.34-2.30 (m, 4H), 2.28 (s, 3H), 2.00-1.88 (m, 4H), 174-1.59 (m, 12H), 1.25 (d, 6H, J = 6.8 Hz); ESMS m/e: 538.3 (M + H)+. Example 86
Figure imgf000086_0001
1-(4-CHLOROPHENYL)-Λ/-(3-{4-[5-(ISOBUTYRYLAMINO)-2-METHYLPHENYL]-1- PIPERIDINYL}PROPYL)CYCLOBUTANECARBOXAMIDE: Example 86 was prepared from 1-(4-chlorophenyl)cyclobutanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4- methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 7.46 (d, 1H, J = 1.6 Hz), 7.34 (s, 4H), 7.28-7.23 (m, 2H), 7.10 (d, 1H, J = 8.4 Hz), 6.45 (brs, 1H), 3.31 (dd, 2H, J = 5.6, 11.6 Hz), 2.95 (d, 2H, J = 11.6 Hz), 2.88-2.81 (m, 2H), 2.68 (m, 1H), 2.54-2.44 (m, 3H), 2.33 (t, 2H, J = 6.4 Hz), 2.29 (s, 3H), 2.11-1.90 (m, 4H), 176-1.63 (m, 6H), 1.26 (d, 6H, J = 7.2 Hz); ESMS m/e: 510.3 (M + H)+.
Example 87
Figure imgf000086_0002
Λ/-(3-{4-[3-(BUTYRYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-1-(4-FLUOROPHENYL) CYCLOHEXANECARBOXAMIDE: Example 87 was prepared from 1-(4-fluorophenyl) cyclohexanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}butanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 7.52 (s, 1H), 7.44 (s, 1H), 7.41-7.37 (m, 2H), 7.29-7.23 (m, 2H), 7.02-6.97 (m, 2H), 6.93 (d, 1H, J = 6.8 Hz), 6.80 (br s, 1H), 3.29 (dd, 2H, J = 5.6, 11.6 Hz), 2.92 (d, 2H, J = 11.6 Hz), 2.46 (m, 1H), 2.36-2.30 (m, 6H), 1.96-1.30 (m, 18H), 1.01 (t, 3H, J = 7.6 Hz), ESMS m/e: 508.3 (M + H)+.
Example 88
Figure imgf000086_0003
2-(4-CHLOROPHENYL)-Λ/-(3-{4-[6-(ISOBUTYRYLAMINO)-2-PYRIDINYL]-1-PIPERIDINYL} PROPYL)-2-METHYLPROPANAMIDE: Example 88 was prepared from 2-(4-chlorophenyl)-2- methylpropanoic acid and N-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methyl propanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 8.08 (d, 1H, J = 8.4 Hz), 7.82 (s, 1H), 7.67 (t, 1H, J = 7.6 Hz), 7.33-7.27 (m, 4H), 6.88 (d, 1H, J = 7.2 Hz), 6.57 (br s, 1H), 3.33 (dd, 2H, J = 6.0, 12.0 Hz), 2.94 (d, 2H, J = 11.6 Hz), 2.58-2.53 (m, 2H), 2.37 (t, 2H, J = 6.4 Hz), 1.97 (t, 2H, J = 11.2 Hz), 1.87 (d, 2H, J = 13.2 Hz), 1.67-1.58 (m, 4H), 1.57 (s, 6H), 1.28 (d, 6H, J = 7.2 Hz); ESMS m/e: 485.3 (M + H)+.
Example 89
Figure imgf000087_0001
1-(4-CHLOROPHENYL)-Λ/-(3-{4-[5-(ISOBUTYRYLAMINO)-2-METHYLPHENYL]-1- PIPERIDINYL}PROPYL)CYCLOPROPANECARBOXAMIDE: Example 89 was prepared from 1-(4-chlorophenyl)cyclopropanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4- methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 7.40-7.32 (m, 7H), 7.08 (d, 1H, J = 8.4 Hz), 5.70 (br s, 1H), 3.27 (dd, 2H, J = 6.4, 12.4 Hz), 2.88 (d, 2H, J = 11.6 Hz), 2.64 (m, 1H), 2.53 (m, 1H), 2.31 (t, 2H, J = 6.8 Hz), 2.28 (s, 3H), 1.99 (dt, 2H, J = 2.8, 11.2 Hz), 1.67-1.60 (m, 8H), 1.27 (d, 6H, J = 6.8 Hz), 1.03 (dd, 2H, J = 4.0, 6.8 Hz); ESMS m/e: 496.3 (M + H)+.
Example 90
Figure imgf000087_0002
2-(4-CHLOROPHENYL)-Λ/-(3-{4-[6-(ISOBUTYRYLAMINO)-2-PYRIDINYL]-1-PIPERIDINYL} PROPYL)PROPANAMIDE: Example 90 was prepared from 2-(4-chlorophenyl)propanoic acid and N-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamide according procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 8.06 (d, 1H, J = 8.0 Hz), 7.75 (s, 1H), 7.64 (t, 1H, J = 7.6 Hz), 7.34-7.27 (m, 4H), 7.22 (br s, 1H), 6.89 (d, 1H, J = 7.6 Hz), 3.53 (q, 1H, J = 7.2 Hz), 3.36 (m, 1H), 3.29 (m, 1H), 3.05 (d, 1H, J = 11.6 Hz), 2.95 (d, 1H, J = 10.4 Hz), 2.58 (m, 1H), 2.45-2.40 (m, 3H), 2.02-1.63 (m, 8H), 1.50 (d, 3H, J = 7.2 Hz), 1.22 (dd, 6H, J = 1.6, 6.8 Hz); ESMS m/e: 471.2 (M + H)+.
Example 91
χrXn
2-(4-CHLOROPHENYL)-Λ/-(3-{4-[5-(ISOBUTYRYLAMINO)-2-METHYLPHENYL]-1- PIPERIDINYL}PROPYL)-2-METHYLPROPANAMIDE: Example 91 was prepared from 2-(4- chlorophenyl)-2-methylpropanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4- methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 7.41-7.27 (m, 7H), 7.09 (d, 1H, J = 8.0 Hz), 6.59 (br s, 1H), 3.34 (dd, 2H, J = 6.4, 12.0 Hz), 2.93 (d, 2H, J = 11.6 Hz), 2.64 (m, 1H), 2.54 (m, 1H), 2.37 (t, 2H, J = 6.4 Hz), 2.28 (s, 3H), 1.98 (t, 2H, J = 12.4 Hz), 171-1.64 (m, 4H), 1.59 (s, 6H), 1.61-1.55 (m, 2H), 1.28 (d, 6H, J = 6.8 Hz); ESMS m/e: 498.3 (M + H)+.
Example 92
Figure imgf000088_0001
1-(4-FLUOROPHENYL)-Λ/-(3-{4-[5-(ISOBUTYRYLAMINO)-2-METHYLPHENYL]-1- PIPERIDINYL}PROPYL)CYCLOHEXANECARBOXAMIDE: Example 92 was prepared from 1-(4-fluorophenyl)cyclohexanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4- methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 7.46-7.43 (m, 3H), 7.26-7.22 (m, 2H), 7.10 (d, 1H, J = 8.4 Hz), 7.06-7.01 (m, 2H), 6.74 (br s, 1H), 3.31 (dd, 2H, J = 6.0, 12.0 Hz), 2.96 (d, 2H, J = 11.6 Hz), 2.68 (m, 1H), 2.52 (m, 1H), 2.36-2.32 (m, 4H), 2.29 (s, 3H), 2.03-1.90 (m, 4H), 174-1.61 (m, 12H), 1.27 (d, 6H, J = 6.8 Hz); ESMS m/e: 522.3 (M + H)+.
Example 93
Figure imgf000088_0002
1-(4-FLUOROPHENYL)-Λ/-(3-{4-[5-(ISOBUTYRYLAMINO)-2-METHYLPHENYL]-1-
PIPERIDINYL}PROPYL)CYCLOPENTANECARBOXAMIDE: Example 93 was prepared from 1-(4-fluorophenyl)cyclopentanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4- methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 7.43-7.37 (m, 3H), 7.29-7.27 (m, 2H), 7.09 (d, 1H, J = 8.4 Hz), 7.04-7.00 (m, 2H), 6.47 (br s, 1H), 3.29 (dd, 2H, J = 5.6, 12.0 Hz), 2.94 (d, 2H, J = 12.0 Hz), 2.66 (m, 1H), 2.54-2.48 (m, 3H), 2.33-2.30 (m, 2H), 2.29 (s, 3H), 2.03-1.95 (m, 4H), 1.84- 1.60 (m, 10H), 1.26 (d, 6H, J = 6.8 Hz); ESMS m/e: 508.3 (M + H)+.
Example 94
Figure imgf000088_0003
2-METHYL-Λ/-[4-METHYL-3-(1-{3-[(TRIPHENYLACETYL)AMINO]PROPYL}-4- PIPERIDINYL)PHENYL]PROPANAMIDE: Example 94 was prepared from triphenylacetic acid and N-{3-[1 -(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 7.39 (dd, 1H, J = 1.6, 8.0 Hz), 7.35-7.27 (m, 15H), 7.22-7.20 (m, 2H), 7.09 (d, 1H, J = 8.0 Hz), 6.25 (br s, 1H), 3.45 (dd, 2H, J = 6.8, 12.4 Hz), 2.90 (d, 2H, J = 10.8 Hz), 2.63 (m, 1H), 2.52 (m, 1H), 2.33-2.29 (m, 2H), 2.28 (s, 3H), 1.97 (t, 2H, J = 10.0 Hz), 172-1.57 (m, 6H), 1.27 (d, 6H, J = 6.8 Hz); ESMS m/e: 588.3 (M + H)+.
Example 95
Figure imgf000089_0001
Λ/-(3-{4-[3-(ACETYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-2-(4-CHLOROPHENYL) PROPANAMIDE: Example 95 was prepared from 2-(4-chlorophenyl) propanoic acid and N- {3-[1-(3-aminopropyl)-4-piperidinyl]phenyl} acetamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 7.48 (s, 1H), 7.36 (s, 1H), 7.31-7.25 (m, 6H), 6.98-6.93 (m, 2H), 3.51-3.48 (m, 1H), 3.35-3.31 (m, 2H), 3.03 (d, 1H, J = 11.6 Hz), 2.93 (d, 1 H, J = 11.2 Hz), 2.50 (m, 1H), 2.42-2.38 (m, 2H), 2.19 (s, 3H), 2.05-1.96 (m, 2H), 1.90-1.80 (m, 2H), 170-1.59 (m, 4H), 1.51 (d, 3H, J = 7.2 Hz); ESMS m/e: 442.2 (M + H)+.
Example 96
Figure imgf000089_0002
Λ/-(3-{4-[5-(ISOBUTYRYLAMINO)-2-METHYLPHENYL]-1-PIPERIDINYL}PROPYL)-2,2-DI PHENYLPROPANAMIDE: Example 96 was prepared from 2,2-diphenyl propanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methyl phenyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 7.37-7.23 (m, 13H), 7.08 (d, 1 H, J = 8.8 Hz), 6.14 (t, 1 H, J = 5.6 Hz), 3.37 (dd, 2H, J = 6.4, 12.0 Hz), 2.90 (d, 2H, J = 11.6 Hz), 2.63 (m, 1H), 2.49 (m, 1H), 2.31 (t, 2H, J = 6.8 Hz), 2.27 (s, 3H), 2.02 (s, 3H), 1.99-1.94 (m, 2H), 171-1.59 (m, 6H), 1.25 (d, 6H, J = 7.2 Hz); ESMS m/e: 526.3 (M + H)+.
Example 97
Figure imgf000089_0003
Λ/-[3-(1-{3-[(2,2,2-TRIPHENYLACETYL)AMINO]PROPYL}-4-PIPERIDINYL)PHENYL] BUTANAMIDE: Example 97 was prepared from tri phenylacetic acid and N-{3-[1-(3- aminopropyl)-4-piperidinyl]phenyl} butanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 7.39 (d, 2H, J = 10.4 Hz), 7.34-7.21 (m, 17H), 6.90 (d, 1H, J = 7.6 Hz), 6.31 (t, 1H, J = 5.2 Hz), 3.43 (dd, 2H, J = 6.4, 12.4 Hz), 2.87 (d, 2H, J = 12.0 Hz), 2.41 (m, 1H), 2.31 (m, 4H), 1.92 (t, 2H, J = 11.6 Hz), 179-1.66 (m, 6H), 1.59-1.52 (m, 2H), 1.01 (t, 3H, J = 7.2 Hz); ESMS m/e: 574.4 (M + H)+.
Example 98
Figure imgf000090_0001
Λ/-[3-(1-{3-[(2,2-DIPHENYLPROPANOYL)AMINO]PROPYL}-4-PIPERIDINYL)PHENYL] BUTANAMIDE: Example 98 was prepared from 2,2-diphenylpropanoic acid and N-{3-[1-(3- aminopropyl)-4-piperidinyl] phenyl}butanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 7.43 (s, 1H), 7.37-7.22 (m, 13H), 6.91 (d, 1H, J = 7.2 Hz), 6.24 (br s, 1H), 3.37 (dd, 2H, J = 5.6, 11.6 Hz), 2.88 (d, 2H, J = 11.6 Hz), 2.42 (m, 1H), 2.32 (m, 4H), 2.01 (s, 3H), 1.93 (t, 2H, J = 11.6 Hz), 1.81-1.52 (m, 8H), 1.01 (t, 3H, J = 6.8 Hz); ESMS m/e: 512.3 (M + H)+.
Example 99
Figure imgf000090_0002
Λ/-(3-{4-[3-(BUTYRYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-1-(4-CHLOROPHENYL) CYCLOHEXANECARBOXAMIDE: Example 99 was prepared from 1-(4-chlorophenyl cyclohexanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}butanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 7.59 (s, 1H), 7.52 (s, 1 H), 7.38-7.35 (m, 2H), 7.30-7.22 (m, 4H), 6.93 (d, 1H, J = 7.6 Hz), 6.87 (br s, 1H), 3.28 (dd, 2H, J = 6.0, 12.0 Hz), 2.92 (d, 2H, J = 11.6 Hz), 2.45 (m, 1 H), 2.36-2.30 (m, 6H), 1.96-1.33 (m, 18H), 1.00 (t, 3H, J = 7.6 Hz); ESMS m/e: 524.3 (M + H)+.
Example 100
Figure imgf000090_0003
2-(4-CHLOROPHENYL)-Λ/-(3-{4-[5-(ISOBUTYRYLAMINO)-2-METHYLPHENYL]-1- PIPERIDINYL}PROPYL)PROPANAMIDE: Example 100 was prepared from 2-(4- chlorophenyl)propanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2- methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 7.56 (d, 1H, J = 2.0 Hz), 7.34-7.28 (m, 5H), 7.21 (dd, 1H, J = 2.0. 8.0 Hz), 7.09 (d, 1H, J = 8.0 Hz), 6.98 (br s, 1H), 3.55 (q, 1H, J = 7.2 Hz), 3.34 (m, 2H), 3.02 (d, 1H, J = 11.6 Hz), 2.93 (d, 1H, J = 11.6 Hz), 2.68 (m, 1H), 2.51 (m, 1H), 2.39 (dt, 2H, J = 6.8, 2.0 Hz), 2.29 (s, 3H), 2.04-1.97 (m, 2H), 1.80-1.60 (m, 6H), 1.52 (d, 3H, J = 7.2 Hz), 1.24 (dd, 6H, J = 1.6, 6.8 Hz); ESMS m/e: 484.3 (M + H)+.
Example 101
Figure imgf000091_0001
Λ/-(3-{4-[3-(BUTYRYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-1-(4-FLUOROPHENYL) CYCLOPENTANECARBOXAMIDE: Example 101 was prepared from 1-(4-fluorophenyl) cyclopentanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}butanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 7.51 (s, 1H), 7.37-7.24 (m, 6H), 7.02-6.95 (m, 2H), 6.51 (br s, 1H), 3.28 (dd, 2H, J = 5.6, 11.6 Hz), 2.93 (d, 2H, J = 11.6 Hz), 2.53-2.48 (m, 3H), 2.37-2.30 (m, 4H), 1.98-1.92 (m, 4H), 1.82-1.59 (m, 12H), 1.02 (t, 3H, J = 7.6 Hz); ESMS m/e: 494.3 (M + H)+.
Example 102
Figure imgf000091_0002
Λ/-(3-{4-[3-(BUTYRYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-1-(4-CHLOROPHENYL) CYCLOPENTANECARBOXAMIDE: Example 102 was prepared from 1-(4-chlorophenyl) cyclopentanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}butanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 7.51 (s, 1H), 7.42 (s, 1H), 7.34-7.24 (m, 6H), 6.95 (d, 1H, J = 7.6 Hz), 6.57 (br s, 1H), 3.28 (dd, 2H, J = 5.6, 11.6 Hz), 2.92 (d, 2H, J = 12.0 Hz), 2.53-2.43 (m, 3H), 2.37-2.29 (m, 4H), 1.99-1.91 (m, 4H), 1.83-1.58 (m, 12H), 1.02 (t, 3H, J = 7.6 Hz); ESMS m/e: 510.3 (M + H)\
Example 103
Figure imgf000092_0001
Λ/-(3-{4-[3-(ACETYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-2,2-DIPHENYL PROPANAMIDE: Example 103 was prepared from 2,2-diphenyl propanoic acid and N-{3-[1- (3-aminopropyl)-4-piperidinyl]phenyl} acetamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 7.37-7.23 (m, 14H), 6.93 (d, 1 H, J = 7.6 Hz), 6.20 (br s, 1H), 3.37 (dd, 2H, J = 6.4, 12.4 Hz), 2.89 (d, 2H, 7.2 Hz), 2.45 (m, 1H), 2.30 (m, 2H), 2.18 (s, 3H), 2.01 (s, 3H), 1.94 (t, 2H, J = 11.6 Hz), 176-1.53 (m, 6H); ESMS m/e: 484.2 (M + H)+.
Example 104
Figure imgf000092_0002
Λ/-{5-[1-(3-{[BIS(4-FLUOROPHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL]-2- FLUOROPHENYL}BUTANAMIDE: Example 104 was prepared from bis(4-fluoro phenyl)acetic acid and N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl}butanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 8.33-8.14 (m, 1H), 7.89-7.67 (br, 1H), 7.51-6.60 (m, 10H), 4.98-479 (br, 1H), 4.75 (s, 1H), 3.46-3.29 (m, 2H), 3.29-3.08 (m, 2H), 279-2.63 (m, 2H), 2.63-2.46 (m, 1H), 2.46-2.21 (m, 4H), 1.97- 1.60 (m, 8H), 1.01 (t, 3H, J = 7.2 Hz); ESMS m/e: 552.3 (M + H)+.
Example 105
Figure imgf000092_0003
Λ/-(3-{4-[3-(ACETYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-2,2,2-TRIPHENYL ACETAMIDE: Example 105 was prepared from triphenylacetic acid and N-{3-[1-(3- aminopropyl)-4-piperidinyl]phenyl}acetamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 7.34-7.22 (m, 19H), 6.91 (d, 1H, J = 7.6 Hz), 6.30 (t, 1H, J = 5.6 Hz), 3.43 (dd, 2H, J = 6.4, 12.0 Hz), 2.87 (d, 2H, J = 12.0 Hz), 2.42 (m, 1H), 2.30 (t, 2H, J = 6.8 Hz), 2.17 (s, 3H), 1.93 (t, 2H, J = 11.6 Hz), 174-1.66 (m, 4H), 1.60-1.50 (m, 2H); ESMS m/e: 546.2 (M + H)+.
Example 106
Figure imgf000093_0001
Λ/-(3-{4-[3-(BUTYRYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-1-(4-CHLOROPHENYL) CYCLOBUTANECARBOXAMIDE: Example 106 was prepared from 1-(4-chlorophenyl) cyclobutanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}butanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 7.53 (s, 2H), 7.32-7.23 (m, 6H), 6.95 (d, 1H, J = 7.6 Hz), 6.53 (br s, 1H), 3.29 (dd, 2H, J = 6.0, 12.4 Hz), 2.93 (d, 2H, J = 10.8 Hz), 2.86-279 (m, 2H), 2.48-2.41 (m, 3H), 2.37-2.30 (m, 4H), 2.07 (m, 1H), 1.98-1.61 (m, 11H), 1.01 (t, 3H, J = 7.6 Hz); ESMS m/e: 496.3 (M + H)+.
Example 107
Figure imgf000093_0002
Λ/-(3-{4-[3-(BUTYRYLAMINO)-4-FLUOROPHENYL]-1-PIPERIDINYL}PROPYL)-1-(4- FLUOROPHENYL)CYCLOPENTANECARBOXAMIDE: Example 107 was prepared from 1- (4-fluorophenyl)cyclopentanecarboxylic acid and N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2- fluorophenyljbutanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 8.30-8.13 (m, 1H), 8.09-7.95 (br, 1H), 7.47-7.26 (m, 3H), 7.08-6.87 (m, 3H), 675-6.54 (br, 1H), 3.30-3.07 (m, 4H), 2.59-2.44 (m, 3H), 2.44-2.33 (m, 2H), 2.33-2.19 (m, 2H), 1.99-1.69 (m, 16H), 1.02 (t, 3H, J = 7.2 Hz); ESMS m/e: 512.3 (M + H)+.
Example 108
Figure imgf000093_0003
Λ/-{5-[1-(3-{[BIS(4-CHLOROPHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL]-2- FLUOROPHENYL}BUTANAMIDE: Example 108 was prepared from bis(4-chlorophenyl) acetic acid and N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fiuorophenyl}butan amide according to the procedures described in Scheme 10: ESMS m/e: 584.2 (M + H)+.
Example 109
Figure imgf000093_0004
Λ/-{5-[1-(3-{[BIS(4-METHYLPHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL]-2- FLUOROPHENYL}BUTANAMIDE: Example 10 prepared from bis(4-methylphenyl)acetic acid and N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2-fluorophenyl} butanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 8.30-8.13 (m, 1H), 8.08- 7.92 (br, 1H), 7.43-6.89 (m, 9H), 676-6.61 (br, 1H), 4.98-479 (br, 1H), 4.70 (s, 1H), 3.39- 3.16 (m, 4H), 2.83-2.63 (m, 2H), 2.63-2.47 (m, 1H), 2.45-2.12 (m, 4H), 2.27 (s, 6H), 2.02- 1.64 (m, 8H), 1.02 (t, 3H, J = 7.2 Hz); ESMS m/e: 544.4 (M + H)+.
Example 110
Figure imgf000094_0001
Λ/-{5-[1-(3-{[2-(4-CHLOROPHENYL)-2-METHYLPROPANOYL]AMINO}PROPYL)-4- PIPERIDINYL]-2-FLUOROPHENYL}BUTANAMIDE: Example 110 was prepared from 2-(4- chlorophenyl)-2-methylpropanoic acid and N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2- fluorophenyl}butanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) 8.31-8.12 (m, 1H), 7.44-7.15 (m, 5H), 7.12-6.94 (m, 1H), 675-6.61 (br, 1H), 6.61-6.46 (br, 1H), 3.35-3.12 (m, 4H), 270-2.47 (m, 3H), 2.46-2.35 (m, 2H), 2.35-2.21 (m, 2H), 1.92-1.67 (m, 8H), 1.54 (s, 6H), 1.02 (t, 3H, J = 7.2 Hz); ESMS m/e: 502.3 (M + H)+.
Example 111
Figure imgf000094_0002
Λ/-{3-[1-(3-{[2,2-BIS(4-METHYLPHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL]
PHENYLJCYCLOPROPANECARBOXAMIDE: Example 111 was prepared from bis(4- methylphenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclo propanecarboxamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 8.24-8.04 (br, 1H), 8.04-7.95 (br, 1H), 7.59-6.92 (m, 10H), 6.90-676 (m, 1H),
4.98-4.82 (br, 1 H), 472 (s, 1H), 3.42-3.25 (m, 2H), 3.25-3.08 (m, 2H), 275-2.56 (m, 2H),
2.56-2.40 (m, 1H), 2.35-2.17 (m, 2H), 2.26 (s, 6H), 1.99-1.68 (m, 6H), 1.57-1.44 (m, 1H),
1.12-0.99 (m, 2H), 0.87-070 (m, 2H); ESMS m/e: 524.3 (M + H)+; Anal. Calc. for (HCI salt)
C34H42CIF2N302O.29CHCI3: C, 69.23; H, 7.16; N, 7.06. Found: C, 68.96; H, 7.35; N, 7.31.
Example 112
Figure imgf000095_0001
1-(4-CHLOROPHENYL)-/V-[3-(4-{3-[(CYCLOPROPYLCARBONYL)AMINO]PHENYL}-1- PIPERIDINYL)PROPYL]CYCLOPENTANECARBOXAMIDE: Example 112 was prepared from 1-(4-chlorophenyl)cyclopentanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4- piperidinyl]phenyl}cyclopropanecarboxamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 8.03-7.87 (br, 1H), 7.56-7.02 (m, 8H), 6.91-6.65 (br, 1H), 3.30-3.05 (m, 4H), 2.62-2.38 (m, 3H), 2.38-2.21 (m, 2H), 1.98-1.51 (m, 15H), 1.14- 1.01 (m, 2H), 0.93-070 (m, 2H); ESMS m/e: 508.2 (M + H)+.
Example 113
Figure imgf000095_0002
Λ/-{3-[1-(3-{[2,2-BIS(4-CHLOROPHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL] PHENYLJCYCLOPROPANECARBOXAMIDE: Example 113 was prepared from bis(4- chlorophenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclo propanecarboxamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 7.84-7.80 (br, 1H), 7.80-7.69 (br, 1H), 7.64-7.46 (br, 1H), 7.40-6.90 (m, 9H), 6.85-6.66 (m, 1H), 4.94-474 (br, 1 H), 4.69 (s, 1H), 3.41-3.25 (m, 2H), 3.25-3.07 (m, 2H), 277-2.61 (m, 2H), 2.61-2.45 (m, 1H), 2.45-2.17 (m, 2H), 1.99-1.63 (m, 6H), 1.61-1.39 (m, 1H), 1.14-0.94 (m, 2H), 0.92-070 (m, 2H); ESMS m/e: 564.2 (M + H)+.
Example 114
Figure imgf000095_0003
Λ/-[3-(1-{3-[(2,2,2-TRIPHENYLACETYL)AMINO]PROPYL}-4-PIPERIDINYL)PHENYL] CYCLOPROPANECARBOXAMIDE: Example 114 was prepared from triphenylacetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl] phenylcyclopropanecarboxamide according to the procedures described in Scheme 10: ESMS m/e: 572.3 (M + H)+.
Example 115
Figure imgf000096_0001
Λ/-{3-[1-(3-{[2-(4-CHLOROPHENYL)-2-METHYLPROPANOYL]AMINO}PROPYL)-4- PIPERIDINYL]PHENYL}CYCLOPROPANECARBOXAMIDE: Example 115 was prepared from 2-(4-chlorophenyl)-2-methylpropanoic acid and N-{3-[1-(3-amino propyl)-4- piperidinyl]phenyl}cyclopropanecarboxamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) 7.94-7.81 (br, 1H), 7.53-7.40 (br, 1H), 7.39-7.15 (m, 6H), 6.82 (d, 1 H, J = 7.2 Hz), 6.68-6.49 (br, 1H), 3.33-3.19 (m, 2H), 3.19-3.06 (m, 2H), 2.63-2.39 (m, 3H), 2.31-2.09 (m, 2H), 1.89-1.62 (m, 7H), 1.54 (s, 6H), 1.13-0.98 (m, 2H), 0.90-072 (m, 2H); ESMS m/e: 482.2 (M + H)+.
Example 116
Figure imgf000096_0002
Λ/-{3-[1-(3-{[2-(4-CHLOROPHENYL)PROPANOYL]AMINO}PROPYL)-4-PIPERIDINYL] PHENYLCYCLOPROPANECARBOXAMIDE: Example 116 was prepared from 2-(4- chlorophenyl)propanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl
Jcyclopropanecarboxamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCI3) 8.15-7.95 (br, 1H), 7.63-7.44 (br, 1 H), 7.39-7.12 (m, 7H), 6.85 (d, 1H, J = 6.8 Hz), 374-3.55 (m, 1H), 3.45-3.22 (m, 2H), 3.22-3.12 (m, 1H), 3.12-3.00 (m, 1H), 2.66- 2.40 (m, 3H), 2.29-2.09 (m, 2H), 1.92-1.63 (m, 6H), 1.64-1.51 (m, 1H), 1.47 (d, 3H, J = 6.8 Hz), 1.18-0.98 (m, 2H), 0.91-074 (m, 2H); ESMS m/e: 468.2 (M + H)+; Anal. Calc. for (HCI salt) C27H35CI2N302O.28CHCI3: C, 60.91; H, 6.61 ; N, 7.81 ; Found: C, 60.66; H, 6.90; N, 8.19.
Example 117
Figure imgf000096_0003
Λ/-[3-(4-{3-[(CYCLOPROPYLCARBONYL)AMINO]PHENYL}-1-PIPERIDINYL) PROPYL]-1- (2,4-DICHLOROPHENYL)CYCLOPROPANECARBOXAMIDE: Example 117 was prepared from 1-(2,4-dichlorophenyl)cyclopropanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4- piperidinyl]phenyl}cyclopropane carboxamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 8.00-7.82 (br, 1H), 7.52-7.04 (m, 6H), 6.86 (d, 1H, J = 7.2 Hz), 5.92-573 (br, 1 H), 3.35-3.12 (m, 4H), 274-2.58 (m, 2H), 2.58-2.42 (m, 1 H), 2.40-2.20 (m, 2H), 2.01-1.61 (m, 7H), 1.15-0.90 (m, 6H), 0.89-071 (m, 2H); ESMS m/e: 514.2 (M + H)+.
Example 118
Figure imgf000097_0001
1-(4-CHLOROPHENYL)-Λ/-[3-(4-{3-[(CYCLOPROPYLCARBONYL)AMINO]PHENYL}-1- PIPERIDINYL)PROPYL]CYCLOPROPANECARBOXAMIDE: Example 118 was prepared from 1-(4-chlorophenyl)cyclopropanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4- piperidinyl]phenyl}cyclopropanecarboxamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 8.12-7.88 (br, 1H), 7.48-7.14 (m, 7H), 6.85 (d, 1H, J = 7.2 Hz), 5.83-5.66 (br, 1H), 3.29-3.09 (m, 4H), 2.66-2.53 (m, 2H), 2.53-2.40 (m, 1H), 2.37-2.17 (m, 2H), 1.95-1.53 (m, 7H), 1.14-0.91 (m, 6H), 0.89-071 (m, 2H); ESMS m/e: 480.2 (M + H)+; Anal. Calc. (HCI salt) C28H35CI2N302O.38CHCI3: C, 60.64; H, 6.34; N, 7.47. Found: C, 60.38; H, 6.57; N, 7.80.
Example 119
Figure imgf000097_0002
1-(2-CHLORO-4-FLUOROPHENYL)-Λ/-[3-(4-{3-[(CYCLOPROPYLCARBONYL)AMINO] PHENYL}-1-PIPERIDINYL)PROPYL]CYCLOPENTANECARBOXAMIDE: Example 119 was prepared from 1-(2-chloro-4-fluorophenyl)cyclopentanecarboxylic acid and N-{3-[1-(3- aminopropyl)-4-piperidinyl]phenyl}cyclopropane carboxamide according to the procedures described in Scheme 10: ESMS m/e: 526.2 (M + H)+.
Example 120
Figure imgf000097_0003
Λ/-{3-[1-(3-{[2,2-BIS(4-FLUOROPHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL] PHENYLCYCLOPROPANECARBOXAMIDE: Example 120 was prepared from bis(4- fluorophenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclopro panecarboxamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 7.64-7.55 (s, 1H), 7.55-7.47 (s, 1H), 7.47-7.37 (br, 1H), 7.36-7.17 (m, 6H), 7.05- 6.95 (m, 4H), 6.95-6.87 (br, 1H), 4.81 (s, 1H), 3.47-3.35 (m, 2H), 3.07-2.94 (m, 2H), 2.58- 2.41 (m, 3H), 2.15-1.99 (m, 2H), 1.90-179 (m, 2H), 179-1.60 (m, 4H), 1.59-1.44 (m, 1H), 1.13-0.99 ( , 2H), 0.90-075 (m, 2H); ESMS m/e: 532.2 (M + H)+.
Example 121
Figure imgf000098_0001
Λ/-[3-(4-{3-[(CYCLOPROPYLCARBONYL)AMINO]PHENYL}-1-PIPERIDINYL) PROPYLJ-1- (4-FLUOROPHENYL)CYCLOPENTANECARBOXAMIDE: Example 121 was prepared from 1-(4-fluorophenyl)cyclopentanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl] phenyljcyclopropanecarboxamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 7.94-772 (br, 1H), 7.48-6.84 (m, 7H), 6.75 (d, 1H, J = 7.2 Hz), 6.68-6.55 (br, 1H), 3.25-3.05 (m, 4H), 2.58-2.39 (m, 3H), 2.33-2.15 (m, 2H), 2.00-1.48 (m, 15H), 1.13-1.01 (m, 2H), 0.93-073 (m, 2H); ESMS m/e: 492.3 (M + H)+.
Example 122
Figure imgf000098_0002
Λ -(1-{3-[(2,2-DIPHENYLBUTANOYL)AMINO]PROPYL}-4-PIPERIDINYL)PHENYL] CYCLOPROPANECARBOXAMIDE: Example 122 was prepared from 2,2-diphenylbutanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl] phenyljcyclopropanecarboxamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 7.89-774 (br, 1H), 7.48-7.05 (m, 13H), 6.89-674 (d, 1H, J = 7.2 Hz), 6.46-6.25 (br, 1 H), 3.30-3.15 (m, 2H), 3.15-3.01 (m, 2H), 2.38-2.25 (m, 3H), 2.25-2.09 (m, 2H), 1.99-178 (m, 3H), 178-1.60 (m, 5H), 1.60-1.47 (m, 1H), 1.12-1.01 (m, 2H), 0.90-071 (m, 2H), 0.75 (t, 3H, J = 7.2 Hz); ESMS m/e: 524.3 (M + H)+.
Example 123
Figure imgf000098_0003
Λ/-[3-(1-{3-[(2,2-DIPHENYLPROPANOYL)AMINO]PROPYL}-4-PIPERIDINYL)PHENYL] CYCLOPROPANECARBOXAMIDE: Example 123 was prepared from 2,2-diphenylpropanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl] phenyljcyclopropanecarboxamide according to the procedures described in Scheme 10: ESMS m/e: 510.3 (M + H)+.
Example 124
Figure imgf000099_0001
Λ/-{3-[1-(3-{[DIFLUORO(PHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL]-4-METHYL PHENYLJ-2-METHYLPROPANAMIDE: Example 124 was prepared from 2,2-difluoro-2- phenylacetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methyl propanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCI3) δ 8.00 (s, 2H), 7.68-7.63 (m, 3H), 7.49-7.39 (m, 3H), 7.23 (d, 1 H, J = 1.8 Hz), 7.07 (d, 1 H, J = 8.3 Hz), 3.45 (q, 2H, J = 4.9 Hz), 3.11 (d, 2H, J = 10.2 Hz), 276-2.66 (m, 1H), 2.56 (t, 2H, J = 5.0 Hz), 2.44 (septet, 1 H, J = 6.9 Hz), 2.28 (s, 3H), 2.13-2.05 (m, 2H), 1.82-171 (m, 6H), 1.15 (d, 6H, J = 6.9 Hz); ESMS m/e: 472.4 (M + H)+.
Example 125
Figure imgf000099_0002
Λ/-{3-[1-(3-{[DIFLUORO(PHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL] PHENYL}-2- METHYLPROPANAMIDE: Example 125 was prepared from 2,2-difluoro-2-phenylacetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 8.01 (s, 1H), 7.71 (s, 1 H), 7.65-7.62 (m, 2H), 7.50 (s, 1 H), 7.47-7.40 (m, 3H), 7.35 (d, 1H, J = 7.6 Hz), 7.22 (t, 1H, J = 7.2 Hz), 6.95 (d, 1H, J = 7.8 Hz), 3.45 (q, 2H, J = 5.3 Hz), 3.10 (d, 2H, J = 10.9 Hz), 2.59- 2.45 (m, 4H), 2.11-2.02 (m, 2H), 1.89-171 (m, 6H), 1.20 (d, 6H, J = 6.9 Hz); ESMS m/e: 458.4 (M + H)+.
Example 126
Figure imgf000099_0003
Λ/-[3-(1-{3-[(DIPHENYLACETYL)(ETHYL)AMINO]PROPYL}-4-PIPERIDINYL)PHENYL]-2- METHYLPROPANAMIDE: Example 126 was prepared from diphenylacetyl chloride and N- (3-{1-[3-(ethylamino)propyl]-4-piperidinyl}phenyl)-2-methylpropanamide according to the procedures described in Scheme 8: 1H NMR (400 MHz, CDCI3) δ 7.33-7.21 (m, 13H), 6.94 (m, 2H), 4.88 (s, 1H), 3.39 (m, 4H), 2.93 (d, 2H, J = 10.9 Hz), 2.52- 2.36 (m, 7H), 1.97 (t, 2H, J = 10.9 Hz), 1.83-1.58 (m, 6H), 1.24 (d, 6H, J = 7.6 Hz); ESMS m/e: 526.4 (M + H)+.
Example 127
Figure imgf000100_0001
2-(4-CHLOROPHENYL)-Λ/-(3-{4-[2-FLUORO-5-(ISOBUTYRYLAMINO)PHENYL]-1- PIPERIDINYL}PROPYL)-2-METHYLPROPANAMIDE: Example 127 was prepared from 2-(4- chlorophenyl)-2-methylpropanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4- fluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCI3) δ 7.95 (s, 1H), 7.73 (s, 1 H), 7.68 (s, 1 H), 7.43-7.38 (m, 1 H), 7.37- 7.26 (m, 3H), 6.93-6.83 (m, 2H), 3.96-3.61 (m, 1H), 3.26-3.02 (m, 4H), 2.69-2.59 (m, 1H), 2.51-2.40 (m, 2H), 1.90-171 (m, 4H), 1.63-1.47 (m, 4H), 1.18 (d, 6H, J = 6.9 Hz), 1.15 (s, 6 H); ESMS m/e: 502.1 (M + H)+.
Example 128
Figure imgf000100_0002
1-(4-CHLOROPHENYL)-Λ/-(3-{4-[2-FLUORO-5-(ISOBUTYRYLAMINO)PHENYL]-1- PIPERIDINYL}PROPYL)CYCLOPENTANECARBOXAMIDE: Example 128 was prepared from 1-(4-chlorophenyl)cyclopentanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4- piperidinyl]-4-fluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCI3) δ 7.45 (s, 1H), 7.42-7.38 (m, 1H), 7.27-7.17 (m, 4H), 7.12-7.09 (m, 1H), 6.87 (t, 1H, J = 8.6 Hz), 6.49 (t, 1H, J = 5.4 Hz), 3.19 (q, 2H, J = 5.8 Hz), 2.85-279 (m, 2H), 273-2.64 (m, 1H), 2.50-2.35 (m, 3H), 2.23 (t, 2H, J = 6.6 Hz), 1.92-1.85 (m, 4H), 175-1.48 (m, 10H), 1.17 (d, 6H, J = 6.7 Hz); ESMS m/e: 528.2 (M + H)+.
Example 129
Figure imgf000100_0003
Λ/-(3-{4-[2-FLUORO-5-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-1-(4- FLUOROPHENYL)CYCLOPENTANECARBOXAMIDE: Example 129 was prepared from 1- (4-fluorophenyl)cyclopentanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4- fluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCI3) δ 7.53 (s, 1H), 7.42-7.38 (m, 1H), 7.31-7.20 (m, 2H), 6.94-6.83 (m, 4H), 6.46-6.40 (m, 1H), 3.19 (q, 2H, J = 5.6 Hz), 2.85-279 (m, 2H), 273-2.64 (m, 1H), 2.49- 2.38 (m, 3H), 2.22 (t, 2H, J = 6.4 Hz), 1.94-1.84 (m, 5H), 175-1.47 (m, 9H), 1.17 (d, 6H, J = 6.8 Hz); ESMS m/e: 512.3 (M + H)+.
Example 130
Figure imgf000101_0001
1-(4-CHLOROPHENYL)-Λ/-(3-{4-[2-FLUORO-5-(ISOBUTYRYLAMINO)PHENYL]-1- PIPERIDINYL}PROPYL)CYCLOHEXANECARBOXAMIDE: Example 130 was prepared from 1-(4-chlorophenyl)cyclohexanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4- fluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCI3) δ 7.45-7.40 (m, 1H), 7.34-7.29 (m, 3H), 7.24-7.16 (m, 3H), 6.88 (t, 1H, J = 8.7 Hz), 677-672 (m, 1H), 3.21 (q, 2H, J = 5.6 Hz), 2.87-2.81 (m, 2H), 274-2.65 (m, 1H), 2.44 (septet, 1H, J = 6.7 Hz), 2.28-2.21 (m, 4H), 1.92-176 (m, 4H), 1.69-1.69 (m, 4H), 1.56-1.47 (m, 8H), 1.18 (d, 6H, J = 6.7 Hz); ESMS m/e: 542.2 (M + H)+; Anal. Calc. for C31H41CIFN302 • HCI • 0.20 CHCI3: C, 62.20; H, 7.06; N, 6.97. Found: C, 62.24; H, 7.03; N, 6.79.
Example 131
Figure imgf000101_0002
Λ/-(3-{4-[2-FLUORO-5-(ISOBUTYRYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)-1-(4- FLUOROPHENYL)CYCLOHEXANECARBOXAMIDE: Example 131 was prepared from 1-(4- fluorophenyl)cyclohexanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4- fluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 9: H NMR (400 MHz, CDCI3) δ 7.49 (s, 1H), 7.43 (dd, 1H, J = 6.9, 2.5 Hz), 7.36-7.31 (m, 2H), 7.23-7.17 (m, 1H), 6.93 (t, 2H, J = 8.4 Hz), 6.87 (t, 1H, J = 8.9 Hz), 673-6.68 (m, 1H), 3.21 (q, 2H, J = 5.7 Hz), 2.87-2.80 (m, 2H), 273-2.65 (m, 1H), 2.45 (septet, 1 H, J = 6.7 Hz), 2.30- 2.21 (m, 4H), 1.9-177 (m, 5H), 170-1.63 (m, 3H), 1.56-1.45 (m, 8H), 1.17 (d, 6H, J = 6.7 Hz); ESMS m/e: 526.3 (M + H)+.
Example 132
Figure imgf000102_0001
Λ/-{3-[1-(3-{[BIS(4-METHYLPHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL]-4-
FLUOROPHENYLJ-2-METHYLPROPANAMIDE: Example 132 was prepared from bis(4- methylphenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl}-2- methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz,
CDCI3) δ 7.72 (s, 1H), 7.36-7.31 (m, 1H), 7.28-7.21 (m, 1H), 7.12-7.07 (m, 3H), 7.03-6.99 (m,
5H), 6.86-6.80 (m, 1H), 679-675 (m, 1H), 4.74 (s, 1H), 3.33-3.25 (m, 2H), 2.85-277 (m,
■ 2H), 272-2.62 (m, 1H), 2.40 (septet, 1H, J = 6.7 Hz), 2.28 (t, 2H, J = 6.6 Hz), 2.21 (m, 6H),
1.94-1.84 (m, 2H), 1.65-1.52 (m, 6H), 1.71 (d, 6H, J = 6.6 Hz); ESMS m/e: 544.3 (M + H)+; Anal. Calc. for C34H42FN302. HCI • 0.10 CHCI3: C, 70.17; H, 7.35; N, 7.10. Found: C, 70.35;
H, 6.99; N, 7.10.
Example 133
Figure imgf000102_0002
1-(2-CHLORO-4-FLUOROPHENYL)-Λ/-(3-{4-[2-FLUORO-5-(ISOBUTYRYLAMINO)
PHENYL] -1-PIPERIDINYL}PROPYL)CYCLO HEXANECARBOXAMIDE: Example 133 was prepared from 1-(2-chloro-4-fluorophenyl)cyclohexanecarboxylic acid and N-{3-[1-(3-aminop ropyl)-4-piperidinyl]-4-fluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCI3) δ 7.59 (dd, 1H, J = 6.4, 8.5 Hz), 7.44- 7.38 (m, 2H), 7.35-7.30 (m, 1H), 7.13 (dd, 1H, J = 8.5, 3.0 Hz), 7.00-6.91 (m, 2H), 6.05-5.99 (m, 1H), 3.30 (q, 2H, J = 5.7 Hz), 2.92-2.86 (m, 2H), 2.80-271 (m, 1H), 2.52 (septet, 1H, J = 6.7 Hz), 2.34 (t, 2H, J = 5.7 Hz), 2.30-2.24 (m, 3H), 2.13-2.05 (m, 2H), 2.00-1.92 (m, 2H), 1.86-1.69 (m, 4H), 1.66-1.43 (m, 7H), 1.71 (d, 6H, J = 6.7 Hz); ESMS m/e: 560.1 (M + H)+.
Example 134
Figure imgf000102_0003
1-(2-CHLORO-4-FLUOROPHENYL)-Λ/-(3-{4-[5-(ISOBUTYRYLAMINO)-2-METHYL PHENYL]-1-PIPERIDINYL}PROPYL)CYCLOHEXANECARBOXAMIDE: Example 134 was prepared from 1-(2-chloro-4-fluorophenyl)cyclo hexanecarboxylic acid and N-{3-[1-(3-amino propyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCI3) δ 7.55 (dd, 1H, J = 8.9, 6.3 Hz), 7.32 (s, 1H), 7.23-7.18 (m, 2H), 7.06 (dd, 1H, J = 8.5, 3.0 Hz), 7.01-6.92 (m, 2H), 5.99-5.93 (m, 1H), 3.24 (q, 2H, J = 5.9 Hz), 2.85-279 (m, 3H), 2.59-2.50 (m, 1H), 2.44 (septet, 1H, J = 7.0 Hz), 2.41-2.37 (br, 1H), 2.26 (t, 2H, J = 5.7 Hz), 2.19 (s, 3H), 2.07-2.01 (m, 2H), 1.81-1.69 (m, 4H), 1.61-1.37 (m, 10H), 1.17 (d, 6H, J = 7.0 Hz); ESMS m/e: 556.1 (M + H)+.
Example 135
Figure imgf000103_0001
1-(2-CHLORO-4-FLUOROPHENYL)-Λ/-(3-{4-[5-(ISOBUTYRYLAMINO)-2-METHYL PHENYL]-1-PIPERIDINYL}PR0PYL)CYCL0PENTANECARB0XAMIDE: Example 135 was prepared from 1-(2-chloro-4-fluorophenyl)cyclopentanecarboxylic acid and N-{3-[1-(3-amino propyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCI3) δ 7.56 (dd, 1H, J = 8.7, 6.3 Hz), 7.32 (s, 1H), 7.22-7.15 (m, 2H), 7.06 (dd, 1H, J = 8.7, 3.0 Hz), 7.05-6.95 (m, 2H), 5.90-5.84 (m, 1H), 3.21 (q, 2H, J = 5.7 Hz), 2.87-2.80 (m, 2H), 2.59-2.49 (m, 1H), 2.44 (septet, 1H, J = 6.5 Hz), 2.41-2.40 (m, 2H), 2.26 (t, 2H, J = 5.7 Hz), 2.19 (s, 3H), 2.04-1.96 (m, 2H), 1.93-1.85 (m, 2H), 1.82-1.71 (m, 3H), 1.64-1.48 (m, 7H), 1.17 (d, 6H, J = 6.5 Hz); ESMS m/e: 542.2 (M + H)+.
Example 136
Figure imgf000103_0002
Λ/-{3-[1-(3-{[DIFLUORO(PHENYL)ACETYL]AMINO}PROPYL)-4-PIPERIDINYL]-4- FLUOROPHENYLJ-2-METHYLPROPANAMIDE: Example 136 was prepared from 2,2- difluoro-2-phenylacetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl}-2- methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCIs) δ 9.11 (s, 1H), 7.61-7.56 (m, 2H), 7.41-7.34 (m, 4H), 7.21-7.17 (m, 1 H), 7.14 (s, 1H), 6.88 (t, 1H, J = 9.5 Hz), 3.39 (q, 2H, J = 5.7 Hz), 3.08-3.01 (m, 2H), 2.84-274 (m, 1H), 2.50 (t, 2H, J = 5.1 Hz), 2.38 (septet, 1H, J = 7.2 Hz), 2.08-1.99 (m, 2H), 1.81-173 (m, 4H), 1.72- 1.64 (m, 2H), 1.17 (d, 6H, J = 7.2 Hz); ESMS m/e: 476.2 (M + H)+.
Example 137
Figure imgf000104_0001
1-(2-CHLORO-4-FLUOROPHENYL)-/V-(3-{4-[2-FLUORO-5-(ISOBUTYRYLAMINO) PHENYL]-1-PIPERIDINYL}PROPYL)CYCLOPENTANECARBOXAMIDE: Example 137 was prepared from 1-(2-chloro-4-fluorophenyl)cyclopentanecarboxylic acid and N-{3-[1-(3- aminopropyl)-4-piperidinyI]-4-fluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 9: ESMS m/e: 546.1 (M + H)+.
Example 138
Figure imgf000104_0002
1-(2-CHLORO-4-FLUOROPHENYL)-Λ/-(3-{4-[3-(ISOBUTYRYLAMINO)PHENYL]-1-
PIPERIDINYL}PROPYL)CYCLOHEXANECARBOXAMIDE: Example 138 was prepared from 1-(2-chloro-4-fluorophenyl)cyclohexanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4- piperidinyl]phenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCI3) δ 7.52-7.46 (m, 1H), 7.45-7.43 (m, 1H), 7.30 (s, 1H), 7.22 (s, 1H), 7.17 (t, 1H, J = 7.9 Hz), 7.07-7.01 (m, 2H), 6.89-6.84 (m, 1H), 5.99-5.94 (m, 1 H), 3.21 (q, 2H, J = 5.7 Hz), 2.87-2.80 (m, 2H), 2.59-2.49 (m, 1H), 2.44 (septet, 1 H, J = 6.5 Hz), 2.41- 2.40 (m, 2H), 2.26 (t, 2H, J = 5.7 Hz), 2.04-1.96 (m, 2H), 1.93-1.85 (m, 2H), 1.82-171 (m, 4H), 1.64-1.50 (m, 8H), 1.17 (d, 6H, J = 6.5 Hz); ESMS m/e: 542.1 (M + H)+.
Example 139
Figure imgf000104_0003
N-{3-[4-(3-{[(DIMETHYLAMINO)CARBONYL]AMINO}PHENYL)-1-PIPERIDINYL]PROPYL}- 2,2-BIS(4-FLUOROPHENYL)ACETAMIDE: Example 139 was prepared from bis(4-fluoro phenyl)acetic acid and N'-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-N,N-dimethylurea according to the procedures described in Scheme 9: ESMS m/e: 535.4 (M + H)+.
Example 140
Figure imgf000105_0001
Benzyl 3-(1-{3-[(Diphenylacetyl)Amino]Propyl}-4-Piperidinyl)Phenylcarbamate: Example 140 was prepared from diphenylacetyl chloride and benzyl 3-[1-(3-aminopropyl)-4- piperidinyljphenyl carbamate according to the procedures described in Scheme 8: ESMS m/e: 562.5 (M + H)+.
Example 141
Figure imgf000105_0002
Benzyl 3-[1 -(3-{[bis(4-fluorophenyl)acetyl]amino}propyl)-4-piperidinyI]phenylcarbamate:
Example 141 was prepared from bis(4-fluorophenyl)acetic acid and benzyl 3-[1-(3-amino propyl)-4-piperidinyl]phenylcarbamate according to the procedures described in Scheme 9: ESMS m/e: 598.5 (M + H)+.
Example 142
Figure imgf000105_0003
Isopropyl 3-[1-(3-{[2-(4-Chlorophenyl)-2-Methylpropanoyl]Amino}Propyl)-4-Piperidinyl]Phenyl carbamate: Example 142 was prepared from 2-(4-chlorophenyl)-2-methylpropanoic acid and isopropyl 3-[1-(3-aminopropyl)-4-piperidinyl] phenylcarbamate according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCI3) δ 7.29-7.22 (m, 3H), 7.20-7.11 (m, 3H), 7.09-7.06 (m, 1H), 6.79 (d, 1H, J = 7.6 Hz), 6.61 (s, 1H), 6.60-6.50 (m, 1H), 4.94 (septet, 1H, J = 6.7 Hz), 4.05 (q, 1H, J = 6.8 Hz), 3.24 (q, 2H, J = 5.9 Hz), 2.86-279 (m, 2H), 2.36 (tt, 1H, J = 11.9, 3.2 Hz), 2.27 (t, 2H, J = 6.3 Hz), 1.85 (t, 2H, J = 11.9 Hz), 172-1.66 (m, 2H), 1.60- 1.52 (m, 3H), 1.48 (s, 6H), 1.23 (d, 6H, J = 6.7 Hz); ESMS m/e: 500.2 (M + H)+.
Example 143
Figure imgf000106_0001
Isopropyl 3-[1-(3-{[bis(4-chlorophenyl)acetyl]amino}propyl)-4-piperidinyl]phenylcarbamate: Example 143 was prepared from bis(4-chlorophenyl)acetic acid and isopropyl 3-[1-(3- aminopropyl)-4-piperidinyl]phenylcarbamate according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCI3) δ 7.46 (s, 1H), 7.37 (s, 1H), 7.23-7.10 (m, 9H), 7.00 (d, 1 H, J = 7.9 Hz), 6.80 (d, 1H, J = 7.4 Hz), 6.60 (s, 1H), 4.88 (septet, 1H, J = 6.2 Hz), 4.68 (s, 1H), 4.05 (q, 1H, J = 7.3 Hz), 3.32 (q, 2H, J = 5.9 Hz), 2.90-2.83 (m, 2H), 2.44-2.32 (m, 3H), 1.94-1.86 (m, 2H), 178-170 (m, 2H), 1.60 (quintet, 2H, J = 6.4 Hz), 1.56-1.43 ( , 1H), 1.22 (d, 6H, J = 6.2 Hz); ESMS m/e: 582.2 (M + H)+.
Example 144
Figure imgf000106_0002
Isopropyl 3-(1-{3-[(DiphenyIacetyl)Amino]Propyl}-4-Piperidinyl) Phenylcarbamate: Example 144 was prepared from diphenylacetyl chloride and isopropyl 3-[1-(3-aminopropyl)-4- piperidinyl]phenyl carbamate according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCI3) δ 7.25-7.12 (m, 12H), 7.09-7.06 (m, 1H), 7.00-6.94 (m, 1H), 6.79 (d, 1H, J = 7.6 Hz), 6.60(s, 1H), 4.92 (septet, 1H, J = 6.2 Hz), 4.79 (s, 1H), 4.04 (q, 1H, J = 6.4 Hz), 3.30 (q, 2H, J = 5.8 Hz) 2.91-2.83 (m, 2H), 2.42-2.30 (m, 3H), 1.91 (t, 2H, J = 11.4 Hz), 1.74- 1.67 (m, 2H), 1.65-1.51 (m, 3H), 1.21 (d, 6H, J = 6.2 Hz); ESMS m/e: 514.2 (M + H)+.
Example 145
Figure imgf000106_0003
ISOPROPYL 3-[1-(3-{[BIS(4-METHYLPHENYL)ACETYL]AMINO}PROPYL)-4-
PIPERIDINYL]PHENYLCARBAMATE: Example 145 was prepared from bis(4- methylphenyl)acetic acid and isopropyl 3-[1-(3-aminopropyl)-4-piperidinyl]phenylcarbamate according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCI3) δ 7.24 (s, 1H), 7.18-7.06 (m, 4H), 7.06-7.00 (m, 6H), 6.82-678 (m, 2H), 6.62 (s, 1 H), 4.92 (septet, 1 H, J = 6.7 Hz), 4.72 (s, 1H), 4.04 (q, 1H, J = 6.8 Hz), 3.32-3.26 (m, 2H), 2.88-2.81 (m, 2H), 2.41- 2.27 (m, 3H), 2.21 (s, 6H), 1.92-1.83 (m, 2H), 174-1.66 (m, 2H), 1.62-1.46 (m, 3H), 1.21 (d, 6H, J = 6.7 Hz); ESMS m/e: 542.3 (M + H)+. Example 146
Figure imgf000107_0001
ISOPROPYL 3-[1-(3-{[BIS(4-FLUOROPHENYL)ACETYL]AMINO}PROPYL)-4- PIPERIDINYL]PHENYLCARBAMATE: Example 146 was prepared from bis(4-fluoro phenyl)acetic acid and isopropyl 3-[1-(3-aminopropyl)-4-piperidinyl]phenylcarbamate according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCI3) δ 7.43(s, 2H), 7.30-7.19 (m, 4H), 7.11-7.07 (m, 1H), 7.01-6.96 (m, 5H), 6.88 (d, 1H, J = 7.7 Hz), 6.69 (s, 1H), 4.97 (septet, 1 H, J = 6.3 Hz), 4.79 (s, 1H), 4.11 (q, 1H, J = 6.8 Hz), 3.39 (q, 2H, J = 5.6 Hz), 2.98-2.92 (m, 2H), 2.52-2.40 (m, 3H), 1.98 (t, 2H, J = 11.5 Hz), 1.85-178 (m, 2H), 172-1.54 (m, 3H), 1.27 (d, 6H, J = 6.3 Hz); ESMS m/e: 550.3 (M + H)+; Anal. Calc. for C32H37F2N303. 0.87 HCI: C, 66.84; H, 6.61; N, 7.31. Found: C, 66.83; H, 6.48; N, 7.31.
Example 147
Figure imgf000107_0002
ISOPROPYL 3-{1-[3-({[1-(2-CHLORO-4-FLUOROPHENYL)CYCLOHEXYL]CARBONYL} AMINO) PROPYL]-4-PIPERIDINYL}PHENYLCARBAMATE: Example 147 was prepared from 1-(2-chloro-4-fluorophenyl)cyclohexanecarboxylic acid and isopropyl 3-[1-(3-amino propyl)-4- piperidinyl]phenyl carbamate according to the procedures described in Scheme 9: ESMS m/e: 558.1 (M + H)+.
Example 148
Figure imgf000107_0003
N-[4-(1-{3-[(DIPHENYLACETYL)AMINO]PROPYL}-4-PIPE IDINYL)PHENYL]-2-METHYL PROPANAMIDE: Example 148 was prepared from N-(3-bromopropyl)-2,2-diphenyl acetamide and 2-methyl-N-[4-(4-piperidinyl) phenyl] propanamide according to the procedures described in Scheme 14: ESMS m/e: 498.3 (M + H)+.
Example 149
Figure imgf000108_0001
N-[4-(1-{3-[(2,2-DIPHENYLACETYL)AMINO]PROPYL}-4-PIPERIDINYL)PHENYL]BUTAN AMIDE: Example 149 was prepared from N-(3-bromopropyl)-2,2-diphenylacetamide and N- [4-(4-piperidinyl)phenyl]butanamide according to the procedures described in Scheme 14: ESMS m/e: 498.3 (M + H)+.
Example 150
Figure imgf000108_0002
Λ/-[5-(1-{3-[(DIPHENYLACETYL)AMINO]PROPYL}-4-PIPERIDINYL)-2-HYDROXYPHENYL]- 2-METHYLPROPANAMIDE: Example 150 was prepared from diphenylacetyl chloride and N- {5-[1-(3-aminopropyl)-4-piperidinyl]-2-hydroxyphenyl}-2-methylpropanamide according to the procedures described in Scheme 8: 1H NMR (400 MHz, CDCI3) δ 8.18 (s, 1H), 7.30-7.11 (m, 10H), 7.10-6.9 (m, 2H), 674 (d, 1 H, J = 8.3 Hz), 6.63 (dd, 1 H, J = 8.3, 2.0 Hz), 4.93 (s, 1H), 3.51 (t, 1H, J = 5.4 Hz), 3.36 (quintet, 1 H, J = 6.5 Hz), 3.24-3.18 (m, 2H), 3.07-3.00 (m, 2H), 2.54-2.45 (m, 3H), 2.37-2.28 (m, 1H), 2.19-2.09 (m, 2H), 179-1.54 ( , 4H), 1.25 (d, 6H, J = 6.8 Hz); ESMS m/e: 514.3 (M + H)+.
Example 151
Figure imgf000108_0003
N-[3-(1-{3-[(3,3-DIPHENYLPROPANOYL)AMINO]PROPYL}-4-PIPERIDINYL)PHENYL]
CYCLOPROPANECARBOXAMIDE: Example 151 was prepared from 3,3-diphenylpropanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl] phenyl}cyclopropane carboxamide according to the procedures described in Scheme 9: ESMS m/e: 510.4 (M + H)+.
Example 152
Figure imgf000108_0004
N-{3-[4-(3-AMINOPHENYL)-1-PIPERIDINYL]PROPYL}-2,2-DIPHENYLACETAMIDE: Example 152 was prepared via hydrogenation of benzyl 3-(1-{3-[(diphenylacetyl)amino] propyl}-4-piperidinyl)phenylcarbamate according to the procedures described in Scheme 15: ESMS m/e: 428.3 (M + H)+.
Example 153
Figure imgf000109_0001
Λ/-{3-[1-(3-{[(3,4-difluorophenyl)(hydroxy)acetyl]amino}propyl)-4-piperidinyl]-4-methylphenyl}- 2-methylpropanamide: Example 153 was prepared from (3,4-difluorophenyl)(hydroxy)acetic acid and N-{3-[1 -(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 12: ESMS m/e: 488.3 (M + H)+.
Example 154
Figure imgf000109_0002
N-{3-[1-(3-{[hydroxy(diphenyl)acetyl]amino}propyl)-4-piperidinyl]-4-methylphenyl}-2-methyl propanamide: A mixture of hydroxy(diphenyl)acetic acid (100 mg, 0.44 mmol) and 1 ,1'- carbonyldiimidazole (78 mg, 0.48 mmol) in CH2CI2 (5 mL) was stirred at room temperature for 3 h, then a solution of N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methyl propanamide (140 mg, 0.44 mmol) in CH2CI2 (5 mL) was added. The resulting mixture was stirred at room temperature for overnight, evaporated in vacuo, and dissolved in a mixture of EtOAc and 1N NaOH. The organic layer was separated, washed twice with water, dried over MgS0 and concentrated. The residue was purified over preparative TLC (10% 2M NH3/MeOH in 50%EtOAc/ hexane) to give 111 mg (0.21 mmol, 48%) of (N-{3-[1-(3- {[hydroxy(diphe'nyl)acetyl]amino}propyl)-4-piperidinyl]-4-methylphenyl}-2- methylpropanamide: 1H NMR (400 MHz, CDCI3) δ 9.22 (s, 1 H), 8.14 (s, 1 H), 7.80 (s, 1 H), 7.64-7.48 (m, 4 H), 7.32-7.16 (m, 6 H), 6.95 (d, 1 H, J = 8.0 Hz), 6.64 (d, 1 H, J = 8.0 Hz), 5.83-5.62 (br, 1 H), 3.54-3.38 (m, 2 H), 3.11-2.94 (m, 2 H), 279-2.59 (m, 1 H), 2.57-2.41 (m, 2 H), 2.26 (s, 3 H), 2.29-2.16 (m, 1 H), 2.16-1.91 (m, 4 H), 174-1.53 (m, 4 H), 0.86 (d, 6 H, J = 6.8 Hz); ESMS m/e: 528.4 (M + H)+.
Example 155
Figure imgf000109_0003
N-{2,4-difluoro-5-[1-(3-{[hydroxy(diphenyl)acetyl]amino}propyl)-4-piperidinyl]phenyl}-2-methyl propanamide: Example 155 was prepared from hydroxy(diphenyl)acetic acid and N-{5-[1-(3- aminopropyl)-4-piperidinyl]-2,4-difluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 12: 1H NMR (400 MHz, CDCI3) δ 8.96 (s, 1 H), 8.39 (t, 1 H, J = 8.4 Hz), 7.62-7.45 (m, 4 H), 7.38-7.18 (m, 7 H), 6.85-674 (m, 1 H), 5.43-5.14 (br, 1 H), 3.59-3.39 (m, 2 H), 3.11-2.97 (m, 2 H), 2.97-279 (m, 1 H), 2.59-2.45 (m, 2 H), 2.45-2.29 (m, 1 H), 2.14-1.86 (m, 4 H), 1.81-1.56 (m, 4 H), 1.01 (d, 6 H, J = 7.2 Hz); ESMS m/e: 550.4 (M + H)+.
Example 156
Figure imgf000110_0001
N-{3-[1-(3-{[bis(4-fluorophenyl)(hydroxy)acetyl]amino}propyI)-4-piperidinyl]-4-methylphenyl}- 2-methylpropanamide: Example 156 was prepared from bis(4-fluorophenyl)(hydroxy)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl} -2-methylpropanamide according to the procedures described in Scheme 12: 1H NMR (400 MHz, CDCI3) δ 9.44 (s, br, 1 H), 8.18 (s, 1 H), 7.62-7.48 (m, 4 H), 7.32 (s, 1 H), 7.07-7.00 (m, 1 H), 7.00-6.89 (m, 4 H), 672-6.53 (m, 1 H), 5.96-571 (br, 1 H), 3.55-3.44 (m, 2 H), 3.14-3.02 (m, 2 H), 2.83-2.66 (m, 1 H), 2.63-2.49 (m, 2 H), 2.39-2.22 (m, 1 H), 2.29 (s, 3 H), 2.17-1.98 (m, 4 H), 178-1.59 (m, 4 H), 0.92 (d, 6 H, J = 6.8 Hz); ESMS m/e: 564.4 (M + H)+.
Example 157
Figure imgf000110_0002
N-(3-{1-[3-({hydroxy[bis(4-methylphenyl)]acetyl}amino)propyl]-4-piperidinyl}-4-methylphenyl)- 2-methylpropanamide: Example 157 was prepared from hydroxy[bis(4-methylphenyl)]acetic acid and N-{3-[1-(3-aminopropyI)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 12: 1H NMR (400 MHz, CDCI3) δ 8.80-8.59 (s, br, 1 H), 7.91 (s, 1 H), 7.42 (d, 4 H, J = 8.4 Hz), 7.15 (s, 1 H), 7.09 (d, 4 H, J = 8.0 Hz), 7.04 (d, 1 H, J = 8.0 Hz), 6.96-678 (br, 1 H), 5.30-5.05 (br, 1 H), 3.55-3.41 (m, 2 H), 3.15- 3.00 (m, 2 H), 2.82-2.64 (m, 1 H), 2.59-2.46 (m, 2 H), 2.40-2.27 (m, 1 H), 2.30 (s, 6 H), 2.28 (s, 3 H), 2.17-1.95 (m, 4 H), 1.83-1.56 (m, 4 H), 1.02 (d, 6 H, J = 6.8 Hz); ESMS m/e: 556.4 (M + H)+. Example 158
N-{3-[1-(3-{[bis(2-chlorophenyl)(hydroxy)acetyl]amino}propyl)-4-piperidinyl]-4-methylphenyl}- 2-methylpropanamide: Example 158 was prepared from bis(2-chlorophenyl)(hydroxy)acetic acid and N-{3-[1 -(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 12: 1H NMR (400 MHz, CDCI3) δ 8.33 (s, 1 H), 7.43-7.18 (m, 11 H), 7.05 (d, 1 H, J = 8.0 Hz), 5.03 (s, 1 H), 3.60-3.49 (m, 2 H), 3.03-2.91 (m, 2 H), 271-2.54 (m, 1 H), 2.54-2.37 (m, 3 H), 2.25 (s, 3 H), 2.08-1.91 (m, 2 H), 1.84-1.63 (m, 4 H), 1.63-1.50 (m, 2 H), 1.17 (d, 6 H, J = 6.8 Hz); ESMS m/e: 596.3 (M + H)+.
Example 159
Figure imgf000111_0002
N-(2,4-difluoro-5-{1-[3-({hydroxy[bis(4-methylphenyl)]acetyl}amino)propyl]-4-piperidinyl} phenyl)-2-methylpropanamide: Example 159 was prepared from hydroxy[bis(4- methylphenyl)]acetic acid and N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2,4-difluorophenyl}-2- methylpropanamide according to the procedures described in Scheme 12: 1H NMR (400 MHz, CDCI3) δ 878-8.62 (s, br, 1 H), 8.37 (t, 1 H, J = 9.6 Hz), 7.40 (d, 4 H, J = 8.4 Hz), 7.28 (s, 1 H), 7.09 (d, 4 H, J = 8.0 Hz), 6.84-674 (m, 1 H), 5.14-4.82 (br, 1 H), 3.55-3.40 (m, 2 H), 3.11-2.94 (m, 2 H), 2.94-278 (m, 1 H), 2.59-2.46 (m, 2 H), 2.46-2.36 (m, 1 H), 2.31 (s, 6 H), 2.11-1.91 (m, 4 H), 177-1.61 (m, 4 H), 1.04 (d, 6 H, J = 7.2 Hz); ESMS m/e: 578.4 (M + H)+.
Example 160
Figure imgf000111_0003
N-{5-[1-(3-{[bis(4-fluorophenyl)(hydroxy)acetyl]amino}propyl)-4-piperidinyl]-2,4-difluoro phenyl}-2-methylpropanamide: Example 160 was prepared from bis(4-fluoro phenyl) (hydroxy)acetic acid and N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2,4-difluoro phenyl}-2-methyl propanamide according to the procedures described in Scheme 12: 1H NMR (400 MHz, CDCI3) δ 9.31 (s, br, 1 H), 8.44-8.33 (m, 1 H), 7.59-7.45 (m, 4 H), 7.39 (s, 1 H), 6.97 (t, 4 H, J = 8.8 Hz), 6.80 (t, 1 H, J = 9.6 Hz), 5.61-5.36 (br, 1 H), 3.57-3.43 (m, 2 H), 3.14-2.99 (m, 2 H), 2.99-2.84 (m, 1 H), 2.62-2.47 (m, 2 H), 2.47-2.29 (m, 1 H), 2.14-1.93 (m, 4 H), 1.81-1.59 (m, 4 H), 0.98 (apparent t, 6 H, J = 6.8 Hz); ESMS m/e: 586.3 (M + H)+. Example 161
Figure imgf000112_0001
2-methyl-N-{4-methyl-3-[1-(3-{[(2S)-2-phenylpropanoyl]amino}propyl)-4-piperidinyl]phenyl} propanamide: Example 161 was prepared from (2S)-2-phenylpropanoic acid and N-{3-[1-(3- aminopropyl)-4-piperidinyl]-4-methyIphenyl}-2-methylpropanamide according to the procedures described in Scheme 12: 1H NMR (400 MHz, CDCI3) δ 7.61 (s, 1 H), 7.47-7.38 (m, 1 H), 7.37-7.26 (m, 5 H), 7.26-7.18 (m, 1 H), 7.06 (d, 1 H, J = 8.0 Hz), 674-6.64 (m, 1 H), 3.64-3.50 (m, 1 H), 3.38-3.23 (m, 2 H), 2.92 (ABq, 2 H), 270-2.58 (m, 1 H), 2.58-2.42 (m, 1 H), 2.33 (t, 2 H, J = 6.4 Hz), 2.26 (s, 3 H), 2.02-1.88 (m, 2 H), 176-1.55 (m, 6 H), 1.53 (d, 3 H, J = 7.2 Hz), 1.22 (d, 6 H, J = 6.8 Hz); ESMS m/e: 450.2 (M + H)+; HCI salt of 2-methyl-N- {4-methyl-3-[1-(3-{[(2S)-2-phenyl propanoyljamino} propyl)-4-piperidinyl]phenyl}propanamide [α]D = + 22.3° (C=1 , MeOH)
Example 162
Figure imgf000112_0002
(2R)-N-(3-{4-[5-(isobutyrylamino)-2-methylphenyl]-1-piperidinyl}propyl)-2-phenylbutan amide: Example 162 was prepared from (2R)-2-phenylbutanoic acid and N-{3-[1-(3-amino propyl)-4- piperidinyl]-4-methylphenyl}-2-methylpropanamide according procedures described in Scheme 12; ESMS m/e: 464.3 (M + H)+; HCI salt of (2R)-N-(3-{4-[5-(isobutyryl amino)-2- methylphenyl]-1-piperidinyl}propyl)-2-phenylbutanamide [α]D = - 24.5° (C=1.1 , MeOH)
Example 163
Figure imgf000112_0003
(2S)-N-(3-{4-[5-(isobutyrylamino)-2-methylphenyl]-1-piperidinyl}propyl)-2-phenylbutanamide: Example 163 was prepared from (2S)-2-phenylbutanoic acid and N-{3-[1-(3-aminopropyl)-4- piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 12; ESMS m/e: 464.4 (M + H)+; HCI salt of (2S)-N-(3-{4-[5-(isobutyrylamino)-2- methylphenyl]-1-piperidinyl}propyl)-2-phenylbutanamide [α]D = + 25.0° (C=1, MeOH)
Example 164
Figure imgf000113_0001
2-methyl-N-{4-methyl-3-[1-(3-{[(2R)-2-phenylpropanoyl]amino}propyl)-4-piperidinyl]phenyl} propanamide: Example 164 was prepared from (2R)-2-phenylpropanoic acid and N-{3-[1-(3- aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 12: 1H NMR (400 MHz, CDCI3) δ 7.63 (s, 1 H), 7.44 (d, 1 H, J = 2.0 Hz), 7.38-7.26 (m, 5 H), 7.26-7.18 (m, 1 H), 7.06 (d, 1 H, J = 8.0 Hz), 674-6.63 (m, 1 H), 3.63-3.49 (m, 1 H), 3.38-3.23 (m, 2 H), 2.91 (ABq, 2 H), 271-2.58 (m, 1 H), 2.58-2.45 (m, 1 H), 2.32 (t, 2 H, J = 6.4 Hz), 2.26 (s, 3 H), 2.05-1.87 (m, 2 H), 177-1.55 (m, 6 H), 1.53 (d, 3 H, J = 7.2 Hz), 1.22 (d, 6 H, J = 6.8 Hz); ESMS m/e: 450.4 (M + H)+; HCI salt of 2-methyl-N- {4-methyl-3-[1 -(3-{[(2R)-2-phenylpropanoyl]amino}propyl)-4-piperidinyl]phenyl} propanamide [α]D = - 34.3° (C=1 , MeOH)
Example 165
Figure imgf000113_0002
N-{5-[1-(3-{[bis(4-fluorophenyl)acetyl]amino}propyl)-4-piperidinyl]-2,4-difluorophenyl}-2- methylpropanamide: Example 165 was prepared from bis(4-fluorophenyl)acetic acid and N- {5-[1-(3-aminopropyl)-4-piperidinyl]-2,4-difluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCI3) δ 8.25 (t, 1 H, J = 8.4 Hz), 7.67-7.57 (m, 1 H), 7.51 (s, 1 H), 7.36-7.25 (m, 4 H), 7.03-6.91 (m, 4 H), 6.81 (t, 1 H, J = 9.6 Hz), 4.81 (s, 1 H), 3.45-3.31 (m, 2 H), 2.92 (m, 2 H), 2.83-2.67 (m, 1 H), 2.63-2.47 (m, 1 H), 2.47-2.33 (m, 2 H), 2.05-1.90 (m, 2 H), 1.82-172 (m, 2 H), 172-1.56 (m, 4 H), 1.22 (d, 6 H, J = 6.8 Hz); ESMS m/e: 570.2 (M + H)+.
Example 166
Figure imgf000113_0003
(2S)-2-(4-chlorophenyl)-N-(3-{4-[5-(isobutyrylamino)-2-methylphenyl]-1-piperidinyl}propyl) propanamide: Example 166 was prepared from (2S)-2-(4-chlorophenyl)propanoic acid and N-{3-[1 -(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 12; [α]D = + 5.2° (C=1.03, MeOH): 1H NMR (400 MHz, CDCI3) δ 7.55 (d, 1 H, J = 2.0 Hz), 7.46 (s, 1 H), 7.34-7.24 (m, 4 H), 7.23-7.17 (m, 1 H), 7.07 (d, 1 H, J = 8.0 Hz), 7.04-6.97 (m, 1 H), 3.54 (q, 1 H, J =7.2 Hz), 3.41-3.24 (m, 2 H), 2.95 (ABq, 2 H), 272-2.59 (m, 1 H), 2.57-2.45 (m, 1 H), 2.42-2.37 (m, 2 H), 2.27 (s, 3 H), 2.05- 1.91 (m, 2 H), 1.82-1.55 (m, 6 H), 1.50 (d, 3 H, J = 6.8 Hz), 1.22 (d, 6 H, J = 6.8 Hz); ESMS m/e: 484.3 (M + H)+.
Example 167
Figure imgf000114_0001
(2R)-2-(4-chlorophenyl)-N-(3-{4-[5-(isobutyrylamino)-2-methylphenyl]-1-piperidinyl}propyl) propanamide: Example 167 was prepared from (2R)-2-(4-chlorophenyl)propanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 12; [α]D = - 9.3° (C=1.65, MeOH): 1H NMR (400 MHz, CDCI3) δ 7.55 (s, 1 H), 7.36-7.24 (m, 4 H), 7.22-7.12 (m, 2 H), 7.08 (d, 1 H, J = 8.0 Hz), 6.92 (s, 1 H), 3.53 (q, 1 H, J = 7.2 Hz), 3.42-3.23 (m, 2 H), 2.95 (ABq, 2 H), 273-2.59 (m, 1 H), 2.57-2.43 (m, 1 H), 2.42-2.33 (m, 2 H), 2.28 (s, 3 H), 2.08-1.92 (m, 2 H), 1.86-1.56 (m, 6 H), 1.51 (d, 3 H, J = 7.2 Hz), 1.24 (d, 6 H, J = 6.8 Hz); ESMS m/e: 484.3 (M + H)+.
Example 168
Figure imgf000114_0002
-2-(4-fluorophenyl)-N-(3-{4-[5-(isobutyrylamino)-2-methylphenyl]-1-piperidinyl}propyl) propanamide: Example 168 was prepared from (2S)-2-(4-fluorophenyl)propanoic acid and N- {3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 12; [α]D = + 13.5° (C=1.02, MeOH): 1H NMR (400 MHz, CDCI3) δ 7.58-7.49 (m, 2 H), 7.37-7.29 (m, 2 H), 7.26-7.19 (m, 1 H), 7.06 (d, 1 H, J = 8.0 Hz), 7.04-6.92 (m, 3 H), 3.56 (t, 1 H, J = 6.8 Hz), 3.43-3.23 (m, 2 H), 2.95 (ABq, 2 H), 2.63-2.59 (m, 1 H), 2.59-2.45 (m, 1 H), 2.37 (t, 2 H, J = 6.0 Hz), 2.27 (s, 3 H), 2.07-1.90 (m, 2 H), 1.82- 1.57 (m, 6 H), 1.50 (d, 3 H, J = 7.2 Hz), 1.22 (d, 6 H, J = 7.2 Hz); ESMS m/e: 468.3 (M + H)+.
Example 169
Figure imgf000114_0003
(2R)-2-(4-fluorophenyl)-N-(3-{4-[5-(isobutyrylamino)-2-methylphenyl]-1-piperidinyl}propyl) propanamide: Example 169 was prepared from (2R)-2-(4-fluorophenyl)propanoic acid and N- {3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 12; [α]D = - 9.1° (C=1.65, MeOH): 1H NMR (400 MHz, CDCI3) δ 7.51 (d, 1 H, J = 2.0 Hz), 7.37-7.28 (m, 2 H), 7.23-7.14 (m, 2 H), 7.08 (d, 1 H, J = 8.0 Hz), 7.05-6.96 (m, 2 H), 6.90-6.82 (m, 1 H), 3.54 (q, 1 H, J = 7.2 Hz), 3.43-3.23 (m, 2 H), 2.95 (ABq, 2 H), 273-2.59 (m, 1 H), 2.57-2.42 (m, 1 H), 2.42-2.32 (m, 2 H), 2.28 (s, 3 H), 2.07-1.91 (m, 2 H), 1.83-1.57 (m, 6 H), 1.51 (d, 3 H, J = 7.2 Hz), 1.23 (d, 6 H, J = 6.8 Hz); ESMS m/e: 468.3 (M + H)+.
Example 170
Figure imgf000115_0001
N-[5-(1-{3-[(diphenylacetyl)amino]propyl}-4-piperidinyl)-3-pyridinyl]-2-methyl propanamide: Example 170 was prepared from N-(3-bromopropyl)-2,2-diphenylacetamide and 2-methyl-N- [5-(4-piperidinyl)-3-pyridinyl]propanamide according to the procedures described in Scheme 14: 1H NMR (400 MHz, CDCI3) δ 8.47-8.42 (m, 1 H), 8.21-8.16 (m, 1 H), 8.09 (s, 1 H), 7.59 (s, 1 H), 7.35-7.20 (m, 10 H), 6.87 (s, 1 H), 4.91 (s, 1 H), 3.46-3.36 (m, 2 H), 3.01-2.92 (m, 2 H), 2.62-2.47 (m, 2 H), 2.47-2.37 (m, 2 H), 2.11-1.94 (m, 4 H), 1.86-1.59 (m, 4 H), 1.25 (d, 6 H, J = 7.2 Hz); ESMS m/e: 499.4 (M + H)+.
Example 171
Figure imgf000115_0002
N-[3-(1-{3-[(diphenylacetyl)amino]propyl}-4-piperidinyl)-2,4,6-trifluorophenyl]-2-methylpropan amide: Example 171 was prepared from N-(3-bromopropyl)-2,2-diphenylacetamide and 2- methyl-N-[2,4,6-trifluoro-3-(4-piperidinyl)phenyl]propanamide according to the procedures described in Scheme 14; ESMS m/e: 552.3 (M + H)+.
Example 172
Figure imgf000115_0003
N-{5-[1-(3-{[bis(4-fluorophenyl)acetyl]amino}propyl)-4-piperidinyl]-3-pyridinyl}-2-methyl propanamide: Example 172 was prepared from N-(3-bromopropyl)-2,2-bis(4-fluoro phenyl) acetamide and 2-methyl-N-[5-(4-piperidinyl)-3-pyridinyl]propanamide according to the procedures described in Scheme 14: 1H NMR (400 MHz, CDCI3) δ 8.39 (s, 1 H), 8.19 (s, 1 H), 8.17 (S, 1 H), 7.95 (s, 1 H), 7.31-7.20 (m, 5 H), 7.04-6.94 (m, 4 H), 4.82 (s, 1 H), 3.46- 3.35 (m, 2 H), 2.98-2.92 (m, 2 H), 2.62-2.48 (m, 2 H), 2.48-2.38 (m, 2 H), 2.09-1.95 (m, 2 H), 1.87-176 (m, 2 H), 176-1.55 (m, 4 H), 1.25 (d, 6 H, J = 7.6 Hz); ESMS m/e: 535.4 (M + H)+.
Example 173
Figure imgf000116_0001
N-{3-[1-(3-{[bis(4-fluorophenyl)acetyl]amino}propyl)-4-piperidinyl]-2,4,6-trifluorophenyl}-2- methylpropanamide: Example 173 was prepared from N-(3-bromopropyl)-2,2-bis(4-fluoro phenyl)acetamide and 2-methyl-N-[2,4,6-trifluoro-3-(4-piperidinyl)phenyl]propanamide according to the procedures described in Scheme 14; ESMS m/e: 588.3 (M + H)+.
Example 174
Figure imgf000116_0002
N-{3-[1 -(3-{[amino(diphenyl)acetyl]amino}propyl)-4-piperidinyl]-4-fluorophenyl} cyclopropane carboxamide: Example 174 was prepared from amino(diphenyl)acetic acid and Λ/-{3-[1-(3- aminopropyl)-4-piperidinyl]-4-fluorophenyl} cyclopropanecarboxamide according to the procedures described in Scheme 12; ESMS m/e: 529.4 (M + H)+.
Example 175
Figure imgf000116_0003
N-{3-[1-(3-{[(4-fluorophenyl)acetyl]amino}propyl)-4-piperidinyl]-4-methylphenyl}-2-methyl propanamide: Example 175 was prepared from (4-fluorophenyl)acetic acid and N-{3-[1-(3- aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 12: 1H NMR (400 MHz, CDCI3) δ 7.38 (s, 1 H), 7.32 (s, 1 H), 7.28-7.16 (m, 3 H), 7.04-6.90 (m, 3 H), 6.86 (s, 1 H), 3.47 (s, 2 H), 3.27 (q, 2 H, J = 6.0 Hz), 2.95 (d, 2 H, J = 11.6 Hz), 2.69-2.53 (m, 1 H), 2.50-2.32 (m, 3 H), 2.19 (s, 3 H), 2.09- 1.94 (m, 2 H), 174-1.53 (m, 6 H), 1.15 (d, 6 H, J = 7.2 Hz); ESMS m/e: 454.3 (M + H)+. Example 176
Figure imgf000117_0001
Λ/-{5-[1-(3-{[hydroxy(diphenyl)acetyl]amino}propyl)-4-piperidinyl]-3-pyridinyl}-2-methyl propanamide: Example 176 was prepared from hydroxy(diphenyl)acetic acid and Λ/-{5-[1-(3- aminopropyl)-4-piperidinyl]-3-pyridinyl}-2-methylpropanamide according procedures described in Scheme 12; ESMS m/e: 515.4 (M + H)+.
Example 177
Figure imgf000117_0002
Λ/-{5-[1-(3-{[bis(4-fluorophenyl)(hydroxy)acetyl]amino}propyl)-4-piperidinyl]-3-pyridinyl}-2- methylpropanamide: Example 177 was prepared from bis(4-fluorophenyl) (hydroxy)acetic acid and Λ/-{5-[1-(3-aminopropyl)-4-piperidinyl]-3-pyridinyl}-2-methylpropan amide according procedures described in Scheme 12; ESMS m/e: 551.3 (M + H)+.
Example 178
Figure imgf000117_0003
Λ/-(5-{1-[3-({hydroxy[bis(4-methylphenyl)]acetyl}amino)propyl]-4-piperidinyl}-3-pyridinyl)-2- methylpropanamide: Example 178 was prepared from hydroxy[bis(4-methylphenyl)]acetic acid and Λ/-{5-[1-(3-aminopropyl)-4-piperidinyl]-3-pyridinyl}-2-methyl propanamide according procedures described in Scheme 12; ESMS m/e: 543.4 (M + H)+.
II. Synthetic Methods for General Structures
The examples described in the experimental section are merely illustrative of the methods used to synthesize MCH1 antagonists. Additional compounds of the invention can be obtained by the general synthetic procedures described herein or by incorporating variations into these methods. |t may ^e necessary o incorporate protection and deprotection strategies into the generalized synthetic methods in order to synthesize additional examples containing potentially reactive substituents such as amino, amido, carboxylic acid, and hydroxyl groups. Methods for protection and deprotection of such groups are well-known in the art, and may be found, for example in Green, T.VV. and Wuts, P.G.M. (1991) Protection Groups in Organic Synthesis. 2nd Edition John Wiley & Sons, New York.
HI. Oral Compositions
As a specific embodiment of an oral composition of a compound of this invention, 100 mg of one of the compounds described herein is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 hard gel capsule.
IV. Pharmacological Evaluation of Compounds at Cloned rat MCH1 Receptor
The pharmacological properties of the compounds of the present invention were evaluated at the cloned rat MCH1 receptor using the protocols described below.
Host Cells
A broad variety of host cells can be used to study heterologously expressed proteins. These cells include but are not restricted to assorted mammalian lines such as: Cos-7, CHO, LM(tk- ), HEK293, Peak rapid 293, etc.; insect cell lines such as: Sf9, Sf21, etc.; amphibian cells such as xenopus oocytes; and others. COS 7 cells are grown on 150 mm plates in DMEM with supplements (Dulbecco's Modified Eagle Medium with 10% bovine calf serum, 4 mM glutamine, 100 units/ml penicillin/100 Fg/ml streptomycin) at 37°C, 5% C02. Stock plates of COS-7 cells are trypsinized and split 1:6 every 3-4 days. Human embryonic kidney 293 cells are grown on 150 mm plates in DMEM with supplements (10% bovine calf serum, 4 mM glutamine, 100 units/ml penicillin/100 Fg/ml streptomycin) at 37°C, 5% C02. Stock plates of 293 cells are trypsinized and split 1 :6 every 3-4 days.
Human embryonic kidney Peak rapid 293 (Peakr293) cells are grown on 150 mm plates in DMEM with supplements (10% fetal bovine serum, 10% L-glutamine, 50 Fg/ml gentamycin) at 37°C, 5% C02. Stock plates of Peak rapid 293 cells are trypsinized and split 1 :12 every 3- 4 days. Mouse fibroblast LM(tk-) cells are grown on 150 mm plates in DMEM with supplements (Dulbecco's Modified Eagle Medium with 10% bovine calf serum, 4 mM glutamine, 100 units/ml penicillin/100 Fg/ml streptomycin) at 37°C, 5% C02. Stock plates of LM(tk-) cells are trypsinized and split 1:10 every 3-4 days. Chinese hamster ovary (CHO) cells were grown on 150 mm plates in HAM=s F-12 medium with supplements (10% bovine calf serum, 4 mM L-glutamine and 100 units/ml penicillin/ 100 Fg/ml streptomycin) at 37°C, 5% C02. Stock plates of CHO cells are trypsinized and split 1:8 every 3-4 days. Mouse embryonic fibroblast NIH-3T3 cells are grown on 150 mm plates in Dulbecco=s Modified Eagle Medium (DMEM) with supplements (10% bovine calf serum, 4 mM glutamine, 100 units/ml penicillin/100 Fg/ml streptomycin) at 37°C, 5% CO2. Stock plates of NIH-3T3 cells are trypsinized and split 1 :15 every 3-4 days. Sf9 and Sf21 cells are grown in monolayers on 150 mm tissue culture dishes in TMN-FH media supplemented with 10% fetal calf serum, at 27°C, no C02. High Five insect cells are grown on 150 mm tissue culture dishes in Ex-Cell 400™ medium supplemented with L-Glutamine, also at 27°C, no C02. In some cases, cell lines that grow as adherent monolayers can be converted to suspension culture to increase cell yield and provide large batches of uniform assay material for routine receptor screening projects.
Transient expression
DNA encoding proteins to be studied can be transiently expressed in a variety of mammalian, insect, amphibian and other cell lines by several methods including but not restricted to; calcium phosphate-mediated, DEAE-dextran mediated, Liposomal-mediated, viral-mediated, electroporation-mediated and microinjection delivery. Each of these methods may require optimization of assorted experimental parameters depending on the DNA, cell line, and the type of assay to be subsequently employed. A typical protocol for the calcium phosphate method as applied to Peak rapid 293 cells is described as follows: Adherent cells are harvested approximately twenty-four hours before transfection and replated at a density of 3.5 x 106 cells/dish in a 150 mm tissue culture dish and allowed to incubate over night at
37°C at 5% C02. 250 FI of a mixture of CaCI2 and DNA (15 Fg DNA in 250 mM CaCI2) is added to a 5 ml plastic tube and 500 FI of 2X HBS (280 mM NaCl, 10 mM KCI, 1.5 mM Na2HP04, 12 mM dextrose, 50 mM HEPES) is slowly added with gentle mixing. The mixture is allowed to incubate for 20 minutes at room temperature to allow a DNA precipitate to form. The DNA precipitate mixture is then added to the culture medium in each plate and incubated for 5 hours at 37°C, 5% C02. After the incubation, 5ml of culture medium (DMEM, 10% FBS, 10% L-glut and 50 μg/ml gentamycin) is added to each plate. The cells are then incubated for 24 to 48 hours at 37°C, 5% C02. A typical protocol for the DEAE-dextran method as applied to Cos-7 cells is described as follows; Cells to be used for transfection are split 24 hours prior to the transfection to provide flasks which are 70-80% confluent at the time of transfection. Briefly, 8 Fg of receptor DNA plus 8 Fg of any additional DNA needed (e.g. Gα protein expression vector, reporter construct, antibiotic resistance marker, mock vector, etc.) are added to 9 ml of complete DMEM plus DEAE-dextran mixture (10 mg/ml in PBS). Cos-7 cells plated into a T225 flask (sub-confluent) are washed once with PBS and the DNA mixture is added to each flask. The cells are allowed to incubate for 30 minutes at 37°C, 5% C02. Following the incubation, 36 ml of complete DMEM with 80 FM chloroquine is added to each flask and allowed to incubate an additional 3 hours. The medium is then aspirated and 24 ml of complete medium containing 10% DMSO for exactly 2 minutes and then aspirated. The cells are then washed 2 times with PBS and 30 ml of complete DMEM added to each flask. The cells are then allowed to incubate over night. The next day the cells are harvested by trypsinization and reseeded as needed depending upon the type of assay to be performed.
A typical protocol for liposomal-mediated transfection as applied to CHO cells is described as follows; Cells to be used for transfection are split 24 hours prior to the transfection to provide flasks which are 70-80% confluent at the time of transfection. A total of 10Fg of DNA which may include varying ratios of receptor DNA plus any additional DNA needed (e.g. Gα protein expression vector, reporter construct, antibiotic resistance marker, mock vector, etc.) is used to transfect each 75 cm2 flask of cells. Liposomal mediated transfection is carried out according to the manufacturer's recommendations (LipofectAMINE, GibcoBRL, Bethesda, MD). Transfected cells are harvested 24 hours post transfection and used or reseeded according the requirements of the assay to be employed. A typical protocol for the electroporation method as applied to Cos-7 cells is described as follows; Cells to be used for transfection are split 24 hours prior to the transfection to provide flasks which are subconfluent at the time of transfection. The cells are harvested by trypsinization resuspended in their growth media and counted. 4 x 106 cells are suspended in 300 FI of DMEM and placed into an electroporation cuvette. 8 Fg of receptor DNA plus 8 Fg of any additional DNA needed (e.g. Gα protein expression vector, reporter construct, antibiotic resistance marker, mock vector, etc.) is added to the cell suspension, the cuvette is placed into a BioRad Gene Pulser and subjected to an electrical pulse (Gene Pulser settings: 0.25 kV voltage, 950 FF capacitance). Following the pulse, 800 FI of complete DMEM is added to each cuvette and the suspension transferred to a sterile tube. Complete medium is added to each tube to bring the final cell concentration to 1 x 105 cells/100 FI. The cells are then plated as needed depending upon the type of assay to be performed.
A typical protocol for viral mediated expression of heterologous proteins is described as follows for baculovirus infection of insect Sf9 cells. The coding region of DNA encoding the receptor disclosed herein may be subcloned into pBlueBaclll into existing restriction sites or sites engineered into sequences 5' and 3' to the coding region of the polypeptides. To generate baculovirus, 0.5 Fg of viral DNA (BaculoGold) and 3 Fg of DNA construct encoding a polypeptide may be co-transfected into 2 x 106 Spodoptera frugiperda insect Sf9 cells by the calcium phosphate co-precipitation method, as outlined in by Pharmingen (in "Baculovirus Expression Vector System: Procedures and Methods Manual"). The cells then are incubated for 5 days at 27°C. The supernatant of the co-transfection plate may be collected by cenfrifugation and the recombinant virus plaque purified. The procedure to infect cells with virus, to prepare stocks of virus and to titer the virus stocks are as described in Pharmingen=s manual. Similar principals would in general apply to mammalian cell expression via retro-viruses, Simliki forest virus and double stranded DNA viruses such as adeno-, herpes-, and vacinia-viruses, and the like.
Stable expression
Heterologous DNA can be stably incorporated into host cells, causing the cell to perpetually express a foreign protein. Methods for the delivery of the DNA into the cell are similar to those described above for transient expression but require the co-transfection of an ancillary gene to confer drug resistance on the targeted host cell. The ensuing drug resistance can be exploited to select and maintain cells that have taken up the heterologous DNA. An assortment of resistance genes are available including but not restricted to Neomycin, Kanamycin, and Hygromycin. For the purposes of receptor studies, stable expression of a heterologous receptor protein is carried out in, but not necessarily restricted to, mammalian cells including, CHO, HEK293, LM(tk-), etc.
Cell membrane preparation
For binding assays, pellets of transfected cells are suspended in ice-cold buffer (20 mM Tris. HCI, 5 mM EDTA, pH 7.4) and homogenized by sonication for 7 sec. The cell lysates are centrifuged at 200 x g for 5 min at 4°C. The supernatants are then centrifuged at 40,000 x g for 20 min at 4°C. The resulting pellets are washed once in the homogenization buffer and suspended in binding buffer (see methods for radioligand binding). Protein concentrations are determined by the method of Bradford (1976) using bovine serum albumin as the standard. Binding assays are usually performed immediately, however it is possible to prepare membranes in batch and store frozen in liquid nitrogen for future use.
Radioligand binding assays
Radioligand binding assays for the rat MCH1 receptor were carried out using plasmid pcDNA3.1-rMCH1-f (ATCC Patent Deposit Designation No. PTA-3505). Plasmid pcDNA3.1- rMCH1-f comprises the regulatory elements necessary for expression of DNA in a mammalian cell operatively linked to DNA encoding the rat MCH1 receptor so as to permit expression thereof. Plasmid pcDNA3.1-rMCH1-f was deposited on July 05, 2001, with the American Type Culture Collection (ATCC), 12301 Parklawn Drive, Rockville, Maryland 20852, U.S.A. under the provisions of the Budapest Treaty for the International Recognition of the Deposit of Microorganisms for the Purposes of Patent Procedure and was accorded ATCC Patent Deposit Designation No. PTA-3505. Binding assays can also be performed as described hereinafter using plasmid pEXJ.HR-TL231 (ATCC Accession No. 203197) Plasmid pEXJ.HR-TL231 encodes the human MCH1 receptor and was deposited on September 17, 1998, with the American Type Culture Collection (ATCC), 12301 Parklawn Drive, Rockville, Maryland 20852, U.S.A. under the provisions of the Budapest Treaty for the International Recognition of the Deposit of Microorganisms for the Purposes of Patent Procedure and was accorded ATCC Accession No. 203197. Human embryonic kidney Peak rapid 293 cells (Peakr293 cells) were transiently transfected with DNA encoding the MCH1 receptor utilizing the calcium phosphate method and cell membranes were prepared as described above. Binding experiments with membranes from Peakr293 cells transfected with the rat MCH1 receptor were performed with 0.08 nM [3H]Compound A (the synthesis of Compound A is described in detail below) using an incubation buffer consisting of 50 mM Tris pH 7.4, 10 mM MgCI2, 0.16 mM PMSF, 1 mM 1,10 phenantroline and 0.2% BSA. Binding was performed at 25°C for 90 minutes. Incubations were terminated by rapid vacuum filtration over GF/C glass fiber filters, presoaked in 5% PEI using 50 nM Tris pH 7.4 as wash buffer. In all experiments, nonspecific binding is defined using 10 pM Compound A.
Functional assays
Cells may be screened for the presence of endogenous mammalian receptor using functional assays. Cells with no or a low level of endogenous receptor present may be transfected with the exogenous receptor for use in functional assays. A wide spectrum of assays can be employed to screen for receptor activation. These range from traditional measurements of phosphatidyl inositol, cAMP, Ca++, and K+, for example; to systems measuring these same second messengers but which have been modified or adapted to be higher throughput, more generic, and more sensitive; to cell based platforms reporting more general cellular events resulting .from receptor activation such as metabolic changes, differentiation, and cell division/proliferation, for example; to high level organism assays which monitor complex physiological or behavioral changes thought to be involved with receptor activation including cardiovascular, analgesic, orexigenic, anxiolytic, and sedation effects, for example.
Radioligand Binding Assay Results
The compounds described above were assayed using cloned rat MCH The binding affinities of the compounds are shown in Table I. Table
Figure imgf000123_0001
Table I continuted
Example Ki(MCH- No. 1 , nM)
Figure imgf000124_0001
V. Synthesis of radiolabeled Compound A
Described below is the synthesis of Compound A. Compound A is the radiolabeled compound that was used in the radioligand binding assays described above.
Λ/-[3-(1,2,3,6-TETRAHYDRO-4-PYRIDINYL)PHENYL]ACETAMIDE: The reaction of saturated of aqueous Na2CO3 solution (25 mL), tert-butyl 4-{[(trifluoromethyl)sulfonyl]oxy}- 1,2,3,6-tetrahydro-1-pyridine-carboxylate (20 mmol), 3-acetamidophenylboronic acid (30 mmol) and tetrakis-triphenylphosphine palladium (0) (1.15 g) in dimethoxy ethane (40 mL) at reflux temperature overnight gave -erf-butyl 4-[3-(acetylamino)phenyl]-3,6-dihydro-1(2/-/)- pyridine carboxylate. Deprotection of the BOC group using HCI in dioxane followed by basification (pH 11-12) gave the desired product. TERT-BUTYL Λ/-(3-
BROMOPROPYL)CARBAMATE: was prepared from 3-bromopropylamine hydrobromide and BOC20 in the presence of base in dichloromethane. Λ/-{3-[1-(3-AMINOPROPYL)-1 ,2,3,6-TETRAHYDRO-4-PYRIDINYL]PHENYL}ACETAMIDE: The reaction of terf-butyl Λ/-(3-bromopropyl)carbamate and Λ/-[3-(1,2,3,6-tetrahydro-4- pyridinyl) phenyljacetamide in refluxing dioxane with catalytic Bu4NI and base to give -erf- butyl 3-(4-[3-(acetylamino)phenyl]-3,6-dihydro-1(2/-/)-pyridinyl)propylcarbamate. Deprotection of the BOC group using HCI in dioxane followed by basification (pH 11-12) gave the desired product.METHYL (4S)-3-({[3-(4-[3-(ACETYLAMINO)PHENYL]-3,6- DIHYDRO-1(2H)-PYRIDINYL) PROPYL]AMINO}CARBONYL)-4-(3,4-DIFLUOROPHENYL)- 6-(METHOXY METHYL)-2-OXO-1,2,3,4-TETRAHYDRO-5-PYRIMIDINECARBOXYLATE: Prepared from the reaction of 5-methyl 1-(4-nitrophenyl) (6S)-6-(3,4-difluorophenyl)-4- (methoxymethyl)-2-oxo-3,6-dihydro-1 ,5(2 -.)-pyrimidinedicarboxylate (describe in PCT Publication No. WO 00/37026, published June 29, 2000) and Λ/-{3-[1-(3-aminopropyl)- 1 ,2,3,6-tetrahydro-4-pyridinyl]phenyl}acetamide: 1H NMR δ 8.90 (t, 1 H, J=3.6 Hz), 7.75 (s, 1 H), 7.50-7.00 (m, 8 H), 6.68 (s, 1 H), 6.03 (br s, 1 H), 4.67 (s, 2 H), 3.71 (s, 3 H), 3.47 (s, 3 H), 3.38 (ABm, 2 H), 3.16 (m, 2 H), 2.71 (t, 2 H, J =5.4 Hz), 2.56 (m, 4 H), 2.35-1.90 (br, 2 H), 2.17 (s, 3 H), 1.82 (p, 2 H, J=7.2 Hz); ESMS, 612.25 (M+H)+.TRITIATED METHYL (4S)-3- {[(3-{4-[3-(ACETYLAMINO)PHENYL]-1-PIPERIDINYL}PROPYL)AMINO]CARBONYL}-4-(3,4- DIFLUOROPHENYL)-6-(METHOXYMETHYL)-2-OXO-1,2,3,4-TETRAHYDRO-5- PYRIMIDINECARBOXYLATE ([3H] COMPOUND A): This radiochemical synthesis was carried out by Amersham Pharmacia Biotech, Cardiff, Wales. A methanolic solution of methyl (4S)-3-({[3-(4-[3-(acetylamino)phenyl]-3,6-dihydro-1(2H)-pyridinyl)propyl]amino} carbonyl)-4-(3,4-difluorophenyl)-6-(methoxy methyl)-2-oxo-1 ,2,3,4-tetrahydro-5- pyrimidinecarboxylate was exposed to tritium gas at 1 atmosphere pressure in the presence of 5% palladium on carbon with stirring overnight to give the tritiated methyl (4S)-3-{[(3-{4-[3- (acetylamino)phenyl]-1-piperidinyl}propyl)amino]carbonyl}-4-(3,4-difluorophenyl)-6-(methoxy methyl)-2-oxo-1 ,2,3,4-tetrahydro-5-pyrimidinecarboxylate ((+)-isomer). After purification by reverse phase HPLC (Hypersil ODS, 4.6 x 100 mm, methanol:H20:Et3N 10:90:1 to 100:0:1 in 15 min at 1.0 mL/min, with radiochemical and UV detection), this product was used as a radioligand in the MCH1 binding assays. The same procedure was carried out with H2 gas in place of 3H2 to afford the non-radioactive version of Compound A.
VI. In-Vivo Methods
The following in vivo methods were performed to predict the efficacy of MCH1 antagonists for the treatment of obesity (3-day body weight and sweetened condensed milk), depression (forced swim test), anxiety (social interaction test), and urinary disorders (DIRC and CSTI).
Effects of MCH1 Antagonists on Body Weight (3 Day)
Male Long Evans rats (Charles River) weighing 180-200 grams were housed in groups of four on a 12-hour light/dark cycle with free access to food and water. Test compounds were administered twice daily via i.p. injection, 1 hour before the dark cycle and 2 hours after lights on, for three days. All rats were weighed daily after each morning injection. Overall results were expressed as body weight (grams) gained per day (mean ± SEM) and were analyzed by two-way ANOVA. Data for each time point were analyzed by one-way ANOVA followed by post hoc Newman-Keuls test. The data were analyzed using the GraphPad Prism (v2.01) (GraphPad Software, Inc., San Diego, CA). All data were presented as means + S.E.M.
Effects of MCH1 Antagonists on Consumption of Sweetened Condensed Milk
Male C57BIJ6 mice (Charles River) weighing 17-19 grams at the start of experiments were housed in groups of four or five on a 12 hour light/dark cycle with free access to food and water. For 7 days, mice were weighed, placed in individual cages and allowed to drink sweetened condensed milk (Nestle, diluted 1 :3 with water) for 1 hour, 2-4 hours into the light cycle. The amount of milk consumed was determined by weighing the milk bottle before and after each drinking bout. On the test day, mice received i.p. injections of Test Compound (3, 10 or 30 mg/kg in 0.01 % lactic acid), vehicle (0.01 % lactic acid) of d-fenfluramine (10 mg/kg in 0.01 % lactic acid) 30 min. prior to exposure to milk. The amount of milk consumed on the test day (in mis milk/ kg body weight) was compared to the baseline consumption for each mouse determined on the previous 2 days. Data for each time point were analyzed by oneway ANOVA. Forced Swim Test .FST) in the Rat
Animals
Male Sprague-Dawley rats (Taconic Farms, NY) were used in all experiments. Rats were housed 5 per cage and maintained on a 12:12-h light-dark cycle. Rats were handled for 1 minutes each day for 4 days prior to behavioral testing.
Drug Administration
Animals were randomly assigned to receive a single i.p. administration of vehicle (2.5% EtOH / 2.5% Tween-80), imipramine (positive control; 60 mg/kg), or Test Compound 60 minutes before the start of the 5 minute test period. All injections were given using 1 cc tuberculin syringe with 26 3/8 gauge needles (Becton-Dickinson, VWR Scientific, Bridgeport, NJ). The volume of injection was 1 ml/kg.
Experimental Design The procedure used in this study was similar to that previously described (Porsolt, et al., 1978), except the water depth was 31 cm in this procedure. The greater depth in this test prevents the rats from supporting themselves by touching the bottom of the cylinder with their feet. Swim sessions were conducted by placing rats in individual plexiglass cylinders (46 cm tall x 20 cm in diameter) containing 23-25°C water 31 cm deep. Swim tests were conducted always between 900 and 1700 hours and consisted of an initial 15-min conditioning test followed 24h later by a 5-minute test. Drug treatments were administered 60 minutes before the 5-minute test period. Following all swim sessions, rats were removed from the cylinders, dried with paper towels and placed in a heated cage for 15 minutes and returned to their home cages. All test sessions were videotaped using a color video camera and recorded for scoring later.
Behavioral Scoring
The rat's behavior was rated at 5-second intervals during the 5-minute test by a single individual, who was blind to the treatment condition. Scored behaviors were:
1. Immobility- rat remains floating in the water without struggling and was only making those movements necessary to keep its head above water;
2. Climbing - rat was making active movements with its forepaws in and out of the water, usually directed against the walls; 3. Swimming - rat was making active swimming motions, more than necessary to merely maintain its head above water, e.g. moving around in the cylinder; and 4. Diving - entire body of the rat was submerged. Data Analysis
The forced swim test data (immobility, swimming, climbing, diving) were subjected to a randomized, one-way ANOVA and post hoc tests conducted using the Newman-Keuls test. The data were analyzed using the GraphPad Prism (v2.01) (GraphPad Software, Inc., San Diego, CA). All data were presented as means + S.E.M. All data were presented as means + S.E.M.
Forced Swim Test (FST) in the Mouse
Animals DBA/2 mice (Taconic Farms, NY) were used in all experiments. Animals were housed 5 per cage in a controlled environment under a 12:12 hour ligh dark cycle. Animals were handled 1 min each day for 4 days prior to the experiment. This procedure included a mock gavage with a 1.5 inch feeding tube.
Drug Administration
Animals were randomly assigned to receive a single administration of vehicle (5% EtOH/5% Tween-80), Test Compound, or imipramine (60 mg/kg) by oral gavage 1 hour before the swim test.
Experimental Design
The procedure for the forced swim test in the mouse was similar to that described above for the rat, with some modifications. The cylinder used for the test was a 1 -liter beaker (10.5cm diameter X 15 cm height) fill to 800ml (10cm depth) of 23-25°C water. Only one 5-minute swim test was conducted for each mouse, between 1300 and 1700 hours. Drug treatments were administered 30-60 minutes before the 5-minute test period. Following all swim sessions, mice were removed from the cylinders, dried with paper towels and placed in a heated cage for 15 minutes. All test sessions were videotaped using a Sony color video camera and recorder for scoring later.
Behavioral Scoring
The behavior during minutes 2-5 of the test was played back on a TV monitor and scored by the investigator. The total time spent immobile (animal floating with only minimal movements to remain afloat) and mobile (swimming and movements beyond those required to remain afloat) were recorded. Data Analysis
The forced swim test data (time exhibiting immobility, mobility; seconds) were subjected to a randomized, one-way ANOVA and post hoc tests conducted using the Newman-Keuls test. The data were analyzed using the GraphPad Prism (v2.01) (GraphPad Software, Inc., San Diego, CA). All data were presented as means + S.E.M.
Social Interaction Test (SIT)
Rats are allowed to acclimate to the animal care facility for 5 days and are housed singly for 5 days prior to testing. Animals are handled for 5 minutes per day. The design and procedure for the Social Interaction Test is carried out as previously described by Kennett, et al. (1997). On the test day, weight matched pairs of rats (± 5%), unfamiliar to each other, are given identical treatments and returned to their home cages. Animals are randomly divided into 5 treatment groups, with 5 pairs per group, and are given one of the following i.p. treatments: Test Compound (10, 30 or 100 mg/kg), vehicle (1 ml/kg) or chlordiazepoxide (5 mg/kg). Dosing is 1 hour prior to testing. Rats are subsequently placed in a white perspex test box or arena (54 x 37 x 26 cm), whose floor is divided up into 24 equal squares, for 15 minutes. An air conditioner is used to generate background noise and to keep the room at approximately 74°F. All sessions are videotaped using a JVC camcorder (model GR-SZ1, Elmwood Park, NJ) with either TDK (HG ultimate brand) or Sony 30 minute videocassettes.
All sessions are conducted between 1300 - 1630 hours. Active social interaction, defined as grooming, sniffing, biting, boxing, wrestling, following and crawling over or under, is scored using a stopwatch (Sportsline model no. 226, 1/100 sec. discriminability). The number of episodes of rearing (animal completely raises up its body on its hind limbs), grooming (licking, biting, scratching of body), and face washing (i.e. hands are moved repeatedly over face), and number of squares crossed are scored. Passive social interaction (animals are lying beside or on top of each other) is not scored. All behaviors are assessed later by an observer who is blind as to the treatment of each pair. At the end of each test, the box is thoroughly wiped with moistened paper towels. Animals
Male albino Sprague-Dawley rats (Taconic Farms, NY) are housed in pairs under a 12 hr light dark cycle (lights on at 0700 hrs.) with free access to food and water.
Drug Administration Test Compound is dissolved in either 100% DMSO or 5% lactic acid, v/v (Sigma Chemical Co., St. Louis, MO). Chlordiazepoxide (Sigma Chemical Co., St. Louis, MO) is dissolved in double distilled water. The vehicle consists of 50% DMSO (v/v) or 100% dimethylacetamide (DMA). All drug solutions are made up 10 minutes prior to injection and the solutions are discarded at the end of the test day. the volume of drug solution administered is 1 ml/kg.
Data Analysis
The social interaction data (time interacting, rearing and squares crossed) are subjected to a randomized, one-way ANOVA and post hoc tests conducted using the Student-Newman- Keuls test. The data are subjected to a test of normality (Shapiro-Wilk test). The data are analyzed using the GBSTAT program, version 6.5 (Dynamics Microsystems, Inc., Silver Spring, MD, 1997).
In Vivo Models of the Micturition Reflex
The effects of compounds on the micturition reflex were assessed in the "distension-induced rhythmic contraction" (DIRC), as described in previous publications (e.g. Maggi et al, 1987; Morikawa et al, 1992), and Continuous Slow Transvesicular Infusion (CSTI) models in rats.
DIRC Model
Female Sprague Dawley rats weighing approximately 300 g were anesthetized with subcutaneous urethane (1.2 g/kg). The trachea was cannulated with PE240 tubing to provide a clear airway throughout the experiment. A midline abdominal incision was made and the left and right ureters were isolated. The ureters were ligated distally (to prevent escape of fluids from the bladder) and cannulated proximally with PE10 tubing. The incision was closed using 4-0 silk sutures, leaving the PE10 lines routed to the exterior for the elimination of urine. The bladder was canulated via the transurethral route using PE50 tubing inserted 2.5 cm beyond the urethral opening, this cannula was secured to the tail using tape and connected to a pressure transducer. To prevent leakage from the bladder, the cannula was tied tightly to the exterior urethral opening using 4-0 silk. To initiate the micturition reflex, the bladder was first emptied by applying pressure to the lower abdomen, and then filled with normal saline in 100 increments (maximum = 2 ml) until spontaneous bladder contractions occurred (typically 20-40 mmHg at a rate of one contraction every 2 to 3 minutes. Once a regular rhythm was established, vehicle (saline) or Test Compounds were administered i.v. or i.p. to explore their effects on bladder activity. The 5-HT1A antagonist WAY-100635 was given as a positive control. Data were expressed as contraction interval (in seconds) before drug application (basal), or after the application of vehicle or test article.
Continuous Slow Transvesicular Infusion (CSTI) rat Model
Male Sprague Dawley rats weighing approximately 300 g were used for the study. Rats were anaesthetized with pentobarbitone sodium (50 mg/kg, i.p). Through a median abdominal incision, bladder was exposed and a polyethylene cannula (PE 50) was introduced into the bladder through a small cut on the dome of the bladder and the cannula was secured with a purse string suture. The other end of the cannula was exteriorized subcutaneously at the dorsal neck area. Similarly, another cannula (PE 50) was introduced into the stomach through a paramedian abdominal incision with the free end exteriorized subcutaneously to the neck region. The surgical wounds were closed with silk 4-0 suture and the animal was allowed to recover with appropriate post surgical care. On the following day, the animal was placed in a rat restrainer. The open end of the bladder- cannula was connected to a pressure transducer as well as infusion pump through a three-way stopcock. The bladder voiding cycles were initiated by continuous infusion of normal saline at the rate of 100 μl/min. The repetitive voiding contractions were recorded on a Power Lab on-line data acquisition software. After recording the basal voiding pattern for an hour, the test drug or vehicle was administered directly into stomach through the intragastric catheter and the voiding cycles were monitored for 5 hours. Micturition pressure and frequency were calculated before and after the treatment (at every 30 min interval) for each animal. Bladder capacity was calculated from the micturition frequency, based on the constant infusion of 100ul/min. The effect of the test drug was expressed as a percentage of basal, pre-drug bladder capacity. WAY 100635 was used as positive control for comparison.
In Vivo Results- Table 2
Effect of MCH1 antagonist (Example No.) in the following in vivo models: 3-day Body Weight (3D BW), mouse Sweetened Condensed Milk (mSwCM), mouse Forced Swim Test (mFST), rat Forced Swim Test (rFST), DIRC model, or CSTI model.
Figure imgf000132_0001
A = Produced a significant reduction in weight gain relative to vehicle-treated controls B = Produced a significant decrease in consumption of milk relative to vehicle-treated controls C = Produced a significant decrease in immobility relative to vehicle-treated animals when administered orally. D = Produced a significant decrease in immobility or a significant increase in swimming activity relative to vehicle-treated animals E = Produced a significant increase in contraction interval relative to pre-drug interval F = Produced an increase in bladder capacity in rats relative to baseline capacity.
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Claims

What is claimed is:
1. A compound having the structure:
Figure imgf000139_0001
wherein each R, is independently hydrogen; -F; -Cl; -Br; -I; -CN; -N02; straight chained or branched C C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl; C3-C7 cycloalkyl or C3-C7 cycloalkenyl; aryl; heteroaryl; -N(R5)2; -(CH2)mOR5; -COR5; -C02R5; -OCOR5; -CON(R5)2; -N(R5)COR5; -N(R5)CON(R5)2; -OCON(R5)2 or -N(R5)C02R5;
wherein R2 is hydrogen; -F; -Cl; -Br; -I; -CN; -(CH2)mOR5; -(CH2)mSR5; -NH2; straight chained or branched Cι-C7 alkyl, monofluoroalkyl, polyfluoroalkyl; aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more R^
wherein R3 is hydrogen; -F; -Cl; -Br; -I; -CN; -(CH2)mOR5; -(CH2)mSR5; straight chained or branched C C7 alkyl, monofluoroalkyl, polyfluoroalkyl; aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more R^ or wherein R2 and R3 together can be - (CH2)P-;
wherein R is straight chained or branched C C7 alkyl, monofluoroalkyl or polyfluoroalkyl, C3-C6 cycloalkyl, C C7 alkyl-C3-C6 cycloalkyl; -N(R5)2 or -(CH2)mOR5;
wherein each R5 is independently hydrogen; aryl; heteroaryl or straight chained or branched CrC7 alkyl, wherein the alkyl may be substituted with an aryl or heteroaryl;
wherein each R6 is independently hydrogen; straight chained or branched C C alkyl;
wherein each R7 is independently hydrogen; phenyl or straight chained or branched C1-C7 alkyl, wherein the alkyl may be substituted with a phenyl;
wherein each m is independently an integer from 0 to 5 inclusive;
wherein n is an integer from 1 to 5 inclusive;
wherein p is an integer from 2 to 7 inclusive; wherein q is an integer from 0 to 2 inclusive; and wherein each X is independently CRi or N, provided that if one X is N then the remaining X
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , where the compound has the structure:
Figure imgf000140_0001
3. The compound of claim 2, wherein the compound has the structure:
Figure imgf000140_0002
wherein R2 and R3 are each independently hydrogen; -F; -Cl; -Br; -I; -CN; -(CH2)mOR5; - (CH2)mSR5; straight chained or branched C C7 alkyl, monofluoroalkyl, polyfluoroalkyl; aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more Ri; or wherein R2 and R3 together can be -(CH2)P-;
wherein R is straight chained or branched C C7 alkyl, monofluoroalkyl or polyfluoroalkyl, C3-C6 cycloalkyl, -N(R5)2 or -(CH2)mOR5; and X is CH or N.
4. The compound of claim 3, wherein each R^ is independently hydrogen; -F; -Cl; -Br; -I; -CN; -N02; straight chained or branched C C7 alkyl or polyfluoroalkyl; -(CH2)mOR5; -COR5; - C02R5; -OCOR5; -CON(R5)2; -N(R5)COR5 or -N(R5)CON(R5)2;
wherein R2 and R3 are each independently hydrogen; -F; -Cl; -Br; -I; -CN; -(CH2)mSR5; straight chained or branched C C7 alkyl; aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more R^ or wherein R2 and R3 together can be -(CH2)P-;
wherein R is straight chained or branched C C7 alkyl; C3-C6 cycloalkyl; -N(R5)2 or - (CH2)mOR5;
wherein each R5 is independently hydrogen or straight chained or branched CrC3 alkyl, wherein the alkyl may be substituted with a phenyl;
wherein m is an integer 0 to 3 inclusive; wherein n is an integer 1 to 3 inclusive;
wherein p is an integer from 2 to 5 inclusive;
wherein q is 0;
and X is CH.
The compound of claim 4, wherein the compound has the structure:
Figure imgf000141_0001
6. The compound of claim 5, wherein R7 is independently hydrogen or straight chained or branched C C7 alkyl; and R is straight chained or branched C C7 alkyl.
7. The compound of claim 6, wherein each Ri is independently hydrogen; -F; -Cl; -Br; -I or straight chained or branched C C alkyl; and R2 is hydrogen or straight chained or branched C C7 alkyl.
8. The compound of claim 7, wherein n is 2.
9. The compound of claim 8, wherein the compound is selected from the group consisting of:
Figure imgf000141_0002
10. The compound of claim 4, wherein R2 and R3 are independently hydrogen or straight chained or branched C C7 alkyl.
11. The compound of claim 10, wherein each R5 is independently hydrogen or straight chained or branched C C3 alkyl; R7 is independently hydrogen or straight chained or branched C C7 alky;l and R4 is straight chained or branched C C alkyl.
12 The compound of claim 11, wherein each R^ is independently hydrogen; -F; -Cl; -Br; - I or straight chained or branched CrC7 alkyl.
13. The compound of claim 12, wherein n is 2.
14. The compound of claim 13, wherein the compound is selected from the group consisting of:
Figure imgf000142_0001
15. The compound of claim 3, wherein the compound has the structure
Figure imgf000142_0002
16. The compound of claim 4, wherein R2 and R3 together are -(CH2)P.
17. The compound of claim 2, wherein the compound has the structure:
Figure imgf000142_0003
wherein R2 is hydrogen or- OH.
18. The compound of claim 17, wherein R3 is phenyl substituted with one or more R^ moieties; and q = 0.
19. The compound of claim 18, wherein each R5 is independently hydrogen or straight chained or branched C C3 alkyl, wherein the alkyl may be substituted with a phenyl; R7 is independently hydrogen or straight chained or branched C C7 alkyl; and R4 is straight chained or branched C C7 alkyl.
20. The compound of claim 19, wherein each R- is independently hydrogen; -F; -Cl; -Br; - I or straight chained or branched CrC alkyl.
21. The compound of claim 20, wherein n is 2.
22. The compound of claim 21 , wherein X is N.
23. The compound of claim 21 , wherein X is CRi .
24. The compound of claim 23, wherein R2 is OH.
25. The compound of claim 24, wherein the compound is selected from the group consisting of:
Figure imgf000143_0001
26. The compound of claim 2, wherein the compound has the structure:
Figure imgf000143_0002
27. The compound of claim 26, wherein R3 is phenyl substituted with one or more Ri moieties; and q = 0.
28. The compound of claim 27, wherein R5 and R7 are independently hydrogen or straight chained or branched C C7 alkyl; and R4 is straight chained or branched C C alkyl.
29. The compound of claim 28, wherein R2 is hydrogen or -OH.
30. The compound of claim 29, wherein the compound has the structure:
Figure imgf000143_0003
31. The compound of claim 1 , wherein the compound is enantiomerically pure.
32. The compound of claim 1 , wherein the compound is diastereomerically pure.
33. A pharmaceutical composition that comprises a therapeutically effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier.
34. A pharmaceutical composition made by admixing a compound of claim 1 and a pharmaceutically acceptable carrier.
35. A process for making a pharmaceutical composition comprising admixing a compound of claim 1 and a pharmaceutically acceptable carrier.
36. A method of treating a subject suffering from an affective disorder selected from the group consisting of depression, major depression, bipolar disorder, agoraphobia, specific phobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder and anxiety, comprising administering to the subject a therapeutically effective amount of the compound of claim 1.
37. A method of treating a subject suffering from a urinary disorder selected from the group consisting of urinary incontinence, urge incontinence, urinary frequency, urinary urgency, nocturia or enuresis comprising administering to the subject a therapeutically effective amount of the compound of claim 1.
38. A method of treating a subject suffering from an eating disorder selected from the group consisting of obesity, bulimia, bulimia nervosa or anorexia nervosa comprising administering to the subject a therapeutically effective amount of the compound of claim 1.
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ZA200504218B (en) 2006-07-26
WO2004064764A3 (en) 2005-01-13
CN1735595A (en) 2006-02-15
NZ540366A (en) 2008-01-31

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